ENTITYA TYPEA IDA DATABASEA ENTITYB TYPEB IDB DATABASEB EFFECT MECHANISM RESIDUE SEQUENCE TAX_ID CELL_DATA TISSUE_DATA MODULATOR_COMPLEX TARGET_COMPLEX MODIFICATIONA MODASEQ MODIFICATIONB MODBSEQ PMID DIRECT NOTES ANNOTATOR SENTENCE SIGNOR_ID SCORE ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 19819937 f In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254355 0.7 dothiepin chemical CHEBI:36798 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8100134 t miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. SIGNOR-258696 0.8 KMT2A protein Q03164 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression methylation 10090 BTO:0002884 22012064 t irozzo Furthermore, we show that both MLL and AML1/CBFβ are required for maintaining the H3K4-me3 mark at the PU.1 upstream regulatory element (URE) and promoter region, and for full PU.1 gene expression. SIGNOR-255874 0.417 ULK2 protein Q8IYT8 UNIPROT PFKM protein P08237 UNIPROT down-regulates activity phosphorylation Ser762 YEIDLDTsDHAHLEH 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274044 0.2 PHA-665752 chemical CHEBI:90197 ChEBI MET protein P08581 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258265 0.8 CSMD1 protein Q96PZ7 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 22538441 t miannu CSMD1 co-immunoprecipitated with SMAD3, confirming our results that CSMD1 interacts with Smad3 in A375 cells. CSMD1 interacts with Smad3 and induces phosphorylation (p-Smad3). Phosphorylated Smad3 promotes Smad2 phosphorylation and Smad2/3/4 complex formation. SIGNOR-265151 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR POU5F1 protein Q01860 UNIPROT down-regulates phosphorylation 9606 23024368 t inferred from 70% family members gcesareni Phosphorylation of this site downregulates nanog, sox2, rex1 and upregulates bmp4, gata6, ddlx5. SIGNOR-270185 0.2 ATM protein Q13315 UNIPROT BUB3 protein O43684 UNIPROT up-regulates activity phosphorylation Ser135 PCNAGTFsQPEKVYT 9606 BTO:0000567 35085551 t miannu Taken together, we highlight the functional significance of the crosstalk between the kinetochore-oriented signal and double-strand break repair pathways via ATM phosphorylation of Bub3 on Ser135. SIGNOR-277582 0.318 PCDHA9 protein Q9Y5H5 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265662 0.2 Immune complexes stimulus SIGNOR-ST15 SIGNOR FCGR1A protein P12314 UNIPROT up-regulates activity 9606 BTO:0000801 18064051 f lperfetto Immune complexes bind to activating Fc receptors (FcR) and inhibitory FcRs that are expressed by innate immune effector cells such as basophils, mast cells, neutrophils, monocytes and macrophages, in which they trigger the indicated effector responses. SIGNOR-249521 0.7 NRBF2 protein Q96F24 UNIPROT PIK3R4 protein Q99570 UNIPROT down-regulates activity binding 9606 BTO:0001938 phosphorylation:Ser113;Ser120 AEDAEGQsPLSQKYS;SPLSQKYsPSTEKCL 28059666 t miannu NRBF2 S113 and S120 phosphorylation negatively regulates autophagy. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity. SIGNOR-265878 0.656 NDUFA8 protein P51970 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND1-module builds around the Q-module with the help of TIMMDC1/C3ORF1 [47,48], which remains bound to the Q/ND1 subassembly until the last maturation steps. MT-ND1 joins first and then NDUFA3, NDUFA8 and NDUFA13 are added SIGNOR-262159 0.817 NF1 protein P21359 UNIPROT ADCY5 protein O95622 UNIPROT up-regulates 9606 BTO:0000938 24431436 f miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-204140 0.273 MAPK1 protein P28482 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 23405013 t lperfetto Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling SIGNOR-200880 0.314 CDC73 protein Q6P1J9 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR form complex binding 9606 BTO:0000567 20178742 t miannu Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A).  SIGNOR-269836 0.931 NPFFR2 protein Q9Y5X5 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256852 0.252 MAML3 protein Q96JK9 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 12370315 t gcesareni We report here the cloning and characterization of two new genes, maml2 and maml3, that also function as transcriptional coactivators for notch receptors. SIGNOR-254323 0.88 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT up-regulates phosphorylation Ser342 SSRLRSCsVTDAVAE 9606 11742982 t lperfetto Here we show by expression studies in xenopus laevis oocytes that the aldosterone-induced sgk1 kinase interacts with the ubiquitin protein ligase nedd4-2 in a py motif-dependent manner and phosphorylates nedd4-2 on ser444 and, to a lesser extent, ser338. Such phosphorylation reduces the interaction between nedd4-2 and enac, leading to elevated enac cell surface expression. SIGNOR-113052 0.779 PSMD3 protein O43242 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263353 0.892 VAV2 protein P52735 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260582 0.74 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser174 LSPASSGsSASFISD 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248512 0.387 PRKCA protein P17252 UNIPROT GNAZ protein P19086 UNIPROT up-regulates phosphorylation Ser16 EKEAARRsRRIDRHL 9606 BTO:0000671 9166747 t gcesareni Functional role of amino-terminal serine16 and serine27 of g alphaz in receptor and effector coupling. SIGNOR-48677 0.418 PRKCA protein P17252 UNIPROT LMNA protein P02545 UNIPROT up-regulates activity phosphorylation Ser404 RSRGRASsHSSQTQG -1 7925482 t lperfetto Mutation of both Ser-403/Ser-404 within a PKC motif flanking the nuclear localization signal inhibits transport of mutant lamin A to the nucleus in 64% of the cells. It is proposed that phosphorylation of the motif in vivo positively regulates nuclear localization together with the nuclear localization sequence. SIGNOR-248904 0.369 GOLPH3 protein Q9H4A6 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity 9606 BTO:0000018;BTO:0005011 19553991 f Mechanistically, GOLPH3 regulates cell size, enhances growth factor-induced mTOR signaling in human cancer cells and alters response to mTOR inhibitor in vivo. SIGNOR-253554 0.337 INPP5D protein Q92835 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity binding 9606 BTO:0000007 24817116 t lperfetto Of note, SHIP1 was associated with TRAF6 in co-transfected HEK293T cells (Fig. 6A). Moreover, SHIP1 overexpression suppressed TRAF6 autoubiquitination in a dose-dependent manner SIGNOR-261429 0.336 BRCA1 protein P38398 UNIPROT TFF1 protein P04155 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356;BTO:0001033 11244506 f In addition, BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D. SIGNOR-253937 0.304 ADK protein P55263 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5‚Ä≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-267841 0.8 CLK4 protein Q9HAZ1 UNIPROT MITF protein O75030 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr360 ILKASVDyIRKLQRE 9606 BTO:0002427 35092699 t done miannu Mechanistically, wild type CLK4 (WT-CLK4) but not kinase-dead CLK4-K189R mutant phosphorylated MITF at Y360. This modification promoted its interaction with E3 ligase COP1 and its K63-linked ubiquitination at K308/K372, leading to sequestosome 1 recognition and autophagic degradation.  SIGNOR-274116 0.2 GSK3B protein P49841 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates activity phosphorylation Thr73 MKIDEPStPYHSMMG 9913 BTO:0000142 11320080 t Protein phosphatase 1 (PP1) is complexed with inhibitor 2 (I-2) in the cytosol. In rabbit muscle extract PP1.I-2 is activated upon preincubation with ATP/Mg. This activation is caused by phosphorylation of I-2 on Thr(72) by glycogen synthase kinase 3 (GSK3). SIGNOR-251257 0.422 GDNF protein P39905 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252188 0.269 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266475 0.8 DIO1 protein P49895 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 34674502 t scontino Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3. SIGNOR-266954 0.8 ZNF267 protein Q14586 UNIPROT MMP10 protein P09238 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 16054593 t Luana Furthermore, ZNF267 binds to the MMP-10 promoter region as demonstrated by chromatin immunoprecipitation assays. In conclusion, our results suggest that ZNF267 as a negative transcriptional regulator of MMP-10  SIGNOR-266211 0.399 GPR34 protein Q9UPC5 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256967 0.2 T_cell_activation phenotype SIGNOR-PH73 SIGNOR IFNG protein P01579 UNIPROT up-regulates quantity 9606 10653850 f miannu IL-12 Synergizes With IL-18 or IL-1beta for IFN-gamma Production From Human T Cells. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R engagement. SIGNOR-260967 0.7 PRKCA protein P17252 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser24 DMKVRKSsTPEEVKK 9606 BTO:0001271 22855535 t lperfetto Pkc_ phosphorylates cofilin at ser-23 and/or ser-24 during degranulationthese results indicate that a novel pkc_-mediated phosphorylation event regulates cofilin by inhibiting its ability to depolymerize f-actin and bind to 14-3-3_, thereby promoting f-actin polymerization SIGNOR-198482 0.2 INSR protein P06213 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Tyr27 GFDLDLTyIYPNIIA -1 23995781 t miannu Our results show that the kinase region of IRβ subunit physically binds to PTEN and phosphorylates on Y27 and Y174. In the current study, we discovered that IR also downregulates PTEN through tyrosine phosphorylation and suggest that Y27 and 174 are the two key tyrosines. SIGNOR-276470 0.454 MAOB protein P27338 UNIPROT 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-264000 0.8 TNFSF4 protein P23510 UNIPROT TNFRSF4 protein P43489 UNIPROT up-regulates binding 9606 BTO:0000007 9488716 t gcesareni Activation of nf-kappab in ox40-transfected hsb-2 cells was detected by electrophoretic mobility shift assay within 30 min after the binding of the ligand gp34. SIGNOR-54927 0.919 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4A protein P27815 UNIPROT up-regulates activity phosphorylation Ser89 TRMSWPSsFHGTGTG 9534 BTO:0001538 12023945 t done miannu Long PDE4 isoforms from all four sub-families can be phosphorylated by protein kinase A (PKA). This leads to an increase in their activity and may thus contribute to cellular desensitization processes in cells where these isoforms are selectively expressed.These were Ser89Ala-PDE4A8, Ser133Ala-PDE4B1, Ser13Ala-PDE4C2 and Ser126Ala-PDE4D5. SIGNOR-273937 0.2 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization. SIGNOR-109716 0.923 CDH1 protein P12830 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 18662541 t lperfetto In early mitosis, APC/C is activated through binding to Cdc20, and in late M, Cdc20 is replaced by Cdh1, the second activator of APC/C. SIGNOR-274058 0.395 MC3R protein P41968 UNIPROT GNAS protein P84996 UNIPROT up-regulates activity 9606 22215617 t lperfetto We hypothesize that XLαs may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus. SIGNOR-253068 0.528 Av/b1 integrin complex SIGNOR-C175 SIGNOR TERT protein O14746 UNIPROT up-regulates quantity by expression 10090 18757303 f lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. SIGNOR-253274 0.324 ETV2 protein O00321 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24727028 f miannu We have identified a novel positive feed-forward regulatory loop in which etv2 activates expression of genes involved in vasculogenesis, including fli1. SIGNOR-203272 0.2 MAPK1 protein P28482 UNIPROT MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation Ser454 TGSTPPVsPTPSERS 9606 22139079 t Translocation from Nuleus to Cytoplasm gcesareni Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. SIGNOR-195153 0.2 PPM1A protein P35813 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 18586681 t Purified PP2Cα protein efficiently dephosphorylated PAK1 in vitro (Fig. 1, D and E). We previously assessed the time course of phospho-PAK1 dephosphorylation assessed using specific antibodies against either Ser(P)198/203 or Thr(P)422 sites in the PAK1 activation loop. SIGNOR-248491 0.343 DDC protein P20711 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity chemical modification 7955 23940784 t brain lperfetto AADC is responsible for the decarboxylation step in the catecholamine and dopamine biosynthesis. Dopamine and serotonin can be synthesized by AADC from L-3,4-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively [7]. A deficiency in AADC will lead to reduced biogenic monoamines, including dopamine, norepinephrine, epinephrine, and serotonin SIGNOR-263986 0.8 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 22124607 t lperfetto Moreover, we reported that TCPTP knockdown in PTP1B deficient MEFS further enhanced IR activation, consistent with the two PTPs acting in a coordinated manner to attenuate insulin signalling .|Therefore, the inhibition of PTPs such as PTP1B that attenuate IR activation and signalling might be particularly effective in alleviating insulin resistance.|The prototypic family member PTP1B (encoded by PTPN1) dephosphorylates the IR beta subunit Y1162 and Y1163 activation loop autophosphorylation site to attenuate insulin signalling in vivo . SIGNOR-276946 0.78 CDK2 protein P24941 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity phosphorylation Ser211 PGKETNEsPWRSDLL -1 9199329 t lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. SIGNOR-249427 0.296 2-methoxy-N-[3-[4-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]anilino]-6-quinazolinyl]prop-2-enyl]acetamide chemical CHEBI:91331 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191103 0.8 STK19 protein P49842 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity phosphorylation Ser89 FAINNSKsFADINLY 9606 BTO:0003476 30712867 t lperfetto STK19 Phosphorylates NRAS Protein at Serine 89|STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation.| SIGNOR-264566 0.311 NMDA receptor_2C complex SIGNOR-C349 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30037851 t miannu NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS).  SIGNOR-264220 0.8 NFKBIA protein P25963 UNIPROT S100A6 protein P06703 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 12859951 f miannu Transient expression of NF-kappaB (p65) increased S100A6 promoter activity and expression of inhibitor of NF-kappaB (IkappaBalpha) decreased TNFalpha-induced S100A6 promoter activity.  SIGNOR-254804 0.2 PRKACA protein P17612 UNIPROT CIITA protein P33076 UNIPROT down-regulates activity phosphorylation Ser834 QELPGRLsFLGTRLT 9606 BTO:0000984 11416140 t lperfetto Downregulation of ciita function by protein kinase a (pka)-mediated phosphorylationphosphorylation at ciita serines 834 and 1050 accounts for the inhibitory effects of pka on ciita-driven class ii mhc transcription. SIGNOR-108573 0.314 BAD protein Q92934 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203 23725574 f irozzo Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions. SIGNOR-256259 0.7 PRKACA protein P17612 UNIPROT SLC2A2 protein P11168 UNIPROT down-regulates activity phosphorylation Ser505 EFQKKSGsAHRPKAA 9534 BTO:0004055 8626492 t miannu GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity. SIGNOR-250051 0.314 PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 15175348 t lperfetto The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation. SIGNOR-244938 0.275 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI DIO proteinfamily SIGNOR-PF83 SIGNOR up-regulates quantity by expression 9606 29892818 f inferred from family member scontino Dio2 is a cAMP responsive gene. Thus, any signaling pathway or molecule that increases cAMP concentration will stimulate D2 activity. SIGNOR-270243 0.8 MAP2K1 protein Q02750 UNIPROT ARRB2 protein P32121 UNIPROT up-regulates activity phosphorylation Thr382 EFDTNYAtDDDIVFE 9606 BTO:0000007 28169830 t Here, we show that activation of serotonin 5-HT2C receptors, which engage Erk1/2 pathway via a _-arrestin-dependent mechanism, promotes MEK-dependent _-arrestin2 phosphorylation at Thr383 SIGNOR-252027 0.569 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr373 TVLVKDStNRDSLDM 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. SIGNOR-129276 0.392 SCN2A protein Q99250 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 t miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. SIGNOR-253404 0.8 KDM2B protein Q8NHM5 UNIPROT UHRF1 protein Q96T88 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000011 25533466 f miannu We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis. SIGNOR-252245 0.287 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR Enolase proteinfamily SIGNOR-PF74 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f inferred from family member miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-270249 0.2 NOG protein Q13253 UNIPROT BMPR1B protein O00238 UNIPROT down-regulates activity binding 9606 22298955 t lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors.Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors (pmid 12478285) SIGNOR-192802 0.583 EGFR protein P00533 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr154 QLNDSAAyYLNDLDR -1 33139573 t miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. SIGNOR-277227 0.441 bisphenol A chemical CHEBI:33216 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 9751507 t miannu Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings. SIGNOR-268738 0.8 SIRT7 protein Q9NRC8 UNIPROT H3C15 protein Q71DI3 UNIPROT up-regulates activity deacetylation Lys37 APATGGVkKPHRYRP 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275881 0.2 alvocidib hydrochloride chemical CHEBI:90998 ChEBI CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192480 0.8 FER protein P16591 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Tyr374 ELKGRGEyFAIKALK 9606 BTO:0002548 33411917 t miannu We show that the tyrosine kinase FER alters PKCδ function by phosphorylating it on Y374, and that phospho-Y374-PKCδ prevents RAB5 release from nascent late endosomes, thereby inhibiting EGFR degradation and promoting the recycling of endosomal EGFR to the cell surface. SIGNOR-277546 0.2 TNF protein P01375 UNIPROT SCN4A protein P35499 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253481 0.26 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe634 VHHQKLVfFAEDVGS -1 8943232 t lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261770 0.502 EFNA2 protein O43921 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 9330863 t gcesareni The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. Therefore, eph receptors mediate signals that can override cell adhesion. SIGNOR-52269 0.74 DAMPS stimulus SIGNOR-ST18 SIGNOR TLRs proteinfamily SIGNOR-PF20 SIGNOR up-regulates activity binding 9606 25644504 t The innate immune system is present in almost all multicellular organisms and its activation occurs in response to pathogens or tissue injury via pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) SIGNOR-252096 0.7 CEBPA protein P49715 UNIPROT HSD11B1 protein P28845 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19088256 t lperfetto Cotransfection with human CCAAT/enhancer binding protein-alpha (C/EBPalpha) and C/EBPbeta-LAP expression vectors activated the HSD11B1 promoter with the strongest effect within the same region. SIGNOR-268971 0.277 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249348 0.728 CCP110 protein O43303 UNIPROT CETN3 protein O15182 UNIPROT up-regulates activity binding 9606 16760425 t miannu We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis. SIGNOR-265968 0.428 NFIX protein Q14938 UNIPROT ID3 protein Q02535 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268885 0.2 GADD45A protein P24522 UNIPROT CDK11A protein Q9UQ88 UNIPROT down-regulates activity binding 9606 BTO:0000007 26885618 t lperfetto GADD45alpha inhibits CDK11p58 kinase activity|We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58. SIGNOR-273023 0.2 CLU protein P10909 UNIPROT COMMD1 protein Q8N668 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001321 20068069 t miannu CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation. SIGNOR-271432 0.401 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR up-regulates 9606 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268583 0.2 PMCH protein P20382 UNIPROT MCHR1 protein Q99705 UNIPROT up-regulates binding 9606 BTO:0000007 10421367 t gcesareni Here we show that the 353-amino-acid human orphan g-protein-coupled receptor slc-1 expressed in hek293 cells binds mch with sub-nanomolar affinity, and is stimulated by mch to mobilize intracellular ca2+ and reduce forskolin-elevated cyclic amp levels. SIGNOR-69517 0.702 BRAP protein Q7Z569 UNIPROT USP15 protein Q9Y4E8 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 23105109 t miannu Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. SIGNOR-272029 0.27 PPP2CA protein P67775 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT down-regulates dephosphorylation Thr588 PEHQLLKtPSSSSLS 9606 18201571 t gcesareni We report here that (i) mgcracgap is phosphorylated by aurora b and cdk1, (ii) pp2a dephosphorylates aurora b and cdk1 phosphorylated sites and (iii) inhibition of pp2a abrogates mgcracgap/ect2 interaction. Therefore, pp2a may regulate cytokinesis by dephosphorylating mgcracgap and its interacting partners. SIGNOR-160402 0.307 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser296 SPSALSSsPNNLSPT 10090 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-244681 0.2 DYRK2 protein Q92630 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser46 AMDDLMLsPDDIEQW 19965871 t lperfetto Phosphorylation of p53 at Ser-46 is indispensable for the commitment to apoptotic cell death. |Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus. SIGNOR-275578 0.657 STK3 protein Q13188 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation Thr180 DTMAKRNtVIGTPFW 9606 BTO:0000150 20231902 t gcesareni Consistent with previous studies, sts alone induces mst2 cleavage and autophosphorylation of thr180, an indicator of mst2 activation, as well as apoptosis. SIGNOR-164310 0.2 NR3C1 protein P04150 UNIPROT AR protein P10275 UNIPROT down-regulates activity binding 9606 9162033 t gcesareni Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity. SIGNOR-48516 0.527 GSK3B protein P49841 UNIPROT PGR protein P06401 UNIPROT down-regulates quantity by destabilization phosphorylation Ser554 PDSEASQsPQYSFES 9606 23880761 t miannu Here, we have found that glycogen synthase kinase (GSK)-3β phosphorylation of progesterone receptor-A (PR-A) facilitates its ubiquitination. GSK-3β-mediated phosphorylation of serine 390 in PR-A regulates its subsequent ubiquitination and protein stability. SIGNOR-276498 0.28 PRKACA protein P17612 UNIPROT RASGRF1 protein Q13972 UNIPROT up-regulates phosphorylation Ser927 KEKYRRMsLASAGFP 9606 BTO:0000938 10601308 t llicata Phosphorylation of serine 916 of ras-grf1 contributes to the activation of exchange factor activity by muscarinic receptors. SIGNOR-73202 0.502 TFDP1 protein Q14186 UNIPROT TYMS protein P04818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253861 0.411 POMC protein P01189 UNIPROT MC3R protein P41968 UNIPROT up-regulates activity binding BTO:0000614 17702843 t lperfetto Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases. SIGNOR-253073 0.75 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser195 PNSSYPNsPGSSSST 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248301 0.479 4-[2-[(1R)-1-(N-(4-chlorophenyl)sulfonyl-2,5-difluoroanilino)ethyl]-5-fluorophenyl]butanoic acid chemical CHEBI:94983 ChEBI PSEN1 protein P49768 UNIPROT down-regulates chemical inhibition 9606 BTO:0000142 18032377 t gcesareni We employed a combination of chimeric constructs and point mutants to identify structural determinants for ps1-selective inhibition by eln318463. Our studies identified amino acid residues leu(172), thr(281), and leu(282) in ps1 as necessary for ps1-selective inhibition by eln318463. These residues also contributed in part to the ps1-selective inhibition by bms299897. SIGNOR-159344 0.8 ATM protein Q13315 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser560 LARLGCSsCLDYFTT 9606 18769144 t lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively SIGNOR-180751 0.412 glucose chemical CHEBI:17234 ChEBI HK2 protein P52789 UNIPROT up-regulates quantity by stabilization 9606 BTO:0004424 26323688 t Consistently, treatment of cells with 2-deoxy-d-glucose (2DG), which completely inhibits glucose metabolism, leads to HK2 degradation and cell death in combination with C43 SIGNOR-261323 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR PEA15 protein Q15121 UNIPROT up-regulates activity phosphorylation Ser116 KDIIRQPsEEEIIKL 9606 BTO:0000007 12808093 t lperfetto Protein kinase b/akt binds and phosphorylates ped/pea-15, stabilizing its antiapoptotic action. SIGNOR-244326 0.2 maraviroc chemical CHEBI:63608 ChEBI CCL4L1 protein Q8NHW4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194009 0.8 SYNE3 protein Q6ZMZ3 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 t lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. SIGNOR-263284 0.528 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser400 SRDESTDsGLSMSSY 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 24715453 t milica LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP) SIGNOR-230728 0.401 CDR2 protein Q01850 UNIPROT CENPE protein Q02224 UNIPROT up-regulates quantity by expression transcriptional regulation 20383333 f lperfetto Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology SIGNOR-252020 0.2 AURKB protein Q96GD4 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates phosphorylation Ser893 PRYHKRTsSAVWNSP 9606 12925766 t gcesareni Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites. SIGNOR-118011 0.973 SMCR8 protein Q8TEV9 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity binding 9606 BTO:0000007 28195531 t While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion. SIGNOR-252029 0.406 PRKCB protein P05771 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249286 0.36 TFEB protein P19484 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 t lperfetto As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes; SIGNOR-276558 0.419 ABL1 protein P00519 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr393 FGLSRLMtGDTYTAH 9606 10964922 t Manara We demonstrate here that autophosphorylation of ABL1 is intermolecular and stimulates Abl catalytic activity. SIGNOR-260781 0.2 EPB41 protein P11171 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 33187473 t lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] SIGNOR-266035 0.416 MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR BRCA1-C complex complex SIGNOR-C299 SIGNOR form complex binding 25400280 t lperfetto The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2 SIGNOR-263221 0.2 PTP4A3 protein O75365 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by destabilization dephosphorylation 9606 29266303 t lperfetto As expected, PRL3 clearly reduced PTEN phosphorylation at the tyrosine residue and PTEN protein in PRL3 overexpressing LO2 and HepG2 cell lines, with no significant changes in PRL3 (C104S) mutant cells.|PRL3 down-regulates PTEN expression, a negative regulator of the Akt pathway.11 Phosphorylation of PTEN at Tyr336 is required for maintenance of PTEN protein stability and prevention of PTEN degradation.17 We therefore speculated that PRL3 might dephosphorylate PTEN at tyrosine sites and consequently reduce the PTEN protein level. SIGNOR-277010 0.3 AGRP protein O00253 UNIPROT MC3R protein P41968 UNIPROT down-regulates binding 9606 BTO:0001253 9311920 t gcesareni Recombinant agouti-related protein was a potent, selective antagonist of mc3r and mc4r, melanocortin receptor subtypes implicated in weight regulation. SIGNOR-51067 0.611 PRKG1 protein Q13976 UNIPROT CRIP2 protein P52943 UNIPROT unknown phosphorylation Ser104 RAEERKAsGPPKGPS 9534 BTO:0000298 10681529 t lperfetto  Cyclic GMP kinase I phosphorylated CRP2 at Ser-104, because the mutation to Ala completely prevented the in vivo phosphorylation. SIGNOR-249038 0.462 CTBP1 protein Q13363 UNIPROT VDR protein P11473 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 18485278 f miannu We have shown here that the transcriptional repressor protein SLUG inhibits the expression of VDR in human breast cancer cells. SIGNOR-255178 0.359 MAPK8 protein P45983 UNIPROT APP protein P05067 UNIPROT up-regulates phosphorylation Thr743 VEVDAAVtPEERHLS 9606 BTO:0000793 24610780 t lperfetto Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. We found that the threonine 668 within the abetapp intracellular domain (aid or elsewhere aicd) is indeed phosphorylated by jnk1 SIGNOR-204679 0.699 CDK1 protein P06493 UNIPROT NIFK protein Q9BYG3 UNIPROT up-regulates activity phosphorylation Thr238 QGPTPVCtPTFLERR -1 16244663 t miannu The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1. SIGNOR-262696 0.283 PAX3 protein P23760 UNIPROT TBX2 protein Q13207 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002267 25211658 t lperfetto We have recently found that a T-box gene family member, TBX2, is highly overexpressed in both ERMS and ARMS cells (Zhu et al, 2014). The regulation of TBX2 is uncharacterised in RMS cells, but is likely to link TBX2 expression to the known deregulation of signalling pathways in RMS. In melanoma cells, TBX2 is regulated by PAX3 SIGNOR-249596 0.353 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-268073 0.8 teniposide chemical CHEBI:75988 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 1329225 t miannu Recognition of transient DNA breaks induced by teniposide, etoposide, and other podophyllotoxin analogues established not only that their site of activity was DNA but also that their cytotoxic effect was dose-dependent. Extensive investigation has further indicated that a primary mechanism of action of these agents involves inhibition of the catalytic activity of eukaryote topoisomerase II and, more important, the consequent stabilization of the normally transient covalent intermediate formed between the DNA substrate and the enzyme. SIGNOR-259329 0.8 ADRA1B protein P35368 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257190 0.41 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 23422745 t gcesareni The phosphorylation of atr and atm substrates, chk1, chk2, h2ax, and brca1 was significantly reduced or abrogated in mutant cells. SIGNOR-201050 0.793 METTL3 protein Q86U44 UNIPROT USP13 protein Q92995 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 36528756 t lperfetto Furthermore, N6-methyladenosine methyltransferase-like 3 (METTL3) mediated stabilization of USP13 mRNA that required the m6A reader IGF2BP2. SIGNOR-275839 0.2 AKT1 protein P31749 UNIPROT SRPK2 protein P78362 UNIPROT up-regulates phosphorylation Thr492 PSHDRSRtVSASSTG 9606 BTO:0000938 BTO:0000142 19592491 t lperfetto Here we show that srpk2, a protein kinase specific for the serine/arginine (sr) family of splicing factors, triggers cell cycle progression in neurons and induces apoptosis through regulation of nuclear cyclin d1. Akt phosphorylates srpk2 on thr-492 and promotes its nuclear translocation leading to cyclin d1 up-regulation, cell cycle reentry, and neuronal apoptosis. SIGNOR-186760 0.478 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 BTO:0000150 20231902 t gcesareni Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation. SIGNOR-164298 0.2 EFNA3 protein P52797 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates binding 9606 9330863 t gcesareni The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion SIGNOR-52384 0.795 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser29 FLGLHIAsPPNFRLT 9534 BTO:0000298 12756254 t miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. SIGNOR-250125 0.879 PRKACA protein P17612 UNIPROT PLIN1 protein O60240 UNIPROT down-regulates activity phosphorylation Ser220 KAKPSLLsRVGALTN 10090 11751901 t miannu PKA increased lipolysis in cells expressing Peri A because it abrogated the inhibitory actions of Peri A on lipolysis.‚  amino-terminal PKA sites (Ser-81, Ser-222, and Ser-276) SIGNOR-250028 0.483 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-262997 0.706 vitamin K epoxide smallmolecule CHEBI:28371 ChEBI Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI up-regulates quantity precursor of 9606 31226734 t lperfetto The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form SIGNOR-265913 0.8 FGF14 protein Q92915 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253441 0.2 UBE2I protein P63279 UNIPROT MBD4 protein O95243 UNIPROT up-regulates activity sumoylation Lys377 HLHTDILkRGSEMDN 31476572 t lperfetto MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro. SIGNOR-275678 0.2 PLK1 protein P53350 UNIPROT SVIL protein O95425 UNIPROT up-regulates activity phosphorylation Ser238 SFSGRDSsFTEVPRS 9606 BTO:0000007 23750008 t miannu PLK1 phosphorylates Ser238 of SVIL, which can promote the localization of SVIL to the central spindle and association with PRC1. Expression of a PLK1 phosphorylation site mutant, S238A-SVIL, inhibited myosin II activation at the equatorial cortex and induced aberrant furrowing.  SIGNOR-273729 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser1798 GQRKRLIsSVEDFTE 9606 BTO:0000007 15342917 t lperfetto The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1 SIGNOR-252801 0.2 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser43 FGYQRRAsDDGKLTD 10090 BTO:0000944 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-249439 0.616 AP2B1 protein P63010 UNIPROT AP-2 complex complex SIGNOR-C245 SIGNOR form complex binding 31671891 t lperfetto The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit SIGNOR-260422 0.855 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22703233 f lperfetto Our results establish a novel biological role for TGFbeta signaling in controlling expression of genes characteristic for alternatively activated macrophages. We speculate that lack of TbetaRII signaling reduces the anti-inflammatory M2 phenotype of macrophages because of reduced expression of these products. SIGNOR-249550 0.7 VAV1 protein P15498 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates 9606 BTO:0000782 10725744 f lperfetto Vav synergizes with protein kinase c theta to mediate il-4 gene expression in response to cd28 costimulation in t cells SIGNOR-75827 0.605 LYN protein P07948 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity phosphorylation Tyr254 SPPDYSEyMTGKKLP 9606 BTO:0002181 26198631 t miannu In the case of Lyn overexpression, single mutations at either tyrosine 8, 254, or 383 severely reduced Lyn-mediated YY1 phosphorylation, suggesting that these three sites may be targets of Lyn in vivo (Fig. 3, A and B). SIGNOR-276929 0.2 PRKCD protein Q05655 UNIPROT PPP1R14B protein Q96C90 UNIPROT up-regulates activity phosphorylation Thr57 VRRQGKVtVKYDRKE 10606530 t lperfetto Recombinant tagged PHI-1 was phosphorylated by protein kinase C at two sites, one a Ser and one a Thr; phosphorylation enhanced inhibitory potency 50-fold. SIGNOR-265739 0.2 TADA1 protein Q96BN2 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269583 0.698 CDK1 protein P06493 UNIPROT LMNA protein P02545 UNIPROT up-regulates phosphorylation Ser22 QASSTPLsPTRITRL 9606 18815303 t gcesareni Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm SIGNOR-181310 0.552 WDR45 protein Q9Y484 UNIPROT ATG2A protein Q2TAZ0 UNIPROT up-regulates activity binding 9606 BTO:0001938 28561066 t miannu WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation. SIGNOR-268483 0.537 TSPAN33 protein Q86UF1 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates activity binding 10116 30463011 t Simone Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. SIGNOR-261251 0.496 BAD protein Q92934 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity binding 9606 BTO:0002552 17000778 t lperfetto We also demonstrate that bad physically interacts with cytoplasmic p53. bad is able to direct p53 to the mitochondria and forms a p53/bad complex at the mitochondria. the mitochondrial p53/bad complex promotes apoptosis SIGNOR-149815 0.334 Cyclopamine chemical CHEBI:4021 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9534 BTO:0000298 12414725 t gcesareni The steroidal alkaloid cyclopamine has both teratogenic and antitumor activities arising from its ability to specifically block cellular responses to vertebrate Hedgehog signaling. We show here, using photoaffinity and fluorescent derivatives, that this inhibitory effect is mediated by direct binding of cyclopamine to the heptahelical bundle of Smoothened (Smo) SIGNOR-95270 0.8 HOXC11 protein O43248 UNIPROT S100B protein P04271 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17488478 t Luana HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells. SIGNOR-261647 0.255 F2R protein P25116 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257403 0.547 JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 t lperfetto Activation of wild type stat3: il-6 treatment causes stat3 recruitment to receptor tyrosine phosphopeptides (gp130) where it is phosphorylated on tyrosine 705 (y) by jak kinase SIGNOR-236463 0.811 AKT1 protein P31749 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3beta (GSK3B). The AKT-mediated phosphorylation of glycogen synthase kinase 3b on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245416 0.784 PHT-427 chemical CID:44240850 PUBCHEM PDPK1 protein O15530 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 21715304 t gcesareni Consistent with the results described in figures 3c and and4a,4a, treatment of 32d/bcr-abl cells with the bcr-abl inhibitor imatinib, the pi3k inhibitor ly294002 or the akt/pdpk1 inhibitor pht-427 substantially reduced atf5 promoter-directed luciferase activity SIGNOR-174612 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK1 protein Q15835 UNIPROT down-regulates activity phosphorylation Ser21 AFIAARGsFDGSSSQ -1 15946941 t miannu  We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA.Phosphorylation of GRK1 and GRK7 by PKA reduces the ability of GRK1 and GRK7 to phosphorylate rhodopsin in vitro. SIGNOR-276034 0.2 dabrafenib chemical CHEBI:75045 ChEBI NEK11 protein Q8NG66 UNIPROT down-regulates activity chemical inhibition -1 24720932 t miannu Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations SIGNOR-259217 0.8 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CXCL8 protein P10145 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19185596 f miannu S protein is a ligand for human TLR2. S protein utilizes toll-like receptor 2(TLR 2) to increase IL-8 production.Our results show that SARS S protein in a soluble form increased IL-8 production through hTLR2 ligand interaction. we have provided evidence that S protein induces IL-8 in PBMC in vitro and in THP-1 cells. The ability of S protein to increase IL-8 mRNA was mediated by activation of NF-κB possibly via TLR2 ligand and could be inhibited by the NF-κB inhibitor TPCK. The ability to detect elevated NF-κB transcription factor activity in the nucleus in response to S protein suggests that this most likely occurs by the mechanism of induction. Moreover increased secretion of IL-8 and IL-6 cytokines indicated that levels of proinflammatory mediators could be enhanced by S protein interaction with monocyte macrophages and could stimulate NK, neutrophil and monocyte migration to the site of infection. SIGNOR-260974 0.633 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Thr310 VPPLPKVtPTKELQQ 9606 BTO:0000142 15262992 t lperfetto Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd SIGNOR-126855 0.405 WASF3 protein Q9UPY6 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates activity 9534 17623672 f We have also shown that Abl targets and phosphorylates four tyrosine residues in WAVE3 and that the Abl-dependent phosphorylation of WAVE3 is critical for the stimulation of lamellipodia formation and cell migration. SIGNOR-259078 0.7 Survival Factors stimulus SIGNOR-ST8 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity 19282669 f lperfetto Activation of receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs) by growth factors or mitogens leads to the recruitment of an adaptor protein Grb2 (growth factor receptor bound protein) and the guanine nucleotide exchange factor (SOS). The SOS activates Ras to recruit and activate Raf at the plasma membrane by phosphorylation at multiple sites. MEK1/2 is which then phosphorylated at two serine residues that subsequently phosphorylates ERK1/2 on both threonine and tyrosine. Activated ERK1/2 phosphorylates RSK and both RSK and ERK translocate to the nucleus where they activates multiple transcription factors ultimately resulting in effector protein synthesis and causing changes in cell proliferation and survival. ERK phosphorylation of MEK and possibly Raf can inactivate the pathway at those steps creating a negative feedback loop. SIGNOR-250559 0.7 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser287 SVKSPVSsPNNVTLR 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276104 0.29 OXGR1 protein Q96P68 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257042 0.358 BBOX1 protein O75936 UNIPROT succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity chemical modification 9606 11802770 t miannu In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. SIGNOR-269700 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR HSPB8 protein Q9UJY1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser57 DWALPRLsSAWPGTL -1 18298377 t miannu Human small heat shock protein with molecular mass 22 kD (HSP22, HspB8) contains two Ser residues (Ser24 and Ser57) in consensus sequence RXS and is effectively phosphorylated by cAMP-dependent protein kinase in vitro. Mutation S24D did not affect, whereas mutations S57D or S24,57D prevented phosphorylation of HSP22 by cAMP-dependent protein kinase thus indicating that Ser57 is the primary site of phosphorylation. Phosphorylation (or mutation) of Ser57 (or Ser24 and Ser57) resulted in changes of the local environment of tryptophan residues and increased HSP22 susceptibility to chymotrypsinolysis.  SIGNOR-276151 0.2 PCDHAC1 protein Q9H158 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-269037 0.2 COL18A1 protein P39060 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 SIGNOR-252269 0.7 PPP2CB protein P62714 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation 9606 8650155 t gcesareni These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity SIGNOR-252636 0.487 CDK1 protein P06493 UNIPROT TOP1 protein P11387 UNIPROT up-regulates activity phosphorylation Ser394 SKDAKVPsPPPGHKW -1 18408216 t miannu In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells. SIGNOR-276157 0.356 TAF5L protein O75529 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269586 0.675 CENPI protein Q92674 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265213 0.756 CDK11B protein P21127 UNIPROT EIF3F protein O00303 UNIPROT down-regulates phosphorylation Ser46 PAAAPASsSDPAAAA 9606 12446680 t lperfetto The interaction between cdk11p46 and eif3 p47 occurs in vitro and in vivo. In addition, cdk11 protein kinase isolated from cells undergoing apoptosis can phosphorylate eif3 p47in vitro, and serine phosphorylation of eif3 p47 occurs in cells during apoptosis.Purified recombinant cdk11p46 inhibited translation of a reporter gene in vitro in a dose-dependent manner.These data suggest that the function of the caspase-processed cdk11p110 isoform may be to inhibit translation during apoptosis. However, whether or not this inhibition of protein translation occurs in an eif3 p47-dependent or -independent manner remains to be clarified. SIGNOR-95762 0.529 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates quantity by stabilization phosphorylation Ser176 TNAENTAsQSPRTRG 9606 BTO:0000567 19789335 t lperfetto we show that TNFalpha treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser(176) and Ser(184) and Daxx is required for the sustained activation of JNK. Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1. SIGNOR-109680 0.835 RPS6KA1 protein Q15418 UNIPROT ETV1 protein P50549 UNIPROT up-regulates activity phosphorylation Ser191 HRFRRQLsEPCNSFP 9606 12213813 t lperfetto Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation. SIGNOR-249162 0.356 ketoconazole chemical CHEBI:47519 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258060 0.8 PRPF4B protein Q13523 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr417 ISVDGLStPVVLSPG 9606 BTO:0000142;BTO:0000763 10799319 t lperfetto Activated hprp4 phosphorylates residue thr-417 on elk-1 resulting in elk-1 activation. SIGNOR-77135 0.2 SIRT5 protein Q9NXA8 UNIPROT SIRT3 protein Q9NTG7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31608237 f Monia In U2OS cells, SIRT5 silencing resulted in downregulation of SIRT1 and SIRT3 protein levels (Figures 4Ai,ii, compare bars 1 to 5). SIGNOR-261209 0.412 MECOM protein Q03112 UNIPROT GATA1 protein P15976 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000669 15889140 t Luana We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2  SIGNOR-266061 0.325 PPM1D protein O15297 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity dephosphorylation Thr68 SSLETVStQELYSIP -1 16311512 t an in vitro phosphatase assay revealed that Wip1 (WT), but not Wip1 (D314A), dephosphorylates Thr68 on phosphorylated Chk2 in vitro, resulting in the inhibition of Chk2 kinase activity toward glutathione S-transferase-Cdc25C. SIGNOR-248318 0.589 IL1R1 protein P14778 UNIPROT IL1RAP protein Q9NPH3 UNIPROT up-regulates activity binding 9606 BTO:0000007 10854325 t lperfetto Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs) SIGNOR-251981 0.719 DLG4 protein P78352 UNIPROT Scribble_complex_DLG4-LLGL2_variant complex SIGNOR-C505 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270889 0.454 JAK2 protein O60674 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000801 8977526 t irozzo JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation. SIGNOR-256001 0.568 MLNR protein O43193 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256880 0.252 PRKAA2 protein P54646 UNIPROT CDC27 protein P30260 UNIPROT unknown phosphorylation Ser379 NALPRRSsRLFTSDS 9606 SIGNOR-C15 22137581 t lperfetto Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379, respectively) resulted in an almost complete loss of ampk phosphorylation in these proteins SIGNOR-195106 0.264 MAP3K7 protein O43318 UNIPROT NFKBIB protein Q15653 UNIPROT down-regulates phosphorylation 9606 9480845 t gcesareni Overexpression oftak1together with its activator protein,tak1binding protein 1 (tab1), induced thenucleartranslocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene. SIGNOR-55719 0.494 RFX complex complex SIGNOR-C104 SIGNOR HLA-DPB1 protein P04440 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11889043 f Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment. SIGNOR-254007 0.291 FIP1L1 protein Q6UN15 UNIPROT PAPOLA protein P51003 UNIPROT up-regulates binding 9606 14749727 t miannu Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna. SIGNOR-121700 0.783 CSMD1 protein Q96PZ7 UNIPROT C3 protein P01024 UNIPROT down-regulates quantity binding 9606 28345259 t miannu CUB and sushi multiple domains 1 (CSMD1) is a relatively poorly studied large transmembrane protein of 390 kDa composed of 14 N-terminal CUB domains interspersed with complement control protein (CCP) domains followed by 15 consecutive CCP domains. The active domains of CSMD1 were then identified in CCP17-21, which were shown to interact with C4b and C3b and present these complement proteins for degradation by factor SIGNOR-265148 0.2 DUSP5 protein Q16690 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 15713638 t fstefani Here we demonstrate that dusp5, an inducible nuclear phosphatase, interacts specifically with erk2 via a kinase interaction motif (kim) within its amino-terminal noncatalytic domain. This binding determines the substrate specificity of dusp5 in vivo, as it inactivates erk2 but not jun n-terminal protein kinase or p38 map kinase. SIGNOR-134049 0.773 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Ser853 IAEPMRRsVSEAALA 10090 BTO:0000944 11581251 t lperfetto HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme SIGNOR-249202 0.585 P2RY6 protein Q15077 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256947 0.2 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser221 PRTSPIMsPRTSLAE 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248687 0.613 TGFBI protein Q15582 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 26387839 t lperfetto BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers SIGNOR-253269 0.341 BLK protein P51451 UNIPROT CGAS protein Q8N884 UNIPROT down-regulates activity phosphorylation Tyr215 LLNTGSYyEHVKISA 30356214 t lperfetto DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS. SIGNOR-275844 0.2 IRF7 protein Q92985 UNIPROT IFNA1 protein P01562 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16612387 f gcesareni Ikkalfa can also phosphorylate and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production. SIGNOR-146119 0.559 RAB1A protein P62820 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR up-regulates activity binding 9606 BTO:0000567 27334615 t Giulio Thus, these data show ULK1–Rab1a interaction in intact cells and reveal that this interaction is C9orf72 dependent. SIGNOR-261283 0.381 MAPK8 protein P45983 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates quantity by stabilization phosphorylation Ser115 SQFSDCSsAKARGDL 9606 BTO:0002932 34048060 t miannu Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation. SIGNOR-277562 0.275 TMED10 protein P49755 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 16641999 t gcesareni Here we report that tmp21, a member of the p24 cargo protein family, is a component of presenilin complexes and differentially regulates gamma-secretase cleavage SIGNOR-146364 0.638 MAP3K5 protein Q99683 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9534 BTO:0004055 8974401 t lperfetto ASK1 activated SEK1 and MKK3 up to 7.0- and 11.8-fold, respectively SIGNOR-226672 0.583 PPARGC1A protein Q9UBK2 UNIPROT SOD2 protein P04179 UNIPROT up-regulates 10090 18074631 f lperfetto In fact, experiments with either genetic knockouts or RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins such as catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat. SIGNOR-253395 0.381 COX5A protein P20674 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267751 0.796 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Thr231 TRNKVRKtFVGTPCW 9606 BTO:0000007 BTO:0000671 16083423 t gcesareni Phosphorylation by WNK1 or WNK4 markedly increased SPAK and OSR1 activity. Phosphopeptide mapping studies demonstrated that WNK1 phosphorylated kinase-inactive SPAK and OSR1 at an equivalent residue located within the T-loop of the catalytic domain (Thr233 in SPAK, Thr185 in OSR1) and a serine residue located within a C-terminal non-catalytic region (Ser373 in SPAK, Ser325 in OSR1) SIGNOR-160846 0.457 PRKCB protein P05771 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser595 GLMQQQKsFR 9606 11781100 t lperfetto  In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta. SIGNOR-249139 0.336 TNFSF13 protein O75888 UNIPROT TNFRSF17 protein Q02223 UNIPROT up-regulates binding 9606 BTO:0000782 10973284 t gcesareni April is involved in stimulation of b and t cell function. April functions via binding to bcma and taci and competes with tall-i for receptor binding. SIGNOR-81386 0.674 FOXO1 protein Q12778 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 f inferred from family member gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-267787 0.326 AKT proteinfamily SIGNOR-PF24 SIGNOR PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation -1 16340011 t gcesareni It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser 485/Ser 491 phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr 172 by LKB1 and the resulting activation of AMP-activated protein kinase. SIGNOR-252740 0.2 NUAK1 protein O60285 UNIPROT CASP6 protein P55212 UNIPROT down-regulates activity phosphorylation Ser257 TLVNRKVsQRRVDFC -1 15273717 t miannu ARK5 negatively regulates procaspase-6 by phosphorylation at Ser257, leading to resistance to the FasL/Fas system. SIGNOR-250209 0.496 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr74 QINMLYGtITEFCTE 9606 BTO:0000007 18362890 t gcesareni These findings indicate that the phosphorylation of mob1 at thr74 by mst2 is essential to make a complex of mob1, mst2 and ndr1, and to fully activate ndr1 SIGNOR-177977 0.845 naloxone chemical CHEBI:7459 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258770 0.8 ARHGEF11 protein O15085 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260538 0.9 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2Z protein Q9H832 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271313 0.687 tRNA(Asn) smallmolecule CHEBI:29172 ChEBI Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity precursor of 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270467 0.8 idarubicin chemical CHEBI:42068 ChEBI TOP2B protein Q02880 UNIPROT down-regulates activity chemical inhibition 9606 20824055 t miannu Topoisomerase II (Top2) is a nuclear enzyme involved in several metabolic processes of DNA. Chemotherapy agents that poison Top2 are known to induce persistent protein-mediated DNA double strand breaks (DSB). In this report, by using knock down experiments, we demonstrated that Top2α was largely responsible for the induction of γH2AX and cytotoxicity by the Top2 poisons idarubicin and etoposide in normal human cells. SIGNOR-259328 0.8 SP1 protein P08047 UNIPROT CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11013220 f irozzo In this system, the basal transcription level from the p15Ink4B promoter was increased with increasing levels of Sp1, and Sp1 was required for transcriptional induction by Smads. Finally, inactivation of the Sp1 binding sites in the p15Ink4B promoter decreased the basal transcription level and TGF-β responsiveness. SIGNOR-256289 0.544 SRC protein P12931 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity phosphorylation Tyr112 NSYVAGQyDDAASYQ -1 33686238 t miannu Here, we show that tyrosine kinase c-Src interacts with and phosphorylates G6PD at Tyr 112. This phosphorylation enhances catalytic activity of G6PD by dramatically decreasing its Km value and increasing its Kcat value for substrate glucose-6-phosphate. SIGNOR-277550 0.277 ARP2/3 complex SIGNOR-C146 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity binding 9606 BTO:0000132 27871158 t lperfetto The Arp2/3 complex stimulates the assembly of actin filaments. SIGNOR-261838 0.7 JNK proteinfamily SIGNOR-PF15 SIGNOR STMN1 protein P16949 UNIPROT down-regulates phosphorylation 9606 20630875 t inferred from 70% family members gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress. SIGNOR-269982 0.2 BTC protein P35070 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 10209155 t gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4 SIGNOR-67006 0.712 DAPK3 protein O43293 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 15001356 t gcesareni Zip kinase was able to phosphorylate mdm2 at ser166, a site previously reported to be modified by akt kinase, thus demonstrating that zip kinase is a bona fide mdm2-binding protein. SIGNOR-123159 0.348 luminespib chemical CHEBI:83656 ChEBI HSP90AB1 protein P08238 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190041 0.8 SBDS protein Q9Y3A5 UNIPROT EFL1 protein Q7Z2Z2 UNIPROT up-regulates binding 9606 BTO:0001271 21536732 t miannu Sbds stimulates 60s-dependent gtp hydrolysis by efl1 SIGNOR-173533 0.2 FYN protein P06241 UNIPROT JUP protein P14923 UNIPROT up-regulates activity phosphorylation Tyr550 AAGTQQPyTDGVRME 10116 14517306 t Phosphorylation of plakoglobin by Fer and Fyn kinases decreases plakoglobin-desmoplakin interaction and increases plakoglobin-α-catenin association. Fyn mainly phosphorylated Tyr549 and that it phosphorylated Tyr133 with a much lower activity SIGNOR-251176 0.542 Fatty acid stimulus SIGNOR-ST19 SIGNOR PPARG protein P37231 UNIPROT up-regulates 9606 29369787 t miannu Omega 3 fatty acids and fibrates are considered as natural and pharmacological ligands of PPARα, respectively, that reduce inflammation and arteriosclerosis in cardiovascular system SIGNOR-256189 0.7 PTPN12 protein Q05209 UNIPROT ABL1 protein P00519 UNIPROT down-regulates activity dephosphorylation Tyr393 RLMTGDTyTAHAGAK 9534 BTO:0004055 11163214 t lperfetto Several experiments suggest that the pest-type ptps negatively regulate c-abl activity: c-abl was hyperphosphorylated in ptp-pest-deficient cells dephosphorylation of c-abl by pest-type ptp represents a novel mechanism by which c-abl activity is regulated. SIGNOR-235568 0.449 GLS protein O94925 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 22049910 t miannu Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. SIGNOR-260000 0.8 2-acyl-sn-glycero-3-phospho-D-myo-inositol smallmolecule CHEBI:62746 ChEBI 1-phosphatidyl-1D-myo-inositol smallmolecule CHEBI:16749 ChEBI up-regulates quantity precursor of -1 18772128 t miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. SIGNOR-267245 0.8 CSNK1A1 protein P48729 UNIPROT FOXG1 protein P55316 UNIPROT up-regulates phosphorylation Ser19 MIPKSSFsINSLVPE 9606 BTO:0000938 BTO:0000142 17435750 t llicata Cki phosphorylation of ser 19 of foxg1 promotes nuclear import SIGNOR-154386 0.2 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 14579029 t gcesareni Map kinases and mtor mediate insulin-induced phosphorylation ofinsulinreceptor substrate-1 on serine residues 307, 612 and 632 SIGNOR-118881 0.698 DYRK1A protein Q13627 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates activity phosphorylation Ser251 NKVIPAKsPPPPTHS -1 34109727 t miannu Here, we uncovered that dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), a kinase critical in Down's syndrome pathogenesis, directly bound to and phosphorylated MEF2D at Ser251 in vitro. Phosphorylation of MEF2D by DYRK1A significantly increased MEF2D protein level but attenuated its transcriptional activity, which resulted in decreased transcriptions of MEF2D target genes. SIGNOR-277565 0.421 ULK1 protein O75385 UNIPROT YAP1 protein P46937 UNIPROT up-regulates quantity by stabilization phosphorylation Ser227 VQQNMMNsASGPLPD 9606 BTO:0003491 34345207 t miannu Mechanistically, hypoxia stimulates ULK1 to translocate into nucleus, where it interacts with and phosphorylates yes-associated protein (YAP) at Ser227, resulting in YAP stabilization through blockade of ubiquitin-proteasome system (UPS), which in turn facilitates PKM2 transcription, glycolysis, cell proliferation in vitro as well as PDAC growth in mice. SIGNOR-277570 0.2 BRAF protein P15056 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 21900390 f miannu RAF, a cytoplasmic serine-threonine protein kinase, is a member of the RAS-RAF-MEK-ERK cell-signaling pathway [also known as the MAP kinase (MAPK) pathway], and it plays an essential role in mediating cellular differentiation, proliferation, senescence, and survival in response to extracellular cues. Raf phosphorylates and activates MAP-ERK kinase (MEK), which phosphorylates and activates extracellular signal-regulated kinase (ERK). SIGNOR-260082 0.646 calcium(2+) smallmolecule CHEBI:29108 ChEBI SLC25A13 protein Q9UJS0 UNIPROT up-regulates activity chemical activation 9606 12084073 t miannu Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. SIGNOR-265153 0.8 GSK3B protein P49841 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates quantity by destabilization phosphorylation Thr66 NVNTKCItIPRSLDG 9606 18172167 t lpetrilli Mechanistically, axin facilitates gsk3-beta-mediated phosphorylation of smad3 at thr66, which triggers smad3 ubiquitination and degradation. SIGNOR-160318 0.502 SRC protein P12931 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates activity phosphorylation Tyr179 TSCGSPNyAAPEVIS 9606 BTO:0002181 34673141 t miannu We show here that Src signaling leads to direct phosphorylation of the AMPK-α subunit on a novel site, tyrosine 179, resulting in suppression of AMPK-T172 phosphorylation and autophagy upon integrin-mediated cell adhesion. SIGNOR-277573 0.26 PIM1 protein P11309 UNIPROT YWHAZ protein P63104 UNIPROT up-regulates activity phosphorylation Ser64 SSWRVVSsIEQKTEG 9606 BTO:0001321 34697370 t miannu PIM1 phosphorylates the AR and 14-3-3 ζ and coordinates their interaction. PIM1 phosphorylation of the AR and 14-3-3 ζ enhances their interaction and shifts their occupancy on chromatin, resulting in 14-3-3 ζ co-regulation of AR, likely by recruiting other AR co-regulators such as hnRNPK and TRIM28. SIGNOR-277574 0.315 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Thr527 PPKAKDPtVS -1 35080342 t miannu Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. SIGNOR-277578 0.414 MAPK3 protein P27361 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 10980595 t llicata We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway SIGNOR-81460 0.719 RTF1 protein Q92541 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR form complex binding 9606 BTO:0000567 20178742 t miannu Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A).  SIGNOR-269835 0.883 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Thr142 DSVTKLLtDVQLMKG -1 35080342 t miannu Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. SIGNOR-277579 0.414 PTPRR protein Q15256 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0001616 17360477 t Here, we report identification of signal transducer and activator of transcription 3 (STAT3) as a substrate of PTPRT. Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position. SIGNOR-248719 0.2 DDHD2 protein O94830 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI down-regulates quantity chemical modification 9606 22922100 t miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. SIGNOR-269649 0.8 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 BTO:0000443 12220227 t lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. SIGNOR-235983 0.912 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 t miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. SIGNOR-264929 0.8 KAT2A protein Q92830 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269596 0.2 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Ser230 PKYSRQFsLEHVHGS -1 35080342 t miannu Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. SIGNOR-277580 0.414 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Ser326 SSVDTLLsPTALIDS -1 35080342 t miannu Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. SIGNOR-277581 0.414 PAK4 protein O96013 UNIPROT NFE2L2 protein Q16236 UNIPROT down-regulates quantity by destabilization phosphorylation Thr369 ESSSYGDtLLGLSDS 10090 BTO:0000575 35108418 t miannu PAK4 directly phosphorylated Nrf2 at T369, and it led to its nuclear export and proteasomal degradation, all of which impaired antioxidant responses in hepatocytes. SIGNOR-277583 0.2 MAPK3 protein P27361 UNIPROT EPAS1 protein Q99814 UNIPROT up-regulates quantity by stabilization phosphorylation Ser484 SSCSTPNsPEDYYTS 9606 BTO:0006155 35191554 t miannu The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33.Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells. SIGNOR-277584 0.263 ATR protein Q13535 UNIPROT FANCA protein O15360 UNIPROT up-regulates phosphorylation Ser1449 AAPDADLsQEPHLF 9606 19109555 t lperfetto The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site SIGNOR-182953 0.581 PRKCA protein P17252 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Ser2 sLKNEPRV 9606 10441128 t gcesareni Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells. SIGNOR-69930 0.702 CDC14A protein Q9UNH5 UNIPROT CDC25B protein P30305 UNIPROT down-regulates activity dephosphorylation 9606 20956543 t lperfetto Cdc14A inhibits Cdc25A and Cdc25B activity, the latter through direct binding and dephosphorylation ( ).|Together, these data indicate that Cdc14A dephosphorylates Cdc25B, inhibiting its catalytic activity. SIGNOR-276968 0.576 ATM protein Q13315 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates quantity by stabilization phosphorylation Ser31 ALRLLDSsQIVIISA 10090 11459832 t lperfetto Selective induction of e2f1 in response to dna damage, mediated by atm-dependent phosphorylation. We identify a site for atm/atr phosphorylation in the amino terminus of e2f1 and we show that this site is required for atm-mediated stabilization of e2f1. Finally, we also show that e2f1 is required for dna damaged induced apoptosis in mouse thymocytes. SIGNOR-109416 0.666 CSNK2A1 protein P68400 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates phosphorylation Ser739 EIIVLSDsD 9606 21474068 t lperfetto Daxx-sim is phosphorylated by ck2 kinase at residues s737 and s739. Phosphorylation promotes daxx-sim binding affinity toward sumo-1 over sumo-2/3, causing daxx preference for sumo-1 conjugation and interaction with sumo-1-modified factors. SIGNOR-173109 0.332 GCHFR protein P30047 UNIPROT GCH1 protein P30793 UNIPROT down-regulates activity binding 9606 11361142 t miannu The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine SIGNOR-252203 0.859 β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. SIGNOR-266465 0.8 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 t lperfetto Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2. SIGNOR-59631 0.721 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation 9606 23486913 t mTORC1 phosphorylation of EIF4EBP1 causes dissociation of the complex allowing EIF4G1/EIF4G3 to bind and consequent initiation of translation. gcesareni These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. SIGNOR-201541 0.832 ERG protein P11308 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25277175 f miannu Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3. SIGNOR-251554 0.287 CALM3 protein P0DP25 UNIPROT KIF1A protein Q12756 UNIPROT up-regulates activity binding 10116 BTO:0003102 30021165 t miannu To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. In contrast, liprin-α and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines. we can conclude that TANC2 and liprin-α are enriched in dendritic spines and interact with various synaptic proteins. TANC2 and Liprin-α2 Act as Immobile Postsynaptic Posts Able to Recruit KIF1A in a Subset of Dendritic Spines SIGNOR-266890 0.273 MEGF10 protein Q96KG7 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 9606 28526325 f miannu Our results indicate that MEGF10 may be responsible for phagocytic activity targeted toward unwanted substances such as amyloid in cholinergic and glutamatergic neurons. SIGNOR-265166 0.7 RXRA protein P19793 UNIPROT RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates binding 9606 1310351 t inferred from 70% of family members gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-269850 0.713 Naltriben chemical CID:5486827 PUBCHEM OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258424 0.8 bromocriptine chemical CHEBI:3181 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258366 0.8 CDK5 protein Q00535 UNIPROT STMN3 protein Q9NZ72 UNIPROT unknown phosphorylation Ser73 PESPMLSsPPKKKDT -1 22577147 t lperfetto Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta SIGNOR-264894 0.328 PRKCG protein P05129 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249289 0.425 arecoline chemical CHEBI:2814 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258638 0.8 MTOR protein P42345 UNIPROT PRKN protein O60260 UNIPROT down-regulates activity phosphorylation Ser127 AVILHTDsRKDSPPA 9606 BTO:0002181 35191952 t miannu MTOR phosphorylates PARK2 at Ser127 Through biochemical, mutational, and genetic studies, we identified PARK2 as a mTORC1 substrate. mTORC1 phosphorylates PARK2 at Ser127, which blocks its cellular ubiquitination activity, thereby hindering its tumor suppressor effect on eIF4B's stability. SIGNOR-277586 0.2 MAPK8 protein P45983 UNIPROT LAT protein O43561 UNIPROT down-regulates phosphorylation Thr184 PSAPALStPGIRDSA 9606 15192708 t The effect has been demonstrated using Q43561-2 gcesareni Lat, an adapter protein essential for t-cell signaling, is phosphorylated at its thr 155 by erk in response to t-cell receptor stimulation. Thr 155 phosphorylation reduces the ability of lat to recruit plcgamma1 and slp76, leading to attenuation of subsequent downstream events such as [ca2+]i mobilization and activation of the erk pathway.Mutational analysis revealed that t155 but not t94 or t140 is the site of jnk-mediated phosphorylation (figure 2b). Erk also phosphorylated lat at t155 (figure 2c), whereas p38, which was able to phosphorylate atf2, failed to induce threonine phosphorylation of lat (figure 2d). These results indicate that lat is directly phosphorylated by erk and jnk at the same site, t155. SIGNOR-125774 0.313 MAPK3 protein P27361 UNIPROT HDAC6 protein Q9UBN7 UNIPROT up-regulates phosphorylation Ser1035 DHQTPPTsPVQGTTP 9606 24089523 t lperfetto Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1 SIGNOR-202698 0.437 MAPK3 protein P27361 UNIPROT DEPTOR protein Q8TB45 UNIPROT up-regulates quantity by stabilization phosphorylation Ser235 MELLNEKsPSSQETH -1 35216969 t miannu Screening the DEPTOR interactome identified that the association of USP-7 deubiquitinase with DEPTOR was dependent upon S235 phosphorylation. Inhibition of USP-7 activity resulted in DEPTOR polyubiquitination and degradation. A scansite search suggested that ERK1 may be responsible for S235 phosphorylation, which was confirmed through the use of inhibitors, ERK1 knockdown, and an in vitro kinase assay. SIGNOR-277587 0.285 USP7 protein Q93009 UNIPROT DEPTOR protein Q8TB45 UNIPROT up-regulates quantity by stabilization deubiquitination -1 35216969 t miannu Screening the DEPTOR interactome identified that the association of USP-7 deubiquitinase with DEPTOR was dependent upon S235 phosphorylation. Inhibition of USP-7 activity resulted in DEPTOR polyubiquitination and degradation. A scansite search suggested that ERK1 may be responsible for S235 phosphorylation, which was confirmed through the use of inhibitors, ERK1 knockdown, and an in vitro kinase assay. SIGNOR-277588 0.2 BUB1B protein O60566 UNIPROT MCC complex SIGNOR-C382 SIGNOR form complex binding 9606 BTO:0000567 25092294 t miannu The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. SIGNOR-265974 0.978 CDK5RAP2 protein Q96SN8 UNIPROT APP protein P05067 UNIPROT up-regulates quantity by stabilization phosphorylation Thr743 VEVDAAVtPEERHLS 9606 15178331 t Manara The APPcyt is phosphorylated at Thr668 in vivo specifically in the brain. Cyclin‐dependent kinase 5 (Cdk5), a unique member of the Cdk family that is implicated in central nervous system development, participates in this phosphorylation. | In the present study, we demonstrate that APP phosphorylated at Thr668 is less vulnerable to cytoplasmic cleavage by caspase-3 and caspase-8. SIGNOR-260818 0.2 SHH protein Q15465 UNIPROT SMO protein Q99835 UNIPROT up-regulates activity 10090 16885213 f lperfetto Binding of Hh to Ptch relieves the repression of Smo, allowing Smo to signal. SIGNOR-148481 0.739 DPYD protein Q12882 UNIPROT 5-fluorouracil chemical CHEBI:46345 ChEBI down-regulates quantity chemical modification 9606 10499634 t miannu Dihydropyrimidine dehydrogenase (DPD) is responsible for degradation of the pyrimidines uracil and thymine and the inactivation of the chemotherapeutic agent 5-fluorouracil. DPD activity is highly variable in cancer populations, and this variation may influence the antitumor efficacy of 5-fluorouracil. SIGNOR-253987 0.8 LY96 protein Q9Y6Y9 UNIPROT HMGB1 protein P09429 UNIPROT up-regulates activity binding 10090 BTO:0000801 25559892 t gcesareni Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2-deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling. SIGNOR-252058 0.615 cabazitaxel chemical CHEBI:63584 ChEBI TUBB1 protein Q9H4B7 UNIPROT down-regulates activity chemical inhibition 9606 21770474 t miannu Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization SIGNOR-259341 0.8 PLK1 protein P53350 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates quantity by destabilization phosphorylation Thr197 ASTETYStPALLAPS 9606 BTO:0002181 35437307 t miannu We observed that PLK1 could significantly promote the ubiquitination and degradation of Smad4 wild type, Smad4 S171A, Smad4 S187A, Smad4 S191A, respectively, but PLK1-induced the ubiquitination and degradation of Smad4 T197A were obviously inhibited (Fig. 1M). SIGNOR-277591 0.257 PRKAA1 protein Q13131 UNIPROT EGLN1 protein Q9GZT9 UNIPROT down-regulates activity phosphorylation Ser61 HKLVCQGsEGALGHG 9606 BTO:0000599 35538889 t miannu Mechanistically, AMPKα1 directly phosphorylated prolyl hydroxylase domain-containing (PHD)2 at serines 61 and 136, which suppressed PHD2-dependent hydroxylation of hypoxia-inducible factor (HIF)1α and subsequent regulation of hepatic hepcidin-related iron signalling. SIGNOR-277592 0.381 PRKAA1 protein Q13131 UNIPROT EGLN1 protein Q9GZT9 UNIPROT down-regulates activity phosphorylation Ser136 AAAGGQGsAVAAEAE 9606 BTO:0000599 35538889 t miannu Mechanistically, AMPKα1 directly phosphorylated prolyl hydroxylase domain-containing (PHD)2 at serines 61 and 136, which suppressed PHD2-dependent hydroxylation of hypoxia-inducible factor (HIF)1α and subsequent regulation of hepatic hepcidin-related iron signalling. SIGNOR-277593 0.381 TFEB protein P19484 UNIPROT GUSB protein P08236 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 t lperfetto Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants SIGNOR-276553 0.251 SRC protein P12931 UNIPROT AREG protein P15514 UNIPROT up-regulates cleavage 9606 17251915 t lperfetto Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network. SIGNOR-236537 0.352 SRC protein P12931 UNIPROT CAPN2 protein P17655 UNIPROT up-regulates activity phosphorylation Tyr625 RSGTMNSyEMRKALE -1 35697802 t miannu CAPN2 itself was a bone fide substrate of SRC that was primarily phosphorylated at Y625 by SRC and exhibited increased proteolysis activity upon phosphorylation. SIGNOR-277598 0.505 DZIP3 protein Q86Y13 UNIPROT H2AC14 protein Q99878 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271762 0.2 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr81 APAPAAPtPAAPAPA 9606 12531896 t gcesareni Wr1065 activates the jnk (c-jun n-terminal kinase), decreases complex formation between p53 and inactive jnk, and phosphorylates p53 at thr-81, a known site of phosphorylation by jnk. SIGNOR-97405 0.789 BMP4 protein P12644 UNIPROT BMP4 protein P12644 UNIPROT up-regulates binding 9606 11178121 t lperfetto Bmps are dimeric proteins with a single inter-chain disulfide bond. The dimeric conformation is anabsolute requirement for the biological action and interaction with receptors SIGNOR-236169 0.2 ATP2B2 protein Q01814 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 30535804 t lperfetto ATP2B2 encodes the PMCA2 Ca(2+) pump that plays an important role in maintaining ion homeostasis in hair cells among others by extrusion of Ca(2+) from the stereocilia to the endolymph. SIGNOR-262585 0.8 CDK2 protein P24941 UNIPROT MCM3AP protein O60318 UNIPROT up-regulates activity phosphorylation Ser508 FWHRKKIsPNKKPFS 10090 BTO:0000776 11526238 t miannu To study the inducible regulation of GANP DNA-primase during cell activation, we examined phosphorylation induced by various kinds of kinases.We observed that the cell cycle-associated kinase Cdks induced phosphorylation of GANP in vitro. Examination of immunoprecipitates of Cdk2 from B cells revealed phosphorylation of GANP-PD at a consensus sequence of Cdk phosphorylation at Ser502 (S/T-P-X-K/R) (Fig. ​(Fig.1C1C Left; ref. 22). SIGNOR-262734 0.2 KCNH2 protein Q12809 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 35442831 t miannu One such mechanism is operant in colorectal cancer (CRC) cells. On integrin-dependent CRC cell adhesion, the Kv11.1/β1 integrin complex recruits the PI3K p85 subunit, which stimulates AKT phosphorylation and thus regulates autophagy SIGNOR-277613 0.2 ITGB1 protein P05556 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates activity binding 9606 35442831 t miannu One such mechanism is operant in colorectal cancer (CRC) cells. On integrin-dependent CRC cell adhesion, the Kv11.1/β1 integrin complex recruits the PI3K p85 subunit, which stimulates AKT phosphorylation and thus regulates autophagy SIGNOR-277614 0.2 CSNK1G2 protein P78368 UNIPROT IRS4 protein O14654 UNIPROT down-regulates quantity by destabilization phosphorylation Ser859 KDAASKPsGEGSFSK 9606 BTO:0002181 30026872 t miannu IRS4 was phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP). SIGNOR-277615 0.2 RPS6KA1 protein Q15418 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 BTO:0000551 21423205 t lperfetto Rsk1 phosphorylated vasp on t278, a site regulating its binding to actin. SIGNOR-172899 0.462 RNF185 protein Q96GF1 UNIPROT DVL2 protein O14641 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0001957 24727453 t miannu The E3 ligase RNF185 negatively regulates osteogenic differentiation by targeting Dvl2 for degradation. Overexpression of RNF185 decreases the exogenous and endogenous level of Dvl2, promotes the ubiquitination and degradation of Dvl2 SIGNOR-272173 0.479 RPS6KB1 protein P23443 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser15 FSLLRGPsWDPFRDW 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk. SIGNOR-186951 0.314 G3BP1 protein Q13283 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity binding 9606 BTO:0001938;BTO:0000567 25784705 t SARA PKR directly interacts with G3BP1 through the NTF2-like and PXXP domains of G3BP1. The recruitment of inactive PKR to SGs through this interaction correlates with its activation SIGNOR-260981 0.312 KDM4C protein Q9H3R0 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity demethylation Lys37 APSTGGVkKPHRYRP 9606 29207681 t miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation SIGNOR-263868 0.2 KRT14 protein P02533 UNIPROT TNFRSF1A protein P19438 UNIPROT down-regulates activity binding 9606 11684708 t Regulation miannu TRADD specifically bound K18 and K14, type I (acidic) keratins. it is possible that epidermal K14 may function as an inhibitor of TNF–TNFR1 signaling through an association with TRADD. SIGNOR-251906 0.268 INS protein P01308 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity 9606 10358076 f lperfetto Insulin disrupts irs-dependent transactivation by fkhr, and phosphorylation of ser-256 by pkb is necessary and sufficient to mediate this effect. SIGNOR-252952 0.492 FZD1 protein Q9UP38 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates activity binding 9606 23151663 t areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  SIGNOR-258953 0.643 CKM complex complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-273148 0.346 GDNF protein P39905 UNIPROT BIN1 protein O00499 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252178 0.2 CILK1 protein Q9UPZ9 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Thr908 LPSGRPGtTGPAGAQ 9606 SIGNOR-C3 22356909 t gcesareni Our findings demonstrate an important role for ick in modulating the activity of mtorc1 through phosphorylation of raptor thr-908 and thus implicate a potential signaling mechanism by which ick regulates cell proliferation and division. SIGNOR-196198 0.2 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248749 0.727 NXF1 protein Q9UBU9 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 28831067 f lperfetto SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1. SIGNOR-263298 0.7 IKBKE protein Q14164 UNIPROT FAF1 protein Q9UNN5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser556 EREAIRLsLEQALPP 9606 BTO:0002181 30472208 t miannu Upon virus infection, the kinase IKKɛ directly phosphorylates FAF1 at Ser556 and triggers FAF1 de-aggregation. Moreover, Ser556 phosphorylation promotes FAF1 lysosomal degradation, consequently relieving FAF1-dependent suppression of MAVS. SIGNOR-277618 0.287 ASXL3 protein Q9C0F0 UNIPROT CBX5 protein P45973 UNIPROT down-regulates activity binding 9606 BTO:0000972 25450400 t miannu Here, we showed that ASXL3 interacts with HP1α and LSD1, leading to transcriptional repression. SIGNOR-266763 0.254 POMC protein P01189 UNIPROT OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258409 0.636 AKT3 protein Q9Y243 UNIPROT ADAR protein P55265 UNIPROT down-regulates activity phosphorylation Thr1033 RLGERLRtMSCSDKI -1 31095429 t miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively SIGNOR-276191 0.2 AKT2 protein P31751 UNIPROT ADAR protein P55265 UNIPROT down-regulates activity phosphorylation Thr1033 RLGERLRtMSCSDKI -1 31095429 t miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively SIGNOR-276192 0.2 MAPKAPK2 protein P49137 UNIPROT AATF protein Q9NY61 UNIPROT up-regulates phosphorylation Thr366 FTVYRNRtLQKWHDK 9606 22909821 t lperfetto Upon genotoxic stress, aatf is phosphorylated by the checkpoint kinase mk2. Phosphorylation results in the release of aatf from cytoplasmic mrlc3 and subsequent nuclear translocation where aatf binds to the puma, bax and bak promoter regions to repress p53-driven expression of these pro-apoptotic genes. SIGNOR-191935 0.333 CXCL12 protein P48061 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates binding 9606 11859124 t gcesareni To study the role of the sdf-1/cxcr4-chemokine/receptor system as a regulator of vertebrate development, we isolated and characterized a cdna encoding sdf-1 of the lower vertebrate xenopus laevis (xsdf-1). Recombinant xsdf-1 was produced in insect cells, purified, and functionally characterized. Although xsdf-1 is only 64-66% identical with its mammalian counterparts, it is indistinguishable from human (h)sdf-1alpha in terms of activating both x. laevis cxcr4 and hcxcr4. Thus, both xsdf-1 and hsdf-1alpha promoted cxcr4-mediated activation of heterotrimeric g(i2) in a cell-free system and induced release of intracellular calcium ions in and chemotaxis of intact lymphoblastic cells. SIGNOR-115029 0.802 CDK2 protein P24941 UNIPROT ID2 protein Q02363 UNIPROT down-regulates phosphorylation Ser5 sPVRSVRK 9606 SIGNOR-C16 9029153 t lperfetto Id2 acts by forming heterodimers that are unable to bind to specific (e-box) dna sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (cdks). In vitro, id2 can be phosphorylated by either cyclin e-cdk2 or cyclin a-cdk2_ SIGNOR-46397 0.445 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser362 TLKNKTEsSLLAKLE -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276200 0.388 AURKA protein O14965 UNIPROT DLGAP5 protein Q15398 UNIPROT up-regulates quantity by stabilization phosphorylation Ser725 CLSSERMsLPLLAGG 9606 BTO:0000007 15987997 t miannu Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life. SIGNOR-262650 0.74 PLAGL1 protein Q9UM63 UNIPROT ABCC6 protein O95255 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007;BTO:0000599 18850323 f miannu We identified ABCC6 as a target gene for transcriptional induction by PLAG1 and PLAGL1, transcription factors from the PLAG family of cell cycle progression-related DNA-binding proteins. Both these factors are shown to bind to the same single consensus-binding element in the ABCC6 proximal promoter in cell lines of hepatic and renal origin by reporter gene assay, electrophoretic mobility shift assay and chromatin immunoprecipitation. PLAG-mediated ABCC6 transactivation may play an important role in determining the level of tissue-specific expression of this gene. The described mechanism can also find potential application in therapeutic interventions in forms of PXE related to impaired ABCC6 expression. SIGNOR-254926 0.377 SU11274 chemical CID:9549297 PUBCHEM MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207123 0.8 GPR119 protein Q8TDV5 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256911 0.252 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser409 VFPPSITsRGDFLRH 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262721 0.733 CSF2 protein P04141 UNIPROT HBG2 protein P69892 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001571 2479426 f Regulation of expression miannu Granulocyte-macrophage colony-stimulating factor reactivates fetal hemoglobin synthesis in erythroblast clones from normal adults. SIGNOR-251776 0.2 STYX protein Q8WUJ0 UNIPROT FBXW7 protein Q969H0 UNIPROT down-regulates activity binding 9606 28007894 t STYX acts as a direct inhibitor of FBXW7, affecting the cellular levels of its substrates. Furthermore, we find that levels of STYX and FBXW7 are anti-correlated in breast cancer patients, SIGNOR-251663 0.353 GRHL2 protein Q6ISB3 UNIPROT ZEB1 protein P37275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 23814079 f miannu we could further demonstrate that expression of GRHL2 is directly suppressed by the transcription factor zinc finger enhancer-binding protein 1 (ZEB1), which in turn is a direct target for repression by GRHL2, suggesting that the EMT transcription factors GRHL2 and ZEB1 form a double negative regulatory feedback loop in breast cancer cells. SIGNOR-255624 0.443 ITGB1 protein P05556 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253172 0.749 DNA polymerase delta complex SIGNOR-C376 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 24035200 f lperfetto Analysis of the subcellular localization of Pol subunits in response to UV indicates that Pol delta3 is present at sites of DNA damage long before repair is complete, so that Pol delta3 is the form of Pol activity that is likely involved in gap filling reactions during DNA repair SIGNOR-265721 0.7 RPIA protein P49247 UNIPROT D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI down-regulates quantity chemical modification 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267067 0.8 FOXA1 protein P55317 UNIPROT NFIX protein Q14938 UNIPROT up-regulates binding 9606 BTO:0001129 24801505 t miannu Androgen receptor (ar) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between ar and forkhead box (fox) transcription factors, particularly foxa1./ Foxa1 is capable of bringing ar and nfix into proximity, indicating that foxa1 facilitates the ar and nfi interaction by bridging the complex. SIGNOR-205082 0.341 spermidine smallmolecule CHEBI:16610 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 14617280 f apalma Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism SIGNOR-255553 0.7 PDX1 protein P52945 UNIPROT SLC2A2 protein P11168 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11309388 t In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1. SIGNOR-255540 0.537 RPL23 protein P62829 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262477 0.803 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 9606 19584320 t lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-216499 0.469 NRCAM protein Q92823 UNIPROT ANK3 protein Q12955 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 t miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. SIGNOR-266720 0.71 MAPK3 protein P27361 UNIPROT CAPN2 protein P17655 UNIPROT up-regulates phosphorylation Ser50 GTLFQDPsFPAIPSA 9606 14993287 t lperfetto Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo. SIGNOR-123083 0.547 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Sec) smallmolecule CHEBI:29264 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269495 0.8 PRKCA protein P17252 UNIPROT NCF4 protein Q15080 UNIPROT up-regulates activity phosphorylation Thr154 LRRLRPRtRKVKSVS 9606 BTO:0000776 34264265 t miannu In murine and guinea pig neutrophils, PKCδ is required for the phosphorylation of p40phox, a subunit of the NADPH oxidase complex (Li et al., 2016; Someya et al., 1999). In particular, it mediates phosphorylation of the threonine 154 (T154) residue of p40phox, a key regulatory step in the activation of the NADPH oxidase complex in peripheral neutrophils and B cells, in both mice and humans. In conclusion, the EBV-B cells of patients with PKCδ deficiency have impaired ROS production, associated with lower levels of phosphorylation of the cytosolic NADPH oxidase subunit p40phox by PKCδ. SIGNOR-277628 0.2 GSK3B protein P49841 UNIPROT WT1 protein P19544 UNIPROT down-regulates quantity by destabilization phosphorylation Ser208 GCHTPTDsCTGSQAL 9606 33184107 t miannu Glycogen synthase kinase 3β promoted phosphorylation of cugWT1 at S64, resulting in ubiquitination and degradation of the cugWT1 associated with the F-box-/- WD repeat-containing protein 8. SIGNOR-277540 0.288 MAPK8IP2 protein Q13387 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 10490659 t These data demonstrated that JIP2 increases JNK activation by the MLK signaling pathway gcesareni These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins. SIGNOR-70860 0.626 AKT2 protein P31751 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Thr246 LPRPRLNtSDFQKLK 9606 BTO:0000007 12524439 t gcesareni 1) PRAS40 was phosphorylated in vitro by purified Akt on the same site that was phosphorylated in insulin-treated cells; 2) activation of an inducible Akt was alone sufficient to stimulate the phosphorylation of PRAS40; and 3) cells lacking Akt1 and Akt2 exhibit a diminished ability to phosphorylate this protein SIGNOR-248046 0.66 TEF protein Q10587 UNIPROT NPPB protein P16860 UNIPROT unknown transcriptional regulation 15837525 f In comparison to the ANF gene, less is known about BNP promoter consensus elements that regulate gene expression by mechanical or neurohumoral agonists. A number of cis-acting elements for GATA, Nkx2.5, NF-kappaB and TEF transcription factors have recently been identified within the BNP promoter that regulate BNP expression in response to specific agonists. This review focuses on the information available regarding cis-acting determinants responsible for inducible BNP transcription. SIGNOR-253652 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR KLHL3 protein Q9UH77 UNIPROT up-regulates activity phosphorylation Ser433 PMNTRRSsVGVGVVE -1 26435498 t done miannu Consistent with the fact that S433 is a component of Akt and PKA phosphorylation motifs, in vitro kinase assay demonstrated that Akt and PKA can phosphorylate KLHL3 at S433, that was previously reported to be phosphorylated by PKC.  SIGNOR-273824 0.2 MAPK1 protein P28482 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by stabilization phosphorylation Ser566 PTWKEPVsPMELTGP 9606 BTO:0001109 28945223 t miannu In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation.  SIGNOR-276742 0.2 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Ser502 YFLQRRPsMKTLFVD 9534 BTO:0000298 14523239 t lperfetto We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. SIGNOR-249230 0.2 AKT1 protein P31749 UNIPROT CDCA7 protein Q9BWT1 UNIPROT down-regulates phosphorylation Thr163 SRRPRRRtFPGVASR 9606 23166294 t llicata The prosurvival kinase akt phosphorylates cdca7 at threonine 163, promoting binding to 14-3-3, dissociation from myc, and sequestration to the cytoplasm. we have mapped the domains of interaction and have discovered that akt phosphorylates cdca7 near this contact region, leading to loss of its association with myc, binding to 14-3-3 proteins, and exclusion from the nucleus. SIGNOR-252533 0.345 SCF-betaTRCP complex SIGNOR-C5 SIGNOR COMMD1 protein Q8N668 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001321 20068069 t miannu CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation. SIGNOR-271430 0.445 PAK1 protein Q13153 UNIPROT ARPC1B protein O15143 UNIPROT up-regulates phosphorylation Thr21 HAWNKDRtQIAICPN 9606 14749719 t lperfetto The formation of new branched actin filament networks at the cell cortex of migrating cells is choreographed by the actin-related protein (arp) 2/3 complex. Despite the fundamental role of the arp2/3 complex in actin nucleation and branching, upstream signals that control the functions of p41-arc, a putative regulatory component of the mammalian arp2/3 complex. Pak1 phosphorylation of p41-arc regulates its localization with the arp2/3 complex in the cortical nucleation regions of cells. Pak1 phosphorylates p41-arc on threonine 21 SIGNOR-121642 0.546 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser214 LVRSREVsVDEGRAC -1 9677319 t llicata CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. SIGNOR-250944 0.318 MAPK1 protein P28482 UNIPROT HNRNPH1 protein P31943 UNIPROT unknown phosphorylation Ser104 LKHTGPNsPDTANDG 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262776 0.2 afimoxifene chemical CHEBI:44616 ChEBI ESR2 protein Q92731 UNIPROT down-regulates activity chemical inhibition -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258596 0.8 STAT2 protein P52630 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity binding 9606 17923090 t lperfetto We then examined STAT2 acetylation within the b-barrel DBD. A direct interaction between the STAT2-DBD (315485) and STAT1 was detected (Figure 6E) (Li et al., 1997). SIGNOR-217957 0.535 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 18930133 t PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation. SIGNOR-248344 0.413 STXBP4 protein Q6ZWJ1 UNIPROT YAP1 protein P46937 UNIPROT down-regulates activity binding -1 31782549 t WW domain‐containing protein STXBP4 inhibits YAP activity via LATS1‐mediated phosphorylation. SIGNOR-260013 0.2 CSNK2B protein P67870 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser228 PGVTPSKsTSASAIM 9606 BTO:0000938 26917740 t lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. SIGNOR-275744 0.273 PRC1 protein O43663 UNIPROT KIF23 protein Q02241 UNIPROT up-regulates activity binding 9606 15297875 t miannu These data indicate that PRC1 binds to KIF4, MKLP1 and CENP-E during late mitosis; however, it apparently does not interact simultaneously with more than one of these motor proteins. SIGNOR-265989 0.588 NR1H2 protein P55055 UNIPROT BHLHE40 protein O14503 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19032342 f lperfetto LXRα and LXRβ are potent positive regulators for hepatic Dec1 SIGNOR-253690 0.2 FLT3 protein P36888 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15003515 f Flt3 Mutation Activates p21WAF1/CIP1 Gene Expression Through the Action of STAT5. Through the Action of STAT5. Co-transfection of p21 promoter-luciferase constructs with Flt3-ITD plasmid into K562 and BaF3 cells results in the induction of p21 promoter activity and a -692/-684 STAT site is important for the induction. STAT5a binds specifically to this element and Flt3-ITD enhances the protein binding to this site. SIGNOR-261520 0.292 ZEB2 protein O60315 UNIPROT MEOX2 protein P50222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20516212 t Luisa ZEB2 represses GAX transcription through multiple up- stream consensus binding sites. SIGNOR-268951 0.323 AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser227 GARRRGGsASRSLPL 9606 10224060 t lperfetto Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins. SIGNOR-244361 0.2 AKT2 protein P31751 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR up-regulates phosphorylation 9606 BTO:0000887 17964260 t lperfetto Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. SIGNOR-217673 0.306 CTSB protein P07858 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Gly58 RYLYQWLgAPVPYPD -1 9076588 t miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. SIGNOR-256318 0.336 TRIM33 protein Q9UPN9 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 16751102 t gcesareni The ubiquitious nuclear protein transcriptional intermediary factor 1gamma (tif1gamma) selectively binds receptor-phosphorylated smad2/3 in competition with smad4. Rapid and robust binding of tif1gamma to smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to tgfbeta. In human hematopoietic stem/progenitor cells, where tgfbeta inhibits proliferation and stimulates erythroid differentiation, tif1gamma mediates the differentiation response while smad4 mediates the antiproliferative response with smad2/3 participating in both responses. SIGNOR-146986 0.568 CDK2 protein P24941 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity phosphorylation Ser203 DLEFSSGsPGKETNE -1 9199329 t lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. SIGNOR-249426 0.296 TGFBI protein Q15582 UNIPROT A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates activity binding 26387839 t lperfetto BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers SIGNOR-253268 0.285 CAMK4 protein Q16566 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 BTO:0000887;BTO:0001103 12058061 t lperfetto Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs. SIGNOR-236571 0.489 NF1 protein P21359 UNIPROT ADCY8 protein P40145 UNIPROT up-regulates 9606 BTO:0000938 24431436 f miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-204289 0.408 SLBP protein Q14493 UNIPROT H2BC5 protein P58876 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265378 0.2 CD38 protein P28907 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity relocalization 10090 17287729 f lperfetto CD38 is critical for social behaviour by regulating oxytocin secretion|Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38-/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice. SIGNOR-268544 0.373 PP2B proteinfamily SIGNOR-PF18 SIGNOR DNM1L protein O00429 UNIPROT up-regulates activity dephosphorylation 9606 18838687 t inferred from 70% family members When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. SIGNOR-269994 0.2 NFIB protein O00712 UNIPROT NFIX protein Q14938 UNIPROT up-regulates quantity transcriptional regulation 10090 29106906 t Gianni We report that, in the absence of Nfia or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord. SIGNOR-268869 0.43 RPA2 protein P15927 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 f lperfetto The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275706 0.7 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1931 SPTSPTYsPTSPKGS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273049 0.556 DAPK3 protein O43293 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 19851336 t lperfetto More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above. SIGNOR-188789 0.5 GRM3 protein Q14832 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. SIGNOR-264934 0.8 ATG13 protein O75143 UNIPROT RB1CC1 protein Q8TDY2 UNIPROT up-regulates binding 9606 19225151 t gcesareni Atg13 directly binds fip200. SIGNOR-184120 0.917 ELP5 protein Q8TE02 UNIPROT Elongator complex complex SIGNOR-C466 SIGNOR form complex binding 9606 28601220 t miannu Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer. SIGNOR-269712 0.697 INPP5D protein Q92835 UNIPROT SYK protein P43405 UNIPROT down-regulates activity dephosphorylation 9606 32323266 t scontino An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling. SIGNOR-268456 0.428 PRKACA protein P17612 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates phosphorylation 10090 BTO:0000944 23644383 t inferred from 70% of family members milica Here, we show that cyclic amp (camp)-dependent protein kinase (pka) phosphorylates lats and thereby enhances its activity sufficiently to phosphorylate yap on ser381. SIGNOR-269863 0.2 OPRD1 protein P41143 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256683 0.523 FBXL21P protein Q9UKT6 UNIPROT TCAP protein O15273 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 32937135 t lperfetto FBXL21 is a clock-controlled E3 ligase modulating circadian periodicity via subcellular-specific CRYPTOCHROME degradation. How FBXL21 regulates tissue-specific circadian physiology and what mechanism operates upstream is poorly understood. Here we report the sarcomere component TCAP as a cytoplasmic substrate of FBXL21. SIGNOR-264853 0.2 PRKACA protein P17612 UNIPROT AMPK complex SIGNOR-C15 SIGNOR down-regulates activity phosphorylation 10116 17023420 t These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine. SIGNOR-256111 0.388 CBFB protein Q13951 UNIPROT Core Binding Factor complex complex SIGNOR-C214 SIGNOR form complex binding 9606 12495904 t irozzo The core binding factor (CBF) transcription complex, consisting of the interacting proteins RUNX1 and CBFβ, is essential for normal hematopoiesis SIGNOR-255711 0.842 PRKDC protein P78527 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser516 SSTVAGGsQSPKLFS 9606 16600297 t lperfetto Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin SIGNOR-145837 0.687 ITGB1BP1 protein O14713 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257658 0.356 PRKAA1 protein Q13131 UNIPROT RBBP7 protein Q16576 UNIPROT up-regulates activity phosphorylation Ser314 LKLHTFEsHKDEIFQ -1 28143904 t lperfetto AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314| interaction between RBBP7 and HAT1 is required for acetyltransferase activity SIGNOR-264784 0.2 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120164 0.316 CAMK2D protein Q13557 UNIPROT CEACAM1 protein P13688 UNIPROT up-regulates phosphorylation Thr457 CFLHFGKtGRASDQR 9606 BTO:0000149 24302721 t lperfetto Camkiid specifically phosphorylates thr-457 on ceacam1-sf, which in turn regulates the process of lumen formation via apoptosis of the central acinar cells. SIGNOR-203402 0.2 RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 11018021 t Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. lperfetto The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins. SIGNOR-244952 0.738 PRKACA protein P17612 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates activity phosphorylation Ser7 sSAEGAAK 9606 11438671 t miannu PKA preferentially phosphorylates serine 6 in human HMGN1. specific phosphorylation of the NBD of HMGN proteins serves to prevent the interaction of these proteins with their chromatin targets during mitosis. SIGNOR-249993 0.312 PP1 proteinfamily SIGNOR-PF54 SIGNOR Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12840032 t inferred from 70% of family members lperfetto P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases SIGNOR-269901 0.2 IL2RB protein P14784 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t milica In lymphocytes, binding of il-15 to the il-2/15rbg heterodimer induces jak1 activation that subsequently phosphorylates stat3 via the b-chain and jak3/stat5 activation via its g-chain SIGNOR-204972 0.616 PML protein P29590 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 15356634 t gcesareni Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome. SIGNOR-128741 0.528 SLC12A5 protein Q9H2X9 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates activity relocalization 9606 26951057 t miannu As shown in Fig. 2, the intracellular Cl− concentration is regulated mainly by two cation-chloride cotransporters, NKCC1 and KCC2 [32]. NKCC1 imports Cl− whereas KCC2 extrudes intracellular Cl−. SIGNOR-264987 0.8 CSNK2B protein P67870 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Thr112 EGMQIPStQFDAAHP 9606 12432063 t llicata We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin SIGNOR-251067 0.588 ERRFI1 protein Q9UJM3 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity binding -1 18046415 t The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2 SIGNOR-252076 0.661 PRKCE protein Q02156 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251632 0.337 CTDSPL2 protein Q05D32 UNIPROT HBE1 protein P02100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20932329 f Regulation of transcription miannu CTD small phosphatase like 2 (CTDSPL2) can increase ε- and γ-globin gene expression in K562 cells and CD34+ cells derived from umbilical cord blood. SIGNOR-251779 0.2 CSNK2A1 protein P68400 UNIPROT CDC27 protein P30260 UNIPROT up-regulates phosphorylation Ser154 FLWSPFEsLCEIGEK 9606 21209074 t lperfetto We report here that phosphorylation of cdc27, a core subunit of apc, in response to tgf- signaling can facilitate the activation of apc.we have demonstrated that casein kinase ii (ckii) is involved in the phosphorylation of cdc27 in response to tgf- signaling. SIGNOR-170872 0.386 MAPKAPK2 protein P49137 UNIPROT TH protein P07101 UNIPROT up-regulates activity phosphorylation Ser40 GQGAPGPsLTGSPWP -1 11359875 t miannu MAPKAP-K2 phosphorylates both Ser19 and Ser40 of TH. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation. SIGNOR-250150 0.499 CNOT6L protein Q96LI5 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268311 0.805 PRKCA protein P17252 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation 9606 16963226 t gcesareni Pkcalfa, but not pkcbeta, is the predominant cpkc isoenzyme required for cpla2 protein phosphorylation and maximal induction of cpla2 enzymatic activity. SIGNOR-149406 0.557 GNA13 protein Q14344 UNIPROT ARHGEF1 protein Q92888 UNIPROT up-regulates activity binding 9606 14607242 t It turned out that RGS domain of p115RhoGEF is specific for Gα12 and Gα13, and does not bind Gαi, Gαs and Gαq (Kozasa et al., 1998). The binding of Gα13 but not Gα12 stimulated GEF activity for Rho SIGNOR-256521 0.591 SP3 protein Q02447 UNIPROT CBS protein P35520 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12427542 f miannu We previously described essential transactivating roles for specificity protein 1 (Sp1), Sp3, nuclear factor Y (NF-Y), and USF-1 in the regulation of the CBS-1b promoter. SIGNOR-254813 0.2 PLK1 protein P53350 UNIPROT IKBKB protein O14920 UNIPROT down-regulates phosphorylation Ser733 TVREQDQsFTALDWS 9606 18957422 t lperfetto Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma SIGNOR-181798 0.349 MAPK1 protein P28482 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 10737616 t lperfetto Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease. SIGNOR-249416 0.552 PAK4 protein O96013 UNIPROT RAN protein P62826 UNIPROT up-regulates phosphorylation Ser135 DRKVKAKsIVFHRKK 9606 20805321 t lperfetto We show that ran is a substrate for p21-activated kinase 4 (pak4) and that its phosphorylation on serine-135 increases during mitosis.Altogether, our findings strongly suggest that pak4-mediated phosphorylation of gdp- or gtp-bound ran modulates the assembly of complexes that are required at specific subcellular localizations for ran to carry out its functions during mitotic progression. SIGNOR-167667 0.312 TGFB1 protein P01137 UNIPROT TAGLN protein Q01995 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20846954 f Regulation miannu We used diploid human lung fibroblasts (WI38 cells) induced by TGFβ to differentiate into myofibroblast-like cells. In order to characterize this system, we first studied the expression of the myofibroblast marker genes ACTA2 (coding for smooth muscle α-actin; SMA), COL4A1 (encoding collagen type IV α1) and SM22A (coding for smooth muscle protein 22-α). As shown in Figure 1A and B, TGFβ induced the expression all three genes. SIGNOR-251924 0.344 SNTA1 protein Q13424 UNIPROT NOS1 protein P29475 UNIPROT up-regulates relocalization 9606 BTO:0001103 12456711 t gcesareni biochemical studies showed that the N-terminal PDZ domain of nNOS binds to a similar PDZ domain of syntrophin (Fig. 1), a dystrophin-associated protein SIGNOR-236916 0.574 PRKCB protein P05771 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249279 0.36 WWTR1 protein Q9GZV5 UNIPROT TEAD4 protein Q15561 UNIPROT up-regulates binding 9606 23431053 t YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death. gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14. SIGNOR-201459 0.865 JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 9575217 t lperfetto Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein SIGNOR-249507 0.862 CHEK1 protein O14757 UNIPROT MDM4 protein O15151 UNIPROT down-regulates activity phosphorylation Ser342 SKLTHSLsTSDITAI 9606 BTO:0000971 16163388 t llicata MDMX is a direct substrate for Chk1 and Chk2 in vitro. Phosphorylation of MDMX leads to increased binding to MDM2 and more efficient ubiquitination, providing an explanation for the enhanced degradation of MDMX after DNA damage. | Western blot showed that Chk1 modified S342 and S367, but with strong preference for S342. SIGNOR-250770 0.535 KIF3A protein Q9Y496 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272531 0.7 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR MYB protein P10242 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0005790 30335887 t PML/RARa blocks the differentiation and promotes the proliferation of acute promyelocytic leukemia through activating MYB expression by transcriptional and epigenetic regulation mechanisms. SIGNOR-259939 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser295 TKRRKSMsGASPKES 9606 23708659 t lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. SIGNOR-252776 0.2 methysergide chemical CHEBI:584020 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9205951 t miannu The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively. SIGNOR-258616 0.8 PLA2G4A protein P47712 UNIPROT arachidonic acid smallmolecule CHEBI:15843 ChEBI up-regulates chemical modification 9606 6810878 t acerquone Alternatively, a phospholipase a2 may indeed deacylate the phosphatidylinositol, but the point of debate here is whether deacylation constitutes a significant component of the arachidonate liberation. SIGNOR-25633 0.8 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser80 PPNPEDRsPSPEPIY 9606 16420481 t The effect has been demonstrated using Q15637-2 gcesareni Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding. SIGNOR-143837 0.416 SMG1 protein Q96Q15 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates phosphorylation Thr28 AELLGADtQGSEFEF 9606 23356578 t lperfetto Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively SIGNOR-200793 0.971 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR unknown phosphorylation 9606 21071439 t lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-217577 0.392 Riluzole chemical CHEBI:8863 ChEBI KCNN4 protein O15554 UNIPROT up-regulates activity chemical activation 9606 18955585 t Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  SIGNOR-258022 0.8 FST protein P19883 UNIPROT GDF11 protein O95390 UNIPROT down-regulates activity binding 10090 24627466 t lperfetto Follistatin (FST) is a member of the tissue growth factor β family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. |FST315-ΔHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function. SIGNOR-251716 0.685 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Ser261 TGHGLRRsSKFCLKE -1 1848190 t lperfetto We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling. SIGNOR-248854 0.358 UBE2G2 protein P60604 UNIPROT DIO2 protein Q92813 UNIPROT down-regulates quantity by destabilization ubiquitination Lys237 VCIVQRQkIAYLGGK 9606 BTO:0001379 29892818 t scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. SIGNOR-267483 0.2 LCK protein P06239 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Tyr334 MQDNSGTyGKIWEGS 9534 BTO:0000298 11381116 t The tyrosine phosphorylation sites of PKC delta in the H(2)O(2)-treated cells were identified as Tyr-311, Tyr-332, and Tyr-512 by mass spectrometric analysis with the use of the precursor-scan method and by immunoblot analysis with the use of phosphorylation site-specific antibodies. Tyr-311 was the predominant modification site among them. In an in vitro study, phosphorylation at this site by Lck, a non-receptor-type tyrosine kinase, enhanced the basal enzymatic activity and elevated its maximal velocity in the presence of diacylglycerol. phosphorylation at Tyr-311 between the regulatory and catalytic domains is a critical step for generation of the active PKC delta in response to H(2)O(2). SIGNOR-251385 0.506 CCP110 protein O43303 UNIPROT CALM3 protein P0DP25 UNIPROT up-regulates activity binding 9606 16760425 t miannu We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis. SIGNOR-266348 0.334 KIF21B protein O75037 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 28290984 f In this study, we showed that KIF21B is a highly processive MT plus-end directed motor, which can potently induce pausing of MT plus ends. This activity depends on several regions of this large motor protein. SIGNOR-272515 0.7 prostaglandin H2(1-) smallmolecule CHEBI:57405 ChEBI prostaglandin G2(1-) smallmolecule CHEBI:82629 ChEBI up-regulates quantity precursor of -1 7592599 t Luana [14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2, SIGNOR-269769 0.8 PDHX protein O00330 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates activity binding 9606 BTO:0000120 12783165 t miannu In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3. SIGNOR-254904 0.2 ACTB protein P60709 UNIPROT Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270757 0.508 RNF139 protein Q8WU17 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 20068067 t miannu Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner  SIGNOR-271957 0.302 RUVBL2 protein Q9Y230 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269291 0.728 XAV939 chemical CHEBI:62878 ChEBI CTNNB1 protein P35222 UNIPROT down-regulates 9606 19759537 f amattioni Xav939 selectively inhibits beta-catenin-mediated transcription. Xav939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. SIGNOR-188051 0.8 NTN3 protein O00634 UNIPROT NEO1 protein Q92859 UNIPROT up-regulates activity binding 9606 BTO:0001484 28245592 t miannu Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins. SIGNOR-268171 0.709 USF1 protein P22415 UNIPROT MYH9 protein P35579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 11467950 f miannu we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies. SIGNOR-222554 0.2 SRF protein P11831 UNIPROT TAGLN protein Q01995 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21673106 f gcesareni The contractile phenotype of smooth muscle (sm) cells is controlled by serum response factor (srf), which drives the expression of sm-specific genes including sm alpha-actin, sm22, and others. SIGNOR-174393 0.421 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK4 protein P11802 UNIPROT down-regulates activity chemical inhibition -1 29901072 t miannu AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9. SIGNOR-262221 0.8 CASP3 protein P42574 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates cleavage Asp1405 CPGYPETdHGLFEDP 9606 23074268 t gcesareni Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain. SIGNOR-199111 0.326 MIPOL1 protein Q8TD10 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 31609475 f miannu In our results, we also showed that re-expression of MIPOL1 is associated with suppression phosphorylation of AKT and p65, a subunit of NF-ҡB. This suggests that MIPOL1 may inhibit invasion by suppression of phosphorylation of AKT and p65 to further inhibit the expression of MMP-9 SIGNOR-261135 0.2 HDAC7 protein Q8WUI4 UNIPROT PLAG1 protein Q6DJT9 UNIPROT down-regulates deacetylation 9606 16207715 t miannu Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7. SIGNOR-140950 0.258 ARHGAP33 protein O14559 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260491 0.42 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89201 0.55 N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity precursor of 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-266610 0.8 Ternatin chemical CID:5459184 PUBCHEM EEF1A1 protein P68104 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001109 26651998 t Simone Vumbaca Ternatins inhibit protein synthesis with potencies that correlate with their ability to block cell proliferation, and photo-ternatin 5 identified eEF1A as aplausible target. SIGNOR-261126 0.8 FYN protein P06241 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Tyr1387 GRCPSDPyKHSLPSQ -1 10195142 t lperfetto To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain. SIGNOR-247159 0.724 NEDD4 protein P46934 UNIPROT GUCD1 protein Q96NT3 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 24743017 t miannu The E3 ligase NEDD4 regulates GUCD1 degradation. many polyubiquitinylated species of GUCD1 appeared as high molecular weight forms, suggesting that GUCD1 is degraded by the proteasome, after polyubiquitin chain formation, in the presence of NEDD4-1. SIGNOR-272846 0.43 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr360 VSPSPTTyRMFRDKS 9606 BTO:0001271 8622703 t lperfetto We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrose 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr. SIGNOR-40619 0.2 atomoxetine chemical CHEBI:127342 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition -1 9871604 t miannu The gamma-amino alcohol/ether unit contained in venlafaxine, 2 fluoxetine, 3 and tomoxetine 3 has been prepared by a sequence of nitrile aldol reaction and nitrile reduction. Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. SIGNOR-259067 0.8 CCKAR protein P32238 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257361 0.436 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser217 AHYSPRTsPIMSPRT 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252330 0.635 ERCC5 protein P28715 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 f lperfetto The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275709 0.7 MAPK1 protein P28482 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2279 PVQPNPMsPQQHMLP 9606 17623675 t lperfetto Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo. SIGNOR-156887 0.478 PRKACA protein P17612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser284 AGGGRRIsDSHEDTG 9606 20151718 t miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-163756 0.278 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2Z protein Q9H832 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271347 0.771 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser330 SFRVRASsDGEGTMS -1 8349691 t llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. SIGNOR-250908 0.346 dopamine smallmolecule CHEBI:18243 ChEBI 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-264177 0.8 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one chemical CHEBI:94732 ChEBI JNK proteinfamily SIGNOR-PF15 SIGNOR down-regulates chemical inhibition 9606 18922779 t inferred from 70% of family members gcesareni Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell. SIGNOR-269884 0.8 PRKCA protein P17252 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Ser363 ALLQSSAsRKTQKKK 9606 11325528 t lperfetto We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC. SIGNOR-249089 0.441 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR T-reg_differentiation phenotype SIGNOR-PH91 SIGNOR down-regulates 9606 23620016 f In the current study, addition of ERK inhibitors suppressed IL-6-induced RORgammat expression and promoted TGF-beta-induced Foxp3 expression. SIGNOR-254686 0.7 HAUS5 protein O94927 UNIPROT HAUS complex complex SIGNOR-C281 SIGNOR form complex binding 9606 BTO:0000567 19369198 t lperfetto Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC) SIGNOR-262317 0.747 MC1R protein Q01726 UNIPROT TNF protein P01375 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000552 19656324 f miannu Constitutive expression of MC1R in HaCaT keratinocytes inhibits basal and UVB-induced TNF-alpha production. the constitutive activity of MC1R results in elevated intracellular cAMP level, reduced NF-kappaB activity and decreased TNF-alpha transcription SIGNOR-252375 0.293 BCAR1 protein P56945 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 18321991 t gcesareni In this study, we show that, after tyrosine phosphorylation of p130cas mediated by integrin signaling, the phosphorylated p130cas is able to interact with phosphorylated smad3 and in turn prevent transcriptional activation by smad3 SIGNOR-161265 0.281 LPAR4 protein Q99677 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257432 0.358 NPC complex SIGNOR-C263 SIGNOR XPOT protein O43592 UNIPROT up-regulates quantity relocalization 9606 9660920 t miannu Exportin-t Is Predominantly Nuclear, Binds NPCs, and Shuttles Rapidly between Nucleus and Cytoplasm. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus . RanGTP causing a conformational change in exportin-t, which increases the affinity for export sites at the NPC. Exportin-t probably makes a direct contact to the NPC and accounts for the interactions that drive translocation of the tRNA/exportin-t/RanGTP complex out of the nucleus. SIGNOR-261394 0.448 panobinostat chemical CHEBI:85990 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257750 0.8 TGFBI protein Q15582 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 26387839 t lperfetto BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers SIGNOR-253270 0.417 CDK5 protein Q00535 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation Ser83 QQQQQETsPRQQQQQ 9606 BTO:0001130 21799006 t gcesareni Cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins SIGNOR-175696 0.379 HIF-1 complex complex SIGNOR-C418 SIGNOR HK2 protein P52789 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 t miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. SIGNOR-267453 0.312 calcium(2+) smallmolecule CHEBI:29108 ChEBI GSN protein P06396 UNIPROT up-regulates activity chemical activation 9606 BTO:0000132 27871158 t lperfetto Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step. SIGNOR-261844 0.8 MLL3 complex complex SIGNOR-C446 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 34156443 t miannu MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. SIGNOR-268812 0.2 MAPK14 protein Q16539 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 10116 15486195 t miannu Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. SIGNOR-260442 0.325 ERBB4 protein Q15303 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates relocalization 9606 16829981 t gcesareni Like erbb1, erbb4 recruits grb2, shc and stat5. SIGNOR-147850 0.479 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KIFC1 protein Q9BW19 UNIPROT up-regulates quantity by stabilization phosphorylation Ser6 sPLLEVKG -1 24510915 t miannu Tryptic digests of KIFC1 treated with CDK1/CYCLIN B were analyzed by LC-MS/MS revealing phosphorylation at Ser6 (Supplementary Fig S5B). These data indicate that phosphorylation by CDK1/CYLCIN B contributes to KIFC1 stability by protecting KIFC1 from APC/C-mediated ubiquitination and subsequent proteasomal degradation. SIGNOR-266113 0.432 neratinib chemical CHEBI:61397 ChEBI EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258254 0.8 PRKCB protein P05771 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 t gcesareni Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway. SIGNOR-115718 0.333 WNT10A protein Q9GZT5 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131622 0.554 UBE2I protein P63279 UNIPROT CEBPA protein P49715 UNIPROT down-regulates activity sumoylation Lys161 ALRPLVIkQEPREED -1 12511558 t miannu C/EBPalpha interacts directly with the E2 SUMO-conjugating enzyme Ubc9 and can be SUMOylated in vitro using purified recombinant components. Our results indicate that SUMO modification of SC motifs provides a means to rapidly control higher order interactions among transcription factors and suggests that SUMOylation may be a general mechanism to limit transcriptional synergy. SIGNOR-256334 0.2 PBRM1 protein Q86U86 UNIPROT S100A13 protein Q99584 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000562 15601824 f miannu We found that baf180 deficiency leads to a decreased expression of select target genes, such as s100a13 and ra targets rar_2 and crabpii in heart tissues. SIGNOR-132431 0.455 FGFR1 protein P11362 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates activity phosphorylation 10116 BTO:0002809 9182757 t fspada In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway. SIGNOR-236944 0.863 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT down-regulates activity phosphorylation Ser66 TSLVEGRsCGWVPPP -1 14688255 t miannu We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated. SIGNOR-250154 0.686 CHD4 protein Q14839 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263844 0.81 Oxatomide chemical CHEBI:31943 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 t Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells SIGNOR-257791 0.8 CRH protein P06850 UNIPROT KRT1 protein P04264 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15787816 f Regulation of expression miannu CRH also increased AP-1 binding activity, cell granularity, cytokeratin 1 and involucrin expression, and inhibited cytokeratin 14 expression. SIGNOR-251882 0.2 HNF1A protein P20823 UNIPROT AFP protein P02771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11314020 f miannu We investigated AFP gene regulation in AFP-GC by an active transcription factor, HNF1 (hepatocyte nuclear factor 1) and a repressive transcription factor, ATBF1 (AT motif binding factor 1). CAT assays showed the direct inhibition of AFP gene expression by ATBF1. SIGNOR-254435 0.335 NUMA1 protein Q14980 UNIPROT TUBB6 protein Q9BUF5 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-117109 0.2 CDK5 protein Q00535 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates phosphorylation Thr159 DGSEPTKtPGRTSST 9606 BTO:0000938 20513426 t llicata Thr159 phosphorylation negatively regulates the ptdins3 kinase activity of vps34 and autophagy cdk5/p25, a neuronal cdk shown to play a role in alzheimer's disease, can also phosphorylate thr159 of vps34. SIGNOR-165772 0.364 LIMS2 protein Q7Z4I7 UNIPROT IPP complex complex SIGNOR-C380 SIGNOR form complex binding 16493410 t lperfetto Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton. SIGNOR-265764 0.649 TLN1 protein Q9Y490 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257624 0.686 PRDM2 protein Q13029 UNIPROT HMOX1 protein P09601 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8654390 f 2 miannu We show that a portion of MTB-Zf, including an N-terminal zinc-finger domain, binds in vitro to MTE and that the transient coexpression of MTB-Zf cDNA leads to transativation of the heme-oxygenase-1 gene promoter. SIGNOR-241047 0.2 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr93 TSSLPEGyYEEAVPL 9534 9655255 t lperfetto In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110. SIGNOR-246359 0.589 SRC protein P12931 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Tyr654 RNEGVATyAAAVLFR 9606 11279024 t lperfetto Beta-catenin is a good substrate of pp60c- src tyrosine kinase in vitro;this kinase modifies specifically tyr-86 and tyr-654,although consistently detected, this negative effect of tyr-86 phosphorylation on tbp binding was clearly less important than the positive effect observed after tyr-654 phosphorylation. SIGNOR-106454 0.752 IL12A protein P29459 UNIPROT IL12RB2 protein Q99665 UNIPROT up-regulates binding 9606 11086056 t gcesareni Il-12r beta 2 plays an essential role in mediating the biological functions of il-12 in mice. SIGNOR-84361 0.561 SIAH1 protein Q8IUQ4 UNIPROT HIPK2 protein Q9H2X6 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002181 18536714 t miannu  Here we demonstrate that HIPK2 is an unstable protein that colocalizes and interacts with the E3 ubiquitin ligase Siah-1 in unstressed cells. Siah-1 knockdown increases HIPK2 stability and steady-state levels, whereas Siah-1 expression facilitates HIPK2 polyubiquitination, degradation and thereby inactivation.  SIGNOR-276166 0.529 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269379 0.719 CDK4 protein P11802 UNIPROT PELP1 protein Q8IZL8 UNIPROT up-regulates phosphorylation Ser991 PALPPPEsPPKVQPE 9606 BTO:0000150 20807815 t llicata Using site-directed mutagenesis and in vitro kinase assays, we identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we identified pelp1 as a novel substrate of cdks and found that cdk phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function. SIGNOR-167774 0.358 EEF1A1 protein P68104 UNIPROT EEF1A:GTP:aa-tRNA complex SIGNOR-C493 SIGNOR form complex binding 9606 8722040 t miannu The mechanism of elongation factor Tu (EF-Tu) catalyzed aminoacyl-tRNA (aa-tRNA) binding to the A site of the ribosome was studied. Two types of complexes of EF-Tu with GTP and aa-tRNA, EF-Tu.GTP-aa-tRNA (ternary) and (EF-Tu.GTP)2.aa-tRNA (quinternary), can be formed in vitro depending on the conditions. SIGNOR-270809 0.2 NUMB protein P49757 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates binding 9606 20940030 t gcesareni Numb interacts with mdm2, and inhibits its ubiquitin-ligase function on tp53 (which in itself is inhibitory for tp53), thus numb activates (b) tp53 SIGNOR-168454 0.455 DDX5 protein P17844 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 9606 17369852 t miannu Wt p68 co-immunoprecipitates efficiently with hdac1, the k53r p68 does not / sumoylation is important for the interaction of p68 with hdac1 and for transcriptional repression by p68 SIGNOR-153715 0.402 dexchlorpheniramine chemical CHEBI:4464 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7925364 t miannu The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum. SIGNOR-258873 0.8 PPP2R1A protein P30153 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates binding 9606 16039140 t miannu Pr65/a acts as a scaffold protein for binding pp2ac and regulatory b subunits in a heterotrimeric holoenzyme SIGNOR-138883 0.958 AKT proteinfamily SIGNOR-PF24 SIGNOR CCDC88A protein Q3V6T2 UNIPROT unknown phosphorylation Ser1417 INRERQKsLTLTPTR 9606 16139227 t llicata Akt phosphorylates serine at position 1416 in girdin, and phosphorylated girdin accumulates at the leading edge of migrating cells. SIGNOR-140216 0.2 DLG2 protein Q15700 UNIPROT Scribble_complex_DLG2-LLGL1_variant complex SIGNOR-C510 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270909 0.486 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Thr75 VLTGKLTtVFLPIVY -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263597 0.381 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR unknown phosphorylation 9606 21071439 t inferred from 70% family members lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-270150 0.4 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT up-regulates activity phosphorylation Tyr248 HASDVTDySYPATPN 9606 BTO:0000815 17623672 t WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3. SIGNOR-262300 0.564 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB2 protein P05107 UNIPROT up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259023 0.2 LPAR6 protein P43657 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257004 0.2 ACVR1B protein P36896 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 10090 14517293 t gcesareni ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (T²RI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-²-like signaling pathway SIGNOR-235157 0.794 CDK3 protein Q00526 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser106 PLNSVSPsPLMLLHP 26202215 t lperfetto CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3 SIGNOR-273188 0.262 TRIM27 protein P14373 UNIPROT STK38L protein Q9Y2H1 UNIPROT up-regulates activity ubiquitination Lys119 TGHIYAMkILRKSDM 10090 35670107 t K11 corresponds to the 11th Lysine, which is in position 119 in the full length sequence lperfetto TRIM27 catalyzes non-degradative K6- and K11-linked ubiquitination of the serine/threonine kinase 38-like (STK38L) kinase. In turn, STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination of ULK1 SIGNOR-270347 0.2 ARNTL protein O00327 UNIPROT PPARA protein Q07869 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 16556735 t miannu We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression. SIGNOR-268025 0.579 PPP1CA protein P62136 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser469 AHEENPEsILDEHVQ 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248554 0.339 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 21423276 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-172917 0.8 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 9677429 t MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade. lperfetto The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells. SIGNOR-244806 0.2 mTORC1 complex SIGNOR-C3 SIGNOR JMJD1C protein Q15652 UNIPROT up-regulates activity phosphorylation Thr505 KFVSRPPtPKCVIDI 9606 BTO:0000007 32034158 t miannu We show that, by direct interaction with USF-1, JMJD1C is recruited to lipogenic promoters. We also show that JMJD1C is phosphorylated at T505 by mammalian target of rapamyci (mTOR) to be recruited to lipogenic genes in response to insulin/feeding. we detected phosphorylation of WT JMJD1C but not T505A mutant when we co-transfected JMJD1C constructs along with the mTORC1 in 293FT cells SIGNOR-265168 0.243 CDK1 protein P06493 UNIPROT RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser442 STFLAFPsPEKLLRL 9606 SIGNOR-C17 15037602 t lperfetto Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain. SIGNOR-123520 0.472 SLC9A9 protein Q8IVB4 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265608 0.8 BIRC3 protein Q13489 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000815 18570872 t miannu  In this report, we show that cIAP1 and cIAP2 promote cancer cell survival by functioning as E3 ubiquitin ligases that maintain constitutive ubiquitination of the RIP1 adaptor protein. We demonstrate that AEG40730, a compound modeled on BIR-binding tetrapeptides, binds to cIAP1 and cIAP2, facilitates their autoubiquitination and proteosomal degradation, and causes a dramatic reduction in RIP1 ubiquitination. We show that cIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1. SIGNOR-272637 0.737 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT down-regulates activity phosphorylation Ser15 FSFGTLSsWELEAWY 9606 BTO:0000567 12876286 t llicata CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites SIGNOR-250851 0.351 PATZ1 protein Q9HBE1 UNIPROT RNF4 protein P78317 UNIPROT down-regulates binding 9606 10713105 t miannu In vitro and in vivo interaction between rnf4 and patz was demonstrated / patz acted as a transcriptional repressor, whereas its partner rnf4 behaved as a transcriptional activator./ the association of patz with rnf4 switches activation to repression SIGNOR-75775 0.525 ANXA1 protein P04083 UNIPROT FPR1 protein P21462 UNIPROT up-regulates activity binding 9606 BTO:0000007 15187149 t We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2. SIGNOR-259439 0.733 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR MYC protein P01106 UNIPROT up-regulates activity 9606 19855079 t apalma We demonstrate that in addition to blocking myeloid differentiation, PLZF-RARα also promotes proliferation/self-renewal via the aberrant regulation of cell cycle–associated genes such as c-Myc, providing a basis for studying the aberrant response of this leukemia subtype to retinoic acid. SIGNOR-256374 0.2 PIM2 protein Q9P1W9 UNIPROT PFKFB3 protein Q16875 UNIPROT up-regulates quantity by stabilization phosphorylation Ser478 TKKPRINsFEEHVAS 9606 BTO:0002181 33931981 t miannu We used biochemical methods to determine that PIM2 can directly bind and change the phosphorylation of PFKFB3 at Ser478 to enhance PFKFB3 protein stability through the ubiquitin-proteasome pathway. SIGNOR-277554 0.2 AKT3 protein Q9Y243 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-217466 0.396 pentazocine chemical CHEBI:7982 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258766 0.8 PABPC1 protein P11940 UNIPROT EIF4E protein P06730 UNIPROT up-regulates activity binding 9606 30209168 t miannu The binding of PABP to mRNA poly(A) tails is followed by interactions with eukaryotic initiation factor (eIF4G) and other translation factors, including eIF4E, to constitute a translation initiation complex, which mediates cellular mRNA circularization and enhances cap-dependent translation by facilitating ribosome recycling SIGNOR-260968 0.798 JUN protein P05412 UNIPROT CFI protein P05156 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10630630 f miannu The production of CFI by Hep G2 cells was enhanced in a dose- and time-dependent fashion by 12-O-tetradecanoyl-1,2-phorbol 13-acetate (TPA), a potent PKC activator. The enhancement of the activity of transfected chimeric CAT constructs by TPA was abrogated by calphostin C and by pyrrolidine dithiocarbamate (an inhibitor of NF-kappaB and AP-1 transactivation). These results indicate that TPA regulation of CFI gene requires PKC signalling and is mediated by via a TPA response element (TRE) in the CFI promoter region located at -136/-130 and involves the transactivation of AP-1 and NF-kappaB transcription factors SIGNOR-254787 0.2 ATP5F1A protein P25705 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261396 0.2 SSTR2 protein P30874 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256684 0.564 CEP135 protein Q66GS9 UNIPROT SASS6 protein Q6UVJ0 UNIPROT up-regulates activity binding 9606 23511974 t miannu In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation. SIGNOR-269676 0.614 WNT10B protein O00744 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 9606 21872687 f fspada We show that knockdown of Beta-catenin completely prevents the inhibition of adipogenesis and stimulation of osteoblast differentiation by wnt6, wnt10a or wnt10b SIGNOR-176190 0.487 Tosedostat chemical CID:15547703 PUBCHEM ANPEP protein P15144 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207372 0.8 PDCD1 protein Q15116 UNIPROT T cell exhaustion phenotype SIGNOR-PH221 SIGNOR up-regulates 9606 BTO:0000782 28286692 f Barakat Programmed cell death-1 (PD-1) is a major regulator of T-cell exhaustion, and blocking the PD-1 pathway restores T-cell function and improves pathogen control and tumor eradication. Immunotherapy targeting the PD-1 inhibitory receptor pathway has demonstrated significant antitumor activity. SIGNOR-275413 0.7 GP1BA protein P07359 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR form complex binding 9606 BTO:0000132 16293600 t lperfetto The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbα, disulfide-linked to GPIbβ, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1. SIGNOR-261847 0.696 INS protein P01308 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 10090 12530968 f lperfetto The forkhead transcription factor foxo1 is regulated by insulin via akt-dependent phosphorylation and nuclear exclusion. SIGNOR-252627 0.744 SPOP protein O43791 UNIPROT GLI2 protein P10070 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 20463034 t Gianni RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins SIGNOR-268860 0.698 GSK3A protein P49840 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser137 PVSSPQSsPRLPRRP 9606 22778263 t lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. SIGNOR-198130 0.272 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr771 IGTAEPDyGALYEGR 9606 1689310 t llicata We have identified the sites phosphorylated in vitro by epidermal growth factor (egf) receptor kinase in bovine brain phospholipase c-gamma (plc-gamma). They are tyrosine residues 472, 771, 783, and 1254. we propose, therefore, that the phosphorylation of plc-gamma by egf receptor kinase alters its interaction with putative inhibitory proteins and leads to its activation. SIGNOR-20984 0.835 RTKs proteinfamily SIGNOR-PF38 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation 9606 30889378 t miannu The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs. SIGNOR-259030 0.2 AHCYL1 protein O43865 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR up-regulates activity relocalization 10090 BTO:0000988 21317537 t lperfetto WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, SIGNOR-264645 0.2 MAPK13 protein O15264 UNIPROT PRKD1 protein Q15139 UNIPROT down-regulates phosphorylation 9606 19135240 t gcesareni P38delta catalyzes an inhibitory phosphorylation of pkd1, thereby attenuating stimulated insulin secretion. SIGNOR-183280 0.2 BMPR1B protein O00238 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR form complex binding 9606 7791754 t lperfetto Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii). SIGNOR-33431 0.542 CDC14A protein Q9UNH5 UNIPROT WEE1 protein P30291 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser123 EEGFGSSsPVKSPAA 9606 23051732 t lperfetto However, when both Ser-123 and Ser-139 were modified (2A), although Wee1 was still phosphorylated by Cdk1, treatment with active Cdc14A did not decrease the phosphorylation signal to any significant extent ( xref , lane 5), indicating that Cdc14A dephosphorylates Wee1 at Ser-123 and Ser-139 residues.|Our results indicate that Wee1 is a substrate of Cdc14 phosphatases in human cells and that by reversing specific Cdk1 phosphorylation, the Cdc14A isoform induces Wee1 stability, which in turn directly inhibits Cdk1 activity. SIGNOR-276952 0.561 MAP2K7 protein O14733 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation Thr221 AGTSFMMtPYVVTRY 9606 15911620 t lperfetto Two mapkks, sek1 and mkk7, synergistically activate jnk. Sek1 prefers the tyr-185 residue, and mkk7 prefers the thr-183 residue (17, 19). SIGNOR-137609 0.564 FBXW7 protein Q969H0 UNIPROT EGLN2 protein Q96KS0 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 28036276 t lperfetto Mechanistically, we further show that FBW7, an E3 ligase complex component that is frequently downregulated in TNBC, negatively regulates EglN2 protein stability. SIGNOR-261997 0.356 CDC14A protein Q9UNH5 UNIPROT WEE1 protein P30291 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser139 YFLGSSFsPVRCGGP 9606 23051732 t lperfetto However, when both Ser 123 and Ser 139 were modified (2A), although Wee1 was still phosphorylated by Cdk1, treatment with active Cdc14A did not decrease the phosphorylation signal to any significant extent (XREF_FIG, lane 5), indicating that Cdc14A dephosphorylates Wee1 at Ser 123 and Ser 139 residues.|Our results indicate that Wee1 is a substrate of Cdc14 phosphatases in human cells and that by reversing specific Cdk1 phosphorylation, the Cdc14A isoform induces Wee1 stability, which in turn directly inhibits Cdk1 activity. SIGNOR-276953 0.561 MAT2B protein Q9NZL9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001938 30942439 f miannu MAT2B Promotes Proliferation and Inhibits Apoptosis in Osteosarcoma by Targeting Epidermal Growth Factor Receptor and Proliferating Cell Nuclear Antigen SIGNOR-261242 0.7 torin 2 chemical CHEBI:90682 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 23436801 t ATP-competitive inhibitor gcesareni Torin2, a second generation atp-competitive inhibitor that is potent and selective for mtor.. SIGNOR-201499 0.8 CDK2 protein P24941 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates activity phosphorylation 9606 12202491 t lperfetto Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity SIGNOR-264650 0.385 RELA protein Q04206 UNIPROT B2M protein P61769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12480693 f miannu The nuclear factor kappa B (NF-kappa B) subunits p50 and p65 bind to the kappa B box and p65 transactivates beta(2)m. SIGNOR-254657 0.264 IFNL3 protein Q8IZI9 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 12469119 t gcesareni Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha. SIGNOR-96246 0.842 PDCD1 protein Q15116 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0000782 16227604 f Barakat Akt phosphorylation in cells stimulated by CD3/CD28/CTLA-4 or CD3/CD28/PD-1 aAPCs did not have detectable phosphorylated Akt at any time point, indicating that CTLA-4 and PD-1 signaling blocked rather than delayed Akt activation. SIGNOR-275408 0.351 Calcineurin complex SIGNOR-C155 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0001103 15829723 f apalma Calcineurin can activate the transcription factors myocyte enhancer factor-2 and MyoD, which leads to the subsequent induction of myogenin and muscle differentiation (22). In addition, inhibition of calcineurin prevents the initiation of early stages of muscle differentiation SIGNOR-255103 0.268 MAP3K8 protein P41279 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser222 VSGQLIDsMANSFVG 9606 BTO:0000007 15466476 t lperfetto Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases. SIGNOR-129694 0.415 fumarate(2-) smallmolecule CHEBI:29806 ChEBI (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI up-regulates quantity precursor of 9606 30761759 t miannu Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors. SIGNOR-266278 0.8 Integrator complex complex SIGNOR-C265 SIGNOR JUNB protein P17275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 25675981 f lperfetto The Integrator complex controls the termination of transcription at diverse classes of gene targets.|Following INTS3 or INTS9 knockdown, the levels of SDC4, JUNB, FOSL1, and GADD45B increased, suggesting that the Integrator complex negatively regulates the transcription of these genes. SIGNOR-261479 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 28646232 t inferred from 70% family members Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3Œ≤ at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3Œ≤ activity and restores protein synthesis in Tsc2 ‚àí/‚àí MEFs to normal levels SIGNOR-270068 0.2 HIPK2 protein Q9H2X6 UNIPROT PAX6 protein P26367 UNIPROT up-regulates activity phosphorylation Thr373 GRSYDTYtPPHMQTH 9606 BTO:0001938 16407227 t HIPK2 phosphorylates the activation domain of Pax6, which augments Pax6 transactivation by enhancing its interaction with p300. Mass spectrometric analysis identified three Pax6 phosphorylation sites as threonines 281, 304, and 373. SIGNOR-251271 0.476 LY-2157299 chemical CHEBI:137064 ChEBI TGFBR2 protein P37173 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193778 0.8 pictrelisib chemical CHEBI:65326 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 BTO:0000149 21876152 t gcesareni Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed SIGNOR-176301 0.8 PPARG protein P37231 UNIPROT FABP4 protein P15090 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000975 8943212 f fspada We report that insulin and a ppargamma ligand (thiazolidinedione (tzd)) stimulate in a synergistic manner the expression of an adipocyte-specific gene (ap2) in rat adipocytes and 3t3-l1 cells SIGNOR-45294 0.672 Sin3B_complex complex SIGNOR-C409 SIGNOR H3Y1 protein P0DPK2 UNIPROT down-regulates activity binding 9606 21041487 t miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. SIGNOR-266975 0.2 CTDSP1 protein Q9GZU7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser214 PTSSDPGsPFQMPAD 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248801 0.477 MAPK1 protein P28482 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 BTO:0000938 20444238 t gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. SIGNOR-165200 0.48 SRC protein P12931 UNIPROT GRIK2 protein Q13002 UNIPROT up-regulates activity phosphorylation Tyr590 RFSPYEWyNPHPCNP 9606 BTO:0000007 25201974 t miannu GluK2 binds to Src, and the tyrosine residue at position 590 (Y590) on GluK2 is a major site of phosphorylation by Src kinases. GluK2 phosphorylation at Y590 is responsible for increases in whole-cell currents and calcium influx in response to transient kainate stimulation. SIGNOR-276850 0.38 KDM6A protein O15550 UNIPROT ELF4 protein Q99607 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29736013 t miannu Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase SIGNOR-260031 0.283 ATM protein Q13315 UNIPROT PVR protein P15151 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000914 21406724 f The up-regulation of PVR expression involves DNA-damage response (DDR)-dependent pathways, because we found that pharmacologic inhibition of ATM and ATR kinases reduced PVR expression and that PVR was almost exclusively induced on cells expressing the DDR marker γH2AX. SIGNOR-253927 0.253 GOLGA7 protein Q7Z5G4 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity palmitoylation 9606 BTO:0000007 16000296 t miannu Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein. SIGNOR-261354 0.405 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252826 0.908 PRKACA protein P17612 UNIPROT TFAP2A protein P05549 UNIPROT up-regulates phosphorylation Ser239 AEVQRRLsPPECLNA 9606 10037142 t llicata Recombinant ap-2 was phosphorylated in vitro by protein kinase a (pka) at ser239. Mutation of ser239 to ala abolished in vitro phosphorylation of ap-2 by pka, but not the dna binding activity of ap-2. Cotransfection studies showed that pka stimulated the effect of ap-2 on the apoe promoter, but not that of the s239a mutant. SIGNOR-64955 0.2 CEP192 protein Q8TEP8 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity binding 9606 26012549 t miannu These findings demonstrated that Cep192 mediates the AurA-Plk1 interaction and that the formation of the Cep192-AurA-Plk1 complex could be important for activating AurA and Plk1. SIGNOR-266406 0.788 CBX3 protein Q13185 UNIPROT NIPBL protein Q6KC79 UNIPROT up-regulates activity binding 9606 28167679 t miannu The heterochromatin protein HP1γ (also known as CBX3) recruits NIPBL to DNA double-strand breaks (DSBs) through the corresponding HP1-binding motif within the N-terminus. SIGNOR-264524 0.447 CBLC protein Q9ULV8 UNIPROT LRIG1 protein Q96JA1 UNIPROT down-regulates ubiquitination 9606 BTO:0001253 15282549 t gcesareni Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation SIGNOR-127292 0.2 JQ1 chemical CHEBI:137113 ChEBI BRD4 protein O60885 UNIPROT down-regulates activity chemical inhibition -1 20871596 t lperfetto Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains. SIGNOR-261989 0.8 PLEKHG4 protein Q58EX7 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260564 0.368 PLK1 protein P53350 UNIPROT DCTN1 protein Q14203 UNIPROT up-regulates phosphorylation Ser179 SASAGELsSSEPSTP 9606 20679239 t lperfetto Plk1-mediated phosphorylation of p150(glued) at ser-179 positively regulates its accumulation at the nuclear envelope during prophase. SIGNOR-167281 0.538 JAK1 protein P23458 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr304 PNEPVSDyINANIIM 9534 8995399 t lperfetto Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2. SIGNOR-236282 0.759 NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 t lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. SIGNOR-64092 0.808 PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity 9606 21798082 t lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2). SIGNOR-252722 0.8 SYK protein P43405 UNIPROT SH3BP2 protein P78314 UNIPROT up-regulates activity phosphorylation Tyr174 YPTDNEDyEHDDEDD 9534 12709437 t lperfetto By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk. SIGNOR-246587 0.568 IHH protein Q14623 UNIPROT BMP2 protein P12643 UNIPROT up-regulates 9606 22298955 f gcesareni Ihh is found to be required for bmp-induced os-teogenesis of a limb-bud cell line in culture. Ihh sig-naling is directly required for the osteoblast lineage in developing long bones. Ihh functions in conjunction with other factors such as bmps to induce osteoblast differentiation. In vivo, ihh acts on potential progeni-tor cells to promote osteoblast differentiation and prevent chondrocyte differentiation. SIGNOR-195609 0.531 EP300 protein Q09472 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity acetylation 9606 BTO:0003292 28045112 t lperfetto Brd3 interacts with both IRF3 and p300, increases p300-mediated acetylation of IRF3, and enhances the association of IRF3 with p300 upon virus infection.|Brd3 enhances p300-mediated acetylation of IRF3|Importantly, Brd3 promotes the recruitment of IRF3/p300 complex to the promoter of Ifnb1, and increases the acetylation of histone3/histone4 within the Ifnb1 promoter, leading to the enhancement of type I interferon production. SIGNOR-262045 0.2 F2RL1 protein P55085 UNIPROT CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254843 0.2 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser172 GQLVRNDsLWHRSDS 9606 BTO:0002181 34010649 t miannu PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-277559 0.2 frovatriptan chemical CHEBI:134991 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation -1 9986723 t miannu As far as the selectivity against the 5-HT1A receptor, compound 10 shows similar selectivity as VML-251 (4) but has slightly lower selectivity as compared to sumatriptan (1), naratriptan (2), and rizatriptan (3). Although none of the 5-HT1D receptor agonists in the current study demonstrate as good selectivity versus the 5-HT1B receptor, the N-methyl-5-tert-butyltryptamine (10) remains the most selective (4-fold). SIGNOR-259074 0.8 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR PKM protein P14618 UNIPROT down-regulates activity phosphorylation Ser37 MCRLDIDsPPITARN 9606 BTO:0000782 28607489 t lperfetto Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3–CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2.|Phosphomimicking mutants of PFKP (S679E) or PKM2 (S37E) displayed decreased catalytic activity SIGNOR-273032 0.262 proline smallmolecule CHEBI:26271 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264744 0.7 TTC3 protein P53804 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates quantity by destabilization ubiquitination 10090 BTO:0000944 20059950 t gcesareni TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus SIGNOR-252459 0.404 LSM-1231 chemical CHEBI:91471 ChEBI NTRK3 protein Q16288 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258240 0.8 MAP2K6 protein P52564 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates phosphorylation Tyr185 ADSEMTGyVVTRWYR 9606 19230643 t gcesareni Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily . the p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms . p38mapks are activated by dual phosphorylation on a t-x-y motif in the activation loop through the action of map kinase kinases SIGNOR-184138 0.645 SP3 protein Q02447 UNIPROT CADM1 protein Q9BY67 UNIPROT up-regulates quantity by expression transcriptional regulation 18794147 f lperfetto Treatment with mithramycin A, an inhibitor of Sp1 or Sp3 binding, resulted in reduction of Cadm1 gene expression, therefore suggesting a potential role of Sp1/Sp3 in Cadm1 regulation. SIGNOR-268959 0.273 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Thr404 NSHPLSLtSDQYKAY -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178420 0.816 CSNK2A1 protein P68400 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser13 GQDMSQVsGKESPPV 9606 BTO:0001271 21750978 t miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo SIGNOR-174824 0.294 ARNTL protein O00327 UNIPROT CRY2 protein Q49AN0 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253627 0.931 PRKCA protein P17252 UNIPROT ADD3 protein Q9UEY8 UNIPROT down-regulates quantity by destabilization phosphorylation Ser693 KKKFRTPsFLKKNKK -1 11895774 t lperfetto Results of in vitro experiments with recombinant alpha adducin demonstrated that PKC-phosphorylated adducin was proteolyzed by calpain more quickly than unphosphorylated adducin. | Phosphorylation of adducin by PKC may be a common mechanism for regulating adducin proteolysis by several proteases. | The antibody used in panel B is specific for the PKC-phosphorylated form of adducin. This antibody was raised against the phosphopeptide CKKFRTP[pS]FLKKNK, corresponding to amino acids 656-668 of human gamma adducin SIGNOR-249143 0.34 AKT1 protein P31749 UNIPROT NQO1 protein P15559 UNIPROT down-regulates quantity by destabilization phosphorylation Ser40 KGWEVVEsDLYAMNF 9606 BTO:0000007 31358653 t miannu Akt phosphorylates NQO1 on S40 and T128 residues. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase.  SIGNOR-276868 0.377 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Lys) smallmolecule CHEBI:29185 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269490 0.8 MARCHF8 protein Q5T0T0 UNIPROT HLA-DRA protein P01903 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys244 FIIKGLRkSNAAERR 9606 19117940 t miannu Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination. SIGNOR-271411 0.2 HACE1 protein Q8IYU2 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 17694067 t miannu Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1. SIGNOR-271405 0.312 E protein P59637 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000661 16048439 f Luana Overexpression of SARS-CoV E protein in T-cells promoted apoptosis SIGNOR-260208 0.7 MYOD1 protein P15172 UNIPROT RB1 protein P06400 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 10373569 t gcesareni Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator. SIGNOR-238532 0.403 FYN protein P06241 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr759 LYDVSRMyVDPSEIN -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249340 0.557 STAT1 protein P42224 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity binding 9606 19041276 t lperfetto Each STAT1 monomer becomes tyrosine phosphorylated at tyrosine 701 by the JAKs, dissociates from the receptor to form a STAT1-STAT1 homodimer which translocates to the nucleus SIGNOR-249495 0.2 ESR1 protein P03372 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000938 22169964 f miannu In this study, quantitative real-time PCR analysis showed that the gene expression levels of TTX-S (Nav1.1 and Nav1.7) and TTX-R (Nav1.8 and Nav1.9) sodium channel subtypes were elevated in DRGs of αERKO and βERKO mice, whereas Nav1.6 mRNA decreased in αERKOs but showed no changes in βERKO mice SIGNOR-253476 0.2 CDK5 protein Q00535 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Ser522 PAPSAKSsPSKHQPP 9606 BTO:0000938 18003833 t lperfetto These findings suggest that sema3a-induced spine development is regulated by phosphorylation of crmp1 by cdk5. Introduction of crmp1-wt, but not crmp1-t509a/s522a, a crmp1 mutant that cannot be phosphorylated by cdk5, rescued the defect in sema3a responsiveness. SIGNOR-159314 0.607 NUAK2 protein Q9H093 UNIPROT LATS1 protein O95835 UNIPROT down-regulates phosphorylation Ser464 NIPVRSNsFNNPLGN 9606 19927127 t gcesareni Phosphorylation at ser-464 by nuak1 and nuak2 leads to decreased protein level and is required to regulate cellular senescence and cellular ploidy SIGNOR-161796 0.312 PRKACA protein P17612 UNIPROT GLIS2 protein Q9BZE0 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 16537363 t lperfetto Protein kinase a (pka) and glycogen synthase kinase 3beta sequentially phosphorylate gli2 at multiple sites, identified by mutagenesis, thus resulting in a reduction of its transcriptional activity SIGNOR-145131 0.286 8a protein Q7TFA0 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0001950 17597455 f Luana Open Reading Frame 8a of the Human Severe Acute Respiratory Syndrome Coronavirus Not Only Promotes Viral Replication but Also Induces Apoptosis SIGNOR-260206 0.7 WNK3 protein Q9BYP7 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates activity phosphorylation Thr991 SAYTYERtLMMEQRS 9606 24043619 t Manara WNK3, which inhibits the activity of KCC3, promoted phosphorylation of Ser-96 as well as Thr-991 and Thr-1048.  SIGNOR-260912 0.456 PPARGC1A protein Q9UBK2 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f inferred from family member miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-270226 0.257 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 RDPVARTsPLQTPAA 9606 BTO:0000567 10669763 t lperfetto Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both_ in vitro_ and_ in vivo. SIGNOR-74919 0.533 HSPA1A protein P0DMV8 UNIPROT NOD2 protein Q9HC29 UNIPROT up-regulates quantity by stabilization binding 9606 24790089 t miannu The molecular chaperone HSP70 binds to and stabilizes NOD2, an important protein involved in Crohn disease. SIGNOR-252416 0.259 IRAK4 protein Q9NWZ3 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity phosphorylation Thr345 KFAQTVMtSRIVGTT 9606 BTO:0000876 24567333 t lperfetto We show irak4 autophosphorylation occurs by an intermolecular reaction and that autophosphorylation is required for full catalytic activity of the kinase. Phosphorylation of any two of the residues thr-342, thr-345, and ser-346 is required for full activity SIGNOR-204661 0.2 GNA13 protein Q14344 UNIPROT ARHGEF12 protein Q9NZN5 UNIPROT up-regulates activity binding 10090 BTO:0000944 12024019 t P115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G alpha 12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation. SIGNOR-256519 0.763 PRKN protein O60260 UNIPROT PACRG protein Q96M98 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 12150907 t miannu In this study, we found that CHIP promotes Parkin-mediated Pael-R ubiquitination and subsequent degradation. In vitro ubiquitination assays suggested that only a combination of both Parkin and its cofactor CHIP function as a ubiquitin ligase, which is able to sufficiently ubiquitinate Pael-R in vivo (Figure 6).  SIGNOR-272889 0.2 trichostatin A chemical CHEBI:46024 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258016 0.8 AMFR protein Q9UKV5 UNIPROT MFN1 protein Q8IWA4 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 23427266 t miannu Gp78 induces ubiquitylation and proteasomal degradation of Mfn1 and Mfn2. SIGNOR-272886 0.314 Ac-Asp-Glu(3-) smallmolecule CHEBI:76931 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 10085079 t miannu The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. SIGNOR-267540 0.8 STAT6 protein P42226 UNIPROT KLF4 protein O43474 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25934862 f miannu IL-4-induced macrophage polarization involves induction of STAT6 and KLF4 that induce each other and promote M2 polarization. SIGNOR-254519 0.352 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000150 10550055 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-72087 0.51 EGF protein P01133 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9168989 f Regulation miannu We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin. SIGNOR-251785 0.2 PBRM1 protein Q86U86 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270596 0.774 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT down-regulates quantity by destabilization cleavage Asp372 EFEVSFLdSPGAQAQ 9606 BTO:0000567 11815631 t Giulio Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage SIGNOR-260603 0.405 CDK5 protein Q00535 UNIPROT STMN3 protein Q9NZ72 UNIPROT unknown phosphorylation Ser68 PSDLSPEsPMLSSPP -1 22577147 t lperfetto Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta SIGNOR-264893 0.328 SENP1 protein Q9P0U3 UNIPROT AKT1 protein P31749 UNIPROT down-regulates quantity by destabilization desumoylation Lys276 NVVYRDLkLENLMLD 10090 BTO:0002572 23884910 t gcesareni Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity. SIGNOR-252736 0.284 MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Tyr221 HQYFMTEyVATRWYR 9606 BTO:0000567 20667468 t miannu ERK5 is a member of the mitogen-activated protein kinase (MAPK) family that, after stimulation, is activated selectively by dual phosphorylation in the TEY motif by MAPK kinase 5 (MEK5). ERK5 is activated selectively by dual phosphorylation on Thr218 and Tyr220 in the TEY motif by its only upstream kinase, MEK5, a member of the MEK SIGNOR-259825 0.691 NFE2L2 protein Q16236 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000599 26194347 f irozzo Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes. SIGNOR-259285 0.7 CDC25A protein P30304 UNIPROT CDK6 protein Q00534 UNIPROT up-regulates activity dephosphorylation Tyr24 AEIGEGAyGKVFKAR 9606 BTO:0000007 23429262 t lperfetto Invalidation of CDK4 has no impact by itself on the cell proliferation, but invalidation of CDC25A prevents the dephosphorylation of CDK6 (Y24) and CDK4 (Y17) residues, and impedes their association with CCNDs. SIGNOR-267569 0.692 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser115 PAPSSFSsTSVSSLE 9606 15448698 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-129414 0.574 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT unknown dephosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 BTO:0000007 18840653 t We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well. SIGNOR-248398 0.547 ROCK1 protein Q13464 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Ser1137 RSRGNRKsLRRTLKS 9606 18239683 t lperfetto Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres. SIGNOR-160548 0.314 CRB3 protein Q9BUF7 UNIPROT AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR up-regulates binding 10090 BTO:0000150 21145499 t milica Interestingly, knockdown of crb3, which facilitates crumbs complex assembly and localization to the apical junctions disrupted taz/yap interaction with multiple components of the complex, whereas the other knockdowns only disrupted their respective interaction. SIGNOR-170399 0.536 ADRA2C protein P18825 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256842 0.466 NPAS1 protein Q99742 UNIPROT TH protein P07101 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003945 17457889 t lperfetto Overexpression and siRNA experiments revealed that NPAS1, in concert with ARNT, negatively regulates the expression of TH and that this regulation is mediated by a direct binding of NPAS1 on the TH promoter. SIGNOR-253702 0.255 MRPL35 protein Q9NZE8 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262362 0.629 KLF4 protein O43474 UNIPROT TNF protein P01375 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000801 22378047 f miannu KLF4 cooperates with Stat6 to induce M2 genes (Arg-1, Mrc1, Fizz1, PPARγ) and inhibit M1 genes (TNFa, Cox-2, CCL5, iNOS) via sequestration of coactivators required for NF-κB activation. SIGNOR-254520 0.338 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246264 0.564 SLC9A8 protein Q9Y2E8 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265607 0.8 PEX6 protein Q13608 UNIPROT Protein_localization_to_peroxisome phenotype SIGNOR-PH86 SIGNOR up-regulates 9606 26476099 f The Pex1 and Pex6 proteins are members of the AAA family of ATPases and are involved in peroxisome biogenesis. SIGNOR-253617 0.7 F2RL1 protein P55085 UNIPROT TXNIP protein Q9H3M7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 21072196 f miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). SIGNOR-254857 0.2 GNAS protein P63092 UNIPROT ADCY1 protein Q08828 UNIPROT up-regulates activity binding 9606 17652154 t gcesareni Because adenylyl cyclases are directly activated by G(s)alpha and the carboxyl termini of the various Galpha proteins determine their receptor coupling specificity, we proposed a set of chimeric G(s)alpha where the COOH-terminal five amino acids are replaced by those of other Galpha proteins and used these to dissect the potential Galpha linked to a given GPCR SIGNOR-156958 0.612 PKA proteinfamily SIGNOR-PF17 SIGNOR CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 8386317 t miannu CREB is phosphorylated on Ser133 by PKA (protein kinase A), promoting the recruitment of the co-activator proteins CBP (CREB-binding protein) and p300; this has been proposed to increase the transcription of CREB-dependent genes. SIGNOR-263653 0.2 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR BIRC6 protein Q9NR09 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271352 0.417 RAB12 protein Q6IQ22 UNIPROT SLC36A4 protein Q6YBV0 UNIPROT down-regulates quantity by destabilization relocalization 10090 BTO:0002572 23478338 t lperfetto We also found that Rab12 promotes constitutive degradation of PAT4 (proton‐coupled amino‐acid transporter 4|Rab12 regulates lysosomal localization or degradation of amino‐acid transporters. SIGNOR-264763 0.456 FZD3 protein Q9NPG1 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 9606 20828404 t gcesareni Upon ligand binding, non-canonical wnt signaling controls tissue polarity and cell movement through the activation of rhoa, c-jun n-terminal kinase (jnk), and nemo-like kinase (nlk) signaling cascades. SIGNOR-167865 0.351 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 t gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. SIGNOR-163262 0.686 CSNK2A1 protein P68400 UNIPROT WASF2 protein Q9Y6W5 UNIPROT down-regulates phosphorylation Ser482 RRIAVEYsDSEDDSS 9606 19012317 t gcesareni Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo. SIGNOR-182350 0.2 CSNK2A1 protein P68400 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser543 SIADMDFsALLSQIS 9606 10938077 t llicata We demonstrate that casein kinase II (CKII) interacts with p65 in vivo and can phosphorylate p65 at serine 529 in vitro. A CKII inhibitor (PD144795) inhibited TNFalpha-induced p65 phosphorylation in vivo. Furthermore, our results indicate that the association between IkappaBalpha and p65 inhibits p65 phosphorylation by CKII and that degradation of IkappaBalpha allows CKII to phosphorylate p65 to increase NF-kappaB transactivation potential.  SIGNOR-250942 0.455 NPM1 protein P06748 UNIPROT HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30205049 t miannu In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation. SIGNOR-260138 0.359 PRKCA protein P17252 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0000599 15730925 f irozzo PKC-alpha asODN (antisense oligonucleotides) could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC. SIGNOR-256660 0.7 FASN protein P49327 UNIPROT NADP(3-) smallmolecule CHEBI:58349 ChEBI up-regulates quantity chemical modification 9606 15507492 t miannu Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-268087 0.8 HTR2A protein P28223 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257227 0.425 SLC35A2 protein P78381 UNIPROT UDP-D-galactose smallmolecule CHEBI:18307 ChEBI up-regulates quantity relocalization 9606 34384782 t miannu The CMP-sialic acid transporter SLC35A1 and UDP-galactose transporter SLC35A2 are two well-characterized nucleotide sugar transporters with distinctive substrate specificities. Nucleotide sugar transporters (NSTs) transport nucleotide sugars from the cytosol into the lumen of the endoplasmic reticulum or the Golgi apparatus, where the nucleotide sugars serve as substrates for protein glycosylation and glycosphingolipid synthesis. SIGNOR-268465 0.8 CSNK2A1 protein P68400 UNIPROT HES6 protein Q96HZ4 UNIPROT up-regulates activity phosphorylation Ser183 GPGDDLCsDLEEAPE -1 12972610 t llicata Hes6 inhibits the interaction of Hes1 with its transcriptional corepressor Gro/TLE. Moreover, it promotes proteolytic degradation of Hes1. This effect is maximal when both Hes1 and Hes6 contain the WRPW motif and is reduced when Hes6 is mutated to eliminate a conserved site (Ser183) that can be phosphorylated by protein kinase CK2.  SIGNOR-250890 0.512 WT1 protein P19544 UNIPROT RBM4 protein Q9BWF3 UNIPROT down-regulates binding 9606 16934801 t miannu Wilm's tumor protein 1 (wt1), a protein implicated in various cancers and developmental disorders, consists of two major isoforms: wt1(-kts), a transcription factor, and wt1(+kts), a post-transcriptional regulator that binds to rna and can interact with splicing components. Here we show that wt1 interacts with the novel splicing regulator rbm4. / we conclude that the (+kts) form of wt1 is able to inhibit the effect of rbm4 on alternative splicing. SIGNOR-149166 0.372 H2BC11 protein P06899 UNIPROT CENP-A nucleosome complex SIGNOR-C321 SIGNOR form complex binding -1 23324462 t miannu In vitro assembly of both yeast and human CENP-A nucleosomes yields standard octameric structures containing two copies each of CENP-A, H2A, H2B and H4 histones. Human CENP-A also produces rigidified homotypic CENP-A/H4 tetramers in vitro. SIGNOR-263699 0.2 LHX3 protein Q9UBR4 UNIPROT ISL1 protein P61371 UNIPROT up-regulates activity binding 9606 9452425 t miannu The Lhx3-Isl1 C terminus interaction was dependent on the LIM domains of Lhx3. The combinatorial expression of the LIM homeodomain proteins Isl1, Isl2, Lhx1, and Lhx3 in subsets of developing motor neurons correlates with the future organization of these neurons into motor columns with distinct innervation targets, implying a functional role for LIM homeodomain protein combinations in the specification of neuronal identity SIGNOR-220169 0.607 SULT1E1 protein P49888 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification -1 7779757 t Luana HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM. SIGNOR-269749 0.8 TAB3 protein Q8N5C8 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates binding 9606 25290089 t lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205449 0.372 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 17604322 t lperfetto In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE SIGNOR-244573 0.2 TACSTD2 protein P09758 UNIPROT CLDN7 protein O95471 UNIPROT up-regulates quantity binding 9606 BTO:0001109 31177095 t done miannu In summary, our findings provide evidence that Trop-2 is phosphorylated at Ser-322 by PKCα/δ and that this phosphorylation enhances cell motility and decreases claudin-7 localization to cellular borders. SIGNOR-273822 0.402 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1230 RHSLAARyYNWVSFP 9606 BTO:0000394 12881528 t lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. SIGNOR-104072 0.2 Palomid 529 chemical CID:11998575 PUBCHEM MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-199120 0.8 CAD protein P27708 UNIPROT Pyrimidine biosynthesis phenotype SIGNOR-PH187 SIGNOR up-regulates activity 9606 15096496 f The CPSase activity of CAD is the major locus of control of de novo pyrimidine biosynthesis SIGNOR-267196 0.7 GRIK4 protein Q16099 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264945 0.8 CTDSP1 protein Q9GZU7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser206 SSSTYPHsPTSSDPG 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248800 0.477 FKBP15 protein Q5T1M5 UNIPROT WIPF1 protein O43516 UNIPROT up-regulates activity binding 9606 19121306 t Giulio However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin. SIGNOR-260596 0.2 RTN4 protein Q9NQC3 UNIPROT LINGO1 protein Q96FE5 UNIPROT up-regulates binding 9606 BTO:0000938 15694321 t flangone Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1, SIGNOR-133752 0.653 WNT7A protein O00755 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131897 0.632 PSEN1 protein P49768 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates cleavage 9606 SIGNOR-C98 10593990 t Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface. gcesareni Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains. SIGNOR-254308 0.789 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser76 ISNKDQHsISYTLSR -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276134 0.758 CDK13 protein Q14004 UNIPROT EIF4EBP1 protein Q13541 UNIPROT up-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0001109 36882522 t lperfetto CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. SIGNOR-273113 0.2 SMAD1 protein Q15797 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004058 12589053 f lperfetto Overexpression of smad6, a natural antagonist for smad1, blocked ppargamma expression and adipocytic differentiation induced by bmp2 SIGNOR-236227 0.265 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCND3 protein P30281 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189975 0.8 Galanthamine hydrobromide chemical CID:121587 PUBCHEM ACHE protein P22303 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192583 0.8 Y-27632 chemical CHEBI:75393 ChEBI ROCK1 protein Q13464 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207890 0.8 PTEN protein P60484 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity dephosphorylation Ser307 TRRSRTEsITATSPA 10090 25645159 t miannu In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser 307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon HCV infection occurred in a PTEN dependent manner.|In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser-307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon Hepatitis C virus infection occurred in a PTEN-dependent manner. SIGNOR-277078 0.593 AURKA protein O14965 UNIPROT WDR62 protein O43379 UNIPROT up-regulates activity phosphorylation Ser32 VPARRGQsSPPPAPP -1 25501809 t lperfetto AURKA activity promotes WDR62 spindle localization|We next purified recombinant full-length WDR62 (GST–WDR62-FL) for in vitro kinase assays with active AURKA and demonstrated that WDR62 was a direct phosphorylation target of AURKA|In addition, our quantitative phosphoproteomic analysis of in-vitro-phosphorylated WDR62 identified S32 and S33 as significantly phosphorylated in the presence of active AURKA|Alanine replacement of the five putative phosphorylation sites (S32/S33/S49/T50/S52-AAAAA) of WDR62 attenuated interphase microtubule association induced by AURKA coexpression SIGNOR-271712 0.359 PTPN1 protein P18031 UNIPROT NTRK1 protein P04629 UNIPROT down-regulates activity dephosphorylation 9606 28919207 t miannu PTP1B inactivation prevents TrkA exit from soma and causes receptor degradation, suggesting a " gate-keeper " mechanism that ensures targeting of inactive receptors to axons to engage with ligand.|We identify a gate keeping mechanism in which TrkA receptors, destined for transcytosis, are dephosphorylated in neuronal soma by the ER-resident tyrosine phosphatase, PTP1B. SIGNOR-277081 0.385 IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates binding 9606 12438563 t gcesareni Ifn-g Binds to the ifn-g Receptor binding subunit (ifn-gR1;receptor chain 1), a species-specific cell surface transmembrane receptor chain (41, 42). A second transmembrane protein (ifn-gR2) (4345) is required for signal transduction SIGNOR-95626 0.882 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 21059642 t The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). SIGNOR-169334 0.599 ADRB2 protein P07550 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256809 0.646 PTPN1 protein P18031 UNIPROT PTK6 protein Q13882 UNIPROT down-regulates activity dephosphorylation Tyr342 RLIKEDVyLSHDHNI 9606 29142193 t miannu Using a variety of PTEN mutant constructs, we show that protein phosphatase activity of PTEN targets PTK6, with efficiency similar to PTP1B, a phosphatase that directly dephosphorylates PTK6 Y342. SIGNOR-277082 0.557 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t inferred from 70% family members gcesareni Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity. SIGNOR-270204 0.2 PDPK1 protein O15530 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser222 LIDSMANsFVGTRSY 9606 BTO:0000007 15175348 t lperfetto In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation SIGNOR-236633 0.273 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19914161 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161589 0.607 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000887;BTO:0001260 14593115 t gcesareni We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription. SIGNOR-118936 0.639 P2RY11 protein Q96G91 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256788 0.358 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203584 0.769 Histone H2B proteinfamily SIGNOR-PF68 SIGNOR Nucleosome complex SIGNOR-C371 SIGNOR form complex binding -1 21812398 t lperfetto The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. SIGNOR-265310 0.2 TEK protein Q02763 UNIPROT MYH2 protein Q9UKX2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 f lperfetto the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. SIGNOR-241538 0.2 ERG protein P11308 UNIPROT CLDN5 protein O00501 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22235125 t Luana ETS-related gene (ERG) controls endothelial cell permeability via transcriptional regulation of the claudin 5 (CLDN5) gene. SIGNOR-261596 0.225 NRG2 protein O14511 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 BTO:0000150 7514177 t gcesareni Direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3.The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4 SIGNOR-26881 0.814 GOT2 protein P00505 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI down-regulates quantity chemical modification 9606 31422819 t miannu This is a pyridoxal 5√ɬ¢√¢‚Äö¬¨√Ǭ≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √É≈Ω√Ǭ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-268057 0.8 SAFB protein Q15424 UNIPROT FUS protein P35637 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 27731383 t P35637:p.Pro525Leu (mutation disrupting interaction) SAFB1 as well as Matrin3 to regulate splicing and ligand-mediated transcription| In addition, depletion of SAFB1 reduced FUS's localization to chromatin-bound fraction and splicing activity, suggesting SAFB1 could tether FUS to chromatin compartment thorough N-terminal DNA-binding motif. SIGNOR-262821 0.37 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT up-regulates activity phosphorylation Ser27 SFGFTRTsARRRLAD -1 21880142 t miannu Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2. PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites. SIGNOR-266311 0.312 VAC14 protein Q08AM6 UNIPROT FIG4 protein Q92562 UNIPROT up-regulates quantity by stabilization binding 9534 BTO:0000298 20630877 t miannu Our data indentify a novel regulatory mechanism whereby ArPIKfyve enhances Sac3 abundance by attenuating Sac3 proteasome-dependent degradation and suggest that a failure of this mechanism could be the primary molecular defect in the pathogenesis of CMT4J. our data are consistent with the notion that when associated with ArPIKfyve, Sac3 is stabilized and protected from degradation, whereas in the absence of associated ArPIKfyve, Sac3 remains unfolded and, hence, prone to rapid destruction. SIGNOR-253534 0.919 AGRN protein O00468 UNIPROT CHRNB3 protein Q05901 UNIPROT up-regulates activity binding 9606 BTO:0002916 14502292 t miannu Treatment of muscle cells with neural agrin causes tyrosine phosphorylation of the AChR β subunit and induces AChR clustering by promoting anchoring of the receptor protein to postsynaptic cytoskeleton. Regulation of acetylcholine receptor clustering by the tumor suppressor APC. By showing a direct requirement for APC in AChR clustering, our present study suggests that the Wnt/β-catenin pathway may crosstalk with the agrin signaling cascade during the formation of mammalian neuromuscular junction. SIGNOR-264260 0.2 MMP8 protein P22894 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Leu442 TSKGDKElRTGKEKV -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-8 20ADSGEGD a-chain | 442LRTGKEKV a-chain SIGNOR-263626 0.2 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr478 PPPPPPVyEPVSYHV 9606 15623525 t lperfetto Src phosphorylates ezrin at tyrosine 477 and induces a phosphospecific association between ezrin and a kelch-repeat protein family member SIGNOR-132907 0.634 PIM1 protein P11309 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 18593906 t fspada Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42). SIGNOR-252967 0.397 MAPK3 protein P27361 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation Thr277 GSRTAPYtPNLPHHQ 9606 12801888 t llicata Our results suggest that map kinase can phosphorylate thr276 of smad4 and that phosphorylation can lead to enhanced tgf-beta-induced nuclear accumulation and, as a consequence, enhanced transcriptional activity of smad4. SIGNOR-101664 0.429 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t inferred from 70% family members gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3. SIGNOR-270142 0.2 GSK3B protein P49841 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity phosphorylation Ser404 SMRPDVSsPPSSSST 9606 18838540 t gcesareni We found hormone-dependent GR phosphorylation on serine 404 by GSK-3beta [ ]Cells expressing a GR that is incapable of GSK-3beta phosphorylation had a redirection of the global transcriptional response to hormone, including the activation of additional signaling pathways, in part due to the altered ability of unphosphorylatable GR to recruit transcriptional cofactors CBP/p300 and the p65 (RelA) subunit of NF-kappaB SIGNOR-181541 0.521 (S)-duloxetine chemical CHEBI:36795 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition -1 18387300 t Luana Selective inhibition of serotonin (5-HT) and noradrenaline (NA) reuptake (SNRI) has been shown to be an attractive dual pharmacology approach for the treatment of a number of diseases.1,2 For example, dual 5- HT/NA reuptake inhibitor duloxetine (1) has shown clinical efficacy in the treatment of depression, pain, and urinary incontinence. SIGNOR-257776 0.8 SLBP protein Q14493 UNIPROT H2AC12 protein Q96KK5 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265402 0.2 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR2C protein P28335 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257523 0.8 PCSK7 protein Q16549 UNIPROT RELA protein Q04206 UNIPROT up-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 14767066 f lperfetto Treatment with sb203580 significantly reduced this cooperation, consistent with the idea that p38 indirectly stimulates the transactivating activity of p65 through a mechanism involving cbp. SIGNOR-235734 0.2 RELA protein Q04206 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 17350185 t Luana The IL-6 promoter was stimulated by NF-kB RelA protein.  SIGNOR-266088 0.68 MAPK8 protein P45983 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Thr451 PIPKALGtPVLTPPT 9606 15538382 t lperfetto Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment. SIGNOR-130381 0.596 PRKACA protein P17612 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Thr686 QQKIRKYtMRRLLQE 9606 18799465 t lperfetto Pka directly phosphorylated erbb2 on thr-686, a highly conserved intracellular regulatory site that was required for the pka-mediated synergistic enhancement of neuregulin-induced erbb2-erbb3 activation and proliferation in scs. SIGNOR-181191 0.379 AKT1 protein P31749 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Ser196 KLRRRFSsLHFMVEV -1 9812896 t lperfetto Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity SIGNOR-252581 0.767 CID 132010322 chemical CID:132010322 PUBCHEM BRD4 protein O60885 UNIPROT down-regulates activity chemical inhibition 9606 31969702 t Monia ABBV-744 potently inhibited the BD2 domain of BET family proteins with more than 290× selectivity relative to the BD1 domains of BRD2, BRD3 and BRD4 SIGNOR-261102 0.8 PTK7 protein Q13308 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 23151663 t gcesareni Ptk7 has been strongly implicated in pcp and, like many pcp activators, is a negative regulator of beta-catenin-dependent wnt. SIGNOR-199536 0.412 ELOVL6 protein Q9H5J4 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267894 0.8 GRB2 protein P62993 UNIPROT INPP5D protein Q92835 UNIPROT up-regulates activity binding 9606 BTO:0000776 32323266 t scontino An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling. SIGNOR-268449 0.565 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269344 0.719 ANXA1 protein P04083 UNIPROT FPR3 protein P25089 UNIPROT up-regulates activity binding 9606 BTO:0000007 15187149 t We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2. SIGNOR-259438 0.603 XXYLT1 protein Q8NBI6 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 22117070 t Xylosylation in ER membrane gcesareni Xxylt1 acts on the xyl1,3glc-o-linked glycan of notch egf domains. SIGNOR-177745 0.318 DMXL2 protein Q8TDJ6 UNIPROT RAB3GAP1 protein Q15042 UNIPROT up-regulates quantity binding 10116 BTO:0000142 11809763 t miannu We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles. SIGNOR-265582 0.555 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation Tyr255 EEEGAPDyENLQELN 9606 11368773 t lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. SIGNOR-247034 0.761 CBS protein P35520 UNIPROT L-cystathionine dizwitterion smallmolecule CHEBI:58161 ChEBI up-regulates quantity chemical modification 9606 23981774 t lperfetto Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. SIGNOR-275830 0.8 FYN protein P06241 UNIPROT TGFB1I1 protein O43294 UNIPROT up-regulates activity phosphorylation Tyr60 SGDKDHLySTVCKPR 9534 10838081 t miannu Hic-5 is a CAKbeta-binding protein localized at focal adhesions. Here we show that overexpression of CAKbeta or Fyn, but not FAK, enhanced the tyrosine phosphorylation of coexpressed Hic-5 in COS-7 cells. The Y60F mutant of Hic-5 was not phosphorylated, and Hic-5 phosphorylated on tyrosine 60 was bound specifically to the SH2 domain of Csk. Specific phosphorylation of Hic-5 by CAKbeta and Fyn may activate a signaling pathway mediated by Hic-5. SIGNOR-262875 0.347 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000938 16923168 t The effect has been demonstrated using P10636-8 lperfetto Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation. SIGNOR-148970 0.462 SUN1 protein O94901 UNIPROT NUP153 protein P49790 UNIPROT up-regulates activity binding 9606 BTO:0000567 SIGNOR-C303 SIGNOR-C263 28831067 t lperfetto The NXF1:NXT1 complex and NUP153 interact with the amino terminus of SUN1 |In analogy to a proposal made by Chang et al.4, Nesprins could help anchoring SUN1 near the NPC to enable it to fulfill its task in mRNA export. SIGNOR-263294 0.441 CASP8 protein Q14790 UNIPROT BID protein P55957 UNIPROT up-regulates activity cleavage Asp60 GYDELQTdGNRSSHS 9606 BTO:0000093 9727492 t amattioni Caspase-8 cleaves bid at aspartic acid residue 60 (asp60) cleavage of bid by casp8 releases its potent proapoptotic activity SIGNOR-59655 0.875 sabcomeline chemical CHEBI:134846 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10116 9399977 t miannu SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes SIGNOR-258678 0.8 PTPN11 protein Q06124 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates dephosphorylation Tyr577 YMEDSTYyKASKGKL 9606 16920701 t gcesareni Dca concomitantly and significantly increased association of tyrosine phosphatase shp2 with fak. Incubation of immunoprecipitated fak, in vitro, with glutathione-s-transferase-shp2 fusion protein resulted in tyrosine dephosphorylation of fak in a concentration-dependent manner. SIGNOR-148926 0.72 KMT2D protein O14686 UNIPROT MLL2 complex complex SIGNOR-C88 SIGNOR form complex binding 9606 24680668 t miannu The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation. SIGNOR-204816 0.2 PD173955 chemical CHEBI:49791 ChEBI ABL1 protein P00519 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258263 0.8 TGFB1 protein P01137 UNIPROT ITGA3 protein P26006 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001596 1744142 f lperfetto TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way. SIGNOR-253353 0.358 HSPA8 protein P11142 UNIPROT Chaperone-mediated autophagy phenotype SIGNOR-PH118 SIGNOR up-regulates activity -1 2799391 f A 73-kilodalton (kD) intracellular protein was found to bind to peptide regions that target intracellular proteins for lysosomal degradation in response to serum withdrawal. This protein cross-reacted with a monoclonal antibody raised to a member of the 70-kD heat shock protein (hsp70) family, and sequences of two internal peptides of the 73-kD protein confirm that it is a member of this family. SIGNOR-259991 0.7 EGFR protein P00533 UNIPROT HGS protein O14964 UNIPROT up-regulates phosphorylation Tyr329 IDPELARyLNRNYWE 9606 12953068 t lperfetto We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation SIGNOR-86689 0.622 NOTCH3 protein Q9UM47 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 11404076 t gcesareni Both notch 1 and notch 3 ics displace the co-repressor smrt from the dna-binding protein rbp-j kappa on the hes promoter. The latter observation suggests that both notch 3 ic and notch 1 ic can access rbp-j kappa in vivo, and that the difference in activation capacity instead stems from structural differences in the two ics when positioned on rbp-j kappa. SIGNOR-86128 0.852 PTAFR protein P25105 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257262 0.2 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser34 SRSYVTTsTRTYSLG -1 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248880 0.288 MAPK14 protein Q16539 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation 9606 17003045 t gcesareni We show that siah2 is subject to phosphorylation by p38 mapk, which increases siah2-mediated degradation of phd3. SIGNOR-149890 0.2 LTB4R2 protein Q9NPC1 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256817 0.252 MAP4K1 protein Q92918 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 t done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  SIGNOR-273899 0.2 HSP90AB1 protein P08238 UNIPROT FLCN protein Q8NFG4 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 27353360 t miannu Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability. SIGNOR-261418 0.2 RPS6KA3 protein P51812 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-138475 0.2 CSNK2A2 protein P19784 UNIPROT RGS19 protein P49795 UNIPROT unknown phosphorylation Ser24 ADRPPSMsSHDTASP -1 10760275 t llicata Phosphorylation was Mn(2+)-dependent, using both purified CK2 and CCVs. Ser-24 was identified as one of the phosphorylation sites. Our results establish that GAIP is phosphorylated and that only the membrane pool is phosphorylated, suggesting that GAIP can be regulated by phosphorylation events taking place at the level of clathrin-coated pits and vesicles. SIGNOR-251033 0.334 GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268604 0.248 KDM5C protein P41229 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 31691806 f miannu The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. SIGNOR-264313 0.335 IL5RA protein Q01344 UNIPROT SOX4 protein Q06945 UNIPROT up-regulates activity binding 10090 BTO:0003104 11498591 t miannu Sox4 activation by IL-5R_ appears to be direct, with syntenin functioning as an adaptor molecule. Syntenin mediates IL-5–induced Sox4 activation. SIGNOR-223010 0.427 PIAS4 protein Q8N2W9 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Ser8 MWNSGFEsYGSSSYG 9606 20016603 t gcesareni Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair furthermore, phosphorylation of the 34 kda subunit of rpa on ser-4 and ser-8 (ps4/ps8) in response to ir or camptothecin treatment was diminished by pias4 depletion, while pias1 depletion impaired ir-induced but not camptothecin-induced rpa phosphorylation SIGNOR-162164 0.2 RAC1 protein P63000 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0003009; BTO:0000018 22549160 f irozzo The small GTPase Rac1 regulates many cellular processes, including cytoskeletal reorganization, cell migration, proliferation, and survival. We found that silencing of Rac1 expression decreases NSCLC migration and proliferation [.] SIGNOR-259088 0.7 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Thr409 GQGEKSAtPSRKILD 9606 15037602 t lperfetto Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis. The m-phase kinase cyclin b/cdk1 phosphorylates rangap1 efficiently in vitro, and t409 phosphorylation correlates with nuclear accumulation of cyclin b1 in vivo. SIGNOR-216789 0.447 ILK protein Q13418 UNIPROT PPP1R14C protein Q8TAE6 UNIPROT up-regulates activity phosphorylation Thr73 RHQQGKVtVKYDRKE 9606 12804574 t lperfetto Pka predominantly phosphorylated a site distinct from the inhibitory t73 in kepi. Integrin-linked kinase phosphorylated KEPI (T73) and this dramatically increased inhibition of PP1c SIGNOR-101835 0.527 VAV3 protein Q9UKW4 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260584 0.7 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser673 RVQSKIGsLDNITHV -1 10090741 t miannu We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs. SIGNOR-250175 0.44 GMIP protein Q9P107 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260507 0.491 ROS stimulus SIGNOR-ST2 SIGNOR Demyelination phenotype SIGNOR-PH155 SIGNOR up-regulates 9606 32454942 f miannu Next to their interaction with adaptive immune cells, activated microglia can secrete cytotoxic cytokines and oxidative products, such as ROS and NO radicals in MS lesions thereby promoting oxidative stress and contributing to myelin destruction SIGNOR-263828 0.7 KLF11 protein O14901 UNIPROT HBG1 protein P69891 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 10207080 f Regulation miannu Transfection of K562 cells with FKLF cDNA enhanced the expression of the endogenous epsilon- and gamma-globin genes, suggesting an in vivo role of FKLF in fetal and embryonic globin gene expression. SIGNOR-251828 0.2 PTEN protein P60484 UNIPROT NR5A1 protein Q13285 UNIPROT down-regulates activity dephosphorylation 9606 27838257 t miannu The fact that SF-1 and PIP3 is robustly dephosphorylated by PTEN, yet SF-1 and PIP2 is resistant to phosphorylation by p110 PI3-kinases, suggests that nuclear proteins like SF-1 can help decouple PTEN signaling in the nucleus from p110 signaling.|We also showed that PTEN can dephosphorylate the SF-1 and PIP3 product of the IPMK reaction, and that PTEN inhibits SF-1 transcriptional activity. SIGNOR-277117 0.259 PTEN protein P60484 UNIPROT PFKP protein Q01813 UNIPROT down-regulates activity dephosphorylation Ser386 AVRLRGRsFAGNLNT 9606 29038421 f miannu In addition, AKT phosphorylation and PFKP S386 phosphorylation and PFKP expression levels were inversely correlated with PTEN expression levels, suggesting that PTEN inhibits PFKP S386 phosphorylation and reduces PFKP stability through inhibition of AKT.|These results indicate that AKT activation resulted from PTEN loss or EGFR dependent PI3K activation induces PFKP upregulation. SIGNOR-277118 0.2 NEDD4L protein Q96PU5 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates ubiquitination 9606 19917253 t gcesareni Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation SIGNOR-161713 0.797 FOXO3 protein O43524 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress SIGNOR-217881 0.7 GRIA2 protein P42262 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates -1 32527803 f Luana AMPAR surface diffusion tunes short-term plasticity. | Accordingly, recent studies have suggested that about half of synaptic AMPARs are organized in nanoclusters that are aligned with presynaptic transmitter release sites, supporting the concept of functional nanocolumns to increase the fidelity of fast excitatory transmission. This peculiar organization might also support the proposal that we made 10 years ago that fast surface diffusion of AMPARs tunes frequency-dependent short-term plasticity (FD-STP) by allowing the fast replacement of desensitized receptors by naïve ones. SIGNOR-265796 0.7 CREB5 protein Q02930 UNIPROT RASGRP3 protein Q8IV61 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002815 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253808 0.2 Pr3-ANCA complex SIGNOR-C475 SIGNOR Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR up-regulates 9606 BTO:0000133 2161532 f lperfetto ANCA cause normal human neutrophils to undergo an oxidative burst and degranulate. Both ANCA phenotypes (i.e., cytoplasmic-pattern ANCA and myeloperoxidase-specific ANCA) induce neutrophil activation. SIGNOR-270584 0.7 sertindole chemical CHEBI:9122 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 9534 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258547 0.8 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194545 0.8 SRC protein P12931 UNIPROT DAPK1 protein P53355 UNIPROT down-regulates activity phosphorylation Tyr491 CAAWHGYySVAKALC 9606 BTO:0002181 17803936 t miannu  Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation.  SIGNOR-276073 0.276 FGF2 protein P09038 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates binding 9606 1385111 t gcesareni Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides. SIGNOR-18564 0.813 GABRB3 protein P28472 UNIPROT GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR form complex binding 9606 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263747 0.45 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione chemical CHEBI:92539 ChEBI ADRA1D protein P25100 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190642 0.8 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1696 SPSYSPTsPSYSPTS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248774 0.442 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1337 QVFYNSEyGELSEPS 9606 BTO:0000394 12881528 t lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. SIGNOR-104088 0.2 TG protein P01266 UNIPROT Thyroid_hormonogenesis phenotype SIGNOR-PH110 SIGNOR up-regulates 9606 BTO:0004710 30886364 f miannu In humans, the thyroid hormones T3 and T4 are synthesized in the thyroid gland in a process that crucially involves the iodoglycoprotein thyroglobulin. The overall structure of thyroglobulin is conserved in all vertebrates. Upon thyroglobulin delivery from thyrocytes to the follicular lumen of the thyroid gland via the secretory pathway, multiple tyrosine residues can become iodinated to form mono-iodotyrosine (MIT) and/or di-iodotyrosine (DIT); however, selective tyrosine residues lead to preferential formation of T4 and T3 at distinct sites. SIGNOR-259915 0.7 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates 10090 BTO:0002314 22045613 f gcesareni Notch signaling is active in quiescent SCs. SC-specific deletion of recombining binding protein-J (RBP-J), a nuclear factor required for Notch signaling, resulted in the depletion of the SC pool and muscles that lacked any ability to regenerate in response to injury. SIGNOR-244004 0.7 FBN1 protein P35555 UNIPROT MMP1 protein P03956 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16442122 f Regulation of expression miannu In this study we show that a fibrillin-1 fragment containing a EGFEPG sequence that conforms to a putative GxxPG elastin-binding protein (EBP) consensus sequence upregulates the expression and production of matrix metalloproteinase (MMP)-1 by up to ninefold in a cell culture system. Mutations in the gene for fibrillin-1 cause Marfan syndrome (MFS), a common hereditary disorder of connective tissue SIGNOR-251887 0.353 ATP(4-) smallmolecule CHEBI:30616 ChEBI P2RY11 protein Q96G91 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257559 0.8 PTPRJ protein Q12913 UNIPROT CBL protein P22681 UNIPROT down-regulates activity 9606 19836242 f Because c-CBL’s activation is achieved via tyrosine phosphorylation, we tested the effect of DEP-1 on modification of a major site of phosphorylation, namely tyro- sine 731. Upon DEP-1 overexpression, c-CBL displayed reduced phosphorylation on this site compared to control cells (Figure 7B). This result offers a mechanism by which DEP-1 affects EGFR trafficking: by dephosphorylating EGFR, and possibly also SRC family kinases involved in phosphoryla- tion of c-CBL [31, 32], DEP-1 reduces activation of c-CBL and its recruitment to the activated EGFR, hence inhibiting subsequent receptor internalization and degradation. SIGNOR-248839 0.329 PTGER4 protein P35408 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256760 0.469 MYOD1 protein P15172 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001103 16275751 f andrea cerquone perpetuini Together, these results support the notion that Myf5 functions toward myoblast proliferation, whereas MyoD prepares myoblasts for efficient differentiation. SIGNOR-255417 0.7 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT unknown phosphorylation Tyr751 SKDESVDyVPMLDMK 9606 2550144 t llicata We have identified two platelet-derived growth factor (pdgf)-dependent autophosphorylation sites in the beta subunit of the human pdgf receptor (pdgf-r). The major site of phosphorylation (tyr-857) corresponds to the major autophosphorylation site in many other tyrosine kinases. Tyr-751, which lies within the kinase insert region, is a second in vivo site and the major in vitro site. SIGNOR-22993 0.2 SLC27A1 protein Q6PCB7 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264463 0.7 EXOC1 protein Q9NV70 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270784 0.886 TGFB1 protein P01137 UNIPROT COL1A1 protein P02452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000988 35816922 t miannu COL1A1 expression is regulated by upstream genes and the binding of regulatory elements at multiple binding sites upstream of its promoter. During cancer progression, CAFs reorganize and cross-link COL1A1, which accumulates and stiffens in the tumor stroma [12], [18]. This process may involve fibrogenic factors, especially transforming growth factor-beta (TGF-β1). Indeed, a TGF-β1 response sequence was identified 174 nucleotides upstream of the COL1A1 transcription start site, and was shown to up-regulate COL1A1 promoter activity SIGNOR-277678 0.498 TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0000785 15084608 t lperfetto We report here that one important mechanism of nik regulation is through its dynamic interaction with the tumor necrosis factor receptor-associated factor 3 (traf3). Traf3 physically associates with nik via a specific sequence motif located in the n-terminal region of nik; this molecular interaction appears to target nik for degradation by the proteasome. SIGNOR-124233 0.569 SMDT1 protein Q9H4I9 UNIPROT MCU_MICU1_variant complex SIGNOR-C500 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270866 0.621 MAF protein O75444 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20067416 f miannu MMP-13 gene expression is regulated primarily at the transcriptional level. In this study, we investigated the role of c-maf in regulating MMP-13 transcription. Using transient transfection system with an c-maf construct, and MMP-13 promoter-luciferase constructs with specific mutations in transcription factor binding sites, we found that c-maf can significantly enhance MMP-13 promoter activity via the AP-1 sitecv SIGNOR-254560 0.254 BRK1 protein Q8WUW1 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR down-regulates 9606 23939472 f lperfetto We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation.  SIGNOR-261491 0.7 PCSK7 protein Q16549 UNIPROT DDB2 protein Q92466 UNIPROT down-regulates 9606 18806262 f The phosphorylation of DDB2 by p38 promotes its ubiquitination gcesareni The data suggest that p38 mapk is involved in serine phosphorylation of ddb2, which may influence its ubiquitylation following irradiation. SIGNOR-181278 0.2 PAK1 protein Q13153 UNIPROT BCL6 protein P41182 UNIPROT down-regulates activity phosphorylation 9606 22723377 t miannu The transcriptional repressor B-cell lymphoma (BCL)-6 downregulates genes involved in cell-cycle progression and becomes inactivated following phosphorylation by the Rac1 GTPase-activated protein kinase PAK1. SIGNOR-253930 0.2 FOXO3 protein O43524 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates quantity transcriptional regulation 22848740 t We show that FOXO3 binds and activates its own promoter via a positive autoregulatory feedback loop SIGNOR-255757 0.2 TRPV1 protein Q8NER1 UNIPROT PRKCB protein P05771 UNIPROT up-regulates activity binding 9606 BTO:0000007 24920628 t miannu  In the present study, we report that the sensitivity of TRPV1 channels is determined by PKCβII. TRPV1 binds directly to PKCβII and subsequently activates PKCβII. Activated PKCβII then enhances the responsiveness of TRPV1 to thermal and chemical stimuli through a phosphorylation-dependent mechanism. SIGNOR-276639 0.2 NFE2L2 protein Q16236 UNIPROT PGD protein P52209 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 f miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). SIGNOR-267355 0.285 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT up-regulates activity phosphorylation Tyr1102 MLEERKTyVNTTLYE 9606 BTO:0001176 20973951 t miannu This phosphorylation requires a kinase competent Tie2 as well as intact tyrosines 1100 and 1106 (Y1100 and Y1106) on the receptor. This suggests that Y1100 and Y1106 on Tie2 play a role in Grb14 mediated signal transduction downstream of this receptor. SIGNOR-259834 0.2 TNF protein P01375 UNIPROT DIO1 protein P49895 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 9397972 f scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. SIGNOR-267485 0.2 PIN1 protein Q13526 UNIPROT KLF10 protein Q13118 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000018 23994618 t miannu RAF1 phosphorylates the Thr93 site of KLF10 in vivo. Since the phosphorylation of Thr93 enables KLF10 and PIN1 to bind, it seems likely that RAF-1 will have an effect on KLF10 stability that is similar to that of PIN1.PIN1 facilitates KLF10 protein degradation. ( SIGNOR-276503 0.2 CHEK1 protein O14757 UNIPROT ASF1A protein Q9Y294 UNIPROT up-regulates activity phosphorylation Ser166 KLEDAESsNPNLQSL 9606 BTO:0002181 33503415 t miannu Chk1 activated by ataxia telangiectasia mutated (ATM) kinase on DNA breaks in G1 promotes NHEJ through direct phosphorylation of ASF1A at Ser-166. ASF1A phosphorylated at Ser-166 interacts with the repair protein MDC1 and thus enhances MDC1's interaction with ATM and the stable localization of ATM at DNA breaks. SIGNOR-277620 0.424 XRCC5 protein P13010 UNIPROT DNA-PK complex SIGNOR-C107 SIGNOR form complex binding 9606 BTO:0002419 17308091 t miannu complexes formed by interactions between Ku70, Ku80, and DNA-PKcs were well-established SIGNOR-226019 0.957 HTR7 protein P34969 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257256 0.301 DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 20626350 t lperfetto The activity of MAPKs can be also regulated by a family of DUSPs (dual-specificity phosphatases)/MKPs (MAPK phosphatases), which dephosphorylate both phosphotyrosine and phosphothreonine residues MKPs 1, 4, 5 and 7 can dephosphorylate p38_ and p38_ in addition to JNK MAPKs. Importantly, some MKPs are transcriptionally up-regulated by stimuli that activate MAPK signalling, and are thought to play an important role limiting the extent of MAPK activation SIGNOR-166571 0.798 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr455 ALGTPVLtPPTEAAS 9606 BTO:0000848 BTO:0001253 20959475 t lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). SIGNOR-252956 0.703 XRCC6 protein P12956 UNIPROT DNA-PK complex SIGNOR-C107 SIGNOR form complex binding 9606 BTO:0002419 17308091 t miannu complexes formed by interactions between Ku70, Ku80, and DNA-PKcs were well-established SIGNOR-226023 0.963 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity phosphorylation Thr481 HVQRVLRtPGRQSPG 9606 10581160 t Axin residues T609 and S614 are physiological GSK3beta targets. Axin phosphorylation in the regulation of b-catenin stability. When active (left), GSK3b phosphorylates Axin as well as APC and b-catenin. The phosphorylated form of Axin binds strongly to b-catenin and promotes the phosphorylation of b-catenin by GSK3b, leading to strong interaction with b-TrCP SIGNOR-251222 0.918 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Ile536 RSLDRRGiQRAADIE -1 9242537 t lperfetto Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.Va treated with HNE indicated cleavage at Ala341, Ile508, and Thr1767 under conditions, which the cofactor became inactivated, as measured by prothrombinase activity. SIGNOR-263636 0.373 APC-c complex SIGNOR-C150 SIGNOR ANLN protein Q9NQW6 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 16040610 t miannu  Ubiquitination of anillin required a destruction-box and was mediated by Cdh1, an activator of APC/C. Overexpression of Cdh1 reduced the levels of anillin, whereas inactivation of APC/C(Cdh1) increased the half-life of anillin. SIGNOR-272655 0.266 GDF6 protein Q6KF10 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 SIGNOR-C29 16049014 t gcesareni We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10. Thus, the present approach provides a genomic paradigm for matching paralogous polypeptide ligands with a limited number of evolutionarily related receptors capable of activating specific downstream smad proteins. SIGNOR-139093 0.587 APAF1 protein O14727 UNIPROT Apoptosome complex SIGNOR-C230 SIGNOR form complex binding -1 10206961 t lperfetto  APAF-1 binds and hydrolyzes ATP or dATP to ADP or dADP, respectively. The hydrolysis of ATP/dATP and the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9.  SIGNOR-256431 0.869 FGR protein P09769 UNIPROT SDHA protein P31040 UNIPROT unknown phosphorylation Tyr543 CGKISKLyGDLKHLK -1 17997986 t miannu Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are "in vitro" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations. SIGNOR-262872 0.2 JAG1 protein P78504 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 10551863 t Binding Calcium-dependent. gcesareni Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch. SIGNOR-72112 0.624 SPI1 protein P17947 UNIPROT CD14 protein P08571 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12393465 f apalma In patients with t(8;21), expression of the cell surface markers CD11b, CD14, and CD64 was less in comparison to patients without t(8;21) (Figure 5B). CD14 and CD64 promoters have putative PU.1 binding sites but not AML1-, C/EBPα-, or MEF-binding sites suggesting that down-regulation of the function of PU.1 by AML1-ETO could possibly be an important step in progression toward leukemia. SIGNOR-255696 0.404 AKT1 protein P31749 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 12535517 t gcesareni One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73. SIGNOR-252593 0.612 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000763;BTO:0000149 10197981 t lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-244727 0.2 PPP2CA protein P67775 UNIPROT TFCP2 protein Q12800 UNIPROT up-regulates dephosphorylation Ser291 TYVNNSPsPGFNSSH 9606 20682773 t lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. This predominant cis conformation would also limit dephosphorylation of ser-291 and ser-309 by phosphatases such as pp2a SIGNOR-167385 0.2 FGR protein P09769 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). SIGNOR-276188 0.2 ITCH protein Q96J02 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates ubiquitination 9606 15350225 t gcesareni Itch promotes ubiquitination of smad2 and augments smad2 phosphorylation that requires an intact ligase activity of itch. Moreover, itch facilitates complex formation between tgf-beta receptor and smad2 and enhances tgf-beta-induced transcription. SIGNOR-128647 0.464 Laminin-1 complex SIGNOR-C183 SIGNOR A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 9361014 t lperfetto Using integrin-specific antibodies, recognition sites for the alpha1beta1 and alpha2beta1 integrins were identified in the short arms of both laminin alpha1- and alpha2-chain isoforms. Comparisons with a beta-alpha chimeric short arm protein possessing beta1-chain domain VI further localized these activities to alpha-chain domain VI. SIGNOR-253255 0.527 RNA helicases DDX5/DDX17 complex SIGNOR-C34 SIGNOR NFAT5 protein O94916 UNIPROT up-regulates activity binding 9606 BTO:0000815 22266867 t done miannu In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration.  SIGNOR-274112 0.36 PRKAA1 protein Q13131 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser214 GGKERPGsKEEVDED -1 10090741 t miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. SIGNOR-275439 0.2 SYNE4 protein Q8N205 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 t lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. SIGNOR-263288 0.453 IL19 protein Q9UHD0 UNIPROT IL20RA protein Q9UHF4 UNIPROT up-regulates binding 9606 BTO:0000848 11564763 t gcesareni Il-19 signals only through the type i il-20r complex. SIGNOR-110671 0.735 MRPL16 protein Q9NX20 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262377 0.721 NOTCH1 protein P46531 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 19165418 t gcesareni The intracellular part of the notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor rbp-j. SIGNOR-183510 0.949 PRKCA protein P17252 UNIPROT PLEK protein P08567 UNIPROT up-regulates phosphorylation Ser117 ARKSTRRsIRLPETI 9606 8615792 t gcesareni To determine the role of pkc-dependent phosphorylation in pleckstrin function, we mapped the phosphorylation sites in vivo of wild-type and site-directed mutants of pleckstrin expressed in cos cells. Phosphorylation was found to occur almost exclusively on ser-113 and ser-117. Replacing all these sites with glycine decreased phosphorylation by > 90% and reduced pleckstrin's ability to inhibit phosphoinositide hydrolysis by as much as 80%. SIGNOR-40048 0.284 RAD23B protein P54727 UNIPROT RPA1 protein P27694 UNIPROT up-regulates activity binding 24086043 t lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275698 0.557 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr199 VKKSIRDtPAKNAQK 11278991 t llicata Here, we identified that threonine 199 (Thr(199)) of NPM/B23 is the major phosphorylation target site of CDK2-cyclin E in vitro, and the same site is phosphorylated in vivo.|NPM/B23 binds specifically to unduplicated centrosomes and loses its centrosome binding activity when phosphorylated by CDK2-cyclin E SIGNOR-250744 0.414 CNTN6 protein Q9UQ52 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 BTO:0000938 15082708 t gcesareni Here, we establish that nb-3, a member of the f3/contactin family, acts as a novel notch ligand to participate in oligodendrocyte generation. Nb-3 triggers nuclear translocation of the notch intracellular domain and promotes oligodendrogliogenesis from progenitor cells and differentiation of oligodendrocyte precursor cells via deltex1. SIGNOR-124151 0.571 PH 797804 chemical CHEBI:82715 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206079 0.8 dabigatran chemical CHEBI:70752 ChEBI F2 protein P00734 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190314 0.8 CNTF protein P26441 UNIPROT CNTFR protein P26992 UNIPROT up-regulates binding 9606 10966616 t gcesareni Ciliary neurotrophic factor (cntf) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, cntfr, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (lifr) SIGNOR-81379 0.784 XIAP protein P98170 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination -1 15749826 t lperfetto Xiap functions as ubiquitin ligase toward smac to inhibit apoptosis. SIGNOR-134504 0.912 AATK protein Q6ZMQ8 UNIPROT CDK5R1 protein Q15078 UNIPROT up-regulates binding 9606 BTO:0000007 BTO:0000142 14521924 t gcesareni Apoptosis-associated tyrosine kinase is a cdk5 activator p35 binding protein. SIGNOR-118403 0.454 GATA2 protein P23769 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity transcriptional regulation 9606 19772889 t These findings indicate that fatty marrow replacement in AA patients can be explained by downregulation of GATA-2 and overexpression of PPARgamma in MSCs. Decreased expression of GATA-2 might be responsible for the pathogenesis and development of the clinical features of the disease. SIGNOR-259949 0.377 SAR1A protein Q9NR31 UNIPROT SEC23B protein Q15437 UNIPROT up-regulates quantity binding SIGNOR-C370 30605680 t lperfetto Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. SIGNOR-265298 0.684 Selinexor chemical CID:71481097 PUBCHEM XPO1 protein O14980 UNIPROT down-regulates activity chemical inhibition 9606 30510142 t miannu Selinexor (KPT-330) is a first-in-class selective inhibitor of nuclear export (C17H11F6N7O; see ref. 4; for its chemical structure). The drug binds and inhibits exportin XPO-1 that mediates nuclear export of proteins and mRNAs. SIGNOR-262537 0.8 ER stress stimulus SIGNOR-ST9 SIGNOR BID protein P55957 UNIPROT up-regulates 9606 22492984 f gcesareni Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins SIGNOR-196944 0.7 LRRK2 protein Q5S007 UNIPROT RAB5B protein P61020 UNIPROT up-regulates activity phosphorylation Thr6 tARPNGQP 9606 BTO:0000567 25605758 t miannu  Using recombinant proteins, we show here that LRRK2 phosphorylates Rab5b at its Thr6 residue in in vitro kinase assays with mass spectrophotometry analysis. Phosphorylation of Rab5b by LRRK2 on the threonine residue was confirmed by western analysis using cells stably expressing LRRK2 G2019S. The phosphomimetic T6D mutant exhibited stronger GTPase activity than that of the wild-type Rab5b. In addition, phosphorylation of Rab5b by LRRK2 also exhibited GTPase activity stronger than that of the unphosphorylated Rab5b protein. SIGNOR-276873 0.617 FGF12 protein P61328 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253440 0.306 JNK proteinfamily SIGNOR-PF15 SIGNOR SFN protein P31947 UNIPROT down-regulates phosphorylation 9606 15071501 t Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons gcesareni Here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein.Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-191 SIGNOR-269979 0.2 PPP1R9B protein Q96SB3 UNIPROT SPATA13 protein Q96N96 UNIPROT up-regulates activity binding 9606 BTO:0000007 19151759 t miannu Here we show that Asef2, but not Asef, interacts with Neurabin2/Spinophilin, a scaffold protein that binds to Filamentous actin (F-actin). Neurabin2 is required for Asef2-induced filopodia formation. RNA interference experiments showed that Asef2, Neurabin2 and APC are involved in HGF-induced cell migration. Furthermore, knockdown of Neurabin2 resulted in the suppression of Asef2-induced filopodia formation. SIGNOR-269174 0.494 SIK1 protein P57059 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates activity phosphorylation Ser70 RSSHYGGsLPNVNQI 9606 BTO:0000567 16306228 t lperfetto We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression SIGNOR-249169 0.63 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Tyr443 REHPYGRy 9606 BTO:0000567 16179349 t lperfetto We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal. SIGNOR-249292 0.738 UBE2D1 protein P51668 UNIPROT TRIM65 protein Q6PJ69 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000567 24778252 t miannu Ubiquitination assays demonstrate that TRIM65 is an ubiquitin E3 ligase for TNRC6 proteins. The combination of overexpression and knockdown studies establishes that TRIM65 relieves miRNA-driven suppression of mRNA expression through ubiquitination and subsequent degradation of TNRC6. TRIM65 regulates ubiquitination and stability of TNRC6. (A) In vitro ubiquitination of TNRC6A by TRIM65 plus E1, E2 (UBCH5A, also known as UBE2D1), ATP, and HA-Ub. GST-tagged TRIM65 and mutant TRIM65 were purified from bacteria. TRIM65 regulates ubiquitination and stability of TNRC6. (A) In vitro ubiquitination of TNRC6A by TRIM65 plus E1, E2 (UBCH5A, also known as UBE2D1), ATP, and HA-Ub. GST-tagged TRIM65 and mutant TRIM65 were purified from bacteria. SIGNOR-272175 0.303 CDC42 protein P60953 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity binding 10090 BTO:0000142 8107774 t gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. SIGNOR-248253 0.881 MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 21460634 t lperfetto mTORC1, which is often referred to as the gatekeeper to autophagy, is a key regulator of the Ulk1-Atg13-FIP200 kinase complex.11,14,25 Under nutrient-rich conditions, active mTORC1 associates with and inactivates the Ulk1-Atg13-FIP200 complex by phosphorylating Ulk1 and Atg13. SIGNOR-183903 0.844 CAMK2D protein Q13557 UNIPROT TPD52 protein P55327 UNIPROT unknown phosphorylation Ser176 KNSPTFKsFEEKVEN 9606 20946871 t gcesareni Here we demonstrate, using site-specific mutations, that ca(2+)-sensitive phosphorylation at serine 136 modulates the accumulation of d52 at the plasma membrane within 2 min of cell stimulation SIGNOR-168550 0.2 ME1 protein P48163 UNIPROT (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI down-regulates quantity chemical modification 9606 33064660 t miannu Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. SIGNOR-267717 0.8 ABL1 protein P00519 UNIPROT NCK1 protein P16333 UNIPROT up-regulates phosphorylation Tyr105 VDPGERLyDLNMPAY 9606 22327338 t lperfetto Activated c-abl reduces the amplitude of mitogen-activated protein kinases (erk1/2, jnks and p38) activation in a dose-dependent manner by a negative feedback mechanism. By analysis of the adaptor proteins nck1 and grb2 mutants we further show that the negative loop on p38 is mediated by c-abl phosphorylation at tyrosine 105 of the adaptor protein nck1 SIGNOR-196043 0.409 SRC protein P12931 UNIPROT HNF4A protein P41235 UNIPROT down-regulates phosphorylation Tyr286 LQIDDNEyAYLKAII 9606 22308320 t lperfetto Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function. SIGNOR-195896 0.373 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 21035469 t gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-169154 0.579 PTK2 protein Q05397 UNIPROT ACTN4 protein O43707 UNIPROT up-regulates phosphorylation Tyr265 MTYVSSFyHAFSGAQ 9606 23454549 t lperfetto Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin SIGNOR-192191 0.54 SCF-FBW7 complex SIGNOR-C135 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity ubiquitination 9606 20852628 t gcesareni We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it. SIGNOR-243757 0.582 MAPK3 protein P27361 UNIPROT CIITA protein P33076 UNIPROT down-regulates phosphorylation Ser288 PDRPGSTsPFAPSAT 9606 18245089 t gcesareni In this study we show that the extracellular signal-regulated kinases 1 and 2 (erk1/2) interact directly with ciita, targeting serine residues in the amino terminus of the protein, including serine 288. These data suggest a model whereby erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation. SIGNOR-160617 0.348 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192607 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 10567369 t lperfetto An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2 SIGNOR-244858 0.748 BABAM2 protein Q9NXR7 UNIPROT BRCA1-A complex complex SIGNOR-C296 SIGNOR form complex binding 9606 BTO:0000007 20656690 t lperfetto We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1.  SIGNOR-263212 0.2 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser362 TLKNKTEsSLLAKLE -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276201 0.2 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser54 RVKALPLsPRKRLGD 9606 SIGNOR-C83 10339564 t lperfetto Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction. SIGNOR-67544 0.94 DCC protein P43146 UNIPROT MYO10 protein Q9HD67 UNIPROT up-regulates activity binding 10090 BTO:0000938 17237772 t miannu Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin. SIGNOR-268281 0.673 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 18593525 t gcesareni The hrh1 predominantly couples to g?q/11 proteins, leading to the activation of phospholipase c (plc) and subsequent release of the second messengers inositol trisphosphate (ip3) and diacylglycerol (dag) followed by the activation of pkc and the release of [ca2+]i. SIGNOR-179291 0.8 INS protein P01308 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 10090 12530968 f lperfetto The forkhead transcription factor foxo1 is regulated by insulin via akt-dependent phosphorylation and nuclear exclusion. SIGNOR-97392 0.744 CCR3 protein P51677 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 BTO:0000399 10706854 t Activation of ERK2 and p38 by eotaxin is mediated through CCR3. SIGNOR-256092 0.25 GALR2 protein O43603 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257296 0.252 LCK protein P06239 UNIPROT VAV1 protein P15498 UNIPROT unknown phosphorylation Tyr174 EAEGDEIyEDLMRSE -1 10669745 t Lck recognizes preferentially the tyrosine residue of Vav located at position 174 and, with significantly less affinity, those present at positions 142 and 160. It is now clear that this posttranslational modification will be involved in the activation of Vav, in the regulation of the strength of the signals emanating from this molecule, and also in the negative regulation of its function. SIGNOR-251391 0.775 FYN protein P06241 UNIPROT JUP protein P14923 UNIPROT down-regulates activity phosphorylation Tyr550 AAGTQQPyTDGVRME 10116 14517306 t Phosphorylation of plakoglobin by Fer and Fyn kinases decreases plakoglobin-desmoplakin interaction and increases plakoglobin-α-catenin association. Fyn mainly phosphorylated Tyr549 SIGNOR-251177 0.542 CSNK2A1 protein P68400 UNIPROT CAV2 protein P51636 UNIPROT up-regulates activity phosphorylation Ser36 DPEKFADsDQDRDPH 9606 BTO:0001130 12743374 t lperfetto We show that caveolin-2 is phosphorylated in vivo at two serine residues and that the phosphorylation of caveolin-2 is necessary for its actions as a positive regulator of caveolin-1 during organelle biogenesis in prostate cancer cells. Mutation of the primary phosphorylation sites on caveolin-2, serine 23 and 36, reduces the number of plasmalemma-attached caveolae SIGNOR-101110 0.326 citrate(3-) smallmolecule CHEBI:16947 ChEBI D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity precursor of 9606 24068518 t miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. SIGNOR-266241 0.8 LPCAT2 protein Q7L5N7 UNIPROT 1,2-diacyl-sn-glycero-3-phosphocholine chemical CHEBI:57643 ChEBI up-regulates quantity chemical modification 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272764 0.8 PSME1 protein Q06323 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR up-regulates activity binding 35932807 t lperfetto While PA28alpha beta is responsible for promoting peptidase activity of proteasome to facilitate MHC-I antigen processing, but unable to promote protein degradation, PA28gamma is well-known to not only promote peptidase activity but also proteolytic activity of proteasome. SIGNOR-275867 0.59 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1672 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273096 0.745 CCT4 protein P50991 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 t miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). SIGNOR-272866 0.739 PIN1 protein Q13526 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity isomerization 9606 BTO:0000599 23720771 t lperfetto In this study, the association of Par14 with insulin receptor substrate 1 (IRS-1) was demonstrated in HepG2 cells|Therefore, although Pin1 and Par14 associate with different portions of IRS-1, the prolyl cis/trans isomerization in multiple sites of IRS-1 by these isomerases appears to be critical for efficient insulin receptor-induced IRS-1 phosphorylation|Par14 overexpression in HepG2 markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events SIGNOR-265757 0.2 CEP290 protein O15078 UNIPROT RAB8A protein P61006 UNIPROT up-regulates activity binding 9606 18694559 t miannu CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110. CEP290 recruits Rab8a to centrosomes. Depletion of CEP290 results in a significant decrease of Rab8a at the centrosome and at the cilium, raising the possibility that CEP290 first recruits Rab8a through direct protein-protein interactions to the centrosome in cycling cells and later promotes ciliogenesis by allowing the entry of Rab8a into the cilium SIGNOR-252146 0.732 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1735 SPTSPSYsPTSPSYS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248824 0.849 CAD protein P27708 UNIPROT N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI down-regulates quantity chemical modification 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267427 0.8 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL1RN protein P18510 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000130;BTO:0000876 20032313 f miannu The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils. SIGNOR-254794 0.339 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI DIO proteinfamily SIGNOR-PF83 SIGNOR up-regulates activity chemical activation 9606 BTO:0004055 12746313 t inferred from family member scontino Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. SIGNOR-270246 0.8 NOXA1 protein Q86UR1 UNIPROT NOX1 protein Q9Y5S8 UNIPROT up-regulates activity binding 9606 BTO:0000007 20943948 t lperfetto Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation SIGNOR-264710 0.742 PP1 proteinfamily SIGNOR-PF54 SIGNOR NOS3 protein P29474 UNIPROT up-regulates activity dephosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001176 19036824 t lperfetto The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation SIGNOR-264668 0.2 TEX10 protein Q9NXF1 UNIPROT Rix1 complex complex SIGNOR-C373 SIGNOR form complex binding 9606 BTO:0000007 22190735 t miannu LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes. SIGNOR-265472 0.874 DOCK7 protein Q96N67 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 BTO:0000132 29187380 t lperfetto As a GEF, Dock7 exchanges GDP for GTP on Cdc42 and Rac1, causing their activation, followed by activation of downstream effectors, including the dephosphorylation (activation) of cofilin, a key regulator of actin turnover. SIGNOR-261887 0.526 STK3 protein Q13188 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates phosphorylation 9606 21808241 t inferred from 70% of family members gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. SIGNOR-269862 0.604 KDM3A protein Q9Y4C1 UNIPROT H3C15 protein Q71DI3 UNIPROT up-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 16603237 t miannu Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.  SIGNOR-276844 0.2 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates activity phosphorylation Thr210 FTLGSPLtSPGGSPG 9606 BTO:0001131 9630228 t lperfetto Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4. SIGNOR-109776 0.573 ZNRF3 protein Q9ULT6 UNIPROT LRP6 protein O75581 UNIPROT down-regulates ubiquitination 9606 23151663 t gcesareni Znrf3 is associated with the wnt receptor complex, and inhibits wnt by promoting the turnover of frizzled and lrp6. Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation, and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane. SIGNOR-199656 0.642 GTF2E1 protein P29083 UNIPROT TFIIE complex SIGNOR-C458 SIGNOR form complex binding 9606 31064989 t lperfetto The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur. SIGNOR-269360 0.94 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser394 TRQTPVDsPDDSTLS 9606 BTO:0000567 12586835 t gcesareni A physical interaction exists between cdc2 and s6k1, and this interaction is enhanced in mitotic cells. These results suggest that cdc2 provides a signal that triggers inactivation of s6k1 in mitosis, presumably serving to spare energy for costly mitotic processes at the expense of ribosomal protein synthesis. SIGNOR-98211 0.392 PRKCB protein P05771 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Thr19 GAVPSEAtKRDQNLK 9823 21864610 t miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. SIGNOR-262925 0.2 TLE5 protein Q08117 UNIPROT ZNF503 protein Q96F45 UNIPROT down-regulates activity binding 9534 19056829 t miannu these results show that Grg5 can specifically interact with the C-terminus of Nolz1. these data suggest that Nolz1 functions as a repressor molecule, and that Grg5 interactions with Nolz1 serve to modulate Nolz1 repressor function. Mechanistically, Grg5 is known to modulate Grg co-repressor activity, raising the possibility that classical Grg proteins mediate Nolz1-dependent transcriptional repression. GalNolz1ΔC22 showed increased repressor activity compared with GalNolz1, consistent with the ability of Grg5 to modulate Nolz1 repressor function. SIGNOR-261192 0.2 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR up-regulates activity chemical activation 9606 18790874 t brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-263787 0.8 MAPK1 protein P28482 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 15001544 t lperfetto Rin beta-cells exposed to high glucose exhibited increased c-jun n-terminal kinase (jnk) and erk1/2 activity, which was associated with increased irs-1 phosphorylation at serine (ser)(307) and ser(612), respectively, that inhibits coupling of irs-1 to the insulin receptor and is upstream of the inhibition of irs-1 tyrosine phosphorylation. SIGNOR-123173 0.667 MAPKAPK2 protein P49137 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates activity phosphorylation Ser58 VVGARRSsWRVVSSI 9606 BTO:0000007 12861023 t miannu We confirmed that MAPKAPK2 interacted with and phosphorylated 14-3-3zeta in vitro and in HEK293 cells. Mutation analysis showed that MAPKAPK2 phosphorylated 14-3-3zeta at Ser-58. S58D mutation significantly impaired both 14-3-3zeta dimerization and binding to Raf-1. SIGNOR-250151 0.609 RPL9 protein P32969 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262452 0.859 SIRT2 protein Q8IXJ6 UNIPROT PGAM2 protein P15259 UNIPROT up-regulates activity deacetylation Lys100 GGLTGLNkAETAAKH 9606 24786789 t miannu Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2. SIGNOR-266518 0.2 PGM2 protein Q96G03 UNIPROT alpha-D-ribose 1-phosphate(2-) smallmolecule CHEBI:57720 ChEBI down-regulates quantity chemical modification 9606 17804405 t miannu Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. The role of phosphopentomutase is to utilize ribose 1-phosphate and deoxyribose 1-phosphate, which are formed by purine nucleoside phosphorylase and uridine phosphorylase. Using catalytic efficiency as a criterion, PGM2 acted more than 10-fold better as a phosphopentomutase (both on deoxyribose 1-phosphate and on ribose 1-phosphate) than as a phosphoglucomutase. SIGNOR-267075 0.8 NFYA protein P23511 UNIPROT OGG1 protein O15527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14688259 f miannu these results demonstrate that MMS can up-regulate hOGG1 expression through the induction of the transcription factor, NF-YA, and increased transcription level of the hOGG1 gene correlates with an increase in enzyme activity providing functional protection from MMS. SIGNOR-254817 0.268 AURKA protein O14965 UNIPROT PIN1 protein Q13526 UNIPROT down-regulates activity phosphorylation Ser16 PGWEKRMsRSSGRVY 9606 23970419 t llicata Here, we found that aurora a can interact with and phosphorylate pin1 at ser16, which suppresses the g2/m function of pin1 by disrupting its binding ability and mitotic entry. SIGNOR-202487 0.256 PRKAA1 protein Q13131 UNIPROT TBC1D1 protein Q86TI0 UNIPROT down-regulates phosphorylation Ser237 RPMRKSFsQPGLRSL 9606 BTO:0001760 SIGNOR-C15 17995453 t gcesareni In rat l6 myotubes, endogenous tbc1d1 is strongly phosphorylated on ser237 and binds to 14-3-3s in response to the ampk activators aicar SIGNOR-159048 0.404 SP4 protein Q02446 UNIPROT MAOB protein P27338 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11259630 f miannu Cotransfection experiments show that Sp1 and its closely related family member Sp4 can trans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2. SIGNOR-253869 0.2 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR GDF3 protein Q9NR23 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269250 0.452 ERCC4 protein Q92889 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR form complex binding 9606 16338413 t miannu Human ercc1/xpf interaction domains reveals a complementary role for the two proteins in nucleotide excision repair. SIGNOR-142992 0.952 CSNK2A1 protein P68400 UNIPROT FANCD2 protein Q9BXW9 UNIPROT down-regulates activity phosphorylation Ser891 TLSEEKNsECDPTPS 9606 BTO:0000567 31167143 t miannu Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations.  SIGNOR-276728 0.2 INSR protein P06213 UNIPROT IRS2 protein Q9Y4H2 UNIPROT down-regulates activity phosphorylation Tyr632 YHPYPEDyGDIEIGS -1 9195949 t Tyr624 and Tyr628 are involved in the interaction between the IR and the KRLB domain of IRS-2, including tyrosine phosphorylation, and Tyr628 seems to be more important than Tyr624 in this process. the binding between the insulin receptor and the KRLB domain of IRS-2 results in tyrosine phosphorylation of the KRLB domain, and this leads to decreased binding of IRS-2 to the insulin receptor. SIGNOR-251319 0.748 SOD3 protein P08294 UNIPROT hydrogen peroxide smallmolecule CHEBI:16240 ChEBI up-regulates quantity chemical modification 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272273 0.8 DAMPS stimulus SIGNOR-ST18 SIGNOR AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates 9606 25720354 f scontino APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. SIGNOR-267856 0.7 CDK2 protein P24941 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 HPGFDAEsYTFTVPR 23972993 t For phosphorylated residues see Figure 7 lperfetto Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP SIGNOR-274049 0.44 PRKAA1 protein Q13131 UNIPROT ALDH2 protein P05091 UNIPROT up-regulates activity phosphorylation Thr356 GNPFDSKtEQGPQVD 10090 BTO:0000801 30375985 t lperfetto Further studies demonstrate that in the absence of LDLR, AMPK phosphorylates ALDH2 at threonine 356 and enables its nuclear translocation. Nuclear ALDH2 interacts with HDAC3 and represses transcription of a lysosomal proton pump protein ATP6V0E2, critical for maintaining lysosomal function, autophagy, and degradation of oxidized low-density lipid protein. SIGNOR-271863 0.2 PF-04691502 chemical CID:25033539 PUBCHEM AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck;inhibitor of phosphorylation of AktT308 and AktS473 gcesareni SIGNOR-205977 0.8 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR1 protein P30872 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257581 0.8 4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-[4-methyl-6-(4-morpholinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-pyridinone chemical CHEBI:91454 ChEBI INSR protein P06213 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190446 0.8 HIF1A protein Q16665 UNIPROT HIF-1 complex complex SIGNOR-C418 SIGNOR form complex binding 9606 27692180 t miannu HIF-1 consists of two subunits, HIF-1α and HIF-1β. While HIF-1β protein is constitutively expressed and present in excess, HIF-1α protein has a short half-life SIGNOR-267447 0.778 SEC23IP protein Q9Y6Y8 UNIPROT long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity chemical modification 9606 22922100 t miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. SIGNOR-269654 0.8 AURKA protein O14965 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates activity phosphorylation Ser115 ISSTPKTsEEAVDPL 9606 BTO:0002181 25009111 t miannu We report here that Astrin acts as a mitotic phosphoprotein, and Aurora-A phosphorylates Astrin at Ser(115). The phosphorylation-deficient mutant Astrin S115A abnormally activates spindle assembly checkpoint and delays mitosis progression, decreases spindle stability, and induces chromosome misalignment. Mechanistic analyses reveal that Astrin phosphorylation mimicking mutant S115D, instead of S115A, binds and induces ubiquitination and degradation of securin, which sequentially activates Separase, an enzyme required for the separation of sister chromatids.  SIGNOR-276648 0.524 BMP2 protein P12643 UNIPROT OMD protein Q99983 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16970923 f miannu Bmp-2 up regulates osad SIGNOR-149562 0.316 ANKRD28 protein O15084 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates activity binding -1 17023142 t lperfetto Phosphatase Interactor Targeting K protein (PITK) was previously identified as a novel PP1 targeting subunit implicated in modulating the phosphorylation of the transcriptional regulator heterogeneous nuclear ribonucleoprotein K (hnRNP K) SIGNOR-264794 0.455 PRKCZ protein Q05513 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Ser109 KSHSRQAsTDAGTAG 9606 BTO:0002181 25660024 t miannu  Yap and β-catenin are direct substrates of PKCζ.We show here that PKCζ suppresses intestinal stem cell function by promoting the downregulation of β-catenin and Yap through direct phosphorylation.Consistent with MS/MS analysis, mutation to alanine of these two sites completely abolished Yap phosphorylation by PKCζ. Interestingly, S109 and T110 sites were highly conserved among species (Figure S3B), which suggested an important role in Yap regulation. SIGNOR-276876 0.28 perfluorooctanoic acid chemical CHEBI:35549 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 10090 BTO:0000011 16731579 t miannu Taken together, these data show that of the NRs studied, PPARα is the most likely target of PFOA and PFOS, although PPARγ is also activated to some extent. SIGNOR-268788 0.8 GLI1/GLI2 complex SIGNOR-C450 SIGNOR CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000304 32766732 t GLI2 and GLI1 heterodimerize via the Zn-finger domain SimoneGraziosi GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. | RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells SIGNOR-269213 0.549 SLC11A1 protein P49279 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 11909746 f Functional studies in Nramp1 transfected macrophages have demonstrated that the Nramp1 protein plays a vital role in early macrophage activation [10,29,30]. Nramp1 is constitutively expressed in macrophage cell lines of the myeloid lineage (isolated peritoneal, splenic, and liver resident macrophages), and can be induced by treatment of macrophages with IFN-γ, or IFN-γ plus lipopolysaccharide (LPS) SIGNOR-254037 0.7 PC protein P11498 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 24363178 t miannu As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2) SIGNOR-266552 0.8 CSNK1A1 protein P48729 UNIPROT AGO2 protein Q9UKV8 UNIPROT down-regulates activity phosphorylation Ser824 LVDKEHDsAEGSHTS 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276511 0.377 PAX7/MLL1 complex complex SIGNOR-C90 SIGNOR MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 f miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-198638 0.506 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-268128 0.8 MAPKAPK5 protein Q8IW41 UNIPROT DNAJB1 protein P25685 UNIPROT up-regulates phosphorylation Ser151 VNFGRSRsAQEPARK 9606 24309468 t lperfetto Phosphorylation of heat shock protein 40 (hsp40/dnajb1) by mitogen-activated protein kinase-activated protein kinase 5 (mk5/prak). Mk5 phosphorylates hsp40/dnajb1 in vivo at ser-149 or/and ser-151 and ser-171 in the c-terminal domain of hsp40/dnajb1. Mk5 modestly stimulates the atp hydrolyse activity of hsp40/hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by hsp40/dnajb1. SIGNOR-203460 0.44 AKT1 protein P31749 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000007 9829964 t gcesareni When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner. SIGNOR-252549 0.76 NFIL3 protein Q16649 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0003104 10082541 f lperfetto NFIL3 inhibits apoptosis without affecting Bcl-xL expression. SIGNOR-256618 0.7 BTK protein Q06187 UNIPROT WAS protein P42768 UNIPROT unknown phosphorylation Tyr291 AETSKLIyDFIEDQG 9606 10068673 t llicata These results indicate that btk phosphorylates wasp on its tyrosine 291 SIGNOR-86004 0.732 GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263775 0.7 MAPKAPK2 protein P49137 UNIPROT LPCAT2 protein Q7L5N7 UNIPROT up-regulates activity phosphorylation Ser34 PMVPRQAsFFPPPVP 10090 BTO:0002601 20663880 t miannu Mass spectrometry and mutagenesis analyses identified Ser34 of LPCAT2 as the phosphorylation site to enhance the catalytic activities. The experiments using inhibitors and siRNA against MAPK cascades demonstrated that LPCAT2 phosphorylation through LPS-TLR4 signaling may directly depend on MAPK-activated protein kinase 2 (MAPKAP kinase 2 or MK2). SIGNOR-263077 0.2 FBXO22 protein Q8NEZ5 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000356 29945959 t lperfetto FBXO22 elicits its antimetastatic effects by targeting SNAIL, a master regulator of EMT and breast cancer metastasis, for ubiquitin-mediated proteasomal degradation in a glycogen synthase kinase 3β phosphorylation-dependent manner.  SIGNOR-273446 0.2 PRKCZ protein Q05513 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276016 0.2 SLC4A10 protein Q6U841 UNIPROT hydrogencarbonate smallmolecule CHEBI:17544 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 23056253 t miannu The sodium-driven chloride bicarbonate exchanger NCBE (Slc4a10), a member of the SLC4 family of bicarbonate transporters, uses the transmembrane gradient of sodium to drive cellular net uptake of bicarbonate and to extrude chloride, thereby modulating both intracellular pH (pH(i)) and chloride concentration ([Cl(-)](i)) in neurons.  SIGNOR-264687 0.8 CDH11 protein P55287 UNIPROT CTNNA1 protein P35221 UNIPROT unknown binding 9606 BTO:0000150 10029089 t miannu Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin SIGNOR-64859 0.467 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates phosphorylation Tyr686 IITEYCRyGDLVDYL 9606 BTO:0000150;BTO:0000527 19275932 t gcesareni These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis. SIGNOR-184552 0.507 ANGPT1 protein Q15389 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 f lperfetto Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. SIGNOR-241554 0.26 prostaglandin D2(1-) smallmolecule CHEBI:57406 ChEBI PTGDR protein Q13258 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257568 0.8 EPX protein P11678 UNIPROT EPX protein P11678 UNIPROT up-regulates activity post translational modification 9606 BTO:0000399 18694936 t miannu Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism. SIGNOR-261706 0.2 ARHGAP8 protein P85298 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260463 0.438 TPO protein P07202 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI up-regulates quantity chemical modification 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-267040 0.8 CHUK protein O15111 UNIPROT TAX1BP1 protein Q86VP1 UNIPROT up-regulates activity phosphorylation Ser593 NYKELKRsLENPAER 10090 BTO:0002572 21765415 t The effect has been demonstrated using Q86VP1-2 lperfetto Here we demonstrate that tax1bp1 was inducibly phosphorylated on ser593 and ser624 in response to proinflammatory stimuli. The kinase ikkalpha, But not ikkbeta, was required for phosphorylation of tax1bp1 and directly phosphorylated tax1bp1 in response to stimulation with tumor necrosis factor (tnf) or interleukin 1 (il-1). SIGNOR-175058 0.391 APOA1 protein P02647 UNIPROT LCAT protein P04180 UNIPROT up-regulates activity binding 9606 19860440 t miannu Activation of LCAT by apolipoprotein (apo) A-I on nascent (discoidal) high density lipoproteins (HDL) is essential for formation of mature (spheroidal) HDL during the antiatherogenic process of reverse cholesterol transport. After attachment of LCAT to discoidal HDL, the helix 5/5 domains in apoA-I form amphipathic presentation tunnels for migration of hydrophobic acyl chains and amphipathic UC from the bilayer to the phospholipase A2-like and esterification active sites of LCAT, respectively. SIGNOR-252103 0.773 JAG2 protein Q9Y219 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 10958687 t inferred from 70% of family members gcesareni Binding of delta1, jagged1, and jagged2 to notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of notch2 SIGNOR-269935 0.629 ITGB4 protein P16144 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 9428518 t gcesareni Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation. SIGNOR-54700 0.2 ROS stimulus SIGNOR-ST2 SIGNOR NFE2L2 protein Q16236 UNIPROT up-regulates 9606 BTO:0000018 22789539 f miannu Nrf2 is a master transcriptional activator of cytoprotective genes. It activates transcription in response to electrophiles and reactive oxygen species (ROS) (Itoh et al., 1997, Uruno and Motohashi, 2011). Under normal conditions, Nrf2 is constantly ubiquitinated by Keap1 and degraded by the proteasome. Exposure to the stimuli inactivates Keap1 and stabilizes Nrf2. SIGNOR-267353 0.7 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR DDX1 protein Q92499 UNIPROT up-regulates 10090 21703541 f miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. SIGNOR-260190 0.7 AKT2 protein P31751 UNIPROT RALGAPA2 protein Q2PPJ7 UNIPROT down-regulates activity phosphorylation Ser696 TTVGRSFsLSWRSHP 10090 SIGNOR-C469 21148297 t miannu RGC2 is an endogenous substrate for Akt2 downstream of PI 3-kinase SIGNOR-269798 0.43 CFD protein P00746 UNIPROT CFB protein P00751 UNIPROT up-regulates activity cleavage Arg259 GPGEQQKrKIVLDPS 9606 BTO:0000089 26489954 t lperfetto The resulting proconvertase C3bB is subsequently cleaved by factor D (FD), generating the AP C3 convertase C3bBb SIGNOR-263487 0.797 ARID3A protein Q99856 UNIPROT Immunoglobulin mu heavy chain protein P0DOX6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 16738337 t lperfetto In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels.| Figure ​3 shows that both anti-Bright and anti-TFII-I precipitated the bf150 Bright binding site from the B-cell line but not from a T-cell line that contains but does not express the V1 gene. SIGNOR-268532 0.2 Macrophage_activation phenotype SIGNOR-PH126 SIGNOR IL18 protein Q14116 UNIPROT up-regulates quantity 9606 BTO:0000801 10653850 f miannu IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR engagement. SIGNOR-260964 0.7 MBD2/NuRD complex complex SIGNOR-C337 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 27098840 f miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. SIGNOR-263859 0.7 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Ser693 PYKSEMDsMPYTQNF 9606 BTO:0000567 34198826 t miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. SIGNOR-276663 0.252 SALL4 protein Q9UJQ4 UNIPROT HOXA9 protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001883 24051379 f miannu In primary human AML cells, downregulation of SALL4 led to decreased HOXA9 expression and enhanced apoptosis. We found that SALL4 bound a specific region of the HOXA9 promoter in leukemic cells. SALL4 overexpression led to enhanced binding of histone activation markers at the HOXA9 promoter region, as well as increased HOXA9 expression in these cells. SIGNOR-255125 0.388 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 10913145 t gcesareni We find that, in vitro, pak1 phosphorylates op18/stathmin specifically at serine 16 and inactivates its catastrophe promoting activity in biochemical and time lapse microscopy microtubule assembly assays. SIGNOR-79955 0.382 PHF3 protein Q92576 UNIPROT POLR2A protein P24928 UNIPROT down-regulates activity binding 9606 BTO:0000007 phosphorylation:Ser1594 GAMSPSYsPTSPAYE 34667177 t miannu PHF3 interacts with RNA polymerase II through the SPOC domain. PHF3 negatively regulates mRNA levels. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. Our data suggest that PHF3 acts as a prominent effector of neuronal gene regulation by bridging transcription with mRNA decay. PHF3 SPOC preferentially binds RNA Pol II CTD phosphorylated on Serine-2 SIGNOR-266965 0.471 PI3K complex SIGNOR-C156 SIGNOR RAC1 protein P63000 UNIPROT up-regulates 9606 21779497 f gcesareni Pi3k can also activate rac, and this activation is involved in cytoskeleton reorganization. SIGNOR-252707 0.529 BRCC3 protein P46736 UNIPROT BRCA1-A complex complex SIGNOR-C296 SIGNOR form complex binding 9606 BTO:0000007 20656690 t lperfetto We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1.  SIGNOR-263213 0.926 CDK2 protein P24941 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates phosphorylation Thr90 CHLAWVNtPKKQGGL 9606 BTO:0000567 11986303 t lperfetto Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown). SIGNOR-87101 0.256 carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI up-regulates quantity precursor of 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267422 0.8 POLE protein Q07864 UNIPROT DNA polymerase epsilon complex SIGNOR-C377 SIGNOR form complex binding 9606 BTO:0000567 10801849 t lperfetto Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon. SIGNOR-265520 0.921 MAPK14 protein Q16539 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity phosphorylation Thr56 FSSQPGHtPHPAASR 9606 16714293 t gcesareni Bcl-2 phosphorylation by p38 mapkin this study, we identify, by using mass spectrometry techniques and specific anti-phosphopeptide antibodies, ser(87) and thr(56) as the bcl-2 residues phosphorylated by p38 mapk and show that phosphorylation of these residues is always associated with a decrease in the antiapoptotic potential of bcl-2 protein. SIGNOR-146786 0.34 PRKAA1 protein Q13131 UNIPROT TGFB1 protein P01137 UNIPROT down-regulates 9606 BTO:0000887 23324179 f gcesareni Amp-activated protein kinase inhibits tgf-__-, angiotensin ii-, aldosterone-, high glucose-, and albumin-induced epithelial-mesenchymal transition. SIGNOR-200404 0.2 ADRA2C protein P18825 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257094 0.413 NR0B2 protein Q15466 UNIPROT PCK2 protein Q16822 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17094771 f miannu SHP repressed C/EBPalpha (CCAAT/enhancer-binding protein alpha)-driven transcription of PEPCK through direct interaction with C/EBPalpha protein both in vitro and in vivo. The formation of an active transcriptional complex of C/EBPalpha and its binding to DNA was inhibited by SHP, resulting in the inhibition of PEPCK gene transcription. SIGNOR-254832 0.394 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr283 YQPYQSIyVGGMMEG 9606 BTO:0000007 8955135 t lperfetto In the present study, we demonstrate that bcr tyr-246 and at least one of the closely spaced tyrosine residues, tyr-279, tyr-283, and tyr- 289 (3y cluster), are phosphorylated by fes both in vitro and in 32p(i)- labeled cells. tyrosine phosphorylation of bcr by fes suppressed bcr serine/threonine kinase activity toward the 14-3-3 protein and bcr substrate, bap-1. SIGNOR-45343 0.375 Av/b2 integrin complex SIGNOR-C176 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257715 0.62 PRKCZ protein Q05513 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr375 GRGARGGtRGGRGRI 9606 BTO:0004974 14699138 t lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation SIGNOR-249257 0.296 EGFR protein P00533 UNIPROT KCNJ4 protein P48050 UNIPROT up-regulates activity phosphorylation Tyr234 YMTQEGEyLPLDQRD -1 21486282 t miannu These results demonstrate that the EGF receptor tyrosine kinase up-regulates the K(IR) 2.3 channel via phosphorylation of the Y234 residue of the WT protein.  SIGNOR-276322 0.2 HDAC2 protein Q92769 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263838 0.792 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CACNB1 protein Q02641 UNIPROT up-regulates activity phosphorylation Ser161 CEVGFIPsPVKLDSL 9534 BTO:0000298 16406008 t miannu Thus, Ser-447 on Ca(v)2.2 and Ser-161 and Ser-348 of Ca(v)beta1b appear to be both necessary and sufficient for ERK-dependent modulation of these channels. Together, our data strongly suggest that modulation of neuronal N-type VDCCs by ERK involves phosphorylation of Ca(v)2.2alpha1 and to a lesser extent possibly also Ca(v)beta subunits. On the basis of the evidence presented here, it is therefore suggested that ERK-dependent up-regulation of Cav2.2 channels is primarily mediated by phosphorylation of Ser-447 on the I–II loop of Cav2.2 and possibly also the two SP sites conserved on Cavβs. SIGNOR-262966 0.2 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206127 0.8 PRKAA1 protein Q13131 UNIPROT KPNA2 protein P52292 UNIPROT up-regulates phosphorylation Ser105 QAARKLLsREKQPPI 9606 SIGNOR-C15 15342649 t lperfetto Ampk phosphorylated importin alpha1 on ser(105). Accordingly, expression of importin alpha1 proteins bearing k22r or s105a mutations failed to mediate the nuclear import of hur in intact cells. Our results point to importin alpha1 as a critical downstream target of ampk and key mediator of ampk-triggered hur nuclear import. SIGNOR-128629 0.2 (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity precursor of 9606 32439610 t lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. SIGNOR-268225 0.8 LNX1 protein Q8TBB1 UNIPROT GRIN1 protein Q05586 UNIPROT down-regulates quantity by destabilization ubiquitination -1 22889411 t miannu We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo. SIGNOR-272901 0.292 PRKCA protein P17252 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates phosphorylation Ser48 RQGGRTSsQRQRDPE 9606 BTO:0001130 11980664 t llicata Phosphorylation of wild-type nkx3.1 decreased the apparent binding affinity of the protein for the consensus sequence by 3-fold relative to the nonphosphorylated protein (fig. 3) _ . SIGNOR-86723 0.2 PPM1G protein O15355 UNIPROT USP7 protein Q93009 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser18 KAGEQQLsEPEDMEM 22361354 t lperfetto We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. |After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. SIGNOR-276531 0.524 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1665 SPTSPSYsPTSPSYS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248783 0.442 PRKAA1 protein Q13131 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates activity phosphorylation Ser433 PEKELPVsPGHRKTP -1 31805502 t miannu MS-based analysis of immunoprecipitated Nrf2 revealed serine 374, 408 and 433 in human Nrf2 to be hyperphosphorylated as a function of activated AMPK. A direct phosphate-transfer by AMPK to those sites was indicated by in vitro kinase assays with recombinant proteins as well as interaction of AMPK and Nrf2 in cells, evident by co-immunoprecipitation. Mutation of serine 374, 408 and 433 to alanine did not markedly affect half-life, nuclear accumulation or induction of reporter gene expression upon Nrf2 activation with sulforaphane. However, some selected endogenous Nrf2 target genes responded with decreased induction when the identified phosphosites were mutated, whereas others remained unaffected. SIGNOR-277495 0.2 PDPK1 protein O15530 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0000298 10480933 t miannu 90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1. SIGNOR-252763 0.643 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Thr1047 SSSSELStPEKPPHQ 9606 BTO:0000680;BTO:0001573;BTO:0001286 SIGNOR-C17 14551205 t lperfetto Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex SIGNOR-118580 0.502 GRIN2A protein Q12879 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 20950656 t lperfetto In addition, neurons also possess unique systems for local Ca2+ signaling at synapses including; presynaptic voltage-gated Ca2+ channels coupled to the synaptic vesicle membrane fusion machinery [39]; postsynaptic excitatory glutamate receptor channels which flux either Na+ (AMPA receptors) or Ca2+ (NMDA receptors) [40] and [41]; and Ca2+-binding proteins SIGNOR-251578 0.8 RAF1 protein P04049 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates binding 9606 11427728 t gcesareni Raf-1 interacts with the proapoptotic, stress-activated protein kinase ask1 (apoptosis signal-regulating kinase 1) in vitro and in vivo. SIGNOR-109023 0.404 CD19 protein P15391 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 10090 10201980 t lperfetto Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase. SIGNOR-249608 0.568 GDP smallmolecule CHEBI:17552 ChEBI GNAS protein P63092 UNIPROT down-regulates chemical inhibition 9606 17095603 t gcesareni Galfa subunits cycle between inactive (gdp-bound) and active (gtp-bound) states, and the lifetime of the active state is limited by gtp hydrolysis. SIGNOR-150549 0.8 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu60 LERECMEeTCSYEEA -1 9538022 t lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). SIGNOR-263669 0.598 SH3RF1 protein Q7Z6J0 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 t gcesareni Taken together, these findings support a model in which apoptotic stimuli or posh overexpression induce direct association between posh and inactive mlks. SIGNOR-97006 0.516 DPP3 protein Q9NY33 UNIPROT Angiotensin-2 protein P01019-PRO_0000032458 UNIPROT down-regulates quantity by destabilization cleavage -1 34770898 t miannu Human dipeptidyl-peptidase III (hDPP III) is capable of specifically cleaving dipeptides from the N-terminal of small peptides with biological activity such as angiotensin II (Ang II, DRVYIHPF), and participates in blood pressure regulation, pain modulation, and the development of cancers in human biological activities. The binding of Ang II to hDPP III may lead to changes in the shape and size of subsite S1, an important catalytic site, so as to promote the decomposition of the substrate. SIGNOR-268463 0.2 AGRP protein O00253 UNIPROT MC2R protein Q01718 UNIPROT down-regulates activity binding 9606 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and α, β, and γ melanocyte–stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268696 0.452 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr502 TPGTGLGtSPALAGD -1 8349691 t llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. SIGNOR-250906 0.346 FLT3 protein P36888 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15574429 f Expression of FLT3/ITD induces down-regulation of SHP-1 expression and activity SIGNOR-261532 0.374 Kindlin proteinfamily SIGNOR-PF48 SIGNOR Av/b2 integrin complex SIGNOR-C176 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259027 0.366 PRKAA1 protein Q13131 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates activity phosphorylation Ser408 GDMVQPLsPSQGQST -1 31805502 t miannu MS-based analysis of immunoprecipitated Nrf2 revealed serine 374, 408 and 433 in human Nrf2 to be hyperphosphorylated as a function of activated AMPK. A direct phosphate-transfer by AMPK to those sites was indicated by in vitro kinase assays with recombinant proteins as well as interaction of AMPK and Nrf2 in cells, evident by co-immunoprecipitation. Mutation of serine 374, 408 and 433 to alanine did not markedly affect half-life, nuclear accumulation or induction of reporter gene expression upon Nrf2 activation with sulforaphane. However, some selected endogenous Nrf2 target genes responded with decreased induction when the identified phosphosites were mutated, whereas others remained unaffected. SIGNOR-277496 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249646 0.2 TAK-875 chemical CID:24857286 PUBCHEM FFAR1 protein O14842 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-207182 0.8 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Val72 GLTEYRLvSINKSSP -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. SIGNOR-263579 0.43 LRRK2 protein Q5S007 UNIPROT ARFGAP1 protein Q8N6T3 UNIPROT down-regulates phosphorylation 9606 22423108 t gcesareni Arfgap1 is an lrrk2 kinase substrate whose gap activity is inhibited by lrrk2. The phosphorylation of arfgap1 by lrrk2 was subjected to mass spectrometry to determine the sites of phosphorylation. There was 95.3% coverage and serines(s155, s246, s284) and threonine (t189, t216, t292) are phosphorylated by lrrk2. Mutational analysis of these serine and threonine amino acids to alanine reveals that no single amino acid is the predominant phospho-amino acid. SIGNOR-196732 0.597 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000165 10066785 t lperfetto Delta-induced Notch signaling mediated by RBP-J inhibits MyoD expression and myogenesis SIGNOR-219359 0.426 JDP2 protein Q8WYK2 UNIPROT ATF2 protein P15336 UNIPROT down-regulates activity binding 9606 18671972 t miannu JDP2 dimerizes with other AP-1 proteins such as activating transcription factor-2 (ATF2) and Jun to repress transcription from promoters that contain a cyclic AMP-responsive element (CRE). SIGNOR-226395 0.538 trichostatin A chemical CHEBI:46024 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258018 0.8 CBP/p300 complex SIGNOR-C6 SIGNOR DDX5 protein P17844 UNIPROT up-regulates binding 9606 12527917 t miannu Cbp/p300 interact with p68 rna helicase / the atpase activity of p68 is required for the specific transcriptional activation of cbp SIGNOR-97274 0.47 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270416 0.8 FOXO3 protein O43524 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 f lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-236551 0.423 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9606 19433246 t miannu Phthalates are true ligands of PPARs. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARgamma identified MEHP as a selective PPARgamma modulator, and thus a possible contributor to the obesity epidemic. SIGNOR-268747 0.8 CDK8 protein P49336 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser375 PVDEDRLsPLVAADS 9606 18794899 t lperfetto E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1. SIGNOR-181078 0.496 PTPN6 protein P29350 UNIPROT NTRK1 protein P04629 UNIPROT down-regulates activity dephosphorylation Tyr681 DIYSTDYyRVGGRTM 10116 phosphorylation: tyr496 HIIENPQyFSDACVH 14662744 t Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675. SIGNOR-248469 0.489 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser675 PVSGSPDsMNASRLS 9606 BTO:0000007 10195894 t Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. SIGNOR-251276 0.2 TRIP11 protein Q15643 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 9256431 t inferred from family member miannu Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity. SIGNOR-270295 0.431 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser43 FGYQRRAsDDGKLTD 9534 BTO:0004055 12801936 t miannu Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. Cyclic AMP (cAMP) blocks Raf-1 activation by stimulating its phosphorylation on serine 43 (Ser43), serine 233 (Ser233), and serine 259 (Ser259). SIGNOR-250039 0.482 TG101209 chemical CHEBI:90304 ChEBI RET protein P07949 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207269 0.8 7a protein P59635 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 BTO:0000007 16303160 f Luana Expression of SARS-CoV ORF7a block cell cycle arrest in G0/G1 SIGNOR-260207 0.7 CSNK2A1 protein P68400 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser295 LSDTPYDsSASYEKE 9606 21750978 t miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo SIGNOR-174828 0.294 CYSLTR1 protein Q9Y271 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256740 0.2 SMAD7 protein O15105 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity relocalization 9606 21791611 t lperfetto One of the major mechanisms underlying the inhibitory effect of Smad7 on TGF-_ signaling operates through accelerating T_RI turnover by recruiting ubiquitin E3 ligases such as Smurf1 and Smurf2 SIGNOR-227556 0.865 HTR6 protein P50406 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257340 0.351 STAT1 protein P42224 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR form complex binding -1 8943351 t 2 miannu The first STAT-containing transcription factor to be studied, the alpha-interferon-induced ISGF3, is composed of a Stat1:2 heterodimer and a weak DNA-binding protein, p48. The p48 and Stat1:2 heterodimer do not associate stably in the absence of DNA, but we show that amino acids approximately 150 to 250 of Stat1 and a COOH-terminal portion of p48 exhibit physical interaction, implying contact that stabilizes ISGF3 SIGNOR-240606 0.673 MAPK14 protein Q16539 UNIPROT EGFR protein P00533 UNIPROT down-regulates phosphorylation 9606 16932740 t In this case, the phosphorylation of EGFR by p38 or a downstream kinase like MAPKAP-2, triggers receptor internalization. gcesareni In conclusion, the use of pharmacological agents suggests that p38 mapk is the enzyme involved in egfr phosphorylation, as well as internalization, following exposure of cells to various stress-inducing conditions. SIGNOR-149089 0.522 NOTCH1 protein P46531 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates 9606 22298955 f gcesareni Similar synergy is found in notch and bmp crosstalk: activating notch signaling enhanced bmp-induced alp activity and formation of calcified nodules in vitro. SIGNOR-114592 0.36 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1016 DVVDADEyLIPQQGF 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-236527 0.2 PINK1 protein Q9BXM7 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates phosphorylation Ser65 DYNIQKEsTLHLVLR 24784582 t Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential. SIGNOR-270341 0.587 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 22083140 t lperfetto The role of apc is less clear, but it clearly binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex. SIGNOR-227881 0.891 NUAK1 protein O60285 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Ser910 SLLGRSGsYSYLEER 9606 20354225 t gcesareni Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity. SIGNOR-22572 0.521 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MAPK14 protein Q16539 UNIPROT down-regulates 9606 BTO:0000801 11842088 f lperfetto In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. SIGNOR-244665 0.2 CBLB protein Q13191 UNIPROT KIT protein P10721 UNIPROT down-regulates activity ubiquitination 9606 15315962 t miannu KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT. SIGNOR-260105 0.334 NatA complex SIGNOR-C415 SIGNOR HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization acetylation 9606 BTO:0001282 12464182 t miannu In this report, we reveal an important function for ARD1 in mammalian cells as a protein acetyltransferase by direct binding to HIF-1alpha to regulate its stability. We present further evidence showing that ARD1-mediated acetylation enhances interaction of HIF-1alpha with pVHL and HIF-1alpha ubiquitination, suggesting that the acetylation of HIF-1alpha by ARD1 is critical to proteasomal degradation. SIGNOR-267226 0.51 PRKCZ protein Q05513 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser144 GDVGALEsLRGNADL 9606 16287866 t gcesareni Inhibitor sensitivity and interactions with caspase 9 indicate that the predominant kinase that targets ser144 is the atypical protein kinase c isoform zeta (pkczeta). SIGNOR-141629 0.355 RABGGTB protein P53611 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity lipidation 9606 BTO:0000007 18532927 t miannu Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional SIGNOR-265575 0.642 VEPH1 protein Q14D04 UNIPROT LATS1 protein O95835 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 22055343 f In the neuronal differentiation lperfetto Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r8 SIGNOR-177074 0.2 CHEK1 protein O14757 UNIPROT BLM protein P54132 UNIPROT up-regulates phosphorylation Ser646 LKHERFQsLSFPHTK 9606 20719863 t llicata Hese results indicated that chk1-mediated phosphorylation on blm at ser(646) might be a determinant for regulating subnuclear localization and could act as a marker for the activation status of blm in response to dna damage. SIGNOR-167534 0.772 RIMS3 protein Q9UJD0 UNIPROT CACNA1D protein Q01668 UNIPROT up-regulates activity binding 9606 BTO:0005822 28642685 t miannu Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells. SIGNOR-264357 0.2 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 15568999 t gcesareni Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. SIGNOR-131311 0.601 PHLPP2 protein Q6ZVD8 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 t gcesareni Here, we identify a protein phosphatase, ph domain leucine-rich repeat protein phosphatase (phlpp), that specifically dephosphorylates the hydrophobic motif of akt (ser473 in akt1), triggering apoptosis and suppressing tumor growth.[...] These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt. SIGNOR-252602 0.764 UNC5A protein Q6ZN44 UNIPROT Chemorepulsion_of_axon phenotype SIGNOR-PH198 SIGNOR up-regulates 9606 30108487 f miannu Netrin binding to the receptor deleted in colorectal cancer (DCC) results in attractive responses, viahomodimerization of DCC (covered in detail in later sections), whereas heterodimerization between DCC and receptor uncoordinated locomotion 5 (UNC5) converts this attractive response into repulsion SIGNOR-268182 0.7 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Thr2638 VAGQIRAtQQQHDFT 9606 BTO:0000773 12186630 t lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. SIGNOR-249159 0.2 CHKA protein P35790 UNIPROT PLIN2 protein Q99541 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr232 TKLHSRAyQQALSRV 9606 BTO:0000527 34929314 t lperfetto In addition, as a protein kinase, CHKalpha2 phosphorylates PLIN2 at Tyrosine 232 and PLIN3 at Tyrosine 251. Phosphorylated PLIN2 and PLIN3 are separated from lipid droplets and degraded by Hsc70-mediated autophagy, thereby promoting lipid droplet lipolysis, fatty acid oxidation and glioblastoma growth  SIGNOR-267649 0.2 TEC protein P42680 UNIPROT BTK protein Q06187 UNIPROT down-regulates activity phosphorylation Tyr223 LKKVVALyDYMPMNA 9606 12573241 t lperfetto Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the SH3 domain via a transphosphorylation mechanism, which for Bruton's tyrosine kinase (Btk) affects tyrosine 223.|In Btk, the SH3 domain mutation Y223F results in enhanced fibroblast transformation, implying that the SH3 domain may play a negative regulatory role SIGNOR-246652 0.474 TNF protein P01375 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates activity 9606 23685857 f Tumor necrosis factor α (TNF-α, also known as cachectin) is a strong pro-inflammatory cytokine which plays an important role in the immune system during inflammation, cell proliferation, differentiation and apoptosis SIGNOR-258988 0.7 DUSP26 protein Q9BV47 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 20562916 t Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma|Inhibiting DUSP26 expression in the IMR-32 neuroblastoma cell line enhanced doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression as well as apoptosis SIGNOR-248766 0.374 GSK3B protein P49841 UNIPROT ARNTL protein O00327 UNIPROT down-regulates phosphorylation Thr21 DFMSPGPtDLLSSSL 9606 20049328 t lperfetto Gsk3beta phosphorylates bmal1 specifically on ser 17 and thr 21 and primes it for ubiquitylation. In the absence of gsk3beta-mediated phosphorylation, bmal1 becomes stabilized and bmal1 dependent circadian gene expression is dampened. SIGNOR-162790 0.391 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 BTO:0000567 19777442 t inferred from 70% family members gcesareni Erk-1 map kinase prevents tnf-induced apoptosis through bad phosphorylation and inhibition of bax translocation in hela cells. SIGNOR-270037 0.2 NAB2 protein Q15742 UNIPROT EGR1 protein P18146 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000414 20506119 f miannu Our results suggest that in many cells of neuroectodermal and epithelial origin EGR1, EGR2, and EGR3 activate NAB2 transcription which is in turn repressed by NAB2, thus establishing a negative feedback loop. SIGNOR-253886 0.611 CASP3 protein P42574 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 10090 25787076 f miannu The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice. SIGNOR-255337 0.7 CDK1 protein P06493 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Thr706 TTEGGSLtPVRDSPC 9606 20169205 t llicata Cdc2 is the raptor ser696, thr706 kinase SIGNOR-163853 0.394 pemetrexed disodium chemical CHEBI:63722 ChEBI ATIC protein P31939 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 14596699 t miannu Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT). SIGNOR-259292 0.8 perfluorooctanoic acid chemical CHEBI:35549 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 23764977 t miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  SIGNOR-268762 0.8 eribulin mesylate chemical CHEBI:70710 ChEBI TUBA4A protein P68366 UNIPROT down-regulates activity chemical inhibition 9606 16940412 t miannu The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin. SIGNOR-259344 0.8 PRKCA protein P17252 UNIPROT CFTR protein P13569 UNIPROT up-regulates activity phosphorylation Ser686 WTETKKQsFKQTGEF -1 1377674 t lperfetto Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC. SIGNOR-248849 0.408 ACAT1 protein P24752 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates activity acetylation 34289383 t lperfetto We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1) SIGNOR-267634 0.2 DAB2IP protein Q5VWQ8 UNIPROT KIT protein P10721 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27858941 f miannu DAB2IP suppresses transcription of stem cell factor receptor CD117, by interacting with GATA-1 on a silencer element on its gene SIGNOR-254769 0.278 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser59 GGQESQPsPLALLAA 9606 19318349 t gcesareni PKCalpha, which was activated in senescent cells by ROS strongly activated Erk1/2, and the SA-pErk1/2 in turn phosphorylated Sp1 on Ser(59). Sp1-enhanced transcription of p21(Sdi1) resulted in regulation of cellular senescence in primary human diploid fibroblast cells. SIGNOR-248079 0.639 neratinib chemical CHEBI:61397 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194631 0.8 hydromorphone chemical CHEBI:5790 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 19282177 t Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. SIGNOR-258038 0.8 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr498 KTPPAPKtPPSSGEP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249351 0.728 SPX protein Q9BT56 UNIPROT GALR3 protein O60755 UNIPROT up-regulates activity binding 9606 BTO:0000007 24517231 t lperfetto Coevolution of the spexin/galanin/kisspeptin family: Spexin activates galanin receptor type II and III. SIGNOR-268575 0.353 CDK1 protein P06493 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser386 LRGAQAAsPAKGEPS 9606 BTO:0000567 23348582 t phosphorylation site remapping based on mass spec table lperfetto Cdk1-cyclin B1 directly phosphorylates PTP1B at serine 386 in a kinase assay. Recombinant Plk1 phosphorylates PTP1B on serine 286 and 393 in vitro, however, it requires a priming phosphorylation by Cdk1 at serine 386 highlighting a novel co-operation between Cdk1 and Plk1 in the regulation of PTP1B.|Finally, phosphorylation on serine 286 enhanced PTP1B phosphatase activity. SIGNOR-272970 0.516 PTPN11 protein Q06124 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates activity dephosphorylation -1 19066472 t miannu Moreover, SHP-2 was strongly activated on G-CSF stimulation and specifically dephosphorylated p27(Kip1) in vitro.|Most importantly, we could illustrate that SHP-2 modulates p27 (Kip1) stability and contributes to p27 (Kip1)-mediated cell cycle progression. SIGNOR-277168 0.285 DUSP26 protein Q9BV47 UNIPROT TP53 protein P04637 UNIPROT down-regulates dephosphorylation Ser20 PLSQETFsDLWKLLP 9606 20562916 t miannu We found that dusp26 promotes the resistance of human neuroblastoma to doxorubicin-induced apoptosis by acting as a p53 phosphatase to downregulate p53 tumor suppressor function in neuroblastoma cells. / we found that dusp26 binds to p53 and dephosphorylates p53 at ser20 and ser37. SIGNOR-166258 0.374 Spike protein-ACE2 complex SIGNOR-C240 SIGNOR Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 9606 18554741 f miannu Endocytosis of the Receptor-Binding Domain of SARS-CoV Spike Protein Together With Virus Receptor ACE2. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells. SIGNOR-260289 0.7 CoV2 Spike protein-ACE2 complex SIGNOR-C254 SIGNOR Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 9606 32221306 f miannu We demonstrated that SARS-CoV-2 S protein entry on 293/hACE2 cells is mainly mediated through endocytosis, and that PIKfyve, TPC2, and cathepsin L are critical for virus entry. We further found that SARS-CoV-2 S protein could trigger syncytia in 293/hACE2 cells independent of exogenous protease. SIGNOR-260743 0.7 CoV2 spike protein-NRP1 complex SIGNOR-C267 SIGNOR Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 10090 BTO:0000108 33082293 t Luana NRP mediates entry of nanoparticles coated with SARS-CoV-2 (SARS-2) S–derived CendR peptides into cultured cells, olfactory epithelium, and the central nervous system of mice. SIGNOR-262316 0.7 CoV2 Spike protein-ACE2 complex SIGNOR-C254 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 32231345 f doi.org/10.1101/2020.03.09.983247 miannu Unlike SARS-CoV, live SARS-CoV-2-infected cells were found to form typical syncytium, suggesting that SARS-CoV-2 may mainly utilize the plasma membrane fusion pathway to enter and replicate inside host cells. Consistently, in the cell-cell fusion system, SARS-CoV-2 S protein could effectively mediate the formation of syncytium between the effector cell and the target cell in the absence of an exogenous proteolytic enzyme, e.g., trypsin, while SARS-CoV S protein could not. Actually, the plasma membrane fusion pathway is more efficient than the endosomal membrane fusion pathway for most viruses because the latter is more prone to activating the host cell antiviral immunity. SIGNOR-260741 0.7 CoV2 Spike protein-ACE2 complex SIGNOR-C254 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 32221306 f miannu We demonstrated that SARS-CoV-2 S protein entry on 293/hACE2 cells is mainly mediated through endocytosis, and that PIKfyve, TPC2, and cathepsin L are critical for virus entry. We further found that SARS-CoV-2 S protein could trigger syncytia in 293/hACE2 cells independent of exogenous protease. SIGNOR-260744 0.7 EDNRA protein P25101 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256780 0.454 TAL1 protein P17542 UNIPROT ERG protein P11308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001106 21536859 f miannu We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. SIGNOR-253924 0.28 PAK3 protein O75914 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser338 RPRGQRDsSYYWEIE 9606 9823899 t llicata The protein kinase pak3 positively regulates raf-1 activity through phosphorylation of serine 338. SIGNOR-62043 0.537 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser14 LYSFFSPsPARKRHA 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276096 0.274 POU2AF1 protein Q16633 UNIPROT POU2F2 protein P09086 UNIPROT up-regulates binding 9606 BTO:0000776 8654375 t miannu We have shown previously that both octamer binding transcription factors, namely the ubiquitous oct-1 and the b cell-specific oct-2a protein, can be enhanced in transcriptional activity by their association with the b cell-specific coactivator protein bob1, also calledobf-1or oca-b. SIGNOR-42278 0.578 CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR TSC2 protein P49815 UNIPROT up-regulates activity phosphorylation Ser1217 MSLENPLsPFSSDIN 9606 BTO:0000007 32294430 t done miannu We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452.  SIGNOR-274101 0.414 DPF2 protein Q92785 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270719 0.602 TBCK protein Q8TEA7 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 23977024 f miannu Depletion of TBCK significantly inhibits cell proliferation, reduces cell size, and disrupts the organization of actin, but not microtubule. SIGNOR-266701 0.7 (-)-anisomycin chemical CHEBI:338412 ChEBI p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates chemical activation 9606 Other t CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb gcesareni SIGNOR-269916 0.8 TPO protein P07202 UNIPROT 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI up-regulates quantity chemical modification 9606 16098474 t scontino TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. SIGNOR-267030 0.8 PRKACA protein P17612 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser269 PCNKRKYsLNGRQPP 9606 12351631 t lperfetto Here we show that overexpression of pka causes phosphorylation and cytoplasmic accumulation of nf-atc1 in direct opposition to calcineurin by phosphorylating ser-245, ser-269, and ser-294 in the conserved serine-proline repeat domainwe further show that a complete block of nf-atc1 nuclear localization by pka requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (gsk-3) SIGNOR-93535 0.358 nilotinib chemical CHEBI:52172 ChEBI ABL1 protein P00519 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258256 0.8 S1PR2 protein O95136 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257401 0.572 AKT proteinfamily SIGNOR-PF24 SIGNOR MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 19526459 t llicata Here, we present evidence that akt inhibits mad1-mediated transcription repression by physical interaction with and phosphorylation of mad1. SIGNOR-186130 0.2 FLT3 protein P36888 UNIPROT ID1 protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18559972 f apalma In this study, we used specific tyrosine kinase inhibitors to identify critical target genes that are regulated by oncogenic tyrosine kinases. Using oligonucleotide microarrays, we identified genes that are either up- or down-regulated by selective small molecule inhibitors that target the ABL, PDGFβR, or FLT3 kinases. Genes induced by these inhibitors are presumably repressed by activated tyrosine kinases.Among these genes, we detected a 5- to 50-fold reduction in Id1 expression when the cancer cells were treated with inhibitors. SIGNOR-255698 0.266 CSNK1D protein P48730 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 24715453 t milica LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP) SIGNOR-230743 0.4 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr288 QCPVGFNtLAFPSMK -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276129 0.644 ATR protein Q13535 UNIPROT KMT2A protein Q03164 UNIPROT up-regulates phosphorylation Ser516 VHPPLPIsQSPENES 9606 4709074 t lperfetto Mll is phosphorylated at serine 516 by atr in response to genotoxic stress in the s phase, which disrupts its interaction with, and hence its degradation by, the scf(skp2) e3 ligase, leading to its accumulation. SIGNOR-25151 0.284 CRADD protein P78560 UNIPROT Caspase-2 PIDDosome complex SIGNOR-C292 SIGNOR form complex binding 9606 20158568 t miannu The PIDDosome consists of the proteins PIDD, RAIDD and caspase-2. SIGNOR-262642 0.921 HRH2 protein P25021 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256920 0.36 CDK1 protein P06493 UNIPROT PLEC protein Q15149 UNIPROT down-regulates phosphorylation Thr4539 GGLIEPDtPGRVPLD 9606 BTO:0000567 SIGNOR-C17 8626512 t lperfetto Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane. SIGNOR-41319 0.396 CAMK2A protein Q9UQM7 UNIPROT RIMS1 protein Q86UR5 UNIPROT up-regulates phosphorylation Ser288 NGKGALKsERKRVPK 9606 BTO:0000938 BTO:0000142 12871946 t gcesareni Two serine residues in rim1 (ser-241 and ser-287) and one serine residue in rim2 (ser-335) were required for 14-3-3 binding. Incubation with ca2+/calmodulin-dependent protein kinase ii greatly stimulated the interaction of recombinant n-terminal rim but not the s241/287a mutant with 14-3-3, SIGNOR-103890 0.353 trichostatin A chemical CHEBI:46024 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258011 0.8 AXL protein P30530 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr376 DRVKSTAyLSPQELE 9606 BTO:0000007 31230815 t done miannu TAM kinases phosphorylate MLKL to promote necroptosis. MLKL is then recruited to the plasma membrane, where TAM kinases phosphorylate MLKL at Tyr376 (Figure 5G, step 5), promoting its oligomerization and formation of membrane-rupturing pores that result in necrotic cell death (Figure 5G, step 6). SIGNOR-274119 0.2 ritonavir chemical CHEBI:45409 ChEBI CYP3A4 protein P08684 UNIPROT down-regulates activity chemical inhibition -1 18285471 t Luana Ritonavir is the most potent and efficacious inhibitor of cytochrome P4503A (CYP3A SIGNOR-257769 0.8 PRKCD protein Q05655 UNIPROT KCNJ1 protein P48048 UNIPROT up-regulates activity 9606 8621594 t lperfetto To determine whether this channel is a substrate for PKA, ROMK tagged with the hemagglutinin epitope was transiently transfected into HEK293 cells. In vitro labeling of immunoprecipitated proteins from transfected cells showed that ROMK could be phosphorylated by PKA. | Taken together, these results provide strong evidence that direct phosphorylation of the channel polypeptide by PKA is involved in channel regulation and PKA-dependent phosphorylation is essential for ROMK channel activity. SIGNOR-248943 0.312 EGLN3 protein Q9H6Z9 UNIPROT PKM protein P14618 UNIPROT up-regulates activity hydroxylation Pro403 EELRRLApITSDPTE 9606 BTO:0000567 21620138 t Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. SIGNOR-267476 0.447 ARHGAP20 protein Q9P2F6 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260474 0.423 FOXP2 protein O15409 UNIPROT FOXP2 protein O15409 UNIPROT up-regulates activity binding -1 16407075 t miannu Our studies also reveal that the FOXP2 forkhead domain can form a domain-swapped dimer. The most surprising finding from these studies is that the FOXP2 forkhead domain can form a domain-swapped dimer. Disease-related mutations, sequence comparison, and biochemical analyses argue strongly that this domain swapping is a physiologically relevant function evolved in the P branch of FOX proteins. SIGNOR-225738 0.2 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser118 NQQESSDsGTSVSEN 9606 20708156 t gcesareni Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase. SIGNOR-167497 0.352 LSM-1231 chemical CHEBI:91471 ChEBI NTRK1 protein P04629 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258238 0.8 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1802 SNVSSSGsINLLESP -1 8631898 t miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. SIGNOR-250168 0.428 SMURF2 protein Q9HAU4 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates activity ubiquitination 9606 18448069 t lperfetto The association of Smurf2 with Smad7 and its ubiquitination were inhibited by AIMP1, thereby protecting its autocatalytic degradation stimulated by Smad7. SIGNOR-178501 0.865 TNIP1 protein Q15025 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates activity binding 21885437 t lperfetto ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi. SIGNOR-275736 0.443 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 15735019 t miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates SIGNOR-150480 0.634 HCK protein P08631 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity phosphorylation Tyr354 SSNQELIyEGRRLVL 9606 BTO:0002181 28618271 t miannu The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.  SIGNOR-276726 0.2 romidepsin chemical CHEBI:61080 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257997 0.8 RAD51 protein Q06609 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR up-regulates activity binding 10090 BTO:0001275 10525529 t miannu The eukaryotic RecA homologues RAD51 and DMC1 function in homology recognition and formation of joint-molecule recombination intermediates during yeast meiosis. We also show that mouse RAD51 and DMC1 establish protein-protein interactions with each other and with the chromosome core component COR1(SCP3) in a two-hybrid system and in vitro binding analyses. These results suggest that the formation of a multiprotein recombination complex associated with the meiotic chromosome cores is essential for the development and fulfillment of the meiotic recombination process. SIGNOR-264207 0.324 SRC protein P12931 UNIPROT PTPRA protein P18433 UNIPROT up-regulates activity phosphorylation Tyr798 YIDAFSDyANFK 9606 7518772 t The effect has been demonstrated using P18433-2 lperfetto Transient overexpression of c-src together with rptp alpha in human embryonic kidney 293 cells increased phosphorylation of tyr789, suggesting that c-src may phosphorylate rptp alpha in vivo. SIGNOR-111306 0.732 CREB1 protein P16220 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 f gcesareni In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1 SIGNOR-142103 0.252 SLC18A2 protein Q05940 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30465801 t miannu Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. SIGNOR-269190 0.8 ZAP70 protein P43403 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr323 DEPVADPyDQSFESR 10090 BTO:0000782 15735648 t miannu Lck, Fyn, and Zap70 activate p38 even in the absence of Tyr182 phosphorylation.p38 is a substrate for Fyn, Lck and Zap70.Thus, T cell Src family kinases and Zap70 activate p38 by phosphorylating Tyr323. SIGNOR-276030 0.457 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates activity phosphorylation Tyr591 SSDNEYFyVDFREYE 10090 BTO:0001516 16627759 t lperfetto In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated.|This finding suggests that the combination of tyrosine residues 589 and 591 is required for activation of STAT-5 signaling pathways. SIGNOR-271921 0.2 PTPN13 protein Q12923 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates quantity by stabilization dephosphorylation Tyr42 DSMKDEEyEQMVKEL 9606 BTO:0000007 11106428 t Identification of IkappaBalpha as a substrate of Fas-associated phosphatase-1|A full-length FAP-1 protein preferentially dephosphorylates Tyr-42 of IkBa|Moreover, other studies have shown that tyrosine phosphorylation of IkBa on Tyr-42 (which occurs with Fas ligand binging) protected against inducible degradation both in vitro [30] and in vivo [38] SIGNOR-248712 0.453 GATA1 protein P15976 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004475 19825991 f miannu Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein alpha (Cebpa) and core-binding factor, beta subunit (Cbfb), which encode two key hematopoietic transcription factors. SIGNOR-254189 0.412 1-[5-bromo-4-methyl-2-[[(2S)-2-morpholinyl]methoxy]phenyl]-3-(5-methyl-2-pyrazinyl)urea chemical CHEBI:124917 ChEBI CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193787 0.8 PKN1 protein Q16512 UNIPROT CDC25C protein P30307 UNIPROT unknown phosphorylation Ser216 SGLYRSPsMPENLNR 9606 BTO:0000567 15791647 t lperfetto A role for PKN1 in mediating arsenite-induced G(2)/M delay was supported by the finding that expression of a constitutively active form of PKN1 (PKN1AF3) in HeLa cells delayed the mitotic entry of cell cycle. Further experiments indicate that PKN1 directly phosphorylated serine 216 (Ser216) in Cdc25C, which then facilitated association between Cdc25C and 14-3-3. SIGNOR-249277 0.511 E2F1 protein Q01094 UNIPROT MUC4 protein Q99102 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 22537161 f lperfetto Nicotine, IFN-γ and retinoic acid mediated induction of MUC4 in pancreatic cancer requires E2F1 and STAT-1 transcription factors and utilize different signaling cascades SIGNOR-254133 0.2 BCL9 protein O00512 UNIPROT PYGO1 protein Q9Y3Y4 UNIPROT up-regulates binding 9606 BTO:0000776 11955446 t miannu Here we report the identification of two segment polarity genes in drosophila, legless (lgs), and pygopus (pygo), and we show that their products are required for wnt signal transduction at the level of nuclear beta-catenin. Lgs encodes the homolog of human bcl9, and we provide genetic and molecular evidence that these proteins exert their function by physically linking pygo to beta-catenin. SIGNOR-116577 0.904 Naltrindole chemical CHEBI:81528 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258816 0.8 SRF protein P11831 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates 9606 22225874 t FFerrentino Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy. SIGNOR-255965 0.255 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR CDH1 protein P12830 UNIPROT up-regulates 9606 24532814 f milica Adherens junctions and the cadheriBeta-catenin complex have been found to activate the Hippo signaling pathway and inhibit cell growth. Cadherin-mediated stimulation of the Hippo signaling pathway requires cadherin ligation and the formation of a homophilic bond – consistent with a role in cell-cell contact – and works owing to phosphorylation of YAP by Lats and nuclear exclusion of YAP. SIGNOR-230707 0.7 EVL protein Q9UI08 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 18508258 f miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. SIGNOR-268394 0.7 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11689553 f irozzo To identify this pathway, we analyzed TGF-β-responsive elements in the human c-myc promoter and found that Smad proteins directly bound to an element in the c-myc promoter and suppressed c-myc promoter activity. SIGNOR-256291 0.648 (R)-(+)-sulpiride chemical CHEBI:64122 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258735 0.8 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser25 PGTASRPsSSRSYVT -1 2500966 t miannu Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure. SIGNOR-250066 0.313 HMGB2 protein P26583 UNIPROT POU2F1 protein P14859 UNIPROT up-regulates activity binding 10090 BTO:0002910 7720710 t 2 miannu HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins SIGNOR-240151 0.312 CAMK1 protein Q14012 UNIPROT SYN1 protein P17600 UNIPROT down-regulates activity phosphorylation Ser9 NYLRRRLsDSNFMAN -1 10571231 t miannu Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I SIGNOR-250615 0.578 bivalirudin chemical CHEBI:59173 ChEBI F2 protein P00734 UNIPROT down-regulates activity chemical inhibition -1 1290488 t miannu These data demonstrate that hirulog-1 is a specific inhibitor of thrombin forms with high fibrinogen-procoagulant activities and that its Arg-3-Pro-4 bond is slowly cleaved by these thrombin forms. SIGNOR-258346 0.8 CPT1B protein Q92523 UNIPROT O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267130 0.8 wortmannin chemical CHEBI:52289 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 7503989 t gcesareni Wortmannin inhibited the activity of partially purified pi3-kinase from calf thymus, as well as the pi3-kinase activity in anti-pi3-kinase p85 immunoprecipitates from rbl-2h3 cells, at a concentration as low as 1.0 nm and with ic50 values of 3.0 nm. SIGNOR-26677 0.8 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser33 LRRSQRKsGSELPSI -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276116 0.613 CDK2 protein P24941 UNIPROT TPX2 protein Q9ULW0 UNIPROT down-regulates activity phosphorylation Thr72 NLQQAIVtPLKPVDN -1 25688093 t lperfetto In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. |Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle SIGNOR-265099 0.298 SLC25A1 protein P53007 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity relocalization 9606 29651165 t SLC25A1, a mitochondrial carrier that promotes the flux of citrate/isocitrate across the mitochondria, in exchange for the entry of cytosolic malate SIGNOR-267290 0.8 PRKACA protein P17612 UNIPROT ACADVL protein P49748 UNIPROT up-regulates activity phosphorylation Ser586 VVVLSRAsRSLSEGH -1 19889959 t lperfetto As shown in Fig. 2C, an in vitro kinase assay carried out using PKA and a GST fusion protein containing the COOH-terminal 258 amino acids showed the protein to be efficiently phosphorylated in a time-dependent manner. |Furthermore, a phosphorylation-negative mutant (S586A) VLCAD shows reduced electron transfer activity and a strong dominant-negative effect on fatty acid beta-oxidation. SIGNOR-264422 0.2 LATS1 protein O95835 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 t milica In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. SIGNOR-197647 0.834 tyrosine smallmolecule CHEBI:18186 ChEBI tyramine smallmolecule CHEBI:15760 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬¨‚Ć SIGNOR-264175 0.8 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr12 FGSRSSKtFKPKKNI 9606 23431053 t milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity SIGNOR-201314 0.846 TEK protein Q02763 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr1102 MLEERKTyVNTTLYE 14665640 t gcesareni Our results identified a novel interaction between Tie2 with the adapter molecule ShcA and suggested that this interaction may play a role in the regulation of migration and three-dimensional organization of endothelial cells induced by angiopoietin-1. Furthermore, Tyr-1101 of Tie2 was identified as the primary binding site for the SH2 domain of ShcA. SIGNOR-242573 0.562 FFAR2 protein O15552 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257188 0.47 EPHA3 protein P29320 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates activity phosphorylation Tyr602 TYVDPHTyEDPTQAV 9606 11870224 t Eph receptor activation leads to tyrosine phosphorylation of three major autophosphorylation sites. these residues function to regulate kinase activity, their phosphorylation being required for full intrinsic enzyme activity. these tyrosines (EphA3 Y596, Y602 and Y779) as the prominent autophosphorylation sites of EphA3 SIGNOR-251116 0.2 ING2 protein Q9H160 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 14522900 f miannu ING1b and ING2 also repressed the AFP promoter in Hep3B p53-null cell lines, and p53 coexpression enhanced this transcriptional repression. Suppression of AFP gene transcription by ING was strongly dependent on AT-motifs that bind to the hepatocyte nuclear factor 1 (HNF1) transcription factor. SIGNOR-254485 0.2 CTNND1 protein O60716 UNIPROT CDH2 protein P19022 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0003564 14610055 t miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. SIGNOR-252125 0.726 RUBCNL protein Q9H714 UNIPROT STX17 protein P56962 UNIPROT up-regulates activity binding 9606 BTO:0000007 30704899 t miannu Under nutrient-rich conditions, mTORC1 phosphorylates Pacer at serine157 to disrupt the association of Pacer with Stx17 and the HOPS complex and thus abolishes Pacer-mediated autophagosome maturation. These results demonstrate that mTORC1-mediated Pacer phosphorylation at S157 inhibits autophagosome maturation by disrupting the association of Pacer with Stx17 and the HOPS complex SIGNOR-273684 0.2 DIS3L protein Q8TF46 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-261391 0.908 BCL6 protein P41182 UNIPROT CD80 protein P33681 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000776 12860928 f Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells. SIGNOR-253931 0.417 acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 9606 19524112 t miannu The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA. SIGNOR-267520 0.8 MAP2K3 protein P46734 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Tyr182 ADAEMTGyVVTRWYR 9606 BTO:0000007 10066767 t done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. SIGNOR-273949 0.59 CTTNBP2NL protein Q9P2B4 UNIPROT STRN protein O43815 UNIPROT up-regulates activity binding 9606 23015759 t miannu Although CTTNBP2 and CTTNBP2NL are different in terms of tissue and subcellular distribution, our data indicate that, similar to CTTNBP2NL, CTTNBP2 associates with members of the striatin family, namely striatin and zinedin. Moreover, CTTNBP2 is critical for the distribution of striatin and zinedin in dendritic spines. The role of CTTNBP2 in the regulation of the synaptic distribution of striatin and zinedin suggests that CTTNBP2 regulates synaptic signaling through PP2A. SIGNOR-261702 0.665 P2RY11 protein Q96G91 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257435 0.358 SPOP protein O43791 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 20463034 t Gianni RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins SIGNOR-268861 0.692 JAG1 protein P78504 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 10551863 t Binding Calcium-dependent. gcesareni Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch. SIGNOR-269936 0.629 HIF1A protein Q16665 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271569 0.264 MYF6 protein P23409 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 f miannu The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37455 0.7 TCF4 protein P15884 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR form complex binding 9606 16847330 t 2 miannu The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation. SIGNOR-241382 0.69 DZIP3 protein Q86Y13 UNIPROT H2AZ2 protein Q71UI9 UNIPROT up-regulates activity monoubiquitination Lys121 IHKSLIGkKGQQKTA 9606 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271756 0.2 IGF1R protein P08069 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 10090 BTO:0000165 11715022 f lperfetto we show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy. SIGNOR-244403 0.397 SCF-betaTRCP complex SIGNOR-C5 SIGNOR MYC protein P01106 UNIPROT up-regulates quantity ubiquitination 9606 20852628 t gcesareni Here we show that SCF²-TrCP binds to Myc by means of a characteristic phosphodegron and ubiquitylates Myc; this results in enhanced Myc stability. SIGNOR-243542 0.482 LCK protein P06239 UNIPROT ACP1 protein P24666 UNIPROT up-regulates activity phosphorylation Tyr132 QLIIEDPyYGNDSDF 9534 BTO:0004055 9038134 t In co-transfected COS cells, Lck and Fyn caused phosphorylation of LMPTP. Most of the phosphate was located at Tyr-131, and some was also located at Tyr-132. Site-directed mutagenesis showed that Tyr-131 is important for the catalytic activity of LMPTP, and that thiophosphorylation of Tyr-131, and to a lesser degree Tyr-132, is responsible for the activation. SIGNOR-251366 0.361 PDGFRB protein P09619 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr542 SKRKGHEyTNIKYSL 10090 BTO:0000944 8041791 t miannu Upon PDGF stimulation, SHPTP2 binds to the PDGFR and becomes tyrosine-phosphorylated. We have identified tyrosine-542 (pY542TNI) as the major in vivo site of SHPTP2 tyrosine phosphorylation. phosphorylation of SHPTP2 couples Grb2 to PDGFR in vivo, providing a mechanism for Ras activation by PDGFR and for positive signaling via SHPTP2 and Csw. SIGNOR-250260 0.739 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser76 ISNKDQHsISYTLSR 9606 BTO:0000007 12496252 t lperfetto In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation SIGNOR-96739 0.758 APC-c complex SIGNOR-C150 SIGNOR PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization ubiquitination phosphorylation:Ser40 PTAEEKPsPRRSLSQ 33309518 t lperfetto Phosphorylation of multiple residues in the catalytic domain of PPM1D during mitosis, including Ser40 by Cyclin-dependent kinase 1 (CDK1), leads to ubiquitination of PPM1D and subsequent proteasomal degradation by Adenomatous polyposis coli (APC) and cell-division cycle protein 20 (CDC20) SIGNOR-275492 0.317 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexenyl]methyl]-1-piperazinyl]-N-[4-[[(2R)-4-(4-morpholinyl)-1-(phenylthio)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide chemical CHEBI:94128 ChEBI BCL2L2 protein Q92843 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189156 0.8 CBP/p300 complex SIGNOR-C6 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates activity acetylation Lys19 VKRLLGWkKGEQNGQ 9606 BTO:0000567;BTO:0002181;BTO:0000552 17074756 t lperfetto We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfb-dependent manner. the p300-dependent acetylation of smad3 was attenuated when lys19 was mutated, whereas mutation of lys20 had no effect, suggesting that lys19 is acetylated also in smad3. SIGNOR-236126 0.682 CDK2 protein P24941 UNIPROT NFYA protein P23511 UNIPROT up-regulates activity phosphorylation Ser326 FSPKEKDsPHMQDPN 12857729 t llicata Cdk2 phosphorylates two serine residues near the DNA-binding domain of the YA subunit of NF-Y. Cyclin A-cdk2 appears to associate with NF-Y both in vitro and in vivo. Furthermore, YA protein is phosphorylated in parallel with a cell cycle-dependent activation of cdk2 kinase and cyclin A expression. YA phosphorylation is unnecessary for heterotrimer formation with the YB-YC dimer. However, NF-Y containing a phosphorylation-deficient mutant form of YA, YA-aa, has its DNA binding activity impaired. \ To examine whether cdk2 phosphorylates the two serine residues at positions 320 and 326 in YA, we replaced either or both with alanine by site-directed mutagenesis. In a kinase assay using purified GST fusion proteins in vitro, cdk2 phosphorylated the wild type and both of the single-mutant proteins (YA-as and -sa), but not the double-mutant protein (YA-aa) SIGNOR-250743 0.45 FGF6 protein P10767 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 t gcesareni The nine known fgf ligands and the four signaling fgf receptors (and their alternatively spliced variants) are expressed in specific spatial and temporal patterns. The activity of this signaling pathway is regulated by ligand binding specificity, heparan sulfate proteoglycans, and the differential signaling capacity of individual fgf receptors. SIGNOR-42380 0.743 RFX complex complex SIGNOR-C104 SIGNOR HLA-DPA1 protein P20036 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 f The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-253995 0.267 CTF1 protein Q16619 UNIPROT TH protein P07101 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12859689 f miannu CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA. SIGNOR-252219 0.2 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1679 NVKSKIGsTDNIKYQ 9606 BTO:0000567 11029056 t miannu CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA SIGNOR-250001 0.367 threonine smallmolecule CHEBI:26986 ChEBI Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates quantity precursor of 9606 25824639 t miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. SIGNOR-270508 0.8 XL765 chemical CHEBI:71958 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207881 0.8 JAK2 protein O60674 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates phosphorylation Tyr641 KNEFISEyCGEIISQ 9606 24469040 t lperfetto Oncogenic y641 mutations in ezh2 prevent jak2/beta-trcp-mediated degradationbeta-trcp ubiquitinates ezh2 and jak2-mediated phosphorylation on y641 directs beta-trcp-mediated ezh2 degradation. SIGNOR-202711 0.549 CSNK2A1 protein P68400 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser129 SGSPSDNsGAEEMEV 9606 BTO:0000007 21735093 t gcesareni CK2 hyperactivates AKT by phosphorylation at Ser129 SIGNOR-174691 0.379 Av/b1 integrin complex SIGNOR-C175 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269024 0.7 BIRC3 protein Q13489 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 12525502 t miannu  Here we show that cIAP1 and cIAP2 are E3 ubiquitin-protein isopeptide ligases (ubiquitin ligases) for Smac. cIAPs stimulate Smac ubiquitination both in vivo and in vitro, leading to Smac degradation. cIAP1 and cIAP2 associate with overlapping but distinct subsets of E2 (ubiquitin carrier protein) ubiquitin-conjugating enzymes. The substrate-dependent E3 activity of cIAPs is mediated by their RING domains and is dependent on the specific interactions between cIAPs and Smac. SIGNOR-271391 0.784 MAPK1 protein P28482 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 28646232 t Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels SIGNOR-262521 0.325 ABL1 protein P00519 UNIPROT UBE3A protein Q05086 UNIPROT down-regulates activity phosphorylation Tyr659 GDSHPVLyQSLKDLL 9606 23581475 t Manara Our results suggest that c-Abl protects p53 from HPV-E6-E6AP complex-mediated degradation by phosphorylating E6AP and impairing its E3 ligase activity SIGNOR-260930 0.276 NADPH(4-) smallmolecule CHEBI:57783 ChEBI NADP(3-) smallmolecule CHEBI:58349 ChEBI up-regulates quantity precursor of 9606 15507492 t miannu Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-268088 0.8 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18617643 t gcesareni We show for the first time that vegf stimulated phosphorylation of hdac7 at the sites of ser178, ser344, and ser479we found that phospholipase cgamma/protein kinase c/protein kinase d1 (pkd1)-dependent signal pathway mediated hdac7 phosphorylation and cytoplasmic accumulation by vegf. SIGNOR-179430 0.491 SPI1 protein P17947 UNIPROT FCGR1A protein P12314 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12393465 f apalma In patients with t(8;21), expression of the cell surface markers CD11b, CD14, and CD64 was less in comparison to patients without t(8;21) (Figure 5B). CD14 and CD64 promoters have putative PU.1 binding sites but not AML1-, C/EBPŒ±-, or MEF-binding sites suggesting that down-regulation of the function of PU.1 by AML1-ETO could possibly be an important step in progression toward leukemia. SIGNOR-255697 0.538 CPS1 protein P31327 UNIPROT carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity chemical modification 9606 15096496 t CPSase catalyzes the synthesis of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules SIGNOR-267192 0.8 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser239 GAKLRKVsKQEEASG 9606 12576312 t miannu Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro SIGNOR-250063 0.488 CDK1 protein P06493 UNIPROT VCPIP1 protein Q96JH7 UNIPROT down-regulates activity phosphorylation Thr761 GPSSAPAtPTKAPYS 23500464 t lperfetto We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97.  SIGNOR-265037 0.518 PRKAA1 protein Q13131 UNIPROT CYCS protein P99999 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001103 17609368 f gcesareni Severalin vivostudies using aicar to activate ampk chronically determined that mitochondrial enzymes [e.g., cytochromec, uncoupling protein 3 (ucp-3)] (1518) and proteins involved in glucose uptake (glut4) (1820) are increased at the transcriptional level in skeletal muscle. SIGNOR-156772 0.356 PEX14 protein O75381 UNIPROT PEX7 protein O00628 UNIPROT up-regulates activity binding -1 15798189 t miannu The peroxisomal docking complex is a key component of the import machinery for matrix proteins. The core protein of this complex, Pex14, is thought to represent the initial docking site for the import receptors Pex5 and Pex7. SIGNOR-253028 0.887 AKT proteinfamily SIGNOR-PF24 SIGNOR TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser939 SFRARSTsLNERPKS 10090 BTO:0000944 12150915 t lperfetto We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines. SIGNOR-244369 0.2 SETD1B protein Q9UPS6 UNIPROT MLL/SET subcomplex complex SIGNOR-C87 SIGNOR form complex binding 9606 24680668 t miannu Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. SIGNOR-268796 0.894 ADRA2B protein P18089 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256714 0.439 KIRREL3 protein Q8IZU9 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 10090 BTO:0004032 28381988 t miannu We here report that, through its C-terminal PDZ domain-binding motif, Neph2 directly interacts with postsynaptic density (PSD)-95, an abundant excitatory postsynaptic scaffolding protein. Moreover, Neph2 protein is detected in the brain PSD fraction and interacts with PSD-95 in synaptosomal lysates. Functionally, loss of Neph2 in mice leads to age-specific defects in the synaptic connectivity of DG neurons. SIGNOR-269079 0.381 SMARCD2 protein Q92925 UNIPROT Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270753 0.776 CD36 protein P16671 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264453 0.7 Parathyroid hormone-related peptide (1-36) smallmolecule CHEBI:80274 ChEBI PTH1R protein Q03431 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257575 0.8 BIRC5 protein O15392 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 11069302 t amattioni Survivin (an inhibitor of apoptosis) phosphorylation on thr34 may regulate apoptosis at cell division via an interaction with caspase-9. SIGNOR-84065 0.518 N-(2,6-difluorophenyl)-5-[3-[2-[5-ethyl-2-methoxy-4-[4-(4-methylsulfonyl-1-piperazinyl)-1-piperidinyl]anilino]-4-pyrimidinyl]-2-imidazo[1,2-a]pyridinyl]-2-methoxybenzamide chemical CHEBI:91401 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192880 0.8 MAPK8 protein P45983 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 7737130 t gcesareni Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro. SIGNOR-32425 0.771 POU1F1 protein P28069 UNIPROT TSHB protein P01222 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001379 10931853 t scontino CBP and Pit-1 acted synergistically in TRH stimulation of the TSH-β promoter. The human TSH-β promoter contains three well defined Pit-1 DNA-binding sites. SIGNOR-267205 0.449 PRKCA protein P17252 UNIPROT NOS1 protein P29475 UNIPROT unknown -1 1375933 t lperfetto We now report that NOS is stoichiometrically phosphorylated by cAMP dependent protein kinase, protein kinase C, and calcium/calmodulin-dependent protein kinase, with each kinase phosphorylating a different serine site on NOS. SIGNOR-248848 0.492 CBX1 protein P83916 UNIPROT ChAHP complex SIGNOR-C407 SIGNOR form complex binding 10090 BTO:0002896 29795351 t miannu Here we show that ADNP interacts with the chromatin remodeller CHD4 and the chromatin architectural protein HP1 to form a stable complex, which we refer to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. In conclusion, CHD4, ADNP and HP1β/γ form a stable protein complex, which we refer to as ChAHP. SIGNOR-266754 0.366 MAP3K11 protein Q16584 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates phosphorylation Ser138 QKPFEDAsFALRTGE 9606 25519816 t llicata Here we demonstrate that mixed-lineage kinase 3 (mlk3), a map3k family member, phosphorylates pin1 on a ser138 site to increase its catalytic activity and nuclear translocation. SIGNOR-205586 0.265 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser436 TNGSIGHsPLSLSAQ 9606 24614225 t lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204728 0.529 PRKACA protein P17612 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser245 PSTSPRAsVTEESWL 9606 12351631 t lperfetto Here we show that overexpression of pka causes phosphorylation and cytoplasmic accumulation of nf-atc1 in direct opposition to calcineurin by phosphorylating ser-245, ser-269, and ser-294 in the conserved serine-proline repeat domainwe further show that a complete block of nf-atc1 nuclear localization by pka requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (gsk-3) SIGNOR-93531 0.358 AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR SMAD4 protein Q13485 UNIPROT up-regulates binding 9606 9748228 t fspada Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2 SIGNOR-210096 0.2 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser76 ISNKDQHsISYTLSR -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276127 0.644 CTTNBP2NL protein Q9P2B4 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 10116 23015759 f miannu Through alternative splicing, a single CTTNBP2 gene encodes three different transcripts, namely short (S), long (L), and intron forms. The interaction with cortactin is required for the function of CTTNBP2-S in dendritic spine formation because the CTTNBP2-S mutant, which no longer interacts with cortactin, is unable to rescue the spine defects resulting from CTTNBP2 knockdown. Thus CTTNBP2-S may control cortactin–F-actin cytoskeletons and regulate the formation and maintenance of dendritic spines in neurons. SIGNOR-261694 0.7 AXIN1 protein O15169 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni Other proteins, such as the serine/threonine kinase fused (fu), can function in concert with the e3 ligase smurf to regulate ubiquitination and proteolysis of the bmp receptor SIGNOR-195552 0.337 LZTR1 protein Q8N653 UNIPROT KRAS protein P01116 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 31337872 t Gianni We demonstrate that LZTR1 facilitates the polyubiquitination and degradation of RAS via the ubiquitin-proteasome pathway, leading to the inhibition of the RAS/MAPK signaling. SIGNOR-269069 0.252 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser320 HQSLSLAsSPKGTIE 9606 BTO:0002181 34363019 t miannu Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.  SIGNOR-276734 0.2 citrate(3-) smallmolecule CHEBI:16947 ChEBI D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity precursor of 9606 24068518 t miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. SIGNOR-266243 0.8 THBD protein P07204 UNIPROT Thrombin-Thrombomodulin complex SIGNOR-C316 SIGNOR form complex binding 9606 BTO:0000131 29880919 t lperfetto Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC). SIGNOR-267726 0.903 ATR protein Q13535 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser107 SVDSVTDsQKRREIL 9606 15073328 t lperfetto Atm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp). A creb mutant containing ala substitutions at atm phosphorylation sites displayed enhanced transactivation potentialit is, therefore, likely that atm and atr regulate creb phosphorylation collectively in response to stress stimuli. SIGNOR-124060 0.354 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252823 0.908 TGFB1 protein P01137 UNIPROT SLC20A1 protein Q8WUM9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000249 20930330 f miannu TGF-β1 was shown to stimulate ANK and PC-1 expression in articular chondrocytes, and subsequent ePPi level, as well as to increase ePi uptake by inducing PiT-1 expression in a chondrogenic cell line. SIGNOR-252202 0.2 DEF6 protein Q9H4E7 UNIPROT RAP1B protein P61224 UNIPROT up-regulates activity binding 9606 BTO:0000782 26483383 t lperfetto Mechanistic studies revealed that SLAT interacts, through its PH domain, with a key component of inside-out signaling, namely the active form of the small GTPase Rap1 (which has two isoforms, Rap1A and Rap1B). This interaction has been further shown to facilitate the interdependent recruitment of Rap1 and SLAT to the T cell immunological synapse upon TCR engagement. Furthermore, a SLAT mutant lacking its PH domain drastically inhibited LFA-1 activation and CD4(+) T cell adhesion. SIGNOR-253366 0.2 PAK1 protein Q13153 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Ser199 PRPEHTKsVYTRSVI 9534 9032240 t miannu Cdc42 and Rac1 cause alpha-PAK autophosphorylation and kinase activation. SIGNOR-250216 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR ZNF322 protein Q6U7Q0 UNIPROT up-regulates activity phosphorylation Thr234 IVHKRVHtGEKPYKC 9606 BTO:0002552 31399647 t miannu We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A. SIGNOR-276752 0.2 ATF2 protein P15336 UNIPROT ST3GAL5 protein Q9UNP4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002335 21699754 f miannu Our results identified the core promoter region in the hST3Gal V promoter and for the first time demonstrated that ATF2 binding to the CREB/ATF binding site at -143 is essential for transcriptional activation of hST3Gal V in VPA-induced ARPE-19 cells. SIGNOR-253745 0.2 CTDSPL protein O15194 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser195 PNSSYPNsPGSSSST 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248314 0.477 nefazodone chemical CHEBI:7494 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition -1 9871604 t miannu Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. Nefazodone has similar affinities at hSERT, hNET, and hDAT, but has low potency SIGNOR-259068 0.8 EGFR protein P00533 UNIPROT SHC2 protein P98077 UNIPROT up-regulates binding 9606 11350724 t miannu Shc exists in three different isoforms, p46shc, p52shc and p66shc which are tyrosine phosphorylated upon egf stimulation and bind to the activated egfr and grb2. Interestingly, while the 46 and 52 kda isoforms increase mitogenic signalling after egf stimulation and are able to transform nih3t3 cells (pelicci et al. 1992), p66shc has no transforming potential and negatively influences egf-induced c-fos transcription SIGNOR-107750 0.598 AMER1 protein Q5JTC6 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 SIGNOR-C110 21304492 t gcesareni Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6. SIGNOR-171892 0.393 PER1 protein O15534 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267978 0.722 HSPA1A protein P0DMV8 UNIPROT GSTA4 protein O15217 UNIPROT up-regulates activity relocalization phosphorylation:Thr193;Ser189 VKLSNIPtIKRFLEP;QEYTVKLsNIPTIKR 21929724 t lperfetto Model showing Ser189/Thr193 protein kinase dependent phosphorylation of GST A4‐4 has increased affinity for chaperone Hsp70 which activates mitochondrial competent import signals for GSTA4‐4. |Protein kinase A mediated phosphorylation of serine residues of CYPs increases the affinity of proteins for binding to cytoplasmic chaperones such as heat shock proteins (Hsp), Hsp70/Hsp90, resulting in increased mitochondrial translocation SIGNOR-264799 0.2 IL1R1 protein P14778 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000801 9625767 t inferred from 70% of family members lperfetto Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab SIGNOR-269883 0.388 FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 f �The present data provide a direct link between insulin signaling through Irs _ PI 3-kinase _ Akt and adipogenesis through Foxo1 phosphorylation. Inhibition of Foxo1 via phosphorylation appears to be required during the clonal expansion phase, and our data show that unrestrained Foxo1 activity prevents terminal differentiation. SIGNOR-254981 0.7 NOS2 protein P35228 UNIPROT L-citrulline smallmolecule CID:9750 PUBCHEM up-regulates 9606 7537672 f apalma Activation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the ammino acid L-arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline SIGNOR-255382 0.8 CLTB protein P09497 UNIPROT AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR form complex binding 9606 23103167 t lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-260677 0.761 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser396 NTVDLHIsNSHPLSL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178371 0.731 SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Tyr9 ARTTSQLyDAVPIQS 9606 11481331 t lperfetto Using site-directed mutants, we show that, although phosphorylation on tyr-373/376 is important for pdk1 activity, phosphorylation on tyr-9 has no effect on the activity of the kinase. Both of these residues can be phosphorylated by v-src tyrosine kinase in vitro, and co-expression of v-src leads to tyrosine phosphorylation and activation of pdk1. SIGNOR-109533 0.567 NPY protein P01303 UNIPROT NPY1R protein P25929 UNIPROT up-regulates binding 9606 9549761 t gcesareni Analogs of npy and pyy have been synthesized that contain a proline residue in position 34 of the molecule, i.e., [leu31, pro34]npy (fuhlendorff et al., 1990) or [pro34]pyy (grandt et al., 1994b), and are much more potent at y1 than y2receptors. SIGNOR-56522 0.853 RPS6K proteinfamily SIGNOR-PF26 SIGNOR YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 t lperfetto We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue. SIGNOR-252804 0.2 dacomitinib chemical CHEBI:132268 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205936 0.8 AMPK complex SIGNOR-C15 SIGNOR INSR protein P06213 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 22207502 t lperfetto Ampk phosphorylates and activates theinsulinreceptor, providing a direct link between ampk and theinsulin pathway. SIGNOR-216619 0.309 SMAD1 protein Q15797 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR form complex binding 9606 9436979 t lperfetto Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription. SIGNOR-103615 0.657 Dynorphin B chemical CHEBI:80347 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258796 0.8 TGFBI protein Q15582 UNIPROT Av/b5 integrin complex SIGNOR-C178 SIGNOR up-regulates activity binding 26387839 t lperfetto BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers SIGNOR-253271 0.349 S protein P59594 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 16310778 f Luana We demonstrated that the adenovirus-mediated over-expression of SARS-CoV spike (S) protein and its C-terminal domain (S2) induce apoptosis in Vero E6 cells in a time- and dosage-dependent manner SIGNOR-260219 0.7 N protein P59595 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001538 15294014 f Luana In the present paper, we show that SARS-CoV N is capable of inducing apoptosis of COS-1 monkey kidney cells in the absence of growth factors by down-regulating ERK (extracellular-signal-regulated kinase), up-regulating JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) pathways, and affecting their downstream effectors. SIGNOR-260204 0.7 N protein P59595 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001538 17453707 f Luana SARS-CoV Nucleocapsid Protein Induced Apoptosis of COS-1 Mediated by the Mitochondrial Pathway SIGNOR-260205 0.7 N protein P59595 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000161 16845612 f Luana Co-transfection of M and N enhances the induction of apoptosis by M or N alone, which also suggests that the structural proteins of SARS-CoV may play an important role not only in the process of invasion but also in the pathogenetic process in cells. SIGNOR-260199 0.7 M protein P59596 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000161 16845612 f Luana Co-transfection of M and N enhances the induction of apoptosis by M or N alone, which also suggests that the structural proteins of SARS-CoV may play an important role not only in the process of invasion but also in the pathogenetic process in cells. SIGNOR-260198 0.7 3a protein P59632 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates activity 9534 15958670 f Luana These results indicated that the 3a protein induced apoptosis in Vero E6 cells. SIGNOR-260195 0.7 3b protein P59633 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates activity 9534 16965829 f Luana Over-expression of severe acute respiratory syndrome coronavirus 3b protein induces both apoptosis and necrosis in Vero E6 cells SIGNOR-260194 0.7 6 protein P59634 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 18708124 f Luana A SARS-CoV protein, ORF-6, induces caspase-3 mediated, ER stress and JNK-dependent apoptosis SIGNOR-260203 0.7 7a protein P59635 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000018 15564512 f Luana 7a induces apoptosis via a caspase-dependent pathway and in cell lines derived from different organs, including lung, kidney, and liver. | The overexpression of HA-tagged 7a (7a-HA) induces apoptosis in 293T (human kidney epithelial) cells, as evidenced by an increase in caspase-3 protease activity, a hallmark of apoptosis, which is comparable to that caused by the overexpression of BAX, a proapoptotic member of the Bcl-2 family SIGNOR-260197 0.7 7a protein P59635 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 17686858 f Luana Cells expressing the ORF7a or ORF7b protein undergo apoptosis. SIGNOR-260209 0.7 MMP13 protein P45452 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Ala20 VVGTAWTaDSGEGDF -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain SIGNOR-263612 0.2 p38 proteinfamily SIGNOR-PF16 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 BTO:0001286 17254968 t inferred from 70% family members gcesareni We show that prak activates p53 by direct phosphorylation. SIGNOR-270126 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21798082 t lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-252352 0.2 ERG protein P11308 UNIPROT WNT1 protein P04628 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001321 23913826 t Luana Interestingly, our data showed that ERG drastically induced Wnt ligand gene expression. SIGNOR-261597 0.2 histamine smallmolecule CHEBI:18295 ChEBI HRH1 protein P35367 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257512 0.8 AGTR1 protein P30556 UNIPROT PAX2 protein Q02962 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15569307 f Ang II up-regulated Pax-2 gene expression via AT2R in IRPTC (immortalized rat renal proximal tubular cells) SIGNOR-252294 0.258 PRKCB protein P05771 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr434 MSFHRNHtATVRSHA 9606 11123317 t lperfetto Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5.  SIGNOR-249073 0.364 7b protein Q7TFA1 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 17686858 f Luana Cells expressing the ORF7a or ORF7b protein undergo apoptosis. SIGNOR-260210 0.7 AKT1 protein P31749 UNIPROT ADARB1 protein P78563 UNIPROT down-regulates activity phosphorylation Thr553 LQGERLLtMSCSDKI -1 31095429 t miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively SIGNOR-276194 0.2 NR3C1 protein P04150 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8639160 t gcesareni We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins SIGNOR-251680 0.583 AKT1 protein P31749 UNIPROT MST1R protein Q04912 UNIPROT up-regulates phosphorylation Ser1394 VRRPRPLsEPPRPT 9606 14505491 t lperfetto Akt/pkb phosphorylates ron ser-1394, thus providing a docking site for 14-3-3based on these results, we propose a mechanism based on msp-ron-dependent phosphorylation and 14-3-3 association, whereby the function of alpha6beta4 switches from a mechanical adhesive device into a signaling component, and might be critically involved in human epidermal wound healing SIGNOR-252471 0.541 TLN1 protein Q9Y490 UNIPROT ITGB6 protein P18564 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257631 0.571 DROSHA protein Q9NRR4 UNIPROT Microprocessor complex complex SIGNOR-C356 SIGNOR form complex binding 9606 BTO:0000552 24581491 t lperfetto Microprocessor minimally comprises the ribonuclease DROSHA and its double-stranded RNA-binding partner DGCR8 (Denli et al., 2004; Gregory et al., 2004). Microprocessor recognizes pri-miRNA through the stem-loop (Zeng et al., 2005) and the stem-loop-ssRNA junction (Han et al., 2006), and cleaves both the 5′ and 3′ flanking segments to generate pre-miRNA. SIGNOR-264848 0.922 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251594 0.695 ISL1 protein P61371 UNIPROT NLI/Lmx1.1/Isl1 complex SIGNOR-C103 SIGNOR form complex binding 9606 9452425 t miannu Interactions between LIM transcription factors were also evaluated in vivo. Cotransfected FLAG-Lmx1.1 and HA-Isl1 were capable of interacting. the NLI-dependent interaction observed between Isl1 and Lmx1.1 is likely to represent a physiologically significant complex found in the endocrine cells of the pancreas. SIGNOR-220131 0.346 ACLY protein P53396 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity by destabilization chemical modification 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-268082 0.8 HOXC10 protein Q9NYD6 UNIPROT LAMB2 protein P55268 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0000298 10835276 t Luana The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells. SIGNOR-261645 0.2 piroxicam chemical CHEBI:8249 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 9083488 t miannu Meloxicam (5),an NSAID in the enol−carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. This favorable therapeutic index has been confirmed in clinical trials. In subsequent studies we and others discovered that it possessed a selectivity profile for COX-2 superior to several other marketed NSAIDs.1 A comparison of 5 with piroxicam (6) revealed different inhibitory profiles for the two enzymes SIGNOR-258608 0.8 PRKACA protein P17612 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Ser98 RLGRRKGsGPKKERR 10116 BTO:0001556 14636580 t miannu In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function. SIGNOR-249990 0.3 TNF protein P01375 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253480 0.26 PRKCQ protein Q04759 UNIPROT RAPGEF2 protein Q9Y4G8 UNIPROT up-regulates phosphorylation Ser960 KKRVRRSsFLNAKKL 9606 BTO:0000782 18796635 t lperfetto After t-cell activation, the direct phosphorylation of rapgef2 at ser960 by pkc- theta regulates rap1 activation as well as lfa-1 adhesiveness to icam-1. Pkc- theta and its effector rapgef2 are critical factors in tcr signaling to rap1 SIGNOR-181186 0.2 DYRK2 protein Q92630 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 17349958 t llicata Here, we demonstrate that the dual-specificity tyrosine-phosphorylation-regulated kinase 2 (dyrk2) directly phosphorylates p53 at ser46. these findings indicate that dyrk2 regulates p53 to induce apoptosis in response to dna damage. SIGNOR-153544 0.657 GPR132 protein Q9UNW8 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257341 0.397 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9534 BTO:0004055 14993270 t lperfetto We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling. SIGNOR-244862 0.748 MAPK7 protein Q13164 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Thr312 QATQPLAtPVVSVTT 9606 BTO:0000567 10849446 t lperfetto We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo. SIGNOR-236583 0.699 GRK5 protein P34947 UNIPROT ST13 protein P50502 UNIPROT up-regulates activity phosphorylation Ser346 AQNPANMsKYQSNPK 9606 BTO:0000007 21728385 t miannu An in vitro screen for novel GRK substrates revealed Hsp70 interacting protein (Hip) as a substrate. GRK5, but not GRK2, bound to and stoichiometrically phosphorylated Hip in vitro. The primary binding domain of GRK5 was mapped to residues 303-319 on Hip, while the major site of phosphorylation was identified to be Ser-346. GRK5 also bound to and phosphorylated Hip on Ser-346 in cells.we found that the phosphorylation of Ser-346 was required for proper agonist-induced internalization of the chemokine receptor CXCR4. SIGNOR-262877 0.271 LMNA protein P02545 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 23401537 f lperfetto Mammalian lamin meshworks consist of two types of lamin proteins, A type and B type, and it has been reported that nuclear blebs are enriched in A-type lamins. SIGNOR-83706 0.7 LPCAT2 protein Q7L5N7 UNIPROT acyl-CoA(4-) chemical CHEBI:58342 ChEBI down-regulates quantity chemical modification 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272767 0.8 TWIST2 protein Q8WVJ9 UNIPROT F2R protein P25116 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255502 0.2 PLK1 protein P53350 UNIPROT RAP1GAP protein P47736 UNIPROT down-regulates phosphorylation Ser525 AGQKTPDsGHVSQEP 9606 25329897 t lperfetto Plk1 phosphorylates ser525 in conserved 524dsghvs529 degron of rap1gap and promotes its interaction with _-trcp. Together, these results further support a model in which plk1, but not cdk1 or gsk-3_-mediated phosphorylation of rap1gap is a prerequisite for mitotic degradation. SIGNOR-205577 0.464 ELE1-RET fusion protein SIGNOR-FP10 SIGNOR SHC1 protein P29353 UNIPROT up-regulates activity binding 9606 16946010 t miannu RET/PTC is tumorigenic in thyroid follicular cells; it transforms thyroid cells in culture and gives rise to thyroid carcinomas in transgenic mice. effects of RET/PTC activation require signaling along the MAPK pathway and, more specifically, the presence of the functional BRAF kinase. all breakpoints in the RET gene occur within intron 11, leaving intact the TK domain of the receptor and enabling the RET/PTC oncoprotein to bind SHC via Y1062 and activate the RAS-RAF-MAPK cascade SIGNOR-251985 0.2 SRC protein P12931 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr227 KVDATADyICKVKWG 9606 BTO:0000007 32420483 t done miannu  We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. SIGNOR-274108 0.268 PKA proteinfamily SIGNOR-PF17 SIGNOR SLITRK1 protein Q96PX8 UNIPROT up-regulates activity phosphorylation Ser695 DCGSHSLsD -1 19640509 t miannu In our studies, SICD was phosphorylated by PKA, PKC, and CK2, and association of SLITRK1 with 14-3-3 was regulated by phosphorylation at Ser695. Co-precipitation experiments demonstrated much greater recovery of 14-3-3 in SLITRK1 precipitates when wild-type or S695E was used, as compared with S695A, consistent with the results with purified peptides. SIGNOR-273634 0.2 DKC1 protein O60832 UNIPROT TERT protein O14746 UNIPROT up-regulates activity binding 18680434 t lperfetto Dyskerin was recently found to be associated with active human telomerase (34), and mutations in dyskerin or NOP10 or deletion of the H/ACA motif of hTERC result in diminished telomerase activity SIGNOR-263332 0.808 CARM1 protein Q86X55 UNIPROT PAX7 protein P23759 UNIPROT up-regulates methylation 10090 BTO:0002314 BTO:0001103 29681515 t apalma Carm1 specifically methylates Pax7 at multiple arginine residues in the N terminus of Pax7 SIGNOR-255898 0.432 WNT4 protein P56705 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131835 0.634 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 16982699 t gcesareni Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt. SIGNOR-244184 0.2 FFAR1 protein O14842 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256942 0.2 RPS27A protein P62979 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262424 0.784 DUX4 protein Q9UBX2 UNIPROT PITX1 protein P78337 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 17984056 t Luana DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1 SIGNOR-261590 0.311 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 16582879 t Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR SIGNOR-248410 0.78 PGM1 protein P36871 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267929 0.8 TGFBR2 protein P37173 UNIPROT USP2 protein O75604 UNIPROT up-regulates activity phosphorylation Ser207 ENYGRKGsASQVPSQ -1 29490279 t miannu Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1. SIGNOR-273604 0.2 Dynorphin B chemical CHEBI:80347 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258797 0.8 EIF3D protein O15371 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266397 0.928 POMC protein P01189 UNIPROT MC4R protein P32245 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268710 0.77 DDX58 protein O95786 UNIPROT MAVS protein Q7Z434 UNIPROT up-regulates activity binding 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260139 0.935 olanzapine chemical CHEBI:7735 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 10116 BTO:0000529 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258510 0.8 DCK protein P27707 UNIPROT G2/M_transition-checkpoint phenotype SIGNOR-PH146 SIGNOR up-regulates phosphorylation Ser74 27879648 f lperfetto Deoxycytidine kinase (dCK) is a key enzyme in deoxyribonucleoside salvage and the anti-tumor activity for many nucleoside analogs. dCK is activated in response to ionizing radiation (IR)-induced DNA damage and it is phosphorylated on Serine 74 by the Ataxia-Telangiectasia Mutated (ATM) kinase in order to activate the cell cycle G2/M checkpoint. SIGNOR-275806 0.7 CDC14A protein Q9UNH5 UNIPROT CDC25A protein P30304 UNIPROT down-regulates activity dephosphorylation 9606 20956543 f miannu Cdc14A inhibits Cdc25A and Cdc25B activity, the latter through direct binding and dephosphorylation ( ).|Indeed, in vitro dephosphorylation of Cdk1-cyclin B1-phosphorylated Cdc25A by Cdc14A did not inhibit its catalytic activity (data not shown).|Taken together, our results suggest that at the G2/M transition Cdc14A acts on an unknown protein, which in turn inhibits Cdc25A phosphatase activity. SIGNOR-277065 0.517 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 SIGNOR-C110 23151663 t gcesareni Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells. SIGNOR-199504 0.856 RNF146 protein Q9NTX7 UNIPROT TNKS2 protein Q9H2K2 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 21799911 t We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation. SIGNOR-260005 0.598 MYC protein P01106 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150;BTO:0000782 BTO:0000887;BTO:0001260 11313917 f amattioni P27(kip1) gene is a target of transcriptional repression by c-myc. SIGNOR-107032 0.548 ABL1 protein P00519 UNIPROT RAD52 protein P43351 UNIPROT up-regulates activity phosphorylation Tyr104 DLNNGKFyVGVCAFV 9606 BTO:0000007 12379650 t C-Abl tyrosine kinase associates with and phosphorylates Rad52 on tyrosine 104. he functional significance of c-Abl-dependent phosphorylation of Rad52 is underscored by our findings that cells that express the phosphorylation-resistant Rad52 mutant, in which tyrosine 104 is replaced by phenylalanine, exhibit compromised nuclear foci formation in response to IR. SIGNOR-251435 0.672 SCF-FBW7 complex SIGNOR-C135 SIGNOR GFI1 protein Q99684 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000498 31289136 t miannu GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation. SIGNOR-277467 0.2 PPP2CA protein P67775 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity dephosphorylation Ser1981 SLAFEEGsQSTTISS 9606 15510216 t Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro. SIGNOR-248644 0.339 CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Thr507 KFRTKSRtWAGEKSK 9606 20068082 t gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts); SIGNOR-163154 0.851 mTORC1 complex SIGNOR-C3 SIGNOR TFEB protein P19484 UNIPROT down-regulates activity phosphorylation Ser211 LVGVTSSsCPADLTQ 9606 BTO:0000567 SIGNOR-C3 22692423 t gcesareni Our data points to the lysosome as the site where mTORC1-dependent phosphorylation of TFEB occurs. [...]Our study has revealed a specific role for phosphorylation of TFEB S211 in the negative regulation of the nuclear abundance of TFEB. This occurs through the promotion of 14-3-3 binding and the masking of the nearby NLS on TFEB. SIGNOR-248274 0.37 PPP4C protein P60510 UNIPROT PLK1 protein P53350 UNIPROT down-regulates activity dephosphorylation Ser137 LELCRRRsLLELHKR 9606 35546066 t miannu PPP4C dephosphorylated PLK1 at the S137 site, negatively regulating its activity in the DSB response in early embryonic cells. SIGNOR-277076 0.426 GSK3A protein P49840 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser133 LPYSPVSsPQSSPRL 9606 22778263 t lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. SIGNOR-198126 0.272 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 18819921 t Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases. SIGNOR-248387 0.48 RPS6KA3 protein P51812 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates quantity phosphorylation Ser789 DTRSSTCsSGEDSVF 9606 BTO:0001938 24141780 t miannu  Both in vitro and in vivo experiments confirmed the interaction and we show that phosphorylated RSK2 binds to and phosphorylates serine 789 in the C-terminal tail of FGFR1.prevention of FGFR1 phosphorylation by inhibition of RSK2 activity or mutation of serine 789 to alanine reduced FGFR1 endocytosis and ubiquitination explaining mechanistically the prolonged signaling activity. SIGNOR-276599 0.364 GAB2 protein Q9UQC2 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t milica The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival SIGNOR-204966 0.444 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 16679294 t gcesareni Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action SIGNOR-146680 0.263 PSENEN protein Q9NZ42 UNIPROT RYK protein P34925 UNIPROT up-regulates cleavage 9606 19000841 t gcesareni Ryk activity is modulated through cleavage of its icd by gamma-secretase SIGNOR-182145 0.2 CDK2 protein P24941 UNIPROT UBTF protein P17480 UNIPROT up-regulates activity phosphorylation Ser389 INKKQATsPASKKPA 10090 BTO:0000944 SIGNOR-C16 11698641 t lperfetto Phosphorylation of ubf at serine 388 is required for interaction with rna polymerase i and activation of rdna transcription. After g(1) progression ubf is phosphorylated at serine 388 by cdk2/cyclin e and cdk2/cyclin a. Conversion of serine 388 to glycine abolishes ubf activity SIGNOR-235419 0.379 SIRT1 protein Q96EB6 UNIPROT FOXL2 protein P58012 UNIPROT down-regulates deacetylation 9606 19010791 t miannu We find that foxl2 activity is repressed by the sirt1 deacetylase. SIGNOR-182306 0.514 PDGFRB protein P09619 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr154 QLNDSAAyYLNDLDR -1 33139573 t miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. SIGNOR-277233 0.2 GSK3B protein P49841 UNIPROT AKAP11 protein Q9UKA4 UNIPROT down-regulates activity phosphorylation Thr1136 AKEFAPAtPPSTPHN 9606 BTO:0000007 26088133 t lperfetto A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). Using a combination of molecular and cellular approaches we show that GSK3beta phosphorylation of Thr-1132 on AKAP220 initiates recruitment of this kinase into the enzyme scaffold. We also find that AKAP220 anchors GSK3beta and its substrate beta-catenin in membrane ruffles. SIGNOR-264816 0.38 EDN1 protein P05305 UNIPROT EDNRA protein P25101 UNIPROT up-regulates binding 9606 16597412 t gcesareni Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors. SIGNOR-145759 0.877 PIK3CA protein P42336 UNIPROT TPM1 protein P09493 UNIPROT up-regulates activity phosphorylation Ser61 EDELDKYsEALKDAQ -1 16094730 t miannu Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization. SIGNOR-263027 0.2 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser4 sPRRPLIL 9606 22094256 t lperfetto We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627) SIGNOR-177251 0.608 PDP2 protein Q9P2J9 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity dephosphorylation 9606 20208177 t Pyruvate dehydrogenase phosphatase (PDP) is a mitochondrial serine phosphatase that activates phosphorylated pyruvate dehydrogenase complex by dephosphorylation SIGNOR-251665 0.644 CKM complex complex SIGNOR-C406 SIGNOR Core mediator complex complex SIGNOR-C405 SIGNOR down-regulates activity binding -1 23563140 t miannu We found that interaction of the CKM with Mediator's middle module interferes with CTD-dependent RNAPII binding to a previously unknown middle-module CTD-binding site and with the holoenzyme formation process. Taken together, our results reveal the basis for CKM repression, clarify the origin of the connection between CKM subunits and the CTD and suggest that a combination of competitive interactions and conformational changes that facilitate holoenzyme formation underlie the mechanism of transcription regulation by Mediator. SIGNOR-266687 0.754 MAPK3 protein P27361 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates activity phosphorylation Thr906 SLDNNYStPNERGDH 9615 BTO:0000837 32010791 t miannu  Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation. SIGNOR-277506 0.298 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA9 protein Q9Y5G4 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265700 0.2 zotepine chemical CHEBI:32316 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258558 0.8 PRKACA protein P17612 UNIPROT SNAPIN protein O95295 UNIPROT up-regulates activity phosphorylation Ser50 HVHAVREsQVELREQ 11283605 t miannu PKA-phosphorylation of Snapin significantly increases its binding to synaptosomal-associated protein-25 (SNAP-25). Mutation of Snapin serine 50 to aspartic acid (S50D) mimics this effect of PKA phosphorylation SIGNOR-250053 0.312 CASZ1 protein Q86V15 UNIPROT EGFL7 protein Q9UHF1 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001176 24150064 t miannu We have recently demonstrated that a novel transcriptional pathway involving activation of the Epidermal Growth Factor-like Domain 7 (Egfl7) gene by the transcription factor CASTOR (CASZ1) is required for blood vessel assembly and lumen morphogenesis. SIGNOR-266858 0.436 MAX protein P61244 UNIPROT MGA protein Q8IWI9 UNIPROT up-regulates activity binding 9606 7954804 t 2 miannu the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. SIGNOR-240261 0.552 AKT proteinfamily SIGNOR-PF24 SIGNOR GATA2 protein P23769 UNIPROT down-regulates activity phosphorylation Ser401 QTRNRKMsNKSKKSK 9606 BTO:0000876 15837948 t PI-3K/Akt-dependent manner. lperfetto We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity SIGNOR-244271 0.2 clofarabine chemical CHEBI:681569 ChEBI RRM1 protein P23921 UNIPROT down-regulates activity chemical inhibition 9606 1707752 t miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate SIGNOR-258357 0.8 USP6 protein P35125 UNIPROT MMP10 protein P09238 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20418905 f miannu In this study we show that tre17 is sufficient to induce expression of mmp-9 and mmp-10, in a manner requiring its usp activity, but not its ability to bind arf6. Tre17 induces transcription of mmp-9 through activation of nuclear factor-kappab (nf-kappab), mediated in part by the gtpase rhoa and its effector kinase, rock. SIGNOR-164943 0.2 ARNT protein P27540 UNIPROT JUN protein P05412 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 21544813 f lperfetto Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC SIGNOR-253697 0.555 DHX9 protein Q08211 UNIPROT NUP98 protein P52948 UNIPROT up-regulates activity binding 9606 BTO:0000007 28221134 t miannu Here we report on the identification of the DExH/D-box helicase DHX9 as an intranuclear Nup98 binding partner. Various results, including in vitro assays, show that the FG/GLFG region of Nup98 binds to N- and C-terminal regions of DHX9 in an RNA facilitated manner. Importantly, binding of Nup98 stimulates the ATPase activity of DHX9, and a transcriptional reporter assay suggests Nup98 supports DHX9-stimulated transcription. SIGNOR-260954 0.363 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR PKM protein P14618 UNIPROT down-regulates activity phosphorylation Ser37 MCRLDIDsPPITARN 9606 BTO:0001106 28607489 t miannu We show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. Phosphomimicking mutants of PFKP (S679E) or PKM2 (S37E) displayed decreased catalytic activity, which was not further affected by pre-incubation with cyclin D3-CDK6 (Extended Data Fig. 3a, b). SIGNOR-276453 0.262 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser689 SQPGQLMsQPSTASN 9606 10195894 t Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. SIGNOR-251279 0.2 ROCK1 protein Q13464 UNIPROT Brown_adipogenesis phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103 22944199 f gcesareni Other g protein-mediated pathways are the planar cell polarity (pcp) pathway (shown in blue) leading to the activation of rac/rho, c-jun n-terminal kinase (jnk), and/or rho-associated kinase (rock). Jnk can induce jun, which, together with fos, forms the ap-1 early response transcription factor. Both pcp pathways have been implicated in cytoskeletal rearrangements SIGNOR-198840 0.7 PTPN1 protein P18031 UNIPROT ACTN1 protein P12814 UNIPROT up-regulates dephosphorylation Tyr12 DSQQTNDyMQPEEDW 9606 16291744 t gcesareni Here we report that protein-tyrosine phosphatase 1b (ptp 1b) is an ?-Actinin phosphatase. SIGNOR-141634 0.341 AMPK complex SIGNOR-C15 SIGNOR PAK2 protein Q13177 UNIPROT unknown phosphorylation Ser20 APPVRMSsTIFSTGG 9606 22137581 t lperfetto Together, these results indicate that ampk phosphorylates endogenous ppp1r12c at s452 and pak2 at s20 in human cells. SIGNOR-216612 0.244 PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation 9606 19951971 t lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. SIGNOR-249628 0.8 CDK5 protein Q00535 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity phosphorylation Ser203 DLEFSSGsPGKETNE 9606 17440046 t llicata Cdk5 phosphorylated gr at multiple serines, including ser203 and ser211 of its n-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to dna.| the effect of CDK5 on GR-induced transcriptional activity is specific to gene promoter, and possibly, to tissue SIGNOR-154401 0.459 ATF6 protein P18850 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network SIGNOR-260180 0.644 Papain-like proteinase protein P0C6X9-PRO_0000037340 UNIPROT IFNB1 protein P01574 UNIPROT down-regulates quantity by repression 9606 BTO:0000007 17761676 f lperfetto SARS-CoV PLpro domain inhibits activation of IFN-β promoter following engagement of TLR3 or RIG-I pathways independent of its protease activity SIGNOR-260277 0.2 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 BTO:0000007 12612081 t In this study, we investigated the downregulation of insulin receptor (IR) signaling by TCPTP. In response to insulin stimulation, the TC48-D182A and TC45-D182A substrate-trapping mutants formed stable complexes with the endogenous tyrosine-phosphorylated IR beta-subunit in 293 cells.|IR β-subunit phosphorylated on tyrosine and specifically on tyrosines 1162 and 1163 could be coimmunoprecipitated with the TC48-D182A and TC45-D182A mutants but not the wild-type TC48 or TC45 in response to insulin SIGNOR-248385 0.606 STAT1 protein P42224 UNIPROT S100A10 protein P60903 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567;BTO:0002923 12645529 f miannu IFN-gamma induced a rapid tyrosine phosphorylation and nuclear translocation of STAT1 protein, which is involved in the binding to the GAS-2 site in the p11 promoter by EMSA analysis. These data suggest that IFN-gamma-induced p11 expression is mediated through the binding of STAT1 to GAS sites in the p11 promoter. SIGNOR-255237 0.2 trichostatin A chemical CHEBI:46024 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258014 0.8 FOXA1 protein P55317 UNIPROT KRT7 protein P08729 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002861 20043065 f miannu These results suggest that FOXA1 induces not only KRT7 but also LOXL2 in a subset of poor prognostic ESCCs with metastatic lymph nodes. FOXA1 siRNA treatment of esophageal cancer cells reduced the mRNA level of both KRT7 and a stabilizer of epithelial-mesenchymal transition (EMT) regulator LOXL2, and that both FOXA1 and LOXL2 siRNAs reduced invasion and migration of ESCC cells. SIGNOR-254167 0.283 OPRL1 protein P41146 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257001 0.354 iodide smallmolecule CHEBI:16382 ChEBI 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI up-regulates quantity precursor of 9606 16098474 t scontino TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. SIGNOR-268120 0.8 UNC5D protein Q6UXZ4 UNIPROT DCC protein P43146 UNIPROT down-regulates activity binding 9606 BTO:0001484 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268167 0.567 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120172 0.321 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Lys) smallmolecule CHEBI:29185 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270403 0.8 AIMP2 protein Q13155 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 t miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). SIGNOR-270361 0.919 TAF3/TRF3 complex SIGNOR-C23 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 10090 BTO:0000165 17704303 f llicata Here we report that differentiation of myoblast to myotubes involves the disruption of the canonical holo-TFIID and replacement by a novel TRF3/TAF3 (TBP-related factor 3/TATA-binding protein-associated factor 3) complex. SIGNOR-237621 0.7 MAPK1 protein P28482 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates quantity by destabilization phosphorylation Ser197 SATDSDGsPLSNSQP 9606 15632084 t gcesareni In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3. SIGNOR-132971 0.901 FLNA protein P21333 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates binding 9606 BTO:0000848 9006895 t gcesareni Sek-1 binds directly and specifically to the actin-binding protein abp-280. As a consequence, active sek-1 is capable of phosphorylating and activating in vitro added bacterial recombinant sapk. SIGNOR-45887 0.507 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr925 DRSNDKVyENVTGLV 9606 16782899 t llicata Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain SIGNOR-147203 0.476 RPS6KB1 protein P23443 UNIPROT RPS6 protein P62753 UNIPROT up-regulates activity phosphorylation Ser236 AKRRRLSsLRASTSK 10090 15809305 t lperfetto A knockin mouse carrying mutations at all phosphorylation sites in the primary s6k substrate, ribosomal protein s6 (rps6), has provided insight into the physiological role of this protein phosphorylation event. Of the many known substrates of s6k1, it is rps6 that has been shown to be directly involved, via its phosphorylation, in controlling cell size. SIGNOR-135176 0.936 dicyclomine chemical CHEBI:4514 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258388 0.8 KLF2 protein Q9Y5W3 UNIPROT HBE1 protein P02100 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15947087 f Regulation of expression miannu Our results show that KLF2 positively regulates the human (ε) and murine (Ey and βh1) embryonic globin genes at both E10.5 and E12.5, in the yolk sac, which is the site of primitive erythropoiesis. SIGNOR-251830 0.245 GSK3B protein P49841 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR form complex binding 9606 BTO:0000586 9734785 t lperfetto Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level. SIGNOR-227299 0.833 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 23431053 t milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity SIGNOR-201318 0.846 EGR1 protein P18146 UNIPROT TBXA2R protein P21731 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19747485 f Collectively, data establish that regulated WT1 followed by sequential Egr1 and Sp1 binding to elements within Prm1 mediate repression and subsequent induction of TPα during differentiation into the megakaryocytic phenotype, shedding significant insights into factors regulating TPα expression therein. SIGNOR-254253 0.263 PPM1F protein P49593 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 11864573 t The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX. SIGNOR-248530 0.399 RET protein P07949 UNIPROT DOK6 protein Q6PKX4 UNIPROT up-regulates binding 9606 BTO:0000671 15286081 t gcesareni These data identify dok-6 as a novel dok-4/5-related adaptor molecule that may function in vivo to transduce signals that regulate ret-mediated processes such as axonal projection. SIGNOR-127382 0.633 BDKRB2 protein P30411 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257199 0.36 LEF1 protein Q9UJU2 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 24344199 t lperfetto We further demonstrate that Fst is a direct target of the WNT/β-catenin pathway. Activation and inactivation of β-catenin induced and inhibited Fst expression, respectively, in both C2C12 cells and mouse embryos. Specific TCF/LEF1 binding sites within the promoter and intron 1 region of the Fst gene were required for RSPO2 and WNT/β-catenin-induced Fst expression. SIGNOR-251722 0.283 BRSK2 protein Q8IWQ3 UNIPROT WDR45 protein Q9Y484 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001938 28561066 t miannu WIPI4 is stimulated by AMPK, NUAK2 and BRSK2. This finding is supported by the results of our kinome screening, which identified AMPK and the AMKP-related kinases NUAK2 and BRSK2, all of which function downstream of LKB1 (ref. 69) and stimulate the localization of WIPI4 to nascent autophagosomes. SIGNOR-268482 0.25 SIRT1 protein Q96EB6 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates deacetylation Lys64 RAGCCLGkAVRGAKG 9606 17098745 t gcesareni Sirt1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (lys-64 and -70) on smad7. sirt1-mediated deacetylation of smad7 enhanced smad ubiquitination regulatory factor 1 (smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of smad7 in sirt1-overexpressing mesangial cells. SIGNOR-150595 0.452 PF-5274857 chemical CID:56956240 PUBCHEM SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206058 0.8 PRKCQ protein Q04759 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr375 GRGARGGtRGGRGRI 9606 14699138 t lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation SIGNOR-249256 0.307 MAP4K1 protein Q92918 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser556 TKMQPPRsRSSIMSI -1 19706536 t miannu HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKC consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro. SIGNOR-276259 0.506 TRIM27 protein P14373 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates 9606 BTO:0000671 12807881 f miannu We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38. SIGNOR-102025 0.2 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Thr183 ACTNFMMtPYVVTRY 9606 11062067 t phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif gcesareni Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). These results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway. SIGNOR-83744 0.622 CDK1 protein P06493 UNIPROT PDCD1 protein Q15116 UNIPROT down-regulates quantity by destabilization phosphorylation Ser261 PSGMGTSsPARRGSA 9606 BTO:0000007 36104103 t miannu We demonstrated that cyclin-dependent kinase 1-mediated phosphorylation of Ser261 residue primes PD-1 protein nucleus translocation and binding with FBW7. SIGNOR-277605 0.2 IFNB1 protein P01574 UNIPROT MGMT protein P16455 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000711 17564708 f miannu we observed that IFN-beta sensitized TMZ-resistant glioma cells with the unmethylated MGMT promoter and that the mechanism of action was possibly due to attenuation of MGMT expression via induction of TP53. In this context, IFN-beta inactivates MGMT via p53 gene induction and enhances the therapeutic efficacy to TMZ. SIGNOR-255438 0.364 NFIB protein O00712 UNIPROT GAS6 protein Q14393 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268882 0.2 KDM6A protein O15550 UNIPROT SPI1 protein P17947 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29736013 t miannu Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase SIGNOR-260036 0.255 CDK1 protein P06493 UNIPROT SLBP protein Q14493 UNIPROT down-regulates quantity by destabilization phosphorylation Thr62 RRPESFTtPEGPKPR 9606 18490441 t lperfetto Phosphorylation of threonine 61 by cyclin a/Cdk1 triggers degradation of stem-loop binding protein at the end of S phase SIGNOR-265258 0.428 MIB1 protein Q86YT6 UNIPROT JAG1 protein P78504 UNIPROT up-regulates activity ubiquitination 9606 BTO:0001253 18043734 t lperfetto Mib1 is essential for the generation of functional notch ligands and regulates the classical notch ligands dll1, dll4, jag1, and jag2 in vertebrates mib1 is an essential e3 ubiquitin ligase for jag1 in the developing cerebellum. SIGNOR-159480 0.68 FGG protein P02679 UNIPROT Fibrinogen complex SIGNOR-C311 SIGNOR form complex binding -1 25427968 t lperfetto Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aalpha, Bbeta, and gamma, encoded by the FGA, FGB, and FGG gene, respectively). SIGNOR-263393 0.752 IKBKE protein Q14164 UNIPROT IRF1 protein P10914 UNIPROT down-regulates activity phosphorylation Ser221 VSPMPSTsEATTDED 9606 BTO:0000007 24396068 t miannu We demonstrated that IKK-ε phosphorylated the transcription factor IFN regulatory factor 1 (IRF-1) at amino acid (aa) 215/219/221 in primary CD4(+) T cells and blocked its transcriptional activity.  SIGNOR-276479 0.357 PSMD7 protein P51665 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263349 0.903 SIRT3 protein Q9NTG7 UNIPROT CYP11A1 protein P05108 UNIPROT up-regulates quantity by stabilization deacetylation Lys149 KKSAAWKkDRVALNQ 9606 BTO:0002588 22585829 t lperfetto Resveratrol stimulates cortisol biosynthesis by activating SIRT-dependent deacetylation of P450scc.|Stable overexpression of SIRT3 abrogates the cellular content of acetylated P450scc, concomitant with an increase in P450scc protein expression and cortisol secretion. Mutation of K148 and K149 to alanine stabilizes the expression of P450scc and results in a 1.5-fold increase in pregnenolone biosynthesis. SIGNOR-268718 0.2 EGFR protein P00533 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates phosphorylation Tyr4 yTVVYFPV 9606 BTO:0000150 19254954 t llicata Taken together, these results and those of the ms/ms analyses confirmed tyr-3, tyr-7, and tyr-198 to be primary residues phosphorylated by egfr in the gstp1 protein. The phosphorylation increased gstp1 enzymatic activity significantly, SIGNOR-184383 0.448 SRC protein P12931 UNIPROT PRKCI protein P41743 UNIPROT up-regulates phosphorylation Tyr334 RLFFVIEyVNGGDLM 9606 11713277 t llicata Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain. SIGNOR-111928 0.513 PKI-402 chemical CID:44187953 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206250 0.8 PKI-402 chemical CID:44187953 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206256 0.8 SPI1 protein P17947 UNIPROT NAB2 protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16923394 f miannu PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation SIGNOR-256039 0.311 PNMT protein P11086 UNIPROT adrenaline smallmolecule CHEBI:33568 ChEBI up-regulates quantity chemical modification 9606 7961964 t brain lperfetto In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline). SIGNOR-264007 0.8 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 SIGNOR-C83 17015473 t The effect has been demonstrated using Q01196-8 gcesareni Previous studies have shown that phosphorylation of aml1, particularly at serines 276 and 303, affects its transcriptional activation. Here, we report that phosphorylation of aml1 serines 276 and 303 can be blocked in vivo by inhibitors of the cyclin-dependent kinases (cdks) cdk1 and cdk2. Furthermore, these residues can be phosphorylated in vitro by purified cdk1/cyclin b and cdk2/cyclin a. SIGNOR-149976 0.2 ECM stimulus SIGNOR-ST20 SIGNOR A10/b1 integrin complex SIGNOR-C167 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259049 0.7 PSMA5 protein P28066 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263364 0.864 CSNK2A2 protein P19784 UNIPROT CDC37 protein Q16543 UNIPROT up-regulates activity phosphorylation Ser13 VWDHIEVsDDEDETH -1 12930845 t llicata Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. | In this report, we demonstrate that mammalian Cdc37 is phosphorylated on Ser13 in situ in rabbit reticulocyte lysate and in cultured K562 cells and that casein kinase II is capable of quantitatively phosphorylating recombinant Cdc37 at this site. SIGNOR-250982 0.502 MYC protein P01106 UNIPROT PFK proteinfamily SIGNOR-PF79 SIGNOR up-regulates quantity by expression transcriptional regulation 10116 10823814 t C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway. SIGNOR-267587 0.336 IL20 protein Q9NYY1 UNIPROT IL22RA1 protein Q8N6P7 UNIPROT up-regulates binding 9606 11163236 t gcesareni An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis. SIGNOR-151877 0.59 MXD1 protein Q05195 UNIPROT UBTF protein P17480 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000539 15282543 t lperfetto MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter. SIGNOR-269646 0.367 CSNK1A1 protein P48729 UNIPROT OSBP2 protein Q969R2 UNIPROT up-regulates activity phosphorylation 30925160 t lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. SIGNOR-264877 0.2 JAK2 protein O60674 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity phosphorylation Tyr341 GQRDSSYyWEIEASE 10090 BTO:0001482 8876196 t  JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process. SIGNOR-251362 0.601 CTH protein P32929 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. SIGNOR-275820 0.8 serotonin smallmolecule CHEBI:28790 ChEBI HTR2A protein P28223 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264293 0.8 AKT2 protein P31751 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation 9606 16023596 t gcesareni Activated pi3k/akt pathway results in inhibitory phosphorylation of gsk3 SIGNOR-138179 0.538 CUL4A protein Q13619 UNIPROT ARIH1 protein Q9Y4X5 UNIPROT up-regulates activity binding 9606 BTO:0000007 24076655 t miannu Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin. SIGNOR-268847 0.284 TFEB protein P19484 UNIPROT HPS3 protein Q969F9 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 f lperfetto Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14) SIGNOR-276794 0.2 PPP1CC protein P36873 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates dephosphorylation 9606 21750978 t miannu Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway SIGNOR-174865 0.336 MAPK1 protein P28482 UNIPROT NR5A1 protein Q13285 UNIPROT up-regulates activity phosphorylation Ser203 EYPEPYAsPPQPGLP 9534 BTO:0004055 10230405 t lperfetto Here we show that maximal SF-1-mediated transcription and interaction with general nuclear receptor cofactors depends on phosphorylation of a single serine residue (Ser-203) located in a major activation domain (AF-1) of the protein. Moreover, phosphorylation-dependent SF-1 activation is likely mediated by the mitogen-activated protein kinase (MAPK) signaling pathway. SIGNOR-249431 0.475 Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 16440056 f lperfetto The most abundant cytoplasmic dynein complex, cytoplasmic dynein 1, is involved in functions as diverse as spindle-pole organization and nuclear migration during mitosis, the positioning and functioning of the endoplasmic reticulum, the Golgi apparatus, and the nucleus, and also the minus-end-directed transport of vesicles, including endosomes and lysosomes, along microtubules and retrograde axonal transport in neurons. SIGNOR-265059 0.7 MAPK8 protein P45983 UNIPROT NFE2 protein Q16621 UNIPROT down-regulates quantity by destabilization phosphorylation Ser157 LNYSDAEsLELEGTE 19966288 t lperfetto Through use of different approaches including nano-scale proteomics, we show that activated-JNK, or Phospho-JNK (P-JNK), physically interacts with p45/NF-E2 and phosphorylates its Ser157 residue. This reaction leads to the poly-ubiquitination of p45/NF-E2 at one or more of six Lys residues, one of which being also a sumoylation site, and its degradation through the proteasome pathway. SIGNOR-275552 0.42 CDC25C protein P30307 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR up-regulates activity dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 BTO:0001938 10913154 t lperfetto Cyclin B-Cdc2 complexes are maintained in an inactive state until the end of G2 by phosphorylation of the Thr14/Tyr15 residues. Around the time of nuclear translocation of the complex, these residues are dephosphorylated, resulting in the formation of an active cyclin B-Cdc2 complex (2). As mentioned, this dephosphorylation occurs by a Cdc25 protein phosphatase. Three Cdc25 family members have been identified to date, A, B and C, the last one being the active one at the onset of mitosis. The activity of Cdc25C itself can be enhanced through phosphorylation by cyclin B-Cdc2 (9, 10). Therefore, activation of cyclin B-Cdc2 has been proposed to result in an autocatalytic feedback loop to ensure rapid activation of these complexes at the G2/M transition SIGNOR-255037 0.839 ADORA1 protein P30542 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256697 0.435 AMPK complex SIGNOR-C15 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity 9606 30274374 f miannu AMPK inhibits the mTOR pathway through phosphorylation and activation of tuberous sclerosis protein 2 (TSC2) and causes direct activation of unc-51-like autophagy activating kinase 1 (ULK1) via phosphorylation of Ser555, thus promoting initiation of autophagy. SIGNOR-260096 0.549 ILK protein Q13418 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Thr710 DLQEAEKtIGRSRST 9606 12030846 t lperfetto Mypt1 was phosphorylated by ilk and phosphorylation sites in the n- and c-terminal fragments of mypt1 were detected. From sequence analyses, three sites were identified: a primary site at thr(709), and two other sites at thr(695) and thr(495). phosphorylation of the various sites indicated that thr695 was the major inhibitory site, thr709 had only a slight inhibitory effect SIGNOR-87928 0.567 RAP1B protein P61224 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR up-regulates activity binding 10090 BTO:0003104 12808052 t lperfetto The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration|Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity. SIGNOR-253363 0.421 SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates transcriptional regulation 9606 27563484 f ggiuliani Smad1/5/8-Smad4 complex transcribed Runx2 expression, as they complex with Runx2 to initiate other osteoblast gene expression. SIGNOR-255784 0.476 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity phosphorylation Ser87 AAAGPALsPVPPVVH 9606 18570871 t gcesareni Jnk1-mediated phosphorylation of bcl-2 regulates starvation-induced autophagy. SIGNOR-179092 0.564 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR IDH1 protein O75874 UNIPROT down-regulates quantity by destabilization phosphorylation Thr157 GKVEITYtPSDGTQK 34929314 t lperfetto During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome SIGNOR-267621 0.273 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 15659650 t lperfetto Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-217857 0.771 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 8119945 t gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. SIGNOR-36267 0.852 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 f miannu YAP and TAZ are two main downstream effectors of the Hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-277639 0.7 G3BP1 protein Q13283 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity binding 9606 25520508 t miannu We show that G3BP1 can activate effectors of the innate immune transcriptional program, culminating in enhanced expression of a set of cytokines. We demonstrate that a subset of PKR is recruited to SGs, that close-proximity interactions between G3BP1 and PKR complexes increase in response to stress and PKR activation, that once activated PKR no longer associates with SGs, and that the PXXP domain of G3BP1 is essential for PKR recruitment to SGs and PKR activation in cells. Together, these findings suggest that G3BP1 plays an important role in the recruitment of PKR to SGs and suggest that activation of PKR can take place at the SG. SIGNOR-260750 0.312 dexmedetomidine chemical CHEBI:4466 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258908 0.8 CRH protein P06850 UNIPROT CRHR2 protein Q13324 UNIPROT up-regulates activity binding 9606 23504413 t lperfetto The actions of CRH are transduced through CRH receptors, which belong to the class II/secretin-like family of the G-protein coupled receptor (GPCR) superfamily (Martin et al. 2005). There are three types of CRH receptors – type 1 (CRHR1), type 2 (CRHR2) and type 3 (CRHR3). Among these, CRHR3 has not been identified in mammals. |CRH is a high-affinity ligand of CRHR1. It also binds to CRHR2, but with lower affinity SIGNOR-268611 0.915 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr470 AYATEAVyESAEAPG 9606 12601080 t lperfetto Cortactin was first identified as a substrate of v-src (46) that mediates in vitro phosphorylation of residues tyr-421, tyr-466, and tyr-482 at the c terminus of the murine ortholog (47). Phosphorylation of these residues attenuates the f-actin cross-linking activity SIGNOR-98716 0.794 PRKCD protein Q05655 UNIPROT CDH1 protein P12830 UNIPROT down-regulates activity phosphorylation Thr790 TRNDVAPtLMSVPRY 10029 27203386 t Manara Phosphorylation of E-cadherin at threonine 790 by protein kinase Cδ reduces β-catenin binding and suppresses the function of E-cadherin. SIGNOR-260893 0.2 CDC25B protein P30305 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR up-regulates dephosphorylation 9606 7880537 t lperfetto Cdc25 dephosphorylates cdc2/cdk1 within the activation loop of the kinase domain to achieve full activity of the cyclin-cdk complex SIGNOR-217511 0.758 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248755 0.727 ADAM17 protein P78536 UNIPROT GP1BA protein P07359 UNIPROT down-regulates activity cleavage Val466 ATSPTILvSATSLIT 9606 BTO:0000132 25297919 t lperfetto GPIbα is shed by metalloproteases such as ADAM17, a process that releases a soluble GPIbα fragment termed glycocalicin. ADAM17 cleaves within the GPIbα-based peptide (LRGV465LK) through a mechanism that is only partially understood [42]. GPIbα shedding has been shown to be constitutive but it can be increased by activation of protein kinases C (PKC) or inhibition of calmodulin [42, 43]. Shedding leads to decreased receptor density SIGNOR-261861 0.288 CRP protein P02741 UNIPROT CXCL8 protein P10145 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004910 26961257 f miannu In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the “risk” His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained. SIGNOR-252143 0.49 atenolol chemical CHEBI:2904 ChEBI ADRB2 protein P07550 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 10079020 t Luana In our CHO cells transfected with the human β1- and β2-adrenoceptors, the binding affinities of atenolol, metoprolol, betaxolol and practolol correlate with previously published β1- (P=0.03) and β2-adrenoceptor (P=0.03) binding affinities in human lung tissue SIGNOR-258335 0.8 SF3B4 protein Q15427 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270666 0.765 PRKCH protein P24723 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser246 QYQEERRsVKHILFS -1 16479000 t miannu HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. SIGNOR-276049 0.2 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1465 PVDPQVQsAADETAV -1 22302995 t miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. SIGNOR-262908 0.69 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 12270934 t inferred from 70% of family members lperfetto Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. SIGNOR-269913 0.2 NR4A1 protein P22736 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0005761 15666793 f miannu Herein we discuss the evidence that suggests a role for NURR1 (NR4A2) in the expression of CYP11B2 in the glomerulosa as well as in the dysregulation of CYP11B2 gene expression as is seen in aldosterone-producing adenoma (APA), a major cause of endocrine hypertension. NURR1 appears to be important for CYP11B2 transcription and is found at higher levels in glomerulosa and in APA. SIGNOR-254866 0.371 NLRX1 protein Q86UT6 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity relocalization 9606 BTO:0002181 18219313 f lperfetto NLRX1 synergistically potentiated ROS production induced by tumour necrosis factor alpha, Shigella infection and double-stranded RNA, resulting in amplified NF-kappaB-dependent and JUN amino-terminal kinases-dependent signalling. We observed that NLRX1-positive cells showed increased p65 translocation as early as 15 min after infection, an effect that was maintained over time. SIGNOR-260399 0.274 SEC63 protein Q9UGP8 UNIPROT SEC62 protein Q99442 UNIPROT up-regulates activity binding 9606 BTO:0000599 23287549 t lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. SIGNOR-265273 0.958 Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity 9606 BTO:0000007 17715225 f miannu We mapped a strong inhibitory activity to SARS-CoV nonstructural protein 1 (nsp1) and show that expression of nsp1 significantly inhibited the activation of all three virus-dependent signaling pathways. We show that expression of nsp1 significantly inhibited IFN-dependent signaling by decreasing the phosphorylation levels of STAT1 while having little effect on those of STAT2, JAK1, and TYK2. SIGNOR-262502 0.2 YAP1 protein P46937 UNIPROT CDCA5 protein Q96FF9 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 f lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. SIGNOR-276565 0.2 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser437 SGIVTNGsFSSSNAE 9606 BTO:0000007 16862148 t lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). SIGNOR-249305 0.444 PRKCA protein P17252 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 BTO:0000938 BTO:0000671 9679146 t gcesareni These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc. SIGNOR-59229 0.2 PRKAA1 protein Q13131 UNIPROT GFPT1 protein Q06210 UNIPROT up-regulates phosphorylation Ser261 CNLSRVDsTTCLFPV 9606 17941647 t gcesareni Amp-activated protein kinase and calcium/calmodulin-dependent kinase ii were identified to phosphorylate specifically ser243 in vitro. Phosphorylation by these two kinases results in an increase of enzymatic activity by 1.4-fold. These findings suggest for the first time that hgfat1 may be regulated by kinases other than pka. SIGNOR-158490 0.2 EEF1A1 protein P68104 UNIPROT His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269511 0.8 SRC protein P12931 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). SIGNOR-276189 0.2 CAMK2A protein Q9UQM7 UNIPROT ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser272 CSLERQLsLEQEVQQ 9606 BTO:0000567 18978352 t lperfetto Phosphorylation of serine 271 on 5-lipoxygenase and its role in nuclear export|We report here that 5-LO is constitutively phosphorylated on Ser-271 in transfected NIH 3T3 cells. This residue is nested in a classical nuclear export sequence, and phosphorylated Ser-271 5-LO was exclusively found in the nucleus by immunofluorescence and by fractionation techniques|Nuclear export of 5-LO can also be induced by KN-93, an inhibitor of Ca2+/calmodulin-dependent kinase II, and the effects of SB 203,580 plus KN-93 are additive. Finally, HeLa cells, which lack nuclear 5-LO, also lack constitutive phosphorylation of Ser-271. Taken together, these results indicate that the phosphorylation of Ser-271 serves to inhibit the nuclear export of 5-LO. SIGNOR-264408 0.2 TAOK3 protein Q9H2K8 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates phosphorylation 9606 23431053 t inferred from 70% of family members gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2 SIGNOR-269949 0.295 HIF1A protein Q16665 UNIPROT EPO protein P01588 UNIPROT up-regulates quantity by expression transcriptional regulation 8663540 t lperfetto Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor that regulates hypoxia-inducible genes including the human erythropoietin (EPO) gene. SIGNOR-253695 0.629 romidepsin chemical CHEBI:61080 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257992 0.8 mesulergine chemical CHEBI:73378 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258686 0.8 TNK2 protein Q07912 UNIPROT TNK2 protein Q07912 UNIPROT up-regulates phosphorylation Tyr284 LPQNDDHyVMQEHRK 9606 14506255 t llicata Purified ack1 undergoes autophosphorylation, and autophosphorylation enhances kinase activity. We identified tyr284 in the activation loop of ack1 as the primary autophosphorylation site using mass spectrometry. SIGNOR-118201 0.2 AM/b2 integrin complex SIGNOR-C170 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257713 0.46 ATM protein Q13315 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser503 NDEITDEsLENFPSS 9606 16874298 t lperfetto The artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced dna double-strand breaks (dsbs) in an atm and dna-pk dependent process. Here, we show that artemis phosphorylation by atm and dna-pk in vitro is primarily attributable to s503, s516 and s645 and demonstrate atm dependent phosphorylation at serine 645 in vivo SIGNOR-148315 0.603 CSNK2A1 protein P68400 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser422 NNNNRKTsNGDDSLF 9606 21930781 t lperfetto Cftr possesses two ck2 phosphorylation sites (s422 and t1471)this is consistent with an important role for s422 phosphorylation in increasing cftr activity. SIGNOR-176619 0.281 bosutinib chemical CHEBI:39112 ChEBI SRC protein P12931 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258089 0.8 PTPN6 protein P29350 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 9261115 t To determine whether the COOH-terminal or other phosphotyrosine residues within Src are subject to dephosphorylation by SHP-1, the effects of this phosphatase on Src tyrosine phosphorylation were initially examined using CNBr cleavage analysis. As illustrated in Fig.1 A, CNBr treatment of 32P-labeled human Src has been shown previously to yield phosphorylated cleavage fragments of about 31, 9.7, and 4.7 kDa, which, respectively, contain the Src NH2-terminal region encompassing the major sites for serine phosphorylation on Src, Ser-12 and Ser-17 (31-kDa fragment), the inhibitory tyrosine phosphorylation site, Tyr-530 (4.7-kDa fragment), and a key site for autophosphorylation on activated Src, Tyr-419 [} These observations, together with the finding of reduced Src activity in HEY cells expressing a dominant negative form of SHP-1, provide compelling evidence that SHP-1 functions include the positive regulation of Src activation. SIGNOR-248473 0.542 naratriptan chemical CHEBI:7478 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 BTO:0000567 10193663 t Luana This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues  SIGNOR-258338 0.8 CAP1 protein Q01518 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity 9606 BTO:0000567 30894654 f lperfetto In HeLa and metastatic breast cancer cells, depletion of CAP1 leads to activation of FAK and enhanced cell adhesion SIGNOR-264824 0.2 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 BTO:0000938 BTO:0000142 SIGNOR-C110 19303846 t gcesareni DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin. SIGNOR-184789 0.856 PCM1 protein Q15154 UNIPROT CETN1 protein Q12798 UNIPROT up-regulates relocalization 9606 12403812 t miannu Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome SIGNOR-94947 0.416 PDXP protein Q96GD0 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity dephosphorylation Ser166 SSRRRAIsETEENSD 9606 33414453 t miannu Considering the roles of NF2 in actin dynamics and Mdm2 regulation  - , , , it is noteworthy to elucidate whether interaction of PLPP and CIN with NF2 modulates actin dynamics and Mdm2 degradation in neuronal excitability.|Recently, we have reported that PLPP and CIN dephosphorylates Mdm2 at S166 site in activity dependent manners, which inhibits Mdm2 mediated PSD95 degradation by facilitating Mdm2 ubiquitination 38. SIGNOR-277151 0.2 DNA_damage stimulus SIGNOR-ST1 SIGNOR PALB2 protein Q86YC2 UNIPROT up-regulates activity 9606 BTO:0001938 19369211 f lperfetto Consistent with the converging functions of the BRCA proteins in DNA repair, cells harboring mutations with abrogated BRCA1-PALB2 interaction resulted in defective homologous recombination (HR) repair. We propose that, via its direct interaction with PALB2, BRCA1 fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Our findings uncover PALB2 as the molecular adaptor between the BRCA proteins, and suggest that impaired HR repair is one of the fundamental causes for genomic instability and tumorigenesis observed in patients carrying BRCA1, BRCA2, or PALB2 mutations. SIGNOR-244490 0.7 FBXW11 protein Q9UKB1 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates ubiquitination 9606 14988407 t gcesareni We have identified scf(beta-trcp1), a ubiquitin (e3) ligase, as a critical determinant for the protein degradation of smad4 protein. SIGNOR-123060 0.2 PLPPR1 protein Q8TBJ4 UNIPROT RASGEF1B protein Q0VAM2 UNIPROT up-regulates activity binding 9606 27058420 t miannu Oncogenic effects of imbalanced PRG3 are mediated via PRG3-RasGEF1 interaction and Ras activation. PRG3 interacts with RasGEF1 in vivo.We could further show that PRG3 executes the binding to RasGEF1 predominantly via its C-terminal domain (CT) and in the consequence causes Ras activation. SIGNOR-261806 0.2 TFEB protein P19484 UNIPROT IL24 protein Q13007 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 f lperfetto Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14) SIGNOR-276797 0.2 CDK5 protein Q00535 UNIPROT TRIM59 protein Q8IWR1 UNIPROT up-regulates activity phosphorylation Ser308 LIPKMKIsPKRMSCS 31488827 t miannu  Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis-trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation. SIGNOR-272929 0.2 SRC protein P12931 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity phosphorylation Tyr315 RADNDKEyLVLTLTK 9606 BTO:0002035 11948419 t miannu MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e). SIGNOR-275981 0.552 MAPK11 protein Q15759 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 BTO:0000567 9687510 t gcesareni Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha SIGNOR-59447 0.598 choline smallmolecule CHEBI:15354 ChEBI choline phosphate(1-) smallmolecule CHEBI:295975 ChEBI up-regulates quantity precursor of 27149373 t lperfetto Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes SIGNOR-275633 0.8 KDM6A protein O15550 UNIPROT HOXA7 protein P31268 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260024 0.278 EDNRA protein P25101 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 15475516 t gcesareni The response to endothelin-1 (et-1) consisted of two phases in both cell types. The initial, transient phase of contraction and phosphorylation of 20-kda myosin light chain (mlc20) was mediated additively by eta and etb receptors and initiated by galphaq-, ca2+/calmodulin-dependent activation of mlc kinase. SIGNOR-129817 0.523 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr487 SLSNIDFyAQVSDIT 10029 BTO:0000246 12907755 t PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates SIGNOR-248392 0.299 clofarabine chemical CHEBI:681569 ChEBI POLG2 protein Q9UHN1 UNIPROT down-regulates activity chemical inhibition 9606 1707752 t miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase. SIGNOR-258362 0.8 CAMK2G protein Q13555 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser571 PWPLRRTsAQGQPSP 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275780 0.295 PPARA protein Q07869 UNIPROT CPT1A protein P50416 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003204 17150915 f miannu To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA. SIGNOR-255047 0.615 FGF2 protein P09038 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates 9606 20974802 f gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription SIGNOR-168989 0.598 GRB10 protein Q13322 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 10090 BTO:0001516 23246379 t Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation SIGNOR-255945 0.411 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser9 STRSVSSsSYRRMFG -1 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248876 0.288 AKT3 protein Q9Y243 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates phosphorylation Ser387 SKLMRSAsFNTDPYV 9606 23603119 t lperfetto Phosphorylation of argonaute 2 at serine-387 facilitates its localization to processing bodies. , akt3-mediated phosphorylation of ago2 is a molecular switch between target mrna cleavage and translational repression activities of ago2 SIGNOR-201918 0.433 GSK3B protein P49841 UNIPROT PDX1 protein P52945 UNIPROT down-regulates quantity phosphorylation Ser272 LSASPQPsSVAPRRP 10090 BTO:0002284 19833727 t We show that glucose levels modulate PDX1 protein phosphorylation at a novel C-terminal GSK3 consensus that maps to serines 268 and 272. A decrease in glucose levels triggers increased turnover of the PDX1 protein in a GSK3-dependent manner, such that PDX1 phosphomutants are refractory to the destabilizing effect of low glucose SIGNOR-255567 0.2 CHD2 protein O14647 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 29962935 t miannu CHD2 also showed an interaction with MyoD, a master regulator of skeletal muscle differentiation, and together MyoD and CHD2 bind to myogenic gene promoters. SIGNOR-264525 0.2 BMP7 protein P18075 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 SIGNOR-C29 7644468 t acerquone In transfected cos-1 cells, osteogenic protein (op)-1/bmp-7, and less efficiently bmp-4, bound to bmpr-ii. Bmpr-ii bound ligands only weakly alone, but the binding was facilitated by the presence of previously identified type i receptors for bmps. Binding of op-1/bmp-7 to bmpr-ii was also observed in nontransfected cell lines. Moreover, a transcriptional activation signal was transduced by bmpr-ii in the presence of type i receptors after stimulation by op-1/bmp-7. SIGNOR-30512 0.797 FYN protein P06241 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Tyr1267 PATGEQVyQQDWAQN -1 10195142 t lperfetto To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain. SIGNOR-247155 0.724 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT1 protein Q9BQL6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser179 TASGSSVsPGLYSKT 9606 BTO:0000567 35469017 t miannu  CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry. SIGNOR-276721 0.2 PSTPIP1 protein O43586 UNIPROT ABL1 protein P00519 UNIPROT down-regulates 9606 11163214 f lperfetto Cytoskeletal protein pstpip1 directs the pest-type protein tyrosine phosphatase to the c-abl kinase to mediate abl dephosphorylationSeveral experiments suggest that the PEST-type PTPs negatively regulate c-Abl activity SIGNOR-105035 0.615 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LCK protein P06239 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 8618896 t inferred from 70% family members lperfetto Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation. SIGNOR-270177 0.2 GSK3A protein P49840 UNIPROT IL17RA protein Q96F46 UNIPROT down-regulates quantity by destabilization phosphorylation Thr780 MVLTDPHtPYEEEQR 9606 BTO:0000007 26871944 t miannu Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation.  SIGNOR-277206 0.2 TNF protein P01375 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252285 0.7 IKBKE protein Q14164 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser151 VLPSSKRsPSTATLS 9606 BTO:0001061 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276778 0.2 GADD45A protein P24522 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates binding 9606 BTO:0000782 15735649 t gcesareni Both phosphorylation of p38 ty323 and the activity of this phosphorylated species are inhibited by binding gadd45alpha, thus preventing these low-treshold signals from activating p38 SIGNOR-134333 0.473 CCKAR protein P32238 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256763 0.267 EGR1 protein P18146 UNIPROT FCER2 protein P06734 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003076 9300687 f Thus, Egr-1 seems to control the expression of downstream target genes not only as a transcriptional activator, but also as a repressor molecule. In B cells, Egr-1 therefore plays a critical role in integrating the short-lived signal delivered by triggering of the Ag receptor into phenotypic changes, including repression of CD95 and CD23 transcription. SIGNOR-254277 0.2 POLR2B protein P30876 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266162 0.871 CDK5 protein Q00535 UNIPROT AMPH protein P49418 UNIPROT unknown phosphorylation Ser285 NHTLAPAsPAPARPR -1 11113134 t llicata Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells.  SIGNOR-250650 0.536 MAPK15 protein Q8TD08 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 12169099 t gcesareni Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. these data suggest that erks, rather than jnks, are required for c- jun up-regulation. SIGNOR-91375 0.439 ARID5B protein Q14865 UNIPROT GATA3 protein P23771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29326336 f miannu We also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F). SIGNOR-256158 0.34 dasatinib (anhydrous) chemical CHEBI:49375 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191301 0.8 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu86 ENTERTTeFWKQYVD 10090 BTO:0001103 11133752 t lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. SIGNOR-263696 0.67 COLGALT1 protein Q8NBJ5 UNIPROT COL4A1 protein P02462 UNIPROT up-regulates activity glycosylation -1 19075007 t Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. SIGNOR-261155 0.376 Succinyl-CoA GTP variant complex SIGNOR-C399 SIGNOR succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI down-regulates quantity chemical modification 9606 27487822 t miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. SIGNOR-266268 0.8 ZIC1 protein Q15915 UNIPROT GLI1 protein P08151 UNIPROT up-regulates relocalization 9606 11238441 t lperfetto Co-expression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels SIGNOR-105491 0.385 CSNK1A1 protein P48729 UNIPROT GLI3 protein P10071 UNIPROT down-regulates phosphorylation 9606 11955435 t gcesareni In principle, pka, ck-1 and gsk3 can phosphorylate as many as 19 serine residues in gli3: fourpkasites, three primarygsk3sites, four primary ck-1 sites and eight secondary gsk3 and ck-1 sites SIGNOR-116512 0.583 HBA1 protein P69905 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000876 11901318 f Regulation of expression miannu Free hemoglobin enhances tumor necrosis factor-alpha production in isolated human monocytes. SIGNOR-251753 0.2 CYP21A2 protein P08686 UNIPROT 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 25855791 t lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively SIGNOR-268645 0.8 MAPK14 protein Q16539 UNIPROT ADAM17 protein P78536 UNIPROT up-regulates activity phosphorylation Thr735 KPFPAPQtPGRLQPA 10029 BTO:0000246 20188673 t gcesareni We show that p38 MAP kinase, which is activated in response to inflammatory or stress signals, directly activates TACE, a membrane-associated metalloprotease that is also known as ADAM17 and effects shedding in response to growth factors and Erk MAP kinase activation. p38alpha MAP kinase interacts with the cytoplasmic domain of TACE and phosphorylates it on Thr(735), which is required for TACE-mediated ectodomain shedding SIGNOR-163970 0.414 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR TP73 protein O15350 UNIPROT down-regulates phosphorylation Thr86 AASASPYtPEHAASV 9606 12676926 t lperfetto Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86. SIGNOR-216849 0.468 MAPK1 protein P28482 UNIPROT SCNN1G protein P51170 UNIPROT down-regulates quantity by destabilization phosphorylation Thr622 LGTQVPGtPPPKYNT -1 11805112 t lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. SIGNOR-249448 0.367 E2F3 protein O00716 UNIPROT TFDP1 protein Q14186 UNIPROT up-regulates activity binding 10029 BTO:0000246 8832394 t 2 miannu The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3. SIGNOR-240553 0.729 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 12244043 f azuccotti Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes SIGNOR-254989 0.7 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F10 protein P00742 UNIPROT up-regulates activity binding 9606 BTO:0000131 32665005 t lperfetto During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury. SIGNOR-263543 0.638 HNF1A protein P20823 UNIPROT IGF1 protein P05019 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10050749 t lperfetto Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α SIGNOR-251720 0.306 NBEAL2 protein Q6ZNJ1 UNIPROT Platelet_morphogenesis phenotype SIGNOR-PH135 SIGNOR up-regulates 9606 BTO:0000132 28082341 f lperfetto We compared platelet size and number of α-granules for two NBEAL2 and two GATA1-deficient patients and found reduced numbers of α-granules for all, with the defect being more pronounced for NBEAL2 deficiency.  SIGNOR-261882 0.7 LRAT protein O95237 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI down-regulates quantity chemical modification 10090 18093970 t lperfetto We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis SIGNOR-265110 0.8 NR1H3 protein Q13133 UNIPROT BHLHE40 protein O14503 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19032342 f lperfetto LXRα and LXRβ are potent positive regulators for hepatic Dec1 SIGNOR-253691 0.271 STMN3 protein Q9NZ72 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates quantity by destabilization binding 22577147 t lperfetto  Stathmins can thus sequester free tubulin that may result in inhibiting microtubule growth and/or promoting microtubule collapse SIGNOR-264896 0.7 SERPINC1 protein P01008 UNIPROT F12 protein P00748 UNIPROT down-regulates activity cleavage 31030036 t lperfetto Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1 SIGNOR-264139 0.587 EFNA1 protein P20827 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates binding 9606 9576626 t tpavlidou Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity SIGNOR-56910 0.804 CNTF protein P26441 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 10966616 t gcesareni Ciliary neurotrophic factor (cntf) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, cntfr, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (lifr) SIGNOR-81382 0.731 PTPRB protein P23467 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 t gcesareni Identification of tyrosine phosphatases that dephosphorylate the insulin receptor. SIGNOR-75993 0.35 GRK2 protein P25098 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 23074268 t gcesareni We find that two molecules interact with mammalian smo in an activation-dependent manner: g protein-coupled receptor kinase 2 (grk2) leads to phosphorylation of smo, and beta-arrestin 2 fused to green fluorescent protein interacts with smo. Ck1a, grk2, and another still-unidentified protein kinase phosphorylate the c-tail of mammalian smo in the presence of hh proteins SIGNOR-199104 0.2 TFIIH complex SIGNOR-C457 SIGNOR Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 9606 30860024 f lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair. SIGNOR-269322 0.7 PHGDH protein O43175 UNIPROT (R)-2-hydroxyglutarate(2-) smallmolecule CHEBI:15801 ChEBI up-regulates activity chemical modification 25406093 t lperfetto Here we show that, in addition to catalyzing oxidation of 3-phosphoglycerate, PHGDH catalyzes NADH-dependent reduction of alpha-ketoglutarate (AKG) to the oncometabolite d-2-hydroxyglutarate (d-2HG). SIGNOR-268572 0.8 PPARGC1A protein Q9UBK2 UNIPROT CAV3 protein P56539 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0001538 15199055 f Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. SIGNOR-254261 0.2 MSX1 protein P28360 UNIPROT TBP protein P20226 UNIPROT down-regulates activity binding -1 8700832 t 2 miannu Msx-1 is a potent transcriptional repressor and that this activity is independent of its DNA binding function. Here we show that Msx-1 interacts directly with the TATA binding protein (TBP) but not with several other general transcription factors. This interaction is mediated by the Msx-1 homeodomain, specifically through residues in the N-terminal arm. These same N-terminal arm residues are required for repression by Msx-1, suggesting a functional relationship between TBP association and transcriptional repression. SIGNOR-240401 0.406 NEU1 protein Q99519 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates activity 9606 BTO:0000182 19151752 f Giorgia In HT-29 cells cultured with 10% fetal bovine serum (FBS), the phosphorylation of integrin β4 was significantly decreased in NEU1-overexpressing cells and the level seemed to be inversely correlated with the sialidase activity. These results suggest that NEU1 is involved in the regulation of integrin β4 phosphorylation probably through desialylation in colon cancer cells. SIGNOR-260655 0.2 ELANE protein P08246 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage Phe41 DRVYIHPfHLVIHNE -1 11747312 t miannu Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen. SIGNOR-256313 0.278 RNF111 protein Q6ZNA4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity ubiquitination 10090 17341133 t lperfetto Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling. SIGNOR-235388 0.64 SEC23IP protein Q9Y6Y8 UNIPROT SEC23B protein Q15437 UNIPROT up-regulates activity binding 10090 BTO:0000142 10400679 t lperfetto The results showed that the N-terminal region of p125 is important for the interaction with Sec23p. We confirmed the interaction between the two proteins by a yeast two-hybrid assay. Overexpression of p125, like that of mammalian Sec23p, caused disorganization of the endoplasmic reticulum-Golgi intermediate compartment and Golgi apparatus, suggesting its role in the early secretory pathway. SIGNOR-265306 0.353 THR proteinfamily SIGNOR-PF84 SIGNOR RARB protein P10826 UNIPROT up-regulates binding 9606 15650024 t inferred from family member gcesareni Ee report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs SIGNOR-270314 0.2 SNRPD1 protein P62314 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270684 0.905 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1189 RDIYETDyYRKGGKG -1 2449432 t lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106514 0.2 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Thr47 GTESEMEtPSAINGN 9606 10617621 t lperfetto Sapk phosphorylates bcl-x(l) on threonine 47 (thr-47) and threonine 115 (thr-115) in vitro and in vivo. In contrast to wild-type bcl-x(l), a mutant bcl-x(l) with the two threonines substituted by alanines (ala-47, ala-115) is a more potent inhibitor of ionizing radiation-induced apoptosis SIGNOR-73642 0.2 TGFB1 protein P01137 UNIPROT LPP protein Q93052 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 22886954 f miannu Tgf-_1-induced lpp expression dependant on rho kinase during differentiation and migration of bone marrow-derived smooth muscle progenitor cells SIGNOR-191768 0.332 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 t flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. SIGNOR-75910 0.606 MAP3K21 protein Q5TCX8 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser218 VSGQLIDsMANSFVG 9606 23319808 t Manara These experiments showed that MEK1 is phosphorylated by MLK4 on Ser217/221 SIGNOR-260767 0.2 DGC complex SIGNOR-C217 SIGNOR NRXN2 protein P58401 UNIPROT up-regulates activity binding 9606 BTO:0000142 11470830 t miannu In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan. SIGNOR-265449 0.285 PAK1 protein Q13153 UNIPROT HACE1 protein Q8IYU2 UNIPROT down-regulates activity phosphorylation Ser385 LMKNKRDsTEITSIL 9606 BTO:0004980 29362425 t Using a proteomic approach, we identified serine 385 as a target of group-I PAK kinases […] We have established in vitro that HACE1 is a direct target of PAK1 kinase activity. SIGNOR-255537 0.2 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18570873 t gcesareni Mtor may promote g1 progression in part through sgk1 activation and deregulate the cell cycle in cancers through both akt- and sgk-mediated p27 t157 phosphorylation and cytoplasmic p27 mislocalization. SIGNOR-179109 0.845 BMPR1A protein P36894 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR up-regulates activity phosphorylation 10090 19620713 t ggiuliani The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17). SIGNOR-255788 0.678 DTNB protein O60941 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255990 0.443 CAPN3 protein P20807 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity cleavage 9606 25969760 t lperfetto Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains SIGNOR-251605 0.33 MYOG protein P15173 UNIPROT DES protein P17661 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 25653159 f lperfetto Ectopic expression of myogenin and a specific Mef2 isoform induced myogenic differentiation without activating endogenous MyoD expression. Under these conditions, the regulatory sequences of late gene loci were not in close proximity, and these genes were prematurely activated. SIGNOR-241501 0.257 APBA1 protein Q02410 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9534 BTO:0000298 11036064 t miannu Mint1 and Mint2 Interact with the Cytoplasmic Domain of Neurexin I. The interaction of Mint1 with neurexins is mediated by its PDZ domains and allows the formation of mixed CASK-Mint complexes. Both CASK and Mint1 can bind directly to neurexins and to each other. Therefore, the assembly of various multimeric complexes could proceed as CASK could be indirectly recruited to neurexin-bound Mint1 and vice versa. SIGNOR-264038 0.653 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR TDGF1 protein P13385 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269236 0.623 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 10037602 t gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. SIGNOR-64964 0.852 AKT1 protein P31749 UNIPROT SCYL1 protein Q96KG9 UNIPROT up-regulates activity phosphorylation Thr469 STRHRVLtSAFSRAT 9606 BTO:0000567 24769208 t lperfetto In previous work, we demonstrated that TEIF (transcriptional element-interacting factor) distributes in the centrosomes and regulates centrosome status under both physiologic and pathologic conditions.|A consensus motif for Akt phosphorylation (RHRVLT) proved to be involved in centrosomal TEIF localization, and the 469-threonine of this motif may be phosphorylated by Akt both in vitro and in vivo. Elimination of this phosphorylated site on TEIF caused reduced centrosome distribution and centrosome splitting or amplification. SIGNOR-265496 0.258 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr456 PPHLKYLyLVVSDSG 12441334 t JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 SIGNOR-251351 0.805 PKA proteinfamily SIGNOR-PF17 SIGNOR PHKA2 protein P46019 UNIPROT down-regulates activity phosphorylation 9606 10487978 t Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. SIGNOR-267408 0.2 H2BC11 protein P06899 UNIPROT Nucleosome_H2A.Z.1 variant complex SIGNOR-C322 SIGNOR form complex binding -1 24311584 t miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. SIGNOR-263716 0.2 UFL1 protein O94874 UNIPROT H4C1 protein P62805 UNIPROT up-regulates activity ubiquitination Lys32 DNIQGITkPAIRRLA 9606 BTO:0000007;BTO:0001938 30886146 t lperfetto Here we report that UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation. SIGNOR-265072 0.2 ATM protein Q13315 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser107 SVDSVTDsQKRREIL 9606 15073328 t lperfetto Atm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp). A creb mutant containing ala substitutions at atm phosphorylation sites displayed enhanced transactivation potential, SIGNOR-124047 0.537 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR APBB1 protein O00213 UNIPROT unknown phosphorylation 9606 14697653 t inferred from 70% family members lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. SIGNOR-270166 0.2 FOXO proteinfamily SIGNOR-PF27 SIGNOR CDKN1B protein P46527 UNIPROT up-regulates quantity transcriptional regulation 10090 10783894 t gcesareni AFX transcriptionally activates p27kip1, resulting in increased protein levels. SIGNOR-252928 0.2 SGK1 protein O00141 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser214 GGKERPGsKEEVDED 9606 16982696 t lperfetto Second, sgk1 indirectly depolymerized mts through the phosphorylation of tau at ser214 SIGNOR-161288 0.337 NFE2L1 protein Q14494 UNIPROT NQO1 protein P15559 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8962164 f irozzo These results indicated that hARE-mediated expression of the NQO1 gene and its induction by xenobiotics and antioxidants are mediated by Nrf1 and Nrf2. SIGNOR-256280 0.393 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 11691836 t lperfetto The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding SIGNOR-249394 0.649 FOXA1 protein P55317 UNIPROT LOXL2 protein Q9Y4K0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002861 20043065 f miannu These results suggest that FOXA1 induces not only KRT7 but also LOXL2 in a subset of poor prognostic ESCCs with metastatic lymph nodes. FOXA1 siRNA treatment of esophageal cancer cells reduced the mRNA level of both KRT7 and a stabilizer of epithelial-mesenchymal transition (EMT) regulator LOXL2, and that both FOXA1 and LOXL2 siRNAs reduced invasion and migration of ESCC cells. SIGNOR-254166 0.2 TEAD1 protein P28347 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21211055 f gcesareni Tead1 can regulate transcription of the foxo3a gene through the binding to the m-cat element, demonstrated with independent chip-pcr analysis, emsa and luciferase reporter system assay. The over-expression and inhibition analysis suggest that foxo3a was positively regulated by tead1. SIGNOR-170976 0.309 PI-103 chemical CHEBI:90524 ChEBI PIK3CA protein P42336 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258266 0.8 CDK5 protein Q00535 UNIPROT TLN1 protein Q9Y490 UNIPROT up-regulates phosphorylation Ser425 TMLEDSVsPKKSTVL 9606 19363486 t lperfetto Cdk5 phosphorylated talin head at ser 425, inhibiting its binding to smurf1, thus preventing talin head ubiquitylation and degradation. SIGNOR-185210 0.47 E2F4 protein Q16254 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates quantity by repression transcriptional regulation 18504435 t lperfetto This TGF-beta response is triggered through a Smad2/3-dependent hypophosphorylation of Rb and the subsequent association of the Rb/E2F4 repressive complex to CDE/CHR elements in the proximal region of the survivin promoter. SIGNOR-271678 0.34 PRKAA1 protein Q13131 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser295 RYHGHSMsDPGVSYR -1 33022274 t miannu AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex SIGNOR-276837 0.2 Degranulation phenotype SIGNOR-PH92 SIGNOR TNF protein P01375 UNIPROT up-regulates quantity 9606 BTO:0000830 24232182 f apalma Particularly, damage-activated mast cells almost instantly begin to secrete TNFa, histamine and tryptase and then initiate the de novo synthesis of other cytokines, such as interleukin (IL)6 SIGNOR-255347 0.7 TUBB protein P07437 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates binding 9606 17429065 t lpetrilli Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin. SIGNOR-154316 0.2 EN1 protein Q05925 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription SIGNOR-265802 0.464 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87. SIGNOR-244610 0.2 SCNN1A protein P37088 UNIPROT CACNA1H protein O95180 UNIPROT up-regulates activity binding 9606 BTO:0000142 30736831 t miannu This study describes the functional interaction between Cav3.2 calcium channels and the Epithelial Sodium Channel (ENaC). β- and γ-ENaC subunits could be co-immunoprecipitated with Cav3.2 calcium channels from brain lysates, dorsal horn and lumbar dorsal root ganglia. Αβγ-ENaC channels enhanced Cav3.2 calcium channel trafficking to the plasma membrane in tsA-201 cells. This effect was reciprocal such that Cav3.2 channel expression also enhanced β-ENaC trafficking to the cell surface. these findings reveal ENaC as an interactor and potential regulator of Cav3.2 calcium channels expressed in neuronal tissues. SIGNOR-269272 0.2 SETD2 protein Q9BYW2 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 18158893 f gcesareni In response to hypoxia, foxo3a transcript levels accumulate in an hif1-dependent way, resulting in enhanced foxo3a activity. SIGNOR-252986 0.2 CBFB protein Q13951 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates quantity by stabilization binding 10090 BTO:0002883 11179217 t The RUNX genes encode the α subunit of the transcription factor PEBP2/CBF. The β subunit consists of the non-RUNX protein PEBP2β. We found that RUNX1/AML1, which is essential for hematopoiesis, is continuously subjected to proteolytic degradation mediated by the ubiquitin–proteasome pathway. When PEBP2β is present, however, the ubiquitylation of RUNX1 is abrogated and this causes a dramatic inhibition of RUNX1 proteolysis. SIGNOR-255742 0.842 (-)-anisomycin chemical CHEBI:338412 ChEBI FOS protein P01100 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling gcesareni SIGNOR-189626 0.8 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Thr518 SMDNTPHtPTPFKNA 10593981 t llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. SIGNOR-250740 0.711 MRPL2 protein Q5T653 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262374 0.709 SART1 protein O43290 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270623 0.747 ACSL1 protein P33121 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI up-regulates quantity chemical modification 9606 21242590 t miannu Long-chain acyl-CoA synthetases (ACSLs) catalyze the thioesterification of long-chain FAs into their acyl-CoA derivatives. On the other hand, overexpression of ACSL1 resulted in large increases in oleoyl-CoA synthesis and palmitoyl-CoA synthesis in SMC lysates (Fig. 4A). SIGNOR-267877 0.8 FNIP1 protein Q8TF40 UNIPROT HSP90AB1 protein P08238 UNIPROT down-regulates activity binding 9606 BTO:0000007 27353360 t miannu FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle. SIGNOR-261415 0.2 PRKCD protein Q05655 UNIPROT PLSCR3 protein Q9NRY6 UNIPROT up-regulates phosphorylation Thr21 PPPPYPVtPGYPEPA 9606 16267027 t gcesareni Ad198-activated pkc-delta induces phosphorylation of mitochondrial pls3 at thr21;pls3 is a critical downstream effector of pkc-delta in ad198-induced apoptosis. SIGNOR-140759 0.469 PHF5A protein Q7RTV0 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 t lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). SIGNOR-268409 0.907 KLF6 protein Q99612 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 9606 15917248 f fspada We have identified kr?ppel-like factor-6 (klf6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene delta-like 1 (dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation. SIGNOR-137807 0.7 KLF6 protein Q99612 UNIPROT DLK1 protein P80370 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15917248 f Repression of Dlk1 requires HDAC3 deacetylase activity fspada We have identified kr?ppel-like factor-6 (klf6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene delta-like 1 (dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation. SIGNOR-137836 0.286 ITCH protein Q96J02 UNIPROT TRPV4 protein Q9HBA0 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 17110928 t miannu AIP4 ubiquitin ligase is involved in the ubiquitination of both TRPV4 and TRPC4.Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane. SIGNOR-272625 0.385 POLR3G protein O15318 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266127 0.686 LRIG1 protein Q96JA1 UNIPROT ERBB3 protein P21860 UNIPROT down-regulates ubiquitination 9606 16123311 t gcesareni We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation. SIGNOR-139951 0.445 SIRT2 protein Q8IXJ6 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 14522900 f miannu  In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity. SIGNOR-254481 0.314 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr387 RTQTVRGtLAYLPEE -1 11960013 t In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4. SIGNOR-251330 0.2 ZAP70 protein P43403 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 BTO:0000782 9710204 t gcesareni The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2). SIGNOR-59647 0.664 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 10090 BTO:0002883 11684015 t gcesareni Phosphorylation of the RAD51 Tyr-315 residue by BCR/ABL appears essential for enhanced DSB repair and drug resistance SIGNOR-247599 0.764 BMP7 protein P18075 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates activity binding 9606 7791754 t fspada  BMPR-II is a transmembrane serine/threonine kinase that binds BMP-2 and BMP-7 in association with multiple type I receptors, including BMPR-IA/Brk1, BMPR-IB, and ActR-I, which is also an activin type I receptor.  SIGNOR-232216 0.77 DBH protein P09172 UNIPROT noradrenaline smallmolecule CHEBI:33569 ChEBI up-regulates quantity chemical modification 10090 7961964 t brain lperfetto Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway. SIGNOR-264006 0.8 ERBB3 protein P21860 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 16729043 t gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. SIGNOR-146861 0.697 MBTPS1 protein Q14703 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates activity cleavage 10029 BTO:0000246 10644685 t We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2 SIGNOR-267496 0.578 H2BC11 protein P06899 UNIPROT Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR form complex binding -1 20498094 t miannu A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. SIGNOR-263727 0.2 MYCN protein P04198 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000793;BTO:0002104 7923112 f miannu Decreased expression of the N-myc oncogene in neuroblastoma cell lines SH-SY5Y and BE(2)-C, following treatment with retinoic acid, was paralleled by down-regulation of MRP gene expression, contrasting with increased expression of the MDR1 gene. SIGNOR-254616 0.377 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Gln711 PTYKFFEqMQN -1 8943232 t lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261790 0.502 HACD2 protein Q6Y1H2 UNIPROT FASN protein P49327 UNIPROT up-regulates activity chemical activation 9606 18554506 t Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases, SIGNOR-267761 0.2 CXCL8 protein P10145 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection SIGNOR-261030 0.7 MUSK protein O15146 UNIPROT DOK7 protein Q18PE1 UNIPROT up-regulates activity phosphorylation Tyr405 PTSLRAHyDTPRSLC 10090 20603078 t miannu Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes. SIGNOR-273846 0.745 SLC38A1 protein Q9H2H9 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity relocalization 9606 26724577 t Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine. SIGNOR-266912 0.8 GRIN2D protein O15399 UNIPROT NMDA receptor_2D complex SIGNOR-C350 SIGNOR form complex binding 9606 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits SIGNOR-264127 0.65 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161626 0.391 AURKB protein Q96GD4 UNIPROT CDCA2 protein Q69YH5 UNIPROT down-regulates activity phosphorylation Ser977 EPGKRRKsFCISTLA 9606 BTO:0000567 32938714 t done miannu This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin. SIGNOR-274004 0.457 CDK7 protein P50613 UNIPROT MCM2 protein P49736 UNIPROT up-regulates activity phosphorylation Ser41 RTDALTSsPGRDLPP 9606 16899510 t Luana Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. | Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2. SIGNOR-259849 0.304 SMC3 protein Q9UQE7 UNIPROT RAD21L Cohesin complex complex SIGNOR-C355 SIGNOR form complex binding 10090 BTO:0000534 21242291 t miannu RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21. SIGNOR-264537 0.815 RPS6KA3 protein P51812 UNIPROT GSK3A protein P49840 UNIPROT down-regulates activity phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000130 11583116 t lperfetto P90-rsk and akt may promote rapid phosphorylation/inactivation of glycogen synthase kinase 3 in chemoattractant-stimulated neutrophils. These reactions were monitored with a phosphospecific antibody that only recognized the alpha- or beta-isoforms of GSK-3 when these proteins were phosphorylated on serine residues 21 and 9, respectively. SIGNOR-110827 0.268 AURKB protein Q96GD4 UNIPROT KIF2C protein Q99661 UNIPROT up-regulates phosphorylation Ser95 IQKQKRRsVNSKIPA 9606 17567953 t lperfetto Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres. SIGNOR-155890 0.719 oxymetazoline chemical CHEBI:7862 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9913 BTO:0000142 9632357 t miannu Benzylimidazolines may represent a class of 5-HT1D ligands that has yet to be exploited. On the basis of a previous report that the 2-(substituted-benzyl)imidazoline alpha-adrenergic agonist oxymetazoline (8) binds with high affinity at calf brain 5-HT1D receptors, we explored the structure-affinity relationships of a series of related derivatives. SIGNOR-258927 0.8 DOT1L protein Q8TEK3 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20854876 f irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. SIGNOR-256143 0.41 RFX complex complex SIGNOR-C104 SIGNOR HLA-DOA protein P06340 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 f The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-253994 0.334 PLCB3 protein Q01970 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate(6-) smallmolecule CHEBI:203600 ChEBI up-regulates quantity chemical modification 9606 23994464 t apalma The first phase of this signal is likely mediated by phospholipase C≈í‚⧠(PLC≈í‚â§) enzymes leading to the generation of IP3 and concomitant release of Ca2+ from intracellular stores SIGNOR-255018 0.8 DIO3 protein P55073 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI down-regulates quantity chemical modification 9606 12746313 t scontino Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. SIGNOR-266941 0.8 JNK proteinfamily SIGNOR-PF15 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 9606 BTO:0005493 10601313 t lperfetto JNK-mediated phosphorylation of Smad3 outside the -SSXS motif enhances Smad3 nuclear translocation and potentiates transcriptional activation independent of Smad3 phosphorylation by T_RI. SIGNOR-236113 0.2 CAMKK2 protein Q96RR4 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates phosphorylation Thr483 KHIPSLAtVILVKTM 9606 22778263 t lperfetto It has been proposed that a major consequence of relief from autoinhibition is autophosphorylation of thr-482, a post-translational change that likely contributes to the increased autonomous activity of camkk2 SIGNOR-198107 0.2 CTSE protein P14091 UNIPROT A2M protein P01023 UNIPROT down-regulates quantity by destabilization cleavage Phe834 QLEASPAfLAVPVEK -1 12631277 t lperfetto Disruption of structural and functional integrity of alpha 2-macroglobulin by cathepsin E|Analysis of the N-terminal amino-acid sequences of these proteins revealed that alpha 2M was selectively cleaved at the Phe811-Leu812 bond in about 100mer downstream of the bait region. SIGNOR-266977 0.388 MAPK9 protein P45984 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Ser140 GKKATQAsQEY 9606 18158901 t gcesareni H2ax interacts with numerous proteins required for dna damage signaling and repair when phosphorylated on ser-140. Phosphorylation of ser-140 (h2ax139ph) in response to ionizing radiation is mediated by both atm and prkdc. Our data showed that h2ax is phosphorylated by uva-activated jnk. SIGNOR-160210 0.2 JAK1 protein P23458 UNIPROT TYK2 protein P29597 UNIPROT up-regulates phosphorylation Tyr1054 AVPEGHEyYRVREDG 9606 BTO:0000667 30029643 t Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated SIGNOR-256221 0.506 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates relocalization 9606 BTO:0001103 11062529 t gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-252338 0.635 INSR protein P06213 UNIPROT BLVRA protein P53004 UNIPROT up-regulates activity phosphorylation Tyr291 LAEEIQKyCCSRK 15870194 t lperfetto Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK).|in addition to Y198 in the YMKM motif, 2 other tyrosines, Y228 in the YLSF motif and Y291 in the C-terminus of the protein, are directly phosphorylated by IRK SIGNOR-275516 0.492 NFATC2 protein Q13469 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21871017 t miannu NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration SIGNOR-264025 0.38 XAV939 chemical CHEBI:62878 ChEBI TNKS2 protein Q9H2K2 UNIPROT down-regulates activity chemical inhibition -1 20565110 t We report two crystal structures of the PARP domain of human tankyrase-2 (TNKS2). Tankyrases are involved in fundamental cellular processes such as telomere homeostasis and Wnt signaling. SIGNOR-259995 0.8 SIRT1 protein Q96EB6 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20089851 f Regulation miannu SIRT1 deacetylates and activates the FOXOs under oxidative stress, thereby inducing Mn-SOD expression SIGNOR-251763 0.505 MAPK1 protein P28482 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser676 SNGRRKRsPTQSFRF 9606 15657420 t esanto We demonstrate that p90 ribosomal s6 kinase (rsk) is recruited to the nfat-dna transcription complex upon activation.Bound Rsk phosphorylates ser(676) and potentiates nfatc4 dna binding. Ser(676) is also targeted by the erk map kinase. SIGNOR-133272 0.287 DNMT1 protein P26358 UNIPROT DNMT1/DNMT3B complex SIGNOR-C43 SIGNOR form complex binding 9606 12145218 t miannu We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation SIGNOR-90839 0.782 CAMK2A protein Q9UQM7 UNIPROT CAMK2A protein Q9UQM7 UNIPROT down-regulates phosphorylation Thr306 LKGAILTtMLATRNF 9606 1324926 t lperfetto After removal of ca2+/calmodulin, the autonomous kinase undergoes a burst of inhibitory autophosphorylation at sites distinct from the autonomy site. Ca(2+)-independent autophosphorylation occurs within the calmodulin binding domain at thr305, thr306, and ser314 SIGNOR-17316 0.2 CCR1 protein P32246 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 20219869 t areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. SIGNOR-255118 0.316 CRTC2 protein Q53ET0 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity transcriptional regulation 9600 BTO:0000567 26652733 t inferred from family member Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB SIGNOR-270253 0.282 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Ser83 NKEKKAVsPLLLTTT 9606 11152499 t tpavlidou Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites. SIGNOR-85769 0.2 PIAS1 protein O75925 UNIPROT SATB2 protein Q9UPW6 UNIPROT down-regulates activity sumoylation Lys350 PPIPRAVkPEPTNSS 9606 BTO:0000007 14701874 t gianni We found that SATB2 differs from the closely related thymocyte-specific protein SATB1 by modifications of two lysines with the small ubiquitive related modifier (SUMO), which are augmented specifically by the SUMO E3 ligase PIAS1. SIGNOR-269112 0.565 PDK3 protein Q15120 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 16436377 t miannu Pdh2 was found to be very similar to pdh1 / in the mechanism of inactivation by phosphorylation of three sites;and (iv) in the phosphorylation of sites 1 and 2 by pdk3 / (ser-264 (site 1), ser-271 (site 2), and ser-203 (site 3) SIGNOR-143974 0.544 MAPK1 protein P28482 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates phosphorylation Thr679 PGVELLLtPREPALP 9606 BTO:0000671 19261619 t gcesareni Importantly tnf-alpha enhanced the erk pathway-dependent phosphorylation of thr-678 of gef-h1 that was key for activation. SIGNOR-184469 0.365 F2RL1 protein P55085 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257028 0.2 UNII-XH2662798I chemical CID:16156006 PUBCHEM H3-3A protein P84243 UNIPROT down-regulates 9606 20068082 f gcesareni Pf-00477736 also significantly enhances docetaxel efficacy in vitro and in vivo, in association with decreased cdc25c cytoplasmic phosphorylation (ser216) and histone h3 phosphorylation (ser10)(42). SIGNOR-163130 0.8 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates activity phosphorylation Thr228 HEGAVTHtFCGTIEY -1 11733037 t miannu In vitro phosphorylation and activation of p70β by mTOR and PDK1. We observed that the replacement of either Thr241 or Thr401 to Ala in p70β1(T241A, T401A) severely decreased the kinase activity. SIGNOR-250294 0.832 TNF protein P01375 UNIPROT LZTR1 protein Q8N653 UNIPROT down-regulates quantity by destabilization 9606 16356934 f Induction of Apoptosis by Staurosporine, TNFŒ±, and TRAIL Induces Degradation of LZTR-1 by Caspase- and Proteasome-dependent Pathways SIGNOR-253612 0.2 CSNK2A1 protein P68400 UNIPROT IGFBP3 protein P17936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser140 APGNASEsEEDRSAG 9606 BTO:0000093 10650937 t llicata The importance of Ser111 and Ser113 as targets for CK2 has also been shown in our laboratory, as mutation of either residue to alanine caused a major decrease in IGFBP-3 phosphorylation by this enzyme in vitro | These results indicate that IGFBP-3 interaction with acid-labile subunit and with the cell surface, both of which involve basic carboxyl-terminal residues, may be modulated by phosphorylation. Relative resistance to proteolysis and poor binding to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF activity in the extracellular environment. SIGNOR-250904 0.345 MAPK3 protein P27361 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 9606 10669763 t gcesareni Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70 p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both in vitro and in vivo molecular association. SIGNOR-74935 0.541 RANBP3 protein Q9H6Z4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates relocalization 9606 19289081 t gcesareni Ranbp3 directly recognizes dephosphorylated smad2/3, which results from the activity of nuclear smad phosphatases, and mediates nuclear export of smad2/3 in a ran-dependent manner SIGNOR-184608 0.398 MAPK3 protein P27361 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation Ser715 YQSTIPQsPSPAPDD 9606 10828059 t The effect has been demonstrated using Q08499-2 gcesareni These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro. SIGNOR-77578 0.255 PTCH1 protein Q13635 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates binding 9606 11331587 t Type I noncanonical;P-cyclina B (CCNB). gcesareni In addition, we demonstrate that endogenous ptc1 and endogenous cyclin B1 interact in vivo. The findings reported here demonstrate that ptc1 participates in determining the subcellular localization of cyclin B1 and suggest a link between the tumor suppressor activity of ptc1 and the regulation of cell division. Thus, we propose that ptc1 participates in a G2/M checkpoint by regulating the localization of MPF. SIGNOR-199147 0.671 RPS6KA4 protein O75676 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser29 ATKVARKsAPATGGV 10090 12773393 t lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 SIGNOR-249212 0.2 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1361 SYEEHIPyTHMNGGK -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-233560 0.2 Monobutylphthalate chemical CHEBI:88522 ChEBI AHR protein P35869 UNIPROT up-regulates activity chemical activation -1 25081364 t miannu BBP affected hepatocellular carcinoma progression through the aryl hydrocarbon receptor (AhR) and that benzyl butyl phthalate (BBP) stimulated AhR at the cell surface, which then interacted with G proteins and triggered a downstream signaling cascade. BBP activated AhR through a nongenomic action involving G-protein signaling rather than the classical genomic AhR action. SIGNOR-268791 0.8 NR3C1 protein P04150 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 10116 18762022 t The GR directly interferes with Hes1 promoter activity, triggering the recruitment of histone deacetylase (HDAC) activities to the Hes1 gene SIGNOR-253057 0.457 MAPK1 protein P28482 UNIPROT DAZAP1 protein Q96EP5 UNIPROT down-regulates activity phosphorylation Thr269 FTSYIVStPPGGFPP 9606 BTO:0000007 16848763 t miannu Further experiments showed that DAZAP1 was phosphorylated stoichiometrically in vitro by ERK2 (extracellular-signal-regulated protein kinase 2) at two Thr-Pro sequences (Thr269 and Thr315), and that both sites became phosphorylated in HEK-293 (human embryonic kidney 293) cells in response to PMA or EGF (epidermal growth factor), or RAW 264.7 macrophages in response to LPS. Phosphorylation of the ARE-binding protein DAZAP1 by ERK2 induces its dissociation from DAZ SIGNOR-262970 0.2 D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI D-erythrose 4-phosphate(2-) smallmolecule CHEBI:16897 ChEBI up-regulates quantity precursor of 9606 19401148 t miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. SIGNOR-268132 0.8 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr2 tTSQKHRD 9606 16495336 t lperfetto Herein, we demonstrate that b1, vrk1, and vrk2 efficiently phosphorylate the extreme n' terminus of the baf protein. We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain SIGNOR-144799 0.516 MAPK3 protein P27361 UNIPROT MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation Ser21 KRTSSPRsPPSSSEI 9606 25728771 t lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation SIGNOR-264773 0.2 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 3352609 t lperfetto The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases . The ser-51 mutant showed little covalent modification by the endogenous enzymes. Phosphorylation of the serine 51 residue in the alpha-subunit of translational initiation factor 2 in eukaryotes (eif2 alpha) impairs protein synthesis presumably by sequestering eif2b, a rate-limiting pentameric guanine nucleotide exchange protein which catalyzes the exchange of gtp for gdp in the eif2-gdp binary complex SIGNOR-24543 0.886 PRKAA2 protein P54646 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Ser322 TTLPRMKsSSSVTTS 9606 SIGNOR-C15 21945940 t lperfetto Here we show that phosphorylation of vasp by ampk occurs at a novel site, serine 322, and that phosphorylation at this site alters actin filament binding. We also show that inhibition of ampk activity results in the accumulation of vasp at cell-cell adhesions and a concomitant increase in cell-cell adhesion. SIGNOR-176642 0.2 SNAI1 protein O95863 UNIPROT SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR form complex binding 9606 BTO:0000452;BTO:0002625 22223884 t alessandro Therefore, we conclude that the endogenous proteins PARP1, p65NF-κB and Snail1 form a ternary complex in the nuclei of cells that are actively expressing fibronectin SIGNOR-254526 0.44 Enolase proteinfamily SIGNOR-PF74 SIGNOR phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266527 0.8 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 t Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. SIGNOR-248832 0.626 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000763;BTO:0000149 10197981 t lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-244719 0.2 CDON protein Q4KMG0 UNIPROT CDON/SPAG9 complex SIGNOR-C21 SIGNOR form complex binding 9606 BTO:0000222 17074887 t gcesareni In this study, we report that the cdo intracellular region interacts with jlp, a scaffold protein for the p38alpha/beta mapk pathway. SIGNOR-150279 0.477 NFE2L2 protein Q16236 UNIPROT Purine biosynthesis phenotype SIGNOR-PH186 SIGNOR up-regulates 9606 BTO:0000018 22789539 f miannu Nrf2 promotes purine nucleotide synthesis and glutamine use in proliferating cells SIGNOR-267352 0.7 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89154 0.538 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT down-regulates activity phosphorylation Ser146 MEPERRDsQDGSSYR -1 12432067 t miannu Lasp-1 binds to non-muscle filamentous (F) actin in vitro in a phosphorylation-dependent manner. Phosphorylation of recombinant lasp-1 with recombinant PKA increased the Kd and decreased the Bmax for lasp-1 binding to F-actin. PKA-dependent phosphorylation sites in rabbit lasp-1 to S99 and S146 SIGNOR-250074 0.311 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT unknown phosphorylation Tyr564 SKHKEDVyENLHTKN -1 12468540 t gcesareni Incorporation of Pmp at the 536 site led to 4-fold stimulation of the SHP-1 tyrosine phosphatase activity whereas incorporation at the 564 site led to no effect SIGNOR-246240 0.423 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 16046550 t The effect has been demonstrated using Q01196-8 miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. SIGNOR-138969 0.2 SERPINC1 protein P01008 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates binding 9606 8626456 t gcesareni In vitro binding studies revealed that antithrombin iii (atiii)thrombin, heparin cofactor ii (hcii)thrombin, and ?1-antitrypsin (?1AT)trypsin bound to purified lrp. SIGNOR-41232 0.2 EHMT2 protein Q96KQ7 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19822740 f Regulation of transcription miannu G9a activation of the βmaj globin gene was shown to be independent of G9a MT activity. SIGNOR-251788 0.2 NTF4 protein P34130 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates binding 9606 7679912 t gcesareni Its interactions with trkb can be distinguished from those of brain-derived neurotrophic factor (bdnf) with trkb. SIGNOR-31644 0.939 SDHAF2 protein Q9NX18 UNIPROT SDHB protein P21912 UNIPROT up-regulates binding 9606 19628817 t miannu Sdh5 is required for sdh activity and stability / the sdh1-sdh5 interaction is likely to be functionally important because the sdh5_ mutant lacks sdh activity SIGNOR-187239 0.636 Niflumic acid chemical CHEBI:34888 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258062 0.8 AIP protein O00170 UNIPROT TFF1 protein P04155 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21984905 t miannu We show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells. SIGNOR-259911 0.2 FLT3 protein P36888 UNIPROT CISH protein Q9NSE2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15769897 f The STAT5 target gene CIS, a member of the suppressor of cytokine signaling (SOCS) protein family, was highly induced by Flt3-ITD SIGNOR-261542 0.303 DRD2 protein P14416 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256844 0.538 CHEK1 protein O14757 UNIPROT TLK1 protein Q9UKI8 UNIPROT down-regulates phosphorylation Ser743 PHMRRSNsSGNLHMA 9606 12660173 t llicata Chk1 phosphorylates tlk1 on serine 695 (s695) these findings identify an unprecedented functional co- operation between atm and chk1 in propagation of a checkpoint response during s phase and suggest that, through transient inhibition of tlk kinases, the atm_chk1_tlk pathway may regulate processes involved in chromatin assembly. SIGNOR-99653 0.442 PKA proteinfamily SIGNOR-PF17 SIGNOR NOXA1 protein Q86UR1 UNIPROT down-regulates activity phosphorylation Ser461 VPAGPRMsGAPGRLP 9606 BTO:0003250 20943948 t lperfetto On the other hand, our group has shown that protein kinase A (PKA) inhibits Nox1 activity in colon epithelial cells by phosphorylating NoxA1 at two distinct sites, Ser172 and Ser461 SIGNOR-264713 0.2 SRC protein P12931 UNIPROT PLSCR1 protein O15162 UNIPROT up-regulates activity phosphorylation Tyr69 PVPNQPVyNQPVYNQ 9606 12871937 t lperfetto Plscr1 is phosphorylated by c-src, within the tandem repeat sequence 68vynqpvynqp77.|The EGF-mediated Interaction between PLSCR1 and Shc Requires Phosphorylation of Tyr69 and Tyr74 in PLSCR1 SIGNOR-103769 0.488 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity phosphorylation Ser178 LFTQRQNsAPARMLS 9606 12676583 t Manara Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A SIGNOR-260833 0.837 SF3B4 protein Q15427 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 t lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). SIGNOR-268406 0.916 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI L-alanine zwitterion smallmolecule CHEBI:57972 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-268123 0.8 FBP2 protein O00757 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI down-regulates quantity chemical modification 9606 30616754 t lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle SIGNOR-267612 0.8 LOX protein P28300 UNIPROT EFEMP2 protein O95967 UNIPROT up-regulates activity binding 9606 19570982 t miannu Fibulin-4 directly binds LOX, and this interaction enhances fibulin-4 binding to tropoelastin, thus forming a ternary complex that may be critical for elastin cross-linking. SIGNOR-252135 0.577 pazopanib chemical CHEBI:71219 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258261 0.8 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269381 0.719 MSX1 protein P28360 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001103 15192231 f gcesareni We found that msx1 and h1b bind to a key regulatory element of myod, a central regulator of skeletal muscle differentiation, where they induce repressed chromatin. SIGNOR-125765 0.436 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0001938 15254178 t lperfetto Although the stabilization of p53 was apparently concordant with its phosphorylation on N-terminal serine residues in HFFF-2 cells, it did not require the phosphorylation of Ser15 or Ser20 by ATM, a cellular kinase known to phosphorylate and promote the stabilization of p53 in response to DNA damage. SIGNOR-126757 0.838 vorinostat chemical CHEBI:45716 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257917 0.8 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 24715453 t milica LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP) SIGNOR-230733 0.401 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser465 VRRDRSTsIKLQEAP 9606 19261611 t llicata Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding. SIGNOR-184460 0.2 DOK1 protein Q99704 UNIPROT Av/b5 integrin complex SIGNOR-C178 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257692 0.298 DYRK2 protein Q92630 UNIPROT KATNA1 protein O75449 UNIPROT down-regulates quantity by destabilization phosphorylation Thr133 HGNRPSTtVRVHRSS 9606 BTO:0000007 19287380 t miannu DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d). SIGNOR-262849 0.523 GSK3B protein P49841 UNIPROT MITF protein O75030 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001583 21873430 t miannu  Both MITF and USF1 were activated by glycogen synthase kinase (GSK) 3, with GSK3 phosphorylation sites on USF1 identified as the previously described activating site threonine 153 as well as serine 186. SIGNOR-276356 0.446 CBX3 protein Q13185 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-264496 0.2 AMER1 protein Q5JTC6 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates activity relocalization 9606 21304492 t lperfetto Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6. SIGNOR-227991 0.634 PTK2B protein Q14289 UNIPROT PTK2B protein Q14289 UNIPROT up-regulates phosphorylation Tyr402 CSIESDIyAEIPDET 9606 15105428 t llicata Overexpression of pyk2 alone led to its spontaneous activation and tyrosine phosphorylation, resulting in activation of stat5b, indicated by the reporter gfp-stat5b. These effects were completely dependent upon tyr(402), the autophosphorylation site of pyk2, which allows recruitment of src family members for further activating phosphorylations at other sites on pyk2. SIGNOR-124339 0.2 NQO1 protein P15559 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000849 20226854 f irozzo More importantly, our results also indicate that NF-kappaB p50 correlates with the expression of NQO1 and mediates its role in the proliferation of melanoma cells. SIGNOR-256264 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 10831586 t lperfetto Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability. SIGNOR-244622 0.2 ABCA13 protein Q86UQ4 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates quantity relocalization 9606 33478937 t miannu ATP-binding cassette subfamily A member 13 (ABCA13) is predicted to be the largest ABC protein, consisting of 5058 amino acids and a long N-terminal region. Mutations in the ABCA13 gene were reported to increase the susceptibility to schizophrenia, bipolar disorder, and major depression.Here, we examined the biochemical activity of ABCA13 using HEK293 cells transfected with mouse ABCA13. The expression of ABCA13 induced the internalization of cholesterol and gangliosides from the plasma membrane to intracellular vesicles. These findings suggest that ABCA13 accelerates cholesterol internalization by endocytic retrograde transport in neurons and that loss of this function is associated with the pathophysiology of psychiatric disorders. SIGNOR-265158 0.8 ARHGEF12 protein Q9NZN5 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260539 0.902 PLK1 protein P53350 UNIPROT TNKS protein O95271 UNIPROT up-regulates quantity by stabilization phosphorylation Ser978 VVSASLIsPASTPSC 9606 BTO:0000567 21818122 t miannu Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends.  SIGNOR-276242 0.438 SAGA complex complex SIGNOR-C465 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269629 0.2 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Ser4520 GGHGSRHsLASTDEK 9606 15272003 t lperfetto Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc. SIGNOR-127207 0.2 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA9 protein Q9Y5G4 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265678 0.2 MAPKAPK5 protein Q8IW41 UNIPROT MAPK4 protein P31152 UNIPROT up-regulates phosphorylation Ser186 YSHKGYLsEGLVTKW 9606 1319925 t lperfetto This is due to mk5-dependent phosphorylation and only this retarded erk4 species is both phosphorylated on ser(186) and co-immunoprecipitates with wild-type mk5. We conclude that binding between erk4 and mk5 facilitates phosphorylation of ser(186) and stabilization of the erk4-mk5 complex. SIGNOR-17069 0.615 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1665 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203524 0.769 PTPRZ1 protein P23471 UNIPROT ALK protein Q9UM73 UNIPROT down-regulates dephosphorylation 9606 BTO:0000785 17681947 t gcesareni Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation. SIGNOR-157227 0.56 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr1337 QVFYNSEyGELSEPS 9606 20431062 t lperfetto Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk. SIGNOR-165043 0.492 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione chemical CHEBI:74947 ChEBI CRBN protein Q96SW2 UNIPROT up-regulates activity chemical activation 9606 20223979 t gcesareni We identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks SIGNOR-234786 0.8 1124329-14-1 chemical CID:56973724 PUBCHEM TTK protein P33981 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190137 0.8 HTR2C protein P28335 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257295 0.41 HTR1A protein P08908 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256693 0.473 17beta-estradiol smallmolecule CHEBI:16469 ChEBI AKT2 protein P31751 UNIPROT up-regulates 9606 BTO:0000150 12554767 f gcesareni Treatment of cells with estradiol resulted in phosphorylation of akt and a 9-fold increase in akt activity in 10 min. SIGNOR-97798 0.8 NME1 protein P15531 UNIPROT FZD1 protein Q9UP38 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001567 17671192 f miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. SIGNOR-255162 0.2 L-thyroxine smallmolecule CHEBI:18332 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 12746313 t scontino Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. SIGNOR-266940 0.8 PTPN2 protein P17706 UNIPROT SHC1 protein P29353 UNIPROT down-regulates activity dephosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 9488479 t llicata However, TC45 inhibited the EGF-induced association of p52Shc with Grb2, which was attributed to the ability of the PTP to recognize specifically p52Shc phosphorylated on Y239. These results indicate that TC45 recognizes not only selected substrates in a cellular context but also specific sites within substrates and thus may regulate discrete signaling events. SIGNOR-248397 0.553 BCL3 protein P20749 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16384933 f gcesareni One mechanism by which this inhibition occurs is through bcl-3-mediated induction of the p53 inhibitor hdm2. Both stable and transient overexpression of bcl-3 leads to increased hdm2 expression, and small interfering rna (sirna)-mediated knockdown of bcl-3 blocks expression of hdm2. ( articolo-abstract) SIGNOR-143403 0.29 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 21295084 t amattioni Triggering of the DISC leads to caspase-8 activation. Active caspase-8 cleaves caspase-3 which, in type I cells, leads to cell death induction. SIGNOR-256452 0.715 EAPP protein Q56P03 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23542036 f miannu We show here that EAPP stimulates the MDR1 promoter resulting in higher PGP levels. Independently of EAPP, E2F1 also increases the activity of the MDR1 promoter. SIGNOR-253842 0.2 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT down-regulates activity phosphorylation Ser60 RLPGRSTsLVEGRSC -1 14688255 t miannu We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated. SIGNOR-250155 0.686 PIAS1 protein O75925 UNIPROT FHL1 protein Q13642 UNIPROT down-regulates sumoylation Lys144 GTGSFFPkGEDFYCV 9606 17509614 t gcesareni Pias1 (the protein inhibitor of activated stat1) interacts with kyot2 directly and attenuates kyot2-mediated transcriptional repression. We demonstrate that kyot2 is modified by sumoylation at two lysine residues, k144 and k171. Sumoylation of the transfected kyot2 is enhanced by pias1 SIGNOR-154801 0.259 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH1 protein P12830 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265841 0.8 RPL31 protein P62899 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262469 0.859 ACVR1B protein P36896 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 10090 14517293 t gcesareni ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (T²RI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-²-like signaling pathway SIGNOR-235160 0.73 HSPA5 protein P11021 UNIPROT ATF6 protein P18850 UNIPROT down-regulates activity binding 9606 31226023 t miannu Similar to PERK and IRE1, ATF6 is activated by ER stress-induced dissociation from GRP78 SIGNOR-260179 0.815 KDM2A protein Q9Y2K7 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates demethylation 9606 20080798 t lperfetto Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. SIGNOR-217415 0.471 zolpidem chemical CHEBI:10125 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t brain lperfetto The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005). SIGNOR-263802 0.8 SLC27A4 protein Q6P1M0 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264465 0.7 ADSS2 protein P30520 UNIPROT N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI up-regulates quantity chemical modification 9606 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267347 0.8 TTK protein P33981 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates phosphorylation Thr68 SSLETVStQELYSIP 9606 15618221 t lperfetto Ttk/hmps1 directly phosphorylates chk2 on thr-68 in vitro.ablation of ttk expression using small interfering rna results not only in reduced chk2 thr-68 phosphorylation, but also in impaired growth arrest. Our results are consistent with a model in which ttk functions upstream from chk2 in response to dna damage SIGNOR-132665 0.296 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Ser518 GEDPYAGsTDENTDS 9606 20471329 t lperfetto Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523 SIGNOR-165423 0.404 CAMK2B protein Q13554 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates phosphorylation Ser362 FYTLNGSsVDSQPQS 9606 24614225 t lperfetto Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity. SIGNOR-25334 0.2 PHLPP2 protein Q6ZVD8 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001544 19261608 t The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. SIGNOR-248728 0.764 CHUK protein O15111 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 BTO:0000567 SIGNOR-C14 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-52875 0.893 EGFR protein P00533 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates phosphorylation Tyr1289 CPASEQGyEEMRAFQ 9606 BTO:0000150 7929151 t lperfetto The erbb3 protein which possesses little or no intrinsic protein tyrosine kinase activiity is phosphorylated by the activated egf receptor protein tyrosine kinase on tyrosine residues within the yxxm sequence motif. These phosphorylated tyrosine residues interact with the p85 regulatory subunit of pi 3-kinase, which could result in the activation of the p110 catalytic subunit via a conformational mechanism. SIGNOR-34752 0.656 JNK proteinfamily SIGNOR-PF15 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser367 GTQNPVSsPGMSQEL 9606 21364637 t miannu JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells SIGNOR-277644 0.2 MACF1 protein Q9UPN3 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity 9606 BTO:0000938 16815997 f lperfetto In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes. SIGNOR-228000 0.411 IRS1 protein P35568 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 10116 BTO:0001103 21798082 t lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate (pip2). SIGNOR-175668 0.806 CAD protein P27708 UNIPROT glutamine smallmolecule CHEBI:28300 ChEBI down-regulates quantity chemical modification 9606 24332717 t In animals, the first three reactions of the pathway are catalyzed by CAD, an 240 kDa multifunctional protein that combines glutamine-dependent carbamyl phosphate synthetase (GLNCPSase), aspartate transcarbamylase (ATCase), and dihydroorotase (DHOase) activities SIGNOR-267199 0.8 IFNB1 protein P01574 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates activity binding 9534 BTO:0004055 11278538 t lperfetto Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. SIGNOR-219301 0.862 ELP3 protein Q9H9T3 UNIPROT Elongator complex complex SIGNOR-C466 SIGNOR form complex binding 9606 28601220 t miannu Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer. SIGNOR-269710 0.8 GATA1 protein P15976 UNIPROT SPTA1 protein P02549 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10037687 f Regulation of expression miannu GATA-1 and CACCC-related Proteins Are Both Major Activators of the Human Erythroid β-Spectrin Gene Promoter SIGNOR-251928 0.385 LYN protein P07948 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates activity phosphorylation Tyr380 TDSEEQPyLEMDLSS 18086677 t lperfetto The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. SIGNOR-272979 0.316 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK7 protein P50613 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206136 0.8 NEK6 protein Q9HC98 UNIPROT NUP98 protein P52948 UNIPROT down-regulates activity phosphorylation Ser608 VLKNLNNsNLFSPVN -1 21335236 t done miannu To elucidate which of the identified sites can be targeted by CDK1/cyclin B1 and Nek6 in vitro (Figure S1D), we performed phosphorylation reactions using recombinant kinases and unlabeled ATP followed by phosphopeptide mapping (Table S1). MS analysis confirmed phosphorylation of S591 and S822 by Nek6 as well as phosphorylation of T529, T536, S595, S606, and T653 by CDK1. Phosphomimetic Mutants of Nup98 Show Defects in NPC Localization SIGNOR-273892 0.32 RUNX2 protein Q13950 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 20740684 t Accumulated Runx2 suppressed Notch1 transcriptional activity by dissociating the Notch1-IC-RBP-Jk complex gcesareni Runx2 is an inhibitor of the notch1 signaling pathway during normal osteoblast differentiation. The n-terminal domain of runx2 was crucial to the binding and inhibition of the the n-terminus of the notch1 intracellular domain. SIGNOR-167627 0.389 SRC protein P12931 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr252 EAYPEEAyIADLDAK 9606 BTO:0000007 32420483 t done miannu  We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. SIGNOR-274109 0.268 Av/b8 integrin complex SIGNOR-C185 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257730 0.569 PAS complex complex SIGNOR-C190 SIGNOR 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate)(5-) smallmolecule CHEBI:85342 ChEBI up-regulates quantity chemical modification -1 17556371 t miannu Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. we demonstrate a central function for each component of the core protein machinery for PtdIns(3,5)P2 synthesis and turnover in the formation/detachment (or maturation) of transport vesicle intermediates from early endosomes. SIGNOR-253531 0.8 ACP3 protein P15309 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI down-regulates quantity chemical modification -1 18940592 t Luana Specifically, PAP dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine and activates A1-adenosine receptors in dorsal spinal cord. SIGNOR-269740 0.8 XXYLT1 protein Q8NBI6 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 22117070 t Xylosylation in ER membrane gcesareni Xxylt1 acts on the xyl1,3glc-o-linked glycan of notch egf domains. SIGNOR-254333 0.318 MLH1 protein P40692 UNIPROT MLH1/PMS2 complex SIGNOR-C59 SIGNOR form complex binding 9606 10542278 t miannu Hmlh1 and hpms2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hmutl_ SIGNOR-71771 0.749 PPP2R5A protein Q15172 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 9774674 t gcesareni In this report, we show that another wd-40 repeat protein, the balpha subunit of protein phosphatase 2a, associates with the cytoplasmic domain of type i tgf-beta receptors..[..] Furthermore, balpha enhances the growth inhibition activity of tgf-beta in a receptor-dependent manner SIGNOR-60743 0.264 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 19914168 t lpetrilli In contrast, ERK2 phosphorylated all four Smad1 residues almost evenly, while showing a preference for S204 over S208 and S213 in Smad3 SIGNOR-161698 0.736 HCRTR2 protein O43614 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257124 0.252 UBXN2B protein Q14CS0 UNIPROT AURKA protein O14965 UNIPROT down-regulates activity binding 6239 23649807 t lperfetto The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A.|We found that UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 from embryonic extracts SIGNOR-265042 0.309 L-thyroxine smallmolecule CHEBI:18332 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity chemical activation 10116 BTO:0000759 2158622 t inferred from family member miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. SIGNOR-267808 0.8 TNFRSF25 protein Q93038 UNIPROT TRADD protein Q15628 UNIPROT up-regulates binding 9606 14585074 t amattioni Dr3 induces apoptosis by tradd-mediated recruitment of fadd and caspase-8 SIGNOR-100480 0.729 TFE3 protein P19532 UNIPROT CTSA protein P10619 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276815 0.2 CBL protein P22681 UNIPROT MET protein P08581 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19450681 t lperfetto Tyrosine y1001, which when phosphorylated upon met activation, is involved in cbl recruitment, allowing receptor ubiquitination and down regulation SIGNOR-185680 0.721 SHH protein Q15465 UNIPROT PTCH2 protein Q9Y6C5 UNIPROT down-regulates activity binding 9606 BTO:0001253 9811851 t lperfetto Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH. SIGNOR-217776 0.796 TGFBR1 protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0002181 18758450 t lperfetto Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis. SIGNOR-236119 0.438 FGD5 protein Q6ZNL6 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260555 0.2 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1457 SEKAVLTsQKSSEYP 9606 BTO:0000773 11278964 t lperfetto Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion. SIGNOR-106440 0.793 MAPK14 protein Q16539 UNIPROT SUZ12/EZH2 complex SIGNOR-C77 SIGNOR up-regulates phosphorylation 9606 21902831 t lperfetto P38 can phosphorylate the histone-lysine n-methyltransferase ezh2, the catalytic subunit of the polycomb repressive complex 2 (prc2), with phosphorylation of ezh2 necessary for prc2s association with the transcriptional repressor yy1 and subsequent chromatin remodelling. SIGNOR-217676 0.38 CHKA protein P35790 UNIPROT choline phosphate(1-) smallmolecule CHEBI:295975 ChEBI up-regulates quantity chemical modification 27149373 t lperfetto Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes SIGNOR-275636 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GTF2I protein P78347 UNIPROT up-regulates phosphorylation 9606 10648599 t inferred from 70% family members lperfetto Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation. SIGNOR-270169 0.2 acetylsalicylic acid chemical CHEBI:15365 ChEBI PTGS1 protein P23219 UNIPROT down-regulates chemical inhibition 9606 11809688 t gcesareni Nsaids inhibit cyclooxygenase (cox) isozymes, which are responsible for the committed step in prostaglandin biosynthesis, and this has been considered the primary mechanism by which nsaids exert their antitumorigenic effects. SIGNOR-114377 0.8 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser71 RFIGRRQsLIEDARK 9606 12421349 t The effect has been demonstrated using P07101-3 gcesareni Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax SIGNOR-95487 0.27 CAMKK1 protein Q8N5S9 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates phosphorylation Thr183 SDGEFLRtSCGSPNY 9606 21918180 t gcesareni Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli. SIGNOR-176598 0.474 NFIX protein Q14938 UNIPROT NEUROD4 protein Q9HD90 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268905 0.2 HSP90AA1 protein P07900 UNIPROT PAFAH1B1 protein P43034 UNIPROT up-regulates quantity by stabilization binding 9606 20133715 t miannu The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. However, little is known about the regulation of LIS1. Here, we identify a previously uncharacterized mammalian homolog of Aspergillus NudC, NudCL2 (NudC-like protein 2), as a regulator of LIS1. NudCL2 is localized to the centrosome in interphase, and spindle poles and kinetochores during mitosis, a pattern similar to the localization of LIS1 and cytoplasmic dynein. Depletion of NudCL2 destabilized LIS1 and led to phenotypes resembling those of either dynein or LIS1 deficiency. NudCL2 complexed with and enhanced the interaction between LIS1 and Hsp90. Either disruption of the LIS1-Hsp90 interaction with the C terminus of NudCL2 or inhibition of Hsp90 chaperone function by geldanamycin decreased LIS1 stability. SIGNOR-252168 0.502 DPYD protein Q12882 UNIPROT uracil smallmolecule CHEBI:17568 ChEBI down-regulates quantity chemical modification 10499634 t Dihydropyrimidine dehydrogenase (DPD) is responsible for degradation of the pyrimidines uracil and thymine and the inactivation of the chemotherapeutic agent 5-fluorouracil. DPD activity is highly variable in cancer populations, and this variation may influence the antitumor efficacy of 5-fluorouracil. SIGNOR-253988 0.8 MTA1 protein Q13330 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263854 0.812 NUMA1 protein Q14980 UNIPROT TUBD1 protein Q9UJT1 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-117159 0.2 SEC61 complex complex SIGNOR-C368 SIGNOR SEC62 protein Q99442 UNIPROT up-regulates activity binding 33925740 t lperfetto This is where allosteric effectors of the Sec61 complex (BiP together with Sec62/Sec63 complex or TRAP complex) (Figure 2 and Figure 5) and auxiliary membrane protein insertases (EMC and TMCO1 complex) join the game SIGNOR-265275 0.738 PKA proteinfamily SIGNOR-PF17 SIGNOR PHF2 protein O75151 UNIPROT up-regulates activity phosphorylation Ser899 RSKKRKGsDDAPYSP 9606 BTO:0000007 21532585 t miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. Replacement of all of four serine residues by alanines (4SA: Ser 757/Ser 899/Ser 954/Ser 1056) fully abrogated PKA phosphorylation of PHF2 (Fig. 2h). SIGNOR-264511 0.2 TCF4 protein P15884 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20459685 f miannu Cd2+ reduced the interaction of beta-catenin with AJ components (E-cadherin, alpha-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1) were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling. SIGNOR-255389 0.251 SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR JUN protein P05412 UNIPROT down-regulates activity sumoylation Lys254 MESQERIkAERKRMR 9606 BTO:0000567 SIGNOR-C154 16055711 t lperfetto We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. SIGNOR-263005 0.257 Sumanirole maleate chemical CID:9818478 PUBCHEM DRD2 protein P14416 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-207594 0.8 GALR2 protein O43603 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256741 0.426 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1675 SPSYSPTsPSYSPTS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248773 0.442 PKA proteinfamily SIGNOR-PF17 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 26088133 t lperfetto Interestingly, GSK3beta can be released from the multienzyme complex in response to PKA phosphorylation on serine 9, which suppresses GSK3beta activity. SIGNOR-264819 0.2 AKT1 protein P31749 UNIPROT STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr120 IIRLRNKtLTEDEIA 9606 19940129 t llicata Akt interacts with mst1 and phosphorylates a highly conserved residue threonine 120 of mst1, which leads to inhibition of its kinase activity and nuclear translocation as well as the autophosphorylation of thr(183). SIGNOR-252507 0.406 MTA2 protein O94776 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263853 0.815 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser813 DIYSRRLsQETGLEI 9606 1716180 t lperfetto Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response. SIGNOR-21324 0.467 NUAK1 protein O60285 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Ser472 AGVTRSAsSPRLSSS 9606 20354225 t gcesareni Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity. SIGNOR-164751 0.521 glycine smallmolecule CHEBI:15428 ChEBI GLRA1 protein P23415 UNIPROT up-regulates activity chemical activation 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 t miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. SIGNOR-264980 0.8 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 14670075 t lperfetto Our results indicate that two distinct TAK1 complexes are present in cells. One comprises TAK1 complexed with TAB1 and TAB2, and the other TAK1 complexed with TAB1 and TAB3. Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1 in human epithelial KB cells or bacterial lipopolysaccharide in RAW264.7 macrophages SIGNOR-120268 0.934 WT1 protein P19544 UNIPROT REN protein P00797 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18496514 t Here, we show that a splice variant of the Wilms' tumor protein lacking three amino acids WT1(-KTS) suppresses renin gene transcription SIGNOR-252296 0.432 A1/b1 integrin complex SIGNOR-C159 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269008 0.7 SNRPC protein P09234 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270679 0.899 HYDIN protein Q4G0P3 UNIPROT GATA4 protein P43694 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 32376282 t miannu HYDIN promotes expression of Gata4 in cardiomyocyte differentiation. HYDIN functions as a positive regulator of human cardiomyocyte differentiation and promotes expression of cardiac contractile genes in hESC cells. This is mediated through GATA4, a critical transcription factor in heart development. Cardiac-specific Hydin knockdown in vivo leads to Gata4 downregulation and enhanced atrial septal defect (ASD) risk in mice. GATA4 is a fundamental TF in embryonic heart development and cardiac differentiation, and reduction in GATA4 function results in a diverse range of CHDs SIGNOR-265479 0.2 TOR1AIP1 protein Q5JTV8 UNIPROT VIM protein P08670 UNIPROT up-regulates activity binding 9606 BTO:0000452 16361107 t Sara Co-immune precipitation studies revealed association between vimentin and torsinA in a complex. these studies suggest that mutant torsinA interferes with cytoskeletal events involving vimentin, possibly by restricting movement of these particles/filaments, and hence may affect development of neuronal pathways in the brain. SIGNOR-261313 0.2 SIRT1 protein Q96EB6 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-256662 0.7 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT down-regulates activity phosphorylation Ser339 GKRGGHSsVSTESES 9606 10521508 t Manara Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization. SIGNOR-260901 0.2 CYSLTR1 protein Q9Y271 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257019 0.358 MAPK1 protein P28482 UNIPROT CEBPA protein P49715 UNIPROT down-regulates phosphorylation Ser21 PMSSHLQsPPHAPSS 9606 BTO:0000876 14701740 t lperfetto Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21. SIGNOR-120566 0.36 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH1 protein P46531 UNIPROT up-regulates activity cleavage 9606 25610395 t lperfetto The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a γ-secretase substrate. γ-Secretase performs the subsequent cleavage at S3, releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 family of DNA binding proteins. SIGNOR-209717 0.665 SRC protein P12931 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr537 CKNVVPLyDLLLEML 9606 BTO:0000150;BTO:0000567 9500442 t tpavlidou Although the molecular mechanisms underlying ligand-independent activation of era are not completely understood, phosphorylation of a serine residue in af1 has been implicated in the response to epidermal growth factor. Era is also a target for tyrosine phosphorylation, anda single tyrosine residue located immediately adjacent to af2 has been identified as a substrate for src-family tyrosine kinases. SIGNOR-55857 0.769 TNF protein P01375 UNIPROT LPL protein P06858 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16106106 f Regulation miannu TNF-α and IL-6 inhibit lipoprotein lipase SIGNOR-251855 0.4 ML240 chemical CHEBI:143014 ChEBI VCP protein P55072 UNIPROT down-regulates activity chemical inhibition -1 23316025 t Monia Inhibition of p97 by ML240 and ML241 is ATP competitive. To determine the mechanism by which ML240 and ML241 inhibited p97 ATPase, we evaluated rates of ATP hydrolysis at different concentrations of ATP. ML240 and ML241 inhibited p97competitively with respect to ATP with a Kivalues of 0.22 mm and 0.35 mm respectively. SIGNOR-261066 0.8 MAPK12 protein P53778 UNIPROT SNTA1 protein Q13424 UNIPROT up-regulates phosphorylation Ser193 GWDSPPAsPLQRQPS 9606 10212242 t lperfetto Sapk3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the pdz domain of alpha1-syntrophin. The finding that sapk3 co-localizes with _1-syntrophin in skeletal muscle, that it binds to the pdz domain of _1-syntrophin, and that phosphorylation of _1-syntrophin depends on this interaction identifies a novel mechanism for targeting a protein kinase to its substrates. SIGNOR-67061 0.654 CDC14B protein O60729 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser315 LPNNTSSsPQPKKKP 9606 10644693 t The human Cdc14 phosphatases interact with and dephosphorylate the tumor suppressor protein p53|. Furthermore, the hCdc14 phosphatases were found to dephosphorylate p53 specifically at the p34Cdc2/clb phosphorylation site (p53-phosphor-Ser315)|Earlier studies showed that Ser315 phosphorylation increases the sequence-specific DNA binding capacity of p53, suggesting that Ser315 phosphorylation is an activating modification SIGNOR-248332 0.339 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr992 DGPLGPLyASSNPEY -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-106522 0.2 MAVS protein Q7Z434 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity binding 9606 25636800 t miannu After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively. SIGNOR-260144 0.826 KDM4C protein Q9H3R0 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity demethylation Lys37 APATGGVkKPHRYRP 9606 29207681 t miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation SIGNOR-263866 0.2 E2F1 protein Q01094 UNIPROT CTNND2 protein Q9UQB3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001033 21106062 f miannu Coordinated regulation of δ-catenin expression by both the activating transcription factor E2F1 and repressive transcription factor Hes1 in prostate cancer progression. SIGNOR-251876 0.2 JAK2 protein O60674 UNIPROT LEPR protein P48357 UNIPROT up-regulates activity phosphorylation Tyr1141 SKKTFASyMPQFQTC 9606 BTO:0000007 11018044 t miannu LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2. SIGNOR-263494 0.765 PXN protein P49023 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 18650496 f VEGF pathway Gianni Through the interactions of its multiple protein-protein binding modules, many of which are regulated by phosphorylation, paxillin serves as a platform for the recruitment of numerous regulatory and structural proteins that together control the dynamic changes in cell adhesion, cytoskeletal reorganization and gene expression that are necessary for cell migration and survival. SIGNOR-261944 0.7 Mitochondrial Fe-S Cluster Assembly Complex complex SIGNOR-C276 SIGNOR iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI up-regulates quantity chemical modification -1 27519411 t lperfetto As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]¬∑[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry. SIGNOR-262129 0.8 EMX1 protein Q04741 UNIPROT NRP1 protein O14786 UNIPROT up-regulates quantity by expression transcriptional regulation -1 26534986 t Luana EMX1 activates the transcription of Nrp1 in vitro. SIGNOR-261593 0.2 TAF12 protein Q16514 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269580 0.746 4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide chemical CHEBI:49868 ChEBI PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190281 0.8 ACAT1 protein P24752 UNIPROT ME1 protein P48163 UNIPROT up-regulates activity acetylation Lys337 KIWLVDSkGLIVKGR 31735643 t lperfetto PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation. SIGNOR-275571 0.251 GOT2 protein P00505 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 31422819 t miannu This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-268060 0.8 IRF1 protein P10914 UNIPROT SOCS2 protein O14508 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22291912 f miannu SOCS2 induction by LPS was dependent on the type I IFN regulated transcription factors IRF1 and IRF3 as shown by using silencing RNAs for IRFs. SIGNOR-254494 0.315 CPSF3 protein Q9UKF6 UNIPROT CPSF complex complex SIGNOR-C53 SIGNOR form complex binding 9606 BTO:0000007 19224921 t lperfetto The CPSF complex consists of five subunits, named CPSF160, CPSF100, Fip1, CPSF73, and CPSF30. SIGNOR-268333 0.879 CSNK2A1 protein P68400 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Ser45 LFRLSEHsSPEEEAS -1 2557337 t llicata Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase SIGNOR-250928 0.347 MAPK8IP3 protein Q9UPT6 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 10629060 t gcesareni These data demonstrate that jip3 interacts with proteins that can form a mapk signaling module, including jnk, mkk7, and mlk3 SIGNOR-73906 0.692 MYH9 protein P35579 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity binding 9606 BTO:0004953 32685004 t miannu Nuclear MYH9 bound to the CTNNB1 promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote CTNNB1 transcription, which conferred resistance to anoikis in GC cells in vitro and in vivo. SIGNOR-269285 0.257 KDM4C protein Q9H3R0 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 29207681 t miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation SIGNOR-263869 0.2 GSK3B protein P49841 UNIPROT GRB14 protein Q14449 UNIPROT down-regulates activity phosphorylation Ser358 MHPYQGRsGCSSQSI -1 28130417 t lperfetto Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3. SIGNOR-264868 0.329 PAK2 protein Q13177 UNIPROT PRL protein P01236 UNIPROT up-regulates phosphorylation Ser207 LHCLRRDsHKIDNYL 9606 19555049 t gcesareni Phosphorylated form of prolactin has a higher affinity for heparin. SIGNOR-186211 0.344 PRKCA protein P17252 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr375 GRGARGGtRGGRGRI 9606 BTO:0004974 14699138 t lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation SIGNOR-249252 0.294 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates activity dephosphorylation Tyr659 VADERVDyVVVDQQK 9606 11323411 t These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro. SIGNOR-248675 0.952 IKBKB protein O14920 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity phosphorylation Ser141 SRSNSDEsNFSEKLR 9606 BTO:0000007 16818229 t miannu Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling. SIGNOR-276293 0.764 PDE3A protein Q14432 UNIPROT ATP2A2 protein P16615 UNIPROT down-regulates activity binding 9606 BTO:0000199 25593322 t lperfetto Regulation of sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2) activity by phosphodiesterase 3A (PDE3A) in human myocardium: phosphorylation-dependent interaction of PDE3A1 with SERCA2.|PDE3A co-localized with PLB, SERCA2, and an AKAP18 variant|our studies show that PDE3-selective inhibition (but not PDE4 inhibition) potentiates the phosphorylation of PLB by endogenous PKA and stimulation of SERCA2 activity and Ca2+ uptake in SR-enriched vesicles prepared from human myocardium. SIGNOR-262051 0.346 DDIT3 protein P35638 UNIPROT ANKRD1 protein Q15327 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0003324 19299913 f lperfetto Promoter deletion and reporter analysis revealed that hypoxia transcriptionally activates a GADD153 promoter through the AP-1 element in neonatal cardiomyocytes. Ectopic overexpression of GADD153 resulted in the downregulation of CARP expression. SIGNOR-254122 0.277 MECOM protein Q03112 UNIPROT ANGPT2 protein O15123 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15889140 t Luana We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2  SIGNOR-266060 0.2 ELF2 protein Q15723 UNIPROT VCP protein P55072 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 18544453 f These findings indicate that ELF2 transactivates VCP promoter through binding to two motifs, with a predominant contribution of the upstream one. SIGNOR-254283 0.368 ARF6 protein P62330 UNIPROT PIP4K2A protein P48426 UNIPROT up-regulates activity 10116 BTO:0003102 14565977 t miannu Effects of ARF6 upon Axonogenesis Are Mediated by Phosphatidyl-inositol-4-phosphate 5-Kinase α. activated ARF6 stimulates the lipid-modifying enzyme PI(4)P 5-Kinase, leading to local increases in plasma membrane PIP2 and changes in actin dynamics. Alternatively, activation of Rac1 by upstream Rac1 activators or indirectly by ARF6-GTP results in stimulation of actin polymerization.  SIGNOR-264911 0.344 AM/b2 integrin complex SIGNOR-C170 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269019 0.7 ATP13A1 protein Q9HD20 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0004093 29650961 f doi.org/10.1101/185272 francesca Loss of ATP13A3 led to marked inhibition of serum-stimulated proliferation of BOECs, and increased apoptosis in serum-deprived conditions SIGNOR-261217 0.7 SRC protein P12931 UNIPROT CBLC protein Q9ULV8 UNIPROT up-regulates phosphorylation Tyr341 SEEQLQLyWAMDSTF 9606 20525694 t gcesareni Phosphorylation of a critical tyrosine (tyr-341) in the linker region of cbl-c by src or a phosphomimetic mutation of this tyrosine (y341e) is sufficient to increase the e3 activity of cbl-c. SIGNOR-165862 0.552 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Ser28 PQPQHTPsPAAPPAA 9606 22878263 t llicata In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis. SIGNOR-198725 0.42 MAPK12 protein P53778 UNIPROT Satellite_cells_self-renewal phenotype SIGNOR-PH100 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 BTO:0002314 BTO:0001103 29681515 f apalma [...] we observed a significant diminution in the number of symmetric satellite stem cell (YFP–) divisions in p38 gamma siRNA-treated fibers, suggesting that p38 gamma is required for symmetric stem cell maintenance. Thus, loss of p38gamma greatly skewed the ratio of asymmetric to symmetric satellite stem cell divisions to favor asymmetric divisions and myogenic commitment at the expense of self-renewal SIGNOR-255902 0.7 PPP1R1B protein Q9UD71 UNIPROT PPP1CC protein P36873 UNIPROT down-regulates activity binding 9606 BTO:0000938 10604473 t miannu DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚  SIGNOR-264958 0.579 PRKCA protein P17252 UNIPROT FBXW7 protein Q969H0 UNIPROT down-regulates activity phosphorylation Ser18 KRRRTGGsLRGNPSS 9606 BTO:0000567 28850619 t miannu Here, we report that Fbw7α, the only Fbw7 isoform detected in eggs, is phosphorylated by PKC (protein kinase C) at a key residue (S18) in a manner coincident with Fbw7α inactivation. SIGNOR-277249 0.351 FBXW7 protein Q969H0 UNIPROT MED13L protein Q71F56 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 SIGNOR-C135 23322298 t miannu The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association. SIGNOR-266688 0.366 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation 9606 15657420 t inferred from 70% family members lperfetto The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity. SIGNOR-270160 0.2 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser705 TPSAMKSsPQIPHQT 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. SIGNOR-164479 0.553 metformin chemical CHEBI:6801 ChEBI PRKAA1 protein Q13131 UNIPROT up-regulates activity 10116 11602624 f gcesareni Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin€™s inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation SIGNOR-241952 0.8 CDK3 protein Q00526 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser104 FPPLNSVsPSPLMLL 26202215 t lperfetto CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3 SIGNOR-273189 0.262 PPARGC1A protein Q9UBK2 UNIPROT OTC protein P00480 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255056 0.2 sulindac chemical CHEBI:9352 ChEBI RXRA protein P19793 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001109 20541701 t Luana NSAID Sulindac and Its Analogs Bind RXRα and Inhibit RXRα-dependent AKT Signaling SIGNOR-257847 0.8 PLIN3 protein O60664 UNIPROT IGF2R protein P11717 UNIPROT up-regulates activity relocalization 9534 BTO:0004055 9590177 t lperfetto TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi. SIGNOR-253092 0.714 ZNF322 protein Q6U7Q0 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24550733 t lperfetto Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays revealed that Zfp322a binds to Pou5f1 and Nanog promoters and regulates their transcription. SIGNOR-264900 0.2 POMC protein P01189 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11830546 f miannu The expression of the melanoma susceptibility gene product p16 is increased after UVR both in epidermally derived cell lines and in human skin. the increased expression of p16 after exposure to suberythemal doses of UVR is potentiated by α-MSH, a ligand for MC1R, and this effect is mimicked by cAMP, the intracellular mediator of α-MSH signaling via the MC1 receptor. SIGNOR-252377 0.269 bosutinib chemical CHEBI:39112 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190696 0.8 BLOC1S3 protein Q6QNY0 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 22203680 t lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. SIGNOR-265934 0.704 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser78 SSGSPANsFHFKEAW -1 14709557 t miannu AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase SIGNOR-250314 0.474 PPP1CB protein P62140 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates dephosphorylation 9606 21750978 t miannu Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway SIGNOR-174862 0.268 PAK3 protein O75914 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Ser150 TLRRVRIsADAMMQA 9606 BTO:0000887 12242269 t llicata Importantly, cardiac troponin i was found to be phosphorylated at serine 149 of human cardiac troponin i, representing a novel phosphorylation site. These findings suggest a novel mechanism of modulating the calcium sensitivity of cardiac muscle contraction. SIGNOR-92990 0.2 AR protein P10275 UNIPROT CLK3 protein P49761 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 16281084 f After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. SIGNOR-253672 0.2 IL2RB protein P14784 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t milica The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival SIGNOR-204975 0.539 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates chemical inhibition 9606 17891169 t fspada Hydroxamate derivatives are the most powerful category of hdaci, active on class i and ii hdac,especially on hdac1 and hdac2. In the study reported here, we described the anti-leukaemic properties of itf2357, a recently synthesized, orally active hydroxamate derivative. SIGNOR-157857 0.8 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 22514276 t miannu A stable interaction between ?(C)-camkii and the intracellular loop between domains 1 and 2 of na(v)1.5 was observed. This region was also phosphorylated by ?(C)-camkii, specifically at the ser-516 and thr-594 sites.Wild-type (wt) and phosphomutant hna(v)1.5 were co-expressed with gfp-?(C)-camkii in hek293 cells, and i(na) was recorded. As observed in myocytes, camkii shifted wt i(na) availability to a more negative membrane potential and enhanced accumulation of i(na) into an intermediate inactivated state, but these effects were abolished by mutating either of these sites to non-phosphorylatable ala residues. SIGNOR-197058 0.481 RPS4Y1 protein P22090 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262446 0.2 MAPK14 protein Q16539 UNIPROT PIAS2 protein O75928 UNIPROT up-regulates activity phosphorylation Ser113 STSVTPHsPSSPVGS 9606 BTO:0000007 16713578 t miannu The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles SIGNOR-262948 0.322 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. SIGNOR-76013 0.563 GSK3A protein P49840 UNIPROT NIFK protein Q9BYG3 UNIPROT up-regulates activity phosphorylation Thr234 TVDSQGPtPVCTPTF -1 16244663 t miannu The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1. SIGNOR-262697 0.2 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2U protein Q5VVX9 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271337 0.533 PRKAA2 protein P54646 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser78 SSGSPANsFHFKEAW -1 14709557 t miannu AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase SIGNOR-250321 0.48 lapatinib chemical CHEBI:49603 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193627 0.8 SND1 protein Q7KZF4 UNIPROT IGFBP3 protein P17936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23878061 f irozzo Therefore, we concluded that SND1 could affect SMMC-7721 cells proliferation by regulating IGFBP3 expression and IGF signaling pathway. SIGNOR-259140 0.2 FGF12 protein P61328 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253424 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation 10090 14981546 t miannu Phosphorylation of Foxo proteins through FLT3-ITD signaling promotes their translocation from the nucleus into the cytoplasm, which requires the presence of conserved Akt phosphorylation sites in Forkhead transcription factors and PI3K activity. SIGNOR-261526 0.2 Calcineurin complex SIGNOR-C155 SIGNOR FLNA protein P21333 UNIPROT down-regulates dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 t gcesareni We report that a purified c-terminal recombinant region of filamin is a suitable substrate for calcineurin in vitro. Furthermore, 1 microm cyclosporin a (csa), a specific calcineurin inhibitor, reduced the dephosphorylation of the recombinant fragment in 293ft cells SIGNOR-252339 0.269 DOK1 protein Q99704 UNIPROT AE/b7 integrin complex SIGNOR-C186 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257696 0.33 DYRK1A protein Q13627 UNIPROT DYRK1A protein Q13627 UNIPROT up-regulates phosphorylation Tyr319 CQLGQRIyQYIQSRF 9606 10910078 t lperfetto Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site SIGNOR-79760 0.2 ATF1 protein P18846 UNIPROT EGR1 protein P18146 UNIPROT up-regulates quantity by expression transcriptional regulation 10391889 t lperfetto Phosphorylated CREB and ATF1 then bind to the CRE of the egr-1 promoter and cause a stress-dependent transcriptional activation of this gene. SIGNOR-271686 0.279 CD19 protein P15391 UNIPROT VAV1 protein P15498 UNIPROT up-regulates activity binding 10090 25673924 t lperfetto CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades. SIGNOR-242897 0.713 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 15659650 t lperfetto CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37 SIGNOR-217803 0.771 DOK1 protein Q99704 UNIPROT AM/b2 integrin complex SIGNOR-C170 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257682 0.301 CDK1 protein P06493 UNIPROT KAT7 protein O95251 UNIPROT up-regulates phosphorylation Thr88 QQQPTPVtPKKYPLR 9606 18250300 t lperfetto Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate. SIGNOR-160747 0.362 TERB2 protein Q8NHR7 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR up-regulates activity relocalization SIGNOR-C305 27025256 t lperfetto Terb1 and Sun1 are two key proteins linking the meiotic telomeres to the NE. Terb1 participates in telomere fortification by recruiting cohesins to the site SIGNOR-263306 0.2 ASTN1 protein O14525 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000142 28506896 f miannu The role of astrotactin and Brinp proteins has been partially characterized, with ASTN1 and ASTN2 demonstrated to facilitate glial-guided neuronal migration during brain development SIGNOR-269815 0.7 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Ile) smallmolecule CHEBI:29174 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270419 0.8 SPRY4 protein Q9C004 UNIPROT MMP9 protein P14780 UNIPROT down-regulates activity 9606 BTO:0002058 20501643 f miannu When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. SIGNOR-253037 0.27 PTPN5 protein P54829 UNIPROT FYN protein P06241 UNIPROT down-regulates dephosphorylation Tyr420 RLIEDNEyTARQGAK 9606 BTO:0000938 BTO:0000671 11983687 t lperfetto Wild-type step(61) dephosphorylates fyn at tyr(420) but not at tyr(531). These results suggest that step regulates the activity of fyn by specifically dephosphorylating the regulatory tyr(420) and may be one mechanism by which fyn activity is decreased within psds. SIGNOR-86791 0.542 FLNA protein P21333 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity by stabilization binding 9606 11706047 t lperfetto We conclude that FLNa is essential in cells that express it for stabilizing orthogonal actin networks suitable for locomotion.  SIGNOR-261851 0.7 PRKACB protein P22694 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10949026 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. SIGNOR-81145 0.404 MSC protein O60682 UNIPROT TCF3 protein P15923 UNIPROT down-regulates activity binding 9606 BTO:0000776 9584154 t 2 miannu ABF-1 contains a transcriptional repression domain and is capable of inhibiting the transactivation capability of E47 in mammalian cells. SIGNOR-241315 0.475 estriol smallmolecule CHEBI:27974 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258585 0.8 RHEB protein Q15382 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity binding 9606 BTO:0000007 20006481 t lperfetto Rheb stimulates the phosphorylation of mtor and plays an essential role in regulation of s6k and 4ebp1 in response to nutrients and cellular energy status. SIGNOR-162006 0.949 SRC protein P12931 UNIPROT MMP14 protein P50281 UNIPROT unknown phosphorylation Tyr573 GTPRRLLyCQRSLLD 9606 17389600 t llicata We show that mt1-mmp is phosphorylated on the unique tyrosine residue located within this cytoplasmic sequence (tyr(573)) and that this phosphorylation requires the kinase src. accordingly, overexpression of a nonphosphorylable mt1-mmp mutant (y573f) blocked sphingosine-1-phosphate-induced migration of human umbilical vein endothelial cells and ht-1080 (human fibrosarcoma) cells and failed to stimulate migration of cells lacking the enzyme (bovine aortic endothelial cells). SIGNOR-154006 0.446 PRKACA protein P17612 UNIPROT APOBEC3G protein Q9HC16 UNIPROT up-regulates phosphorylation Thr32 PILSRRNtVWLCYEV 9606 18836454 t llicata Here we show that pka binds and specifically phosphorylates a3g at thr32 in vitro and in vivo. This phosphorylation event reduces the binding of a3g to vif and its subsequent ubiquitination and degradation, and thus promotes a3g antiviral activity. SIGNOR-181526 0.33 DSCAML1 protein Q8TD84 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR down-regulates 9606 BTO:0000938 30745319 f miannu Nuclear DSCAM and DSCAML1 impair neurite outgrowth. this demonstrates that enhanced nuclear translocation of the DSCAM and DSCAML1 ICDs profoundly impairs neurite outgrowth and development of primary cortical neurons SIGNOR-264275 0.7 ADAM10 protein O14672 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity cleavage 9606 26284334 t miannu The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin. SIGNOR-259845 0.351 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR PBX3 protein P40426 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17442773 f miannu Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. PBX3, a member of the PBX family of TALE homeobox genes, is upregulated in both NUP98‐HOXA9–transduced adult and cord blood CD34+ cells (Table 3). SIGNOR-261504 0.2 YAP1 protein P46937 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates binding 9606 14765127 t Regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation. gcesareni Here we show that the endogenous yes-associated protein (yap), a mediator of src/yes signaling, interacts with the native runx2 protein, an osteoblast-related transcription factor, and suppresses runx2 transcriptional activity in a dose-dependent manner. SIGNOR-121803 0.461 NLGN2 protein Q8NFZ4 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 18923512 t brain lperfetto Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions. SIGNOR-264193 0.75 ROCK1 protein Q13464 UNIPROT RND3 protein P61587 UNIPROT up-regulates phosphorylation Ser11 RRASQKLsSKSIMDP 9606 15775972 t lperfetto We show that rock phosphorylates endogenous rhoe at serine 11 upon cell stimulation with platelet-derived growth factor. Phosphorylation has no effect on rhoe binding to rock i, but instead increases rhoe protein stability. SIGNOR-134703 0.73 MAPK1 protein P28482 UNIPROT TNKS1BP1 protein Q9C0C2 UNIPROT unknown phosphorylation Thr131 KEEPPPLtPPARCAA 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262782 0.2 PRKACB protein P22694 UNIPROT TENT2 protein Q6PIY7 UNIPROT down-regulates activity phosphorylation Ser116 LSGERRYsMPPLFHT 9606 31057087 t miannu We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. SIGNOR-259403 0.2 RANBP3 protein Q9H6Z4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity relocalization 9606 19289081 t lperfetto RanBP3 directly recognizes dephosphorylated Smad2/3, which results from the activity of nuclear Smad phosphatases, and mediates nuclear export of Smad2/3 in a Ran-dependent manner. SIGNOR-232116 0.398 TNFRSF17 protein Q02223 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates 9606 10903733 f inferred from 70% of family members miannu Overexpression of bcma activates jnk SIGNOR-269887 0.295 Hypoxia stimulus SIGNOR-ST25 SIGNOR EGLN3 protein Q9H6Z9 UNIPROT down-regulates 9606 24990963 f lperfetto There are three EglN family members in humans and mice (EglN1, EglN2, and EglN3). Their enzymatic activity requires oxygen, ascorbic acid, iron, and α-ketoglutarate (α-KG). Under hypoxic conditions, EglNs lose their activity and fail to hydroxylate HIFα, which leads to HIFα stabilization SIGNOR-262002 0.7 beta-alanine smallmolecule CHEBI:16958 ChEBI GLRA1 protein P23415 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9009272 t miannu For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system. SIGNOR-258581 0.8 acetyl-CoA smallmolecule CHEBI:15351 ChEBI malonyl-CoA smallmolecule CHEBI:15531 ChEBI up-regulates quantity precursor of 9606 20952656 t miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA SIGNOR-267108 0.8 SEC24D protein O94855 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 t lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat SIGNOR-265291 0.68 regorafenib chemical CHEBI:68647 ChEBI FGFR2 protein P21802 UNIPROT down-regulates activity chemical inhibition 9606 26254357 t miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF SIGNOR-259178 0.8 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR IGFBP5 protein P24593 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136601 0.316 AKT2 protein P31751 UNIPROT PPIF protein P30405 UNIPROT up-regulates activity phosphorylation Ser31 LPAARACsKGSGDPS 9606 BTO:0002004 25650317 t miannu In turn, mitochondrial Akt2 phosphorylates Ser31 in cyclophilin D (CypD), a regulator of organelle functions. Akt2-phosphorylated CypD supports mitochondrial bioenergetics and opposes tumor cell death, conferring resistance to PI3K therapy. SIGNOR-276875 0.2 oxymetazoline chemical CHEBI:7862 ChEBI ADRA1A protein P35348 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258462 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 20974802 t inferred from 70% family members gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. SIGNOR-270024 0.2 KRN-633 chemical CID:9549295 PUBCHEM KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193588 0.8 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273052 0.556 RAR proteinfamily SIGNOR-PF45 SIGNOR THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 t inferred from 70% family members gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. SIGNOR-269955 0.2 DNM2 protein P50570 UNIPROT VAV1 protein P15498 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000584 23537630 t Disruption of the Dyn2-Vav1 interaction targets Vav1 to the lysosome for degradation via an interaction with the cytoplasmic chaperone Hsc70, resulting in a dramatic reduction of Vav1 protein stability. SIGNOR-259080 0.501 SHC1 protein P29353 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates activity 10090 BTO:0000944 17673906 f inferred from 70% of family members lperfetto We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. SIGNOR-269903 0.2 SLC16A2 protein P36021 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI down-regulates quantity relocalization 9606 28153798 t scontino T4 and T3 are released from the thyroid cell through transporters present at the basolateral plasma membrane of thyrocytes (Fig. 1). The most important transporter known to be responsible for thyroid hormone transport is the SLC16A2 monocarboxylate transporter 8 (MCT8), which can promote both uptake and efflux of TH and is involved in the release of TH from the thyroid gland. SIGNOR-267140 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR SH2B2 protein O14492 UNIPROT unknown phosphorylation Ser598 SARSRSNsAERLLEA 10090 16141217 t Serine 588 of APS is a newly identified target for protein kinase B in intact cells and in vitro. The precise function of this PKB-mediated phosphorylation event is not entirely clear but may be responsible for regulating cellular localization and will be the subject of future investigation. SIGNOR-251487 0.2 AMG 900 chemical CID:24856041 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189495 0.8 wortmannin chemical CHEBI:52289 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 BTO:0001271 7503989 t gcesareni Wortmannin inhibited the activity of partially purified pi3-kinase from calf thymus, as well as the pi3-kinase activity in anti-pi3-kinase p85 immunoprecipitates from rbl-2h3 cells, at a concentration as low as 1.0 nm and with ic50 values of 3.0 nm. SIGNOR-252663 0.8 P2RY13 protein Q9BPV8 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256749 0.2 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser296 KQRRSIIsPNFSFMG 9606 16286470 t lperfetto The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain SIGNOR-141593 0.798 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser274 ASPQRSRsPSPQPSS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248520 0.387 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 9606 18174237 t gcesareni Constitutive activation of the c-jun n-terminal kinase (jnk) pathway in sup-t1 cells promoted phosphorylation and degradation of bimel via the proteosome. SIGNOR-160323 0.75 NFE2L2 protein Q16236 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22493435 t miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 SIGNOR-254653 0.418 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation 9606 8381049 t inferred from 70% family members gcesareni Activated map kinase phosphorylates cpla2 at ser-505, causing increased enzymatic activity of cpla2, which is only realized upon translocation of cpla2 to the membrane. SIGNOR-270096 0.2 GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263779 0.7 TRiC complex SIGNOR-C539 SIGNOR CDC20 protein Q12834 UNIPROT up-regulates quantity by stabilization binding 9606 36185250 t miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). SIGNOR-272869 0.54 SATB2 protein Q9UPW6 UNIPROT BCL11B protein Q9C0K0 UNIPROT down-regulates quantity transcriptional regulation 9606 31666685 t gianni Satb2 represses the transcription of Nr4a2. The misexpression of Nr4a2 together with Ctip2 induces expression of SubC-specific genes in wild-type Rsp, and simultaneous knockdown of these two genes in Rsp Satb2-mutant cells prevents their fate transition to SubC identity. Thus, Satb2 serves as a determinant gene in the Rsp regionalization by repressing Nr4a2 and Ctip2 during cortical development SIGNOR-268931 0.509 LATS1 protein O95835 UNIPROT AMOT protein Q4VCS5 UNIPROT up-regulates quantity by stabilization phosphorylation Ser175 QGHVRSLsERLMQMS 24101513 t lperfetto Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130 SIGNOR-275843 0.538 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 23764977 t miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  SIGNOR-268763 0.8 lenvatinib chemical CHEBI:85994 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191454 0.8 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206382 0.8 Cytosolic DNA stimulus SIGNOR-ST30 SIGNOR POLR3A protein O14802 UNIPROT up-regulates 9606 BTO:0000007 19631370 t miannu These results suggest that RNA Pol-III is a cytosolic DNA sensor involved in innate immune responses. Here we show that the cytosolic poly(dA-dT) DNA is converted into 5′-ppp RNA to induce IFN-β through the RIG-I pathway. Biochemical purification led to the identification of DNA-dependent RNA polymerase III (Pol-III) as the enzyme responsible for synthesizing 5′-ppp RNA from the poly(dA-dT) template. Inhibition of RNA Pol-III prevents IFN-β induction by transfection of DNA or infection with DNA viruses. SIGNOR-265564 0.7 PTCHD1 protein Q96NR3 UNIPROT DLG4 protein P78352 UNIPROT up-regulates quantity binding 10090 BTO:0000142 29118110 t miannu Using Western blotting, we validated our MS approach confirming the binding of Dgl4 (also known as PSD95) and VPS35 to the recombinant Ptchd1 C terminus. Endogenous DLG4 and VPS35 from membrane and soluble mouse brain fractions were recovered specifically on the GST fusion proteins containing the cytoplasmic but not the extracellular, negative control sequences of Ptchd1 (Fig. 5E). Binding of DLG4 was dependent on the PDZ-binding motif in Ptchd1, whereas VPS35 binding was not (Fig. 5E). These results demonstrate a biochemical interaction of Ptchd1 with postsynaptic trafficking proteins in the mouse brain. Together, these data suggest that loss of Ptchd1 results in severe alterations in synaptic function in the dentate gyrus SIGNOR-266652 0.2 HNF4A protein P41235 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18805788 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-181271 0.2 GNG12 protein Q9UBI6 UNIPROT PLCE1 protein Q9P212 UNIPROT up-regulates binding 9606 17251915 t gcesareni In the non-canonical wntpathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor SIGNOR-152612 0.2 PPP4C protein P60510 UNIPROT HDAC3 protein O15379 UNIPROT down-regulates activity dephosphorylation Ser424 DHDNDKEsDVEI 9606 15805470 t Here we demonstrate that, in addition to protein-protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity.|Significantly, both overexpression and siRNA knock-down approaches, and analysis of cells devoid of PP4c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4(c). SIGNOR-248548 0.387 KLC1 protein Q07866 UNIPROT TOR1A protein O14656 UNIPROT up-regulates activity binding 10116 14970196 t Monia We identified the light chain subunit (KLC1) of kinesin-I as an interacting partner for torsinA, with binding occurring between the tetratricopeptide repeat domain of KLC1 and the carboxyl-terminal region of torsinA. Coimmunoprecipitation analysis demonstrated that wildtype torsinA and kinesin-I form a complex in vivo. These studies suggest that wild-type torsinA undergoes anterograde transport along microtubules mediated by kinesin and may act as a molecular chaperone regulating kinesin activity and/or cargo binding. SIGNOR-261172 0.399 MAPK8 protein P45983 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 t lperfetto Kinase assays showed that c-jun n-terminal kinase (jnk) was also activated with activation kinetics corresponding to that of k8 phosphorylation. Furthermore, k8 was also phosphorylated on ser-73 by jnk in vitro. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. SIGNOR-114083 0.383 TAOK proteinfamily SIGNOR-PF21 SIGNOR STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 t milica In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2. SIGNOR-230713 0.2 DIABLO protein Q9NR28 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates binding 9606 10929711 t gcesareni Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. mitochondrial survivin associated with smac/diablo, delaying its release. SIGNOR-80212 0.586 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2Q1 protein Q7Z7E8 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271372 0.415 SRGAP1 protein Q7Z6B7 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260515 0.542 MYCBP2 protein O75592 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001321 32814769 t miannu We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. SIGNOR-267147 0.425 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PTPRR protein Q15256 UNIPROT up-regulates activity phosphorylation 11493009 t inferred from 70% family members lperfetto Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL. SIGNOR-270147 0.2 SIN3B protein O75182 UNIPROT Sin3B_complex complex SIGNOR-C409 SIGNOR form complex binding 9606 BTO:0000007 21041482 t miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. SIGNOR-266967 0.757 SRC protein P12931 UNIPROT VCL protein P18206 UNIPROT down-regulates activity phosphorylation Tyr1133 WVRKTPWyQ 9534 15229287 t lperfetto The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreadingWhen phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail. SIGNOR-247428 0.751 VAMP3 protein Q15836 UNIPROT LE-TGN SNARE complex SIGNOR-C157 SIGNOR form complex binding 9606 BTO:0000567 18195106 t lperfetto We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport SIGNOR-253082 0.715 SHANK2 protein Q9UPX8 UNIPROT Postsynaptic density assembly phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 28179641 f miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SIGNOR-264606 0.7 TGFB1 protein P01137 UNIPROT KRT1 protein P04264 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16258965 f Regulation miannu TGFβ1 and TGFβ2 induce loss of epithelial morphology, cytokeratin, and membrane-associated Zonula Occludens-1 and increase the smooth muscle markers calponin and caldesmon SIGNOR-251884 0.2 NTRK2 protein Q16620 UNIPROT FRS3 protein O43559 UNIPROT up-regulates activity phosphorylation Tyr417 EPPRQLNyIQVELKG 9606 11432792 t miannu The tyrosine phosphoryla tion of FRS2/SNT2 was stimulated dependently on the TrkB activation. to explore the possibility that tyrosine residues 417 and 455 on FRS2/SNT2 function as the binding sites for Shp2, we coexpressed Y417F or Y455F phenylalanine mutants and the Y417/455F double phenylalanine mutant of Myc/Histagged FRS2/SNT2 with TrkB. The active TrkB induced somewhat reduced tyrosine phosphorylation of all of the phenylalanine mutants of FRS2/SNT2 in comparison with tyrosine phosphorylation of the wild type SIGNOR-250202 0.585 TCAP protein O15273 UNIPROT TTN protein Q8WZ42 UNIPROT up-regulates activity binding 9606 BTO:0001103 32937135 t lperfetto TCAP, a core sarcomeric component capping the titin proteins, was identified as a positive hit (Figure 1A). TCAP is a small (19 kDa), highly abundant cytoplasmic protein expressed exclusively in skeletal muscle and the heart (Valle et al., 1997). TCAP interacts with titin through its N-terminal beta sheet to anchor titin to the Z-disc SIGNOR-264854 0.905 Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates quantity chemical modification 9606 20223217 t miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. SIGNOR-270442 0.8 KDM2B protein Q8NHM5 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000011 25533466 f miannu We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis. SIGNOR-252246 0.2 EPB41 protein P11171 UNIPROT NUMA1 protein Q14980 UNIPROT up-regulates activity relocalization 9606 23870127 t lperfetto These results indicate that 4.1 proteins recruit NuMA and dynein to the anaphase cell cortex through their conserved CTD (Figure 2I). SIGNOR-266012 0.549 PRRX1 protein P54821 UNIPROT MAFK protein O60675 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221932 0.276 FANCD2 protein Q9BXW9 UNIPROT D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR form complex binding 9606 BTO:0000567 18212739 t lperfetto These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3).  SIGNOR-263255 0.735 NEIL2 protein Q969S2 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). SIGNOR-275719 0.7 RPN1 protein P04843 UNIPROT OPRM1 protein P35372 UNIPROT up-regulates binding 9606 19289571 t miannu Ribophorin i (rpni), a component of the oligosaccharide transferase complex, could directly interact with mor. Rpni can be shown to participate in mor export by the intracellular retention of the receptor after small interfering rna knockdown of endogenous rpni. SIGNOR-184651 0.255 MAPK12 protein P53778 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 t lperfetto Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. SIGNOR-114067 0.2 RCHY1 protein Q96PM5 UNIPROT POLH protein Q9Y253 UNIPROT down-regulates activity monoubiquitination Lys682 SAVSHQGkRNPKSPL 9606 21791603 t miannu Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709). SIGNOR-272730 0.563 PIAS1 protein O75925 UNIPROT RPA2 protein P15927 UNIPROT up-regulates sumoylation 9606 20016603 t gcesareni Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair SIGNOR-162153 0.2 PLCB1 protein Q9NQ66 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates quantity chemical modification -1 23880553 t miannu Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate. SIGNOR-256497 0.8 RAD52 protein P43351 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 27649245 f lperfetto Homologous recombination (HR) plays an important role in maintaining genomic integrity. It is responsible for repair of the most harmful DNA lesions, DNA double-strand breaks and inter-strand DNA cross-links. HR function is also essential for proper segregation of homologous chromosomes in meiosis, maintenance of telomeres, and resolving stalled replication forks. Defects in HR often lead to genetic diseases and cancer. Rad52 is one of the key HR proteins, which is evolutionarily conserved from yeast to humans| in mammals, Rad52 knockouts showed no significant DNA repair or recombination phenotype. |These new findings indicate an important backup role for Rad52, which complements the main HR mechanism in mammals. SIGNOR-251507 0.7 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser397 SMVGGERsPPRILPP 9606 21059642 t The effect has been demonstrated using Q01196-8 lperfetto Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). SIGNOR-216912 0.348 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT up-regulates phosphorylation Tyr420 RLIEDNEyTARQGAK 9606 22080863 t lperfetto Previously, we reported that sfks can serve as bona fide substrates for tcptp and that tcptp dephosphorylates the y418 activation loop autophosphorylation site (corresponding to y394 in lck and y417 in fyn) to inactivate sfks SIGNOR-177109 0.2 ENG protein P17813 UNIPROT GDF2 protein Q9UK05 UNIPROT up-regulates activity binding 9606 BTO:0003767 21737454 t miannu Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. We found that mouse and human endoglin ECD-Fc bound directly, specifically, and with high affinity to bone morphogenetic proteins 9 and 10 (BMP9 and BMP10) in surface plasmon resonance (Biacore) and cell-based assays. SIGNOR-276656 0.74 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2M protein P61081 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271366 0.689 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser406 CQAVFPPsITSRGDF 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262720 0.733 SLC5A5 protein Q92911 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity relocalization 10116 28192058 t scontino Active iodide (I-) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na+/I- symporter (NIS). In the thyroid, NIS-mediated I- uptake plays a pivotal role in thyroid hormone (TH) biosynthesis.  SIGNOR-266960 0.8 MAPK8 protein P45983 UNIPROT CDT1 protein Q9H211 UNIPROT up-regulates quantity by stabilization phosphorylation Ser491 GSCCTIMsPGEMEKH 9606 BTO:0000567 21930785 t miannu  We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2.  SIGNOR-276360 0.376 RUNX1 protein Q01196 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 19334039 f lperfetto AML1/RUNX1 mutants play a central role in the pathogenesis of MDS/AML. Both AML1 mutants are initiating factors for MDS-genesis by inhibiting differentiation of hematopoietic stem cells, and Ni-type mutant requires acquisition of proliferation ability. SIGNOR-249631 0.7 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CEBPD protein P49716 UNIPROT down-regulates binding 9606 12524424 t fspada C/ebpbeta and c/ebpdelta were found to physically interact with smad3 and smad4, and smad3 cooperated with smad4 and tgf-beta signaling to repress the transcriptional activity of c/ebps. SIGNOR-97120 0.328 sorafenib tosylate chemical CHEBI:50928 ChEBI RET protein P07949 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. SIGNOR-259229 0.8 SMURF1 protein Q9HCE7 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 11278251 t miannu Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with TbetaR-I via Smad7, with subsequent enhancement of turnover of TbetaR-I and Smad7.  SIGNOR-272941 0.878 CCL2 protein P13500 UNIPROT CCR2 protein P41597 UNIPROT up-regulates activity binding 9606 20219869 t areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.  SIGNOR-255113 0.782 PLK3 protein Q9H4B4 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000452 11447225 t lperfetto Upon exposure of cells to hydrogen peroxide (h(2)o(2)) phosphorylation of p53 was rapidly induced in human fibroblast gm00637, and this phosphorylation occurred on serine 9, serine 15, serine 20, but not on serine 392. In addition, h(2)o(2)-induced phosphorylation of p53 was followed by induction of p21, suggesting functional activation of p53. Ectopic expression of a plk3 dominant negative mutant, plk3(k52r), in gm00637 cells suppressed h(2)o(2)-induced serine 20 phosphorylation. Taken together, our studies strongly suggest that the oxidative stress-induced activation of p53 is at least in part mediated by plk3. SIGNOR-109239 0.694 sitaxentan chemical CHEBI:135736 ChEBI EDNRA protein P25101 UNIPROT down-regulates activity chemical inhibition -1 9171878 t miannu Discovery of TBC11251, a potent, long acting, orally active endothelin receptor-A selective antagonist.The optimal compound discovered during these studies, 15q (TBC11251), binds competitively to human ETA receptors with a Ki of 0.43 +/- 0.03 nM and an IC50 of 1.4 nM (IC50 for ETB = 9800 nM). This compound inhibits ET-1-induced stimulation of phosphoinositide turnover with a Ki of 0.686 nM and a pA2 of 8.0. SIGNOR-258610 0.8 FANCD2 protein Q9BXW9 UNIPROT Fanconi anemia ID complex complex SIGNOR-C302 SIGNOR form complex binding 9606 BTO:0000007 17412408 t lperfetto Immunoprecipitation of HA-FLAG-tagged FANCI expressed in 293T cells with antibodies against either HA or FLAG, but not MYC, resulted in coimmunoprecipitation of endogenous FANCD2|The FANCI protein associates with FANCD2 and, together, as the FANCI-FANCD2 (ID) complex, localize to chromatin in response to DNA damage. SIGNOR-263268 0.955 CRHR1 protein P34998 UNIPROT Corticotropin protein P01189-PRO_0000024969 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 23504413 f lperfetto CRH, as a principal mediator of endocrine stress response, activates the HPA axis (Hypothalamic–pituitary–adrenal axis) by binding to the CRHR1 in the anterior pituitary. This, through a cascade of reactions, increases the expression of proopiomelanocortin (POMC) gene and the subsequent release of POMC-derived peptides, adrenocorticotropic hormone (ACTH) and β-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal cortex (Vale et al. 1981). SIGNOR-268613 0.2 THEM4 protein Q5T1C6 UNIPROT AKT1 protein P31749 UNIPROT down-regulates binding 9606 11598301 t gcesareni Here, we describe a protein partner for pkbalpha termed ctmp, or carboxyl-terminal modulator protein, that binds specifically to the carboxyl-terminal regulatory domain of pkbalpha at the plasma membrane. Binding of ctmp reduces the activity of pkbalpha by inhibiting phosphorylation on serine 473 and threonine 308. SIGNOR-111003 0.686 MARK2 protein Q7KZI7 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser886 PVDPRRRsLPAGDAL 9606 22072711 t The effect has been demonstrated using Q92974-2 gcesareni We also show that par1b-induced serine 885/serine 959 phosphorylation inhibits rhoa-specific gef activity of gef-h1. As a consequence, gef-h1 phosphorylated on both of the serine residues loses the ability to stimulate rhoa and thereby fails to induce rhoa-dependent stress fiber formation SIGNOR-177096 0.517 VDR protein P11473 UNIPROT CYP3A4 protein P08684 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12147248 f miannu Expression of cytochrome P450 3A4 (CYP3A4) is induced by 1,25-dihydroxyvitamin D(3)(1,25(OH)(2)D(3)) in Caco-2 cells. However, since a typical vitamin D responsive element has not been found in the 5(')-flanking region of the CYP3A4 gene, the mechanism of 1,25(OH)(2)D(3)-induced CYP3A4 mRNA expression is poorly understood. In the present study, we demonstrated that vitamin D receptor (VDR) is a critical factor for the induction using the antisense oligonucleotide technique. SIGNOR-255600 0.413 ECM stimulus SIGNOR-ST20 SIGNOR Av/b2 integrin complex SIGNOR-C176 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259054 0.7 CDC14A protein Q9UNH5 UNIPROT IREB2 protein P48200 UNIPROT up-regulates activity dephosphorylation Ser157 LQKAGKLsPVKVQPK 9606 18574241 t IRP2 Ser-157 is phosphorylated by Cdk1/cyclin B1 during G(2)/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. Ser-157 phosphorylation during G(2)/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, whereas Ser-157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis. SIGNOR-248829 0.355 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr565 KKKTEGTyDLPYWDR -1 23770091 t done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. SIGNOR-273945 0.357 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252758 0.719 CASP1 protein P29466 UNIPROT Caspase 1 complex complex SIGNOR-C220 SIGNOR form complex binding cleavage:Asp119 PAPQAVQdNPAMPTS 7721861 t lperfetto The interleukin-1 beta-converting enzyme is a heterodimeric cysteine protease that is produced as a 45-kDa precursor. The full-length precursor form of the enzyme was expressed in Escherichia coli as insoluble inclusion bodies. Following solubilization and refolding of the 45-kDa protein, autoproteolytic conversion to a heterodimeric form containing 10- and 20-kDa subunits was observed. SIGNOR-256386 0.2 SDC3 protein O75056 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 10090 BTO:0002314 20696709 t gcesareni Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-€“converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size. SIGNOR-244072 0.387 ABL1 protein P00519 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates phosphorylation Tyr28 SRIGDELyLEPLEDG 9606 11971963 t gcesareni C-abl phosphorylates the rad9 bcl-2 homology 3 domain (tyr-28) in vitro and in cells exposed to dna-damaging agents. The results also demonstrate that c-abl-mediated phosphorylation of rad9 induces binding of rad9 to the antiapototic bcl-x(l) protein SIGNOR-86186 0.49 CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser293 GSTKRRKsMSGASPK 9606 20068082 t gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). SIGNOR-163146 0.851 IL18 protein Q14116 UNIPROT IL18R1 protein Q13478 UNIPROT up-regulates binding 9606 9792649 t gcesareni Acpl was required for il-18 responsiveness in terms of nf?B Induction and jnk activation SIGNOR-60991 0.829 PRKAA1 protein Q13131 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates activity phosphorylation Ser510 SPVSRTPsLPAVDTS 9606 27256105 t Luana Mechanically, we found that AMPKα1 directly phosphorylated protein inhibitor of activated STAT-1 (PIAS1), the SUMO E3-ligase of Runx2, at serine 510, to promote its SUMO E3-ligase activity. Finally, mutation of protein inhibitor of activated STAT-1 at serine 510 suppressed m SIGNOR-259866 0.2 ACTG1 protein P63261 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity binding 9606 28233384 t lperfetto Here, we report the highest resolution, cryo-EM structures of actin filaments with bound ATP analog β,γ-imidoadenosine 5′-triphosphate (AMPPNP) (3.1 Å) and ADP with inorganic phosphate (ADP-Pi) (3.1 Å) as well as a 3.6-Å resolution structure of the ADP filament. These structures of the three well-characterized nucleotide states of actin monomers and filaments SIGNOR-261878 0.7 HMGCS2 protein P54868 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI down-regulates quantity chemical modification 29597274 t lperfetto Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis SIGNOR-267658 0.8 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation 9606 12832467 t lperfetto Efficient rsk activation by erk requires its interaction through a docking site located near the c terminus of rsk SIGNOR-102645 0.749 PTPN5 protein P54829 UNIPROT GRIA2 protein P42262 UNIPROT down-regulates activity dephosphorylation 9606 21883219 t miannu One study showed that stimulation of the metabotrophic glutamate receptor mGluR5 leads to a STEP mediated tyrosine dephosphorylation of GluA2 and internalization of GluA1 and GluA2, although the tyrosine residue on GluA2 that is dephosphorylated by STEP remains unidentified. SIGNOR-277040 0.422 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269351 0.719 RRM2B protein Q7LG56 UNIPROT RRM1 protein P23921 UNIPROT up-regulates activity binding 9606 BTO:0001061 14583450 t miannu Taken together, we conclude that UV-induced activation of p53R2 transcription and binding of p53R2 to hRRM1 to form RR holoenzyme are impaired in the p53-mutant cell line PC3. SIGNOR-259366 0.932 Mob1 proteinfamily SIGNOR-PF42 SIGNOR LATS2 protein Q9NRM7 UNIPROT up-regulates binding 9606 21084559 t Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. SIGNOR-269957 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser52 TRRTRTFsATVRASQ 9606 BTO:0000671 15910284 t lperfetto These and other results demonstrate that crhsp24 is phosphorylated at ser52 by pkbalpha in response to igf-1, at ser52 by pkbalpha and rsk in response to egf SIGNOR-137430 0.2 XBP1 protein P17861-2 UNIPROT Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR down-regulates 9606 15598891 f miannu ATF6 and XBP1 are transcription factors activated specifically in response to endoplasmic reticulum (ER) stress. Three cis-acting elements capable of binding to ATF6, XBP1 or both have been identified to date, namely ER stress-response element (ERSE), unfolded protein response element (UPRE) and ERSE-II. ERSE controls the expression of ER-localized molecular chaperones such as BiP that can refold unfolded proteins in the ER; transcription from ERSE is fully activated by ATF6 even in the absence of XBP1. In contrast, transcription from UPRE depends solely on XBP1 and it has been suggested that UPRE may control the expression of components of the ER-associated degradation system that can degrade unfolded proteins in the ER. SIGNOR-260186 0.7 LCK protein P06239 UNIPROT MED28 protein Q9H204 UNIPROT up-regulates phosphorylation Tyr64 ASLVSQDyVNGTDQE 9606 16899217 t gcesareni Y64 of magicin is phosphorylated by lck creating a sh2-grb2 binding motif SIGNOR-148704 0.45 NFE2L2 protein Q16236 UNIPROT NQO1 protein P15559 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8962164 f irozzo These results indicated that hARE-mediated expression of the NQO1 gene and its induction by xenobiotics and antioxidants are mediated by Nrf1 and Nrf2. SIGNOR-256279 0.5 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIK5 protein Q16478 UNIPROT up-regulates activity chemical activation 9606 27586965 t miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors SIGNOR-264474 0.8 3-phosphonatooxypyruvate(3-) smallmolecule CHEBI:18110 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity precursor of 9606 25406093 t lperfetto PHDGH catalyzes the first reaction of de novo serine biosynthesis, producing 3-phosphohydroxypyruvate by NAD+-coupled oxidation of 3-phosphoglycerate (3PG).|The PHGDH reaction is reversible and, under standard conditions, thermodynamically favors the direction from 3-phosphohydroxypyruvate to 3PG. SIGNOR-268566 0.8 EGFR protein P00533 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 11823423 t Cbl binds directly to Tyr1045 receptors gcesareni Consistent with a negative role for c-Cbl, here we report that defective Tyr1045 of EGFR, an inducible c-Cbl docking site, enhances the mitogenic response to EGF SIGNOR-114701 0.883 LARP1 protein Q6PKG0 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity binding 9606 BTO:0002181 28650797 t SARA LARP1-mTORC1 interaction occurs through direct protein-protein contacts. phosphorylated LARP1 facilitates mTORC1-dependent phosphorylation of S6K1 and 4EBP1 on the LARP1-containing mRNPs by scaffolding mTORC1. SIGNOR-260993 0.306 AR protein P10275 UNIPROT NRAS protein P01111 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 16281084 f After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. SIGNOR-253676 0.286 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity phosphorylation Thr336 KDRWRSMtVVPYLED 9606 BTO:0000007;BTO:0000567 12805220 t lperfetto It was shown that thr336 and thr366 are the major autophosphorylation sites of mouse lkb1 (sapkota et al., 2002). We confirmed these data on the human orthologues thr336 and thr363. Moreover, the enhanced stoichiometry of lkb1 autophosphorylation by strad enabled us to identify two novel sites: thr185 and thr402. We show that increased lkb1 autophosphorylation of all sites correlates with the activation of its catalytic activity. SIGNOR-101844 0.2 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser141 MASQKRPsQRHGSKY -1 2413024 t lperfetto MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. SIGNOR-248869 0.502 TRIM41 protein Q8WV44 UNIPROT PRKCE protein Q02156 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 17893151 t miannu RINCK induces the ubiquitination of PKC both in vitro and in cells. Overexpression of RINCK reduces the levels of PKC in cells, whereas genetic knockdown of endogenous RINCK increases the levels of PKC. The RINCK-mediated ubiquitination is likely to be polyubiquitination, because the ubiquitinated PKCβII was detected as a high molecular weight smear. SIGNOR-271668 0.2 CTDP1 protein Q9Y5B0 UNIPROT CDK1 protein P06493 UNIPROT down-regulates activity dephosphorylation 9606 26653855 t miannu Thus, Fcp1 coordinates Cdk1 and Gwl inactivation to derepress PP2A-B55, generating a dephosphorylation switch that drives mitosis progression.|We can not exclude that, in addition to S90 and S453, other Cdk1 phosphorylation sites in Gwl are dephosphorylated by Fcp1; nevertheless, assaying S67-Ensa kinase activity of V5-GwlS90A and V5-GwlS453A mutant proteins, isolated from transfected and prometaphase arrested HeLa cells, revealed that both mutants had significantly reduced S67-Ensa kinase activity compared to V5-GwlWT (XREF_FIG).|We show here that activation of PP2A-B55, a major mitosis exit phosphatase, required the phosphatase Fcp1 downstream Cdk1 inactivation in human cells. SIGNOR-277141 0.339 C5AR1 protein P21730 UNIPROT Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 9108406 f lperfetto We report here that the anaphylatoxins C3a and C5a are chemotactic factors for the human mast cell line HMC-1, human cord blood-derived mast cells (CBMC) and cutaneous mast cells in vitro. SIGNOR-263460 0.7 PP1 proteinfamily SIGNOR-PF54 SIGNOR MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 12840032 t lperfetto P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3) SIGNOR-264664 0.2 MYOD1 protein P15172 UNIPROT CCND3 protein P30281 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 10373569 t gcesareni Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator. SIGNOR-238526 0.382 porfimer chemical CHEBI:60652 ChEBI FCGR1A protein P12314 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000876 2544592 t miannu Inhibition of the high affinity Fc receptor (Fc gamma RI) on human monocytes by porphyrin photosensitization is highly specific and mediated by the generation of superoxide radicals. SIGNOR-259303 0.8 CTDP1 protein Q9Y5B0 UNIPROT WEE1 protein P30291 UNIPROT up-regulates activity dephosphorylation 9606 27670139 t miannu At mitosis exit, Fcp1 promoted inhibitory Cdk1 phosphorylation by dephosphorylating Wee1, and ubiquitin dependent cyclin B degradation by dephosphorylating Cdc20 and USP44.|This lead us to hypothesize that, during prolonged mitosis in AMCDs treated cancer cells, progressive Fcp1 induced Wee1 reactivation might lead to progressive loss of Cdk1 activity that weakens the SAC to a point in which the mitotic state could not be sustained . SIGNOR-277142 0.39 PPM1G protein O15355 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity dephosphorylation 9606 22361354 t miannu After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. |ATM Dependent Downregulation of USP7 and HAUSP by PPM1G Activates p53 Response to DNA Damage.|DNA Damage Leads to ATM Dependent USP7S Dephosphorylation by PPM1G. SIGNOR-277158 0.308 PPM1F protein P49593 UNIPROT LATS1 protein O95835 UNIPROT down-regulates activity dephosphorylation Thr1079 EHAFYEFtFRRFFDD 9606 30863499 t lperfetto POPX2 is capable of dephosphorylating LATS1 at Thr1079 (Figure xref ), which is a residue critical for LATS1 activity.|POPX2 might negatively regulate the activities of MST1 and LATS1 through dephosphorylation.|We found that POPX2 could dephosphorylate LATS1 on Threonine-1079, leading to inactivation of LATS1 kinase. SIGNOR-276989 0.2 tamsulosin chemical CHEBI:9398 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258471 0.8 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273085 0.745 EGLN3 protein Q9H6Z9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates activity hydroxylation 9606 BTO:0000567 21620138 t inferred from family member Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1Œ± and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. SIGNOR-270290 0.447 VPS72 protein Q15906 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269290 0.66 PHF21A protein Q96BD5 UNIPROT KDM1A protein O60341 UNIPROT down-regulates activity binding -1 16140033 t miannu BHC80 Inhibits LSD1 Demethylase Activity In Vitro. in contrast to CoREST, which is a positive regulator of LSD1 activity, the in vitro evidence presented above suggests that BHC80 may function to inhibit LSD1 activity. SIGNOR-264505 0.704 HMGB1 protein P09429 UNIPROT HOXD9 protein P28356 UNIPROT up-regulates activity binding 10090 BTO:0000944 8890171 t miannu We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain.ƒ‚‚ The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein. SIGNOR-236956 0.34 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 21576360 t When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita SIGNOR-256247 0.782 AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 17522231 f lperfetto These results suggest that when SARS-CoV binds ACE2 it is internalized and penetrates early endosomes in a clathrin-dependent manner |The clathrin-dependent endocytosis is initiated by the binding of adaptor protein 2 (AP2) complexes to the cytoplasmic tail of the cell-surface receptors, which recruits clathrins SIGNOR-260704 0.7 DHPS protein P49366 UNIPROT EIF5A protein P63241 UNIPROT up-regulates activity post translational modification -1 32142284 t miannu Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation. SIGNOR-266374 0.932 ABL2 protein P42684 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Tyr292 RLGHCHTyWAVSEEL 9606 BTO:0000007 30842273 t miannu The data in this study show that IRF3 is physically associated with c-Abl in vivo and directly binds to c-Abl in vitro. IRF3 is phosphorylated by c-Abl and c-Abl-related kinase, Arg, mainly at Y292. SIGNOR-277441 0.2 DYRK1A protein Q13627 UNIPROT LIN52 protein Q52LA3 UNIPROT up-regulates activity phosphorylation Ser28 FEKLDRAsPDLWPEQ 9606 BTO:0001583 21498570 t miannu Here we report that DYRK1A can specifically phosphorylate LIN52 on serine residue 28, and that this phosphorylation is required for DREAM assembly. SIGNOR-262846 0.668 EN2 protein P19622 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. SIGNOR-265775 0.427 IL4R protein P24394 UNIPROT IRS2 protein Q9Y4H2 UNIPROT up-regulates phosphorylation 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica Irs-1 and a homologous protein, irs-2 (also known as 4-phosphotyrosine substrate), are recruited to phosphorylated y497 of IL-4R After ligand binding, leading to phosphorylation and activation of irs-1 and irs-2. SIGNOR-100771 0.575 HCRTR2 protein O43614 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256872 0.267 CSNK2A2 protein P19784 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT down-regulates activity phosphorylation Ser575 AGESLDQsMEEEEEE 9606 BTO:0000567 12591939 t llicata We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified SIGNOR-250985 0.381 CCNA1 protein P78396 UNIPROT WT1 protein P19544 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19082485 f irozzo This study identified WT1 as a repressed target of cyclin A1 and suggests that the suppression of WT1 in cyclin A1-overexpressing leukemias might play a role in the growth and suppression of apoptosis in these leukemic cells. SIGNOR-255905 0.398 DOK4 protein Q8TEW6 UNIPROT FYN protein P06241 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 t gcesareni Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells. SIGNOR-100999 0.551 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1C protein P49918 UNIPROT down-regulates phosphorylation Ser282 FFAKRKRsAPEKSSG 9606 BTO:0000150 23421998 t lperfetto Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination SIGNOR-201042 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270375 0.8 CHMP4A protein Q9BY43 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 t miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. SIGNOR-265529 0.696 PLCE1 protein Q9P212 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates chemical modification 9606 17251915 t gcesareni Typically galfas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152771 0.8 RAC1 protein P63000 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates activity binding 9606 27571105 t areggio Although there are other activators of PCP, Wnt5a can activate the PCP pathway by forming a complex with Fzd and Ror2 receptors, activating DVL, which in turn activates Rho-family small GTPases, including RhoA and Rac, and their downstream effectors, Rho-associated protein kinase (ROCK), the actin-binding protein, Filamin A and c-Jun N-terminal protein kinase (JNK) SIGNOR-258972 0.413 CREBBP protein Q92793 UNIPROT DDX21 protein Q9NR30 UNIPROT down-regulates activity acetylation Lys18 LESDTAMkKGETLRK 28790157 t lperfetto Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21. SIGNOR-275902 0.247 PRKN protein O60260 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. SIGNOR-272749 0.2 CSNK2A1 protein P68400 UNIPROT MYCN protein P04198 UNIPROT unknown phosphorylation Ser263 GEDTLSDsDDEDDEE -1 1425701 t llicata Analysis of phosphorylation sites in synthetic peptides of this acidic region identified the major sites phosphorylated by CKII as Ser261 and Ser263. SIGNOR-250921 0.458 CTNNB1 protein P35222 UNIPROT AFF3 protein P51826 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26214578 f irozzo We demonstrate that AFF3 is a new target of Wnt/β-catenin pathway involved in ACC, acting on transcription and RNA splicing. SIGNOR-259192 0.287 PPP2CA protein P67775 UNIPROT TRPM8 protein Q7Z2W7 UNIPROT down-regulates activity dephosphorylation Ser9 SFRAARLsMRNRRND 9606 BTO:0000007 20110357 t done miannu Using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. the intracellular serine/threonine protein phosphatase 2A (PP2A) dephosphorylates TRPM8 Ser-9 and Thr-17 inhibiting the channel activity. SIGNOR-273794 0.2 APOE protein P02649 UNIPROT MAPT protein P10636 UNIPROT up-regulates activity binding 7566652 t lperfetto Isoform specific interactions of ApoE have been shown with the microtubule-associated protein tau, which forms the neurofibrillary tangle in this disease.|Phosphorylation of serine262 in domain I of tau decreases tau binding to microtubules and also abolishes binding by ApoE3. SIGNOR-262588 0.584 WNK4 protein Q96J92 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates activity phosphorylation Thr231 TRNKVRKtFVGTPCW 16990453 t lperfetto Vitari et al. (76) and Moriguchi et al. (52) demonstrated that WNK4 bound and phosphorylated PASK at Thr-233 and Ser-373 in mammalian cells.| this phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1 SIGNOR-264640 0.521 C1D protein Q13901 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates activity binding 9606 BTO:0000567 9405624 t 2 miannu SUN-CoR is a protein involved in transcriptional repression by nuclear hormone receptors. The C terminus of SUN-CoR interacts with TR and RevErb in vitro and associates with RevErb in cells, SUN-CoR potentiates repression by both receptors in cells, and the N terminus of SUN-CoR contains an intrinsic repression domain. SIGNOR-241272 0.319 AXIN1 protein O15169 UNIPROT RNF111 protein Q6ZNA4 UNIPROT up-regulates binding 9606 16601693 t gcesareni Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia. Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia. SIGNOR-145845 0.627 MSH release-inhibiting hormone smallmolecule CID:56842142 PUBCHEM MC4R protein P32245 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257538 0.8 PRKACA protein P17612 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11035810 t gcesareni Phosphorylation of ser21 and inactivation of glycogen synthase kinase 3 by protein kinase a. SIGNOR-83221 0.379 MAPK1 protein P28482 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by destabilization phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 11733495 t gcesareni Moreover, the inhibition of erks 1 and 2 with a mek inhibitor, u1026, lead to an inhibition in the decay of ppargamma proteins, indicating that serine phosphorylation influences the degradation of ppargamma in fat cells. SIGNOR-112544 0.469 STK11 protein Q15831 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17108107 t gcesareni We show that lkb1 physically associates with p53 in the nucleus and directly or indirectly phosphorylates p53 ser15 (previously shown to be phosphorylated by amp-dependent kinase) and p53 ser392 SIGNOR-150830 0.747 CDK1 protein P06493 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity phosphorylation 9606 BTO:0003918 19917720 t lperfetto Cyclin-Dependent Kinase 1-Mediated Bcl-xL/Bcl-2 Phosphorylation Acts as a Functional Link Coupling Mitotic Arrest and Apoptosis|These findings suggest a model whereby a switch in the duration of CDK1 activation, from transient during mitosis to sustained during mitotic arrest, dramatically increases the extent of Bcl-xL/Bcl-2 phosphorylation, resulting in inactivation of their antiapoptotic function. Thus, phosphorylation of antiapoptotic Bcl-2 proteins acts as a sensor for CDK1 signal duration and as a functional link coupling mitotic arrest to apoptosis. SIGNOR-267986 0.553 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser330 MEEDSYDsFGEPSYP -1 9558331 t llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. SIGNOR-250934 0.312 VCAM1 protein P19320 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR up-regulates activity binding 9606 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253241 0.661 CKM complex complex SIGNOR-C406 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo. SIGNOR-273170 0.2 PIM3 protein Q86V86 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 16403219 t miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. SIGNOR-250399 0.353 RNF144A protein P50876 UNIPROT PRKDC protein P78527 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 24979766 t miannu We show that RNF144A induces ubiquitination of DNA-PKcs in vitro and in vivo and promotes its degradation. SIGNOR-272213 0.549 SUN1 protein O94901 UNIPROT MAJIN protein Q3KP22 UNIPROT up-regulates activity binding 9606 BTO:0000007 SIGNOR-C303 SIGNOR-C305 33015044 t lperfetto In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | It will be of great interest to test this hypothesis to fully understand the mechanisms of stable telomere–NE connection and telomere movement along the NE driven by the LINC complex. SIGNOR-263300 0.2 CTNND1 protein O60716 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000414 14610055 t miannu P120 regulates E-cadherin turnover at the cell membrane. Because direct binding of p120 to E-cadherin is required, it is possible that p120 binding blocks the interaction of an unknown binding partner (or event) that targets E-cadherin for degradation SIGNOR-252123 0.946 SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887 10713164 t gcesareni Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip. SIGNOR-75788 0.585 C1QBP protein Q07021 UNIPROT KRT1 protein P04264 UNIPROT up-regulates activity binding 9606 14691569 t Regulation of binding miannu Cytokeratin 1 binds to both gC1qR and u-PAR. Our data suggest that formation of HK (and Factor XII) binding sites along endothelial cell membranes consists of bimolecular com-plexes of gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1, with gC1qR binding being favored. SIGNOR-251881 0.381 HES1 protein Q14469 UNIPROT RCAN1 protein P53805 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000667 15866158 t Increased Calcineurin/NFAT activity by Notch signaling involves downregulation of Calcipressin, an endogenous Calcineurin inhibitor, through a HES-1-dependent mechanism .... Chromatin immunoprecipitation (ChIP) analysis of keratinocytes overexpressing HES-1 showed that this protein can bind to the HES binding sites present in both distal and proximal promoters SIGNOR-252026 0.2 ULK1 protein O75385 UNIPROT SEC23B protein Q15437 UNIPROT up-regulates quantity by stabilization phosphorylation Ser186 SCEGISKsYVFRGTK 9606 BTO:0000007 30596474 t lperfetto Here, we show that the F-box protein FBXW5 targets SEC23B, a component of COPII, for proteasomal degradation and that this event limits the autophagic flux in the presence of nutrients. In response to starvation, ULK1 phosphorylates SEC23B on Serine 186, preventing the interaction of SEC23B with FBXW5 and, therefore, inhibiting SEC23B degradation. SIGNOR-265285 0.2 BRCA1 protein P38398 UNIPROT AKT1 protein P31749 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0002572 19074868 t gcesareni The BRCA1-BRCT domains bind to phosphorylated AKT (pAKT) and lead to its ubiquitination toward protein degradation SIGNOR-252435 0.52 NR3C1 protein P04150 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15591535 f gcesareni Our data suggest a mechanism for transrepression between two nuclear receptors, gr and ngfi-b. SIGNOR-132251 0.329 VRK2 protein Q86Y07 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates phosphorylation Ser31 PQDELDFsILFDYEY 9606 23105117 t gcesareni We demonstrate that vrk2 directly interacts and phosphorylates nfat1 in ser-32 within its n-terminal transactivation domain. SIGNOR-199263 0.376 MEFV protein O15553 UNIPROT Pyrin inflammasome complex SIGNOR-C226 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256413 0.597 STAG1 protein Q8WVM7 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1‚ÄìInt14 (Integrator subunits)¬† SIGNOR-267729 0.913 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Pro48 RSFLLRNpNDKYEPF -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. SIGNOR-263577 0.43 RNA Polymerase III complex SIGNOR-C389 SIGNOR transfer RNA smallmolecule CHEBI:17843 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-266143 0.8 AKT3 protein Q9Y243 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates phosphorylation Ser387 SKLMRSAsFNTDPYV 9606 18476811 t lperfetto Phosphorylation of argonaute 2 at serine-387 facilitates its localization to processing bodies, akt3-mediated phosphorylation of ago2 is a molecular switch between target mrna cleavage and translational repression activities of ago2 SIGNOR-178416 0.433 MKNK1 protein Q9BUB5 UNIPROT SPRY2 protein O43597 UNIPROT down-regulates phosphorylation Ser121 VSSGSRSsTRTSTSS 9606 19864419 t llicata The spry2/nedd4 association involves the ww domains of nedd4 and requires phosphorylation of the mnk2 kinase sites, ser(112) and ser(121), on spry2. mnk2 silencing decreased spry2-nedd4 interactions and also augmented the ability of spry2 to inhibit fibroblast growth factor signaling. endogenous and overexpressed nedd4 polyubiquitinate spry2 via lys(48) on ubiquitin and decrease its stability. SIGNOR-188893 0.51 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 BTO:0000007 18840653 t We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well. SIGNOR-248400 0.547 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr101 EGLSMGNyIGLINRI -1 16373505 t Manara PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR. SIGNOR-260782 0.2 CSNK2A1 protein P68400 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity phosphorylation Ser558 AEQMANDsDDSISAA -1 28436950 t miannu Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. SIGNOR-265896 0.2 MMP20 protein O60882 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272365 0.7 AKAP11 protein Q9UKA4 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity binding 9606 BTO:0000007 phosphorylation:Thr1136 AKEFAPAtPPSTPHN 26088133 t lperfetto A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). Using a combination of molecular and cellular approaches we show that GSK3beta phosphorylation of Thr-1132 on AKAP220 initiates recruitment of this kinase into the enzyme scaffold. We also find that AKAP220 anchors GSK3beta and its substrate beta-catenin in membrane ruffles. SIGNOR-264817 0.38 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC1 protein Q96A08 UNIPROT down-regulates activity monoubiquitination Lys36 KKRKRTRkESYSIYI 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271992 0.2 TGFBR1 protein P36897 UNIPROT TP63 protein Q9H3D4 UNIPROT unknown phosphorylation Ser160 SSTFDALsPSPAIPS 9606 23166821 t llicata We show that phosphorylation of _np63_ at s66/68 in response to ultraviolet (uv) irradiation is mediated by alk5 SIGNOR-199781 0.2 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2W protein Q96B02 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271340 0.677 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR down-regulates quantity by destabilization chemical inhibition 9606 19029980 t Retinoic acid and arsenic synergize to clear LICs through cooperative PML-RARA degradation, this combination does not enhance differentiation. SIGNOR-259926 0.8 COL1A1 protein P02452 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 35267698 t lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. SIGNOR-272346 0.623 PLK1 protein P53350 UNIPROT GTSE1 protein Q9NYZ3 UNIPROT up-regulates phosphorylation Ser435 RSIRRRDsCLNSKTK 9606 20577264 t lperfetto In this study, we show that g2 and s-phase-expressed 1 (gtse1) protein, a negative regulator of p53, is required for g2 checkpoint recovery and that plk1 phosphorylation of gtse1 at ser 435 promotes its nuclear localization, and thus shuttles p53 out of the nucleus to lead to its degradation during the recovery. SIGNOR-166417 0.724 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1654 SPSYSPTsPSYSPTS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248771 0.442 CREB1 protein P16220 UNIPROT MITF protein O75030 UNIPROT up-regulates quantity by expression transcriptional regulation 10841026 t lperfetto Therefore, the molecular steps linking cAMPto melanogenesis up-regulation appear currently better elucidated. cAMP activates PKA, and PKA phosphorylates and activates CREB which, when activated, binds to the CRE domain present in the microphthalmia promoter,thereby up-regulating its transcription. SIGNOR-249619 0.619 PIK3R1 protein P27986 UNIPROT PI3K complex SIGNOR-C156 SIGNOR form complex binding 9606 19805105 t miannu Phosphoinositol 3- kinase alpha (PI3Kα) is a heterodimeric enzyme formed by a catalytic subunit (p110α, encoded by PIK3CA) and one of several regulatory subunits (a major one being p85α, encoded by PI3KR1). SIGNOR-255300 0.934 CDK1 protein P06493 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser432 SAYGGLTsPGLSYSL 9606 9524113 t lperfetto With regard to k8 phosphorylation at ser-431, it increases dramatically upon stimulation of cells with epidermal growth factor (egf) or after mitotic arrest and is the major k8 phosphorylated residue after incubating k8 immunoprecipitates with mitogen-activated protein or cdc2 kinases. SIGNOR-56054 0.25 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194343 0.8 FOXS1 protein O43638 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by repression transcriptional regulation 9913 18288644 t Luana Fkhl18 suppressed the transcriptional activity of FoxO3a and FoxO4. SIGNOR-261610 0.2 IQSEC2 protein Q5JU85 UNIPROT GRIA1 protein P42261 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 27009485 t miannu BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors. SIGNOR-264912 0.2 COL4A1 protein P02462 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253242 0.481 CEBPB protein P17676 UNIPROT SFTPD protein P35247 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001910 11912209 t Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D. SIGNOR-254045 0.254 STAT6 protein P42226 UNIPROT ALOX15 protein P16050 UNIPROT up-regulates 9606 BTO:0000018 12517954 f lperfetto IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300. SIGNOR-254101 0.334 RPL24 protein P83731 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262475 0.841 GATA4 protein P43694 UNIPROT TDO2 protein P48775 UNIPROT down-regulates quantity by repression transcriptional regulation BTO:0000575 19003156 t lperfetto GATA4 inhibits expression of the tryptophan oxygenase gene by binding to the TATA box in fetal hepatocytes. SIGNOR-268994 0.255 nitric oxide smallmolecule CHEBI:16480 ChEBI DNM1L protein O00429 UNIPROT up-regulates activity 33850055 f lperfetto Upon viral infection, DDAH2 relocated to mitochondria, where it induced the production of nitric oxide (NO) and the activation of dynamin-related protein 1 (Drp1) SIGNOR-275650 0.8 NRG1 protein Q02297 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 BTO:0000887 7477375 t gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4 direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3. SIGNOR-26061 0.868 ATF2 protein P15336 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 22685333 f Luana ATF2 contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death. SIGNOR-261324 0.7 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 21310273 t miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans SIGNOR-267814 0.8 RPS6K proteinfamily SIGNOR-PF26 SIGNOR WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Thr929 STIIRSKtFSPGPQS 9606 BTO:0000149 24269383 t llicata Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2. SIGNOR-252810 0.2 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-252921 0.2 TOMM70 protein O94826 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 t lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. SIGNOR-267677 0.2 EPS15 protein P42566 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates quantity by stabilization binding 24789820 t lperfetto Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth SIGNOR-260713 0.679 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120236 0.321 D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI up-regulates quantity precursor of 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267062 0.8 MEN1 protein O00255 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 11526476 t lperfetto Menin represses p65-mediated transcriptional activation on nf-kappab sites in a dose-dependent and specific manner. SIGNOR-217406 0.432 lysophosphatidylserine 14:0(1-) chemical CHEBI:72402 ChEBI GPR174 protein Q9BXC1 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257503 0.8 CAMK2A protein Q9UQM7 UNIPROT PEA15 protein Q15121 UNIPROT up-regulates phosphorylation Ser116 KDIIRQPsEEEIIKL 9606 15916534 t gcesareni Pea-15 is a phosphoprotein containing a ser-104 phosphorylated by protein kinase c and a ser-116 phosphorylated by camkii (calcium/calmodulin-dependent protein kinase ii) or akt. Phosphorylation of ser-104 is implicated in the regulation of glucose metabolism, while phosphorylation at ser-116 is required for pea-15 recruitment to the disc (death-initiation signalling complex) SIGNOR-137614 0.2 SB 203580 chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 BTO:0000567 10702313 t gcesareni Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme. SIGNOR-75389 0.8 RET protein P07949 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 21454698 t gcesareni The identification of focal adhesion kinase (fak) as a direct substrate for ret kinase revealed (i) a ret-fak transactivation mechanism consisting of direct phosphorylation of fak tyr-576/577 by ret and a reciprocal phosphorylation of ret by fak, which crucially is able to rescue the kinase-impaired ret k758m mutant and (ii) that fak binds ret via its ferm domain. Interestingly, this interaction is abolished upon ret phosphorylation, indicating that ret binding to the ferm domain of fak is a priming step for ret-fak transactivation. SIGNOR-173017 0.623 HMGB1 protein P09429 UNIPROT HOXB3 protein P14651 UNIPROT up-regulates activity binding -1 8890171 t miannu We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein. SIGNOR-219902 0.302 GOT1 protein P17174 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-267505 0.8 PPP2CA protein P67775 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 18586681 t Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. SIGNOR-248641 0.364 SKIL protein P12757 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates binding 9606 SIGNOR-C85 12419246 t gcesareni Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad8. SIGNOR-95474 0.459 metformin chemical CHEBI:6801 ChEBI NDUFS1 protein P28331 UNIPROT down-regulates activity chemical inhibition 9606 24843020 t Federica In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration SIGNOR-261080 0.8 ATP5F1D protein P30049 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261402 0.2 CDC14A protein Q9UNH5 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser315 LPNNTSSsPQPKKKP 9606 10644693 t The human Cdc14 phosphatases interact with and dephosphorylate the tumor suppressor protein p53|. Furthermore, the hCdc14 phosphatases were found to dephosphorylate p53 specifically at the p34Cdc2/clb phosphorylation site (p53-phosphor-Ser315)|Earlier studies showed that Ser315 phosphorylation increases the sequence-specific DNA binding capacity of p53, suggesting that Ser315 phosphorylation is an activating modification SIGNOR-248828 0.41 entinostat chemical CHEBI:132082 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257962 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000567 12853467 t gcesareni These findings suggest that PKB-dependent binding of 14-3-3s to phospho-Ser483 of cardiac PFK-2 mediates the stimulation of glycolysis by growth factor. SIGNOR-248031 0.2 PPP2CA protein P67775 UNIPROT MKNK1 protein Q9BUB5 UNIPROT down-regulates dephosphorylation Thr250 NSCTPITtPELTTPC 9606 20927323 t gcesareni Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e. SIGNOR-168310 0.493 PKA proteinfamily SIGNOR-PF17 SIGNOR PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Thr34 MIRRRRPtPAMLFRL 9606 BTO:0000938 10604473 t miannu DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚  SIGNOR-264956 0.2 AKT3 protein Q9Y243 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 t gcesareni Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155. SIGNOR-81122 0.522 AKT proteinfamily SIGNOR-PF24 SIGNOR PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 BTO:0000007 BTO:0001253 18296647 t gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. SIGNOR-160982 0.2 SMARCD1 protein Q96GM5 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269785 0.673 CDK1 protein P06493 UNIPROT ORC1 protein Q13415 UNIPROT up-regulates phosphorylation Ser273 VAFSEITsPSKRSQP 9606 11931757 t lperfetto Horc1p contains three (s/t)px(k/r) consensus sites for cdk phosphorylation (ser258, ser273, and thr375). These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability. SIGNOR-116325 0.621 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RCAN1 protein P53805 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000165 12063245 t inferred from 70% family members lperfetto Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. SIGNOR-270149 0.2 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR LATS1 protein O95835 UNIPROT down-regulates 9606 23450633 f gcesareni Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism. SIGNOR-201522 0.7 PLK1 protein P53350 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT up-regulates activity phosphorylation Ser311 SDALTDDsMSMTDSS 9606 BTO:0001061 26438599 t miannu Plk1 phosphorylates axin2 at Ser311.  SIGNOR-277180 0.499 ADRA1D protein P25100 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257191 0.41 CCT129202 chemical CID:16202152 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190877 0.8 PK proteinfamily SIGNOR-PF80 SIGNOR HIF-1 complex complex SIGNOR-C418 SIGNOR up-regulates activity binding 9606 BTO:0000567 21620138 t inferred from family member PKM2 interacts directly with the HIF-1Œ± subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, SIGNOR-270311 0.398 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR Caspase 3 complex complex SIGNOR-C221 SIGNOR down-regulates activity 9606 BTO:0002882 11684015 f lperfetto BCR/ABL Tyrosine Kinase Enhances Expression of RAD51 by Stimulation of STAT5-Mediated Transactivation and Inhibition of Caspase-3-Dependent Degradation| SIGNOR-271705 0.2 MRGPRX2 protein Q96LB1 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256787 0.2 GLI2 protein P10070 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 f lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. SIGNOR-209632 0.702 AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-257606 0.7 vorinostat chemical CHEBI:45716 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257916 0.8 INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr580 LRKTRDQyLMWLTQK 9534 BTO:0000298 8385099 t The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-252691 0.601 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 BTO:0002181 16046550 t The effect has been demonstrated using Q01196-8. gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-138957 0.599 SELE protein P16581 UNIPROT ITGAL protein P20701 UNIPROT up-regulates 9606 BTO:0000130 23994464 f apalma This deceleration is due to the expression of E-selectins on the inflamed endothelium which provides increased number of binding sites for PSGL-1 and also triggers an intermediate-affinity conformational state of the beta2-integrin LFA-1 on neutrophils. SIGNOR-255968 0.415 ROCK1 protein Q13464 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser13 ITSAARRsYVSSGEM -1 12686604 t lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro. SIGNOR-100181 0.317 CREBL2 protein O60519 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 21728997 f Luana Accordingly, the results of QPCR and immunoblot analysis showed that during adipogenesis, both the mRNA (Figures 4D and 4E) and protein (Figure 4F) levels of PPARγ , as well as C/EBPα, in 3T3-L1 preadipocytes transfected with either siCREBL2-1 or siCREBL2-2 were significantly decreased compared with the control (P < 0.05), suggesting that knockdown of CREBL2 protein suppress 3T3-L1 preadipocyte differentiation via inhibition of PPARγ and C/EBPα expression. SIGNOR-261573 0.2 MBD2 protein Q9UBB5 UNIPROT CHD4 protein Q14839 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000776 23071088 f lperfetto MBD2 and multiple domains of CHD4 are required for transcriptional repression by Mi-2/NuRD complexes SIGNOR-254102 0.616 RUNX3 protein Q13761 UNIPROT HSPD1 protein P10809 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002384 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255086 0.2 Starvation stimulus SIGNOR-ST4 SIGNOR AMPK complex SIGNOR-C15 SIGNOR up-regulates 9606 BTO:0001760 20810907 f lperfetto L6 myotubes were incubated in serum-containing or serum-free medium for 3 h. Levels of phosphorylated AMPK, Akt, and ATM were greater in serum-starved cells than in control cells. SIGNOR-209894 0.7 IKBKB protein O14920 UNIPROT PFKFB3 protein Q16875 UNIPROT down-regulates activity phosphorylation Ser269 QGRIGGDsGLSSRGK -1 27585591 t miannu IKKβ promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3.We demonstrate that IKKβ directly interacts with and phosphorylates 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase isoform 3 (PFKFB3), a major driver of aerobic glycolysis, at Ser269 upon glutamine deprivation to inhibit its activity, thereby down-regulating aerobic glycolysis when glutamine levels are low. SIGNOR-277278 0.294 CBX7 protein O95931 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000196 19706751 f miannu We confirmed by coimmunoprecipitation that CBX7 physically interacts with the HDAC2 protein and is able to inhibit its activity. Then, we showed that both these proteins bind the E-cadherin promoter and that CBX7 up-regulates E-cadherin expression. SIGNOR-253767 0.392 2-[[(1R)-1-[7-methyl-2-(4-morpholinyl)-4-oxo-9-pyrido[1,2-a]pyrimidinyl]ethyl]amino]benzoic acid chemical CHEBI:91359 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190200 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SCNN1G protein P51170 UNIPROT down-regulates quantity by destabilization phosphorylation -1 11805112 t inferred from 70% family members lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. SIGNOR-270061 0.2 ruxolitinib chemical CHEBI:66919 ChEBI JAK3 protein P52333 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258278 0.8 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr93 GHITTTPtPTQFLCP 9606 BTO:0000848 21177766 t lperfetto P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286) SIGNOR-170776 0.271 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser138 SLQLGAVsPGTLTPT 26933062 t lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. SIGNOR-276592 0.397 ETF complex SIGNOR-C463 SIGNOR FADH2 smallmolecule CHEBI:17877 ChEBI up-regulates quantity chemical modification 9606 33450351 t miannu ETF is a two-electron and two-proton transporter as its FAD undergoes successive reduction via two-consecutive one-electron transfer steps, with the formation of an intermediate one-electron red flavin semiquinone species (FAD•−), which is then fully reduced to FADH2 with the uptake of one additional electron and two protons (Fig. 4a). SIGNOR-269455 0.8 SMAD2 protein Q15796 UNIPROT SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR form complex binding 9606 26194464 t MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. SIGNOR-255023 0.554 RNF7 protein Q9UBF6 UNIPROT PMAIP1 protein Q13794 UNIPROT down-regulates activity ubiquitination 9606 23136067 t miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. SIGNOR-271446 0.399 EGFR protein P00533 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1248 PTAENPEyLGLDVPV 9606 BTO:0000356 12354693 t llicata Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c-erbB-2 receptor via EGFR. | In summary, c-erbB-2 up-regulation switches on the cell migration program by modulating the time course of PLC-gamma1 activation. SIGNOR-251094 0.597 RIMBP2 protein O15034 UNIPROT RIMS1 protein Q86UR5 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264361 0.515 belinostat chemical CHEBI:61076 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257747 0.8 TRIM13 protein O60858 UNIPROT AKT1 protein P31749 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21333377 t miannu Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT.  We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro. SIGNOR-271852 0.36 CERT1 protein Q9Y5P4 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI up-regulates quantity relocalization 9606 18184806 t miannu In mammalian cells, ceramide is synthesized in the endoplasmic reticulum and transferred to the Golgi apparatus for conversion to sphingomyelin. Ceramide transport occurs in a nonvesicular manner and is mediated by CERT, a cytosolic 68-kDa protein with a C-terminal steroidogenic acute regulatory protein-related lipid transfer (START) domain. The CERT START domain efficiently transfers natural D-erythro-C16-ceramide, but not lipids with longer (C20) amide-acyl chains. SIGNOR-268496 0.8 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser299 KMAFRAKsKSCHDLS -1 9677319 t llicata CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. SIGNOR-250946 0.318 serotonin smallmolecule CHEBI:28790 ChEBI HTR1F protein P30939 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264297 0.8 CPT1A protein P50416 UNIPROT (R)-carnitine smallmolecule CHEBI:16347 ChEBI down-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267120 0.8 CREB1 protein P16220 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 10090 BTO:0000142 17584923 f Luana These findings, together with studies in Aplysia and Drosophila, strongly suggest that CREB is an evolutionary conserved component of the molecular cascade of events leading to memory consolidation. SIGNOR-265773 0.7 GAS7 protein O60861 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23840221 f miannu Downregulation of gas7 using short-hairpin rna decreased the expression of runx2, a master regulator of osteogenesis, and its target genes (alkaline phosphatase, type i collagen, osteocalcin, and osteopontin). SIGNOR-202242 0.2 BDKRB2 protein P30411 UNIPROT Vascular_Permeability phenotype SIGNOR-PH140 SIGNOR up-regulates 9606 28966616 f lperfetto BK binds receptor B2 (B2R) and triggers inflammation, edema, and symptoms of anaphylaxis. SIGNOR-263540 0.7 SPC24 protein Q8NBT2 UNIPROT Ndc80 complex complex SIGNOR-C361 SIGNOR form complex binding 27881301 t lperfetto Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits SIGNOR-265185 0.938 MAPK3 protein P27361 UNIPROT ERBB4 protein Q15303 UNIPROT down-regulates activity phosphorylation Ser1051 NRSEIGHsPPPAYTP 9606 BTO:0000007 31053301 t miannu We also identified Ser-1026 as an ErbB4-specific ERK target site in the CYT-1 region. Moreover, double mutations (Thr-674/Ser-1026 to Ala) significantly upregulated ErbB4 activation, indicating that Thr-674 and Ser-1026 are cooperatively involved in negative feedback regulation.  SIGNOR-277449 0.514 CKM complex complex SIGNOR-C406 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates quantity by destabilization phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-273147 0.421 MYO7A protein Q13402 UNIPROT TIP-LINK complex complex SIGNOR-C291 SIGNOR form complex binding 10090 BTO:0000630 23217710 t lperfetto The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction. SIGNOR-262577 0.629 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr178 LKICDFGtACDIQTH -1 20538596 t lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-227536 0.2 SCF-FBW7 complex SIGNOR-C135 SIGNOR SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 30865892 t miannu Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation. SIGNOR-277444 0.2 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 7535770 t gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. SIGNOR-28063 0.338 AE/b7 integrin complex SIGNOR-C186 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257727 0.464 LIF protein P15018 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 16051226 t gcesareni Lif binds at low-affinity to lifr, the structure of which is closely related to that of gp130 (42). Lifr then becomes heterodimerized with gp130 to form the high-affinity and signaling-competent complex (43). Osm utilizes this type of heterodimer, i.e. the lifr/gp130 complex (43, 44). SIGNOR-139102 0.75 naloxone chemical CHEBI:7459 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258941 0.8 SPRY4 protein Q9C004 UNIPROT TIMP1 protein P01033 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002058 20501643 f miannu When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. SIGNOR-253038 0.2 FZD2 protein Q14332 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity binding 9606 23151663 t areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  SIGNOR-258959 0.636 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Ser372 PSPEPSMsPKMHRRR -1 12361598 t miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) SIGNOR-265962 0.53 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Ser474 RTHFPQFsYSASIRE 10090 BTO:0000944 15367694 t Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes SIGNOR-248631 0.737 PLPPR1 protein Q8TBJ4 UNIPROT RASGEF1A protein Q8N9B8 UNIPROT up-regulates activity binding 9606 BTO:0002036 27058420 t miannu Oncogenic effects of imbalanced PRG3 are mediated via PRG3-RasGEF1 interaction and Ras activation. PRG3 interacts with RasGEF1 in vivo.We could further show that PRG3 executes the binding to RasGEF1 predominantly via its C-terminal domain (CT) and in the consequence causes Ras activation. SIGNOR-261807 0.2 CDK5 protein Q00535 UNIPROT PEBP1 protein P30086 UNIPROT down-regulates quantity by destabilization phosphorylation Thr42 DELGKVLtPTQVKNR 9606 BTO:0000007 25104559 t miannu  Here, we demonstrate that RKIP is a substrate of cyclin-dependent kinase 5 (CDK5) in neurons and that the phosphorylation of RKIP at T42 causes the release of Raf-1. Moreover, T42 phosphorylation promotes the exposure and recognition of the target motif "KLYEQ" in the C-terminus of RKIP by chaperone Hsc70 and the subsequent degradation of RKIP via chaperone-mediated autophagy (CMA).  SIGNOR-276672 0.343 RNF128 protein Q8TEB7 UNIPROT CD83 protein Q01151 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys192 LPVTSPNkHLGLVTP 9606 BTO:0000007 19542455 t miannu In this study, we show that GRAIL can down-modulate the expression of CD83 (previously described as a cell surface marker for mature dendritic cells) on CD4 T cells. GRAIL-mediated down-modulation of CD83 is dependent on an intact GRAIL extracellular protease-associated domain and an enzymatically active cytosolic RING domain, and proceeds via the ubiquitin-dependent 26S proteosome pathway. Ubiquitin modification of lysine residues K168 and K183, but not K192, in the cytoplasmic domain of CD83 was shown to be necessary for GRAIL-mediated degradation of CD83. SIGNOR-271849 0.359 PRKX protein P51817 UNIPROT PKD1 protein P98161 UNIPROT up-regulates phosphorylation Ser4166 EPLPSRSsRGSKVSP 9606 17980165 t lperfetto The possibility of functional interactions between pkd1-encoded polycystin-1 and prkx was suggested by the renal co-distribution of prkx and polycystin-1 and the binding and phosphorylation of the c-terminal of polycystin-1 by prkx at s4166 in vitro. Taken together these results suggest that prkx can reverse the abnormalities in epithelial adhesion, migration and morphogenesis associated with pkd1 inhibition and cyst formation in adpkd. SIGNOR-158852 0.26 ARHGAP1 protein Q07960 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260459 0.903 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr740 RNLYSGDyYRIQGRA 9606 16186108 t gcesareni Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues. SIGNOR-140763 0.388 ASIP protein P42127 UNIPROT MC3R protein P41968 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268703 0.525 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Ser645 LNEKARLsYSDKNLI 9606 15731106 t gcesareni Taken together, our results demonstrate that serine 643 of pkc-delta is a major autophosphorylation site, and phosphorylation of this site plays an important role in controlling its enzymatic activity and biological function. The enzymatic activity of pkc-deltas643a mutant as measured by phosphorylating the pkc-delta pseudosubstrate region-derived substrate was also reduced more than 70% in comparison to that of pkc-deltawt. SIGNOR-134207 0.2 GUCY1B1 protein Q02153 UNIPROT GUCY1A3-B3 complex SIGNOR-C140 SIGNOR form complex binding 9606 10977868 t gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity SIGNOR-243986 0.2 COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR 26S Proteasome complex SIGNOR-C307 SIGNOR up-regulates activity binding 9606 26497135 t miannu The COP9 signalosome (CSN) and the proteasomal LID are conserved macromolecular complexes composed of at least eight subunits with molecular weights of approximately 350 kDa. CSN and LID are part of the ubiquitin–proteasome pathway and cleave isopeptide linkages of lysine side chains on target proteins. CSN cleaves the isopeptide bond of ubiquitin-like protein Nedd8 from cullins, whereas the LID cleaves ubiquitin from target proteins sentenced for degradation. The evolutionary conserved ubiquitin proteasome pathway (UPP) mediates degradation of intracellular proteins in all eukaryotes. This essential process requires three protein complexes: E3 ubiquitin ligases as e.g., cullin-RING ligases (CRLs), CSN and the 26S proteasome. SIGNOR-270795 0.328 Frizzled proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 22944199 t amattioni When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp. SIGNOR-253124 0.2 RALBP1 protein Q15311 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260513 0.565 MST1 protein P26927 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation Thr183 DTMAKRNtVIGTPFW 9606 11805089 t llicata We directly show that okadaic acid induces phosphorylation in the activation loop of mst, and, once phosphorylated, mst is rapidly translocated to the nucleus. when thr183 in mst1 was mutated to ala, no band could be detected by oa treatment,2 indicating that thr183 was the site of phosphorylation. SIGNOR-114289 0.539 EGR1 protein P18146 UNIPROT COL7A1 protein Q02388 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21931594 f Regulation miannu Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1) SIGNOR-251920 0.2 BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR PER1 protein O15534 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. SIGNOR-267970 0.706 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 BTO:0000671 15694384 t llicata Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925. SIGNOR-133849 0.2 TAF12 protein Q16514 UNIPROT ATF7 protein P17544 UNIPROT up-regulates activity binding 9534 BTO:0004055 15735663 t miannu We show that overexpression of hsTAF12 potentiates ATF7-induced transcriptional activation through direct interaction with ATF7, suggesting that TAF12 is a functional partner of ATF7. SIGNOR-225249 0.53 CHEK1 protein O14757 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates phosphorylation Ser331 HPWVRANsRRVLPPS 9606 17276342 t lperfetto Chk1 phosphorylates aurora-b and enhances its catalytic activity in vitro. SIGNOR-152926 0.367 AXIN2 protein Q9Y2T1 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity binding 9606 BTO:0000142;BTO:0000671;BTO:0000763 SIGNOR-C110 10911903 t gcesareni It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains. SIGNOR-79950 0.825 IFNA1 protein P01562 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates binding 9606 11278538 t gcesareni Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. SIGNOR-104641 0.61 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CFI protein P05156 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10630630 f miannu The production of CFI by Hep G2 cells was enhanced in a dose- and time-dependent fashion by 12-O-tetradecanoyl-1,2-phorbol 13-acetate (TPA), a potent PKC activator. The enhancement of the activity of transfected chimeric CAT constructs by TPA was abrogated by calphostin C and by pyrrolidine dithiocarbamate (an inhibitor of NF-kappaB and AP-1 transactivation). These results indicate that TPA regulation of CFI gene requires PKC signalling and is mediated by via a TPA response element (TRE) in the CFI promoter region located at -136/-130 and involves the transactivation of AP-1 and NF-kappaB transcription factors SIGNOR-254786 0.2 SH3GLB1 protein Q9Y371 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 11894095 t gcesareni Cbl rapidly recruits cin85 (cbl-interacting protein of 85k;ref. 6) and endophilins (regulatory components of clathrin-coated vesicles) to form a complex with activated egf receptors, thus controlling receptor internalization. SIGNOR-115826 0.377 ARHGEF6 protein Q15052 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 BTO:0000599 23776207 f lperfetto Expression of the phospho-mimicking ACAP4 mutant promotes ARF6-dependent cell migration. SIGNOR-272237 0.7 D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI up-regulates quantity precursor of 9606 24929114 t miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. SIGNOR-268143 0.8 MAPK3 protein P27361 UNIPROT ERBB4 protein Q15303 UNIPROT down-regulates activity phosphorylation Thr699 TELVEPLtPSGTAPN 9606 BTO:0000007 31053301 t miannu We also identified Ser-1026 as an ErbB4-specific ERK target site in the CYT-1 region. Moreover, double mutations (Thr-674/Ser-1026 to Ala) significantly upregulated ErbB4 activation, indicating that Thr-674 and Ser-1026 are cooperatively involved in negative feedback regulation.  SIGNOR-277448 0.514 AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 11108261 t lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. SIGNOR-244255 0.2 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser393 NLQIRETsLDTKSVS -1 7822264 t llicata On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II. SIGNOR-250629 0.437 PRKAA1 protein Q13131 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSSN 10116 11069105 t AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells. AMPK-mediated PFK-2 activation is likely to be involved in the stimulation of heart glycolysis during ischaemia. SIGNOR-260012 0.453 IRF5 protein Q13568 UNIPROT IL10 protein P22301 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000801 22025054 f lperfetto IRF5 is directly recruited to gene promoters associated with the M1 phenotype (including Il12b), but it represses Il10, probably also by binding to an ISRE in the gene promoter SIGNOR-249509 0.434 L-thyroxine smallmolecule CHEBI:18332 ChEBI iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity precursor of 9606 12746313 t scontino Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. SIGNOR-266946 0.8 LYST protein Q99698 UNIPROT RAB5C protein P51148 UNIPROT down-regulates activity binding 7227 33725482 t lperfetto Mauve interacts with Rab5, Msps, and gamma-tubulin|Mauve/LYST opposes Rab5, which promotes vesicle fusion affecting PCM recruitment SIGNOR-266003 0.2 GRIK2 protein Q13002 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264343 0.7 CHFR protein Q96EP1 UNIPROT CHFR protein Q96EP1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 17442268 t miannu In this study, we identified USP7 (also known as HAUSP), which is a member of a family of proteins that cleave polyubiquitin chains and/or ubiquitin precursors, as an interacting protein with Chfr by immunoaffinity purification and mass spectrometry, and their interaction greatly increases the stability of Chfr. In fact, USP7 can remove ubiquitin moiety from the autoubiquitinated Chfr both in vivo and in vitro, which results in the accumulation of Chfr in the cell.  USP7 mediates deubiquitination of Chfr. SIGNOR-271461 0.2 AMPK complex SIGNOR-C15 SIGNOR MLXIPL protein Q9NP71 UNIPROT down-regulates phosphorylation 10116 21892142 t lperfetto AMPK has also been suggested to phosphorylate the glucose-sensitive transcription factor ChREBP89 which dictates expression of an overlapping lipogenic gene signature with Srebp1 SIGNOR-216561 0.406 ESPL1 protein Q14674 UNIPROT RAD21 protein O60216 UNIPROT down-regulates quantity by destabilization cleavage 9606 15737063 t lperfetto In order to segregate sister chromatids to opposite poles in anaphase, cohesin has to be removed from chromosomes. In budding yeast, the prevalent mode of cohesin removal is by proteolytic cleavage of the Scc1 subunit at the onset of anaphase by the endopeptidase separase SIGNOR-275537 0.771 WNT2B protein Q93097 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131777 0.614 FYN protein P06241 UNIPROT KIRREL1 protein Q96J84 UNIPROT up-regulates activity phosphorylation Tyr605 MKDPTNGyYNVRAHE 9606 BTO:0000007 18258597 t miannu Here we have characterized Neph1, another SD component, as a novel substrate of SFK. Fyn interacts with and phosphorylates the cytoplasmic domain of Neph1 in vitro and in intact cells. Both tyrosine 637 and 638 of Neph1 are crucial for Neph1-Grb2 binding. SIGNOR-262745 0.2 IMP smallmolecule CHEBI:17202 ChEBI 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI up-regulates quantity precursor of 9606 19480389 t miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). SIGNOR-267333 0.8 SRC protein P12931 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Tyr216 KLDSGGFyITSRTQF 9606 BTO:0000150 12753909 t lperfetto This study establishes that her2/hrg signaling selectively upregulates tyr phosphorylation of c-src at tyr-215 located within the sh2 domain, increases c-src kinase activity SIGNOR-236246 0.2 CDK2 protein P24941 UNIPROT RAD9A protein Q99638 UNIPROT unknown phosphorylation Ser328 VLPSISLsPGPQPPK 9606 SIGNOR-C83 23028682 t llicata The forced activation of cyclin a-cdk2 in these cells by the overexpression of cyclin a,triggered rad9 phosphorylation at serine 328 and thereby promoted the interaction of rad9 with bcl-xl and the subsequent initiation of the apoptotic program. SIGNOR-199020 0.409 PTGES protein O14684 UNIPROT prostaglandin E2 smallmolecule CHEBI:15551 ChEBI up-regulates quantity chemical modification 9606 21983014 t The mPGES-1, one of three PGE2 synthases, is barely basally expressed, but is inducible by different stimuli and frequently co-expressed with COX-2. COX-2, mPGES-1 and PGE2 are enhanced during pain, inflammatory processes and in several cancer cells SIGNOR-254263 0.8 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 9606 17548358 t gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. SIGNOR-155377 0.338 HOXA9 protein P31269 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001412 17327400 t Luana Thus Pim1 appears to be a direct transcriptional target of HOXA9 and a mediator of its antiapoptotic and proproliferative effects in early cells.  SIGNOR-261632 0.2 GRPR protein P30550 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000189 17251915 t gcesareni Gastrin-releasing peptide receptors (grpr) are coupled primarily to galfaq, and are highly expressed in many cancers, including small-cell lung cancer SIGNOR-152679 0.503 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase. SIGNOR-76100 0.309 DPP10 protein Q8N608 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity relocalization 9534 BTO:0000298 15454437 t Luisa Coexpression of DPP10 changes the subcellular localization of Kv4.2 expressed in COS-7 cells by promoting surface trafficking.DPP10 accelerates Kv4.2 inactivation at high and low voltages SIGNOR-269006 0.549 IKBKE protein Q14164 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 SIGNOR-C13 15489227 t gcesareni Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro. SIGNOR-129939 0.449 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR VWF protein P04275 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000394 20658528 t lperfetto We also show that major circadian transcriptional regulators CLOCK and Bmal1 directly regulate the activity of vWF promoter and that lack of Bmal1 results in upregulation of vWF both at mRNA and protein level. Here we report a direct regulation of vWF expression in endothelial cells by biological clock gene Bmal1. This study establishes a mechanistic connection between Bmal1 and cardiovascular phenotype. SIGNOR-253703 0.329 PALB2 protein Q86YC2 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates binding 9606 19423707 t miannu We propose that both palb2 chromatin association and its oligomerization serve to secure the brca2 x rad51 repair machinery at the sites of dna damage. SIGNOR-185656 0.744 CDKN2B protein P42772 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 BTO:0000763 9042862 t gcesareni We present evidence that the different subcellular location of p15 and p27 ensures the prior access of p15 to cdk4. In the cell, p15 is localized mostly in the cytoplasm, whereas p27 is nuclear. p15 prevails over p27 or a p27 construct consisting of the cdk inhibitory domain tagged with a nuclear localization signal. However, when p15 and p27 are forced to reside in the same subcellular location, either the cytoplasm or the nucleus, p15 no longer prevents p27 from binding to cdk4. These properties allow p15 and p27 to coordinately inhibit cdk4 and cdk2. SIGNOR-46758 0.875 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRB2 protein P07550 UNIPROT up-regulates chemical activation 9606 22863277 t gcesareni In contrast, stimulation of gs-coupled receptors by glucagon or epinephrine activates lats1/2 kinase activity, thereby inhibiting yap function. SIGNOR-198501 0.8 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT2 protein P31751 UNIPROT down-regulates activity chemical inhibition 25309440 t lperfetto Different agents were used to inhibit either the PI3K/Akt or MEK/ERK pathways. The PI3K inhibitor, LY294002, and the Akt inhibitor, Akt inhibitor VIII, were used to inhibit the PI3K/Akt pathway. SIGNOR-262011 0.8 Thrombin smallmolecule CHEBI:9574 ChEBI F2RL3 protein Q96RI0 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257487 0.8 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr966 QICKGMEyLGTKRYI 9606 BTO:0000007 20304997 t lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236290 0.2 romidepsin chemical CHEBI:61080 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257990 0.8 MAPK3 protein P27361 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 15456867 t gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation SIGNOR-129589 0.705 SMAD6 protein O43541 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity binding 9606 9892110 t lperfetto SMAD6 functions as a negative regulator of the TGFB and BMP signaling pathways by interacting with other SMADs and/or TBRI. SIGNOR-64079 0.73 SHH protein Q15465 UNIPROT GLI2 protein P10070 UNIPROT up-regulates activity 9606 BTO:0001593 16880529 f lperfetto Finally, Sonic hedgehog (Shh) stimulates BMP-2 promoter activity and osteoblast differentiation, and the effects of Shh are mediated by Gli2. SIGNOR-148349 0.719 tRNA(Ile) smallmolecule CHEBI:29174 ChEBI Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270425 0.8 PAK6 protein Q9NQU5 UNIPROT SYNJ1 protein O43426 UNIPROT up-regulates activity phosphorylation -1 22371566 t miannu We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. SIGNOR-263022 0.2 SCAP protein Q12770 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity binding 10029 12242332 t miannu Insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis. SIGNOR-256210 0.715 MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 BTO:0001939 15520018 t miannu Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways. SIGNOR-250112 0.552 GSK3B protein P49841 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser129 ICPSLPYsPVSSPQS 9606 22778263 t lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. SIGNOR-198134 0.276 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser567 DSSRFPMsPRPDSVH 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249398 0.585 AKAP11 protein Q9UKA4 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR down-regulates activity binding 26088133 t lperfetto A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). SIGNOR-264818 0.435 PRKACA protein P17612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 9606 20151718 t miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-163760 0.278 CAV1 protein Q03135 UNIPROT SLC1A3 protein P43003 UNIPROT down-regulates activity binding 9606 BTO:0000938 26690923 t miannu EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers. SIGNOR-264808 0.2 NFATC2 protein Q13469 UNIPROT MYOF protein Q9NZM1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 23612709 f miannu Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin SIGNOR-255465 0.2 DDX1 protein Q92499 UNIPROT DDX21 protein Q9NR30 UNIPROT up-regulates activity binding 10090 21703541 t miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. SIGNOR-260191 0.326 DBP protein Q10586 UNIPROT ALDOB protein P05062 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 8383844 f miannu Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators SIGNOR-253833 0.2 SH3GL1 protein Q99961 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 25517094 f miannu Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. SIGNOR-263885 0.7 PIM1 protein P11309 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 t tpavlidou Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene. SIGNOR-252966 0.397 epinastine chemical CHEBI:51032 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 t Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells SIGNOR-257779 0.8 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr226 GSSGSLStSSSSSPP 9606 phosphorylation:Ser237 SSPPGTPsPADAKAP 22369944 t fspada However, the acquisition of dna binding and transactivation capacity of c/ebpbeta is delayed until further phosphorylation (on ser(184) or thr(179)) by gsk3beta occurs. SIGNOR-210129 0.469 ZNF217 protein O75362 UNIPROT CoREST-HDAC complex complex SIGNOR-C105 SIGNOR form complex binding 9606 BTO:0000567 11171972 t miannu Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function. SIGNOR-222118 0.551 TALDO1 protein P37837 UNIPROT sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI down-regulates quantity chemical modification 9606 19401148 t miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. SIGNOR-267089 0.8 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270380 0.8 CTNND2 protein Q9UQB3 UNIPROT ERBIN protein Q96RT1 UNIPROT up-regulates activity binding 9606 BTO:0000938 11821434 t miannu We characterized the interactions between the Erbin PDZ domain and both ARVCF and δ-catenin in vitro and in vivo. endogenous δ-catenin and Erbin co-localized in and co-immunoprecipitated from neurons. These results suggest that δ-catenin and ARVCF may function to mediate the association of Erbin with the junctional cadherin-catenin complex. SIGNOR-252120 0.2 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 12950161 t lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases SIGNOR-86680 0.346 romidepsin chemical CHEBI:61080 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257996 0.8 MT-ND4 protein P03905 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 SIGNOR-262146 0.78 vitamin D smallmolecule CHEBI:27300 ChEBI calcidiol smallmolecule CHEBI:17933 ChEBI up-regulates quantity precursor of 9606 BTO:0000759 30080183 t lperfetto Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. SIGNOR-270567 0.8 GDNF protein P39905 UNIPROT DCX protein O43602 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization. SIGNOR-252172 0.352 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM TEC protein P42680 UNIPROT down-regulates activity chemical inhibition -1 24556163 t miannu This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine SIGNOR-262235 0.8 EIF3_complex complex SIGNOR-C401 SIGNOR 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates activity 9606 15703437 f lperfetto EIF3 and, to some extent, eIF1A have been implicated in preventing reassociation of free 40S and 60S subunits and in dissociation of empty 80S ribosomes SIGNOR-269149 0.408 PPP2CA protein P67775 UNIPROT FCAR protein P24071 UNIPROT up-regulates activity dephosphorylation Ser284 LTFARTPsVCK -1 30766540 t lperfetto Furthermore, FcalphaRI activation is induced by protein phosphatase 2A (PP2A) after it dephosphorylates a single serine residue (S263) in the FcalphaRI intracellular tail SIGNOR-264858 0.328 PTAFR protein P25105 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257436 0.388 3-(2-Carboxyethyl)-4,6-dichloro-1H-indole-2-carboxylic acid chemical CID:446916 PUBCHEM GPR17 protein Q13304 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257502 0.8 GATA2 protein P23769 UNIPROT GATA2 protein P23769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27545880 f irozzo GATA-2 phosphorylation facilitates GATA-2 chromatin occupancy at GATA-2 target genes. GATA-2 stimulates GATA2 transcription through positive autoregulation SIGNOR-256090 0.2 MAPK3 protein P27361 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser295 PARPRSPsQTRKGPP 9606 BTO:0000142 15262992 t lperfetto Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2. SIGNOR-126871 0.277 S1PR3 protein Q99500 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257263 0.377 DOK1 protein Q99704 UNIPROT Av/b2 integrin complex SIGNOR-C176 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257684 0.301 ESR1 protein P03372 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 11517191 f ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression SIGNOR-253940 0.49 cholesterol smallmolecule CHEBI:16113 ChEBI SOAT1 protein P35610 UNIPROT up-regulates activity chemical activation 9606 BTO:0000759 31848472 t miannu Excess cholesterol is esterified by acyl coenzyme A:cholesterol acyltransferase (ACAT; also known as SOAT) to cholesteryl esters SIGNOR-265159 0.8 NAD(1-) smallmolecule CHEBI:57540 ChEBI SIRT1 protein Q96EB6 UNIPROT up-regulates activity binding 9606 10693811 t gcesareni Here we show that yeast and mouse Sir2 proteins are nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases SIGNOR-238539 0.8 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000887 11160134 t lperfetto Thus, at least three kinases mediate phosphorylation of ser307, including jnk, serine kinases in the pi 3-kinase cascade that are activated byinsulinor igf-1, and mek1-sensitive kinase cascades during tnf-alfa stimulation. SIGNOR-244784 0.2 PLXNB3 protein Q9ULL4 UNIPROT FSCN1 protein Q16658 UNIPROT up-regulates activity 10090 BTO:0000526 21706053 f miannu Sema5A regulates the phosphorylation states of fascin-1 through plexin-B3. SIGNOR-268374 0.342 LRP6 protein O75581 UNIPROT LPR5/6 complex SIGNOR-C219 SIGNOR form complex binding 9606 27821587 t miannu Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are co-receptors for Wnt ligands. SIGNOR-256175 0.381 AURKB protein Q96GD4 UNIPROT CHMP4C protein Q96CF2 UNIPROT up-regulates phosphorylation Ser214 ARRSRAAsSQRAEEE 9606 22724069 t lperfetto Moreover, we find that the cpc's catalytic subunit, aurora b kinase, phosphorylates one of the three human snf7 paralogues-chmp4c-in its c-terminal tail, a region known to regulate its ability to form polymers and associate with membranes. Phosphorylation at these sites appears essential for chmp4c function because their mutation leads to cytokinesis defects. The introduction of the s214a and s215a mutations together with s210a almost completely abolished aurora b phosphorylation SIGNOR-197971 0.482 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser137 QHSSPAVsDSLPSNS 9606 BTO:0000671 12628002 t lperfetto Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149) SIGNOR-99131 0.691 AGO2 protein Q9UKV8 UNIPROT RISC(DICER1/AGO2/TARBP2) complex SIGNOR-C32 SIGNOR form complex binding 9606 16142218 t lperfetto Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si_ or mi_riscs in mammalian cells, but it may also facilitate the cleavage of pre_mirnas by dicer. SIGNOR-140220 0.902 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr323 GCHLLVAtPGRLVDM 9606 16280325 t lperfetto Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis. SIGNOR-216872 0.345 IL10RA protein Q13651 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 26260587 t lperfetto IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-249545 0.419 FZD4 protein Q9ULV1 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates activity binding 9606 27096005 t areggio Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin. SIGNOR-258961 0.569 apigenin chemical CHEBI:18388 ChEBI CYP2C9 protein P11712 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189802 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250558 0.2 CEBPA protein P49715 UNIPROT Mast-Cell_diff phenotype SIGNOR-PH117 SIGNOR down-regulates activity 10090 BTO:0000725 23990620 f Notably, enforced overexpression of C/EBP-α in BMCPs results in exclusive differentiation into basophils, whereas conditional deletion of C/EBP-α in these same cells promotes mast cell differentiation,1 suggesting that C/EBP-α is an essential “switch factor” for basophil lineage choice SIGNOR-259967 0.7 MFGE8 protein Q08431 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity 10116 BTO:0000801 19020771 f Giorgia In our current study, we have shown that after LPS-stimulation, MFG-E8-mediated apoptotic cell phagocytosis suppresses various ERK1/2, p38, JNK, and NFκB activation, resulting in a lower TNF-α release. We also explored whether MFG-E8 helps to suppress the proinflammatory pathway within RPMs. We hence incubated the macrophages with apoptotic cells and stimulated them with LPS and examined the activation of MAP kinase and NFkB pathways after the exogenous addition of recombinant MFG-E8 (rMFG-E8). While apoptotic cells alone had no effect on these pathways, the addition of rMFG-E8 to apoptotic cells prior to phagocytosis and LPS stimulation had a marked suppressive effect on all of the investigated pathways, particularly on the p38 and NFκB pathways that play a key role in the cytokine response of macrophages SIGNOR-260652 0.2 PRKCA protein P17252 UNIPROT KCNQ2 protein O43526 UNIPROT up-regulates quantity phosphorylation Ser558 SKRKFKEsLRPYDVM 10029 BTO:0000246 12754513 t lperfetto Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(DeltaA) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. | These results suggest that Ser534 and 541 are key sites for PKC phosphorylation, although we have not ruled out the possibility that other PKC sites are involved in this process. SIGNOR-249210 0.33 MUL1 protein Q969V5 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates quantity by destabilization ubiquitination Lys284 LENLMLDkDGHIKIT 9606 22410793 t gcesareni The results of the functional studies suggest that the degradation of Akt by MULAN suppresses cell proliferation and viability. SIGNOR-252460 0.488 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity phosphorylation Thr533 TGSDNTDtEGS 9606 17936701 t miannu PVHL Acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-κB Agonist Card9 by CK2 SIGNOR-257601 0.352 GABARAP protein O95166 UNIPROT GPHN protein Q9NQX3 UNIPROT up-regulates activity binding 9606 BTO:0000938 25882190 t miannu The GABA(A)R-associated protein GABARAP was found to bind to the gamma2 subunit of GABA(A)Rs. Here we show that GABARAP interacts with gephyrin in both biochemical assays and transfected cells. Our data indicate that GABARAP-gephyrin interactions are not important for postsynaptic GABA(A)R anchoring but may be implicated in receptor sorting and/or targeting mechanisms. SIGNOR-264971 0.578 POU5F1 protein Q01860 UNIPROT ZFP42 protein Q96MM3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254944 0.477 MRPL20 protein Q9BYC9 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262373 0.725 FZD4 protein Q9ULV1 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 25902418 t areggio Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain. SIGNOR-258967 0.693 PP2 chemical CHEBI:78331 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 BTO:0001760 12351660 t gcesareni Treatment of l6 cells with pp2 or su6656, specific inhibitors of src family kinases, and transient transfection of dominant-inhibitory src inhibited the formation of myotubes and expression of myogenin. SIGNOR-93549 0.8 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates phosphorylation Tyr619 NKVDDCNyAIKRIRL 9606 17998206 t lperfetto We show that perk is capable of autophosphorylating on tyrosine residues in vitro and in vivo. We further show that tyrosine 615, which is embedded in a highly conserved region of the kinase domain of perk, is essential for autocatalytic activity. SIGNOR-159156 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT2 protein Q96AC1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser180 PGSGSIYsSPGLYSK 9606 BTO:0000567 35469017 t miannu  CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry. SIGNOR-276715 0.2 TET2 protein Q6N021 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 f irozzo Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation. SIGNOR-255704 0.7 MRPS27 protein Q92552 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261446 0.686 PPARA protein Q07869 UNIPROT SLC25A20 protein O43772 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19577614 f miannu CACT is upregulated by PPARalpha and PPARdelta, probably by binding to a functional PPRE at position +45 to +57 relative to the transcription start site. The upregulation of CACT by PPARalpha and PPARdelta, which are both important for the regulation of fatty acid oxidation in tissues during fasting, may increase the import of acylcarnitine into the mitochondrial matrix during fasting. SIGNOR-255049 0.502 AXIN1 protein O15169 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates 9606 16601693 f gcesareni Axin promotes smad3 phosphorylation;phosphorylated smad3 dissociates from the axin complex and then combines with smad4 to activate transcription in the nucleus. SIGNOR-145848 0.652 PRKCZ protein Q05513 UNIPROT PIAS4 protein Q8N2W9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser18 MVMSFRVsDLQMLLG 27162139 t lperfetto In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFbeta signaling pathway through the site-specific ubiquitination of PIAS4.FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCzeta and GSK3beta. Specifically, PKCzeta phosphorylation of PIAS4 and GSK3beta phosphorylation of FIEL1 are both essential for the degradation of PIAS4.|These experiments suggested that PKCzeta is an authentic regulator of PIAS4 protein stability; Q21 and phosphorylated S18 of PIAS4 are both required for FIEL1 interaction. SIGNOR-275513 0.502 KRN-633 chemical CID:9549295 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193582 0.8 UBE3A protein Q05086 UNIPROT RAD23B protein P54727 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 10373495 t miannu  Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP.  E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B. SIGNOR-272551 0.414 IARS1 protein P41252 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 t miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). SIGNOR-270354 0.2 18-hydroxycorticosterone smallmolecule CHEBI:16485 ChEBI aldosterone smallmolecule CHEBI:27584 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268686 0.8 ACTL6A protein O96019 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 t miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270620 0.806 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser281 DGTGDTSsEEDEDEE 9606 11278496 t lperfetto TAFII 250 Phosphorylates Human Transcription Factor IIA on Serine Residues Important for TBP Binding and Transcription ActivityAdditional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels SIGNOR-246634 0.664 TBX3 protein O15119 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25595898 f miannu AKT phosphorylation potentiates the ability of TBX3 to repress the transcription of the E-cadherin gene SIGNOR-223537 0.42 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.737 HCRTR2 protein O43614 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257216 0.426 ALDH1A2 protein O94788 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI down-regulates quantity chemical modification 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265125 0.8 PBK protein Q96KB5 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation Ser469 IRRSGSTsPLGFARA 9606 BTO:0002181 31378785 t miannu We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1.  SIGNOR-277474 0.2 GRK7 protein Q8WTQ7 UNIPROT GRK7 protein Q8WTQ7 UNIPROT unknown phosphorylation Ser490 YAKDIAEiDDFSEVR 9606 15946941 t Manara In the absence of PKA, GRK1 and GRK7 are autophosphorylated | The mutants, S490A-GRK7 and S490E-GRK7, do not undergo autophosphorylation, indicating that Ser490 is the only autophosphorylation site in GRK7 SIGNOR-260838 0.2 GRIN1 protein Q05586 UNIPROT NMDA receptor_2C complex SIGNOR-C349 SIGNOR form complex binding 9606 BTO:0000938 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits SIGNOR-264124 0.595 EFEMP2 protein O95967 UNIPROT ELN protein P15502 UNIPROT up-regulates activity binding 9606 19570982 t miannu Fibulin-4 directly binds LOX, and this interaction enhances fibulin-4 binding to tropoelastin, thus forming a ternary complex that may be critical for elastin cross-linking. SIGNOR-252136 0.574 PP2B proteinfamily SIGNOR-PF18 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 t inferred from 70% family members lperfetto Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes. SIGNOR-269988 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003858 12734180 f miannu The suppressive effect of IGF-1 and OP-1 on MMP-13 expression was due in part to down-regulation of the expression of pro-inflammatory cytokines and the activity of their intermediate molecules, including NF-kappaB and AP-1 factors. SIGNOR-254800 0.314 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser459 TSSSPPIsPASSDLS 9606 BTO:0000007 16141410 t In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity SIGNOR-251243 0.406 TBX21 protein Q9UL17 UNIPROT IL10 protein P22301 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000782 20154735 f azuccotti Similarly, an increase in IL-10 expression was observed in mice deficient for the TH1 cell-specific transcription factor T-bet (also known as TBX21) that were infected with M.tuberculosis, suggesting that T-bet might have a role in the negative regulation of IL-10 expression by TH1 cells SIGNOR-254524 0.458 TEAD1 protein P28347 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21527258 f gcesareni We found that the expression of myf5 and cyclind1 remained significantly elevated upon induction of differentiation in cells that were overexpressing hyap1 s127a compared to cells transfected with wildtype hyap and empty vector;yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor. SIGNOR-173445 0.325 AKT3 protein Q9Y243 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates activity phosphorylation Thr151 FCNGRGNtSGSHIVN 9606 BTO:0002181 35675814 t miannu AKT-Mediated UPF1 Phosphorylation at T151 Promotes UPF1 Helicase Activity SIGNOR-277596 0.2 Histone H2A proteinfamily SIGNOR-PF70 SIGNOR Nucleosome complex SIGNOR-C371 SIGNOR form complex binding -1 21812398 t lperfetto The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. SIGNOR-265309 0.2 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 18819921 t gcesareni Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion. SIGNOR-181323 0.622 USF2 protein Q15853 UNIPROT FMR1 protein Q06787 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001363; BTO:0000142 11058604 f miannu We have also shown that USF1, USF2, and alpha-Pal/Nrf-1 are the major transcription factors that bind the promoter in brain and testis extracts and suggest that elevated levels of these factors account in part for elevated FMR1 expression in these organs. SIGNOR-254883 0.273 SMARCA4 protein P51532 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270738 0.864 BARD1 protein Q99728 UNIPROT BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR form complex binding 25400280 t lperfetto Intriguingly, another BRCA1 complex, the BRCA1–A complex, which itself contains RAP80 along with MERIT40, BRCC36/45 and Abraxas, has been reported to inhibit DNA end resection, suggesting that, in some contexts, BRCA1 may function to limit and/or prevent over resection of DNA breaks. SIGNOR-263223 0.786 MMP3 protein P08254 UNIPROT SPP1 protein P10451 UNIPROT up-regulates activity cleavage 25545242 t lperfetto In this study, we found a novel motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved mouse OPN binds to α9β1 integrin. Importantly, this novel motif is involved in the development of anti-type II collagen antibody-induced arthritis (CAIA). This study provides the first in vitro and in vivo evidence that OPN cleavage by MMP-3/7 is an important regulatory mechanism for CAIA. SIGNOR-253320 0.656 CTNNB1 protein P35222 UNIPROT SOX2 protein P48431 UNIPROT down-regulates activity binding 9606 BTO:0000093 24291232 t flangone The interaction between Sox2 and _-catenin provides a novel mechanism underlying the functional dichotomy of BC cells, which carries potential therapeutic implications. SIGNOR-241994 0.697 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ARHGEF2 protein Q92974 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 18211802 t inferred from 70% family members gcesareni Activates rhoa and as a result regulates actin assembly. SIGNOR-270138 0.2 WNT9B protein O14905 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 20093360 t gcesareni We find that wnt9b binds to a different part of the lrp6 extracellular domain SIGNOR-163552 0.614 NR3C1 protein P04150 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity 10090 11742987 f gcesareni The MAP kinase p38 is also a target for negative regulation by glucocorticoids SIGNOR-251675 0.49 PAK1 protein Q13153 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser338 RPRGQRDsSYYWEIE 9606 18775988 t gcesareni P21-activated protein kinases (paks) are serine/threonine protein kinases that phosphorylate raf-1 at ser-338 and ser-339. SIGNOR-180808 0.585 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 18819921 t gcesareni We have identified ptp1b and tcptp as negative regulators of the hepatocyte growth factor receptor, the met receptor-tyrosine kinase. In vivo, loss of ptp1b or tcptp enhances hepatocyte growth factor-mediated phosphorylation of met. SIGNOR-181331 0.48 AKT1 protein P31749 UNIPROT CLK2 protein P49760 UNIPROT up-regulates phosphorylation Thr127 RRRRRSRtFSRSSSQ 9606 BTO:0000567 20682768 t lperfetto Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva SIGNOR-167340 0.398 MAPKAPK2 protein P49137 UNIPROT ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser272 CSLERQLsLEQEVQQ -1 11844797 t miannu Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). when stimulated with only exogenous arachidonic acid, activity for the S271A mutant was significantly lower as compared with wild type 5-LO. SIGNOR-250143 0.526 GSK3B protein P49841 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0000671 18701453 t lperfetto We found that gsk-3Beta phosphorylates and inactivates 4e-bp1, thereby increasing eif4e-dependent protein synthesis. upon stimulation, 4e-bp1 is phosphorylated on several threonine and serine residues, including thr-37/46 (36). This results in dissolution of the complex, freeing eif4e to bind with mrna cap to promote translation initiation. SIGNOR-236660 0.372 CDK2 protein P24941 UNIPROT ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr116 LASELAKtPQKSVSF 9606 SIGNOR-C83 11931757 t lperfetto We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability. SIGNOR-116364 0.745 TRIM28 protein Q13263 UNIPROT ALDOA protein P04075 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17900823 f miannu We previously reported that ZNF224, a novel Krüppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor. SIGNOR-255628 0.2 PTPN13 protein Q12923 UNIPROT TRIP6 protein Q15654 UNIPROT down-regulates activity dephosphorylation Tyr55 PLPSEQCyQAPGGPE 10090 BTO:0002572 17591779 t PTPL1/FAP-1 negatively regulates TRIP6 function in lysophosphatidic acid-induced cell migration.|Here we further demonstrate that a switch from c-Src-mediated phosphorylation to PTPL1/Fas-associated phosphatase-1-dependent dephosphorylation serves as an inhibitory feedback control mechanism of TRIP6 function in LPA-induced cell migration. PTPL1 dephosphorylates phosphotyrosine 55 of TRIP6 in vitro and inhibits LPA-induced tyrosine phosphorylation of TRIP6 in cells. SIGNOR-248713 0.444 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr464 QEGSIEVyEDAGSHY 9606 BTO:0000763 20861316 t lperfetto We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity SIGNOR-167993 0.304 GSK3A protein P49840 UNIPROT STMN3 protein Q9NZ72 UNIPROT up-regulates activity phosphorylation Ser60 SFEVILKsPSDLSPE -1 22577147 t lperfetto Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta SIGNOR-264883 0.254 CSNK1D protein P48730 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10734067 t gcesareni Here we show that the direct association between a p53 n-terminal peptide and mdm2 is disrupted by phosphorylation of the peptide on thr(18) but not by phosphorylation at other n-terminal sites, including ser(15) and ser(37). Thr(18) was phosphorylated in vitro by casein kinase (ck1). SIGNOR-75889 0.56 TLRs proteinfamily SIGNOR-PF20 SIGNOR TLRs proteinfamily SIGNOR-PF20 SIGNOR up-regulates activity binding 9606 24352680 t lperfetto Upon activation, tlrs hetero- or homodimerize inducing the recruitment of adaptor proteins via the cytoplasmic tir domain SIGNOR-216301 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser52 TRRTRTFsATVRASQ 9606 BTO:0000671 15910284 t lperfetto These and other results demonstrate that crhsp24 is phosphorylated at ser52 by pkbalpha in response to igf-1, at ser52 by pkbalpha and rsk in response to egf SIGNOR-252814 0.2 PTPN1 protein P18031 UNIPROT STAT5B protein P51692 UNIPROT down-regulates activity dephosphorylation Tyr699 TAKAVDGyVKPQIKQ 9534 BTO:0004055 10993888 t A Cytosolic Protein-tyrosine Phosphatase PTP1B Specifically Dephosphorylates and Deactivates Prolactin-activated STAT5a and STAT5b SIGNOR-248429 0.662 SERPINE1 protein P05121 UNIPROT Fibrinolysis phenotype SIGNOR-PH6 SIGNOR down-regulates 9606 19387897 f miannu Plasma PAI-1 levels robustly fluctuate in a circadian manner and consequently contribute to hypofibrinolysis during the early morning. The circadian expression of PAI-1 gene is thought to be directly regulated by the circadian clock proteins such as CLOCK and BMAL1/BMAL2 which drive the endogenous biological clock. Plasma PAI-1 levels are increased in the beginning of the active phase in both diurnal humans and in nocturnal rodents, suggesting that the rhythmic PAI-1 expression is commonly indispensable for organisms. SIGNOR-267984 0.7 NFE2L2 protein Q16236 UNIPROT GSTA1 protein P08263 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24024136 t irozzo In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs). SIGNOR-256278 0.349 NDUFC1 protein O43677 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. SIGNOR-262173 0.783 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 16782899 t llicata Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain SIGNOR-147195 0.476 SLBP protein Q14493 UNIPROT H3Y2 protein P0DPK5 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265416 0.2 CAMTA1 protein Q9Y6Y1 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0005397 21385898 f irozzo Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma. SIGNOR-259100 0.7 MMP2 protein P08253 UNIPROT PZP protein P20742 UNIPROT down-regulates quantity by destabilization cleavage Thr718 PYVPQLGtYNVIPLN -1 9344465 t lperfetto The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. SIGNOR-261796 0.335 clotrimazole chemical CHEBI:3764 ChEBI KCNN4 protein O15554 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9730970 t miannu IK was blocked by the classical inhibitors of the Gardos channel charybdotoxin (IC50 28 nM) and clotrimazole (IC50 153 nM) as well as by nitrendipine (IC50 27 nM), Stichodactyla toxin (IC50 291 nM), margatoxin (IC50 459 nM), miconazole (IC50 785 nM), econazole (IC50 2.4 microM), and cetiedil (IC50 79 microM). Finally, 1-ethyl-2-benzimidazolinone, an opener of the T84 cell IK channel, activated hIK with an EC50 of 74 microM. SIGNOR-258832 0.8 NEIL3 protein Q8TAT5 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). SIGNOR-275720 0.7 MTA1/DJ1 complex complex SIGNOR-C123 SIGNOR TH protein P07101 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000793 21368136 f 1 miannu we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3. SIGNOR-239773 0.466 PCSK6 protein P29122 UNIPROT VWF protein P04275 UNIPROT up-regulates activity cleavage 8218226 t Giorgia Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine SIGNOR-260367 0.297 PRL protein P01236 UNIPROT KRT5 protein P13647 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20103718 f Regulation miannu PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes. SIGNOR-251903 0.267 PYG proteinfamily SIGNOR-PF96 SIGNOR alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 3346228 t miannu Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267954 0.8 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr293 HRIDGKTyVIKRVKY 9606 BTO:0001282 16373505 t PKR autophosphorylates on Y101, Y162, and Y293. The introduction of the Y293F mutation causes significant defects in PKR autophosphorylation and eIF2α phosphorylation, providing evidence for a critical function of this phosphorylated residue. SIGNOR-251114 0.2 CDK6 protein Q00534 UNIPROT CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR form complex binding 8114739 t lperfetto Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells. SIGNOR-273028 0.934 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914168 t lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 SIGNOR-161694 0.591 SRC protein P12931 UNIPROT SRC protein P12931 UNIPROT down-regulates activity phosphorylation Tyr530 FTSTEPQyQPGENL 9606 8755732 t lperfetto Rapid digestion of pp60c-src tyrosine kinase (src TK) in combination with electrospray ionization mass spectrometry enabled the determination of the time course for autophosphorylation of three tyrosine sites (Y338, Y419, and Y530) and a correlation with src TK activity. Here, conditions were identified which promoted essentially complete autophosphorylation of y530. Phosphorylation of y530 was directly correlated to a decrease in tyrosine kinase activity SIGNOR-43315 0.2 MDH1 protein P40925 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266285 0.8 CSNK1D protein P48730 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10606744 t gcesareni Protein kinase ck1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15. SIGNOR-73270 0.56 NR3C1 protein P04150 UNIPROT CEBPD protein P49716 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000011 10649448 t gcesareni We conclude that glucocorticoid-induced adipogenesis from bone marrow stromal cells is mediated through a reaction cascade in which dexamethasone transcriptionally activates C/EBPδ; C/EBPδ then binds to PPARγ2 promoter and transactivates PPARγ2 gene expression. SIGNOR-253061 0.321 icariin chemical CHEBI:78420 ChEBI PDE5A protein O76074 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193363 0.8 ULK2 protein Q8IYT8 UNIPROT ENO1 protein P06733 UNIPROT down-regulates activity phosphorylation Ser115 ANAILGVsLAVCKAG 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274038 0.2 IKBKG protein Q9Y6K9 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR form complex binding 10090 SIGNOR-C14 SIGNOR-C14 19666475 t lperfetto Proinflammatory NF-kappaB activation requires the IkappaB (inhibitor of NF-kappaB) kinase (IKK) complex that contains two catalytic subunits named IKKalpha and IKKbeta and a regulatory subunit named NF-kappaB essential modulator (NEMO). SIGNOR-209762 0.929 MCF2L protein O15068 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260560 0.741 HTR1D protein P28221 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257208 0.252 NDUFC2 protein O95298 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. SIGNOR-262174 0.803 Fibrin complex SIGNOR-C317 SIGNOR PLAT protein P00750 UNIPROT up-regulates 9606 BTO:0000131 1447176 f lperfetto The presence of fibrin greatly accelerates the activation of plasminogen by tPA and hence can exert a regulatory influence over plasminogen activation SIGNOR-263536 0.2 lysophosphatidic acid smallmolecule CHEBI:132742 ChEBI LPAR2 protein Q9HBW0 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257529 0.8 ITCH protein Q96J02 UNIPROT GLI1 protein P08151 UNIPROT down-regulates ubiquitination 9606 20818436 t gcesareni The consequent activation of_ itch, together with the recruitment of gli1 through direct binding with_ numb, allows gli1 to enter into the complex, resulting in gli1 ubiquitination and degradation. we demonstrate that the hedgehog transcription factor gli1 is targeted by numb for itch-dependent ubiquitination, which suppresses hedgehog signals, thus arresting growth and promoting cell differentiation SIGNOR-167838 0.56 RNF220 protein Q5VTB9 UNIPROT SIN3B protein O75182 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 20170641 t miannu Here we identify RNF220 (RING finger protein 220) as a novel ubiquitin ligase for Sin3B. RNF220 specifically interacts with Sin3B both in vitro and in vivo. Sin3B can be regulated by the ubiquitin-proteasome system. Co-expression of RNF220 promotes the ubiquitination and proteasomal degradation of Sin3B. SIGNOR-271943 0.439 SALL4 protein Q9UJQ4 UNIPROT ABCA3 protein Q99758 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21526180 f miannu we demonstrated that SALL4 was able to bind to the promoter region of ABCA3 and activate its expression while regulating the expression of ABCG2 indirectly. SALL4 expression was positively correlated to those of ABCG2 and ABCA3 in primary leukemic patient samples SIGNOR-255121 0.285 WWTR1 protein Q9GZV5 UNIPROT TEAD1 protein P28347 UNIPROT up-regulates binding 9606 23431053 t YAP/TAZ mainly bind to the transcription factors TEAD1?????_?4 to regulate genes involved in cell proliferation and cell death. gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead1?_?_?4. SIGNOR-192768 0.863 PTPN22 protein Q9Y2R2 UNIPROT LCK protein P06239 UNIPROT down-regulates dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 BTO:0000007 16461343 t gcesareni Native ptpn22 dephosphorylated lck at its activating tyrosine residues tyr-394. SIGNOR-144341 0.741 DUSP16 protein Q9BY84 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity dephosphorylation 9606 25077541 t miannu MKP7 represses mTOR function.|These results suggest that MKP7 could directly dephosphorylate pmTOR and pPRAS40 and forming complexes with these two proteins ( xref ). SIGNOR-277067 0.278 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Thr189 NRYSFYStCSGQKAI -1 23444369 t miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. SIGNOR-273493 0.27 CBL protein P22681 UNIPROT SORBS2 protein O94875 UNIPROT down-regulates ubiquitination 9606 12475393 t gcesareni Cbl-argbp2 complex mediates ubiquitination and degradation of c-abl SIGNOR-96325 0.526 ELP1 protein O95163 UNIPROT Elongator complex complex SIGNOR-C466 SIGNOR form complex binding 9606 28601220 t miannu Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer. SIGNOR-269708 0.2 PPP2R1A protein P30153 UNIPROT PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR form complex binding 9606 23454242 t gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. SIGNOR-243427 0.922 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG -1 17711846 t done miannu Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626). SIGNOR-274098 0.397 DNMT3A protein Q9Y6K1 UNIPROT TIMP2 protein P16035 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19786833 f irozzo Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. SIGNOR-255807 0.2 STUB1 protein Q9UNE7 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. SIGNOR-272752 0.431 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Ser4 sQKHRDFV 9606 16495336 t gcesareni We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell SIGNOR-144795 0.516 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM5C protein P41229 UNIPROT up-regulates activity chemical activation 29981745 t lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. SIGNOR-273468 0.8 TFE3 protein P19532 UNIPROT GBA protein P04062 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276822 0.2 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273047 0.556 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser270 EFRPRSKsQSSSNCS 9606 BTO:0000975;BTO:0001760;BTO:0000142 9312143 t lperfetto Turnover of the active fraction of irs1 involves raptor-mtor- and s6k1-dependent serine phosphorylation in cell culture models of tuberous sclerosiss6k1 phosphorylates irs1 in vitro on multiple residues showing strong preference for rxrxxs/t over s/t,p sites. SIGNOR-51216 0.78 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Thr211 EYLDDRNtFRHSVVV 9606 22611192 t gcesareni We show that aurora b phosphorylates p53 at s183, t211, and s215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and puma). SIGNOR-197606 0.708 5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine chemical CID:11617559 PUBCHEM CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258119 0.8 PP1 proteinfamily SIGNOR-PF54 SIGNOR TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 16501611 t lperfetto Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. SIGNOR-264670 0.2 SPTAN1 protein Q13813 UNIPROT Non-erythrocytic spectrin complex SIGNOR-C385 SIGNOR form complex binding 9606 24302288 t lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell SIGNOR-266026 0.557 SIRT7 protein Q9NRC8 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity deacetylation Lys37 APSTGGVkKPHRYRP 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275878 0.2 SLC9A4 protein Q6AI14 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265594 0.8 MAP2K6 protein P52564 UNIPROT PAK6 protein Q9NQU5 UNIPROT up-regulates phosphorylation Tyr566 KSLVGTPyWMAPEVI 9606 15550393 t llicata Moreover, pak6 was directly activated by mkk6, and mutation of tyrosine 566 in a consensus mkk6 site (threonine-proline-tyrosine, tpy) in the activation loop of the pak6 kinase domain prevented activation by mkk6. SIGNOR-130975 0.2 DYRK1A protein Q13627 UNIPROT DYRK1A protein Q13627 UNIPROT up-regulates activity phosphorylation Ser529 SNSGRARsDPTHQHR 9606 BTO:0001938 17229891 t llicata In the present study, we show that DYRK1A autophosphorylates, via an intramolecular mechanism, on Ser-520, in the PEST domain of the protein. | Instead, we demonstrate that this phosphorylation allows the binding of 14-3-3beta, which in turn stimulates the catalytic activity of DYRK1A. SIGNOR-251090 0.2 RBPJ protein Q06330 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 9606 21873209 t lperfetto When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects. SIGNOR-209702 0.949 DHODH protein Q02127 UNIPROT orotate smallmolecule CHEBI:30839 ChEBI up-regulates quantity chemical modification 9606 30449682 t miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway SIGNOR-267433 0.8 FOXD2 protein O60548 UNIPROT PRKAR1A protein P10644 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 12621056 t Luana Elevating the amounts of FOXD2 expression vector up to 12-fold relative to the RIα1b reporter construct demonstrated that maximal induction of the RIα1b promoter by FOXD2 was at least 5.8-fold SIGNOR-261605 0.2 NARS1 protein O43776 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270458 0.8 CKM complex complex SIGNOR-C406 SIGNOR CCNH protein P51946 UNIPROT down-regulates activity phosphorylation Ser304 YEDDDYVsKKSKHEE 9606 10993082 t lperfetto Cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity SIGNOR-273141 0.446 CD38 protein P28907 UNIPROT NADP(+) smallmolecule CHEBI:18009 ChEBI down-regulates quantity chemical modification 9606 18626062 t miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. SIGNOR-264247 0.8 NFATC2 protein Q13469 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000776 11163226 f scontino In this study, the roles of NFATc1 and NFATc2 in T and B cells were examined. These results further characterize NFAT as a transcription factor family that plays a critical role in the regulation of lymphocyte effector differentiation. SIGNOR-270538 0.7 RBL2 protein Q08999 UNIPROT RAD50 protein Q92878 UNIPROT up-regulates activity binding 9606 BTO:0004784 16600870 t lperfetto We propose that p130, forming a complex with Rad50 through RINT-1, blocks telomerase-independent telomere lengthening in normal cells.  SIGNOR-265029 0.308 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu76 CSFEEAReVFENTER 10090 BTO:0001103 11133752 t lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. SIGNOR-263694 0.67 PRKCA protein P17252 UNIPROT TRPM4 protein Q8TD43 UNIPROT up-regulates phosphorylation Ser1152 SERLKRTsQKVDLAL 9606 15590641 t gcesareni Phorbol ester-induced activation of protein kinase c (pkc) increased the ca(2+) sensitivity of wild-type trpm4 but not of two mutants mutated at putative pkc phosphorylation sites. SIGNOR-132247 0.2 IFIH1 protein Q9BYX4 UNIPROT MAVS protein Q7Z434 UNIPROT up-regulates activity binding 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260140 0.807 PTPRJ protein Q12913 UNIPROT FLT3 protein P36888 UNIPROT down-regulates activity dephosphorylation 9606 21262971 t miannu Moreover, activated FLT3 could be dephosphorylated by recombinant DEP-1 in vitro.|The data indicate that DEP-1 is negatively regulating FLT3 signaling activity and that its loss may contribute to but is not sufficient for leukemogenic cell transformation. SIGNOR-277092 0.503 TGFBR1 protein P36897 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity 9606 19726546 t lperfetto Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity. SIGNOR-227499 0.625 CSNK2A1 protein P68400 UNIPROT CCNF protein P41002 UNIPROT down-regulates activity phosphorylation Ser621 GYEGDQEsEGEKEGD 9606 29021214 t miannu We determined that casein kinase II (CK2) can phosphorylate Ser621 and thereby regulate the E3 ligase activity of the SCF(cyclin F) complex. SIGNOR-266373 0.251 UNC13B protein O14795 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 31679900 f miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle. MUNC13 is proposed to tether synaptic vesicles by bridging between vesicle and plasma membrane via its C2C-domain and C1/C2B-domains SIGNOR-264386 0.7 CDK5 protein Q00535 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates phosphorylation Ser400 IHKVILGsPAHRAGL 9606 21701498 t lperfetto Here we report that cyclin-dependent kinase-5 (cdk5), a kinase implicated in the pathogenesis of several neurodegenerative diseases, is responsible for phosphorylating htra2 at s400.We have shown previously that phosphomimetic mutants of htra2 at s400 result in increased proteolytic activity and contribute to enhanced resistance to mitochondrial stress SIGNOR-174598 0.468 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75025 0.783 PIK3CG protein P48736 UNIPROT TPM2 protein P07951 UNIPROT up-regulates activity phosphorylation Ser61 EDEVEKYsESVKEAQ -1 16094730 t miannu Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization. SIGNOR-263028 0.341 CSNK2A1 protein P68400 UNIPROT RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser358 AKVLASLsDDEDEEE 9606 16428860 t lperfetto Phosphorylation of rangap1 stabilizes its interaction with ran and ranbp1. Serine-358 (358s) was identified as the major phosphorylation site. Experiments using purified recombinant kinase and specific inhibitors such as drb and apigenin strongly suggest that casein kinase ii (ck2) is the responsible kinase SIGNOR-143948 0.315 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GRB10 protein Q13322 UNIPROT up-regulates phosphorylation 9606 15952796 t inferred from 70% family members lperfetto Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation SIGNOR-270178 0.2 bradykinin smallmolecule CHEBI:3165 ChEBI BDKRB1 protein P46663 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257464 0.8 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12226093 t The effect has been demonstrated using P10636-8 lperfetto Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease. SIGNOR-92603 0.754 CASP8 protein Q14790 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni Downstream of caspase-8 activation, apoptosis induction takes place SIGNOR-90612 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Ser416 GFPSKTDsPSCEYSR 9606 BTO:0000007 27846390 t lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  SIGNOR-262980 0.2 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 BTO:0000150 17567956 t gcesareni In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943) SIGNOR-155987 0.347 MTSS1 protein O43312 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 16280553 t lperfetto Mim-b binds and activates rac via its irsp53/mim domain SIGNOR-141573 0.2 PIM2 protein Q9P1W9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 24142698 t Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis SIGNOR-268148 0.378 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR Core Binding Factor complex complex SIGNOR-C214 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-255970 0.2 PRKCB protein P05771 UNIPROT TYR protein P14679 UNIPROT up-regulates phosphorylation Ser527 DYHSLYQsHL 9606 BTO:0000848 10347209 t llicata We conclude that pkc-beta activates tyrosinase directly by phosphorylating serine residues at positions 505 and 509 in the cytoplasmic domain of this melanosome-associated protein. our results strongly suggest that direct phosphorylation of tyrosinase by pkc-_ leads to its activation. SIGNOR-67870 0.421 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Ser474 RTHFPQFsYSASIRE 9606 18160256 t Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248632 0.737 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT unknown phosphorylation Ser16 PPSEGEEsTVRFARK -1 2377895 t lperfetto Thus four peptides containing six major sites of intrapeptide autophosphorylation of protein kinase C have been identified. | Phosphoamino acid analyses indicated that only the NH2-terminal peptide contained phosphoserine. The modified residue was determined to be Ser16 SIGNOR-248863 0.2 DOK1 protein Q99704 UNIPROT AD/b2 integrin complex SIGNOR-C172 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257685 0.301 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Ser358 ELRKTQTsMSLGTTR -1 24012422 t gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays SIGNOR-266439 0.743 CRX protein O43186 UNIPROT RS1 protein O15537 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18927113 f miannu Our in vitro and in vivo results indicate that two CRE sites in the minimal RS1 promoter region control retinal RS1 expression and establish CRX as a key factor driving this expression. SIGNOR-253822 0.337 MSH release-inhibiting hormone smallmolecule CID:56842142 PUBCHEM MC3R protein P41968 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257537 0.8 TRiC complex SIGNOR-C539 SIGNOR Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates quantity by stabilization binding 9606 36185250 t miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). SIGNOR-272868 0.2 MAP3K1 protein Q13233 UNIPROT FADD protein Q13158 UNIPROT down-regulates activity phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 15001534 t gcesareni The results clearly show that fadd phosphorylation at ser194 affects functions both upstream and downstream of the mekk1/mkk7/jnk1 pathway and is closely associated with chemosensitivity in prostate cancer cells SIGNOR-123168 0.482 EFNA2 protein O43921 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates binding 9606 9330863 t gcesareni The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. SIGNOR-52206 0.798 STX16 protein O14662 UNIPROT LE-TGN SNARE complex SIGNOR-C157 SIGNOR form complex binding 9606 BTO:0000567 18195106 t lperfetto We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport SIGNOR-253079 0.798 PLK1 protein P53350 UNIPROT SUZ12 protein Q15022 UNIPROT down-regulates quantity by destabilization phosphorylation Ser541 KRTKASMsEFLESED 25855382 t lperfetto PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|In SUZ12, residues 539, 541 and 546 phosphorylated by Plk1 in vitro SIGNOR-275555 0.37 tolazoline chemical CHEBI:28502 ChEBI ADRA2B protein P18089 UNIPROT down-regulates activity chemical inhibition 9606 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258913 0.8 ARHGAP40 protein Q5TG30 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260497 0.384 PELP1 protein Q8IZL8 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18682536 t gcesareni MNAR functionally interacts with both NH2- and COOH-terminal GR domains to modulate transactivation SIGNOR-251681 0.534 GNAI3 protein P08754 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 8327893 t gcesareni Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required SIGNOR-38029 0.578 TPH2 protein Q8IWU9 UNIPROT 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI up-regulates quantity chemical modification 9606 31024440 t brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. SIGNOR-264012 0.8 ID3 protein Q02535 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR down-regulates activity binding 10090 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241155 0.458 PTPRZ1 protein P23471 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates activity dephosphorylation Tyr1105 RNEEENIySVPHDST 10090 BTO:0000601 16513268 t Protein tyrosine phosphatase receptor type Z is involved in hippocampus-dependent memory formation through dephosphorylation at Y1105 on p190 RhoGAP| Furthermore, Ptprz selectively dephosphorylated pY1105 of p190 RhoGAP in vitro, and the tyrosine phosphorylation at Y1105 controls p190 RhoGAP activity in vivo. SIGNOR-248451 0.427 HNF4A protein P41235 UNIPROT GFER protein P55789 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 18513187 f miannu We also confirmed that activation and repression of hHSS transcription induced by Sp1 and HNF4alpha resulted from binding of these factors to these two cis-elements respectively. Overexpression of HNF4alpha led to a dramatic repression of the promoter activity and, in contrast, the activity was markedly elevated by overexpression of Sp1. SIGNOR-254449 0.2 CTNND2 protein Q9UQB3 UNIPROT CDH5 protein P33151 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 t miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. SIGNOR-252132 0.321 CHUK protein O15111 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000876 SIGNOR-C14 SIGNOR-C13 15611276 t lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. SIGNOR-132568 0.842 PIAS1 protein O75925 UNIPROT STAT1 protein P42224 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 t milica Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna. SIGNOR-202039 0.787 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr589 SHDSEENyVPMNPNL 10090 BTO:0000944 10978177 t HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin SIGNOR-251315 0.492 HABP4 protein Q5JVS0 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates activity binding 10116 15862299 t llicata MEF2C DNA-binding activity is inhibited through its interaction with the regulatory protein Ki-1/57. SIGNOR-238283 0.344 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser693 ASITSMLsPSFTPTS 9606 22966201 t llicata Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress. SIGNOR-199000 0.328 FLT3 protein P36888 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15498859 f Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells. SIGNOR-261519 0.43 GRPR protein P30550 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257247 0.271 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 15780598 t lperfetto JAK2 and STAT3 are dephosphorylated by PTP1B in vitro SIGNOR-133852 0.789 HMGB1 protein P09429 UNIPROT HOXB1 protein P14653 UNIPROT up-regulates activity binding -1 8890171 t miannu We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein. SIGNOR-219853 0.302 ROCK1 protein Q13464 UNIPROT MPRIP protein Q6WCQ1 UNIPROT down-regulates phosphorylation 9606 17761936 t gcesareni Enhanced rho kinase activity induces endothelial barrier dysfunction by a contractile mechanism via inactivation of myosin phosphatase (mp).. SIGNOR-157593 0.301 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR BHLHE40 protein O14503 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19032342 f lperfetto DEC1 (BHLHB2/Stra13/Sharp2)-a basic helix-loop-helix transcription factor-is known to be involved in various biological phenomena including clock systems and metabolism. In the clock systems, Dec1 expression is dominantly up-regulated by CLOCK : BMAL1 heterodimer, and it exhibits circadian rhythm in the suprachiasmatic nucleus (SCN)-the central circadian pacemaker-and other peripheral tissues. SIGNOR-253707 0.652 CASP8 protein Q14790 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261744 0.338 FES protein P07332 UNIPROT FES protein P07332 UNIPROT up-regulates phosphorylation Tyr713 REEADGVyAASGGLR 9606 8663427 t llicata Substitution of kinase domain tyrosine residues 713 or 811 with phenylalanine resulted in a loss of the 10- and 4-kda phosphopeptides, respectively, identifying these tyrosines as in vitro autophosphorylation sites. Cnbr cleavage analysis of fes isolated from 32po4-labeled 293t cells showed that tyr-713 and tyr-811 are also autophosphorylated in vivo. . Mutagenesis of tyr-713 reduced both autophosphorylation of tyr-811 and transphosphorylation of bcr, a recently identified fes substrate, supporting a major regulatory role for tyr-713. SIGNOR-42655 0.2 CAMK2A protein Q9UQM7 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation 15621017 t Thus, the increased immunoreactivity of CaMKII-α of the remaining neurons may be the consequence of the altered calcium dynamics in neurons. There is evidence indicating that CaMKII might participate in tau phosphorylation in AD. SIGNOR-255490 0.579 DAPK1 protein P53355 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates phosphorylation Thr119 LSRRLKVtGDLFDIM 9606 19395874 t gcesareni We found that DAPk phosphorylates Beclin 1 on T119, a critical residue within its BH3 domain, and thus promotes Beclin 1 dissociation from Bcl-X(L) and autophagy induction. Here we report that T119 phosphorylation also reduces the interaction between Beclin 1 and Bcl-2, in line with the high degree of structural homology between the BH3 binding pockets of Bcl-2 and Bcl-X(L) proteins. SIGNOR-185589 0.72 RPS6KB1 protein P23443 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 7838153 t gcesareni Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii. SIGNOR-34117 0.582 PRKCA protein P17252 UNIPROT PTGIR protein P43119 UNIPROT unknown phosphorylation Ser328 TPLSQLAsGRRDPRA 9606 BTO:0000007 9722557 t lperfetto These results indicate that PKC-dependent phosphorylation is of critical importance to homologous regulation of hIP. Ser-328 is a primary site for PKC phosphorylation of hIP. SIGNOR-249011 0.329 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates activity phosphorylation Ser370 TRQTPVDsPDDTALS -1 11733037 t miannu In vitro phosphorylation and activation of p70β by mTOR and PDK1. replacement of Ser383 to Gly (S383G) reduced but still retained nearly half of the kinase activity of the wild-type. SIGNOR-250293 0.832 JAK2 protein O60674 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates activity phosphorylation Tyr250 PFLLDEDyEKVLGYV BTO:0000007 12540842 t lperfetto To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase |On the other hand, the phosphorylation levels of Y22F, Y310F, and Y322F by GST-JH1 were reduced to 80€“60% of the levels of wild-type STAP-2, which suggests that these three are potential phosphorylation sites by activated JAK2. SIGNOR-249371 0.349 GRK6 protein P43250 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. SIGNOR-251205 0.292 SH3RF1 protein Q7Z6J0 UNIPROT MAP3K12 protein Q12852 UNIPROT up-regulates binding 9606 BTO:0000938 11416147 t gcesareni One explanation as provided by our model is that mlk3 and dlk interact indirectly via posh with mutual activation when both are wild-type the multidomain protein posh binds to the constitutively active form of rac1, which is known to regulate the activity of mlks, while jip1 binds to mlks and additional components of the jnk pathway and appears to be capable of activating mlks SIGNOR-108577 0.384 BRD4 protein O60885 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity binding 9606 32544088 t lperfetto In this study, we explored the role of Brd4 and its interaction with the p300 acetyltransferase in the regulation of Nox4 and the in vivo efficacy of a BET inhibitor to reverse established age-associated lung fibrosis. |Together, these studies suggest that Brd4 enhances p300-mediated histone acetylation. SIGNOR-262064 0.436 TP53 protein P04637 UNIPROT AIFM2 protein Q9BRQ8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12135761 t miannu The p53 tumor suppressor protein induces cell cycle arrest or apoptosis in response to cellular stresses. We have identified PRG3 (p53-responsive gene 3), which is induced specifically under p53-dependent apoptotic conditions in human colon cancer cells, and encodes a novel polypeptide of 373 amino acids with a predicted molecular mass of 40.5 kDa. these results support the hypothesis that the expression of the PRG3 gene in cells undergoing p53‐dependent apoptosis involves direct activation of its promoter by p53. SIGNOR-261808 0.482 JAK2 protein O60674 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249490 0.703 KLF3 protein P57682 UNIPROT CEBPA protein P49715 UNIPROT down-regulates transcriptional regulation 9606 18391014 f fspada We find that c/ebpalpha is derepressed in klf3 and ctbp knockout fibroblasts and adipocytes from klf3 knockout mice. SIGNOR-210117 0.305 phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266532 0.8 IFNG protein P01579 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18647246 f miannu NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B. SIGNOR-252410 0.285 HACD proteinfamily SIGNOR-PF86 SIGNOR ELOVL proteinfamily SIGNOR-PF93 SIGNOR up-regulates activity binding 18554506 t miannu Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle. SIGNOR-267915 0.2 SLRP proteinfamily SIGNOR-PF31 SIGNOR ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t Proteoglycans are ubiquitous in connective tissue, and muscle ECM is no exception. A number of PGsare present in muscle ECM, and many belong to the family of small leucine-rich proteoglycans (SLRPs). SIGNOR-255345 0.7 pipamperone chemical CHEBI:78549 ChEBI HTR1B protein P28222 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0001311 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258573 0.8 ACACB protein O00763 UNIPROT malonyl-CoA smallmolecule CHEBI:15531 ChEBI up-regulates quantity chemical modification 9606 20952656 t miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA SIGNOR-267110 0.8 IRX1 protein P78414 UNIPROT EGR1 protein P18146 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. SIGNOR-261661 0.2 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1672 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273071 0.635 GATA3 protein P23771 UNIPROT CEBPB protein P17676 UNIPROT down-regulates binding 10090 15632071 t fspada In the present study, we demonstrate that both gata-2 and gata-3 form protein complexes with ccaat/enhancer binding protein alpha (c/ebpalpha) and c/ebpbeta, members of a family of transcription factors that are integral to adipogenesis. []the interaction between gata and c/ebp factors is critical for the ability of gata to suppress adipocyte differentiation. SIGNOR-132952 0.359 ABL1 protein P00519 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr219 SIQGHNDyMCPATNQ 9606 BTO:0000150 20101225 t gcesareni Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes. SIGNOR-163562 0.458 adapalene chemical CHEBI:31174 ChEBI RARB protein P10826 UNIPROT up-regulates activity chemical activation 9606 BTO:0000404 30836068 t miannu Adapalene, the third-generation synthetic retinoid,selectively bound to specific RAR, thus activating genes responsible forcellular differentiation. It showed greatest affinity for subtypes RARβindermalfibroblasts (Kd value 34 nM) and RARγin the epidermis (Kdvalue 130 nM) SIGNOR-258487 0.8 LPCAT1 protein Q8NF37 UNIPROT 1,2-diacyl-sn-glycero-3-phosphocholine chemical CHEBI:57643 ChEBI up-regulates quantity chemical modification 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272760 0.8 MET-enkephalin smallmolecule CHEBI:6618 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257554 0.8 SEMA3B protein Q13214 UNIPROT NRP1 protein O14786 UNIPROT up-regulates activity binding 9606 25335892 t miannu Further examination of the composition of the functional Sema3B receptor revealed that, unlike Sema3A, which signals exclusively using the NP1 receptor, Sema3B utilizes both NP1 and NP2 for signal transduction. SIGNOR-261814 0.748 GDF6 protein Q6KF10 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 16049014 t lperfetto We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10. Thus, the present approach provides a genomic paradigm for matching paralogous polypeptide ligands with a limited number of evolutionarily related receptors capable of activating specific downstream smad proteins. SIGNOR-217526 0.595 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000567 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-252612 0.737 AIMP1 protein Q12904 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity binding 9606 18448069 t lperfetto Here, we report that AIMP1 negatively regulates TGF-_ signaling via stabilization of Smurf2. SIGNOR-227470 0.399 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser315 LPNNTSSsPQPKKKP 10116 BTO:0001009 12064478 t llicata  the present study it is shown that in apoptotic PC12 cells the levels of p53 and Cdk5 increase concomitantly. Further, Cdk5/p25 effectively phosphorylates recombinant p53 in vitro. Transient transfection of Cdk5/p25 into cells results in an increase in p53 levels, as well as the expression of the p53-responsive genes p21 and Bax. Furthermore, evidence is provided that increased Cdk5 activity increases p53 transcriptional activity significantly, suggesting that p53 is modulated in situ by Cdk5.  SIGNOR-250674 0.57 ethanol chemical CHEBI:16236 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 8355 BTO:0000964 8700149 t inferred from family member miannu Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations. SIGNOR-267794 0.8 PRKAA1 protein Q13131 UNIPROT PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 BTO:0000876 BTO:0000671 SIGNOR-C15 12065600 t llicata Ipfk-2 was phosphorylated on the homologous serine (ser-461) and activated by ampk in vitro. SIGNOR-89760 0.385 afimoxifene chemical CHEBI:44616 ChEBI ESR1 protein P03372 UNIPROT down-regulates activity chemical inhibition -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258595 0.8 CSNK2A1 protein P68400 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Thr23 ESPPVSDtPDEGDEP 9606 BTO:0001271 21750978 t miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo SIGNOR-174836 0.294 KDM6A protein O15550 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys28 LATKAARkSAPATGG 9606 24561908 t This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions. miannu Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation. SIGNOR-260017 0.2 PHLPP1 protein O60346 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 23431053 t gcesareni Here, we report that phlpp1 is a binding protein for mst1 and it modulates the hippo pathway by dephosphorylating mst1 at the inhibitory thr(387) of mst1. SIGNOR-201262 0.3 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates quantity by destabilization phosphorylation Ser276 VHPATPIsPGRASGM 9606 BTO:0002181 16046550 t miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. SIGNOR-268221 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP3K11 protein Q16584 UNIPROT down-regulates phosphorylation Ser674 PGRERGEsPTTPPTP 9606 BTO:0000938 12458207 t lperfetto Negative regulation of mixed lineage kinase 3 by protein kinase b/akt leads to cell survivalthe expression of activated akt1 inhibits mlk3-mediated cell death in a manner dependent on serine 674 phosphorylation. SIGNOR-96062 0.2 (S)-adrenaline smallmolecule CHEBI:40751 ChEBI ADRA1A protein P35348 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258454 0.8 HIVEP2 protein P31629 UNIPROT SSTR2 protein P30874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001976 10207097 t Luana Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain. SIGNOR-261617 0.421 CDKN2A protein P42771 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 8891723 t miannu The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-44557 0.866 RXRG protein P48443 UNIPROT GLI2 protein P10070 UNIPROT up-regulates quantity transcriptional regulation 31390799 f SimoneGraziosi Despite RXRγ being heavily down-regulated upon silencing (average silencing was about 80%), the reduction in Gli2 expression levels was statistically significant only for Clobetasol-treated but not for Gefitinib-treated cells. SIGNOR-269267 0.262 NEDD4L protein Q96PU5 UNIPROT NF2 protein P35240 UNIPROT up-regulates activity ubiquitination Lys396 QITEEEAkLLAQKAA 9606 33058421 t miannu Merlin ubiquitination is mediated by the E3 ubiquitin ligase, NEDD4L, which requires a scaffold protein, AMOTL1, to approach Merlin. Several NF2-patient-derived Merlin mutations disrupt its binding to AMOTL1 and its regulation by the AMOTL1-NEDD4L apparatus. Lysine (K) 396 is the major ubiquitin conjugation residue. Disruption of Merlin ubiquitination by the K396R mutation or NEDD4L depletion diminishes its binding to Lats1 and inhibits Lats1 activation. These effects are also accompanied by loss of Merlin's anti-mitogenic and tumor suppressive properties. Thus, we propose that dephosphorylation and ubiquitination compose an intramolecular relay to activate Merlin functions in activating the Hippo pathway during growth control. SIGNOR-263662 0.264 TGFB1 protein P01137 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11331591 f lperfetto Tgf-b caused a 50% reduction of cbfa1 mrna. SIGNOR-235998 0.351 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR ERP44 protein Q9BS26 UNIPROT up-regulates 9606 11847130 f miannu Like many ER folding factors, ERp44 transcripts are induced by agents that cause the accumulation of unfolded proteins in the ER. SIGNOR-261047 0.7 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT unknown phosphorylation Thr1047 SSSSELStPEKPPHQ 9606 BTO:0000680;BTO:0001573;BTO:0001286 14551205 t llicata In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. SIGNOR-117339 0.502 CTDSP1 protein Q9GZU7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16882717 t lpetrilli In human cells, rnai-mediated depletion of scp1 and scp2 increases the extent and duration of smad1 phosphorylation in response to bmp, the transcriptional action of smad1, and the strength of endogenous bmp gene responses. The present identification of the scp family as smad c-terminal phosphatases sheds light on the events that attenuate smad signaling and reveals unexpected links to the essential phosphatases that control rna polymerase ii in eukaryotes. SIGNOR-148396 0.477 C1S protein P09871 UNIPROT Complement C1 complex complex SIGNOR-C309 SIGNOR form complex binding -1 29449492 t lperfetto The complement system is part of our innate immune system. The classical complement pathway is triggered by activation of the C1 initiation complex upon binding to cell surfaces. C1, or C1qr2s2, consists of four proteases, C1r and C1s, that associate with C1q, which contains antibody-binding sites.|The reconstruction reveals densities for all C1q collagen-like triple helices and gC1q modules, C1r and C1s proteases SIGNOR-263394 0.693 MCF2 protein P10911 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260556 0.744 CSNK2A1 protein P68400 UNIPROT NOL3 protein O60936 UNIPROT up-regulates activity phosphorylation Thr149 SEAVQSGtPEEPEPE 9606 BTO:0000007 12191471 t miannu Phosphorylation of ARC at T149 Is Required for Its Antiapoptotic Effect. Here we report that the function of ARC is regulated by protein kinase CK2. ARC at threonine 149 is phosphorylated by CK2. This phosphorylation targets ARC to mitochondria. ARC is able to bind to caspase-8 only when it is localized to mitochondria but not to the cytoplasm. SIGNOR-262837 0.329 NFATC2 protein Q13469 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 11956291 f IRF4 synergizes with NFATc2 and the IL-4-inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production SIGNOR-254502 0.524 PDPK2P protein Q6A1A2 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 15505410 t gcesareni Akt to the plasma membrane where it is phosphorylated and activated by phosphoinositide-dependent kinase (pdk) 1 and pdk2. SIGNOR-129965 0.2 SIK2 protein Q9H0K1 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity phosphorylation Ser794 QHLRLSTsSGRLLYA 24841198 t lperfetto SIK2 is known to attenuate insulin signaling by phosphorylating IRS-1/Ser789 SIGNOR-265745 0.585 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser381 GYSFVAPsILFKRNA 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro. SIGNOR-131395 0.2 TUBGCP3 protein Q96CW5 UNIPROT g-TuRC complex complex SIGNOR-C282 SIGNOR form complex binding -1 31862189 t lperfetto Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.” SIGNOR-262327 0.773 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1044 YPFVRTGsPRRIQLS 9606 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. site-directed mutagenesis of s1044 to an alanine resulted in the specific loss of d5 when this mutant was ectopically expressed in t98g cells and labelled by [32p]orthophosphate (figure 4b), proving that phosphorylation of s1044 gave rise to the tryptic phosphopeptide d5: tgspr. SIGNOR-104660 0.844 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161569 0.325 metformin chemical CHEBI:6801 ChEBI G6PC1 protein P35575 UNIPROT up-regulates quantity by expression 9606 17909097 f gcesareni In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp. SIGNOR-158056 0.8 PLK1 protein P53350 UNIPROT OPTN protein Q96CV9 UNIPROT up-regulates phosphorylation Ser177 SSGSSEDsFVEIRMA 9606 22365832 t lperfetto Here we show that at mitotic entry, plk1 phosphorylates optineurin (optn) at serine 177 and that this dissociates optn from the golgi-localized gtpase rab8, inducing its translocation into the nucleus. SIGNOR-196367 0.52 EGLN3 protein Q9H6Z9 UNIPROT ADRB2 protein P07550 UNIPROT up-regulates quantity by stabilization hydroxylation Pro395 VGHQGTVpSDNIDSQ 9606 BTO:0000007 19584355 t lperfetto We further show that the interaction of pVHL with beta(2)AR is dependent on proline hydroxylation (proline-382 and -395) and that the dioxygenase EGLN3 interacts directly with the beta(2)AR to serve as an endogenous beta(2)AR prolyl hydroxylase. Under hypoxic conditions, receptor hydroxylation and subsequent ubiquitylation decrease dramatically, thus attenuating receptor degradation and down-regulation. SIGNOR-262007 0.323 EFNA1 protein P20827 UNIPROT EPHA1 protein P21709 UNIPROT up-regulates binding 9606 9330863 t gcesareni The eph family receptors and ligands. SIGNOR-51932 0.824 CSNK1A1 protein P48729 UNIPROT LGALS3 protein P17931 UNIPROT up-regulates phosphorylation Ser6 sLHDALSG 9606 BTO:0000150 15121858 t llicata These results indicate that phosphorylation of gal-3 promotes its nuclear export after apoptotic stimuli through enhanced nuclear export. SIGNOR-124583 0.313 SP3 protein Q02447 UNIPROT KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 15708372 t We characterized four Sp1/Sp3 binding sites in the proximal promoter of the PSA gene. In a luciferase assay, these sites contributed to the basal promoter activity in prostate cancer cells. In an electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we confirmed that Sp1 and Sp3 bind to these sites. Overexpression of wild-type Sp1 and Sp3 further upregulated the promoter activity, whereas overexpression of the Sp1 dominant-negative form or addition of mithramycin A significantly reduced the promoter activity and the endogenous mRNA level of PSA. SIGNOR-253665 0.2 PRKCA protein P17252 UNIPROT MBD4 protein O95243 UNIPROT up-regulates activity phosphorylation Ser262 SGFVQSDsKRESVCN 23195996 t lperfetto Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12] SIGNOR-275672 0.2 PPM1A protein P35813 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation 9606 16751101 t lperfetto Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads. SIGNOR-217628 0.655 EGFR protein P00533 UNIPROT NCK2 protein O43639 UNIPROT up-regulates binding 9606 10026169 t esanto Growth factor binding to receptor protein tyrosine kinases (r-ptks)1 induces their dimerization and trans-phosphorylation, creating docking sites for proteins containing sh2 and ptb protein interaction domains. Nck binds to the pdgf and egfr receptors (figure 3c). SIGNOR-64731 0.408 R547 chemical CID:6918852 PUBCHEM CCNB1 protein P14635 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206349 0.8 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1195 HGHVSDAsISLGESV -1 22302995 t miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. SIGNOR-262905 0.69 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser295 FKLGGRDsRSGSPMA -1 2413024 t lperfetto MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. SIGNOR-248875 0.502 CDC14B protein O60729 UNIPROT USP9X protein Q93008 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser2547 YEGSEEVsPPQTKDQ 32152317 t Phosphosites were derived from Figure S1 lperfetto Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis. SIGNOR-275613 0.2 RPS6KA1 protein Q15418 UNIPROT CCT2 protein P78371 UNIPROT up-regulates phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 21440620 t lperfetto Furthermore, both the s260a and s260d mutants showed a decreased folding capacity as compared to cells expressing the wild-type cct_ subunit ( fig.?_5e), suggesting that a cyclic phosphorylation of the s260 site by s6k1 is likely to be important for chaperonin function and that mutation of this site interferes with this process. SIGNOR-172986 0.251 UNC5 proteinfamily SIGNOR-PF98 SIGNOR DCC protein P43146 UNIPROT down-regulates activity binding 9606 BTO:0001484 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268168 0.2 BLOC-1 complex SIGNOR-C381 SIGNOR serotonin smallmolecule CHEBI:28790 ChEBI up-regulates quantity relocalization 9606 23805129 t lperfetto The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). |VMAT2 also appears to mediate histamine transport into dense granules SIGNOR-265999 0.8 CDK5 protein Q00535 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity phosphorylation Thr212 VIEPLPVtPTRDVAT 9534 BTO:0004055 11604394 t lperfetto Our previous work revealed that the neuronal p35/Cdk5 kinase associates with Pak1 in a RacGTP-dependent manner, causing hyperphosphorylation and down-regulation of Pak1 kinase activity. We have now demonstrated direct phosphorylation of Pak1 on threonine 212 by the p35/Cdk5 kinase. SIGNOR-249328 0.52 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation 9606 BTO:0001103 21798082 t lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-252841 0.908 GSK3B protein P49841 UNIPROT BCL2L12 protein Q9HB09 UNIPROT up-regulates phosphorylation Ser156 SESPRPCsLPIRPCY 9606 BTO:0000527 22262180 t lperfetto Gsk3b phosphorylates bcl2l12 at s156. Ectopic expression of gfp-fused bcl2l12 or bcl2l12a in u87mg cells leads to repression of apoptotic markers and protects against staurosporine (sts) insults, indicating an antiapoptotic role for both bcl2l12 and bcl2l12a. In contrast, no anti-apoptotic ability was seen in bcl2l12(s156a) SIGNOR-195512 0.345 LRP6 protein O75581 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity relocalization 9606 16890161 t amattioni The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism. SIGNOR-148668 0.829 NR1I3 protein Q14994 UNIPROT UGT1A1 protein P22309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18172616 f miannu This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities. SIGNOR-254438 0.457 SSH1 protein Q8WYL5 UNIPROT CORO1B protein Q9BR76 UNIPROT up-regulates activity dephosphorylation Ser2 sFRKVVRQ 9606 17350576 t Coronin 1B inhibits filament nucleation by Arp2/3 complex and this inhibition is attenuated by phosphorylation of Coronin 1B at Serine 2, a site targeted by SSH1L. Coronin 1B also directs SSH1L to lamellipodia where SSH1L likely regulates Cofilin activity via dephosphorylation SIGNOR-248763 0.458 MRAP2 protein Q96G30 UNIPROT MC3R protein P41968 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 t miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. SIGNOR-252367 0.519 TLN1 protein Q9Y490 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257616 0.576 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270415 0.8 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser73 SAVRLRSsVPGVRLL -1 11895474 t miannu In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK.  SIGNOR-250243 0.312 HSP90AB1 protein P08238 UNIPROT FLCN protein Q8NFG4 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 27353360 t miannu Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability. SIGNOR-261417 0.2 AKT2 protein P31751 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 BTO:0000093 11504915 t lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.. Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. SIGNOR-109736 0.542 MMP13 protein P45452 UNIPROT FGB protein P02675 UNIPROT down-regulates quantity by destabilization cleavage Arg124 LQQERPIrNSVDELN -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain SIGNOR-263615 0.2 PLCB2 protein Q00722 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity 23994464 f apalma The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release SIGNOR-255013 0.8 KAT2B protein Q92831 UNIPROT H3Y1 protein P0DPK2 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkATAWQAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269614 0.2 KASH5 protein Q8N6L0 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 t lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. SIGNOR-263290 0.2 MAPK8 protein P45983 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 7737130 t gcesareni Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro. SIGNOR-32421 0.771 Anthra[2,1-d]thiazol-2-ylamine chemical CID:90872293 PUBCHEM KCNN1 protein Q92952 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 18955585 t Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  SIGNOR-258023 0.8 CAMK2A protein Q9UQM7 UNIPROT HOMER proteinfamily SIGNOR-PF59 SIGNOR down-regulates activity phosphorylation -1 18480293 t miannu Homer3 is phosphorylated at Ser120, Ser159, and Ser176 by CaMKII in vitro. Homer3 phosphorylation reduces its affinity for target molecules and modulates the Ca2+ signaling patterns induced by mGluR1α activation SIGNOR-264699 0.404 SP1 protein P08047 UNIPROT GGH protein Q92820 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31739835 t miannu Overexpression of Sp1 led to enhanced GGH promoter activity and GGH mRNA expression in allele-specific manners. These findings suggested that Sp1 acted as a positive regulator of human GGH transcription through the rs3758149 polymorphism in CEM/C1 cells. SIGNOR-261350 0.2 MYF5 protein P13349 UNIPROT DES protein P17661 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 8382796 t lperfetto Desmin, the muscle specific intermediate filament (IF) protein, is expressed at low levels in myoblasts and at the onset of differentiation its expression increases several fold. In an effort to explore the mechanism involved in the tissue-specific and developmentally regulated expression of desmin, we have isolated the mouse desmin gene.Co-transfection of myoD, myogenin, MRF4 and Myf5, with the desmin-CAT construct into 10T-1/2 cells demonstrated that all these factors could transactivate desmin gene expression SIGNOR-241494 0.243 DDHD1 protein Q8NEL9 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI down-regulates quantity chemical modification 9606 22922100 t miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. SIGNOR-269650 0.8 LATS2 protein Q9NRM7 UNIPROT ABL1 protein P00519 UNIPROT down-regulates activity phosphorylation Thr178 VYHYRINtASDGKLY -1 23852372 t miannu  Inhibition of c-Abl by Lats2 was mediated through Lats2 interaction with and phosphorylation of c-Abl.  Lats2 phosphorylates c-Abl at Thr197 in vitro. SIGNOR-276497 0.369 MAP3K6 protein O95382 UNIPROT MAP3K6 protein O95382 UNIPROT up-regulates activity phosphorylation Thr806 GITPCTEtFTGTLQY 9606 17210579 t Manara These results suggested that the induction of ASK2 phosphorylation in the presence of ASK1 is the consequence of autophosphorylation of ASK2. ASK1 thus appears to not only support the effective protein expression but also confer the kinase activity to ASK2. SIGNOR-260774 0.2 TLN1 protein Q9Y490 UNIPROT Av/b2 integrin complex SIGNOR-C176 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257622 0.64 FILIP1L protein Q4L180 UNIPROT FLNC protein Q14315 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0000165 32444788 t miannu We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells. SIGNOR-262618 0.254 tRNA(Pro) smallmolecule CHEBI:29177 ChEBI Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270433 0.8 DOCK3 protein Q8IZD9 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260548 0.642 RPS6K proteinfamily SIGNOR-PF26 SIGNOR METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 BTO:0000007;BTO:0000567 15861136 t gcesareni Pkb and ribosomal s6 kinase (rsk) both phosphorylated mettl1 at ser27 in vitro. SIGNOR-252800 0.2 FHL2 protein Q14192 UNIPROT SPHK1 protein Q9NYA1 UNIPROT down-regulates activity binding 10090 BTO:0000562 16888242 t llicata FHL2/SLIM3 decreases cardiomyocyte survival by inhibitory interaction with sphingosine kinase-1. SIGNOR-237775 0.434 tadalafil chemical CHEBI:71940 ChEBI PDE11A protein Q9HCR9 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000815 21189023 t Luana All of the final compounds and intermediates synthesized were screened for in vitro tumor cell growth inhibition activity using the human MDA-MB-231 breast tumor cell line and for inhibition of recombinant human PDE5 at a single concentration of 10 μM. For compounds showing >60% inhibition, the IC50 was determined by testing a range of eight concentrations with quadruple replicates per concentration, tadalafil used as a positive control.| Conversely, tadalafil possessed a selectivity index of just 16.6 for PDE5 versus PDE11 SIGNOR-257888 0.8 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2K protein P61086 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271367 0.748 EGR1 protein P18146 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 9606 BTO:0001412 1864967 f irozzo Finally, we demonstrate that dexamethasone, an inhibitor of monocytic differentiation, blocks the associated increases in EGR-1 and EGR-2 expression. Taken together, the results indicate that the EGR-1 and EGR-2 early response genes are involved in the induction of myeloid leukemia cell differentiation along the monocytic lineage and in the activation of human monocytes. SIGNOR-256088 0.7 CDK1 protein P06493 UNIPROT KIF11 protein P52732 UNIPROT up-regulates phosphorylation Thr926 LDIPTGTtPQRKSYL 9606 9235942 t lperfetto The kinesin-related motor hseg5 is essential for centrosome separation, and its association with centrosomes appears to be regulated by phosphorylation of tail residue threonine 927 by the p34(cdc2) protein kinase.Phosphorylation also enhanced the specific binding of p150(glued) to the tail domain of hseg5 in vitro SIGNOR-50169 0.657 PTPRC protein P08575 UNIPROT LYN protein P07948 UNIPROT down-regulates activity dephosphorylation Tyr397 RVIEDNEyTAREGAK 10090 BTO:0000776 10415030 t CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508) SIGNOR-248353 0.652 GNGT1 protein P63211 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 12507995 t gcesareni Therefore, we conclude that in vivo, g beta gamma activates pi3k gamma by a mechanism assigning specific roles for both pi3k gamma subunits, i.e., membrane recruitment is mediated via the noncatalytic p101 subunit, and direct stimulation of g beta gamma with p110 gamma contributes to activation of pi3k gamma. SIGNOR-96831 0.465 RAB21 protein Q9UL25 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 t lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 SIGNOR-260620 0.4 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr293 HRIDGKTyVIKRVKY -1 16373505 t Manara PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR. SIGNOR-260784 0.2 PLEKHG6 protein Q3KR16 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260568 0.302 TWIST1 protein Q15672 UNIPROT PFDN4 protein Q9NQP4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255532 0.2 CTNNB1 protein P35222 UNIPROT KLF4 protein O43474 UNIPROT up-regulates activity binding 10090 24482235 t flangone The interaction of Beta-catenin with Tcf is important for Beta-catenin s's function in iPSCs induction. In addition, Beta-catenin interacts with Oct4, Sox2, and Klf4, respectively. In the reprogramming process, Beta-catenin further enhances expression of pluripotency-related genes. SIGNOR-242100 0.673 Kindlin proteinfamily SIGNOR-PF48 SIGNOR Av/b6 integrin complex SIGNOR-C179 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259008 0.344 BTF3 protein P20290 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 17312387 f In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. SIGNOR-253948 0.253 TGFb proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 protein P37173 UNIPROT up-regulates activity binding 9606 22326956 t miannu TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-256178 0.2 GRN protein P28799 UNIPROT TNFRSF1A protein P19438 UNIPROT down-regulates binding 9606 21393509 t gcesareni Collectively, these findings demonstrate that pgrn is a ligand of tnfr, an antagonist of tnf signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. SIGNOR-172684 0.505 IRAK4 protein Q9NWZ3 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Thr133 KLPTDNQtKKPETYL 9606 BTO:0000130 17217339 t lperfetto Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.We found that thr133, ser288 and thr356, targets for irak-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after lps stimulation. We conclude that irak-4 phosphorylates p47phox and regulates nadph oxidase activation after lps stimulation. SIGNOR-152023 0.389 PTGER3 protein P43115 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257111 0.273 CHEK2 protein O96017 UNIPROT BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Thr182 SHFVRVStAQKSKKG 9606 BTO:0002181 26028025 t miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.Phosphorylation on BLM Thr171 and Ser175 depends on prior phosphorylation at Thr182 by Chk1/Chk2. Thr182 phosphorylation not only controls BLM ubiquitylation and degradation during mitosis but is also a determinant for its localization on the ultrafine bridges. SIGNOR-276908 0.542 SCNN1G protein P51170 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 26772908 t miannu The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na(+) ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na(+) in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity. SIGNOR-269277 0.8 SYK protein P43405 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Tyr125 VDPDNEAyEMPSEEG 9606 BTO:0000975;BTO:0000142 11744621 t llicata Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers. SIGNOR-113061 0.512 SH3GLB1 protein Q9Y371 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates 9606 BTO:0000567 16227588 f gcesareni Here, we provide evidence that bif-1 plays a regulatory role in apoptotic activation of not only bax but also bak and appears to be involved in suppression of tumorigenesis. while bif-1 did not directly interact with bak, it heterodimerized with bax on mitochondria in intact cells, and this interaction was enhanced by apoptosis induction and preceded the bax conformational change. SIGNOR-141163 0.2 SCF-SKP2 complex SIGNOR-C136 SIGNOR E2F1 protein Q01094 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 10559858 t miannu P45 SKP2 binds to a specific domain of E2F-1. We propose a model in which an SCFSKP2-dependent ubiquitination pathway contributes to the timely ubiquitination and degradation of E2F-1 in the S/G2 phases of the cell cycle. SIGNOR-272557 0.39 NLGN2 protein Q8NFZ4 UNIPROT NRXN2 protein Q9P2S2 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264156 0.823 MAPK1 protein P28482 UNIPROT PFAS protein O15067 UNIPROT up-regulates phosphorylation Thr619 GQGDAPPtPLPTPVD 9606 32485148 t miannu T619 in PFAS is required to mediate ERK2-dependent purine synthesis stimulation. We demonstrate that ERK2, but not ERK1, phosphorylates the purine synthesis enzyme PFAS (phosphoribosylformylglycinamidine synthase) at T619 in cells to stimulate de novo purine synthesis. The expression of nonphosphorylatable PFAS (T619A) decreases purine synthesis, RAS-dependent cancer cell-colony formation, and tumor growth. Thus, ERK2-mediated PFAS phosphorylation facilitates the increase in nucleic acid synthesis required for anabolic cell growth and proliferation. SIGNOR-267306 0.2 LHX4 protein Q969G2 UNIPROT POU1F1 protein P28069 UNIPROT up-regulates quantity by expression transcriptional regulation 10029 BTO:0000246 15998782 t Luana We show that normal LHX4 binds to a human-specific element and subsequently activates transcription from the proximal upstream regulatory sequence of POUIF1, a gene encoding a POU homeodomain transcription factor known as the main regulator of GH expression. SIGNOR-266056 0.528 PRKCQ protein Q04759 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity phosphorylation Ser716 HILERFGsLTMDGGL 9606 31792381 t TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation SIGNOR-272472 0.2 GPR132 protein Q9UNW8 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257187 0.2 GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263780 0.7 TLR2 protein O60603 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266746 0.626 TFEB protein P19484 UNIPROT NDUFA13 protein Q9P0J0 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). SIGNOR-276701 0.2 HCK protein P08631 UNIPROT HCK protein P08631 UNIPROT up-regulates activity phosphorylation Tyr411 RVIEDNEyTAREGAK 9606 BTO:0000007 10934191 t Hck transiently expressed in human embryonic kidney 293T cells was found to be phosphorylated at Tyr-29 and Tyr-388, proving that Hck can also undergo autophosphorylation at both sites in vivo. autophosphorylation of Tyr-29 contributes significantly to the activation of Hck. SIGNOR-251266 0.2 DYRK1A protein Q13627 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser330 RLSPIMAsTELDEVQ 9606 19188143 t lperfetto Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition. SIGNOR-106833 0.366 FLT1 protein P17948 UNIPROT PHACTR1 protein Q9C0D0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21939755 f miannu Recently, we identified a new Vascular Endothelial Growth Factor (VEGF)-A(165)-induced gene Phactr-1, (Phosphatase Actin Regulator-1). We found that neuropilin-1 (NRP-1) and VEGF-R1 depletion inhibited Phactr-1 mRNA expression while NRP-2 and VEGF-R2 depletion had no effect. SIGNOR-260060 0.263 furtrethonium chemical CHEBI:134764 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258643 0.8 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2D4 protein Q9Y2X8 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271341 0.726 PRKCA protein P17252 UNIPROT INSR protein P06213 UNIPROT unknown phosphorylation Ser1062 AVKTVNEsASLRERI -1 7926007 t lperfetto Identification of serines-1035/1037 in the kinase domain of the insulin receptor as protein kinase C alpha mediated phosphorylation sites. SIGNOR-248905 0.354 DNMT3A protein Q9Y6K1 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 27639498 f irozzo The DNA methyltransferase 3 genes (DNMT3A and DNMT3B) encode methyltransferases that catalyze the addition of a methyl group to the cytosine residue of CpG dinucleotide; therefore they play an essential role in DNA methylation and gene silencing regulatory processes. DNMT3A function is involved in hematopoietic stem cells (HSCs) renewal and myeloid differentiation. SIGNOR-255714 0.7 PSME3 protein P61289 UNIPROT SIRT7 protein Q9NRC8 UNIPROT down-regulates quantity by destabilization binding 27511885 t lperfetto Here, the authors show that energy stress induces an AMPK-dependent phosphorylation of Sirt7, which promotes its ubiquitin-independent degradation by REGγ, resulting in the down-regulation of rRNA transcription and cell survival.|These results strongly suggest that the phosphorylation status of SirT7 at T153 plays a crucial role in determining its subcellular distribution, degradation and binding to REGγ. SIGNOR-275866 0.2 MRPL22 protein Q9NWU5 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262371 0.679 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR unknown phosphorylation 9606 16046471 t lperfetto Rela is phosphorylated at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) .we now present evidence that suggests that the upstream kinase ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. .Ikkbeta Plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. . SIGNOR-217427 0.865 PRKCA protein P17252 UNIPROT PEA15 protein Q15121 UNIPROT down-regulates phosphorylation Ser104 TKLTRIPsAKKYKDI 9606 BTO:0000149 15917297 t miannu Pea-15 is phosphorylated on two ser residues, ser104 and ser116. Protein kinase c (pkc) phosphorylates ser104 / we report that phosphorylation of pea-15 blocks its interaction with erk1/2 in vitro and in vivo and that phosphorylation of both ser104 and ser116 is required for this effect. SIGNOR-137841 0.393 DAMPS stimulus SIGNOR-ST18 SIGNOR MEFV protein O15553 UNIPROT up-regulates activity 16037825 f lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-256422 0.7 GSK3B protein P49841 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Ser1490 AILNPPPsPATERSH 9606 SIGNOR-C110 16341017 t gcesareni Glycogen synthase kinase 3 (gsk3), which is known for its inhibitory role in wnt through the promotion of beta-catenin phosphorylation and degradation, mediates the phosphorylation and activation of lrp6. We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin. SIGNOR-143041 0.786 PI3K complex SIGNOR-C156 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000830 15526160 t miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254951 0.282 GLI3 protein P10071 UNIPROT MYCN protein P04198 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin. .Hedgehog Signals induce cellular proliferation through upregulation of n-myc, cyclin d/e, and foxm1. SIGNOR-188881 0.364 BTF3 protein P20290 UNIPROT IRAG1 protein Q9Y6F6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000584 17312387 f In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. SIGNOR-253946 0.2 CHFR protein Q96EP1 UNIPROT PBK protein Q96KB5 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 24012691 t miannu CHFR ubiquitinates and degrades TOPK. Our in vivo ubiquitination assays revealed that the polyubiquitination of TOPK occurs only in the presence of full length CHFR but not with the ΔRING or Δcysteine-rich domain deletion mutants (Fig. 2a). SIGNOR-271471 0.352 PHF12 protein Q96QT6 UNIPROT TLE6 protein Q9H808 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 t miannu We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE. SIGNOR-266991 0.2 Upf-EJC complex SIGNOR-C367 SIGNOR Nonsense-mediated mRNA decay phenotype SIGNOR-PH175 SIGNOR up-regulates 9606 BTO:0000567 17803942 t miannu The three Up-frameshift (Upf) proteins, Upf1, Upf2, and Upf3 that together form the Upf complex, constitute the conserved core of NMD from yeast to humans. hUpf3b Forms Multiple Contacts with the EJC and Depends on hUpf2 for Complex Formation with hUpf1. the hUpf complex communicates with the EJC and triggers NMD in the cytoplasm. SIGNOR-265239 0.7 DAB2IP protein Q5VWQ8 UNIPROT NRAS protein P01111 UNIPROT down-regulates activity gtpase-activating protein 9606 27858941 t miannu The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP. SIGNOR-254747 0.473 PRKACA protein P17612 UNIPROT TAL1 protein P17542 UNIPROT up-regulates phosphorylation Ser172 NRVKRRPsPYEMEIT 9606 22310283 t llicata The phosphorylation of serine 172 of tal1 specifically destabilizes tal1 interaction with histone demethylase lsd1 and, therefore, leads to the activation of the certain tal1 target genes in differentiated erythroid cells or t-cell leukemia. SIGNOR-195983 0.2 ATXN2L protein Q8WWM7 UNIPROT DDX6 protein P26196 UNIPROT unknown binding 9606 23209657 t miannu Ataxin-2-like associates with known interaction partners of ataxin-2, the rna helicase ddx6 SIGNOR-199948 0.555 UCHL3 protein P15374 UNIPROT UBA52 protein P62987 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270827 0.794 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI Citric_Acid_Cycle phenotype SIGNOR-PH191 SIGNOR up-regulates 9606 15953811 f miannu A branch-point metabolite α-ketoglutarate is generated in the TCA cycle during the oxidation of carbohydrates and fatty acids and by glutamate dehydrogenase during the oxidative deamination of glutamate. The enzymes that form the mitochondrial α-ketoglutarate– dehydrogenase complex (KGDHC), a key and arguably rate-limiting enzyme system of the tricarboxylic acid cycle, might mediate the interaction of these processes. SIGNOR-267821 0.7 SFPQ protein P23246 UNIPROT TH protein P07101 UNIPROT down-regulates quantity by repression transcriptional regulation 20938049 t lperfetto It has been reported that DJ-1 is a neuroprotective transcriptional co-activator that sequesters a transcriptional co-repressor polypyrimidine tract-binding protein-associated splicing factor (PSF) from the TH gene promoter. SIGNOR-271697 0.2 PPP3CC protein P48454 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 10195903 t Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. SIGNOR-248529 0.373 MAPK8 protein P45983 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation Ser62 LLPTPPLsPSRRSGL 9606 BTO:0000007;BTO:0000567 10551811 t lperfetto The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71. SIGNOR-236018 0.573 HOXA10 protein P31260 UNIPROT EMX2 protein Q04743 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15494461 f miannu EMSA demonstrated HOXA10-Pbx2 binding as a heterodimer to an enhancer of the EMX2 gene, a known target of HOXA10 regulation. SIGNOR-254465 0.325 EIF2S1 protein P05198 UNIPROT HBG2 protein P69892 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24714526 f miannu Reduction of globin inclusions and induction of ATF4 and HbF by the HRI-eIF2αP signaling provide strong bases for targeting this pathway for novel pharmaceutical therapy of hemoglobinopathy. SIGNOR-251818 0.2 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser338 DEASATVsKTETSQV -1 9099669 t lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. SIGNOR-248967 0.45 MAPK13 protein O15264 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser396 TFDSLPSsPSSATPH -1 11500363 t miannu eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. eEF2K[S359A] was phosphorylated (presumably at Ser396) by the high concentrations of SAPK4/p38 used in this experiment. However, the inhibition of eEF2K under these conditions was reduced from 82% in the wild-type enzyme to 19% in eEF2K[S359A] SIGNOR-250089 0.56 GTF2I protein P78347 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity binding 9606 BTO:0000007 12493763 t lperfetto We identify a new family of HDAC1,2-associated complexes containing BHC110. Moreover, we define the polypeptide composition of a novel member of this family containing the candidate gene for X-linked mental retardation XFIM and the initiator-binding protein TFII-I. SIGNOR-268539 0.414 MYC protein P01106 UNIPROT PPAT protein Q06203 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 t miannu PPAT, catalyzing the first step of purine synthesis, and DHODH, an enzyme generating uridine in the middle of the pyrimidine synthesis pathway, were validated as direct c-MYC target genes by all criteria. SIGNOR-267381 0.2 NFX1 protein Q12986 UNIPROT SIN3A protein Q96ST3 UNIPROT up-regulates activity binding 9606 BTO:0004117 18505829 t miannu we investigated the mechanism of NFX1-91 repression of the hTERT promoter and demonstrated that NFX1-91 interacts with the corepressor mSin3A/HDAC to maintain the deacetylated status at the hTERT promoter, thus providing a mechanism by which NFX1-91 represses hTERT expression. SIGNOR-226360 0.381 STAT3 protein P40763 UNIPROT SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR form complex binding 9606 26194464 t MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. SIGNOR-255024 0.566 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000776 17339337 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-153483 0.783 ADCY7 protein P51828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 t miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. SIGNOR-265007 0.8 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 17828307 t gcesareni Fak y397 phosphorylation promotes src sh2 domain binding to fak, presumably leading to conformational src activation with a fak-src complex. SIGNOR-157763 0.2 GABRA6 protein Q16445 UNIPROT GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263768 0.522 DAB2IP protein Q5VWQ8 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity binding 9606 27858941 t miannu DAB2IP also mediates recruitment of PP2A to ASK1, binding both proteins through its C2 domain; this favors removal of the inhibitory S967 phosphorylation and further activation of ASK1 SIGNOR-254748 0.835 PRKCA protein P17252 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Thr107 PKKERRRtESINSAF 9606 BTO:0000007 14636580 t lperfetto In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. In addition, phosphopeptide mapping analysis of wild-type and mutant forms of HAND1 shows that three of these conserved residues, T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues.  SIGNOR-249244 0.292 PTPN11 protein Q06124 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR down-regulates activity dephosphorylation 9606 16767162 t miannu Tyr148 of beta-catenin is an shp2 target dephosphorylation site. Together, these results suggest that beta-catenin plays a suppressor role in cell transformation and that shp2, by dephosphorylating beta-catenin, promotes mitogenic, cell survival and transformation signals. SIGNOR-265824 0.41 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser356 DIKSNNWsLEDVTAS 9606 16216881 t lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. SIGNOR-140998 0.2 MAP2K7 protein O14733 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 11062067 t Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif gcesareni Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)these results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway. SIGNOR-83732 0.564 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1784 TPTSPNYsPTSPSYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203556 0.769 L3MBTL2 protein Q969R5 UNIPROT RNF168 protein Q8IYW5 UNIPROT down-regulates quantity binding 9606 31225475 t miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. SIGNOR-266788 0.248 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser54 RVKALPLsPRKRLGD 9606 10339564 t lperfetto Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction. SIGNOR-217276 0.94 BMPR1A protein P36894 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates activity phosphorylation 9606 19620713 t lperfetto Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. SIGNOR-255261 0.675 PRKCA protein P17252 UNIPROT TACSTD2 protein P09758 UNIPROT down-regulates activity phosphorylation Ser322 GELRKEPsL 9606 BTO:0001109 31177095 t done miannu  Analyses using HCT116 cells expressing WT Trop-2 (HCT116/WT) or Trop-2 alanine-substituted at Ser-303 (HCT116/S303A) or Ser-322 (HCT116/S322A) revealed that Trop-2 is phosphorylated at Ser-322. sing protein kinase C (PKC) inhibitors and PKC-specific siRNAs, we found that PKCα and PKCδ are responsible for Trop-2 phosphorylation. SIGNOR-273821 0.2 DYRK1B protein Q9Y463 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 10090 15546868 t lperfetto Mirk phosphorylates p27 at ser-10, thus stabilizing p27 and blocking its nuclear export and degradation SIGNOR-235805 0.362 RBM7 protein Q9Y580 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR up-regulates activity relocalization 9606 BTO:0000007 30824372 t miannu Here, we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates RNA polymerase II (Pol II) transcription and promotes cell viability by activating the positive transcription elongation factor b (P-TEFb) via its release from the inhibitory 7SK small nuclear ribonucleoprotein (7SK snRNP). these findings establish that RBM7 binds 7SK snRNP and that genotoxic stress activates P-TEFb by relocating it from 7SK snRNP to the CTD of Pol II. SIGNOR-261182 0.2 DGC complex SIGNOR-C217 SIGNOR GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265436 0.2 HSPA1B protein P0DMV9 UNIPROT NOD2 protein Q9HC29 UNIPROT up-regulates quantity by stabilization binding 9606 24790089 t miannu The molecular chaperone HSP70 binds to and stabilizes NOD2, an important protein involved in Crohn disease. SIGNOR-252417 0.2 CDK5 protein Q00535 UNIPROT HTR6 protein P50406 UNIPROT down-regulates activity phosphorylation Ser350 ERQASLAsPSLRTSH 10090 BTO:0000942 32047117 t lperfetto Cdk5 phosphorylates the 5-HT6R on serine 350 (Ser350)|This suggests that the 5-HT6R is unable to interact with GPRIN1 when it is phosphorylated by Cdk5. SIGNOR-264407 0.382 FUS protein P35637 UNIPROT DLG4 protein P78352 UNIPROT up-regulates quantity post transcriptional regulation 10090 BTO:0000142 32118033 t lperfetto These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.|As seen in Figure 7 (top panel), both PSD-95 Q1-Q2 and Shank1a GQ probes pulled down endogenous FUS, whereas their M2 mutants did not, indicating that the GQ structure is sufficient for recognition. SIGNOR-262103 0.273 PTEN protein P60484 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity 9606 18794881 f lperfetto The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3)). SIGNOR-209856 0.721 ESR1 protein P03372 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 15808510 t gcesareni Ikkalpha in conjunction with eralpha and aib1/src-3, is important in activating the transcription of estrogen-responsive genes, including cyclin d1. SIGNOR-135053 0.745 AKAP9 protein Q99996 UNIPROT TRIP10 protein Q15642 UNIPROT up-regulates activity binding 9606 BTO:0000182;BTO:0000666 27039663 t Giulio Mechanistically, AKAP-9 interacted with cdc42 interacting protein 4 (CIP4) and regulated its expression. CIP4 levels were interrelated to the AKAP-9 level in CRC cells. Functionally, AKAP-9 was essential for TGF-β1-induced epithelial-mesenchymal transition of CRC cells, and CIP4 played a critical role in mediating the function of AKAP-9. Importantly, CIP4 expression was significantly up-regulated in human CRC tissues.|Co-immunoprecipitation assay revealed that AKAP-9 and CIP4 physically interacted with each other in Lovo and HT29 cells (Fig. 4B and C). SIGNOR-260303 0.527 TFEB protein P19484 UNIPROT NDUFS4 protein O43181 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). SIGNOR-276705 0.248 PRKCA protein P17252 UNIPROT EDF1 protein O60869 UNIPROT down-regulates activity phosphorylation Thr91 GRQSKGLtQKDLATK 9606 BTO:0001949 10816571 t lperfetto EDF-1 was phosphorylated in vitro by PKC in the presence of Ca2+ and phospholipids | This results shows that introduction of a single negative charge by phosphorylation at Thr-91 inhibited CaM-EDF-1 interactions. SIGNOR-249041 0.305 AUTS2 protein Q8WXX7 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 25533347 f miannu AUTS2 is involved in neurite outgrowth and branch formation in neurons. SIGNOR-266818 0.7 ITGAL protein P20701 UNIPROT AKAP9 protein Q99996 UNIPROT up-regulates activity binding 9606 BTO:0001945 16339516 t Giulio However, association of CG-NAP/AKAP450 was signifi-cantly enhanced at 37°C in LFA-1-activated cells triggered toundergo motility. Taken together, our findings provide the first definitiveevidence that the protein CG-NAP/AKAP450 is a key scaffoldingcomponent of the multimolecular complex assembled in T cellsupon LFA cross-linking and is functionally indispensable for cellpolarity and migration induced by this integrin. SIGNOR-260304 0.2 BMPR2 protein Q13873 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR form complex binding 9606 7791754 t lperfetto Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii). SIGNOR-33443 0.612 CDC42BPB protein Q9Y5S2 UNIPROT MSN protein P26038 UNIPROT up-regulates activity phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 10947843 t Manara In this study, we have shown that MRCKb phosphorylated moesin at Thr-558 | We have shown that the phosphorylation is important to the formation of ®lopodia, and that MRCK may regulate this formation through the phosphorylation of ERM proteins at the tip of ®lopodia. SIGNOR-260802 0.2 MSH release-inhibiting hormone smallmolecule CID:56842142 PUBCHEM MC5R protein P33032 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257539 0.8 ABL1 protein P00519 UNIPROT RAD52 protein P43351 UNIPROT up-regulates activity phosphorylation Tyr104 DLNNGKFyVGVCAFV 9606 BTO:0000007 12379650 t gcesareni We show here that c-Abl tyrosine kinase associates with and phosphorylates Rad52 on tyrosine 104. Importantly, the very same site of Rad52 is phosphorylated on exposure of cells to ionizing radiation (IR). SIGNOR-247661 0.672 EIF1 protein P41567 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR up-regulates activity relocalization 9606 20921384 t lperfetto Genetic and biochemical studies have revealed several eukaryotic factors involved in selecting the correct initiation codon (3–6). Further analyses pointed toward eukaryotic initiation factor 1 (eIF1) as the key mediator of this process (7–10). eIF1 binds near the P-site of the small ribosomal subunit (11); this binding is thought to lead to an open conformation of the preinitiation complex favoring scanning SIGNOR-269143 0.541 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser719 PCTPRLRsVSSYGNI 9606 SIGNOR-C3 18722121 t llicata Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity SIGNOR-252772 0.2 MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr842 CTETFTGtLQYMAPE 9606 17937911 t lperfetto Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling. SIGNOR-158431 0.2 NMDA receptor_2A complex SIGNOR-C347 SIGNOR CTTN protein Q14247 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 14684878 t miannu Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors. SIGNOR-266599 0.285 PRKCD protein Q05655 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity phosphorylation -1 15894802 t inferred from family member lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-270275 0.404 NLGN3 protein Q9NZ94 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264142 0.834 PRKCH protein P24723 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates quantity by stabilization 9606 28939105 f miannu The results of our present study show that PKCη positively regulates the anti-apoptotic Bcl-2 family protein Mcl-1 by preventing its degradation via the proteasomal pathway involving Mcl-1 ubiquitin ligase Mule. SIGNOR-261908 0.2 OPA3 protein Q9H6K4 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 20372962 f lperfetto Optic atrophy 3 as a protein of the mitochondrial outer membrane induces mitochondrial fragmentation|Together, these results indicate that OPA3, as an integral MOM protein, has a crucial role in mitochondrial fission, and provides a direct link between mitochondrial morphology and optic atrophy. SIGNOR-272988 0.7 TCF20 protein Q9UGU0 UNIPROT MMP3 protein P08254 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7760812 t Luana This result indicates that expression of SPBP is sufficient to transactivate a minimal promoter containing a single copy of the SPRE, as well as the full-length stromelysin promoter. SIGNOR-266223 0.426 pentazocine chemical CHEBI:7982 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258935 0.8 sonidegib chemical CHEBI:90863 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0000527 21679342 t gcesareni Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date. SIGNOR-174593 0.8 NMBR protein P28336 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257422 0.41 clozapine chemical CHEBI:3766 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258513 0.8 HOXA13 protein P31271 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000942 21829694 t Luana Analysis of normalized luciferase expression confirmed that wt HOXA13 regulates gene expression through the EphA7 cis-regulatory DNA element SIGNOR-261631 0.295 P2RY12 protein Q9H244 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256991 0.2 MAPK1 protein P28482 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1457 HSKSPAYtPQNLDSE 9606 16314496 t fstefani We demonstrate that erk phosphorylates trap220/med1 in vivo at two specific sites: threonine 1032 and threonine 1457. importantly, we found that erk phosphorylation significantly increases the stability and half-life of trap220/med1 in vivo and correlates with increased thyroid hormone receptor-dependent transcription. SIGNOR-142462 0.361 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL2 protein P13500 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 f Both NF-κBs bind to a conserved DNA motif (80) that is found in numerous IL-1–responsive genes, in particular the ones encoding IκBα (81), IL-6 (82), IL-8 (18, 83,84), monocyte chemoattractant protein 1 (MCP1) (28), and cyclooxygenase 2 (COX2) SIGNOR-254509 0.567 PRKCD protein Q05655 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Thr46 PHRYRPGtVALREIR 9606 19363025 t gcesareni We identify protein kinase c-delta as the kinase responsible for h3t45ph in vitro and in vivo. Given the nucleosomal position of h3t45, we postulate that h3t45ph induces structural change within the nucleosome to facilitate dna nicking and/or fragmentation. SIGNOR-185144 0.2 KDM4C protein Q9H3R0 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 29207681 t miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation SIGNOR-263865 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT1 protein Q9BQL6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser174 LESSPTAsGSSVSPG 9606 BTO:0000567 35469017 t miannu CDK1–cyclin B1 mediates KIND1 and KIND2 phosphorylation at mitotic entry . MS of KIND1 and KIND2 immunoprecipitates from STLC-arrested HeLa cells confirmed the phosphorylation of KIND1-S179 and KIND2-S181 and revealed phosphorylation of closely adjacent serine residues (KIND1: SSphS174GphS176PVphS179PGLYSK; KIND2: GphS175GphS177IYphS180phS181PGLYSK), although to a weaker extent (Supplementary Table 2). SIGNOR-276719 0.2 MKRN1 protein Q9UHC7 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002552 23104211 t miannu Biochemical analyses confirmed that MKRN1 targets p14ARF for ubiquitination and subsequent proteasome-dependent degradation.The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro. SIGNOR-272036 0.374 GABRD protein O14764 UNIPROT GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263773 0.395 AKT proteinfamily SIGNOR-PF24 SIGNOR COPS6 protein Q7L5N1 UNIPROT up-regulates phosphorylation Ser60 DHWIRMRsQEGRPVQ 9606 23095642 t llicata Mechanistic studies show that akt causes csn6 phosphorylation at ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of csn6. SIGNOR-199254 0.2 CUL3 protein Q13618 UNIPROT KCTD10 protein Q9H3F6 UNIPROT up-regulates activity binding 9606 19782033 t miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. SIGNOR-264234 0.508 TEK protein Q02763 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 f lperfetto the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. SIGNOR-241535 0.248 RPS6K proteinfamily SIGNOR-PF26 SIGNOR EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 11500364 t lperfetto We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity SIGNOR-252775 0.2 RPS6KA1 protein Q15418 UNIPROT MITF protein O75030 UNIPROT down-regulates phosphorylation Ser409 HGLSLIPsTGLCSPD 9606 10673502 t The effect has been demonstrated using O75030-9 gcesareni The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73, whereas serine 409 serves as a substrate for p90 rsk-1. An unphosphorylatable double mutant at these two residues is at once profoundly stable and transcriptionally inert. SIGNOR-75034 0.419 MAP3K3 protein Q99759 UNIPROT WDR62 protein O43379 UNIPROT up-regulates quantity by stabilization binding 30566428 t lperfetto Specifically, we demonstrate that MEKK3 interacts with WDR62 to stabilize WDR62 and regulates JNK activity in a synergic way. On the other hand, JNK activity also regulates the phosphorylation of WDR62 at T1053 in a feedback loop which facilities the recruitment of FBW7 degradation of WDR62 SIGNOR-271714 0.2 L-thyroxine smallmolecule CHEBI:18332 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 1400883 t scontino The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production. SIGNOR-266943 0.8 TP53 protein P04637 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates binding 9606 16990795 t gcesareni P52 cooperates with p53 to regulate other known p53 target genes. SIGNOR-149811 0.435 PTPN2 protein P17706 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity dephosphorylation 9606 15780598 t lperfetto Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5. SIGNOR-134620 0.758 ROCK1 protein Q13464 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser38 LGPGTRLsLARMPPP -1 12686604 t lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro. SIGNOR-100188 0.317 phosphatidic acid smallmolecule CHEBI:16337 ChEBI long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity precursor of 9606 22922100 t miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. SIGNOR-269658 0.8 Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT IRF7 protein Q92985 UNIPROT down-regulates activity 9606 17715225 f miannu SARS-CoV nsp1 inhibits virus-dependent activation of IRF3 and IRF7. SIGNOR-262504 0.2 PPP1R9A protein Q9ULJ8 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates activity binding 10090 BTO:0001976 15996550 t miannu The Rho Family GEF Lfc Interacts with Neurabin and Spinophilin. Neurabin and spinophilin are homologous protein phosphatase 1 and actin binding proteins that regulate dendritic spine function. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc SIGNOR-269177 0.347 TBC1D4 protein O60343 UNIPROT SLC2A4 protein P14672 UNIPROT down-regulates 9606 12637568 f gcesareni These findings strongly indicate that insulin-stimulated phosphorylation of as160 is required for glut4 translocation and that this phosphorylation signals translocation through inactivation of the rab gap function. SIGNOR-99303 0.653 ETS2 protein P15036 UNIPROT IBSP protein P21815 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11175361 t miannu Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin SIGNOR-259873 0.2 CDK1 protein P06493 UNIPROT CC2D1A protein Q6P1N0 UNIPROT up-regulates activity phosphorylation Ser208 PASTPTYsPAPTQPA SIGNOR-C17 20171170 t nucleus lperfetto We identified the Ser208 residue of Aki1 as a cyclin B1–Cdk1 phosphorylation site. Furthermore, cyclin B1–Cdk1 inhibitor treatment was shown to attenuate the level of Aki1 in complex with Scc1, suggesting that Aki1 phosphorylation by cyclin B1–Cdk1 contributes to Aki1–Scc1 complex formation. SIGNOR-268297 0.2 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Thr278 LARRRKAtQVGEKTP -1 8182057 t miannu The vasodilator-stimulated phosphoprotein (VASP) is a major substrate for cAMP-dependent- (cAK) and cGMP-dependent protein kinase (cGK) in human platelets and other cardiovascular cells.‚  three VASP phosphorylation sites are phosphorylated by cAK and cGK. Thr, Ser I, and Ser 2 correspond to Thr278, Ser157, Ser239 of the VASP protein, respectively SIGNOR-250065 0.488 GAST protein P01350 UNIPROT SLC4A2 protein P04920 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000269 22228178 f Gastrin inhibited proliferation of colon cancer cells by suppressing expression of EGR1 and AE2 and by blocking ERK phosphorylation. SIGNOR-254251 0.281 AKT3 protein Q9Y243 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 t gcesareni Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155. SIGNOR-81118 0.522 RPL10L protein Q96L21 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262500 0.774 CSNK2A2 protein P19784 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity phosphorylation Ser59 SETNQNSsSDSEAER -1 11711551 t llicata We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. SIGNOR-251045 0.386 HRK protein O00198 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates binding 9606 9130713 t gcesareni Hrk, physically interacts with the death-repressor proteins bcl2 and bcl2l1. Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by bcl2 and bcl2l1. SIGNOR-47797 0.622 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270374 0.8 TCL1A protein P56279 UNIPROT AKT1 protein P31749 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation SIGNOR-81680 0.823 PRKCD protein Q05655 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Ser28 LEEGASGsTPPEELP 9606 16963224 t llicata Activated pkc delta was able to phosphorylate shca at ser29, as determined by mass spectrometry. SIGNOR-149402 0.55 AKT proteinfamily SIGNOR-PF24 SIGNOR TBC1D4 protein O60343 UNIPROT unknown phosphorylation Ser588 RMRGRLGsVDSFERS 10090 BTO:0000011 11994271 t gcesareni To determine directly whether AS160 was a substrate for Akt, we examined the phosphorylation of recombinant AS160, as well as mutant forms with Ser-588, Thr-642, or both converted to Ala, by recombinant Akt 1. SIGNOR-245268 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr8 MSSILPFtPPVVKRL 9606 BTO:0000763 12193595 t lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-244735 0.2 estramustine chemical CHEBI:4868 ChEBI MAP2 protein P11137 UNIPROT down-regulates activity chemical inhibition -1 1647395 t miannu Estramustine is a novel anti-microtubule drug shown to bind MAP-1 and MAP-2 (microtubule-associated proteins) in vitro. In this paper we have shown that estramustine specifically binds MAP-1A in Du 145a cells, resulting in disruption of MAP-1A microtubules and inhibition of type IV collagenase secretion. SIGNOR-259298 0.8 CSNK1A1 protein P48729 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser87 KTVEGAGsIAAATGF 9606 BTO:0000938 10617630 t lperfetto In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its c terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.From these data we conclude that _-synuclein is predominantly phosphorylated at serine residue 129. However, a second serine at position 87 is also used for phosphorylation to some extent. together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of _-synuclein could affect its binding to membranes. SIGNOR-73799 0.379 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183620 0.2 PRKACA protein P17612 UNIPROT GPKOW protein Q92917 UNIPROT up-regulates activity phosphorylation Ser27 SFGFTRTsARRRLAD -1 21880142 t miannu PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites. SIGNOR-266309 0.312 CSNK2A1 protein P68400 UNIPROT MYF5 protein P13349 UNIPROT up-regulates activity phosphorylation Ser49 HKAELQGsDEDEHVR -1 9461343 t llicata Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity.  SIGNOR-250923 0.312 AKT proteinfamily SIGNOR-PF24 SIGNOR VCP protein P55072 UNIPROT up-regulates phosphorylation Ser746 AMRFARRsVSDNDIR 9606 BTO:0000150 16551632 t llicata Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I SIGNOR-145288 0.2 SUFU protein Q9UMX1 UNIPROT GLI2 protein P10070 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 20463034 t Gianni We show that loss of suppressor of fused (Sufu; an inhibitory effector for Gli proteins) results in destabilization of Gli2 and Gli3 full-length activators but not of their C-terminally processed repressors, whereas overexpression of Sufu stabilizes them. SIGNOR-268867 0.906 GNB/GNG complex SIGNOR-C202 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates 23994464 t apalma Similar to PLCβ activation, PI3K-activation by neutrophil GPCRs also occurs primarily through Gβγ subunits, through the unique PI3Kγ isoform which is directly activated by Gβγ dimers SIGNOR-255010 0.468 GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268590 0.2 TP53 protein P04637 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10029407 f miannu p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1. SIGNOR-255434 0.371 CHD2 protein O14647 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 10090 26895424 f miannu We show in mouse cells that the cNHEJ-dependent fusion of chromosomes containing uncapped telomeres requires the activity of CHD2. Together, these findings argue that the chromatin response mediated by CHD2 is triggered by the presence of DSBs and promotes repair of these lesions by the canonical KU-dependent NHEJ pathway. SIGNOR-264529 0.7 MAPK3 protein P27361 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Ser523 GVSDVPTsPTLQRPT 9606 16705159 t 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner SIGNOR-146747 0.503 BCL6 protein P41182 UNIPROT LITAF protein Q99732 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001518 23795761 f miannu BCL6 silencing increased LITAF expression, and chromatin immunoprecipitation and luciferase reporter assays demonstrated a direct transcriptional repression of LITAF by BCL6. SIGNOR-253758 0.359 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270406 0.8 tubastatin A chemical CHEBI:94186 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207450 0.8 RFX complex complex SIGNOR-C104 SIGNOR HLA-DMB protein P28068 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11889043 f Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment. SIGNOR-254016 0.371 Glycine cleavage system complex SIGNOR-C437 SIGNOR carbon dioxide smallmolecule CHEBI:16526 ChEBI up-regulates quantity chemical modification 9606 16051266 t lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. SIGNOR-268244 0.8 PPP2CA protein P67775 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT down-regulates dephosphorylation Ser387 ETGLYRIsGCDRTVK 9606 18201571 t gcesareni We report here that (i) mgcracgap is phosphorylated by aurora b and cdk1, (ii) pp2a dephosphorylates aurora b and cdk1 phosphorylated sites and (iii) inhibition of pp2a abrogates mgcracgap/ect2 interaction. Therefore, pp2a may regulate cytokinesis by dephosphorylating mgcracgap and its interacting partners. SIGNOR-160398 0.307 COL3A1 protein P02461 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t Collagen is the major structural protein in skeletal muscle ECM;... type III collagen appears to be more evenly distributed between endomysium and epimysium SIGNOR-254664 0.7 PTX3 protein P26022 UNIPROT CFH protein P08603 UNIPROT up-regulates activity binding 9606 19050261 t miannu Our findings identify PTX3 as a unique FH ligand in that it can bind both of the two hot-spots of FH, namely SCR7 and SCR19-20 and indicate that PTX3 participates in the localization of functionally active FH. PTX3 binds FH without interfering with its complement inhibitory function. Therefore PTX3 may contribute to focusing FH regulatory action, prevent excessive complement activation, and thus exert an important function in the control of inflammation in response to tissue injury. SIGNOR-252140 0.407 PRKACA protein P17612 UNIPROT TRIM71 protein Q2Q1W2 UNIPROT up-regulates quantity by stabilization phosphorylation Ser3 sFPETDFQ -1 31160797 t miannu  These observations suggested that LINK-A expression potentially inhibits PKA phosphorylation/activity and PKA-mediated phosphorylation of TRIM71 at Ser3. SIGNOR-277454 0.2 MAPK12 protein P53778 UNIPROT EEF2K protein O00418 UNIPROT unknown phosphorylation Ser396 TFDSLPSsPSSATPH -1 12171600 t miannu We have also shown that JNK11, JNK22 and SAPK3 p38 phosphorylate eEF2 kinase very poorly at Ser-396 SIGNOR-250137 0.334 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr444 NSLTPKStPVKTLPF 9606 SIGNOR-C83 9840932 t lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk3 SIGNOR-62357 0.711 GSK3B protein P49841 UNIPROT JUN protein P05412 UNIPROT down-regulates activity phosphorylation Ser243 PGETPPLsPIDMESQ 9606 BTO:0000007 16023596 t lperfetto The c-jun and c-myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.Phosphorylation of Thr-239 and Ser-243 is required for Fbw7-mediated c-Jun disappearance SIGNOR-235892 0.7 SP1 protein P08047 UNIPROT ENG protein P17813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002741 21146604 f miannu In hepatic stellate cells, TGF-β1 upregulates endoglin expression most likely via the ALK5 pathway and requires the SP1 transcription factor. SIGNOR-255201 0.2 FGR protein P09769 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Tyr374 PLPPAPAyLSSPLAL 9606 BTO:0000007 23131831 t miannu Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.  SIGNOR-276368 0.333 PIM proteinfamily SIGNOR-PF34 SIGNOR CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 20307683 t lperfetto Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellshere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo SIGNOR-259424 0.2 GTF2I protein P78347 UNIPROT USF2 protein Q15853 UNIPROT up-regulates activity binding 9606 21282467 t lperfetto TFII-I has been shown to interact with USF and to associate with either E-box elements or initiator sequences to activate gene transcription SIGNOR-268537 0.354 SYK protein P43405 UNIPROT LAT2 protein Q9GZY6 UNIPROT up-regulates activity phosphorylation Tyr233 EEDGEPDyVNGEVAA 10090 BTO:0001930 14722116 t miannu Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases. SIGNOR-273577 0.576 EGFR protein P00533 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Tyr370 SLEISQSyTTTQRES -1 25601159 t miannu Here, we show that upon irradiation stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Tyr370 (Y370) at the site of DNA double-strand breaks. SIGNOR-276872 0.408 BABAM2 protein Q9NXR7 UNIPROT BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR form complex binding 9606 BTO:0000007 14636569 t lperfetto These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer SIGNOR-263209 0.2 PLCG1 protein P19174 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 9606 10913276 t gcesareni We provide evidence that sos1, a p21ras-specific guanine nucleotide exchange factor, directly binds to the sh3 domain of plc-gamma1, and that the sh3 domain of plc-gamma1 is involved in sos1-mediated p21ras activation. SIGNOR-80024 0.632 PIAS1 protein O75925 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity sumoylation Lys276 NVVYRDLkLENLMLD 10090 BTO:0002572 23884910 t gcesareni Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity. SIGNOR-252735 0.387 CSNK2A1 protein P68400 UNIPROT WASF2 protein Q9Y6W5 UNIPROT down-regulates phosphorylation Ser484 IAVEYSDsEDDSSEF 9606 19012317 t gcesareni Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo. SIGNOR-182354 0.2 AKT1 protein P31749 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates activity phosphorylation Ser193 GLPERSVsLTGAPES 9606 17177604 t lperfetto Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome. SIGNOR-252497 0.692 NR1I3 protein Q14994 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 12896978 t gcesareni Therefore, both car-rxr heterodimers and car monomers can contribute to the gene activating function of pbrems in car target genes. SIGNOR-104441 0.479 SLC27A2 protein O14975 UNIPROT fatty acyl-CoA smallmolecule CHEBI:37554 ChEBI up-regulates quantity chemical modification 9606 10198260 t lperfetto Very-long-chain acyl-CoA synthetases (VLCS) activate very-long-chain fatty acids (VLCFA) containing 22 or more carbons to their CoA derivatives. SIGNOR-260415 0.8 PTTG1 protein O95997 UNIPROT TIMP2 protein P16035 UNIPROT down-regulates quantity 9606 19351864 f miannu Suppressing PTTG expression by siRNA decreased cell motility in both PTTG-HA/EC9706 and KYSE150 cells. By using mass spectrometric analysis, we identified that PTTG up-regulated S100A4 and galectin-1 secretion and down-regulated tissue inhibitor of metalloproteinase-2 secretion to the culture media. SIGNOR-255069 0.2 CBL protein P22681 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates quantity by destabilization binding 9606 12496371 t miannu In our present study, we demonstrate that ligand-mediated stimulation causes EphA2 to be internalized and degraded. The mechanism of this response involves ligand-mediated autophosphorylation of EphA2, which promotes an association between EphA2 and the c-Cbl adaptor protein. We also show that c-Cbl promotes stimulation-dependent EphA2 degradation.  SIGNOR-272590 0.623 ZFYVE9 protein O95405 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity relocalization 9606 20515759 t lperfetto Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor. SIGNOR-165786 0.906 6-{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine chemical CHEBI:40629 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189347 0.8 CDK1 protein P06493 UNIPROT NDUFB6 protein O95139 UNIPROT up-regulates activity phosphorylation Thr5 tPDEKLRL 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275589 0.2 MAPKAPK2 protein P49137 UNIPROT TSC2 protein P49815 UNIPROT unknown phosphorylation Ser1254 TALYKSLsVPAASTA 9606 12582162 t llicata Both in vitro and in vivo experiments demonstrate that the p38-activated kinase mk2 (also known as mapkapk2) is directly responsible for the phosphorylation of ser(1210). SIGNOR-98201 0.645 RNF31 protein Q96EP0 UNIPROT NR0B1 protein P51843 UNIPROT up-regulates quantity by stabilization monoubiquitination 9606 BTO:0002588 19237537 t miannu RNF31 promotes monoubiquitination of DAX-1 in an RBR domain-dependent manner. In conclusion, our results suggest that the major DAX-1 modification observed in different experimental settings is likely to be monoubiquitination at one or more lysine residues (multiubiquitination) possibly located within the LBD of DAX-1. RNF31 stabilizes endogenous DAX-1. SIGNOR-271786 0.448 AKT1 protein P31749 UNIPROT VIM protein P08670 UNIPROT up-regulates quantity by stabilization phosphorylation Ser39 TTSTRTYsLGSALRP 9606 20856200 t llicata The binding of akt (tail region) to vim (head region) results in vim ser39 phosphorylation enhancing the ability of vim to induce motility and invasion while protecting vim from caspase-induced proteolysis. SIGNOR-252511 0.632 olanzapine chemical CHEBI:7735 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258506 0.8 PRKCA protein P17252 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates phosphorylation Ser1494 TLTRDYNsLTRSEHS 9606 15121854 t lperfetto Egf stimulates a pkc-?-Dependent pathway that results in the phosphorylation of the ?4 Integrin subunit on serine residues and its redistribution to actin-rich structures together, these results highlight the importance of serine phosphorylation in regulating type ii hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of ?4, and argue for a key role for pkc-? In regulating these structures SIGNOR-124498 0.511 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251592 0.695 motesanib chemical CHEBI:51098 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194560 0.8 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI up-regulates quantity precursor of 9606 32041144 t miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. SIGNOR-267553 0.8 SAGA complex complex SIGNOR-C465 SIGNOR H3-2 protein Q5TEC6 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269633 0.2 AURKB protein Q96GD4 UNIPROT SKA3 protein Q8IX90 UNIPROT up-regulates activity phosphorylation Ser159 SPRSPQLsDFGLERY -1 22371557 t miannu Aurora B directly phosphorylated Ska1 and Ska3 in vitro, and expression of phosphomimetic mutants of Ska1 and Ska3 impaired Ska KT recruitment and formation of stable KT-MT fibers (K-fibers), disrupting mitotic progression. We propose that Aurora B phosphorylation antagonizes the interaction between the Ska complex and the KMN network, thereby controlling Ska recruitment to KTs and stabilization of KT-MT attachments. SIGNOR-262661 0.466 PCM1 protein Q15154 UNIPROT PCNT protein O95613 UNIPROT up-regulates relocalization 9606 12403812 t miannu Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome SIGNOR-95117 0.675 EDNRB protein P24530 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257428 0.412 FAAP100 protein Q0VG06 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 t lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263244 0.2 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr686 IITEYCRyGDLVDYL -1 19275932 t miannu C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis.  SIGNOR-276142 0.507 PPM1E protein Q8WY54 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 11864573 t The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX. SIGNOR-248761 0.307 PLK1 protein P53350 UNIPROT NUDC protein Q9Y266 UNIPROT up-regulates activity phosphorylation Ser326 QHPEMDFsKAKFN 9606 BTO:0000567 12852857 t lperfetto Here, we characterize the interaction between plk1 and nudc, show that plk1 phosphorylates nudc at conserved s274 and s326 residues in vitro, and present evidence that nudc is also a substrate for plk1 in vivo. Downregulation of nudc by rna interference results in multiple mitotic defects, including multinucleation and cells arrested at the midbody stage, which are rescued by ectopic expression of wild-type nudc, but not by nudc with mutations in the plk1 phosphorylation sites. SIGNOR-103407 0.719 TSHB protein P01222 UNIPROT TSHR protein P16473 UNIPROT up-regulates binding 9606 12045258 t gcesareni Two novel human glycoprotein hormonelike genes, alpha2 (a2) and beta5 (b5), recently have been identified. Using a yeast two-hybrid assay, the two subunits were found as potential heterodimerization partners. SIGNOR-88653 0.711 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr199 VKKSIRDtPAKNAQK 9606 12058066 t lperfetto However, under the experimental conditions used here, the t199 residue was the most likely candidate to be phosphorylated by cyclin b/cdc2 these results strongly support the concept that the rna binding activity of b23.1 is inactivated by cyclin b/cdc2-mediated phosphorylation. SIGNOR-216845 0.417 SALL4 protein Q9UJQ4 UNIPROT CECR2 protein Q9BXF3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 33144328 t miannu SALL4 activates Cecr2 by directly binging to its promotor region and CECR2 in turn promotes reprogramming through forming a SMARCA1-contained chromatin remodeling complex with its DTT domain.  SIGNOR-263893 0.2 CNOT4 protein O95628 UNIPROT RBM15 protein Q96T37 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 26575292 t miannu We demonstrate that RBM15 is methylated by protein arginine methyltransferase 1 (PRMT1) at residue R578, leading to its degradation via ubiquitylation by an E3 ligase (CNOT4).  SIGNOR-271466 0.367 ANP32A protein P39687 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 BTO:0000567 12522243 t PHAP proteins promoted caspase-9 activation after apoptosome formation, whereas ProT negatively regulated caspase-9 activation by inhibiting apoptosome formation. SIGNOR-259082 0.281 YARS1 protein P54577 UNIPROT Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates quantity chemical modification 9606 16429158 t miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr SIGNOR-270522 0.8 VARS1 protein P26640 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 30755602 t miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. SIGNOR-270529 0.8 WNT3A protein P56704 UNIPROT FZD2 protein Q14332 UNIPROT up-regulates binding 9606 19910923 t gcesareni It was also shown that wnt5a inhibits the beta-catenin pathway by competing with wnt3a for binding to fz2, and that the impairment of clathrin-mediated internalization does not affect this wnt5a inhibitory action. SIGNOR-189117 0.743 NUP98 protein P52948 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262098 0.692 GSK3B protein P49841 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates phosphorylation Ser1359 VPRPHVQsVLLTPQD 9606 19797085 t llicata In addition, we show that the beta-trcp-mediated degradation requires phosphorylation of phlpp1 by casein kinase i and glycogen synthase kinase 3beta (gsk-3beta), and activation of the phosphatidylinositol 3-kinase/akt pathway suppresses the degradation of phlpp1 by inhibiting the gsk-3beta activity. SIGNOR-188330 0.36 Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity binding 9606 17761676 t lperfetto PLpro interacts with IRF-3, and inhibits the phosphorylation and nuclear translocation of IRF-3, thereby disrupting the activation of type I IFN responses through either Toll-like receptor 3 or retinoic acid inducible gene I/melanoma differentiation-associated gene 5 pathways. SIGNOR-260276 0.2 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser208 DAGSPNLsPNPMSPA -1 15241418 t llicata Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. We propose that under physiological conditions, phosphorylation of Smad3 by CDK inhibits its transcriptional activity, contributing to a decreased level of p15 and an increased level of c-Myc, thus facilitating cell cycle progression from G1 to S phase. SIGNOR-250750 0.733 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 BTO:0000567 BTO:0000887;BTO:0001103 8454633 t gcesareni Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190. SIGNOR-39159 0.385 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25B protein P30305 UNIPROT up-regulates phosphorylation Thr355 NKRRRSVtPPEEQQE 9606 23708659 t lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. SIGNOR-252779 0.2 LRIG1 protein Q96JA1 UNIPROT ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates ubiquitination 9606 16123311 t inferred from 70% of family members gcesareni We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation. SIGNOR-269872 0.727 N-(6-fluoro-1H-indazol-5-yl)-6-methyl-2-oxo-4-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-pyridine-5-carboxamide chemical CHEBI:91332 ChEBI ROCK2 protein O75116 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 19740074 t miannu We also observed that several ROCK (Rho kinase) inhibitors such as Y-27632 and H-1152, suppressed LRRK2 with similar potency to which they inhibited ROCK2. In contrast, GSK429286A, a selective ROCK inhibitor, did not significantly inhibit LRRK2. SIGNOR-262230 0.8 dopamine smallmolecule CHEBI:18243 ChEBI noradrenaline smallmolecule CHEBI:33569 ChEBI up-regulates quantity precursor of 10090 7961964 t brain lperfetto Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway. SIGNOR-264182 0.8 RAPGEF5 protein Q92565 UNIPROT NRAS protein P01111 UNIPROT up-regulates guanine nucleotide exchange factor 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-183738 0.415 ITGB1 protein P05556 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253178 0.913 QSOX2 protein Q6ZRP7 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 18034316 f miannu a pro-apoptotic member of the QSOX superfamily, QSOXN, was described (Wittke et al. 2003). QSOXN was shown to sensitize neuroblastoma cells to INFγ-induced apoptosis, by still unknown mechanisms. In this context, absence of QSOX in fetal epithelia may prevent apoptosis. SIGNOR-261365 0.7 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RXRG protein P48443 UNIPROT up-regulates activity chemical activation 9606 17132853 t miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. SIGNOR-256193 0.8 PLEKHA7 protein Q6IQ23 UNIPROT PDZD11 protein Q5EBL8 UNIPROT up-regulates activity binding 10116 BTO:0003618 30463011 t Simone Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. The PLEKHA7-PDZD11 Complex Clusters ADAM10 at Junctions through Tspan33 SIGNOR-261253 0.389 C6 protein P13671 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 t lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer SIGNOR-263442 0.481 SEC13 protein P55735 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262091 0.585 MMP13 protein P45452 UNIPROT COL2A1 protein P02458 UNIPROT down-regulates quantity by destabilization cleavage Gly906 EGPPGPQgLAGQRGI 9606 8609233 t miannu Although it appears that MMP-1 and MMP-13 both cleave type II collagen initially at the same site, MMP-13 affects a secondary cleavage to produce a 1/4-size collagen fragment with an NH2 terminus three amino acids removed from the primary cleavage site.The present work has demonstrated expression of MMP-13 in human osteoarthritic cartilage and shown that MMP-13 has significant type II collagen degrading activity. SIGNOR-256340 0.56 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation 9606 19433246 t miannu Phthalates are true ligands of PPARs. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARgamma identified MEHP as a selective PPARgamma modulator, and thus a possible contributor to the obesity epidemic. SIGNOR-268746 0.8 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 10482988 t miannu Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. SIGNOR-251148 0.434 PPM1D protein O15297 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates activity dephosphorylation 9606 23907458 t miannu Activating dephosphorylation of RUNX2 by Wip1 increases its transcriptional activity on the Bax promoter. SIGNOR-277110 0.455 HSPA9 protein P38646 UNIPROT MVD protein P53602 UNIPROT down-regulates activity binding 9534 12646231 t miannu Mortalin binds to mevalonate pyrophosphate decarboxyl ase in mammalian cell. Mot-2 inactivates MPD resulting in decreased amounts of the steady state Ras protein. SIGNOR-265890 0.349 BRCA1 protein P38398 UNIPROT RNASEL protein Q05823 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15940267 f miannu We propose that BRCA1 may be an upstream regulator of RNaseL, acting in concert with IFN-gamma to transcriptionally activate 2,5 OAS, leading to the downstream activation of RNaseL and apoptosis. SIGNOR-253762 0.32 CDK9 protein P50750 UNIPROT NCOA2 protein Q15596 UNIPROT up-regulates activity phosphorylation Ser493 LSPRHRMsSPGVAGS 9606 BTO:0000801 29170386 t Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties. SIGNOR-256098 0.248 PTPN1 protein P18031 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2114 RDIYKNDyYRKRGEG 9606 17416557 t gcesareni In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products. SIGNOR-154203 0.381 PRKAA1 protein Q13131 UNIPROT SIRT7 protein Q9NRC8 UNIPROT down-regulates quantity by destabilization phosphorylation Thr153 TLTHMSItRLHEQKL 27511885 t lperfetto Here, the authors show that energy stress induces an AMPK-dependent phosphorylation of Sirt7, which promotes its ubiquitin-independent degradation by REGγ, resulting in the down-regulation of rRNA transcription and cell survival.|These results strongly suggest that the phosphorylation status of SirT7 at T153 plays a crucial role in determining its subcellular distribution, degradation and binding to REGγ. SIGNOR-275864 0.2 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120152 0.316 MAPK1 protein P28482 UNIPROT PTPRR protein Q15256 UNIPROT up-regulates activity phosphorylation Thr361 EPFVSIPtPREKVAM 11493009 t lperfetto Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL. SIGNOR-249438 0.817 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR HSPA5 protein P11021 UNIPROT down-regulates 9606 31226023 f miannu In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation. SIGNOR-260163 0.7 AMER1 protein Q5JTC6 UNIPROT APC protein P25054 UNIPROT up-regulates relocalization 9606 23151663 t gcesareni Apc membrane recruitment protein 1 (amer1;alsoknownas wtx) SIGNOR-199375 0.728 PP1 proteinfamily SIGNOR-PF54 SIGNOR CDC25C protein P30307 UNIPROT up-regulates binding 9606 14592972 t lperfetto Pp1 recognizes cdc25 directly by interacting with a pp1-binding motif in the cdc25 n-terminus. SIGNOR-264654 0.2 IKK-complex complex SIGNOR-C14 SIGNOR HES1 protein Q14469 UNIPROT up-regulates quantity by expression 9606 22056382 f Tnf-α enhanced the transcriptional activity of a classical Notch target gene via Ikk2 by inducing histone H3 phosphorylation SIGNOR-253586 0.2 SLC36A2 protein Q495M3 UNIPROT proline smallmolecule CHEBI:26271 ChEBI up-regulates quantity relocalization 9606 12748860 t lperfetto Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut. SIGNOR-264742 0.8 ATR protein Q13535 UNIPROT USP28 protein Q96RU2 UNIPROT up-regulates activity phosphorylation Ser67 DERVKEPsQDTVATE 31938050 t lperfetto Here we report that the deubiquitylase USP28 is recruited to sites of DNA damage in cisplatin-treated cells. ATR phosphorylates USP28 and increases its enzymatic activity.|Representative immunoblots of n = 3. C Immunoblotting of total and phosphorylated USP28 at serine 67 and 714 in A431 cells exposed to indicated concentrations of CPPD for 6 h. SIGNOR-275850 0.2 ALOX15 protein P16050 UNIPROT 15(S)-HETE smallmolecule CHEBI:15558 ChEBI up-regulates quantity chemical modification 9606 12517954 t lperfetto In A549 cells activation of 15-LOX by IL-4 required the coactivation of histone acetyltransferases CREB-binding protein/p300 and led to a sizable production of 15(S)-HETE SIGNOR-254094 0.8 MAPKAPK2 protein P49137 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 15688025 t gcesareni Hdm2 phosphorylation by mapkap kinase 2 enhances hdm2 activity and promote the degradation of p53. SIGNOR-133560 0.371 CHMP4C protein Q96CF2 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 t miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. SIGNOR-265528 0.632 NEDD4 protein P46934 UNIPROT SPRY2 protein O43597 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 19864419 t miannu Endogenous and overexpressed Nedd4 polyubiquitinate Spry2 via Lys(48) on ubiquitin and decrease its stability.  SIGNOR-271425 0.399 PTPRD protein P23468 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 27225731 f miannu LAR (for leukocyte common antigen-related) is a family of receptor protein tyrosine phosphatases (LAR-RPTPs) with three known members: LAR/PTPRF, PTPδ/PTPRD, and PTPσ/PTPRS. In mammals, LAR-RPTPs have been shown to regulate dendrite and excitatory synapse development and maintenance SIGNOR-264089 0.7 linifanib chemical CHEBI:91435 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193660 0.8 NR3C1 protein P04150 UNIPROT NR4A3 protein Q92570 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15591535 f gcesareni We now show that the other nur factors, nurr1 and nor-1, are also subject to antagonism by gr and that this transrepression appears to involve direct protein-protein interactions between the dbds of gr and nur factors. SIGNOR-132309 0.295 FFAR1 protein O14842 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257071 0.312 DCAF7 protein P61962 UNIPROT DYRK1A protein Q13627 UNIPROT up-regulates activity binding 9534 BTO:0000298 14593110 t Giorgia Two isoforms of DYRK, DYRK1A and DYRK1B, co-immunoprecipitate with HAN11 when coexpressed in COS cells indicating that the proteins interact in mammalian cells. HAN11 might target DYRKs to cytosolic locations for regulation of specific cellular functions. SIGNOR-260630 0.733 STAT1 protein P42224 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19643666 t lperfetto Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways. SIGNOR-249565 0.665 PRKCH protein P24723 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 t gcesareni Furthermore, several pkc isotypes phosphorylate gsk-3 in vitro and in vivo. in the presence of atp, several isoforms (?, ___, _, ?, And of pkc phosphorylated both gsk-3? At ser 21 and gsk-3_ at ser 9 SIGNOR-115730 0.327 PRKACA protein P17612 UNIPROT ABCA1 protein O95477 UNIPROT up-regulates activity phosphorylation Ser2054 GGNKRKLsTAMALIG 10090 BTO:0000801 12196520 t miannu Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ABCA1 phosphorylation may affect ApoA-I-dependent phospholipid efflux by either altering the conformation of the protein to a more active state or by affecting the interaction between ABCA1 and its partner proteins. SIGNOR-250327 0.486 AMPK complex SIGNOR-C15 SIGNOR RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 10090 SIGNOR-C15 SIGNOR-C3 18439900 t lperfetto These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK SIGNOR-263046 0.501 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGC5 protein Q9Y5F6 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265705 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Ser1678 ITSEEERsPAKRGRK -1 30685087 t lperfetto Nuclear import of 53BP1 is required for proper localization of 53BP1 and maintenance of genome integrity. 53BP1 has a classical bipartite nuclear localization signal (NLS) of sequence 1666-GKRKLITSEEERSPAKRGRKS-1686. Ser1678 within the 53BP1 NLS can be phosphorylated by CDK1/cyclin B, and a phosphomimetic substitution of Ser1678 with aspartate has been shown to negatively regulate nuclear import of 53BP1. SIGNOR-264444 0.562 ZNF462 protein Q96JM2 UNIPROT PBX1 protein P40424 UNIPROT down-regulates activity binding 9534 BTO:0000298 17353115 t miannu We demonstrated that ZFPIP is expressed in embryonic female genital tract but also in other PBX1 expression domains such as the developing head and the limb buds. We further showed that ZFPIP is able to bind physically and in vivo to PBX1 and moreover, that it prevents the binding of HOXA9/PBX complexes to their consensus DNA site. We suggest that ZFPIP is a new type of PBX1 partner that could participate in PBX1 function during several developmental pathways. SIGNOR-264477 0.313 oligopeptide smallmolecule CHEBI:25676 ChEBI peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity precursor of 9606 31810556 t scontino While peptides loaded onto MHC class I molecules are 8‚Äì11 amino acid residues long (a restriction based on the size and conformation of the peptide-binding groove of MHC class I molecules), peptides translocated by TAP can be significantly longer. These peptides will be trimmed to the correct length by ERAP-1. SIGNOR-267770 0.8 TBK1 protein Q9UHD2 UNIPROT TNIP1 protein Q15025 UNIPROT down-regulates quantity by destabilization phosphorylation Ser123 PPSSGTSsEFEVVTP 36574265 t lperfetto TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1 SIGNOR-275734 0.383 CSNK2B protein P67870 UNIPROT EIF5 protein P55010 UNIPROT up-regulates activity phosphorylation Ser390 KEAEEESsGGEEEDE 9606 BTO:0001938 11861906 t llicata Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis. SIGNOR-251070 0.387 PRKD1 protein Q15139 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Thr112 EGMQIPStQFDAAHP 9606 BTO:0001130 19141652 t lperfetto This study provides evidence that pkd1 interacts with and phosphorylates beta-catenin at thr(112) and thr(120) we postulate that pkd1 phosphorylation is required to maintain _-catenin transcription activity. SIGNOR-183384 0.397 SGK1 protein O00141 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000007 11154281 t lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. SIGNOR-252988 0.787 SDHD protein O14521 UNIPROT SDH complex SIGNOR-C400 SIGNOR form complex binding 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. SIGNOR-266274 0.924 beta-Funaltrexamine chemical CHEBI:81527 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258773 0.8 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser249 LSPIDMEsQERIKAE 9606 1846781 t lperfetto Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity. SIGNOR-21780 0.337 tRNA(Arg) smallmolecule CHEBI:29171 ChEBI Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270369 0.8 TGFBI protein Q15582 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates activity 10090 BTO:0004093 25786978 t lperfetto First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs. SIGNOR-253284 0.36 NCOA3 protein Q9Y6Q9 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 15808510 f gcesareni Ikkalpha in conjunction with eralpha and aib1/src-3, is important in activating the transcription of estrogen-responsive genes, including cyclin d1. SIGNOR-135056 0.488 EGFR protein P00533 UNIPROT SCAMP3 protein O14828 UNIPROT up-regulates activity phosphorylation Tyr41 QYATLDVyNPFETRE -1 9658162 t miannu In our efforts to identify cellular tyrosine kinases that phosphorylate SCAMPs, we are quite intrigued by the observation that among a number of kinases, only the EGFR exhibits activity toward SCAMPs. EGF catalyzes the progressive phosphorylation of the SCAMPs up to 1 h poststimulation and may enhance colocalization of the EGFR and SCAMP3 within the cell interior. EGF also induces SCAMP-EGFR association, as detected by coimmunoprecipitation, and phosphorylation of SCAMP3 is stimulated by the EGFR in vitro. These results suggest that phosphorylation of SCAMPs, either directly or indirectly, may be functionally linked to the internalization/down-regulation of the EGFR. we have observed that there are two tyrosines conserved in SCAMP1 and SCAMP3, which are not found in SCAMP2. Of these two tyrosines (Tyr37 and Tyr73 in SCAMP1; Tyr 41 and Tyr83 in SCAMP3), we consider Tyr37/41 to be a more likely site for tyrosine phosphorylation SIGNOR-262858 0.408 SOHLH1 protein Q5JUK2 UNIPROT ZP1 protein P60852 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 16690745 t Luana Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters. SIGNOR-266077 0.2 NCOA4 protein Q13772 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 10347167 t miannu Identification of ara70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma. / ppargamma and ara70 interact in the absence of the ppargamma ligand 15-deoxy-delta12,14-prostaglandin j2, although the addition of exogenous ligand enhances this interaction. SIGNOR-67687 0.461 2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[8-[[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetyl]amino]octyl]acetamide chemical CID:121427831 PUBCHEM BRD3 protein Q15059 UNIPROT down-regulates quantity chemical inhibition 9606 29764999 t Monia DBET6 induces efficient degradation of BET proteins and inhibits the proliferation of GBM cells SIGNOR-261096 0.8 fosinoprilat chemical CHEBI:116962 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition -1 9187274 t miannu We analyzed the inhibition of angiotensin I and AcSDKP hydrolysis as well as that of three synthetic ACE substrates by wild-type ACE and the N and C domains by using a range of specific ACE inhibitors. We demonstrate that captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, with K(i) values in the subnanomolar range. SIGNOR-258613 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR CAD protein P27708 UNIPROT down-regulates activity phosphorylation Ser1406 GAGGRRLsSFVTKGY -1 17485345 t miannu The multifunctional protein CAD initiates de novo pyrimidine biosynthesis in mammalian cells. CAD is activated by MAP kinase (Erk1/2) just prior to the S phase of the cell cycle, when the demand for pyrimidine nucleotides is greatest, and down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. MAP kinase phosphorylates Thr456, while PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation.  SIGNOR-267442 0.2 TP53 protein P04637 UNIPROT MLH1 protein P40692 UNIPROT up-regulates quantity transcriptional regulation 9606 15781865 t .... numerous potentially novel targets, including the DNA mismatch repair genes MLH1 and PMS2. Both of these genes were determined to be responsive to DNA damage and p53 activation in normal human fibroblasts, and have p53-response elements within their first intron. SIGNOR-257605 0.594 citrate(3-) smallmolecule CHEBI:16947 ChEBI PFK proteinfamily SIGNOR-PF79 SIGNOR down-regulates activity binding 9606 31751601 t miannu Once in the cytoplasm, citrate is able to inhibit phosphofructokinase 1 (PFK1) [4], the enzyme that is in charge of the “committed” step in glycolysis and converts fructose-6-phosphate to fructose-1, 6-bisphosphate (Fig. 1). In addition, citrate can inhibit PFK2, a bifunctional enzyme that regulates the rates of glycolysis and gluconeogenesis. Thus, a high level of citrate can lead to the reduction of glycolysis by directly inhibiting PFK1 and PFK2 and indirectly inhibiting PK. SIGNOR-267579 0.8 NCOA2 protein Q15596 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 24239470 t miannu The NCOA2 gene encodes a transcriptional coactivator (SRC-2) that modulates gene expression by hormone receptors, including AR. NCOA2 is both amplified and rarely mutated in prostate cancers, with higher NCOA2 levels resulting in increased androgen signaling readout. Furthermore, as mentioned previously, SRC-3, a close homolog encoded by NCOA3, is a substrate of SPOP whose protein levels are increased by SPOP mutation, potentially linking these common point mutations to the androgen axis SIGNOR-251531 0.898 RASSF1 protein Q9NS23 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 21808241 t Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage milica Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization. SIGNOR-175793 0.802 CSNK2A1 protein P68400 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates activity phosphorylation Ser422 IACDEEFsDSEDEGE 9606 BTO:0000567 12082111 t llicata HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2. SIGNOR-250887 0.61 PAX6 protein P26367 UNIPROT CTNND2 protein Q9UQB3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16973151 f Indirect:regulation of expression miannu In Pax6 mutant embryos, delta-catenin expression was severely reduced in the optic vesicle neural ectoderm, in the ventricular zone of the neocortex and in the external granule layer of the cerebellum. We identified a Pax6 binding site in delta-catenin promoter that is conserved between mice and humans and which is effectively bound by Pax6 in vitro. Our results suggest that Pax6 regulates delta-catenin expression during CNS development in mice. SIGNOR-251878 0.386 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI HNF4G protein Q14541 UNIPROT down-regulates quantity by repression 9606 9792724 f miannu Retinoic acid mediates down-regulation of the alpha-fetoprotein gene through decreased expression of hepatocyte nuclear factors. The levels of HNF1 and HNF4 mRNA were also decreased following RA treatment. SIGNOR-254444 0.8 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000567 BTO:0000562 12853467 t lperfetto These findings suggest that pkb-dependent binding of 14-3-3s to phospho-ser483 of cardiac pfk-2 mediates the stimulation of glycolysis by growth factor. SIGNOR-252464 0.643 CDK4 protein P11802 UNIPROT RUNX3 protein Q13761 UNIPROT down-regulates phosphorylation Ser356 SSSGGDRsPTRMLAS 9606 SIGNOR-C18 19351720 t llicata Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation. SIGNOR-185120 0.408 BECN1 protein Q14457 UNIPROT Vps34 Complex I complex SIGNOR-C242 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260315 0.935 SPDEF protein O95238 UNIPROT MMP9 protein P14780 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003160 22761428 f miannu Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells. SIGNOR-255218 0.368 ROBO proteinfamily SIGNOR-PF14 SIGNOR CDC25B protein P30305 UNIPROT down-regulates phosphorylation Ser323 QRLFRSPsMPCSVIR 9606 BTO:0000567;BTO:0000938 BTO:0000142 15150265 t lperfetto P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteinsphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 SIGNOR-124843 0.2 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT down-regulates activity phosphorylation Ser481 KEDGHRTsTSAVPNL -1 8810272 t miannu Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin. SIGNOR-250331 0.316 TLR9 protein Q9NR96 UNIPROT TIRAP protein P58753 UNIPROT up-regulates activity binding 10090 22664090 t scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266748 0.451 PTPN6 protein P29350 UNIPROT ZAP70 protein P43403 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 10458769 t miannu We propose that shp1 can dephosphorylate sites in zap-70 and syk that are involved in coupling these kinases to downstream signaling cascades, including erk2 and elements of the il-2 gene. SIGNOR-70237 0.57 LYN protein P07948 UNIPROT HCLS1 protein P14317 UNIPROT unknown phosphorylation Tyr222 MEAPTTAyKKTTPIE -1 10066823 t HS1 was shown to undergo a process of sequential phosphorylation both in vitro and in vivo, which is synergistically mediated by Syk and Src family protein-tyrosine kinases and essential for B cell antigen receptor-mediated apoptosis. We have now identified tyrosine 222 as the HS1 residue phosphorylated by the Src family protein kinases c-Fgr and Lyn SIGNOR-251399 0.702 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258210 0.8 GPER1 protein Q99527 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates 9606 19549922 f gcesareni Gpr30 also stimulates the pi3k pathway, elevating cellular pip3 levels, which is also predicted to activate nr5a receptors by direct binding of pip3 to the ligand binding domain . SIGNOR-186206 0.8 Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR down-regulates 9606 15623580 f lperfetto All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage. SIGNOR-273457 0.7 SP4 protein Q02446 UNIPROT CRX protein O43186 UNIPROT up-regulates activity binding 9606 15781457 t miannu Sp4 directly binds Crx. Sp4 and Sp1 produce much higher levels of transcriptional activation when co-transfected with Crx, they may additionally act by directly increasing the rate of transcriptional initiation by the general transcriptional apparatus through their activation domains. SIGNOR-225333 0.396 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f irozzo However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins. SIGNOR-255855 0.2 EZH2 protein Q15910 UNIPROT HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20565746 t miannu These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression. SIGNOR-260068 0.405 MMP2 protein P08253 UNIPROT DCN protein P07585 UNIPROT down-regulates quantity by destabilization cleavage Ser240 ISRVDAAsLKGLNNL -1 9148753 t miannu Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues. SIGNOR-256350 0.682 PPP3CB protein P16298 UNIPROT DNM2 protein P50570 UNIPROT unknown dephosphorylation Ser764 LQSASSHsPTPQRRP 10116 20496096 t CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII). SIGNOR-248363 0.254 MTA1 protein Q13330 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001211 22184117 f miannu The receptor tyrosine kinase EphA2 is a direct target gene of hypermethylated in cancer 1 (HIC1). we observe that inactivation of endogenous HIC1 through RNA interference in normal breast epithelial cells results in the up-regulation of EphA2 and is correlated with increased cellular migration. chromatin immunoprecipitation (ChIP) and sequential ChIP experiments demonstrate that endogenous HIC1 proteins are bound, together with the MTA1 corepressor, to the EphA2 promoter in WI38 cells. SIGNOR-254242 0.292 RBP2 protein P50120 UNIPROT all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI up-regulates quantity relocalization 9606 31963453 t lperfetto Either acting on the producing cell (autocrine signaling) or the receiving cell (paracrine signaling), RA is transferred into the nucleus by Cellular retinoic acid-binding protein 2 (CRABP2) [18]. Once inside the nucleus, RA binds to specific nuclear transcription factors named Retinoic acid receptors (RARs) SIGNOR-265130 0.8 TGFB1 protein P01137 UNIPROT COL4A1 protein P02462 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000764 20846954 f Regulation miannu We used diploid human lung fibroblasts (WI38 cells) induced by TGFβ to differentiate into myofibroblast-like cells. In order to characterize this system, we first studied the expression of the myofibroblast marker genes ACTA2 (coding for smooth muscle α-actin; SMA), COL4A1 (encoding collagen type IV α1) and SM22A (coding for smooth muscle protein 22-α). As shown in Figure 1A and B, TGFβ induced the expression all three genes. SIGNOR-251922 0.375 H4C1 protein P62805 UNIPROT Nucleosome complex SIGNOR-C371 SIGNOR form complex binding -1 21812398 t lperfetto The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. SIGNOR-265311 0.2 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNA12 protein Q03113 UNIPROT up-regulates binding 10090 BTO:0000944 15856019 t inferred from 70% family members milica Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. SIGNOR-269968 0.2 GNG12 protein Q9UBI6 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000586 16293724 t gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. SIGNOR-141795 0.374 SCF-betaTRCP complex SIGNOR-C5 SIGNOR BHLHE40 protein O14503 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 25202122 t miannu During unperturbed cell cycles, DEC1 is a highly unstable protein that is targeted for proteasome-dependent degradation by the SCF(βTrCP) ubiquitin ligase in cooperation with CK1. SIGNOR-276853 0.352 CERS5 protein Q8N5B7 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI up-regulates quantity chemical modification 9606 26887952 t done miannu  Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity.  SIGNOR-273996 0.8 IKBKB protein O14920 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572;BTO:0000801 SIGNOR-C14 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation SIGNOR-235400 0.92 ELAVL3 protein Q14576 UNIPROT ANK3 protein Q12955 UNIPROT down-regulates quantity post transcriptional regulation 9606 BTO:0000938 29614249 t miannu NElavl (composed of Elavl2, Elavl3, and Elavl4) proteins are the RNA-binding proteins that is specifically expressed in neurons, regulate the alternative splicing of target RNAs, and promote neuronal differentiation and maturation. Here, we found that the alternative splicing of AnkyrinG exon 34 was misregulated in the cerebella of Elavl3-/- mice. AnkyrinG is an essential factor for the formation of neuronal polarity and is required for normal neuronal functions. SIGNOR-266861 0.252 LYN protein P07948 UNIPROT CD79B protein P40259 UNIPROT up-regulates activity phosphorylation Tyr196 GMEEDHTyEGLDIDQ -1 9531288 t Y182 of CD79a appears to be the initial and preferred site of Ag receptor phosphorylation by Src family kinases. In vitro, Src family Lyn and Fyn predominantly phosphorylate this residue in CD79a, and Y195 does so in CD79b SIGNOR-251398 0.665 SRC protein P12931 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Tyr4473 VEIGNPTyKMYEGGE 9606 18381291 t lperfetto The observation that the wild type protein was phosphorylated to a higher level than the y4473f mutant again indicates that phosphorylation of the tyr4473 residue by v-src is occurring in these cellsmutation of tyr4473 to alanine, which abolishes snx17 binding, resulted in impaired receptor recycling and reduced amounts of the mature form of lrp1 on the cell surface SIGNOR-178159 0.402 PRKG1 protein Q13976 UNIPROT PPP1R17 protein O96001 UNIPROT up-regulates phosphorylation Thr119 KKPRRKDtPALHMSP 9606 BTO:0001011 10051666 t miannu Recombinant human G-substrate was phosphorylated efficiently by cGMP-dependent protein kinase exclusively at Thr residues, and it was recognized by antibodies specific for rabbit phospho-G-substrate. The amino acid sequences surrounding the sites of phosphorylation in G-substrate are related to those around Thr-34 and Thr-35 of the dopamine- and cAMP-regulated phosphoprotein DARPP-32 and inhibitor-1, respectively, two potent inhibitors of protein phosphatase 1. SIGNOR-263147 0.645 CORT protein O00230 UNIPROT SSTR4 protein P31391 UNIPROT up-regulates binding 9606 BTO:0000938 11011067 t gcesareni Cortistatin is known to bind all five cloned somatostatin receptors and share many pharmacological and functional properties with somatostatin including the depression of neuronal activity. SIGNOR-82493 0.636 DGC complex SIGNOR-C217 SIGNOR GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265439 0.2 RPS6KB1 protein P23443 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 15905173 t lperfetto Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain SIGNOR-102051 0.96 NTRK2 protein Q16620 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9507002 t gcesareni Our present study established that n-shc and sck are expressed in a region-specific manner in the brain and that n-shc is a higher affinity adapter molecule than sck for trka and trkb receptors SIGNOR-55864 0.745 SP3 protein Q02447 UNIPROT SLC9A3 protein P48764 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 16464174 f Co-transfection of Sp1 or Sp3 into SL2 cells activated the NHE3-reporter constructs, suggesting that Sp1 and Sp3 act as positive regulators of the NHE3 expression. In addition, overexpression of EGR-1 was sufficient to transactivate the NHE3-reporter gene activity SIGNOR-254271 0.2 PHC1 protein P78364 UNIPROT Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR form complex binding 9606 31608994 t miannu PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b SIGNOR-266809 0.813 PTPRA protein P18433 UNIPROT SRC protein P12931 UNIPROT up-regulates dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 BTO:0000938 7691597 t gcesareni Endogenous pp60c-src kinase activity is enhanced in the rptp alpha-transfected cells, which may be due to direct dephosphorylation of the regulatory tyr residue at position 527 in pp60c-src by rptp alpha. SIGNOR-32014 0.732 PIAS1 protein O75925 UNIPROT SATB2 protein Q9UPW6 UNIPROT down-regulates activity sumoylation Lys233 YKKYKKIkVERVERE 9606 14701874 t gianni We found that SATB2 differs from the closely related thymocyte-specific protein SATB1 by modifications of two lysines with the small ubiquitive related modifier (SUMO), which are augmented specifically by the SUMO E3 ligase PIAS1. SIGNOR-268932 0.565 CHUK protein O15111 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2407 AKVSGRPsSRKAKSP 9606 SIGNOR-C14 15494311 t Translocation from Nucleus to Cytoplasm gcesareni Nf-kappab transcription requires ikkalpha to phosphorylate smrt on chromatin, stimulating the exchange of corepressor for coactivator complexes. Ikk directly phosphorylates smrt to stimulate nuclear export. Ikkalpha orchestrates smrt derepression, a prerequisite for nf-kappab transcription and survival. SIGNOR-129956 0.426 NFATC1 protein O95644 UNIPROT MYH7 protein P12883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 17111365 f Regulation miannu Transient transfection assays demonstrated that the calcineurin/NFATc1 signaling pathway is essential for MyHCbeta promoter activation during transformation of C2C12 myotubes but is not sufficient for complete fast MyHCIId/x promoter inhibition. Along with NFATc1, myocyte enhancer factor-2D (MEF-2D) and the myogenic transcription factor MyoD transactivated the MyHCbeta promoter in calcium-ionophore-treated myotubes in a calcineurin-dependent manner. SIGNOR-251956 0.278 FGF13 protein Q92913 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253423 0.365 MECP2 protein P51608 UNIPROT GAMT protein Q14353 UNIPROT up-regulates quantity by expression post transcriptional regulation 10090 BTO:0000614 18511691 t Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. SIGNOR-264678 0.283 Cyclopamine chemical CHEBI:4021 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0001757 12202832 t gcesareni We investigate the therapeutic efficacy of the Hh pathway antagonist cyclopamine in preclinical models of medulloblastoma, the most common malignant brain tumor in children. Cyclopamine treatment of murine medulloblastoma cells blocked proliferation in vitro and induced changes in gene expression consistent with initiation of neuronal differentiation and loss of neuronal stem cell-like character. SIGNOR-174432 0.8 MAPK1 protein P28482 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 19237534 t lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309. SIGNOR-184172 0.341 OGG1 protein O15527 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 10090 26221032 f miannu Cut repeats from the CUX1 protein were recently shown to stimulate 8-oxoguanine DNA glycosylase 1 (OGG1), an enzyme that removes oxidized purines from DNA and introduces a single strand break through its apurinic/apyrimidinic lyase activity to initiate base excision repair. SIGNOR-263959 0.7 RAD51AP1 protein Q96B01 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 17996711 f miannu Homologous recombination (HR) repairs chromosome damage and is indispensable for tumor suppression in humans. RAD51 mediates the DNA strand-pairing step in HR. RAD51 associated protein 1 (RAD51AP1) is a RAD51-interacting protein whose function has remained elusive. Biochemical and cytological results show that RAD51AP1 functions at a step subsequent to the assembly of the RAD51-ssDNA nucleoprotein filament. Purified RAD51AP1 binds both dsDNA and a D loop structure and, only when able to interact with RAD51, greatly stimulates the RAD51-mediated D loop reaction. SIGNOR-261961 0.7 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation 9606 15356145 t inferred from 70% family members lperfetto Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623. SIGNOR-270000 0.2 CHUK protein O15111 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 16103118 t gcesareni Ikkalpha regulates subcellular localization and proteolysis of cyclin d1 by phosphorylation of cyclin d1 at thr286. SIGNOR-139570 0.388 CTSD protein P07339 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Ala92 DHIGFQEaYRRFYGP -1 9076588 t miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. SIGNOR-256319 0.319 1-[6-(2-hydroxypropan-2-yl)-2-pyridinyl]-6-[4-(4-methyl-1-piperazinyl)anilino]-2-prop-2-enyl-3-pyrazolo[3,4-d]pyrimidinone chemical CHEBI:91414 ChEBI WEE1 protein P30291 UNIPROT down-regulates chemical inhibition 9606 20068082 t gcesareni Mk-1775 (merck). This wee1 inhibitor (ic50, 5.2nm) potentiates the activity of dna-damaging agents (e.g., gemcitabine, cisplatin, carboplatin) in vitro and in vivo, particularly in p53-negative cancers SIGNOR-163173 0.8 HNF1B protein P35680 UNIPROT UMOD protein P07911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18846391 f miannu UMOD transcription is activated by the transcription factor HNF1B. SIGNOR-254441 0.373 CSNK2A1 protein P68400 UNIPROT BRCA1 protein P38398 UNIPROT unknown phosphorylation Ser1572 ESGISLFsDDPESDP -1 10403822 t llicata  Subsequent studies showed that BRCA1 was phosphorylated in vitro by CK2. An analysis by site directed mutagenesis of BRCA1 showed that in vitro phosphorylation by CK2 required a serine at aa1572. These data implicate CK2 as a potential mediator of BRCA1 activity. SIGNOR-250832 0.379 CSNK2A2 protein P19784 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser112 KRAGGEEsQFEMDI 9606 BTO:0000007 9806882 t lperfetto The kinase is quite distinct from casein kinase 2, which also phosphorylates Ser-111 of 4E-BP1. The possible importance of these kinases in the phosphorylation of 4E-BP1 in fat cells is discussed. It is suggested that the phosphorylation of Ser-111 might be a priming event that facilitates the subsequent phosphorylation of Thr-36, Thr-45, Ser-64 and Thr69 by a rapamycin-sensitive process that initiates the dissociation of 4E-BP1 from eIF4E and hence the formation of the eIF4F complex. SIGNOR-249334 0.339 MAPK1 protein P28482 UNIPROT ESPL1 protein Q14674 UNIPROT down-regulates phosphorylation Ser1126 IAPSTNSsPVLKTKP 9606 11747808 t lperfetto Both cdc2/cyclinb1 and mapk (erk2) efficiently phosphorylate separase at its major inhibitory site in vitro SIGNOR-113130 0.28 TUFM protein P49411 UNIPROT ATG5 protein Q9H1Y0 UNIPROT down-regulates activity binding 9606 33113344 t miannu PINK1 interacts with the autophagy effector TUFm and phosphorylates TUFm at Ser222. These results indicated that p222-hTUFm sequestered more monomer Atg5 and reduced the conjugated Atg5-Atg12 complex to subdue mitophagy. SIGNOR-266383 0.434 MAPK1 protein P28482 UNIPROT PPP1R9B protein Q96SB3 UNIPROT unknown phosphorylation Ser15 GPGGPLRsASPHRSA 9606 15728359 t lperfetto We have identified three sites phosphorylated by ERK2 (Ser-15 and Ser-205) and cyclin-dependent PK 5 (Cdk5) (Ser-17), within the actin-binding domain of spinophilin. SIGNOR-249435 0.475 KIF3A protein Q9Y496 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272538 0.7 LYN protein P07948 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity phosphorylation Tyr8 MASGDTLyIATDGSE 9606 BTO:0002181 26198631 t miannu In the case of Lyn overexpression, single mutations at either tyrosine 8, 254, or 383 severely reduced Lyn-mediated YY1 phosphorylation, suggesting that these three sites may be targets of Lyn in vivo (Fig. 3, A and B). SIGNOR-276930 0.2 ZBTB43 protein O43298 UNIPROT BDP1 protein A6H8Y1 UNIPROT unknown binding 9606 16542149 t miannu The zinc finger protein ZNF297B interacts with BDP1, a subunit of TFIIIB. Due to the essential role of BDP1 in Pol III transcription, we propose that ZNF297B may also regulate these transcriptional pathways. SIGNOR-225852 0.465 PRKCE protein Q02156 UNIPROT PRKCE protein Q02156 UNIPROT down-regulates phosphorylation Ser729 QEEFKGFsYFGEDLM 9606 11964154 t llicata Protein kinase-inactive mutants of pkcepsilon were not phosphorylated at ser(729) in cells, and phosphorylation of this site leads to dephosphorylation of the activation-loop thr(566) SIGNOR-117324 0.2 SMAD3/PIAS3 complex SIGNOR-C204 SIGNOR STAT3 protein P40763 UNIPROT down-regulates 9606 26194464 t mrosina In summary, the TGF-b/IL-6/TCR-pERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation SIGNOR-255036 0.631 MIOS protein Q9NXC5 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR form complex binding 9606 23723239 t miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 SIGNOR-255301 0.944 NEDD4L protein Q96PU5 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 t miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). SIGNOR-253464 0.287 MED8 protein Q96G25 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266659 0.793 metformin chemical CHEBI:6801 ChEBI CRTC2 protein Q53ET0 UNIPROT down-regulates 9606 20577053 f gcesareni It has been proposed that metformin stimulates crtc2 phosphorylation in response to metabolic signals such as energy stress through the lkb1-ampk/sik1 pathways, which promotes binding to 14-3-3 proteins, thereby sequestering crtc2 from the nucleus to the cytoplasm SIGNOR-166361 0.8 KMT2C protein Q8NEZ4 UNIPROT MLL3 complex complex SIGNOR-C446 SIGNOR form complex binding 9606 34156443 t miannu MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. SIGNOR-268809 0.2 PPP3CC protein P48454 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Ser198 IRTHLSQsPRVPSKC 10090 19560418 t These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 SIGNOR-248525 0.262 MAPK1 protein P28482 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by stabilization phosphorylation Thr1065 AKRPRVGtPLATEDS 9606 BTO:0001109 28945223 t miannu In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation.  SIGNOR-276744 0.2 FYN protein P06241 UNIPROT DCC protein P43146 UNIPROT up-regulates activity phosphorylation Tyr1420 TEDSANVyEQDDLSE 10090 BTO:0001909 15557120 t miannu Fyn tyrosine kinase, but not Src, regulates the phosphorylation of DCC in N1E-115 neuroblastoma cells.Both DCC phosphorylation and Netrin-1-induced axon outgrowth are impaired in Fyn(-/-) CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1. these results show that DCC is phosphorylated by Fyn, but not Src, in N1E-115 cells, and that tyrosines 1261 and 1418 are the major phosphorylation sites of Fyn in vivo. SIGNOR-268176 0.554 calcium(2+) smallmolecule CHEBI:29108 ChEBI Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 29953871 f miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. SIGNOR-264953 0.7 EGFR protein P00533 UNIPROT EPB41 protein P11171 UNIPROT down-regulates phosphorylation Tyr660 RLDGENIyIRHSNLM 9606 1647028 t lperfetto The phosphorylation site has been localized to the 8-kda domain, which has one tyrosine, tyrosine-418. The 8-kda region is required for the assembly of the spectrin/actin complex, and phosphorylation by egfr reduced the ability of protein 4.1 to promote the assembly of the spectrin/actin/protein 4.1 ternary complex SIGNOR-20452 0.409 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr237 KQEKTPKtPKGPSSV 9606 14670079 t gcesareni We further demonstrate that phospho-mkk1/mkk2 antibodies recognize npm on the c-terminal region, which is phosphorylated by cdc2 (cell division control kinase-2) during g2/m-phase. biochemical and immunocytochemistry analyses verified that the phospho-mkk1/mkk2 antibodies cross-reacted with npm that was phosphorylated at thr234 and thr237 during g2/m-phase, which are the same sites that are targeted by cdc2 (cell division cycle protein-2) during mitosis. SIGNOR-120334 0.533 RELA protein Q04206 UNIPROT IEX-1L protein O75353 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9703517 f gcesareni Transcription factors of the nuclear factor-kappab/rel (nf-kappab) family may be important in cell survival by regulating unidentified, anti-apoptotic genes. One such gene that protects cells from apoptosis induced by fas or tumor necrosis factor type alpha (tnf), iex-1l, is described here. SIGNOR-59542 0.2 PRKACA protein P17612 UNIPROT PJA2 protein O43164 UNIPROT up-regulates activity phosphorylation Thr389 RVITQREtENNQMTS -1 21423175 t miannu In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h). SIGNOR-276325 0.2 ATP7A protein Q04656 UNIPROT SOD3 protein P08294 UNIPROT up-regulates activity 10090 29301787 t lperfetto Copper transporter ATP7A (copper-transporting/ATPase) is required for full activation of SOD3 (extracellular superoxide dismutase), which is secreted from vascular smooth muscle cells (VSMCs) and anchors to endothelial cell surface to preserve endothelial function by scavenging extracellular superoxide. SIGNOR-272267 0.683 mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction SIGNOR-256064 0.7 CAMK2A protein Q9UQM7 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr574 VDNIRSAtPEALAFV 9606 BTO:0000938 BTO:0000142 12486117 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. SIGNOR-96628 0.38 TRAF7 protein Q6Q0C0 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 15001576 f miannu Overexpression of traf7 induced caspase-dependent apoptosis. SIGNOR-256666 0.7 HHIP protein Q96QV1 UNIPROT SHH protein Q15465 UNIPROT down-regulates activity binding 10090 10050855 t lperfetto Hip encodes a membrane glycoprotein that binds to all three mammalian hedgehog proteins with an affinity comparable to that of ptc-1. our findings support a model in which hip attenuates hedgehog signalling as a result of binding to hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any hedgehog signal. SIGNOR-65078 0.893 NMDA receptor_2B complex SIGNOR-C348 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30037851 t miannu NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS).  SIGNOR-264219 0.8 LCK protein P06239 UNIPROT CCDC50 protein Q8IVM0 UNIPROT down-regulates activity phosphorylation Tyr304 SSHKGFHyKH 9606 BTO:0000567 19059208 t miannu We found that Ymer was considerably phosphorylated on tyrosine residues also via Src family kinases such as Lck. A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling. SIGNOR-262855 0.2 naproxen chemical CHEBI:7476 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition -1 9057869 t miannu Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). SIGNOR-258603 0.8 CNR1 protein P21554 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity 9606 BTO:0002036 25012566 f lperfetto We subsequently analyzed whether Gαo modulates the cellular activities of Necdin. Notably, expression of Gαo significantly augmented Necdin-mediated cellular responses, such as proliferation and differentiation. Moreover, activation of type 1 cannabinoid receptor (CB1R), a Gi/oα-coupled receptor, augmented cell growth suppression, which was mediated by Gαo and Necdin in U87MG cells containing CB1R, Gαo, and Necdin as normal components. SIGNOR-253389 0.444 CSNK2A1 protein P68400 UNIPROT SSRP1 protein Q08945 UNIPROT down-regulates activity phosphorylation Ser688 KRRRSEDsEEEELAS 9606 15659405 t llicata CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity. SIGNOR-250961 0.69 PIM1 protein P11309 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 16146838 f lperfetto The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. SIGNOR-256657 0.7 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1679 NVKSKIGsTDNIKYQ -1 8631898 t miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. SIGNOR-250164 0.428 TP53 protein P04637 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 20181957 t miannu P53 directly induces the expression of Siah-1 and in turn formation of a unique SCF-like complex (SCF(TBL1)) comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin β-like 1 (TBL1), and APC SIGNOR-271953 0.381 IL6 protein P05231 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity 10116 BTO:0001103 23869758 f andrea cerquone perpetuini IL-6 induced dose-dependent increase in satellite cell proliferation by activating the JAK2/STAT3/cyclin D1 pathway.Treatment with 1 ng/ml IL-6 for 3 h significantly increased p-STAT3+/MyoD+ cell numbers by 44% compared to control media only . SIGNOR-255415 0.747 POU5F1 protein Q01860 UNIPROT DKK1 protein O94907 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254934 0.357 TTI1 protein O43156 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000007 20427287 t miannu MTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. Furthermore, using immunoprecipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. SIGNOR-272004 0.642 DLG3 protein Q92796 UNIPROT Scribble_complex_DLG3-LLGL2_variant complex SIGNOR-C504 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270885 0.495 CDC7 protein O00311 UNIPROT RAD18 protein Q9NS91 UNIPROT unknown phosphorylation Ser434 IQEVLSSsESDSCNS 9606 21098111 t llicata Although the cdc7/rad18 interaction and phosphorylation at s434 are induced by dna damage, s434 was also observed to be phosphorylated basally SIGNOR-170049 0.502 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIK1 protein P39086 UNIPROT up-regulates activity chemical activation 9606 27586965 t miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors SIGNOR-264470 0.8 IKBKE protein Q14164 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150;BTO:0000551 23691078 t lperfetto Ikbke phosphorylation and inhibition of foxo3a: a mechanism of ikbke oncogenic functionhere we report that ikbke regulates foxo3a through phosphorylation of foxo3a-ser644. The phosphorylation of foxo3a resulted in its degradation and nuclear-cytoplasmic translocation. SIGNOR-252949 0.417 IKZF1 protein Q13422 UNIPROT Lymphopoiesis phenotype SIGNOR-PH111 SIGNOR up-regulates activity 9606 BTO:0000725 25085254 f The Ikaros family of DNA binding proteins are critical regulators of lymphocyte differentiation. In multipotent hematopoietic progenitors, Ikaros supports transcriptional priming of genes promoting lymphocyte differentiation. SIGNOR-259958 0.7 FIP1L1 protein Q6UN15 UNIPROT CPSF complex complex SIGNOR-C53 SIGNOR form complex binding 9606 14749727 t miannu Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna. SIGNOR-121649 0.897 pentazocine chemical CHEBI:7982 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258934 0.8 WNT3A protein P56704 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 t gcesareni We demonstrate here that prototype canonical Wnt3a and noncanonical Wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-LRP5/6 and Ror1/2, respectively-through a common mechanism that involves their Wnt-dependent coupling to the Frizzled (Fzd) coreceptor and recruitment of shared components, including dishevelled (Dvl), axin, and glycogen synthase kinase 3 (GSK3) SIGNOR-169654 0.625 PPP1R8 protein Q12972 UNIPROT EZH2 protein Q15910 UNIPROT up-regulates activity binding 9606 phosphorylation:Thr416 EANSRCQtPIKMKPN 23241245 t Recruited NIPP1 enables the net phosphorylation of EZH2 by inhibiting its dephosphorylation by PP1. SIGNOR-255665 0.367 SMO protein Q99835 UNIPROT GATA3 protein P23771 UNIPROT up-regulates activity 17139329 t fferrentino That GATA is a downstream effector of the hedgehog pathway. SIGNOR-253527 0.2 ITGA4 protein P13612 UNIPROT A4/b7 integrin complex SIGNOR-C187 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253293 0.853 MAPK1 protein P28482 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 10737616 t lperfetto Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease. SIGNOR-249417 0.552 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120080 0.781 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 SIGNOR-C15 21205641 t gcesareni In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-170859 0.483 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM3 protein Q14832 UNIPROT up-regulates activity chemical activation 9606 25042998 t miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate SIGNOR-264075 0.8 TTK protein P33981 UNIPROT USP16 protein Q9Y5T5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr554 EVLTSSPtRNLNGAY 9606 BTO:0002181 28380042 t miannu  Usp16 is a TTK phosphorylation substrate.  SIGNOR-277351 0.378 PTPRG protein P23470 UNIPROT KIT protein P10721 UNIPROT down-regulates activity dephosphorylation Tyr730 DMKPGVSyVVPTKAD -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254710 0.2 SMARCE1 protein Q969G3 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270744 0.784 CDK2 protein P24941 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr821 KISEGLPtPTKMTPR 9606 SIGNOR-C83 9139732 t miannu We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein. SIGNOR-47895 0.88 CSNK2B protein P67870 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT down-regulates activity phosphorylation Ser575 AGESLDQsMEEEEEE 9606 BTO:0000567 12591939 t llicata We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified SIGNOR-251063 0.332 AKT proteinfamily SIGNOR-PF24 SIGNOR ZNF322 protein Q6U7Q0 UNIPROT up-regulates activity phosphorylation Ser224 EKSYRHRsAFIVHKR 9606 BTO:0002552 31399647 t miannu We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A. SIGNOR-276755 0.2 (-)-anisomycin chemical CHEBI:338412 ChEBI JUND protein P17535 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling gcesareni SIGNOR-189672 0.8 DIABLO protein Q9NR28 UNIPROT BIRC3 protein Q13489 UNIPROT down-regulates quantity binding 9606 14960576 t amattioni Smac/diablo selectively causes the rapid degradation of c-iap1 and c-iap2 in hela cells. Smac binding to c-iap via its n-terminal iap-binding motif is the prerequisite for this effect SIGNOR-121886 0.784 PER2 protein O15055 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 22260161 f apalma We have previously shown that PER2 is a downstream CCAAT-enhancer-binding protein (C/EBP)-target gene, and its disruption might be involved in the initiation and progression of acute myelogenous leukemia (AML) SIGNOR-256370 0.7 terazosin chemical CHEBI:9445 ChEBI ADRA1B protein P35368 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001260 9379432 t miannu Pharmacological management of benign prostatic hyperplasia (BPH) has most successfully been achieved by administration of α1 antagonists, which function via relaxation of prostatic smooth muscle. Terazosin2 (2), doxazosin3 (3), and alfuzosin4 (4), agents currently approved for this indication SIGNOR-258669 0.8 RNF31 protein Q96EP0 UNIPROT CASP1 protein P29466 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0005111 32122970 t miannu HOIP forms a constitutive interaction with caspase-1 and mediates the linear ubiquitination of the CARD pro-domain. Upon engagement of apoptosis, caspase-1 and caspase-8 cleave HOIP at Asp-348 and Asp-387, limiting the ability of LUBAC to ubiquitinate substrates. SIGNOR-272191 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation 9606 8816480 t inferred from 70% family members gcesareni In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1 SIGNOR-270112 0.2 PLK3 protein Q9H4B4 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser370 TSVTPDVsDNEPDHY 9606 20940307 t gcesareni Plk3 phosphorylates pten on thr-366 and ser-370. Plk3-mediated phosphorylation facilitates pten stabilization, thereby negatively regulating the pi3k/pdk1/akt1 signaling axis SIGNOR-168469 0.341 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 t lperfetto Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-217853 0.771 SRC protein P12931 UNIPROT FHIT protein P49789 UNIPROT up-regulates activity phosphorylation Tyr114 FHRNDSIyEELQKHD -1 15835917 t lperfetto The human tumor suppressor Fhit is a homodimeric histidine triad (HIT) protein of 147 amino acids which has Ap3A hydrolase activity. We have recently discovered that Fhit is phosphorylated in vivo and is phosphorylated in vitro by Src kinaseMALDI-TOF and HPLC-ESI tandem mass spectrometry of intact Fhit and proteolytic peptides of Fhit demonstrated that Fhit is phosphorylated on Y114 on either one or both subunitsThe decreases in the values of Km and kcat for the phosphorylated forms in comparison to those of unphosphorylated Fhit favor the formation and lifetime of the Fhit_Ap3A complex, which may enhance the tumor suppressor activity of Fhit. SIGNOR-247134 0.478 tamsulosin chemical CHEBI:9398 ChEBI ADRA1B protein P35368 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258470 0.8 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR DUSP1 protein P28562 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0001103 17158101 f Andrea Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis SIGNOR-255744 0.278 CTNNB1 protein P35222 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f Simone Vumbaca we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells. SIGNOR-255654 0.7 ABL2 protein P42684 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr686 IITEYCRyGDLVDYL -1 19275932 t miannu C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis.  SIGNOR-276140 0.308 KIF5C protein O60282 UNIPROT Organelle_transport phenotype SIGNOR-PH159 SIGNOR up-regulates 9606 BTO:0000938 9438838 f miannu The kinesin superfamily of proteins plays a major role in this complex organelle transport. Kinesin is primarily associated with anterogradely transported membranous organelles in nerve axons. KIF5B and HsuKHC are expressed ubiquitously in many tissues, whereas KIF5A, KIF5C, and HsnKHC are specific to nerve tissue. SIGNOR-264066 0.7 SPI1 protein P17947 UNIPROT ITGAM protein P11215 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12393465 f apalma CD11b is regulated by PU.1 and its promoter contains putative binding sites of AML1. In this case AML1-ETO interaction and down-regulation of important myeloid transcription factors like PU.1 and AML1 could explain the lower CD11b expression SIGNOR-255661 0.564 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258111 0.8 PTPRJ protein Q12913 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr1021 PNEGDNDyIIPLPDP 9606 12062403 t Primary sequence determinants responsible for site-selective dephosphorylation of the PDGF beta-receptor by the receptor-like protein tyrosine phosphatase DEP-1|DEP-1 dephosphorylation of original and chimeric phospho-peptides spanning the preferred pY1021 SIGNOR-248704 0.564 RUNX2 protein Q13950 UNIPROT COL1A2 protein P08123 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 f gcesareni In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast SIGNOR-107166 0.437 MSI2 protein Q96DH6 UNIPROT NUMB protein P49757 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001271 21084860 f miannu Msi2 was shown to be upregulated in blast crisis cml and to negatively regulate expression ofnumb. SIGNOR-169848 0.429 GPR132 protein Q9UNW8 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257275 0.2 TCF4 protein P15884 UNIPROT CNTNAP2 protein Q9UHC6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22777675 f miannu we show that TCF4 can transactivate the NRXN1β and CNTNAP2 promoters in luciferase assays. SIGNOR-255390 0.335 Caspase 1 complex complex SIGNOR-C220 SIGNOR IL1B protein P01584 UNIPROT up-regulates activity cleavage Asp27 DDLFFEAdGPKQMKC -1 1919001 t lperfetto IL-1 converting enzyme (ICE) specifically cleaves the human IL-1 beta precursor at two sequence-related sites: Asp27-Gly28 (site 1) and Asp116-Ala117 (site 2). Cleavage at Asp116-Ala117 results in the generation of mature, biologically active IL-1 beta.  SIGNOR-256375 0.795 AURKB protein Q96GD4 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates activity phosphorylation Ser960 SRLSPPHsPRDFTRM 9606 BTO:0000567 17488622 t miannu The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity. SIGNOR-276062 0.252 SRC protein P12931 UNIPROT CNKSR1 protein Q969H4 UNIPROT up-regulates activity phosphorylation Tyr665 KEQNRELySEGLGAW 26319181 t lperfetto We identified Tyr 26 as a PDGF-induced and, additionally, Tyr 519 and Tyr 665 as SRC-induced tyrosine phosphorylation sites. Phosphomimetic mutants indicate that phosphorylation of Tyr 519 recruits CNK1 to the nucleus and additional phosphorylation of Tyr 26 enables CNK1 to promote SRE-dependent gene expression. SIGNOR-275920 0.485 MTNR1B protein P49286 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256850 0.428 Gbeta proteinfamily SIGNOR-PF4 SIGNOR UBTF protein P17480 UNIPROT down-regulates phosphorylation 9606 11741541 t inferred from 70% family members lperfetto Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna SIGNOR-270080 0.2 POMC protein P01189 UNIPROT MC4R protein P32245 UNIPROT up-regulates activity binding 9606 20694162 t miannu α-MSH can activate both melanocortin 4 receptors (MC4R) and melanocortin 1 receptors (MC1R) SIGNOR-252373 0.77 PRKG1 protein Q13976 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization SIGNOR-186788 0.277 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269374 0.719 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI CEBPA protein P49715 UNIPROT up-regulates 9606 11279134 f fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin SIGNOR-209992 0.8 AMPK complex SIGNOR-C15 SIGNOR TSC1 protein Q92574 UNIPROT up-regulates phosphorylation 9606 19584320 t lperfetto Under energy starvation conditions, the amp-activated protein kinase (ampk) phosphorylates tsc2 and enhances its activity. SIGNOR-216487 0.411 PRKCZ protein Q05513 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates activity phosphorylation Thr305 TDAATMKtFCGTPEY 9606 BTO:0000007 9512493 t lperfetto The activation of PKBbeta and PKBgamma by PDK1 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma). PKBgamma which had been activated by PDK1 possessed a substrate specificity identical with that of PKBalpha and PKBbeta towards a range of peptides. The activation of PKBgamma and its phosphorylation at Thr305 was triggered by insulin-like growth factor-1 in 293 cells. SIGNOR-248996 0.53 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity phosphorylation Tyr934 PAHASDEiYEIMQKC 9606 19275932 t Manara C-Abl phosphorylates three tyrosine residues on PDGFR-β (Y686, Y934, Y970) | These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis. SIGNOR-260931 0.507 CUL3 protein Q13618 UNIPROT ARIH1 protein Q9Y4X5 UNIPROT up-regulates activity binding 9606 BTO:0000007 24076655 t miannu Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin. SIGNOR-268846 0.319 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules SIGNOR-251601 0.695 SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates transcriptional regulation 10090 BTO:0000165 11073979 f ggiuliani As shown in Fig. 8A, overexpression of Smad5 by itself induced Runx2 expression even in the absence of BMP-2 (lane 5). Western blot analysis also confirmed the induced level of Runx2 protein in C2C12-Sm5 cells (Fig. 8B) SIGNOR-255783 0.582 CNR1 protein P21554 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257346 0.252 PAK1 protein Q13153 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 12876277 t lperfetto We find that adhesion to fibronectin induces pak1-dependent phosphorylation of mek1 on s298 and that this phosphorylation is necessary for efficient activation of mek1 and subsequent mapk activation. SIGNOR-244924 0.564 FOXO4 protein P98177 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 f lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-236557 0.345 PHKA1 protein P46020 UNIPROT PHKA1 protein P46020 UNIPROT up-regulates activity phosphorylation Ser985 SNVSPAIsIHEIGAV -1 10487978 t miannu Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation) SIGNOR-250282 0.2 NFASC protein O94856 UNIPROT ANK3 protein Q12955 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 t miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. SIGNOR-266717 0.735 Non-structural protein 10 protein P0C6X7-PRO_0000037317 UNIPROT MT-CO2 protein P00403 UNIPROT down-regulates activity binding 9606 16157265 t lperfetto This result suggests that the nsp10 protein could affect the activities of NADH and cytochrome oxidase II via a direct interaction while being involved in viral replication. SIGNOR-260254 0.2 LPAR2 protein Q9HBW0 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257257 0.252 AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244160 0.2 SMARCB1 protein Q12824 UNIPROT Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270755 0.833 RELA protein Q04206 UNIPROT PCK2 protein Q16822 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000759 20137375 f miannu NF-kappaB p65 was shown to inhibit transcription of phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiting enzyme in gluconeogenesis in the liver SIGNOR-255072 0.269 E2F1 protein Q01094 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 9606 23213415 t gcesareni Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes SIGNOR-199952 0.638 ITGB4 protein P16144 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257720 0.57 CDK1 protein P06493 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser154 AKPEPSPsPRITRKS 9606 21565170 t gcesareni We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5 SIGNOR-173677 0.304 PPP2CB protein P62714 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates dephosphorylation Thr216 RSSSSEStGTPSNPD 9606 11983168 t fstefani Cyclin g also binds in vivo and in vitro to mdm2 and markedly stimulates the ability of pp2a to dephosphorylate mdm2 at t216. Our data imply that the function of cyclin g is to serve as a negative regulator of p53 by activating mdm2 through dephosphorylation. SIGNOR-86736 0.374 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001938 10913154 t lperfetto Cyclin B-Cdc2 complexes are maintained in an inactive state until the end of G2 by phosphorylation of the Thr14/Tyr15 residues. Around the time of nuclear translocation of the complex, these residues are dephosphorylated, resulting in the formation of an active cyclin B-Cdc2 complex (2). As mentioned, this dephosphorylation occurs by a Cdc25 protein phosphatase. Three Cdc25 family members have been identified to date, A, B and C, the last one being the active one at the onset of mitosis. The activity of Cdc25C itself can be enhanced through phosphorylation by cyclin B-Cdc2 (9, 10). Therefore, activation of cyclin B-Cdc2 has been proposed to result in an autocatalytic feedback loop to ensure rapid activation of these complexes at the G2/M transition SIGNOR-251510 0.839 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR NOS2 protein P35228 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 f apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255353 0.447 carbachol chemical CHEBI:3385 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258620 0.8 CDK11A protein Q9UQ88 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Ser174 TPAVPPVsEDEDDDD 19520772 t lperfetto CDK11p58 phosphorylation of PAK1 Ser174 promotes DLC2 binding and roles on cell cycle progression|We show that PAK1 is a substrate of CDK11p58 and can be strongly activated upon phosphorylation. SIGNOR-273026 0.392 ATP smallmolecule CHEBI:15422 ChEBI PRKAG1 protein P54619 UNIPROT down-regulates chemical inhibition 9606 SIGNOR-C15 21399626 t gcesareni Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive SIGNOR-172822 0.8 ATM protein Q13315 UNIPROT WRAP53 protein Q9BUR4 UNIPROT up-regulates activity phosphorylation Ser64 PVAGSAVsQELREGD 9606 BTO:0001938 27715493 t done miannu Here, we show that in response to various types of DNA damage, including IR and UV, WRAP53β is phosphorylated on serine residue 64 by ATM with a time-course that parallels its accumulation at DNA lesions. Interestingly, recruitment of phosphorylated WRAP53β (pWRAP53βS64) to sites of such DNA damage promotes its interaction with γH2AX at these locations.  SIGNOR-273511 0.344 PAX7-FOXO1 fusion protein SIGNOR-FP11 SIGNOR PDGFA protein P04085 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 t miannu Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA. SIGNOR-251567 0.2 P2RY11 protein Q96G91 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257386 0.358 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 12586835 t gcesareni The activation of p70s6k is associated with multiple phosphorylations at two sets of sites. The first set, s411, s418, t421, and s424, reside within the autoinhibitory domain, mutations of s371 abolished kinase activity. In mitotic hela cells, when the activity of cdc2 is high, s6k1 is phosphorylated at multiple ser/thr, pro (s/tp) sites, including ser(371), ser(411), thr(421), and ser(424). SIGNOR-98215 0.392 SLBP protein Q14493 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265417 0.2 D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI IDH1 protein O75874 UNIPROT up-regulates activity chemical activation 9606 32943735 t Wild-type IDH1 and IDH2 catalyze the reaction by converting isocitrate and NADP+ into α-KG and CO2 with the concomitant generation of NADPH in the cytosol and mitochondrial matrix SIGNOR-267369 0.8 AURKA protein O14965 UNIPROT MBD3 protein O95983 UNIPROT up-regulates phosphorylation Ser85 RQRVRYDsSNQVKGK 9606 BTO:0000567 12354758 t llicata These results suggest that the biochemical changes of mbd3 may be intimately related to the targeting of mbd3 to centrosomes. aurora-a phosphorylates mbd3 SIGNOR-93697 0.29 TLN1 protein Q9Y490 UNIPROT ITGB4 protein P16144 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257627 0.484 pazopanib hydrochloride chemical CHEBI:71217 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 17620431 t miannu The present study describes an orally bioavailable, ATP-competitive, multitargeted kinase inhibitor, pazopanib (GW786034), and the drug concentration requirement for maximal in vivo activity. Pazopanib is a low nanomolar inhibitor of VEGFR, PDGFR, and c-Kit tyrosine kinases. Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. SIGNOR-259168 0.8 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT down-regulates phosphorylation Tyr981 LPLDKDYyVVREPGQ 9606 9391116 t gcesareni We found that jak3 is autophosphorylated on multiple sites including y980 and y981. Compared with the activity of wild-type (wt) jak3, mutant y980f demonstrated markedly decreased kinase activity, and optimal phosphorylation of jak3 on other sites was dependent on y980 phosphorylation. The mutant y980f also exhibited reduced phosphorylation of its substrates, gammac and stat5a. In contrast, mutant y981f had greatly increased kinase activity, whereas the double mutant, yy980/981ff, had intermediate activity. SIGNOR-53594 0.2 PRKD3 protein O94806 UNIPROT GIT1 protein Q9Y2X7 UNIPROT unknown phosphorylation Ser46 RSLGRHIsIVKHLRH 9606 22893698 t lperfetto We propose that phosphorylation of git1 on serine 46 by pkd3 represents a molecular switch by which git1 localization, paxillin trafficking, and cellular protrusive activity are regulated. SIGNOR-191839 0.368 TP53 protein P04637 UNIPROT PMAIP1 protein Q13794 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14500851 f gcesareni P53 has the ability to activate transcription of various proapoptotic genes, including those encoding members of the bcl-2 family, such as the bh-3 only proteins bax, noxa, and puma pmaip1 may thus represent a mediator of tp53-dependent apoptosis. SIGNOR-118048 0.69 CKM complex complex SIGNOR-C406 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation -1 25344755 t lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues SIGNOR-273159 0.378 Laminin-5 complex SIGNOR-C184 SIGNOR A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates activity binding 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253219 0.528 ARHGEF9 protein O43307 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260534 0.828 PTPN13 protein Q12923 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation 9606 19307596 t miannu Mechanistically, RIL suppresses Src activation through interacting with Src and PTPL1, allowing PTPL1 dependent dephosphorylation of Src at the activation loop.|Our results reveal a novel Src inactivation cycle in which reversion-induced LIM preferentially recognizes active Src and facilitates PTPL1-mediated inactivation of Src. SIGNOR-277125 0.521 STUB1 protein Q9UNE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 14701756 t gcesareni These results suggest that chip can interact with the smad1/smad4 proteins and block bmp signal transduction through the ubiquitin-mediated degradation of smad proteins. SIGNOR-120731 0.334 LRSAM1 protein Q6UWE0 UNIPROT TSG101 protein Q99816 UNIPROT down-regulates quantity monoubiquitination 9606 BTO:0000007 15256501 t miannu Tal increases ubiquitylation of Tsg101 and affects its solubility in a RING- and PTAP-dependent manner.  Tal-mediated ubiquitylation of Tsg101 inactivates this sorting function and concomitantly translocates Tsg101 from relatively insoluble membrane subdomains. Presumably, the coordinated action of Tal and a deubiquitylation enzyme (DUB) enables recycling of Tsg101 and reloading of cargo. SIGNOR-271509 0.542 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192895 0.8 ITCH protein Q96J02 UNIPROT BCL10 protein O95999 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000661 15082780 t miannu The HECT domain ubiquitin ligases NEDD4 and Itch promote ubiquitination and degradation of Bcl10, thus downmodulating NF-kappa B activation.  SIGNOR-271414 0.28 CDK1 protein P06493 UNIPROT UBA1 protein P22314 UNIPROT up-regulates phosphorylation Ser4 sPLSKKRR 9606 9099746 t lperfetto Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Each serine residue was independently mutated to an alanine and analyzed by two-dimensional electrophoresis;only serine 4 was phosphorylated. Disruption of the basic amino acids within the nls resulted in loss of exclusive nuclear localization and a 90-95% decrease in the phosphorylation of ha1-e1 SIGNOR-47162 0.414 GTF2H1 protein P32780 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 t lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269316 0.902 CHAMP1 protein Q96JM3 UNIPROT MAD2L2 protein Q9UI95 UNIPROT up-regulates activity binding 9606 21063390 t miannu Here, we report a novel regulator for accurate chromosome segregation, chromosome alignment-maintaining phosphoprotein (CAMP). We identified CAMP as a MAD2L2-interacting protein. Spindle localization of MAD2L2 was abrogated by CAMP depletion (Supplementary Figure S2A) SIGNOR-264904 0.511 raloxifene chemical CHEBI:8772 ChEBI ESR1 protein P03372 UNIPROT down-regulates activity chemical inhibition -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258582 0.8 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 11279134 f lperfetto The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin SIGNOR-250561 0.401 EIF2B2 protein P49770 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269125 0.794 GNB3 protein P16520 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 14668344 t gcesareni Expression of the g__ sequestrant, _-transducin, inhibits both ras activation and membrane translocation of _-arrestin1, suggesting that g__ dimers from g_i2 and g_q activate different effectors to coordinately regulate the pi 3-kinase/akt pathway. , these data indicate that _-thrombin stimulates rapid pi 3-kinase activity and akt phosphorylation by the g__ dimers released from a ptx-sensitive g protein. SIGNOR-120264 0.374 RFX complex complex SIGNOR-C104 SIGNOR HLA-DMA protein P28067 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 f The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-253993 0.333 DDHD2 protein O94830 UNIPROT long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity chemical modification 9606 22922100 t miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. SIGNOR-269652 0.8 Erythrocytic spectrin complex SIGNOR-C384 SIGNOR Cell_shape phenotype SIGNOR-PH182 SIGNOR up-regulates 9606 24302288 f lperfetto Spectrin is multifunctional, and spectrin-based networks are important for maintaining the shape and mechanical properties of erythrocytes. SIGNOR-266032 0.7 COX5B protein P10606 UNIPROT Oxidative_phosphorylation phenotype SIGNOR-PH78 SIGNOR up-regulates 10090 23021218 f lperfetto PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). SIGNOR-253102 0.7 ABCA7 protein Q8IZY2 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 9606 27472885 f miannu Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-β in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD. SIGNOR-265175 0.7 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity dephosphorylation 9606 20208177 t Pyruvate dehydrogenase phosphatase (PDP) is a mitochondrial serine phosphatase that activates phosphorylated pyruvate dehydrogenase complex by dephosphorylation SIGNOR-251664 0.722 PRKDC protein P78527 UNIPROT JUN protein P05412 UNIPROT unknown phosphorylation Ser249 LSPIDMEsQERIKAE -1 8464713 t lperfetto Here, we show that the DNA-PK modifies c-Jun in vitro and that serine residue 249 (Ser-249) is required for phosphorylation to occur. This residue corresponds to one of three sites of c-Jun that are phosphorylated in vivo and which negatively regulate c-Jun DNA binding in vitro. However, we find that phosphorylation of c-Jun by the DNA-PK does not interfere with DNA binding, indicating that phosphorylation at other sites is required for this effect. SIGNOR-248934 0.416 MRPS25 protein P82663 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261448 0.693 monoisononyl phthalate chemical CHEBI:132593 ChEBI OXER1 protein Q8TDS5 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. SIGNOR-268778 0.8 NUMA1 protein Q14980 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates binding 9606 11956313 t Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-256541 0.2 PEX6 protein Q13608 UNIPROT PEX1 protein O43933 UNIPROT up-regulates activity binding 10029 12717447 t Pex26 recruits Pex6–Pex1 complexes to peroxisomes. Pex26 anchors Pex6 and Pex1 through Pex26–Pex6 and Pex6–Pex1 interactions. SIGNOR-253615 0.655 WNT6 protein Q9Y6F9 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 9606 21872687 f fspada We show that knockdown of Beta-catenin completely prevents the inhibition of adipogenesis and stimulation of osteoblast differentiation by wnt6, wnt10a or wnt10b SIGNOR-176193 0.474 FHIT protein P49789 UNIPROT AKT2 protein P31751 UNIPROT down-regulates 9606 BTO:0000551 16407838 f miannu Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis SIGNOR-143703 0.252 risperidone chemical CHEBI:8871 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258525 0.8 LTB4R protein Q15722 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257086 0.41 GAPDH protein P04406 UNIPROT 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI up-regulates quantity chemical modification 9606 11724794 t miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion SIGNOR-266494 0.8 CSNK2A1 protein P68400 UNIPROT NKX2-5 protein P52952 UNIPROT up-regulates activity phosphorylation Ser164 FKQQRYLsAPERDQL 9534 BTO:0004055 9858576 t llicata Mutational analysis and in vitro kinase assays suggested that this 40-kDa Csx/Nkx2.5 kinase is a catalytic subunit of casein kinase II (CKII) that phosphorylates the serine residue between the first and second helix of the homeodomain. This CKII site is phosphorylated in vivo. CKII-dependent phosphorylation of the homeodomain increased Csx/Nkx2. 5 DNA binding. Serine-to-alanine mutation at the CKII phosphorylation site reduced transcriptional activity when the carboxyl-terminal repressor domain was deleted. SIGNOR-250924 0.338 SLBP protein Q14493 UNIPROT H2AJ protein Q9BTM1 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265412 0.2 leukotriene A4(1-) smallmolecule CHEBI:57463 ChEBI leukotriene C4(2-) smallmolecule CHEBI:57973 ChEBI up-regulates quantity precursor of 9606 27365393 t miannu Leukotriene C4 synthase (LTC4S) catalyzes the formation of the proinflammatory lipid mediator leukotriene C4 (LTC4). SIGNOR-277260 0.8 AP1 complex SIGNOR-C154 SIGNOR CCL2 protein P13500 UNIPROT up-regulates activity transcriptional regulation 9606 21561061 t Luana 3b Potentiates AP-1-Dependent MCP-1 Promoter Activity SIGNOR-260764 0.6 CAMK2A protein Q9UQM7 UNIPROT CD44 protein P16070 UNIPROT up-regulates activity phosphorylation Ser706 LNGEASKsQEMVHLV 9606 BTO:0000452 11463356 t lperfetto In previous studies we have demonstrated that a key control point for this receptor is the phosphorylation of CD44 on a conserved cytoplasmic serine residue, Ser(325). This modification is not required for efficient ligand binding, but is an essential component of CD44-dependent cell migration on a hyaluronan substratum. We demonstrate here that cd44 is phosphorylated to high stoichiometry in resting cells and that ca(2+)/calmodulin-dependent protein kinase ii is a cd44 ser(325) kinase. SIGNOR-109502 0.2 5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine chemical CID:11617559 PUBCHEM CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259743 0.8 KAT6A protein Q92794 UNIPROT TP53 protein P04637 UNIPROT up-regulates acetylation Lys382 QSTSRHKkLMFKTEG 9606 BTO:0001271 SIGNOR-C54 23431171 t miannu We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression SIGNOR-201486 0.656 PKNOX1 protein P55347 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 20864515 f miannu Prep1 overexpression in HepG2 liver cells upregulated SYP and SHP1 and inhibited insulin-induced IR and IRS1/2 phosphorylation and was accompanied by reduced glycogen content. SIGNOR-254924 0.2 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser465 HNPISSVs 9606 9136927 t lperfetto Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro SIGNOR-249648 0.651 FANCD2 protein Q9BXW9 UNIPROT BRCA2 protein P51587 UNIPROT up-regulates activity binding 9606 BTO:0005035 phosphorylation:Ser331 KSKGRASsSGNQESS 19861535 t lperfetto Fanconi anemia complementation group FANCD2 protein serine 331 phosphorylation is important for fanconi anemia pathway function and BRCA2 interaction SIGNOR-263238 0.805 ANGPTL1 protein O95841 UNIPROT TEK protein Q02763 UNIPROT up-regulates binding 9606 15284220 t gcesareni In experiments with human endothelial cell lines, ang3 was identified as an antagonist of tie2 and ang4 was identified as an agonist of tie2. SIGNOR-127354 0.52 PTK2 protein Q05397 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 9566877 t Luana  In vitro, FAK directly phosphorylated Shc Tyr-317 to promote Grb2 binding. FAK can associate and directly phosphorylate Shc at Tyr-317 to promote Grb2 binding and low-level signaling to ERK2. SIGNOR-259854 0.661 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE 9606 10377430 t lperfetto Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus. SIGNOR-252872 0.756 AMPK complex SIGNOR-C15 SIGNOR FOXO4 protein P98177 UNIPROT up-regulates phosphorylation 9606 17900900 t lperfetto The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation SIGNOR-216484 0.336 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser37 EDLTDELsLNKISAD -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276207 0.2 MSN protein P26038 UNIPROT MSN/PDZD8 complex SIGNOR-C61 SIGNOR form complex binding 9606 21549406 t miannu These results demonstrated that both human moesin and its newly identified binding partner, pdzd8 had similar effects on host mt networks, suggesting that they are likely to function as part of a stable mt regulatory complex. SIGNOR-173647 0.323 MAPK10 protein P53779 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 15071501 f gcesareni Demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria; these results strongly indicate that jnk regulates the activity of bax by phosphorylating 14-3-3 proteins. SIGNOR-124001 0.262 WWC1 protein Q8IX03 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity 9606 BTO:0000007 20159598 f Hippo pathway Gianni These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis. SIGNOR-261954 0.454 TRIM23 protein P36406 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity ubiquitination 9606 BTO:0003682 19176615 t miannu We show here that the upregulation of NF-kappaB by UL144 is dependent upon cellular tripartite motif 23 (TRIM23) protein. We propose a mechanism by which UL144 activates NF-kappaB through a direct interaction with the cellular protein TRIM23 in a complex containing TRAF6. we propose that TRIM23 mediates TRAF6 autoubiquitination in the presence of UL144, resulting in the virally controlled activation of NF-κB stimulation at early times of HCMV infection. SIGNOR-266655 0.318 RPS6KA4 protein O75676 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 10090 12773393 t lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 SIGNOR-265355 0.2 RPS6KB1 protein P23443 UNIPROT PIP5K1C protein O60331 UNIPROT down-regulates quantity by destabilization phosphorylation Ser555 RYRRRTQsSGQDGRP 27780861 t miannu Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIγ90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIγ90 phosphorylation is essential for cell migration and invasion. These data suggest that S6K1-mediated PIPKIγ90 phosphorylation regulates cell migration and invasion by controlling PIPKIγ90 degradation. SIGNOR-277283 0.2 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates activity phosphorylation Tyr502 TTANVVYyVGENVVN 9606 12637538 t lperfetto Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr(432), Tyr(463), and Tyr(502)), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr(463)) leads to PKD activation. SIGNOR-247328 0.42 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Ser3205 TPLPEDNsMNVDQDG 9606 BTO:0000773 12186630 t lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. SIGNOR-249157 0.2 WWP1 protein Q9H0M0 UNIPROT TP73 protein O15350 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25071155 t miannu WWP1 in complex with WWP2 specifically regulates ΔNp73.  In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73.  SIGNOR-272232 0.287 AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 22798428 t gcesareni Akt negatively regulates the raf and gsk-3 kinases and the cell cycle regulatory transcription factor fkhr. SIGNOR-252531 0.688 SIRT7 protein Q9NRC8 UNIPROT RAN protein P62826 UNIPROT down-regulates activity deacetylation Lys37 HLTGEFEkKYVATLG 31075303 t Ran ID inferred from sequence: KRHLTGEFEKKYVATLGVEV lperfetto N this study, we demonstrated that SIRT7 interacts with a small GTPase, Ras-related nuclear antigen (Ran), and deacetylates Ran at K37. |The nuclear export by CRM1 requires an interaction with the small GTPase Ras-related nuclear antigen (Ran), which cycles between GTP- and GDP-bound states. The binding of Ran GTP to CRM1 in the nucleus increases the affinity of CRM1 for cargo proteins [[18], [19], [20]]. Interestingly, Ran is a lysine-acetylated protein SIGNOR-275849 0.2 PF-03814735 chemical CID:49830590 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205950 0.8 CSNK1A1 protein P48729 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates activity phosphorylation Thr232 LTLWTSDtQGDEAEA 9606 BTO:0000007 9360956 t llicata This protein kinase has been identified as casein kinase Ialpha (CKIalpha) by peptide mapping analysis and sequencing. Among mammalian 14-3-3, only 14-3-3 tau possesses a phosphorylatable residue at the same position (Ser-233), and we show that this residue is also phosphorylated by CKI. In addition, we show that 14-3-3 zeta is exclusively phosphorylated on Thr-233 in human embryonic kidney 293 cells. The residue 233 is located within a region shown to be important for the association of 14-3-3 to target proteins. | We have now shown that in vivo phosphorylation of 14-3-3 zeta at the CKIalpha site (Thr-233) negatively regulates its binding to c-Raf, and may be important in Raf-mediated signal transduction. SIGNOR-250796 0.561 EGFR protein P00533 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr354 LMLRLQDyEEKTKKA 9606 BTO:0000017 15647376 t lperfetto Ezrin was initially identified as a substrate for tyrosine phosphorylation by egfr (bretscher, 1989) and phosphorylation of residues y145 and y353 were detected to high stoichiometry after egf treatment . Phosphorylation of ezrin at y353 has been delineated to signal survival during epithelial cell differentiation via the phosphatidylinositol 3-kinase (pi3k)/akt pathway. SIGNOR-133215 0.545 MEF2A protein Q02078 UNIPROT MYH10 protein P35580 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 t lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation SIGNOR-238763 0.322 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267529 0.8 SOX6 protein P35712 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26893351 t We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST SIGNOR-255824 0.296 PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 f lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-256229 0.7 TP53INP1 protein Q96A56 UNIPROT GABARAP protein O95166 UNIPROT up-regulates binding 9606 22421968 t gcesareni Tp53inp1 is also able to interact with atg8-family proteins SIGNOR-196664 0.351 ADAMTS4 protein O75173 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage Glu392 PRNITEGeARGSVIL 9606 9202061 t lperfetto Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE373 SIGNOR-266984 0.758 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t gcesareni Ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase. SIGNOR-76096 0.309 nitrendipine chemical CHEBI:7582 ChEBI KCNN4 protein O15554 UNIPROT down-regulates activity chemical inhibition 9606 9730970 t miannu IK was blocked by the classical inhibitors of the Gardos channel charybdotoxin (IC50 28 nM) and clotrimazole (IC50 153 nM) as well as by nitrendipine (IC50 27 nM), Stichodactyla toxin (IC50 291 nM), margatoxin (IC50 459 nM), miconazole (IC50 785 nM), econazole (IC50 2.4 microM), and cetiedil (IC50 79 microM). Finally, 1-ethyl-2-benzimidazolinone, an opener of the T84 cell IK channel, activated hIK with an EC50 of 74 microM. SIGNOR-258831 0.8 CDK1 protein P06493 UNIPROT RAB1A protein P62820 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000567 1902553 t Giulio We now present biochemical evidence for a mitosis-specific p34cdc2 phosphorylation of RablAp and Rab4p.We also show that the distribution of RablAp and Rab4p between cytosolic and membrane-bound forms is different in interphase and mitotic cells. SIGNOR-261284 0.506 EGFR protein P00533 UNIPROT ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR up-regulates binding 9606 11279155 t inferred from 70% of family members gcesareni These results demonstrate that egfr-erbb2 oligomers are potent activators of mapk and akt, and this signaling does not require egfr kinase activity SIGNOR-269876 0.657 TBR1 protein Q16650 UNIPROT AUTS2 protein Q8WXX7 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 20615956 t miannu Tbr1 implements frontal identity in part by direct promoter binding and activation of Auts2, a frontal cortex gene implicated in autism. SIGNOR-266836 0.366 CFH protein P08603 UNIPROT CRP protein P02741 UNIPROT down-regulates activity binding 9606 BTO:0004910 26961257 t miannu In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the “risk” His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained. SIGNOR-252145 0.567 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1542 EEQQLEEsGPHDLTE 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm SIGNOR-72072 0.813 TSC1 protein Q92574 UNIPROT RHEB protein Q15382 UNIPROT down-regulates activity binding 9606 20006481 t lperfetto Tsc1 and tsc2 proteins, which together inhibit rheb through the gap activity of tsc2. SIGNOR-162096 0.909 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser396 NTVDLHIsNSHPLSL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178399 0.816 TAP1 protein Q03518 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI down-regulates quantity relocalization 9606 31810556 t scontino Following cytosolic proteolysis, antigenic peptides are recruited to the ER and translocated to its lumen by the Transporter associated with Antigen Processing (TAP). SIGNOR-267778 0.8 A4/b1 integrin complex SIGNOR-C162 SIGNOR JAG1 protein P78504 UNIPROT up-regulates quantity by expression 10090 25786978 f lperfetto First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs. SIGNOR-253287 0.307 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 18372406 t gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-178141 0.692 PLK1 protein P53350 UNIPROT WDCP protein Q9H6R7 UNIPROT up-regulates activity phosphorylation Ser686 RSDVFRDsFSHSPGA 9606 BTO:0000007 30297404 t miannu PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11. we performed in vitro kinase assays followed by mass spectrometry and found that two sites (S686 and S695) in this cluster were phosphorylated. Thus, all of these results are in agreement that this cluster is phosphorylated by PLK1. SIGNOR-273730 0.2 ARHGAP4 protein P98171 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260460 0.457 TERF1 protein P54274 UNIPROT Shelterin complex complex SIGNOR-C306 SIGNOR form complex binding 9606 15383534 t lperfetto Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins. SIGNOR-263316 0.744 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 10090 BTO:0000944 11579209 t lperfetto Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor. SIGNOR-235499 0.78 AKT1 protein P31749 UNIPROT TENT2 protein Q6PIY7 UNIPROT down-regulates activity phosphorylation Ser116 LSGERRYsMPPLFHT 9606 BTO:0000007 31057087 t miannu We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. SIGNOR-259405 0.2 CSNK2A1 protein P68400 UNIPROT CERS6 protein Q6ZMG9 UNIPROT up-regulates activity phosphorylation Ser346 DRSDIESsSDEEDSE 9606 BTO:0000007 26887952 t miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  SIGNOR-273992 0.2 CRX protein O43186 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation -1 18849347 f miannu Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity. SIGNOR-253815 0.376 RRAGC protein Q9HB90 UNIPROT RAGBC complex SIGNOR-C115 SIGNOR form complex binding 9606 20381137 t gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant SIGNOR-228173 0.784 SIRT7 protein Q9NRC8 UNIPROT H3-2 protein Q5TEC6 UNIPROT up-regulates activity deacetylation Lys37 APATGGVkKPHRYRP 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275877 0.2 ULK1 protein O75385 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni Here we report that ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. Thus, we propose that ulk1 is not only involved in the induction of autophagy, but also in terminating signaling events that trigger autophagy. In our model, phosphorylation of ampk by ulk1 represents a negative feedback circuit. SIGNOR-173050 0.483 RABGEF1 protein Q9UJ41 UNIPROT RAB5A protein P20339 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 27411398 t lperfetto AP-1/sigma1A-ArfGAP1-Rabex-5 complex formation leads to more endosomal Rabex-5 and enhanced, Rab5GTP-stimulated Vps34 PI3-kinase activity, which is essential for multivesicular body endosome formation. SIGNOR-260707 0.921 zolmitriptan chemical CHEBI:10124 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 10193663 t Luana This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues  SIGNOR-258341 0.8 NFATC2 protein Q13469 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates binding 9606 11796223 t lperfetto Upon dephosphorylation by calcineurin, nfatc2, also referred to as nfatp/nfat1, translocates to the nucleus where it directly associates with mef2a and -d. Nfatc2 stimulates mef2-dependent transcription by facilitating recruitment of the p300 coactivator to mef2-response elements. SIGNOR-117589 0.565 CUL1 protein Q13616 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR form complex binding 9606 10023660 t gcesareni The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin. SIGNOR-64502 0.884 CAMK2A protein Q9UQM7 UNIPROT ID1 protein P41134 UNIPROT up-regulates activity phosphorylation Ser36 GEVVRCLsEQSVAIS 9606 BTO:0001620 29079782 t miannu Here we show that CaMKII can directly phosphorylate Beclin 1 at Ser90 to promote K63-linked ubiquitination of Beclin 1 and activation of autophagy. SIGNOR-277367 0.2 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser32 LLDDRHDsGLDSMKD 10398585 t lperfetto Serine 32 and serine 36 of IkappaBalpha are directly phosphorylated by protein kinase CKII in vitro|Phosphorylation of IkappaBalpha at serine 32 (S32) and serine 36 (S36) is necessary for this stimuli-induced degradation SIGNOR-249332 0.567 TNFRSF1B protein P20333 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 17151142 f [...] TNF-alpha is critical for p38 activation during the early stages of myoblast differentiation SIGNOR-253601 0.305 eribulin mesylate chemical CHEBI:70710 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates activity chemical inhibition 9606 16940412 t miannu The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin. SIGNOR-259444 0.8 TUBGCP6 protein Q96RT7 UNIPROT g-TuRC complex complex SIGNOR-C282 SIGNOR form complex binding -1 31862189 t lperfetto Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.” SIGNOR-262330 0.776 TSC22D3 protein Q99576 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 BTO:0000007 11468175 t GILZ inhibits NF-kappaB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-kappaB subunits. SIGNOR-253299 0.365 PHF2 protein O75151 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 21532585 t miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. SIGNOR-264520 0.2 Ku-0063794 chemical CHEBI:85572 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 BTO:0000887;BTO:0001260 20884880 t gcesareni Sgk-1 activation in response to stretch is blocked by insulin-like growth factor (igf)-1 receptor inhibitor and mammalian target of rapamycin complex (mtorc)2 inhibitor (ku-0063794) but not mtorc1 inhibitor (rapamycin). SIGNOR-168188 0.8 SETBP1 protein Q9Y6X0 UNIPROT HOXA9 protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001271 22566606 f miannu Setbp1 activates hoxa9 and hoxa10 expression in myeloid progenitors SIGNOR-197321 0.43 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT up-regulates activity phosphorylation Tyr992 LSRGQEVyVKKTMGR -1 11513602 t lperfetto Isoelectric focusing electrophoresis and mass spectrometric analysis of a tie2 autophosphorylation time course showed that tyr992 on the putative activation loop was phosphorylated first followed by tyr1108 in the c-terminal tail autophosphorylation of tie2 to produce ptie2 resulted in a 100-fold increase in kcat and a 460-fold increase in kcat/km. SIGNOR-109790 0.2 SF3B3 protein Q15393 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 t lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). SIGNOR-268405 0.93 HACD3 protein Q9P035 UNIPROT FASN protein P49327 UNIPROT up-regulates activity chemical activation 9606 18554506 t Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases, SIGNOR-267762 0.2 FYN protein P06241 UNIPROT ITCH protein Q96J02 UNIPROT down-regulates activity phosphorylation Tyr420 QFNQRFIyGNQDLFA 10090 BTO:0002417 16387660 t gcesareni Tyrosine phosphorylation of Itch appears to reduce its interaction with its substrate JunB. The turnover of JunB is accelerated in Fyn-deficient T cells, which is further reconstituted by Itch Tyr371 mutation SIGNOR-245332 0.374 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 t Multiple autophosphorylation sites on Jak2, including Y1007 and Y1008. Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. SIGNOR-251357 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CACNB1 protein Q02641 UNIPROT up-regulates activity phosphorylation Ser348 IVYIKITsPKVLQRL 9534 BTO:0000298 16406008 t miannu Thus, Ser-447 on Ca(v)2.2 and Ser-161 and Ser-348 of Ca(v)beta1b appear to be both necessary and sufficient for ERK-dependent modulation of these channels. Together, our data strongly suggest that modulation of neuronal N-type VDCCs by ERK involves phosphorylation of Ca(v)2.2alpha1 and to a lesser extent possibly also Ca(v)beta subunits. On the basis of the evidence presented here, it is therefore suggested that ERK-dependent up-regulation of Cav2.2 channels is primarily mediated by phosphorylation of Ser-447 on the I–II loop of Cav2.2 and possibly also the two SP sites conserved on Cavβs. SIGNOR-262965 0.2 EIF2B3 protein Q9NR50 UNIPROT EIF2S3 protein P41091 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269136 0.724 SALL4 protein Q9UJQ4 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21526180 f miannu we demonstrated that SALL4 was able to bind to the promoter region of ABCA3 and activate its expression while regulating the expression of ABCG2 indirectly. SALL4 expression was positively correlated to those of ABCG2 and ABCA3 in primary leukemic patient samples SIGNOR-255122 0.268 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu72 CSYEEAFeALESSTA -1 10556651 t lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. SIGNOR-263683 0.655 CAMK2A protein Q9UQM7 UNIPROT SLN protein O00631 UNIPROT down-regulates activity phosphorylation Thr5 tRELFLNF 10116 23455424 t lperfetto SLN is also phosphorylated by CaMKII at Thr 5, and a phosphorylation mimic (Thr5Glu mutation) abolishes the inhibitory function of ectopically expressed SLN in adult rat ventricular myocytes| Thr 5 interacts with SERCA Trp 932, and phosphorylation at this site would cause a steric clash that destabilizes binding SIGNOR-264778 0.243 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1651 SPTSPSYsPTSPSYS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248818 0.849 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10230396 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-67392 0.41 RUNX1 protein Q01196 UNIPROT GP1BA protein P07359 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17725493 f miannu We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. SIGNOR-254195 0.377 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120040 0.781 PKA proteinfamily SIGNOR-PF17 SIGNOR NR5A2 protein O00482 UNIPROT up-regulates activity phosphorylation Ser510 LPEIRAIsMQAEEYL 9606 BTO:0000093 16109788 t miannu  PKA-mediated phosphorylation increases the interaction between GATA3 and LRH-1 and the requirement for PKA in aromatase PII promoter stimulation involves at least three specific amino acid residues: GATA3 Ser308, GATA4 Ser261, and LRH-1 Ser469.  SIGNOR-276041 0.2 ATM protein Q13315 UNIPROT NOP53 protein Q9NZM5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser233 ARLHTKPsQAPAVEV 9606 BTO:0000007 27829214 t miannu PICT-1 S233 and T289 were identified as the key phosphorylation sites in this pathway, as mutating both to alanine abolished UVB-induced increase of PICT-1 phosporylation. Inhibition of PIKKs or ATM (with wortmannin and KU55933, respectively) prevented the agglomeration and degradation of PICT-1, suggesting that ATM is a key regulator of PICT-1.  SIGNOR-273506 0.2 HMGA1 protein P17096 UNIPROT KITLG protein P21583 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 15378028 f miannu Human KIT ligand promoter is positively regulated by HMGA1 in breast and ovarian cancer cells. SIGNOR-254426 0.334 VARS1 protein P26640 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 30755602 t miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. SIGNOR-270528 0.8 KIFC1 protein Q9BW19 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 33361741 f miannu Kinesin Family Member C1 (KIFC1) Regulated by Centrosome Protein E (CENPE) Promotes Proliferation, Migration, and Epithelial-Mesenchymal Transition of Ovarian Cancer SIGNOR-266114 0.7 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR ATF2 protein P15336 UNIPROT up-regulates activity binding 9606 10085140 t lperfetto Here we report that the transcription factor atf-2 (also called cre-bp1) is bound by a hetero-oligomer of smad3 and smad4 upon tgf-beta stimulation. Both of these actions are shown to be responsible for the synergistic stimulation of ATF-2 trans-activating capacity. SIGNOR-65583 0.581 PRKCD protein Q05655 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser64 PRGRPKGsKNKGAAK 9606 10617144 t fspada In this study, we showed that the pkc-mediated phosphorylation of hmg-i exerted a very potent inhibition on the binding of this protein to the at-rich promoter regions of both pkc g and ng genes. The purified hmg-i can be phosphorylated by pkc a,b, g, and d but is poorly phosphorylated by pkc e and z. We have mapped two major sites of phosphorylation by pkc at ser44 and ser64 SIGNOR-73610 0.266 STAT5A protein P42229 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004408 15353555 f miannu Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors. SIGNOR-255682 0.7 KANK1 protein Q14678 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT down-regulates activity binding 10090 BTO:0000944 19171758 t miannu In this study, we report that Kank disrupts the function of active Rac1 through IRSp53. The binding between IRSp53 and Kank inhibits the association of active Rac1 with IRSp53 rather than the association of active cdc42 with IRSp53. Kank inhibits the formation of lamellipodia and membrane ruffles induced by active Rac1 in NIH3T3 cells. Kank interacts with IRSp53 through their coiled-coil domains. Kank affected the interaction between IRSp53 and Rac1 and partially affected that between IRSp53 and cdc42 (Fig. 3). SIGNOR-265553 0.348 SNW1 protein Q13573 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates binding 9606 BTO:0000222 BTO:0000887 10713164 t gcesareni We present evidence that skip interacts with the cbf1 corepressor complex and that skip has a role in orchestrating the conversion of cbf1 from an smrt-hdac-tethered transcriptional repressor to a notchic-tethered activation complex. SIGNOR-75785 0.574 COL1A2 protein P08123 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253248 0.457 MEIS1 protein O00470 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 f irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. SIGNOR-255865 0.7 S100A4 protein P26447 UNIPROT MYH9 protein P35579 UNIPROT down-regulates activity binding 10090 BTO:0005138 16707441 t miannu Our results show that S100A4 regulates cell polarization during directed motility by affecting the localization of protrusions through interactions with myosin-IIA, with S100A4 expressing cells displaying few side protrusions and extensive forward protrusions during chemotaxis compared with control cells. The mechanisms by which these antibodies and S100A4 increase protrusive activity and promote cellular motility are not well understood, but the observation that S100A4 can inhibit the actin-activated ATPase of myosin-IIA (34) suggests that S100A4 could function as a myosin-IIA inhibitor in vivo. SIGNOR-269282 0.427 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI 10090 BTO:0002572 SIGNOR-C3 20670887 t lperfetto Specifically as part of mTORC1, mTOR directly phosphorylates the ribo- somal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-167184 0.924 GGCX protein P38435 UNIPROT vitamin K epoxide smallmolecule CHEBI:28371 ChEBI up-regulates activity chemical modification 9606 31226734 t lperfetto GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form. SIGNOR-265917 0.8 CCL25 protein O15444 UNIPROT ACKR4 protein Q9NPB9 UNIPROT up-regulates activity binding 9606 BTO:0001938 23341447 t Luana  In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines. SIGNOR-268418 0.65 PRKG1 protein Q13976 UNIPROT RYR1 protein P21817 UNIPROT unknown phosphorylation Ser2843 KKKTRKIsQSAQTYD -1 8380342 t lperfetto Automated Edman sequence analysis of the major phosphopeptide obtained from PK-A and PK-G phosphorylation and one phosphopeptide obtained from PK-CaM phosphorylation yielded the sequence KISQTAQTYDPR (residues 2841€“2852) with serine 2843 as phosphorylation site SIGNOR-248918 0.399 SRC protein P12931 UNIPROT FCRL3 protein Q96P31 UNIPROT up-regulates activity phosphorylation Tyr650 PMELEPMySNVNPGD -1 12051764 t miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. SIGNOR-274008 0.2 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR FGA protein P02671 UNIPROT up-regulates activity binding 9606 BTO:0000132 16418530 t lperfetto In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. SIGNOR-253359 0.563 ALDH1A2 protein O94788 UNIPROT all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI up-regulates quantity chemical modification 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265126 0.8 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Met) smallmolecule CHEBI:29173 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270395 0.8 TNFAIP3 protein P21580 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates quantity ubiquitination 9606 15258597 t A20The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation. SIGNOR-259977 0.641 MAPK8 protein P45983 UNIPROT RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 16551633 t gcesareni Under stress conditions, hyperphosphorylated by activated jnk on ser-56, ser-70, thr-82 and ser-260. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear rxralpha levels, via a multistep, jnk-dependent mechanism involving ser260, nuclear export, and proteasomal degradation. SIGNOR-145297 0.442 RPL36 protein Q9Y3U8 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262464 0.849 SEC16A protein O15027 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 t lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat SIGNOR-265293 0.716 GSK3A protein P49840 UNIPROT MAF protein O75444 UNIPROT up-regulates phosphorylation 9606 18042454 t miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. SIGNOR-159358 0.2 KDM6A protein O15550 UNIPROT HOXC6 protein P09630 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260028 0.262 ABL2 protein P42684 UNIPROT CRK protein P46108 UNIPROT down-regulates phosphorylation 9606 BTO:0000149 15886098 t amattioni Abl2 kinase activity toward crk leads to increased phosphorylation of crk, inhibiting this cytoskeletal regulator by promoting intramolecular over intermolecular associations. SIGNOR-136958 0.686 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser683 TKEFFRRsKIAVFDK -1 8848293 t lperfetto Only two peptides containing Ser-662 and Ser-696 were found to be efficiently phosphorylated by protein kinase C (PKC). The peptide including Ser-696 was also phosphorylated by protein kinase G (PKG). SIGNOR-248954 0.697 PTGS2 protein P35354 UNIPROT episterol ester smallmolecule CHEBI:52393 ChEBI down-regulates quantity chemical modification 9606 19126760 t miannu After biosynthesis, 2-AG is partially degraded by postsynaptic COX-2, and partly released to the extracellular space.¬† SIGNOR-264270 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 10864927 t lperfetto Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-216765 0.839 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe635 HHQKLVFfAEDVGSN -1 10605825 t lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. SIGNOR-261774 0.502 MYOG protein P15173 UNIPROT FBXO32 protein Q969P5 UNIPROT down-regulates activity binding 9534 19631210 t llicata Myogenin had a MAFbx-recognition motif and interacted with MAFbx. MAFbx activated polyubiquitination of myogenin. The results of this study suggest that MAFbx functions as an F-box protein for ubiquitination of myogenin. SIGNOR-237854 0.526 PPARGC1A protein Q9UBK2 UNIPROT COX4I1 protein P13073 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000443 23021218 f lperfetto PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). SIGNOR-253098 0.408 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120120 0.316 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1060 HGHVSDAsIRVGENV -1 22302995 t miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. SIGNOR-262900 0.69 PLCG1 protein P19174 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 17562871 f gcesareni We propose that the association of plcgamma1 with complexes containing git1 and beta-pix is essential for its role in integrin-mediated cell spreading and motility. As a component of this complex, plcgamma1 is also involved in the activation of cdc42 and rac1. SIGNOR-155747 0.519 CDC73 protein Q6P1J9 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 16630820 t gcesareni Parafibromin/hyrax activates wnt/wg target gene transcription by direct association with beta-catenin/armadillo SIGNOR-146282 0.683 PIM1 protein P11309 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 20307683 t lperfetto Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellshere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo SIGNOR-164642 0.493 MAPKAPK3 protein Q16644 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser244 PPLRRSPsRTEKQEE -1 15850461 t miannu Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. SIGNOR-263082 0.495 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120108 0.316 IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates activity binding 9606 BTO:0000801 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249484 0.882 HSPB1 protein P04792 UNIPROT CASP3 protein P42574 UNIPROT down-regulates 9606 10544189 f gcesareni Hsp27 overexpression delays poly(adp-ribose)polymerase cleavage and procaspase-3 activation. SIGNOR-71869 0.582 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 17601773 t lperfetto Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity. SIGNOR-217312 0.344 PCSK1 protein P29120 UNIPROT IAPP protein P10997 UNIPROT up-regulates activity cleavage Lys72 VGSNTYGkRNAVEVL -1 10931181 t lperfetto The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule SIGNOR-261782 0.457 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE11A protein Q9HCR9 UNIPROT up-regulates activity phosphorylation Ser162 RALLRKAsSLPPTTA -1 18312413 t miannu The N-terminus has two phosphorylation sites for cyclic nucleotide monophosphate-dependent protein kinases (Ser117, Ser168). Phosphorylation of both by cAMP-dependent protein kinase decreased the EC50 value for cGMP from 72 to 23 μm. Effect of phosphorylations at Ser117 and Ser162. Here, serine phosphorylation by the catalytic subunit of cAK, albeit not known whether at position 117, 162 or both, increased cGMP affinity about threefold. SIGNOR-276179 0.2 UBE2G2 protein P60604 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by destabilization ubiquitination 9606 BTO:0001379 29892818 t inferred from family member scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. SIGNOR-270244 0.2 MAPK8 protein P45983 UNIPROT AIMP1 protein Q12904 UNIPROT down-regulates phosphorylation Ser140 KKEKKQQsIAGSADS 9606 20510162 t llicata We further demonstrated that serine-140 residue of aimp1 was phosphorylated by jnk and alanine mutation of serine-140 suppressed lps-induced cell surface altogether, these results suggest that aimp1 is phosphorylated by jnk through tlr-myd88 pathway and lose the regulatory activity for er retention of gp96expression of gp96. SIGNOR-165763 0.486 ULK1 protein O75385 UNIPROT FBP1 protein P09467 UNIPROT down-regulates activity phosphorylation Ser88 LVMNMLKsSFATCVL 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274031 0.2 ATP8B1 protein O43520 UNIPROT ATP2B2 protein Q01814 UNIPROT up-regulates 9606 BTO:0000630 19478059 f lperfetto Consequently ATP8B1 deficiency, with a secondary disturbance of membrane lipid asymmetry, likely inhibits PMCA2 activity and affects the efficiency of mechanotransduction. SIGNOR-262584 0.2 IRX1 protein P78414 UNIPROT RALGPS1 protein Q5JS13 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. SIGNOR-261668 0.2 RPS7 protein P62081 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262417 0.812 UBE2D2 protein P62837 UNIPROT VPS18 protein Q9P253 UNIPROT up-regulates activity binding 9606 BTO:0000007 16203730 t miannu VPS18 Ubiquitylates SNK in Vitro and in Vivo. The ubiquitylation of proteins by hVPS18 was selectively mediated by UbcH4.  SIGNOR-271549 0.325 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000938 17591690 t gcesareni Here, we demonstrate for the first time that cdk5 interacts with p53 and increases its stability through posttranslational regulation, leading to accumulation of p53, particularly in the nucleus. We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 in vitro, SIGNOR-156414 0.722 MAML1 protein Q92585 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 11101851 t gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes0 SIGNOR-84919 0.87 LRRK2 protein Q5S007 UNIPROT MSN protein P26038 UNIPROT up-regulates activity phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 8537411 t lperfetto This led to the discovery that moesin, a protein which anchors the actin cytoskeleton to the plasma membrane, is efficiently phosphorylated by lrrk2, at thr558. Moesin phosphorylation could be essential to support the cytoskeletal changes accompanying this process. SIGNOR-39433 0.568 AKT proteinfamily SIGNOR-PF24 SIGNOR FAS protein P25445 UNIPROT down-regulates 9606 15004527 f gcesareni Akt may serve to stimulate certain proteins (e.g., Ikk) involved in the prevention of apoptosis such as nf-kb as well as repress other proteins normally involved in the induction of apoptosis such as the forkhead transcription factors (fkhr, now know as foxo3), creb, glycogen synthetase-3 kinase-beta (gsk-3beta), fas, caspase-9 and cell cycle inhibitors such as p27 SIGNOR-123239 0.2 ADCK5 protein Q3MIX3 UNIPROT SOX9 protein P48436 UNIPROT up-regulates activity phosphorylation Ser181 YQPRRRKsVKNGQAE 32277958 t lperfetto Here we investigated the mechanism of ADCK5 involved in regulating invasion and migration of lung cancer cells, and showed that ADCK5 might regulate the expression of tumor oncogene human pituitary tumor transforming gene-1 (PTTG1) by phosphorylating transcription factor SOX9|Mutagenesis of potential serine phosphorylation sites on SOX9 indicated that serine 181 might be required to maintain transcription activation of SOX9 as well as increase PTTG1 levels. SIGNOR-264567 0.2 MMP26 protein Q9NRE1 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272370 0.7 F12 protein P00748 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 t lperfetto Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1. SIGNOR-261856 0.449 ATM protein Q13315 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates activity phosphorylation Ser26 LRGNPSSsQVDEEQM 9606 BTO:0002137 26774286 t In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7 SIGNOR-259942 0.436 MAPK3 protein P27361 UNIPROT MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation Thr30 PSSSEIFtPAHEENV 9606 25728771 t lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation SIGNOR-264772 0.2 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT down-regulates activity phosphorylation Thr514 SVTPKTVtPASSAKT 9606 phosphorylation:Ser522 PASSAKTsPAKQQAP 25040932 t lperfetto Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition SIGNOR-264840 0.713 RBX1 protein P62877 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates ubiquitination 9606 SIGNOR-C5 11295495 t gcesareni The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk. SIGNOR-106781 0.427 CFAP53 protein Q96M91 UNIPROT ODAD4 protein Q96NG3 UNIPROT up-regulates activity binding 10090 BTO:0000379 33347437 t miannu CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B). SIGNOR-265543 0.2 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT down-regulates dephosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 16778204 t gcesareni Ptprj expression induces dephosphorylation of the ret(c634r) and, probably via an indirect mechanism, ret/ptc1 oncoproteins on two key ret autophosphorylation sites (tyr1062 and tyr905). in line with this finding, adoptive ptprj expression reduced the oncogenic activity of ret SIGNOR-147161 0.281 BAIAP2 protein Q9UQB8 UNIPROT ENAH protein Q8N8S7 UNIPROT up-regulates activity binding 9606 BTO:0000452 11696321 t miannu We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia. SIGNOR-268423 0.551 L-serine chemical CHEBI:17115 ChEBI PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates activity chemical activation 9606 23064226 t inferred from family member We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation. SIGNOR-270286 0.8 NKX2-5 protein P52952 UNIPROT LYL1 protein P12980 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19608273 f Sequence analysis of the LYL1 promoter region revealed potential binding sites for transcription factors HOXA10, LMO2 and NKX2-5. Overexpression analysis, reporter gene assays and chromatin immuno-precipitation confirmed their activating impact on LYL1 expression. In conclusion, we identified multiple mechanisms which activate LYL1 in leukemic cells, including structural genomic alterations, namely microdeletion or amplification, together with the involvement of prominent oncogenic transcription factors. SIGNOR-253655 0.319 PTPN6 protein P29350 UNIPROT ACTG1 protein P63261 UNIPROT down-regulates dephosphorylation Tyr218 DIKEKLCyVALDFEQ 9606 BTO:0000776 12646642 t gcesareni Our data suggest that shp-1 plays a pivotal role in reorganization of cytoskeletal architecture inducing actin dephosphorylation. These results clearly demonstrate the direct interaction of shp-1 with actin SIGNOR-99565 0.2 lurasidone chemical CHEBI:70735 ChEBI ADRA2A protein P08913 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 20404009 t Luana Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 2C receptors. SIGNOR-257842 0.8 SMURF2 protein Q9HAU4 UNIPROT SKIL protein P12757 UNIPROT down-regulates activity ubiquitination 9606 BTO:0002181;BTO:0005493 11389444 t lperfetto Tgf-beta also induces the association of smurf2 with the transcriptional co-repressor snon and we show that smad2 can function to mediate this interaction. This allows smurf2 hect domain to target snon for ubiquitin-mediated degradation by the proteasome. SIGNOR-236090 0.728 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT up-regulates activity phosphorylation Ser225 TRRVKTQsESGDVSR -1 27292631 t miannu We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment. SIGNOR-274060 0.308 SCF-betaTRCP complex SIGNOR-C5 SIGNOR NHEJ1 protein Q9H9Q4 UNIPROT down-regulates quantity by destabilization ubiquitination Thr181 LIRDRLKtEPFEENS 9606 BTO:0000567 25661488 t miannu Here we report that Akt phosphorylates XLF (XRCC4 like factor, also called NHEJ1) at T181, to dissociate XLF from the XRCC4 (X-ray repair cross-complementing protein 4)/DNA ligase IV (LIG4) complex and subsequently triggers XLF cytoplasmic translocation, leading to XLF ubiquitination by SCFβ-TRCP in a CKI-dependent manner. SIGNOR-276882 0.328 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 12747827 t lperfetto Our data demonstrate that the TOS motif functions as a docking site for the mTOR/raptor complex, which is required for multisite phosphorylation of 4E-BP1, eIF4E release from 4E-BP1, and cell growth. SIGNOR-236678 0.753 CTNNB1 protein P35222 UNIPROT CCN4 protein O95388 UNIPROT up-regulates quantity transcriptional regulation 10116 BTO:0002409 10716946 t This study identifies WISP-1 as a beta-catenin-regulated gene that can contribute to tumorigenesis. The promoter of WISP-1 was cloned and shown to be activated by both Wnt-1 and beta-catenin expression. SIGNOR-256270 0.2 CARM1 protein Q86X55 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates activity methylation Arg223 PAPTPNPrASLNHST 9606 BTO:0000725 24332853 t miannu We have found that PRMT4 is highly expressed in HSPCs, where it functions as an inhibitor of myeloid differentiation (Figure 7G). In these cells, PRMT4 methylates RUNX1 at R223, promoting the assembly of a DPF2-containing transcriptional co-repressive complex, and repressing transcription at the miR-223 locus. SIGNOR-261967 0.286 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. SIGNOR-266499 0.8 UBE2N protein P61088 UNIPROT UBE2V1 protein Q13404 UNIPROT up-regulates activity binding 9606 20551964 t lperfetto Ubc13, the partner of rnf8 and rnf168, usually cooperates with an e2-like protein, uev1 (also known as ube2v1) or mms2 (also known as ube2v2), for the synthesis of lys63-linked polyubiquitin chains. SIGNOR-166177 0.848 BRCA1 protein P38398 UNIPROT ESR1 protein P03372 UNIPROT down-regulates activity 9606 BTO:0000356;BTO:0001033 11244506 f The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-alpha] in human breast and prostate cancer cell lines. SIGNOR-253974 0.745 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1336 RFMDGSPyAHMFEMS 9606 BTO:0000007 11024032 t Tyr-1252, Tyr-1336, and Tyr-1472 of GluRε2 are phosphorylated in 293T cells when active Fyn is co-expressed. SIGNOR-251173 0.759 CHUK protein O15111 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation 9606 BTO:0000093 18490760 t gcesareni Insulin activation of mtor requires akt in a manner that involves ikkalpha, preferentially to ikkbeta, and tsc2 phosphorylation SIGNOR-178664 0.3 AKT1 protein P31749 UNIPROT PDE3B protein Q13370 UNIPROT up-regulates activity phosphorylation Ser318 CKIFRRPsLPCISRE 10090 BTO:0000011 10454575 t gcesareni PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B. SIGNOR-252554 0.679 afimoxifene chemical CHEBI:44616 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258594 0.8 HLX protein Q14774 UNIPROT JUN protein P05412 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20008130 t Luana In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells. SIGNOR-261623 0.2 amisulpride chemical CHEBI:64045 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258365 0.8 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 22021368 f apalma In normal hematopoiesis, AML1 suppresses NF-κB signaling and thus may contribute to inhibition of excessive proliferation of hematopoietic cells. SIGNOR-255692 0.7 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT down-regulates activity phosphorylation Tyr897 GACEHRGyLYLAIEY -1 11080633 t lperfetto The Tie2 nucleotide binding loop is in an inhibitory conformation, which is not seen in other kinase structures, while its activation loop adopts an activated-like conformation in the absence of phosphorylation. Tyr-897, located in the N-terminal domain, may negatively regulate the activity of Tie2 by preventing dimerization of the kinase domains or by recruiting phosphatases when it is phosphorylated. SIGNOR-246662 0.2 PKC proteinfamily SIGNOR-PF53 SIGNOR AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser180 TIFASCDsKRTDVTG -1 19761816 t miannu Taken together this data shows that AQP4 in gliomas is the target of PKC phosphorylation, and albeit significantly phosphorylated at rest, phosphorylation can be further enhanced by PKC activation.This data suggests that in gliomas water permeability through AQP4 is under the regulation of PKC via phosphorylation of S180. SIGNOR-276260 0.2 ASPA protein P45381 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity chemical modification 9606 17194761 t miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. SIGNOR-267528 0.8 HTR7 protein P34969 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257168 0.284 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser392 VSGASPEsISSLLSE -1 22302995 t miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. SIGNOR-262909 0.69 SF3A1 protein Q15459 UNIPROT SF3a complex SIGNOR-C345 SIGNOR form complex binding 9606 BTO:0000567 8349644 t miannu Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. SIGNOR-263948 0.973 PRMT5 protein O14744 UNIPROT HOXA9 protein P31269 UNIPROT up-regulates activity methylation Arg140 KPEPLSArRGDCPTL 9606 BTO:0000007 22269951 t lperfetto Hoxa9 methylation by prmt5 is essential for endothelial cell expression of leukocyte adhesion molecules. / prmt5 is a critical coactivator component in a newly defined, hoxa9-containing transcription complex./ Hoxa9 is methylated on arg140 by prmt5. SIGNOR-195526 0.474 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates activity dephosphorylation Tyr588 QLKPLKTyVDPHTYE -1 21538645 t gcesareni The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates SIGNOR-246035 0.646 RPL10A protein P62906 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262489 0.844 PSMC6 protein P62333 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263370 0.851 BMS 794833 chemical CID:44155856 PUBCHEM MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190422 0.8 MAPK1 protein P28482 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000007;BTO:0000150 21502402 t gcesareni We identified the serine 68 (s68) as a major phosphorylation site of twist1 by mass spectrometry and with specific antibodies. This s68 is phosphorylated by p38, jnk and erk1/2 in vitro, and its phosphorylation levels positively correlate with twist1 protein levels in hek293 and breast cancer cells. SIGNOR-173401 0.309 AKT1 protein P31749 UNIPROT FSTL1 protein Q12841 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18718903 f miannu Akt1 Overexpression in Skeletal Muscle Increases Capillary Vessel Formation and Up-regulates Fstl1 Expression SIGNOR-266605 0.392 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser316 VEEEPLNsEDDVSDE 9606 11278496 t lperfetto Taf(ii) 250 phosphorylates human transcription factor iia on serine residues important for tbp binding and transcription activity. SIGNOR-105688 0.664 BTK protein Q06187 UNIPROT GTF2I protein P78347 UNIPROT up-regulates activity phosphorylation Tyr248 EESEDPDyYQYNIQA 9534 BTO:0004055 11373296 t lperfetto These residues, tyr248, tyr357, and tyr462, were also found to be the major sites for btk-dependent phosphorylation of bap/tfii-i in vivo. Residues tyr357 and tyr462 are contained within the loop regions of adjacent helix-loop-helix-like repeats within bap/tfii-i. Mutation of either tyr248, tyr357, or tyr462 to phenylalanine reduced transcription from a c-fos promoter relative to wild-type bap/tfii-i in transfected cos-7 cells, consistent with the interpretation that phosphorylation at these sites contributes to transcriptional activation. SIGNOR-108338 0.531 DYRK1A protein Q13627 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates phosphorylation Ser167 FLISPPAsPPVGWKQ 9606 12809556 t gcesareni In the present study, dyrk1a is shown to directly interact with and phosphorylate rcan1 at ser112 and thr192 residues. Dyrk1a-mediated phosphorylation of rcan1 at ser112 primes the protein for the gsk3_-mediated phosphorylation of ser108. SIGNOR-102290 0.579 CHRM2 protein P08172 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256964 0.332 diazepam chemical CHEBI:49575 ChEBI GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t brain lperfetto The traditional BZ site agonists (GABA-enhancing CNS depressants such as diazepam) are active on the GABAA-Rs containing a gamma2 subunit (Pritchett et al., 1989), a beta subunit, and one of the alpha subunits, alpha1, 2, 3, or 5. SIGNOR-263799 0.8 TNFRSF1A protein P19438 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates 9606 10795740 t We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-256251 0.826 HNRNPH1 protein P31943 UNIPROT SRC protein P12931 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 BTO:0000938 9858532 t lperfetto HnRNP H is a component of a splicing enhancer complex that activates a c-src alternative exon in neuronal cells. SIGNOR-261273 0.295 RET protein P07949 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 16153436 t gcesareni We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1). SIGNOR-140298 0.444 ID2 protein Q02363 UNIPROT TCF12 protein Q99081 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C128 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241131 0.567 RPL11 protein P62913 UNIPROT TP73 protein O15350 UNIPROT up-regulates binding 9606 25301064 t miannu We report that rpl5 and rpl11 can also enhance the transcriptional activity of a p53 homolog tap73 SIGNOR-205514 0.366 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser40 ASAAGGLsPVTNLTV 9606 BTO:0000017 28192398 t miannu We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation.  SIGNOR-277343 0.615 ARID1B protein Q8NFD5 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 t lperfetto We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. SIGNOR-241713 0.779 CSNK2A1 protein P68400 UNIPROT SP1 protein P08047 UNIPROT down-regulates activity phosphorylation Thr579 GDGIHDDtAGGEEGE 9606 9153193 t llicata Casein kinase II-mediated phosphorylation of the C terminus of Sp1 decreases its DNA binding activity. | Mutation of a consensus CKII site at amino acid 579, within the second zinc finger, eliminates phosphorylation of this site and the CKII-mediated inhibition of Sp1 binding. SIGNOR-250954 0.346 ULK2 protein Q8IYT8 UNIPROT FBP1 protein P09467 UNIPROT down-regulates activity phosphorylation Ser88 LVMNMLKsSFATCVL 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274039 0.2 TCEA1 protein P23193 UNIPROT UBR5 protein O95071 UNIPROT up-regulates binding 9606 21127351 t miannu We show that the e3 ubiquitin ligase ubr5 associates with the cdk9 subunit of positive transcription elongation factor b to mediate its polyubiquitination in human cells. Tfiis also binds ubr5 to stimulate cdk9 polyubiquitination. SIGNOR-170258 0.365 UNG protein P13051 UNIPROT 5-fluorouracil chemical CHEBI:46345 ChEBI down-regulates quantity by destabilization chemical modification 9606 27875297 t lperfetto Uracil N-glycosylase 2 (UNG2), the nuclear isoform of UNG, catalyzes the removal of uracil or 5-fluorouracil lesions that accumulate in DNA following treatment with the anticancer agents 5-fluorouracil and 5-fluorodeoxyuridine (floxuridine), a 5-fluorouracil metabolite. By repairing these DNA lesions before they can cause cell death, UNG2 promotes cancer cell survival and is therefore critically involved in tumor resistance to these agents.  SIGNOR-264888 0.8 AMPK complex SIGNOR-C15 SIGNOR CFTR protein P13569 UNIPROT down-regulates activity phosphorylation Ser737 EPLERRLsLVPDSEQ 9606 19095655 t Luana AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites.|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions SIGNOR-250350 0.397 TWIST1 protein Q15672 UNIPROT GDF15 protein Q99988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255527 0.281 GATA1 protein P15976 UNIPROT ZNF268 protein Q14587 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001271 22235304 f miannu Here we found that gata-1, a master regulator of erythropoiesis, repressed the promoter activity and transcription of znf268 SIGNOR-195410 0.379 EFNA5 protein P52803 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52473 0.943 CDK1 protein P06493 UNIPROT LIG1 protein P18858 UNIPROT up-regulates activity phosphorylation Ser76 EEEDEALsPAKGQKP 9606 BTO:0000567 12851383 t lperfetto We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner. SIGNOR-103242 0.371 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser788 PIPHIPRsPYKFPSS -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250759 0.858 ULK2 protein Q8IYT8 UNIPROT FBP1 protein P09467 UNIPROT down-regulates activity phosphorylation Ser63 HLYGIAGsTNVTGDQ 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274040 0.2 PRKCA protein P17252 UNIPROT STXBP1 protein P61764 UNIPROT unknown phosphorylation Ser306 VSQEVTRsLKDFSSS -1 12519779 t lperfetto Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation. SIGNOR-249182 0.386 NLK protein Q9UBE8 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT down-regulates quantity phosphorylation 9606 BTO:0000007 16714285 t miannu NLK Augments the Ubiquitylation Activity of NARF against TCF/LEF. ctivation of NLK induced by unknown ligands leads to the phosphorylation of TCF/LEF. NARF then acts on TCF/LEF as an E3 ubiquitin-ligase and, together with E1 and E2 ubiquitylation enzymes, catalyze the ubiquitylation of TCF/LEF. Finally, ubiquitylated TCF/LEF is degraded by the 26 S proteasome. SIGNOR-271597 0.763 AKT proteinfamily SIGNOR-PF24 SIGNOR PLN protein P26678 UNIPROT down-regulates activity phosphorylation Thr17 SAIRRAStIEMPQQA 10090 BTO:0003265 19696029 t Akt interacts with and phosphorylates PLN at Thr(17), the Ca(2+)-calmodulin-dependent kinase IIdelta site, whereas silencing Akt signaling, through the knock-out of phosphatidylinositol-dependent kinase-1, resulted in reduced phosphorylation of PLN at Thr(17). SIGNOR-252035 0.2 EDNRB protein P24530 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257379 0.559 BMPR1A protein P36894 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 10090 19620713 f ggiuliani The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17). SIGNOR-255785 0.301 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 BTO:0000782 12151396 t gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. SIGNOR-91075 0.346 LCK protein P06239 UNIPROT CD3G protein P09693 UNIPROT up-regulates activity phosphorylation 10090 2470098 t Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex. SIGNOR-259928 0.541 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR USP37 protein Q86T82 UNIPROT up-regulates activity phosphorylation Ser628 MVNSCITsPSTPSKK 9606 BTO:0000007;BTO:0000567 21596315 t lperfetto There is positive reinforcement of this signaling mechanism because phosphorylation of Ser628 by CDK2/cyclin E and CDK2/cyclin A complexes produces maximal USP37 activity SIGNOR-265046 0.51 AKT2 protein P31751 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLPRPE 10090 BTO:0000944 11313479 t Phosphorylation of AFX by PKB occurs in the nucleus. Phosphorylation of S193 reduces the rate of nuclear import. PKB-mediated phosphorylation of AFX, therefore, attenuates the import of the transcription factor, which shifts the localization of the protein from the nucleus to the cytoplasm and results in the inhibition of AFX transcriptional activity. SIGNOR-251491 0.593 YAP1 protein P46937 UNIPROT CDC6 protein Q99741 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 f lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. SIGNOR-276564 0.272 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Ser12 LASDFAFsPPPGGGG -1 31306665 t lperfetto Recently, Liu et al. [3] identified CyclinE/CDK2 to be the kinase phosphorylating OCT4 on serine 12 (S12), serine 355 (S355) and threonine 322 (T322) by elegantly combining genetics and biochemistry. Knockout of all five G1 cyclins (D1, D2, D3, E1 and E2) in mESCs (coined Q-KO cells) and consequent inactivation of CDK2/4/ 6 leads to perturbation of the pluripotent state and to the adaption of the trophectoderm cell fate. This was attributed to reduced phosphorylation of OCT4 (as well as SOX2 and NANOG) leading to an increase of protein turnover [3]. SIGNOR-264438 0.324 SWI/SNF complex complex SIGNOR-C92 SIGNOR CCND1 protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12138206 f irozzo INI1/hSNF5 is a component of the ATP-dependent chromatin remodeling hSWI/SNF complex [.]. Our data suggest that one of the mechanisms by which INI1/hSNF5 exerts its tumor suppressor function is by mediating the cell cycle arrest due to the direct recruitment of HDAC activity to the cyclin D1 promoter thereby causing its repression and G(0)-G(1) arrest. These results together indicate that cyclin D1 is a direct target for repression by INI1/hSNF5. SIGNOR-256293 0.481 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK7 protein P50613 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207087 0.8 ULK2 protein Q8IYT8 UNIPROT HK1 protein P19367 UNIPROT up-regulates activity phosphorylation Ser124 NIVHGSGsQLFDHVA 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274042 0.2 AMPK complex SIGNOR-C15 SIGNOR RBBP7 protein Q16576 UNIPROT up-regulates activity phosphorylation Ser314 LKLHTFEsHKDEIFQ -1 28143904 t lperfetto AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314| interaction between RBBP7 and HAT1 is required for acetyltransferase activity SIGNOR-264789 0.261 Gbeta proteinfamily SIGNOR-PF4 SIGNOR STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation 9606 25846811 t inferred from 70% family members lperfetto Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK. SIGNOR-270071 0.2 EIF2B2 protein P49770 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269140 0.739 S100A9 protein P06702 UNIPROT TLR4 protein O00206 UNIPROT up-regulates activity binding 9606 28137827 t miannu RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells. S100A9 binds to TLR4 and induces signaling pathways,promoting leukemic cell differentiation and proliferation arrest. Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-kB. SIGNOR-261918 0.527 SMAD6 protein O43541 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity binding 9606 20663871 t lperfetto The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-_ (TGF-_) family signaling. I-Smads inhibit TGF-_ family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation. SIGNOR-167160 0.73 NAD(1-) smallmolecule CHEBI:57540 ChEBI NADH smallmolecule CHEBI:16908 ChEBI up-regulates quantity precursor of 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-268113 0.8 MAPK14 protein Q16539 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates phosphorylation Ser7 sPAPLSPL 9606 22128155 t gcesareni Ogether, our results suggest that p38 phosphorylation of foxo3a on ser-7 is essential for its nuclear relocalization in response to doxorubicin SIGNOR-177927 0.512 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MCL1 protein Q07820 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 18676833 t inferred from 70% family members fstefani We then showed that erk could phosphorylate mcl-1 at two consensus residues, thr 92 and 163, which is required for the association of mcl-1 and pin1, resulting in stabilization of mcl-1. SIGNOR-270042 0.2 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser37 KHSSYPDsEGAPDSL 9606 10618498 t lperfetto Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability SIGNOR-73891 0.439 lurasidone chemical CHEBI:70735 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10030 20404009 t Luana In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype. SIGNOR-259463 0.8 NFY complex SIGNOR-C1 SIGNOR TOP2A protein P11388 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25328138 t lperfetto The expression of human TOP2A is controlled by its promoter region that contains two GC boxes and five CCAAT boxes. NF-Y recognizes and binds to the ICBs. This binding of NF-Y to the TOP2A promoter can be promoted by HMGB1/2 and inhibited by pRb. SIGNOR-242526 0.274 MAGEC2 protein Q9UBF1 UNIPROT TRIM28 protein Q13263 UNIPROT up-regulates activity binding 9606 BTO:0000594 28394358 t lperfetto In this study, we demonstrated that the tripartite motif-containing protein 28 (TRIM28) binds directly to and promotes FBP1 for ubiquitination and degradation. MAGE-A3 and MAGE-C2, which are known to be overexpressed in HCC, can enhance TRIM28-dependent degradation of FBP1 by forming ubiquitin ligase complexes with TRIM28. SIGNOR-267593 0.52 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT down-regulates phosphorylation Thr1491 DYHFVNAtEESDALA 9606 BTO:0000938 19824698 t lperfetto We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. eduction in the gtp-bound form of lrrk2 caused by t1491d mutation might have lowered the kinase activity, implicating the autophosphorylation of the roc domain in a negative feedback regulation of the kinase activity of lrrk2. SIGNOR-188425 0.2 PHA-680632 chemical CID:11249084 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206097 0.8 CSNK2A1 protein P68400 UNIPROT IP6K2 protein Q9UHH9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser347 RPEVVLDsDAEDLED 9606 BTO:0000007 21262846 t miannu CK2 physiologically phosphorylates IP6K2 at amino acid residues S347 and S356 contained within a PEST sequence, a consensus site for ubiquitination. HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of IP6K2 enhances its ubiquitination and subsequent degradation. SIGNOR-273624 0.257 TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 8242752 t lperfetto The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents. SIGNOR-37145 0.872 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser175 SPASSGSsASFISDT 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252343 0.635 THRA protein P10827 UNIPROT RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates binding 9606 15650024 t inferred from 70% of family members gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. SIGNOR-269851 0.407 SRC protein P12931 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity phosphorylation 9606 BTO:0002181 26198631 t miannu YY1 phosphorylation is mediated by Src family kinases. SIGNOR-276940 0.288 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI L-asparagine zwitterion smallmolecule CHEBI:58048 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-268069 0.8 DYRK1A protein Q13627 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates phosphorylation 9606 BTO:0000142 19383720 t gcesareni Dyrk1a physically interacts with the nicd inducing its phosphorylation in the ankyrin domain, thereby attenuating notch . SIGNOR-254313 0.405 ATM protein Q13315 UNIPROT XRCC6 protein P12956 UNIPROT up-regulates activity phosphorylation Ser33 ASGDYKYsGRDSLIF 9606 BTO:0001546 26337656 t done miannu Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks. SIGNOR-274021 0.702 CAMK2A protein Q9UQM7 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Ser230 PKYSRQFsLEHVHGS BTO:0000664 11447121 t llicata Ser230 is located in the regulatory domain of HSF1, and promotes the magnitude of the inducible transcriptional activity. Ser230 lies within a consensus site for calcium/calmodulin-dependent protein kinase II (CaMKII), and CaMKII overexpression enhances both the level of in vivo Ser230 phosphorylation and transactivation of HSF1. The importance of Ser230 was further established by the S230A HSF1 mutant showing markedly reduced activity relative to wild-type HSF1 when expressed in hsf1(-/-) cells. SIGNOR-250631 0.492 AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2. SIGNOR-251550 0.7 PAMPs stimulus SIGNOR-ST11 SIGNOR MPO-ANCA complex SIGNOR-C474 SIGNOR up-regulates quantity 9606 BTO:0000133 15972951 f lperfetto In the early phase, LPS enhanced anti-MPO IgG-induced glomerular neutrophil accumulation. |using bacterial lipopolysaccharide (LPS) as the proinflammatory stimulus. SIGNOR-270586 0.7 P2RY10 protein O00398 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257121 0.2 ATR protein Q13535 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates quantity by stabilization phosphorylation Ser31 ALRLLDSsQIVIISA 10090 BTO:0001372 11459832 t lperfetto These results thus suggest that this serine 31 residue is indeed an atm/atr phosphorylation site and in fact is the major site for atm/atr-mediated phosphorylation within e2f1. Thus, it is possible that the atm/atr-mediated phosphorylation inhibits the binding and function of skp2 and thus prevents the normal degradation of e2f1 SIGNOR-109420 0.385 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Ser332 STPKSKQsPISTPTS 9606 14741103 t llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. SIGNOR-250667 0.415 ESR1 protein P03372 UNIPROT SCN1A protein P35498 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 BTO:0001264 22169964 f miannu 17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice SIGNOR-253468 0.27 CDK2 protein P24941 UNIPROT GRK2 protein P25098 UNIPROT down-regulates phosphorylation Ser670 KMKNKPRsPVVELSK 9606 20080565 t gcesareni We report that grk2 protein levels are transiently down-regulated during the g2/m transition by a mechanism involving cdk2-mediated phosphorylation of grk2 at serine670, which triggers binding to the prolyl-isomerase pin1 and subsequent degradation. SIGNOR-163279 0.2 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr242 FFQQQMIyDSPPSRA 9606 19881549 t lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis SIGNOR-236314 0.692 IL12A protein P29459 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 t gcesareni Like il-12, il-23 binds to the il-12r subunit il-12rbeta1. SIGNOR-87677 0.554 CSNK1A1 protein P48729 UNIPROT ERG protein P11308 UNIPROT down-regulates quantity by destabilization phosphorylation Ser39 EMTASSSsDYGQTSK -1 26344095 t miannu Using in vitro kinase assays, we further demonstrated that deletion of degron 1 largely abolished CKI-mediated phosphorylation of ERG (Figure S5B), indicating that serine residues within degron 1 are the major CKI phosphorylation sites. SIGNOR-276935 0.2 PRKCA protein P17252 UNIPROT EIF4G1 protein Q04637 UNIPROT up-regulates activity phosphorylation Ser1185 RTPATKRsFSKEVEE 9606 BTO:0000007 21576361 t miannu Phospho-proteomic and mutational analyses revealed that eIF4G1 is a substrate for PKCα at Ser1186.  SIGNOR-276327 0.261 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity precursor of 9606 15096496 t CPSase catalyzes the synthesis of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules SIGNOR-267191 0.8 TNF protein P01375 UNIPROT SCN3A protein Q9NY46 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253485 0.2 PRKAA2 protein P54646 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Ser177 AKELDQGsLCTSFVG 9606 SIGNOR-C14 21673972 t lperfetto These results demonstrate that the ikk is a direct substrate of ampk_2 and that its phosphorylation on ser177 and ser181no initiates the activation of the ampk_2 in endothelial cells which in turn phosphorylates and activates the _-subunit of the ikk. The latter also induces a higher rate of ikk auto-inactivation and thus attenuates the activation of nf_b and the expression of inflammatory genes SIGNOR-174401 0.259 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 21157483 t lperfetto Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.Recent findings have revealed novel important roles for mTORC2 in the phosphorylation of AGC kinase family members. mTORC2 phosphorylates and activates Akt, SGK, and PKC, which regulate cell survival, cell cycle progression and anabolism SIGNOR-217004 0.634 EEF1G protein P26641 UNIPROT EEF1B complex complex SIGNOR-C460 SIGNOR form complex binding 9606 23699257 t lperfetto An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. The requirement for a guanine nucleotide exchange factor, the eEF1B complex, which in metazoans is composed of the subunits α, δ, and γ (also called eEF1B, eEF1D, and eEF1G, respectively) SIGNOR-269391 0.981 PRKG1 protein Q13976 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 10101032 t Translocation from Endosome to Lysosome fspada Ser396 and ser398 are also potential phosphorylation sites for capk, cgmp-dependent protein kinase, and camk ii. Elevation of intracellular camp content has been shown to attenuate histamine-induced accumulation of ip in c6 glioma cells (peakman and hill, 1994) and in ddt1 mf-2 smooth muscle cells (sipma et al., 1995 SIGNOR-66019 0.2 PAS complex complex SIGNOR-C190 SIGNOR 1-phosphatidyl-1D-myo-inositol 3-phosphate smallmolecule CHEBI:17283 ChEBI down-regulates quantity chemical modification -1 18950639 t miannu PtdIns(3,5)P2 is synthesized from PtdIns(3)P through the action of mammalian PIKfyve or the yeast counterpart Fab1, both sole enzymes for PtdIns(3,5)P2 synthesis. PIKfyve and Fab1, in turn, are activated by the orthologous proteins, mammalian ArPIKfyve and yeast Vac14, to upregulate intracellular PtdIns(3,5)P2 production. PtdIns(3,5)P2 turnover is catalyzed, at least in part, by mammalian Sac3 or its yeast counterpart Fig4 SIGNOR-253533 0.8 GOLPH3 protein Q9H4A6 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 19553991 f Mechanistically, GOLPH3 regulates cell size, enhances growth factor-induced mTOR signaling in human cancer cells and alters response to mTOR inhibitor in vivo. SIGNOR-253555 0.3 GOT2 protein P00505 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 31422819 t miannu This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267517 0.8 HAUS2 protein Q9NVX0 UNIPROT HAUS complex complex SIGNOR-C281 SIGNOR form complex binding 9606 BTO:0000567 19369198 t lperfetto Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC) SIGNOR-262323 0.814 RIT1 protein Q92963 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 10090 BTO:0000944 23791108 t It is possible that RIT1 interacts with RAF1 and that gain-of-function mutations in RIT1 and RAF1 exert similar effects in heart development. SIGNOR-251650 0.531 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR up-regulates activity ubiquitination -1 12485996 t lperfetto Auto‐ubiquitylation stimulates the ubiquitin ligase activity of BRCA1/BARD1|Secondly, BRCA1/BARD1 catalyses the formation of multiple polyubiquitin chains on itself. Remarkably, this auto‐polyubiquitylation potentiates the E3 ubiquitin ligase activity of the BRCA1/BARD1 complex >20‐fold. SIGNOR-263233 0.786 TACR1 protein P25103 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256776 0.2 SUB1 protein P53999 UNIPROT REST-CoREST complex SIGNOR-C111 SIGNOR up-regulates activity binding 9606 20080105 t 1 miannu We have found that PC4 directly interacts with the REST–CoREST complex. we found that there was a substantial reduction of REST–CoREST complex on the SCN2 promoter upon PC4 silencing in 293T cells. SIGNOR-239325 0.324 MRPL13 protein Q9BYD1 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262380 0.741 NT5E protein P21589 UNIPROT adenosine smallmolecule CHEBI:16335 ChEBI up-regulates quantity chemical modification -1 31461341 t Luana Ecto-5'-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5'-monophosphate to adenosine. SIGNOR-269742 0.8 IL6ST protein P40189 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 9126968 t milica Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase. SIGNOR-250574 0.352 ACTB protein P60709 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270698 0.484 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr681 DIYSTDYyRVGGRTM 9606 9099755 t gcesareni In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785 SIGNOR-47179 0.2 IL10 protein P22301 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 23357618 f miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. SIGNOR-253504 0.2 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CDC25A protein P30304 UNIPROT up-regulates ubiquitination 9606 15340381 t lperfetto Scfb-trcp has recently been shown to degrade phosphorylated cdc25a in the s and g2 phases. SIGNOR-217178 0.492 SIRT1 protein Q96EB6 UNIPROT XPA protein P23025 UNIPROT up-regulates activity deacetylation Lys215 QENREKMkQKKFDKK 9606 30327428 t miannu SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR SIGNOR-258986 0.525 NUP133 protein Q8WUM0 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262089 0.735 bortezomib chemical CHEBI:52717 ChEBI PSMD2 protein Q13200 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 21504411 t miannu Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma. SIGNOR-259313 0.8 GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263815 0.8 valrubicin chemical CHEBI:135876 ChEBI TOP2B protein Q02880 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000096 16019763 t miannu Valrubicin (N-trifluoroacetyladriamycin-14-valerate) is a semi-synthetic derivative of the anthracycline doxorubicin. Valrubicin inhibits the incorporation of nucleosides into nucleic acids, causing extensive chromosomal damage and cell-cycle arrest in the G2 phase. Its principal metabolites inhibit topoisomerase II, thus arresting DNA synthesis. SIGNOR-259384 0.8 CDK1 protein P06493 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 SIGNOR-C17 21902831 t gcesareni Phosphorylation of myod at s200 is common to other cdks, such as the mitotic cyclin b/cdk1, which may prevent inappropriate myod accumulation during mitosis. SIGNOR-176505 0.372 SETD1B protein Q9UPS6 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 32546567 t miannu SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks. SIGNOR-265577 0.2 SUN1 protein O94901 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 t lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. SIGNOR-263282 0.508 SPI1 protein P17947 UNIPROT TAL1 protein P17542 UNIPROT down-regulates activity binding 9606 BTO:0000567 16298389 t irozzo PU.1/Spi-1 binds to the human TAL-1 silencer to mediate its activity.By expressing a mutant protein containing only the ETS domain of PU.1 in human erythroleukemic HEL cells, we demonstrated that PU.1 mediates the transcriptional repression activity of the silencer. Our data clearly demonstrate that PU.1 mediates TAL-1 silencer activity SIGNOR-256048 0.45 EDN1 protein P05305 UNIPROT MC1R protein Q01726 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9767234 f miannu MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression. SIGNOR-252386 0.357 DOLK protein Q9UPQ8 UNIPROT dolichyl beta-D-mannosyl phosphate smallmolecule CHEBI:17624 ChEBI up-regulates quantity chemical modification -1 16923818 t lperfetto Dolichol kinase (DK) catalyzes the CTP-dependent phosphorylation of dolichol in the biosynthesis de novo and possibly the recycling of dolichyl monophosphate in yeast and mammals. SIGNOR-262567 0.8 RPS28 protein P62857 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262423 0.896 TAB3 protein Q8N5C8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 14670075 t lperfetto We have identified a new binding partner of the tgfbeta (transforming growth factor-beta)-activated protein kinase (tak1), termed tab.two distinct tak1 complexes are present in cells. One comprises tak1 complexed with tab1 and tab2, and the other tak1 complexed with tab1 and tab3 (tak1-binding protein-3). Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1. SIGNOR-120325 0.827 FOXO3 protein O43524 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14981546 f Induction of Foxo3a phosphorylation by FLT3-ITD receptors in Ba/F3 cells correlates with the suppression of Foxo-target genes p27Kip1 and the proapoptotic Bcl-2 family member Bim SIGNOR-261527 0.737 BMP15 protein O95972 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 BTO:0000975 16446785 t lperfetto Here we have performed a detailed in situ hybridization analysis of the spatial and temporal expression patterns of the bmp ligands (bmp-2, -3, -3b, -4, -6, -7, -15), receptors (bmpr-ia, -ib, -ii), and bmp antagonist, follistatin, in rat ovaries over the normal estrous cycle. SIGNOR-217538 0.528 PAM16 protein Q9Y3D7 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 t lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. SIGNOR-267699 0.67 Aflibercept chemical SID:134445687 ChEBI VEGFB protein P49765 UNIPROT down-regulates activity chemical inhibition 9606 22813448 t miannu Aflibercept, a fusion protein with binding domains from native VEGF receptors, binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity.This soluble decoy receptor is produced by fusing all-human DNA sequences of the second immunoglobulin (Ig) domain of human VEGF receptor (VEGFR) 1 to the third Ig domain of human VEGFR-2, which then is fused to the Fc region of human IgG-1.2 Aflibercept binds to all VEGF-A and VEGF-B isoforms, as well as the highly related placental growth factor. SIGNOR-259387 0.8 MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates 10090 7791789 f lperfetto The upregulation of p21 occurred at the levels of mrna and protein, SIGNOR-235831 0.41 IL31RA protein Q8NI17 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 18926762 t gcesareni Il-31 can activate janus kinase (jak) 1 and jak2 signaling molecules after binding to its receptor complex. SIGNOR-161430 0.39 SREBF1 protein P36956 UNIPROT ACLY protein P53396 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11994399 f Luana SREBP-1c–responsive genes include those for ATP citrate lyase (which produces acetyl-CoA) and acetyl-CoA carboxylase and fatty acid synthase (which together produce palmitate [C16:0]). SIGNOR-267956 0.473 alvocidib chemical CHEBI:47344 ChEBI CDK4 protein P11802 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258172 0.8 CDX2 protein Q99626 UNIPROT MUC2 protein Q02817 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0004055 12559945 t COS-7 cells were transiently transfected with a CDX1 or CDX2 expression construct and then used for the luciferase assay, reverse transcription-polymerase chain reaction, and electrophoretic mobility shift assay (EMSA). The CDX2 expression construct activated the MUC2 promoter and increased the endogenous MUC2 mRNA level, while the CDX1 one did not. SIGNOR-253966 0.2 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine chemical CHEBI:91419 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190176 0.8 MAPK14 protein Q16539 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 t lperfetto All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below). SIGNOR-154779 0.709 PTPN18 protein Q99952 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr1196 GAVENPEyLTPQGGA 9606 BTO:0000007 25081058 t lperfetto PTPN18 knockdown selectively enhances the EGF-induced tyrosine phosphorylation of the HER2 Y1112, Y1196 and Y1248 sites. |Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop. SIGNOR-262596 0.658 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1714 SPTSPSYsPTSPSYS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248786 0.442 DOK1 protein Q99704 UNIPROT ITGB6 protein P18564 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257693 0.2 CASP7 protein P55210 UNIPROT Caspase 7 complex complex SIGNOR-C232 SIGNOR form complex binding cleavage:Asp206 SGPINDTdANPRYKI 11701129 t lperfetto The quaternary structure of caspase-7 comprises two closely associated heterodimers, with each heterodimer consisting of a large and a small subunit. SIGNOR-256394 0.2 PRKAA1 protein Q13131 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 SIGNOR-C15 15866171 t gcesareni Ampk activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate ampk-dependent cell-cycle arrest SIGNOR-135960 0.458 AKT proteinfamily SIGNOR-PF24 SIGNOR GRIN2C protein Q14957 UNIPROT up-regulates activity phosphorylation Ser1081 GSRPRHAsLPSSVAE 10090 BTO:0004278 19477150 t miannu Here, we demonstrate that PKB/Akt directly phosphorylates NR2C on serine 1096 (S1096). In addition, we identify 14-3-3epsilon as an NR2C interactor, whose binding is dependent on S1096 phosphorylation. These data are all consistent with a model in which NR1 and NR2C oligomerize, PKB phosphorylates S1096, and 14-3-3ε binds to phosphorylated NR2C thereby promoting NR2C-containing NMDA receptor surface expression in cerebellar granule cells. SIGNOR-262620 0.2 CSNK1E protein P49674 UNIPROT TCF3 protein P15923 UNIPROT up-regulates phosphorylation 9606 11524435 t gcesareni Tcf3 is a substrate for both glycogen synthase kinase (gsk) 3 and casein kinase (ck) 1epsilon, and phosphorylation of tcf3 by ckiepsilon stimulates its binding to beta-catenin, an effect reversed by gsk3. SIGNOR-110056 0.2 BTK protein Q06187 UNIPROT DAPP1 protein Q9UN19 UNIPROT up-regulates activity phosphorylation Tyr139 KVEEPSIyESVRVHT BTO:0000776 10880360 t lperfetto Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins. SIGNOR-249313 0.658 NBEAL2 protein Q6ZNJ1 UNIPROT Platelet_alpha_granule_formation phenotype SIGNOR-PH136 SIGNOR up-regulates 9606 BTO:0000132 28082341 f lperfetto We compared platelet size and number of α-granules for two NBEAL2 and two GATA1-deficient patients and found reduced numbers of α-granules for all, with the defect being more pronounced for NBEAL2 deficiency.  SIGNOR-261883 0.7 MTA2 protein O94776 UNIPROT FSHR protein P23945 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001238 23086931 f miannu Chromatin modifier MTA2 participates in the down-regulation of FSHR transcription. MTA2 is a potent corepressor of FSHR transcription, because it can recruit histone deacetylase-1 onto the FSHR promoter and participates in the down-regulation of FSHR expression upon FSH treatment. SIGNOR-254226 0.251 MAPK1 protein P28482 UNIPROT PPARG protein P37231 UNIPROT down-regulates relocalization 9606 18596912 t fspada The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform SIGNOR-179400 0.469 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258233 0.8 IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10116 BTO:0001103 21798082 t lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate (pip2). SIGNOR-252694 0.759 PTPRB protein P23467 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t gcesareni Identification of tyrosine phosphatases that dephosphorylate the insulin receptor. SIGNOR-76001 0.35 GCSH protein P23434 UNIPROT Glycine cleavage system complex SIGNOR-C437 SIGNOR form complex binding 9606 16051266 t lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. SIGNOR-268241 0.727 BTF3 protein P20290 UNIPROT SSPN protein Q14714 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000584 17312387 f In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. SIGNOR-253951 0.2 clofarabine chemical CHEBI:681569 ChEBI POLG protein P54098 UNIPROT down-regulates activity chemical inhibition 9606 1707752 t miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase. SIGNOR-258361 0.8 ZBTB32 protein Q9Y2Y4 UNIPROT ZBTB16/ZBTB32 complex SIGNOR-C80 SIGNOR form complex binding 9606 10572087 t miannu We show that fazf is a transcriptional repressor and it readily forms heterodimers with plzf. SIGNOR-72380 0.368 palbociclib chemical CHEBI:85993 ChEBI CDK6 protein Q00534 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205707 0.8 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2L5 protein A0A1B0GUS4 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271365 0.2 ATF6 protein P18850 UNIPROT XBP1 protein P17861-2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network SIGNOR-260184 0.675 KDM4B protein O94953 UNIPROT BBC3 protein Q9BXH1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001109 28073943 f miannu JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. SIGNOR-263732 0.2 PRKCA protein P17252 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser371 AHSSHLKsKKGQSTS -1 9571186 t lperfetto Here, we demonstrate that cotransfection of p53 with either PKC alpha or PKC zeta increases p53's transcriptional activity. Mutagenesis of p53 indicates that serine 371 is the major site for phosphorylation by PKC alpha in vitro. SIGNOR-248999 0.448 CASK protein O14936 UNIPROT Exocytosis phenotype SIGNOR-PH157 SIGNOR up-regulates 9606 BTO:0000938 11036064 f miannu As neurexins have been proposed to function in neuronal cell adhesion, it is possible that they define specific sites at the plasma membrane and that Mint complexes and Mint1-CASK complexes on neurexin are involved in the localized recruitment of Munc18 to the sites of exocytosis. In support of this hypothesis, both CASK and Mint1 have been reported to be localized at synapses SIGNOR-264044 0.7 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Thr305 TDAATMKtFCGTPEY 10090 15367694 t Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes SIGNOR-248654 0.727 PRKG2 protein Q13237 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Ser553 KNAHAKAsRTSSKHK 9606 BTO:0002181 21177494 t miannu  PKGII directly phosphorylated and stimulated SHP-1 activity SIGNOR-276288 0.2 MITF protein O75030 UNIPROT MLANA protein Q16655 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000848 12819038 f miannu The results of the present work demonstrate that the essential melanocyte-specific transcription factor MITF regulates expression of the genes encoding the melanoma tumor markers MLANA and SILV. MITF up- or down-regulation is seen to correspondingly modulate expression of MLANA and SILV in parallel directions, at both mRNA and protein levels. SIGNOR-254590 0.481 Ub:HECT_E3 complex SIGNOR-C518 SIGNOR Protein_ubiquitination phenotype SIGNOR-PH214 SIGNOR up-regulates 9606 34199813 f miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. SIGNOR-271382 0.7 ARRY-520 chemical CID:44224257 PUBCHEM KIF11 protein P52732 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189891 0.8 PPP2R5B protein Q15173 UNIPROT BCL2 protein P10415 UNIPROT down-regulates dephosphorylation Ser70 RDPVARTsPLQTPAA 9606 18845789 t gcesareni Pp2a directly interacts with the bh4 domain of bcl2 as a docking site to potentially bridge pp2a to bcl2's flexible loop domain containing the target serine 70 phosphorylation site. SIGNOR-181559 0.305 DYRK1A protein Q13627 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 19383720 t gcesareni Dyrk1a physically interacts with the nicd inducing its phosphorylation in the ankyrin domain, thereby attenuating notch . SIGNOR-185494 0.405 MAPK3 protein P27361 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates phosphorylation Ser359 SALSYLQsPITTSPS 9606 10617468 t lperfetto Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein. SIGNOR-73629 0.778 CBLB protein Q13191 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0000661 8626404 t lperfetto Here we show that in unstimulated Jurkat cells Cbl is co-immunoprecipitated with monoclonal antibody against Grb2. SIGNOR-236051 0.584 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269385 0.719 SIRT7 protein Q9NRC8 UNIPROT FBL protein P22087 UNIPROT up-regulates activity deacetylation Lys205 RDLINLAkKRTNIIP 30540930 t lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) SIGNOR-275892 0.274 UIMC1 protein Q96RL1 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates binding 9606 BTO:0000150 17525342 t gcesareni Rap80 specifically recruits brca1 to dna damage sites and functions with brca1 in g2/m checkpoint control SIGNOR-155201 0.907 AMPK complex SIGNOR-C15 SIGNOR GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser8 MPLNRTLsMSSLPGL -1 22233421 t miannu Recombinant muscle GYS1 (glycogen synthase 1) and recombinant liver GYS2 were phosphorylated by recombinant AMPK (AMP-activated protein kinase) in a time-dependent manner and to a similar stoichiometry. The phosphorylation site in GYS2 was identified as Ser7, which lies in a favourable consensus for phosphorylation by AMPK. Phosphorylation of GYS1 or GYS2 by AMPK led to enzyme inactivation by decreasing the affinity for both UDP-Glc (UDP-glucose) [assayed in the absence of Glc-6-P (glucose-6-phosphate)] and Glc-6-P (assayed at low UDP-Glc concentrations). SIGNOR-263102 0.479 (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 9606 33064660 t miannu Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. SIGNOR-267721 0.8 PPM1D protein O15297 UNIPROT RPS6KA3 protein P51812 UNIPROT down-regulates activity dephosphorylation Ser227 DHEKKAYsFCGTVEY 10090 15206906 t RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity SIGNOR-248320 0.368 PHKG1 protein Q16816 UNIPROT PYG proteinfamily SIGNOR-PF96 SIGNOR up-regulates activity phosphorylation 9606 BTO:0002049 22225877 t It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15 SIGNOR-267960 0.671 PARP1 protein P09874 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity relocalization 9606 17891139 t miannu We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus. SIGNOR-261321 0.575 CSNK1A1 protein P48729 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity phosphorylation Ser75 LGYEPEGsASPTPPY -1 17318175 t lperfetto Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling. SIGNOR-249189 0.776 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t gcesareni Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190. SIGNOR-75902 0.385 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser288 PESEDEEsYDTESEF 9606 BTO:0000782 8622692 t llicata Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation. SIGNOR-40506 0.567 SF3b complex SIGNOR-C442 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 32140746 f lperfetto The SF3b complex is an intrinsic component of the functional U2 small nuclear ribonucleoprotein (snRNP). As U2 snRNP enters nuclear pre-mRNA splicing, SF3b plays key roles in recognizing the branch point sequence (BPS) and facilitating spliceosome assembly and activation. SIGNOR-268414 0.7 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT up-regulates phosphorylation Thr320 AISDTTTtFCGTPEY 9606 16790420 t llicata Full-length sgk3 contains a complete phox homology (px) domain that targets the protein to endosomes. Both a functional px domain and pi3k activation are necessary for phosphorylation of sgk3 at two regulatory sites (thr-320 and ser-486) and subsequent induction of kinase activity. Pdk1 phosphorylates endosome-associated sgk3 at thr-320 SIGNOR-147213 0.473 PRKCA protein P17252 UNIPROT HNRNPA1 protein P09651 UNIPROT down-regulates phosphorylation Ser95 RAVSREDsQRPGAHL 9606 7727389 t gcesareni A survey of seven protein kinases showed that a1 was heavily phosphorylated by protein kinase c (pkc) and also was phosphorylated by casein kinase iiamino acid sequencing revealed that these sites were ser95, ser192, and ser199;phosphorylation at ser192 was more abundant than at ser95 and ser199. Phosphorylation by pkc inhibited the strand annealing activity of a1. SIGNOR-32291 0.2 CENPK protein Q9BS16 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265212 0.713 TRAF2 protein Q12933 UNIPROT BIRC2 protein Q13490 UNIPROT up-regulates activity binding 9606 BTO:0000459 18621737 t lperfetto Through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2. SIGNOR-179449 0.868 4-methylumbelliferone chemical CHEBI:17224 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258057 0.8 SL-327 chemical CHEBI:92211 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 BTO:0000938 BTO:0000142 11160424 t lperfetto The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity SIGNOR-244955 0.8 FRAT2 protein O75474 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity binding -1 11738041 t gcesareni The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation. SIGNOR-244030 0.683 FYN protein P06241 UNIPROT IFITM3 protein Q01628 UNIPROT up-regulates quantity phosphorylation Tyr20 NSGQPPNyEMLKEEH 10090 BTO:0000452 24627473 t miannu We determined that both mouse and human IFITM3 are phosphorylated by the protein-tyrosine kinase FYN on tyrosine 20 (Tyr(20)). Phosphorylation of IFITM3 on Tyr20 Leads to Plasma Membrane Accumulation. SIGNOR-266304 0.464 PHLPP1 protein O60346 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity dephosphorylation Ser338 RPRGQRDsSYYWEIE 10090 24530606 t gcesareni PHLPP1 and PHLPP2 dephosphorylate RAF1 to reduce its signaling, increase the invasive and migratory activities of CRC cells, and activate the epithelial-mesenchymal transition. In Apc(Min) mice, loss of PHLPP1 promotes tumor progression. SIGNOR-237449 0.275 ROCK1 protein Q13464 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates activity phosphorylation Ser1236 PKPKPRPsITKATWE 9534 BTO:0000298 19103606 t miannu these results indicate that Rho-kinase can phosphorylate p190A RhoGAP at Ser1150 in COS7 cells. Similarly, the immunoblot analysis, through the use of the anti-p190A RhoGAP-pT1226 and -pS1236 antibodies, revealed that Rho-kinase can phosphorylate p190A RhoGAP at Thr1226 and Ser1236 in COS7 cells SIGNOR-276176 0.424 CDK4 protein P11802 UNIPROT RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Ser207 TSVRRRTsFYLPKDA 9606 SIGNOR-C18 18071316 t llicata This skp2-dependent destruction of rassf1a requires phosphorylation of the latter on serine-203 by cyclin d-cyclin-dependent kinase 4. SIGNOR-159849 0.419 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RXRB protein P28702 UNIPROT up-regulates activity chemical activation 9606 18321241 t miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). SIGNOR-259238 0.8 CSNK1E protein P49674 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Ser143 FHPNVSSsHENLEPE 9606 22609948 t lperfetto We demonstrated that dvl2 is phosphorylated at s143 and t224 in a manner that requires both non-canonical wnt5a ligand and casein kinase 1 epsilon (ck1_), and that this event is critical to interact with plk1 in early stages of the cell cycle SIGNOR-197063 0.68 BCOR protein Q6W2J9 UNIPROT Noncanonical PRC1 complex SIGNOR-C151 SIGNOR form complex binding 10090 25533466 t miannu inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. SIGNOR-255276 0.562 Tert-butyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate chemical CID:46907787 PUBCHEM BRD2 protein P25440 UNIPROT down-regulates activity chemical inhibition 9606 30080437 t Simone Vumbaca Through the integrative analyses of ChIP-seq and CAGE data, we elucidate the involvement of BRD2 in gene regulation upon BET inhibition by JQ1 in H23 cells. SIGNOR-261124 0.8 KDM5D protein Q9BY66 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-264309 0.2 SLC9A5 protein Q14940 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265604 0.8 EIF3_complex complex SIGNOR-C401 SIGNOR EIF4G1 protein Q04637 UNIPROT up-regulates activity stabilization 9606 17581632 t lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit SIGNOR-269155 0.624 vandetanib chemical CHEBI:49960 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258308 0.8 EEF1A2 protein Q05639 UNIPROT Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269537 0.8 CD40 protein P25942 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 BTO:0000782;BTO:0000776 19904719 f fstefani Cd40 has been found to be essential in mediating a broad variety of immune and inflammatory responses including t cell-dependent immunoglobulin class switching, memory b cell development SIGNOR-189109 0.7 UBE3A protein Q05086 UNIPROT PSMD7 protein P51665 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 28559284 t lperfetto Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits. SIGNOR-265134 0.274 PTPN11 protein Q06124 UNIPROT PDCD1 protein Q15116 UNIPROT down-regulates activity dephosphorylation 9606 32437509 t miannu Related to the latter notion, we recently showed that SHP2 dephosphorylates PD-1 to disassemble the PD-1:SHP2 complex ( xref ). SIGNOR-277052 0.645 DNA polymerase delta complex SIGNOR-C376 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9534 BTO:0004055 12930972 f lperfetto Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA). SIGNOR-265513 0.7 PJA2 protein O43164 UNIPROT PRKAR1B protein P31321 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21423175 t miannu Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits SIGNOR-271857 0.2 PLCG1 protein P19174 UNIPROT ITPRIPL1 protein Q6GPH6 UNIPROT up-regulates 9606 BTO:0000938 21368195 f gcesareni Recruitment of g protein also can activate phospholipase c (plc) that in turn increases inositol triphosphate (ip3) levels and induces ca2+ release from internal stores SIGNOR-172500 0.2 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7222 FRSRGRRsKPSSRAA 9606 BTO:0004905 21295697 t lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. SIGNOR-264426 0.446 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 11904305 t gcesareni Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. sa-perk1/2 activates the transcription factor, sp1, via ser59 phosphorylation downstream of pkc_, leading to transcription of p21sdi1 and resulting in replicative senescence of hdf cells. SIGNOR-116174 0.639 APH1A protein Q96BI3 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t Gamma secretase subunit that leads to PS1/PS2 eterodimer complex stabilisation. gcesareni By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. SIGNOR-93262 0.946 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270383 0.8 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser126 NPEAESSsKEGELDA -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276115 0.698 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser40 GQGAPGPsLTGSPWP 9606 12421349 t The effect has been demonstrated using P07101-3 gcesareni Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax SIGNOR-95483 0.27 TCL1B protein O95988 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t gcesareni In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation. SIGNOR-81716 0.546 SRC protein P12931 UNIPROT ARAF protein P10398 UNIPROT up-regulates phosphorylation Tyr301 LGYRDSGyYWEVPPS 9534 BTO:0004055 9020159 t lperfetto A-raf behaves like raf-1, being weakly activated by oncogenic ras more strongly activated by oncogenic src, and these signals synergize to give maximal activation. Activation of Raf-1 and A-Raf by Src requires tyrosine phosphorylation at residues 340 and 341 in Raf-1 and 301 and 302 in A-Raf. SIGNOR-236037 0.467 PIH1D1 protein Q9NWS0 UNIPROT R2TP core co-chaperone complex SIGNOR-C515 SIGNOR form complex binding 9606 29662061 t miannu  Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90.  SIGNOR-270926 0.838 PRKCA protein P17252 UNIPROT NPHS1 protein O60500 UNIPROT up-regulates activity phosphorylation Thr1125 QWTGERDtQSSTVST 9606 BTO:0000007 21321125 t llicata Binding of _-arrestin2 to the nephrin intracellular domain depended on phosphorylation of nephrin threonine residues 1120 and 1125 by pkc_. SIGNOR-172056 0.2 FBXO22 protein Q8NEZ5 UNIPROT BSG protein P35613 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007;BTO:0003227;BTO:0005816 28117675 t lperfetto F-Box Protein FBXO22 Mediates Polyubiquitination and Degradation of CD147 to Reverse Cisplatin Resistance of Tumor Cells SIGNOR-273452 0.437 CREB1 protein P16220 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20577053 f gcesareni In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1 SIGNOR-166346 0.252 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203572 0.769 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1738 SPSYSPTsPSYSPTS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248813 0.849 Complement C1 complex complex SIGNOR-C309 SIGNOR C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263424 0.629 TAF8 protein Q7Z7C8 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263927 0.867 TGFB1 protein P01137 UNIPROT MYOG protein P15173 UNIPROT down-regulates 10090 14739161 f lperfetto Tgf-beta was shown to inhibit myogenin and mef2d expression and myotube formation in c2c12. SIGNOR-235728 0.261 4-{[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]amino}benzoic acid chemical CHEBI:64210 ChEBI RARB protein P10826 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 t Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  SIGNOR-258035 0.8 HOXB8 protein P17481 UNIPROT PBX1 protein P40424 UNIPROT up-regulates activity binding 9606 BTO:0001545 11571641 t miannu the ability of HoxB8 to heterodimerizes with endogenous Pbx proteins on DNA alters gene transcription in a manner that prevents progression through an intrinsic genetic differentiation program. In conjunction with Pbx, HoxB8 could alter transcription of Pbx target genes by direct or indirect mechanisms. SIGNOR-223153 0.513 THR proteinfamily SIGNOR-PF84 SIGNOR RARG protein P13631 UNIPROT up-regulates binding 9606 15650024 t inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. SIGNOR-270315 0.2 AURKA protein O14965 UNIPROT NEDD9 protein Q14511 UNIPROT up-regulates activity phosphorylation Ser296 PVARRHQsLSPNHPP 9606 BTO:0000093 16184168 t miannu HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins. SIGNOR-262654 0.587 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258633 0.8 U2AF2 protein P26368 UNIPROT U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR form complex binding 9606 8647433 t miannu The splicing factor u2af (u2 snrnp auxiliary factor) is a heterodimer with subunits of 65 and 35 kd (u2af65 and u2af35). SIGNOR-41948 0.2 HCFC1 protein P51610 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. SIGNOR-267165 0.587 SGK3 protein Q96BR1 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 12054501 t lperfetto Human serum and glucocorticoid-inducible kinase-like kinase (SGKL) phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9 through direct interaction SIGNOR-249166 0.453 AMPK complex SIGNOR-C15 SIGNOR CDC27 protein P30260 UNIPROT unknown phosphorylation Ser379 NALPRRSsRLFTSDS 9606 22137581 t lperfetto Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379, respectively) resulted in an almost complete loss of ampk phosphorylation in these proteins SIGNOR-216434 0.274 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR BIRC6 protein Q9NR09 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271318 0.388 BUB1 protein O43683 UNIPROT CENPE protein Q02224 UNIPROT up-regulates activity relocalization 11402067 t lperfetto Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity SIGNOR-252016 0.823 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr387 RPGPGTLyDVPRERV 10090 12972425 t lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs SIGNOR-246413 0.796 CCL11 protein P51671 UNIPROT CCR3 protein P51677 UNIPROT up-regulates binding 9606 24702154 t Eotaxin (CCL11) is a specific ligand for CCR3 and serves as a potent chemoattractant for eosinophils SIGNOR-254356 0.934 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 17350953 t gcesareni Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kda fk506- and rapamycin-binding protein (fkbp12, or fkbp) and the fkbp-rapamycin binding (frb) domain of the mammalian target of rapamycin (mtor) kinase. autophagy is negatively regulated by the mammalian target of rapamycin (mtor) and can be induced in all mammalian cell types by the mtor inhibitor rapamycin. SIGNOR-153608 0.8 MACROD2 protein A1Z1Q3 UNIPROT 2''-O-acetyl-ADP-D-ribose(2-) smallmolecule CHEBI:83767 ChEBI down-regulates quantity chemical modification 9606 32257385 t miannu MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins SIGNOR-269839 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates binding 9606 23400686 t gcesareni Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1. SIGNOR-200875 0.2 CTDSP2 protein O14595 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser213 NLSPNPMsPAHNNLD 9606 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248295 0.399 EEF1A1P5 protein Q5VTE0 UNIPROT Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269544 0.8 JAG1 protein P78504 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 18660822 t Binding Calcium-dependent gcesareni Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch. SIGNOR-179625 0.629 GRM6 protein O15303 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. SIGNOR-264937 0.8 MAP3K7 protein O43318 UNIPROT RAB1A protein P62820 UNIPROT up-regulates activity phosphorylation Thr75 AGQERFRtITSSYYR -1 27482120 t miannu TAK1 preferentially phosphorylates the inactive (GDP-bound) state of Rab1. Phosphorylation of Rab1 disrupts interaction with GDP dissociation inhibitor 1 (GDI1), but not guanine exchange factor (GEF) or GTPase-activating protein (GAP) enzymes, and is exclusive to membrane-localized Rab1, suggesting phosphorylation may stimulate Rab1 membrane association. Furthermore, we found phosphorylation of Rab1 at T75 to be essential for Rab1 function. SIGNOR-277270 0.2 AKT2 protein P31751 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates activity phosphorylation Thr346 APRPRVEtSRAVPLA -1 27505672 t miannu  Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex.  SIGNOR-277271 0.383 AKT1 protein P31749 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates activity phosphorylation Thr346 APRPRVEtSRAVPLA -1 27505672 t miannu  Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex.  SIGNOR-277272 0.619 PPM1D protein O15297 UNIPROT MDM4 protein O15151 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser403 DLAHSSEsQETISSM 33309518 t lperfetto PPM1D also inhibits p53 activity by dephosphorylating Ser395 and stabilizing MDM2 and by dephosphorylating Ser403 on MDMX SIGNOR-275491 0.442 GSK3B protein P49841 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity by destabilization phosphorylation Ser184 GKTTTTNsKREEKLF 9606 BTO:0002548 27572267 t miannu We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP. SIGNOR-277275 0.312 GSK3B protein P49841 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity by destabilization phosphorylation Thr180 QVLSGKTtTTNSKRE 9606 BTO:0002548 27572267 t miannu We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP. SIGNOR-277276 0.312 IL23R protein Q5VWK5 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates 9606 BTO:0000782 12023369 f gcesareni Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12. SIGNOR-87838 0.574 PDCD1 protein Q15116 UNIPROT DNM1L protein O00429 UNIPROT down-regulates activity 9606 BTO:0000782 34535949 f Barakat Mechanistically, we provided evidence that PD1 signaling downregulates Drp1 activating phosphorylation on Ser616 (and consequently mitochondrial fragmentation) via the inhibition of ERK1/2 and mTOR kinases. SIGNOR-275406 0.2 GSK3B protein P49841 UNIPROT GLI2 protein P10070 UNIPROT down-regulates quantity by destabilization phosphorylation Ser820 VSSAYTVsRRSSGIS 9606 BTO:0000007 16611981 t lperfetto The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3. SIGNOR-148472 0.544 AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation. SIGNOR-244296 0.2 NEK2 protein P51955 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization phosphorylation Thr194 EEKLFNVtSTLRINT 10090 BTO:0000584 34315872 t miannu NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen.  SIGNOR-277315 0.2 IL4 protein P05112 UNIPROT IL13RA1 protein P78552 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica It is now known that this alternate receptor is a heterodimer, the type ii il-4 receptor or the il-13 receptor, which is comprised of IL-4R And IL-13R1. SIGNOR-100759 0.773 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1167 ESAPAESsPSKIMSK 9606 8816480 t gcesareni In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1 SIGNOR-43943 0.621 TRIM47 protein Q96LD4 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates quantity ubiquitination 10090 BTO:0000575 29291351 t gianni CYLD is progressively degraded upon interaction with the E3 ligase TRIM47 in proportion to NASH severity SIGNOR-266443 0.2 SMAD1 protein Q15797 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 22298955 t gcesareni Smad1 interacts with runx2 on the promoter of target genes and controls osteoblast gene expression and differentiation SIGNOR-195642 0.554 CCNT1 protein O60563 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15546612 f gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. SIGNOR-130634 0.2 SPI1 protein P17947 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26622774 f miannu In the present study, PU.1 siRNA was demonstrated to efficiently inhibit the transcription level of oncogene MEIS1 in the human acute myeloid non-MLL leukemia U937 cell line. In addition, PU.1, as a positive regulator of MEIS1, performed a crucial role in maintaining cell proliferation. SIGNOR-256002 0.381 UBE2I protein P63279 UNIPROT JUN protein P05412 UNIPROT down-regulates activity sumoylation Lys254 MESQERIkAERKRMR 9606 SIGNOR-C154 16055711 t lperfetto We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. SIGNOR-263001 0.43 TCF3 protein P15923 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 22577461 f miannu E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r. SIGNOR-197523 0.437 CDK14 protein O94921 UNIPROT CCNY protein Q8ND76 UNIPROT down-regulates quantity by destabilization phosphorylation Ser73 STIFLSKsQTDVREK 9606 BTO:0000599 24794231 t lperfetto Phosphorylation of cyclin Y by CDK14 induces its ubiquitination and degradation|Phosphorylation of CCNY at Serines 71 and 73 creates a putative phospho-degron that controls its association with an SCF complex SIGNOR-273007 0.824 PAK1 protein Q13153 UNIPROT VIM protein P08670 UNIPROT unknown phosphorylation Ser56 SRSLYASsPGGVYAT 9606 BTO:0000887;BTO:0001260 15766329 t llicata In the present study, pak1 was able to phosphorylate vimentin on ser-56 in vitro. SIGNOR-134520 0.2 3-phenanthryl hydrogen sulfate chemical CHEBI:37459 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition -1 7576010 t miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. SIGNOR-258438 0.8 CDK1 protein P06493 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates phosphorylation Thr159 DGSEPTKtPGRTSST 9606 20513426 t llicata We show that vps34 is phosphorylated on thr159 by cdk1, thr159 phosphorylation negatively regulates the ptdins3 kinase activity of vps34 and autophagy SIGNOR-165768 0.43 MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity BTO:0001103 7532173 f Simone Vumbaca These results suggest that at least initially, the muscle-forming regions contained cells with myogenic potential, and that this potential is lost in the myogenin mutants as development proceeds. SIGNOR-255644 0.7 CDK1 protein P06493 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser36 PRKQPPVsPGTALVG 9606 17960875 t gcesareni Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation. SIGNOR-158604 0.392 RAB6A protein P20340 UNIPROT VPS13B protein Q7Z7G8 UNIPROT up-regulates activity binding 10116 BTO:0003102 25492866 t miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. We show that COH1 forms a physical and functional complex with RAB6. Our results point to a role of COH1 as a RAB6 effector protein. Depletion of COH1 leads to decreased neurite outgrowth in cultured primary hippocampal neurons. These results establish a critical role for RAB6-dependent function of COH1 in neuritogenesis by regulating Golgi complex organization. SIGNOR-266869 0.38 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates phosphorylation Ser141 TVKQKYLsFTPPEKD 9606 BTO:0000007 16204230 t gcesareni Pak2 is autophosphorylated at eight sites;ser-141 and ser-165 in the regulatory domain and thr-402 in the activation loop are identified as key sites in activation of the protein kinase. SIGNOR-140907 0.2 HES1 protein Q14469 UNIPROT NEUROG2 protein Q9H2A3 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 f lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production SIGNOR-265142 0.324 PICALM protein Q13492 UNIPROT CLTCL1 protein P53675 UNIPROT up-regulates binding 9606 BTO:0001271;BTO:0000785 16491119 t miannu Calm interacts with the clathrin heavy chain through its c-terminal third and with phophoinositides through its ap180 n-terminal homology (anth) domain, promoting assembly of clathrin triskelia into clathrin cagesin vitro SIGNOR-144733 0.718 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity phosphorylation Ser408 GPLPRAPsISTVEPK 9606 26190112 t Luana AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. SIGNOR-259863 0.339 MED27 protein Q6P2C8 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266662 0.8 NOL9 protein Q5SY16 UNIPROT Rix1 complex complex SIGNOR-C373 SIGNOR form complex binding 9606 BTO:0000007 22190735 t miannu LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes. SIGNOR-265470 0.79 MYCN protein P04198 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000931 23175188 f miannu Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. SIGNOR-255145 0.384 MIB2 protein Q96AX9 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates activity polyubiquitination Lys377 NEPSLQSkLQDEANY 9606 BTO:0000815 29642005 t miannu Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2) regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation.  We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD association. MIB2 Ubiquitylates RIPK1 at Lysines K377 and K634 SIGNOR-272662 0.299 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser213 QNIPAHYsPRTSPIM 9606 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248516 0.387 SMAD1 protein Q15797 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates binding 9606 SIGNOR-C85 21454478 t lperfetto Upon ligand binding, the specific heteromeric transmembrane serine/threonine kinase receptor complexes undergo phosphorylation/activation and subsequently phosphorylate the two ser residues in the c-terminal sxs motif of specific r-smads, smad1/5/8 for bmp pathway and smad2/3 for tgf-_/activin signaling. The activated r-smads then associate with co-smad, smad4. The heteromeric complexes translocate into the nucleus, where they bind to dna directly or indirectly to regulate the transcription of specific genes. SIGNOR-172990 0.657 MORF4L1 protein Q9UBU8 UNIPROT Sin3B_complex complex SIGNOR-C409 SIGNOR form complex binding 9606 BTO:0000007 21041482 t miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. our data suggest that the tethering of HDAC1, as part of this complex, to these loci promotes histone deacetylation within the coding region and prevents uncontrolled RNAP II progression at transcribed loci. SIGNOR-266966 0.797 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser21 TPPSTALsPGKMSEA 9606 21059642 t The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). SIGNOR-273031 0.563 N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-268103 0.8 CLK1 protein P49759 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser50 RNRYRDVsPFDHSRI 9606 10480872 t gcesareni The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation. SIGNOR-70563 0.353 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7314 KSASRPGsRAGSRAG 9606 BTO:0004905 21295697 t lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. SIGNOR-264431 0.446 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation Tyr323 STVSFNPyEPELAPW 9606 BTO:0000776 9820500 t lperfetto These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520 SIGNOR-246605 0.2 SMAD1 protein Q15797 UNIPROT SMAD6 protein O43541 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 t Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation SIGNOR-268935 0.561 MBTPS1 protein Q14703 UNIPROT CREB3L2 protein Q70SY1 UNIPROT up-regulates cleavage 9606 BTO:0000938 BTO:0000142 17178827 t miannu Bbf2h7 is cleaved by s1p in response to er stress / cleaved fragments of the bbf2h7 n-terminal portion containing the bzip domain translocate into nuclei SIGNOR-151309 0.543 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 9335504 t llicata In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1 SIGNOR-52678 0.591 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation Ser273 RPASVNGsPSATSES 9606 BTO:0000007 16446428 t gcesareni Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222 SIGNOR-249580 0.644 HLA-DRA protein P01903 UNIPROT Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 BTO:0000776 21178476 f scontino Fusion with a B cell requires a ternary complex of gHgLgp42. Fusion is triggered by an interaction between gp42 and HLA class II. SIGNOR-266630 0.7 GSK3B protein P49841 UNIPROT STK38 protein Q15208 UNIPROT down-regulates activity phosphorylation Ser6 sTPCSSMS -1 22142472 t miannu GSK-3β phosphorylated STK38 on residues S6 and T7 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively.  Our results indicate that that GSK-3β inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress. SIGNOR-276392 0.281 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser171 PLCLSPAsSGSSASF 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248510 0.387 LRFN4 protein Q6PJG9 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu The SALM (synaptic adhesion-like molecule) family of adhesion molecules, also known as Lrfn, belongs to the superfamily of leucine-rich repeat (LRR)-containing adhesion molecules. Proteins of the SALM family, which includes five known members (SALMs 1-5), have been implicated in the regulation of neurite outgrowth and branching, and synapse formation and maturation.SALM3 and SALM5, but not other SALMs, possess synaptogenic activity, inducing presynaptic differentiation in contacting axons. SIGNOR-264092 0.7 CCNE1 protein P24864 UNIPROT CDK2 protein P24941 UNIPROT up-regulates binding 9606 23437375 t gcesareni Our results suggest that ad-induced cyclin e activates cdk2 that targets the transcriptional repressor prb/cyclin e activates the cdk2 kinase necessary for the actual initiation of dna replication SIGNOR-201506 0.954 EGLN2 protein Q96KS0 UNIPROT ADSL protein P30566 UNIPROT up-regulates activity hydroxylation Pro24 LASRYASpEMCFVFS 9606 BTO:0000007 31729379 t miannu ADSL is hydroxylated by EglN2 on Proline 24. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. ADSL regulates cMYC protein level through adenosine levels SIGNOR-266613 0.2 WNT2B protein Q93097 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors andinitiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131780 0.583 GADD45B protein O75293 UNIPROT CDK11A protein Q9UQ88 UNIPROT down-regulates activity binding 9606 BTO:0000007 26885618 t lperfetto Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 |We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58. SIGNOR-273024 0.2 CUL1 protein Q13616 UNIPROT RNF7 protein Q9UBF6 UNIPROT up-regulates activity binding 9606 10851089 t miannu SAG was found to be the second family member of Rbx (RING box protein) or ROC (Regulator of cullins) or Hrt that is a component of SCF E3 ubiquitin ligase. Indeed, like ROC1/Rbx1/Hrt1, SAG binds to Cul1 and SAG-Cul1 complex has ubiquitin ligase activity to promote poly-ubiquitination of E2/Cdc34.  SIGNOR-271444 0.852 NUP62 protein P37198 UNIPROT TUBG1 protein P23258 UNIPROT up-regulates activity binding 9606 BTO:0000567 24107630 t Simone Furthermore, we found interactions and co-localization with γ-tubulin and SAS-6. Our results also point to a potential role of Nup62 in targeting gamma-tubulin and SAS-6 to the centrioles. SIGNOR-261257 0.2 GSK3A protein P49840 UNIPROT FCAR protein P24071 UNIPROT down-regulates activity phosphorylation Ser284 LTFARTPsVCK 10090 BTO:0001516 30766540 t lperfetto GSK-3 is constitutively active in the absence of cytokine stimulation and can phosphorylate S263, keeping FcalphaRI in the inactive state. SIGNOR-264856 0.2 RPS6KA5 protein O75582 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 10464286 t gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-265348 0.2 TNFRSF13C protein Q96RJ3 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates 9606 BTO:0000776 24432023 f lperfetto Non-canonical nf-kb signaling initiated by baff influences b cell biology at multiple junctures. SIGNOR-204361 0.7 STOML2 protein Q9UJZ1 UNIPROT ATP smallmolecule CHEBI:15422 ChEBI up-regulates quantity 9606 20359165 f Giorgia In addition, mitochondrial and whole-cell ATP levels in resting SLP-2hi T cells were significantly higher than those in SLP-2lo T cells (P < 0.05) (Fig. 7d). Such an increase in ATP levels in SLP-2hi T cells correlated with increased resistance to depletion of mitochondrial ATP with oligomycin SIGNOR-260384 0.8 NOTCH proteinfamily SIGNOR-PF30 SIGNOR PIN1 protein Q13526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 19151708 f lperfetto Previously, we have shown that commitment of the C2C12 cells to the osteoblastic lineage occurs around 24h after BMP treatment, when the osteoblast specific transcription factor Cbfa1 and the novel osteoblast related genes Tcf7 and Hey1 become regulated SIGNOR-254342 0.2 ITGA2 protein P17301 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253171 0.749 PPARD protein Q03181 UNIPROT HSD11B2 protein P80365 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001975 15591138 f miannu Peroxisome proliferator-activated receptor delta suppresses 11beta-hydroxysteroid dehydrogenase type 2 gene expression in human placental trophoblast cells. SIGNOR-255050 0.319 TKT protein P29401 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI down-regulates quantity chemical modification 9606 24929114 t miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. SIGNOR-267086 0.8 ARRB2 protein P32121 UNIPROT ADRB1 protein P08588 UNIPROT down-regulates activity binding -1 2163110 t The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors SIGNOR-256502 0.481 TNF protein P01375 UNIPROT SERPINA3 protein P01011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002600 11027208 f miannu We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. SIGNOR-254809 0.2 ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 17306385 t miannu Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase SIGNOR-256168 0.773 GTF3C5 protein Q9Y5Q8 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR form complex binding 9606 29378333 t lperfetto Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains SIGNOR-266184 0.91 TNPO1 protein Q92973 UNIPROT FUS protein P35637 UNIPROT up-regulates activity relocalization -1 23056579 t lperfetto The C-terminal nuclear localization sequence of FUsed in Sarcoma (FUS-NLS) is critical for its nuclear import mediated by transportin (Trn1). SIGNOR-262101 0.662 CAMK4 protein Q16566 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 7925472 t gcesareni Serine 16 of oncoprotein 18 is a major cytosolic target for the ca2+/calmodulin-dependent kinase-gr. SIGNOR-34743 0.468 PAMPs stimulus SIGNOR-ST11 SIGNOR MBL2 protein P11226 UNIPROT up-regulates activity binding 17204478 t lperfetto In the lectin pathway, mannose-binding lectin (MBL) and ficolins bind to pathogens and activate MBL-associated serine protease-2 (MASP-2) SIGNOR-263405 0.7 CCL5 protein P13501 UNIPROT CCR1 protein P32246 UNIPROT up-regulates binding 9606 10734056 t RANTES interacts with specific cell surface receptors, which are coupled to pertussis toxin-sensitive guanine nucleotide regulatory proteins (G protein) to activate effectors such as phospholipase C (PLC), ion channels, phospholipase D, and protein kinase C. In addition to the CCR1 receptor, RANTES activates several members of the CC subfamily of chemokine receptors including CCR3, CCR4, and CCR5 SIGNOR-254367 0.763 HAUS6 protein Q7Z4H7 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 19029337 f miannu FAM29A interacts with the NEDD1-gamma-tubulin complex and recruits this complex to the spindle, which, in turn, promotes MT polymerization. SIGNOR-261420 0.7 IL1R1 protein P14778 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 9625767 t lperfetto Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab SIGNOR-249515 0.2 GSK3B protein P49841 UNIPROT PSEN1 protein P49768 UNIPROT down-regulates activity phosphorylation Ser353 SHLGPHRsTPESRAA 9606 BTO:0000007 SIGNOR-C110 17360711 t gcesareni We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin. SIGNOR-153627 0.604 HNF4A protein P41235 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 f inferred from family member gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-270255 0.26 MAPK14 protein Q16539 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity 9606 20626350 f lperfetto On the other hand, p38 alfa may negatively modulate akt activity, indipendently of pi3k by regulating the interaction between caveolin 1 and pp2a through a mechanism dependent on cell attachment. SIGNOR-166591 0.413 DUSP2 protein Q05923 UNIPROT MAPK4 protein P31152 UNIPROT down-regulates activity dephosphorylation 9606 28252035 t miannu DUSP2 can dephosphorylate both ERK3 and ERK4 when expressed in mammalian cells.|Finally, we demonstrate that DUSP2 inhibits ERK3 and ERK4 mediated activation of MK5. SIGNOR-277068 0.36 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR EP300 protein Q09472 UNIPROT up-regulates activity binding 9606 BTO:0000007 28630438 t miannu NUP98-HOXA9 has an activator-repressor role in transcriptional regulation driven by p300 and HDAC1 interactions. The chromosomal translocation t(7;11)(p15, p15), encoding the fusion protein NUP98-HOXA9 (NHA9), is a rare poor risk cytogenetic event in AML associated with a particularly poor prognosis.In summary, NHA9 deregulates the expression of key leukemic genes, including MEIS1-HOXA9-PBX3 complex, through the enhancer binding and the direct interaction of the fusion protein with HDAC and p300 transcriptional regulators. SIGNOR-261497 0.2 WNT5B protein Q9H1J7 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131882 0.622 RIPK3 protein Q9Y572 UNIPROT GLUD1 protein P00367 UNIPROT up-regulates binding 9606 19632174 t gcesareni Rip3 directly interacts with glycogen phosphorylase (pygl), glutamate ammonia ligase (glul), and glutamate dehydrogenase 1 (glud1). Rip kinase activity is required to enhance the activities of all three enzymes both in vivo and in vitro. SIGNOR-187314 0.426 TLN1 protein Q9Y490 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 10090 BTO:0000132 SIGNOR-C167 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257593 0.79 ACVR1 protein Q04771 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation Ser463 SPHNPISsVS 10090 9748228 t gcesareni Biochemical analysis revealed that constitutively active ALK2 associated with and phosphorylated Smad1 on the COOH-terminal SSXS motif, and also regulated Smad5 and Smad8 phosphorylation. SIGNOR-247674 0.691 INS protein P01308 UNIPROT RHOQ protein P17081 UNIPROT up-regulates 9606 12687004 f gcesareni Exo70 translocates to the plasma membrane in response to insulin through the activation of tc10, where it assembles a multiprotein complex that includes sec6 and sec8 SIGNOR-100483 0.291 CSNK1A1 protein P48729 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser100 ESEDSQEsVDSVTDS 9606 9931297 t lperfetto Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement. SIGNOR-64258 0.317 PLK1 protein P53350 UNIPROT TPT1 protein P13693 UNIPROT down-regulates phosphorylation Ser46 TEGNIDDsLIGGNAS 9606 12167714 t lperfetto Plk phosphorylates tctp on two serine residues. These results suggest that phosphorylation decreases the microtubule-stabilizing activity of tctp and promotes the increase in microtubule dynamics that occurs after metaphase SIGNOR-91344 0.705 Class I MHC:Antigen complex SIGNOR-C426 SIGNOR Cytotoxic_T-lymphocyte_activation phenotype SIGNOR-PH195 SIGNOR up-regulates 9606 31810556 f scontino High-affinity peptide/MHC class I complexes that successfully pass the aforementioned “quality controls” will be transported through the Golgi apparatus to the cell membrane to elicit antigen-specific CD8+ T cell responses. SIGNOR-267875 0.7 CDC16 protein Q13042 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 t lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. SIGNOR-252006 0.918 MDM2 protein Q00987 UNIPROT EID1 protein Q9Y6B2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 11073989 t miannu Degradation of EID-1 occurs via ubiquitin-dependent proteolysis and correlates with MDM2 binding. These results are consistent with a model wherein destruction of EID-1 is linked to its ability to interact with MDM2 via either p300 or pRB. SIGNOR-272582 0.434 H2BC11 protein P06899 UNIPROT Nucleosome_H2A.Z.2 variant complex SIGNOR-C323 SIGNOR form complex binding -1 24311584 t miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. SIGNOR-263710 0.2 SMOC1 protein Q9H4F8 UNIPROT SPARC protein P09486 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20359165 f lperfetto The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells SIGNOR-260401 0.41 PRKCE protein Q02156 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr52 HKHKHEMtLKFGPAR 9606 BTO:0000848;BTO:0001286 22304920 t lperfetto Pkc_ phosphorylation of atf2 on thr52. Pkc_ promotes oncogenic functions of atf2 in the nucleus while blocking its apoptotic function at mitochondria SIGNOR-195761 0.292 Melanotan II chemical CID:92432 PUBCHEM MC4R protein P32245 UNIPROT up-regulates activity binding BTO:0000614 17702843 t lperfetto Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases. SIGNOR-253066 0.8 GEM protein P55040 UNIPROT CACNB2 protein Q08289 UNIPROT down-regulates activity binding 9606 14701738 t miannu Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively. SIGNOR-261720 0.2 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu57 EVRKGNLeRECVEET -1 10556651 t lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. SIGNOR-263677 0.655 PPP6C protein O00743 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity dephosphorylation Ser834 GSHTSGQsNGRDHQA 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276514 0.334 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2E1 protein P51965 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271359 0.582 RFX complex complex SIGNOR-C104 SIGNOR HLA-DQA1 protein P01909 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 f The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-253991 0.289 triprolidine chemical CHEBI:84116 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 10029 7925364 t miannu The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum. SIGNOR-258870 0.8 CLK3 protein P49761 UNIPROT USP13 protein Q92995 UNIPROT up-regulates activity phosphorylation Tyr708 EPLTMPGyGGAASAG 9606 BTO:0003911 32453420 t done miannu CLK3 directly phosphorylated USP13 at Y708, which promoted its binding to c-Myc, thereby preventing Fbxl14-mediated c-Myc ubiquitination and activating the transcription of purine metabolic genes. SIGNOR-274122 0.2 KRAS protein P01116 UNIPROT MAP4K5 protein Q9Y4K4 UNIPROT up-regulates 9606 BTO:0001271 9949177 f fstefani Bcr-abl_mediated ras activation is crucial for the ability of bcr-abl to activate gckr and is consistent with the previously known requirement for ras in bcr-abl_induced sapk activation how ras activates gckr remains enigmatic. SIGNOR-64262 0.2 PRKCE protein Q02156 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Ser139 EEWTRHGsFVNKPTR 10090 BTO:0000944 12052829 t lperfetto Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms. SIGNOR-263048 0.2 selumetinib chemical CHEBI:90227 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258280 0.8 KHDRBS1 protein Q07666 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity post transcriptional regulation 10090 BTO:0000232 22196734 t Gianni Activity-dependent alternative splicing of Nrxn1 requires the KH-domain RNA binding protein SAM68 which associates with RNA response elements in the Nrxn1 pre-mRNA. Our findings uncover SAM68 as a key regulator of dynamic control of Nrxn1 molecular diversity and activity-dependent alternative splicing in the central nervous system. SIGNOR-269057 0.338 PAK1 protein Q13153 UNIPROT TBCB protein Q99426 UNIPROT up-regulates phosphorylation Ser128 VRSFLKRsKLGRYNE 9606 BTO:0000150 15831477 t lperfetto P21-activated kinase 1 regulates microtubule dynamics by phosphorylating tubulin cofactor b. Pak1 directly phosphorylated tcob in vitro and in vivo on serines 65 and 128 and colocalized with tcob on newly polymerized microtubules and on centrosomes. Pak1 phosphorylation is necessary for normal tcob function SIGNOR-135460 0.46 levomethadone chemical CHEBI:136003 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258808 0.8 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 SIGNOR-C9 15241418 t llicata We found that ser 203 and ser 207 were phosphorylated by map kinase and that thr 178 was phosphorylated mostly by cdk and to a lesser extent by map kinase SIGNOR-126744 0.736 CDK2 protein P24941 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 SIGNOR-C16 20530684 t gcesareni The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry. SIGNOR-165872 0.748 MAPK14 protein Q16539 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20162623 f Indirect:regulation miannu Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6). SIGNOR-251838 0.2 ATF4 protein P18848 UNIPROT EPRS1 protein P07814 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269419 0.2 CDK1 protein P06493 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates phosphorylation Thr90 CHLAWVNtPKKQGGL 9606 11986303 t lperfetto Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%. SIGNOR-87097 0.357 CSNK2B protein P67870 UNIPROT CD163 protein Q86VB7 UNIPROT up-regulates activity phosphorylation Ser1085 RQRLAVSsRGENLVH -1 11298324 t llicata Interaction of CD163 with the regulatory subunit of casein kinase II (CKII) and dependence of CD163 signaling on CKII and protein kinase C. | Inhibition studies using specific kinase inhibitors reveal that both CKII and PKC are involved in the CD163 signaling mechanism resulting in the secretion of proinflammatory cytokines. SIGNOR-251056 0.312 CUDC-907 chemical CID:54575456 PUBCHEM HDAC1 protein Q13547 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191157 0.8 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9606 BTO:0000567 9687510 t lperfetto Thus, MAPK1/ERK1 and MAPK2/ERK2 activate three closely related protein kinases known as MAPK_activated protein kinases_1a, _1b and _1c (MAPKAP_K1a/b/c; also known as RSK1/2/3) SIGNOR-59363 0.749 mTORC1 complex SIGNOR-C3 SIGNOR ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR down-regulates activity phosphorylation 9606 23863160 t lperfetto Several studies published simultaneously illustrated that the equivalent mammalian ULK1Atg13FIP200 complex was also negatively regulated by mTORC1 in an analogous manner [17,18,24]. In mammalian cells, amino acid starvation or rapamycin treatment causes dephosphorylation of both Atg13 and ULK1, indicating that an mTORC1 input regulates the ULK1Atg13FIP200 complex mTORC1 modulates the kinase activity of ULK1 directly, with rapamycin treatment of cells leading to enhanced ULK1 kinase activity, whereas Rheb overexpression causes a decrease in ULK1 kinase activity SIGNOR-209904 0.56 STK11 protein Q15831 UNIPROT PRMT5 protein O14744 UNIPROT up-regulates activity phosphorylation Thr144 VLTNHIHtGHHSSMF -1 30289978 t miannu We found that PRMT5 is a bona fade substrate for LKB1. We identified T132, 139 and 144 residues, located in the TIM-Barrel domain of PRMT5, as target sites for LKB1 phosphorylation. The point mutation of PRMT5 T139/144 to A139/144 drastically decreased its methyltransferase activity, due probably to the loss of its interaction with regulatory proteins such as MEP50, pICln and RiOK1.  SIGNOR-277412 0.2 MAPK14 protein Q16539 UNIPROT F3 protein P13726 UNIPROT down-regulates phosphorylation Ser290 GQSWKENsPLNVS 9606 23195225 t lperfetto We previously showed that the phosphorylation of ser253 within the cytoplasmic domain of human tissue factor (tf) initiates the incorporation and release of this protein into cell-derived microparticles. Furthermore, subsequent phosphorylation of ser258 terminates this process. Our current study has identified p38_ as a major kinase, responsible for the phosphorylation of ser258 within the cytoplasmic domain of tf SIGNOR-199868 0.296 DTNBP1 protein Q96EV8 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 22203680 t lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. SIGNOR-265933 0.801 TRADD protein Q15628 UNIPROT BIRC2 protein Q13490 UNIPROT up-regulates activity binding 9606 BTO:0000007;BTO:0001412;BTO:0000567 8943045 t amattioni The recruitment of TRAF2 and c-IAP1 to TNF-R1 is TNF-dependent, is mediated by TRADD. N-terminal domain of tradd may become accessible to traf2, thereby permitting recruitment of the traf2/ciap1 heterocomplex. SIGNOR-45134 0.686 COL1A2 protein P08123 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t Collagen is the major structural protein in skeletal muscle ECM;...Several studies suggest that perimysial collagen is predominantly type I SIGNOR-254663 0.7 DYNLL1 protein P63167 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260501 0.276 GTF2H4 protein Q92759 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 t lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269315 0.908 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Thr8 MSSILPFtPPVVKRL 9606 12193595 t lperfetto We show that phosphorylation of Smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (ERK1) increases the amount of Smad2 protein and leads to enhanced transcriptional activity.[] A site of ERK-dependent phosphorylation on Smad2 was located to Thr8 SIGNOR-227514 0.738 FOXO proteinfamily SIGNOR-PF27 SIGNOR Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 15109499 f gcesareni Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. SIGNOR-252932 0.7 CSNK2A1 protein P68400 UNIPROT EEF1B2 protein P24534 UNIPROT unknown phosphorylation Ser112 GSDDEEEsEEAKRLR -1 8547318 t llicata EF-1 beta was highly phosphorylated by casein kinase II, with up to 1.3 mol of phosphate incorporated per mol protein. From microsequence analysis and manual Edman degradation, the majority of the phosphate was shown to be present in serine 106 in the peptide DLFGS106DDEEES112EEA. Serine 112 was also phosphorylated by casein kinase II, but to a lesser extent. SIGNOR-250855 0.35 RAP1GDS1 protein P52306 UNIPROT RAP1A protein P62834 UNIPROT up-regulates binding 9606 21242305 t miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob SIGNOR-171482 0.43 PRRX1 protein P54821 UNIPROT SRF protein P11831 UNIPROT up-regulates binding 9606 BTO:0000567 9334314 t miannu The human homeodomain proteinphox1interacts functionally with serum response factor (srf) to impart serum responsive transcriptional activity to srf-binding sites in a hela cell cotransfection assay. SIGNOR-52657 0.453 PTPN2 protein P17706 UNIPROT KRAS protein P01116 UNIPROT down-regulates activity dephosphorylation 9606 33122197 t miannu Mechanistically, PTPN2 negatively regulates tyrosine phosphorylation of KRAS, which, in turn, affects the activation KRAS and its downstream signaling. SIGNOR-277039 0.28 PTPN2 protein P17706 UNIPROT STAT5A protein P42229 UNIPROT down-regulates activity dephosphorylation 9606 15780598 t lperfetto Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5. SIGNOR-133547 0.723 NR3C1 protein P04150 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 8878484 t fspada We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter. SIGNOR-44376 0.545 MAP3K3 protein Q99759 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates phosphorylation Ser167 FLISPPAsPPVGWKQ 9606 BTO:0000782 16126726 t gcesareni Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation SIGNOR-138945 0.459 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM2 protein P0DP24 UNIPROT up-regulates chemical activation 9606 10884684 t miannu Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘openÂ’ conformations SIGNOR-266317 0.8 RAMAC protein Q9BTL3 UNIPROT RNMT protein O43148 UNIPROT up-regulates activity binding 9606 27422871 t lperfetto Maturation and translation of mRNA in eukaryotes requires the addition of the 7-methylguanosine cap. In vertebrates, the cap methyltransferase, RNA guanine-7 methyltransferase (RNMT), has an activating subunit, RNMT-Activating Miniprotein (RAM). Here we report the first crystal structure of the human RNMT in complex with the activation domain of RAM. SIGNOR-268344 0.2 EDA protein Q92838 UNIPROT EDAR protein Q9UNE0 UNIPROT up-regulates binding 9606 18304980 t gcesareni Ultimately, in mammals, eda-a1 and eda-a2 trimers each bind a different receptor, edar and xedar, respectively, through their trimerized tnf domain. SIGNOR-161109 0.741 RPS6KA3 protein P51812 UNIPROT HMGN2 protein P05204 UNIPROT down-regulates activity phosphorylation Ser25 KDEPQRRsARLSAKP 9606 BTO:0000567 11438671 t lperfetto We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets. SIGNOR-249102 0.294 STK3 protein Q13188 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity phosphorylation Thr622 KEGGVTFtWVEKDIS -1 35722967 t miannu Hippo pathway component MST2 kinase phosphorylates STAT3 at T622, which is located in the SH2 domain of STAT3. This phosphorylation blocks the SH2 domain in one STAT3 molecule to bind with the phosphorylated Y705 site in another STAT3 molecule, which further counteracts IL6-induced STAT3 dimerization and activation. SIGNOR-277599 0.2 RUNX1 protein Q01196 UNIPROT HHEX protein Q03014 UNIPROT up-regulates quantity transcriptional regulation 9606 28213513 t We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML. SIGNOR-256305 0.274 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation 9606 12912994 t gcesareni Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5. SIGNOR-104634 0.753 AKT1 protein P31749 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates activity phosphorylation Ser571 RMRSRSRsFSRHRSC 9606 BTO:0000759 17554339 t lperfetto Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1alpha At ser570 Is required for akt to inhibit recruitment of pgc-1alpha To chromatin. SIGNOR-252502 0.458 PPP5C protein P53041 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity dephosphorylation Thr838 GINPCTEtFTGTLQY 9606 BTO:0000567 11689443 t lperfetto Pp5 directly dephosphorylated an essential phospho-threonine residue within the kinase domain of ask1 and thereby inactivated ask1 activity in vitro and in vivo. SIGNOR-111301 0.584 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-263008 0.706 PIP3 smallmolecule CHEBI:16618 ChEBI ZFYVE1 protein Q9HBF4 UNIPROT up-regulates chemical activation 9606 18725538 t gcesareni Dfcp1 contains two fyve domains (thus explaining its pi(3)p binding) SIGNOR-180527 0.8 PTPRE protein P23469 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Thr185 HDHTGFLtEYVATRW 9606 12754301 t llicata The effect of PTP epsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTP epsilon. Nonetheless, PTP epsilon is present in a molecular complex with ERK, providing PTP epsilon with opportunity to act on ERK proteins also directly. We conclude that PTP epsilon is a physiological inhibitor of ERK signaling|These enzymes are joined by the large family of dual-specificity phosphatases, which are structurally similar to tyrosine phosphatases but which can dephosphorylate both residues of the activation loop SIGNOR-248449 0.399 CREB1 protein P16220 UNIPROT MUC4 protein Q99102 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001861 19757157 f lperfetto Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level. SIGNOR-254091 0.2 MC4R protein P32245 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257270 0.255 TP53 protein P04637 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity binding 9606 14586398 t miannu We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. We show that ets-1 and p53 associate physically in vitro and in vivo and that their interaction, rather than a direct binding of p53 to the TXSA promoter, is required for transcriptional repression of TXSA by wild-type p53. SIGNOR-254087 0.546 JNK proteinfamily SIGNOR-PF15 SIGNOR PPM1J protein Q5JR12 UNIPROT down-regulates phosphorylation 9606 18553930 t inferred from 70% family members gcesareni Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells. SIGNOR-269981 0.2 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR CDKN2A protein Q8N726 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22469984 t irozzo The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a SIGNOR-259360 0.345 BST1 protein Q10588 UNIPROT cyclic ADP-ribose smallmolecule CHEBI:31445 ChEBI up-regulates quantity chemical modification 9606 18626062 t miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. SIGNOR-264248 0.8 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 30230471 f lperfetto In keeping with the overall improvement in insulin sensitivity we found that insulin-induced IR Y1162/Y1163 tyrosine phosphorylation and activation and downstream PI3K/AKT signaling in the liver (as monitored by AKT Ser-473 phosphorylation) were dramatically enhanced by POMC TCPTP deficiency (Figure 4h).|This would suggest that TCPTP deletion, or decreased TCPTP in POMC neurons in response to feeding, represses HGP by enhancing IR signaling and permitting POMC neurons to be activated by insulin. SIGNOR-276957 0.606 PPM1A protein P35813 UNIPROT STING1 protein Q86WV6 UNIPROT down-regulates activity dephosphorylation Ser358 VPSTSTMsQEPELLI 9606 25815785 t lperfetto Collectively, our findings suggest that the overexpression of PPM1A antagonizes the STING- and TBK1-induced type I interferon signaling pathway.|First, PPM1A directly dephosphorylated STING, likely via its S358 site (Figs.|Moreover, our study demonstrates that while TBK1 enhances STING aggregation in a kinase activity-dependent manner, PPM1A suppresses STING aggregation by dephosphorylating both STING and TBK1. SIGNOR-276958 0.2 CGP-42112A chemical CHEBI:147302 ChEBI AGTR2 protein P50052 UNIPROT down-regulates activity chemical inhibition -1 32278693 t Luana CGP42112A is an angiotensin AT2 (Angiotensin receptor 2) receptor agonist that may alleviate the virus-induced lung injury SIGNOR-262311 0.8 PTPN6 protein P29350 UNIPROT SH3BP2 protein P78314 UNIPROT down-regulates dephosphorylation 9606 16649996 t gcesareni Shp-1 dephosphorylates 3bp2 and potentially downregulates 3bp2-mediated t cell antigen receptor signaling SIGNOR-146508 0.552 LMO3 protein Q8TAP4 UNIPROT NHLH2 protein Q02577 UNIPROT up-regulates activity binding 9606 21573214 t miannu Here we found that LMO3 forms a complex with HEN2 and acts as an upstream mediator for transcription of Mash1 in neuroblastoma. SIGNOR-254827 0.421 MAOA protein P21397 UNIPROT (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI up-regulates quantity chemical modification 9606 BTO:0000142 20493079 t Luana The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. SIGNOR-269745 0.8 PTPRJ protein Q12913 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK 9606 22898603 t lperfetto In addition, our work further reveals that above a threshold expression level, DEP-1 can also dephosphorylate Src Y418 and attenuate downstream signaling and biologic responses, consistent with the quiescent behavior of confluent endothelial cells that express the highest levels of endogenous DEP-1. SIGNOR-276978 0.621 SRC protein P12931 UNIPROT WNK4 protein Q96J92 UNIPROT down-regulates activity phosphorylation Tyr1115 PVWMNYSySSLCLSS 9606 BTO:0002181 25805816 t miannu Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c-Src: Tyr(1092), Tyr(1094), and Tyr(1143), and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4.  SIGNOR-276895 0.2 ATM protein Q13315 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser114 EETRTPEsQPDTPPG 9606 21824916 t lperfetto We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro. SIGNOR-176008 0.474 PTPN1 protein P18031 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation 9606 18253097 t lperfetto The protein tyrosine phosphatase, PTP1B, is known to negatively regulate EGF-induced signaling in several cell types by dephosphorylating the epidermal growth factor receptor (EGFR).|Together, these findings provide evidence that PTP1B plays a role in the negative regulation of EGFR signaling in rat corneal endothelial cells, at least at the level of Tyr992 phosphorylation. SIGNOR-276981 0.751 STK17A protein Q9UEE5 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000776 17339337 t gcesareni Genetic and biochemical studies have shown that ser20 phosphorylation in the transactivation domain of p53 mediates p300-catalyzed dna-dependent p53 acetylation and b-cell tumor suppression. a cell-free ser20 phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser20 kinases. SIGNOR-153532 0.29 MAPK1 protein P28482 UNIPROT ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser664 QLPYYYLsPDRIPNS 9606 BTO:0000567 12670876 t lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. SIGNOR-264409 0.39 EXOC3 protein O60645 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270778 0.934 PTPN13 protein Q12923 UNIPROT EFNB1 protein P98172 UNIPROT up-regulates activity dephosphorylation 9606 23811940 t lperfetto Loss of PTPN13 function increases EFNB1 phosphorylation, enhances EFNB1 's interaction with ERBB1 and correlates with potentiated ERK1/2 activation.|Moreover, acquisition of PTPN13 loss-of-function mutations or its decreased expression (due to HPV infection or epigenetic silencing) may further enhance ERBB1 and EFNB1 mediated signals. SIGNOR-277002 0.697 PTPRO protein Q16827 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK 9606 25301722 t lperfetto SRC activation triggered by loss of PTPRO leads to c-CBL degradation.|These data corroborate that PTPRO directly dephosphorylates SRC at Y416. SIGNOR-277004 0.432 DUSP6 protein Q16828 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation 9606 20638106 t lperfetto Dual-specificity phosphatase six (DUSP6, MKP3, or PYST1) dephosphorylates phosphotyrosine and phosphothreonine residues on ERK-2 (MAPK1) to inactivate the ERK-2 kinase. SIGNOR-277006 0.901 GSK3B protein P49841 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 23584478 t lperfetto Glycogen synthase kinase-3_ positively regulates protein synthesis and cell proliferation through the regulation of translation initiation factor 4E-binding protein 1We found that GSK-3_ phosphorylates and inactivates 4E-BP1, thereby increasing eIF4E-dependent protein synthesis. SIGNOR-201699 0.372 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCNE1 protein P24864 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189978 0.8 CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity binding 9606 BTO:0000782 15735151 t gcesareni Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1 SIGNOR-134219 0.914 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser436 TNGSIGHsPLSLSAQ 9606 BTO:0000938 24614225 t lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204700 0.524 ESR1 protein P03372 UNIPROT F12 protein P00748 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 9794469 f miannu Transcription of the FXII gene is stimulated by estrogens through specific interaction of the estrogen receptor alpha (ER alpha) with an estrogen response element present on FXII promoter. SIGNOR-254072 0.2 FBXO32 protein Q969P5 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 10090 20871233 f Atrogin-1, but not MuRF-1, was induced at both the gene and protein level as ApcMin/+ mice aged from 3 to 6 months of age, going from a pre-cachectic to a cachectic state. Atrogin-1 mRNA and protein levels were also elevated in ApcMin/+ mice when we over-expressed IL-6 in the circulation. SIGNOR-255341 0.7 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Thr74 SAHARKEtEFLRLKR 9606 12493777 t lperfetto We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo SIGNOR-96687 0.2 L-dopa smallmolecule CHEBI:15765 ChEBI dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Subsequently, L-DOPA is converted into 3,4-dihydroxyphenethylamine (dopamine) through decarboxylation by the enzyme L-3,4-dihydroxyphenylalanine decarboxylase (DOPA decarboxylase) in the pre-synaptic terminal SIGNOR-264174 0.8 PPM1G protein O15355 UNIPROT SRSF3 protein P84103 UNIPROT down-regulates activity dephosphorylation 9606 34290239 t miannu Here, we found that the PPM1G regulated SRSF3, and high levels of PPM1G decreased SRSF3 activity in HCC cells.|PPM1G interacted with SRSF3 and dephosphorylated SRSF3. SIGNOR-277048 0.2 WNT5A protein P41221 UNIPROT FZD5 protein Q13467 UNIPROT up-regulates binding 9606 9054360 t gcesareni These results identify hfz5 as a receptor for wnt-5a. SIGNOR-46897 0.826 PRKCB protein P05771 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity phosphorylation Ser466 SKASSRRsSFSMEEG 10090 23599343 t This occurs following PKCβ phosphorylation of TFEB on three serine residues located in its last 15 amino acids. This post-translational modification stabilizes and increases the activity of this transcription factor. SIGNOR-255315 0.336 GALR2 protein O43603 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256884 0.426 IMP smallmolecule CHEBI:17202 ChEBI GDP smallmolecule CHEBI:17552 ChEBI up-regulates quantity precursor of 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-268130 0.8 ANAPC4 protein Q9UJX5 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 t lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. SIGNOR-252004 0.9 LYN protein P07948 UNIPROT PAG1 protein Q9NWQ8 UNIPROT up-regulates activity phosphorylation Tyr417 LVPKENDyESISDLQ 9534 16920712 t miannu Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn. SIGNOR-262899 0.714 ATG4B protein Q9Y4P1 UNIPROT GABARAP protein O95166 UNIPROT up-regulates activity cleavage -1 16303767 t lperfetto In vivo and in vitro biochemical analyses have shown that human atg4b is an authentic cysteine protease essential for cleavage of the c terminus of each atg8 homolog to expose the c-terminal gly SIGNOR-141929 0.856 HBB protein P68871 UNIPROT EDN1 protein P05305 UNIPROT down-regulates activity 9606 8573884 f Regulation of localization miannu Hb inhibitory activity toward ET-1 production might be related to Hb mediated endothelial oxidative injury. SIGNOR-251766 0.278 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Thr178 NHNHRIRtNPAIVKT 10090 BTO:0001103 17609368 t gcesareni AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter SIGNOR-228642 0.483 GSK3A protein P49840 UNIPROT GPSM3 protein Q9Y4H4 UNIPROT down-regulates quantity by destabilization phosphorylation Ser35 STTRPWRsAPPSPPP 9606 BTO:0000876 22843681 t lperfetto Co-immunoprecipitation of endogenous GPSM3 and 14-3-3 proteins from the human monocytic cell line THP-1 suggests basal phosphorylation of GPSM3 at serine 35 as potentially mediated by GSK3alpha. The GPSM3/14-3-3 interaction is seen to stabilize GPSM3 from degradation and also support the nuclear exclusion of both proteins. SIGNOR-264863 0.2 ZBTB20 protein Q9HC78 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 23776228 t miannu Zinc finger and BTB domain-containing 20 (ZBTB20), a member of BTB/POZ family, functions in neurogenesis and represses α-fetoprotein gene transcription in liver. SIGNOR-266867 0.451 NMDA receptor_2A complex SIGNOR-C347 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264132 0.7 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 t flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. SIGNOR-75926 0.366 TET1 protein Q8NFU7 UNIPROT HOXA9 protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27708339 t irozzo Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9. SIGNOR-259094 0.311 fulvestrant chemical CHEBI:31638 ChEBI ESR2 protein Q92731 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000150 12113237 t miannu Fulvestrant (Faslodex, formerly ICI 182,780) is a potent steroidal antiestrogen that mediates its effects by estrogen receptor downregulation. SIGNOR-259304 0.8 F2RL1 protein P55085 UNIPROT RAB3A protein P20336 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254836 0.2 LMX1B protein O60663 UNIPROT LMX1B/SFPQ/PSPC1 complex complex SIGNOR-C106 SIGNOR form complex binding 10090 23308148 t miannu LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo. SIGNOR-223966 0.349 ULK3 protein Q6PHR2 UNIPROT GLI1 protein P08151 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 19878745 t Manara We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro. | Our data suggest that serine/threonine kinase ULK3 is involved in the SHH pathway as a positive regulator of GLI proteins. SIGNOR-260797 0.66 DNMT3A protein Q9Y6K1 UNIPROT CDKN2B protein P42772 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 26350239 f miannu Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family SIGNOR-261509 0.354 BAX protein Q07812 UNIPROT CYCS protein P99999 UNIPROT up-regulates 9606 18097445 f gcesareni This process of mitochondrial outer membrane permeabilization (momp) results in the release of cycs.it is commonly thought that bax and bak form pores in membranes SIGNOR-160039 0.687 LYN protein P07948 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates activity phosphorylation Tyr448 TILTEVNyEVSNKDD 18086677 t lperfetto The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. SIGNOR-272980 0.316 SRC protein P12931 UNIPROT KIT protein P10721 UNIPROT up-regulates activity phosphorylation Tyr900 EHAPAEMyDIMKTCW 9606 12878163 t lperfetto C-src phosphorylates tyr900 in the second part of the kinase domain of c-kit. SIGNOR-103999 0.395 TEAD1 protein P28347 UNIPROT MSLN protein Q13421 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17909009 f miannu The presence of TEF-1 was required for MSLN protein overexpression as determined by TEF-1 knockdown experiments. SIGNOR-255395 0.285 RPS6 protein P62753 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262418 0.883 JUN protein P05412 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 19299913 f lperfetto Promoter deletion and reporter analysis revealed that hypoxia transcriptionally activates a GADD153 promoter through the AP-1 element in neonatal cardiomyocytes. Ectopic overexpression of GADD153 resulted in the downregulation of CARP expression. SIGNOR-254123 0.596 CLU protein P10909 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR up-regulates activity binding 9606 BTO:0001321 20068069 t miannu CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation. SIGNOR-271429 0.318 KPNB1 protein Q14974 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates activity relocalization 9534 17596301 t lperfetto Although ORF6 causes a relocalization of KPNA2 from the cytosol to the ER/Golgi membrane, KPNA2 is not directly involved in the translocation of the STAT1:STAT2:IRF9 (ISGF3) complex into the nucleus; rather, KPNA1 interacts with KPNB1 to initiate ISGF3's nuclear localization. SIGNOR-260274 0.273 KMT2E protein Q8IZD2-8 UNIPROT NCR2 protein O95944 UNIPROT up-regulates activity binding 9606 BTO:0000737 23958951 t miannu We identify natural cytotoxicity receptor NKp44 (NKp44L), a novel isoform of the mixed-lineage leukemia-5 protein, as a cellular ligand for NKp44. Unlike the other MLL family members, NKp44L is excluded from the nucleus, but expressed at the cell-surface level; its subcellular localization is being associated with the presence of a specific C-terminal motif. Strikingly, NKp44L has not been detected on circulating cells isolated from healthy individuals, but it is expressed on a large panel of the tumor and transformed cells. SIGNOR-260042 0.52 CEBPA protein P49715 UNIPROT F9 protein P00740 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 8075306 f Transactivation by the CCAAT/enhancer binding protein alpha of the wild-type and mutated factor IX promoter (-192 to +38) resulted in an approximately four-fold and approximately two-fold, respectively, increase of CAT activity SIGNOR-254040 0.29 GSK3B protein P49841 UNIPROT MAML1 protein Q92585 UNIPROT down-regulates phosphorylation 9606 19740771 t gcesareni We found that gsk3beta inhibits maml1 transcriptional activity by directly targeting the n-terminal domain of maml1 SIGNOR-187896 0.2 dacomitinib chemical CHEBI:132268 ChEBI ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates chemical inhibition 9606 23405260 t inferred from 70% of family members gcesareni The goal of this study was to compare dacomitinib (pf-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple her family receptors (her-1 (egfr), her-2 and her-4 tyrosine kinases), to cetuximab, the current fda approved anti-egfr medication for hnscc and erlotinib, an egfr specific small molecule tyrosine kinase inhibitor. SIGNOR-269871 0.8 GRM5 protein P41594 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. SIGNOR-264936 0.8 AKT1 protein P31749 UNIPROT FANCA protein O15360 UNIPROT unknown phosphorylation Ser1149 CLRSRDPsLMVDFIL -1 11855836 t FANCA is phosphorylated at Ser1149 by Akt. The biological significance of FANCA phosphorylation and its regulation by Akt remains unclear at this time. SIGNOR-252567 0.471 LRRK1 protein Q38SD2 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates activity phosphorylation Thr1430 EMFGHWAtNCNDDET 25413345 t Phosphosite positions are derived from Figure 1 lperfetto LRRK1 phosphorylates CLIP-170 at Thr1384, located in its C-terminal zinc knuckle motif, and this promotes the association of CLIP-170 with dynein-dynactin complexes. SIGNOR-275469 0.408 ESR1 protein P03372 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 BTO:0001264 22169964 f miannu 17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice SIGNOR-253469 0.2 ATG4B protein Q9Y4P1 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates activity cleavage -1 16303767 t lperfetto In mammals, at least three atg8 homologs, lc3, gabarap, and gate-16, have been identified (fig. 1a), all of which have structural ubiquitin folds (1416). In vivo and in vitro biochemical analyses have shown that human atg4b is an authentic cysteine protease essential for cleavage of the c terminus of each atg8 homolog to expose the c-terminal gly SIGNOR-141932 0.838 EGLN3 protein Q9H6Z9 UNIPROT BCL2L11 protein O43521-1 UNIPROT up-regulates quantity by stabilization hydroxylation Pro67 PQGPLAPpASPGPFA 9606 31375625 t lperfetto EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance|EglN3 Hydroxylates BIM-EL at the Proline67/70 Residues SIGNOR-262003 0.256 HCRTR2 protein O43614 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256729 0.252 CCL7 protein P80098 UNIPROT Macrophage_activation phenotype SIGNOR-PH126 SIGNOR up-regulates 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260850 0.7 TGFBR1 protein P36897 UNIPROT VPS39 protein Q96JC1 UNIPROT up-regulates activity binding 9534 12941698 t miannu TLP interacts with TGF-β and activin receptors in vivo. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling. SIGNOR-261375 0.2 DAPK3 protein O43293 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 12429016 t gcesareni Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge. SIGNOR-95524 0.526 MAPKAPK2 protein P49137 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation 9606 17292828 t amattioni Mk2 was required for the degradation of cdc25a. Mk2 phosphorylates cdc25a in vitro. Phosphorylation of cdc25a in vivo has been shown to facilitate its ubiquitin-mediated proteolysis SIGNOR-152996 0.372 PIK3C3 protein Q8NEB9 UNIPROT AKT1 protein P31749 UNIPROT up-regulates relocalization 9606 10698680 t lperfetto One of the best characterized targets of pi3k lipid products is the protein kinase akt or protein kinase b (pkb). In quiescent cells, pkb resides in the cytosol in a low-activity conformation. Upon cellular stimulation, pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1). SIGNOR-252632 0.445 ziprasidone chemical CHEBI:10119 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9760039 t miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). SIGNOR-258833 0.8 MAPK3 protein P27361 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Thr43 KVTTVVAtPGQGPDR 9606 BTO:0000150;BTO:0000680 16039586 t lperfetto Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin. SIGNOR-138898 0.298 MBTPS1 protein Q14703 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity cleavage 10029 BTO:0000246 10644685 t We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2 SIGNOR-267497 0.543 EEF1A2 protein Q05639 UNIPROT Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269533 0.8 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 BTO:0000567 17615152 t gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-156864 0.692 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR up-regulates 9606 24890514 f apalma The Erk1/2 pathway has a central role in CSF-1R-regulated myeloid differentiation. CSF-1 induces early (peaking at ‚àº5 min) and persistent (starting at 1 h) waves of MEK/Erk1/2 phosphorylation SIGNOR-255573 0.7 FASN protein P49327 UNIPROT Lipogenesis phenotype SIGNOR-PH30 SIGNOR up-regulates 9606 20373869 f lperfetto Fatty acid synthase (FASN) is a key enzyme involved in neoplastic lipogenesis SIGNOR-242874 0.7 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT down-regulates quantity by destabilization phosphorylation Ser129 PYPSPVLsEEEDLPL 9606 BTO:0000567 10618498 t llicata Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo SIGNOR-251039 0.312 FLT3 protein P36888 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Tyr88 KGSLPEFyYRPPRPP 10090 BTO:0001516 28522571 t lperfetto FLT3 and FLT3-ITD phosphorylate and inactivate the cyclin-dependent kinase inhibitor p27 Kip1 in acute myeloid leukemia|P27Kip1 (p27) can prevent cell proliferation by inactivating cyclin-dependent kinases. This function is impaired upon phosphorylation of p27 at tyrosine residue 88. SIGNOR-269208 0.294 PCDH19 protein Q8TAB3 UNIPROT GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates quantity by stabilization binding 10116 BTO:0003102 29360992 t miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  SIGNOR-267216 0.2 HAUS6 protein Q7Z4H7 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity binding 9606 BTO:0000567 19029337 t miannu FAM29A recruits NEDD1 to spindle MTs. Ectopically expressed NEDD1 and FAM29A interact with each other. SIGNOR-261421 0.806 AKT1 protein P31749 UNIPROT CCT2 protein P78371 UNIPROT unknown phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 19332537 t llicata Furthermore, ha-tagged akt can phosphorylate gst-cct_ protein in vitro SIGNOR-184922 0.2 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 22298955 t inferred from 70% family members gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps SIGNOR-270213 0.2 DOK7 protein Q18PE1 UNIPROT CRKL protein P46109 UNIPROT up-regulates activity binding 10090 BTO:0000165 20603078 t miannu Here, we identify two tyrosine residues in Dok-7 that are phosphorylated by Agrin stimulation, and show that two proteins, Crk and Crk-L, are recruited to these phosphorylation sites in Dok-7. SIGNOR-273848 0.35 AKT1 protein P31749 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser644 NLMFRKFsLERPFRP -1 24548923 t miannu Here we show that Akt-mediated NF-κB activation is mediated at least in part through direct phosphorylation of the adaptor protein Carma1, which we previously demonstrated could interact with Akt in a TCR ligation-dependent manner. The putative Akt phosphorylation sites in Carma1 are distinct from known PKC consensus sites. Mutation of S551, S637 and S645 in Carma1 to non-phosphorylatable residues decreased phosphorylation of GST-Carma1-linker construct by Akt in vitro.  SIGNOR-276255 0.537 EP300 protein Q09472 UNIPROT MN1 protein Q10571 UNIPROT up-regulates binding 9606 12569362 t miannu Our results indicate that mn1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate rar/rxr-mediated transcription through interaction with p160 and p300. SIGNOR-97899 0.349 GTF2H2 protein Q13888 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 t lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269311 0.862 MECP2 protein P51608 UNIPROT SST protein P61278 UNIPROT up-regulates quantity by expression post transcriptional regulation 10090 18511691 t Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. SIGNOR-264676 0.301 MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 11460167 t lperfetto Tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a SIGNOR-217445 0.718 SUFU protein Q9UMX1 UNIPROT GLIS2 protein Q9BZE0 UNIPROT down-regulates relocalization 9606 BTO:0001130 16316410 t gcesareni Negative regulation of gli1 and gli2 activator function by suppressor of fused through multiple mechanisms.Together, these observations reveal that su(fu) regulates the activity of gli1 and gli2 through distinct cytoplasmic and nuclear mechanisms. SIGNOR-142608 0.269 SOX4 protein Q06945 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0001271 24183681 f apalma Collectively, our experiments identified the oncogene Sox4 as a factor mediating increased serial-replating ability and blocked differentiation of Cebpa-deficient progenitors. SIGNOR-255676 0.7 PRKCZ protein Q05513 UNIPROT MARK2 protein Q7KZI7 UNIPROT down-regulates phosphorylation Thr596 RGVSSRStFHAGQLR 9606 15084291 t lperfetto Hpar-1b is phosphorylated by apkc on threonine 595 importantly, phosphorylation of hpar-1b on t595 negatively regulates the kinase activity and plasma membrane localization of hpar-1b in vivo. SIGNOR-124217 0.269 NARS2 protein Q96I59 UNIPROT tRNA(Asn) smallmolecule CHEBI:29172 ChEBI down-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270461 0.8 AURKA protein O14965 UNIPROT WDR62 protein O43379 UNIPROT up-regulates activity phosphorylation Ser33 PARRGQSsPPPAPPI -1 25501809 t lperfetto AURKA activity promotes WDR62 spindle localization|We next purified recombinant full-length WDR62 (GST–WDR62-FL) for in vitro kinase assays with active AURKA and demonstrated that WDR62 was a direct phosphorylation target of AURKA|In addition, our quantitative phosphoproteomic analysis of in-vitro-phosphorylated WDR62 identified S32 and S33 as significantly phosphorylated in the presence of active AURKA|Alanine replacement of the five putative phosphorylation sites (S32/S33/S49/T50/S52-AAAAA) of WDR62 attenuated interphase microtubule association induced by AURKA coexpression SIGNOR-271713 0.359 E2F1 protein Q01094 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253855 0.507 PKN1 protein Q16512 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation 9606 17251915 t gcesareni At the same time, rho signals to c-jun n-terminal kinase (jnk) and p38 through rock and protein kinase n (pkn), leading to the transcriptional regulation of jun SIGNOR-152765 0.386 L-thyroxine smallmolecule CHEBI:18332 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 8755651 t scontino Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5‚Äô-position) to yield T3 SIGNOR-266948 0.8 RIPK1 protein Q13546 UNIPROT FAS protein P25445 UNIPROT up-regulates activity binding 9606 18545270 t lperfetto The death domain of the rip1 kinase binds to death receptors such as fas that is required for caspase 8 activation and apoptosis SIGNOR-177949 0.637 MAPK8IP2 protein Q13387 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 9733513 t gcesareni Thus, both jip1 and jip2 selectively bind the mapkk isoform mkk7. SIGNOR-59944 0.668 GLUD1 protein P00367 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9913 11254391 t Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate. SIGNOR-266916 0.8 KLF8 protein O95600 UNIPROT HBB protein P68871 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 10756197 t Luana These results establish KLF8 as a CACCC-box binding protein that associates with CtBP and represses transcription. SIGNOR-266052 0.2 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 21798082 t gcesareni Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor. SIGNOR-175665 0.864 BIRC3 protein Q13489 UNIPROT BIRC2 protein Q13490 UNIPROT up-regulates activity binding 9606 23070005 t amattioni Ligand-stimulated aggregation of receptor complexes causes recruitment of multiple traf2 trimers, which in turn leads to cIAP1 or cIAP2 dimerization. SIGNOR-199088 0.474 EP300 protein Q09472 UNIPROT MAML1 protein Q92585 UNIPROT up-regulates acetylation 9606 17300219 t gcesareni The n-terminal domain of maml1 directly interacts with both p300 and histones, and the p300-maml1 complex specifically acetylates histone h3 and h4 tails in chromatin. Furthermore, p300 acetylates maml1 and evolutionarily conserved lysine residues in the maml1 n-terminus are direct substrates for p300-mediated acetylation. SIGNOR-153035 0.636 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 10660534 t lperfetto Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function SIGNOR-74848 0.717 MDK protein P21741 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 18469519 t gcesareni We showed that mk binds to the notch2 receptor in hacat keratinocytes. We further found that mk activates notch2 SIGNOR-161427 0.469 MAPK7 protein Q13164 UNIPROT KLF4 protein O43474 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23612709 f miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion SIGNOR-255455 0.44 L-ornithine smallmolecule CHEBI:15729 ChEBI M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates activity 25386178 f apalma In general, M2 type macrophages act as anti-inflammatory cells via diversion of arginine away from NOS or via the synthesis of downstream products derived from the ornithine that is generated via arginase SIGNOR-256075 0.7 ponatinib chemical CHEBI:78543 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206277 0.8 PTPRB protein P23467 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1356 YVHVNATyVNVKCVA 9606 21454675 t gcesareni Receptor-type protein tyrosine phosphatase beta (rptp-beta) directly dephosphorylates and regulates hepatocyte growth factor receptor (hgfr/met) function. SIGNOR-173004 0.372 ALDH5A1 protein P51649 UNIPROT 4-oxobutanoate smallmolecule CHEBI:57706 ChEBI down-regulates quantity chemical modification 9606 19300440 t miannu Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix. SIGNOR-266616 0.8 PRKACA protein P17612 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Ser17 DASQRRRsLEPAENV 9606 11804588 t llicata Pka activated src both in vitro and in vivo by phosphorylating src on serine 17 SIGNOR-114277 0.368 APC protein P25054 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR form complex binding 9606 9734785 t lperfetto Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level. SIGNOR-227296 0.846 SPOP protein O43791 UNIPROT INF2 protein Q27J81 UNIPROT down-regulates activity binding 9606 BTO:0000007 28448495 t miannu SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J). SIGNOR-272798 0.2 SMARCB1 protein Q12824 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 t miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. SIGNOR-132930 0.895 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ARHGAP31 protein Q2M1Z3 UNIPROT up-regulates activity phosphorylation Thr789 PPAPPPPtPLEESTP 9534 BTO:0000298 16024771 t miannu CdGAP interacts with and is phosphorylated by ERK-1 and RSK-1 in vitro. A putative DEF (docking for ERK FXFP) domain located in the proline-rich region of CdGAP is required for efficient binding and phosphorylation by ERK1/2. We identify Thr776 as an in vivo target site of ERK1/2 and as an important regulatory site of CdGAP activity. Together, these data suggest that CdGAP is a novel substrate of ERK1/2 and mediates cross talk between the Ras/mitogen-activated protein kinase pathway and regulation of Rac1 activity. SIGNOR-263057 0.2 TOMM6 protein Q96B49 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 t lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. SIGNOR-267676 0.621 MAPK3 protein P27361 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser548 SSPSPPCsPLMADPL 9606 BTO:0000149 24269383 t llicata We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro. SIGNOR-203290 0.273 PIAS1 protein O75925 UNIPROT FHL1 protein Q13642 UNIPROT down-regulates sumoylation Lys300 PRGPGLVkAPVWWPM 9606 17509614 t gcesareni Pias1 (the protein inhibitor of activated stat1) interacts with kyot2 directly and attenuates kyot2-mediated transcriptional repression. We demonstrate that kyot2 is modified by sumoylation at two lysine residues, k144 and k171. Sumoylation of the transfected kyot2 is enhanced by pias1 SIGNOR-154805 0.259 RUNX3 protein Q13761 UNIPROT ING4 protein Q9UNL4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002384 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255096 0.2 CCKAR protein P32238 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257303 0.442 IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 BTO:0000801 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249506 0.695 ID1 protein P41134 UNIPROT AKT1 protein P31749 UNIPROT up-regulates binding 9606 BTO:0004136 26084673 t apalma We have determined that Id1 physically interacts with AKT1, through its C-terminal region, and promotes AKT1 phosphorylation; SIGNOR-255658 0.34 TLR4 protein O00206 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity phosphorylation 9606 28137827 t miannu Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation. SIGNOR-261928 0.426 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248737 0.727 TGFBR1 protein P36897 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates binding 9606 9435577 t lperfetto These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells. SIGNOR-227531 0.349 EIF3I protein Q13347 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 9774674 t gcesareni Another receptor-associated protein is trip-1, which interacts with and is phosphorylated by tbrii and contains five wd-40 repeats. The association of wd-40 repeat proteins may then allow them to play a role in signaling by the serine/threonine kinase receptors. SIGNOR-60700 0.33 Neuronal AP-3 complex SIGNOR-C445 SIGNOR Platelet_dense_granule_formation phenotype SIGNOR-PH181 SIGNOR up-regulates 9606 BTO:0000132 12019270 f miannu BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules|Interestingly, immunofluorescence and in vitro binding experiments demonstrated that pallidin/BLOC-1 is able to associate with actin filaments. We propose that BLOC-1 mediates the biogenesis of lysosome-related organelles by a mechanism that may involve self-assembly and interaction with the actin cytoskeleton. SIGNOR-268523 0.7 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser584 ETSIFTPsPCKIPPP 9606 BTO:0000680;BTO:0001573;BTO:0001286 SIGNOR-C17 14551205 t lperfetto Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex SIGNOR-118576 0.502 CLASP1 protein Q7Z460 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates activity binding 9606 BTO:0000567 15631994 t lperfetto CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. SIGNOR-265091 0.714 POLR1A protein O95602 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266152 0.837 MAPK13 protein O15264 UNIPROT EEF2K protein O00418 UNIPROT down-regulates phosphorylation Ser359 GTEEKCGsPQVRTLS 9606 18337751 t gcesareni The phosphorylation of eef2k at ser359 is of particular interest. First, the phosphorylation of this site strongly decreases the activity of eef2k even at high calcium concentrations (knebel et al, 2001), that is, desensitizes eef2k to the activating effects of elevated ca2+ levels. third, although p38 map kinase (also termed sapk4 can phosphorylate ser359 in vitro (knebel et al, 2001), this enzyme is not known to be active basally or to be regulated by amino acids. SIGNOR-177986 0.56 KRAS protein P01116 UNIPROT TCF3 protein P15923 UNIPROT up-regulates phosphorylation 9606 BTO:0000776 9528794 t gcesareni Our results are consistent with a model in which notch and deltex act on e47 by inhibiting signaling through ras. SIGNOR-56144 0.316 PRKACA protein P17612 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS -1 12853467 t miannu PFK-2 that was phosphorylated on Ser466, but not Ser483, by PKA did not bind to 14-3-3s‚  SIGNOR-250025 0.454 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 19143636 t lperfetto Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor. SIGNOR-209859 0.392 SMOC1 protein Q9H4F8 UNIPROT COL1A2 protein P08123 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20359165 f lperfetto The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells SIGNOR-260404 0.2 WNT9A protein O14904 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000887 22309736 t gcesareni We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles. SIGNOR-195972 0.2 SIGMAR1 protein Q99720 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization stabilization 9606 BTO:0000815 29117944 t Barakat We propose that Sigma1 is a ligand-operated scaffolding protein that promotes the stability, processing, assembly, and trafficking of specific proteins in the secretory pathway of cancer cells. In support of this hypothesis, we found that siRNA-mediated knockdown of Sigma1 resulted in a significant decrease in PD-L1 protein levels in triple-negative MDA-MB-231 breast cancer and androgen-independent PC3 prostate cancer cells SIGNOR-274974 0.2 CDK2 protein P24941 UNIPROT SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr244 GRAKGSEtPGATPGS 9606 SIGNOR-C16 12105215 t gcesareni To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptide). Three phosphorylation sites were identified as thr244, thr248, and thr313 SIGNOR-90434 0.353 LYL1 protein P12980 UNIPROT ERG protein P11308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21536859 f miannu We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. SIGNOR-253923 0.2 SCF-FBW7 complex SIGNOR-C135 SIGNOR BIRC2 protein Q13490 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16510124 t miannu Since Fbxo7 is one component of the SCF complex, we tried to determine whether overexpression of Fbxo7 could promote cIAP1 ubiquitination in the hope to reveal functional aspects of the cIAP1–Fbxo7 interaction. cIAP1-Flag was co-expressed with or without Fbxo7 in 293T cells. In conclusion, our results show that overexpression of Fbxo7 promotes the ubiquitination of cIAP1. SIGNOR-271553 0.313 F12 protein P00748 UNIPROT KLKB1 protein P03952 UNIPROT up-regulates activity cleavage Arg390 CTTKTSTrIVGGTNS 9606 BTO:0000131 28966616 t lperfetto FXIIa activates two serine proteinases, factor XI (FXI) and plasma prekallikrein (PK) that drive the coagulation and kallikrein–kinin systems, respectively SIGNOR-263518 0.589 KLF4 protein O43474 UNIPROT SRF protein P11831 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001260 21673106 t gcesareni Klf4 antagonizes contractile gene expression through diverse mechanisms including (i) inhibiting the binding of srf-myocd or srf-mrtfs to the carg box by direct association with srf. SIGNOR-174258 0.376 PPP2CA protein P67775 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity dephosphorylation Thr216 RSSSSEStGTPSNPD 10090 11983168 t cyclin G also binds in vivo and in vitro to Mdm2 and markedly stimulates the ability of PP2A to dephosphorylate Mdm2 at T216. Consistent with these data, cyclin G null cells have both Mdm2 that is hyperphosphorylated at T216 and markedly higher levels of p53 protein when compared to wild-type cells SIGNOR-248636 0.431 GSK3A protein P49840 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity phosphorylation Thr312 TMKTFCGtPEYLAPE 10090 BTO:0005655 23142783 t gcesareni GSK3_ negatively regulates AKT activation by phosphorylating AKT at T312 in the substrate binding site, which inhibited IL-1-induced AKT activation and function. SIGNOR-252455 0.622 UBE2N protein P61088 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates activity ubiquitination -1 19240029 t miannu We used MuRF1 as the E3 as it functions with all these E2s to ubiquitinate one of its typical substrates, troponin I Although UbcH1 and UbcH13/Uev1a support ubiquitination of troponin I by MuRF1, these E2s do not support ubiquitination of S5a, unlike Class I E2s. SIGNOR-272737 0.519 MAP1B protein P46821 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000938 10649507 t lperfetto MAP1B is a microtubule-associated phosphoprotein that is particularly highly expressed in developing neurons.  SIGNOR-264844 0.7 JAG2 protein Q9Y219 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 10958687 t gcesareni Binding of delta1, jagged1, and jagged2 to notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of notch2 SIGNOR-81367 0.62 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser262 LRIAKTPsPPEEPSP 9606 BTO:0000142 15262992 t lperfetto Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd SIGNOR-126839 0.405 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR MCM3 protein P25205 UNIPROT up-regulates phosphorylation Thr722 EEMPQVHtPKTADSQ 9606 21965652 t lperfetto In this study, we demonstrate that mcm3 is a substrate of cyclin e/cdk2 and can be phosphorylated by cyclin e/cdk2 at thr-722. SIGNOR-216694 0.619 BBC3 protein Q9BXH1 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates binding 9606 15694340 t gcesareni Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1. SIGNOR-133817 0.743 PPP2R2A protein P63151 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 9774674 t lperfetto In this report, we show that another WD-40 repeat protein, the B_ subunit of protein phosphatase 2A, associates with the cytoplasmic domain of type I TGF-_ receptors. [...] We therefore conclude that B_ specifically and directly associates with the type I receptor cytoplasmic domain in vitro. SIGNOR-227517 0.516 PIM2 protein Q9P1W9 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by stabilization phosphorylation Thr454 RAPIIAVtRNPQTAR 9606 24142698 t Manara Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. SIGNOR-260905 0.378 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR IREB2 protein P48200 UNIPROT down-regulates phosphorylation Ser157 LQKAGKLsPVKVQPK 9606 18574241 t lperfetto Irp2 ser-157 is phosphorylated by cdk1/cyclin b1 during g(2)/m / ser-157 phosphorylation during g(2)/m reduces irp2 rna-binding activity SIGNOR-216888 0.36 PRKACA protein P17612 UNIPROT CA9 protein Q16790 UNIPROT up-regulates phosphorylation Thr443 RRQHRRGtKGGVSYR 9606 22037869 t llicata Here, we report that thr443 phosphorylation at the intracellular domain of ca ix by protein kinase a (pka) is critical for its activation in hypoxic cells, with the fullest activity of ca ix also requiring dephosphorylation of ser448. SIGNOR-176973 0.2 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259017 0.373 DOK1 protein Q99704 UNIPROT A4/b7 integrin complex SIGNOR-C187 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257697 0.33 PLK1 protein P53350 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2439 SFLSGEPsQADVQPL 9606 BTO:0000552 31597699 t miannu As shown in Fig. S4D, the C-terminal NOTCH1 fragment was readily phosphorylated by PLK1. Additionally, when the two putative phosphorylation sites, Ser-1791 and Ser-2349, were replaced by Ala, WT NOTCH1-IC but not the mutant was efficiently phosphorylated (Fig. S4E). We found that mutation of Ser-1791/2349 promotes NOTCH1-IC stabilization (Fig. S4F). SIGNOR-277490 0.411 BMS-754807 chemical CHEBI:88339 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190497 0.8 DHODH protein Q02127 UNIPROT coenzyme Q10 smallmolecule CHEBI:46245 ChEBI down-regulates quantity chemical modification 9606 30449682 t miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway SIGNOR-267431 0.8 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16371461 t lperfetto Phosphorylated gli3 can bind beta-trcp directly both in vitro and in vivo, resulting in polyubiquitination of gli3 and processing through proteasome activity SIGNOR-143171 0.657 TRAF2 protein Q12933 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates polyubiquitination 9606 20047764 t miannu Here, we show that the TRAF family proteins directly bind TICAM-1 and demonstrate that TRAF2 and TRAF6 bind different sites of the N-terminal TICAM-1 and accelerate its polyubiquitination. we speculate that polyubiquitination of TICAM-1 by TRAF2 and TRAF6 is required for TICAM-1 to induce IRF-3 and NF-κB activation. This is supported by the observation that polyubiquitination of TICAM-1 was required for TRAF3-binding to TICAM-1 SIGNOR-271427 0.443 WNT4 protein P56705 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 9753670 f gcesareni Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. SIGNOR-60373 0.317 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser14 LYSFFSPsPARKRHA 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276089 0.292 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR LATS1 protein O95835 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 15688006 t Two of these, S909 and T1079, were required for Lats1 activation. milica Since the N-terminal half of Lats1 (residues 1¬ñ588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1. SIGNOR-270217 0.2 (4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-[3-(4,4-diphenyl-1-piperidinyl)propyl] ester O3-methyl ester chemical CHEBI:103931 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258464 0.8 CSNK2A1 protein P68400 UNIPROT CTNNA1 protein P35221 UNIPROT down-regulates phosphorylation Ser641 TPEELDDsDFETEDF 9606 BTO:0000527 19941816 t gcesareni We demonstrate here that egfr activation results in disruption of the complex of beta-catenin and alpha-catenin, thereby abrogating the inhibitory effect of alpha-catenin on beta-catenin transactivation via ck2alpha-dependent phosphorylation of alpha-catenin at s641. SIGNOR-161847 0.399 AKT1 protein P31749 UNIPROT VCP protein P55072 UNIPROT up-regulates phosphorylation Ser748 RFARRSVsDNDIRKY 9606 BTO:0000150 16551632 t llicata Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I SIGNOR-252493 0.523 RNF8 protein O76064 UNIPROT BLM protein P54132 UNIPROT up-regulates activity ubiquitination 9606 BTO:0001938 23708797 t miannu Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of .  SIGNOR-272115 0.343 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219328 0.749 MAP1LC3B protein Q9GZQ8 UNIPROT NBR1 protein Q14596 UNIPROT down-regulates binding 9606 BTO:0000007 19250911 t gcesareni We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1. SIGNOR-184252 0.573 CDK5 protein Q00535 UNIPROT STXBP2 protein Q15833 UNIPROT down-regulates phosphorylation Thr572 IGSSHILtPTRFLDD 9606 BTO:0000938 17716669 t lperfetto It was shown that munc18 inhibition of neuronal syntaxin 1 can be overcome by cdk5 phosphorylation, indicating that structural change disrupts the syntaxin-munc18 interaction. SIGNOR-157528 0.2 NCBP3 protein Q53F19 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 26382858 f lperfetto The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. SIGNOR-268362 0.7 PPP2CA protein P67775 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR form complex binding 9606 23454242 t gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. SIGNOR-243442 0.828 PROK1 protein P58294 UNIPROT PROKR1 protein Q8TCW9 UNIPROT up-regulates binding 9606 12054613 t gcesareni The present study demonstrates that eg-vegf/prokineticin 1 and a peptide closely related to eg-vegf, prokineticin 2, are cognate ligands of two orphan g-protein-coupled receptors designated zaq (=eg-vegf/pk-r1) and i5e (=eg-vegf/pk-r2) SIGNOR-89084 0.422 DCTPP1 protein Q9H773 UNIPROT dCMP 3'-end residue smallmolecule CHEBI:53119 ChEBI up-regulates quantity by expression chemical modification 10116 31377845 t lperfetto Our data indicate that DCTPP1 is crucially involved in the provision of dCMP for thymidylate biosynthesis, introducing a new player in the regulation of pyrimidine dNTP levels and the maintenance of genomic integrity SIGNOR-261333 0.8 HAT1 protein O14929 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys6 kGGKGLGK -1 11585814 t lperfetto During nucleosome assembly in vivo, newly synthesized histone H4 is specifically diacetylated on lysines 5 and 12 within the H4 NH(2)-terminal tail domain. The highly conserved "K5/K12" deposition pattern of acetylation is thought to be generated by the Hat1 histone acetyltransferase, which in vivo is found in the HAT-B complex. SIGNOR-264791 0.2 EGR1 protein P18146 UNIPROT COL10A1 protein Q03692 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21931594 f Regulation miannu Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1) SIGNOR-251921 0.2 glutamic acid smallmolecule CHEBI:18237 ChEBI NMDA receptor_2A complex SIGNOR-C347 SIGNOR up-regulates activity chemical activation 9606 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate SIGNOR-264128 0.8 PRKD1 protein Q15139 UNIPROT RIN1 protein Q13671 UNIPROT unknown phosphorylation Ser292 QLLRRESsVGYRVPA 9606 21209314 t llicata Here, we report the identification of serine 292 in rin1 as an in vivo pkd phosphorylation site. we demonstrate that phosphorylation at serine 292 controls rin1-mediated inhibition of cell migration by modulating the activation of abl kinases. SIGNOR-170877 0.412 wortmannin chemical CHEBI:52289 ChEBI PIK3C3 protein Q8NEB9 UNIPROT down-regulates chemical inhibition 9534 BTO:0001444 22253445 t lperfetto From these results, we conclude that LY294002 and wortmannin inhibit SARS pseudovirus entry by targeting PI4KB and that PI4KB is involved in SARS-CoV S-mediated entry into VeroE6 cells. SIGNOR-260730 0.8 T_cell_activation phenotype SIGNOR-PH73 SIGNOR IFNG protein P01579 UNIPROT up-regulates quantity 9606 BTO:0002417 32454942 f miannu interferon gamma- (IFNγ-) and interleukin-17- (IL-17-) secreting CD4+ T cells are believed to be the pathogenic initiators of MS [22], and in MS patients, the increased production of either IFNγ or IL-17 is associated with pathology SIGNOR-263818 0.7 pazopanib hydrochloride chemical CHEBI:71217 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-200809 0.8 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation 9606 19620713 t gcesareni Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. SIGNOR-187181 0.721 TNFSF13B protein Q9Y275 UNIPROT TNFRSF13B protein O14836 UNIPROT up-regulates binding 9606 10956646 t gcesareni Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys. SIGNOR-81360 0.773 ADORA2B protein P29275 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256910 0.516 Dinaciclib chemical CID:46926350 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191325 0.8 STK26 protein Q9P289 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 19386264 t lperfetto Activation of ezrin is mediated by initial pip2 binding and subsequent phosphorylation of threonine 567. Mst4 phosphorylates the regulatory t567 residue of ezrin. SIGNOR-185563 0.2 NCSTN protein Q92542 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR form complex binding 9606 25610395 t lperfetto -Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2) SIGNOR-209711 0.964 NR1D1 protein P20393 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 12821652 f miannu Mutations of the 5' or 3' half-sites of the response element totally abrogated PPARgamma binding and transcriptional activation, identifying this site as a novel type of functional PPARgamma response element. Finally, ectopic expression of Rev-Erbalpha in 3T3-L1 preadipocytes potentiated adipocyte differentiation induced by the PPARgamma ligand rosiglitazone. These results identify Rev-Erbalpha as a target gene of PPARgamma in adipose tissue and demonstrate a role for this nuclear receptor as a promoter of adipocyte differentiation. SIGNOR-268023 0.7 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr366 ASSSTSVtPDVSDNE -1 12297295 t llicata We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).  SIGNOR-250940 0.667 SARS1 protein P49591 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 24095058 t miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis SIGNOR-270497 0.8 CEBPA protein P49715 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 25451943 f gcesareni Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) ² plays an essential role. SIGNOR-250562 0.7 ROCK2 protein O75116 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 14701738 f miannu Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively. SIGNOR-261722 0.7 CTBP1 protein Q13363 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23303449 f irozzo Our findings suggest an important role of CtBP1 in the transcriptional control of p16INK4a and Brca1[.]. Additionally, the inhibitor of cyclin-dependent protein kinases (CDKs), p16INK4a, whose loss has been related to the pathogenesis of melanoma, was repressed by CtBP1 as well. SIGNOR-259195 0.422 ROCK1 protein Q13464 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 12185584 t lperfetto Here we found that rho-kinase has an activity for mrlc diphosphorylation at both threonine 18 and serine 19 in nonmuscle cells using sequential column chromatographies. SIGNOR-91542 0.608 GSK3B protein P49841 UNIPROT DEK protein P35659 UNIPROT down-regulates quantity by destabilization phosphorylation Thr67 KKKVERLtMQVSSLQ 9606 BTO:0002181 21282377 t miannu  These data suggest that the E3 ligase SCFFbxw7-α degrades p-DEK in a GSK-3β–dependent manner.Therefore, the phosphorylation of DEK by GSK-3β is a crucial step to mediate Tpm RNA splicing. SIGNOR-276303 0.413 DAMPS stimulus SIGNOR-ST18 SIGNOR AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR up-regulates 9606 25720354 f scontino APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. SIGNOR-267854 0.7 INSR protein P06213 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 11075717 t gcesareni The npxy motif around 960-tyr residue of the insulin receptor binds to the n-terminal ptb domain of shc. SIGNOR-84251 0.698 RPS6KA1 protein Q15418 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-119221 0.2 PTPRC protein P08575 UNIPROT SKAP1 protein Q86WV1 UNIPROT up-regulates activity dephosphorylation Tyr232 EEEKEETyDDIDGFD 9606 BTO:0000661 11909961 t Mutational analysis demonstrated the pivotal role of Tyr-232 in SKAP55 in the association with CD45. In Jurkat cells, anti-CD3 antibody stimulation promoted SKAP55 tyrosine phosphorylation and translocation from the cytoplasm to the membrane. Overexpression of SKAP55 in these cells induced transcriptional activation of the IL-2 promoter, while mutant SKAP55-Y232F totally suppressed the promoter activity. Furthermore, overexpression of SKAP55-Y232F also caused the tyrosine hyperphosphorylation of Fyn with a decreased kinase activity. Thus, SKAP55 is an essential adapter to couple CD45 with the Src family kinases for dephosphorylation and, thus, positively regulates TCR signaling. SIGNOR-248360 0.368 RUNX2 protein Q13950 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15564063 f miannu Increased expression of RUNX2 in OA cartilage may contribute to increased expression of MMP-13. FGF2, which is present in OA synovial fluid, activated RUNX2 via the MEK/ERK pathway and increased MMP-13 expression. SIGNOR-255078 0.484 FOXA1 protein P55317 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 16331276 f miannu We identified a foxa1 binding site within the brca1-responsive element of the p27(kip1) promoter and showed that foxa1 activated the promoter alone and in conjunction with brca1. SIGNOR-142940 0.327 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 1373652 t gcesareni The question of whether protein tyrosine phosphatases (ptpases) dephosphorylate a multiply phosphorylated peptide in a random or ordered manner was investigated using the synthetic triphosphotyrosyl peptide trdiy(p)etdy(p)y(p)rk, corresponding to the major sites of autophosphorylation of the insulin receptor, as a substrate for four purified ptpases. SIGNOR-18018 0.606 KDM6B protein O15054 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity demethylation 9606 24561908 t This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions. miannu Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation. SIGNOR-265361 0.2 RPL39L protein Q96EH5 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262491 0.716 ALK protein Q9UM73 UNIPROT ALK protein Q9UM73 UNIPROT up-regulates activity phosphorylation Tyr1278 FGMARDIyRASYYRK -1 15938644 t llicata ALK SelectiVely Phosphorylates the First Tyrosine in Its A-Loop Peptide. SIGNOR-250575 0.2 NGF protein P01138 UNIPROT NGFR protein P08138 UNIPROT up-regulates binding 9606 BTO:0000007 10764727 t gcesareni The low affinity neurotrophin receptor p75ntr can mediate cell survival as well as cell death of neural cells by ngf and other neurotrophins. SIGNOR-76832 0.83 LRP5 protein O75197 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization relocalization 9606 11336703 t lperfetto Lrp-5, a close homolog of lrp-6 (hey et al., 1998), functions as a coreceptor for wnt proteins in mammalian cells and that it can transduce the canonical wnt signals, at least in part by binding and recruiting axin to membranes SIGNOR-227930 0.672 PPP1CA protein P62136 UNIPROT PFN1 protein P07737 UNIPROT up-regulates dephosphorylation Ser138 MASHLRRsQY 9606 22479341 t lperfetto Knockdown of the catalytic subunit of pp1 (pp1c_), but not pp2a (pp2ac_), increased ps137-pfn1 levels. Pp1c_ binds pfn1 in cultured cells, and this interaction was increased by a phosphomimetic mutation of pfn1 at ser-137 (s137d). Together, these data define pp1 as the principal phosphatase for ser-137 of pfn1 SIGNOR-196816 0.248 RAB38 protein P57729 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR up-regulates activity relocalization 9606 23247405 t lperfetto Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. SIGNOR-260697 0.362 RPL21 protein P46778 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262478 0.851 GATA2 protein P23769 UNIPROT GATA1 protein P15976 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21853041 f miannu GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1. SIGNOR-256062 0.419 CREBBP protein Q92793 UNIPROT RELA protein Q04206 UNIPROT up-regulates acetylation 9606 SIGNOR-C6 16382138 t gcesareni Rela is also acetylated at several sites by p300 and cbp SIGNOR-143396 0.874 CDK1 protein P06493 UNIPROT RCC1 protein P18754 UNIPROT up-regulates activity phosphorylation Ser11 KRIAKRRsPPADAIP -1 15014043 t miannu Human RCC1 is phosphorylated on Ser 2 and Ser 11 in mitosis by Cdc2 kinase. We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of human RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. SIGNOR-262702 0.517 RPEL1 protein Q2QD12 UNIPROT D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI up-regulates quantity chemical modification 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267069 0.8 EFNA5 protein P52803 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9330863 t gcesareni Members of the epha subfamily of receptor tyrosine kinases and their ephrin-a ligands have been implicated in the guidance of retinal axons along the anterior-posterior axis of the chick optic tectum. SIGNOR-52467 0.919 AKT2 protein P31751 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 15531580 t llicata Purified akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an atp-dependent manner. ezrin activation after initiation of na+-glucose cotransport requires akt2 expression SIGNOR-130260 0.383 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 16046550 t The effect has been demonstrated using Q01196-8. gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-138908 0.348 SELENOS protein Q9BQE4 UNIPROT DERL1 protein Q9BUN8 UNIPROT up-regulates activity binding 9606 BTO:0000567 15215856 t miannu VIMP mediates p97 binding to hDerlin-1. these data suggest that Derlin-1 and VIMP form a membrane protein complex that serves as a receptor for p97. SIGNOR-261370 0.2 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser923 DELRDSDsVCDSGVE 9606 BTO:0000459 SIGNOR-C13 10469655 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-70465 0.848 RTKs proteinfamily SIGNOR-PF38 SIGNOR A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates activity phosphorylation 9606 30889378 t miannu The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs. SIGNOR-259032 0.2 FES protein P07332 UNIPROT FES protein P07332 UNIPROT up-regulates phosphorylation Tyr811 RPSFSTIyQELQSIR 9606 8663427 t llicata Substitution of kinase domain tyrosine residues 713 or 811 with phenylalanine resulted in a loss of the 10- and 4-kda phosphopeptides, respectively, identifying these tyrosines as in vitro autophosphorylation sites. Cnbr cleavage analysis of fes isolated from 32po4-labeled 293t cells showed that tyr-713 and tyr-811 are also autophosphorylated in vivo. . Mutagenesis of tyr-713 reduced both autophosphorylation of tyr-811 and transphosphorylation of bcr, a recently identified fes substrate, supporting a major regulatory role for tyr-713. SIGNOR-42659 0.2 CHIR-98014 chemical CID:53396311 PUBCHEM GSK3B protein P49841 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190988 0.8 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1109 FDEIELAyRRRPPRS -1 11024032 t Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro. SIGNOR-251171 0.759 AKT proteinfamily SIGNOR-PF24 SIGNOR PDE3B protein Q13370 UNIPROT up-regulates activity phosphorylation Ser295 VIRPRRRsSCVSLGE 10090 BTO:0000944 10454575 t PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B SIGNOR-251483 0.2 GSK3B protein P49841 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 BTO:0001103 15829723 f apalma GSK-3beta is a serine/threonine kinase that can block translation that is initiated by eukaryotic initiation factor-2B (24) and may thereby reduce protein synthesis. SIGNOR-255110 0.7 MAP2K1 protein Q02750 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 12270934 f lperfetto We further show that activation of mek1 significantly enhances the transactivation of the c/ebpalpha minimal promoter during the early phase of the differentiation process. SIGNOR-235325 0.266 PIP3 smallmolecule CHEBI:16618 ChEBI WIPI1 protein Q5MNZ9 UNIPROT up-regulates chemical activation 9606 22082875 t gcesareni We identified the human wipi protein family and found that wipi-1 specifically binds ptdins(3)p, accumulates at the phagophore and becomes a membrane protein of generated autophagosomes. SIGNOR-177169 0.8 RPS6KA5 protein O75582 UNIPROT NR4A1 protein P22736 UNIPROT unknown phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 BTO:0000007 16223362 t lperfetto In the present paper, we have re-examined the phosphorylation of Nur77 on Ser354. Using a combination of cell-permeable kinase inhibitors and mouse knockin mutations, we show that Nur77 is phosphorylated by RSK in response to mitogenic stimulation of cells. Phosphorylation of Nur77 on Ser354 did not, however, appear to affect the transcriptional activity of Nur77, or its ability to bind 14-3-3 proteins in vivo. SIGNOR-249296 0.391 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000552 15254178 t lperfetto Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation. We next aimed to identify novel factors that control damage-induced p53 phosphorylation in a keratinocyte model system, and discovered that the epithelial stem cell marker _Np63_ is a novel ATM regulator that controls p53 Serine-15 phosphorylation through transcription of the ATM kinase. SIGNOR-126753 0.838 PIK-90 chemical CID:6857685 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206232 0.8 CYP24A1 protein Q07973 UNIPROT calcitetrol smallmolecule CHEBI:47799 ChEBI up-regulates quantity chemical modification 30080183 t lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). SIGNOR-270571 0.8 TGFB1 protein P01137 UNIPROT ENG protein P17813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002741 21146604 f miannu In hepatic stellate cells, TGF-β1 upregulates endoglin expression most likely via the ALK5 pathway and requires the SP1 transcription factor. SIGNOR-255202 0.699 ZNF140 protein P52738 UNIPROT FCGR3B protein O75015 UNIPROT down-regulates quantity by repression transcriptional regulation BTO:0002269 11470777 t Luana Thus, these results indicate that these cloned ZNF140 and ZNF91 proteins function as repressors for the human Fc gamma RIIB transcription. SIGNOR-266214 0.2 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Asn) smallmolecule CHEBI:29172 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269482 0.8 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Ser191 YSFYSTCsGQKAIKK -1 23444369 t miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. SIGNOR-273487 0.27 CCAR2 protein Q8N163 UNIPROT SUV39H1 protein O43463 UNIPROT down-regulates activity binding 26158765 t lperfetto Besides SIRT1, CCAR2 inhibits the activity of the histone-modifying enzymes SUV39H1 and HDAC3 [9, 10], thus playing an important role in chromatin structure regulation. SIGNOR-267664 0.353 [5-fluoro-1-(4-isopropylbenzylidene)-2-methylinden-3-yl]acetic acid chemical CHEBI:59660 ChEBI RXRA protein P19793 UNIPROT down-regulates activity chemical inhibition 9606 20541701 t Luana NSAID Sulindac and Its Analogs Bind RXRα and Inhibit RXRα-dependent AKT Signaling SIGNOR-258031 0.8 CSNK1E protein P49674 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Thr50 FSTTPGGtRIIYDRK 9606 BTO:0000150 24247720 t lperfetto Mechanistic investigations showed that ck1_ interacted with and phosphorylated 4e-bp1 at two novel sites t41 and t50, which were essential for 4e-bp1 inactivation along with increased mrna translation and cell proliferation. SIGNOR-203276 0.2 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR WIPI2 protein Q9Y4P8 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 30898011 t miannu Here we show that WIPI2/ATG18B (WD repeat domain, phosphoinositide interacting 2), an autophagy-related (ATG) protein that plays a critical role in autophagosome biogenesis, is a direct substrate of CUL4-RING ubiquitin ligases (CRL4s) SIGNOR-272302 0.2 prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI CTNNB1 protein P35222 UNIPROT up-regulates 9606 BTO:0000725 23645839 f apalma Prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion SIGNOR-255685 0.8 TNF protein P01375 UNIPROT GCH1 protein P30793 UNIPROT up-regulates activity 9606 9204951 f miannu The de novo synthesis of 6-BH4 depends on the induction of GTP-CH-1, e.g., by tumor necrosis factor-alpha (TNF alpha). SIGNOR-252210 0.25 MAP2K1 protein Q02750 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser304 LSSYGMDsRPPMAIF -1 8226933 t MEK1 and MEK2 can also be activated by autophosphorylation. Tyrosine 304 may be a candidate for the autophosphorylation site in MEK1. SIGNOR-251415 0.2 SPP1 protein P10451 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates binding 9606 10835423 t gcesareni Among others, vitronectin (vn)1- (11, 13, 14) and osteopontin (opn)-coated (15-20) substrates have been shown to support cell adhesion via avb3. SIGNOR-77910 0.604 MKNK1 protein Q9BUB5 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation 9606 9878069 t gcesareni Mnk1 and mnk2 regulate protein synthesis by phosphorylating the initiation factor eif4e. SIGNOR-62936 0.77 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser341 GTMSRPAsVDGSPVS -1 12351658 t IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. SIGNOR-251294 0.644 MAP3K7 protein O43318 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity phosphorylation 10094049 t lperfetto The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway|Activated TAK1 phosphorylates NIK, which stimulates IKK-alpha activity. Our results indicate that TAK1 links TRAF6 to the NIK-IKK cascade in the IL-1 signalling pathway. SIGNOR-262833 0.545 SRC protein P12931 UNIPROT HCN4 protein Q9Y3Q4 UNIPROT up-regulates phosphorylation Tyr531 RRQYQEKyKQVEQYM 9606 17977941 t fspada These results demonstrate that src tyrosine kinase enhances hcn4 currents by shifting their activation to more positive potentials and increasing the whole cell channel conductance as well as speeding the channel kinetics. The tyrosine residue that mediates most of src s actions on hcn4 channels is tyr531. SIGNOR-158707 0.379 SKP2 protein Q13309 UNIPROT IDH2 protein P48735 UNIPROT down-regulates quantity by destabilization ubiquitination phosphorylation:Thr197 GTFKMVFtPKDGSGV 34929314 t lperfetto During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome SIGNOR-267626 0.2 PRKCG protein P05129 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr434 MSFHRNHtATVRSHA 9606 11123317 t lperfetto Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5.  SIGNOR-249072 0.348 AKT3 protein Q9Y243 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates phosphorylation 9606 BTO:0000150 20231902 t inferred from 70% of family members gcesareni Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation. SIGNOR-269941 0.274 AV412 chemical CID:11700696 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190053 0.8 PCDHA4 protein Q9UN74 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265665 0.2 CYP24A1 protein Q07973 UNIPROT propan-2-ol smallmolecule CHEBI:17824 ChEBI up-regulates quantity chemical modification 30080183 t lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). SIGNOR-270574 0.8 Ub:RING_E3 complex SIGNOR-C519 SIGNOR Protein_ubiquitination phenotype SIGNOR-PH214 SIGNOR up-regulates 9606 34199813 f miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. SIGNOR-271383 0.7 CSNK2A1 protein P68400 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser11 DFGFFSSsESGAPEA -1 3128543 t llicata To date, the only evidence for a functional distinction of LCa and LCb is the preferential phosphorylation of LCb, which takes place at serine residues and is mediated by coated vesicle-associated casein kinase II. As a first step toward determining the function of light chain diversity, we have mapped the in vitro phosphorylation sites on LCb. We use [32P]ATP to phosphorylate LCb within coated vesicles, followed by sequencing of 32P-labeled chymotryptic peptides thereof, to identify serine residues at positions 11 and 13 as the phosphorylation sites. SIGNOR-250842 0.313 KANSL2 protein Q9H9L4 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. SIGNOR-267163 0.655 perfluorohexanesulfonic acid chemical CHEBI:132448 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 23764977 t miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  SIGNOR-268764 0.8 TLN1 protein Q9Y490 UNIPROT A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257613 0.611 WWP2 protein O00308 UNIPROT SLC11A2 protein P49281 UNIPROT down-regulates quantity ubiquitination 10029 BTO:0000246 18776082 t lperfetto Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2|This promotes DMT1 ubiquitination and degradation by WWP2. SIGNOR-268852 0.304 lovastatin chemical CHEBI:40303 ChEBI HMGCR protein P04035 UNIPROT down-regulates activity chemical inhibition -1 1597859 t miannu A series of N-heteroaryl-substituted mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and in vivo, and to lower plasma cholesterol in a hypercholesterolemic dog model. The goal of the strategy employed was to design an inhibitor which possessed the pharmacological properties of lovastatin (1), and the physicochemical properties (increased hydrophilicity) of pravastatin (2). SIGNOR-258351 0.8 PTGER3 protein P43115 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256859 0.433 MAPK14 protein Q16539 UNIPROT RBSN protein Q9H1K0 UNIPROT up-regulates phosphorylation 9606 16138080 t gcesareni We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes. SIGNOR-140146 0.2 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser54 RVKALPLsPRKRLGD 9606 SIGNOR-C83 9889196 t lperfetto Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2. SIGNOR-63891 0.94 D-thyroxine smallmolecule CHEBI:30659 ChEBI THRB protein P10828 UNIPROT up-regulates activity chemical activation 9606 BTO:0003736 6777394 t miannu The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response. SIGNOR-258401 0.8 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Ser2056 VQSYSYSsQDPRPAT 9606 17189255 t llicata Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, in addition, our data suggest that dna-pkcs- and atm-mediated dna-pkcs phosphorylations are cooperative and required for the full activation of dna-pkcs and the subsequent dsb repair. SIGNOR-151445 0.2 AMPK complex SIGNOR-C15 SIGNOR NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251618 0.266 TLN1 protein Q9Y490 UNIPROT AX/b2 integrin complex SIGNOR-C171 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257621 0.482 UBE4B protein O95155 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 15611659 t miannu We further demonstrate that Ufd2 directly and efficiently ubiquitylates securin in vitro and is required for securin polyubiquitylation in vivo. This is the first description of a physiologic substrate for Ufd2, establishing this E4 enzyme as an important regulator of chromosome condensation and separation during mitosis in human cells.  SIGNOR-271523 0.2 SETDB2 protein Q96T68 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity methylation Lys 10 RTKQTARkSTGGKAP 9606 BTO:0000007 20404330 t miannu Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression. SIGNOR-263894 0.2 NLK protein Q9UBE8 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates quantity phosphorylation 9606 BTO:0000007 16714285 t miannu NLK Augments the Ubiquitylation Activity of NARF against TCF/LEF. ctivation of NLK induced by unknown ligands leads to the phosphorylation of TCF/LEF. NARF then acts on TCF/LEF as an E3 ubiquitin-ligase and, together with E1 and E2 ubiquitylation enzymes, catalyze the ubiquitylation of TCF/LEF. Finally, ubiquitylated TCF/LEF is degraded by the 26 S proteasome. SIGNOR-271596 0.751 RAD23B protein P54727 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR up-regulates activity binding 24086043 t lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275696 0.558 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT up-regulates phosphorylation Ser251 PLSPFPVsPLAGPGS 9606 10330152 t lperfetto The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a). SIGNOR-67528 0.579 ACVR1B protein P36896 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by stabilization 9606 2920215 f Regulation miannu Activin, also named FSH-releasing protein, was previously shown to induce hemoglobin accumulation in K562 cells and potentiate the proliferation and differentiation of CFU-E in human bone marrow cultures. SIGNOR-251768 0.2 sorafenib chemical CHEBI:50924 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 21654832 t gcesareni Inhibition of map kinases mek, jnk, p38, and multikinases (braf, craf, vegfp by sorafenib) in wm-115 and m14 human melanoma cell lines led to either significant reduction or complete inhibition of the plk-1 protein expression. SIGNOR-174039 0.8 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Ser172 SLDRPFIsEGTTLKD 9606 8576253 t lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta SIGNOR-246728 0.711 FOXE1 protein O00358 UNIPROT TGFB3 protein P10600 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 21177256 f miannu The MSX1 and TGF-β3 up-regulation in response to FOXE1 at both transcriptional and translational levels and the recruitment of FOXE1 to specific binding motifs, together with the transactivation of the promoters of these genes, indicate that MSX1 and TGF-β3 are direct FOXE1 targets. SIGNOR-254174 0.356 ATM protein Q13315 UNIPROT RNF20 protein Q5VTR2 UNIPROT up-regulates activity phosphorylation Ser172 SSSEEMEsQLQERVE 9606 BTO:0000007 21362549 t miannu ATM-Mediated Phosphorylation of RNF20 and RNF40 in Response to DNA Damage and Its Requirement for Damage-Induced H2B Monoubiquitylation  SIGNOR-276314 0.536 CAMK2B protein Q13554 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000661 9686569 t gcesareni Stimulation via cd2 activated multiple signal transduction pathways, resulting in phosphorylation of distinct sites of stathmin. Ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. SIGNOR-59358 0.494 TALDO1 protein P37837 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity chemical modification 9606 19401148 t miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (‚Äúdihydroxyacetone‚Äù) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. SIGNOR-267091 0.8 IKBKE protein Q14164 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 t gcesareni All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below). SIGNOR-154775 0.41 SB 505124 chemical CHEBI:100922 ChEBI ACVR1B protein P36896 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206736 0.8 PKC proteinfamily SIGNOR-PF53 SIGNOR MBD4 protein O95243 UNIPROT up-regulates activity phosphorylation Ser262 SGFVQSDsKRESVCN 23195996 t lperfetto Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12] SIGNOR-275674 0.2 RHEB protein Q15382 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity binding 9606 BTO:0000007 15854902 t lperfetto Rheb binds and regulates the mTOR kinase. SIGNOR-135770 0.949 GTF2H1 protein P32780 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates quantity by destabilization phosphorylation Thr433 DCDFGDLtPLDF -1 10428966 t TFIIH-mediated phosphorylation of E2F-1 plays a role in triggering E2F-1 degradation during S phase. E2F-1 activation domain interacts with a kinase activity which phosphorylates two sites, Ser403 and Thr433, within the activation domain. We demonstrate that TFIIH is responsible for the E2F-1 phosphorylation observed in cell extracts and that endogenous E2F-1 interacts in vivo with p62, a component of TFIIH, during S phase. SIGNOR-251260 0.445 SNX9 protein Q9Y5X1 UNIPROT DNM1 protein Q05193 UNIPROT up-regulates binding 9606 BTO:0000567 15703209 t miannu Snx9 binds directly to bothdynamin-1 anddynamin-2. Moreover by stimulatingdynaminassembly, snx9 stimulatesdynamin's basal gtpase activity and potentiates assembly-stimulated gtpase activity on liposomes. SIGNOR-133892 0.78 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI serotonin smallmolecule CHEBI:28790 ChEBI up-regulates quantity precursor of 9606 31024440 t brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT SIGNOR-264186 0.8 TAF9 protein Q16594 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269582 0.517 CBLB protein Q13191 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 11375397 t lperfetto Cbl proteins function as ubiquitin protein ligases for the activated epidermal growth factor receptor and, thus, negatively regulate its activity. SIGNOR-236519 0.75 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89162 0.538 HDLBP protein Q00341 UNIPROT CSF1R protein P07333 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 33941620 t miannu Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. SIGNOR-266696 0.349 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr36 LPPGDYStTPGGTLF 10090 BTO:0002572 SIGNOR-C3 20670887 t lperfetto Specifically as part of mTORC1, mTOR directly phosphorylates the ribo- somal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-167180 0.924 EXOSC2 protein Q13868 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-261387 0.948 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser381 CIPTAGMsPSRSNTI 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249459 0.618 AP3S1 protein Q92572 UNIPROT AP-3 complex complex SIGNOR-C247 SIGNOR form complex binding 9606 21097499 t lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) SIGNOR-260680 0.884 dothiepin chemical CHEBI:36798 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8100134 t miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. SIGNOR-258699 0.8 AIP protein O00170 UNIPROT TFF1 protein P04155 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 21984905 t In this study, we show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells. SIGNOR-253643 0.2 PAK1 protein Q13153 UNIPROT PGAM proteinfamily SIGNOR-PF78 SIGNOR down-regulates phosphorylation 9606 BTO:0000130 12189148 t Activated pak1|inferred from family member gcesareni Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity. SIGNOR-270283 0.2 AKT2 protein P31751 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t gcesareni FOXO4 transcription factor, also referred to AFX, contains three putative phosphorylation motif sites for protein kinase B (PKB), Thr32, Ser197, and Ser262, and it is proposed that phosphorylated FOXO4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression.[...]These results indicate that phosphorylation at Thr32 and Ser197 is indispensable, whereas that at Ser262 is not critical, for regulation of the nuclear localization and transcriptional activity of FOXO4 SIGNOR-248055 0.593 NFIL3 protein Q16649 UNIPROT PER1 protein O15534 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11316793 t miannu E4BP4, a basic leucine zipper transcription factor, contains a DNA-binding domain closely related to DBP, HLF, and TEF, which are PAR proteins. Here, we show that the phase of e4bp4 mRNA rhythm is opposite to that of the dbp, hlf, and tef rhythms in the suprachiasmatic nucleus (SCN), the mammalian circadian center, and the liver. The protein levels of E4BP4 and DBP also fluctuate in almost the opposite phase. All PAR proteins activate, whereas E4BP4 suppresses the mPer1 promoter through the same sequence SIGNOR-268056 0.352 RBPJ protein Q06330 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15866158 t Induction of the p21WAF1/Cip1 gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-J_ protein to the p21 promoter. SIGNOR-252032 0.312 GLI1 protein P08151 UNIPROT MYCN protein P04198 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin SIGNOR-188872 0.411 TP53INP2 protein Q8IXH6 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 19056683 t gcesareni Tp53inp2 is a scaffold protein that recruits lc3 and/or lc3-related proteins to the autophagosome membrane by interacting with the transmembrane protein vmp1 SIGNOR-182614 0.417 MOB1A protein Q9H8S9 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates binding 9606 21084559 t Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1 SIGNOR-269866 0.94 a7/b1 integrin complex SIGNOR-C126 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269007 0.7 VHL protein P40337 UNIPROT DAB2 protein P98082 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000037 15824735 f miannu three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL. SIGNOR-255602 0.2 quetiapine chemical CHEBI:8707 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 10116 BTO:0000529 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258535 0.8 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser122 NIIHGSDsVESAEKE -1 8810265 t miannu For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown. SIGNOR-250301 0.2 LAT protein O43561 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. SIGNOR-246055 0.2 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1110 GSVQNPVyHNQPLNP 9606 8845374 t lperfetto The c-terminal autophosphorylation domain of egfr was extensively phosphorylated by c-src./These studies revealed that y1086 was phosphorylated to a significantly higher extent by c-src than by egfr. Additionally, y1101 was identified as a unique c-src phosphorylation site. SIGNOR-44243 0.609 KCNC2 protein Q96PR1 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 11506885 t miannu Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height SIGNOR-265585 0.8 FOXJ1 protein Q92949 UNIPROT EFHC1 protein Q5JVL4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 t miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). SIGNOR-266934 0.363 3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea chemical CHEBI:91362 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192814 0.8 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120088 0.316 SIRT7 protein Q9NRC8 UNIPROT H3-2 protein Q5TEC6 UNIPROT up-regulates activity deacetylation Lys19 TGGKAPRkQLATKAA 22722849 t lperfetto SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. SIGNOR-275871 0.2 AREL1 protein O15033 UNIPROT MTX2 protein O75431 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 34584540 t lperfetto Therefore, these results implied that AREL1 ubiquitinates and promotes the degradation of MTX2. SIGNOR-267674 0.2 AKT2 protein P31751 UNIPROT MTOR protein P42345 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 12782654 f gcesareni It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). However, the mechanism by which akt activates mtor is not fully understood. The known pathway by which akt activates mtor is via direct phosphorylation and tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor. SIGNOR-101324 0.624 CDK2 protein P24941 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser263 CKLFDSPsLCSSSTR 9606 17110335 t gcesareni We show here that dna-responsive checkpoints activate pp2a/b56delta phosphatase complexes to dephosphorylate cdc25 at a site distinct from ser287 (t138), the phosphorylation of which is required for 14-3-3 release. SIGNOR-150839 0.824 PTPRK protein Q15262 UNIPROT ZNRF3 protein Q9ULT6 UNIPROT up-regulates activity dephosphorylation 9606 BTO:0003009 31934854 t We show that PTPRK acts via the transmembrane E3 ubiquitin ligase ZNRF3, a negative regulator of Wnt signaling promoting Wnt receptor degradation, which is also expressed in the organizer. SIGNOR-260110 0.361 HIPK2 protein Q9H2X6 UNIPROT PAX6 protein P26367 UNIPROT up-regulates activity phosphorylation Thr281 QRRQASNtPSHIPIS 9606 BTO:0001938 16407227 t HIPK2 phosphorylates the activation domain of Pax6, which augments Pax6 transactivation by enhancing its interaction with p300. Mass spectrometric analysis identified three Pax6 phosphorylation sites as threonines 281, 304, and 373. SIGNOR-251269 0.476 MAPK8 protein P45983 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 9030579 t llicata The a/b domain of human ppargamma1 was phosphorylated in vivo, and this was abolished either by mutation of serine 84 to alanine (s84a) or coexpression of a phosphoprotein phosphatase. In vitro, this domain was phosphorylated by erk2 and jnk, and this was markedly reduced in the s84a mutant. Thus, phosphorylation of a mitogen-activated protein kinase site in the a/b region of ppargamma inhibits both ligand-independent and ligand-dependent transactivation functions. SIGNOR-46518 0.542 BAG5 protein Q9UL15 UNIPROT PRKN protein O60260 UNIPROT down-regulates activity binding 9606 BTO:0000007 15603737 t Monia Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity Immunoprecipitation (IP) of GFP-parkin resulted in the coimmunoprecipitation of both Hsp70 and BAG5 or BAG5(DARA) (Figure 4A). Furthermore, IP of GFP-parkin resulted in the coimmunoprecipitation of BAG5 or BAG5 (DARA) in the absence of overexpressed Hsp70. Taken together, these data demonstrate that BAG5 can directly inhibit parkin-mediated autoubiquitinylation independently of Hsp70. SIGNOR-261198 0.2 LCK protein P06239 UNIPROT LCP2 protein Q13094 UNIPROT unknown phosphorylation Tyr423 NSLNEEWyVSYITRP -1 8702662 t Ability of p56lck to phosphorylate Tyr-423/426 within SLP-76 in vitro SIGNOR-251381 0.744 MELK protein Q14680 UNIPROT EZH2 protein Q15910 UNIPROT up-regulates quantity by stabilization phosphorylation Ser220 RPPRKFPsDKIFEAI 9606 BTO:0002030 31434700 t miannu We observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination.  SIGNOR-277480 0.334 PRKD1 protein Q15139 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates activity phosphorylation Ser259 FPLRKTAsEPNLKVR 9534 BTO:0004055 15367659 t lperfetto Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes. SIGNOR-249270 0.531 GAS2L3 protein Q86XJ1 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 24706950 f miannu Previous work has shown that members of the growth-arrest-specific 2 (GAS2) family mediate the crosstalk between filamentous actin (F-actin) and MTs, but the molecular basis of this process remained unclear. By using fluorescence microscopy, we demonstrate that three members of this family, GAS2-like 1, GAS2-like 2 and GAS2-like 3 (G2L1, G2L2 and G2L3, also known as GAS2L1, GAS2L2 and GAS2L3, respectively) are differentially involved in mediating the crosstalk between F-actin and MTs.  SIGNOR-273702 0.7 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr167 NKDYHLQtCCGSLAY 9606 16216881 t gcesareni We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk. SIGNOR-141022 0.2 TESK1 protein Q15569 UNIPROT TESK1 protein Q15569 UNIPROT up-regulates activity phosphorylation Ser220 EPLAVVGsPYWMAPE -1 10207045 t Manara These results suggest that autophosphorylation of Ser-215 is an important step to positively regulate the kinase activity of TESK1. SIGNOR-260825 0.2 AKT1 protein P31749 UNIPROT BTK protein Q06187 UNIPROT down-regulates quantity by destabilization phosphorylation Ser51 FERGRRGsKKGSIDV 9606 BTO:0003289 23754751 t miannu The activated serine/threonine kinase Akt/protein kinase B (PKB) phosphorylated Btk on two sites prior to 14-3-3ζ binding. The interaction sites were mapped to phosphoserine pS51 in the pleckstrin homology domain and phosphothreonine pT495 in the kinase domain.  SIGNOR-276466 0.301 GSK1059615 chemical CHEBI:71955 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252667 0.8 SOSTDC1 protein Q6X4U4 UNIPROT WNT10B protein O00744 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242698 0.39 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK2 protein P24941 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258087 0.8 ELOVL proteinfamily SIGNOR-PF93 SIGNOR 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267902 0.8 phenylalanine smallmolecule CHEBI:28044 ChEBI Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates quantity precursor of 9606 20223217 t miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. SIGNOR-270444 0.8 CCR4-NOT complex complex SIGNOR-C439 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI down-regulates quantity by destabilization chemical modification 9606 31320642 t lperfetto CCR4-NOT is a conserved multiprotein complex which regulates eukaryotic gene expression principally via shortening of poly(A) tails of messenger RNA or deadenylation. |The poly(A) tails at 3′ ends of eukaryotic mRNAs are crucial for their cytoplasmic stability and to enhance the initiation of translation. Newly synthesized metazoan mRNAs possess long poly(A) tails1, and following export to the cytoplasm the tails are reported to be ~60–80 nucleotides on average at steady state2. Poly(A) tails are also important for translational efficiency at the embryonic stage2 and the length of the poly(A) tail was reported to be correlated with translational efficiency3. The multisubunit CCR4-NOT complex is principally responsible for efficient processive shortening of poly(A) tails, or deadenylation, in addition to other function SIGNOR-268312 0.8 LEF1 protein Q9UJU2 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 16936075 f The other members of the Lef1 HMGB1 protein super-family, Tcf1 and Tcf3, were also expressed in the PSM and the newly formed somites, although at a lower level than was Lef1. gcesareni Furthermore, we show that direct activation is mediated by binding of the tcf-lef/ - catenin complex to the myf5 epaxial enhancer and to a newly identified element upstream of this enhancer. SIGNOR-149170 0.255 SMAD5 protein Q99717 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation 9606 20957627 t gcesareni Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. SIGNOR-168737 0.661 AURKB protein Q96GD4 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser278 QKVAERRsSPLLRRK 9606 22865920 t lperfetto We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions SIGNOR-198650 0.26 GHSR protein Q92847 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257054 0.358 SHMT2 protein P34897 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity chemical modification 9606 32439610 t lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. SIGNOR-268227 0.8 RPS6KA5 protein O75582 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 12628924 t lperfetto Transcriptional activation of the nf-kappab p65 subunit by mitogen- and stress-activated protein kinase-1 (msk1)mutational analysis of p65 revealed ser276 as a target for phosphorylation and transactivation in response to tnf. Moreover, we identified msk1 as a nuclear kinase for p65, since msk1 associates with p65 in a stimulus-dependent way and phosphorylates p65 at ser276. SIGNOR-217424 0.605 CSNK2A1 protein P68400 UNIPROT PRPF3 protein O43395 UNIPROT up-regulates phosphorylation Thr494 TEAVQDPtKVEAHVR 9606 17932117 t lperfetto Our findings provide new insights into the biology of hprp3p and suggest that the loss of hprp3p phosphorylation at thr494 is a key step for initiating thr494met aberrant interactions within u4/u6 snrnp complex and that these are likely linked to the rp18 phenotype. SIGNOR-158319 0.2 FGG protein P02679 UNIPROT FN1 protein P02751 UNIPROT down-regulates activity binding 9606 2243140 t Regulation miannu Fibrinogen y-chain carboxyterminal (GQQHHLGGAKQAGDV) peptides inhibit fibrinogen, fibronectin (Fn), vitronectin, and von Willebrand factor (vWF) binding to the platelet glycoprotein Ilb-Illa complex (GP lIbII1a). SIGNOR-251970 0.534 HIF1A protein Q16665 UNIPROT KDM5C protein P41229 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271564 0.261 STK4 protein Q13043 UNIPROT Mob1 proteinfamily SIGNOR-PF42 SIGNOR up-regulates phosphorylation 9606 21808241 t MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction. SIGNOR-269856 0.897 CC2D1A protein Q6P1N0 UNIPROT RAD21 protein O60216 UNIPROT up-regulates activity binding 20171170 t centrosome lperfetto Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A is localized in the cytosol, nucleus, and centrosome. Aki1 plays distinct roles depending on its localization. | In the centrosome, it regulates spindle pole localization of the cohesin subunit Scc1, thereby mediating centriole cohesion during mitosis. SIGNOR-268294 0.2 SF3B1 protein O75533 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 t lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). SIGNOR-268403 0.937 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation 9606 10980595 t inferred from 70% family members llicata We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway SIGNOR-270014 0.2 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser170 SFKLSGFsFKKNKKE 9534 BTO:0000298 8557118 t lperfetto PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. SIGNOR-248939 0.372 P2RY10 protein O00398 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257287 0.2 UHMK1 protein Q8TAS1 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 10831586 t lperfetto Hkis is a nuclear protein that binds the c-terminal domain of p27(kip1) and phosphorylates it on s10 in vitro and in vivo, promoting its nuclear export to the cytoplasm.Phosphorylation at serine 10, a major phosphorylation site of p27(kip1), increases its protein stability SIGNOR-77705 0.375 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation 9606 7618106 t lperfetto The tcf protein elk-1 is phosphorylated by the jnk and erk groups of mitogen-activated protein (map) kinases causing increased dna binding, ternary complex formation, and transcriptional activation SIGNOR-29923 0.584 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 BTO:0000671 15694384 t llicata Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925. SIGNOR-133845 0.2 F11 protein P03951 UNIPROT F9 protein P00740 UNIPROT up-regulates activity cleavage 9606 BTO:0000131 20110423 t lperfetto Factor XI (FXI) is the zymogen of an enzyme (FXIa) that contributes to hemostasis by activating factor IX.|The characterization of the apple disk structure, and its relationship to the catalytic domain, have provided new insight into the mechanism of FXI activation, the interaction of FXIa with the substrate factor IX, and the binding of FXI to platelets. SIGNOR-263537 0.462 FOXO3 protein O43524 UNIPROT GALT protein P07902 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000975 17975019 f miannu Our finding that FOXO3 regulates the expression of Galt and enhances its transcriptional activity indicates that it is the repression of FOXO3 by PRL acting through RS that prevents Galt expression in the ovary and causes follicular death. SIGNOR-254186 0.2 SRC protein P12931 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates activity phosphorylation Tyr594 TYVDPHTyEDPNQAV 9606 24457997 t gcesareni SRC phosphorylates EPHA2 on Tyr594|. It is therefore likely that this phosphorylation site is included in the binding motif of an additional signalling molecule required for cell transformation. SIGNOR-246104 0.43 KLF7 protein O75840 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0004055 14729953 f miannu KLF7 stimulates p21WAF1/Cip1 transcription SIGNOR-224624 0.274 OGDC complex SIGNOR-C397 SIGNOR NADH smallmolecule CHEBI:16908 ChEBI up-regulates quantity chemical modification 9606 15953811 t miannu The Œ±-ketoglutarate‚Äìdehydrogenase complex is a complex including multiple copies of three proteins: E1k (Œ±-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. SIGNOR-266259 0.8 ADRB2 protein P07550 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256952 0.412 CSNK2A1 protein P68400 UNIPROT TTI1 protein O43156 UNIPROT down-regulates phosphorylation Ser828 DVADGNVsDFDNEEE 9606 23263282 t lperfetto Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1 SIGNOR-200240 0.2 PRKAA1 protein Q13131 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 SIGNOR-C15 11971957 t gcesareni Mutation of serine 259 increased the basal raf-1 activity and rendered it largely resistant to inhibition by pka. SIGNOR-86133 0.349 SIRT7 protein Q9NRC8 UNIPROT FBL protein P22087 UNIPROT up-regulates activity deacetylation Lys121 GESVYGEkRVSISEG 30540930 t lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) SIGNOR-275895 0.274 AKT proteinfamily SIGNOR-PF24 SIGNOR NCOR1 protein O75376 UNIPROT down-regulates phosphorylation Ser1450 TVRSRHTsVVSSGPS 9606 BTO:0001271 23940660 t lperfetto Akt-induced phosphorylation of n-cor at serine 1450 contributes to its misfolded conformational dependent loss (mcdl) in acute myeloid leukemia of the m5 subtype. SIGNOR-244318 0.2 doramapimod chemical CHEBI:40953 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190332 0.8 Neurokinin B smallmolecule CHEBI:80312 ChEBI TACR3 protein P29371 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257588 0.8 CREBBP protein Q92793 UNIPROT FBL protein P22087 UNIPROT down-regulates activity acetylation Lys205 RDLINLAkKRTNIIP 30540930 t lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) SIGNOR-275896 0.273 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT up-regulates activity phosphorylation Ser398 DSLPSSPsSATPHSQ -1 14709557 t miannu Stimulation of the AMP-activated Protein Kinase Leads to Activation of Eukaryotic Elongation Factor 2 Kinase and to Its Phosphorylation at a Novel Site, Serine 398. phosphorylation of eEF2 kinase at Ser-398 leads to an increase in its activity. SIGNOR-250157 0.474 UPF2 protein Q9HAU5 UNIPROT Upf-EJC complex SIGNOR-C367 SIGNOR form complex binding 9606 BTO:0000567 17803942 t miannu The three Up-frameshift (Upf) proteins, Upf1, Upf2, and Upf3 that together form the Upf complex, constitute the conserved core of NMD from yeast to humans. hUpf3b Forms Multiple Contacts with the EJC and Depends on hUpf2 for Complex Formation with hUpf1 SIGNOR-265238 0.972 MAPK8 protein P45983 UNIPROT APP protein P05067 UNIPROT up-regulates phosphorylation Thr743 VEVDAAVtPEERHLS 9606 BTO:0000793 12917434 t lperfetto Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. We found that the threonine 668 within the abetapp intracellular domain (aid or elsewhere aicd) is indeed phosphorylated by jnk1 SIGNOR-117852 0.699 MAML3 protein Q96JK9 UNIPROT NOTCH4 protein Q99466 UNIPROT up-regulates binding 9606 12370315 t esanto Whereas maml1 and maml2 functioned efficiently as coactivators with each of the notch receptors to transactivate a notch target hes1 promoter construct, maml3 functioned more efficiently with icn4 than with other forms of icn. SIGNOR-94103 0.862 BTC protein P35070 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 23382875 t gcesareni Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4. SIGNOR-200813 0.737 RUNX3 protein Q13761 UNIPROT ELANE protein P08246 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004850 14594802 f miannu We find that LEF-1 and CBFalpha co-activate ELA2 expression. SIGNOR-254554 0.2 PRKD3 protein O94806 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates activity phosphorylation Ser498 RPLSRTQsSPLPQSP 18692497 t lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. SIGNOR-275928 0.268 MRPS17 protein Q9Y2R5 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 BTO:0000934 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261453 0.2 PRKD2 protein Q9BZL6 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser155 GRLKRERsMSENAVR 34010649 t lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-275947 0.2 GATA3 protein P23771 UNIPROT PPARG protein P37231 UNIPROT down-regulates transcriptional regulation 9606 15632071 f fspada Constitutive expression of both gata-2 and gata-3 suppressed adipocyte differentiation, partially through direct binding to the peroxisome proliferator-activated receptor gamma (ppargamma) promoter and suppression of its basal activity SIGNOR-210025 0.355 JAK2 protein O60674 UNIPROT BRD4 protein O60885 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr97 VKLNLPDyYKIIKTP 9606 BTO:0002181 34290255 t miannu JAK2 induces tyrosine phosphorylation of BRD4 at Y97/Y98, resulting in BRD4 stabilization.  SIGNOR-277313 0.33 GLI3 protein P10071 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17419683 f lperfetto Binding of n-shh to ptch1 inhibits repression of smo, leading to activationof some genes and de-repression of others through the effects of smo on the gli family of transcription factors. SIGNOR-154240 0.697 erlotinib hydrochloride chemical CHEBI:53509 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191502 0.8 PRKCA protein P17252 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser706 ARIIGEKsFRRSVVG 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275955 0.371 PPP2R1B protein P30154 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 9606 19114990 t lperfetto Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity SIGNOR-217872 0.941 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser280 RSPSPQPsSHVAPQD 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248377 0.598 48S_initiation_complex complex SIGNOR-C454 SIGNOR 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR up-regulates activity binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269169 0.2 SMURF1 protein Q9HCE7 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. SIGNOR-195654 0.542 Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 BTO:0000143 25195934 f miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270750 0.7 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 20331961 t milica The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits). SIGNOR-164679 0.437 HSP90AB1 protein P08238 UNIPROT CBLL1 protein Q75N03 UNIPROT up-regulates quantity binding 9606 BTO:0000007 31952268 t miannu By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity. SIGNOR-271475 0.2 FOXO3 protein O43524 UNIPROT NOTCH3 protein Q9UM47 UNIPROT down-regulates quantity transcriptional regulation 10090 24749067 f gcesareni We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration. SIGNOR-244079 0.311 COP1 protein Q8NHY2 UNIPROT DCX DET1-COP1 complex SIGNOR-C24 SIGNOR form complex binding 9606 17452440 t lperfetto Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes SIGNOR-154514 0.2 KANSL3 protein Q9P2N6 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 26243146 f miannu Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. SIGNOR-267169 0.7 CDH4 protein P55283 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265866 0.506 TNIK protein Q9UKE5 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity phosphorylation Thr322 SNVNRNStIENTRRH 9606 BTO:0002181 21690388 t miannu Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.  SIGNOR-276334 0.2 GDF5 protein P43026 UNIPROT ID3 protein Q02535 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004291 16716349 f Regulation miannu GDF5 induces ID1 and ID3 in HUVSMC by a smad-dependent, MAPK-independent pathway. GDF5 binds to specific receptors, thereby inducing phosphorylation and translocation of smad1 to the nucleus where it is involved in the regulation of transcription. SIGNOR-251872 0.2 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser244 LRASTSKsESSQK 9606 21233202 t lperfetto In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity SIGNOR-171247 0.607 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLPRPE 10090 BTO:0000944 11313479 t Phosphorylation of AFX by PKB occurs in the nucleus. Phosphorylation of S193 reduces the rate of nuclear import. PKB-mediated phosphorylation of AFX, therefore, attenuates the import of the transcription factor, which shifts the localization of the protein from the nucleus to the cytoplasm and results in the inhibition of AFX transcriptional activity. SIGNOR-252873 0.756 PBX1 protein P40424 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 21746878 t miannu We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. SIGNOR-267241 0.27 PKA proteinfamily SIGNOR-PF17 SIGNOR GATA4 protein P43694 UNIPROT up-regulates activity phosphorylation Ser262 IKPQRRLsASRRVGL 9606 BTO:0000093 16109788 t miannu  PKA-mediated phosphorylation increases the interaction between GATA3 and LRH-1 and the requirement for PKA in aromatase PII promoter stimulation involves at least three specific amino acid residues: GATA3 Ser308, GATA4 Ser261, and LRH-1 Ser469.  SIGNOR-276043 0.2 PLK3 protein Q9H4B4 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser73 VSTQELYsIPEDQEP -1 16481012 t miannu Plk3 phosphorylates Chk2 at two residues, serine 62 (S62) and serine 73 (S73) in vitro, and this phosphorylation facilitates subsequent phosphorylation of Chk2 on T68 by ATM in response to DNA damage. When the Chk2 mutant construct GFP-Chk2 S73A (serine 73 mutated to alanine) is transfected into cells, it no longer associates with a large complex in vivo, and manifests a significant reduction in kinase activity.  SIGNOR-276051 0.645 mTORC2 complex SIGNOR-C2 SIGNOR mTORC2 complex SIGNOR-C2 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000944 20022946 t lperfetto These data suggest that mTORC1- and likely mTORC2-associated mTOR Ser-2481 autophosphorylation directly monitors intrinsic mTORC-specific catalytic activity SIGNOR-235484 0.677 PRKCA protein P17252 UNIPROT TP73 protein O15350 UNIPROT up-regulates activity phosphorylation Ser388 VPQPLVDsYRQQQQL 9606 19158275 t miannu Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388.  SIGNOR-276235 0.2 NDUFA2 protein O43678 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. SIGNOR-262154 0.857 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 t gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation SIGNOR-252454 0.634 INHA protein P05111 UNIPROT TGFBR3 protein Q03167 UNIPROT down-regulates binding 9606 10746731 t gcesareni Type iii tgf-beta receptor, betaglycan, can function as an inhibin co-receptor with actrii. Betaglycan binds inhibin with high affinity and enhances binding in cells co-expressing actrii and betaglycan. ability of betaglycan to facilitate inhibin antagonism of activin SIGNOR-76470 0.578 CCT239065 chemical CID:44131523 PUBCHEM BRAF protein P15056 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190907 0.8 CSNK1E protein P49674 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation -1 17525164 t miannu AMPK enhances mPer2 degradation and CKIɛ activity by phosphorylating Ser-389 of CKIɛ. One of the regulators of the period length is casein kinase Iepsilon (CKIepsilon), which by phosphorylating and inducing the degradation of the circadian clock component, mPer2, shortens the period length. AMPK phosphorylates Ser-389 of CKIepsilon, resulting in increased CKIepsilon activity and degradation of mPer2.  SIGNOR-276065 0.898 LYN protein P07948 UNIPROT SLAMF1 protein Q13291 UNIPROT unknown phosphorylation Tyr327 ETNSITVyASVTLPE 9606 15315965 t llicata Cd150-mediated akt phosphorylation required syk and sh2d1a, was negatively regulated by lyn and btk, but was ship independent. Lyn directly phosphorylated y327 in cd150, but the akt pathway did not depend on cd150 tyrosine phosphorylation and cd150-shp-2 association. SIGNOR-127997 0.305 AKT1 protein P31749 UNIPROT YWHAZ protein P63104 UNIPROT unknown phosphorylation Ser58 VVGARRSsWRVVSSI 9606 BTO:0000007 11956222 t llicata Ese data indicate that pkb/akt phosphorylates ser-58 on 14-3-3zeta both in vitro and in intact cells. The functional relevance of this phosphorylation remains to be determined. SIGNOR-116587 0.659 PPP2CA protein P67775 UNIPROT MAP2K2 protein P36507 UNIPROT down-regulates dephosphorylation 9606 20626350 t gcesareni In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a. SIGNOR-166652 0.471 CEBPA protein P49715 UNIPROT SFTPD protein P35247 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001910 11912209 t Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D. SIGNOR-254042 0.262 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 t gcesareni Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190. SIGNOR-75898 0.385 RACK1 protein P63244 UNIPROT LARP4B protein Q92615 UNIPROT up-regulates activity binding 9606 BTO:0005238 20573744 t miannu Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. Biochemical studies further show that the protein interacts with two key factors of the translational machinery, namely, the cytoplasmic poly(A) binding protein (PABPC1) and the receptor for activated C Kinase (RACK1). The biochemical and functional data of LARP4B presented in this study suggest a possible mode of action of LARP4B in translation. Assuming that LARP4B interacts with mRNA-associated PABPC1 and RACK1 simultaneously, it may form a bridge between the 3′ end of mRNAs and the initiating ribosome. This process would lead to mRNA circularization, possibly in an analogous way as it has been described for PABPC1 and eIF4G, the scaffold protein of the cap-binding complex. SIGNOR-260941 0.2 MAPK11 protein Q15759 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20162623 f Indirect:regulation miannu Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6). SIGNOR-251833 0.2 NMUR2 protein Q9GZQ4 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257402 0.252 CSNK1A1 protein P48729 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 10617630 t lperfetto In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2.| together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of alpha-synuclein could affect its binding to membranes. SIGNOR-73795 0.379 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR POU5F1 protein Q01860 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269254 0.834 Class I MHC:Antigen complex SIGNOR-C426 SIGNOR T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 31810556 f scontino High-affinity peptide/MHC class I complexes that successfully pass the aforementioned “quality controls” will be transported through the Golgi apparatus to the cell membrane to elicit antigen-specific CD8+ T cell responses. SIGNOR-267775 0.7 HNF4A protein P41235 UNIPROT CYP27A1 protein Q02318 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 11867220 f miannu Therefore, Sp1, Sp3 and HNF4 co-operate in the expression of the human CYP27 gene in HepG2 cells. SIGNOR-255198 0.306 CAMK2G protein Q13555 UNIPROT RYR1 protein P21817 UNIPROT unknown phosphorylation Ser2843 KKKTRKIsQSAQTYD 8380342 t llicata Phosphorylation of serine 2843 in ryanodine receptor-calcium release channel of skeletal muscle by cAMP-, cGMP- and CaM-dependent protein kinase. SIGNOR-250704 0.403 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates phosphorylation Ser741 TKADKRRsVRIGSYI 9606 7539802 t miannu Phosphorylation of kit/scfr by pkc-_ in vitro: identification of ser-741 and ser-746 as the major phosphorylation sites for pkc / pkc, which acts in an scf-stimulated feedback loop, that negatively controls kit/scfr kinase activity SIGNOR-28601 0.511 WNT5A protein P41221 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 18697834 t Simone Vumbaca Wnt1, Wnt3a and Wnt5a all induced a statistically greater degree of proliferation than control cells SIGNOR-255651 0.828 RPS6KA1 protein Q15418 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser293 GSTKRRKsMSGASPK 9606 23708659 t lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. SIGNOR-202113 0.373 PTPRG protein P23470 UNIPROT BMX protein P51813 UNIPROT down-regulates activity dephosphorylation Tyr40 LTKTNLSyYEYDKMK -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254693 0.263 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2054 LLKNGANkDMQNNRE 9606 17636029 t gcesareni This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60. SIGNOR-156919 0.424 NPY protein P01303 UNIPROT Food intake phenotype SIGNOR-PH152 SIGNOR down-regulates 9606 BTO:0000614 10195157 f miannu Neuropeptide Y (NPY) stimulates food intake and promotes weight gain, whereas melanocortins have the opposite effect. SIGNOR-263505 0.7 SEPTIN12 protein Q8IYM1 UNIPROT SEPTIN6 protein Q14141 UNIPROT down-regulates binding 9606 BTO:0000567 18047794 t miannu Sept12 interacts with sept6 and this interaction alters the filament structure of sept6 in hela cells. SIGNOR-159537 0.2 UBE4B protein O95155 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002552 21317885 t miannu We show that ubiquitination factor E4B (UBE4B), an E3 and E4 ubiquitin ligase, physically interacts with p53 and Hdm2 (also known as Mdm2 in mice). UBE4B promotes p53 polyubiquitination and degradation and inhibits p53-dependent transactivation and apoptosis.  SIGNOR-271907 0.405 AKT proteinfamily SIGNOR-PF24 SIGNOR GABRB2 protein P47870 UNIPROT up-regulates activity phosphorylation Ser472 SRLRRRAsQLKITIP 9606 BTO:0000007 12818177 t miannu Here we report that Akt phosphorylates, both in vitro and in vivo, the type A gamma-aminobutyric acid receptor (GABA(A)R), the principal receptor mediating fast inhibitory synaptic transmission in the mammalian brain. Akt-mediated phosphorylation increases the number of GABA(A)Rs on the plasma membrane surface, thereby increasing the receptor-mediated synaptic transmission in neurons. These results identify the GABA(A)R as a novel substrate of Akt, thereby linking Akt to the regulation of synaptic strength. SIGNOR-262619 0.2 CDK1 protein P06493 UNIPROT KIF4A protein O95239 UNIPROT up-regulates activity phosphorylation Thr1161 FFNPVCAtPNSKILK 9606 29771379 t miannu Identification of Cdk phosphorylation of Kif4A at T1161 in early mitosis. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization. SIGNOR-265994 0.501 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7230 KPSSRAAsPTRSSSS 9606 BTO:0004905 21295697 t lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. SIGNOR-264428 0.446 WNT5B protein Q9H1J7 UNIPROT PPARG protein P37231 UNIPROT up-regulates 9606 19577541 f fspada Wnt5b additionally appears to be a potent enhancer of adipogenic capacity by stimulation of ppargamma SIGNOR-186625 0.255 UMPS protein P11172 UNIPROT orotidine 5'-phosphate(3-) smallmolecule CHEBI:57538 ChEBI down-regulates quantity chemical modification 9606 18020427 t miannu Orotate phosphoribosyltransferase (OPRTase, EC 2.4.2.10) catalyzes the Mg2+-dependent condensation of orotic acid (OA) with PRPP (5-alpha-d-phosphorylribose 1-diphosphate) to yield diphosphate (PPi) and the nucleotide OMP (orotidine 5'-monophosphate). SIGNOR-253581 0.8 MMP2 protein P08253 UNIPROT A2M protein P01023 UNIPROT down-regulates quantity by destabilization cleavage Arg719 VMGRGHArLVHVEEP -1 9344465 t lperfetto The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. SIGNOR-261739 0.62 EIF2AK1 protein Q9BQI3 UNIPROT HBA1 protein P69905 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19946423 f Regulation of expression miannu Translation of α- and β-globin is tightly controlled by eIF2 and downregulated by HRI. SIGNOR-251781 0.2 MAPK8 protein P45983 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr455 ALGTPVLtPPTEAAS 9606 15538382 t lperfetto Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment. SIGNOR-252965 0.703 CHKB protein Q9Y259 UNIPROT choline phosphate(1-) smallmolecule CHEBI:295975 ChEBI up-regulates quantity chemical modification 27149373 t lperfetto Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes SIGNOR-275634 0.8 DNMT3A protein Q9Y6K1 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 26350239 f miannu Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family SIGNOR-255809 0.387 NOTCH proteinfamily SIGNOR-PF30 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates BTO:0001103 12361602 f apalma Taken together, these results show that Notch-1 activity promotes myogenic cell proliferation and that attenuation of Notch-1 activity by its antagonist Numb causes cells to exit from the cell cycle, express MRFs, and undergo myogenic differentiation. SIGNOR-255376 0.7 CDC7 protein O00311 UNIPROT MCM4 protein P33991 UNIPROT up-regulates phosphorylation 9606 21070963 t gcesareni Activation of the eukaryotic replicative dna helicase, the mcm2-7 complex, requires phosphorylation by cdc7/dbf4 (dbf4-dependent kinase or ddk), which, in turn, depends on prior phosphorylation of mcm2-7 by an unknown kinase (or kinases).we propose that the resulting mec1 modification of mcm4 and mcm6 further activates ddk phosphorylation of mcm2-7 ( fig. 7aii ). SIGNOR-169453 0.957 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr33 KFKNEDLtDELSLNK -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276205 0.2 ABL1 protein P00519 UNIPROT MUC1 protein P15941 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr1243 NGGSSLSyTNPAVAA 9606 16888623 t Manara The results demonstrate that ABL1 phosphorylates MUC1 on Tyr-60 and forms a complex with MUC1 by binding of the ABL1 SH2 domain to the pTyr-60 site.  SIGNOR-260830 0.467 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 t The effect has been demonstrated using Q01196-8 miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. SIGNOR-138985 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Ser497 GSLCSVFsPSFVQWE 9606 BTO:0000007 27846390 t lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  SIGNOR-262983 0.2 TDRD3 protein Q9H7E2 UNIPROT SNRPN protein P63162 UNIPROT unknown binding -1 15955813 t miannu the TDRD3 GST-Tudor protein interacted strongly with methylated SmB/B′ and SmD but not with SmE. These results suggest that the Tudor domains of SMN and SPF30 likely interact with assembled snRNPs, whereas the Tudor domain of TDRD3 might bind unassembled methylated Sm proteins. SIGNOR-253518 0.2 IFNA1 protein P01562 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR up-regulates activity binding 9606 11278538 t miannu Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. SIGNOR-260334 0.629 MARK2 protein Q7KZI7 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser355 EADLPEPsEKQPAAA -1 10090741 t miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. SIGNOR-275436 0.695 FAM20C protein Q8IXL6 UNIPROT FGF23 protein Q9GZV9 UNIPROT down-regulates activity phosphorylation Ser180 IPRRHTRsAEDDSER 9606 24706917 t Manara Here we show that Fam20C directly phosphorylates FGF23 on Ser(180) | Our above results support, phosphorylation of FGF23 at Ser180 inhibits O-glycosylation and would therefore promote hormone proteolysis and thus inactivation.  SIGNOR-260925 0.625 SIM1 protein P81133 UNIPROT AHR-ARNT complex SIGNOR-C125 SIGNOR down-regulates activity binding -1 9020169 t 2 miannu SIM1 can inhibit AHR·ARNT binding to the XRE and can inhibit expression from an XRE-driven reporter gene indicates that SIM1 may act as negative regulator of transcription as well as a positive regulator. The above inhibitory effects may result from SIM1 competing with AHR for binding to ARNT, although we cannot exclude the possibility that SIM1 may also have other inhibitory effects of AHR·ARNT activity. In a similar fashion, SIM1 may act as a negative regulator of all ARNT-dependent genes. SIGNOR-240811 0.42 SIRT7 protein Q9NRC8 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity deacetylation Lys38 PSTGGVKkPHRYRPG 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275884 0.2 TGFB2 protein P61812 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252283 0.7 NOTCH proteinfamily SIGNOR-PF30 SIGNOR HEY2 protein Q9UBP5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12548545 f gcesareni SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function. SIGNOR-254338 0.2 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity phosphorylation Ser980 VHAPRRCsDGGAHGY 9606 10693759 t lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. SIGNOR-75359 0.445 U2AF2 protein P26368 UNIPROT ZRSR2/U2AF2 complex SIGNOR-C81 SIGNOR form complex binding 9606 9237760 t miannu Recognition of a functional 3' splice site in pre-mrna splicing requires a heterodimer of the proteins u2af65/u2af35. SIGNOR-50173 0.771 palbociclib chemical CHEBI:85993 ChEBI CCND2 protein P30279 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205701 0.8 FASLG protein P48023 UNIPROT FAS protein P25445 UNIPROT up-regulates activity binding 9606 14965271 t lperfetto Fas (CD95) is activated by its natural ligand FasL SIGNOR-216292 0.9 PRKAA2 protein P54646 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 SIGNOR-C15 20647423 t gcesareni Ampk recruitment and h2b ser36 phosphorylation colocalized within genes activated by ampk-dependent pathways, both in promoters and in transcribed regions. SIGNOR-166905 0.2 SIX1 protein Q15475 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 9826681 f gcesareni We have demonstrated by studies of transgenic mice the importance of the mef3 motif present in the myogeninpromoter for its activation and have characterized the mef3 binding activity as consisting of two skeletal-muscle specific members of the six family, six1 and six4. SIGNOR-62104 0.452 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr265 KDPKRRMtIAQSLEH 9606 15611134 t gcesareni Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates. SIGNOR-132467 0.2 NDUFA9 protein Q16795 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5) SIGNOR-262160 0.824 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation -1 15133517 t inferred from 70% family members miannu To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291‚Äì356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target. SIGNOR-270193 0.2 CDK7 protein P50613 UNIPROT RARA protein P10276 UNIPROT unknown phosphorylation Ser77 EIVPSPPsPPPLPRI 9606 11955452 t llicata Thus, we demonstrate that the cdk7 kinase of tfiih phosphorylates the nuclear receptor, then allowing ligand-dependent control of the activation of the hormone-responsive genes. SIGNOR-116582 0.527 AKT1 protein P31749 UNIPROT HNRNPA1 protein P09651 UNIPROT down-regulates phosphorylation Ser199 SQRGRSGsGNFGGGR 9606 18562319 t gcesareni Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199. SIGNOR-252519 0.422 IRX1 protein P78414 UNIPROT PHYHIPL protein Q96FC7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. SIGNOR-261659 0.2 WIF1 protein Q9Y5W5 UNIPROT WNT8A protein Q9H1J5 UNIPROT down-regulates binding 9606 10201374 t gcesareni Here we describe wnt-inhibitory factor-1 (wif-1), a secreted protein that binds to wnt proteins and inhibits their activities. SIGNOR-66892 0.542 ITGB3 protein P05106 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253206 0.913 Terfenadine chemical CHEBI:9453 ChEBI KCNH2 protein Q12809 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9395068 t miannu We have previously shown that terfenadine can inhibit both Kv1.5 and HERG with its effects on HERG being approximately 10‐fold more potent SIGNOR-258673 0.8 PTPRJ protein Q12913 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12771128 t gcesareni A dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation. SIGNOR-101282 0.471 MAP3K8 protein P41279 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 BTO:0000776; BTO:0000801 16484370 f Mitogen-activated protein 3 kinase Tpl2, levels of which are markedly reduced in nfkb1(-/-) cells, is required for extracellular signal-regulated kinase (ERK) activation in bone marrow-derived macrophages and B cells stimulated with diverse TLR ligands SIGNOR-256078 0.363 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t inferred from 70% family members gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3. SIGNOR-270015 0.2 PDE2A protein O00408 UNIPROT PRKACA protein P17612 UNIPROT down-regulates activity binding 36476859 t lperfetto We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice.  SIGNOR-275730 0.375 PTPRG protein P23470 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity dephosphorylation Tyr313 SSEPVGIyQGFEKKT -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254716 0.2 HRAS protein P01112 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-175192 0.652 ADK protein P55263 UNIPROT adenosine smallmolecule CHEBI:16335 ChEBI down-regulates quantity chemical modification 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5‚Ä≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-267838 0.8 TRIP11 protein Q15643 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 9256431 t inferred from 70% of family members miannu Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity. SIGNOR-269879 0.431 AURKA protein O14965 UNIPROT NDEL1 protein Q9GZM8 UNIPROT down-regulates quantity by destabilization phosphorylation Ser251 LTPSARIsALNIVGD 10090 17060449 t miannu Here, we show that Aurora-A phosphorylates NDEL1 at Ser251 at the beginning of mitotic entry. Interestingly, NDEL1 phosphorylated by Aurora-A was rapidly downregulated thereafter by ubiquitination-mediated protein degradation. SIGNOR-263159 0.586 DLG3 protein Q92796 UNIPROT NMDA proteinfamily SIGNOR-PF56 SIGNOR up-regulates activity relocalization BTO:0000227 32904533 t lperfetto DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses. SIGNOR-266005 0.2 CSNK2A1 protein P68400 UNIPROT TFAP2A protein P05549 UNIPROT up-regulates phosphorylation Ser429 TDNNAKSsDKEEKHR 9606 21777522 t lperfetto Ck2 phosphorylates ap-2_ and increases its transcriptional activity SIGNOR-175130 0.312 ACVR1B protein P36896 UNIPROT TDP2 protein O95551 UNIPROT up-regulates activity phosphorylation Thr88 PKTYVDLtNEETTDS 9606 BTO:0000007 18039968 t miannu ALK4 phosphorylated TTRAP in vitro (Fig. 6A). The band migrating at the position of TTRAP was excised and analyzed by LC-MS/MS. One TTRAP peptide was phosphorylated either on T88 and T92, or on T92 only (Fig. 6B). SIGNOR-262611 0.284 STK25 protein O00506 UNIPROT PDCD10 protein Q9BUL8 UNIPROT unknown phosphorylation Ser39 ELERVNLsAAQTLRA 9606 19370760 t llicata Stk25 phosphorylates ccm3 at serine 39 and threonine 43 SIGNOR-185388 0.791 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-268074 0.8 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259808 0.8 nitric oxide smallmolecule CHEBI:16480 ChEBI M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 24669294 f apalma While investigating the factors that regulate macrophage arginine metabolism, Mills and colleagues found that macrophages activated in mouse strains with Th1 and Th2 backgrounds differed qualitatively in their ability to respond to the classic stimuli IFN-γ or lipopolysaccharide (LPS) or both and defined an important metabolic difference in the pathway: M1 macrophages made the toxic nitric oxide (NO), whereas M2 macrophages made the trophic polyamines SIGNOR-255556 0.7 FGFR3 protein P22607 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation Tyr240 RREDKFMyFEFPQPL 9606 BTO:0000527 22891331 t llicata Fgfrs phosphorylate pten at tyrosine 240 SIGNOR-191797 0.436 KCNB2 protein Q92953 UNIPROT VAPA protein Q9P0L0 UNIPROT up-regulates quantity relocalization 9606 BTO:0000007 29941597 t lperfetto Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions. SIGNOR-262124 0.2 ANKLE2 protein Q86XL3 UNIPROT VRK1 protein Q99986 UNIPROT down-regulates 9606 22770216 f miannu Lem4 inhibits the activity of baf's kinase vrk-1 during mitotic exit SIGNOR-198103 0.79 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity precursor of 26083061 t lperfetto Mitochondrial aconitase and succinate dehydrogenase were among the earliest mammalian Fe-S proteins identified.|The enzymatic activity of both proteins depends on the presence of intact Fe-S clusters SIGNOR-262132 0.8 PPARG protein P37231 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates quantity by repression 9606 BTO:0000801 17681149 f lperfetto Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways SIGNOR-249555 0.6 IYD protein Q6PHW0 UNIPROT 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI down-regulates quantity chemical modification 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-267032 0.8 ACTL6A protein O96019 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 t miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. SIGNOR-132916 0.846 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 9606 SIGNOR-C3 20516213 t fstefani The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly. SIGNOR-165799 0.7 SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR SMAD4 protein Q13485 UNIPROT up-regulates binding 9606 SIGNOR-C85 21454478 t inferred from 70% family members lperfetto Upon ligand binding, the specific heteromeric transmembrane serine/threonine kinase receptor complexes undergo phosphorylation/activation and subsequently phosphorylate the two ser residues in the c-terminal sxs motif of specific r-smads, smad1/5/8 for bmp pathway and smad2/3 for tgf-_/activin signaling. The activated r-smads then associate with co-smad, smad4. The heteromeric complexes translocate into the nucleus, where they bind to dna directly or indirectly to regulate the transcription of specific genes. SIGNOR-269952 0.2 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 9606 23431053 t milica MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation SIGNOR-201302 0.621 RXRB protein P28702 UNIPROT RARB protein P10826 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 1310351 f gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-16680 0.651 SH3RF1 protein Q7Z6J0 UNIPROT MAP3K10 protein Q02779 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 t gcesareni Taken together, these findings support a model in which apoptotic stimuli or posh overexpression induce direct association between posh and inactive mlks. SIGNOR-97003 0.362 LYN protein P07948 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr753 ERDINSLyDVSRMYV -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249383 0.603 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI beta-alanine zwitterion smallmolecule CHEBI:57966 ChEBI up-regulates quantity precursor of 9606 22718265 t miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. SIGNOR-267544 0.8 CAPN2 protein P17655 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Gly71 FSASVLTgKLTTVFL -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263581 0.302 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr258 DMKETKYtVDKRFGM 9606 11152499 t tpavlidou We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity. SIGNOR-85777 0.2 PTPN11 protein Q06124 UNIPROT IRF8 protein Q02556 UNIPROT down-regulates activity dephosphorylation 9606 27769062 t miannu We found that Bcr-abl-induced, Shp2 dependent dephosphorylation of Icsbp impaired repression of GAS2 by this transcription factor. SIGNOR-277173 0.36 serotonin smallmolecule CHEBI:28790 ChEBI HTR4 protein Q13639 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264294 0.8 ABR protein Q12979 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260525 0.482 FYN protein P06241 UNIPROT DLG2 protein Q15700 UNIPROT up-regulates activity phosphorylation Tyr348 TRPPEPVySTVNKLC -1 13129934 t miannu Recombinant PSD-93 was phosphorylated by Fyn in vitro, and Tyr-384 was identified as a major phosphorylation site. In COS7 cells, exogenously expressed PSD-93 was phosphorylated, dependent on its membrane localization. In addition, tyrosine-phosphorylated PSD-93 was able to bind to Csk, a negative regulator of Src family kinases, in vitro as well as in a brain lysate. SIGNOR-262874 0.375 MAPK14 protein Q16539 UNIPROT CFLAR protein O15519 UNIPROT up-regulates phosphorylation 9606 19597496 t There are three isoforms of cellular FLIP (c-FLIP): FLIPL, FLIPS and FLIPR gcesareni Here we demonstrate that m. tuberculosis?induced Tnf triggered reactive oxygen species?dependent Activation of ask1 and the tyrosine kinase c-abl (a000161) in mouse macrophages and that flips was phosphorylated on tyr211 and ser4 by c-abl and p38, respectively. SIGNOR-187001 0.38 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr472 EPIQEANyVPMTPGT 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236412 0.751 ROCK1 protein Q13464 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Thr232 YSSNSGPtRREDKFM 9606 15793569 t llicata In addition, active rhoa is able to stimulate the phospholipid phosphatase activity of pten in human embryonic kidney cells and leukocytes, and this regulation seems to require rhoa's downstream effector, rhoa-associated kinase (rock). together with the observation that individual substitution of ser 229 and thr 223 restored some of the rescuing ability (fig. 4b), we conclude that effective regulation of pten by sdf-1 may require more than one of these residues. SIGNOR-134855 0.642 UPF3B protein Q9BZI7 UNIPROT Upf-EJC complex SIGNOR-C367 SIGNOR form complex binding 9606 BTO:0000567 17803942 t miannu The three Up-frameshift (Upf) proteins, Upf1, Upf2, and Upf3 that together form the Upf complex, constitute the conserved core of NMD from yeast to humans. hUpf3b Forms Multiple Contacts with the EJC and Depends on hUpf2 for Complex Formation with hUpf1 SIGNOR-265236 0.961 MAPK3 protein P27361 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation 9606 19282669 t gcesareni Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. SIGNOR-184583 0.719 FYN protein P06241 UNIPROT ACP1 protein P24666 UNIPROT up-regulates activity phosphorylation Tyr133 LIIEDPYyGNDSDFE 9534 BTO:0004055 9038134 t We identify Tyr-131 as the major phosphorylation site and Tyr-132 as a minor site and the Src family PTKs Lck and Fyn as enzymes capable of phosphorylating these sites in vivo and in vitro. Both Tyr-131 and Tyr-132 are located next to the catalytic pocket of LMPTP, and especially, Tyr-131 seems to be important for the activity of LMPTP. Phosphorylation of Tyr-131 or Tyr-132, particularly the former, caused an increase in the activity of LMPTP. SIGNOR-251150 0.39 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 15611135 t gcesareni We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines. SIGNOR-132563 0.263 BMPR1B protein O00238 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 10090 BTO:0000165 10564272 f lperfetto We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2 SIGNOR-235625 0.667 PSMD2 protein Q13200 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263344 0.888 FLNA protein P21333 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity 9606 18667433 f areggio Additionally, the association of Ror2 with the actin-binding protein filamin A is required for Wnt5a-induced JNK activation and polarized cell migration.  SIGNOR-258973 0.488 PI-103 chemical CHEBI:90524 ChEBI PIK3C2B protein O00750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206160 0.8 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR TSPYL2 protein Q9H2G4 UNIPROT up-regulates activity phosphorylation Ser20 RRLSSSEsPQRDPPP 9606 BTO:0000567 11395479 t llicata We observed that a CDA1 mutant with the two consensus CDK phosphorylation sites abolished (S20A and T340A) disabled its capacity to inhibit cell growth, indicating that these sites are important for the function of this protein. Furthermore, we showed that these sites are phosphorylated by cyclin/CDKs in vitro, suggesting that these kinases may regulate CDA1 function in vivo.  SIGNOR-250752 0.344 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser27 TASRPSSsRSYVTTS -1 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248879 0.288 WNT5A protein P41221 UNIPROT FZD2 protein Q14332 UNIPROT up-regulates activity binding 9606 19008118 t FFerrentino Perhaps through Wnt5a acting via FZD2, might also inhibit adipocyte differentiation. SIGNOR-253520 0.757 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser626 SLECDMEsIIRSELM 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249687 0.509 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18423396 f fspada Moreover, expression of p27(kip1), an inhibitor of the cell cycle, was down regulated in an akt1/pkbalpha-specific manner during adipocytedifferentiation. SIGNOR-178269 0.845 CCN4 protein O95388 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 10116 11782444 t Here it is shown that WISP-1 can activate the antiapoptotic Akt/PKB signaling pathway. SIGNOR-256269 0.2 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH11 protein P55287 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265829 0.8 TAL1 protein P17542 UNIPROT TSG101 protein Q99816 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 17229889 t miannu These data suggest that Tal mediates polyubiquitylation of the lysine residues in the VPS28-binding region of TSG101, leading to subsequent degradation of TSG101. SIGNOR-271636 0.2 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser511 DSPFYRDsLPGSQRK 9606 BTO:0000150 17693255 t gcesareni Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression. SIGNOR-157300 0.627 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-267503 0.8 MAPK11 protein Q15759 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity 9606 BTO:0001255 12839928 f miannu Activation of p38 MAPK is required for arsenite-induced apoptosis and MEK1,2 dephosphorylation in human skin fibroblasts. Our data suggest the presence of a continuous negative feedback from p38α and p38β to MEK1,2 as simultaneous inhibition of p38α and p38β isoforms in normal quiescent cells resulted in accumulation of phosphorylated MEK1,2 (Fig. 2A) ⇓ . This negative regulation of MEK1,2 in normal cells could be considered a means to control MEK1,2-mediated proliferation and expression of transformation-related genes. SIGNOR-263512 0.457 lanreotide chemical CHEBI:135901 ChEBI SSTR5 protein P35346 UNIPROT up-regulates activity chemical activation 9606 26416534 t miannu Lanreotide Autogel (known as lanreotide Depot in the USA) is a synthetic octapeptide analog of somatostatin with a longer half-life than the native molecule and with selectivity for somatostatin receptor (SSTR) 2 and, to a lesser extent, SSTR 5 SIGNOR-259243 0.8 1-acyl-sn-glycerol 3-phosphate(2-) smallmolecule CHEBI:57970 ChEBI phosphatidic acid smallmolecule CHEBI:16337 ChEBI up-regulates quantity precursor of 9606 21173190 t lperfetto The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬† SIGNOR-267016 0.8 FLT3 protein P36888 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates activity 9606 BTO:0002144 28194038 f inferred from family member FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity SIGNOR-270268 0.267 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr611 ETLPISStPSKSVLP 9606 22094256 t lperfetto We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627) SIGNOR-177255 0.608 CDON protein Q4KMG0 UNIPROT MAP3K7 protein O43318 UNIPROT unknown binding 10090 SIGNOR-C21 22337877 t lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts SIGNOR-235554 0.2 RARB protein P10826 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 f lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. SIGNOR-268549 0.2 HK3 protein P52790 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266447 0.8 SERPINA1 protein P01009 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates binding 9606 8626456 t gcesareni In vitro binding studies revealed that antithrombin iii (atiii)thrombin, heparin cofactor ii (hcii)thrombin, and ?1-antitrypsin (?1AT)trypsin bound to purified lrp SIGNOR-41180 0.328 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser343 TTPGPSLsQGVSVDE 9606 10608806 t lperfetto In this report, we showed that atm phosphorylates a p95 peptide (ser-343) and a mre11 peptide (ser-264) in vitro, suggesting that atm may regulate the function of p95?Mre11? Rad50 repair complex in response to dna damage. SIGNOR-73432 0.851 NR1I3 protein Q14994 UNIPROT CYP2B6 protein P20813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19702527 f miannu Human CYP2B6 is closely regulated by constitutive androstane receptor (CAR/NR1I3) which can activate CYP2B6 expression upon ligand binding. SIGNOR-254863 0.483 IQSEC2 protein Q5JU85 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 27009485 t miannu BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors. SIGNOR-264915 0.2 ETS1 protein P14921 UNIPROT BAX protein Q07812 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 17213822 f miannu Our results suggest that the interaction between ETS1 and GFI1 facilitates their binding to specific sites on the Bax promoter and represses Bax expression in vivo. SIGNOR-254204 0.2 ABL1 protein P00519 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity phosphorylation Tyr433 KIPQDGDyEFLKSWT 10116 21715626 t Manara In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1. SIGNOR-260927 0.349 pazopanib hydrochloride chemical CHEBI:71217 ChEBI FGF1 protein P05230 UNIPROT down-regulates activity chemical inhibition -1 17620431 t miannu Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases.  SIGNOR-259166 0.8 PRKACA protein P17612 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates phosphorylation Ser338 IEKRYRSsINDKIIE 9606 16381800 t llicata Sterol regulatory element-binding protein 1 is negatively modulated by pka phosphorylation. ser338 of srebp-1a and ser314 of srebp-1c are pka phosphorylation sites. SIGNOR-143392 0.2 TRIP12 protein Q14669 UNIPROT RNF168 protein Q8IYW5 UNIPROT down-regulates activity ubiquitination 9606 BTO:0001938 22884692 t miannu Here, we show that TRIP12 and UBR5, two HECT domain ubiquitin E3 ligases, control accumulation of RNF168, a rate-limiting component of a pathway that ubiquitylates histones after DNA breakage. We find that RNF168 can be saturated by increasing amounts of DSBs. Depletion of TRIP12 and UBR5 allows accumulation of RNF168 to supraphysiological levels, followed by massive spreading of ubiquitin conjugates and hyperaccumulation of ubiquitin-regulated genome caretakers such as 53BP1 and BRCA1. SIGNOR-266783 0.477 KDM4C protein Q9H3R0 UNIPROT JAG1 protein P78504 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23698634 f miannu The expression of KDM4C gene was increased in spheres from colorectal cancer (CRC) cells and the knockdown (KD) of KDM4C eliminated colonosphere formation. KDM4C KD decreased the expression of JAG1 gene, and the downregulation of JAG1 gene recapitulated the impaired colonosphere formation. SIGNOR-254542 0.2 PRKCD protein Q05655 UNIPROT BAG3 protein O95817 UNIPROT up-regulates phosphorylation Ser187 SSSSSSAsLPSSGRS 9606 23108398 t lperfetto Pkc_-mediated phosphorylation of bag3 at ser187 site induces epithelial-mesenchymal transition and enhances invasiveness in thyroid cancer fro cells. we showed that bag3 was implicated in epithelial-mesenchymal transition (emt) procedure, and phosphorylation state at ser187 site had a critical role in emt regulation by bag3. SIGNOR-199316 0.253 MAPK1 protein P28482 UNIPROT TPPP protein O94811 UNIPROT down-regulates activity phosphorylation Ser160 GVTKAISsPTVSRLT -1 17693641 t miannu Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP. SIGNOR-262928 0.362 MAPK3 protein P27361 UNIPROT EWSR1 protein Q01844 UNIPROT unknown phosphorylation Thr79 QPPTGYTtPTAPQAY 9606 19076070 t lperfetto Here we report that ews and ews-fli1 become phosphorylated at thr79 in the n-terminal domain in response to mitogens or dna damage. Mitogen-induced phosphorylation of ews and ews-fli1 was weak and catalysed by erk1 (extracellular signal-regulated kinase 1) and erk2. SIGNOR-182782 0.268 MASP2 protein O00187 UNIPROT C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 17204478 t lperfetto MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a). SIGNOR-263431 0.794 MTX2 protein O75431 UNIPROT SAM complex complex SIGNOR-C422 SIGNOR form complex binding 31387448 t lperfetto The SAM complex of the outer membrane mediates insertion of β-barrel proteins into the outer membrane. hSam50 associates with MTX1 and MTX2. SIGNOR-267682 0.728 CDK2 protein P24941 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Thr395 PLPSGLLtPPQSGKK 9606 19561641 t gcesareni Phosphorylation of threonine 395 has been linked to the proteasome-mediated degradation of full length cyclin e SIGNOR-186418 0.954 CSNK2A1 protein P68400 UNIPROT OTUD5 protein Q96G74 UNIPROT up-regulates activity phosphorylation Ser177 EVGAGYNsEDEYEAA -1 22245969 t miannu Here we show that phosphorylation of the human deubiquitinase DUBA (OTUD5) at a single residue, Ser177, is both necessary and sufficient to activate the enzyme. Treatment with CK2 could activate DUBA purified from E. coli, and this activity was associated with a species monophosphorylated at Ser177 (Fig. 1d). SIGNOR-265872 0.2 CHEK1 protein O14757 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates activity phosphorylation Ser331 KSKGRASsSGNQESS 9606 BTO:0005035 19861535 t lperfetto In this study, we report a novel phosphorylation site serine 331 (S331) of FANCD2, the pivotal downstream player of the Fanconi anemia pathway. Phosphorylation of S331 is important for its DNA damage-inducible monoubiquitylation, resistance to DNA cross-linkers, and in vivo interaction with FANCD1/BRCA2.|In vitro and in vivo experiments show that phosphorylation of S331 is mediated by CHK1, SIGNOR-263252 0.603 DNMT1 protein P26358 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000775 32905139 t Gianni Our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35) SIGNOR-269053 0.502 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT unknown phosphorylation Tyr69 ERQLNGTyAIAGGKA 9606 BTO:0000661 7961936 t We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. SIGNOR-251396 0.602 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR TSC2 protein P49815 UNIPROT up-regulates activity phosphorylation Ser1217 MSLENPLsPFSSDIN 9606 BTO:0000007 32294430 t done miannu We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452.  SIGNOR-274099 0.481 GCG protein P01275 UNIPROT LATS1 protein O95835 UNIPROT up-regulates 9606 23075495 f gcesareni On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz. SIGNOR-199202 0.276 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr637 KFGSLDTyLKKNKNC 9606 BTO:0000007 19364823 t 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2. SIGNOR-235885 0.2 KDM6B protein O15054 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 22025054 t lperfetto JMJD3 seems to function by controlling expression of the transcription factor IRF4, which in turn is required for M2 polarization of macrophages in vitro and in vivo. Although this pathway is strongly supported by genetic. SIGNOR-249540 0.433 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89193 0.55 MAP3K7 protein O43318 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 17110930 t Barakat Upon TNFα stimulation, MEKK1, ASK1, and TAK1 phosphorylate and activate MKK7, which in turn activates JNK SIGNOR-274146 0.63 FASN protein P49327 UNIPROT malonyl-CoA smallmolecule CHEBI:15531 ChEBI down-regulates quantity chemical modification 9606 15507492 t Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-267212 0.8 MN1 protein Q10571 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 10090 17494859 f irozzo MN1 is a unique oncogene in hematopoiesis that both promotes proliferation/self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment. SIGNOR-256016 0.7 POU3F4 protein P49335 UNIPROT POU3F3 protein P20264 UNIPROT up-regulates activity binding -1 9105675 t miannu POU proteins (Brain-1, Brain-2, Brain-4 and SCIP) serve as transcriptional transactivators. if they were to form homomeric and heteromeric complexes with each other, depending on the particular combination, they might have different DNA-binding specificities and, thus, activate different genes. SIGNOR-220127 0.319 PRKAA1 protein Q13131 UNIPROT UCP3 protein P55916 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001103 17609368 f gcesareni Severalin vivostudies using aicar to activate ampk chronically determined that mitochondrial enzymes [e.g., cytochromec, uncoupling protein 3 (ucp-3)] (1518) and proteins involved in glucose uptake (glut4) (1820) are increased at the transcriptional level in skeletal muscle. SIGNOR-156831 0.335 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. SIGNOR-270796 0.8 STAT3 protein P40763 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22669242 f miannu Thus we infected C2C12 myofibers with a recombinant adenovirus expressing a mutant, constitutively activated STAT3 (cSTAT3) known to possess increased DNA binding/transcriptional activity. Consistent with wasting, atrogin-1 expression was also markedly increased (Fig. 3A). Thus STAT3 activation is by itself sufficient to induce muscle fiber wasting in cell culture. SIGNOR-255331 0.285 PCCA protein P05165 UNIPROT PCC complex SIGNOR-C414 SIGNOR form complex binding 9606 15890657 t miannu Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively. SIGNOR-267182 0.887 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation Thr69 SRDPVARtSPLQTPA 9606 10567572 t gcesareni G(2)/m-phase cells proved more susceptible to death signals, and phosphorylation of bcl-2 appeared to be responsible, as a ser70ala substitution restored resistance to apoptosis. We noted that ask1 and jnk1 were normally activated at g(2)/m phase, and jnk was capable of phosphorylating bcl-2.. SIGNOR-72361 0.564 zotepine chemical CHEBI:32316 ChEBI DRD4 protein P21917 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258555 0.8 A6/b4 integrin complex SIGNOR-C174 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 9428518 t miannu Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation. SIGNOR-259033 0.405 MYD88 protein Q99836 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity binding 9606 BTO:0000776 17548806 t lperfetto St2825 interfered with recruitment of irak1 and irak4 by myd88, causing inhibition of il-1beta-mediated activation of nf-kappab transcriptional activity. SIGNOR-155385 0.945 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser259 SQRQRSTsTPNVHMV 9534 BTO:0004055 12801936 t miannu Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. Cyclic AMP (cAMP) blocks Raf-1 activation by stimulating its phosphorylation on serine 43 (Ser43), serine 233 (Ser233), and serine 259 (Ser259). SIGNOR-250041 0.482 PHLPP1 protein O60346 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Ser474 RTHFPQFsYSASIRE 9606 BTO:0001544 19261608 t The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. SIGNOR-248328 0.606 MAP3K21 protein Q5TCX8 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser222 LIDSMANsFVGTRSY 9606 23319808 t Manara These experiments showed that MEK1 is phosphorylated by MLK4 on Ser217/221 SIGNOR-260768 0.2 ASXL1 protein Q8IXJ9 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates activity binding 9606 16606617 t irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. SIGNOR-255931 0.287 MYF5 protein P13349 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 f miannu The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37409 0.7 IL10RA protein Q13651 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 22933625 f apalma Recent findings have shown that IL-10 stimulation of macrophages isolated from skeletal muscles increases the phagocytic activity of macrophages SIGNOR-255443 0.7 NAIP protein Q13075 UNIPROT NLRC4 inflammasome complex SIGNOR-C223 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256403 0.519 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 8702662 t lperfetto A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function SIGNOR-42960 0.797 GRM8 protein O00222 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264351 0.7 GOT2 protein P00505 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI down-regulates quantity chemical modification 9606 31422819 t miannu This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-268058 0.8 PI3K complex SIGNOR-C156 SIGNOR superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity 23994464 f apalma The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release SIGNOR-255011 0.8 MEF2D protein Q14814 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 t lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation SIGNOR-238751 0.346 TUT4 protein Q5TAX3 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR down-regulates 25480299 f lperfetto Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells. SIGNOR-268355 0.7 olanzapine chemical CHEBI:7735 ChEBI HTR1F protein P30939 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258512 0.8 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI up-regulates quantity precursor of 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-268131 0.8 ID1 protein P41134 UNIPROT CASK protein O14936 UNIPROT unknown binding 9606 15694377 t miannu We identified a novel CASK-interacting protein, inhibitor of differentiation 1 (Id1) SIGNOR-225149 0.415 MCUB protein Q9NWR8 UNIPROT MCU_MICUB_variant complex SIGNOR-C499 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270863 0.2 PTPRF protein P10586 UNIPROT LRRC4B protein Q9NT99 UNIPROT up-regulates activity binding 9606 19467332 t miannu The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively. SIGNOR-264049 0.601 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates phosphorylation Tyr759 LYDVSRMyVDPSEIN 9606 BTO:0000776 11606584 t gcesareni By measuring the ability of human plcgamma2 to restore calcium responses to the b-cell receptor stimulation or oxidative stress in a b-cell line (dt40) deficient in plcgamma2, we have demonstrated that two tyrosine residues, tyr(753) and tyr(759), were important for the plcgamma2 signaling function.Of the two kinases that previously have been proposed to phosphorylate plcgamma2, btk, and syk, purified btk had much greater ability to phosphorylate recombinant plcgamma2 in vitro, whereas syk efficiently phosphorylated adapter protein blnk. SIGNOR-111073 0.769 PTPN21 protein Q16825 UNIPROT SRC protein P12931 UNIPROT up-regulates dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 15143158 t gcesareni Ptpd1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (egf) signaling. SIGNOR-124774 0.628 C3 convertase complex (C3bBb) complex SIGNOR-C314 SIGNOR C3 protein P01024 UNIPROT up-regulates activity cleavage Arg671 QPAARRRrSVQLTEK 9606 BTO:0000089 26489954 t lperfetto In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC). SIGNOR-263477 0.903 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11013220 f irozzo Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β. SIGNOR-256287 0.587 POU5F1 protein Q01860 UNIPROT SOX17 protein Q9H6I2 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 f lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) SIGNOR-253167 0.627 PTPN11 protein Q06124 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 11085989 f miannu We show here that leptin can activate ERK signaling in thehypothalamus and that this stimulation is likely to occur viatwo pathways, both involving SHP-2.We have shown above that SHP-2 is a positive mediator of ERK activation by ObRb and that this requires both the phosphatase activity and tyrosine phosphorylation of SHP-2. Furthermore,Tyr-985 is required for maximal ERK phosphorylation. SIGNOR-263500 0.861 THPO protein P40225 UNIPROT MPL protein P40238 UNIPROT up-regulates binding 9606 11784712 t miannu Thrombopoietin(tpo) controls the formation of megakaryocytes and platelets from hematopoietic stem cells via activation of the c-mplreceptorand multiple downstream signal transduction pathways. SIGNOR-113955 0.773 PTEN protein P60484 UNIPROT KIF11 protein P52732 UNIPROT up-regulates activity dephosphorylation Thr926 LDIPTGTtPQRKSYL 9606 27492783 t lperfetto PTEN significantly reduces EG5 phosphorylation at Thr926 (XREF_FIG), suggesting PTEN may target this EG5 site for dephosphorylation. SIGNOR-277000 0.466 NSMCE3 protein Q96MG7 UNIPROT NSMCE1 protein Q8WV22 UNIPROT up-regulates activity binding -1 20864041 t miannu MAGE-G1 enhances NSE1 ubiquitin ligase activity in vitro. SIGNOR-265489 0.2 SNRPD1 protein P62314 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270635 0.814 CDK4 protein P11802 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates phosphorylation Ser632 LVVSRNLsPPNCTEL 9606 BTO:0000150 SIGNOR-C18 17334399 t lperfetto In particular, we have identified ser 632 of brca1 as a cyclin d1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin d1/cdk4 activity resulted in increased brca1 dna binding at particular promoters in vivo. SIGNOR-153450 0.651 pazopanib chemical CHEBI:71219 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 18620382 t Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. SIGNOR-257735 0.8 OPRL1 protein P41146 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257209 0.359 COPS6 protein Q7L5N1 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270768 0.929 CRP protein P02741 UNIPROT GCH1 protein P30793 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004602 17942113 f miannu The gene expression and enzymatic activity of GTPCH1, the first enzyme in the de novo biosynthesis of BH(4), were significantly inhibited by CRP. SIGNOR-252216 0.282 HCK protein P08631 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates activity phosphorylation Tyr787 LTPSPKSyENLWFQA -1 9790917 t Hck becomes activated upon G-CSF treatment and is, in turn, able to phosphorylate the G-CSF-R, indicating a clear functional and physical involvement in G-CSF signaling. the ability of Hck to phosphorylate the G-CSF-R in vitro, both Y728 and Y763 fit the Src consensus phosphorylation site. we investigated the activation of Hck by the G-CSF-R in intact cells as well as in vitro. These studies revealed recruitment of Hck to activated G-CSF-R, mediated by direct binding via its SH2 domain to multiple phosphotyrosines of the receptor. In addition, we show that Hck becomes activated upon G-CSF treatment and is, in turn, able to phosphorylate the G-CSF-R, indicating a clear functional and physical involvement in G-CSF signaling. SIGNOR-251264 0.393 SH3RF1 protein Q7Z6J0 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 12514131 t gcesareni We confirmed that posh binds activated rac1 and find that it also binds all mlk family members tested and interacts with mkk4/7 as well as jnk1 and jnk2. SIGNOR-96955 0.336 NTRK2 protein Q16620 UNIPROT FYN protein P06241 UNIPROT up-regulates binding 9606 BTO:0000938 9648856 t gcesareni All these data suggest the involvement of fyn in the neurotrophin signal transduction pathways downstream of trkb. We investigated whether fyn is involved in the trk-dependent signal transduction pathways of neurotrophin. The fyn-src homology domain 2 (sh2) was observed to associate in vitro with the intracellular domain of trkb (icd-trkb). SIGNOR-58424 0.389 PLK1 protein P53350 UNIPROT ATXN10 protein Q9UBB4 UNIPROT down-regulates phosphorylation Ser77 QVENLASsLQLITEC 9606 21857149 t lperfetto Phosphorylation of ataxin-10 by polo-like kinase 1 is required for cytokinesis. Plk1 phosphorylates ataxin-10 at s77 and t82 in vitro. we found that ataxin-10 is ubiquitinated, and is subject to proteasome-dependent degradation, which is delayed in the 2a mutant. We propose a model in which plk1 phosphorylation of ataxin-10 influences its degradation and cytokinesis SIGNOR-176122 0.36 DVL1 protein O14640 UNIPROT JUN protein P05412 UNIPROT up-regulates binding 9606 BTO:0000007 18347071 t gcesareni In this study, we discovered two novel interactions between dvl and c-jun and between dvl and beta-catenin in the nucleus that mediate the formation of a dvlc-junbeta-catenintcf functional complex. SIGNOR-178038 0.47 Caspase 3 complex complex SIGNOR-C221 SIGNOR IL18 protein Q14116 UNIPROT up-regulates activity cleavage Asp71 PLFEDMTdSDCRDNA 9606 BTO:0001370 9334240 t lperfetto We also found two precursor hIL-18 (prohIL-18)-processing activities in the cytosol of THP.1 cells. These activities were blocked separately by the caspase inhibitors Ac-YVAD-CHO and Ac-DEVD-CHO. Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products. SIGNOR-256378 0.496 methyltestosterone chemical CHEBI:27436 ChEBI AR protein P10275 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 17202804 t miannu GnRH antagonizes testosterone activation of the human androgen receptor in SCL60 cells. Gonadotropin-Releasing Hormone Functionally Antagonizes Testosterone Activation of the Human Androgen Receptor in Prostate Cells through Focal Adhesion Complexes Involving Hic-5 SIGNOR-259266 0.8 GSK3B protein P49841 UNIPROT USF1 protein P22415 UNIPROT up-regulates activity phosphorylation Ser186 APRTHPYsPKSEAPR 9606 BTO:0001583 21873430 t miannu  Both MITF and USF1 were activated by glycogen synthase kinase (GSK) 3, with GSK3 phosphorylation sites on USF1 identified as the previously described activating site threonine 153 as well as serine 186. SIGNOR-276354 0.291 ROCK1 protein Q13464 UNIPROT PFN1 protein P07737 UNIPROT down-regulates phosphorylation Ser138 MASHLRRsQY 9606 22479341 t lperfetto We previously identified pfn1 as a huntingtin aggregation inhibitor, and others have implicated it as a tumor-suppressor. Rho-associated kinase (rock) directly phosphorylates pfn1 at ser-137 to prevent its binding to polyproline sequences. This negatively regulates its anti-aggregation activity. SIGNOR-196820 0.275 PINK1 protein Q9BXM7 UNIPROT LETM1 protein O95202 UNIPROT up-regulates activity phosphorylation Thr192 ILNGHSLtRRERRQF -1 29123128 t lperfetto Here we demonstrate that PINK1 directly interacts with and phosphorylates LETM1 at Thr192 in vitro.|Phosphorylated LETM1 or the phospho-mimetic LETM1-T192E increase calcium release in artificial liposomes and facilitates calcium transport in intact mitochondria. SIGNOR-262540 0.366 MAP3K7 protein O43318 UNIPROT PTPN3 protein P26045 UNIPROT unknown phosphorylation Ser359 PAMRRSLsVEHLETK 9606 9341175 t gcesareni Mutation of ser359 and ser853 to alanine significantly reduced the association between 14-3-3beta and ptph1. Furthermore, association of ptph1 and 14-3-3beta was detected in several cell lines and was regulated in response to extracellular signals SIGNOR-52781 0.267 NOXA1 protein Q86UR1 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity 9606 19879762 t lperfetto BH3-only proteins containing only a single BH domain and including Puma, Noxa, Bid and Bad as well as other factors are particularly important for such neutralisation, binding and regulating the anti-apoptotic Bcl-2 proteins to promote apoptosis SIGNOR-209684 0.2 AKAP5 protein P24588 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity relocalization 10116 10939335 t In this report, we demonstrate that glutamate receptors and PKA are recruited into a macromolecular signaling complex through direct interaction between the MAGUK proteins, PSD-95 and SAP97, and AKAP79/150 SIGNOR-261292 0.542 vatalanib chemical CHEBI:90620 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207642 0.8 CTNNA3 protein Q9UI47 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity relocalization 9606 BTO:0000586 21598020 t miannu Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14 SIGNOR-265493 0.747 DYRK1B protein Q9Y463 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr288 VDLACTPtDVRDVDI 9606 BTO:0000567 17046823 t lperfetto Further, we found that not only gsk-3beta but also dyrk1b modulates cyclin d1 subcellular localization by the phosphorylation of thr(288). These results suggest that dif-3 induces degradation of cyclin d1 through the gsk-3beta- and dyrk1b-mediated threonine phosphorylation in hela cells SIGNOR-150126 0.42 CAMK2B protein Q13554 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 t gcesareni All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below). SIGNOR-154771 0.38 FZR1 protein Q9UM11 UNIPROT TK1 protein P04183 UNIPROT down-regulates quantity by destabilization binding -1 14701726 t miannu We show that hTK1 is degraded via a ubiquitin-proteasome pathway in mammalian cells and that anaphase-promoting complex/cyclosome (APC/C) activator Cdh1 is not only a necessary but also a rate-limiting factor for mitotic degradation of hTK1. By in vitro ubiquitinylation assays, we demonstrated that hTK1 is targeted for degradation by the APC/C-Cdh1 ubiquitin ligase dependent on this KEN box motif. SIGNOR-272945 0.348 BCAR1 protein P56945 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 BTO:0000182 27447856 t lperfetto One such SH2-domain containing protein is the p85 subunit of PI3K, as its docking with tyrosine-phosphorylated p130cas activates the p110alpha subunit| tyrosine-165 and tyrosine-128 on p130cas both are phosphorylated to a greater extent in parental versus paxillin Y88F mutan SIGNOR-263980 0.544 A8/b1 integrin complex SIGNOR-C165 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates 15721307 f lperfetto We previously showed that α8β1-mediated adhesion of cells to fibronectin resulted in phosphorylation of FAK | FAK can activate PI3 kinase, either directly or indirectly through Src kinase [23]. SIGNOR-253309 0.535 PRKAA2 protein P54646 UNIPROT TSC1 protein Q92574 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 14651849 t gcesareni Under energy starvation conditions, the amp-activated protein kinase (ampk) phosphorylates tsc2 and enhances its activity. SIGNOR-119541 0.532 SMARCA2 protein P51531 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270742 0.804 RIMBP3B protein A6NNM3 UNIPROT RIMS3 protein Q9UJD0 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264374 0.268 RLF protein Q13129 UNIPROT RIT1 protein Q92963 UNIPROT up-regulates activity binding 9606 10545207 t miannu Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors. SIGNOR-220799 0.314 MTOR protein P42345 UNIPROT TFEB protein P19484 UNIPROT down-regulates activity phosphorylation Ser142 AGNSAPNsPMAMLHI 9606 BTO:0000007 22343943 t Here, we have used an mTORC1 in-vitro kinase assay and a phosphoantibody to demonstrate that serine S142, which we previously found to be phosphorylated by ERK2, is also phosphorylated by mTOR and that this phosphorylation has a crucial role in controlling TFEB subcellular localization and activity. SIGNOR-255310 0.49 MAPK3 protein P27361 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 10669763 t gcesareni The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-Œ± or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-74943 0.541 UMPS protein P11172 UNIPROT orotidine 5'-phosphate(3-) smallmolecule CHEBI:57538 ChEBI up-regulates quantity chemical modification 9606 2912371 t miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). SIGNOR-267438 0.8 CDK5 protein Q00535 UNIPROT TPPP protein O94811 UNIPROT down-regulates activity phosphorylation Ser160 GVTKAISsPTVSRLT -1 17693641 t miannu Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP. SIGNOR-262931 0.413 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser554 PDSEASQsPQYSFES 9606 11110801 t llicata In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676). SIGNOR-84992 0.453 NUP35 protein Q8NFH5 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262080 0.615 PIM proteinfamily SIGNOR-PF34 SIGNOR RPS19 protein P39019 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 16266891 t gcesareni The pim-1/rps19 interaction was demonstrated both in vitro and in living cells and led to phosphorylation of rps19 in an in vitro kinase assay. SIGNOR-259412 0.2 PIM2 protein Q9P1W9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 16146838 f lperfetto The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. SIGNOR-256575 0.7 acetoacetyl-CoA smallmolecule CHEBI:15345 ChEBI (3S)-3-hydroxy-3-methylglutaryl-CoA(5-) smallmolecule CHEBI:43074 ChEBI up-regulates quantity precursor of 29597274 t lperfetto Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis SIGNOR-267652 0.8 FABP5 protein Q01469 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264459 0.7 SMURF1 protein Q9HCE7 UNIPROT UVRAG protein Q9P2Y5 UNIPROT down-regulates activity ubiquitination Lys559 DTSLDFSkENKKKGE 9606 BTO:0000007 30686098 t miannu Here we report that UVRAG is ubiquitinated by SMURF1 at lysine residues 517 and 559, which decreases the association of UVRAG with RUBCN and promotes autophagosome maturation. However, the deubiquitinase ZRANB1 specifically cleaves SMURF1-induced K29 and K33-linked polyubiquitin chains from UVRAG, thereby increasing the binding of UVRAG to RUBCN and inhibiting autophagy flux.  SIGNOR-273653 0.2 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates activity dephosphorylation Tyr960 GHQKRIAySLLGLKD -1 21538645 t gcesareni The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates SIGNOR-246023 0.646 LRRK1 protein Q38SD2 UNIPROT CDK5RAP2 protein Q96SN8 UNIPROT up-regulates activity phosphorylation Ser140 SLAEAGGsEIQRVKE 9606 BTO:0000567 26192437 t lperfetto Interestingly, LRRK1 in turn phosphorylates CDK5RAP2(Cep215), a human homologue of Drosophila Centrosomin (Cnn), in its gamma-tubulin-binding motif, thus promoting the interaction of CDK5RAP2 with gamma-tubulin. LRRK1 phosphorylation of CDK5RAP2 Ser 140 is necessary for CDK5RAP2-dependent microtubule nucleation. SIGNOR-275468 0.519 MDM2 protein Q00987 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000038 26718225 t miannu  Here, we found that nuclear EGFR induced phosphorylation of PPARγ at Tyr-74 leading to PPARγ ubiquitination and degradation by mouse double minute 2 (MDM2) ubiquitin ligase.  SIGNOR-277191 0.398 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1327 CCSPPPDyNSVVLYS 9606 9722576 t lperfetto Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for src homology 2 domain-containing molecules. By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor. SIGNOR-59758 0.2 ABL1 protein P00519 UNIPROT WASL protein O00401 UNIPROT up-regulates activity phosphorylation Tyr175 EITTNRFyGPQVNNI -1 16199863 t Abl phosphorylates N-WASP on tyrosines 175 and 256. Phosphorylation at this site stabilizes the active conformation of N-WASP, resulting in comet tail elongation. SIGNOR-251436 0.566 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT down-regulates activity phosphorylation Ser737 EPLERRLsLVPDSEQ 9606 19095655 t Luana AMPK phosphorylates CFTR in vitro at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites. SIGNOR-21316 0.467 MLNR protein O43193 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256737 0.252 PTPN22 protein Q9Y2R2 UNIPROT ZAP70 protein P43403 UNIPROT down-regulates activity dephosphorylation Tyr493 LGADDSYyTARSAGK 9606 16461343 t In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22. SIGNOR-248838 0.694 RPL18A protein Q02543 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262480 0.817 ELOVL2 protein Q9NXB9 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267890 0.8 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Platelet_morphogenesis phenotype SIGNOR-PH135 SIGNOR up-regulates 9606 BTO:0000132 27871158 f lperfetto Each step in platelet shape change involves the participation of a variety of actin filament-related proteins that are highly concentrated in platelets (Fig. 1). In resting human platelets, the actin filaments from the core to the membrane skeleton are tightly bound to the plasma membrane by GP1b/IX-filamin A complexes  SIGNOR-261839 0.7 AKT1 protein P31749 UNIPROT MAP2K4 protein P45985 UNIPROT down-regulates phosphorylation Ser80 IERLRTHsIESSGKL 9606 BTO:0000007 11707464 t lperfetto Akt phosphorylated sek1 on serine 78. SIGNOR-236494 0.58 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr583 RRPPGLEyCYNPSHN 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1 SIGNOR-236183 0.2 PIK3CA protein P42336 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, which recruit akt to the plasma membrane through its pleckstrin homology (ph) domain, permitting its activation by pdks. SIGNOR-65409 0.8 IL6R protein P08887 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0000785 11238858 t gcesareni Part of the receptor for interleukin 6. Binds to il6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with il6st. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis. SIGNOR-105504 0.741 L-arginine chemical CHEBI:16467 ChEBI ARG1 protein P05089 UNIPROT up-regulates BTO:0000801 BTO:0001103 25386178 f apalma In mammalian cells, arginine can be catabolized by four classes of enzymes (Figure ​(Figure1):1): NOS, arginase, arginine decarboxylase (ADC), and arginine:glycine amidinotransferase (AGAT) SIGNOR-255555 0.8 ULK1 protein O75385 UNIPROT RB1CC1 protein Q8TDY2 UNIPROT up-regulates phosphorylation 9606 19597335 t gcesareni Ulk1 and ulk2 are the kinase phosphorylating their binding proteins atg13 and fip200. Atg13 directly binds fip200 and mediates the interaction between fip200 and ulks. SIGNOR-186992 0.911 ARHGEF25 protein Q86VW2 UNIPROT RAC1 protein P63000 UNIPROT up-regulates guanine nucleotide exchange factor 10090 16314529 t gcesareni Exogenous expression of geft promotes myogenesis ofc2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process. SIGNOR-236882 0.606 CRBN protein Q96SW2 UNIPROT SALL4 protein Q9UJQ4 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 32071327 t miannu Thalidomide-induced teratogenicity is dependent on its binding to cereblon (CRBN), the substrate receptor of the Cul4A-DDB1-CRBN-RBX1 E3 ubiquitin ligase complex. Thalidomide binding to CRBN elicits subsequent ubiquitination and proteasomal degradation of CRBN neosubstrates including SALL4, a transcription factor of which polymorphisms phenocopy thalidomide-induced limb defects in humans. SIGNOR-272206 0.2 threonine smallmolecule CHEBI:26986 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264761 0.7 MSX1 protein P28360 UNIPROT DLX5 protein P56178 UNIPROT down-regulates activity binding 10090 BTO:0000946 9111364 t 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. SIGNOR-240987 0.398 INTS10 protein Q9NVR2 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261473 0.772 glutamic acid smallmolecule CHEBI:18237 ChEBI NMDA receptor_2C complex SIGNOR-C349 SIGNOR up-regulates activity chemical activation 9606 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate SIGNOR-264130 0.8 AP3B1 protein O00203 UNIPROT AP-3 complex complex SIGNOR-C247 SIGNOR form complex binding 9606 21097499 t lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) SIGNOR-260681 0.908 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI THBD protein P07204 UNIPROT up-regulates quantity by expression 9606 22406829 f miannu In carcinomas the expression of thrombomodulin (TM) is inversely correlated with tumour progression and metastasis. The expression of TM is negatively regulated by NF-?B- and GSK3-?-dependent signalling pathways and positively regulated by retinoic acid and transcription factor Sp1 in PrEC, LNCaP and PC-3 cells, but not in DU-145 cells. SIGNOR-255217 0.8 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser105 TGAGAAGsPAQQHAH 9606 BTO:0000567 26183396 t miannu In this study, we found that Cdk1 (Cyclin-dependent kinase 1) directly phosphorylated TAZ on six novel sites independent of the Hippo pathway, which further resulted in TAZ degradation through proteasome system. SIGNOR-276927 0.261 prostaglandin E2 smallmolecule CHEBI:15551 ChEBI GNG12 protein Q9UBI6 UNIPROT up-regulates chemical activation 9606 16293724 t gcesareni Although pge2 promotes nucleotide exchange on gas and subsequent dissociation of gtp-bound gas from gbg subunits. SIGNOR-141820 0.8 MAPK14 protein Q16539 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser567 SLAWLSDsPLFDLIK 9606 20871633 t llicata P38 bypasses the cell cycle-associated hierarchical phosphorylation and directly phosphorylates rb on ser567, which is not phosphorylated during the normal cell cycle. Phosphorylation by p38, but not cdks, triggers an interaction between rb and the human homolog of murine double minute 2 (hdm2), leading to degradation of rb, release of e2f1 and cell death. SIGNOR-168178 0.52 PTPN1 protein P18031 UNIPROT EPOR protein P19235 UNIPROT down-regulates activity dephosphorylation 9606 14527337 t lperfetto In vivo interaction between EPO-R and PTP1B suggested that PTP1B dephosphorylates the EPO-R intracellularly.|Protein tyrosine phosphatase 1B participates in the down-regulation of erythropoietin receptor signalling. SIGNOR-276994 0.471 PTPN13 protein Q12923 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity dephosphorylation 9606 17638892 t miannu Finally, we report that PTPL1 expression is sufficient to block the IRS-1/phosphatidylinositol 3-kinase/Akt signaling pathway, to inhibit the insulin-like growth factor-I effect on cell survival, and to induce apoptosis.|We first show by complementary approaches that PTPL1 specifically dephosphorylates insulin receptor substrate-1 (IRS-1) in vitro and in cellulo. SIGNOR-277053 0.479 GIT1 protein Q9Y2X7 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity binding 9606 BTO:0000599 23325602 t miannu We found both MAT2B variants interact with GIT1. MAT2B directly promoted binding of GIT1 and ERK2 to MEK1. MAT2B and GIT1 interact and are overexpressed in most human liver and colon cancer specimens. SIGNOR-261245 0.4 FFAR4 protein Q5NUL3 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257246 0.252 FYN protein P06241 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr323 DEPVADPyDQSFESR 9606 15735648 t fstefani T cell src family kinases and zap70 activate p38 by phosphorylating tyr323. SIGNOR-134293 0.467 CAMK2G protein Q13555 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD 8663317 t llicata Phosphopeptide mapping analysis and Western blotting studies demonstrated that in vitro, CaMK II phosphorylates only Ser63 (corresponding to Ser133 of CREB), which is essential for the activation, and not Ser72 (corresponding to Ser142 of CREB), which is a negative regulation site. SIGNOR-250692 0.303 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Thr694 LPDMSVKtPKISMPD 10090 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262768 0.259 NRAS protein P01111 UNIPROT RAF1 protein P04049 UNIPROT up-regulates relocalization 9606 21779497 t Translocation from Cytosol to Membrane gcesareni The raf family of proteins (raf-1, a-raf, and b-raf) bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175231 0.865 MYC protein P01106 UNIPROT HK2 protein P52789 UNIPROT up-regulates quantity transcriptional regulation 9606 17785433 t Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration. SIGNOR-259986 0.378 telmisartan chemical CHEBI:9434 ChEBI AGTR1 protein P30556 UNIPROT down-regulates activity chemical inhibition 9606 9878991 t miannu Telmisartan is a nonpeptide angiotensin II receptor antagonist which selectively and insurmountably inhibits the angiotensin II AT1 receptor subtype without affecting other receptor systems involved in cardiovascular regulation. SIGNOR-259072 0.8 MAPK1 protein P28482 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 19723873 t gcesareni Phosphorylation of cebpb at thr(235) peaked at 16 hours in il-1beta-stimulated cells. The mek inhibitor u0126 inhibited this phosphorylation and reduced mmp-1 gene induction. SIGNOR-187798 0.705 VEGFD protein O43915 UNIPROT FLT4 protein P35916 UNIPROT up-regulates binding 9606 9435229 t gcesareni Vegf-d is a ligand for both vegf receptors (vegfrs) vegfr-2 (flk1) and vegfr-3 (flt4) and can activate these receptors. SIGNOR-55065 0.2 NHLH2 protein Q02577 UNIPROT MAOA protein P21397 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 22169038 f miannu SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter SIGNOR-254829 0.408 ESR2 protein Q92731 UNIPROT TGFA protein P01135 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 11517191 f ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression SIGNOR-253944 0.262 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser189 DEEFREPsTGKTCLP -1 19661060 t miannu We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-276233 0.2 atropine chemical CHEBI:16684 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258391 0.8 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr478 PPPPPPVyEPVSYHV 9606 22397367 t lperfetto Ezrin, a member of the erm family of proteins, is frequently over-expressed in human breast cancers, and is required for motility and invasion of epithelial cells. In particular, ezrin phosphorylation on y477 by src is specific to ezrin within the erm family, and is required for hgf-induced scattering of epithelial cells. SIGNOR-196443 0.634 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT1 protein P31749 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000782 25336630 t miannu stimulations were performed in the presence or absence of Akt inhibitor VIII, which selectively inhibits Akt1/Akt2 activity. SIGNOR-262227 0.8 KCNQ3 protein O43525 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 19298256 t miannu KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. SIGNOR-265984 0.8 GSK3B protein P49841 UNIPROT EIF2B1 protein Q14232 UNIPROT down-regulates binding 9606 21798082 t gcesareni Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b). SIGNOR-175436 0.2 873837-23-1 chemical CID:46930994 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190467 0.8 IFNB1 protein P01574 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates binding 9606 11278538 t gcesareni Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. SIGNOR-104663 0.862 NKX2-2 protein O95096 UNIPROT ERMN protein Q8TAM6 UNIPROT up-regulates quantity by expression transcriptional regulation 21221725 t lperfetto Further study revealed that Nkx2.2 could bind JN promoter and its overexpression increase the promoter activity of JN. SIGNOR-268965 0.251 PPP1CA protein P62136 UNIPROT AURKA protein O14965 UNIPROT down-regulates dephosphorylation 9606 11551964 t gcesareni Pp1 is shown to dephosphorylate active stk15 and abolish its activity in vitro. SIGNOR-110411 0.446 PRKG1 protein Q13976 UNIPROT SEPTIN3 protein Q9UH03 UNIPROT up-regulates activity phosphorylation Ser91 SQVSRKAsSWNREEK -1 15107017 t miannu Mutation of Ser-91 to Ala in recombinant Sept3 also abolished PKG phosphorylation, confirming that Ser-91 is the major site in vitro. Therefore Sept3 is phosphorylated on Ser-91 in nerve terminals and its phosphorylation may contribute to the regulation of its subcellular localization in neurons. SIGNOR-263183 0.2 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity precursor of 9606 27487822 t miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. SIGNOR-266265 0.8 MAML2 protein Q8IZL2 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12386158 f gcesareni Similarly, maml1 and maml2 amplified notch ligand (both jagged2 and delta1)-induced transcription of the hes-1 gene, whereas maml3 displayed little effect. SIGNOR-94276 0.38 alectinib chemical CHEBI:90936 ChEBI ALK protein Q9UM73 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190961 0.8 MAPK1 protein P28482 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser548 SSPSPPCsPLMADPL 9606 BTO:0000149 24269383 t llicata We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro. SIGNOR-203286 0.271 DUSP3 protein P51452 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates activity dephosphorylation Tyr1221 SPAFDNLyYWDQDPP 9606 BTO:0002552 21262974 t Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR. | We found that VHR decreased ErbB2 phosphorylation in vitro and in a cellular context, and the dephosphorylation of ErbB2 was more evident at Tyr-877 and Tyr-1221 than those at Tyr-1139 and Tyr-1248 (supplemental Fig. S1). Our data indicated that VHR was a cellular PTP against EGFR and ErbB2. SIGNOR-248534 0.271 CENPK protein Q9BS16 UNIPROT SOX6 protein P35712 UNIPROT up-regulates activity binding 10029 BTO:0000246 10996314 t miannu Here we report the cloning of a novel cDNA, termed Solt, from a mouse testis cDNA library. Its gene product, Solt, interacts with the leucine zipper region of SoxLZ/Sox6. In transient transfection assays with SoxLZ/Sox6 containing the transactivation domain of herpes simplex virus VP16, the expression of a luciferase reporter gene under the control of a promoter containing a synthetic cis element that is bound by the HMG box of SoxLZ/Sox6 was poorly enhanced in the presence of Solt. SIGNOR-221820 0.483 PPP2CB protein P62714 UNIPROT PRKCB protein P05771 UNIPROT down-regulates activity dephosphorylation Thr500 WDGVTTKtFCGTPDY 10116 8749392 t Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme. SIGNOR-248585 0.458 FYN protein P06241 UNIPROT AGAP2 protein Q99490 UNIPROT up-regulates phosphorylation Tyr1038 ESWIRAKyEQLLFLA 9606 16841086 t llicata We demonstrate that fyn is essential for phosphorylating pike-a and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with pike-a and phosphorylates it on both y682 and y774 residues. Tyrosine phosphorylation in pike-a is required for its association with active fyn but not for akt. Mutation of d into a in pike-a protects it from caspase cleavage and promotes cell survival. SIGNOR-147932 0.445 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser326 PPKMWKTsPDPSPVS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248692 0.613 SH3GL3 protein Q99963 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 25517094 f miannu Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. SIGNOR-263884 0.7 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000567 12853467 t 14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling. SIGNOR-252575 0.643 EEF1B complex complex SIGNOR-C460 SIGNOR EEF1A2 protein Q05639 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. SIGNOR-269388 0.715 17beta-estradiol smallmolecule CHEBI:16469 ChEBI ESR1 protein P03372 UNIPROT up-regulates chemical activation 9606 BTO:0000150 17478088 t gcesareni Oestrogen receptors (er)alpha and beta modify the expression of genes involved in cell growth, proliferation and differentiation through binding to oestrogen response elements (eres) located in a number of gene promoters. SIGNOR-154660 0.8 S1PR3 protein Q99500 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256790 0.2 WDR18 protein Q9BV38 UNIPROT Rix1 complex complex SIGNOR-C373 SIGNOR form complex binding 9606 BTO:0000007 22190735 t miannu LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes. SIGNOR-265471 0.866 DIABLO protein Q9NR28 UNIPROT BIRC3 protein Q13489 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000891 10929711 t amattioni Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. SIGNOR-80209 0.784 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 BTO:0000938 BTO:0000142 11160424 t gcesareni The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. SIGNOR-104921 0.8 CSNK2A1 protein P68400 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates phosphorylation Ser2 sGDEMIFD 9606 BTO:0000567 16225457 t lperfetto The n-terminal domain of the human eif2beta subunit and the ck2 phosphorylation sites are required for its function. These results suggest that ser2 and ser67 contribute to the important role of the n-terminal region of eif2beta for its function in mammals. SIGNOR-140994 0.356 ERBB2 protein P04626 UNIPROT GRB2 protein P62993 UNIPROT up-regulates relocalization 9606 14967450 t gcesareni All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor SIGNOR-121968 0.845 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates activity phosphorylation Ser59 GDSCPHGsPQGPLAP 10090 12818176 t miannu JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity. SIGNOR-250130 0.677 SLC6A3 protein Q01959 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30465801 t miannu Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. SIGNOR-269196 0.8 PRKG2 protein Q13237 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Thr143 RCFTRKYtLPPGVDP 9606 19593530 t 11383510: to test the hypothesis that cGK could inhibit platelet aggregation by phosphorylating Hsp27 and interfering with the MAPKAP kinase phosphorylation of Hsp27, the known MAPKAP kinase 2-phosphorylation sites (Ser15, Ser78, and Ser82) as well as Thr143 were replaced by negatively charged amino acids, which are considered to mimic phosphate groups, and tested in actin polymerization experiments. Mimicry at the MAPKAP kinase 2 phosphorylation sites led to mutants with a stimulating effect on actin polymerization lperfetto Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization SIGNOR-186947 0.2 vorapaxar chemical CHEBI:82702 ChEBI F2R protein P25116 UNIPROT down-regulates activity chemical inhibition -1 18447380 t Luana The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described.  SIGNOR-257792 0.8 PPP1CA protein P62136 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12840032 t inferred from 70% of family members fstefani P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases SIGNOR-269906 0.2 NDFIP1 protein Q9BT67 UNIPROT NEDD4 protein P46934 UNIPROT up-regulates activity relocalization 9606 BTO:0002181 26363003 t SARA Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2. SIGNOR-260997 0.607 INHBA protein P08476 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates activity binding 9606 8622651 t gcesareni Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB. SIGNOR-235142 0.779 EEF1A1 protein P68104 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269506 0.8 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257985 0.8 TFIIH complex SIGNOR-C457 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 30860024 f lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair. SIGNOR-269323 0.7 FGD4 protein Q96M96 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260554 0.604 PRKCD protein Q05655 UNIPROT MEP1B protein Q16820 UNIPROT down-regulates quantity phosphorylation Ser687 KKYRERMsSNRPNLT 9534 BTO:0001538 12941954 t miannu These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate. SIGNOR-263171 0.312 MAPK12 protein P53778 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity phosphorylation Ser201 SGDSDASsPRSNCSD 10090 BTO:0005930 20026657 t miannu  We determined that p38-gamma directly phosphorylated MyoD on Ser199 and Ser200, which results in enhanced occupancy of MyoD on the promoter of myogenin together with markedly decreased transcriptional activity. Phosphorylation of MyoD by p38-γ directs the assembly of a repressive transcriptional complex at the Myogenin promoter. SIGNOR-276273 0.422 PEX26 protein Q7Z412 UNIPROT PEX6 protein Q13608 UNIPROT up-regulates activity binding 10029 12717447 t Pex26 recruits Pex6–Pex1 complexes to peroxisomes. Pex26 anchors Pex6 and Pex1 through Pex26–Pex6 and Pex6–Pex1 interactions. SIGNOR-253614 0.772 RXRB protein P28702 UNIPROT NR1H2 protein P55055 UNIPROT up-regulates binding 9606 14993927 t gcesareni We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active. SIGNOR-123094 0.683 N-(4-methoxyphenyl)sulfonyl-N-[2-[2-(1-oxido-4-pyridin-1-iumyl)ethenyl]phenyl]acetamide chemical CHEBI:91440 ChEBI PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193309 0.8 NHS protein Q6T4R5 UNIPROT ABI2 protein Q9NYB9 UNIPROT up-regulates activity binding 9606 BTO:0000723 20332100 t miannu NHS may preferentially bind one or more Abi's in vivo, and it is also likely that specificity is governed by spatiotemporal expression of both proteins. Abi2 is highly expressed in the lens and plays a pivotal role in the development of the anterior and posterior sutures. This suggests that an NHS–Abi2 interaction may be physiologically important for lens development and that null mutations in the NHS gene could cause congenital cataract by disruption of this interaction and the actin cytoskeleton. SIGNOR-253579 0.2 TNFRSF1B protein P20333 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates binding 9606 8069916 t gcesareni Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2. SIGNOR-33133 0.709 PRKACA protein P17612 UNIPROT EEF2K protein O00418 UNIPROT up-regulates activity phosphorylation Ser366 SPQVRTLsGSRPPLL -1 11171059 t miannu EEF-2K can be phosphorylated in vitro by cAMP-dependent protein kinase (PKA) and that this induces significant Ca(2+)/calmodulin (CaM)-independent eEF-2K activity. sites of phosphorylation were Ser-365 and Ser-499 SIGNOR-250354 0.31 MAPK13 protein O15264 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 BTO:0000782 8325880 t gcesareni Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase. SIGNOR-25826 0.389 L-thyroxine smallmolecule CHEBI:18332 ChEBI iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity precursor of 9606 8755651 t scontino Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5‚Äô-position) to yield T3 SIGNOR-266950 0.8 TRIP11 protein Q15643 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity binding 9606 9256431 t inferred from family member miannu Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity. SIGNOR-267803 0.431 GPR119 protein Q8TDV5 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257153 0.252 CSNK2B protein P67870 UNIPROT SET protein Q01105-2 UNIPROT down-regulates phosphorylation Ser9 SAPAAKVsKKELNSN 9606 BTO:0000938 BTO:0000142 23374587 t The effect has been demonstrated using Q01105-2 miannu Ckii-mediated phosphorylation at ser9 hinders nuclear import of set SIGNOR-200806 0.248 MCL1 protein Q07820 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 17289999 t gcesareni Which of the multiple pro-survival proteins that can bind Bax (fig. S15A) can functionally restrain it? Mcl-1 must, because neutralizing Mcl-1 by enforced Noxa expression rendered MEFs containing only Bax (Bak KO cells) sensitive to the Bad BH3 mimetic ABT-737 (Fig. 4A), which inactivates Bcl-2, Bcl-xL, and Bcl-w SIGNOR-151787 0.726 vadimezan chemical CHEBI:75934 ChEBI NQO1 protein P15559 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191397 0.8 IKBKB protein O14920 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity phosphorylation Ser136 ATNNLSRsNSDESNF 9606 BTO:0000007 16818229 t miannu Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling. SIGNOR-276290 0.764 CCIN protein Q13939 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 BTO:0001277 11090452 t miannu The results suggest that the affinity of calicin to F-actin allows targeting of calicin at the subacrosomal space of round spermatids, and that its ability to form homomultimers contributes to the formation of a rigid calyx. SIGNOR-268503 0.7 CoREST-HDAC complex complex SIGNOR-C105 SIGNOR SCN2A protein Q99250 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 16140033 f lperfetto This suggests that the HDACs in the LSD1 complex are likely to function upstream of CoREST/LSD1, generating a hypoacetylated histone substrate, which can then be better recognized by CoREST/LSD1. Further supporting this model, we found that inhibition of HDAC activity by TSA resulted in derepression of two LSD1 target genes, the human neuronal-specific sodium channel (SCN) genes, SCNA2 and SCNA3 (Figure 1H). SIGNOR-268541 0.277 IDH2 protein P48735 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 26178471 t lperfetto Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (Œ±-KG) SIGNOR-261827 0.8 VEPH1 protein Q14D04 UNIPROT LATS2 protein Q9NRM7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 22055343 f In the neuronal differentiation lperfetto Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r9 SIGNOR-177077 0.2 AR protein P10275 UNIPROT TMPRSS2 protein O15393 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24505269 t miannu Recurrent gene fusion between the androgen-regulated gene TMPRSS2 and members of the ETS transcription factor family, most commonly ERG, are present in about 50% of prostate cancer cases. Presence of this fusion gene is a critical event in the development of prostate cancer. the more aggressive phenotype that arises with the presence of TMPRSS2-ERG at least in part is caused by changes in the tumor stroma. SIGNOR-251545 0.593 NMBR protein P28336 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways. SIGNOR-107028 0.252 HNF1A protein P20823 UNIPROT ALDOB protein P05062 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8383844 f miannu Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators SIGNOR-253834 0.316 MYT1L protein Q9UL68 UNIPROT HES1 protein Q14469 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0002572 28379941 t miannu ChIP–seq experiments showed that 80% of Myt1l targets, including the transcription factor Hes1, were co-bound by the repressive Sin3b–HDAC1 complex early during reprogramming SIGNOR-266775 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR SH2B2 protein O14492 UNIPROT up-regulates activity phosphorylation Ser598 SARSRSNsAERLLEA 10090 16141217 t gcesareni This study identifies APS as a novel physiological substrate for PKB and the first serine phosphorylation site on APS SIGNOR-248042 0.2 RCOR1 protein Q9UKL0 UNIPROT REST protein Q13127 UNIPROT up-regulates activity binding 9606 BTO:0000007 10449787 t miannu We show here that CoREST, a newly identified human protein, functions as a corepressor for REST. A single zinc finger motif in REST is required for CoREST interaction. Together, REST and CoREST mediate repression of the type II sodium channel promoter in nonneural cells, and the REST/CoREST complex may mediate long-term repression essential to maintenance of cell identity. SIGNOR-220618 0.76 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation 9606 19282669 t lperfetto Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. SIGNOR-244699 0.2 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser141 TVKQKYLsFTPPEKD -1 10075701 t miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197. SIGNOR-250228 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDCA5 protein Q96FF9 UNIPROT up-regulates activity phosphorylation Ser79 AVQSPRRsPRISFFL 9606 BTO:0000567 20551060 t miannu Phosphorylation and activation of cell division cycle associated 5 by mitogen-activated protein kinase play a crucial role in human lung carcinogenesis. Our data suggest that transactivation of CDCA5 and its phosphorylation at Ser209 by ERK play an important role in lung cancer proliferation, and that the selective suppression of the ERK-CDCA5 pathway could be a promising strategy for cancer therapy. SIGNOR-262969 0.2 GTP smallmolecule CHEBI:15996 ChEBI Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 t lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. SIGNOR-269118 0.8 ABL1 protein P00519 UNIPROT RAPH1 protein Q70E73 UNIPROT up-regulates activity phosphorylation Tyr513 GKQLYMNyQEALKRT -1 20417104 t miannu Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C). SIGNOR-262608 0.288 ACLY protein P53396 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI down-regulates quantity by destabilization chemical modification 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-267101 0.8 BCL10 protein O95999 UNIPROT CBM complex SIGNOR-C555 SIGNOR form complex binding 9606 15122200 t miannu CARMA1, the adaptor protein BCL-10 (B-cell lymphoma 10) and the caspase-like protein MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) form a signalling complex that has a key role in antigen-receptor-mediated activation of the nuclear factor-κB (NF-κB) and JUN N-terminal kinase (JNK) pathways. SIGNOR-276294 0.826 EXOC4 protein Q96A65 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270779 0.923 CASP3 protein P42574 UNIPROT RAD51 protein Q06609 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0002882 11684015 t lperfetto The RAD51 protein has been shown to be a substrate for caspase-3|he activated caspase-3 fragments (19 kDa and 17 kDa) and caspase-3 cleaved RAD51 fragment (∼23 kDa) was detected by Western analysis (Figure 3E). Activation of caspase-3 and the signature proteolytic degradation product of RAD51 only occurred in parental 32Dcl3 cells after treatment with cisplatin SIGNOR-271709 0.478 FZD5 protein Q13467 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 18077588 t areggio Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction. SIGNOR-258966 0.727 HDAC1 protein Q13547 UNIPROT HSPA5 protein P11021 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19417144 f miannu We show the involvement of HDAC1 in the negative regulation of the Grp78 promoter not only by its induction in the presence of the HDAC inhibitors trichostatin A and MS-275 but also by exogenous overexpression and small interfering RNA knockdown of specific HDACs. SIGNOR-254227 0.264 AP1G2 protein O75843 UNIPROT NEDD4 protein P46934 UNIPROT up-regulates activity binding 9606 BTO:0001950 18772139 t miannu Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination. SIGNOR-272636 0.41 KATNAL2 protein Q8IYT4 UNIPROT TUBE1 protein Q9UJT0 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0001363 29136647 t miannu KATNAL2 does not sever microtubules composed of α- and β-tubulin but does interact with δ- and ε-tubulin SIGNOR-267176 0.2 CAMK2B protein Q13554 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation 9606 BTO:0000567 15980064 t lperfetto These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo. SIGNOR-217493 0.2 MAPK10 protein P53779 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr275 TTGTKSNtPTSSVPS 9606 15767678 t gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. SIGNOR-134533 0.738 PLK1 protein P53350 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1525 PIKYLEEsDEDDLF 9606 18171681 t llicata Plk1 phosphorylates ser(1337) and ser(1524) of topoiialpha plk1-associated phosphorylation is essential for the functions of topoiialpha in mitosis SIGNOR-160237 0.492 HLTF protein Q14527 UNIPROT OCA2 protein Q04671 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000847 22234890 f miannu The SNP rs12913832 has strong statistical association with human pigmentation. It is located within an intron of the nonpigment gene HERC2, 21 kb upstream of the pigment gene OCA2, and the region surrounding rs12913832 is highly conserved among animal species.In darkly pigmented human melanocytes carrying the rs12913832 T-allele, we detected binding of the transcription factors HLTF, LEF1, and MITF to the HERC2 rs12913832 enhancer, and a long-range chromatin loop between this enhancer and the OCA2 promoter that leads to elevated OCA2 expression. SIGNOR-254425 0.359 MAPK1 protein P28482 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction SIGNOR-259920 0.613 ATM protein Q13315 UNIPROT UCHL3 protein P15374 UNIPROT up-regulates activity phosphorylation Ser75 EEEEKIKsQGQDVTS 27941124 t lperfetto The deubiquitinase UCHL3 is phosphorylated and activated by ATM. UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2. |Mutation of S75 (S75A) abolished the pSQ/TQ signal, suggesting that S75 is a major ATM phosphorylation site following DNA damage SIGNOR-275910 0.336 MAPK9 protein P45984 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 20220133 t gcesareni Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset. SIGNOR-164093 0.384 INSR protein P06213 UNIPROT GYS1 protein P13807 UNIPROT up-regulates activity 9606 BTO:0000887;BTO:0001103 10909964 f lperfetto In skeletal muscle, insulin activates glycogen synthase by reducing phosphorylation at both NH2- and COOH-terminal sites of the enzyme and by elevating the levels of glucose-6-phosphate, an allosteric activator of glycogen synthase. SIGNOR-236803 0.373 PSEN1 protein P49768 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR up-regulates cleavage 9606 10593990 t Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface. lperfetto Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains. SIGNOR-217743 0.956 acetylsalicylic acid chemical CHEBI:15365 ChEBI PTGS2 protein P35354 UNIPROT down-regulates chemical inhibition 9606 11809688 t gcesareni Nsaids inhibit cyclooxygenase (cox) isozymes, which are responsible for the committed step in prostaglandin biosynthesis, and this has been considered the primary mechanism by which nsaids exert their antitumorigenic effects. SIGNOR-114380 0.8 VCP protein P55072 UNIPROT UFD1 protein Q92890 UNIPROT up-regulates activity binding 9606 20442859 t miannu These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes. SIGNOR-252424 0.2 F2RL2 protein O00254 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257409 0.358 IKZF3 protein Q9UKT9 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates activity 10090 BTO:0004731 14718515 f Here we show that the Ikaros family member, Aiolos, is specifically required for the generation of these plasma cells. Failure to generate high affinity plasma cells in the BM and to sustain serum antibody titers is apparent after both primary and secondary immunization of Aiolos−/− mice with a range of hapten concentrations. SIGNOR-259952 0.7 GRID1 protein Q9ULK0 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264951 0.8 VAV1 protein P15498 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 7809090 t gcesareni Here we report that both in cell extracts and within intact mammalian cells vav binds to grb2 (sem-5/ash/drk), an adaptor molecule which plays a key role in ras activation. SIGNOR-33840 0.302 Av/b1 integrin complex SIGNOR-C175 SIGNOR POU5F1 protein Q01860 UNIPROT up-regulates quantity by expression 10090 18757303 f lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. SIGNOR-253272 0.34 PKA proteinfamily SIGNOR-PF17 SIGNOR SMN complex complex SIGNOR-C158 SIGNOR up-regulates quantity by stabilization phosphorylation 9606 BTO:0000007 19103745 t lperfetto PKA increases SMN complex formation and SMN stability. SIGNOR-253122 0.2 YAP1 protein P46937 UNIPROT MYF6 protein P23409 UNIPROT down-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 f gcesareni Myf6 (mrf4) is repressed by hyap1 s127a overexpression. SIGNOR-199075 0.2 DACH1 protein Q9UI36 UNIPROT Six1/Dach complex SIGNOR-C122 SIGNOR form complex binding 10090 14628042 t llicata The phosphatase function of Eya switches the function of Six1-Dach from repression to activation, SIGNOR-238026 0.614 CD163 protein Q86VB7 UNIPROT hb:hp complex SIGNOR-C149 SIGNOR down-regulates quantity by destabilization binding 9606 11854029 t miannu CD163 was identified as the endocytic receptor binding hemoglobin (Hb) in complex with the plasma protein haptoglobin (Hp). This specific receptor-ligand interaction leading to removal from plasma of the Hp-Hb complex-but not free Hp or Hb-now explains the depletion of circulating Hp in individuals with increased intravascular hemolysis. SIGNOR-251823 0.735 PIAS3 protein Q9Y6X2 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 14691252 t lperfetto We have further shown that PIAS3, Smad3, and p300 can form a ternary complex, which is significantly increased by TGF-_ treatment. Taken together, these results suggest that PIAS3 stimulates Smad transcriptional activity through formation of a complex with Smad proteins and p300/CBP. SIGNOR-217725 0.58 CDK2 protein P24941 UNIPROT SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr248 GSETPGAtPGSKIWD 9606 SIGNOR-C16 12105215 t gcesareni To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptides. Three phosphorylation sites were identified as thr244, thr248, and thr313 SIGNOR-90438 0.353 DPYD protein Q12882 UNIPROT thymine smallmolecule CHEBI:17821 ChEBI down-regulates quantity chemical modification 10499634 t Dihydropyrimidine dehydrogenase (DPD) is responsible for degradation of the pyrimidines uracil and thymine and the inactivation of the chemotherapeutic agent 5-fluorouracil. DPD activity is highly variable in cancer populations, and this variation may influence the antitumor efficacy of 5-fluorouracil. SIGNOR-253989 0.8 PRKACA protein P17612 UNIPROT GNA13 protein Q14344 UNIPROT down-regulates activity phosphorylation Thr203 ILLARRPtKGIHEYD 9534 12399457 t miannu PKA directly phosphorylates Galpha(13). Galpha(13)-T203A mutant (in COS-7 cells) could not be phosphorylated by PKA. PKA blocks Rho activation by phosphorylation of Galpha(13) Thr(203). SIGNOR-249985 0.373 SRC protein P12931 UNIPROT PTK2B protein Q14289 UNIPROT up-regulates phosphorylation Tyr402 CSIESDIyAEIPDET 9606 15695828 t llicata These data indicate that pyk2 activation via phosphorylation at tyr-402 requires ?V?3 Ligation and src activity. SIGNOR-133870 0.608 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation 9606 12510059 t inferred from 70% family members gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. SIGNOR-270132 0.2 CDK5R1 protein Q15078 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates activity binding 9606 BTO:0000938 10604467 t Cyclin-dependent kinase 5 (Cdk5) is required for proper development of the mammalian central nervous system. To be activated, Cdk5 has to associate with its regulatory subunit, p35. We have found that p25, a truncated form of p35, accumulates in neurons in the brains of patients with Alzheimer's disease. This accumulation correlates with an increase in Cdk5 kinase activity. Unlike p35, p25 is not readily degraded, and binding of p25 to Cdk5 constitutively activates Cdk5, changes its cellular location and alters its substrate specificity. SIGNOR-268153 0.942 RAC1 protein P63000 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT up-regulates binding 9606 11130076 t gcesareni Here we demonstrate that irsp53, a substrate for insulin receptor with unknown function, is the 'missing link' between rac and wave. Activated rac binds to the amino terminus of irsp53, and carboxy-terminal src-homology-3 domain of irsp53 binds to wave to form a trimolecular complex. SIGNOR-85302 0.729 CDK1 protein P06493 UNIPROT PTHLH protein P12272 UNIPROT down-regulates phosphorylation Thr121 YKEQPLKtPGKKKKG 9606 10373465 t lperfetto Phosphorylation at the cyclin-dependent kinases site (thr85) of parathyroid hormone-related protein negatively regulates its nuclear localization SIGNOR-68544 0.2 RPS6KA5 protein O75582 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 BTO:0000150 BTO:0000975 11145955 t gcesareni Phosphorylation on ser383 and ser389 of elk-1 by mapk enhances this basal binding but, most importantly, elk-1 exhibits new interactions with p300. SIGNOR-85514 0.2 Daunorubicin hydrochloride chemical CHEBI:31456 ChEBI TOP2B protein Q02880 UNIPROT down-regulates activity chemical inhibition 9606 1963303 t miannu DNA topoisomerase II as the primary target of anti-tumor anthracyclines.Such studies have also given evidence of the peculiar features of the drug interference with DNA topoisomerase II activity. In contrast to other cytotoxic topoisomerase II inhibitors (acridines, epipodophyllotoxins), anthracyclines produce persistent DNA cleavable complexes. This property is more evident with doxorubicin derivatives than with daunorubicin derivatives. SIGNOR-259323 0.8 fulvestrant chemical CHEBI:31638 ChEBI ESR1 protein P03372 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000150 12113237 t miannu Fulvestrant (Faslodex, formerly ICI 182,780) is a potent steroidal antiestrogen that mediates its effects by estrogen receptor downregulation. SIGNOR-259305 0.8 TRPV4 protein Q9HBA0 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000443 23021218 f lperfetto TRPV4 negatively regulated the expression of PGC1α, UCP1, and cellular respiration. Additionally, it potently controlled the expression of multiple proinflammatory genes involved in the development of insulin resistance. SIGNOR-253095 0.2 BRCA2 protein P51587 UNIPROT D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR form complex binding 9606 BTO:0000567 18212739 t lperfetto These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3).  SIGNOR-263256 0.792 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161573 0.325 MAPK1 protein P28482 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation Thr84 TVGGPAPtPLLPPSA 9606 12478298 t lperfetto In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites SIGNOR-96418 0.652 STX10 protein O60499 UNIPROT LE-TGN SNARE complex SIGNOR-C157 SIGNOR form complex binding 9606 BTO:0000567 18195106 t lperfetto We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport SIGNOR-253080 0.753 CHFR protein Q96EP1 UNIPROT PLK1 protein P53350 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 17442268 t miannu Chfr, a mitotic stress checkpoint, plays an important role in cell cycle progression, tumor suppression and the processes that require the E3 ubiquitin ligase activity mediated by the RING finger domain. Chfr stimulates the formation of polyubiquitin chains by ub-conjugating enzymes, and induces the proteasome-dependent degradation of a number of cellular proteins including Plk1 and Aurora A. SIGNOR-271464 0.481 UBE2O protein Q9C0C9 UNIPROT SMAD6 protein O43541 UNIPROT down-regulates ubiquitination Lys173 LLLEQELkTVTYSLL 9606 23455153 t gcesareni We showed that ube2o functions as an e2-e3 hybrid to monoubiquitinate smad6 at lysine 174 SIGNOR-192255 0.476 TAOK1 protein Q7L7X3 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2. SIGNOR-201324 0.375 ABL1 protein P00519 UNIPROT ATR protein Q13535 UNIPROT up-regulates phosphorylation Tyr291 DTDQLKLyEEPLSKL 9606 20798688 t lperfetto C-abl can phosphorylate atr on y291 and y310 and this phosphorylation appears to have a positive role in atr activation under genotoxic stress. SIGNOR-167632 0.583 F2RL3 protein Q96RI0 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256915 0.2 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr833 EQCEYLSyDASQWEF 9606 20431062 t lperfetto Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk. SIGNOR-165051 0.492 BCOR protein Q6W2J9 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity binding 9606 10898795 t miannu BCoR can interact w Because HDACs appear to be involved in repression by an increasing number of transcriptional repressors, we tested whether BCoR can associate with HDACs. BCoR can interact with HDAC1, HDAC3, and HDAC-B/5 more strongly than with HDAC-A/4, HDAC-C, HDAC-D, and HDAC-E. SIGNOR-252237 0.318 CARD11 protein Q9BXL7 UNIPROT BCL10 protein O95999 UNIPROT up-regulates binding 9606 12356734 t gcesareni Card11 cooperates with bcl10 in a card domain-dependent manner.;These results implicate card11 in factor- specific activation of nf-kappab SIGNOR-93869 0.84 MBD3/NuRD complex complex SIGNOR-C338 SIGNOR NOTCH2 protein Q04721 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000578 31659254 t miannu Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. We demonstrated that ZNF774 recruits the NuRD complex to the NOTCH2 promoter and represses NOTCH2 transcription. SIGNOR-265561 0.275 AGPAT3 protein Q9NRZ7 UNIPROT 1-acyl-sn-glycerol 3-phosphate(2-) smallmolecule CHEBI:57970 ChEBI down-regulates quantity chemical modification 9606 21173190 t lperfetto The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬† SIGNOR-267009 0.8 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates 9606 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268579 0.2 1-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-2-methoxyphenyl)-3-(1-(thiazol-2-yl)ethyl)urea chemical CID:9869779 PUBCHEM CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258126 0.8 CDK1 protein P06493 UNIPROT VIM protein P08670 UNIPROT down-regulates phosphorylation Ser55 TSRSLYAsSPGGVYA 9606 7983050 t llicata These results strongly suggest that cdc2 kinase is the kinase which phosphorylates vimentin ser55 in the entire cytoplasm during mitosis and that the appearance of immunoreactivities with antibody 4a4 in cell staining indeed reflect the vimentin phosphorylation by cdc2 kinase. immunofluorescent evidence using antibody 4a4 and biochemical analysis using vimentin ser55 peptide showed that the degree of disassembly of vimentin filament of various cell types at early mitotic phase correlated well with the amount of mitotically activated cdc2 kinase. SIGNOR-35492 0.369 IDH2 protein P48735 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 29090344 t miannu Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases. SIGNOR-253134 0.8 RIMS3 protein Q9UJD0 UNIPROT RAB3C protein Q96E17 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 31679900 t miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle SIGNOR-264380 0.262 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22469984 t irozzo The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a SIGNOR-256122 0.345 ABT-737 chemical CID:11228183 PUBCHEM BCL2L2 protein Q92843 UNIPROT down-regulates chemical inhibition 9606 17200714 t gcesareni A cell-permeant compound, abt-737, binds with high affinity to bcl2, bcl2l1, and bcl2l2, antagonizes their antiapoptotic function, and induces apoptosis in select human tumor cell lines, primary patient-derived cells. SIGNOR-151790 0.8 CSNK1E protein P49674 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Ser1430 LGYVPHPsSLSGSLP 9606 16513652 t gcesareni We find that ckiepsilon binds to lrp5 and lrp6 in vitro and in vivo and identify three ckiepsilon-specific phosphorylation sites in lrp6. Two of the identified phosphorylation sites, ser1420 and ser1430, influence wnt signaling in vivo, SIGNOR-145053 0.265 NRXN3 protein Q9HDB5 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626546 t miannu The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites SIGNOR-265456 0.819 BMPR2 protein Q13873 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates binding 9606 7791754 t gcesareni Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor. SIGNOR-33434 0.702 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 16476742 t lperfetto In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin SIGNOR-144478 0.46 VAV1 protein P15498 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0001271 9209406 t gcesareni Recently, we have shown that the proto-oncogene vav product (vav) is also tyrosine-phosphorylated by treatment with gm-csf and epo and is constitutively associated with the sh3 domain of grb2/ash in ut-7. SIGNOR-49362 0.673 TFDP1 protein Q14186 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253862 0.492 FBN1 protein P35555 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity 9606 17242066 f Regulation miannu Fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling. SIGNOR-251889 0.372 PTPRJ protein Q12913 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates dephosphorylation 9606 11259588 t miannu Cd148 can dephosphorylate lat and plc?1 In vitro. / plc?1 Undergoes inducible tyrosine phosphorylation following tcr stimulation (46), and this phosphorylation is required to stimulate its catalytic activity SIGNOR-105790 0.376 GRK1 protein Q15835 UNIPROT GRK1 protein Q15835 UNIPROT down-regulates activity phosphorylation Thr492 QDVGAFStVKGVAFD -1 1527025 t The major autophosphorylation site yielded the following sequence: DVGAFS488T489VKGVAFEK, where Ser488 and Thr489 are phosphorylated. Additionally, a minor autophosphorylation site was identified at Ser21. we speculate that autophosphorylation of RK may lower the affinity of the enzyme for Rho* via repulsion between phosphorylated sites on Rho* and the kinase. SIGNOR-251188 0.2 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Cys) smallmolecule CHEBI:29167 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269484 0.8 MAPK1 protein P28482 UNIPROT LIMA1 protein Q9UHB6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser362 PVHPKPLsPDSRASS 9606 BTO:0001033 23188829 t miannu Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover. SIGNOR-263054 0.2 L-serine zwitterion smallmolecule CHEBI:33384 ChEBI L-cystathionine dizwitterion smallmolecule CHEBI:58161 ChEBI up-regulates quantity precursor of 9606 23981774 t lperfetto Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. SIGNOR-275827 0.8 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB7 protein P26010 UNIPROT up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259009 0.2 CDK1 protein P06493 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates phosphorylation Ser728 VVKQEQLsPKKKENN 9606 SIGNOR-C17 22163316 t gcesareni We demonstrate that aib1 is phosphorylated on ser728 and ser867 by cdk1/cyclin b at the onset of mitosis and remains phosphorylated until exit from m phase. SIGNOR-195233 0.376 IRF9 protein Q00978 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity binding 9606 BTO:0000567 9242679 t lperfetto Coimmunoprecipitation assays demonstrate p48 association with STAT2 but not STAT1.The studies demonstrate the in vivo existence of a STAT2.p48 complex and a distinct STAT2.STAT1 complex after IFN-alpha stimulation. Data suggest that distinct bipartite complexes STAT2.p48 and STAT2.STAT1 translocate to the nucleus and associate on the DNA target site as ISGF3. SIGNOR-217806 0.919 CKM complex complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-273152 0.346 CAMKK1 protein Q8N5S9 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10833263 t llicata Protein kinase B (PKB) was recently reported to be activated on the phosphorylation of Thr(308) by Ca(2+)/calmodulin-dependent protein kinase kinase alpha (CaM-kinase kinase alpha), suggesting that PKB was regulated through not only the phosphoinositide 3-kinase pathway but also the Ca(2+)/calmodulin protein kinase pathway. SIGNOR-252609 0.387 PRKACA protein P17612 UNIPROT GMFB protein P60983 UNIPROT up-regulates activity phosphorylation Ser83 QHDDGRVsYPLCFIF -1 9030586 t miannu Protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor of extracellular signal-regulated kinase (ERK) and enhancer of p38; both are subfamilies of mitogen-activated protein (MAP) kinase, suggesting GMF as a bifunctional regulator of the MAP kinase cascades. PKA is capable of phosphorylating threonine 26 and serine 82. SIGNOR-249983 0.312 PTK2 protein Q05397 UNIPROT ATP2B4 protein P23634-6 UNIPROT up-regulates activity phosphorylation Tyr1176 LDGEVTPyANTNNNA 9606 12540962 t miannu Results of co-immunoprecipitation, treatment with tyrosine kinase inhibitors and integrin inhibition experiments suggest that FAK is responsible for PMCA4b tyrosine phosphorylation during platelet activation. equence analysis indicates that Y(1176) is a likely substrate for focal adhesion kinase (FAK), while Y(1122) is not located in a tyrosine phosphorylation motif. SIGNOR-263194 0.2 superoxide smallmolecule CHEBI:18421 ChEBI SOD2 protein P04179 UNIPROT up-regulates activity precursor of 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272284 0.8 CTLA4 protein P16410 UNIPROT T cell exhaustion phenotype SIGNOR-PH221 SIGNOR up-regulates 9606 BTO:0000782 26086965 f Barakat Both PD-1 and CTLA-4 inhibited the activity of Akt, a crucial molecular in regulating glucose metabolism of T cells by elevating glucose transporter 1 expression and glycolysis, suggesting that glucose metabolism may contribute to T-cell exhaustion SIGNOR-275415 0.7 cyclosporin A chemical CHEBI:4031 ChEBI PPP3CA protein Q08209 UNIPROT down-regulates chemical inhibition 9606 15276472 t gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. SIGNOR-127225 0.8 PTPN1 protein P18031 UNIPROT NTRK2 protein Q16620 UNIPROT down-regulates activity dephosphorylation Tyr707 DVYSTDYyRVGGHTM 9606 26214522 t Luana Collectively, these data establish a direct enzyme-substrate interaction between PTP1B and phosphorylated Y705/706 (p-Y705/706) TRKB, the critical autophosphorylation sites that mediate BDNF-induced signaling.| Therefore, the data are consistent with a role of PTP1B as an inhibitor of BDNF/TRKB signaling SIGNOR-264553 0.388 Early macropinosomes phenotype SIGNOR-PH228 SIGNOR Late macropinosomes phenotype SIGNOR-PH229 SIGNOR up-regulates 9606 39000072 f miannu The early macropinosomes continue to mature into late macropinosomes, which fuse with lysosomes and degrade their cargos. SIGNOR-277789 0.7 TP73 protein O15350 UNIPROT BBC3 protein Q96PG8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17700533 f miannu Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis. SIGNOR-255467 0.451 MAPK3 protein P27361 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser643 KILIASPsPTHIHKE 9606 BTO:0000567 18519666 t lperfetto We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_ SIGNOR-178735 0.687 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser244 GTHYSVQsDIWSMGL 9606 8131746 t gcesareni Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf SIGNOR-36453 0.556 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR IFITMs proteinfamily SIGNOR-PF49 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 25599080 f miannu The IFITM (interferon-induced transmembrane) proteins comprise a family of interferon-induced antiviral cell-intrinsic restriction factors with high constitutive expression in many cells, including barrier epithelial cells. As their names imply, the expression of human IFITM1, IFITM2, and IFITM3 is also strongly upregulated by both type I and type II interferons SIGNOR-260220 0.2 CAPN1 protein P07384 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Phe59 GVTVETVfSVDEFSA -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263580 0.302 CSNK2A1 protein P68400 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Ser1001 SKESEHDsDESSDDD 9606 10066810 t gcesareni Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein, SIGNOR-65281 0.453 ELK1 protein P19419 UNIPROT MUC4 protein Q99102 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001861 19757157 t lperfetto Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level. SIGNOR-254096 0.2 SPI1 protein P17947 UNIPROT B-Lymphocyte_diff phenotype SIGNOR-PH113 SIGNOR up-regulates activity 10090 10203717 f PU.1 regulates the expression of several genes, including those encoding immunoglobulins, receptors and enzymes. The expression of these genes is crucial for macrophage and B-cell differentiation and for the functional activity of neutrophils. SIGNOR-259955 0.7 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser574 NSNSCRSsTTTCPEQ 9606 BTO:0000007 16862148 t lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). SIGNOR-249303 0.444 SMAD1 protein Q15797 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0002729 23993924 f flangone Engagement of BMP4-mediated signaling in adult mouse ovary-derived OSCs cultured in vitro drives differentiation of these cells into IVD oocytes through Smad1/5/8 activation and transcriptional up-regulation of key meiosis-initiating genes. SIGNOR-255259 0.7 DNMT1 protein P26358 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 23242655 f Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells. SIGNOR-254027 0.408 DOK1 protein Q99704 UNIPROT ITGB1 protein P05556 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257669 0.321 AURKB protein Q96GD4 UNIPROT HDAC9 protein Q9UKV0 UNIPROT down-regulates phosphorylation Ser239 QKVAERRsSPLLRRK 9606 22865920 t lperfetto We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions SIGNOR-198654 0.265 DIO2 protein Q92813 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI down-regulates quantity chemical modification 9606 8755651 t scontino Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5‚Äô-position) to yield T4 SIGNOR-266949 0.8 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2N protein P61088 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271320 0.85 AP-2 complex complex SIGNOR-C245 SIGNOR SYNJ1 protein O43426 UNIPROT up-regulates activity binding 10116 15496985 t Giorgia Some of the more minor interactors are very strongly enriched (AAK, auxilin, Dab2, eps15, epsin1 and synaptojanin170). All these enriched proteins have multiple copies of short alpha‐appendage interaction motifs SIGNOR-260396 0.5 PPP2CA protein P67775 UNIPROT HDAC2 protein Q92769 UNIPROT down-regulates activity dephosphorylation Ser394 EDAVHEDsGDEDGED 9606 30050113 t miannu In contrast, in the present work, PPP2CA reduced HDAC2 S394 phosphorylation.|We postulated that PPP2CA would negatively regulate phospho dependent HDAC2 activity. SIGNOR-277049 0.284 PKA proteinfamily SIGNOR-PF17 SIGNOR GNMT protein Q14749 UNIPROT unknown phosphorylation Ser10 DSVYRTRsLGVAAEG -1 12697024 t miannu Activation of cAMP-dependent protein kinase by dibutyryl-cAMP, reported to cause GNMT phosphorylation under cell-free conditions, also had little effect on hepatocytic AdoMet and AdoHcy levels. Phosphorylation of GNMT would thus seem to play no role in regulation of the intracellular AdoMet/AdoHcy ratio, but could be involved in other GNMT functions, such as the binding of folates or aromatic hydrocarbons. The amino acid sequence surrounding Ser-10 (Val-Tyr-Arg-Thr-Arg-SerLeu-Gly-Val-Ala-Ala) could possibly qualify as a recognition site for AMPK as well as for PKA [32], the latter enzyme being capable of phosphorylating GNMT in intact hepatocytes (present study) as well as under cell-free conditions SIGNOR-263151 0.2 PTK2B protein Q14289 UNIPROT SNCA protein P37840 UNIPROT unknown phosphorylation Tyr125 VDPDNEAyEMPSEEG 9534 BTO:0000298 12096713 t lperfetto The present report demonstrates that the protein tyrosine kinase Pyk2/RAFTK is involved in cell stress-induced tyrosine phosphorylation of alpha S. Hyperosmotic stress induced tyrosine phosphorylation of alpha S via Pyk2/RAFTK at tyrosine residue 125. SIGNOR-249151 0.32 TFEB protein P19484 UNIPROT FABP3 protein P05413 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 f lperfetto On the contrary, proteins increasing the most included those degraded by autophagy (e.g., SQSTM1/p62 and GABARAPL2 SIGNOR-276790 0.2 TNF protein P01375 UNIPROT SCN3A protein Q9NY46 UNIPROT up-regulates activity 10090 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253494 0.2 MAPK1 protein P28482 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR unknown phosphorylation 9606 21071439 t lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-217574 0.386 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr319 TSVYESPySDPEELK 10090 BTO:0000782 10037717 t the protein tyrosine kinase (PTK) ZAP-70 is rapidly phosphorylated on several tyrosine residues, presumably by two mechanisms: an autophosphorylation and a trans-phosphorylation by the Src-family PTK Lck. we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function SIGNOR-251393 0.602 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120124 0.316 axitinib chemical CHEBI:66910 ChEBI PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 21297102 t gcesareni Inhibitors for fgf (azd4547), vegf, or pdgf receptors (axitinib), but not that for tgf receptor (ly364947), significantly decreased the abundance of (pcna) in endothelial cells. SIGNOR-171869 0.8 THR proteinfamily SIGNOR-PF84 SIGNOR RARB protein P10826 UNIPROT up-regulates activity binding 9606 15650024 t inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs SIGNOR-267780 0.2 MAPK9 protein P45984 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 20630875 t gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress. SIGNOR-166698 0.259 BCL10 protein O95999 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14695475 f Barakat The adaptor protein Bcl10 promotes activation of NF-κB transcription factors through paracaspase- and UBC13-dependent ubiquitination of NEMO. SIGNOR-274145 0.506 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 23431053 t milica Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by Casein Kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ SIGNOR-201170 0.401 PPM1D protein O15297 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 19713933 t lperfetto In addition, wip1 can dephosphorylate atm, as well as other components of the dna damage checkpoint, such as p38. SIGNOR-187770 0.455 STAT3 protein P40763 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0003298 BTO:0001103 30029643 f In summary, our results indicate IL-15 can stimulate the proliferation of FAPs through Jak-STAT pathway. SIGNOR-256256 0.7 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RARB protein P10826 UNIPROT up-regulates activity chemical activation 9606 18321241 t miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). SIGNOR-259235 0.8 PRKAA1 protein Q13131 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser635 DTHFRSPsSSVGSPP 9606 SIGNOR-C15 19815529 t llicata We show that ampk down-regulates rrna synthesis under glucose restriction by phosphorylating the rna polymerase i (pol i)-associated transcription factor tif-ia at a single serine residue (ser-635). SIGNOR-188403 0.2 PAICS protein P22234 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 33179964 t miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). SIGNOR-267321 0.8 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser25 PCLIIEDsQPESQVL 9606 12697768 t llicata To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1 SIGNOR-100641 0.869 CDK3 protein Q00526 UNIPROT CABLES1 protein Q8TDN4 UNIPROT unknown phosphorylation Ser273 PGQGGSTsAFEQLQR 9534 11733001 t miannu P70ik3-1 is phosphorylated by either cyclin A/cdk3 or cyclin E/cdk3 reconstituted in COS7 cells. Accordingly, we can conclude that in COS7 cells, Ser274 in p70ik3-1 is phosphorylated by endogenous kinases other than cdk5 (Fig. 4), at least one of which is cdk3 as shown in this work. Currently, however, the question of how ik3-1 function is modified by its cdk3-mediated phosphorylation of Ser274 remains to be adressed. SIGNOR-250679 0.493 MAPK3 protein P27361 UNIPROT PGR protein P06401 UNIPROT down-regulates phosphorylation Ser294 APMAPGRsPLATTVM 9606 BTO:0000150 10655479 t gcesareni Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation. SIGNOR-74716 0.543 RUNX2 protein Q13950 UNIPROT COL1A1 protein P02452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 f Osteoblast-like cell lines lpetrilli In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast differentiation, including alkaline phosphatase, a1 and a2 collagen, osteopontin and osteoprotegerin ligand. SIGNOR-107163 0.463 MEN1 protein O00255 UNIPROT MLL-ENL fusion protein SIGNOR-FP7 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 t irozzo We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]. SIGNOR-255866 0.2 TAL1 protein P17542 UNIPROT UBE2H protein P62256 UNIPROT up-regulates quantity by expression transcriptional regulation 20028976 t lperfetto Tal1 expression activated UBE2H expression, whereas Tal1 knock-down reduced UBE2H expression and ubiquitin transfer activity.|Binding of Tal1 to UBE2H was confirmed by chromatin immunoprecipitation. SIGNOR-269000 0.332 BIRC7 protein Q96CA5 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates binding 9606 BTO:0000848 15485396 t gcesareni These results suggest that ml-iap might regulate apoptosis by sequestering smac and preventing it from antagonizing xiap-mediated caspases, rather than by direct caspases. SIGNOR-129869 0.687 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL -1 20044479 t lperfetto IGF-1R Directly Interacts with and Phosphorylates PDK1 in Vitro SIGNOR-236548 0.347 clomipramine chemical CHEBI:47780 ChEBI SLC6A3 protein Q01959 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 t miannu At the human dopamine transporter, sertraline and nomifensine were the most potent with KD's of 25±2 and 56±3, respectively. Except for these two compounds, most antidepressants were not potent at the human dopamine transporter. SIGNOR-258875 0.8 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 12747827 t lperfetto Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e. SIGNOR-236690 0.753 STOML2 protein Q9UJZ1 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21746876 f Giorgia We performed real-time RT-PCR to measure the levels of PGC-1alpha mRNA and found that these were increased in SLP-2hi cells (Fig. 3h), supporting the idea that upregulation of SLP-2 expression is associated with an increase in the expression of mitochondrially targeted genes. SIGNOR-260379 0.2 WNK3 protein Q9BYP7 UNIPROT SLC12A4 protein Q9UP95 UNIPROT down-regulates activity phosphorylation 21613606 t lperfetto We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs SIGNOR-264627 0.476 FHL1 protein Q13642 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 9418910 t With differential splicing resulting in deletion of an exon, KyoT2 lacked two LIM domains from the C terminus and had a frameshift in the last exon, creating the RBP-J-binding region in the C terminus gcesareni It was demonstrated by emsa that kyot2 can form a complex with dna-bound rbp-j, but the dna-binding affinity of the kyot2rbp-j complex is greatly weakened and it exists mostly dissociated from dna SIGNOR-54277 0.669 PPP3CA protein Q08209 UNIPROT DNM2 protein P50570 UNIPROT unknown dephosphorylation Ser764 LQSASSHsPTPQRRP 10116 20496096 t CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII). SIGNOR-248677 0.269 ABCA7 protein Q8IZY2 UNIPROT APP protein P05067 UNIPROT down-regulates quantity relocalization 9606 BTO:0000142 27472885 f miannu Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-β in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD. SIGNOR-265176 0.415 HIPK2 protein Q9H2X6 UNIPROT MECP2 protein P51608 UNIPROT up-regulates activity phosphorylation Ser80 AVPEASAsPKQRRSI 9606 19820693 t Luana Here, we identify the homeodomain-interacting protein kinase 2 (HIPK2) as a kinase that binds MeCP2 and phosphorylates it at Ser 80 in vitro and in vivo. SIGNOR-264549 0.491 MYC protein P01106 UNIPROT CCND2 protein P30279 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7526316 t gcesareni C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation. SIGNOR-27446 0.462 GNGT1 protein P63211 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000938 16537363 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-252687 0.401 PNCK protein Q6P2M8 UNIPROT EIF4G3 protein O43432 UNIPROT up-regulates phosphorylation Ser1156 NTFMRGGsSKDLLDN 9606 22514323 t lperfetto Here we report that activity-dependent translational initiation in cultured rat hippocampal neurons is enhanced by camki-mediated phosphorylation of ser1156 in eukaryotic initiation factor eif4gii (4gii). SIGNOR-197190 0.2 ERRFI1 protein Q9UJM3 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates activity binding -1 18046415 t The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2 SIGNOR-252077 0.73 EGFR protein P00533 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t lperfetto Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. SIGNOR-24778 0.414 PJA1 protein Q8NG27 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000165 28067271 t Biochemical and genetic evidence demonstrates that the MYOD-induced E3 ubiquitin ligase Praja1 (PJA1) is involved in regulating EZH2 levels upon p38α activation. EZH2 premature degradation in proliferating myoblasts is prevented by low levels of PJA1, its cytoplasmic localization and the lower activity towards unphosphorylated EZH2 SIGNOR-255664 0.501 GRB2 protein P62993 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t milica The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival SIGNOR-204969 0.909 Fibrinolysis phenotype SIGNOR-PH6 SIGNOR Fibrin complex SIGNOR-C317 SIGNOR down-regulates 9606 BTO:0000131 1447176 f lperfetto The fibrinolytic system is sequentially composed of plasminogen activation and fibrin degradation [1, 2]. Three distinct inhibitors of the fibrinolytic system that differently regulate these two steps are plasminogen activator inhibitor type-1 (PAI-1), α2-antiplasmin (α2AP) and thrombin activatable fibrinolysis inhibitor (TAFI) [3]. PAI-1 limits the amount of free tissue-type plasminogen activator (tPA) both in plasma and on vascular endothelial cells (VECs), and regulates plasminogen activation potential to dissolve fibrin SIGNOR-263532 0.7 GUCA2B protein Q16661 UNIPROT GUCY2C protein P25092 UNIPROT up-regulates binding 9606 10845107 t gcesareni Guanylins activate two receptors, gc-c and ok-gc, which are expressed in intestine and/or kidney. SIGNOR-78120 0.604 GATA1 protein P15976 UNIPROT GFI1B protein Q5VTD9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19965638 f miannu HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. SIGNOR-254430 0.516 tandutinib chemical CHEBI:90237 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258299 0.8 RNF19A protein Q9NV58 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT up-regulates quantity ubiquitination 9606 BTO:0000007 12750386 t miannu Ubiquitylation of synphilin-1 by Dorfin. A, synphilin-1 is ubiquitylated in HEK293 cells. Several lines of evidence have suggested that derangements in the ubiquitin-proteasome protein degradation pathway may have a prominent role in the pathogenesis of PD (5). Our present study shows that Dorfin, an E3 ubiquityl ligase, is colocalized with ubiquitin in LBs of PD and physically binds to ubiquitylate synphilin-1, which is known to be a major component of LBs SIGNOR-271455 0.464 GRK2 protein P25098 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates activity phosphorylation Ser358 EFCIPTSsNIEQQNS 9606 BTO:0000007 12123746 t gcesareni These results suggest that two C-terminal amino acids, Ser(355) and Thr(357), are required for short-term homologous desensitization and agonist-induced phosphorylation of mu-opioid receptors expressed in HEK 293 cells SIGNOR-249661 0.2 COX4I1 protein P13073 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267744 0.745 SMURF2 protein Q9HAU4 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001593 BTO:0000140 22298955 t lperfetto Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps SIGNOR-153420 0.725 AKT2 protein P31751 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000150 10576742 t lperfetto Akt (protein kinase b), a member of a different signaling pathway that also regulates these responses, interacted with raf and phosphorylated this protein at a highly conserved serine residue in its regulatory domain in vivo. This phosphorylation of raf by akt inhibited activation of the raf-mek-erk signaling pathway and shifted the cellular response in a human breast cancer cell line from cell cycle arrest to proliferation. SIGNOR-235678 0.431 GSK3B protein P49841 UNIPROT CEBPA protein P49715 UNIPROT up-regulates activity phosphorylation Thr230 GHPTPPPtPVPSPHP 10090 BTO:0000944 10567568 t Glycogen synthase kinase 3 (GSK3) phosphorylates T222 and T226, causing a conformational change in C/EBPα. GSK3-mediated phosphorylation does not, in itself, dramatically alter the activity of C/EBPα in our assays. phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes. SIGNOR-251232 0.387 UBR2 protein Q8IWV8 UNIPROT RECQL4 protein O94761 UNIPROT up-regulates binding 9606 BTO:0000567 15317757 t miannu The isolated recql4, assayed as a complex with ubr1 and ubr2, exhibited dna-stimulated atpase activity but was inactive as either dna helicase or dna translocase / the discovery, in the present work, that these ub ligases, ubr1 and ubr2, interact with the putative helicase recql4 (fig. 2), and that recql4 is a long-lived, non-ubiquitylated protein in hela cells SIGNOR-128214 0.545 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10085140 t lperfetto On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38. SIGNOR-65593 0.786 AURKB protein Q96GD4 UNIPROT NINL protein Q9Y2I6 UNIPROT up-regulates phosphorylation Ser585 RLPKNRHsPSWSPDG 9606 20864540 t lperfetto Importantly, nlp is characterized as a novel substrate of aurora b and can be phosphorylated by aurora b. The specific phosphorylation sites are mapped at ser-185, ser-448, and ser-585. The phosphorylation at ser-448 and ser-585 is likely required for nlp association with aurora b and localization at midbody. Meanwhile, the phosphorylation at ser-185 is vital to nlp protein stability. Disruptions of these phosphorylation sites abolish cytokinesis and lead to chromosomal instability. SIGNOR-168053 0.254 TRHR protein P34981 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0001379 23248581 t scontino TRH receptors are textbook calcium-mobilizing receptors: they are coupled to Gq and G11, which activate phospholipase Cβ (PLCβ). SIGNOR-267202 0.469 nisoxetine chemical CHEBI:73410 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 18487050 t Luana For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428.  SIGNOR-257797 0.8 CSNK2A1 protein P68400 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser423 LNSGDDVsEQDVPDL -1 12107178 t llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. SIGNOR-250873 0.435 CPI-0610 carboxylic acid chemical CID:67815062 PUBCHEM BRD4 protein O60885 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0004479 26815195 t Monia Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610). SIGNOR-261101 0.8 CSNK2A1 protein P68400 UNIPROT PTGES3 protein Q15185 UNIPROT up-regulates phosphorylation Ser113 WKDWEDDsDEDMSNF 9606 15040786 t gcesareni Several lines of evidence suggest that a cpges-activating protein kinase is ck-ii (casein kinase ii). Recombinant cpges was phosphorylated directly by and associated with ck-ii in vitro, resulting in marked reduction of the k m for the substrate pgh2. SIGNOR-123594 0.36 SLC38A9 protein Q8NBW4 UNIPROT leucine smallmolecule CHEBI:25017 ChEBI up-regulates quantity relocalization 9606 29053970 t SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins SIGNOR-255313 0.8 MYCT1 protein Q8N699 UNIPROT CCNE2 protein O96020 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30283340 f miannu MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. SIGNOR-261733 0.2 AURKB protein Q96GD4 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates phosphorylation Thr892 KPRYHKRtSSAVWNS 9606 12925766 t gcesareni Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites. SIGNOR-118019 0.973 JUN protein P05412 UNIPROT GLS protein O94925 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28111979 t Luana The transcription factor c-Jun can directly bind to the GLS gene promoter and enhance expression SIGNOR-268035 0.357 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 15143153 t gcesareni These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling. SIGNOR-124737 0.632 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu69 EETCSYEeAFEALES -1 10556651 t lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. SIGNOR-263682 0.655 MAPK8 protein P45983 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr265 GQSSAAAtPSTTGTK 9606 15767678 t gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. SIGNOR-134541 0.715 AURKB protein Q96GD4 UNIPROT CDCA2 protein Q69YH5 UNIPROT down-regulates activity phosphorylation Ser981 RRKSFCIsTLANTKA 9606 BTO:0000567 32938714 t done miannu This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin. SIGNOR-274001 0.457 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr589 SHDSEENyVPMNPNL 9606 BTO:0000018 10734310 t miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. SIGNOR-250288 0.661 PLK1 protein P53350 UNIPROT USP16 protein Q9Y5T5 UNIPROT up-regulates activity phosphorylation Ser330 ILKAFGNsTEKLDEE -1 26323689 t done miannu Plk1 phosphorylates and activates Usp16. In vitro phosphorylation of Usp16 with single (S330A, S386A, or S486A) or collective 3A (S330A/S386A/S486A) mutation showed that Plk1 phosphorylated Usp16 at all three sites (Fig. S2 D). SIGNOR-274016 0.35 SRC protein P12931 UNIPROT CELF2 protein O95319 UNIPROT up-regulates activity phosphorylation Tyr63 LKELFEPyGAVYQIN -1 17855367 t miannu Site-directed mutagenesis of putative tyrosine phosphorylation sites in CUGBP2 identified tyrosine 39 as a c-Src target, and a CUGBP2 with a mutated tyrosine 39 displayed an attenuated ability to bind COX-2 mRNA. SIGNOR-263195 0.327 FOXO1 protein Q12778 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000165 15125842 t The IGF-1/PI3K/Akt pathway, which has been shown to induce hypertrophy, prevents induction of requisite atrophy mediators, namely the muscle-specific ubiquitin ligases MAFbx and MuRF1. Moreover, the mechanism for this inhibition involves Akt-mediated inhibition of the FoxO family of transcription factors; SIGNOR-256258 0.251 Riluzole chemical CHEBI:8863 ChEBI KCNN1 protein Q92952 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 18955585 t Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  SIGNOR-258021 0.8 KDM4C protein Q9H3R0 UNIPROT H2AX protein P16104 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29207681 f miannu Knockdown of JMJD2C gene led to the up-regulation of basal γ-H2AX expression. and γ-H2AX together with its phosphorylated C-terminal (Sre residues 139–140, γ-H2AX) are crucial for DNA repair SIGNOR-263872 0.2 imatinib methanesulfonate chemical CHEBI:31690 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck;VIRAL ABL gcesareni SIGNOR-193387 0.8 lysine smallmolecule CHEBI:25094 ChEBI Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270410 0.8 phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI GSN protein P06396 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000132 12788695 t lperfetto We further measured the ability of ppIs phosphorylated in positions D-3 and D-4 to release the F-actin capping proteins CapZ and gelsolin from OG-permeabilized platelets (Fig. 7A). Ten percent of platelet CapZ and gelsolin is found in the OG-insoluble fraction (4). PI3,4,5P3 and PI3,4P2 release both CapZ and gelsolin from these preparations. SIGNOR-261841 0.8 FYN protein P06241 UNIPROT SLAMF1 protein Q13291 UNIPROT up-regulates activity phosphorylation Tyr327 ETNSITVyASVTLPE 9534 BTO:0000298 11806999 t All 3 tyrosines of CD150 (Tyr281, Tyr307, Tyr327) are phosphorylated by the src kinase Fyn. CD150 is unique among its homologues in the immunoglobulin superfamily in that it is able to bind SAP, a floating SH2 domain, in the absence of tyrosine phosphorylation. In this study, using a detailed mutagenesis mapping approach we have shown that SAP binding to CD150 is in fact bimodal. Prior to tyrosine phosphorylation, SAP binds the membrane-proximal motif surrounding Tyr281. Following tyrosine phosphorylation by tyrosine kinases such as Fyn, SAP binds additionally to the distal motif surrounding Tyr327. SIGNOR-251183 0.647 zotepine chemical CHEBI:32316 ChEBI HTR1D protein P28221 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000529 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258550 0.8 ATM protein Q13315 UNIPROT CCDC6 protein Q16204 UNIPROT up-regulates phosphorylation Thr434 TPPPSPNtQTPVQPP 9606 BTO:0000551 23108047 t miannu Phosphorylation of ccdc6 at thr434 by atm during dna damage response prevents fbxw7-mediated ccdc6 degradation. SIGNOR-199276 0.278 MAPK14 protein Q16539 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 9606 20626350 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni The p38 mapk pathway can positevely regulate nf-kb activity by different mechanisms, including chromatin remodelling through ser10 phosphorylation of histone h3 at nf-kb dependent promoters such as il-8 and mcp or by impinging on ikk or the p65 subunit in a direct or indirect manner. SIGNOR-166602 0.2 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252845 0.908 DNAJC6 protein O75061 UNIPROT HSPA8 protein P11142 UNIPROT up-regulates activity relocalization 24789820 t lperfetto Hsc70, recruited by the J-domain protein auxilin, mediates clathrin uncoating and release of a free vesicle, primed to fuse with a target membrane. SIGNOR-260719 0.88 GRIK2 protein Q13002 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264943 0.8 IRF2BPL protein Q9H1B7 UNIPROT PDYN protein P01213 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 17627301 t miannu EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function. SIGNOR-267156 0.266 CARS1 protein P49589 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. SIGNOR-270805 0.8 AKT2 protein P31751 UNIPROT SRSF5 protein Q13243 UNIPROT up-regulates activity phosphorylation Ser86 GRGRGRYsDRFSSRR 10116 15684423 t miannu Here we show that Akt2 kinase phosphorylated SRp40 in vivo and in vitro. Mutation of Ser86 on SRp40 blocked in vitro phosphorylation. SIGNOR-262633 0.37 SLC34A2 protein O95436 UNIPROT EGF protein P01133 UNIPROT down-regulates 9606 BTO:0000195 BTO:0000763 11171583 f miannu In vivo and in vitro studies showed that egf treatment decreased intestinal napi-iib mrna abundance by _50%, suggesting possible transcriptional regulation. SIGNOR-105161 0.359 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 7545671 t gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-28796 0.579 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide chemical CHEBI:91447 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194919 0.8 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21798082 t gcesareni Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-252843 0.908 FGF14 protein Q92915 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253413 0.563 HSF2 protein Q03933 UNIPROT HSPA6 protein P17066 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12813038 f miannu These experiments suggest that HSF2 is involved in the stress response, but unlike the ubiquitous HSF1 operates in a cell-line specific manner through differential expression of alternatively spliced isoforms. Curiously, HSF2A could not be activated by heat shock in cells deficient in functional HSF1 and required the expression of HSF1 for heat induction of the hsp70B gene in cells. SIGNOR-254478 0.345 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR IL16 protein Q14005 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 14768064 t inferred from 70% family members lperfetto The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 in antigen receptor-, sdf1alpha- and il-2-activated t cells. Genetic and pharmacological-inhibitor experiments showed that the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response. SIGNOR-270168 0.2 1-[2-[(diphenylmethylene)amino]oxyethyl]-3,6-dihydro-2H-pyridine-5-carboxylic acid chemical CHEBI:92744 ChEBI SLC6A1 protein P30531 UNIPROT down-regulates activity chemical inhibition -1 7851497 t miannu Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1. SIGNOR-258479 0.8 CDS2 protein O95674 UNIPROT CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI up-regulates chemical modification 9606 25375833 t lperfetto CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). SIGNOR-267020 0.8 CIC protein Q96RK0 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR up-regulates activity binding 10090 BTO:0000142 32229723 t miannu Mechanistically, we demonstrated that CIC represses VGF expression by tethering SIN3-HDAC to form a transcriptional corepressor complex. Mass spectrometry analysis of CIC-interacting proteins further identified the BRG1-containing mSWI/SNF complex whose function is necessary for transcriptional repression by CIC. CIC interacts with mSWI/SNF complex during neurogenesis. CIC tethers SIN3-HDAC corepressor complex and mSWI/SNF complex to VGF promoter during neurogenesis. SIGNOR-269207 0.273 mTORC1 complex SIGNOR-C3 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000944 18372248 t lperfetto We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competition. We also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1. SIGNOR-235518 0.83 SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 21779497 t lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-175259 0.771 ZNF804A protein Q7Z570 UNIPROT BIRC3 protein Q13489 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 23434502 t miannu ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). SIGNOR-269467 0.2 AMPK complex SIGNOR-C15 SIGNOR HNF4A protein P41235 UNIPROT down-regulates phosphorylation Ser303 DPDAKGLsDPGKIKR 9606 12740371 t lperfetto Here we demonstrate that ampk directly phosphorylates hnf4 and represses its transcriptional activity. Ampk-mediated phosphorylation of hnf4 on serine 304 had a 2-fold effect SIGNOR-216511 0.311 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207944 0.8 androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI testosterone smallmolecule CHEBI:17347 ChEBI up-regulates quantity precursor of 9606 BTO:0001363 16166196 t lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. SIGNOR-268665 0.8 PIK3AP1 protein Q6ZUJ8 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000801 22187458 t gcesareni This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Therefore, bcap is an essential activator of the pi3k pathway downstream of tlr signaling, providing a brake to limit potentially pathogenic excessive tlr responses. SIGNOR-191664 0.394 Phagocytosis phenotype SIGNOR-PH97 SIGNOR TGFB1 protein P01137 UNIPROT up-regulates quantity BTO:0000801 22933625 f apalma Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype SIGNOR-255444 0.7 KMN network complex SIGNOR-C366 SIGNOR Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 18007590 f lperfetto Based on our results, we propose that the cooperative action of CENP-A NAC/CAD subunits and the KMN network drives efficient chromosome segregation and bipolar spindle assembly during mitosis. SIGNOR-265220 0.7 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL 9534 BTO:0000298 8557118 t lperfetto PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. SIGNOR-248937 0.372 PRKACA protein P17612 UNIPROT PACSIN2 protein Q9UNF0 UNIPROT down-regulates activity phosphorylation Ser313 ADLNRTLsRREKKKA 9606 BTO:0000007 31801866 t done miannu PKCα phosphorylates PACSIN2 at serine 313 in the linker region and decreases its membrane binding and tubulation activities. Phosphorylation of PACSIN2 at S313 negatively regulated protein interaction between NS5A and core, which affected viral assembly SIGNOR-273799 0.2 Calcineurin complex SIGNOR-C155 SIGNOR NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-252323 0.822 CSNK2A1 protein P68400 UNIPROT IL16 protein Q14005 UNIPROT up-regulates activity phosphorylation Ser743 MPLQPNAsLNEEEGT -1 12450396 t llicata We now show that N-terminal to the NLS domain of pro-IL-16 are protein kinase CK2 substrate and cdc2 kinase substrate sites which, along with the NLS, constitute a dual phosphorylation-regulated CcN motif which regulates nuclear localization of pro-IL-16. In addition, we demonstrate that mutation of either site is associated with impairment of the N-terminal domain's ability to induce G(0)/G(1) cell cycle arrest. | Thus, we confirm that the N-terminal (42SLNEE46) sequence of pro-IL-16 is in fact a site for protein kinase CK2 phosphorylation. SIGNOR-250905 0.331 ADCYAP1 protein P18509 UNIPROT VIPR1 protein P32241 UNIPROT up-regulates binding 9606 11897681 t gcesareni Pacap binds to a pacap-specific receptor (pac1) and to vpac receptors (vpac1 and vpac2), which share high affinity for vasoactive intestinal polypeptide (vip). SIGNOR-116066 0.807 SCF-SKP2 complex SIGNOR-C136 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 phosphorylation:Thr187 NAGSVEQtPKKPGLR 10559916 t lperfetto SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27|We conclude that the stable interaction of p27 with SKP2 is highly specific and dependent upon phosphorylation of p27 on T187. SIGNOR-267557 0.683 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT down-regulates phosphorylation Ser1112 LLEDGSEsPAKRICP 9606 BTO:0001938 11157749 t gcesareni When expressed in u2os cells, the phosphorylation-deficient mutant p130(delta)(cdk4), in which the cdk4 specific sites were mutated to alanine residues, imposed a more sustained g1 arrest than a constitutively active prb(delta)(cdk), known to repress all cellular e2f activity SIGNOR-104656 0.844 MAPK1 protein P28482 UNIPROT UBAP2L protein Q14157 UNIPROT unknown phosphorylation Thr844 IPFPTPTtPLTGRDG 10090 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262774 0.2 MFF protein Q9GZY8 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity relocalization 9606 21149567 t gcesareni Mff functions as an essential factor in mitochondrial recruitment of Drp1. SIGNOR-245957 0.62 MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity phosphorylation 9606 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 whic in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. SIGNOR-209759 0.718 WNT9B protein O14905 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-132114 0.59 WWTR1 protein Q9GZV5 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001615 22470139 f miannu Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation. SIGNOR-255605 0.2 Laminin-1 complex SIGNOR-C183 SIGNOR a7/b1 integrin complex SIGNOR-C126 SIGNOR up-regulates activity binding 1839357 t lperfetto By using specific proteolytically derived fragments of laminin, it was determined that the alpha 7 beta 1 complex binds selectively to the E8 region, which represents part of the long arm of laminin. SIGNOR-253257 0.539 CHEK1 protein O14757 UNIPROT E2F6 protein O75461 UNIPROT down-regulates activity phosphorylation Ser52 EDNVQYVsMRKALKV -1 23954429 t miannu the checkpoint kinase Chk1 phosphorylates E2F6 leading to its dissociation from promoters. SIGNOR-266371 0.556 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity phosphorylation Thr183 DTMAKRNtVIGTPFW 9534 BTO:0004055 12223493 t lperfetto Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationWe define Thr(183) in subdomain VIII as a primary site of phosphoactivation. Thr(187) is also critical for kinase activity. SIGNOR-247577 0.2 prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI PTGER4 protein P35408 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257572 0.8 ADP chemical CHEBI:16761 ChEBI P2RY13 protein Q9BPV8 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257561 0.8 (+)-pilocarpine chemical CHEBI:8207 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258629 0.8 REN protein P00797 UNIPROT ATP6AP2 protein O75787 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000142;BTO:0000671;BTO:0001260 12045255 t gcesareni We report the expression cloning of the human renin receptor complementary dna encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein. Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin i and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of map kinases erk1 and erk2 SIGNOR-88416 0.779 CUDC-101 chemical CID:24756910 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191145 0.8 RBKS protein Q9H477 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity chemical modification 9606 25749547 t miannu Human ribokinase (RK) is a member of the ribokinase family, and is the first enzyme responsible for D-ribose metabolism, since D-ribose must first be converted into D-ribose-5-phosphate to be further metabolized and incorporated into ATP or other high energy phosphorylated compounds. SIGNOR-267073 0.8 CBLB protein Q13191 UNIPROT PIK3R2 protein O00459 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000661 11087752 t miannu Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. it can be postulated that Cbl-b, as an E3 Ub ligase, may play a general role in functional regulation of its target proteins through ubiquitination in a protein degradation-independent manner. SIGNOR-271424 0.481 GXYLT2 protein A0PJZ3 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 22117070 t Xylosylation in ER membrane. gcesareni Recently, we have shown (28) that two members of the human glycosyltransferase 8 family (gt8) (29), gxylt1 and gxylt2 (glucoside-xylosyltransferase 1/2), are able to transfer the first alfa1,3-linked xylose to o-glucosylated mammalian notch egf repeats. SIGNOR-254314 0.391 AKT1 protein P31749 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 17287208 t lperfetto Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo. SIGNOR-252499 0.798 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f irozzo However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins. SIGNOR-255853 0.2 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1672 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203528 0.769 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 17535811 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-155242 0.764 ING3 protein Q9NXR8 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269294 0.668 CSNK2A1 protein P68400 UNIPROT EEF1B2 protein P24534 UNIPROT unknown phosphorylation Ser106 DDIDLFGsDDEEESE -1 8547318 t llicata EF-1 beta was highly phosphorylated by casein kinase II, with up to 1.3 mol of phosphate incorporated per mol protein. From microsequence analysis and manual Edman degradation, the majority of the phosphate was shown to be present in serine 106 in the peptide DLFGS106DDEEES112EEA. Serine 112 was also phosphorylated by casein kinase II, but to a lesser extent. SIGNOR-250854 0.35 PRKACA protein P17612 UNIPROT SOX9 protein P48436 UNIPROT up-regulates phosphorylation Ser181 YQPRRRKsVKNGQAE 9606 15889150 t llicata We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta. SIGNOR-137085 0.446 CAMTA1 protein Q9Y6Y1 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0005397 21385898 f irozzo Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma. SIGNOR-259099 0.7 IKBKE protein Q14164 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 23691078 t lperfetto Ikbke phosphorylation and inhibition of foxo3a: a mechanism of ikbke oncogenic functionhere we report that ikbke regulates foxo3a through phosphorylation of foxo3a-ser644. The phosphorylation of foxo3a resulted in its degradation and nuclear-cytoplasmic translocation. SIGNOR-202054 0.417 PTPN12 protein Q05209 UNIPROT ABL1 protein P00519 UNIPROT down-regulates activity dephosphorylation 10090 11163214 t gcesareni Several experiments suggest that the PEST-type PTPs negatively regulate c-Abl activity: c-Abl was hyperphosphorylated in PTP-PEST-deficient cells; disruption of the c-Abl-PSTPIP1-PEST-type PTP ternary complex by overexpression of PSTPIP1 mutants increased c-Abl phosphotyrosine content SIGNOR-246222 0.449 CHUK protein O15111 UNIPROT FOXA2 protein Q9Y261 UNIPROT down-regulates phosphorylation Ser107 AGMGPHLsPSLSPLG 9606 22196886 t lperfetto Here, we show that ikk_, an important downstream kinase of tnf_, interacts with and phosphorylates foxa2 at s107/s111, thereby suppressing foxa2 transactivation activity and leading to decreased numb expression SIGNOR-195312 0.2 Hexokinase proteinfamily SIGNOR-PF76 SIGNOR Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates activity 9606 18350175 f inferred from family member The first step in metabolism of glucose (Glc) is usually phosphorylation, catalyzed by hexokinase. SIGNOR-270310 0.7 Serdemetan chemical CID:11609586 PUBCHEM MDM2 protein Q00987 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193504 0.8 clozapine chemical CHEBI:3766 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10116 BTO:0000601 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258517 0.8 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr3 tSQKHRDF 9606 16495336 t gcesareni We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell SIGNOR-144803 0.516 WNK3 protein Q9BYP7 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates activity phosphorylation Ser96 IEDLSQNsITGEHSQ 9606 24043619 t Manara WNK3, which inhibits the activity of KCC3, promoted phosphorylation of Ser-96 as well as Thr-991 and Thr-1048.  SIGNOR-260911 0.456 RPS6KA4 protein O75676 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser196 EEKERTFsFCGTIEY 9606 BTO:0001253 17429437 t gcesareni Ser-343 and ser-196 are autophosphorylated by the c-terminal kinase domain, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain. SIGNOR-154324 0.2 PTPN6 protein P29350 UNIPROT IL2RB protein P14784 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 9520455 t gcesareni We have found that il-2 induces association of shp-1 with the il-2 receptor complex, and that once shp-1 is recruited to the activated receptor it is able to decrease tyrosine phosphorylation of il-2rbeta and the associated tyrosine kinases jak1 and jak3. SIGNOR-55989 0.511 IL6ST protein P40189 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 32234467 f miannu Interleukin-6 (IL-6) is an important member of the cytokine network and plays a central role in acute inflammation. IL-6 binds to its receptor IL-6R to form a complex, and then binds to the membrane protein gp130 to initiate intracellular signal transduction. IL-6 is the terminal helper factor of cytotoxic T lymphocyte (CTL), which can induce CTL activity and make immature thymocytes develop into CTL. In addition, IL-6 is a pro-inflammatory regulator of T cells. SIGNOR-261028 0.7 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation. SIGNOR-252852 0.908 ADAM17 protein P78536 UNIPROT TGFA protein P01135 UNIPROT up-regulates activity cleavage 9606 26284334 t miannu ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF SIGNOR-259841 0.502 STAT3 protein P40763 UNIPROT PLK1 protein P53350 UNIPROT up-regulates quantity by expression transcriptional regulation 22108192 t lperfetto Stat3 directly activated transcription of PLK1 in esophageal cancer cells and mouse embryonic fibroblast cell NIH3T3. SIGNOR-271690 0.311 PRKCA protein P17252 UNIPROT GFPT1 protein Q06210 UNIPROT down-regulates activity phosphorylation Ser205 AVGTRRGsPLLIGVR -1 10806197 t lperfetto Phosphorylation of human glutamine:fructose-6-phosphate amidotransferase by cAMP-dependent protein kinase at serine 205 blocks the enzyme activity. SIGNOR-249040 0.312 PRKCA protein P17252 UNIPROT NPHS1 protein O60500 UNIPROT up-regulates activity phosphorylation Thr1120 EYEESQWtGERDTQS 9606 BTO:0000007 21321125 t llicata Binding of _-arrestin2 to the nephrin intracellular domain depended on phosphorylation of nephrin threonine residues 1120 and 1125 by pkc_. SIGNOR-178695 0.2 TG101209 chemical CHEBI:90304 ChEBI JAK3 protein P52333 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207266 0.8 SETD2 protein Q9BYW2 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity trimethylation Lys37 APATGGVkKPHRYRP 9606 16118227 t Gianni Our results suggest that HYPB HMTase may coordinate histone methylation and transcriptional regulation in mammals and open perspective for the further study of the potential roles of HYPB protein in hematopoiesis and pathogenesis of HD. SIGNOR-269071 0.2 SELENOS protein Q9BQE4 UNIPROT VCP protein P55072 UNIPROT up-regulates activity binding 9606 BTO:0000567 15215856 t miannu VIMP mediates p97 binding to hDerlin-1. these data suggest that Derlin-1 and VIMP form a membrane protein complex that serves as a receptor for p97. SIGNOR-261371 0.2 CSNK1A1 protein P48729 UNIPROT CTPS2 protein Q9NRF8 UNIPROT down-regulates phosphorylation Ser568 LSSSDRYsDASDDSF 9606 20739275 t gcesareni Hctps2 ser(568) was phosphorylated by casein kinase 1 both in vitro and in vivo. Mutation of ser(568) (s568a) significantly increased hctps2 activity, demonstrating that ser(568) is a major inhibitory phosphorylation site. SIGNOR-167623 0.2 PIK3C3 protein Q8NEB9 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 10698680 f acerquone Pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1) SIGNOR-75376 0.445 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DHPS protein P49366 UNIPROT up-regulates activity phosphorylation Ser233 KNHIPVFsPALTDGS 9606 BTO:0002524 32989218 t miannu  The Ser-233 phosphorylation of DHPS by ERK1/2 is important for its function in cell proliferation. SIGNOR-277822 0.2 MAP4K2 protein Q12851 UNIPROT MAP4K2 protein Q12851 UNIPROT up-regulates activity phosphorylation Ser170 ASVAKRRsFIGTPYW 9606 BTO:0002524 37595580 t miannu MAP4K2 is autophosphorylated at S170 for activation SIGNOR-277826 0.2 CDKN1A protein P38936 UNIPROT CDK3 protein Q00526 UNIPROT down-regulates binding 9606 7626805 t gcesareni P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage. We have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases. SIGNOR-29954 0.664 PHF2 protein O75151 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 21532585 t miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. SIGNOR-264521 0.2 NFIB protein O00712 UNIPROT WNT5A protein P41221 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268883 0.2 metformin chemical CHEBI:6801 ChEBI NR0B2 protein Q15466 UNIPROT up-regulates quantity by expression 9606 17909097 f gcesareni As shown in fig. 3a, metformin (0.5 to 2 mmol/l) induced shp gene expression and repressed the camp/dex-induced expression of pepck and g6pase in a dose-dependent manner in h4iie cells SIGNOR-158068 0.8 LYL1 protein P12980 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21261500 f miannu TAL1 and LYL1 are two leukemic members of the bHLH family of transcription factors. TAL1 and LYL1 activate expression of MEF2C SIGNOR-254208 0.344 PTPN5 protein P54829 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates binding 9606 BTO:0000938 23932588 t A study conducted by Zhang et al. showed that STEP is significantly less efficient than PTPSL and HePTP at dephosphorylating p38a. gcesareni First [] step prevents upstream activating kinases from promiscuously binding and activating p38a. Second, by blocking access to the mapk insert pocket, through the stepcat interaction, step can prevent the binding of allosteric signaling molecules that induce autoactivation of p38a. SIGNOR-194829 0.479 PRKCA protein P17252 UNIPROT CTPS1 protein P17812 UNIPROT up-regulates phosphorylation Ser462 TLFQTKNsVMRKLYG 9606 17463002 t llicata These data indicated that protein kinase c phosphorylation at ser(462) stimulates human ctp synthetase 1 activity, whereas phosphorylation at thr(455) inhibits activity. SIGNOR-154617 0.2 PEA15 protein Q15121 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates 9606 11702783 f inferred from 70% of family members gcesareni Here, we report that pea-15, a protein variably expressed in multiple cell types, blocks erk-dependent transcription and proliferation by binding erks and preventing their localization in the nucleus._ Pea-15 can redirect the biological outcome of map kinase signaling by regulating the subcellular localization of erk map kinase. SIGNOR-269925 0.862 GOLGA2 protein Q08379 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 16489344 t Giulio Previous studies have implicated the GM130–GRASP65 complex in diverse Golgi functions. Therefore, GM130–GRASP65 interactions are required for Golgi ribbon formation.|A surprising clue came from the observation that GM130 was required for stability of GRASP65. SIGNOR-260601 0.875 PRKCD protein Q05655 UNIPROT TRIM28 protein Q13263 UNIPROT down-regulates phosphorylation Ser473 SGVKRSRsGEGEVSG 9606 18590578 t gcesareni This work demonstrates that tif1beta is phosphorylated on ser473, the alteration of which is dynamically associated with cell cycle progression and functionally linked to transcriptional regulation. Phosphorylation of tif1beta/ser473 is mediated by the pkcdelta pathway and is closely linked to cell proliferation. Phosphorylation of tif1beta/ser473 coincides with the induction of cell cycle gene cyclin a2 at the s-phase. Promoter of cyclin a2 gene is occupied by tif1beta and such occupancy is inversely correlated with ser473 phosphorylation. Non-phosphorylated tif1beta/ser473 allowed greater tif1beta association with the regulatory regions and the consequent repression of these genes. SIGNOR-179250 0.2 STUB1 protein Q9UNE7 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 14701756 t miannu We demonstrate that the coexpression of Smad1 and Smad4 with the CHIP protein results in the degradation of the Smad proteins through a ubiquitin-mediated process.  SIGNOR-272947 0.405 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR GSK3B protein P49841 UNIPROT up-regulates activity phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 BTO:0001253 15020233 t lperfetto In vitro kinase assay was carried out using a recombinant human active mek1 and we found that gsk-3beta was phosphorylated on tyr(216) by this kinase in a dose- and time-dependent manner. Further, the pretreatment of fibroblasts with u0126 inhibited serum-induced nuclear translocation of gsk-3beta. These results suggested that mek1/2 induces tyrosine phosphorylation of gsk-3beta and this cellular event might induce nuclear translocation of gsk-3beta. SIGNOR-244780 0.2 CALM3 protein P0DP25 UNIPROT EEF2K protein O00418 UNIPROT up-regulates binding 9606 11015200 t miannu The calmodulin-binding region is located between amino acids 51 and 96 SIGNOR-266337 0.473 KDM5A protein P29375 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR down-regulates binding 7227 BTO:0000782 20231316 t lperfetto In this study, we show that the histone demethylase kdm5a associated with rbp-j protein and is essential for notch/rbp-j target gene silencing in vitro. SIGNOR-219250 0.393 MAP4K1 protein Q92918 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates phosphorylation Ser281 WHKTTQMsAAGTYAW 9606 11053428 t gcesareni Hpk1 also phosphorylated mlk-3 activation loop in vitro, and ser281 was found to be the major phosphorylation site, indicating that hpk1 also activates mlk-3 via phosphorylation of the kinase activation loop. SIGNOR-83415 0.556 TP53 protein P04637 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 19007744 t Cytosolic p53 lperfetto Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis SIGNOR-99712 0.739 RISC(DICER1/AGO2/TARBP2) complex SIGNOR-C32 SIGNOR NcRNA_processing phenotype SIGNOR-PH95 SIGNOR up-regulates 9606 23661684 f lperfetto SIGNOR-255323 0.7 pazopanib chemical CHEBI:71219 ChEBI CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 18620382 t Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. SIGNOR-257740 0.8 L-thyroxine smallmolecule CHEBI:18332 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity chemical activation 10116 BTO:0000759 2158622 t inferred from 70% of family members miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. SIGNOR-269881 0.8 TLR4 protein O00206 UNIPROT MAP3K8 protein P41279 UNIPROT up-regulates activity 10090 16484370 f Our findings indicate that the Tpl2/MEK/ERK signaling module is a master regulator of ERK-dependent gene expression downstream of TLRs in different hemopoietic cells SIGNOR-256083 0.399 TAL1 protein P17542 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 21261500 f miannu TAL1 and LYL1 are two leukemic members of the bHLH family of transcription factors. TAL1 and LYL1 activate expression of MEF2C SIGNOR-254209 0.335 MAPK1 protein P28482 UNIPROT CIITA protein P33076 UNIPROT down-regulates phosphorylation Ser288 PDRPGSTsPFAPSAT 9606 18245089 t gcesareni Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. ... Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation. SIGNOR-160613 0.442 CREB1 protein P16220 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity binding 9606 15126506 t lperfetto We provide evidence that the acetyltransferase creb-binding protein (cbp) binds foxo resulting in acetylation of foxo. This acetylation inhibits foxo transcriptional activity SIGNOR-252894 0.529 ITGA7 protein Q13683 UNIPROT a7/b1 integrin complex SIGNOR-C126 SIGNOR form complex binding 9606 BTO:0000222;BTO:0002319 10199978 t lperfetto The alpha7beta1 integrin is a laminin receptor on the surface of skeletal myoblasts and myofibers. Alternative forms of both the alpha7 and beta1 chains are expressed in a developmentally regulated fashion during myogenesis. These different alpha7beta1 isoforms localize at specific sites on myofibers and appear to have distinct functions in skeletal muscle. SIGNOR-241508 0.764 IL21 protein Q9HBE4 UNIPROT IL21R protein Q9HBE5 UNIPROT up-regulates binding 9606 16424177 t gcesareni Il-21 mediates its biological effects via the il-21r in conjunction with the common receptor gamma-chain that is also shared by members of the il-2 family SIGNOR-143849 0.898 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT unknown phosphorylation Ser33 LPENNVLsPLPSQAM 9606 16552184 t llicata Here, we report for the first time that cyclin dependent kinase 9, whose well-known substrate is rna polymerase ii, can also phosphorylate p53. Specifically, ser33 on the n-terminus and, ser315 and ser392 on the c-terminus of p53 were found to be phosphorylated. The precise biological role of this phosphorylation remains to be elucidated. SIGNOR-145315 0.55 perfluorodecanoic acid chemical CHEBI:35546 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 23764977 t miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  SIGNOR-268770 0.8 MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000132 SIGNOR-C2 21592956 t lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. SIGNOR-217869 0.928 RNF8 protein O76064 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 31225475 f miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. SIGNOR-266790 0.7 P2RY2 protein P41231 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-265342 0.2 BRIP1 protein Q9BX63 UNIPROT BRCA1-B complex complex SIGNOR-C298 SIGNOR form complex binding 25400280 t lperfetto Another BRCA1 complex, the BRCA1–B complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‐phase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‐phase checkpoint activation SIGNOR-263219 0.661 SDC4 protein P31431 UNIPROT FN1/SDC4 complex SIGNOR-C210 SIGNOR form complex binding 23290138 t apalma We found that binding of ECM glycoprotein Fibronectin (FN) to Sdc4 stimulates the ability of Wnt7a to induce the symmetric expansion of satellite stem cells SIGNOR-255286 0.7 RPL36A protein P83881 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262492 0.819 PPP2CA protein P67775 UNIPROT RPS3 protein P23396 UNIPROT down-regulates dephosphorylation Ser6 sKKRKFVA 9606 15950189 t lperfetto We identified that pp2a interacts with wild-type rps3, but not with mutants (s6a/t221a) (fig. 8), and that it associates with the n-terminal region of rps3 (fig. 2). From our results presented here, we conclude that pp2a is involved in the dephosphorylation of phosphorylated rps3 by pkc, and that serine 6 on the n-terminal region of rps3 appears to mediate the pp2a recruitment. SIGNOR-137963 0.402 aloxistatin chemical CHEBI:101381 ChEBI CTSL protein P07711 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 32142651 t miannu Full inhibition was attained when camostat mesylate and E-64d, an inhibitor of CatB/L, were added (Figure 4A; Figure S3B), indicating that SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. SIGNOR-260282 0.8 BAX protein Q07812 UNIPROT VDAC1 protein P21796 UNIPROT up-regulates activity binding 10365962 t lperfetto The recombinant pro-apoptotic proteins Bax and Bak accelerate the opening of VDAC SIGNOR-249613 0.574 MOB1B protein Q7L9L4 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates binding 9606 21084559 t Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. SIGNOR-269865 0.919 CSNK2A1 protein P68400 UNIPROT SIRT1 protein Q96EB6 UNIPROT unknown phosphorylation Ser661 GAEVYSDsEDDVLSS 9606 19236849 t llicata We demonstrate that sirt1 is a substrate for protein kinase ck2 both in vitro and in vivo. Both, deletion construct analyses and serine-to-alanine mutations identified sirt1 ser-659 and ser-661 as major ck2 phosphorylation sites that are phosphorylated in vivo as well. SIGNOR-184155 0.627 PPP2CA protein P67775 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 12840032 t inferred from 70% of family members gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). SIGNOR-269918 0.634 MAPK14 protein Q16539 UNIPROT DLX5 protein P56178 UNIPROT up-regulates activity phosphorylation Ser34 MHHPSQEsPTLPESS 10090 18056716 t ggiuliani We show that Dlx5 is a novel substrate for p38 MAPK in vitro and in vivo and that Ser-34 and Ser-217 are the sites phosphorylated by p38 SIGNOR-255792 0.295 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TOB1 protein P50616 UNIPROT down-regulates phosphorylation 9606 12050114 t inferred from 70% family members gcesareni Tob is rapidly phosphorylated at Ser 152, Ser 154, and Ser 164 by Erk1 and Erk2 upon growth-factor stimulation. SIGNOR-270210 0.2 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser312 TESITATsPASMVGG -1 12351658 t IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. SIGNOR-251293 0.644 MSX2 protein P35548 UNIPROT DLX5 protein P56178 UNIPROT down-regulates activity binding 10090 BTO:0000947 9111364 t 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. SIGNOR-240990 0.553 TAOK1 protein Q7L7X3 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2. SIGNOR-201321 0.302 MOB1A protein Q9H8S9 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates binding 9606 21084559 t Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1 SIGNOR-169755 0.862 PPP2CA protein P67775 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates dephosphorylation Thr32 QSRPRSCtWPLQRPE 9606 20110348 t gcesareni Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a. SIGNOR-163684 0.412 ATRX protein P46100 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR up-regulates activity binding 9606 25417162 t lperfetto ATRX is a required specificity determinant for PRC2 targeting and function. SIGNOR-241890 0.342 CALM1 protein P0DP23 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates binding 9606 11796223 t inferred from 70% of family members gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-269892 0.763 IL1RAP protein Q9NPH3 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates binding 9606 12530978 t gcesareni Here we report that the soluble form of the il-1 receptor accessory protein (acp) increases the affinity of binding of human il-1alpha and il-1beta to the soluble human type ii il-1 receptor by approximately 100-fold, SIGNOR-97396 0.719 AGRP protein O00253 UNIPROT MC1R protein Q01726 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268699 0.452 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR NFY complex SIGNOR-C1 SIGNOR up-regulates activity binding 9606 BTO:0000972 18025157 t We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. SIGNOR-255747 0.2 ZAP70 protein P43403 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates activity phosphorylation Tyr614 KSTGSVDyLALDFQP 9606 BTO:0000782 11572860 t lperfetto In the present study, we found that gab2 is phosphorylated by zap-70, associates with the tcr signaling complex, and acts as an inhibitory adaptor molecule via recruitment of shp-2 following tcr ligation. SIGNOR-110731 0.472 FYN protein P06241 UNIPROT TRIO protein O75962 UNIPROT up-regulates activity phosphorylation Tyr2681 LLNPNYIyDVPPEFV -1 23230270 t miannu Here, we demonstrate that Trio is phosphorylated by Src family kinases in the embryonic rat cortex in response to netrin-1. In vitro, Trio was predominantly phosphorylated at Tyr(2622) by the Src kinase Fyn. SIGNOR-273855 0.2 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1784 TPTSPNYsPTSPSYS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248790 0.442 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT up-regulates phosphorylation Tyr465 VPVDPATyGQFYGGD 9606 10210201 t lperfetto Identification of tyr438 as the major in vitro c-src phosphorylation site in human gelsolin recently SIGNOR-67014 0.575 PTH1R protein Q03431 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 28363951 t lperfetto This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11. SIGNOR-270550 0.279 MED17 protein Q9NVC6 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266669 0.827 ARRB1 protein P49407 UNIPROT KIF3A protein Q9Y496 UNIPROT up-regulates binding 9606 18497258 t gcesareni Kif3a is essential for shh-mediated signaling in mammalian systems (5), and we identified kif3a as a arr1 binding partner in a proteomics screen (18). To test whether arrs, smo, and kif3a might work in concert. SIGNOR-178672 0.532 PTK2 protein Q05397 UNIPROT TRIO protein O75962 UNIPROT up-regulates activity phosphorylation Tyr2796 KDNFDSFySEVAELG 9534 12551902 t lperfetto A FAK phosphorylation site, tyrosine residue 2737, was identified in subdomain I of the Trio kinase domain. Additionally, in vitro phosphorylation assays and in vivo co-expression studies indicated that Trio enhances FAK kinase activity. SIGNOR-249188 0.488 8-Hydroxy-7-(6-sulfo-naphthalen-2-ylazo)-quinoline-5-sulfonic acid chemical CID:92577 PUBCHEM DUSP26 protein Q9BV47 UNIPROT down-regulates activity chemical inhibition -1 19233143 t lperfetto Phosphatase activity of dual-specificity protein phosphatase 26 (DUSP26) was decreased by the inhibitor in a dose-dependent manner. Kinetic studies with NSC-87877 and DUSP26 revealed a competitive inhibition. SIGNOR-261979 0.8 PHKG2 protein P15735 UNIPROT PYG proteinfamily SIGNOR-PF96 SIGNOR up-regulates activity phosphorylation 9606 BTO:0002049 22225877 t miannu It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15 SIGNOR-267962 0.65 SMURF1 protein Q9HCE7 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 17317136 t gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. SIGNOR-153399 0.646 CSNK2B protein P67870 UNIPROT EIF5 protein P55010 UNIPROT up-regulates activity phosphorylation Ser174 DKENGSVsSSETPPP 9606 BTO:0001938 11861906 t llicata Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis. SIGNOR-251068 0.387 CFL1 protein P23528 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR down-regulates 9606 16226035 f miannu This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. SIGNOR-268382 0.7 AMPK complex SIGNOR-C15 SIGNOR FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation 9606 18394876 t lperfetto The energy sensor AMP-activated protein kinase (AMPK) has been shown to directly phosphorylate FoxO factors at six regulatory sites that are distinct from the Akt phosphorylation sites, resulting in FoxO activation. SIGNOR-216478 0.355 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates activity phosphorylation Thr228 HEGAVTHtFCGTIEY -1 11733037 t miannu  Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities. SIGNOR-250273 0.596 TCAP protein O15273 UNIPROT Sarcomere_organization phenotype SIGNOR-PH165 SIGNOR up-regulates activity binding 9606 BTO:0001103 9804419 t lperfetto The giant muscle protein titin (connectin) is essential in the temporal and spatial control of the assembly of the highly ordered sarcomeres (contractile units) of striated muscle.  SIGNOR-264855 0.7 PLK1 protein P53350 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007;BTO:0001914 23887393 t gcesareni Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency SIGNOR-243522 0.548 WWTR1 protein Q9GZV5 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-256668 0.7 ZMYND8 protein Q9ULU4 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27477906 t lperfetto Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported SIGNOR-262038 0.2 PHLPP1 protein O60346 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 t gcesareni Here, we identify a protein_ phosphatase, ph domain leucine-rich repeat protein_ phosphatase_ (phlpp), that specifically_ dephosphorylates_ the hydrophobic motif of_ akt_ (ser473 in akt1), triggering_ apoptosis_ and suppressing_ tumor_ growth. SIGNOR-135005 0.751 Aflibercept chemical SID:134445687 ChEBI VEGFA protein P15692 UNIPROT down-regulates activity chemical inhibition 9606 22813448 t miannu Aflibercept, a fusion protein with binding domains from native VEGF receptors, binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity.This soluble decoy receptor is produced by fusing all-human DNA sequences of the second immunoglobulin (Ig) domain of human VEGF receptor (VEGFR) 1 to the third Ig domain of human VEGFR-2, which then is fused to the Fc region of human IgG-1.2 Aflibercept binds to all VEGF-A and VEGF-B isoforms, as well as the highly related placental growth factor. SIGNOR-259386 0.8 FOXO3 protein O43524 UNIPROT TSC22D3 protein Q99576 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001482 15705665 t We have analyzed the promoter of human gilz (glucocorticoid-induced leucine zipper), a dexamethasone-inducible gene that is involved in regulating apoptosis, and identified six glucocorticoid (GC)-responsive elements and three Forkhead responsive elements (FHREs). SIGNOR-255950 0.404 Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR tRNA(Phe) smallmolecule CHEBI:29184 ChEBI down-regulates quantity chemical modification 9606 20223217 t miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. SIGNOR-270438 0.8 RIT2 protein Q99578 UNIPROT POU4F1 protein Q01851 UNIPROT up-regulates activity binding 9606 BTO:0000934 12934100 t miannu we describe the evidence for a functional interaction between Brn-3a and Rin and demonstrate the role of Rin in modulating the activation of the Brn-3a regulated egr-1 promoter by the N-terminal domain of Brn-3a. SIGNOR-224546 0.541 BRK1 protein Q8WUW1 UNIPROT WRC complex complex SIGNOR-C191 SIGNOR form complex binding 9606 21107423 t miannu WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems SIGNOR-253570 0.859 ADIPOQ protein Q15848 UNIPROT ADIPOR1 protein Q96A54 UNIPROT up-regulates binding 9606 16622416 t milica Two adiponectin receptors, adipor1 and adipor2, have recently been identified. SIGNOR-146170 0.664 SMO protein Q99835 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates binding 9606 23074268 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-199165 0.404 DKK1 protein O94907 UNIPROT KREMEN1 protein Q96MU8 UNIPROT up-regulates binding 9606 12050670 t gcesareni Dkk1 has been shown to inhibitwnt by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to blockwnt/betBeta-catenin. Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of thewntreceptor lrp6 from the plasma membrane. SIGNOR-88838 0.832 MTOR protein P42345 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr390 DSKFTRQtPVDSPDD 9606 11914378 t Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain,[…] Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings. SIGNOR-255841 0.552 paroxetine chemical CHEBI:7936 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 t miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. SIGNOR-258739 0.8 USP6 protein P35125 UNIPROT MMP9 protein P14780 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20418905 f miannu In this study we show that tre17 is sufficient to induce expression of mmp-9 and mmp-10, in a manner requiring its usp activity, but not its ability to bind arf6. Tre17 induces transcription of mmp-9 through activation of nuclear factor-kappab (nf-kappab), mediated in part by the gtpase rhoa and its effector kinase, rock. SIGNOR-164946 0.333 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259707 0.8 CSNK2A1 protein P68400 UNIPROT L1CAM protein P32004 UNIPROT unknown phosphorylation Ser1181 GEYRSLEsDNEEKAF 10116 BTO:0000142 8592152 t llicata Serine to alanine substitutions in these peptides indicate that the CKII phosphorylation site is at Ser1,181. | Finally, in vivo radiolabeling indicates that Ser1,181 is phosphorylated in newborn rat brain. These data show that CKII is associated with and able to phosphorylate L1. SIGNOR-250913 0.47 AURKB protein Q96GD4 UNIPROT NINL protein Q9Y2I6 UNIPROT up-regulates phosphorylation Ser185 WDSEDFGsPQKSCSP 9606 20864540 t lperfetto Importantly, nlp is characterized as a novel substrate of aurora b and can be phosphorylated by aurora b. The specific phosphorylation sites are mapped at ser-185, ser-448, and ser-585. The phosphorylation at ser-448 and ser-585 is likely required for nlp association with aurora b and localization at midbody. Meanwhile, the phosphorylation at ser-185 is vital to nlp protein stability. Disruptions of these phosphorylation sites abolish cytokinesis and lead to chromosomal instability. SIGNOR-168045 0.254 GPR17 protein Q13304 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256971 0.2 INTS4 protein Q96HW7 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261467 0.755 lapatinib chemical CHEBI:49603 ChEBI EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258234 0.8 PIAS1 protein O75925 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates sumoylation 9606 15028714 t lperfetto These data demonstrate that pias1 protein positively modulates tgf-beta responses as a sumo e3 ligase for smad4 SIGNOR-123462 0.403 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr447 SEELDENyVPMNPNS 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236420 0.751 RNF146 protein Q9NTX7 UNIPROT TNKS protein O95271 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 21799911 t We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation. SIGNOR-260004 0.713 NCK1 protein P16333 UNIPROT WASL protein O00401 UNIPROT up-regulates binding 9606 11340081 t gcesareni Nck and cdc42 activate n-wasp by redundant mechanisms. SIGNOR-107634 0.771 4E2RCat chemical CID:2287236 PUBCHEM EIF4E protein P06730 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000414 21507972 t miannu Characterization of 4E2RCat, an inhibitor of eIF4E-eIF4G interaction. Herein we describe a molecule from this screen that prevents the interaction between eIF4E (the cap-binding protein) and eIF4G (a large scaffolding protein), inhibiting cap-dependent translation. This inhibitor significantly decreased human coronavirus 229E (HCoV-229E) replication, reducing the percentage of infected cells and intra- and extracellular infectious virus titers. SIGNOR-260187 0.8 FFAR4 protein Q5NUL3 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257045 0.252 Varespladib chemical CID:155815 PUBCHEM PLA2G1B protein P04054 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207633 0.8 ITGB1BP1 protein O14713 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257650 0.318 MAK protein P20794 UNIPROT MAK protein P20794 UNIPROT up-regulates activity phosphorylation Tyr159 SQPPYTDyVSTRWYR 9606 21986944 t Manara We conclude that dual phosphorylation on the TDY motif is crucial for MAK activity, and that the autokinase activity is required for this phosphorylation SIGNOR-260780 0.2 CAMK2D protein Q13557 UNIPROT KCNQ1 protein P51787 UNIPROT down-regulates activity phosphorylation Ser484 PHFMRTNsFAEDLDL 29410121 t lperfetto CaMKII regulates KCNQ1 at S484 during sustained β-AR stimulation to inhibit IKs. The ability of CaMKII to inhibit IKs may contribute to arrhythmogenicity during HF. SIGNOR-275479 0.2 ACVR1B protein P36896 UNIPROT TDP2 protein O95551 UNIPROT up-regulates activity phosphorylation Thr92 VDLTNEEtTDSTTSK 9606 BTO:0000007 18039968 t miannu ALK4 phosphorylated TTRAP in vitro (Fig. 6A). The band migrating at the position of TTRAP was excised and analyzed by LC-MS/MS. One TTRAP peptide was phosphorylated either on T88 and T92, or on T92 only (Fig. 6B).We tested in vivo phosphorylation of Strep-TTRAP by co-expression with mouse Alk4 in HEK293T cells, and affinity-purified TTRAP. In this preparation TTRAP-specific peptides were reproducibly found in both the singly (T92) and doubly phosphorylated form (T88/T92). mutant TTRAPT88A,T92A is not able to rescue the TtrapMO phenotype, suggesting that phosphorylation of Ttrap on Thr88 and Thr92 is essential for Ttrap function. SIGNOR-262612 0.284 DYRK1A protein Q13627 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity SIGNOR-183677 0.321 FCER1G protein P30273 UNIPROT FCER1G/FCER1G complex SIGNOR-C199 SIGNOR form complex binding 9606 BTO:0000830 16470226 t Alessandro Palma FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling. SIGNOR-254961 0.2 MTR protein Q99707 UNIPROT (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI down-regulates quantity chemical modification 9606 10520212 t lperfetto Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. SIGNOR-253144 0.8 PIK-90 chemical CID:6857685 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206229 0.8 HK1 protein P19367 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266455 0.8 ELL protein P55199 UNIPROT ELL/ICE1 complex SIGNOR-C48 SIGNOR form complex binding 9606 BTO:0001271 22195968 t miannu The ell-ice complex is called lec for its proposed role in transcriptional regulation of the littlesnrna genes. SIGNOR-193458 0.553 HES1 protein Q14469 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000931 11054669 f miannu Our data show that functional sympathetic neuronal differentiation of neuroblastoma cells is associated with transient activation of HES-1 and down-regulation of HASH-1 expression. SIGNOR-254824 0.452 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR PAX7 protein P23759 UNIPROT down-regulates quantity by repression transcriptional regulation 20887952 t The results presented above demonstrate a signal-dependent interaction between p38a, YY1, and EZH2 on the chromatin of the Pax7 regulatory elements that coincides with p38-mediated repression of Pax7 at early stages of myoblast differentiation. SIGNOR-253598 0.375 AXIN1 protein O15169 UNIPROT RNF111 protein Q6ZNA4 UNIPROT up-regulates binding 9606 14657019 t gcesareni Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia. Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia. SIGNOR-119660 0.627 HOXA9 protein P31269 UNIPROT MSI2 protein Q96DH6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20805843 f gcesareni Nup98-hoxa9 oncogene binds the putative element at 5.7 kb upstream of transcription start site to trigger the upregulated expression of musashi2 gene (b). The elevated level of musashi2 leads to the downregulation of numb, by binding to the 3' utr of numb mrna to inhibit translation SIGNOR-167725 0.439 Brivanib alaninate chemical CID:11154925 PUBCHEM FGFR3 protein P22607 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190723 0.8 BMPR1B protein O00238 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates activity phosphorylation 9606 19620713 t lperfetto Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. SIGNOR-255260 0.667 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr763 DMKGDVKyADIESSN 9823 10391677 t miannu Activation of the beta-receptor for platelet-derived growth factor (PDGF) by its ligand leads to autophosphorylation on a number of tyrosine residues. Here we show that Tyr763 in the kinase insert region is a novel autophosphorylation site, which after phosphorylation binds the protein tyrosine phosphatase SHP-2. SIGNOR-250258 0.2 SEPTIN7 protein Q16181 UNIPROT CENPE protein Q02224 UNIPROT up-regulates activity binding 9606 BTO:0000567 18460473 t lperfetto These findings reveal a key role for the SEPT7-CENP-E interaction in the distribution of CENP-E to the kinetochore and achieving chromosome alignment. We propose that SEPT7 forms a link between kinetochore distribution of CENP-E and the mitotic spindle checkpoint. SIGNOR-252040 0.2 TFEB protein P19484 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 t lperfetto We found that the main regulator of the starvation-induced transcriptional program, TFEB, counteracts protein synthesis inhibition by directly activating expression of GADD34, a component of the protein phosphatase 1 complex that dephosphorylates eIF2α. SIGNOR-276789 0.2 dothiepin chemical CHEBI:36798 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8100134 t miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. SIGNOR-258697 0.8 KCNJ5 protein P48544 UNIPROT KCNJ5/KCNJ3 complex SIGNOR-C56 SIGNOR form complex binding 9606 BTO:0000562 22362083 t miannu The muscarinic k(+) channel (i (k,ach)) is a heterotetramer composed of girk1 (kir3.1) andgirk4(kir3.4) subunits of a g protein-coupled inwardly rectifying channel, and plays an important role in mediating electrical responses to the vagal stimulation in the heart. SIGNOR-196205 0.484 EP300 protein Q09472 UNIPROT XBP1 protein P17861-2 UNIPROT up-regulates quantity by stabilization acetylation 9606 BTO:0000007 20955178 t miannu P300 increases the acetylation and protein stability of XBP1s, and enhances its transcriptional activity, whereas SIRT1 deacetylates XBP1s and inhibits its transcriptional activity.. The mRNA encoding the active spliced form of XBP1 (XBP1s) is generated from the unspliced form by IRE1 (inositol-requiring enzyme 1) during the UPR. SIGNOR-260429 0.289 UNC5 proteinfamily SIGNOR-PF98 SIGNOR Chemorepulsion_of_axon phenotype SIGNOR-PH198 SIGNOR up-regulates 9606 30108487 f miannu Netrin binding to the receptor deleted in colorectal cancer (DCC) results in attractive responses, viahomodimerization of DCC (covered in detail in later sections), whereas heterodimerization between DCC and receptor uncoordinated locomotion 5 (UNC5) converts this attractive response into repulsion SIGNOR-268177 0.7 PAX6 protein P26367 UNIPROT PCSK1 protein P29120 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19034419 f miannu PAX6 can bind to the promoter and directly upregulate production of prohormone convertase (PC)1/3, an enzyme essential for conversion of proinsulin to insulin. SIGNOR-254900 0.34 CAMK1 protein Q14012 UNIPROT EIF4G3 protein O43432 UNIPROT unknown phosphorylation Ser1156 NTFMRGGsSKDLLDN 9606 14507913 t llicata Endogenous eIF4GII immunoprecipitated from HEK293T cells was phosphorylated by CaMKI, in vitro as was a recombinant fragment of eIF4GII encompassing the central and C-terminal regions. The latter phosphorylation occurred with favorable kinetics (Km = 1 microm; kcat = 1.8 s-1) at a single site, Ser1156, located in a segment of eIF4GII aligning with the phosphoregion of eIF4GI. Phosphopeptide mapping and back phosphorylation experiments revealed [Ca2+]i-dependent, CaMKI site-specific, eIF4GII phosphorylation in vivo. SIGNOR-250613 0.485 MTR protein Q99707 UNIPROT methionine smallmolecule CHEBI:16811 ChEBI up-regulates quantity chemical modification 9606 10520212 t lperfetto Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. SIGNOR-253143 0.8 LYN protein P07948 UNIPROT PPP1R8 protein Q12972 UNIPROT down-regulates activity phosphorylation Tyr264 FAFSGGLyGGLPPTH -1 11104670 t Tyrosine phosphorylation of NIPP1 by Lyn was abolished by the Tyr-264 to Asp mutation. SIGNOR-251405 0.317 PAX5 protein Q02548 UNIPROT PRDM1 protein O75626 UNIPROT down-regulates quantity transcriptional regulation 10090 9120274 t Gianni Overexpression of BSAP reduced Blimp-1 expression in CH12.LX.A2 clones but not in MPC11 clones. In addition, overexpression of BSAP in CH12.LX.A2 cells suppressed spontaneous appearance of cells with high Syndecan-1 expression and high amounts of intracytosolic as well as secreted Ig synthesi SIGNOR-269085 0.516 H4C1 protein P62805 UNIPROT Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR form complex binding -1 20498094 t miannu A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. SIGNOR-263726 0.2 DISC1 protein Q9NRI5 UNIPROT KIF5B protein P33176 UNIPROT up-regulates activity binding 9606 BTO:0000938 17202468 t miannu We identified Kinesin-1, a microtubule-dependent and plus-end directed motor, as a DISC1-interacting molecule. Our results show that DISC1 links Kinesin-1 to the NUDEL/LIS1/14-3-3ε complex, serves as the cargo receptor, and regulates the transport of the complex to axons, leading to axon elongation. DISC1 directly interacted with kinesin heavy chain of Kinesin-1. Kinesin-1 interacted with the NUDEL/LIS1/14-3-3ε complex through DISC1 SIGNOR-252161 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270408 0.8 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89170 0.538 PITX2 protein Q99697 UNIPROT TBX1 protein O43435 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20129917 f Regulation miannu Pitx2 activated Tbx4, Tbx15, and Mga and repressed Tbx1, Tbx2, Tbx5, and Tbx6 expression. SIGNOR-251870 0.43 VEGFA protein P15692 UNIPROT DLL4 protein Q9NR61 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22426001 f gcesareni Activation triggered by vegf-a (also known as vegf) has been shown to induce expression of thenotchligand dll4 in angiogenic vessels. SIGNOR-196736 0.485 DKK1 protein O94907 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 19874086 f Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6. gcesareni It has been shown that both sclerostin and dkk1 act physiologically as downstream molecules of bmp signaling to inhibit canonical wnt signaling and therefore negatively regulate bone mass. SIGNOR-188961 0.724 STMN1 protein P16949 UNIPROT TTL protein Q8NG68 UNIPROT down-regulates binding 9606 23624152 t miannu Stathmin depresses ttl tubulin tyrosination activityin vitro. SIGNOR-193465 0.398 ERG protein P11308 UNIPROT TDRD1 protein Q9BXT4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003215 23319146 f miannu In the prostate cancer cell line VCaP, downregulation of ERG by shRNA lead to a lower expression level of TDRD1 and resulted in a decreased activity of the TDRD1 promoter. SIGNOR-254067 0.2 KIF5A protein Q12840 UNIPROT Organelle_transport phenotype SIGNOR-PH159 SIGNOR up-regulates 9606 BTO:0000938 9438838 f miannu The kinesin superfamily of proteins plays a major role in this complex organelle transport. Kinesin is primarily associated with anterogradely transported membranous organelles in nerve axons. KIF5B and HsuKHC are expressed ubiquitously in many tissues, whereas KIF5A, KIF5C, and HsnKHC are specific to nerve tissue. SIGNOR-264067 0.7 IL3 protein P08700 UNIPROT IL3RA protein P26951 UNIPROT up-regulates binding 9606 1465408 t fspada These results show the generation of an il-3 analog with increased biological and binding activities and support a model where the c terminus of il-3 interacts with the alpha chain of the il-3 receptor, making this region a useful focus for the development of more potent il-3 agonists or antagonists SIGNOR-19538 0.884 MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates phosphorylation 9606 11782488 t gcesareni Kato et al. reported that mek5 specifically activates bmk1 but not other mammalian map kinasesin vivo. SIGNOR-113770 0.691 AKT proteinfamily SIGNOR-PF24 SIGNOR STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr120 IIRLRNKtLTEDEIA 9606 19940129 t llicata Akt interacts with mst1 and phosphorylates a highly conserved residue threonine 120 of mst1, which leads to inhibition of its kinase activity and nuclear translocation as well as the autophosphorylation of thr(183). SIGNOR-161829 0.2 YY1 protein P25490 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates activity binding 9606 BTO:0000664 12913000 t Taken together, these results indicate that transcription factor YY1 may modulate Notch signaling via association with the high molecular weight Notch complex [..] both YY1 and N1IC were present in a large complex of the nucleus to suppress the luciferase reporter activity transactivated by Notch signaling. SIGNOR-254305 0.607 LRRK2 protein Q5S007 UNIPROT SH3GL2 protein Q99962 UNIPROT down-regulates phosphorylation Ser75 LSMINTMsKIRGQEK 9606 22998870 t gcesareni We show that lrrk2 affects synaptic endocytosis by phosphorylating endophilin-a1 at s75. SIGNOR-192072 0.484 ARHGAP23 protein Q9P227 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260479 0.529 IFNAR complex SIGNOR-C243 SIGNOR JAK1 protein P23458 UNIPROT up-regulates activity binding 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260147 0.727 AURKB protein Q96GD4 UNIPROT CENPA protein P49450 UNIPROT unknown phosphorylation Ser7 sRKPEAPR 9606 BTO:0000567 11756469 t llicata CENP-A–GST constructs were prepared in which Ser7 was mutated to alanine or glutamic acid. Phosphorylation of these proteins by Aurora B was reduced by 50%, demonstrating that Ser7 is a kinase substrate | Therefore, under the short term induction conditions used in these experiments, we can conclude that CENP-A Ser7 mutations do not grossly interfere with kinetochore formation, spindle assembly, or cell cycle progression. SIGNOR-250585 0.815 CSNK2A1 protein P68400 UNIPROT XPC protein Q01831 UNIPROT up-regulates activity phosphorylation Ser94 VIKDEALsDGDDLRD 9606 BTO:0000552 29660033 t miannu CK2 kinase mediates XPC phosphorylation at serine 94, and also promotes recruitment of ubiquitinated XPC to the chromatin after UVB irradiation. SIGNOR-277389 0.2 NGEF protein Q8N5V2 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260562 0.661 phenylalanine smallmolecule CHEBI:28044 ChEBI GCHFR protein P30047 UNIPROT down-regulates activity chemical inhibition 9606 11361142 t miannu The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine SIGNOR-252205 0.8 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser740 SFTALDWsWLQTEEE 9606 SIGNOR-C14 SIGNOR-C14 10195894 t lperfetto Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response SIGNOR-236048 0.2 PI4K2A protein Q9BTU6 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates phosphorylation Ser984 ALALCSGsFPTDKEE 9606 18082599 t gcesareni These results indicate that plx1 phosphorylates claspin on s934, which is relatively close to the plx1-docking site at t906. Human claspin also contains a serine at position 984 in a homologous sequence SIGNOR-159937 0.2 PPP2CA protein P67775 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12840032 t gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). SIGNOR-103162 0.633 crizotinib chemical CHEBI:64310 ChEBI ALK protein Q9UM73 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258101 0.8 AMPK complex SIGNOR-C15 SIGNOR HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 21892142 t lperfetto Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs) SIGNOR-216596 0.317 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 10090 12242151 t lperfetto We find short peptides representing the alpha-helical BH3 domains of BID or BIM are capable of inducing oligomerization of BAK and BAX to release cytochrome c. SIGNOR-92939 0.826 Blood vessel damage stimulus SIGNOR-ST26 SIGNOR VWF protein P04275 UNIPROT up-regulates 9606 NBK559062 f lperfetto Exposed VWF bound to collagen from vascular injury and endothelial damage adheres to the GPIb receptor on platelets to initiate signaling pathways for platelet activation, the next step in primary hemostasis. VW|VWF released by Weibel-Palade bodies or alpha-granules can enter circulation or accumulate in the subendothelial matrix binding to collagen through its A3 domain. Once exposed under high shear stress conditions in the arterial circulation, VWF can bind to platelets via its A1 domain. SIGNOR-261862 0.7 glutaryl-CoA(5-) smallmolecule CHEBI:57378 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271812 0.8 PKC proteinfamily SIGNOR-PF53 SIGNOR GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation -1 15894802 t inferred from 70% family members lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-269972 0.2 Neurophysin 1 protein P01178-PRO_0000020496 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates quantity binding 9606 BTO:0000427 9511957 t miannu  Neurophysins I and II (NPI and NPII) serve in the neurosecretory granules of the posterior pituitary as carrier proteins for the neurophyseal hormones oxytocin (OT) and vasopressin (VP), respectively, until the latter are released into blood.  SIGNOR-270351 0.2 EFNA1 protein P20827 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 9576626 t gcesareni Ephrins are cell-surface tethered guidance cues that bind to eph receptor tyrosine kinases in trans on opposing cells. SIGNOR-56968 0.81 E2F1 protein Q01094 UNIPROT SERPINB5 protein P36952 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001938 20197383 f lperfetto Importantly, we show that E2F1-mediated upregulation of maspin is enhanced by chemotherapeutic drugs, and inhibition of maspin expression significantly impairs the ability of E2F1 to promote chemotherapy-induced apoptosis. Summarily, our data indicate that maspin is an important effector of E2F1-induced chemosensitization. SIGNOR-254135 0.2 PRKAA1 protein Q13131 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates activity phosphorylation 9606 SIGNOR-C15 21892142 t lperfetto Ampk was recently found to phosphorylate a conserved serine near the cleavage site within srebp1, suppressing its activation SIGNOR-176497 0.367 CSNK1E protein P49674 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity phosphorylation Tyr116 EILALQIyCRNESRG 9606 BTO:0002181 32779804 t miannu We found that the interaction of CK1ε with TRAF3Y116F, TRAF3Y446F were markedly decreased compared with interactions with WT TRAF3 by Co‐IP (Figure 6C); as expected, TRAF3Y116F and TRAF3Y446F mutants exhibited reduced K63‐linked ubiquitination (Figure 6D). These data suggest that the phosphorylation of TRAF3 at Tyr 116 and Tyr 446 regulate CK1ε‐induced K63‐linked ubiquitination. SIGNOR-277525 0.312 SIRT7 protein Q9NRC8 UNIPROT DDB1 protein Q16531 UNIPROT down-regulates activity deacetylation 28886238 t lperfetto Here, we show that DDB1 is acetylated and acetylation promotes DDB1 binding to CUL4. We also identify nucleolar sirtuin 7 (SIRT7) as a major deacetylase that negatively regulates DDB1-CUL4 interaction. SIGNOR-275900 0.364 SKP2 protein Q13309 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates ubiquitination 9606 15314162 t gcesareni We found that skp2, the f-box component of scfskp2, physically interacted with smad4 at the physiological levels. Several cancer-derived unstable mutants exhibited significantly increased binding to skp2, which led to their increased ubiquitination and accelerated proteolysis. These results suggest an important role for the scfskp2 complex in switching cancer mutants of smad4 to undergo polyubiquitination-dependent degradation. SIGNOR-127964 0.406 MAVS protein Q7Z434 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity binding 9606 25636800 t miannu Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1.  SIGNOR-260143 0.793 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu47 RANSFLEeMKKGHLE -1 9538022 t lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). SIGNOR-263665 0.598 LSM-1231 chemical CHEBI:91471 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258237 0.8 3-(4-quinolinylmethylamino)-N-[4-(trifluoromethoxy)phenyl]-2-thiophenecarboxamide chemical CHEBI:91433 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-195543 0.8 GFPT1 protein Q06210 UNIPROT Protein_glycosylation phenotype SIGNOR-PH144 SIGNOR up-regulates 9606 21310273 f miannu GFPT1 is the key enzyme of the hexosamine pathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation. SIGNOR-267820 0.7 L-thyroxine smallmolecule CHEBI:18332 ChEBI Thermogenesis phenotype SIGNOR-PH192 SIGNOR up-regulates 9606 24692351 f scontino TH plays a significant role in energy expenditure through both central and peripheral actions. TH maintains basal metabolic rate, facilitates adaptive thermogenesis, modulates appetite and food intake, and regulates body weight. SIGNOR-267492 0.7 PARD6A protein Q9NPB6 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 23151663 f gcesareni In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. SIGNOR-199530 0.619 PTPN12 protein Q05209 UNIPROT PTK2B protein Q14289 UNIPROT down-regulates activity dephosphorylation Tyr580 YIEDEDYyKASVTRL 10116 11337490 t Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-PEST-mediated dephosphorylation|CAKbeta was found to be a substrate for PTP-PEST. Both the major autophosphorylation site of CAKbeta (Tyr(402)) and activation loop tyrosine residues, Tyr(579) and Tyr(580), were targeted for dephosphorylation by PTP-PEST. Dephosphorylation of CAKbeta by PTP-PEST dramatically inhibited CAKbeta kinase activity. SIGNOR-248664 0.56 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR MYLPF protein Q96A32 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136726 0.34 GSK3B protein P49841 UNIPROT EIF2B4 protein Q9UI10 UNIPROT down-regulates binding 9606 21798082 t gcesareni Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b). SIGNOR-175572 0.2 ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 14967450 t miannu All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor SIGNOR-256162 0.2 EEF2K protein O00418 UNIPROT EEF2 protein P13639 UNIPROT down-regulates phosphorylation Thr59 GETRFTDtRKDEQER 9606 2261989 t gcesareni Ef-2 kinase phosphorylates ef-2 at 3 threonine residues: thr-53, thr-56, thr-58. Phosphorylation of thr56 and thr58 was found to be an ordered process, modification of thr56 preceding, and apparently being required for, phosphorylation of thr58. SIGNOR-22928 0.78 CYP11B2 protein P19099 UNIPROT 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI down-regulates quantity chemical modification 9606 BTO:0000050 9814482 t lperfetto Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. SIGNOR-268677 0.8 AP-3 complex complex SIGNOR-C247 SIGNOR Platelet_dense_granule_formation phenotype SIGNOR-PH181 SIGNOR up-regulates 9606 BTO:0000132 12019270 f lperfetto BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules|Interestingly, immunofluorescence and in vitro binding experiments demonstrated that pallidin/BLOC-1 is able to associate with actin filaments. We propose that BLOC-1 mediates the biogenesis of lysosome-related organelles by a mechanism that may involve self-assembly and interaction with the actin cytoskeleton. SIGNOR-265942 0.7 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 t irozzo Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. SIGNOR-255878 0.2 HCK protein P08631 UNIPROT HCK protein P08631 UNIPROT up-regulates phosphorylation Tyr411 RVIEDNEyTAREGAK 9606 BTO:0000007 10934191 t gcesareni Tyr(416) is the autophosphorylation site in the activation loop. Autophosphorylation of tyr(416) is required for hck activation. SIGNOR-80340 0.2 MET protein P08581 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity phosphorylation Tyr56 DRPQEVSyTDTKVIG 9606 BTO:0000972 30711629 t miannu  MET phosphorylated and activated GSK3B at tyrosine 56, which decreased the expression of PDL1 by liver cancer cells.  SIGNOR-277428 0.313 nalbuphine chemical CHEBI:7454 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 19282177 t Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. SIGNOR-258041 0.8 PSEN1 protein P49768 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR up-regulates cleavage 9606 10497236 t Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface. lperfetto Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains. SIGNOR-217746 0.956 RAD23B protein P54727 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 9606 16401726 f miannu The XPCB domain of Rad23 binds Png1, which in turn facilitates the substrate recognition of Rad23. Through interactions with Ub chains and the proteasome mediated by the UBA and UBL domains in Rad23, Rad23 facilitates substrate transfer to the proteasome. SIGNOR-261062 0.7 HECTD3 protein Q5T447 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates activity polyubiquitination Lys231 KVYQMKSkPRGYCLI 9606 BTO:0000007 24287696 t miannu HECTD3, a new E3 ubiquitin ligase, interacts with caspase-8 death effector domains and ubiquitinates caspase-8 with K63-linked polyubiquitin chains that do not target caspase-8 for degradation but decrease the caspase-8 activation. HECTD3 ubiquitinates caspase-8 with K63-linked polyubiquitin chains at K215. SIGNOR-272077 0.342 Volasertib chemical CID:10461508 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190290 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR MFN2 protein O95140 UNIPROT up-regulates activity phosphorylation Ser442 AEEIRRLSVLVDDYQ 10090 BTO:0004578 20303493 t Barakat Mitofusin 2 (Mfn2) is an important suppressor of vascular smooth muscle cell (VSMC) proliferation. It contains a protein kinase A (PKA) phosphorylation site at serine 442 (S442) and can be phosphorylated by PKA SIGNOR-274137 0.2 PRKAA1 protein Q13131 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser170 PSALNRTsSDSALHT 9606 SIGNOR-C15 21892142 t gcesareni Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation SIGNOR-176426 0.528 MAP2K3 protein P46734 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity phosphorylation 9534 BTO:0000298 7839144 t Luana Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-260723 0.716 SMARCD1 protein Q96GM5 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270604 0.812 PRKACA protein P17612 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Ser633 WRRKRKEsSNTDSAG 9606 BTO:0001853 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251616 0.373 SMO protein Q99835 UNIPROT ARRB2 protein P32121 UNIPROT up-regulates binding 9606 23074268 t The binding occours if Smo is phosphorylated gcesareni Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2 SIGNOR-199153 0.647 ZAP70 protein P43403 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 BTO:0000782 9710204 t gcesareni The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2). SIGNOR-59651 0.664 RPS8 protein P62241 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262416 0.903 CLOCK protein O15516 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR form complex binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. SIGNOR-267965 0.519 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. SIGNOR-266500 0.8 HDAC2 protein Q92769 UNIPROT CCND1 protein P24385 UNIPROT up-regulates binding 9606 15713663 t gcesareni Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5. SIGNOR-134062 0.481 NTN1 protein O95631 UNIPROT DCC protein P43146 UNIPROT up-regulates activity binding 9606 BTO:0001484 25881791 t miannu DCC (Deleted in Colorectal Cancer) is a single-pass transmembrane protein that belongs to the immunoglobulin superfamily. It was originally identified as a prognostic tumor marker and then subsequently found to be a receptor for netrin-1. DCC plays a key role in axon guidance and also in a number of other important cellular processes. SIGNOR-268162 0.907 CDK1 protein P06493 UNIPROT RAP1GAP protein P47736 UNIPROT unknown phosphorylation Ser484 SLIVPGKsPTRKKSG 9606 1406653 t lperfetto Two of the sites of phosphorylation by cyclic amp (camp)-dependent kinase were localized to serine residues 490 and 499, and one site of phosphorylation by p34cdc2 was localized to serine 484. SIGNOR-18735 0.457 HNF1A protein P20823 UNIPROT SLCO1B3 protein Q9NPD5 UNIPROT up-regulates quantity by expression transcriptional regulation 16741617 t lperfetto Farnesoid X receptor, hepatocyte nuclear factors 1alpha and 3beta are essential for transcriptional activation of the liver-specific organic anion transporter-2 gene.|This study demonstrated that the transcription of the LST-2 gene is regulated by three transcription factors, FXR, HNF1alpha, and HNF3beta. SIGNOR-268988 0.254 LFNG protein Q8NES3 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 11346656 t Fucosylation gcesareni These observations indicate that the fringe proteins directly modify notch2, which is consistent with the recent finding that fringe is a glycosyltransferase that directly modifies notch. It was further indicated that lfng does this at a site from the n terminus through the 15th egf repeat of notch2, and mfng does so at a site from the 23rd through the 29th egf repeat of notch2. SIGNOR-107702 0.685 NTN1 protein O95631 UNIPROT ACTB protein P60709 UNIPROT up-regulates quantity post transcriptional regulation 443947 BTO:0001036 16980963 t miannu Netrin-1 induces β-actin translation driven by its 3’UTR. SIGNOR-268161 0.284 F2RL1 protein P55085 UNIPROT KLF6 protein Q99612 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254841 0.2 ZIC3 protein O60481 UNIPROT GLI3 protein P10071 UNIPROT up-regulates binding 9606 17764085 t lperfetto Zic3 functions as a transcriptional coactivator of gli3 when it physically associates with gli3 SIGNOR-157637 0.382 PLK3 protein Q9H4B4 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates phosphorylation Ser657 ETTSATSsPYRDTQS 9606 BTO:0000567 18519666 t lperfetto Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1 alpha under hypoxic conditionsplk3 can potentially inhibit hif-1_ by physical interaction and direct phosphorylation SIGNOR-178743 0.355 CDH24 protein Q86UP0 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265862 0.532 FFAR4 protein Q5NUL3 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256916 0.252 CDK1 protein P06493 UNIPROT KIFC1 protein Q9BW19 UNIPROT up-regulates quantity by stabilization phosphorylation Ser6 sPLLEVKG -1 24510915 t miannu We confirmed that CDK1 phosphorylates Ser6 (Supplementary Fig S5B) and demonstrated that KIFC1 displays CDK1-mediated resistance to ubiquitination by the APC/C (Fig S5C). SIGNOR-277294 0.469 SMO protein Q99835 UNIPROT ARRB2 protein P32121 UNIPROT up-regulates binding 9606 15618519 t The binding occours if Smo is phosphorylated gcesareni Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2 SIGNOR-132759 0.647 ANGPT4 protein Q9Y264 UNIPROT TEK protein Q02763 UNIPROT up-regulates binding 9606 BTO:0004980 BTO:0000763 15284220 t gcesareni In experiments with human endothelial cell lines, ang3 was identified as an antagonist of tie2 and ang4 was identified as an agonist of tie2. SIGNOR-127351 0.687 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-138479 0.2 ALDH1A3 protein P47895 UNIPROT all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI up-regulates quantity chemical modification 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265129 0.8 SDC4 protein P31431 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 9606 23151663 t gcesareni Like other wnt co-receptors, syndecan 4 directly interacts with dvl during pcp 1. SIGNOR-199632 0.363 IRF7 protein Q92985 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16612387 f miannu Ikkalfa can also phosphorylate and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production. SIGNOR-263128 0.2 TRH protein P20396 UNIPROT TRHR protein P34981 UNIPROT up-regulates activity binding 9606 BTO:0001379 27515033 t scontino When TRH reaches the pars distalis of the pituitary, it regulates cells that express TRH receptor-1 (TRH-R1), such as the thyrotrophs. These cell types are subject to a multifactorial regulation that determines the extent and specificity of their response to TRH. SIGNOR-267200 0.753 CSNK2A1 protein P68400 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser129 SGSPSDNsGAEEMEV 9606 15818404 t gcesareni Akt/pkb ser129 is phosphorylated by ck2 in vitro and in vivo;(4) such a phosphorylation of activated akt/pkb correlates with a further increase in catalytic activity. SIGNOR-135203 0.379 F3 protein P13726 UNIPROT Factor FVIIa:TF complex SIGNOR-C319 SIGNOR form complex binding 9606 BTO:0000131 32665005 t lperfetto During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury. SIGNOR-263556 0.932 F2 protein P00734 UNIPROT F2RL3 protein Q96RI0 UNIPROT up-regulates binding 9606 22318735 t gcesareni Thrombin activates platelets by binding and cleaving protease-activated receptors 1 and 4 (par1 and par4). SIGNOR-196003 0.685 chlorphenamine chemical CHEBI:52010 ChEBI HRH3 protein Q9Y5N1 UNIPROT down-regulates activity chemical inhibition -1 12781173 t Luana Identification of a dual histamine H1/H3 receptor ligand based on the H1 antagonist chlorpheniramine. SIGNOR-257897 0.8 SMO protein Q99835 UNIPROT TIAM1 protein Q13009 UNIPROT up-regulates binding 9606 BTO:0000785 23074268 t gcesareni This latter work suggested that inactive smo prevents rac1 activation by interacting with the rac guanine nucleotide exchange factor (gef) t-lymphoma invasion and metastasis 1 (tiam1). This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1 SIGNOR-199192 0.27 FASN protein P49327 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 15507492 t miannu Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-268086 0.8 MAPK1 protein P28482 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Ser395 PSVNPSIsPAHGVAR 9606 10660621 t lperfetto Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene. SIGNOR-74876 0.371 Viral_replication stimulus SIGNOR-ST23 SIGNOR Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR up-regulates 9606 31226023 f miannu Double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. SIGNOR-260587 0.7 SF1 protein Q15637 UNIPROT EWSR1 protein Q01844 UNIPROT down-regulates binding 9606 9660765 t miannu Here we report that zfm1 also interacts withews / overexpression of zfm1 in hepg2 cells represses the transactivation of reporter gene expression driven by gal4-ews-ntd fusion protein and this repression correlates with zfm1 binding to ews. SIGNOR-58928 0.427 UBE2D3 protein P61077 UNIPROT ZSWIM2 protein Q8NEG5 UNIPROT up-regulates activity binding 9606 BTO:0000007 16522193 t miannu MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin.  SIGNOR-271557 0.337 CIB2 protein O75838 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR up-regulates activity binding 9606 35408910 t miannu So far, two integrins have been found to interact with CIB2: αIIbβ3 is expressed by platelets and megakaryocytes and, apparently, a common target for all CIB family members, at odds with α7Bβ1D, which seems to be CIB2-specific and is expressed in skeletal muscles. SIGNOR-269669 0.2 TXNIP protein Q9H3M7 UNIPROT DDIT4 protein Q9NX09 UNIPROT up-regulates quantity by stabilization binding 9606 21460850 t miannu  In the present study, we identify TXNIP that inhibits mTOR activity by binding to and stabilizing Redd1 protein.  SIGNOR-277470 0.522 MAPK3 protein P27361 UNIPROT BAG3 protein O95817 UNIPROT down-regulates quantity by destabilization phosphorylation Ser377 PVPCPPPsPGPSAVP 9606 BTO:0002181 34215846 t miannu We further demonstrated BAG3, a HSP70 co-chaperone, is a bona fide substrate of SCFFBXO22. FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BAG3 phosphorylation at S377. SIGNOR-277318 0.317 HRAS protein P01112 UNIPROT GATA2 protein P23769 UNIPROT up-regulates activity phosphorylation Ser192 PSTTGAAsPASSSAG 9606 25056917 f Oncogenic Ras enhanced S192-dependent GATA-2 phosphorylation, nuclear foci localization, and transcriptional activation. These studies define a mechanism that controls a key regulator of hematopoiesis and a dual mode of impairing GATA-2-dependent genetic networks: mutational disruption of chromatin occupancy yielding insufficient GATA-2, and oncogenic Ras-mediated amplification of GATA-2 activity SIGNOR-259945 0.363 SFRP1 protein Q8N474 UNIPROT Wnt proteinfamily SIGNOR-PF40 SIGNOR down-regulates binding 9606 BTO:0000782 10347172 t gcesareni Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling. SIGNOR-262527 0.786 CSTF3 protein Q12996 UNIPROT CSTF complex complex SIGNOR-C441 SIGNOR form complex binding 9606 10669729 t lperfetto We therefore first identified regions of the CstF subunits, CstF-77, CstF-64, and CstF-50, required for interaction with each other.  SIGNOR-268367 0.954 ERG protein P11308 UNIPROT ADAMTS1 protein Q9UHI8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 19396168 f miannu ADAMTS1 and CXCR4, two candidate genes strongly associated with cell migration, were upregulated in the presence of ERG overexpression. SIGNOR-253910 0.2 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1948 SPTSPGYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273086 0.745 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273087 0.745 RBM42 protein Q9BTD8 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270645 0.313 MAPK14 protein Q16539 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates activity phosphorylation Ser93 ALQRQPPsPKQLEEE -1 10206983 t miannu The noncatalytic N terminus of HePTP binds Erk and p38 and is phosphorylated at Ser-72 and Thr-45 by these kinases. the N terminus of HePTP binds Erk and p38 but may release them upon phosphorylation.it is clear that phosphorylation of HePTP at Thr-45 and/or Ser-72 is not required for inhibition of MAP kinase. Rather, it seems that phosphorylation has the opposite effect, namely to lessen the inhibitory effect of HePTP. SIGNOR-250109 0.585 TAF1C protein Q15572 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR form complex binding 9606 30693017 t lperfetto SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation. SIGNOR-269564 0.798 SWI/SNF complex complex SIGNOR-C92 SIGNOR CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18332116 f irozzo HSNF5 reexpression in MRT cells caused SWI/SNF recruitment and activation of p15INK4b and p16INK4a, but not of p14ARF.Reexpression of hSNF5 in MRT cells overcomes epigenetic silencing and mediates transcriptional activation of p15INK4b and p16INK4a SIGNOR-256299 0.358 TP53BP2 protein Q13625 UNIPROT PPP1R14A protein Q96A00 UNIPROT down-regulates binding 9606 8549741 t gcesareni The phosphorylase phosphatase activity of pp1 was inhibited by p53bp2 at nanomolar concentrations. SIGNOR-39666 0.2 MAPK1 protein P28482 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates 9606 BTO:0000130 16709866 f gcesareni The role of members of the arrestin family to mediate kinase activation is also a well-established phenomenon, including activation of members of the src family, erk1/2, and jnk3. Activation often includes the recruitment and interaction of arrestins with upstream mapks (ask1, mek3, mkk3, and mek kinase-2). SIGNOR-146751 0.326 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT down-regulates activity phosphorylation Ser222 EVEEEADsCFGDDED 9606 BTO:0000567 11546811 t lperfetto The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm. SIGNOR-110395 0.403 INS protein P01308 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization 9606 17360977 f lperfetto Research has focused on insulin receptor substrate (IRS)-1 as a locus for insulin resistance. Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signal. Insulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 SIGNOR-236737 0.668 MAPK10 protein P53779 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 20395206 t gcesareni With epidermal growth factor treatment, overexpression of erk8 in jb6 cl41 cells caused an increased phosphorylation of c-jun at ser(63) and ser(73), resulting in increased activator protein-1 transactivation. SIGNOR-164800 0.883 SLC2A5 protein P22732 UNIPROT D-fructofuranose smallmolecule CHEBI:37721 ChEBI up-regulates quantity relocalization 9606 28083649 t Although increased dietary fructose consumption is associated with metabolic impairments, the mechanisms and regulation of intestinal fructose absorption are poorly understood. GLUT5 is considered to be the main intestinal fructose transporter. SIGNOR-267493 0.8 PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr1179 GLENGLNyIDLDLVK 9606 10660596 t gcesareni The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. SIGNOR-74856 0.894 PTPRG protein P23470 UNIPROT INSR protein P06213 UNIPROT up-regulates activity dephosphorylation Tyr999 YASSNPEyLSASDVF -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254703 0.373 MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f lperfetto We observed that the homeodomain factor pbx1, which cooperates with myod to stimulate myogenin expression, is constitutively bound to the myogenin promoter in a swi/snf-independent manner, suggesting a two-step mechanism in which myod initially interacts indirectly with the myogenin promoter and attracts chromatin-remodeling enzymes, which then facilitate direct binding by myod and other regulatory proteins. SIGNOR-135984 0.437 POT1 protein Q9NUX5 UNIPROT POT1/ACD complex SIGNOR-C64 SIGNOR form complex binding 9606 17237768 t miannu We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme. SIGNOR-152324 0.88 PAK1 protein Q13153 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser305 IKRSKKNsLALSLTA 9606 BTO:0000149 12374744 t lperfetto Pak1 directly phosphorylated the activation function-2 domain of the er at the n-terminal residue ser305, and its mutation to ala (s305a) abolished the pak1-mediated phosphorylation and transactivation functions of the er SIGNOR-94206 0.549 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 1756735 t gcesareni The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2. SIGNOR-21556 0.675 NSMCE3 protein Q96MG7 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR form complex binding -1 27427983 t miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks SIGNOR-265485 0.2 aclidinium chemical CHEBI:65346 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 9606 19653626 t Luana This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. SIGNOR-258151 0.8 CTNNB1 protein P35222 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity binding 10090 BTO:0003346 16847334 t Oncogenic beta-catenin resists proteasomal degradation by inhibiting PPARgamma activity, which requires its TCF/LEF binding domain SIGNOR-256072 0.554 LPAR2 protein Q9HBW0 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256927 0.252 dopamine smallmolecule CHEBI:18243 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258377 0.8 FZD1 protein Q9UP38 UNIPROT CEBPA protein P49715 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma) SIGNOR-80595 0.2 PAK proteinfamily SIGNOR-PF13 SIGNOR MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser298 RTPGRPLsSYGMDSR 9606 BTO:0000567 16129686 t gcesareni Inhibition of pak kinase activity dramatically decreased phosphorylation of mek1 at ser(298) in response to either pdgf or egf. SIGNOR-140039 0.2 FNTB protein P49356 UNIPROT MRAS protein O14807 UNIPROT up-regulates activity 9606 24294527 t lperfetto Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. SIGNOR-242562 0.276 R547 chemical CID:6918852 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258273 0.8 RNF4 protein P78317 UNIPROT NFYC protein Q13952 UNIPROT up-regulates activity binding 9606 15496512 t miannu Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter. SIGNOR-252231 0.2 ESR1 protein P03372 UNIPROT GREB1 protein Q4ZG55 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 17666587 f miannu Long-range activation of GREB1 by estrogen receptor via three distal consensus estrogen-responsive elements in breast cancer cells. . GREB1 (gene regulated by estrogen in breast cancer 1) is an ER target gene that regulates estrogen-induced proliferation in breast cancer cells. SIGNOR-254074 0.703 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser615 VPESSKIsQENEIGK 9606 10839545 t lperfetto In vivo, nbs was phosphorylated on many serine residues, of which s343, s397 and s615 were phosphorylated by atm in vitro. Reconstituting nbs cells with a mutant form of nbs that cannot be phosphorylated at selected, atm-dependent serine residues led to a specific reduction in clonogenic survival after gamma-radiation. SIGNOR-78034 0.851 SDC4 protein P31431 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 23151663 t gcesareni Like other wnt co-receptors, syndecan 4 directly interacts with dvl during pcp 1. SIGNOR-199638 0.249 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr1179 GLENGLNyIDLDLVK 9606 17827393 t gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157730 0.864 CDK4 protein P11802 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 t gcesareni In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-176518 0.287 MAPK1 protein P28482 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Thr57 NFDFVTEtPLEGDFA 9606 19364816 t lperfetto We have shown that erk2 interacts with and phosphorylates p21cip1, promoting p21cip1_ubiquitination. We identified two erk2 phosphorylation sites, thr57 and ser130, in p21cip1_and showed that phosphorylation of these residues increases p21cip1_cytoplasmic distribution and proteasome-dependent degradation. SIGNOR-185219 0.372 CSNK1A1 protein P48729 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser79 QRMGSSEsTDSGFCL 9606 20348946 t lperfetto Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a SIGNOR-164734 0.339 SMAD1 protein Q15797 UNIPROT HAND1 protein O96004 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 t Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation SIGNOR-268936 0.2 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser923 DELRDSDsVCDSGVE 9606 BTO:0000567 SIGNOR-C13 10469655 t lperfetto All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391). SIGNOR-70449 0.737 PGK2 protein P07205 UNIPROT 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. SIGNOR-266503 0.8 2-cyclohexyl-6-methoxy-N-(1-propan-2-yl-4-piperidinyl)-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine chemical CHEBI:95074 ChEBI EHMT1 protein Q9H9B1 UNIPROT down-regulates activity chemical inhibition -1 26320100 t miannu Using a small-molecule screen, we found that UNC0638, a selective inhibitor of EHMT1 and EHMT2 histone methyltransferases, induces γ-globin expression. SIGNOR-262239 0.8 BTK protein Q06187 UNIPROT ITK protein Q08881 UNIPROT up-regulates phosphorylation Tyr180 ETVVIALyDYQTNDP 9606 12573241 t lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanismthe major phosphorylation sites were identified as conserved tyrosines, for itk y180 SIGNOR-98036 0.475 IL1B protein P01584 UNIPROT LPL protein P06858 UNIPROT down-regulates activity 9606 1572904 f Regulation miannu IL-1 beta also depressed adipoconversion, inhibited markedly LPL activity, and partially reduced GPDH activity. SIGNOR-251856 0.294 MMP9 protein P14780 UNIPROT HAPLN1 protein P10915 UNIPROT down-regulates quantity by destabilization cleavage His31 LDHDRAIhIQAENGP -1 7694569 t miannu Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix. SIGNOR-256328 0.348 AREL1 protein O15033 UNIPROT SEPTIN4 protein O43236 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23479728 t lperfetto Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists SIGNOR-267670 0.2 PVR protein P15151 UNIPROT TIGIT protein Q495A1 UNIPROT up-regulates activity binding 9606 30591568 t lperfetto Poliovirus receptor (PVR/CD155) is a ligand of the paired NK receptors, DNAM-1 (activating) and TIGIT (inhibiting). NK cells can kill cancer cells expressing PVR via the DNAM-1-mediated activating signaling (11,12). SIGNOR-261425 0.867 BCL3 protein P20749 UNIPROT CTCF protein P49711 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004298 21912613 f miannu In the present study, we report that regulation of CTCF by extracellular stress signals is dependent upon activations of an oxidative stress-regulated protein Bcl-3. We found that activated Bcl-3 was able to bind to the κB sites identified in the CTCF promoter region. Bcl-3 was activated by UV irradiation to interact with NF-κB p50 by forming a Bcl-3/p50 heterodimer complex. The Bcl-3/p50 complex suppressed CTCF promoter activity to down-regulate CTCF transcription. SIGNOR-253757 0.306 dovitinib; bis(lactic acid) chemical CID:56973714 PUBCHEM KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191421 0.8 CSNK2A1 protein P68400 UNIPROT SSB protein P05455 UNIPROT up-regulates phosphorylation Ser366 GKKTKFAsDDEHDEH 9606 18257391 t gcesareni Prior studies indicate that hla is activated by phosphorylation of serine-366 by protein kinase ck2, neutralizing a negative effect of a short basic motif (sbm) SIGNOR-160761 0.342 TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 18545270 t lperfetto Tradd recruits fadd SIGNOR-177958 0.773 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EGFR protein P00533 UNIPROT down-regulates phosphorylation Thr693 RELVEPLtPSGEAPN 9606 10816576 t lperfetto It is likely that the map2 and ert kinases account for the phosphorylation of the egf receptor at thr669 (egf receptor (krel veplt669psgeapnqallr)) observed in cultured cells.Phosphorylation at ser-695 is partial and occurs only if thr-693 is phosphorylated. Phosphorylation at thr-678 and thr-693 by prkd1 inhibits egf-induced mapk8/jnk1 activation. SIGNOR-244529 0.2 MAPK1 protein P28482 UNIPROT NR4A2 protein P43354 UNIPROT up-regulates phosphorylation Ser126 SVYYKPSsPPTPTTP 9606 BTO:0000938 BTO:0000142 17681692 t llicata We have shown that erk2 is a kinase to phosphorylate nurr1 on multiple sites. S126 and t132, which are located near af1 core of nurr1, are dominant sites phosphorylated by erk2. reporter gene assays show that nurr1delta124-133/t185a, an erk2 phospho-site mutant form, could not further increase its transcriptional activity on th promoter, suggesting that nurr1 phosphorylation by erk2 may regulate its transcriptional activity on th promoter. SIGNOR-157167 0.404 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr128 SKAQQGLyQVPGPSP 9606 11019781 t lperfetto Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas. SIGNOR-82760 0.259 MAPK3 protein P27361 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser343 KSDCQPNsPTESCSS 9606 BTO:0000782;BTO:0000785 9649500 t gcesareni Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway. SIGNOR-58493 0.415 ALDOA protein P04075 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266479 0.8 GALP protein Q9UBC7 UNIPROT GALR2 protein O43603 UNIPROT up-regulates binding 9606 10601261 t gcesareni Galp is therefore an endogenous ligand that preferentially binds the galr2 receptor SIGNOR-73143 0.442 masitinib chemical CHEBI:63450 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258245 0.8 SMAD2 protein Q15796 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR form complex binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 t gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235188 0.709 EREG protein O14944 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0000150 9419975 t Epiregulin may be a mediator of localized cell proliferation gcesareni Chemical cross-linking experiments showed that [125i]epiregulin directly bound to each of egfr and erbb-4 but not to erbb-2 and erbb-3. remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling. SIGNOR-54351 0.889 HTR2A protein P28223 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257137 0.591 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252877 0.697 ERBB3 protein P21860 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 16729043 t gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. SIGNOR-146870 0.331 ME1 protein P48163 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity chemical modification 9606 33064660 t miannu Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. SIGNOR-267723 0.8 N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide chemical CHEBI:94793 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck lperfetto SIGNOR-244820 0.8 NR5A2 protein O00482 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 f miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254872 0.418 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1924 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273088 0.745 IFTAP protein Q86VG3 UNIPROT BTF3 protein P20290 UNIPROT down-regulates activity binding 9606 BTO:0000567 18433331 t lperfetto Furthermore, we co-immunoprecipitated HEPIS with BTF3, a component of the RNA pol II initiation complex, and observed reduced proliferation of HeLa cells transfected with the HEPIS gene. SIGNOR-260252 0.2 ITGB4 protein P16144 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 9428518 t gcesareni Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation. SIGNOR-54703 0.2 FBXW11 protein Q9UKB1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 9784611 t gcesareni we conclude that beta-trcp is a component of an e3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated beta-catenin.We Found that the binding of beta-trcp to beta-catenin was direct SIGNOR-60751 0.736 TNFRSF11A protein Q9Y6Q6 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 9606 10075662 f miannu RANK activates NF-κB by interacting with TRAF6 via a novel TRAF6 interaction motif and TRAF6 potentially activates NIK, leading to NF-κB activation. SIGNOR-253047 0.262 ITGB1BP1 protein O14713 UNIPROT AX/b2 integrin complex SIGNOR-C171 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257652 0.318 PPP2CB protein P62714 UNIPROT PRKCB protein P05771-2 UNIPROT down-regulates activity dephosphorylation Thr641 TRHPPVLtPPDQEVI 10116 8749392 t Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme. SIGNOR-248587 0.458 NFY complex SIGNOR-C1 SIGNOR CCNB1 protein P14635 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 BTO:0000887;BTO:0001103 10362252 f lperfetto In conclusion, our data demonstrate that nf-y is required for cyclin b1 promoter activity. SIGNOR-235834 0.363 MAPK14 protein Q16539 UNIPROT MEF2A protein Q02078 UNIPROT unknown phosphorylation Ser408 SIKSEPIsPPRDRMT 9606 BTO:0000938 BTO:0000887 12586839 t lperfetto A p38 mapk-induced phosphopeptide with no mapk consensus the phosphorylation site is identified as ser-408 SIGNOR-98224 0.646 CAMK1 protein Q14012 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 BTO:0000887 11114197 t gcesareni Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation. SIGNOR-85018 0.429 PRKCD protein Q05655 UNIPROT DAP3 protein P51398 UNIPROT up-regulates phosphorylation Thr237 ITRVRNAtDAVGIVL 9606 18227431 t amattioni Dap3 is phosphorylated by protein kinase cdelta on thr237. Dap3 was originally identified as a pro-apoptotic protein. The mutation of the phosphorylation site thr237 to alanine reversed the cell death caused by the wild-type dap3 SIGNOR-160488 0.2 BCOR protein Q6W2J9 UNIPROT BCL6 protein P41182 UNIPROT up-regulates activity binding 9606 BTO:0000007 10898795 t miannu In this study we have shown that BCoR interacts with BCL-6 and potentiates transcriptional repression by BCL-6 with striking specificity. SIGNOR-252235 0.882 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252657 0.8 NANOG protein Q9H9S0 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003298 22795133 t lperfetto Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation SIGNOR-253157 0.443 AKT proteinfamily SIGNOR-PF24 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000222 BTO:0000887;BTO:0001760 10576741 t gcesareni The stage-specific inhibitory action of Akt correlated with its stage-specific ability to form a complex with Raf, suggesting the existence of differentially expressed mediators of an inhibitory Akt-Raf complex. SIGNOR-72669 0.2 CDK5 protein Q00535 UNIPROT EPRS1 protein P07814 UNIPROT down-regulates phosphorylation Ser886 LSQSSDSsPTRNSEP 9606 BTO:0000801 21220307 t lperfetto Ser(886) phosphorylation is required for the interaction of nsap1, which blocks eprs binding to target mrnas. The same phosphorylation event induces subsequent binding of ribosomal protein l13a and gapdh and restores mrna binding. Ifn-_ activates cdk5 to phosphorylate ser(886) in the linker domain of glutamyl-prolyl trna synthetase (eprs), the initial event in assembly of the gait complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of ser(999), the second essential event in gait pathway activation SIGNOR-171138 0.2 HDAC1 protein Q13547 UNIPROT VDR protein P11473 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 18485278 f miannu We have shown here that the transcriptional repressor protein SLUG inhibits the expression of VDR in human breast cancer cells. SIGNOR-255179 0.393 NKX2-1 protein P43699 UNIPROT SFTPB protein P07988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004299 18003659 f miannu TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. SIGNOR-254172 0.484 CSNK1A1 protein P48729 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 16341017 t gcesareni We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin. SIGNOR-143037 0.534 DCN protein P07585 UNIPROT FBN1 protein P35555 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0000951 17200203 f Regulation miannu Decorin Induces Fibrillin-1 Protein Expression in NRK Cells via IGF-IR. we report a novel mechanism of action that involves two key molecules: decorin, a small leucine-rich proteoglycan, and the IGF-IR. These two players, together with the downstream signaling pathway evoked by decorin-mediated activation of the receptor, lead to an enhanced translation of fibrillin-1 and its deposition in the extracellular environment both in vitro and in vivo. SIGNOR-251893 0.577 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0001271 BTO:0000671 14551213 t gcesareni The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases these include epidermal growth factor receptor (egfr) kinase,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1 SIGNOR-118600 0.709 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 BTO:0003807 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-235937 0.74 TTM complex complex SIGNOR-C305 SIGNOR Shelterin complex complex SIGNOR-C306 SIGNOR up-regulates activity relocalization 9606 BTO:0000007 33015044 t lperfetto The shelterin complex has six proteins, containing TRF1, TRF2, POT1, RAP1, TIN2, and TPP1. The shelterin complex is localized to the chromosome end and protects telomeric DNA (Palm and de Lange, 2008). The TTM complex acts as a “linker” and bridges the LINC and shelterin complexes together. The connection between TTM and shelterin complexes is well-known, which is mediated by TERB1 and TRF1 SIGNOR-263308 0.2 MC4R protein P32245 UNIPROT GNAS protein P84996 UNIPROT up-regulates activity 9606 22215617 t lperfetto We hypothesize that XLαs may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus. SIGNOR-253067 0.501 3-[(2-Bromo-4,5-dimethoxyphenyl)methyl]-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one chemical CID:44436444 PUBCHEM ACHE protein P22303 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001239 17888667 t Luana AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE. SIGNOR-257760 0.8 GFI1 protein Q99684 UNIPROT BAX protein Q07812 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 17213822 f miannu Our results suggest that the interaction between ETS1 and GFI1 facilitates their binding to specific sites on the Bax promoter and represses Bax expression in vivo. SIGNOR-254203 0.2 125-L-serine-2-133-interleukin 2 (human reduced) smallmolecule SID:46508054 ChEBI IL2RG protein P31785 UNIPROT up-regulates activity chemical activation 9606 18031103 t miannu Aldesleukin (recombinant IL-2) has similar pharmacodynamic properties to endogenous IL-2 and, when administered to patients with cancer, stimulates the antitumour immune response. SIGNOR-259390 0.8 ABL1 protein P00519 UNIPROT WASL protein O00401 UNIPROT unknown phosphorylation Tyr175 EITTNRFyGPQVNNI 10090 16199863 t gcesareni Mutation of both tyrosines 175 and 256 to phenylalanine was required to abolish Abl-mediated phosphorylation of N-WASP in the presence of Grb2 [€] suggesting that phosphorylation at tyrosine 175 is not critical for comet tail formation by Shigella SIGNOR-247666 0.566 DLG3 protein Q92796 UNIPROT Scribble_complex_DLG3-LLGL1_variant complex SIGNOR-C507 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270897 0.519 Hexocyclium chemical CHEBI:5707 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258397 0.8 ACOT8 protein O14734 UNIPROT glutaryl-CoA(5-) smallmolecule CHEBI:57378 ChEBI down-regulates quantity chemical modification 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271814 0.8 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCND1 protein P24385 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189972 0.8 AR protein P10275 UNIPROT SERPINB5 protein P36952 UNIPROT down-regulates quantity by repression transcriptional regulation 16304843 t lperfetto In addition, androgen receptor (AR) can recognize and bind to the ARE element, and then inhibit the activity of maspin promoter SIGNOR-253685 0.411 risperidone chemical CHEBI:8871 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258840 0.8 PRKG1 protein Q13976 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser784 GVPFRRPsTFGIPRL 9606 BTO:0000671 12082086 t lperfetto G-kinase phosphorylated tfii-i in vitro and in vivo on ser(371) and ser(743) outside of the interaction domain. G-kinase strongly enhanced tfii-i transactivation of a serum-response element-containing promoter in cos7 cells SIGNOR-89853 0.555 CAMKK2 protein Q96RR4 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 BTO:0000567 SIGNOR-C15 15980064 t gcesareni These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo. SIGNOR-138364 0.607 AARS1 protein P49588 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 32314272 t miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). SIGNOR-270448 0.8 KIF13A protein Q9H1H9 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR up-regulates relocalization 9606 30404817 t lperfetto Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis. SIGNOR-260703 0.299 aliskiren chemical CHEBI:601027 ChEBI REN protein P00797 UNIPROT down-regulates activity chemical inhibition 9606 18307734 t Luana Aliskiren has a low bioavailality (between 2.6 and 5.0%) compensated by its high potency to inhibit renin (IC50: 0.6 nmol/L) and a long plasma half-life (23–36 h) SIGNOR-257771 0.8 UV stress stimulus SIGNOR-ST7 SIGNOR KRT14 protein P02533 UNIPROT up-regulates 9606 11875647 f miannu UVB increases keratin 5 and keratin 14 expression through direct activation of the EGF receptor in SVHK. SIGNOR-251900 0.7 THOC2 protein Q8NI27 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 t miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. SIGNOR-268509 0.941 pyruvate smallmolecule CHEBI:15361 ChEBI (S)-lactate smallmolecule CHEBI:16651 ChEBI up-regulates quantity precursor of 9606 24929216 t lperfetto Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. SIGNOR-267655 0.8 RIPK1 protein Q13546 UNIPROT IKBKG protein Q9Y6K9 UNIPROT up-regulates activity binding 9606 SIGNOR-C14 16603398 t lperfetto Interestingly, polyubiquitinated rip1 recruits ikk through the binding between the polyubiquitin chains and nemo, a regulatory subunit of the ikk complex. Mutations of nemo that disrupt its polyubiquitin binding also abolish ikk activation. SIGNOR-145858 0.912 INSR protein P06213 UNIPROT DOK4 protein Q8TEW6 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 f gcesareni Irs5/dok4 and irs6/dok5 represent two new signaling proteins with potential roles in insulin and igf-1 action. SIGNOR-101005 0.378 CHEK2 protein O96017 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates quantity by stabilization phosphorylation Ser364 PLLSRMGsLRAPVDE 9606 12717439 t lperfetto We report that checkpoint kinase 2 (chk2) regulates e2f-1 activity in response to the dna-damaging agent etoposide. A chk2 consensus phosphorylation site in e2f-1 is phosphorylated in response to dna damage SIGNOR-100898 0.5 CHEK2 protein O96017 UNIPROT SOD1 protein P00441 UNIPROT up-regulates activity phosphorylation Ser99 KDGVADVsIEDSVIS 4932 24647101 t ROS signaling is mediated by Mec1/ATM and its effector Dun1/Cds1 kinase, through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60, 99. In the nucleus, Sod1 binds to the promoters and regulates the expression of oxidative resistance and repair genes. SIGNOR-262795 0.384 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254354 0.7 STAT3 protein P40763 UNIPROT VEGFA protein P15692 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12545153 t luana Stat3 directly regulated the promoter of the VEGF gene. Blockade of activated Stat3 by ectopic expression of dominant-negative Stat3 significantly inhibited VEGF expression, and the growth and metastasis of human pancreatic cancer cells.  SIGNOR-259456 0.778 AKT1 protein P31749 UNIPROT RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 t llicata Akt regulates ranbp3 phosphorylation in vitro and in vivo SIGNOR-252504 0.366 TNFRSF17 protein Q02223 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates 9606 10903733 f miannu Overexpression of bcma activates the p38 mapk SIGNOR-79495 0.2 WNT6 protein Q9Y6F9 UNIPROT MYF5 protein P13349 UNIPROT up-regulates 9606 9753670 f gcesareni Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. SIGNOR-60415 0.314 MAPK3 protein P27361 UNIPROT MAGEA11 protein P43364 UNIPROT up-regulates phosphorylation Ser174 ESPSPPQsPQEESFS 9606 BTO:0000848 19828458 t llicata Mage-11 ser-174 appears to be a post-translational regulatory site phosphorylated by erk1, based on the inhibitory effect of the s174a mutation in the context of shorter ar nh2-terminal fragments (19), and the greater transcriptional activity of gal-mage-11 fusion proteins containing the s174d phosphomimetic. SIGNOR-188466 0.304 RPS6K proteinfamily SIGNOR-PF26 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 7838153 t gcesareni Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii. SIGNOR-252807 0.2 CAMK2A protein Q9UQM7 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000661 16982419 t gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. In vitro, ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. Altogether, our results favor an association of cam kinase ii activity with costimulatory signals of t lymphocyte activation and phosphorylation of stathmin on ser16. SIGNOR-149640 0.377 arachidonic acid smallmolecule CHEBI:15843 ChEBI FOS protein P01100 UNIPROT up-regulates 9606 15878913 f miannu AA increases PC-3 prostate tumor cell growth, total DNA content and endogenous PGE 2 levels via induction of c-fos , cPLA 2 and cox-2 mRNA transcription. SIGNOR-255392 0.8 PCDHAC1 protein Q9H158 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-269032 0.2 P2RY1 protein P47900 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257339 0.402 UCHL5 protein Q9Y5K5 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates quantity by stabilization binding 9606 17052192 t gcesareni Smad7 can act as an adaptor able to recruit uch37 to the type i tgf-beta receptor. Consequently, uch37 dramatically up-regulates tgf-beta-dependent gene expression by de-ubiquitinating and stabilizing the type i tgf-beta receptor. SIGNOR-150135 0.484 NUMB protein P49757 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates BTO:0001103 12361602 t apalma Therefore, these genetic data further support the hypothesis that activation of Notch-1 promotes a less committed myogenic phenotype and that the attenuation of Notch-1 activity by Numb promotes progression along the myogenic lineage toward a myoblast cell fate. SIGNOR-255375 0.79 spironolactone chemical CHEBI:9241 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition -1 18038968 t Luana Results of the RALES trial (Randomized Aldactone Evaluation Study) demonstrated that the published MR antagonist spironolactone, added to standard therapy, reduced mortality due to all causes by 30% as well as reduced hospitalizations and improved cardiac function in patients with severe heart failure.2 SIGNOR-257762 0.8 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 14963330 t gcesareni Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program SIGNOR-121895 0.743 AKT2 protein P31751 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE 9606 10377430 t lperfetto Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus. SIGNOR-68656 0.644 RASGEF1A protein Q8N9B8 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-183826 0.402 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr179 GGPAQDIyQVPPSAG 10090 12972425 t lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs SIGNOR-246389 0.796 WWTR1 protein Q9GZV5 UNIPROT NKX2-1 protein P43699 UNIPROT up-regulates binding 9606 BTO:0000887 16397409 t gcesareni Taz also binds to the transcription factor ttf-1 that is involved in formation and differentiation of the lungs and respiratory epithelia, and stimulates the production of pulmonary surfactant. SIGNOR-143472 0.435 ZMYND8 protein Q9ULU4 UNIPROT CD44 protein P16070 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 27477906 t lperfetto Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported SIGNOR-262039 0.2 CASP1 protein P29466 UNIPROT Pyrin inflammasome complex SIGNOR-C226 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256412 0.724 p38 proteinfamily SIGNOR-PF16 SIGNOR NFATC4 protein Q14934 UNIPROT down-regulates phosphorylation Ser170 GGAFFSPsPGSSSLS 9606 11997522 t lperfetto Phosphorylation of nfatc4 by p38 mitogen-activated protein kinasesthe p38 map kinase phosphorylates multiple residues, including ser(168) and ser(170), in the nfat homology domain of nfatc4. Replacement of ser(168,170) with ala promotes nuclear localization of nfatc4 and increases nfat-mediated transcription activity. SIGNOR-87397 0.2 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates phosphorylation Tyr771 ADIESSNyMAPYDNY 9606 1314164 t llicata Mutagenesis studies show that tyr740 and 751 are involved in the pdgf-stimulated binding of phosphatidylinositol (pi) 3 kinase, and tyr771 is required for efficient binding of gap, the gtpase activator of ras. SIGNOR-16892 0.2 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr627 KGDKQVEyLDLDLDS 10090 BTO:0000944 10978177 t HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin SIGNOR-251316 0.492 MYCT1 protein Q8N699 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30283340 f miannu MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. SIGNOR-261730 0.2 RPS6KA3 protein P51812 UNIPROT NR4A1 protein P22736 UNIPROT unknown phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 BTO:0000007 16223362 t lperfetto In the present paper, we have re-examined the phosphorylation of Nur77 on Ser354. Using a combination of cell-permeable kinase inhibitors and mouse knockin mutations, we show that Nur77 is phosphorylated by RSK in response to mitogenic stimulation of cells. Phosphorylation of Nur77 on Ser354 did not, however, appear to affect the transcriptional activity of Nur77, or its ability to bind 14-3-3 proteins in vivo. SIGNOR-249295 0.477 NF2 protein P35240 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates binding 9606 24012335 t The opposite changes in Lats/YAP and Mst1/2 phosphorylation upon loss of NF2 therefore argue against the generally assumed linear model in which NF2 signals through activation of Mst1/2 flangone As expected, the nf2-/- fc-912 cells were defective in lats1/2 phosphorylation (figure s2e-f). Subcellular fractionation revealed a significant increase of endogenous lats1/2 in the cytoplasmic relative to the membrane fraction in the nf2-/- fc-912 schwann cells compared to the nf2+/+ fh-912 schwann cells (figure 2e). This localization defect was rescued by re-expression of nf2 SIGNOR-202607 0.716 KIF1C protein O43896 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272517 0.7 COL6A6 protein A6NMZ7 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. SIGNOR-254677 0.7 DAMPS stimulus SIGNOR-ST18 SIGNOR AIM2 protein O14862 UNIPROT up-regulates activity 16037825 f lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-256419 0.7 venlafaxine chemical CHEBI:9943 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9615 20378347 t Luana The cycloalkanol ethylamine scaffold was successfully utilized in the discovery and development of dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitors (SNRIs).1 Drugs such as venlafaxine (1) and duloxetine (2) possessing norepinephrine reuptake inhibition, either selectively or in combination with serotonin reuptake inhibition were approved for major depressive disorder (MDD). SIGNOR-257835 0.8 PPP1CC protein P36873 UNIPROT CASP2 protein P42575 UNIPROT up-regulates activity dephosphorylation Ser164 STDTVEHsLDNKDGP -1 19531356 t llicata nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2. SIGNOR-248503 0.2 PP121 chemical CHEBI:50915 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252655 0.8 CSNK1D protein P48730 UNIPROT BACE1 protein P56817 UNIPROT unknown phosphorylation Ser498 DDFADDIsLLK 9606 BTO:0000007 11278841 t llicata Here, we report that BACE can be phosphorylated within its cytoplasmic domain at serine residue 498 by casein kinase 1. Phosphorylation exclusively occurs after full maturation of BACE by propeptide cleavage and complex N-glycosylation. | After reinternalization, BACE wild type as well as BACE S498D are efficiently retrieved from early endosomal compartments and further targeted to later endosomal compartments and/or the trans-Golgi network. In contrast, nonphosphorylatable BACE S498A is retained within early endosomes. SIGNOR-250797 0.375 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser469 AHEENPEsILDEHVQ 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248497 0.272 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation Ser52 MILLSELsRRRIRSI 9606 30070006 t gcesareni The integrated stress response is characterized by the phosphorylation of eukaryotic initiation factor-2α (eIF2α) on serine 51 by one out of four specific kinases (EIF2AK1 to 4) SIGNOR-246153 0.757 CUL1 protein Q13616 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001271 SIGNOR-C5 12835716 t lperfetto Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2 SIGNOR-102725 0.627 hydromorphone chemical CHEBI:5790 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 19282177 t Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. SIGNOR-258143 0.8 GABRG2 protein P18507 UNIPROT GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263767 0.635 PRKG1 protein Q13976 UNIPROT LASP1 protein Q14847 UNIPROT down-regulates activity phosphorylation Ser146 MEPERRDsQDGSSYR 9606 12571245 t lperfetto Studies with human lasp mutants identified serine 146 as a specific phosphorylation site for cgk and cak in vivo. Lasp is an actin-binding protein, and the phospho-lasp-mimicking mutant s146d showed reduced binding affinity for f-actin in cosedimentation experiments. SIGNOR-97946 0.367 NRF1 protein Q16656 UNIPROT TFB2M protein Q9H5Q4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15684387 f lperfetto Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC SIGNOR-268997 0.54 etorphine chemical CHEBI:4912 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258804 0.8 NUP155 protein O75694 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262082 0.745 CSNK2A1 protein P68400 UNIPROT ERCC3 protein P19447 UNIPROT down-regulates activity phosphorylation Ser751 FGTMSSMsGADDTVY -1 15549133 t miannu Phosphorylation of S751 by CKII inhibits 5′ incision. SIGNOR-276013 0.2 MAPK1 protein P28482 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser294 QLSKWPGsPTSRSSD 9606 18204439 t lperfetto Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation. SIGNOR-160407 0.71 ARNTL protein O00327 UNIPROT VWF protein P04275 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000394 20658528 t lperfetto We also show that major circadian transcriptional regulators CLOCK and Bmal1 directly regulate the activity of vWF promoter and that lack of Bmal1 results in upregulation of vWF both at mRNA and protein level. Here we report a direct regulation of vWF expression in endothelial cells by biological clock gene Bmal1. This study establishes a mechanistic connection between Bmal1 and cardiovascular phenotype. SIGNOR-253704 0.33 SLC38A9 protein Q8NBW4 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000007 29053970 f Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. SIGNOR-255311 0.469 VEGFA protein P15692 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 16301830 f VEGF as a key mediator of angiogenesis in cancer. SIGNOR-256597 0.7 GSK3B protein P49841 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates phosphorylation Ser55 CPTYFPPsPTGSLTQ 9606 16484495 t llicata We show here that gsk3beta phosphorylates and stabilizes the orphan nuclear receptor rev-erbalpha, a negative component of the circadian clock. SIGNOR-144566 0.285 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Ser118 DKSTQTPsPPCQAFN 9606 12591950 t lperfetto Biml (bim long) was induced and phosphorylated parallel to jnk activitythese data demonstrate that biml is phosphorylated in vivo on thr-56 and that jnk also phosphorylates biml on at least one serine residue (ser-44 and/or ser-58) SIGNOR-98388 0.2 RPL17 protein P18621 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262482 0.753 CSNK1A1L protein Q8N752 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 12000790 t gcesareni We show that a complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45). SIGNOR-87430 0.491 CPS1 protein P31327 UNIPROT glutamine smallmolecule CHEBI:28300 ChEBI down-regulates quantity chemical modification 9606 15096496 t CPSase catalyzes the synthesis of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules SIGNOR-267198 0.8 p38 proteinfamily SIGNOR-PF16 SIGNOR FOXC1 protein Q12948 UNIPROT up-regulates quantity by stabilization phosphorylation Ser272 SSLSSGSsPPGSLPS 31650548 t lperfetto P38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation. SIGNOR-275912 0.2 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. SIGNOR-40349 0.716 SLC36A2 protein Q495M3 UNIPROT alanine smallmolecule CHEBI:16449 ChEBI up-regulates quantity relocalization 9606 12748860 t lperfetto Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut. SIGNOR-264740 0.8 HDAC1 protein Q13547 UNIPROT SERPINB5 protein P36952 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 18247378 t miannu We found that maspin is selectively upregulated in IFIXα-expressing cells and involved in anti-invasive activity of IFIXα. We also present evidence indicating that IFIXα downregulates histone deacetylase 1 (HDAC1), which is possibly involved in the silencing of the maspin gene in human breast cancer cells. To confirm these results, we performed a luciferase assay using a maspin-promoter-luciferase plasmid. The results showed that HDAC1 overexpression suppressed the activity of the maspin promoter (Figure 3C). Therefore, our results suggest that IFIXα enhances maspin expression through the downregulation of HDAC1. SIGNOR-268494 0.423 MAPK3 protein P27361 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Ser497 GSLCSVFsPSFVQWE 9606 27846390 t lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  SIGNOR-262982 0.317 TRIB3 protein Q96RU7 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity binding 9606 BTO:0000007 BTO:0000759 12791994 t llicata TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase. SIGNOR-237850 0.603 AKT1 protein P31749 UNIPROT IRAK1 protein P51617 UNIPROT down-regulates activity phosphorylation Thr100 LRARDIItAWHPPAP 9606 BTO:0000007 11976320 t gcesareni CaMKKc and Akt overexpression increases IRAK1 phosphorylation at Thr100, and point mutation of this site abrogates the inhibitory effect of Akt on IRAK1-mediated NF-kappaB activation. SIGNOR-252551 0.394 fludrocortisone chemical CHEBI:50885 ChEBI NR3C2 protein P08235 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258706 0.8 MLL2 complex complex SIGNOR-C88 SIGNOR PAX7/MLL2 complex complex SIGNOR-C91 SIGNOR form complex binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-198623 0.2 Starvation stimulus SIGNOR-ST4 SIGNOR AMPK complex SIGNOR-C15 SIGNOR up-regulates 9606 23000343 f lperfetto Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activationSTARV SIGNOR-209796 0.7 MAPK3 protein P27361 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Thr1179 NYGTNPGtPPASTSP 9606 12163482 t lperfetto Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein SIGNOR-91143 0.271 FGD3 protein Q5JSP0 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260553 0.634 F7 protein P08709 UNIPROT F10 protein P00742 UNIPROT up-regulates activity binding 9606 BTO:0000131 SIGNOR-C319 29880919 t lperfetto TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively. SIGNOR-263545 0.521 IL27 protein Q8NEV9 UNIPROT IL27RA protein Q6UWB1 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 14764690 t gcesareni Wsx-1 and glycoprotein 130 constitute a signal-transducing receptor for il-27. SIGNOR-121799 0.7 TET1 protein Q8NFU7 UNIPROT PTEN protein P60484 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27121319 t irozzo We also found that TET1 directly binds to the promoter region of PTEN and activates its transcription through demethylation of CpG islands SIGNOR-259096 0.381 FOXO4 protein P98177 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260091 0.266 PRKACA protein P17612 UNIPROT ITPR1 protein Q14643 UNIPROT down-regulates activity phosphorylation Ser1598 RNAARRDsVLAASRD -1 12529267 t miannu IP(3)R-I was phosphorylated by PKA and PKG in vitro and exclusively by PKG in vivo. Sequential phosphorylation by PKA and by PKG-Ialpha in vitro showed that PKA phosphorylated the same site as PKG (presumably S(1755)) and an additional PKA-specific site (S(1589)). Phosphorylation of IP(3)R-I in microsomes by PKG, PKA, or a combination of PKG and PKA inhibited IP(3)-induced Ca(2+) release to the same extent, implying that inhibition was mediated by phosphorylation of the PKG-specific site. SIGNOR-249996 0.537 pralatrexate chemical CHEBI:71223 ChEBI TYMS protein P04818 UNIPROT down-regulates activity chemical inhibition 9606 23409799 t miannu Pralatrexate is a small molecule with a chemical formula C23H23N7O5 and a molecular weight of 477.48 g/mol (Box 1). It competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase. SIGNOR-259352 0.8 SIRT1 protein Q96EB6 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 19299583 t lperfetto Using Per2:luciferase transcriptional reporter assays in HEK293 cells (Fig. 2C-E; S2), we show that inhibition of NAMPT by FK866 led to a significant increase in the CLOCK:BMAL1-driven transcription of the Per2:luciferase reporter (Fig. 2C), indicating that reduced NAMPT-mediated NAD+ biosynthesis released CLOCK:BMAL1 from the SIRT1-dependent suppression. SIGNOR-253722 0.771 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR ID2 protein Q02363 UNIPROT down-regulates phosphorylation Ser5 sPVRSVRK 9606 9029153 t lperfetto Id2 acts by forming heterodimers that are unable to bind to specific (e-box) dna sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (cdks). In vitro, id2 can be phosphorylated by either cyclin e-cdk2 or cyclin a-cdk2_ SIGNOR-216698 0.445 KAT6B protein Q8WYB5 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 SIGNOR-C54 11965546 t miannu Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation. SIGNOR-117335 0.41 DDX5 protein P17844 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 15660129 t miannu The dead box protein p68: a novel transcriptional coactivator of the p53 tumour suppressor SIGNOR-133341 0.69 CDK1 protein P06493 UNIPROT CDC27 protein P30260 UNIPROT up-regulates phosphorylation Ser426 TQPNINDsLEITKLD 9606 14657031 t lperfetto Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation SIGNOR-119873 0.692 ZMYM2 protein Q9UBW7 UNIPROT NANOG protein Q9H9S0 UNIPROT down-regulates activity binding 10090 BTO:0004593 31363497 t miannu In this work, we identified ZMYM2/ZFP198, which physically associates with NANOG as a key negative regulator of NANOG-mediated reprogramming of both epiblast stem cells and somatic cells. SIGNOR-269802 0.304 PTGER4 protein P35408 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257032 0.317 TNF protein P01375 UNIPROT MPO-ANCA complex SIGNOR-C474 SIGNOR up-regulates 10090 BTO:0000133 15972951 f lperfetto Second, LPS-mediated aggravation of anti-MPO IgG-induced glomerulonephritis was attenuated, but not prevented, by pretreatment with neutralizing anti-TNF-α antibodies. SIGNOR-270588 0.2 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CCNA2 protein P20248 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193537 0.8 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates activity phosphorylation Ser416 SVDDLANsGQVGTAR 9606 9155023 t lperfetto Tbetarii kinase is regulated intricately by autophosphorylation on at least three serine residues. Phosphorylation of ser416 inhibits receptor function. SIGNOR-48412 0.2 MAP4K1 protein Q92918 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates 9606 10224067 f gcesareni These studies establish that hpk1 acts as an upstream activator for the tak1-sek-jnk1 module in relaying the tgf-_ signal into the nuclei in 293t cells. SIGNOR-67321 0.537 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Ser157 GSILSDIsFDKTDES 9606 19468302 t llicata Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex. SIGNOR-185746 0.657 ERN1 protein O75460 UNIPROT OS9 protein Q13438 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18417469 f miannu Here we characterize the function in ER quality control of two proteins derived from alternative splicing of the OS-9 gene. OS-9.1 and OS-9.2 are ubiquitously expressed in human tissues and are amplified in tumors. They are transcriptionally induced upon activation of the Ire1/Xbp1 ER-stress pathway. SIGNOR-261063 0.435 DYDC1 protein Q8WWB3 UNIPROT Acrosome_assembly phenotype SIGNOR-PH156 SIGNOR up-regulates 9606 19545932 f miannu Knockdown of Dydc1 blocks spermatogenesis and acrosome biogenesis SIGNOR-263881 0.7 MAPK3 protein P27361 UNIPROT SCNN1B protein P51168 UNIPROT down-regulates quantity by destabilization phosphorylation Thr615 QALPIPGtPPPNYDS -1 11805112 t lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. SIGNOR-249447 0.282 PTGER3 protein P43115 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257203 0.252 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser232 NRYGMGTsVERAAAS -1 7782287 t gcesareni Sites 1, 2, and 3 in the E1 mutants were phosphorylated either individually or in the presence of the other sites by the dihydrolipoamide acetyltransferase-protein X-E1 kinase indicating a site-independent mechanism of phosphorylation. SIGNOR-32977 0.786 CLTA protein P09496 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR form complex binding 9606 24789820 t lperfetto AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly.  SIGNOR-260667 0.756 LCK protein P06239 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr200 SMESIDDyVNVPESG 9606 BTO:0000782 16938345 t gcesareni Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation. SIGNOR-149182 0.748 CYP11B1 protein P15538 UNIPROT 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI down-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268683 0.8 WASHC1 protein A8K0Z3 UNIPROT WASH complex complex SIGNOR-C258 SIGNOR form complex binding 23721880 t lperfetto The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53. SIGNOR-261020 0.2 ERG protein P11308 UNIPROT EPB41L3 protein Q9Y2J2 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20860828 f miannu EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression. SIGNOR-253918 0.2 MSH2 protein P43246 UNIPROT MSH2/MSH6 complex SIGNOR-C60 SIGNOR form complex binding 9606 15064730 t miannu The human msh2/6 complex is essential for mismatch recognition during the repair of replication errors. SIGNOR-123702 0.805 H2AC4 protein P04908 UNIPROT Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR form complex binding -1 21812398 t miannu The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. SIGNOR-263719 0.2 PRKCI protein P41743 UNIPROT LLGL2 protein Q6P1M3 UNIPROT up-regulates activity phosphorylation Ser653 LKKSLRQsFRRMRRS 9615 BTO:0000837 12725730 t miannu This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner. SIGNOR-263180 0.709 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser710 GEKSFRRsVVGTPAY 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275960 0.2 BMS-265246 chemical CID:5329775 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190434 0.8 CSNK2A1 protein P68400 UNIPROT SLK protein Q9H2G2 UNIPROT down-regulates phosphorylation Ser348 SDLSIASsEEDKLSQ 9606 16837460 t gcesareni Slk down-regulation by v-src is indirect and is accompanied by slk hyperphosphorylation on serine residues. Deletion analysis revealed that casein kinase ii (ck2) sites at position 347/348 are critical for v-src-dependent modulation of slk activity. SIGNOR-147883 0.2 ANK2 protein Q01484 UNIPROT DCTN4 protein Q9UJW0 UNIPROT up-regulates quantity relocalization 10090 BTO:0001103 19109891 t miannu We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4. SIGNOR-266713 0.61 TYMS protein P04818 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI down-regulates quantity chemical modification 9606 21876188 t lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. SIGNOR-268231 0.8 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 16782899 t gcesareni Here we report that fak directly interacts with the hepatocyte growth factor receptor c-met. Phosphorylation of c-met at tyr-1349 and, to a lesser extent, tyr-1356 is required for its interaction with the band 4.1 and ezrin/radixin/moesin homology domain (ferm domain) of fak. met-fak interaction leads to fak activation and subsequent contribution to hepatocyte growth factor-induced cell motility and cell invasion. SIGNOR-147179 0.476 JAK2 protein O60674 UNIPROT SLC6A8 protein P48029 UNIPROT down-regulates activity relocalization 443947 BTO:0000964 22407360 t miannu Janus-activated kinase-2 (JAK2) participates in the regulation of the Na⁺-coupled glucose transporter SGLT1 and the Na⁺-coupled amino acid transporter SLC6A19. JAK2 is a novel regulator of the creatine transporter SLC6A8, which downregulates the carrier, presumably by interference with carrier protein insertion into the cell membrane. SIGNOR-265807 0.2 SLA protein Q13239 UNIPROT KIT protein P10721 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0001538 24284075 t miannu In this report, we show that SLAP associates with both wild-type and oncogenic c-Kit (c-Kit-D816V). The association involves the SLAP SH2 domain and receptor phosphotyrosine residues different from those mediating Src interaction. Association of SLAP triggers c-Kit ubiquitylation which, in turn, is followed by receptor degradation SIGNOR-263143 0.2 KRAS protein P01116 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. SIGNOR-175204 0.907 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser82 NPEDRSPsPEPIYNS 9606 23175611 t The effect has been demonstrated using Q15637-2 gcesareni Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding. SIGNOR-199797 0.416 CSNK2A1 protein P68400 UNIPROT SLITRK1 protein Q96PX8 UNIPROT up-regulates activity phosphorylation Ser695 DCGSHSLsD -1 19640509 t miannu In our studies, SICD was phosphorylated by PKA, PKC, and CK2, and association of SLITRK1 with 14-3-3 was regulated by phosphorylation at Ser695. Co-precipitation experiments demonstrated much greater recovery of 14-3-3 in SLITRK1 precipitates when wild-type or S695E was used, as compared with S695A, consistent with the results with purified peptides. SIGNOR-273633 0.2 MBD5 protein Q9P267 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 20700456 f miannu The human proteins MBD5 and MBD6 associate with heterochromatin but they do not bind methylated DNA.Our data suggest that MBD5 and MBD6 are unlikely to be methyl-binding proteins, yet they may contribute to the formation or function of heterochromatin. One isoform of MBD5 is highly expressed in oocytes, which suggests a possible role in epigenetic reprogramming after fertilization. SIGNOR-266773 0.7 CRTC2 protein Q53ET0 UNIPROT TSC22D3 protein Q99576 UNIPROT up-regulates quantity transcriptional regulation 9606 26652733 t CRTC2 knockdown attenuates glucocorticoid-responsive GILZ mRNA expression in HeLa cells SIGNOR-256109 0.2 EFNB1 protein P98172 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9330863 t gcesareni The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. SIGNOR-52517 0.753 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDK7 protein P50613 UNIPROT up-regulates activity phosphorylation Thr170 GSPNRAYtHQVVTRW -1 11113184 t lperfetto Activating phosphorylation of CDK7 by CDC2 and CDK2. The ability of pure CDK2-cyclin A to activate CDK7 in T170-dependent fashion (Fig. ​(Fig.3C,3C, lane 2) strongly suggested a direct phosphorylation mechanism. Tryptic phosphopeptide mapping confirmed that both CDK2-cyclin A (Fig. ​(Fig.4A)4A) and CDC2-cyclin B (Fig. ​(Fig.4D)4D) phosphorylated CDK7 on both S164 and T170. SIGNOR-270806 0.63 PRKCA protein P17252 UNIPROT CFLAR protein O15519 UNIPROT up-regulates quantity by stabilization phosphorylation Ser193 LQAAIQKsLKDPSNN 9606 BTO:0000664 19343040 t miannu  Here, we identify serine 193 as a novel in vivo phosphorylation site of all c-FLIP proteins. c-FLIP S193 phosphorylation is mediated by PKCa and PKCb.S193 phosphorylation increases the stability of the short c-FLIP proteins SIGNOR-276147 0.2 Saracatinib chemical CID:10302451 PUBCHEM SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206691 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR CDK18 protein Q07002 UNIPROT up-regulates activity phosphorylation Ser14 KNFKRRFsLSVPRTE 28361970 t lperfetto We previously revealed that PCTK3 is activated by two pathways: interaction with cytoplasmic cyclin A and phosphorylation at Ser-12 by protein kinase A (PKA)12. Activated PCTK3 phosphorylates retinoblastoma protein (Rb) in vitro.  SIGNOR-264559 0.2 FST protein P19883 UNIPROT INHBA protein P08476 UNIPROT down-regulates activity binding 10090 BTO:0005787 24627466 t lperfetto Follistatin (FST) is a member of the tissue growth factor β family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. |FST315-ΔHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function. SIGNOR-251715 0.84 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 BTO:0000150 20530684 t lperfetto The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry. SIGNOR-216721 0.597 NAB2 protein Q15742 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 22128144 f miannu In the present study, we investigated the molecular basis for the differential regulation of TRAIL in helped versus helpless CD8(+) T cells by comparing their transcriptional profiles, and have identified a transcriptional corepressor, NGFI-A binding protein 2 (Nab2), that is selectively induced in helped CD8(+) T cells. Enforced expression of Nab2 prevents TRAIL induction after restimulation of primary helpless CD8(+) T cells, and expression of a dominant-negative form of Nab2 in helped CD8(+) T cells impairs their secondary proliferative response that is reversible by TRAIL blockade. SIGNOR-253893 0.2 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Thr378 ESQAGSDtDVEEGKA 9606 18678890 t gcesareni The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites. SIGNOR-179887 0.353 NKD1 protein Q969G9 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates binding 9606 20858476 t gcesareni Naked (nkd)1 and nkd2 are mammalian homologs of drosophila naked cuticle, which negatively regulates canonical wnt signaling by binding dishevelled. various reports using cell culture assays indicate that nkd-mediated wnt antagonism involves dvl degradation SIGNOR-167984 0.696 UQCR10 protein Q9UDW1 UNIPROT Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 t lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits SIGNOR-262199 0.925 HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes. SIGNOR-235478 0.874 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates activity phosphorylation Ser166 LGARAKEsLDLRAHL -1 11121119 t lperfetto In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Overphosphorylation of troponin I reduced its affinity for troponin C, as measured by isothermal titration microcalorimetry. Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation. SIGNOR-249069 0.349 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2V2 protein Q15819 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271369 0.455 diethylstilbestrol chemical CHEBI:41922 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258598 0.8 MEN1 protein O00255 UNIPROT MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 t irozzo We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]. SIGNOR-255868 0.2 LCK protein P06239 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates 9606 17998336 f gcesareni The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1. SIGNOR-159164 0.565 CLASP1 protein Q7Z460 UNIPROT MAPRE1 protein Q15691 UNIPROT up-regulates activity binding 9606 BTO:0000567 15631994 t lperfetto CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. SIGNOR-265094 0.593 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914168 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161678 0.607 SRC protein P12931 UNIPROT SPTAN1 protein Q13813 UNIPROT up-regulates phosphorylation Tyr1176 AVQQQEVyGMMPRDE 9606 11971983 t llicata Using mutagenesis on recombinant peptides, we identified the residue y1176 located in the calpain cleavage site of alpha ii-spectrin, near the sh3 domain, as an in vitro substrate for src kinase and lmw-ptp a. phosphorylation of this residue decreases spectrin sensitivity to calpain in vitro. SIGNOR-86718 0.544 very long-chain (R)-3-hydroxyacyl-CoA(4-) smallmolecule CHEBI:85440 ChEBI very long-chain 2,3-trans-enoyl CoA(4-) smallmolecule CHEBI:83728 ChEBI up-regulates quantity precursor of 9606 18554507 t miannu Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle. SIGNOR-267916 0.8 CIITA protein P33076 UNIPROT HLA-DRB5 protein Q30154 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002417 10886240 f These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma. SIGNOR-254013 0.447 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates phosphorylation Ser787 KAPEKRAsPSKPASA 9606 10791892 t gcesareni Ser787 in the proline-rich region of human map4 is a critical phosphorylation site that reduces its activity to promote tubulin polymerization. Phosphorylation on ser-787 negatively regulates map4 activity to promote microtubule assembly. SIGNOR-77087 0.511 regorafenib chemical CHEBI:68647 ChEBI TAP1 protein Q03518 UNIPROT down-regulates activity chemical inhibition 9606 26254357 t miannu It is suggested that in vitro, regorafenib is an inhibitor of ABCB1 and ABCG2, but not a substrate, and that its active metabolites, M2 (N-Oxide metabolite) and M5 (N-Oxide/N-desmethyl metabolite), are substrates of ABCB1 and ABCG3 SIGNOR-259204 0.8 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR DLX5 protein P56178 UNIPROT up-regulates transcriptional regulation 10090 BTO:0000165 12815054 f ggiuliani Over-expression of Smad1 or Smad5, mediators of BMP-signaling, also induced Dlx5 expression even in the absence of BMP-2 treatment concomitant with positive ALP staining SIGNOR-255837 0.32 SH2B2 protein O14492 UNIPROT INSR protein P06213 UNIPROT down-regulates binding 9606 BTO:0000975 11498022 t lperfetto APS couples c-Cbl to the insulin receptor, resulting in ubiquitination of the insulin receptor. SIGNOR-109694 0.605 TFEB protein P19484 UNIPROT NDUFA1 protein O15239 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). SIGNOR-276700 0.2 ATP5F1B protein P06576 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261397 0.2 PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 dacomitinib chemical CHEBI:132268 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 23405260 t gcesareni The goal of this study was to compare dacomitinib (pf-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple her family receptors (her-1 (egfr), her-2 and her-4 tyrosine kinases), to cetuximab, the current fda approved anti-egfr medication for hnscc and erlotinib, an egfr specific small molecule tyrosine kinase inhibitor. SIGNOR-200902 0.8 BMS-740808 chemical CID:6914623 PUBCHEM F10 protein P00742 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190488 0.8 Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity binding 9606 30205058 t miannu The exocyst is a multisubunit protein complex that was first identified and characterized in budding yeast. This complex mediates the tethering of secretory vesicles to the plasma membrane prior to fusion mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Sec3 interacts with PI(4,5)P2 (red dots) in the plasma membrane. Its interaction with the t-SNARE protein Sso promotes the assembly of the Sso–Sec9 binary t-SNARE complex. SIGNOR-270793 0.442 adapalene chemical CHEBI:31174 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9606 30836068 t miannu Adapalene, the third-generation synthetic retinoid,selectively bound to specific RAR, thus activating genes responsible forcellular differentiation. It showed greatest affinity for subtypes RARβ in dermal fibroblasts (Kd value 34 nM) and RARγ in the epidermis (Kdvalue 130 nM) SIGNOR-258488 0.8 PRKD1 protein Q15139 UNIPROT ATP7B protein P35670 UNIPROT up-regulates activity phosphorylation Ser481 ILAKSPQsTRAVAPQ 9606 BTO:0000599 21189263 t lperfetto ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking. SIGNOR-272293 0.301 DNAJC14 protein Q6Y2X3 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR down-regulates 9606 15525720 f lperfetto Mutations in the gene encoding DJ-1 have also been linked to familial Parkinson€™s disease. Other studies have suggested that DJ-1 protects cells from oxidative damage, and mutations in DJ-1 may therefore contribute to in- creased levels of oxidative stress. SIGNOR-249698 0.7 PRKCI protein P41743 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251635 0.2 HNRNPA1 protein P09651 UNIPROT Alternative_Splicing_Regulation phenotype SIGNOR-PH204 SIGNOR up-regulates 9606 17371836 f We demonstrate that Sam68 binds the mRNA for Bcl-x and affects its alternative splicing SIGNOR-268687 0.7 TOM40 complex complex SIGNOR-C421 SIGNOR Insertion into mitochondrial membrane phenotype SIGNOR-PH193 SIGNOR up-regulates 18423394 f lperfetto The sorting and assembly pathway of outer membrane proteins involves three machineries: the translocase of the outer membrane (TOM complex) the sorting and assembly machinery (SAM complex) and the MDM complex (mitochondrial distribution and morphology). SIGNOR-267688 0.7 HRAS protein P01112 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 10116 BTO:0000452 1749429 t lperfetto Expression of oncogenic ha-ras augments transactivation by c-jun and stimulates its phosphorylation. Here we describe the mapping of the ha-ras-responsive phosphorylation sites to serines 63 and 73 of c-jun. Site-directed mutagenesis indicates that phosphorylation of these serines is essential for stimulation of c-jun activity and for cooperation with ha-ras in ocogenic transformation. SIGNOR-236682 0.514 NKX3-1 protein Q99801 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16697957 t miannu Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events. SIGNOR-251547 0.516 CSNK2A1 protein P68400 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates phosphorylation 9606 2861485 t gcesareni Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex.CK1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays. SIGNOR-23958 0.308 perfluorooctanoic acid chemical CHEBI:35549 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 9606 BTO:0000150 35370244 t miannu Detailed in vitro studies on the effects of perfluorooctanoic acid (PFOA) have demonstrated that activation of peroxisome proliferator-activated receptor α (PPARα) is a key process by which PFOA affects the malignancy of estrogen receptor α (ERα)-positive breast cancer cells. SIGNOR-268753 0.8 NCOR1 protein O75376 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22395773 t FFerrentino In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription. SIGNOR-253507 0.696 TFAP2D protein Q7Z6R9 UNIPROT ST8SIA2 protein Q92186 UNIPROT up-regulates quantity by expression transcriptional regulation 9031 24462686 t lperfetto We use chromatin immunoprecipitation and gel shift assays to demonstrate direct interaction between AP-2 and the ST8SIA2 promoter.|We show that ST8SIA2 is induced by AP-2δ overexpression in chick retina. We use chromatin immunoprecipitation and gel shift assays to demonstrate direct interaction between AP-2δ and the ST8SIA2 promoter. SIGNOR-268992 0.343 EGLN2 protein Q96KS0 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity hydroxylation 9606 24990963 t lperfetto Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase.|Here we report that EglN2 can hydroxylate FOXO3a on two specific prolyl residues in vitro and in vivo. Hydroxylation of these sites prevents the binding of USP9x deubiquitinase, thereby promoting the proteasomal degradation of FOXO3a. SIGNOR-261998 0.291 CHEK1 protein O14757 UNIPROT MDM4 protein O15151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 18356162 t lperfetto The chk1 and chk2 kinases have also been shown to phosphorylate ser367, leading to 14-3-3 binding (34_36, 38, 44). In both cases, the outcome differed: in chk1-mediated phosphorylation, mdmx was translocated to the cytoplasm;in chk2-mediated phosphorylation, mdmx was degraded (34_36, 38, 44). It is possible that the damage response is mediated through additional phosphorylation sites other than ser367 and that, depending on the type of damage, certain sites will be modified, leading to different outcomes. SIGNOR-178067 0.535 SP1 protein P08047 UNIPROT NDUFV1 protein P49821 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000931 17786189 f miannu Sp1 role in the regulation of complex I subunits, was demonstrated by the ability of the Sp1/DNA binding inhibitor, mithramycin, to inhibit the transcription of NDUFV1 and NDUFV2, in neuroblastoma cells. In addition, Sp1 activated NDUFV2 promoter by binding to its three GC-boxes. Both activation and binding were inhibited by mithramycin. SIGNOR-255206 0.2 HDAC1 protein Q13547 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 23242655 f Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells. SIGNOR-254029 0.644 17beta-estradiol smallmolecule CHEBI:16469 ChEBI estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity precursor of 9606 BTO:0000056 16166196 t lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. SIGNOR-268662 0.8 PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 AKT1 protein P31749 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue. SIGNOR-252526 0.681 SLC9A6 protein Q92581 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265605 0.8 TRAF6 protein Q9Y4K3 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity ubiquitination 9606 18758450 t lperfetto Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis. SIGNOR-180562 0.2 p38 proteinfamily SIGNOR-PF16 SIGNOR CDC25B protein P30305 UNIPROT down-regulates activity phosphorylation Ser375 ARVLRSKsLCHDEIE 9606 11333986 t lperfetto P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteins phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 SIGNOR-107416 0.2 FZR1 protein Q9UM11 UNIPROT ANLN protein Q9NQW6 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000567 16040610 t miannu  Ubiquitination of anillin required a destruction-box and was mediated by Cdh1, an activator of APC/C. Overexpression of Cdh1 reduced the levels of anillin, whereas inactivation of APC/C(Cdh1) increased the half-life of anillin. SIGNOR-272654 0.268 DCTN6 protein O00399 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity binding 9534 BTO:0004055 phosphorylation:Thr186 KTMKGSStPVKN 23455152 t lperfetto Here, we show that the p27/p25 heterodimer undergoes mitotic phosphorylation by cyclin‐dependent kinase 1 (Cdk1) at a single site, p27 Thr186, to generate an anchoring site for polo‐like kinase 1 (Plk1) at kinetochores. SIGNOR-264798 0.382 GRK3 protein P35626 UNIPROT CCR5 protein P51681 UNIPROT down-regulates activity phosphorylation Ser342 ASSVYTRsTGEQEIS 9534 BTO:0000298 10085131 t gcesareni Phosphoamino acid analysis revealed that RANTES-induced CCR5 phosphorylation selectively occurs on serine residues. Our findings with receptor mutants indicate that serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. SIGNOR-249675 0.2 DNAJC11 protein Q9NVH1 UNIPROT Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 10090 BTO:0000312 25111180 f Homozygous mutant mice developed locomotion defects, muscle weakness, spasticity, limb tremor, leucopenia, thymic and splenic hypoplasia, general wasting and early lethality. Neuropathological analysis showed severe vacuolation of the motor neurons in the spinal cord, originating from dilatations of the endoplasmic reticulum and notably from mitochondria that had lost their proper inner membrane organization. T SIGNOR-261147 0.7 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191024 0.8 celecoxib chemical CHEBI:41423 ChEBI PTGS2 protein P35354 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190928 0.8 SMARCE1 protein Q969G3 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 t miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. SIGNOR-132942 0.88 ponatinib chemical CHEBI:78543 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206280 0.8 SNRPE protein P62304 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270630 0.828 OPTN protein Q96CV9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0005118 22194658 f same result in PC12 cell miannu SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA. SIGNOR-259876 0.7 SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-39237 0.888 SIRT4 protein Q9Y6E7 UNIPROT GLUD2 protein P49448 UNIPROT down-regulates activity glycosylation 9606 16959573 t miannu We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. SIGNOR-268559 0.487 CASP8 protein Q14790 UNIPROT CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 9727491 t gcesareni Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them. SIGNOR-58118 0.731 CREB1 protein P16220 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15955695 f miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. SIGNOR-253791 0.286 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BAG3 protein O95817 UNIPROT up-regulates activity phosphorylation Thr285 GSPARSStPLHSPSP 9606 BTO:0000016 27659916 t miannu ERK-dependent phosphorylation of BIS following H2O2 treatment. SIGNOR-274071 0.2 ASNS protein P08243 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267531 0.8 CHAF1B protein Q13112 UNIPROT MGMT protein P16455 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 15657354 f miannu Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT. SIGNOR-254570 0.298 Erythrocytic spectrin complex SIGNOR-C384 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates binding 9606 24302288 t lperfetto Spectrin is a member of the F-actin-crosslinking protein superfamily. SIGNOR-266030 0.7 2-(Decan-2-ylamino)ethyl 4-aminobenzoate chemical CID:50729 PUBCHEM TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000664 18258442 t Luana As shown in Table 1 all of the bisanthrapyrazoles inhibited the decatenation activity of human topoisomerase IIα in the low micromolar concentration range SIGNOR-257768 0.8 CSNK2A2 protein P19784 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates activity phosphorylation Ser87 GDDEDACsDTEATEA -1 8288648 t llicata Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action. SIGNOR-251022 0.312 ATP5PB protein P24539 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261401 0.2 PRKCA protein P17252 UNIPROT TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser162 FDIVSRGsTADLDGL 9606 19661060 t Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-260886 0.357 LRRC4 protein Q9HBW1 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 19467332 t miannu A possible function for the NGL–PSD-95 interaction is to couple trans-synaptic adhesion events to the recruitment of PSD-95 and other PSD-95-associated postsynaptic proteins. PSD-95 and liprin-α may be key synaptic scaffolding proteins that couple trans-synaptic adhesions to the assembly of synaptic proteins/vesicles SIGNOR-264051 0.435 HPS6 protein Q86YV9 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR form complex binding 9606 15030569 t lperfetto Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS8 SIGNOR-260690 0.771 GADD45A protein P24522 UNIPROT CDK1 protein P06493 UNIPROT down-regulates binding 9606 SIGNOR-C17 10362260 t gcesareni Gadd45 has now been found to directly inhibit the activity of cdc2/cyclin b1 complex SIGNOR-68221 0.698 AP3M2 protein P53677 UNIPROT Neuronal AP-3 complex SIGNOR-C445 SIGNOR form complex binding 9606 BTO:0000938 19497727 t miannu Mammals contain more than one AP-3 complex owing to the existence of pairs of genes encoding β3, μ3, and σ3 subunits (A and B isoforms). While both σ3A and σ3B are expressed ubiquitously and seem to be functionally equivalent, the B isoforms of β3 and μ3 display rather restricted expression patterns, mostly in cells of neuronal origin. This has led to the notion of the existence of two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising δ, β3A, μ3A, and σ3(A or B) subunits, and a brain-specific AP-3 complex containing δ, β3B, μ3B, and σ3(A or B) SIGNOR-268520 0.738 SMC3 protein Q9UQE7 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates activity binding 9534 BTO:0000318 9528857 t 2 miannu We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions. SIGNOR-241278 0.301 P2RY14 protein Q15391 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257210 0.2 DEPTOR protein Q8TB45 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-205600 0.717 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates activity phosphorylation Ser370 TRQTPVDsPDDTALS -1 11733037 t miannu  Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities. SIGNOR-250371 0.596 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252353 0.783 RPTOR protein Q8N122 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-205627 0.858 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates 9606 BTO:0000759 24692351 f scontino TH stimulates both lipolysis and lipogenesis, although the direct action is lipolysis with lipogenesis thought to be stimulated to restore fat stores. Fatty acids produced from TH-induced lipolysis are the substrate for the increase in thermogenesis. SIGNOR-267488 0.7 LAMA2 protein P24043 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255984 0.424 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 19237534 t lperfetto In vitro, lsf is phosphorylated by cyclin e/cyclin-dependent kinase 2 (cdk2), cyclin c/cdk2, and cyclin c/cdk3, predominantly on s309. Phosphorylation by cyclin c/cyclin-dependent kinase 2 following mitogenic stimulation of murine fibroblasts inhibits transcriptional activity of lsf during g1 progression SIGNOR-216713 0.2 CAMK2B protein Q13554 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Thr472 ICALRHLtSRHQEAE 9606 BTO:0000938 24117889 t lperfetto Camkii represses transcriptionally active _-catenin to mediate acute ethanol neurodegeneration and can phosphorylate _-catenincamkii can directly phosphorylate _-catenin. Using targeted mutagenesis we identified camkii phosphorylation sites within human _-catenin at t332, t472, and s552. SIGNOR-202833 0.293 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2D1 protein P51668 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271311 0.827 FOXL2 protein P58012 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19010791 f miannu Foxl2 can directly activate the transcription of sirt1 SIGNOR-182300 0.514 MAPK8 protein P45983 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 12058028 t gcesareni The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro. SIGNOR-89440 0.659 NEDD4 protein P46934 UNIPROT AP1G2 protein O75843 UNIPROT up-regulates activity monoubiquitination 9606 BTO:0001950 18772139 t miannu Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination. SIGNOR-272634 0.41 A11/b1 integrin complex SIGNOR-C168 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269017 0.7 ADRB1 protein P08588 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256901 0.377 RAB2A protein P61019 UNIPROT TRIP11 protein Q15643 UNIPROT up-regulates activity binding 9606 BTO:0000567 25473115 t Sara Vesicle-associated Rab2 then mediates attachment to the Rab2 binding site within the central coiled-coil region of GMAP-210, bringing the vesicle into closer proximity to the target membrane. GMAP-210 function in vivo is dependent upon its ability to tether membranes, which is mediated exclusively by the amino-terminal ALPS motif. Binding to Rab2 is also important for GMAP-210 function, although it is dispensable for tethering per se. SIGNOR-261300 0.404 ATG14 protein Q6ZNE5 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates activity binding 10090 BTO:0000944 19270693 t lperfetto Characterization of the new proteins revealed that atg14l enhances vps34 lipid kinase activity and upregulates autophagy, SIGNOR-235448 0.877 SMURF1 protein Q9HCE7 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity ubiquitination 9606 12738770 t lperfetto Smurf1 interacts directly with Cbfa1 and mediates Cbfa1 degradation in a ubiquitin- and proteasome-dependent manner. SIGNOR-236083 0.518 UCHL5 protein Q9Y5K5 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates deubiquitination 9606 16027725 t gcesareni Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases SIGNOR-138876 0.386 3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol chemical CHEBI:94691 ChEBI PIK3CG protein P48736 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258300 0.8 CDK2 protein P24941 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 17409098 t gcesareni Ubiquitination and subsequent degradation play a critical role in regulating the levels of p27 during cell cycle progression. Here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3). SIGNOR-154188 0.95 KRAS protein P01116 UNIPROT CARM1 protein Q86X55 UNIPROT down-regulates activity 9606 BTO:0000304 27840030 f lperfetto Interestingly, overexpression of KRASG12V (an activating mutant) in BxPC-3 cells, a PDAC cell line carrying wild-type KRAS, led to a 40% decrease of CARM1 protein and consequent hypomethylation or activation of MDH1|These observations indicate that KRAS suppresses CARM1-mediated MDH1 methylation, contributing to Gln metabolism in pancreatic cancer. SIGNOR-267640 0.275 TRIM27 protein P14373 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates 9606 BTO:0000671 12807881 f miannu We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38. SIGNOR-102022 0.2 DNA_damage stimulus SIGNOR-ST1 SIGNOR MLH1/PMS2 complex SIGNOR-C59 SIGNOR up-regulates -1 10542278 f miannu HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay. SIGNOR-259062 0.7 RNF167 protein Q9H6Y7 UNIPROT VAMP3 protein Q15836 UNIPROT down-regulates quantity by destabilization ubiquitination Lys77 KYWWKNCkMWAIGIT 9606 BTO:0000007 23353890 t miannu Here, we show that Godzilla/RNF167 regulates endosome recycling by the ubiquitylation of VAMP3 on Lys66, Lys68 and Lys77; namely, two adjacent Lys residues on the both sides of the critical interface of SNARE complex are ubiquitylated. In agreement with VAMP3 being a target for Goliath family ubiquitin ligases, we show that recycling endosome trafficking is abrogated in response to their activity. While we observed ubiquitylation of VAMP3 by Godzilla, we are unable to describe the nature of this ubiquitination, be it mono-ubiquitin or extended ubiquitin chains. SIGNOR-272095 0.334 CAMK2A protein Q9UQM7 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization phosphorylation Ser87 PLKQKQPsFSAKKMT 9606 BTO:0000567 24781523 t miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase SIGNOR-276381 0.314 EIF3_complex complex SIGNOR-C401 SIGNOR 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR up-regulates activity binding 9606 16920360 t miannu EIF3 binds 40S and inhibits the association of 60S. Structural analysis suggests that eIF3 performs this scaffolding function by binding to the 40S subunit on its solvent-exposed surface rather than on its interface with the 60S subunit, where the decoding sites exist. This location of eIF3 seems ideally suited for its other proposed regulatory functions, including reinitiating translation on polycistronic mRNAs and acting as a receptor for protein kinases that control protein synthesis. SIGNOR-266401 0.598 JMJD1C protein Q15652 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 32034158 t miannu We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state. SIGNOR-265169 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR PTPN11 protein Q06124 UNIPROT down-regulates activity phosphorylation Thr73 YGGEKFAtLAELVQY 9606 BTO:0002181 25802336 t miannu  We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.  SIGNOR-276893 0.2 ABL1 protein P00519 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 11781820 t lperfetto Phosphorylation of tyr412 can occur autocatalytically by a trans-mechanism and cause activation of otherwise inactive c-abl, suggesting a positive feedback loop on c-abl activity. SIGNOR-113659 0.2 HAUS1 protein Q96CS2 UNIPROT HAUS complex complex SIGNOR-C281 SIGNOR form complex binding 9606 BTO:0000567 19369198 t lperfetto Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC) SIGNOR-262319 0.8 GSK3B protein P49841 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT down-regulates binding 9606 17726008 t gcesareni Gsk3beta binding to mekk4 blocks mekk4 dimerization that is required for mekk4 activation, effectively inhibiting mekk4 stimulation of the jnk and p38 mapk pathways SIGNOR-157541 0.375 RUBCN protein Q92622 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates binding 9606 19270693 t gcesareni The run or cysteine-rich domain of rubicon appears to be inhibitory to the binding of rubicon to beclin 1 and vps34 SIGNOR-184547 0.2 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248746 0.727 Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR Microtubule-based_movement phenotype SIGNOR-PH170 SIGNOR up-regulates 16440056 f lperfetto Dyneins are large multi-subunit protein complexes that undertake a wide range of roles within the cell. They are adenosine triphosphate (ATP)–driven, microtubule minus-end-directed molecular motors that can be divided, based on function, into two classes: axonemal and cytoplasmic dyneins SIGNOR-265019 0.7 PRKCA protein P17252 UNIPROT CASR protein P41180 UNIPROT down-regulates phosphorylation Thr888 FKVAARAtLRRSNVS 9606 21135065 t llicata Casr(t888) is a protein kinase c (pkc) phosphorylation site in the receptor's intracellular domain that has previously been identified as a critical negative regulator of casr downstream signaling in vitro, thus, casr(t888) represents a functionally important, inhibitory phosphorylation site that contributes to the control of pth secretion. SIGNOR-170334 0.358 MLST8 protein Q9BVC4 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-205609 0.882 pevonedistat chemical CHEBI:145535 ChEBI UBE2F protein Q969M7 UNIPROT down-regulates quantity chemical inhibition 9606 BTO:0001109 19360080 t Monia MLN4924 is a potent and selective inhibitor of NEDD8-activating enzyme; A single dose of MLN4924 resulted in a dose- and time-dependent decrease of NEDD8–cullin levels as early as 30 min after administration of compound SIGNOR-261067 0.8 PP1 proteinfamily SIGNOR-PF54 SIGNOR GSK3B protein P49841 UNIPROT up-regulates activity dephosphorylation Ser9 SGRPRTTsFAESCKP 26088133 t lperfetto Anchored PP1 may relieve PKA-mediated inhibition of GSK3beta by dephosphorylating Ser-9, providing bi-directional control of AKAP220 complex formation in response to cAMP. SIGNOR-264820 0.2 CASP2 protein P42575 UNIPROT Caspase-2 PIDDosome complex SIGNOR-C292 SIGNOR form complex binding 9606 20158568 t miannu The PIDDosome consists of the proteins PIDD, RAIDD and caspase-2. SIGNOR-262641 0.858 DUSP6 protein Q16828 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates dephosphorylation 9606 22521266 t gcesareni Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase). SIGNOR-252903 0.439 PYGM protein P11217 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI down-regulates quantity chemical modification 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [‚Ķ] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267389 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Thr143 AVSPGTLtPTGVVSG 26933062 t lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. SIGNOR-276591 0.397 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 17466630 t lperfetto Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle. SIGNOR-216884 0.429 MASP2 protein O00187 UNIPROT C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Gly1446 TPLQLFEgRRNRRRR -1 17204478 t lperfetto MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a). SIGNOR-263437 0.794 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KMT5A protein Q9NQR1 UNIPROT up-regulates quantity by stabilization phosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 t lperfetto First, we found that pr-set7 is phosphorylated at ser 29 (s29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinb complex, s29 phosphorylation also functions to stabilize pr-set7 by directly inhibiting its interaction with the anaphase-promoting complex (apc), an e3 ubiquitin ligase. SIGNOR-216856 0.2 CDK2 protein P24941 UNIPROT PRKAR1A protein P10644 UNIPROT up-regulates phosphorylation Ser83 DSREDEIsPPPPNPV 9606 SIGNOR-C16 16582606 t gcesareni In this context, we have identified rialpha as a novel substrate for the g(1)/s-cyclin-dependent kinase, cdk2/cyclin e, and found that rialpha is specifically phosphorylated at the serine residue. SIGNOR-145577 0.349 WWTR1 protein Q9GZV5 UNIPROT PPARG protein P37231 UNIPROT down-regulates binding 9606 22153608 t gcesareni Kmp also enhanced the association of taz with ppar_, thereby suppressing the gene transcription of ppar_ targets and resulting in diminished adipocyte differentiation. SIGNOR-195215 0.316 SPI1 protein P17947 UNIPROT IRF8 protein Q02556 UNIPROT up-regulates activity binding 9606 BTO:0001413 11483597 t miannu We found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP. SIGNOR-222880 0.612 PIN1 protein Q13526 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity isomerization 9606 phosphorylation:Ser416;Ser497;Thr345 GFPSKTDsPSCEYSR;GSLCSVFsPSFVQWE;GADSDVEtPSNFGKY 27846390 t lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  SIGNOR-263015 0.2 KAT6A protein Q92794 UNIPROT TP53 protein P04637 UNIPROT up-regulates acetylation Lys120 FLHSGTAkSVTCTYS 9606 BTO:0001271 SIGNOR-C54 23431171 t miannu We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression SIGNOR-201482 0.656 PRKCA protein P17252 UNIPROT SPAG1 protein Q07617 UNIPROT unknown phosphorylation Ser326 VERDLKNsEAASETQ -1 11517287 t lperfetto In-vitro incubation with [_-32P]ATP showed that HSD-3.8 protein can be phosphorylated by PKC. The phosphate is probably linked to the serine residue presenting the sequence X LysXX SerX. SIGNOR-249109 0.312 PDGFRA protein P16234 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 15489898 t gcesareni The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells. SIGNOR-247984 0.468 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser454 YVPMNPNsPPRQHSS 10029 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249396 0.585 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys21 EGPRDGLkKERLLDD 9606 7479976 t gcesareni Here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha. SIGNOR-26573 0.522 IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 23124025 t lperfetto Although the receptor-associated tyrosine kinases Jak2 and Tyk2 are activated after the recruitment of IL-13 to its receptor (containing IL-4R and IL-13R1), IL-4 stimulates Jak1 activation. SIGNOR-249529 0.705 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273098 0.745 DET1 protein Q7L5Y6 UNIPROT DCX DET1-COP1 complex SIGNOR-C24 SIGNOR form complex binding 9606 17452440 t lperfetto Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes SIGNOR-154508 0.786 TGFBR1 protein P36897 UNIPROT TP63 protein Q9H3D4 UNIPROT unknown phosphorylation Ser68 FLEQPICsVQPIDLN 9606 23166821 t llicata We show that phosphorylation of _np63_ at s66/68 in response to ultraviolet (uv) irradiation is mediated by alk5 SIGNOR-199785 0.2 PHF10 protein Q8WUB8 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270716 0.622 TP53 protein P04637 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR up-regulates binding 9606 10207072 t gcesareni Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo. SIGNOR-66956 0.91 CXCL1 protein P09341 UNIPROT GLI2 protein P10070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16885213 f gcesareni The data suggest that smo is in fact the source of two signals relevant to the activation of gli: one involving g(i) and the other involving events at smo's c-tail independent of g(i). SIGNOR-148457 0.2 MARK2 protein Q7KZI7 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser960 SRLSPPHsPRDFTRM 9606 22072711 t The effect has been demonstrated using Q92974-2 gcesareni We also show that par1b-induced serine 885/serine 959 phosphorylation inhibits rhoa-specific gef activity of gef-h1. As a consequence, gef-h1 phosphorylated on both of the serine residues loses the ability to stimulate rhoa and thereby fails to induce rhoa-dependent stress fiber formation SIGNOR-177100 0.517 CBX4 protein O00257 UNIPROT ZEB2 protein O60315 UNIPROT down-regulates quantity by destabilization sumoylation Lys391 QTGLLKIkTEPLDFN 9534 16061479 t Luisa Pc2 can act directly as an E3 ligase for SIP1 sumoylation.SIP1 sumoylation having a negative effect on its repression of E-cadherin transcription. SIGNOR-268955 0.337 brimonidine chemical CHEBI:3175 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258902 0.8 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189168 0.8 ARHGAP30 protein Q7Z6I6 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260487 0.435 RNF128 protein Q8TEB7 UNIPROT ARHGDIA protein P52565 UNIPROT up-regulates quantity by stabilization polyubiquitination 9606 BTO:0000661 17114425 t miannu We found that RhoGDIα and RhoGDIβ are ubiquitin E3 substrates of GRAIL. GRAIL uses nonlysine 48-ubiquitin linkage in polyubiquitinating RhoGDI. GRAIL was subsequently demonstrated to bind and ubiquitinate RhoGDI, although GRAIL-mediated ubiquitination of RhoGDI did not result in proteosomal degradation. Our data suggest that ubiquitination of RhoGDI by GRAIL does not result in proteolytic degradation. In fact, GRAIL activity appeared to increase RhoGDI stability. SIGNOR-271622 0.269 SMAD5 protein Q99717 UNIPROT GATA3 protein P23771 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 t Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation SIGNOR-268943 0.315 THR proteinfamily SIGNOR-PF84 SIGNOR RARA protein P10276 UNIPROT up-regulates activity binding 9606 15650024 t inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. SIGNOR-267779 0.2 COPII vesicle complex SIGNOR-C370 SIGNOR Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 9606 30605680 f lperfetto Coat protein complex (COP) II vesicles export newly synthesized secretory proteins from the endoplasmic reticulum (ER) SIGNOR-265297 0.7 YWHAG protein P61981 UNIPROT GEM protein P55040 UNIPROT up-regulates quantity by stabilization binding 9534 14701738 t miannu In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase SIGNOR-261713 0.269 RAP1GDS1 protein P52306 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 21242305 t miannu Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc SIGNOR-171347 0.617 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT unknown phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 BTO:0001412 8692915 t gcesareni Treatment with ionizing radiation is associated with c-Abl-dependent tyrosine phosphorylation of SHPTP1. The results demonstrate that the SH3 domain of c-Abl interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that c-Abl phosphorylates C terminal Y536 and Y564 sites. SIGNOR-246231 0.423 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Ser90 QHVRSHSsPASLQLG 26375055 t lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity SIGNOR-276518 0.261 Nucleosome_H2A.Z.1 variant complex SIGNOR-C322 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR down-regulates 9606 15623580 f lperfetto All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage. SIGNOR-273455 0.7 EEF1A1P5 protein Q5VTE0 UNIPROT Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269553 0.8 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr259 ASVDSSLyNLPRSYS 9606 BTO:0000007 19881549 t lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis SIGNOR-236310 0.692 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR ROR2 protein Q01974 UNIPROT down-regulates activity phosphorylation Ser864 PKPSSHHsGSGSTST 9606 21078818 t gcesareni We identify ror2 ser 864 as a critical residue phosphorylated by gsk3 and required for noncanonical receptor activation by wnt5a, analogous to the priming phosphorylation of low-density receptor-related protein 6 (lrp6) in response to wnt3a. SIGNOR-228026 0.338 crizotinib chemical CHEBI:64310 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191136 0.8 GATA6 protein Q92908 UNIPROT CYP11A1 protein P05108 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002850 15284005 f miannu The transcription factor GATA6, which regulates the promoter activity of CYP17 and CYP11A, was increased in the PCOS compared to normal theca cells. SIGNOR-254197 0.331 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr234 AQPEQDEyDIPRHLL 10090 12972425 t lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs SIGNOR-246397 0.796 PTPN1 protein P18031 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates activity dephosphorylation Tyr152 ISEDIKSyYTVRQLE -1 11506178 t Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions. SIGNOR-248424 0.2 PAMPs stimulus SIGNOR-ST11 SIGNOR TLR4 protein O00206 UNIPROT up-regulates activity 9606 BTO:0000801 19946286 f lperfetto The lipopolysaccharide (LPS) of Gram negative bacteria is a wellknown inducer of the innate immune response1. Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common pattern in structurally diverse LPS molecules. SIGNOR-249516 0.7 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1213 GSSDDVRyVNAFKFM 9606 11583921 t tpavlidou Vegfr-1 mutated at y1213, y1242, and y1333 were constructed and expressed in pae cells, to the same level as that of pae/vegfr-1 cells. The mutated vegfr-1 y1213f expressed in pae cells was kinase inactive. SIGNOR-110850 0.2 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity phosphorylation Thr531 NTTGSDNtDTEGS 9606 17936701 t PVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2. SIGNOR-266900 0.352 NOTCH1 protein P46531 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 10713164 t gcesareni SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function. SIGNOR-75782 0.585 PLK1 protein P53350 UNIPROT CEP55 protein Q53EZ4 UNIPROT up-regulates phosphorylation Ser436 PTAALNEsLVECPKC 9606 16198290 t lperfetto Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. s425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436...enabling it to relocate to the midbody to function in mitotic exit and cytokinesis. SIGNOR-140898 0.568 GRK2 protein P25098 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 t Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. SIGNOR-251446 0.2 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273103 0.745 PLEKHA7 protein Q6IQ23 UNIPROT TSPAN33 protein Q86UF1 UNIPROT up-regulates activity binding 10116 BTO:0003618 30463011 t Simone Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. SIGNOR-261250 0.409 PAK2 protein Q13177 UNIPROT MKNK1 protein Q9BUB5 UNIPROT down-regulates activity phosphorylation Ser39 RRGRATDsLPGKFED 9606 BTO:0000007 15234964 t miannu Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits phosphorylation and interaction of eIF4G with Mnk. When 293T cells are subjected to apoptotic induction by hydrogen peroxide, Mnk1 is phosphorylated at both Thr(22) and Ser(27). These results indicate a role for Pak2 in the down-regulation of translation initiation in apoptosis by phosphorylation of Mnk1. SIGNOR-250221 0.43 ARAF protein P10398 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation 9606 21779497 t gcesareni Active raf phosphorylates mek. SIGNOR-175142 0.744 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176837 0.775 ABCC4 protein O15439 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR up-regulates activity binding 9606 BTO:0000132 23805129 t lperfetto The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2).  SIGNOR-265996 0.2 CSNK2A2 protein P19784 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation -1 8954982 t llicata Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149. SIGNOR-251036 0.329 GSK3B protein P49841 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 BTO:0000671 18701453 t lperfetto We found that gsk-3Beta phosphorylates and inactivates 4e-bp1, thereby increasing eif4e-dependent protein synthesis. upon stimulation, 4e-bp1 is phosphorylated on several threonine and serine residues, including thr-37/46 (36). This results in dissolution of the complex, freeing eif4e to bind with mrna cap to promote translation initiation. SIGNOR-236026 0.372 HPN protein P05981 UNIPROT F7 protein P08709 UNIPROT up-regulates activity cleavage Arg212 NASKPQGrIVGGKVC -1 7814421 t lperfetto Hepsin, a putative membrane-associated serine protease, activates human factor VII and initiates a pathway of blood coagulation on the cell surface leading to thrombin formation|In contrast, an activation cleavage site factor VII mutant, R152E factor VII, was not cleaved by hepsin-transfected cells, suggesting that factor VII and S344A factor VII were activated on these cells by cleavage of the Arg152-Ile153 peptide bond. I SIGNOR-263638 0.354 dehydroepiandrosterone chemical CHEBI:28689 ChEBI androst-5-ene-3beta,17beta-diol smallmolecule CHEBI:2710 ChEBI up-regulates quantity precursor of 9606 BTO:0001363 30943210 t lperfetto Testicular 17betaHSD3 converts DHEA to androstenediol and androstenedione to testosterone SIGNOR-268659 0.8 CDK1 protein P06493 UNIPROT CDC7 protein O00311 UNIPROT up-regulates phosphorylation Thr376 QVAPRAGtPGFRAPE 9606 10846177 t gcesareni Hucdc7 and ask proteins can also be phosphorylated by cdks in vitro. Among four possible cdk phosphorylation sites of hucdc7, replacement of thr-376, corresponding to the activating threonine of cdk, with alanine (t376a mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue. SIGNOR-78311 0.55 TBR1 protein Q16650 UNIPROT FOXP2 protein O15409 UNIPROT up-regulates activity binding 9606 25232744 t miannu We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. SIGNOR-266831 0.572 RAF1 protein P04049 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 15849194 t Ser112 corresponds to EIRSRHSsYPAGTED lperfetto Raf-1 protects cells from apoptosis, independently of its signals to MEK and ERK, by translocating to the mitochondria where it binds Bcl-2 and displaces BAD|Upon phosphorylation by Pak1, Raf-1 translocates to mitochondria and phosphorylates BAD at Ser-112. SIGNOR-81165 0.645 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A11 protein P48066 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206990 0.8 NTN4 protein Q9HB63 UNIPROT UNC5 proteinfamily SIGNOR-PF98 SIGNOR up-regulates activity binding 9606 BTO:0001484 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268184 0.595 palbociclib chemical CHEBI:85993 ChEBI CDK4 protein P11802 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205704 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 25846811 t lperfetto Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK. SIGNOR-244595 0.2 CHEK2 protein O96017 UNIPROT RASGRF1 protein Q13972 UNIPROT down-regulates phosphorylation Ser287 PITHDDVsSIFLNSE 9606 17110335 t miannu During interphase, cdc25 is inhibited by ser287 phosphorylation (xenopus cdc25;ser 216 in human cdc25c) and this inhibitory phosphorylation is maintained by dna-responsive checkpoints / s287 is targeted by many kinases, including chk1, chk2, ctak-1, pka, p38 and mapkap kinase-2 suggesting that phosphorylation of this site may integrate multiple signaling inputs. SIGNOR-150843 0.379 PRKCB protein P05771 UNIPROT MEP1B protein Q16820 UNIPROT down-regulates quantity phosphorylation Ser687 KKYRERMsSNRPNLT 9534 12941954 t miannu These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate. SIGNOR-263173 0.2 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258183 0.8 SRC protein P12931 UNIPROT TXK protein P42681 UNIPROT up-regulates activity phosphorylation Tyr420 RYVLDDEyVSSFGAK 9606 11353545 t lperfetto We further demonstrate that Rlk can be phosphorylated and activated by Src kinases, leading to a decrease in its half-life. A specific tyrosine in the activation loop of Rlk, Y420, is required for phosphorylation and activation, as well as for decreased stability, but is not required for lipid RAFT association. SIGNOR-247346 0.354 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser44 LENDFFNsPPRKTVR 9606 15004009 t lperfetto Cdk2/cyclin e-mediated phosphorylation at ser 44 activates tif-ia SIGNOR-216682 0.486 SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR MBD4 protein O95243 UNIPROT up-regulates activity sumoylation Lys215 TSTHLLLkEDEGVDD 31476572 t lperfetto MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro. SIGNOR-275680 0.2 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Thr171 RGTLRKGtLGSKGQK -1 23444369 t miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. SIGNOR-273488 0.27 PKI-402 chemical CID:44187953 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206259 0.8 RET protein P07949 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates binding 9606 12087092 t amattioni Dok proteins directly associate with tyrosine 1062 of ret and could be its substrates. Phosphorylation of dok1 is necessary for interaction with ras-gap in vitro and in vivo. Dok1 is a negative regulator for the ras/erk signaling pathway activated by ret. SIGNOR-90158 0.597 MBD4 protein O95243 UNIPROT CYP27B1 protein O15528 UNIPROT up-regulates quantity by expression transcriptional regulation 23195996 t lperfetto Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12] SIGNOR-275682 0.385 MBD4 protein O95243 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 23195996 f lperfetto The base excision repair DNA N-glycosylase MBD4 (also known as MED1), an interactor of the DNA mismatch repair protein MLH1, plays a central role in the maintenance of genomic stability of CpG sites by removing thymine and uracil from G:T and G:U mismatches, respectively.  SIGNOR-275683 0.7 MBD4 protein O95243 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23195996 f lperfetto The base excision repair DNA N-glycosylase MBD4 (also known as MED1), an interactor of the DNA mismatch repair protein MLH1, plays a central role in the maintenance of genomic stability of CpG sites by removing thymine and uracil from G:T and G:U mismatches, respectively.  SIGNOR-275684 0.7 UVB radiation stimulus SIGNOR-ST17 SIGNOR DDB1 protein Q16531 UNIPROT up-regulates 24086042 f lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). SIGNOR-275685 0.7 GNAO1 protein P09471 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates -1 10224115 f G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics. SIGNOR-256525 0.7 RNF8 protein O76064 UNIPROT H2AC11 protein P0C0S8 UNIPROT up-regulates ubiquitination 9606 20551964 t gcesareni Rnf8 and ubc13 ubiquitylate h2a and h2ax, but other substrates probably exist. SIGNOR-166174 0.2 PYY protein P10082 UNIPROT NPY5R protein Q15761 UNIPROT up-regulates binding 9606 11825645 t esanto Maml3 forms complexes in vivo with icn and csl and functiosn as transcriptional coactivators for notch signaling. SIGNOR-114749 0.629 NOX1 protein Q9Y5S8 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264714 0.7 TGFBR1 protein P36897 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 9606 19726546 t lperfetto Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity. SIGNOR-227496 0.284 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252083 0.2 phosphatidic acid smallmolecule CHEBI:16337 ChEBI MAPK1 protein P28482 UNIPROT up-regulates chemical activation 9606 BTO:0000887;BTO:0001103 20231899 t gcesareni In addition, extracellular signal-regulated kinase (erk) is stimulated by ampk-induced pld1 activation through the formation of phosphatidic acid (pa), which is a product of pld SIGNOR-164289 0.8 CHRM2 protein P08172 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256828 0.377 glycogen smallmolecule CHEBI:28087 ChEBI alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity precursor of 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [‚Ķ] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267391 0.8 TFAP4 protein Q01664 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates activity binding 9606 BTO:0001109 19505873 t miannu We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads. SIGNOR-226590 0.286 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates phosphorylation 9606 16862148 t acerquone Rock phosphorylates filgap, and this phosphorylation stimulates its racgap activity and is a requirement for filgap-mediated bleb formation SIGNOR-148262 0.444 NOTCH1 protein P46531 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19151708 f gcesareni Notch1 directly induces transcription of pin1 SIGNOR-183458 0.393 PRKCZ protein Q05513 UNIPROT STK11 protein Q15831 UNIPROT up-regulates phosphorylation Ser307 IRQIRQHsWFRKKHP 9606 BTO:0000887;BTO:0001103;BTO:0001260 19414597 t llicata Here, we have identified s307 as a novel phosphorylation site in lkb1 and provide evidence that, in multiple cell types, phosphorylation of this site by protein kinase c ? (pkc-?) Induces nucleocytoplasmic transport of lkb1. SIGNOR-185640 0.326 ITGAX protein P20702 UNIPROT AX/b2 integrin complex SIGNOR-C171 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253193 0.824 ERCC6 protein Q03468 UNIPROT RAD23B protein P54727 UNIPROT up-regulates activity 24086043 f lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275694 0.467 Thrombin-Thrombomodulin complex SIGNOR-C316 SIGNOR PROC protein P04070 UNIPROT up-regulates activity cleavage 9606 BTO:0000131 29880919 t lperfetto Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC). SIGNOR-263526 0.709 ACTB protein P60709 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270717 0.476 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 25309941 f Following GSK3β activation, NF-κB is translocated from the cytoplasm to the nucleus and binds transcriptional sites with CBP leading to an increase in the transcription of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6). SIGNOR-255489 0.7 TGFB3 protein P10600 UNIPROT TGFB3 protein P10600 UNIPROT up-regulates binding 9606 16885528 t gcesareni The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge SIGNOR-148611 0.2 NLGN3 protein Q9NZ94 UNIPROT NRXN2 protein P58401 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264157 0.824 RNF31 protein Q96EP0 UNIPROT IKBKG protein Q9Y6K9 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 24469399 t miannu Involvement of Gln271 and Asp275 of NEMO in LUBAC-mediated linear polyubiquitination.vHOIP NZF1 also recognizes NEMO, and this recognition is involved in linear polyubiquitination of NEMO. Linear chains conjugated to NEMO are recognized by NEMO in trans on another IKK complex, thereby inducing multimerization of the IKK complex and trans autophosphorylation of IKK2. SIGNOR-272052 0.844 Gbeta proteinfamily SIGNOR-PF4 SIGNOR STAT5A protein P42229 UNIPROT up-regulates phosphorylation 9606 BTO:0000975 10194762 t inferred from 70% family members gcesareni Serine 780 is the only substrate in full-length stat5a for active erk SIGNOR-270004 0.2 GATA1 protein P15976 UNIPROT NBEAL2 protein Q6ZNJ1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000132 28082341 f lperfetto In conclusion, we herein show a long-distance regulatory region with GATA1 binding sites as being a strong enhancer for NBEAL2 expression. SIGNOR-261881 0.383 CNTNAP2 protein Q9UHC6 UNIPROT CNTN1 protein Q12860 UNIPROT up-regulates activity relocalization 10090 BTO:0001221 11069942 t Gianni These results suggest that the targeting of contactin to different axonal domains may be determined, in part, via its association with Caspr. SIGNOR-269074 0.489 HDAC5 protein Q9UQL6 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates binding 9606 11062529 t gcesareni The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis. SIGNOR-84026 0.684 PPP2CA protein P67775 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Ser12 KSKPKDAsQRRRSLE 9606 BTO:0001938 18069897 t gcesareni We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC SIGNOR-247970 0.44 DDX5 protein P17844 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 10090 BTO:0000165 17960593 t miannu P68 (ddx5) interacts with runx2 and regulates osteoblast differentiation. / p68 is a novel co-activator for runx2 SIGNOR-236974 0.465 DLGAP5 protein Q15398 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 9115257 t miannu SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area. SIGNOR-264213 0.401 SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 11154281 t lperfetto We show here that sgk1, like akt, promotes cell survival and that it does so in part by phosphorylating and inactivating fkhrl1. However, sgk and akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on fkhrl1. While both kinases can phosphorylate thr-32, sgk displays a marked preference for ser-315 whereas akt favors ser-253. SIGNOR-236607 0.787 ATG12/5/16L1 complex SIGNOR-C109 SIGNOR Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates -1 23321721 f lperfetto Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation SIGNOR-226702 0.7 CDH15 protein P55291 UNIPROT CDON protein Q4KMG0 UNIPROT up-regulates activity binding 9606 12634428 t lperfetto Cdo binds promyogenic cadherins form complexes with n- and m-cadherin. SIGNOR-99250 0.478 ACIN1 protein Q9UKV3 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 10490026 f Cleaved by CASP3 amattioni Acinus induces apoptotic chromatin condensation after cleavage by caspase-3 without inducing dna fragmentation. SIGNOR-70797 0.7 125-L-serine-2-133-interleukin 2 (human reduced) smallmolecule SID:46508054 ChEBI IL2RA protein P01589 UNIPROT up-regulates activity chemical activation 9606 18031103 t miannu Aldesleukin (recombinant IL-2) has similar pharmacodynamic properties to endogenous IL-2 and, when administered to patients with cancer, stimulates the antitumour immune response. SIGNOR-259388 0.8 JNK proteinfamily SIGNOR-PF15 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 15916964 t lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities SIGNOR-137627 0.2 regorafenib chemical CHEBI:68647 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259211 0.8 MAPK8 protein P45983 UNIPROT SFN protein P31947 UNIPROT down-regulates phosphorylation Ser186 FHYEIANsPEEAISL 9606 15071501 t JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8 gcesareni Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-187. SIGNOR-124016 0.345 GRB14 protein Q14449 UNIPROT INSR protein P06213 UNIPROT down-regulates activity binding 24535599 t lperfetto Growth factor receptor-bound protein 14 (Grb14) interacts with insulin receptor (IR) through the between PH and SH2 (BPS) domain. Grb14-IR complex formation is initiated by insulin stimulation, and the binding event results in the inhibition of insulin signalling. SIGNOR-264873 0.751 MGluR proteinfamily SIGNOR-PF55 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264690 0.7 TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity binding 9606 9020361 t lperfetto NIK binds to Traf2 and stimulates NF-kappaB activity. SIGNOR-46215 0.569 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid chemical CHEBI:76223 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 22091869 t Luana  Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2.  SIGNOR-258324 0.8 ACP1 protein P24666 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 10090 19088431 t LMWPTP dephosphorylated pY(527)-Src and pY(416)-Src in vitro, with greater specificity for pY(527)Src. Activation of LMWPTP produced strong activation of Src mediated by fast dephosphorylation of pY(527)-Src, followed by slower deactivation of this kinase via dephosphorylation of pY(416)Src. SIGNOR-248454 0.449 NAT8L protein Q8N9F0 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 19524112 t miannu The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA. SIGNOR-267524 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR TH protein P07101 UNIPROT up-regulates phosphorylation 9606 7901013 t inferred from 70% family members gcesareni In this paper we have studied the phosphorylation and activation of alternatively spliced forms of human th by mapkap kinase-1 , mapkap kinase-2, map kinase, and cam kinase-11 SIGNOR-270055 0.2 PRKCD protein Q05655 UNIPROT ADRA2A protein P08913 UNIPROT up-regulates activity phosphorylation Ser247 RRTRVPPsRRGPDAV 10029 BTO:0000246 11732925 t lperfetto Taken together, these results indicate that S232 acts as a selective, PKC-sensitive, modulator of effector coupling of the alpha(2A)AR to inositol phosphate stimulation. This represents one mechanism by which cells route stimuli directed to multifunctional receptors to selected effectors so as to attain finely targeted signaling. SIGNOR-249126 0.513 EFL1 protein Q7Z2Z2 UNIPROT EIF6 protein P56537 UNIPROT up-regulates 9606 BTO:0001271 21536732 f miannu Human sbds is an essential cofactor for the efl1 gtpase, and together they cooperate to directly catalyze the release of eif6 from mammalian pre-60s ribosomal subunits SIGNOR-173492 0.2 NAALAD2 protein Q9Y3Q0 UNIPROT N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI up-regulates quantity chemical modification 9606 10085079 t miannu The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. SIGNOR-267543 0.8 TFDP1 protein Q14186 UNIPROT RRM1 protein P23921 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253866 0.286 CCL19 protein Q99731 UNIPROT ACKR4 protein Q9NPB9 UNIPROT up-regulates activity binding 9606 BTO:0001938 23341447 t Luana  In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines. SIGNOR-268416 0.65 SIRT1 protein Q96EB6 UNIPROT CRTC1 protein Q6UUV9 UNIPROT up-regulates deacetylation 9606 BTO:0000938 BTO:0000142 22179316 t miannu Sirt1 deacetylates and activates torc1 SIGNOR-191568 0.285 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0002552 17967874 t gcesareni The increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. SIGNOR-158636 0.838 PI-103 chemical CHEBI:90524 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252651 0.8 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates phosphorylation Ser49 IEGMILLsELSRRRI 9606 10563826 t lperfetto The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases present in the reticulocyte lysate. These findings support the hypothesis that the serine 48 residue is required for high-affinity interaction between eif2 alpha(p) and eif2b. SIGNOR-72152 0.886 EGFR protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 14967450 t lperfetto The egf-r coimmunoprecipitated with p85 alpha SIGNOR-252672 0.773 AMPK complex SIGNOR-C15 SIGNOR HDAC4 protein P56524 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 BTO:0000887 21565617 t lperfetto We show here that in liver, class iia hdacs (hdac4, 5, and 7) are phosphorylated and excluded from the nucleus by ampk family kinases. SIGNOR-216658 0.275 RHOBTB1 protein O94844 UNIPROT PDE5A protein O76074 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 30896450 t miannu RhoBTB1 augmented the cGMP response to nitric oxide by restraining the activity of phosphodiesterase 5 (PDE5) by acting as a substrate adaptor delivering PDE5 to the Cullin-3 E3 Ring ubiquitin ligase complex for ubiquitination inhibiting PDE5. SIGNOR-272312 0.2 EXOC7 protein Q9UPT5 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates 9606 12687004 f gcesareni So, the exocyst might have a crucial role in the targeting of the glut4 vesicle to the plasma membrane, perhaps directing the vesicle to the precise site of fusion SIGNOR-100242 0.529 RNF138 protein Q8WVD3 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 16714285 t miannu Here, we show that NARF induces the ubiquitylation of TCF/LEF in vitro and in vivo, and functions as an E3 ubiquitin-ligase that specifically cooperates with the E2 conjugating enzyme E2-25K. We found that NLK augmented NARF binding and ubiquitylation of TCF/LEF, and this required NLK kinase activity. The ubiquitylated TCF/LEF was subsequently degraded by the proteasome. SIGNOR-271595 0.312 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates activity phosphorylation Thr87 GVPAEGRtPPPFPGE 9606 BTO:0000887 11342557 t lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation SIGNOR-107680 0.346 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI citrate(3-) smallmolecule CHEBI:16947 ChEBI up-regulates quantity precursor of 9606 3013232 t miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. SIGNOR-266237 0.8 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Thr2214 GGRSVPTtPLQVAAP 9606 18794356 t miannu Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore. SIGNOR-181026 0.382 TGFB2 protein P61812 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 11157754 t gcesareni We show that tbetarii-b, an alternatively spliced variant of the tgf-beta type ii receptor, is a tgf-beta2 binding receptor, which mediates signalling via the smad pathway in the absence of any tgf-beta type iii receptor SIGNOR-104795 0.744 BCAR1 protein P56945 UNIPROT PKN3 protein Q6P5Z2 UNIPROT up-regulates activity binding 10090 BTO:0002572 30422386 t lperfetto Taken together, the data suggest that p130Cas expression induces PKN3 activation and this activation is independent of p130Cas–PKN3 interaction. SIGNOR-264573 0.2 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser499 VKSRWSGsQQVEQPT 9606 12551925 t gcesareni For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1. SIGNOR-97644 0.539 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206385 0.8 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227878 0.891 CHMP2A protein O43633 UNIPROT Viral_budding phenotype SIGNOR-PH125 SIGNOR up-regulates -1 30989108 f miannu ESCRT-III has been proposed to assemble inside the membrane neck formed at a late stage of a budding vesicle or an enveloped virus. The membrane neck needs to be constricted to proceed to membrane fission, thereby splitting the vesicle or virus from the cellular membrane. CHMP2A and CHMP3 are engaged late in ESCRT-III assembly, recruit VPS4 (31, 42), and block Snf7 (CHMP4) polymerization SIGNOR-260844 0.7 KLF4 protein O43474 UNIPROT HSPA8 protein P11142 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0003292 18379898 f miannu The results showed the upregulation of the HSP73 constitutive expression by KLF4 overexpression in both C2C12 cells and murine RAW264.7 macrophages; in response to heat stress, however, few changes were observed in the levels of HSP73 by KLF4 overexpression. SIGNOR-254544 0.2 RABEP1 protein Q15276 UNIPROT RAB5A protein P20339 UNIPROT up-regulates binding 9606 11452015 t miannu We have previously shown that rab5, which regulates various steps of transport along the early endocytic pathway, is activated by a complex consisting of rabex-5, a rab5 nucleotide exchange factor, and the effector rabaptin-5. SIGNOR-109352 0.927 PRKCD protein Q05655 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 16418226 t gcesareni Abrogation of pkcdelta activity inhibited insulin-induced stat3 phosphorylation, pkcdelta-stat3 association and nuclear translocation. SIGNOR-143828 0.579 CDK2 protein P24941 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Ser387 LSEQNRAsPLPSGLL 9606 19561641 t gcesareni Phosphorylation of threonine 395 has been linked to the proteasome-mediated degradation of full length cyclin e SIGNOR-186414 0.954 OTUB1 protein Q96FW1 UNIPROT ESR1 protein P03372 UNIPROT down-regulates activity deubiquitination 19383985 t lperfetto OTU Domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER) alpha and affects ERalpha transcriptional activity.|We show that OTUB1 negatively regulates transcription mediated by ERalpha in transient reporter gene assays and transcription mediated by endogenous ERalpha in Ishikawa endometrial cancer cells. SIGNOR-276529 0.527 PPP2CA protein P67775 UNIPROT CILK1 protein Q9UPZ9 UNIPROT down-regulates dephosphorylation Tyr159 SKPPYTDyVSTRWYR 9606 15988018 t lperfetto In addition, mass spectrometry showed that pp2a treatment completely abolished the dually phosphorylated form, leaving only the singly phosphorylated form (data not shown). We conclude that a portion of ick in unstimulated and asynchronized hek293t cells is dually phosphorylated on the tdy motif. SIGNOR-138432 0.2 flumazenil chemical CHEBI:5103 ChEBI GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t brain lperfetto Receptors containing the alpha4 or alpha6 subunits, together with beta and gamma2, do not bind the traditional BZ agonists, including zolpidem, but demonstrate high affinity for some ligands, notably the imidazobenzodiazepines such as flumazenil and Ro15-4513, or bretazenil SIGNOR-263807 0.8 TRAF3 protein Q13114 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16306937 f miannu TRAF3 is essential for the induction of type I interferons (IFN) and the anti-inflammatory cytokine interleukin-10 (IL-10), but is dispensable for expression of pro-inflammatory cytokines. SIGNOR-256077 0.336 perfluorononanoic acid chemical CHEBI:38397 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 23764977 t miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  SIGNOR-268769 0.8 ESCRT-III complex SIGNOR-C379 SIGNOR Cytoskeleton_organization phenotype SIGNOR-PH89 SIGNOR up-regulates 9606 26775243 f miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. SIGNOR-265535 0.7 PTPN1 protein P18031 UNIPROT SRC protein P12931 UNIPROT up-regulates dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 12857726 t gcesareni The tyrosine kinase pp60c-src has also been identified as a good substrate of ptp1b leading to an activation of this kinase (27). SIGNOR-103607 0.772 PRKCG protein P05129 UNIPROT STXBP1 protein P61764 UNIPROT unknown phosphorylation Ser306 VSQEVTRsLKDFSSS -1 12519779 t lperfetto Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation. SIGNOR-249184 0.394 orotate smallmolecule CHEBI:30839 ChEBI orotidine 5'-phosphate(3-) smallmolecule CHEBI:57538 ChEBI up-regulates quantity precursor of 9606 2912371 t miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). SIGNOR-267434 0.8 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 10090 BTO:0000165 17151142 f lperfetto These results indicate that TNF-alpha regulates myogenesis and muscle regeneration as a key activator of p38. SIGNOR-235370 0.379 dexamethasone chemical CHEBI:41879 ChEBI CEBPD protein P49716 UNIPROT up-regulates quantity by expression 9606 8754811 f fspada The differentiation of 3t3 preadipocytes into adipocytes is accompanied by a transient induction of c/ebpbeta and c/ebpdelta expression in response to treatment of the cells with methylisobutylxanthine (mix) and dexamethasone (dex), respectively SIGNOR-43254 0.8 HDAC1 protein Q13547 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 9606 BTO:0000887 11684023 t gcesareni Interaction of myod with hdac1 in undifferentiated myoblasts mediates repression of muscle-specific gene expression. SIGNOR-111243 0.563 GOPC protein Q9HD26 UNIPROT ADRB1 protein P08588 UNIPROT down-regulates relocalization 9606 15358775 t miannu Overexpression of cal reduces surface expression of beta1ar. Interaction with cal promotes retention of beta1ar within the cell SIGNOR-128791 0.349 SLC25A13 protein Q9UJS0 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity relocalization 9606 12084073 t miannu Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. SIGNOR-265155 0.8 AMPK complex SIGNOR-C15 SIGNOR AMOTL1 protein Q8IY63 UNIPROT up-regulates quantity by stabilization phosphorylation Ser793 SSLRPARsVPSIAAA 9606 BTO:0000007 25373897 t miannu we show that AMPK directly phosphorylates S793 of AMOTL1. AMPK activation stabilizes and increases AMOTL1 steady-state protein levels, contributing to YAP inhibition. SIGNOR-263105 0.2 MAPK3 protein P27361 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Thr577 AENGLLMtPCYTANF 9606 10980595 t llicata We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway SIGNOR-81464 0.719 SCF-betaTRCP complex SIGNOR-C5 SIGNOR ATF4 protein P18848 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 11238952 t miannu Here we show that the F-box protein betaTrCP, the receptor component of the SCF E3 ubiquitin ligase responsible for IkappaBalpha and beta-catenin degradation, is colocalized in the nucleus with ATF4, a member of the ATF-CREB bZIP family of transcription factors, and controls its stability. ATF4 ubiquitination in HeLa cells is enhanced in the presence of betaTrCP. SIGNOR-272580 0.333 SIK2 protein Q9H0K1 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Ser1490 AILNPPPsPATERSH 9606 BTO:0006293 35277657 t miannu Mechanistically, SIK2, phosphorylated by CK1α, directly phosphorylated LRP6 in a SIK2 kinase activity-dependent manner, leading to Wnt/β-catenin signaling pathway activation. SIGNOR-275399 0.2 PPAT protein Q06203 UNIPROT 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI up-regulates quantity chemical modification 9606 8106516 t Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed‚Äù SIGNOR-267190 0.8 HSPA1A protein P0DMV8 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates binding 9606 21730050 t gcesareni Interestingly, FKBP51 forms complexes in mitochondria with the glucocorticoid receptor and the Hsp90/Hsp70-based chaperone heterocomplex SIGNOR-251668 0.618 BKM120 chemical CHEBI:71954 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190386 0.8 RUNX2 protein Q13950 UNIPROT ELANE protein P08246 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004850 14594802 f miannu We find that LEF-1 and CBFalpha co-activate ELA2 expression. SIGNOR-254552 0.259 PIEZO1 protein Q92508 UNIPROT Hair cells mechanotransduction channel complex SIGNOR-C290 SIGNOR form complex binding 10090 BTO:0000630 23217710 t lperfetto The pore forming subunits of the hair cells mechanotransduction channel still need to be identified, but some candidates have emerged including TMC-1,TMC-2 (Kawashima et al., 2011), Piezo1 and Piezo2 (Coste et al., 2010; Coste et al., 2012). SIGNOR-262571 0.397 CSNK2B protein P67870 UNIPROT CDC34 protein P49427 UNIPROT unknown phosphorylation Ser231 FGDDEDDsGTEES 9606 BTO:0000567 11546811 t llicata CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm.  SIGNOR-251059 0.358 ARNT protein P27540 UNIPROT CYP1A1 protein P04798 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17012224 t miannu Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1. SIGNOR-259910 0.632 MAPK14 protein Q16539 UNIPROT RBSN protein Q9H1K0 UNIPROT up-regulates phosphorylation Ser215 ESLSTHTsPSQSPNS 9606 16138080 t lperfetto We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes SIGNOR-140143 0.2 GNAI2 protein P04899 UNIPROT TNFAIP8 protein O95379 UNIPROT up-regulates activity binding 9606 20607800 t TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation SIGNOR-256492 0.2 CCNA1 protein P78396 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001884 15829981 f miannu SiRNA mediated silencing of cyclin A1 in highly cyclin A1 expressing ML1 leukemic cells significantly slowed S phase entry, decreased proliferation and inhibited colony formation.  SIGNOR-255734 0.7 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser300 SMSDPGVsYRTREEI -1 11486000 t lperfetto Activity of the mammalian pyruvate dehydrogenase complex is regulated by phosphorylation-dephosphorylation of the alpha subunit of the pyruvate dehydrogenase (e1) component. Phosphorylation is carried out by four pyruvate dehydrogenase kinase (pdk) isoenzymes. SIGNOR-109651 0.866 1038915-60-4 chemical CID:24958200 PUBCHEM PARP2 protein Q9UGN5 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194402 0.8 LRRK2 protein Q5S007 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation 9606 22303461 t gcesareni Lrrk2 directly phosphorylates tubulin-associated tau, but not free tau;(iii) lrrk2 phosphorylates tau at thr181 as one of the target sites;. furthermore, we revealed that lrrk2-mediated phosphorylation of tau reduces its tubulin-binding ability. SIGNOR-195756 0.543 HRAS protein P01112 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9534 BTO:0004055 8052307 t lperfetto In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-252689 0.84 GSK3B protein P49841 UNIPROT EIF2B3 protein Q9NR50 UNIPROT down-regulates binding 9606 21798082 t gcesareni Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b). SIGNOR-175520 0.264 RBPJ protein Q06330 UNIPROT MAML3 protein Q96JK9 UNIPROT up-regulates binding 9606 21873209 t gcesareni When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects. SIGNOR-176200 0.873 GDF11 protein O95390 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates binding 9606 12414726 t gcesareni Here we demonstrate using genetic and biochemical studies that actriib and its subfamily receptor, actriia, cooperatively mediate the gdf11 signal in patterning the axial vertebrae, and that gdf11 binds to both actriia and actriib, and induces phosphorylation of smad2 SIGNOR-95309 0.644 CH5132799 chemical CID:49784945 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252648 0.8 SRC protein P12931 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Tyr21 IENEEQEyVQTVKSS 9606 24103589 t lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].Finally in 2013 caron et al. showed the relevance of y21 phosphorylation for the anxa1 stability. In fact the authors demonstrated that the tyrosine 21 phosphorylation is crucial for anxa1 sumoylation induced by egf SIGNOR-202796 0.398 SMN complex complex SIGNOR-C158 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 9323129 f lperfetto These findings suggest a role for SMN and SIP1 in spliceosomal snRNP biogenesis and function and provide a likely molecular mechanism for the cause of SMA SIGNOR-253123 0.7 CUL5 protein Q93034 UNIPROT DAB1 protein O75553 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 24210661 t miannu SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SIGNOR-272140 0.333 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT unknown phosphorylation Tyr178 EEAERKLySGAQTDG 9606 BTO:0000661 7961936 t We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. SIGNOR-251392 0.602 Caspase 3 complex complex SIGNOR-C221 SIGNOR CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9922454 t amattioni Caspase-3 is required for the activation of caspases 6 SIGNOR-256467 0.602 pimozide chemical CHEBI:8212 ChEBI STAT5A protein P42229 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001545 23264850 t miannu We have identified the psychotropic drug pimozide as an effective inhibitor of STAT5 function. Pimozide inhibits the tyrosine phosphorylation of STAT5, leading to the death of AML cells through the induction of apoptosis. SIGNOR-260125 0.8 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 BTO:0000195 17289681 t The effect has been demonstrated using P34152-3 gcesareni We propose that fak/c-src bipartite enzyme is a sensor of cytoplasmic shrinkage, and that the phosphorylation on fak tyr-861 by src and subsequent reorganization of f-actin can initiate an anti-apoptotic signaling pathway that protects cells from hyperosmotic stress. SIGNOR-152971 0.634 SYVN1 protein Q86TM6 UNIPROT NFE2L2 protein Q16236 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 29731393 t miannu NRF2 is negatively regulated by three E3 ubiquitin ligase complexes: the KEAP1-CUL3-RBX1 complex, the β-TrCP-SKP1-CUL1-RBX1 complex, and HRD1. SIGNOR-267360 0.2 CSNK2A1 protein P68400 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Thr236 VEKFKDNtIPDKVKK 9606 15064744 t lperfetto Inhibition of protein kinase ck2 enzyme activity in vivo resulted in an enhanced nuclear localization of cdc25c. Thus, phosphorylation of cdc25c at threonine 236 is an important signal for the retention of cdc25c in the cytoplasm SIGNOR-123713 0.307 AKT1 protein P31749 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR up-regulates phosphorylation 9606 BTO:0000887 17964260 t lperfetto Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. SIGNOR-217670 0.597 apraclonidine chemical CHEBI:2788 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation -1 8784451 t miannu we describe full details of our studies with 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline (AGN 193080, 3), a potent, selective α2 adrenoceptor agonist that does not cross the blood−brain barrier. SIGNOR-258498 0.8 N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide chemical CHEBI:125619 ChEBI HTR1A protein P08908 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207779 0.8 CH5132799 chemical CID:49784945 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190943 0.8 MAOB protein P27338 UNIPROT (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI up-regulates quantity chemical modification 9606 BTO:0000142 20493079 t Luana The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. SIGNOR-269747 0.8 p38 proteinfamily SIGNOR-PF16 SIGNOR CDC25C protein P30307 UNIPROT down-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR 9606 11333986 t lperfetto P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteins phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 SIGNOR-107420 0.2 PIP3 smallmolecule CHEBI:16618 ChEBI WDR45B protein Q5MNZ6 UNIPROT up-regulates activity chemical activation 9606 BTO:0001938 28561066 t miannu All WIPI members fold into seven-bladed β-propeller proteins that bind PtdIns3P and co-localize at nascent autophagosomes. SIGNOR-268476 0.8 FGF18 protein O76093 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 t tpavlidou Fgfs bind and activate high-affinity receptor tyrosine kinases. The cloning of fgf receptors (fgfrs) has identified four distinct genes SIGNOR-42368 0.719 MAPK1 protein P28482 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 10090 BTO:0000944 15060146 t miannu Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation. SIGNOR-260086 0.323 GSK3A protein P49840 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Ser1490 AILNPPPsPATERSH 9606 35487243 t miannu Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493 SIGNOR-275398 0.617 N-(1,3-benzodioxol-5-ylmethyl)-4-(4-benzofuro[3,2-d]pyrimidinyl)-1-piperazinecarbothioamide chemical CHEBI:91389 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189525 0.8 ESR1 protein P03372 UNIPROT CYP19A1 protein P11511 UNIPROT down-regulates quantity by repression transcriptional regulation 11973645 t lperfetto By binding to S1, ERalpha down-regulates the aromatase promoter activity. SIGNOR-271683 0.531 vitamin K epoxide smallmolecule CHEBI:28371 ChEBI VKORC1L1 protein Q8N0U8 UNIPROT up-regulates activity chemical activation 9606 31226734 t lperfetto This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR) SIGNOR-265916 0.8 CDK5 protein Q00535 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser129 ICPSLPYsPVSSPQS 9606 22778263 t lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. SIGNOR-198111 0.2 4-(4-fluoronaphthalen-1-yl)-6-isopropylpyrimidin-2-amine chemical CID:196968 PUBCHEM HTR2B protein P41595 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206658 0.8 CDK5RAP2 protein Q96SN8 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19282672 t Giulio These data indicate that CDK5RAP2 is a positive regulator of both the BUBR1 promoter and the MAD2 promoter SIGNOR-260313 0.313 PIK3R3 protein Q92569 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 9415396 t gcesareni The region between the src homology 2 (sh2) domains of p55pik bound to the nh2 terminus region of p110alpha SIGNOR-252723 0.731 SIRT1 protein Q96EB6 UNIPROT 2''-O-acetyl-ADP-D-ribose(2-) smallmolecule CHEBI:83767 ChEBI up-regulates quantity chemical modification 9606 18662546 t miannu The SIRT1 catalytic reaction involves the breakdown of one NAD+ molecule for each deacetylated acetyl lysine and the generation of nicotinamide and O-acetyl-ADP-ribose. SIGNOR-267963 0.8 SMAD3 protein P84022 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14993291 f gcesareni Smad3 is required for both tgf-beta-induced repression of c-myc and subsequent growth arrest in keratinocytes SIGNOR-123087 0.672 PKN1 protein Q16512 UNIPROT PGAM1 protein P18669 UNIPROT down-regulates phosphorylation Ser23 WNLENRFsGWYDADL 9606 BTO:0000130 12189148 t llicata Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity. SIGNOR-91606 0.256 PER2 protein O15055 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 22260161 f apalma We have previously shown that PER2 is a downstream CCAAT-enhancer-binding protein (C/EBP)-target gene, and its disruption might be involved in the initiation and progression of acute myelogenous leukemia (AML) SIGNOR-256371 0.7 KDM5B protein Q9UGL1 UNIPROT SOX2 protein P48431 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000815 31776402 t lperfetto Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes. SIGNOR-273450 0.314 EPHB3 protein P54753 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates activity phosphorylation Tyr614 VYIDPFTyEDPNEAV -1 9674711 t Tyrosine-614, the major autophosphorylation site of the receptor tyrosine kinase HEK2, functions as multi-docking site for SH2-domain mediated interactions. a single amino acid substitution (Y614F) clearly reduces the phosphotyrosine content of HEK2 and abrogates its ability to bind rasGAP, Crk and Fyn indicating that this residue functions as major phosphorylation and multi-docking site. SIGNOR-251126 0.2 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR GRB10 protein Q13322 UNIPROT up-regulates binding 9606 15722337 t miannu The interaction of phosphorylated grb10 with 14-3-3 may lead to the translocation of grb10 back to the cytosol SIGNOR-134198 0.2 CEP43 protein O95684 UNIPROT MAPRE1 protein Q15691 UNIPROT up-regulates relocalization 9606 16314388 t miannu Fop also binds to eb1 and is required for localizing eb1 to the centrosome SIGNOR-142400 0.2 NGFR protein P08138 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14699954 f amattioni Neurotrophin binding to p75ntr has also been shown to induce apoptosis SIGNOR-256655 0.7 TLR9 protein Q9NR96 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266749 0.45 PGLS protein O95336 UNIPROT 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI down-regulates quantity chemical modification 9606 31586547 t miannu The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG). SIGNOR-267057 0.8 MAML1 protein Q92585 UNIPROT CCNT1 protein O60563 UNIPROT up-regulates relocalization 9606 15546612 t gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. SIGNOR-130712 0.2 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 23863160 t lperfetto Raptor phosphorylation by ULK1 was sufficient to completely block Rheb-induced mTORC1 activity in cells as well as mTORC1 kinase activity invitro SIGNOR-209910 0.56 levomilnacipran chemical CHEBI:136040 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 18468895 t Luana Studies on a series of milnacipran analogs containing a heteroaromatic group as potent norepinephrine and serotonin transporter inhibitors SIGNOR-257946 0.8 HOXC13 protein P31276 UNIPROT FOXN1 protein O15353 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21191399 f miannu Hoxc13-dependent activation of foxn1 is part of a regulatory cascade controlling the expression of terminal differentiation markers. SIGNOR-170850 0.542 CEBPA protein P49715 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003697 18583320 t Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells. SIGNOR-254043 0.341 TYK2 protein P29597 UNIPROT TYK2 protein P29597 UNIPROT up-regulates activity phosphorylation Tyr1055 VPEGHEYyRVREDGD 9606 BTO:0000452 8702790 t lperfetto These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055The K930R mutant, bearing a mutation in the ATP binding site, is catalytically inactive (Fig. 3B, lanes 5 and 6). This protein is not basally phosphorylated, while the wt and the Y1054F/Y1055F proteins are (Fig. 3A), suggesting that autophosphorylation is responsible for the basal level of phosphorylation. SIGNOR-43092 0.2 ANKRD26 protein Q9UPS8 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 21669876 f lperfetto Ankrd26 gene disruption enhances adipogenesis of mouse embryonic fibroblasts. SIGNOR-266071 0.7 MAPK8 protein P45983 UNIPROT APLP2 protein Q06481 UNIPROT up-regulates phosphorylation Thr736 VEVDPMLtPEERHLN 9606 14970211 t lperfetto Phosphorylation at the thr(668) residue of app (with respect to the numbering conversion for the app 695 isoform) and the thr(736) residue of aplp2 (with respect to the numbering conversion for the aplp2 763 isoform) in their cytoplasmic domains acts as a molecular switch for their protein-protein interaction and is implicated in neural function(s) and/or alzheimer's disease pathogenesis. Here we demonstrate that both app and aplp2 can be phosphorylated by jnk at the thr(668) and thr(736) residues, respectively, in response to cellular stress. SIGNOR-122196 0.37 NR2C2 protein P49116 UNIPROT LHCGR protein P22888 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0000318 10644740 t Luana Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription. SIGNOR-266217 0.2 F2RL3 protein Q96RI0 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257245 0.2 tri-mu-sulfido-mu3-sulfido-triiron chemical CHEBI:21137 ChEBI SDH complex SIGNOR-C400 SIGNOR form complex binding 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. SIGNOR-267734 0.8 KIF7 protein Q2M1P5 UNIPROT GLI1 protein P08151 UNIPROT up-regulates quantity by stabilization binding 10090 19549984 t lperfetto Kif7 physically interacted with Gli transcription factors and controlled their proteolysis and stability, and acted both positively and negatively in Hh signaling. SIGNOR-209608 0.607 SMC3 protein Q9UQE7 UNIPROT MXD3 protein Q9BW11 UNIPROT down-regulates activity binding 9534 BTO:0000318 9528857 t 2 miannu We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions. SIGNOR-241281 0.301 GNG2 protein P59768 UNIPROT GNB1 protein P62873 UNIPROT up-regulates activity binding 10696571 t GNG2 dissociates from the activated receptor, bound with GNB1 as stable dimer. SIGNOR-251106 0.939 SP2 protein Q02086 UNIPROT IRF1 protein P10914 UNIPROT up-regulates activity binding 9606 BTO:0000552 19482358 t miannu Sp2 could be also able to interact with IRF-1 and this interaction is also observed on DNA indicating that by this way Sp2 is able to modulate IRF-1 transcriptional activity. SIGNOR-226478 0.345 regorafenib chemical CHEBI:68647 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259453 0.8 canagliflozin chemical CHEBI:73274 ChEBI SLC5A2 protein P31639 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190850 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR HNRNPA1 protein P09651 UNIPROT down-regulates phosphorylation Ser199 SQRGRSGsGNFGGGR 9606 18562319 t gcesareni Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199. SIGNOR-179059 0.2 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT up-regulates phosphorylation Tyr8 MEELQDDyEDMMEEN 9606 10942405 t llicata Our findings suggest that, upon phosphorylation by p72syk, y8 and y21 act as docking sites for the sh2 domain of lyn, which subsequently phosphorylates band 3 at additional secondary sites. SIGNOR-80792 0.462 AKT1 protein P31749 UNIPROT ATXN1 protein P54253 UNIPROT up-regulates quantity by stabilization phosphorylation Ser775 ATRKRRWsAPESRKL 9606 BTO:0000567 12757707 t Interaction of Ataxin-1 and 14-3-3 Requires Akt Phosphorylation at S776. 14-3-3 protein, a multifunctional regulatory molecule, mediates the neurotoxicity of ataxin-1 by binding to and stabilizing ataxin-1, thereby slowing its normal degradation. SIGNOR-252561 0.42 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 15905173 t lperfetto Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain SIGNOR-137251 0.2 AMPK complex SIGNOR-C15 SIGNOR PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser314 IQEVRSKsDPIMLLK -1 33022274 t miannu In vitro kinase assay revealed that PDHA could be readily phosphorylated by active AMPK complex in a dose-dependent manner (Figure 6C).  SIGNOR-276836 0.257 GMPS protein P49915 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 24462112 t miannu In response to genotoxic stress or nucleotide deprivation, gmps becomes nuclear and facilitates p53 stabilization by promoting its transfer from mdm2 to a gmps-usp7 deubiquitylation complex. SIGNOR-204409 0.387 EEF2 protein P13639 UNIPROT Translational_regulation phenotype SIGNOR-PH202 SIGNOR up-regulates 9606 30082469 f gianni … several key regulators of nervous system translation, including eukaryotic initiation factor 2α (eIF2α), the mechanistic (or mammalian) target of rapamycin complex 1 (mTORC1), and the eukaryotic elongation factor 2 (eEF2). These pathways regulate the overall rate of protein synthesis in neurons and have selective effects on the translation of specific messenger RNAs (mRNAs SIGNOR-268628 0.7 CYC-116 chemical CID:6420138 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191221 0.8 NFYC protein Q13952 UNIPROT NFY complex SIGNOR-C1 SIGNOR form complex binding 9606 BTO:0000801;BTO:0000876 9885213 t lperfetto Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding. SIGNOR-63019 0.966 ITLN1 protein Q8WWA0 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 35186726 f ITLN1 increases Akt phosphorylation in adipocytes, osteoblasts, and mesenchymal cells. |n mesenchymal stem cells, ITLN1 also leads to Akt-mediated proliferation, resistance to oxidative stress, and secretion of proangiogenic factors SIGNOR-272499 0.319 DIABLO protein Q9NR28 UNIPROT CASP9 protein P55211 UNIPROT up-regulates 9606 10929711 f gcesareni Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. SIGNOR-80215 0.726 PKI-402 chemical CID:44187953 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206253 0.8 PDHA2 protein P29803 UNIPROT PDH complex SIGNOR-C402 SIGNOR form complex binding 9606 20160912 t miannu The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. SIGNOR-267832 0.656 JUN protein P05412 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20338993 f miannu The activated c-Jun protein has been proven to activate binding to the MMP-13 promoter and also upregulate the amount of MMP-13. SIGNOR-254539 0.403 SNAI2 protein O43623 UNIPROT HPGD protein P15428 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004078 17575121 f miannu the Slug protein, but not ZEB1, binds to the PGDH promoter and represses transcription. SIGNOR-255172 0.267 EGFR protein P00533 UNIPROT VAV2 protein P52735 UNIPROT up-regulates phosphorylation Tyr159 HDLGEDIyDCVPCED 9606 12454019 t miannu To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor. SIGNOR-95976 0.61 MSTN protein O14793 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 19357233 f miannu In the current study, it was demonstrated that myostatin inhibits activation of Akt, in both myoblasts and myotubes. SIGNOR-255339 0.504 MMP11 protein P24347 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272356 0.7 PRKCZ protein Q05513 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser323 MVGGKPGsFRVRASS 9606 15069075 t gcesareni Thus, pkc-zeta might promote feedback ir/irs-1 complex formation and irs-1 tyrosine phosphorylation through phosphorylation of ser318. SIGNOR-123738 0.716 SP1 protein P08047 UNIPROT CYP27A1 protein Q02318 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11867220 f miannu Therefore, Sp1, Sp3 and HNF4 co-operate in the expression of the human CYP27 gene in HepG2 cells. SIGNOR-255199 0.324 N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide chemical CHEBI:91409 ChEBI AXL protein P30530 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190401 0.8 2-cyclopentyl-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid chemical CHEBI:95066 ChEBI SGK2 protein Q9HBY8 UNIPROT down-regulates activity chemical inhibition -1 18794135 t lperfetto GSK650394 quantitatively inhibits the activity of SGK1 and SGK2 in a scintillation proximity assay. SIGNOR-262018 0.8 2-[(3-bromo-5-tert-butyl-4-hydroxyphenyl)methylidene]propanedinitrile chemical CHEBI:93757 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189368 0.8 U0126 chemical CHEBI:90693 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 9873633 t lperfetto The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2. SIGNOR-244958 0.8 CAPN2 protein P17655 UNIPROT GSK3A protein P49840 UNIPROT up-regulates activity cleavage 9606 25969760 t lperfetto Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase SIGNOR-251612 0.2 PRKCE protein Q02156 UNIPROT OCLN protein Q16625 UNIPROT up-regulates phosphorylation Thr438 LYKRNFDtGLQEYKS 9606 21545357 t lperfetto Thr403, thr404, thr424 and thr438 in the occludin c-terminal domain are the predominant sites of pkc_-dependent phosphorylation . The present study demonstrates that pkc_ phosphorylates occludin on specific threonine residues and promotes assembly of epithelial tight junctions. SIGNOR-173643 0.2 L-thyroxine smallmolecule CHEBI:18332 ChEBI THRA protein P10827 UNIPROT up-regulates activity chemical activation 10116 BTO:0000759 2158622 t miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. SIGNOR-258382 0.8 CCL1 protein P22362 UNIPROT CCR8 protein P51685 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000785 12645948 t gcesareni Ccl1 activates the mapk pathway in ccr8-transfected cho cells. SIGNOR-99401 0.715 SENP1 protein Q9P0U3 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates desumoylation 9606 17981124 t miannu Sumo-specific protease 1 is essential for stabilization of hif1alpha during hypoxia / our results support a model in which sumoylated hif1_ is unstable but can be stabilized when sumo is removed by senp1 SIGNOR-158891 0.331 RHAG protein Q02094 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 t lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  SIGNOR-266020 0.412 SIRT4 protein Q9Y6E7 UNIPROT GLUD1 protein P00367 UNIPROT down-regulates activity glycosylation 9606 16959573 t miannu We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. SIGNOR-267828 0.604 PEX14 protein O75381 UNIPROT PEX5 protein P50542 UNIPROT up-regulates activity binding -1 15798189 t miannu The peroxisomal docking complex is a key component of the import machinery for matrix proteins. The core protein of this complex, Pex14, is thought to represent the initial docking site for the import receptors Pex5 and Pex7. SIGNOR-253027 0.931 SMURF2 protein Q9HAU4 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps SIGNOR-193378 0.725 NR3C1 protein P04150 UNIPROT KAT2B protein Q92831 UNIPROT up-regulates activity relocalization 32917954 t SimoneGraziosi NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase SIGNOR-269233 0.529 TBX2 protein Q13207 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24470334 f TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells SIGNOR-251562 0.7 VAV2 protein P52735 UNIPROT RAC1 protein P63000 UNIPROT up-regulates guanine nucleotide exchange factor 9606 10982832 t miannu Vav2 activates rac1 / vav2 is an exchange factor for rho family gtpases. SIGNOR-81645 0.752 RET protein P07949 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 16153436 t lperfetto We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1). SIGNOR-244643 0.444 MLF1 protein P58340 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 15861129 f miannu Mlf1 induces p53-dependent cell cycle arrest SIGNOR-135943 0.293 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser343 TVSKTETsQVAPA -1 11910029 t lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. SIGNOR-249148 0.45 MAPK1 protein P28482 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation -1 8929531 t lperfetto The rapid phosphorylation of bad following il-3 connects a proximal survival signal with the bcl-2 family, modulating this checkpoint for apoptosis.phosphorylatedBAD is bound to 14-3-3 within the cytosol, while only nonphosphorylated BAD is heterodimerized with membrane-bound BCL-XL. SIGNOR-44858 0.438 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11485553 t lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. SIGNOR-109563 0.666 MAP4K2 protein Q12851 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 t done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  SIGNOR-273900 0.2 VARS1 protein P26640 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 30755602 t miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. SIGNOR-270527 0.8 IGF2 protein P01344 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity binding 9606 22810696 t lperfetto These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients. SIGNOR-251495 0.815 RABEP1 protein Q15276 UNIPROT RABGEF1 protein Q9UJ41 UNIPROT up-regulates binding 9606 11452015 t miannu We show that rabaptin-5 increases the exchange activity of rabex-5 on rab5. SIGNOR-109395 0.941 FOXO3 protein O43524 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-217887 0.7 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 7737130 t gcesareni Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro. SIGNOR-32429 0.686 IFNG protein P01579 UNIPROT RFX5 protein P48382 UNIPROT up-regulates activity 9606 BTO:0000567 9177217 f 2 miannu Transcriptional Activation by the RFX5 Activation Domain Is IFN-_-Inducible in HeLa Cells. SIGNOR-241368 0.287 BCL2L1 protein Q07817 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 t gcesareni Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax SIGNOR-152983 0.737 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT down-regulates activity phosphorylation Ser23 YLQARKPsDCDSKEL -1 15946941 t done miannu PKA Phosphorylates GRK7 on Ser23 and Ser36. Phosphorylation by PKA inhibits GRK7 activity SIGNOR-274081 0.2 GATA1 protein P15976 UNIPROT KIT protein P10721 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27858941 f miannu DAB2IP suppresses transcription of stem cell factor receptor CD117, by interacting with GATA-1 on a silencer element on its gene SIGNOR-254771 0.405 LRIG3 protein Q6UXM1 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates 9606 23723069 f miannu Lrig3 opposes lrig1 negative regulatory activity and stabilizes erbb receptors. SIGNOR-202183 0.283 Caspase 3 complex complex SIGNOR-C221 SIGNOR BAD protein Q92934 UNIPROT up-regulates activity cleavage 9606 BTO:0000938 15231831 t lperfetto Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant. SIGNOR-256455 0.516 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI FGFR3 protein P22607 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258105 0.8 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0003316 10781582 t lperfetto Serine 15 phosphorylation of p53 leads to a stabilization of p53 by reducing its interaction with murine double minute 2, a negative regulatory partner[...]These results strongly suggest that both ERKs and p38 kinase have a direct role in UVB-induced phosphorylation of p53 at serine 15 in vivo. SIGNOR-226614 0.764 BRSK1 protein Q8TDC3 UNIPROT WEE1 protein P30291 UNIPROT unknown phosphorylation Ser642 KKMNRSVsLTIY -1 15150265 t llicata HsSAD1 protein produced in Sf9 cells phosphorylated the GST-fused human wild-type Wee1A fragment but not its S642A mutant produced inEscherichia coli (Fig. 2). The kinase-dead hsSAD1 mutant (K59A) failed to phosphorylate the wild-type Wee1A fragment. SIGNOR-250601 0.45 6alpha-methylprednisolone chemical CHEBI:6888 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 6749443 t bronchial ashma gcesareni SIGNOR-251696 0.8 PRKCA protein P17252 UNIPROT NOXO1 protein Q8NFA2 UNIPROT up-regulates phosphorylation Thr346 AIQSRCCtVTRRALE 9606 23957209 t llicata Phosphorylation of thr341 allows noxo1 to sufficiently interact with noxa1, an interaction that participates in nox1 activation. SIGNOR-202482 0.2 SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR KLF16 protein Q9BXK1 UNIPROT up-regulates activity phosphorylation Tyr10 AAVACVDyFAADVLM 22203677 t lperfetto Phosphorylation of KLF16 was confirmed by in vivo (32)P incorporation and controlled by a Y10F site-directed mutant. Inhibition of Src-type tyrosine kinase signaling as well as the nonphosphorylatable Y10F mutation disrupted KLF16-mediated gene silencing, demonstrating that its function is regulatable rather than constitutive. SIGNOR-275586 0.2 Av/b6 integrin complex SIGNOR-C179 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269028 0.7 PDE2A protein O00408 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR down-regulates activity binding 36476859 t lperfetto We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice.  SIGNOR-275731 0.392 MDC1 protein Q14676 UNIPROT RNF8 protein O76064 UNIPROT up-regulates relocalization 9606 18678647 t gcesareni Rnf8 relocalizes to dna damage sites via a phospho-dependent interaction with mdc1 SIGNOR-179820 0.748 TRIM8 protein Q9BZR9 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity polyubiquitination Lys158 ALIHRDLkPPNLLLV 22084099 t K63 miannu These results suggest that TRIM8 could mediate K63-linked polyubiquitination of TAK1 at residue K158.These results suggest that TRIM8 is involved in TNFα- and IL-1β–induced NF-κB activation by mediating K63-linked TAK1 polyubiquitination and subsequent activation. SIGNOR-271890 0.349 ARHGEF5 protein Q12774 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260533 0.601 MTF1 protein Q14872 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15378601 f miannu MRE-binding transcription factor-1 (MTF-1) is a highly conserved heavy metal-induced transcriptional activator. MTF-1 also activates transcription in response to oxidative stress and regulates the expression of several cytoprotective factor genes, including MT, gamma-glutamylcysteine synthetase, and Cu/Zn-superoxide dismutase. SIGNOR-254601 0.29 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea chemical CHEBI:91327 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207302 0.8 RBX1 protein P62877 UNIPROT DCX DET1-COP1 complex SIGNOR-C24 SIGNOR form complex binding 9606 17452440 t lperfetto Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes SIGNOR-154511 0.864 PIAS4 protein Q8N2W9 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates binding 9606 SIGNOR-C9 12904571 t gcesareni Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity. SIGNOR-104541 0.539 MMP14 protein P50281 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272382 0.7 ASIP protein P42127 UNIPROT ATRN protein O75882 UNIPROT up-regulates binding 9606 BTO:0001253 11137996 t gcesareni Attractin is a low-affinity receptor for agouti protein, but not agrp, in vitro and in vivo. SIGNOR-85496 0.4 CHM protein P24386 UNIPROT RABGGTA protein Q92696 UNIPROT down-regulates activity binding 9606 BTO:0000007 18532927 t miannu Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. SIGNOR-265570 0.761 SLC24A1 protein O60721 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264400 0.8 MAPK3 protein P27361 UNIPROT SP3 protein Q02447 UNIPROT up-regulates phosphorylation Ser73 CSKIGPPsPGDDEEE 9606 17685427 t gcesareni Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73. SIGNOR-157276 0.303 EFNA2 protein O43921 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates binding 9606 10072375 t tpavlidou Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8) SIGNOR-65416 0.811 AMPK complex SIGNOR-C15 SIGNOR EEF2K protein O00418 UNIPROT up-regulates phosphorylation Ser398 DSLPSSPsSATPHSQ 9606 22669845 t lperfetto In response to genotoxic stress, eef2k was activated by ampk (adenosine monophosphate-activated protein kinase)-mediated phosphorylation on serine 398. Activated eef2k phosphorylated eef2 and induced a temporary ribosomal slowdown at the stage of elongation SIGNOR-216503 0.404 CSNK2A1 protein P68400 UNIPROT SIRT1 protein Q96EB6 UNIPROT unknown phosphorylation Ser659 FHGAEVYsDSEDDVL 9606 19236849 t llicata We demonstrate that sirt1 is a substrate for protein kinase ck2 both in vitro and in vivo. Both, deletion construct analyses and serine-to-alanine mutations identified sirt1 ser-659 and ser-661 as major ck2 phosphorylation sites that are phosphorylated in vivo as well. SIGNOR-184151 0.627 IFNB1 protein P01574 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates binding 9606 11278538 t gcesareni Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. SIGNOR-105934 0.662 FARP2 protein O94887 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19276662 f Regulation of expression miannu FIR induced the expression of IAP1, IAP2, XIAP Survivin, MnSOD, TNFalpha, pAKT and IL-1alpha SIGNOR-251761 0.2 FYN protein P06241 UNIPROT LCP2 protein Q13094 UNIPROT down-regulates phosphorylation 9606 9047237 t lperfetto P59fyn_phosphorylated slp-76 at intermediate levels but, significantly, this phosphorylation failed to induce vav?SLP-76 complex formation SIGNOR-46851 0.745 EIF4E2 protein O60573 UNIPROT EIF4E2/GIGYF1 complex complex SIGNOR-C256 SIGNOR form complex binding 9606 30917308 t lperfetto 4EHP forms complexes with the GYF domain-containing proteins GIGYF1 and GIGYF2, which are critical for this translational repression SIGNOR-261010 0.628 LTBP1 protein Q14766 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates activity binding 9606 BTO:0003247 8432736 t lperfetto Together these data form strong support for the hypothesis that the LTBP plays an essential role in the activation of latent TGF-b in heterotypic cultures. SIGNOR-235754 0.623 PAMPs stimulus SIGNOR-ST11 SIGNOR FCN3 protein O75636 UNIPROT up-regulates activity binding -1 11907111 t lperfetto H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. SIGNOR-263406 0.7 CSNK2A1 protein P68400 UNIPROT ABCF1 protein Q8NE71 UNIPROT unknown phosphorylation Ser140 AALIQDQsEEEEEEE 9606 17894550 t gcesareni We demonstrate that abc50 is a phosphoprotein and is phosphorylated at two sites by ck2. These sites, ser-109 and ser-140, lie in the nterminal part of abc50 but are not required for the binding of abc50 to eif2. SIGNOR-157937 0.2 MAPK8 protein P45983 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates phosphorylation 9606 14517246 t gcesareni Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin SIGNOR-118220 0.835 CAMK2A protein Q9UQM7 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser142 RKILNDLsSDAPGVP 9606 9668047 t gcesareni Phosphorylation of creb1 at ser142 and ser143 is selectively activated by ca(2+) influx;phosphorylation of ser142 and ser143, disrupts the interaction of creb with its cofactor cbp. Phosphorylation of serine 142 in creb by camkii leads to dissociation of the creb dimer. SIGNOR-59137 0.577 PRKACA protein P17612 UNIPROT KCNJ12 protein Q14500 UNIPROT down-regulates activity phosphorylation Ser431 QRPYRREsEI 9534 11181181 t miannu Phosphorylation of the Kir2.2 C terminus by protein kinase A inhibited the association with SAP97.‚  SIGNOR-249998 0.286 enalaprilat (anhydrous) chemical CHEBI:4786 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition 10116 7527095 t miannu The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively. SIGNOR-258429 0.8 GDNF protein P39905 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252186 0.2 CDON/SPAG9 complex SIGNOR-C21 SIGNOR ABL1 protein P00519 UNIPROT unknown binding 9606 19470755 t lperfetto We report that abl associates with both cdo and jlp during myoblast differentiation SIGNOR-217019 0.502 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 10090 BTO:0000011 16731579 t miannu Human, mouse, and rat PPARα were activated by PFOA isomers and PFOS. SIGNOR-268789 0.8 DHRS9 protein Q9BPW9 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity chemical modification 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS11 SIGNOR-265117 0.8 BCL2L1 protein Q07817 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 9463381 t amattioni Bcl-xl bind to bax or five other pro-apoptotic relatives (bak, bad, bik, bid or bim) SIGNOR-55549 0.737 AKT1 protein P31749 UNIPROT TP53RK protein Q96S44 UNIPROT up-regulates phosphorylation Ser250 RLRGRKRsMVG 9606 17712528 t gcesareni Here we show that such an activation of prpk is mediated by another kinase, akt/pkb, which phosphorylates prpk at ser250. SIGNOR-252503 0.301 ICAM4 protein Q14773 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 t lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  SIGNOR-266019 0.34 CSNK1D protein P48730 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Thr1479 SSSSTKGtYFPAILN 9606 35487243 t miannu Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493 SIGNOR-275402 0.2 PTPN6 protein P29350 UNIPROT KIT protein P10721 UNIPROT down-regulates binding 9606 9528781 t miannu Shp-1 binds and negatively modulates the c-kit receptor by interaction with tyrosine 569 in the c-kit juxtamembrane domain. SIGNOR-56104 0.558 ROCK1 protein Q13464 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Ser20 KRPQRATsNVFAMFD -1 21457715 t Giulio Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation. SIGNOR-260307 0.632 RAF1 protein P04049 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 17535812 t lperfetto The activation of several major anti-apoptotic signaling pathways correlates with an increase in the phosphorylation of bad on ser-112, ser-136, and ser-155. These phosphorylation events result in bad inactivation through sequestration by 14-3-3 proteins SIGNOR-155293 0.645 WNT3A protein P56704 UNIPROT FBN1 protein P35555 UNIPROT up-regulates quantity by stabilization 10090 17943183 f Regulation miannu Wnt3a markedly stimulated matrix assembly of microfibrillar proteins, including Fbn-1, by cultured fibroblasts, suggesting that Wnts contribute to increased microfibrillar matrices in Tsk skin.Wnt3a stimulates Fbn-1 matrix formation. SIGNOR-251894 0.276 DUSP6 protein Q16828 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 12840032 t inferred from 70% of family members gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). SIGNOR-269926 0.901 STAG proteinfamily SIGNOR-PF52 SIGNOR Cohesin complex complex SIGNOR-C304 SIGNOR form complex binding 28430577 t lperfetto Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin SIGNOR-263314 0.916 CSNK1A1 protein P48729 UNIPROT TP53 protein P04637 UNIPROT unknown phosphorylation Ser20 PLSQETFsDLWKLLP 9606 20041275 t llicata Our data support the concept that non-primed phosphorylation of p53 by ck1 is an isoform-specific reaction preferentially affecting s20 SIGNOR-162648 0.581 SIRT1 protein Q96EB6 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity deacetylation Lys14 VKEGWLHkRGEYIKT 10090 BTO:0000562 21775285 t gcesareni We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation. SIGNOR-252456 0.619 TTM complex complex SIGNOR-C305 SIGNOR Cohesin complex complex SIGNOR-C304 SIGNOR up-regulates activity relocalization 27025256 t lperfetto Terb1 and Sun1 are two key proteins linking the meiotic telomeres to the NE. Terb1 participates in telomere fortification by recruiting cohesins to the site SIGNOR-263307 0.2 CEBPB protein P17676 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 11884404 f fferrentino Overexpression and ribozyme-mediated targeting of transcriptional coactivators CREB-binding protein and p300 revealed their indispensable roles in adipocyte differentiation through the regulation of peroxisome proliferator-activated receptor gamma. SIGNOR-250564 0.7 calcium(2+) smallmolecule CHEBI:29108 ChEBI PLA2G4A protein P47712 UNIPROT up-regulates relocalization 9606 9430701 t gcesareni Cytosolic phospholipase a2 (cpla2) is a calcium-sensitive 85-kda enzyme that hydrolyzes arachidonic acid-containing membrane phospholipids to initiate the biosynthesis of eicosanoids and platelet-activating factor, potent inflammatory mediators. The calcium-dependent activation of the enzyme is mediated by an n-terminal c2 domain, which is responsible for calcium-dependent translocation of the enzyme to membranes and that enables the intact enzyme to hydrolyze membrane-resident substrates. cytosolic phospholipase a2 (cpla2) associates with natural membranes in response to physiological increases in ca2+, resulting in the selective hydrolysis of arachidonyl phospholipids. SIGNOR-54943 0.8 MAPK14 protein Q16539 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8702807 f gcesareni This result suggests that the p38mapk cascade could be involved in the negative regulation of cyclin d1 transcription and thus antagonize the mitogen-dependent stimulation of cyclin d1 transcription mediated, at least in part, by the p42/p44mapk cascade. SIGNOR-43096 0.437 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT unknown phosphorylation Ser33 LPENNVLsPLPSQAM 9606 9372954 t llicata We have mapped a major site of phosphorylation by cak to ser-33 of p53 and have demonstrated as well that p53 is phosphorylated at this site in vivo. SIGNOR-53311 0.47 PIM3 protein Q86V86 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 t done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  SIGNOR-273897 0.2 AMPK complex SIGNOR-C15 SIGNOR RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser621 PKINRSAsEPSLHRA 9606 9091312 t lperfetto Ampk also phosphorylated full-length, kinase-defective raf-1 (k375m) to generate two [32p]phosphopeptides, one co-migrating with synthetic tryptic peptide containing phospho-ser621 and the other with phospho-ser259 SIGNOR-216616 0.302 glyburide chemical CHEBI:5441 ChEBI CFTR protein P13569 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000944 1281220 t miannu The sulfonylureas, tolbutamide and glibenclamide, inhibited whole-cell CFTR Cl- currents at half-maximal concentrations of approximately 150 and 20 microM, respectively. SIGNOR-258344 0.8 AKT2 protein P31751 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates phosphorylation 9606 BTO:0000150 20231902 t inferred from 70% of family members gcesareni Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation. SIGNOR-269937 0.264 ITCH protein Q96J02 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates ubiquitination 9606 BTO:0001253 10940313 t gcesareni Itch binds to the n-terminal portion of the notch intracellular domain via its ww domains and promotes ubiquitination of notch through its hect ubiquitin ligase domain. SIGNOR-254331 0.629 PTPN1 protein P18031 UNIPROT TYK2 protein P29597 UNIPROT down-regulates activity dephosphorylation 9606 15780598 t lperfetto Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5. SIGNOR-134564 0.631 NEK7 protein Q8TDX7 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity phosphorylation Ser56 NDDPLLRsAGKVRDI 9606 BTO:0000565 28630147 t miannu Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C). SIGNOR-266416 0.379 STAT5A protein P42229 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000830 20535135 f miannu Specifically, SCF-induced activation of JAK2 in human mast cells has been shown to activate STAT5 and STAT6. STAT5 contributes to mast cell homeostasis, by mediating proliferation, survival, and mediator release. SIGNOR-256233 0.7 MRAP protein Q8TCY5 UNIPROT MC3R protein P41968 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 t miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. SIGNOR-252366 0.487 UHMK1 protein Q8TAS1 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Ser299 GRDSRSGsPMARR 9606 BTO:0000142 16401070 t lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. Mass spectrometry and peptide sequencing allowed us to identify serine 164 of mbp as the unique site phosphorylated by kis. Phosphorylation of synthetic peptides indicated the importance of the proline residue at position +1. SIGNOR-143485 0.2 BTC protein P35070 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000142 22232668 t gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4 SIGNOR-195347 0.712 U0126.EtOH chemical CHEBI:90692 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck lperfetto SIGNOR-244961 0.8 ABL1 protein P00519 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 11593427 t gcesareni Jak2 peptide substrate studies indicated that the Bcr-Abl and Abl tyrosine kinases specifically phosphorylated Y1007 of Jak2 but only poorly phosphorylated Y1008. Phosphorylation of Y1007 of Jak2 is known to be critical for its tyrosine kinase activation. SIGNOR-245365 0.42 VAPB protein O95292 UNIPROT VAPB-PTPIP51 complex complex SIGNOR-C275 SIGNOR form complex binding 10116 BTO:0000142 30841933 t lperfetto Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction. SIGNOR-262118 0.625 IL17B protein Q9UHF5 UNIPROT IL17RB protein Q9NRM6 UNIPROT up-regulates binding 9606 BTO:0000130 BTO:0000975;BTO:0000142;BTO:0000671 10749887 t gcesareni Here we report on the discovery of a novel il-17 homolog (il-17b), together with the identification of a novel cell surface receptor that specifically binds to it. We detail the molecular cloning, tissue distribution, and expression of both il-17b and il-17br, describe thein vivo activity of il-17b, and demonstrate binding to il-17br. SIGNOR-76544 0.742 HP protein P00738 UNIPROT hb:hp complex SIGNOR-C149 SIGNOR form complex binding 9606 11854029 t miannu CD163 was identified as the endocytic receptor binding hemoglobin (Hb) in complex with the plasma protein haptoglobin (Hp). This specific receptor-ligand interaction leading to removal from plasma of the Hp-Hb complex-but not free Hp or Hb-now explains the depletion of circulating Hp in individuals with increased intravascular hemolysis. SIGNOR-255283 0.2 JNK proteinfamily SIGNOR-PF15 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser37 YLDSGIHsGATTTAP 9606 20419129 t lperfetto Specifically, we provide evidence that jnk binds to e-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by gsk-3beta. SIGNOR-165026 0.2 Neuronal AP-3 complex SIGNOR-C445 SIGNOR AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 t miannu Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-268525 0.371 DAXX protein Q9UER7 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates binding 9606 23405218 t gcesareni The optimal function of mdm2 requires daxx, which stabilizes mdm2 through the deubiquitinase hausp/usp7 and also directly promotes mdm2's ubiquitin ligase activity towards p53. SIGNOR-200892 0.66 PPP2CA protein P67775 UNIPROT DDHD1 protein Q8NEL9 UNIPROT unknown dephosphorylation Ser727 TIPSPVTsPVLSRRH -1 11328814 t miannu Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity SIGNOR-262976 0.2 AARS1 protein P49588 UNIPROT Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI up-regulates quantity chemical modification 9606 32314272 t miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). SIGNOR-270447 0.8 DCK protein P27707 UNIPROT 2'-deoxyadenosine 5'-monophosphate(2-) smallmolecule CHEBI:58245 ChEBI up-regulates quantity chemical modification 20637175 t lperfetto Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis SIGNOR-275808 0.8 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser7 sSSSYRRM -1 2500966 t miannu Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure. SIGNOR-250071 0.313 TMED5 protein Q9Y3A6 UNIPROT TMED10 protein P49755 UNIPROT up-regulates activity binding 9606 BTO:0000567 19948005 t Sara P28 forms hetero-oligomeric complexes with p23. p23 is a major determinant for efficient targeting of p28 to the ERGIC SIGNOR-261298 0.584 PKA proteinfamily SIGNOR-PF17 SIGNOR AQP2 protein P41181 UNIPROT up-regulates activity phosphorylation Ser256 REVRRRQsVELHSPQ 9615 BTO:0000837 12194985 t lperfetto For Ser-256 in AQP2, this hypothesis is in line with data from Zeleninaet al. (35), who showed that in isolated rat inner medulla prostaglandin E2 induces internalization of AQP2 without decreasing the amount of PKA-phosphorylated AQP2.|Phosphorylation of Ser-256 Is Necessary and Sufficient for Localization of AQP2 in the Apical Plasma Membrane SIGNOR-264563 0.2 MAP4K3 protein Q8IVH8 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates phosphorylation Thr538 LGDAKTNtFCGTPDY 9606 BTO:0000782 21983831 t llicata We report that the kinase glk (map4k3) directly activated pkc-? During tcr signaling. SIGNOR-176744 0.388 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr406 DASSQDCyDIPRAFP 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236396 0.751 SEMA3A protein Q14563 UNIPROT NRP1 protein O14786 UNIPROT down-regulates binding 9606 10196546 t gcesareni Semaphorins a and e act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors. SIGNOR-66661 0.911 AKT1 protein P31749 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 BTO:0000150 20231902 t gcesareni Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation. SIGNOR-252509 0.363 CDK5 protein Q00535 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Ser75 NSSDTVTsPQRAGPL 9606 BTO:0000938 10544291 t llicata These results present compelling evidence that cdk5/p35 kinase is responsible for the novel phosphorylation of c-src at ser75 in neuronal cells, raising the intriguing possibility that c-src acts as an effector of cdk5/p35 kinase during neuronal development. SIGNOR-71950 0.398 RXRB protein P28702 UNIPROT THRB protein P10828 UNIPROT up-regulates binding 9606 10976919 t gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr SIGNOR-81455 0.624 GOT1 protein P17174 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI down-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-268062 0.8 SMAD7 protein O15105 UNIPROT SMURF proteinfamily SIGNOR-PF29 SIGNOR up-regulates activity relocalization 9606 19352540 t lperfetto Smad7 also recruits the HECT type of E3 ubiquitin ligases, Smurf1 and Smurf2. It binds to Smurfs in the nucleus and translocates into the cytoplasm in response to TGF-_ and recruits the ubiquitin ligases to the activated type I receptor ALK5/T_RI, leading to the degradation of the receptor through the proteasomal pathway. SIGNOR-253258 0.895 selumetinib chemical CHEBI:90227 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258281 0.8 ROCK2 protein O75116 UNIPROT SH3GL2 protein Q99962 UNIPROT down-regulates phosphorylation Thr14 KKQFHKAtQKVSEKV 9606 16164598 t llicata We identified the phosphorylation site of endophilin a1 at thr-14 endophilin t14d inhibited egf receptor internalization. Furthermore, phosphorylation of endophilin by rho-kinase inhibited the binding to cin85. SIGNOR-140466 0.415 CDX2 protein Q99626 UNIPROT LCT protein P09848 UNIPROT up-regulates quantity by expression transcriptional regulation 9148757 t By electrophoretic mobility-shift assay it was shown that the factor Cdx-2 (a homoeodomain-protein related to caudal) binds to a TTTAC sequence in the CE-LPH1. Furthermore it was demonstrated that Cdx-2 is able to activate reporter gene transcription by binding to CE-LPH1. SIGNOR-253964 0.37 RBPJ protein Q06330 UNIPROT GTF2A2 protein P52657 UNIPROT up-regulates binding 9606 9620850 t Inhibits transcription gcesareni Rbp interacts with two transcriptional coactivators: dtafii110, a subunit of tfiid, and tfiia to repress transcription. The domain of dtafii110 targeted by rbp is the same domain that interacts with tfiia SIGNOR-57832 0.2 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser338 DEASATVsKTETSQV -1 11910029 t lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. SIGNOR-249147 0.45 AKT1 protein P31749 UNIPROT ACAP1 protein Q15027 UNIPROT unknown phosphorylation Ser554 SIRPRPGsLRSKPEP 9606 16256741 t llicata Akt phosphorylates s554 in acap1 SIGNOR-252483 0.496 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI cortisol smallmolecule CHEBI:17650 ChEBI up-regulates quantity precursor of 9606 BTO:0000050 9814482 t lperfetto Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. SIGNOR-268675 0.8 RXRB protein P28702 UNIPROT NR2F2 protein P24468 UNIPROT up-regulates binding 9606 10900149 t gcesareni Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site. SIGNOR-79452 0.278 antigen smallmolecule CHEBI:59132 ChEBI BCR-Mk complex SIGNOR-C433 SIGNOR up-regulates activity binding 9606 BTO:0000776 32323266 t scontino The recognition of antigen by the BCR initiates BCR signaling cascade. SIGNOR-268202 0.8 R547 chemical CID:6918852 PUBCHEM CDK4 protein P11802 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206364 0.8 15(S)-HETE smallmolecule CHEBI:15558 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9606 12517954 t lperfetto 15(S)-HETE is a ligand for PPARγ in IL-4-stimulated A549 cells SIGNOR-254095 0.8 ELP1 protein O95163 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 12058026 f gcesareni Ikap efficiently and specifically enhanced jnk activation induced by ectopic expression of mekk1 and ask1, upstream activators of jnk SIGNOR-89334 0.2 EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10090 BTO:0000944 7518560 t lperfetto Erbb1 recruites grb2 through sh2 domain;from these studies, we concluded that grb2 binds directly to the egfr at y-1068, to a lesser extent at y-1086, and indirectly at y-1173. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc). SIGNOR-235721 0.921 BCL2L1 protein Q07817 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates binding 9606 17446862 t gcesareni The anti-apoptotic proteins bcl-2 and bcl-x(l) bind and inhibit beclin-1, an essential mediator of autophagy. SIGNOR-154480 0.916 TNFSF15 protein O95150 UNIPROT TNFRSF25 protein Q93038 UNIPROT up-regulates binding 9606 14585074 t amattioni The ligand of dr3 is tl1a SIGNOR-103078 0.767 INSR protein P06213 UNIPROT GRB7 protein Q14451 UNIPROT up-regulates binding 9606 10803466 t gcesareni Insulin induces the ir-grb7 interaction in cells expressing physiological levels of the proteins, suggesting that grb7 is implicated in insulin signaling. SIGNOR-77153 0.428 RB1 protein P06400 UNIPROT ABL1 protein P00519 UNIPROT down-regulates binding 9606 8242749 t gcesareni A domain in the c-terminus of rb, outside of the a/b pocket, binds to the atp-binding lobe of the c-abl tyrosine kinase, resulting in kinase inhibition. SIGNOR-37139 0.552 CD38 protein P28907 UNIPROT NMN(+) smallmolecule CHEBI:14648 ChEBI down-regulates quantity chemical modification 9606 18626062 t miannu CD38 is also able to catalyze the degradation of the NAD precursor nicotinamide mono-nucleotide (NMN) into nicotinamide SIGNOR-264252 0.8 SMAD6 protein O43541 UNIPROT NR2C2 protein P49116 UNIPROT down-regulates binding 9606 11737269 t lperfetto Smad6 interacts with tak1 and tab1, and smad7 with tab1 SIGNOR-112636 0.2 6-bromo-3-(1-methyl-4-pyrazolyl)-5-(3-piperidinyl)-7-pyrazolo[1,5-a]pyrimidinamine chemical CHEBI:131165 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206835 0.8 ILK protein Q13418 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates activity phosphorylation Thr710 DLQEAEKtIGRSRST -1 12030846 t miannu MYPT1 was phosphorylated by ILK and phosphorylation sites in the N- and C-terminal fragments of MYPT1 were detected. From sequence analyses, three sites were identified: a primary site at Thr(709), and two other sites at Thr(695) and Thr(495). ILK produced an intermediate level of inhibition SIGNOR-262885 0.567 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser434 SFEPKIRsPRRFIGS 10090 BTO:0002572 12782654 t lperfetto S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation. SIGNOR-101332 0.96 VARLITINIB chemical CID:42642648 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189903 0.8 PKMYT1 protein Q99640 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 BTO:0000567 9001210 t Preference on the part of Myt1Hu for the cyclin-bound form of Cdc2 lperfetto Myt1hu preferentially phosphorylates cdc2 on threonine 14 in a cyclin-dependent manner;phosphorylation of threonine 14 and tyrosine 15 is inhibitory. SIGNOR-45729 0.741 FOXI1 protein Q12951 UNIPROT CFTR protein P13569 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20972246 f miannu Results of transiently transfected vas deferens cells with either the -33G wild-type or the -33A variant CFTR directed luciferase reporter gene confirmed that the -33A variant, which alters the FOXI1 (Forkhead box I1) binding, significantly decreases the CFTR promoter activity. SIGNOR-254176 0.255 KAT5 protein Q92993 UNIPROT SRSF2 protein Q01130 UNIPROT down-regulates acetylation Lys52 IPRDRYTkESRGFAF 9606 21157427 t miannu In this study, we provide the first evidence that the acetyltransferase tip60 acetylates srsf2 on its lysine 52 residue inside the rna recognition motif, and promotes its proteasomal degradation. SIGNOR-170594 0.479 MDH1 protein P40925 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI down-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-268099 0.8 EGFR protein P00533 UNIPROT SCAMP3 protein O14828 UNIPROT unknown phosphorylation Tyr41 QYATLDVyNPFETRE -1 9658162 t llicata SCAMP3 Is Tyrosine Phosphorylated by EGFR in Vitro SIGNOR-251096 0.408 (2S)-N1-[5-(2-tert-butyl-4-thiazolyl)-4-methyl-2-thiazolyl]pyrrolidine-1,2-dicarboxamide chemical CHEBI:91449 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252658 0.8 PPP4C protein P60510 UNIPROT CDK1 protein P06493 UNIPROT down-regulates activity dephosphorylation 9606 18347064 t miannu PP4c efficiently dephosphorylates Cdk1 sites of NDEL1 but does not dephosphorylate the Aurora A site.|We also found that PP4c negatively regulates Cdk1 activity in interphase. SIGNOR-277162 0.407 FYN protein P06241 UNIPROT PGD protein P52209 UNIPROT up-regulates activity phosphorylation Tyr481 GTVSSSSyNA 9606 30824700 t lperfetto 6PGD is phosphorylated at tyrosine (Y) 481 by Src family kinase Fyn. This phosphorylation enhances 6PGD activity by increasing its binding affinity to NADP+ and therefore activates the PPP for NADPH and ribose-5-phosphate, which consequently detoxifies intracellular reactive oxygen species (ROS) and accelerates DNA synthesis. SIGNOR-265758 0.2 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT down-regulates phosphorylation Ser241 RRIPYRYsDELNEII 9606 17197699 t gcesareni Enzymatic activity, inhibited; SIGNOR-151767 0.2 TRAF1 protein Q13077 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates binding 9606 8069916 t gcesareni Traf1 and traf2 can form homo- and heterotypic dimers. SIGNOR-34768 0.62 TLR4 protein O00206 UNIPROT Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 9606 20596954 f fstefani Regulation of toll-like receptor signaling in the innate immunity. SIGNOR-166488 0.7 Vicriviroc Malate chemical CID:10218922 PUBCHEM CCR5 protein P51681 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207657 0.8 POLR3B protein Q9NW08 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266132 0.858 bufexamac chemical CHEBI:31317 ChEBI HDAC10 protein Q969S8 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000664 21258344 t Luana  We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor. SIGNOR-257891 0.8 PRKACA protein P17612 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity phosphorylation Thr288 APSSRRTtLCGTLDY -1 11039908 t miannu Aurora2 is regulated by phosphorylation. phosphorylation occurs on a conserved residue, Threonine 288, within the activation loop of the catalytic domain of the kinase and results in a significant increase in the enzymatic activity. Threonine 288 resides within a consensus motif for the cAMP dependent kinase and can be phosphorylated by PKA in vitro. SIGNOR-250337 0.491 CDS2 protein O95674 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI down-regulates quantity chemical modification 9606 25375833 t lperfetto CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). SIGNOR-267021 0.8 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI MAPK10 protein P53779 UNIPROT down-regulates chemical inhibition 9606 11717429 t gcesareni We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm). To determine whether jnk activity is required for stress-induced translocation of bax to the mitochondria, we examined the effect of sp600125, a jnk inhibitor. SIGNOR-111980 0.8 RAE1 protein P78406 UNIPROT NUP98 protein P52948 UNIPROT up-regulates activity binding 9606 16036565 t miannu Nup98 is a major interacting partner of Rae1 and known to beinvolved in mRNA export. SIGNOR-260868 0.882 CREB1 protein P16220 UNIPROT NR2F6 protein P10588 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15955695 f miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. SIGNOR-253793 0.268 RAD51 protein Q06609 UNIPROT BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR form complex binding 9606 BTO:0000007 14636569 t lperfetto These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer SIGNOR-263206 0.743 N-(3-methoxy-5-methyl-2-pyrazinyl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]-3-pyridinesulfonamide chemical CHEBI:94573 ChEBI EDNRA protein P25101 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207902 0.8 AKT1 protein P31749 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser365 GQRDRSSsAPNVHIN 9606 10869359 t Akt phosphorylates both S364 and S428. Akt downregulates B-Raf activity in vivo SIGNOR-251471 0.47 TRAF6 protein Q9Y4K3 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR down-regulates quantity ubiquitination 9606 BTO:0000007 28980855 t inferred from family member The Lys63-linked ubiquitination of HK2 catalyzed by the E3 ligase TRAF6 was critical for the subsequent recognition of HK2 by the autophagy receptor protein SQSTM1/p62 for the process of selective autophagic degradation. SIGNOR-270271 0.2 CDK1 protein P06493 UNIPROT DUT protein P33316-2 UNIPROT up-regulates quantity phosphorylation Ser11 SEETPAIsPSKRARP -1 8631817 t miannu DUTPase Is Phosphorylated at a Consensus Cyclin-dependent Protein Kinase Site: in Vitro Phosphorylation of Ser-11 by p34cdc2. It is conceivable that the exclusive phosphorylation of DUT-N may play a role in nuclear targeting of this protein. Taken a step further, Ser-11 may confer the ability of DUT-N to localize in specific regions of the nucleus where the dUTPase function is required. The Ser-11 Ala mutant should aid in the testing of these hypotheses. SIGNOR-262693 0.393 RCHY1 protein Q96PM5 UNIPROT POLH protein Q9Y253 UNIPROT down-regulates activity monoubiquitination Lys694 SPLACTNkRPRPEGM 9606 21791603 t miannu Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709). SIGNOR-272732 0.563 CDH23 protein Q9H251 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265861 0.292 F2RL3 protein Q96RI0 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22318735 t gcesareni Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13). SIGNOR-196012 0.463 TFAP4 protein Q01664 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity binding 9606 BTO:0001109 19505873 t miannu We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads. SIGNOR-226593 0.364 HDAC3 protein O15379 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates binding 9606 23213415 t gcesareni We show here that smad7 can form a complex with endogenous histone deacetylase proteins hdac-1 and hdac-3 in nih 3t3 mouse fibroblast cells SIGNOR-199967 0.348 ATM protein Q13315 UNIPROT RNF40 protein O75150 UNIPROT up-regulates phosphorylation 9606 21763684 t gcesareni E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm. SIGNOR-175003 0.455 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates 9606 18481201 f lperfetto Pd98059, a specific inhibitor of mek in addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. SIGNOR-244877 0.62 DNER protein Q8NFT8 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000938 15965470 t gcesareni Dner binds to notch1 at cell-cell contacts and activates notch signaling in vitro. SIGNOR-138346 0.439 JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 21576360 t When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita SIGNOR-256248 0.799 CAMK2B protein Q13554 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates phosphorylation Ser772 LFKKIFPsLELNITD 9606 24614225 t lperfetto Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity. SIGNOR-91403 0.2 SMURF2 protein Q9HAU4 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR down-regulates ubiquitination 9606 22298955 t inferred from 70% of family members gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps SIGNOR-269845 0.778 UBE3A protein Q05086 UNIPROT PSMD2 protein Q13200 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 28559284 t lperfetto Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits. SIGNOR-265133 0.28 SAGA complex complex SIGNOR-C465 SIGNOR H3-5 protein Q6NXT2 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269634 0.2 NFKB1 protein P19838 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR form complex binding 9606 9450761 t gcesareni Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna SIGNOR-55375 0.701 SOCS1 protein O15524 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 24890514 f apalma Socs1 associates with CSF-1R pTyr-697 and pTyr721 binding sites to inhibit proliferation by an unknown mechanism SIGNOR-255575 0.7 GAB2 protein Q9UQC2 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 24737791 t milica The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival SIGNOR-252677 0.501 SOCS1 protein O15524 UNIPROT IFNG protein P01579 UNIPROT down-regulates 9606 21628332 f lperfetto SOCS1 inhibits macrophage responses to IFN-g, and SOCS1-deficient mice develop symptoms of severe systemic autoimmune and inflammatory disease. SIGNOR-249571 0.537 USP1 protein O94782 UNIPROT DGCR8 protein Q8WYQ5 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0002181 34188037 t miannu  Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8's binding partner RNF168 to MDC1 and RNF8 at DSBs.  SIGNOR-277308 0.2 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9727491 t gcesareni Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them. SIGNOR-256466 0.724 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PPARG protein P37231 UNIPROT down-regulates activity relocalization 9606 18596912 t inferred from 70% family members lperfetto The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform SIGNOR-270008 0.2 WNK4 protein Q96J92 UNIPROT SLC12A3 protein P55017 UNIPROT down-regulates activity 22342722 f lperfetto Evidences from early studies using Xenopus oocytes and mammalian cells indicate that WNK4 inhibits NCC and PHAII-causing mutations relieve the inhibition SIGNOR-264632 0.597 CDH17 protein Q12864 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265856 0.693 PIK3C3 protein Q8NEB9 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 10090 19270693 t lperfetto The beclin 1-vps34 interaction regulates autophagy. SIGNOR-184521 0.934 CASP8AP2 protein Q9UKL3 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates binding 9606 SIGNOR-C13 22075988 t gcesareni In addition, both cleavage products of c-flip turned out to be inducers of nf-kb activity by binding to the ikk complex. SIGNOR-177104 0.248 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207084 0.8 LYN protein P07948 UNIPROT FCGR2A protein P12318 UNIPROT up-regulates activity phosphorylation Tyr304 TDDDKNIyLTLPPND -1 8756631 t lperfetto Phosphorylation of FcgammaRIIa/c by Lyn is clearly dependent on the presence of Y-298, since all mutants lacking this residue are not phosphorylated by this PTK. This result suggests that Y-298 might be the only tyrosine residue of FcgammaRIIa/c phos- phorylated by Lyn. SIGNOR-249379 0.591 UVRAG protein Q9P2Y5 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 9606 BTO:0000567 17106237 t lperfetto UVRAG interacts with Beclin 1, leading to activation of autophagy and thereof inhibition of tumorigenesis. SIGNOR-150825 0.856 THRA protein P10827 UNIPROT RARG protein P13631 UNIPROT up-regulates binding 9606 15650024 t gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. SIGNOR-133246 0.394 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser669 DFKDRVQsKIGSLDN -1 8999860 t miannu Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules SIGNOR-250287 0.318 NUAK1 protein O60285 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 21317932 t gcesareni Here we showed that in the presence of wild-type lkb1, nuak1 directly interacts with and phosphorylates p53 in vitro and in vivo. SIGNOR-172008 0.527 DVL3 protein Q92997 UNIPROT FRAT1 protein Q92837 UNIPROT up-regulates binding 9606 BTO:0000567 BTO:0000671 12556519 t gcesareni These results indicate that cki epsilon-dependent phosphorylation of dvl enhances the formation of a complex of dvl-1 with frat-1 and that this complex leads to the activation of the wnt signaling pathway. SIGNOR-97877 0.435 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr464 QEGSIEVyEDAGSHY 9606 11113114 t gcesareni Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity. SIGNOR-85005 0.427 NUMB protein P49757 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 20940030 f gcesareni Numb interacts with mdm2, and inhibits its ubiquitin-ligase function on tp53 (which in itself is inhibitory for tp53), thus numb activates (b) tp53. SIGNOR-168457 0.53 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr423 NSLNEEWyVSYITRP 9606 BTO:0000782 8702662 t lperfetto A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function SIGNOR-42972 0.797 PTPN12 protein Q05209 UNIPROT PTK2B protein Q14289 UNIPROT down-regulates activity dephosphorylation Tyr579 RYIEDEDyYKASVTR 9606 11337490 t lperfetto Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-pest-mediated dephosphorylation. / dephosphorylation of tyr402 and tyr579/580 by ptp-pest SIGNOR-107502 0.56 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser170 SFKLSGFsFKKNKKE -1 1560845 t gcesareni Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin SIGNOR-249670 0.719 DLG4 protein P78352 UNIPROT Scribble_complex_DLG4-LLGL1_variant complex SIGNOR-C509 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270905 0.459 FCHO2 protein Q0JRZ9 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates quantity by stabilization binding 24789820 t lperfetto Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth SIGNOR-260717 0.558 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr900 FGLSRDVyEEDSYVK 9606 16928683 t gcesareni Mass spectrometric analysis revealed that ret tyr(900) was autophosphorylation site. Tyr900 can partially replace the function of tyr905 as a local switch for kinase activation SIGNOR-148992 0.2 CSNK2A1 protein P68400 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT down-regulates activity phosphorylation Ser390 LFPVCHDsDESDTAK -1 25066127 t miannu This modulation can be directly attributed to CK2-mediated phosphorylation of Dnmt3a. We also find that CK2-mediated phosphorylation is required for localization of Dnmt3a to heterochromatin. SIGNOR-276650 0.2 N-[3-[[5-iodo-4-[3-[[oxo(thiophen-2-yl)methyl]amino]propylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide chemical CHEBI:91439 ChEBI IKBKE protein Q14164 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190792 0.8 SMAD2 protein Q15796 UNIPROT SMAD2/SMURF2 complex SIGNOR-C11 SIGNOR form complex binding 9606 11389444 t gcesareni We show that in the presence of tgf-beta, smad2 interacts through its proline-rich ppxy motif with the tryptophan-rich ww domains of smurf2, a recently identified e3 ubiquitin ligases. SIGNOR-108487 0.77 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159377 0.2 VX-745 chemical CHEBI:90528 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207684 0.8 NANOG protein Q9H9S0 UNIPROT GATA6 protein Q92908 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 f lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) SIGNOR-253160 0.471 AKT1 protein P31749 UNIPROT TBC1D4 protein O60343 UNIPROT unknown phosphorylation Thr642 QFRRRAHtFSHPPSS 9606 16880201 t llicata 14-3-3 proteins interact with as160 in an insulin- and akt-dependent manner via an akt phosphorylation site, thr-642. SIGNOR-252494 0.755 F2R protein P25116 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates 9606 BTO:0000007 22972936 f inferred from 70% of family members milica Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase. SIGNOR-269860 0.2 CEBPA protein P49715 UNIPROT Granulocyte_differentiation phenotype SIGNOR-PH102 SIGNOR up-regulates activity 10090 BTO:0000725 19706798 f Conditional cebpa deficiency in adult mice blocks the transition from common myeloid progenitors (CMP) to granulocyte monocyte progenitors (GMP) resulting in the accumulation of myeloid blasts SIGNOR-259966 0.7 INTS12 protein Q96CB8 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261470 0.74 NFE2L2 protein Q16236 UNIPROT CAT protein P04040 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22493435 t miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 SIGNOR-254651 0.437 3-isobutyl-1-methylxanthine chemical CHEBI:48518 ChEBI CEBPB protein P17676 UNIPROT up-regulates quantity by expression 9606 8754811 f fspada The differentiation of 3t3 preadipocytes into adipocytes is accompanied by a transient induction of c/ebpbeta and c/ebpdelta expression in response to treatment of the cells with methylisobutylxanthine (mix) and dexamethasone (dex), respectively SIGNOR-43310 0.8 CHRM3 protein P20309 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257224 0.371 Immune complexes stimulus SIGNOR-ST15 SIGNOR FCAR protein P24071 UNIPROT up-regulates activity relocalization 12768205 f lperfetto Both monomeric and dimeric IgA can bind to FcalphaRI, and monomeric or dimeric IgA immune complexes can activate phagocytosis and other immune responses through the clustering of FcalphaRI SIGNOR-264859 0.7 PTPN1 protein P18031 UNIPROT CAV1 protein Q03135 UNIPROT unknown dephosphorylation Tyr14 VDSEGHLyTVPIREQ -1 16388599 t The scaffolding protein caveolin-1 is also a participant in these pathways and is specifically phosphorylated on tyrosine 14, when these pathways are activated. Here, we provide evidence that PTP1B can efficiently catalyze the removal of the phosphoryl group from phosphocaveolin-1. SIGNOR-248430 0.555 PRKCB protein P05771 UNIPROT ICOSLG protein O75144 UNIPROT up-regulates activity phosphorylation Ser285 RDRCLQHsYAGAWAV 9606 BTO:0000567 24837102 t done miannu PKCα and PKCβ are required for phosphorylation of ICOSL and ICOSL-mediated cytokine induction  SIGNOR-273797 0.2 ruxolitinib chemical CHEBI:66919 ChEBI JAK1 protein P23458 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206667 0.8 CSNK2A1 protein P68400 UNIPROT SHOX protein O15266 UNIPROT up-regulates phosphorylation Ser106 EKREDVKsEDEDGQT 9606 16325853 t lperfetto We show also that casein kinase ii phosphorylates shox on serine 106 efficiently in vitro. S106a shox mutant, defective in phosphorylation, does not activate transcription and fails to induce cell-cycle arrest and apoptosis SIGNOR-142875 0.344 2-(2H-Benzo[b][1,4]oxazin-4(3H)-yl)-N-benzyl-5,6,7,8-tetrahydroquinazolin-4-amine chemical CID:49830260 PUBCHEM VCP protein P55072 UNIPROT down-regulates activity chemical inhibition -1 23316025 t Luana Inhibition of p97 by ML240 and ML241 is ATP competitive. To determine the mechanism by which ML240 and ML241 inhibited p97 ATPase, we evaluated rates of ATP hydrolysis at different concentrations of ATP. ML240 and ML241 inhibited p97competitively with respect to ATP with a Kivalues of 0.22 mm and 0.35 mm respectively. SIGNOR-261093 0.8 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser383 IHFWSTLsPIAPRSP 10090 BTO:0000944 7889942 t lperfetto We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-235455 0.545 E2F1 protein Q01094 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22832221 f gcesareni Brca1/e2f1/ctipbinding to atm promoter activates atm transcription. SIGNOR-198470 0.666 DIABLO protein Q9NR28 UNIPROT XIAP protein P98170 UNIPROT down-regulates activity binding 9606 BTO:0000567 10929711 t amattioni Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. SIGNOR-80218 0.912 ketanserin chemical CHEBI:6123 ChEBI SLC18A1 protein P54219 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000318 8643547 t miannu Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2. SIGNOR-258493 0.8 STAT5A protein P42229 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 18270368 t We demonstrate that the signal transducer and activator of transcription 5 (STAT5)-signaling cytokines, IL-2, IL-15 and to a lesser extent IL-7, induce FOXP3 up-regulation in vitro in activated human Teff cell SIGNOR-254365 0.494 CAMK2A protein Q9UQM7 UNIPROT HOMER3 protein Q9NSC5 UNIPROT down-regulates activity phosphorylation Ser176 ERLKKMLsEGSVGEV -1 18480293 t miannu Homer3 is phosphorylated at Ser120, Ser159, and Ser176 by CaMKII in vitro. Homer3 phosphorylation reduces its affinity for target molecules and modulates the Ca2+ signaling patterns induced by mGluR1α activation SIGNOR-262686 0.2 SIRT2 protein Q8IXJ6 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates deacetylation 9606 BTO:0000887;BTO:0001103 12887892 t gcesareni Sir2-mediated deacetylation of myod can be expected to inhibit its transcriptional capabilities. SIGNOR-104251 0.384 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Thr284 CPGRDRRtEEENLRK 9606 20959462 t llicata Importantly, the aurora b-mediated phosphorylation on ser(269) or thr(284) significantly compromises p53 transcriptional activity. SIGNOR-168749 0.708 TTK protein P33981 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto Ttk phosphorylation of thr735 was associated with partial inhibition of nuclear targeting of c-abl. SIGNOR-181064 0.283 CASP1 protein P29466 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261747 0.325 4-(3-chloro-2-fluorophenoxy)-1-[[6-(2-thiazolylamino)-2-pyridinyl]methyl]-1-cyclohexanecarboxylic acid chemical CHEBI:125340 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194411 0.8 ATM protein Q13315 UNIPROT SMC1A protein Q14683 UNIPROT up-regulates activity phosphorylation Ser966 GEDSVSGsQRISSIY 9606 BTO:0005521 11877376 t Atm phosphorylates Smc1 on serines 957 and 966 in vitro and in vivo, and expression of an Smc1 protein mutated at these phosphorylation sites abrogates the ionizing irradiation-induced S phase cell cycle checkpoint SIGNOR-255589 0.693 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea chemical CHEBI:91327 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207299 0.8 SETBP1 protein Q9Y6X0 UNIPROT HOXA10 protein P31260 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001271 22566606 f miannu Setbp1 activates hoxa9 and hoxa10 expression in myeloid progenitors SIGNOR-197318 0.351 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CCNE1 protein P24864 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193543 0.8 AKT2 protein P31751 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 9829964 t gcesareni Creb is a nuclear target for activation via the growth factor-dependent ser/thr kinase akt/pkb. When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp. SIGNOR-62253 0.493 CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000567 9390557 t lperfetto Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade. SIGNOR-53582 0.623 EXOC5 protein O00471 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270780 0.917 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates activity phosphorylation Tyr516 PVIENPQyFGITNSQ 10090 BTO:0000944 10533983 t miannu TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. Mutagenesis of Y484 inhibits the interaction between Shc and TrkB, and also block the E3DNF-inducible tyrosine phoslphorylation of Shc SIGNOR-250204 0.2 RELN protein P78509 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 10090 17584923 f Luana Reln, encoding an extracellular signaling molecule essential for neuronal lamination and synaptic plasticity SIGNOR-265772 0.7 COL2A1 protein P02458 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR up-regulates activity binding 9606 BTO:0000249 25169886 t lperfetto Isolation, cloning, and sequence analysis of the integrin subunit alpha10, a beta1-associated collagen binding integrin expressed on chondrocytes. SIGNOR-253347 0.468 ATR protein Q13535 UNIPROT XPC protein Q01831 UNIPROT up-regulates binding 9606 23422745 t gcesareni Atrand atm physically interacted with xpc and promptly localized to the uv damage sites. SIGNOR-201112 0.49 KCNIP4 protein Q6PIL6 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity relocalization 8355 BTO:0000964 24811166 t Luisa KChIP4 increased the current amplitude of Kv4.2, decelerated the inactivation, and accelerated the recovery from inactivation of Kv4.2. KChIP.is known to promote the translocation of Kv4.2 from the endoplasmic reticulum or Golgi to the cell surface SIGNOR-269004 0.765 CTDSP2 protein O14595 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser208 DAGSPNLsPNPMSPA 9606 BTO:0000007 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248294 0.399 copper(1+) smallmolecule CHEBI:49552 ChEBI SOD2 protein P04179 UNIPROT up-regulates activity chemical activation 1542024 t lperfetto Copper as a cofactor and regulator of copper,zinc superoxide dismutase SIGNOR-272300 0.8 BZW2 protein Q9Y6E2 UNIPROT ATF4 protein P18848 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31643092 f miannu Subsequent research reveals that BZW2 induces ATF4 translation which is a pro‐oncogenic transcription factor SIGNOR-261222 0.422 PPP2CA protein P67775 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation Ser664 QSAFAGFsFVNPKFE 9606 11959144 t PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex SIGNOR-248639 0.385 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120112 0.316 BCOR protein Q6W2J9 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates activity binding 9606 BTO:0000007 10898795 t miannu BCoR can interact w Because HDACs appear to be involved in repression by an increasing number of transcriptional repressors, we tested whether BCoR can associate with HDACs. BCoR can interact with HDAC1, HDAC3, and HDAC-B/5 more strongly than with HDAC-A/4, HDAC-C, HDAC-D, and HDAC-E. SIGNOR-252236 0.385 TAOK3 protein Q9H2K8 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2 SIGNOR-201333 0.295 ATG2B protein Q96BY7 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001938 28561066 f miannu WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation. SIGNOR-268486 0.7 PELI2 protein Q9HAT8 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates ubiquitination 9606 17997719 t gcesareni These studies suggest that pellino isoforms may be the e3 ubiquitin ligases that mediate the il-1-stimulated formation of k63-pub-irak1 in cells, which may contribute to the activation of ikkbeta and the transcription factor nf-kappab, as well as other pathways dependent on irak1/4. SIGNOR-159058 0.772 vincaleukoblastine sulfate chemical CHEBI:9984 ChEBI TUBA1A protein Q71U36 UNIPROT down-regulates activity chemical inhibition 9606 15579115 t miannu Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. SIGNOR-259255 0.8 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr88 KHLVALYtRDEHFAI -1 8349691 t llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. SIGNOR-250911 0.346 mifepristone chemical CHEBI:50692 ChEBI NR3C1 protein P04150 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258709 0.8 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR GAP43 protein P17677 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 26865625 t miannu  In this study, we demonstrated for the first time that growth-associated protein 43 (GAP43), a well known growth cone protein that promotes axonal regeneration, can be induced in rat brain astrocytes by the proinflammatory endotoxin lipopolysaccharide via both nuclear factor-κB and signal transducer and activator of transcription 3-mediated transcriptional activation. SIGNOR-266770 0.2 KIFC1 protein Q9BW19 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 33361741 f miannu Kinesin Family Member C1 (KIFC1) Regulated by Centrosome Protein E (CENPE) Promotes Proliferation, Migration, and Epithelial-Mesenchymal Transition of Ovarian Cancer SIGNOR-266117 0.7 CEBPG protein P53567 UNIPROT LTF protein P02788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 15588942 f miannu C/EBP_ interacts with C/EBP_ through the leucine-zipper–containing domain. C/EBP_ and C/EBP_ synergistically activate transcription of lactoferrin promoter SIGNOR-225015 0.2 DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9534 BTO:0004055 10196136 t lperfetto We have recently found that Dvl-1 directly binds to Axin and that the binding of Dvl-1 to Axin does not affect the interaction of GSK-3beta with Axin. It is possible that the binding of Dvl to Axin induces the structural change of the Axin complex; therefore GSK-3beta does not effectively phosphorylate Axin. This is the first demostration showing that Dvl inhibits the function of GSK-3beta directly. SIGNOR-227917 0.7 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr1214 VCDPKFHyDNTAGIS 9606 18840653 t gcesareni Vegfr2 contains several critical tyrosine residues that are autophosphorylated following activation. Our phosphorylation assays showed that tcptp was able to target specific tyrosines in vegfr2. The autophosphorylation sites tyr1054/1059 and tyr1214 were dephosphorylated by tcptp. Tyr996 was a tcptp target as well. SIGNOR-181546 0.547 EIF1B protein O60739 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR up-regulates activity relocalization 9606 20921384 t lperfetto Genetic and biochemical studies have revealed several eukaryotic factors involved in selecting the correct initiation codon (3–6). Further analyses pointed toward eukaryotic initiation factor 1 (eIF1) as the key mediator of this process (7–10). eIF1 binds near the P-site of the small ribosomal subunit (11); this binding is thought to lead to an open conformation of the preinitiation complex favoring scanning SIGNOR-269145 0.475 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236404 0.751 E2F1 protein Q01094 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23542036 f miannu We show here that EAPP stimulates the MDR1 promoter resulting in higher PGP levels. Independently of EAPP, E2F1 also increases the activity of the MDR1 promoter. SIGNOR-253841 0.2 MAPK3 protein P27361 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 12110590 t gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. SIGNOR-90533 0.728 NLRP3 protein Q96P20 UNIPROT NLRP3 inflammasome complex SIGNOR-C225 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256410 0.737 SLC2A3 protein P11169 UNIPROT glucose chemical CHEBI:17234 ChEBI up-regulates quantity relocalization 9606 23506862 t miannu GLUThe SLC2A3 gene encoding GLUT3 was first cloned from a human fetal skeletal muscle cell line (Kayano et al., 1988). It shares ~64% sequence identity with SLC2A1. GLUT3 has a higher apparent affinity (lower Km) and a higher maximum turnover number for glucose than the other Class 1 GLUT proteins, and its principal physiological substrate is clearly D-glucose T1 plays a critical role in cerebral glucose uptake as the major GLUT isoform expressed in brain endothelial cells. SIGNOR-267461 0.8 MMP1 protein P03956 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272377 0.7 CNKSR1 protein Q969H4 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates binding 9606 22830020 t gcesareni Cnk1 binds to rassf1a and promotes apoptosis through a pathway that requires rassf1a and mst kinases. SIGNOR-198432 0.412 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9534 8622669 t lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40427 0.734 SMURF proteinfamily SIGNOR-PF29 SIGNOR TGFBR2 protein P37173 UNIPROT down-regulates activity ubiquitination 9606 22298955 t lperfetto Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. SIGNOR-253265 0.2 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAPK7 protein Q13164 UNIPROT down-regulates chemical inhibition 9606 BTO:0000142 11782488 t gcesareni Bmk1 activation by h2o2 was inhibited by both pd98059 and u0126, which were reported to inhibit mek5 as well as mek1/2. SIGNOR-113773 0.8 UPF2 protein Q9HAU5 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000142 31636381 f miannu Our data indicate that proper synaptic plasticity and cognitive function requires UPF2.  SIGNOR-265235 0.7 MAPK14 protein Q16539 UNIPROT ELK3 protein P41970 UNIPROT up-regulates phosphorylation Ser363 LSPVAPLsPARLQGP 9606 9130707 t gcesareni Tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387. Mutation of these sites to alanine severely reduces c-fos sre-dependent transcription mediated by sap-1a and p38 map kinase. SIGNOR-47685 0.387 SIK2 protein Q9H0K1 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser794 QHLRLSTsSGRLLYA 9606 12624099 t lperfetto Sik2 could phosphorylate ser(794) of human irs-1 SIGNOR-99059 0.585 AURKB protein Q96GD4 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14583461 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. SIGNOR-118890 0.2 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser1985 DSVTRATsDNLQVRG 28882890 t Phosphosite is derived from Figure 2 lperfetto C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation| Of 19 native NaV1.5 phosphorylation sites identified, two C-terminal phosphoserines at positions 1938 and 1989 showed increased phosphorylation in the CaMKIIδc-Tg compared with the WT ventricles. SIGNOR-275783 0.481 NEDD4L protein Q96PU5 UNIPROT SCN1A protein P35498 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 t miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). SIGNOR-253457 0.296 PRKACA protein P17612 UNIPROT RYR2 protein Q92736 UNIPROT up-regulates activity phosphorylation Ser2808 YNRTRRIsQTSQVSV -1 14532276 t miannu PKA-mediated hyperphosphorylation of a conserved serine, Ser-2843 in skeletal RyR and Ser-2809 in cardiac RyR, results in an aberrant SR function during heart failure. hyperphosphorylated RyRs are leaky and therefore lead to a reduced SR Ca2+ load and impaired contractile function in heart failure SIGNOR-250079 0.459 MAPK1 protein P28482 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation 9606 19282669 t gcesareni Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. SIGNOR-161518 0.716 YARS1 protein P54577 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 16429158 t miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr SIGNOR-270520 0.8 YY1 protein P25490 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15291746 f miannu These results designate YY1 as the factor responsible for the intron 1-mediated boost of the HSD3B2 gene basal promoter activity. SIGNOR-255619 0.2 AHR protein P35869 UNIPROT CYP1A1 protein P04798 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17012224 t miannu Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1. SIGNOR-259909 0.671 GSK3A protein P49840 UNIPROT ANKRD28 protein O15084 UNIPROT down-regulates activity phosphorylation Ser1007 INRYTNTsKTVSFEA -1 phosphorylation:Ser1011 TNTSKTVsFEALPIM 17023142 t lperfetto We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K SIGNOR-264792 0.2 LGALS3 protein P17931 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates quantity by stabilization 9606 BTO:0000664 21821001 f miannu Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells. SIGNOR-261905 0.257 MMP12 protein P39900 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272357 0.7 TLR4 protein O00206 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 28137827 t miannu Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation. SIGNOR-263652 0.426 NEK6 protein Q9HC98 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 t done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  SIGNOR-273894 0.2 NOTCH1 protein P46531 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11591772 f lperfetto Nf-kappab activity is regulated by notch-1 via transcriptional control of nf-kappab. SIGNOR-110963 0.385 PTPRO protein Q16827 UNIPROT VCP protein P55072 UNIPROT down-regulates activity dephosphorylation 9606 23533167 t miannu An important aspect of this study is that tyrosine dephosphorylation of VCP by PTPRO sensitizes HepG2 cells to Doxorubicin, a chemotherapeutic drug commonly used for a variety of cancers. SIGNOR-277063 0.433 DMTF1 protein Q9Y222 UNIPROT BCL3 protein P20749 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 f Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  SIGNOR-261583 0.2 DYRK2 protein Q92630 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser30 TPRSRERsPSPLRGN 9606 BTO:0000671 15910284 t lperfetto Dyrk2 (dual-specificity tyrosine-phosphorylated and -regulated protein kinase 2) phosphorylated crhsp24 at ser30, ser32 and ser41 in vitro, and ser41 was identified as a site phosphorylated in cells. SIGNOR-137474 0.263 Caspase 3 complex complex SIGNOR-C221 SIGNOR ACIN1 protein Q9UKV3 UNIPROT up-regulates cleavage 9606 10490026 t amattioni Induces apoptotic chromatin condensation after activation by casp3 SIGNOR-256449 0.613 FLT3 protein P36888 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000222;BTO:0001946 BTO:0000887;BTO:0001103 23704355 f gcesareni Here we report the identification of flt3l (fms-like tyrokine kinase 3 ligand) signaling as a novel regulator of skeletal myogenesis SIGNOR-202105 0.7 SMO protein Q99835 UNIPROT GNB1 protein P62873 UNIPROT up-regulates binding 9606 16885213 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-148537 0.358 AURKA protein O14965 UNIPROT FAF1 protein Q9UNN5 UNIPROT down-regulates activity phosphorylation Ser291 DVHMVSDsDGDDFED 9606 18790738 t llicata This study reports that aurora-a (aur-a) phosphorylates fas-associated factor-1 (faf1) at ser-289 and ser-29 our findings support the negative feedback regulation of aur-a via phosphorylation of the death-promoting protein, faf1 SIGNOR-180891 0.2 ARF6 protein P62330 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 BTO:0003102 14565977 f miannu ARNO and ARF6 regulate axonal elongation and branching through downstream activation of phosphatidylinositol 4-phosphate 5-kinase alpha SIGNOR-264908 0.7 MMP25 protein Q9NPA2 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272392 0.7 CSNK2A2 protein P19784 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser281 DGTGDTSsEEDEDEE -1 11278496 t llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. SIGNOR-250996 0.382 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity phosphorylation Thr533 TGSDNTDtEGS 9606 17936701 t PVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2. SIGNOR-269111 0.352 seliciclib chemical CHEBI:45307 ChEBI CCNB1 protein P14635 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206562 0.8 CSNK2A2 protein P19784 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser228 PGVTPSKsTSASAIM 9606 BTO:0000938 26917740 t lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. SIGNOR-275740 0.312 873837-23-1 chemical CID:46930994 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190470 0.8 CDK4 protein P11802 UNIPROT MYOG protein P15173 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 t gcesareni In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-176530 0.335 CAMK4 protein Q16566 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 BTO:0000887 11114197 t gcesareni Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs. SIGNOR-85110 0.489 AKT1 protein P31749 UNIPROT MVD protein P53602 UNIPROT up-regulates activity phosphorylation Ser96 LARKRRNsRDGDPLP 10090 25378391 t miannu Akt modulated the pathway by phosphorylating mevalonate diphosphate decarboxylase (MDD) at Ser96. These data suggest that Akt regulates Rac1 activity by directly phosphorylating MDD at Ser96, which augments Rac1 geranylgeranylation. SIGNOR-265891 0.2 CHEK2 protein O96017 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser376 PLLPRVSsYLVPIQF 9606 BTO:0001938 17101782 t lperfetto Chk2 mediates stabilization of the foxm1 transcription factor to stimulate expression of dna repair genesthis phosphorylation of foxm1 on serine residue 361 caused increased stability of the foxm1 protein SIGNOR-150746 0.709 RBPJ protein Q06330 UNIPROT CIR1 protein Q86X95 UNIPROT up-regulates binding 9606 9874765 t amattioni In the mechanism of cbf1-mediated repression, cbf1 binds to a unique corepressor cir. Targeting of cir to cbf1 is an important component of repression. Cir binds to histone deacetylase and to sap30 and serves as a linker between cbf1 and the histone deacetylase complex. SIGNOR-62932 0.66 AKT1 protein P31749 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Thr246 LPRPRLNtSDFQKLK 9606 BTO:0000007 12524439 t gcesareni Treatment of these cells with 4-hydroxytamoxifen stimulated the phosphorylation of wt PRAS40 but not the mutant PRAS40 in which Thr-246 was mutated. These results demonstrate that activation of Akt alone is sufficient to induce phosphorylation of PRAS40 SIGNOR-252544 0.774 HSP90AA1 protein P07900 UNIPROT PPP5C protein P53041 UNIPROT up-regulates binding 9606 15577939 t miannu Hsp90 causes substantial activation of ppp5 by competing for tpr_phosphatase domain contacts and allowing access to the catalytic site. SIGNOR-131564 0.762 PRKCA protein P17252 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Ser561 PRKFSKFsLYKQLHR 9606 10441128 t gcesareni Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells. SIGNOR-69934 0.702 EIF5B protein O60841 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates activity binding 9606 30211544 t lperfetto eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC. SIGNOR-269121 0.608 HSP90AA1 protein P07900 UNIPROT FLCN protein Q8NFG4 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 27353360 t Here we show that the stability of the tumour suppressor folliculin (FLCN) depends on the chaperone function of Hsp90. SIGNOR-256505 0.31 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates activity chemical activation 9606 18321241 t miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). SIGNOR-259241 0.8 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser235 IAKRRRLsSLRASTS 9606 17360704 t gcesareni We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism. SIGNOR-252813 0.2 PRKACA protein P17612 UNIPROT TPH1 protein P17752 UNIPROT up-regulates activity phosphorylation Ser58 RKSKRRNsEFEIFVD -1 9109552 t miannu The activation of tryptophan hydroxylase by protein kinase A is mediated by the phosphorylation of serine-58 within the regulatory domain of the enzyme. SIGNOR-250062 0.357 N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-6-quinazolinyl]-2-propenamide chemical CHEBI:91467 ChEBI ERBB4 protein Q15303 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189945 0.8 glutamic acid smallmolecule CHEBI:18237 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264752 0.7 JUN protein P05412 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding 9606 1904542 t irozzo The proteins encoded by the proto-oncogenes c-fos and c-jun (Fos and Jun, respectively) form a heterodimeric complex that regulates transcription by interacting with the DNA-regulatory element known as the activator protein 1 (AP-1) binding site. SIGNOR-256363 0.951 G3BP2 protein Q9UN86 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 23279204 f SARA G3BP1 and G3BP2 form homo‐ and hetero‐multimers to induce SGs SIGNOR-260983 0.7 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249668 0.397 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252980 0.509 POU5F1 protein Q01860 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22795133 f lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) SIGNOR-253161 0.511 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265814 0.7 AKT1 protein P31749 UNIPROT TKT protein P29401 UNIPROT up-regulates activity phosphorylation Thr382 GCATRNRtVPFCSTF 9606 BTO:0000567 24981175 t lperfetto Akt phosphorylates TKT on Thr382, markedly enhancing enzyme activity and increasing carbon flow through the nonoxidative PPP, thereby increasing purine synthesis. SIGNOR-265101 0.286 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI PRIM2 protein P49643 UNIPROT up-regulates activity chemical activation 26083061 t lperfetto Human DNA primase, are Fe-S proteins. The loss of an iron-sulfur cluster in RAD3 helicase results in a failure to unwind DNA1 SIGNOR-262134 0.8 ZAP70 protein P43403 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 t gcesareni The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2). SIGNOR-59659 0.664 TLR4 protein O00206 UNIPROT TIRAP protein P58753 UNIPROT up-regulates binding 9606 11544529 t fstefani Mal (myd88-adapter-like) is required for toll-like receptor-4 signal transduction. SIGNOR-110337 0.771 AMPK complex SIGNOR-C15 SIGNOR NAMPT protein P43490 UNIPROT up-regulates quantity 10090 18477450 f gcesareni Activated AMPK was required to promote GR-induced transcription of the NAD+ biosynthetic enzyme Nampt SIGNOR-238824 0.275 CREB1 protein P16220 UNIPROT NR2F1 protein P10589 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000152 15955695 f miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. SIGNOR-253792 0.274 CTSS protein P25774 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 11920402 f lperfetto Cathepsins K and S have been implicated in various aspects of extracellular matrix degradation and inflammatory responses. SIGNOR-253319 0.7 WASHC2C protein Q9Y4E1 UNIPROT WASH complex complex SIGNOR-C258 SIGNOR form complex binding 23721880 t lperfetto The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53. SIGNOR-261016 0.2 SLC24A4 protein Q8NFF2 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264397 0.8 NFKB1 protein P19838 UNIPROT BMP4 protein P12644 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000018 17350185 t Luana  The effect of TNF-alpha on the Bmp4 promoter is mediated through NF-kB. SIGNOR-266086 0.2 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation Tyr785 NSLISSDyELLSDPT 9606 18250158 t lperfetto The phosphorylation of wt jak3 and y980f/y981f/y785f mutant jak3 is presumably mediated through autophosphorylation at distinct jak3 sites within this model systemhosphorylation of jak3 on y785 has been reported to create a binding site for the adaptor protein sh2b-beta SIGNOR-160660 0.2 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCA protein P17252 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191490 0.8 SNS-314 Mesylate chemical CID:24995523 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207105 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT2 protein Q96AC1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser177 LITPGSGsIYSSPGL 9606 BTO:0000567 35469017 t miannu CDK1–cyclin B1 mediates KIND1 and KIND2 phosphorylation at mitotic entry . MS of KIND1 and KIND2 immunoprecipitates from STLC-arrested HeLa cells confirmed the phosphorylation of KIND1-S179 and KIND2-S181 and revealed phosphorylation of closely adjacent serine residues (KIND1: SSphS174GphS176PVphS179PGLYSK; KIND2: GphS175GphS177IYphS180phS181PGLYSK), although to a weaker extent (Supplementary Table 2). SIGNOR-276713 0.2 IL17RA protein Q96F46 UNIPROT IL17R complex complex SIGNOR-C260 SIGNOR form complex binding 9606 BTO:0001946 32024054 t lperfetto Importantly, IL-17 was involved in increased collagen production in cardiac fibroblasts in response to HG, with both subunits of the IL-17RA and IL-17RC heterodimer complex being important to mediating this response. SIGNOR-261335 0.53 TAOK2 protein Q9UL54 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity binding 9606 10497253 t lperfetto Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7. SIGNOR-70950 0.634 ARPC1A protein Q92747 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 t The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc SIGNOR-251515 0.873 POU5F1 protein Q01860 UNIPROT FOXA2 protein Q9Y261 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 f lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) SIGNOR-253165 0.436 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser280 VDGTGDTsSEEDEDE 9606 11278496 t lperfetto TAFII 250 Phosphorylates Human Transcription Factor IIA on Serine Residues Important for TBP Binding and Transcription ActivityAdditional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels SIGNOR-246630 0.664 PFDN1 protein O60925 UNIPROT Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR form complex binding 9606 32699605 t miannu The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6) SIGNOR-270932 0.948 CSNK2A1 protein P68400 UNIPROT SET protein Q01105-2 UNIPROT down-regulates phosphorylation Ser9 SAPAAKVsKKELNSN 9606 BTO:0000938 BTO:0000142 23374587 t The effect has been demonstrated using Q01105-2 miannu Ckii-mediated phosphorylation at ser9 hinders nuclear import of set SIGNOR-200798 0.372 RELA protein Q04206 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR up-regulates binding 9606 10207072 t lperfetto Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo. SIGNOR-217655 0.845 BAX protein Q07812 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 10629050 t Following Bid-induced conformational change lperfetto Following bid-induced conformational change, bax oligomerizes and inserts tightly within the outer mitochondrial membrane. The integration of bax in the outer mitochondrial membrane is followed by cytochrome crelease SIGNOR-73895 0.2 SRC protein P12931 UNIPROT PBK protein Q96KB5 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr272 DFDDEAYyAALGTRP 9606 BTO:0000038 27016416 t miannu Phosphorylation of TOPK at Y74, Y272 by Src increases the stability of TOPK and promotes tumorigenesis of colon SIGNOR-277217 0.404 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT up-regulates activity phosphorylation Thr1225 SRRPRLEtILSLLVS -1 27292631 t miannu We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment. SIGNOR-274063 0.308 ABL1 protein P00519 UNIPROT RB1 protein P06400 UNIPROT unknown phosphorylation Tyr805 RIPGGNIyISPLKSP 9606 BTO:0001271 16158058 t llicata Rb-induced apoptosis is compromised by abl-catalysed phosphorylation of rb at y805. SIGNOR-140396 0.552 AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188) SIGNOR-244300 0.2 IL6R protein P08887 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 23869758 t miannu On binding of IL-6 to its receptor IL-6R, JAK2 is phosphorylated, then STAT3 is phosphorylated by JAK2 SIGNOR-254405 0.551 ponatinib chemical CHEBI:78543 ChEBI RIPK3 protein Q9Y572 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000661 25801024 t Federica Discovery of ponatinib as the first-in-class dual inhibitor of RIPK1 and RIPK3 SIGNOR-261083 0.8 ICI D1694 chemical CHEBI:5847 ChEBI TYMS protein P04818 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206403 0.8 SRC protein P12931 UNIPROT ENO1 protein P06733 UNIPROT up-regulates phosphorylation Tyr44 SGASTGIyEALELRD 9606 24841372 t lperfetto The present finding suggested that the tyrosine residue at position 44 in chicken alpha-enolase is the phosphorylation site by the tyrosine kinase. Our data suggest that eno1 was upregulated by caga protein through activating the src and mek/erk signal pathways SIGNOR-205092 0.419 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT up-regulates activity phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000782 11700305 t lperfetto We identify catalytic domain fragments of protein kinase c (pkc) delta and pkcbetai/ii as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin cd18 chain. The sites phosphorylated in vitro were identified as ser-745 and thr-758. Pkc-mediated phosphorylation of cd18 after cell stimulation could lead to the recruitment of 14-3-3 proteins to the activated integrin, which may play a role in regulating its adhesive state or ability to signal. SIGNOR-111495 0.335 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 t Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. SIGNOR-252861 0.908 PRKACA protein P17612 UNIPROT PDE4B protein Q07343 UNIPROT up-regulates activity phosphorylation Ser56 NLQLPPLsQRQSERA 9534 BTO:0000298 12441002 t miannu PKA-mediated phosphorylation of Ser-56 in UCR1 of PDE4B4 leads to activation of this long isoform SIGNOR-250024 0.588 RAB10 protein P61026 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 t lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 SIGNOR-260618 0.399 NR3C1 protein P04150 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates quantity transcriptional regulation 10090 22848740 t miannu We show that FOXO3 is an immediate early glucocorticoid receptor (GR) target, whose transcription is even further enhanced by conditions that mimic metabolic stress. SIGNOR-255759 0.425 CRYAA protein P02489 UNIPROT CRYBB2 protein P43320 UNIPROT up-regulates activity binding 9606 22982024 t miannu Aberrant protein interactions can lead to aggregation and insolubilization, such as occurs during cataract formation. Deamidation, a prevalent age-related modification in the lens of the eye, decreases stability of the major lens proteins, crystallins. Deamidation did not disrupt specific αA/βB2 interactions but favored aggregation before complex formation with αA. We conclude that deamidation contributes to cataract formation through destabilization of crystallins before they can be rescued by α-crystallin. SIGNOR-252155 0.2 SLIT1 protein O75093 UNIPROT GPC1 protein P35052 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 10364234 t gcesareni Slit family proteins are functional ligands of glypican-1 in nervous tissue and suggest that their interactions may be critical for certain stages of central nervous system histogenesis. SIGNOR-68327 0.39 MAPK14 protein Q16539 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates activity phosphorylation Thr250 NSCTPITtPELTTPC 9606 9155017 t lperfetto Mnk1, but not mnk2, also binds strongly to the stress-activated kinase, p38. Erk and p38 phosphorylate MNK1 and Mnk2. SIGNOR-48342 0.658 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1248 PTAENPEyLGLDVPV -1 1706616 t  Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. SIGNOR-251128 0.2 RHOA protein P61586 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates activity binding 9606 25010901 t gcesareni Rho-associated coiled-coil containing kinases (ROCK) were originally identified as effectors of the RhoA small GTPase SIGNOR-196740 0.803 MAML1 protein Q92585 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity acetylation 9606 17300219 t gcesareni We speculated that maml1, in addition to recruiting p300, might directly interact with histones to facilitate histone acetylation. We had observed acetylation of the histones h3 and h4. SIGNOR-153041 0.2 CENPX protein A8MT69 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265201 0.2 LY294002 chemical CHEBI:65329 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 t gcesareni Here we show that inhibition of pi3-k activity by the pharmacological agent ly294002 affects early processes of myoblast differentiation including the transcriptional activation of myogenin. SIGNOR-252647 0.8 SLC9A5 protein Q14940 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265595 0.8 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18805788 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-252922 0.2 ERCC6 protein Q03468 UNIPROT NEIL1 protein Q96FI4 UNIPROT up-regulates activity binding 9606 19179336 t Regulation miannu CSB stimulates NEIL1 incision activity in vitro, and CSB and NEIL1 co-immunoprecipitate and co-localize in HeLa cells. SIGNOR-251931 0.351 APC-c complex SIGNOR-C150 SIGNOR CLSPN protein Q9HAW4 UNIPROT down-regulates quantity by destabilization ubiquitination 18662541 t lperfetto Claspin Is Degraded in G0 and G1 via the APC/CCdh1 Ubiquitin Ligase SIGNOR-274056 0.262 GOPC protein Q9HD26 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates binding 9606 21311563 t gcesareni Npist binds beclin 1 by a ccd SIGNOR-171896 0.538 IGF2 protein P01344 UNIPROT IGF2R protein P11717 UNIPROT up-regulates binding 9606 11867533 t fspada Insulin-like growth factor ii receptor (igf2r) is a multifunctional cell surface receptor implicated in tumour suppression. Its growth inhibitory activity has been associated with an ability to bind igf-ii. SIGNOR-115250 0.751 WNT11 protein O96014 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131634 0.642 UHRF1 protein Q96T88 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005192 20037778 f miannu we find UHRF1 plays an important role in inhibiting MDR1 promoter activity by directly binding to the MDR1 promoter. Overexpression of UHRF1 in NCI/ADR-RES cells can induce deacetylation of histones H3 and H4 on the MDR1 promoter, which is facilitated by recruitment of HDAC1 to the MDR1 promoter. SIGNOR-254224 0.2 NRTN protein Q99748 UNIPROT RET protein P07949 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9182803 t gcesareni A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling SIGNOR-49122 0.704 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii SIGNOR-203568 0.769 sirolimus chemical CHEBI:9168 ChEBI CD80 protein P33681 UNIPROT down-regulates quantity by repression 9606 18652845 f miannu Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells. SIGNOR-255475 0.8 UGP2 protein Q16851 UNIPROT UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI up-regulates quantity chemical modification 9606 8631325 t miannu UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. SIGNOR-267928 0.8 LAMB3 protein Q13751 UNIPROT Laminin-5 complex SIGNOR-C184 SIGNOR form complex binding 9211848 t lperfetto Like the other laminins (3), Ln-5 comprises three disul- fide-bonded subunits: a3, b3, and g2. SIGNOR-253236 0.633 tamoxifen chemical CHEBI:41774 ChEBI GPER1 protein Q99527 UNIPROT up-regulates chemical activation 9606 15539556 t gcesareni The finding that the antiestrogens tamoxifen and ici 182,780, and an environmental estrogen, ortho,para-dichlorodiphenyldichloroethylene (o,p'-dde), have high binding affinities to the receptor and mimic the actions of e2 has important implications for both the development and treatment of estrogen-dependent breast cancer. SIGNOR-130395 0.8 MAP2K6 protein P52564 UNIPROT CRK protein P46108 UNIPROT up-regulates phosphorylation 9606 8663074 t gcesareni Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub-family of the mitogen-activated protein kinase superfamily. SIGNOR-42384 0.2 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser248 DLDILHNsSQMKSMS 9606 BTO:0000567 25670858 t lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. SIGNOR-265227 0.571 CSF3 protein P09919 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 16492764 t gcesareni The gcsf:gcsf-r complex formed a 2:2 stoichiometry by means of a cross-over interaction between the ig-like domains of gcsf-r and gcsf. the ig-like domain cross-over structure necessary for gcsf-r activation is consistent with previously reported thermodynamic and mutational analyses. SIGNOR-144743 0.757 ESRRA protein P11474 UNIPROT NR2F6 protein P10588 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000156 15955695 f miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. SIGNOR-253796 0.25 NHLH2 protein Q02577 UNIPROT ASCL1 protein P50553 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21573214 f miannu Overexpression of both LMO3 and HEN2 induced expression of Mash1, suggesting that they might function as a transcriptional activator for Mash1. SIGNOR-254823 0.243 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser326 PPKMWKTsPDPSPVS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248378 0.598 tRNA(His) smallmolecule CHEBI:29178 ChEBI His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates quantity precursor of 9606 10430027 t miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. SIGNOR-270491 0.8 Caspase 8 complex complex SIGNOR-C231 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni Downstream of caspase-8 activation, apoptosis induction takes place SIGNOR-256549 0.7 dasatinib (anhydrous) chemical CHEBI:49375 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191304 0.8 NOTCH proteinfamily SIGNOR-PF30 SIGNOR MAML3 protein Q96JK9 UNIPROT up-regulates binding 9606 12370315 t flangone Genetic ablation or activation of the pathway reveals that Notch signalling promotes differentiation of the hair follicle, sebaceous gland and interfollicular epidermal lineages SIGNOR-254346 0.2 CSNK2A1 protein P68400 UNIPROT FKBP4 protein Q02790 UNIPROT down-regulates activity phosphorylation Thr143 EFKGEDLtEEEDGGI -1 9405642 t llicata Thr-143 in the hinge I region was identified as the major phosphorylation site for CK2. | Most importantly, CK2-phosphorylated FKBP52 did not bind to HSP90 SIGNOR-250865 0.349 SYNE2 protein Q8WXH0 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 t lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. SIGNOR-263283 0.529 Matrine chemical CHEBI:6700 ChEBI OPRK1 protein P41145 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-194316 0.8 RAD21 protein O60216 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR form complex binding 28430577 t lperfetto Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin SIGNOR-263311 0.966 CSNK2A2 protein P19784 UNIPROT CASQ2 protein O14958 UNIPROT unknown phosphorylation Ser385 DDDDDDNsDEEDNDD -1 1985907 t llicata Both cardiac and skeletal muscle calsequestrins were phosphorylated by casein kinase II, but cardiac calsequestrin was phosphorylated to a higher stoichiometry and at least 50 times more rapidly. The site of rapid phosphorylation of cardiac calsequestrin was localized to the distinct COOH terminus, where a cluster of three closely spaced serine residues are found (S378DEESN-DDSDDDDE-COOH). SIGNOR-250980 0.382 CDKN1B protein P46527 UNIPROT CDK1 protein P06493 UNIPROT down-regulates binding 9606 15340381 t gcesareni P21 and p27 are key inhibitors of both cdk1 and cdk2. SIGNOR-128445 0.676 IRF4 protein Q15306 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 11956291 f IRF4 synergizes with NFATc2 and the IL-4-inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production SIGNOR-254501 0.539 TCF7L2 protein Q9NQB0 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates activity transcriptional regulation 20492721 f FFerrentino These findings suggested that miR-210 could promote adipogenesis by repressing WNT signaling through targeting Tcf7l2. SIGNOR-253519 0.7 SRSF7 protein Q16629 UNIPROT NXF1 protein Q9UBU9 UNIPROT up-regulates binding 9606 18364396 t miannu 9g8 and srp20 also enhance the tap rna-binding activity SIGNOR-161338 0.656 DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity ubiquitination 9606 11153911 t gcesareni The human Deltex (DTX1) gene encodes a cytoplasmic protein that functions as a positive regulator of the Notch signaling pathway. SIGNOR-85942 0.772 CHEK2 protein O96017 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates activity phosphorylation Ser364 PLLSRMGsLRAPVDE 9606 12717439 t Manara Therefore, Chk2 phosphorylates and activates E2F-1 in response to DNA damage, resulting in apoptosis. | These results suggest that the Ser 364 site is phosphorylated by Chk2 and that anti-P-Ser 364 recognises the phosphorylated site in E2F-1. SIGNOR-260822 0.5 CTSG protein P08311 UNIPROT SERPIND1 protein P05546 UNIPROT down-regulates activity cleavage Val458 QATTVTTvGFMPLST -1 2318847 t miannu Amino acid sequence analysis led to the conclusion that both neutrophil elastase and cathepsin G cleave HC at Ile66, which does not affect HC activity, and at Val439, near the reactive site Leu444, which inactivates HC. SIGNOR-256509 0.455 SERPINC1 protein P01008 UNIPROT F10 protein P00742 UNIPROT down-regulates activity cleavage 31030036 t lperfetto Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1 SIGNOR-264138 0.872 PAK1 protein Q13153 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 12151336 t gcesareni Histone h3 is a substrate of pak1 both in vitro and in vivo, and it specifically interacted with pak1 but not pak2 or pak3. Site-directed mutagenesis indicated that pak1 phosphorylates histone h3 on ser10. SIGNOR-265363 0.2 migalastat chemical CHEBI:135923 ChEBI GLA protein P06280 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0003676 10866822 t Federica 1-Deoxygalactonojirimycin was the most potent inhibitor of a-Gal A with an IC50 value of 0.04mm. SIGNOR-261076 0.8 MAPK3 protein P27361 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation Ser62 LLPTPPLsPSRRSGL -1 32482868 t lperfetto ERK1 phosphorylates MYC Ser62 resulting in MYC stabilization and activation SIGNOR-236250 0.695 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates activity phosphorylation Tyr702 FGMSRDVySTDYYRV 10090 BTO:0000944 10533983 t miannu TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. Mutagenesis of Y484 inhibits the interaction between Shc and TrkB, and also block the E3DNF-inducible tyrosine phoslphorylation of Shc SIGNOR-250205 0.2 UVB radiation stimulus SIGNOR-ST17 SIGNOR calciol smallmolecule CHEBI:28940 ChEBI up-regulates quantity chemical modification 9606 BTO:0001253 30080183 t lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin SIGNOR-270562 0.7 CD19 protein P15391 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0000899 10201980 t lperfetto Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase. SIGNOR-252669 0.502 NR4A3 protein Q92570 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 30455429 f miannu Over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax. SIGNOR-259398 0.7 SREBF2 protein Q12772 UNIPROT NPC1L1 protein Q9UHC9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21123766 f miannu Our results showed a positive correlation between changes in NPC1L1 and changes in both SREBP-2 and HNF-4α mRNA expression, a finding that supports the notion that these transcription factors stimulate intestinal NPC1L1 expression. SIGNOR-254452 0.582 Integrator complex complex SIGNOR-C265 SIGNOR NcRNA_processing phenotype SIGNOR-PH95 SIGNOR up-regulates 9606 26220997 f lperfetto  In vivo knockdown and rescue experiments confirmed that the 3′ end processing of HVS pre-miRNAs also depends on Integrator activity. Interaction between Integrator and HVS primary miRNA (pri-miRNA) substrates that contain only the miRNA 3′ box was confirmed by coimmunoprecipitation and an in situ proximity ligation assay (PLA) SIGNOR-261475 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NUP153 protein P49790 UNIPROT unknown phosphorylation 9606 19767751 t inferred from 70% family members llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. SIGNOR-270159 0.2 SMAD3 protein P84022 UNIPROT CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 23032366 f lperfetto PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A. SIGNOR-245441 0.545 SST protein P61278 UNIPROT SSTR4 protein P31391 UNIPROT up-regulates binding 9606 10433861 t gcesareni The five receptor subtypes bind the natural SST peptides, SST-14 and SST-28, with low nanomolar affinity. SIGNOR-82496 0.769 SOD1 protein P00441 UNIPROT VDAC1 protein P21796 UNIPROT down-regulates activity binding 10090 BTO:0001279 20797535 t P00441:p.Gly38Arg (mutation causing interaction) Misfolded Mutant SOD1 Directly Inhibits VDAC1 Conductance in a Mouse Model of Inherited ALS|With conformation-specific antibodies, we now demonstrate that misfolded mutant SOD1 binds directly to the voltage-dependent anion channel (VDAC1), an integral membrane protein imbedded in the outer mitochondrial membrane. SIGNOR-262798 0.435 BCL11A protein Q9H165 UNIPROT HBG2 protein P69892 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004408 29606353 t Gianni Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching. SIGNOR-269066 0.458 PPP2CA protein P67775 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity dephosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0001023 16596250 t Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation. SIGNOR-248617 0.443 topotecan chemical CHEBI:63632 ChEBI TOP1MT protein Q969P6 UNIPROT down-regulates activity chemical inhibition 9606 11166732 t miannu Topotecan is a topoisomerase I inhibitor which is currently evaluated as an adjuvant agent for malignant glioma. SIGNOR-259318 0.8 RLIM protein Q9NVW2 UNIPROT ZFP42 protein Q96MM3 UNIPROT down-regulates quantity by destabilization ubiquitination 22596162 t lperfetto RNF12 causes ubiquitination and proteasomal degradation of REX1, and Rnf12 knockout embryonic stem cells show an increased level of REX1. SIGNOR-269002 0.343 ATG3 protein Q9NT62 UNIPROT GABARAP protein O95166 UNIPROT up-regulates activity binding -1 16303767 t lperfetto Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme) SIGNOR-141868 0.841 MYC protein P01106 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates quantity by stabilization 9606 26049753 f Overexpression of c-MYC resulted in SIRT1 deubiquitination, whereas c-MYC knockdown led to decrease in SIRT1 protein stability and expression. SIGNOR-261558 0.589 DAXX protein Q9UER7 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates binding 9606 9743501 t gcesareni Daxx was found to activate the jnk kinase kinase ask1, and overexpression of a kinase-deficient ask1 mutant inhibited fas- and daxx-induced apoptosis and jnk activation. SIGNOR-60164 0.835 SLC9A1 protein P19634 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265600 0.8 TRIB3 protein Q96RU7 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity binding 9606 BTO:0000007 BTO:0000759 12791994 t llicata TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase. SIGNOR-252644 0.603 CHMP2B protein Q9UQN3 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 t miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. SIGNOR-265530 0.67 RPS6KB1 protein P23443 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 2846551 t gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. SIGNOR-23757 0.249 FLT3 protein P36888 UNIPROT SPI1 protein P17947 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14592841 f This data confirms that PU.1 is a downstream target of activated C/EBPα and is suppressed in FLT3/ITD-expressing cells as a result of C/EBPα suppression. SIGNOR-261530 0.61 SDCBP protein O00560 UNIPROT SOX4 protein Q06945 UNIPROT up-regulates activity binding 10090 BTO:0003104 11498591 t miannu Sox4 activation by IL-5R_ appears to be direct, with syntenin functioning as an adaptor molecule. Syntenin mediates IL-5–induced Sox4 activation. SIGNOR-223089 0.553 TP53 protein P04637 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7 EXOC5 protein O00471 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270788 0.94 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 BTO:0000671 18986304 t llicata Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143). SIGNOR-182053 0.2 dutasteride chemical CHEBI:521033 ChEBI ESR2 protein Q92731 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-191445 0.8 VCP protein P55072 UNIPROT DERL1 protein Q9BUN8 UNIPROT up-regulates activity binding 9606 BTO:0000567 15215856 t miannu VIMP mediates p97 binding to hDerlin-1. these data suggest that Derlin-1 and VIMP form a membrane protein complex that serves as a receptor for p97. SIGNOR-261372 0.88 alvocidib chemical CHEBI:47344 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191532 0.8 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates activity phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 12637538 t Manara We show that Abl directly phosphorylates PKD at Tyr(463) in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of PKD SIGNOR-260791 0.345 NFE2L2 protein Q16236 UNIPROT KRT16 protein P08779 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18629308 f miannu When overexpressed in HaCaT cells, NRF2 was also directly involved in not only the up-regulation of the detoxification gene thioredoxin but also K16 gene expression. SIGNOR-254645 0.2 resiquimod chemical CHEBI:36706 ChEBI TLR8 protein Q9NR97 UNIPROT up-regulates activity chemical activation 9606 15661881 t miannu Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively. SIGNOR-259247 0.8 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 22049910 t Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. SIGNOR-266907 0.8 CHUK protein O15111 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 BTO:0000551 22505454 t gcesareni Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites. SIGNOR-196953 0.404 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK4 protein P11802 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206130 0.8 PTPN6 protein P29350 UNIPROT JAK1 protein P23458 UNIPROT down-regulates dephosphorylation 9606 BTO:0000150;BTO:0001271;BTO:0000785;BTO:0000661;BTO:0003076 14624462 t gcesareni We find, for the first time, that shp-1 down-regulates the level of tyk2 kinase in h9 cells and of jak1 kinase in htb26 cells, by accelerating their degradation. SIGNOR-119197 0.631 CSNK2A1 protein P68400 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Thr250 KEEVVGLtETSSQPK 9606 BTO:0000776 7678037 t llicata These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase erine threonine phosphorylation and may stimulate CKII activity in B cells. SIGNOR-250917 0.312 INVS protein Q9Y283 UNIPROT DVL1 protein O14640 UNIPROT down-regulates ubiquitination 9606 15852005 t gcesareni Inversin inhibits the canonical wnt pathway by targeting cytoplasmic dishevelled (dsh or dvl1) for degradation SIGNOR-135766 0.63 TLE5 protein Q08117 UNIPROT SIX3 protein O95343 UNIPROT down-regulates activity binding -1 12441302 t lperfetto Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. AES abrogates SIX3- and SIX6-induced phenotypes SIGNOR-234586 0.2 ETS1 protein P14921 UNIPROT SLC26A3 protein P40879 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 7935445 f miannu Ets-1 activates the DRA promoter in B cells. SIGNOR-254085 0.2 AKT1 protein P31749 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser652 LERPFRPsVTSVGHV -1 24548923 t miannu Akt phosphorylates S637 and S645 in the linker region of Carma1  SIGNOR-276620 0.537 CDKN1A protein P38936 UNIPROT PCNA protein P12004 UNIPROT down-regulates binding 9606 22911014 t gcesareni P21 exerts its effect on the cell cycle not only by inhibiting cyclin/cdk complexes, but also by inhibiting proliferating cell nuclear antigen (pcna) SIGNOR-191939 0.755 CDK1 protein P06493 UNIPROT ESPL1 protein Q14674 UNIPROT down-regulates phosphorylation Ser1126 IAPSTNSsPVLKTKP 9606 11747808 t lperfetto Both cdc2/cyclinb1 and mapk (erk2) efficiently phosphorylate separase at its major inhibitory site in vitro SIGNOR-113126 0.588 CDKN2A protein P42771 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 16161044 t gcesareni In addition, cytoplasmic p16 bound cyclin dependent kinase (cdk)4/6, potentially indicating that p16 could have a function in the cytoplasm. SIGNOR-140412 0.866 vatalanib chemical CHEBI:90620 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207645 0.8 CAMK2A protein Q9UQM7 UNIPROT LRRC7 protein Q96NW7 UNIPROT unknown phosphorylation Ser1439 IQTKGQRsMDGYPEQ 11160423 t llicata In contrast, phosphorylation of densin-180 by CaMKII at serine-1397 only slightly decreases its affinity for CaMKII. The specific interaction of densin-180 with holoenzymes of CaMKII containing only alpha-subunit and the increased affinity of CaMKII for densin-180 after autophosphorylation suggest that densin-180 may be involved in localization of activated CaMKII synthesized in dendrites. SIGNOR-250634 0.437 PRL protein P01236 UNIPROT KRT14 protein P02533 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 20103718 f Regulation miannu PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes. SIGNOR-251902 0.285 CUDC-907 chemical CID:54575456 PUBCHEM HDAC10 protein Q969S8 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191206 0.8 SMURF1 protein Q9HCE7 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27858941 t miannu DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1 SIGNOR-254776 0.265 AKT1 protein P31749 UNIPROT SH2B2 protein O14492 UNIPROT unknown phosphorylation Ser598 SARSRSNsAERLLEA 10090 16141217 t Serine 588 of APS is a newly identified target for protein kinase B in intact cells and in vitro. The precise function of this PKB-mediated phosphorylation event is not entirely clear but may be responsible for regulating cellular localization and will be the subject of future investigation. SIGNOR-252577 0.409 GSK3B protein P49841 UNIPROT RXRA protein P19793 UNIPROT up-regulates activity phosphorylation Ser78 PMGPHSMsVPTTPTL 9606 BTO:0000007 29137318 t miannu GSK3β-induced RXRα phosphorylation decreased for RXRα-S49A, RXRα-S66A and RXRα-S78A in HEK293 cells compared with RXRα WT by western blot analysis.  SIGNOR-277371 0.278 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 9753485 t Crohn's Disease gcesareni SIGNOR-251703 0.8 PTPN1 protein P18031 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2110 FGLARDIyKNDYYRK 9606 17416557 t gcesareni In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products. SIGNOR-154199 0.381 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH10 protein Q9Y6N8 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265828 0.8 Calcineurin complex SIGNOR-C155 SIGNOR NFATC3 protein Q12968 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-252312 0.558 EP300 protein Q09472 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates acetylation 9606 BTO:0000887 SIGNOR-C6 10944526 t gcesareni Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo. SIGNOR-81053 0.668 LDHA protein P00338 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0000164 9192621 f The lactate dehydrogenase-A gene (LDH-A), whose product participates in normal anaerobic glycolysis and is frequently increased in human cancers, was identified as a c-Myc-responsive gene. SIGNOR-259370 0.7 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1161 FGMTRDIyETDYYRK 9606 8940173 t lperfetto Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor SIGNOR-45122 0.564 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK -1 8756661 t lperfetto these data suggest that phosphorylation of ZAP-70 is initiated by a heterologous trans-phosphorylation of ZAP-70 by Lck on Tyr- 493. SIGNOR-226628 0.602 PIAS1 protein O75925 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates sumoylation 9606 20016603 t gcesareni Pias1 and pias4 are recruited to dna-damage sites and mediate 53bp1 recruitment and sumoylation. SIGNOR-162156 0.507 Org 27569 chemical CID:44828492 PUBCHEM CNR1 protein P21554 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-195097 0.8 GSK690693 chemical CHEBI:90677 ChEBI AKT3 protein Q9Y243 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193006 0.8 RND1 protein Q92730 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 17251915 t gcesareni In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor SIGNOR-152811 0.327 PCDHA3 protein Q9Y5H8 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265668 0.2 hydrosulfide smallmolecule CHEBI:29919 ChEBI Vasodilation phenotype SIGNOR-PH223 SIGNOR up-regulates 26539823 f lperfetto We have recently shown, that in arterial (HAEC) end venular (HUVEC) endothelial cells, GPBAR1 agonism increases the expression/ activity of cystathione-γ-liase (CSE, CTH, EC 4.4.1), a key enzyme in the “trans-sulfuration pathway” that generates hydrogen sulfide (H2S), a vasodilatory agent SIGNOR-275831 0.7 heme smallmolecule CHEBI:30413 ChEBI FBXO22 protein Q8NEZ5 UNIPROT up-regulates activity chemical activation 9606 31257023 t Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22. SIGNOR-259332 0.8 PI4KB protein Q9UBF8 UNIPROT phosphatidylinositol 4-phosphate smallmolecule CHEBI:37530 ChEBI up-regulates quantity chemical modification 9534 22253445 t lperfetto Interestingly, we found that PI4P, the product of PI4KB catalysis, creates a lipid microenvironment that is required for SARS-CoV S-mediated entry. SIGNOR-260732 0.8 HLX protein Q14774 UNIPROT CDKN1C protein P49918 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003980 20008130 t Luana In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells. SIGNOR-261620 0.2 CDK1 protein P06493 UNIPROT NUP98 protein P52948 UNIPROT down-regulates activity phosphorylation Thr670 IAKPIPQtPESAGNK 9606 21335236 t gcesareni We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks. SIGNOR-172225 0.407 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates activity phosphorylation Ser387 ETGLYRIsGCDRTVK 9606 BTO:0000567 12689593 t lperfetto We also report that aurora b phosphorylates mgcracgap on serine residues and that this modification induces latent gap activity toward rhoa in vitro. SIGNOR-100569 0.771 PRKCH protein P24723 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251634 0.2 CYSLTR1 protein Q9Y271 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257225 0.379 nocodazole chemical CHEBI:34892 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194838 0.8 OGDHL protein Q9ULD0 UNIPROT OGDC complex SIGNOR-C397 SIGNOR form complex binding 9606 15953811 t miannu The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. SIGNOR-267833 0.642 MRPL36 protein Q9P0J6 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262361 0.711 TAOK2 protein Q9UL54 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2. SIGNOR-201327 0.278 PRKCZ protein Q05513 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 14657655 t gcesareni Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent. SIGNOR-119889 0.58 AP-2 complex complex SIGNOR-C245 SIGNOR AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR form complex binding 9606 24789820 t lperfetto AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly.  SIGNOR-260663 0.61 CBLB protein Q13191 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 10542134 t miannu Here we describe that overexpression of cbl-b, a homologue of the c-cbl protooncogene, inhibits EGFR-induced apoptosis in MDA-MB-468 breast cancer cells. Overexpression of cbl-b results in a shortened duration of EGFR activation upon EGF stimulation. This is demonstrated by decreased amounts of phosphorylated EGFR as well as by inhibition of multiple downstream signaling pathways. The inhibition of signaling by cbl-b results from increased ubiquitination and degradation of the activated EGFR.  SIGNOR-272934 0.75 MAPK8 protein P45983 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 14967141 t gcesareni Jnk phosphorylates bad at threonine 201, thereby inhibiting bad association with the antiapoptotic molecule bcl-x(l) SIGNOR-121940 0.673 PRKCA protein P17252 UNIPROT GPM6A protein P51674 UNIPROT up-regulates activity phosphorylation Thr10 ENMEEGQtQKGCFEC 10116 BTO:0001009 12359212 t miannu In summary, a CNS neuron-specific membrane glycoprotein, M6a, could act as a novel NGF-gated Ca2+ channel through the phosphorylation with PKC and augments [Ca2+]i in M6a-S cells. SIGNOR-263163 0.329 FABP3 protein P05413 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264457 0.7 AMBRA1 protein Q9C0C7 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 9606 BTO:0000459 20921139 t lperfetto we show that the BECLIN 1-VPS34 complex is tethered to the cytoskeleton through an interaction between the BECLIN 1-interacting protein AMBRA1 and dynein light chains 1/2. SIGNOR-168252 0.778 TBX2 protein Q13207 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity binding 9606 24470334 t We have found that TBX2 is highly up regulated in both ERMS and ARMS subtypes of RMS and demonstrate that TBX2 is a repressor of myogenesis by binding to MyoD and myogenin and inhibiting their activity. SIGNOR-251560 0.315 GATA1 protein P15976 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR up-regulates activity 10090 12032775 f Studies involving point mutants of GATA-1 have shown that a direct physical interaction between GATA-1 and FOG-1 is essential for normal human erythroid and megakaryocyte maturation in vivo. SIGNOR-259961 0.7 lurasidone chemical CHEBI:70735 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10030 20404009 t Luana Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 2C receptors. SIGNOR-259465 0.8 ABL1 protein P00519 UNIPROT APBB1 protein O00213 UNIPROT up-regulates phosphorylation Tyr547 VQKFQVYyLGNVPVA 9606 15031292 t lperfetto The c-abl tyrosine kinase phosphorylates the fe65 adaptor protein to stimulate fe65/amyloid precursor protein nuclear signaling. Here, we show that active c-abl stimulates app/fe65-mediated gene transcription and that this effect is mediated by phosphorylation of fe65 on tyrosine 547 within its second ptb domain. SIGNOR-123476 0.424 CSNK1E protein P49674 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates phosphorylation Ser268 PQVRVGGsSVDLHRF 9606 BTO:0000782 3133391 t gcesareni Moreover, in response to wnt3a, p120-catenin is phosphorylated at ser268, a modification dependent on ck1epsilon activity, which disrupts its interaction with e-cadherin and, subsequently, with lrp5/6, promoting the release of ck1epsilon/p120-catenin from the wnt receptor complex. SIGNOR-24443 0.292 SLC9A1 protein P19634 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265591 0.8 MOG protein Q16653 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 33290135 f SimoneGraziosi Myelin oligodendrocyte glycoprotein (MOG) is a nervous system protein expressed by oligodendrocytes to constitute the myelin sheath. SIGNOR-269232 0.7 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser649 VPPSPSLsRHSSPHQ -1 2117608 t llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. SIGNOR-250880 0.335 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline chemical CHEBI:94782 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190919 0.8 RBX1 protein P62877 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates ubiquitination 9606 SIGNOR-C5 14676825 t gcesareni Mechanism of processing of the nf-kappa b2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of nedd8-modification on the scf(beta-trcp) ubiquitin ligase. SIGNOR-120342 0.285 CSNK2A1 protein P68400 UNIPROT SEC63 protein Q9UGP8 UNIPROT up-regulates activity phosphorylation Ser574 EEVSDKGsDSEEEET 9606 23287549 t lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. SIGNOR-265269 0.295 IRS1 protein P35568 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 10090 BTO:0000887 14623899 t lperfetto As shown previously, IRS-1 was required for insulin-stimulated phosphorylation of Akt in 32D cells, which is consistent with the binding and activation of PI3K by IRS-1 during insulin stimulation SIGNOR-236618 0.712 MMP1 protein P03956 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272354 0.7 CSNK2A1 protein P68400 UNIPROT SSRP1 protein Q08945 UNIPROT down-regulates activity phosphorylation Ser510 SSSNEGDsDRDEKKR 9606 BTO:0000007 15659405 t llicata CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity. SIGNOR-250959 0.69 nitric oxide smallmolecule CHEBI:16480 ChEBI GUCY1A3-B3 complex SIGNOR-C140 SIGNOR up-regulates activity chemical activation 9606 15036565 t gcesareni One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP) SIGNOR-243967 0.8 SNCA protein P37840 UNIPROT ER stress stimulus SIGNOR-ST9 SIGNOR up-regulates 9606 12666095 f lperfetto Furthermore, mutant isoforms of alpha-synuclein more readily oligomerize, and it has been suggested that its tendency to aggregate into misfolded structures may confer toxic properties to the protein. SIGNOR-249702 0.7 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAP2K1 protein Q02750 UNIPROT down-regulates activity phosphorylation Thr286 VEGDAAEtPPRPRTP 10090 BTO:0000944 11684694 t llicata Phosphorylation of MEK1 by cdk5/p35 down-regulates the mitogen-activated protein kinase pathway. | suggesting that Thr286 in MEK1 is a site of cdk5/p35 phosphorylation that inhibits MEK1 activity. SIGNOR-250653 0.479 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Thr402 PEQSKRStMVGTPYW -1 10075701 t miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites SIGNOR-250230 0.2 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser24 APIRRRSsNYRAYAT 9606 18550549 t gcesareni Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144. SIGNOR-178884 0.275 PELI3 protein Q8N2H9 UNIPROT JUN protein P05412 UNIPROT up-regulates 9606 12874243 f gcesareni Pellino3 leads to activation of c-jun and elk-1, but not nf-kappab SIGNOR-103989 0.282 KAT6A/KAT6B complex SIGNOR-C54 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0001271;BTO:0000876 11742995 t lperfetto The activation domain of aml1 is required for its interaction with moz / moz activates aml1_mediated transcription SIGNOR-217201 0.418 AKT1 protein P31749 UNIPROT TARBP2 protein Q15633 UNIPROT up-regulates activity phosphorylation Ser286 LRSCSLGsLGALGPA -1 27407113 t miannu We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells.  SIGNOR-274067 0.2 tRNA(Cys) smallmolecule CHEBI:29167 ChEBI Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI up-regulates quantity precursor of 9606 11347887 t miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. SIGNOR-270475 0.8 MAP1LC3B protein Q9GZQ8 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 17580304 t gcesareni Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation. SIGNOR-156356 0.831 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 8887554 t lperfetto We show that mapkap kinase-2 phosphorylates creb at ser133 in vitro. SIGNOR-44384 0.679 IL6 protein P05231 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates 10090 23531613 f AMPK phosphorylation was increased nearly fourfold (Fig. 2C) with the high dose of IL-6 SIGNOR-255338 0.248 PGM1 protein P36871 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267930 0.8 CAMK2A protein Q9UQM7 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates phosphorylation Ser868 ITRGEWQsEAQDTMK 9606 BTO:0000938 BTO:0000142 20643921 t gcesareni Nmda-dependent internalization of gabab receptors requires activation of ca2+/calmodulin-dependent protein kinase ii (camkii), which associates with gabab receptors in vivo and phosphorylates serine 867 (s867) in the intracellular c terminus of the gabab1 subunit. SIGNOR-166846 0.239 AXIN1 protein O15169 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT up-regulates binding 9606 BTO:0000007 12878610 t gcesareni Mekk4, also binds to axin in vivo and mediates axin-induced jnk activation. SIGNOR-104003 0.43 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser630 VLSSTFLsPQCSPQH 9606 BTO:0000007 16141410 t In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity SIGNOR-251248 0.406 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JAK2 protein O60674 UNIPROT down-regulates phosphorylation Ser523 GVSDVPTsPTLQRPT 9534 BTO:0004055 16705159 t 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner SIGNOR-244553 0.2 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser36 PSEGRQPsPSPSPTE 9606 BTO:0001271 15093545 t The effect has been demonstrated using P29590-4 gcesareni We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3). SIGNOR-124240 0.366 RET protein P07949 UNIPROT AFAP1L2 protein Q8N4X5 UNIPROT up-regulates activity phosphorylation Tyr54 SSSSDEEyIYMNKVT 9606 BTO:0000007 19060924 t miannu RET/PTC induced robust tyrosine phosphorylation of XB130, which promoted its subsequent association with the p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase). We identified tyrosine 54 of XB130 as the major target of RET/PTC-mediated phosphorylation and a critical binding site for the SH2 domains of p85alpha. SIGNOR-263192 0.337 AKT2 protein P31751 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 t gcesareni Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155. SIGNOR-81114 0.504 USP9X protein Q93008 UNIPROT SMN1 protein Q16637 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 23112048 t lperfetto Ubiquitin-specific Protease 9x Deubiquitinates and Stabilizes the Spinal Muscular Atrophy Protein-Survival Motor Neuron SIGNOR-253113 0.284 glutamine smallmolecule CHEBI:28300 ChEBI Glutaminolysis phenotype SIGNOR-PH119 SIGNOR up-regulates activity 9606 BTO:0000567 22749528 f Luana Leucine and Glutamine Activate Glutaminolysis and mTORC1 SIGNOR-268009 0.7 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT up-regulates activity phosphorylation Thr320 AISDTTTtFCGTPEY 10548550 t miannu SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB. SIGNOR-250279 0.473 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MMP9 protein P14780 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15536164 f miannu Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kappaB, a transcription factor that is activated in FAP nerves and SG. SIGNOR-254798 0.428 FOXM1 protein Q08050 UNIPROT SLC27A2 protein O14975 UNIPROT up-regulates quantity by expression 9606 31949772 f lperfetto FOXM1 as a prognostic biomarker promotes endometrial cancer progression via transactivation of SLC27A2 expression. SIGNOR-260414 0.2 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR BRCA1-A complex complex SIGNOR-C296 SIGNOR form complex binding 9606 BTO:0000007 20656690 t lperfetto We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1.  SIGNOR-263216 0.768 mTORC2 complex SIGNOR-C2 SIGNOR ELP1 protein O95163 UNIPROT up-regulates activity phosphorylation Ser1174 SETSSVVsGSEMSGK 29925953 t lperfetto Human ELP1 S1174 phosphorylation was triggered by insulin treatment, as shown by the specific phosphorylated (p)ELP1 (S1174) antibody, and addition of a phosphorylation-mutant variant of the ELP1 protein (ELP1(S1174A)) to ELP1-depleted BRAFV600E melanoma cells failed to rescue cell survival |In line with these findings, mTORC2 activity, but not mTORC1, was required for the insulin-induced phosphorylation of Elp1 S1174 SIGNOR-275542 0.2 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252976 0.509 GEM protein P55040 UNIPROT ROCK2 protein O75116 UNIPROT down-regulates activity binding 9606 14701738 t miannu Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively. SIGNOR-261711 0.294 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273053 0.556 NR4A3 protein Q92570 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 30455429 t miannu NR4A3 physically interacted with an anti-apoptotic Bcl-2 protein hence sequestering it from blunting apoptosis. SIGNOR-259399 0.2 HOXB1 protein P14653 UNIPROT OTX2 protein P32243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000946 9556594 t Luana Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively SIGNOR-261633 0.277 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates activity phosphorylation Ser337 DPRGRLRsADSENAL 9606 12761205 t lperfetto Inhibition of mitogen-activated kinase kinase kinase 3 activity through phosphorylation by the serum- and glucocorticoid-induced kinase 2 SIGNOR-101216 0.2 ACVR1 protein Q04771 UNIPROT ACVR1/BMPR2 complex SIGNOR-C30 SIGNOR form complex binding 9606 7791754 t lperfetto Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor. SIGNOR-33287 0.702 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176801 0.775 CDX2 protein Q99626 UNIPROT TFF3 protein Q07654 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0004055 17182120 t The transcription of human TFF3 reporter genes was significantly up-regulated by the transient overexpression of CDX2 in COS-7 cells and AGS gastric cells. SIGNOR-253967 0.401 CDK5 protein Q00535 UNIPROT CDK5R1 protein Q15078 UNIPROT down-regulates phosphorylation Ser8 MGTVLSLsPSYRKAT 9606 18326489 t lperfetto When overexpressed with cdk5, a large fraction of the double mutant p35(s8a/t138a) co-sedimented with microtubules (fig. 5b), further supporting the idea that the phosphorylation at these two residues by cdk5 is inhibitory to the microtubule association. SIGNOR-177963 0.942 JUN protein P05412 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto Functional data suggest that c-Jun is not merely a target for activation by many of the extracellular stimuli, but that it plays a role in mediating the cellular response. In the case of growth control, three lines of evidence suggest that the transcription factor AP-1, which is composed of Fos–Jun and Jun–Jun dimers, mediates cell proliferation in response to external growth signals in the form of peptide growth factors. SIGNOR-233467 0.7 NPM1 protein P06748 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates quantity binding 10090 BTO:0002572 18625840 t gcesareni We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7 , a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc. NPM was required for nucleolar localization and stabili- zation of Fbw7 SIGNOR-245084 0.495 CH5132799 chemical CID:49784945 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190949 0.8 EYA3 protein Q99504 UNIPROT H2AX protein P16104 UNIPROT down-regulates dephosphorylation Tyr143 ATQASQEy 9606 20965415 t gcesareni Tyr142 is dephosphorylated by the tyr phosphatases eya1 and eya3. SIGNOR-168927 0.2 ANAPC1 protein Q9H1A4 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 t lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. SIGNOR-252001 0.876 LRRC4 protein Q9HBW1 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 25526788 f miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. SIGNOR-264054 0.361 SRC protein P12931 UNIPROT BCKDK protein O14874 UNIPROT up-regulates activity phosphorylation Tyr246 RRLCEHKyGNAPRVR 9606 BTO:0001615 32238881 t lperfetto Src phosphorylated BCKDK at the tyrosine 246 (Y246) site in vitro and ex vivo. Knockdown and knockout of Src downregulated the phosphorylation of BCKDK. Importantly, phosphorylation of BCKDK by Src enhanced the activity and stability of BCKDK, thereby promoting the migration, invasion, and EMT of CRC cells. SIGNOR-275583 0.2 silodosin chemical CHEBI:135929 ChEBI ADRA1A protein P35348 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206914 0.8 CDK2 protein P24941 UNIPROT UBE2A protein P49459 UNIPROT up-regulates phosphorylation Ser120 LDEPNPNsPANSQAA 9606 11953320 t llicata Hhr6a is phosphorylated in vitro by cdk-1 and -2 on ser120, a residue conserved in all hhr6a homologues, resulting in a 4-fold increase in its ubiquitin-conjugating activity. SIGNOR-116508 0.381 EGR1 protein P18146 UNIPROT COL4A1 protein P02462 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21931594 f Regulation miannu Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1) SIGNOR-251917 0.2 RIPK2 protein O43353 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates activity phosphorylation Ser176 KWRMMSLsQSRSSKS 9606 16824733 t amattioni In summary, our results indicate that s176 is a regulatory autophosphorylation site for rip2 and that s176 phosphorylation can be used to monitor the activation state of rip2. SIGNOR-229701 0.2 CEBPA protein P49715 UNIPROT FTO protein Q9C0B1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 24877091 f lperfetto CCAAT/Enhancer-Binding Protein 𝛼 Is a Crucial SIGNOR-261805 0.352 CSNK2B protein P67870 UNIPROT USO1 protein O60763 UNIPROT up-regulates activity phosphorylation Ser942 EEEDELEsGDQEDED -1 10931861 t llicata Phosphorylation is mediated by casein kinase II (CKII) or a CKII-like kinase. | Serine 941 in the Acidic Domain of p115 Is Essential for Reassembly of Golgi Cisternae SIGNOR-251082 0.341 BAK1 protein Q16611 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 11175253 t amattioni Allosteric activation of bak induces its intramembranous oligomerization into a proposed pore for cytochrome c efflux SIGNOR-105203 0.2 APOA1 protein P02647 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates 9606 20642861 t miannu ApoA-I increases cholesterol release in mature human adipocytes. SIGNOR-252104 0.8 CDK1 protein P06493 UNIPROT GOLGA2 protein Q08379 UNIPROT down-regulates phosphorylation Ser37 REYQQRNsPGVPTGA 9606 9753325 t lperfetto Cdc2 kinase directly phosphorylates the cis-golgi matrix protein gm130 and is required for golgi fragmentation in mitosis. Mitotic fragmentation of the golgi apparatus can be largely explained by disruption of the interaction between gm130 and the vesicle-docking protein p115. Here we identify a single serine (ser-25) in gm130 as the key phosphorylated target and cdc2 as the responsible kinase SIGNOR-60281 0.66 GNG2 protein P59768 UNIPROT SRC protein P12931 UNIPROT up-regulates activity 15345719 f In this study, we investigated the possible role of the Gβγ heterodimer in signaling Gi-induced Src activation SIGNOR-251108 0.444 TAOK2 protein Q9UL54 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity binding -1 10497253 t lperfetto Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7. SIGNOR-70947 0.656 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CITED1 protein Q99966 UNIPROT up-regulates binding 9606 9660950 t lperfetto The transcriptional coactivator cpb/p300 associates with nf-kappa b p65 through two sites, an n-terminal domain that interacts with the c-terminal region of unphosphorylated p65, and a second domain that only interacts with p65 phosphorylated on serine 276. SIGNOR-216331 0.2 EIF2S1 protein P05198 UNIPROT ATF4 protein P18848 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24714526 f miannu Reduction of globin inclusions and induction of ATF4 and HbF by the HRI-eIF2αP signaling provide strong bases for targeting this pathway for novel pharmaceutical therapy of hemoglobinopathy. SIGNOR-251820 0.625 DNM2 protein P50570 UNIPROT MYO1C protein O00159 UNIPROT up-regulates binding 9606 17257598 t miannu Dynamin bind directly to the sh3 domain of myo1e / an intriguing possibility is that binding of dynamin and synaptojanin to myo1e tail may activate motor activity since it has been demonstrated that myo1e atpase activity is autoinhibited by its sh3 domain SIGNOR-152910 0.362 CREB1 protein P16220 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 17668895 f gcesareni Phosphorylation of creb by msk has been linked to the of nur77, nor1 and c-fos downstream of mapkin various cell types SIGNOR-157151 0.649 TEAD1 protein P28347 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22286761 f gcesareni Yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor. SIGNOR-195534 0.275 PRDM14 protein Q9GZV8 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 31583686 f SimoneGraziosi SOX17 regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and suppressing somatic differentiation. SIGNOR-269261 0.7 UBE2A protein P49459 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination Lys164 AVVISCAkDGVKFSA 9606 19706603 t gcesareni Pcna is mono-ubiquitinated through rad6 and rad18, modified by lysine-63-linked multi-ubiquitination--which additionally requires mms2, ubc13 and rad5--and is conjugated to sumo by ubc9. The first of these is monoubiquitination of lysine 164 on one or more of the pcna subunits by the e2-e3 complex of rad6-rad18. SIGNOR-187761 0.489 HRH1 protein P35367 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257251 0.2 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser251 KNDYRKLsMQCKDFV 9606 BTO:0000007 14983059 t gcesareni There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712. SIGNOR-122978 0.417 AKT1 protein P31749 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 11108261 t lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. SIGNOR-84963 0.756 EXTL1 protein Q92935 UNIPROT SHH protein Q15465 UNIPROT down-regulates binding 9606 BTO:0000142 15614771 t gcesareni A study in mice suggests that ext1 proteins might negatively regulate shh signaling by synthesizing hspgs, which sequester the ligand SIGNOR-132606 0.299 GLS2 protein Q9UI32 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 22049910 t miannu Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. SIGNOR-266911 0.8 PRKACA protein P17612 UNIPROT AANAT protein Q16613 UNIPROT up-regulates activity phosphorylation Ser205 HPFLRRNsGC -1 11336675 t miannu AANAT1–207 was phosphorylated in vitro at both PKA sites, Thr-31 and Ser-205. regulation is achieved by binding to 14-3-3, which structurally modulates the substrate binding sites, leading to measurable effects on the affinity of AANAT for its substrates with an accompanying increase in activity at low substrate concentrations.  SIGNOR-250324 0.326 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr742 HMVQTNHyQVSGYPG 9606 BTO:0000195 17289681 t The effect has been demonstrated using P34152-3 gcesareni We propose that fak/c-src bipartite enzyme is a sensor of cytoplasmic shrinkage, and that the phosphorylation on fak tyr-861 by src and subsequent reorganization of f-actin can initiate an anti-apoptotic signaling pathway that protects cells from hyperosmotic stress. SIGNOR-152967 0.634 SKP2 protein Q13309 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates ubiquitination 9606 15998794 t gcesareni Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. SIGNOR-138490 0.763 N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide chemical CHEBI:94793 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189930 0.8 STAT1/STAT3 complex SIGNOR-C118 SIGNOR JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR form complex binding 10090 15284024 t lperfetto Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. SIGNOR-235658 0.693 BRCA1-B complex complex SIGNOR-C298 SIGNOR G1/S_transition_checkpoint phenotype SIGNOR-PH147 SIGNOR up-regulates 25400280 f lperfetto Another BRCA1 complex, the BRCA1–B complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‐phase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‐phase checkpoint activation SIGNOR-263225 0.7 SMAD4 protein Q13485 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR form complex binding 9606 9436979 t lperfetto Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription. SIGNOR-103618 0.657 PP1 proteinfamily SIGNOR-PF54 SIGNOR NEK2 protein P51955 UNIPROT down-regulates dephosphorylation 9606 17283141 t lperfetto Nek2 is activated by autophosphorylation, and its dephosphorylation is catalyzed by pp1 SIGNOR-264667 0.2 MICU2 protein Q8IYU8 UNIPROT MCU_MICUB_variant complex SIGNOR-C499 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270860 0.645 POT1/ACD complex SIGNOR-C64 SIGNOR Shelterin complex complex SIGNOR-C306 SIGNOR form complex binding 9606 15383534 t lperfetto Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins. SIGNOR-263318 0.856 RPRD1B protein Q9NQG5 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004953 30518842 t lperfetto These results indicated that CREPT regulates the Cyclin B1 expression via directly targeting its promoter region during transcription. SIGNOR-265500 0.2 CDC14B protein O60729 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT unknown dephosphorylation Ser368 PNPSTSAsPKKSPPP 9606 17488717 t Here, we demonstrate that SIRT2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1, and dephosphorylated by the phosphatases CDC14A and CDC14B. Overexpression of SIRT2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation|Additionally, we found that SIRT2, like other Cdk1 targets, can be dephosphorylated by the phosphatases CDC14A and CDC14B. In contrast to a published report (8), we did not observe any degradation of SIRT2 by the 26 S proteasome in response to CDC14B overexpression|However, we cannot exclude the possibility that phosphorylation of serine 368 might affect the activity of SIRT2 on other unidentified acetylated substrates. SIGNOR-248338 0.415 KMT2A protein Q03164 UNIPROT KAT8 protein Q9H7Z6 UNIPROT up-regulates binding 9606 15960975 t miannu Mll1 and mof can form a stable complex in vivo / given that an interaction of dmof with msl1 through its zinc finger is essential for correct targeting of mof to the male x chromosome SIGNOR-138245 0.466 ADAMTS13 protein Q76LX8 UNIPROT VWF protein P04275 UNIPROT down-regulates activity cleavage 9606 23020315 t miannu Proteolytic degradation of VWF by ADAMTS-13 downregulates the proinflammatory potential of VWF.  SIGNOR-251966 0.617 N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide chemical CHEBI:95008 ChEBI BCL2L1 protein Q07817 UNIPROT down-regulates chemical inhibition 9606 Other t The effect has been demonstrated using Q07817-1 gcesareni SIGNOR-207462 0.8 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser24 GYLRKPKsMHKRFFV -1 8349691 t llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. SIGNOR-250907 0.346 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation 9606 10197981 t lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 SIGNOR-66749 0.736 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser386 ARVGGASsLENTVDL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178367 0.731 PRKCG protein P05129 UNIPROT STXBP1 protein P61764 UNIPROT down-regulates activity phosphorylation Ser313 SLKDFSSsKRMNTGE 9913 BTO:0000259 12519779 t lperfetto Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation. SIGNOR-249187 0.394 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr387 VYFTYDPySEEDPDE -1 10214954 t Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510. SIGNOR-251377 0.629 PRKAA1 protein Q13131 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr101 IVLNKGKtIFRFSAT 9606 BTO:0002181 30759345 t miannu AMPK was found to phosphorylate Nav1.5 at threonine (T) 101, which then regulates the interaction between Nav1.5 and the autophagic adaptor protein, microtubule-associated protein 1 light chain 3 (LC3), by exposing the LC3-interacting region adjacent to T101 in Nav1.5. SIGNOR-277432 0.2 CDK5R1 protein Q15078 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates binding 9606 15013773 t miannu In brain, p35 or p25 exists with and activates cdk5 SIGNOR-123387 0.942 MAPK1 protein P28482 UNIPROT STIM1 protein Q13586 UNIPROT up-regulates phosphorylation Ser575 LVEKLPDsPALAKKA 9606 BTO:0000222 22298426 t gcesareni The netrin-2-mediated nfatc3 activation was coincident with robust interactions between cdo and stim1 in myoblasts and the erk-mediated stim1 phosphorylation at serine 575 SIGNOR-192788 0.358 MAX protein P61244 UNIPROT MYC protein P01106 UNIPROT up-regulates binding 9606 8425218 t esanto In vivo transactivation assays suggest that myc-max and mad-max complexes have opposing functions in transcription and that max plays a central role in this network of transcription factors SIGNOR-39137 0.733 SMUG1 protein Q53HV7 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). SIGNOR-275712 0.7 TUBB protein P07437 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 17429065 t lperfetto Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin. SIGNOR-232113 0.2 BCORL1 protein Q5H9F3 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity binding 9606 BTO:0000567 17379597 t irozzo BCoR-L1 interacts with Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its function as transcriptional corepressor. SIGNOR-259114 0.493 MAP3K6 protein O95382 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 RHTDDEMtGYVATRW 9534 8622669 t Manara These data indicate that MKK6 phosphorylates p38 MAP kinase on Thr-180 and Tyr-182, the sites of phosphorylation that activate p38 MAP kinase SIGNOR-260916 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR B2M protein P61769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12480693 f miannu The nuclear factor kappa B (NF-kappa B) subunits p50 and p65 bind to the kappa B box and p65 transactivates beta(2)m. SIGNOR-254658 0.349 MYF6 protein P23409 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity BTO:0001103 7532173 f Simone Vumbaca Finally, MRF4 may be responsible for the final myogenic events of the fully differentiated myofiber SIGNOR-255645 0.7 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide chemical CHEBI:91447 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194922 0.8 VASP protein P50552 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 18508258 f miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. SIGNOR-268390 0.7 Vincristine sulfate chemical CHEBI:79401 ChEBI TUBB4A protein P04350 UNIPROT down-regulates activity chemical inhibition 9606 30599272 t miannu Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. SIGNOR-259250 0.8 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000142 20308788 t The effect has been demonstrated using P10636-8 lperfetto Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro. SIGNOR-164671 0.2 BCLAF1 protein Q9NYF8 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17938203 f Luana These results demonstrate that Btf positively regulates TP53 expression through CPE-TP53. SIGNOR-261568 0.423 ACD protein Q96AP0 UNIPROT RPA1 protein P27694 UNIPROT down-regulates activity binding SIGNOR-C306 18680434 t lperfetto The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA SIGNOR-263328 0.2 AKT2 protein P31751 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t gcesareni We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-78681 0.275 Caspase 3 complex complex SIGNOR-C221 SIGNOR IL18 protein Q14116 UNIPROT up-regulates activity cleavage Asp76 MTDSDCRdNAPRTIF 9606 BTO:0001370 9334240 t lperfetto Involvement of caspase-1 and caspase-3 in the production and processing of mature human interleukin 18 in monocytic THP.1 cells.|Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products. SIGNOR-256379 0.496 ADAM17 protein P78536 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates cleavage 10090 23729744 t apalma Receptor–ligand engagement triggers a second NECD cleavage (S2 cleavage) by a metalloproteinase ADAM (known as Kuzbanian in Drosophila melanogaster) SIGNOR-255371 0.729 CSNK2A2 protein P19784 UNIPROT MYCN protein P04198 UNIPROT unknown phosphorylation Ser263 GEDTLSDsDDEDDEE -1 1425701 t llicata Analysis of phosphorylation sites in synthetic peptides of this acidic region identified the major sites phosphorylated by CKII as Ser261 and Ser263. SIGNOR-251015 0.375 SRC protein P12931 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates activity phosphorylation Tyr99 REMLEGFyEEISKGR 10090 24331927 t miannu Our results show that only Src can efficiently phosphorylate FHOD1 at Y99 to enable the downstream activation by ROCK. SIGNOR-276612 0.311 PTPN2 protein P17706 UNIPROT EGFR protein P00533 UNIPROT down-regulates dephosphorylation 9606 15592458 t gcesareni Here, we report that the 45-kda variant of the protein tyrosine phosphatase tcptp (tc45) can recognize delta egfr as a cellular substrate SIGNOR-132316 0.62 GSK3A protein P49840 UNIPROT GYS1 protein P13807 UNIPROT down-regulates phosphorylation Ser641 YRYPRPAsVPPSPSL 9606 BTO:0000887;BTO:0001103 14593110 t gcesareni Glycogen synthase kinase-3 (gsk-3) phosphorylates four serine residues in the cooh terminus of glycogen synthase. Phosphorylation of one of these residues, ser640 (site 3a), causes strong inactivation of glycogen synthase SIGNOR-118927 0.421 RPS6KA5 protein O75582 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni Msk (mitogen- and stress-activated kinase) 1 and 2 can directly phosphorylate and activate transcription factors such as creb, atf1, the nf- b isoform p65 and stat (signal transducer and activator of transcription) 1 and 3 SIGNOR-166664 0.393 TGFBR1 protein P36897 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 10090 BTO:0005065 17673906 t lperfetto We now report that upon TGF-_ stimulation, T_RI phosphorylates ShcA on serine and, to a lesser degree, on tyrosine to activate Erk MAP kinases. SIGNOR-227503 0.529 GSK3B protein P49841 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser129 QKRREILsRRPSYRK 10116 12162494 t GSK-3 can phosphorylate CREB at S129 Transactivation of CREB is significantly reduced (p ≤ 0.05) by 86% for the S129A mutant SIGNOR-251233 0.682 ERBB2 protein P04626 UNIPROT MSI1 protein O43347 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20443831 f gcesareni We investigated the possibilities that erbb2 may regulate downstream mediators of notch1 signaling to induce musashi1 (which enhances notch1 signaling). SIGNOR-165195 0.269 VWF protein P04275 UNIPROT F8 protein P00451 UNIPROT up-regulates quantity by stabilization 9606 32644488 f lperfetto VWF plays a crucial role in hemostasis through platelet adhesion facilitation and coagulation factor VIII stabilization SIGNOR-261865 0.781 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation Thr185 HDHTGFLtEYVATRW 9606 BTO:0003807 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244792 0.2 PRKCD protein Q05655 UNIPROT NCF4 protein Q15080 UNIPROT up-regulates activity phosphorylation Thr154 LRRLRPRtRKVKSVS 9606 BTO:0000738 9804763 t lperfetto P40(phox) is phosphorylated on threonine 154 and serine 315 during activation of the phagocyte NADPH oxidase. Implication of a protein kinase c-type kinase in the phosphorylation process. SIGNOR-249012 0.362 PIM proteinfamily SIGNOR-PF34 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser186 RQRKRHKsDSISLSF 9606 BTO:0000785 18467333 t gcesareni Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt. SIGNOR-259434 0.2 PTK6 protein Q13882 UNIPROT PTK6 protein Q13882 UNIPROT up-regulates phosphorylation Tyr342 RLIKEDVyLSHDHNI 9606 BTO:0000150 12121988 t miannu Autophosphorylation increases enzyme activity of wild-type brk but not of a y342a mutant form of brk. SIGNOR-90604 0.2 IRX1 protein P78414 UNIPROT ANPEP protein P15144 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. SIGNOR-261663 0.2 ID1 protein P41134 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0004136 26084673 t apalma We have determined that Id1 physically interacts with AKT1, through its C-terminal region, and promotes AKT1 phosphorylation; SIGNOR-255942 0.34 DUSP9 protein Q99956 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 21908610 t gcesareni In addition, although mutation of ser-58 to either alanine or glutamic acid does not affect the intrinsic catalytic activity of dusp9/mkp-4, phospho-mimetic (ser-58 to glu) substitution inhibits both the interaction of dusp9/mkp-4 with erk2 and p38? In vivo and its ability to dephosphorylate and inactivate these map kinases. SIGNOR-176586 0.687 PHLPP2 protein Q6ZVD8 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 t gcesareni Here, we identify a protein phosphatase, ph domain leucine-rich repeat protein phosphatase (phlpp), that specifically dephosphorylates the hydrophobic motif of akt (ser473 in akt1), triggering apoptosis and suppressing tumor growth.[...] These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt. SIGNOR-135046 0.764 MMP19 protein Q99542 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage -1 10922468 t lperfetto Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|It has been suggested that MMPs play a role in the hydrolysis of COMP and, therefore, compromise the integrity of the cartilage ECM structure leading to the ultimate loss of joint function SIGNOR-266980 0.409 MAP3K1 protein Q13233 UNIPROT CRTC1 protein Q6UUV9 UNIPROT up-regulates phosphorylation 9606 18784253 t miannu We report on the activation oftorc1through mekk1-mediated phosphorylation. SIGNOR-180816 0.326 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(His) smallmolecule CHEBI:29178 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269488 0.8 ATM protein Q13315 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser1407 KSQNSQEsTADESED 9606 12086603 t lperfetto These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint SIGNOR-90117 0.781 GNB1 protein P62873 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000938 16537363 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-145119 0.546 SFPQ protein P23246 UNIPROT TOP1 protein P11387 UNIPROT up-regulates binding 9606 9756848 t miannu We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i SIGNOR-60563 0.379 monoisononyl phthalate chemical CHEBI:132593 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. SIGNOR-268780 0.8 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation 9606 21798082 t lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-175288 0.907 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser294 RAANLWPsPLMIKRS 9606 BTO:0000150 23390529 t lperfetto The pi3k/akt pathway is necessary to activate cdk2, which phosphorylates eralphaser294, and mediates the binding between pin1 and eralpha SIGNOR-200867 0.49 PRKCA protein P17252 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser172 DQVQRRGsLPPRQVP 9606 BTO:0000007 20110267 t llicata Phosphorylation of nadph oxidase activator 1 (noxa1) on serine 282 by map kinases and on serine 172 by protein kinase c and protein kinase a prevents nox1 hyperactivation. SIGNOR-163667 0.294 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr941 EETGTEEyMKMDLGP 9606 17827393 t gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157754 0.864 bisphenol A chemical CHEBI:33216 ChEBI TPO protein P07202 UNIPROT down-regulates activity chemical inhibition -1 17379648 t miannu Half-maximal inhibition of TPO by BPA and F21388 occurred at 174 and 37.5 mol/liter in the guaiacol assay. SIGNOR-268786 0.8 PIM proteinfamily SIGNOR-PF34 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 17643117 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation. SIGNOR-259409 0.2 CDK1 protein P06493 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates activity phosphorylation Ser104 FSFDTDRsPAPMSCD 9606 22071694 t lperfetto Furthermore, active recombinant Cdk1/cyclin B1 phosphorylates BimEL and BimL in vitro and Serine 44 on BimL has been identified as a Cdk1 phosphorylation site. Collectively, these results suggest that Cdk1/cyclin B1-dependent hyper-phosphorylation of Bim during prolonged mitotic arrest is an important cell death signal. SIGNOR-267985 0.414 PROK2 protein Q9HC23 UNIPROT PROKR2 protein Q8NFJ6 UNIPROT up-regulates binding 9606 12024206 t gcesareni We have cloned two closely related receptors for pk1 and pk2. These receptors, named prokineticin receptor 1 and 2 (pkr1 and pkr2) SIGNOR-87919 0.652 CHEK2 protein O96017 UNIPROT PSME3 protein P61289 UNIPROT up-regulates activity phosphorylation Ser247 EKIKRPRsSNAETLY 9606 BTO:0001938 25361978 t miannu REGγ interacts with DBC1 and is phosphorylated by Chk2. SIGNOR-273611 0.356 ABL1 protein P00519 UNIPROT PRDX2 protein P32119 UNIPROT down-regulates activity phosphorylation Tyr193 NVDDSKEyFSKHN -1 20178744 t miannu Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation. SIGNOR-276280 0.288 SKI protein P12755 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 10575014 t lperfetto Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling. SIGNOR-232123 0.717 hydrogen peroxide smallmolecule CHEBI:16240 ChEBI ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 35681445 f lperfetto The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment. SIGNOR-272278 0.7 NCOA1 protein Q15788 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 BTO:0000149 12954634 t miannu Ncoa-1/src-1 is an essential coactivator of stat5 that binds to the fdl motif in the alpha-helical region of the stat5 transactivation domain. SIGNOR-100258 0.414 CIITA protein P33076 UNIPROT HLA-A protein P04439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 10329350 f Transfection of CIITA in JEG-3 cells also upregulated functional HLA-B and HLA-C expression. SIGNOR-254020 0.499 FOXO3 protein O43524 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-256645 0.7 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser750 QTEEEEHsCLEQAS 9606 SIGNOR-C14 SIGNOR-C14 10195894 t lperfetto Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response SIGNOR-66352 0.2 POGLUT1 protein Q8NBL1 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates glycosylation 9606 22872643 t O-glycosilation gcesareni O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus. SIGNOR-254319 0.59 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH24 protein Q86UP0 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265840 0.8 AREG protein P15514 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 10085134 t Amphiregulin is an autocrine growth factor gcesareni The epidermal growth factor receptor (EGFR) mediates the actions of a family of bioactive peptides that include epidermal growth factor (EGF) and amphiregulin (AR) SIGNOR-65576 0.763 (2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzazepin-5-yl]amino]-1-oxopropan-2-yl]butanamide chemical CHEBI:131158 ChEBI APP protein P05067 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206850 0.8 GSK3B protein P49841 UNIPROT MAF protein O75444 UNIPROT down-regulates phosphorylation 9606 18042454 t miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. SIGNOR-159438 0.263 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG 10090 22848740 t When AMPK is stimulated, pre-existing FOXO3 becomes reverted toward an active form. SIGNOR-255756 0.397 CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR TSC2 protein P49815 UNIPROT up-regulates activity phosphorylation Ser1452 LPSSSPRsPSGLRPR 9606 BTO:0000007 32294430 t done miannu We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452.  SIGNOR-274102 0.414 CDK5 protein Q00535 UNIPROT APP protein P05067 UNIPROT unknown phosphorylation Thr743 VEVDAAVtPEERHLS 10116 BTO:0000938 10936190 t llicata In vitro, active cyclin-dependent kinase 5 (Cdk5) phosphorylated the cytoplasmic domain of APP at Thr(668). Treatment of mature neurons with an antisense oligonucleotide to Cdk5 suppressed Cdk5 expression and significantly diminished the level of phosphorylated APP. The expression of APP was unaffected in antisense-treated neurons. These results indicate that in neurons APP is phosphorylated by Cdk5, and that this may play a role in its localization. SIGNOR-250651 0.582 DUSP5 protein Q16690 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 10224087 t gcesareni Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway SIGNOR-67358 0.751 CSNK2A3 protein Q8NEV1 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser230 VTPSKSTsASAIMNG 9606 BTO:0000938 26917740 t lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. SIGNOR-275743 0.272 SRSF11 protein Q05519 UNIPROT APOE protein P02649 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 10090 31269452 t miannu We demonstrate that SFRS11 directly binds to the 3' UTR of LRP8 mRNA, as well as to the third exon of apoE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling. SIGNOR-269671 0.2 CNTF protein P26441 UNIPROT CRLF1 protein O75462 UNIPROT up-regulates binding 9606 11294841 t lperfetto We recently demonstrated that cardiotrophin-like cytokine (clc) associates with the soluble orphan receptor cytokine-like factor-1 (clf) to form a heterodimeric cytokine that displayed activities only on cells expressing the tripartite cntf receptor on their surface SIGNOR-106635 0.399 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193549 0.8 SOX6 protein P35712 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0003298 26893351 t In adipocytes, in addition to the direct regulation of PPARγ andC/EBP expression, we showed that SOX6 inhibitsWNT signaling by binding to β-catenin, potentially leading to its degradation SIGNOR-255825 0.639 TNPO1 protein Q92973 UNIPROT PER1 protein O15534 UNIPROT up-regulates activity relocalization 9606 29377895 t lperfetto The non-classical nuclear import carrier Transportin 1 modulates circadian rhythms through its effect on PER1 nuclear localization SIGNOR-262102 0.272 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH15 protein P55291 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265832 0.8 PD173074 chemical CHEBI:63448 ChEBI FGFR3 protein P22607 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205728 0.8 RELA protein Q04206 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20975042 t svumbaca In addition, we show that the transcription of IL1B depends on a positively acting p65/c-Rel/ikbb complex SIGNOR-256237 0.536 DPF2 protein Q92785 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates activity binding 9606 24332853 t miannu The interaction between RUNX1 and DPF2 is dependent on the RUNX1 methylation status SIGNOR-261966 0.2 TIMM22 protein Q9Y584 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 t lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). SIGNOR-267706 0.664 PRKACA protein P17612 UNIPROT CDK16 protein Q00536 UNIPROT down-regulates phosphorylation Ser153 SRRLRRVsLSEIGFG 9606 BTO:0000142 22184064 t llicata Here, we report that cdk16 is activated by membrane-associated cyclin y (ccny). Treatment of transfected human cells with the protein kinase a (pka) activator forskolin blocked, while kinase inhibition promoted, ccny-dependent targeting of cdk16-green fluorescent protein (gfp) to the cell membrane. Ccny binding to cdk16 required a region upstream of the kinase domain and was found to be inhibited by phosphorylation of serine 153, a potential pka phosphorylation site. SIGNOR-191623 0.319 ECM stimulus SIGNOR-ST20 SIGNOR A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259046 0.7 SP7 protein Q8TDD2 UNIPROT IFITM5 protein A6NNB3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23530031 f miannu Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation. SIGNOR-254219 0.373 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser531 RTHSAGTsPTITHQK -1 12351658 t IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. SIGNOR-251297 0.644 PLK4 protein O00444 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser325 PTTVNKRsVNVNAAS 33351100 t lperfetto We found that PLK4-mediated phosphorylation of NEDD1 at its S325 amino acid residue directly promotes both NEDD1 binding to SAS-6 and recruiting SAS-6 to the centrosome. |Collectively, our results demonstrate that PLK4-regulated NEDD1 facilitates initiation of the cartwheel assembly and of daughter centriole biogenesis in mammals. SIGNOR-272996 0.576 TP53 protein P04637 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15377670 f miannu We isolated a p53-regulated gene named ndrg1 (n-myc down-regulated gene 1). Its expression is induced by dna damage in a p53-dependent fashion. SIGNOR-129183 0.509 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR HES1 protein Q14469 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001938 24300895 f These data indicate that basal NFκB activity at the conserved +26/+34 site of the HES1 gene promotes its expression, and that glucocorticoids can silence HES1 by inhibiting this activity. SIGNOR-253063 0.2 CSNK2A1 protein P68400 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser18 SPADDSLsNSEEEPD 9606 21559372 t llicata Further investigation revealed that il-6 stabilizes twist in scchn cell lines through casein kinase 2 (ck2) phosphorylation of twist residues s18 and s20, and that this phosphorylation inhibits degradation of twist. SIGNOR-173668 0.2 SRC protein P12931 UNIPROT CACNA1C protein Q13936 UNIPROT up-regulates activity phosphorylation Tyr2217 ELQDSRVyVSSL 9606 BTO:0000007 17942635 t miannu Cotransfection of human embryonic kidney (HEK)-293 cells with hCa(v)1.2b and c-Src resulted in tyrosine phosphorylation of the calcium channel, which was prevented by nitration of tyrosine residues by peroxynitrite. Whole cell calcium currents were reduced by 58 + 5% by the Src kinase inhibitor PP2 and 64 + 6% by peroxynitrite.  SIGNOR-276081 0.454 SRC protein P12931 UNIPROT CDCP1 protein Q9H5V8 UNIPROT unknown phosphorylation Tyr734 KDNDSHVyAVIEDTM 9606 14739293 t lperfetto Phosphorylation of gp140 and p80 are mediated by Src family kinases at multiple Tyr residues including Tyr(734). SIGNOR-246457 0.544 PTGIR protein P43119 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256949 0.252 MYC protein P01106 UNIPROT SFRP1 protein Q8N474 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004896; BTO:0004300 17485441 f gcesareni c-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity SIGNOR-245360 0.363 NDUFB2 protein O95178 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 SIGNOR-262165 0.776 ATR protein Q13535 UNIPROT XPA protein P23025 UNIPROT up-regulates activity phosphorylation Ser196 RSLEVWGsQEALEEA 9606 30327428 t ATR mediated phosphorylation of XPA on S196 enhances cAMP-mediated optimization of NER, and is promoted by SIRT1-mediated deacetylation of XPA on K63, K67 and K215. SIGNOR-258985 0.505 CDK19 protein Q9BWU1 UNIPROT PAK1 protein Q13153 UNIPROT unknown phosphorylation Ser174 TPAVPPVsEDEDDDD 9606 19520772 t llicata Here, we identified p21 activated kinase 1 (pak1) as a new cdk11(p58) substrate and we mapped a new phosphorylation site of ser174 on pak1 SIGNOR-185000 0.337 CAMK2A protein Q9UQM7 UNIPROT NOX5 protein Q96PH1 UNIPROT unknown phosphorylation Thr540 KRLSRSVtMRKSQRS -1 21642394 t miannu In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475. SIGNOR-276330 0.2 DNMT3B protein Q9UBC3 UNIPROT DPP6 protein P42658 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000596 23409053 t lperfetto In the absence of Dnmt3b, Dnmt3a was associated with Dpp6 gene promoter and regulated its expression and methylation in P19 cells. SIGNOR-268964 0.333 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser159 KKKKKRFsFKKSFKL -1 8557118 t gcesareni PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. SIGNOR-243199 0.372 HAP1 protein P54257 UNIPROT KIF5C protein O60282 UNIPROT up-regulates activity binding 9606 31757889 t miannu HAP1 and GRIP1 are kinesin-1 adaptors that have been implicated individually in the transport of vesicular cargoes in the dendrites of neurons. We find that HAP1a and GRIP1 form a protein complex in the brain, and co-operate to activate the kinesin-1 subunit KIF5C in vitro SIGNOR-264062 0.411 MARCHF1 protein Q8TCQ1 UNIPROT HLA-DRB3 protein P79483 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys254 FIYFRNQkGHSGLQP 9606 19117940 t miannu Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination. SIGNOR-271410 0.2 spiperone chemical CHEBI:9233 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258894 0.8 CAMK2A protein Q9UQM7 UNIPROT NOX5 protein Q96PH1 UNIPROT unknown phosphorylation Ser544 RSVTMRKsQRSSKGS -1 21642394 t miannu In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475. SIGNOR-276331 0.2 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 17158707 t lperfetto The JNK-mediated phosphorylation of both Ser63 and Ser73 within the transactivation domain of c-Jun (Table _(Table1)1) potentiates its transcriptional activity SIGNOR-53784 0.2 RXRA protein P19793 UNIPROT RARB protein P10826 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-16668 0.668 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Thr355 NFSSSPStPVGSPQG 9606 19801649 t llicata Mlk2 inhibits e47 transactivation activity on the trkb promote SIGNOR-161544 0.2 FYN protein P06241 UNIPROT NOX4 protein Q9NPH5 UNIPROT down-regulates activity phosphorylation Tyr566 LSNQNNSyGTRFEYN -1 27525436 t miannu We found that direct phosphorylation of tyrosine 566 on NOX4 was critical for this FYN-mediated negative regulation. SIGNOR-277273 0.274 KDM4B protein O94953 UNIPROT TP53I3 protein Q53FA7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001109 28073943 f miannu JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. SIGNOR-263731 0.2 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206133 0.8 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates phosphorylation Tyr1009 LDTSSVLyTAVQPNE 9606 1396585 t llicata These data show that tyrosine phosphorylation of plc-gamma is dependent on autophosphorylation of the pdgf beta-receptor at tyr1009 and tyr1021. SIGNOR-18575 0.2 SPI1 protein P17947 UNIPROT EGR2 protein P11161 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16923394 f miannu PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation SIGNOR-256040 0.379 DYNLL2 protein Q96FJ2 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT down-regulates binding 9606 20921139 t gcesareni The beclin 1 vps34 complex is tethered to the cytoskeleton through an interaction between the beclin 1 interacting protein ambra1 and dynein light chains 1/2 SIGNOR-168289 0.44 ATM protein Q13315 UNIPROT KHSRP protein Q92945 UNIPROT up-regulates phosphorylation Ser274 MILIQDGsQNTNVDK 9606 21329876 t lperfetto The atm kinase directly binds to and phosphorylates ksrp, leading to enhanced interaction between ksrp and pri-mirnas and increased ksrp activity in mirna processing SIGNOR-172123 0.433 UMPS protein P11172 UNIPROT UMP smallmolecule CHEBI:16695 ChEBI up-regulates quantity chemical modification 9606 2912371 t miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). SIGNOR-267440 0.8 TCF3 protein P15923 UNIPROT CR2 protein P20023 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11739509 f miannu We have previously described the presence of an intronic element that is required for both cell- and stage-specific expression of CR2. In this study, we report the identification of a cell type-specific repressor element within the proximal promoter. By supershift analysis this element binds members of the basic helix-loop-helix family of proteins, in particular E2A gene products. Mutational analysis demonstrates that binding of E2A proteins is critical for functioning of this repressor. Thus, E2A activity is key not only for early B cell development, but also for controlling CR2 expression, a gene expressed only during later stages of ontogeny. SIGNOR-255387 0.285 CCKBR protein P32239 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257412 0.488 PAX3 protein P23760 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222 18854138 f gcesareni Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. SIGNOR-181621 0.492 PCSK1 protein P29120 UNIPROT Corticotropin protein P01189-PRO_0000024969 UNIPROT up-regulates quantity cleavage 24631756 t lperfetto POMC is post-translationally cleaved by prohormone convertase enzymes 1 and 2 (PC1, PC2) into ACTH, an N-terminal glycopeptide SIGNOR-268724 0.2 EGFR protein P00533 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr320 RKDTKEIyTHFTCAT -1 33139573 t miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. SIGNOR-277228 0.441 UBR5 protein O95071 UNIPROT SOX2 protein P48431 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys115 YKYRPRRkTKTLMKK 9606 BTO:0002428 30894683 t miannu We identified UBR5 as a major ubiquitin E3 ligase that induces SOX2 degradation through ubiquitinating SOX2 at lysine 115. SIGNOR-277446 0.258 GSK3B protein P49841 UNIPROT TCAP protein O15273 UNIPROT down-regulates quantity by destabilization phosphorylation Ser157 GALRRSLsRSMSQEA 9606 32937135 t lperfetto GSK-3beta phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation.|These results show direct GSK-3beta phosphorylation of TCAP S157 and FBXL21 T33 sites. SIGNOR-264852 0.2 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr373 ASDTDSSyCIPTAGM 9606 19881549 t lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis SIGNOR-236318 0.692 CHMP6 protein Q96FZ7 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 t miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. SIGNOR-265526 0.661 SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR RORC protein P51449 UNIPROT up-regulates 9606 26194464 t MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. SIGNOR-255026 0.438 TGFB1 protein P01137 UNIPROT CDK4 protein P11802 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000763 8402878 f gcesareni Here we show that tgf beta 1 induces suppression of cdk4 synthesis in g1 in mink lung epithelial cells. SIGNOR-39045 0.286 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser5 sESFTMAS 9606 19647517 t lperfetto Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry SIGNOR-187396 0.961 RIMBP3C protein A6NJZ7 UNIPROT RIMS1 protein Q86UR5 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264362 0.268 HCRTR1 protein O43613 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256876 0.252 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR LATS1 protein O95835 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0005907 25026211 t miannu CRL4 DCAF1 ubiquitylates and inhibits Lats. SIGNOR-272229 0.368 tolcapone chemical CHEBI:63630 ChEBI COMT protein P21964 UNIPROT down-regulates activity chemical inhibition 9606 9681662 t Simone Vumbaca Entacapone and tolcapone were powerful inhibitors of COMT and their IC50 estimates were 151 and 773 nM (P=0.008), respectively, in the liver; consistent results were obtained with the other tissues. SIGNOR-261091 0.8 GATA1 protein P15976 UNIPROT KLF1 protein Q13351 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 8195185 f irozzo Regulation of the Erythroid Kruppel-like Factor (EKLF) Gene Promoter by the Erythroid Transcription Factor GATA-l.Accordingly,we have also demonstrated that GATA-2, like GATA-1, is able to activate the EKLF promoter in NIH3T3. SIGNOR-256051 0.515 TNFRSF17 protein Q02223 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates 9606 10903733 f miannu Overexpression of bcma activates the p38 mapk SIGNOR-79498 0.2 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 21902831 t lperfetto Cyclin e/cdk2 can phosphorylate myod at serine 200, which causes ubiquitination and degradation of this transcription factor during g1, preventing its accumulation and a commitment to differentiation. SIGNOR-216706 0.537 RABGEF1 protein Q9UJ41 UNIPROT RAB5A protein P20339 UNIPROT up-regulates binding 9606 11452015 t miannu We have previously shown that rab5, which regulates various steps of transport along the early endocytic pathway, is activated by a complex consisting of rabex-5, a rab5 nucleotide exchange factor, and the effector rabaptin-5. SIGNOR-109398 0.921 JUN protein P05412 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 23151663 f amattioni Planar cell polarity (PCP) signalling is prominently involved in the regulation of cell polarity, cell motility and morphogenetic movements, throught the activation of JUN transcription factor. SIGNOR-229760 0.7 FZR1 protein Q9UM11 UNIPROT UBE2S protein Q16763 UNIPROT up-regulates activity binding 9606 19822757 t lperfetto Ube2S depends on the cell cycle-dependent association with the APC/C activators Cdc20 and Cdh1 for its activity SIGNOR-265081 0.751 afatinib chemical CHEBI:61390 ChEBI ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0000150 22418700 t gcesareni Afatinib is an oral, erbb family blocker, which covalently binds and irreversibly blocks all kinase-competent erbb family members. SIGNOR-259442 0.8 INTS8 protein Q75QN2 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261472 0.732 MAPK3 protein P27361 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 12792650 t lperfetto Inhibition of caspase-9 through phosphorylation at thr 125 by erk mapk SIGNOR-101548 0.551 PRKCA protein P17252 UNIPROT INSR protein P06213 UNIPROT unknown phosphorylation Thr1362 YEEHIPYtHMNGGKK -1 8463287 t lperfetto Therefore, the present study directly identifies threonine 1336 in the HIR as a phosphorylation site for insulin and PMA. SIGNOR-248933 0.354 MLH1 protein P40692 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 10090 9500552 f Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer SIGNOR-257595 0.7 TAF5 protein Q15542 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263929 0.894 pazopanib chemical CHEBI:71219 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 18620382 t Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. SIGNOR-257738 0.8 ERBB4 protein Q15303 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 16729043 t gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. SIGNOR-146885 0.381 MORF4L1 protein Q9UBU8 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269299 0.75 C1QB protein P02746 UNIPROT Complement C1q complex SIGNOR-C308 SIGNOR form complex binding -1 29449492 t lperfetto C1q comprises 18 polypeptide chains; three chains of C1q-A, -B, and -C trimerize to form six collagen-like triple helices connected to six globular (trimeric) ligand-recognition (gC1q) modules (fig. S1B) (1). SIGNOR-263388 0.631 cyclosporin A chemical CHEBI:4031 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR down-regulates chemical inhibition 9606 15276472 t gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. SIGNOR-252307 0.8 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR SERPINE1 protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9606191 f lperfetto Here we report the identification of smad3/smad4 binding sequences, termed caga boxes, within the promoter of the human pai-1 gene. SIGNOR-57776 0.574 AXIN1 protein O15169 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 10829020 t gcesareni We found that in contrast to axin, dvl2 activation of jnk does not require mekk1. SIGNOR-77591 0.529 MAP3K3 protein Q99759 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation 9606 12912994 t gcesareni Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5. SIGNOR-104637 0.708 CDH12 protein P55289 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265852 0.489 FBXW7 protein Q969H0 UNIPROT ZNF322 protein Q6U7Q0 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002552 phosphorylation:Ser391;Ser396 SEKGLELsPPHASEA;ELSPPHAsEASQMS 28581525 t lperfetto CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction. SIGNOR-264898 0.2 dapagliflozin chemical CHEBI:85078 ChEBI SLC5A2 protein P31639 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191289 0.8 TP53 protein P04637 UNIPROT PMAIP1 protein Q13794 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10807576 f Nuclear p53 amattioni Expression of noxa was dependent on p53. Noxa represent a mediator of p53-dependent apoptosis. SIGNOR-76152 0.69 agomelatine chemical CHEBI:134990 ChEBI HTR2C protein P28335 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189474 0.8 MAPK3 protein P27361 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Thr388 VYFKPSLtPSGEFRK 9606 19767751 t llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. SIGNOR-188147 0.4 NR5A1 protein Q13285 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19022561 f miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254869 0.485 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser710 GEKSFRRsVVGTPAY 9606 12058027 t miannu In cells transfected with pkc? Or pkc? The phosphorylation of ser876 was markedly more pronounced than the phosphorylation of ser706/ser710 / the phosphorylation of ser706/ser710 in pkd2 reflects the activation of the kinase. SIGNOR-89415 0.2 TFCP2 protein Q12800 UNIPROT TF protein P02787 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20796026 f miannu Ectopic expression of CP2 led to increased transferrin expression at both the mRNA and protein levels, whereas knockdown of CP2 down-regulated transferrin mRNA and protein expression. SIGNOR-255429 0.2 MAP3K1 protein Q13233 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000944 8131746 t lperfetto Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity. SIGNOR-244881 0.646 ASXL1 protein Q8IXJ9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 26470845 f lperfetto Consistently, our results show that ASXL1 mutations are associated with lower expression levels of p15INK4B and a proliferative advantage of hematopoietic progenitors in primary bone marrow cells, and that depletion of ASXL1 in multiple cell lines results in resistance to growth inhibitory signals. SIGNOR-241614 0.7 BMS-265246 chemical CID:5329775 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190431 0.8 CREB1 protein P16220 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity transcriptional regulation 9600 BTO:0000567 26652733 t inferred from family member Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB SIGNOR-270250 0.2 p38 proteinfamily SIGNOR-PF16 SIGNOR CDT1 protein Q9H211 UNIPROT up-regulates quantity by stabilization phosphorylation Ser491 GSCCTIMsPGEMEKH 9606 BTO:0000567 21930785 t miannu  We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2.  SIGNOR-276363 0.2 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Thr336 GDDEASAtVSKTETS -1 9099669 t lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. SIGNOR-248969 0.45 CRBN protein Q96SW2 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR form complex binding 9606 22649780 t gcesareni The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors SIGNOR-234805 0.78 FOXJ3 protein Q9UPW0 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 19914232 t Luana Foxj3 transcriptionally activates Mef2c and regulates adult skeletal muscle fiber type identity. SIGNOR-261606 0.322 SIRT6 protein Q8N6T7 UNIPROT TNF protein P01375 UNIPROT up-regulates deacetylation Lys20 AEEALPKkTGGPQGS 9606 23552949 t gcesareni Sirt6 regulates tnf-alfa secretion through hydrolysis of long-chain fatty acyl lysine SIGNOR-201662 0.32 luminespib chemical CHEBI:83656 ChEBI HSP90AA1 protein P07900 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190038 0.8 LCK protein P06239 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Tyr313 SSEPVGIyQGFEKKT 9534 BTO:0000298 11381116 t The tyrosine phosphorylation sites of PKC delta in the H(2)O(2)-treated cells were identified as Tyr-311, Tyr-332, and Tyr-512 by mass spectrometric analysis with the use of the precursor-scan method and by immunoblot analysis with the use of phosphorylation site-specific antibodies. Tyr-311 was the predominant modification site among them. In an in vitro study, phosphorylation at this site by Lck, a non-receptor-type tyrosine kinase, enhanced the basal enzymatic activity and elevated its maximal velocity in the presence of diacylglycerol. phosphorylation at Tyr-311 between the regulatory and catalytic domains is a critical step for generation of the active PKC delta in response to H(2)O(2). SIGNOR-251384 0.506 Sitagliptin phosphate monohydrate chemical CID:11591741 PUBCHEM DPP4 protein P27487 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206923 0.8 SRC protein P12931 UNIPROT MMP3 protein P08254 UNIPROT up-regulates activity 23967200 f C-Src-induced STAT3 activation regulates MMP3 levels SIGNOR-251109 0.347 DAGLB protein Q8NCG7 UNIPROT episterol ester smallmolecule CHEBI:52393 ChEBI up-regulates quantity chemical modification 9606 26787883 t miannu Diacylglycerol lipases (DAGLŒ± and DAGLŒ≤) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. SIGNOR-264265 0.8 SOX9 protein P48436 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000849 19273910 f miannu Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen. SIGNOR-255190 0.381 MEN1 protein O00255 UNIPROT RELA protein Q04206 UNIPROT down-regulates binding 9606 SIGNOR-C13 11526476 t miannu Menin represses p65-mediated transcriptional activation on nf-kappab sites in a dose-dependent and specific manner. SIGNOR-110067 0.474 HMGA2 protein P52926 UNIPROT E4F1 protein Q66K89 UNIPROT down-regulates binding 9606 14645522 t miannu Here we show that hmga2 associates with the e1a-regulated transcriptional repressor p120(e4f), interfering with p120(e4f) binding to the cyclin a promoter SIGNOR-119537 0.378 MK-8245 chemical CID:24988881 PUBCHEM SCD protein O00767 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194420 0.8 SRC protein P12931 UNIPROT GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates phosphorylation 9606 BTO:0000938 BTO:0000142;BTO:0000671 11882681 t inferred from family member gcesareni These findings indicate that glyr function is upregulated by ptks and this modulation is dependent on the tyrosine-413 residue of the beta subunit. SIGNOR-270262 0.273 A10/b1 integrin complex SIGNOR-C167 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269016 0.7 RPS11 protein P62280 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262441 0.883 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser531 GSRSRTPsLPTPPTR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249344 0.728 58131-57-0 chemical CID:42640 PUBCHEM MDM4 protein O15151 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194856 0.8 SMAD7 protein O15105 UNIPROT STRAP protein Q9Y3F4 UNIPROT up-regulates binding 9606 10757800 t gcesareni Strap recruits smad7 to the activated type i receptor and forms a complex SIGNOR-76771 0.594 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates activity phosphorylation Ser215 PLTSPGGsPGGCPGE 9606 BTO:0001131 9630228 t lperfetto Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4. SIGNOR-109781 0.573 RASSF6 protein Q6ZTQ3 UNIPROT STK3 protein Q13188 UNIPROT down-regulates binding 9606 22830020 t gcesareni When rassf 6 is bound to mst2, rassf 6 inhibits mst2 activity, thus, inhibiting its role in the hippo pathway. SIGNOR-198463 0.648 ATR protein Q13535 UNIPROT MCC protein P23508 UNIPROT up-regulates activity phosphorylation Ser118 SELRSELsQSQHEVN 9606 BTO:0001109 21779472 t miannu MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity. SIGNOR-273514 0.2 SRC protein P12931 UNIPROT GLRB protein P48167 UNIPROT up-regulates phosphorylation Tyr435 RDFELSNyDCYGKPI 9606 BTO:0000938 BTO:0000142;BTO:0000671 11882681 t gcesareni These findings indicate that glyr function is upregulated by ptks and this modulation is dependent on the tyrosine-413 residue of the beta subunit. SIGNOR-115705 0.273 SMAD4 protein Q13485 UNIPROT SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR form complex binding 9606 9436979 t lperfetto Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription. SIGNOR-255833 0.2 MMP24 protein Q9Y5R2 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272391 0.7 PRKACA protein P17612 UNIPROT AICDA protein Q9GZX7 UNIPROT unknown phosphorylation Thr27 WAKGRREtYLCYVVK 9606 18417471 t llicata We have found using sf9 insect cells to overexpress human gst-aid that a small fraction of the enzyme is phosphorylated at ser38 and thr27 and at two residues not reported previously, ser41 and ser43 SIGNOR-178248 0.33 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL -1 SIGNOR-C3 10567431 t lperfetto We report here that a mammalian recombinant p70alpha polypeptide, extracted in an inactive form from rapamycin-treated cells, can be directly phosphorylated by the mTOR kinase in vitro predominantly at the rapamycin-sensitive site Thr-412. mTOR-catalyzed p70alpha phosphorylation in vitro is accompanied by a substantial restoration in p70alpha kinase activity toward its physiologic substrate SIGNOR-72357 0.96 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser795 TASTRKVsLAPQANL 9606 1716180 t lperfetto Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response. SIGNOR-21320 0.467 WNT1 protein P04628 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131568 0.689 SRC protein P12931 UNIPROT KCNA3 protein P22001 UNIPROT up-regulates phosphorylation Tyr499 EGEEQSQyMHVGSCQ 9606 11812778 t gcesareni The shaker family k+ channel protein, kv1.3, is tyrosine phosphorylated by v-src kinase at tyr137 and tyr449 to modulate current magnitude and kinetic properties. SIGNOR-114645 0.315 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI AFP protein P02771 UNIPROT down-regulates quantity by repression 9606 9792724 f miannu In this report, we show a distinctive effect of all-trans-retinoic acid (RA) in Hep3B cells. RA caused a marked decrease in AFP transcripts. SIGNOR-254443 0.8 3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea chemical CHEBI:91362 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001109;BTO:0000018 19567821 t miannu The protein kinases, Aurora A, B, and C have critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. GSK1070916, is a novel ATP competitive inhibitor that is highly potent and selective for Aurora B/C kinases. SIGNOR-262226 0.8 CDK13 protein Q14004 UNIPROT CyclinK/CDK13 complex SIGNOR-C38 SIGNOR form complex binding 9606 22012619 t miannu We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells SIGNOR-176844 0.915 GNG3 protein P63215 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 16537363 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-252684 0.358 AKT3 protein Q9Y243 UNIPROT STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr387 TMKRRDEtMQPAKPS 9606 23431053 t gcesareni Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt. SIGNOR-201129 0.263 Dinaciclib chemical CID:46926350 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191322 0.8 NR3C1 protein P04150 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 t We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα SIGNOR-256116 0.467 WT1 protein P19544 UNIPROT AREG protein P15514 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10490105 t lperfetto The Wilms Tumor Suppressor WT1 Encodes a Transcriptional Activator of amphiregulin SIGNOR-251745 0.405 ACACA protein Q13085 UNIPROT Food intake phenotype SIGNOR-PH152 SIGNOR down-regulates 9606 BTO:0003336 25343030 f miannu Leptin exerts an inhibitory effect on AMPK in the hypothalamus, thereby stimulating ACC and subsequently suppressing food intake. SIGNOR-263509 0.7 OGA protein O60502 UNIPROT PFK proteinfamily SIGNOR-PF79 SIGNOR up-regulates activity deglycosylation 9606 26399441 t lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. SIGNOR-267609 0.2 RET protein P07949 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 8183561 t gcesareni We have shown that the sh2 domain of the adaptor protein shc coimmunoprecipitates with all the ret. SIGNOR-36902 0.642 CDH8 protein P55286 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265870 0.665 ZNF148 protein Q9UQR1 UNIPROT SOX18 protein P35713 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 18496767 f miannu co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells SIGNOR-254821 0.26 PPP2CA protein P67775 UNIPROT TRPM8 protein Q7Z2W7 UNIPROT down-regulates activity dephosphorylation Thr17 MRNRRNDtLDSTRTL 9606 BTO:0000007 20110357 t done miannu Using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. the intracellular serine/threonine protein phosphatase 2A (PP2A) dephosphorylates TRPM8 Ser-9 and Thr-17 inhibiting the channel activity. SIGNOR-273793 0.2 trametinib chemical CHEBI:75998 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates activity chemical inhibition 9606 26347206 t miannu Trametinib (Mekinist™) is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 with anticancer activity against metastatic melanoma carrying the BRAF V600 mutation. SIGNOR-259448 0.8 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT up-regulates activity phosphorylation Ser1009 DESSDDDsDSEEPSK 9606 BTO:0000661 10066810 t llicata Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment.  SIGNOR-251031 0.445 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 9606 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252822 0.908 AKT1 protein P31749 UNIPROT MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr299 QSRKRLAtSSASSQS 9606 BTO:0002181 32123010 t miannu Here, we report that AKT phosphorylates MASTL at residue T299, which plays a critical role in its activation. SIGNOR-277515 0.2 LRIG3 protein Q6UXM1 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates 9606 23723069 f miannu Lrig3 opposes lrig1 negative regulatory activity and stabilizes erbb receptors. SIGNOR-202180 0.31 RAC1 protein P63000 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 21712438 f gcesareni Hypertonicity activates p38 via a rac1-osm-mekk3-mkk3-p38 pathway. SIGNOR-174602 0.517 MYCT1 protein Q8N699 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000670;BTO:0000738 30283340 f miannu Overexpression of MYCT1 Inhibits Proliferation and Induces Apoptosis in Human Acute Myeloid Leukemia HL-60 and KG-1a Cells in vitro and in vivo SIGNOR-261728 0.7 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates phosphorylation Tyr591 SSDNEYFyVDFREYE 9606 11971190 t lperfetto Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation SIGNOR-117575 0.2 EIF6 protein P56537 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR up-regulates quantity binding 9606 10085284 t lperfetto The beta4 integrin interactor p27(BBP/eIF6) is an essential nuclear matrix protein involved in 60S ribosomal subunit assembly. SIGNOR-269151 0.505 SOX6 protein P35712 UNIPROT HBG2 protein P69892 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004911 20395365 f Regulation miannu BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. SIGNOR-251808 0.316 MID1 protein O15344 UNIPROT HMG20B protein Q9P0W2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 28760657 t miannu The E3 ubiquitin ligase MID1/TRIM18 promotes atypical ubiquitination of the BRCA2-associated factor 35, BRAF35. MID1 is implicated in BRAF35 ubiquitination promoting atypical poly-ubiquitination via K6-, K27- and K29-linkages. We found that MID1 depletion alters BRAF35 localization in these structures and increases BRAF35 stability affecting its cytoplasmic abundance SIGNOR-272317 0.246 CSNK2A1 protein P68400 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates activity phosphorylation Ser102 KDGNGYIsAAELRHV -1 26675311 t miannu Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third. SIGNOR-266354 0.432 alogliptin chemical CHEBI:72323 ChEBI DPP4 protein P27487 UNIPROT down-regulates activity chemical inhibition -1 22475866 t Luana Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization. SIGNOR-258333 0.8 BAX protein Q07812 UNIPROT DIABLO protein Q9NR28 UNIPROT up-regulates relocalization 9606 14585074 t Translocation from Mitochondria to Cytosol amattioni Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi SIGNOR-87109 0.525 PRKCA protein P17252 UNIPROT MYL9 protein P24844 UNIPROT down-regulates phosphorylation Ser3 sKRAKAKT 9606 22136066 t lperfetto Rlc can also be phosphorylated at ser1/ser2/thr9 by protein kinase c (pkc). Biophysical studies show that phosphorylation at these sites leads to an increase in the km of myosin light chain kinase (mlck) for rlc, thereby indirectly inhibiting myosin ii activity SIGNOR-192792 0.282 CRTC2 protein Q53ET0 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity binding 9606 26652733 t We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR). SIGNOR-256101 0.298 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19114991 t lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity SIGNOR-182971 0.733 VAV1 protein P15498 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 7227 23525006 t We identify the GTP exchange factor (GEF) Vav as a key regulator of Rac activity downstream of RTKs in a developmentally regulated cell migration event SIGNOR-259081 0.756 PMF1 protein Q6P1K2 UNIPROT MIS12 complex complex SIGNOR-C362 SIGNOR form complex binding -1 27881301 t lperfetto Human MIS12C (also known as MIND complex or Mtw1 complex in Saccharomyces cerevisiae) contains the MIS12, PMF1, NSL1, and DSN1 subunits SIGNOR-265192 0.829 Serum stimulus SIGNOR-ST3 SIGNOR PRKAA2 protein P54646 UNIPROT down-regulates 9606 19584320 f miannu Ampk is activated under conditions of low energy charge and typically inhibits anabolic reactions and promotes catabolism SIGNOR-186644 0.7 CREB1 protein P16220 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000763 20660310 f Luana Beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state SIGNOR-261288 0.7 Brivanib alaninate chemical CID:11154925 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190726 0.8 Immunoglobulin mu heavy chain protein P0DOX6 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR form complex binding 9606 BTO:0000776 32323265 t scontino An antibody is composed of two identical HCs and two identical LCs (either kappa or lambda ), consisting of variable (V) and constant (C) regions linked by disulfide bonds. Pro- genitor B cells rearrange their Ig heavy chain (HC) genes to differentiate into precursor B (pre- B) cells that express μ HCs. SIGNOR-268187 0.2 NXPH1 protein P58417 UNIPROT NRXN1 protein P58400 UNIPROT up-regulates binding 9606 BTO:0000938 9856994 t gcesareni Purification of neurexin ialpha revealed that it is tightly complexed to a secreted glycoprotein called neurexophilin 1 SIGNOR-62699 0.564 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr444 NSLTPKStPVKTLPF 9606 9840932 t lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk3 SIGNOR-217256 0.707 CHEK2 protein O96017 UNIPROT SOD1 protein P00441 UNIPROT up-regulates activity phosphorylation Ser60 DNTAGCTsAGPHFNP 4932 24647101 t ROS signaling is mediated by Mec1/ATM and its effector Dun1/Cds1 kinase, through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60, 99. In the nucleus, Sod1 binds to the promoters and regulates the expression of oxidative resistance and repair genes. SIGNOR-262794 0.384 THAP12 protein O43422 UNIPROT EIF2S1 protein P05198 UNIPROT unknown phosphorylation Ser52 MILLSELsRRRIRSI -1 10542257 t lperfetto The mammalian kinases PKR and HRI and the yeast kinase GCN2 specifically phosphorylate Ser-51 on the alpha subunit of the translation initiation factor eIF2.  SIGNOR-249029 0.2 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI 1-phosphatidyl-1D-myo-inositol 4-phosphate smallmolecule CHEBI:17526 ChEBI up-regulates quantity precursor of 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269097 0.8 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249685 0.397 Clinofibrate chemical CHEBI:31412 ChEBI HMGCR protein P04035 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191085 0.8 DUSP4 protein Q13115 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 8626452 t fstefani Here we characterize a new map kinase phosphatase, mkp-2, that is induced in human peripheral blood t cells with phorbol 12-myristate 13-acetate and is expressed in a variety of nonhematopoietic tissues as well. We show that the in vivo substrate specificities of individual phosphatases are unique. Pac1, mkp-2, and mkp-1 recognize erk and p38, erk and jnk, and erk, p38, and jnk, respectively. SIGNOR-40926 0.752 YES1 protein P07947 UNIPROT YES1 protein P07947 UNIPROT up-regulates activity phosphorylation Tyr426 RLIEDNEyTARQGAK 9606 9794236 t lperfetto Autophosphorylation of Src and Yes blocks their inactivation by Csk phosphorylation SIGNOR-247014 0.2 SRC protein P12931 UNIPROT KRT19 protein P08727 UNIPROT unknown phosphorylation Tyr391 LEGQEDHyNNLSASK 9606 21049038 t llicata Human k19 tyrosine 391 is phosphorylated, potentially by src kinase, and is the first well-defined tyrosine phosphorylation site of any keratin protein. SIGNOR-169273 0.293 AKT proteinfamily SIGNOR-PF24 SIGNOR BEX1 protein Q9HBH7 UNIPROT up-regulates quantity by stabilization phosphorylation Ser102 KLREKQLsHSLRAVS 10116 BTO:0001009 16498402 t miannu Phosphorylation of Bex1 in Ser105 by the serine–threonine kinase AKT stabilizes Bex1 and protects it from proteasomal degradation SIGNOR-262614 0.2 BZW2 protein Q9Y6E2 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity binding 9606 31643092 t miannu BZW2, as an evolutionary highly conserved protein, interacts with eIF2 and eIF3 and promotes ternary complex formation in vitro SIGNOR-261220 0.255 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252836 0.908 AKT proteinfamily SIGNOR-PF24 SIGNOR CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Ser196 KLRRRFSsLHFMVEV -1 9812896 t Akt phosphorylated recombinant Casp9 in vitro on serine-196 and inhibited its protease activity. SIGNOR-251473 0.2 MAPK14 protein Q16539 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates quantity by destabilization phosphorylation Ser310 LYNFMCNsSCVGGMN -1 30301786 t miannu P38α phosphorylates and destabilizes p63. SIGNOR-277414  0.312 UBE2I protein P63279 UNIPROT PLAG1 protein Q6DJT9 UNIPROT down-regulates sumoylation Lys263 CNVSVPIkDELLPVM 9606 15208321 t miannu Sumoylation decreases the transcriptional activity of plag1 / plag1 is sumoylated at 2 specific lysine residues (lys-244 and lys-263) SIGNOR-126048 0.281 SSH1 protein Q8WYL5 UNIPROT CORO1B protein Q9BR76 UNIPROT up-regulates dephosphorylation Ser2 sFRKVVRQ 9606 17350576 t gcesareni Coronin 1b inhibits filament nucleation by arp2/3 complex and this inhibition is attenuated by phosphorylation of coronin 1b at serine 2, a site targeted by ssh1l. SIGNOR-153604 0.458 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1191 GELSRSPsPFTHTHL 9606 BTO:0000551 19683496 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-187599 0.51 GATA2 protein P23769 UNIPROT SPI1 protein P17947 UNIPROT down-regulates activity binding 9606 BTO:0000664 10411939 t irozzo Here we demonstrate that a region of the PU.1 Ets domain (the winged helix–turn–helix wing) interacts with the conserved carboxyl-terminal zinc finger of GATA-1 and GATA-2 and that GATA proteins inhibit PU.1 transactivation of critical myeloid target genes. SIGNOR-256071 0.595 IRF5 protein Q13568 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 22378047 f lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249562 0.7 REL protein Q04864 UNIPROT REL/RELA complex SIGNOR-C68 SIGNOR form complex binding 9606 BTO:0000671 9056676 t miannu Tnf-alpha induces the formation of a specific kappab binding complex, mainly composed of nf-kappab subunits rela and c-rel. SIGNOR-46945 0.662 LFNG protein Q8NES3 UNIPROT DLL3 protein Q9NYJ7 UNIPROT up-regulates binding 9606 10934472 t gcesareni We find that mammalian lunatic fringe (lfng) inhibits jagged1-mediated signalling and potentiates delta1-mediated signalling through notch1. SIGNOR-80524 0.46 NFE2L2 protein Q16236 UNIPROT NQO1 protein P15559 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24024136 t irozzo In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs). SIGNOR-256275 0.5 ITGB1BP1 protein O14713 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257646 0.756 N-[(4-chlorophenyl)methyl]-2-[(2R,6S)-5,12-dioxo-2-phenyl-1-oxa-4-azacyclododec-8-en-6-yl]acetamide chemical CHEBI:94175 ChEBI SHH protein Q15465 UNIPROT down-regulates chemical inhibition 9606 BTO:0000527 21679342 t gcesareni More recently, robotnikinin was identified as a compound that binds to shh and blocks its ability to induce pathway activity at the level of ptch. SIGNOR-174429 0.8 IL3 protein P08700 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates 10090 10082541 f lperfetto We previously reported that NFIL3 is an IL-3-responsive gene in Baf-3 cells SIGNOR-242763 0.542 WDCP protein Q9H6R7 UNIPROT KIF2A protein O00139 UNIPROT up-regulates activity binding 9606 BTO:0000007 30297404 t miannu PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11.  SIGNOR-273732 0.2 SRC protein P12931 UNIPROT CHRNA7 protein P36544 UNIPROT down-regulates phosphorylation Tyr442 KILEEVRyIANRFRC 9606 BTO:0000938 16251431 t lperfetto Alpha7 neuronal nicotinic acetylcholine receptors are negatively regulated by tyrosine phosphorylation and src-family kinasesmutant alpha7 nachrs lacking cytoplasmic loop tyrosine residues because of alanine replacement of tyr-386 and tyr-442 were more active than wild-type receptorsexpression of active src reduced _7 nachr activity SIGNOR-141311 0.2 MCM complex SIGNOR-C268 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 19946136 f The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. SIGNOR-261678 0.7 MT-ND5 protein P03915 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 SIGNOR-262148 0.762 CSNK2A1 protein P68400 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser712 EEEESDSsETEKEDD -1 21296876 t miannu CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis SIGNOR-276249 0.2 IRF4 protein Q15306 UNIPROT CD68 protein P34810 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000801 12676954 f However, our data show that PU.1/IRF-4 and IRF-8 heterocomplexes down-regulate CD68 promoter activity in macrophages and repression is dependent on the integrity of both the IRF and PU.1 half-sites of this composite element. SIGNOR-254284 0.302 BID protein P55957 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 11175253 t amattioni Activated tbid results in an allosteric activation of bak SIGNOR-105210 0.816 SOCS1 protein O15524 UNIPROT JAK1 protein P23458 UNIPROT down-regulates binding 9606 23663276 t milica Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna. SIGNOR-202042 0.721 EIF3_complex complex SIGNOR-C401 SIGNOR Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity stabilization 9606 17581632 t lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit SIGNOR-269154 0.622 PRKCE protein Q02156 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 15355962 t gcesareni Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth. SIGNOR-128718 0.2 LHB protein P01229 UNIPROT LHCGR protein P22888 UNIPROT up-regulates binding 9606 10446903 t gcesareni Hcg is a heterodimeric glycoprotein hormone, consisting of a common? -subunit and a hormone-specific ?-Subunit (2). It binds to the lh receptor (lhr). SIGNOR-70028 0.671 YY2 protein O15391 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 15087442 t Luana YY2 activated the p53 promoter. However, in contrast to YY1, which represses the activity of c-Fos, YY2 increased the activity of the c-Fos promoter. SIGNOR-266213 0.59 NEK1 protein Q96PY6 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates activity binding 28426283 t lperfetto It was reported that NEK1 associates with ATR/ATRIP and primes it for activation in response to a variety of genotoxic agents SIGNOR-275842 0.286 SLC9A4 protein Q6AI14 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265603 0.8 DRD4 protein P21917 UNIPROT GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 21303898 t miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC SIGNOR-264995 0.438 SIRT1 protein Q96EB6 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity deacetylation 9606 BTO:0000007 14976264 t lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-122408 0.909 LSM-1988 chemical CHEBI:92015 ChEBI PARP1 protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189394 0.8 afatinib chemical CHEBI:61390 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189356 0.8 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-217008 0.634 SCF-FBW7 complex SIGNOR-C135 SIGNOR FOXM1 protein Q08050 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 26912724 t miannu GSK3 phosphorylates FoxM1 on serine 474 which induces FoxM1 ubiquitination mediated by FBXW7. SIGNOR-277209 0.309 CSNK2A1 protein P68400 UNIPROT AIP protein O00170 UNIPROT unknown phosphorylation Ser43 FHYRTLHsDDEGTVL 9534 12361709 t llicata Protein kinase CK2 (CK2) was identified as the 45-kDa kinase from COS 1 cell or liver extracts that was responsible for phosphorylation of serine 43 in the XAP2 peptide 39-57. Loss of phosphorylation at any or all of the serine residues did not significantly affect the ability of XAP2-FLAG to bind to the murine AhR in rabbit reticulocyte lysate or Hsp90 in COS-1 cells. SIGNOR-250824 0.312 ITGB4 protein P16144 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 9428518 t gcesareni Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation. SIGNOR-54615 0.2 IDH1 protein O75874 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 26178471 t lperfetto Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (Œ±-KG) SIGNOR-261828 0.8 FHIT protein P49789 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 BTO:0000551 15313915 f miannu We found that this synergistic inhibition of tumor cell growth corresponded with the fhit-mediated inactivation of mdm2, which thereby blocked the association of mdm2 with p53, thus stabilizing the p53 protein. SIGNOR-127915 0.486 ABL1 protein P00519 UNIPROT ROBO1 protein Q9Y6N7 UNIPROT down-regulates phosphorylation Tyr1073 PSGQPTPyATTQLIQ 9606 10892742 t gcesareni Abl functions to antagonize robo signaling both abl and ena can directly bind to robo's cytoplasmic domain. SIGNOR-78993 0.589 RAD51C protein O43502 UNIPROT XRCC3 protein O43542 UNIPROT up-regulates activity relocalization 9606 23438602 f lperfetto It is likely that the recruitment of RAD51C to the sites of DNA lesions can promote XRCC3 phosphorylation and activate the DNA damage response pathway(s) in the S and G2 phases.  SIGNOR-263260 0.653 TP73 protein O15350 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 17700533 f miannu Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death. SIGNOR-255473 0.7 NUP93 protein Q8N1F7 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262081 0.71 RBM15 protein Q96T37 UNIPROT RBM15/NXF1 complex SIGNOR-C67 SIGNOR form complex binding 9606 17001072 t miannu Rbm15 binds to nxf1 and the two proteins cooperate in stimulating rte-mediated mrna export and expression. SIGNOR-149883 0.502 CDK8 protein P49336 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Thr2511 VPEHPFLtPSPESPD -1 25344755 t lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues SIGNOR-273178 0.534 CASP3 protein P42574 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000142 10200555 f amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation SIGNOR-66860 0.7 RPS6KA4 protein O75676 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni Msk1 and msk2 directly phosphorilate and activate transcription factors such as creb1, atf1. SIGNOR-166661 0.599 EFNA1 protein P20827 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9330863 t gcesareni Transmembrane ligands for eph receptors also exhibit properties of signal transducing molecules, suggesting that bidirectional signaling occurs when receptor-expressing cells contact ligand-expressing cells. SIGNOR-52005 0.81 APOA5 protein Q6Q788 UNIPROT LPL protein P06858 UNIPROT up-regulates activity binding 9606 21773006 t Regulation miannu Apo A5 binds to and enhances the activity of lipoprotein lipase (LPL) enzyme SIGNOR-251845 0.707 TRAF7 protein Q6Q0C0 UNIPROT MAP3K3 protein Q99759 UNIPROT up-regulates binding 9606 15001576 t miannu Traf7 specifically interacts with and activates mekk3. SIGNOR-123221 0.497 SP1 protein P08047 UNIPROT DHCR24 protein Q15392 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22431021 f miannu activation of Sp1 by oxidative stress is involved in the promotion of expression of DHCR24 by HCV. SIGNOR-255200 0.2 NDC80 protein O14777 UNIPROT Ndc80 complex complex SIGNOR-C361 SIGNOR form complex binding 27881301 t lperfetto Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits SIGNOR-265188 0.966 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser25 PPSPEVGsPLLCRPA 9606 11110801 t llicata In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676). SIGNOR-84988 0.453 CSTF2 protein P33240 UNIPROT CSTF complex complex SIGNOR-C441 SIGNOR form complex binding 9606 10669729 t lperfetto We therefore first identified regions of the CstF subunits, CstF-77, CstF-64, and CstF-50, required for interaction with each other.  SIGNOR-268366 0.927 ATF4 protein P18848 UNIPROT WARS1 protein P23381 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269429 0.2 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 10090 BTO:0002572;BTO:0000801 21232017 t lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-235407 0.891 ACVR1 protein Q04771 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation Ser465 HNPISSVs 9534 9748228 t ALK2 receptor specifically interacts with and phosphorylates Smad1 protein. ALK2 Activates Smad1 and Induces BMP-specific Signals. Biochemical analysis revealed that constitutively active ALK2 associated with and phosphorylated Smad1 on the COOH-terminal SSXS motif SIGNOR-251439 0.691 ERBB3 protein P21860 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 16729043 t gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. SIGNOR-146864 0.5 DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 20837657 t lperfetto In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization. SIGNOR-227911 0.7 TRIM65 protein Q6PJ69 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0003172 31332286 t miannu Ubiquitin ligase TRIM65 promotes colorectal cancer metastasis by targeting ARHGAP35 for protein degradation SIGNOR-272256 0.2 MAPKAPK5 protein Q8IW41 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 BTO:0001286 17254968 t gcesareni Furthermore, we show that prak activates p53 by direct phosphorylation. We propose that phosphorylation of p53 by prak following activation of p38 mapk by ras plays an important role in ras-induced senescence and tumor suppression. SIGNOR-152850 0.751 CRIPAK protein Q8N1N5 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9606 BTO:0000150 BTO:0000149 16278681 t gcesareni We further found that cripak interacted with pak1 through the n-terminal regulatory domain and inhibited pak1 kinase in both in vitro and in vivo assays. SIGNOR-141467 0.425 VAV1 protein P15498 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0000782 9200440 t gcesareni Hese data imply that c-cbl is a molecular adapter that regulates the function of vav SIGNOR-49188 0.68 GSK3B protein P49841 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser33 LPENNVLsPLPSQAM 9606 11483158 t Glycogen synthase kinase3 beta phosphorylates serine 33 of p53 and activates p53's transcriptional activity. SIGNOR-251258 0.717 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates binding 9606 23400686 t gcesareni Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1. SIGNOR-252534 0.845 KLF14 protein Q8TD94 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates quantity by repression transcriptional regulation 19088080 f lperfetto Mechanistically, KLF14 represses the TGFbetaRII promoter via a co-repressor complex containing mSin3A and HDAC2. SIGNOR-271696 0.2 2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[8-[[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetyl]amino]octyl]acetamide chemical CID:121427831 PUBCHEM BRD4 protein O60885 UNIPROT down-regulates quantity chemical inhibition 9606 29764999 t Monia DBET6 induces efficient degradation of BET proteins and inhibits the proliferation of GBM cells SIGNOR-261094 0.8 SRGAP3 protein O43295 UNIPROT RAC2 protein P15153 UNIPROT down-regulates 9606 12447388 f miannu Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo. SIGNOR-95921 0.533 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser555 RALSNSVsNMGLSES 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249681 0.509 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Thr231 TRNKVRKtFVGTPCW 9606 17190791 t gcesareni Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1). SIGNOR-151671 0.457 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR form complex binding 9606 BTO:0000007 14636569 t lperfetto These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer SIGNOR-263208 0.831 PTPN11 protein Q06124 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates dephosphorylation Tyr718 IPERDSRySQPLHEE 9606 19287004 t lperfetto Previously we have shown that tyrosine 718 of ask1 when phosphorylated is critical for socs1 binding and socs1-mediated degradation of ask1we identified jak2 and shp2 as a tyr-718-specific kinase and phosphatase, respectively. SIGNOR-184604 0.375 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR FANCD2 protein Q9BXW9 UNIPROT up-regulates activity ubiquitination 9606 BTO:0003323 12485996 t lperfetto The major genetic evidence supporting ubiquitin ligase function for BRCA1 in vivo comes from studies on the FANCD2 protein. Whereas in wild‐type cells the FANCD2 protein co‐localizes with BRCA1 in nuclear foci and becomes monoubiquitylated in response to DNA damage, HCC1937 cells, which encode a mutated form of BRCA1, are largely defective for both monoubiquitylation of FANCD2 and foci formation SIGNOR-263237 0.699 MAPK3 protein P27361 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 12955074 t gcesareni Mutant p53 is constitutively phosphorylated at serine 15 in uv-induced mouse skin tumors: involvement of erk1/2 map kinase. SIGNOR-100270 0.696 PRKACA protein P17612 UNIPROT IGF2R protein P11717 UNIPROT unknown phosphorylation Ser2347 TTCCRRSsNVSYKYS 9606 8318012 t lperfetto Pka phosphorylates the cytoplasmic mpr 300 domain at ser20 and at a non-identified site, SIGNOR-37839 0.2 SEC24B protein O95487 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 t lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat SIGNOR-265290 0.708 Av/b3 integrin complex SIGNOR-C177 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269026 0.7 PPP3CA protein Q08209 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-176379 0.56 STAT3 protein P40763 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30029643 f Taken together, our data show IL-15 can enhance the collagen deposition in vivo after muscle damage and this process can be prevented by blocking Jak-STAT pathway. SIGNOR-256257 0.7 E2F1 protein Q01094 UNIPROT CCNE1 protein P24864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253854 0.67 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation 9606 7478566 t gcesareni For example, inactivation of sos through phosphorylation by the downstream mapk SIGNOR-26338 0.621 ANXA3 protein P12429 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity 9606 BTO:0000018 27995049 f miannu We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells. SIGNOR-262210 0.2 ABL1 protein P00519 UNIPROT PSTPIP1 protein O43586 UNIPROT unknown phosphorylation Tyr345 PERNEGVyTAIAVQE 9606 11163214 t Manara PSTPIP1 was phosphorylated by ABL1, and growth factor–induced PSTPIP1 phosphorylation was diminished in Abl null fibroblasts. SIGNOR-260809 0.615 GATA1 protein P15976 UNIPROT HBG2 protein P69892 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004911 20395365 f Regulation miannu BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. SIGNOR-251804 0.386 GNG2 protein P59768 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 17419683 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt. SIGNOR-154255 0.455 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates activity phosphorylation Ser622 ILSTAMLsLGSGISQ 9534 BTO:0000298 11865049 t llicata The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly.  SIGNOR-250815 0.734 PP1 proteinfamily SIGNOR-PF54 SIGNOR CDK9 protein P50750 UNIPROT up-regulates dephosphorylation Ser175 FGLARAFsLAKNSQP 9606 21533037 t lperfetto Protein phosphatase-1 activates cdk9 by dephosphorylating ser175 SIGNOR-264671 0.2 6-bromo-3-(1-methyl-4-pyrazolyl)-5-(3-piperidinyl)-7-pyrazolo[1,5-a]pyrimidinamine chemical CHEBI:131165 ChEBI CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206838 0.8 CH5132799 chemical CID:49784945 PUBCHEM PIK3C2B protein O00750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190940 0.8 ATM protein Q13315 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0000887 18534819 f lperfetto The decreased atm expression suggests that atm is involved in the development of insulin resistance through down-regulation of akt activity. SIGNOR-244392 0.46 DUSP6 protein Q16828 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 12840032 t gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). SIGNOR-103146 0.901 Cy3-bifunctional dye zwitterion chemical CHEBI:37990 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  SIGNOR-257859 0.8 EIF3J protein O75822 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266391 0.775 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation 9606 18498746 t gcesareni Jnk phosphorylates two members of the bh3-only sub of bcl2-related proteins (bim and bmf). SIGNOR-178686 0.75 HSPA8 protein P11142 UNIPROT RNF5 protein Q99942 UNIPROT up-regulates activity binding 9606 BTO:0000007 21148293 t miannu JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation. JB12 drives Hsc70 to associate with CFTR and the RMA1 E3 complex SIGNOR-271493 0.396 APBA1 protein Q02410 UNIPROT CASK protein O14936 UNIPROT up-regulates activity binding 9534 11036064 t miannu Interaction with Munc18 increases Mint1 binding to CASK. SIGNOR-264041 0.846 NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 f We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα. SIGNOR-256117 0.472 BMP2 protein P12643 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 9606 22298955 f gcesareni Neogenin, a transmembranous protein, was re-ported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation SIGNOR-195564 0.686 MAPK3 protein P27361 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates activity phosphorylation -1 9155018 t These results indicate that MNK1 is a novel class of protein kinase that is activated through both the ERK and p38 MAP kinase signaling pathways SIGNOR-253012 0.557 DIABLO protein Q9NR28 UNIPROT XIAP protein P98170 UNIPROT down-regulates quantity binding 9606 BTO:0000007;BTO:0000567 14523016 t amattioni Smac3, a novel Smac/DIABLO splicing variant, accelerates XIAP auto-ubiquitination and destruction SIGNOR-118411 0.912 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000443 12270934 t lperfetto Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. SIGNOR-244795 0.2 CREB1 protein P16220 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity binding 9606 15126506 t lperfetto We provide evidence that the acetyltransferase creb-binding protein (cbp) binds foxo resulting in acetylation of foxo. This acetylation inhibits foxo transcriptional activity SIGNOR-124711 0.313 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates activity phosphorylation Tyr177 ADAEKPFyVNVEFHH 9606 8622703 t lperfetto We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrosine 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr. SIGNOR-40611 0.2 PTPN6 protein P29350 UNIPROT NTRK1 protein P04629 UNIPROT down-regulates activity dephosphorylation Tyr680 RDIYSTDyYRVGGRT 10116 phosphorylation: tyr496 HIIENPQyFSDACVH 14662744 t Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675. SIGNOR-248468 0.489 NTRK1 protein P04629 UNIPROT SH2B1 protein Q9NRF2 UNIPROT up-regulates binding 9606 BTO:0000938 15082760 t lperfetto The adapter protein sh2-b has been shown to bind to activated nerve growth factor (ngf) receptor trka and has been implicated in ngf-induced neuronal differentiation and the survival of sympathetic neurons. SIGNOR-124198 0.524 PP121 chemical CHEBI:50915 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206295 0.8 (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol chemical CHEBI:94701 ChEBI RRM2 protein P31350 UNIPROT down-regulates activity chemical inhibition -1 7048062 t miannu In vitro biological activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. 2-F-araATP was a potent inhibitor of ribonucleotide reductase SIGNOR-258405 0.8 P-TEFb complex SIGNOR-C238 SIGNOR MLLT3 protein P42568 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0000007 17135274 t miannu Phosphorylation of Af9 and Enl by P-TEFb promotes their proteolysis SIGNOR-266800 0.687 RBL2 protein Q08999 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity transcriptional regulation 10090 10801445 f gcesareni Furthermore, muscle cells overexpressing p130 had reduced levels of the muscle-promoting factor MyoD. In addition, p130 repressed the transactivation capacity of MyoD, an effect abolished by co-transfection of pRb SIGNOR-241943 0.379 Wnt proteinfamily SIGNOR-PF40 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization 17081971 f The central player in the canonical Wnt cascade is β-catenin, a cytoplasmic protein whose stability is regulated by the destruction complex. SIGNOR-256240 0.2 IL22RA1 protein Q8N6P7 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 12087100 f gcesareni Il-22 also induced serine phosphorylation of stat3 on ser(727). SIGNOR-90162 0.637 CALM3 protein P0DP25 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates binding 9606 11796223 t inferred from 70% of family members miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-269891 0.661 STAT3 protein P40763 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 10347215 f lperfetto The data presented this far show that the JAK-STAT signaling pathway and specifically Stat3 and Jak1 are required for induction of IL-10-dependent anti-inflammatory and developmental responses in macrophages. SIGNOR-249547 0.7 2-(hydroxymethyl)-4-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)phenol chemical CHEBI:64064 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 20590599 t Luana The affinity measurements (log KD values of −5.73, −9.26 and −6.33 for β1, β2 and β3, respectively), show that salmeterol has high affinity for the β2-adrenoceptor.  SIGNOR-257852 0.8 SMO protein Q99835 UNIPROT GNAT2 protein P19087 UNIPROT up-regulates binding 9606 16885213 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-148534 0.264 PRDM16 protein Q9HAZ2 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887;BTO:0001103 18719582 t _activating its transcriptional function fspada Prdm16 stimulates brown adipogenesis by binding to ppar-gamma (peroxisome-proliferator-activated receptor-gamma) and activating its transcriptional function SIGNOR-180298 0.482 NOTCH2 protein Q04721 UNIPROT TCF3 protein P15923 UNIPROT down-regulates binding 9606 9528794 t gcesareni In an effort to identify processes that regulate e47, and potentially b-cell development, we found that activated notch1 and notch2 effectively inhibit e47 activity. SIGNOR-56222 0.276 calciol smallmolecule CHEBI:28940 ChEBI vitamin D smallmolecule CHEBI:27300 ChEBI up-regulates quantity precursor of 9606 BTO:0001253 30080183 t lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin SIGNOR-270564 0.8 PFKL protein P17858 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. SIGNOR-266468 0.8 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 BTO:0000567 17615152 t gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo. SIGNOR-156868 0.692 Hypoxia stimulus SIGNOR-ST25 SIGNOR KDM4B protein O94953 UNIPROT up-regulates 9606 30759871 f miannu The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. KDM4 enzymes are generally over-expressed in cancers, making them compelling targets for study and therapeutic inhibition. One of these family members, KDM4B, is especially interesting due to its regulation by multiple cellular stimuli, including DNA damage, steroid hormones, and hypoxia. SIGNOR-263735 0.7 ABL1 protein P00519 UNIPROT VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 11790798 t gcesareni Thus, the c-terminal tail of vav serves as a direct substrate of bcr-abl in vitro. SIGNOR-114091 0.41 GNB1 protein P62873 UNIPROT GNB/GNG complex SIGNOR-C202 SIGNOR form complex binding 9606 23994464 t apalma Instead, our current understanding is that the majority of GPCR signal transduction in neutrophils occurs through the GŒ≤Œ≥ subunit SIGNOR-255004 0.939 VRK1 protein Q99986 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr73 ADQTPTPtRFLKNCE 9606 15105425 t gcesareni Vrk1 phosphorylates atf2 mainly on thr-73, stabilizing the atf2 protein and increasing its intracellular level. SIGNOR-124334 0.379 PRKAR2A protein P13861 UNIPROT PRKAR2A protein P13861 UNIPROT up-regulates activity phosphorylation Ser99 SRFNRRVsVCAETYN -1 6293815 t miannu RII subunit containing the 'autophosphorylation' site (Ser-95) SIGNOR-250073 0.2 TH protein P07101 UNIPROT L-dopa smallmolecule CHEBI:15765 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH). SIGNOR-263991 0.8 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205746 0.8 NF1 protein P21359 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR up-regulates 9606 BTO:0000938 24431436 f miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-267846 0.408 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1931 SPTSPTYsPTSPKGS 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176833 0.775 SIRT7 protein Q9NRC8 UNIPROT H3-5 protein Q6NXT2 UNIPROT up-regulates activity deacetylation Lys37 TPSTCGVkPHRYRPG 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275879 0.2 alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity precursor of 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267935 0.8 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Thr166 LYCDPRGtLRKGTLG -1 23444369 t miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. SIGNOR-273491 0.27 IL23A protein Q9NPF7 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 12023369 t gcesareni Like il-12, il-23 binds to the il-12r subunit il-12rbeta1. SIGNOR-87739 0.631 MBP protein P02686 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 31066630 f SimoneGraziosi Myelin basic protein (MBP) is essential for the compaction of the two adjacent cytoplasmic membrane surfaces into the major dense line of myelin. SIGNOR-269230 0.7 IL17A protein Q16552 UNIPROT IL17RA protein Q96F46 UNIPROT up-regulates binding 9606 BTO:0000782 9367539 t gcesareni Binding studies suggest that recombinant hil-17 binds to the hil-17r with low affinity. Monoclonal antibodies (mabs) generated against the hil-17r were able to block the il-17-induced production of cytokine from human foreskin fibroblast (hff) cells. SIGNOR-53249 0.922 TNFSF11 protein O14788 UNIPROT Osteoclast_differentiation phenotype SIGNOR-PH76 SIGNOR up-regulates 9606 17572386 f miannu Osteoclasts are fully differentiated, multi-nucleated cells originating from the hematopoietic monocyte-macrophage linage. RANKL, a member of the tumor necrosis factor (TNF) superfamily, and its receptor RANK are essential regulators of osteoclast maturation and activation SIGNOR-253044 0.7 ACD protein Q96AP0 UNIPROT POT1/ACD complex SIGNOR-C64 SIGNOR form complex binding 9606 17237768 t miannu We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme. SIGNOR-152318 0.88 IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr387 RTQTVRGtLAYLPEE -1 11960013 t In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4. SIGNOR-251329 0.673 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIA1 protein P42261 UNIPROT up-regulates activity chemical activation 10090 15115814 t lperfetto AMPA glutamate receptor subunit (GluR1) SIGNOR-261432 0.8 CREB1 protein P16220 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 20577053 f gcesareni In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1 SIGNOR-268145 0.252 IFNW1 protein P05000 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates binding 9606 11278538 t gcesareni Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. SIGNOR-105982 0.752 KLF15 protein Q9UIH9 UNIPROT RHO protein P08100 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 f miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. SIGNOR-253817 0.276 SIRT1 protein Q96EB6 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity deacetylation 24870244 t lperfetto The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1alpha and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1alpha. SIGNOR-275499 0.2 AMPK complex SIGNOR-C15 SIGNOR EPM2A protein O95278 UNIPROT up-regulates activity phosphorylation Ser25 PELLVVGsRPELGRW 9606 BTO:0000007 21728993 t miannu In the present study, we demonstrate that laforin is a phosphoprotein, as indicated by two-dimensional electrophoresis, and we identify Ser(25) as the residue involved in this modification. We also show that Ser(25) is phosphorylated both in vitro and in vivo by AMPK.  SIGNOR-276338 0.357 nintedanib chemical CHEBI:85164 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 18559524 t Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. SIGNOR-257805 0.8 EP300 protein Q09472 UNIPROT TP53 protein P04637 UNIPROT up-regulates acetylation Lys382 QSTSRHKkLMFKTEG 9606 BTO:0000567 11070080 t gcesareni P300 acetylates and activates the tumor suppressor p53 after dna damage. SIGNOR-84074 0.909 SATB1 protein Q01826 UNIPROT CD52 protein P31358 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 17343824 f miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. SIGNOR-255131 0.2 PFDN4 protein Q9NQP4 UNIPROT Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR form complex binding 9606 32699605 t miannu The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6) SIGNOR-270933 0.94 PRKCA protein P17252 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Ser544 RSVTMRKsQRSSKGS 9606 24505490 t llicata A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498. SIGNOR-204550 0.2 FBXO32 protein Q969P5 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0000165 19319192 t miannu We previously showed that the level of MAFbx protein increased in skeletal muscle during aging and/or food deprivation. Immunoprecipitation of the SCFMAFbx complexes from mouse atrophic muscles exhibited ubiquitination activity by using MyoD as substrate. Food deprivation and oxidative stress–induced atrophy increase polyubiquitination by the SCFMAFbx pathway and degradation of MyoD by the proteasome SIGNOR-271802 0.577 CSNK2A1 protein P68400 UNIPROT MAPK9 protein P45984 UNIPROT unknown phosphorylation Ser407 STEQTLAsDTDSSLD 9606 11062067 t lperfetto The phosphorylation of thr-404 and ser-407 is not increased in response to other agonists that activate mkk7 and sapk1/jnk, suggesting that phosphorylation of these residues is catalysed by another protein kinase, such as ck2, which also phosphorylates thr-404 and ser-407 in vitro. SIGNOR-83711 0.222 PRKCA protein P17252 UNIPROT CORO1B protein Q9BR76 UNIPROT down-regulates phosphorylation Ser2 sFRKVVRQ 9606 16027158 t lperfetto We have identified serine 2 (ser-2) on coronin 1b as the major residue phosphorylated by pkc in vivo.In this work, we show that coronin 1b interacts in vivo with the arp2/3 complex and that this interaction is inhibited by pkc phosphorylation. SIGNOR-138733 0.33 CREB5 protein Q02930 UNIPROT LY96 protein Q9Y6Y9 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002813 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253806 0.2 GSK3B protein P49841 UNIPROT SRC protein P12931 UNIPROT down-regulates activity phosphorylation Ser43 QTPSKPAsADGHRGP 9606 BTO:0002181 33388549 t miannu Concurrently, ROCK1 was able to phosphorylate GSK-3β at Ser9, which phosphorylated Src at Ser51 and Ser492 residues, leading to Src inactivation SIGNOR-277543 0.391 PMS2 protein P54278 UNIPROT MLH1/PMS2 complex SIGNOR-C59 SIGNOR form complex binding 9606 10542278 t miannu Hmlh1 and hpms2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hmutl_ SIGNOR-71777 0.749 PAK2 protein Q13177 UNIPROT NF2 protein P35240 UNIPROT down-regulates phosphorylation Ser518 DTDMKRLsMEIEKEK 9606 18071304 t lperfetto Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth, SIGNOR-159768 0.491 AGTR1 protein P30556 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32201502 f MIANNU Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis. SIGNOR-260233 0.7 EPHB2 protein P29323 UNIPROT SYNJ1 protein O43426 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 15821731 t lperfetto Ephb2 causes tyrosine phosphorylation in the proline-rich domain of synaptojanin 1, and inhibits both the interaction with endophilin and the 5'-phosphatase activity of synaptojanin 1 SIGNOR-135274 0.551 PKI-402 chemical CID:44187953 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252654 0.8 NEK2 protein P51955 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates phosphorylation Ser507 TDLCFLNsPIFKQKK 9606 17621308 t lperfetto Here we show that nek2a phosphorylates human sgo1 and such phosphorylation is essential for faithful chromosome congression in mitosis. phosphorylation sites were mapped to ser(14) and ser(507) SIGNOR-156882 0.2 MTOR protein P42345 UNIPROT EIF4EBP2 protein Q13542 UNIPROT down-regulates phosphorylation 9606 23100465 t gcesareni Here, we show that cancer cells acquire resistance to astori by downregulating eukaryotic translation initiation factor (eif4e)-binding proteins (4e-bps-eif4ebp1, eif4ebp2). SIGNOR-199258 0.651 MTA1 protein Q13330 UNIPROT MTA1/DJ1 complex complex SIGNOR-C123 SIGNOR form complex binding 9606 21368136 t 1 miannu We found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3. SIGNOR-239739 0.333 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser125 HGSDSVEsAEKEIGL -1 8810265 t miannu For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown. SIGNOR-250198 0.2 BRSK2 protein Q8IWQ3 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates phosphorylation Thr183 SDGEFLRtSCGSPNY 9606 21918180 t gcesareni Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli. SIGNOR-176594 0.294 CSNK2A2 protein P19784 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates activity phosphorylation Thr519 EDPYAGStDENTDSE 9606 BTO:0000567 15367657 t llicata XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on S518, T519, and T523 largely determines aprataxin binding to XRCC1 though its FHA domain | In addition, we present data to show that the acute loss of aprataxin by small interfering RNA (siRNA) renders HeLa cells sensitive to MMS through a mechanism that destabilizes XRCC1. SIGNOR-251051 0.472 HDAC5 protein Q9UQL6 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates deacetylation 9606 22298955 t gcesareni Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation SIGNOR-195606 0.47 YWHAQ protein P27348 UNIPROT PRKD1 protein Q15139 UNIPROT down-regulates -1 10092600 f lperfetto 14-3-3tau strongly down-regulates pkcmu kinase activity in vitro SIGNOR-65951 0.333 LTK protein P29376 UNIPROT CBL protein P22681 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9223670 t gcesareni Although c-cbl is found to be phosphorylated by ltk and therefore is a second candidate linking ltk with the pi3-kinase pathway along with irs-1, we found that the p85 subunit of pi3 kinase directly binds to tyrosine 753 of ltk, which is located within a yxxm motif, a consensus binding amino acid sequence for the sh2 domain of p85. SIGNOR-49528 0.376 PAX7 protein P23759 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 BTO:0001103;BTO:0002314 22493066 f lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells SIGNOR-219371 0.7 valsartan chemical CHEBI:9927 ChEBI AGTR1 protein P30556 UNIPROT down-regulates activity chemical inhibition 9606 8577935 t miannu The binding characteristics of the angiotensin AT1 receptor antagonist valsartan were investigated in different animal species and tissues. SIGNOR-258489 0.8 TRIM24 protein O15164 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001130 19909775 t miannu We found that trim24/transcriptional intermediary factor 1alpha (tif1alpha), which is known as a ligand-dependent nuclear receptor co-regulator, interacts with ar and enhances transcriptional activity of ar SIGNOR-189113 0.405 MAPT protein P10636 UNIPROT Neurofibrillary tangle formation phenotype SIGNOR-PH58 SIGNOR down-regulates 9606 11578751 f lperfetto Tau is a multifunctional microtubule-associated protein that plays major roles in the assembly of microtubules, the stabilization of microtubules against dynamic instability, and in bridging these polymers with other cytoskeletal filaments 43, 44, 45, 46 and 47. In normal brain, the equilibrium between phosphorylations and dephosphorylations of tau modulates the stability of the cytoskeleton and consequently axonal morphology. The earliest modification found in Alzheimer brains consists of hyperphosphorylations on tau by the action of different protein kinase and phosphatase systems that appear to lead to structural and conformational changes in this protein, thus affecting its binding with tubulin and the capacity to promote microtubule assembly SIGNOR-251639 0.7 SP1 protein P08047 UNIPROT ASNS protein P08243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 11867623 t Luana Sp1 and Sp3 Activate Transcription Driven by the AS Promoter SIGNOR-268019 0.2 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7234 RAASPTRsSSSASQS 9606 BTO:0004905 21295697 t lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. SIGNOR-264429 0.446 AXIN1 protein O15169 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity binding 9606 17529994 t amattioni The axin dix domain has a novel structural fold largely composed of beta-strands that engage in head-to-tail self-interaction to form filaments in the crystal SIGNOR-155218 0.2 PML protein P29590 UNIPROT ZFYVE9 protein O95405 UNIPROT up-regulates binding 9606 15356634 t gcesareni Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome. SIGNOR-128744 0.556 MAPK3 protein P27361 UNIPROT MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity. SIGNOR-48355 0.496 WZ4002 chemical CHEBI:61400 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207827 0.8 COPS5 protein Q92905 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates ubiquitination 9606 11818334 t gcesareni We report a novel mechanism of smad4 degradation. Jab1 interacts directly with smad4 and induces its ubiquitylation for degradation SIGNOR-114697 0.444 BIRC2 protein Q13490 UNIPROT CASP2 protein P42575 UNIPROT down-regulates binding 9606 16701639 t gcesareni However, among hiap1, hiap2 and xiap, only hiap2 binds and inhibits caspase-2. SIGNOR-146738 0.512 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 16085715 t gcesareni Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp. SIGNOR-139477 0.627 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser83 PRRSPRIsFFLEKEN -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276119 0.613 CASP1 protein P29466 UNIPROT AIM2 inflammasome complex SIGNOR-C222 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256400 0.782 NR0B2 protein Q15466 UNIPROT HNF4A protein P41235 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10594021 f gcesareni Here we show that shp inhibits transactivation by the orphan receptor hepatocyte nuclear factor 4 (hnf-4) and the retinoid x receptor (rxr) by at least two mechanisms shp also competes with coactivators for binding to ligand-activated rxr, and based on the ligand-dependent interaction with other nuclear receptors, it is likely that coactivator competition is a general feature of shp-mediated repression. SIGNOR-73032 0.439 AKT1 protein P31749 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates phosphorylation 9606 21777568 t gcesareni We found that Akt phosphorylates Osterix and that Akt activation increases protein stability, osteogenic activity and transcriptional activity of Osterix. We also found that BMP-2 increases the protein level of Osterix in an Akt activity-dependent manner. SIGNOR-195549 0.433 BLM protein P54132 UNIPROT UIMC1 protein Q96RL1 UNIPROT up-regulates activity binding 9606 BTO:0001938 23708797 t miannu Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of .  SIGNOR-272116 0.334 ENOBOSARM chemical CID:11326715 PUBCHEM AR protein P10275 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-195892 0.8 PHKG2 protein P15735 UNIPROT PYGM protein P11217 UNIPROT up-regulates activity phosphorylation Ser15 QEKRKQIsVRGLAGV 9606 BTO:0002049 22225877 t It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15 SIGNOR-267400 0.543 HDAC4 protein P56524 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates deacetylation 9606 16613856 t gcesareni Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation. SIGNOR-146122 0.539 GUCY1A1 protein Q02108 UNIPROT GUCY1A3-B3 complex SIGNOR-C140 SIGNOR form complex binding 9606 10977868 t gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity SIGNOR-243983 0.2 LCK protein P06239 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates phosphorylation Tyr759 LYDVSRMyVDPSEIN 9606 12181444 t gcesareni In vitro phosphorylation experiments with recombinant plcgamma2 and recombinant lck, fyn, and lyn tyrosine kinases showed that phosphorylation of plcgamma2 led to activation of the recombinant enzyme. SIGNOR-91477 0.539 RNF139 protein Q8WU17 UNIPROT SREBF2 protein Q12772 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 20068067 t miannu Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner  SIGNOR-271958 0.49 mTORC2 complex SIGNOR-C2 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser436 INQSTLPsQQNRFPD 9606 BTO:0002036 34343821 t miannu Here we report the ability of mTORC2 to directly phosphorylate YAP at serine 436 (Ser436) positively regulating YAP activity. SIGNOR-277569 0.284 TRAF2 protein Q12933 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity binding 9606 9774977 t lperfetto Traf2 is a strong activator of ask1 SIGNOR-60747 0.726 UBE2V1 protein Q13404 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 11057907 t lperfetto We find that traf6, a ring domain protein, functions together with ubc13/uev1a to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (k63) of ubiquitin SIGNOR-83603 0.687 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser692 GQLMSQPsTASNSLP 9606 10195894 t Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. SIGNOR-251280 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS3 protein P23396 UNIPROT unknown phosphorylation 9606 15950189 t inferred from 70% family members llicata Erk phosphorylates threonine 42 residue of ribosomal protein s3. SIGNOR-270145 0.2 PRKD1 protein Q15139 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Ser298 EKLAKHEsQQDYSKG 9606 20363754 t lperfetto Pkd phosphorylates cortactin in vitro and in vivo at serine 298 thereby generating a 14-3-3 binding motif. In vitro, a phosphorylation-deficient cortactin-s298a protein accelerated vca-arp-cortactin-mediated synergistic actin polymerization and showed reduced f-actin binding SIGNOR-164756 0.432 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 10090 26260587 t lperfetto IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-249546 0.793 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 9606 BTO:0005248 8758906 t irozzo We demonstrated that Bcr-Abl co-immunoprecipitates with, and constitutively phosphorylates, the common βc,subunit of the interleukin 3 and granulocyte/macrophage-colony stimulating factor receptors.We demonstrate that Bcr-Abl interacts with the common βc subunit of the IL-3 family of receptors and phosphorylates it on tyrosine. SIGNOR-255999 0.2 IRAK4 protein Q9NWZ3 UNIPROT PELI2 protein Q9HAT8 UNIPROT up-regulates phosphorylation 9606 12860405 t gcesareni Pellino2 is one of the firstsubstrates identified for irak1 andirak4. SIGNOR-103717 0.623 CCL2 protein P13500 UNIPROT CCR4 protein P51679 UNIPROT up-regulates activity binding 9606 17160712 t gcesareni CCR2 and CCR4 are two cell surface receptors that bind CCL2 SIGNOR-237555 0.479 nilutamide chemical CHEBI:7573 ChEBI AR protein P10275 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194649 0.8 MAP2K2 protein P36507 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 BTO:0000142 1411546 t gcesareni The primary structure of mek, a protein kinase that phosphorylates the erk gene product SIGNOR-19244 0.732 CDC14A protein Q9UNH5 UNIPROT WEE1 protein P30291 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser139 YFLGSSFsPVRCGGP 9606 BTO:0000007 23051732 t lperfetto In particular, we found that Cdc14A inhibits Wee1 degradation through the dephosphorylation of Ser-123 and Ser-139 residues.  SIGNOR-267470 0.561 PTPN13 protein Q12923 UNIPROT STK25 protein O00506 UNIPROT down-regulates activity dephosphorylation 9606 17657516 t To investigate dephosphorylation of CCM3 by FAP-1, phosphorylated GST-CCM3 was incubated with cdFAP-1, and reactions were analyzed by autoradiography. Again, GST-STK25 phosphorylated GST-CCM3 and possessed autophosphorylation activity. cdFAP-1 of 0.005 U were sufficient to dephosphorylate GST-CCM3 as well as the kinase GST-STK25.|More recently, the Golgi matrix protein GM130 was shown to function as a scaffold protein for STK25 and to activate STK25 through stimulation of autophosphorylation. SIGNOR-248711 0.431 NOG protein Q13253 UNIPROT BMP7 protein P18075 UNIPROT down-regulates activity binding -1 12478285 t We report the crystal structure of the antagonist Noggin bound to BMP-7, which shows that Noggin inhibits BMP signalling by blocking the molecular interfaces of the binding epitopes for both type I and type II receptors. SIGNOR-256484 0.858 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation 9606 7618106 t lperfetto The tcf protein elk-1 is phosphorylated by the jnk and erk groups of mitogen-activated protein (map) kinases causing increased dna binding, ternary complex formation, and transcriptional activation SIGNOR-252081 0.2 KAT5 protein Q92993 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000007 21936881 t llicata Tip60 regulates myoblast differentiation by enhancing the transcriptional activity of MyoD via their physical interactions. SIGNOR-237675 0.372 PRKCB protein P05771 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity phosphorylation Ser467 KASSRRSsFSMEEGD 10090 BTO:0000968 23599343 t This occurs following PKCβ phosphorylation of TFEB on three serine residues located in its last 15 amino acids. This post-translational modification stabilizes and increases the activity of this transcription factor. SIGNOR-255316 0.336 DUSP7 protein Q16829 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 BTO:0000150 BTO:0001253 9788880 t gcesareni Pyst2 preferentially dephosphorylates and inactivates p42 map kinase in vitro and in vivo SIGNOR-60871 0.789 MAPK12 protein P53778 UNIPROT NUP62 protein P37198 UNIPROT down-regulates quantity by destabilization phosphorylation Ser272 SGTSTTTsTAATATA 9606 BTO:0000007 30401435 t miannu We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1).  SIGNOR-277416 0.2 SNX5 protein Q9Y5X3 UNIPROT DOCK1 protein Q14185 UNIPROT up-regulates activity binding 9606 BTO:0000567 18596235 t miannu SNX5 Is a Novel Binding Partner of the DHR1 Domain of DOCK180. In summary, we found that DOCK180 regulates transport of CI-MPR via SNX5 binding. SIGNOR-269441 0.352 DUSP4 protein Q13115 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR 10116 7535768 t Dephosphorylation and Inactivation of ERKs|A single protein kinase, MEK, activates ERK2 by phosphorylating threonine 183 and tyrosine 185 SIGNOR-248718 0.752 Histone H2A proteinfamily SIGNOR-PF70 SIGNOR Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR form complex binding -1 21812398 t miannu The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. SIGNOR-267756 0.2 KIF2C protein Q99661 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272535 0.7 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Ser1137 EGPTRRLsLPGQLGA 9606 10488078 t lperfetto Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a) SIGNOR-70718 0.312 ATM protein Q13315 UNIPROT PPM1G protein O15355 UNIPROT up-regulates activity phosphorylation Ser183 GTGEEPGsQGLNGEA -1 26324325 t ATM indeed mediated PPM1G phosphorylation at S183, and mutation of this residue (S183A) abrogated detection with the phospho-specific antibody SIGNOR-255591 0.308 1-[4-Amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-2-fluoroethanone chemical CID:644243 PUBCHEM RPS6KA2 protein Q15349 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0002135 31505737 t miannu Since p90RSK was activated in the diabetic hearts in mice, we investigated whether FMK (an inhibitor of p90RSK) could protect INS-1 cells (a pancreatic β-cell line) from HG-induced β-cell dysfunction and glucotoxicity. SIGNOR-262231 0.8 WWC1 protein Q8IX03 UNIPROT STK3 protein Q13188 UNIPROT up-regulates activity 9606 BTO:0000007 20159598 f Hippo pathway Gianni These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis. SIGNOR-261953 0.375 PGD protein P52209 UNIPROT D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI up-regulates quantity chemical modification 9606 34775382 t miannu 6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule. SIGNOR-267061 0.8 ELF1 protein P32519 UNIPROT FCER1A protein P12319 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000732 11971001 f Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1|These up-regulating effects of PU.1 and YY1 with GATA-1 were inhibited by overexpression of Elf-1, indicating that Elf-1 serves as a repressor for the alpha-chain gene expression SIGNOR-254287 0.2 SRC protein P12931 UNIPROT FXN protein Q16595 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr118 EDLADKPyTFEDYDV 9606 BTO:0000007 25948553 t lperfetto We found that frataxin can be phosphorylated by Src. Phosphorylation occurs primarily on Y118 and promotes frataxin ubiquitination, a signal for degradation. SIGNOR-275585 0.2 BUB1 protein O43683 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity relocalization 11402067 t lperfetto Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity SIGNOR-252017 0.717 SNRNP200 protein O75643 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270624 0.775 CRHR1 protein P34998 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 22869609 t lperfetto Previous studies have indicated that CRHR could couple to multiple Galpha proteins including Gs, Gi, and Gq/11 and then go on to induce changes in AC activity and activation of PLC-beta3 SIGNOR-268618 0.433 TP53 protein P04637 UNIPROT NR4A3 protein Q92570 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30455429 t miannu We showed that p53 directly bound the promoter of NR4A3 gene and induced its transcription. p53 transactivates the NR4A3 promoter in H1299 cells. SIGNOR-256200 0.267 RNF170 protein Q96K19 UNIPROT ITPR1 protein Q14643 UNIPROT down-regulates activity polyubiquitination 9606 BTO:0000567 21610068 t miannu In summary, here we present evidence that RNF170 is an E3 ligase that mediates IP3 receptor ubiquitination and processing by the UPP and that it is recruited to activated IP3 receptors by the erlin1/2 complex to which it is constitutively bound. SIGNOR-271913 0.442 CSF2 protein P04141 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 10572088 t gcesareni We have determined the nmr structure of a ligand-binding domain of the granulocyte colony-stimulating factor (g-csf) receptor comparisons between the spectra of the 15n-labelled domain with and without g-csf indicate that the major ligand-recognition site is on the fg loop just upstream of the wsxws sequence. SIGNOR-72458 0.852 OTUD5 protein Q96G74 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates activity deubiquitination 9606 BTO:0000007 17991829 t miannu TRAF3 is an E3 ubiquitin ligase that preferentially assembled lysine-63-linked polyubiquitin chains. DUBA selectively cleaved the lysine-63-linked polyubiquitin chains on TRAF3, resulting in its dissociation from the downstream signaling complex containing TANK-binding kinase 1. SIGNOR-265873 0.766 FCAR protein P24071 UNIPROT Cytokine_production phenotype SIGNOR-PH166 SIGNOR up-regulates 9606 BTO:0000130;BTO:0000801;BTO:0000876;BTO:0000399 30766540 f lperfetto IgA-mediated immune effector responses such as phagocytosis, antibody-dependent cell-mediated cytotoxicity, respiratory burst and cytokine release are mediated through FcalphaRI (CD89), an IgA-specific receptor that is expressed on monocytes, eosinophils, neutrophils and macrophages SIGNOR-264860 0.7 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT down-regulates phosphorylation Thr179 FAKTFVGtPYYMSPE 9606 17197699 t gcesareni Enzymatic activity, inhibited; SIGNOR-151771 0.2 phosphatidylglycerol(1-) smallmolecule CHEBI:60523 ChEBI CRLS1 protein Q9UJA2 UNIPROT up-regulates activity chemical activation 10090 16678169 t lperfetto The mitochondrial phospholipid cardiolipin is synthesized from cytidinediphosphate-diacylglycerol and phosphatidylglycerol, a process catalyzed by the enzyme cardiolipin synthase. SIGNOR-267029 0.8 ARIH1 protein Q9Y4X5 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002181 33879767 t miannu We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation. SIGNOR-277553 0.2 PIN4 protein Q9Y237 UNIPROT rRNA_transcription phenotype SIGNOR-PH145 SIGNOR up-regulates 9606 BTO:0000567 12860119 f lperfetto Par14 is a pre-rRNA processing factor involved in mammalian ribosome biogenesis, Par14 deficiency slowed cell growth (Fig. 3A) and reduced the production of 18 and 28 S rRNAs  SIGNOR-265755 0.7 TP53 protein P04637 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates 9606 15073170 f gcesareni Rather, p53 expression stimulates the serine/threonine kinase ribosomal s6 kinase 1 (rsk1), which in turn phosphorylates the p65 subunit of nf-kb. SIGNOR-252816 0.365 PKA proteinfamily SIGNOR-PF17 SIGNOR HDAC4 protein P56524 UNIPROT up-regulates activity phosphorylation -1 30661366 t miannu  In vitro kinase assays have established that Ser584 and Ser265/266 are phosphorylated by protein kinase A (PKA). Overexpression of site-specific HDAC4 mutants (S584A, S265/266A) in HEK 293T cells, followed by HDAC activity assays, revealed the mutants to be less active than the wild-type protein. SIGNOR-277424 0.2 NME2 protein P22392 UNIPROT KCNN4 protein O15554 UNIPROT up-regulates phosphorylation His358 FRQVRLKhRKLREQV 9606 17157250 t lperfetto Ndpk-b directly binds and activates kca3.1 by phosphorylating histidine 358 in the carboxyl terminus of kca3.1 SIGNOR-151130 0.43 PRKCQ protein Q04759 UNIPROT PKCtheta/Nfix complex SIGNOR-C121 SIGNOR form complex binding 10090 BTO:0000165 20178747 t llicata In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A. SIGNOR-238019 0.2 PTEN protein P60484 UNIPROT SP1 protein P08047 UNIPROT down-regulates activity dephosphorylation 9606 21603612 t miannu Moreover, PTEN downregulates p75NTR expression by decreasing DNA-binding activity of Sp1 .|PTEN dephosphorylates the Sp1 transcription factor , the phosphorylation status of which directly impacts its ability to bind to some DNA promoter regions , . SIGNOR-277119 0.431 STAT5A protein P42229 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 18270368 t We demonstrate that the signal transducer and activator of transcription 5 (STAT5)-signaling cytokines, IL-2, IL-15 and to a lesser extent IL-7, induce FOXP3 up-regulation in vitro in activated human Teff cell SIGNOR-254301 0.494 TWIST2 protein Q8WVJ9 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002590 17487558 f miannu Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells SIGNOR-255513 0.282 BCKDK protein O14874 UNIPROT BCKDHA protein P12694 UNIPROT down-regulates phosphorylation Ser337 TYRIGHHsTSDDSSA 9606 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000671 3947057 t gcesareni Phosphorylation sites and inactivation of branched-chain alpha-ketoacid dehydrogenase isolated from rat heart, bovine kidney, and rabbit liver, kidney, heart, brain, and skeletal muscle. SIGNOR-25084 0.593 AURKAIP1 protein Q9NWT8 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261461 0.647 MAPK12 protein P53778 UNIPROT SH3BP5 protein O60239 UNIPROT unknown phosphorylation Ser351 PGSLDLPsPVSLSEF -1 15158451 t miannu Activated SAPK3 phosphorylates the mitochondrial protein Sab. we have identified serine 321 as the major site of phosphorylation by both SAPK3 and JNK2. SAPK3 but not JNK2 also phosphorylates serine 391 SIGNOR-250140 0.453 PPP2CA protein P67775 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates activity dephosphorylation Thr117 DGCTWKGtLKEYESC 10090 17188031 t We show that the Thr117 residue in TRAF2 is phosphorylated following TNFalpha stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity. SIGNOR-248640 0.2 MARK2 protein Q7KZI7 UNIPROT PARD3 protein Q8TEW0 UNIPROT up-regulates phosphorylation Ser873 VDDQKAGsPSRDVGP 9606 22883624 t gcesareni Gab1 brings par1 and par3 into a transient complex, stimulating par3 phosphorylation by par1 SIGNOR-198742 0.507 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SIRT2 protein Q8IXJ6 UNIPROT down-regulates phosphorylation Ser368 PNPSTSAsPKKSPPP 9606 BTO:0000938 18332217 t lperfetto We define ser-331 as the site phosphorylated by cyclin e-cdk2, cyclin a-cdk2, and p35-cdk5 both in vitro and in cells. Importantly, phosphorylation at ser-331 inhibits the catalytic activity of sirt2. SIGNOR-216725 0.404 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation 9606 21798082 t lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the FoxO family, and stimulates protein synthesis via the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3b (GSK3B). SIGNOR-175285 0.866 TNFRSF17 protein Q02223 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates 9606 10903733 f miannu Overexpression of bcma activates jnk SIGNOR-79492 0.2 iodide smallmolecule CHEBI:16382 ChEBI diiodine smallmolecule CHEBI:17606 ChEBI up-regulates quantity precursor of 9606 23349248 t miannu After transport through the apical membrane, I‚àí is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO). SIGNOR-268119 0.8 CASP1 protein P29466 UNIPROT NLRC4 inflammasome complex SIGNOR-C223 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256402 0.703 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000586 16293724 t lperfetto This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. SIGNOR-227885 0.891 ALDH9A1 protein P49189 UNIPROT 4-(trimethylammonio)butanoate smallmolecule CHEBI:16244 ChEBI up-regulates quantity chemical modification 9606 11802770 t miannu Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). SIGNOR-269693 0.8 SRC protein P12931 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation Tyr88 PQSSSPVyGSSAKTS 9606 BTO:0000182 27447856 t lperfetto Here, we demonstrate that Src kinase directly phosphorylates Y88 paxillin|In this study, we also show how pY88 paxillin transduces a signal to activate Akt SIGNOR-263977 0.801 BMPR1B protein O00238 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR up-regulates phosphorylation 9606 9335504 t inferred from 70% of family members llicata The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. SIGNOR-269846 0.697 GRPEL1 protein Q9HAV7 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 t lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. SIGNOR-267691 0.594 SETD5 protein Q9C0A6 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 32299058 f The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression SIGNOR-268627 0.7 GSK3B protein P49841 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates quantity by destabilization phosphorylation Thr266 ARHLQENtQSHMRML 9606 BTO:0002181 30806153 t miannu TRAF6 was phosphorylated at Thr266 by GSK3B in most clinical CRC, which triggered K48-linked polyubiquitination and degradation of TRAF6 and thereby attenuated its inhibitory activity towards the autophagy-dependent CTNNB1 signaling. SIGNOR-277438 0.491 SHC1 protein P29353 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 BTO:0000782 8995379 t gcesareni T cell activation effects an increase in grap association with p36/38, shc, sos, and dynamin. SIGNOR-45528 0.52 ZM447439 chemical CHEBI:91376 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207920 0.8 PPAT protein Q06203 UNIPROT Purine biosynthesis phenotype SIGNOR-PH186 SIGNOR up-regulates activity 9606 28029518 f The first reaction in the de novo purine biosynthetic pathway is the conversion of PRPP to 5-phosphoribosylamine (PRA) by PRPP amidotransferase (PPAT) and is presumed to be rate-limiting. SIGNOR-267188 0.7 oxybutynin chemical CHEBI:7856 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 22243489 t Luana  Compared to the reference compound oxybutynin, an antagonist used for the treatment of OAB,(5) the newly synthesized 1,4-dioxane derivatives exhibit a higher potency. SIGNOR-258328 0.8 L-homocysteine zwitterion smallmolecule CHEBI:58199 ChEBI L-cystathionine dizwitterion smallmolecule CHEBI:58161 ChEBI up-regulates quantity precursor of 9606 23981774 t lperfetto Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. SIGNOR-275826 0.8 MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 MCM6 protein Q14566 UNIPROT MCM complex SIGNOR-C268 SIGNOR form complex binding 9606 19946136 t The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. SIGNOR-261676 0.771 SNAI1 protein O95863 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0000567 29305973 f miannu Our findings show that Snai1 mediates repression of PXDN and consolidate a role for this ECM-modifier during EMT. SIGNOR-265252 0.7 VHL protein P40337 UNIPROT SPARC protein P09486 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000037 15824735 f miannu three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL. SIGNOR-255603 0.2 NUP62 protein P37198 UNIPROT p62_complex complex SIGNOR-C259 SIGNOR form complex binding 10116 BTO:0000154 2050741 t Simone Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function. SIGNOR-261258 0.938 CD74 protein P04233 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates binding 9606 BTO:0000007;BTO:0000876 19665027 t miannu Cd74 forms functional complexes with cxcr4 that mediate mif-specific signaling. SIGNOR-187461 0.546 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20643654 t lperfetto Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr373/376, and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr9 and then Tyr373/376 SIGNOR-166714 0.347 RORA protein P35398 UNIPROT ITPR1 protein Q14643 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001011 19381306 t miannu RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice. SIGNOR-266847 0.244 S1PR1 protein P21453 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256713 0.483 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LIMA1 protein Q9UHB6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser604 FQSTSVKsPKTVSPP 9606 BTO:0001033 23188829 t miannu Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover. SIGNOR-263063 0.2 Caspase 3 complex complex SIGNOR-C221 SIGNOR BRCA1 protein P38398 UNIPROT down-regulates quantity by destabilization cleavage Asp1155 ETPDDLLdDGEIKED 9606 12149654 t miannu We demonstrate the cleavage and the consequential downregulation of full-length BRCA1 by caspase-3 during UV-induced apoptosis. Finally, mutation of a caspase-3 specific cleavage site (D/A1154) rendered BRCA1 non-cleavable. SIGNOR-256432 0.485 PIM1 protein P11309 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 31575057 t gcesareni Pim-1, PKC, and Akt1 kinases phosphorylate Thr-145 and Ser-146 sites on p21 protein. Phosphorylation at Thr-145 promotes cytoplasmic translocation and stability of p21. Ser-146 phosphorylation mediated by Akt1 enhances p21 stabilization and promotes cell survival. SIGNOR-262961 0.493 USP6 protein P35125 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 20418905 f miannu These data confirm that tre17 activates nfkappab in a usp-dependent manner SIGNOR-164949 0.2 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGC3 protein Q9UN70 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265696 0.2 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11689553 t irozzo To identify this pathway, we analyzed TGF-β-responsive elements in the human c-myc promoter and found that Smad proteins directly bound to an element in the c-myc promoter and suppressed c-myc promoter activity. SIGNOR-256290 0.649 GATOR1 complex SIGNOR-C192 SIGNOR RRAGA protein Q7L523 UNIPROT down-regulates activity gtpase-activating protein -1 23723238 t GATOR1 has GTPase-activating protein (GAP) activity for RagA and RagB, and its components are mutated in human cancer. SIGNOR-253562 0.874 ATM protein Q13315 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Ser112 KRAGGEEsQFEMDI 9606 11146653 t lperfetto Here we report that atm... phosphorylates 4e-bp1 at ser 111cells lacking atm kinase activity exhibit a significant decrease in the insulin-induced dissociation of 4e-bp1 from eif-4e. SIGNOR-85619 0.527 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 16046550 t The effect has been demonstrated using Q01196-8 gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-138932 0.2 CDK2 protein P24941 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates phosphorylation Thr847 FRYIPPNtPENFWEV 9606 19202191 t llicata Collectively, these findings thereby provided strong support for ctip thr-847 indeed being a cdk target. it is established that both cdk-dependent and checkpoint-dependent phosphorylations are required for activation of sae2/ctip in vivo SIGNOR-183840 0.602 SIK1 protein P57059 UNIPROT CRTC1 protein Q6UUV9 UNIPROT down-regulates phosphorylation Ser167 MTPTQPEsFSSGSQD 9606 16817901 t miannu These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities. SIGNOR-147669 0.507 RHOA protein P61586 UNIPROT EZR protein P15311 UNIPROT up-regulates activity phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0000132 35267019 t miannu Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. SIGNOR-268429 0.751 MAPK3 protein P27361 UNIPROT SULT4A1 protein Q9BR01 UNIPROT down-regulates phosphorylation Thr11 SEAETPStPGEFESK 9606 BTO:0000938 BTO:0000142 20920535 t gcesareni The phosphorylation of sult4a1 allows interaction with pin1, which then promotes degradation of the sulfotransferase. SIGNOR-168248 0.2 SLC20A2 protein Q08357 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI up-regulates quantity relocalization 9606 11009570 t lperfetto SIGNOR-270580 0.8 KIT protein P10721 UNIPROT SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates phosphorylation 9606 15526160 t apalma Binding of SCF to c-Kit leads to a rapid increase in SFK kinase activity SIGNOR-254995 0.577 IL2 protein P60568 UNIPROT IL2RA protein P01589 UNIPROT up-regulates binding 9606 16477002 t miannu Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c). SIGNOR-144537 0.925 PPP3CC protein P48454 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 t In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. SIGNOR-248524 0.382 entinostat chemical CHEBI:132082 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257904 0.8 DIO proteinfamily SIGNOR-PF83 SIGNOR 3,3',5'-triiodo-L-thyronine smallmolecule CHEBI:11684 ChEBI up-regulates quantity small molecule catalysis 20978344 t inferred from family member The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4) SIGNOR-270305 0.8 CRY1 protein Q16526 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267975 0.938 MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation 9606 SIGNOR-C3 19690328 t lperfetto The complementary inhibitory mechanism in which mtorc1 phosphorylates the autophagy regulatory complex containing unc-51-like kinase 1 (ulk1), the mammalian atg13 protein, and focal adhesion kinase interacting protein of 200 kd (fip200) has also been elucidated. SIGNOR-187611 0.844 MTCH1 protein Q9NZJ7 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 12377771 f SARA PSAP is an important regulator of apoptosis SIGNOR-260994 0.7 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR TJP2 protein Q9UDY2 UNIPROT up-regulates 9606 21529719 f milica Another junction protein, the tight junction protein ZO-2, binds to YAP/TAZ, facilitating their nuclear translocation. SIGNOR-230703 0.7 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192868 0.8 KIF5A protein Q12840 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 31753031 t miannu Postsynaptic density protein 95 (PSD-95) is transported by KIF5 to dendritic regions SIGNOR-264065 0.318 AL/b2 integrin complex SIGNOR-C169 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269018 0.7 CCP110 protein O43303 UNIPROT Centrosome_separation phenotype SIGNOR-PH177 SIGNOR down-regulates 9606 12361598 f miannu Reduction in CP110 Protein Levels or Loss of CP110 Phosphorylation Promotes Centrosome Separation. SIGNOR-265964 0.7 AT9283 chemical CID:11696609 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190014 0.8 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Thr301 PPGEDSDtDVDDDSR 9606 18678890 t gcesareni The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites. SIGNOR-179883 0.353 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCI protein P41743 UNIPROT up-regulates activity binding 9606 14967450 t PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. SIGNOR-242581 0.8 FGF9 protein P31371 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15780951 f FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1 gcesareni Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts SIGNOR-134797 0.312 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 14744793 t lperfetto Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1.|this activation promotes the phosphorylation of Sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased Sp1 binding and enhanced p21(waf1/cip1) transcription. SIGNOR-249480 0.639 MAML1 protein Q92585 UNIPROT CCNC protein P24863 UNIPROT up-regulates relocalization 9606 15546612 t gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. SIGNOR-130709 0.423 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT up-regulates activity phosphorylation Ser27 SFGFTRTsARRRLAD 21880142 t miannu Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2. PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites. SIGNOR-266299 0.312 STUB1 protein Q9UNE7 UNIPROT IRS4 protein O14654 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002181 30026872 t miannu IRS4 was phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP). SIGNOR-277616 0.2 chlorphenamine chemical CHEBI:52010 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 t Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells SIGNOR-257786 0.8 STAT3 protein P40763 UNIPROT KRT17 protein Q04695 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 21796151 f miannu IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms. SIGNOR-255234 0.262 CDK7 protein P50613 UNIPROT PCGF6 protein Q9BYE7 UNIPROT unknown phosphorylation Ser30 LPPPPPVsPPALTPA -1 12167161 t llicata In addition, we find that serine 32 of MBLR is specifically phosphorylated during mitosis, most likely by CDK7, a component of the basal transcriptional machinery. | These results indicate that, at least in vitro, MBLR is a substrate for CDK7 phosphorylation. SIGNOR-250769 0.309 KLF6 protein Q99612 UNIPROT ATF3 protein P18847 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001321 18755691 t Luana KLF6 binds directly to and activates the ATF3 promoter. SIGNOR-266051 0.402 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser422 LSTPVVLsPGPQKP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-34665 0.584 PRKCQ protein Q04759 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser1101 GCRRRHSsETFSSTP 10090 15364919 t Manara Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). SIGNOR-260906 0.553 NFE2L2 protein Q16236 UNIPROT GCLC protein P48506 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24024136 t irozzo In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs). SIGNOR-256277 0.483 NEDD4L protein Q96PU5 UNIPROT CLCN5 protein P51795 UNIPROT down-regulates quantity by destabilization ubiquitination 9267 BTO:0003069 15489223 t miannu The presence of albumin triggers the formation of an endocytic complex that includes ClC-5. (iii) Nedd4-2 is recruited to this complex and ubiquitinates ClC-5. This ubiquitination by Nedd4-2 shunts ClC-5 into the albumin uptake/degradative pathway. SIGNOR-272665 0.296 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Ser2155 GFAEAIHsPQVAGVP 9606 18794356 t miannu Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore. SIGNOR-181014 0.382 NLK protein Q9UBE8 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 20118921 t gcesareni Nlk-phosphorylated notch1icd is impaired in its ability to form a transcriptionally_ active_ ternary_ complex. SIGNOR-163697 0.39 SFRP1 protein Q8N474 UNIPROT WNT1 protein P04628 UNIPROT down-regulates binding 9606 10523516 t gcesareni Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling. SIGNOR-71423 0.776 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation Ser225 VGSKTPAsPVVVQQG 9606 14532121 t gcesareni Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation. SIGNOR-118542 0.2 SLC27A6 protein Q9Y2P4 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264467 0.7 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser21 KSGNKPPsKTCLKEE 9606 7993631 t gcesareni We found that pkc specifically eliminates rapid inactivation of a cloned human a-type k+ channel (hkv3.4), converting this channel from a rapidly inactivating a type to a noninactivating delayed rectifier type. SIGNOR-35626 0.2 CBL protein P22681 UNIPROT FLT3 protein P36888 UNIPROT down-regulates activity binding 10090 BTO:0001516 19276253 t Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo. SIGNOR-255739 0.447 mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-256063 0.7 prostaglandin E2 smallmolecule CHEBI:15551 ChEBI PTGER3 protein P43115 UNIPROT up-regulates chemical activation 9606 15299086 t gcesareni Pge2 is the ligand for four ep receptor subtypes termed ep1 to ep4. SIGNOR-127738 0.8 CDK2 protein P24941 UNIPROT DLG1 protein Q12959 UNIPROT up-regulates phosphorylation Ser158 FVSHSHIsPIKPTEA 9606 19066288 t llicata We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor. phosphorylation on ser158 and ser442 enhances nuclear expression of dlg1 SIGNOR-182761 0.286 MDH2 protein P40926 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI down-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-268100 0.8 NTN1 protein O95631 UNIPROT NEO1 protein Q92859 UNIPROT up-regulates activity binding 9606 BTO:0001484 28245592 t miannu Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins. SIGNOR-268169 0.818 PRKCA protein P17252 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 10101032 t Translocation from Endosome to Lysosome fspada In this study, we demonstrated that ser396 and ser398 are phosphorylated by pkc and, that phosphorylation of ser398 is particularly involved in pmainduced desensitization of the h1r. SIGNOR-66015 0.2 MAPK3 protein P27361 UNIPROT GRB10 protein Q13322 UNIPROT unknown phosphorylation Ser418 QQRKALLsPFSTPVR -1 15952796 t lperfetto We identified Ser150, Ser418, and Ser476 of human Grb10 as MAPK-mediated in vitro phosphorylation sites. SIGNOR-249406 0.303 PRKCA protein P17252 UNIPROT NR1H4 protein Q96RI1 UNIPROT up-regulates phosphorylation Ser164 CKGFFRRsITKNAVY 9606 18755856 t llicata Phosphorylation of farnesoid x receptor by protein kinase c promotes its transcriptional activity. pkcalpha phosphorylates in vitro fxr in its dna-binding domain on s135 and s154. SIGNOR-180541 0.331 DOCK8 protein Q8NF50 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 28028151 t lperfetto Recently, DOCK8 was identified as a guanine-nucleotide exchange factor (GEF) for Cdc42 activation and has been associated with human mental retardation.  SIGNOR-268412 0.757 POMC protein P01189 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates activity 9606 BTO:0000848 16274845 f miannu Alpha-MSH is an anti-inflammatory peptide which signals by binding to the melanocortin-1 receptor (MC1R) and elevating cyclic AMP in several different cells and tissues. The carboxyl terminal peptides of alpha-MSH (KPV/GKPV) are the smallest minimal sequences that prevent inflammation, but it is not known if they operate via MC1R or cyclic AMP. Immobilized alpha-melanocyte stimulating hormone 10-13 (GKPV) inhibits tumor necrosis factor-alpha stimulated NF-kappaB activity. SIGNOR-252371 0.259 MLH1/PMS2 complex SIGNOR-C59 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 10090 29175432 f MLH1 and PMS2 proteins form the MutLα heterodimer, which plays a major role in DNA mismatch repair (MMR) in humans SIGNOR-257600 0.7 lurasidone chemical CHEBI:70735 ChEBI ADRA2C protein P18825 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 20404009 t Luana Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 2C receptors. SIGNOR-257837 0.8 sunitinib chemical CHEBI:38940 ChEBI PDGFRA protein P16234 UNIPROT down-regulates chemical inhibition 9606 21423276 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-172923 0.8 POLR2L protein P62875 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 9606 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266151 0.904 folic acid smallmolecule CHEBI:27470 ChEBI dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI up-regulates quantity precursor of 9606 BTO:0000575 19706381 t lperfetto However, since the synthesis of folic acid (FA, pteroylglutamic acid) as a provitamin in 1945, DHFR has taken on another role: reduction of FA to 7,8-DHF (Fig. 1) SIGNOR-268263 0.8 SKA1 protein Q96BD8 UNIPROT SKA complex complex SIGNOR-C364 SIGNOR form complex binding -1 22483620 t lperfetto We show that the structure of the Ska core complex is a W-shaped dimer of coiled coils, formed by intertwined interactions between Ska1, Ska2, and Ska3. SIGNOR-265197 0.908 PJA1 protein Q8NG27 UNIPROT SPTBN1 protein Q01082 UNIPROT down-regulates ubiquitination 9606 16247473 t gcesareni The present study indicates that praja, a ring finger e3 ubiquitin ligase, interacts with elf and ubiquitinates it. SIGNOR-141216 0.413 ESR1 protein P03372 UNIPROT UGT1A4 protein P22310 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 19546240 f miannu our data indicate that up-regulation of UGT1A4 expression by E(2) is mediated by both ER alpha and Sp1 and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy. SIGNOR-254075 0.304 CHEK2 protein O96017 UNIPROT TTK protein P33981 UNIPROT unknown phosphorylation Thr288 SPDCDVKtDDSVVPC 9606 19151762 t llicata Phosphorylation at ttk/hmps1 thr288 is enhanced by chk2 in vitro and in vivo after ir SIGNOR-183470 0.296 PTTG1 protein O95997 UNIPROT ESPL1 protein Q14674 UNIPROT down-regulates activity binding 9606 15737063 t lperfetto Prior to anaphase, separase is kept inactive by its inhibitor securin SIGNOR-275538 0.944 NatA complex SIGNOR-C415 SIGNOR H2AX protein P16104 UNIPROT down-regulates activity acetylation 9606 BTO:0001109 21351257 t miannu The human protein N(α)-terminal acetyltransferase A complex (hNatA), composed of the catalytic hNaa10p (hArd1) and auxiliary hNaa15p (hNat1/NATH/Tubedown) subunits, was reported to be important for cell survival and growth of various types of cancer.  lack of acetylation by hNatA activated H2A.X and Chk2 in both HCT116 cell lines independent of TP53 status (Fig. 6). SIGNOR-267227 0.2 paroxetine chemical CHEBI:7936 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 18487050 t Luana For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428.  SIGNOR-257795 0.8 F11 protein P03951 UNIPROT HGF protein P14210 UNIPROT up-regulates activity cleavage Arg494 CAKTKQLrVVNGIPT -1 12372819 t miannu the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain. SIGNOR-256514 0.318 PIM proteinfamily SIGNOR-PF34 SIGNOR MARK3 protein P27448 UNIPROT down-regulates phosphorylation Ser96 KTQLNPTsLQKLFRE 9606 15319445 t gcesareni Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1. SIGNOR-259432 0.2 CDK3 protein Q00526 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser118 LHPPPQLsPFLQPHG 26202215 t lperfetto CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3 SIGNOR-273187 0.262 U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 11739736 f miannu The essential splicing factor U2AF (U2 auxiliary factor) is a heterodimer composed of 65-kDa (U2AF(65)) and 35-kDa (U2AF(35)) subunits. U2AF(35) has multiple functions in pre-mRNA splicing. First, U2AF(35) has been shown to function by directly interacting with the AG at the 3' splice site. Second, U2AF(35) is thought to play a role in the recruitment of U2AF(65) by serine-arginine-rich (SR) proteins in enhancer-dependent splicing. SIGNOR-263945 0.7 TLX1 protein P31314 UNIPROT PPP2CB protein P62714 UNIPROT down-regulates activity binding 9606 BTO:0000661 15897879 t 2 miannu HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade. SIGNOR-240722 0.305 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK -1 10734133 t miannu Interestingly, all PTPs that were tested could completely dephosphorylate the receptor, given sufficient time, including a negative control (PTP-PEST) that failed to bind IRK as a trapping mutant. SIGNOR-75894 0.385 SIRT7 protein Q9NRC8 UNIPROT SAR1A protein Q9NR31 UNIPROT up-regulates activity deacetylation 9606 BTO:0002181 28790157 t SARA SIRT7 interacts with the helicase DDX21. Deacetylation by SIRT7 is required for DDX21 activity and R-loop unwinding SIGNOR-260978 0.2 PEX5 protein P50542 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity binding 9606 BTO:0000007 ubiquitination:Lys209 VAKVDDPkLANSEFL 26344566 t Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy.  SIGNOR-262793 0.38 IHH protein Q14623 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity binding 9606 BTO:0001253 9811851 t lperfetto Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH. SIGNOR-61311 0.832 TDP2 protein O95551 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0002181 21980489 t miannu TTRAP associates with TRAF6.The TAK1-TTRAP-TRAF6 complex is stabilized by ubiquitylation and recruited to TβRI. SIGNOR-277189 0.386 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one chemical CHEBI:94732 ChEBI MAPK9 protein P45984 UNIPROT down-regulates chemical inhibition 9606 18922779 t BI-78D3 is substrate competitive. gcesareni Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell. SIGNOR-181650 0.8 aliskiren fumarate chemical CHEBI:53777 ChEBI REN protein P00797 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189483 0.8 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR DKK1 protein O94907 UNIPROT up-regulates activity 15229249 f Exposure of the cultures to beta-amyloid peptide (βAP) induced the expression of the secreted glycoprotein Dickkopf-1 (DKK1).  SIGNOR-255482 0.7 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Thr387 HKKLMFKtEGPDSD 9606 BTO:0001321 15659650 t lperfetto Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-217861 0.771 PRKACA protein P17612 UNIPROT PHKA1 protein P46020 UNIPROT up-regulates activity phosphorylation Ser1018 QVEFRRLsISAESQS 10487978 t miannu Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. Ser1018 within this multiphosphorylation domain is phosphorylated by PKA and is a major site of regulatory phosphorylation in vivo SIGNOR-250026 0.419 MAPK3 protein P27361 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser93 ALQRQPPsPKQLEEE -1 16226275 t lperfetto First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.| SIGNOR-249475 0.68 MRPL23 protein Q16540 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262370 0.2 CDK1 protein P06493 UNIPROT PBK protein Q96KB5 UNIPROT unknown phosphorylation Thr9 EGISNFKtPSKLSEK 9606 SIGNOR-C17 15541388 t llicata Topk-thr-9 was phosphorylated by cdk1/cyclin b and topk significantly associates with mitotic spindles. SIGNOR-130439 0.567 GATA1 protein P15976 UNIPROT GP1BA protein P07359 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17725493 f miannu We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. SIGNOR-254191 0.527 CASP3 protein P42574 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261743 0.414 PIM1 protein P11309 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 17643117 t gcesareni Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation. SIGNOR-265366 0.2 ATF4 protein P18848 UNIPROT SIGMAR1 protein Q99720 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22079628 f miannu we have demonstrated that Sig-1Rs were transcriptionally upregulated by ATF4 in ER stress. SIGNOR-253750 0.391 ASPSCR1 protein Q9BZE9 UNIPROT VCPKMT protein Q9H867 UNIPROT up-regulates binding 9606 23349634 t gcesareni In the case of vcp, methylation by mettl21d was stimulated by the addition of the ubx cofactor aspscr1, which we show directly interacts with the methyltransferase. SIGNOR-200572 0.349 TM9SF4 protein Q92544 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 29125601 f miannu In the present study, we report a novel autophagy-related protein TM9SF4, which plays a functional role in the induction phase of autophagic process. Overexpression of TM9SF4 promoted autophagic flux in HEK293 cells. SIGNOR-266704 0.7 TET1 protein Q8NFU7 UNIPROT ZNF382 protein Q96SR6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27708339 t irozzo Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9. SIGNOR-259095 0.2 ULK1 protein O75385 UNIPROT GABARAP protein O95166 UNIPROT up-regulates binding 9606 BTO:0000567;BTO:0000938 BTO:0000142 11146101 t gcesareni N-terminal proline/serine rich (ps) domain of ulk1 (amino acid 287-416) is required for ulk1-gate-16 and ulk1-gabarap protein interactions SIGNOR-85614 0.657 AMPK complex SIGNOR-C15 SIGNOR MCU protein Q8NE86 UNIPROT up-regulates activity phosphorylation Ser57 TVHQRIAsWQNLGAV -1 30858581 t lperfetto Cellular ATP levels drop during early mitosis, and the mitochondrial Ca2+ transients boost mitochondrial respiration to restore energy homeostasis. This is achieved through mitosis-specific MCU phosphorylation and activation by the mitochondrial translocation of energy sensor AMP-activated protein kinase (AMPK). |In vitro kinase assays showed that AMPK immunoprecipitated from cells as well as recombinant AMPK phosphorylated MCU at Ser57 SIGNOR-275548 0.2 ANKS1B protein Q7Z6G8 UNIPROT Postsynaptic density assembly phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 26356309 f miannu AIDA-1 is highly enriched in postsynaptic density (PSD) fractions and is considered a major component of the PSD complex. SIGNOR-264226 0.7 ATP smallmolecule CHEBI:15422 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5√¢‚Ǩ¬≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-267837 0.8 4-{[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]amino}benzoic acid chemical CHEBI:64210 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 t Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  SIGNOR-258140 0.8 BAP1 protein Q92560 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 26416890 f lperfetto The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and is Disrupted in Cancer. SIGNOR-241660 0.7 DNMT3B protein Q9UBC3 UNIPROT BAG3 protein O95817 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 18413740 f lperfetto In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+) SIGNOR-254111 0.2 RUNX3 protein Q13761 UNIPROT ING1 protein Q9UK53 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002384 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255099 0.25 PIM2 protein Q9P1W9 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 16403219 t miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. SIGNOR-250394 0.4 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser389 LSPIAPRsPAKLSFQ 10090 BTO:0000944 7889942 t lperfetto We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erki phosphorylates five c-terminal sites in elk-i (s324,t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-235471 0.545 acetyl-CoA smallmolecule CHEBI:15351 ChEBI malonyl-CoA smallmolecule CHEBI:15531 ChEBI up-regulates quantity precursor of 9606 20952656 t miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA SIGNOR-267107 0.8 ABL1 protein P00519 UNIPROT CRK protein P46108 UNIPROT down-regulates activity phosphorylation Tyr221 GGPEPGPyAQPSVNT 9606 21779437 t lperfetto Negative regulation of crk by abl is essential for the antitumorigenic effects of ephrinb2,similar pathways may operate for crkl SIGNOR-175135 0.754 PFKFB4 protein Q16877 UNIPROT beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI up-regulates quantity chemical modification 9606 15170386 t Fru-2,6-P2 (fructose 2,6-bisphosphate) is a signal molecule that controls glycolysis. Since its discovery more than 20 years ago, inroads have been made towards the understanding of the structure‚Äì function relationships in PFK-2 (6-phosphofructo-2-kinase)/ FBPase-2 (fructose-2,6-bisphosphatase), the homodimeric bifunctional enzyme that catalyses the synthesis and degradation of Fru-2,6-P2 SIGNOR-267264 0.8 PRKCD protein Q05655 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 10636859 t gcesareni Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation. SIGNOR-73967 0.2 PRKCA protein P17252 UNIPROT ITPKA protein P23677 UNIPROT down-regulates activity -1 9374536 t lperfetto In contrast, phosphorylation of the A isoform with PKC caused a significant decrease in activity whether assayed in the presence or absence of calcium/calmodulin (to _25% of the unphosphorylated enzyme activity). SIGNOR-248991 0.378 AHCYL1 protein O43865 UNIPROT SLC4A4 protein Q9Y6R1 UNIPROT up-regulates activity binding 9606 BTO:0000007 21317537 t miannu IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities. SIGNOR-263135 0.693 RB1 protein P06400 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 21524151 f lperfetto Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time. SIGNOR-245486 0.7 RPS6KA1 protein Q15418 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0001103 21798082 t lperfetto Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization. SIGNOR-175687 0.365 ROCK1 protein Q13464 UNIPROT Satellite_cells_self-renewal phenotype SIGNOR-PH100 SIGNOR up-regulates transcriptional regulation BTO:0001103 23290138 f apalma FN in the satellite cell niche is required for the maintenance of the overall satellite cell pool during muscle regeneration. Moreover, FN is necessary to potentiate Wnt7a signaling through the Fzd7/Scd4 receptor complex, which controls the regulation of satellite stem cell numbers SIGNOR-255850 0.7 zileuton chemical CHEBI:10112 ChEBI ALOX5 protein P09917 UNIPROT down-regulates activity chemical inhibition 10116 1848634 t miannu 5-lipoxygenase inhibitory activity of zileuton. SIGNOR-258363 0.8 BMS-754807 chemical CHEBI:88339 ChEBI IGF1R protein P08069 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001802 19996272 t lperfetto BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR SIGNOR-262027 0.8 MYD88 protein Q99836 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity binding 10090 BTO:0000906 16306937 t Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6. SIGNOR-256079 0.716 PLCG1 protein P19174 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates quantity chemical modification 9606 23140367 t miannu Phospholipase C (PLC) converts phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). SIGNOR-251558 0.8 SLC16A3 protein O15427 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 26384349 f lperfetto Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival. SIGNOR-242468 0.7 CNTRL protein Q7Z7A1 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR down-regulates 9606 18694559 f miannu CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110. CP110 in this complex is to keep CEP290 inactive in growing cells until cells are ready to undergo ciliogenesis as they transit into the quiescent state SIGNOR-252150 0.7 FUS protein P35637 UNIPROT MATR3 protein P43243 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 27731383 t P35637:p.Pro525Leu (mutation disrupting interaction) Moreover, FUS interacts with another nuclear matrix-associated protein Matrin3, which is muted in a subset of familial ALS cases and reportedly interacts with TDP-43. Interestingly, ectopic ALS-linked FUS mutant sequestered endogenous Matrin3 and SAFB1 in the cytoplasmic aggregates. SIGNOR-262822 0.499 RNF19A protein Q9NV58 UNIPROT CASR protein P41180 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16513638 t miannu Coexpression with dorfin decreased the amount of total CaR protein and increased CaR ubiquitination, whereas a dominant negative fragment of dorfin had opposite effects. dorfin-mediated proteasomal degradation of immature CaR occurs from the endoplasmic reticulum. Because endogenous CaR in Madin-Darby canine kidney cells is also subject to degradation from the endoplasmic reticulum, dorfin-mediated ubiquitination may contribute to a general mechanism for CaR quality control during biosynthesis. SIGNOR-271456 0.39 CSNK1A1 protein P48729 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity. SIGNOR-183661 0.2 MCHR2 protein Q969V1 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257390 0.41 RELA protein Q04206 UNIPROT JUN protein P05412 UNIPROT up-regulates binding 9606 SIGNOR-C13 18174238 t gcesareni Chromatin immunoprecipitation (chip) analysis confirmed the serum-induced recruitment of jund to the promoter in vivo and showed that the presence of jund was dependent on the presence of p65 and p50, indicating a protein-protein-dependent mechanism of jund recruitment SIGNOR-160330 0.708 SHH protein Q15465 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity binding 9606 14556242 t lperfetto In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling.Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other. SIGNOR-118615 0.941 SCN11A protein Q9UI33 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. SIGNOR-253453 0.7 FYN protein P06241 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates phosphorylation Tyr1325 RLLEGNFyGSLFSVP 9606 19834457 t gcesareni The nr2a subunit of the nmda receptor is tyrosine-phosphorylated, with tyr 1325 as its one of the major phosphorylation site. Tyr 1325 phosphorylation site is required for src-induced potentiation of the nmda receptor channel in the striatum. Tyr 1325 was most prominently phosphorylated by fyn in vitro. SIGNOR-188527 0.724 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates binding 9606 14967450 t PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. gcesareni The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. SIGNOR-121956 0.8 gefitinib chemical CHEBI:49668 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192623 0.8 AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 24130457 f lperfetto AP-2 is the core-organizing element in clathrin-mediated endocytosis. During the formation of clathrin-coated vesicles, clathrin and endocytic accessory proteins interact with AP-2 in a temporally and spatially controlled manner SIGNOR-260705 0.7 JAZF1 protein Q86VZ6 UNIPROT NR2C2 protein P49116 UNIPROT down-regulates binding 9606 15302918 t miannu Tip27 interacts specifically with tak1 / tip27 functions as a tak1-selective repressor SIGNOR-127900 0.465 ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 t miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. SIGNOR-265003 0.8 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr730 PNLFVALyDFVASGD 9606 16912036 t Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. SIGNOR-260810 0.2 TRAF6 protein Q9Y4K3 UNIPROT Osteoclast_differentiation phenotype SIGNOR-PH76 SIGNOR up-regulates 9606 17572386 f miannu TRAF6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation. SIGNOR-253046 0.7 HSPG2 protein P98160 UNIPROT PTPRS protein Q13332 UNIPROT up-regulates binding 9606 11865065 t gcesareni We demonstrate here that cptpsigma is a heparin-binding protein and that its basal lamina ligands include the heparan sulfate proteoglycans (hspgs) agrin and collagen xviii. SIGNOR-115246 0.255 RPS6KA1 protein Q15418 UNIPROT CDC34 protein P49427 UNIPROT down-regulates quantity by destabilization phosphorylation Thr162 KGKDREYtDIIRKQV -1 27786305 t miannu RSK1 phosphorylated Thr162 on UBE2R1.RSK1 induced self-ubiquitination and destabilisation of UBE2R1 by phosphorylation. SIGNOR-277330 0.342 neratinib chemical CHEBI:61397 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194628 0.8 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr84 EHSDSEMyVMPAEEN 9606 BTO:0000776 12456653 t llicata The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex. SIGNOR-96048 0.798 IQSEC2 protein Q5JU85 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 27009485 f miannu These data demonstrate that the reduction of BRAG1 results in a reduction of synaptic transmission. Together with the data showing that overexpression of BRAG1 enhances synaptic transmission, these data highlight the role of BRAG1 in the bidirectional regulation of synaptic transmission. SIGNOR-264905 0.7 RPS6KA3 protein P51812 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity 9606 20383198 f lperfetto We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions. SIGNOR-252038 0.2 CRBN protein Q96SW2 UNIPROT IKZF3 protein Q9UKT9 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000725 29496670 t miannu IMiD compounds cause selective ubiquitination and degradation of IKZF1 in CD34+ cells by the CRBN E3 ubiquitin ligase. SIGNOR-272319 0.599 tyrphostin AG 1478 chemical CHEBI:75404 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189377 0.8 EGFR protein P00533 UNIPROT KCNN1 protein Q92952 UNIPROT up-regulates activity phosphorylation Tyr109 KRKRLSDyALIFGMF 9606 BTO:0000007 23496660 t miannu These results demonstrate the novel information that hSKCa1 channels are inhibited by genistein, T25 and AG556 via EGFR tyrosine kinase inhibition, which is related to the phosphorylation of Tyr(109) in the N-terminus.  SIGNOR-276490 0.2 PAX7-FOXO1 fusion protein SIGNOR-FP11 SIGNOR JARID2 protein Q92833 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23435416 t lperfetto JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells| we demonstrated that JARID2 is a direct transcriptional target of the PAX3-FOXO1 fusion protein.| Therefore, JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS SIGNOR-249597 0.2 SLC25A1 protein P53007 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI up-regulates quantity relocalization 9606 29651165 t SLC25A1, a mitochondrial carrier that promotes the flux of citrate/isocitrate across the mitochondria, in exchange for the entry of cytosolic malate SIGNOR-267289 0.8 CTR9 protein Q6PD62 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR form complex binding 9606 BTO:0000567 20178742 t miannu Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A).  SIGNOR-269834 0.94 NFE2 protein Q16621 UNIPROT HBD protein P02042 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000426 16287851 f Regulation of expression miannu NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells. SIGNOR-251843 0.366 MOB1A protein Q9H8S9 UNIPROT LATS1 protein O95835 UNIPROT up-regulates binding 9606 21084559 t Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1 SIGNOR-169752 0.94 CXCR4 protein P61073 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 BTO:0005387 19584257 f lperfetto However, we show that soluble factors secreted by SUM102 breast cancer cells stimulated the expression of MMP-1 and CXCR4 in HMFs. As a result, these stromal cells acquired an invasive and migratory phenotype SIGNOR-252266 0.7 GSK3B protein P49841 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Thr447 NASGSTStPAPSRTA 10653665 t Thr 446 and Ser 450, which are phosphorylated by glycogen synthase kinase-3 (GSK-3). Phosphorylation resulted in a 6-fold increase in V(max) and the conversion of citrate dependence from sigmoidal, displaying negative cooperativity, to hyperbolic. SIGNOR-251219 0.371 PLK1 protein P53350 UNIPROT IKBKB protein O14920 UNIPROT down-regulates phosphorylation Ser750 QTEEEEHsCLEQAS 9606 18957422 t lperfetto Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma SIGNOR-181806 0.349 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193534 0.8 HDAC2 protein Q92769 UNIPROT BHC complex complex SIGNOR-C353 SIGNOR form complex binding 9606 BTO:0000567; BTO:0000007 15325272 t miannu BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells SIGNOR-264499 0.691 NXF1 protein Q9UBU9 UNIPROT RBM15/NXF1 complex SIGNOR-C67 SIGNOR form complex binding 9606 17001072 t miannu Rbm15 binds to nxf1 and the two proteins cooperate in stimulating rte-mediated mrna export and expression. SIGNOR-149880 0.502 MAPK1 protein P28482 UNIPROT PARP1 protein P09874 UNIPROT up-regulates phosphorylation Ser372 VAATPPPsTASAPAA 9606 BTO:0000938 BTO:0000142 16627622 t esanto Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation. SIGNOR-146220 0.533 MIF protein P14174 UNIPROT HBB protein P68871 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16636133 f Regulation of expression miannu MIF inhibits cytodifferentiation and hemoglobin synthesis of MEL cells. SIGNOR-251831 0.2 SWI/SNF complex complex SIGNOR-C92 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates activity binding 9606 20506188 t miannu Our findings indicate that RUNX1 interacts with the human SWI/SNF complex to control hematopoietic-specific gene expression. SIGNOR-261965 0.433 HBB protein P68871 UNIPROT ADAMTS13 protein Q76LX8 UNIPROT down-regulates activity 9606 15367436 f Regulation of binding miannu Incubation of hemoglobin, recombinant and from lysed erythrocytes, with normal plasma revealed an ADAMTS13 inhibitory effect at hemoglobin concentrations of 2 g/L or higher. SIGNOR-251748 0.2 SMAD7 protein O15105 UNIPROT MAP3K1 protein Q13233 UNIPROT down-regulates 9606 10085121 f lperfetto Overexpression of smad7 can inhibit the mekk-1-mediated stimulation of smad2 transcriptional activity SIGNOR-65572 0.268 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 9534 BTO:0000298 10212258 t gcesareni Mutation of Rad51 Tyr315, but not Tyr205, Tyr191, or Tyr54 to phenylalanine abolished Rad51 tyrosine phosphorylation by c-Abl (Fig. 3 b). These results strongly suggest that c-Abl phosphorylates Rad51 Tyr315 in vivo SIGNOR-247594 0.764 RHOA protein P61586 UNIPROT PKN2 protein Q16513 UNIPROT up-regulates activity binding 10090 BTO:0004732 27270401 t no miannu PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. SIGNOR-275466 0.826 TOP2B protein Q02880 UNIPROT SST protein P61278 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24463367 f lperfetto While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development SIGNOR-242305 0.2 EHF protein Q9NZC4 UNIPROT DCDC2 protein Q9UHG0 UNIPROT down-regulates quantity by repression transcriptional regulation 22733135 f Mechanistically, we found that the ETS transcription factor ESE3/EHF, which is expressed in normal prostate and frequently lost in prostate tumors, maintained DCDC2 repressed by binding to a novel identified ETS binding site in the gene promoter. SIGNOR-254279 0.267 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate(5-) smallmolecule CHEBI:57923 ChEBI 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) smallmolecule CHEBI:57795 ChEBI up-regulates quantity precursor of 9606 18429927 t miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns SIGNOR-269806 0.8 PRKCA protein P17252 UNIPROT L1CAM protein P32004 UNIPROT down-regulates activity phosphorylation Thr1172 ARPMKDEtFGEYRSL 9606 BTO:0000304 20335502 t miannu CKII phosphorylates T1172 of the L1 CD and phosphorylation of T1172 is responsible for loss of 2C2 signal. SIGNOR-276283 0.2 BCL3 protein P20749 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 9606 15469820 t gcesareni We show that bcl-3 is a substrate for the protein kinase gsk3 and that gsk3-mediated bcl-3 phosphorylation, which is inhibited by akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with hdac1, -3, and -6 SIGNOR-129801 0.437 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT up-regulates activity binding 9606 12040173 t lperfetto The binding of tnf to tnf-r1 triggers a series of intracellular events that ultimately result in the activation of two major transcription factors, nuclear factor kb (nf-kb) and c-jun. SIGNOR-88216 0.928 RASSF1 protein Q9NS23 UNIPROT STK3 protein Q13188 UNIPROT up-regulates activity binding 9606 22195963 t lperfetto Mutant K-Ras promotes MST2 activation in two ways (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex (Matallanas et al., 2008) and by forming an activating K-Ras-RASSF1A€“MST2 complex, as reported here. SIGNOR-249588 0.688 PHLPP1 protein O60346 UNIPROT AKT2 protein P31751 UNIPROT unknown dephosphorylation 9606 BTO:0000527 15808505 t gcesareni These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt / phlpp1 specifically modulates the phosphorylation of hdm2 and gsk-3alpha through akt2, whereas phlpp2 specifically modulates the phosphorylation of p27 through akt3 SIGNOR-135008 0.606 PAMPs stimulus SIGNOR-ST11 SIGNOR AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates 9606 25720354 f scontino APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. SIGNOR-267857 0.7 CILK1 protein Q9UPZ9 UNIPROT CILK1 protein Q9UPZ9 UNIPROT up-regulates phosphorylation Tyr159 SKPPYTDyVSTRWYR 9606 15988018 t lperfetto Ick is activated by dual phosphorylation of the tdy motif. Phosphorylation of tyr-159 in the tdy motif requires ick autokinase activity SIGNOR-138424 0.2 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Thr21 YGGAGGYtQSPGGFG 9606 14872059 t lperfetto Replication protein a (rpa) is a single-stranded dna (ssdna) binding protein involved in various processes, including nucleotide excision repair and dna replication. The 32 kda subunit of rpa (rpa32) is phosphorylated in response to various dna-damaging agents, and two protein kinases, ataxia-telangiectasia mutated (atm) and the dna-dependent protein kinase (dna-pk) have been implicated in dna damage-induced phosphorylation of rpa32we show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro. SIGNOR-121869 0.597 MAP2K2 protein P36507 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 BTO:0000142 1411546 t inferred from 70% of family members gcesareni The primary structure of mek, a protein kinase that phosphorylates the erk gene product SIGNOR-269895 0.2 PTPRC protein P08575 UNIPROT JAK3 protein P52333 UNIPROT down-regulates activity dephosphorylation 10090 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling SIGNOR-248359 0.468 HSPB1 protein P04792 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by stabilization binding 9606 18241680 t miannu GTP cyclohydrolase I (GCH), an oligomeric protein composed of 10 identical subunits, is required for the synthesis of neurotransmitters; mutations in GCH are associated with dopa-responsive dystonia (DRD) and hyperphenylalaninemia. Mutated GCH proteins are unstable and prone to dominant-negative effect. We show herein that expression of the GCH mutant GCH-201E or the splicing variant GCH-II caused intracellular inclusion bodies. When Hsp27 was expressed together with the GCH mutants, Hsp27 expression decreased the formation of inclusion bodies by GCH (as assessed by immunofluorescence) and decreased the amount of insoluble GCH mutant proteins (as assessed by Western blot). we demonstrated that Hsp27 increases the expression of the wild-type GCH protein, causes the appearance of the soluble GCH-II protein, and decreases the quantities of insoluble mutated GCH protein. Therefore, it is likely that Hsp27 improves the folding of mutated GCH proteins, so they can stay in free cytosolic compartment. SIGNOR-252222 0.2 G8RGG88B68 smallmolecule SID:135317436 ChEBI IFNAR2 protein P48551 UNIPROT up-regulates activity chemical activation -1 15898717 t miannu To significantly improve the pharmacological properties of the drug, a pegylated form of IFNalpha(2a) was developed (PEGASYS). This 40 kDa PEG-conjugated IFNalpha(2a) ((40)PEG-IFNalpha(2a)) is obtained by the covalent binding of one 40 kDa branched PEG-polymer to a lysine side-chain of IFNalpha(2a). Here, we report the detailed structural, kinetic, and thermodynamic analysis of the binding to the extracellular domain of the receptor IFNAR2 of (40)PEG-IFNalpha(2a) and its isolated positional isomers modified at K31, K134, K131, K121, K164, and K70, respectively, in comparison with unmodified IFNalpha(2a). SIGNOR-259391 0.8 EGLN3 protein Q9H6Z9 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity binding 9606 BTO:0000007 23732909 t lperfetto Here we report that EGLN3, but not EGLN1 or -2, interacts with and inhibits K63-linked ubiquitination of IKKγ. The effect appears to be related to inhibition of IKKγ ubiquitination mediated by cIAP1 rather than to stimulation of IKKγ deubiquitination by the deubiquitinases A20 and CYLD (cylindromatosis). EGLN3 does not affect the protein levels of cIAP1 or its E2 ubiquitin-conjugating enzymes UbcH5 and Ubc13. EGLN3 hydroxylase activity is not responsible for its effect on IKKγ ubiquitination and NF-κB signaling. Instead, interaction with IKKγ is required for the ability of EGLN3 to inhibit IKKγ ubiquitination and IKK-NF-κB signaling. SIGNOR-262005 0.332 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BANP protein Q8N9N5 UNIPROT down-regulates activity phosphorylation Thr337 VKSFSRRtPNSSSYC 9606 BTO:0000567 26080397 t miannu ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68. SIGNOR-266203 0.2 7-Hydroxystaurosporine chemical CID:72271 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 20068082 t gcesareni The clinical use of ucn-01, the first chk1 inhibitor evaluated in humans, is limited by its prolonged plasma half-life due to extensive plasma binding to alfa1 acidic glycoprotein SIGNOR-163222 0.8 CREBBP protein Q92793 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity acetylation 9606 25545885 t miannu C-terminal acetylation of p53 by p300/CBP and PCAF promotes an open conformation of p53 by preventing the occlusion of the DNA binding domain by the C-terminal tail. This enhances p53 transcriptional activity, leading to growth arrest and/or apoptosis SIGNOR-261495 0.91 RHOA protein P61586 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 23450633 f gcesareni Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism. SIGNOR-192114 0.7 propan-2-ol smallmolecule CHEBI:17824 ChEBI TLCD3B protein Q71RH2 UNIPROT up-regulates activity binding 9606 BTO:0000140 30010626 t lperfetto Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2 SIGNOR-270575 0.8 Cyclopamine chemical CHEBI:4021 ChEBI CXCL1 protein P09341 UNIPROT down-regulates chemical inhibition 9606 16885213 t gcesareni Cyclopamine and other inhibitors of hh signaling were found to inhibit smo coupling to gi in a manner consistent with inverse agonism. SIGNOR-148469 0.8 ROCK1 protein Q13464 UNIPROT LPP protein Q93052 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 22886954 f miannu Inactivation of rho kinase (rok) with rok inhibitors significantly inhibited lpp mrna expression SIGNOR-198118 0.2 RPS6KA1 protein Q15418 UNIPROT YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 t lperfetto We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue. SIGNOR-182497 0.559 ADGRG1 protein Q9Y653 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0000142 31515243 t lperfetto Binding of collagen III to ADGRG1 provides a canonical example of adhesion GPCR interactions with ECM proteins (Luo et al., 2011). Identified by an in vitro biotinylation/proteomics approach, extracellular interactions with collagen III were subsequently proven capable of activating ADGRG1-mediated signaling via Gα12/13 followed by RhoA activation to regulate corticogenesis SIGNOR-272344 0.2 PKCtheta/Nfix complex SIGNOR-C121 SIGNOR MEF2A protein Q02078 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000165 20178747 t llicata In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A. SIGNOR-238022 0.344 KAT2A protein Q92830 UNIPROT H3-2 protein Q5TEC6 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269599 0.2 CDK1 protein P06493 UNIPROT CREM protein Q03060 UNIPROT down-regulates quantity by destabilization phosphorylation Ser277 ASPGSLHsPQQLAEE 10090 BTO:0001077 11466319 t miannu  The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway.  SIGNOR-275979 0.301 MAPK1 protein P28482 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser287 WEPPGRAsPSQGSSP 9606 14697653 t lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. SIGNOR-120455 0.262 EIF5 protein P55010 UNIPROT 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269163 0.777 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI up-regulates quantity precursor of 9606 32041144 t miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. SIGNOR-267550 0.8 SMURF2 protein Q9HAU4 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps. SIGNOR-193119 0.481 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PLCB1 protein Q9NQ66 UNIPROT up-regulates activity phosphorylation -1 11287604 t inferred from 70% family members lperfetto Plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982 SIGNOR-270200 0.2 Kindlin proteinfamily SIGNOR-PF48 SIGNOR AE/b7 integrin complex SIGNOR-C186 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259010 0.391 AP2S1 protein P53680 UNIPROT AP-2 complex complex SIGNOR-C245 SIGNOR form complex binding 31671891 t lperfetto The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit SIGNOR-260421 0.913 GXYLT2 protein A0PJZ3 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 22117070 t Xylosylation in ER membrane. gcesareni Recently, we have shown (28) that two members of the human glycosyltransferase 8 family (gt8) (29), gxylt1 and gxylt2 (glucoside-xylosyltransferase 1/2), are able to transfer the first alfa1,3-linked xylose to o-glucosylated mammalian notch egf repeats. SIGNOR-177714 0.391 KRN-633 chemical CID:9549295 PUBCHEM FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193585 0.8 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI 9606 17474719 t gcesareni In mammals, pdhc is tightly regulated by phosphorylation-dephosphorylation of three serine residues in the thiamin-dependent pyruvate dehydrogenase (e1) component. In vivo, inactivation of human pdhc correlates mostly with phosphorylation of serine 264, which is located at the entrance of the substrate channel leading to the active site of e1. SIGNOR-154656 0.674 leukotriene B4(1-) smallmolecule CHEBI:57461 ChEBI LTB4R protein Q15722 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257534 0.8 NLGN3 protein Q9NZ94 UNIPROT NRXN3 protein Q9HDB5 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264167 0.819 CHUK protein O15111 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates activity phosphorylation Ser870 KEDSAYGsQSVEQEA 10090 BTO:0000785 15084608 t lperfetto Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52. SIGNOR-124230 0.784 Pravadoline chemical CID:56463 PUBCHEM PTGS2 protein P35354 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206322 0.8 FH protein P07954 UNIPROT ATF2 protein P15336 UNIPROT up-regulates activity binding -1 28628081 t miannu Glucose deficiency induces AMPK activation, which phosphorylates FH at Ser75 and promotes its binding to ATF2 and the enrichment of the FH–ATF2 complex on the promoter regions of ATF2-targeted genes. SIGNOR-266314 0.2 SMAD7 protein O15105 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates 9606 17438144 f gcesareni Smad7 repressed smad3/4-, smad2/4-, and smad1/4-enhanced reporter gene expression. SIGNOR-154390 0.563 CDH1 protein P12830 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR up-regulates activity binding 9606 24336504 t miannu Additionally, the E-cadherin associated protein _-catenin regulates YAP directly by sequestering YAP/14-3-3 complexes in the cytoplasm. SIGNOR-265821 0.673 PTPRG protein P23470 UNIPROT SHC1 protein P29353 UNIPROT down-regulates activity dephosphorylation Tyr349 EEPPDHQyYNDFPGK -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254723 0.2 GOT2 protein P00505 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267513 0.8 CDH19 protein Q9H159 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265858 0.32 PPP2R1A protein P30153 UNIPROT MAPT protein P10636 UNIPROT down-regulates dephosphorylation 9606 15525651 t gcesareni Galpha12 directly interacts with pp2a: evidence for galpha12-stimulated pp2a phosphatase activity and dephosphorylation of microtubule-associated protein, tau. SIGNOR-130136 0.2 MAP3K1 protein Q13233 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 12049732 t miannu ERK1/2 MAP kinases are important regulators in cellular signaling, whose activity is normally reversibly regulated by threonine-tyrosine phosphorylation. In contrast, we have found that stress-induced ERK1/2 activity is downregulated by ubiquitin/proteasome-mediated degradation of ERK1/2. The PHD domain of MEKK1, a RING finger-like structure, exhibited E3 ubiquitin ligase activity toward ERK2 in vitro and in vivo. Therefore, MEKK1 functions not only as an upstream activator of the ERK and JNK through its kinase domain, but also as an E3 ligase through its PHD domain, providing a negative regulatory mechanism for decreasing ERK1/2 activity. SIGNOR-272609 0.524 FOXO1 protein Q12778 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20577053 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-166349 0.2 471905-41-6 chemical CID:9803433 PUBCHEM APP protein P05067 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194358 0.8 TRIM25 protein Q14258 UNIPROT ZFHX3 protein Q15911 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002999 22452784 t miannu In the present study we show that EFP (oestrogen-responsive finger protein) is an E3 ubiquitin ligase mediating oestrogen-induced ATBF1 protein degradation. Knockdown of EFP increases ATBF1 protein levels, whereas overexpression of EFP decreases ATBF1 protein levels. SIGNOR-272048 0.462 PRKCA protein P17252 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser447 SQRSSYVsMRIDTHA -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262754 0.342 CAMK2G protein Q13555 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity phosphorylation 12609872 t inferred from family member llicata Direct phosphorylation of the GluR1 subunit of postsynaptic AMPA receptors by Ca(2+)/calmodulin-dependent protein kinase II (CaM-KII) is believed to be one of the major contributors to the enhanced strength of glutamatergic synapses in CA1 area of hippocampus during long-term potentiation. | Validity of the approach was confirmed by modeling, and silence analysis was applied then to the GluR1 AMPA receptor mutated at S831, the site phosphorylated by CaM-KII during long-term potentiation. Silence analysis indicates that a negative charge at S831 is a critical determinant for the enhanced channel function as a charge carrier. Silence and variance analyses, when applied to the same sets of data, were in agreement on the receptor regulation upon mutations. SIGNOR-270234 0.615 CEP250 protein Q9BV73 UNIPROT Centrosome_separation phenotype SIGNOR-PH177 SIGNOR down-regulates 9606 BTO:0000567 24769208 f lperfetto C-NAP1 which is located in the proximal ends of the centriole is an important factor for maintaining cohesion of centrioles in interphase SIGNOR-265498 0.7 ezogabine chemical CHEBI:68584 ChEBI KCNQ3 protein O43525 UNIPROT up-regulates chemical activation 9606 Other t Selleck;anticonvulsant for KCNQ2/3 currents gcesareni SIGNOR-206541 0.8 HIPK3 protein Q9H422 UNIPROT FADD protein Q13158 UNIPROT down-regulates activity phosphorylation Ser194 QNRSGAMsPMSWNSD -1 11034606 t FIST/HIPK3 causes FADD phosphorylation, thereby promoting FIST/HIPK3-FADD-Fas interaction.¬† Phosphorylation occurs on Ser194 close to the COOH terminus of human FADD| Fas ligand-induced activation of Jun NH(2)-terminal kinase is impaired by overexpressed active FIST/HIPK3 SIGNOR-251272 0.447 PTPN1 protein P18031 UNIPROT AGO2 protein Q9UKV8 UNIPROT down-regulates activity dephosphorylation Tyr393 ASFNTDPyVREFGIM 9606 25175024 t miannu Taken together, our results indicate that Tyr 393 of AGO2 is hyperphosphorylated in response to PTP1B inactivation and may contribute to H-RAS V12 -induced development of senescence.|We identified phospho-Tyr 393 of argonaute 2 (AGO2) as a direct substrate of PTP1B. SIGNOR-277120 0.2 DRD1 protein P21728 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257181 0.285 DIO proteinfamily SIGNOR-PF83 SIGNOR 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 20978344 t inferred from family member miannu The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4) SIGNOR-267809 0.8 PEA15 protein Q15121 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates 9606 11702783 f gcesareni Here, we report that pea-15, a protein variably expressed in multiple cell types, blocks erk-dependent transcription and proliferation by binding erks and preventing their localization in the nucleus._ Pea-15 can redirect the biological outcome of map kinase signaling by regulating the subcellular localization of erk map kinase. SIGNOR-111502 0.759 LRP2 protein P98164 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates quantity binding 9606 BTO:0000142 26872844 t miannu LRP2 Promotes SHH Activity in Neurogenic Niches of the Developing and Adult Brain. In the RDVM, LRP2 forms a co-receptor complex with PTCH1 facilitating SHH binding and internalization of SHH/PTCH1 complexes, a prerequisite for pathway activation (Fig. 3B). SIGNOR-265257 0.475 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 19723038 t lperfetto The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases. These include epidermal growth factor receptor (egfr) kinase, src, janus-activated kinases (jak), and extracellular signal-regulated kinase (erk). SIGNOR-187775 0.793 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SCRIB protein Q14160 UNIPROT unknown phosphorylation Ser1448 TSRQSPAsPPPLGGG 9606 BTO:0000007 20622900 t miannu HScrib is a substrate of ERK and PKA. Under normal growth conditions, hScrib is phosphorylated at S853, most likely by ERK, and at S1445 by PKA. Interestingly, stimulation of MAPK by osmotic stress results in a marked loss of phosphorylation at the PKA site S1445, but a concomitant increase in phosphorylation at S1448, presumably also by ERK. At present, we have no information as to what are the functional consequences of ERK or PKA phosphorylation of hScrib. However, we can speculate that this will most likely affect the ability of hScrib to interact with some of its cellular partners, and studies are currently in progress to investigate these aspects further. SIGNOR-263064 0.2 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser392 FKTEGPDsD 9606 23603988 t gcesareni We recently demonstrated that through their physical interaction, cdk9 phosphorylates p53 on ser-392, leading to p53 stability and accumulation SIGNOR-201931 0.55 IL33 protein O95760 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 BTO:0006111 36660926 t miannu IL-33 secreted by pericytes and CAFs promotes M2 polarization and induced MMP9 expression in M2 TAMs facilitating metastasis development via the IL-33-ST2-NF-κB-MMP9-laminin pathway in a mouse model of pancreatic cancer SIGNOR-277712 0.7 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252748 0.753 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr446 GTEPEPVySMEAADY 9606 12601080 t lperfetto Cortactin was first identified as a substrate of v-src (46) that mediates in vitro phosphorylation of residues tyr-421, tyr-466, and tyr-482 at the c terminus of the murine ortholog (47). Phosphorylation of these residues attenuates the f-actin cross-linking activity SIGNOR-98712 0.794 PPM1D protein O15297 UNIPROT GPI protein P06744 UNIPROT down-regulates activity dephosphorylation 9606 28185954 t miannu The WIP1 mediated inhibition of NLK activity markedly decreased the phosphorylation of lymphoid enhancer binding factor 1 (LEF1), enhancing its interaction with beta-catenin.|Wip1 directly dephosphorylates NLK and increases Wnt activity during germ cell development. SIGNOR-277155 0.241 DOK1 protein Q99704 UNIPROT ITGB5 protein P18084 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257691 0.298 EZR protein P15311 UNIPROT FES protein P07332 UNIPROT up-regulates relocalization 9606 18046454 t miannu The recruitment and the activation of fes to the cell-cell contacts in confluent cells depend on its interaction with ezrin. SIGNOR-159496 0.404 SMAD3 protein P84022 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 14638857 t gcesareni Nicd and smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and smad3 could be recruited to csl-binding sites on dna in the presence of csl and nicd SIGNOR-119374 0.559 EPGN protein Q6UW88 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0001801 16469638 t gcesareni They both bind to betacellulin and the heparin-binding ligand, hb-egf, as well as to two low-affinity ligands, epiregulin and epigen. SIGNOR-144399 0.403 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR PRDM14 protein Q9GZV8 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269234 0.615 NTHL1 protein P78549 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). SIGNOR-275717 0.7 PDE1A protein P54750 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI down-regulates quantity chemical modification 9606 22014080 t PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C hydrolyses cAMP and cGMP with similar Km values SIGNOR-253398 0.8 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates activity phosphorylation Thr103 LIDATGDtPGAEDDE 9534 BTO:0000298 12756254 t miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. SIGNOR-250128 0.879 PRKACA protein P17612 UNIPROT MYOM2 protein P54296 UNIPROT down-regulates phosphorylation Ser76 RVCAKRVsTQEDEEQ 9606 BTO:0000887 9529381 t llicata This binding is regulated in vitro by phosphorylation of a single serine residue (ser76) in the immediately adjacent amino-terminal domain mp1. M-protein phosphorylation by camp-dependent kinase a inhibits binding to myosin lmm. SIGNOR-56395 0.2 BRCA1 protein P38398 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 15549093 f lperfetto The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination SIGNOR-251499 0.7 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI MET protein P08581 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258214 0.8 CAPN3 protein P20807 UNIPROT CDK5R1 protein Q15078 UNIPROT up-regulates activity cleavage 9606 25969760 t lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain SIGNOR-251604 0.264 ASPA protein P45381 UNIPROT acetic acid smallmolecule CHEBI:15366 ChEBI up-regulates quantity chemical modification 9606 17194761 t miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. SIGNOR-267527 0.8 P2RY13 protein Q9BPV8 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256892 0.2 p38 proteinfamily SIGNOR-PF16 SIGNOR EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation -1 12171600 t inferred from 70% family members miannu Inhibition of eEF2 kinase resulting from phosphorylation of Ser-396 by SAPK2a p38 was approx.25%. SIGNOR-270127 0.2 PIM proteinfamily SIGNOR-PF34 SIGNOR RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 19911008 t llicata In this study we show that phosphorylation of rela/p65 at ser276 prevents its degradation by ubiquitin-mediated proteolysis. importantly, we identify pim-1 as a further kinase responsible for the phosphorylation of rela/p65 at ser276. SIGNOR-259411 0.2 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser932 CDSGVETsFRKLSFT 9606 BTO:0000567 SIGNOR-C13 10469655 t lperfetto All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391). SIGNOR-70457 0.737 DSCAML1 protein Q8TD84 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR down-regulates 9606 30745321 f miannu The DSCAM/L1 transcriptome data sets also contained a significant number of genes known to regulate synapse formation or function.Increased nuclear DSCAM levels inhibit synapse formation SIGNOR-264281 0.7 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. SIGNOR-252867 0.756 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation 9606 17900900 t lperfetto The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation SIGNOR-252886 0.398 L-serine chemical CHEBI:17115 ChEBI D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity precursor of 10090 BTO:0000142 12393813 t lperfetto High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media. SIGNOR-268271 0.8 PAK1 protein Q13153 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates activity phosphorylation Ser158 REGTRVQsVEQIREV 9606 12872159 t lperfetto Pak1 phosphorylates ctbp selectively on ser158 within a putative regulatory loop, triggering ctbp cellular redistribution and blocking ctbp ak1 superphosphorylates ctbp and inhibits ctbp dehydrogenase activitycorepressor functions. SIGNOR-103943 0.412 NLK protein Q9UBE8 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation Ser166 TYSDEHFsPGSHPSH 9606 12556497 t gcesareni Regulation of lymphoid enhancer factor 1/t-cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in wnt/beta-catenin signaling.Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk. SIGNOR-97808 0.751 PRKCB protein P05771 UNIPROT BTK protein Q06187 UNIPROT down-regulates activity phosphorylation Ser180 GSLKPGSsHRKTKKP 9606 BTO:0003076 11598012 t lperfetto We provide direct evidence that PKCbeta acts as a feedback loop inhibitor of Btk activation. Inhibition of PKCbeta results in a dramatic increase in B-cell receptor (BCR)-mediated Ca2+ signaling. We identified a highly conserved PKCbeta serine phosphorylation site in a short linker within the Tec homology domain of Btk. Mutation of this phosphorylation site led to enhanced tyrosine phosphorylation and membrane association of Btk, and augmented BCR and FcepsilonRI-mediated signaling in B and mast cells, respectively. | This deductive analysis indicated that PKCbeta phosphorylates S180 in the region bisecting the Btk motif (BM) and the PRR of the TH domain. SIGNOR-249110 0.39 sirolimus chemical CHEBI:9168 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 16452206 f gcesareni We now show that mtor inhibition induces insulin receptor substrate-1 expression and abrogates feedback the pathway, resulting in akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, rad001. SIGNOR-144156 0.8 CREB1 protein P16220 UNIPROT NR4A3 protein Q92570 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 17668895 f gcesareni Phosphorylation of creb by msk has been linked to the transcription of nur77, nor1 and c-fos downstream of mapk signalling in various cell types. SIGNOR-157154 0.339 CLN8 protein Q9UBY8 UNIPROT SET protein Q01105 UNIPROT down-regulates activity binding 9606 BTO:0000007 30453012 t miannu CLN8 interacts with ceramide binding proteins PP2A and I2PP2A. We showed that the phosphorylation levels of several substrates of PP2A, namely Akt, S6 kinase, and GSK3β, were decreased in CLN8 disease patient fibroblasts. This reduction can be reversed by inhibiting PP2A phosphatase activity with cantharidin, suggesting a higher PP2A activity in CLN8-deficient cells. The phosphorylation levels of PP2A substrates are decreased in the absence of CLN8. SIGNOR-265584 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017877 t lperfetto We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1 SIGNOR-252798 0.2 IL15RA protein Q13261 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity 9606 30029643 f areggio In addition, level of mRNAs encoding C/EBPa, PPARg and FABP4, the classic adipogenic markers, was significantly lower in samples administrated with IL-15 SIGNOR-256228 0.2 U0126 chemical CHEBI:90693 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 9873633 t gcesareni The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. U0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2. SIGNOR-62895 0.8 CSNK2A2 protein P19784 UNIPROT PPP1R8 protein Q12972 UNIPROT up-regulates activity phosphorylation Thr161 LGLPEEEtELDNLTE -1 9407077 t llicata Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2. SIGNOR-251024 0.485 JAK3 protein P52333 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity phosphorylation Tyr1035 IETDKEYyTVKDDRD -1 12559972 t Phosphorylation by recombinant JAK3 of a peptide substrate corresponding to the JAK1 activation loop (KAIETDKEYYTVKD) SIGNOR-251364 0.516 SLC18A2 protein Q05940 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR up-regulates activity binding 9606 BTO:0000132 23805129 t lperfetto The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). |VMAT2 also appears to mediate histamine transport into dense granules SIGNOR-265997 0.2 SPOP protein O43791 UNIPROT DEK protein P35659 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25278611 t miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E). SIGNOR-272826 0.449 MAPK3 protein P27361 UNIPROT PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation Ser12 ESPLCPLsPLEAGDL 9606 10187842 t lperfetto We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution. SIGNOR-249473 0.585 BMP1 protein P13497 UNIPROT COL5A2 protein P05997 UNIPROT up-regulates activity cleavage Glu1253 SEVKMDAeFRHDSGY 9606 BTO:0002974 11741999 t miannu BMP-1 Can Efficiently Cleave Pro-α1(V) N-propeptides and Pro-α2(V) C-propeptides and Less Efficiently Cleave Pro-α1(V) C-propeptides in Vitro. BMP-1 efficiently cleaves pro-α2(V) C-propeptides at a single site between residues 1250 (Glu) and 1251 (Asp). SIGNOR-256343 0.591 PRKACA protein P17612 UNIPROT PPP1R8 protein Q12972 UNIPROT down-regulates activity phosphorylation Ser178 TAHNKRIsTLTIEEG -1 9407077 t miannu NIPP-1 is the RNA-binding subunit of a major species of protein phosphatase-1 in the nucleus. The purified recombinant protein was a potent (Ki = 9.9 +/- 0.3 pM) and specific inhibitor of protein phosphatase-1 and was stoichiometrically phosphorylated by protein kinases A and CK2. At physiological ionic strength, phosphorylation by these protein kinases drastically decreased the inhibitory potency of free NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A SIGNOR-250032 0.497 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser676 LSQRFTFsPGQDIQL 9606 11110801 t llicata In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676). SIGNOR-84996 0.453 AKT1 protein P31749 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser134 ANLNRSTsVPENPKS 9606 BTO:0000731 24291004 t lperfetto Akt1 impairs glucocorticoid-induced gene expression by direct phosphorylation of nr3c1 at position s134 and blocking glucocorticoid-induced nr3c1 translocation to the nucleus SIGNOR-252543 0.499 PRKACA protein P17612 UNIPROT GP1BB protein P13224 UNIPROT down-regulates activity phosphorylation Ser191 ARAAARLsLTDPLVA -1 2504723 t miannu Platelet glycoprotein Ib beta is phosphorylated on serine 166 by cyclic AMP-dependent protein kinase. phosphorylation of this residue may contribute to the inhibitory actions of cyclic AMP by inhibiting collagen-induced polymerization of actin. SIGNOR-249986 0.317 MASP2 protein O00187 UNIPROT C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Arg756 KGQAGLQrALEILQE -1 17204478 t lperfetto MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a). SIGNOR-263434 0.794 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR MYH3 protein P11055 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136647 0.46 TWIST1 protein Q15672 UNIPROT MYB protein P10242 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255529 0.248 CYP11B1 protein P15538 UNIPROT cortisol smallmolecule CHEBI:17650 ChEBI up-regulates quantity chemical modification 9606 BTO:0000050 9814482 t lperfetto Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. SIGNOR-268678 0.8 U2AF1 protein Q01081 UNIPROT U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR form complex binding 9606 8647433 t miannu The splicing factor u2af (u2 snrnp auxiliary factor) is a heterodimer with subunits of 65 and 35 kd (u2af65 and u2af35). SIGNOR-41945 0.2 NR3C1 protein P04150 UNIPROT PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19805059 t miannu GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription SIGNOR-268049 0.479 POU5F1 protein Q01860 UNIPROT LEFTY2 protein O00292 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254940 0.429 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT down-regulates activity phosphorylation Thr2068 LLDEYNVtPSPPGTV 9606 BTO:0000007 12794074 t lperfetto We show that gsk-3beta directly binds at c-terminal of the notch2 ankyrin repeats and phosphorylates thr-2068 and/or ser-2070, thr-2074, and thr-2093. SIGNOR-101570 0.494 AMPA proteinfamily SIGNOR-PF58 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264941 0.8 SMAD3 protein P84022 UNIPROT CEBPB protein P17676 UNIPROT down-regulates activity binding 10090 12524424 t gcesareni Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPAR2 and leptin promoters SIGNOR-250567 0.58 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation 9606 21902831 t lperfetto As a permissive environment is created at these loci, p38 further stimulates gene expression through the phosphorylation of additional myogenic transcription factors, including mef2c and e47. SIGNOR-176551 0.683 CDK1 protein P06493 UNIPROT NUCKS1 protein Q9H1E3 UNIPROT down-regulates activity phosphorylation Ser181 LKATVTPsPVKGKGK -1 12413487 t miannu putative phosphorylation site for Cdk1 is present in the DNA-binding domain peptide. This site, corresponding to Ser 181 in the NUCKS primary structure, is phosphorylated in vitro by Cdk1 with a Km of approximately 35 μM [7]. Phosphorylation of Ser 181 in the synthetic, DNA-binding domain peptide reduces its affinity for DNA-by 100%. SIGNOR-261959 0.487 TNF protein P01375 UNIPROT DNAH10 protein Q8IVF4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000667 31836722 f miannu The protein expression of DNAH10 was assessed by Western blot analysis after stimulation of primary keratinocytes (P4) with inflammatory cytokine TNFα or growth factor TGF-β1 and their combination (Fig. 5C). Treatment with TNFα, TGF-β1, and their combination down regulated the expression of DNAH10 in keratinocytes after a 24-h-stimulation. SIGNOR-265551 0.2 TP53 protein P04637 UNIPROT BCL2 protein P10415 UNIPROT down-regulates quantity by repression transcriptional regulation 10329733 f lperfetto P53 suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor. SIGNOR-271677 0.739 SLC20A1 protein Q8WUM9 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI up-regulates quantity relocalization 9606 11009570 t lperfetto Three families of NPCs have been reported to date. The type I family consists of a single species (NaPi-1), which has thus far been found only in rabbit kidney.28 The type II family consists of six species homologues, NaPi 2 to 7, that are expressed predominantly in renal epithelial tissues.The type III family is the most recently identified and consists of two members, Pit-1 (also called Glvr-1) and Pit-2 (also called Ram-1).34 SIGNOR-270579 0.8 ANGPT2 protein O15123 UNIPROT TEK protein Q02763 UNIPROT up-regulates binding 9606 9723709 t lperfetto Angiopoietin-1 and -2, bound to tek with similar affinities, and angiopoietin-1 effectively induced tek phosphorylation in hematopoietic cells. Angiopoietin-2 also induced a low level of tek phosphorylation and weakened the phosphorylation induced by angiopoietin-1 SIGNOR-59808 0.923 JUN protein P05412 UNIPROT SERPINA3 protein P01011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002600 11027208 f miannu We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. SIGNOR-254808 0.2 KCNC1 protein P48547 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 11506885 t miannu Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height SIGNOR-265586 0.8 MRPL17 protein Q9NRX2 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262340 0.7 XL-647 chemical CID:10458325 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207857 0.8 FZD3 protein Q9NPG1 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 14977528 t gcesareni Gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families. SIGNOR-122889 0.246 TAF3 protein Q5VWG9 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263930 0.812 P2RY13 protein Q9BPV8 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257299 0.2 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1665 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273041 0.556 EGFR protein P00533 UNIPROT MYC protein P01106 UNIPROT up-regulates activity 10090 26592448 f Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro-proliferative transcription factor c-MYC SIGNOR-252092 0.478 PRKCZ protein Q05513 UNIPROT TRAF2 protein Q12933 UNIPROT unknown phosphorylation Ser55 QCGHRYCsFCLASIL 9606 BTO:0000785 19336568 t llicata Here, we report that protein kinase czeta phosphorylates traf2 at ser(55), within the ring domain of the protein, after tnfalpha stimulation SIGNOR-184941 0.411 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 21620960 t gcesareni Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. SIGNOR-174021 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR TOB1 protein P50616 UNIPROT down-regulates phosphorylation 9606 12050114 t inferred from 70% family members gcesareni Tob is rapidly phosphorylated at Ser 152, Ser 154, and Ser 164 by Erk1 and Erk2 upon growth-factor stimulation. SIGNOR-270123 0.2 USP39 protein Q53GS9 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270640 0.701 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 t Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. SIGNOR-248830 0.626 GRIK5 protein Q16478 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity relocalization 9606 BTO:0002609 12393813 t lperfetto Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine SIGNOR-268276 0.8 SP1 protein P08047 UNIPROT CYP1B1 protein Q16678 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12801909 f miannu It was suggested that mutual interaction of XRE2 and XRE3 is important for transcriptional regulation, and that the Sp1 binding to the Sp1-like motif (-824) enhances both the constitutive and inducible transcriptional activities of the human CYP1B1 gene. SIGNOR-255196 0.27 FGFR2 protein P21802 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). SIGNOR-276184 0.2 CRYAB protein P02511 UNIPROT CRYGD protein P07320 UNIPROT up-regulates activity binding -1 20621668 t miannu Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age. SIGNOR-253621 0.535 A5/b1 integrin complex SIGNOR-C163 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269012 0.7 HTRA2 protein O43464 UNIPROT PEA15 protein Q15121 UNIPROT down-regulates binding 9606 15328349 t gcesareni Htra2 promotes cell death by binding and degrading the anti-apoptotic protein pea15 SIGNOR-126966 0.498 gefitinib chemical CHEBI:49668 ChEBI EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition 9606 15284455 t SimoneGraziosi Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within the EGFR kinase domain.  SIGNOR-269264 0.8 PRKCA protein P17252 UNIPROT HES1 protein Q14469 UNIPROT down-regulates activity phosphorylation Ser38 ASEHRKSsKPIMEKR -1 9389649 t lperfetto Endogenous HES-1 DNA-binding activity is post-translationally inhibited during NGF signaling in vivo, and phosphorylation of PKC consensus sites in the HES-1 DNA-binding domain inhibits DNA binding by purified HES-1 in vitro. SIGNOR-248993 0.335 PITX2 protein Q99697 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 20978076 f gcesareni We show that pitx2 is crucial for the onset of myod gene expression in limb muscle progenitors and that it acts on the myod core enhancer. SIGNOR-169107 0.447 SP1 protein P08047 UNIPROT RHO protein P08100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 15781457 f miannu Sp4 and Sp1 are activators of the rod opsin promoter SIGNOR-225385 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 BTO:0000551 21423205 t lperfetto Rsk1 phosphorylated vasp on t278, a site regulating its binding to actin. SIGNOR-252802 0.2 G6PD protein P11413 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity chemical modification 9606 24769394 t miannu The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle SIGNOR-267052 0.8 Opsonization phenotype SIGNOR-PH150 SIGNOR Membrane attack complex complex SIGNOR-C313 SIGNOR up-regulates -1 30552328 f lperfetto CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers SIGNOR-263455 0.7 RFX complex complex SIGNOR-C104 SIGNOR HLA-DMB protein P28068 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 f The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-253999 0.371 ILF3 protein Q12906 UNIPROT NF90-NF45 complex SIGNOR-C443 SIGNOR form complex binding -1 18458058 t miannu Nuclear factor 90 (NF90) and its C-terminally extended isoform, NF110, have been isolated as DNA- and RNA-binding proteins together with the less-studied protein NF45. These complexes have been implicated in gene regulation, but little is known about their cellular roles and whether they are redundant or functionally distinct. We show that heterodimeric core complexes, NF90-NF45 and NF110-NF45, exist within larger complexes that are more labile and contain multiple NF90/110 isoforms and additional proteins. This study identified NF45 as an unstable regulatory subunit of NF90-NF45 complexes and uncovered their critical role in normal cell division. Furthermore, the study revealed that NF90 is functionally distinct from NF110 and is more important for cell growth. SIGNOR-268488 0.591 MECP2 protein P51608 UNIPROT DEAF1 protein O75398 UNIPROT up-regulates activity binding 10090 BTO:0000142 29636529 t Gianni We show that MeCP2 enhances Deaf1 binding to its HTR1A site and co-immunoprecipitates with Deaf1 in cells and brain tissue.To address the role of MeCP2 in HTR1A regulation in vivo, mice with conditional knockout of MeCP2 in adult 5-HT neurons (MeCP2 cKO) were generated. These mice exhibited increased 5-HT1A autoreceptor levels and function, consistent with MeCP2 enhancement of Deaf1 repression in 5-HT neurons. SIGNOR-269063 0.2 NFATC1 protein O95644 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000776 11163226 f scontino In this study, the roles of NFATc1 and NFATc2 in T and B cells were examined. These results further characterize NFAT as a transcription factor family that plays a critical role in the regulation of lymphocyte effector differentiation. SIGNOR-270537 0.7 ACTB protein P60709 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 t miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270619 0.489 SMAD3 protein P84022 UNIPROT SMAD3/JUN complex SIGNOR-C86 SIGNOR form complex binding 9606 9732876 t gcesareni These results show a ligand-dependent association of smad3 with c-jun SIGNOR-59873 0.741 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194548 0.8 CBX4 protein O00257 UNIPROT ZEB2 protein O60315 UNIPROT down-regulates quantity by destabilization sumoylation Lys866 PLNLTFIkKEFSNSN 9534 BTO:0001538 16061479 t Luisa Pc2 can act directly as an E3 ligase for SIP1 sumoylation.SIP1 sumoylation having a negative effect on its repression of E-cadherin transcription. SIGNOR-269113 0.337 AKT proteinfamily SIGNOR-PF24 SIGNOR ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation 9606 22085529 t miannu Both mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinases (ERK) 1/2 and phosphatidylinositide-3-OH kinase (PI3K)/Akt pathways regulate activation of E-twenty-six (ETS)-like transcription factor 1 (Elk-1) in U138 glioblastoma cells. The phosphatidylinositide-3-OH kinase (PI3K)/Akt pathway was also involved in the Elk-1 activation. Activation of the Elk-1 led to an increased survival and a proliferative response with the EGF stimulation in the U138 glioblastoma cells. SIGNOR-259029 0.2 tofacitinib citrate chemical CHEBI:71197 ChEBI JAK3 protein P52333 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207311 0.8 MMP7 protein P09237 UNIPROT SPP1 protein P10451 UNIPROT up-regulates activity cleavage 25545242 t lperfetto In this study, we found a novel motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved mouse OPN binds to α9β1 integrin. Importantly, this novel motif is involved in the development of anti-type II collagen antibody-induced arthritis (CAIA). This study provides the first in vitro and in vivo evidence that OPN cleavage by MMP-3/7 is an important regulatory mechanism for CAIA. SIGNOR-253321 0.694 THR proteinfamily SIGNOR-PF84 SIGNOR GATA2 protein P23769 UNIPROT down-regulates activity binding 9606 BTO:0001073 29407449 t scontino We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2. SIGNOR-267275 0.2 RRM2 protein P31350 UNIPROT Ribonucleotide reductase complex SIGNOR-C233 SIGNOR form complex binding 9606 14583450 t miannu Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2. SIGNOR-259364 0.93 MAP3K20 protein Q9NYL2 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation Ser165 HNHTTHMsLVGTFPW 9606 15342622 t gcesareni Ionizing radiation induces mrk autophosphorylation and activation. Within the mrk kinase loop between the dfg (subdomain vii) and ape (subdomain viii) residues, there are three conserved threonine/serine residues (thr161, thr162, and ser165) that are important for activation. SIGNOR-128573 0.2 AKT1 protein P31749 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 31575057 t gcesareni Pim-1, PKC, and Akt1 kinases phosphorylate Thr-145 and Ser-146 sites on p21 protein. Phosphorylation at Thr-145 promotes cytoplasmic translocation and stability of p21. Ser-146 phosphorylation mediated by Akt1 enhances p21 stabilization and promotes cell survival. SIGNOR-157790 0.834 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser74 TPHLPPCsPPKQGKK 9606 SIGNOR-C83 9889196 t lperfetto Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2. SIGNOR-63895 0.94 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR AR protein P10275 UNIPROT down-regulates activity dephosphorylation Ser83 QQQQQETsPRQQQQQ 9606 27858941 t miannu DAB2IP acts as a scaffold protein for PP2A to suppress DHT-elicited S81 phosphorylation of the AR, preventing its nuclear translocation and binding to androgen response elements. In addition, DAB2IP can compete with the AR for binding to c-Src, thus blocking the non-genomic AR pathway SIGNOR-254759 0.301 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation 9606 9792677 t gcesareni Rsk-b is a p38alphamapk substrate, and activated by p38alphamapk and, more weakly, by erk1 SIGNOR-60995 0.587 TUBB1 protein Q9H4B7 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10116 17118269 f lperfetto However, evidence suggests that the detyrosination/tyrosination cycle of alpha-tubulin may be linked in some cell types to cell division and proliferationNF-Y SIGNOR-242138 0.7 GSK3B protein P49841 UNIPROT JUN protein P05412 UNIPROT down-regulates activity phosphorylation Ser249 LSPIDMEsQERIKAE -1 1846781 t lperfetto Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity. SIGNOR-18684 0.7 AFF2 protein P51816 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR up-regulates activity binding 9606 17135274 t miannu Af4 associates with P-TEFb and stimulates its kinase activity. P-TEFb also phosphorylates AF4 which down-regulates its transactivation activity, providing a negative feedback mechanism for the control of P-TEFb elongation activity SIGNOR-266801 0.398 FBXO5 protein Q9UKT4 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates ubiquitination 9606 11751633 t gcesareni Emi1 binds cdh1 and inhibits apc-cdh1 activity. SIGNOR-113385 0.746 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 BTO:0000938 BTO:0000142 11160424 t lperfetto The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. SIGNOR-244930 0.8 ZAP70 protein P43403 UNIPROT DBNL protein Q9UJU6 UNIPROT up-regulates phosphorylation Tyr344 PPEQETFyEQPPLVQ 9606 BTO:0000782 14557276 t lperfetto We found an interaction between the tyrosine kinase zap-70 and hip-55, which was induced by tcr stimulation. Zap-70 phosphorylated hip-55 at tyr-334 and tyr-344, which were shown to be the tyrosine phosphorylation sites of hip-55 in stimulated t cells.Our results demonstrate for the first time that hip-55 is an important adaptor protein for the jnk kinase cascade in tcr signaling. SIGNOR-118695 0.625 AKT1 protein P31749 UNIPROT ACLY protein P53396 UNIPROT unknown phosphorylation Ser455 PAPSRTAsFSESRAD 10116 BTO:0000443 12107176 t gcesareni Taken together, these results demonstrate that serine 454 of ATP-citrate lyase is a novel and major in vivo substrate for protein kinase B. SIGNOR-245255 0.437 PTPMT1 protein Q8WUK0 UNIPROT phosphatidylglycerol(1-) smallmolecule CHEBI:60523 ChEBI up-regulates chemical modification 10090 21641550 t lperfetto PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle. We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. Loss of PTPMT1 leads to dramatic diminution of cardiolipin, which can be partially reversed by the expression of catalytic active PTPMT1. Our study identifies PTPMT1 as the mammalian PGP phosphatase and points to its role as a regulator of cardiolipin biosynthesis. SIGNOR-267025 0.8 FYN protein P06241 UNIPROT ARHGAP33 protein O14559 UNIPROT down-regulates phosphorylation Tyr406 PLLTYQLyGKFSEAM 9606 16777849 t acerquone Tcgap interacted with fyn and was phosphorylated by fyn, with tyr-406 in the gap domain as a major fyn-mediated phosphorylation site. Fyn suppressed the gap activity of wild-type tcgap SIGNOR-147156 0.473 Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 BTO:0000567 12670868 t miannu The Set1/Ash2 HMT methylates histone H3 at Lys 4 (K4), but not if the neighboring K9 residue is already methylated. SIGNOR-264482 0.2 CYFIP1 protein Q7L576 UNIPROT WRC complex complex SIGNOR-C191 SIGNOR form complex binding 9606 21107423 t miannu WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems SIGNOR-253568 0.901 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LIFR protein P42702 UNIPROT down-regulates phosphorylation 9606 7777512 t inferred from 70% family members gcesareni Thus, our results identify the human lifr as a substrate for mapk and suggest a mechanism of heterologous receptor regulation of lifr signaling occurring at ser-1044. SIGNOR-270134 0.2 NSMCE4A protein Q9NXX6 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR form complex binding -1 27427983 t miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks SIGNOR-265486 0.826 PTPN2 protein P17706 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 15780598 t lperfetto Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5. SIGNOR-93998 0.725 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr566 SLNQEDIyITTESLT 10029 BTO:0000246 12907755 t PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates SIGNOR-248394 0.299 CSNK1A1 protein P48729 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity binding 9606 SIGNOR-C110 19293931 t gcesareni In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)] SIGNOR-184696 0.561 NBR1 protein Q14596 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 19250911 t gcesareni Nbr1 and p62 interact and form oligomers. SIGNOR-184273 0.484 FGF11 protein Q92914 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates activity binding 9606 BTO:0000199 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253418 0.2 GTF3C3 protein Q9Y5Q9 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR form complex binding 9606 29378333 t lperfetto Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains SIGNOR-266186 0.877 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT down-regulates activity phosphorylation Ser36 ELQRRRRsLALPGLQ 9606 15946941 t Luana Phosphorylation of GRK1 and GRK7 by cAMP-dependent Protein Kinase Attenuates Their Enzymatic Activities | We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA. SIGNOR-260840 0.2 ERBB2 protein P04626 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates relocalization 9606 16729043 t gcesareni Erbb3 is characterized by a large number of binding sites for phosphatidylinositol-3-kinase (pi3k), while erbb2 has only few interaction partners with shc as the most frequent one. SIGNOR-146855 0.533 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000551 19683496 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-187603 0.51 ZEB1 protein P37275 UNIPROT GRHL2 protein Q6ISB3 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 23814079 f miannu we could further demonstrate that expression of GRHL2 is directly suppressed by the transcription factor zinc finger enhancer-binding protein 1 (ZEB1), which in turn is a direct target for repression by GRHL2, suggesting that the EMT transcription factors GRHL2 and ZEB1 form a double negative regulatory feedback loop in breast cancer cells. SIGNOR-255623 0.443 GRK3 protein P35626 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates activity phosphorylation Thr182 VKALDFRtPRNAKII 8355 BTO:0000512 11060299 t gcesareni These results demonstrate that the T180A mutation probably blocks GRK3- and arr3-mediated desensitization of MOR by preventing a critical agonist-dependent receptor phosphorylation and suggest a novel GRK3 site of regulation not yet described for other G-protein-coupled receptors SIGNOR-247915 0.2 ATF2 protein P15336 UNIPROT SIRT4 protein Q9Y6E7 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0002572 33861966 t miannu Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). SIGNOR-267831 0.2 MAFA protein Q8NHW3 UNIPROT NKX6-1 protein P78426 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17149590 f miannu the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. SIGNOR-254564 0.44 PRKG1 protein Q13976 UNIPROT PRKG1 protein Q13976 UNIPROT up-regulates phosphorylation Ser65 TTRAQGIsAEPQTYR 9606 12080049 t miannu Serines 64 and 79 are homologous residues that are juxtaposed to the autoinhibitory pseudosubstrate site in cgmp-dependent protein kinase type ialpha and type ibeta (pkg-ialpha and pkg-ibeta), respectively. Autophosphorylation of this residue is associated with activation of type i pkgs. SIGNOR-89839 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 t Luana Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. SIGNOR-260755 0.2 STAT3 protein P40763 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression 9606 BTO:0001103 21408055 f andrea cerquone perpetuini Additionally, cMyc, a STAT3 downstream gene, was significantly up-regulated in SCs at T24 versus PRE [...]An increase in the number of cMyc+ SCs indicated that human SCs were induced to proliferate under the control of STAT3 signaling. SIGNOR-255413 0.744 CKM complex complex SIGNOR-C406 SIGNOR E2F1 protein Q01094 UNIPROT down-regulates activity phosphorylation Ser375 PVDEDRLsPLVAADS 9606 18794899 t lperfetto E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1. SIGNOR-273149 0.37 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates activity phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 12817019 t lperfetto Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase. SIGNOR-102511 0.797 CYP19A1 protein P11511 UNIPROT testosterone smallmolecule CHEBI:17347 ChEBI down-regulates quantity chemical modification 9606 BTO:0000975 27702664 t lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively SIGNOR-268671 0.8 RPS6KA5 protein O75582 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 12763138 t gcesareni The stat3-mediated transactivation was reduced by blocking the stat3 serine phosphorylation with the mek inhibitor u0126 or by expression of kinase-inactive msk1. SIGNOR-101251 0.393 PIM1 protein P11309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18593906 t gcesareni We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro. SIGNOR-179296 0.39 MAPK14 protein Q16539 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 12058028 t gcesareni The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro. SIGNOR-89436 0.456 BMPR1A protein P36894 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR up-regulates activity phosphorylation 9606 9442019 t ggiuliani In this study, we isolated human Smad5 and found that Smad5 was involved in BMP-2 signaling cascades, which mediate the bone-inducing effects of BMP-2. Smad5 was directly serine-phosphorylated by BMPIR through a physical interaction. The activated Smad5 subsequently formed a complex with DPC4, and this complex was then translocated to the nucleus. SIGNOR-255779 0.678 CDK1 protein P06493 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Ser370 PLGPLAGsPVIAAAN 9606 7592773 t lperfetto Four residues within this domain, thr-344, thr-360, ser-362, and ser-370, conform to the minimal consensus sequence for p34cdc2 phosphorylationthe high stoichiometry of phosphorylation suggests that phosphorylation could regulate functional properties of ckii and that it could in some way participate in the burst of phosphorylation that accompanies the activation of p34graphic at the ggraphic-m transition SIGNOR-29521 0.361 CREB1 protein P16220 UNIPROT BDNF protein P23560 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000142 32603820 t miannu Brain-derived neurotrophic factor (BDNF) is a critical molecule for learning and memory. Brain BDNF levels correlate with cognitive status. Activation of CREB facilitates the transcription of crucial proteins for activity-dependent plasticity particularly BDNF. SIGNOR-265062 0.502 EXOC2 protein Q96KP1 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270777 0.928 PRKG1 protein Q13976 UNIPROT PTS protein Q03393 UNIPROT up-regulates phosphorylation Ser19 AQVSRRIsFSASHRL 9606 BTO:0000142 10531334 t gcesareni Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps. Addition of cgmp stimulated phosphotransferase activity 2-fold. Extracts from transfected cos-1 cells overexpressing cgkii stimulated ser(19) phosphorylation more than 100-fold.In assays with purified enzymes, wild-type but not ptps-s19a was a specific substrate for the cgmp-dependent protein kinase (cgk) type i and ii. Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps SIGNOR-71680 0.259 SLC1A5 protein Q15758 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity relocalization 9606 26724577 t Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine. SIGNOR-266914 0.8 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP -1 15241418 t llicata Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. | Thr 8 and the four sites in the linker (Thr 178, Ser 203, Ser 207 and Ser 212). Each of the five sites was phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo. SIGNOR-250749 0.733 CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 BTO:0000876 BTO:0001103 19436055 f apalma As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of beta-c, Src homology 2 and phosphotyrosine binding domain proteins are recruited to the active receptor and initiate the major tyrosine phosphorylation-dependent signaling pathways, including the Jak/signal transducer and activator of transcription, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3 (PI-3) kinase pathways SIGNOR-255586 0.2 PRPS1 protein P60891 UNIPROT 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI up-regulates quantity chemical modification 9606 16939420 t miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. SIGNOR-267079 0.8 glucose chemical CHEBI:17234 ChEBI Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity by stabilization 9606 BTO:0004424 26323688 t inferred from family member Consistently, treatment of cells with 2-deoxy-d-glucose (2DG), which completely inhibits glucose metabolism, leads to HK2 degradation and cell death in combination with C43 SIGNOR-270265 0.8 KCNB1 protein Q14721 UNIPROT VAPA protein Q9P0L0 UNIPROT up-regulates quantity relocalization 9606 BTO:0000007 29941597 t lperfetto Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions. SIGNOR-262122 0.2 RNF111 protein Q6ZNA4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000165;BTO:0000222 17341133 t lperfetto Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblastsarkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling. SIGNOR-236873 0.672 CDK5 protein Q00535 UNIPROT PARP1 protein P09874 UNIPROT down-regulates activity phosphorylation Ser785 LRGGSDDsSKDPIDV -1 21922195 t miannu These results would suggest that the phosphorylation of PARP-1 via Cdk5's kinase activity is necessary for its persistence at damage sites.Based on these results and the recruitment data, we hypothesize that the phosphorylation of the PARP-1 protein by Cdk5 on one or more of the serines 782, 785, and 786 results in an attenuation of its ribosylating activity facilitating its persistence at the sites of DNA damage. SIGNOR-276358 0.261 GABRD protein O14764 UNIPROT GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263746 0.394 FBXO32 protein Q969P5 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 10090 11717410 f Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases SIGNOR-255342 0.7 ENO3 protein P13929 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI down-regulates quantity chemical modification 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266530 0.8 TNKS protein O95271 UNIPROT RNF146 protein Q9NTX7 UNIPROT up-regulates activity 9606 BTO:0000007 21478859 f lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. SIGNOR-263338 0.713 HSPA1A protein P0DMV8 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates 9606 16172114 f gcesareni Hsp70 inhibited stress-induced jnk activation and jnk with sp600125 or by expression of a dominant negative mutant of jnk-blocked bax translocation as effectively as hsp70 overexpression SIGNOR-140553 0.494 alanine smallmolecule CHEBI:16449 ChEBI Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI up-regulates quantity precursor of 9606 32314272 t miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). SIGNOR-270452 0.8 CBL protein P22681 UNIPROT LRIG1 protein Q96JA1 UNIPROT down-regulates ubiquitination 9606 BTO:0001253 15282549 t gcesareni We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation. SIGNOR-127289 0.572 CABLES1 protein Q8TDN4 UNIPROT CDK2 protein P24941 UNIPROT down-regulates activity binding -1 25361894 t miannu Our study also showed that Cables1 increases the level of p21 and decreases the level of pRb, but does not affect the other cell cycle-related proteins we studied. Induction of apoptosis by Cables1, which occurs partially through inhibiting Cdk2 activity and upregulating p21, is prevented by Akt phosphorylation and 14-3-3 binding. SIGNOR-276759 0.472 TRIM13 protein O60858 UNIPROT CD3D protein P04234 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 17314412 t miannu RFP2, a gene frequently lost in various malignancies, encodes a protein with RING finger, B-box, and coiled-coil domains that belongs to the RBCC/TRIM family of proteins.Rfp2 Regulates the Stability of the ERAD Substrate CD3-δ. In summary, these experiments demonstrate that Rfp2 functions as a RING-dependent ERAD E3 ubiquitin ligase and regulates the degradation of the ER substrate, CD3-δ. SIGNOR-271644 0.2 Neuregulin proteinfamily SIGNOR-PF37 SIGNOR ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 t Does not bind to the ERBB1, ERBB2 and ERBB3 receptors gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. SIGNOR-269970 0.2 ARHGAP27 protein Q6ZUM4 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260482 0.572 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269364 0.719 ATM protein Q13315 UNIPROT COP1 protein Q8NHY2 UNIPROT down-regulates phosphorylation Ser387 SDDSRTAsQLDEFQE 9606 16931761 t lperfetto Atm engages autodegradation of the e3 ubiquitin ligase cop1 after dna damage. We observed that in response to dna damage, atm phosphorylated cop1 on ser(387) and stimulated a rapid autodegradation mechanism SIGNOR-149082 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250556 0.2 HECW2 protein Q9P2P5 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 BTO:0000093 27119228 t miannu NEDL2 acts as a scaffold protein to promote GDNF-stimulated Akt activation. biochemical analysis indicated that NEDL2 appears to act like a scaffold protein to recruit SHC, Grb2, PI3K (p110 and p85), PDK1 and Akt together to promote the signaling transduction. NEDL2 binds p85, p110 and Akt with different domains SIGNOR-269458 0.2 DMTF1 protein Q9Y222 UNIPROT ECT2 protein Q9H8V3 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004532 19816943 f Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  SIGNOR-261589 0.2 KIF1A protein Q12756 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272522 0.7 CSNK2A1 protein P68400 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT down-regulates activity phosphorylation Ser740 TKAQRENsPAAFPDR 9606 BTO:0000567 12591939 t llicata We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified SIGNOR-250845 0.381 DAB2IP protein Q5VWQ8 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 27858941 f miannu DAB2IP inactivation promotes tumor growth and survival, development, and proliferation of CSC, and resistance to chemo- and radiotherapy. It induces EMT, increases cell migration and invasion, and counteracts pro-apoptotic signaling. SIGNOR-254779 0.7 ECM stimulus SIGNOR-ST20 SIGNOR AD/b2 integrin complex SIGNOR-C172 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259055 0.7 TESK2 protein Q96S53 UNIPROT CFL1 protein P23528 UNIPROT down-regulates activity phosphorylation Ser3 sGVAVSDG 9606 BTO:0000567 11418599 t lperfetto Like tesk1, tesk2 phosphorylated cofilin specifically at ser-3 and induced formation of actin stress fibers and focal adhesions. SIGNOR-108753 0.517 CSNK2A1 protein P68400 UNIPROT TCOF1 protein Q13428 UNIPROT up-regulates activity phosphorylation Thr210 TSSSSDEtDVEGKPS 9606 BTO:0000567 25064736 t lperfetto Phosphorylated Thr 210 in Treacle is the major interaction site for NBS1|A purified GST fragment of this region was efficiently phosphorylated by CK2 in vitro (Supplementary Fig. 4; T-2) and this fragment pulled down the MRN complex from Hela nuclear extracts only when previously phosphorylated by CK2 SIGNOR-265086 0.31 PRKCQ protein Q04759 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251636 0.2 SRC protein P12931 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates activity phosphorylation Tyr773 DTANNPLyKEATSTF 9606 BTO:0003904 11723131 t lperfetto The phosphorylation level of beta(3) integrin was modulated using a temperature-sensitive v-Src kinase. Increased beta(3) phosphorylation abolished alpha(v)beta(3)- but not alpha(5)beta(1)-mediated adhesion to fibronectin. Thus, phosphorylation of the cytoplasmic domain of beta(3) is a negative regulator of alpha(v)beta(3)-fibronectin binding strength. SIGNOR-247202 0.647 PTPN1 protein P18031 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1016 DVVDADEyLIPQQGF -1 8621392 t We have shown previously that amino acid residues flanking the phosphotyrosine are important for efficient PTP1 catalysis (Table 1 and Refs. 9, 10, and 17). For example, the kcat/Km value for the undecapeptide, EGFR988-989 (epidermal growth factor autophosphorylation site Tyr992, residues 988-998) (Asp-Ala-Asp-Glu-pTyr-Leu-Ile-Pro-Gln-Gln-Gly) is 3220-fold higher than that of phosphotyrosine (Table 1). We further demonstrated that a minimum of six amino acid residues are required for the most efficient PTP1 binding and catalysis. SIGNOR-248407 0.751 ING1 protein Q9UK53 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT down-regulates activity binding 9606 14522900 t miannu We found that p33(ING1b) physically interacts with hSIR2, reverses its ability to induce the AFP promoter, and induces acetylation of p53 residues at Lys(373) and/or Lys(382). SIGNOR-254486 0.463 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates activity phosphorylation Ser660 FSAERRNsILTETLH -1 1377674 t miannu CFTR is phosphorylated directly by PKA and PKC in vivo. phosphorylation by PKA is necessary to allow ATP hydrolysis by CFTR and that ATP hydrolysis is necessary for channel opening. CF-2 was phosphorylated by PKA in vitro on serines 660,700, 737, 813 and most likely on both serines 768 and 795. SIGNOR-250349 0.467 KMT2A protein Q03164 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0002181 22012064 t irozzo Similar to CBFβ, we show that MLL binds to AML1 abrogating its proteasome-dependent degradation.Furthermore, we demonstrate that MLL binds to a region of AML1 (that is conserved in AML2 and AML3) and increases AML1 (AML2 and AML3) protein levels SIGNOR-255707 0.549 MAPK14 protein Q16539 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 t lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK SIGNOR-264446 0.284 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine chemical CHEBI:91419 ChEBI CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190182 0.8 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194334 0.8 LSM-1131 chemical CHEBI:91398 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189873 0.8 3-methyladenine chemical CHEBI:38635 ChEBI PIK3C3 protein Q8NEB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205636 0.8 AMPK complex SIGNOR-C15 SIGNOR MAPK14 protein Q16539 UNIPROT up-regulates activity 10090 20660302 f P38 MAPK mediates the effect of AMPK on Gr induced transcriptional activity SIGNOR-255951 0.284 CTNNB1 protein P35222 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 19175684 f gcesareni In-teractions between beta-catenin and runx2 play an im-portant role in bmp-9-induced osteogenic differentia-tion of mscs. SIGNOR-183532 0.453 ACVR2A protein P27037 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates binding 9606 9748228 t fspada The major bmp7 type i receptor observed was alk2, SIGNOR-60234 0.65 ULK2 protein Q8IYT8 UNIPROT PRKAG3 protein Q9UGI9 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. SIGNOR-173095 0.2 DPM1 protein O60762 UNIPROT DPM complex complex SIGNOR-C289 SIGNOR form complex binding 9606 10835346 t lperfetto Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3. SIGNOR-262563 0.779 CUDC-101 chemical CID:24756910 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191148 0.8 R547 chemical CID:6918852 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206358 0.8 MAP3K6 protein O95382 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates quantity by stabilization phosphorylation Thr838 GINPCTEtFTGTLQY 9606 17210579 t Manara ASK2 Activates ASK1 by Phosphorylation SIGNOR-260832 0.531 vatalanib chemical CHEBI:90620 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207648 0.8 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity dephosphorylation 9606 23015147 t Calcineurin is known to facilitate the nuclear translocation of the nuclear factor of activated T cells (NFAT). SIGNOR-253329 0.818 MAP3K11 protein Q16584 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates 9606 9733513 f gcesareni This scaffold protein selectively enhanced jnk activation by the mlk signaling pathway. SIGNOR-59884 0.33 FLT3 protein P36888 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10090 10080542 t gcesareni FL stimulation induces association of Grb2 with Flt3, SHP-2,and Shc SIGNOR-245060 0.591 ENMD-2076 chemical CID:16041424 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191469 0.8 JUN protein P05412 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding 9606 25875593 t irozzo C-Fos dimerizes with c-Jun to form the transcription activator protein-1 (AP-1) which binds to the specific recognition site. SIGNOR-256367 0.951 ixazomib citrate chemical CHEBI:90939 ChEBI PSMB5 protein P28074 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194536 0.8 TET3 protein O43151 UNIPROT OGT protein O15294 UNIPROT up-regulates binding 9606 23353889 t miannu Tet2 and tet3 associate with the o_glcnac transferase ogt / tet2 and tet3 promote ogt_mediated glcnacylation SIGNOR-200729 0.455 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK6 protein Q00534 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189996 0.8 SGX-523 chemical CHEBI:90624 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206905 0.8 WWTR1 protein Q9GZV5 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates binding 9606 20466877 t gcesareni Taz physically interacts with myod through the ww domain and activates myod-dependent gene transcription. SIGNOR-165414 0.279 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207666 0.8 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates chemical activation 9606 8276865 t gcesareni Lpa activates its own g protein-coupled receptor(s). SIGNOR-36389 0.8 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 RDPVARTsPLQTPAA 9534 BTO:0004055 10677502 t lperfetto Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70. SIGNOR-219217 0.533 ACTL6A protein O96019 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270718 0.677 CCT137690 chemical CID:25154041 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190892 0.8 B-WICH complex complex SIGNOR-C447 SIGNOR MYC protein P01106 UNIPROT up-regulates activity binding 9606 BTO:0000567 25883140 t miannu The B-WICH complex allows c-Myc to bind to a site in the IGS. c-Myc requires the B-WICH complex to remodel chromatin for its function. SIGNOR-268842 0.299 NONO protein Q15233 UNIPROT TOP1 protein P11387 UNIPROT up-regulates binding 9606 BTO:0000017 9756848 t miannu We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i SIGNOR-60557 0.381 RPS6KB1 protein P23443 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates 9606 17181399 f gcesareni Finally, downregulation of p70 s6 kinase by sirna significantly enhanced the fgf-2-stimulated vegf release and phosphorylation of sapk/jnk. SIGNOR-149367 0.43 GAB1 protein Q13480 UNIPROT ARHGAP32 protein A7KAX9 UNIPROT up-regulates relocalization 9606 12819203 t gcesareni Gc-gap, a rho family gtpase-activating protein that interacts with signaling adapters gab1 and gab2. SIGNOR-102586 0.319 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 11208622 t ashma gcesareni SIGNOR-251687 0.8 AGO2 protein Q9UKV8 UNIPROT DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR form complex binding 9606 23661684 t miannu SIGNOR-143102 0.807 FOXO1 protein Q12778 UNIPROT FSHB protein P01225 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004467 24065703 f miannu We demonstrate that FOXO1 represses basal and GnRH-induced Fshb transcription in LβT2 cells. SIGNOR-254185 0.353 BRCA1 protein P38398 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 15549093 f lperfetto The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination SIGNOR-251500 0.7 EPC1 protein Q9H2F5 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269305 0.649 crizotinib chemical CHEBI:64310 ChEBI ALK protein Q9UM73 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191133 0.8 MAPK3 protein P27361 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation 9606 14967450 t gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-121994 0.487 XL147 chemical CHEBI:71957 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207854 0.8 FLT3LG protein P49771 UNIPROT FLT3 protein P36888 UNIPROT up-regulates binding 9606 BTO:0001271 12681969 t gcesareni Flt3 is activated by binding of its natural flt3-ligand (flt3-l), SIGNOR-99750 0.881 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 25901680 f lperfetto Ribosomes are translational machineries that catalyse protein synthesis. SIGNOR-262412 0.7 AMG-208 chemical CHEBI:90626 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189507 0.8 SKI protein P12755 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates binding 9606 12419246 t gcesareni Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad5. SIGNOR-195630 0.686 TOP2B protein Q02880 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 24463367 f lperfetto Topoisomerase IIbeta is required for proper retinal development and survival of postmitotic cells SIGNOR-242533 0.7 PDE4DIP protein Q5VU43 UNIPROT PRKAR1A protein P10644 UNIPROT up-regulates binding 9606 21569246 t miannu Mmgl acts as a dual-specific akap by anchoring pka regulatory isoforms r1a and r2a. SIGNOR-173769 0.32 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 BTO:0000007 22863277 t milica The cAMP signaling cascade can activate protein kinase a (PKA) SIGNOR-198492 0.8 WWTR1 protein Q9GZV5 UNIPROT PAX3 protein P23760 UNIPROT up-regulates binding 10090 BTO:0000165;BTO:0000222 16300735 t gcesareni These results indicate that pax3 specifically interacts with taz both in vitro and in vivo. SIGNOR-236879 0.466 alvocidib chemical CHEBI:47344 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191529 0.8 torin 2 chemical CHEBI:90682 ChEBI RPS6KB1 protein P23443 UNIPROT down-regulates 9606 23436801 f gcesareni Torin2 inhibited mtorc1-dependent t389 phosphorylation on s6k (rps6kb1) SIGNOR-201502 0.8 GPER1 protein Q99527 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000130 22203955 t gcesareni However, grpr preferentially couples to galfaq proteins. SIGNOR-195320 0.2 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCE protein Q02156 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191496 0.8 TP53INP1 protein Q96A56 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 22421968 t gcesareni Tp53inp1-lc3 interaction occurs via a functional lc3-interacting region (lir). SIGNOR-196670 0.354 6alpha-methylprednisolone chemical CHEBI:6888 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 1159081 t inflammation gcesareni SIGNOR-251697 0.8 PD318088 chemical CID:10231331 PUBCHEM MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205737 0.8 regorafenib chemical CHEBI:68647 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206418 0.8 olaparib chemical CHEBI:83766 ChEBI PARP2 protein Q9UGN5 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-195019 0.8 BTRC protein Q9Y297 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR form complex binding 9606 10023660 t gcesareni The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin. SIGNOR-64496 0.818 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 11790798 t lperfetto Thus, the c-terminal tail of vav serves as a direct substrate of bcr-abl in vitro. SIGNOR-114094 0.2 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr751 SKDESVDyVPMLDMK 9606 18567737 t gcesareni Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr. SIGNOR-179076 0.679 TWIST1 protein Q15672 UNIPROT CSNK2A1 protein P68400 UNIPROT down-regulates 9606 22975381 f amattioni Ck2-mediated phosphorylation at ser392 of p53 was attenuated in the presence of recombinant twist1 SIGNOR-192064 0.2 DCC protein P43146 UNIPROT Chemoattraction_of_axon phenotype SIGNOR-PH197 SIGNOR up-regulates 9606 BTO:0001484 25881791 f miannu DCC constitutively expresses on the axonal surface. Netrin-1-binding to DCC induces chemoattraction SIGNOR-268163 0.7 PRKCH protein P24723 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser595 GLMQQQKsFR 9606 11781100 t lperfetto  In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta. SIGNOR-249140 0.313 AMG 900 chemical CID:24856041 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189498 0.8 AVP protein P01185 UNIPROT BAD protein Q92934 UNIPROT down-regulates 9606 BTO:0000938 BTO:0000142 18402937 f gcesareni Vp induces phosphorylation of the pro-apoptotic protein bad and prevents cytochrome c release. SIGNOR-178197 0.2 2-(6,7-dimethoxy-4-quinazolinyl)-5-(2-pyridinyl)-1,2,4-triazol-3-amine chemical CHEBI:91330 ChEBI ATM protein Q13315 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191094 0.8 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207669 0.8 ULK2 protein Q8IYT8 UNIPROT PRKAB1 protein Q9Y478 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity SIGNOR-173092 0.335 MK-2461 chemical CID:44137946 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194367 0.8 QRICH1 protein Q2TAL8 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 33384352 f miannu QRICH1 promotes cell death and its translation is upregulated by the PERK-eIF2α axis under ER stress. SIGNOR-269399 0.7 sapitinib chemical CHEBI:132986 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190149 0.8 masitinib chemical CHEBI:63450 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194257 0.8 WAY-600 chemical CID:25229526 PUBCHEM MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck;ATP-competitive inhibitor mTOR gcesareni SIGNOR-207788 0.8 CRP protein P02741 UNIPROT LPL protein P06858 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18708524 f Regulation of expression miannu C-reactive protein enhances macrophage lipoprotein lipase expression. SIGNOR-251852 0.38 ERBB4 protein Q15303 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 16729043 t gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. SIGNOR-146888 0.325 alvocidib chemical CHEBI:47344 ChEBI CDK4 protein P11802 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192038 0.8 ezogabine chemical CHEBI:68584 ChEBI KCNQ2 protein O43526 UNIPROT up-regulates chemical activation 9606 Other t Selleck;anticonvulsant for KCNQ2/3 currents gcesareni SIGNOR-206483 0.8 PIDD1 protein Q9HB75 UNIPROT Caspase-2 PIDDosome complex SIGNOR-C292 SIGNOR form complex binding 9606 20158568 t miannu The PIDDosome consists of the proteins PIDD, RAIDD and caspase-2. SIGNOR-262643 0.844 CASP3 protein P42574 UNIPROT DNA_fragmentation phenotype SIGNOR-PH22 SIGNOR up-regulates 9606 10200555 f amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation SIGNOR-66863 0.7 PIK-75 Hydrochloride chemical CID:45265864 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252652 0.8 UBAP2 protein Q5T6F2 UNIPROT ANXA2 protein P07355 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0002181 27121050 t Sara UBAP2 formed a complex with Annexin A2 and promoted the degradation of Annexin A2 protein by ubiquitination SIGNOR-261314 0.348 Elongator complex complex SIGNOR-C466 SIGNOR TUBA8 protein Q9NY65 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 t miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. SIGNOR-269721 0.254 PHA-848125 chemical CID:16718576 PUBCHEM CCNA2 protein P20248 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206148 0.8 GSK1059615 chemical CHEBI:71955 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192780 0.8 DUSP4 protein Q13115 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 16849326 t gcesareni This result suggests that dusp4 represses gluconeogenesis through dephosphorylation of p38 SIGNOR-147958 0.651 GW 3965 chemical CHEBI:79995 ChEBI NR1H3 protein Q13133 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-193015 0.8 SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 11404076 t gcesareni We find that Notch 3 IC, like Notch 1 IC, can bind the SKIP and PCAF proteins SIGNOR-108499 0.585 rosiglitazone chemical CHEBI:50122 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9534 7768881 t An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma) SIGNOR-251646 0.8 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser253 SVEFEVEsLDSEDYS 9606 12167711 t gcesareni Hypophosphorylation of mdm2 augments p53 stability. SIGNOR-91195 0.352 ADIPOR1 protein Q96A54 UNIPROT APPL1 protein Q9UKG1 UNIPROT up-regulates binding 9606 16622416 t milica Appl1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin. SIGNOR-146212 0.745 NODAL protein Q96S42 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0004094 15531507 f Regulation miannu Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7. SIGNOR-251935 0.7 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates transcriptional regulation 9606 27563484 f ggiuliani Smad1/5/8-Smad4 complex transcribed Runx2 expression, as they complex with Runx2 to initiate other osteoblast gene expression. SIGNOR-255836 0.578 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A12 protein P48065 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207031 0.8 PHA-767491 chemical CID:11715767 PUBCHEM CDK7 protein P50613 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206112 0.8 PF-03814735 chemical CID:49830590 PUBCHEM PTK2 protein Q05397 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205959 0.8 NOD2 protein Q9HC29 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 18079694 f miannu Nod1 and Nod2 stimulation activates NF-kappaB through RICK, a caspase-recruitment domain-containing kinase. SIGNOR-252412 0.378 MAPK3 protein P27361 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation 9606 23583303 t gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-201687 0.487 SP6 protein Q3SY56 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates quantity by repression transcriptional regulation 19088080 f lperfetto Mechanistically, KLF14 represses the TGFbetaRII promoter via a co-repressor complex containing mSin3A and HDAC2. SIGNOR-271695 0.313 motesanib chemical CHEBI:51098 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194563 0.8 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation 9606 21808241 t inferred from 70% family members gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. SIGNOR-270218 0.2 IL13 protein P35225 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding 9606 12704343 t milica Both il-4 and il-13 use the IL-4R Chain as a component of their receptors. SIGNOR-100753 0.893 SOX2 protein P48431 UNIPROT NR2E1 protein Q9Y466 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22194602 f miannu Sox2 positively regulates tlx expression SIGNOR-191714 0.382 dacomitinib chemical CHEBI:132268 ChEBI ERBB4 protein Q15303 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205942 0.8 CNTF protein P26441 UNIPROT CNTFR protein P26992 UNIPROT up-regulates binding 9606 10812968 t amattioni Signal transduction by cntf requires that it bind first to cntfr alpha. Cntf activates downstream signaling molecules SIGNOR-77408 0.784 TRPC6 protein Q9Y210 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates activity 9606 27383564 f gcesareni TRPC6 channel-dependent [Ca2+]i elevation and sequential activation of the calcineurin. SIGNOR-253328 0.2 AMOTL2 protein Q9Y2J4 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 BTO:0001176 21937427 f lperfetto Taking together, our data indicate that Amotl2 plays a pivotal role in polarity, migration and proliferation of angiogenic endothelial cells. SIGNOR-271872 0.7 TIAM1 protein Q13009 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 12393875 t gcesareni Lpa-induced rac activation requires tiam1 SIGNOR-94691 0.74 FOS protein P01100 UNIPROT JUN protein P05412 UNIPROT up-regulates activity binding 10090 2516828 t The cFos proto-oncoprotein associates with cJun to form a heterodimer with increased DNA binding and transcriptional activities. SIGNOR-252087 0.951 Frizzled proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates binding 19279717 t apalma Wnt signaling is transduced through Fz independent of LRP5/6 leading to the activation of Dsh. SIGNOR-255891 0.2 GTF3C6 protein Q969F1 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR form complex binding 9606 29378333 t lperfetto Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains SIGNOR-266183 0.864 MIB1 protein Q86YT6 UNIPROT DLL3 protein Q9NYJ7 UNIPROT up-regulates activity ubiquitination 9606 16140393 t lperfetto Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity. SIGNOR-209672 0.356 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI Glutaminolysis phenotype SIGNOR-PH119 SIGNOR up-regulates activity 9606 BTO:0000567 22749528 f Luana Leucine and Glutamine Activate Glutaminolysis and mTORC1 SIGNOR-268016 0.7 GNAI3 protein P08754 UNIPROT TNFAIP8 protein O95379 UNIPROT up-regulates activity binding 9606 20607800 t TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation SIGNOR-256490 0.2 seliciclib chemical CHEBI:45307 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206568 0.8 NFIL3 protein Q16649 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 10090 BTO:0003104 10082541 f lperfetto the effect of NFIL3 on cytokine-mediated cell survival was independent of an effect on cell proliferation. SIGNOR-242760 0.7 CSNK2A1 protein P68400 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Thr1343 FSDFDEKtDDEDFVP 9606 9804834 t llicata Casein kinase II catalyzes a mitotic phosphorylation on threonine 1342 of human DNA topoisomerase IIalpha SIGNOR-250966 0.613 Telatinib chemical CID:9808844 PUBCHEM FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207221 0.8 4-[6-[4-(1-piperazinyl)phenyl]-3-pyrazolo[1,5-a]pyrimidinyl]quinoline chemical CHEBI:91387 ChEBI BMPR1A protein P36894 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193642 0.8 MTX1 protein Q13505 UNIPROT SAM complex complex SIGNOR-C422 SIGNOR form complex binding 31387448 t lperfetto The SAM complex of the outer membrane mediates insertion of β-barrel proteins into the outer membrane. hSam50 associates with MTX1 and MTX2. SIGNOR-267684 0.685 GSK1059615 chemical CHEBI:71955 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192693 0.8 RHEB protein Q15382 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT down-regulates activity binding -1 25660019 t Luana Rheb GTPase directly binds and activates PERK in vitro SIGNOR-260873 0.2 HIP1 protein O00291 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 11007801 f miannu Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain. SIGNOR-256646 0.7 TNFAIP3 protein P21580 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity deubiquitination 9606 18164316 t lperfetto A20 is a deubiquitinating enzyme (dub) for lys63-linked polyubiquitinated signaling mediators such as traf6 SIGNOR-160223 0.69 CENPE protein Q02224 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity 10090 BTO:0000452 12925705 f lperfetto CENP-E is required for efficient recruitment of BubR1, Mad1, and Mad2 to attached and newly unattached kinetochores SIGNOR-252044 0.621 XAV939 chemical CHEBI:62878 ChEBI TNKS protein O95271 UNIPROT down-regulates chemical inhibition 9606 19759537 t gcesareni Xav939 inhibits the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2. SIGNOR-188054 0.8 RASSF5 protein Q8WWW0 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates activity binding 9606 22195963 t lperfetto NORE1A can heterodimerize with RASSF1A and, thus, mediate K-Ras regulation of RASSF1A SIGNOR-249587 0.527 TGFB1 protein P01137 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 19114990 t lperfetto While association of the TGF_RI receptor with p85 requires TGF-_ stimulation. SIGNOR-217960 0.26 3-(3-oxo-1H-indol-2-ylidene)-1H-indol-2-one chemical CHEBI:92322 ChEBI GSK3B protein P49841 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193402 0.8 IGF1R protein P08069 UNIPROT IRS2 protein Q9Y4H2 UNIPROT up-regulates phosphorylation 9606 10471495 t flangone Our results reveal that igf-1 receptors promote beta-cell development and survival through the irs-2 signalling pathway. SIGNOR-70477 0.795 TGFB1 protein P01137 UNIPROT RNF111 protein Q6ZNA4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14657019 f lpetrilli Expression of arkadia is down-regulated by tgf-beta. SIGNOR-119669 0.2 IL1A protein P01583 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 21304099 f lperfetto Interleukin-1 in the pathogenesis and treatment of inflammatory diseases SIGNOR-171873 0.7 GLS protein O94925 UNIPROT Glutaminolysis phenotype SIGNOR-PH119 SIGNOR up-regulates activity 9606 28053289 f Glutaminase is the rate-limiting enzyme in glutaminolysis and it is encoded by two different genes, GLS and GLS2. SIGNOR-259999 0.7 A5/b1 integrin complex SIGNOR-C163 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity 15721307 f lperfetto Previous reports indicated that the prosurvival signal mediated through α5β1-fibronectin interactions was due to increased Bcl-2 levels SIGNOR-253310 0.2 SNS-314 Mesylate chemical CID:24995523 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207102 0.8 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 20663147 t gcesareni Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation. SIGNOR-167152 0.838 APOC3 protein P02656 UNIPROT LPL protein P06858 UNIPROT down-regulates activity 9606 17315402 f Regulation miannu Apolipoprotein CIII inhibits the lipoprotein lipase. SIGNOR-251850 0.633 AGPAT3 protein Q9NRZ7 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI up-regulates chemical modification 9606 12401205 t gcesareni Pa can be generated by the acylation of lyso-pa by lyso-pa acyl transferases SIGNOR-94864 0.8 MPO-ANCA complex SIGNOR-C474 SIGNOR ROS stimulus SIGNOR-ST2 SIGNOR up-regulates -1 2161532 f lperfetto ANCA-induced release of ROS measured by chemiluminescence. SIGNOR-270590 0.7 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser359 SPSTPVGsPQGLAGT 9606 19801649 t llicata Mlk2 inhibits e47 transactivation activity on the trkb promote SIGNOR-161531 0.2 F2 protein P00734 UNIPROT F2RL2 protein O00254 UNIPROT up-regulates binding 9606 11356985 t gcesareni as noted previously, the human form of par-3 activated phosphoinositide signaling in response to thrombin when overexpressed in cos-7 cells SIGNOR-108225 0.638 KITLG protein P21583 UNIPROT KIT protein P10721 UNIPROT up-regulates binding 9606 1698556 t gcesareni We have also provided biological and physical evidence that scf is a ligand for the c-kit receptor. SIGNOR-21193 0.933 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR IL10 protein P22301 UNIPROT up-regulates quantity 10090 BTO:0004732 26208884 f The mitogen activated protein kinases ERK1/2 play an important role in response to toll like receptor (TLR) activation and cytokine production, including IL-10 and IL-12. SIGNOR-256080 0.2 regorafenib chemical CHEBI:68647 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206415 0.8 GSK690693 chemical CHEBI:90677 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193000 0.8 STC2 protein O76061 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 10090 BTO:0000298 29207625 f lperfetto STC2 activates STAT3 signaling pathway in the hypothalamus and GT1-7 cells SIGNOR-260406 0.2 Brivanib alaninate chemical CID:11154925 PUBCHEM FGFR2 protein P21802 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190720 0.8 seliciclib chemical CHEBI:45307 ChEBI CCNE1 protein P24864 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206565 0.8 SKP1 protein P63208 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR form complex binding 9606 10023660 t gcesareni The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin. SIGNOR-64514 0.892 ARSA protein P15289 UNIPROT HBA1 protein P69905 UNIPROT up-regulates activity acetylation 9606 237937 t Regulation miannu ASA acetylates hemoglobin. Purified acetylated hemoglobin had a slightly increased oxygen affinity and decreased heme-heme interaction. SIGNOR-251773 0.2 6-[difluoro-[6-(1-methyl-4-pyrazolyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl]quinoline chemical CHEBI:91417 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193522 0.8 orantinib chemical CHEBI:91088 ChEBI PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207441 0.8 PI-103 chemical CHEBI:90524 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206163 0.8 GDF2 protein Q9UK05 UNIPROT ALPL protein P05186 UNIPROT up-regulates 9606 19175684 f gcesareni Wnt3a and bmp-9 enhanced each other's ability to induce alp in mscs SIGNOR-183535 0.258 MK-2461 chemical CID:44137946 PUBCHEM MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194384 0.8 LRIG1 protein Q96JA1 UNIPROT LRIG3 protein Q6UXM1 UNIPROT down-regulates 9606 23723069 f miannu Lrig1 destabilizes lrig3, limiting lrig3's positive effects on receptors and identifying lrig3 as a new target of lrig1. SIGNOR-202177 0.443 MKNK1 protein Q9BUB5 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni Mnk1 and mnk2 regulate protein synthesis by phosphorylating the initiation factor eif4e. SIGNOR-166646 0.77 MET protein P08581 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 8662889 t gcesareni To efficiently promote transformation met requires direct binding with grb2. SIGNOR-42358 0.272 Tert-butyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate chemical CID:46907787 PUBCHEM BRD4 protein O60885 UNIPROT down-regulates activity chemical inhibition 9606 20871596 t Simone Vumbaca JQ1 displaces BRD4 from nuclear chromatin in cells SIGNOR-261123 0.8 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates activity phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 BTO:0000567 12637538 t Abl Phosphorylates and Activates PKD through Tyr463 Phosphorylation SIGNOR-251430 0.345 COL2A1 protein P02458 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR up-regulates binding 9606 9685391 t gcesareni We have isolated a novel collagen type ii binding integrin, a10b1, SIGNOR-59349 0.468 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr471 YEDAGSHyLCLLKAR 9606 12408982 t gcesareni Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity. SIGNOR-95242 0.427 SGI-1776 chemical CID:24795070 PUBCHEM PIM3 protein Q86V86 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206896 0.8 BUB1 protein O43683 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR up-regulates 9606 20888775 f gcesareni The multidomain protein kinases bub1 and bubr1 (mad3 in yeast, worms and plants) are central components of the mitotic checkpoint for spindle assembly (sac) SIGNOR-168192 0.7 6-propyl-2-thiouracil smallmolecule CHEBI:8502 ChEBI DIO1 protein P49895 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001379 27347897 t scontino The activity of D1 but not D2 or D3 is inhibited by 6n-propylthiouracil (PTU). SIGNOR-267280 0.8 CUL4A protein Q13619 UNIPROT DCX DET1-COP1 complex SIGNOR-C24 SIGNOR form complex binding 9606 17452440 t lperfetto Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes SIGNOR-154502 0.897 CCT129202 chemical CID:16202152 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190880 0.8 F2R protein P25116 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22972936 t milica Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase. SIGNOR-199010 0.547 3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol chemical CHEBI:94691 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207248 0.8 CADM2 protein Q8N3J6 UNIPROT Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 BTO:0000962 17967169 f Gianni The adhesion molecule Necl-3/SynCAM-2 localizes to myelinated axons, binds to oligodendrocytes and promotes cell adhesion. SIGNOR-268856 0.7 progesterone smallmolecule CHEBI:17026 ChEBI COMT protein P21964 UNIPROT down-regulates 17138778 f Regulation of expression miannu Catechol-O-methyltransferase expression was down-regulated by progesterone or estrogen. SIGNOR-251960 0.8 CHIR-124 chemical CID:11502647 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190973 0.8 dacomitinib chemical CHEBI:132268 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205939 0.8 FOXO3 protein O43524 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 15109499 f gcesareni Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. SIGNOR-241949 0.7 CDK18 protein Q07002 UNIPROT RB1 protein P06400 UNIPROT unknown phosphorylation -1 28361970 t lperfetto Activated PCTK3 phosphorylates retinoblastoma protein (Rb) in vitro.  SIGNOR-264558 0.291 R406 chemical CID:11984591 PUBCHEM SYK protein P43405 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206340 0.8 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide chemical CHEBI:91447 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194913 0.8 GSK256066 chemical CID:9827968 PUBCHEM PDE4B protein Q07343 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192982 0.8 LHX2 protein P50458 UNIPROT CGA protein P01215 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0001538 7513049 t Luana In Cos cells, LH-2 activated the a-subunit promoter approximately twofold SIGNOR-266055 0.269 LTBR protein P36941 UNIPROT Lymphoma phenotype SIGNOR-PH14 SIGNOR up-regulates 9606 17633025 f lperfetto The lymphotoxin-beta receptor (ltbetar, tnfrsf3) signaling pathway activates gene transcription programs and cell death important in immune development and host defense. SIGNOR-156902 0.7 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation Ser143 PPFPSRDsGRLSPDL 9606 21658950 t miannu Phosphorylation by Aurora B is required for full Haspin activity toward H3T3 in mitosis SIGNOR-262656 0.2 NUMA1 protein Q14980 UNIPROT TUBB protein P07437 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-116900 0.378 SFPQ protein P23246 UNIPROT LMX1B/SFPQ/PSPC1 complex complex SIGNOR-C106 SIGNOR form complex binding 10090 23308148 t miannu LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo. SIGNOR-223970 0.457 CSNK2A2 protein P19784 UNIPROT HNRNPC protein P07910 UNIPROT unknown phosphorylation Ser260 SEGGADDsAEEGDLL -1 12564933 t llicata Protein kinase CK2 phosphorylates hnRNP-C1/C2 at S247 SIGNOR-251007 0.332 U0126.EtOH chemical CHEBI:90692 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207606 0.8 A6/b1 integrin complex SIGNOR-C164 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269013 0.7 Caspase 3 complex complex SIGNOR-C221 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni Caspase-3 is responsible for apoptosis execution SIGNOR-256474 0.7 Bafetinib chemical CID:24853523 PUBCHEM BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190224 0.8 OGT protein O15294 UNIPROT PYGL protein P06737 UNIPROT up-regulates activity glycosylation Ser430 VDRLRRMsLIEEEGS 9606 BTO:0002181 34939084 t Luana O-GlcNAcylation at Ser-430 promotes PYGL activity SIGNOR-267988 0.2 PPP1R2 protein P41236 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates binding 9606 18250156 t gcesareni Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1. SIGNOR-160651 0.791 NCOR2 protein Q9Y618 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887 10713164 t Ncor2 is a Skip corepressor gcesareni Protein-protein interaction assays demonstrated interaction between skip and the corepressor smrt. SIGNOR-74227 0.574 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193531 0.8 HDAC1 protein Q13547 UNIPROT RELA protein Q04206 UNIPROT down-regulates binding 9606 SIGNOR-C13 17183360 t gcesareni Phosphorylation at thr505 by the chk1 inhibits rela transactivation and results in its increased association with hdac1. SIGNOR-151425 0.588 AKT1 protein P31749 UNIPROT PRKACA protein P17612 UNIPROT up-regulates 9606 BTO:0000938 16537363 f gcesareni Indicating that akt positively regulates shh signaling by controlling pka-mediated gli inactivation. SIGNOR-252490 0.254 MAPK8 protein P45983 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000150 21502402 t gcesareni Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. SIGNOR-173417 0.313 Arry-380 chemical CID:42598643 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189882 0.8 PTPRB protein P23467 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 21454675 t fstefani Expression of rptp-beta inhibits both mek1/2 and erk1/2 phosphorylation. SIGNOR-173000 0.39 imatinib methanesulfonate chemical CHEBI:31690 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193393 0.8 pelitinib chemical CHEBI:38927 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205755 0.8 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide chemical CHEBI:131156 ChEBI CHEK2 protein O96017 UNIPROT down-regulates chemical inhibition 9606 20068082 t gcesareni Azd7762 is equally potent against chk2 in vitro. SIGNOR-163119 0.8 DAPK1 protein P53355 UNIPROT CAMKK2 protein Q96RR4 UNIPROT unknown phosphorylation Ser511 RREERSLsAPGNLLT 9606 BTO:0000938 BTO:0000142 15209507 t lperfetto Dapk phosphorylates camkks511 was identified as the phosphorylation site SIGNOR-126245 0.287 IL7 protein P13232 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 20089933 t milica This receptor (il-7r) is a heterodimer consisting of the il-7r chain and the common cytokine ? -chain. SIGNOR-163545 0.699 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr465 GEEELSNyICMGGKG 9606 17827393 t gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157738 0.864 EIF4A2 protein Q14240 UNIPROT eIF4F_complex complex SIGNOR-C44 SIGNOR form complex binding 9606 BTO:0000671 11408474 t miannu Eif4a interacts with a scaffold protein, eif4g, to form complexes that also contain the cap-binding protein eif4e, which binds the cap structure (m7gpppn_) at the 5_-end of the mrna. These complexes are termed eif4f. SIGNOR-108512 0.81 CEBPA protein P49715 UNIPROT USF1 protein P22415 UNIPROT up-regulates activity binding 9606 BTO:0004116 7862113 t irozzo Our studies show that the human C/EBPa protein stimulates USF to bind to a USF consensus element within C/EBPa promoter and activates it by two- to threefold.The mechanism by which C/EBPa enhances USF binding and transactivation is currently under study. SIGNOR-255701 0.323 nintedanib chemical CHEBI:85164 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190302 0.8 NEK2 protein P51955 UNIPROT NEK11 protein Q8NG66 UNIPROT up-regulates phosphorylation 9606 15161910 t esanto Nek2 directly phosphorylated nek11 in the c-terminal non-catalytic region and elevated nek11 kinase activity. SIGNOR-124944 0.402 AMPK complex SIGNOR-C15 SIGNOR PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 BTO:0000876 BTO:0000671 12065600 t lperfetto Ipfk-2 was phosphorylated on the homologous serine (ser-461) and activated by ampk in vitro. SIGNOR-216639 0.378 WNT1 protein P04628 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 11448771 t gcesareni Wnt signaling is mediated by the frizzled (fz) family of seven-pass transmembrane receptors that bind wnt via the conserved amino-terminal cysteine-rich domain (crd) SIGNOR-109250 0.714 SP1 protein P08047 UNIPROT ID1 protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 f We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. SIGNOR-255748 0.2 SP1 protein P08047 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8921911 f miannu Studies using two mutant versions of this promoter, in which the Sp1 and C/EBP-related factor binding sites were deleted, respectively, revealed that Sp1 and C/EBP-related factors activate the transcription of SOD1 gene. the binding of Sp1 to the proximal upstream region of the Cu/Zn SOD might explain the expression of Cu/Zn SOD in a wide variety of cells. SIGNOR-253899 0.297 GNAO1 protein P09471 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates 9606 12665513 f lperfetto These results suggest that go alpha q205l activates p38 through taos and mek3/6. SIGNOR-235539 0.2 DYRK2 protein Q92630 UNIPROT KATNA1 protein O75449 UNIPROT down-regulates quantity by destabilization phosphorylation Ser42 QMNKYLYsVKDTYLQ 9606 BTO:0000007 19287380 t miannu DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d). SIGNOR-262848 0.523 TAOK1 protein Q7L7X3 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates phosphorylation 9606 23431053 t inferred from 70% of family members gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2. SIGNOR-269938 0.378 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser463 SPHNPISsVS 9606 9136927 t fspada Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro SIGNOR-210084 0.721 RBPJ protein Q06330 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates binding 10090 17158101 t gcesareni Notch induction of mkp-1 depends on an rbp-j-dependent mechanism. SIGNOR-236851 0.251 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser673 RVQSKIGsLDNITHV 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto Mark and pka phosphorylate several sites within the repeats (notably the kxgs motifs including ser262, ser324, and ser356, plus ser320)tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process SIGNOR-171058 0.44 RZZ complex complex SIGNOR-C357 SIGNOR DCTN2 protein Q13561 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 20462495 t lperfetto ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores SIGNOR-265017 0.435 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MCM4 protein P33991 UNIPROT down-regulates phosphorylation Ser54 ELQPMPTsPGVDLQS 9606 BTO:0000567 12714602 t lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. SIGNOR-217348 0.686 PHACTR1 protein Q9C0D0 UNIPROT PPP1CA protein P62136 UNIPROT up-regulates activity binding 9606 BTO:0001949 21939755 t miannu Phactr-1 was previously identified as protein phosphatase 1 (PP1) α-interacting protein that possesses actin-binding domains. We showed that Phactr-1 depletion decreased PP1 activity, disrupted the fine-tuning of actin polymerization and impaired lamellipodial dynamics. Taken together our results strongly suggest that Phactr-1 is a key component in the angiogenic process. SIGNOR-260062 0.552 PRKACA protein P17612 UNIPROT STMN2 protein Q93045 UNIPROT down-regulates activity phosphorylation Ser97 AAEERRKsQEAQVLK 9534 BTO:0000298 9525956 t miannu Using in vitro phosphorylated recombinant protein, four phosphorylation sites were identified in the SCG10 sequence. Ser-50 and Ser-97 were the target sites for protein kinase A. phosphorylation negatively regulates the microtubule-depolymerizing activity of SCG10 and that all four sites participate in this regulation SIGNOR-250057 0.314 NFIX protein Q14938 UNIPROT ANOS1 protein P23352 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268884 0.2 CYFIP1 protein Q7L576 UNIPROT WAVE complex complex SIGNOR-C271 SIGNOR form complex binding 9606 BTO:0000567 15070726 t lperfetto Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex.  SIGNOR-261873 0.903 PPARGC1A protein Q9UBK2 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 17476214 t miannu Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. Chromatin immunoprecipitation (ChIP) assays in HepG2 cells indicate that PGC-1α is present near RORE on the proximal Bmal1 promoter.These results indicate that PGC-1α activates Bmal1 transcription by altering the local chromatin environment from a repressive to an active state. SIGNOR-268030 0.502 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1169 VQQDGKDyIPINAIL 9606 9299537 t lperfetto Tyr-1169 and tyr-1213 on flt-1 were found to be auto-phosphorylated these results strongly suggest that tyr-1169 on flt-1 is a major binding site for plcgamma and important for flt-1 signal transduction within the cell SIGNOR-50834 0.2 LRP5 protein O75197 UNIPROT LPR5/6 complex SIGNOR-C219 SIGNOR form complex binding 9606 27821587 t miannu Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are co-receptors for Wnt ligands. SIGNOR-256176 0.381 DYRK1A protein Q13627 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates activity phosphorylation Ser251 NKVIPAKsPPPPTHS 9606 BTO:0000007 34109727 t miannu DYRK1A phosphorylates MEF2D and decreases its transcriptional activity SIGNOR-277901 0.421 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser396 DDKKAKTsTRSSAKT 9606 BTO:0000007 14761950 t lperfetto Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells. SIGNOR-121709 0.381 AR protein P10275 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 11916967 f lperfetto Transcription assays demonstrated that liganded ar repressed beta-catenin/t cell factor-responsive reporter gene activity SIGNOR-116260 0.719 MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 11460167 t lperfetto The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination SIGNOR-109497 0.755 RPS6KA1 protein Q15418 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 14625384 t gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-265346 0.2 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR1 protein Q92633 UNIPROT up-regulates chemical activation 10116 BTO:0003293 8276865 t milica LPA activates its own G protein-coupled receptor(s) leading to stimulation of phospholipase C and inhibition of adenylate cyclase. SIGNOR-37365 0.8 CSNK2A1 protein P68400 UNIPROT HSPH1 protein Q92598 UNIPROT down-regulates activity phosphorylation Ser509 PTEENEMsSEADMEC -1 12558502 t llicata Protein kinase CK2 phosphorylates Hsp105 alpha at Ser509 and modulates its function. | the phosphorylation of Hsp105 alpha at Ser(509) abolished the inhibitory activity of Hsp105 alpha in vitro. SIGNOR-250901 0.334 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser662 GLGRSITsPTTLYDR 9606 BTO:0001938 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. SIGNOR-104683 0.844 FN1/SDC4 complex SIGNOR-C210 SIGNOR WNT7A protein O00755 UNIPROT up-regulates 23290138 t apalma We found that binding of ECM glycoprotein Fibronectin (FN) to Sdc4 stimulates the ability of Wnt7a to induce the symmetric expansion of satellite stem cells SIGNOR-255287 0.317 HTR4 protein Q13639 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257041 0.252 PRKACB protein P22694 UNIPROT PHKA2 protein P46019 UNIPROT down-regulates activity phosphorylation 9606 10487978 t Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. SIGNOR-267412 0.307 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT up-regulates phosphorylation Ser373 RASSRASsRPRPDDL 9606 16474210 t lperfetto We previously showed that follicle-stimulating hormone (fsh) promoted phosphorylation of cx43 in rat primary granulosa cells. We further identified ser365, ser368, ser369, and ser373 in the carboxy-terminal tail as the major sites of phosphorylation by fsh, and found that the phosphorylation of these residues was essential for channel activity. SIGNOR-144473 0.451 AKT1 protein P31749 UNIPROT LARP1 protein Q6PKG0 UNIPROT down-regulates activity phosphorylation Ser847 EHRPRTAsISSSPSE 9606 BTO:0002181 28650797 t SARA LARP1 is a direct substrate of Akt/S6K1 and mTORC1. Akt is a physiologically relevant primary kinase for S770/S979 phosphorylation of LARP1|Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation. SIGNOR-260991 0.292 MAPK3 protein P27361 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser294 QLSKWPGsPTSRSSD 9606 19282669 t lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-252961 0.582 DYRK1A protein Q13627 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna SIGNOR-171034 0.438 POU5F1 protein Q01860 UNIPROT AKT1 protein P31749 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004180 23041284 t flangone Furthermore, in ECCs, unphosphorylated Oct4 bound to the AKT1 promoter and repressed its transcription. SIGNOR-252635 0.469 IRF4 protein Q15306 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22378047 f lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249559 0.7 PRKD1 protein Q15139 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Thr120 QFDAAHPtNVQRLAE 9606 BTO:0001130 19141652 t lperfetto This study provides evidence that pkd1 interacts with and phosphorylates beta-catenin at thr(112) and thr(120) we postulate that pkd1 phosphorylation is required to maintain _-catenin transcription activity. SIGNOR-183388 0.397 PINK1 protein Q9BXM7 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser179 RRYVYYYsYLLKNHL 9606 BTO:0000948 37940999 t miannu PINK1 interacts with and phosphorylates PTEN at Serine179, resulting in the activation of AKT and the inhibition of PTEN nuclear import.  SIGNOR-277915 0.482 PIM1 protein P11309 UNIPROT SKP2 protein Q13309 UNIPROT up-regulates activity phosphorylation Ser72 PPRKRLKsKGSDKDF 9606 20663873 t miannu We found that expression of Pim-1 increases the level of Skp2 through direct binding and phosphorylation of multiple sites on this protein. Along with known Skp2 phosphorylation sites including Ser(64) and Ser(72), we have identified Thr(417) as a unique Pim-1 phosphorylation target. Phosphorylation of Thr(417) controls the stability of Skp2 and its ability to degrade p27. SIGNOR-259819 0.346 PDGFRB protein P09619 UNIPROT FYN protein P06241 UNIPROT up-regulates activity phosphorylation Tyr28 SLNQSSGyRYGTDPT -1 9425276 t miannu PDGF-induced phosphorylation of Tyr28 in the N-terminus of Fyn affects Fyn activation. We show here that Fyn, a member of the Src family, is phosphorylated on Tyr28 in the unique N-terminal part of the molecule after interaction with the intracellular domain of the PDGF beta-receptor. Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn. SIGNOR-250253 0.563 AKAP8L protein Q9ULX6 UNIPROT DHX9 protein Q08211 UNIPROT up-regulates activity binding 9606 11402034 t miannu We report evidence for a novel nuclear export signal in HAP95 and showed that the domains involved in RHA binding and nuclear localization are required for CTE activation. Finally, we showed that HAP95 synergizes significantly with RHA on CTE-mediated reporter gene expression and promotes nuclear export of unspliced mRNA in transfected cells. Taken together, these data support the proposal that HAP95 specifically facilitates CTE-mediated gene expression by directly binding to RHA. SIGNOR-260950 0.56 RABEPK protein Q7Z6M1 UNIPROT IGF2R protein P11717 UNIPROT up-regulates activity relocalization 9230071 t lperfetto P40 is a very potent transport factor in that the pure, recombinant protein can stimulate, significantly, an in vitro transport assay that measures transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network. The functional importance of p40 is confirmed by the finding that anti-p40 antibodies inhibit in vitro transport. Finally, p40 shows synergy with Rab9 in terms of its ability to stimulate mannose 6-phosphate receptor transport. These data are consistent with a model in which p40 and Rab9 act together to drive the process of transport vesicle docking. SIGNOR-253090 0.358 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Tyr288 SVIPDSGyISEVRNF 9606 BTO:0002181 37977223 t miannu  To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. SIGNOR-277865 0.582 POU5F1 protein Q01860 UNIPROT TBX18 protein O95935 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254945 0.329 IL1B protein P01584 UNIPROT ITGA3 protein P26006 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001596 1744142 f lperfetto TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way. SIGNOR-253355 0.2 ILK protein Q13418 UNIPROT IPP complex complex SIGNOR-C380 SIGNOR form complex binding 16493410 t lperfetto Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton. SIGNOR-265762 0.894 G3BP1 protein Q13283 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25520508 f miannu Ras-GTPase-activating protein (SH3 domain) binding protein 1 (G3BP1) is a stress granule-resident protein that nucleates stress granule assembly and is also inactivated or coopted by many viruses to promote productive infection SIGNOR-260747 0.7 LHX2 protein P50458 UNIPROT MSX1 protein P28360 UNIPROT down-regulates activity binding -1 9697309 t 2 miannu Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity SIGNOR-241327 0.49 PP121 chemical CHEBI:50915 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206298 0.8 bortezomib chemical CHEBI:52717 ChEBI PSMB2 protein P49721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 21504411 t miannu Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma. SIGNOR-259309 0.8 Caspase 3 complex complex SIGNOR-C221 SIGNOR CASP9 protein P55211 UNIPROT up-regulates activity cleavage Asp330 LRTFDQLdAISSLPT 9606 BTO:0001412 15657060 t lperfetto In turn, casp3 directs feedback cleavage of casp9 at asp-330 to generate p37 and p10 subunits. SIGNOR-256440 0.623 KCNQ2 protein O43526 UNIPROT KCNQ3 protein O43525 UNIPROT up-regulates activity binding 10116 BTO:0000938 9836639 t The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date, however, the genes that encode subunits of this important channel have not been identified. The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current. SIGNOR-268833 0.498 LYN protein P07948 UNIPROT CD79A protein P11912 UNIPROT up-regulates activity phosphorylation Tyr188 EYEDENLyEGLNLDD -1 9531288 t Y182 of CD79a appears to be the initial and preferred site of Ag receptor phosphorylation by Src family kinases. In vitro, Src family Lyn and Fyn predominantly phosphorylate this residue in CD79a, and Y195 does so in CD79b. phosphorylation of Y182 alone can lead to further kinase activation and/or effector focusing necessary for phosphorylation of certain downstream targets, such as p62, p110, and Shc, but not others, such as Vav. SIGNOR-251397 0.728 ERG protein P11308 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19396168 f miannu ADAMTS1 and CXCR4, two candidate genes strongly associated with cell migration, were upregulated in the presence of ERG overexpression. SIGNOR-253911 0.2 POLR1G protein O15446 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266155 0.2 PIP3 smallmolecule CHEBI:16618 ChEBI WIPI2 protein Q9Y4P8 UNIPROT up-regulates chemical activation 9606 22082875 t gcesareni We identified the human wipi protein family and found that wipi-1 specifically binds ptdins(3)p, accumulates at the phagophore and becomes a membrane protein of generated autophagosomes. SIGNOR-177226 0.8 MCF2 protein P10911 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260558 0.769 GRIPAP1 protein Q4V328 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates activity binding 9606 BTO:0002181;BTO:0000142 17761173 t Giorgia To examine whether GRASP‐1 interacts with MEKK1 and JNK1 in neurons, co‐immunoprecipitation experiments were performed with detergent‐solubilized extracts from cultured cortical neurons. Both antiJNK1 and anti‐MEKK1 antibodies immunoprecipitated GRASP‐1 from neuronal lysates. These results suggest that GRASP‐1 interacts with MEKK1 and JNK1 in neurons. SIGNOR-260640 0.317 HNRNPU protein Q00839 UNIPROT HOXA2 protein O43364 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 f lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. SIGNOR-262284 0.2 Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 28347630 f miannu Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation SIGNOR-266830 0.7 LTC4S protein Q16873 UNIPROT leukotriene A4(1-) smallmolecule CHEBI:57463 ChEBI down-regulates quantity chemical modification 9606 27365393 t miannu Leukotriene C4 synthase (LTC4S) catalyzes the formation of the proinflammatory lipid mediator leukotriene C4 (LTC4). SIGNOR-277258 0.8 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273089 0.745 CyclinE1/CDK3 complex SIGNOR-C546 SIGNOR G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 37104883 f lperfetto Among them, CDK3 is critically important because it triggers the transitions of G0 to G1 and G1 to S phase through binding to cyclin C and cyclin E1, respectively. SIGNOR-273191 0.7 ERBB2 protein P04626 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21743488 f gcesareni We demonstrate that her2 overexpression in this cellular model of dcis drives transcriptional upregulation of multiple components of the notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising notch3, its cleaved intracellular domain and the transcriptional regulator hes1. SIGNOR-174747 0.412 PRKCB protein P05771 UNIPROT CASR protein P41180 UNIPROT down-regulates activity phosphorylation Thr888 FKVAARAtLRRSNVS 9606 BTO:0000007 12356761 t lperfetto Expression of a mutant CaR in which the major PKC phosphorylation site is altered by substitution of alanine for threonine (T888A) eliminated oscillatory behavior, producing [Ca(2+)](i) responses almost identical to those produced by the wild type CaR exposed to PKC inhibitors. These results support a model in which phosphorylation of the CaR at the inhibitory threonine 888 by PKC provides the negative feedback needed to cause [Ca(2+)](i) oscillations mediated by this receptor. SIGNOR-249176 0.324 oxytocin smallmolecule CHEBI:7872 ChEBI OXTR protein P30559 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257556 0.8 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Lys1022 GGKSRLKkSQFLIKT -1 7989361 t lperfetto The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994. SIGNOR-263627 0.584 PRKCQ protein Q04759 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates activity phosphorylation Thr219 SAINSREtMFHKERF 9606 16252004 t lperfetto Critical role of novel Thr-219 autophosphorylation for the cellular function of PKCtheta in T lymphocytes. SIGNOR-249298 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction SIGNOR-259919 0.2 NCOA2 protein Q15596 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 12503607 t gcesareni Transcriptional coactivator for steroid receptors and nuclear receptors.nteracts with casp8ap2 and ttll5/stamp. Interacts with esr1, rara and rxra. SIGNOR-96827 0.615 CLIP2 protein Q9UDT6 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 15631994 f lperfetto CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. SIGNOR-265095 0.7 IL6 protein P05231 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 f lperfetto Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS SIGNOR-260256 0.7 CDK2 protein P24941 UNIPROT PTHLH protein P12272 UNIPROT down-regulates phosphorylation Thr121 YKEQPLKtPGKKKKG 9606 10373465 t llicata Phosphorylation at the cyclin-dependent kinases site (thr85) of parathyroid hormone-related protein negatively regulates its nuclear localization SIGNOR-68548 0.38 sirolimus chemical CHEBI:9168 ChEBI CD40 protein P25942 UNIPROT down-regulates quantity by repression 9606 18652845 f miannu Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells. SIGNOR-255474 0.8 ELANE protein P08246 UNIPROT SERPIND1 protein P05546 UNIPROT down-regulates activity cleavage Val458 QATTVTTvGFMPLST -1 2318847 t miannu Amino acid sequence analysis led to the conclusion that both neutrophil elastase and cathepsin G cleave HC at Ile66, which does not affect HC activity, and at Val439, near the reactive site Leu444, which inactivates HC. SIGNOR-256510 0.462 STAT5A protein P42229 UNIPROT SOCS2 protein O14508 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12468433 t We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling SIGNOR-261547 0.654 TRIM25 protein Q14258 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys10 FAEDKTYkYICRNFS 9606 BTO:0000007 22626058 t k48 miannu We report here that RLR activation triggers MAVS ubiquitination on lysine 7 and 10 by the E3 ubiquitin ligase TRIM25 and marks it for proteasomal degradation concomitantly with downstream signaling.  SIGNOR-272042 0.761 PPP6C protein O00743 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity dephosphorylation 9606 19198648 t miannu In addition, siRNA knockdown of either PP6R1 or PP6 significantly decreased IR activation of DNA-PK, suggesting that PP6 activates DNA-PK by association and dephosphorylation.|PP6 may dephosphorylate sites in DNA-PKcs to reduce binding with heterodimer Ku proteins, because DNA-PK activation completely depends on Ku-mediated complex formation with DNA. SIGNOR-277164 0.554 MAPK3 protein P27361 UNIPROT MAZ protein P56270 UNIPROT up-regulates phosphorylation Thr72 AAPAPPPtPQAPAAE 9606 11809795 t lperfetto Together, these results show that activation of saf-1 in response to il-1 and -6 is mediated via map kinase-regulated phosphorylation. SIGNOR-114475 0.304 SMURF2 protein Q9HAU4 UNIPROT SMAD9 protein O15198 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps SIGNOR-193390 0.63 MAPK14 protein Q16539 UNIPROT GATA2 protein P23769 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 25056917 t P38α promotes multi‐site GATA‐2 phosphorylation, increasing its localization in nuclear foci enriched in an active form of RNA polymerase II and its capacity to regulate endogenous target genes. SIGNOR-259946 0.273 MN1 protein Q10571 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 17494859 f irozzo MN1 is a unique oncogene in hematopoiesis that both promotes proliferation/self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment. SIGNOR-256015 0.7 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 19115199 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-182988 0.738 CDK1 protein P06493 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 10931950 t gcesareni Phosphorylation of kip1 on thr-187, by cdk1 and cdk2 leads to protein ubiquitination and proteasomal degradation. SIGNOR-80230 0.676 RPS6K proteinfamily SIGNOR-PF26 SIGNOR GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 11584304 t lperfetto S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity. SIGNOR-252788 0.2 MAPK1 protein P28482 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser435 TLASERSsPQRKSQR -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414. An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262747 0.29 YBX1 protein P67809 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001023 17072343 f miannu YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. SIGNOR-255610 0.328 PNPLA6 protein Q8IY17 UNIPROT 2-(((R)-2,3-Dihydroxypropyl)phosphoryloxy)-N,N,N-trimethylethanaminium smallmolecule CID:439285 PUBCHEM up-regulates quantity chemical modification 9606 25033069 t PNPLA6 encodes NTE, a lysophospholipase that converts lysophosphatidylcholine (LPC) to glycerophosphocholine. PNPLA6 is expressed in neurons throughout the brain, particularly in the cortex, Purkinje cells of the cerebellum, and hippocampus SIGNOR-253611 0.8 CEBPB protein P17676 UNIPROT HSD11B1 protein P28845 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19088256 t lperfetto In conclusion, C/EBPalpha and C/EBPbeta control basal transcription, and TNF-alpha upregulates 11beta-HSD1, most likely by p38 MAPK-mediated increased binding of C/EBPbeta to the human HSD11B1 promoter. SIGNOR-268972 0.288 PLK1 protein P53350 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser260 SLDSEDYsLSEEGQE 9606 12383858 t gcesareni Here we show that the oncogenic and cell cycle-regulatory protein kinase, polo-like kinase-1 (plk1), phosphorylates mdm2 at one of these residues, ser260, and stimulates mdm2-mediated turnover of p53. These data are consistent with the idea that deregulation of plk1 during tumourigenesis may help suppress p53 function. SIGNOR-94272 0.477 PRKAA2 protein P54646 UNIPROT HIPK2 protein Q9H2X6 UNIPROT down-regulates activity phosphorylation Ser121 LMRRSTVsLLDTYQK 23871434 t Phosphosite positions are derived from Figure S5 lperfetto AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro SIGNOR-275486 0.2 CTSG protein P08311 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Arg41 TNATLDPrSFLLRNP -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Arg41-Ser42 activation site SIGNOR-263561 0.577 HRH3 protein Q9Y5N1 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256968 0.263 CTSG protein P08311 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage Phe41 DRVYIHPfHLVIHNE -1 11747312 t miannu Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen. SIGNOR-256312 0.628 MAP3K7 protein O43318 UNIPROT TAB1 protein Q15750 UNIPROT up-regulates activity phosphorylation Ser457 TQSSSSSsDGGLFRS 9606 BTO:0000007 22216226 t miannu We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro.  SIGNOR-276367 0.927 CLU protein P10909 UNIPROT LRP2 protein P98164 UNIPROT up-regulates quantity binding 10090 32332780 t miannu Our results demonstrate that circulating ApoJ is retained in muscle via LRP2 and that LRP2 signaling could play a role in the maintenance of ApoJ homeostasis in circulation, at least in part. SIGNOR-265256 0.577 NFKBIZ protein Q9BYH8 UNIPROT IL17A protein Q16552 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000782 20383124 t Luana In cooperation with RORγt and RORα, IκBζ enhances Il17a expression by binding directly to the regulatory region of the Il17a gene.  SIGNOR-266210 0.389 TDGF1 protein P13385 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0002314 BTO:0000887;BTO:0001103 23129614 f miannu Cripto, a regulator of early embryogenesis, is a novel regulator of muscle regeneration and satellite cell progression toward the myogenic lineage. SIGNOR-192439 0.7 SRC protein P12931 UNIPROT EMD protein P50402 UNIPROT down-regulates phosphorylation Tyr95 KGYNDDYyEESYFTT 9606 BTO:0000567 BTO:0000887 19789182 t llicata Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf SIGNOR-188316 0.463 UHRF1 protein Q96T88 UNIPROT RIF1 protein Q5UIP0 UNIPROT down-regulates activity polyubiquitination 9606 BTO:0002181 26727879 t miannu UHRF1 mediates K63-linked polyubiquitination of RIF1, and results in its dissociation from 53BP1 and DSBs thereby facilitating HR initiation.  SIGNOR-277193 0.2 SMURF1 protein Q9HCE7 UNIPROT TRIB2 protein Q92519 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 24089522 t miannu  In this study, we found that TRIB2 was up-regulated and exhibited high stability in liver cancer cells compared with other cells. We performed a structure-function analysis of TRIB2 and identified a domain (amino acids 1-5) at the N terminus that interacted with the E3 ubiquitin ligase Smurf1 and was critical for protein stability. Deletion of this domain extended TRIB2 half-life time accompanied with a more significant malignant property compared with wild type TRIB2. SIGNOR-275432 0.42 THRA protein P10827 UNIPROT GATA2 protein P23769 UNIPROT down-regulates activity binding 9606 BTO:0001073 29407449 t scontino We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2. SIGNOR-267257 0.2 BLK protein P51451 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268211 0.633 IPO5 protein O00410 UNIPROT DSCAML1 protein Q8TD84 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 30745319 t miannu DSCAM and DSCAML1 specifically interacted with the importin beta IPO5, whereas deletion of the identified NLSs abolished this specific interaction and suppressed nuclear translocation of the DSCAM/L1 ICDs in cell lines and cultured neurons. This suggests a direct role of IPO5 in the nuclear import of the DSCAM/L1 ICDs. SIGNOR-264274 0.2 TRIM21 protein P19474 UNIPROT GMPS protein P49915 UNIPROT down-regulates ubiquitination 9606 24462112 t miannu Cytoplasmic sequestration of gmps requires ubiquitylation by trim21, a ubiquitin ligase associated with autoimmune disease. SIGNOR-204478 0.331 PTPRJ protein Q12913 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 12771128 t gcesareni A dominant-negative mutant of high cell density-enhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation. SIGNOR-101279 0.416 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK9 protein P50750 UNIPROT down-regulates activity chemical inhibition -1 29901072 t miannu AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9. SIGNOR-262217 0.8 MAML2 protein Q8IZL2 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 12370315 f gcesareni We recently cloned a mammalian homologue of the mastermind gene of drosophila melanogaster, maml1 (mastermind-like-1 molecule) and determined that it functions as a transcriptional coactivator for notch receptors. SIGNOR-254307 0.858 CDK1 protein P06493 UNIPROT ABI1 protein Q8IZP0 UNIPROT down-regulates activity phosphorylation Ser216 VPNDYMTsPARLGSQ 9606 BTO:0000567 21900237 t lperfetto We identified serine 216 of Abi1 as a target of CDK1/cyclin B kinase that is phosphorylated in cells at the onset of mitosis.|Bcr-Abl-induced actin polymerization requires the Abi1 pathway, as the blockade of the signal transduction from Bcr-Abl to Abi1 abolishes the F-actin assembly|serine phosphorylation of Abi1 by CDK1/cyclin B serves as a cell cycle-dependent regulatory mechanism that inhibits actin assembly SIGNOR-264421 0.429 AKT1 protein P31749 UNIPROT CCDC88A protein Q3V6T2 UNIPROT unknown phosphorylation Ser1417 INRERQKsLTLTPTR 9606 16139227 t llicata Akt phosphorylates serine at position 1416 in girdin, and phosphorylated girdin accumulates at the leading edge of migrating cells. SIGNOR-252482 0.614 PTPRG protein P23470 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity dephosphorylation Tyr315 MPMDTSVyESPYSDP -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254733 0.263 PIK3CB protein P42338 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242652 0.7 LDHB protein P07195 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0000164 34929314 f lperfetto LDHB is a glycolytic enzyme that catalyzes the conversion of lactic acid and NAD+ into pyruvate, NADH and H+.  SIGNOR-267654 0.7 SUPT7L protein O94864 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269585 0.656 SHMT1 protein P34896 UNIPROT 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI down-regulates quantity chemical modification 9606 11802770 t miannu HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. SIGNOR-269687 0.8 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates 9606 22683405 f inferred from 70% of family members milica In response to growth inhibitory signal (e.g. cell¬ñcell contact), MST1/2 in active form phosphorylates LATS1/2 that sequentially phosphorylates YAP at Ser-127. SIGNOR-269943 0.7 MAPK12 protein P53778 UNIPROT CARM1 protein Q86X55 UNIPROT down-regulates activity phosphorylation Ser595 GPAISMAsPMSIPTN 10090 29681515 t apalma Here, we identify a role for the mitogen-activated protein kinase (MAPK) p38g/MAPK12 as a critical regulator of satellite stem cell fate through phosphorylation of Carm1. SIGNOR-255897 0.347 PTPN6 protein P29350 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 18377662 t Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175 SIGNOR-248474 0.654 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK1 protein P06493 UNIPROT down-regulates activity chemical inhibition -1 29901072 t miannu AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9. SIGNOR-262218 0.8 TP63 protein Q9H3D4 UNIPROT PERP protein Q96FX8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21965674 f miannu SATB2 attenuates p63-mediated gene expression of perp (p53 apoptosis effector related to PMP-22), a critical downstream target gene during development, and specifically decreases p63 perp promoter binding. SIGNOR-255136 0.608 CDK4 protein P11802 UNIPROT TOB2 protein Q14106 UNIPROT up-regulates activity phosphorylation Ser254 PAPQSQLsPNAKEFV -1 32404348 t miannu Taken together, these observations strongly support the notion that several different CDK-cyclin complexes are involved in the phosphorylation of Tob2 at S254.A more detailed regulatory context of Tob2 phosphorylation at S254 is provided by our findings from mass-spec and in vitro kinase analyses that suggest connections to PP2B and PP2C phosphatases and CDK-cyclin complexes, particularly CDK1, CDK2, and CDK4 (Table 1; Supplemental Table S2).One possibility is that the phosphorylation of S254 helps stabilize the interaction of Tob2 with the Ccr4–Not complex, which could contribute to Tob2's ability to recruit the entire Ccr4–Not complex and thus further enhances deadenylation. SIGNOR-273602 0.2 SIRT1 protein Q96EB6 UNIPROT ADAMTS5 protein Q9UNA0 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21337390 f miannu The inhibition of SIRT1 by siRNA induced OA-like gene expression changes, namely the significant down-regulation of aggrecan and up-regulation of COL10A1 and ADAMTS-5. SIGNOR-255140 0.268 Ethylketocyclazocine chemical CHEBI:4901 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258780 0.8 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR IFIH1 protein Q9BYX4 UNIPROT up-regulates 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260142 0.7 verapamil chemical CHEBI:9948 ChEBI SCN2A protein Q99250 UNIPROT down-regulates activity chemical inhibition 10116 1658608 t miannu This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner. SIGNOR-258355 0.8 bethanechol chemical CHEBI:3084 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258622 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser272 CSLERQLsLEQEVQQ 9606 BTO:0000567 12670876 t lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. SIGNOR-264443 0.2 NRG1 protein Q02297 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates binding 9606 BTO:0000150 7514177 t gcesareni Direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3. SIGNOR-26875 0.784 SATB1 protein Q01826 UNIPROT IL23A protein Q9NPF7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000664 17343824 f miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. SIGNOR-255132 0.2 TLR4 protein O00206 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 20596954 f fstefani Regulation of toll-like receptor signaling in the innate immunity. SIGNOR-166485 0.7 Raf265 derivative chemical CID:23654923 PUBCHEM RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206394 0.8 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 BTO:0000938 12040039 t gcesareni Stress in primary cultured cns neurons induces phosphorylation of c-jun serines 63 and 73 and increased c-jun protein. Jnk2/3 activity selectively targets c-jun. SIGNOR-88208 0.881 PTEN protein P60484 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 f miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). SIGNOR-260055 0.2 CDK10 protein Q15131 UNIPROT ETS2 protein P15036 UNIPROT down-regulates quantity by destabilization phosphorylation Ser220 PKGGLLDsMCPASTP 9606 24218572 t Manara Altogether, these results suggest that CDK10/cyclin M directly controls ETS2 degradation through the phosphorylation of these two serines. SIGNOR-260913 0.543 TFEB protein P19484 UNIPROT CLCN7 protein P51798 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276536 0.334 thiocyanate smallmolecule CHEBI:18022 ChEBI Cell_killing phenotype SIGNOR-PH149 SIGNOR up-regulates 9606 BTO:0000133 9922160 f lperfetto Myeloperoxidase plays a fundamental role in oxidant production by neutrophils. The enzyme uses hydrogen peroxide to oxidize chloride (Cl-), bromide (Br-), iodide (I-), and the pseudohalide thiocyanate (SCN-) to their respective hypohalous acids.| Our results show that thiocyanate is an important substrate of myeloperoxidase in most environments and that hypothiocyanate is likely to contribute to leukocyte antimicrobial activity. SIGNOR-270592 0.7 NR2F2 protein P24468 UNIPROT NR2F1 protein P10589 UNIPROT up-regulates binding 9606 10900149 t gcesareni Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site. SIGNOR-79443 0.259 2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]-4-quinazolinyl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide chemical CHEBI:91367 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258181 0.8 FER protein P16591 UNIPROT JUP protein P14923 UNIPROT down-regulates activity phosphorylation Tyr550 AAGTQQPyTDGVRME 10116 BTO:0004604 14517306 t The tyrosine kinase Fer, which modifies beta-catenin Tyr142, lessening its association with alpha-catenin, phosphorylates plakoglobin Tyr549 and exerts the contrary effect: it raises the binding of plakoglobin to alpha-catenin. Fer stimulation, through modification of Tyr549, causes diminished binding of plakoglobin to components of desmosomes (desmoplakin) and increased interaction with adherens junction proteins (α-catenin) SIGNOR-251135 0.505 Caspase 8 complex complex SIGNOR-C231 SIGNOR RIPK1 protein Q13546 UNIPROT down-regulates activity cleavage Asp324 RMQSLQLdCVAVPSS 9606 BTO:0000007;BTO:0000093;BTO:0000567 10521396 t amattioni These results suggested that the aspartic acid at position 324 is the cleavage site of ripk1. In this study we found that receptor-interacting protein (ripk1) is cleaved by casp8 when cells undergo tnf-induced apoptosis. The cleavage of ripk1 abolished its nf-kb inducing ability. SIGNOR-256442 0.907 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-81129 0.523 LRRK2 protein Q5S007 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 BTO:0000007 22012985 f gcesareni We report that LRRK2 activates a calcium-dependent protein kinase kinase-² (CaMKK-²)/adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway which is followed by a persistent increase in autophagosome formation. SIGNOR-237005 0.7 PIK3CG protein P48736 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242658 0.7 DLL3 protein Q9NYJ7 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-254316 0.469 WNT3A protein P56704 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 15454084 t gcesareni Here, we report that ryk directly binds wnt-1 and wnt-3a via its wif domain and is required for the tcf. SIGNOR-129580 0.754 FUS protein P35637 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 BTO:0000007 33082139 f P35637:p.Pro525Leu (mutation increasing interaction); P35637:p.Pro521Gly (mutation increasing interaction) When mTORC2 is inhibited, FUS is recruited to polyribosomes to promote translation inhibition and polyribosome stalling. Panel iv, ALS-FUS R521G and P525L mutants that localize more prominently to the cytoplasm also associate more abundantly with polyribosomes to inhibit translation and protein synthesis. SIGNOR-262820 0.7 BCOR protein Q6W2J9 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates activity binding 9606 BTO:0000007 10898795 t miannu BCoR can interact w Because HDACs appear to be involved in repression by an increasing number of transcriptional repressors, we tested whether BCoR can associate with HDACs. BCoR can interact with HDAC1, HDAC3, and HDAC-B/5 more strongly than with HDAC-A/4, HDAC-C, HDAC-D, and HDAC-E. SIGNOR-252238 0.531 SGK1 protein O00141 UNIPROT MKNK1 protein Q9BUB5 UNIPROT down-regulates activity phosphorylation Ser353 S-->K -1 28545025 t miannu We show that SGK1 phosphorylates MNK1 at a conserved site, which represses its activity.  SIGNOR-277357 0.2 PIM2 protein Q9P1W9 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser467 LQLYQVDsRTYLLDF 9606 BTO:0001555 31358902 t miannu Specifically, we found that PIM2 bound to AMPKα1, and directly phosphorylated it on Thr467. Phosphorylation of AMPKα1 by PIM2 led to decreasing AMPKα1 kinase activity, which in turn promoted aerobic glycolysis and tumor growth. SIGNOR-277471 0.2 pyruvate smallmolecule CHEBI:15361 ChEBI acetyl-CoA smallmolecule CHEBI:15351 ChEBI up-regulates quantity precursor of 9606 29059435 t miannu The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics. SIGNOR-266542 0.8 TNF protein P01375 UNIPROT NOTCH4 protein Q99466 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004914 14586405 f We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues. SIGNOR-253607 0.317 SP1 protein P08047 UNIPROT TINF2 protein Q9BSI4 UNIPROT up-regulates quantity by expression transcriptional regulation 21731707 t lperfetto Transfection of a plasmid carrying the Sp1 transcription factor into Sp-deficient SL2 cells strongly activated TIN2 promoter-driven luciferase reporter expression. SIGNOR-271698 0.2 MAPK3 protein P27361 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 12169099 t gcesareni Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. SIGNOR-91383 0.773 CDC5L protein Q99459 UNIPROT HNRNPM protein P52272 UNIPROT up-regulates activity binding 9606 BTO:0000567 20467437 t 1 miannu hnRNP-M interacts directly with CDC5L and PLRG1 in vivo. we investigated whether the function of hnRNP-M in alternative splicing was affected by the central region mapped as essential for binding to the CDC5L/PLRG1 proteins. We conclude that loss of the CDC5L/PLRG1 interaction domain in hnRNP-M correlates with a loss of ability to modulate alternative splice site selection in this assay. SIGNOR-239410 0.619 ITGB1BP1 protein O14713 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257655 0.282 SIAH2 protein O43255 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. SIGNOR-272748 0.443 CDK14 protein O94921 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity 24794231 t lperfetto Compared with the wild-type CDK14, CDK14D256A mutant showed 2-fold reduced phosphorylation of LRP6 at Ser-1490, a known substrate of the CDK14/CCNY complex| It is also reported to be required for maximal phosphorylation of LRP6 on Ser 1490 and activation of Wnt signaling  SIGNOR-273019 0.339 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR LCN2 protein P80188 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15536164 f miannu Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kappaB, a transcription factor that is activated in FAP nerves and SG. SIGNOR-254796 0.34 MAPK1 protein P28482 UNIPROT PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation Ser21 LEAGDLEsPLSEEFL 9606 BTO:0000599 10187842 t lperfetto We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution. SIGNOR-249434 0.56 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser289 RSHSESAsPSALSSS 10090 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-249440 0.616 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates binding 9606 21902831 t lperfetto In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-216969 0.443 BTRC protein Q9Y297 UNIPROT CDC25A protein P30304 UNIPROT up-regulates ubiquitination 9606 SIGNOR-C5 15340381 t gcesareni Scfb-trcp has recently been shown to degrade phosphorylated cdc25a in the s and g2 phases. SIGNOR-128436 0.507 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr231 NQDDVGVyTCLVVNG 9606 BTO:0000763 20861316 t lperfetto Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity SIGNOR-167989 0.304 JUN protein P05412 UNIPROT SMAD3/JUN complex SIGNOR-C86 SIGNOR form complex binding 9606 9732876 t gcesareni These results show a ligand-dependent association of smad3 with c-jun SIGNOR-59867 0.741 ADA protein P00813 UNIPROT adenosine smallmolecule CHEBI:16335 ChEBI up-regulates quantity chemical modification -1 15926889 t Luana Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates SIGNOR-269735 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TCF3 protein P15923 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 BTO:0000944 14592976 t inferred from 70% family members lperfetto Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG) SIGNOR-270139 0.2 CD27 protein P26842 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12324477 f gcesareni Cd40 ligation up-regulated bcl-2 and bcl-xl as much as 9.7- (p < 0.01) and 6.8-fold (p < 0.01), respectively (fig. 2, b and c). Under similar conditions, cd27 ligation also up-regulated bcl-2 and bcl-xl as much as 5.0- (p < 0.01) and 3.9-fold (p < 0.01), respectively. SIGNOR-93317 0.2 SMARCB1 protein Q12824 UNIPROT SMARCA2 protein P51531 UNIPROT up-regulates activity binding 9606 10078207 t miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. SIGNOR-65181 0.921 PLCB1 protein Q9NQ66 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates quantity chemical modification -1 23880553 t miannu Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate. SIGNOR-256496 0.8 RNF5 protein Q99942 UNIPROT STING1 protein Q86WV6 UNIPROT down-regulates quantity by destabilization ubiquitination Lys150 EISAVCEkGNFNVAH 9606 BTO:0000007 19285439 t miannu The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection. SIGNOR-271484 0.2 MMP17 protein Q9ULZ9 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272385 0.7 MRAP2 protein Q96G30 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 t miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. SIGNOR-252363 0.518 GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263778 0.7 Caspase 3 complex complex SIGNOR-C221 SIGNOR SPTAN1 protein Q13813 UNIPROT down-regulates cleavage 9606 BTO:0000150;BTO:0000567 9624143 t amattioni Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis. SIGNOR-256450 0.662 COMT protein P21964 UNIPROT 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-263998 0.8 Ankyrin complex complex SIGNOR-C383 SIGNOR SPTB protein P11277 UNIPROT up-regulates activity binding 9606 BTO:0000424 22465511 t lperfetto The junctional complex is focused around a hub or ‘junction’ arising from lateral connections between protein 4.1, actin and beta spectrin (the first of which stabilises the actin spectrin association via direct binding to both proteins [8]). SIGNOR-266023 0.435 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser525 YGMIERLsPGTRKIE 9606 BTO:0000007 33217317 t miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. SIGNOR-265952 0.2 PAK1 protein Q13153 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates activity phosphorylation Ser67 RQLRKVRsVELDQLP 9606 BTO:0000007 12228228 t lperfetto We found that pak1 phosphorylated mekk1 on serine 67 of its amino-terminal regulatory domain. mekk1 activity was increased modestly following pak phosphorylation. SIGNOR-236006 0.518 CHD7 protein Q9P2D1 UNIPROT SETDB1/NLK/CHD7 complex SIGNOR-C189 SIGNOR form complex binding 10090 21952300 t FFerrentino The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1)42. SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3‑L1 cells42,43. SIGNOR-253526 0.479 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR KIT protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29236325 f irozzo We report here that AML1/ETO transactivates c-KIT expression through directly binding to and mediating the long-range interaction between the promoter and intronic enhancer regions of c-KIT. SIGNOR-255699 0.2 SRC protein P12931 UNIPROT CHN2 protein P52757 UNIPROT down-regulates phosphorylation Tyr21 VSSDAEEyQPPIWKS 9606 17560670 t llicata Here we report that beta2-chimaerin is tyrosine-phosphorylated by src-family kinases (sfks) upon cell stimulation with epidermal growth factor (egf). Mutational analysis identified tyr-21 in the n-terminal regulatory region as a major phosphorylation site. these results suggest tyr-21 phosphorylation as a novel, sfk-dependent mechanism that negatively regulates beta2-chimaerin rac-gap activity. SIGNOR-155713 0.2 IKBKE protein Q14164 UNIPROT REL/RELA complex SIGNOR-C68 SIGNOR up-regulates phosphorylation 9606 16888014 t lperfetto The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel. SIGNOR-217664 0.405 INSR protein P06213 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Tyr368 STKMHGDyTLTLRKG 9534 BTO:0000298 8385099 t The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-251320 0.656 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser422 RFHSLPFsLTKMPNT 9606 BTO:0000938 24614225 t lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204720 0.529 SRP72 protein O76094 UNIPROT SRP68 protein Q9UHB9 UNIPROT up-regulates activity binding -1 30649417 t miannu Taken together our data show that binding of the SRP68/72 heterodimer follows an ultrasensitive response dependent on the SRP72 C-terminus. Although the large solenoids of SRP68/72 have not been structurally characterized due to intrinsic flexibility, they serve as important contact sites in ribosome interaction. SIGNOR-261164 0.989 DDB2 protein Q92466 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates binding 9606 BTO:0000567 9418871 t miannu We show that ddb, a putative dna repair protein, associates with the activation domain of e2f1 / expression of ddb specifically stimulated e2f1-activated transcription SIGNOR-54102 0.374 VPS4A protein Q9UN37 UNIPROT CHMP2A protein O43633 UNIPROT up-regulates activity cleavage -1 30989108 t Giorgia Here, we show, using high-speed atomic force microscopy and electron microscopy, that the AAA-type adenosine triphosphatase VPS4 constricts and cleaves ESCRT-III CHMP2A-CHMP3 helical filaments in vitro. Our results demonstrate that VPS4 actively constricts ESCRT-III filaments and cleaves them before their complete disassembly. We propose that the formation of ESCRT-III dome-like end caps by VPS4 within a membrane neck structure constricts the membrane to set the stage for membrane fission. SIGNOR-260846 0.908 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates activity phosphorylation Thr63 LSSAWPGtLRSGMVP 9606 BTO:0000887 11342557 t lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation SIGNOR-107688 0.312 ANXA1 protein P04083 UNIPROT FPR2 protein P25090 UNIPROT up-regulates activity binding 9606 BTO:0000007 15187149 t We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2. SIGNOR-259437 0.629 tyrphostin B42 chemical CHEBI:131968 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity chemical inhibition 9606 11368440 t gcesareni The Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Ralpha mRNA and protein expression in parallel SIGNOR-238542 0.8 CAMK2D protein Q13557 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 19725819 f areggio In the cytoplasm where the activated CaMKII localises it induces signalling pathways that are mainly involved in mitochondrial biogenesis and expression of contractile protein SIGNOR-255955 0.7 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 BTO:0000567 10669763 t lperfetto In endothelial cells, tumor necrosis factor alpha (tnf-alpha) induces dephosphorylation and subsequent ubiquitin-dependent degradation of the antiapoptotic protein bcl-2. Here, we investigate the role of different putative phosphorylation sites to facilitate bcl-2 degradation SIGNOR-74927 0.533 PKA proteinfamily SIGNOR-PF17 SIGNOR SI protein P14410 UNIPROT unknown phosphorylation Ser7 sGLEISLI -1 8521865 t miannu This paper reports the phosphorylation of the intracellular N-terminal tail of sucrase-isomaltase by protein kinase A and shows that this phosphorylation is targeted to Ser6 within a sequence Arg/Lys/Lys-Phe-Ser, which is conserved in all sucrase-isomaltase sequences known so far. SIGNOR-263157 0.2 MAPK3 protein P27361 UNIPROT BAZ1B protein Q9UIG0 UNIPROT up-regulates phosphorylation Ser158 KSDGACDsPSSDKEN 9606 19776015 t gcesareni Wstf, a specific component of two chromatin remodeling complexes (swi/snf-type winac and iswi-type wich), was phosphorylated by the stimulation of mapk cascades in vitro and in vivo. Ser-158 residue in the wac (wstf/acf1/cbpq46) domain, located close to the n terminus of wstf, was identified as a major phosphorylation target SIGNOR-188164 0.2 AP3M1 protein Q9Y2T2 UNIPROT AP-3 complex complex SIGNOR-C247 SIGNOR form complex binding 9606 21097499 t lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) SIGNOR-260682 0.87 PLK1 protein P53350 UNIPROT MAD2L1BP protein Q15013 UNIPROT down-regulates activity phosphorylation Ser102 KHFYRKPsPQAEEML 9606 BTO:0000567 31118282 t miannu Purified Plk1 bound to p31comet and phosphorylated it, resulting in the suppression of its activity (with TRIP13) to disassemble checkpoint complexes. We conclude that Plk1 phosphorylates p31 on S102 and on five additional sites. The phosphorylation of the additional sites was possibly not detectable in HeLa cell extracts due to the opposing action of protein phosphatases. SIGNOR-265970 0.385 CDKN1B protein P46527 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR down-regulates activity binding 9606 17409098 t lperfetto P27, an important cell cycle regulator, blocks the g(1)/s transition in cells by binding and inhibiting cdk2/cyclin a and cdk2/cyclin e complexes (cdk2/e). SIGNOR-217505 0.878 NCSTN protein Q92542 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 BTO:0000975 14572442 t Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation gcesareni Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. SIGNOR-118852 0.965 TFAP2A protein P05549 UNIPROT CRABP2 protein P29373 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002828 17187826 f miannu Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. SIGNOR-255400 0.349 NBEAL2 protein Q6ZNJ1 UNIPROT IQGAP1 protein P46940 UNIPROT down-regulates 10090 BTO:0000132 29187380 f lperfetto We found that the level of Iqgap1, a protein that stabilizes the active forms of Cdc42 and Rac1, was also significantly higher in Nbeal2−/− platelets SIGNOR-261890 0.2 WNT5A protein P41221 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 BTO:0000393 21903638 t gcesareni It has been shown that wnt5a activates the calcium signaling pathway in the presence of receptor fz2, 3, 4, 6 and receptor fz 5. SIGNOR-176579 0.696 P2RY10 protein O00398 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257005 0.2 HIF-1 complex complex SIGNOR-C418 SIGNOR Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity transcriptional regulation 9606 BTO:0000889 17785433 t Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration SIGNOR-267494 0.362 TET2 protein Q6N021 UNIPROT OGT protein O15294 UNIPROT up-regulates binding 9606 23353889 t miannu Tet2 and tet3 associate with the o_glcnac transferase ogt / tet2 and tet3 promote ogt_mediated glcnacylation SIGNOR-200695 0.455 PPP5C protein P53041 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity dephosphorylation Ser338 RPRGQRDsSYYWEIE -1 16892053 t Protein phosphatase 5 (PP5) was identified as an inactivator that associates with Raf-1 on growth factor stimulation and selectively dephosphorylates an essential activating site, Ser 338. The PP5-mediated dephosphorylation of Ser 338 inhibited Raf-1 activity and downstream signalling to MEK SIGNOR-248537 0.439 USP8 protein P40818 UNIPROT STAM protein Q92783 UNIPROT up-regulates quantity binding 9606 BTO:0000567 16520378 t Stability of the UBPY binding partner STAM is dramatically compromised in UBPY knockdown cells. SIGNOR-266904 0.55 GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263774 0.7 DLG4 protein P78352 UNIPROT Postsynaptic density assembly phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 17243894 f miannu PSD-95 (the best-studied scaffold protein of the PSD, which binds to NR2 subunits of NMDA receptors) was found to be highly abundant in the adult forebrain PSD SIGNOR-264230 0.7 CSNK2A1 protein P68400 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity phosphorylation Ser58 ESETNQNsSSDSEAE -1 11711551 t llicata We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. SIGNOR-250962 0.365 NR3C1 protein P04150 UNIPROT RXRA protein P19793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12573484 f gcesareni Physiological concentrations of glucocorticoids increase cellular cyp2c9 (and cyp3a5) but also car, rxr and pxr levels via a gr-mediated mechanism SIGNOR-98102 0.441 resiquimod chemical CHEBI:36706 ChEBI TLR7 protein Q9NYK1 UNIPROT up-regulates activity chemical activation 9606 15661881 t miannu Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively. SIGNOR-259246 0.8 SAV1 protein Q9H4B6 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 21084559 t Sav1 interacts with Mst1/2 through the SARAH domains present in both Sav1 and Mst1/2. gcesareni Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst. SIGNOR-169832 0.882 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 27418133 f The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-?-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-? skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-?/SNAIL signaling restores the production of pro-inflammatory cytokines SIGNOR-253587 0.7 PPARGC1A protein Q9UBK2 UNIPROT Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 9606 23277535 f gcesareni PGC1a is a positive regulator of mitochondrial biogenesis and respiration, adaptive thermogenesis, gluconeogenesis as well as many other metabolic proc SIGNOR-228618 0.7 PRKACA protein P17612 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser429 PQRERKSsSSSEDRN -1 11510412 t miannu Direct phosphorylation of B-Raf by PKA exerts a negative effect on its kinase activity, essentially via phosphorylation of Ser429 SIGNOR-250339 0.623 IMPDH2 protein P12268 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30518405 f miannu We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. SIGNOR-260959 0.2 MC3R protein P41968 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257230 0.252 ROCK1 protein Q13464 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation 9606 15068801 t gcesareni Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter. SIGNOR-123717 0.3 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr291 DDQRSMGyDDLDYGM -1 11382764 t lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 SIGNOR-246496 0.92 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN4 protein O15554 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 18955585 t Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  SIGNOR-258025 0.8 NFIX protein Q14938 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268908 0.2 episterol ester smallmolecule CHEBI:52393 ChEBI CNR1 protein P21554 UNIPROT up-regulates activity chemical activation 9606 BTO:0000142 29751000 t miannu 2-AG is an endocannabinoid that activates the cannabinoid CB1 receptor. SIGNOR-264266 0.8 CSNK2A2 protein P19784 UNIPROT EIF2B5 protein Q13144 UNIPROT up-regulates activity phosphorylation Ser718 KEAEEESsEDD 9606 11500362 t llicata Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.  SIGNOR-250990 0.377 SOX2 protein P48431 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 16153702 f flangone Our results suggest that OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal by activating their own genes and genes encoding components of key signaling pathways and by repressing genes that are key to developmental processes. SIGNOR-242064 0.7 KAT8 protein Q9H7Z6 UNIPROT MSL acetyltransferase complex SIGNOR-C344 SIGNOR form complex binding 9606 BTO:0000567 16227571 t miannu We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. SIGNOR-263943 0.803 PPARGC1A protein Q9UBK2 UNIPROT MSTN protein O14793 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 23217713 t miannu PGC-1 alpha specifically induces IGF1 and represses myostatin, and expression of PGC-1a 4 in vitro and in vivo induces robust skeletal muscle hypertrophy SIGNOR-256151 0.369 CAMK2B protein Q13554 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity phosphorylation Ser251 GKLGGQDsFESIESY BTO:0003637 12475968 t llicata Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1  SIGNOR-250684 0.314 LCK protein P06239 UNIPROT LCP2 protein Q13094 UNIPROT unknown phosphorylation Tyr426 NEEWYVSyITRPEAE -1 8702662 t Ability of p56lck to phosphorylate Tyr-423/426 within SLP-76 in vitro SIGNOR-251382 0.744 PTK2 protein Q05397 UNIPROT ACTN1 protein P12814 UNIPROT down-regulates phosphorylation Tyr12 DSQQTNDyMQPEEDW 9606 23454549 t lperfetto Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin . SIGNOR-192126 0.556 EFNA1 protein P20827 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9576626 t tpavlidou Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity SIGNOR-56904 0.81 PRKCA protein P17252 UNIPROT SNAP25 protein P60880 UNIPROT up-regulates phosphorylation Ser187 RIMEKADsNKTRIDE 9606 BTO:0000938 18171919 t llicata Phosphorylation of snap-25 at ser187 mediates enhancement of exocytosis by a phorbol ester in ins-1 cells. SIGNOR-160313 0.359 Calcineurin complex SIGNOR-C155 SIGNOR NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 BTO:0000782 14722106 t gcesareni Once activated, calcineurin directly dephosphorylates NFAT proteins that are present in a hyperphosphorylated latent form in the cytoplasm and induces their rapid translocation into the nucleus, where in concert with nuclear partner proteins such as the AP-1 transcription factor complex, they are able to bind cooperatively to their target promoter elements and activate the transcription of specific NFAT target genes SIGNOR-252313 0.822 GRK3 protein P35626 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. SIGNOR-251460 0.2 CREB1 protein P16220 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 f gcesareni In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1 SIGNOR-268144 0.252 YBX1 protein P67809 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17072343 f miannu YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. SIGNOR-255611 0.272 CDK2 protein P24941 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser286 TSGGVSEsPSGFSKH 9606 21765472 t lperfetto Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency SIGNOR-175079 0.535 ITCH protein Q96J02 UNIPROT JUNB protein P17275 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0001045 11828324 t miannu Itch promotes Ub conjugation to JunB Molecularly, Itch associated with and induced ubiquitination of JunB, a transcription factor that is involved in TH2 differentiation. However, in Itch−/− T cells under the same conditions, degradation of JunB was markedly delayed. SIGNOR-272619 0.417 ATR protein Q13535 UNIPROT MCC protein P23508 UNIPROT up-regulates activity phosphorylation Ser120 LRSELSQsQHEVNED 9606 BTO:0001109 21779472 t miannu MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity. SIGNOR-273515 0.2 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser705 TPSAMKSsPQIPHQT 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. SIGNOR-164412 0.626 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser465 LKHVTQSsRKLIRAD 9606 15381704 t The effect has been demonstrated using P28329-3 gcesareni Protein kinase c isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity. SIGNOR-129284 0.29 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250553 0.2 PTPRB protein P23467 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates dephosphorylation 9606 12840032 t gcesareni When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well SIGNOR-103165 0.443 PCSK5 protein Q92824 UNIPROT OXT protein P01178 UNIPROT down-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270327 0.251 RET/PTC2 protein Q15300 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 12637586 t Manara In addition, RET/PTC-mediated cellular transformation and proliferation of transformed cells require tyrosine 705 phosphorylation of STAT3 in NIH3T3 cells. We conclude that STAT3 activation by the RET/PTC tyrosine kinase is one of the critical signaling pathways for the regulation of specific genes, such as cyclin D1, vascular endothelial growth factor, and intercellular adhesion molecule 1, and for cellular transformation. SIGNOR-260917 0.2 CTDP1 protein Q9Y5B0 UNIPROT MASTL protein Q96GX5 UNIPROT down-regulates activity dephosphorylation Ser453 NFELVDSsPCKKIIQ 9606 26653855 t lperfetto Taken together, these data suggest that Fcp1 bound and dephosphorylated Gwl at S90 and S453, and possibly at other Cdk1 dependent sites, during mitosis exit and that Fcp1 catalyzed dephosphorylation lowered Gwl activity towards Ensa and ARPP19, allowing PP2A-B55 to autoactivate.|Together, these data indicate that Fcp1 dependent dephosphorylation greatly reduces S67-Ensa kinase activity of Gwl and that, downstream inactivation of Cdk1, Fcp1 deficit substantially blunts inactivation of Gwl. SIGNOR-276971 0.444 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1178 IMSKHLDsPPAIPPR 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-235925 0.702 KDM6A protein O15550 UNIPROT ERG protein P11308 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29736013 t miannu Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase SIGNOR-260033 0.2 DLG4 protein P78352 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 9278515 t brain lperfetto The PDZ domains of PSD-95 and related proteins interact with the COOH-terminal sequences of K+channels and NMDA2 receptors (3). By these interactions, PSD-95 may mediate the clustering of K+ channels and NMDA receptors at synapses. SIGNOR-264194 0.804 CAV1 protein Q03135 UNIPROT SLC1A2 protein P43004 UNIPROT down-regulates activity binding 9606 BTO:0000938 26690923 t miannu EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers. SIGNOR-264809 0.251 TP53 protein P04637 UNIPROT SLC2A4 protein P14672 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27692180 t miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. SIGNOR-267465 0.342 ID2 protein Q02363 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR down-regulates activity binding 10090 BTO:0004058 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241143 0.561 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Ala657 MVGGVVIaTVIVITL -1 10605825 t lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. SIGNOR-261738 0.502 ECM stimulus SIGNOR-ST20 SIGNOR AE/b7 integrin complex SIGNOR-C186 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259040 0.7 RORA protein P35398 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24737872 t miannu As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression. SIGNOR-268002 0.676 MTA1 protein Q13330 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000812 18719363 f miannu MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG. SIGNOR-254597 0.436 AURKA protein O14965 UNIPROT LDHB protein P07195 UNIPROT up-regulates activity phosphorylation Ser162 PKHRVIGsGCNLDSA 9606 BTO:0000567 31804482 t miannu Aurora-A-mediated phosphorylation of LDHB serine 162 significantly increases its activity in reducing pyruvate to lactate, which efficiently promotes NAD+ regeneration, glycolytic flux, lactate production and bio-synthesis with glycolytic intermediates.  SIGNOR-277493 0.2 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser326 PPKMWKTsPDPSPVS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248523 0.387 Gbeta proteinfamily SIGNOR-PF4 SIGNOR FOS protein P01100 UNIPROT up-regulates phosphorylation 9606 7816602 t inferred from 70% family members lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. SIGNOR-270105 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR INSIG2 protein Q9Y5U4 UNIPROT down-regulates activity 10090 BTO:0000759 21723501 f MTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2. SIGNOR-256212 0.2 CDK2 protein P24941 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser477 NSMNKLPsVSQLINP 9606 18769144 t lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively SIGNOR-180759 0.248 FOXO proteinfamily SIGNOR-PF27 SIGNOR GK protein P32189 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18805788 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription foxo1 localizes to the nucleus, where it represses hnf-4-dependent activity of the gk promoter as a corepressor. SIGNOR-252919 0.2 ROCK1 protein Q13464 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Thr7 tSAARRSY -1 12686604 t lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro. SIGNOR-100192 0.317 SP1 protein P08047 UNIPROT KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 15708372 t We characterized four Sp1/Sp3 binding sites in the proximal promoter of the PSA gene. In a luciferase assay, these sites contributed to the basal promoter activity in prostate cancer cells. In an electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we confirmed that Sp1 and Sp3 bind to these sites. Overexpression of wild-type Sp1 and Sp3 further upregulated the promoter activity, whereas overexpression of the Sp1 dominant-negative form or addition of mithramycin A significantly reduced the promoter activity and the endogenous mRNA level of PSA. SIGNOR-253664 0.2 olanzapine chemical CHEBI:7735 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10116 BTO:0000601 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258509 0.8 SIRT1 protein Q96EB6 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates deacetylation 9606 22223095 t gcesareni The acetylation marks on notch1-icd are removed by the deacetylase sirt1, suggesting that both deacetylation of notch1-icd and of histones inhibit notch signaling. SIGNOR-195333 0.434 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PAPOLA protein P51003 UNIPROT up-regulates activity phosphorylation Ser558 GSSQGRNsPAPAVTA 10090 BTO:0000964 34048556 t lperfetto Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity. SIGNOR-268343 0.2 ADK protein P55263 UNIPROT ATP smallmolecule CHEBI:15422 ChEBI down-regulates quantity chemical modification 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5√¢‚Ǩ¬≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-267839 0.8 AURKB protein Q96GD4 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser38 LGPGTRLsLARMPPP -1 12686604 t lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro. SIGNOR-100169 0.449 PRKACA protein P17612 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates phosphorylation Ser879 LIDRNQKsDKKPDRE 9606 BTO:0000763 22798526 t lperfetto We showed that pkc_ phosphorylation of p120 at serine (s)879 in response to thrombin or lipopolysaccharide challenge reduced p120 binding affinity for ve-cadherin and mediated aj disassembly secondary to ve-cadherin internalization SIGNOR-198288 0.2 CBP/p300 complex SIGNOR-C6 SIGNOR SMAD1 protein Q15797 UNIPROT up-regulates binding 9606 12419246 t lperfetto Thus, Ski/SnoN represses TGFβ signaling by multiple mechanisms. In addition to recruitment of a transcriptional repressor complex and dissociation of the transcriptional coactivator p300/CBP from the Smads SIGNOR-217217 0.406 MAP3K14 protein Q99558 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity phosphorylation 9606 20651737 t lperfetto As nik levels increase, nik presumably becomes activated by autophosphorylation (p). SIGNOR-167063 0.2 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr585 PPGLEYCyNPSHNPE 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1 SIGNOR-236187 0.2 GAB1 protein Q13480 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 11043767 t lperfetto We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1. SIGNOR-252676 0.491 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RXRB protein P28702 UNIPROT up-regulates activity chemical activation 9606 17132853 t miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. SIGNOR-256191 0.8 YY1 protein P25490 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR up-regulates quantity by expression 17158804 t YY1 REPO domain is necessary and sufficient for PcG transcriptional repression, Polycomb recruitment to DNA, and methylation of histone H3 on lysine 27 SIGNOR-253595 0.591 NFKB1 protein P19838 UNIPROT IEX-1L protein O75353 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9703517 f gcesareni Transcription factors of the nuclear factor-kappab/rel (nf-kappab) family may be important in cell survival by regulating unidentified, anti-apoptotic genes. One such gene that protects cells from apoptosis induced by fas or tumor necrosis factor type alpha (tnf), iex-1l, is described here. Its transcription induced by tnf was decreased in cells with defective nf-kappab activation, rendering them sensitive to tnf-induced apoptosis, which was abolished by transfection with iex-1l. SIGNOR-59539 0.2 PPM1D protein O15297 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 11101524 t lperfetto Wip1 selectively inactivates p38 by specific dephosphorylation of its conserved threonine residue SIGNOR-84793 0.455 PRPF19 protein Q9UMS4 UNIPROT RPA2 protein P15927 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000567 24332808 t miannu PRP19 is a ubiquitin ligase involved in pre-mRNA splicing and the DNA damage response (DDR). PRP19 ubiquitylates RPA and promotes ATRIP recruitment. SIGNOR-272075 0.458 CYSLTR2 protein Q9NS75 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256746 0.2 IRF1 protein P10914 UNIPROT IRF8 protein Q02556 UNIPROT up-regulates activity binding 9606 11483597 t miannu We found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP. SIGNOR-222841 0.404 PDX1 protein P52945 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000627 8866550 f inferred from family member miannu The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription. SIGNOR-270264 0.589 CAMK1G protein Q96NX5 UNIPROT EIF4G3 protein O43432 UNIPROT up-regulates phosphorylation Ser1156 NTFMRGGsSKDLLDN 9606 22514323 t lperfetto Here we report that activity-dependent translational initiation in cultured rat hippocampal neurons is enhanced by camki-mediated phosphorylation of ser1156 in eukaryotic initiation factor eif4gii (4gii). SIGNOR-197149 0.2 CDK2 protein P24941 UNIPROT LIG3 protein P49916 UNIPROT down-regulates phosphorylation Ser210 TTTGQVTsPVKGASF 9606 17040896 t llicata Dna ligase iii_ is specifically phosphorylated in replicating cells by the cell cycle kinase cdk2. However, in response to oxidative dna damage, dna ligase iii_ is dephosphorylated in a pathway that is dependent upon the dna damage-activated, phosphatidylinositol 3-phosphate (pi3)1-related kinase atm. SIGNOR-150121 0.428 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMPH protein P49418 UNIPROT unknown phosphorylation Ser276 PLPSPTAsPNHTLAP -1 11113134 t llicata Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells.  SIGNOR-250645 0.361 RET protein P07949 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates binding 9606 8631863 t gcesareni Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell SIGNOR-41699 0.523 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr716 RPPSAELySNALPVG -1 8940081 t miannu The SH2 domain of Grb7 can directly bind to the autophosphorylated PDGF beta-receptor in vitro. Grb7 association to the PDGF beta-receptor was dramatically reduced by replacement of tyrosine residues 716 or 775 with phenylalanine residues. SIGNOR-250256 0.2 PI4K2B protein Q8TCG2 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269100 0.8 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0001321 15659650 t lperfetto CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37 SIGNOR-217799 0.771 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89158 0.538 NRP1 protein O14786 UNIPROT PHACTR1 protein Q9C0D0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21939755 f miannu Recently, we identified a new Vascular Endothelial Growth Factor (VEGF)-A(165)-induced gene Phactr-1, (Phosphatase Actin Regulator-1). We found that neuropilin-1 (NRP-1) and VEGF-R1 depletion inhibited Phactr-1 mRNA expression while NRP-2 and VEGF-R2 depletion had no effect. SIGNOR-260061 0.2 GSK1059615 chemical CHEBI:71955 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192774 0.8 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273078 0.635 UBE3A protein Q05086 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 9497376 t miannu E6AP and E6 together provide the E3-ubiquitin protein ligase activity in the transfer of ubiquitin to p53. In vitro studies have shown that E6AP can form a high energy thiolester bond with ubiquitin and, in the presence of E6, transfer ubiquitin to p53. In this study we have addressed the role of E6AP in vivo in the degradation of p53.  SIGNOR-272552 0.672 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT down-regulates activity phosphorylation Ser203 APAPDEGsDLFYDDY 9606 BTO:0000567 11546811 t lperfetto The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm. SIGNOR-110383 0.403 PRKD1 protein Q15139 UNIPROT PTRH2 protein Q9Y3E5 UNIPROT up-regulates phosphorylation Ser5 sLVMEYLA 9606 18703509 t lperfetto Overexpression of constitutively active pkd or pkd activation by treatment with phorbol 12-myristate 13-acetate results in phosphorylation of two serine residues (ser5 and ser87) in a form of bit1 that is confined to the cytoplasm and concomitantly increases the apoptotic activity of cytoplasmic bit1 SIGNOR-180085 0.305 APIP protein Q96GX9 UNIPROT APAF1 protein O14727 UNIPROT down-regulates binding 9606 15262985 t acerquone Taken together, these results suggest that apip functions to inhibit muscle ischemic damage by binding to apaf-1 in the apaf-1/caspase-9 apoptosis pathway. SIGNOR-126797 0.541 BLK protein P51451 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268217 0.633 SLC36A1 protein Q7Z2H8 UNIPROT alanine smallmolecule CHEBI:16449 ChEBI up-regulates quantity relocalization 9606 12748860 t lperfetto Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut. SIGNOR-264739 0.8 MAPK12/CARM1 complex SIGNOR-C218 SIGNOR SNTB1 protein Q13884 UNIPROT up-regulates activity binding 29681515 t apalma Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated SIGNOR-255978 0.376 Alkannin chemical CHEBI:2578 ChEBI PK proteinfamily SIGNOR-PF80 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0000093;BTO:0000018 21516121 t inferred from family member lperfetto Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2. SIGNOR-270284 0.8 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates activity phosphorylation Tyr421 RLPSSPVyEDAASFK -1 15169891 t lperfetto Erk phosphorylation and a mimicking S405,418D double mutation enhanced cortactin binding and activation of N-WASP. In contrast, Src phosphorylation inhibited the ability of cortactin previously phosphorylated by Erk, and that of S405,418D double mutant cortactin, to bind and activate N-WASP. Furthermore, Y-->D mutation of three tyrosine residues targeted by Src (Y421, Y466, and Y482) inhibited the ability of S405,418D cortactin to activate N-WASP. SIGNOR-246513 0.794 WNT5A protein P41221 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates binding 9606 19910923 t gcesareni Fz2 was also required for the wnt3a-dependent accumulation of beta-catenin, and wnt5a competed with wnt3a for binding to fz2 in vitro and in intact cells, thereby inhibiting the beta-catenin pathway.Wnt5a Internalized fz2 probably with ror1 or ror2 through the clathrin-mediated route, whereas wnt5a competed with wnt3a for binding to fz2 to inhibit the beta-catenin pathway. SIGNOR-189120 0.757 AREL1 protein O15033 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002552 23479728 t lperfetto Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists| SIGNOR-267668 0.385 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser441 GHSPLSLsAQSVMEE 9606 BTO:0000938 24614225 t lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204708 0.524 HARS1 protein P12081 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. SIGNOR-270803 0.8 haloperidol chemical CHEBI:5613 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258373 0.8 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates activity phosphorylation Tyr500 TSLGSQSyEDMRGIL 10090 BTO:0000776 10933394 t lperfetto Experiments with purified proteins demonstrated that CD19-Y513 was Lyn's initial phosphorylation and binding site. This led to processive phosphorylation of CD19-Y482, which recruited a second Lyn molecule, allowing for transphosphorylation and amplification of Lyn activation|Tyrosine phosphorylation of CD19 following BCR and/or CD19 ligation provides Src homology 2 (SH2) recognition motifs that recruit regulatory molecules to the cell surface. CD19 dually phosphorylated at CD19€“Y482 and CD19€“Y513 binds the tandem SH2 domains of phosphatidylinositol 3-kinase (PI 3-kinase) p85 subuni SIGNOR-249376 0.764 BCOR protein Q6W2J9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0004850 26847029 f irozzo Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes. SIGNOR-256011 0.7 BMP4 protein P12644 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 BTO:0001253 7673243 t lperfetto We have isolated a cdna encoding a novel transmembrane serine/threonine kinase from human skin fibroblasts which we demonstrate here to be a type ii receptor that binds bmp-4. This receptor (brk-3) is distantly related to other known type ii receptors and is distinguished from them by an extremely long carboxyl-terminal sequence following the intracellular kinase domain. SIGNOR-217535 0.847 HDAC2 protein Q92769 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity deacetylation -1 11486036 t miannu Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs. SIGNOR-268836 0.76 CIITA protein P33076 UNIPROT HLA-DPB1 protein P04440 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11889043 f Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment. SIGNOR-254006 0.488 ZW10 protein O43264 UNIPROT RZZ complex complex SIGNOR-C357 SIGNOR form complex binding 9606 20462495 t lperfetto The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico. SIGNOR-265012 0.831 SLBP protein Q14493 UNIPROT H2AC7 protein P20671 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265399 0.2 KLK3 protein P07288 UNIPROT PTHLH protein P12272 UNIPROT up-regulates activity binding -1 8683730 t lperfetto Prostate-specific antigen was found to specifically cleave PTHrP 1-141 in a time- and dose-dependent manner.|The preferred PSA cleavage site of PTHrP 1-141 was determined to be at the carboxyl-terminus of phenylalanine 23, consistent with chymotryptic-like enzymatic activity of PSA. Cleavage of PTHrP by PSA completely abolished the ability of PTHrP to stimulate cAMP production. SIGNOR-270548 0.432 GNAS protein P63092 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 22179044 t gcesareni Notably, the fzd7 receptor complex was associated with g_?(s) and pi(3)k and these components were required for wnt7a to activate the akt/mtor growth pathway in myotubes. These data led us to hypothesize that g_?s Mediates the activation of pi3kinase following wnt7a binding to fzd7. SIGNOR-252678 0.364 Complement C1 complex complex SIGNOR-C309 SIGNOR C2 protein P06681 UNIPROT up-regulates activity cleavage Ser20 LYPGLADsAPSCPQN 31331124 t lperfetto C1s subsequently activate serum proteins C4 and C2. C4 is cleaved to fragment C4a, which is an anaphylatoxin, and to fragment C4b, which is deposited on the adjacent surfaces. C2 is cleaved to a fragment C2b, and larger fragment C2a, which binds noncovalently to C4b on the target cell membrane. This forms the C4b2a complex SIGNOR-263421 0.477 CSNK1D protein P48730 UNIPROT PRH1 protein P02810 UNIPROT up-regulates phosphorylation Ser24 QDLDEDVsQEDVPLV 9606 BTO:0000007 BTO:0000671 10684652 t lperfetto Ser22 may be phosphorylated by a g-ck that recognizes an atypical substrate sequence or by a novel kinase. While prp1 secreted from salivary glands is fully phosphorylated at ser8 and 22 SIGNOR-75272 0.2 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CEBPA protein P49715 UNIPROT down-regulates activity binding 9606 12524424 t lperfetto C/EBPbeta and C/EBPdelta were found to physically interact with Smad3 and Smad4, and Smad3 cooperated with Smad4 and TGF-beta signaling to repress the transcriptional activity of C/EBPs. SIGNOR-250571 0.375 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser392 FKTEGPDsD 10747897 t miannu We demonstrate that anisomycin- and tumor necrosis factor--induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase SIGNOR-250114 0.764 PLEKHG1 protein Q9ULL1 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260563 0.329 ITCH protein Q96J02 UNIPROT TNIP2 protein Q8NFZ5 UNIPROT down-regulates ubiquitination 9606 16469705 t gcesareni Here we show that tnfa-mediated jnk activation accelerates turnover of the NF-kappaBinduced antiapoptotic protein c-flip, an inhibitor of caspase-8. This is not due to direct c-flip phosphorylation but depends on jnk-mediated phosphorylation and activationof the e3ubiquitin ligaseitch, which speci?cally Ubiquitinates c-flip and induces its proteasomal degradation. SIGNOR-144453 0.272 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 15618519 t gcesareni Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms. SIGNOR-132672 0.2 KDM6A protein O15550 UNIPROT ETV6 protein P41212 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29736013 t miannu Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase SIGNOR-260032 0.305 MAFA protein Q8NHW3 UNIPROT PC protein P11498 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17149590 f miannu the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. SIGNOR-254561 0.252 RCHY1 protein Q96PM5 UNIPROT POLH protein Q9Y253 UNIPROT down-regulates activity monoubiquitination Lys686 HQGKRNPkSPLACTN 9606 21791603 t miannu Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709). SIGNOR-272731 0.563 DTX1 protein Q86Y01 UNIPROT TCF3 protein P15923 UNIPROT down-regulates 9606 BTO:0000776 9528794 f gcesareni Our experiments indicate that deltex expression alone is suffcient to inhibit e47. SIGNOR-56141 0.278 MAPK9 protein P45984 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 8846788 t lperfetto However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity. SIGNOR-247062 0.472 MAPK1 protein P28482 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation Thr277 GSRTAPYtPNLPHHQ 9606 12801888 t lpetrilli Phosphorylation of thr276 is shown to be important for tgf-?-Induced nuclear accumulation and, as a consequence, transcriptional activity of smad4. these results suggest that smad4 can be phosphorylated by erk2 at thr276. SIGNOR-101660 0.525 PRPS2 protein P11908 UNIPROT 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI up-regulates quantity chemical modification 9606 16939420 t miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. SIGNOR-267082 0.8 SH3BP4 protein Q9P0V3 UNIPROT TFRC protein P02786 UNIPROT down-regulates binding 9606 16325581 t miannu Here, we report that ttp (sh3bp4), a sh3-containing protein, specifically regulates the internalization of the transferrin receptor (tfr). / overexpression of ttp specifically inhibits tfr internalization SIGNOR-142840 0.36 ITGA8 protein P53708 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253181 0.812 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89264 0.402 MAPK9 protein P45984 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser605 LFVQLLYsPIENIQR 9606 18423204 t amattioni Beta-catenin, upon entering the nucleus, in turn activates transcription of downstream target genes. Jnk2 phosphorylates Beta-catenin on critical residues (ser191 and ser605). Jnk activity is required for Beta-catenin nuclear localization in response to wnt. SIGNOR-178262 0.658 S1PR1 protein P21453 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates 9606 9488656 f gcesareni Edg-1 is known to activate the mitogen-activated protein (map) kinase known as extracellular signal-regulated kinase 2 (erk-2) through pertussis toxin (ptx)sensitive giprotein SIGNOR-54770 0.483 NEK11 protein Q8NG66 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser82 GSSESTDsGFCLDSP 9606 19734889 t lperfetto Nek11 regulates cdc25a degradation and the ir-induced g2/m checkpointincubation of wild-type cdc25a with nek11 led to a marked increase in phosphorylation of ser 82 and 88 as detected with the phosphospecific antibody recognizing these sites SIGNOR-187867 0.428 CDK1 protein P06493 UNIPROT PAPOLA protein P51003 UNIPROT up-regulates activity phosphorylation Ser558 GSSQGRNsPAPAVTA 10090 BTO:0000964 34048556 t lperfetto Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity. SIGNOR-268340 0.261 PTPN1 protein P18031 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity dephosphorylation Tyr446 GTEPEPVySMEAADY 9534 BTO:0004055 18387954 t Here, we have identified cortactin, a central regulator of actin cytoskeletal dynamics, as a substrate of PTP1B. A trapping mutant of PTP1B binds cortactin at the phosphorylation site Tyr446, |Cortactin exerts its effects on the actin cytoskeleton by interacting directly with the Arp2/3 complex , F-actin |Src phosphorylates murine cortactin predominantly at three key sites in vitro, Tyr421, Tyr466, and Tyr482 (corresponding to Tyr421, Tyr470, and Try486 in human cortactin), resulting in decreased actin cross-linking activity SIGNOR-248432 0.531 UBE2D3 protein P61077 UNIPROT MPG protein P29372 UNIPROT up-regulates activity binding -1 25207814 t miannu Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. We observed that PP2Ac was ubiquitinated in the presence of UbcH5a-c and UbcH6, similar to results obtained with MID1-catalyzed ubiquitination of alpha4 (Figure 2E) SIGNOR-271928 0.2 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr811 ADDSSSStSSDSLGG -1 8349691 t llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. SIGNOR-250910 0.346 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr66 CERSGQRtASVLWPW 9534 BTO:0001538 12138165 t T66E mutations interfered with the ability of IRAK to autophosphorylate. Thr-66 mutations abolished the capacity of IRAK to dimerize. SIGNOR-251327 0.2 RAPH1 protein Q70E73 UNIPROT VASP protein P50552 UNIPROT up-regulates activity binding 9606 20417104 t miannu Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins. SIGNOR-268426 0.596 RPL26 protein P61254 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262497 0.857 3-(dibutylamino)-1-[1,3-dichloro-6-(trifluoromethyl)-9-phenanthrenyl]-1-propanol chemical CHEBI:94392 ChEBI KCNH2 protein Q12809 UNIPROT down-regulates activity chemical inhibition -1 19222165 t Luana 4 inhibited cloned hERG potassium ion channel repolarization with an IC50 comparable to other antimalarial agents in this class (Table 6). SIGNOR-257816 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CAD protein P27708 UNIPROT up-regulates activity phosphorylation Thr456 KVYFLPItPHYVTQV -1 17485345 t miannu The multifunctional protein CAD initiates de novo pyrimidine biosynthesis in mammalian cells. CAD is activated by MAP kinase (Erk1/2) just prior to the S phase of the cell cycle, when the demand for pyrimidine nucleotides is greatest, and down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. MAP kinase phosphorylates Thr456, while PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation.  SIGNOR-267441 0.2 NANOGP8 protein Q6NSW7 UNIPROT JUN protein P05412 UNIPROT down-regulates quantity by repression transcriptional regulation 10900 BTO:0000667 23839044 f Luana Constitutive NanogP8 overexpression in adult L1 mice reduced CD34+α6+ and Lrig-1+ bulge stem cells, impaired keratinocyte migration, and repressed the expression of many stem cell-associated genes, including Bmp5, Fgfr2, Jmjd1a, and Jun. SIGNOR-266091 0.2 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates quantity by stabilization phosphorylation Ser346 RAPSRKDsLESDSST 9606 21317289 t gcesareni We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation SIGNOR-172003 0.444 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t lperfetto Many cellular receptors signal via tyrosine phosphorylation. The tyrosine kinases required for this activity are often recruited upon ligand bindingAlternatively, receptors themselves have kinase activity, like insulin receptors. In either case, the receptors are returned to their original state through the activity of protein-tyrosine phosphatases (PTPs)The major candidate PTPs previously implicated in IRK dephosphorylation are PTP-1b and LAR. SIGNOR-76017 0.563 NME1 protein P15531 UNIPROT KSR1 protein Q8IVT5 UNIPROT unknown phosphorylation Ser406 TRLRRTEsVPSDINN -1 12105213 t miannu Mutation of Ser392 to alanine consistently reduced Nm23-H1 phosphorylation, confirming it as a site of Nm23-H1 kinase activity The unique phosphorylation pattern of KSR by Nm23-H1 will be the subject of further investigation to determine its effects on KSR protein binding, subcellular localization, response to various signals, etc. SIGNOR-250299 0.559 PRKACA protein P17612 UNIPROT WT1 protein P19544 UNIPROT down-regulates phosphorylation Ser393 KTCQRKFsRSDHLKT 9606 9366517 t llicata Pka phosphorylated wt1 at ser-365 and ser-393 in vitro, as well as at additional sites, and this phosphorylation abolished the dna-binding activity of wt1 in vitro. Using wt1 mutants in which ser-365 and ser-393 were mutated to ala individually and in combination, we showed that phosphorylation of these sites was critical for inhibition of dna binding in vivo. SIGNOR-53176 0.347 DAAM1 protein Q9Y4D1 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 9606 19365405 t gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. SIGNOR-185268 0.816 MEF2D protein Q14814 UNIPROT MYH10 protein P35580 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 t lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation SIGNOR-238766 0.328 DDB1 protein Q16531 UNIPROT DDB2/DDB1 complex SIGNOR-C39 SIGNOR form complex binding 9606 BTO:0000567 9418871 t miannu Ddb was identified as a heterodimeric protein (48 and 127 kda) that binds to uv-damaged dna SIGNOR-54093 0.936 RB1 protein P06400 UNIPROT ITGA10 protein O75578 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24287699 f lperfetto Integrin α10 expression is pRb-dependent in mouse osteoblasts|pRb-activated expression of integrin α10 mRNA is effectively translated into higher levels of integrin α10 protein as visualized by immunofluorescence SIGNOR-253348 0.2 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates activity phosphorylation Tyr360 VSPSPTTyRMFRDKS 9534 8622703 t Manara These results indicate that tyrosine phosphorylation of Bcr by Bcr-Abl inhibits Bcr‚Äôs serine/threonine kinase activity. SIGNOR-262530 0.2 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr382 DHYRYSDtTDSDPEN 9606 21779440 t gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity SIGNOR-161122 0.622 MITF protein O75030 UNIPROT TYR protein P14679 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000847 10080955 f miannu Microphthalmia transcription factor MITF, a melanocyte-specific basic helix-loop-helix protein, has been shown to transactivate tyrosinase and TRP-1 genes in vitro by binding to a shared regulatory sequence known as M box. both activation of positive factors such as MITF and inactivation of negative regulatory factors may be required for TRP-1 gene expression during melanocytic differentiation. SIGNOR-254593 0.594 F2R protein P25116 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257127 0.424 RLIM protein Q9NVW2 UNIPROT LDB1 protein Q86U70 UNIPROT down-regulates quantity by destabilization polyubiquitination 10029 BTO:0000246 11882901 t miannu Here we identify RLIM as a ubiquitin protein ligase that is able to target CLIM cofactors for degradation through the 26S proteasome pathway.  SIGNOR-272617 0.583 SIRT1 protein Q96EB6 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity deacetylation 9606 14976264 t lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress SIGNOR-122405 0.909 PRKCB protein P05771 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser42 AKKKSKIsASRKLQL 9606 15769444 t lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. SIGNOR-134624 0.2 IL10 protein P22301 UNIPROT SCN1A protein P35498 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 23357618 f miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. SIGNOR-253497 0.2 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT down-regulates activity phosphorylation Ser146 MEPERRDsQDGSSYR 9606 22665060 t llicata Phosphorylation of lasp-1 by pka at serine 146 induces translocation of the lasp-1/zo-2 complex from the cytoplasm to the nucleus. Interaction occurs within the carboxyterminal proline-rich motif of zo-2 and the sh3 domain in lasp-1. SIGNOR-197720 0.311 Calcineurin complex SIGNOR-C155 SIGNOR MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 f gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-252309 0.38 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Thr334 ALPPGPPtGATANRL 9606 BTO:0000007 10542239 t llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T SIGNOR-250812 0.2 CARM1 protein Q86X55 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 24332853 f miannu PRMT4 blocks myeloid differentiation of human hematopoietic stem/progenitor cells While PRMT4 promotes differentiation in several biological systems including T cell, adipocyte and muscle development, it blocks differentiation in the hematopoietic system, allowing HSPCs to maintain stemness.  SIGNOR-261968 0.7 YWHAQ protein P27348 UNIPROT GEM protein P55040 UNIPROT up-regulates quantity by stabilization binding 9534 14701738 t miannu In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase SIGNOR-261724 0.269 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194337 0.8 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Arg) smallmolecule CHEBI:29171 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270363 0.8 Tandospirone citrate chemical CHEBI:32182 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258861 0.8 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-52863 0.817 MAPK14 protein Q16539 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 12181443 f lperfetto We show [] that the kinase activity and s473 phosphorylation of akt induced by lpa and s1p requires both mitogen-activated protein (map) kinase kinase (mek) and p38 map kinase. [] among different stimuli tested, platelet-derived growth factor stimulates s473 phosphorylation of akt in a mek- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1?stimulated Akt s473 phosphorylation require p38 but not mek. SIGNOR-244465 0.631 IQSEC2 protein Q5JU85 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity relocalization 10090 BTO:0000142 18164504 t miannu Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull down assay demonstrated that IQ-ArfGEF/BRAG1 activated Arf6 more potently than Arf1.IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. Taken together, IQ-ArfGEF/BRAG1 forms a postsynaptic protein complex containing PSD-95 and NMDA receptors at excitatory synapses, where it may function as a GEF for Arf6. SIGNOR-264907 0.485 terbutaline chemical CHEBI:9449 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) SIGNOR-257871 0.8 PTK6 protein Q13882 UNIPROT EPS8 protein Q12929 UNIPROT up-regulates activity phosphorylation Tyr498 YAFSSNIyTRGSHLD 9606 BTO:0000007 27738316 t miannu Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis. SIGNOR-263189 0.365 RFX4 protein Q33E94 UNIPROT IFT172 protein Q9UG01 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19887680 f miannu We find that Ift172, which encodes an intraflagellar transport protein necessary for ciliogenesis, is a direct transcriptional target of Rfx4 SIGNOR-223319 0.353 PINK1 protein Q9BXM7 UNIPROT CYCS protein P99999 UNIPROT down-regulates quantity 9606 BTO:0000938 20012177 t lperfetto There is a strong cyto-protective role of PINK1 in maintaining mitochondrial homeostasis via different mechanisms. Overexpression of wild-type PINK1 in SH-SY5Y neuroblastoma cells stabilizes respiring mitochondrial networks through various mechanisms that include maintaining mitochondrial membrane potential, reducing basal and neurotoxin-induced ROS, suppression of cytochrome c release, reversal of toxin-induced fission, and suppression of autophagy SIGNOR-249704 0.391 ESR1 protein P03372 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000150 16169518 t gcesareni Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k. SIGNOR-140470 0.613 MACROH2A1 protein O75367 UNIPROT rRNA_transcription phenotype SIGNOR-PH145 SIGNOR down-regulates 16428466 f miannu These data unambiguously identify mH2A as a strong transcriptional repressor and show that the repressive effect of mH2A is realized on at least two different transcription activation chromatin-dependent pathways: histone acetylation and nucleosome remodeling. SIGNOR-272930 0.7 SMURF1 protein Q9HCE7 UNIPROT HOMER2 protein Q9NSB8 UNIPROT unknown ubiquitination -1 20804422 t miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. SIGNOR-272699 0.2 CERS4 protein Q9HA82 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI up-regulates quantity chemical modification 9606 26887952 t done miannu  Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity.  SIGNOR-273998 0.8 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR FGG protein P02679 UNIPROT up-regulates activity binding 9606 BTO:0000132 16418530 t lperfetto In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. SIGNOR-253360 0.547 RORC protein P51449 UNIPROT IL17A protein Q16552 UNIPROT up-regulates transcriptional regulation 9606 16990136 t mrosina We found that RORgt is required for the constitutive expression of IL-17 in intestinal lamina propria T cells and for the in vitro differentiation of Th17 cells from naive CD4+ T cells SIGNOR-255029 0.556 Cap-binding complex complex SIGNOR-C440 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates relocalization 9606 32873578 t lperfetto The largely nuclear cap-binding complex (CBC) binds to the 5′ caps of RNA polymerase II (RNAPII)-synthesized transcripts and serves as a dynamic interaction platform for a myriad of RNA processing factors that regulate gene expression. SIGNOR-268360 0.8 AVPR1B protein P47901 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257063 0.271 C5 convertase complex complex SIGNOR-C312 SIGNOR C5 protein P01031 UNIPROT up-regulates activity cleavage Arg677 KEILRPRrTLQKKIE 31331124 t lperfetto Association of C3b with C3 convertases (C3bBb or C4b2a) results in formation of C5 convertases, C3bBbC3b and C4b2aC3b, which initiate the lytic pathway by cleavage of C5 to C5a and C5b SIGNOR-263452 0.539 STK11 protein Q15831 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 SIGNOR-C15 14976552 t gcesareni We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli SIGNOR-122725 0.611 CDC25A protein P30304 UNIPROT PKM protein P14618 UNIPROT up-regulates activity dephosphorylation Ser37 MCRLDIDsPPITARN 9606 27485204 t lperfetto Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2 dependent beta-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop.|Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2-dependent \u03b2-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop. SIGNOR-276967 0.5 E2F1 protein Q01094 UNIPROT DLK1 protein P80370 UNIPROT up-regulates quantity by expression transcriptional regulation 19874716 t lperfetto Using luciferase reporter assay, ChIP assay and EMSA, we found that the -211/-194 region of the pref-1 promoter is essential for the binding of E2F1 as well as E2F1-dependent transcriptional activation. SIGNOR-271684 0.2 KIT protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity 9534 BTO:0001538 7509796 t Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells SIGNOR-255949 0.709 ITCH protein Q96J02 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization ubiquitination Lys371 PTSMVLTkVSASTVP 9606 BTO:0002181 19881509 t Giorgia These data collectively indicate that AIP4 is the E3 ligase for MAVS.|We generated single substitutions (K362A, K371A or K420A) and combined point substitutions of MAVS and tested their degradation. K371A or K420A MAVS showed partial resistance to PCBP2-induced degradation (data not shown), whereas MAVS with the combined substitutions K371A and K420A (KK-AA) completely withstood the degradation SIGNOR-260362 0.631 porfimer chemical CHEBI:60652 ChEBI LDLR protein P01130 UNIPROT up-regulates activity chemical activation 9606 1450993 t miannu Porphyrins are transported in blood mainly by lipoproteins, and the low density lipoprotein (LDL) receptor-mediated pathway is probably one of the important factors involved in the selective accumulation of porphyrins by tumor tissues, as cancer cells generally express much more LDL receptors than normal cells. SIGNOR-259302 0.8 PTPN1 protein P18031 UNIPROT TRPV6 protein Q9H1D0 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 17197020 t gcesareni We conclude that phosphorylation/dephosphorylation of tyrosines in position 161 and 162 is essential for regulation of ca2+ influx through trpv6 ca2+ channels in hek293 cells. Co-transfection with src led to tyrosine phosphorylation of trpv6 which could be dephosphorylated by ptp1b. y161/162 are essential for tyrosine phosphorylation-dependent modulation of trpv6-mediated ca2+ entry. SIGNOR-151711 0.615 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. SIGNOR-116274 0.804 TBK1 protein Q9UHD2 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser536 SGDEDFSsIADMDFS 9606 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-129951 0.602 PIGG protein Q5H8A4 UNIPROT PIGO protein Q8TEQ8 UNIPROT up-regulates quantity by stabilization binding 10029 BTO:0000246 15632136 t miannu We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O. SIGNOR-261359 0.407 Non-structural protein 10 protein P0C6X7-PRO_0000037317 UNIPROT IFTAP protein Q86VG3 UNIPROT unknown binding 4932 18433331 t lperfetto In our previous work, we isolated a gene from a cDNA library of human embryo lung tissue, which en- coded a novel protein that specifically interacted with nsp-10 of SARS-CoV in a yeast trap experiment.|Since nsp- 10 of SARS-CoV is involved in viral genomic replica- tion and was observed to interact with ATF5, the cellular initiation factor of the RNA pol II complex (13), we in- ferred that HEPIS may also be involved in cellular gene transcription. Therefore, the significance of HEPIS ex- pression in cells needed to be further investigated. The work we describe here suggests that HEPIS represses cel- lular transcription initiation through interaction with a component of the RNA pol II complex SIGNOR-260251 0.2 JAK2 protein O60674 UNIPROT IFNGR2 protein P38484 UNIPROT up-regulates activity binding 9606 BTO:0000801 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249489 0.688 HCK protein P08631 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr753 ERDINSLyDVSRMYV -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249363 0.532 CDC25B protein P30305 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 25384584 t lperfetto CDC25B facilitates dephosphorylation of the key cell cycle regulator CDC2 (also called CDK1) at Tyr15 or Thr14, thereby initiating the G 2 /M transition ( xref ).|CDC25B facilitates dephosphorylation of the key cell cycle regulator CDC2 (also called CDK1) at Tyr15 or Thr14, thereby initiating the G2/M transition ( ). SIGNOR-276970 0.823 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-70440 0.2 tolbutamide chemical CHEBI:27999 ChEBI CFTR protein P13569 UNIPROT down-regulates activity chemical inhibition 10090 1281220 t miannu The sulfonylureas, tolbutamide and glibenclamide, inhibited whole-cell CFTR Cl- currents at half-maximal concentrations of approximately 150 and 20 microM, respectively. SIGNOR-258345 0.8 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257973 0.8 PRKCA protein P17252 UNIPROT SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization phosphorylation Ser297 GLRYNRLsAIPRSLA 29383184 t lperfetto PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8. SIGNOR-275567 0.2 CHEK2 protein O96017 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity phosphorylation Ser612 MYLSPVRsPKKKGST 9606 BTO:0000093 17380128 t lperfetto Phosphorylation of prb at ser612 by chk1/2 leads to a complex between prb and e2f-1 after dna damageprb inhibits cell cycle progression through interactions with the e2f family of transcription factors. Here, we report that dna damage induced not only the dephosphorylation of prb at cdk phosphorylation sites and the binding of prb to e2f-1, but also the phosphorylation of prb at ser612. Phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1 SIGNOR-153908 0.433 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000763 12193595 t miannu Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction. SIGNOR-91718 0.711 MYO5A protein Q9Y4I1 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates activity binding 9606 21077886 t miannu Another potential role of myosin Va in LDCV exocytosis lies in facilitating the formation of the SNARE complex, which is needed for fusion of the vesicle with the plasma membrane. Notably, myosin Va binds to at least two SNARE proteins in a Ca2+-dependent manner: at micromolar Ca2+-levels, it binds to VAMP2 located in the membrane of the cargo vesicle via its globular tail domain SIGNOR-269281 0.462 VAV1 protein P15498 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 BTO:0000725 9151714 t Barakat In summary, we demonstrate here that Y315 in ZAP-70 is required to interact with the Vav SH2 domain, and is critical for ZAP-70–mediated gene activation. SIGNOR-274150 0.832 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273090 0.745 NOTCH proteinfamily SIGNOR-PF30 SIGNOR MAML2 protein Q8IZL2 UNIPROT up-regulates binding 9606 12386158 t gcesareni Other than a role in t-cell development, the hox genes may be involved in alternative notchregulated processes in hematopoietic stem cells. Notch signaling is clearly important for self-renewal of hematopoietic progenitors (reviewed by radkte et al. 57). Interestingly, hoxa5, a9 and a10 were found to be part of the stem cell profile' SIGNOR-254347 0.2 PRKAA2 protein P54646 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates quantity by destabilization phosphorylation Ser334 AVLDRGTsTTTVFNF 9606 BTO:0000007 25799226 t miannu Taken together, these results imply that nicotine acts via AMPKα2 to phosphorylate MKP1 at Ser334, instigating MKP1 ubiquitination and proteasome-mediated degradation. SIGNOR-276890 0.276 HTR4 protein Q13639 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257367 0.252 AKT1 protein P31749 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Thr235 QARKRKRtSIENRVR 9606 BTO:0004180 23041284 t flangone Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG. SIGNOR-252545 0.469 AGTR1 protein P30556 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 32201502 f MIANNU Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis. SIGNOR-260234 0.7 TCL1A protein P56279 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates binding 9606 10983986 t miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation SIGNOR-81434 0.486 PPP5C protein P53041 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity dephosphorylation Thr842 CTETFTGtLQYMAPE 10090 11689443 t llicata After exposure of cells to H2O2, ASK1 is transiently activated by autophosphorylation at Thr845. The protein then associates with PP5 (protein serine/threonine phosphatase 5), which inactivates ASK1 by dephosphorylation of Thr845. SIGNOR-248540 0.584 USP5 protein P45974 UNIPROT UBC protein P0CG48 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270822 0.841 ADAM17 protein P78536 UNIPROT MUC1 protein P15941 UNIPROT down-regulates cleavage 9606 12441351 t gcesareni These characteristics along with studies conducted with cell lines genetically deficient in various adams (for a disintegrin and metalloprotease) identified tumor necrosis factor-alpha converting enzyme (tace)/adam 17 as a muc1 sheddase. SIGNOR-95630 0.313 ARF6 protein P62330 UNIPROT Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 14973189 f lperfetto ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface SIGNOR-272153 0.7 POLR3A protein O14802 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266133 0.863 TLRs proteinfamily SIGNOR-PF20 SIGNOR TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-252095 0.2 ANAPC5 protein Q9UJX4 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 t lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. SIGNOR-252005 0.92 PGM2 protein Q96G03 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267933 0.8 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR PER3 protein P56645 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253683 0.587 MEF2D protein Q14814 UNIPROT Myog/SWI/SNF complex complex SIGNOR-C94 SIGNOR form complex binding 9606 BTO:0001103 17194702 t miannu Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle SIGNOR-151679 0.632 PYG proteinfamily SIGNOR-PF96 SIGNOR glycogen smallmolecule CHEBI:28087 ChEBI down-regulates quantity chemical modification 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267953 0.8 MAPK8 protein P45983 UNIPROT PPM1J protein Q5JR12 UNIPROT down-regulates phosphorylation Ser93 HAGRAVQsPPDTGRR 9606 18553930 t gcesareni Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells. SIGNOR-178930 0.351 RB1 protein P06400 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates binding 9606 21902831 t gcesareni Cycline/cdk2 blocks myod-induced gene expression through the phosphorylation of rb, preventing rb from binding and transactivating myod, and triggering s phase entry instead of differentiation. SIGNOR-176563 0.403 Caspase 3 complex complex SIGNOR-C221 SIGNOR AKT1 protein P31749 UNIPROT down-regulates activity cleavage -1 10579725 t lperfetto P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro SIGNOR-256447 0.621 PRKACA protein P17612 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Ser17 DASQRRRsLEPAENV 9606 11804588 t gcesareni PKA activated Src both in vitro and in vivo by phosphorylating Src on serine 17 within its amino terminus SIGNOR-247988 0.368 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates activity phosphorylation Ser540 MDSEEPDsRGGSPQM 9606 BTO:0000007 11500362 t We identify multiple phosphorylation sites in the largest, catalytic, subunit (epsilon) of mammalian eIF2B. Glycogen synthase kinase 3 (GSK3) is responsible for phosphorylating Ser535. This regulatory phosphorylation event requires both the fourth site (Ser539) and a distal region, which acts to recruit GSK3 to eIF2Bepsilon in vivo. eIF2Bϵ from mammals or insects is a substrate for glycogen synthase kinase 3 (GSK3), and this inhibits the activity of eIF2B SIGNOR-251237 0.561 DUSP6 protein Q16828 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates dephosphorylation 9606 22521266 t gcesareni Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase). SIGNOR-197194 0.439 PRKCA protein P17252 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Ser139 EEWTRHGsFVNKPTR 10090 BTO:0000944 12052829 t lperfetto Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms. SIGNOR-263047 0.41 LRP6 protein O75581 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity 15229249 f We speculate that DKK1 produced by βAP-treated neurons suppresses the canonical Wnt signaling pathway by interacting with LRP5/6 and therefore facilitates GSK3β activation. SIGNOR-255484 0.786 KPNA2 protein P52292 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity relocalization 9606 32979938 t miannu The results from Figure 1C suggest that ORF6 inhibits IFN-β production through IRF3 or a component downstream of IRF3. Thus, we examined the effect of ORF6 on IRF3 nuclear translocation. Upon poly(I:C) treatment, IRF3 translocated to the cell nucleus in the absence of ORF6, whereas the expression of ORF6 blocked its nuclear translocation (Figure 2D). Karyopherin α 1–6 (KPNA1–6) are importing factors for nuclear translocation of cargos, including IRF3, IRF7, and STAT1 (Chook and Blobel, 2001). Co-immunoprecipitation showed that ORF6 selectively interacted with KPNA2, but not the other KPNAs (Figure 2E), suggesting that ORF6 inhibits IFN-β production by binding to KPNA2 to block IRF3 nuclear translocation (Figure 2F). SIGNOR-262514 0.2 NFKB1 protein P19838 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9733516 f gcesareni Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2 SIGNOR-59954 0.542 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Ser5099 DVEFDIKsPKFKAEA 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262763 0.259 TNKS1BP1 protein Q9C0C2 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268304 0.626 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 t miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. SIGNOR-264924 0.8 FBXW7 protein Q969H0 UNIPROT GATA2 protein P23769 UNIPROT down-regulates quantity by destabilization ubiquitination Thr176 HLFGFPPtPPKEVSP 9606 BTO:0000007 25670854 t irozzo Here, we demonstrate that F-box/WD repeat-containing protein 7 (Fbw7/Fbxw7), a component of Skp1, Cullin 1, F-box-containing complex (SCF)-type E3 ligase, is an E3 ligase for GATA2. GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation. SIGNOR-256005 0.397 MECP2 protein P51608 UNIPROT MGMT protein P16455 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 15657354 f Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT. SIGNOR-254035 0.311 CNOT11 protein Q9UKZ1 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268308 0.816 PDPK1 protein O15530 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates phosphorylation Thr774 GYGDRTStFCGTPEF 9606 10753910 t miannu It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively) SIGNOR-76640 0.548 FNIP1 protein Q8TF40 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates activity binding 9606 BTO:0000007 27353360 t miannu FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle. SIGNOR-261413 0.563 CSNK1D protein P48730 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 SIGNOR-C110 12000790 t gcesareni We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the beta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or epsilon isoform, all detected in association with axin by lc/ms. SIGNOR-87433 0.537 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser552 VVRTPPKsPSSAKSR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251590 0.695 PRKDC protein P78527 UNIPROT HNRNPU protein Q00839 UNIPROT up-regulates phosphorylation Ser59 AMEPGNGsLDLGGDS 9606 19351595 t lperfetto We identify heterogeneous nuclear ribonucleoprotein u (hnrnp-u), also termed scaffold attachment factor a (saf-a), as a specific substrate for dna-pk. We show that hnrnp-u is phosphorylated at ser59 by dna-pk in vitro and in cells in response to dna double-strand breaks SIGNOR-185058 0.383 SMARCC1 protein Q92922 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270696 0.826 TSC22D3 protein Q99576 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000011 12671681 f In this study, we showed that GILZ, which is transcriptionally induced by GCs, inhibits the transcription of the PPAR-γ2 gene and blocks adipocyte differentiation SIGNOR-253296 0.271 PRDM16 protein Q9HAZ2 UNIPROT SKI protein P12755 UNIPROT up-regulates binding 9606 19049980 t miannu Biochemical analysis demonstrated that mel1 interacts with ski and inhibits tgf-_ signaling by stabilizing the inactive smad3-ski complex on the promoter of tgf-_ target genes. SIGNOR-182529 0.331 PAMPs stimulus SIGNOR-ST11 SIGNOR SLC11A1 protein P49279 UNIPROT up-regulates 9606 BTO:0000801 11909746 f Functional studies in Nramp1 transfected macrophages have demonstrated that the Nramp1 protein plays a vital role in early macrophage activation [10,29,30]. Nramp1 is constitutively expressed in macrophage cell lines of the myeloid lineage (isolated peritoneal, splenic, and liver resident macrophages), and can be induced by treatment of macrophages with IFN-γ, or IFN-γ plus lipopolysaccharide (LPS) SIGNOR-254039 0.7 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation 9606 19620713 t lperfetto Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. SIGNOR-255263 0.721 (~{s})-(4-Fluoranyl-2-Propyl-Phenyl)-(1~{h}-Imidazol-2-Yl)methanol chemical CID:126961334 PUBCHEM F2RL1 protein P55085 UNIPROT down-regulates activity chemical inhibition -1 28445455 t Simone Vumbaca The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. | Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. SIGNOR-261118 0.8 RPS6KA3 protein P51812 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-70432 0.2 RNF8 protein O76064 UNIPROT ACD protein Q96AP0 UNIPROT up-regulates quantity by stabilization polyubiquitination Lys147 QDLDVQKkLYDCLEE 9606 22101936 t miannu The Rnf8 RING-finger domain is essential for Tpp1 stability and retention at telomeres. Rnf8 physically interacts with Tpp1 to generate Ubc13-dependent Lys63 polyubiquitin chains that stabilize Tpp1 at telomeres. The conserved Tpp1 residue Lys233 is important for Rnf8-mediated Tpp1 ubiquitylation and localization to telomeres. SIGNOR-272722 0.2 Elongator complex complex SIGNOR-C466 SIGNOR TUBA3E protein Q6PEY2 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 t miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. SIGNOR-269718 0.254 MMP26 protein Q9NRE1 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272393 0.7 TRAF6 protein Q9Y4K3 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000007 17135271 t These data establish a signaling cascade in which regulated site-specific Lys-63-linked TRAF6 auto-ubiquitination is the critical upstream mediator of IKK. SIGNOR-252099 0.2 sulpiride chemical CHEBI:32168 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition -1 7576010 t miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. When receptors were labeled with [lzs1]-NCQ-298, D2 and D3 receptors displayed similar potencies for sulpiride, a D2 receptor antagonist (Figure 3A, Table I). SIGNOR-258431 0.8 PRKCA protein P17252 UNIPROT NRGN protein Q92686 UNIPROT up-regulates activity phosphorylation Ser36 AAAKIQAsFRGHMAR -1 8080473 t lperfetto Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM. SIGNOR-248913 0.402 ARID5B protein Q14865 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29326336 f miannu ARID5B transcriptionally activates the oncogene MYC in T-ALL cells SIGNOR-256156 0.278 AKT1 protein P31749 UNIPROT RARA protein P10276 UNIPROT down-regulates phosphorylation Ser96 FVCQDKSsGYHYGVS 9606 BTO:0000551 16417524 t miannu We report that akt, which is constitutively activated in nsclc cells, phosphorylates raralpha and inhibits its transactivation. / mutation of ser96 to alanine abrogated the suppressive effect of akt. SIGNOR-252489 0.585 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT up-regulates activity phosphorylation Tyr486 SRRIAVEySDSDDDS 9606 17623672 t WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3. SIGNOR-259077 0.564 PTH1R protein Q03431 UNIPROT CYP27B1 protein O15528 UNIPROT up-regulates quantity 28363951 f lperfetto These PTH actions are mainly mediated by Gsalpha signaling, which induces the expression of the gene encoding 25-hydroxyvitamin D 1alpha-hydroxylase (Cyp27b1) and destabilizes the transcript encoding vitamin D 24-hydroxylase (Cyp24a1) SIGNOR-270554 0.307 CD40 protein P25942 UNIPROT BIK protein Q13323 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 12324477 f gcesareni Bik expression was weakly but significantly down-regulated by cd27 but up-regulated by cd40. SIGNOR-93390 0.2 EED protein O75530 UNIPROT SUZ12/EED complex SIGNOR-C76 SIGNOR form complex binding 9606 16712789 t miannu Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2. SIGNOR-146755 0.942 MAPK1 protein P28482 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity phosphorylation Ser226 IDENCLLsPLAGEDD -1 9199329 t lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. SIGNOR-249428 0.607 MAPK8 protein P45983 UNIPROT YWHAB protein P31946 UNIPROT down-regulates phosphorylation Ser186 FYYEILNsPEKACSL 9606 15696159 t llicata The c-jun n-terminal kinase (jnk) protein is activated in the cellular response to dna damage and phosphorylates 14-3-3 on ser 184 these results support a role for 14-3-3 proteins in inhibiting c-abl-mediated apoptosis by sequestering c-abl into the cytoplasm. these findings support a model in which jnk phosphorylation of 14-3-3 proteins induces dissociation of the c-abl_14-3-3 complex and thereby targeting of c-abl to the nucleus. SIGNOR-133875 0.2 ID1 protein P41134 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity binding 10090 BTO:0000222 8380166 t 2 miannu Id1 and Id2 interacted strongly with MyoD and Myf-5.Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-240265 0.49 NOS3 protein P29474 UNIPROT nitric oxide smallmolecule CHEBI:16480 ChEBI up-regulates quantity chemical modification 9606 24379783 t lperfetto Nitric oxide (NO) is a major mediator of endothelial function and is synthesized in endothelial cells by endothelial nitric oxide synthase (eNOS). SIGNOR-251629 0.8 MGluR proteinfamily SIGNOR-PF55 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. SIGNOR-264930 0.8 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser91 ASFHAYDsHTNTYYL 9606 BTO:0000007 21321328 t miannu We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity. SIGNOR-263130 0.595 CDK1 protein P06493 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 SIGNOR-C17 16287866 t gcesareni Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle. SIGNOR-141621 0.44 SLBP protein Q14493 UNIPROT H2BU1 protein Q8N257 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265388 0.2 SNAP23 protein O00161 UNIPROT STX11-SNAP23 SNARE complex complex SIGNOR-C272 SIGNOR form complex binding 9606 BTO:0000132 22767500 t lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23.  SIGNOR-261895 0.735 PLK1 protein P53350 UNIPROT ATXN10 protein Q9UBB4 UNIPROT down-regulates phosphorylation Thr82 ASSLQLItECFRCLR 9606 21857149 t lperfetto Phosphorylation of ataxin-10 by polo-like kinase 1 is required for cytokinesis. Plk1 phosphorylates ataxin-10 at s77 and t82 in vitro. we found that ataxin-10 is ubiquitinated, and is subject to proteasome-dependent degradation, which is delayed in the 2a mutant. We propose a model in which plk1 phosphorylation of ataxin-10 influences its degradation and cytokinesis SIGNOR-176126 0.36 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914168 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161634 0.391 OFD1 protein O75665 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR down-regulates quantity by destabilization binding 9606 34027042 t miannu We showed for the first time that the centrosomal protein OFD1, which is mutated in Oral-Facial-Digital type I syndrome, inhibits early phases of the LC3-mediated autop hagic cascade by acting as a receptor for unc-51-like kinase (ULK1) complex turnover. we demon strated that OFD1 is a novel autophagy receptor which selectively promotes the autophagic degradation of ATG13 via direct interaction with the C3/GABARAP family of proteins (Figure 1). SIGNOR-269106 0.2 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161658 0.325 GRK6 protein P43250 UNIPROT GRK6 protein P43250 UNIPROT unknown phosphorylation Thr485 LDIEQFStVKGVELE 9534 BTO:0000298 10334944 t GRK6 Is Autophosphorylated in COS-7 Cells. GRK6, like GRK5, is autophosphorylated on Ser484 and Thr485. Whether the autophosphorylation of GRK6 modulates its activity remains however to be established. SIGNOR-251212 0.2 CTNNB1 protein P35222 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 18316399 t Simone Vumbaca Together, these results suggest that B-Cat increases MyoD binding to E box elements SIGNOR-255653 0.416 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269357 0.719 CSNK1D protein P48730 UNIPROT KIR3DL1 protein P43629 UNIPROT up-regulates phosphorylation Ser385 AGNRTANsEDSDEQD 9606 17911614 t gcesareni In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover. SIGNOR-158121 0.2 PIN1 protein Q13526 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates quantity by destabilization binding 9606 16699525 t lperfetto Here we report that activation of IRF3 is negatively regulated by the peptidyl-prolyl isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339–Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication. SIGNOR-252256 0.628 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-252600 0.634 FOXJ1 protein Q92949 UNIPROT DNAI1 protein Q9UI46 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 t miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). SIGNOR-266932 0.375 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273101 0.745 CNR1 protein P21554 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257003 0.444 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR GORASP1 protein Q9BQQ3 UNIPROT down-regulates activity phosphorylation Ser373 FEVSFLDsPGAQAQA 10116 15678101 t Giulio The pS376 antibody gave the strongest staining when Golgi apparatus fragmentation is initiated during prophase and in metaphase when it has become converted into a haze of small vesicles and some larger tubulovesicular remnants (Figure 4A). Therefore, GRASP65, like GM130, is phosphorylated in mitotic entry on Cdk1–cyclin B sites during the period when the Golgi apparatus is fragmented. SIGNOR-260606 0.558 FGFR2 protein P21802 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17543283 f lperfetto Furthermore, in cultures receiving FGF-2 before adipogenic induction, mRNA expression of peroxisome proliferator-activated receptor gamma (PPARgamma), a key transcription factor in adipogenesis, was upregulated. SIGNOR-236220 0.286 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser10 TRSVSSSsYRRMFGG -1 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248877 0.288 TWIST2 protein Q8WVJ9 UNIPROT AKR1C2 protein P52895 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255498 0.2 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI up-regulates quantity precursor of 9606 9914248 t miannu Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine. SIGNOR-267292 0.8 6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)-4-pyrimidinyl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one chemical CHEBI:91348 ChEBI SYK protein P43405 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258295 0.8 HIP1 protein O00291 UNIPROT REST protein Q13127 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21832040 f miannu HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK). SIGNOR-255076 0.2 ACOT4 protein Q8N9L9 UNIPROT glutarate(2-) smallmolecule CHEBI:30921 ChEBI up-regulates quantity chemical modification 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271817 0.8 NR5A1 protein Q13285 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 f miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254868 0.419 EREG protein O14944 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 16829981 t gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4 SIGNOR-147856 0.575 PPP2R2A protein P63151 UNIPROT PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR form complex binding 9606 23454242 t gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. SIGNOR-243430 0.898 SNX9 protein Q9Y5X1 UNIPROT DNM2 protein P50570 UNIPROT up-regulates binding 9606 BTO:0000567 15703209 t miannu Snx9 binds directly to bothdynamin-1 anddynamin-2. Moreover by stimulatingdynaminassembly, snx9 stimulatesdynamin's basal gtpase activity and potentiates assembly-stimulated gtpase activity on liposomes. SIGNOR-133976 0.804 AMPK complex SIGNOR-C15 SIGNOR CRY1 protein Q16526 UNIPROT down-regulates phosphorylation Ser71 ANLRKLNsRLFVIRG 9606 phosphorylation:Ser71 ANLRKLNsRLFVIRG 21892142 t lperfetto Ampk was shown to regulate the stability of the core clock component cry1 though phosphorylation of cry1 ser71, which stimulates the direct binding of the fbox protein fbxl3 to cry1, targeting it for ubiquitin-mediated degradation SIGNOR-216546 0.349 MAPT protein P10636 UNIPROT Neurofibrillary tangle formation phenotype SIGNOR-PH58 SIGNOR up-regulates 9606 11578751 f lperfetto Tau is a multifunctional microtubule-associated protein that plays major roles in the assembly of microtubules, the stabilization of microtubules against dynamic instability, and in bridging these polymers with other cytoskeletal filaments 43, 44, 45, 46 and 47. In normal brain, the equilibrium between phosphorylations and dephosphorylations of tau modulates the stability of the cytoskeleton and consequently axonal morphology. The earliest modification found in Alzheimer brains consists of hyperphosphorylations on tau by the action of different protein kinase and phosphatase systems that appear to lead to structural and conformational changes in this protein, thus affecting its binding with tubulin and the capacity to promote microtubule assembly SIGNOR-251642 0.7 G6PC2 protein Q9NQR9 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-266583 0.8 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248745 0.727 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PTPRR protein Q15256 UNIPROT up-regulates activity phosphorylation 11493009 t inferred from 70% family members lperfetto Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL. SIGNOR-270021 0.2 MAPK1 protein P28482 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Ser497 GSLCSVFsPSFVQWE 9606 BTO:0000007 27846390 t lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  SIGNOR-262981 0.306 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273105 0.745 GNA13 protein Q14344 UNIPROT ARHGEF11 protein O15085 UNIPROT up-regulates activity binding 9606 11799111 t This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho SIGNOR-256517 0.624 carbachol chemical CHEBI:3385 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258621 0.8 CAK complex complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser371 AHSSHLKsKKGQSTS 9606 9315650 t llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase. SIGNOR-269327 0.446 HAX1 protein O00165 UNIPROT ATP2A2 protein P16615 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 18971376 t lperfetto The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates its protein levels to promote cell survival.|Importantly, HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels. SIGNOR-262052 0.378 DLX5 protein P56178 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity transcriptional regulation 9031 17335796 t gcesareni Dlx5 initiates a complete osteogenic differentiation in these early primary cells, by triggering Runx2, osteopontin, alkaline phosphatase, and other gene expression according to the sequential temporal sequence observed during skull osteogenesis €œin vivo€. SIGNOR-245340 0.381 BAF250b E3 ligase complex SIGNOR-C522 SIGNOR Histone H2B proteinfamily SIGNOR-PF68 SIGNOR down-regulates activity ubiquitination 9606 BTO:0000567 20086098 t miannu In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro SIGNOR-271441 0.2 MAPK9 protein P45984 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates phosphorylation Thr320 SKYNAEStERESQDT 9606 18667537 t llicata This jnk phosphorylation of ps1 at ser(319)thr(320) enhances the stability of the ps1 c-terminal fragment that is necessary for gamma-secretase activity. SIGNOR-179680 0.383 NFRKB protein Q6P4R8 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270856 0.611 CHL1 protein O00533 UNIPROT ANK1 protein P16157 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 t miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. SIGNOR-266724 0.512 TRAPPC9 protein Q96Q05 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity binding 9606 BTO:0000007 15951441 t miannu We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates. SIGNOR-269672 0.491 STAT5A protein P42229 UNIPROT SLCO1B3 protein Q9NPD5 UNIPROT up-regulates quantity by expression transcriptional regulation 15840840 t lperfetto PRL enhanced the binding of Stat5a to the OATP1B3 promoter and DNA-protein binding was inhibited in competition assays by excess OATP1B3 and Stat5 consensus oligomers but not by mutant Stat5 oligomers.|PRL and GH induction of Oatp1b2 and OATP1B3 promoter activity required cotransfection of Stat5a and PRLRL or GHR. SIGNOR-268990 0.2 PTPN5 protein P54829 UNIPROT GRIN2A protein Q12879 UNIPROT down-regulates activity dephosphorylation 9606 27857196 t miannu STEP inhibition by TC-2153 enhanced Tyr phosphorylation of GluN2A (XREF_FIG, 1 EGTA+TC-2153, n = 5, P < 0.05 compared with 1mM EGTA) without altering phosphorylation of Src (XREF_FIG, 1 EGTA+TC-2153, n = 5, P> 0.05 compared with 1 EGTA).|These findings confirm that not only GluN2B and Fyn but also GluN2A are substrates of STEP. SIGNOR-277089 0.443 NCOA2 protein Q15596 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity binding 10090 BTO:0000801 29170386 t Here we report that GRIP1 loss in macrophages attenuates glucocorticoid induction of several anti-inflammatory targets, and that GC treatment of quiescent macrophages globally directs GRIP1 toward GR binding sites dominated by palindromic GC response elements (GRE), suggesting a non-redundant GRIP1 function as a GR coactivator. SIGNOR-256095 0.833 PTPN22 protein Q9Y2R2 UNIPROT ZAP70 protein P43403 UNIPROT down-regulates dephosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000007 16461343 t miannu Native ptpn22 dephosphorylated lck and zap70 at their activating tyrosine residues tyr-394 and tyr-493, respectively, but not at the regulatory tyrosines tyr-505 (lck) or tyr-319 (zap70). SIGNOR-144345 0.694 MAPK8 protein P45983 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 19279717 f areggio To date it is not clear whether any genes are transcribed downstream of these two GTPases for non-canonical signaling. The prevailing dogma remains that their primary roles are indeed solely for cytoskeletal modulation SIGNOR-258976 0.7 ATM protein Q13315 UNIPROT UFL1 protein O94874 UNIPROT up-regulates activity phosphorylation Ser462 DDDSDDEsQSSHTGK 9606 BTO:0001938 30886146 t lperfetto Furthermore, ATM phosphorylates UFL1 at serine 462, enhancing UFL1 E3 ligase activity and promoting ATM activation in a positive feedback loop. SIGNOR-265075 0.2 REN protein P00797 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage 9606 16816138 t Angiotensinogen, an _-glycoprotein, is released from the liver (152, 250, 444) and is cleaved in the circulation by the enzyme renin that is secreted from the juxtaglomerular apparatus of the kidney (245, 250, 540, 631) to form the decapeptide angiotensin (ANG) I SIGNOR-252297 0.926 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 8638164 t lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. . These results define tab2 as an adaptor linking tak1 and traf6 and as a mediator of tak1 activation in the il-1 signaling pathway . taken together, these results indicate that polyubiquitination of rip1 mediates the independent recruitment of tab2 and nemo, which in turn recruits tak1 and ikk, respectively, to tnf-r1. SIGNOR-105860 0.934 CD274 protein Q9NZQ7 UNIPROT PDCD1 protein Q15116 UNIPROT up-regulates binding 9606 BTO:0000782 11015443 t miannu Pd-l1, was found to bind pd-1 specifically. The functional significance of this interaction has been demonstrated in t cell assays, in which engagement of pd-1 by pd-l1 leads to the inhibition of tcr-mediated lymphocyte proliferation and cytokine secretion. SIGNOR-82604 0.935 OTUD7A protein Q8TE49 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates activity deubiquitination 9606 BTO:0000007 18178551 t lperfetto NF-kappaB Suppression by the Deubiquitinating Enzyme Cezanne|Our study provides several lines of evidence to suggest that Cezanne suppresses TNFR signaling to NF-κB by targeting RIP1 for deubiquitination. SIGNOR-268410 0.2 SNAI1 protein O95863 UNIPROT CLDN7 protein O95471 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 19277896 f lperfetto We propose that CtBP1 is recruited by SNAI1P at the CLDN7 gene promoter indirectly through another yet to be identified protein. Based on our observations, we propose a model for SNAI1P-mediated down regulation of human CLDN7 gene expression by chromatin remodeling SIGNOR-254104 0.415 FOXP3 protein Q9BZS1 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 24315995 f alessandro FoxP3, a lineage-specification factor, executes its multiple activities mostly through transcriptional regulation of target genes. We identified an interleukin-10 (IL-10)-producing FoxP3(+) T regulatory cell population that contributes to IL-10-dependent type 2 cytokine bias in breast-cancer patients. Although genetic ablation of FOXP3 inhibited IL10 transcription, genome-wide analysis ruled out its role as a transcription factor for IL10 SIGNOR-254525 0.506 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val58 KGVTVETvFSVDEFS -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263591 0.404 ARID1B protein Q8NFD5 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270702 0.799 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PPARG protein P37231 UNIPROT up-regulates 9606 11279134 f fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin SIGNOR-209998 0.8 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1080 IFYYFSNsPSKRLRE 9606 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. SIGNOR-104671 0.844 DGC complex SIGNOR-C217 SIGNOR NRXN3 protein Q9HDB5 UNIPROT up-regulates activity binding 9606 BTO:0000142 11470830 t miannu In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan. SIGNOR-265450 0.305 KLC2 protein Q9H0B6 UNIPROT FYCO1 protein Q9BQS8 UNIPROT up-regulates activity binding 9606 BTO:0000567 25855459 t Giulio Interestingly, bead capture assays indicated that the middle part of FYCO1 (residues 585–1233) interacts directly with the KLC2 light chain of kinesin 1 (Fig. 3a and Extended Data Fig. 7a, b). Residues 735–773 of FYCO1 were found to be necessary for its kinesin-1 binding (Fig. 3c and Extended Data Fig. 7b, c), and FYCO1(Δ735–773)-positive LEs failed to translocate to the cell periphery (Extended Data Fig. 7e). SIGNOR-260599 0.351 MCHR2 protein Q969V1 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257268 0.57 TESK2 protein Q96S53 UNIPROT DSTN protein P60981 UNIPROT down-regulates activity phosphorylation Ser3 sGVQVADE 9606 BTO:0001363 11418599 t lperfetto The present study provides evidence that TESK2 can phosphorylate cofilin and ADF specifically at Ser-3. Since actin-depolymerizing and -severing activities of cofilin/ADF are abrogated by phosphorylation at Ser-3, TESK2 seems to play an important role in actin filament dynamics by inhibiting cofilin/ADF activity. SIGNOR-246707 0.432 ATG9A protein Q7Z3C6 UNIPROT YWHAE protein P62258 UNIPROT up-regulates activity binding 9606 25266655 t miannu Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK. SIGNOR-266368 0.2 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 SIGNOR-C15 21205641 t gcesareni In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-170863 0.483 NET1 protein Q7Z628 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260561 0.825 SRC protein P12931 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Tyr89 GSLPEFYyRPPRPPK 9606 BTO:0000150 17254967 t lperfetto Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27 SIGNOR-152839 0.51 AKT proteinfamily SIGNOR-PF24 SIGNOR BCL2L11 protein O43521 UNIPROT down-regulates activity phosphorylation Ser87 FIFMRRSsLLSRSSS 9606 16282323 t lperfetto Recombinant Akt could directly phosphorylate a GST-Bim(EL) fusion protein and identified the Akt phosphorylation site in the Bim(EL) domain as Ser(87). Further, we demonstrated that cytokine stimulation promotes Bim(EL) binding to 14-3-3 proteins. Finally, we show that mutation of Ser(87) dramatically increases the apoptotic potency of Bim(EL). SIGNOR-141581 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 16407412 t inferred from 70% family members gcesareni Using mass spectrometry, we identified raf-1 phosphorylation on three sp motif sites: s289/s296/s301. These sites were phosphorylated by extracellular signal-regulated kinase (erk)-1 in vitro, and their phosphorylation in vivo was dependent on endogenous erk activity. Functionally, erk-1 expression sustains raf-1 activation in a manner dependent on raf-1 phosphorylation on the identified sites, and s289/296/301a substitution markedly decreases the in vivo activity of raf-1 s259a. SIGNOR-270010 0.2 ABT-737 chemical CID:11228183 PUBCHEM BCL2L2 protein Q92843 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189174 0.8 MTOR protein P42345 UNIPROT EIF4EBP2 protein Q13542 UNIPROT down-regulates phosphorylation 9606 14967450 t gcesareni Here, we show that cancer cells acquire resistance to astori by downregulating eukaryotic translation initiation factor (eif4e)-binding proteins (4e-bps-eif4ebp1, eif4ebp2). SIGNOR-122014 0.651 afatinib chemical CHEBI:61390 ChEBI EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258169 0.8 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr523 AGSTDENtDSEEHQE 9606 20471329 t lperfetto Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523 SIGNOR-165435 0.404 USP13 protein Q92995 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0002181 SIGNOR-C242 21962518 t Giulio Similarly, the overexpression of USP13 reduced the levels of ubiquitinated Beclin1 which was inhibited by spautin-1 (Figure 4E) SIGNOR-260295 0.511 SIRT3 protein Q9NTG7 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity deacetylation Lys321 SDPIMLLkDRMVNSN 9606 BTO:0000007 25152236 t lperfetto SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells|SIRT3 deacetylates PDHA1 lysine 321 (K321) SIGNOR-267636 0.492 HOMER1 protein Q86YM7 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity binding 9606 BTO:0000938 17243894 t miannu It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD SIGNOR-264243 0.734 PLG protein P00747 UNIPROT APOH protein P02749 UNIPROT down-regulates activity cleavage Lys336 HSSLAFWKTDASDVK 9606 BTO:0000131 9596664 t lperfetto Plasmin can reduce the function of human beta2 glycoprotein I by cleaving domain V into a nicked form| The cleavage site of r-Domain V and beta2GPI by plasmin was proved to be Lys 317-Thr 318 by amino acid sequence analysis of the digest and of the C-terminal peptide isolated by high-performance liquid chromatography. The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI. SIGNOR-266996 0.469 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr410 GVVDSGVyAVPPPAE 9606 12601080 t lperfetto Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas. SIGNOR-98569 0.259 EGFR protein P00533 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity 10090 BTO:0000667 15284024 f JAK activation occurs upon ligand-mediated receptor multimerization because two JAKs are brought into close proximity, allowing trans-phosphorylation. The activated JAKs subsequently phosphorylate additional targets, including both the receptors and the major substrates, STATs. lperfetto Two possibilities for STAT activation exist: a janus kinase (JAK)-dependent and a JAK-independent mechanism. Herein, we demonstrate that EGFR overexpression in primary esophageal keratinocytes activates STAT in a JAK-dependent fashion SIGNOR-235655 0.616 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HDAC6 protein Q9UBN7 UNIPROT up-regulates phosphorylation Ser1035 DHQTPPTsPVQGTTP 9606 24089523 t lperfetto Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1 SIGNOR-244545 0.2 CTDSP1 protein Q9GZU7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000007 17035229 t SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248797 0.494 GABRA3 protein P34903 UNIPROT GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263756 0.588 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR form complex binding 9606 24789820 t lperfetto AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly.  SIGNOR-260664 0.8 CAMK2B protein Q13554 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser418 TTENRFHsLPFSLTK 9606 24614225 t lperfetto Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity. SIGNOR-25329 0.2 NFIB protein O00712 UNIPROT RBFOX3 protein A6NFN3 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268912 0.2 QRICH1 protein Q2TAL8 UNIPROT VARS2 protein Q5ST30 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269409 0.2 TRIM21 protein P19474 UNIPROT FASN protein P49327 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 27758890 t FASN acetylation enhanced its association with the E3 ubiquitin ligase TRIM21. Acetylation destabilized FASN and resulted in decreased de novo lipogenesis and tumor cell growth. FASN acetylation was frequently reduced in human hepatocellular carcinoma samples, which correlated with increased HDAC3 expression and FASN protein levels. SIGNOR-267368 0.2 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA10 protein Q9Y5H3 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265704 0.2 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252752 0.753 CYP17A1 protein P05093 UNIPROT 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI down-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268655 0.8 SNAP25 protein P60880 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR form complex binding 9606 BTO:0000938 30267828 t miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. SIGNOR-263967 0.957 ATM protein Q13315 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 9168117 t acerquone Our results demonstrate that the sh3 domain of c-abl interacts with a dpapnpphfp motif (residues 1,373-1,382) of atm.These findings indicate that atm is involved in the activation of c-abl by dna damag SIGNOR-48822 0.734 PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation Tyr31 FLSEETPySYPTGNH 9606 15688067 t miannu Paxillin is phosphorylated by FAK–Src on Tyr31 and Tyr118, and this can also promote SH2-mediated binding of Crk to paxillin. Overexpressing paxillin that is mutated at these phosphorylation sites inhibits the turnover of focal contacts6 and cell motility, which therefore supports the presence of multiple routes for FAK–Src-mediated signalling in modulating the dynamics of cell adhesion sites. SIGNOR-28247 0.912 N-acetylserotonin smallmolecule CHEBI:17697 ChEBI ASMT protein P46597 UNIPROT up-regulates activity chemical activation -1 22775292 t miannu Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. Melatonin synthesis requires serotonin, which is first acetylated by the arylalkylamine N-acetyltransferase (AA-NAT) to produce N-acetyl serotonin (NAS) (Fig. 1A). Then, acetyl serotonin methyltransferase (ASMT, also known as hydroxyindole O-methyltransferase or HIOMT) produces melatonin by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to NAS. SIGNOR-265476 0.8 PTPRB protein P23467 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates dephosphorylation 9606 12840032 t inferred from 70% of family members gcesareni When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well SIGNOR-269931 0.443 PCSK7 protein Q16549 UNIPROT CEBPA protein P49715 UNIPROT down-regulates phosphorylation 9606 BTO:0000130 19544470 t gcesareni Addition of active p38a induced phosphorylation of wild-type c/ebp_? (c/ebp_?WT) on serine 21 SIGNOR-186202 0.2 CRP protein P02741 UNIPROT IL10 protein P22301 UNIPROT down-regulates quantity post transcriptional regulation 9606 16917108 f Regulation miannu CRP significantly decreased IL-10 mRNA stability SIGNOR-251825 0.479 USP24 protein Q9UPU5 UNIPROT EP300 protein Q09472 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000018 27991932 t lperfetto In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. |Knockdown of USP24 decreases Bax and p300 levels SIGNOR-275607 0.274 MAPK3 protein P27361 UNIPROT HDAC6 protein Q9UBN7 UNIPROT up-regulates phosphorylation Thr1031 ASSTDHQtPPTSPVQ 9606 24089523 t lperfetto Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1 SIGNOR-202702 0.437 PRKCA protein P17252 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates phosphorylation Ser40 SREVFDFsQRRKEYE 9606 12198130 t miannu Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress SIGNOR-91826 0.516 MAPK3 protein P27361 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser759 KTPDGNKsPAPKPSD 9606 BTO:0000887;BTO:0001260 11983427 t amattioni The actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759. This phosphorylation leads to markedly diminished actin affinity. SIGNOR-86741 0.46 RPS6KA3 protein P51812 UNIPROT ATF4 protein P18848 UNIPROT up-regulates phosphorylation Ser245 TRGSPNRsLPSPGVL 9606 15109498 t lperfetto Here, we show that rsk2 is required for osteoblast differentiation and function. We identify the transcription factor atf4 as a critical substrate of rsk2 that is required for the timely onset of osteoblast differentiation, for terminal differentiation of osteoblasts, and for osteoblast-specific gene expression SIGNOR-124436 0.622 GRB2 protein P62993 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 11823423 t GRB2 is an adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway. gcesareni The underlying mechanism seems to involve recruitment of a grb2 c-cbl complex to grb2-specific docking sites of egfr, and concurrent acceleration of receptor ubiquitylation and desensitization. SIGNOR-114704 0.901 MAPK14 protein Q16539 UNIPROT PXN protein P49023 UNIPROT unknown phosphorylation Ser85 HQQPQSSsPVYGSSA 9606 14970194 t llicata Here, we show that paxillin is phosphorylated by p38mapk in vitro and in nerve growth factor (ngf)-induced pc-12 cells. Ser 85 (ser 83 for endogenous paxillin) is identified as one of major phosphorylation sites by phosphopeptide mapping and mass spectrometry. SIGNOR-122108 0.335 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation Thr69 SRDPVARtSPLQTPA 9606 18570871 t gcesareni Together, our findings demonstrate that jnk1-mediated multisite phosphorylation of bcl-2 stimulates starvation-induced autophagy by disrupting the bcl-2/beclin 1 complex. SIGNOR-179096 0.564 GALR2 protein O43603 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257136 0.316 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr380 YAGGRGSyGDLGGPI 9606 12052863 t lperfetto We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown). SIGNOR-88915 0.608 CSNK2A1 protein P68400 UNIPROT DDX58 protein O95786 UNIPROT down-regulates phosphorylation Thr770 DSILRLQtWDEAVFR 9606 21068236 t lperfetto Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of rig-i are phosphorylated by casein kinase ii (ck2) in the resting state of the cell and dephosphorylated when cells are infected by rna virus. Mutation at aa position 770 or 854 to 855 of rig-i renders it constitutively active SIGNOR-169408 0.2 GSK3A protein P49840 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser129 ICPSLPYsPVSSPQS 9606 22778263 t lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. SIGNOR-198122 0.272 KIF14 protein Q15058 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 32348467 f miannu  We show that RNAi depletion of KIF14 specifically leads to defects in ciliogenesis and basal body (BB) biogenesis, as its absence hampers the efficiency of primary cilium formation and the dynamics of primary cilium elongation, and disrupts the localization of the distal appendage proteins SCLT1 and FBF1 and components of the IFT-B complex.  SIGNOR-266421 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DHPS protein P49366 UNIPROT up-regulates activity phosphorylation Ser233 KNHIPVFsPALTDGS 9606 BTO:0000007 32989218 t miannu The Ser-233 phosphorylation of DHPS by ERK1/2 is important for its function in cell proliferation. SIGNOR-266376 0.2 PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 15175348 t lperfetto In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation SIGNOR-244934 0.275 amitriptyline chemical CHEBI:2666 ChEBI CHRM4 protein P08173 UNIPROT down-regulates activity chemical inhibition 10029 8100134 t miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. SIGNOR-258704 0.8 GAST protein P01350 UNIPROT EGR1 protein P18146 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000269 22228178 f Gastrin inhibited proliferation of colon cancer cells by suppressing expression of EGR1 and AE2 and by blocking ERK phosphorylation. SIGNOR-254252 0.35 ROCK1 protein Q13464 UNIPROT LIMK2 protein P53671 UNIPROT up-regulates activity phosphorylation Thr526 NGKSYDEtVDIFSFG 9534 BTO:0000298 11018042 t lperfetto Specific Activation of LIM kinase 2 via Phosphorylation of Threonine 505 by ROCK, a Rho-dependent Protein Kinase SIGNOR-249053 0.617 NF1 protein P21359 UNIPROT ADCY2 protein Q08462 UNIPROT up-regulates 9606 24431436 f miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-203983 0.29 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu72 EEAREVFeDSDKTNE -1 9538022 t lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). SIGNOR-263673 0.598 PLK1 protein P53350 UNIPROT RIOK2 protein Q9BVS4 UNIPROT up-regulates activity phosphorylation Ser548 KSSLEAAsFWGE -1 21880710 t miannu Here, we report that the atypical protein kinase Rio2 is a novel substrate of Plk1 and can be phosphorylated by Plk1 at Ser-335, Ser-380, and Ser-548. Overexpression of Rio2 causes a prolonged mitotic exit whereas knockdown of Rio2 accelerates mitotic progression, suggesting that Rio2 is required for the proper mitotic progression. SIGNOR-262939 0.439 PRPS2 protein P11908 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI down-regulates quantity chemical modification 9606 16939420 t miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. SIGNOR-267081 0.8 CTDSPL protein O15194 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000007 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248310 0.476 CTSS protein P25774 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Gly58 RYLYQWLgAPVPYPD -1 9076588 t miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. SIGNOR-256323 0.314 PTPRG protein P23470 UNIPROT PXN protein P49023 UNIPROT up-regulates activity dephosphorylation Tyr118 VGEEEHVySFPNKQK -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254721 0.262 CREB1 protein P16220 UNIPROT PAX3 protein P23760 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 21902831 f gcesareni Chen et al. showed that phosphorylated creb is present at high levels in cells of the dermomyotome that express pax3, myod and myf5 and that this phosphorylation is critical for the induction of these genes. SIGNOR-176539 0.319 CTDNEP1 protein O95476 UNIPROT LPIN1 protein Q14693 UNIPROT up-regulates activity dephosphorylation Ser106 IPMHLATsPILSEGA 9606 BTO:0001131 17420445 t Dullard significantly dephosphorylates mouse lipin 1b only in BHK cells (Fig. 5A). This is most clearly seen by using the antibody prepared against the phosphorylation site Ser-106.|Dephosphorylation of lipin results in its translocation to the nuclear envelope and endoplasmic reticulum membranes from the cytosol and generation of diacylglycerol SIGNOR-248346 0.771 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 20068231 t gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. SIGNOR-163266 0.686 PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 AMPK complex SIGNOR-C15 SIGNOR PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser486 DDEITEAKsGTATPQRS -1 17023420 t We show that AMPK α-Ser485/491 can be a site for autophosphorylation, which may play a role in limiting AMPK activation in response to energy depletion or other regulators SIGNOR-256113 0.823 EIF4B protein P23588 UNIPROT EIF4A1 protein P60842 UNIPROT up-regulates activity binding -1 11418588 t Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability SIGNOR-261293 0.862 CSKMT protein A8MUP2 UNIPROT CS protein O75390 UNIPROT down-regulates activity methylation Lys395 LLEQGKAkNPWPNVD 34929314 t lperfetto A mitochondrial matrix-located methyltransferase, methyltransferase-like protein 12 (METTL12), has been reported to methylate CS on the lysine 368 (K368) [15] and K395 residues [16] which are near the active site of CS. The methylation on K395 inhibits CS activity, which can be antagonized by its substrate oxaloacetate. SIGNOR-267638 0.2 COL4A6 protein Q14031 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 35267698 t lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. SIGNOR-272352 0.397 LIMS1 protein P48059 UNIPROT IPP complex complex SIGNOR-C380 SIGNOR form complex binding 16493410 t lperfetto Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton. SIGNOR-265763 0.739 TTL protein Q8NG68 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates tyrosination 9606 22020298 t miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization SIGNOR-266826 0.2 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 12747827 t lperfetto Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e. SIGNOR-236698 0.753 SNRPD2 protein P62316 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270661 0.763 NFATC2 protein Q13469 UNIPROT MYOF protein Q9NZM1 UNIPROT up-regulates transcriptional regulation 9606 23612709 f Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin SIGNOR-255461 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR PTPN11 protein Q06124 UNIPROT down-regulates activity phosphorylation Ser189 GGGERFDsLTDLVEH 9606 BTO:0002181 25802336 t miannu  We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.  SIGNOR-276894 0.2 CLK4 protein Q9HAZ1 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3 SIGNOR-181052 0.275 GNB/GNG complex SIGNOR-C202 SIGNOR PLCB3 protein Q01970 UNIPROT up-regulates 23994464 t apalma However, it was later shown that other PLCβ isoforms (particularly PLCβ2 and PLCβ3) can also be directly activated by Gβγ subunits SIGNOR-255016 0.368 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CTTN protein Q14247 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 20444238 t inferred from 70% family members gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. SIGNOR-270051 0.2 RAB38 protein P57729 UNIPROT AP-1 complex complex SIGNOR-C248 SIGNOR up-regulates activity relocalization 9606 23247405 t lperfetto Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. SIGNOR-260701 0.2 DDB1 protein Q16531 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR form complex binding 9606 22649780 t gcesareni The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors SIGNOR-234802 0.917 SGK3 protein Q96BR1 UNIPROT FLII protein Q13045 UNIPROT up-regulates phosphorylation Thr818 LHRPRHAtVSRSLEG 9606 19293151 t lperfetto Here we show that flii is an in vivo substrate of cisk that functions downstream of pi 3-kinase. Cisk can associate with flii and phosphorylate flii at residues ser(436) and thr(818).We demonstrate here that cisk can enhance er transcription, which is dependent on its kinase activity, and mutation of cisk phosphorylation sites on flii attenuates its activity as an er co-activator. SIGNOR-184692 0.363 GHSR protein Q92847 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256782 0.287 BTRC protein Q9Y297 UNIPROT YAP1 protein P46937 UNIPROT down-regulates ubiquitination 9606 SIGNOR-C5 23431053 t gcesareni This cascade of phosphorylation allows the binding of scfbetatrcp that promotes the ubiquitination and degradation of yap. SIGNOR-201138 0.528 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser639 YMPMSPKsVSAPQQI 10116 BTO:0000452 11287630 t lperfetto Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten SIGNOR-106590 0.757 BRD2 protein P25440 UNIPROT ZMYND8 protein Q9ULU4 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 29018219 t lperfetto ZMYND8 and BRD2 therefore work together to protect H4Ac domains from HDAC activity.|Further, when BRD2 was depleted, ZMYND8 accumulation was lost (Fig. 2e), indicating that either BRD2, or the underlying H4Ac, is required for ZMYND8 loading. SIGNOR-262036 0.291 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-189141 0.391 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR ABL1 protein P00519 UNIPROT down-regulates phosphorylation 9606 18794806 t inferred from 70% family members lperfetto Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3 SIGNOR-270219 0.2 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT down-regulates activity phosphorylation Ser325 LTSVSRGsSLKILSK 9606 10521508 t Manara Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization. SIGNOR-260899 0.2 BMS-754807 chemical CHEBI:88339 ChEBI INSR protein P06213 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001802 19996272 t lperfetto BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR SIGNOR-262026 0.8 POLR2E protein P19388 UNIPROT PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR form complex binding 9606 30484152 t miannu The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92.  SIGNOR-270923 0.2 oxotremorine M chemical CHEBI:38322 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258656 0.8 LAMTOR3 protein Q9UHA4 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates binding 9606 15547943 t lperfetto We analyzed the ability of mp1 to bind to mek1, erk1, and to itself, and the regulation of these interactions. Gel filtration of cell lysates revealed two major mp1 peaks: a broad high molecular weight peak and a 28 kda complex. An mp1 mutant that lost mek1 binding no longer enhanced rasv12-stimulated erk1 activity, and functioned as a dominant negative, consistent with the concept that mp1 function depends on facilitating these oligomerizations. SIGNOR-244874 0.6 protein P0DOX5 UNIPROT Pr3-ANCA complex SIGNOR-C475 SIGNOR form complex binding 9606 27464484 t lperfetto Although the majority of PR3-ANCAs are of the IgG isotype, the results of one study showed that PR3-ANCAs of the IgA isotype were present in up to 30% of patients with GPA SIGNOR-270594 protein P0DOX5 UNIPROT MPO-ANCA complex SIGNOR-C474 SIGNOR form complex binding 9606 27464484 t lperfetto Although MPO-ANCAs of the IgA isotype are sometimes found in patients with IgA nephropathy or IgA vasculitis45, isotypes other than IgG have not been reported in patients with typical AAV, with the exception of a single patient with pauci-immune crescentic glomerulonephritis SIGNOR-270595 RELA protein Q04206 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 27337441 t lperfetto Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation SIGNOR-251737 0.68 TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 BTO:0000007 7758105 t lperfetto We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed. SIGNOR-32739 0.798 MCU_MICUB_variant complex SIGNOR-C499 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270864 0.8 RIPK3 protein Q9Y572 UNIPROT OGDC complex SIGNOR-C397 SIGNOR up-regulates activity phosphorylation -1 29358703 t miannu Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135. SIGNOR-268066 0.2 Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR ATP smallmolecule CHEBI:15422 ChEBI down-regulates quantity chemical modification 9606 11376933 t miannu To date, ten different mammalian isoforms of adenylyl cyclase (AC) have been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for different cells to respond diversely to similar stimuli. The product of the enzymatic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a crucial role for a variety of fundamental physiological cell functions ranging from cell growth and differentiation, to transcriptional regulation and apoptosis. SIGNOR-267843 0.8 CRK protein P46108 UNIPROT MAP4K5 protein Q9Y4K4 UNIPROT up-regulates activity binding -1 9788432 t lperfetto Two novel candidates for signalling partners of Crk family adapter proteins, the hematopoietic progenitor kinase 1 (HPK1) and the kinase homologous to SPS1/STE20 (KHS), were found to bind with great selectivity to the first SH3 domains of c-Crk and CRKL.|These results make it likely that HPK1 and KHS participate in the signal transduction of Crk family adapter proteins in certain cell types. SIGNOR-262830 0.371 CAK complex complex SIGNOR-C456 SIGNOR CDK12 protein Q9NYV4 UNIPROT up-regulates activity phosphorylation Thr893 SEESRPYtNKVITLW 24662513 t lperfetto Although Cdk12/CycK kinase complex lacking T-loop phosphorylation showed some basal activity towards a CTD substrate prephosphorylated at position Ser7, its activity was significantly increased upon coexpression with the CAK from S. cerevisiae (Supplementary Fig. 9a). Mutation of T893 to E to mimic phosphorylation showed no effect on basal kinase activity. Quantitative phosphorylation of a single residue occurred upon coexpression with Cak1, as determined by ESI mass spectrometry (Supplementary Fig. 9b). SIGNOR-275510 0.519 PIAS4 protein Q8N2W9 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR down-regulates activity binding 9606 12904571 t lperfetto Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity. SIGNOR-217731 0.586 PTH1R protein Q03431 UNIPROT SOST protein Q9BQB4 UNIPROT down-regulates quantity 28363951 f lperfetto Furthermore, PTH acts on osteocytes to suppress the expression of sclerostin, an inhibitor of canonical Wnt signaling (Li, et al. 2005; Semenov, et al. 2005)). PTH action on sclerostin is primarily through cAMP signaling (Keller and Kneissel 2005) and mediated by Myocyte enhancer factor-2 (MEF2) transcriptional regulators (Leupin, et al. 2007). Using the cAMP signaling pathway in osteoblasts, PTH also inhibits the expression of Dickkopf 1 (Dkk1) (Guo et al. 2010a), which is another Wnt pathway inhibitor  SIGNOR-270552 0.39 AKT3 protein Q9Y243 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 9829964 t gcesareni When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp. SIGNOR-62257 0.475 ILK protein Q13418 UNIPROT NACA protein E9PAV3 UNIPROT up-regulates phosphorylation Ser1906 PELEEQDsTQATTQQ 9606 15299025 t lperfetto The inactivation of gsk3? In response to adhesion and ilk activation (6) would then result in a thr-159-hypophosphorylated ?-Nac that would become unavailable for proteasome degradation but would become a substrate for the ilk kinase activity on residue ser-43. The ser-43-phosphorylated ?-Nac would preferentially interact with c-jun (30), translocate to the nucleus, and potentiate transcription SIGNOR-127631 0.402 CSNK2A1 protein P68400 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser529 GLPNGLLsGDEDFSS 9606 10938077 t gcesareni Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II.|Furthermore, our results indicate that the association between IkappaBalpha and p65 inhibits p65 phosphorylation by CKII and that degradation of IkappaBalpha allows CKII to phosphorylate p65 to increase NF-kappaB transactivation potential. SIGNOR-149635 0.455 CTNNB1 protein P35222 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16510874 f gcesareni Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro.Chromatin Immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp. SIGNOR-19153 0.736 IL11 protein P20809 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity binding 9606 28232471 t miannu Because GP130 is known to interact with other ligand-receptor pairs, we measured the expression of additional GP130 signaling partners in both organoids and PSCs in trans-well cultures. Of the GP130 ligands found to be expressed in PSCs, Il6, Il11, and leukemia inhibitory factor (Lif) were the most highly up-regulated in trans-well cultures when compared with PSC monocultures (Fig. 3 C). Both IL-11 and LIF are reported to have roles in cancer progression SIGNOR-277689 0.703 GUCY1A3-B3 complex SIGNOR-C140 SIGNOR 3',5'-cyclic GMP smallmolecule CHEBI:16356 ChEBI up-regulates quantity chemical modification 9606 10977868 t gcesareni Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types SIGNOR-244105 0.8 SIRT2 protein Q8IXJ6 UNIPROT AFP protein P02771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 14522900 f miannu  In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity. SIGNOR-254487 0.259 SREBF2 protein Q12772 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12923220 t lperfetto IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells|evidence that IDH1 may regulate lipogenesis in hepatic cells SIGNOR-253133 0.281 N-formyl-L-methionyl-L-leucyl-L-phenylalanine smallmolecule CHEBI:53490 ChEBI FPR1 protein P21462 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257492 0.8 LYN protein P07948 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates phosphorylation 9606 11517336 t gcesareni Gadd34 was tyrosine-phosphorylated in vivo in a lyn-dependent manner. SIGNOR-109934 0.34 NAE complex SIGNOR-C131 SIGNOR CUL9 protein Q8IWT3 UNIPROT up-regulates activity neddylation 9606 25504797 t lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. SIGNOR-243169 0.46 PRKCQ protein Q04759 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser246 QYQEERRsVKHILFS 9606 BTO:0000782 16479000 t miannu PKC θ is required for HePTP translocation to the immune synapse. PKC θ phosphorylates HePTP at S225 in primary T cells. SIGNOR-276045 0.2 SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR JUN protein P05412 UNIPROT down-regulates activity sumoylation Lys226 HPRLQALkEEPQTVP 9606 BTO:0000567 SIGNOR-C154 16055711 t lperfetto We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. SIGNOR-263006 0.257 KPNA4 protein O00629 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 20454918 t gcesareni Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. SIGNOR-254322 0.291 DSCAM protein O60469 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR down-regulates 9606 BTO:0000938 30745320 f miannu The DSCAM/L1 transcriptome data sets also contained a significant number of genes known to regulate synapse formation or function.Increased nuclear DSCAM levels inhibit synapse formation SIGNOR-264321 0.7 TWIST2 protein Q8WVJ9 UNIPROT GDF15 protein Q99988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255496 0.2 CHD8 protein Q9HCK8 UNIPROT NEFM protein P07197 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 t Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells SIGNOR-268917 0.2 sapitinib chemical CHEBI:132986 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 20145185 t AZD8931 has a unique pharmacologic profile providing equipotent EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. gcesareni In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. SIGNOR-163727 0.8 MAPK14 protein Q16539 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates activity phosphorylation Thr431 ASTLDEAtPTLTNQS 9606 19393267 t lperfetto Egfr-mediated phosphorylation of tab1 was completely inhibited by a chemical inhibitor and sirna of p38alpha. The phosphorylation of tab1 was occurred at ser-423 and thr-431, the residues underlying the p38-mediated feedback inhibition of tak1. SIGNOR-185584 0.817 IHH protein Q14623 UNIPROT PTCH2 protein Q9Y6C5 UNIPROT down-regulates activity binding 9606 BTO:0001253 9811851 t lperfetto Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH. SIGNOR-61314 0.784 AHSA1 protein O95433 UNIPROT HSP90AB1 protein P08238 UNIPROT up-regulates activity binding 9606 16696853 t miannu The N-terminal region of Aha1 interacts with the central domain of Hsp90 and stimulates Hsp90 ATPase activity SIGNOR-252212 0.681 FLT3 protein P36888 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates activity 9606 BTO:0002144 28194038 f Here, we report that FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity SIGNOR-259982 0.7 NXPH1 protein P58417 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates binding 9606 BTO:0000938 9856994 t gcesareni Purification of neurexin ialpha revealed that it is tightly complexed to a secreted glycoprotein called neurexophilin 1 SIGNOR-62775 0.564 STK11 protein Q15831 UNIPROT MARK3 protein P27448 UNIPROT up-regulates activity phosphorylation Ser215 KLDTFCGsPPYAAPE 9606 BTO:0000568 12879020 t lperfetto Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211. SIGNOR-104059 0.32 NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 t lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 0.808 SMURF1 protein Q9HCE7 UNIPROT FAF2 protein Q96CS3 UNIPROT unknown ubiquitination -1 20804422 t miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. SIGNOR-272698 0.284 CAMK2A protein Q9UQM7 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Thr594 LHGKKNStVDCNGVV 9606 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275772 0.383 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI AURKA protein O14965 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258232 0.8 EGR3 protein Q06889 UNIPROT NAB2 protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000848 20506119 f miannu In melanoma and carcinoma cells EGR1 activates NAB2 expression. we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells. Here, we show that like EGR1, EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NAB2 promoter and are more potent activators of NAB2 transcription than EGR2. SIGNOR-253882 0.499 HOXC13 protein P31276 UNIPROT LAMB2 protein P55268 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0000298 10835276 t Luana The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells. SIGNOR-261644 0.2 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr101 EGLSMGNyIGLINRI 9606 BTO:0001282 16373505 t PKR autophosphorylates on Y101, Y162, and Y293. unctional characterization of Y101F and Y162F mutants revealed that phosphorylation at these sites is needed for efficient dsRNA binding and kinase dimerization and activation. SIGNOR-251112 0.2 PRKCI protein P41743 UNIPROT ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr359 YLYEKANtPELKKSV 9606 BTO:0000551 21189248 t gcesareni Our data support a model in which pkc?-Mediated phosphorylation regulates ect2 binding to the oncogenic pkc?-Par6 complex thereby activating rac1 activity and driving transformed growth and invasion. SIGNOR-170790 0.487 UCHL1 protein P09936 UNIPROT UBC protein P0CG48 UNIPROT up-regulates quantity cleavage 9606 9521656 t lperfetto These data suggest that the physiological role of UCH is to hydrolyze small adducts of ubiquitin and to generate free monomeric ubiquitin from ubiquitin proproteins, but not to deubiquitinate ubiquitin-protein conjugates or disassemble polyubiquitin chains SIGNOR-249693 0.859 Tuberoinfundibular peptide of 39 residues smallmolecule CHEBI:80275 ChEBI PTH2R protein P49190 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257576 0.8 RHOA protein P61586 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity binding 10090 BTO:0004732 27270401 t no miannu PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. SIGNOR-275465 0.847 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 21697284 t gcesareni Cocrystallization of the met kinase domain in complex with nvp-bvu972 revealed a key role for y1230 in binding of nvp-bvu972, as previously reported for multiple other selective met inhibitors. SIGNOR-174555 0.8 EZH2 protein Q15910 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23836662 f miannu We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. SIGNOR-254146 0.509 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser385 MARVGGAsSLENTVD -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178391 0.816 SAV1 protein Q9H4B6 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity binding 9606 BTO:0000007 19212654 t miannu The human WW45 protein enhances MST1-mediated apoptosis in vivo In this model, hWW45 binds both MST1 and LATS through its coiled-coil domains and WW domains, respectively, and facilitates the phosphorylation of LATS by MST1. This model could explain the enhanced apoptotic efficacy of MST1 with the over-expression of hWW45 and the attenuated MST1-induced apoptosis with the down-regulation of endogenous hWW45. SIGNOR-263661 0.892 GNB5 protein O14775 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates activity binding 9606 BTO:0004032 21303898 t miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC SIGNOR-264996 0.432 AR protein P10275 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates quantity by repression binding 9606 9162033 t lperfetto Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity SIGNOR-48513 0.527 SRC protein P12931 UNIPROT WNK4 protein Q96J92 UNIPROT down-regulates activity phosphorylation Tyr1113 PSPVWMNySYSSLCL 9606 BTO:0002181 25805816 t miannu Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c-Src: Tyr(1092), Tyr(1094), and Tyr(1143), and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4.  SIGNOR-276897 0.2 SMURF proteinfamily SIGNOR-PF29 SIGNOR BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 22298955 t inferred from 70% family members gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps. SIGNOR-270215 0.2 PIK3IP1 protein Q96FE7 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates activity binding 9606 24316979 t miannu We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. SIGNOR-260073 0.281 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2029 NAVDDLGkSALHWAA 9606 17636029 t gcesareni This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60. SIGNOR-156911 0.424 MARCHF9 protein Q86YJ5 UNIPROT PTPRA protein P18433 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271540 0.2 CNOT4 protein O95628 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268302 0.769 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1742 KAQAKVGsLDNAHHV 9606 BTO:0000567 11029056 t miannu CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA SIGNOR-250003 0.367 LPAR5 protein Q9H1C0 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257205 0.339 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Ser645 LNEKARLsYSDKNLI 9606 9305920 t gcesareni Taken together, our results demonstrate that serine 643 of pkc-delta is a major autophosphorylation site, and phosphorylation of this site plays an important role in controlling its enzymatic activity and biological function. The enzymatic activity of pkc-deltas643a mutant as measured by phosphorylating the pkc-delta pseudosubstrate region-derived substrate was also reduced more than 70% in comparison to that of pkc-deltawt. SIGNOR-51000 0.2 RAB32 protein Q13637 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR up-regulates activity relocalization 9606 23247405 t lperfetto Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. SIGNOR-260695 0.307 MAPK14 protein Q16539 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation Thr255 ITTPELTtPCGSAEY 9606 9155017 t gcesareni Mnk1, but not mnk2, also binds strongly to the stress-activated kinase, p38. SIGNOR-48346 0.658 NUMA1 protein Q14980 UNIPROT TUBB4B protein P68371 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-117078 0.379 BCL2 protein P10415 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates binding 9606 18570871 t gcesareni In mammalian cells, the antiapoptotic protein, bcl-2, binds to beclin 1 during nonstarvation conditions and inhibits its autophagy function. SIGNOR-179084 0.732 KCNQ3 protein O43525 UNIPROT KCNQ2 protein O43526 UNIPROT up-regulates activity binding 10116 BTO:0000938 9836639 t The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date, however, the genes that encode subunits of this important channel have not been identified. The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current. SIGNOR-268832 0.498 CDK5RAP2 protein Q96SN8 UNIPROT CEP152 protein O94986 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 t lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. SIGNOR-271721 0.746 HIC1 protein Q14526 UNIPROT LRP8 protein Q14114 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001938;BTO:0000815 24076391 f miannu The Reelin receptors ApoER2 and VLDLR are direct target genes of HIC1. ectopic expression of HIC1 in U2OS and MDA-MB-231 cell lines decreases expression of the ApoER2 and VLDLR genes, encoding two canonical tyrosine kinase receptors for Reelin. SIGNOR-254243 0.2 AURKB protein Q96GD4 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Ser12 YSSSQRVsSYRRTFG -1 12686604 t lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro. SIGNOR-100107 0.527 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 9047237 t lperfetto Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient. SIGNOR-46859 0.797 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. SIGNOR-164404 0.626 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPC5 protein Q9UL62 UNIPROT down-regulates activity phosphorylation Ser794 SGGARAKsKSVSFNL 9606 BTO:0000007 21734191 t done miannu Together, these results suggest that TRPC5 is directly phosphorylated by G(s)/cAMP/PKA at positions S794 and S796. These inhibitory effects were blocked by the protein kinase A (PKA) inhibitors, KT-5720 and H-89, as well as by two point mutations at consensus PKA phosphorylation sites on TRPC5 (S794A and S796A). SIGNOR-273790 0.2 PRKCA protein P17252 UNIPROT LMNA protein P02545 UNIPROT unknown phosphorylation Ser525 NTWGCGNsLRTALIN -1 8477740 t lperfetto An interphase-specific phosphorylation at Ser525 matching the PKC consensus sequence and of peptides phosphorylated by unknown kinases was determined. SIGNOR-248935 0.369 KPNA4 protein O00629 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20454918 t gcesareni Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. SIGNOR-165314 0.291 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000763;BTO:0000149 10197981 t lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-244723 0.2 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser60 PHVLEALsPPQTSGL 9606 SIGNOR-C3 20516213 t fstefani The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly. SIGNOR-165791 0.7 ABL1 protein P00519 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation Tyr81 MQQCDSPyVVKYYGS 9606 BTO:0000938 22590567 t llicata We demonstrate that c-abl kinase phosphorylates mst2 at an evolutionarily conserved site, y81, within the kinase domain. We further show that the phosphorylation of mst2 by c-abl leads to the disruption of the interaction with raf-1 proteins and the enhancement of homodimerization of mst2 proteins. It thereby enhances the mst2 activation and induces neuronal cell death. SIGNOR-197538 0.2 NEK3 protein P51956 UNIPROT NEK3 protein P51956 UNIPROT down-regulates activity phosphorylation Thr165 FACTYVGtPYYVPPE -1 27489110 t Manara Autophosphorylation at Thr-165 is required for NEK3 kinase activity in vitro. SIGNOR-260919 0.2 MAPK3 protein P27361 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 20974802 t gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. SIGNOR-169004 0.319 SOCS1 protein O15524 UNIPROT IRAK1 protein P51617 UNIPROT down-regulates binding 9606 12433373 t flangone Coimmunoprecipitation analyses demonstrated association of socs-1 with irak...This Finding suggests that socs-1 might suppress myd88-dependent signal pathways at least by binding to irak SIGNOR-95528 0.41 WT1 protein P19544 UNIPROT NPHS1 protein O60500 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15504938 t The Wilms tumor suppressor gene (WT1) is a zinc-finger-containing transcription factor that is coexpressed with NPHS1 in differentiated podocytes; gel shift binding assays demonstrate that a recombinant WT1 protein can bind and activate the 186-bp NPHS1 fragment in a sequence-specific manner SIGNOR-252299 0.501 AR protein P10275 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16697957 t miannu Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events. SIGNOR-251546 0.516 GSK3B protein P49841 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization phosphorylation Ser183 SNLLQSPsSILSTLD 9606 BTO:0000567 21757741 t miannu Here, we demonstrate that glycogen synthase kinase-3β (GSK3β) phosphorylates securin to promote its proteolysis via SCF(βTrCP) E3 ubiquitin ligase. SIGNOR-276345 0.2 ATF4 protein P18848 UNIPROT LARS1 protein Q9P2J5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269420 0.2 GDP smallmolecule CHEBI:17552 ChEBI GNAI1 protein P63096 UNIPROT down-regulates chemical inhibition 9606 12040175 t gcesareni Galfa subunits cycle between inactive (gdp-bound) and active (gtp-bound) states, and the lifetime of the active state is limited by gtp hydrolysis. SIGNOR-88226 0.8 SMURF1 protein Q9HCE7 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 11278251 t miannu Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with TbetaR-I via Smad7, with subsequent enhancement of turnover of TbetaR-I and Smad7.  SIGNOR-272943 0.681 Goserelin chemical CHEBI:5523 ChEBI LHCGR protein P22888 UNIPROT up-regulates activity chemical activation 9606 BTO:0001033 11900209 t miannu LHRH analogues, such as goserelin, reduce circulating concentrations of oestrogen in premenopausal women via an inhibitory effect on the hypothalamic–pituitary–ovarian axis. At the cellular level, LHRH analogues bind to LHRH receptors on pituitary gland cells, an action which causes an initial surge in the secretion of luteinizing hormone (LH). Once bound to ligand, these LHRH receptors form clusters, which are then sequestered within the cell, thereby reducing the number of unoccupied LHRH receptors. SIGNOR-259162 0.8 IFNAR complex SIGNOR-C243 SIGNOR CCL7 protein P80098 UNIPROT up-regulates quantity by expression 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260852 0.279 HSP90AA1 protein P07900 UNIPROT NOS3 protein P29474 UNIPROT up-regulates binding 9606 9580552 t miannu The binding of hsp90 to enos enhances the activation of enos. SIGNOR-57211 0.75 RBBP5 protein Q15291 UNIPROT MLL/SET subcomplex complex SIGNOR-C87 SIGNOR form complex binding 9606 24680668 t miannu Dimethylation of h3k4 requires a sub-complexincluding wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. SIGNOR-204825 0.902 CREBBP protein Q92793 UNIPROT IRF9 protein Q00978 UNIPROT up-regulates activity acetylation Lys81 TGGPAVWkTRLRCAL 9606 BTO:0000007 17923090 t lperfetto CBP was also the most effective one among the acetyltransferases tested for catalyzing IRF9 acetylation in 293T cells. [²] Figure 5 (F) K81 acetylation is required for IRF9 dimerization between the N-terminal 1-118 and the C-terminal 340-393 regions. In the left panel, Myc-DBD (1- 118) of IRF9 was cotransfected with 118-393, 118-339, or 1-393 (FL) of IRF9 in 293T cells. Anti-IRF9 (C-terminal region) precipitates were analyzed with anti-Myc or anti-IRF9. Anti-IRF9 precipitates, prepared from 293T cells cotransfected with the C-terminal fragment 118-393 of IRF9 and Myctagged DBD of different forms, were analyzed with anti-Myc or anti-IRF9 (right panel). SIGNOR-217787 0.368 CTH protein P32929 UNIPROT L-selenocystathionine zwitterion smallmolecule CHEBI:62226 ChEBI down-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. SIGNOR-275823 0.8 SRC protein P12931 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Tyr66 DTAGQEDyDRLRPLS 9606 BTO:0000567 23027962 t lperfetto When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity SIGNOR-271701 0.654 PRKCB protein P05771 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Thr276 DGIMYYLtPQWDKIL 9823 21864610 t miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. SIGNOR-262926 0.2 F2RL2 protein O00254 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256761 0.2 MAPK9 protein P45984 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 18174237 t gcesareni Constitutive activation of the c-jun n-terminal kinase (jnk) pathway in sup-t1 cells promoted phosphorylation and degradation of bimel via the proteosome. SIGNOR-250136 0.622 LAT protein O43561 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. SIGNOR-246065 0.389 MECP2 protein P51608 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000478 26214522 f Luana  We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models. SIGNOR-264552 0.2 RPS6KA2 protein Q15349 UNIPROT L1CAM protein P32004 UNIPROT up-regulates activity phosphorylation Ser1152 RSKGGKYsVKDKEDT 10116 BTO:0001009 8663493 t lperfetto Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152. SIGNOR-248949 0.494 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CEBPB protein P17676 UNIPROT up-regulates activity phosphorylation Thr235 SSSSPPGtPSPADAK 9606 BTO:0000551 19723873 t gcesareni Phosphorylation of cebpb at thr(235) peaked at 16 hours in il-1beta-stimulated cells. The mek inhibitor u0126 inhibited this phosphorylation and reduced mmp-1 gene induction. SIGNOR-238303 0.2 PPP1R8 protein Q12972 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity binding -1 1322907 t We have purified two of these nuclear inhibitors of PP-1 (NIPP-1a and NIPP-1b) until homogeneity. SIGNOR-255657 0.641 NME1 protein P15531 UNIPROT L1CAM protein P32004 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17671192 f miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. SIGNOR-255161 0.2 GSK3A protein P49840 UNIPROT RICTOR protein Q6R327 UNIPROT down-regulates quantity by destabilization phosphorylation Thr1695 EAEAVLAtPPKQPIV 9606 BTO:0002181 25897075 t miannu We show that this process is dependent on glycogen synthase kinase 3 (GSK3): GSK3 was associated with rictor and directly phosphorylated the Thr-1695 site in a putative CDC4 phospho-degron motif of rictor; mutation of this site impaired the interaction between rictor and FBXW7, decreased rictor ubiquitination, and increased rictor stability.  SIGNOR-276899 0.395 CENPO protein Q9BU64 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265209 0.821 C1QBP protein Q07021 UNIPROT C1QB protein P02746 UNIPROT down-regulates activity binding SIGNOR-C308 28018340 t lperfetto Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping. SIGNOR-263403 0.347 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Thr157 VLYSQKAtPGSSRKT 9606 BTO:0000567 15525512 t llicata Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.  SIGNOR-250609 0.992 RAP1A protein P62834 UNIPROT CAMK1 protein Q14012 UNIPROT up-regulates activity 9606 21791615 f miannu The present study indicates that Epac1 and Rap1 are involved in activation of CaMKI for Ser47 phosphorylation in GCM1. We found here that cAMP-dependent activation of Epac1 and Rap1 but not PKA is able to activate CaMKI to mediate Ser47 (S47) phosphorylation in GCM1. SIGNOR-262683 0.296 PRKACA protein P17612 UNIPROT CLDN3 protein O15551 UNIPROT unknown phosphorylation Thr192 PPREKKYtATKVVYS 9606 15905176 t llicata Our results suggest that claudin-3 phosphorylation by pka, a kinase frequently activated in ovarian cancer, may provide a mechanism for the disruption of tjs in this cancer. SIGNOR-137291 0.312 TERF2IP protein Q9NYB0 UNIPROT Shelterin complex complex SIGNOR-C306 SIGNOR form complex binding 9606 BTO:0000567 15383534 t lperfetto Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins. SIGNOR-263319 0.827 CSNK2A2 protein P19784 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation Ser146 FYKRRGAsDLSSEEG -1 8954982 t llicata Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149. SIGNOR-251034 0.329 MLL/SET subcomplex complex SIGNOR-C87 SIGNOR MLL2 complex complex SIGNOR-C88 SIGNOR form complex binding 9606 24680668 t miannu The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation. SIGNOR-204822 0.799 CDK2 protein P24941 UNIPROT RNF4 protein P78317 UNIPROT up-regulates activity phosphorylation Thr26 RTREATStPEISLEA 9606 BTO:0002181 25948581 t miannu Here we reported that CDK2 could phosphorylate RNF4 on T26 and T112 and enhance RNF4 E3 ligase activity, which is important for MDC1 degradation and proper HR repair during S phase.  SIGNOR-276900 0.2 FGF2 protein P09038 UNIPROT HBA1 protein P69905 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8142649 f Regulation miannu Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production. SIGNOR-251796 0.2 PCDHA13 protein Q9Y5I0 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265672 0.2 MMP12 protein P39900 UNIPROT F12 protein P00748 UNIPROT down-regulates quantity by destabilization cleavage Gly376 SMTRVVGgLVALRGA -1 10930399 t lperfetto The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage. SIGNOR-263611 0.336 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120100 0.316 ATM protein Q13315 UNIPROT USP28 protein Q96RU2 UNIPROT down-regulates activity phosphorylation Ser495 STSTESSsQDVESTF 31938050 t lperfetto Once all the three conservative SQ sites (S67, S495, and S714), in USP28, were mutated to alanine, the pS/TQ antibody completely could not recognize the immunoprecipitated Flag-USP28-3S/A (Figure ​Figure55D), suggesting that in response to 5'-AZA-induced stress, ATM phosphorylates USP28 at all these three sites.|We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1. We also provided evidence that ATM-mediated phosphorylation of USP28 resulted in its disassociation from KLHL2 and UCK1 destabilization. SIGNOR-275854 0.317 DCK protein P27707 UNIPROT 2'-deoxyguanosine 5'-monophosphate(2-) smallmolecule CHEBI:57673 ChEBI up-regulates quantity chemical modification 20637175 t lperfetto Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis SIGNOR-275809 0.8 MAPK1 protein P28482 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser279 SSPTAPLsPMSPPGY 9606 BTO:0000567 9535909 t lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. SIGNOR-249402 0.596 GPI protein P06744 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Glucose 6-phosphate isomerase (GPI) catalyzes the interconversion of G6P into fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway (Figure 1). As a result of this reversible reaction, products of the hexose-monophosphate shunt can be recycled to G6P. SIGNOR-266461 0.8 INSR protein P06213 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Tyr580 LRKTRDQyLMWLTQK 9534 BTO:0000298 8385099 t The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-251321 0.656 TNF protein P01375 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20509143 f miannu we show that TNFα treatment of human breast cancer cells up-regulates SLUG with a dependency on canonical NF-κB/HIF1α signaling, which is strongly enhanced by p53 inactivation. SIGNOR-255152 0.312 cinolazepam chemical CHEBI:59514 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t brain lperfetto The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005). SIGNOR-263801 0.8 EID2 protein Q8N6I1 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 14612439 t gcesareni In this study, we examined the effect of eid-2 on smad-mediated tgf- signaling. Here, we show that eid-2 inhibits tgf- /smad transcriptional responses. Eid-2 interacts constitutively with smad proteins, and most strongly with smad3. SIGNOR-119171 0.406 PKN1 protein Q16512 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser886 PVDPRRRsLPAGDAL 9606 14970201 t lperfetto Here we identify a region in the carboxyl terminus of gef-h1 that is important for suppression of its guanine nucleotide exchange activity by microtubules. This portion of the protein includes a coiled-coil motif, a proline-rich motif that may interact with src homology 3 domain-containing proteins, and a potential binding site for 14-3-3 proteins. We show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules. SIGNOR-122191 0.295 SRC protein P12931 UNIPROT ITGB2 protein P05107 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000876 25624455 t miannu PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role. SIGNOR-254740 0.437 ALK protein Q9UM73 UNIPROT STAT3 protein P40763 UNIPROT up-regulates binding 9606 BTO:0000785 14968112 t gcesareni Npm-alk has been shown to activate signal transducer and activator of transcription (stat) 3, a transcriptional regulator of cyclin d3.Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1. SIGNOR-122085 0.451 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser712 EEEESDSsETEKEDD 21296876 t lperfetto Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2. SIGNOR-275500 0.2 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RUNX3 protein Q13761 UNIPROT down-regulates phosphorylation Ser356 SSSGGDRsPTRMLAS 9606 19351720 t lperfetto Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation. SIGNOR-216980 0.528 FERMT2 protein Q96AC1 UNIPROT FBLIM1 protein Q8WUP2 UNIPROT up-regulates activity binding 9606 BTO:0000007 26037143 t miannu Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration. SIGNOR-266108 0.775 PRKCA protein P17252 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Ser109 KERRRTEsINSAFAE 9606 14636580 t lperfetto In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. In addition, phosphopeptide mapping analysis of wild-type and mutant forms of HAND1 shows that three of these conserved residues, T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues.  SIGNOR-249242 0.292 PAK4 protein O96013 UNIPROT PXN protein P49023 UNIPROT unknown phosphorylation Ser272 ELDELMAsLSDFKIQ 9606 BTO:0001130 20406887 t llicata We find that pak4 is localised at focal adhesions, is immunoprecipitated with paxillin and phosphorylates paxillin on serine 272. SIGNOR-164889 0.522 N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-(2,6-dimethoxyphenoxy)ethanamine chemical CHEBI:64098 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258472 0.8 PTPN13 protein Q12923 UNIPROT PDCD10 protein Q9BUL8 UNIPROT down-regulates dephosphorylation 9606 17657516 t gcesareni We also show that ccm3 directly binds to serine/threonine kinase 25 (stk25, ysk1, sok1) and the phosphatase domain of fas-associated phosphatase-1 (fap-1, ptpn13, ptp-bas, ptp-bl). SIGNOR-157076 0.584 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 t Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. SIGNOR-252568 0.754 GOLGA3 protein Q08378 UNIPROT GOPC protein Q9HD26 UNIPROT up-regulates activity binding 9606 BTO:0000567 15951434 t miannu Golgin-160 belongs to the golgin family of Golgi-localized proteins, which have been implicated in Golgi structure and function. PIST (also known as GOPC, CAL, and FIG) has been implicated in the trafficking of a subset of plasma membrane proteins, supporting a role of golgin-160 in vesicular trafficking. binding of golgin-160, TC10, and syntaxin-6 to PIST may coordinate membrane trafficking of some plasma membrane proteins in cell types where these proteins are expressed. SIGNOR-261234 0.493 CSNK2A1 protein P68400 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity phosphorylation Ser131 DESLANLsEDEYYSE 9606 BTO:0002181 25999347 t miannu We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites. SIGNOR-276902 0.323 MAPK1 protein P28482 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser183 PPTQKPPsPPMSGRG 9606 21419341 t lperfetto Our mass spectrometry also identified abi1 s183 and s225 on abi1 (numbering corresponds to abi1 isoform 1) as sites phosphorylated on endogenous protein and in the wildtype erk-dependent in vitro phosphorylated sample. these data indicate erk phosphorylation of abi1 is required for basal and egf-induced wrc interaction with the wrp2/3 complex. SIGNOR-172869 0.421 LNX1 protein Q8TBB1 UNIPROT CLDN17 protein P56750 UNIPROT down-regulates quantity by destabilization ubiquitination -1 22889411 t miannu We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo. SIGNOR-272900 0.298 MASTL protein Q96GX5 UNIPROT ENSA protein O43768 UNIPROT up-regulates activity phosphorylation Ser67 KGQKYFDsGDYNMAK -1 21164014 t gcesareni We identified cyclic adenosine monophosphate€“regulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry. SIGNOR-243690 0.722 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser525 TSMKPRSsRGSIFTF -1 12242273 t miannu These results demonstrate that the effect of PKA stimulation to increase cardiac INa requires at least 2 processes: phosphorylation of consensus sites in the I-II interdomain linker, and one or more additional molecular events mediated by the kinase, that could include phosphorylation of other substrates/proteins. SIGNOR-275991 0.2 PELP1 protein Q8IZL8 UNIPROT Rix1 complex complex SIGNOR-C373 SIGNOR form complex binding 9606 BTO:0000007 22190735 t miannu LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes. SIGNOR-265469 0.793 AKT1 protein P31749 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates 9606 9415393 f Translocation from intracellular compartment to cell surface in muscle and adipose tissue gcesareni Akt is not only capable of stimulating the translocation of glut4 to the cell surface. Endogenous akt is likely to play a significant physiological role in insulin-stimulated glucose uptake in insulin targets such as muscle and adipose tissue SIGNOR-252580 0.565 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 12024016 t gcesareni Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner. SIGNOR-87845 0.813 IL1B protein P01584 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0000801 24166242 t lperfetto Pro-IL-1beta, mIL-1beta and mIL-beta all bind to IL-1RI, which recruits the IL-1 receptor accessory protein (IL-1RAcP) as a co-receptor. SIGNOR-249511 0.903 tandutinib chemical CHEBI:90237 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258298 0.8 AEBP2 protein Q6ZN18 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR form complex binding 9606 23110252 t lperfetto The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48). SIGNOR-241903 0.862 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR MOV10 protein Q9HCE1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32496609 f miannu Mov10 is a processing body (P-body) protein and an interferon-stimulated gene that can affect replication of retroviruses, hepatitis B virus, and hepatitis C virus (HCV). SIGNOR-261137 0.2 MAPK1 protein P28482 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 10737616 t lperfetto Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease. SIGNOR-249418 0.552 EGFR protein P00533 UNIPROT CCDC50 protein Q8IVM0 UNIPROT down-regulates activity phosphorylation Tyr279 TDGEDADyTHFTNQQ 9606 BTO:0000567 19059208 t miannu We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling. SIGNOR-262851 0.425 TWIST1 protein Q15672 UNIPROT CTPS1 protein P17812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255518 0.2 PRKACA protein P17612 UNIPROT RAP1B protein P61224 UNIPROT up-regulates phosphorylation Ser179 PGKARKKsSCQLL 9606 19651783 t llicata These results provide a mechanistic explanation for the differential effects of rap1 phosphorylation by pka on effector protein interaction. camp is one among several pathways leading to rap1 activation SIGNOR-187410 0.505 NOG protein Q13253 UNIPROT BMP4 protein P12644 UNIPROT down-regulates binding 9606 12700180 t lperfetto Noggin acts by binding bmps, thus preventing them from binding to their receptors (180). Noggin binds with various degrees of affinity bmp-2, -4, -5, -6, and -7, gdf-5, gdf-6, and vg1, but not other members of the tgf- family of peptides SIGNOR-100660 0.808 Normorphine chemical CHEBI:7633 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258823 0.8 UTS2R protein Q9UKP6 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257426 0.41 SF1 protein Q15637 UNIPROT LHB protein P01229 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004467 19106114 f miannu The human LHB promoter also contains low and high affinity SF1 binding sites. Mutation of these elements or depletion of endogenous SF1 impaired basal and ligand-induced transcription. SIGNOR-254915 0.2 IL20 protein Q9NYY1 UNIPROT IL20RB protein Q6UXL0 UNIPROT up-regulates binding 9606 11163236 t gcesareni An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis. SIGNOR-151874 0.76 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7322 RAGSRAGsRASSRRG 9606 BTO:0004905 21295697 t lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. SIGNOR-264433 0.446 POU3F4 protein P49335 UNIPROT POU3F2 protein P20265 UNIPROT up-regulates activity binding -1 9105675 t miannu POU proteins (Brain-1, Brain-2, Brain-4 and SCIP) serve as transcriptional transactivators. if they were to form homomeric and heteromeric complexes with each other, depending on the particular combination, they might have different DNA-binding specificities and, thus, activate different genes. SIGNOR-220080 0.316 RAD21 protein O60216 UNIPROT ERG protein P11308 UNIPROT down-regulates activity relocalization 9606 BTO:0001545 26607380 t miannu Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity. SIGNOR-261515 0.2 (4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-[3-(4,4-diphenyl-1-piperidinyl)propyl] ester O3-methyl ester chemical CHEBI:103931 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258463 0.8 PRKACA protein P17612 UNIPROT PLIN1 protein O60240 UNIPROT down-regulates activity phosphorylation Ser81 EPVVRRLsTQFTAAN 10090 BTO:0000944 11751901 t miannu PKA increased lipolysis in cells expressing Peri A because it abrogated the inhibitory actions of Peri A on lipolysis.  amino-terminal PKA sites (Ser-81, Ser-222, and Ser-276) SIGNOR-250492 0.483 PPP3CA protein Q08209 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR form complex binding 9606 14623295 t miannu Calcineurin is a heterodimer consisting of a catalytic subunit with a molecular mass of about 59 kDa (calcienurin A or CNA) and a regulatory subunit with a molecular mass of 19 kDa (calcineurin B or CNB). SIGNOR-255291 0.953 GSK3B protein P49841 UNIPROT CTPS1 protein P17812 UNIPROT down-regulates activity phosphorylation Ser571 RDTYSDRsGSSSPDS 9606 BTO:0000007 17681942 t miannu Mutation of Ser-571 demonstrated that Ser-571 was the major site phosphorylated by GSK3 in intact human embryonic kidney 293 cells by GSK3 in vitro. Furthermore, mutation of Ser-575 prevented the phosphorylation of Ser-571, suggesting that phosphorylation of Ser-575 was necessary for priming the GSK3 phosphorylation of Ser-571. Incubation with an alkaline phosphatase increased CTPS1 activity in a time-dependent manner, demonstrating that phosphorylation inhibits CTPS1 activity. SIGNOR-276070 0.2 SRC protein P12931 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Tyr289 MELQTYRyHGHSMSD 9606 BTO:0000007 26848621 t miannu Src inactivated PDH through direct phosphorylation of tyrosine-289 of PDH E1α subunit (PDHA1).  SIGNOR-277204 0.356 D-glucitol smallmolecule CHEBI:17924 ChEBI TARDBP protein Q13148 UNIPROT down-regulates activity relocalization 9606 BTO:0000312 33172210 f We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne SIGNOR-262817 0.8 seliciclib chemical CHEBI:45307 ChEBI CCNA2 protein P20248 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206559 0.8 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9606 BTO:0000938 12040039 t lperfetto Stress in primary cultured cns neurons induces phosphorylation of c-jun serines 63 and 73 and increased c-jun protein. Thus, neuronal stress selectively activates JNK2/3 in the presence of mechanisms maintaining constitutive JNK1 activity, and this JNK2/3 activity selectively targets c-Jun, which is isolated from constitutive JNK1 activity. SIGNOR-236149 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation 10090 BTO:0000944 15851026 t inferred from 70% family members lperfetto Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation. SIGNOR-270108 0.2 BRAF protein P15056 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity relocalization 9606 19861538 f miannu The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression. SIGNOR-251987 0.253 PTPRE protein P23469 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9534 15522235 t llicata PTPepsilonM activated c-Src kinase probably by directly dephosphorylating phospho-Tyr527, a negative regulatory site of c-Src. SIGNOR-238074 0.411 CAMK2A protein Q9UQM7 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Thr160 NKLRRYTtFSKRKTG 10753652 t llicata Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. | Microsequencing of these phosphorylated peptides identified that both Ser-103 and a novel residue, Thr-160 in the MADS box of SRF, were sites of phosphorylation. | The location of Thr-160 in the 3-D structure of SRF suggests that its phosphorylation by nuclear CaMKII may directly influence DNA binding of SRF and other MADS box factors. SIGNOR-250639 0.377 PML protein P29590 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 15356634 t lperfetto Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome. SIGNOR-232090 0.528 PSMC2 protein P35998 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263374 0.873 CDK1 protein P06493 UNIPROT TK1 protein P04183 UNIPROT down-regulates phosphorylation Ser13 LPTVLPGsPSKTRGQ 9606 BTO:0000567 12435275 t gcesareni Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase. SIGNOR-95574 0.52 RPS6KA1 protein Q15418 UNIPROT METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 BTO:0000007;BTO:0000567 15861136 t gcesareni Pkb and ribosomal s6 kinase (rsk) both phosphorylated mettl1 at ser27 in vitro. SIGNOR-135948 0.329 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser180 GSSASFIsDTFSPYT 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248515 0.387 PLAAT3 protein P53816 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates 9606 17374643 f miannu The alpha-isoform of the regulatory subunit a of protein phosphatase 2a (pr65alpha) as a new interaction partner of hrsl3 / we demonstrate that hrsl3 binds to the endogenous pr65alpha, thereby partially sequestering the catalytic subunit pr36 from the pr65 protein complex, and inhibiting pp2a catalytic activity. SIGNOR-153772 0.2 EPHA8 protein P29322 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates activity phosphorylation Tyr616 FYAEPHTyEEPGRAG 9606 BTO:0000007 10498895 t Tyr-615 and Tyr-838 are major autophosphorylation sites of the EphA8 receptor. phosphorylation of Tyr-615 is critical for determining the association with Fyn whereas the integrity of Tyr-838 phosphorylation is required for efficient phosphorylation at Tyr-615 as well as other major sites. SIGNOR-251120 0.2 Endothelin-1 smallmolecule CHEBI:80240 ChEBI EDNRA protein P25101 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257482 0.8 SATB2 protein Q9UPW6 UNIPROT UPF3B protein Q9BZI7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 23925499 f miannu chromatin immunoprecipitation demonstrates that SATB2 binds to the UPF3B promoter, and a luciferase reporter assay confirmed that SATB2 expression significantly activates gene transcription using the UPF3B promoter. SIGNOR-255137 0.34 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Thr520 DNTPHTPtPFKNALE 9606 10593981 t llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. SIGNOR-250741 0.711 pralatrexate chemical CHEBI:71223 ChEBI DHFR protein P00374 UNIPROT down-regulates activity chemical inhibition 9606 23409799 t miannu Pralatrexate is a small molecule with a chemical formula C23H23N7O5 and a molecular weight of 477.48 g/mol (Box 1). It competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase. SIGNOR-259353 0.8 ERG protein P11308 UNIPROT TDRD1 protein Q9BXT4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 23555854 f miannu we report that ERG and TDRD1 are co-expressed in human prostate cancers and we provide a mechanistic explanation for the observed co-expression. We demonstrate that ERG activates TDRD1 transcription by inducing loss of DNA methylation at the TDRD1 promoter-associated CpG island. SIGNOR-254068 0.2 CHRM5 protein P08912 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257291 0.358 MAPK13 protein O15264 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 BTO:0000782;BTO:0001271 8125092 t gcesareni Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase. SIGNOR-36362 0.389 CKM complex complex SIGNOR-C406 SIGNOR E2F1 protein Q01094 UNIPROT down-regulates activity phosphorylation Ser375 PVDEDRLsPLVAADS 9606 22945643 t lperfetto Cdk8 regulates e2f1 transcriptional activity through s375 phosphorylation. SIGNOR-273138 0.37 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr382 DHYRYSDtTDSDPEN 9606 21779440 t gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity SIGNOR-89826 0.667 AKT2 protein P31751 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates activity binding 9606 BTO:0000222 16982699 t gcesareni Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation. SIGNOR-149705 0.669 AKT1 protein P31749 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 11108261 t lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. SIGNOR-84971 0.756 FADS1 protein O60427 UNIPROT arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity chemical modification 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267911 0.8 CTNNB1 protein P35222 UNIPROT TCF4 protein P15884 UNIPROT up-regulates activity binding 9606 BTO:0000007 11713476 t amattioni beta-catenin interacts with the TCF/Lef family transcription factors. SIGNOR-178042 0.677 MICU1 protein Q9BPX6 UNIPROT MCU_MICU3_variant complex SIGNOR-C501 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270871 0.687 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273043 0.556 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 10085140 t gcesareni On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38. SIGNOR-65597 0.786 CHRM1 protein P11229 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256735 0.384 AKT proteinfamily SIGNOR-PF24 SIGNOR ALYREF protein Q86V81 UNIPROT up-regulates phosphorylation Thr219 GGGTRRGtRGGARGR 9606 18562279 t llicata Nuclear akt directly binds aly and phosphorylates it on the t219 residue. gfp-aly t219d displayed comparable activity to gfp control and wild-type aly, indicating that aly phosphorylation by akt is sufficient to enhance mrna export. SIGNOR-179054 0.2 FUS protein P35637 UNIPROT VPS16 protein Q9H269 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0001279 28515487 f This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease SIGNOR-262808 0.2 PRKD2 protein Q9BZL6 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity phosphorylation Ser155 FPLRKTVsEPNLKLR 18692497 t Conserved Phosphorylated residue Ser259 and Ser498 refer to HDAC5 sequence. Phospho-residues in HDAC7 were derived by aligning HDAC5 and HDAC7 lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. SIGNOR-275933 0.448 GMPS protein P49915 UNIPROT guanosine 5'-monophosphate smallmolecule CHEBI:17345 ChEBI up-regulates quantity chemical modification 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267338 0.8 CADPS2 protein Q86UW7 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 24363652 t miannu CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly. SIGNOR-264341 0.257 MAPK1 protein P28482 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 12792650 t lperfetto Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK SIGNOR-101544 0.549 CHRM5 protein P08912 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257125 0.255 STAT1 protein P42224 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 21433395 f miannu The signal transducer and activator of transcription (STAT) family of transcription factors transduce signals from a variety of extracellular stimuli, and are important mediators of inflammation, cell survival, differentiation, and proliferation. STATs are activated in response to growth factors, cytokines, and G-CSF binding to cell surface receptor tyrosine kinases. Although structurally similar, the seven STAT family members possess diverse biological roles. For example, STAT1 activation is pro-inflammatory and anti-proliferative, while STAT3 activation is anti-inflammatory and pro-apoptotic. SIGNOR-263651 0.7 TP53RK protein Q96S44 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17712528 t gcesareni The intrinsic transcriptional activity of p53 was up-regulated by a transient transfection of prpk to cos-7 cells. Prpk was shown to bind to p53 and to phosphorylate p53 at ser-15. SIGNOR-157471 0.75 PRKN protein O60260 UNIPROT SEPTIN5 protein Q99719 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 14559152 t miannu SEPT5_v2 is highly homologous to another septin, SEPT5, which was recently identified as a target for parkin-mediated ubiquitination. SEPT5_v2 binds to parkin at the amino terminus and in the ring finger domains.Parkin ubiquitinates SEPT5_v2 in vitro, and both SEPT5_v1 and SEPT5_v2 accumulate in brains of patients with ARJP, suggesting that parkin is essential for the normal metabolism of these proteins. SIGNOR-272673 0.2 TLR9 protein Q9NR96 UNIPROT TICAM2 protein Q86XR7 UNIPROT up-regulates activity binding 10090 22664090 t scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266750 0.411 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI beta-alanine zwitterion smallmolecule CHEBI:57966 ChEBI up-regulates quantity precursor of 9606 22718265 t miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. SIGNOR-267547 0.8 MAPK1 protein P28482 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 12223490 t gcesareni We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage. SIGNOR-92593 0.542 AKT2 protein P31751 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates phosphorylation Ser193 GLPERSVsLTGAPES 10116 17177604 t lperfetto AKT phosphorylates the mRNA decay-promoting factor KSRP at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents KSRP interaction with the exoribonucleolytic complex exosome. This impairs KSRP’s ability to promote rapid mRNA decay. SIGNOR-151220 0.35 TSC1 protein Q92574 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity 9606 BTO:0000007;BTO:0001938 12271141 f lperfetto These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor. Here, we show that hamartin and tuberin function together to inhibit mammalian target of rapamycin (mtor)-mediated signaling to eukaryotic initiation factor 4e-binding protein 1 (4e-bp1) and ribosomal protein s6 kinase 1 (s6k1). SIGNOR-93130 0.695 CYP2R1 protein Q6VVX0 UNIPROT calcidiol smallmolecule CHEBI:17933 ChEBI up-regulates quantity chemical modification 9606 BTO:0000759 30080183 t lperfetto Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. SIGNOR-270568 0.8 SHOX protein O15266 UNIPROT NPPB protein P16860 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17881654 f miannu The ability of SHOX to transactivate the NPPB endogenous promoter was demonstrated in luciferase reporter assays using serial deletions of the NPPB promotor region. Binding of SHOX to the NPPB promoter was also demonstrated in vivo by chromatin fixation and immunoprecipitation. We also demonstrate the lack of promoter activation in two SHOX mutants from patients with Leri-Weill syndrome. SIGNOR-255138 0.295 MAPK8IP1 protein Q9UQF2 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 20508646 t Interferes with binding to Noth1-ICD. gcesareni Here, we show that jip1 suppresses notch1 activity. Jip1 was found to physically associate with either intracellular domain of notch1 or rbp-jk and interfere with the interaction between them. SIGNOR-165713 0.2 MAPK1 protein P28482 UNIPROT GORASP2 protein Q9H8Y8 UNIPROT unknown phosphorylation Thr225 QMAGTPItPLKDGFT 9606 BTO:0000567 11408587 t lperfetto Furthermore, ERK2 directly phosphorylated GRASP55 on the same residues that generated the MPM2 phospho-epitope.|The obvious next challenge is to demonstrate the precise role of these phosphorylation events. SIGNOR-249404 0.639 FOXO proteinfamily SIGNOR-PF27 SIGNOR PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 16670091 f lperfetto  FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect.  SIGNOR-252910 0.2 FZD9 protein O00144 UNIPROT SPRY4 protein Q9C004 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15705594 f miannu In NSCLC cells, Wnt-7a and Fzd-9 induced both cadherin and Sprouty-4 expression and stimulated the JNK pathway, but not beta-catenin/T cell factor activity. SIGNOR-253035 0.285 CTNNBIP1 protein Q9NSA3 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10898789 t gcesareni We identify a novel beta-catenin-interacting protein, icat, that was found to inhibit the interaction of beta-catenin with tcf-4 and represses beta-catenin-tcf-4-mediated transactivation. SIGNOR-79399 0.809 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267530 0.8 MACF1 protein Q9UPN3 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization 9606 BTO:0000938 16815997 f lperfetto In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes. SIGNOR-227997 0.411 AL/b2 integrin complex SIGNOR-C169 SIGNOR ICAM1 protein P05362 UNIPROT up-regulates activity binding 10090 BTO:0003104 12808052 t lperfetto The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration|Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity. SIGNOR-253364 0.829 ACSL5 protein Q9ULC5 UNIPROT long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI down-regulates quantity chemical modification 9606 24269233 t ACSs catalyze the conversion of FAs to their active form acyl-CoAs. The human genome codes for 26 ACS isozymes, which are classified into six subfamilies based on their substrate specificities toward the chain length of FAs and on sequence similarity SIGNOR-267713 0.8 CACNA1A protein O00555 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 30849329 f miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). SIGNOR-264328 0.7 TWIST1 protein Q15672 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002590 17487558 f miannu Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells SIGNOR-255515 0.267 PBRM1 protein Q86U86 UNIPROT CRABP2 protein P29373 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15601824 f miannu We found that baf180 deficiency leads to a decreased expression of select target genes, such as s100a13 and ra targets rar_2 and crabpii in heart tissues. SIGNOR-131552 0.431 PRKCG protein P05129 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr375 GRGARGGtRGGRGRI 9606 BTO:0004974 14699138 t lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation SIGNOR-249255 0.297 EGFR protein P00533 UNIPROT CALM2 protein P0DP24 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t miannu Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. SIGNOR-266319 0.352 MYC protein P01106 UNIPROT PTBP1 protein P26599 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20010808 t We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2, SIGNOR-268689 0.45 UBE2D1 protein P51668 UNIPROT TRIM2 protein Q9C040 UNIPROT up-regulates activity binding 9606 BTO:0000567 18687884 t miannu Here, we show that TRIM RING finger protein TRIM2, highly expressed in the nervous system, is an UbcH5a-dependent ubiquitin ligase. We further demonstrate that TRIM2 binds to neurofilament light subunit (NF-L) and regulates NF-L ubiquitination. Together, our results indicate that TRIM2 is an ubiquitin ligase that binds to and ubiquitinates NF-L and that TRIM2 deficiency leads to neurodegeneration in mice likely by altering NF-L metabolism with consequent NF-L accumulation in axons and impairment of axonal transport. SIGNOR-271775 0.281 LARP4B protein Q92615 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 20573744 f miannu Our data suggest LARP4B to act as a general stimulatory factor of translation, associated in poly(A)-mRNA-bound mRNP complexes. Under physiological conditions, LARP4B co-sedimented with polysomes in cellular extracts, suggesting a role in translation. In agreement with this notion, overexpression of LARP4B stimulated protein synthesis, whereas knockdown of the factor by RNA interference impaired translation of a large number of cellular mRNAs. SIGNOR-260942 0.7 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT down-regulates phosphorylation Ser41 SLSESEEsQDSSDSI 9606 20730097 t lperfetto Although the functional impact of ck-mediated atf1 phosphorylation is still unclear, we found that mutation of ser-36 and ser-41 increased cbp kix domain binding by up to four fold (fig. 2g). This result is consistent with the negative impact of ck-mediated phosphorylation on cbp binding affinity of creb that we previously reported SIGNOR-167552 0.301 IL18 protein Q14116 UNIPROT IFNG protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10653850 f miannu IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR engagement. SIGNOR-260860 0.478 CIITA protein P33076 UNIPROT HLA-DRA protein P01903 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002417 10886240 f These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma. SIGNOR-254008 0.602 MAPK8 protein P45983 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser83 PKFKVKSsPLIEKLQ -1 15850461 t miannu CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. SIGNOR-263086 0.29 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR PPARG protein P37231 UNIPROT down-regulates activity 9606 17139329 f fferrentino Phosphorylation of receptor-regulated SMADs (for example, SMAD1 or SMAD3) stimulates dimer formation with SMAD4 and translocation to the nucleus, where the SMADs regulate the transcription of target gene SMAD3 binds to C/EBPs and inhibits their transcriptional activity, including their ability to transactivate the Pparg2 promoter SIGNOR-253537 0.419 GSK3B protein P49841 UNIPROT GRB14 protein Q14449 UNIPROT down-regulates activity phosphorylation Ser362 QGRSGCSsQSISPMR -1 28130417 t lperfetto Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3. SIGNOR-264867 0.329 CREBBP protein Q92793 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates acetylation 9606 BTO:0000887 SIGNOR-C6 10944526 t gcesareni Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo. SIGNOR-81050 0.6 UNII-XH2662798I chemical CID:16156006 PUBCHEM Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates 9606 20068082 f gcesareni Pf-00477736 also significantly enhances docetaxel efficacy in vitro and in vivo, in association with decreased cdc25c cytoplasmic phosphorylation (ser216) and histone h3 phosphorylation (ser10)(42). SIGNOR-265352 0.8 GSK3B protein P49841 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates phosphorylation Ser303 RVKEEPPsPPQSPRV 9606 8940068 t gcesareni Sequential phosphorylation by mitogen-activated protein kinase and glycogen synthase kinase 3 represses transcriptional activation by heat shock factor-1. SIGNOR-44995 0.539 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser512 PPKSGDRsGYSSPGS 9606 BTO:0000590 9771888 t lperfetto Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. SIGNOR-249353 0.728 MAPK14 protein Q16539 UNIPROT ZFP36 protein P26651 UNIPROT down-regulates activity phosphorylation 10029 BTO:0005787 25815583 t TTP appears to be a p38α/β MAPK target and pretreating skeletal muscle with a p38α/β MAPK inhibitor reduces TTP phosphorylation. SIGNOR-253596 0.364 DAGLA protein Q9Y4D2 UNIPROT 2-arachidonoylglycerol smallmolecule CHEBI:52392 ChEBI up-regulates quantity chemical modification 9606 26787883 t miannu Diacylglycerol lipases (DAGLŒ± and DAGLŒ≤) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. SIGNOR-264264 0.8 MAPKAPK2 protein P49137 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser244 PPLRRSPsRTEKQEE -1 15850461 t miannu Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. SIGNOR-263080 0.49 G6PC3 protein Q9BUM1 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-266570 0.8 CSNK2A1 protein P68400 UNIPROT CDC25B protein P30305 UNIPROT up-regulates activity phosphorylation Ser186 EAGSGAAsSSGEDKE -1 12527891 t llicata Mass spectrometry analysis demonstrates that at least two serine residues, Ser-186 and Ser-187, are phosphorylated in vivo. | Finally, we demonstrate that phosphorylation of CDC25B by protein kinase CK2 increases the catalytic activity of the phosphatase in vitro as well as in vivo. SIGNOR-250836 0.344 PAK1 protein Q13153 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates phosphorylation Thr261 QYGLKMKtSRAFFSE 9606 BTO:0000150 18283314 t llicata We found that pak1 phosphorylated ebp1 in vitro and mapped the phosphorylation site to threonine 261. these studies demonstrate for the first time that ebp1 is a substrate of pak1 and the importance of the pak1 phosphorylation site for the functional activity of ebp1 in breast cancer cells. SIGNOR-160963 0.2 NFYC protein Q13952 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15496512 f miannu Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter. SIGNOR-252234 0.2 TRAF6 protein Q9Y4K3 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates polyubiquitination 9606 20047764 t miannu Here, we show that the TRAF family proteins directly bind TICAM-1 and demonstrate that TRAF2 and TRAF6 bind different sites of the N-terminal TICAM-1 and accelerate its polyubiquitination. we speculate that polyubiquitination of TICAM-1 by TRAF2 and TRAF6 is required for TICAM-1 to induce IRF-3 and NF-κB activation. This is supported by the observation that polyubiquitination of TICAM-1 was required for TRAF3-binding to TICAM-1 SIGNOR-271428 0.824 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates phosphorylation Ser346 RAPSRKDsLESDSST 9606 21317289 t gcesareni We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation SIGNOR-200496 0.444 PRKCD protein Q05655 UNIPROT BLVRA protein P53004 UNIPROT up-regulates activity phosphorylation Ser237 SFHFKSGsLENVPNV 22584576 t lperfetto LC-MS/MS analysis of PKCdelta-activated intact hBVR identified phosphorylated serine positions 21, 33, 230, and 237, corresponding to the hBVR Src homology-2 domain motif (Ser(230) and Ser(237)), flanking the ATP-binding motif (Ser(21)) and in PHPS sequence (Ser(33)) as targets of PKCdelta. |PKCdelta potentiated hBVR reductase activity and accelerated the rate of bilirubin formation. SIGNOR-275526 0.2 STAT1 protein P42224 UNIPROT TLR3 protein O15455 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16628196 f miannu The activation of STAT1 by IFNs not only induces chemokine production, but also results in the expression of IRF-7 and TLR3, thus amplifying the dsRNA-provoked reaction in a positive-feedback manner during viral infection. SIGNOR-255230 0.458 PRKG1 protein Q13976 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 15107581 t Translocation from Endosome to Lysosome fspada A specific pkg inhibitor inhibits h1r downregulation in cho cells (37). However, direct activation of pkg in these cells does not cause h1r down-regulation, indicating that more studies are required to clarify the role of pkg in h1r down-regulation. SIGNOR-124360 0.2 NLGN4Y protein Q8NFZ3 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 18923512 t brain lperfetto Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions. SIGNOR-264190 0.2 DUSP1 protein P28562 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 9020184 t gcesareni Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2. SIGNOR-46079 0.781 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser487 AQLAGSDsDLDSDDE 9606 20864032 t lperfetto Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. ere, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2) SIGNOR-168036 0.2 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser235 SPQDSPPsKASPAQD 9606 21215781 t lperfetto Cdk5 regulates app (amyloid precursor protein) processing and tau hyperphosphorylationtau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules SIGNOR-171018 0.754 LE-TGN SNARE complex SIGNOR-C157 SIGNOR IGF2R protein P11717 UNIPROT up-regulates activity relocalization 9606 18195106 t lperfetto These findings place the retromer complex upstream of both STX10 function and the GCC185 tethering complex in MPR transport. Together, our data suggest that STX10, STX16, Vti1a, and VAMP3 are important for the trafficking of both CD- and CI-MPRs.|Thus, MPRs must pass through a compartment of pH ≤ 5.5 before returning to the Golgi to carry out their biological function. SIGNOR-253083 0.465 UV stress stimulus SIGNOR-ST7 SIGNOR CDKN2A protein P42771 UNIPROT up-regulates 9606 11830546 f miannu The expression of the melanoma susceptibility gene product p16 is increased after UVR both in epidermally derived cell lines and in human skin. The increased expression of p16 after exposure to suberythemal doses of UVR is potentiated by α-MSH, a ligand for MC1R, and this effect is mimicked by cAMP, the intracellular mediator of α-MSH signaling via the MC1 receptor. SIGNOR-252376 0.7 PIM1 protein P11309 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 16403219 t miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. SIGNOR-250390 0.379 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser713 GAEIVYKsPVVSGDT 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251591 0.695 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. SIGNOR-216801 0.373 BCAR1 protein P56945 UNIPROT EGR1 protein P18146 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22431919 f miannu In MCF-7 cells, we identified a positive feedback loop where p130(Cas) positively regulates EGR1 and NAB2, which in turn induce p130(Cas) expression. SIGNOR-253892 0.2 RACK1 protein P63244 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 9606 24726876 t miannu RACK1 Mediates the Formation of the IRF3-RACK1-PP2A Complex and Promotes the Dephosphorylation of IRF3.Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection. SIGNOR-260945 0.2 DGC complex SIGNOR-C217 SIGNOR GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265435 0.2 TP53BP1 protein Q12888 UNIPROT H4C1 protein P62805 UNIPROT unknown binding 9606 17190600 t gcesareni Here we demonstrate that this link occurs through direct binding of 53bp1 and crb2 to histone h4. SIGNOR-151654 0.2 CDK8 protein P49336 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2516 FLTPSPEsPDQWSSS -1 25344755 t lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues SIGNOR-273177 0.534 SYMPK protein Q92797 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 16230528 f lperfetto Reconstitution experiments reveal that symplekin, previously shown to be necessary for cytoplasmic poly(A) tail elongation and translational activation of mRNAs during Xenopus oocyte maturation, is the essential heat-labile component. SIGNOR-268368 0.7 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates activity chemical activation 9606 17132853 t miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. SIGNOR-256197 0.8 IL1B protein P01584 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity 9606 BTO:0002417 32454942 f miannu IL-1β, an inflammatory cytokine primarily expressed in activated macrophages, monocytes, and microglia, significantly contributes to MS development. IL-1β promotes differentiation of T cells into Th17 cells via the STAT3 pathway and thereby promotes and aggravates the inflammatory environment in the CNS SIGNOR-263820 0.572 PTEN protein P60484 UNIPROT EGR2 protein P11161 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 f miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). SIGNOR-260049 0.31 Cy3-bifunctional dye zwitterion chemical CHEBI:37990 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  SIGNOR-257858 0.8 YES1 protein P07947 UNIPROT SOCS1 protein O15524 UNIPROT down-regulates activity phosphorylation Tyr80 LLDACGFyWGPLSVH -1 31101761 t miannu SOCS1 is phosphorylated on Y80 by SRC family kinase members SRC and YES1. SIGNOR-276858 0.2 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR PTGS2 protein P35354 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004850 23645839 f miannu AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Here, we show that AE also induces expression of the Cox-2 gene and activates β-catenin in mouse bone marrow cells. SIGNOR-255683 0.2 IMP smallmolecule CHEBI:17202 ChEBI 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI up-regulates quantity precursor of 9606 19480389 t miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. Humans and other mammals have two IMPDH genes, encoding hIMPDH1 and hIMPDH2. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). SIGNOR-267330 0.8 PIM1 protein P11309 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 t tpavlidou Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene. SIGNOR-179304 0.396 SSTR4 protein P31391 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256823 0.426 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000887;BTO:0001103 14579029 t gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. SIGNOR-118857 0.767 sunitinib chemical CHEBI:38940 ChEBI CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition 9606 17367763 t miannu Sunitinib (SU-11248, Sutent) inhibits at least eight receptor protein-tyrosine kinases including vascular endothelial growth factor receptors 1-3 (VEGFR1-VEGFR3), platelet-derived growth factor receptors (PDGFRalpha and PDGFRbeta), stem cell factor receptor (Kit), Flt-3, and colony-stimulating factor-1 receptor (CSF-1R). SIGNOR-259319 0.8 CBX1 protein P83916 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-264491 0.2 VARS1 protein P26640 UNIPROT tRNA(Val) smallmolecule CHEBI:29183 ChEBI down-regulates quantity chemical modification 9606 30755602 t miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. SIGNOR-270525 0.8 RACGAP1 protein Q9H0H5 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260512 0.569 ORC2 protein Q13416 UNIPROT ORC complex SIGNOR-C419 SIGNOR form complex binding 9606 32808929 t lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA SIGNOR-267566 0.97 AURKA protein O14965 UNIPROT DLGAP5 protein Q15398 UNIPROT up-regulates quantity by stabilization phosphorylation Ser830 QEHARHIsFGGNLIT 9606 BTO:0000007 15987997 t miannu Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life. SIGNOR-262652 0.74 AGTR1 protein P30556 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257223 0.477 Cortistatin14 smallmolecule CID:16133803 PUBCHEM MRGPRX2 protein Q96LB1 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257544 0.8 RIPK1 protein Q13546 UNIPROT Necrosis phenotype SIGNOR-PH3 SIGNOR up-regulates 9606 14965271 f amattioni Fas-induced necrosis requires rip SIGNOR-121901 0.7 PPP2CB protein P62714 UNIPROT KRT8 protein P05787 UNIPROT unknown dephosphorylation Ser432 SAYGGLTsPGLSYSL 9606 BTO:0000182 16554440 t K8 Ser431-P is a physiologic substrate to PP2A during hyposmotic conditions and possibly other biologic contexts. SIGNOR-248588 0.2 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu79 EEAREVFeNTERTTE 10090 BTO:0001103 11133752 t lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. SIGNOR-263685 0.67 GATAD2B protein Q8WXI9 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263857 0.776 ABL1 protein P00519 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity phosphorylation Tyr88 KGSLPEFyYRPPRPP 9606 BTO:0000007;BTO:0000567 17254966 t gcesareni A conserved tyrosine residue (Y88) in the Cdk-binding domain of p27 can be phosphorylated by the Src-family kinase Lyn and the oncogene product BCR-ABL SIGNOR-245293 0.578 PI3K complex SIGNOR-C156 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-252706 0.7 PDZRN3 protein Q9UPQ7 UNIPROT MUSK protein O15146 UNIPROT down-regulates quantity ubiquitination 9534 BTO:0000298 17576800 t miannu We have identified a PDZ domain containing RING finger 3 (PDZRN3) as a synapse-associated E3 ubiquitin ligase and have demonstrated that it regulates the surface expression of muscle-specific receptor tyrosine kinase (MuSK), the key organizer of postsynaptic development at the mammalian neuromuscular junction. PDZRN3 binds to MuSK and promotes its ubiquitination. Together, these data demonstrate that PDZRN3 is a catalytically active RING-type E3 ubiquitin ligase SIGNOR-271664 0.559 ARID3A protein Q99856 UNIPROT Immunoglobulin delta heavy chain protein P0DOX3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 16738337 t lperfetto In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels.| Figure ​3 shows that both anti-Bright and anti-TFII-I precipitated the bf150 Bright binding site from the B-cell line but not from a T-cell line that contains but does not express the V1 gene. SIGNOR-268531 0.2 MAPKAPK5 protein Q8IW41 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0001286 17254968 t llicata Furthermore, we show that prak activates p53 by direct phosphorylation. prak phosphorylates p53 at ser37 SIGNOR-152847 0.751 TOP2B protein Q02880 UNIPROT PBX3 protein P40426 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24463367 f lperfetto While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development SIGNOR-242308 0.2 GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263813 0.8 CASP6 protein P55212 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261759 0.379 NR0B2 protein Q15466 UNIPROT ESR2 protein Q92731 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10648597 f gcesareni These novel insights provide a mechanistic explanation for the inhibitory role of shp in nuclear receptor signaling, and they may explain how shp functions as a negative coregulator or corepressor for ligand-activated receptors, a novel and unique function for an orphan nuclear receptor. SIGNOR-74291 0.609 YARS1 protein P54577 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 16429158 t miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr SIGNOR-270521 0.8 ITGB1 protein P05556 UNIPROT Av/b1 integrin complex SIGNOR-C175 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253202 0.829 PTPN3 protein P26045 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity dephosphorylation Tyr537 CKNVVPLyDLLLEML 9606 26079946 t miannu Our recent studies further demonstrated that PTPH1 dephosphorylates estrogen receptor at Y537, increases estrogen receptor stability and nuclear accumulation, and enhances breast cancer sensitivity to anti-estrogens [ ]. SIGNOR-277127 0.2 Ethylketocyclazocine chemical CHEBI:4901 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258799 0.8 AKT2 protein P31751 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 t gcesareni Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155. SIGNOR-81110 0.504 MAPK1 protein P28482 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates 9606 BTO:0000801 11842088 f gcesareni In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. SIGNOR-114771 0.489 AKT proteinfamily SIGNOR-PF24 SIGNOR ADAR protein P55265 UNIPROT down-regulates activity phosphorylation Thr1033 RLGERLRtMSCSDKI -1 31095429 t miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively, and overexpression of the phosphomimic mutants ADAR1p110 (T738D) and ADAR2 (T553D) resulted in a 50-100% reduction in editase activity. SIGNOR-266357 0.2 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000132 21592956 t lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. SIGNOR-217012 0.634 IKK-complex complex SIGNOR-C14 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR down-regulates phosphorylation 9606 10195894 t lperfetto Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response SIGNOR-216373 0.838 PTPN11 protein Q06124 UNIPROT KRAS protein P01116 UNIPROT up-regulates activity dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t irozzo Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. SIGNOR-255982 0.646 RPL37 protein P61927 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262463 0.83 IL12A protein P29459 UNIPROT IFNG protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10653850 f miannu IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12 SIGNOR-260859 0.373 PPARG protein P37231 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19041764 t miannu  Rosiglitazone treatment induced aortic expression of Bmal1 mRNA, and ChIP and promoter assays revealed that Bmal1 is a direct PPARgamma target gene. These studies have uncovered a role for vascular PPARgamma as a peripheral factor participating in regulation of cardiovascular rhythms. SIGNOR-268026 0.408 GNB5 protein O14775 UNIPROT ADCY5 protein O95622 UNIPROT down-regulates activity binding 9606 BTO:0004032 21303898 t miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC SIGNOR-264998 0.432 MTOR protein P42345 UNIPROT ELP1 protein O95163 UNIPROT up-regulates activity phosphorylation Ser1174 SETSSVVsGSEMSGK 29925953 t lperfetto Human ELP1 S1174 phosphorylation was triggered by insulin treatment, as shown by the specific phosphorylated (p)ELP1 (S1174) antibody, and addition of a phosphorylation-mutant variant of the ELP1 protein (ELP1(S1174A)) to ELP1-depleted BRAFV600E melanoma cells failed to rescue cell survival |In line with these findings, mTORC2 activity, but not mTORC1, was required for the insulin-induced phosphorylation of Elp1 S1174 SIGNOR-275541 0.2 PTK6 protein Q13882 UNIPROT EPS8 protein Q12929 UNIPROT up-regulates activity phosphorylation Tyr535 LKTQPKKyAKSKYDF 9606 BTO:0000007 28214294 t miannu Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis. SIGNOR-263191 0.365 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 BTO:0000782 9710204 t lperfetto Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2. SIGNOR-59623 0.721 KANSL1 protein Q7Z3B3 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. SIGNOR-267164 0.658 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr418 LSGEDDAyCTFPSRD -1 10214954 t Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510. SIGNOR-251378 0.629 PTK6 protein Q13882 UNIPROT ARAP1 protein Q96P48 UNIPROT up-regulates activity phosphorylation Tyr231 PEFDDSDyDEVPEEG 9606 BTO:0000007 20554524 t miannu ARAP1 associated with PTK6 in an EGF/EGF receptor (EGFR)-dependent manner. In addition, the SH2 domain of PTK6, particularly the Arg(105) residue that contacts the phosphate group of the tyrosine residue, was essential for the association. Moreover, PTK6 phosphorylated residue Tyr(231) in the N-terminal domain of ARAP1. Expression of ARAP1, but not of the Y231F mutant, inhibited the down-regulation of EGFR in HEK293 cells expressing PTK6. These results demonstrate that PTK6 enhances EGFR signaling by inhibition of EGFR down-regulation through phosphorylation of ARAP1 in breast cancer cells. SIGNOR-263188 0.463 mTORC2 complex SIGNOR-C2 SIGNOR SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser422 AEAFLGFsYAPPTDS 9606 18925875 t lperfetto Mtorc2 immunoprecipitated from wild-type, but not from mlst8- or rictor-knockout cells, phosphorylated sgk1 at ser(422) SIGNOR-217016 0.653 DNA-PK complex SIGNOR-C107 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 10854421 f miannu The DNA-dependent protein kinase (DNA-PK), consisting of Ku and the DNA-PK catalytic subunit (DNA-PKcs), and the DNA ligase IV-XRCC4 complex function together in the repair of DNA double-strand breaks by non-homologous end joining. SIGNOR-264531 0.7 DCC protein P43146 UNIPROT CACNA1C protein Q13936 UNIPROT up-regulates activity 9606 12827203 t miannu DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER. SIGNOR-268291 0.2 SLBP protein Q14493 UNIPROT H2BC11 protein P06899 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265381 0.2 SALL4 protein Q9UJQ4 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 23954296 f miannu Our shRNA-mediated SALL4 knockdown system and SALL4 overexpression system revealed that SALL4 suppresses the expression of adhesion gene CDH1, and positively regulates the CDH1 suppressor ZEB1. SIGNOR-255124 0.309 CAD protein P27708 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267418 0.8 APOH protein P02749 UNIPROT cardiolipin smallmolecule CHEBI:28494 ChEBI down-regulates quantity by destabilization binding 9606 9596664 t lperfetto The most relevant physiological role of beta2GPI is supposed to be the regulation of the function of anionic phospholipids like cardiolipin (CL). |Anticardiolipin antibodies or lupus anticoagulants are strongly associated with thrombosis. In these autoimmune diseases with anti-phospholipid antibody syndrome, beta2GPI is a cofactor in the recognition of the phospholipid antigen, CL, by anti-CL antibodies. SIGNOR-266998 0.8 AKT1 protein P31749 UNIPROT ZYX protein Q15942 UNIPROT down-regulates phosphorylation Ser142 PQPREKVsSIDLEID 9606 17572661 t llicata Akt binds and phosphorylates zyxin on serine 142, leading to its association with acinus zyxin is a substrate of caspases, but akt phosphorylation fails to protect its proteolytic degradation SIGNOR-156122 0.425 DFFB protein O76075 UNIPROT DNA_fragmentation phenotype SIGNOR-PH22 SIGNOR up-regulates 9606 BTO:0000661 9422513 f Cleavage of ICAD/DFF-45 amattioni The specific cleavage of icad/dff-45 by caspase-3 relieves the inhibition and promotes the endonuclease activity of cad, resulting in apoptotic dna fragmentation SIGNOR-54358 0.7 NGF protein P01138 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0001676 16190874 f miannu We examined intracellular signals required for NGF-induced expression of the GCH gene in PC12D cells. The activity of GCH was increased up to 5-fold after the NGF treatment. The human GCH promoter activity was significantly enhanced by NGF treatment. SIGNOR-252228 0.252 MAPK8 protein P45983 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation Ser71 SRRSGLCsPSYVAVT 9606 BTO:0000007;BTO:0000567 10551811 t lperfetto The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71. SIGNOR-236384 0.573 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser235 IAKRRRLsSLRASTS 9606 17360704 t gcesareni We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism. SIGNOR-153618 0.607 TNFRSF21 protein O75509 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR down-regulates 9606 32454942 f miannu Further, data from our laboratories indicate that selective agonism of TNFR2 rescues neurons from oxidative stress-induced cell death [160] and excitotoxic cell death [161, 162]. Similarly, TNFR2 activation induces expression of antiapoptotic and detoxifying proteins and protects OPCs against oxidative stress. SIGNOR-263830 0.7 IRF2 protein P14316 UNIPROT CIITA protein P33076 UNIPROT up-regulates quantity by expression transcriptional regulation 11464288 t lperfetto In addition to IRF-1, IRF-2, another member of the IRF family, also activates the human CIITA type IV promoter, and IRF-2 cooperates with IRF-1 to activate the promoter in transient transfection assays. SIGNOR-271681 0.505 ACAN protein P16112 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 10922468 t lperfetto Degradation of aggrecan, the major proteoglycan of the cartilage ECM responsible for the load-bearing and elastic properties of this tissue, is one of the earliest detectable events in arthritic cartilage degeneration. MMPs have been implicated in proteolysis and the subsequent loss of aggrecan from cartilage during arthritis SIGNOR-266982 0.7 HERPUD1 protein Q15011 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates quantity by stabilization relocalization 9606 29295953 t miannu A key inhibitor of the turnover and Nt-arginylation of BiP was HERP (homocysteine-responsive ER protein), a 43-kDa ER membrane-integrated protein that is an essential component of ER-associated protein degradation.  SIGNOR-261346 0.421 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17339337 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability. We have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-153463 0.783 PRKACA protein P17612 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 15328002 t gcesareni Two amino acid residues (ser396, ser398) on hr1 were determined to be pkc phosphorylation sites by in vitro phosphorylation studies.Site-directed mutagenesis studies suggests that the ser398 residue was primarily involved in pkc-mediated desensitization. Possibly, phosphorylation of the residues is required for receptor transport from endosomes to lysosomes. SIGNOR-128415 0.2 IL12A protein P29459 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 10653850 f miannu IL-12 Synergizes With IL-18 or IL-1beta for IFN-gamma Production From Human T Cells. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R engagement. SIGNOR-260966 0.7 GSK3B protein P49841 UNIPROT GFI1 protein Q99684 UNIPROT down-regulates quantity by destabilization phosphorylation Ser94 EDFWRPPsPSASPAS 9606 BTO:0000498 31289136 t miannu GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation. SIGNOR-277466 0.2 SRC protein P12931 UNIPROT JUP protein P14923 UNIPROT up-regulates activity phosphorylation Tyr644 RNEGTATyAAAVLFR 9606 14517306 t lperfetto Tyrosine phosphorylation of plakoglobin causes contrary effects on its association with desmosomes and adherens junction components and modulates beta-catenin-mediated transcriptionFor instance, Src, which mainly phosphorylates Tyr86 in beta-catenin, modifies Tyr643 in plakoglobin, decreasing the interaction with E-cadherin and alpha-catenin and increasing the interaction with the alpha-catenin-equivalent protein in desmosomes, desmoplakin. SIGNOR-247310 0.655 GPR132 protein Q9UNW8 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256802 0.2 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP9 protein P55211 UNIPROT up-regulates activity -1 10988287 f lperfetto One indirect means through which caspase-8 might regulate caspase-9 activation is through a bcl-2-regulated pathway. SIGNOR-256479 0.591 HEY2 protein Q9UBP5 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 16682003 t The NotchIC-RBP-Jkappa complex activates target genes, such as those encoding the Hrt and Hes families. The interaction did not interfere with the formation or DNA-binding of the NotchIC-RBP-Jkappa complex, indicating direct inhibition by Hrt and Hes as co-repressors. gcesareni Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression. SIGNOR-146690 0.759 ILK protein Q13418 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Thr696 ARQSRRStQGVTLTD 9606 12030846 t lperfetto Mypt1 was phosphorylated by ilk and phosphorylation sites in the n- and c-terminal fragments of mypt1 were detected. From sequence analyses, three sites were identified: a primary site at thr(709), and two other sites at thr(695) and thr(495) SIGNOR-87924 0.567 CDK1 protein P06493 UNIPROT TPX2 protein Q9ULW0 UNIPROT down-regulates activity phosphorylation Thr72 NLQQAIVtPLKPVDN -1 25688093 t lperfetto In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. |Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle SIGNOR-265096 0.621 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 18621737 t gcesareni A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution. SIGNOR-179452 0.888 PYGB protein P11216 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 3346228 t miannu Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267396 0.8 MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates transcriptional regulation 9606 25211658 t P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells SIGNOR-251574 0.41 PPP2CA protein P67775 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation Ser645 LNEKARLsYSDKNLI 9606 11959144 t PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex SIGNOR-248638 0.385 WNT9A protein O14904 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000887 22309736 t gcesareni we provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase SIGNOR-195975 0.409 MAP3K11 protein Q16584 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates phosphorylation Ser257 ISGQLVDsIAKTRDA 9606 15328343 t gcesareni These data suggest that mlk-3 phosphorylates sek1 directly and that it does so specifically on those residues known to activate sek1 in vivo. SIGNOR-128420 0.609 ABI1 protein Q8IZP0 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 9010225 t gcesareni Our results are in agreement with previous report showing that abi-1, the putative mouse homologue of e3b1, is a abl binding protein SIGNOR-45994 0.876 MAPKAPK2 protein P49137 UNIPROT EEF2K protein O00418 UNIPROT unknown phosphorylation Ser377 PPLLRPLsENSGDEN -1 12171600 t miannu Identification of Ser-377 as the site on eEF2 kinase phosphorylated in vitro by MAPKAP-K2, MAPKAP-K3 and MAPKAP-K5. Maximal phosphorylation of eEF2 kinase by MAPKAP-K2 (Figure 5) or MAPKAP-K5 (results not shown) had no effect on its activity. SIGNOR-249710 0.358 E2F4 protein Q16254 UNIPROT PPARG protein P37231 UNIPROT down-regulates transcriptional regulation 9606 12110166 f During terminal adipocyte differentiation fspada we show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation SIGNOR-210050 0.472 ASPM protein Q8IZT6 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates quantity by expression transcriptional regulation 16123590 f Here, we report that downregulation of endogenous ASPM by siRNA decreases protein levels of endogenous BRCA1. ASPM localizes to the centrosome in interphase and to the spindle poles from prophase through telophase. These findings indicate that ASPM may be involved in mitotic spindle function, possibly, through regulation of BRCA1. SIGNOR-253936 0.276 AURKA protein O14965 UNIPROT FADD protein Q13158 UNIPROT up-regulates phosphorylation Ser203 MSWNSDAsTSEAS 9606 21978935 t lperfetto Here, we report that aur-a phosphorylates s203 of the fas associated with death domain protein (fadd)phosphorylation of s203 by aur-a serves to prime fadd for plk1-mediated phosphorylation at s194 SIGNOR-176739 0.349 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 t miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. SIGNOR-264927 0.8 U0126 chemical CHEBI:90693 ChEBI MAPK7 protein Q13164 UNIPROT down-regulates chemical inhibition 9606 BTO:0000938 BTO:0000142 11160424 t gcesareni Pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity and neuronal survival. Interestingly, erk5 activation by egf in cos7 cells is also blocked by these inhibitors suggesting that the erk5 pathway may also regulate cellular processes credited previously to erk1/2. SIGNOR-104945 0.8 PPARA protein Q07869 UNIPROT AQP3 protein Q92482 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003204 17150915 f miannu To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA. SIGNOR-255045 0.301 CCNC protein P24863 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates phosphorylation 9606 15546612 t Leads to a following ubiquitination and degradation gcesareni Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. SIGNOR-254309 0.458 HES5 protein Q5TA89 UNIPROT NEUROG1 protein Q92886 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 f lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production SIGNOR-265141 0.415 CEBPB protein P17676 UNIPROT Neurodegeneration phenotype SIGNOR-PH139 SIGNOR up-regulates activity 10090 BTO:0000078 32795415 f Gianni In the absence of COP1, c/EBPβ accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures. SIGNOR-261926 0.7 NLGN4X protein Q8N0W4 UNIPROT NRXN2 protein P58401 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264160 0.759 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates 9606 BTO:0000007;BTO:0000782 11073940 f gcesareni Mekk2 activated bmk1/erk5 to a greater extent, which might correlate with a higher affinity mekk2-mek5 interaction. A dominant negative form of mek5 blocked the activation of bmk1/erk5 by mekk2 SIGNOR-84184 0.753 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser555 RALSNSVsNMGLSES 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252977 0.509 MAPK10 protein P53779 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 20630875 t gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress. SIGNOR-166690 0.306 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Arg41 TNATLDPrSFLLRNP -1 10978167 t lperfetto Thrombin cleaved PAR1E at the Arg41-Ser42 activation site at concentrations known to induce cellular activation, supporting a native conformation of the recombinant polypeptide. SIGNOR-263569 0.883 BCHE protein P06276 UNIPROT acetylcholine smallmolecule CHEBI:15355 ChEBI down-regulates quantity chemical modification 15841900 t The other subgroup, butyrylcholinesterase (BuChE) (or acyl- choline acyl-hydrolase, EC 3.1.1.8) also known as plasma, serum, benzoyl, false, butyryl, nonspecific, or type II ChE. BuChE exists in plasma and has more than eleven isoenzy- me variants. BuChE is also present in liver, smooth muscle, intestines, pancreas, heart and white matter of brain |It hydrolyzes butyrylcholine 4 times more rapidly than acetylcholine. SIGNOR-253982 0.8 DYRK2 protein Q92630 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser32 RSRERSPsPLRGNVV 9606 BTO:0000671 15910284 t lperfetto Dyrk2 (dual-specificity tyrosine-phosphorylated and -regulated protein kinase 2) phosphorylated crhsp24 at ser30, ser32 and ser41 in vitro, and ser41 was identified as a site phosphorylated in cells. SIGNOR-137478 0.263 NANOG protein Q9H9S0 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 f lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) SIGNOR-253162 0.453 HRC protein P23327 UNIPROT ATP2A2 protein P16615 UNIPROT down-regulates activity binding 10116 BTO:0001879 28784772 t miannu Furthermore, a Ser96Asp HRC variant, which mimics constitutive phosphorylation of Ser96, diminished delayed aftercontractions in HRC null cardiac myocytes. This HRC phosphomimetic variant was also able to rescue the aftercontractions elicited by the Ser96Ala variant, demonstrating that phosphorylation of Ser96 is critical for the cardioprotective function of HRC. Phosphorylation of HRC on Ser96 regulated the interactions of HRC with both triadin and SERCA2a, suggesting a unique mechanism for regulation of SR Ca homeostasis.  SIGNOR-273662 0.382 phosphatidic acid smallmolecule CHEBI:16337 ChEBI RAC1 protein P63000 UNIPROT up-regulates chemical activation 9606 18480413 t gcesareni The c-terminal polybasic motif of rac1 is responsible for direct interaction with pa, SIGNOR-178632 0.8 CDK1 protein P06493 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR form complex binding 9606 25603287 t lperfetto The central mitotic kinase, cyclin-dependent kinase-1 (human cdk1 is present through all stages of the cell cycle, but its activity is cell-cycle regulated by phosphorylation/dephosphorylation and cyclin binding.Cdk1-cyclin b phosphorylates ser/thr residues directly preceding pro; thus, it is classified as a proline-directed kinase. SIGNOR-205593 1 TACR1 protein P25103 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256919 0.2 NFE2 protein Q16621 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000426 16287851 f Regulation of expression miannu NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells. SIGNOR-251839 0.493 SLC9A2 protein Q9UBY0 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265601 0.8 vincaleukoblastine sulfate chemical CHEBI:9984 ChEBI TUBD1 protein Q9UJT1 UNIPROT down-regulates activity chemical inhibition 9606 15579115 t miannu Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. SIGNOR-259257 0.8 SNAPIN protein O95295 UNIPROT SNAP25 protein P60880 UNIPROT up-regulates activity binding 9606 BTO:0000793 18167355 t miannu In the present study, we used yeast two-hybrid analysis to identify a new binding partner of torsinA, the SNARE-associated protein snapin. We have reported that snapin shows a robust interaction with wild type and mutant torsinA. we have demonstrated that this portion of torsinA and/or the adjacent linker region has the additional role of recruiting snapin. we found that snapin, which binds SNAP-25 (synaptosome-associated protein of 25,000 Da) and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild type and mutant torsinA. SIGNOR-261171 0.6 WNT5A protein P41221 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 22773843 t areggio Purified human RYK binds to mouse Wnt1, 3a and 5a expressed in HEK293 cells. Separate experiments show that human RYK also immunopreciptitates human VANGL2 when the proteins are co-expressed in HEK293 cells. SIGNOR-258970 0.776 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide chemical CHEBI:131156 ChEBI CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190203 0.8 TAC1 protein P20366 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity 35045339 f lperfetto Social touch-like tactile stimulation activates a tachykinin 1-oxytocin pathway to promote social interactions|Functionally, activation of PVH-projecting Tac1+ neurons increases firing of oxytocin neurons, promotes social interactions, and increases preference for the social touch context, whereas reducing activity of Tac1+ neurons abolishes ST-induced oxytocin neuronal firing. SIGNOR-268576 0.575 PSMB8 protein P28062 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization 9606 BTO:0003445 19443843 t Gianni Surprisingly, siRNA knockdown of PSMB8 (LMP7), an ‘immunoproteasome’ component, reversed IFNγ-induced sensitivity to Fas ligation and prevented Fas/IFNγ-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-XL. Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-XL levels after IFNγ treatment SIGNOR-261974 0.2 PTPRB protein P23467 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1356 YVHVNATyVNVKCVA 9606 21454675 t Receptor-type protein tyrosine phosphatase beta (RPTP-beta) directly dephosphorylates and regulates hepatocyte growth factor receptor (HGFR/Met) function.|Expression of RPTP-β in primary human keratinocytes reduces both basal and HGF-induced Met phosphorylation at tyrosine 1356 and inhibits downstream MEK1/2 and Erk activation SIGNOR-248440 0.372 ACOT8 protein O14734 UNIPROT succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI down-regulates quantity chemical modification 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271810 0.8 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Thr305 TDAATMKtFCGTPEY 9606 18160256 t llicata Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248611 0.473 IKBKE protein Q14164 UNIPROT CDK2AP1 protein O14519 UNIPROT unknown phosphorylation Ser46 LSDYGPPsLGYTQGT -1 22427660 t lperfetto CDK2AP1 is phosphorylated at a conserved Ser-46 site in the N-terminal "intrinsically disordered" region by IkappaB kinase epsilon. SIGNOR-264780 0.2 NDN protein Q99608 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates activity binding 10090 BTO:0000920 24392139 t lperfetto Necdin interacts with E2F transcription factors and suppresses E2F1-dependent transcriptional activation of the cyclin-dependent kinase Cdk1 gene. Here we show that necdin serves as a suppressor of NPC proliferation in the embryonic neocortex. SIGNOR-253382 0.584 GRM1 protein Q13255 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264347 0.7 LRRK2 protein Q5S007 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 23754980 t gcesareni Subsequent assays confirmed a direct interaction between the lrrk2 roccor domain and all three human dvl proteins, these data are consistent with a role for lrrk2 in the activation of canonical wnt signaling bringing dvl proteins to cellular membranes. SIGNOR-202187 0.492 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT down-regulates quantity by destabilization phosphorylation Ser144 DSPALEVsDSESDEA 9606 BTO:0000567 10618498 t llicata Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo SIGNOR-251040 0.312 GATA3 protein P23771 UNIPROT ERG protein P11308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21536859 f miannu We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. SIGNOR-253920 0.2 AMPK complex SIGNOR-C15 SIGNOR CHKA protein P35790 UNIPROT up-regulates activity phosphorylation Ser279 KKLHKLLsYNLPLEL 9606 BTO:0000527 34929314 t lperfetto Glucose deprivation induces the binding of choline kinase α2 (CHKα2) to lipid droplets, followed by a continuous PTMs to promote lipolysis of lipid droplets, which are in turn mediated by AMPK-dependent CHKα2 Serine 279 phosphorylation and KAT5-dependent CHKα2 Lysine 247 acetylation. SIGNOR-267647 0.2 RPS6KB1 protein P23443 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017876 t llicata Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation. SIGNOR-176862 0.658 TAF4 protein O00268 UNIPROT ATF7 protein P17544 UNIPROT down-regulates activity binding 9534 BTO:0004055 15735663 t miannu These results not only demonstrate an interaction between ATF7 and TAF4 but also indicate, as in the case of TAF12 (see Figure 3e), that no additional cellular component is required for this binding. They also suggest that TAF4 may interfere with the formation of ATF7–TAF12 subcomplexes, thereby inhibiting ATF7-induced transactivation. SIGNOR-225300 0.406 ID1 protein P41134 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR down-regulates activity binding 10090 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241128 0.572 SLC27A2 protein O14975 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264462 0.7 SOX17 protein Q9H6I2 UNIPROT SOX17/POU5F1 complex SIGNOR-C451 SIGNOR form complex binding 23474895 t SimoneGraziosi Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm|We show that Sox17 partners with Oct4 and binds to a unique ‘compressed' Sox/Oct motif that earmarks endodermal genes. This is in contrast to the pluripotent state where Oct4 selectively partners with Sox2 at ‘canonical' binding sites. SIGNOR-269220 0.627 CDK1 protein P06493 UNIPROT RCC1 protein P18754 UNIPROT up-regulates activity phosphorylation Ser2 sPKRIAKR -1 15014043 t miannu Human RCC1 is phosphorylated on Ser 2 and Ser 11 in mitosis by Cdc2 kinase. We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of human RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. SIGNOR-262701 0.517 PRKCG protein P05129 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates phosphorylation Thr603 PCCIVTStYGWTANM 9606 24117238 t lperfetto Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_, and, more interestingly, this threonine residue set serves as a 'phosphorylation switch' for hsp90_ binding or release of pkc_. Moreover, phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity. SIGNOR-202820 0.26 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1763 TPTSPSYsPTSPSYS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248789 0.442 PFAS protein O15067 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure. SIGNOR-267312 0.8 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser249 AVIPINGsPRTPRRG 9606 1756735 t lperfetto The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2. SIGNOR-21548 0.675 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000763 12193595 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-91734 0.738 CNTF protein P26441 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 9143707 t gcesareni Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2. SIGNOR-47991 0.669 EGFR protein P00533 UNIPROT PLD2 protein O14939 UNIPROT up-regulates activity phosphorylation Tyr179 RLLTMSFyRNYHAMT 9606 9837959 t llicata Using transiently transfected human embryonic kidney fibroblasts (HEK293), we demonstrate here that PLD1 activity, and to a lesser extent PLD2 activity, is stimulated in response to epidermal growth factor (EGF). PLD2, but not PLD1, associates with the EGF receptor in a ligand-independent manner and becomes tyrosine-phosphorylated upon EGF receptor activation. Tyrosine 11 (Tyr-11) of PLD2 was identified as the specific phosphorylation site. Mutation of this residue to phenylalanine enhanced basal activity almost 2-fold SIGNOR-251095 0.531 AKT proteinfamily SIGNOR-PF24 SIGNOR DOCK6 protein Q96HP0 UNIPROT up-regulates activity phosphorylation Ser1194 GQRSRLAsMLDSDTE 23462102 t lperfetto Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching SIGNOR-275667 0.2 NEDD4 protein P46934 UNIPROT SAG protein P10523 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25216516 t miannu Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. degradation.  SIGNOR-272843 0.381 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR MECOM protein Q03112 UNIPROT up-regulates quantity by expression methylation 10090 BTO:0001271 22553314 t irozzo We hypothesize, based on our ChIP data, that MLL-AF9 up-regulates EVI1 transcription via H3K79 methylation, which is known to be a major gene regulatory mechanism used by some MLL-fusion proteins in leukemia. SIGNOR-255858 0.2 CHEK1 protein O14757 UNIPROT ERRFI1 protein Q9UJM3 UNIPROT down-regulates activity phosphorylation Ser251 RRLRRSHsGPAGSFN -1 22505024 t miannu Our results suggest that Chk1 phosphorylates Mig-6 on Ser 251, resulting in the inhibition of Mig-6, and that Chk1 acts as a positive regulator of EGF signalling. This is a novel function of Chk1. SIGNOR-276411 0.332 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 3930339 t ulcerative colitis gcesareni SIGNOR-251702 0.8 PRKDC protein P78527 UNIPROT LIG4 protein P49917 UNIPROT down-regulates phosphorylation Ser668 DVEFCVMsGTDSQPK 9606 15194694 t lperfetto Using tandem mass spectrometry, we identified a dna-pk phosphorylation site at thr-650 in human lig4 and a potential second phosphorylation site at ser-668 or ser-672. Phosphorylation of lig4 per se was not required for lig4 dna end joining activity. Substitution of these amino acids with alanine, individually or in combination, led to changes in lig4 protein stability of mouse lig4. The phosphomimetic mutation s650d returned lig4 stability to that of the wild-type protein. Furthermore dna-pk was found to negatively regulate lig4 protein stability. SIGNOR-125869 0.8 POU5F1 protein Q01860 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 19968627 f miannu p21 protein levels were repressed by Oct-4 and were induced by the down-regulation of Oct-4 in ZHBTc4 ES cells. SIGNOR-255043 0.411 XRCC4 protein Q13426 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 10854421 f miannu The DNA-dependent protein kinase (DNA-PK), consisting of Ku and the DNA-PK catalytic subunit (DNA-PKcs), and the DNA ligase IV-XRCC4 complex function together in the repair of DNA double-strand breaks by non-homologous end joining. SIGNOR-264530 0.7 MED14 protein O60244 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266676 0.832 RET protein P07949 UNIPROT DOK5 protein Q9P104 UNIPROT up-regulates binding 9606 11470823 t gcesareni Dok-4 and dok-5 enhance c-ret-dependent activation of mitogen-activated protein kinase SIGNOR-109516 0.608 QRICH1 protein Q2TAL8 UNIPROT IARS1 protein P41252 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269406 0.2 AP-2 complex complex SIGNOR-C245 SIGNOR AAK1 protein Q2M2I8 UNIPROT up-regulates activity binding 10116 BTO:0000142 15496985 t Giorgia We therefore characterised protein ligands using liquid chromatography tandem mass spectrometry (LC‐MS/MS) and confirmed this using Western blotting to recognise both major and minor bands. Some of the more minor interactors are very strongly enriched (AAK, auxilin, Dab2, eps15, epsin1 and synaptojanin170). All these enriched proteins have multiple copies of short alpha‐appendage interaction motifs SIGNOR-260393 0.641 ATP(4-) smallmolecule CHEBI:30616 ChEBI P2RY4 protein P51582 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257564 0.8 methoxamine chemical CHEBI:6839 ChEBI ADRA1A protein P35348 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258455 0.8 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Ser444 GKDSATTsTLSKDSL 9606 BTO:0000567 34198826 t miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. SIGNOR-276664 0.252 PAFAH1B1 protein P43034 UNIPROT DYNC1H1 protein Q14204 UNIPROT up-regulates activity binding 10090 BTO:0000938 11163259 t miannu We demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL. LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex SIGNOR-252158 0.883 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser641 GKVYGKTsHLRAHLR 9606 16943418 t gcesareni The hdac inhibitor tsa-induced cell-specific phosphatase release from the promoter, which serves as an 'on' mechanism for sp1 phosphorylation by phosphatidylinositol 3-kinase/protein kinase czeta (pi3k/pkczeta) at ser641, leading to p107 repressor derecruitment and lhr transcriptional activation. SIGNOR-149287 0.497 LPAR3 protein Q9UBY5 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257406 0.412 FYN protein P06241 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268207 0.619 USP9X protein Q93008 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates deubiquitination Lys519 DYPRQSIkETPCWIE 9606 19135894 t gcesareni Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4. SIGNOR-183285 0.633 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI L-alanine zwitterion smallmolecule CHEBI:57972 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-268122 0.8 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1924 SPTSPKYsPTSPTYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203596 0.769 MAPK3 protein P27361 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 BTO:0000150 18676833 t fstefani We then showed that erk could phosphorylate mcl-1 at two consensus residues, thr 92 and 163, which is required for the association of mcl-1 and pin1, resulting in stabilization of mcl-1. SIGNOR-179812 0.448 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr200 LPLLVQRtIARTIVL -1 8576253 t giulio giuliani From our present data, it is not easy to deduce the mechanistic significance of serine 172 and threonine 176 of TŒ≤R-I in TGF-Œ≤ signaling. Although it was reported that TGF-Œ≤-induced phosphorylation of these residues was not detected in vivo(22), it is still possible that TŒ≤R-II may phosphorylate these residues as minor phosphorylation site(s). SIGNOR-255962 0.711 NOX4 protein Q9NPH5 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264717 0.7 FHOD1 protein Q9Y613 UNIPROT ACTB protein P60709 UNIPROT up-regulates quantity by stabilization binding 9606 14576350 t miannu Fhos, a mammalian formin, directly binds to F-actin via a region N-terminal to the FH1 domain and forms a homotypic complex via the FH2 domain to promote actin fiber formation SIGNOR-276613 0.35 IL4R protein P24394 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica Irs-1 and a homologous protein, irs-2 (also known as 4-phosphotyrosine substrate), are recruited to phosphorylated y497 of IL-4R After ligand binding, leading to phosphorylation and activation of irs-1 and irs-2. SIGNOR-100768 0.547 MAPK10 protein P53779 UNIPROT STMN2 protein Q93045 UNIPROT down-regulates phosphorylation Ser62 ELILKPPsPISEAPR 9606 11718727 t gcesareni We demonstrate that purified scg10 can be phosphorylated by two subclasses of mitogen-activated protein (map) kinases, c-jun n-terminal/stress-activated protein kinase (jnk/sapk) and p38 map kinase;jnk3/sapkbeta phosphorylation occurs at ser-62 and ser-73, residues that result in reduced microtubule-destabilizing activity for scg10. SIGNOR-112110 0.455 SATB1 protein Q01826 UNIPROT SPARC protein P09486 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 17343824 f miannu In this study, a SATB1 eukaryotic expression plasmid was transfected into the human erythroleukemia K562 cell line and individual clones that stably over-expressed the SATB1 protein were isolated. Microarray analysis revealed that hundreds of genes were either up- or down-regulated in the SATB1 over-expressing K562 cell lines. One of these was the extra-cellular matrix glycoprotein, SPARC (human secreted protein acidic and rich in cysteine). siRNA knock-down of SATB1 also reduced SPARC expression, which was consistent with elevated SPARC levels in the SATB1 over-expressing cell line. SIGNOR-255128 0.2 TLN1 protein Q9Y490 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR up-regulates activity binding 9606 BTO:0000132 16418530 t lperfetto In response to agonist stimulation, the alphaIIbbeta3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. This process contributes to both normal hemostasis and thrombosis. Activation of alphaIIbbeta3 is believed to occur in part via engagement of the beta3 cytoplasmic tail with talin; however, the role of the alphaIIb tail and its potential binding partners in regulating alphaIIbbeta3 activation is less clear. We report that calcium and integrin binding protein 1 (CIB1), which interacts directly with the alphaIIb tail, is an endogenous inhibitor of alphaIIbbeta3 activation; overexpression of CIB1 in megakaryocytes blocks agonist-induced alphaIIbbeta3 activation, whereas reduction of endogenous CIB1 via RNA interference enhances activation. CIB1 appears to inhibit integrin activation by competing with talin for binding to alphaIIbbeta3, thus providing a model for tightly controlled regulation of alphaIIbbeta3 activation. SIGNOR-253358 0.686 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr162 QLAAKLAyLQILSEE 9606 BTO:0001282 16373505 t PKR autophosphorylates on Y101, Y162, and Y293. unctional characterization of Y101F and Y162F mutants revealed that phosphorylation at these sites is needed for efficient dsRNA binding and kinase dimerization and activation. SIGNOR-251113 0.2 MAPKAPK3 protein Q16644 UNIPROT HSPB1 protein P04792 UNIPROT unknown phosphorylation Ser15 FSLLRGPsWDPFRDW -1 8774846 t miannu MAPKAP kinase-3 and MAPKAP kinase-2 phosphorylated peptide substrates with similar kinetic constants and phosphorylated the same serine residues in HSP27 at the same relative rates.The three serine residues in HSP27 phosphorylated by MAPKAPK2 were also phosphorylated at the same relative rates by MAPKAP-K3 (Ser-82>>Ser-78 >Ser-15) SIGNOR-250159 0.672 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000142 10226025 t acerquone We have partially purified a kinase from brain extract that phosphorylates Ser473 of PKBalpha in a PtdIns(3,4,5)P3-dependent manner and that is immunoprecipitated with PDK1 antibodies. SIGNOR-67367 0.737 NLRP1 inflammasome complex SIGNOR-C224 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256380 0.2 L-thyroxine(1-) chemical CHEBI:60302 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258051 0.8 2-N,6-N-Bis(2,3-dihydroxy-N-benzoyl)-L-serine amide chemical CHEBI:1219 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation -1 7576010 t miannu D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole. SIGNOR-258437 0.8 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT down-regulates activity phosphorylation Ser87 VRPSDEDsSSLESAA -1 12852856 t lperfetto Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction SIGNOR-103352 0.688 PP1 proteinfamily SIGNOR-PF54 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 9606 14633703 t lperfetto Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-264659 0.452 CEP290 protein O15078 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 18694559 f miannu CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110 SIGNOR-252147 0.7 EEF1B complex complex SIGNOR-C460 SIGNOR EEF1A1P5 protein Q5VTE0 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. SIGNOR-269389 0.2 HTR1A protein P08908 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257088 0.305 CSNK1A1 protein P48729 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-250785 0.29 HIPK2 protein Q9H2X6 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 21715331 t lperfetto Homeodomain-interacting protein kinase-2 stabilizes p27(kip1) by its phosphorylation at serine 10 and contributes to cell motility SIGNOR-174617 0.256 PAK3 protein O75914 UNIPROT PAK3 protein O75914 UNIPROT up-regulates activity phosphorylation Ser154 VNNQKYMsFTSGDKS -1 11278486 t miannu Both in vivo and in vitro analyses demonstrate that, although most phosphorylation events in the PAK N-terminal regulatory domain play no direct role in activation, a phosphorylation of alphaPAK serine 144 or betaPAK serine 139, which lie in the kinase inhibitory domain, significantly contribute to activation.  SIGNOR-250245 0.2 MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Thr530 YLSELPPtPLHVSED 9606 20027304 t This phosphorylation increased sirt1 nuclear localization gcesareni Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53. SIGNOR-162322 0.62 CCL3 protein P10147 UNIPROT CCR5 protein P51681 UNIPROT up-regulates activity binding 10090 15075201 t lperfetto The purpose of this study was to determine whether certain chemokines, which are highly expressed in injured skeletal muscle, are involved in the repair and functional recovery of the muscle after traumatic injury. In wild-type control mice, mRNA transcripts of macrophage inflammatory protein (MIP)-1􏰂, MIP-1􏰃, and monocyte chemoattractant protein (MCP)-1 as well as their major receptors, CCR5 and CCR2, increased after freeze injury and gradu- ally returned to control (uninjured) levels by 14 days. SIGNOR-251724 0.738 CDH22 protein Q9UJ99 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265860 0.338 SGK1 protein O00141 UNIPROT NDRG2 protein Q9UN36 UNIPROT up-regulates phosphorylation Thr348 GNRSRSRtLSQSSES 9606 BTO:0000567 BTO:0000887;BTO:0001103;BTO:0000763 15461589 t llicata Sgk1 phosphorylated ndrg2 at thr330, ser332 and thr348 in vitro. for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, the phosphorylation of thr348 by sgk1 may prime for phosphorylation at ser344 SIGNOR-129680 0.404 MAPK1 protein P28482 UNIPROT MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation Ser21 KRTSSPRsPPSSSEI 9606 25728771 t lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation SIGNOR-264775 0.2 MECP2 protein P51608 UNIPROT DLX5 protein P56178 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 19195802 f Expression of DLX5 is controlled by MECP2, and defect in MECP2 induced an over-expression of DLX5 in lymphocytes as well as in the brain SIGNOR-254034 0.387 HIF1A protein Q16665 UNIPROT TM9SF4 protein Q92544 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001545 25961573 t miannu Here, we investigated the impact of hypoxia on TM9SF4 expression in leukemic cells and identified TM9SF4 as a direct target of HIF-1α, downregulated in these cells by hypoxia. Then, we found that the hypoxia-mediated downregulation of TM9SF4 expression is associated with a decrease of cell adhesion of leukemic cells to fibronectin, thus demonstrating that human TM9SF4 is a new molecule involved in leukemic cell adhesion. SIGNOR-266705 0.2 CABIN1 protein Q9Y6J0 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates 9606 17172641 f gcesareni Thus, cabin1 recruits chromatin-modifying enzymes, both histone deacetylases and a histone methyltransferase, to repress mef2 transcriptional activity. SIGNOR-151205 0.656 P300/PCAF complex SIGNOR-C7 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates binding 9606 BTO:0000150 15009097 t lperfetto Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo. SIGNOR-217233 0.676 IFNLR1 protein Q8IU57 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15120645 t gcesareni Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain. SIGNOR-124480 0.771 INSR protein P06213 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates activity phosphorylation Tyr398 ARVKEEGyELPYNPA 10029 BTO:0000246 11551902 t Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398. p62(dok) is a direct substrate for the IR tyrosine kinase and that phosphorylation at Tyr(362) and Tyr(398) plays an essential role for p62(dok) to interact with its effectors and negatively regulate the insulin signaling pathway. SIGNOR-251308 0.543 captopril chemical CHEBI:3380 ChEBI ACE2 protein Q9BYF1 UNIPROT down-regulates activity chemical inhibition -1 9187274 t Monia The interaction of captopril at one active site of wild-type ACE impeding substrate interaction with the other active site. SIGNOR-261069 0.8 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273081 0.635 CREB5 protein Q02930 UNIPROT CFB protein P00751 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002809 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253802 0.2 TFEB protein P19484 UNIPROT APOA4 protein P06727 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) SIGNOR-276783 0.2 TTK protein P33981 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 19332559 t llicata Ttk/hmps1 mediates the p53-dependent postmitotic checkpoint by phosphorylating p53 at thr18. phosphorylation at thr18 enhances p53-dependent activation of not only p21 but also lats2, two mediators of the postmitotic checkpoint. SIGNOR-184931 0.513 SRCAP protein Q6ZRS2 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 20432434 t miannu The SNF2-related CBP activator protein (SRCAP) serves as a coactivator for several nuclear receptors including the androgen receptor (AR). SRCAP is an ATPase that is the core subunit of a large multiprotein complex and was shown to incorporate the histone variant H2A.Z into nucleosomes. In this report, we demonstrate that SRCAP is expressed in the epithelium of normal prostate and in prostate carcinoma cells, and is associated with AR in the nucleus SIGNOR-255221 0.42 ETV3 protein P41162 UNIPROT DDX20 protein Q9UHI6 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 22028472 t miannu ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation. SIGNOR-262779 0.729 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser937 SNLTRSSsSDSIHSV 9606 BTO:0000150 19567672 t llicata Pkd-mediated phosphorylation of serines 937 and 978 regulates ssh1l subcellular localization by binding of 14-3-3 proteins 14-3-3 proteins associate with ssh1l when phosphorylated at serines 937 and 978, thereby sequestering ssh1l in the cytoplasm and preventing translocation of the phosphatase to f-actin_rich membrane protrusions SIGNOR-186467 0.492 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192620 0.8 PPP2CA protein P67775 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates dephosphorylation Ser526 MSGTGMRsVTGTPYW 9606 20448038 t lperfetto Pp2ac binds to the phosphorylated mekk3 and subsequently dephosphorylate mekk3 at thr-516, ser-520, and ser-526 residues to terminate mekk3-mediated ikkbeta/Nf-kappaB Activation SIGNOR-165233 0.379 DIO proteinfamily SIGNOR-PF83 SIGNOR iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 34674502 t scontino Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule.¬† SIGNOR-267045 0.8 Daunorubicin hydrochloride chemical CHEBI:31456 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 1963303 t miannu DNA topoisomerase II as the primary target of anti-tumor anthracyclines.Such studies have also given evidence of the peculiar features of the drug interference with DNA topoisomerase II activity. In contrast to other cytotoxic topoisomerase II inhibitors (acridines, epipodophyllotoxins), anthracyclines produce persistent DNA cleavable complexes. This property is more evident with doxorubicin derivatives than with daunorubicin derivatives. SIGNOR-259322 0.8 5-chloro-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine chemical CHEBI:91338 ChEBI ALK protein Q9UM73 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207132 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 BTO:0004249 23125836 f miannu PKA is activated by Group I mGluRs in ACC neurons. The cAMP signaling pathway contributes to the activity-dependent synaptic plasticity in the anterior cingulate cortex SIGNOR-264961 0.7 JAK2 protein O60674 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000801 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249493 0.695 trichostatin A chemical CHEBI:46024 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257937 0.8 CLU protein P10909 UNIPROT IKBKB protein O14920 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001321 20068069 t miannu CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation. SIGNOR-271433 0.2 MAPK6 protein Q16659 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 BTO:0000551 22505454 t gcesareni Here, we report that erk3 interacted with and phosphorylated steroid receptor coactivator 3 (src-3), an oncogenic protein overexpressed in multiple human cancers at serine 857 (s857) SIGNOR-196957 0.459 PLK1 protein P53350 UNIPROT TNKS protein O95271 UNIPROT up-regulates quantity by stabilization phosphorylation Thr930 LAHGADPtMKNQEGQ 9606 BTO:0000567 21818122 t miannu Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends.  SIGNOR-276243 0.438 CRHR1 protein P34998 UNIPROT POMC protein P01189 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 23504413 f lperfetto CRH, as a principal mediator of endocrine stress response, activates the HPA axis (Hypothalamic–pituitary–adrenal axis) by binding to the CRHR1 in the anterior pituitary. This, through a cascade of reactions, increases the expression of proopiomelanocortin (POMC) gene and the subsequent release of POMC-derived peptides, adrenocorticotropic hormone (ACTH) and β-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal cortex (Vale et al. 1981). SIGNOR-268612 0.639 SNX6 protein Q9UNH7 UNIPROT IGF2R protein P11717 UNIPROT down-regulates quantity binding 9606 BTO:0000567 32150533 t miannu Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures. SIGNOR-269443 0.371 CREB1 protein P16220 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 21902831 f gcesareni Chen et al. showed that phosphorylated creb is present at high levels in cells of the dermomyotome that express pax3, myod and myf5 and that this phosphorylation is critical for the induction of these genes. SIGNOR-176536 0.473 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR STAT5A protein P42229 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002882 8642285 t irozzo Phosphorylation of STAT1 and STAT5 was directly due to the tyrosine kinase activity of Bcr/Abl since it could be activated or deactivated by temperature shifting of cells expressing the Bcr/Abl ts mutant.These data suggest that STATs can be activated directly by Bcr/Abl, possibly bypassing JAK family kinase activation. SIGNOR-255813 0.2 PIK3CG protein P48736 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates binding 9606 9768361 t gcesareni Recent reports have also shown that the phosphoinositide-dependent protein kinase-1 (pdk-1), which binds with high affinity to the pi 3-kinase lipid product phosphatidylinositol-3,4,5-trisphosphate (ptdins-3,4,5-p), phosphorylates and potently activates two other pi 3-kinase targets, the protein kinases akt/pkb and p70s6k. SIGNOR-60567 0.617 SAGA complex complex SIGNOR-C465 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269636 0.2 JAK1 protein P23458 UNIPROT IFNGR2 protein P38484 UNIPROT up-regulates activity phosphorylation 9606 19041276 t lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249491 0.646 F2RL1 protein P55085 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254839 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EWSR1 protein Q01844 UNIPROT unknown phosphorylation 9606 19076070 t inferred from 70% family members lperfetto Here we report that ews and ews-fli1 become phosphorylated at thr79 in the n-terminal domain in response to mitogens or dna damage. Mitogen-induced phosphorylation of ews and ews-fli1 was weak and catalysed by erk1 (extracellular signal-regulated kinase 1) and erk2. SIGNOR-270172 0.2 BBC3 protein Q9BXH1 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 1557433 t gcesareni The first Helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma SIGNOR-20064 0.503 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2049 DAAVVLLkNGANKDM 9606 17636029 t gcesareni This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60. SIGNOR-156915 0.424 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB5 protein P18084 UNIPROT up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259005 0.2 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1931 SPTSPTYsPTSPKGS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273074 0.635 KCNS1 protein Q96KK3 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 10029 BTO:0000246 10484328 t miannu We describe the cloning and characterization of the first human members, hKv9.1 and hKv9.3, of the electrically silent delayed-rectifying-like K+ channel subfamily. SIGNOR-269449 0.8 POGLUT1 protein Q8NBL1 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates glycosylation 9606 22872643 t O-glycosilation gcesareni O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus. SIGNOR-198713 0.59 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-262996 0.784 MRPL53 protein Q96EL3 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262345 0.648 PTH1R protein Q03431 UNIPROT SLC34A1 protein Q06495 UNIPROT down-regulates quantity 28363951 f lperfetto PTH inhibits reabsorption of phosphate from the glomerular filtrate in RPT by decreasing the abundance of sodium-phosphate co-transporters NPT2a and NPT2c on the apical membrane, thus enhancing renal phosphate excretion SIGNOR-270556 0.313 NRL protein P54845 UNIPROT RBP3 protein P10745 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 f miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. SIGNOR-253818 0.381 CCND3 protein P30281 UNIPROT Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR up-regulates 10090 BTO:0000165 21898542 f gcesareni Our findings suggest that cyclin D3 primes myoblasts for differentiation by enhancing muscle specific gene expression and cell cycle exit SIGNOR-241960 0.7 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr280 HRFHPEPyGLEDDQR -1 11382764 t lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 SIGNOR-246492 0.92 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Phe43 ATLDPRSfLLRNPND -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. SIGNOR-263570 0.883 MAPK14 protein Q16539 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR up-regulates activity phosphorylation 10029 BTO:0005787 20887952 t The chromatin redistribution of PRC2 in differentiating SCs is regulated by the p38a kinase, which promotes the formation of a complex containing p38a, EZH2, and YY1, via direct phosphorylation of EZH2. SIGNOR-253599 0.332 MDM2 protein Q00987 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001109 10640274 t miannu We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1alpha subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation. SIGNOR-271385 0.628 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation Tyr139 EKLRVLGyNQNGEWS -1 34144039 t miannu  PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. SIGNOR-277302 0.308 CSNK2A1 protein P68400 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Ser267 PPTTSSDsEEEQEDE 9606 BTO:0000007 22025562 t miannu  Together, our findings provide evidence for CK1α-mediated destruction of c-Myc and identify c-Myc S252 as a crucial CK1α phosphorylation site for c-Myc degradation. SIGNOR-276388 0.518 MAPK8 protein P45983 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation 9606 17525747 t gcesareni Our studies revealed a novel mechanism in which phosphorylation of jnk2 is mediated by jnk1 before phosphorylation of p53, and then p53 is directly phosphorylated by jnk2 at ser6. SIGNOR-155205 0.575 MYC protein P01106 UNIPROT CDC25A protein P30304 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11154267 t lperfetto Expression of Cdc25A is transcriptionally regulated by Myc and E2F-1 , both of which are expressed in MCF-7 cells in response to estrogen SIGNOR-245465 0.612 GNAQ protein P50148 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 17606614 t gcesareni Recently, the dbl-family guanine nucleotide exchange factor (gef) p63rhogef/geft has been described as a novel mediator of galpha(q/11) signaling to rhoa based on its ability to synergize with galpha(q/11) resulting in enhanced rhoa signaling in cells. SIGNOR-156534 0.593 CREB5 protein Q02930 UNIPROT TNFRSF11B protein O00300 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253812 0.2 CAMKK1 protein Q8N5S9 UNIPROT CAMK4 protein Q16566 UNIPROT up-regulates phosphorylation Thr200 EHQVLMKtVCGTPGY 9606 15143065 t lperfetto In response to an increase in intracellular Ca2+, CaMKIV binds Ca2+/CaM and becomes phosphorylated on T200 by CaMKK. SIGNOR-124732 0.604 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity precursor of 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-268107 0.8 ARHGEF7 protein Q14155 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 17562871 f gcesareni We propose that the association of plcgamma1 with complexes containing git1 and beta-pix is essential for its role in integrin-mediated cell spreading and motility. As a component of this complex, plcgamma1 is also involved in the activation of cdc42 and rac1. SIGNOR-155744 0.622 DNAJC3 protein Q13217 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT down-regulates activity binding 9606 BTO:0000567 25329545 t gcesareni The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK SIGNOR-246201 0.604 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI DIO2 protein Q92813 UNIPROT up-regulates quantity by expression 9606 29892818 f scontino Dio2 is a cAMP responsive gene. Thus, any signaling pathway or molecule that increases cAMP concentration will stimulate D2 activity. SIGNOR-267281 0.8 PRRX1 protein P54821 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221899 0.311 CEBPD protein P49716 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 23028973 f CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. SIGNOR-254060 0.275 CDK1 protein P06493 UNIPROT TK1 protein P04183 UNIPROT down-regulates phosphorylation Ser13 LPTVLPGsPSKTRGQ 9606 14697231 t gcesareni Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase. SIGNOR-120368 0.52 Complement C1 complex complex SIGNOR-C309 SIGNOR C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Gly1446 TPLQLFEgRRNRRRR -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263439 0.629 isoleucine smallmolecule CHEBI:24898 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264749 0.7 okadaic acid chemical CHEBI:44658 ChEBI STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates 9606 23493077 f inferred from 70% of family members gcesareni Okadaic acid has been frequently used to enhance the phosphorylation of mst1 and mst2 and to trigger the activation of the hippo pathway. SIGNOR-269947 0.8 N-tert-butyl-3-[[5-methyl-2-[4-[2-(1-pyrrolidinyl)ethoxy]anilino]-4-pyrimidinyl]amino]benzenesulfonamide chemical CHEBI:91408 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258301 0.8 TARS1 protein P26639 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 25824639 t miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. SIGNOR-270505 0.8 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser301 SSSPNNLsPTGWSQP 10090 BTO:0000944 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-249443 0.616 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273062 0.635 RALGAPB protein Q86X10 UNIPROT RalGAP1 complex SIGNOR-C468 SIGNOR form complex binding 10090 BTO:0000011 21148297 t miannu Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. SIGNOR-269792 0.422 TNF protein P01375 UNIPROT TNFRSF21 protein O75509 UNIPROT up-regulates binding 9606 BTO:0000142 9714541 t gcesareni We report the identification and initial characterization of dr6, a new member of the tnf receptor family possessing a cytoplasmic death domain. SIGNOR-59745 0.343 AT-406 chemical CID:25022340 PUBCHEM BIRC2 protein Q13490 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189954 0.8 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192904 0.8 CDK6 protein Q00534 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr401 SKALRIStPLTGVRY 9606 BTO:0001938 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. all three residues selectively targeted by cdk4(6), t401 (n-terminus), s672 (spacer region) and s1035 (c-terminus) SIGNOR-104719 0.667 FAM107A protein O95990 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation SIGNOR-81800 0.2 CSNK2A1 protein P68400 UNIPROT ANP32B protein Q92688 UNIPROT up-regulates phosphorylation Thr244 GEKRKREtDDEGEDD 9606 17178712 t gcesareni Here, we are able to report that casein kinase 2 (ck2) phosphorylates april on residue threonine244 (thr(244)) and demonstrate that the ck2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes cd83 expression in activated jurkat t cells by interfering with the nucleocytoplasmic translocation of cd83 mrna SIGNOR-151261 0.235 MIB1 protein Q86YT6 UNIPROT MIB1 protein Q86YT6 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 12351649 t miannu The RING finger motifs of DIP-1 have E3 ligase activity that can auto-ubiquitinate DIP-1 in vitro. In vivo, DIP-1 is detected as a polyubiquitinated protein, suggesting that the intracellular levels of DIP-1 are regulated by the ubiquitin-proteasome system.  SIGNOR-272603 0.2 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser122 DQHLMKCsPAQLLCS 9606 SIGNOR-C17 10864927 t gcesareni Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-78416 0.852 PKA proteinfamily SIGNOR-PF17 SIGNOR PHF2 protein O75151 UNIPROT up-regulates activity phosphorylation Ser954 QKSKKKKsAKRKLTP 9606 BTO:0000007 21532585 t miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. Replacement of all of four serine residues by alanines (4SA: Ser 757/Ser 899/Ser 954/Ser 1056) fully abrogated PKA phosphorylation of PHF2 (Fig. 2h). SIGNOR-264512 0.2 degarelix chemical CHEBI:135961 ChEBI GNRHR protein P30968 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001033 22416801 t miannu  Two GnRH antagonists are currently available: abarelix and degarelix.  SIGNOR-259160 0.8 Temsirolimus chemical CHEBI:79699 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 21081844 t gcesareni Temsirolimus, an inhibitor of mammalian target of rapamycin (mtor) complex 1, is approved for the treatment of metastatic renal cell carcinoma (rcc). SIGNOR-169712 0.8 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT up-regulates activity phosphorylation Thr316 GTASSRKtLWNQELY -1 21880142 t miannu Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2.PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites. SIGNOR-266310 0.312 SRC protein P12931 UNIPROT TIAM1 protein Q13009 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 12810717 t gcesareni Tiam1 cooperated with src to induce activation of rac1 in vivo and the formation of membrane ruffles. SIGNOR-102354 0.643 MAK protein P20794 UNIPROT MAK protein P20794 UNIPROT up-regulates activity phosphorylation Thr157 LRSQPPYtDYVSTRW 9606 21986944 t Manara We conclude that dual phosphorylation on the TDY motif is crucial for MAK activity, and that the autokinase activity is required for this phosphorylation SIGNOR-260779 0.2 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Ser358 ELRKTQTsMSLGTTR 10090 24012422 t gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays SIGNOR-266427 0.743 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0001321 15659650 t lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-74835 0.783 PPP2CA protein P67775 UNIPROT PRKCB protein P05771 UNIPROT down-regulates activity dephosphorylation Thr500 WDGVTTKtFCGTPDY 10116 8749392 t Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme. SIGNOR-248620 0.434 DGC complex SIGNOR-C217 SIGNOR NRXN2 protein Q9P2S2 UNIPROT up-regulates activity binding 9606 BTO:0000142 11470830 t miannu In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan. SIGNOR-265448 0.285 BAZ1B protein Q9UIG0 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Tyr143 ATQASQEy 9606 19092802 t gcesareni We show that wstf phosphorylates tyr 142 of h2a.x, and that wstf activity has an important role in regulating several events that are critical for the dna damage response SIGNOR-182831 0.2 CDK5 protein Q00535 UNIPROT DLC1 protein Q96QB1 UNIPROT up-regulates activity phosphorylation Ser557 LEEFDVFsPKQDLVP 9606 BTO:0002181 25452387 t miannu The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin.  SIGNOR-276443 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Glu) smallmolecule CHEBI:29175 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270379 0.8 formestane chemical CHEBI:75172 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates activity chemical inhibition -1 7083195 t miannu Recently, it was discovered that 4-hydroxy-4-androstene-3,17-dione, 4-androstene-3,6,17-trione, and 1,4,6-androstatriene-3,17-dione, compounds previously reported to be competitive inhibitors of aromatase, cause a time-dependent loss of aromatase activity in human placental microsomes. SIGNOR-258407 0.8 ACSS3 protein Q9H6R3 UNIPROT acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI up-regulates quantity chemical modification 10843999 t lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. SIGNOR-271832 0.8 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-238804 0.509 CAMK2B protein Q13554 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 24117889 t lperfetto Camkii represses transcriptionally active beta-catenin to mediate acute ethanol neurodegeneration and can phosphorylate beta-catenin. Using targeted mutagenesis we identified camkii phosphorylation sites within human beta-catenin at t332, t472, and s552 SIGNOR-202825 0.293 TLR4 protein O00206 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 9606 28137827 t miannu Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation. SIGNOR-261930 0.438 clozapine chemical CHEBI:3766 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). SIGNOR-258835 0.8 VRK1 protein Q99986 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 9606 17938195 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni We show that histone h3 is phosphorylated by vaccinia-related kinase 1 (vrk1). Direct phosphorylation of thr3 and ser10 in h3 by vrk1 both in vitro and in vivo was observed. Loss of vrk1 activity was associated with a marked decrease in h3 phosphorylation during mitosis. SIGNOR-158436 0.2 ALK protein Q9UM73 UNIPROT STAT3 protein P40763 UNIPROT up-regulates binding 9606 BTO:0000785 16084951 t gcesareni Npm-alk has been shown to activate signal transducer and activator of transcription (stat) 3, a transcriptional regulator of cyclin d3.Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1. SIGNOR-139460 0.451 MAPK1 protein P28482 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser343 KSDCQPNsPTESCSS 9606 BTO:0000782;BTO:0000785 9649500 t gcesareni Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway. SIGNOR-58485 0.502 APP protein P05067 UNIPROT NAE1 protein Q13564 UNIPROT up-regulates activity binding 9606 BTO:0000590 25568892 t lperfetto Alzheimer's disease (AD) is the gradual loss of the cognitive function due to neuronal death. Currently no therapy is available to slow down, reverse or prevent the disease. Here we analyze the existing data in literature and hypothesize that the physiological function of the Amyloid Precursor Protein (APP) is activating the AppBp1 pathway and this function is gradually lost during the progression of AD pathogenesis. SIGNOR-251577 0.725 UBXN8 protein O00124 UNIPROT VCP protein P55072 UNIPROT down-regulates quantity relocalization 9606 21949850 t SARA The human protein named Rep8 or Ubxd6 as a new cofactor of p97. Rep8 tethers p97 to the ER membrane for efficient ER-associated degradation. SIGNOR-261002 0.535 PDYN protein P01213 UNIPROT OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258415 0.654 TP53 protein P04637 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates 9606 15073170 f gcesareni Rather, p53 expression stimulates the serine/threonine kinase ribosomal s6 kinase 1 (rsk1), which in turn phosphorylates the p65 subunit of nf-kb. SIGNOR-124038 0.365 FYN protein P06241 UNIPROT TXK protein P42681 UNIPROT up-regulates activity phosphorylation Tyr420 RYVLDDEyVSSFGAK 11353545 t lperfetto We further demonstrate that Rlk can be phosphorylated and activated by Src kinases, leading to a decrease in its half-life. A specific tyrosine in the activation loop of Rlk, Y420, is required for phosphorylation and activation, as well as for decreased stability, but is not required for lipid RAFT association. SIGNOR-249341 0.354 MIF protein P14174 UNIPROT CD74 protein P04233 UNIPROT up-regulates binding 9606 12782713 t miannu Mif binds to the extracellular domain of cd74, and cd74 is required for mif-induced activation of the extracellular signal-regulated kinase-1/2 map kinase cascade, cell proliferation, and pge2 production. SIGNOR-101526 0.724 PPM1F protein P49593 UNIPROT CAMK1 protein Q14012 UNIPROT down-regulates activity dephosphorylation 9606 11726284 t miannu Calmodulin-dependent protein kinase phosphatase (CaMKP) dephosphorylates and concomitantly deactivates multifunctional Ca(2+)/calmodulin-dependent protein kinases , such as CaMKI, CaMKII, and CaMKIV. SIGNOR-277111 0.474 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates activity phosphorylation Tyr246 SCGVDGDyEDAELNP 9606 BTO:0000007 8955135 t In the present study, we demonstrate that BCR Tyr-246 and at least one of the closely spaced tyrosine residues, Tyr-279, Tyr-283, and Tyr-289 (3Y cluster), are phosphorylated by FES both in vitro and in 32Pi-labeled cells. Co-expression of BCR and FES in human 293T cells stimulated the tyrosine autophosphorylation of FES. By contrast, tyrosine phosphorylation of BCR by FES suppressed BCR serine/threonine kinase activity toward the 14-3-3 protein and BCR substrate, BAP-1.  SIGNOR-251137 0.375 ADRA2B protein P18089 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257201 0.358 PRKCA protein P17252 UNIPROT PRKG1 protein Q13976 UNIPROT up-regulates phosphorylation Thr59 THIGPRTtRAQGISA 9606 12609995 t gcesareni Antibodies generated against phosphorylated threonine 58 were used to demonstrate phosphorylation in response to pma treatment of the cells with kinetics similar to vasodilator-stimulated phosphoprotein phosphorylation. A phospho-mimetic mutation at this site (t58e) generated a partially activated pkg that was more sensitive to cgmp levels. A phospho- mutation (t58a) revealed that this residue is important but not sufficient for pkg activation by pkc. SIGNOR-98803 0.35 CSNK1A1 protein P48729 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser82 GSSESTDsGFCLDSP 9606 20348946 t lperfetto Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a SIGNOR-164738 0.339 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val76 LTGKLTTvFLPIVYT -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263592 0.404 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 9606 10567572 t gcesareni G(2)/m-phase cells proved more susceptible to death signals, and phosphorylation of bcl-2 appeared to be responsible, as a ser70ala substitution restored resistance to apoptosis. We noted that ask1 and jnk1 were normally activated at g(2)/m phase, and jnk was capable of phosphorylating bcl-2.. SIGNOR-72125 0.564 BRCA1 protein P38398 UNIPROT TOP1 protein P11387 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002201 28415827 t miannu Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1. Taken together, we conclude that BRCA1 is the E3 ligase for topoI, and the rate of topoI proteasomal degradation determines CPT response. SIGNOR-277353 0.475 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates relocalization 9606 11062529 t gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-84041 0.613 GRIA4 protein P48058 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264950 0.8 ITGB6 protein P18564 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257724 0.472 RPS6KA3 protein P51812 UNIPROT TINF2 protein Q9BSI4 UNIPROT unknown phosphorylation Ser295 FPFRNLGsPTQVISK 9606 23977114 t lperfetto Phosphorylation of serines 295 and 330 appeared to be mediated, at least in part, by the mitotic kinase rsk2. The consequence of tin2 phosphorylation during mitosis remains to be determined SIGNOR-202532 0.35 RBCK1 protein Q9BYM8 UNIPROT BACH1 protein O14867 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 17682061 t miannu HOIL-1 bound Bach1 in vivo and thus stimulated its polyubiquitination in vitro. These results suggest that heme regulates the polyubiquitination of Bach1 and subsequent degradation and that HOIL-1 may function as an E3 ligase in this process. SIGNOR-236971 0.351 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000093 10581258 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-72703 0.764 GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268595 0.2 PRKCA protein P17252 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates phosphorylation Ser1360 VLRSPSGsQRPSVSD 9606 15121854 t lperfetto Egf stimulates a pkc-?-Dependent pathway that results in the phosphorylation of the ?4 Integrin subunit on serine residues and its redistribution to actin-rich structures together, these results highlight the importance of serine phosphorylation in regulating type ii hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of ?4, and argue for a key role for pkc-? In regulating these structures SIGNOR-124494 0.511 FYN protein P06241 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 16938345 t gcesareni Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk. SIGNOR-148931 0.739 sapitinib chemical CHEBI:132986 ChEBI SHC3 protein Q92529 UNIPROT down-regulates chemical inhibition 9606 BTO:0000551 20145185 t gcesareni In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. SIGNOR-163733 0.8 CSNK1A1 protein P48729 UNIPROT CBX4 protein O00257 UNIPROT down-regulates quantity by destabilization phosphorylation Thr437 ARSISTPtCLGGSPA 9606 BTO:0002181 32111827 t miannu The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα.  SIGNOR-277512 0.2 NME2 protein P22392 UNIPROT NME2 protein P22392 UNIPROT up-regulates activity phosphorylation His118 QVGRNIIhGSDSVKS -1 8132589 t miannu Using site-directed mutagenesis of the cDNA encoding NM23-H2, we have created a mutant substituting for the amino acid histidine 118, the presumed site of phosphorylation in the formation of the phosphoenzyme intermediate, the nonphosphorylatable amino acid phenylalanine. The H118F mutant protein is shown to be catalytically inactive SIGNOR-250304 0.2 CDK2 protein P24941 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 10550055 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-72091 0.663 Av/b3 integrin complex SIGNOR-C177 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257719 0.67 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266521 0.8 DUSP1 protein P28562 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 10617468 t inferred from 70% of family members gcesareni The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1. SIGNOR-269910 0.2 PIP3 smallmolecule CHEBI:16618 ChEBI AKT1 protein P31749 UNIPROT up-regulates activity relocalization 9606 23633519 t lperfetto Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. SIGNOR-252641 0.8 PRKCH protein P24723 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser185 SAYVGRLsARPKLKA -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276015 0.2 MAP3K20 protein Q9NYL2 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 11416147 t gcesareni We show here that members of the mixed-lineage kinase (MLK) family (including MLK1, MLK2, MLK3, and dual leucine zipper kinase [DLK]) are expressed in neuronal cells and are likely to act between Rac1/Cdc42 and MKK4 and -7 in death signaling. SIGNOR-243345 0.2 MAP3K7 protein O43318 UNIPROT TAB1 protein Q15750 UNIPROT up-regulates activity phosphorylation Ser456 HTQSSSSsSDGGLFR 9606 BTO:0000007 22216226 t miannu We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro.  SIGNOR-276365 0.927 PRKACA protein P17612 UNIPROT HNRNPD protein Q14103 UNIPROT up-regulates phosphorylation Ser87 SNSSPRHsEAATAQR 9606 11903055 t gcesareni Protein kinase a enhances, whereas glycogen synthase kinase-3 beta inhibits, the activity of the exon 2-encoded transactivator domain of heterogeneous nuclear ribonucleoprotein d in a hierarchical fashion. SIGNOR-116144 0.355 MAPK3 protein P27361 UNIPROT STMN1 protein P16949 UNIPROT down-regulates activity phosphorylation Ser25 QAFELILsPRSKESV 9606 9731215 t lperfetto Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs. SIGNOR-249482 0.563 MET-enkephalin smallmolecule CHEBI:6618 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257551 0.8 PRKCA protein P17252 UNIPROT HLA-A protein P04439 UNIPROT unknown phosphorylation Ser359 SAQGSDVsLTACKV 2941417 t lperfetto As shown in Fig. 6A, the HLA heavy chain was phosphorylated by kinase C. | The major site of in vivo phosphorylation of the HLA-B7 heavy chain was localized to Ser-335 which is conserved in all specificitie SIGNOR-248891 0.328 NFIA protein Q12857 UNIPROT WNT5A protein P41221 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268877 0.2 PCSK7 protein Q16549 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates phosphorylation 9606 BTO:0000222 BTO:0000887 16364914 t gcesareni Ksrp phosphorylated by p38 displays compromised binding to are-containing transcripts and fails to promote their rapid decay,although it retains the ability to interact with the mrna degradation machinery. SIGNOR-143167 0.2 ZFP36 protein P26651 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 25815583 t The TTP binding site in the 3′ UTR of MyoD would permit TTP-mediated mRNA decay SIGNOR-253597 0.296 RELA protein Q04206 UNIPROT CD80 protein P33681 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12860928 f Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells. SIGNOR-253935 0.3 MAPKAPK2 protein P49137 UNIPROT BAG2 protein O95816 UNIPROT up-regulates phosphorylation Ser20 GRFCRSSsMADRSSR 9606 BTO:0000567 15271996 t lperfetto We provided definite evidence that mapkapk2 phosphorylates bag2 at ser 20 in vitro and in vivo. These results demonstrate that bag2 is a novel component of the p38 mapk signaling pathways. SIGNOR-126953 0.373 CDKN1A protein P38936 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 9606 24470334 f The cell cycle regulator p21 is induced early in myoblast differentiation and functions to block cell cycle progression SIGNOR-251564 0.7 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Thr112 EGMQIPStQFDAAHP 9606 BTO:0000007 12432063 t llicata We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin SIGNOR-250848 0.541 GSK3B protein P49841 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation 9606 33081032 t miannu GSK3β regulates S6K1 activity positively through modulating phosphorylation of S6K1 at p.Ser371. SIGNOR-263513 0.367 NCOA2 protein Q15596 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 11851396 t gcesareni Here, it is demonstrated that mutation of the h11 phenylalanine residues diminishes the ability of rxr to associate with the p160 coactivators tif2 and p/cip, but has little effect on ligand-dependent interactions of the receptor with the unrelated coactivator tif1. SIGNOR-114847 0.79 WDR48 protein Q8TAF3 UNIPROT USP1 protein O94782 UNIPROT up-regulates activity binding 9606 BTO:0000567 18082604 t lperfetto In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM). SIGNOR-263274 0.945 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser296 SPSALSSsPNNLSPT 10090 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-143692 0.622 CSNK1D protein P48730 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 11165242 t miannu Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2). SIGNOR-268000 0.865 VAV1 protein P15498 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 9013873 f lperfetto Vav may link gp130 activation to downstream mapk activation in hematopoietic cells. SIGNOR-244640 0.523 RBL2 protein Q08999 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 10090 BTO:0000165 10801445 f gcesareni Although forced expression of either p130 or pRb in mouse C2 myoblasts efficiently blocked cell cycle progression, only p130 inhibited the differentiation program. SIGNOR-267287 0.7 EEF1A1 protein P68104 UNIPROT Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269518 0.8 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR G0/G1_transition phenotype SIGNOR-PH219 SIGNOR up-regulates 12640120 f lperfetto Transition through this point requires cdk6/4-cyclin D, since inhibition with TAT-p16INK4A during the first 3 to 5 h prevents cell cycle entry and maintains both naive and memory T cells in G0. SIGNOR-273193 0.7 ROCK1 protein Q13464 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 19279717 f areggio To date it is not clear whether any genes are transcribed downstream of these two GTPases for non-canonical signaling. The prevailing dogma remains that their primary roles are indeed solely for cytoskeletal modulation SIGNOR-258975 0.7 TRIM63 protein Q969Q1 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys262 DSDDALLkMTISQQE -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). SIGNOR-272740 0.413 CAK complex complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT unknown phosphorylation Ser33 LPENNVLsPLPSQAM 9606 9372954 t llicata We have mapped a major site of phosphorylation by cak to ser-33 of p53 and have demonstrated as well that p53 is phosphorylated at this site in vivo. SIGNOR-269326 0.446 SGK1 protein O00141 UNIPROT NDRG1 protein Q92597 UNIPROT down-regulates phosphorylation Ser330 LMRSRTAsGSSVTSL 9606 20416281 t llicata Ndrg1/cap43 is phosphorylated at serine/threonine sites in its c-terminal domain by serum- and glucocorticoid-regulated kinase 1 (sgk1). we further introduced mutations at the serine and threonine sites at 328 [t328a], 330 [s330a] and 346 [t346a], which are susceptible to phosphorylation by sgk1, and also constructed double mutants [t328a, s330a], [t328a, t346a] and [s330a, t346a]. Expression of all these mutants, with the exception of [s330a, t346a], suppressed the production of cxc chemokine to similar levels as their wild-type counterpart. SIGNOR-164898 0.586 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 t milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. SIGNOR-202030 0.916 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12226093 t The effect has been demonstrated using P10636-8 lperfetto Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease. SIGNOR-92607 0.754 AMPK complex SIGNOR-C15 SIGNOR Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 20647423 t lperfetto Ampk recruitment and h2b ser36 phosphorylation colocalized within genes activated by ampk-dependent pathways, both in promoters and in transcribed regions. SIGNOR-216471 0.2 TRIM59 protein Q8IWR1 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity 9606 BTO:0000567; BTO:0002181 22588174 f Giorgia TRIM59 also inhibited the phosphorylation of IRF3 and IRF7, which induces dimerization, suggesting that TRIM59 negatively regulates kinases for IRF3/7 (IKKe/TBK1) or their upstream signal SIGNOR-260373 0.263 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 15611135 t gcesareni We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines. SIGNOR-132551 0.263 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR CEBPA protein P49715 UNIPROT down-regulates activity binding 9606 BTO:0001412 11283671 t irozzo AML1–ETO inhibits CEBPA autoregulation in myeloid cells.[…]It was also demonstrated that AML1–ETO and C/EBPα physically interact in vivo. SIGNOR-255700 0.2 GSK3B protein P49841 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 9606 16023596 t gcesareni Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation. SIGNOR-138603 0.709 cyclosporin A chemical CHEBI:4031 ChEBI TTN protein Q8WZ42 UNIPROT up-regulates 9606 17636278 f Regulation of transcription Cyclosporine A induces titin expression via MAPK/ERK signalling and improves proliferative and invasive potential of human trophoblast cells. SIGNOR-251975 0.8 DNA_damage stimulus SIGNOR-ST1 SIGNOR TAOK1 protein Q7L7X3 UNIPROT up-regulates 9606 17396146 f lperfetto These findings indicate that TAO kinases are regulators of p38-mediated responses to DNA damage and are intermediates in the activation of p38 by ATM. SIGNOR-226599 0.7 PPP1CB protein P62140 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 16501611 t Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. SIGNOR-248573 0.29 MT-ND3 protein P03897 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. SIGNOR-262145 0.772 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258188 0.8 MAPK14 protein Q16539 UNIPROT ELK3 protein P41970 UNIPROT up-regulates phosphorylation Ser357 IHFWSSLsPVAPLSP 9606 9130707 t gcesareni Tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387. Mutation of these sites to alanine severely reduces c-fos sre-dependent transcription mediated by sap-1a and p38 map kinase. SIGNOR-47681 0.387 KLF5 protein Q13887 UNIPROT PPARG protein P37231 UNIPROT up-regulates transcriptional regulation 10090 16054042 f fspada Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter. SIGNOR-210010 0.608 SYVN1 protein Q86TM6 UNIPROT CLU protein P10909 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 17451556 t miannu We also report that the ER-associated ubiquitin ligase Hrd1/synoviolin can interact with, and ubiquitinate clusterin. The fact that cleaved endogenous clusterin appears, under certain conditions, to be subject to polyubiquitination (Figure 2C) and proteasomal degradation (1, 2) strongly suggests that it passed through the secretory pathway before reaching the cytosol. SIGNOR-272629 0.326 LIMK1 protein P53667 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser3 sGVAVSDG 9606 18079118 t gcesareni Our results suggest that limk1-mediated cofilin phosphorylation is required for accurate spindle orientation by stabilizing cortical actin networks during mitosis SIGNOR-159885 0.807 CNR1 protein P21554 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256724 0.521 DLGAP3 protein O95886 UNIPROT SHANK2 protein Q9UPX8 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264593 0.78 CLTCL1 protein P53675 UNIPROT AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 t lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-260673 0.72 MRPL12 protein P52815 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262381 0.642 CTNND1 protein O60716 UNIPROT CDH3 protein P22223 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0003564 14610055 t miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. SIGNOR-252124 0.742 EZH2 protein Q15910 UNIPROT DACT3 protein Q96B18 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004094 22144423 f miannu For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci. SIGNOR-254142 0.254 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR TNNT3 protein P45378 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136942 0.311 EPB42 protein P16452 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 t lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  SIGNOR-266014 0.404 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGC5 protein Q9Y5F6 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265683 0.2 CHFR protein Q96EP1 UNIPROT SMARCB1 protein Q12824 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 22285184 t miannu Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination. SIGNOR-271458 0.321 HNF4A protein P41235 UNIPROT C1QTNF5 protein Q9BXJ0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000224 20621834 f miannu Here we demonstrate the mechanism by which the CTRP5 gene is transcriptionally activated in the liver. CTRP5 is activated by HNF4alpha via the region -206/-167 of the human CTRP5 promoter. SIGNOR-254448 0.2 PRKCB protein P05771 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251630 0.314 FLT3 protein P36888 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates activity binding 10090 BTO:0001516 23246379 t These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K–Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells. SIGNOR-255947 0.371 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1924 SPTSPKYsPTSPTYS 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176829 0.775 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser27 GNDPLTSsPGRSSRR 9606 BTO:0000567 16899510 t gcesareni In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells. SIGNOR-148713 0.961 OPTN protein Q96CV9 UNIPROT SNAP25 protein P60880 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22194658 f same result in PC12 cell miannu SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA. SIGNOR-259880 0.2 nitric oxide smallmolecule CHEBI:16480 ChEBI Demyelination phenotype SIGNOR-PH155 SIGNOR up-regulates 9606 32454942 f miannu Next to their interaction with adaptive immune cells, activated microglia can secrete cytotoxic cytokines and oxidative products, such as ROS and NO radicals in MS lesions thereby promoting oxidative stress and contributing to myelin destruction SIGNOR-263829 0.7 denopamine chemical CHEBI:135359 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  SIGNOR-257860 0.8 DLGAP1 protein O14490 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 9115257 t miannu SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area. SIGNOR-264209 0.931 ZWILCH protein Q9H900 UNIPROT RZZ complex complex SIGNOR-C357 SIGNOR form complex binding 9606 BTO:0000567 20462495 t lperfetto The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico. SIGNOR-265014 0.739 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258848 0.8 NUAK1 protein O60285 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 21317932 t gcesareni Here we showed that in the presence of wild-type lkb1, nuak1 directly interacts with and phosphorylates p53 in vitro and in vivo. SIGNOR-172012 0.527 LIN28A protein Q9H9Z2 UNIPROT IGF2 protein P01344 UNIPROT up-regulates quantity by expression translation regulation 9606 17473174 t miannu Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency SIGNOR-277339 0.406 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser83 PTIPGVTsPSSDEPP 9606 BTO:0000007 11691836 t lperfetto The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding SIGNOR-249391 0.649 AKT1 protein P31749 UNIPROT AR protein P10275 UNIPROT down-regulates activity phosphorylation Ser792 CVRMRHLsQEFGWLQ 9534 BTO:0001538 11404460 t lperfetto Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Here, we demonstrate that akt phosphorylates the androgen receptor (ar) at ser-210 and ser-790 SIGNOR-108508 0.604 MET protein P08581 UNIPROT MET protein P08581 UNIPROT up-regulates phosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 8302603 t lperfetto Previous work has shown that autophosphorylation of p190met enhances its enzymatic activity and that the major phosphorylation site is tyr1235, located in the catalytic domainonly the replacement of both tyr1234 and tyr1235 yielded a mutant which completely lost the ability to be activated by autophosphorylation SIGNOR-37727 0.2 GRK3 protein P35626 UNIPROT CCR5 protein P51681 UNIPROT down-regulates activity phosphorylation Ser349 STGEQEIsVGL 9534 BTO:0000298 10085131 t gcesareni Phosphoamino acid analysis revealed that RANTES-induced CCR5 phosphorylation selectively occurs on serine residues. Our findings with receptor mutants indicate that serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. SIGNOR-249679 0.2 ING1 protein Q9UK53 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 14522900 f miannu  In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity. SIGNOR-254483 0.312 PRKAA1 protein Q13131 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser486 DDEITEAKsGTATPQRS -1 17023420 t We show that AMPK α-Ser485/491 can be a site for autophosphorylation, which may play a role in limiting AMPK activation in response to energy depletion or other regulators SIGNOR-256114 0.2 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates activity phosphorylation Tyr570 INGNNYVyIDPTQLP 9606 12824176 t lperfetto Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth./ Tyr-568 and tyr-570 are significantly phosphorylated SIGNOR-102637 0.2 PRKACA protein P17612 UNIPROT ARFGEF1 protein Q9Y6D6 UNIPROT up-regulates activity phosphorylation Ser883 EIAGKKIsMKETKEL 9606 BTO:0000599 16467138 t lperfetto Within 20 min after addition of 8-Br-cAMP, BIG1 accumulated in nuclei, and this effect was blocked by protein kinase A (PKA) inhibitors H-89 and PKI, suggesting a dependence on PKA-catalyzed phosphorylation. |Mutant BIG1 (S883A) in which Ala replaced Ser-883, a putative PKA phosphorylation site, did not move to the nucleus with cAMP addition, whereas replacement with Asp (S883D) resulted in nuclear accumulation of BIG1 without or with cAMP exposure, consistent with the mechanistic importance of a negative charge at that site SIGNOR-272146 0.2 PRKG1 protein Q13976 UNIPROT SF1 protein Q15637 UNIPROT down-regulates activity phosphorylation Ser20 PSKKRKRsRWNQDTM 10116 BTO:0000947 10449420 t lperfetto PKG phosphorylates SF1 at Ser20, which inhibits the SF1-U2AF65 interaction leading to a block of pre-spliceosome assembly. Mutation of Ser20 to Ala or Thr also inhibits the interaction with U2AF65, indicating that Ser20 is essential for binding. SIGNOR-249018 0.449 MAPK14 protein Q16539 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity phosphorylation Ser87 AAAGPALsPVPPVVH 9606 19336399 t gcesareni The protein's reduced antiapoptotic capacity was related to phosphorylation of its threonine 56 and serine 87 residues by virally activated p38mapk SIGNOR-184936 0.34 PRKCA protein P17252 UNIPROT SDC4 protein P31431 UNIPROT up-regulates activity phosphorylation Ser179 MKKKDEGsYDLGKKP 10116 BTO:0001176 11916978 t lperfetto The phosphorylation state of Ser(183) in the cytoplasmic tail of syndecan-4 determines the binding affinity of the cytoplasmic tail to phosphatidylinositol 4,5-bisphosphate (PIP(2)), the capacity of the tail to multimerize, and its ability to activate protein kinase C (PKC) alpha. We sought to identify the kinase responsible for this phosphorylation and to determine its downstream effects on PKCalpha activity and on endothelial cell function. Among several PKC isoenzymes tested, only PKCalpha and -delta were able to specifically phosphorylate Ser(183) in vitro. However, studies in cultured endothelial cells showed that the phosphorylation level of syndecan-4 was significantly reduced in endothelial cells expressing a dominant negative (DN) PKCdelta but not a DN PKCalpha mutant. SIGNOR-249149 0.721 CSNK1A1 protein P48729 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser513 GEDEESEsD -1 9045708 t llicata Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells.  SIGNOR-250793 0.328 AKT2 protein P31751 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 17845852 f gcesareni Ras and akt signaling enhances the nuclear localization of gli1, counteracting its suppression by other modifiers that retain it in the cytoplasm, such as suppressor of fused (sufu). SIGNOR-157770 0.279 NR3C1 protein P04150 UNIPROT JUN protein P05412 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8639160 t gcesareni We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins SIGNOR-251679 0.733 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 10915800 t lperfetto Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo. SIGNOR-244754 0.2 TSHB protein P01222 UNIPROT TSH complex SIGNOR-C412 SIGNOR form complex binding 9606 BTO:0001379 8196184 t scontino TSH is a heterodimer composed of common alpha subunit and unique beta subunit encoded by genes located on different chromosomes. It is known that the expression of these subunit genes is regulated in different mechanism by several extracellular factors. SIGNOR-267047 0.667 CRTC2 protein Q53ET0 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity transcriptional regulation 9606 26652733 t inferred from family member miannu Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB SIGNOR-267788 0.282 DGC complex SIGNOR-C217 SIGNOR GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265432 0.2 AR protein P10275 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 15861399 f miannu AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation SIGNOR-251539 0.7 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 20068231 t gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. SIGNOR-163250 0.786 FGG protein P02679 UNIPROT VTN protein P04004 UNIPROT down-regulates activity binding 9606 2243140 t Regulation miannu Fibrinogen y-chain carboxyterminal (GQQHHLGGAKQAGDV) peptides inhibit fibrinogen, fibronectin (Fn), vitronectin, and von Willebrand factor (vWF) binding to the platelet glycoprotein Ilb-Illa complex (GP lIbII1a). SIGNOR-251969 0.431 MRPL54 protein Q6P161 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262336 0.645 RXRB protein P28702 UNIPROT PPARD protein Q03181 UNIPROT up-regulates binding 9606 11237216 t gcesareni Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology SIGNOR-105451 0.536 NR5A2 protein O00482 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 f miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254870 0.358 CDK1 protein P06493 UNIPROT KIF11 protein P52732 UNIPROT up-regulates activity phosphorylation Thr926 LDIPTGTtPQRKSYL 9606 19001501 t done miannu Nek6 phosphorylated Eg5 at several sites in vitro and one of these sites, Ser1033, is phosphorylated in vivo during mitosis. Whereas CDK1 phosphorylates nearly all Eg5 at Thr926 during mitosis, Nek6 phosphorylates approximately 3% of Eg5, primarily at the spindle poles.  SIGNOR-273887 0.657 BTAF1 protein O14981 UNIPROT TBP protein P20226 UNIPROT up-regulates activity binding 9986 15509807 t miannu We present evidence that the NC2alpha subunit interacts with BTAF1. Addition of NC2alpha or the NC2 complex can stimulate the ability of BTAF1 to interact with TBP. SIGNOR-263919 0.73 DDB1 protein Q16531 UNIPROT RAD23B protein P54727 UNIPROT up-regulates 24086044 f lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). SIGNOR-275689 0.63 PTGFR protein P43088 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256810 0.357 FZD1 protein Q9UP38 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma) SIGNOR-80598 0.281 CAMK2A protein Q9UQM7 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Thr140 LRYLKYRtKTRASAT 9606 BTO:0000975 15107581 t Translocation from Endosome to Lysosome gcesareni As we have shown previously, human h1r can be phosphorylated in vitro by several kinases includingpka, pkc, pkg, and camk ii in summary, these data suggest that thr140, thr142, ser396, ser398, and thr478 can be phosphorylated by the kinases described above (table 2). SIGNOR-124348 0.286 NCOR2 protein Q9Y618 UNIPROT PGR protein P06401 UNIPROT down-regulates acetylation 9606 BTO:0000150;BTO:0001130 12771131 t gcesareni In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases. SIGNOR-101289 0.605 IRAK4 protein Q9NWZ3 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser345 QARPGPQsPGSPLEE 9606 BTO:0000130 17217339 t lperfetto Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.These results strongly support the observation that irak-4 is a kinase for p47phox in vivo. We also detected the signature of phosphorylation at ser320 and ser345 SIGNOR-152019 0.389 ITCH protein Q96J02 UNIPROT TRPC4 protein Q9UBN4 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 17110928 t miannu Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane. SIGNOR-272624 0.357 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr206 PNAILKLtDFGFAKE -1 7592979 t miannu In Vitro Activation of MAPKAP Kinase 2 by p38/40. the constitutively active mutant T205E,T317E shows no changes in activity after treatment with the p38/40 fraction SIGNOR-250101 0.76 AURKB protein Q96GD4 UNIPROT MYBBP1A protein Q9BQG0 UNIPROT unknown phosphorylation Ser1303 ARKKARLsLVIRSPS 9606 20177074 t lperfetto We identified mybbp1a as a novel aurora b substrate and serine 1303 as the major phosphorylation site SIGNOR-163903 0.398 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RRM1 protein P23921 UNIPROT up-regulates activity phosphorylation Ser559 PYETYEGsPVSKGIL 9606 32712628 t miannu Here, we report that RRM1 is phosphorylated at Ser 559 by CDK2/cyclin A during S/G2 phase. And this S559 phosphorylation of RRM1enhances RNR enzymatic activity and is required for maintaining sufficient dNTPs during normal DNA replication. SIGNOR-277522 0.327 ARRB2 protein P32121 UNIPROT KIF3A protein Q9Y496 UNIPROT up-regulates binding 9606 16908539 t gcesareni We demonstrate that _-arrestins mediate the activity-dependent interaction of smo and the kinesin motor protein kif3a. SIGNOR-148773 0.623 CAMK2A protein Q9UQM7 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Thr642 RSVKRNStVDCNGVV 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275786 0.282 PDHA1 protein P08559 UNIPROT PDH complex SIGNOR-C402 SIGNOR form complex binding 9606 20160912 t miannu The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. SIGNOR-266544 0.801 EPHA4 protein P54764 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates activity phosphorylation Tyr596 LNQGVRTyVDPFTYE -1 8622893 t Two dimensional phosphopeptide mapping and site-directed mutagenesis defined juxtamembrane residue Y602 as a major site of in vitro autophosphorylation in Sek, whilst Y596 was phosphorylated to a lower stoichiometry. SIGNOR-251118 0.2 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr603 LKTPSAAyLWVGTGA -1 10210201 t llicata Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624. SIGNOR-250782 0.575 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR HDAC5 protein Q9UQL6 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 12058061 t gcesareni In the cytoplasm, 14-3-3 proteins bind the phosphorylated hdac5 and retain it in the cytosol. SIGNOR-89444 0.2 SOSTDC1 protein Q6X4U4 UNIPROT BMP4 protein P12644 UNIPROT down-regulates activity 10090 18032587 f lperfetto SOSTDC1 is orthologous to a recently characterized murine antagonist of BMPs-2, -4, and -7 SIGNOR-242749 0.684 CASP6 protein P55212 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261750 0.37 SMARCB1 protein Q12824 UNIPROT CCNA2 protein P20248 UNIPROT down-regulates 9606 12226744 f miannu We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6. SIGNOR-92782 0.351 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates activity phosphorylation Ser495 KTMIRKRsFGNPFEG 9534 BTO:0000298 32913128 t miannu  Here we show that stimulation of cAMP-dependent protein kinase A (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues.  SIGNOR-277238 0.2 JAK1 protein P23458 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr327 NSKPKKSyIATQGCL 9534 8995399 t lperfetto Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2 SIGNOR-236274 0.759 CDC34 protein P49427 UNIPROT SCF-FBW7 complex SIGNOR-C135 SIGNOR up-regulates activity binding 9606 25425648 t miannu The ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase SCF are capable of building polyubiquitin chains onto protein substrates both rapidly and processively; this may be explained at least in part by the atypically fast rate of Cdc34 and SCF association.Here, we use protein cross-linking to demonstrate that the Cdc34-SCF interaction occurs in multiple conformations, where several residues from the Cdc34 acidic tail are capable of contacting a broad region of the SCF basic canyon. Similar patterns of cross-linking are also observed between Cdc34 and the Cul1 paralog Cul2, implicating the same mechanism for the Cdc34-SCF interaction in other members of the cullin-RING ubiquitin ligases. SIGNOR-277333 0.796 TRIO protein O75962 UNIPROT DCC protein P43146 UNIPROT up-regulates quantity binding 10116 BTO:0004102 23230270 t miannu TrioY2622 is required for both netrin-1-induced activation of Rac1 and enhanced association with DCC. Phosphorylation of Trio at Tyr2622 participates in maintaining the level of surface DCC at the growth cone plasma membrane leading to axon outgrowth. Therefore, we propose that TrioY2622 is essential for the proper assembly and stability of the DCC/Trio signaling complex at the cell surface of growth cones in order to mediate netrin-1-induced cortical axon outgrowth. SIGNOR-273856 0.589 OSM protein P13725 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0001271 9143707 t gcesareni Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2. SIGNOR-48114 0.741 all-cis-5,8,11,14,17-icosapentaenoic acid smallmolecule CHEBI:28364 ChEBI FBN1 protein P35555 UNIPROT up-regulates quantity by expression 9606 16467281 f Regulation of expression miannu It was found that EPA increased collagen and elastic fibers (tropoelastin and fibrillin-1) expression by increasing transformin growth factor-beta expression in aged human skin. SIGNOR-251910 0.8 WNT5A protein P41221 UNIPROT MYF5 protein P13349 UNIPROT up-regulates activity 10090 BTO:0000887;BTO:0001103 9753670 f gcesareni Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. SIGNOR-60376 0.296 EGR1 protein P18146 UNIPROT CHGA protein P10645 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001007 12456801 t Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation. SIGNOR-254265 0.2 PKN1 protein Q16512 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser246 QACARTFsRMSLLHK 9606 BTO:0000150 15833848 t lperfetto Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functionswe found for the first time that pak1 promotes transcription repression activity of snail from e-cadherin, occludin, and aromatase promoters. Pak1 regulates the repressor activity of snail by phosphorylating on ser(246). Pak1 phosphorylation of snail supports snail's accumulation in the nucleus as well as its repressor functions. SIGNOR-135609 0.2 CDC34 protein P49427 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR up-regulates activity binding 9606 25425648 t miannu The ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase SCF are capable of building polyubiquitin chains onto protein substrates both rapidly and processively; this may be explained at least in part by the atypically fast rate of Cdc34 and SCF association.Here, we use protein cross-linking to demonstrate that the Cdc34-SCF interaction occurs in multiple conformations, where several residues from the Cdc34 acidic tail are capable of contacting a broad region of the SCF basic canyon. Similar patterns of cross-linking are also observed between Cdc34 and the Cul1 paralog Cul2, implicating the same mechanism for the Cdc34-SCF interaction in other members of the cullin-RING ubiquitin ligases. SIGNOR-277334 0.76 PAK4 protein O96013 UNIPROT MZF1 protein P28698 UNIPROT up-regulates activity phosphorylation Ser27 VMVKLEDsEEEGEAA -1 30622337 t miannu  Here, we link ErbB2 activation to invasion via ErbB2-induced, SUMO-directed phosphorylation of a single serine residue, S27, of the transcription factor myeloid zinc finger-1 (MZF1).  Phosphorylation of MZF1-S27 is an early response to ErbB2 activation and results in increased transcriptional activity of MZF1.The phosphorylation of MZF1-S27 is preceded by poly-SUMOylation of K23, which can make S27 accessible to efficient phosphorylation by PAK4. SIGNOR-277422 0.2 SARS1 protein P49591 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 24095058 t miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis SIGNOR-270496 0.8 RNF126 protein Q9BV68 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 23418353 t miannu RNF126 and Rabring7 associate with the EGFR through a ubiquitin-binding zinc finger domain and both E3 ubiquitin ligases promote ubiquitylation of EGFR. In HeLa cells depleted of either RNF126 or Rabring7 the EGFR is retained in a late endocytic compartment and is inefficiently degraded. SIGNOR-272103 0.334 TFE3 protein P19532 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276816 0.287 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000938 BTO:0000142 SIGNOR-C110 19303846 t gcesareni DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin. SIGNOR-184781 0.856 PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR DCK protein P27707 UNIPROT down-regulates activity dephosphorylation Ser74 EFEELTMsQKNGGNV 24462681 t lperfetto Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation SIGNOR-275802 0.2 STK4 protein Q13043 UNIPROT H2BC3 protein P33778 UNIPROT unknown phosphorylation Ser15 APAPKKGsKKAITKA 9606 21212262 t lperfetto The mst1 is a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn activates its downstream targets, jnk/p38, histone h2b and foxo. Mst1 induces apoptosis by phosphorylating histone h2b on a relatively conserved site, ser-14 in mammalian cells SIGNOR-171009 0.2 CPT1C protein Q8TCG5 UNIPROT (R)-carnitine smallmolecule CHEBI:16347 ChEBI down-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267122 0.8 SRGAP2 protein O75044 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260516 0.57 CDK1 protein P06493 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT up-regulates activity phosphorylation Thr1238 ASWDQPGtPGREPTQ 9606 BTO:0000567 37584777 t phosphorylation site remapping based on mass spec table lperfetto CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects. SIGNOR-272966 0.2 MYCN protein P04198 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18566016 f miannu In primary neuroblastomas, high CTSD messenger RNA (mRNA) levels were associated with amplified MYCN, a strong predictive marker of adverse outcome. Chromatin immunoprecipitation and luciferase promoter assays revealed that MYCN protein binds to the CTSD promoter and activates its transcription, suggesting a direct link between deregulated MYCN and CTSD mRNA expression. SIGNOR-254618 0.2 MYC protein P01106 UNIPROT IMPDH2 protein P12268 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 t miannu Here, we report that the majority of genes in human purine and pyrimidine biosynthesis pathway were induced and directly bound by c-Myc in the P493-6 human Burkitt's lymphoma model cell line. The mRNA levels of IMPDH1 and IMPDH2, the rate-limiting enzyme in purine de novo synthesis, increased with MYC induction both in vitro and in vivo. SIGNOR-267377 0.298 LPAR4 protein Q99677 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256928 0.358 Ionizing radiation stimulus SIGNOR-ST16 SIGNOR ELE1-RET fusion protein SIGNOR-FP10 SIGNOR up-regulates 9606 23128507 f miannu In PTC, genomic rearrangements juxtapose the RET tyrosine kinase domain to unrelated genes, thereby creating dominantly transforming oncogenes, denominated RET/PTC. The RET/PTC rearrangements are the 2nd most common genetic alteration described in PTC and observed in ∼13–43% of cases, mostly in pediatric cancers or in individuals exposed to ionizing radiation from nuclear accidents SIGNOR-251984 0.7 MCF2 protein P10911 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260557 0.651 PPARD protein Q03181 UNIPROT SLC25A20 protein O43772 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19577614 f miannu CACT is upregulated by PPARalpha and PPARdelta, probably by binding to a functional PPRE at position +45 to +57 relative to the transcription start site. The upregulation of CACT by PPARalpha and PPARdelta, which are both important for the regulation of fatty acid oxidation in tissues during fasting, may increase the import of acylcarnitine into the mitochondrial matrix during fasting. SIGNOR-255048 0.308 Sin3B_complex complex SIGNOR-C409 SIGNOR H3C15 protein Q71DI3 UNIPROT down-regulates activity binding 9606 BTO:0000007 21041486 t miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. SIGNOR-266974 0.2 ADORA2B protein P29275 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257414 0.279 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258082 0.8 PTPN2 protein P17706 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity dephosphorylation 9606 15780598 t lperfetto Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5. SIGNOR-133279 0.723 CDK1 protein P06493 UNIPROT RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser428 EPAPVLSsPPPADVS 9606 SIGNOR-C17 15037602 t lperfetto Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain. SIGNOR-123516 0.472 PTEN protein P60484 UNIPROT GLI1 protein P08151 UNIPROT down-regulates 9606 17157787 f PTEN is a suppressor of RAS-AKT function gcesareni Moreover, suppressors of ras akt function, such as the tumor-suppressor pten, and the attenuation of ras signaling involved in senescence, could be thus viewed as modulators of the gli code SIGNOR-151134 0.361 EGLN3 protein Q9H6Z9 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization hydroxylation 9606 24990963 t lperfetto There are three EglN family members in humans and mice (EglN1, EglN2, and EglN3). Their enzymatic activity requires oxygen, ascorbic acid, iron, and α-ketoglutarate (α-KG). Under hypoxic conditions, EglNs lose their activity and fail to hydroxylate HIFα, which leads to HIFα stabilization SIGNOR-262000 0.79 EP300 protein Q09472 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by destabilization acetylation Lys70 EGILRRLkKYDNCWL 9606 BTO:0000007 21726808 t lperfetto Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase|P300 Acetylates and Destabilizes PEPCK1|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 SIGNOR-267597 0.526 LTB4R protein Q15722 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256970 0.268 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10801407 t gcesareni The tumour suppressor protein p53 is stabilised and activated in response to ionising radiation. This is known to depend on the kinase atm;recent results suggest atm acts via the downstream kinase chk2/hcds1, which stabilises p53 at least in part by direct phosphorylation of residue serine 20 SIGNOR-77144 0.783 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Thr19 GAVPSEAtKRDQNLK 9823 21864610 t miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. SIGNOR-262919 0.337 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 BTO:0000567 11672426 f lperfetto Conversely, only activation of the TNFR1 could stimulate mitogen-activated protein kinase (MAPK) or p38 MAPK activities in a time-dependent manner. SIGNOR-226637 0.379 Pentostatin chemical CID:439693 PUBCHEM ADA protein P00813 UNIPROT down-regulates activity chemical inhibition 9606 2433905 t miannu 2'-Chloropentostatin is a new inhibitor of adenosine deaminase isolated from the fermentation broth of an unidentified actinomycete, ATCC 39365. It contains the aglycone of coformycin, i.e. 3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-o1, coupled to the unusual carbohydrate, 2'-chloro-2'-deoxyribose. 2'-Chloropentostatin is a slightly weaker inhibitor of rat and human adenosine deaminases than coformycin, and considerably weaker than pentostatin. Unlike pentostatin, which appears to undergo a two-stage interaction with adenosine deaminase, 2'-chloropentostatin forms a single enzyme-inhibitor complex. The enzyme-inhibitor complex between adenosine deaminase and 2'-chloropentostatin was much more rapidly dissociable than the complex with pentostatin. SIGNOR-259261 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR RGCC protein Q9H4X1-2 UNIPROT up-regulates activity phosphorylation Ser45 ERMKRRSsASVSDSS 9606 BTO:0000567 19162005 t miannu Akt phosphorylated GST-RGC-32 in vitro, and CDC2 was also able to phosphorylate RGC-32.  Akt failed to phosphorylate RGC-32 S45A-S47A mutant. These data indicate that Ser 45 and Ser 47 may be the RGC-32 phosphorylation sites for Akt kinase. SIGNOR-262629 0.2 UTS2R protein Q9UKP6 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257319 0.252 ABL1 protein P00519 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Tyr368 CGGARICyIFHETFG 9606 BTO:0000793 29022905 t miannu In this study, we found that c-Abl phosphorylated Drp1 at tyrosine 266, 368 and 449 in vitro and in vivo, which augmented the GTPase activity of Drp1 and promoted Drp1-mediated mitochondrial fragmentation. SIGNOR-277329 0.263 PHB2 protein Q99623 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 10090 BTO:0000165 BTO:0000887 15173318 t lperfetto Phb2 interacts with both myod and mef2, and represses both myod- and mef2-dependent gene transcription. Furthermore, binding of phb2 to both myod and mef2 significantly decreases upon myogenic differentiation. SIGNOR-235843 0.372 E2F1 protein Q01094 UNIPROT RRM1 protein P23921 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253852 0.303 PRKCD protein Q05655 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 t gcesareni Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm. SIGNOR-97287 0.262 testolactone chemical CHEBI:9460 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates activity chemical inhibition -1 7083195 t miannu Recently, it was discovered that 4-hydroxy-4-androstene-3,17-dione, 4-androstene-3,6,17-trione, and 1,4,6-androstatriene-3,17-dione, compounds previously reported to be competitive inhibitors of aromatase, cause a time-dependent loss of aromatase activity in human placental microsomes.We report here that 1,4-androstadiene 3,17-dione (Ki 0.32 microM; kinact 0.91 X 10(-3)/sec) and testolactone (Ki 35 microM; kinact 0.36 X 10(-3)/sec) also cause a similar loss of aromatase activity. SIGNOR-258406 0.8 FOXP2 protein O15409 UNIPROT MET protein P08581 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002881 21832174 t Gianni FOXP2 binds directly to the 5' regulatory region of MET, and overexpression of FOXP2 results in transcriptional repression of MET. The expression of MET in restricted human neocortical regions, and its regulation in part by FOXP2, is consistent with genetic evidence for MET contributing to ASD risk. SIGNOR-269054 0.426 tRNA(Met) smallmolecule CHEBI:29173 ChEBI Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270401 0.8 SIRT7 protein Q9NRC8 UNIPROT FBL protein P22087 UNIPROT up-regulates activity deacetylation Lys206 DLINLAKkRTNIIPV 30540930 t lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) SIGNOR-275893 0.274 CDON/SPAG9 complex SIGNOR-C21 SIGNOR MAPK14 protein Q16539 UNIPROT up-regulates activity binding 9606 BTO:0000222 17074887 t p38 MAPK is activated by phosphorylation in response to CDO-BOC interactions. Activated p38 MAPK may translocate into the nucleus to further activate myogenic related transcription factors. gcesareni One way this occurs is via the interaction of JLP with the Cdo cytoplasmic tail. JLP is, in turn, bound to p38α/β. This interaction facilitates p38 activation during differentiation and is important for Cdo's effects in myogenesis. SIGNOR-272542 0.493 MAPK1 protein P28482 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates activity phosphorylation Ser167 FLISPPAsPPVGWKQ 10090 BTO:0000165 12063245 t lperfetto Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. SIGNOR-249198 0.274 MYO1E protein Q12965 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 10116 BTO:0000142 17257598 f miannu We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta. SIGNOR-265426 0.7 GPR35 protein Q9HC97 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257204 0.2 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Tyr654 RNEGVATyAAAVLFR 9606 BTO:0001271 17318191 t lperfetto Bcr-abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylationthe notion that y86 and y654 are located respectively within the n_ and c_terminal transcriptional domains of __catenin suggests that one or both residues might regulate the transactivating function of __catenin. In this regard, phosphorylation of y654 was reported to strengthen __catenin association with the basal transcription factor tata_binding protein (tbp) SIGNOR-153431 0.2 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176813 0.775 ITGB1BP1 protein O14713 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257648 0.756 PRKCA protein P17252 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 15107581 t Translocation from Endosome to Lysosome fspada The peptide p9-s396a/s398a (both ser396 and ser398 to alanines) was phosphorylated only slightly or not phosphorylated by these kinases. Thus both ser396 and ser398 can be phosphorylated by camk ii and pkc SIGNOR-124352 0.2 FGFR1 protein P11362 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates 9606 12270934 f lperfetto Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors SIGNOR-244865 0.315 PRKCA protein P17252 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates activity phosphorylation Ser53 HPQLHIEsKIYKMMQ -1 31096047 t miannu In the present study we analyzed the CK1δ kinase domain for phosphorylation sites targeted by PKCα. Several phosphorylation sites were identified in vitro by initially using GST-CK1δ wild type and phosphorylation-site mutant protein fragments originating from the CK1δ kinase domain. Residues S53, T176, and S181 could finally be confirmed as targets for PKCα. Determination of kinetic parameters of full-length wild type and mutant GST-CK1δ-mediated substrate phosphorylation revealed that integrity of residue T176 is crucial for maintaining CK1δ kinase activity. SIGNOR-277451 0.2 F5 protein P12259 UNIPROT Factor Va-Xa complex SIGNOR-C318 SIGNOR form complex binding -1 2026608 t lperfetto The binding of factor Xa to factor Va in the presence of Ca2+ ions and phospholipid is fundamental for the activation of prothrombin to thrombin. |Regardless of which protein was labeled, a factor Xa-Va complex (s20,w = 9.8) was formed. The interaction is specific and reversible. I SIGNOR-263558 0.766 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GRB10 protein Q13322 UNIPROT up-regulates phosphorylation 9606 15952796 t inferred from 70% family members lperfetto Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation SIGNOR-270077 0.2 cyclosporin A chemical CHEBI:4031 ChEBI PPP3CB protein P16298 UNIPROT down-regulates chemical inhibition 9606 15276472 t gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. SIGNOR-127228 0.8 PAFAH1B2 protein P68402 UNIPROT APP protein P05067 UNIPROT up-regulates 9606 23238734 f miannu We provide evidence that the loss of pafah1b2 potently reduces a_ by promoting the degradation of its immediate precursor, the _ctf. SIGNOR-200188 0.2 CEBPA protein P49715 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 17671233 f irozzo C/EBPα binds and activates the PU.1 distal enhancer to induce monocyte lineage commitment.Transcriptional induction of PU.1 by C/EBPα may play a role in myeloid lineage specification. SIGNOR-256055 0.543 FN1 protein P02751 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates 9606 20457810 f fspada We conclude that, by interacting with fibronectin, pref-1 activates integrin downstream signaling to activate mek/erk and to inhibit adipocyte differentiation. SIGNOR-165350 0.588 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXA2 protein Q9Y261 UNIPROT down-regulates activity phosphorylation Thr156 KTYRRSYtHAKPPYS 9606 14500912 t Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins. This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects. Mutant Foxa-2T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression. SIGNOR-254974 0.2 IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 11960013 t lperfetto In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant-negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAK-1. SIGNOR-117315 0.673 MAPK12 protein P53778 UNIPROT SNTA1 protein Q13424 UNIPROT up-regulates phosphorylation Ser201 PLQRQPSsPGPTPRN 9606 BTO:0001103 10212242 t lperfetto Sapk3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the pdz domain of alpha1-syntrophin. The finding that sapk3 co-localizes with _1-syntrophin in skeletal muscle, that it binds to the pdz domain of _1-syntrophin, and that phosphorylation of _1-syntrophin depends on this interaction identifies a novel mechanism for targeting a protein kinase to its substrates. SIGNOR-67065 0.654 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL11 protein P51671 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16604092 f miannu Rosmarinic acid also inhibited TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, as well as nuclear translocation of NF-kappaB heterodimer induced by TNF-alpha. This suggests that rosmarinic acid downregulates the expression of CCL11 and CCR3 via the inhibition of NF-kappaB activation signaling. SIGNOR-254661 0.265 A2/b1 integrin complex SIGNOR-C160 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257702 0.586 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity phosphorylation Ser87 AAAGPALsPVPPVVH 9606 10567572 t gcesareni Jnk1-mediated phosphorylation of bcl-2 regulates starvation-induced autophagy. SIGNOR-48038 0.564 TAF8 protein Q7Z7C8 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269573 0.544 TFE3 protein P19532 UNIPROT RRAGC protein Q9HB90 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276827 0.343 MAPK1 protein P28482 UNIPROT STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 25846811 t lperfetto Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK. SIGNOR-209876 0.411 UBE2J1 protein Q9Y385 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by destabilization ubiquitination 9606 BTO:0001379 29892818 t inferred from family member scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. SIGNOR-270242 0.387 ALDH1A1 protein P00352 UNIPROT all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI up-regulates quantity chemical modification 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265123 0.8 CSNK2A2 protein P19784 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Ser483 KRSRAIHsSDEGEDQ 9606 12769847 t llicata We identify two phosphorylation sites in the VCA domain of WASP at serines 483 and 484. S483 and S484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the VCA domain for the Arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length WASP molecule.  SIGNOR-251048 0.354 DLL4 protein Q9NR61 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209735 0.629 SRC protein P12931 UNIPROT SH3GL1 protein Q99961 UNIPROT down-regulates phosphorylation Tyr315 QPSCKALyDFEPEND 9606 16054026 t lperfetto Further, we identified an interaction between fak's second pro-rich motif and endophilin a2's sh3 domain. This interaction served as an autophosphorylation-dependent scaffold to allow src phosphorylation of endophilin a2 at tyr315. Tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp. Together, these results suggest a regulatory mechanism of cell invasion whereby fak promotes cell-surface presentation of mt1-mmp by inhibiting endophilin a2-dependent endocytosis. SIGNOR-139150 0.624 CSNK2A1 protein P68400 UNIPROT KIR3DL1 protein P43629 UNIPROT up-regulates quantity by stabilization phosphorylation Ser388 RTANSEDsDEQDPEE -1 17911614 t miannu Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of Ser(394) by protein kinase C slightly suppresses KIR3DL1 inhibitory function, and reduces receptor internalization and turnover.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII. It seems that phosphorylation of 3DL1 by CK does not significantly affect receptor inhibitory function or turnover, at least in the assays that we have used so far. SIGNOR-276078 0.2 DAPK1 protein P53355 UNIPROT TPM1 protein P09493 UNIPROT up-regulates activity phosphorylation Ser283 HALNDMTsI 9606 BTO:0000007 17895359 t miannu We identified, for the first time, death-associated protein kinase 1 (DAP kinase 1) as the kinase that phosphorylates tropomyosin-1 in response to ERK activation by hydrogen peroxide (H(2)O(2)). We also report that the phosphorylation of tropomyosin-1 mediated by DAP kinase occurs on Ser283. Our finding that tropomyosin-1 is phosphorylated downstream of ERK and DAP kinase and that it helps regulate the formation of stress fibers will aid understanding the role of this protein in regulating the endothelial functions associated with cytoskeletal remodeling. SIGNOR-262845 0.28 F2R protein P25116 UNIPROT TNFRSF12A protein Q9NP84 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254846 0.2 PRKCE protein Q02156 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0001253 16418226 t gcesareni Abrogation of pkcdelta activity inhibited insulin-induced stat3 phosphorylation, pkcdelta-stat3 association and nuclear translocation. SIGNOR-143832 0.408 SLC38A2 protein Q96QD8 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity relocalization 9606 26724577 t Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine. SIGNOR-266913 0.8 RITA1 protein Q96K30 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 21102556 t gcesareni Thus, we propose that rita acts as a negative modulator of the notch signalling pathway, controlling the level of nuclear rbp-j/cbf-1, where its amounts are limiting. SIGNOR-170089 0.427 CAMK2G protein Q13555 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 11114197 t gcesareni Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation. SIGNOR-85098 0.404 CRP protein P02741 UNIPROT NOS3 protein P29474 UNIPROT down-regulates quantity by destabilization 17942113 f miannu C-reactive protein (CRP), a cardiovascular risk marker, induces endothelial dysfunction. CRP decreases endothelial nitric oxide synthase (eNOS) expression and bioactivity in human aortic endothelial cells (HAECs). CRP treatment significantly decreased levels of BH4 thereby promoting eNOS uncoupling. we found that CRP decreased the eNOS dimer/monomer ratio further supporting eNOS uncoupling. SIGNOR-252217 0.475 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Ser12 LASDFAFsPPPGGGG -1 31306665 t lperfetto Recently, Liu et al. [3] identified CyclinE/CDK2 to be the kinase phosphorylating OCT4 on serine 12 (S12), serine 355 (S355) and threonine 322 (T322) by elegantly combining genetics and biochemistry. Knockout of all five G1 cyclins (D1, D2, D3, E1 and E2) in mESCs (coined Q-KO cells) and consequent inactivation of CDK2/4/ 6 leads to perturbation of the pluripotent state and to the adaption of the trophectoderm cell fate. This was attributed to reduced phosphorylation of OCT4 (as well as SOX2 and NANOG) leading to an increase of protein turnover [3]. SIGNOR-264437 0.324 CBL protein P22681 UNIPROT LCK protein P06239 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11904433 t miannu Coexpression in 293T cells demonstrated that Lck kinase activity and Cbl ubiquitin ligase activity were essential for Lck ubiquitination and negative regulation of Lck-dependent serum response element-luciferase reporter activity. The Lck SH3 domain was pivotal for Cbl-Lck association and Cbl-mediated Lck degradation, with a smaller role for interactions mediated by the Cbl tyrosine kinase-binding domain. SIGNOR-272614 0.699 GRIN1 protein Q05586 UNIPROT NMDA receptor_2D complex SIGNOR-C350 SIGNOR form complex binding 9606 BTO:0000938 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits SIGNOR-264126 0.65 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser205 GVRRRRLsNVSLTGV 9606 10867018 t llicata Activation of the serine/threonine kinase, protein kinase d (pkd/pkc mu) via a phorbol ester/pkc-dependent pathway involves phosphorylation events. the second autophosphorylation site (ser(203)) lies in that region of the regulatory domain SIGNOR-78676 0.2 RNF123 protein Q5XPI4 UNIPROT CBX5 protein P45973 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 23077635 t miannu In the present study, we report that HP1α and β undergo proteasomal degradation in lamin A/C knock-down cells and show by ectopic expression, RNAi and binding studies that the RING finger ubiquitin ligase RNF123 is directly involved in HP1 degradation. SIGNOR-272035 0.2 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Ser368 NTSPRAIsRVDRERK 9606 BTO:0000007 10542239 t llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T SIGNOR-250808 0.2 CDK19 protein Q9BWU1 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Thr2511 VPEHPFLtPSPESPD -1 25344755 t lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues SIGNOR-273137 0.307 SMARCA4 protein P51532 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270608 0.83 CBX3 protein Q13185 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-264494 0.2 Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT STING1 protein Q86WV6 UNIPROT down-regulates activity binding 9606 22312431 t miannu Here we show that human coronavirus (HCoV) NL63 and severe acute respiratory syndrome (SARS) CoV papain-like proteases (PLP) antagonize innate immune signaling mediated by STING (stimulator of interferon genes, also known as MITA/ERIS/MYPS). STING resides in the endoplasmic reticulum and upon activation, forms dimers which assemble with MAVS, TBK-1 and IKKε, leading to IRF-3 activation and subsequent induction of interferon (IFN). We found that expression of the membrane anchored PLP domain from human HCoV-NL63 (PLP2-TM) or SARS-CoV (PLpro-TM) inhibits STING-mediated activation of IRF-3 nuclear translocation and induction of IRF-3 dependent promoters. Both catalytically active and inactive forms of CoV PLPs co-immunoprecipitated with STING SIGNOR-260247 0.2 TANK protein Q92844 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates activity binding 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262714 0.723 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates binding 9606 BTO:0001130 1010227 t gcesareni Progressive increase in akt activation during prostate cancer progression led to increase phosphorylation of foxo3a and binding with 14-3-3, which potentially affected its transcriptional activity in age-specific manner. SIGNOR-252819 0.702 Blood vessel damage stimulus SIGNOR-ST26 SIGNOR F3 protein P13726 UNIPROT up-regulates 9606 BTO:0000131 32665005 f lperfetto During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury. SIGNOR-263541 0.7 17beta-estradiol smallmolecule CHEBI:16469 ChEBI MAPK15 protein Q8TD08 UNIPROT up-regulates chemical activation 9606 BTO:0000150 11043579 t gcesareni Estrogen rapidly activates the mitogen-activated protein kinases, erk-1 and erk-2, via an as yet unknown mechanism. SIGNOR-83277 0.8 CNOT10 protein Q9H9A5 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268305 0.735 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89186 0.55 TRIM25 protein Q14258 UNIPROT SFN protein P31947 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0000298 12075357 t miannu Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3 sigma, a negative cell cycle regulator that causes G2 arrest. SIGNOR-271548 0.589 NR4A3 protein Q92570 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000815;BTO:0002552 30455429 f miannu NR4A3 exhibits p53-independent anti-proliferative functions. Ectopic expression of NR4A3 inhibits the growth of MDA-MB-231 and H1299 cancer cell lines. SIGNOR-256201 0.7 TLN1 protein Q9Y490 UNIPROT A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257628 0.458 AURKB protein Q96GD4 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. SIGNOR-98293 0.2 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000575 16469705 t gcesareni This is not due to direct c-FLIP phosphorylation but depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, SIGNOR-245310 0.644 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1693 SPTSPSYsPTSPSYS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248821 0.849 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GRIP1 protein Q9Y3R0 UNIPROT up-regulates activity phosphorylation Ser734 SLKGKPLsEAIHLLQ -1 11301320 t miannu Here we show that epidermal growth factor regulates the activities of the p160 GRIP1 through the extracellular signal-regulated kinase (ERK) family of mitogen-activated protein kinases. ERKs phosphorylate GRIP1 at a specific site, Ser-736, the integrity of which is required for full growth factor induction of GRIP1 transcriptional activation and coactivator function. SIGNOR-263056 0.2 RIPK1 protein Q13546 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 21133840 t simone vumbaca RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of Œ∫B kinase) complex SIGNOR-256022 0.534 MAPK3 protein P27361 UNIPROT ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser272 CSLERQLsLEQEVQQ 9606 BTO:0000567 12670876 t lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. SIGNOR-264441 0.334 CASP1 protein P29466 UNIPROT NLRP3 inflammasome complex SIGNOR-C225 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256409 0.753 CDK1 protein P06493 UNIPROT NDUFV3 protein P56181 UNIPROT up-regulates activity phosphorylation Ser105 QPSSGREsPRH 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275593 0.2 SRC protein P12931 UNIPROT WASF1 protein Q92558 UNIPROT up-regulates phosphorylation Tyr125 PIPLQETyDVCEQPP 9606 16317717 t lperfetto The wave/scar proteins regulate actin polymerisation at the leading edge of motile cells via activation of the arp2/3 complex in response to extracellular cues.Src-dependent phosphorylation of scar1 promotes its association with the arp2/3 complex SIGNOR-142724 0.417 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR5 protein P35346 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257585 0.8 TEAD1 protein P28347 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 20153295 f lperfetto We found that the expression of myf5 and cyclind1 remained significantly elevated upon induction of differentiation in cells that were overexpressing hyap1 s127a compared to cells transfected with wildtype hyap and empty vector;yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor. SIGNOR-235849 0.275 fexofenadine chemical CHEBI:5050 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 t Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells SIGNOR-257785 0.8 A6/b1 integrin complex SIGNOR-C164 SIGNOR SOX2 protein P48431 UNIPROT up-regulates quantity by expression 10090 18757303 f lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. SIGNOR-253279 0.377 AMPK complex SIGNOR-C15 SIGNOR CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser170 PSALNRTsSDSALHT 9606 21892142 t lperfetto Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation SIGNOR-216541 0.424 CSNK2A2 protein P19784 UNIPROT MYF5 protein P13349 UNIPROT up-regulates activity phosphorylation Ser133 NAIRYIEsLQELLRE -1 9461343 t llicata Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity.  SIGNOR-251016 0.312 SAGA complex complex SIGNOR-C465 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR down-regulates 9606 15970593 f lperfetto Transcription initiation is a major regulatory step in eukaryotic gene expression. Co-activators establish transcriptionally competent promoter architectures and chromatin signatures to allow the formation of the pre-initiation complex (PIC), comprising RNA polymerase II (Pol II) and general transcription factors (GTFs).|this observation appears remarkably prevalent for chromatin-modifying and remodeling complexes. Here, we use the modular organization of the evolutionary conserved Spt-Ada-Gcn5 acetyltransferase (SAGA) complex as a paradigm to illustrate how co-activators share and combine a relatively limited set of functional tools. SIGNOR-269569 0.7 AMPK complex SIGNOR-C15 SIGNOR ALDH2 protein P05091 UNIPROT up-regulates activity phosphorylation Thr356 GNPFDSKtEQGPQVD 10090 BTO:0000801 30375985 t lperfetto Further studies demonstrate that in the absence of LDLR, AMPK phosphorylates ALDH2 at threonine 356 and enables its nuclear translocation. Nuclear ALDH2 interacts with HDAC3 and represses transcription of a lysosomal proton pump protein ATP6V0E2, critical for maintaining lysosomal function, autophagy, and degradation of oxidized low-density lipid protein. SIGNOR-271862 0.254 MCHR2 protein Q969V1 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256938 0.252 MAPK14 protein Q16539 UNIPROT NFATC4 protein Q14934 UNIPROT down-regulates activity phosphorylation Ser170 GGAFFSPsPGSSSLS 10029 BTO:0001131 11997522 t miannu P38 MAP kinase phosphorylates Ser168 and Ser170 of NFATc4. Mutational replacement of Ser168,170 with Ala promotes NFATc4 nuclear localization and increases NFATc4-mediated transcription activity. SIGNOR-250108 0.411 NMDA receptor_2C complex SIGNOR-C349 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264134 0.7 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 10037602 t gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. SIGNOR-64972 0.852 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser551 ELQAPVRsPITRSFA 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249397 0.585 TP63 protein Q9H3D4 UNIPROT SYNE3 protein Q6ZMZ3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0005098 28595999 t lperfetto Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by a marked decrease in expression of several nuclear envelope-associated components (Lamin B1, Lamin A/C, Sun1, Nesprin-3, Plectin) compared with controls. Furthermore, chromatin immunoprecipitation-quantitative PCR assay showed enrichment of p63 on Sun1, Syne3, and Plec promoters, suggesting them as p63 targets. SIGNOR-263280 0.2 CIITA protein P33076 UNIPROT HLA-DMB protein P28068 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 9300700 f The class II transactivator (CIITA) is a highly specific transcription factor that activates only genes known to be involved in the class II MHC processing pathway, including class II MHC, invariant chain, and HLA-DMA/B genes. SIGNOR-254014 0.358 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition 9606 31908417 t miannu The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs. SIGNOR-262251 0.8 PTPRH protein Q9HD43 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase SIGNOR-76080 0.273 EREG protein O14944 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000150 22891299 t gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4. SIGNOR-191788 0.695 AURKA protein O14965 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates activity phosphorylation 7227 16824953 t lperfetto INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop SIGNOR-252047 0.714 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation Ser93 RVPKDRPsLTVTPKR 9606 BTO:0000567 21658950 t miannu Phosphorylation by Aurora B is required for full Haspin activity toward H3T3 in mitosis SIGNOR-262657 0.2 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates activity phosphorylation Ser407 STEQTLAsDTDSSLD -1 11062067 t MKK7 also phosphorylates JNK2 alpha 2 at Thr-404 and Ser-407 in vitro. Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. SIGNOR-251416 0.622 IKBKE protein Q14164 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Ser419 TPDDFLNsVDEMDTG 9606 28481329 t miannu Virus-activated kinase IKKɛ phosphorylated YAP at Ser403 and thereby triggered degradation of YAP in lysosomes and, consequently, relief of YAP-mediated inhibition of the cellular antiviral response.  SIGNOR-277355 0.451 GABA-B receptor complex SIGNOR-C336 SIGNOR GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 30541966 t miannu GABAB receptors are G protein-coupled receptors that mediate slow and prolonged inhibitory action, via activation of Gαi/o-type proteins. GABAB receptors mediate their inhibitory action through activating inwardly rectifying K+ channels, inactivating voltage-gated Ca2+ channels, and inhibiting adenylate cyclase. SIGNOR-265064 0.458 NPFFR2 protein Q9Y5X5 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256988 0.276 TANC2 protein Q9HCD6 UNIPROT KIF1A protein Q12756 UNIPROT up-regulates activity binding 10116 BTO:0003102 30021165 t miannu Kinesin-3 Family Member KIF1A Interacts with Liprin-α and TANC2. TANC2 and Liprin-α Recruit KIF1A-Driven DCVs in Dendritic Spines. Upon Ca2+/CaM binding, KIF1A is activated, allowing for DCV loading and motility. KIF1A-driven DCVs are recruited in dendritic spines by liprin-α and TANC2, which ensure a precise mechanism of synaptic tagging for the vesicles. SIGNOR-266891 0.25 IL1B protein P01584 UNIPROT IL1RAP protein Q9NPH3 UNIPROT up-regulates binding 9606 9820540 t gcesareni The recently described il-1r accessory protein (il-1r acp) interacts with il-1beta and the il-1 type-ir (il-1ri). SIGNOR-61744 0.862 F2RL3 protein Q96RI0 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257157 0.2 TNFRSF14 protein Q92956 UNIPROT TRAF5 protein O00463 UNIPROT up-regulates activity binding 9606 9153189 t lperfetto ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5|synergistic activation of NF-κB by ATAR and TRAF5 293 cells SIGNOR-262592 0.614 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates activity chemical activation 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258763 0.8 STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates activity phosphorylation -1 14976552 t lperfetto We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP_activated protein kinase (AMPK). SIGNOR-242602 0.595 FFAR1 protein O14842 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257338 0.2 PTPRO protein Q16827 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Ser727 NTIDLPMsPRTLDSL 9606 24708807 t miannu In addition, this group found that PTPRO dephosphorylated STAT3 at Y705 and S727 then attenuated STAT3 signalling. SIGNOR-277061 0.384 PPP1R3B protein Q86XI6 UNIPROT GYS1 protein P13807 UNIPROT up-regulates binding 9606 BTO:0000759 36551183 t miannu In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2) SIGNOR-271734 0.714 PALB2 protein Q86YC2 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity binding 9606 BTO:0001938 19369211 t lperfetto The BRCA1-PALB2 interaction is required for homologous recombination repair.Here, we report that PALB2, the partner and localizer of BRCA2, binds directly to BRCA1, and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex. SIGNOR-244487 0.845 SKI protein P12755 UNIPROT EP300 protein Q09472 UNIPROT down-regulates binding 9606 SIGNOR-C6 10575014 t gcesareni Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling. SIGNOR-72664 0.2 DNMT3B protein Q9UBC3 UNIPROT DPP6 protein P42658 UNIPROT down-regulates quantity by repression transcriptional regulation 23409053 t lperfetto Dnmt3b was responsible for transcriptional silencing of Dpp6 gene as depletion of Dnmt3b resulted in increased mRNA and protein expression of Dpp6. SIGNOR-268963 0.333 MAPK1 protein P28482 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 18204439 t lperfetto Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation. SIGNOR-160415 0.71 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Thr256 SQMKSMStFIEEAYK 9606 BTO:0000567 25670858 t lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. SIGNOR-265229 0.571 MRPL10 protein Q7Z7H8 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262383 0.649 NGF protein P01138 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates binding 9606 11114882 t gcesareni Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb. SIGNOR-85114 0.955 RPS6KA2 protein Q15349 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates activity phosphorylation Ser351 GRRGRLPsKPKQPPD 10116 11883936 t From PMID 9395454: We have shown that the in vitro phosphorylation of Ser350 located within the "A-box," a motif necessary for DNA binding by NGFI-B, results in a decrease in the binding of NGFI-B to its response element lperfetto Phosphorylation of a residue in the DNA-binding region (Ser-350 of NGFI-B and 354 of Nur77) has been described in detail to have effect on the transcriptional function of the protein [11, 24]. Growth-related kinase pp90rsk, but not ERK1 (pp44mapk), was shown to phosphorylate recombinant Nur77 in vitro in the DNA binding domain, but not the amino-terminus, using an immune complex kinase as- say [11]. SIGNOR-249429 0.375 sodium(1+) chemical CHEBI:29101 ChEBI Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 29863287 f miannu Axonal excitability is an important determinant for the accuracy, direction, and velocity of neuronal signaling. The mechanisms underlying spike generation in the axonal initial segment and transmitter release from presynaptic terminals have been intensely studied and revealed a role for several specific ionic conductances, including the persistent sodium current (INaP ). SIGNOR-265182 0.7 TFEB protein P19484 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates quantity by expression transcriptional regulation 30145926 f lperfetto Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB SIGNOR-276802 0.292 HAUS4 protein Q9H6D7 UNIPROT HAUS complex complex SIGNOR-C281 SIGNOR form complex binding 9606 BTO:0000567 19369198 t lperfetto Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC) SIGNOR-262324 0.816 5-[6-[(4-methyl-1-piperazinyl)methyl]-1-benzimidazolyl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]-2-thiophenecarboxamide chemical CHEBI:91333 ChEBI PLK1 protein P53350 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258221 0.8 DLK1 protein P80370 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates activity binding 10090 BTO:0002572 21419176 t gcesareni Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts. SIGNOR-172830 0.497 DCTN2 protein Q13561 UNIPROT Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR up-regulates activity relocalization 25364732 t lperfetto ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores SIGNOR-265018 0.2 GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 RIPK1 protein Q13546 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity phosphorylation Ser15 NVIKMKSsDFLESAE -1 18408713 t miannu These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1) SIGNOR-276162 0.2 MAPK1 protein P28482 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser345 QARPGPQsPGSPLEE 9606 BTO:0000130 16778989 t gcesareni Erk1/2 are the kinases involved in p47phox_ phosphorylation on ser345 in gm-csfprimed human neutrophils._ Phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells SIGNOR-147170 0.461 CTNND1 protein O60716 UNIPROT ZBTB33 protein Q86T24 UNIPROT down-regulates 9606 23481205 f gcesareni Nuclear signaling is affected by the interaction ofp120with kaiso, a transcription factor regulatingwnt-responsive genes. in addition, p120 cytoplasmic localization results in sequestration of kaiso in the cytoplasm and its inactivation SIGNOR-192369 0.817 TBK1 protein Q9UHD2 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity binding 9606 18353649 t lperfetto Whereas nemo assembles some but not all ikk complexes [12,13], recent reports provide strong experimental evidence for a role of tank [also called traf-interacting protein (i-traf)], nak-associated protein (nap1) and similar to nap1 tbk1 adaptor (sintbad) in the assembly of tbk1 and ikk-e kinase complexes that phosphorylate irf3 and irf7 and promote type i ifn gene induction SIGNOR-178053 0.63 RNF34 protein Q969K3 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates quantity by destabilization ubiquitination 26971449 t lperfetto We then examined the effect of necdin on ubiquitin-dependent degradation of PGC-1α using Rnf34, a PGC-1α E3 ubiquitin ligase22. Rnf34 reduced the PGC-1α level, and necdin completely inhibited the reduction (Fig. 4i). In addition, necdin strongly suppressed Rnf34-mediated ubiquitination of PGC-1α (Fig. 4j). Necdin also protected PGC-1α against ubiquitination mediated by Fbxw7, another PGC-1α E3 ubiquitin ligase23 (Fig. 4k). These data indicate that necdin stabilizes PGC-1α by inhibiting its degradation in the ubiquitin-proteasomal system. SIGNOR-253393 0.325 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 17998206 t lperfetto The endoplasmic reticulum (er)-resident protein kinase perk attenuates protein synthesis in response to er stress through the phosphorylation of translation initiation factor eif2_ at serine 51 / a modification that blocks initiation SIGNOR-159160 0.757 SMC3 protein Q9UQE7 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR form complex binding 28430577 t lperfetto Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin SIGNOR-263312 0.909 SELENOF protein O60613 UNIPROT UGGT2 protein Q9NYU1 UNIPROT up-regulates activity binding 9606 24415556 t miannu The enzymatic activity of UGGT2 is enhanced by complex formation with Sep15 SIGNOR-261373 0.2 KCNQ2 protein O43526 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 19298256 t miannu KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. SIGNOR-265982 0.8 PPP5C protein P53041 UNIPROT CILK1 protein Q9UPZ9 UNIPROT down-regulates activity dephosphorylation Thr157 IRSKPPYtDYVSTRW 9606 16954377 t llicata MAK and MRK require dual phosphorylation in a TDY motif catalyzed by an unidentified human threonine kinase and tyrosine autophosphorylation.| Protein phosphatase 5 (PP5) interacts with MRK in a complex and dephosphorylates MRK at T157 in vitro and in situ. SIGNOR-248541 0.2 PINK1 protein Q9BXM7 UNIPROT HIF3A protein Q9Y2N7 UNIPROT down-regulates activity phosphorylation Thr12 LQRARSTtELRKEKS 9606 BTO:0000793 27551449 t Parkinson miannu Here we show that IPAS is a key molecule involved in neuronal cell death in Parkinson's disease (PD). IPAS was ubiquitinated by Parkin for proteasomal degradation following carbonyl cyanide m-chlorophenyl hydrazone treatment. Phosphorylation of IPAS at Thr12 by PTEN-induced putative kinase 1 (PINK1) was required for ubiquitination to occur. SIGNOR-263090 0.354 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CDC25B protein P30305 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 21807946 t miannu  Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104). SIGNOR-276353 0.386 PTPN3 protein P26045 UNIPROT VCP protein P55072 UNIPROT down-regulates activity dephosphorylation Tyr796 GGTGGSVyTEDNDDD 9606 BTO:0000007 10364224 t Identification of VCP as a substrate of PTPH1in vivo.|The tyrosines (Tyr796 and Tyr805) at the C terminus of VCP have been reported to be the major sites of phosphorylation, with Tyr805 accounting for more than 90% of the tyrosine phosphorylation on the protein |The Y796F/Y805F VCP mutant was not associated with any of the PTPH1 constructs. SIGNOR-248460 0.491 SNARE_complex complex SIGNOR-C346 SIGNOR Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 30267828 f miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. SIGNOR-265065 0.7 NCL protein P19338 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 16508016 t Regulation miannu Nucleolin binds human β-globin mRNA. A Nucleolin-Binding 3′ Untranslated Region Element Stabilizes β-Globin mRNA In Vivo SIGNOR-251844 0.2 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 14556242 t gcesareni Two genes were newly identified to be shh responsive in neuroepithelial cell line mns-70: the metal-binding protein ceruloplasmin (cp) and the serine protease inhibitor inter-alpha-trypsine inhibitor heavy chain h3 (itih3). cp appeared to be regulated by gli-independent pathways. SIGNOR-118612 0.2 CCL21 protein O00585 UNIPROT ACKR4 protein Q9NPB9 UNIPROT up-regulates activity binding 9606 BTO:0001938 23341447 t Luana  In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines. SIGNOR-268417 0.652 WWTR1 protein Q9GZV5 UNIPROT TEAD proteinfamily SIGNOR-PF22 SIGNOR up-regulates activity binding 9606 23431053 t miannu YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death SIGNOR-230722 0.895 GRK2 protein P25098 UNIPROT IGF1R protein P08069 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1278 EPGFREVsFYYSEEN -1 22509025 t miannu GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting β-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated β-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation SIGNOR-276413 0.2 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11013220 f irozzo Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β. SIGNOR-256286 0.588 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 BTO:0000671 15694384 t llicata Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925. SIGNOR-133841 0.2 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT down-regulates activity phosphorylation Thr509 PVCEVSVtPKTVTPA 9606 phosphorylation:Ser522 PASSAKTsPAKQQAP 25040932 t lperfetto Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition SIGNOR-264839 0.713 SL1 complex complex SIGNOR-C464 SIGNOR UBTF protein P17480 UNIPROT up-regulates activity binding 9606 15970593 t lperfetto Therefore, we propose that SL1 directs PIC formation, functioning in core promoter binding, RNA polymerase I recruitment, and UBF stabilization and that SL1-promoter complex formation is a necessary prerequisite to the assembly of functional and stable PICs that include the UBF activator in mammalian cells. SIGNOR-269567 0.652 PRKCA protein P17252 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity phosphorylation Thr115 ADRRKAAtMRERRRL 9534 1335366 t lperfetto FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains. SIGNOR-248845 0.371 RYK protein P34925 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 9606 15454084 t gcesareni Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled. SIGNOR-129568 0.496 CDK1 protein P06493 UNIPROT UBE2A protein P49459 UNIPROT up-regulates phosphorylation Ser120 LDEPNPNsPANSQAA 9606 11953320 t llicata Hhr6a is phosphorylated in vitro by cdk-1 and -2 on ser120, a residue conserved in all hhr6a homologues, resulting in a 4-fold increase in its ubiquitin-conjugating activity. SIGNOR-116504 0.377 ZBTB16 protein Q05516 UNIPROT RSAD2 protein Q8WXG1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003846 19523849 t lperfetto Promoter regions from the PLZF-regulated transcripts Rsad2 and Ifit2 were fused to luciferase and activity was measured after IFN treatment. Overexpression of PLZF in RCC1 or ACHN cells produced a dose-dependent induction of the reporter promoters.  SIGNOR-261023 0.2 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 15611135 t gcesareni We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines. SIGNOR-132559 0.263 SRC protein P12931 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates activity phosphorylation Tyr322 GDGPAVDyENQDVAS 9606 12540842 t lperfetto To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src. SIGNOR-247337 0.415 GABRG2 protein P18507 UNIPROT GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263752 0.643 (5Z)-5-(quinoxalin-6-ylmethylidene)-1,3-thiazolidine-2,4-dione chemical CHEBI:45302 ChEBI PIK3CG protein P48736 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000099 31195053 t miannu We identified the protective effect of the PI3Kγ inhibitor AS605240 against stroke-related injury in the mouse model of transient intraluminal middle cerebral artery occlusion (tMCAO). in this study, the effects of AS605240 on astrocytes were studied in cell cultures. SIGNOR-262224 0.8 DYRK1A protein Q13627 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr529 TPGSRSRtPSLPTPP 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna SIGNOR-171038 0.438 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr676 FGMSRDIySTDYYRV 9606 9099755 t gcesareni In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785 SIGNOR-47171 0.2 CHEK1 protein O14757 UNIPROT FANCE protein Q9HB96 UNIPROT up-regulates phosphorylation Thr346 LGLLRLCtWLLALSP 9606 17296736 t llicata Chk1 directly phosphorylates the fance subunit of the fa core complex on two conserved sites (threonine 346 and serine 374). chk1-mediated phosphorylation of fance is required for the fanconi anemia/brca pathway. SIGNOR-153027 0.705 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR CREB3L1 protein Q96BA8 UNIPROT up-regulates 9606 16417584 f miannu Oasis (old astrocyte specifically induced substance) is an er stress transducer in astrocytes, a membrane-bound transcription factor that activates genes in the er stress response / when unfolded proteins accumulate in the er, oasis is cleaved at the membrane to release its cytoplasmic domain, which then enters the nucleus and activates target genes. SIGNOR-143823 0.7 CDK1 protein P06493 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates phosphorylation Ser428 FAQSAPGsPLSSQPV 9606 20810654 t gcesareni We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis. SIGNOR-167826 0.38 CKM complex complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-273144 0.346 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. SIGNOR-129292 0.29 Phenelzine chemical CHEBI:8060 ChEBI MAOA protein P21397 UNIPROT down-regulates activity chemical inhibition -1 18426226 t Luana Phenylethylhydrazine stoichiometrically reduces the covalent FAD moieties of MAO A and of MAO B. Molecular oxygen is required for the inhibition reactions, and the level of O2 consumption for phenylethylhydrazine is 6-7-fold higher with either MAO A or MAO B than for the corresponding reactions with benzylhydrazine or phenylhydrazine. SIGNOR-257777 0.8 GPR35 protein Q9HC97 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256996 0.252 UQCRB protein P14927 UNIPROT Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 t lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits SIGNOR-262194 0.924 AIFM2 protein Q9BRQ8 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0003000 12135761 f miannu The PRG3 gene is a potential p53 target gene in a p53‐dependent apoptosis pathway. These results clearly indicate that the ectopic expression of PRG3 induces apoptosis. SIGNOR-261809 0.7 PYGB protein P11216 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI down-regulates quantity chemical modification 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [‚Ķ] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267395 0.8 TRAF6 protein Q9Y4K3 UNIPROT MALT1 protein Q9UDY8 UNIPROT up-regulates ubiquitination 9606 BTO:0000782 17948050 t gcesareni Traf6 associates with malt1 in response to t-cell activation and can function as an e3 ligase for malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of malt1. Multiple lysine residues in the c-terminus of malt1 serve as acceptor sites for the assembly of polyubiquitin chains. (articolo-abstract) SIGNOR-158554 0.746 MAPK14 protein Q16539 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20162623 f Indirect:regulation miannu Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6). SIGNOR-251837 0.2 ILF2 protein Q12905 UNIPROT NF90-NF45 complex SIGNOR-C443 SIGNOR form complex binding -1 18458058 t miannu Nuclear factor 90 (NF90) and its C-terminally extended isoform, NF110, have been isolated as DNA- and RNA-binding proteins together with the less-studied protein NF45. These complexes have been implicated in gene regulation, but little is known about their cellular roles and whether they are redundant or functionally distinct. We show that heterodimeric core complexes, NF90-NF45 and NF110-NF45, exist within larger complexes that are more labile and contain multiple NF90/110 isoforms and additional proteins. This study identified NF45 as an unstable regulatory subunit of NF90-NF45 complexes and uncovered their critical role in normal cell division. Furthermore, the study revealed that NF90 is functionally distinct from NF110 and is more important for cell growth. SIGNOR-268487 0.591 MYO9A protein B2RTY4 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260508 0.546 CDK1 protein P06493 UNIPROT RPA2 protein P15927 UNIPROT up-regulates activity phosphorylation Ser23 GAGGYTQsPGGFGSP 9606 1318195 t llicata Cdc2 family kinases phosphorylate a human cell dna replication factor, rpa, and activate dna replication. therefore, the serines on rpa p34 that were necessary for phosphorylation by cdc2 kinase were also necessary for phosphorylation in the cell SIGNOR-16971 0.52 DNA_damage stimulus SIGNOR-ST1 SIGNOR SLX4 protein Q8IY92 UNIPROT up-regulates -1 10542278 f miannu HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay. SIGNOR-259063 0.7 ITGB1 protein P05556 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253184 0.773 CXCL8 protein P10145 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252288 0.7 CUL3 protein Q13618 UNIPROT TNFAIP1 protein Q13829 UNIPROT up-regulates activity binding 9606 19782033 t miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. SIGNOR-264232 0.473 propionic acid chemical CHEBI:30768 ChEBI FFAR2 protein O15552 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257489 0.8 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser675 QDYKKRLsVELTSSL 9606 BTO:0000007 16476742 t lperfetto In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin SIGNOR-144482 0.46 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB6 protein P18564 UNIPROT up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259007 0.2 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Ser400 PINACELsPKGKEQA -1 12361598 t miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) SIGNOR-265956 0.53 Caspase 3 complex complex SIGNOR-C221 SIGNOR GSN protein P06396 UNIPROT down-regulates activity cleavage Asp403 WRDPDQTdGLGLSYL 9606 9671712 t miannu We showed that human gelsolin was cleaved during Fas-mediated apoptosis in vivo and that the caspase-3 cleavage site of human gelsolin was at D352 of DQTD352G. gelsolin seems to have dual functions, i.e., it both prevents and, once cleaved, induces cell death. SIGNOR-256433 0.624 DDC protein P20711 UNIPROT 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI down-regulates quantity chemical modification 9606 31024440 t brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT SIGNOR-264013 0.8 MAML1 protein Q92585 UNIPROT CDK8 protein P49336 UNIPROT up-regulates binding 9606 15546612 t gcesareni Mastermind recruits cycc:cdk8 to phosphorylate the notch icd and coordinate activation with turnover SIGNOR-130715 0.581 CSNK1A1 protein P48729 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017877 t llicata Phosphorylation of all three serine residues in the deptor degron (ser286, ser287, and ser291) is necessary for - and directly mediates - the interaction with _trcp. ck1 phosphorylated the degron of deptor, as shown by western blotting with the phospho-specific antibody (fig. S3e-f). In contrast, mtor alone was unable to induce phosphorylation of deptor on ser286, ser287, and ser291. SIGNOR-176875 0.2 FYN protein P06241 UNIPROT CD300LF protein Q8TDQ1 UNIPROT up-regulates activity phosphorylation Tyr263 AEDQEPTyCNMGHLS 17202342 t lperfetto Y236 (YVTM) and Y263 (YCNM) fit with the consensus motif reported to bind the p85α regulatory subunit of PI3K (16). |The association between IREM-1 and p85α was only perceived in the presence of c-Fyn, suggesting that tyrosine phosphorylation of IREM-1 cytoplasmic tail of IREM-1 was required for the interaction. SIGNOR-275620 0.35 IFNGR1 protein P15260 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 17063185 t flangone Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively SIGNOR-150194 0.691 RAD50 protein Q92878 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR form complex binding 17713585 t lperfetto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50. SIGNOR-251506 0.911 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity phosphorylation Ser124 PALKRSHsDSLDHDI 9606 12676583 t Manara Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A SIGNOR-260835 0.837 KDM5C protein P41229 UNIPROT SYN1 protein P17600 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 31691806 f miannu The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. SIGNOR-264314 0.352 TKT protein P29401 UNIPROT sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI up-regulates quantity chemical modification 9606 24929114 t miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. SIGNOR-267087 0.8 HCRTR2 protein O43614 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257350 0.252 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Ser582 LNKLQQHsDKIIRLY 9606 18680479 t miannu We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / autophosphorylation outside the activation segment was also important for activity in vitro, since s582a/s582d and y811f mutants exhibited decreased activity SIGNOR-179896 0.2 SMAD7 protein O15105 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates activity relocalization 9606 21791611 t lperfetto One of the major mechanisms underlying the inhibitory effect of Smad7 on TGF-_ signaling operates through accelerating T_RI turnover by recruiting ubiquitin E3 ligases such as Smurf1 and Smurf2 SIGNOR-175269 0.878 IDH1 protein O75874 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI down-regulates quantity 9606 26178471 t lperfetto Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG) SIGNOR-253137 0.8 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 10085140 t gcesareni On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38. SIGNOR-65601 0.786 ROCK1 protein Q13464 UNIPROT SOX9 protein P48436 UNIPROT up-regulates phosphorylation Ser181 YQPRRRKsVKNGQAE 9606 20039424 t lperfetto Rho kinase-dependent activation of sox9 in chondrocytes. In vitro, rock directly phosphorylated sox9 at ser(181), and the overexpression of rock or the activation of the rhoa pathway in sw1353 chondrosarcoma cells increased sox9(ser181) phosphorylation SIGNOR-162643 0.31 NMBR protein P28336 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257373 0.449 IL17RC protein Q8NAC3 UNIPROT IL17R complex complex SIGNOR-C260 SIGNOR form complex binding 9606 BTO:0001946 32024054 t lperfetto Importantly, IL-17 was involved in increased collagen production in cardiac fibroblasts in response to HG, with both subunits of the IL-17RA and IL-17RC heterodimer complex being important to mediating this response. SIGNOR-261336 0.53 JAK2 protein O60674 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr327 NSKPKKSyIATQGCL 9534 BTO:0004055 8995399 t lperfetto Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2 SIGNOR-236270 0.786 PRKD1 protein Q15139 UNIPROT FAM83G protein A6ND36 UNIPROT up-regulates activity phosphorylation Ser356 YALVKAKsVDEIAKI 10029 32570757 t lperfetto Taken together, these data demonstrate that FAM83G S356 phosphorylation modulates HSP27 phosphorylation and apoptosis regulation and that HSP27 is a counterpart of FAM83G.|an active form of PKD1/PKCm could phosphorylate the FAM83G peptide, including the S356 portion.|We also demonstrated that the phosphorylation of the FAM83G S356 residue was required for the reduction of the live cell number, as the CHO cells were unaffected upon the overexpression of a FAM83G S356A mutant resistant to S356 phosphorylation. SIGNOR-264764 0.2 EGR1 protein P18146 UNIPROT HPSE protein Q9Y251 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001671;BTO:0001345 16007175 t Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer. SIGNOR-254267 0.378 GATA3 protein P23771 UNIPROT FOXC2 protein Q99958 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22120723 f miannu We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. SIGNOR-254089 0.337 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1B protein Q01064 UNIPROT down-regulates activity chemical inhibition 9606 22014080 t Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors. SIGNOR-253400 0.8 GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268597 0.2 Activated PSC phenotype SIGNOR-PH224 SIGNOR TGFB2 protein P61812 UNIPROT up-regulates quantity 9606 BTO:0000988 38540204 t miannu Resident fibroblasts, especially PSC, have the ability to transdifferentiate from a “quiescent” retinoid/lipid storing phenotype in the normal pancreas to an “activated” α-smooth muscle-actin-producing myofibroblastic phenotype through tumor-derived stimuli such as cytokines (interleukin(IL)-1, IL-6, and IL-8 and tumor necrosis factor (TNF)-α), growth factors (platelet-derived growth factor (PDGF) and tumor growth factor (TGF)-β), and reactive oxygen species [33]. Activated PSCs can, in turn, produce autocrine factors such as PDGF, TGF-β, and cytokines, which may contribute to a looping mechanism promoting a desmoplastic reaction SIGNOR-277674 0.7 UCK1 protein Q9HA47 UNIPROT cytidine 5'-monophosphate(2-) smallmolecule CHEBI:60377 ChEBI up-regulates quantity chemical modification 11306702 t lperfetto Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. SIGNOR-275859 0.8 SLBP protein Q14493 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265373 0.2 TFAP2B protein Q92481 UNIPROT CRYAB protein P02511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21556774 t miannu Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53 SIGNOR-253637 0.2 MECP2 protein P51608 UNIPROT CRH protein P06850 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000142 17108082 t Luana Collectively, these results point to a specific association between WT MeCP2 and the methylated promoter region of Crh in vivo. In contrast, the MeCP2308 protein was not detected at the Crh promoter. | Thus, the results of seqChIP indicate that MeCP2 preferentially associates with a transcriptionally inactive, dimethyl-histone H3 Lys-9-rich form of the Crh promoter in mice. SIGNOR-264548 0.479 LCK protein P06239 UNIPROT SH2B3 protein Q9UQQ2 UNIPROT up-regulates phosphorylation Tyr273 LEMPDNLyTFVLKVK 9606 9169414 t lperfetto In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation. SIGNOR-48850 0.586 ADCY5 protein O95622 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 t miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. SIGNOR-264999 0.8 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr373 ASDTDSSyCIPTAGM 9606 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236408 0.751 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser268 VALPPGAsPQRSRSP 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252342 0.635 KAT5 protein Q92993 UNIPROT CHKA protein P35790 UNIPROT up-regulates activity acetylation Lys247 MPFNKEPkWLFGTME 9606 34929314 t lperfetto Glucose deprivation induces the binding of choline kinase α2 (CHKα2) to lipid droplets, followed by a continuous PTMs to promote lipolysis of lipid droplets, which are in turn mediated by AMPK-dependent CHKα2 Serine 279 phosphorylation and KAT5-dependent CHKα2 Lysine 247 acetylation. SIGNOR-267648 0.2 CDH1 protein P12830 UNIPROT AE/b7 integrin complex SIGNOR-C186 SIGNOR up-regulates binding 9606 BTO:0000782 7969453 t gcesareni Here we show that heterotypic adhesive interactions between epithelial cells and intraepithelial lymphocytes in vitro are mediated by e-cadherin and the alpha e beta 7 integrin. SIGNOR-35210 0.639 CSNK1E protein P49674 UNIPROT CDH1 protein P12830 UNIPROT down-regulates activity phosphorylation Ser844 GSGSEAAsLSSLNSS 17353278 t lperfetto Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846 SIGNOR-274047 0.262 CDK1 protein P06493 UNIPROT MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr207 PRQDYSRtPGQVLSL 8355 22354989 t gcesareni We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop SIGNOR-249653 0.492 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Thr100 TNTYYLQtFGHNTMD 9606 BTO:0000007 21321328 t miannu We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity. SIGNOR-263129 0.595 APOB protein P04114 UNIPROT VLDL_assembly phenotype SIGNOR-PH62 SIGNOR up-regulates 9606 23721961 f miannu Apolipoprotein B is a structural protein that is an integral component of chylomicrons, as well as very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) particles. In man, VLDL contains only ApoB100, the full length protein SIGNOR-252115 0.7 ETV6 protein P41212 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15958056 f Regulation of expression miannu Upon erythropoietin exposure, overexpressed TEL stimulated hemoglobin synthesis SIGNOR-251793 0.2 ARHGEF15 protein O94989 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260541 0.537 NR3C1 protein P04150 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19805059 t miannu GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription SIGNOR-268051 0.301 SIM2 protein Q14190 UNIPROT ARNT protein P27540 UNIPROT up-regulates activity binding -1 9020169 t 2 miannu We demonstrate that both SIM1 and SIM2 can heterodimerize via their helix-loop-helix·PAS regions with ARNT, but not with AHR, and that they do not form homodimers. Furthermore, SIM1 may have a dual role, both negatively affecting AHR·ARNT binding to the XRE and also acting in concert with ARNT as a novel DNA-binding heterodimer. SIGNOR-240808 0.51 LEPR protein P48357 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity binding 9606 BTO:0000007 11018044 t miannu LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2. SIGNOR-263495 0.75 JAK1 protein P23458 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates activity phosphorylation Tyr446 AAVAFQGyLRQTRCA 10433356 t Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation of the receptor-associated Janus tyrosine kinases, JAK1 and Tyk2. These kinases then phosphorylate specific tyrosine residues (Y446 and Y496) on the intracellular domain of the IL-10R1 chain. Once phosphorylated, these tyrosine residues (and their flanking peptide sequences) serve as temporary docking sites for the latent transcription factor, STAT3 (signal transducer and activator of transcription-3). SIGNOR-251338 0.802 PLK1 protein P53350 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser637 HSLLERYsVNEGLVA 9606 BTO:0000567 phosphorylation:Thr550 PPINGSStPNPKIAS 19509060 t lperfetto Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation. SIGNOR-272991 0.603 SREBF1 protein P36956 UNIPROT LRP1 protein Q07954 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20980003 f miannu In the present study we report that specific silencing of either SREBP-1 or SREBP-2 enhanced LRP1 whereas overexpression of the active SREBP isoforms decreased LRP1 expression. SIGNOR-254462 0.281 MAPK3 protein P27361 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity phosphorylation Ser982 KKKSEPSsPDHGSST -1 11287604 t lperfetto Plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982 SIGNOR-106565 0.422 CDK1 protein P06493 UNIPROT RRM2 protein P31350 UNIPROT down-regulates phosphorylation Thr33 SLVDKENtPPALSGT 9606 22632967 t gcesareni We found that, during g2, following cdk-mediated phosphorylation of thr33, rrm2 is degraded via scf(cyclin f) to maintain balanced dntp pools and genome stability. SIGNOR-197630 0.517 TFIIH complex SIGNOR-C457 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10949034 t lperfetto Activation of estrogen receptor alpha by s118 phosphorylation involves a ligand-dependent interaction with tfiih and participation of cdk7. SIGNOR-269356 0.305 HNF4A protein P41235 UNIPROT NPC1L1 protein Q9UHC9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21123766 f miannu Our results showed a positive correlation between changes in NPC1L1 and changes in both SREBP-2 and HNF-4α mRNA expression, a finding that supports the notion that these transcription factors stimulate intestinal NPC1L1 expression. SIGNOR-254460 0.263 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 9606 BTO:0000887 20151718 t miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-163768 0.277 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 8119945 t gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. SIGNOR-36279 0.852 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-269969 0.2 KDM5B protein Q9UGL1 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-264303 0.2 NR1D2 protein Q14995 UNIPROT ARNTL protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24577401 t miannu A retinoic acid receptor-related orphan receptor (ROR) response element within the BMAL1 promoter is responsive to both ROR and REV-ERB (encoded by the genes NR1D1 and NR1D2); ROR activates the transcription of BMAL1, whereas REV-ERB suppresses its transcription. SIGNOR-268006 0.48 RAP1A protein P62834 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR up-regulates activity binding 10090 BTO:0003104 12808052 t lperfetto The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration|Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity. SIGNOR-253362 0.459 GRPR protein P30550 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257046 0.271 ESR2 protein Q92731 UNIPROT CRH protein P06850 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000614 8408641 t lperfetto Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction.|Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro. SIGNOR-268722 0.395 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser672 VRGPVSGsPDSMNAS 9606 BTO:0000007 10195894 t Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. SIGNOR-251275 0.2 DUSP26 protein Q9BV47 UNIPROT NTRK1 protein P04629 UNIPROT down-regulates activity dephosphorylation 9606 28701747 t miannu NEAP and DUSP26 dephosphorylated TrkA and FGFR1 directly.|We found that NEAP, but not its phosphatase-defective mutant, suppressed nerve growth factor (NGF) receptor TrkA and fibroblast growth factor receptor 1 (FGFR1) activation in PC12 cells SIGNOR-277105 0.379 PTGS2 protein P35354 UNIPROT prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI up-regulates chemical modification 9606 20219869 t apalma NSAIDs are strong inhibitors of cycloxygenases (COX), and thereby impair the metabolism of arachidonic acid that is necessary for the synthesis of prostaglandins SIGNOR-255359 0.8 TGIF1 protein Q15583 UNIPROT WWP1 protein Q9H0M0 UNIPROT up-regulates binding 9606 15359284 t gcesareni We demonstrate that tiul1 degrades not only the activated type i receptor in association with smad7 but also smad2 in association with tgif.the steady-state levels of tgif are not affected by tiul1, but the interaction of tiul1 with tgif allows this ubiquitin ligase to target smad2 for degradation. SIGNOR-128854 0.336 CCK protein P06307 UNIPROT CCKBR protein P32239 UNIPROT up-regulates binding 9606 10368033 t gcesareni Cck8 interacts with nanomolar affinities with two different receptors designated cck-a and cck-b SIGNOR-66339 0.866 SETD2 protein Q9BYW2 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity methylation Lys525 QLNMLGEkLLGPNAS 9606 BTO:0000007 28753426 t Gianni SETD2 enhances antiviral immunity by directly methylating STAT1 on K525. Mechanistically, SETD2 directly mediates STAT1 methylation on lysine 525 via its methyltransferase activity, which reinforces IFN-activated STAT1 phosphorylation and antiviral cellular response. SIGNOR-269091 0.269 PKN1 protein Q16512 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser637 VDLSKVTsKCGSLGN 9606 BTO:0000938 BTO:0000975 11104762 t The effect has been demonstrated using P10636-8 lperfetto Phosphorylation of tau is regulated by pknthere is a pkn-specific phosphorylation site, ser-320, in mbdsthus pkn serves as a regulator of microtubules by specific phosphorylation of tau, which leads to disruption of tubulin assembly. SIGNOR-84958 0.335 DUSP9 protein Q99956 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 BTO:0000887 11988087 t This interaction is observed for Mus musculus Pyst3 gene, which encodes for DUSP9 gcesareni These properties define the ability of this enzyme to dephosphorylate and inactivate erk1/2 and p38a, but not jnk (c-jun n-terminal kinase) in vivo. SIGNOR-87150 0.689 MK-2206 chemical CHEBI:67271 ChEBI AKT3 protein Q9Y243 UNIPROT down-regulates chemical inhibition 9606 BTO:0001286 21841310 t gcesareni Treatment with the pi3k inhibitor ly294002 or the akt inhibitor mk2206 diminished s473 phosphorylation. SIGNOR-176049 0.8 PRKCQ protein Q04759 UNIPROT WIPF1 protein O43516 UNIPROT up-regulates activity phosphorylation Ser488 RNESRSGsNRRERGA -1 12504004 t lperfetto TCR engagement also causes PKCtheta-dependent phosphorylation of WIP, causing the disengagement of WASP from the WIP-WASP complex, thereby releasing it from WIP inhibition. These results suggest that the ZAP-70-CrkL-WIP pathway and PKCtheta link TCR to WASP activation. | These results suggest that phosphorylation at S488 disrupts WIP binding to WASP. SIGNOR-249181 0.329 TFAP2B protein Q92481 UNIPROT PTGDS protein P41222 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002605 15743775 f miannu Deletion and mutation of the AP-2 element at -98 in the L-PGDS gene promoter result in a drastic decrease in the reporter activity (Figs. 1 and 2). Results from the EMSA and ChIP assay demonstrated that AP-2β bound to the AP-2 element both in vitro and in TE671 cells SIGNOR-255425 0.2 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI AXL protein P30530 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258109 0.8 3-phosphonatooxypyruvate(3-) smallmolecule CHEBI:18110 ChEBI O-phosphonato-L-serine(2-) smallmolecule CHEBI:57524 ChEBI up-regulates quantity precursor of 3702 30034403 t lperfetto Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction. SIGNOR-268563 0.8 KLF4 protein O43474 UNIPROT PBX1 protein P40424 UNIPROT up-regulates activity binding 9606 BTO:0000093 21746878 t miannu We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. SIGNOR-267237 0.457 KDM4C protein Q9H3R0 UNIPROT H2AC4 protein P04908 UNIPROT down-regulates activity demethylation Lys 10 GRGKQGGkARAKAKT 9606 29207681 t miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation SIGNOR-263863 0.2 DUSP19 protein Q8WTR2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 11959861 t gcesareni Skrp1 was highly specific for c-jun n-terminal kinase (jnk) in vitro and effectively suppressed the jnk activation in response to tumor necrosis factor alpha or thapsigargin skrp1 does not bind directly to its target jnk, but co-precipitation of skrp1 with the mapk kinase mkk7, a jnk activator, was found in vitro and in vivo. SIGNOR-117260 0.431 PRKCG protein P05129 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser185 SAYVGRLsARPKLKA -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276019 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser12 KTLYSFFsPSPARKR 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276091 0.292 SIRT1 protein Q96EB6 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity 10090 BTO:0000165 12887892 t gcesareni Sir2 forms a complex with the acetyltransferase PCAF and MyoD and, when overexpressed, retards muscle differentiation SIGNOR-241963 0.605 FGF2 protein P09038 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 15765505 f gcesareni Runx2 is an important mediator of the expression of bmp-2 in response to fgf stimulation in cranial bone development. SIGNOR-134512 0.451 SARS1 protein P49591 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 24095058 t miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis SIGNOR-270495 0.8 MAPK3 protein P27361 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser345 QARPGPQsPGSPLEE 9606 BTO:0000130 16778989 t gcesareni Inhibitors of the erk1/2 pathway abrogated gm-csf-induced phosphorylation of ser345, while p38 mapk inhibitor abrogated tnf-alpha-induced phosphorylation of ser345.These results show that the ala-mutated p47phox acts as a dominant-negative inhibitor of endogenous p47phox and clearly indicate that phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells. SIGNOR-147174 0.431 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity binding 9606 33358571 t miannu The multifunctional cytokine TGF-β has been identified as a potent inducer of CTGF expression, activating CTGF transcription through the canonical Smad signaling pathway. It is worth noting that TGF-β synergizes with Hippo–Yes-associated protein (YAP) signaling, a key regulator of tumorigenesis, to induce the expression of CTGF by the formation of a YAP-TEAD4-Smad3-p300 complex on the CTGF promoter SIGNOR-277684 0.574 SLBP protein Q14493 UNIPROT H2AB1 protein P0C5Y9 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265411 0.2 GLI3 protein P10071 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19860666 t gcesareni GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin SIGNOR-188884 0.697 ATG12 protein O94817 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 4932 23321721 f lperfetto Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation SIGNOR-219396 0.7 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser74 TPHLPPCsPPKQGKK 9606 SIGNOR-C83 10339564 t lperfetto Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction. SIGNOR-67548 0.94 L-tryptophan smallmolecule CHEBI:16828 ChEBI 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI up-regulates quantity precursor of 9606 31024440 t brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. SIGNOR-264184 0.8 TRIM63 protein Q969Q1 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys365 SLASQATkDGKKDKK -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). SIGNOR-272741 0.413 PLK4 protein O00444 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates phosphorylation Ser595 ISFSSNSsFVLKILE 9606 20531387 t lperfetto Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. Plk4 also phosphorylates s595 of cpap SIGNOR-166007 0.791 G6PC1 protein P35575 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity chemical modification 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-266564 0.8 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252864 0.756 MPO-ANCA complex SIGNOR-C474 SIGNOR superoxide smallmolecule CHEBI:18421 ChEBI up-regulates 10090 BTO:0000133 15972951 f lperfetto Anti-MPO IgG (250 μg/ml) induces significant superoxide anion production in TNF-α-primed peritoneal exudate cells from WT C57BL/6 mice (black bars) as compared to normal mouse IgG (250 μg/ml) or buffer alone. SIGNOR-270589 0.8 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 8548810 t amattioni The c-iaps associate with traf1 and traf2 SIGNOR-39596 0.888 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser274 ASPQRSRsPSPQPSS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252328 0.635 FANCL protein Q9NW38 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 t lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263245 0.906 SOCS3 protein O14543 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity binding 9606 23454976 t miannu SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition SIGNOR-253051 0.722 (-)-anisomycin chemical CHEBI:338412 ChEBI PCSK7 protein Q16549 UNIPROT up-regulates chemical activation 9606 BTO:0000142 16581040 t gcesareni These results indicate that activation of p38 mapk by anisomycin induces ltd and subsequently occludes electrically induced ltd SIGNOR-145496 0.8 BUB1 protein O43683 UNIPROT BUB1 protein O43683 UNIPROT up-regulates activity phosphorylation Ser969 FTAKCETsGFQCVEM -1 26658523 t miannu  Conversely, Bub1 is an active kinase regulated by intra-molecular phosphorylation at the P+1 loop. SIGNOR-277186 0.2 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine smallmolecule CHEBI:44811 ChEBI PTAFR protein P25105 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257567 0.8 PAMPs stimulus SIGNOR-ST11 SIGNOR AIM2 inflammasome complex SIGNOR-C222 SIGNOR up-regulates activity 16037825 f miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-263126 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-251523 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 27846390 t inferred from 70% family members lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.¬† SIGNOR-269999 0.2 NLRX1 protein Q86UT6 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity relocalization 9606 BTO:0002181 18219313 f Giorgia NLRX1 synergistically potentiated ROS production induced by tumour necrosis factor alpha, Shigella infection and double-stranded RNA, resulting in amplified NF-kappaB-dependent and JUN amino-terminal kinases-dependent signalling. We observed that NLRX1-positive cells showed increased p65 translocation as early as 15 min after infection, an effect that was maintained over time. SIGNOR-260358 0.261 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120192 0.321 STK11 protein Q15831 UNIPROT SIK1 protein P57059 UNIPROT up-regulates activity phosphorylation Thr182 KSGEPLStWCGSPPY 9606 18946175 t miannu Salt inducible kinase (SIK) 1, a member of the AMP-activated kinase (AMPK) family, is activated by the AMPK-activator LKB1 which phosphorylates SIK1 at Thr182. SIGNOR-262844 0.567 ASXL1 protein Q8IXJ9 UNIPROT RARA protein P10276 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16606617 f irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. SIGNOR-255933 0.455 RPL39 protein P62891 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262490 0.837 PP1 proteinfamily SIGNOR-PF54 SIGNOR PYGL protein P06737 UNIPROT down-regulates activity dephosphorylation Ser15 QEKRRQIsIRGIVGV 9606 22225877 t GP is the first protein whose function was discovered to be regulated by reversible protein phosphorylation, which is controlled by phosphorylase kinase (PhK) and protein phosphatase 1 (PP1). Here we report that lysine acetylation negatively regulates GP activity by both inhibiting enzyme activity directly and promoting dephosphorylation SIGNOR-267403 0.2 GIGYF2 protein Q6Y7W6 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates activity binding 10090 20670374 t miannu We demonstrated that, in cultured cells and mammalian brains, GIGYF2 interacts and colocalises with Grb10, promoting ligand‐induced ubiquitination of IGF‐1R, and thereby regulates receptor degradation SIGNOR-260057 0.614 MAPK3 protein P27361 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser641 DIKILIAsPSPTHIH 9606 BTO:0000567 18519666 t lperfetto We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_ SIGNOR-178731 0.687 MAPK1 protein P28482 UNIPROT DYNC1I2 protein Q13409 UNIPROT unknown phosphorylation Ser87 YWVPPPMsPSSKSVS 10090 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262772 0.2 SYNJ1 protein O43426 UNIPROT MYO1E protein Q12965 UNIPROT up-regulates activity binding 10116 BTO:0000142 17257598 t miannu We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta. SIGNOR-265423 0.437 NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24024136 t irozzo In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs). SIGNOR-256276 0.667 RBCK1 protein Q9BYM8 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18711448 t miannu Here we show that the E3 ubiquitin ligase RBCC protein interacting with PKC1 (RBCK1) catalyzes the ubiquitination and degradation of IRF3. We transfected 293 cells with expression plasmids for Flag-IRF3, HA-ubiquitin, and HA-RBCK1. Coimmunoprecipitation and western blot analysis indicated that RBCK1 significantly polyubiquitinated IRF3 (Figure 4D). SIGNOR-271737 0.33 STAT5A protein P42229 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12468433 t We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling SIGNOR-261548 0.622 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Thr331 LTEDSTQtSDTATNS -1 7836371 t gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. SIGNOR-249676 0.2 PPP2CA protein P67775 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates dephosphorylation Ser253 APRRRAVsMDNSNKY 9606 20110348 t gcesareni Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a. SIGNOR-163680 0.412 L-serine chemical CHEBI:17115 ChEBI glycine smallmolecule CHEBI:15428 ChEBI up-regulates quantity precursor of 9606 32439610 t lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. SIGNOR-268222 0.8 MAPK14 protein Q16539 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser347 FTGLKCPsLAGKPKV 9606 BTO:0000130 14970175 t amattioni P38-mapk can directly phosphorylate and inhibit the activities of caspase-8 SIGNOR-122103 0.566 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser178 TATETQCsVPIQCTD 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262716 0.733 TAF7 protein Q15545 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263928 0.897 midostaurin chemical CHEBI:63452 ChEBI PRKCA protein P17252 UNIPROT down-regulates activity chemical inhibition 16969355 t lperfetto Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases SIGNOR-261981 0.8 MAML1 protein Q92585 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 11390662 t gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1.Maml1 functions as a transcriptional co-activator for notch signalling. SIGNOR-86117 0.921 GEMIN6 protein Q8WXD5 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 t lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. SIGNOR-253120 0.827 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIA2 protein P42262 UNIPROT up-regulates activity chemical activation 9606 30825796 t miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by Œ±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses SIGNOR-264609 0.8 BCL11A protein Q9H165 UNIPROT HBG2 protein P69892 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20712774 f Regulation miannu BCL11A maintains silencing of gamma-globin expression in adult erythroid cells and functions as a direct transcriptional regulator of the fetal to adult hemoglobin switch in humans. we found that BCL11A plays a central role in the evolutionarily divergent globin gene switches of mammals. As a factor critical for gamma-globin gene silencing, BCL11A should be considered as a therapeutic target to increase HbF in a directed manner in beta-thalassemia patients. SIGNOR-251775 0.458 KCNQ5 protein Q9NR82 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 19298256 t miannu KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. SIGNOR-265983 0.8 CSNK2A1 protein P68400 UNIPROT PIN4 protein Q9Y237 UNIPROT down-regulates activity phosphorylation Ser19 AGKGGAAsGSDSADK 9606 BTO:0000567 12860119 t lperfetto As proved by MALDI-TOF mass spectrometry and MS/MS fragmentation, hPar14 is phosphorylated at Ser19 in vitro and in vivo. In human HeLa cells the protein is most likely modified by casein kinase 2 (CK2). |In contrast to wild-type hPar14, the in vitro DNA-binding affinity of the Glu19 mutant is strongly reduced, suggesting that only the dephosphorylated protein is the active DNA-binding form of hPar14 in the nucleus. SIGNOR-265753 0.331 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser293 GSTKRRKsMSGASPK 9606 12676583 t Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. SIGNOR-99733 0.837 SIRT5 protein Q9NXA8 UNIPROT HMGCS2 protein P54868 UNIPROT up-regulates activity post translational modification Lys83 YNNVEAGkYTVGLGQ 9606 BTO:0000007 24315375 t desuccinylation lperfetto We demonstrate that SIRT5 regu-lates succinylation of the rate-limiting ketogenicenzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(HMGCS2) both in vivo and in vitro.|Succinylation of Lysine Residues within the SubstrateBinding Pocket Inhibits HMGCS2 Activity|Here, we use a label-freequantitative proteomic approach to characterizethe lysine succinylome in liver mitochondria and itsregulation by the desuccinylase SIRT5 SIGNOR-267641 0.35 calcium(2+) smallmolecule CHEBI:29108 ChEBI PPP3CA protein Q08209 UNIPROT up-regulates chemical activation 9606 22944199 t lperfetto Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell). SIGNOR-198819 0.8 PRKCA protein P17252 UNIPROT UGT1A3 protein P35503 UNIPROT up-regulates activity phosphorylation Ser43 IDGSHWLsMREVLRE -1 26094731 t done miannu Curcumin and calphostin C suppressed the activity and phosphorylation of recombinant UGT1A3 expressed in Sf9 cells. These results indicate that UGT1A3 undergoes phosphorylation, which is required for its catalytic activity. Calphostin C is a highly specific protein kinase C (PKC) inhibitor, so three predicted PKC phosphorylation sites in UGT1A3 were examined. In conclusion, phosphorylation plays an important role in UGT1A3 activity, and the serine at site 43 in UGT1A3 is most likely a phosphorylation site. SIGNOR-273823 0.2 N-[5-[(2R)-2-methoxy-1-oxo-2-phenylethyl]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-1-piperazinyl)benzamide chemical CHEBI:94490 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191277 0.8 PTEN protein P60484 UNIPROT ABI1 protein Q8IZP0 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser216 VPNDYMTsPARLGSQ 9606 32673396 t lperfetto After dephosphorylation by PTEN, Abi1 is degraded by calpains.|We demonstrate that PTEN dephosphorylation of Abi1 at Y213 and S216 results in Abi1 degradation through the calpain pathway. SIGNOR-276949 0.243 KLF2 protein Q9Y5W3 UNIPROT THBD protein P07204 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19661484 f miannu Thrombomodulin upregulation was independent of NF-kappaB signaling, a principal target of proteasome inhibitors, but was instead a direct consequence of increased expression of the Krüppel-like transcription factors, KLF2 and KLF4. SIGNOR-254543 0.44 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates activity phosphorylation Tyr589 TGSSDNEyFYVDFRE 10090 BTO:0001516 16627759 t lperfetto In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated.|This finding suggests that the combination of tyrosine residues 589 and 591 is required for activation of STAT-5 signaling pathways. SIGNOR-271926 0.2 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR SP1 protein P08047 UNIPROT up-regulates activity binding 9606 BTO:0001412 18025157 t We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. SIGNOR-255749 0.2 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates activity phosphorylation Ser821 ARDIKNDsNYVVKGN 9823 7539802 t lperfetto We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling. SIGNOR-248897 0.511 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation 9606 31226734 t lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. SIGNOR-265920 0.67 ATF2 protein P15336 UNIPROT FGF21 protein Q9NSA1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0005787 25055037 f miannu The increased production of reactive oxygen species, subsequent induction of p38 MAPK (mitogen-activated protein kinase) and activation of an ATF2 (activating transcription factor 2)-binding site at the proximal promoter region of the FGF21 gene was found to be a major mechanism linking mitochondrial dysfunction with enhanced FGF21 gene transcription in myogenic cells. SIGNOR-253743 0.353 F2 protein P00734 UNIPROT F5 protein P12259 UNIPROT up-regulates activity cleavage Arg1046 HHAPLSPrTFHPLRS -1 10026263 t lperfetto Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 SIGNOR-263631 0.878 midostaurin chemical CHEBI:63452 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258247 0.8 AURKA protein O14965 UNIPROT TACC3 protein Q9Y6A5 UNIPROT up-regulates activity phosphorylation Ser558 ESALRKQsLYLKFDP 9606 BTO:0001109 17545617 t miannu We show that this conserved serine on human TACC3 (Ser(558)) is also phosphorylated by Aurora A. Moreover, phosphorylation of TACC3 by Aurora A in human cells is essential for its proper localization to centrosomes and proximal mitotic spindles. Inhibition of Aurora A with the selective small molecule inhibitor MLN8054 in cultured human tumor cells resulted in mislocalization of TACC3 away from mitotic spindles in a concentration-dependent manner. SIGNOR-262655 0.934 GPR119 protein Q8TDV5 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257040 0.281 KIF13A protein Q9H1H9 UNIPROT TTC19 protein Q6DKK2 UNIPROT up-regulates activity binding 9606 20208530 t miannu We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B. SIGNOR-265540 0.443 BTK protein Q06187 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation 9606 BTO:0000776 9012831 t gcesareni We now describe a protein, bap-135, that is associated with btk in b cells and is a substrate for phosphorylation by btk.Taken together, these observations suggest that bap-135 may reside downstream of btk in a signaling pathway originating at the bcr. SIGNOR-46060 0.531 KPNA2 protein P52292 UNIPROT RNMT protein O43148 UNIPROT down-regulates activity binding 9606 26942677 t lperfetto KPNA2 Inhibits RNMT Activity|We report that CDK1-cyclin B1 phosphorylates the RNMT regulatory domain on T77 during G2/M phase of the cell cycle. RNMT T77 phosphorylation activates the enzyme both directly and indirectly by inhibiting interaction with KPNA2, an RNMT inhibitor. SIGNOR-265502 0.421 GSK3B protein P49841 UNIPROT DCX protein O43602 UNIPROT up-regulates activity phosphorylation Ser332 STPKSKQsPISTPTS 9606 21159948 t lperfetto Gsk3b phosphorylates dcx at the distinct site of ser327 and thereby contributes to dcx function in the restriction of axon branching. Together, our data define a jip3-regulated gsk3_/dcx signaling pathway that restricts axon branching in the mammalian brain.Gsk3_ induces the phosphorylation of dcx at ser327, which contributes to dcx function in the inhibition of axon branching and self-contact. SIGNOR-170755 0.275 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 18267068 t gcesareni Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. SIGNOR-160787 0.601 GATA4 protein P43694 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0002320 21598020 t miannu GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter SIGNOR-265815 0.253 NTRK2 protein Q16620 UNIPROT FRS3 protein O43559 UNIPROT up-regulates activity phosphorylation Tyr455 PARSSDSyAVIDLKK 9606 11432792 t miannu The tyrosine phosphoryla tion of FRS2/SNT2 was stimulated dependently on the TrkB activation. to explore the possibility that tyrosine residues 417 and 455 on FRS2/SNT2 function as the binding sites for Shp2, we coexpressed Y417F or Y455F phenylalanine mutants and the Y417/455F double phenylalanine mutant of Myc/Histagged FRS2/SNT2 with TrkB. The active TrkB induced somewhat reduced tyrosine phosphorylation of all of the phenylalanine mutants of FRS2/SNT2 in comparison with tyrosine phosphorylation of the wild type SIGNOR-250203 0.585 NAE1 protein Q13564 UNIPROT NAE complex SIGNOR-C131 SIGNOR form complex binding 9606 25504797 t lperfetto the NEDD8 E1-activating enzyme (NAE) is a heterodimer of APPBP1 and UBA3 corresponding to the N-terminal and C-terminal of the single polypeptide of the ubiquitin E1 respectively SIGNOR-242907 0.965 clozapine chemical CHEBI:3766 ChEBI HTR1F protein P30939 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258518 0.8 GSK3B protein P49841 UNIPROT BORA protein Q6PGQ7 UNIPROT up-regulates phosphorylation Ser278 PISSPTFsPIEFQIG 9606 23442801 t lperfetto It suggests that gsk3_ activity is required for hbora-mediated mitotic entry through ser274 and ser278 phosphorylation SIGNOR-201519 0.26 MAPK3 protein P27361 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser282 TAPLSPMsPPGYKLV 9606 BTO:0000567 9535909 t lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. SIGNOR-249467 0.626 adenosine smallmolecule CHEBI:16335 ChEBI ADORA3 protein P0DMS8 UNIPROT up-regulates activity binding -1 14662005 t Luana Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A1, A2A, A2B and A3. SIGNOR-268422 0.8 PTGFR protein P43088 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257193 0.41 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM5 protein P41594 UNIPROT up-regulates activity chemical activation 9606 25042998 t miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate SIGNOR-264070 0.8 PPP1CB protein P62140 UNIPROT AHCYL1 protein O43865 UNIPROT unknown dephosphorylation Ser68 RSLSRSIsQSSTDSY 10090 17635105 t Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1. SIGNOR-248571 0.2 GAD2 protein Q05329 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI down-regulates quantity chemical modification 9606 32041144 t miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. SIGNOR-267554 0.8 PPP3CC protein P48454 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10195903 t Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. SIGNOR-248528 0.373 A5/b1 integrin complex SIGNOR-C163 SIGNOR JAG1 protein P78504 UNIPROT up-regulates quantity by expression 10090 25786978 f lperfetto First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs. SIGNOR-253288 0.31 PIK3AP1 protein Q6ZUJ8 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000801 22187458 t gcesareni Bcap is constitutively phosphorylated and associated with the p85 subunit of pi3k in macrophages. Tlr signaling causes the phosphorylation of the small amount of bcap that is associated with membranes in the resting state or the translocation of phosphorylated bcap from the cytoplasm to the membrane. This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Bcap is an essential activator of the pi3k pathway downstream of tlr signaling SIGNOR-252701 0.502 TBX2 protein Q13207 UNIPROT MYOG protein P15173 UNIPROT down-regulates activity binding 9606 24470334 t We have found that TBX2 is highly up regulated in both ERMS and ARMS subtypes of RMS and demonstrate that TBX2 is a repressor of myogenesis by binding to MyoD and myogenin and inhibiting their activity. SIGNOR-251561 0.252 PPP2CB protein P62714 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates activity dephosphorylation Thr117 DGCTWKGtLKEYESC 10090 17188031 t We show that the Thr117 residue in TRAF2 is phosphorylated following TNFalpha stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity. SIGNOR-248597 0.2 olaparib chemical CHEBI:83766 ChEBI PARP1 protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-195016 0.8 LPAR1 protein Q92633 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256975 0.41 EGR1 protein P18146 UNIPROT GDF15 protein Q99988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 17715378 f Isochaihulactone treatment increased the luciferase activity of NAG-1 in A549 cells transfected with the NAG-1 promoter construct. This induction increased expression of NAG-1 that was p53-independent and Sp1-dependent. Our findings suggest that NAG-1 expression is up-regulated by isochaihulactone through an ERK-dependent pathway involving the activation of EGR-1. SIGNOR-254266 0.388 DNA_damage stimulus SIGNOR-ST1 SIGNOR ERCC6 protein Q03468 UNIPROT up-regulates 24086043 f lperfetto TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. SIGNOR-275691 0.7 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 15809340 t gcesareni Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively. SIGNOR-135185 0.928 VRK2 protein Q86Y07 UNIPROT DCX DET1-COP1 complex SIGNOR-C24 SIGNOR up-regulates activity binding 9606 BTO:0000007 24298020 t miannu Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not.The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.COP1 functions as an E3 ligase by forming a supercomplex that also includes heterodimeric substrate receptor DET1, adaptor DDB1, scaffold Cul4A, and RBX1 to recruit the E2 enzyme SIGNOR-272874 0.332 CDK2 protein P24941 UNIPROT NPM1 protein P06748 UNIPROT unknown phosphorylation Ser70 EAMNYEGsPIKVTLA 9606 BTO:0001271 19933706 t gcesareni Simultaneous inactivation of two cdk phosphorylation sites at ser10 and ser70 (npm-aa) induced g(2)/m cell cycle arrest, phosphorylation of cdk1 at tyr15 (cdc2(tyr15)) and increased cytoplasmic accumulation of cdc25c. SIGNOR-161805 0.578 SKP2 protein Q13309 UNIPROT CDT1 protein Q9H211 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 10790373 t miannu  Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3. SIGNOR-272565 0.68 CDK2 protein P24941 UNIPROT ARID4A protein P29374 UNIPROT down-regulates phosphorylation Ser864 RKILGQSsPEKKIRI 9606 21148318 t gcesareni In the present study we identified rbp1 as a novel cdk substrate. Rbp1 is phosphorylated by cdk2 on serines 864 and 1007, which are n- and c-terminal to the lxcxe motif, respectively. Cdk2-mediated phosphorylation of rbp1 or prb destabilizes their interaction in vitro, with concurrent phosphorylation of both proteins leading to their dissociation SIGNOR-170455 0.437 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser44 ESEESQDsSDSIGSS 9606 20730097 t lperfetto We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf4 SIGNOR-167572 0.2 SIRT1 protein Q96EB6 UNIPROT EP300 protein Q09472 UNIPROT down-regulates deacetylation Lys1020 EERSTELkTEIKEEE 9606 BTO:0000150 19047049 t gcesareni Sirt1 induces deacetylation and repression of p300 itself (81). Mutational analysis demonstrated that sirt1 repression of p300 involves both lysine 1020 and lysine 1024 SIGNOR-182507 0.829 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr1021 PNEGDNDyIIPLPDP 9606 18567737 t gcesareni Interestingly, resveratrol increased the activity of protein tyrosine phosphatase ptp1b, which dephosphorylates pdgf-stimulated phosphorylation at tyrosine-751 and tyrosine-716 on pdgfr with concomitant reduction in akt and erk1/2 kinase activity. these results for the first time provide evidence that the stilbene resveratrol targets ptp1b to inhibit pdgfr mitogenic signaling. SIGNOR-179068 0.679 CIITA protein P33076 UNIPROT HLA-G protein P17693 UNIPROT unknown transcriptional regulation 9606 BTO:0000776 11137218 f The X1 box is the binding site for the ubiquitous RFX complex consisting of three subunits; the X2 box is bound by the X2BP/ATF/CREB family factors. The basic S-X-Y regulatory module interacts with CIITA, which is expressed constitutively in APCs, but may be inducible in others cell types by IFN-gamma|We propose that the X region in the HLA-G gene promoter might participate to the combination of factors which play a role in HLA-G gene activation SIGNOR-254021 0.459 AKT proteinfamily SIGNOR-PF24 SIGNOR HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue. SIGNOR-186772 0.2 RPS6KA1 protein Q15418 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser353 VQNKRRRsVTPPEEQ 9606 23708659 t lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. SIGNOR-202121 0.255 SRC protein P12931 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 14551213 t lperfetto In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727.The involvement of tyrosine kinases such as c-Src and Janus kinase 2 and 3 (JAK2 and JAK3) in Galpha16QL-induced activation of STAT3 was illustrated by the combined use of selective inhibitors and dominant negative mutants. SIGNOR-247341 0.781 STAG2 protein Q8N3U4 UNIPROT CD69 protein Q07108 UNIPROT up-regulates 9606 14660624 f miannu Stag2 is able to enhance the activity of the tumor necrosis factor alpha, the cd69, and the human immunodeficiency virus long terminal repeat promoters in a nf-kappab-dependent manner. SIGNOR-119985 0.2 isoprenaline chemical CHEBI:64317 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8982677 t miannu K i values of the agonists for [~25I]iodocyanopindolol binding to the COS-7 cell membranes are shown in Table 1. In the membranes expressing one of the 13-adrenoceptor subtypes, both isoproterenol and T-0509 caused monophasic dis- placement of [~25I]iodocyanopindolol, suggesting a single binding site of the agonists. SIGNOR-258577 0.8 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser329 STISGRLsPIMTEQD 9606 11311120 t lperfetto The kinase dyrk1a phosphorylates the transcription factor fkhr at ser329 in vitro, a novel in vivo phosphorylation siteser(329) phosphorylation also decreases the ability of fkhr to stimulate gene transactivation and reduces the proportion of fkhr present in the nucleus SIGNOR-252909 0.52 AMPK complex SIGNOR-C15 SIGNOR LIPE protein Q05469 UNIPROT down-regulates phosphorylation Ser855 EPMRRSVsEAALAQP 9606 9636039 t lperfetto Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase. SIGNOR-216507 0.377 AMPK complex SIGNOR-C15 SIGNOR PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Ser505 GSVKRVTsGPSLGSL 9606 BTO:0000887;BTO:0001103 20231899 t lperfetto Ampk-wild type (wt) stimulates pld activity, while ampk-dominant negative (dn) inhibits it. Ampk regulates pld1 activity through phosphorylation of the ser-505 and this phosphorylation is increased by the presence of amp. SIGNOR-216643 0.244 HNF1B protein P35680 UNIPROT FXYD2 protein P54710 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000482 24204001 f miannu Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg(2+) reabsorption in the DCT. SIGNOR-254909 0.297 AMER1 protein Q5JTC6 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000007 21304492 t lperfetto Knockdown of Amer1 reduces Wnt-induced LRP6 phosphorylation, Axin translocation to the plasma membrane and formation of LRP6 signalosomesThe generation of PtdIns(4,5)P2 in regions of receptor activity triggers the recruitment of Amer1 proteins, which in turn promote LRP6 phosphorylation by recruiting Axin/GSK3_ and CK1gamma to LRP6. SIGNOR-24265 0.455 PRKACA protein P17612 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates phosphorylation 9606 19047375 t gcesareni B2 adrenergic receptor stimulation induces the pka dependent phosphorylation of heptp and releases bound p38 mapk SIGNOR-182522 0.368 SEMA3A protein Q14563 UNIPROT PLXNA4 protein Q9HCM2 UNIPROT up-regulates activity binding 9606 BTO:0001176;BTO:0002036 25335892 t miannu We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.  SIGNOR-261811 0.754 VAV1 protein P15498 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260581 0.756 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR E2 conjugating enzyme proteinfamily SIGNOR-PF105 SIGNOR up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-270841 0.2 FUBP1 protein Q96AE4 UNIPROT CDKN2B protein P42772 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19637194 f irozzo The cell cycle inhibitor p15 was also up-regulated upon FBP1 knockdown. Our analysis of HCC cells after FBP1 knockdown suggests that p15 mRNA levels may also (directly or indirectly) depend on FBP1 activity. SIGNOR-259126 0.259 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1540 KSPEKRSsLPRPSSI -1 8631898 t miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. SIGNOR-250163 0.428 PPP2CB protein P62714 UNIPROT RALA protein P11233 UNIPROT down-regulates dephosphorylation Ser183 RARKMEDsKEKNGKK 9606 17540176 t miannu Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function SIGNOR-155349 0.293 RYK protein P34925 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 15454084 t gcesareni Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled. SIGNOR-129571 0.429 PPBP protein P02775 UNIPROT OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258412 0.358 PTEN protein P60484 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity dephosphorylation Tyr397 SVSETDDyAEIIDEE 9606 BTO:0000356 10400703 t The tumor suppressor PTEN is a phosphatase with sequence homology to tensin. PTEN dephosphorylates phosphatidylinositol 3,4, 5-trisphosphate (PIP3) and focal adhesion kinase (FAK), and it can inhibit cell growth, invasion, migration, and focal adhesions. We investigated molecular interactions of PTEN and FAK in glioblastoma and breast cancer cells lacking PTEN. The PTEN trapping mutant D92A bound wild-type FAK, requiring FAK autophosphorylation site Tyr397 SIGNOR-248547 0.815 PRKCA protein P17252 UNIPROT MET protein P08581 UNIPROT down-regulates phosphorylation Ser985 PHLDRLVsARSVSPT 9606 8294430 t fstefani These data show that phosphorylation of ser985 is a key mechanism for the negative regulation of hgf/sf receptor. SIGNOR-37718 0.258 PRKCD protein Q05655 UNIPROT DAB2 protein P98082 UNIPROT down-regulates phosphorylation Ser24 QAAPKAPsKKEKKKG 9606 BTO:0000782 15280374 t gcesareni Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2. SIGNOR-127198 0.3 MECP2 protein P51608 UNIPROT YBX1 protein P67809 UNIPROT up-regulates activity binding 16251272 t lperfetto In this study, we show that MeCP2 interacts with the RNA-binding protein Y box-binding protein 1 and regulates splicing of reporter minigenes. Importantly, we found aberrant alternative splicing patterns in a mouse model of RTT. Thus, we uncovered a previously uncharacterized function of MeCP2 that involves regulation of splicing, in addition to its role as a transcriptional repressor. SIGNOR-277700 0.521 MECP2 protein P51608 UNIPROT TET1 protein Q8NFU7 UNIPROT up-regulates activity binding 28594324 t lperfetto MeCP2 and its partners, splicing factor Y-box binding protein 1 (YB-1) and methylcytosine dioxygenase 1 (Tet1), bind to BDNF chromatin in naı ̈ve but dissociate during conditioning|Knockdown of MeCP2 shows it is instrumental for splicing and inhibits Tet1 and CTCF binding thereby negatively impacting DNA methylation and conditioning-dependent splicing regulation. Thus, mutations in MECP2 can have secondary effects on DNA methylation and alternative splicing. SIGNOR-277701 0.439 Activated PSC phenotype SIGNOR-PH224 SIGNOR ACTA2 protein P62736 UNIPROT up-regulates quantity 9606 BTO:0000988 28232471 t miannu Upon activa- tion, PSCs express the myofibroblast protein α-smooth mus- cle actin (αSMA, gene name Acta2) and secrete factors that stimulate tumor growth, cell survival, and metastasis. As a result of the selective high expression of αSMA, we refer to these periglandular FAP+ αSMAhigh fibroblasts as myofibroblastic CAFs (myCAFs). SIGNOR-277677 0.7 SMAD1/4 complex SIGNOR-C85 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates activity binding 9606 15573378 t ggiuliani The Runx2 WT and deletion constructs (1 –495, 1–464, and 1–432) all physically interact with the BMP2 responsive Smad 1 SIGNOR-255782 0.566 Food intake phenotype SIGNOR-PH152 SIGNOR folic acid smallmolecule CHEBI:27470 ChEBI up-regulates 9606 19706381 f lperfetto The U.S. Reference Daily Intake (Daily Value) for FA is 0.4 mg for adults to aid in the prevention of birth defects and anemia, or double this amount for pregnant or lactating women. SIGNOR-268262 0.7 CDK1 protein P06493 UNIPROT MAP3K11 protein Q16584 UNIPROT down-regulates activity phosphorylation Ser548 GQAWGRQsPRRLEDS -1 35843311 t miannu Using in vitro kinase assays and phosphomutants, we determined that CDK1 phosphorylates MLK3 on Ser548 and decreases MLK3 activity during mitosis, whereas CDK2 phosphorylates MLK3 on Ser770 and increases MLK3 activity during G1/S and G2 phases. SIGNOR-277603 0.2 GNB2 protein P62879 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates 9606 23074268 f gcesareni Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance. SIGNOR-199132 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation 9606 12110590 t inferred from 70% family members gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. SIGNOR-270073 0.2 ING1 protein Q9UK53 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001938 15662138 f miannu Ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells. SIGNOR-254490 0.494 7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-2-ol chemical CHEBI:111176 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258725 0.8 EGFR protein P00533 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates phosphorylation Tyr66 LHQEDNDyINASLIK 9606 9355745 t llicata After binding to egfr, ptp1b becomes tyrosine-phosphorylated at tyr-66 phosphorylation of ptp1b by egfr enhances its catalytic activity SIGNOR-52950 0.751 RASA1 protein P20936 UNIPROT HRAS protein P01112 UNIPROT down-regulates binding 9606 10394594 t lperfetto The Ras protein sits at the center of a many-tiered cascade of molecular interactions. Most of the proteins along this cascade are activated by phosphorylation, but Ras uses a bound guanine nucleotide to toggle between its “on” and “off” states. Ras hydrolyzes GTP to GDP fairly quickly, turning itself “off,” and a collection of GTPase-activating proteins (GAPs) speed up the processthe complex between human h-ras bound to guanosine diphosphate and the guanosine triphosphatase (gtpase)-activating domain of the human gtpase-activating protein p120gap (gap-334) in the presence of aluminum fluoride was solved. SIGNOR-68990 0.842 glutamic acid smallmolecule CHEBI:18237 ChEBI KAR proteinfamily SIGNOR-PF57 SIGNOR up-regulates activity chemical activation 9606 15919192 t miannu Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1‚Äì4); five kainate receptor genes (GluR5‚Äì7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits. SIGNOR-264694 0.8 SOX6 protein P35712 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003298 26893351 f We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARŒ≥, C/EBPŒ± and MEST SIGNOR-255822 0.287 CDK1 protein P06493 UNIPROT CDC25A protein P30304 UNIPROT up-regulates phosphorylation Ser18 RRLLFACsPPPASQP 9606 12411508 t lperfetto Mitotic stabilization of cdc25a reflects its phosphorylation on ser17 and ser115 by cyclin b-cdk1, modifications required to uncouple cdc25a from its ubiquitin-proteasome-mediated turnover. SIGNOR-95260 0.836 NDUFA13 protein Q9P0J0 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND1-module builds around the Q-module with the help of TIMMDC1/C3ORF1 [47,48], which remains bound to the Q/ND1 subassembly until the last maturation steps. MT-ND1 joins first and then NDUFA3, NDUFA8 and NDUFA13 are added SIGNOR-262153 0.785 RPA3 protein P35244 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 f lperfetto The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275707 0.7 AKT1 protein P31749 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 19526459 t llicata Here, we present evidence that akt inhibits mad1-mediated transcription repression by physical interaction with and phosphorylation of mad1. SIGNOR-252525 0.37 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA4 protein Q9Y5G9 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265697 0.2 PDGFRB protein P09619 UNIPROT TNK2 protein Q07912 UNIPROT up-regulates activity phosphorylation Tyr635 PLPPPPAyDDVAQDE 9606 BTO:0002036 25257795 t miannu  Mutational analysis suggested that Y635 of ACK1 is a PDGFR-β phosphorylation site and that the ACK1 Y635F mutant abrogated the sequential activation of AKT.  SIGNOR-276854 0.366 PRKCD protein Q05655 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 t gcesareni All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below). SIGNOR-154791 0.571 PDE4DIP protein Q5VU43 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates binding 9606 21569246 t miannu This study ascribes a novel function to mmgl isoform 4: it meets all criteria for classification as an akap, and we show that is involved in the phosphorylation of cmybpc as well as ctni, hence mmgl is an important regulator of cardiac contractility. SIGNOR-173766 0.315 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr498 KTPPAPKtPPSSGEP -1 9199504 t miannu Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective. SIGNOR-250086 0.505 PRKACA protein P17612 UNIPROT TFAM protein Q00059 UNIPROT up-regulates phosphorylation Ser55 SCPKKPVsSYLRFSK 9606 23201127 t llicata Here, we demonstrate that tfam is phosphorylated within its hmg box 1 (hmg1) by camp-dependent protein kinase in mitochondria. Hmg1 phosphorylation impairs the ability of tfam to bind dna and to activate transcription. SIGNOR-199934 0.2 ADAM10 protein O14672 UNIPROT BTC protein P35070 UNIPROT up-regulates activity cleavage 9606 26284334 t miannu Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin SIGNOR-259839 0.381 trichostatin A chemical CHEBI:46024 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257942 0.8 PTPRG protein P23470 UNIPROT CDK2 protein P24941 UNIPROT down-regulates activity dephosphorylation Tyr15 EKIGEGTyGVVYKAR -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254695 0.302 ACTL6A protein O96019 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269827 0.83 MRPS5 protein P82675 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261441 0.734 GRK2 protein P25098 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity phosphorylation Ser330 GGLCDLSsRY 9606 12639913 t gcesareni Mutagenesis studies revealed that Thr312 and Ser329/330 in the C-terminal tail are potential sites for PKA and GRK phosphorylation and may play an essential role in the recruitment of beta-arrestin to the activated receptor. SIGNOR-249673 0.2 ABT-737 chemical CID:11228183 PUBCHEM BCL2L1 protein Q07817 UNIPROT down-regulates chemical inhibition 9606 Other t The effect has been demonstrated using Q07817-1 gcesareni SIGNOR-189171 0.8 fentanyl chemical CHEBI:119915 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258937 0.8 CSNK2A1 protein P68400 UNIPROT TLE1 protein Q04724 UNIPROT up-regulates phosphorylation Ser253 DNLVVDVsNEDPSSP 9606 22354967 t lperfetto These results show that tle1 is necessary for the maintenance of neuronal survival. Experiments using pharmacological inhibitors as well as expression of point mutants indicate that phosphorylation of tle1 by casein kinase-2 (ck2) at ser-239 and ser-253 is necessary for its survival-promoting activity. SIGNOR-196146 0.325 MK-2206 chemical CHEBI:67271 ChEBI AKT2 protein P31751 UNIPROT down-regulates chemical inhibition 9606 BTO:0001286 21841310 t gcesareni Treatment with the pi3k inhibitor ly294002 or the akt inhibitor mk2206 diminished s473 phosphorylation. SIGNOR-176046 0.8 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation 9606 21460634 t lperfetto Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition. SIGNOR-216464 0.469 MECP2 protein P51608 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 23242655 f Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells. SIGNOR-254024 0.399 MAPK1 protein P28482 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2315 RSPQPVPsPRPQSQP 9606 17623675 t gcesareni Erk2-mediated c-terminal serine phosphorylation of p300 (ser-2279, ser-2315, and ser-2366) is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression. SIGNOR-156891 0.478 CFLAR protein O15519 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates activity binding 9606 9794838 t amattioni Flip can be incorporated into the disc complex and blocks processing and activation of pro-caspase8 SIGNOR-61122 0.761 NUP153 protein P49790 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262069 0.73 AP1 complex SIGNOR-C154 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 amitriptyline chemical CHEBI:2666 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 10029 8100134 t miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. SIGNOR-258702 0.8 IRF4 protein Q15306 UNIPROT IRF5 protein Q13568 UNIPROT down-regulates activity 9606 BTO:0000801 22378047 t lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249560 0.433 CAPN1 protein P07384 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR up-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain SIGNOR-251581 0.559 CSNK2A2 protein P19784 UNIPROT HSPH1 protein Q92598 UNIPROT down-regulates activity phosphorylation Ser509 PTEENEMsSEADMEC -1 12558502 t llicata Protein kinase CK2 phosphorylates Hsp105 alpha at Ser509 and modulates its function. | the phosphorylation of Hsp105 alpha at Ser(509) abolished the inhibitory activity of Hsp105 alpha in vitro. SIGNOR-251008 0.333 MTOR protein P42345 UNIPROT ATG13 protein O75143 UNIPROT down-regulates phosphorylation 9606 19211837 t gcesareni Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2. SIGNOR-183965 0.637 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Thr) smallmolecule CHEBI:29180 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269497 0.8 SIAH1 protein Q8IUQ4 UNIPROT NUMB protein P49757 UNIPROT down-regulates ubiquitination 9606 11752454 t gcesareni We report that siah-1 interacts directly with and promotes the degradation of the cell fate regulator numb. SIGNOR-113469 0.409 belinostat chemical CHEBI:61076 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257955 0.8 CSNK2A1 protein P68400 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser511 PIGEDEEsESD -1 9045708 t llicata Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells.  SIGNOR-250953 0.351 CDK8 protein P49336 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15546612 f gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. SIGNOR-130637 0.2 COX6C protein P09669 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267750 0.739 CDK1 protein P06493 UNIPROT EP300 protein Q09472 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2039 GLGQVGIsPLKPGTV 9606 BTO:0000551 24530506 t miannu In this study, we found that p300 was highly phosphorylated and its level was decreased during mitosis and tumorigenesis. In vitro and in vivo experiments aimed showed that cyclin-dependent kinase 1 (CDK1) and ERK1/2 phosphorylated p300 on Ser1038 and Ser2039. Mutations of Ser1038 and Ser2039 increased p300 protein stability and levels.  SIGNOR-276456 0.413 EGR2 protein P11161 UNIPROT CEBPB protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16054051 t fspada Ectopic expression of krox20 can transactivate the c/ebpbeta promoter and increase c/ebpbeta gene expression in 3t3-l1 preadipocytes SIGNOR-139292 0.514 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203536 0.769 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ARHGEF2 protein Q92974 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 18211802 t inferred from 70% family members gcesareni Activates rhoa and as a result regulates actin assembly. SIGNOR-270007 0.2 LHX3 protein Q9UBR4 UNIPROT CGA protein P01215 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001379 10931853 t scontino Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). P-Lim binds to CBP in TRH-dependent manner on this site and that these proteins synergistically activate the human α-GSU promoter during TRH stimulation. SIGNOR-267207 0.396 NODAL protein Q96S42 UNIPROT TDGF1 protein P13385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003879 20383200 f Regulation miannu Nodal induced LIF and Cripto-1 expressions through Smad2 signaling pathway. SIGNOR-251942 0.647 GSK3B protein P49841 UNIPROT HNRNPD protein Q14103 UNIPROT down-regulates activity phosphorylation Ser83 DEGHSNSsPRHSEAA 9606 BTO:0001271 11903055 t lperfetto In kinase assays pka phosphorylated ser-87 of hnrnp d, whereas glycogen synthase kinase-3 beta (gsk-3 beta) phosphorylated ser-83, but only if ser-87 had been pre-phosphorylated by pka. Phosphorylation of ser-87 enhanced, whereas phosphorylation of ser-83 repressed, transactivation. SIGNOR-102582 0.353 HNF1A protein P20823 UNIPROT SLC22A9 protein Q8IVM8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 20829431 t lperfetto Luciferase reporter gene constructs containing the OAT5 (SLC22A10) and OAT7 (SLC22A9) promoter regions were transactivated by HNF-1 in HepG2 cells. SIGNOR-268982 0.2 JAK2 protein O60674 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation 9606 9575217 t gcesareni Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein SIGNOR-56894 0.861 PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr382 DHYRYSDtTDSDPEN 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248546 0.2 PTPN12 protein Q05209 UNIPROT PTK2B protein Q14289 UNIPROT down-regulates activity dephosphorylation Tyr402 CSIESDIyAEIPDET 10116 11337490 t Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-PEST-mediated dephosphorylation|CAKbeta was found to be a substrate for PTP-PEST. Both the major autophosphorylation site of CAKbeta (Tyr(402)) and activation loop tyrosine residues, Tyr(579) and Tyr(580), were targeted for dephosphorylation by PTP-PEST. Dephosphorylation of CAKbeta by PTP-PEST dramatically inhibited CAKbeta kinase activity. SIGNOR-248662 0.56 PAX3 protein P23760 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 t FGFR4 is a transcriptional target of PAX3 and the PAX3-FOXO1 fusion protein found in ARMS. SIGNOR-251572 0.373 Sin3B_complex complex SIGNOR-C409 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity binding 9606 BTO:0000007 21041486 t inferred from 70% of family members miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. SIGNOR-269844 0.2 canertinib chemical CHEBI:61399 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258200 0.8 MMP10 protein P09238 UNIPROT HAPLN1 protein P10915 UNIPROT down-regulates quantity by destabilization cleavage His31 LDHDRAIhIQAENGP -1 7694569 t miannu Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix. SIGNOR-256331 0.329 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 18819921 t Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases. SIGNOR-248411 0.622 SF3B1 protein O75533 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 25428262 f irozzo We have shown that SF3B1 knockdown in four myeloid cell lines resulted in inhibition of cell growth and disruption of the cell cycle.Taken together, these data show that SF3B1 knockdown results in inhibition of cell growth, induction of cell cycle arrest and impairment of erythroid differentiation in myeloid cell lines. SIGNOR-256003 0.7 CASP3 protein P42574 UNIPROT IKBKB protein O14920 UNIPROT down-regulates cleavage Asp546 ALQTDIVdLQRSPMG 9606 11741536 t gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. SIGNOR-112796 0.372 CIITA protein P33076 UNIPROT HLA-C protein P10321 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002269 11053628 f miannu Transfection of CIITA in JEG-3 cells also upregulated functional HLA-B and HLA-C expression. SIGNOR-253775 0.454 linagliptin chemical CHEBI:68610 ChEBI DPP4 protein P27487 UNIPROT down-regulates activity chemical inhibition 9606 18052023 t Luana Herein, we report the discovery of the novel, potent, and selective DPP-4 inhibitor 1 (BI 1356)9 originating from the class of xanthines (Chart 1) SIGNOR-257764 0.8 FER protein P16591 UNIPROT PECAM1 protein P16284 UNIPROT up-regulates activity phosphorylation Tyr713 KKDTETVySEVRKAV 9606 BTO:0000007 12972546 t miannu PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1. SIGNOR-262866 0.328 IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates activity binding 9606 BTO:0000801 18852293 t lperfetto IL-4 signals through the type I (IL-4Ralpha/common gamma-chain [gammac]) and the type II (IL-4Ralpha/-13Ralpha1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. SIGNOR-249527 0.941 LYN protein P07948 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr904 EEEGRDEyDEVAMPV -1 10942405 t Lyn phosphorylates Y904 and Y359 of band 3. The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton movements, and anion transport. SIGNOR-251414 0.344 BDKRB2 protein P30411 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257090 0.435 Galanin smallmolecule CHEBI:80161 ChEBI GALR1 protein P47211 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257494 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR DUSP1 protein P28562 UNIPROT down-regulates phosphorylation 9606 16286470 t inferred from 70% family members lperfetto The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain SIGNOR-270093 0.2 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG2-LLGL1_variant complex SIGNOR-C510 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270908 0.532 SEC31B protein Q9NQW1 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 t lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat SIGNOR-265287 0.656 CAMK2A protein Q9UQM7 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275770 0.383 USP24 protein Q9UPU5 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000018 27991932 t lperfetto In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. |Knockdown of USP24 decreases Bax and p300 levels SIGNOR-275606 0.2 RNF144B protein Q7Z419 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001109 12853982 t miannu P53RFP, a p53-inducible RING-finger protein, regulates the stability of p21WAF1. Here we report the isolation of a novel transcriptional target of p53, designated p53RFP (p53-inducible RING-finger protein), whose product has E3 ubiquitin ligase activity. Its expression was negatively correlated to that of p21(WAF1) protein; p53RFP is likely to play a role in the regulation of this protein, probably through interaction with, and ubiquitination of, p21(WAF1). SIGNOR-271478 0.366 KATNB1 protein Q9BVA0 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates 9606 BTO:0000567 10751153 f miannu Katanin, a heterodimeric microtubule-severing ATPase, is found localized at mitotic spindle poles. In this paper we demonstrate that human p60 katanin and the C-terminal domain of human p80 katanin both bind microtubules in vitro. Association of these two proteins results in an increased microtubule affinity and increased microtubule-severing activity in vitro. Association of these subunits in transfected HeLa cells increases microtubule disassembly activity and targeting to spindle poles.  SIGNOR-267181 0.7 YAP1 protein P46937 UNIPROT TEAD4 protein Q15561 UNIPROT up-regulates activity binding 9606 33358571 t miannu The multifunctional cytokine TGF-β has been identified as a potent inducer of CTGF expression, activating CTGF transcription through the canonical Smad signaling pathway. It is worth noting that TGF-β synergizes with Hippo–Yes-associated protein (YAP) signaling, a key regulator of tumorigenesis, to induce the expression of CTGF by the formation of a YAP-TEAD4-Smad3-p300 complex on the CTGF promoter SIGNOR-277685 0.925 TACR1 protein P25103 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257423 0.409 MAPK1 protein P28482 UNIPROT GIGYF2 protein Q6Y7W6 UNIPROT unknown phosphorylation Ser30 SITSPPLsPALPKYK 10090 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262775 0.2 CAMK2G protein Q13555 UNIPROT ADCY3 protein O60266 UNIPROT down-regulates activity phosphorylation Ser1076 NVASRMEsTGVMGNI 9606 BTO:0000007 8798667 t llicata Phosphorylation and inhibition of type III adenylyl cyclase by calmodulin-dependent protein kinase II in vivo. | Site-directed mutagenesis of a CaM kinase II consensus site (Ser-1076 to Ala-1076) in III-AC greatly reduced Ca2+-stimulated phosphorylation and inhibition of III-AC in vivo. SIGNOR-250691 0.36 PRKCG protein P05129 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Thr366 QSSASRKtQKKKKKK 9606 BTO:0004737 11325528 t lperfetto We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC. SIGNOR-249094 0.286 LRAT protein O95237 UNIPROT all-trans-retinyl ester smallmolecule CHEBI:63410 ChEBI up-regulates quantity chemical modification 10090 18093970 t lperfetto We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis SIGNOR-265111 0.8 TEAD4 protein Q15561 UNIPROT CCN2 protein P29279 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33358571 t miannu The multifunctional cytokine TGF-β has been identified as a potent inducer of CTGF expression, activating CTGF transcription through the canonical Smad signaling pathway. It is worth noting that TGF-β synergizes with Hippo–Yes-associated protein (YAP) signaling, a key regulator of tumorigenesis, to induce the expression of CTGF by the formation of a YAP-TEAD4-Smad3-p300 complex on the CTGF promoter SIGNOR-277686 0.2 HAUS complex complex SIGNOR-C281 SIGNOR NEDD1 protein Q8NHV4 UNIPROT up-regulates activity relocalization 9606 19427217 t lperfetto Under NuMA and HAUS6 codepletion conditions, NEDD1 levels on spindle microtubules remained low, suggesting that the suppression observed is not caused by more efficient localization of NEDD1 to spindle microtubules (Figure S9D). Taken together, our results suggest that HAUS and NuMA exert opposing activities necessary for robust bipolar spindle formation. SIGNOR-262331 0.526 PTPN12 protein Q05209 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates dephosphorylation 9606 11432829 t gcesareni This function correlated with the ability of ptp-pest to induce dephosphorylation of shc, pyk2, fak and cas, and inactivate the ras pathway. SIGNOR-109035 0.553 ARNT protein P27540 UNIPROT FOS protein P01100 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21544813 f lperfetto Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC SIGNOR-253696 0.291 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser146 RPSQRHGsKYLATAS -1 2413024 t miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 SIGNOR-250011 0.353 RAD21L1 protein Q9H4I0 UNIPROT RAD21L Cohesin complex complex SIGNOR-C355 SIGNOR form complex binding 10090 BTO:0000534 21242291 t miannu RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21. SIGNOR-264535 0.78 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248738 0.727 CDK1 protein P06493 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 SIGNOR-C17 14749395 t lperfetto Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21. SIGNOR-121601 0.372 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRA1D protein P25100 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258459 0.8 SRC protein P12931 UNIPROT HLA-A protein P04439 UNIPROT unknown phosphorylation Tyr344 SDRKGGSyTQAASSD 9606 6304688 t lperfetto Hla-a2 and hla-b7 antigens are phosphorylated in vitro by rous sarcoma virus kinase (pp60v-src) at a tyrosine residue encoded in a highly conserved exon of the intracellular domain. SIGNOR-25566 0.368 FRS2 protein Q8WU20 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 11997436 t gcesareni Complex formation between grb2 and frs2_ is mediated by y196, y306, y349, and y392 of frs2_ (designated direct grb2-binding sites;ref. 1). In addition, frs2_ recruits grb2 indirectly by means of the protein tyrosine phosphatase shp2 by way of residues y436 and y471 (designated shp2-binding sites;ref. 2). SIGNOR-87169 0.346 glucocorticoid smallmolecule CHEBI:24261 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity binding 9606 18049904 t miannu Glucocorticoid action in cells is mediated by a specific receptor protein, the glucocorticoid receptor (GR). GR is a member of a superfamily of ligand-inducible transcription factors that control a variety of physiological functions; such as, metabolism, development, and reproduction. SIGNOR-268048 0.8 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 21098032 t gcesareni Kinase activity of plk3 was significantly activated by hyperosmotic stimulation. Further downstream, active plk3 phosphorylated atf-2 at the thr-71 site in vivo and in vitro. SIGNOR-170004 0.2 NGLY1 protein Q96IV0 UNIPROT RAD23B protein P54727 UNIPROT up-regulates activity binding 9606 16401726 t miannu The XPCB domain of Rad23 binds Png1, which in turn facilitates the substrate recognition of Rad23. Through interactions with Ub chains and the proteasome mediated by the UBA and UBL domains in Rad23, Rad23 facilitates substrate transfer to the proteasome. SIGNOR-261061 0.814 AZ 960 chemical CID:25099184 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190128 0.8 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CEBPB protein P17676 UNIPROT down-regulates activity binding 9606 12524424 t lperfetto C/EBPbeta and C/EBPdelta were found to physically interact with Smad3 and Smad4, and Smad3 cooperated with Smad4 and TGF-beta signaling to repress the transcriptional activity of C/EBPs. SIGNOR-97117 0.561 JAK2 protein O60674 UNIPROT KDM3A protein Q9Y4C1 UNIPROT up-regulates activity phosphorylation Tyr1101 PDLGPKMyNAYGLIT 9606 BTO:0000567 30377265 t miannu KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2 phosphorylates KDM3A at tyrosine 1101 residue. SIGNOR-277884 0.2 PLK1 protein P53350 UNIPROT AHR protein P35869 UNIPROT down-regulates activity phosphorylation Ser489 ENNFFNEsMNECRNW -1 37988371 t miannu In this study, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, leading to epithelial-mesenchymal transition (EMT) and metastatic events.  SIGNOR-277885 0.253 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser14 LYSFFSPsPARKRHA 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276100 0.267 HNF1B protein P35680 UNIPROT AFP protein P02771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 7549116 f miannu HNF-1 beta was found to be more potent than HNF-1 alpha in activating the AFP promoter in the HepG2 cells. SIGNOR-254638 0.323 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 21389315 f irozzo Consequently, cell cycle and apoptosis analyses suggest that MLL-AF4 conveys a selective proliferation coupled to a survival advantage, which correlates with changes in the expression of genes involved in apoptosis, sensing DNA damage and DNA repair. SIGNOR-255872 0.7 PRKCA protein P17252 UNIPROT F3 protein P13726 UNIPROT up-regulates phosphorylation Ser285 RKAGVGQsWKENSPL 9606 23195225 t lperfetto We previously showed that the phosphorylation of ser253 within the cytoplasmic domain of human tissue factor (tf) initiates the incorporation and release of this protein into cell-derived microparticles. Furthermore, subsequent phosphorylation of ser258 terminates this process. The phosphorylation of ser253 is known to be mediated by protein kinase c_ SIGNOR-199872 0.2 PKG proteinfamily SIGNOR-PF77 SIGNOR 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. SIGNOR-266504 0.8 ACVR2B protein Q13705 UNIPROT ACVR1B protein P36896 UNIPROT up-regulates activity phosphorylation Thr206 VQRTVARtIVLQEII 9606 8622651 t miannu Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB. SIGNOR-235146 0.678 FOXO proteinfamily SIGNOR-PF27 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12913110 f lperfetto FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. SIGNOR-252914 0.2 RXRB protein P28702 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 10976919 t gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr SIGNOR-81452 0.638 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr387 RTQTVRGtLAYLPEE 9606 14625308 t lperfetto Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signalingthis identifies irak-1 as a novel type of adapter protein, which employs its own kinase activity to introduce negative charges adjacent to the protein interaction domain, which anchors irak-1 at the active receptor complex. Thus, irak-1 regulates its own availability as an adapter molecule by sequential autophosphorylation. SIGNOR-119216 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation Ser262 TFRPRSSsNASSVST 10090 10217147 t Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. SIGNOR-251478 0.2 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR4 protein Q13639 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257524 0.8 Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR Cilium_movement phenotype SIGNOR-PH171 SIGNOR up-regulates 16440056 f lperfetto Axonemal dyneins are responsible for the movement of cilia and flagella. SIGNOR-265021 0.7 PTPRB protein P23467 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 19136612 t VE-PTP/VEGFR2 complex formation resumes with time, leading to dephosphorylation and deactivation of VEGFR2 (right). B) In VE-PTP-deficient cells, such as after siRNA treatment, VEGFR2 activation (middle) is exaggerated, leading to increased phosphorylation at the Y951 and Y1175 phosphorylation sites SIGNOR-248441 0.465 BRCC3 protein P46736 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR down-regulates deubiquitination 9606 20656690 t gcesareni Brcc36 regulates the abundance of lys(63)-linked ubiquitin chains at chromatin and that one of its substrates is diubiquitinated histone h2a SIGNOR-265312 0.2 RNF146 protein Q9NTX7 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 21799911 t By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins. SIGNOR-259997 0.658 GSK3B protein P49841 UNIPROT CTNND1 protein O60716 UNIPROT unknown phosphorylation Ser252 MEGYRAPsRQDVYGP -1 12885254 t GSK3beta selectively phosphorylates p120 on S252 and T310 in Vitro SIGNOR-251234 0.396 CSNK2B protein P67870 UNIPROT HOXB6 protein P17509 UNIPROT unknown phosphorylation Ser214 LLSASQLsAEEEEEK -1 10327653 t llicata Using two-dimensional tryptic phosphopeptide mapping and purified protein kinases, we demonstrate that Hoxb-6 is phosphorylated in vitro by casein kinase II and cAMP-dependent protein kinase. The casein kinase II phosphorylation site was mapped to serine-214.  SIGNOR-251071 0.312 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269336 0.719 CEBPE protein Q15744 UNIPROT LTF protein P02788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 15588942 f miannu C/EBP_ interacts with C/EBP_ through the leucine-zipper–containing domain. C/EBP_ and C/EBP_ synergistically activate transcription of lactoferrin promoter SIGNOR-225012 0.377 CEBPB protein P17676 UNIPROT SLC5A8 protein Q8N695 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20082847 t Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription. SIGNOR-254054 0.2 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr826 LPTPTKMtPRSRILV 9606 SIGNOR-C18 9139732 t miannu We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein. SIGNOR-47899 0.928 CACNA1E protein Q15878 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30849329 t miannu CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. SIGNOR-264322 0.8 BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 10629050 t amattioni Bid, a bh3-domain-only protein which interacts with bax, was able to trigger a conformational change in bax. SIGNOR-73902 0.818 Kindlin proteinfamily SIGNOR-PF48 SIGNOR AM/b2 integrin complex SIGNOR-C170 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259025 0.415 RAB7A protein P51149 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity binding 10116 16040606 t Sara Rab7-Rac1 interaction may mediate late endosomal transport between microtubules and microfilaments SIGNOR-261304 0.28 CDK1 protein P06493 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates phosphorylation Thr286 VEGDAAEtPPRPRTP 9606 8114697 t gcesareni P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well SIGNOR-36112 0.474 bortezomib chemical CHEBI:52717 ChEBI PSMB5 protein P28074 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000567 19428245 t Luana MG-132, which was one of the first synthetic inhibitors, interacts reversibly with the N-terminal threonine residue of the β5 active site. SIGNOR-257820 0.8 PRDM1 protein O75626 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 31583686 f SimoneGraziosi SOX17 regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and suppressing somatic differentiation. SIGNOR-269263 0.7 PRKCB protein P05771 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates activity phosphorylation Ser582 LWHFRYEsLKHPKAY 9606 BTO:0000007 23824069 t miannu  Remarkably we find that PKCβ phosphorylates Ser582 in the helical domain of the PI3Kγ catalytic subunit p110γ in response to clustering of the high-affinity IgE receptor (FcεRI) and/or store-operated Ca²⁺- influx in mast cells. Phosphorylation of p110γ correlates with the release of the p84 PI3Kγ adapter subunit from the p84-p110γ complex.As functional p84-p110γ is key to GPCR-mediated p110γ signaling, this suggests that PKCβ-mediated p110γ phosphorylation disconnects PI3Kγ from its canonical inputs from trimeric G proteins, and enables p110γ to operate downstream of Ca²⁺ and PKCβ. SIGNOR-276496 0.515 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM BMX protein P51813 UNIPROT down-regulates activity chemical inhibition -1 24556163 t miannu This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine SIGNOR-262232 0.8 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Tyr66 DTAGQEDyDRLRPLS 9606 BTO:0000567 23027962 t lperfetto When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity SIGNOR-271699 0.2 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 12058066 t lperfetto Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association. SIGNOR-216662 0.414 homocysteine smallmolecule CHEBI:17230 ChEBI methionine smallmolecule CHEBI:16811 ChEBI up-regulates quantity precursor of 9606 10520212 t lperfetto Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. SIGNOR-253140 0.8 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr25 APPPQPPtPALPHPP 9606 8846784 t lperfetto Here we show that in vitro rk phosphorylates human gst-mapkap kinase-2 at thr25 in the proline-rich n-terminal region thr222 and ser272 in the catalytic domain and thr334 in the c-terminal domain. Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation SIGNOR-44351 0.76 YWHAH protein Q04917 UNIPROT KCNK18 protein Q7Z418 UNIPROT down-regulates activity binding -1 18397886 t miannu Phosphorylation of serine 264 in mouse TRESK was required for the binding of 14-3-3η. In the present study, we report that 14-3-3 proteins directly bind to the intracellular loop of TRESK and control the kinetics of the calcium-dependent regulation of the channel. Coexpression of 14-3-3η with TRESK blocked, whereas the coexpression of a dominant negative form of 14-3-3η accelerated the return of the K+ current to the resting state after the activation mediated by calcineurin in Xenopus oocytes. SIGNOR-263155 0.314 AP1B1 protein Q10567 UNIPROT AP-1 complex complex SIGNOR-C248 SIGNOR form complex binding 9606 21097499 t lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) SIGNOR-260685 0.814 ALDH9A1 protein P49189 UNIPROT 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI down-regulates quantity chemical modification 9606 11802770 t miannu Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). SIGNOR-269692 0.8 FAM20C protein Q8IXL6 UNIPROT HRC protein P23327 UNIPROT up-regulates activity phosphorylation Ser96 EKEDEDVsKEYGHLL 10116 BTO:0001879 28784772 t miannu Here, we demonstrate that family with sequence similarity 20C (Fam20C), a recently characterized protein kinase in the secretory pathway, phosphorylates HRC on Ser96. HRC Ser96 phosphorylation was confirmed in cells and human hearts.The pSer96-HRC binds tighter to triadin than S96A-HRC, which cannot be phosphorylated. Conversely, S96A-HRC or unphosphorylated Ser96-HRC binds tighter to SERCA2a. This suggests that Ser96-HRC phosphorylation (P) regulates HRC’s interactions with the major SR Ca-cycling proteins. SIGNOR-273639 0.378 CAMK2B protein Q13554 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275773 0.394 RNF168 protein Q8IYW5 UNIPROT H2AX protein P16104 UNIPROT unknown ubiquitination Lys14 TGGKARAkAKSRSSR 9606 22980979 t lperfetto We find that K63 ubiquitin chains are conjugated to RNF168-dependent H2A/H2AX monoubiquitination at K13-15 and not on K118-119. SIGNOR-262063 0.2 2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[8-[[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetyl]amino]octyl]acetamide chemical CID:121427831 PUBCHEM BRD2 protein P25440 UNIPROT down-regulates quantity chemical inhibition 9606 29764999 t Monia DBET6 induces efficient degradation of BET proteins and inhibits the proliferation of GBM cells SIGNOR-261095 0.8 CREB1 protein P16220 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 20660310 f amattioni beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state SIGNOR-229777 0.7 ULK2 protein Q8IYT8 UNIPROT DENND3 protein A2RUS2 UNIPROT up-regulates activity phosphorylation Ser472 THRRMVVsMPNLQDI 9606 25925668 t lperfetto ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. SIGNOR-264732 0.2 TGM2 protein P21980 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 16407273 t gcesareni Tg2 is able to phosphorylate purified histone proteins, and h3 and h1 in chromatin preparations, and it is associated with chromatin in breast cancer cells. SIGNOR-265369 0.2 PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates relocalization 9606 14718519 t lpetrilli We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI. SIGNOR-120734 0.685 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 7529876 t llicata We found that maximal kinase activity of fak immune complexes requires phosphorylation of both tyrosines 576 and 577. Our results indicate that phosphorylation of fak by src (or other src family kinases) is an important step in the formation of an active signaling complex. SIGNOR-27879 0.2 NDUFB4 protein O95168 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 SIGNOR-262167 0.79 RELA protein Q04206 UNIPROT IL1B protein P01584 UNIPROT down-regulates activity transcriptional regulation 10090 BTO:0000801 23667107 t lperfetto Early Inhibition of IL-1 beta Expression by IFN-gamma Is Mediated by Impaired Binding of NF-kappa B to the IL-1 beta Promoter but Is Independent of Nitric Oxide|We report that IFN-γ suppressed bacterial RNA and LPS induced IL-1β transcription in primary murine macrophages SIGNOR-251736 0.536 PP1 proteinfamily SIGNOR-PF54 SIGNOR PYG proteinfamily SIGNOR-PF96 SIGNOR down-regulates activity dephosphorylation 9606 BTO:0002049 22225877 t GP is the first protein whose function was discovered to be regulated by reversible protein phosphorylation, which is controlled by phosphorylase kinase (PhK) and protein phosphatase 1 (PP1). Here we report that lysine acetylation negatively regulates GP activity by both inhibiting enzyme activity directly and promoting dephosphorylation SIGNOR-267961 0.396 RHEB protein Q15382 UNIPROT FKBP8 protein Q14318 UNIPROT down-regulates binding 9606 17991864 t gcesareni Rheb interacts directly with fkbp38 and prevents its association with mtor in a guanosine 5'-triphosphate (gtp)-dependent manner. SIGNOR-159016 0.55 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 SIGNOR-C15 19584320 t gcesareni In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-186637 0.483 SLBP protein Q14493 UNIPROT H3Y1 protein P0DPK2 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265419 0.2 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser1934 LFRQQAGsGLSEEDA 28882890 t Phosphosite is derived from Figure 2 lperfetto C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation| Of 19 native NaV1.5 phosphorylation sites identified, two C-terminal phosphoserines at positions 1938 and 1989 showed increased phosphorylation in the CaMKIIδc-Tg compared with the WT ventricles. SIGNOR-275782 0.481 PAK5 protein Q9P286 UNIPROT SYNJ1 protein O43426 UNIPROT up-regulates activity phosphorylation -1 22371566 t miannu We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. SIGNOR-263026 0.2 TBK1 protein Q9UHD2 UNIPROT STX17 protein P56962 UNIPROT up-regulates activity phosphorylation Ser202 SQQEKIDsIADHVNS 9606 BTO:0000007 30827897 t done miannu Stx17 is phosphorylated by TBK1 whereby phospho-Stx17 controls the formation of the ATG13+FIP200+ mammalian pre-autophagosomal structure (mPAS) in response to induction of autophagy. TBK1 phosphorylates Stx17 at S202. SIGNOR-273812 0.296 SLC24A5 protein Q71RS6 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264398 0.8 AFDN protein P55196 UNIPROT RIN1 protein Q13671 UNIPROT up-regulates activity binding 9606 10545207 t miannu Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors. SIGNOR-220926 0.2 FBXW7 protein Q969H0 UNIPROT GATA3 protein P23771 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 24820417 t miannu Fbw7 promotes degradation of GATA3 in a Thr-156-dependent manner.  SIGNOR-276635 0.412 KCTD13 protein Q8WZ19 UNIPROT RHOA protein P61586 UNIPROT down-regulates quantity binding 9606 19782033 t miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. SIGNOR-264236 0.386 TRIM71 protein Q2Q1W2 UNIPROT LIN28B protein Q6ZN17 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001950 24602972 t miannu In cells, TRIM71 negatively regulates Lin28B protein stability by catalyzing polyubiquitination.  SIGNOR-272054 0.542 JAK2 protein O60674 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000876 BTO:0001103 19436055 t apalma The GM-CSF receptor does not have intrinsic tyrosine kinase activity, but associates with the tyrosine kinase Jak2 that is required for Œ≤c transphosphorylation and the initiation of signaling and biological activity SIGNOR-255584 0.568 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser616 DDGYMPMsPGVAPVP 10116 11287630 t lperfetto Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten SIGNOR-106582 0.757 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Thr452 GLEKTQTtPNGSLQA 9606 BTO:0000007 16862148 t lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). SIGNOR-249310 0.444 ROBO3 protein Q96MS0 UNIPROT CFL1 protein P23528 UNIPROT up-regulates quantity by expression post transcriptional regulation -1 16226035 t miannu Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. SIGNOR-268379 0.2 NEDD4L protein Q96PU5 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 t miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). SIGNOR-253462 0.292 ADORA1 protein P30542 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257092 0.341 2-oxoglutaric acid smallmolecule CHEBI:30915 ChEBI OXGR1 protein Q96P68 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257555 0.8 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI HIF1A protein Q16665 UNIPROT up-regulates activity chemical activation 20383689 t lperfetto HIF prolyl hydroxylase-3 mediates alpha-ketoglutarate-induced apoptosis and tumor suppression|The hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) are enzymes that are functionally inactivated in hypoxia, as they use both oxygen and alpha-ketoglutarate as substrates to hydroxylate target prolyl residues. SIGNOR-253138 0.8 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249640 0.741 FOXA1 protein P55317 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 19127412 f miannu Overexpression of foxa1 promoted apoptosis SIGNOR-256642 0.7 CAMK2A protein Q9UQM7 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser561 PFLSRHNsKSSIFSF 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275784 0.282 NR3C1 protein P04150 UNIPROT KLF9 protein Q13886 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 t We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα SIGNOR-256119 0.327 COL1A2 protein P08123 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 11007770 f gcesareni The present study was designed to further characterize tgfbeta up-regulation of col1a2 and more generally, to increase our understanding of the tgfbeta signaling pathway that controls ecm accumulation. SIGNOR-82405 0.7 PTPRG protein P23470 UNIPROT ABL1 protein P00519 UNIPROT down-regulates activity dephosphorylation Tyr413 TAPESLAyNKFSIKS -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254691 0.347 BID protein P55957 UNIPROT CYCS protein P99999 UNIPROT up-regulates activity 9606 9727492 f Translocation from Mitochondria to Cytosol lperfetto TBID induces first the clustering of mitochondria around the nuclei and release of cytochrome c. SIGNOR-59224 0.574 PHF20 protein Q9BVI0 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. SIGNOR-267159 0.67 ZNF804A protein Q7Z570 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity binding 9606 BTO:0005397 34364876 t miannu Together these results indicate the formation of ZNF804A:STAT2 protein complex and its translocation from the cytoplasm into the nucleus upon IFN stimulation, suggesting that it may function as a signal transducer that activates IFN-mediated gene expression programs. SIGNOR-269460 0.2 RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity binding 9606 22252525 t gcesareni The mechanism by which pak1 induced cancer growth might involve activation of jnk in the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor. SIGNOR-195414 0.645 PPP1CA protein P62136 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates activity dephosphorylation Ser988 PPLFPIKsFVKTKCK 9606 BTO:0000007 17603999 t Protein kinases involved in the DNA damage checkpoint control, such as ATM, ATR, and hCds1/Chk2, have been shown to phosphorylate and activate BRCA1 upon DNA damage. |Altogether, these results indicate that PP1α specifically dephosphorylates BRCA1 at multiple serine sites, including S988 [12], S1423, and S1524. SIGNOR-248560 0.385 DOT1L protein Q8TEK3 UNIPROT H3-3A protein P84243 UNIPROT unknown methylation Lys80 REIAQDFkTDLRFQS 9606 12123582 t miannu HDOT1L Is a Nucleosomal H3-K79-Specific HMTase. We identified a human DOT1-like (DOT1L) protein and demonstrated that this protein possesses intrinsic H3-K79-specific histone methyltransferase (HMTase) activity in vitro and in vivo. Furthermore, we found that K79 methylation level is regulated throughout the cell cycle. By using two different methods, we demonstrate that the K79 methylation level decreases during S phase, reaches its lowest level in G2, increases during M phase, and maintains at a high level during G1 phase. SIGNOR-267143 0.2 POU5F1 protein Q01860 UNIPROT GATA6 protein Q92908 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22795133 f lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) SIGNOR-253159 0.491 EDN1 protein P05305 UNIPROT EDNRB protein P24530 UNIPROT up-regulates binding 9606 16597412 t gcesareni Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors. SIGNOR-145762 0.946 cholesta-5,7-dien-3beta-ol smallmolecule CHEBI:17759 ChEBI cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates quantity precursor of 9606 9634533 t miannu In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme sterol D7 -reductase. This NADPH-dependent enzyme catalyzes the reduction of the D7 -diene bond in 7-DHC, to form cholesterol. SIGNOR-267250 0.8 SIRT2 protein Q8IXJ6 UNIPROT NEDD4 protein P46934 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23175188 f miannu SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16. SIGNOR-255144 0.265 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227874 0.891 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 10090 BTO:0002572 20610653 f lperfetto Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-216322 0.7 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser287 SVKSPVSsPNNVTLR 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276110 0.357 TYK2 protein P29597 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS -1 7657660 t lperfetto Co-expression of Stat1 with Tyk2, Jak1, or Jak2 resulted in the specific tyrosine phosphorylation of Stat1 at Tyr701Phosphorylation of purified Stat1 was necessary and sufficient for the acquisition of DNA binding activity. SIGNOR-246943 0.766 IL10 protein P22301 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0000938 BTO:0001264 23357618 f miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. SIGNOR-253503 0.266 DLGAP2 protein Q9P1A6 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264591 0.2 neuropeptide FF receptor agonist smallmolecule CHEBI:141000 ChEBI NPFFR2 protein Q9Y5X5 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257550 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 3627513 t lperfetto The trna methylase mettl1 is phosphorylated and inactivated by pkb and rsk in vitro and in cells SIGNOR-244307 0.2 FBXO11 protein Q86XK2 UNIPROT TP53 protein P04637 UNIPROT down-regulates neddylation Lys320 SSSPQPKkKPLDGEY 9606 17098746 t miannu Fbxo11 promotes the neddylation of p53 and inhibits its transcriptional activity / we found that fbxo11 also neddylates p53 on two lysines, lys-320 and lys-321 SIGNOR-150669 0.657 RPS6KA3 protein P51812 UNIPROT KRT18 protein P05783 UNIPROT unknown phosphorylation Ser53 ISVSRSTsFRGGMGS -1 7523419 t lperfetto Ser-52 in K18 is not glycosylated and matches consensus sequences for phosphorylation by CAM kinase, S6 kinase and protein kinase C, and all these kinases can phosphorylate K18 in vitro predominantly at that site. SIGNOR-248895 0.304 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161577 0.325 BAG1 protein Q99933 UNIPROT BCL2 protein P10415 UNIPROT up-regulates activity binding 9606 BTO:0000661 7834747 t lperfetto Cloning and functional analysis of BAG-1: A novel Bcl-2-binding protein with anti-cell death activity| SIGNOR-254118 0.424 DIO proteinfamily SIGNOR-PF83 SIGNOR L-thyroxine smallmolecule CHEBI:18332 ChEBI down-regulates quantity chemical modification 9606 34674502 t scontino Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule.¬† SIGNOR-267043 0.8 BRAP protein Q7Z569 UNIPROT CDC14A protein Q9UNH5 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 19152073 t k63 miannu Brap2 promotes Lys-63 linked ubiquitination of HsCdc14A. Collectively, these results support the idea that Brap2 facilitates Lys-63 linked ubiquitin modification of HsCdc14A, which may not be targeted for degradation, but mainly for protein–protein interactions or other regulatory functions. SIGNOR-271777 0.343 FLNA protein P21333 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity binding 9606 20156194 t miannu We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself SIGNOR-260628 0.262 RAB3GAP1 protein Q15042 UNIPROT RAB3A protein P20336 UNIPROT down-regulates activity gtpase-activating protein 10116 BTO:0000142 11809763 t miannu Rab3A, a member of the Rab3 small G protein family, regulates Ca(2+)-dependent exocytosis of neurotransmitter. The cyclical activation and inactivation of Rab3A are essential for the Rab3A action in exocytosis. GDP-Rab3A is activated to GTP-Rab3A by Rab3 GDP/GTP exchange protein (Rab3 GEP), and GTP-Rab3A is inactivated to GDP-Rab3A by Rab3 GTPase-activating protein (Rab3 GAP). SIGNOR-265580 0.451 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI LATS1 protein O95835 UNIPROT up-regulates 9606 23075495 f gcesareni On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz. SIGNOR-199196 0.8 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269376 0.719 HIPK2 protein Q9H2X6 UNIPROT ZBTB4 protein Q9P1Z0 UNIPROT down-regulates activity phosphorylation Thr795 AAERPGGtPTPVIAY -1 19448668 t miannu The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4. SIGNOR-262880 0.387 TNF protein P01375 UNIPROT Demyelination phenotype SIGNOR-PH155 SIGNOR up-regulates 9606 24507514 f miannu TNF-a is the most comprehensively studied cytokine in both EAE and MS. Most TNF-a overexpressing transgenic animals showed spontaneous pathology, characterized by progressive demyelination and macrophage infiltration SIGNOR-263834 0.7 ATF1 protein P18846 UNIPROT PCSK1 protein P29120 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8999965 f miannu it was shown that both CREB-1 and ATF-1 transactivate the human PC1 promoter in transient transfection experiments. SIGNOR-253742 0.2 IL1B protein P01584 UNIPROT GDF5 protein P43026 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003742 19818765 f Regulation miannu GDF-5 is suppressed by IL-1beta and enhances TGF-beta3-mediated chondrogenic differentiation in human rheumatoid fibroblast-like synoviocytes. SIGNOR-251864 0.267 ITGB4 protein P16144 UNIPROT A6/b4 integrin complex SIGNOR-C174 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253200 0.761 PRKD1 protein Q15139 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates activity phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000661 1370476 t lperfetto Thus, phosphorylation of PLC-gamma 1 by PKC or PKA at serine 1248 may modulate the interaction of PLC-gamma 1 with the protein tyrosine kinase or the protein tyrosine phosphatase; this altered interaction may, at least in part, be responsible for the decreased tyrosine phosphorylation of PLC-gamma 1 seen in PMA- and forskolin-treated Jurkat cells. SIGNOR-248846 0.413 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CAD protein P27708 UNIPROT up-regulates activity phosphorylation Ser1859 PPRIHRAsDPGLPAE 9606 BTO:0000007 23429703 t Activation of mTORC1 led to the acute stimulation of metabolic flux through the de novo pyrimidine synthesis pathway. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. SIGNOR-267197 0.2 LPAR1 protein Q92633 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 10090 BTO:0000944 15856019 t milica Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. SIGNOR-236985 0.432 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Ser539 SLFNVSPsCSSFNSP 9606 20640476 t lperfetto AMPK can directly phosphorylate PGC-1a at Thr177 and Ser538 in in vitro assays PGC-1a phosphorylation might not directly affect its intrinsic coactivation activity, but, rather, release it from its repressor protein p160myb [79] and/or allow deacetylation and subsequent activation by SIRT1 SIGNOR-209940 0.483 TLR4 protein O00206 UNIPROT JUN protein P05412 UNIPROT up-regulates activity 9606 BTO:0000801 19592489 f lperfetto The transcription factor AP-1 consists of a variety of dimers composed of members of the Jun, Fos, and ATF families of proteins. The Jun proteins can both homo- and heterodimerize with Fos members to form transcriptionally active complexes. The stimulation of macrophage TLR4 receptor rapidly activates not only the NF-kappaB pathway but also MAPK pathways, including JNK, ERK, and p38. Many of the downstream targets of MAPK pathways are transcription factors that include c-Jun. SIGNOR-249518 0.454 SYK protein P43405 UNIPROT FCGR2C protein P31995 UNIPROT up-regulates activity phosphorylation Tyr287 PEETNNDyETADGGY -1 8756631 t miannu Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation SIGNOR-262674 0.2 INPP4B protein O15327 UNIPROT phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI down-regulates quantity chemical modification 9606 21127264 t gcesareni Collectively this data indicates INPP4B is the only PtdIns(3,4)P2 4-phosphatase expressed in breast cancer cells and suggests a correlation between INPP4B and hormone receptor status in human breast cancer SIGNOR-252433 0.8 UDP(3-) smallmolecule CHEBI:58223 ChEBI P2RY6 protein Q15077 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257565 0.8 HRAS protein P01112 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. SIGNOR-175189 0.749 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation 9606 10197981 t lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 SIGNOR-236242 0.702 PCBP2 protein Q15366 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002181 19881509 t Giorgia PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4. SIGNOR-260360 0.631 ANK3 protein Q12955 UNIPROT DMD protein P11532 UNIPROT up-regulates quantity relocalization 10090 BTO:0001103 19109891 t miannu We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4. SIGNOR-266715 0.375 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-268072 0.8 CARM1 protein Q86X55 UNIPROT MDH1 protein P40925 UNIPROT down-regulates activity acetylation Arg230 FVTTVQQrGAAVIKA 9606 27840030 t lperfetto Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer|Arginine methylation at R248 negatively regulates MDH1 activity|PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization SIGNOR-267639 0.362 PRKDC protein P78527 UNIPROT GOLPH3 protein Q9H4A6 UNIPROT up-regulates activity phosphorylation Thr148 KETQPPEtVQNWIEL -1 BTO:0000567 24485452 t In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents SIGNOR-253558 0.323 PML protein P29590 UNIPROT KAT6A/PML complex SIGNOR-C55 SIGNOR form complex binding 9606 BTO:0001271 23431171 t miannu We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression SIGNOR-201489 0.503 CP protein P00450 UNIPROT SMO protein Q99835 UNIPROT down-regulates binding 9606 16885213 t gcesareni Genetic and biochemical studies imply that smo can adopt an active conformation but that it is normally repressed by patched (ptch), a 12-transmembrane protein considered the receptor for hh SIGNOR-148451 0.2 RPS6KA4 protein O75676 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 10090 12773393 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 SIGNOR-249211 0.2 TAX1BP1 protein Q86VP1 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates activity binding 21885437 t lperfetto ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi. SIGNOR-275737 0.478 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Ser206 ATPPTLSsTVLIVRN 9606 BTO:0001938 12815053 t lperfetto Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation. SIGNOR-249219 0.555 NOTCH1 protein P46531 UNIPROT ZMIZ1 protein Q9ULJ6 UNIPROT up-regulates activity binding 10090 BTO:0001825 26522984 t miannu The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions SIGNOR-263937 0.463 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10230394 t gcesareni Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A|Collectively, these results implicate PKA as the principal mitochondria-based S112 kinase. SIGNOR-67383 0.523 PKC proteinfamily SIGNOR-PF53 SIGNOR SCN2A protein Q99250 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 32599005 t lperfetto For example, protein kinase A (PKA) and protein kinase C (PKC) have been shown to phosphorylate multiple serine residues on the interdomain I-II and III-IV linkers of Nav1.2, significantly reducing current and increasing firing thresholds SIGNOR-275750 0.2 CHUK protein O15111 UNIPROT COPS5 protein Q92905 UNIPROT down-regulates activity phosphorylation Ser201 KPPDEGPsEYQTIPL -1 31950832 t lperfetto Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. SIGNOR-275507 0.33 EIF2S3 protein P41091 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 t lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. SIGNOR-269116 0.938 pimozide chemical CHEBI:8212 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258379 0.8 NFKB1 protein P19838 UNIPROT BIRC2 protein Q13490 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9733516 f gcesareni Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2 SIGNOR-59948 0.419 AMPK complex SIGNOR-C15 SIGNOR CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 10090 BTO:0000575 20577053 t lperfetto Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2 SIGNOR-216576 0.424 CSNK1D protein P48730 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Ser143 FHPNVSSsHENLEPE 9606 22609948 t lperfetto Ck1_/__dependent phosphorylation of dvl2 at s143 and t224and that this event is critical to interact with plk1 in early stages of the cell cycle SIGNOR-197547 0.519 PTPRC protein P08575 UNIPROT LCK protein P06239 UNIPROT up-regulates activity dephosphorylation Tyr505 FTATEGQyQPQP 10090 BTO:0000782 17719247 t CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56(lck) tyrosine kinase phosphorylation sites. We propose that high wild-type CD45 expression is necessary to dephosphorylate p56(lck) pTyr-394, suppressing CD4 T+ cell lineage commitment and hyperactivity. SIGNOR-259933 0.789 HBA1 protein P69905 UNIPROT AHSP protein Q9NZD4 UNIPROT down-regulates activity 9606 2545495 f Regulation miannu EDRF is rapidly inactivated by hemoglobin and superoxide. SIGNOR-251751 0.772 PGS1 protein Q32NB8 UNIPROT 1-(3-sn-phosphatidyl)-sn-glycerol 3-phosphate(3-) smallmolecule CHEBI:60110 ChEBI up-regulates chemical modification 9606 29034233 t lperfetto After activation of PA by the CDP-DAG synthase TAMM41 (Kutik et al., 2008), the phosphatidylglycerol phosphate synthase (PGS1) catalyzes the committed step by converting CDP-DAG to phosphatidylglycerol phosphate (PGP) SIGNOR-267023 0.8 ELANE protein P08246 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Ala36 PESKATNaTLDPRSF -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus SIGNOR-263565 0.441 EIF2S2 protein P20042 UNIPROT EGLN1 protein Q9GZT9 UNIPROT up-regulates quantity translation regulation 9606 BTO:0000007 29530922 t miannu DAP5 is involved in PHD2 translation. Distinct responses to DAP5 depletion (under hypoxia) of primary MEFs versus malignant glioma cells suggest that DAP5-mediated control of PHD2 may have special significance in cancer. Neoplastic cells may exploit DAP5 for managing chronic oxygen deprivation, possibly contributing to their adaptation to growth/proliferation under hypoxia. SIGNOR-266386 0.2 PTPN6 protein P29350 UNIPROT CSF2RB protein P32927 UNIPROT down-regulates dephosphorylation Tyr628 PPPGSLEyLCLPAGG 9606 9162089 t gcesareni However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2. SIGNOR-48561 0.501 Crenolanib chemical CID:10366136 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191124 0.8 HDAC4 protein P56524 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates binding 9606 BTO:0000887 10737771 t gcesareni We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2. SIGNOR-76234 0.701 PTPN6 protein P29350 UNIPROT KCNH2 protein Q12809 UNIPROT down-regulates dephosphorylation 9606 12361947 t gcesareni Our results show that erg-1 is a shp-1 substrate constituting the first report that an ion current is regulated by shp-1. SIGNOR-94007 0.2 ATM protein Q13315 UNIPROT XPA protein P23025 UNIPROT unknown phosphorylation Ser196 RSLEVWGsQEALEEA -1 16540648 t llicata Kinase phosphorylation assays were done with synthesized short peptides (20-mer) with the sequences at Ser173 and Ser196 of XPA, respectively. Both peptides seemed to be good substrates for DNA-PK, ATR ( Fig. 2D), and ATM (data not shown). SIGNOR-250580 0.609 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273051 0.556 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation Thr308 KDGATMKtFCGTPEY 10090 BTO:0000944 15367694 t Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes SIGNOR-248629 0.89 PRRX1 protein P54821 UNIPROT MAF protein O75444 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221893 0.36 FOXL2 protein P58012 UNIPROT CCND2 protein P30279 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21862621 f miannu We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation. SIGNOR-254178 0.401 FOXO1 protein Q12778 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 f inferred from family member gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-270251 0.326 MAPK1 protein P28482 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser65 PCSSVPSsPSFCAPS 9606 BTO:0000567 11416124 t lperfetto These residues are phosphorylated by erk2 but not by p38, jnk, and erk5 in vitro. However, the contribution of the mek/erk pathway to mafa phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs mafa capacity to activate transcription. SIGNOR-108564 0.34 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 9606 SIGNOR-C15 21205641 t gcesareni In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-170867 0.483 PRKAA1 protein Q13131 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 BTO:0000887 SIGNOR-C15 21565617 t gcesareni We show here that in liver, class iia hdacs (hdac4, 5, and 7) are phosphorylated and excluded from the nucleus by ampk family kinases. SIGNOR-173689 0.275 ERCC3 protein P19447 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 t lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269313 0.888 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 t lperfetto When subjected to phosphorylation by erk, the most efficient decrease in erk phosphorylation was observed with the s353a mutantamong the mechanisms underlying k protein ability to confer increased transcriptional output are interconversion of duplex and single-stranded dna (59) and association with the c/ebp_ (60), each of which could be better affected by the phosphorylated form of the k protein, which may increase affinity to associated proteins or dna. SIGNOR-105754 0.2 CASP7 protein P55210 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261757 0.349 ARX protein Q96QS3 UNIPROT EBF3 protein Q9H4W6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19627984 f Regulation of expression miannu Arx is sufficient to repress Ebf3 endogenous expression and that its silencing in Arx mutant tissues partially rescues tangential cell movement. SIGNOR-251971 0.308 E2F1 protein Q01094 UNIPROT MT1G protein P13640 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000394 15735762 f lperfetto The E2F transcription factors induce the expression of many genes in response to specific extracellular stimuli. Here, we show that human metallothionein 1G (hMT1G) promoter is upregulated by E2F1 upon VEGF stimulation of human aortic endothelial cells. SIGNOR-254132 0.339 GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 sorafenib tosylate chemical CHEBI:50928 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. SIGNOR-259226 0.8 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates activity phosphorylation Ser207 AARFTLGsPLTSPGG 9606 BTO:0001131 9630228 t lperfetto Dominant-negative cki? Induces nuclear import of nf-at4these results demonstrated that the cki? Phosphorylation sites identified in vitro were also specifically phosphorylated by cki? In vivo, and that these residues were crucial for the masking of the nls of nf-at4. SIGNOR-109800 0.573 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-81137 0.523 IFNW1 protein P05000 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates binding 9606 11278538 t gcesareni Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. SIGNOR-105979 0.721 PAWR protein Q96IZ0 UNIPROT WT1 protein P19544 UNIPROT down-regulates activity binding 9606 BTO:0000007 8943350 t 2 miannu We identified par-4 (for prostate apoptosis response) as a WT1-interacting protein that itself functions as a transcriptional repressor. Functionally, par-4 inhibited transcription activated by WT1 SIGNOR-240596 0.514 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 BTO:0000007 11691836 t lperfetto The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding SIGNOR-249392 0.649 FOXJ1 protein Q92949 UNIPROT DNAH11 protein Q96DT5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 t miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). SIGNOR-266931 0.368 PRKCA protein P17252 UNIPROT GJB1 protein P08034 UNIPROT up-regulates activity phosphorylation Ser229 QRRSNPPsRKGSGFG -1 8390988 t lperfetto Phosphorylation of connexin-32 by protein kinase C prevents its proteolysis by mu-calpain and m-calpain. |In agreement with other authors (see Saez et al., 1990b), we have found that phosphorylation of connexin-32 by protein kinase A and protein kinase C occurs in serine residues, although we have detected trace amounts of phosphothreonine in connexin-32 phosphorylated by protein kinase C (results not shown). Indeed, Se233 has been shown to be the major phosphorylation site catalyzed by protein kinase A. However, Ser233, Ser239, and perhaps other serines are phosphorylated by protein kinase C (Saez et al., 1990b). SIGNOR-248919 0.369 RAD50 protein Q92878 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates binding 9606 BTO:0000150 10426999 t amattioni Brca1 interacts in vitro and in vivo with hrad50. Brca1 is important for the cellular responses to dna damage that are mediated by the hrad50-hmre11-p95 complex. SIGNOR-69701 0.78 risperidone chemical CHEBI:8871 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258530 0.8 FBXO31 protein Q5XUX0 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002181 29343641 t miannu FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2. SIGNOR-277379 0.423 PRKAA1 protein Q13131 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 BTO:0000567 SIGNOR-C15 18303014 t gcesareni The central finding of this report is that rosiglitazone rapidly stimulates no production and enos ser-1177 phosphorylation in an ampk-dependent manner SIGNOR-160838 0.287 CHD8 protein Q9HCK8 UNIPROT DCX protein O43602 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 t Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells SIGNOR-268915 0.2 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9606 BTO:0000007 10191262 t lperfetto This is followed by the ptdins(3,4,5)p3-independent phosphorylation at thr256 that activates sgk, and is catalysed by pdk1 SIGNOR-236796 0.635 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Ser387 LSLPSTQsLNIKSEP 9606 9858528 t The effect has been demonstrated using Q06413-3 lperfetto Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain SIGNOR-62788 0.683 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser115 PAPSSFSsTSVSSLE 9606 20305697 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-164629 0.574 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257986 0.8 TP53 protein P04637 UNIPROT FNTB protein P49356 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26469958 f lperfetto In this study, we provided evidence that p53 induces the expression of a group of enzymes of the MVA pathway including 3'-hydroxy-3'-methylglutaryl-coenzyme A reductase, MVA kinase, farnesyl diphosphate synthase and farnesyl diphosphate farnesyl transferase 1, in the human glioblastoma multiforme cell line, U343 cells, and in normal human astrocytes, NHAs. SIGNOR-242353 0.2 PBX2 protein P40425 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription SIGNOR-265804 0.253 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.737 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr476 EANYVPMtPGTFDFS 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249464 0.618 TFIIIB complex SIGNOR-C393 SIGNOR RNA Polymerase III complex SIGNOR-C389 SIGNOR up-regulates activity binding 9606 9308965 t lperfetto Transcription by RNA polymerase III (Pol III) requires multiple general initiation factors that, in isolated form, assemble onto the promoter in an ordered fashion. Here, it is shown that all components required for transcription of the VA1 and tRNA genes, including TFIIIB, TFIIIC, and RNA Pol III, can be coimmunopurified from a HeLa cell line that constantly expresses a FLAG epitope-tagged subunit of human RNA Pol III. SIGNOR-266181 0.645 GSK3B protein P49841 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates binding 9606 17726008 t gcesareni Here we show that similar to the interaction with traf4 and axin, the kinase domain of mekk4 interacts with the multifunctional serine/threonine kinase gsk3beta. Gsk3beta binding to mekk4 blocks mekk4 dimerization that is required for mekk4 activation, effectively inhibiting mekk4 stimulation of the jnk and p38 mapk pathways SIGNOR-157544 0.294 SATB1 protein Q01826 UNIPROT TAF11 protein Q15544 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17343824 f miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. SIGNOR-255130 0.2 PRKCA protein P17252 UNIPROT TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser189 DEEFREPsTGKTCLP 9606 19661060 t Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-260884 0.357 CTH protein P32929 UNIPROT L-homocysteine zwitterion smallmolecule CHEBI:58199 ChEBI down-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. SIGNOR-275825 0.8 PLK2 protein Q9NYY3 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates phosphorylation Ser595 ISFSSNSsFVLKILE 9606 20531387 t lperfetto Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. Plk4 also phosphorylates s595 of cpap SIGNOR-166003 0.561 RNF7 protein Q9UBF6 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates activity ubiquitination 9606 23136067 t miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. SIGNOR-271450 0.2 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Thr309 SDGATMKtFCGTPEY 10090 BTO:0000944 15367694 t Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes SIGNOR-248633 0.737 CDH11 protein P55287 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265851 0.639 PRKAR2B protein P31323 UNIPROT PRKACA protein P17612 UNIPROT down-regulates activity binding 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258754 0.877 CHD8 protein Q9HCK8 UNIPROT TYMS protein P04818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 19255092 t miannu In order to identify CHD8 target genes, we performed a transcriptomic analysis of CHD8-depleted cells, finding out that CHD8 controls the expression of cyclin E2 (CCNE2) and thymidylate synthetase (TYMS), two genes expressed in the G1/S transition of the cell cycle. CHD8 was also able to co-activate the CCNE2 promoter in transient transfection experiments. Chromatin immunoprecipitation experiments demonstrated that CHD8 binds directly to the 5' region of both CCNE2 and TYMS genes. SIGNOR-268805 0.287 GAS6 protein Q14393 UNIPROT TYRO3 protein Q06418 UNIPROT up-regulates binding 9606 7867073 t gcesareni We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function. SIGNOR-34414 0.588 TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 BTO:0000007 8565075 t lperfetto The strong interaction between tradd and fadd occurs via their death domains. SIGNOR-39951 0.773 USF1 protein P22415 UNIPROT FMR1 protein Q06787 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001363; BTO:0000142 11058604 f miannu We have also shown that USF1, USF2, and alpha-Pal/Nrf-1 are the major transcription factors that bind the promoter in brain and testis extracts and suggest that elevated levels of these factors account in part for elevated FMR1 expression in these organs. SIGNOR-254882 0.319 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR E2F5 protein Q15329 UNIPROT up-regulates activity phosphorylation Thr261 SQSLTPVtPQKSSMA 9606 10783242 t miannu Here we show that E2F-5 is phosphorylated by the cyclin E-Cdk2 complex, which functions in the late G1 phase, but not by the early-G1-phase-acting cyclin D-CDK complex. A phosphorylation site in the trans-activation domain of E2F-5 stimulates transcription and cell-cycle progression by the recruitment of the p300/CBP family of co-activators, whose binding to E2F-5 is stabilized upon phosphorylation by cyclin E-Cdk2. SIGNOR-262732 0.627 FANCE protein Q9HB96 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 t lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263247 0.836 FAM83H protein Q6ZRV2 UNIPROT CSNK1A1L protein Q8N752 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 t miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. SIGNOR-273755 0.2 HTR2B protein P41595 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257138 0.534 CREB5 protein Q02930 UNIPROT ATF2 protein P15336 UNIPROT up-regulates activity binding 9534 BTO:0000318 8378084 t miannu CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription SIGNOR-219655 0.619 SLC24A2 protein Q9UI40 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264394 0.8 RET protein P07949 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 12242309 t lperfetto Overexpressed rai resulted in the potentiation of the ret-dependent activation of phosphatidylinositol 3-kinase (pi3k) and akt. The ret/ptc receptor tyrosine kinase that responds to glial cell-line-derived neurotrophic factor also phosphorylated akt tyrosine residue 315 promoting activation of akt SIGNOR-244443 0.328 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser172 LCLSPASsGSSASFI 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248511 0.387 C5AR1 protein P21730 UNIPROT CR1 protein P17927 UNIPROT up-regulates quantity by expression 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263466 0.462 ARHGEF4 protein Q9NR80 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260531 0.653 PGM2 protein Q96G03 UNIPROT 2-deoxy-D-ribose 5-phosphate smallmolecule CHEBI:16132 ChEBI up-regulates quantity chemical modification 9606 17804405 t miannu Biochemical characterization of phosphoglucomutase (PGM) isozymes indicated that one of them, designated PGM2 in man (PGM1 in mouse) was more active as a phosphopentomutase than as a phosphoglucomutase, whereas mammalian PGM1 (equivalent to PGM2 in mouse) has a phosphopentomutase activity representing only about 0.2% of its phosphoglucomutase activity. Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. SIGNOR-267095 0.8 PRKACA protein P17612 UNIPROT DUOX1 protein Q9NRD9 UNIPROT up-regulates phosphorylation Ser1217 SHHFRRRsFRGFWLT 9606 19144650 t llicata We analyzed the duox1 phosphorylation state with an anti-rxx(ps/pt) antibody that could potentially recognize phosphorylation on ser955 and ser1217 but not on thr1007. duox1 but not duox2 activity is stimulated by forskolin (ec50 = 0.1 _m) via protein kinase a-mediated duox1 phosphorylation on serine 955. duox1 is positively regulated by the camp-dependent protein kinase a (pka)6 cascade SIGNOR-183445 0.2 p38 proteinfamily SIGNOR-PF16 SIGNOR FOXC1 protein Q12948 UNIPROT up-regulates quantity by stabilization phosphorylation Ser241 PSPPQPLsPAAALGS 31650548 t lperfetto P38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation. SIGNOR-275914 0.2 ETS1 protein P14921 UNIPROT CD8A protein P01732 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8413295 f miannu Taken together, these results suggest that the human CD8 alpha gene is regulated by the interaction of multiple T-cell nuclear proteins with a transcriptional enhancer located in the last intron of the gene. Site-directed mutation of the Ets-1 and GATA-3 sites dramatically reduced enhancer activity. SIGNOR-254078 0.259 PRKACA protein P17612 UNIPROT CAD protein P27708 UNIPROT down-regulates activity phosphorylation Ser1406 GAGGRRLsSFVTKGY 11986331 t miannu CAD is down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation. SIGNOR-250344 0.312 CDK2 protein P24941 UNIPROT NFYA protein P23511 UNIPROT up-regulates activity phosphorylation Ser320 GEGGRFFsPKEKDSP 12857729 t llicata Cdk2 phosphorylates two serine residues near the DNA-binding domain of the YA subunit of NF-Y. Cyclin A-cdk2 appears to associate with NF-Y both in vitro and in vivo. Furthermore, YA protein is phosphorylated in parallel with a cell cycle-dependent activation of cdk2 kinase and cyclin A expression. YA phosphorylation is unnecessary for heterotrimer formation with the YB-YC dimer. However, NF-Y containing a phosphorylation-deficient mutant form of YA, YA-aa, has its DNA binding activity impaired. \ To examine whether cdk2 phosphorylates the two serine residues at positions 320 and 326 in YA, we replaced either or both with alanine by site-directed mutagenesis. In a kinase assay using purified GST fusion proteins in vitro, cdk2 phosphorylated the wild type and both of the single-mutant proteins (YA-as and -sa), but not the double-mutant protein (YA-aa) SIGNOR-250742 0.45 ASH2L protein Q9UBL3 UNIPROT HMT complex SIGNOR-C19 SIGNOR form complex binding 9606 17500065 t lperfetto The evolutionarily conserved hdpy-30, ash2l, rbbp5, and wdr5 likely constitute a subcomplex that is shared by all human set1-like hmt complexes. SIGNOR-154760 0.869 DAB2IP protein Q5VWQ8 UNIPROT AR protein P10275 UNIPROT down-regulates activity binding 9606 27858941 t miannu DAB2IP acts as a scaffold protein for PP2A to suppress DHT-elicited S81 phosphorylation of the AR, preventing its nuclear translocation and binding to androgen response elements. In addition, DAB2IP can compete with the AR for binding to c-Src, thus blocking the non-genomic AR pathway SIGNOR-254758 0.334 SOCS3 protein O14543 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity 9606 24600449 f miannu A main role of SOCS3 results from its binding to both the JAK kinase and the cytokine receptor, which results in the inhibition of STAT3 activation. SIGNOR-255330 0.697 RBBP4 protein Q09028 UNIPROT HNuRF complex SIGNOR-C448 SIGNOR form complex binding 9606 BTO:0000007 14609955 t miannu hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays. SIGNOR-268816 0.673 TBK1 protein Q9UHD2 UNIPROT REL/RELA complex SIGNOR-C68 SIGNOR up-regulates phosphorylation 9606 16888014 t lperfetto The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel. SIGNOR-217667 0.584 CYSLTR1 protein Q9Y271 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256883 0.2 MASP1 protein P48740 UNIPROT C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263432 0.59 ACTB protein P60709 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270711 0.481 nafamostat chemical CHEBI:135466 ChEBI TMPRSS2 protein O15393 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002750 27550352 t Monia Nafamostat also blocked MERS-CoV infection in vitro. This inhibition was most likely a result of inhibition of TMPRSS2 on the plasma membrane. Because MERS-CoV may infect cells via a TMPRSS2-independent endocytotic pathway, we evaluated the effects of nafamostat on MERS-CoV infection using an in vitro virus infection assay SIGNOR-261065 0.8 HDAC1 protein Q13547 UNIPROT CCND1 protein P24385 UNIPROT up-regulates binding 9606 15713663 t gcesareni Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5. SIGNOR-134059 0.685 SLITRK5 protein O94991 UNIPROT SHH protein Q15465 UNIPROT down-regulates activity binding 10090 BTO:0001593 34326333 t miannu SLITRK5 interacts with SHH and PTCH1. Mechanistically, SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain. SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation. Thus, SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts that may be attractive as a therapeutic target to enhance bone formation. SIGNOR-268437 0.2 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT unknown phosphorylation Ser584 ETSIFTPsPCKIPPP 9606 14551205 t llicata In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. SIGNOR-118588 0.502 GRK2 protein P25098 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates phosphorylation Thr123 IVKCQKLtDDHVQFL 9606 BTO:0000801 17055984 t lperfetto Phosphorylation of p38 by grk2 at the docking groove unveils a novel mechanism for inactivating p38mapk p38 associates with grk2 endogenously and is phosphorylated by grk2 at thr-123, a residue located at its docking groove. Mimicking phosphorylation at this site impairs the binding and activation of p38 by mkk6 and diminishes the capacity of p38 to bind and phosphorylate its substrates SIGNOR-150152 0.2 DSCAM protein O60469 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 10116 BTO:0000938 18585357 f miannu DSCAM is required for commissural axon guidance in vivo. DSCAM promotes axonal growth but is dispensable for cell body migration and for axon turning toward a local source of netrin-1 in whole spinal cord turning assays. SIGNOR-268396 0.7 GNAI3 protein P08754 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates activity binding 9606 19703466 t Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma) SIGNOR-256500 0.578 GABRB1 protein P18505 UNIPROT GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR form complex binding 9606 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263763 0.601 GSK3A protein P49840 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation 9606 20932480 t miannu Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687 SIGNOR-168385 0.2 lofexidine chemical CHEBI:51368 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 22341244 t Luana Lofexidine was selected because its scaffold is similar to that of the imidazolines of the present study and, as emerged from our functional study (Table 2), it displayed significant α2A- and α2C-AR agonism.  SIGNOR-258331 0.8 PPP2R5D protein Q14738 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity binding 9606 BTO:0000007 16239230 t gcesareni ... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259. SIGNOR-243420 0.426 LTBR protein P36941 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates 9606 17633025 f lperfetto The lymphotoxin-beta receptor (ltbetar, tnfrsf3) signaling pathway activates gene transcription programs and cell death important in immune development and host defense. SIGNOR-156899 0.7 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA12 protein O60330 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265698 0.2 AMER1 protein Q5JTC6 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity relocalization 9606 SIGNOR-C110 21304492 t gcesareni Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6. SIGNOR-171886 0.78 KMT2E protein Q8IZD2 UNIPROT RARA protein P10276 UNIPROT up-regulates activity binding 9606 21205756 t miannu MLL5 binds to retinoic acid receptor α (RARα) and induces transcriptional activation of RARα target genes by methylation of lysine residues of histone H3. SIGNOR-260041 0.34 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates binding 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni In this study, we demonstrate that akt also regulates the activity of fkhrl1, a member of the forkhead family of transcription factors. In the presence of survival factors, akt phosphorylates fkhrl1, leading to fkhrl1's association with 14-3-3 proteins and fkhrl1's retention in the cytoplasm. Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183608 0.2 YBX1 protein P67809 UNIPROT MMP13 protein P45452 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17822788 f miannu YB-1 binds to the MMP-13 promoter sequence and represses MMP-13 transactivation via the AP-1 site. SIGNOR-255615 0.2 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser347 TFPAQSLsPEPLPQE 9606 14697653 t lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. SIGNOR-120479 0.271 XPOT protein O43592 UNIPROT NPC complex SIGNOR-C263 SIGNOR up-regulates activity binding 9606 BTO:0000007 9660920 t miannu Exportin-t Is Predominantly Nuclear, Binds NPCs, and Shuttles Rapidly between Nucleus and Cytoplasm. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus . RanGTP causing a conformational change in exportin-t, which increases the affinity for export sites at the NPC. Exportin-t probably makes a direct contact to the NPC and accounts for the interactions that drive translocation of the tRNA/exportin-t/RanGTP complex out of the nucleus. SIGNOR-261393 0.448 Caspase 3 complex complex SIGNOR-C221 SIGNOR GSN protein P06396 UNIPROT down-regulates cleavage 9606 BTO:0000130 9323209 t amattioni Caspase-3 mediates cleavage of gelsolin, generating a fragment that severs actin filaments in an unregulated fashion. The cleavage of gelsolin causes cells to round up, detach and undergo nuclear fragmentation. SIGNOR-256461 0.624 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr162 QLAAKLAyLQILSEE -1 16373505 t Manara PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR. SIGNOR-260783 0.2 MAT2B protein Q9NZL9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001938 30942439 f miannu MAT2B Promotes Proliferation and Inhibits Apoptosis in Osteosarcoma by Targeting Epidermal Growth Factor Receptor and Proliferating Cell Nuclear Antigen SIGNOR-261243 0.7 SLC12A1 protein Q13621 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity phosphorylation 21613606 t lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  SIGNOR-264635 0.8 PRKCA protein P17252 UNIPROT CYBA protein P13498 UNIPROT up-regulates phosphorylation Thr147 ERPQIGGtIKQPPSN -1 19948736 t Manara Phosphorylation of p22phox on threonine 147 enhances NADPH oxidase activity by promoting p47phox binding. | Threonine 147 of p22phox Is Phosphorylated by PKC-α and PKC-δ in Vitro SIGNOR-260891 0.2 ZSTK-474 chemical CHEBI:90545 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252646 0.8 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr319 TSVYESPySDPEELK -1 10202147 t done miannu  In this report, we identify Tyr319 as a functionally important phosphorylation site in the ZAP-70 interdomain B region. Phosphorylation of Tyr319 promoted the association of ZAP-70 with the SH2 domains of two key signaling molecules, Lck and PLC-gamma1. These studies suggest that Tyr319 phosphorylation is required for the assembly of a ZAP-70-containing signaling complex that leads to the activation of the PLC-gamma1- and Ras-dependent signaling cascades in antigen-stimulated T cells. SIGNOR-273948 0.602 AKT1 protein P31749 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 BTO:0000130 10559253 t esanto Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis. SIGNOR-252586 0.575 MCHR1 protein Q99705 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257147 0.413 UNC13A protein Q9UPW8 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity transcriptional regulation 9606 BTO:0000938 30267828 t miannu In neuronal exocytosis, Munc18-1 (aSM-protein) and Munc13-1/2 (similar to CATCHRs) arethe relevant proteins responsible for SNARE-complex formation. Munc18-1 associates with syntaxin-1 in its‘closed’ conformation, i.e. with the regulatory Habc-domain folded against the SNARE (H3-)-domain. Opening-up of syntaxin is catalyzed by the Mun-domainwithin Munc13-1/2 and allows assembly with the partnerSNARE SNAP-25 and possibly VAMP2. SIGNOR-263971 0.467 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr534 SRTPSLPtPPTREPK 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249324 0.754 CACNA1A protein O00555 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 20655485 t miannu The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release. SIGNOR-266708 0.8 TLK1 protein Q9UKI8 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity phosphorylation -1 11314006 t The effect has been demonstrated using Q9UKI8-2 lperfetto Purified tlk1b phosphorylated histone h3 at s(10) with high specificity both in a mix of core histones and in isolated chromatin, suggesting that histone h3 is a physiological substrate for tlk1b. Phosphorylation of H3 has been linked to the activation of the immediate-early genes upon mitogenic stimulation, and to chromatin condensation during mitotic/meiotic events. SIGNOR-265370 0.2 CEBPD protein P49716 UNIPROT KLF5 protein Q13887 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16054042 f fspada Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter. SIGNOR-210007 0.504 CRYBB2 protein P43320 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 16319073 f miannu At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency. SIGNOR-252151 0.7 WWTR1 protein Q9GZV5 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22470139 f miannu Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation. SIGNOR-255607 0.536 PIK3CA protein P42336 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 21779497 f gcesareni Pi3k can also activate rac, and this activation is involved in cytoskeleton reorganization. SIGNOR-175238 0.552 FOXO3 protein O43524 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR up-regulates quantity by expression transcriptional regulation 20978344 f inferred from family member Forkhead box O3 (FoxO3) was identified as a key molecule inducing D2 expression and thereby increasing intracellular T3 production. Accordingly, FoxO3-depleted primary myoblasts also had a differentiation deficit that could be rescued by high levels of T3. SIGNOR-270245 0.349 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Ala617 ISEVKMDaEFRHDSG -1 8943232 t lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261737 0.502 IMPDH2 protein P12268 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30518405 f miannu We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. SIGNOR-260957 0.2 morphine chemical CHEBI:17303 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258932 0.8 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates activity phosphorylation Thr145 AGNKRLStIDESGSI 9606 BTO:0000567 14744859 t llicata It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1 SIGNOR-250589 0.771 WWP2 protein O00308 UNIPROT TP73 protein O15350 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25071155 t miannu WWP2 ubiquitinates p73 and controls its protein stability. In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73.  SIGNOR-272233 0.287 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser66 GVYATRSsAVRLRSS -1 2500966 t miannu Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure. SIGNOR-250068 0.313 PTPRJ protein Q12913 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr813 NSLFTPDyELLTEND 9606 28912580 t miannu These results support PTPRJ preferentially dephosphorylating Y813 and Y868 in JAK2.|We revealed that PTPRJ negatively regulates leptin signaling by dephosphorylating specific tyrosine residues (Y813 and Y868) in JAK2, the simultaneous phosphorylation of which plays a pivotal role in JAK2 activation. SIGNOR-277093 0.329 5-{3-[4-(2,3-Dichlorophenyl)piperidin-1-yl]propoxy}-1,3-benzothiazole chemical CID:56599142 PUBCHEM DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 9606 BTO:0002181 22025698 t Luana Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands.  SIGNOR-258322 0.8 PHLPP1 protein O60346 UNIPROT PRKCB protein P05771 UNIPROT down-regulates quantity dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 BTO:0000067 18162466 t gcesareni Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC betaII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle SIGNOR-237047 0.347 Caspase 3 complex complex SIGNOR-C221 SIGNOR Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 10090 25787076 f miannu The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice. SIGNOR-256476 0.7 ID2 protein Q02363 UNIPROT TCF3 protein P15923 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C127 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241140 0.603 HNF4A protein P41235 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20577053 f gcesareni Pgc1alfa is thought to mediate transcription downstream of the nuclear receptor hepatocyte nuclear factor 4alfa (hnf4alfa) and the transcription factor foxo1 in the promoters of key gluconeogenic enzymes, including glucose-6-phosphatase (g6pase) and phosphoenolpyruvate carboxylase (pepck) SIGNOR-166358 0.356 hydrogen peroxide smallmolecule CHEBI:16240 ChEBI TXN protein P10599 UNIPROT up-regulates chemical activation 9606 15556622 t gcesareni We show that 10 and 50 microm h2o2 and short-term exposure to shear stress significantly increased trx-1 mrna and protein levels in endothelial cells. SIGNOR-131049 0.8 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 9381178 t Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival. SIGNOR-252563 0.817 AKT proteinfamily SIGNOR-PF24 SIGNOR ADRB2 protein P07550 UNIPROT down-regulates phosphorylation Ser346 LLCLRRSsLKAYGNG 9606 11809767 t lperfetto Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation. SIGNOR-114470 0.2 ADRA2B protein P18089 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256993 0.315 RANBP2 protein P49792 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262088 0.612 ATM protein Q13315 UNIPROT AURKB protein Q96GD4 UNIPROT down-regulates 9606 18250156 f gcesareni Furthermore, atm-mediated i-2 phosphorylation results in the inhibition of the aurora-b kinase, the down-regulation of histone h3 serine 10 phosphorylation, and the activation of the g2/m checkpoint. SIGNOR-160644 0.442 SMO protein Q99835 UNIPROT GNG12 protein Q9UBI6 UNIPROT up-regulates binding 9606 17251915 t gcesareni As pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp. SIGNOR-152817 0.2 RELA protein Q04206 UNIPROT NPPB protein P16860 UNIPROT unknown transcriptional regulation 15837525 f In comparison to the ANF gene, less is known about BNP promoter consensus elements that regulate gene expression by mechanical or neurohumoral agonists. A number of cis-acting elements for GATA, Nkx2.5, NF-kappaB and TEF transcription factors have recently been identified within the BNP promoter that regulate BNP expression in response to specific agonists. This review focuses on the information available regarding cis-acting determinants responsible for inducible BNP transcription. SIGNOR-253651 0.2 ABL1 protein P00519 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity phosphorylation Tyr425 SDKYGLGyQLCDNSV 9606 27899378 t Manara C-ABL can directly phosphorylate PLK1 and activate PLK1. | The above results indicate that c-ABL–mediated PLK1 Y425 phosphorylation regulates PLK1 ubiquitination and stability. SIGNOR-260935 0.294 ARPC4 protein P59998 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 t The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc SIGNOR-251517 0.964 beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI PFKL protein P17858 UNIPROT up-regulates activity binding 9606 19454274 t The PFKFB enzymes synthesize fructose-2,6-bisphosphate (F2,6BP) which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. PFK-1 is inhibited by ATP when energy stores are abundant and F2,6BP can override this inhibition and enhance glucose uptake and glycolytic flux SIGNOR-267266 0.8 PRKCE protein Q02156 UNIPROT NLRP5 protein P59047 UNIPROT up-regulates activity phosphorylation Ser331 MQRKKESsVTEFISR 9606 BTO:0000007 19542546 t miannu MATER protein as substrate of PKCepsilon in human cumulus cells. we performed coimmunoprecipitation experiments using HEK293T cells expressing human MATER; a similar approach was then followed in human cumulus/follicular cells. In MATER(+)HEK293T cells, we observed that this protein acts as a phosphorylation substrate of PKCepsilon. Since PKCepsilon is known to collaborate with antiapoptotic signalling pathways, this suggests a novel mechanism for the function of MATER in follicular maturation. SIGNOR-263175 0.2 VRK1 protein Q99986 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 15378002 t flangone Vrk1 phosphorylates c-jun in ser63 and ser73 in vitro...VRK1 Activates c-jun dependent transcription SIGNOR-127073 0.527 CPT1C protein Q8TCG5 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267134 0.8 BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 12242151 t gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma SIGNOR-92945 0.818 CDK1 protein P06493 UNIPROT SAMHD1 protein Q9Y3Z3 UNIPROT down-regulates phosphorylation Thr592 DVIAPLItPQKKEWN 9606 23602554 t llicata Cyclin a2/cdk1 phosphorylates samhd1 at the threonine 592 residue both in vitro and in vivo. Phosphorylation of samhd1 thr592 correlates with loss of its ability to restrict hiv-1. SIGNOR-201913 0.505 levomilnacipran chemical CHEBI:136040 ChEBI SLC6A3 protein Q01959 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 18468895 t Luana Studies on a series of milnacipran analogs containing a heteroaromatic group as potent norepinephrine and serotonin transporter inhibitors SIGNOR-257944 0.8 H2AZ2 protein Q71UI9 UNIPROT Nucleosome_H2A.Z.2 variant complex SIGNOR-C323 SIGNOR form complex binding -1 24311584 t miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. SIGNOR-263709 0.2 PIGBOS1 protein A0A0B4J2F0 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0002181 31653868 f miannu Here, we characterize a microprotein called PIGBOS and reveal a role for a mitochondrial protein in UPR signaling. Together, these results showed that loss of PIGBOS increases cellular sensitivity to ER stress, which in turn increases apoptosis and links PIGBOS levels to the ability of cells to survive stress. SIGNOR-261042 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183616 0.2 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr759 LYDVSRMyVDPSEIN 9606 BTO:0000776 11507089 t lperfetto These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2. SIGNOR-109758 0.769 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI MAPK9 protein P45984 UNIPROT down-regulates chemical inhibition 9606 11717429 t gcesareni We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm). SIGNOR-111986 0.8 SND1 protein Q7KZF4 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 30365124 f irozzo SND1 upregulation is a common phenomenon in different human malignant tissues. We found that SND1 overexpression significantly promoted cell proliferation and tumor growth in vitro and in vivo. SIGNOR-259135 0.7 perifosine chemical CHEBI:67272 ChEBI AKT1 protein P31749 UNIPROT down-regulates chemical inhibition 9606 22090271 t Perifosine causes decrease in Akt Ser473 and Thr308 phosphorylation gcesareni Perifosine is an alkylphospholipid that targets the pleckstrin homology domain of akt and blocks its membrane translocation, hence preventing akt phosphorylation and activation SIGNOR-252630 0.8 TPH1 protein P17752 UNIPROT 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI up-regulates quantity chemical modification 9606 31024440 t brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. SIGNOR-264010 0.8 FLT3 protein P36888 UNIPROT IDH1 protein O75874 UNIPROT up-regulates activity phosphorylation Tyr42 VELDLHSyDLGIENR -1 34289383 t lperfetto Moreover, in an in vitro kinase assay, purified recombinant FLT3 (rFLT3) phosphorylated recombinant IDH2 R140Q mutant but did not alter its catalytic activity (Figure 1C), whereas rFLT3 phosphorylated mIDH1 protein and enhanced its catalytic activity SIGNOR-267629 0.435 HMGN1 protein P05114 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR down-regulates -1 12213813 f lperfetto In vitro, binding of HMGN1 proteins to the nucleosomes reduces chromatin compaction and promotes overall accessibility to the nucleosomes SIGNOR-262989 0.7 AMBRA1 protein Q9C0C7 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 dephosphorylation:Ser52 KRVELPDsPRSTFLL 23524951 t lperfetto In this condition, AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. SIGNOR-272963 0.575 STAT1 protein P42224 UNIPROT NOS2 protein P35228 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19029990 t lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. SIGNOR-249497 0.439 IL10RA protein Q13651 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity binding 9606 BTO:0000801;BTO:0000776 10347215 t miannu Specifically, il-10 effects the activation of jak1 (associated with the il-10 receptor alpha Chain) and tyk2 (associated with the il-10 receptor beta Chain) and induces the activation of stat1, stat3, and, in some cells, stat5. SIGNOR-68010 0.802 ITSN1 protein Q15811 UNIPROT CDC42 protein P60953 UNIPROT up-regulates binding 9606 15824104 t gcesareni Full-length intersectin-l exhibited little ability to stimulate nucleotide exchange on cdc42 SIGNOR-135377 0.843 BCL2L11 protein O43521 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000972 17960585 f miannu Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells. SIGNOR-260426 0.7 TSC22D3 protein Q99576 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity relocalization 9606 20018851 t GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells. SIGNOR-256147 0.404 CFL2 protein Q9Y281 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR down-regulates quantity binding 9606 BTO:0000132 27871158 t lperfetto Cofilin also binds to actin and contributes to the disassembly of actin filaments and the subsequent release of actin monomers. SIGNOR-261837 0.7 MAPK14 protein Q16539 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates activity phosphorylation Ser505 LNTSYPLsPLSDFAT 9606 BTO:0000132 8910365 t lperfetto These results provide the first direct evidence that p38 kinase is responsible for cpla2 phosphorylation in sfllrn-stimulated platelets and is involved in the early phosphorylation of cpla2 in thrombin-stimulated platelets SIGNOR-44673 0.655 PDGFRB protein P09619 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 7535778 t miannu Tyrosine phosphorylation has been shown to increase the enzymatic activity of plc-? / we show that the human pdgf ?- And ?-Receptors differ quantitatively in their abilities to associate with and phosphorylate plc-? And to stimulate inositol phosphate production. SIGNOR-28179 0.854 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates phosphorylation 9606 17573348 t gcesareni Here we show in vitro that lkb1 phosphorylates and activates mark2 SIGNOR-156126 0.57 glycine smallmolecule CHEBI:15428 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264745 0.7 PCDHA1 protein Q9Y5I3 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265663 0.2 POLG protein P54098 UNIPROT DNA polymerase gamma complex SIGNOR-C378 SIGNOR form complex binding -1 19837034 t lperfetto Here, we report a crystal structure of human DNA Pol gamma holoenzyme. The holoenzyme is a heterotrimer containing one Pol gammaA subunit and a dimeric Pol gammaB subunit. SIGNOR-265719 0.738 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120248 0.321 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR glutamine smallmolecule CHEBI:28300 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270389 0.8 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249323 0.754 dactolisib chemical CHEBI:71952 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 BTO:0000848 21803746 t ATP-competitive inhibitor of PI3K and mTOR gcesareni While the pi3k inhibitors, ly294002 or wortmannin, in the presence of plx4032 were individually inactive against pprm cell lines (fig. S4), the dual pi3k and mtorc1/2 inhibitor bez235 was highly specific (vs. parental lines) and potent in growth-inhibiting pprm cell lines SIGNOR-175712 0.8 MTNR1A protein P48039 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256985 0.252 CDC25A protein P30304 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 BTO:0000093 15672448 t gcesareni We found that cdc25a physically interacted with and de-phosphorylated phospho-erk both in vitro and in cell culture. SIGNOR-133392 0.404 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270382 0.8 PTPN11 protein Q06124 UNIPROT ITK protein Q08881 UNIPROT down-regulates activity dephosphorylation 9606 33624224 t miannu Using genetic and pharmacological approaches, we discovered that SHP2 dephosphorylates ITK specifically downstream of PD-1 and that this event was associated with PD-1 inhibitory cellular functions. SIGNOR-277174 0.33 NUMB protein P49757 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 BTO:0000150 18492217 t gcesareni Numb can actually interact in vivo with endogenous mdm2 and p53, resulting in a trimeric complex between the three proteins [10]. This interaction appears to regulate the stability of p53, as reduction of numb levels by rna interference (rnai) causes a decrease in the half-life of p53 and consequently a reduction in steady-state levels of the protein. Consistent with this observation, overexpression of numb increases the level of p53 in both unstressed and stressed cells. SIGNOR-178668 0.53 HTR4 protein Q13639 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257416 0.252 CLIP1 protein P30622 UNIPROT DCTN1 protein Q14203 UNIPROT up-regulates activity binding 9606 15381688 t miannu MT-unbound CLIP-170 can adopt a folded conformation through an intramolecular interaction of its terminal domains. Binding to MTs correlates with the unfolding of CLIP-170, which allows the interaction of the COOH-terminal domain with its binding partners, such as dynactin, resulting in their recruitment to the MT tip. The NH2 terminus of p150Glued binds directly to the COOH terminus of CLIP-170 through its second metal-binding motif. SIGNOR-252164 0.773 CRP protein P02741 UNIPROT CCL2 protein P13500 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004910 26961257 f miannu In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the “risk” His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained. SIGNOR-252144 0.452 MEN1 protein O00255 UNIPROT MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 t irozzo We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]. SIGNOR-255867 0.2 ROCK1 protein Q13464 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Ser1131 AARERKRsRGNRKSL 9606 18239683 t lperfetto Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres. SIGNOR-160544 0.314 REST protein Q13127 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR down-regulates 9606 17453016 f NRSF represses neuronal differentiation by binding to conserved NRS elements (NRSEs) in gene promoters in non-neuronal cells, where it associates with one of several large repressor complexes, including the transcriptional co-repressor mSIN3a/b, nuclear receptor co-repressor 1 (N-CoR1), and coREST/histone deacetylase 2 (HDAC2). In this way, NRSF keeps neural-specific genes turned off in non-neuronal cells. SIGNOR-268622 0.7 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1675 SPSYSPTsPSYSPTS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248809 0.849 CDK1 protein P06493 UNIPROT KAT7 protein O95251 UNIPROT up-regulates phosphorylation Thr85 TRSQQQPtPVTPKKY 9606 18250300 t lperfetto Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate. SIGNOR-160743 0.362 ATR protein Q13535 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates phosphorylation Ser68 EELDTLAsQALSQCP 9606 15451423 t lperfetto When dna is damaged, the atr-atrip complex is recruited to chromatin and is activated to transduce the checkpoint signal, but the precise kinase activation mechanism remains unknown. Here, we show that atrip is phosphorylated in an atr-dependent manner after genotoxic stimuli. The serine 68 and 72 residues are important for the phosphorylation in vivo and are required exclusively for direct modification by atr in vitro. SIGNOR-129469 0.874 LCK protein P06239 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity phosphorylation Tyr315 RADNDKEyLVLTLTK 9606 BTO:0002035 11948419 t miannu MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e). SIGNOR-275983 0.382 KAT5 protein Q92993 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys21 GGAKRHRkVLRDNIQ 9606 12776177 t lperfetto Thus, the TIP60 HAT complex is recruited to MYC-target genes and, probably with other other HATs, contributes to histone acetylation in response to mitogenic signals. SIGNOR-262061 0.2 PB28 dihydrochloride chemical CID:46861545 PUBCHEM TMEM97 protein Q5BJF2 UNIPROT up-regulates activity chemical activation 9606 BTO:0000093 16891467 t Federica Cyclohexylpiperazine derivative PB28, a σ2 agonist and σ1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer SIGNOR-261110 0.8 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 21798082 t gcesareni Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-175291 0.754 ETV2 protein O00321 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0001086 24583263 f irozzo Using the embryoid body differentiation system, we demonstrate that co-expression of Gata2 augments the activity of Etv2 in promoting endothelial and hematopoietic lineage differentiation. SIGNOR-256009 0.7 AX/b2 integrin complex SIGNOR-C171 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269020 0.7 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser698 PEWPRRAsCTSSTSG -1 2117608 t llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. SIGNOR-250883 0.335 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 15829723 t apalma IGF-I binding to its receptor activates the kinase activity of the receptor, which then recruits the insulin response substrate-1, causing activation of phosphatidyl-inositol-3 kinase (PI3K) to phosphorylate Akt. SIGNOR-255104 0.864 GSK3B protein P49841 UNIPROT TOP2A protein P11388 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1361 SPPKTKTsPKLSNKE 9606 BTO:0003492 21254166 t miannu  This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361. SIGNOR-276301 0.355 FPR1 protein P21462 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256961 0.252 AURKA protein O14965 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser93 SSLLSRSsSGYFSFD 9606 BTO:0002181 23912711 t miannu  We observed that BimEL is phosphorylated by Aurora A early in mitosis and reversed by PP2A after mitotic exit. Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL.  SIGNOR-276247 0.384 AVPR2 protein P30518 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256897 0.272 SLC24A3 protein Q9HC58 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264396 0.8 CSNK2A1 protein P68400 UNIPROT CAV1 protein Q03135 UNIPROT unknown phosphorylation Ser88 FDGIWKAsFTTFTVT -1 8058322 t llicata Here, we have identified this serine kinase activity as a casein kinase II-like enzyme, since the phosphorylation of caveolin-rich membrane domains is stimulated and inhibited by known effectors of casein kinase II (poly-L-lysine, endogenous polyamines, and a casein kinase II inhibitor peptide), but is unaffected by modulators of other known kinases. In support of these observations, caveolin contains a consensus sequence for casein kinase II phosphorylation in its cytoplasmic N-terminal domain (Ser-88) SIGNOR-250835 0.36 TBK1 protein Q9UHD2 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser293 VELFGPIsLEQVRFP 9606 22412986 t lperfetto Activation of interferon regulatory factor 5 by site specific phosphorylation. Although the gene induction by irf5 in the presence of tbk-1 was modest, phosphorylation by tbk-1 produced a significant shift in the mobility of irf5 in sds-page. For this reason we identified the residues that are phosphorylated on irf5 by tbk-1 with mass spectrometry. Ser-158 and ser-309 were found to be phosphorylated SIGNOR-196532 0.557 PPP6C protein O00743 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity dephosphorylation Thr187 CDIQTHMtNNKGSAA 9606 17079228 t Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway|From proteomic analysis of TAK1-binding proteins, we identified protein phosphatase 6 (PP6), a type-2A phosphatase, and demonstrated that PP6 associated with and inactivated TAK1 by dephosphorylation of Thr-187. SIGNOR-248292 0.38 PP1 proteinfamily SIGNOR-PF54 SIGNOR AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser217 YTRTGSEsPKVCSDQ 9606 17318175 t lperfetto The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-264660 0.2 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser358 WPLSRTRsEPLPPSA 9606 18339811 t Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs. SIGNOR-248605 0.2 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates activity phosphorylation Ser77 PGPFATRsPLFIFMR 10090 12818176 t miannu JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity. SIGNOR-250131 0.677 dexamethasone chemical CHEBI:41879 ChEBI PPARG protein P37231 UNIPROT up-regulates quantity by expression 10090 11279134 f lperfetto The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin SIGNOR-235328 0.8 NANOG protein Q9H9S0 UNIPROT SOX17 protein Q9H6I2 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 f lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) SIGNOR-253168 0.484 GABARAP protein O95166 UNIPROT GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates activity binding 9606 BTO:0000938 25882190 t miannu GABARAP was originally isolated as a binding partner of the GABAA receptor γ2-subunit in a yeast two-hybrid screen, and was suggested to have a role in the targeting and clustering of GABAA receptors. SIGNOR-264972 0.2 RPS6KA3 protein P51812 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr451 KRTRSKGtLRYMSPE 9606 BTO:0001286 17404396 t gcesareni Our data indicated that phosphorylation of pkr at thr(451) is mediated through erk2 and rsk2, but not through p38 kinase. SIGNOR-154183 0.2 MAPKAPK2 protein P49137 UNIPROT KRT20 protein P35900 UNIPROT up-regulates activity phosphorylation Ser13 RSFHRSLsSSLQAPV -1 20724476 t miannu P38 phosphorylates the type II keratin, K8 at Ser73, whereas MK2 phosphorylates the binding partners K18 at Ser52 and K20 at Ser13. SIGNOR-263072 0.2 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR G3BP1 protein Q13283 UNIPROT up-regulates activity binding 30804210 t SARA The RGG domain of G3BP1 could mediate the direct binding of HCV-dsRNA and poly(IC) SIGNOR-260979 0.7 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser88 DSGFCLDsPGPLDSK 9606 BTO:0000017 28192398 t miannu We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation.  SIGNOR-277342 0.638 XL765 chemical CHEBI:71958 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207878 0.8 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser464 LLKHVTQsSRKLIRA 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni Protein kinase c isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity. SIGNOR-129280 0.29 CHRNA7 protein P36544 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 27167578 t Here, we demonstrate a role for α7 nAChR/G protein interaction in the activation of the small (monomeric) RhoA GTPase leading to cytoskeletal changes during neurite growth. Treatment of PC12 cells with the α7 nAChR agonist choline or PNU-282987 was associated with an increase in RhoA activity and an inhibition in neurite growth. SIGNOR-253985 0.2 CHEK1 protein O14757 UNIPROT E2F6 protein O75461 UNIPROT down-regulates activity phosphorylation Ser12 RPARKLPsLLLDPTE -1 23954429 t miannu the checkpoint kinase Chk1 phosphorylates E2F6 leading to its dissociation from promoters. SIGNOR-266370 0.556 CUDC-101 chemical CID:24756910 PUBCHEM HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20143778 t miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. SIGNOR-262256 0.8 MAP3K10 protein Q02779 UNIPROT NEUROD1 protein Q13562 UNIPROT up-regulates activity binding -1 12881483 t lperfetto we identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2). Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2 SIGNOR-234599 0.339 PRKD1 protein Q15139 UNIPROT RIN1 protein Q13671 UNIPROT down-regulates phosphorylation Ser351 RPLLRSMsAAFCSLL 9606 11784866 t gcesareni Rin1 also binds to 14-3-3 proteins through a sequence including serine 351. Mutation of this residue abolished the 14-3-3 binding capacity of rin1 and led to more efficient blockade of ras-mediated transformation. The mutant protein, rin1(s351a), showed a shift in localization to the plasma membrane. Serine 351 is a substrate for protein kinase d (pkd [also known as pkcmu]) in vitro and in vivo. These data suggest that the normal localization and function of rin1, as well as its ability to compete with raf, are regulated in part by 14-3-3 binding, which in turn is controlled by pkd phosphorylation. SIGNOR-113960 0.412 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2C protein O00762 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271356 0.598 AP1 complex SIGNOR-C154 SIGNOR CD3 complex SIGNOR-C432 SIGNOR up-regulates activity binding 9606 16473826 t scontino When T cells encounter antigens via the T cell antigen receptor (TCR), information about the quantity and quality of antigen engagement is relayed to the intracellular signal transduction machinery. The TCR itself lacks a significant intracellular domain. Instead, it is associated with CD3 molecules that contain intracellular signaling domains that couple the TCR/CD3 complex to the downstream signaling machinery. SIGNOR-267994 0.327 MAPK1 protein P28482 UNIPROT NR4A2 protein P43354 UNIPROT up-regulates phosphorylation Thr132 SSPPTPTtPGFQVQH 9606 BTO:0000938 BTO:0000142 17681692 t llicata We have shown that erk2 is a kinase to phosphorylate nurr1 on multiple sites. S126 and t132, which are located near af1 core of nurr1, are dominant sites phosphorylated by erk2. reporter gene assays show that nurr1delta124-133/t185a, an erk2 phospho-site mutant form, could not further increase its transcriptional activity on th promoter, suggesting that nurr1 phosphorylation by erk2 may regulate its transcriptional activity on th promoter. SIGNOR-157171 0.404 DYRK1A protein Q13627 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000938 20696760 t gcesareni Dyrk1a phosphorylates p53 and inhibits proliferation of embryonic neuronal cells. we found that dyrk1a phosphorylates p53 at ser-15 in vitro and in immortalized rat embryonic hippocampal progenitor h19-7 cells. In addition, dyrk1a-induced p53 phosphorylation at ser-15 led to a robust induction of p53 target genes SIGNOR-167407 0.427 FLT1 protein P17948 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr155 LNDSAAYyLNDLDRI -1 33139573 t miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. SIGNOR-277229 0.26 RUNX3 protein Q13761 UNIPROT PEA15 protein Q15121 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002384 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255097 0.2 HDAC1 protein Q13547 UNIPROT CLDN7 protein O95471 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 19277896 t lperfetto ChIP assays revealed that SNAI1P is recruited on the CLDN7 gene promoter along with the co-repressor CtBP1 and the effector HDAC1.|These data further suggest that HDAC1 is involved in the SNAI1P-mediated repression of the human CLDN7 gene promoter. SIGNOR-254106 0.2 MAPK14 protein Q16539 UNIPROT EEA1 protein Q15075 UNIPROT up-regulates phosphorylation 9606 16138080 t gcesareni We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes. SIGNOR-140085 0.47 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr207 YYDTHTNtYYLRTFG 9606 16669787 t miannu We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1 SIGNOR-146517 0.539 IFNAR complex SIGNOR-C243 SIGNOR Macrophage_activation phenotype SIGNOR-PH126 SIGNOR up-regulates 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260848 0.7 MRPS28 protein Q9Y2Q9 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-267732 0.623 PBX1 protein P40424 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 15149596 t Pbx is constitutively bound close to the Myogenin promoter and can recruit MyoD lperfetto These domains are necessary for the stable binding of myod to the myogenin promoter through an interaction with an adjacent protein complex containing the homeodomain protein pbx, which appears to be constitutively bound at this site SIGNOR-124834 0.419 ATM protein Q13315 UNIPROT FANCA protein O15360 UNIPROT up-regulates phosphorylation Ser1449 AAPDADLsQEPHLF 9606 19109555 t lperfetto The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site SIGNOR-182949 0.417 SCN8A protein Q9UQD0 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. SIGNOR-253452 0.7 ATP5PO protein P48047 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261403 0.2 CBS protein P35520 UNIPROT L-homocysteine zwitterion smallmolecule CHEBI:58199 ChEBI down-regulates quantity chemical modification 9606 23981774 t lperfetto Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. SIGNOR-275828 0.8 MAPK1 protein P28482 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation Ser272 SNHGLAIsPGMKTRI 9606 8846784 t fstefani Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk. SIGNOR-44339 0.521 OGT protein O15294 UNIPROT PFKL protein P17858 UNIPROT down-regulates activity glycosylation Ser529 CVIPATIsNNVPGTD 9606 BTO:0000007 22923583 t lperfetto O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway| O-GlcNAc transferase (OGT) catalyzes the transfer of N-acetylglucosamine from uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) to serine or threonine residues SIGNOR-267585 0.281 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000762 12509763 t lperfetto Substrates for ERK1/2 include nuclear proteins such as C-JUN, this leads to activation of the AP-1 transcription factor, which is made up of FOS-JUN heterodimers. SIGNOR-253214 0.2 MVD protein P53602 UNIPROT KRAS protein P01116 UNIPROT up-regulates quantity by stabilization 9534 12646231 f miannu An overexpression of mot-2 resulted in reduced level of Ras and phosphorylated ERK2. These were rescued by co-expression of MPD from an exogenous promoter demonstrating a functional link between mot-2, MPD, and Ras. Ras and its oncogenic forms act as key players in controlling proliferation of normal and cancerous cells. Assigning mot-2 upstream of p21Ras offers an important mechanism for influence over cell proliferation. Therefore, we ra tionaled to investigate if overexpression of MPD could affect the steady state levels of Ras by affecting its prenylationTransient transfections of MPD-myc in COS 7 cells resulted in higher stable levels of Ras as compared to the untransfected cells (Fig. 3A, compare lanes 4 and 8 and Fig. 3B) SIGNOR-265887 0.2 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 15774499 t gcesareni The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. SIGNOR-134654 0.392 IFNG protein P01579 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 20525234 f miannu Pro-inflammatory cytokines like interferon-γ (IFN-γ) induce expression of GTP-cyclohydrolase I in various brain cells. SIGNOR-252223 0.254 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159454 0.259 FAM83G protein A6ND36 UNIPROT CSNK1A1 protein P48729 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 t miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. SIGNOR-273745 0.381 YAP1 protein P46937 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates binding 9606 23431053 t YAP can specifically recognize the phosphorylated SMAD linker sequence containing the PY motif, and its presence is required for efficient transcription of BMP target genes. gcesareni Yap binds to the phosphorylated smad1 to activate gene transcription. SIGNOR-201462 0.56 SSH3 protein Q8TE77 UNIPROT CFL1 protein P23528 UNIPROT up-regulates activity dephosphorylation Ser3 sGVAVSDG 9606 14531860 t Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH). SIGNOR-248759 0.71 STAT4 protein Q14765 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 22740693 f miannu It suggests that HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4. SIGNOR-255246 0.312 SUZ12 protein Q15022 UNIPROT SUZ12/EZH2 complex SIGNOR-C77 SIGNOR form complex binding 9606 16712789 t miannu Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2. SIGNOR-146764 0.961 CDC14A protein Q9UNH5 UNIPROT KMT5A protein Q9NQR1 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 t The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC(cdh1)-mediated ubiquitination of PR-Set7 and subsequent proteolysis. SIGNOR-248835 0.2 AIRE protein O43918 UNIPROT ICA1 protein Q05084 UNIPROT down-regulates quantity by repression transcriptional regulation 22447927 t lperfetto Sequence variation in promoter of Ica1 gene, which encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune regulator (AIRE) to increase its binding and down-regulate expression. SIGNOR-268973 0.369 ZEB1 protein P37275 UNIPROT FBP1 protein P09467 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000762 30616754 t lperfetto Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells|we confirmed DNA methylation in the promoter contributed to the decrease of FBP1 expression in lung cancer cells. We identified Zinc finger E-box-binding homeobox 1 (ZEB1) bond to FBP1 promoter to enhance DNA methylation in lung cancer cells. SIGNOR-267596 0.2 ANKRD11 protein Q6UB99 UNIPROT CORO1B protein Q9BR76 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 29274743 t miannu Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.  SIGNOR-266737 0.2 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates activity phosphorylation Thr221 KDEILPTtPISEQKG 9606 19059439 t Manara Here we show that PKCδ phosphorylates rpS3 resulting in its mobilization in the nucleus to repair damaged DNA SIGNOR-260895 0.2 GDNF protein P39905 UNIPROT RET protein P07949 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9182803 t gcesareni A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling SIGNOR-49094 0.907 CSNK2A1 protein P68400 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT down-regulates activity phosphorylation Ser393 VCHDSDEsDTAKAVE -1 25066127 t miannu This modulation can be directly attributed to CK2-mediated phosphorylation of Dnmt3a. We also find that CK2-mediated phosphorylation is required for localization of Dnmt3a to heterochromatin. SIGNOR-276649 0.2 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21071439 t lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-188916 0.532 Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 20498094 f miannu A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. SIGNOR-263728 0.7 TNKS2 protein Q9H2K2 UNIPROT TERF1 protein P54274 UNIPROT down-regulates activity ADP-ribosylation -1 11739745 t lperfetto Tankyrase 2 poly(ADP-ribosyl)ated itself and TRF1. Overexpression of tankyrase 2 in the nucleus released endogenous TRF1 from telomeres. SIGNOR-263376 0.566 GPR183 protein P32249 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257202 0.263 PRDM1 protein O75626 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12032779 f miannu Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. SIGNOR-253828 0.447 NLK protein Q9UBE8 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT down-regulates phosphorylation Thr212 TYSNEHFtPGNPPPH 9606 12556497 t llicata Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk. SIGNOR-97873 0.763 RBM38 protein Q9H0Z9 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 9606 17050675 t Luana Here, we found that RNPC1, an RNA-binding protein and a target of the p53 family, is required for maintaining the stability of the basal and stress-induced p21 transcript. SIGNOR-275391 0.324 KLKB1 protein P03952 UNIPROT MST1 protein P26927 UNIPROT up-regulates activity cleavage Arg483 DQRRSKLrVVGGHPG -1 10068459 t miannu Proteolytic cleavage of pro-MSP at a single site yields active MSP, a disulfide-linked alphabeta-chain heterodimer. human kallikrein cleaved only at Arg483–Val484, the cleavage site for formation of a- and b-chains. SIGNOR-256511 0.33 PDGFRB protein P09619 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 10733900 t amattioni Crk could bind to both pdgf alpha- and beta-receptors in vivo SIGNOR-75884 0.592 diazepam chemical CHEBI:49575 ChEBI GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t brain lperfetto The traditional BZ site agonists (GABA-enhancing CNS depressants such as diazepam) are active on the GABAA-Rs containing a gamma2 subunit (Pritchett et al., 1989), a beta subunit, and one of the alpha subunits, alpha1, 2, 3, or 5. SIGNOR-263798 0.8 GSK3B protein P49841 UNIPROT SPI1 protein P17947 UNIPROT down-regulates quantity by destabilization phosphorylation Ser41 EYYPYLSsDGESHSD 9606 BTO:0002181 33188146 t miannu We demonstrate that GSK3β phosphorylates PU.1 at Ser41 and Ser140 leading to its recognition and subsequent ubiquitin-mediated degradation by E3 ubiquitin ligase FBW7. SIGNOR-277541 0.2 FAM83H protein Q6ZRV2 UNIPROT CSNK1A1 protein P48729 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 t miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. SIGNOR-273747 0.395 PAK1 protein Q13153 UNIPROT AURKA protein O14965 UNIPROT up-regulates phosphorylation Thr288 APSSRRTtLCGTLDY 9606 24867643 t lperfetto The upstream pak1 kinase can phosphorylate aurora a at t288, autophosphorylation appears to be the essential mode of activation. Our experiments suggest that phosphorylation of t288 is important for regulation of the aurora2 kinase both for its activity and its stability SIGNOR-205110 0.392 MMP12 protein P39900 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Leu433 REYHTEKlVTSKGDK -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-12 20ADSGEGD a-chain| 540FVSETESRG a-chain|433LVTSKGDK a-chain SIGNOR-263624 0.2 ERN1 protein O75460 UNIPROT XBP1 protein P17861-2 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 31226023 t miannu Upon activation by oligomerization and autophosphorylation, the cytosolic RNase domain of IRE1 mediates an unconventional splicing of the mRNA of X-box-binding protein 1 (XBP1). The spliced and frameshifted transcript encodes XBP1S, a bZIP transcription factor inducing the expression of numerous UPR effector genes that enhance ER folding capacity. SIGNOR-260183 0.637 ITGA6 protein P23229 UNIPROT A6/b1 integrin complex SIGNOR-C164 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253179 0.813 TGFb proteinfamily SIGNOR-PF5 SIGNOR SNAI1 protein O95863 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 29305973 t miannu Epithelial-mesenchymal transition (EMT) takes place, namely fibrosis, development and cancer. the process of EMT is integral to a number of physiological and disease states. TGF-β1 is a major effector of this process that activates various key transcription factors such as Snai1. SIGNOR-265251 0.2 PRKCD protein Q05655 UNIPROT FSCN1 protein Q16658 UNIPROT down-regulates activity phosphorylation Ser39 KVNASASsLKKKQIW 9606 BTO:0000931 8647875 t lperfetto Phosphorylation of human fascin inhibits its actin binding and bundling activities. SIGNOR-248944 0.33 FGF11 protein Q92914 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253446 0.2 CDK1 protein P06493 UNIPROT UBA1 protein P22314 UNIPROT up-regulates phosphorylation Ser4 sPLSKKRR 9606 BTO:0000150 7673335 t lperfetto Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Each serine residue was independently mutated to an alanine and analyzed by two-dimensional electrophoresis;only serine 4 was phosphorylated. Disruption of the basic amino acids within the nls resulted in loss of exclusive nuclear localization and a 90-95% decrease in the phosphorylation of ha1-e1 SIGNOR-31157 0.414 GSK3B protein P49841 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates activity phosphorylation Ser793 PRPSPLPsPQPAPRR 9606 BTO:0000007 17711861 t miannu  The activation of MLK3 by GSK-3beta occurred via phosphorylation of MLK3 on two amino acid residues, Ser(789) and Ser(793), that are located within the C-terminal regulatory domain of MLK3.  SIGNOR-276072 0.342 ANXA1 protein P04083 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 27426034 f miannu Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines. we set out to examine the relationship between the different subcellular distributions of ANXA1 and the upregulation of inflammatory cytokines. When BV-2 microglial cells were transfected with ANXA1-S27A constructs following by OGD/R treatment, the pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, were found to be expressed at lower levels than those of control groups SIGNOR-261941 0.339 FUS protein P35637 UNIPROT GEMIN6 protein Q8WXD5 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 23022481 t lperfetto Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells SIGNOR-262106 0.2 GSK3B protein P49841 UNIPROT STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization phosphorylation Ser393 LTPEKGQsQGLIWDF 9606 BTO:0002181 31843895 t miannu GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation. SIGNOR-276764 0.293 RASGEF1C protein Q8N431 UNIPROT NRAS protein P01111 UNIPROT up-regulates binding 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-161511 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270388 0.8 GSK3A protein P49840 UNIPROT MAF protein O75444 UNIPROT down-regulates phosphorylation 9606 18042454 t miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. SIGNOR-159361 0.2 RB1 protein P06400 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR down-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245483 0.7 PTBP2 protein Q9UKA9 UNIPROT SRC protein P12931 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000567 11003644 t lperfetto Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA. SIGNOR-261267 0.289 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 21079800 t gcesareni Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis. SIGNOR-169694 0.695 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Thr289 AGPKASPtPQKTSAK 9606 14741103 t llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. SIGNOR-250656 0.415 ANXA1 protein P04083 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 27426034 f miannu Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines. we set out to examine the relationship between the different subcellular distributions of ANXA1 and the upregulation of inflammatory cytokines. When BV-2 microglial cells were transfected with ANXA1-S27A constructs following by OGD/R treatment, the pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, were found to be expressed at lower levels than those of control groups SIGNOR-261940 0.385 MAPK14 protein Q16539 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates phosphorylation Ser211 PGKETNEsPWRSDLL 10090 20660302 t We demonstrate here that AMPK differentially modulates glucocorticoid action by phosphorylating the human GR at serine 211 indirectly through the activation of p38 MAPK SIGNOR-255952 0.49 MAPK3 protein P27361 UNIPROT NOS2 protein P35228 UNIPROT up-regulates phosphorylation Ser745 KSRQNLQsPTSSRAT 9606 BTO:0000007 17804409 t esanto Erk phosphorylated inos on ser745. Mutation of ser745 to ala did not affect basal inos activity but eliminated inos phosphorylation and activation in response to b1r agonist. SIGNOR-157711 0.361 ATP5MC1 protein P05496 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261399 0.2 SMAD6 protein O43541 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates binding 9606 19352540 t gcesareni Mad6-pellino-1 interaction abrogated signaling mediated by a complex of irak1. SIGNOR-185128 0.338 FLT4 protein P35916 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 9927207 t llicata We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites. SIGNOR-64190 0.575 CASP3 protein P42574 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni Caspase-3 is responsible for apoptosis execution SIGNOR-89244 0.7 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr941 EETGTEEyMKMDLGP 10116 BTO:0000443 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-235975 0.912 methiothepin chemical CHEBI:64203 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258853 0.8 AMPK complex SIGNOR-C15 SIGNOR CSNK1E protein P49674 UNIPROT up-regulates activity phosphorylation Ser389 RGAPANVsSSDLTGR -1 17525164 t miannu AMPK enhances mPer2 degradation and CKIɛ activity by phosphorylating Ser-389 of CKIɛ. One of the regulators of the period length is casein kinase Iepsilon (CKIepsilon), which by phosphorylating and inducing the degradation of the circadian clock component, mPer2, shortens the period length. AMPK phosphorylates Ser-389 of CKIepsilon, resulting in increased CKIepsilon activity and degradation of mPer2.  SIGNOR-276064 0.266 CUDC-101 chemical CID:24756910 PUBCHEM HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20143778 t miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. SIGNOR-262259 0.8 PPP2CA protein P67775 UNIPROT RBL1 protein P28749 UNIPROT up-regulates dephosphorylation 9606 15467457 t miannu Pocket protein family consists of the retinoblastoma tumor suppressor protein (prb) and the functionally and structurally related proteins p107 and p130./dephosphorylation of p130 and p107 in cell extracts is inhibited by concentrations of okadaic acid known to inhibit pp2a, but not pp1. Finally, the pp2a catalytic subunit pp2a/c) specifically interacts with both p130 and p107 / the cell cycle repressor activity of pocket proteins is inactivated by cdk mediated phosphorylation. SIGNOR-129749 0.607 DNMT1 protein P26358 UNIPROT BAG4 protein O95429 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 18413740 f lperfetto In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+) SIGNOR-254112 0.2 DUSP9 protein Q99956 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates binding 9606 21908610 t inferred from 70% of family members gcesareni Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein. SIGNOR-269902 0.2 doxepin chemical CHEBI:4710 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 t miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. SIGNOR-258879 0.8 GSK3B protein P49841 UNIPROT OSBP2 protein Q969R2 UNIPROT up-regulates activity phosphorylation 30925160 t lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. SIGNOR-264874 0.2 VRK1 protein Q99986 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr3 tSQKHRDF 9606 16495336 t gcesareni We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell SIGNOR-144791 0.873 NME1 protein P15531 UNIPROT MMP2 protein P08253 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001567 17671192 f miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. SIGNOR-255165 0.337 RPS4X protein P62701 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262447 0.848 AURKA protein O14965 UNIPROT RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Ser207 TSVRRRTsFYLPKDA 9606 17563743 t llicata Aurora-a appears to phosphorylate rassf1a at threonine202 and/or serine203 that reside within the known microtubule-binding domain of rassf1a. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of rassf1a, disrupt rassf1a interactions with microtubules and abolish its ability to induce m-phase cell cycle arrest. SIGNOR-155815 0.459 CDK1 protein P06493 UNIPROT SUN1 protein O94901 UNIPROT down-regulates activity phosphorylation Ser48 KLDPVFDsPRMSRRS 9606 BTO:0000567 25482198 t miannu Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions. SIGNOR-263099 0.365 dabrafenib chemical CHEBI:75045 ChEBI NEK9 protein Q8TD19 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0005011 29112787 t Monia We have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and our studies suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations. We confirmed NEK9 to be a potent target of dabrafenib by in vitro kinase assays, with inhibition of NEK9 observed in the single-digit nanomolar range. SIGNOR-261072 0.8 SRC protein P12931 UNIPROT DGKA protein P23743 UNIPROT up-regulates phosphorylation Tyr335 ILPPSSIyPSVLASG 9606 17700527 t llicata Diacylglycerol kinase-alpha phosphorylation by src on y335 is required for activation, membrane recruitment and hgf-induced cell motility. SIGNOR-157365 0.471 RALA protein P11233 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates activity phosphorylation Thr451 PIPKALGtPVLTPPT 10090 11689711 t gcesareni We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT. SIGNOR-248003 0.2 STK11 protein Q15831 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates phosphorylation Thr109 QWARLLQtSNITKSE 9606 20400510 t esanto Lkb1 suppresses p21-activated kinase-1 (pak1) by phosphorylation of thr109 in the p21-binding domain. SIGNOR-164814 0.249 G3BP1 protein Q13283 UNIPROT G3BP2 protein Q9UN86 UNIPROT up-regulates activity binding 9606 BTO:0000007 23279204 t miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. SIGNOR-260862 0.47 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one chemical CHEBI:94732 ChEBI MAPK8 protein P45983 UNIPROT down-regulates chemical inhibition 9606 18922779 t BI-78D3 is substrate competitive. gcesareni Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell. SIGNOR-181647 0.8 CTDSPL protein O15194 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity dephosphorylation Ser811 IYISPLKsPYKISEG 9606 15051889 t ppRB (RB phosphorylated at Ser-807/811|Possible Mechanisms of HYA22 Action in Tumorigenesis: Dephosphorylation of RB by Transient Expression of HYA22 Isoforms. SIGNOR-248305 0.302 ZAP70 protein P43403 UNIPROT SH2B3 protein Q9UQQ2 UNIPROT up-regulates phosphorylation Tyr273 LEMPDNLyTFVLKVK 9606 BTO:0000782 9169414 t lperfetto In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation. SIGNOR-48854 0.37 ASNS protein P08243 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267535 0.8 CRYAB protein P02511 UNIPROT CRYGS protein P22914 UNIPROT up-regulates activity binding -1 20621668 t miannu Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age. SIGNOR-253623 0.554 NUP98 protein P52948 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 20498086 f miannu The export of mRNAs is a multistep process, involving the packaging of mRNAs into messenger ribonucleoprotein particles (mRNPs), their transport through nuclear pore complexes, and mRNP remodeling events prior to translation. Ribonucleic acid export 1 (Rae1) and Nup98 are evolutionarily conserved mRNA export factors that are targeted by the vesicular stomatitis virus matrix protein to inhibit host cell nuclear export. these data suggest that the Rae1*Nup98 complex directly binds to the mRNP at several stages of the mRNA export pathway. SIGNOR-260872 0.7 Protocadherin_beta proteinfamily SIGNOR-PF102 SIGNOR ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-269039 0.2 FFAR2 protein O15552 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257276 0.378 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1717 SPSYSPTsPSYSPTS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248811 0.849 ZIC1 protein Q15915 UNIPROT GLI3 protein P10071 UNIPROT up-regulates relocalization 9606 11238441 t lperfetto Co-expression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels SIGNOR-105497 0.365 RPS6K proteinfamily SIGNOR-PF26 SIGNOR IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0001103 21798082 t lperfetto Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization. SIGNOR-252787 0.2 PTPN11 protein Q06124 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr751 SKDESVDyVPMLDMK -1 7545675 t Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides SIGNOR-248668 0.739 ROCK1 protein Q13464 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser637 VPVARKLsAREQRDC 10090 31063459 t lperfetto We have also previously reported that ROCK1-mediated Drp1S600 phosphorylation resulted in enhanced mitochondrial fission in podocytes SIGNOR-262549 0.319 NSMCE2 protein Q96MF7 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR form complex binding -1 27427983 t miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks SIGNOR-265484 0.879 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Thr360 SGISSVPtPSPLGPL 9606 BTO:0000527 19941816 t lperfetto Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity SIGNOR-244525 0.2 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Thr686 VKDSQVGtVNYMPPE 9606 19120698 t llicata Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity, autophosphorylation at the p+1 loop (t686) is associated with the active kinase. SIGNOR-183030 0.2 Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR Respiratory electron transport chain phenotype SIGNOR-PH141 SIGNOR up-regulates 30030361 f lperfetto The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA). SIGNOR-262139 0.7 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Tyr34 KDQFPEVyVPTVFEN 9606 BTO:0000567 23027962 t lperfetto When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity SIGNOR-271700 0.2 STAT3 protein P40763 UNIPROT SALL4 protein Q9UJQ4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000815 19151334 f miannu We further tested the functional relationship between STAT3 and SALL4 using MDA-MB-231, a breast cell line carrying constitutive SALL4 expression and STAT3 activity. Down-regulation of the STAT3 activity using a dominant-negative construct resulted in a significant decrease in the expression of SALL4. SIGNOR-255244 0.565 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18570873 t lperfetto Mtor may promote g1 progression in part through sgk1 activation and deregulate the cell cycle in cancers through both akt- and sgk-mediated p27 t157 phosphorylation and cytoplasmic p27 mislocalization. SIGNOR-244202 0.2 Verdinexor chemical CID:71492799 PUBCHEM XPO1 protein O14980 UNIPROT down-regulates chemical inhibition 9606 30541831 t Simone Vumbaca We show that KPT-335 inhibits XPO1-mediated nuclear export, leading to nuclear accumulation of RSV M protein and a reduction inRSV titers. SIGNOR-261129 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates activity dephosphorylation Ser667 SSLIRKRsTRRSVRG 9606 BTO:0000007 24333728 t Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp SIGNOR-272508 0.2 CSNK2A1 protein P68400 UNIPROT CACNA1S protein Q13698 UNIPROT up-regulates activity phosphorylation Ser1575 PEICRTVsGDLAAEE -1 20937870 t miannu To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2. SIGNOR-263114 0.2 PRKG1 protein Q13976 UNIPROT RGS2 protein P41220 UNIPROT up-regulates activity phosphorylation Ser64 KPKTGKKsKQQAFIK -1 14608379 t lperfetto Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction.  SIGNOR-249241 0.671 COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR 26S Proteasome complex SIGNOR-C307 SIGNOR up-regulates activity binding 9606 26497135 t miannu The COP9 signalosome (CSN) and the proteasomal LID are conserved macromolecular complexes composed of at least eight subunits with molecular weights of approximately 350 kDa. CSN and LID are part of the ubiquitin–proteasome pathway and cleave isopeptide linkages of lysine side chains on target proteins. CSN cleaves the isopeptide bond of ubiquitin-like protein Nedd8 from cullins, whereas the LID cleaves ubiquitin from target proteins sentenced for degradation. The evolutionary conserved ubiquitin proteasome pathway (UPP) mediates degradation of intracellular proteins in all eukaryotes. This essential process requires three protein complexes: E3 ubiquitin ligases as e.g., cullin-RING ligases (CRLs), CSN and the 26S proteasome. SIGNOR-270794 0.321 G6PD protein P11413 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 24769394 t miannu G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress SIGNOR-267050 0.8 ABL1 protein P00519 UNIPROT WRN protein Q14191 UNIPROT up-regulates phosphorylation 9606 BTO:0000567;BTO:0001271 12944467 t gcesareni We thus hypothesized that wrn may interact with the abl tyrosine kinase in the dna damage response. Here, we provide evidence for a functional and physical interaction between wrn and c-abl, including wrn relocalization in response to dna damage, suggesting that this protein-protein interaction participates in a shared pathway of genome surveillance. SIGNOR-86497 0.42 RABEPK protein Q7Z6M1 UNIPROT M6PR protein P20645 UNIPROT up-regulates activity relocalization 9230071 t lperfetto P40 is a very potent transport factor in that the pure, recombinant protein can stimulate, significantly, an in vitro transport assay that measures transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network. The functional importance of p40 is confirmed by the finding that anti-p40 antibodies inhibit in vitro transport. Finally, p40 shows synergy with Rab9 in terms of its ability to stimulate mannose 6-phosphate receptor transport. These data are consistent with a model in which p40 and Rab9 act together to drive the process of transport vesicle docking. SIGNOR-253091 0.358 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR USP37 protein Q86T82 UNIPROT up-regulates activity phosphorylation Ser628 MVNSCITsPSTPSKK 9606 BTO:0000007;BTO:0000567 21596315 t lperfetto There is positive reinforcement of this signaling mechanism because phosphorylation of Ser628 by CDK2/cyclin E and CDK2/cyclin A complexes produces maximal USP37 activity SIGNOR-265053 0.458 TWIST1 protein Q15672 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20646316 f miannu Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. SIGNOR-255524 0.488 PGD protein P52209 UNIPROT NADP(3-) smallmolecule CHEBI:58349 ChEBI down-regulates quantity chemical modification 9606 34775382 t miannu 6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule. SIGNOR-268112 0.8 SPAST protein Q9UBP0 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates cleavage -1 15716377 f Gianni Using real-time imaging, we show that Spastin severs microtubules when added to permeabilized, cytosol-depleted cells stably expressing GFP-tubulin. SIGNOR-269046 0.7 TSHZ3 protein Q63HK5 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 19343227 t miannu We carried out yeast two-hybrid studies with a PTB domain of FE65, focusing on those genes that might be involved in nuclear signaling, and identified and validated Teashirt proteins as FE65 interacting proteins in neurons. Using reporter systems, we observed that FE65 could simultaneously recruit SET, a component of the inhibitor of acetyl transferase, and Teashirt, which in turn recruited histone deacetylases, to produce a powerful gene-silencing complex.Endogenous HDAC1 was co-immunoprecipitated with FE65 when both FE65 and Teashirt3 were co-transfected (lane 4), but not when Teashirt3 or FE65 was omitted (lane 5 and 6), confirming that the association of HDAC1 with FE65 is dependent on, and mediated, by Teashirt3. SIGNOR-264814 0.2 AGRP protein O00253 UNIPROT MC3R protein P41968 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268704 0.611 MAPK1 protein P28482 UNIPROT LIMA1 protein Q9UHB6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser604 FQSTSVKsPKTVSPP 9606 23188829 t miannu Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover. SIGNOR-263055 0.2 PRKAA1 protein Q13131 UNIPROT SCD protein O00767 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21478464 f miannu Tr4 transactivation is inhibited via phosphorylation by metformin-induced amp-activated protein kinase (ampk) at the amino acid serine 351, which results in the suppression of scd1 gene expression. SIGNOR-173161 0.278 STK38 protein Q15208 UNIPROT RAB11FIP5 protein Q9BXF6 UNIPROT up-regulates activity phosphorylation Ser307 FTHKRTYsDEANQMR 10090 BTO:0000142 22445341 t miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. SIGNOR-263035 0.2 MMP21 protein Q8N119 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272389 0.7 ER stress stimulus SIGNOR-ST9 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates 9606 22492984 f gcesareni Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins SIGNOR-196941 0.7 JUN protein P05412 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding -1 2467839 t irozzo The protein products of the fos (Fos) and jun (Jun) proto-oncogenes have been shown to associate with a DNA element known as the transcription factor activator protein-1 (AP-1) binding site. Jun (previously known as the Fos-binding protein p39) and Fos form a protein complex in the nucleus. These data demonstrate a cooperative interaction between the protein products of two proto-oncogenes with a DNA element involved in transcriptional regulation. SIGNOR-256361 0.951 AMBRA1 protein Q9C0C7 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates activity binding 9606 BTO:0000567 25438055 t phosphorylation site remapping based on mass spec table lperfetto We found that AMBRA1 favours the interaction between c-Myc and its phosphatase PP2A and that, when mTOR is inhibited, it enhances PP2A activity on this specific target, thereby reducing the cell division rate. As expected, such a de-regulation of c-Myc correlates with increased tumorigenesis in AMBRA1-defective systems, thus supporting a role for AMBRA1 as a haploinsufficient tumour suppressor gene. SIGNOR-272964 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr67 LSILSGGtPKRCLDL 9606 10864927 t lperfetto Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-216777 0.839 PTK6 protein Q13882 UNIPROT PTK6 protein Q13882 UNIPROT up-regulates activity phosphorylation Tyr447 RLSSFTSyENPT 9606 12121988 t lperfetto Mutation of a C-terminal tyrosine (Tyr-447) increases enzyme activity and SH2 domain accessibility, consistent with a role for this residue in autoinhibition. | These results suggest that the Y447F and W44A mutations disrupt the normal intramolecular regulation of Brk and increase the catalytic activity of Brk. SIGNOR-249152 0.2 Late macropinosomes phenotype SIGNOR-PH229 SIGNOR Lysosome fusion phenotype SIGNOR-PH231 SIGNOR up-regulates 9606 39000072 f miannu The fusion of matured macropinosomes with lysosomes is promoted by TRPML1, and degradation of macropinosomes is inhibited by mTORC1. SIGNOR-277787 0.7 PRKD1 protein Q15139 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Ser154 STLYRTQsSSNLAEL 9606 BTO:0000738 23129748 t miannu  PKD1 phosphorylates p85α to enhance its interaction with PTEN, leading to polarized PTEN activity, thereby regulating neutrophil migration.  SIGNOR-276426 0.2 MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000132 SIGNOR-C2 21592956 t lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. SIGNOR-244417 0.928 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Thr393 DFVGHQGtVPSDNID -1 8662852 t we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). SIGNOR-251200 0.682 SYN1 protein P17600 UNIPROT ACTB protein P60709 UNIPROT up-regulates activity binding 9606 BTO:0000938 15265865 t miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. SIGNOR-269184 0.304 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser407 DSQGRNCsTNDSLL -1 8662852 t we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). SIGNOR-251197 0.682 PRKCA protein P17252 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 t llicata Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm. SIGNOR-97279 0.2 MAPK3 protein P27361 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 19282669 t lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-184577 0.582 MAPK9 protein P45984 UNIPROT KLF13 protein Q9Y2Y9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser123 APPSPAWsEPEPEAG 10090 37029927 t miannu TGF-β-mediated downregulation of KLF13 by HDAC-mediated epigenetic silencing and JNK-induced phosphorylation abrogates the latter’s inhibitory effect on TGF-β signaling. SIGNOR-277795 0.2 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252874 0.697 ZNF318 protein Q5VUA4 UNIPROT AR protein P10275 UNIPROT down-regulates activity binding 9606 16469430 t Monia Using different promoters and cells, we confirmed that AR-mediated transactivation was repressed by TZF in a dose-dependent manner (Fig. 1A and B). Endogenous ARmediated transactivation was also inhibited by expression of TZF; These results indicate that amino acid residues 512–663 are essential for the repressive effect of TZF on AR-mediated transactivation. SIGNOR-261187 0.379 GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263808 0.8 YBX1 protein P67809 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10644769 f miannu these results indicate a role for both NF-Y and Sp1 in the transcriptional activation of the MDR1 gene by genotoxic stress, and indicate that YB-1, if involved, is not sufficient to mediate this activation. SIGNOR-253873 0.391 HSP90AA1 protein P07900 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 18591668 t lpetrilli The data in fig. 5 suggest that hsp90 specifically interacts with t?RI And t?RII In vitro and in vivo. Coupled with our data showing that loss of hsp90 function decreases t?R Levels and blocks tgf?-Induced smad2/3 activation and transcription, this result suggests that hsp90 controls tgf? Signaling as an essential component for stabilizing t?Rs. SIGNOR-179271 0.392 PPP2CA protein P67775 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser87 PLKQKQPsFSAKKMT 9606 BTO:0000567 24781523 t miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase SIGNOR-276378 0.3 MYC protein P01106 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12835716 t gcesareni C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a SIGNOR-102743 0.757 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1A protein P50416 UNIPROT down-regulates binding 9606 17452323 t Carnitine palmitoyltransferase 1 (CPT1) catalyzes the conversion of palmitoyl-CoA to palmitoylcarnitine in the presence of l-carnitine, thus facilitating the entry of fatty acids to mitochondria, in a process that is physiologically inhibited by malonyl-CoA SIGNOR-267758 0.8 PGK1 protein P00558 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. SIGNOR-266505 0.8 CSNK2A1 protein P68400 UNIPROT ARRB2 protein P32121 UNIPROT unknown phosphorylation Thr382 EFDTNYAtDDDIVFE -1 11877451 t llicata We found that arrestin-3 is constitutively phosphorylated at Thr-382 and becomes dephosphorylated upon beta(2)-adrenergic receptor activation in COS-1 cells. Casein kinase II (CKII) appears to be the major kinase mediating arrestin-3 phosphorylation, since 1) Thr-382 is contained within a canonical consensus sequence for CKII phosphorylation and 2) wild type arrestin-3 but not a T382A mutant is phosphorylated by CKII in vitro. | However, additional analysis reveals that arrestin-3 phosphorylation may regulate formation of a large arrestin-3-containing protein complex. SIGNOR-250829 0.325 PTH1R protein Q03431 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 23151663 t gcesareni Parathyroid hormone (pth) binding to its receptor pth1r induces association of the pthpth1r complex with lrp6and phosphorylation of pppsp sites by protein kinase_ a, which in turn triggers wnt. SIGNOR-199533 0.343 SMAD6 protein O43541 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity binding 10116 11737269 t lperfetto Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads. SIGNOR-235571 0.552 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys122 SPVEDNEkDLVKLAK -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. SIGNOR-272743 0.475 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAMAC protein Q9BTL3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 YLKRPPEsPPIVEEW 9606 BTO:0001581 27452456 t miannu ERK1/2 phosphorylates RAM serine-36, targeting it for ubiquitination and proteasomal degradation, ultimately resulting in changes in gene expression associated with loss of pluripotency. SIGNOR-277819 0.2 STAT3 protein P40763 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16510571 f lperfetto Mutagenesis of STAT3 binding sites within the cyclin D1 promoter and chromatin immunoprecipitation studies showed an association between STAT3 and the transcriptional regulation of the human cyclin D1 gene. SIGNOR-253049 0.78 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Ser408 RIPASQTsVPFDHLG 9606 BTO:0000007 10542239 t llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T SIGNOR-250810 0.2 VAMP2 protein P63027 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR form complex binding 9606 30267828 t miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. SIGNOR-263966 0.931 (S)-adrenaline smallmolecule CHEBI:40751 ChEBI ADRA1D protein P25100 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258452 0.8 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 29955047 t lperfetto Collectively, our findings indicate that TC-PTP negatively regulates Flk-1 and JNK signaling via direct dephosphorylation of Flk-1 on its Y1173 residue, which contributes to increased epidermal apoptosis in response to UVB exposure.|Use of a TC-PTP substrate trapping mutant for immunoprecipitation analysis showed that TC-PTP dephosphorylates four different tyrosine residues of Flk-1 -- Y1052, Y1057, Y1212, and Y994 -- in human umbilical vein endothelial cells; however, it did not dephosphorylate the Y1173 residue of Flk-1 38. SIGNOR-276962 0.547 PLCE1 protein Q9P212 UNIPROT PRKCA protein P17252 UNIPROT up-regulates 9606 12645577 f miannu TNF-alpha Binds to tnfr1 and activates pc-plc to induce pkc? And c-src activation SIGNOR-99307 0.428 NFIB protein O00712 UNIPROT NFIC protein P08651 UNIPROT down-regulates activity binding 9606 BTO:0000567 9099724 t 2 miannu Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function. SIGNOR-240880 0.369 GRK6 protein P43250 UNIPROT MC1R protein Q01726 UNIPROT down-regulates activity phosphorylation 9606 15650023 t miannu Overexpression of GRK6 Inhibits Agonist-Induced cAMP Production in HBL Human Melanoma Cells, without Affecting MC1R Gene Expression SIGNOR-252389 0.318 ACACB protein O00763 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI down-regulates quantity chemical modification 9606 20952656 t miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA SIGNOR-267106 0.8 ETS1 protein P14921 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 11175361 f miannu Ets1 and Ets2 seem to play opposing roles in apoptosis. While Ets1 seems to activate pro-apoptotic pathways, Ets2 seems to inhibit apoptosis SIGNOR-259869 0.7 SHC1 protein P29353 UNIPROT INPP5D protein Q92835 UNIPROT up-regulates binding 9606 BTO:0000776 10207047 t gcesareni The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation. SIGNOR-66949 0.683 WNT1 protein P04628 UNIPROT FZD6 protein O60353 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni Distinctly, wnt1 signals through fzd receptors 1 and 6 in the epaxial domain of the somite, to regulate myf5 expression via the canonical bcatenin pathway. SIGNOR-198846 0.679 TAB2 protein Q9NYJ8 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates binding 9606 25290089 t lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205446 0.558 CS protein O75390 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI down-regulates quantity chemical modification 9606 3013232 t miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. SIGNOR-266239 0.8 clofarabine chemical CHEBI:681569 ChEBI RRM2 protein P31350 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000664 1707752 t miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate SIGNOR-258356 0.8 RAB1A protein P62820 UNIPROT USO1 protein O60763 UNIPROT up-regulates activity binding -1 10903204 t Giulio Here, the tethering factor p115 was shown to be a Rab1 effector that binds directly to activated Rab1. SIGNOR-261287 0.79 STUB1 protein Q9UNE7 UNIPROT CFTR protein P13569 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11146634 t miannu Here we show that CHIP functions with Hsc70 to sense the folded state of CFTR and targets aberrant forms for proteasomal degradation by promoting their ubiquitination.  SIGNOR-272584 0.483 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Ser170 ESLDWDSsLVKTFKL 9606 19468302 t llicata Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex. SIGNOR-185750 0.657 SREBF2 protein Q12772 UNIPROT HMGCR protein P04035 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000759 31848472 t miannu The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription SIGNOR-265161 0.506 PK proteinfamily SIGNOR-PF80 SIGNOR phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI down-regulates quantity chemical modification 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266539 0.8 SMARCD2 protein Q92925 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270733 0.74 SIRT1 protein Q96EB6 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization deacetylation 9606 25280219 t SIRT1 overexpression was associated with down-modulation of p53 activity in FLT3-ITD AML CD34+ cells. SIRT1 can negatively regulate p53 by deacetylating several lysine sites SIGNOR-261562 0.796 TFEB protein P19484 UNIPROT SGSH protein P51688 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276546 0.319 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 t miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. SIGNOR-264920 0.8 ITGB1BP1 protein O14713 UNIPROT Av/b2 integrin complex SIGNOR-C176 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257653 0.285 MAPK1 protein P28482 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr451 KRTRSKGtLRYMSPE 9606 9528799 t gcesareni Our results provide strong evidence that dsrna binding is required for dimerization of full-length pkr molecules in vivo, leading to autophosphorylation in the activation loop and stimulation of the eif2alpha kinase function of pkr. SIGNOR-56337 0.2 LCK protein P06239 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 BTO:0000782 16938345 t gcesareni Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation. SIGNOR-149186 0.748 SRPK1 protein Q96SB4 UNIPROT SRPK1 protein Q96SB4 UNIPROT up-regulates phosphorylation Ser309 RPNKQEEsESPVERP 9606 22727668 t llicata We found that activated akt binds and induces srpk1 autophosphorylation because akt-mediated phosphorylation depends on the kinase activity of srpk1 SIGNOR-197985 0.2 PLK1 protein P53350 UNIPROT MRE11 protein P49959 UNIPROT down-regulates activity phosphorylation Ser649 EVIEVDEsDVEEDIF 9606 BTO:0001938 28512243 t miannu Plk1 phosphorylates Mre11 at S649.Mre11 phosphorylation at S649/S688 inhibits its binding to dsDNA and antagonizes the ATM signaling. SIGNOR-265943 0.2 CSNK1A1L protein Q8N752 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 19293931 t gcesareni Ck1 also phosphorylates lrp6 at the second ser residue in the pppspxs motif ck1_ in the lrp5/e-cadherin/p120-catenin complex temporally coincides with p120-catenin phosphorylation in ser268. moreover, and considering the close similarity between the catalytic domains of ck1_ and ck1_, it is possible that ck1_ is indeed responsible for the phosphorylation at ser1420 and ser1430 in lrp5/6 that negatively affects wnt signaling by still not defined mechanisms SIGNOR-184699 0.257 BIRC3 protein Q13489 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 18621737 t amattioni In this report, we show that ciap1 and ciap2 promote cancer cell survival by functioning as e3 ubiquitin ligases that maintain constitutive ubiquitination of the rip1 adaptor protein. SIGNOR-179443 0.737 ARF5 protein P84085 UNIPROT Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 14973189 f lperfetto ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface SIGNOR-272152 0.7 FADS6 protein Q8N9I5 UNIPROT arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity chemical modification 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267914 0.8 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 8974401 t lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-236116 0.734 PRKACA protein P17612 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 16885213 t gcesareni In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed in vertebrates, pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation SIGNOR-148478 0.445 MKRN1 protein Q9UHC7 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys292 EEENLRKkGEPHHEL 9606 BTO:0002552 19536131 t miannu Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. K291 and K292 of p53 are required for MKRN1-mediated degradation and ubiquitination of p53 SIGNOR-271847 0.442 p38 proteinfamily SIGNOR-PF16 SIGNOR CDC25B protein P30305 UNIPROT down-regulates activity phosphorylation Ser323 QRLFRSPsMPCSVIR 9606 11333986 t lperfetto P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteins phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 SIGNOR-107412 0.2 ATM protein Q13315 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Ser1197 HIQTPMLsQEQAQPP 9606 15173573 t lperfetto Tonebp/orebp contains atm consensus phosphorylation sites at ser-1197, ser-1247, and ser-1367. In conclusion, signaling via atm is necessary for full activation of tonebp/orebp SIGNOR-125073 0.274 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser293 TYRYHGHsMSDPGVS -1 7782287 t gcesareni Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase. SIGNOR-33137 0.666 CDK1 protein P06493 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Ser537 GTFSPGAsPGSEART 9606 BTO:0000567 31981797 t miannu CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines. SIGNOR-276833 0.412 acadesine chemical CHEBI:28498 ChEBI PRKAG1 protein P54619 UNIPROT up-regulates chemical activation 9606 SIGNOR-C15 16879084 t gcesareni The activation of the ampk pathway by exendin-4 was induced by aicar, which was inhibited by compound c. SIGNOR-148337 0.8 MAPK14 protein Q16539 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates activity phosphorylation 9606 21902831 t lperfetto Through phosphorylation of mef2d, p38 recruits an ash2l-containing complex to myogenic loci during differentiation, which results in the marking of these genes for expression. SIGNOR-176554 0.596 NTF4 protein P34130 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates binding 9606 11114882 t gcesareni Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb. SIGNOR-85117 0.692 DLX5 protein P56178 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates -1 19195802 f Luana DLX5 and adjacent DLX6 are homeobox genes working in neurogenesis. SIGNOR-265797 0.7 PPP5C protein P53041 UNIPROT CDC37 protein Q16543 UNIPROT down-regulates activity dephosphorylation Ser13 VWDHIEVsDDEDETH 9606 18922470 t Activation of protein kinase clients by the Hsp90 system is mediated by the cochaperone protein Cdc37. Cdc37 requires phosphorylation at Ser13|PP5/Ppt1 regulates phosphorylation of Ser13-Cdc37 in vivo, directly affecting activation of protein kinase clients by Hsp90-Cdc37. SIGNOR-248539 0.658 ZAP70 protein P43403 UNIPROT DUSP3 protein P51452 UNIPROT up-regulates phosphorylation Tyr138 SPTLVIAyLMMRQKM 9606 12447358 t gcesareni We report here that vhr, a vaccinia virus vh1-related dual-specific protein phosphatase that inactivates the mitogen-activated kinases erk2 and jnk, is phosphorylated at y138 by zap-70. Tyr138 phosphorylation was required for vhr to inhibit the erk2-elk-1 pathway SIGNOR-95877 0.546 PRKACA protein P17612 UNIPROT TBXA2R protein P21731 UNIPROT unknown phosphorylation Ser331 STRPRSLsLQPQLTQ 9606 12147288 t llicata Ser-331 was found to be involved in pka-mediated phosphorylation. SIGNOR-90976 0.471 FADS3 protein Q9Y5Q0 UNIPROT arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity chemical modification 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267913 0.8 BAD protein Q92934 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity relocalization 9606 BTO:0000007 15694340 t lperfetto Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. SIGNOR-133756 0.793 CDK1 protein P06493 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Thr537 LGQNKAHtPFRESKL 9606 20368358 t llicata We show here that cyclin-dependent kinase 1 (cdk1) phosphorylates t537 in the core domain of mcak and attenuates its microtubule-destabilizing activity in vitro and in vivo. Phosphorylation of mcak by cdk1 promotes the release of mcak from centrosomes and is required for proper spindle formation. SIGNOR-164761 0.672 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser370 TSVTPDVsDNEPDHY 9606 21779440 t gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity SIGNOR-89818 0.667 AKT proteinfamily SIGNOR-PF24 SIGNOR TTC3 protein P53804 UNIPROT up-regulates phosphorylation Ser378 AYTPRSLsAPIFTTS 9606 20059950 t llicata Phosphorylation of ttc3 at ser378 is required for efficient biological function together, these observations support that ttc3 is a phosphorylation target of akt both in an in vitro and in a cellular context SIGNOR-162984 0.2 UBQLN2 protein Q9UHD9 UNIPROT HNRNPU protein Q00839 UNIPROT up-regulates quantity by stabilization binding 25616961 t lperfetto Confirmation of binding of recombinant full-length hnRNPA1 and hnRNPU proteins with ubiquilin-2 by GST-pull-down assays|Additionally, our evidence that ubiquilin-2 is in- volved in stabilizing hnRNPA1 protein SIGNOR-262271 0.339 AKT2 protein P31751 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 15004527 t gcesareni Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity SIGNOR-123243 0.508 HOXA10 protein P31260 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000661 21261500 f miannu Overexpression of HOXA9 or HOXA10 in JURKAT cells by lentiviral transduction resulted in decreased expression of MEF2C, indicating repression by these homeodomain proteins. HOXA9/10 inhibits expression of MEF2C via NMYC SIGNOR-254212 0.287 POMT complex SIGNOR-C372 SIGNOR DGC complex SIGNOR-C217 SIGNOR up-regulates activity glycosylation 9606 BTO:0000007 14699049 t miannu we showed that coexpression of both POMT1 and POMT2 (another gene homologous to yeast protein O-mannosyltransferases) was necessary for the enzyme activity, but expression of either POMT1 or POMT2 alone was insufficient. The requirement of an active enzyme complex of POMT1 and POMT2 suggests that the regulation of protein O-mannosylation is complex. Further, protein O-mannosylation appears to be required for normal structure and function of α-dystroglycan in muscle and brain. SIGNOR-265431 0.412 sertindole chemical CHEBI:9122 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258549 0.8 perfluorohexanesulfonic acid chemical CHEBI:132448 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 23764977 t miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  SIGNOR-268766 0.8 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 11278991 t lperfetto We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication. SIGNOR-216674 0.414 JAK3 protein P52333 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Tyr415 ALGINSGySKRALML 9606 20176813 t miannu We identified three kinases capable of phosphorylating pld2 in vitro-epidermal growth factor receptor (egfr), jak3, and src (with jak3 reported for the first time in this study)-that phosphorylate an inhibitory, an activator, and an ambivalent (one that can yield either effect) site, respectively. Mass spectrometry analyses indicated the target of each of these kinases as y(296) for egfr, y(415) for jak3, and y(511) for src. SIGNOR-163858 0.416 ACE2 protein Q9BYF1 UNIPROT Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT up-regulates activity cleavage His42 RVYIHPFhLVIHNES -1 11815627 t miannu The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus. SIGNOR-260221 0.2 RXRA protein P19793 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 10976919 t inferred from family member gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr). SIGNOR-270292 0.715 bisindolylmaleimide i chemical CID:2396 PUBCHEM PRKCA protein P17252 UNIPROT down-regulates chemical inhibition 9606 Other t CellSignaling gcesareni SIGNOR-190344 0.8 ME2 protein P23368 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity chemical modification 9606 24769394 t miannu The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle SIGNOR-267054 0.8 APC-c complex SIGNOR-C150 SIGNOR KIF18A protein Q8NI77 UNIPROT down-regulates quantity by destabilization ubiquitination -1 24510915 t miannu Biochemical studies on the kinesins confirmed KIFC1, KIF18A, KIF2C, and KIF4A as APC/C substrates. Furthermore, we showed that the APC/CCDH1-dependent degradation of KIFC1 regulates the bipolar spindle formation and proper cell division. Our in vitro degradation assays showed a time-dependent degradation for four of the five potential substrates tested: KIF18A, KIF2C, KIFC1 and KIF4A were readily degraded in vitro, however remained stable in the presence of either APC/C inhibitor (Fig​(Fig4A4A and Supplementary Fig S3A). SIGNOR-266110 0.3 PRKCA protein P17252 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser368 QRPSSRAsSRASSRP 10116 10871288 t lperfetto Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication. SIGNOR-249048 0.55 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t gcesareni Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation. SIGNOR-124949 0.804 BCL2L1 protein Q07817 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity binding 9606 9539746 t lperfetto Bcl2l1 associates with casp9 and apaf-1 in mammalian cells.Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation SIGNOR-56402 0.703 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161565 0.325 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1387 EDCSGLSsQSDILTT 9606 BTO:0000773 11278964 t lperfetto Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion. SIGNOR-106432 0.793 RAB1A protein P62820 UNIPROT ULK1 protein O75385 UNIPROT up-regulates activity relocalization 9606 27334615 t Sara C9orf72 acts as an effector of Rab1a that recruits active Rab1a to theULK1 complex to promote translocation of the ULK1 complex to thephagophore during autophagy initiation SIGNOR-261299 0.547 NOTCH proteinfamily SIGNOR-PF30 SIGNOR HEYL protein Q9NQ87 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 11044625 f gcesareni The intracellular part of the notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor rbp-j. SIGNOR-254339 0.2 SRC protein P12931 UNIPROT PKP3 protein Q9Y446 UNIPROT up-regulates activity phosphorylation Tyr195 PGGLDDRySLVSEQL 9606 BTO:0000552 25501895 t done miannu We have discovered that reactive oxygen species (ROS) trigger the c-Src kinase-mediated tyrosine (Tyr)-195 phosphorylation of PKP3. This modification is associated with a change in the subcellular distribution of the protein. Specifically, PKP3 bearing phospho-Tyr-195 is released from the desmosomes, suggesting that phospho-Tyr-195 is relevant for the control of desmosome disassembly and function, at least in cells exposed to ROS.  SIGNOR-273807 0.311 CDK1 protein P06493 UNIPROT CGAS protein Q8N884 UNIPROT down-regulates activity phosphorylation Ser305 MKRKRGGsPAVTLLI 32351706 t lperfetto The major mitotic kinase CDK1-cyclin B complex phosphorylates human cGAS at S305 or mouse cGAS at S291, which inhibits its ability to synthesize cGAMP upon mitotic entry. SIGNOR-276526 0.2 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Thr713 SKRNSVDtATSSSLS -1 2117608 t llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. SIGNOR-250884 0.335 IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Ser659 WPNVPDPsKSHIAQW -1 8511589 t lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238621 0.2 MYO5A protein Q9Y4I1 UNIPROT ACTB protein P60709 UNIPROT up-regulates activity binding 9606 21077886 t miannu Myosin Va regulates exocytosis of large dense-core vesicles (LDCVs). interestingly, inhibition of myosin Va potentiates LDCV exocytosis to the same extent as F-actin depolymerization does, suggesting that myosin Va cooperates with the actin cytoskeleton to impede or control LDCV exocytosis SIGNOR-269280 0.419 PRKACA protein P17612 UNIPROT LCK protein P06239 UNIPROT unknown phosphorylation Ser42 TLLIRNGsEVRDPLV -1 8506364 t miannu Ser-42 can be phosphorylated by either protein kinase A or protein kinase C SIGNOR-249999 0.334 (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one chemical CHEBI:125500 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258774 0.8 LPAR3 protein Q9UBY5 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257357 0.478 CSNK2A1 protein P68400 UNIPROT HNRNPC protein P07910 UNIPROT down-regulates activity phosphorylation Ser260 SEGGADDsAEEGDLL 9606 15687492 t gcesareni In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C. SIGNOR-133540 0.364 MECP2 protein P51608 UNIPROT GPRIN1 protein Q7Z2K8 UNIPROT up-regulates quantity by expression post transcriptional regulation 10090 18511691 t Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. SIGNOR-264679 0.303 SMO protein Q99835 UNIPROT KIF7 protein Q2M1P5 UNIPROT up-regulates activity relocalization 10090 19666503 t lperfetto Here, we demonstrate that Kif7, a mammalian homologue of Drosophila Costal2 (Cos2), is a cilia-associated protein that regulates signaling from the membrane protein Smoothened (Smo) to Gli transcription factorsIn response to activation of Smo Kif7 at the cilia tip may antagonize Sufu to promote activation of Gli proteins. SIGNOR-209605 0.617 ARID5B protein Q14865 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29326336 f miannu We also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F). SIGNOR-256159 0.2 CDK7 protein P50613 UNIPROT RARG protein P13631 UNIPROT up-regulates activity phosphorylation Ser77 SEEMVPSsPSPPPPP 9534 10748061 t Luana RARg Is Phosphorylated by cdk7 in Its B and F Regions | Mutation into alanine of Ser-77 and Ser-79 located in the A/B region reduced the transcriptional activity of hRARg1 (Fig. 9A), confirming that these phosphorylation sites are required for optimal transcription. SIGNOR-259853 0.393 NLGN4X protein Q8N0W4 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264165 0.759 STK11 protein Q15831 UNIPROT PRMT5 protein O14744 UNIPROT up-regulates activity phosphorylation Thr139 TNLARVLtNHIHTGH -1 30289978 t miannu We found that PRMT5 is a bona fade substrate for LKB1. We identified T132, 139 and 144 residues, located in the TIM-Barrel domain of PRMT5, as target sites for LKB1 phosphorylation. The point mutation of PRMT5 T139/144 to A139/144 drastically decreased its methyltransferase activity, due probably to the loss of its interaction with regulatory proteins such as MEP50, pICln and RiOK1.  SIGNOR-277411 0.2 CSNK2A1 protein P68400 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-250830 0.29 KDM1A protein O60341 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 BTO:0000567 15620353 t miannu Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription. SIGNOR-264507 0.2 CTNNB1 protein P35222 UNIPROT SCRIB protein Q14160 UNIPROT up-regulates activity binding 9606 BTO:0000938 21255999 t miannu Cadherins mediate the localization of vesicles to presynaptic compartments through multiple mechanisms. Cadherin-bound β-catenin then recruits scribble (Scrib) which acts as a scaffold for the further recruitment of proteins that mediate the localization of SVs. SIGNOR-265826 0.431 IKK-complex complex SIGNOR-C14 SIGNOR IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser43 PAMLHLPsEQGAPET 9606 SIGNOR-C14 17977820 t lperfetto In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I SIGNOR-216403 0.929 MYC protein P01106 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 11804592 t gcesareni Through its direct interaction with smads, c-myc binds to the sp1-smad complex on the promoter of the p15(ink4b) gene, thereby inhibiting the tgf-beta-induced transcriptional activity of sp1 and smad/sp1-dependent transcription of the p15(ink4b) gene. These results suggest that oncogenic c-myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of smads. SIGNOR-114284 0.672 CHD8 protein Q9HCK8 UNIPROT SOX11 protein P35716 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 t Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells SIGNOR-268923 0.2 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1710 HVTSKCGsLKNIRHR 9606 BTO:0000567 11029056 t miannu CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA SIGNOR-250002 0.367 AMP smallmolecule CHEBI:456215 ChEBI MLXIPL protein Q9NP71 UNIPROT down-regulates activity chemical inhibition 10116 26984404 t We discovered that protein-free extracts of high fat-fed livers contained, in addition to ketone bodies, a new metabolite, identified as AMP, which specifically activates the interaction between ChREBP and 14-3-3. SIGNOR-255668 0.8 PAPOLB protein Q9NRJ5 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization chemical modification 9606 19224921 t lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. SIGNOR-268328 0.8 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1222 PAFDNLYyWDQDPPE -1 1706616 t  Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. SIGNOR-251130 0.2 tiotropium chemical CHEBI:90960 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition -1 8441333 t miannu A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed "kinetic receptor subtype selectivity" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors. SIGNOR-258485 0.8 CHUK protein O15111 UNIPROT COPS5 protein Q92905 UNIPROT down-regulates activity phosphorylation Thr205 EGPSEYQtIPLNKIE -1 31950832 t lperfetto Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. SIGNOR-275508 0.33 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT up-regulates activity phosphorylation Tyr210 SMAIHEVyQELIQDV -1 12923183 t In vitro kinase assays indeed demonstrated that Lck can phosphorylate wild-type IBP but not the Y210F mutant. IBP Binds PI(3,4,5)P3 upon Phosphorylation by Lck SIGNOR-251372 0.514 UBR5 protein O95071 UNIPROT RNF168 protein Q8IYW5 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0001938 22884692 t miannu Here, we show that TRIP12 and UBR5, two HECT domain ubiquitin E3 ligases, control accumulation of RNF168, a rate-limiting component of a pathway that ubiquitylates histones after DNA breakage. We find that RNF168 can be saturated by increasing amounts of DSBs. Depletion of TRIP12 and UBR5 allows accumulation of RNF168 to supraphysiological levels, followed by massive spreading of ubiquitin conjugates and hyperaccumulation of ubiquitin-regulated genome caretakers such as 53BP1 and BRCA1. SIGNOR-266782 0.453 CSNK2A1 protein P68400 UNIPROT SPTBN1 protein Q01082 UNIPROT down-regulates phosphorylation Thr2159 NGATEQRtSSKESSP 9606 BTO:0000938 17088250 t miannu We show here that the short c-terminal splice variant of betaii-spectrin (betaiisigma2) is a substrate for phosphorylation. In vitro, protein kinase ck2 phosphorylates ser-2110 and thr-2159 / phosphorylation of ?II?2 C-terminal fragment inhibits its interaction with ?II N-terminal fragment. SIGNOR-150471 0.34 LPAR2 protein Q9HBW0 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257169 0.446 ATM protein Q13315 UNIPROT RRM2B protein Q7LG56 UNIPROT up-regulates phosphorylation Ser72 TAEEVDLsKDLPHWN 9606 19015526 t lperfetto Atm-mediated serine 72 phosphorylation stabilizes ribonucleotide reductase small subunit p53r2 protein against mdm2 to dna damage SIGNOR-182423 0.526 DDX3X protein O00571 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity binding 9606 33627125 t miannu DDX3X enhances transcription by interacting with transcription factors to promote their binding to the promoter of the target gene. The best characterized mechanism is its cooperation with the transcription factor SP1. The downstream genes of DDX3X-SP1-mediated transactivation include P21, KRAS, and MDM2 SIGNOR-269202 0.36 PRKD1 protein Q15139 UNIPROT DLC1 protein Q96QB1 UNIPROT down-regulates phosphorylation Ser1244 NTLKRENsSPRVMQR 9606 21087603 t gcesareni The tumor suppressor protein dlc1 is regulated by pkd-mediated gap domain phosphorylation.Our results thus show that pkd-mediated phosphorylation of dlc1 on serine 807 negatively regulates dlc1 cellular function. SIGNOR-169994 0.379 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1948 SPTSPGYsPTSPTYS 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176841 0.775 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252751 0.753 PIK3R4 protein Q99570 UNIPROT Vps34 Complex II complex SIGNOR-C241 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260321 0.881 GNGT1 protein P63211 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 23074268 t gcesareni Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance. SIGNOR-199144 0.383 PLK1 protein P53350 UNIPROT NUDC protein Q9Y266 UNIPROT up-regulates activity phosphorylation Ser274 KKINPENsKLSDLDS 9606 BTO:0000567 12852857 t lperfetto Here, we characterize the interaction between plk1 and nudc, show that plk1 phosphorylates nudc at conserved s274 and s326 residues in vitro, and present evidence that nudc is also a substrate for plk1 in vivo. Downregulation of nudc by rna interference results in multiple mitotic defects, including multinucleation and cells arrested at the midbody stage, which are rescued by ectopic expression of wild-type nudc, but not by nudc with mutations in the plk1 phosphorylation sites. SIGNOR-103403 0.719 MID1IP1 protein Q9NPA3 UNIPROT ACACB protein O00763 UNIPROT up-regulates activity binding 10029 20952656 t miannu Recently, we reported the discovery that MIG12, a 183 amino acid protein, binds to ACC1 and ACC2, which induces polymerization and subsequently increases the enzymatic activity of the protein SIGNOR-267112 0.283 SLC9A7 protein Q96T83 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265597 0.8 ARHGAP12 protein Q8IWW6 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260469 0.526 GSK3B protein P49841 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 10116 11018017 t Phosphorylation of Thr 58, likely mediated by GSK-3 but dependent on the prior phosphorylation of Ser 62, is associated with degradation of Myc. SIGNOR-252080 0.709 SMARCB1 protein Q12824 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270710 0.85 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192892 0.8 F2 protein P00734 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 t lperfetto Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1. SIGNOR-261859 0.562 POLR2H protein P52434 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266149 0.908 bepotastine chemical CHEBI:71204 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 t Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells SIGNOR-257781 0.8 Ac-Asp-Glu(3-) smallmolecule CHEBI:76931 ChEBI N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI up-regulates quantity precursor of 9606 10085079 t miannu The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. SIGNOR-268124 0.8 DRAM2 protein Q6UX65 UNIPROT RHOC protein P08134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30755245 f irozzo Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. SIGNOR-259143 0.2 CYP19A1 protein P11511 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification 9606 395188 t lperfetto Studies show that aromatization (a reaction sequence unique in steroid biosynthesis) of androgens to estrogens is not limited to the female reproductive organs but also occurs in extragonadal tissue. Aromatization involves the loss of the angular C-19 methyl group and cis elimination of the 1beta and 2beta hydrogens from the androgen precursors, androstenedione and testosterone, to yield estrone and estradiol, respectively. In men, the production of estrone is 18 ug/day and is mainly extraglandular. Aromatase activity has also been shown in a variety of tissues in mammalian and other species. SIGNOR-251528 0.8 TLN1 protein Q9Y490 UNIPROT ITGB3 protein P05106 UNIPROT up-regulates activity binding 10090 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257625 0.784 DRD5 protein P21918 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257311 0.413 TP53 protein P04637 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts SIGNOR-255669 0.7 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 t lperfetto Autophosphorylation of jak2 on tyrosines 221 and 570 regulates its activity with phosphorylation of tyrosine 221 increasing kinase activity SIGNOR-236506 0.2 PTPN21 protein Q16825 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 15143158 t Dephosphorylation of Y527 was more pronounced in cells expressing PTPD1 at each time point tested. PTPD1C1108S drastically inhibited Y527 dephosphorylation|Activation of src requires dephosphorylation of src residue Y527. This promotes displacement of the SH2 domain from this residue and subsequent autophosphorylation of residue Y416 within the activation loop SIGNOR-248725 0.628 GSK3B protein P49841 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates phosphorylation Ser556 AQKSEGKsLPSSPSS 9606 16174773 t lperfetto Synphilin-1 s556a mutant, which is less phosphorylated by gsk3beta, formed more inclusion bodies than wild type synphilin-1. Mutation analysis showed that ser556 is a major gsk3beta phosphorylation site in synphilin-1 SIGNOR-140609 0.5 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257907 0.8 DRD1 protein P21728 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257068 0.288 LYN protein P07948 UNIPROT LPXN protein O60711 UNIPROT up-regulates activity phosphorylation Tyr72 NIQELNVySEAQEPK 9606 BTO:0000007 17640867 t miannu Of a total of 11 tyrosine sites in LPXN, we mutated Tyr(22), Tyr(72), Tyr(198), and Tyr(257) to phenylalanine and demonstrated that LPXN was phosphorylated by Lyn only at Tyr(72) and that this tyrosine site is proximal to the LD3 domain. We further show that LPXN suppressed the secretion of interleukin-2 by BCR-activated A20 B cells and that this inhibition was abrogated in the Y72F LPXN mutant, indicating that the phosphorylation of Tyr(72) is critical for the biological function of LPXN. SIGNOR-262892 0.384 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates 9606 BTO:0000671 9335553 f gcesareni These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling. SIGNOR-52707 0.632 PPME1 protein Q9Y570 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates activity demethylation Leu309 RRTPDYFl -1 18394995 t lperfetto Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans. SIGNOR-265748 0.902 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr340 RGQRDSSyYWEIEAS 9606 7692235 t gcesareni We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain. SIGNOR-32081 0.588 RUNX3 protein Q13761 UNIPROT CAPN10 protein Q9HC96 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255091 0.2 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269384 0.719 AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR RABGEF1 protein Q9UJ41 UNIPROT up-regulates activity relocalization 10090 27411398 t lperfetto AP-1/sigma1A-ArfGAP1-Rabex-5 complex formation leads to more endosomal Rabex-5 and enhanced, Rab5GTP-stimulated Vps34 PI3-kinase activity, which is essential for multivesicular body endosome formation. SIGNOR-260706 0.328 FCN2 protein Q15485 UNIPROT MASP2 protein O00187 UNIPROT up-regulates activity binding 17204478 t lperfetto In the lectin pathway, mannose-binding lectin (MBL) and ficolins bind to pathogens and activate MBL-associated serine protease-2 (MASP-2) SIGNOR-263413 0.627 Neuromedin B smallmolecule CHEBI:80139 ChEBI NMBR protein P28336 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257547 0.8 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation 9606 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation SIGNOR-216396 0.885 SLC9A3 protein P48764 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265593 0.8 PRKCA protein P17252 UNIPROT GRIN2A protein Q12879 UNIPROT unknown phosphorylation Ser1416 ASYCSRDsRGHNDVY 10116 11104776 t lperfetto PKC-dependent phosphorylation of NR2A(Ser(1416)) as a key mechanism in inhibiting alphaCaMKII-binding and promoting dissociation of alphaCaMKII.NR2A complex. SIGNOR-249065 0.519 ADAM12 protein O43184 UNIPROT SDC4 protein P31431 UNIPROT up-regulates binding 9606 BTO:0000975 12509413 t gcesareni The adam12 cysteine-rich domain (radam12-cys) supports cell attachment using syndecan-4 as a primary cell surface receptor that subsequently triggers beta(1) integrin-dependent cell spreading, stress fiber assembly, and focal adhesion formation. SIGNOR-96931 0.443 LGALS3 protein P17931 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000664 21821001 f miannu The aim of this study was to investigate the role of inducible galectin-3 in leukemic cells escape of apoptotic stimuli. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. SIGNOR-261904 0.7 RPS6KA1 protein Q15418 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser721 TPRLRSVsSYGNIRA 9606 SIGNOR-C3 18722121 t llicata Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity SIGNOR-180462 0.562 MTMR3 protein Q13615 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity 9606 BTO:0000007 SIGNOR-C3 26787466 t lperfetto The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity. SIGNOR-245105 0.361 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2D1 protein P51668 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271345 0.712 RELA protein Q04206 UNIPROT REL/RELA complex SIGNOR-C68 SIGNOR form complex binding 9606 BTO:0000671 9056676 t miannu Tnf-alpha induces the formation of a specific kappab binding complex, mainly composed of nf-kappab subunits rela and c-rel. SIGNOR-46948 0.662 FGF2 protein P09038 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15780951 f gcesareni Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/ fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts SIGNOR-134791 0.458 ARHGAP21 protein Q5T5U3 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260475 0.613 CDK2 protein P24941 UNIPROT MCM3 protein P25205 UNIPROT up-regulates phosphorylation Thr722 EEMPQVHtPKTADSQ 9606 SIGNOR-C16 21965652 t gcesareni In this study, we demonstrate that mcm3 is a substrate of cyclin e/cdk2 and can be phosphorylated by cyclin e/cdk2 at thr-722. SIGNOR-176656 0.788 STK3 protein Q13188 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Thr1079 EHAFYEFtFRRFFDD 9606 BTO:0000007 15688006 t Two of these, S909 and T1079, were required for Lats1 activation. milica Since the N-terminal half of Lats1 (residues 1–588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1. SIGNOR-132927 0.604 CRK protein P46108 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 BTO:0000007 11314030 t llicata Tyrosine phosphorylation FAK was strictly dependent upon c-Crk II expression | Crk-inducible FAK tyrosine phosphorylation was completely abrogated by co-expression with R38K Crk (lane 2), and decreased by co-expression with W170K Crk (lane 3), indicating that the SH2 domain of c-Crk is absolutely essential for this effect. In contrast, mutants in the C-terminus of Crk that include Y222F c-Crk, which abrogates the c-Abl phosphorylation site, and W276K Crk, which mutates the C-terminal SH3 domain, modestly increased FAK activation compared to wild-type c-Crk II. SIGNOR-250777 0.722 EPHA4 protein P54764 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates activity phosphorylation Tyr602 TYVDPFTyEDPNQAV -1 8622893 t Two dimensional phosphopeptide mapping and site-directed mutagenesis defined juxtamembrane residue Y602 as a major site of in vitro autophosphorylation in Sek, whilst Y596 was phosphorylated to a lower stoichiometry. Complimentary approaches of in vitro binding assays and BIAcore analysis revealed a high affinity association between the Y602 Sek autophosphorylation site and the cytoplasmic tyrosine kinase p59fyn, an interaction mediated through the SH2 domain of this intracellular signalling molecule. SIGNOR-251119 0.2 LMAN2 protein Q12907 UNIPROT SERPINA1 protein P01009 UNIPROT up-regulates quantity by stabilization binding 9606 20477988 t miannu Identification of α1‐antitrypsin as interaction partner of VIP36. The complex formed by VIP36 and alpha1-AT in the Golgi recycled back to the ER. The combined data are most consistent with a function of VIP36 in post-ER quality control of alpha1-AT. We propose that VIP36 acts in post‐ER quality control in the Golgi by binding incompletely folded α1‐AT, which inadvertently escaped ER quality control, and by recycling it back to the ER for an additional round of quality control. SIGNOR-261356 0.41 MRPS35 protein P82673 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261442 0.666 GATA3 protein P23771 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 16386358 t Experimental data indeed supports the existence of a positive circuit involvingGATA-3 that excludes IL-4 and STAT-6, specifically in mouse cells SIGNOR-254297 0.2 GNAI2 protein P04899 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR down-regulates binding 9606 8327893 t gcesareni Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required SIGNOR-267849 0.619 STK38 protein Q15208 UNIPROT YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation Ser109 KSHSRQAsTDAGTAG 9606 25601544 t Luana We performed mass spectrometry to determine additional sites on YAP1 targeted by NDR, identifying three additional serines, namely S61, S109, and S164, to also be phosphorylated by NDR in vitro  SIGNOR-259856 0.392 CEBPA protein P49715 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12032779 f miannu Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. SIGNOR-253830 0.503 PAK4 protein O96013 UNIPROT RAN protein P62826 UNIPROT unknown phosphorylation Ser135 DRKVKAKsIVFHRKK 9606 20805321 t llicata We show that ran is a substrate for p21-activated kinase 4 (pak4) and that its phosphorylation on serine-135 increases during mitosis. our study suggests that pak4-mediated phosphorylation of gdp- or gtp-bound ran regulates the assembly of ran-dependent complexes on the mitotic spindle SIGNOR-167671 0.312 testosterone smallmolecule CHEBI:17347 ChEBI AR protein P10275 UNIPROT up-regulates activity chemical activation 9606 15861399 t miannu Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions. SIGNOR-251553 0.8 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr287 RDPLLEVyDVPPSVE 10090 12972425 t lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs SIGNOR-246405 0.796 PAX7 protein P23759 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 29681515 f apalma Carm1 specifically methylates Pax7 at multiple arginine residues in the N terminus of Pax7, facilitating the recruitment of the ASH2L:MLL1/2:WDR5:RBBP5 histone H3 lysine 4 (H3K4) methyltransferase complex to the proximal promoter of Myf5 resulting in permissive H3K4 tri-methylation (H3K4me3) of the surrounding chromatin SIGNOR-255899 0.506 ATM protein Q13315 UNIPROT NKX3-1 protein Q99801 UNIPROT down-regulates quantity by destabilization phosphorylation Thr166 KNLKLTEtQVKIWFQ 9606 BTO:0002181 23890999 t miannu ATM phosphorylates NKX3.1 on T166 and then T134, resulting in NKX3.1 ubiquitination and degradation resulting from an apparent regulatory interaction. SIGNOR-276500 0.37 IHH protein Q14623 UNIPROT BMP2 protein P12643 UNIPROT up-regulates 9606 14973297 f gcesareni Ihh is found to be required for bmp-induced os-teogenesis of a limb-bud cell line in culture. Ihh sig-naling is directly required for the osteoblast lineage in developing long bones. Ihh functions in conjunction with other factors such as bmps to induce osteoblast differentiation. In vivo, ihh acts on potential progeni-tor cells to promote osteoblast differentiation and prevent chondrocyte differentiation. SIGNOR-122200 0.531 Laminin-5 complex SIGNOR-C184 SIGNOR A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates activity binding 8832392 t lperfetto The initial adhesion of PA-JEB and normal keratinocytes to laminin-1 and laminin-5, both ligands for alpha 6 beta 1 and alpha 6 beta 4, was similar. SIGNOR-253253 0.581 PP1 proteinfamily SIGNOR-PF54 SIGNOR CCND3 protein P30281 UNIPROT up-regulates dephosphorylation Thr283 QGPSQTStPTDVTAI 9606 16331257 t lperfetto These results support the hypothesis that pp1 constitutively keeps cyclin d3 in a stable, dephosphorylated state SIGNOR-264662 0.2 ATM protein Q13315 UNIPROT USP28 protein Q96RU2 UNIPROT down-regulates activity phosphorylation Ser714 ESSTNSSsQDYSTSQ 31938050 t lperfetto Once all the three conservative SQ sites (S67, S495, and S714), in USP28, were mutated to alanine, the pS/TQ antibody completely could not recognize the immunoprecipitated Flag-USP28-3S/A (Figure ​Figure55D), suggesting that in response to 5'-AZA-induced stress, ATM phosphorylates USP28 at all these three sites.|We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1. We also provided evidence that ATM-mediated phosphorylation of USP28 resulted in its disassociation from KLHL2 and UCK1 destabilization. SIGNOR-275853 0.317 ENPP1 protein P22413 UNIPROT Bone_mineralization phenotype SIGNOR-PH69 SIGNOR up-regulates 9606 19049325 f miannu PC-1 and Tnap work together to produce normally mineralized bone matrix through the generation and hydrolysis of pyrophosphate. SIGNOR-252195 0.7 PIP3 smallmolecule CHEBI:16618 ChEBI PLEKHG1 protein Q9ULL1 UNIPROT up-regulates chemical activation 9606 21041639 t gcesareni Phosphatidylinositol-3,4,5-trisphosphate (pip3), the product of pi3k activity and a key signaling molecule, acts by recruiting pleckstrin-homology (ph) domain-containing proteins to cell membranes SIGNOR-169179 0.8 TGFB1 protein P01137 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8142649 f Regulation miannu Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production. SIGNOR-251797 0.265 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr753 YACASPKtPIQAGGY 9606 19933846 t gcesareni Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity. SIGNOR-161819 0.63 NAA35 protein Q5VZE5 UNIPROT NatC complex SIGNOR-C417 SIGNOR form complex binding 9606 19398576 t miannu We here identify and characterize the human NatC (hNatC) complex, containing the catalytic subunit hMak3 and the auxiliary subunits hMak10 and hMak31. This complex associates with ribosomes, and hMak3 acetylates Met-Leu protein N termini in vitro, suggesting a model in which the human NatC complex functions in cotranslational N-terminal acetylation. SIGNOR-267234 0.752 CHEK1 protein O14757 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates phosphorylation Thr309 LRKGRGEtRICKIYD 9606 15665856 t gcesareni We demonstrate that chk1 interacts with rad51, and that rad51 is phosphorylated on thr 309 in a chk1-dependent manner SIGNOR-133375 0.836 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates activity phosphorylation Ser923 DELRDSDsVCDSGVE 9606 BTO:0000007 SIGNOR-C13 11158290 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-104803 0.848 PAX6 protein P26367 UNIPROT CDX2/PAX6/P300 complex SIGNOR-C33 SIGNOR form complex binding 9606 10506141 t lperfetto In the present study, we investigated the interaction of cdx-2 and pax-6 with p300, a co-activator coupled to the basal transcription machinery. In transient transfection-expression experiments, we found that the transactivating effects of cdx-2 and pax-6 on the glucagon gene were greatly enhanced by the additional expression of p300. SIGNOR-70963 0.476 YWHAB protein P31946 UNIPROT NEFL protein P07196 UNIPROT down-regulates activity binding 9606 23230147 t miannu These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments. SIGNOR-252396 0.257 TFEB protein P19484 UNIPROT HPS4 protein Q9NQG7 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 f lperfetto Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14) SIGNOR-276795 0.296 2'-deoxyguanosine smallmolecule CHEBI:17172 ChEBI 2'-deoxyguanosine 5'-monophosphate(2-) smallmolecule CHEBI:57673 ChEBI up-regulates quantity precursor of 20637175 t lperfetto Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis SIGNOR-275812 0.8 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT up-regulates activity sumoylation Lys160 EAHQWFLkHEARPLA 9534 BTO:0000298 9756909 t lperfetto We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins |We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites. The PML mutant with Lys to Arg substitutions in all three sites is expressed normally, but cannot be sentrinized|Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. SIGNOR-270540 0.771 NF90-NF45 complex SIGNOR-C443 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates quantity by repression 10116 25566957 f miannu In the present study, we investigated the expression profiles of NF45 in the sciatic nerve of adult rats following crush injury.  in the TNF-α-induced Schwann cell proliferation assay, protein level of NF45 and cyclin E was elevated while expression of p21 was down-regulated. Further, when NF45 was knocked down, Schwann cell proliferation was interrupted and the expression of cyclin E was attenuated, while the expression of p21 was up-regulated. To repress the expression of p21 is one of the basic mechanisms for NF45-regulated cell proliferation. SIGNOR-268491 0.25 SMAD4 protein Q13485 UNIPROT SMAD4/JUN complex SIGNOR-C10 SIGNOR form complex binding 9606 9312063 t gcesareni Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter. SIGNOR-50589 0.663 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. SIGNOR-75934 0.366 G3BP2 protein Q9UN86 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 BTO:0000007 23279204 f miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. SIGNOR-260864 0.7 RABGGTB protein P53611 UNIPROT RAB5A protein P20339 UNIPROT up-regulates activity lipidation 9606 BTO:0000007 18532927 t miannu Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional SIGNOR-265573 0.469 NFYA protein P23511 UNIPROT SOX18 protein P35713 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 18496767 f miannu co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells SIGNOR-254818 0.2 RORB protein Q92753 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24737872 t miannu As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression. SIGNOR-268003 0.491 PBK protein Q96KB5 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser380 EPDHYRYsDTTDSDP 9606 BTO:0000567 24012691 t miannu PTEN is phosphorylated by TOPK and is required for mitotic entry. In addition, reduced PTEN phosphorylation levels upon TOPK knockdown correlated with decreased Akt activation (Fig. 4e) suggesting that TOPK mediated phosphorylation may lead to PTEN inactivation. By using various PTEN mutants in a kinase assay we concluded that TOPK phosphorylates PTEN at S380 residue in vitro (Fig. 4c). SIGNOR-271472 0.518 MAP3K7 protein O43318 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 9480845 f lperfetto These results suggest that tak1 induces nf-kappa b activation through a novel nik-independent signaling pathway. SIGNOR-55713 0.581 KLF2 protein Q9Y5W3 UNIPROT RELN protein P78509 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21530336 t Luana KLF2 transactivates the reelin promoter in K562 cells. SIGNOR-266048 0.2 MAPK1 protein P28482 UNIPROT RGS19 protein P49795 UNIPROT up-regulates phosphorylation Ser151 EDYVSILsPKEVSLD 9606 10993892 t gcesareni Phosphorylation of gaip by erk2 were abrogated when serine at position 151 in the rgs domain was substituted by an alanine residue using site-directed mutagenesis. Furthermore, the lysosomal-autophagic pathway was not stimulated in s151a-gaip mutant-expressing cells when compared with wild-type gaip-expressing cells. These results demonstrate that the gtpase-activating protein activity of gaip is stimulated by erk2 phosphorylation. SIGNOR-82083 0.487 APLNR protein P35414 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256824 0.41 RNF146 protein Q9NTX7 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity ubiquitination 9606 BTO:0000007 21799911 t By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins. SIGNOR-259998 0.514 GDP smallmolecule CHEBI:17552 ChEBI PRPS1 protein P60891 UNIPROT down-regulates activity chemical inhibition 29074724 t lperfetto PRPS1 is inhibited by the nucleotide biosynthesis products ADP, AMP, and GDP SIGNOR-265738 0.8 CCL5 protein P13501 UNIPROT CCR3 protein P51677 UNIPROT up-regulates binding 9606 10734056 t In addition to the CCR1 receptor, RANTES activates several members of the CC subfamily of chemokine receptors including CCR3, CCR4, and CCR5 SIGNOR-254370 0.759 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266520 0.8 HRH1 protein P35367 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257376 0.403 FUS protein P35637 UNIPROT CSDE1 protein O75534 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 9606 BTO:0000551 32808651 t lperfetto These findings demonstrated that LINC00205 facilitates malignant phenotypes in LC by recruiting FUS to stabilize CSDE1, suggesting LINC00205 as a potential target for LC therapy.|Subsequent RIP assay con- firmed such prediction, as CSDE1 mRNA was evidently precipitated by anti-FUS (Figure 3A). SIGNOR-262110 0.2 MAP4K1 protein Q92918 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser559 QPPRSRSsIMSITAE -1 19706536 t miannu HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKC consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro. SIGNOR-276258 0.506 PPP2CA protein P67775 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity dephosphorylation Ser317 ENVKYSSsQPEPRTG 9606 17015476 t Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo. SIGNOR-248616 0.475 PTP4A1 protein Q93096 UNIPROT CDK2 protein P24941 UNIPROT up-regulates 9606 14643450 f gcesareni Cells overexpressing either prl-1 or prl-2 exhibited enhanced cyclin-dependent kinase 2 (cdk2) activity and significantly lower p21cip1/waf1 protein levels SIGNOR-119418 0.2 WT1 protein P19544 UNIPROT PODXL protein O00592 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11719225 t Binding of WT1 to conserved elements within the Podocalyxin gene promoter results in potent transcriptional activation, and the specific expression pattern of Podocalyxin in the developing kidney mirrors that of WT1 itself. SIGNOR-252300 0.419 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Ser170 RDSEGFNsPKQCDSS -1 12361598 t miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) SIGNOR-265958 0.53 PDGFRA protein P16234 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 BTO:0000567 20802513 t miannu Focal adhesion kinase (FAK) has a crucial role in integration of signals from integrins and growth factor receptors. In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor Met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate FAK on Tyr194 in the FERM domain (band 4.1 and ezrin/radixin/moesin homology domain). Upon binding to Met or phosphoinositides, FAK may undergo conformational changes, which renders Tyr194 accessible for phosphorylation. Substitution of Tyr194 with Phe significantly suppresses the activation of FAK by Met. SIGNOR-259400 0.408 RPS6KA3 protein P51812 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates activity phosphorylation Ser25 KRRSARLsAKPPAKV 9606 11438671 t lperfetto We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets. SIGNOR-249101 0.371 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269350 0.719 PRKCZ protein Q05513 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser311 RTYETFKsIMKKSPF 9606 SIGNOR-C13 17183360 t gcesareni Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) SIGNOR-151432 0.537 ABL1 protein P00519 UNIPROT RAPH1 protein Q70E73 UNIPROT up-regulates activity phosphorylation Tyr426 LLRASGIyYVPKGKA -1 20417104 t miannu Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C). SIGNOR-262606 0.288 MYT1L protein Q9UL68 UNIPROT SIN3B protein O75182 UNIPROT up-regulates activity binding 10090 BTO:0002572 28379941 t miannu We found that the pan neuron-specific transcription factor Myt1-like (Myt1l) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. SIGNOR-266774 0.462 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT up-regulates activity phosphorylation Ser1255 CLTERAMsWQDRARQ -1 27292631 t miannu We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment. SIGNOR-274059 0.308 IRF2 protein P14316 UNIPROT DST protein Q03001 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15560761 f miannu Transient transfection studies with BPAG1 promoter-luciferase reporter gene plasmids and IRF1 and IRF2 expression plasmids revealed that IRF1 and IRF2 directly down-regulated BPAG1 gene transcription in cultured normal human epidermal keratinocytes. SIGNOR-254493 0.2 PDPK1 protein O15530 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 15802604 t gcesareni We demonstrate that 3-phosphoinositide-dependent kinase 1 (pdk1) has an essential role in this pathway by regulating the activation of pkc and through signal-dependent recruiting of both pkc and card11 to lipid rafts. SIGNOR-134866 0.531 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR H4C1 protein P62805 UNIPROT up-regulates activity ubiquitination -1 12485996 t lperfetto Strikingly, as well as H2AX, the nucleosome core histones H2A, H2B, H3 and H4 were all ubiquitylated efficiently by BRCA1/BARD1, while the linker histone H1 was not (Figure 3).| Generally, histone proteins are required for compaction of nuclear DNA into chromatin, and their modification is thought to loosen this compaction. Therefore, one might envisage that ubiquitylation of γH2AX by BRCA1/BARD1 at DNA breaks modulates local chromatin packaging to facilitate the action of DNA repair enzymes. SIGNOR-263234 0.2 PRKCE protein Q02156 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 21349850 t gcesareni Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth. SIGNOR-172239 0.2 MAOA protein P21397 UNIPROT 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-263999 0.8 PKN1 protein Q16512 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser339 PRGQRDSsYYWEIEA 9606 15849194 t llicata P21-activated kinase 1 (pak1)-dependent phosphorylation of raf-1 regulates its mitochondrial localization, phosphorylation of bad, and bcl-2 association. moreover, the mitochondrial translocation of raf-1 and the interaction between raf-1 and bcl-2 are regulated by raf-1 phosphorylation at ser-338/ser-339. SIGNOR-135679 0.2 fentanyl chemical CHEBI:119915 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258939 0.8 ID2 protein Q02363 UNIPROT TCF4 protein P15884 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C129 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241376 0.614 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 9381178 t Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival. SIGNOR-251470 0.2 SYK protein P43405 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates activity phosphorylation Tyr381 SESSDDDyDDVDIPT 9606 11514608 t lperfetto BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. BCR-mediated activation of HPK1 was impaired in Syk- or BASH-deficient B cells. The functional SH2 domain of BASH and Tyr-379 within HPK1 which we identified as a Syk-phosphorylation site were both necessary for interaction of both proteins and efficient HPK1 activation after BCR stimulation. SIGNOR-246567 0.354 FYN protein P06241 UNIPROT MED28 protein Q9H204 UNIPROT up-regulates phosphorylation Tyr64 ASLVSQDyVNGTDQE 9606 BTO:0001271;BTO:0000661 16899217 t fstefani To unravel the cellular functions of magicin, we used a yeast two-hybrid system and identified fyn tyrosine kinase as a specific binding partner for magicin. Fyn phosphorylates magicin in vitro. SIGNOR-148700 0.457 ADAM17 protein P78536 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity cleavage 9606 BTO:0000782 9034190 t lperfetto We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. [...]This enzyme (called the tnf-alpha-converting enzyme, or tace) is a new member of the family of mammalian adamalysins (or adams), for which no physiological catalytic function has previously been identified. SIGNOR-46754 0.693 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 16046550 t The effect has been demonstrated using Q01196-8. gcesareni Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction. SIGNOR-138912 0.348 BRCA1 protein P38398 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates activity ubiquitination 9606 BTO:0003323 SIGNOR-C297 12485996 t lperfetto The major genetic evidence supporting ubiquitin ligase function for BRCA1 in vivo comes from studies on the FANCD2 protein. Whereas in wild‐type cells the FANCD2 protein co‐localizes with BRCA1 in nuclear foci and becomes monoubiquitylated in response to DNA damage, HCC1937 cells, which encode a mutated form of BRCA1, are largely defective for both monoubiquitylation of FANCD2 and foci formation SIGNOR-263236 0.839 MAPK1 protein P28482 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser282 TAPLSPMsPPGYKLV 9606 BTO:0000567 9535909 t lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. SIGNOR-249403 0.596 MTNR1A protein P48039 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256849 0.476 PRDM16 protein Q9HAZ2 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 BTO:0000222 BTO:0000887;BTO:0001103 18719582 f fspada Loss of prdm16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of prdm16 in myoblasts induces their differentiation into brown fat cells. SIGNOR-180301 0.7 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser62 IDLKRGGsSDDRQIV 9534 BTO:0001538 23519612 t miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. SIGNOR-262712 0.323 linifanib chemical CHEBI:91435 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258242 0.8 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser77 PTAGALYsGSEGDSE -1 2046671 t llicata Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Nevertheless, additional mutation of serines 77 and 79 was required before phosphorylation and enhanced binding were completely abolished. Thus, serines 77 and 79 could also be recognized by CKII if serines 83 and 85 were mutated. SIGNOR-250955 0.533 SRP19 protein P09132 UNIPROT SRP54 protein P61011 UNIPROT up-regulates activity binding -1 30649418 t miannu Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54. SIGNOR-261168 0.962 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PTTG1 protein O95997 UNIPROT up-regulates phosphorylation 9606 10906323 t inferred from 70% family members gcesareni Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function. SIGNOR-270155 0.2 PRKCZ protein Q05513 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser975 VRMKRPSsVKSLRSE -1 15081397 t lperfetto PKCzeta phosphorylates KIBRA at serine 975 and 978 SIGNOR-249262 0.726 AGRN protein O00468 UNIPROT LRP4 protein O75096 UNIPROT up-regulates activity binding 9606 BTO:0000887 23458718 t miannu AGRN is released by the nerve and binds to LRP4, which then binds to MuSK. This interaction leads to MuSK autophosphorylation and activation of its kinase function, leading to anterograde signalling by subsequent phosphorylation of DOK7 (not shown), which binds MuSK as a dimer. SIGNOR-273849 0.843 UVRAG protein Q9P2Y5 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 9606 21311563 t lperfetto Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP(3)R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes SIGNOR-171902 0.856 HCK protein P08631 UNIPROT HCK protein P08631 UNIPROT up-regulates activity phosphorylation Tyr51 ASPHCPVyVPDPTST 9606 BTO:0000007 10934191 t Hck transiently expressed in human embryonic kidney 293T cells was found to be phosphorylated at Tyr-29 and Tyr-388, proving that Hck can also undergo autophosphorylation at both sites in vivo. autophosphorylation of Tyr-29 contributes significantly to the activation of Hck. SIGNOR-251265 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PAK1 protein Q13153 UNIPROT down-regulates phosphorylation 9606 14993270 t inferred from 70% family members gcesareni Activated erk can phosphorylate t292 in the prs, and this blocks the ability of pak to phosphorylate s298 and of rac-pak signaling to enhance mek1-erk complex formation. SIGNOR-270186 0.2 POLR2K protein P53803 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266168 0.827 TNKS protein O95271 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19759537 t lperfetto Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. SIGNOR-187972 0.765 F2R protein P25116 UNIPROT THBS1 protein P07996 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254850 0.307 DLG4 protein P78352 UNIPROT LRFN1 protein Q9P244 UNIPROT up-regulates activity binding 9606 BTO:0000938 21736948 t miannu SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. Interactions between SALMs 1–3 and PSD-95 family proteinscould serve a number of functions. SALM1 and SALM2, which lack the ability to interact with a presynaptic ligand and thus cannot be directly targeted to sites of early synaptic adhesion, may require PSD-95 binding for their localization to early synapses. SIGNOR-264095 0.766 HIF1AN protein Q9NWT6 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates hydroxylation Asn1955 LEASADAnIQDNMGR 9606 18299578 t gcesareni We show that fih-1 hydroxylates notch icd at two residues (n(1945) and n(2012)) that are critical for the function of notch icd as a transactivator within cells and during neurogenesis and myogenesis in vivo. Fih-1 negatively regulates notch activity and accelerates myogenic differentiation. SIGNOR-161057 0.566 SREBF1 protein P36956 UNIPROT FASN protein P49327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20373869 t lperfetto Ultimately, both the AKT and MAPK transduction pathways regulate FASN expression through the modulation of expression of sterol regulatory element-binding protein (SREBP)-1c, which binds to regulatory elements in the FASN promoter. Proto-oncogene FBI-1 (Pokemon), a transcription factor of the bric--brac tramtrack broad complex/pox viruses and zinc fingers (BTB/POZ) domain family, interacts directly with SREBP-1c through its DNA-binding domain to synergistically activate the transcription of FASN SIGNOR-242884 0.509 MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 11062067 t amattioni Jnk full activation requires the phosphorylation of a threonine and a tyrosine residue in a thr-pro-tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (mkk)4 and mkk7. Mkk7 shows a striking preference for the threonine residue (thr-183). SIGNOR-83736 0.687 CDK2 protein P24941 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Ser399 GLLTPPQsGKKQSSG 9606 14536078 t amattioni Phosphorylation-triggered ubiquitination has been proposed to be the major pathway regulating cyclin e protein abundance. Cdk2 activity is required for cyclin e turnover in vivo because it phosphorylates s384. Mutation of ser384 to alanine also rendered cyclin e resistant to degradation SIGNOR-118555 0.954 PRKCA protein P17252 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Ser139 EEWTRHGsFVNKPTR 10090 12052829 t lperfetto Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms. SIGNOR-249150 0.41 SKP1 protein P63208 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR form complex binding 9606 15340381 t gcesareni The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions. SIGNOR-243554 0.94 CDK5 protein Q00535 UNIPROT SYN1 protein P17600 UNIPROT up-regulates phosphorylation Ser553 ARPPASPsPQRQAGP 9606 10880969 t lperfetto Synapsin i (syni), a major sv phosphoprotein involved in the regulation of sv trafficking and neurotransmitter release, is one of the presynaptic substrates of cdk5, which phosphorylates it in its c-terminal region at ser(549) (site 6) and ser(551) (site 7). Phosphorylation of syni by cdk5 is physiologically regulated and enhances its binding to f-actin. SIGNOR-78887 0.58 PCC complex SIGNOR-C414 SIGNOR (S)-methylmalonyl-CoA(5-) smallmolecule CHEBI:57327 ChEBI up-regulates quantity chemical modification 9606 15890657 t miannu Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively. SIGNOR-267186 0.8 Caspase 3 complex complex SIGNOR-C221 SIGNOR PTCH1 protein Q13635 UNIPROT down-regulates activity cleavage Asp1405 CPGYPETdHGLFEDP 9606 12907805 t lperfetto Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain. SIGNOR-256438 0.326 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser428 IPKRLRRsLPPGLLR 9606 19261611 t llicata Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding. SIGNOR-184452 0.2 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21071439 t llicata We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-169522 0.532 LYN protein P07948 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268215 0.696 MAPK1 protein P28482 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Thr794 LEMLVPStPTSTSGA 9606 15125835 t lperfetto Both cdk1 and erk2 induced phosphorylation of the wild-type nir2. Substitution of t794 by alanine reduced the phosphorylation by erk2, whereas the double mutations t794/1223a completely abolished it. The requirement of multiple nir2 phosphorylation sites for plk1 binding may provide a mechanism that sets a threshold for the nir2-plk1 interaction during mitosis. SIGNOR-124650 0.2 EGFR protein P00533 UNIPROT CCDC50 protein Q8IVM0 UNIPROT down-regulates activity phosphorylation Tyr304 SSHKGFHyKH 9606 BTO:0000567 19059208 t miannu We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling. SIGNOR-262852 0.425 Scribble_complex_DLG5-LLGL2_variant complex SIGNOR-C506 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 f miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270894 0.7 CERS3 protein Q8IU89 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI up-regulates quantity chemical modification 9606 26887952 t done miannu  Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity.  SIGNOR-273995 0.8 SIM1 protein P81133 UNIPROT ARNT protein P27540 UNIPROT down-regulates activity binding -1 SIGNOR-C125 9020169 t 2 miannu SIM1 can inhibit AHR·ARNT binding to the XRE and can inhibit expression from an XRE-driven reporter gene indicates that SIM1 may act as negative regulator of transcription as well as a positive regulator. The above inhibitory effects may result from SIM1 competing with AHR for binding to ARNT, although we cannot exclude the possibility that SIM1 may also have other inhibitory effects of AHR·ARNT activity. In a similar fashion, SIM1 may act as a negative regulator of all ARNT-dependent genes. SIGNOR-240756 0.546 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr1197 LESEEELySSCRQLR 9606 BTO:0000776 11507089 t lperfetto These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2. SIGNOR-109746 0.769 PLK1 protein P53350 UNIPROT STAG2 protein Q8N3U4 UNIPROT down-regulates activity dephosphorylation Thr1109 MWLSREQtLHTPVMM 9606 BTO:0000567 15737063 t lperfetto Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase SIGNOR-275533 0.727 PPIF protein P30405 UNIPROT ATP5PO protein P48047 UNIPROT up-regulates activity binding 9606 BTO:0000007 32814770 t lperfetto We here hypothesized that CypD phosphorylation on its residue S191 induces its translocation and binding to the OSCP to favor mPTP opening.  SIGNOR-264881 0.2 PPP3CB protein P16298 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10195903 t Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. SIGNOR-248383 0.341 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271805 0.8 PPP2R2A protein P63151 UNIPROT WEE1 protein P30291 UNIPROT up-regulates quantity by stabilization dephosphorylation 9606 BTO:0000018 33108758 t miannu Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression. SIGNOR-266381 0.393 3-[[3-[(dimethylamino)methyl]anilino]-phenylmethylidene]-N,N-dimethyl-2-oxo-1H-indole-6-carboxamide chemical CHEBI:91423 ChEBI MAP2K5 protein Q13163 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190374 0.8 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Ser974 EESLAEMsIMTTELQ 9606 18055457 t lperfetto Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta SIGNOR-159574 0.275 PRKCD protein Q05655 UNIPROT CYTH1 protein Q15438 UNIPROT unknown phosphorylation Ser394 ARKKKVSsTKRH 9606 BTO:0001948 11438522 t lperfetto We show here that a serine/threonine motif within the short polybasic stretch of cytohesin-1 is phosphorylated by purified protein kinase C delta in vitro. Furthermore, the respective residues are also found to be phosphorylated after phorbol ester stimulation in vivo. Biochemical and functional analyses show that phosphorylated cytohesin-1 is able to tightly associate with the actin cytoskeleton, and we further demonstrate that phosphorylation of the protein is required for maximal leukocyte function antigen-1-mediated adhesion of Jurkat cells to intercellular adhesion molecule 1.  SIGNOR-249098 0.329 LPAR4 protein Q99677 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257258 0.2 LRP1B protein Q9NZR2 UNIPROT DVL2 protein O14641 UNIPROT down-regulates activity binding 9606 28408316 t irozzo In this study, we have shown that LRP1B inhibited the activity of beta-catenin/TCF signaling possibly by interacting with DVL2. The molecular mechanism study revealed that LRP1B interacted with DVL2, inhibited the interaction between DVL2 and Axin, and negatively regulated beta-catenin/TCF signaling. SIGNOR-259090 0.393 PPP3CB protein P16298 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates relocalization 9606 11062529 t gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-84047 0.712 PSMD8 protein P48556 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263345 0.912 CDK2 protein P24941 UNIPROT USP37 protein Q86T82 UNIPROT up-regulates activity phosphorylation Ser628 MVNSCITsPSTPSKK 9606 SIGNOR-C83 21596315 t lperfetto There is positive reinforcement of this signaling mechanism because phosphorylation of Ser628 by CDK2/cyclin E and CDK2/cyclin A complexes produces maximal USP37 activity SIGNOR-265045 0.458 SMURF2 protein Q9HAU4 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001593 BTO:0000140 22298955 t lperfetto Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps SIGNOR-120647 0.714 PDK2 protein Q15119 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 16436377 t gcesareni Kinetic and regulatory properties of recombinant human pdh2 and pdh1 were compared in this study. Site-specific phosphorylation/dephosphorylation of the three phosphorylation sites by four pdh kinases (pdk1-4) and two pdh phosphatases (pdp1-2) were investigated by substituting serines with alanine or glutamate in pdhs. SIGNOR-143970 0.529 SOSTDC1 protein Q6X4U4 UNIPROT WNT9B protein O14905 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242739 0.28 tibolone chemical CHEBI:32223 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation 9606 19464167 t Luana In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1). SIGNOR-257821 0.8 MAPK3 protein P27361 UNIPROT MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation Ser454 TGSTPPVsPTPSERS 9606 BTO:0000150;BTO:0000551 22139079 t Translocation from Nuleus to Cytoplasm gcesareni Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. SIGNOR-195157 0.2 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser529 KGAKVFGsLERGLDK 9606 16216881 t lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. SIGNOR-141018 0.2 ITGAV protein P06756 UNIPROT Av/b1 integrin complex SIGNOR-C175 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253201 0.829 MYOG protein P15173 UNIPROT MYOG protein P15173 UNIPROT up-regulates transcriptional regulation 9606 SIGNOR-C92 17194702 t miannu Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle SIGNOR-151694 0.2 GNA13 protein Q14344 UNIPROT ARHGEF1 protein Q92888 UNIPROT up-regulates binding 9606 9641916 t gcesareni Galpha13 bound tightly top115 rhogefand stimulated its capacity to catalyze nucleotide exchange onrho. SIGNOR-58417 0.591 PTPN9 protein P43378 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 22394684 t lperfetto Results are presented as mean \u00b1 SD from three independent experiments. (B) PTPMeg2 inhibits STAT3-mediated transcriptional activity in a dose dependent manner.|These results indicate that PTPMeg2 inhibits STAT3 activation with certain specificity.|In this study, we demonstrated that PTPMeg2 dephosphorylates STAT3 at the Tyr705 residue by a direct interaction. SIGNOR-276976 0.443 MAPK1 protein P28482 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser312 TESITATsPASMVGG 9606 BTO:0004980 17242212 t gcesareni Our data suggest that il-6 impairs the vasodilator effects of insulin that are mediated by the irs-1/pi3-kinase/akt/enos pathway through activation of jnk and erk1/2. SIGNOR-152418 0.667 TUBA3E protein Q6PEY2 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. SIGNOR-269726 0.7 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser321 SKPSGNDsCELRNLK -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276213 0.2 vildagliptin chemical CHEBI:135285 ChEBI DPP4 protein P27487 UNIPROT down-regulates activity chemical inhibition 9606 19149538 t Luana Various classes of structurally different DPP IV inhibitors are currently being explored and few of them such as Sitagliptin and Vildagliptin were successfully launched. SIGNOR-257812 0.8 JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30029643 f areggio Taken together, our data show IL-15 can enhance the collagen deposition in vivo after muscle damage and this process can be prevented by blocking Jak-STAT pathway. SIGNOR-256231 0.7 CALM3 protein P0DP25 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates activity binding 9606 11807557 t miannu Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. SIGNOR-266346 0.461 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257933 0.8 NLRX1 protein Q86UT6 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates activity binding 9606 BTO:0000567; BTO:0002181 18200010 t Giorgia Here we describe human NLRX1, a highly conserved nucleotide-binding domain (NBD)- and leucine-rich-repeat (LRR)-containing family member (known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH- and MAVS-mediated interferon-beta promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Co-immunoprecipitation studies demonstrate that HA–NLRX1 interacts with MAVS but not with other known mitochondrial outer membrane proteins (BCL2 and BCL2L1), indicating specificity of the NLRX1–MAVS interaction. Finally, endogenous NLRX1 associates strongly with endogenous MAVS after immunoprecipitation with two different MAVS antibodies SIGNOR-260357 0.744 WDR62 protein O43379 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity relocalization 10090 30566428 t lperfetto In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis SIGNOR-271718 0.572 PAK1 protein Q13153 UNIPROT NET1 protein Q7Z628 UNIPROT down-regulates activity phosphorylation Ser152 PTPAKRRsSALWSEM -1 15684429 t miannu In this work we show that the Rac/Cdc42hs-regulated protein kinase PAK1 down-regulates the activity of the RhoA-specific guanine nucleotide exchange factor NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues down-regulates the activity of NET1 as an exchange factor in vitro and its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody that recognizes NET1 phosphorylated on serine 152, we show that PAK1 phosphorylates NET1 on this site in cells and that Rac1 stimulates serine 152 phosphorylation in a PAK1-dependent manner. SIGNOR-263019 0.251 PRKCA protein P17252 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Thr276 GFRKRWFtMDDRRLM -1 12893243 t lperfetto The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5). SIGNOR-249225 0.322 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1763 TPTSPSYsPTSPSYS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248825 0.849 MAPK3 protein P27361 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation Thr202 HDHTGFLtEYVATRW 1712480 t lperfetto Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.| SIGNOR-249471 0.2 Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 25195934 f miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270621 0.7 MAPK11 protein Q15759 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser771 SASSTLGsPENEEHI 9606 SIGNOR-C3 21757713 t llicata Arsenite treatment of cells activates p38_ and induces interaction between p38_ and raptor, a regulatory component of mtorc1, resulting in phosphorylation of raptor on ser(863) and ser(771). The phosphorylation of raptor on these sites enhances mtorc1 activity, and contributes largely to arsenite-induced mtorc1 activation. SIGNOR-174870 0.359 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000763 12193595 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-91738 0.738 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ERF protein P50548 UNIPROT down-regulates phosphorylation 9606 7588608 t lperfetto Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf SIGNOR-216852 0.374 CSNK1E protein P49674 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C110 12000790 t gcesareni We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/ms. SIGNOR-87444 0.737 CDK1 protein P06493 UNIPROT CENPA protein P49450 UNIPROT down-regulates quantity by destabilization phosphorylation Ser68 LIRKLPFsRLAREIC 9606 BTO:0000567 34758320 t miannu Here, we report that the phosphorylation of CENP-A Ser68 primes the ubiquitin-proteasome-mediated proteolysis of CENP-A during mitotic phase in human cultured cells.the mitotic CENP-A degradation specifically depends on Cdk1 activity. SIGNOR-277576 0.666 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT up-regulates phosphorylation Ser19 KLQYYYSsSEDEDSD 9606 16717095 t lperfetto Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2. SIGNOR-146829 0.36 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-263009 0.2 CAMK1 protein Q14012 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser637 VPVARKLsAREQRDC 31063459 t lperfetto For example, protein kinase A (PKA) phosphorylation of Drp1S600 has been reported to decrease Drp1 GTPase activity in vitro (23, 24), whereas phosphorylation of the same conserved serine residue by Ca2+-calmodulin–dependent protein kinase Iα (CaMKIα) in Drp1 isoform 3 has been reported to cause a significant increase in mitochondrial fission SIGNOR-262552 0.339 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 t gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. SIGNOR-163246 0.786 TOR1A protein O14656 UNIPROT SNAPIN protein O95295 UNIPROT up-regulates activity binding 9606 BTO:0000793 18167355 t Monia In the present study, we used yeast two-hybrid analysis to identify a new binding partner of torsinA, the SNARE-associated protein snapin. We have reported that snapin shows a robust interaction with wild type and mutant torsinA. we have demonstrated that this portion of torsinA and/or the adjacent linker region has the additional role of recruiting snapin. we found that snapin, which binds SNAP-25 (synaptosome-associated protein of 25,000 Da) and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild type and mutant torsinA. SIGNOR-261170 0.434 AMPK complex SIGNOR-C15 SIGNOR NR2C2 protein P49116 UNIPROT down-regulates phosphorylation Ser351 HVISRDQsTPIIEVE 9606 21478464 t lperfetto Tr4 transactivation is inhibited via phosphorylation bymetformin-induced amp-activated protein kinase (ampk) at the amino acid serine 351, which results in the suppression of scd1 gene expression SIGNOR-216537 0.2 SAGA complex complex SIGNOR-C465 SIGNOR H3C15 protein Q71DI3 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269643 0.2 AGTR2 protein P50052 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 SIGNOR-252268 0.7 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser439 SIGHSPLsLSAQSVM 9606 BTO:0000938 24614225 t lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204732 0.529 DAB2IP protein Q5VWQ8 UNIPROT HRAS protein P01112 UNIPROT down-regulates activity gtpase-activating protein 9606 27858941 t miannu The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP. SIGNOR-254745 0.583 PPP1CA protein P62136 UNIPROT PREX1 protein Q8TCU6 UNIPROT up-regulates activity dephosphorylation Ser834 LSLGPRLsLCEDSPM 9606 22242915 t lperfetto MS analysis of wild-type P-Rex1 and a PP1\u03b1-binding-deficient mutant revealed that endogenous PP1\u03b1 dephosphorylates P-Rex1 on at least three residues, Ser834, Ser1001 and Ser1165.|The phosphatase activity of PP1\u03b1 is required for P-Rex1 activation. SIGNOR-277022 0.2 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000459 18621737 t amattioni c-IAPs are ubiquitin ligases capable of promoting polymerization of non-degradative Lys-63-linked polyubiquitin chains on the critical adapter in the canonical NF-_B signaling pathway, RIP1. c-IAPs are E3 ligases and RIP1 ubiquitination is critical for propagation of TNF_-induced NF-_B activation SIGNOR-179439 0.759 monobenzyl phthalate chemical CHEBI:132612 ChEBI SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression 10116 16257484 f miannu DIDP, BBP and DOP stimulate NIS mRNA expression. Here, hNIS promoter construct (N3) was up-regulated 2.5-fold by DIDP, 2.6-fold by BBP and 2.4-fold by DOP in the presence of TSH. Likewise, these phthalates also enhanced rNIS endogenous mRNA expression, which increased ca. 2-fold after 48 h of treatment compared with the expression level generated by TSH only. At 72 h, mRNA content was unchanged. SIGNOR-268743 0.8 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 18930133 t PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation. SIGNOR-248486 0.313 AKT proteinfamily SIGNOR-PF24 SIGNOR DLX5 protein P56178 UNIPROT up-regulates phosphorylation 9606 21619873 t gcesareni Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5. SIGNOR-173976 0.2 Immunoglobulin lambda-1 light chain protein P0DOX8 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR form complex binding 9606 BTO:0000776 32323265 t scontino An antibody is composed of two identical HCs and two identical LCs (either kappa or lambda ), consisting of variable (V) and constant (C) regions linked by disulfide bonds. Pro- genitor B cells rearrange their Ig heavy chain (HC) genes to differentiate into precursor B (pre- B) cells that express μ HCs. SIGNOR-268190 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MAP2K1 protein Q02750 UNIPROT down-regulates activity phosphorylation Thr386 IGLNQPStPTHAAGV 9606 BTO:0000007 10567369 t lperfetto An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2 SIGNOR-244561 0.2 MAPK3 protein P27361 UNIPROT RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 17604322 t lperfetto In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE SIGNOR-88662 0.502 MAPK3 protein P27361 UNIPROT STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 25846811 t lperfetto Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK. SIGNOR-209880 0.398 NEK7 protein Q8TDX7 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity phosphorylation Ser607 NLIDLAGsERCSTAH 9606 BTO:0000565 28630147 t miannu Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C). SIGNOR-266417 0.379 EIF2B3 protein Q9NR50 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269126 0.827 SMAD9 protein O15198 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation 9606 20957627 t gcesareni Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. SIGNOR-168740 0.672 LEF1 protein Q9UJU2 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 17081971 f amattioni The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells. SIGNOR-229767 0.7 MAPK8 protein P45983 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser226 IDENCLLsPLAGEDD 9606 12351702 t gcesareni Taken together, these findings suggest that jnk-mediated phosphorylation of the gr-ser226 enhances gr nuclear export and may contribute to termination of gr-mediated transcription. SIGNOR-93558 0.623 PDYN protein P01213 UNIPROT OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258416 0.655 NAE complex SIGNOR-C131 SIGNOR ANAPC2 protein Q9UJX6 UNIPROT up-regulates activity neddylation 9606 25504797 t lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. SIGNOR-243175 0.379 GPS1 protein Q13098 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270774 0.921 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser50 SPTFRSDsPVPTAPT 9606 BTO:0000007 33217317 t miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. SIGNOR-265951 0.2 MYD88 protein Q99836 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity binding 9606 12297423 t Signaling between MyD88 and TRAF6 is mediated by members of the IL-1R-associated kinase (IRAK) family; however, the exact function of each IRAK protein remains controversial. IRAK-1 is required for the optimal transduction of IL-1R- and TLR-mediated signals, but IRAK-1 can be replaced by other IRAKs. Surprisingly, gene targeting studies show that the newest IRAK protein, IRAK-4, has an essential role in mediating signals initiated by IL-1R and TLR engagement. SIGNOR-252097 0.945 CSNK2A1 protein P68400 UNIPROT EEF1D protein P29692 UNIPROT unknown phosphorylation Ser162 DDIDLFGsDNEEEDK 9606 BTO:0000567 21936567 t lperfetto Direct phosphorylation of eef1d by ck2 was shown by performing ck2 assays with eef1d -flag from hela cells. Dramatic increases in eef1d phosphorylation following _-phosphatase treatment and phospho- eef1d antibody recognizing eef1d ps162 indicated phosphorylation at the ck2 site in cells. SIGNOR-176632 0.333 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT down-regulates activity dephosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 16778204 t The receptor-type protein tyrosine phosphatase J antagonizes the biochemical and biological effects of RET-derived oncoproteins.|PTPRJ expression induces dephosphorylation of the RET(C634R) and, probably via an indirect mechanism, RET/PTC1 oncoproteins on two key RET autophosphorylation sites (Tyr1062 and Tyr905). This results in a significant decrease of RET-induced Shc and extracellular signal-regulated kinase 1/2 phosphorylation levels SIGNOR-248701 0.281 BMP1 protein P13497 UNIPROT COL7A1 protein Q02388 UNIPROT up-regulates quantity cleavage Ala2821 RPLPSYAaDTAGSQL 9606 BTO:0000667 11986329 t miannu  We show that bone morphogenetic protein-1 (BMP-1), which exhibits procollagen C-proteinase activity, cleaves the C-terminal propeptide from human procollagen VII. The cleavage occurs at the BMP-1 consensus cleavage site SYAA/DTAG within the NC-2 domain. Proteinases of the bone morphogenetic protein-1 family convert procollagen VII to mature anchoring fibril collagen. SIGNOR-256338 0.587 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 9606 12270934 t lperfetto Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. SIGNOR-235940 0.74 CBLB protein Q13191 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity 9606 BTO:0004175 27773928 f miannu We have also shown that the E3 ubiquitin ligase Cbl-b is crucial for activation of the p53 pathway through ubiquitinating and promoting degradation of Siva1, the E3 ubiquitin ligase targeting ARF, a positive regulator of p53. On the basis of our data presented in the study, we propose the model (Figure 2i) that Cbl-b negatively regulates Siva1 by ubiquitination and subsequent degradation of Siva1, which is followed by stabilization of ARF. This in turn downregulates MDM2, thereby promoting the induction of p53 and activation of its downstream targets. SIGNOR-261320 0.2 magnesium(2+) chemical CHEBI:18420 ChEBI Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-267755 0.8 SMARCB1 protein Q12824 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270737 0.844 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Ser577 RKPGLRRsPIKKVRK 9606 9840932 t lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk5 SIGNOR-217252 0.707 BAG3 protein O95817 UNIPROT HSPA8 protein P11142 UNIPROT up-regulates activity binding -1 27474740 t lperfetto Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co-chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70. SIGNOR-254116 0.78 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates quantity by stabilization phosphorylation Ser342 LAHDRAPsRKDSLES 9606 21317289 t gcesareni We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation. SIGNOR-171999 0.444 MAP1LC3B protein Q9GZQ8 UNIPROT ATG3 protein Q9NT62 UNIPROT up-regulates binding 9606 22170151 t gcesareni Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe. SIGNOR-191549 0.828 NACC1 protein Q96RE7 UNIPROT ZBTB14 protein O43829 UNIPROT up-regulates activity binding -1 19121354 t miannu NAC1 potentiated ZF5 mediated repression in Gal4-DBD fusion transient assays. GST pulldown assays further confirmed protein–protein interactions between these proteins and NAC1. SIGNOR-226443 0.292 ATM protein Q13315 UNIPROT ZNF148 protein Q9UQR1 UNIPROT up-regulates phosphorylation Ser202 GEKPFQCsQCDMRFI 9606 17560543 t lperfetto Here we found that zbp-89 is phosphorylated by atm kinase in vitro and in vivo. Disruption of the atm phosphorylation motif (202)sq within the zinc finger domain of zbp-89 attenuated its ability to enhance p21(waf1) activation by butyrate. Moreover, disruption of the atm phosphorylation site abrogated the ability of zbp-89 to potentiate butyrate induction of endogenous p21(waf1) expression. SIGNOR-155634 0.368 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser636 SGDYMPMsPKSVSAP 10116 11287630 t lperfetto Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten SIGNOR-106586 0.757 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT up-regulates cleavage 9606 22972936 t Thrombin acts on protease-activated receptors (PARs), a subfamily of G protein-coupled receptors (GPCR) that participate in a variety of biological process, including chemokine and cytokine release, tissue remodeling, inflammation, proliferation, and angiogenesis. gcesareni The par1 receptor subtype is activated when the n terminus is proteolytically cleaved by the serine protease thrombin, resulting in an irreversible activation of the receptor. Thrombin activates platelets by binding and cleaving protease-activated receptors 1 and 4 (par1 and par4). SIGNOR-199007 0.883 SDC3 protein O75056 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity binding 10090 BTO:0002314 20696709 t gcesareni Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-€“converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size. SIGNOR-254329 0.391 GPR119 protein Q8TDV5 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257241 0.252 CSNK1D protein P48730 UNIPROT MTSS1 protein O43312 UNIPROT down-regulates quantity by destabilization phosphorylation Ser322 SSVSSHDsGFISQDA 9606 BTO:0000567 24318128 t miannu Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation.  SIGNOR-276611 0.333 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser39 TTSTRTYsLGSALRP 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248885 0.288 ZBED1 protein O96006 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by repression transcriptional regulation 7227 BTO:0001138 22021382 f 1 miannu XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression. SIGNOR-239736 0.2 FHL5 protein Q5TD97 UNIPROT CREM protein Q03060 UNIPROT up-regulates activity binding 9606 10086359 t miannu ACT (for activator of CREM in testis), a LIM-only protein which specifically associates with CREM. ACT is expressed coordinately with CREM in a tissue- and developmentally regulated manner. It strongly stimulates CREM transcriptional activity in yeast and mammalian cells and contains an intrinsic activation function. SIGNOR-222111 0.652 PKC proteinfamily SIGNOR-PF53 SIGNOR NOXO1 protein Q8NFA2 UNIPROT up-regulates activity phosphorylation Ser159 SRAAGRLsIHSLEAQ 9606 28336130 t lperfetto Importantly, the constitutive activity of NoxO1 can be modulated. NoxO1 phosphorylation by PKC at Ser154 doubles its binding ability to NoxA1, which in turn acts as a molecular switch, allowing optimal interaction of NoxO1 with p22phox SIGNOR-264728 0.2 KNG1 protein P01042 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 t lperfetto Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1. SIGNOR-261858 0.429 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1665 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248750 0.727 WNT1 protein P04628 UNIPROT MYF5 protein P13349 UNIPROT up-regulates activity 10090 BTO:0000887;BTO:0001103 22944199 f gcesareni In explant cultures of mouse paraxial mesoderm, Wnt1 induced expression of the MRF Myf5, whereas Wnt7a or Wnt6 preferentially activated the MRF MyoD SIGNOR-198849 0.343 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 t gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation SIGNOR-252440 0.426 α-D-glucose smallmolecule CHEBI:17925 ChEBI Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 23680095 t miannu Glycolysis is a cytoplasmic non-oxidative reaction for glucose degradation that is composed of 9 pro cesses. A non-specific HK enzyme by using ATP phosphorylates glucose following entrance to the cell and converts it to G6P. SIGNOR-267959 0.7 GSK3B protein P49841 UNIPROT FOXM1 protein Q08050 UNIPROT down-regulates quantity by destabilization phosphorylation Ser474 S-->A 9606 BTO:0002181 26912724 t miannu GSK3 phosphorylates FoxM1 on serine 474 which induces FoxM1 ubiquitination mediated by FBXW7. SIGNOR-277208 0.362 MAPK1 protein P28482 UNIPROT PARVA protein Q9NVD7 UNIPROT up-regulates activity phosphorylation Ser4 sPQKSPSV 9606 22955285 t lperfetto Actopaxin (alpha-parvin) is a paxillin, integrin-linked kinase, and F-actin binding focal adhesion protein with several serine phosphorylation sites in the amino terminus that contribute to the regulation of cell spreading and migration.|Actopaxin phosphorylation of Ser4/8 enhances cell migration whereas a nonphosphorylatable (Quint) mutant suppresses migration in U2OS osteosarcoma cells (7). SIGNOR-265760 0.262 ESR1 protein P03372 UNIPROT TFF1 protein P04155 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 11517191 f ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression SIGNOR-253938 0.744 BRCA1 protein P38398 UNIPROT BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR form complex binding 25400280 t lperfetto Intriguingly, another BRCA1 complex, the BRCA1–A complex, which itself contains RAP80 along with MERIT40, BRCC36/45 and Abraxas, has been reported to inhibit DNA end resection, suggesting that, in some contexts, BRCA1 may function to limit and/or prevent over resection of DNA breaks. SIGNOR-263224 0.786 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr8 MSSILPFtPPVVKRL 9606 BTO:0000763 12193595 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-91746 0.738 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr252 PINGSPRtPRRGQNR 9606 1756735 t lperfetto The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2. SIGNOR-21560 0.675 HOXA7 protein P31268 UNIPROT KRT10 protein P13645 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11435435 f miannu Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes. SIGNOR-254472 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser540 HVSEDSSsPERTSPP 9606 19107194 t lperfetto We identified cyclinb/cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates sirt1. Mutation of two residues phosphorylated by cyclin b/cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in sirt1-deficient cells SIGNOR-216841 0.488 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 14670079 t lperfetto We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication. SIGNOR-216690 0.414 ITGA5 protein P08648 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253177 0.913 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Tyr1387 GRCPSDPyKHSLPSQ -1 10195142 t lperfetto To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain. SIGNOR-247171 0.584 pregnenolone smallmolecule CHEBI:16581 ChEBI progesterone smallmolecule CHEBI:17026 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 2243100 t lperfetto Three beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) catalyze the oxidative conversion of delta 5-3 beta-hydroxysteroids to the delta 4-3-keto configuration and is therefore essential for the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens. SIGNOR-268630 0.8 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 10482988 t miannu Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. SIGNOR-251147 0.434 selumetinib chemical CHEBI:90227 ChEBI ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001950 25487801 t Luana Inhibitors of MEK1/2 (trametinib) and/or ERK1/2 (selumetinib) had the strongest and most conserved inhibitory activities, suggesting that MEK1/2 and ERK1/2 may have unique capabilities as stand-alone or combinatorial therapies for MERS-CoV infections.  SIGNOR-262313 0.8 PTPN9 protein P43378 UNIPROT GHR protein P10912 UNIPROT down-regulates dephosphorylation 9606 12907755 t fspada Using ghr hyper-phosphorylated by elk kinase, we have identified tc-ptp, ptp- , pyst-2, sap1, meg-2, ptp1b, and ptph1 as having substrate specificity for this receptor. In addition, we have shown that these same ptps (or rather their nonmutated counterparts) can dephosphorylate the ghr. SIGNOR-104577 0.319 IGF1 protein P05019 UNIPROT IGF1R protein P08069 UNIPROT up-regulates binding 9606 19029956 t lperfetto At the cellular level, the ligands IGF1, IGF2 and insulin bind to various members of the insulin receptor (IR) - IGF1 receptor (IGF1R) family. SIGNOR-182484 0.956 CHEK1 protein O14757 UNIPROT BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Thr182 SHFVRVStAQKSKKG 9606 BTO:0002181 26028025 t miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.Phosphorylation on BLM Thr171 and Ser175 depends on prior phosphorylation at Thr182 by Chk1/Chk2. Thr182 phosphorylation not only controls BLM ubiquitylation and degradation during mitosis but is also a determinant for its localization on the ultrafine bridges. SIGNOR-276909 0.772 PDK2 protein Q15119 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 19951971 t lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. The phosphorylation of AKT on Ser473 by PDK2 acts as a €œgain control€ for AKT and regulates its degree of activation. The sirolimus-insensitive mTORC2 complex exhibits PDK2 activity SIGNOR-249630 0.74 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser276 PQRSRSPsPQPSSHV 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248376 0.598 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2B protein P63146 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271334 0.746 ROCK1 protein Q13464 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Ser365 RLDRTGSsPTQGIVN 9606 15767678 t gcesareni Identification of rock1 as an upstream activator of the jip-3 to jnk signaling axis in response to uvb damage. phosphorylation of jip-3 by rock1 was crucial for the recruitment of jnk. Inhibition of the activity of rock1 in keratinocytes resulted in decreased activation of the jnk pathway and thus a reduction in apoptosis. SIGNOR-134588 0.338 MC4R protein P32245 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257336 0.252 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 1303753 t gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. SIGNOR-16239 0.563 CAMK2A protein Q9UQM7 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1303 NKLRRQHsYDTFVDL BTO:0003036 8940188 t llicata By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons. SIGNOR-250630 0.688 FOXO3 protein O43524 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12913110 f lperfetto In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal. SIGNOR-209657 0.762 AURKB protein Q96GD4 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation Ser265 QKVAERRsSPLLRRK 9606 22865920 t lperfetto We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions SIGNOR-198646 0.267 ADAM10 protein O14672 UNIPROT EGF protein P01133 UNIPROT up-regulates activity cleavage 9606 26284334 t miannu Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin SIGNOR-259840 0.548 MAPK1 protein P28482 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser333 KGLVSPQsPQKSDCQ 9606 BTO:0000782;BTO:0000785 9649500 t gcesareni Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway. SIGNOR-58481 0.502 NDUFS4 protein O43181 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. SIGNOR-262178 0.841 Shikonin chemical CHEBI:81068 ChEBI PK proteinfamily SIGNOR-PF80 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0000093;BTO:0000018 21516121 t inferred from family member lperfetto Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2. SIGNOR-270289 0.8 ATF2 protein P15336 UNIPROT POLB protein P06746 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001025 10518804 f miannu We identified the heterodimeric transcription factor ATF2/CREB as constitutively binding to the essential cAMP response element (CRE) site within the Ca2+-regulated DNA polymerase beta promoter and contributing to the activation of this promoter. SIGNOR-253744 0.2 BLOC1S5 protein Q8TDH9 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 22203680 t lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. SIGNOR-265938 0.68 TFEB protein P19484 UNIPROT GNS protein P15586 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276540 0.317 PRKACA protein P17612 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates phosphorylation 9606 12536214 t inferred from family member gcesareni We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus. SIGNOR-270232 0.488 nilotinib chemical CHEBI:52172 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 19108785 t irozzo Nilotinib is an oral second-generation bcr-abl TKI indicated for the treatment of imatinib resistant or -intolerant Ph+ CML-CP and -AP in adults. Nilotinib binds to inactive configuration of the abl kinase, thus preventing the tyrosine phosphorylation of proteins involved in bcr-abl signal transduction. Nilotinib binds to the inactive (unphosphorylated) configuration of the abl TK, with the P-Ioop folding over, disrupting the ATP binding site and catalytic activity of the enzyme. SIGNOR-255818 0.8 PLK1 protein P53350 UNIPROT SNCB protein Q16143 UNIPROT down-regulates activity phosphorylation Ser118 LMEPEGEsYEDPPQE 9606 19889641 t lperfetto Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. SIGNOR-176079 0.324 PRKCE protein Q02156 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249281 0.404 MCHR2 protein Q969V1 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257180 0.41 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr511 SKLQNLSyTEILKIR 9606 15952790 t llicata We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts. SIGNOR-138154 0.59 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT up-regulates activity phosphorylation Ser36 ELQRRRRsLALPGLQ 8355 BTO:0001175 18803695 t miannu Recently, we have defined sites of phosphorylation by cAMP-dependent protein kinase (PKA) in the amino termini of both GRK1 and GRK7 in vitro. To determine the conditions under which GRK7 is phosphorylated in vivo, we have generated an antibody that recognizes GRK7 phosphorylated on Ser36, the PKA phosphorylation site. Using this phospho-specific antibody, we have shown that GRK7 is phosphorylated in vivo and is located in the cone inner and outer segments of mammalian, amphibian and fish retinas. The conservation of phosphorylation at Ser36 in GRK7 in these different species (which span a 400 million-year evolutionary period), and its light-dependent regulation, indicates that phosphorylation plays an important role in the function of GRK7 SIGNOR-263152 0.2 DNMT3B protein Q9UBC3 UNIPROT BAG1 protein Q99933 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 18413740 f lperfetto DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation SIGNOR-254109 0.331 PRKACA protein P17612 UNIPROT KCNJ3 protein P48549 UNIPROT unknown phosphorylation Ser385 NSKERHNsVECLDGL 9606 19151997 t llicata Using this approach, we identified s385 as an in vitro phosphorylation site. Mutation of this residue to alanine resulted in a reduced sensitivity of kir3.1* currents to h89 and forskolin, confirming an in vivo role for this novel site of the kir3.1 channel subunit in its regulation by pka. SIGNOR-183475 0.326 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 14633987 t lperfetto These results suggest that TAB2 and TAB3 function redundantly as mediators of TAK1 activation in IL-1 and TNF signal transduction. SIGNOR-119370 0.934 LZTR1 protein Q8N653 UNIPROT KRAS protein P01116 UNIPROT down-regulates activity ubiquitination Lys170 IRQYRLKkISKEEKT 9606 BTO:0000007 30442762 t Gianni By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. SIGNOR-269068 0.252 SEC13 protein P55735 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR form complex binding 9606 23723239 t miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 SIGNOR-255305 0.858 PRKCA protein P17252 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000751 11700305 t lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | SIGNOR-249121 0.347 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MEF2D protein Q14814 UNIPROT down-regulates quantity by destabilization phosphorylation Ser98 KGFNGCDsPEPDGED 10090 BTO:0000944 25733682 t miannu  MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitin-proteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding.  SIGNOR-276887 0.268 MTOR protein P42345 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction SIGNOR-255108 0.7 BFAR protein Q9NZS9 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates binding 9606 BTO:0000093 11733517 t gcesareni We also demonstrate that the mitochondrial protein bar, which has been shown to simultaneously bind caspase-8 and bcl-2 SIGNOR-112585 0.377 ATG7 protein O95352 UNIPROT MAP1LC3C protein Q9BXW4 UNIPROT up-regulates activity binding 10090 22170151 t lperfetto Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe SIGNOR-191540 0.781 CDC26 protein Q8NHZ8 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 t lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. SIGNOR-252011 0.846 ATR protein Q13535 UNIPROT CDS1 protein Q92903 UNIPROT up-regulates 9606 15530773 f gcesareni The pikk kinases serve as transducers of the damege signel, ultimately phosphorylating and activating the downstream effector kinases: checkpoint kinases 1 and 2. SIGNOR-130187 0.355 ERBB2 protein P04626 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 1676673 t gcesareni Activated egfr binds the sh2 domain of phospholipase c-gamma (plc-gamma), activating plc-gamma-mediated downstream signaling. SIGNOR-20815 0.634 FAM83H protein Q6ZRV2 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 t miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. SIGNOR-273768 0.331 SP1 protein P08047 UNIPROT TNC protein P24821 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000452 15001984 t Luana Sp1 and Ets1 are potent transactivators of the TN-C promoter. SIGNOR-261600 0.2 ECM stimulus SIGNOR-ST20 SIGNOR A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259043 0.7 PRKCA protein P17252 UNIPROT KCNJ1 protein P48048 UNIPROT down-regulates activity phosphorylation Thr193 KKRAKTItFSKNAVI -1 22139477 t miannu The giant patch clamp together with site direct mutagenesis revealed that Thr-193 is the phosphorylation site on PKC that regulates the pH(i) sensitivity of ROMK1 channels. Mutation of PKC-induced phosphorylation sites (T193A) decreases the pH(i) sensitivity and increases the interaction of channel-PIP(2).  SIGNOR-276389 0.2 PRKCZ protein Q05513 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser978 KRPSSVKsLRSERLI -1 15081397 t lperfetto PKCzeta phosphorylates KIBRA at serine 975 and 978 SIGNOR-249263 0.726 PRKACA protein P17612 UNIPROT WT1 protein P19544 UNIPROT down-regulates phosphorylation Ser365 KDCERRFsRSDQLKR 9606 9366517 t llicata Pka phosphorylated wt1 at ser-365 and ser-393 in vitro, as well as at additional sites, and this phosphorylation abolished the dna-binding activity of wt1 in vitro. Using wt1 mutants in which ser-365 and ser-393 were mutated to ala individually and in combination, we showed that phosphorylation of these sites was critical for inhibition of dna binding in vivo. SIGNOR-53172 0.347 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 17311928 t inferred from 70% family members llicata Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1 SIGNOR-270154 0.2 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Thr733 LPPVFSGtPKGSGAG 9606 BTO:0000567 20667468 t miannu Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803. SIGNOR-259822 0.2 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr340 RGQRDSSyYWEIEAS 9606 10998357 t gcesareni We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain. SIGNOR-82150 0.588 PPM1A protein P35813 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity dephosphorylation Ser608 ENTEDQYsLVEDDED 10090 BTO:0000944 15016818 t Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes|PP2C_ dephosphorylates the p85 subunit of PI3K, and dephosphorylation of the p85 subunit of PI3K at Ser608 increases its activity SIGNOR-252724 0.33 WNT3A protein P56704 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity 9606 18772438 f gcesareni Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki. SIGNOR-180803 0.676 ruxolitinib phosphate chemical CHEBI:66917 ChEBI JAK1 protein P23458 UNIPROT down-regulates activity chemical inhibition 9606 23061804 t miannu Ruxolitinib is a selective inhibitor of Janus kinases (JAK) 1 and 2, which are involved in the signalling pathway of various cytokines and growth factors essential to haematopoiesis. SIGNOR-259170 0.8 lofepramine chemical CHEBI:47782 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 9537821 t miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. SIGNOR-258882 0.8 IGF1 protein P05019 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity binding 9606 21798082 t lperfetto Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor. SIGNOR-175662 0.956 PTPN11 protein Q06124 UNIPROT PTK2B protein Q14289 UNIPROT down-regulates activity dephosphorylation Tyr906 CQLPPEGyVVVVKNV 9606 10880513 t miannu We demonstrate that RAFTK is a direct substrate of SHP2 both in vitro and in vivo, and that Tyr(906) in the C-terminal domain of RAFTK mediates its interaction with SHP2. |We demonstrate that RAFTK is a direct substrate of SHP2 both in vitro and in vivo, and that Tyr(906) in the C-terminal domain of RAFTK mediates its interaction with SHP2. Moreover, overexpression of dominant negative SHP2 blocked the protective effect of IL-6 against Dex-induced apoptosis. These findings demonstrate that SHP2 mediates the anti-apoptotic effect of IL-6 and suggest SHP2 as a novel therapeutic target in MM..... 1) RAFTK is a substrate of SHP2 in vitro and 2) dephosphorylation of RAFTK by SHP2 inhibits its kinase activity. SIGNOR-277084 0.714 ERG protein P11308 UNIPROT EZH2 protein Q15910 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25277175 f miannu Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3. SIGNOR-251555 0.351 JAK1 protein P23458 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity phosphorylation Tyr690 NLQERRKyLKHRLIV 9020188 t STAT2 plays a pivotal role in IFN-a signaling. It is recruited to the activated receptor first and, after phosphorylation by JAK kinases on tyrosine 690, provides a docking site for the SH2 domain of STAT1. SIGNOR-251344 0.759 TGFBR1 protein P36897 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 26194464 f MARCO ROSINA TbRI phosphorylates not only the C-termini of R-Smads but also activates various protein kinases including mitogen-activated protein kinases (MAPKs): extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK (p38), which then phosphorylate the variable linker regions of R-Smad SIGNOR-255033 0.318 BUB1 protein O43683 UNIPROT BUB3 protein O43684 UNIPROT up-regulates activity relocalization 11402067 t lperfetto Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity SIGNOR-252019 0.942 CARS1 protein P49589 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 11347887 t miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. SIGNOR-270473 0.8 bisphenol F chemical CHEBI:34575 ChEBI AHR protein P35869 UNIPROT up-regulates activity chemical activation -1 31995776 t miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity.In our study, BPs showed AhR agonist activity only at the highest concentrations, and the mixture did not differ from the single BPs. SIGNOR-268737 0.8 CSNK2A1 protein P68400 UNIPROT PTPRJ protein Q12913 UNIPROT up-regulates activity phosphorylation Thr1318 YQNTTAMtIYENLAP 9606 BTO:0002181 24583284 t miannu CK2-dependent phosphorylation of DEP-1 T1318 promotes Y1320 phosphorylation and Src activation upon VEGF stimulation. SIGNOR-277876 0.2 leuprolide chemical CHEBI:6427 ChEBI GNRHR protein P30968 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257499 0.8 CDK1 protein P06493 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr620 RAARFVStPFHEIMS 9606 17785528 t lperfetto Here, we demonstrate that bubr1 is phosphorylated on the cdk1 site t620, which triggers the recruitment of plk1 and phosphorylation of bubr1 by plk1 both in vitro and in vivo. Phosphorylation does not appear to be required for spindle checkpoint function but instead is important for the stability of kinetochore-microtubule (kt-mt) interactions SIGNOR-157642 0.768 CREB1 protein P16220 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10540320 f miannu Our data suggest that intracellular cAMP may directly affect expression of the immunoregulatory cytokine IL-10 in monocytic cells via activation of the eukaryotic transcription factors CREB-1 and ATF-1 and their binding to CRE1 and CRE4 in the upstream enhancer of the IL-10 promoter SIGNOR-254522 0.44 PPM1G protein O15355 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates activity dephosphorylation Thr198 PGLRRRQt 9606 27822412 t miannu By using genomic phosphatase screening, we identified a PPM family phosphatase, PPM1G, which could reduce p27 phosphorylation at T198.|Functionally, ectopic expression of PPM1G enhanced p27 protein stability and delayed cell cycle progression from G1 to S phase. SIGNOR-277112 0.2 LCK protein P06239 UNIPROT CD5 protein P06127 UNIPROT up-regulates activity phosphorylation Tyr487 DNSSDSDyDLHGAQR 9606 BTO:0000782 11298344 t lperfetto Tyrosine phosphorylation of cd5 requires lck activity. We propose that t cell activation mediates cd5 tyrosine phosphorylation at residues y429 and y463 mainly through the activation of lck SIGNOR-106803 0.557 PRKCE protein Q02156 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates phosphorylation Ser268 PQVRVGGsSVDLHRF 9606 21251911 t lperfetto We find that ctnnd1/p120ctn phosphorylation at serine 268 (p-s268) occurs in a strictly pkc_-dependent manner,serine/threonine phosphorylation of p120-ctn has been reported to affect the integrity of ajs [12], [24] and [25]. Xia et al. (2003) reported that several residues (ser122, ser252, ser268, ser288, thr310, ser312, ser873, and thr910) in p120ctn can be either phosphorylated or dephosphorylated upon pkc activation SIGNOR-171712 0.2 CDK1 protein P06493 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT up-regulates activity phosphorylation Ser1252 QPTLPSSsPVPIPVS 9606 BTO:0000567 37584777 t phosphorylation site remapping based on mass spec table lperfetto CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects. SIGNOR-272968 0.2 drospirenone chemical CHEBI:50838 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000671 1493716 t miannu Dihydrospirorenone is a potent aldosterone antagonist 8 times as potent as spironolactone and antiandrogenic (0.3 times cyproterone acetate). The high binding affinity of dihydrospirorenone to the binding sites of the mineralocorticoid receptor of rat kidney with an RBA value of 230% compared to aldosterone is remarkable. This reflects the strong antimineralocorticoid activity of this compound which was evaluated in adrenalectomized rats. SIGNOR-258349 0.8 EIF4E2/GIGYF1 complex complex SIGNOR-C256 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 30917308 f lperfetto 4EHP forms complexes with the GYF domain-containing proteins GIGYF1 and GIGYF2, which are critical for this translational repression SIGNOR-261012 0.7 CSNK2A1 protein P68400 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity phosphorylation Ser689 KGVDFESsEDDDDDP -1 28436950 t miannu Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. SIGNOR-265895 0.2 MMP1 protein P03956 UNIPROT COL2A1 protein P02458 UNIPROT down-regulates quantity by destabilization cleavage Gly774 RGDVGEKgPEGAPGK -1 17318226 t lperfetto In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4.  SIGNOR-272338 0.456 SMURF1 protein Q9HCE7 UNIPROT RAD23A protein P54725 UNIPROT unknown ubiquitination -1 20804422 t miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. SIGNOR-272691 0.297 MAPK11 protein Q15759 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 t lperfetto Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. SIGNOR-114063 0.403 CDK5 protein Q00535 UNIPROT TPX2 protein Q9ULW0 UNIPROT up-regulates quantity by stabilization phosphorylation Ser486 LPITVPKsPAFALKN 9606 BTO:0003897 31272499 t lperfetto CDK5-mediated phosphorylation and stabilization of TPX2 promotes hepatocellular tumorigenesis SIGNOR-265100 0.276 PRKACA protein P17612 UNIPROT KCNJ2 protein P63252 UNIPROT down-regulates activity phosphorylation Ser425 PRPLRREsEI -1 19843922 t miannu PKA consensus site S425 required for PKA-mediated effects on Kir2.1 channels. PKA activation reduced outward IK1 for heteromeric Kir2.1 WT+V227F channels after 2 hours of PKA activation. SIGNOR-276267 0.2 wortmannin chemical CHEBI:52289 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 8162590 t gcesareni The microbial product wortmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase. SIGNOR-252666 0.8 EIF4E2/GIGYF2 complex complex SIGNOR-C257 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 BTO:0000568 22751931 f lperfetto A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development|m4EHP and/or GIGYF2 proteins repress translation. SIGNOR-261013 0.7 WNT5A protein P41221 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131838 0.696 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser554 RTPPKSPsSAKSRLQ -1 8999860 t miannu Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules SIGNOR-250283 0.318 OTULIN protein Q96BN8 UNIPROT UBC protein P0CG48 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270820 0.705 SRC protein P12931 UNIPROT SH3PXD2A protein Q5TCZ1 UNIPROT up-regulates activity phosphorylation 20943948 t lperfetto  Recently, we have shown that tyrosine kinase c-Src substrate Tks4 and Tks5 proteins are novel members of the organizer superfamily SIGNOR-264706 0.646 JMY protein Q8N9B5 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000567 20498093 t lperfetto Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes. SIGNOR-261005 0.315 TAB1 protein Q15750 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity binding 10116 BTO:0003324 16407200 t lperfetto In contrast to MKK3-induced p38 kinase downstream effects, TAB-1-induced p38 kinase activation does not induce expression of pro-inflammatory genes, cardiac marker gene expression, or changes in cellular morphology. Rather, TAB-1 binds to p38 and prevents p38 nuclear localization. SIGNOR-143576 0.817 RPS6KA3 protein P51812 UNIPROT CENPE protein Q02224 UNIPROT up-regulates activity 9606 BTO:0000567 20383198 f lperfetto We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions. SIGNOR-252037 0.2 PRKCB protein P05771 UNIPROT OCLN protein Q16625 UNIPROT up-regulates activity phosphorylation Ser340 DKRFYPEsSYKSTPV 9615 BTO:0000837 11502742 t lperfetto Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X. SIGNOR-249106 0.466 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR CCNA1 protein P78396 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11090075 f Overexpression of cyclin A1 observed in APL cells is caused by the expression of the aberrant fusion proteins, PML-RARα and PLZF-RARα. PML-RARα itself can lead to activation of the cyclin A1 promoter.Since both fusion proteins disrupt the normal RARα function, our results strongly suggested that the RARα pathway negatively regulates the expression of cyclin A1 and that this negative regulation is disrupted by the aberrant fusion proteins. SIGNOR-255725 0.2 EEF1A1P5 protein Q5VTE0 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269546 0.8 AXIN2 protein Q9Y2T1 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates activity binding 9606 BTO:0000142;BTO:0000671;BTO:0000763 10911903 t lperfetto It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains. SIGNOR-228003 0.73 TCL1A protein P56279 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t lperfetto Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation SIGNOR-244449 0.823 FBLN5 protein Q9UBX5 UNIPROT ELN protein P15502 UNIPROT up-regulates binding 9606 19570982 t miannu Our data show that fibulin-5 can interact with tropoelastin or with fibrillin-1, implying a chaperone role for fibulin-5 in directing elastin onto microfibrils SIGNOR-186603 0.752 BMP2 protein P12643 UNIPROT SHH protein Q15465 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19855020 f gcesareni On the other hand, bmp activity negatively regulates shh transcription and a bmp-shh nega-tive-feedback loop serves to confine shh expression during limb development. SIGNOR-188853 0.53 TEAD1 protein P28347 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 20153295 f lperfetto We found that the expression of myf5 and cyclind1 remained significantly elevated upon induction of differentiation in cells that were overexpressing hyap1 s127a compared to cells transfected with wildtype hyap and empty vector;yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor. SIGNOR-235599 0.325 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA3 protein Q9Y5H0 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265677 0.2 TMLHE protein Q9NVH6 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI down-regulates quantity chemical modification 9606 11431483 t miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. SIGNOR-269682 0.8 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Thr63 LSSAWPGtLRSGMVP 9606 22721717 t lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation SIGNOR-197949 0.312 NEK6 protein Q9HC98 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 20595392 t done miannu Our data also show that NEK6 interacts with STAT3, an oncogenic transcription factor, and phosphorylates STAT3 on Ser(727), which is important for transcriptional activation. These results demonstrate that NEK6 interacts with and phosphorylates STAT3, an event that could play an important role in oncogenesis. For the maximal activation of STAT3 signaling, phosphorylation of both Tyr705 and Ser727 is required. Phosphorylation of Tyr705 induces dimerization, nuclear translocation, and DNA binding of the STAT3 protein, whereas phosphorylation of Ser727 is important for transcriptional activation. SIGNOR-273901 0.338 SLIT2 protein O94813 UNIPROT ROBO4 protein Q8WZ75 UNIPROT up-regulates binding 9606 BTO:0000938 12941633 t gcesareni We show that robo4 binds slit and inhibits cellular migration in a heterologous expression system, analogous to the role of known robo receptors in the nervous system. SIGNOR-86380 0.654 NMS protein Q5H8A3 UNIPROT NMUR1 protein Q9HB89 UNIPROT up-regulates binding 9606 BTO:0000142 15635449 t gcesareni Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan g protein-coupled receptor fm-4/tgr-1, which was identified to date as the neuromedin u (nmu) receptor, and designate this peptide 'neuromedin s (nms)' because it is specifically expressed in the suprachiasmatic nuclei (scn) of the hypothalamus. SIGNOR-133074 0.718 SMAD2 protein Q15796 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates binding 10090 BTO:0000165 BTO:0001760 SIGNOR-C8 11160896 t lperfetto Our studies indicate that smad2 and 4 (smad2/4) complexes cooperate with mef2 regulatory proteins in a gal4-based one-hybrid reporter gene assay. SIGNOR-235846 0.399 POU5F1 protein Q01860 UNIPROT TBXT protein O15178 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254929 0.2 DOCK6 protein Q96HP0 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 23462102 t lperfetto Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton. SIGNOR-275671 0.663 SYK protein P43405 UNIPROT IL15RA protein Q13261 UNIPROT up-regulates activity phosphorylation Tyr227 AVSLLACyLKSRQTP 9606 BTO:0001154 11714793 t lperfetto Mutation of a defined region of the intracellular signaling portion of IL-15Ralpha (Tyr227) abrogates both the IL-15Ralpha/Syk association and IL-15Ralpha phosphorylation. Taken together, this suggests that Syk kinase physically and functionally associates with the IL-15Ralpha chain in B cells and that Syk plays a key role in mediating IL-15-induced signal transduction, thus accounting for the distinct functional consequences of IL-15 vs IL-2 binding to B cells SIGNOR-246556 0.335 ADRA2A protein P08913 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256841 0.446 PRKCG protein P05129 UNIPROT GRK2 protein P25098 UNIPROT up-regulates phosphorylation Ser29 ATPAARAsKKILLPE 9606 11042191 t acerquone Phosphorylation of grk2 by protein kinase c abolishes its inhibition by calmodulinin vitro, grk2 was preferentially phosphorylated by pkc isoforms alpha, gamma, and delta SIGNOR-83231 0.2 RPS6KA1 protein Q15418 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9606 BTO:0000007 20048145 t lperfetto Herein, we demonstrate that the n-terminal kinase domain (ntk) of rsk1 is necessary for interactions with pkarialpha. Substitution of the activation loop phosphorylation site (ser-221) in the ntk with the negatively charged asp residue abrogated the association between rsk1 and pkarialpha. SIGNOR-162681 0.2 TAF3 protein Q5VWG9 UNIPROT TAF3/TRF3 complex SIGNOR-C23 SIGNOR form complex binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 18851836 t lperfetto We recently identified taf3 as a subunit specifically associated with trf3 to form a complex that is required for myogenic differentiation SIGNOR-181611 0.685 ZC3H12A protein Q5D1E8 UNIPROT GATA2 protein P23769 UNIPROT up-regulates quantity post transcriptional regulation 9606 BTO:0000007 30842549 t Here, we show that Regnase-1 regulates self-renewal of HSPCs through modulating the stability of Gata2 and Tal1 mRNA SIGNOR-259943 0.2 PRL protein P01236 UNIPROT LPL protein P06858 UNIPROT down-regulates activity 9606 12679477 f Regulation miannu PRL inhibits lipoprotein lipase activity in human white adipose tissue SIGNOR-251851 0.334 SLC2A1 protein P11166 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity relocalization 9606 23506862 t miannu GLUT1 plays a critical role in cerebral glucose uptake as the major GLUT isoform expressed in brain endothelial cells. SIGNOR-267458 0.8 SREBF2 protein Q12772 UNIPROT PON1 protein P27169 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20728021 t miannu we conclude that quercetin exhibits its antiatherogenic property by eliciting the translocation of the mature SREBP2 from endoplasmic reticulum to the nucleus, where it binds to SRE-like sequence in the PON1 promoter and up-regulates PON1 gene transcription and PON1 activity. SIGNOR-255224 0.301 LRRC4 protein Q9HBW1 UNIPROT CDK4 protein P11802 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000142 25526788 f miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. SIGNOR-264059 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT2 protein Q96AC1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser186 YSSPGLYsKTMTPTY 9606 BTO:0000567 35469017 t miannu  CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry. SIGNOR-276714 0.2 PAK1 protein Q13153 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser675 QDYKKRLsVELTSSL 9606 21822311 t lperfetto Pak1 directly phosphorylates _-catenin proteins at ser675 site and this leads to more stable and transcriptional active _-catenin SIGNOR-175944 0.539 Succinyl-CoA GTP variant complex SIGNOR-C399 SIGNOR succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity chemical modification 9606 27487822 t miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. SIGNOR-266270 0.8 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser172 LCLSPASsGSSASFI 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252316 0.635 NTRK2 protein Q16620 UNIPROT KCNA3 protein P22001 UNIPROT down-regulates phosphorylation Tyr162 SFDAILYyYQSGGRI 9606 BTO:0000938 BTO:0000671 19166614 t gcesareni Previously we have shown that acute brain-derived neurotrophic factor (bdnf) activation of neurotrophin receptor tyrosine kinase b (trkb) suppresses the shaker voltage-gated potassium channel (kv1.3) via phosphorylation of multiple tyrosine residues in the n and c terminal aspects of the channel protein. SIGNOR-183519 0.386 FGFR2 protein P21802 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates 10090 BTO:0000011 12270934 f lperfetto Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors SIGNOR-244868 0.307 MED11 protein Q9P086 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266670 0.779 CDKL5 protein O76039 UNIPROT MECP2 protein P51608 UNIPROT unknown phosphorylation -1 16935860 t Luana Phosphorylation assays performed with the wild-type protein confirm its capability to mediate the modification of MeCP2 in vitro, whereas Rett missense mutations within the conserved catalytic domain abrogate or significantly impair the enzymatic activity SIGNOR-264702 0.619 Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR Histone H2A proteinfamily SIGNOR-PF70 SIGNOR down-regulates activity ubiquitination 9606 25519132 t miannu Mechanism of transcriptional activation. PRC1 can monoubiquitinate H2AK119 through its RING1B component.  SIGNOR-266815 0.2 PPARG protein P37231 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 20553736 f lperfetto Pigment epithelium-derived factor induces interleukin-10 expression in human macrophages by induction of PPAR gamma. SIGNOR-271688 0.377 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 SIGNOR-C110 11955436 t gcesareni Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-116520 0.856 BCL11A protein Q9H165 UNIPROT HBG1 protein P69891 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004911 20395365 f Regulation miannu BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. SIGNOR-251802 0.458 SMAD7 protein O15105 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates binding 9606 11737269 t lpetrilli Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads. SIGNOR-112645 0.562 SKP2 protein Q13309 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity ubiquitination 9606 SIGNOR-C136 20852628 t gcesareni The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain SIGNOR-243548 0.726 ATR protein Q13535 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser343 TTPGPSLsQGVSVDE 9606 17526493 t gcesareni We demonstrate that mrn and atr/atr-interacting protein (trip) interact with each other, and the forkhead-associated/breast cancer c-terminal domains (fha/brct) of nbs1 play a significant role in mediating this interaction. Mutations in the fha/brct domains do not prevent atr activation but specifically impair atr-mediated nbs1 phosphorylation at ser-343, which results in a defect in the s-phase checkpoint. SIGNOR-155214 0.777 IRF3 protein Q14653 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216316 0.7 GPHN protein Q9NQX3 UNIPROT GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates quantity by stabilization binding 10116 BTO:0000938 21994384 t miannu we demonstrate that GABA(A)Rs and gephyrin are intimately associated at inhibitory synapses in cultured rat neurons. Our results suggest that the direct binding of gephyrin to residues 360-375 of the α1 subunit and its modulation are likely to be important determinants for the stabilization of GABA(A)Rs at synaptic sites, thereby modulating the strength of synaptic inhibition. SIGNOR-264964 0.2 DUSP4 protein Q13115 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity dephosphorylation 10116 7535768 t inferred from 70% of family members Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK SIGNOR-269933 0.752 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 21035469 t gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-169150 0.579 PLN protein P26678 UNIPROT ATP2A2 protein P16615 UNIPROT down-regulates activity binding 10090 12838339 t Heart failure can be traced, in part, to alterations in the activity of the sarcoplasmic reticulum Ca2+ pump that are induced by its interactions with phospholamban, a reversible inhibitor. SIGNOR-252031 0.745 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 16287866 t lperfetto Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle. SIGNOR-216876 0.429 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser218 VSGQLIDsMANSFVG 10090 BTO:0000944 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-235475 0.78 CENPM protein Q9NSP4 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265211 0.689 L-tryptophan smallmolecule CHEBI:16828 ChEBI 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI up-regulates quantity precursor of 9606 31024440 t brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. SIGNOR-264185 0.8 UVB radiation stimulus SIGNOR-ST17 SIGNOR cholesta-5,7-dien-3beta-ol smallmolecule CHEBI:17759 ChEBI down-regulates quantity chemical modification 9606 BTO:0001253 30080183 t lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin SIGNOR-270563 0.7 SYK protein P43405 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr783 EGRNPGFyVEANPMP 9606 8657103 t lperfetto Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771. SIGNOR-246576 0.765 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation Thr228 HEGAVTHtFCGTIEY 9606 9445476 t gcesareni A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-55371 0.596 GART protein P22102 UNIPROT 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI down-regulates quantity chemical modification 9606 34283828 t miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). SIGNOR-267298 0.8 AMPK complex SIGNOR-C15 SIGNOR HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser358 WPLSRTRsEPLPPSA 9606 21892142 t lperfetto Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs). SIGNOR-216558 0.281 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr383 HYRYSDTtDSDPENE 9606 18321849 t gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity SIGNOR-161126 0.622 LEPR protein P48357 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity binding 9606 11085989 t miannu Because the long leptin receptor lacking tyrosine 985 exhibits a significantly reduced ability to activate ERK phosphorylation, this residue is at least in part mediating stimulation of the ERK pathway by ObRb. This residue binds SHP-2 and is required for tyrosine phosphorylation of SHP-2 SIGNOR-263506 0.483 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 10090 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells SIGNOR-248349 0.484 PLK1 protein P53350 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 19889641 t lperfetto Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. SIGNOR-189045 0.358 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR CBFB protein Q13951 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f irozzo However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins. SIGNOR-255854 0.2 E2F2 protein Q14209 UNIPROT CCNE1 protein P24864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8649818 f gcesareni We have found that cell cycle regulation of cyclin e transcription is mediated by e2f binding sites present in the promoter SIGNOR-42020 0.591 AMPK complex SIGNOR-C15 SIGNOR HIPK2 protein Q9H2X6 UNIPROT down-regulates activity phosphorylation Thr1116 AALGSTGtVAHLVAS 23871434 t Phosphosite positions are derived from Figure S5 lperfetto AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro SIGNOR-275484 0.251 PRKACA protein P17612 UNIPROT RGS13 protein O14921 UNIPROT up-regulates quantity by stabilization phosphorylation Thr41 SFENLMAtKYGPVVY 20974683 t miannu Phosphorylation of RGS13 by the cyclic AMP-dependent protein kinase inhibits RGS13 degradation.we show that PKA activation also leads to increased steady-state RGS13 expression through RGS13 phosphorylation, which inhibits RGS13 protein degradation. RGS13 phosphorylation was diminished by mutation of an N-terminal Thr residue (T41) identified as a phosphorylation site by mass spectrometry. SIGNOR-259835 0.34 PRKCE protein Q02156 UNIPROT GLS protein O94925 UNIPROT up-regulates activity phosphorylation Ser314 RYVGKEPsGLRFNKL 9606 BTO:0002552 29515166 t miannu PKCε is the kinase that phosphorylates GAC at Ser314. SIGNOR-277387 0.2 PTPN6 protein P29350 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity dephosphorylation 9606 31130074 t miannu Mechanistically, the association of EHEC Tir with SHP-1 facilitated the recruitment of SHP-1 to TAK1 and inhibited TAK1 phosphorylation, which then negatively regulated K63-linked polyubiquitination of TAK1 and downstream signal transduction.|SHP-1 inhibits TAK1 activity to down-regulate signal transduction and subsequent cytokine production.Innate immune responses are achieved by the activation of several pathogen-recognition receptors (PRPs), including TLRs, retinoic acid inducible gene I (RIG-I)-like receptors (RLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). SIGNOR-277128 0.3 MOB1B protein Q7L9L4 UNIPROT LATS1 protein O95835 UNIPROT up-regulates binding 9606 21084559 t Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. SIGNOR-169795 0.919 Class II MHC:Antigen complex SIGNOR-C429 SIGNOR Helper_T-lymphocyte_activation phenotype SIGNOR-PH196 SIGNOR up-regulates 9606 31810556 f scontino Once they are formed, peptide/MHC class II molecules complexes are very stable and allow for sustained antigen presentation increasing the chances to encounter the matching CD4+ T lymphocytes. Once CD4+ T cells have become acti- vated, they in turn trigger macrophages to eliminate pathogens that have been previously internalized, and B lymphocytes to produce pathogen- specific antibodies. SIGNOR-267874 0.7 PHLPP2 protein Q6ZVD8 UNIPROT PRKCB protein P05771 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 18162466 t These data reveal that PHLPP controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation.|n contrast, results from siRNA depletion and overexpression experiments indicate that the hydrophobic motif site (Ser660) is regulated by PHLPP isoforms, SIGNOR-248727 0.334 NFYA protein P23511 UNIPROT NFY complex SIGNOR-C1 SIGNOR form complex binding 9606 9885213 t lperfetto Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding. SIGNOR-63013 0.963 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser257 QIRLRRDsKEANARR -1 BTO:0002320 9677319 t lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. SIGNOR-249002 0.292 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-268075 0.8 RPL11 protein P62913 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262488 0.87 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser217 YTRTGSEsPKVCSDQ 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248496 0.272 GOT1 protein P17174 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI down-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √É≈Ω√Ǭ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-268061 0.8 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120008 0.781 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser726 DTSPRHLsNVSSTGS -1 12435421 t miannu Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly SIGNOR-250009 0.443 DTNBP1 protein Q96EV8 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates activity binding 10116 BTO:0000601 20531346 t miannu Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation. Although dysbindin-1, WAVE2 and Abi-1 form a ternary complex, dysbindin-1 promoted the binding of WAVE2 to Abi-1. SIGNOR-265660 0.36 simvastatin chemical CHEBI:9150 ChEBI HMGCR protein P04035 UNIPROT down-regulates activity chemical inhibition -1 1433193 t miannu Substitution of hydroxy and hydroxyalkyl functionality at C-7 of the hexahydronaphthalene nucleus of simvastatin has provided novel analogs. The synthetic strategy employed epoxidation or Lewis acid-catalyzed aldol reaction of the 8-keto silyl enol ether as a key reactive intermediate. These analogs were evaluated as potential hypocholesterolemic agents via initial determination of their ability to inhibit HMG-CoA reductase in vitro. SIGNOR-258348 0.8 PROX1 protein Q92786 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0001033 27476001 f miannu Our present study reveals that DAB2IP prevents EMT and metastasis of prostate cancer through targeting PROX1 gene transcription and destabilizing HIF1α protein, which provides a new insight into mechanism that DAB2IP regulates EMT and PCa metastasis. SIGNOR-254767 0.7 FCHO1 protein O14526 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates quantity by stabilization binding 24789820 t lperfetto Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth SIGNOR-260715 0.501 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser251 KNDYRKLsMQCKDFV 9606 16331690 t gcesareni There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712. SIGNOR-142953 0.417 HBB protein P68871 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000876 11901318 f Regulation of expression miannu Free hemoglobin enhances tumor necrosis factor-alpha production in isolated human monocytes. SIGNOR-251752 0.304 MSL1 protein Q68DK7 UNIPROT H2BC21 protein Q16778 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271977 0.2 PRKCD protein Q05655 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity phosphorylation Ser418 KTQTPPVsPAPQPTE 10029 26490115 t Manara Together these findings demonstrate that phosphorylation of cortactin on S405 and S418 residues is required for its interaction with WAVE2 in MCP1-induced cytoskeleton remodeling, facilitating HASMC migration. In addition, the MCP1-induced cortactin phosp SIGNOR-260890 0.248 MEF2C protein Q06413 UNIPROT JUN protein P05412 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9069290 f gcesareni One consequence of mef2c activation is increased c-jun gene transcription. Our results show that p38 may influence host defence and inflammation by maintaining the balance of c-jun protein consumed during infection SIGNOR-47139 0.604 RIPK3 protein Q9Y572 UNIPROT RIPK3 protein Q9Y572 UNIPROT up-regulates activity phosphorylation Thr182 GSGEPGGtLGYLAPE -1 29883609 t miannu This suggests that Thr182 is a likely auto-phosphorylation target and may be involved in RIP3 activity. SIGNOR-277396 0.2 AURKB protein Q96GD4 UNIPROT NDC80 protein O14777 UNIPROT down-regulates phosphorylation Ser44 KPTFGKLsINKPTSE 9606 20471944 t lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). SIGNOR-165558 0.841 LTK protein P29376 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 BTO:0000938 9223670 t gcesareni Although c-cbl is found to be phosphorylated by ltk and therefore is a second candidate linking ltk with the pi3-kinase pathway along with irs-1, we found that the p85 subunit of pi3 kinase directly binds to tyrosine 753 of ltk, which is located within a yxxm motif, a consensus binding amino acid sequence for the sh2 domain of p85 SIGNOR-49622 0.256 F11 protein P03951 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 t lperfetto Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1. SIGNOR-261857 0.471 SREBF2 protein Q12772 UNIPROT ABCG5 protein Q9H222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21123766 f miannu these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α. SIGNOR-254455 0.432 PRKAA2 protein P54646 UNIPROT PROX1 protein Q92786 UNIPROT down-regulates quantity by destabilization phosphorylation Ser79 KLLKRANsYEDAMMP 9606 BTO:0002181 36433955 t miannu Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation. SIGNOR-277608 0.2 WNT3A protein P56704 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 BTO:0000222 10601008 t gcesareni Here we focus on the role of Wnts, their putative receptors Frizzled and the soluble antagonist Frzb1 in regulating mammalian myogenesis. Although it is becoming evident that the signaling downstream of Frizzled receptors is much more complex than anticipated, it is conceivable that it may lead to transcriptional activation of Myf5 and MyoD and to initiation of myogenesis. SIGNOR-73039 0.625 TRAF3 protein Q13114 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates quantity by destabilization binding 10090 15084608 t lperfetto Traf3 is physically associated with nik via a specific sequence motif located in the n-terminal region of nik; this molecular interaction appears to target nik for degradation by the proteasome. SIGNOR-124236 0.654 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL -1 10734133 t gcesareni Interestingly, all PTPs that were tested could completely dephosphorylate the receptor, given sufficient time, including a negative control (PTP-PEST) that failed to bind IRK as a trapping mutant. SIGNOR-262291 0.385 CDK1 protein P06493 UNIPROT CDC16 protein Q13042 UNIPROT up-regulates phosphorylation Ser560 KTLKNIIsPPWDFRE 9606 14657031 t lperfetto Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation SIGNOR-119762 0.623 AKT proteinfamily SIGNOR-PF24 SIGNOR IRAK1 protein P51617 UNIPROT down-regulates activity phosphorylation Thr100 LRARDIItAWHPPAP 9606 BTO:0000007 11976320 t gcesareni CaMKKc and Akt overexpression increases IRAK1 phosphorylation at Thr100, and point mutation of this site abrogates the inhibitory effect of Akt on IRAK1-mediated NF-kappaB activation. SIGNOR-248008 0.2 CYSLTR2 protein Q9NS75 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256889 0.2 MYCT1 protein Q8N699 UNIPROT CCND2 protein P30279 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30283340 f miannu MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. SIGNOR-261731 0.2 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser13 ESFTMASsPAQRRRG 9606 16446360 t gcesareni In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2 SIGNOR-143984 0.961 PPP1CC protein P36873 UNIPROT IFIH1 protein Q9BYX4 UNIPROT up-regulates activity dephosphorylation Ser88 EALRRTGsPLAARYM 9606 23499489 t lperfetto Exogenous PP1alpha or PP1gamma substantially decreased the S88 phosphorylation of Flag-MDA5|we identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation. SIGNOR-264579 0.249 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR AMBRA1 protein Q9C0C7 UNIPROT up-regulates activity phosphorylation 10090 20921139 t lperfetto When autophagy is induced, ulk1 phosphorylates ambra1, releasing the autophagy core complex from dynein. Its subsequent relocalization to the endoplasmic reticulum enables autophagosome nucleation. Ambra1-dlc1 dissociates from the dynein complex upon ulk1-dependent ambra1 phosphorylation. SIGNOR-219388 0.655 DYRK1A protein Q13627 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 24119401 t lperfetto Dyrk1a controls the rate of cycd1 degradation by directly phosphorylating cycd1 at thr 286 and thereby regulates the fraction of cycling cells. SIGNOR-202838 0.405 tRNA(Glu) smallmolecule CHEBI:29175 ChEBI Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270385 0.8 AKAP8L protein Q9ULX6 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 11402034 f miannu These results support the proposal that both RHA and HAP95 facilitated the nuclear export of unspliced, CTE-containing mRNA in human cells. we have extended this earlier study by mapping the functional domains of HAP95 and providing strong evidence for a direct role of HAP95 in RHA-mediated nuclear export of CTE-containing mRNA. SIGNOR-260949 0.7 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 10398585 t lperfetto Serine 32 and serine 36 of IkappaBalpha are directly phosphorylated by protein kinase CKII in vitro|Phosphorylation of IkappaBalpha at serine 32 (S32) and serine 36 (S36) is necessary for this stimuli-induced degradation SIGNOR-249333 0.567 MAPK3 protein P27361 UNIPROT POU5F1 protein Q01860 UNIPROT down-regulates phosphorylation Ser111 ESNSDGAsPEPCTVT 9606 23024368 t gcesareni Phosphorylation of this site downregulates nanog, sox2, rex1 and upregulates bmp4, gata6, ddlx5. SIGNOR-192101 0.35 CTSB protein P07858 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Arg95 GFQEAYRrFYGPV -1 9076588 t miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. SIGNOR-256320 0.336 RAPGEF4 protein Q8WZA2 UNIPROT RAP1B protein P61224 UNIPROT up-regulates activity guanine nucleotide exchange factor 9534 BTO:0000298 10777494 t miannu Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well. SIGNOR-263955 0.804 AKT1 protein P31749 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates phosphorylation 9606 20086174 t inferred from 70% of family members llicata We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2. SIGNOR-269945 0.406 MARCHF1 protein Q8TCQ1 UNIPROT HLA-DRA protein P01903 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys244 FIIKGLRkSNAAERR 9606 19117940 t miannu Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination. SIGNOR-271412 0.2 KIF3B protein O15066 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272537 0.7 POLR2H protein P52434 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266140 0.863 Gbeta proteinfamily SIGNOR-PF4 SIGNOR APBB1 protein O00213 UNIPROT unknown phosphorylation 9606 14697653 t inferred from 70% family members lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. SIGNOR-270054 0.2 SAV1 protein Q9H4B6 UNIPROT STK3 protein Q13188 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0005238 16930133 t Hippo pathway Gianni Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation. SIGNOR-261957 0.827 DUSP10 protein Q9Y6W6 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 10391943 t gcesareni Mkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk, but not mapk/erk. p38 is a preferred substrate SIGNOR-68983 0.682 MORF4L2 protein Q15014 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269300 0.663 PAX8 protein Q06710 UNIPROT TG protein P01266 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11786384 t miannu The transcription factor Pax8 plays an important role in the expression of the differentiated phenotype of thyroid follicular cells. It has recently been shown that Pax8 is necessary for thyroglobulin (Tg) gene expression. SIGNOR-251998 0.47 PRKG1 protein Q13976 UNIPROT SLC6A4 protein P31645 UNIPROT up-regulates phosphorylation Thr276 SIWKGVKtSGKVVWV 9606 BTO:0000567 17913921 t gcesareni These results are consistent with the hypothesis that pkg phosphorylates hsert at thr-276 and increases its activity by modifying the substrate permeation pathway formed, in part, by tm5. SIGNOR-158186 0.391 CDK1 protein P06493 UNIPROT UBA1 protein P22314 UNIPROT up-regulates phosphorylation Ser835 ELKATLPsPDKLPGF 9606 BTO:0000567 7724583 t lperfetto Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Thus, the serine at position 835 is a phosphorylation site. Taking these findings into consideration, we consider that cyclin b might be one of the substrates targeted by the specific ubiquitin conjugation pathway activated by the phosphorylation of e1 with cdc2 kinase. SIGNOR-32225 0.414 CSNK2A1 protein P68400 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation Ser518 PSTSKAVsPPHLDGP 9606 BTO:0000551 16873060 t gcesareni Here we show that ck2 regulates pml protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at ser517. SIGNOR-148306 0.348 PHF2 protein O75151 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 21532585 t miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. SIGNOR-264517 0.2 SP1 protein P08047 UNIPROT UGT1A4 protein P22310 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 19546240 f miannu our data indicate that up-regulation of UGT1A4 expression by E(2) is mediated by both ER alpha and Sp1 and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy. SIGNOR-254076 0.2 mTORC1 complex SIGNOR-C3 SIGNOR GRB10 protein Q13322 UNIPROT up-regulates phosphorylation 9606 21659604 t lperfetto The adaptor protein grb10 was identified as an mtorc1 substrate that mediates the phosphoinositide 3-kinase. SIGNOR-217063 0.365 3,5-dichloro-N-[[(2S)-1-ethyl-2-pyrrolidinyl]methyl]-2-hydroxy-6-methoxybenzamide chemical CHEBI:92070 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258856 0.8 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser43 FGYQRRAsDDGKLTD 9606 11971957 t gcesareni Serine 43 phosphorylation decreased the binding to ras in serum-starved but not in mitogen-stimulated cells. However, the kinase activity of a rafs43a mutant was fully inhibited by pka. SIGNOR-86145 0.482 CSNK2A1 protein P68400 UNIPROT MYB protein P10242 UNIPROT down-regulates activity phosphorylation Ser11 RPRHSIYsSDEDDED -1 7735324 t llicata For c-Myb mutational analysis of the CKII phosphorylation sites showed altered steady state DNA binding. Replacing Ser-11/12 by alanine residues resulted in increased DNA binding compared to wt c-Myb or Myb Asp-11/12 as demonstrated by up to 10-fold differences in the dissociation constants.  SIGNOR-250918 0.346 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser653 PSLSRHSsPHQSEDE 11427888 t Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. SIGNOR-251241 0.673 JAK1 protein P23458 UNIPROT IL2RB protein P14784 UNIPROT up-regulates activity phosphorylation Tyr536 LPLNTDAyLSLQELQ 9534 BTO:0000298 8700888 t In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc. SIGNOR-251341 0.616 SP3 protein Q02447 UNIPROT ITGA11 protein Q9UKX5 UNIPROT up-regulates quantity by expression 9606 BTO:0001282 16300938 t lperfetto We speculate that the "mesenchymal signature" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors. SIGNOR-253351 0.2 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates activity phosphorylation Ser416 SVDDLANsGQVGTAR 9606 BTO:0000972 phosphorylation:Ser213 TRKLMEFsEHCAIIL 9155023 t lperfetto Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. In contrast, phosphorylation of Ser409 and Ser416, located in a segment corresponding to the substrate recognition T-loop region in a three-dimensional structural model of protein kinases, is enhanced by receptor dimerization and can occur via an intermolecular mechanism. Phosphorylation of Ser409 is essential for TbetaRII kinase signaling, while phosphorylation of Ser416 inhibits receptor function. SIGNOR-246737 0.2 ATM protein Q13315 UNIPROT CCAR2 protein Q8N163 UNIPROT up-regulates activity phosphorylation Thr454 AAEAAPPtQEAQGET 9606 22735644 t lperfetto  Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death.  SIGNOR-267661 0.57 COL21A1 protein Q96P44 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates activity binding 9606 BTO:0001282 17318226 t lperfetto The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75.  SIGNOR-272343 0.2 RIMS1 protein Q86UR5 UNIPROT CACNA1D protein Q01668 UNIPROT up-regulates activity binding 9606 BTO:0005822 28642685 t miannu Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells. SIGNOR-264358 0.373 CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 15829969 t lperfetto During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9. SIGNOR-135384 0.785 MERTK protein Q12866 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr376 DRVKSTAyLSPQELE 9606 BTO:0000007 31230815 t done miannu TAM kinases phosphorylate MLKL to promote necroptosis. MLKL is then recruited to the plasma membrane, where TAM kinases phosphorylate MLKL at Tyr376 (Figure 5G, step 5), promoting its oligomerization and formation of membrane-rupturing pores that result in necrotic cell death (Figure 5G, step 6). SIGNOR-274118 0.2 PTPN11 protein Q06124 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity dephosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000007 12270932 t SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei|In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr(701) and the serine residue Ser(727) |Overexpression of SHP-2 in 293T cells inhibited IFNgamma-dependent Stat1 phosphorylation and suppressed Stat1-dependent induction of luciferase activity. SIGNOR-248672 0.733 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser285 VDAQGTLsKIFKLGG -1 2413024 t lperfetto MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. SIGNOR-248874 0.502 SMO protein Q99835 UNIPROT FYN protein P06241 UNIPROT up-regulates phosphorylation 9606 18455992 t gcesareni Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion. SIGNOR-178607 0.404 CDK1 protein P06493 UNIPROT REPS2 protein Q8NFH8 UNIPROT down-regulates activity phosphorylation Ser463 RPRSRSYsSTSIEEA 10029 10764745 t miannu Phosphorylation of POB1 and Epsin by p34cdc2 kinase. Their phosphorylation sites (Ser411 of POB1 and Ser357 of Epsin) were determined. Phosphorylated Epsin and EpsinS357D formed a complex with α-adaptin less efficiently than wild type Epsin. SIGNOR-262724 0.347 CDK5RAP2 protein Q96SN8 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity binding 9606 BTO:0000567 19282672 t Giulio We show here that inhibition of CDK5RAP2 expression causes chromosome mis-segregation, fails to maintain the spindle checkpoint, and is associated with reduced expression of the spindle checkpoint proteins BUBR1 and MAD2 and an increase in chromatin-associated CDC20.|We found that the APC activator CDC20, but not others we exam-ined, was present in the CDK5RAP2 immunocomplex in HeLa cell extracts (Fig. 3A). CDK5RAP2 was detected in the CDC20 immunocomplex as well (Fig. 3B). SIGNOR-260311 0.318 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR RAF1 protein P04049 UNIPROT up-regulates activity dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000007 16239230 t gcesareni ... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259. SIGNOR-243534 0.502 anthraflavic acid chemical CHEBI:34250 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258156 0.8 CSNK1A1 protein P48729 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser291 CGSSGYFsSSPTLSS 9606 22017877 t llicata Phosphorylation of all three serine residues in the deptor degron (ser286, ser287, and ser291) is necessary for - and directly mediates - the interaction with _trcp. ck1 phosphorylated the degron of deptor, as shown by western blotting with the phospho-specific antibody (fig. S3e-f). In contrast, mtor alone was unable to induce phosphorylation of deptor on ser286, ser287, and ser291. SIGNOR-176879 0.2 TFE3 protein P19532 UNIPROT CTSF protein Q9UBX1 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276817 0.2 ARNTL protein O00327 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR form complex binding -1 22653727 t lperfetto Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex|The structure of the CLOCK:BMAL1 complex is a starting point for understanding at an atomic level the mechanism driving the mammalian circadian clock. SIGNOR-253708 0.771 ORC complex SIGNOR-C419 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 32808929 f lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA SIGNOR-267561 0.7 SIRT7 protein Q9NRC8 UNIPROT H3C15 protein Q71DI3 UNIPROT up-regulates activity deacetylation Lys19 TGGKAPRkQLATKAA 22722849 t lperfetto SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. SIGNOR-275875 0.2 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser939 SFRARSTsLNERPKS 9606 12150915 t gcesareni We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex. SIGNOR-91041 0.719 CTBP1 protein Q13363 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21681822 t irozzo Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells. SIGNOR-259196 0.586 LTB4R protein Q15722 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256834 0.252 PRKACA protein P17612 UNIPROT ESR1 protein P03372 UNIPROT down-regulates phosphorylation Ser236 IDKNRRKsCQACRLR 9606 9891036 t lperfetto Phosphorylation of human estrogen receptor alpha by protein kinase a regulates dimerizationeralpha is phosphorylated by protein kinase a (pka) on serine-236 within the dna binding domain. Mutation of serine-236 to glutamic acid prevents dna binding by inhibiting dimerization by eralpha SIGNOR-63984 0.467 NFKB1 protein P19838 UNIPROT CD80 protein P33681 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000776 12860928 f Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells. SIGNOR-253934 0.302 Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 25195934 f miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270741 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 20974802 t lperfetto We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. SIGNOR-244662 0.2 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB2 protein Q9Y5G2 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265688 0.2 WWP2 protein O00308 UNIPROT WWP1 protein Q9H0M0 UNIPROT up-regulates activity binding 9606 BTO:0000007 25071155 t miannu WWP1 in complex with WWP2 specifically regulates ΔNp73.  In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73.  SIGNOR-272231 0.2 FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 11717410 f Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases SIGNOR-255344 0.7 ADRA2A protein P08913 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256698 0.537 MAP3K1 protein Q13233 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser218 VSGQLIDsMANSFVG 10090 BTO:0000944 8131746 t lperfetto Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity. SIGNOR-235587 0.646 ABL1 protein P00519 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity phosphorylation Tyr153 LAYILSMePCGHCLI 9606 15657060 t Manara We show that ABL1 phosphorylates caspase-9 on Tyr-153 in vitro and in cells treated with DNA damaging agents. ! Moreover, inhibition of ABL1 with STI571 blocked DNA damage-induced autoprocessing of caspase-9 to the p35 subunit and activation of caspase-3. SIGNOR-260792 0.527 CSNK2A1 protein P68400 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser63 NVKVETQsDEENGRA 9606 BTO:0001271 21750978 t miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo SIGNOR-174832 0.294 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 9606 21808241 t The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction. SIGNOR-175805 0.845 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257909 0.8 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Ser890 RQRKRKLsFRRRTDK 9606 10488078 t lperfetto Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a) SIGNOR-70726 0.312 PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15526160 t miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254950 0.784 MFGE8 protein Q08431 UNIPROT GRK2 protein P25098 UNIPROT up-regulates quantity by expression 10090 BTO:0000763 22634615 f Giorgia Our findings showed MFG-E8–mediated upregulation of GRK2, which can be correlated with reduction of surface CXCR2. The MFG-E8 effect is mediated by αvβ3 integrin to upregulate GRK2 expression and results in downregulation of surface CXCR2 levels in neutrophils, leading to decrease of neutrophil migration SIGNOR-260648 0.2 DMTF1 protein Q9Y222 UNIPROT AREG protein P15514 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 t Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  SIGNOR-261582 0.2 MYOD1 protein P15172 UNIPROT SP1 protein P08047 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 9148896 t lperfetto These data suggest a regulatory model in which MyoD activation during myogenesis causes the down-regulation of Sp1, which contributes to the repression of GLUT1 gene transcription and, therefore, leads to the reduction in GLUT1 expression and glucose transport. SIGNOR-241765 0.381 AKT1 protein P31749 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 16982699 t gcesareni Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation.[...] We next investigated if phosphorylation of p21-t145 interfered with akt2 binding. As shown in fig. ?Fig.8e8e (right lane), phosphorylation of p21 on t145 effectively prevented akt2 interaction. SIGNOR-149698 0.834 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 9606 15568999 t lperfetto In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 SIGNOR-249574 0.2 serotonin smallmolecule CHEBI:28790 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity precursor of 9606 31024440 t brain lperfetto Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA). SIGNOR-264187 0.8 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2G2 protein P60604 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271310 0.711 Gbeta proteinfamily SIGNOR-PF4 SIGNOR EWSR1 protein Q01844 UNIPROT unknown phosphorylation 9606 19076070 t inferred from 70% family members lperfetto Here we report that ews and ews-fli1 become phosphorylated at thr79 in the n-terminal domain in response to mitogens or dna damage. Mitogen-induced phosphorylation of ews and ews-fli1 was weak and catalysed by erk1 (extracellular signal-regulated kinase 1) and erk2. SIGNOR-270062 0.2 INS protein P01308 UNIPROT LPL protein P06858 UNIPROT up-regulates activity 9606 21966368 f Regulation miannu Insulin has a major effect on LPL regulation in adipose tissue since in mature adipocytes insulin not only increases the level of LPL mRNA but also regulates LPL activity through both posttranscriptional and posttranslational mechanisms SIGNOR-251858 0.476 PPP3CC protein P48454 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Thr290 NKLKPPGtPPPSSRK 10090 19560418 t These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 SIGNOR-248526 0.262 ZDHHC13 protein Q8IUH4 UNIPROT MC1R protein Q01726 UNIPROT up-regulates activity palmitoylation 10090 BTO:0000847 28869973 t miannu Collectively these results suggest that ZDHHC13 phosphorylation by ATR following UVB irradiation promotes its interaction with MC1R to stimulate MC1R palmitoylation.Activating MC1R palmitoylation rescues the defect of MC1R RHC variants SIGNOR-273518 0.278 CAMK2A protein Q9UQM7 UNIPROT CD44 protein P16070 UNIPROT up-regulates phosphorylation Ser706 LNGEASKsQEMVHLV 9606 9580567 t gcesareni We demonstrate here that cd44 is phosphorylated to high stoichiometry in resting cells and that ca(2+)/calmodulin-dependent protein kinase ii is a cd44 ser(325) kinase. SIGNOR-57376 0.2 ANK2 protein Q01484 UNIPROT CACNA1B protein Q00975 UNIPROT up-regulates quantity binding 10090 BTO:0000142 24394417 t miannu Here, we demonstrate that ankyrin-B associates with Cav2.1 and Cav2.2 in cortex, cerebellum, and brain stem. Additionally, using in vitro and in vivo techniques, we demonstrate that ankyrin-B, via its membrane-binding domain, associates with a highly conserved motif in the DII/III loop domain of Cav2.1 and Cav2.2. Collectively, our findings identify an interaction between ankyrin-B and both Cav2.1 and Cav2.2 at the amino acid level that is necessary for proper Cav2.1 and Cav2.2 targeting in vivo. SIGNOR-266707 0.266 EXT1/EXT2 complex SIGNOR-C51 SIGNOR heparan sulfate octasaccharide smallmolecule CHEBI:142519 ChEBI up-regulates quantity chemical modification 9606 20377530 t miannu HS (heparan sulfate) is synthesized by HS co-polymerases encoded by the EXT1 and EXT2 genes (exostosin 1 and 2), which are known as causative genes for hereditary multiple exostoses, a dominantly inherited genetic disorder characterized by multiple cartilaginous tumours. SIGNOR-264016 0.8 FAM83H protein Q6ZRV2 UNIPROT CSNK1E protein P49674 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 t miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. SIGNOR-273764 0.336 NCAPH2 protein Q6IBW4 UNIPROT Condensin II complex SIGNOR-C342 SIGNOR form complex binding 9606 32445620 t miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263910 0.899 PTGER3 protein P43115 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 12038972 t gcesareni Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i) SIGNOR-88192 0.477 ARHGAP11B protein Q3KRB8 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260468 0.469 RIPK1 protein Q13546 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity binding 10090 BTO:0000452 10795740 t gcesareni We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-245026 0.662 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252484 0.754 CITED2 protein Q99967 UNIPROT MMP1 protein P03956 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003859 12960175 f miannu CITED2 plays a major role in shear-induced down-regulation of MMP-1 and MMP-13 via a transforming growth factor-beta-dependent pathway. SIGNOR-253778 0.364 UBE2D3 protein P61077 UNIPROT UBR5 protein O95071 UNIPROT up-regulates activity ubiquitination -1 11714696 t miannu Using an in vitro reconstitution, specific E2 (ubiquitin-conjugating) enzymes (human UbcH4, UbcH5B, and UbcH5C) transferred ubiquitin molecules to hHYD, leading to the ubiquitination of TopBP1. TopBP1 was usually ubiquitinated and degraded by the proteosome, whereas X-irradiation diminished the ubiquitination of TopBP1 probably via the phosphorylation, resulting in the stable colocalization of up-regulated TopBP1 with gamma-H2AX nuclear foci in DNA breaks. SIGNOR-272669 0.474 NCSTN protein Q92542 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 12471034 t Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation gcesareni Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. SIGNOR-96253 0.965 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ABI1 protein Q8IZP0 UNIPROT down-regulates activity phosphorylation Ser216 VPNDYMTsPARLGSQ 9606 BTO:0000567 21900237 t lperfetto We identified serine 216 of Abi1 as a target of CDK1/cyclin B kinase that is phosphorylated in cells at the onset of mitosis.|Bcr-Abl-induced actin polymerization requires the Abi1 pathway, as the blockade of the signal transduction from Bcr-Abl to Abi1 abolishes the F-actin assembly|serine phosphorylation of Abi1 by CDK1/cyclin B serves as a cell cycle-dependent regulatory mechanism that inhibits actin assembly SIGNOR-264452 0.429 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR COIL protein P38432 UNIPROT up-regulates phosphorylation Ser184 NEEAKRKsPKKKEKC 9606 BTO:0000567;BTO:0000938 11102515 t lperfetto In particular, we have recently found that the cdk2/cyclin e complex can phosphorylate coilin in vitro . there is but a single consensus cdk2/cyclin e phosphorylation site in coilin, located at serine 184. when serine 184 was mutated to an alanine (s184a), mimicking a dephosphorylated state, a nucleolar mislocalization similar to that of gfp-coilin(1__†€ †_248) was observed SIGNOR-216733 0.389 PRKCA protein P17252 UNIPROT RALB protein P11234 UNIPROT unknown phosphorylation Ser198 KSSKNKKsFKERCCL 9606 20940393 t llicata Here we test this hypothesis and show that ralb is phosphorylated at s198 by protein kinase c (pkc). this indicates phosphorylation of ralb is important for the development of lung metastasis in human bladder cancer cells. SIGNOR-168532 0.294 SGK3 protein Q96BR1 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 11154281 t lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. SIGNOR-249135 0.446 PRKAA1 protein Q13131 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser92 VAELTSLsDEDSGKG 9606 19923321 t lperfetto Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively. SIGNOR-161783 0.2 CDK5 protein Q00535 UNIPROT VRK3 protein Q8IV63 UNIPROT up-regulates activity phosphorylation Ser108 RPPTPKSsPQKTRKS 27346674 t lperfetto Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding|Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation| SIGNOR-275544 0.363 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176809 0.775 RORA protein P35398 UNIPROT NLGN1 protein Q8N2Q7 UNIPROT up-regulates quantity by expression transcriptional regulation 28608249 t lperfetto Some genes which are directly regulated by RORA such as NLGN1 and NTRK2 have been shown to be associated with increased susceptibility to ASD (Correia et al. 2010; Ylisaukko-oja et al. 2005). SIGNOR-265136 0.2 3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid chemical CHEBI:91194 ChEBI LPAR1 protein Q92633 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193558 0.8 ECM stimulus SIGNOR-ST20 SIGNOR AM/b2 integrin complex SIGNOR-C170 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259052 0.7 POLR1D protein P0DPB5 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266158 0.891 IKBKG protein Q9Y6K9 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR form complex binding 9606 SIGNOR-C14 12192055 t lperfetto The n-terminal domain of ikkgamma is required both for the binding of ikkalfa and ikkbeta and their assembly into a high-molecular-weight complex essential for activation SIGNOR-217436 0.929 NCOA1 protein Q15788 UNIPROT PGR protein P06401 UNIPROT up-regulates 9606 10449719 f miannu Progesterone receptor (pr) functions as a transcription factor that modulates the transcription of target genes in response to progesterone and other signals. The transcriptional activity of pr requires the involvement of coactivators such as steroid receptor coactivator-1 (src-1). SIGNOR-70149 0.674 CDK2 protein P24941 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 17361108 t gcesareni Our results demonstrate that cdk2 is capable of autophosphorylation at thr160. SIGNOR-153636 0.2 HIF1A protein Q16665 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 25750431 t svumbaca The results of this study show that the absence of HIFs in MPs has no impact on the resolution of inflammation in two sterile models of skeletal muscle regeneration SIGNOR-256236 0.343 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19114991 t lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity SIGNOR-182979 0.748 PSMA7 protein O14818 UNIPROT XBP1 protein P17861 UNIPROT down-regulates quantity by destabilization binding -1 19941857 t 1 miannu We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination. SIGNOR-239042 0.322 PPARG protein P37231 UNIPROT CPT1B protein Q92523 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15356291 f miannu Mutation analysis indicated that the MEF2 site contributed to the activation of the CPT1beta promoter by PPAR in C2C12 cells. The reporter construct containing the PPRE and the MEF2C site was synergistically activated by co-expression of PPAR, retinoid X receptor (RXR) and MEF2C in non-muscle cells. Moreover, protein-binding assays demonstrated that MEF2C and PPAR specifically bound to one another in vitro. Also for the synergistic activation of the CPT1beta gene promoter by MEF2C and PPARalpha-RXRalpha, a precise arrangement of its binding sites was essential. SIGNOR-254581 0.395 JAK3 protein P52333 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT unknown phosphorylation Tyr691 PKGTQADyAEVKFQ 9606 11733002 t lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. however, it is not clear whether y691 is capable of binding sap or a similar protein. Future studies will attempt to elucidate the signaling activities associated with y691 SIGNOR-112487 0.2 PRKACA protein P17612 UNIPROT NOLC1 protein Q14978 UNIPROT up-regulates phosphorylation Ser623 KGEKRASsPFRRVRE 9606 12167624 t gcesareni Here we demonstrate that protein kinase a (pka)-dependent phosphorylation of nopp140 at ser 627, together with c/ebpbeta, induces agp gene expression synergistically. SIGNOR-91186 0.312 EIF3C protein Q99613 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266398 0.931 STK3 protein Q13188 UNIPROT Mob1 proteinfamily SIGNOR-PF42 SIGNOR up-regulates phosphorylation 9606 21808241 t The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction. SIGNOR-269855 0.855 NARS2 protein Q96I59 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270463 0.8 NDUFB6 protein O95139 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 SIGNOR-262169 0.822 KIF17 protein Q9P2E2 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272530 0.7 EEF1A1P5 protein Q5VTE0 UNIPROT Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269555 0.8 MAPK1 protein P28482 UNIPROT LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Thr891 NSETSSDtPEMSLSA 10090 BTO:0000944 11581251 t lperfetto Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL. SIGNOR-249413 0.376 NANOGP8 protein Q6NSW7 UNIPROT BMP5 protein P22003 UNIPROT down-regulates quantity by repression transcriptional regulation 10900 BTO:0000667 23839044 f Luana Constitutive NanogP8 overexpression in adult L1 mice reduced CD34+α6+ and Lrig-1+ bulge stem cells, impaired keratinocyte migration, and repressed the expression of many stem cell-associated genes, including Bmp5, Fgfr2, Jmjd1a, and Jun. SIGNOR-266089 0.2 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257915 0.8 HACD proteinfamily SIGNOR-PF86 SIGNOR FASN protein P49327 UNIPROT up-regulates activity chemical activation 9606 18554506 t Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases, SIGNOR-267764 0.2 KCNJ10 protein P78508 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 24561201 t miannu KCNJ10 encodes Kir4.1, a member of the K+ channel family known as inwardly rectifying K+ (Kir) channels. Kir4.1 channels may comprise either Kir4.1 homomers or Kir4.1/Kir5.1 heteromers SIGNOR-269446 0.8 JUN protein P05412 UNIPROT SMAD4/JUN complex SIGNOR-C10 SIGNOR form complex binding 9606 9312063 t gcesareni Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter. SIGNOR-51110 0.663 TYRO3 protein Q06418 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr376 DRVKSTAyLSPQELE 9606 BTO:0000007 31230815 t done miannu TAM kinases phosphorylate MLKL to promote necroptosis. MLKL is then recruited to the plasma membrane, where TAM kinases phosphorylate MLKL at Tyr376 (Figure 5G, step 5), promoting its oligomerization and formation of membrane-rupturing pores that result in necrotic cell death (Figure 5G, step 6). SIGNOR-274120 0.2 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Ser328 ERALTEDsTQTSDTA -1 7836371 t gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. SIGNOR-247763 0.2 UHMK1 protein Q8TAS1 UNIPROT PIMREG protein Q9BSJ6 UNIPROT up-regulates phosphorylation Ser131 GAQKGSGsPTHSLSQ 9606 23419774 t lperfetto Cats is a substrate of kis and mapped the phosphorylation site to cats serine 131 (s131). Kis enhances the transcriptional repressor activity of cats SIGNOR-192702 0.2 P-TEFb complex SIGNOR-C238 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001545 19516275 f miannu Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) inhibits the positive transcription elongation factor b (P-TEFb), which is a key RNA polymerase II (Pol II) transcriptional regulator. In transfected cells, mutated NPM1 associated with, and sequestered, HEXIM1 in cytoplasm, resulting in higher transcription of RNA pol II target genes, among which were some positive regulators of cell-cycle progression such as cyclin D1 and anti-apoptotic proteins such as Mcl-1 SIGNOR-260137 0.7 RNF41 protein Q9H4P4 UNIPROT PRKN protein O60260 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 18541373 t miannu Here we further demonstrated that overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage-dependent and proteasome-dependent manner. More importantly, Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells, indicating Parkin is an Nrdp1 substrate. SIGNOR-272639 0.2 PDPK1 protein O15530 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-126069 0.501 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser813 DIYSRRLsQETGLEI 9606 10581361 t lperfetto Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function SIGNOR-72728 0.52 CDK9 protein P50750 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Ser211 VAQTPMPsEYQNMTV 9606 23603988 t lperfetto We showed that cdk9 phosphorylates pirh2 on ser-211 and thr-217 residues through their physical interaction. Phosphorylation of pirh2 renders it inactive and may contribute to p53-inhibition of transcriptional elongation of the hiv-1 ltr. SIGNOR-201923 0.472 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI up-regulates quantity precursor of 9606 31586547 t miannu The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG). SIGNOR-267056 0.8 MTA1 protein Q13330 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR up-regulates activity binding 10090 24089055 t lperfetto Here we provide genetic and biochemical evidence that metastasis-associated protein 1 (MTA1), a widely upregulated gene product in human cancers, is an integral component of the circadian molecular machinery. | The CLOCK-BMAL1 heterodimer activates MTA1 transcription through a conserved E-box element at its promoter. MTA1, in turn, interacts with and recruits CLOCK-BMAL1 at its own and CRY1 promoters and promotes their transcription. SIGNOR-253723 0.2 PRKG2 protein Q13237 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization SIGNOR-186943 0.2 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 14963330 t lperfetto Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program SIGNOR-178690 0.743 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexenyl]methyl]-1-piperazinyl]-N-[4-[[(2R)-4-(4-morpholinyl)-1-(phenylthio)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide chemical CHEBI:94128 ChEBI BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 23336025 t gcesareni Bcl-2 inhibitors physically antagonize their anti-apoptotic actions to create a synergistic effect. Numerous compounds have been specifically developed or identified as bcl-2 inhibitors. These compounds include abt-737 and abt-263, obatoclax, gossypol. SIGNOR-200460 0.8 ZWINT protein O95229 UNIPROT KNL1 complex complex SIGNOR-C363 SIGNOR form complex binding 27881301 t lperfetto KNL1C (known as Spc105 complex in S. cerevisiae) contains the KNL1 and ZWINT subunits. SIGNOR-265194 0.2 KAT2B protein Q92831 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR form complex binding 9606 21131905 t lperfetto Histone acetyltransferases (hats) gcn5 and pcaf (gcn5/pcaf) and cbp and p300 (cbp/p300) are transcription co-activators. SIGNOR-170276 0.768 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR SP1 protein P08047 UNIPROT up-regulates activity phosphorylation Ser59 GGQESQPsPLALLAA 10090 BTO:0000944 11598016 t gcesareni Mutation of Sp1 Ser59 abrogates the cyclin A€“CDK augmentation of Sp1-dependent transcriptional transactivation SIGNOR-248240 0.423 GCG protein P01275 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates 9606 23075495 f gcesareni On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz. SIGNOR-199205 0.2 UQCR11 protein O14957 UNIPROT Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 t lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits SIGNOR-262196 0.837 ceramide 1-phosphate(2-) smallmolecule CHEBI:84404 ChEBI PRKCA protein P17252 UNIPROT up-regulates activity chemical activation 9606 19948174 t miannu Here we demonstrate that C1P induces translocation of protein kinase C-alpha (PKC-alpha) from the soluble to the membrane fraction of bone marrow-derived macrophages. SIGNOR-268502 0.8 POLE4 protein Q9NR33 UNIPROT DNA polymerase epsilon complex SIGNOR-C377 SIGNOR form complex binding 9606 BTO:0000567 10801849 t lperfetto Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon. SIGNOR-265521 0.913 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1668 SPSYSPTsPSYSPTS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248808 0.849 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser238 QGTPLTCsPNVENRG 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276112 0.357 PRKCA protein P17252 UNIPROT GJB1 protein P08034 UNIPROT up-regulates activity phosphorylation Ser233 NPPSRKGsGFGHRLS 8390988 t lperfetto Phosphorylation of connexin-32 by protein kinase C prevents its proteolysis by mu-calpain and m-calpain. |In agreement with other authors (see Saez et al., 1990b), we have found that phosphorylation of connexin-32 by protein kinase A and protein kinase C occurs in serine residues, although we have detected trace amounts of phosphothreonine in connexin-32 phosphorylated by protein kinase C (results not shown). Indeed, Se233 has been shown to be the major phosphorylation site catalyzed by protein kinase A. However, Ser233, Ser239, and perhaps other serines are phosphorylated by protein kinase C (Saez et al., 1990b). SIGNOR-248920 0.369 TPX2 protein Q9ULW0 UNIPROT CLASP1 protein Q7Z460 UNIPROT up-regulates activity binding 9606 BTO:0000567 phosphorylation:Ser121;Ser125 PAQPQRRsLRLSAQK;QRRSLRLsAQKDLEQ 26240182 t lperfetto Phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a.|This suggests that TPX2 phosphorylation positively regulates the function of CLASP1.| This is in accord with a phosphoproteomics study that identified S121 and S125 as potential phosphorylation sites for Aurora A in mitotic HeLa cells SIGNOR-265090 0.477 ROCK2 protein O75116 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates phosphorylation Ser447 YHRSIRHsSIQE 9606 BTO:0000782 20697158 t miannu Carock2 phosphorylated irf4 at either of 2 distinct phosphorylation sites, s446 and s447 / rock2-mediated phosphorylation of irf4 regulated the synthesis of il-17 and il-21 and the differentiation of th17 cells. SIGNOR-167467 0.427 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 1303753 t gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. SIGNOR-16243 0.563 AKT1 protein P31749 UNIPROT PALLD protein Q8WX93 UNIPROT unknown phosphorylation Ser1118 VRRPRSRsRDSGDEN 9606 20471940 t llicata Akt1, but not akt2, phosphorylates palladin at ser507 in a domain that is critical for f-actin bundling. SIGNOR-252510 0.416 DNMT3A protein Q9Y6K1 UNIPROT DNMT1/DNMT3A complex SIGNOR-C42 SIGNOR form complex binding 9606 12145218 t miannu We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation SIGNOR-90842 0.774 ADORA2A protein P29274 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257151 0.266 DVL1 protein O14640 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 9606 27571105 t areggio Although there are other activators of PCP, Wnt5a can activate the PCP pathway by forming a complex with Fzd and Ror2 receptors, activating DVL, which in turn activates Rho-family small GTPases, including RhoA and Rac, and their downstream effectors, Rho-associated protein kinase (ROCK), the actin-binding protein, Filamin A and c-Jun N-terminal protein kinase (JNK) SIGNOR-258971 0.609 KATNA1 protein O75449 UNIPROT KATNB1 protein Q9BVA0 UNIPROT up-regulates activity binding 9606 BTO:0000567 10751153 t miannu In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer SIGNOR-267174 0.778 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1948 SPTSPGYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273036 0.556 phenformin chemical CHEBI:8064 ChEBI KCNJ8 protein Q15842 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000783 BTO:0001260 20188727 t lperfetto Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel |Phenformin but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). SIGNOR-262030 0.8 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-176370 0.818 CBLC protein Q9ULV8 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 12226085 t miannu In summary, we have shown that CBLC and AIP4 can interact and that these two E3 ligases could contribute to down-regulate EGFR signaling by ubiquitination.  SIGNOR-272605 0.763 AURKB protein Q96GD4 UNIPROT KIF4A protein O95239 UNIPROT up-regulates activity phosphorylation Thr799 PPKLRRRtFSLTEVR -1 28992084 t miannu Using in vitro kinase assays, we found that active AMPK and Aurora B phosphorylated KIF4A at Ser801 and Thr799 respectively in a time-dependent manner (Figure 5D). KIF4A is phosphoregulated by AMPK and Aurora B. Although AMPK phosphorylation increased the ATPase activity of KIF4A, Aurora B phosphorylation resulted in a stronger increase (Figure 5I), which might be consistent with the more powerful kinase function of Aurora B during mitosis. SIGNOR-265992 0.531 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 27126896 f Luana  Importantly, asparagine/glutamine pre-load only results in mTOR activation following amino acid stimulation (Fig. 5a), indicating that it is their exchange factor roles that elicit mTORC1 activation. SIGNOR-268017 0.8 MTA1 protein Q13330 UNIPROT MTA3 protein Q9BTC8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18719363 f miannu MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG. SIGNOR-254595 0.64 MYC protein P01106 UNIPROT MYCT1 protein Q8N699 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11909865 t miannu MT-MC1 is a widely expressed nuclear protein whose overexpression, unlike that of c-Myc targets reported previously, recapitulates multiple c-Myc phenotypes. These include promotion of apoptosis, alteration of morphology, enhancement of anchorage-independent growth, tumorigenic conversion, promotion of genomic instability, and inhibition of hematopoietic differentiation. The MT-MC1 promoter is a direct c-Myc target; it contains two consensus E-box elements, both of which bind c-Myc. SIGNOR-261736 0.302 TAOK1 protein Q7L7X3 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 BTO:0000007 9786855 t lperfetto The activation of and binding to MEK3 by TAO1 implicates TAO1 in the regulation of the p38-containing stress-responsive MAP kinase pathway SIGNOR-60818 0.56 CKM protein P06732 UNIPROT N-phosphocreatine smallmolecule CHEBI:17287 ChEBI up-regulates quantity chemical modification 9606 18502307 t miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. SIGNOR-265788 0.8 TRAF6 protein Q9Y4K3 UNIPROT TAB1 protein Q15750 UNIPROT up-regulates activity binding 9606 25290089 t lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205455 0.86 ARID1B protein Q8NFD5 UNIPROT Histone H2B proteinfamily SIGNOR-PF68 SIGNOR down-regulates activity ubiquitination -1 20086098 t miannu The immunopurified BAF250b E3 ubiquitin ligase was found to target histone H2B at lysine 120 for monoubiquitination in vitro.  SIGNOR-271442 0.2 CLASP2 protein O75122 UNIPROT CLIP2 protein Q9UDT6 UNIPROT up-regulates activity binding 9606 BTO:0000567 15631994 t lperfetto CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. SIGNOR-265093 0.607 FGF9 protein P31371 UNIPROT BMP2 protein P12643 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15780951 f FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1. gcesareni Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts. SIGNOR-134794 0.383 CDK5 protein Q00535 UNIPROT LMTK2 protein Q8IWU2 UNIPROT down-regulates phosphorylation 9606 12832520 t gcesareni Cprk displays catalytic activity in in vitro kinase assays and is itself phosphorylated by cdk5/p35. Cdk5/p35 inhibits cprk activity. SIGNOR-102717 0.511 ABL1 protein P00519 UNIPROT ATR protein Q13535 UNIPROT up-regulates phosphorylation Tyr310 FPFEAEAyRNIEPVY 9606 20798688 t lperfetto C-abl can phosphorylate atr on y291 and y310 and this phosphorylation appears to have a positive role in atr activation under genotoxic stress. SIGNOR-167636 0.583 PPP2R5C protein Q13362 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates binding 9606 16456541 t gcesareni B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk SIGNOR-144328 0.395 DAB2IP protein Q5VWQ8 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR down-regulates 9606 27858941 f miannu DAB2IP inactivation promotes tumor growth and survival, development, and proliferation of CSC, and resistance to chemo- and radiotherapy. It induces EMT, increases cell migration and invasion, and counteracts pro-apoptotic signaling. SIGNOR-254778 0.7 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI up-regulates quantity precursor of 9606 19524112 t miannu The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA. SIGNOR-267519 0.8 SMARCE1 protein Q969G3 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270720 0.741 Av/b8 integrin complex SIGNOR-C185 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269029 0.7 GDF5 protein P43026 UNIPROT Ossification phenotype SIGNOR-PH74 SIGNOR up-regulates 9606 21976273 f miannu Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. SIGNOR-252419 0.7 PTPN1 protein P18031 UNIPROT TRPV6 protein Q9H1D0 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000007 17197020 t llicata In HEK293 cells, transfected with the Ca2+ channel protein TRPV6, Ca2+ influx is increased and TRPV6 is tyrosine phosphorylated following addition of the tyrosine phosphatase inhibitor|PTP1B interacts with the N-terminal domain of TRPV6 within a region of amino acids 1-191 as shown by co-immunoprecipitation, bimolecular fluorescence complementation and the yeast 2-hybrid system. Point mutation of both tyrosines 161 and 162 in the TRPV6 protein abolishes the DMHV-effect on Ca2+ influx and tyrosine phosphorylation by Src. Single mutations of Y161 or Y162 shows that each of both tyrosines alone is sufficient for the DMHV-effect. We conclude that phosphorylation/dephosphorylation of tyrosines in position 161 and 162 is essential for regulation of Ca2+ influx through TRPV6 Ca2+ channels in HEK293 cells. SIGNOR-248433 0.615 SH2B2 protein O14492 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 10029 BTO:0000977 10854852 t lperfetto APS-mediated recruitment of c-Cbl to the insulin receptor led to rapid ubiquitination of the insulin receptor beta-subunit in CHO. T-APS but not in parental CHO.T cells. These results suggest that the function of APS is to facilitate coupling of the insulin receptor to c-Cbl in order to catalyse the ubiquitination of the receptor and initiation of internalisation or degradation. SIGNOR-78337 0.632 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 t MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction. SIGNOR-175841 0.846 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB4 protein Q9UN71 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265679 0.2 NDN protein Q99608 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000671 24349431 t lperfetto Deletion mapping demonstrated that the C-terminus of cystin and both termini of necdin are required for their mutual interaction. Speculating that these two proteins may function to regulate gene expression, we developed a luciferase reporter assay and observed that necdin strongly activated the Myc P1 promoter, and cystin did so more modestly. SIGNOR-253381 0.268 PRKCD protein Q05655 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity phosphorylation Ser405 KTQTPPVsPAPQPTE 10029 26490115 t Manara Together these findings demonstrate that phosphorylation of cortactin on S405 and S418 residues is required for its interaction with WAVE2 in MCP1-induced cytoskeleton remodeling, facilitating HASMC migration. In addition, the MCP1-induced cortactin phosphorylation is dependent on PLCβ3-mediated PKCδ activation SIGNOR-260889 0.248 MAPK8 protein P45983 UNIPROT JUND protein P17535 UNIPROT up-regulates phosphorylation Ser100 LGLLKLAsPELERLI 9606 22327296 t gcesareni Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase. SIGNOR-196038 0.789 RPS6KA5 protein O75582 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser40 GQGAPGPsLTGSPWP 9606 12421349 t The effect has been demonstrated using P07101-3 gcesareni Recombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax. studies on th from several species suggest that ser40 is the main site involved in direct activation of th SIGNOR-95491 0.343 LRFN5 protein Q96NI6 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 27225731 f miannu These results suggest that postsynaptic SALM5 promotes synapse development by trans-synaptically interacting with presynaptic LAR-RPTPs and is important for the regulation of excitatory synaptic strength. SIGNOR-264085 0.7 LRRK2 protein Q5S007 UNIPROT RAB10 protein P61026 UNIPROT down-regulates activity phosphorylation Thr73 AGQERFHtITTSYYR 9606 BTO:0000007 26824392 t Giulio To investigate whether the phosphorylation of Rab10 by LRRK2 is direct, we performed an in vitro kinase assay using recombinant components. Notably, we found that both wt and LRRK2-G2019S, but neither kinase inactive D1994A mutant nor small molecule-inhibited LRRK2, efficiently phosphorylated Rab10, proving a direct kinase-substrate relationship (Figure 2C). Furthermore, incubation of Rab10 with LRRK2 followed by tryptic digestion and MS analysis unambiguously identified T73 as the major phosphorylation site (Figure 2—figure supplement 1B)|In pathogenic conditions, in which LRRK2 is hyperactive, RabGTPases have strongly diminished affinities for GDIs. SIGNOR-261277 0.336 CD79B protein P40259 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268189 0.641 OXTR protein P30559 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257178 0.428 ENAH protein Q8N8S7 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 18508258 f miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. SIGNOR-268389 0.7 MAP1LC3C protein Q9BXW4 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001623 20921139 f lperfetto We assessed both conversion of LC3-I to its cleaved and lipidated form LC3-II and its translocation to autophagic structures, two steps in autophagosome formation SIGNOR-219399 0.7 AURKB protein Q96GD4 UNIPROT CPC complex SIGNOR-C554 SIGNOR form complex binding 9606 23175282 t miannu It is now known that the chromosomal passenger complex (CPC) is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin (also known as Dasra)5–7 (Figure 1A). SIGNOR-275426 0.857 IKBKB protein O14920 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway SIGNOR-252947 0.679 STAT5A protein P42229 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21261500 f miannu STAT5 binds directly to the promoter region and potently mediates repression of MEF2C, probably via HDAC recruitment. SIGNOR-254207 0.281 RBPJ protein Q06330 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 12361602 t apalma Notch is cleaved and translocates to the nucleus, where it activates a family of transcription factors, exemplified by Suppressor of Hairless and CBF/RJBk SIGNOR-255379 0.949 CDC20 protein Q12834 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 16896351 t lperfetto In addition to E2 enzymes, APC/C activity is also strictly dependent on one of several co-activator proteins that associate with APC/C during specific periods of the cell cycle. The best studied of these are Cdc20 and Cdh1 SIGNOR-252014 0.873 hexestrol chemical CHEBI:31669 ChEBI AKR1C2 protein P52895 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193300 0.8 CYP19A1 protein P11511 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification 9606 BTO:0000975 27702664 t lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively SIGNOR-268669 0.8 KATNB1 protein Q9BVA0 UNIPROT KATNA1 protein O75449 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 10751153 t miannu In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer SIGNOR-267173 0.778 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 11062067 t Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif. gcesareni A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) and p38 subs of map kinases, respectively. Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). SIGNOR-83721 0.733 okadaic acid chemical CHEBI:44658 ChEBI STK4 protein Q13043 UNIPROT up-regulates 9606 23493077 f gcesareni Okadaic acid has been frequently used to enhance the phosphorylation of mst1 and mst2 and to trigger the activation of the hippo pathway. SIGNOR-201554 0.8 MAPK14 protein Q16539 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser389 ARIQAAAsTPTNATA 9606 BTO:0000142 18451303 t gcesareni Here, we show that p38 mitogen-activated protein kinase (mapk) also inactivates gsk3beta by direct phosphorylation at its c terminus, and this inactivation can lead to an accumulation of beta-catenin. SIGNOR-178603 0.294 EGLN3 protein Q9H6Z9 UNIPROT PKM protein P14618 UNIPROT up-regulates activity hydroxylation Pro408 LAPITSDpTEATAVG 9606 BTO:0000567 21620138 t Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. SIGNOR-267477 0.447 CXCL1 protein P09341 UNIPROT GLI3 protein P10071 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16885213 f gcesareni The data suggest that smo is in fact the source of two signals relevant to the activation of gli: one involving g(i) and the other involving events at smo's c-tail independent of g(i). SIGNOR-148460 0.2 DNAH17 protein Q9UFH2 UNIPROT Cilium_movement phenotype SIGNOR-PH171 SIGNOR up-regulates 9606 BTO:0001277 31178125 f miannu Our study provides a comprehensive analysis of ODA heavy chain distribution in human spermatozoa and demonstrates the importance of DNAH17 (β-HC) in sperm flagellum structure and motility. We demonstrate that DNAH17 (β-HC) mutations are associated with a loss of ODAs and male infertility but not with PCD. SIGNOR-265549 0.7 MAPK8 protein P45983 UNIPROT PKMYT1 protein Q99640 UNIPROT up-regulates phosphorylation 9606 BTO:0001286 19204086 t The results showed that residues 140 to 205 of JNK1 have the ability to interact with Myt1. gcesareni A kinase assay using gst-myt1 revealed that active jnk1 or jnk3, but not jnk2, phosphorylated myt1 in vitro. SIGNOR-183899 0.342 E2F1 protein Q01094 UNIPROT NOX4 protein Q9NPH5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002195 18554521 f lperfetto Positive regulation of the NADPH oxidase NOX4 promoter in vascular smooth muscle cells by E2F SIGNOR-254134 0.2 SRC protein P12931 UNIPROT RACK1 protein P63244 UNIPROT up-regulates phosphorylation Tyr228 LNEGKHLyTLDGGDI 9606 12400005 t gcesareni We found that rack1 is a src substrate. Moreover, src activity is necessary for both the tyrosine phosphorylation of rack1 and the binding of rack1 to src's sh2 domain that occur following pkc activation. To identify the tyrosine(s) on rack1 that is phosphorylated by src, we generated and tested a series of rack1 mutants. We found that src phosphorylates rack1 on tyr 228 and/or tyr 246 SIGNOR-94796 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MEF2C protein Q06413 UNIPROT down-regulates activity phosphorylation Ser396 NIKSEPVsPPRDRTT BTO:0003166 16478538 t llicata Phosphorylation-facilitated sumoylation of MEF2C negatively regulates its transcriptional activity. | Intriguingly, we show that phosphorylation of S396 in MEF2C, a residue in close proximity to the major sumoylation site (K391) and known to be phosphorylated in vivo, enhances sumoylation of delta- N2-MEF2C in vitro. The S396A mutation reduces sumoylation of MEF2C in vivo and enhances the transcription activity of MEF2C in reporter assays. | CDK1/Cyclin B1 phosphorylated GST-MEF2C-ΔN2-WT to a greater extent than the MEF2C-ΔN2-S396A mutant, suggesting that Cdk1/Cyclin B1 can phosphorylate MEF2C at S396. SIGNOR-250719 0.369 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 BTO:0000150 21316371 t gcesareni In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943) SIGNOR-171907 0.347 PRKG2 protein Q13237 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity phosphorylation Ser712 SDKRRPPsAELYSNA 9606 BTO:0000498 29935031 t miannu PKG II inhibited PDGFRβ activation in gastric cancer via phosphorylating Ser712 of this RTK. SIGNOR-277401 0.275 EIF2AK2 protein P19525 UNIPROT NLRC4 inflammasome complex SIGNOR-C223 SIGNOR up-regulates activity binding 9606 BTO:0000007 22801494 t miannu Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. SIGNOR-263121 0.313 STK16 protein O75716 UNIPROT STK16 protein O75716 UNIPROT unknown phosphorylation Thr185 EGSRQALtLQDWAAQ -1 18184589 t Manara Indeed, our kinetic analysis of MPSK1 autophosphorylation showed that autophosphorylation is a slow process and that two of the three identified sites are largely buried in unphosphorylated MPSK1. However, two autophosphorylation sites are located in the P + 1 loop and phosphorylation at these locations might affect substrate recognition. SIGNOR-260803 0.2 sunitinib chemical CHEBI:38940 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 21423276 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-172908 0.8 TAC1 protein P20366 UNIPROT TACR2 protein P21452 UNIPROT up-regulates binding 9606 8925404 t gcesareni The mammalian tachykinins include substance p, neurokinin a and neurokinin b, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated nk1, nk2 and nk3, respectively. The interaction of tachykinin with its receptor activates gq, which in turn activates phospholipase c to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (ip3) and diacylglycerol (dag). SIGNOR-44773 0.87 FGF5 protein P12034 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8386828 t gcesareni Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2 SIGNOR-38995 0.701 codeine chemical CHEBI:16714 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258933 0.8 PRKACA protein P17612 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates activity phosphorylation Ser279 KVAERRSsPLLRRKD 9606 22865920 t lperfetto PKA/Cdk5-mediated phosphorylation of HDAC5 at Ser279 within the NLS promotes nuclear localization of HDAC5 and interaction with the nuclear corepressor complex SIGNOR-198658 0.2 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120204 0.321 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser326 PPKMWKTsPDPSPVS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252335 0.635 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser276 PLPSPTAsPNHTLAP 9606 BTO:0000142 15262992 t lperfetto Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd SIGNOR-126847 0.405 lipopolysaccharide smallmolecule CHEBI:16412 ChEBI TLR4 protein O00206 UNIPROT up-regulates activity chemical activation 10090 9851930 t The mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane. SIGNOR-252075 0.8 PLP1 protein P60201 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 26519753 f SimoneGraziosi Proteolipid protein (PLP) is a major component only in the CNS myelin of terrestrial species and is involved in compaction of the extracellular apposition. SIGNOR-269265 0.7 FBXW7 protein Q969H0 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity ubiquitination 9606 SIGNOR-C135 20852628 t gcesareni We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it. SIGNOR-243545 0.753 KDM5C protein P41229 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-264306 0.2 PP1 proteinfamily SIGNOR-PF54 SIGNOR CAD protein P27708 UNIPROT down-regulates activity dephosphorylation Ser1406 GAGGRRLsSFVTKGY -1 4092695 t lperfetto Cyclic AMP-dependent protein kinase phosphorylates two serine residues on the protein termed sites 1 and 2| Site 1: Arg-Leu-Ser(P)-Ser-Phe-Val-Thr-Lys Site 2: Ile-His-Arg-Ala-Ser(P)-Asp-Pro-Gly-Leu-Pro-Ala-Glu-Glu-Pro-Lys | Both phosphorylation and activation can be reversed using purified preparations of the catalytic subunits of protein phosphatases 1- and -2A, and inactivation also correlates better with dephosphorylation of site 1 rather than site 2. SIGNOR-264653 0.2 SYK protein P43405 UNIPROT LAT2 protein Q9GZY6 UNIPROT up-regulates activity phosphorylation Tyr136 EDDDANSyENVLICK 10090 BTO:0001930 14722116 t miannu Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases. SIGNOR-273576 0.576 nociceptin smallmolecule CHEBI:80266 ChEBI OPRL1 protein P41146 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257553 0.8 barium(2+) chemical CHEBI:37136 ChEBI KCNJ13 protein O60928 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9620703 t miannu Figure 4 shows the response of Kir7.1 to increasing [Ba2+]o. The EC50 for Ba2+ block was 1 mM (Figure 4C), independent of the type of cell in which the channel was expressed. Other known inward rectifier K+ channels are sensitive to inhibition at much lower concentrations SIGNOR-258925 0.8 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr485 GGLSDGPySNPYENS 12441334 t JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 SIGNOR-251353 0.805 PTCH1 protein Q13635 UNIPROT CDON/BOC/PTCH1 complex SIGNOR-C95 SIGNOR form complex binding 10090 21664576 t lperfetto Secreted Hedgehog (HH) ligands signal through the canonical receptor Patched (PTCH1). However, recent studies implicate three additional HH-binding, cell-surface proteins, GAS1, CDO, and BOC, as putative coreceptors for HH ligands. SIGNOR-209602 0.568 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr242 FFQQQMIyDSPPSRA 10090 10978177 t HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin SIGNOR-251310 0.492 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr317 PPTPGNTyQIPRTFP 9606 BTO:0000007 19881549 t lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis SIGNOR-236306 0.692 PLK1 protein P53350 UNIPROT RAD21 protein O60216 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser454 EPSRLQEsVMEASRT 9606 BTO:0000567 15737063 t lperfetto We suspected that the observed enhancement of Scc1's cleavability in the presence of Plk1 might be due to phosphorylation at two sites that are directly adjacent to the cleavage sites, Ser175 and Ser454, which we had found to be phosphorylated in mitosis in vivo (Table 1). We therefore mutated these two residues to alanine, thereby creating mutant Scc1-S175A/S454A (see Figure 1C), and tested the cleavability of this mutant in the absence or presence of Plk1 in vitro. |Scc1 phosphorylation is dispensable for cohesin dissociation from chromosomes in early mitosis but enhances the cleavability of Scc1 by separase. SIGNOR-275536 0.727 GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263776 0.7 GYPA protein P02724 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 t lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  SIGNOR-266018 0.37 MTOR protein P42345 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C3 21659604 t gcesareni The adaptor protein grb10 was identified as an mtorc1 substrate that mediates the phosphoinositide 3-kinase. SIGNOR-174071 0.422 HBEGF protein Q99075 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 14967450 t Heparin-binding EGF-like growth factor??is synthesized as a membrane-anchored mitogenic and chemotactic glycoprotein. gcesareni Ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4 SIGNOR-121977 0.759 DHX9 protein Q08211 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 11402034 f miannu These results support the proposal that both RHA and HAP95 facilitated the nuclear export of unspliced, CTE-containing mRNA in human cells. we have extended this earlier study by mapping the functional domains of HAP95 and providing strong evidence for a direct role of HAP95 in RHA-mediated nuclear export of CTE-containing mRNA. SIGNOR-260948 0.7 SRC protein P12931 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Tyr88 KGSLPEFyYRPPRPP 9606 BTO:0000150 17254967 t lperfetto Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27 SIGNOR-152835 0.51 NR2F2 protein P24468 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 10900149 t lperfetto Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site SIGNOR-79446 0.285 ISCU protein Q9H1K1 UNIPROT Mitochondrial Fe-S Cluster Assembly Complex complex SIGNOR-C276 SIGNOR form complex binding -1 27519411 t lperfetto As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry. SIGNOR-262128 0.721 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK2 protein P24941 UNIPROT down-regulates activity chemical inhibition -1 29901072 t miannu AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9. SIGNOR-262219 0.8 PRDM1 protein O75626 UNIPROT PAX5 protein Q02548 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12052884 f miannu Blimp-1-dependent repression of pax-5 is required for differentiation of b cells to immunoglobulin m-secreting plasma cells SIGNOR-89032 0.516 WWTR1 protein Q9GZV5 UNIPROT TEAD3 protein Q99594 UNIPROT up-regulates binding 9606 23431053 t YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death. gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14. SIGNOR-201415 0.686 SMC4 protein Q9NTJ3 UNIPROT Condensin I complex SIGNOR-C341 SIGNOR form complex binding 9606 32445620 t miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263904 0.935 LINC complex complex SIGNOR-C303 SIGNOR Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 24481844 f lperfetto The extensive covalent and non-covalent attachments as well as the binding avidity between three KASH domains with three SUN domains are thought to enable the LINC complex to transmit force between the cytoskeleton and the nucleoskeleton SIGNOR-263293 0.7 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17960585 f miannu Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells. SIGNOR-260425 0.477 TFDP1 protein Q14186 UNIPROT DHFR protein P00374 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253860 0.415 USP9X protein Q93008 UNIPROT RPS27A protein P62979 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270826 0.483 BACE2 protein Q9Y5Z0 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe634 VHHQKLVfFAEDVGS 9606 10931940 t lperfetto BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Figure 6 Preferred BACE1 and BACE2 cleavage sites. (A) Sequence of APP indicating α- and β-cleavage sites, BACE1- and BACE2-cleavage sites, and the location of mutations analyzed here. APP numbering is that of the 770-aa isoform. SIGNOR-261773 0.56 AP3B2 protein Q13367 UNIPROT Neuronal AP-3 complex SIGNOR-C445 SIGNOR form complex binding 9606 BTO:0000938 19497727 t miannu Mammals contain more than one AP-3 complex owing to the existence of pairs of genes encoding β3, μ3, and σ3 subunits (A and B isoforms). While both σ3A and σ3B are expressed ubiquitously and seem to be functionally equivalent, the B isoforms of β3 and μ3 display rather restricted expression patterns, mostly in cells of neuronal origin. This has led to the notion of the existence of two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising δ, β3A, μ3A, and σ3(A or B) subunits, and a brain-specific AP-3 complex containing δ, β3B, μ3B, and σ3(A or B) SIGNOR-268521 0.648 PRLHR protein P49683 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256837 0.281 beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of -1 30553771 t PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species SIGNOR-267274 0.8 ETS1 protein P14921 UNIPROT MMP9 protein P14780 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22270366 f miannu VEGF-induced MMP-9 and MMP-13 promoter activities were down-regulated in ETS-1 siRNA-transfected cells. it is hypothesized that the activation of PI3K/AKT and p38 MAPK by VEGF results in ETS-1 gene expression, which activates MMP-9 and MMP-13, leading to the invasion and scattering of SKOV-3 cells. SIGNOR-254083 0.385 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Thr269 GGKRSRLtPVSPESS 9606 BTO:0000551 20974803 t lperfetto Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis. SIGNOR-216936 0.355 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BAG3 protein O95817 UNIPROT up-regulates activity phosphorylation Ser289 RSSTPLHsPSPIRVH 9606 BTO:0000016 27659916 t miannu ERK-dependent phosphorylation of BIS following H2O2 treatment. SIGNOR-274070 0.2 CREB5 protein Q02930 UNIPROT DGKG protein P49619 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253804 0.2 RUNX2/EP300 complex SIGNOR-C211 SIGNOR BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002648 12697832 f Giulio Giuliani In agreement with our studies in ROS 17/2.8 cells, coexpression of p300 and Runx2/Cbfa1 resulted in marked enhancement of the OC promoter activity, further indicating that both factors cooperate to stimulate this promoter. SIGNOR-255420 0.434 PAFAH1B1 protein P43034 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity binding 10090 BTO:0000938 11163259 t miannu We demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL. LIS1 is required for the proper distribution of NUDEL and cellular components regulated by CDHC function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex SIGNOR-252157 0.838 NHS protein Q6T4R5 UNIPROT WRC complex complex SIGNOR-C191 SIGNOR up-regulates activity relocalization 9606 20332100 t miannu Excessive cell spreading and lamellipod extension as a result of NHS knockdown is likely to be a result of loss of WAVE complex regulation, leading to overactive WAVE activity or a dysregulation of nascent focal adhesions in lamellipodia.WAVE and NHS protein partners Abi1 and HSPC300, and the p34 subunit of the Arp2/3 complex, consistently localized at the edges of cells treated with NHS siRNA, independent of EGF stimulation and WAVE complex activation. These data show that localization of Abi1 and HSPC300 was altered in the absence of NHS. SIGNOR-253577 0.2 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates 10090 10564272 f lperfetto We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2 SIGNOR-235622 0.628 CAMK2G protein Q13555 UNIPROT TH protein P07101 UNIPROT up-regulates activity phosphorylation Ser19 KGFRRAVsELDAKQA 1680128 t llicata  In both isoforms, Ser-40 was found to be phosphorylated by PKA, and Ser-19 and Ser-40 were found to be phosphorylated by CaM-PK II. The putative phosphorylation site generated by alternative splicing (Ser-31) was phosphorylated specifically by CaM-PK II in TH-2 only. | Unlike TH-1, phosphorylation of TH-2 by CaM-PK II resulted in an increase of the Ki value for dopamine. SIGNOR-250709 0.338 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273040 0.556 SETDB2 protein Q96T68 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity methylation Lys 10 RTKQTARkSTGGKAP 9606 BTO:0000007 20404330 t miannu Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression. SIGNOR-263896 0.2 SRC protein P12931 UNIPROT ANXA1 protein P04083 UNIPROT unknown phosphorylation Thr216 AGERRKGtDVNVFNT 9606 24103589 t lperfetto Location of sites in human lipocortin i that are phosphorylated by protein tyrosine kinases and protein kinases a and cthe primary site of phosphorylation by protein kinase c was also near the amino terminus at ser-27. The major site of phosphorylation by adenosine cyclic 3',5'-phosphate dependent protein kinase was on the carboxy-terminal half of the molecule at thr-216 SIGNOR-202800 0.398 CDK1 protein P06493 UNIPROT NDUFB6 protein O95139 UNIPROT up-regulates activity phosphorylation Ser29 WLKDQELsPREPVLP 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275591 0.2 SRF protein P11831 UNIPROT IL6 protein P05231 UNIPROT up-regulates 9606 22225874 t FFerrentino Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy. SIGNOR-255966 0.285 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Thr417 SLPQATVtPPRKEER 9606 BTO:0000680;BTO:0001573;BTO:0001286 SIGNOR-C17 14551205 t lperfetto Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex SIGNOR-118584 0.502 CALM2 protein P0DP24 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates binding 9606 11796223 t miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-266327 0.598 DNA polymerase gamma complex SIGNOR-C378 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates -1 19837034 f lperfetto DNA Pol gamma, in contrast to the many nuclear DNA polymerases (DNAPs) that have specialized functions, is solely responsible for DNA replication and repair in mitochondria.  SIGNOR-265720 0.7 CTH protein P32929 UNIPROT L-cysteine zwitterion smallmolecule CHEBI:35235 ChEBI up-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. SIGNOR-275818 0.8 DERA protein Q9Y315 UNIPROT 2-deoxy-D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:62877 ChEBI down-regulates quantity chemical modification 9606 25229427 t miannu Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase. SIGNOR-267097 0.8 ATR protein Q13535 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser345 LVQGISFsQPTCPDH 9606 15775976 t gcesareni Atr activation typically leads to chk1 phosphorylation and activation. In response to genotoxic stress, chk1 is phosphorylated on serines 317 (s317) and 345 (s345) by the ataxia-telangiectasia-related (atr) protein kinase. SIGNOR-134716 0.923 FOXC1 protein Q12948 UNIPROT SOX4 protein Q06945 UNIPROT up-regulates quantity by expression transcriptional regulation 31650548 f lperfetto Therefore, FOXC1 is strongly suggested as a pro-metastatic gene in CRC by transcriptionally activating MMP10, SOX4 and SOX15 SIGNOR-275917 0.325 APOB protein P04114 UNIPROT LDL_assembly phenotype SIGNOR-PH63 SIGNOR up-regulates 9606 23721961 f miannu Apolipoprotein B is a structural protein that is an integral component of chylomicrons, as well as very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) particles. SIGNOR-252116 0.7 MEF2A protein Q02078 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15728583 t lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation SIGNOR-238748 0.362 ATR protein Q13535 UNIPROT XPA protein P23025 UNIPROT up-regulates phosphorylation Ser196 RSLEVWGsQEALEEA 9606 16540648 t miannu Atr was the major kinase responsible for the cellular phosphorylation of xpa following uv irradiation / we propose that the phosphorylation of xpa by atr checkpoint may positively regulate ner activity and thus may facilitate the cells to recover from ner-related dna damages. SIGNOR-145190 0.505 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 10090 BTO:0000944 18042541 t gcesareni Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural subunit (A), catalytic subunit (C), and a variable regulatory subunit (B). SIGNOR-243530 0.671 GSK3B protein P49841 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates activity phosphorylation Ser163 PDKQFLIsPPASPPV 10090 BTO:0000165 12063245 t lperfetto Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. SIGNOR-249359 0.497 KLF1 protein Q13351 UNIPROT KLF8 protein O95600 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 18687676 t Luana Here we report that Klf8 is repressed by Klf3 in vivo and is up-regulated by Klf1. Transcript analysis indicates that Klf8 has two promoters, both containing multiple CACCC elements. Transactivation assays and chromatin immunoprecipitation experiments indicate that Klf3 represses Klf8 directly and that Klf1 activates Klf8 directly.  SIGNOR-266050 0.253 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK. SIGNOR-252079 0.2 VWF protein P04275 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 t lperfetto Many studies have contributed to shed light on the importance of von Willebrand factor (VWF) interaction with its platelet receptors, glycoprotein (GP) Ib-IX-V and αIIbβ3 integrin, in promoting primary platelet adhesion and aggregation following vessel injury SIGNOR-261853 0.675 SFPQ protein P23246 UNIPROT NONO/SFPQ complex SIGNOR-C62 SIGNOR form complex binding 9606 9756848 t miannu We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i SIGNOR-60560 0.698 PRKAA1 protein Q13131 UNIPROT TET2 protein Q6N021 UNIPROT up-regulates quantity by stabilization phosphorylation Ser99 GGIKRTVsEPSLSGLL 9606 BTO:0001025 30022161 t We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo SIGNOR-256134 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFB6 protein O95139 UNIPROT up-regulates activity phosphorylation Ser29 WLKDQELsPREPVLP 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275599 0.251 DOK1 protein Q99704 UNIPROT A3/b1 integrin complex SIGNOR-C161 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257672 0.321 diazepam chemical CHEBI:49575 ChEBI GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t brain lperfetto The traditional BZ site agonists (GABA-enhancing CNS depressants such as diazepam) are active on the GABAA-Rs containing a gamma2 subunit (Pritchett et al., 1989), a beta subunit, and one of the alpha subunits, alpha1, 2, 3, or 5. SIGNOR-263797 0.8 CDK1 protein P06493 UNIPROT USP24 protein Q9UPU5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1616 NSHSPAGsAAISQQD 9606 BTO:0000018 27991932 t lperfetto Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. SIGNOR-275605 0.2 GRIPAP1 protein Q4V328 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates activity binding 9606 BTO:0002181 17761173 t Giulio We investigated signal transduction pathways that might lie downstream of GRASP-1 and found that GRASP-1 potently activates JNK pathway signaling, with no effect on ERK signaling. Such JNK pathway activating activity requires binding of GRASP-1 to both JNK and the upstream JNK pathway activator MEKK-1. SIGNOR-260607 0.317 ANKRD11 protein Q6UB99 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 29274743 t miannu Ankrd11 knockdown decreases the levels of bdnf and Trkb mRNAs. Next, we examine whether ANKRD11 accesses the Trkb promoter in cortical neurons. We performed the chromatin immunoprecipitation assay (ChIP) using an ANKRD11 antibody followed by PCR to amplify the Trkb promoter region. We found that ANKRD11 binds to the Trkb promoter (Fig. 6E). As expected, the level of ANKRD11 binding was decreased in the Ankrd11 knockdown condition. SIGNOR-266731 0.2 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Thr300 TPVVSVAtPTLPGQG 9606 9858528 t The effect has been demonstrated using Q06413-3 lperfetto Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain SIGNOR-62796 0.683 MAPK3 protein P27361 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 19282669 t lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-184573 0.582 LCK protein P06239 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT unknown phosphorylation Tyr691 PKGTQADyAEVKFQ 9606 11733002 t lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. however, it is not clear whether y691 is capable of binding sap or a similar protein. Future studies will attempt to elucidate the signaling activities associated with y691 SIGNOR-112499 0.262 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203512 0.769 WNT11 protein O96014 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131637 0.566 JAK3 protein P52333 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 9606 18250158 t gcesareni For these assays, coexpression of wt jak3 with stat5a was found to result in tyrosine phosphorylation of stat5a (lane 2) mediated by jak3, since stat5a coexpressed with the kinase-inactive k855a mutant form of jak3 was not tyrosine phosphorylated. SIGNOR-160672 0.849 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK 9606 16049944 t lperfetto Zap-70 is modified by auto-phosphorylation of various tyrosine residues and is activated by specific phosphorylation of the tyrosine residue y-493 SIGNOR-139098 0.2 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. SIGNOR-252868 0.756 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS -1 7657660 t lperfetto Stat1 was phosphorylated at tyr 701 in jak immune complex kinase reaction. The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-g, They become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases. SIGNOR-30905 0.782 CSNK2A2 protein P19784 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Ser289 PPQDQESsPIENDSS 9606 BTO:0000776 7678037 t llicata These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells. SIGNOR-251012 0.312 CCL25 protein O15444 UNIPROT CCR9 protein P51686 UNIPROT up-regulates binding 9606 11159507 t gcesareni Ccr9 is a specific receptor for the beta-chemokine teck/ccl25. SIGNOR-104902 0.798 mTORC1 complex SIGNOR-C3 SIGNOR ATP6V1A protein P38606 UNIPROT up-regulates quantity by expression 10090 21804531 f Giorgia These data suggested that V-ATPase mRNA levels were upregulated by mTORC1 through a transcriptional mechanism. Tfeb is required for mTORC1-induced V-ATPase expression. SIGNOR-260636 0.261 LTK protein P29376 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9223670 t gcesareni Recently, we demonstrated that ltk utilizes shc and irs-1 as two major substrates and while both equally activate the ras pathway, only irs-1 suppresses apoptosis of hematopoietic cells. SIGNOR-49531 0.319 cabazitaxel chemical CHEBI:63584 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates activity chemical inhibition 9606 21770474 t miannu Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization SIGNOR-259445 0.8 CAV1 protein Q03135 UNIPROT HMGA1 protein P17096 UNIPROT up-regulates activity relocalization 9606 22706202 t miannu CAV1 was shown to stimulate GLUT3 transcription via an HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization. SIGNOR-254428 0.268 dexamethasone chemical CHEBI:41879 ChEBI SCNN1A protein P37088 UNIPROT up-regulates 9606 BTO:0000018 10722699 f Regulation of expression miannu Dexamethasone induces α-ENaCmRNA expression in lung epithelial A549 cells SIGNOR-251945 0.8 PTPRB protein P23467 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates dephosphorylation 9606 12840032 t inferred from 70% of family members gcesareni When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well SIGNOR-269911 0.2 TP53 protein P04637 UNIPROT G6PD protein P11413 UNIPROT down-regulates activity binding 9606 BTO:0001938;BTO:0001109 21336310 t miannu The p53 protein binds to glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the PPP, and prevents the formation of the active dimer. SIGNOR-267468 0.57 PRKAA1 protein Q13131 UNIPROT ACACA protein Q13085 UNIPROT down-regulates activity phosphorylation Ser1201 IPTLNRMsFSSNLNH 10116 7907095 t miannu We have isolated and purified from rat livers a novel kinase that phosphorylates and inactivates the carboxylase Ser1200 isphosphorylated by both CAMP-dependent protein kinase and AMP-activated protein kinase SIGNOR-250400 0.688 Caspase 8 complex complex SIGNOR-C231 SIGNOR BID protein P55957 UNIPROT up-regulates activity cleavage Asp60 GYDELQTdGNRSSHS 9606 BTO:0000093 9727492 t amattioni Caspase-8 cleaves bid at aspartic acid residue 60 (asp60) cleavage of bid by casp8 releases its potent proapoptotic activity SIGNOR-256443 0.875 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser299 KMAFRAKsKSCHDLS -1 9677319 t lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. SIGNOR-249008 0.292 NCBP1 protein Q09161 UNIPROT IRF8 protein Q02556 UNIPROT up-regulates activity binding 9606 BTO:0001413 11483597 t miannu we found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP. SIGNOR-222939 0.2 NR3C1 protein P04150 UNIPROT NR3C2 protein P08235 UNIPROT up-regulates 9606 11154266 f lperfetto These results indicate that functional interactions between the glucocorticoid and mineralocorticoid receptors in activating specific gene transcription are probably more complex than has been previously appreciated. SIGNOR-85987 0.523 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation 9606 16082221 t gcesareni Atm directly and indirectly induces mdm2 and mdmx phosphorylation, resulting in decreased activity and stability of these proteins. We recently provided a mechanism for the reduced stability of mdm2 and mdmx by showing that atm-dependent phosphorylation lowers their affinity for the deubiquitinating enzyme hausp. SIGNOR-139403 0.725 TPO protein P07202 UNIPROT 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI up-regulates quantity chemical modification 9606 16098474 t scontino TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. SIGNOR-266957 0.8 STK38 protein Q15208 UNIPROT RAB3IP protein Q96QF0 UNIPROT up-regulates activity phosphorylation Ser288 KGHTRNKsTSSAMSG 10090 BTO:0000142 22445341 t miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. SIGNOR-263036 0.374 RPS6KA4 protein O75676 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation 9606 11909979 t gcesareni Msk1 and msk2 directly phosphorilate and activate transcription factors such as creb1, atf1. SIGNOR-116252 0.599 NR1D1 protein P20393 UNIPROT OPHN1 protein O60890 UNIPROT up-regulates activity binding 9606 BTO:0000132 35267019 t miannu Rev-erbα regulates OPHN-1-mediated RhoA/ERM signalling in platelets., The results of the co-immunoprecipitation revealed that Rev-erbα coimmunoprecipitated with OPHN-1 in both mouse and human platelets and this interaction significantly increased upon stimulation with agonist U46619. SIGNOR-268428 0.2 HNF1A protein P20823 UNIPROT UGT1A9 protein O60656 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000195 15044625 t Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter. SIGNOR-253973 0.269 PLK1 protein P53350 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity phosphorylation Thr466 REAWRIFtPLLHQIE 9606 BTO:0000007 29138396 t lperfetto We find that Plk1 interacts with and directly phosphorylates glucose-6-phosphate dehydrogenase (G6PD). By activating G6PD through promoting the formation of its active dimer, Plk1 increases PPP flux and directs glucose to the synthesis of macromolecules.|the kinase domain of Plk1 phosphorylates T406, T466 of G6PD SIGNOR-267581 0.353 PRKCZ protein Q05513 UNIPROT YWHAB protein P31946 UNIPROT down-regulates activity phosphorylation Thr143 SGDNKQTtVSNSQQA 9534 BTO:0004055 10620507 t lperfetto Our results with the 14-3-3 mutants indirectly imply a new phosphorylation site, 130Ser (and to a lesser extent 141Thr), in 14-3-3b that regulates the association}dissociation of 14-3-3b and PKC-f. SIGNOR-249035 0.376 RAB6A protein P20340 UNIPROT VPS13B protein Q7Z7G8 UNIPROT down-regulates activity binding 9606 BTO:0000007 25492866 t miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 Golgi Localization Is Mediated by Active RAB6 . COH1 Interacts with All Three Mammalian RAB6 Homologues SIGNOR-269203 0.38 TLR4 protein O00206 UNIPROT TIRAP protein P58753 UNIPROT up-regulates activity binding 9606 BTO:0000007 11544529 t gcesareni Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. SIGNOR-252064 0.771 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273069 0.635 TIMM9 protein Q9Y5J7 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 t lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). SIGNOR-267704 0.568 GATA1 protein P15976 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity relocalization 9606 BTO:0000150 25726523 t lperfetto GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. SIGNOR-275664 0.531 GATA1 protein P15976 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates activity relocalization 9606 BTO:0000150 25726523 t lperfetto GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. SIGNOR-275665 0.567 FGR protein P09769 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity phosphorylation Tyr394 LNTIGLIyEKISLPK 9606 BTO:0002181 28618271 t miannu The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.  SIGNOR-276722 0.2 CHUK protein O15111 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 15808510 t gcesareni Ikkalpha phosphorylates eralpha, aib1/src-3, and histone h3. SIGNOR-135050 0.404 YY1 protein P25490 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 8266081 t miannu Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc.Yin-Yang-1 (YY1) regulates the transcription of many genes, including the oncogenes c-fos and c-myc. Depending on the context, YY1 acts as a transcriptional repressor, a transcriptional activator, or a transcriptional initiator. In cotransfections, c-Myc inhibits both the repressor and the activator functions of YY1, which suggests that one way c-Myc acts is by modulating the activity of YY1. SIGNOR-268794 0.56 MPG protein P29372 UNIPROT STK36 protein Q9NRP7 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 25278022 t miannu  Here, we show that MID1 catalyzes the ubiquitination and proteasomal cleavage of the GLI3 regulator Fu. SIGNOR-272466 0.2 PFKFB3 protein Q16875 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI down-regulates quantity chemical modification -1 9404080 t A full-length cDNA, which encodes a human placental fructose-6-phosphate,2-kinase/ fructose-2,6-bisphosphatase, was constructed and expressed in¬†Escherichia coli. [...]The expressed enzyme was bifunctional with¬†Vmax¬†values of 142 and 0.2 milliunits/mg for the kinase and phosphatase activities, respectively. SIGNOR-267271 0.8 ASIP protein P42127 UNIPROT MC5R protein P33032 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268713 0.514 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR SALL4 protein Q9UJQ4 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269252 0.734 CCL2 protein P13500 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 f miannu High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity. SIGNOR-261027 0.7 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. SIGNOR-266501 0.8 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of 9606 30616754 t lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle SIGNOR-267588 0.8 suprofen chemical CHEBI:9362 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001061 18667313 t Luana Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2.  SIGNOR-257809 0.8 ZNRF3 protein Q9ULT6 UNIPROT LRP6 protein O75581 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22575959 t Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. SIGNOR-260112 0.642 CASP7 protein P55210 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261746 0.323 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser43 PAMLHLPsEQGAPET 9606 SIGNOR-C14 12657630 t IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376|Thus far, we have no compelling evidence that inducible phosphorylation of these IKKgamma domains is important for their assigned functions. SIGNOR-251287 0.962 TTL protein Q8NG68 UNIPROT TUBA1A protein Q71U36 UNIPROT down-regulates tyrosination 9606 22020298 t miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization SIGNOR-176912 0.513 SRGAP3 protein O43295 UNIPROT RAC1 protein P63000 UNIPROT down-regulates 9606 12447388 f miannu Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo. SIGNOR-95918 0.547 IKK-complex complex SIGNOR-C14 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 23332762 t lperfetto Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation. SIGNOR-216399 0.266 PRKCB protein P05771 UNIPROT STXBP1 protein P61764 UNIPROT unknown phosphorylation Ser306 VSQEVTRsLKDFSSS -1 12519779 t lperfetto Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation. SIGNOR-249183 0.406 D-serine smallmolecule CHEBI:16523 ChEBI NMDA receptor_2D complex SIGNOR-C350 SIGNOR up-regulates activity chemical activation 9606 BTO:0002609 12393813 t lperfetto D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically SIGNOR-268280 0.8 MAP2K7 protein O14733 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 9890973 t Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif gcesareni Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)these results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway. SIGNOR-63972 0.564 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser262 TFRPRSSsNASSVST 10090 10217147 t Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. SIGNOR-252862 0.908 GRIA4 protein P48058 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 30825796 f miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses SIGNOR-264614 0.7 GRIK4 protein Q16099 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264345 0.7 BMPR1A protein P36894 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates binding 9606 10712517 t gcesareni Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors SIGNOR-75649 0.475 IL6ST protein P40189 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 16306329 f mrosina Upon formation of the IL-6/IL-6Ralpha/gp130 hexameric signaling complex, two distinct signaling pathways are activated: 1) Janus kinase (JAK)/signal transducers and activator of transcription (STAT) and 2) the Src homology 2-containing tyrosine phosphatase (SHP-2)/extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathways SIGNOR-255022 0.281 MAPK1 protein P28482 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr201 DIPEKPKtPQQLWYT 9606 11741541 t lperfetto Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna SIGNOR-112809 0.402 GNAL protein P38405 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR up-regulates activity binding 9606 BTO:0004032 21303898 t miannu D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum. SIGNOR-267852 0.628 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser138 MEDLTNVsSLLNMER 9606 25670858 t lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. SIGNOR-265228 0.571 ROCK1 protein Q13464 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates phosphorylation Ser1150 LERGRKVsIVSKPVL 9606 BTO:0000887;BTO:0001260 19103606 t gcesareni Rho-kinase, an effector of rhoa, phosphorylated p190a rhogap at ser(1150) and attenuated p190a rhogap activity in cos7 cells. SIGNOR-182849 0.424 GNAI1 protein P63096 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity binding 10090 BTO:0000944 11099498 t These findings indicate that both G alpha(i) and G beta gamma stimulate Rac and Cdc42 pathways with lysophosphatidic acid-induced cell spreading on fibronectin SIGNOR-256530 0.447 BCL2 protein P10415 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates 9606 14585074 f amattioni Bcl- confers protection to apoptosis by interference with bax/bak-mediated release of the pro-apoptotic mitochodrial factors smac/diablo and htra2/omi SIGNOR-88885 0.471 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 t lperfetto In this study, we showed that mad1 is a substrate of p90 ribosomal kinase (rsk) and p70 s6 kinase (s6k). Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway SIGNOR-252811 0.2 RPS6KB1 protein P23443 UNIPROT RPS6 protein P62753 UNIPROT up-regulates activity phosphorylation Ser235 IAKRRRLsSLRASTS 10090 15809305 t lperfetto A knockin mouse carrying mutations at all phosphorylation sites in the primary s6k substrate, ribosomal protein s6 (rps6), has provided insight into the physiological role of this protein phosphorylation event. Of the many known substrates of s6k1, it is rps6 that has been shown to be directly involved, via its phosphorylation, in controlling cell size. SIGNOR-135172 0.936 SIAH1 protein Q8IUQ4 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20940030 t gcesareni The overexpression of siah1 causes the re-localization of notch from the cell surface to the cytoplasm and to the nucleus, which is indicative of notch activation SIGNOR-168460 0.263 CAMK2A protein Q9UQM7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation Ser240 SDQQLNQsMDTGSPA 9606 SIGNOR-C8 11027280 t gcesareni Smad2 is a target substrate for cam kinase ii in vitro at serine-110, -240, and -260. furthermore, cam kinase ii blocked nuclear accumulation of a smad2 and induced smad2-smad4 hetero-oligomerization independently of tgfbeta receptor activation, while preventing tgfbeta-dependent smad2-smad3 interactions. SIGNOR-82970 0.53 RPS6KB1 protein P23443 UNIPROT TARBP2 protein Q15633 UNIPROT up-regulates activity phosphorylation Ser286 LRSCSLGsLGALGPA -1 27407113 t miannu We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells.  SIGNOR-274068 0.328 LYN protein P07948 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr771 IGTAEPDyGALYEGR -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249381 0.642 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 21159646 t gcesareni In comparison, in the same assay conditions, the previously reported mps1 inhibitor sp600125 (13) was 10-fold less potent than nms-p715 on mps1 and, in addition, it was highly unspecific, being more active on at least 12 kinases including mitotic kinases. SIGNOR-170611 0.8 PPM1D protein O15297 UNIPROT UNG protein P13051 UNIPROT down-regulates activity dephosphorylation 9606 15327777 t miannu PPM1D dephosphorylation of UNG2 is correlated with reduced UNG2 activity on uracil-containing templates.|This result suggests that PPM1D specifically inhibits UNG2 and not other uracil DNA glycosylases. SIGNOR-277156 0.385 LCK protein P06239 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity phosphorylation Tyr394 LNTIGLIyEKISLPK 9606 BTO:0002181 28618271 t miannu The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.  SIGNOR-276723 0.2 azelastine chemical CHEBI:2950 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 21381763 t Luana Azelastine was used as a standard, with affinities (pKi) for H1 and H3 8.9 and 6.8, respectively.  SIGNOR-257894 0.8 PLAG1 protein Q6DJT9 UNIPROT IGF2 protein P01344 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14695992 f miannu Plag1 has been shown be a transcriptional activator of igf2 SIGNOR-120363 0.427 MAFA protein Q8NHW3 UNIPROT SLC2A2 protein P11168 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17149590 f miannu the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. SIGNOR-254565 0.38 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation 10090 8387505 t lperfetto The pp90rsk phosphothreonine content paralleled the ERK1 activity more closely than the phosphoserine level. These results provide compelling evidence that in fibroblasts and PC12 cells ERK1 plays a direct role in the phosphorylation of pp90rsk and that pp90rsk represents a physiologically relevant substrate of extracellular-regulated kinases SIGNOR-38999 0.707 PAK1 protein Q13153 UNIPROT NET1 protein Q7Z628 UNIPROT down-regulates activity phosphorylation Ser152 PTPAKRRsSALWSEM -1 15684429 t miannu In this work we show that the Rac/Cdc42hs-regulated protein kinase PAK1 down-regulates the activity of the RhoA-specific guanine nucleotide exchange factor NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues down-regulates the activity of NET1 as an exchange factor in vitro and its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody that recognizes NET1 phosphorylated on serine 152, we show that PAK1 phosphorylates NET1 on this site in cells and that Rac1 stimulates serine 152 phosphorylation in a PAK1-dependent manner. SIGNOR-263017 0.251 POU4F1 protein Q01851 UNIPROT SCN9A protein Q15858 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000931 24493753 f miannu In neuroblastoma ND7 cells, a nuclear interaction between the developmentally regulated transcription factor Brn-3a and AR resulted in a complex which bound to multiple elements within the promoter region of SCN9A (Nav1.7) and upregulated channel expression. SIGNOR-253465 0.302 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4B protein Q07343 UNIPROT up-regulates activity phosphorylation Ser133 GHSQRREsFLYRSDS 9534 BTO:0001538 12023945 t done miannu Long PDE4 isoforms from all four sub-families can be phosphorylated by protein kinase A (PKA). This leads to an increase in their activity and may thus contribute to cellular desensitization processes in cells where these isoforms are selectively expressed.These were Ser89Ala-PDE4A8, Ser133Ala-PDE4B1, Ser13Ala-PDE4C2 and Ser126Ala-PDE4D5. SIGNOR-273940 0.2 RARA protein P10276 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates 9606 10607566 f gcesareni We shown that retinoic acid (ra) decreases the activity of the beta-catenin-lef/tcf signaling pathway SIGNOR-73274 0.383 MAPK1 protein P28482 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser222 TSPARLGsQHSPGRT 9606 21419341 t lperfetto Our mass spectrometry also identified abi1 s183 and s225 on abi1 (numbering corresponds to abi1 isoform 1) as sites phosphorylated on endogenous protein and in the wildtype erk-dependent in vitro phosphorylated sample. these data indicate erk phosphorylation of abi1 is required for basal and egf-induced wrc interaction with the wrp2/3 complex. SIGNOR-172873 0.421 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Ser723 ELDYPMGsFEPSPYP 9606 BTO:0000567 34198826 t miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. SIGNOR-276658 0.252 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR BACE1 protein P56817 UNIPROT up-regulates activity phosphorylation Thr252 YTGSLWYtPIRREWY 10116 BTO:0001009 26317805 t miannu First, we show that BACE1 is phosphorylated by the p25/Cdk5 complex at Thr252 and that this phosphorylation increases BACE1 activity.  SIGNOR-276934 0.383 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Ser727 PMGSFEPsPYPTTSS 9606 BTO:0000567 34198826 t miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. SIGNOR-276659 0.252 QRICH1 protein Q2TAL8 UNIPROT WARS2 protein Q9UGM6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269411 0.2 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RXR proteinfamily SIGNOR-PF44 SIGNOR up-regulates activity chemical activation 9606 18321241 t miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). SIGNOR-259240 0.8 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser649 VPPSPSLsRHSSPHQ -1 6772446 t Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-. SIGNOR-253007 0.673 TWIST1 protein Q15672 UNIPROT F2R protein P25116 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255520 0.2 ASH1L protein Q9NR48 UNIPROT NRXN1 protein Q9ULB1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000942 27229316 t Gianni Our results reveal that a novel process of activity-dependent transcriptional repression exists in neurons and that Ash1L mediates the long-term repression of nrxn1α, thus implicating an important role for epigenetic modification in brain functioning. SIGNOR-269056 0.262 DTNA protein Q9Y4J8 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255989 0.455 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser101 AAPEAGAsPVEKEAP -1 8034575 t lperfetto Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites. SIGNOR-248909 0.719 TGFBR2 protein P37173 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0001660 9435577 t lperfetto These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells. SIGNOR-227521 0.459 DAB2IP protein Q5VWQ8 UNIPROT KRAS protein P01116 UNIPROT down-regulates activity gtpase-activating protein 9606 27858941 t miannu The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP. SIGNOR-254746 0.497 MAPK8 protein P45983 UNIPROT OSBP2 protein Q969R2 UNIPROT up-regulates activity phosphorylation 30925160 t lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. SIGNOR-264876 0.2 RPS14 protein P62263 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262438 0.912 RPL36AL protein Q969Q0 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262493 0.781 AURKA protein O14965 UNIPROT TPX2 protein Q9ULW0 UNIPROT up-regulates activity phosphorylation Ser121 PAQPQRRsLRLSAQK 9606 BTO:0000567 26240182 t lperfetto Here we show that TPX2, a microtubule-bundling protein and activator of Aurora A, plays an important role. TPX2 was phosphorylated by Aurora A during mitosis. Its phospho-null mutant caused short metaphase spindles coupled with low microtubule flux rate. Interestingly, phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a.|This suggests that TPX2 phosphorylation positively regulates the function of CLASP1.| This is in accord with a phosphoproteomics study that identified S121 and S125 as potential phosphorylation sites for Aurora A in mitotic HeLa cells SIGNOR-265089 0.963 regorafenib chemical CHEBI:68647 ChEBI EPHA2 protein P29317 UNIPROT down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259210 0.8 PI4K2B protein Q8TCG2 UNIPROT 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI down-regulates quantity chemical modification 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269099 0.8 CTNNBIP1 protein Q9NSA3 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity binding -1 12408824 t llicata The crystal structure of the beta-catenin/ICAT complex reveals the inhibitory mechanism of ICAT. SIGNOR-238012 0.809 glutamic acid smallmolecule CHEBI:18237 ChEBI NMDA receptor_2D complex SIGNOR-C350 SIGNOR up-regulates activity chemical activation 9606 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate SIGNOR-264131 0.8 RXRB protein P28702 UNIPROT PPARA protein Q07869 UNIPROT up-regulates binding 9606 11237216 t gcesareni Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology SIGNOR-105448 0.546 PKC proteinfamily SIGNOR-PF53 SIGNOR PPP1R14B protein Q96C90 UNIPROT up-regulates activity phosphorylation Thr57 VRRQGKVtVKYDRKE 10606530 t lperfetto Recombinant tagged PHI-1 was phosphorylated by protein kinase C at two sites, one a Ser and one a Thr; phosphorylation enhanced inhibitory potency 50-fold. SIGNOR-265740 0.2 UCHL3 protein P15374 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270832 0.867 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 9606 19115199 t lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-217613 0.738 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20044479 t lperfetto We have described that upon ligand binding, igf-1r directly interacts with and phosphorylates pdk1 at tyr373/376 SIGNOR-236544 0.347 DZIP3 protein Q86Y13 UNIPROT H2AC7 protein P20671 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271753 0.2 SMARCC1 protein Q92922 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270709 0.824 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL6 protein P05231 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 f Both NF-κBs bind to a conserved DNA motif (80) that is found in numerous IL-1–responsive genes, in particular the ones encoding IκBα (81), IL-6 (82), IL-8 (18, 83,84), monocyte chemoattractant protein 1 (MCP1) (28), and cyclooxygenase 2 (COX2) SIGNOR-254511 0.621 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates ubiquitination 9606 10023660 t lperfetto These results indicate that the cul1/skp1/beta-trcp complex forms a ubiquitin ligase that mediates the degradation of beta-catenin. SIGNOR-217181 0.718 CAMK2A protein Q9UQM7 UNIPROT CAMK2A protein Q9UQM7 UNIPROT down-regulates phosphorylation Ser314 MLATRNFsGGKSGGN 9606 1324926 t lperfetto After removal of ca2+/calmodulin, the autonomous kinase undergoes a burst of inhibitory autophosphorylation at sites distinct from the autonomy site. Ca(2+)-independent autophosphorylation occurs within the calmodulin binding domain at thr305, thr306, and ser314 SIGNOR-17308 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation 9606 23616010 t lperfetto Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1. SIGNOR-233520 0.2 DLGAP5 protein Q15398 UNIPROT SHANK2 protein Q9UPX8 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264599 0.464 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser813 DIYSRRLsQETGLEI 9606 1377674 t lperfetto Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function SIGNOR-18253 0.52 TBPL2 protein Q6SJ96 UNIPROT TAF3/TRF3 complex SIGNOR-C23 SIGNOR form complex binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 18851836 t lperfetto We recently identified taf3 as a subunit specifically associated with trf3 to form a complex that is required for myogenic differentiation SIGNOR-181614 0.685 TSPOAP1 protein O95153 UNIPROT RIMS2 protein Q9UQ26 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264368 0.2 INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr368 STKMHGDyTLTLRKG 9534 8385099 t The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-252692 0.601 POT1 protein Q9NUX5 UNIPROT RPA2 protein P15927 UNIPROT down-regulates activity binding SIGNOR-C306 18680434 t lperfetto The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA SIGNOR-263324 0.416 PARP1 protein P09874 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 11907276 f amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-111680 0.7 HOXB3 protein P14651 UNIPROT OTX2 protein P32243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000946 9556594 t Luana Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively SIGNOR-261635 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2039 GLGQVGIsPLKPGTV 9606 BTO:0000551 24530506 t miannu In this study, we found that p300 was highly phosphorylated and its level was decreased during mitosis and tumorigenesis. In vitro and in vivo experiments aimed showed that cyclin-dependent kinase 1 (CDK1) and ERK1/2 phosphorylated p300 on Ser1038 and Ser2039. Mutations of Ser1038 and Ser2039 increased p300 protein stability and levels.  SIGNOR-276458 0.2 8-Hydroxy-7-(6-sulfo-naphthalen-2-ylazo)-quinoline-5-sulfonic acid chemical CID:92577 PUBCHEM PTPN6 protein P29350 UNIPROT down-regulates activity chemical inhibition -1 19233143 t lperfetto In this study, we screened protein tyrosine phosphatases (PTPs) by in vitro phosphatase assays to identify PTPs that are inhibited by 8-hydroxy-7-(6-sulfonaphthalen-2-yl)diazenyl-quinoline-5-sulfonic acid (NSC-87877), a potent inhibitor of SHP-1 and SHP-2 PTPs. SIGNOR-261978 0.8 MRPL30 protein Q8TCC3 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262365 0.661 SLC24A5 protein Q71RS6 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264393 0.8 PLK1 protein P53350 UNIPROT RIOK2 protein Q9BVS4 UNIPROT up-regulates activity phosphorylation Ser335 TKEGSEFsFSDGEVA -1 21880710 t miannu Here, we report that the atypical protein kinase Rio2 is a novel substrate of Plk1 and can be phosphorylated by Plk1 at Ser-335, Ser-380, and Ser-548. Overexpression of Rio2 causes a prolonged mitotic exit whereas knockdown of Rio2 accelerates mitotic progression, suggesting that Rio2 is required for the proper mitotic progression. F urthermore, time-lapse imaging data show that overexpression of Rio2 but not Rio2 S3A results in a slowed metaphase-anaphase transition. Collectively, these findings strongly indicate that the Plk1-mediated phosphorylation of Rio2 regulates metaphase-anaphase transition during mitotic progression. SIGNOR-262937 0.439 CSNK2A2 protein P19784 UNIPROT CCAR2 protein Q8N163 UNIPROT up-regulates activity phosphorylation Thr454 AAEAAPPtQEAQGET 9606 24962073 t lperfetto CK2alphawas bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2alphawas evidenced by co-immunoprecipitation of CK2alphaand DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. |In our results, CK2alpha affected the|These results suggest that DBC1 may be involved in the progression of gastric carcinoma by inducing the EMT and that it is closely associated with CK2alpha-mediated phosphorylation of DBC1. phosphorylation of Thr454 on DBC1 SIGNOR-267667 0.2 RPAP3 protein Q9H6T3 UNIPROT R2TP core co-chaperone complex SIGNOR-C515 SIGNOR form complex binding 9606 29662061 t miannu  Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90.  SIGNOR-270927 0.891 AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244156 0.2 PIK-75 Hydrochloride chemical CID:45265864 PUBCHEM PRKDC protein P78527 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206214 0.8 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser451 NGFYHFGsTSSSPPI 9606 BTO:0000007 16141410 t In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity SIGNOR-251245 0.406 PARD6A protein Q9NPB6 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity binding 9606 BTO:0000007 22544755 t lperfetto The Par complex member Par-6, previously thought to inhibit aPKC, is a potent activator of aPKC in our assays. Par-6 and aPKC interact via PB1 domain heterodimerization, and this interaction activates aPKC by displacing the pseudosubstrate, although full activity requires the Par-6 CRIB-PDZ domains. SIGNOR-227489 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Thr82 HSMSVPTtPTLGFST 9606 17604322 t lperfetto In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE SIGNOR-262960 0.2 SUCLA2 protein Q9P2R7 UNIPROT Succinyl-CoA ATP variant complex SIGNOR-C398 SIGNOR form complex binding 9606 32627745 t miannu Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS). SIGNOR-266262 0.986 estrone smallmolecule CHEBI:17263 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of -1 8099587 t Luana 17 beta-HSD type 2 was capable of catalyzing the interconversion of testosterone and androstenedione as well as estradiol and estrone.  SIGNOR-269763 0.8 CDT1 protein Q9H211 UNIPROT MCM complex SIGNOR-C268 SIGNOR up-regulates activity binding 9606 BTO:0000007 14672932 t Chromosomal DNA replication requires the recruitment of the six-subunit minichromosome maintenance (Mcm) complex to chromatin through the action of Cdc6 and Cdt1. SIGNOR-261679 0.781 C5 protein P01031 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 cleavage:Arg751 HKDMQLGrLHMKTLL 30552328 t complement C5b fragment: PRO_0000005989 lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer SIGNOR-263440 0.606 PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 10660596 t gcesareni The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. SIGNOR-74860 0.894 BRCA2 protein P51587 UNIPROT BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR form complex binding 9606 BTO:0000007 14636569 t lperfetto These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer SIGNOR-263207 0.761 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser422 LSTPVVLsPGPQKP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252084 0.2 7-[4-[4-(2,3-Dichlorophenyl)-1,4-diazepan-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one chemical CID:56597938 PUBCHEM DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 9606 BTO:0002181 22025698 t Luana Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands.  SIGNOR-258320 0.8 trimipramine chemical CHEBI:9738 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 9537821 t miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. SIGNOR-258741 0.8 PTK2 protein Q05397 UNIPROT ACTN1 protein P12814 UNIPROT down-regulates activity phosphorylation Tyr12 DSQQTNDyMQPEEDW 9534 BTO:0004055 11369769 t lperfetto The cytoskeletal/non-muscle isoform of alpha-actinin is phosphorylated on its actin-binding domain by the focal adhesion kinase tyrosine 12 is the site of phosphorylation. The wild type recombinant protein was not phosphorylated in cells lacking the focal adhesion kinase (fak).Tyrosine phosphorylation reduced the amount of alpha-actinin that cosedimented with actin filaments. SIGNOR-108329 0.556 CSNK2A2 protein P19784 UNIPROT EIF2B5 protein Q13144 UNIPROT up-regulates activity phosphorylation Ser717 LKEAEEEsSEDD 9606 11500362 t llicata Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.  SIGNOR-250989 0.377 PZP protein P20742 UNIPROT MMP2 protein P08253 UNIPROT down-regulates activity binding -1 9344465 t lperfetto Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. SIGNOR-261804 0.335 SUN1 protein O94901 UNIPROT NXF1 protein Q9UBU9 UNIPROT up-regulates activity binding 9606 BTO:0000567 SIGNOR-C303 28831067 t lperfetto SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1. SIGNOR-263296 0.361 RSPO1 protein Q2MKA7 UNIPROT ZNRF3 protein Q9ULT6 UNIPROT down-regulates relocalization 9606 23151663 t gcesareni This is counteracted by respondin 1, which induces znrf3 internalization SIGNOR-199629 0.795 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser293 FNTLAFPsMKRKDVV 9606 BTO:0000007 12496252 t lperfetto In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation SIGNOR-96735 0.758 GRSF1 protein Q12849 UNIPROT FASTKD5 protein Q7L8L6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25683715 f miannu DHX30 siRNA treatment resulted in an increase of FASTKD2 levels, and FASTKD5 was increased in cells treated with siRNA for GRSF1. SIGNOR-261224 0.377 SNRPD1 protein P62314 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270660 0.735 ABL1 protein P00519 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr222 IGAGKGKyYAVNFPM 10116 25219501 t Manara C-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer's disease. SIGNOR-260928 0.289 PKA proteinfamily SIGNOR-PF17 SIGNOR AQP5 protein P55064 UNIPROT up-regulates activity phosphorylation Ser156 STDSRRTsPVGSPAL 9606 BTO:0000007 26569106 t lperfetto AQP5 can be directly phosphorylated by PKA at Ser 156 |Our data hint at a mechanism whereby phosphorylation of Ser 156 in AQP5 increases its membrane localization, thereby enhancing cancer cell proliferation. SIGNOR-272087 0.2 NR1D1 protein P20393 UNIPROT NPAS2 protein Q99743 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 20817722 t miannu In this study, we found that NPAS2, like BMAL1, is a direct target gene of RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding. SIGNOR-267981 0.616 DDX21 protein Q9NR30 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 21703541 t miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. SIGNOR-260192 0.269 GSK3B protein P49841 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser270 KMALTKAsSVASSDK 9606 BTO:0002181 27432879 t miannu Our previous study showed, by mass spectrometry analysis, that GSK-3β phosphorylates Foxp3 at Ser270 and Ser274 SIGNOR-277244 0.288 BMS-554417 chemical CID:54754526 PUBCHEM INSR protein P06213 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190458 0.8 CIB2 protein O75838 UNIPROT TMC2 protein Q8TDI7 UNIPROT up-regulates activity binding 10090 BTO:0004744 28663585 t miannu  Furthermore, we report that calcium and integrin-binding protein 2 binds to the components of the hair cell mechanotransduction complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib2 mutations. We conclude that calcium and integrin-binding protein 2 is required for normal operation of the mechanotransducer channels and is involved in limiting the growth of transducing stereocilia. SIGNOR-269665 0.359 GARS1 protein P41250 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI down-regulates quantity chemical modification 9606 24898252 t miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. SIGNOR-270478 0.8 ZNRF1 protein Q8ND25 UNIPROT CAV1 protein Q03135 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys39 MADELSEkQVYDAHT 9606 BTO:0000007 28593998 t miannu The ubiquitin ligase ZNRF1 promotes caveolin-1 ubiquitination and degradation to modulate inflammation. ZNRF1 mediates CAV1 polyubiquitination at lysine 39 and promote CAV1 degradation to modulate TLR4-mediated immune response. SIGNOR-272327 0.372 ponatinib chemical CHEBI:78543 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 23430109 t lperfetto AP24534 also inhibited SRC (IC50: 5.4 nM) and members of the VEGFR, FGFR, and PDGFR families of receptor tyrosine kinases (Table 1 and Table S1) SIGNOR-261984 0.8 MECP2/SIN3A/HDAC complex complex SIGNOR-C360 SIGNOR BDNF protein P23560 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004102 14593184 t Luana Moreover, increased Bdnf transcription involves dissociation of the MeCP2–histone deacetylase–mSin3A repression complex from its promoter. SIGNOR-265071 0.379 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser152 PASSVSSsPSPPFGH 9606 12151396 t gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. SIGNOR-91067 0.346 KEL protein P23276 UNIPROT EDN3 protein P14138 UNIPROT up-regulates activity cleavage Trp117 YCHLDIIwINTPEQT -1 10438732 t miannu These data demonstrate that the Kell blood group protein is a proteolytic enzyme that processes big ET-3, generating ET-3, a potent bioactive peptide with multiple biological roles. SIGNOR-256354 0.663 asparagine smallmolecule CHEBI:22653 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264753 0.7 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser91 ASFHAYDsHTNTYYL 9606 BTO:0000007 21321328 t miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). SIGNOR-276308 0.595 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser327 DPEMEEDsYDSFGEP -1 9558331 t llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. SIGNOR-250933 0.312 PDPK1 protein O15530 UNIPROT PRKCE protein Q02156 UNIPROT up-regulates phosphorylation Thr566 LNGVTTTtFCGTPDY 9606 11964154 t llicata In the present study, we analysed the contribution of the phosphoinositide-dependent kinase 1 (pdk-1) and pkcepsilon kinase activity in controlling the phosphorylation of thr(566) and ser(729). pdk-1 phosphorylation of the activation loop triggers autophosphorylation of the hydrophobic motif SIGNOR-117320 0.555 HMGB1 protein P09429 UNIPROT HOXD11 protein P31277 UNIPROT up-regulates activity binding -1 8890171 t 2 miannu We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein. SIGNOR-240559 0.297 DBP protein Q10586 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 8383844 f inferred from family member miannu Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators SIGNOR-270225 0.2 CDK3 protein Q00526 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation Ser63 GILARRPsYRKILKD 9606 BTO:0000527 BTO:0000142 18794154 t lperfetto Cyclin-dependent kinase 3-mediated activating transcription factor 1 phosphorylation enhances cell transformationwe found that cdk3 phosphorylates activating transcription factor 1 (atf1) at serine 63 and enhances the transactivation and transcriptional activities of atf1. SIGNOR-180920 0.2 CDK2 protein P24941 UNIPROT CROCC protein Q5TZA2 UNIPROT down-regulates phosphorylation Ser1460 APRPVPGsPARDAPA 9606 22610972 t llicata Finally, phosphorylation of tax1bp2 at serine-763 by cyclin-dependent kinase (cdk)2 abolished the tax1bp2-mediated p38 activation and tumor-suppressive activity, indicating that tax1bp2 can adapt cdk2 signaling to the p38/p53/p21 pathway. SIGNOR-197593 0.2 MTHFD2L protein Q9H903 UNIPROT (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI up-regulates quantity chemical modification 10116 21163947 t lperfetto Conversion of these 1-carbon units to formate requires several folate-interconverting enzymes in mitochondria. The enzyme(s) responsible for conversion of 5,10-methylene-tetrahydrofolate (CH(2)-THF) to 10-formyl-THF in adult mammalian mitochondria are currently unknown. A new mitochondrial CH(2)-THF dehydrogenase isozyme, encoded by the MTHFD2L gene, has now been identified.  SIGNOR-268252 0.8 PRKAA1 protein Q13131 UNIPROT HNF4A protein P41235 UNIPROT down-regulates activity phosphorylation Ser303 DPDAKGLsDPGKIKR 9606 SIGNOR-C15 12740371 t lperfetto Here we demonstrate that ampk directly phosphorylates hnf4 and represses its transcriptional activity. Ampk-mediated phosphorylation of hnf4 on serine 304 had a 2-fold effect SIGNOR-101101 0.289 TNK2 protein Q07912 UNIPROT TNK2 protein Q07912 UNIPROT up-regulates activity phosphorylation Tyr284 LPQNDDHyVMQEHRK -1 16472662 t Purified ACK1 undergoes autophosphorylation at Tyr284, and autophosphorylation increases kinase activity SIGNOR-251184 0.2 Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 12670868 t miannu The Set1/Ash2 HMT methylates histone H3 at Lys 4 (K4), but not if the neighboring K9 residue is already methylated. SIGNOR-264483 0.2 KDR protein P35968 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 10090 22264731 t VEGF pathway Gianni Here we show that genetic or pharmacological FAK inhibition in ECs prevents VEGF-stimulated permeability downstream of VEGF receptor or Src tyrosine kinase activation in vivo. VEGF promotes tension-independent FAK activation SIGNOR-261945 0.475 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258001 0.8 PHF2 protein O75151 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity demethylation 9606 21532585 t miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2‚ÄìARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. SIGNOR-265343 0.2 PRKACB protein P22694 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. SIGNOR-81141 0.404 PTPN6 protein P29350 UNIPROT VAV1 protein P15498 UNIPROT down-regulates activity dephosphorylation 9606 30567306 t miannu SHP-1 dephosphorylates and inactivates the guanine exchange factor Vav1. SIGNOR-277171 0.561 ITPRIPL1 protein Q6GPH6 UNIPROT ITPR1 protein Q14643 UNIPROT up-regulates binding 9606 BTO:0000938 21368195 t Induces Ca2+ release that increases the binding affinity of Shh for Boc. gcesareni Recruitment of g protein also can activate phospholipase c (plc) that in turn increases inositol triphosphate (ip3) levels and induces ca2+ release from internal stores. SIGNOR-172497 0.2 AURKB protein Q96GD4 UNIPROT ZWINT protein O95229 UNIPROT up-regulates activity phosphorylation Ser250 PTRPQEQsTGDTMGR -1 21775627 t lperfetto Zwint-1 is a novel Aurora B substrate required for the assembly of a dynein-binding platform on kinetochores|During prometaphase, AurB phosphorylation of zwint-1 is required for recruitment of ZW10-, pT89 dynein-, and RZZ-dependent proteins to kinetochores. This is defective after AurB inhibition or after expression of the triple-A zwint-1 mutant. Triple-E mutant zwint-1 mimics phospho–zwint-1 in RZZ recruitment, even after AurB inhibition SIGNOR-265009 0.636 ANKRD26 protein Q9UPS8 UNIPROT PIDD1 protein Q9HB75 UNIPROT up-regulates activity relocalization 9606 BTO:0004790 33350486 t lperfetto Here, we demonstrate that PIDD1 is recruited to mature centrosomes by the centriolar distal appendage protein ANKRD26.|We propose that PIDDosome activation can in both cases be promoted by an ANKRD26-dependent local increase in PIDD1 concentration close to the centrosome. SIGNOR-266068 0.2 MARCHF5 protein Q9NX47 UNIPROT SOD1 protein P00441 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0004055 19741096 t lperfetto Mitochondrial ubiquitin ligase MITOL ubiquitinates mutant SOD1 and attenuates mutant SOD1-induced reactive oxygen species generation SIGNOR-272982 0.2 RASGEF1B protein Q0VAM2 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-183832 0.384 MYOD1 protein P15172 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR form complex binding 10090 BTO:0001103 18094043 t lperfetto MyoD omodimers or heterodimers of MyoD plus E12 or E47 serve as transcription factor complexes that bind to CANNTG consensus sites in the promoter regions of genes, performing major functions in specification and differentiation of skeletl muscle precursor cells. SIGNOR-241548 0.799 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499-2 UNIPROT down-regulates phosphorylation Ser579 YQSTIPQsPSPAPDD 9606 10828059 t The effect has been demonstrated using Q08499-5 llicata The pde4d2 isoform is inhibited by erk2 phosphorylation SIGNOR-77563 0.36 RPS6KB1 protein P23443 UNIPROT PDPK1 protein O15530 UNIPROT down-regulates activity phosphorylation Ser549 VWRQRYQsHPDAAVQ 9606 35318320 t miannu Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT. SIGNOR-273844 0.716 FOXO1 protein Q12778 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22521266 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-197197 0.2 FYN protein P06241 UNIPROT KCND3 protein Q9UK17 UNIPROT up-regulates activity phosphorylation Tyr108 GKLHYPRyECISAYD 9606 BTO:0000007 22198508 t miannu These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels. SIGNOR-276396 0.2 PRKCA protein P17252 UNIPROT CSPG4 protein Q6UVK1 UNIPROT up-regulates activity phosphorylation Thr2252 YLRKRNKtGKHDVQV 9606 BTO:0002035 15504744 t miannu Protein kinase C (PKC)-alpha phosphorylation of recombinant NG2 cytoplasmic domain and phorbol ester-induced PKC-dependent phosphorylation of full-length NG2 expressed in U251 cells are both blocked by mutation of Thr(2256), identifying this residue as a primary phosphorylation site. PKC-alpha-mediated NG2 phosphorylation at Thr(2256) is therefore a key step for initiating cell polarization and motility. SIGNOR-263162 0.2 ATF4 protein P18848 UNIPROT ASNS protein P08243 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002182 18940792 f miannu C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene. SIGNOR-253838 0.636 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser68 PPQTSGLsPSRLSKS 9606 SIGNOR-C3 20516213 t fstefani The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly. SIGNOR-165795 0.7 SMAD6 protein O43541 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates binding 9606 11737269 t lpetrilli Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads. SIGNOR-112642 0.55 FADS3 protein Q9Y5Q0 UNIPROT long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI down-regulates quantity chemical modification 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267909 0.8 Phenelzine chemical CHEBI:8060 ChEBI SLC6A3 protein Q01959 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 t miannu At the human dopamine transporter, sertraline and nomifensine were the most potent with KD's of 25±2 and 56±3, respectively. Except for these two compounds, most antidepressants were not potent at the human dopamine transporter. SIGNOR-258745 0.8 EGFR protein P00533 UNIPROT PIK3C2B protein O00750 UNIPROT up-regulates phosphorylation 9606 BTO:0000017 10805725 t gcesareni The n-terminal region of pi3k-c2beta was found to selectively interact with the egf receptor in vitro, suggesting that it mediates the association of this pi3k with the receptor. SIGNOR-77195 0.451 CBX3 protein Q13185 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity binding 9606 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-265324 0.2 CLK2 protein P49760 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser50 RNRYRDVsPFDHSRI 9606 10480872 t gcesareni The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation. SIGNOR-70603 0.328 BGJ-398 chemical CHEBI:63451 ChEBI FGFR1 protein P11362 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190263 0.8 NCSTN protein Q92542 UNIPROT APH1A protein Q96BI3 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t gcesareni We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch). SIGNOR-93313 0.967 PRKACB protein P22694 UNIPROT NGFR protein P08138 UNIPROT up-regulates phosphorylation Ser303 PEGEKLHsDSGISVD 9606 BTO:0000938 12682012 t llicata Pka phosphorylates the p75 receptor and regulates its localization to lipid rafts. activation of camp?PKA Is required for translocation of p75ntr to lipid rafts, and for biochemical and biological activities of p75ntr, such as inactivation of rho and the neurite outgrowth. SIGNOR-99755 0.609 Silmitasertib chemical CID:24748573 PUBCHEM CSNK2A2 protein P19784 UNIPROT down-regulates activity chemical inhibition 9606 21159648 t Federica In this study, we describe CX-4945, a potent and selective orally bioavailable small molecule inhibitor of CK2. SIGNOR-261130 0.8 MAP4K3 protein Q8IVH8 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 9820741 t gcesareni With regard to at least mekk1, serine/threonine kinases such as nik,glkand hpk1 appear also to be important for regulation SIGNOR-61814 0.429 LRRC4C protein Q9HCJ2 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 19467332 t miannu A possible function for the NGL–PSD-95 interaction is to couple trans-synaptic adhesion events to the recruitment of PSD-95 and other PSD-95-associated postsynaptic proteins. PSD-95 and liprin-α may be key synaptic scaffolding proteins that couple trans-synaptic adhesions to the assembly of synaptic proteins/vesicles SIGNOR-264050 0.373 PRKCB protein P05771 UNIPROT ORAI1 protein Q96D31 UNIPROT down-regulates phosphorylation Ser30 TTSGSRRsRRRSGDG 9606 20534587 t llicata We propose that pkc suppresses soce and crac channel function by phosphorylation of orai1 at n-terminal serine residues ser-27 and ser-30. SIGNOR-166044 0.2 MAP3K13 protein O43283 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation 9606 11726277 t gcesareni Lzk directly phosphorylated and activated mkk7. SIGNOR-112349 0.567 PRKACA protein P17612 UNIPROT RARA protein P10276 UNIPROT down-regulates activity phosphorylation Ser369 YVRKRRPsRPHMFPK 9606 20215566 t miannu  Mutagenesis of serine 219 (S219) and S369 at the PKA sites on RARA to either double alanines or double glutamic acids showed that both PKA sites are important for RARA activity.  SIGNOR-276282 0.379 PPP1CB protein P62140 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 16501611 t Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. SIGNOR-248572 0.29 TOMM70 protein O94826 UNIPROT HSP90AA1 protein P07900 UNIPROT up-regulates activity binding 9534 12526792 t miannu The Tom70 receptor is a membrane-localized cochaperone that integrates the Hsp70/Hsp90 chaperones with mitochondrial preprotein targeting and translocation. In mammals, preprotein in the cytosol is associated with both Hsp90 and Hsp70 in a multichaperone complex, and docking of Hsp90 and/or Hsp70 onto Tom70 is essential for preprotein targeting. SIGNOR-261379 0.2 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr26 SQPHGSVtQSQGSSS 9606 BTO:0000007 12024051 t gcesareni We show here that autophosphorylation of chk2 produced in a cell-free system requires trans phosphorylation by a wortmannin-sensitive kinase, probably atm or atr SIGNOR-87850 0.829 UBE2L3 protein P68036 UNIPROT NEDD4 protein P46934 UNIPROT up-regulates activity ubiquitination -1 19240029 t miannu Only UbcH5 and Related Class I E2s Support Ubiquitination of S5a—UbcH5 belongs to the Class I family of E2s which contains a catalytic core (UBC domain) without a distinct Ub binding domain (38). To test whether other Class I E2s can also support ubiquitination of S5a, we assayed the ubiquitination of S5a with UbcH7 and the E3s, Nedd4, or Parkin. With either of these E3s, UbcH7 supported ubiquitination of S5a (Fig. 8, A and B). In addition, another Class I E2, Ubc4, a close homolog of UbcH5, supported ubiquitination of S5a by the APC, a multimeric Ring finger E3 responsible for cell cycle progression through mitosis (39) (Fig. 8C). Thus, multiple Class I E2s can support ubiquitination of S5a by various types of E3s (Table 1). SIGNOR-272735 0.559 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser391 RSSMNNGsPTALSGS 9606 BTO:0000007 16862148 t lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). SIGNOR-249309 0.444 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser212 DETERAYsFCGTIEY 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro. SIGNOR-131387 0.2 FGF2 protein P09038 UNIPROT HBB protein P68871 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8142649 f Regulation miannu Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production. SIGNOR-251795 0.2 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser717 GVARVRKsKGKYAYL -1 8848293 t lperfetto Only two peptides containing Ser-662 and Ser-696 were found to be efficiently phosphorylated by protein kinase C (PKC). The peptide including Ser-696 was also phosphorylated by protein kinase G (PKG). SIGNOR-248955 0.697 MRTFB protein Q9ULH7 UNIPROT SRF protein P11831 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 21673106 t gcesareni Similarly, the myocd-related transcription factor (mrtf) family of proteins, mrtf-a and mrtf-b, are also involved in the transcriptional regulation of contractile gene markers as coactivators of srf. SIGNOR-174316 0.2 MMP8 protein P22894 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272375 0.7 WNT1 protein P04628 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131574 0.78 GSK3B protein P49841 UNIPROT PIAS1 protein O75925 UNIPROT down-regulates quantity by destabilization phosphorylation Ser13 ELKQMVMsLRVSELQ 10090 BTO:0002268 26157031 t miannu We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model. We found that GSK3β phosphorylation of PIAS1 provided a phosphodegron for HECTD2 targeting.  SIGNOR-276924 0.338 CHUK protein O15111 UNIPROT BCL3 protein P20749 UNIPROT up-regulates activity phosphorylation Ser454 PSPAPGGs -1 28689659 t miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  SIGNOR-277363 0.439 MAPK1 protein P28482 UNIPROT CDC42EP1 protein Q00587 UNIPROT unknown phosphorylation Ser113 SPAPPAIsPIIKNAI 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262765 0.2 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Ser242 NQRKAKRsLAPRFDL 9606 11152499 t tpavlidou We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity. SIGNOR-85765 0.2 HSP90AA1 protein P07900 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates binding 9606 21511880 t gcesareni We report the crucial underlying role of the intranuclear heat shock protein 90 molecular chaperone complex in pulsatile GR regulation. Pharmacological interference of heat shock protein 90 (HSP90) with geldanamycin during the intranuclear chaperone cycle completely ablated GR's cyclical activity, cyclical cAMP response element-binding protein (CREB) binding protein (CBP)/p300 recruitment, and the associated cyclical acetylation at the promoter region. SIGNOR-251667 0.724 prostaglandin E2 smallmolecule CHEBI:15551 ChEBI PTGER2 protein P43116 UNIPROT up-regulates chemical activation 9606 15299086 t gcesareni Pge2 acts via four ep receptors termed ep1 to ep4. SIGNOR-127735 0.8 ZNF423 protein Q2M1K9 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates activity 10090 BTO:0000011 20200519 f Ectopic expression of Zfp423 in non-adipogenic NIH 3T3 fibroblasts robustly activates expression of Pparg in undifferentiated cells and permits cells to undergo adipocyte differentiation under permissive conditions. Short hairpin RNA (shRNA)-mediated reduction of Zfp423 expression in 3T3-L1 cells blunts preadipocyte Pparg expression and diminishes the ability of these cells to differentiate. SIGNOR-255928 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR KLHL3 protein Q9UH77 UNIPROT up-regulates activity phosphorylation Ser433 PMNTRRSsVGVGVVE -1 26435498 t done miannu Consistent with the fact that S433 is a component of Akt and PKA phosphorylation motifs, in vitro kinase assay demonstrated that Akt and PKA can phosphorylate KLHL3 at S433, that was previously reported to be phosphorylated by PKC.  SIGNOR-273825 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR DLC1 protein Q96QB1 UNIPROT unknown phosphorylation Ser766 VTRTRSLsACNKRVG 10116 BTO:0000443 16338927 t gcesareni We have demonstrated that Ser-322 is phosphorylated upon insulin stimulation of intact cells and that this site is directly phosphorylated in vitro by PKB and ribosomal S6 kinase, members of the AGC (protein kinases A, G, and C) family of insulin-stimulated protein kinases SIGNOR-247997 0.2 farnesol chemical CHEBI:28600 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258159 0.8 cysteine smallmolecule CHEBI:15356 ChEBI Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI up-regulates quantity precursor of 9606 11347887 t miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. SIGNOR-270476 0.8 CAMK2A protein Q9UQM7 UNIPROT PDC protein P20941 UNIPROT unknown phosphorylation Ser73 ERVSRKMsIQEYELI 11331285 t llicata In this study, we report that Pd was rapidly phosphorylated by Ca(2+)/calmodulin-dependent kinase II, resulting in 100-fold greater inhibition of Gbetagamma binding than cAMP-dependent protein kinase phosphorylation. Furthermore, Pd phosphorylation by Ca(2+)/calmodulin-dependent kinase II at Ser-54 and Ser-73 led to binding of the phosphoserine-binding protein 14-3-3. SIGNOR-250637 0.312 PRKCI protein P41743 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000527 21419810 t lperfetto In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer SIGNOR-172894 0.325 MAPK11 protein Q15759 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 20551513 f gcesareni Mechanistic analysis revealed that the tak1-mkk3/6-p38 mapk axis phosphorylated runx2, promoting its association with the coactivator creb-binding protein (cbp), which is re-quired to regulate osteoblast genetic programs. SIGNOR-166167 0.289 RNF8 protein O76064 UNIPROT L3MBTL2 protein Q969R5 UNIPROT up-regulates activity ubiquitination 9606 31225475 t miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. SIGNOR-266787 0.244 HIF1AN protein Q9NWT6 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates hydroxylation Asn2022 INSHADVnAVDDLGK 9606 18299578 t gcesareni We show that fih-1 hydroxylates notch icd at two residues (n(1945) and n(2012)) that are critical for the function of notch icd as a transactivator within cells and during neurogenesis and myogenesis in vivo. Fih-1 negatively regulates notch activity and accelerates myogenic differentiation. SIGNOR-161061 0.566 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates activity phosphorylation Ser147 EDLCQAFsDVILAVN 9606 BTO:0000567 11242082 t lperfetto Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation. SIGNOR-105719 0.919 FLT3 protein P36888 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity 9606 28213513 f Our finding that RUNX1 protein levels are dependent on FLT3-ITD signaling in AML cells and that, together, they synergize to generate AML. […]Our work demonstrated that Tyr phosphorylation within the ID region of RUNX1 is critical for its oncogenic potential, SIGNOR-256307 0.369 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Thr239 VPEMPGEtPPLSPID 9606 1846781 t lperfetto Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity. SIGNOR-21784 0.337 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000142 20308788 t The effect has been demonstrated using P10636-8 lperfetto Abnormal hyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in alzheimer's disease (ad). Gsk-3beta phosphorylated tau at many sites, with ser199, thr205, and ser396 being the most favorable sites in cells. SIGNOR-164655 0.728 MAPK9 protein P45984 UNIPROT ELK3 protein P41970 UNIPROT down-regulates activity phosphorylation 11042694 t miannu JNK binds to the J box in the middle of the protein, and binding is required for phosphorylation of the adjacent EXport motif. Both the binding and phosphorylation sites (the JEX element) are important for Net export. SIGNOR-250138 0.328 TFE3 protein P19532 UNIPROT ATG16L1 protein Q676U5 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells SIGNOR-276807 0.269 RPS6KB1 protein P23443 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Thr491 PQQRNALtPTTIPDG 9606 18769144 t lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively SIGNOR-180784 0.2 purmorphamine chemical CHEBI:63053 ChEBI SMO protein Q99835 UNIPROT up-regulates chemical activation 9606 17419683 t gcesareni The activity of smo toward gi was stimulated severalfold with the synthetic agonist purmorphamine and inhibited almost completely by cyclopamine and other antagonists of shh. SIGNOR-154282 0.8 TWIST2 protein Q8WVJ9 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255499 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR GLI1 protein P08151 UNIPROT down-regulates activity phosphorylation Thr374 PGCTKRYtDPSSLRK 9534 BTO:0000298 16293631 t miannu Here, we report that activation of PKA retains Gli1 in the cytoplasm.Mutation analysis identifies Thr374 as a major PKA site determining Gli1 protein localization.  SIGNOR-276044 0.2 CTNNB1 protein P35222 UNIPROT SOX2 protein P48431 UNIPROT up-regulates activity binding 10090 BTO:0002572 BTO:0002181 24482235 t flangone The interaction of Beta-catenin with Tcf is important for Beta-catenin s's function in iPSCs induction. In addition, Beta-catenin interacts with Oct4, Sox2, and Klf4, respectively. In the reprogramming process, Beta-catenin further enhances expression of pluripotency-related genes. SIGNOR-242087 0.697 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR NOS2 protein P35228 UNIPROT up-regulates transcriptional regulation BTO:0001103 20219869 f Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-256250 0.447 PRKCZ protein Q05513 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization phosphorylation Ser45 GATTTAPsLSGKGNP 9606 BTO:0002181 25660024 t miannu  Yap and β-catenin are direct substrates of PKCζ. Similar MS/MS analysis to map the sites phosphorylated in β-catenin by PKCζ identified S45 and several sites of low abundance that included S552 and S675 (Figure S3C). SIGNOR-276878 0.582 MTOR protein P42345 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-205615 0.897 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr488 GAEDSGDtEDELRRV 9606 20471329 t lperfetto Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair SIGNOR-165427 0.404 TGFBR2 protein P37173 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 19114990 t lperfetto in immunoprecipitation esperiments, the TGF _ RII receptor was found to be constitutively associated with p85, the regulatory subunity of PI3K SIGNOR-217830 0.459 ESR2 protein Q92731 UNIPROT SCN1A protein P35498 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 BTO:0001264 22169964 f miannu 17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice SIGNOR-253472 0.2 MAPK11 protein Q15759 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation 9606 10085140 t gcesareni Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target SIGNOR-65586 0.747 CDK2 protein P24941 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 SIGNOR-C16 12058066 t gcesareni Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association. SIGNOR-89609 0.578 AKT proteinfamily SIGNOR-PF24 SIGNOR EDC3 protein Q96F86 UNIPROT down-regulates activity phosphorylation Ser161 SFRRRHNsWSSSSRH 10029 BTO:0000246 20051463 t miannu Together these data show that recombinant EDC3 co-immunoprecipitates with endogenous 14-3-3 isoforms in response to insulin in vivo and is phosphorylated at the putative 14-3-3 binding and AKT phosphorylation site Ser-161. Collectively, these data suggest that Ser-161 in EDC3 is phosphorylated in response to insulin principally by AKT and that this subsequently triggers 14-3-3 binding. Constitutive 14-3-3 binding to EDC3 alters p-body morphology and function SIGNOR-262631 0.2 CHCHD1 protein Q96BP2 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261460 0.668 KDM4B protein O94953 UNIPROT BBC3 protein Q96PG8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001109 28073943 f miannu JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. SIGNOR-263733 0.2 ATM protein Q13315 UNIPROT PEX5 protein P50542 UNIPROT up-regulates activity phosphorylation Ser141 DYNETDWsQEFISEV 9606 BTO:0000007 26344566 t Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy.  SIGNOR-262792 0.51 NLK protein Q9UBE8 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT down-regulates phosphorylation Thr201 PHHVHPLtPLITYSN 9606 12556497 t llicata Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk. SIGNOR-97819 0.763 ITGB1BP1 protein O14713 UNIPROT Av/b8 integrin complex SIGNOR-C185 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257668 0.285 CAPN2 protein P17655 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase SIGNOR-251613 0.289 CHEK1 protein O14757 UNIPROT WEE1 protein P30291 UNIPROT up-regulates phosphorylation 9606 20068082 t gcesareni Chk1 also phosphorylates and stabilizes wee1. SIGNOR-163164 0.595 MED28 protein Q9H204 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266674 0.832 MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr813 GDNVLINtYSGVLKI 9606 17937911 t lperfetto Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling. SIGNOR-158423 0.2 MAPK1 protein P28482 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT down-regulates activity phosphorylation Ser274 DPLPGPGsPSHSAPD 10116 BTO:0000951 15834132 t miannu Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events. SIGNOR-262841 0.273 HIC1 protein Q14526 UNIPROT STAT3 protein P40763 UNIPROT down-regulates quantity by repression binding 9606 BTO:0000815 24067369 t miannu HIC1 interacts with the DNA binding domain of STAT3 and suppresses the binding of STAT3 to its target gene promoters. HIC1 C-terminal domain binds to STAT3. HIC1 mutant defective in STAT3 interaction reduced its repressive effect on STAT3 DNA binding activity, the reporter activity and gene expression of the VEGF and c-Myc genes, and cell growth in MDA-MB 231 cells. SIGNOR-254246 0.375 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates activity phosphorylation Tyr817 LAKASPVyLDILG 10090 BTO:0000944 10533983 t miannu TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. the Y785F mutation abolish the BDNF-inducible tyrosine phosphorylation of PLCy, but receptors containing this mutation are also defective in the ability to induce the tyrosine phosphorylation of the c-cbl proto-oncogene product. SIGNOR-250312 0.2 CSNK1E protein P49674 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser45 GATTTAPsLSGKGNP 9606 BTO:0000007 12176352 t gcesareni Using mass spectrometry and phosphopeptide-specific antibodies, we show that a complex of axin and casein kinase I (CKI) induces Beta-catenin phosphorylation at a single site: serine 45 (S45). SIGNOR-244102 0.643 CSRP3 protein P50461 UNIPROT MYOG protein P15173 UNIPROT up-regulates activity binding 10090 BTO:0004058 9234731 t 2 miannu we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements. SIGNOR-241113 0.534 MAPK12 protein P53778 UNIPROT MAPK12/CARM1 complex SIGNOR-C218 SIGNOR form complex binding 29681515 t apalma Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated SIGNOR-255981 0.347 SMURF2 protein Q9HAU4 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps SIGNOR-192898 0.533 BRD7 protein Q9NPI1 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270601 0.659 fluoxymesterone chemical CHEBI:5120 ChEBI AR protein P10275 UNIPROT up-regulates activity chemical activation 9606 10077001 t miannu The anabolic steroids, oxandrolone and fluoxymesterone, have high inhibition constants for binding, yet induce the N/C interaction and stabilize AR at relatively low ligand concentrations and are AR agonists in vivo. SIGNOR-259264 0.8 FCAR protein P24071 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 9606 30766540 f lperfetto IgA-mediated immune effector responses such as phagocytosis, antibody-dependent cell-mediated cytotoxicity, respiratory burst and cytokine release are mediated through FcalphaRI (CD89), an IgA-specific receptor that is expressed on monocytes, eosinophils, neutrophils and macrophages SIGNOR-264861 0.7 CKM complex complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-273140 0.346 Food intake phenotype SIGNOR-PH152 SIGNOR vitamin D smallmolecule CHEBI:27300 ChEBI up-regulates quantity 9606 30080183 f lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin. Vitamin D can also be obtained from nutrition. SIGNOR-270565 0.7 TAF1 protein P21675 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Thr55 DDIEQWFtEDPGPDE 9606 15053879 t llicata Phosphorylation on thr-55 by taf1 mediates degradation of p53 SIGNOR-123651 0.668 IRF2 protein P14316 UNIPROT TAP1 protein Q03518 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15778351 f miannu We also show that this cytokine-dependent expression of TAP1 transcripts depends on STAT1 and IFN regulatory factor-2 (IRF-2), but not on IRF-1, and provide evidence that IRF-2 constitutively binds to the TAP1 gene promoter and enhances TAP1 promoter activity. SIGNOR-254530 0.2 CSNK2A1 protein P68400 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates phosphorylation Ser121 YRIQEQEsSGEEDSD 9606 9405437 t gcesareni Recombinant inh2 was phosphorylated by kinases in cytosols prepared from g1 and s phase cells. The amount of inh2 kinase attributed to casein kinase 2, based on inhibition by heparin, increased 2.6-fold from g1 to s phase SIGNOR-53857 0.312 RUSC1 protein Q9BVN2 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates binding 9606 15024033 f miannu Overexpression studies in PC12 cells indicate that Nesca facilitates neurotrophin-dependent neurite outgrowth at nonsaturating doses of nerve growth factor (NGF). SIGNOR-272776 0.7 TUT1 protein Q9H6E5 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 21102410 f miannu Star-PAP is a poly (A) polymerase (PAP) that is putatively required for 3'-end cleavage and polyadenylation of a select set of pre-messenger RNAs (mRNAs) SIGNOR-272322 0.7 NAT8L protein Q8N9F0 UNIPROT acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI down-regulates quantity chemical modification 9606 19524112 t miannu The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA. SIGNOR-267522 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR FANCA protein O15360 UNIPROT unknown phosphorylation Ser1149 CLRSRDPsLMVDFIL -1 11855836 t FANCA is phosphorylated at Ser1149 by Akt. The biological significance of FANCA phosphorylation and its regulation by Akt remains unclear at this time. SIGNOR-251476 0.2 CAMK2D protein Q13557 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Thr642 RSVKRNStVDCNGVV 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275792 0.285 TBK1 protein Q9UHD2 UNIPROT DDAH2 protein O95865 UNIPROT down-regulates activity phosphorylation Thr211 DHPYASLtLPDDAAA 33850055 t lperfetto TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o SIGNOR-275647 0.2 MAPK3 protein P27361 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser441 SPRRFIGsPRTPVSP 10116 15774499 t lperfetto Thr 421/Ser 424 have been reported to be targeted by ERK1, 2 (39), JNK or p38 MAPKs (36). Interestingly, with a comparable kinetics, FSH represses ERK1, 2 constitutive phosphorylation in Sertoli cells isolated from 19-d-old rats SIGNOR-111515 0.591 HES5 protein Q5TA89 UNIPROT ATOH1 protein Q92858 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 f lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production SIGNOR-265145 0.415 COLGALT1 protein Q8NBJ5 UNIPROT COL1A2 protein P08123 UNIPROT up-regulates activity glycosylation -1 19075007 t Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. SIGNOR-261153 0.405 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19763573 f miannu PSC833, cyclosporine analogue, downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-kappaB. SIGNOR-254654 0.264 GSK3B protein P49841 UNIPROT NBR1 protein Q14596 UNIPROT down-regulates activity phosphorylation Thr586 HNTPVDVtPCMSPLP -1 24879152 t lperfetto The autophagy receptor NBR1 (neighbor of BRCA1 gene 1) binds UB/ubiquitin and the autophagosome-conjugated MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) proteins, thereby ensuring ubiquitinated protein degradation|Here we show that NBR1 is a substrate of GSK3. NBR1 phosphorylation by GSK3 at Thr586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation. SIGNOR-261795 0.439 RAC1 protein P63000 UNIPROT WAVE complex complex SIGNOR-C271 SIGNOR up-regulates activity 9606 27871158 t lperfetto Cdc42 can induce Arp2/3-mediated filopodia formation through the activation of WASp (Wiskott-Aldrich syndrome proteins) and neuronal N-WASp (Rohatgi et al., 1999). Similarly, Rac1-enhanced lamellipodia formation is related to Arp2/3 activation by the WAVE (WASP-family verprolin-homologous) complex SIGNOR-261877 0.609 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Ser497 SSNIQMDsGYNTQNC 9606 18378770 t gcesareni Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp). SIGNOR-178150 0.779 CTNNB1 protein P35222 UNIPROT CLDN2 protein P57739 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0003569 14751232 f lperfetto Furthermore, claudin-2 promoter activity was found to be enhanced by the TCF-4/beta-catenin transcription complex. SIGNOR-254114 0.311 F2R protein P25116 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates 9606 22972936 t milica Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase. SIGNOR-192042 0.582 IPP complex complex SIGNOR-C380 SIGNOR ACTB protein P60709 UNIPROT up-regulates activity relocalization 27590440 t lperfetto Apart from binding with integrins on the membrane, IPP complex can interact with the cytoskeleton as well as many signaling proteins inside the cell. Up to now, dozens of IPP complex-related proteins have been identified. One of these proteins is parvin that binds to F-actin, thus connecting ECM with cytoskeleton.17 In the following, we will discuss PINCH-interacting proteins and their roles. SIGNOR-265768 0.356 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 17151142 t miannu TNF-α has two distinct plasma membrane receptors known as p55 and p75. These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling SIGNOR-253591 0.923 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser168 YREPLCLsPASSGSS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248509 0.387 PRKCA protein P17252 UNIPROT MEP1B protein Q16820 UNIPROT down-regulates quantity phosphorylation Ser687 KKYRERMsSNRPNLT 9534 BTO:0001538 12941954 t miannu These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate. SIGNOR-263172 0.2 PSMA2 protein P25787 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263367 0.847 PPARG protein P37231 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 12821652 t miannu Mutations of the 5' or 3' half-sites of the response element totally abrogated PPARgamma binding and transcriptional activation, identifying this site as a novel type of functional PPARgamma response element. Finally, ectopic expression of Rev-Erbalpha in 3T3-L1 preadipocytes potentiated adipocyte differentiation induced by the PPARgamma ligand rosiglitazone. These results identify Rev-Erbalpha as a target gene of PPARgamma in adipose tissue and demonstrate a role for this nuclear receptor as a promoter of adipocyte differentiation. SIGNOR-268022 0.28 DDX17 protein Q92841 UNIPROT RNA helicases DDX5/DDX17 complex SIGNOR-C34 SIGNOR form complex binding 9606 BTO:0000887;BTO:0001103 17011493 t lperfetto We have found that the rna helicases p68/p72 are myod-associated proteins and that the noncoding rna sra also immunoprecipitates with myod. In vitro and in vivo experiments indicated that both p68/p72 and sra are coactivators of myod. SIGNOR-149961 0.435 RPS10 protein P46783 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262442 0.897 (E)-3-tosylacrylonitrile chemical CHEBI:85928 ChEBI PTPN1 protein P18031 UNIPROT down-regulates chemical inhibition 9606 Other t The anti-inflammatory compound BAY 11-7082 is a potent inhibitor of Protein Tyrosine Phosphatases. gcesareni SIGNOR-190254 0.8 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR PIM2 protein Q9P1W9 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269241 0.27 UBE2I protein P63279 UNIPROT ZHX1 protein Q9UKY1 UNIPROT up-regulates quantity by stabilization sumoylation Lys626 KKKSKALkEEKMEID 9606 BTO:0000007 23686912 t miannu Here, we report that the SUMO-E2 conjugating enzyme Ubc9 was identified to interact with ZHX1 by an interaction screen using a yeast two-hybrid system. This interaction was confirmed by co-immunoprecipitation and co-localization assays. Further study showed that ZHX1 is SUMOylated by Ubc9 with SUMO1 at the sites K159, K454, and K626. Furthermore, we demonstrated that the SUMOylation of ZHX1 regulated the stability, ubiquitination and transcriptional activity of ZHX1. The sumoylation of zinc‐fingers and homeoboxes 1 (ZHX1) by ubc9 regulates its stability and transcriptional repression activity. However, in the current work, we demonstrated that ZHX1 was only SUMOylated by SUMO1. SIGNOR-263901 0.464 AKT proteinfamily SIGNOR-PF24 SIGNOR PDE3B protein Q13370 UNIPROT up-regulates activity phosphorylation Ser318 CKIFRRPsLPCISRE 10090 BTO:0000011 10454575 t gcesareni PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B. SIGNOR-248027 0.2 RXRA protein P19793 UNIPROT CPT1B protein Q92523 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15356291 f miannu Mutation analysis indicated that the MEF2 site contributed to the activation of the CPT1beta promoter by PPAR in C2C12 cells. The reporter construct containing the PPRE and the MEF2C site was synergistically activated by co-expression of PPAR, retinoid X receptor (RXR) and MEF2C in non-muscle cells. Moreover, protein-binding assays demonstrated that MEF2C and PPAR specifically bound to one another in vitro. Also for the synergistic activation of the CPT1beta gene promoter by MEF2C and PPARalpha-RXRalpha, a precise arrangement of its binding sites was essential. SIGNOR-254582 0.2 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9534 7839144 t lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-232156 0.716 AT9283 chemical CID:11696609 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190011 0.8 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 17189255 t gcesareni Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, we have reported here that atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster. SIGNOR-151449 0.2 RAD51C protein O43502 UNIPROT RAD51B/RAD51C complex SIGNOR-C65 SIGNOR form complex binding 9606 11751636 t miannu We show that two of them, rad51b and rad51c, are associated in a stable complex. Rad51b-rad51c complex has ssdna binding and ssdna-stimulated atpase activities. SIGNOR-113388 0.646 tRNA(Leu) smallmolecule CHEBI:29169 ChEBI Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270417 0.8 PECAM1 protein P16284 UNIPROT CD38 protein P28907 UNIPROT up-regulates activity binding 9606 18626062 t miannu As a receptor, CD38 interacts with its ligand CD31 [15,16]. CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), is a 130 kDa type I transmembrane glycoprotein that consists of six extracellular immunoglobulin-like homology domains, a 19-residue transmembrane domain, and a 118-residue cytoplasmic tail SIGNOR-264254 0.496 HDAC2 protein Q92769 UNIPROT ZNF318 protein Q5VUA4 UNIPROT up-regulates activity binding 9606 BTO:0001321 16469430 t Monia A central domain of TZF is required for repression of AR-mediated transactivation. The results revealed that HDAC2 was coimmunoprecipitated with TZF (Fig. 6A), These results indicate that AR, TZF and HDAC2 form a ternary complex during the repression of AR-mediated transactivation. SIGNOR-261188 0.335 LPAR3 protein Q9UBY5 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256890 0.435 SOX9 protein P48436 UNIPROT PRAME protein P78395 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000849 19273910 f miannu Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen. SIGNOR-255191 0.323 AKT1 protein P31749 UNIPROT HTRA2 protein O43464 UNIPROT down-regulates phosphorylation Ser212 RVRVRLLsGDTYEAV 9606 17311912 t lperfetto Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212 SIGNOR-252500 0.328 CRBN protein Q96SW2 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 31591562 t miannu CRBN functions as a substrate receptor of the E3 ubiquitin ligase CRL4, whose substrate specificity is modulated by thalidomide and its analogs.When thalidomide binds to CRBN, substrate specificity of CRL4CRBN is altered and CRBN neomorphically binds to ∆Np63, TAp63 and other neosubstrates and ubiquitinates them for proteasomal degradation. SIGNOR-272214 0.2 ITCH protein Q96J02 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 12226085 t miannu In summary, we have shown that CBLC and AIP4 can interact and that these two E3 ligases could contribute to down-regulate EGFR signaling by ubiquitination.  SIGNOR-272604 0.47 S1PR2 protein O95136 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000007 10488065 t gcesareni Edg-3 and edg-5 couple not only to gibut also to gqand g13. SIGNOR-70667 0.51 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1E protein P28566 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257519 0.8 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 20385093 t gcesareni A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution. SIGNOR-164785 0.888 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120048 0.781 MAPK1 protein P28482 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser291 TYVNNSPsPGFNSSH 9606 19237534 t lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309. SIGNOR-184168 0.341 SMARCC1 protein Q92922 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270736 0.814 NUP43 protein Q8NFH3 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262087 0.682 CAMK2A protein Q9UQM7 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser362 FYTLNGSsVDSQPQS 9606 BTO:0004553 24614225 t gianni NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity. SIGNOR-266442 0.312 TEX12 protein Q9BXU0 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR form complex binding 9606 22394509 t miannu The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region. SIGNOR-264203 0.639 PCBP2 protein Q15366 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity binding 9606 BTO:0002181 19881509 t Giorgia Only AIP4 associated with PCBP2 and caused MAVS degradation. The interaction between PCBP2 and AIP4 was abrogated when the linker region or WB2 of PCBP2 was deleted, which confirmed our previous data indicating that this region was critical for PCBP2-mediated degradation of MAVS SIGNOR-260361 0.599 PTK6 protein Q13882 UNIPROT ARHGAP5 protein Q13017 UNIPROT up-regulates phosphorylation Tyr1109 KGYSDEIyVVPDDSQ 9606 BTO:0000150 18829532 t lperfetto Breast tumor kinase phosphorylates p190rhogap to regulate rho and ras and promote breast carcinoma growth, migration, and invasion. Brk phosphorylates p190 at the y(1105) residue both in vitro and in vivo, thereby promoting the association of p190 with p120rasgap (p120). As a consequence, brk stimulates p190 and attenuates p120 functions, leading to rhoa inactivation and ras activation, respectively. SIGNOR-181452 0.2 haloperidol chemical CHEBI:5613 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258680 0.8 AKT1 protein P31749 UNIPROT LARP1 protein Q6PKG0 UNIPROT down-regulates activity phosphorylation Ser1056 EGRKRCPsQSSSRPA 9606 BTO:0002181 28650797 t SARA LARP1 is a direct substrate of Akt/S6K1 and mTORC1. Akt is a physiologically relevant primary kinase for S770/S979 phosphorylation of LARP1|Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation. SIGNOR-260992 0.292 CEBPB protein P17676 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003697 18583320 t Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells. SIGNOR-254046 0.373 CAMK4 protein Q16566 UNIPROT PHB2 protein Q99623 UNIPROT down-regulates phosphorylation Ser91 RARPRKIsSPTGSKD 9606 BTO:0000887 21689744 t lperfetto Here we show that calcium/calmodulin-dependent kinase iv (camk iv) specifically binds to the c terminus of phb2 and phosphorylates phb2 at serine 91. Camk iv effectively decreased phb2-mediated repression of mef2 activity through phosphorylation SIGNOR-174437 0.344 CSNK2A1 protein P68400 UNIPROT SEC63 protein Q9UGP8 UNIPROT up-regulates activity phosphorylation Ser748 DSEGFEDsFEEEEEE 9606 BTO:0000599 23287549 t lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. SIGNOR-265271 0.295 PAK2 protein Q13177 UNIPROT CASP7 protein P55210 UNIPROT down-regulates phosphorylation Thr173 FRGDRCKtLLEKPKL 9606 BTO:0000150 21555521 t gcesareni Pak2 can bind with caspase-7 and phosphorylate caspase-7 at the ser-30, thr-173, and ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis. SIGNOR-173663 0.357 PRKCA protein P17252 UNIPROT PLCB3 protein Q01970 UNIPROT down-regulates phosphorylation Ser1105 LDRKRHNsISEAKMR 9606 9660757 t gcesareni These data establish that direct phosphorylation by pka of ser1105 in the putative g-box of plcbeta3 inhibits galphaq-stimulated plcbeta3 activity. SIGNOR-58859 0.459 FOXO4 protein P98177 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260102 0.266 MAPK14 protein Q16539 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation Ser474 RTHFPQFsYSASIRE 9606 12181443 f lperfetto We show [] that the kinase activity and s473 phosphorylation of akt induced by lpa and s1p requires both mitogen-activated protein (map) kinase kinase (mek) and p38 map kinase. [] among different stimuli tested, platelet-derived growth factor stimulates s473 phosphorylation of akt in a mek- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1?stimulated Akt s473 phosphorylation require p38 but not mek. SIGNOR-91408 0.413 axitinib chemical CHEBI:66910 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258073 0.8 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR CCNA1 protein P78396 UNIPROT up-regulates activity 9606 11090075 t apalma We show that the ectopic expression of PML-RARα is sufficient to elevate levels of cyclin A1 in U937 myeloid leukemia cells and cyclin A1 is negatively regulated by the RARα pathway. SIGNOR-256373 0.2 UCK2 protein Q9BZX2 UNIPROT uridine 5'-monophosphate(2-) smallmolecule CHEBI:57865 ChEBI up-regulates quantity chemical modification 11306702 t lperfetto Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. SIGNOR-275860 0.8 ASPG protein Q86U10 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity chemical modification 9606 24657844 t miannu Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia. SIGNOR-267538 0.8 PHKG2 protein P15735 UNIPROT PYGL protein P06737 UNIPROT up-regulates activity phosphorylation Ser15 QEKRRQIsIRGIVGV 9606 BTO:0002049 22225877 t It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15 SIGNOR-267401 0.642 KDM3B protein Q7LBC6 UNIPROT UCP1 protein P25874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0005964 19194461 t miannu We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression. SIGNOR-266638 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR proline smallmolecule CHEBI:26271 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270429 0.8 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr88 KHLVALYtRDEHFAI -1 8349691 t llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. SIGNOR-251076 0.325 NTRK3 protein Q16288 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000938 10235685 t gcesareni Unglycosylated trka core protein is phosphorylated even in the absence of ligand stimulation and displays constitutive kinase activity as well as constitutive interaction with the signaling molecules shc and plc-gamma. SIGNOR-67404 0.603 MDM2 protein Q00987 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression 9606 18292944 f amattioni Overexpression of hdm2 resulted in a decrease in the level of p21waf1 SIGNOR-160977 0.663 Caspase 7 complex complex SIGNOR-C232 SIGNOR PARP1 protein P09874 UNIPROT down-regulates cleavage 9606 11058599 t amattioni Caspase-7 cleaves parp;redundancy exists between the caspase-3 and -7 at the level of parp proteolysis. SIGNOR-256470 0.708 NFYC protein Q13952 UNIPROT GFI1B protein Q5VTD9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19965638 f miannu HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. SIGNOR-254433 0.305 PTPN6 protein P29350 UNIPROT TYK2 protein P29597 UNIPROT down-regulates 9606 BTO:0000150;BTO:0001271;BTO:0000785;BTO:0000661;BTO:0003076 14624462 f lperfetto We find, for the first time, that shp-1 down-regulates the level of tyk2 kinase in h9 cells and of jak1 kinase in htb26 cells, by accelerating their degradation SIGNOR-119200 0.59 AIM2 inflammasome complex SIGNOR-C222 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256382 0.2 26S Proteasome complex SIGNOR-C307 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates quantity destabilization 10090 BTO:0003569 9233789 t Here we show that the ubiquitin-dependent proteolysis system is involved in the regulation of beta-catenin turnover. beta-catenin, but not E-cadherin, p120(cas) or alpha-catenin, becomes stabilized when proteasome-mediated proteolysis is inhibited and this leads to the accumulation of multi-ubiquitinated forms of beta-catenin. SIGNOR-270947 0.391 CSNK1A1 protein P48729 UNIPROT BHLHE40 protein O14503 UNIPROT down-regulates quantity by destabilization phosphorylation Ser243 GSDTDTDsGYGGESE 9606 BTO:0002181 25202122 t miannu CK1α-mediated phosphorylation of DEC1 on a conserved degron is required for DEC1 degradation.  SIGNOR-276851 0.2 etoposide chemical CHEBI:4911 ChEBI TOP2B protein Q02880 UNIPROT down-regulates activity chemical inhibition 9606 16101488 t miannu Etoposide is an important chemotherapeutic agent that is used to treat a wide spectrum of human cancers. It has been in clinical use for more than two decades and remains one of the most highly prescribed anticancer drugs in the world. The primary cytotoxic target for etoposide is topoisomerase II. SIGNOR-259326 0.8 belinostat chemical CHEBI:61076 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257959 0.8 PPM1L protein Q5SGD2 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity dephosphorylation -1 12556533 t miannu Co-immunoprecipitation experiments indicated that PP2Cepsilon associates stably with TAK1 and attenuates the binding of TAK1 to MKK4 or MKK6.|PP2Cepsilon dephosphorylated TAK1 in vitro. SIGNOR-277114 0.602 STAT1 protein P42224 UNIPROT KRT17 protein Q04695 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21796151 f miannu IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms. SIGNOR-255233 0.2 sildenafil chemical CHEBI:9139 ChEBI PDE5A protein O76074 UNIPROT down-regulates activity chemical inhibition -1 10385692 t Luana Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. SIGNOR-258343 0.8 BCL2 protein P10415 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 GRK1 protein Q15835 UNIPROT RHO protein P08100 UNIPROT up-regulates activity phosphorylation Ser338 DEASATVsKTETSQV -1 8617805 t That light-dependent phosphorylation of Rho is mediated primarily by RK. Addition of an inhibitory antibody against rhodopsin kinase (RK) lowered phosphorylation at Ser334, Ser338, and Ser343, without changing the ratio between phosphorylation sites. upon illumination, Ser334c, Ser338, and Ser343 are phosphorylated. SIGNOR-251190 0.921 TRIM28 protein Q13263 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 17900823 f inferred from family member miannu We previously reported that ZNF224, a novel Kr√ºppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor. SIGNOR-270228 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AR protein P10275 UNIPROT down-regulates phosphorylation Ser516 VSRVPYPsPTCVKSE 9606 BTO:0001130 18511414 t lperfetto Map kinase-dependent phosphorylation at ar ser-515 was supported by the decrease in intensity of the slower migrating 23-kda band after treatment with both egf and increasing concentrations of the map kinase inhibitor, u0126 SIGNOR-244606 0.2 ASXL2 protein Q76L83 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity binding 9606 21047783 t miannu ASXL2, which does not bind HP1, promotes differentiation by binding to PPARγ and increasing the level of methylated H3K4, leading to the elevation of PPARγ activity. Our genome-wide analysis confirmed the physiological roles of ASXL1 and ASXL2 in adipogenesis at the molecular level, supporting the hypothesis that ASXL1 is an authentic corepressor of PPARγ, whereas ASXL2 is a PPARγ coactivator, and that together ASXL1 and ASXL2 fine-tune adipogenesis via differential regulation of PPARγ. SIGNOR-260063 0.2 glutamic acid smallmolecule CHEBI:18237 ChEBI AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity chemical activation 9606 15919192 t miannu Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1‚Äì4); five kainate receptor genes (GluR5‚Äì7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits. SIGNOR-264696 0.8 MAP3K5 protein Q99683 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates phosphorylation Ser98 GGRRPGTsPALLQGT 9606 17325029 t lperfetto P21cip1 is phosphorylated in vitro by both ask1 and jnk1 at s98. /phosphorylation of p21cip1 at s98, which in vivo appears to be regulated by ask1, may therefore mediate negative feedback in the ask1 signaling pathway. SIGNOR-153440 0.576 CHUK protein O15111 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates binding 9606 12789342 t gcesareni Ikk-alpha interacts with creb-binding protein and in conjunction with rel a is recruited to nf-kappab-responsive promoters and mediates the cytokine-induced phosphorylation and subsequent acetylation of specific residues in histone h3. SIGNOR-101539 0.532 MAPK8 protein P45983 UNIPROT MFN2 protein O95140 UNIPROT down-regulates quantity phosphorylation Ser27 HMAEVNASPLKHFVT 9606 BTO:0001938 22748923 t Barakat We demonstrate that a critical component of the mitochondrial fusion apparatus, the mitofusin Mfn2, is a target for phosphorylation in response to a variety of cellular stresses. We provide direct evidence that JNK mediates this phosphorylation. SIGNOR-274138 0.439 VRK1 protein Q99986 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 17938195 t gcesareni We show that histone h3 is phosphorylated by vaccinia-related kinase 1 (vrk1). Direct phosphorylation of thr3 and ser10 in h3 by vrk1 both in vitro and in vivo was observed. Loss of vrk1 activity was associated with a marked decrease in h3 phosphorylation during mitosis. SIGNOR-265371 0.2 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 9606 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89209 0.55 PPP3CC protein P48454 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18177723 f lperfetto Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy SIGNOR-251735 0.2 RNA helicases DDX5/DDX17 complex SIGNOR-C34 SIGNOR NFAT5 protein O94916 UNIPROT up-regulates activity binding 9606 BTO:0000815 22266867 t done miannu In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration.  SIGNOR-274113 0.36 ABL1 protein P00519 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Tyr394 QSQESEDySQPSTSS 9606 12110584 t gcesareni C-abl binds and phosphorylates mdm2 in vivo and in vitro;phosphorylation of mdm2 by c-abl impairs the inhibition of p53 by mdm2. SIGNOR-90512 0.704 PRKG2 protein Q13237 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Thr430 LEIIRGRtKQHGQFS -1 35226996 t miannu Recombinant PKG II inhibited the epidermal growth factor (EGF)-induced activation of the EGF receptor via phosphorylating the T406 of the extracellular domain and blocked EGF-triggered proliferation of various cancer cells. SIGNOR-277589 0.2 ABL1 protein P00519 UNIPROT EGFR protein P00533 UNIPROT up-regulates phosphorylation Tyr1197 STAENAEyLRVAPQS 9606 16943190 t lperfetto we show that activated Abl phosphorylates the EGFR primarily on tyrosine 1173Furthermore, we show that activated Abl allows the ligand-activated EGFR to escape Cbl-dependent down-regulation by inhibiting the accumulation of Cbl at the plasma membrane in response to epidermal growth factor stimulation and disrupting the formation of the EGFR.Cbl complex without affecting Cbl protein stability. These findings reveal a novel role for Abl in promoting increased cell-surface expression of the EGFR and suggest that Abl/EGFR signaling may cooperate in human SIGNOR-149277 0.429 CTDSP1 protein Q9GZU7 UNIPROT TWIST1 protein Q15672 UNIPROT down-regulates activity dephosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000007 26975371 t gcesareni These results indicate that SCP1 is the phosphatase that counter-regulates the MAPK-mediated phosphorylation of S68-Twist1. SIGNOR-245962 0.2 WNT9B protein O14905 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-132111 0.607 PPM1L protein Q5SGD2 UNIPROT ERN1 protein O75460 UNIPROT up-regulates activity dephosphorylation 9606 24327956 t miannu Overall, our study establishes that PP2Ce mediated IRE1 regulation in ER stress signaling is a potentially important molecular basis for its genetic contribution to metabolic syndrome.Lin et al. [36] have reported that different durations and composition of ER stress signaling pathways can dictate cell fate and the balance between survival and death.|Recombinant wildtype PP2Ce, but not a phosphatase-dead mutant (PP2Ce-D302A), effectively dephosphorylated the phosphor-Ser724 site of IRE1\u03b1 protein (p-IRE1\u03b1)  (A). SIGNOR-277074 0.314 CHUK protein O15111 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates quantity by destabilization phosphorylation Thr559 TGDYIPGtETHMAPE 9606 BTO:0000776 20501937 t lperfetto Upon activation by nik, ikkalfa phosphorylates nik, triggering its proteolysis. SIGNOR-165622 0.685 TRIM27 protein P14373 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates 9606 BTO:0000671 12807881 f inferred from 70% of family members miannu We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38. SIGNOR-269915 0.274 MAPK8 protein P45983 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 t lperfetto The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity. SIGNOR-235766 0.904 CDK1 protein P06493 UNIPROT USP9X protein Q93008 UNIPROT up-regulates activity phosphorylation Ser2547 YEGSEEVsPPQTKDQ 32152317 t Phosphosites were derived from Figure S1 lperfetto Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis. SIGNOR-275608 0.283 serotonin smallmolecule CHEBI:28790 ChEBI HTR6 protein P50406 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264295 0.8 TAK-960 chemical CID:53357478 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207200 0.8 HTRA2 protein O43464 UNIPROT XIAP protein P98170 UNIPROT down-regulates binding 9606 11583623 t gcesareni Here we report that a serine protease called htra2/omi is released from mitochondria and inhibits the function of xiap by direct binding in a similar way to diablo. SIGNOR-110834 0.702 SEMA5A protein Q13591 UNIPROT PLXNB3 protein Q9ULL4 UNIPROT up-regulates activity binding 10090 BTO:0000944 15218527 t miannu Plexin-B3 is a functional receptor for semaphorin 5A. Here we show that plexin-B3 is a high-affinity receptor specific for Sema5A. We further demonstrate that plexin-B3 activation by Sema5A mediates functional responses in plexin-B3-expressing cells (either fibroblasts, epithelial and primary endothelial cells). SIGNOR-268373 0.607 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr677 LPITGPEyATPIIMD -1 23770091 t done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. SIGNOR-273943 0.357 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 18160256 t Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248653 0.727 nintedanib chemical CHEBI:85164 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 18559524 t Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. SIGNOR-257799 0.8 HDAC4 protein P56524 UNIPROT MMP13 protein P45452 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005173 17656568 f miannu We have hypothesized that histone deacetylases (HDACs) are involved with PTH-induced MMP-13 gene expression in the osteoblastic cell line, UMR 106-01. We have shown that PTH profoundly regulates HDAC4 in UMR 106-01 cells through a PKA-dependent pathway, leading to removal of HDAC4 from the MMP-13 promoter and its enhanced transcription. SIGNOR-254235 0.332 JARID2 protein Q92833 UNIPROT NKX2-5 protein P52952 UNIPROT down-regulates activity binding 10116 BTO:0003324 15542826 t miannu JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4. SIGNOR-224787 0.467 PIK3C2A protein O00443 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates 9606 9430633 f gcesareni Activation of pi 3-kinase causes plc gamma ph domain-mediated membrane targeting and plc gamma activation. SIGNOR-54707 0.382 KREMEN2 protein Q8NCW0 UNIPROT LRP6 protein O75581 UNIPROT down-regulates binding 9606 12050670 t gcesareni Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to block wnt/beta-catenin signalling. Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of the wnt receptor lrp6 from the plasma membrane. SIGNOR-88894 0.625 GMNN protein O75496 UNIPROT CDT1 protein Q9H211 UNIPROT down-regulates activity binding 9606 BTO:0002181 11125146 t Here we show that geminin interacts tightly with Cdt1, a recently identified replication initiation factor necessary for MCM loading. SIGNOR-261680 0.972 PDX1 protein P52945 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000627 8866550 f inferred from family member miannu The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription. SIGNOR-267798 0.589 ERG protein P11308 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22140532 f miannu ERG deregulation induces PIM1 over-expression and aneuploidy in prostate epithelial cells. The up-regulation of PIM1 induced by tERG over-expression significantly modified Cyclin B1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability. SIGNOR-254065 0.2 MAPK14 protein Q16539 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates activity phosphorylation 10090 20682789 t ggiuliani We therefore propose that Osterix binds to Sp1 sequences on target gene promoters and that its phosphorylation by p38 enhances recruitment of coactivators to form transcriptionally active complexes SIGNOR-255791 0.418 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser491 GSDSDLDsDDEFVPY 9606 23263282 t lperfetto Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. Here, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2) SIGNOR-200206 0.2 UGP2 protein Q16851 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI down-regulates quantity chemical modification 9606 8631325 t miannu UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. SIGNOR-267926 0.8 RIPK2 protein O43353 UNIPROT IKBKG protein Q9Y6K9 UNIPROT up-regulates activity 9606 SIGNOR-C14 16493424 f miannu In the case of NOD2, activation of RICK leads to K63 (Lys63)-linked polyubiquitylation of IKKgamma, the scaffold of the inhibitor of NF-kappaB (IkappaB)-kinase complex (the IKK complex), which also consists of IKKalpha and IKKbeta. This is followed by the phosphorylation of IKKbeta, as well as the phosphorylation of IkappaB and the release of nuclear factor-kappaB (NF-kappaB) for translocation to the nucleus. So, in activating the IKK complex, RICK either activates an E3 ubiquitin ligase that promotes K63-linked polyubiquitylation or inhibits an enzyme (such as cylindromatosis protein, CYLD) that de-ubiquitylates proteins that are modified with K63-linked polyubiquitin, so RICK does not require its own kinase activity for this function. SIGNOR-252413 0.664 SMURF1 protein Q9HCE7 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 22298955 t Ubiquitin-mediated proteolysis. gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. SIGNOR-195663 0.76 IRX1 protein P78414 UNIPROT BPI protein P17213 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. SIGNOR-261652 0.2 ASPG protein Q86U10 UNIPROT L-asparagine zwitterion smallmolecule CHEBI:58048 ChEBI down-regulates quantity chemical modification 9606 24657844 t miannu Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia. SIGNOR-267537 0.8 FGG protein P02679 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 16418530 f lperfetto In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. SIGNOR-253373 0.7 APOBEC3A protein P31941 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 f lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). SIGNOR-261332 0.7 SERPINA1 protein P01009 UNIPROT F12 protein P00748 UNIPROT down-regulates activity binding 9606 BTO:0000131 26707513 t lperfetto C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1). SIGNOR-263515 0.336 CCT8 protein P50990 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 t miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). SIGNOR-272862 0.758 PTPRK protein Q15262 UNIPROT EGFR protein P00533 UNIPROT unknown dephosphorylation Tyr1197 STAENAEyLRVAPQS 10029 BTO:0000246 16263724 t RPTP-kappa also reduced epidermal growth factor-dependent EGFR tyrosine phosphorylation in CHO cells. Purified RPTP-kappa preferentially dephosphorylated EGFR tyrosines 1068 and 1173 in vitro. SIGNOR-248723 0.601 CREB3L1 protein Q96BA8 UNIPROT CREB3L1 protein Q96BA8 UNIPROT up-regulates activity binding -1 12805554 t miannu E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins SIGNOR-224205 0.2 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser1101 GCRRRHSsETFSSTP 10029 BTO:0000246 15364919 t lperfetto Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). SIGNOR-249267 0.632 RHO protein P08100 UNIPROT GNAT1 protein P11488 UNIPROT up-regulates activity binding 9606 8673138 t We report that his affected descendants carry a missense mutation in the gene encoding the a subunit of rod transducin — the G-protein that couples rhodopsin to cGMP-phosphodiesterase in the phototransduction cascade. SIGNOR-260007 0.785 AKT proteinfamily SIGNOR-PF24 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro SIGNOR-244275 0.2 MARS1 protein P56192 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 t miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). SIGNOR-270352 0.2 nintedanib chemical CHEBI:85164 ChEBI FGFR4 protein P22455 UNIPROT down-regulates activity chemical inhibition -1 18559524 t Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. SIGNOR-257803 0.8 JQ1 chemical CHEBI:137113 ChEBI BRD3 protein Q15059 UNIPROT down-regulates activity chemical inhibition -1 20871596 t lperfetto Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains. SIGNOR-261988 0.8 SMAD6 protein O43541 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity binding 9606 22298955 t Create a non-functional complex with smad4 and competes with R-smad. lperfetto On the other hand, Smad6 competes with R-Smad and forms a non-functional complex with Smad4, which will inhibit BMP signaling in bone formation. Smad6 is involved in a negative feedback loop regulating BMP signaling and is required to limit BMP signaling during endochondral bone formation. SIGNOR-195648 0.556 CDCA7L protein Q96GN5 UNIPROT MAOB protein P27338 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20980443 f miannu we identified two novel transcriptional repressors of MAO B, E2F-associated phosphoprotein (EAPP) and R1 (RAM2/CDCA7L/JPO2), that down-regulate MAO B via MAO B core promoter, which contains Sp1 sites. SIGNOR-253768 0.293 MAPK6 protein Q16659 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser189 YSHKGHLsEGLVTKW 9606 8621539 t lperfetto Ser189 of erk3, which corresponds to thr183, one of the activating phosphorylation sites of erk2, is autophosphorylated in vitro and phosphorylated in vivo. SIGNOR-40097 0.2 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257998 0.8 ZW10 protein O43264 UNIPROT NRZ complex complex SIGNOR-C358 SIGNOR form complex binding 25364732 t lperfetto NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay. SIGNOR-265023 0.841 IFNL3 protein Q8IZI9 UNIPROT IFNLR1 protein Q8IU57 UNIPROT up-regulates binding 9606 12469119 t gcesareni Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha. SIGNOR-96243 0.844 CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity binding 9606 21078818 t gcesareni Phosphorylated lrp5/6 leads to inhibition of the so-called beta-catenin destruction complex (which includes axin, gsk3, dvl, ck1, and the tumor suppressor adenomatous polyposis coli), resulting in the stabilization and translocation of beta-catenin in the nucleus, where it activates target genes through binding to tcf/lef transcription factors. SIGNOR-169632 0.914 COL4A3 protein Q01955 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 35267698 t lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. SIGNOR-272351 0.41 beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI PFKP protein Q01813 UNIPROT up-regulates activity binding 9606 19454274 t The PFKFB enzymes synthesize fructose-2,6-bisphosphate (F2,6BP) which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. PFK-1 is inhibited by ATP when energy stores are abundant and F2,6BP can override this inhibition and enhance glucose uptake and glycolytic flux SIGNOR-267268 0.8 DCC protein P43146 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding 9606 15494734 t miannu Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling. SIGNOR-268372 0.516 CSNK1A1 protein P48729 UNIPROT SRPK2 protein P78362 UNIPROT up-regulates activity phosphorylation Ser497 SRTVSASsTGDLPKA 9606 BTO:0000007 29153836 t no miannu  Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins. SIGNOR-275460 0.252 MAPK3 protein P27361 UNIPROT CEBPA protein P49715 UNIPROT down-regulates phosphorylation Ser21 PMSSHLQsPPHAPSS 9606 BTO:0000876 14701740 t lperfetto Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21. SIGNOR-120570 0.379 CTCF protein P49711 UNIPROT APP protein P05067 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11706010 f miannu Depleting HeLa cell nuclear extract of endogenous CTCF specifically reduced transcriptional activity from the APP promoter. CTCF activates transcription from the APP promoter and that the activation domain is located on the N-terminal side of the zinc finger domain. SIGNOR-253823 0.267 clozapine chemical CHEBI:3766 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 10116 BTO:0000529 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258515 0.8 PTPN1 protein P18031 UNIPROT STAT5B protein P51692 UNIPROT down-regulates dephosphorylation Tyr699 TAKAVDGyVKPQIKQ 9606 BTO:0000149 10993888 t gcesareni A cytosolic protein-tyrosine phosphatase ptp1b specifically dephosphorylates and deactivates prolactin-activated stat5a and stat5b. SIGNOR-82042 0.662 GRK2 protein P25098 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 10852916 t llicata We found that grk-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and pld2. These findings suggest that gpcrs may be able to indirectly stimulate pld2 activity via their ability to regulate grk-promoted phosphorylation of synuclein. SIGNOR-78333 0.2 LRFN5 protein Q96NI6 UNIPROT PTPRD protein P23468 UNIPROT up-regulates activity binding 9606 BTO:0000938 27225731 t miannu SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1). SIGNOR-264086 0.281 PKN1 protein Q16512 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Ser374 GLYSRSGsLSGRSSL -1 10467162 t lperfetto Autophosphorylation of wild-type PKN increased the protein kinase activity, however, substitution of Thr64, Ser374, or Thr531 in the regulatory region of PKN with alanine, abolished this effect. SIGNOR-249021 0.2 MYOD1 protein P15172 UNIPROT ITGA7 protein Q13683 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 8798472 t lperfetto Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development. SIGNOR-241518 0.291 MYD88 protein Q99836 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 28404732 t miannu In innate immunity, nearly all Toll-like receptors (TLRs), as well as the receptors of the interleukin 1 (IL-1) family of cytokines, initiate signaling by recruiting the adaptor protein MyD88. This is followed by the interaction of IL-1-receptor (IL-R)-associated kinase 4 (IRAK4) with MyD88 and then the interaction of other IRAK family members with IRAK4, to form an oligomeric complex, termed the Myddosome (8, 9). IRAK1 and IRAK2 can then interact with TRAF6 (10, 11) and induce TRAF6 dimerization (12), which triggers the activation of its E3 ligase activity SIGNOR-260160 0.92 IL3 protein P08700 UNIPROT IL3RA protein P26951 UNIPROT up-regulates binding 9606 11700046 t gcesareni The results demonstrate that both the association and dissociation rates for the binding of il-3 to the il-3ralpha are altered by truncation and by amino acid substitution at individual sites. Intracellular signaling studies using k116w and e43n demonstrate that differences in the il-3alpha binding characteristics are reflected in magnitude and kinetics of stat5 phosphorylation. SIGNOR-111404 0.884 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH7 protein Q9ULB5 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265847 0.8 CSKMT protein A8MUP2 UNIPROT CS protein O75390 UNIPROT down-regulates activity methylation Lys395 LLEQGKAkNPWPNVD 34929314 t lperfetto A mitochondrial matrix-located methyltransferase, methyltransferase-like protein 12 (METTL12), has been reported to methylate CS on the lysine 368 (K368) [15] and K395 residues [16] which are near the active site of CS. The methylation on K395 inhibits CS activity, which can be antagonized by its substrate oxaloacetate. SIGNOR-267637 0.2 KLHL3 protein Q9UH77 UNIPROT WNK1 protein Q9H4A3 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000567 23387299 t miannu CUL3 assembles with BTB proteins to form Cullin-RING E3 ubiquitin ligase complexes. To explore how a CUL3-KLHL3 complex might operate, we immunoprecipitated KLHL3 and found that it associated strongly with WNK isoforms and CUL3. These results suggest that the CUL3-KLHL3 E3 ligase complex regulates blood pressure via its ability to interact with and ubiquitylate WNK isoforms. SIGNOR-272099 0.58 CSNK2B protein P67870 UNIPROT BRCA1 protein P38398 UNIPROT unknown phosphorylation Ser1572 ESGISLFsDDPESDP -1 10403822 t llicata Subsequent studies showed that BRCA1 was phosphorylated in vitro by CK2. An analysis by site directed mutagenesis of BRCA1 showed that in vitro phosphorylation by CK2 required a serine at aa1572. These data implicate CK2 as a potential mediator of BRCA1 activity. SIGNOR-251055 0.351 JAK3 protein P52333 UNIPROT JAK1 protein P23458 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 17259970 t milica Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity. SIGNOR-152917 0.516 PRKCI protein P41743 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates quantity by stabilization phosphorylation Ser345 RGDGSGFsL 9606 BTO:0002181 23249950 t miannu APKC associates and phosphorylates Par6 on S345. aPKC expression stabilizes Par6 protein levels. We show that the aPKC, PKCι, interacts with TGF-β receptors through Par6 and that these proteins localize to the leading edge of migrating cells. Furthermore, Par6 phosphorylation on serine 345 by TGF-β receptors is enhanced in the presence of aPKC. aPKC kinase activity, as well as an association with Par6, were found to be important for Par6 phosphorylation. SIGNOR-276432 0.861 MAP3K5 protein Q99683 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 8974401 t lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-45366 0.616 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KAT5 protein Q92993 UNIPROT up-regulates activity phosphorylation Ser86 TKNGLPGsRPGSPER 9606 BTO:0000567 12468530 t llicata Baculovirus-based expression and purification of Tip60 combined with mass spectrometry allowed the identification of serines 86 and 90 as two major sites of phosphorylation in vivo. The phosphorylation of Tip60 was found to modulate its histone acetyltransferase activity. One of the identified phosphorylated serines, Ser-90, was within a consensus cyclin B/Cdc2 site. Ser-90 was specifically phosphorylatedin vitro by the cyclin B/Cdc2 complex. SIGNOR-250641 0.428 FRK protein P42685 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr407 SGLSMSSySVPRTPD 9606 BTO:0002035 35723276 t miannu Mechanistically, FRK interacted with and phosphorylated YAP on Tyr391/407/444, which recruited the classical E3 ubiquitin ligase Siah1 to catalyze ubiquitination and eventually degradation of YAP.  SIGNOR-275456 0.278 F2RL1 protein P55085 UNIPROT CTSD protein P07339 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 21072196 f miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). SIGNOR-254860 0.2 D-thyroxine smallmolecule CHEBI:30659 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity chemical activation 9606 BTO:0003736 6777394 t inferred from 70% of family members miannu The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response. SIGNOR-269878 0.8 cholesta-5,7-dien-3beta-ol smallmolecule CHEBI:17759 ChEBI calciol smallmolecule CHEBI:28940 ChEBI up-regulates quantity precursor of 9606 BTO:0001253 30080183 t lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin SIGNOR-270561 0.8 SIRT1 protein Q96EB6 UNIPROT NCOR1 protein O75376 UNIPROT up-regulates 9606 22395773 t FFerrentino In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription. SIGNOR-253505 0.64 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser638 PQCSPQHsPLGAVKS 9606 BTO:0000007 16141410 t In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity SIGNOR-251250 0.406 CSNK2A2 protein P19784 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser423 LNSGDDVsEQDVPDL -1 12107178 t llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. SIGNOR-250994 0.424 FBXO22 protein Q8NEZ5 UNIPROT BSG protein P35613 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 28117675 t miannu FBXO22 mediates poly-ubiquitination and degradation of CD147. Classically, F-box protein together with Skp1 and Cullin 1 constitute Skp-Cullin-F box ubiquitin E3 ligase (SCFs) SIGNOR-272787 0.437 N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide chemical CHEBI:94793 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189933 0.8 URB597 chemical CID:1383884 PUBCHEM FAAH protein O00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207615 0.8 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT down-regulates quantity phosphorylation Ser642 PRLGSTFsLDTSMSM 9606 BTO:0000782 11024037 t lperfetto However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway.  SIGNOR-249057 0.327 HEY1 protein Q9Y5J3 UNIPROT MYOG protein P15173 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 19917614 f lperfetto Our results indicate instead that hey1 is recruited to the promoter regions of myogenin and mef2c, two genes whose induction is critical for myogenesis. SIGNOR-235822 0.379 PIK3AP1 protein Q6ZUJ8 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000801 22187458 t gcesareni Bcap is constitutively phosphorylated and associated with the p85 subunit of pi3k in macrophages. Tlr signaling causes the phosphorylation of the small amount of bcap that is associated with membranes in the resting state or the translocation of phosphorylated bcap from the cytoplasm to the membrane. This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Bcap is an essential activator of the pi3k pathway downstream of tlr signaling SIGNOR-191673 0.61 nintedanib chemical CHEBI:85164 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition -1 18559524 t Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. SIGNOR-257804 0.8 AKT1 protein P31749 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Ser48 QLSLRTVsLGAGAKD 9606 BTO:0001345 25071014 t miannu We find that AKT phosphorylation of NPM-Ser48 prevents oligomerization that results in nucleoplasmic localization of ARF, constitutive MDM2 inhibition and stabilization of p53. SIGNOR-276667 0.549 PRKCA protein P17252 UNIPROT ANXA2 protein P07355 UNIPROT unknown phosphorylation Ser26 TPPSAYGsVKAYTNF 9606 BTO:0000452 2946940 t lperfetto The protein-tyrosine kinase substrate p36 is also a substrate for protein kinase C in vitro and in vivo. | We present evidence suggesting that protein kinase C mediates phosphorylation of serine 25. SIGNOR-248892 0.363 MMP9 protein P14780 UNIPROT Cellular_extravasation phenotype SIGNOR-PH225 SIGNOR up-regulates 9606 BTO:0000584 38339310 f miannu Given that MMP-9 is able to degrade the ECM, which is an essential step in tumor cell extravasation and metastasis, and it is highly expressed in PDAC, CXCL12 may be playing a similar role in upregulating MMPs in PDAC SIGNOR-277734 0.7 CUDC-101 chemical CID:24756910 PUBCHEM HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20143778 t miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. SIGNOR-262258 0.8 SSTR3 protein P32745 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256677 0.562 ARRB2 protein P32121 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000971 12488444 t miannu Our current results demonstrated that the binding of Mdm2 to beta-arrestin 2 was significantly enhanced by stimulation of GPCRs. Activation of GPCRs led to formation of a ternary complex of Mdm2, beta-arrestin 2, and GPCRs and thus recruited Mdm2 to GPCRs at plasma membrane. Moreover, the binding of beta-arrestin 2 to Mdm2 suppressed the self-ubiquitination of Mdm2 and consequently reduced the Mdm2-mediated p53 degradation and ubiquitination. SIGNOR-272592 0.444 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser71 RFIGRRQsLIEDARK 9606 7901013 t The effect has been demonstrated using P07101-3 gcesareni Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax SIGNOR-34686 0.27 PRKCA protein P17252 UNIPROT RGS7 protein P49802 UNIPROT down-regulates activity phosphorylation -1 12077120 t miannu TNF-α rapidly increases the concentration of functionally active RGS7 protein through two mechanisms. TNF-induced dephosphorylation of serine 434 liberates RGS7 from 14-3-3 binding and inhibition. , PKC α catalyzes the incorporation of phosphate into a truncation of RGS7 fused to maltose-binding protein (MBP.RGS7315–469). SIGNOR-263165 0.372 PRPF4 protein O43172 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270622 0.699 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates 9606 23075495 f inferred from 70% of family members gcesareni On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz. SIGNOR-269867 0.8 IKBKB protein O14920 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 19188143 t gcesareni Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway SIGNOR-183684 0.679 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 f Numerous studies have implicated the critical importance of the Ras/Erk pathway in cell division and survival SIGNOR-254948 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DUSP1 protein P28562 UNIPROT down-regulates phosphorylation 9606 16286470 t inferred from 70% family members lperfetto The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain SIGNOR-270189 0.2 CAMK2G protein Q13555 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 BTO:0000887 11114197 t gcesareni Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation. SIGNOR-85102 0.404 AKT1 protein P31749 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-254372 0.7 CSNK2A1 protein P68400 UNIPROT SPTBN1 protein Q01082 UNIPROT down-regulates phosphorylation Ser2110 PEPSTKVsEEAESQQ 9606 17088250 t miannu We show here that the short c-terminal splice variant of betaii-spectrin (betaiisigma2) is a substrate for phosphorylation. In vitro, protein kinase ck2 phosphorylates ser-2110 and thr-2159 / phosphorylation of ?II?2 C-terminal fragment inhibits its interaction with ?II N-terminal fragment. SIGNOR-150467 0.34 PIP3 smallmolecule CHEBI:16618 ChEBI Macropinosomes formation phenotype SIGNOR-PH227 SIGNOR up-regulates 9606 BTO:0001033 29572236 f miannu PIP3 produced by type I PI3Ks is required for macropinosome closure; in some cell types, PIP3 is also required for membrane ruffling SIGNOR-277769 0.7 methiothepin chemical CHEBI:64203 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258892 0.8 Activated PSC phenotype SIGNOR-PH224 SIGNOR TGFB1 protein P01137 UNIPROT up-regulates quantity 9606 BTO:0000988 38540204 t miannu Resident fibroblasts, especially PSC, have the ability to transdifferentiate from a “quiescent” retinoid/lipid storing phenotype in the normal pancreas to an “activated” α-smooth muscle-actin-producing myofibroblastic phenotype through tumor-derived stimuli such as cytokines (interleukin(IL)-1, IL-6, and IL-8 and tumor necrosis factor (TNF)-α), growth factors (platelet-derived growth factor (PDGF) and tumor growth factor (TGF)-β), and reactive oxygen species [33]. Activated PSCs can, in turn, produce autocrine factors such as PDGF, TGF-β, and cytokines, which may contribute to a looping mechanism promoting a desmoplastic reaction SIGNOR-277673 0.7 Caspase 3 complex complex SIGNOR-C221 SIGNOR IKBKB protein O14920 UNIPROT down-regulates cleavage Asp546 ALQTDIVdLQRSPMG 9606 11741536 t gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. SIGNOR-256435 0.372 pazopanib chemical CHEBI:71219 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258260 0.8 RELA protein Q04206 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9733516 f gcesareni Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2. SIGNOR-59957 0.531 NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys6 kGGKGLGK 9606 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. by comparing the substrate specificities of the MSL and NSL complexes, we obtain evidence that MOF HAT activity is differentially regulated by assembly into the MSL complex, where it acetylates nucleosomal histone H4 on lysine 16, and the NSL complex, where it also acetylates nucleosomal histone H4 on lysines 5 and 8. SIGNOR-267167 0.2 BLVRA protein P53004 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation Thr500 WDGVTTKtFCGTPDY 9606 17227757 t llicata Human biliverdin reductase, a previously unknown activator of protein kinase c ?II the phosphorylation of thr500 was confirmed by immunoblotting of hbvr.pkc betaii immunocomplex. SIGNOR-152181 0.312 EDN3 protein P14138 UNIPROT EDNRB protein P24530 UNIPROT up-regulates binding 9606 BTO:0000975 8086489 t gcesareni These results demonstrate that lys-161 of the receptor is important for high affinity binding with et-3 which, in part, confers the non-selective binding characteristics of the etb receptor for et isopeptides. SIGNOR-36017 0.79 PKM protein P14618 UNIPROT HIF-1 complex complex SIGNOR-C418 SIGNOR up-regulates activity binding 9606 BTO:0000567 21620138 t PKM2 interacts directly with the HIF-1α subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, SIGNOR-267473 0.398 LCK protein P06239 UNIPROT EZR protein P15311 UNIPROT unknown phosphorylation Tyr146 KEVHKSGyLSSERLI -1 12560083 t Lck phosphorylated ezrin in vitro, and the major phosphotyrosine was identified as Y145. Whether tyrosine phosphorylation of ezrin is an alternative mechanism to regulate dynamic changes of the actin cytoskeleton, as has been suggested in EGF-, PDGF- or HGF-treated epithelial cells, is still unclear. Alternatively, Lck-induced tyrosine phosphorylation of ezrin may be linked to its other functions, including participation in signaling pathways that control proliferation and apoptosis SIGNOR-251374 0.519 AKT proteinfamily SIGNOR-PF24 SIGNOR BAX protein Q07812 UNIPROT down-regulates activity phosphorylation Ser184 VAGVLTAsLTIWKKM 9606 BTO:0003473 14766748 t lperfetto Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophilsWe suggest that Bax is regulated by phosphorylation of Ser(184) in an Akt-dependent manner and that phosphorylation inhibits Bax effects on the mitochondria by maintaining the protein in the cytoplasm, heterodimerized with antiapoptotic Bcl-2 family members SIGNOR-209651 0.2 UBE2E1 protein P51965 UNIPROT MPG protein P29372 UNIPROT up-regulates activity binding -1 25207814 t miannu Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. We observed that PP2Ac was ubiquitinated in the presence of UbcH5a-c and UbcH6, similar to results obtained with MID1-catalyzed ubiquitination of alpha4 (Figure 2E) SIGNOR-271929 0.2 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation -1 16326050 t miannu Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast SIGNOR-268749 0.8 RFX complex complex SIGNOR-C104 SIGNOR HLA-DOB protein P13765 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 f The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-254000 0.26 FZR1 protein Q9UM11 UNIPROT SKIL protein P12757 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 11741538 t miannu  We demonstrate that the anaphase-promoting complex (APC) is a ubiquitin ligase required for the destruction of SnoN and that the APC pathway is regulated by TGF-beta. The destruction box of SnoN is required for its degradation in response to TGF-beta signaling. Furthermore, the APC activator CDH1 and Smad3 synergistically regulate SnoN degradation. Under these circumstances, CDH1 forms a quaternary complex with SnoN, Smad3, and APC.  SIGNOR-272621 0.393 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Ser371 VRRVPGSsGHLHKTE 9606 16083423 t gcesareni Phosphorylation by WNK1 or WNK4 markedly increased SPAK and OSR1 activity. Phosphopeptide mapping studies demonstrated that WNK1 phosphorylated kinase-inactive SPAK and OSR1 at an equivalent residue located within the T-loop of the catalytic domain (Thr233 in SPAK, Thr185 in OSR1) and a serine residue located within a C-terminal non-catalytic region (Ser373 in SPAK, Ser325 in OSR1) SIGNOR-253553 0.457 PLK1 protein P53350 UNIPROT MAP9 protein Q49MG5 UNIPROT up-regulates phosphorylation Ser289 SDENKENsFSADHVT 9606 20615875 t lperfetto We also demonstrate that asap is a novel substrate of plk1 phosphorylation and have identified serine 289 as the major phosphorylation site by plk1 in vivo. Asap phosphorylated on serine 289 is localized to centrosomes during mitosis, but this phosphorylation is not required for its plk1-dependent localization at the spindle poles. We show that phosphorylated asap on serine 289 contributes to spindle pole stability in a microtubule-dependent manner SIGNOR-166564 0.279 RAB7A protein P51149 UNIPROT NTRK1 protein P04629 UNIPROT down-regulates activity binding 10116 16306406 t Sara Endogenous TrkA and Rab7 form a complex. Inhibition of Rab7 potentiates the signaling of TrkA in response to brief stimulations with NGF SIGNOR-261305 0.484 APC-c complex SIGNOR-C150 SIGNOR SKIL protein P12757 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11741538 t miannu  We demonstrate that the anaphase-promoting complex (APC) is a ubiquitin ligase required for the destruction of SnoN and that the APC pathway is regulated by TGF-beta. The destruction box of SnoN is required for its degradation in response to TGF-beta signaling. Furthermore, the APC activator CDH1 and Smad3 synergistically regulate SnoN degradation. Under these circumstances, CDH1 forms a quaternary complex with SnoN, Smad3, and APC.  SIGNOR-272622 0.329 YWHAE protein P62258 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates binding 9606 12042314 t miannu 14-3-3_, 14-3-3_, and 14-3-3_ (but not 14-3-3_ and 14-3-3_) could form a complex with p27kip1 / we discovered that akt-mediated p27kip1phosphorylation directly induces p27kip1binding to 14-3-3 and cytoplasmic localization through phosphorylating the newly identified thr198residue. SIGNOR-88297 0.52 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0000007 11154276 t lperfetto Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 akt decreased ask1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus akt site at serine 83 of ask1. SIGNOR-104646 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR SH3RF1 protein Q7Z6J0 UNIPROT down-regulates phosphorylation Ser304 KNTKKRHsFTSLTMA 9606 17535800 t miannu We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac, as does phosphomimetic s304d and s304e mutation of posh. SIGNOR-155229 0.2 1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester chemical CHEBI:92418 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258634 0.8 SMAD3 protein P84022 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity binding 10090 BTO:0000165 11711431 t azuccotti We show that the TGF-beta intracellular effector Smad3, but not Smad2, mediates the inhibition of myogenic differentiation in MyoD-expressing C3H10T1/2 cells and C2C12 myoblasts by repressing the activity of the MyoD family of transcriptional factors. SIGNOR-252071 0.72 TYK2 protein P29597 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates activity phosphorylation Tyr481 PSSSIDEyFSEQPLK 9606 7526154 t lperfetto In this report, we demonstrate that the alpha subunit of the type I IFN receptor (IFN-R) corresponds to the product of a previously cloned receptor subunit cDNA and, further, that the p135tyk2 tyrosine kinase directly binds and tyrosine phosphorylates this receptor subunit.These data support the hypothesis that the Tyk2 protein functions as part of a receptor complex to initiate intracellular signaling in response to type I IFNs SIGNOR-246939 0.908 CSNK2A2 protein P19784 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser280 VDGTGDTsSEEDEDE -1 11278496 t llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. SIGNOR-250995 0.382 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203588 0.769 CSNK2A2 protein P19784 UNIPROT ARRB2 protein P32121 UNIPROT unknown phosphorylation Thr382 EFDTNYAtDDDIVFE -1 11877451 t llicata We found that arrestin-3 is constitutively phosphorylated at Thr-382 and becomes dephosphorylated upon beta(2)-adrenergic receptor activation in COS-1 cells. Casein kinase II (CKII) appears to be the major kinase mediating arrestin-3 phosphorylation, since 1) Thr-382 is contained within a canonical consensus sequence for CKII phosphorylation and 2) wild type arrestin-3 but not a T382A mutant is phosphorylated by CKII in vitro. | However, additional analysis reveals that arrestin-3 phosphorylation may regulate formation of a large arrestin-3-containing protein complex. SIGNOR-250977 0.315 WNK1 protein Q9H4A3 UNIPROT OXSR1 protein O95747 UNIPROT up-regulates phosphorylation Thr185 TRNKVRKtFVGTPCW 9606 17190791 t gcesareni Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1) SIGNOR-151663 0.497 LPAR1 protein Q92633 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 20331961 t milica The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits). SIGNOR-230761 0.432 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates activity phosphorylation Ser959 DHSVRINsVGSTASS 9823 BTO:0004007 7539802 t lperfetto We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling. SIGNOR-248900 0.511 CHFR protein Q96EP1 UNIPROT KIF22 protein Q14807 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 19321445 t miannu Chfr ubiquitinates Kif22 and promotes its degradation. SIGNOR-271469 0.408 Fanconi anemia ID complex complex SIGNOR-C302 SIGNOR BRCA1 protein P38398 UNIPROT up-regulates 18985065 f lperfetto Once monoubiquitinated, the ID complex becomes associated with chromatin and is redistributed to DNA-damage sites, forming foci that are visible by immunofluorescence and colocalizing with other DNA-repair molecules, notably BRCA1, BRCA2 and γH2AX. SIGNOR-263271 0.826 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation Thr642 TRQPVELtPTDKLFI 9606 17115692 t lperfetto The catalytic or kinase domain requires phosphorylation at three sites for full activation (24, 25): ? Phosphorylation of threonine 500 (thr-500) in the activation loop by the upstream kinase pdk-1 is a prerequisite for the maturation of the enzyme (26), which subsequently leads to autophosphorylation at threonine 641 (thr-641) in the turn motif and serine 660 (ser-660) in the hydrophobic motif SIGNOR-150865 0.2 AT9283 chemical CID:11696609 PUBCHEM ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190008 0.8 CSNK2A1 protein P68400 UNIPROT WASF2 protein Q9Y6W5 UNIPROT down-regulates phosphorylation Ser488 YSDSEDDsSEFDEDD 9606 19012317 t gcesareni Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo. SIGNOR-182358 0.2 SIRT2 protein Q8IXJ6 UNIPROT PGAM1 protein P18669 UNIPROT up-regulates activity deacetylation Lys100 GGLTGLNkAETAAKH 9606 24786789 t miannu Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2. SIGNOR-266517 0.283 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1092 TFLPVPEyINQSVPK 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-236523 0.2 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser99 HFAIAADsEAEQDSW -1 8349691 t llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. SIGNOR-250909 0.346 RCOR1 protein Q9UKL0 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity binding -1 16140033 t miannu CoREST protects LSD1 from proteasomal degradation and also plays an indispensable role in LSD1-mediated demethylation of nucleosomal substrates in vitro. in contrast to CoREST, which is a positive regulator of LSD1 activity, the in vitro evidence presented above suggests that BHC80 may function to inhibit LSD1 activity. SIGNOR-264506 0.954 IL15RA protein Q13261 UNIPROT TYK2 protein P29597 UNIPROT up-regulates 9606 30029643 t Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated SIGNOR-256253 0.247 ponatinib chemical CHEBI:78543 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 23430109 t lperfetto We assessed the in vitro activity of ponatinib against clinically relevant FLT3-ITD mutant isoforms that confer resistance to AC220 or sorafenib. Substitution of the FLT3 "gatekeeper" phenylalanine with leucine (F691L) conferred mild resistance to ponatinib, but substitutions at the FLT3 activation loop (AL) residue D835 conferred a high degree of resistance. SIGNOR-261983 0.8 UBE3A protein Q05086 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR down-regulates activity ubiquitination 9606 BTO:0000007 28559284 t Through quantitative proteomics and reporter assays, we found that the UBE3AT485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A SIGNOR-270339 0.312 PTPN11 protein Q06124 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9615 BTO:0000837 16611743 t lperfetto In addition, SHP-2 dephosphorylates tyrosine-phosphorylated Stat1/3/5A (Ohtani et al., 2000; Wu et al., 2002; Chen et al., 2003), and downregulates Stat3-mediated biological actions (Ohtani et al., 2000).|Inhibition of collagen-induced Stat3 tyrosine-705 (Stat3-p-Tyr) SIGNOR-272404 0.761 SLC9A6 protein Q92581 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265596 0.8 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 SIGNOR-C110 23151663 t gcesareni Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells. SIGNOR-199512 0.856 TACR1 protein P25103 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257048 0.306 ACD protein Q96AP0 UNIPROT RPA2 protein P15927 UNIPROT down-regulates activity binding SIGNOR-C306 18680434 t lperfetto The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA SIGNOR-263327 0.2 SMDT1 protein Q9H4I9 UNIPROT MCU_MICU2_variant complex SIGNOR-C502 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270875 0.618 BST1 protein Q10588 UNIPROT NADP(+) smallmolecule CHEBI:18009 ChEBI down-regulates quantity chemical modification 9606 18626062 t miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. SIGNOR-264251 0.8 NLK protein Q9UBE8 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates activity phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 BTO:0000007 26588989 t done miannu NLK inhibits mTORC1 lysosomal localization and thereby suppresses mTORC1 activation. Mechanistically, NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment.  SIGNOR-273908 0.333 PAX6 protein P26367 UNIPROT GCG protein P01275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000120 12783165 f miannu In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3. SIGNOR-254905 0.595 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser175 EEEEDLSsPPGLPEP 9606 14697653 t lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. SIGNOR-120467 0.271 SPRED1 protein Q7Z699 UNIPROT NF1 protein P21359 UNIPROT up-regulates quantity binding 9606 BTO:0000007 32697994 t miannu Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS. SIGNOR-273660 0.622 WNT5A protein P41221 UNIPROT GSK3B protein P49841 UNIPROT up-regulates 9606 21078818 f gcesareni We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3) SIGNOR-169669 0.404 β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35 Three different subunits have been identified in humans: PFK-M (muscle), PFK-L (liver), and PFK-P (platelet).The subunits are expressed in a tissue-specific manner and, in erythrocytes, 5 isoenzymes of varying subunit composition (M4, M3L1, M2L2, ML3, and L4) can be identified. SIGNOR-266463 0.8 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser235 SPQDSPPsKASPAQD 9606 21215781 t lperfetto Cdk5 regulates app (amyloid precursor protein) processing and tau hyperphosphorylationtau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules SIGNOR-251587 0.695 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr128 SKAQQGLyQVPGPSP 9606 22710723 t lperfetto Furthermore, we demonstrate that src phosphorylates p130cas y128. We engineered crc cells homozygous for a p130cas y128f knock-in mutant and found that these cells exhibit significantly reduced migration and colony formation SIGNOR-197927 0.796 BUB1 protein O43683 UNIPROT H2AC11 protein P0C0S8 UNIPROT unknown phosphorylation Thr121 AVLLPKKtESHHKAK 9606 19965387 t lperfetto the localization of hBub1 kinase usually defines the centromere-specific phosphorylation of H2A-T120. Accordingly, hSgo1 localized along the whole chromosome length in H2B-hBub1deltaN cells (Fig. 6D), indicating that H2A-pT120 plays a predominant role in defining shugoshin localization sites on the human chromosomes SIGNOR-265261 0.2 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1437 RYPDSYEsMSEPPIA -1 22302995 t miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. SIGNOR-262907 0.69 PTEN protein P60484 UNIPROT ABI1 protein Q8IZP0 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr213 PPTVPNDyMTSPARL 9606 32673396 t lperfetto After dephosphorylation by PTEN, Abi1 is degraded by calpains.|We demonstrate that PTEN dephosphorylation of Abi1 at Y213 and S216 results in Abi1 degradation through the calpain pathway. SIGNOR-276948 0.243 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates activity phosphorylation Ser100 HLSGRKLsLQERSQG 9534 BTO:0000298 32913128 t miannu  Here we show that stimulation of cAMP-dependent protein kinase A (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues.  SIGNOR-277239 0.2 TP53 protein P04637 UNIPROT GADD45A protein P24522 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23576563 f gcesareni P53 acetylated at k120 subsequently bound to the promoters of its target apoptotic genes, bax and gadd45, to promote their expression and lead to apoptosis. SIGNOR-201679 0.646 ARHGEF26 protein Q96DR7 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260545 0.568 PKC proteinfamily SIGNOR-PF53 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates activity dephosphorylation Ser661 SSNDSRSsLIRKRST 9606 BTO:0000007 24333728 t Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp SIGNOR-272512 0.2 practolol chemical CHEBI:258351 ChEBI ADRB1 protein P08588 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 10079020 t Luana In our CHO cells transfected with the human β1- and β2-adrenoceptors, the binding affinities of atenolol, metoprolol, betaxolol and practolol correlate with previously published β1- (P=0.03) and β2-adrenoceptor (P=0.03) binding affinities in human lung tissue SIGNOR-258336 0.8 GSK3B protein P49841 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 BTO:0000007 14570592 t lperfetto However, in the present study, we clearly demonstrate that GSK3_ is capable of catalysing the autophosphorylation of Tyr216 in vitro. SIGNOR-236564 0.2 HLF protein Q16534 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 23415677 f miannu Ectopic hlf expression inhibits apoptosis in murine and human cells, suggesting that hlf is regulating a conserved transcriptional program that inhibits cell death. SIGNOR-256647 0.7 PDPK1 protein O15530 UNIPROT PKN2 protein Q16513 UNIPROT up-regulates phosphorylation Thr816 GYGDRTStFCGTPEF 9606 10753910 t miannu It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively) SIGNOR-76710 0.692 ITCH protein Q96J02 UNIPROT NFE2 protein Q16621 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 18718448 t lperfetto Itch regulates p45/NF-E2 in vivo by Lys63-linked ubiquitination| Interestingly, Itch suppressed the transactivation activity of p45/NF-E2 by adding a Lys63-linked polyubiquitin chain. Confocal microscopy revealed that ubiquitinated p45/NF-E2 became localized in the cytoplasm when Itch was over-expressed. Thus, Itch-mediated ubiquitination of p45/NF-E2 does not target the protein for proteasomal degradation, but instead retains p45/NF-E2 in the cytoplasm, where it cannot function as a transactivator. SIGNOR-275553 0.423 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 9606 18160256 t Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248655 0.89 Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 9606 14684878 f miannu Dendritic spines are small protrusions found on dendrites of principal neurons of mammalian brain. Serving as postsynaptic compartments for individual excitatory inputs, spines show rapid movements and shape changes that are influenced by synaptic activity. The structural modifications of spines are believed to represent morphological correlates of synaptic plasticity. The form and motility of spines are determined mainly by the actin cytoskeleton SIGNOR-266596 0.7 CDK7 protein P50613 UNIPROT CAK complex complex SIGNOR-C456 SIGNOR form complex binding 9606 30860024 t lperfetto CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269319 0.958 FOXO1 protein Q12778 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22521266 t gcesareni Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase). SIGNOR-197200 0.439 KDM4B protein O94953 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity demethylation 9606 30759871 t miannu The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. The majority of studies regarding its function describe it as an activator that removes repressive H3K9me3 and H3K9me2 at or near regulated promoters in order to facilitate expression of the indicated pathways. SIGNOR-265359 0.2 THOC7 protein Q6I9Y2 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 t miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. SIGNOR-268507 0.911 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates activity phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 BTO:0000782 12817019 t lperfetto Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase. SIGNOR-102507 0.797 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Thr100 TNTYYLQtFGHNTMD 9606 BTO:0000007 21321328 t miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). SIGNOR-276307 0.595 DNA polymerase epsilon complex SIGNOR-C377 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 10801849 f lperfetto HeLa pol epsilon was initially purified as a soluble factor that restored repair synthesis to cytosol-depleted, UV-irradiated permeabilized human fibroblasts (11). By reconstituting the nucleotide excision repair (NER) process from purified proteins, Shivji et al. (12) further showed that mammalian pol epsilon was the most efficient enzyme in performing gap-filling DNA synthesis during NER. SIGNOR-265722 0.7 PPM1K protein Q8N3J5 UNIPROT BCKDHA protein P12694 UNIPROT up-regulates activity dephosphorylation Ser337 TYRIGHHsTSDDSSA 10090 19411760 t BCKD is inhibited by phosphorylation of its E1alpha subunit at Ser293, which is catalyzed by BCKD kinase. During BCAA excess, phosphorylated Ser293 (pSer293) becomes dephosphorylated through the concerted inhibition of BCKD kinase and the activity of an unknown intramitochondrial phosphatase. Using unbiased, proteomic approaches, we have found that a mitochondrial-targeted phosphatase, PP2Cm, specifically binds the BCKD complex and induces dephosphorylation of Ser293 in the presence of BCKD substrates SIGNOR-248758 0.774 HLA-DRB1 protein P01911 UNIPROT Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 BTO:0000776 21178476 f scontino Fusion with a B cell requires a ternary complex of gHgLgp42. Fusion is triggered by an interaction between gp42 and HLA class II. SIGNOR-266631 0.7 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Arg534 KSRSLDRrGIQRAAD -1 7989361 t lperfetto The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994. SIGNOR-263629 0.584 KNL1 protein Q8NG31 UNIPROT BUB1 protein O43683 UNIPROT up-regulates binding 9606 17981135 t gcesareni Association of the amino and middle domain of blinkin with the tpr domains in the amino termini of bubr1 and bub1 is essential for bubr1 and bub1 to execute their distinct mitotic functions SIGNOR-158378 0.2 Norbinaltorphimine chemical CHEBI:81529 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258819 0.8 STAT3 protein P40763 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27141364 t irozzo STAT3 and HIF-1α cooperatively enhance PD-L1 expression in EML4-ALK-translocated pADC cells under hypoxia.The protein-DNA binding assay revealed that pSTAT3 was bound to the PD-L1 promoter region in H23 cells transfected with EML4-ALK. SIGNOR-259188 0.477 SCN4A protein P35499 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. SIGNOR-253451 0.7 GNAL protein P38405 UNIPROT ADCY5 protein O95622 UNIPROT up-regulates activity binding 9606 BTO:0004032 21303898 t miannu D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum. SIGNOR-264997 0.599 CDON protein Q4KMG0 UNIPROT SPAG9 protein O60271 UNIPROT up-regulates activity binding 9606 BTO:0000222 17074887 t lperfetto In this study, we report that the cdo intracellular region interacts with jlp, a scaffold protein for the p38alpha/beta mapk pathway. SIGNOR-150282 0.477 PRKCB protein P05771 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 17010989 t lperfetto Pkc-betaii sensitizes cardiac myofilaments to ca2+ by phosphorylating troponin i on threonine-144. SIGNOR-149957 0.2 UGP2 protein Q16851 UNIPROT UTP(4-) smallmolecule CHEBI:46398 ChEBI down-regulates quantity chemical modification 9606 8631325 t miannu UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. SIGNOR-267927 0.8 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr368 SEHAQDTyLVLDKWL 12441334 t JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 SIGNOR-251348 0.805 ACTR5 protein Q9H9F9 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270850 0.691 Neuregulin proteinfamily SIGNOR-PF37 SIGNOR ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR up-regulates activity binding 9606 18415007 t miannu The neuregulin family consists of four genes, NRG1-4 which can each encode products containing a domain related to the epidermal growth factor family of ligands. they may be released by regulated proteolysis to act as soluble proteins which can interact and activate members of the EGF receptor family of receptor tyrosine kinases SIGNOR-256161 0.906 HIPK2 protein Q9H2X6 UNIPROT PAX6 protein P26367 UNIPROT up-regulates activity phosphorylation Thr304 QPIPQPTtPVSSFTS 9606 BTO:0001938 16407227 t HIPK2 phosphorylates the activation domain of Pax6, which augments Pax6 transactivation by enhancing its interaction with p300. Mass spectrometric analysis identified three Pax6 phosphorylation sites as threonines 281, 304, and 373. SIGNOR-251270 0.476 STUB1 protein Q9UNE7 UNIPROT CBX4 protein O00257 UNIPROT down-regulates quantity by destabilization ubiquitination Lys280 GMQAVKIkSGEVAEG 9606 BTO:0002181 32111827 t miannu The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα.  SIGNOR-277514 0.2 ROCK1 protein Q13464 UNIPROT PPP1R12B protein O60237 UNIPROT down-regulates phosphorylation Thr646 ARQTRRStQGVTLTD 9606 22937917 t lperfetto Phosphorylation of ppp1r12b on threonine 646 by rho kinase inhibits the activity of the pp1c-ppp1r12b complex. SIGNOR-198812 0.569 BLK protein P51451 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268214 0.633 RUNX3 protein Q13761 UNIPROT DNASE1 protein P24855 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002384 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255092 0.2 PYCARD protein Q9ULZ3 UNIPROT BAX protein Q07812 UNIPROT up-regulates relocalization 9606 16964285 t gcesareni Asc directly induces bax-mediated apoptosis. Asc induces the translocation of bax to the mitochondria, bax-dependent cycs release from the mitochondria and casp9 activation. SIGNOR-149522 0.36 E2F1 protein Q01094 UNIPROT DHFR protein P00374 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253853 0.516 PRKACA protein P17612 UNIPROT ADD2 protein P35612 UNIPROT down-regulates activity phosphorylation Ser713 KKKFRTPsFLKKSKK -1 8810272 t miannu Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of - and -adducin, respectively, were identified as the major phosphorylation sites common for PKA and PKC. Phosphorylation by PKA, but not PKC, reduced the affinity of adducin for spectrin-F-actin complexes as well as the activity of adducin in promoting binding of spectrin to F-actin. SIGNOR-250332 0.286 GABARAP protein O95166 UNIPROT TBC1D25 protein Q3MII6 UNIPROT up-regulates binding 9606 21383079 t gcesareni In this study, we report evidence demonstrating that oatl1, a putative rab guanosine triphosphatase-activating protein (gap), is a novel binding partner of atg8 homologues in mammalian cells. Oatl1 is recruited to isolation membranes and autophagosomes through direct interaction with atg8 homologues and is involved in the fusion between autophagosomes and lysosomes through its gap activity. SIGNOR-172536 0.587 TRIM63 protein Q969Q1 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates activity 10090 25549588 f areggio Muscle-specific ubiq- uitin ligases, muscle-specific RING-finger 1 (MURF1; also known as TRIM63)12 and atrogin 1 (also known as MAFBX), are markedly induced in almost all types of atrophy. SIGNOR-254993 0.7 PHF7 protein Q9BWX1 UNIPROT SMARCD3 protein Q6STE5 UNIPROT form complex binding 9606 33941892 t miannu Mechanistically, PHF7 localizes to cardiac super enhancers in fibroblasts, and through cooperation with the SWI/SNF complex, it increases chromatin accessibility and transcription factor binding at these sites. Furthermore, PHF7 recruits cardiac transcription factors to activate a positive transcriptional autoregulatory circuit in reprogramming. PHF7 interacts with SMARCD3 to promote reprogramming. SIGNOR-269816 0.2 PDGFA protein P04085 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252286 0.7 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser396 GHQGTVPsDNIDSQG -1 8662852 t we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). SIGNOR-251195 0.682 perfluorononanoic acid chemical CHEBI:38397 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation -1 31332417 t miannu In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group. SIGNOR-268756 0.8 DHCR7 protein Q9UBM7 UNIPROT cholesta-5,7-dien-3beta-ol smallmolecule CHEBI:17759 ChEBI down-regulates quantity chemical modification 9606 9634533 t miannu In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme sterol D7 -reductase. This NADPH-dependent enzyme catalyzes the reduction of the D7 -diene bond in 7-DHC, to form cholesterol. SIGNOR-267251 0.8 KDM5D protein Q9BY66 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-265336 0.2 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Thr295 AEALNQVtQRASRRS 9606 19366211 t gcesareni These results implicate pkcdelta-thr(295) autophosphorylation as a lipid-dependent modification that links pkcdelta-thr(505) phosphorylation to src-dependent regulation of pkcdelta catalytic function. SIGNOR-185283 0.2 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176821 0.775 PRKCA protein P17252 UNIPROT EGLN2 protein Q96KS0 UNIPROT down-regulates phosphorylation Ser132 GGDAPSPsKRPWARQ 9606 18710826 t tpavlidou Thus, recombinant phd1 was examined for in vitro phosphorylation using protein kinase a, protein kinase calpha, casein kinase i and ii and erk2. The protein was most strongly phosphorylated by protein kinase calpha, and the phosphorylation sites were found to be ser-132, ser-226 and ser-234.Mutation Of ser-132 or ser-234 to asp or glu diminished the enzymatic activity to 25-60%, while mutation of ser-226 scarcely influenced the activity. SIGNOR-180199 0.341 BCL2 protein P10415 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 9463381 t amattioni Bcl-2 bind to bax or five other pro-apoptotic relatives (bak, bad, bik, bid or bim) SIGNOR-55546 0.663 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 8702662 t lperfetto A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function SIGNOR-42956 0.797 Brivanib alaninate chemical CID:11154925 PUBCHEM FGFR1 protein P11362 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190717 0.8 SP3 protein Q02447 UNIPROT SLC19A3 protein Q9BZV2 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 15217784 f miannu In transiently transfected Drosophila SL2 cells, both SP1 and SP3 transactivated the SLC19A3 minimal promoter in a dose-dependent manner and in combination demonstrated an additive stimulatory effect. SIGNOR-255214 0.3 DMC1 protein Q14565 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR up-regulates activity binding 10090 BTO:0001275 10525529 t miannu The eukaryotic RecA homologues RAD51 and DMC1 function in homology recognition and formation of joint-molecule recombination intermediates during yeast meiosis. We also show that mouse RAD51 and DMC1 establish protein-protein interactions with each other and with the chromosome core component COR1(SCP3) in a two-hybrid system and in vitro binding analyses. These results suggest that the formation of a multiprotein recombination complex associated with the meiotic chromosome cores is essential for the development and fulfillment of the meiotic recombination process. SIGNOR-264208 0.342 SRC protein P12931 UNIPROT CNKSR1 protein Q969H4 UNIPROT up-regulates activity phosphorylation Tyr519 PPREEDCySETEAED 26319181 t lperfetto We identified Tyr 26 as a PDGF-induced and, additionally, Tyr 519 and Tyr 665 as SRC-induced tyrosine phosphorylation sites. Phosphomimetic mutants indicate that phosphorylation of Tyr 519 recruits CNK1 to the nucleus and additional phosphorylation of Tyr 26 enables CNK1 to promote SRE-dependent gene expression. SIGNOR-275918 0.485 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Ser281 NRRQLAFsTVGTPDY 9606 BTO:0000007 16314523 t lperfetto Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity. SIGNOR-142514 0.2 IGF1 protein P05019 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates 10090 10448861 f lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. SIGNOR-235825 0.267 SIRT7 protein Q9NRC8 UNIPROT DDX21 protein Q9NR30 UNIPROT up-regulates activity deacetylation Lys18 LESDTAMkKGETLRK 28790157 t lperfetto Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21. SIGNOR-275901 0.262 PRKCI protein P41743 UNIPROT VIM protein P08670 UNIPROT up-regulates activity phosphorylation Ser34 SRSYVTTsTRTYSLG 9606 BTO:0001033 33525953 t miannu Results suggest that aPKCs target multiple activation sites (Ser33/39/56) on Vimentin and therefore is essential for VIF dynamics regulation during the metastasis of prostate cancer cells. SIGNOR-277623 0.2 PI3K complex SIGNOR-C156 SIGNOR IRS1 protein P35568 UNIPROT down-regulates activity 9606 11160134 f lperfetto Ly294002 or wortmannin were used to determine whether pi 3-kinasedependent pathways mediate ser307 phosphorylation during insulin/igf-1 or TNF-alpha Stimulation. As expected, the pi-3 kinase inhibitors ly294002 or wortmannin inhibited activation of pkb/akt in insulin or igf-1 stimulated 3t3-l1 preadipocytes, but were without effect on erk1/2. these results suggest that elements of the pi 3-kinase cascade mediate insulin/igf-1stimulated phosphorylation of ser307 SIGNOR-252717 0.759 PPP2R5B protein Q15173 UNIPROT KIF20A protein O95235 UNIPROT up-regulates activity dephosphorylation Ser878 RILRSRRsPLLKSGP 9606 BTO:0000567 27939310 t miannu We identify MKlp2 as an essential protein for promoting abscission, which may regulate tethering and stabilizing of the PM to the microtubule cytoskeleton. Aurora B phosphorylation of MKlp2 S878 in the LAM is a key inhibitory signal for abscission. Conversely, B56-PP2A promotes abscission by opposing Aurora B phosphorylation of MKlp2 S878. SIGNOR-262660 0.2 Laminin-5 complex SIGNOR-C184 SIGNOR A3/b1 integrin complex SIGNOR-C161 SIGNOR up-regulates activity binding 2032285 t lperfetto Epiligrin, a new cell adhesion ligand for integrin alpha 3 beta 1 in epithelial basement membranes. SIGNOR-253252 0.526 ROS stimulus SIGNOR-ST2 SIGNOR FOXL2 protein P58012 UNIPROT up-regulates quantity by expression 9606 19010791 f miannu Transcriptional upregulation of foxl2 during oxidative and heat stress SIGNOR-182303 0.7 STK4 protein Q13043 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3 SIGNOR-181060 0.349 AKT1 protein P31749 UNIPROT LONP1 protein P36776 UNIPROT up-regulates activity phosphorylation Ser173 VFLKRDDsNESDVVE 9606 BTO:0001061 31406245 t lperfetto In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity. SIGNOR-265724 0.255 RIMBP3 protein Q9UFD9 UNIPROT RIMS2 protein Q9UQ26 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264365 0.365 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr232 GGLPEVAtPESEEAF 9606 BTO:0004971 7816602 t lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. SIGNOR-235877 0.784 PLK1 protein P53350 UNIPROT KIF2C protein Q99661 UNIPROT up-regulates activity phosphorylation Ser715 MQLEEQAsRQISSKK 9606 BTO:0002181 26206521 t miannu Active PLK1, in turn, phosphorylates MCAK at Ser715 which promotes its microtubule depolymerase activity essential for faithful chromosome segregation. SIGNOR-276931 0.804 POU5F1 protein Q01860 UNIPROT PAX6 protein P26367 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 f lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) SIGNOR-253163 0.467 RNF5 protein Q99942 UNIPROT SLC26A4 protein O43511 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 22750442 t miannu E3 ubiquitin ligase Rma1 is involved in Pendrin degradation SIGNOR-271497 0.2 DHFR protein P00374 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI down-regulates quantity chemical modification 9606 21876184 t lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. SIGNOR-268257 0.8 Normorphine chemical CHEBI:7633 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258824 0.8 6-(7-hydroxy-5,6-dihydropyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthalenecarboxamide chemical CHEBI:94965 ChEBI CYP17A1 protein P05093 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207141 0.8 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CCT2 protein P78371 UNIPROT up-regulates phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 21440620 t lperfetto Furthermore, both the s260a and s260d mutants showed a decreased folding capacity as compared to cells expressing the wild-type cct_ subunit ( fig.?_5e), suggesting that a cyclic phosphorylation of the s260 site by s6k1 is likely to be important for chaperonin function and that mutation of this site interferes with this process. SIGNOR-252780 0.2 VPS39 protein Q96JC1 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity relocalization 9534 12941698 t miannu The data demonstrating binding of TLP to TGF-β and activin type II receptors and selective inhibition of Smad3/Smad4 complex formation by deregulated TLP suggest that TLP is involved in localizing these receptors and Smad4 to specific intracellular compartments, where it regulates formation of Smad3/Smad4 but not Smad2/Smad4 complexes. SIGNOR-261377 0.323 AP-1 complex complex SIGNOR-C248 SIGNOR SORT1 protein Q99523 UNIPROT up-regulates quantity binding 9606 BTO:0000007 31767632 t miannu The short intracellular domain of sortilin binds several cytoplasmic adaptor proteins (e.g., the AP-1 complex and GGA1 to -3), most of which target two well-defined motifs: a C-terminal acidic cluster dileucine motif and a YXXΦ motif in the proximal third of the domain. Both motifs contribute to endocytosis as well as Golgi-endosome trafficking of sortilin. SIGNOR-273720 0.437 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BIRC2 protein Q13490 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9916987 f gcesareni The iaps have been shown to be induced by nf-kappab or v-rel in multiple cell lines and conversely, hiap1 and hiap2 have been shown to activate nf-kappab possibly forming a positive feed-back loop. SIGNOR-64100 0.533 BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 24832651 f lperfetto The exact function of the BRCC complex in HR is not entirely elucidated, but its E3 ligase activity may promote the mobilization and stabilization of the complex at broken chromatin sites were the complex can stabilize the formation of RAD51 filaments thus facilitating the repair process SIGNOR-263204 0.7 PTPN6 protein P29350 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr86 VADIDGQyAMTRAQR 9606 20840866 t lperfetto In the present investigation, we demonstrate that SHP-1 dephosphorylates \u03b2-catenin on tyrosines 86 and 654 and promotes its proteasomal degradation.|SHP-1 inhibits \u03b2-catenin function by inducing its degradation and interfering with its association with TATA-binding protein. SIGNOR-277013 0.539 KLK2 protein P20151 UNIPROT NCOA4 protein Q13772 UNIPROT up-regulates 9606 BTO:0001130 24122203 f miannu Klk2may cooperate with the ar coregulator, ara70, to enhance ar transactivation SIGNOR-202885 0.311 F2RL1 protein P55085 UNIPROT AREG protein P15514 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 f miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). SIGNOR-254855 0.2 USP1 protein O94782 UNIPROT FANCI protein Q9NVI1 UNIPROT down-regulates activity deubiquitination SIGNOR-C302 18985065 t lperfetto Phosphorylation of FANCI may also turn the ubiquitinated ID complex into a poor substrate for deubiquitination by the USP1–UAF1 complex, resulting in increased levels of monoubiquitinated FANCD2. SIGNOR-263272 0.652 RUNX3 protein Q13761 UNIPROT TIAL1 protein Q01085 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002384 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255088 0.2 nitric oxide smallmolecule CHEBI:16480 ChEBI ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 35681445 f lperfetto The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment. SIGNOR-272279 0.7 EGFR protein P00533 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr168 TLMEKDSyPRFLKSP 9606 12588871 t gcesareni Phosphorylation on tyr(168) was mediated by the epidermal growth factor receptor (egfr). We show here that endogenous rgs16 is phosphorylated after epidermal growth factor stimulation of mcf-7 cells. SIGNOR-98267 0.425 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257932 0.8 Immunoglobulin lambda-1 light chain protein P0DOX8 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR form complex binding 9606 BTO:0000776 20176268 t scontino Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes. SIGNOR-268198 0.2 SEMA3F protein Q13275 UNIPROT NRP2 protein O60462 UNIPROT up-regulates binding 9606 16816121 t esanto In the nervous system, neuropilins mediate axon retraction and guidance by binding class iii semaphorins. We found that sema3f could compete with metabolically labeled vegf-c for the binding to np1-ig and np2-ig fusion proteins. SIGNOR-147608 0.632 MAP3K11 protein Q16584 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001538 9003778 t lperfetto Immunoprecipitated mlk-3 catalyzed the phosphorylation of sek1 in vitro, and co-transfected mlk-3 induced phosphorylation of sek1 and mkk3 at sites required for activation, suggesting direct regulation of these protein kinases. SIGNOR-45788 0.47 ABL1 protein P00519 UNIPROT DDX5 protein P17844 UNIPROT up-regulates phosphorylation Tyr593 NGMNQQAyAYPATAA 9606 17018282 t llicata These results suggested that p68 was phosphorylated by c-abl in ht-29 cells under stimulation of pdgf. we demonstrated that tyrosine phosphorylation of p68 at y593 mediated pdgf-stimulated epithelial-mesenchymal transition (emt). We showed that pdgf treatment led to phosphorylation of p68 at y593 in the cell nucleus. The y593-phosphorylated p68 (referred to as phosphor-p68) promotes beta-catenin nuclear translocation via a wnt-independent pathway. SIGNOR-149988 0.365 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto Gsk3b phosphorylates tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules SIGNOR-171046 0.728 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser174 LSPASSGsSASFISD 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248681 0.613 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser641 KVTSKCGsLGNIHHK -1 10090741 t miannu We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs. SIGNOR-250174 0.44 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR ACTA1 protein P68133 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136175 0.351 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser910 KALGERVsIL 9606 19029298 t llicata We show that pkd1-ser916 autophosphorylation does not necessarily correlate with pkd1 activity. Rather, autophosphorylation at ser916 is required for subsequent autophosphorylation at ser748. SIGNOR-182480 0.2 CAPRIN1 protein Q14444 UNIPROT G3BP1 protein Q13283 UNIPROT up-regulates activity binding 9606 17210633 t SARA Caprin-1 and G3BP-1 were directly or indirectly associated in a stable complex. The Caprin-1/G3BP-1 complex occurs in cytoplasmic RNA granules SIGNOR-260982 0.606 MED22 protein Q15528 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266661 0.737 RPS6KA1 protein Q15418 UNIPROT ETV1 protein P50549 UNIPROT up-regulates activity phosphorylation Ser216 PMYQRQMsEPNIPFP 9606 12213813 t lperfetto Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation. SIGNOR-249163 0.356 DVL3 protein Q92997 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity 9606 19279717 t areggio Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin SIGNOR-258980 0.354 CDK7 protein P50613 UNIPROT RARG protein P13631 UNIPROT up-regulates activity phosphorylation Ser79 EMVPSSPsPPPPPRV 9534 BTO:0001538 10748061 t miannu That phosphorylation of serines 77 and 79 by cdk7 could be responsible for efficient transcription was further supported by the observation that overexpressed cdk7 significantly enhanced transcription by hRARγ1WT but not by hRARγ1S77A/S79A (Fig. 9 B).  SIGNOR-277896 0.393 CDK7 protein P50613 UNIPROT RARG protein P13631 UNIPROT up-regulates activity phosphorylation Ser79 EMVPSSPsPPPPPRV 9534 BTO:0001538 10748061 t miannu That phosphorylation of serines 77 and 79 by cdk7 could be responsible for efficient transcription was further supported by the observation that overexpressed cdk7 significantly enhanced transcription by hRARγ1WT but not by hRARγ1S77A/S79A (Fig. 9 B).  SIGNOR-277897 0.393 FES protein P07332 UNIPROT FES protein P07332 UNIPROT up-regulates activity phosphorylation Tyr139 Y-->K -1 18775312 t miannu In addition, we analyzed Fes SH2-kinase that had been autophosphorylated on the kinase activation segment (Y713) in complex with a substrate peptide. SIGNOR-277898 0.2 PRKDC protein P78527 UNIPROT MITF protein O75030 UNIPROT up-regulates activity phosphorylation Ser431 S-->C 9606 BTO:0000848 38316520 t miannu These results suggest that DNA-PK can target MITF-S325 for phosphorylation. In melanocytes and melanoma cells, MITF is rapidly phosphorylated by DNA-PK and interacts with NBS1–RAD50 but not MRE11, destabilizing the MRN complex. SIGNOR-277899 0.2 PRKCA protein P17252 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity by destabilization phosphorylation Ser423 GRAGPFSsSRCGASV -1 35931119 t miannu Through mass spectrometry, we identified that ULK1 is O-GlcNAcylated at Ser409, which is distinct from the previously reported Thr635/Thr754 sites. It has been demonstrated that PKCα mediates phosphorylation of ULK1 at Ser423, which attenuates its stability by shunting ULK1 to the chaperone-mediated autophagy (CMA) pathway.  SIGNOR-277900 0.2 CAMK1 protein Q14012 UNIPROT PPME1 protein Q9Y570 UNIPROT up-regulates activity phosphorylation Ser15 MHLGRLPsRPPLPGS 9606 BTO:0002181 24841198 t miannu CaMKI Is the Upstream Kinase for Phosphorylation of PME-1/Ser15 SIGNOR-277827 0.404 PRKD1 protein Q15139 UNIPROT KAT7 protein O95251 UNIPROT up-regulates quantity by stabilization phosphorylation Thr331 LRLQGQItEGSNMIK 9606 BTO:0002181 33014433 t miannu We show that PKD1 directly interacts and phosphorylates KAT7 at Thr97 and Thr331 in vitro and in vivo. PKD1-mediated phosphorylation of KAT7 enhances its expression levels and stability by reducing its ubiquitination-mediated degradation.  SIGNOR-277828 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR BRSK2 protein Q8IWQ3 UNIPROT up-regulates activity phosphorylation Thr260 VDAARRLtLEHIQKH -1 16870137 t miannu BRSK2 is activated by cyclic AMP-dependent protein kinase A through phosphorylation at Thr260 SIGNOR-276056 0.2 PRKD1 protein Q15139 UNIPROT KAT7 protein O95251 UNIPROT up-regulates quantity by stabilization phosphorylation Thr97 KKYPLRQtRSSGSET 9606 BTO:0002181 33014433 t miannu We show that PKD1 directly interacts and phosphorylates KAT7 at Thr97 and Thr331 in vitro and in vivo. PKD1-mediated phosphorylation of KAT7 enhances its expression levels and stability by reducing its ubiquitination-mediated degradation.  SIGNOR-277829 0.2 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT down-regulates phosphorylation Ser44 ESEESQDsSDSIGSS 9606 20730097 t lperfetto These data suggested that atf1 is always hyperphosphorylated on the ck sites in vivo. Also, the antibody reactivity suggested that in addition to ser-36 and ser-41, ser-38 and ser-44 were phosphorylated in vivo. To accommodate these findings, we propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. SIGNOR-167556 0.301 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 9922370 t lperfetto Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity SIGNOR-244688 0.2 PHF6 protein Q8IWS0 UNIPROT UBTF protein P17480 UNIPROT down-regulates binding 9606 BTO:0001271 23229552 t miannu We demonstrate that phf6 is a nucleolus, ribosomal rna promoter-associated protein. Phf6 directly interacts with upstream binding factor (ubf) through its phd1 domain and suppresses ribosomal rna (rrna) transcription by affecting the protein level of ubf SIGNOR-200133 0.284 SRMS protein Q9H3Y6 UNIPROT MAP2K4 protein P45985 UNIPROT down-regulates activity phosphorylation Tyr307 LATGRFPyPKWNSVF 9606 BTO:0002181 37020040 t miannu SRMS directly phosphorylates MKK4 and inhibits MKK4-JNK-c-Jun activation upon platinum treatment. Platinum treatment-induced ROS activates SRMS, which inhibits MKK4 kinase activity by directly phosphorylating MKK4 at Y269 and Y307, and consequently attenuates MKK4-JNK activation. SIGNOR-277902 0.2 SRMS protein Q9H3Y6 UNIPROT MAP2K4 protein P45985 UNIPROT down-regulates activity phosphorylation Tyr269 RDAGCRPyMAPERID 9606 BTO:0002181 37020040 t miannu SRMS directly phosphorylates MKK4 and inhibits MKK4-JNK-c-Jun activation upon platinum treatment. Platinum treatment-induced ROS activates SRMS, which inhibits MKK4 kinase activity by directly phosphorylating MKK4 at Y269 and Y307, and consequently attenuates MKK4-JNK activation. SIGNOR-277903 0.2 PLK1 protein P53350 UNIPROT STK3 protein Q13188 UNIPROT down-regulates activity phosphorylation Ser15 KSKLKKLsEDSLTKQ 9606 BTO:0002181 37739411 t miannu  We conclude that TRIM69A promotes multi-site phosphorylation of MST2.We demonstrate that TRIM69 stimulates formation of an MST2-PLK1 complex and promotes phosphorylation of MST2 at S15, a known PLK1 site. PLK1-mediated MST2 phosphorylation at S15 is necessary for subsequent phosphorylation of NEK2A to dissociate c-NAP1 from daughter centrioles (7). Thus, we provide a new molecular mechanism by which TRIM69 promotes MST2- and PLK1-mediated centrosome disjunction. SIGNOR-277904 0.337 PKA proteinfamily SIGNOR-PF17 SIGNOR SNAI2 protein O43623 UNIPROT down-regulates quantity by destabilization phosphorylation Ser247 KYQCKNCsKTFSRMS 9606 BTO:0001950 37596321 t miannu  PKA-dependent phosphorylation is pivotal for FBXO28-mediated SNAI2 degradation.  SIGNOR-277905 0.2 mTORC1 complex SIGNOR-C3 SIGNOR EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser72 KSERYSSsGSPANSF 9606 BTO:0000093 35513296 t miannu Our phosphoproteomics analysis add to this body of knowledge as it indicates that mTORC1 modulates additional phosphorylation sites in eEF2K, such as Y69, S70, S72, and S74, which is consistent with our previous findings SIGNOR-277906 0.348 CHEK1 protein O14757 UNIPROT PLK1 protein P53350 UNIPROT down-regulates activity phosphorylation Ser529 ILHLSNGsVQINFFQ 9606 BTO:0000567 37596441 t miannu  Chk1 directly phosphorylates Plk1 to disturb its interaction with Sgo1.  SIGNOR-277913 0.318 CHEK1 protein O14757 UNIPROT PLK1 protein P53350 UNIPROT down-regulates activity phosphorylation Thr539 INFFQDHtKLILCPL 9606 BTO:0000567 37596441 t miannu  Chk1 directly phosphorylates Plk1 to disturb its interaction with Sgo1.  SIGNOR-277914 0.318 VRK2 protein Q86Y07 UNIPROT GAPDH protein P04406 UNIPROT up-regulates activity phosphorylation Ser151 LKIISNAsCTTNCLA 9606 BTO:0000578 37450367 t miannu Mechanistically, FBXW10 promotes GAPDH polyubiquitination and activation; VRK2-dependent phosphorylation of GAPDH Ser151 residue is critical for GAPDH ubiquitination and activation.  SIGNOR-277840 0.2 MAPK3 protein P27361 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser868 ITRGEWQsEAQDTMK 9606 BTO:0000007 37686242 t miannu We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. SIGNOR-277854 0.28 MAPK3 protein P27361 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr873 WQSEAQDtMKTGSST 9606 BTO:0000007 37686242 t miannu We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. SIGNOR-277855 0.28 MAPK1 protein P28482 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser868 ITRGEWQsEAQDTMK 9606 BTO:0000007 37686242 t miannu We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. SIGNOR-277856 0.2 MAPK1 protein P28482 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr873 WQSEAQDtMKTGSST 9606 BTO:0000007 37686242 t miannu We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. SIGNOR-277857 0.2 AMPK complex SIGNOR-C15 SIGNOR NEDD4L protein Q96PU5 UNIPROT up-regulates activity phosphorylation Ser795 VDLKPNGsEIMVTNE -1 21501591 t miannu Expression of wild type Nedd4-2 or of Nedd4-2S795A lacking an AMPK phosphorylation consensus sequence downregulated Kir2.1 currents. The effect of wild type Nedd4-2 but not of Nedd4-2S795A was significantly augmented by additional coexpression of AMPK.  SIGNOR-277858 0.258 TRAF7 protein Q6Q0C0 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 15001576 f miannu Overexpression of traf7 induced caspase-dependent apoptosis. SIGNOR-123218 0.7 MAPK14 protein Q16539 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser937 FLGGSQVsPSRAKAP 9606 BTO:0002181 38307877 t miannu Here, we show that SHH inactivates p38α (MAPK14) in a smoothened-dependent manner, conversely, p38α directly phosphorylates GLI1 on Ser937/Ser941 (human/mouse) to induce GLI1's proteasomal degradation and negates the transcription of SHH signaling.  SIGNOR-277916 0.274 MAPK14 protein Q16539 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser941 S-->A 9606 BTO:0002181 38307877 t miannu Here, we show that SHH inactivates p38α (MAPK14) in a smoothened-dependent manner, conversely, p38α directly phosphorylates GLI1 on Ser937/Ser941 (human/mouse) to induce GLI1's proteasomal degradation and negates the transcription of SHH signaling.  SIGNOR-277917 0.274 CSNK1A1 protein P48729 UNIPROT ATM protein Q13315 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1270 SHFDEVKsIANQIQE 9606 BTO:0002181 37075701 t miannu Mechanistically, CK1α phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia telangiectasia mutated (ATM), a primary initiator of DNA double-strand break (DSB)-response signaling, which is compromised in ENZA-resistant cells and patients. Inhibition of CK1α stabilizes ATM, resulting in the restoration of DSB signaling, and thus increases ENZA-induced cell death and growth arrest. SIGNOR-277918 0.2 GSK3B protein P49841 UNIPROT AURKA protein O14965 UNIPROT down-regulates quantity by destabilization phosphorylation Ser283 GWSVHAPsSRRTTLC 9606 38442201 t miannu EEF1A2 bridged the interactions between the SKP1-CUL1-FBXW7 (SCF) ubiquitin ligase complex, the kinase GSK3β, and Aurora-A, thereby facilitating the phosphorylation of Aurora-A in a degron site that was recognized by FBXW7. SIGNOR-277919 0.54 STK4 protein Q13043 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity phosphorylation Thr1061 KMDWIFHtIKQHALN -1 38060450 t miannu MST1/2 and HGK inhibit catalytic activity of p110α through phosphorylation at T1061  SIGNOR-277920 0.2 MAP4K4 protein O95819 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity phosphorylation Thr1061 KMDWIFHtIKQHALN -1 38060450 t miannu MST1/2 and HGK inhibit catalytic activity of p110α through phosphorylation at T1061  SIGNOR-277921 0.2 STK3 protein Q13188 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity phosphorylation Thr1061 KMDWIFHtIKQHALN -1 38060450 t miannu MST1/2 and HGK inhibit catalytic activity of p110α through phosphorylation at T1061  SIGNOR-277922 0.2 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Tyr86 VADIDGQyAMTRAQR 9606 BTO:0001271 17318191 t lperfetto Bcr_abl_mediated phosphorylation of y86 could induce a conformational change of __catenin impairing its binding to axin SIGNOR-153435 0.2 ZMYND11 protein Q15326 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity binding 24675531 t miannu We found that full-length BS69 specifically interacted with H3K36me3 in native nucleosome co-immunoprecipitation (co-IP) experiments. We propose that BS69 specifically associates with H3K36me3-enriched chromatin through the PWWP domain, which facilitates the recruitment of MYND-bound transcription and chromatin remodeling factors including EZH2, HDAC1, Brg1 and E2F6 to target gene loci, thereby repressing target gene transcription. SIGNOR-265353 0.2 PCDH19 protein Q8TAB3 UNIPROT GABRA4 protein P48169 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C327,SIGNOR-C326,SIGNOR-C333 29360992 t miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  SIGNOR-267220 0.2 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Tyr381 VIHSPGFyTGKPGYK 9606 BTO:0002181 37977223 t miannu  To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. SIGNOR-277866 0.582 CDK2 protein P24941 UNIPROT NPAT protein Q14207 UNIPROT up-regulates phosphorylation Thr1350 ISRTTSAtPLKDNTQ 9606 10995387 t llicata Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter. SIGNOR-82141 0.458 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Tyr473 RNPKGFGyVTFMHLE 9606 BTO:0002181 37977223 t miannu  To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. SIGNOR-277867 0.582 MAPK14 protein Q16539 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser982 VVGANRAsHRAAAPP 9606 BTO:0002181 38307877 t miannu Here, we show that SHH inactivates p38α (MAPK14) in a smoothened-dependent manner, conversely, p38α directly phosphorylates GLI1 on Ser937/Ser941 (human/mouse) to induce GLI1's proteasomal degradation and negates the transcription of SHH signaling.  SIGNOR-277917  0.274 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A10/b1 integrin complex SIGNOR-C167 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259021 0.457 GART protein P22102 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI down-regulates quantity chemical modification 9606 34283828 t miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). SIGNOR-267299 0.8 PRKCB protein P05771 UNIPROT CYTH2 protein Q99418 UNIPROT down-regulates activity phosphorylation Ser392 AARKKRIsVKKKQEQ 9606 BTO:0000567 10531036 t lperfetto ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'. SIGNOR-249024 0.312 125-L-serine-2-133-interleukin 2 (human reduced) smallmolecule SID:46508054 ChEBI IL2RB protein P14784 UNIPROT up-regulates activity chemical activation 9606 18031103 t miannu Aldesleukin (recombinant IL-2) has similar pharmacodynamic properties to endogenous IL-2 and, when administered to patients with cancer, stimulates the antitumour immune response. SIGNOR-259389 0.8 SBDS protein Q9Y3A5 UNIPROT EIF6 protein P56537 UNIPROT up-regulates 9606 BTO:0001271 21536732 f miannu Human sbds is an essential cofactor for the efl1 gtpase, and together they cooperate to directly catalyze the release of eif6 from mammalian pre-60s ribosomal subunits SIGNOR-173536 0.53 estrone smallmolecule CHEBI:17263 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of 9606 BTO:0000056 16166196 t lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. SIGNOR-268661 0.8 CUL3 protein Q13618 UNIPROT TBCB protein Q99426 UNIPROT down-regulates quantity ubiquitination 10090 BTO:0000142 18680552 t miannu Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. SIGNOR-268945 0.247 AKT proteinfamily SIGNOR-PF24 SIGNOR NR4A1 protein P22736 UNIPROT down-regulates activity phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 BTO:0000782 11274386 t lperfetto We show that akt interacts with nur77 and inactivates nur77 by phosphorylation at ser-350 SIGNOR-105927 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 21902831 t lperfetto Phosphorylation of myod at s200 is common to other cdks, such as the mitotic cyclin b/cdk1, which may prevent inappropriate myod accumulation during mitosis. SIGNOR-216860 0.325 MIS12 protein Q9H081 UNIPROT MIS12 complex complex SIGNOR-C362 SIGNOR form complex binding -1 27881301 t lperfetto Human MIS12C (also known as MIND complex or Mtw1 complex in Saccharomyces cerevisiae) contains the MIS12, PMF1, NSL1, and DSN1 subunits SIGNOR-265190 0.858 SEC23A protein Q15436 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 t lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat SIGNOR-265289 0.789 meloxicam chemical CHEBI:6741 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 9083488 t miannu Meloxicam (5),an NSAID in the enol−carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. This favorable therapeutic index has been confirmed in clinical trials. In subsequent studies we and others discovered that it possessed a selectivity profile for COX-2 superior to several other marketed NSAIDs.1 A comparison of 5 with piroxicam (6) revealed different inhibitory profiles for the two enzymes SIGNOR-258609 0.8 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI up-regulates quantity precursor of 9606 34775382 t miannu 6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule. SIGNOR-267059 0.8 sertindole chemical CHEBI:9122 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258843 0.8 CREB5 protein Q02930 UNIPROT JUN protein P05412 UNIPROT up-regulates activity binding 9534 BTO:0000318 8378084 t miannu CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription SIGNOR-219634 0.523 SOSTDC1 protein Q6X4U4 UNIPROT WNT1 protein P04628 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242704 0.28 ARHGAP30 protein Q7Z6I6 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260486 0.377 CSNK2A1 protein P68400 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser7 sSAEGAAK 9606 10739259 t gcesareni Peptide mass and sequence analysis showed major and minor phosphorylation sites, respectively, at ser24 and ser28 in hmg-17, and ser20 and ser24 in hmg-14 a third phosphorylation site in hmg-14 was located at either ser6 or ser7phosphorylation of ser6 and ser7 may compromise the binding of hmgn1 protein to the binding domain of importin proteins, which in turn affects the nuclear transport and sub-cellular localization of hmgn1 protein. Protein kinase ck2 could potentially be an enzyme that regulates this process. SIGNOR-76266 0.2 FANCM protein Q8IYD8 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates relocalization 9606 20372056 t gcesareni The enzymatic activity of fan cm is then required to remodel and stabilize the fork to allow topbp1 access to activate atr , in a 9-1-1-independent manner. SIGNOR-164765 0.429 GAR1 protein Q9NY12 UNIPROT TERT protein O14746 UNIPROT up-regulates activity binding 18680434 t lperfetto A complex of four proteins (GAR1, NHP2, NOP10, and the putative pseudouridine synthase dyskerin) associates with snoRNAs to form small nucleolar ribonucleoprotein particles (snoRNPs), and the binding of this complex to the H/ACA domain of TERC may have a role in the biogenesis of the telomerase RNP SIGNOR-263333 0.428 B4GALT1 protein P15291 UNIPROT UDP-D-galactose smallmolecule CHEBI:18307 ChEBI down-regulates quantity chemical modification 9606 16157350 t miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. SIGNOR-268467 0.8 CSNK1A1 protein P48729 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser94 QISTIAEsEDSQESV 9606 9931297 t lperfetto Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement. SIGNOR-64250 0.317 NRF1 protein Q16656 UNIPROT RETREG3 protein Q86VR2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23939472 f miannu We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. SIGNOR-261367 0.2 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT up-regulates activity phosphorylation Ser2280 LSPSKSerPAKLN -1 26051540 t irozzo Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment. SIGNOR-259121 0.452 CDK2 protein P24941 UNIPROT TK1 protein P04183 UNIPROT down-regulates phosphorylation Ser13 LPTVLPGsPSKTRGQ 9606 14697231 t gcesareni Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase. SIGNOR-120372 0.3 PPARGC1A protein Q9UBK2 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates quantity by repression transcriptional regulation 10090 BTO:0001103 20404331 f lperfetto In mouse muscles, overexpression of PGC-1beta (like PGC-1alpha) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFkappaB SIGNOR-217978 0.371 CHEK2 protein O96017 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr284 APTRTPAtAPVPARA 9606 18971944 t llicata Chk2 formed a complex with xrcc1, the ber scaffold protein, and phosphorylated xrcc1 in vivo and in vitro at thr(284). our results are consistent with the phosphorylation of xrcc1 by atm-chk2 facilitating recruitment of downstream ber proteins to the initial damage recognition/excision step to promote ber. SIGNOR-181816 0.53 PDK1 protein Q15118 UNIPROT PKN2 protein Q16513 UNIPROT up-regulates activity phosphorylation Thr816 GYGDRTStFCGTPEF 9606 BTO:0000007 10753910 t miannu PDK1 phosphorylates the PRKs at their conserved activation loop threonines (Thr-774 and Thr-816 for PRK1 and PRK2, respectively) both in vitro and in vivo. SIGNOR-250265 0.344 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser679 SPDSMNAsRLSQPGQ 9606 BTO:0000007 10195894 t Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. SIGNOR-251277 0.2 FGF13 protein Q92913 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253427 0.273 TOMM5 protein Q8N4H5 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 t lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. SIGNOR-267675 0.62 TLR4 protein O00206 UNIPROT TLR4 protein O00206 UNIPROT up-regulates binding 9606 24352680 t fstefani Upon activation, tlrs hetero- or homodimerize inducing the recruitment of adaptor proteins via the cytoplasmic tir domain SIGNOR-203484 0.2 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 BTO:0001950 21561061 t Luana 3b Induces Phosphorylation of c-Jun (Ser-63) throughActivation of the JNK Pathway.| An enhanced phosphorylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP SIGNOR-260758 0.2 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB7 protein Q9Y5F8 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265689 0.2 CBM complex SIGNOR-C555 SIGNOR T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 35230873 f miannu The CBM complex not only induces a productive immune response in activated effector T cells but also controls peripheral tolerance by promoting the development and function of regulatory T (Treg) cells  SIGNOR-276297 0.7 MAPK1 protein P28482 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 21666810 t fstefani Like mk2, mk5 could be phosphorylated and activated by p38mapk and erk2 in vitro, but not by sapk?/Jnk3 SIGNOR-174076 0.492 PPP2R5C protein Q13362 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization dephosphorylation Thr55 DDIEQWFtEDPGPDE 9606 BTO:0001938 17245430 t Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis. To investigate the molecular mechanisms, we have shown that the endogenous B56gamma protein level and association with p53 increase after DNA damage. Finally, we demonstrate that Thr55 dephosphorylation is required for B56gamma3-mediated inhibition of cell proliferation and cell transformation. SIGNOR-268154 0.595 A-966492 chemical CID:16666333 PUBCHEM PARP1 protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205698 0.8 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Thr338 VPVKSRKtTLEQPPS 9606 BTO:0001061 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276775 0.629 SIRT7 protein Q9NRC8 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity deacetylation Lys37 APATGGVkKPHRYRP 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275876 0.2 TFE3 protein P19532 UNIPROT MYH9 protein P35579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 11467950 f miannu we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies. SIGNOR-222504 0.2 TNF protein P01375 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253477 0.2 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 BTO:0000007 16582879 t Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR SIGNOR-248408 0.78 PKN1 protein Q16512 UNIPROT PGAM proteinfamily SIGNOR-PF78 SIGNOR down-regulates phosphorylation 9606 BTO:0000130 12189148 t inferred from family member llicata Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity. SIGNOR-270282 0.33 DBP protein Q10586 UNIPROT CYP7A1 protein P22680 UNIPROT up-regulates quantity by expression transcriptional regulation 8617210 f lperfetto While TEF stimulates transcription from the albumin promoter more potently than DBP, only DBP is capable of activating transcription efficiently from the cholesterol 7 alpha hydroxylase (C7alphaH) promoter. SIGNOR-254121 0.369 RNA helicases DDX5/DDX17 complex SIGNOR-C34 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 17011493 t miannu We have found that the rna helicases p68/p72 are myod-associated proteins and that the noncoding rna sra also immunoprecipitates with myod. In vitro and in vivo experiments indicated that both p68/p72 and sra are coactivators of myod. SIGNOR-149967 0.428 OFD1 protein O75665 UNIPROT IFT88 protein Q13099 UNIPROT up-regulates activity binding 9606 BTO:0001086 20230748 t Regulation of binding miannu Ofd1 acts at the distal centriole to build distal appendages, recruit Ift88, and stabilize centriolar microtubules at a defined length. SIGNOR-251973 0.422 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120132 0.316 ADNP protein Q9H2P0 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 12888219 f miannu Mouse ADNP was shown to be expressed at the time of neural tube closure, detected at E7.5 and increased on E9.5. Expression was augmented in the brain (E12.5), sustained throughout embryogenesis and regulated by VIP. In conclusion, ADNP is identified here as a new key gene essential for organogenesis in the developing embryo and may be implicated as a clinical target associated with proper neurodevelopment. SIGNOR-266758 0.7 PTPN22 protein Q9Y2R2 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity dephosphorylation 9606 28786745 t miannu Further, this explains how loss of PTPN22 and subsequent enhanced NLRP3 phosphorylation mediate a decrease in NLRP3 inflammasome activation.|Upon NLRP3 activation, PTPN22 dephosphorylates NLRP3 and thereby protects it from degradation, allowing robust inflammasome activity (summarized in Fig.S6). SIGNOR-277056 0.363 YY2 protein O15391 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 15087442 t Luana YY2 activated the p53 promoter. However, in contrast to YY1, which represses the activity of c-Fos, YY2 increased the activity of the c-Fos promoter. SIGNOR-266212 0.401 STAT6 protein P42226 UNIPROT SLC26A4 protein O43511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24429829 f miannu We then examined the ability of STAT6 to bind each of the N4 GAS motifs in vivo with a site-specific ChIP assay, the results of which showed that STAT6 interacted with only the N4 GAS motif that was functionally implicated in increasing the activity of the pendrin promoter following IL-4 treatment. SIGNOR-255250 0.2 WNT10B protein O00744 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131628 0.579 Caspase 3 complex complex SIGNOR-C221 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity cleavage -1 10579725 t lperfetto P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro SIGNOR-256446 0.66 RIMBP2 protein O15034 UNIPROT RIMS2 protein Q9UQ26 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264366 0.547 tetra-mu3-sulfido-tetrairon chemical CHEBI:49883 ChEBI SDH complex SIGNOR-C400 SIGNOR form complex binding 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. SIGNOR-267733 0.8 PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates relocalization 10116 8645147 t Activated hyperphosphorylated Akt-1 bound to Ptd Ins(3,4,5)P3 -containing vesicles in a similar manner to the inactive dephosphorylated enzyme SIGNOR-254982 0.8 ABT-737 chemical CID:11228183 PUBCHEM BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189159 0.8 UPF3B protein Q9BZI7 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates activity binding -1 18066079 t miannu UPF2 and UPF3b increase UPF1 ATPase activity SIGNOR-265247 0.957 MRPS26 protein Q9BYN8 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261447 0.693 EGFR protein P00533 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates phosphorylation Tyr8 MPPYTVVyFPVRGRC 9606 BTO:0000150 19254954 t llicata Taken together, these results and those of the ms/ms analyses confirmed tyr-3, tyr-7, and tyr-198 to be primary residues phosphorylated by egfr in the gstp1 protein. The phosphorylation increased gstp1 enzymatic activity significantly, SIGNOR-184387 0.448 PLAAT3 protein P53816 UNIPROT PPP2CB protein P62714 UNIPROT down-regulates 9606 17374643 f miannu The alpha-isoform of the regulatory subunit a of protein phosphatase 2a (pr65alpha) as a new interaction partner of hrsl3 / we demonstrate that hrsl3 binds to the endogenous pr65alpha, thereby partially sequestering the catalytic subunit pr36 from the pr65 protein complex, and inhibiting pp2a catalytic activity. SIGNOR-153775 0.2 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser402 ISNSHPLsLTSDQYK -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178379 0.731 Odanacatib chemical CID:10152654 PUBCHEM CTSK protein P43235 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-195007 0.8 CHUK protein O15111 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates phosphorylation Ser1382 MKSRFVDsGEMSESF 9606 BTO:0000551 17434128 t lperfetto Phosphorylation of cbp by ikkalpha promotes cell growth by switching the binding preference of cbp from p53 to nf-kappabhere, we show that ikkalpha phosphorylates cbp at serine 1382 and serine 1386 and consequently increases cbp's hat and transcriptional activities SIGNOR-154329 0.532 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207938 0.8 TGFB1 protein P01137 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 26194464 t MARCO ROSINA TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI). SIGNOR-255030 0.848 EEF1A1P5 protein Q5VTE0 UNIPROT Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269554 0.8 BTRC protein Q9Y297 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates ubiquitination 9606 BTO:0000007 BTO:0001253 18296647 t gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. SIGNOR-160985 0.435 SLN protein O00631 UNIPROT ATP2A2 protein P16615 UNIPROT down-regulates activity binding -1 23455424 t lperfetto The structure suggests a mechanism for selective Ca2+ loading and activation of SERCA, and provides new insight into how SLN and PLB inhibition arises from stabilization of this E1 intermediate state without bound Ca2+. SIGNOR-264779 0.519 CD19 protein P15391 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity 9606 10706702 f lperfetto CD19 is a coreceptor on B cells that enhances the increase in cytoplasmic calcium and ERK2 activation when coligated with the B cell Ag receptor. SIGNOR-249609 0.398 putrescine smallmolecule CHEBI:17148 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 14617280 f apalma Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism SIGNOR-255551 0.7 COPS7B protein Q9H9Q2 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270760 0.892 NTN4 protein Q9HB63 UNIPROT NEO1 protein Q92859 UNIPROT up-regulates activity binding 9606 BTO:0001484 28245592 t miannu Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins. SIGNOR-268170 0.552 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu54 EMKKGHLeRECMEET -1 9538022 t lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). SIGNOR-263666 0.598 MAPK3 protein P27361 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser636 SGDYMPMsPKSVSAP 9606 12510059 t gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. SIGNOR-249409 0.696 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75629 0.783 POU5F1 protein Q01860 UNIPROT LEFTY1 protein O75610 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254938 0.514 MAPK1 protein P28482 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity phosphorylation Thr212 VIEPLPVtPTRDVAT 10116 BTO:0001260 15542607 t lperfetto We also show that ERK2 phosphorylates PAK1 on Thr(212) in vitro and that Thr(212) is phosphorylated in smooth muscle cells following PDGF-BB treatment in an adhesion- and MEK/ERK-dependent fashion. Expression of a phosphomimic variant, PAK-T212E, does not alter ERK association, but markedly attenuates downstream ERK signaling. Taken together, these data suggest that PAK1 may facilitate ERK signaling by serving as a scaffold to recruit Raf, MEK, and ERK to adhesion complexes, and that subsequent growth factor-stimulated phosphorylation of PAK-Thr(212) by ERK may serve to provide a negative feedback signal SIGNOR-249432 0.411 MCHR1 protein Q99705 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256905 0.252 PTPN1 protein P18031 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation -1 10660596 t lperfetto Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein. SIGNOR-74852 0.771 NR3C1 protein P04150 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7569975 f andrea cerquone perpetuini Here it is shown that the synthetic glucocorticoid dexamethasone induces the transcription of the IKBc gene, which results in an increased rate of IKBa protein synthesis SIGNOR-255688 0.333 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr534 NFLMDNAyFCEADAK 10029 12907755 t PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates SIGNOR-248420 0.48 CTCF protein P49711 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12032779 f miannu Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. SIGNOR-253827 0.636 SF3a complex SIGNOR-C345 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 8349644 f miannu Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. SIGNOR-263950 0.7 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-252634 0.81 thromboxane smallmolecule CHEBI:26995 ChEBI TBXA2R protein P21731 UNIPROT up-regulates activity chemical activation 19747485 t Thromboxane plays an essential role in hemostasis, regulating platelet aggregation and vessel tone. In humans, it signals through the TPalpha and TPbeta isoforms that are transcriptionally regulated by distinct promoters Prm1 and Prm3, respectively. SIGNOR-254264 0.8 CDK5 protein Q00535 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates activity phosphorylation Ser408 SIKSEPIsPPRDRMT 9606 BTO:0004102 12691662 t lperfetto Cdk5-mediated inhibition of the protective effects of transcription factor mef2 in neurotoxicity-induced apoptosis.We have identified the prosurvival transcription factor mef2 as a direct nuclear target of cdk5. Cdk5 phosphorylates mef2 at a distinct serine in its transactivation domain to inhibit mef2 activity. SIGNOR-100574 0.52 PKN3 protein Q6P5Z2 UNIPROT ARHGAP18 protein Q8N392 UNIPROT up-regulates activity phosphorylation Ser156 QKRVETVsQTLRKKN -1 33092266 t lperfetto We present strong evidence that PKN3-ARHGAP18 interaction is increased upon ARHGAP18 phosphorylation and that the phosphorylation of ARHGAP18 by PKN3 enhances its GAP domain activity and contributes to negative regulation of active RhoA.|These results support our data from phosphoproteomic screen and suggest that ARHGAP18 can be phosphorylated by PKN3 on Thr154, Ser156 and Thr158. SIGNOR-264571 0.2 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT down-regulates activity phosphorylation 9606 15586017 t Regulation of localization miannu The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane. SIGNOR-251949 0.779 CDK2 protein P24941 UNIPROT CCNO protein P22674 UNIPROT up-regulates activity phosphorylation Ser81 PSAARGGsPLPGPAQ 9606 BTO:0000007 25364462 t lperfetto Phosphorylation of cyclin O, a novel cyclin family protein containing a cyclin-like domain, is involved in the activation of cyclin-dependent kinase 2|This activity was reduced in cells overexpressing cyclin O, in which the 81st serine had been replaced with alanine (S81A). These results suggest that cyclin O is a novel cyclin family protein that regulates CDK2 kinase activity, which is mediated by the phosphorylation of the 81st serine residue of cyclin O|CKD2 phosphorylates the 81st serine residue of cyclin O SIGNOR-275615 0.465 AMPK complex SIGNOR-C15 SIGNOR ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR up-regulates activity phosphorylation 9606 23863160 t lperfetto Under energy deprivation, AMPK positively regulates ULK1 to induce autophagy, with various studies revealing that AMPK binds to and phosphorylates ULK1 SIGNOR-209913 0.409 MAPK1 protein P28482 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 15456867 t gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation SIGNOR-129585 0.716 pipamperone chemical CHEBI:78549 ChEBI HTR1D protein P28221 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000529 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258574 0.8 GNRH1 protein P01148 UNIPROT AR protein P10275 UNIPROT down-regulates activity binding 9606 BTO:0000007 17202804 t miannu GnRH antagonizes testosterone activation of the human androgen receptor in SCL60 cells. Gonadotropin-Releasing Hormone Functionally Antagonizes Testosterone Activation of the Human Androgen Receptor in Prostate Cells through Focal Adhesion Complexes Involving Hic-5 SIGNOR-259267 0.471 SHH protein Q15465 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0002314 18662193 f gcesareni In addition, shh reactivation plays a regulatory role on myogenesis, as its inhibition impairs the activation of the myogenic regulatory factors myf-5 and myod, decreases the up-regulation of insulin-like growth factor (igf)-1 and reduces the number of myogenic satellite cells at injured site. SIGNOR-179632 0.438 MAPK1 protein P28482 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2366 MEQGHFAsPDQNSML 9606 17623675 t lperfetto Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo. SIGNOR-156895 0.478 CDC25A protein P30304 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates activity dephosphorylation 9606 21670150 t miannu In this study, we revealed that Cdc25A enhances Foxo1 stability by dephosphorylating Cdk2, and Foxo1 was shown to directly regulate transcription of the metastatic factor MMP1. SIGNOR-277139 0.318 SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR FOS protein P01100 UNIPROT down-regulates activity sumoylation Lys265 SISSMELkTEPFDDF 9606 SIGNOR-C154 16055711 t lperfetto We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. SIGNOR-263014 0.2 TACR2 protein P21452 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257131 0.409 ATF4 protein P18848 UNIPROT SARS1 protein P49591 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269424 0.2 BRIP1 protein Q9BX63 UNIPROT BLM protein P54132 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 21240188 t irozzo In this work, FANCJ and BLM were found to interact physically and functionally in human cells and co-localize to nuclear foci in response to replication stress. The cellular level of BLM is strongly dependent upon FANCJ, and BLM is degraded by a proteasome-mediated pathway when FANCJ is depleted. SIGNOR-259186 0.642 AANAT protein Q16613 UNIPROT N-acetylserotonin smallmolecule CHEBI:17697 ChEBI up-regulates quantity chemical modification -1 22775292 t miannu Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. Melatonin synthesis requires serotonin, which is first acetylated by the arylalkylamine N-acetyltransferase (AA-NAT) to produce N-acetyl serotonin (NAS) (Fig. 1A). Then, acetyl serotonin methyltransferase (ASMT, also known as hydroxyindole O-methyltransferase or HIOMT) produces melatonin by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to NAS. SIGNOR-265478 0.8 PP2B proteinfamily SIGNOR-PF18 SIGNOR DNM2 protein P50570 UNIPROT unknown dephosphorylation 10116 20496096 t inferred from 70% family members CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII). SIGNOR-269990 0.2 GTF2H5 protein Q6ZYL4 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 t lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269310 0.873 Oxytocin protein P01178-PRO_0000020495 UNIPROT OXTR protein P30559 UNIPROT up-regulates activity binding 9606 11274341 t lperfetto The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation.| The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via G(q) proteins to phospholipase C-beta. SIGNOR-268545 0.2 trametinib chemical CHEBI:75998 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001950 25487801 t Luana Inhibitors of MEK1/2 (trametinib) and/or ERK1/2 (selumetinib) had the strongest and most conserved inhibitory activities, suggesting that MEK1/2 and ERK1/2 may have unique capabilities as stand-alone or combinatorial therapies for MERS-CoV infections.  SIGNOR-262312 0.8 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr486 YPAEDSTyDEYENDL 9606 12601080 t lperfetto Cortactin was first identified as a substrate of v-src (46) that mediates in vitro phosphorylation of residues tyr-421, tyr-466, and tyr-482 at the c terminus of the murine ortholog (47). Phosphorylation of these residues attenuates the f-actin cross-linking activity SIGNOR-98720 0.794 IL21R protein Q9HBE5 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 BTO:0000876 BTO:0000763;BTO:0001253 15667561 f gcesareni Interleukin 24 (il-24) is a new member of the il-10 family of cytokines and it signals through two heterodimeric receptors: il-20r1/il-20r2 and il-22r1/il-20r2. Upon binding to its receptors, il-24 induces rapid activation of stat-1 and stat-3 transcription factors, SIGNOR-133379 0.593 NUF2 protein Q9BZD4 UNIPROT Ndc80 complex complex SIGNOR-C361 SIGNOR form complex binding 27881301 t lperfetto Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits SIGNOR-265187 0.973 ATF4 protein P18848 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260170 0.809 CLN8 protein Q9UBY8 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 9606 BTO:0000007 30453012 t miannu CLN8 interacts with ceramide binding proteins PP2A and I2PP2A. We showed that the phosphorylation levels of several substrates of PP2A, namely Akt, S6 kinase, and GSK3β, were decreased in CLN8 disease patient fibroblasts. This reduction can be reversed by inhibiting PP2A phosphatase activity with cantharidin, suggesting a higher PP2A activity in CLN8-deficient cells. The phosphorylation levels of PP2A substrates are decreased in the absence of CLN8. SIGNOR-265583 0.2 FOXP2 protein O15409 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 25232744 t miannu By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets. SIGNOR-266834 0.324 AKT2 protein P31751 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t gcesareni We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-78689 0.275 AKT1 protein P31749 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates activity phosphorylation Ser50 RNRYRDVsPFDHSRI 10090 BTO:0000944 11579209 t lperfetto Phosphorylation of ptp1b at ser(50) by akt impairs its ability to dephosphorylate the insulin receptor. SIGNOR-252542 0.732 NUMA1 protein Q14980 UNIPROT TUBA3E protein Q6PEY2 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-116738 0.25 sorafenib tosylate chemical CHEBI:50928 ChEBI RAF1 protein P04049 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu This effort culminated in the identification of the clinical candidate BAY 43-9006 (Sorafenib, Nexavar), which has recently been approved by the FDA for advanced renal cell carcinoma in phase III clinical trials. Sorafenib inhibited the kinase activity of both C-RAF and B-RAF (wild type and V600E mutant). SIGNOR-259228 0.8 PCSK7 protein Q16549 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation 9606 12435397 t gcesareni In vivo p38-dependent phosphorylation reduced trans-repressional abilities of tel through ets-binding consensus site SIGNOR-95622 0.2 POLR1H protein Q9P1U0 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16373708 f miannu ZNRD1 could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene but not alter the expression of MDR-associated protein, glutathione S-transferase activity, or intracellular glutathione content in leukemia cells. SIGNOR-259907 0.2 CAMK2A protein Q9UQM7 UNIPROT Chemoattraction_of_axon phenotype SIGNOR-PH197 SIGNOR up-regulates 9606 15363394 f miannu In this study, we have identified CaMKII and CaN-PP1 as the downstream effectors of localized Ca2+ signals in mediating attractive and repulsive turning responses of growth cones, respectively. Local Ca2+ elevation activates CaMKII and CaN-PP1 for attraction and repulsion, respectively. SIGNOR-268385 0.7 trichostatin A chemical CHEBI:46024 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258012 0.8 CSNK2A1 protein P68400 UNIPROT ARNT protein P27540 UNIPROT down-regulates phosphorylation Ser77 DKERFARsDDEQSSA 9606 16129408 t gcesareni Here, we show that arnt and alt arnt proteins are differentially phosphorylated by protein kinase ckii in vitro. Phosphorylation had an inhibitory effect on dna-binding to an e-box probe by alt arnt, but not arnt, homodimers. This inhibitory phosphorylation occurs through ser77. SIGNOR-140034 0.346 STAT5A protein P42229 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates quantity transcriptional regulation 9606 26059451 t … these data suggest that STAT5A positively regulates levels of DNMT3A, resulting in inactivation of tumor suppressor genes by epigenetic mechanisms in AML cells SIGNOR-255631 0.332 SRC protein P12931 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr104 RSPSTGLyDNLEKYH 9606 BTO:0000007 24996174 t miannu In this study, we investigated the potential regulation of SIRT2 function by c-Src. We found that the protein levels of SIRT2 were decreased by c-Src, and subsequently rescued by the addition of a Src specific inhibitor, SU6656, or by siRNA-mediated knockdown of c-Src. The c-Src interacts with and phosphorylates SIRT2 at Tyr104. SIGNOR-263104 0.296 3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea chemical CHEBI:91362 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192811 0.8 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser152 PASSVSSsPSPPFGH 9606 12050114 t gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk SIGNOR-88728 0.359 CDR2 protein Q01850 UNIPROT TTK protein P33981 UNIPROT up-regulates quantity by expression transcriptional regulation 20383333 f lperfetto Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology SIGNOR-252021 0.2 SOX6 protein P35712 UNIPROT HBG1 protein P69891 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004911 20395365 f Regulation miannu BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. SIGNOR-251810 0.305 MAP2K4 protein P45985 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity phosphorylation 9534 BTO:0000298 7839144 t Luana Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-260722 0.574 GATA1 protein P15976 UNIPROT GP6 protein Q9HCN6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12377757 f miannu We have determined that the GP6 sequence -191 to -39 represents the core promoter and that transcription is driven largely by GATA-1 (-176) and c-Ets-1 (-45) sites within this segment. SIGNOR-254081 0.285 SPAG4 protein Q9NPE6 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 t lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. SIGNOR-263285 0.363 CEP41 protein Q9BYV8 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates activity binding 9606 BTO:0000007 31885126 t miannu We performed these assays in HEK 293T cells and observed CEP41 binds HIF1α under both normoxic and hypoxic conditions. Of note, we found hypoxia induces more expression of HIF1α and increases its binding to CEP41 (Fig 8B and C). Hence, these results suggest CEP41 modulates the activation of HIF1α via a physical interaction SIGNOR-269662 0.2 CACNA1B protein Q00975 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 20655485 t miannu The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release. SIGNOR-265069 0.8 EFNA1 protein P20827 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9576626 t tpavlidou Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity SIGNOR-56907 0.816 DYRK1A protein Q13627 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser329 STISGRLsPIMTEQD 9606 BTO:0000887;BTO:0001103 11311120 t lperfetto The kinase dyrk1a phosphorylates the transcription factor fkhr at ser329 in vitro, a novel in vivo phosphorylation siteser(329) phosphorylation also decreases the ability of fkhr to stimulate gene transactivation and reduces the proportion of fkhr present in the nucleus SIGNOR-106829 0.52 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR PTPN1 protein P18031 UNIPROT up-regulates activity binding 16115959 t lperfetto N this study, we demonstrate an essential role for protein-tyrosine phosphatase (PTP)-1B in this process. In resting platelets, c-Src forms a complex with alphaIIbbeta3 and Csk, which phosphorylates c-Src tyrosine 529 to maintain c-Src autoinhibition. Fibrinogen binding to alphaIIbbeta3 triggers PTP-1B recruitment to the alphaIIbbeta3-c-Src-Csk complex in a manner that is dependent on c-Src and specific tyrosine (tyrosine 152 and 153) and proline (proline 309 and 310) residues in PTP-1B. Studies of PTP-1B-deficient mouse platelets indicate that PTP-1B is required for fibrinogen-dependent Csk dissociation from alphaIIbbeta3, dephosphorylation of c-Src tyrosine 529, and c-Src activation. SIGNOR-261800 0.459 CSNK1D protein P48730 UNIPROT PER3 protein P56645 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 11865049 t miannu We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. SIGNOR-267998 0.712 ETS1 protein P14921 UNIPROT TBXAS1 protein P24557 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14586398 f miannu We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. SIGNOR-254088 0.2 RPL7 protein P18124 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262455 0.858 NPM1 protein P06748 UNIPROT CENPA protein P49450 UNIPROT up-regulates activity binding 9606 BTO:0000567 19410544 t miannu Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURPA minority of NPM1 cofractionated with prenucleosomal CENP-A, consistent with only a small proportion of total NPM1 stably associated with CENP-A. The partial overlap of NPM1 and HJURP with each other supports their formation of distinct prenucleosomal complexes with CENP-A. it is also possible that NPM1 plays a non essential role in the assembly of CENP-A nucleosomes or the nucleophosmin paralogues NPM2 and NPM3 may compensate for the absence of NPM1. SIGNOR-263708 0.547 ARID2 protein Q68CP9 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270597 0.776 CELF4 protein Q9BZC1 UNIPROT TNNT2 protein P45379 UNIPROT up-regulates quantity post transcriptional regulation 9606 11158314 f miannu We also demonstrated that CUG-binding protein (CUG-BP) binds a conserved CUG motif within a human cTNT MSE and positively regulates MSE-dependent exon inclusion. Alternative splicing of cardiac troponin T (cTNT) exon 5 undergoes a developmentally regulated switch such that exon inclusion predominates in embryonic, but not adult, striated muscle. SIGNOR-264256 0.368 CDKN2A protein P42771 UNIPROT CDK2 protein P24941 UNIPROT down-regulates binding 9606 10022885 t gcesareni However, induction of p16(ink4a) also causes marked inhibition of cdk2 activity. SIGNOR-64431 0.493 NCSTN protein Q92542 UNIPROT APH1A protein Q96BI3 UNIPROT up-regulates binding 9606 BTO:0000142 12471034 t gcesareni We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch). SIGNOR-96250 0.967 HDAC4 protein P56524 UNIPROT HOXB13 protein Q92826 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19013255 f miannu Recruitment of HDAC4 by transcription factor YY1 represses HOXB13 to affect cell growth in AR-negative prostate cancers. SIGNOR-254232 0.264 EGFR protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000093 BTO:0000150 26918608 t lperfetto P85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation. SIGNOR-252671 0.773 trimethyl-[(5-methyl-2-furanyl)methyl]ammonium chemical CHEBI:94038 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258647 0.8 ER stress stimulus SIGNOR-ST9 SIGNOR ERN1 protein O75460 UNIPROT up-regulates 9606 18065414 f miannu Our findings suggest that MTHFR is up-regulated by ER stress and that this effect is mediated by IRE1 and c-Jun. SIGNOR-253145 0.7 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Ser801 VPLLREAsARDRQSA 9534 14523239 t lperfetto We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. SIGNOR-249232 0.2 DUSP3 protein P51452 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Tyr204 HTGFLTEyVATRWYR 9534 BTO:0004055 10224087 t Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2 SIGNOR-248535 0.651 CAMK2A protein Q9UQM7 UNIPROT ANKS1B protein Q7Z6G8 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 27477489 t miannu CaMKII-mediated displacement of AIDA-1 out of the postsynaptic density core. The present study indicates that CaMKII activation is necessary for the NMDA-induced movement of AIDA-1 out of the PSD core. SIGNOR-264231 0.259 ALDOA protein P04075 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266487 0.8 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser40 GQGAPGPsLTGSPWP 9606 7901013 t The effect has been demonstrated using P07101-3 gcesareni Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax SIGNOR-34682 0.27 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t inferred from 70% family members gcesareni Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus SIGNOR-270005 0.2 GABRB3 protein P28472 UNIPROT GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR form complex binding 9606 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263772 0.461 MED6 protein O75586 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266677 0.844 IRS4 protein O14654 UNIPROT SSH1 protein Q8WYL5 UNIPROT up-regulates activity binding 9606 BTO:0002181 25100728 t miannu Insulin Receptor Substrate-4 Binds to Slingshot-1 Phosphatase and Promotes Cofilin Dephosphorylation. In addition, IRS4 co-localized with SSH1 in F-actin-rich membrane protrusions in insulin-stimulated cells, which suggests that the association of IRS4 with SSH1 contributes to localized activation of cofilin in membrane protrusions. SIGNOR-277617 0.316 diethylstilbestrol chemical CHEBI:41922 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258597 0.8 RUNX1 protein Q01196 UNIPROT ELANE protein P08246 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004850 14594802 f miannu We find that LEF-1 and CBFalpha co-activate ELA2 expression. SIGNOR-254553 0.324 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 10090 15367694 t Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes SIGNOR-248627 0.89 GLI2 protein P10070 UNIPROT OLIG2 protein Q13516 UNIPROT up-regulates quantity transcriptional regulation 9606 NBK6142 f SimoneGraziosi Therefore, Gli2 activity regulates the late phase of Olig2 gene expression in the ventral neuroepithelium and its subsequent production of OPC cells. SIGNOR-269219 0.362 EP300 protein Q09472 UNIPROT TP53 protein P04637 UNIPROT up-regulates acetylation Lys373 SSHLKSKkGQSTSRH 9606 BTO:0000567 11070080 t gcesareni P300 acetylates and activates the tumor suppressor p53 after dna damage. SIGNOR-84070 0.909 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914161 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161553 0.547 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Thr309 TMKTFCGtPEYLAPE 9606 18160256 t Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248612 0.473 HNRNPA2B1 protein P22626 UNIPROT CDK5R1 protein Q15078 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24792867 f miannu Hnrnpa2/b1 protein directly interacts with the r1 and r2 regions ofcdk5r13_-utr and displays a negative regulatory activity on its expression SIGNOR-205023 0.2 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser268 SDEFRPRsKSQSSSN -1 12351658 t IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. SIGNOR-251288 0.644 TARBP2 protein Q15633 UNIPROT RISC(DICER1/AGO2/TARBP2) complex SIGNOR-C32 SIGNOR form complex binding 9606 16142218 t lperfetto Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si_ or mi_riscs in mammalian cells, but it may also facilitate the cleavage of pre_mirnas by dicer. SIGNOR-140229 0.901 COL3A1 protein P02461 UNIPROT ADGRG1 protein Q9Y653 UNIPROT up-regulates activity binding 22238662 t Using the N-terminal fragment of GPR56 (GPR56(N)) as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56(N), the ligand binding domain. SIGNOR-253979 0.2 HAUS7 protein Q99871 UNIPROT HAUS complex complex SIGNOR-C281 SIGNOR form complex binding 9606 BTO:0000567 19369198 t lperfetto Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC) SIGNOR-262318 0.668 MAPK8 protein P45983 UNIPROT CDC25B protein P30305 UNIPROT down-regulates quantity by destabilization phosphorylation Ser101 ASESSLSsESSESSD 9606 BTO:0000567 21807946 t miannu  Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104). SIGNOR-276352 0.288 MAPK8IP3 protein Q9UPT6 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates binding 9606 15767678 t gcesareni The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk. SIGNOR-134561 0.653 STAT3 protein P40763 UNIPROT IL10 protein P22301 UNIPROT up-regulates transcriptional regulation 9606 28713870 f svumbaca These data argue that, in TH2 cells, STAT3 is required for T cell IL-10 production, which in turn reinforces its own expression SIGNOR-256234 0.782 promethazine chemical CHEBI:8461 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 t Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells SIGNOR-257788 0.8 genistein chemical CHEBI:28088 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258599 0.8 SMAD7 protein O15105 UNIPROT ACVRL1 protein P37023 UNIPROT down-regulates 9606 BTO:0000975 12023024 f gcesareni Smad7, induced by alk1 activation, recruits pp1? To alk1 and thereby inhibits tgf-?/Alk1-induced smad1/5 phosphorylation in ecs. SIGNOR-87673 0.554 Motilin smallmolecule CHEBI:80269 ChEBI MLNR protein O43193 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257542 0.8 ZNF774 protein Q6NX45 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR up-regulates activity binding 9606 BTO:0000578 31659254 t miannu Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. We demonstrated that ZNF774 recruits the NuRD complex to the NOTCH2 promoter and represses NOTCH2 transcription. SIGNOR-265558 0.25 RARG protein P13631 UNIPROT RXRB protein P28702 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. SIGNOR-16662 0.702 SATB2 protein Q9UPW6 UNIPROT NR4A2 protein P43354 UNIPROT down-regulates quantity transcriptional regulation 9606 31666685 t gianni Satb2 represses the transcription of Nr4a2. The misexpression of Nr4a2 together with Ctip2 induces expression of SubC-specific genes in wild-type Rsp, and simultaneous knockdown of these two genes in Rsp Satb2-mutant cells prevents their fate transition to SubC identity. Thus, Satb2 serves as a determinant gene in the Rsp regionalization by repressing Nr4a2 and Ctip2 during cortical development SIGNOR-268930 0.299 D-thyroxine smallmolecule CHEBI:30659 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity chemical activation 9606 BTO:0003736 6777394 t inferred from family member miannu The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response. SIGNOR-267802 0.8 LAMTOR complex SIGNOR-C26 SIGNOR RAGAC complex SIGNOR-C113 SIGNOR up-regulates activity relocalization 9606 BTO:0000007 SIGNOR-C3 20381137 t lperfetto We identify the trimeric Ragulator protein complex as a new component of the mTORC1 pathway that interacts with the Rag GTPases, is essential for localizing them and mTORC1 to the lysosomal surface, and is necessary for the activation of the mTORC1 pathway by amino acids. SIGNOR-228155 0.874 CDK1 protein P06493 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser367 GTQNPVSsPGMSQEL 26933062 t lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. SIGNOR-276587 0.435 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 t llicata CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. SIGNOR-250947 0.318 PKA proteinfamily SIGNOR-PF17 SIGNOR GATA3 protein P23771 UNIPROT up-regulates activity phosphorylation Ser308 IKPKRRLsAARRAGT 9606 BTO:0000093 16109788 t miannu  PKA-mediated phosphorylation increases the interaction between GATA3 and LRH-1 and the requirement for PKA in aromatase PII promoter stimulation involves at least three specific amino acid residues: GATA3 Ser308, GATA4 Ser261, and LRH-1 Ser469.  SIGNOR-276042 0.2 PRKACA protein P17612 UNIPROT AKAP12 protein Q02952 UNIPROT up-regulates activity phosphorylation Ser627 KKRVRRPsESDKEDE -1 14657015 t lperfetto Following receptor activation, gravin binding to the receptor increases, a process dependent upon PKA-catalyzed phosphorylation of two canonical PKA sites (Ser696–698 and Ser772) located within the AKAP domain of gravin. SIGNOR-271841 0.2 IKBKB protein O14920 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C14 23332762 t gcesareni Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation. SIGNOR-192614 0.266 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000763 12193595 t gcesareni We show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity. SIGNOR-91714 0.711 silodosin chemical CHEBI:135929 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 10029 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258450 0.8 histidine smallmolecule CHEBI:27570 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264762 0.7 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr809 DIMNDSNyIVKGNAR 9606 BTO:0001271 15297464 t lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins. SIGNOR-127618 0.2 PLK3 protein Q9H4B4 UNIPROT VRK1 protein Q99986 UNIPROT up-regulates phosphorylation Ser342 DDGKLDLsVVENGGL 9606 19103756 t llicata Vrk1 does not phosphorylate plk3, but plk3 phosphorylates the c-terminal region of vrk1 in ser342. Vrk1 with substitutions in s342 is catalytically active but blocks golgi fragmentation, indicating that its specific phosphorylation is necessary for this process. SIGNOR-182858 0.486 NPNT protein Q6UXI9 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 23612709 f miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion SIGNOR-255458 0.7 CDK4 protein P11802 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates phosphorylation Thr90 CHLAWVNtPKKQGGL 9606 BTO:0000567 11986303 t lperfetto Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown). SIGNOR-87105 0.227 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-217137 0.753 MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Ser212 EENGPPSsPDLDRIA -1 SIGNOR-C3 SIGNOR-C3 18372248 t lperfetto In this study, we used two-dimensional phosphopeptide mapping in conjunction with mutational analysis to show that in addition to ser-183, mtorc1 also phosphorylates ser-212 and ser-221 in pras40 when assayed in vitro. SIGNOR-178124 0.901 GH1 protein P01241 UNIPROT GHR protein P10912 UNIPROT up-regulates binding 9606 7862673 t gcesareni The hghr only binds primate gh. Arg43 in hghr interacts with asp171 of hgh. SIGNOR-34129 0.854 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT up-regulates activity phosphorylation Tyr163 YEHKEIEyVETVTSR -1 21840312 t miannu Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility. SIGNOR-263038 0.398 ARHGAP11B protein Q3KRB8 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260467 0.481 DACT1 protein Q9NYF0 UNIPROT DVL2 protein O14641 UNIPROT down-regulates binding 9606 16446366 t gcesareni Dapper 1 antagonizes wnt signaling by promoting dishevelled degradation SIGNOR-144053 0.783 MYC protein P01106 UNIPROT HNRNPA1 protein P09651 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20010808 t We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2, SIGNOR-268690 0.468 DACH2 protein Q96NX9 UNIPROT MYOG protein P15173 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000165 17075071 t Luana We confirmed Dach2 is a Mgn transcriptional repressor that mediates HDAC-dependent regulation by (i) overexpressing Dach2 in myotubes harboring the 133-bp Mgn promoter and (ii) rescuing TSA-mediated Mgn repression by Dach2 knockdown. SIGNOR-261579 0.375 L-tyrosine zwitterion smallmolecule CHEBI:58315 ChEBI 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI up-regulates quantity precursor of 9606 16098474 t scontino TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. SIGNOR-266955 0.8 NSD3 protein Q9BZ95 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity methylation Lys366 RLVMVLysVVPTC 9606 BTO:0002181 29101251 t irozzo We found that lysine methyltransferase NSD3 interacts with and directly monomethylates IRF3 in the nucleus, leading to the enhanced IRF3 transcriptional activity and antiviral immune responses. SIGNOR-259198 0.2 ACTB protein P60709 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270739 0.497 ABL1 protein P00519 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity phosphorylation Tyr30 FATTDDFyDDPCFDSP 9606 BTO:0000007 12415271 t We have found that c-Abl can phosphorylate MyoD at a conserved N-terminal tyrosine (Tyr30) that is located within the transactivation domain. Mutation of Tyr30 to Phe does not interfere with the function of MyoD, but theTyr30Phe mutant becomes resistant to the inhibitory effect of DNA damage. SIGNOR-253055 0.29 PRKCD protein Q05655 UNIPROT SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization phosphorylation Ser297 GLRYNRLsAIPRSLA 29383184 t lperfetto PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8. SIGNOR-275565 0.2 IL31 protein Q6EBC2 UNIPROT IL31RA protein Q8NI17 UNIPROT up-regulates binding 9606 15184896 t gcesareni Here we identify a four-helix bundle cytokine we have called interleukin 31 (il-31), which is preferentially produced by t helper type 2 cells. Il-31 signals through a receptor composed of il-31 receptor a and oncostatin m receptor. SIGNOR-125313 0.634 PRKACA protein P17612 UNIPROT IMMT protein Q16891 UNIPROT down-regulates activity phosphorylation Ser528 ELQFRRLsQEQVDNF -1 27153535 t miannu PKA directly phosphorylated the Ser528 residue of MIC60. Phosphorylation of MIC60 Interrupts Parkin Recruitment and Formation of the MICOS Complex SIGNOR-266302 0.2 CDK19 protein Q9BWU1 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2516 FLTPSPEsPDQWSSS -1 25344755 t lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues SIGNOR-273135 0.307 EPO protein P01588 UNIPROT EPOR protein P19235 UNIPROT up-regulates binding 10090 9442088 t gcesareni Binding of erythropoietin (epo) to the epo receptor (epor) initiates a signaling cascade resulting in tyrosine phosphorylation of several proteins and induction of ap-1 transcription factor(s). SIGNOR-55300 0.872 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser923 DELRDSDsVCDSGVE 10090 BTO:0000944 SIGNOR-C14 SIGNOR-C13 11297557 t lperfetto The i b kinase (ikk) complex rapidly phosphorylates nf- b1 p105 on serine 927 in the pest region romashkova et al. demonstrated that akt binds to and activates inhibitor of kappa b kinase-alfa (ikkalfa), which in turn phosphorylates and thereby promotes the degradation of the inhibitory cofactor of nf-kb, i-kb the scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk. SIGNOR-235434 0.737 PRKCZ protein Q05513 UNIPROT MYH10 protein P35580 UNIPROT down-regulates phosphorylation Ser1937 RGGPISFsSSRSGRR 9606 16611744 t lperfetto After egf stimulation, apkc_ translocates from the nucleus to the cytoplasm (figure 3) and is therefore able to interact with myosin ii-b. apkc_ phosphorylates nmhc ii-b on ser1937, which is located on the nonhelical tailpiece, leading to filament disassembly at certain sites of the cell SIGNOR-146100 0.272 RAB9A protein P51151 UNIPROT PLIN3 protein O60664 UNIPROT up-regulates activity 18195106 t lperfetto Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector SIGNOR-253089 0.574 AMPK complex SIGNOR-C15 SIGNOR YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation Ser94 RLRKLPDsFFKPPEP 9606 BTO:0002181 25751140 t miannu Moreover, AMPK directly phosphorylates YAP Ser 94, a residue essential for the interaction with TEAD, thus disrupting the YAP-TEAD interaction. SIGNOR-277638 0.303 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation 9606 10197981 t lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 SIGNOR-66778 0.738 TUT7 protein Q5VYS8 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR down-regulates 25480299 f lperfetto Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells. Consistently, purified TUT4/7 selectively recognize and uridylate RNAs with short A-tails (less than ∼ 25 nt) in vitro. PABPC1 antagonizes uridylation of polyadenylated mRNAs, contributing to the specificity for short A-tails. SIGNOR-268345 0.7 UQCRQ protein O14949 UNIPROT Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 t lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits SIGNOR-262197 0.924 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1333 DYNSVVLySTPPI 9606 9722576 t lperfetto Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for src homology 2 domain-containing molecules. By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor. SIGNOR-59762 0.2 TRIM25 protein Q14258 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys7 kTYKYICR 9606 BTO:0000007 22626058 t K48 miannu We report here that RLR activation triggers MAVS ubiquitination on lysine 7 and 10 by the E3 ubiquitin ligase TRIM25 and marks it for proteasomal degradation concomitantly with downstream signaling.  SIGNOR-272041 0.761 SRC protein P12931 UNIPROT KRAS protein P01116 UNIPROT up-regulates phosphorylation 9606 9096340 t gcesareni Expression of v-src, a transforming nonreceptor tyrosine kinase, results in ras activation, and ras function in nih 3t3 cells suppresses transformation by v-src, indicating that in these cells ras-dependent signaling pathways are required for v-src to exert its biological effects. SIGNOR-47152 0.644 EPHB1 protein P54762 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity relocalization 26319181 t lperfetto The phosphorylated CNK1 interacts with ephrinB1. The binding of ephrinB1 to CNK1 connects RhoA and p115RhoGEF with ephrinB1-associated MKK4, promoting JNK activation and cell migration. SIGNOR-275922 0.2 TFEB protein P19484 UNIPROT PSAP protein P07602 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276545 0.313 CSNK2A1 protein P68400 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser170 KEGDVDVsDSDDEDD 9606 18559419 t llicata Here we show that ck2 phosphorylates the transcription initiation factor tif-ia at serines 170 and 172 (ser170/172), and this phosphorylation triggers the release of tif-ia from pol i after transcription initiation. SIGNOR-178939 0.206 CDK5 protein Q00535 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Ser242 IPNGFGTsPLTPSAR 10090 BTO:0000142 12796778 t llicata Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function. SIGNOR-250677 0.763 PPARA protein Q07869 UNIPROT ACSL1 protein P33121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003204 17150915 f miannu To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA. SIGNOR-255044 0.533 tadalafil chemical CHEBI:71940 ChEBI PDE5A protein O76074 UNIPROT down-regulates activity chemical inhibition 9606 21189023 t Luana All of the final compounds and intermediates synthesized were screened for in vitro tumor cell growth inhibition activity using the human MDA-MB-231 breast tumor cell line and for inhibition of recombinant human PDE5 at a single concentration of 10 μM. For compounds showing >60% inhibition, the IC50 was determined by testing a range of eight concentrations with quadruple replicates per concentration, tadalafil used as a positive control.| Conversely, tadalafil possessed a selectivity index of just 16.6 for PDE5 versus PDE11 SIGNOR-257887 0.8 TNIK protein Q9UKE5 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates phosphorylation Ser177 QALKDARsPSPAHIV 9606 BTO:0000586 20530691 t llicata Here, we report that tnik is an activating kinase for tcf4 and essential for colorectal cancer growth. Tnik, but not its catalytically inactive mutant, phosphorylated the conserved serine 154 residue of tcf4. SIGNOR-165946 0.536 BRCA1-C complex complex SIGNOR-C299 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 25400280 f lperfetto The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2 SIGNOR-263228 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000567 12853467 t 14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling. SIGNOR-251484 0.2 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr463 MLAGVSEyELPEDPR 10116 BTO:0003293 19224897 t lperfetto This second-stage autophosphorylation occurs on Y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of Y463 in the juxtamembrane region, Y766 in the C-terminal tail, and Y585 in the kinase insert region SIGNOR-235762 0.2 MAPK3 protein P27361 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser296 KQRRSIIsPNFSFMG 9606 16286470 t lperfetto The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain SIGNOR-141605 0.778 KDM3A protein Q9Y4C1 UNIPROT H3-5 protein Q6NXT2 UNIPROT up-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 16603237 t miannu Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.  SIGNOR-276847 0.2 KLF6 protein Q99612 UNIPROT DLK1 protein P80370 UNIPROT down-regulates transcriptional regulation 9606 15917248 f Repression of dlk1 requires hdac3 deacetylase activity fspada We have identified krappel-like factor-6 (klf6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene delta-like 1 (dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation. SIGNOR-210016 0.286 ATM protein Q13315 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser345 LVQGISFsQPTCPDH 9606 20068082 t gcesareni Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation. SIGNOR-163110 0.84 PTEN protein P60484 UNIPROT PINK1 protein Q9BXM7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 f miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). SIGNOR-260056 0.482 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Ser306 GPMRRSKsPADSGND 9606 14741103 t llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. SIGNOR-250658 0.415 RLN2 protein P04090 UNIPROT RXFP1 protein Q9HBX9 UNIPROT up-regulates binding 9606 BTO:0000142 11809971 t gcesareni Lgr7 and lgr8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (camp)-dependent pathway SIGNOR-114549 0.751 PRKCB protein P05771 UNIPROT EEF1A1 protein P68104 UNIPROT up-regulates activity phosphorylation Ser53 AAEMGKGsFKYAWVL 10090 20923971 t miannu PKCβI phosphorylates eEF1A at Ser53.our proteomics exploration of cPKC signaling in the nuclei of C2C12 cells demonstrated that the up-regulation of eEF1A intranuclear content, evoked by insulin, is associated with an increase in the phosphorylation of the Ser53 residue of the protein. SIGNOR-263167 0.2 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 23431053 t milica MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation SIGNOR-201274 0.593 PRKCD protein Q05655 UNIPROT HNRNPK protein P61978 UNIPROT unknown phosphorylation Ser302 GRGGRGGsRARNLPL 9606 10329716 t Manara We have shown that PKCδ binds and phosphorylates K protein. These observations broaden the range of K protein interactions. PKCδ targets Ser302, which is located in the middle of what appears to be a highly interactive KI domain SIGNOR-260877 0.35 BCOR protein Q6W2J9 UNIPROT HOXA5 protein P20719 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 26847029 f irozzo Importantly, our results showed that BCOR is a repressor of HoxA cluster of genes (HoxA5, HoxA7 and HoxA9) in myeloid cells. Knock-down of HoxA5, HoxA7 and HoxA9 significantly decreased the clonogenic growth of Bcor mutant and wild type cells, demonstrating the Hox genes, as targets of BCOR, played an important role in mediating BCOR’s function in regulating myeloid cell proliferation. SIGNOR-256012 0.2 JUN protein P05412 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18641051 f lperfetto Taken together, our findings suggest that c-Jun, a transcription factor downstream of the JNK signaling pathway, up-regulates Adapt78 expression in response to TG-induced ER stress and contributes to protection against TG-induced cell death. SIGNOR-253148 0.28 N-(2-chlorophenyl)-4-[[2-[4-[2-(4-ethyl-1-piperazinyl)-2-oxoethyl]anilino]-5-fluoro-4-pyrimidinyl]amino]benzamide chemical CHEBI:91365 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190029 0.8 EIF3F protein O00303 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates deubiquitination Lys1759 CGVLLSRkRRRQHGQ 9606 21124883 t gcesareni The activated form of notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. The enzyme accounting for this deubiquitinase activity is eif3f, known so far as a translation initiation factor. SIGNOR-170158 0.431 TIMM23 protein O14925 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 t lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. SIGNOR-267697 0.634 NCOA1 protein Q15788 UNIPROT ASXL1 protein Q8IXJ9 UNIPROT up-regulates activity binding 9606 BTO:0000567 16606617 t irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation.Therefore, both the ability to bind SRC-1 and the autonomous activation of ASXL1 are required for its coactivator function. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. SIGNOR-255924 0.287 STAT5A protein P42229 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0001096 14530308 f apalma Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells SIGNOR-256663 0.7 HNRNPU protein Q00839 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 t lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. SIGNOR-262281 0.2 lenalidomide chemical CHEBI:63791 ChEBI CRBN protein Q96SW2 UNIPROT up-regulates activity chemical activation 9606 26131937 t gcesareni Lenalidomide, like thalidomide and pomalidomide, binds CRBN and induces degradation of specific substrates SIGNOR-236891 0.8 CDK1 protein P06493 UNIPROT RCC1 protein P18754 UNIPROT up-regulates activity phosphorylation Ser387 GQDEDAWsPVEMMGK -1 15014043 t miannu We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of human RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. However, when both S2 and S11 were simultaneously mutated to As, the resulting 6His-RCC1S2,11A failed to be phosphorylated, whereas all of the other double mutants were phosphorylated (Fig. 1C). As expected, mutating all four sites to As (the 6His-RCC1S2,11,387A-T274A) also blocked phosphorylation (Fig. 1C). SIGNOR-262703 0.517 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 18439900 t lperfetto The phosphorylation of raptor by ampk is required for the inhibition of mtorc1 and cell-cycle arrest induced by energy stress. SIGNOR-216430 0.449 PDGFB protein P01127 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity binding 9606 11331882 t miannu Pdgf-b activates both pdgfr-alpha and pdgfr-beta SIGNOR-107397 0.707 TFAP2B protein Q92481 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization binding 9606 21556774 t miannu These data suggest that AP-2Œ≤ enhances transactivation of p53 and regulates CRYAB transcription via p53. Further study demonstrated that AP-2Œ≤ interacts with p53 and augments its protein stability. Taken together, our results indicate that AP-2Œ≤ up-regulates the transcription of the CRYAB gene through stabilizing p53. SIGNOR-255422 0.341 STK4 protein Q13043 UNIPROT AR protein P10275 UNIPROT down-regulates 21512132 f lperfetto Mst1 plays a critical role in the regulation of programmed cell death and it has been implicated in PCa development. Interestingly, MST1 has been detected in AR-chromatin complexes, and forced expression of MST1 reduces AR binding to androgen-responsive elements along the PSA promoter. SIGNOR-151712 0.2 AKT3 protein Q9Y243 UNIPROT BMI1 protein P35226 UNIPROT up-regulates activity phosphorylation Ser316 ANRPRKSsVNGSSAT 22505453 t lperfetto the polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate SIGNOR-249583 0.261 HDAC1 protein Q13547 UNIPROT DNMT1 protein P26358 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23242655 f Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells. SIGNOR-254028 0.778 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser450 SHNSALYsQVQKSGA 9606 15574499 t amattioni Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility. SIGNOR-131556 0.255 MAPK14 protein Q16539 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000887 18026121 t lperfetto Targeting of ash2l to specific genes is mediated by the transcriptional regulator mef2d. Furthermore, this interaction is modulated during differentiation through activation of the p38 mapk signaling pathway via phosphorylation of mef2d. SIGNOR-159331 0.596 UBN2 protein Q6ZU65 UNIPROT HIRA complex 2 complex SIGNOR-C462 SIGNOR form complex binding 9606 30285846 t miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. SIGNOR-269436 0.381 KIF7 protein Q2M1P5 UNIPROT GLI2 protein P10070 UNIPROT up-regulates quantity by stabilization binding 9606 19549984 t lperfetto Kif7 physically interacted with Gli transcription factors and controlled their proteolysis and stability, and acted both positively and negatively in Hh signaling. SIGNOR-209611 0.569 irinotecan chemical CHEBI:80630 ChEBI TOP1 protein P11387 UNIPROT down-regulates activity chemical inhibition 9606 15170677 t miannu Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin; CPT-11) is a widely used potent antitumor drug that inhibits mammalian DNA topoisomerase I (Topo I) SIGNOR-259316 0.8 FGF11 protein Q92914 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253426 0.2 TSSK3 protein Q96PN8 UNIPROT TSSK3 protein Q96PN8 UNIPROT up-regulates activity phosphorylation Ser166 PKSHRELsQTFCGST -1 16336268 t Manara We elucidated the mechanism of regulation of TSSK3 activity showing that autophosphorylation and PDK1 phosphorylation in the ‘activation loop’ are necessary for activation. SIGNOR-260785 0.2 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Thr183 ACTNFMMtPYVVTRY 9606 BTO:0000007 9890973 t phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif gcesareni Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). These results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway. SIGNOR-63976 0.622 FOXA1 protein P55317 UNIPROT HSPA1B protein P0DMV9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 19486887 f miannu The results showed overexpression of Foxa1 promoted the expression of HSP72, while Foxa1 depletion, induced by antisense oligonucleotides, decreased the expression of HSP72 in MCF-7 cells under normal and heat stress condition. SIGNOR-254165 0.2 LYN protein P07948 UNIPROT KCND3 protein Q9UK17 UNIPROT up-regulates activity phosphorylation Tyr108 GKLHYPRyECISAYD 9606 BTO:0000007 22198508 t miannu These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels. SIGNOR-276395 0.2 PDIA6 protein Q15084 UNIPROT ERN1 protein O75460 UNIPROT down-regulates activity 10090 BTO:0000944 24508390 t A resident ER protein disulfide isomerase, PDIA6, limits the duration of IRE1α activity by direct binding to cysteine148 in the luminal domain of the sensor, SIGNOR-256536 0.322 SATB1 protein Q01826 UNIPROT NUMB protein P49757 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000725 23563689 f miannu Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc SIGNOR-224835 0.342 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr766 ALTSNQEyLDLSMPL 10116 19224897 t lperfetto This second-stage autophosphorylation occurs on y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of y463 in the juxtamembrane region, y766 in the c-terminal tail, and y585 in the kinase insert region (1). The third-stage autophosphorylation takes place on the second tyrosine in the activation loop (y654), resulting in an additional 10-fold increase in the intrinsic tyrosine kinase activity of fgfr1. SIGNOR-236203 0.2 NCSTN protein Q92542 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates binding 9606 10993067 t Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation gcesareni Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. SIGNOR-81936 0.94 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 BTO:0003316 11777913 t miannu 4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E. SIGNOR-250098 0.444 linifanib chemical CHEBI:91435 ChEBI PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193666 0.8 calcium(2+) smallmolecule CHEBI:29108 ChEBI PLA2G4A protein P47712 UNIPROT up-regulates relocalization 9606 8027085 t gcesareni Cytosolic phospholipase a2 (cpla2) is a calcium-sensitive 85-kda enzyme that hydrolyzes arachidonic acid-containing membrane phospholipids to initiate the biosynthesis of eicosanoids and platelet-activating factor, potent inflammatory mediators. The calcium-dependent activation of the enzyme is mediated by an n-terminal c2 domain, which is responsible for calcium-dependent translocation of the enzyme to membranes and that enables the intact enzyme to hydrolyze membrane-resident substrates. cytosolic phospholipase a2 (cpla2) associates with natural membranes in response to physiological increases in ca2+, resulting in the selective hydrolysis of arachidonyl phospholipids. SIGNOR-35874 0.8 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr771 ADIESSNyMAPYDNY -1 7545675 t Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides SIGNOR-248415 0.679 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT up-regulates sumoylation Lys65 QQCQAEAkCPKLLPC 9534 9756909 t lperfetto We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation. SIGNOR-261788 0.771 SRF protein P11831 UNIPROT CNN1 protein P51911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 21673106 f gcesareni In particular, high expression of vsmc-specific genes, such as smooth muscle -actin (sma), calponin1 (cnn), and sm22 (sm22) are associated with the contractile vsmc phenotype. Transcription of contractile genes is regulated by srf through a dna sequence motif known as the carg box (cc(a/t)6gg), which is present in the promoters of vsmc-specific genes. SIGNOR-174358 0.369 TLR4 protein O00206 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 10090 22664090 t gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-252065 0.762 BMP2 protein P12643 UNIPROT SMAD9 protein O15198 UNIPROT up-regulates 9606 22298955 f gcesareni Neogenin, a transmembranous protein, was re-ported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation. SIGNOR-195567 0.634 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR GYS1 protein P13807 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136553 0.2 CSNK2A1 protein P68400 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1112 VPIAVGEsDFENLNT 9606 BTO:0000938 19064667 t lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. SIGNOR-275753 0.2 ABCC8 protein Q09428 UNIPROT KATP channel complex SIGNOR-C274 SIGNOR form complex binding 9606 28842488 t lperfetto ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits. SIGNOR-262056 0.641 DLL1 protein O00548 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 23111325 t gcesareni In this study, we demonstrate that dll1 can activate notch signaling mostly through notch2 receptor and can contribute to drug resistance to bortezomib, both in murine and human mm cells. SIGNOR-199320 0.62 IKBKE protein Q14164 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity phosphorylation 9606 15489227 t miannu Constitutive and interleukin-1-inducible Phosphorylation of p65 NF-{kappa}B at Serine 536 Is Mediated by Multiple Protein Kinases Including I{kappa}B Kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF Family Member-Associated (TANK)-binding Kinase 1 (TBK1). Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro. SIGNOR-217379 0.432 CD79A protein P11912 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000776 12324477 f gcesareni Bcr ligation activated mitochondrial apoptotic pathways including down-regulation of bcl-x(l). SIGNOR-93481 0.272 AMPK complex SIGNOR-C15 SIGNOR SREBF1 protein P36956 UNIPROT down-regulates phosphorylation Ser396 TAVHKSKsLKDLVSA 9606 21459323 t lperfetto Here we demonstrate that ampk interacts with and directly phosphorylates sterol regulatory element binding proteins (srebp-1c and -2). Ser372 SIGNOR-216533 0.323 MTOR protein P42345 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity phosphorylation Ser2481 TVPESIHsFIGDGLV 9606 BTO:0000782 SIGNOR-C2 SIGNOR-C2 10702316 t lperfetto We report here the identification of a FRAP autophosphorylation site. This site, Ser-2481, is located in a hydrophobic region near the conserved carboxyl-terminal FRAP tail. We demonstrate that the COOH-terminal tail is required for FRAP kinase activity and for signaling to the translational regulator p70(s6k) (ribosomal subunit S6 kinase). SIGNOR-75394 0.2 D-fructofuranose 6-phosphate(2-) smallmolecule CHEBI:61527 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 21310273 t miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans SIGNOR-267813 0.8 ARNT protein P27540 UNIPROT TH protein P07101 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003945 17457889 f lperfetto Overexpression and siRNA experiments revealed that NPAS1, in concert with ARNT, negatively regulates the expression of TH and that this regulation is mediated by a direct binding of NPAS1 on the TH promoter. SIGNOR-253701 0.2 SGCA protein Q16586 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255985 0.539 PRKD1 protein Q15139 UNIPROT OSBP protein P22059 UNIPROT down-regulates phosphorylation Ser240 TALQRSLsELESLKL 9606 21285358 t gcesareni Pkd attenuates the function of both cert and osbp by phosphorylation at their respective ser(132) and ser(240) residues (phosphorylation inhibition) SIGNOR-171756 0.455 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257454 0.8 LPAR4 protein Q99677 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257325 0.2 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation 9606 18394876 t gcesareni The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1 SIGNOR-253002 0.673 PJA2 protein O43164 UNIPROT PRKAR1A protein P10644 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21423175 t miannu Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits SIGNOR-271855 0.387 DRD2 protein P14416 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257096 0.4 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr8 MSSILPFtPPIVKRL 9606 15241418 t lperfetto We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity SIGNOR-232138 0.748 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA3 protein Q9Y5H0 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265699 0.2 CDC14B protein O60729 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity dephosphorylation 9606 18662541 t lperfetto Cdc14B activates APC/C Cdh1 after DNA damage in G2.|Importantly, after DNA damage, thein vivo phosphorylation of wild type Cdh1 - but not that of Cdh1 (4xA) - increased after Cdc14B silencing (XREF_FIG), indicating that in response to genotoxic stress, Cdc14B dephosphorylates Cdh1 on the four sites phosphorylated by Cdk2. SIGNOR-277017 0.318 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 19723038 t gcesareni The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases these include epidermal growth factor receptor (egfr) kinase,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1 SIGNOR-187779 0.709 MAPK14 protein Q16539 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Thr299 AGLTPPTtPPHKANQ 9606 BTO:0000887 11741533 t gcesareni Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298 SIGNOR-112774 0.568 PAK1 protein Q13153 UNIPROT SYN1 protein P17600 UNIPROT up-regulates activity phosphorylation Ser605 AGPTRQAsQAGPVPR 10116 BTO:0001009 12237306 t miannu Synapsin I is phosphorylated at Ser603 by p21-activated kinases. the Ser603 residue must be one of the pivotal sites for the release SIGNOR-250235 0.355 FBXW11 protein Q9UKB1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10074433 t gcesareni We conclude that beta-trcp is a component of an e3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated beta-catenin. we found that the binding of beta-trcp to beta-catenin was direct. SIGNOR-65429 0.736 EEF1A2 protein Q05639 UNIPROT His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269531 0.8 PRKCD protein Q05655 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Ser167 LFPSFIHsQKRNPQT 9935 24211614 t Manara Endothelin-1 stimulates catalase activity through the PKCδ-mediated phosphorylation of serine 167. SIGNOR-260904 0.27 CDK1 protein P06493 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser705 TPSAMKSsPQIPHQT 9606 SIGNOR-C17 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. SIGNOR-164495 0.462 MAPK1 protein P28482 UNIPROT MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation Ser454 TGSTPPVsPTPSERS 9606 18694962 t Translocation from Nuleus to Cytoplasm gcesareni Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. SIGNOR-179959 0.2 ADNP protein Q9H2P0 UNIPROT ChAHP complex SIGNOR-C407 SIGNOR form complex binding 10090 BTO:0002896 29795351 t miannu Here we show that ADNP interacts with the chromatin remodeller CHD4 and the chromatin architectural protein HP1 to form a stable complex, which we refer to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. we have discovered ChAHP, a gene-regulatory complex that consists of the chromatin remodeller CHD4, the DNA-binding factor ADNP, and the heterochromatin proteins HP1β and HP1γ. By locally restricting access to DNA, ChAHP prevents endodermal gene transcription in mouse ES cells and during neuroectodermal differentiation. SIGNOR-266751 0.299 DCAF7 protein P61962 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181; BTO:0003484 16887337 f Giorgia HAN11 and mDia1 repressed DYRK1A-dependent GLI1 transcriptional activity. The studies of SZ95 cells suggest that HAN11 reduces GLI1-dependent transcription by decreasing the nuclear pool of GLI1. SIGNOR-260634 0.264 ROR2 protein Q01974 UNIPROT FLNA protein P21333 UNIPROT up-regulates binding 9606 18667433 t gcesareni Additionally, the association of ror2 with the actin-binding protein filamin a is required for wnt5a-induced jnk activation and polarized cell migration. SIGNOR-179668 0.415 ROMO1 protein P60602 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 t lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. SIGNOR-267690 0.392 FOXO proteinfamily SIGNOR-PF27 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-256644 0.7 PRKACA protein P17612 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser172 DQVQRRGsLPPRQVP 9606 20110267 t llicata We identified ser-282 as target of mapk and ser-172 as target of pkc and pka in vitro and in a transfected human embryonic kidney 293 (hek293) cell model using site directed mutagenesis and phosphopeptide mapping analysis. In hek293 cells, phosphorylation of these sites occurred at a basal level and down-regulated constitutive nox1 activity. I SIGNOR-163663 0.33 RBX1 protein P62877 UNIPROT BAF250b E3 ligase complex SIGNOR-C522 SIGNOR form complex binding 9606 BTO:0000567 20086098 t miannu In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro SIGNOR-271439 0.598 STAT1 protein P42224 UNIPROT RELA protein Q04206 UNIPROT down-regulates binding 9606 SIGNOR-C13 16481475 t gcesareni Acetylated stat1 is able to interact with nf-kappab p65. As a consequence, p65 dna binding, nuclear localization, and expression of anti-apoptotic nf-kappab target genes decrease. SIGNOR-144561 0.533 BAMBI protein Q13145 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 2662247 t gcesareni Bmp-2 mediates phosphorylated smad1 (psmad1) or, with loss of bmprii, psmad3-dependent recruitment of disheveled (dvl) to promote rhoa-rac1 signaling necessary for motility. SIGNOR-23037 0.499 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248740 0.727 MZF1 protein P28698 UNIPROT CCN2 protein P29279 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25899830 f miannu we report the regulation of the CTGF and NOV genes by Myeloid Zinc Finger-1 (MZF-1), a hematopoietic transcription factor. We show the interaction of MZF-1 with the CTGF and NOV promoters in several cell types. Up-regulation of MZF-1 via calcitriol and vitamin A induces expression of CTGF and NOV, implicating a role for these vitamins in the functions of these two genes. Lastly, knockdown of MZF1 reduces levels of CTGF and NOV. SIGNOR-226307 0.2 dasatinib (anhydrous) chemical CHEBI:49375 ChEBI ABL1 protein P00519 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258063 0.8 MAP3K7 protein O43318 UNIPROT KSR1 protein Q8IVT5 UNIPROT down-regulates phosphorylation Ser406 TRLRRTEsVPSDINN 9606 11741534 t gcesareni C-tak1 constitutively associates with mammalian ksr1 and phosphorylates serine 392 to confer 14-3-3 binding and cytoplasmic sequestration of ksr1 in unstimulated cells. In response to signal activation, the phosphorylation state of s392 is reduced, allowing the ksr1 complex to colocalize with activated ras and raf-1 at the plasma membrane SIGNOR-112779 0.2 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser380 EPDHYRYsDTTDSDP 9606 21779440 t gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity SIGNOR-161118 0.622 naltrexone chemical CHEBI:7465 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258946 0.8 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr386 YRARVANyQRDGPMC 9606 BTO:0000093 12777400 t lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases SIGNOR-101310 0.346 MAPK9 protein P45984 UNIPROT RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 16551633 t gcesareni Under stress conditions, hyperphosphorylated by activated jnk on ser-56, ser-70, thr-82 and ser-260. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear rxralpha levels, via a multistep, jnk-dependent mechanism involving ser260, nuclear export, and proteasomal degradation. SIGNOR-145301 0.248 GSK3B protein P49841 UNIPROT NFE2L1 protein Q14494 UNIPROT down-regulates phosphorylation Ser379 SQDFLLFsPEVESLP 9606 BTO:0000938 23623971 t lperfetto Glycogen synthase kinase 3 regulates expression of nuclear factor-erythroid-2 related transcription factor-1 (nrf1) and inhibits pro-survival function of nrf1 SIGNOR-193450 0.409 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser952 DSRSHQNsPTELNKD 9606 BTO:0001938 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. SIGNOR-104691 0.844 tryptophan smallmolecule CHEBI:27897 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264743 0.7 ER stress stimulus SIGNOR-ST9 SIGNOR ATF4 protein P18848 UNIPROT up-regulates 9606 23205607 f lperfetto Reporter gene analyses using the 5'-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress SIGNOR-253728 0.7 BRSK1 protein Q8TDC3 UNIPROT CDC25C protein P30307 UNIPROT down-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR 9606 BTO:0000567 15150265 t lperfetto Overexpression of hssad1 resulted in an increased phosphorylation of cdc25c on ser-216 in vivo. Phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 SIGNOR-107408 0.495 TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 10973958 t lperfetto The pathway restricted (r)Smads (e.g. Smad1, 2, 3, and 5) are serine/threonine kinase activated proteins that interact in an unphosphorylated state with a TGF-b superfamily receptor. Upon ligand binding they are phosphorylated by the receptor and released. SIGNOR-249549 0.818 NEK6 protein Q9HC98 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000007 20595392 t done miannu Our data also show that NEK6 interacts with STAT3, an oncogenic transcription factor, and phosphorylates STAT3 on Ser(727), which is important for transcriptional activation. These results demonstrate that NEK6 interacts with and phosphorylates STAT3, an event that could play an important role in oncogenesis. For the maximal activation of STAT3 signaling, phosphorylation of both Tyr705 and Ser727 is required. Phosphorylation of Tyr705 induces dimerization, nuclear translocation, and DNA binding of the STAT3 protein, whereas phosphorylation of Ser727 is important for transcriptional activation. SIGNOR-273902 0.338 HP protein P00738 UNIPROT HBB protein P68871 UNIPROT down-regulates quantity binding 9606 9315856 t Regulation of binding miannu Haptoglobin forms a complex of extremely high affinity with Hb via a well-characterized globin site. Our results show that upon Hb-haptoglobin binding, the globin radical, loses its ability to be terminated by forming globin dimers. SIGNOR-251815 0.765 ATG4B protein Q9Y4P1 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates cleavage 9606 BTO:0000007;BTO:0000567 15187094 t gcesareni Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16. SIGNOR-125449 0.796 PRKCA protein P17252 UNIPROT ADD2 protein P35612 UNIPROT down-regulates phosphorylation Ser713 KKKFRTPsFLKKSKK 9606 9679146 t gcesareni Pkc phosphorylation of native and recombinant adducin inhibited actin capping measured using pyrene-actin polymerization and abolished activity of adducin in recruiting spectrin to ends and sides of actin filaments SIGNOR-59299 0.2 MKNK2 protein Q9HBH9 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 9606 17724079 t lperfetto Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes. SIGNOR-157537 0.577 TFE3 protein P19532 UNIPROT GLA protein P06280 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276823 0.2 SSTR4 protein P31391 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256959 0.252 TBK1 protein Q9UHD2 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity phosphorylation 9606 15489227 t miannu Constitutive and interleukin-1-inducible Phosphorylation of p65 NF-{kappa}B at Serine 536 Is Mediated by Multiple Protein Kinases Including I{kappa}B Kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF Family Member-Associated (TANK)-binding Kinase 1 (TBK1). Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro. SIGNOR-260157 0.578 ATM protein Q13315 UNIPROT TOP2B protein Q02880 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1135 HDDSSSDsGTPSGPD 9606 32015321 t miannu Specifically, DNA damage signal, triggered by teniposide (VM-26) treatment, activates ATM, cooperating with CK1 to phosphorylate TOP2β on Ser1134 and Ser1130, respectively, in a canonical degron motif to facilitate β-TrCP binding and subsequent degradation.ATM binds with and phosphorylates TOP2β at Ser1134 to promote its degradation by VM-26. SIGNOR-277510 0.421 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 9606 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252821 0.908 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT down-regulates activity phosphorylation Thr233 DDEDDSGtEES 9606 11546811 t lperfetto The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm. SIGNOR-110407 0.403 EXOSC1 protein Q9Y3B2 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-261381 0.959 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Ser360 RKTQTSMsLGTTREK -1 24012422 t gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays SIGNOR-266440 0.743 TUBA1C protein Q9BQE3 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. SIGNOR-269728 0.7 ETF complex SIGNOR-C463 SIGNOR FAD smallmolecule CHEBI:16238 ChEBI down-regulates quantity chemical modification 9606 33450351 t miannu ETF is a two-electron and two-proton transporter as its FAD undergoes successive reduction via two-consecutive one-electron transfer steps, with the formation of an intermediate one-electron red flavin semiquinone species (FAD•−), which is then fully reduced to FADH2 with the uptake of one additional electron and two protons (Fig. 4a). SIGNOR-269454 0.8 LNX1 protein Q8TBB1 UNIPROT ABCA1 protein O95477 UNIPROT down-regulates quantity by destabilization ubiquitination -1 22889411 t miannu We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo. SIGNOR-272902 0.244 KAT2B protein Q92831 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11062529 t gcesareni The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis. SIGNOR-84032 0.555 CXCL1 protein P09341 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 16885213 f gcesareni The data suggest that smo is in fact the source of two signals relevant to the activation of gli: one involving g(i) and the other involving events at smo's c-tail independent of g(i). SIGNOR-148454 0.2 PRKCA protein P17252 UNIPROT DGKZ protein Q13574 UNIPROT unknown phosphorylation Ser265 SKKKKRAsFKRKSSK 9716136 t lperfetto Two isoforms of protein kinase C, but not others, regulate the localization of DGK-zeta. |The PSD in MARCKS is phosphorylated by PKC, which suggested that DGK-zeta may also be a substrate for PKC, and that this couldregulate its intracellular location. SIGNOR-249010 0.517 PPP2CB protein P62714 UNIPROT MYC protein P01106 UNIPROT down-regulates dephosphorylation Ser62 LLPTPPLsPSRRSGL 9606 16987807 t esanto Phosphorylation at ser-62 by pro-directed kinases (p-k) is a prerequisite for gsk3-dependent phosphorylation of thr-58. This triggers binding of pin1, subsequently protein phosphatase 2a (pp2a)-dependent dephosphorylation of ser-62, and then recruitment of scf-fbw7 to the thr-58-phosphorylated myc. Scf-fbw7 polyubiquitinylates myc (branching through lys-48), leading to its proteasomal degradation. SIGNOR-149726 0.279 CALM1 protein P0DP23 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates activity binding 9606 11807557 t miannu Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. SIGNOR-253410 0.462 FGF10 protein O15520 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 9582367 t gcesareni Rfgf-10 bound the kgfr with high affinity comparable to that of kgf SIGNOR-57380 0.89 ARFGEF1 protein Q9Y6D6 UNIPROT ARF1 protein P84077 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000599 14973189 t lperfetto Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1) is an approximately 200-kDa brefeldin A-inhibited guanine nucleotide-exchange protein that preferentially activates ADP-ribosylation factor 1 (ARF1) and ARF3.  SIGNOR-272147 0.584 SYK protein P43405 UNIPROT FCGR2A protein P12318 UNIPROT up-regulates activity phosphorylation Tyr304 TDDDKNIyLTLPPND -1 8756631 t lperfetto To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and pointFyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation. SIGNOR-246551 0.659 CSNK1E protein P49674 UNIPROT ROR2 protein Q01974 UNIPROT up-regulates phosphorylation 9606 15375164 t gcesareni We also show that ror2 is phosphorylated by ckiepsilon on serine/threonine residues. SIGNOR-129117 0.271 AKT2 protein P31751 UNIPROT ATP7A protein Q04656 UNIPROT up-regulates quantity by stabilization phosphorylation Ser1424 SYELPARsQIGQKSP 10090 29301787 t lperfetto Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus|Immunoprecipitation, in vitro kinase assay, and mass spectrometry analysis reveal that insulin stimulates Akt2 binding to ATP7A to induce phosphorylation at Ser1424/1463/1466 SIGNOR-272269 0.263 SMARCD2 protein Q92925 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270706 0.754 CDK7 protein P50613 UNIPROT XRN2 protein Q9H0D6 UNIPROT up-regulates activity phosphorylation Thr439 FTPSGILtPHALGSR 9606 26728557 t Luana CDKs and Xrn2 phosphorylation promote transcription termination. | Cdk7 phosphorylated Xrn2-Thr439 but was less efficient than Cdk9. | SIGNOR-259851 0.249 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-81161 0.41 tRNA(Ser) smallmolecule CHEBI:29179 ChEBI Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates quantity precursor of 9606 24095058 t miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis SIGNOR-270499 0.8 C1R protein P00736 UNIPROT Complement C1 complex complex SIGNOR-C309 SIGNOR form complex binding -1 29449492 t lperfetto The complement system is part of our innate immune system. The classical complement pathway is triggered by activation of the C1 initiation complex upon binding to cell surfaces. C1, or C1qr2s2, consists of four proteases, C1r and C1s, that associate with C1q, which contains antibody-binding sites.|The reconstruction reveals densities for all C1q collagen-like triple helices and gC1q modules, C1r and C1s proteases SIGNOR-263395 0.693 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT up-regulates activity phosphorylation Tyr133 NFLSEDKyPLIMVPD 9606 18976935 t lperfetto Here, we report that the T cell receptor (TCR)-induced translocation of SLAT to the immunological synapse required Lck-mediated phosphorylation of two tyrosine residues located in an immunoreceptor tyrosine-based activation motif-like sequence but was independent of the SLAT PH domain. This subcellular relocalization was coupled to, and necessary for, activation of the NFAT pathway|These results indicate that SLAT undergoes Lck-dependent phosphorylation on Tyr-144 and Tyr-133 upon TCR and CD28 stimulation. SIGNOR-253367 0.514 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252351 0.2 APP protein P05067 UNIPROT Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR up-regulates 9606 11578751 f lperfetto Neurodegeneration in Alzheimer's disease is a pathologic condition of cells rather than an accelerated way of aging. The senile plaques are generated by a deposition in the human brain of fibrils of the β-amyloid peptide (Aβ), a fragment derived from the proteolytic processing of the amyloid precursor protein (APP). Tau protein is the major component of paired helical filaments (PHFs), which form a compact filamentous network described as neurofibrillary tangles (NFTs). SIGNOR-251638 0.7 MEN1 protein O00255 UNIPROT HOXA9 protein P31269 UNIPROT up-regulates quantity by expression methylation 9606 BTO:0004730 16415155 t irozzo Men1 excision causes reduction of Hoxa9 expression, colony formation by hematopoietic progenitors, and the peripheral white blood cell count. Menin directly activates Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitating methylation of H3K4, and recruiting the methylated H3K4 binding protein chd1 to the locus.  SIGNOR-255894 0.49 TJP1 protein Q07157 UNIPROT NHS protein Q6T4R5 UNIPROT up-regulates activity binding 10090 19447104 t miannu NHS-A is a novel interactor of ZO-1 and is expected to have a role at tight junctions. Its recruitment to these junctions is dependent upon their assembly. SIGNOR-253567 0.2 CHEK2 protein O96017 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto Tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process SIGNOR-171026 0.2 MAML1 protein Q92585 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 11101851 t gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1. SIGNOR-84838 0.782 SIAH2 protein O43255 UNIPROT AKAP1 protein Q92667 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18323779 t miannu Seven In-Absentia Homolog 2 (Siah2), an E3-ubiquitin ligase whose expression is induced in hypoxic conditions, formed a complex and degraded AKAP121. SIGNOR-272641 0.521 NOTCH2 protein Q04721 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity binding 9606 BTO:0003960 31699119 t miannu  NOTCH2 attenuated the TRAF6-AKT signaling axis via an interaction between the NOTCH2 intracellular domain (N2ICD) and TRAF6, which inhibited epithelial-mesenchymal transition (EMT) and eventually suppressed NPC metastasis. SIGNOR-265562 0.316 EPAS1 protein Q99814 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20534544 f Regulation miannu We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200-3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2alpha, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. SIGNOR-251792 0.25 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 BTO:0000782 15623513 t lperfetto Protein kinase d1 (pkd1) was activated after tcr engagement, interacted with hdac7, and phosphorylated three serines (ser155, ser318, and ser448) at its n terminus, leading to its export from the nucleus. SIGNOR-132894 0.491 GH1 protein P01241 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001939 15665309 t Luana Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells SIGNOR-261629 0.2 UCHL5 protein Q9Y5K5 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates binding 9606 16027725 t gcesareni Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases. SIGNOR-138879 0.649 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCR3 protein P51677 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16604092 f miannu Rosmarinic acid also inhibited TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, as well as nuclear translocation of NF-kappaB heterodimer induced by TNF-alpha. This suggests that rosmarinic acid downregulates the expression of CCL11 and CCR3 via the inhibition of NF-kappaB activation signaling. SIGNOR-254660 0.26 WNT3A protein P56704 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have a complex and partially overlapping pattern of expression in different regions of the embryo, and many of them (fz1, 3, 7, 8 and 9) have specific expression in the epithelial somites as well as in the newly formed myotomes. SIGNOR-169651 0.788 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr212 TNTYYLRtFGHNTMD 9606 12145304 t gcesareni Oxidative stress-responsive kinase-1 (osr1) is a known upstream regulator of n(k)ccs. these results suggest that, globally, osr1 is involved in the regulation of bp and renal tubular na(+) reabsorption mainly via the activation of nkcc1 and nkcc2. SIGNOR-90931 0.539 RNF43 protein Q68DV7 UNIPROT FZD2 protein Q14332 UNIPROT up-regulates relocalization 9606 23151663 t gcesareni Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation61 (see above), and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane SIGNOR-199585 0.313 SP1 protein P08047 UNIPROT GP6 protein Q9HCN6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001549 12359731 f miannu Deletion analyses and site-directed mutagenesis identified Sp1(227), GATA(177), and Ets(48) sites as essential for GPVI expression. We show that transcription factors GATA-1, Fli-1, and Sp1 can bind to and activate this promoter. SIGNOR-254159 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR F3 protein P13726 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001949 12744731 f miannu In conclusion, NF-kappaB could be activated promptly after HUVEC incubated with TNF-alpha, then it was bound to TF promotor to start the TF transcription, TF mRNA expression was upregulated, that leaded to the increase of TF expression on the HUVEC surface and activated the coagulation cascade. SIGNOR-254810 0.251 FOXO proteinfamily SIGNOR-PF27 SIGNOR NOTCH3 protein Q9UM47 UNIPROT down-regulates quantity transcriptional regulation 10090 24749067 f gcesareni We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration. SIGNOR-252941 0.2 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248743 0.727 SKI protein P12755 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR down-regulates activity binding 9606 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-253301 0.766 PRKCA protein P17252 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser13 ITSAARRsYVSSGEM -1 2155236 t lperfetto Glial fibrillary acidic protein (GFAP), the intermediate filament component of astroglial cells, can serve as an excellent substrate for both cAMP-dependent protein kinase and protein kinase C, in vitro. GFAP phosphorylated by each protein kinase does not polymerize, and the filaments that do polymerize tend to depolymerize after phosphorylation. Dephosphorylation of phospho-GFAP by phosphatase led to a recovery of the polymerization competence of GFAP. Most of the phosphorylation sites for cAMP-dependent protein kinase and protein kinase C on GFAP are the same, Ser-8, Ser-13, and Ser-34. cAMP-dependent protein kinase has one additional phosphorylation site, Thr-7. SIGNOR-248860 0.374 lysophosphatidic acid smallmolecule CHEBI:132742 ChEBI LPAR6 protein P43657 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257533 0.8 JAK3 protein P52333 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Tyr371 ADFAPEDySSFQHIR 9606 BTO:0001372 23263556 t miannu  Here we found that IL-7-Jak3 signals activated the transcription factor NFATc1 in DN thymocytes by phosphorylating Tyr371 in the regulatory region of NFATc1.  SIGNOR-276435 0.391 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates activity chemical inhibition 9606 7566123 t Monia Consistent with an essential role for FRAP kinase activity in vivo, autophosphorylation of FRAP is inhibited by FKBP12-rapamycin. SIGNOR-261074 0.8 PRKCA protein P17252 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Ser98 RLGRRKGsGPKKERR 9606 14636580 t lperfetto In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. In addition, phosphopeptide mapping analysis of wild-type and mutant forms of HAND1 shows that three of these conserved residues, T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues.  SIGNOR-249243 0.292 TFIIF complex SIGNOR-C394 SIGNOR RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity relocalization 9606 18218714 t lperfetto Transcription processes in eukaryotes begin with the formation of a pre-initiation complex (PIC), composed of RNA polymerase II (Pol II) associated with five general transcription factors: TFIIB, TFIID, TFIIE, TFIIF, and TFIIH SIGNOR-266199 0.725 MAML3 protein Q96JK9 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 12370315 t gcesareni We report here the cloning and characterization of two new genes, maml2 and maml3, that also function as transcriptional coactivators for notch receptors. SIGNOR-94100 0.877 CDK1 protein P06493 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation Ser83 QQQQQETsPRQQQQQ 9606 BTO:0001130 21799006 t gcesareni At first, the data show that cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins although ar was reported as substrates for cdk9 (5) as well as cdk1 SIGNOR-175692 0.546 GPR132 protein Q9UNW8 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256945 0.2 MAP4K4 protein O95819 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 t gcesareni Hpk1 binds and phosphorylates mekk1 directly SIGNOR-44040 0.539 DAPK1 protein P53355 UNIPROT MYL12A protein P19105 UNIPROT up-regulates activity phosphorylation Ser19 KRPQRATsNVFAMFD 9606 BTO:0000567 11485996 t miannu DAPK Phosphorylates Myosin II RLC in Vitro and in Vivo. Together these results show that similar to the conventional MLCKs, Ser-19 is the primary RLC residue phosphorylated by DAPK and that phosphorylation of Thr-18 is also possible. SIGNOR-262842 0.278 NR3C1 protein P04150 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity 10090 BTO:0000944 11742987 f gcesareni Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. SIGNOR-251677 0.522 PARP1 protein P09874 UNIPROT SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR form complex binding 9606 22223884 t alessandro Therefore, we conclude that the endogenous proteins PARP1, p65NF-κB and Snail1 form a ternary complex in the nuclei of cells that are actively expressing fibronectin SIGNOR-254528 0.496 glycogen smallmolecule CHEBI:28087 ChEBI α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity precursor of 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [‚Ķ] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267397 0.8 WNT2 protein P09544 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131727 0.607 ARHGEF28 protein Q8N1W1 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260546 0.745 GGCX protein P38435 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 31539109 f miannu GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05). SIGNOR-261233 0.2 MAML3 protein Q96JK9 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 12370315 t gcesareni We report here the cloning and characterization of two new genes, maml2 and maml3, that also function as transcriptional coactivators for notch receptors. SIGNOR-94097 0.746 tetra-mu3-sulfido-tetrairon chemical CHEBI:49883 ChEBI BRCA1-B complex complex SIGNOR-C298 SIGNOR form complex binding 25400280 t lperfetto Another BRCA1 complex, the BRCA1‚ÄìB complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‚Äêphase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‚Äêphase checkpoint activation SIGNOR-269475 0.8 ACVR1 protein Q04771 UNIPROT AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR up-regulates phosphorylation 9606 9748228 t fspada Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2 SIGNOR-210093 0.2 FSTL1 protein Q12841 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0001176;BTO:0002320 18718903 f miannu In this study, Fstl1 was shown to activate Akt signaling in cardiac myocytes and inhibit apoptosis. Thus, Fstl1 can function as a survival factor for both cardiac myocytes and endothelial cells via the activation of Akt signaling.  SIGNOR-266604 0.392 CSNK1D protein P48730 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser400 SRDESTDsGLSMSSY 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 24715453 t milica LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP) SIGNOR-230738 0.4 MLL Fusion fusion protein SIGNOR-FP14 SIGNOR MECOM protein Q03112 UNIPROT up-regulates quantity by expression methylation 10090 BTO:0001271 22553314 t miannu We hypothesize, based on our ChIP data, that MLL-AF9 up-regulates EVI1 transcription via H3K79 methylation, which is known to be a major gene regulatory mechanism used by some MLL-fusion proteins in leukemia. SIGNOR-260107 0.2 Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 11376933 t miannu To date, ten different mammalian isoforms of adenylyl cyclase (AC) have been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for different cells to respond diversely to similar stimuli. The product of the enzymatic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a crucial role for a variety of fundamental physiological cell functions ranging from cell growth and differentiation, to transcriptional regulation and apoptosis. SIGNOR-267844 0.8 MYOD1 protein P15172 UNIPROT MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR form complex binding 9606 BTO:0001103 17194702 t miannu Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes SIGNOR-151682 0.419 AKT1 protein P31749 UNIPROT PHB2 protein Q99623 UNIPROT down-regulates binding 10090 15173318 t lperfetto Akt binds prohibitin 2 and relieves its repression of myod and muscle differentiation SIGNOR-252541 0.499 PKA proteinfamily SIGNOR-PF17 SIGNOR SYN3 protein O14994 UNIPROT down-regulates activity phosphorylation 9606 10571231 t miannu Synapsins are exclusively localized to synaptic vesicles, which they coat as peripheral membrane proteins; they probably constitute one of the most abundant neuronal PKA substrates. Our study reveals an unexpectedly dynamic state of synapsins in nerve terminals: any changes in PKA or CaM Kinase I activity will modulate the amount of synapsin on synaptic vesicles. PKA Activation Triggers Synapsin Dissociation SIGNOR-264110 0.2 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM8 protein O00222 UNIPROT up-regulates activity chemical activation 9606 25042998 t miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate SIGNOR-264073 0.8 UTS2R protein Q9UKP6 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257252 0.268 SRF protein P11831 UNIPROT PLG protein P00747 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15514113 f miannu We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1. SIGNOR-255226 0.249 CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Thr245 GFGTSPLtPSARISA 10090 BTO:0000142 12796778 t llicata Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function. SIGNOR-250652 0.2 HUWE1 protein Q7Z6Z7 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000093 28939105 t miannu Mule was identified as Mcl-1 ubiquitin ligase E3 to promote Mcl-1 degradation via the proteasomal pathway [46]. We found that knockdown of Mule (Fig. 4C) but not β-TRCP or FBXW7 (data not shown) prevented Mcl-1 downregulation caused by PKCη depletion. SIGNOR-261909 0.516 RASGEF1A protein Q8N9B8 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-183823 0.411 CTNNA2 protein P26232 UNIPROT YAP1 protein P46937 UNIPROT down-regulates binding 9606 23431053 t In keratinocytes, YAP strongly interacts with a-catenin, and this interaction is mediated by 14-3-3. gcesareni The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation. SIGNOR-201245 0.335 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258004 0.8 NuA4 complex complex SIGNOR-C459 SIGNOR Histone H2A proteinfamily SIGNOR-PF70 SIGNOR down-regulates activity acetylation 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269287 0.2 PRKAA2 protein P54646 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000007 11069105 t miannu AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells.  activation of PFK-2 was due to the phosphorylation of Ser466 SIGNOR-250323 0.43 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB7 protein Q9Y5F8 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265711 0.2 TBK1 protein Q9UHD2 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 21329883 t lperfetto Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, tbk1 is recruited to the exocyst, where it activates akt. Akt is a direct tbk1 substrate that connects tbk1 to prosurvival signaling. SIGNOR-252608 0.417 CKM complex complex SIGNOR-C406 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914161 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-273151 0.421 MITF protein O75030 UNIPROT OCA2 protein Q04671 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000847 22234890 f miannu the SNP rs12913832 has strong statistical association with human pigmentation. It is located within an intron of the nonpigment gene HERC2, 21 kb upstream of the pigment gene OCA2, and the region surrounding rs12913832 is highly conserved among animal species.In darkly pigmented human melanocytes carrying the rs12913832 T-allele, we detected binding of the transcription factors HLTF, LEF1, and MITF to the HERC2 rs12913832 enhancer, and a long-range chromatin loop between this enhancer and the OCA2 promoter that leads to elevated OCA2 expression. SIGNOR-254556 0.361 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257972 0.8 PTPN2 protein P17706 UNIPROT GJA1 protein P17302 UNIPROT up-regulates dephosphorylation Tyr265 KDCGSQKyAYFNGCS 9606 BTO:0000671 24849651 t lperfetto Tc-ptp dephosphorylates cx43 residues y247 and y265, dephosphorylation maintained cx43 gap junctions at the plaque and partially reversed the channel closure caused by v-src-mediated phosphorylation of cx43. SIGNOR-205101 0.33 CSNK1D protein P48730 UNIPROT TOP2B protein Q02880 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1132 QNQHDDSsSDSGTPS 9606 32015321 t miannu Specifically, DNA damage signal, triggered by teniposide (VM-26) treatment, activates ATM, cooperating with CK1 to phosphorylate TOP2β on Ser1134 and Ser1130, respectively, in a canonical degron motif to facilitate β-TrCP binding and subsequent degradation.CK1 binds with and phosphorylates TOP2β at Ser1130 to promote its degradation by VM-26. SIGNOR-277509 0.2 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK4 protein P11802 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189990 0.8 PTPRK protein Q15262 UNIPROT EGFR protein P00533 UNIPROT unknown dephosphorylation Tyr1092 TFLPVPEyINQSVPK 10029 BTO:0000246 16263724 t RPTP-kappa also reduced epidermal growth factor-dependent EGFR tyrosine phosphorylation in CHO cells. Purified RPTP-kappa preferentially dephosphorylated EGFR tyrosines 1068 and 1173 in vitro. SIGNOR-248722 0.601 HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto BRAF kinase is a downstream target of KRAS and activates the MAPK pathway. SIGNOR-160043 0.874 dopamine smallmolecule CHEBI:18243 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258716 0.8 MFF protein Q9GZY8 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 33610749 f lperfetto These proteins include the classical mitochondrial fusion (MFN1, MFN2, and OPA1) and fission proteins (DRP1, MFF, FIS1, etc.) as well as several other proteins that are directly or indirectly involved in these processes (e.g. YME1L, OMA1, INF2, GDAP1, MIC13, etc. SIGNOR-272983 0.7 SRC protein P12931 UNIPROT SH3GL1 protein Q99961 UNIPROT unknown phosphorylation Tyr315 QPSCKALyDFEPEND 9606 16054026 t llicata These results identified y315 of endophilin a2 as a major phosphorylation site by fak/src complex. tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp. SIGNOR-139154 0.624 zotepine chemical CHEBI:32316 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 20223878 t Luana These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. SIGNOR-257828 0.8 CSNK2A1 protein P68400 UNIPROT EGR1 protein P18146 UNIPROT down-regulates activity phosphorylation Ser378 RICMRNFsRSDHLTT 10090 BTO:0000944 8662759 t llicata Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10. SIGNOR-250856 0.477 MAP2K2 protein P36507 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258997 0.732 JAK2 protein O60674 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates activity phosphorylation Tyr310 LPNQEENyVTPIGDG BTO:0000007 12540842 t lperfetto To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase |On the other hand, the phosphorylation levels of Y22F, Y310F, and Y322F by GST-JH1 were reduced to 80€“60% of the levels of wild-type STAP-2, which suggests that these three are potential phosphorylation sites by activated JAK2. SIGNOR-249372 0.349 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 19188143 t gcesareni Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183644 0.697 LARP4B protein Q92615 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 20573744 f miannu Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. SIGNOR-260939 0.7 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Thr53 PPGSLSStPLSTPCS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159466 0.259 LYN protein P07948 UNIPROT LYN protein P07948 UNIPROT up-regulates activity phosphorylation Tyr397 RVIEDNEyTAREGAK -1 8530369 t Lyn is a member of the Src family of protein-tyrosine kinases that can readily undergo autophosphorylation in vitro. The site of autophosphorylation is Tyr397. Autophosphorylation results in a 17-fold increase in protein-tyrosine kinase activity. SIGNOR-251402 0.2 PI3K complex SIGNOR-C156 SIGNOR Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 23994464 f apalma The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release SIGNOR-255012 0.7 OPRL1 protein P41146 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256722 0.44 DUSP1 protein P28562 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR 10116 7535768 t We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively SIGNOR-248465 0.798 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR MYCN protein P04198 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269257 0.366 ALYREF protein Q86V81 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 t miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. SIGNOR-268511 0.883 PIM1 protein P11309 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 16403219 t lperfetto All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death. SIGNOR-249607 0.379 MAPK1 protein P28482 UNIPROT KLC1 protein Q07866 UNIPROT down-regulates phosphorylation Ser460 YKACKVDsPTVTTTL 9606 21385839 t gcesareni Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1mutation of klc1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residueklc1ser460 is a predicted mitogen-activated protein kinase (mapk) target site, and we show that extracellular-signal-regulated kinase (erk) phosphorylates this residue in vitro. SIGNOR-172638 0.274 ERG protein P11308 UNIPROT ICAM1 protein P05362 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22235125 f miannu It has been shown that ERG is a positive regulator of several EC-restricted genes including VE-cadherin, endoglin, and von Willebrand factor, and a negative regulator of other genes such as interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1. SIGNOR-253917 0.2 GRIA1 protein P42261 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 30825796 f miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses SIGNOR-264615 0.7 aspartic acid smallmolecule CHEBI:22660 ChEBI Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270378 0.8 PPP2CB protein P62714 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 19607706 t Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha|Chronic Ser 177/181 phosphorylation of IKKβ was due to UVB-induced inhibition of the catalytic subunit of the Ser-Thr phosphatase PP2A (PP2Ac) SIGNOR-248580 0.262 MAP4K2 protein Q12851 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 9712898 t gcesareni The mekk1 associated with the gck carboxyl terminus is catalytically active. SIGNOR-59682 0.546 RNF168 protein Q8IYW5 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR up-regulates quantity ubiquitination 9606 31225475 t miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. SIGNOR-266784 0.2 ZNF165 protein P49910 UNIPROT SMURF2 protein Q9HAU4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 26567849 t Luana ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1. SIGNOR-266095 0.271 ITGB1BP1 protein O14713 UNIPROT A3/b1 integrin complex SIGNOR-C161 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257641 0.756 4-fluoro-N-{2-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]ethyl}benzamide chemical CHEBI:64101 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258858 0.8 PBX4 protein Q9BYU1 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription SIGNOR-265806 0.2 EEF1A2 protein Q05639 UNIPROT Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269535 0.8 RUVBL1 protein Q9Y265 UNIPROT R2SP co-chaperone complex SIGNOR-C517 SIGNOR form complex binding 9606 29844425 t miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. SIGNOR-270939 0.517 CDK1 protein P06493 UNIPROT NUP98 protein P52948 UNIPROT down-regulates activity phosphorylation Ser612 LNNSNLFsPVNRDSE 9606 21335236 t gcesareni We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks. SIGNOR-172217 0.407 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr494 TPLHRDKtPLHQKHA 9606 9840932 t lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk4 SIGNOR-217264 0.707 LMO2 protein P25791 UNIPROT TAL1 protein P17542 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 9020185 t miannu Transcriptional activity of tal1 in t cell acute lymphoblastic leukemia (t-all) requires rbtn1 or -2 SIGNOR-46161 0.923 PRKD1 protein Q15139 UNIPROT PTRH2 protein Q9Y3E5 UNIPROT up-regulates phosphorylation Ser87 GKVAAQCsHAAVSAY 9606 18703509 t lperfetto Overexpression of constitutively active pkd or pkd activation by treatment with phorbol 12-myristate 13-acetate results in phosphorylation of two serine residues (ser5 and ser87) in a form of bit1 that is confined to the cytoplasm and concomitantly increases the apoptotic activity of cytoplasmic bit1 SIGNOR-180089 0.305 IKBKE protein Q14164 UNIPROT REL protein Q04864 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C68 16888014 t miannu The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel. SIGNOR-148620 0.361 CAMK1 protein Q14012 UNIPROT CAMK1 protein Q14012 UNIPROT up-regulates activity phosphorylation Thr177 DPGSVLStACGTPGY -1 8253780 t llicata CaM kinase I was autophosphorylated in a Ca2+/CaM-dependent manner at a threonyl residue (Thr-177) which is located at a position equivalent to that of the threonyl residue (Thr-197) autophosphorylated in cAMP-dependent protein kinase. SIGNOR-250612 0.2 Caspase 9 complex complex SIGNOR-C229 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 15657060 t lperfetto Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3. SIGNOR-256448 0.623 PRKCA protein P17252 UNIPROT DLX3 protein O60479 UNIPROT down-regulates activity phosphorylation Ser138 KPRTIYSsYQLAALQ -1 11343707 t lperfetto Dlx3 is primarily phosphorylated by PKC alpha. By deletion and mutational analysis, we show that the serine residue S(138), located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3. SIGNOR-249096 0.312 PPP2CB protein P62714 UNIPROT ELF1 protein P32519 UNIPROT down-regulates activity dephosphorylation Thr231 CPKYIKWtQREKGIF 9606 18714041 t Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response SIGNOR-248591 0.2 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation 9606 SIGNOR-C15 17900900 t gcesareni The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation SIGNOR-252981 0.509 IL1A protein P01583 UNIPROT MC1R protein Q01726 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000847 9767234 f miannu MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression. SIGNOR-252387 0.2 GTP smallmolecule CHEBI:15996 ChEBI GNAS protein P63092 UNIPROT up-regulates chemical activation 9606 17095603 t gcesareni Galfa subunits cycle between inactive (gdp-bound) and active (gtp-bound) states, and the lifetime of the active state is limited by gtp hydrolysis. SIGNOR-150552 0.8 AKT1 protein P31749 UNIPROT STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr387 TMKRRDEtMQPAKPS 9606 23431053 t gcesareni Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt. SIGNOR-252537 0.406 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates phosphorylation 9606 12270934 t lperfetto Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. SIGNOR-244798 0.2 PRKCG protein P05129 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser497 ATVKSRWsGSQQVEQ 9606 8288587 t gcesareni Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. SIGNOR-37541 0.381 2-acyl-sn-glycero-3-phospho-D-myo-inositol smallmolecule CHEBI:62746 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of -1 18772128 t miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. SIGNOR-268105 0.8 (2s)-1-{[5-(3-Methyl-1h-Indazol-5-Yl)pyridin-3-Yl]oxy}-3-Phenylpropan-2-Amine chemical CID:11314340 PUBCHEM AKT1 protein P31749 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258064 0.8 TLRs proteinfamily SIGNOR-PF20 SIGNOR TICAM2 protein Q86XR7 UNIPROT up-regulates activity binding 9606 20404851 t lperfetto These differences are explained by the discovery of TIR domain’containing adaptor molecules, including MyD88, TIRAP (Mal), TRIF and TRAM, which are recruited by distinct TLRs and activate distinct signaling pathways SIGNOR-216307 0.2 CDK12 protein Q9NYV4 UNIPROT CyclinK/CDK12 complex SIGNOR-C37 SIGNOR form complex binding 9606 22012619 t miannu We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells SIGNOR-176789 0.941 RARA protein P10276 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 t gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. SIGNOR-133231 0.407 PLK2 protein Q9NYY3 UNIPROT FBXW7 protein Q969H0 UNIPROT down-regulates phosphorylation Ser176 KRKLDHGsEVRSFSL 9606 22399798 t lperfetto Plk2 regulates centriole duplication through phosphorylation-mediated degradation of fbxw7 (human cdc4).Plk2 phosphorylates fbxw7 on serine 176 SIGNOR-196448 0.496 GRM5 protein P41594 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264348 0.7 TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000007 27383048 t miannu Upon stimulation with TNFα, TNFR1 recruits TRADD, which provides a scaffold for the assembly of complex I at the plasma membrane by binding with RIP1, TRAF2 and cIAP. SIGNOR-42980 0.866 SNRPA protein P09012 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270678 0.819 MED18 protein Q9BUE0 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266672 0.877 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR T-reg_differentiation phenotype SIGNOR-PH91 SIGNOR down-regulates 9606 21364186 f Lowering the extent of costimulation of P2X in T cells diminishes the extent of ERK phosphorylation without affecting TCR-mediated nuclear translocation of NFAT (10). In Tregs, this mechanism would favor the stability of their transcriptional program through the stabilization of nuclear complexes of NFAT and Foxp3 (47). SIGNOR-254687 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BANP protein Q8N9N5 UNIPROT down-regulates activity phosphorylation Thr352 PSEPMMStPPPASEL 9606 BTO:0000567 26080397 t miannu ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68. SIGNOR-266204 0.2 GSK3B protein P49841 UNIPROT ZNF322 protein Q6U7Q0 UNIPROT down-regulates quantity by destabilization phosphorylation Ser391 SEKGLELsPPHASEA 9606 BTO:0002552 28581525 t lperfetto CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction. SIGNOR-264891 0.2 RPA1 protein P27694 UNIPROT BRIP1 protein Q9BX63 UNIPROT up-regulates activity binding 9606 17596542 t irozzo Our data are consistent with a model in which FANCJ associates with RPA in a DNA damage-inducible manner and through the protein interaction RPA stimulates FANCJ helicase to better unwind duplex DNA substrates. These findings identify RPA as the first regulatory partner of FANCJ. SIGNOR-259187 0.684 SCF-betaTRCP complex SIGNOR-C5 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 11359933 t miannu Smad3 interacts with a RING finger protein, ROC1, through its C-terminal MH2 domain in a ligand-dependent manner. An E3 ubiquitin ligase complex ROC1-SCF(Fbw1a) consisting of ROC1, Skp1, Cullin1, and Fbw1a (also termed betaTrCP1) induces ubiquitination of Smad3.  SIGNOR-272944 0.434 PRKCA protein P17252 UNIPROT LRRK1 protein Q38SD2 UNIPROT up-regulates activity phosphorylation Ser1064 NRKVTIYsFTGNQRN -1 36040231 t miannu PKCα unexpectedly does not activate LRRK1 by phosphorylating the kinase domain, but instead phosphorylates a cluster of conserved residues (Ser1064, Ser1074 and Thr1075) located within a region of the CORB domain of the GTPase domain. we postulate that phosphorylation of Ser1064, Ser1074 and Thr1075 activates LRRK1 by promoting interaction and stabilization of the αC-helix on the kinase domain. SIGNOR-276866 0.2 EZH2 protein Q15910 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates activity 10090 15520282 f We report that Ezh2 expression was developmentally regulated in the myotome compartment of mouse somites and that its down-regulation coincided with activation of muscle gene expression and differentiation of satellite-cell-derived myoblasts SIGNOR-255719 0.7 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Ser405 EVSRIPAsQTSVPFD 9606 BTO:0000007 10542239 t llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T SIGNOR-250809 0.2 TFEB protein P19484 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276537 0.443 USP7 protein Q93009 UNIPROT UBA52 protein P62987 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270823 0.724 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-267504 0.8 FZD5 protein Q13467 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 10937998 f fspada Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma) SIGNOR-80610 0.2 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR3 protein P32745 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257583 0.8 PKC proteinfamily SIGNOR-PF53 SIGNOR GSTA4 protein O15217 UNIPROT up-regulates activity phosphorylation Thr193 VKLSNIPtIKRFLEP 9534 12646569 t lperfetto Mutational analysis show that the putative mitochondrial targeting signal resides within the C-terminal 20 amino acid residues of the protein and that the targeting signal requires activation by phosphorylation at the C-terminal-most protein kinase A (PKA) site at Ser-189 or protein kinase C (PKC) site at Thr-193. SIGNOR-264795 0.2 EDNRA protein P25101 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257052 0.392 NAE1 protein Q13564 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000938 25568892 f lperfetto Overexpression of AppBp1 in primary neurons induces apoptosis through the neddylation pathway SIGNOR-256651 0.7 EXOC1 protein Q9NV70 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270776 0.864 SMAD4 protein Q13485 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11689553 t lperfetto Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter. SIGNOR-251493 0.625 CDK1 protein P06493 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity phosphorylation Ser91 EGMGEEPsPFRGRSR 24677263 t lperfetto CDK1-mediated Bcl-2 serine 70 phosphorylation enhances its pro-apoptotic function, whereas CDK1-mediated Bad serine 128 phosphorylation promotes apoptosis.  SIGNOR-267921 0.2 STAG2 protein Q8N3U4 UNIPROT RAD21 protein O60216 UNIPROT up-regulates quantity by stabilization binding 9606 28430577 t miannu Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin SIGNOR-261511 0.964 TWIST1 protein Q15672 UNIPROT FN1 protein P02751 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003879 20646316 f miannu Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. SIGNOR-255521 0.42 HHEX protein Q03014 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates activity 10090 BTO:0000089 26728554 f Hhex is a potential therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal. SIGNOR-256306 0.7 ADAMTS5 protein Q9UNA0 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage Glu392 PRNITEGeARGSVIL 9606 9202061 t lperfetto Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE374 SIGNOR-266985 0.756 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR ACTL6B protein O94805 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136212 0.273 PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr383 HYRYSDTtDSDPENE 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248545 0.2 TP53 protein P04637 UNIPROT BID protein P55957 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16151013 t Nuclear p53 lperfetto Bid is a p53 primary-response gene. SIGNOR-140248 0.499 PPP2CA protein P67775 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization dephosphorylation Thr55 DDIEQWFtEDPGPDE 9606 17245430 t A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55| In this study, we reported that the specific B regulatory subunits of PP2A B56gamma1 and B56gamma3 mediate dephosphorylation of p53 at Thr55. Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis SIGNOR-248618 0.573 PAX3 protein P23760 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 23384562 f gcesareni Direct molecular regulation of the myogenic determination gene myf5 by pax3, with modulation by six1/4 factors, is exemplified by the -111 kb-myf5 enhancer. SIGNOR-200862 0.485 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates activity phosphorylation Ser746 RRSVRIGsYIERDVT 9823 7539802 t lperfetto We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling. SIGNOR-248899 0.511 SCF-SKP2 complex SIGNOR-C136 SIGNOR IDH1 protein O75874 UNIPROT down-regulates quantity by destabilization ubiquitination phosphorylation:Thr157 GKVEITYtPSDGTQK 34929314 t lperfetto During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome SIGNOR-267623 0.2 ERBB2 protein P04626 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 8816440 t Most breast, skin, lung, ovary, and gastrointestinal tract tumors express ErbB-3, and heterodimerization of this receptor with ErbB-2, may be involved in some cancers. gcesareni Although erbb-2 binds neither ligand, even in a heterodimeric receptor complex, it is the preferred heterodimer partner of the three other members, and it favors interaction with erbb-3. SIGNOR-43841 0.571 PINK1 protein Q9BXM7 UNIPROT MFN1 protein Q8IWA4 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000793 20871098 f Barakat Ubiquitination of MFN-1 or MFN-2 was induced in untransfected cells and cells transfected with control siRNA. However, ubiquitination of MFN-1 and MFN-2 was significantly reduced when treated with either PINK1 siRNA combination. These results suggest that PINK1 is required for the ubiquitination of MFN-1 and MFN-2. SIGNOR-274135 0.686 SLBP protein Q14493 UNIPROT H2AC11 protein P0C0S8 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265403 0.2 GSK3B protein P49841 UNIPROT STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization phosphorylation Ser381 RKFNILTsNQKTLTP 9606 BTO:0002181 31843895 t miannu GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation. SIGNOR-276763 0.293 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser15 SSYRGRKsGNKPPSK 9606 7993631 t gcesareni We found that pkc specifically eliminates rapid inactivation of a cloned human a-type k+ channel (hkv3.4), converting this channel from a rapidly inactivating a type to a noninactivating delayed rectifier type. SIGNOR-35622 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr384 GTMKRNAtSPQVQRP 9606 20086174 t lperfetto We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2. SIGNOR-244349 0.2 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys126 DNEKDLVkLAKRLKK -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. SIGNOR-272746 0.475 PABPC1 protein P11940 UNIPROT eIF4F_complex complex SIGNOR-C44 SIGNOR up-regulates activity binding 9606 30209168 t miannu The binding of PABP to mRNA poly(A) tails is followed by interactions with eukaryotic initiation factor (eIF4G) and other translation factors, including eIF4E, to constitute a translation initiation complex, which mediates cellular mRNA circularization and enhances cap-dependent translation by facilitating ribosome recycling SIGNOR-260943 0.82 GSK3B protein P49841 UNIPROT AREL1 protein O15033 UNIPROT down-regulates quantity by destabilization phosphorylation Thr783 IAAPTHStLPTAHTC 27162139 t lperfetto These experiments suggested that GSK3beta phosphorylation of FIEL1 is required for PIAS4 targeting, and FIEL1 residues P779 and phosphorylated T783 are both required for PIAS4 interaction |FIEL1 T783A mutant overexpression completely failed to decrease PIAS4 protein level. SIGNOR-275528 0.321 ITGA9 protein Q13797 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253183 0.773 NDUFS5 protein O43920 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. SIGNOR-262179 0.816 WWTR1 protein Q9GZV5 UNIPROT LTBR protein P36941 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001615 22470139 f miannu Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation. SIGNOR-255604 0.2 CNKSR1 protein Q969H4 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 15845549 t gcesareni Here we demonstrate that the connector enhancer of ksr1, cnk1, mediates src-dependent tyrosine phosphorylation and activation of raf-1. Cnk1 binds preactivated raf-1 and activated src and forms a trimeric complex. SIGNOR-135674 0.699 ARF6 protein P62330 UNIPROT Macropinosomes recycle phenotype SIGNOR-PH230 SIGNOR up-regulates 9606 39000072 t miannu ARF6 plays a role in the promotion of the recycling of macropinosomes to the plasma membrane  SIGNOR-277785 0.7 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr203 HQHYYYDtHTNTYYL 9606 16669787 t miannu We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1 SIGNOR-146513 0.539 PKA proteinfamily SIGNOR-PF17 SIGNOR ENAH protein Q8N8S7 UNIPROT up-regulates activity phosphorylation 9606 15066263 t miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts SIGNOR-268285 0.2 OPRM1 protein P35372 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257106 0.49 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser236 AKRRRLSsLRASTSK 9606 17360704 t gcesareni We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism. SIGNOR-153622 0.607 DHX30 protein Q7L2E3 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25683715 f miannu DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU. SIGNOR-261228 0.7 NMUR1 protein Q9HB89 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256894 0.41 EEF1A1P5 protein Q5VTE0 UNIPROT Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269560 0.8 PPM1B protein O75688 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity dephosphorylation -1 22750291 t lperfetto PPM1B dephosphorylates TBK1 in vivo and in vitro.|These results demonstrate that PPM1B inhibits TBK1 mediated antiviral signaling by directly dephosphorylating TBK1 at Ser172. SIGNOR-276985 0.359 BMPR1A protein P36894 UNIPROT FAM83G protein A6ND36 UNIPROT up-regulates activity phosphorylation Ser616 PSVASSVsEEYFEVR -1 24554596 t lperfetto These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway. SIGNOR-264767 0.382 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Thr308 KDGATMKtFCGTPEY 10090 BTO:0000944 15367694 t Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes SIGNOR-252614 0.89 ZHX1 protein Q9UKY1 UNIPROT ZMYND11 protein Q15326 UNIPROT down-regulates activity binding 9606 BTO:0000007 17127430 t miannu Corepressor BS69 interacts with ZHX1, a member of the ZHX family having zinc-fingers and homeoboxes. Although BS69 was originally found as a corepressor interacting with ZHX1, BS69 was also found to function as a transcriptional activator in HEK293 cells, in which the activation required the MYND domain of BS69. Co-transfection of BS69 with a mutant form of ZHX1, which cannot interact with BS69, led to increase the transcriptional activation of BS69, suggesting that transcriptional activation mediated by BS69 is suppressed by ZHX1. SIGNOR-263898 0.504 DLL4 protein Q9NR61 UNIPROT KDR protein P35968 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18339870 f gcesareni Dll4 down-regulates vascular endothelial growth factor (vegf) receptor 2 and nrp1 expression and inhibits vegf function SIGNOR-178026 0.487 HDAC4 protein P56524 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates binding 9606 10737771 t gcesareni We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2. SIGNOR-76237 0.68 Starvation stimulus SIGNOR-ST4 SIGNOR SIRT1 protein Q96EB6 UNIPROT up-regulates activity 9606 BTO:0000759 15744310 f AMPK pathway Gianni We show here that the Sir2 homologue, SIRT1—which modulates ageing in several species —controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1α. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. SIGNOR-261951 0.7 CDK1 protein P06493 UNIPROT CDC25A protein P30304 UNIPROT up-regulates phosphorylation Ser116 PQKLLGCsPALKRSH 9606 SIGNOR-C17 12411508 t lperfetto Mitotic stabilization of cdc25a reflects its phosphorylation on ser17 and ser115 by cyclin b-cdk1, modifications required to uncouple cdc25a from its ubiquitin-proteasome-mediated turnover. SIGNOR-95256 0.836 MAPK9 protein P45984 UNIPROT KLF13 protein Q9Y2Y9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser123 APPSPAWsEPEPEAG 10090 37029927 t miannu TGF-β-mediated downregulation of KLF13 by HDAC-mediated epigenetic silencing and JNK-induced phosphorylation abrogates the latter’s inhibitory effect on TGF-β signaling. SIGNOR-277809 0.2 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 22749528 f Luana Leucine and Glutamine Activate Glutaminolysis and mTORC1 SIGNOR-268015 0.8 SRC protein P12931 UNIPROT VIL1 protein P09327 UNIPROT up-regulates activity phosphorylation Tyr256 LKAALKLyHVSDSEG 9606 15342783 t lperfetto These data suggest that phosphorylation of villin by c-src is involved in the actin cytoskeleton remodeling necessary for cell migration.To further investigate the role of tyrosine phosphorylated villin in cell migration, we used phosphorylation site mutants (tyrosine to phenylalanine or tyrosine to glutamic acid) in HeLa cells. We determined that tyrosine phosphorylation at residues 60, 81, and 256 of human villin played an essential role in cell migration as well as in the reorganization of the actin cytoskeleton SIGNOR-247433 0.371 TRiC complex SIGNOR-C539 SIGNOR STAT3 protein P40763 UNIPROT up-regulates quantity by stabilization binding 9606 36185250 t miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). SIGNOR-272870 0.395 quizartinib chemical CHEBI:90217 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 19754199 t Compound 7 (AC220) (quizartinib) was identified from this series to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties, excellent PK profile, and superior efficacy and tolerability in tumor xenograft models. SIGNOR-255666 0.8 LEF1 protein Q9UJU2 UNIPROT ALX4 protein Q9H161 UNIPROT up-regulates quantity by expression binding 10090 BTO:0003952 11696550 t miannu Alx4 Stably Interacts with LEF-1. LEF-1 enhances Alx4 binding to DNA, suggesting that both interaction with LEF-1 and DNA binding are required to mediate its effects on the N-CAM promoter. SIGNOR-254547 0.456 PRKDC protein P78527 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Thr7 tQDQPMEE 9606 BTO:0000567 2507541 t lperfetto Here we show that the dsDNA-activated protein kinase from human HeLa cells phosphorylates 2 threonine residues in the sequence PEETQTQDQPME at the amino terminus of human hsp90 alpha. SIGNOR-248888 0.437 CSNK2A1 protein P68400 UNIPROT CAV2 protein P51636 UNIPROT up-regulates activity phosphorylation Ser23 DDSYSHHsGLEYADP 9606 BTO:0001130 12743374 t lperfetto We show that caveolin-2 is phosphorylated in vivo at two serine residues and that the phosphorylation of caveolin-2 is necessary for its actions as a positive regulator of caveolin-1 during organelle biogenesis in prostate cancer cells. Mutation of the primary phosphorylation sites on caveolin-2, serine 23 and 36, reduces the number of plasmalemma-attached caveolae SIGNOR-101106 0.326 ERG protein P11308 UNIPROT ICAM2 protein P13598 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10574717 f miannu The Ets family member Erg was found to be constitutively expressed in HUVEC, and TNF-(alpha) down-regulated Erg protein levels. Furthermore, an Erg cDNA transactivated the ICAM-2 promoter when transiently transfected into both HeLa cells and HUVEC. SIGNOR-253913 0.2 ATM protein Q13315 UNIPROT ABRAXAS1 protein Q6UWZ7 UNIPROT up-regulates activity phosphorylation Ser404 MKGFGEYsRSPTF 9606 BTO:0000007 26778126 t In this study, we demonstrate that ionizing radiation (IR)-induces ATM-dependent phosphorylation of serine 404 (S404) next to the pSPxF motif. Crystal structures of BRCT/Abraxas show that phosphorylation of S404 is important for extensive interactions through the N-terminal sequence outside the pSPxF motif and leads to formation of a stable dimer. SIGNOR-255587 0.2 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser752 KMKKTSTsTETRSSS 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. SIGNOR-131403 0.2 CBX5 protein P45973 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-264490 0.2 PRKACA protein P17612 UNIPROT PHKA2 protein P46019 UNIPROT down-regulates activity phosphorylation 9606 10487978 t Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. SIGNOR-267410 0.307 IFNB1 protein P01574 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates activity binding 9534 BTO:0004055 11278538 t lperfetto Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. SIGNOR-219304 0.662 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1647 SPSYSPTsPSYSPTS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248770 0.442 FGF14 protein Q92915 UNIPROT SCN1A protein P35498 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253421 0.368 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser343 TTPGPSLsQGVSVDE 9606 10802669 t gcesareni We show that atm physically interacts with and phosphorylates nibrin on serine 343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (s343a) does not completely complement radiosensitivity in nbs cells. SIGNOR-77149 0.851 NME1 protein P15531 UNIPROT LPAR1 protein Q92633 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001567 17671192 f miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. SIGNOR-255163 0.415 EP300 protein Q09472 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys28 LATKAARkSAPSTGG 9606 SIGNOR-C6 21131905 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 fspada These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription. SIGNOR-170266 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270396 0.8 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR2B protein P41595 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257522 0.8 CDK1 protein P06493 UNIPROT PTTG2 protein Q9NZH5 UNIPROT up-regulates activity phosphorylation Ser165 LFQLGPPsPVKMPSP 9606 BTO:0000567 10656688 t miannu HPTTG is phosphorylated by Cdc2 at Ser165. we show that hPTTG is phosphorylated during mitosis. The direct phosphorylation of hPTTG by Cdc2 is interesting in itself since the substrates of this master mitotic kinase are supposed to play important roles in the initiation and progression of mitosis. SIGNOR-262700 0.295 PLD3 protein Q8IV08 UNIPROT APP protein P05067 UNIPROT up-regulates quantity binding 9606 BTO:0000007 24336208 t Monia Furthermore, PLD3 can be co-immunoprecipitated with APP in cultured cells (Extended Data Figure 4). Together, these studies demonstrate that PLD3 plays a role in APP processing. Over-expression of PLD3 leads to a significant decrease in intracellular APP and extracellular Aβ42 and Aβ40, while knock-down of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a two-fold increased risk for LOAD and that PLD3 influences APP processing. SIGNOR-261200 0.381 PLK1 protein P53350 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 24413556 t miannu Phosphorylation by Cyclin B-Cdk1 allows Haspin to bind Plk1-PBD. Phosphorylation of Haspin at T128 and Plk1 target sites is required for full H3T3ph generation and normal Aurora B localization in mitosis. SIGNOR-275421 0.2 NEUROG3 protein Q9Y4Z2 UNIPROT NEUROD4 protein Q9HD90 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19028584 f miannu Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. SIGNOR-254631 0.249 KRAS protein P01116 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k. SIGNOR-175207 0.702 dimethyloxalylglycine chemical CHEBI:102218 ChEBI EGLN1 protein Q9GZT9 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000018 28900510 t lperfetto We treated the A549 cells with the following EGLN/PHD inhibitors: dimethyloxalyglycine (DMOG), CoCl2, inhibitors of dioxygenases, and BAY 85-3494 (BAY), a specific inhibitor of EGLNs with highest potency against EGLN1. SIGNOR-261991 0.8 ATF2 protein P15336 UNIPROT PLAT protein P00750 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 8647095 f lperfetto We suggest that the mechanism for the transcriptional down-regulation of t-PA by PMA in HT-1080 cells requires CREB-1 binding to the t-PACRE while ATF-2, by associating with the same site, plays a role in PMA-mediated induction of t-PA in HeLa cells. SIGNOR-253724 0.2 Riluzole chemical CHEBI:8863 ChEBI KCNN3 protein Q9UGI6 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 18955585 t Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  SIGNOR-258019 0.8 FN1 protein P02751 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253250 0.738 PTPN6 protein P29350 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation 9606 18508557 t gcesareni Stat3 may also be a substrate of shp1 SIGNOR-178699 0.469 PPM1D protein O15297 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity dephosphorylation Ser1981 SLAFEEGsQSTTISS 9606 18265945 t lperfetto More recently, Shreeram et al.  have also shown that Wip1 dephosphorylates human ATM at Ser367 as well as Ser1981.|Thus, overexpression of Wip1 in an oncogenic context could contribute to tumor promotion by inhibiting both p53 and ATM functions. SIGNOR-276954 0.501 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT2 protein Q96AC1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser175 GPLITPGsGSIYSSP 9606 BTO:0000567 35469017 t miannu  CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry. SIGNOR-276716 0.2 GNAI1 protein P63096 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates activity binding 9606 19703466 t GTP-bound, active WT Gαi1 acts to inhibit AC, resulting in a decreased concentration of intracellular cAMP. SIGNOR-256498 0.533 FUBP1 protein Q96AE4 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19637194 f irozzo FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In addition, mRNA levels of the death ligands tumor necrosis factor (TNF) α and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) were significantly increased. SIGNOR-259129 0.2 DNM1 protein Q05193 UNIPROT SYP protein P08247 UNIPROT up-regulates activity binding 9606 10823955 t miannu The GTPase dynamin I is required for synaptic vesicle (SV) endocytosis. Our observation that dynamin binds to the SV protein synaptophysin in a Ca2+-dependent fashion suggested the possibility that a dynamin/synaptophysin complex functions in SV recycling. SIGNOR-264119 0.339 AMPK complex SIGNOR-C15 SIGNOR ATG9A protein Q7Z3C6 UNIPROT up-regulates activity phosphorylation Ser761 QSIPRSAsYPCAAPR 9606 25266655 t miannu Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK. SIGNOR-266365 0.251 PRKACA protein P17612 UNIPROT RAP1GAP protein P47736 UNIPROT unknown phosphorylation Ser499 PFGSRRSsAIGIENI -1 1406653 t miannu We have localized two of the sites of phosphorylation in vitro by cAMP-dependent kinase to serine residues 490 and 499. raplGAP undergoes phosphorylation at specific sites in vivo, the effects of phosphorylation on raplGAP have remained elusive. SIGNOR-250044 0.314 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75637 0.783 SYCE2 protein Q6PIF2 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR form complex binding 9606 22394509 t miannu The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region. SIGNOR-264198 0.681 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL 10090 BTO:0000944 SIGNOR-C3 17510057 t lperfetto mTORC1 catalyzes the phosphorylation of eIF4E binding protein-1 (4EBP1, also known as PHAS-I) and p70 S6 kinase 1 (S6K1)Phosphorylation of S6K1 at Thr-389 SIGNOR-235507 0.96 ICAM3 protein P32942 UNIPROT AD/b2 integrin complex SIGNOR-C172 SIGNOR up-regulates activity binding 8777714 t lperfetto A novel leukointegrin, alpha d beta 2, binds preferentially to ICAM-3. SIGNOR-253371 0.597 AKT1S1 protein Q96B36 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-205597 0.795 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser626 SLECDMEsIIRSELM -1 17711846 t done miannu Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626). SIGNOR-274097 0.397 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser104 GKGSQPPsPPSPAPS 9606 15448698 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-129402 0.574 WNT10A protein Q9GZT5 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131616 0.607 PI3K complex SIGNOR-C156 SIGNOR BTK protein Q06187 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000899 10201980 t lperfetto Activation of Btk occurs by transphosphorylation of tyrosine 551 in the catalytic domain, resulting in a dramatic increase in the catalytic activity of the kinase (11, 12, 13). This allows for autophosphorylation at tyrosine 223 in the SH3 domain (14). Both Lyn and Syk have been demonstrated to be involved in BCR-mediated Btk activation (11), but processes that drive colocalization of these kinases are ill-defined. Recently, it was suggested that phosphatidylinositol 3-kinase (PI3-K) is also involved in Btk activation SIGNOR-252709 0.463 CDKN1A protein P38936 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity 9606 10439039 f gcesareni P21 may inhibit cell cycle progression by preventing the phosphorylation of prb. SIGNOR-69925 0.704 SRC protein P12931 UNIPROT LASP1 protein Q14847 UNIPROT up-regulates activity phosphorylation Tyr171 IPTSAPVyQQPQQQP 9606 BTO:0000132 19718473 t lperfetto Integrin-dependent translocation of LASP-1 to the cytoskeleton of activated platelets correlates with LASP-1 phosphorylation at tyrosine 171 by Src-kinase SIGNOR-271706 0.255 PES1 protein O00541 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0002882 15169904 f miannu Pescadillo (PES1) and the upstream binding factor (UBF1) play a role in ribosome biogenesis, which regulates cell size, an important component of cell proliferation. We have investigated the effects of PES1 and UBF1 on the growth and differentiation of cell lines derived from 32D cells, an interleukin-3 (IL-3)-dependent murine myeloid cell line. Parental 32D cells and 32D IGF-IR cells (expressing increased levels of the type 1 insulin-like growth factor I [IGF-I] receptor [IGF-IR]) do not express insulin receptor substrate 1 (IRS-1) or IRS-2. 32D IGF-IR cells differentiate when the cells are shifted from IL-3 to IGF-I. Ectopic expression of IRS-1 inhibits differentiation and transforms 32D IGF-IR cells into a tumor-forming cell line. We found that PES1 and UBF1 increased cell size and/or altered the cell cycle distribution of 32D-derived cells but failed to make them IL-3 independent. PES1 and UBF1 also failed to inhibit the differentiation program initiated by the activation of the IGF-IR, which is blocked by IRS-1. 32D IGF-IR cells expressing PES1 or UBF1 differentiate into granulocytes like their parental cells. In contrast, PES1 and UBF1 can transform mouse embryo fibroblasts that have high levels of endogenous IRS-1 and are not prone to differentiation. Our results provide a model for one of the theories of myeloid leukemia, in which both a stimulus of proliferation and a block of differentiation are required for leukemia development. SIGNOR-260078 0.7 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249667 0.509 PRKACA protein P17612 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser174 KGMLARGsYSIKSRF 9606 18768928 t llicata The results indicate that phosphorylation of gdi_ at ser174 by pka suppresses rhoa activity, providing a potential protective signaling mechanism for inflammatory injury. SIGNOR-180576 0.364 CREBBP protein Q92793 UNIPROT FBL protein P22087 UNIPROT down-regulates activity acetylation Lys206 DLINLAKkRTNIIPV 30540930 t lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) SIGNOR-275897 0.273 CSNK2A1 protein P68400 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates activity phosphorylation Thr118 TNLGEKLtDEEVDEM -1 26675311 t miannu Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third. SIGNOR-266355 0.432 Wnt proteinfamily SIGNOR-PF40 SIGNOR LPR5/6 complex SIGNOR-C219 SIGNOR up-regulates activity binding 9606 23209147 t miannu FZD and LRP5/6 transduce Wnt signal via engaging downstream cytoplasmic components, among which two scaffolding proteins, Dishevelled and Axin, have prominent roles. SIGNOR-256174 0.801 ASDURF protein L0R819 UNIPROT PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR form complex binding 9606 30484152 t miannu The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92.  SIGNOR-270922 0.2 TNC protein P24821 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR up-regulates activity binding 9606 BTO:0000801;BTO:0001336 24241034 t lperfetto Synovial fibroblasts and macrophages derived from arthritic joints spontaneously secreted tenascin-C and osteopontin. Synovial fibroblasts and macrophages obtained from patients with RA expressed α9β1 integrins, a common receptor for osteopontin and tenascin-C. SIGNOR-253312 0.416 KAT2B protein Q92831 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates acetylation 9606 22120716 t gcesareni In earlier studies, we demonstrated that maml1 enhanced p300 acetyltransferase activity, which increased the acetylation of notch by p300.Acetylation controls notch stability and function in t-cell leukemia. SIGNOR-254311 0.585 PIP3 smallmolecule CHEBI:16618 ChEBI MAPKAP1 protein Q9BPZ7 UNIPROT up-regulates activity chemical activation 9606 26293922 t gcesareni PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with SIN1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation SIGNOR-252429 0.8 ARHGEF3 protein Q9NR81 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260530 0.768 ILK protein Q13418 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 12144526 t miannu Phosphopeptide mapping, phospho amino acid analysis and immunoblotting using phospho-specific antibodies indicated that ilk predominantly phosphorylated the site critical for potent inhibition, i.e. Thr(38) of cpi-17 SIGNOR-90828 0.53 AURKA protein O14965 UNIPROT KNSTRN protein Q9Y448 UNIPROT down-regulates activity phosphorylation 9606 BTO:0001938 22535524 t lperfetto The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation. SIGNOR-252052 0.263 AKT2 protein P31751 UNIPROT ANKRD2 protein Q9GZV1 UNIPROT up-regulates phosphorylation Ser99 QERVRKTsLDLRREI 10090 BTO:0000165;BTO:0000222 21737686 t llicata In vitro and in vivo studies confirmed that akt phosphorylates ankrd2 at ser-99. moreover, the forced expression of a phosphorylation-defective mutant form of ankrd2 in c2c12 myoblasts promoted a faster differentiation program, implicating akt-dependent phosphorylation at ser-99 in the negative regulation of myogenesis in response to stress conditions. SIGNOR-236978 0.424 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser411 RNCSTNDsLL -1 8662852 t we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). SIGNOR-251198 0.682 PIM proteinfamily SIGNOR-PF34 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 18593906 t tpavlidou Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene. SIGNOR-259427 0.401 HNRNPH1 protein P31943 UNIPROT TERF2 protein Q15554 UNIPROT down-regulates quantity post transcriptional regulation 10116 BTO:0001009 27117401 t miannu During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels. SIGNOR-266807 0.341 TAL1 protein P17542 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates activity 10090 BTO:0004911 29713515 f The truncated form TAL1-s is required for erythroid progenitors differentiation, while the full-length protein TAL1-l is required for megakaryocytic differentiation of progenitor cells. SIGNOR-259970 0.7 S1PR5 protein Q9H228 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256676 0.47 CBL protein P22681 UNIPROT CFLAR protein O15519 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 phosphorylation:Ser2;Tyr182 sAEVIHQV;VQGAGTSyRNVLQAA 19597496 t CFLAR has to be phosphorylated on Tyr211 and Ser4 by c-Abl and p38, respectively. This phosphorylation facilitated specific interaction between FLIPS and the ubiquitin E3 ligase c-Cbl gcesareni We therefore conclude that c-cbl is a e3 ubiquitin ligase for flips and that the interaction of flips with c-cbl requires phosphorylation of both ser4 and tyr211 of flips.This interaction triggered proteasomal degradation of FLIP(S), which promoted activation of caspase-8 and apoptosis. SIGNOR-186998 0.2 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser196 EKSPSVCsPLNMTSS 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276107 0.29 LEF1 protein Q9UJU2 UNIPROT IL4 protein P05112 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 18579517 f We identified a high affinity LEF-1-binding site in the negative regulatory element of the IL-4 promoter. Knockdown LEF-1 expression by LEF-1-specific small interfering RNA resulted in an increase in the IL-4 mRNA expression SIGNOR-254504 0.357 CDK1 protein P06493 UNIPROT USP1 protein O94782 UNIPROT up-regulates activity phosphorylation Ser313 ATSDTLEsPPKIIPK -1 23116119 t miannu In this study, we show that Ser313 phosphorylation in USP1 is required for its interaction with UAF1 and for the stimulation of USP1's activity. We further demonstrated that CDK1 is responsible for Ser313 phosphorylation, and protein phosphatase treatment of USP1 can lead to inactivation of USP1/UAF1. SIGNOR-276423 0.379 TFEB protein P19484 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Here we show that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism via Ppargc1α and Ppar1α. SIGNOR-276708 0.389 CREBBP protein Q92793 UNIPROT FBL protein P22087 UNIPROT down-regulates activity acetylation Lys121 GESVYGEkRVSISEG 30540930 t lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) SIGNOR-275899 0.273 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr651 ALGGKAAyRTSPRLK -1 10210201 t llicata Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624. SIGNOR-250783 0.575 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 10634209 t lperfetto TNF-induced apoptosis is mediated primarily through the activation of type I receptors SIGNOR-226676 0.923 MAPK3 protein P27361 UNIPROT CIITA protein P33076 UNIPROT up-regulates phosphorylation Ser280 TVHGLPTsPDRPGST 9606 BTO:0000782;BTO:0000801 17095509 t gcesareni We found that in these cells, lipopolysaccharide stimulates the expression of mhc ii genes via the activation of erk1/2, which is mediated by toll-like receptor 4. Erk1/2 then phosphorylates the serine at position 357, which is located in a degron of ciita isoform 1 that leads to its monoubiquitylation. SIGNOR-150545 0.348 MTF1 protein Q14872 UNIPROT GCLC protein P48506 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15378601 f miannu MRE-binding transcription factor-1 (MTF-1) is a highly conserved heavy metal-induced transcriptional activator. MTF-1 also activates transcription in response to oxidative stress and regulates the expression of several cytoprotective factor genes, including MT, gamma-glutamylcysteine synthetase, and Cu/Zn-superoxide dismutase. SIGNOR-254599 0.29 PAK1 protein Q13153 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser886 PVDPRRRsLPAGDAL 9606 19667072 t gcesareni We identify gef-h1 as a binding target and substrate for p21-activated kinase 1 (pak1), we show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules. SIGNOR-187573 0.36 MRPL38 protein Q96DV4 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262359 0.678 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser397 SMVGGERsPPRILPP 9606 BTO:0000007 21059642 t The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). SIGNOR-273030 0.563 Wnt proteinfamily SIGNOR-PF40 SIGNOR FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t inferred from 70% family members gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-269960 0.2 ITGA11 protein Q9UKX5 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253187 0.694 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC7 protein O00311 UNIPROT up-regulates activity phosphorylation Thr376 QVAPRAGtPGFRAPE 10846177 t llicata Among four possible Cdk phosphorylation sites of huCdc7, replacement of Thr-376, corresponding to the activating threonine of Cdk, with alanine (T376A mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue. In vitro, Cdk2-Cyclin E, Cdk2-Cyclin A, and Cdc2-Cyclin B, but not Cdk4-Cyclin D1, phosphorylates the Thr-376 residue of huCdc7, suggesting possible regulation of huCdc7 by Cdks. SIGNOR-250725 0.603 IL22 protein Q9GZX6 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 17208301 t gcesareni See table 2 SIGNOR-151880 0.683 XPO1 protein O14980 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates relocalization 9606 11074002 t gcesareni We demonstrate that inhibition of crm1-mediated nuclear export by treatment of cells with leptomycin b results in endogenous smad4 accumulating very rapidly in the nucleus. SIGNOR-84247 0.305 CDK1 protein P06493 UNIPROT STIM1 protein Q13586 UNIPROT down-regulates phosphorylation Ser668 IGEETDSsPGRKKFP 9606 19881501 t gcesareni Stim1 is phosphorylated during mitosis. Removal of ten mpm-2 recognition sites by truncation at amino acid 482 abolished mpm-2 recognition of mitotic stim1, and significantly rescued stim1 rearrangement and soce response in mitosis. We identified ser 486 and ser 668 as mitosis-specific phosphorylation sites, and stim1 containing mutations of these sites to alanine also significantly rescued mitotic soce. SIGNOR-189017 0.352 FLT3 protein P36888 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity 10090 BTO:0001516 23246379 f miannu Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation. These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells. SIGNOR-260081 0.548 PRKCQ protein Q04759 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates phosphorylation 9606 23352416 t gcesareni At the same time, ea causes pkc?-Mediated phosphorylation and activation of the transcription factor heat shock factor 1, an inducer of glucose dependence. SIGNOR-200576 0.356 SRC protein P12931 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Tyr1474 GSSNGHVyEKLSSIE -1 11483655 t lperfetto We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases SIGNOR-247180 0.576 ATF4 protein P18848 UNIPROT AARS2 protein Q5JTZ9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269415 0.246 DUSP1 protein P28562 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 10617468 t inferred from 70% of family members gcesareni The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1. SIGNOR-269930 0.828 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58467 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267324 0.8 STAT4 protein Q14765 UNIPROT LAMTOR5 protein O43504 UNIPROT up-regulates activity binding 9606 22740693 t miannu It suggests that HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4. here we first report that the transcription factor STAT4 plays a role in regulating S100A4 mediated by HBXIP in breast cancer. SIGNOR-255247 0.333 MAPK8 protein P45983 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 7824938 t gcesareni Activating transcription factor-2 (atf2) was found to be a target of the jnk signal transduction pathway. Atf2 was phosphorylated by jnk on two closely spaced threonine residues within the nh2-terminal activation domain. SIGNOR-33914 0.771 RPL22L1 protein Q6P5R6 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262498 0.726 MECOM protein Q03112 UNIPROT GATA2 protein P23769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000565 15889140 t Luana Evi1 directly binds to the promoter region of GATA-2 and thus enhances the GATA-2 transcription. SIGNOR-266062 0.367 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9913 11254391 t miannu Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate. SIGNOR-266915 0.8 CDC25A protein P30304 UNIPROT DYRK2 protein Q92630 UNIPROT down-regulates activity dephosphorylation 9606 34363019 t miannu Finally, DYRK2 is dephosphorylated by CDC25A, suggesting a feedback regulatory loop.|Notably, the co-expression of CDC25A inhibited the DYRK2 pro-apoptotic effect (Fig.\u00a06D), concurring with a possible inhibitory role on DYRK2 activity and further suggesting that the effect of DYRK2 was dependent on CDC25A. SIGNOR-277098 0.2 CYP11B1 protein P15538 UNIPROT corticosterone smallmolecule CHEBI:16827 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268682 0.8 TTL protein Q8NG68 UNIPROT TUBA4A protein P68366 UNIPROT down-regulates tyrosination 9606 22020298 t miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization SIGNOR-176927 0.29 PHF12 protein Q96QT6 UNIPROT TLE2 protein Q04725 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 t miannu We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE. SIGNOR-266992 0.2 BIRC5 protein O15392 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates binding 9606 17546047 t gcesareni Mitochondrial survivin associated with smac/diablo, delaying its release. SIGNOR-155361 0.586 PCGF2 protein P35227 UNIPROT Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR form complex binding 9606 31608994 t miannu PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b SIGNOR-266813 0.768 P2RY10 protein O00398 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256726 0.2 IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 23663276 t milica Il-6 family members typically signal through the common gp130 receptor, with the janus kinase/signal transducer and activator of transcription (jak/stat) pathway being the major intracellular mediator of their effects. SIGNOR-202036 0.663 CTH protein P32929 UNIPROT hydrosulfide smallmolecule CHEBI:29919 ChEBI up-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. SIGNOR-275819 0.8 NFIX protein Q14938 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268887 0.2 SPOP protein O43791 UNIPROT DAXX protein Q9UER7 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0002181 16524876 t Gianni These results suggest that SPOP/Cul3-ubiquitin ligase plays an essential role in the control of Daxx level and, thus, in the regulation of Daxx-mediated cellular processes, including transcriptional regulation and apoptosis. SIGNOR-268858 0.497 MAPK10 protein P53779 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr265 GQSSAAAtPSTTGTK 9606 15767678 t gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. SIGNOR-134529 0.738 risperidone chemical CHEBI:8871 ChEBI HTR1D protein P28221 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000529 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258527 0.8 ILK protein Q13418 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates activity phosphorylation Thr696 ARQSRRStQGVTLTD -1 12030846 t miannu MYPT1 was phosphorylated by ILK and phosphorylation sites in the N- and C-terminal fragments of MYPT1 were detected. From sequence analyses, three sites were identified: a primary site at Thr(709), and two other sites at Thr(695) and Thr(495). ILK produced an intermediate level of inhibition SIGNOR-262886 0.567 GSK3B protein P49841 UNIPROT RICTOR protein Q6R327 UNIPROT down-regulates quantity by destabilization phosphorylation Thr1695 EAEAVLAtPPKQPIV 9606 BTO:0002181 25897075 t miannu We show that this process is dependent on glycogen synthase kinase 3 (GSK3): GSK3 was associated with rictor and directly phosphorylated the Thr-1695 site in a putative CDC4 phospho-degron motif of rictor; mutation of this site impaired the interaction between rictor and FBXW7, decreased rictor ubiquitination, and increased rictor stability.  SIGNOR-276898 0.419 IL7 protein P13232 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 t gcesareni The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, il-15, il-2, il21 SIGNOR-108864 0.699 WNT9A protein O14904 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-132076 0.625 GPT2 protein Q8TD30 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 11863375 t Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate, and thereby has a key role in the intermediary metabolism of glucose and amino acids. Two ALT isoenzymes are known to exist, but only one ALT gene has been cloned, GPT. In this study, we cloned a homolog of GPT and named it GPT2, and the corresponding protein ALT2 SIGNOR-266925 0.8 AKT1 protein P31749 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 17053147 t gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. SIGNOR-252496 0.446 PHIP protein Q8WWQ0 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity binding 9534 BTO:0001538 12242307 t miannu We have recently reported the isolation of a PH domain-interacting protein, PHIP, which selectively binds to the IRS-1 PH domain and is stably associated with IRS-1 in mammalian cells. Here we demonstrate that overexpression of PHIP in fibroblasts enhances insulin-induced transcriptional responses in a mitogen-activated protein kinase-dependent manner. SIGNOR-266962 0.527 GHSR protein Q92847 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257167 0.358 MRPL32 protein Q9BYC8 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262339 0.698 NANOG protein Q9H9S0 UNIPROT PAX6 protein P26367 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 f lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) SIGNOR-253164 0.446 MSH6 protein P52701 UNIPROT BLM protein P54132 UNIPROT up-regulates binding 9606 SIGNOR-C60 15064730 t miannu We show that the recombinant hmsh2/6 protein complex stimulated the ability of the bloom's syndrome gene product, blm, to process holliday junctions in vitro SIGNOR-123705 0.618 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 9687510 t gcesareni Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. SIGNOR-59435 0.601 APOBEC3C protein Q9NRW3 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 f lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). SIGNOR-261326 0.7 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Ser821 YLRQFSGsLKPEDAE 9534 BTO:0000298 14523239 t lperfetto We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. SIGNOR-249233 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270366 0.8 Naloxone benzoylhydrazone chemical CID:9601084 PUBCHEM OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258422 0.8 TOPORS protein Q9NS56 UNIPROT TP53 protein P04637 UNIPROT down-regulates ubiquitination 9606 phosphorylation:Ser718 KDRDGYEsSYRRRTL 19473992 t lperfetto Plk1-mediated phosphorylation of topors regulates p53 stabilityherein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. SIGNOR-185848 0.473 CSNK2A1 protein P68400 UNIPROT PDCD5 protein O14737 UNIPROT up-regulates phosphorylation Ser119 NRRKVMDsDEDDDY 9606 19616514 t lperfetto Programmed cell death 5 (pdcd5), a protein involved in cell death and down-regulated in different forms of human tumors. Pdcd5 is phosphorylated in vitro by both ck2alpha subunit and by the ck2 holoenzyme at a residue, s118, which is found phosphorylated in vivo. Transfection of the non-phosphorylatable mutant (s118a) impairs the pdcd5 acceleration of either doxorubimicin- or uv-induced apoptosis in u2os cells SIGNOR-187106 0.2 PRKAB1 protein Q9Y478 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 SIGNOR-C15 11729179 t gcesareni Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no. SIGNOR-112367 0.2 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser527 PHLDGPPsPRSPVIG 9606 BTO:0001271 15093545 t The effect has been demonstrated using P29590-4 gcesareni We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3). SIGNOR-124252 0.366 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 21808241 t gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. SIGNOR-175821 0.621 PKN1 protein Q16512 UNIPROT PGAM1 protein P18669 UNIPROT down-regulates phosphorylation Ser118 QVKIWRRsYDVPPPP 9606 BTO:0000130 12189148 t llicata Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity. SIGNOR-91602 0.256 SGK1 protein O00141 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000007 11154281 t lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. SIGNOR-252987 0.787 AMPK complex SIGNOR-C15 SIGNOR SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Thr101 IVLNKGKtIFRFSAT 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275769 0.324 MAPK1 protein P28482 UNIPROT DUSP16 protein Q9BY84 UNIPROT up-regulates quantity by stabilization phosphorylation Ser446 TNKLCQFsPVQELSE 9534 15689616 t lperfetto Phosphorylation of Ser-446 determines stability of MKP-7.|We also determined that MKP-7 phosphorylated at Ser-446 has a longer half-life than unphosphorylated form of the wild type protein, as does a phospho-mimic mutant of MKP-7. These results indicate that activation of the ERK pathway strongly blocks JNK activation through stabilization of MKP-7 mediated by phosphorylation. SIGNOR-249389 0.801 RAPH1 protein Q70E73 UNIPROT EVL protein Q9UI08 UNIPROT up-regulates activity binding 9606 20417104 t miannu Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins. SIGNOR-268427 0.353 MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 SIGNOR-C2 21157483 t lperfetto Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.Recent findings have revealed novel important roles for mTORC2 in the phosphorylation of AGC kinase family members. mTORC2 phosphorylates and activates Akt, SGK, and PKC, which regulate cell survival, cell cycle progression and anabolism SIGNOR-170604 0.928 TNF protein P01375 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32446778 f doi: 10.1016/j.cytogfr.2020.05.003 miannu Interleukin-6 (IL-6) deserves a more extensive discussion in view of its involvement in the coronavirus-induced cytokine storm. The production of this cytokine is increased by IL-1β and tumor necrosis factor (TNF- α) SIGNOR-260856 0.518 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser345 RPASVDGsPVSPSTN -1 12351658 t IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. SIGNOR-251295 0.644 SREBF1 protein P36956 UNIPROT ELOVL proteinfamily SIGNOR-PF93 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 18226595 t Luana These data demonstrated that Elovl-6 is regulated directly and primarily by SREBP-1c. SIGNOR-267944 0.464 ATP2A1 protein O14983 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9986 28487373 t lperfetto SERCA1, the sarco(endo)plasmic reticulum Ca2+-ATPase of skeletal muscle, is essential for muscle relaxation and maintenance of low resting Ca2+ levels in the myoplasm. SIGNOR-265928 0.8 STK4 protein Q13043 UNIPROT SAV1 protein Q9H4B6 UNIPROT up-regulates -1 16930133 t lperfetto In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. The stabilizing effect of Mst was much greater on N-terminally truncated hSav mutants, as long as they retained the ability to bind Mst. Mst mutants that lacked the C-terminal coiled-coil domain and were unable to bind to hSav, also failed to stabilize or phosphorylate hSav SIGNOR-217833 0.882 TPP1 protein O14773 UNIPROT Telomere_maintenance phenotype SIGNOR-PH148 SIGNOR up-regulates 9606 22101936 f miannu The mammalian shelterin component TPP1 has essential roles in telomere maintenance and, together with POT1, is required for the repression of DNA damage signaling at telomeres.  SIGNOR-272723 0.7 WDR5 protein P61964 UNIPROT HMT complex SIGNOR-C19 SIGNOR form complex binding 9606 17500065 t lperfetto The evolutionarily conserved hdpy-30, ash2l, rbbp5, and wdr5 likely constitute a subcomplex that is shared by all human set1-like hmt complexes. SIGNOR-154766 0.889 NFIX protein Q14938 UNIPROT ROBO1 protein Q9Y6N7 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268907 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252350 0.2 NPFFR2 protein Q9Y5X5 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256709 0.252 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Tyr141 AITSPFKyQSLLTKN 10029 BTO:0000246 8557631 t Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors. SIGNOR-251300 0.385 ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates -1 10542278 f miannu HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay. SIGNOR-259064 0.7 CDK1 protein P06493 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Thr269 GGKRSRLtPVSPESS 9606 SIGNOR-C17 20974803 t gcesareni Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis. SIGNOR-169016 0.35 FZD5 protein Q13467 UNIPROT CEBPA protein P49715 UNIPROT down-regulates 9606 10937998 f fspada Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma) SIGNOR-80607 0.2 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates activity phosphorylation Ser328 VLPSISLsPGPQPPK 9606 BTO:0000567 12734188 t lperfetto Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9. SIGNOR-101047 0.369 PTN protein P21246 UNIPROT ALK protein Q9UM73 UNIPROT up-regulates binding 9606 11278720 t gcesareni We conclude from this series of experiments that ptn specifically binds to the alk orphan receptor as a high affinity ligand at least in part via the putative ligand binding domain described above. SIGNOR-106411 0.563 FEZF2 protein Q8TBJ5 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by repression transcriptional regulation 23677067 f lperfetto FEZF2, a novel 3p14 tumor suppressor gene, represses oncogene EZH2 and MDM2 expression and is frequently methylated in nasopharyngeal carcinoma. SIGNOR-268974 0.2 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser255 SSQMKSMsTFIEEAY 9606 BTO:0000567 25670858 t lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. SIGNOR-265226 0.571 TET1 protein Q8NFU7 UNIPROT SLIT2 protein O94813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27708339 t irozzo Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9. SIGNOR-259093 0.2 MAPK14 protein Q16539 UNIPROT EZH2 protein Q15910 UNIPROT up-regulates activity phosphorylation 9606 SIGNOR-C77 21902831 t lperfetto P38 can phosphorylate the histone-lysine n-methyltransferase ezh2, the catalytic subunit of the polycomb repressive complex 2 (prc2), with phosphorylation of ezh2 necessary for prc2s association with the transcriptional repressor yy1 and subsequent chromatin remodelling. SIGNOR-176548 0.38 ROCK1 protein Q13464 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Thr1141 NRKSLRRtLKSGLGD 9606 18239683 t lperfetto Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres. SIGNOR-160552 0.314 GNA12 protein Q03113 UNIPROT RFFL protein Q8WZ73 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 22609986 f miannu LPA and Gα12 may upregulate the expression of an E3 ubiquitin ligase that catalyzes the polyubiquitination of PRR5L. SIGNOR-271496 0.2 NDC1 protein Q9BTX1 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262073 0.514 HACD proteinfamily SIGNOR-PF86 SIGNOR very long-chain 2,3-trans-enoyl CoA(4-) smallmolecule CHEBI:83728 ChEBI up-regulates quantity chemical modification 9606 18554507 t miannu Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle. SIGNOR-267918 0.8 PTPN22 protein Q9Y2R2 UNIPROT CD247 protein P20963 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 16461343 t amattioni T cell signaling is negatively regulated by the activity of protein-tyrosine phosphatases. Native ptpn22 dephosphorylated tcrzeta in vitro and in cells. SIGNOR-144337 0.458 AKT2 protein P31751 UNIPROT CHUK protein O15111 UNIPROT up-regulates phosphorylation Thr23 EMRERLGtGGFGNVC 9606 SIGNOR-C14 19609947 t gcesareni Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-187010 0.509 TSHB protein P01222 UNIPROT SLC5A5 protein Q92911 UNIPROT up-regulates quantity by stabilization 9606 14623893 f miannu Uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane SIGNOR-251994 0.389 UBE2G2 protein P60604 UNIPROT DIO2 protein Q92813 UNIPROT down-regulates quantity by destabilization ubiquitination Lys244 KIAYLGGkGPFSYNL 9606 BTO:0001379 29892818 t scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. SIGNOR-267484 0.2 KDM6A protein O15550 UNIPROT FLI1 protein Q01543 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29736013 t miannu Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase SIGNOR-260034 0.2 MTOR protein P42345 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000527 16740698 t miannu Serine phosphorylation and maximal activation of stat3 during cntf signaling is mediated by the rapamycin target mtor. / a stat3 peptide was efficiently phosphorylated on ser727 in a cntf-dependent manner by mtor SIGNOR-146915 0.738 CTNNB1 protein P35222 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 15735151 f gcesareni Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation (fig 2?2),), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1 SIGNOR-134216 0.794 PRKCB protein P05771 UNIPROT LMNB1 protein P20700 UNIPROT unknown phosphorylation Ser395 LKLSPSPsSRVTVSR -1 8034666 t lperfetto Beta II PKC-mediated phosphorylation of lamin B is confined to two sites, Ser395 and Ser405 | Comparative tryptic phosphopeptide mapping demonstrates that the beta II PKC site, Ser405, is a prominent target of mitotic lamin B phosphorylation in vivo. beta II PKC translocates to the nucleus during the G2/M phase of cell cycle concomitant with phosphorylation of Ser405, indicating a physiologic role for nuclear beta II PKC activation in mitotic lamin B phosphorylation in vivo. SIGNOR-248911 0.477 AKT1 protein P31749 UNIPROT CFLAR protein O15519 UNIPROT down-regulates quantity phosphorylation Ser273 LLRDTFTsLGYEVQK 9606 19339247 t gcesareni TNFalpha enhanced FLIP(L) serine phosphorylation, which was increased by activated Akt-1. Serine 273, a putative Akt-1 phosphorylation site in FLIP(L), was critical for the activation-induced reduction of FLIP(L). Thus, these observations document a novel mechanism where by TNFalpha facilitates the reduction of FLIP(L) protein, which is dependent on the phosphatidylinositol 3-kinase/Akt signaling. SIGNOR-252548 0.479 VEGFA protein P15692 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252275 0.7 PAX1 protein P15863 UNIPROT MEOX2 protein P50222 UNIPROT up-regulates activity binding -1 11423130 t miannu We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family. SIGNOR-222232 0.419 CDK1 protein P06493 UNIPROT CEP55 protein Q53EZ4 UNIPROT down-regulates phosphorylation Ser425 NREKVAAsPKSPTAA 9606 16198290 t lperfetto Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis. SIGNOR-140882 0.46 PAK1 protein Q13153 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser101 LESFKKQsFVLKEGV 9606 15225553 t lperfetto Pak1 binds and phosphorylates rhogdi both in vitro and in vivo at ser101 and ser174. This resulted in dissociation of rac1-rhogdi, but not rhoa-rhogdi, complexes, as determined by in vitro assays of complexation and in vivo by coimmunoprecipitation analysis. We observed that cdc42-induced rac1 activation is inhibited by expression of pak1 autoinhibitory domain. The dissociation of rac1 from rhogdi and its subsequent activation stimulated by pdgf or egf is also attenuated by pak1 autoinhibitory domain, and this is dependent on the ability of rhogdi to be phosphorylated at ser101/174. SIGNOR-126650 0.595 HIF1A protein Q16665 UNIPROT CCL2 protein P13500 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001496 17474992 t lperfetto These findings suggest that both MCP-1 and MCP-5 are HIF-1 target genes and that HIF-1α is involved in transcriptional induction of these two chemokines in astrocytes by hypoxia. SIGNOR-251719 0.412 PTPRJ protein Q12913 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 12771128 t inferred from 70% of family members gcesareni A dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation. SIGNOR-269919 0.471 PRKCA protein P17252 UNIPROT FLNC protein Q14315 UNIPROT up-regulates quantity by stabilization phosphorylation Ser2236 ERLGSFGsITRQQEG 10090 BTO:0000165 32444788 t miannu We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells. In vitro kinase assays combined with LC-MS confirmed hFLNc-S2233 as a substrate of Akt, whereas PKCα preferentially targeted S2236. SIGNOR-262617 0.344 SETDB1/NLK/CHD7 complex SIGNOR-C189 SIGNOR PPARG protein P37231 UNIPROT down-regulates activity 10090 21952300 f FFerrentino The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1). SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3-L1 cells SIGNOR-253524 0.432 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser428 EPAPVLSsPPPADVS 9606 15037602 t lperfetto Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain. SIGNOR-216781 0.447 SRC protein P12931 UNIPROT NDUFV2 protein P19404 UNIPROT up-regulates activity phosphorylation Tyr193 VQINDNYyEDLTAKD 9606 BTO:0001583 22823520 t miannu Phosphorylation-site analysis selects c-Src targets, including NDUFV2 (NADH dehydrogenase [ubiquinone] flavoprotein 2) at Tyr(193) of respiratory complex I and SDHA (succinate dehydrogenase A) at Tyr(215) of complex II. The phosphorylation of these sites by c-Src is supported by an in vivo assay using cells expressing their phosphorylation-defective mutants.  SIGNOR-276419 0.328 HGF protein P14210 UNIPROT MET protein P08581 UNIPROT up-regulates binding 9606 8380735 t gcesareni Hgf is the ligand for p190met, the receptor tyrosine kinase encoded by the met proto-oncogene. SIGNOR-38429 0.927 C3 convertase complex (C3bBb) complex SIGNOR-C314 SIGNOR C5 convertase complex (C3bBbC3b) complex SIGNOR-C315 SIGNOR form complex binding 9606 BTO:0000089 26489954 t lperfetto In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC). SIGNOR-263479 0.2 LPAR3 protein Q9UBY5 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257297 0.461 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates activity phosphorylation Ser625 TAMLSLGsGISQCGY 9534 BTO:0000298 11865049 t llicata The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly.  SIGNOR-250816 0.734 ADAM9 protein Q13443 UNIPROT FGFR2 protein P21802 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0000007 22632802 t Giulio Truncated FGFR2 was observed in cells transfected with wild-type ADAM9, but not in those with inactive mutant ADAM9 (Figure 5E). In line with this, cells transfected with wild-type ADAM9 showed reduced pErK1/2 in response to FGF2 as compared to controls or cells expressing mutant ADAM9.|Here we show that MT1-MMP forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9, hence protecting FGFR2 from ADAM9-mediated ectodomain shedding on the cell surface. SIGNOR-260300 0.26 belinostat chemical CHEBI:61076 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257741 0.8 EEF1A2 protein Q05639 UNIPROT Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269522 0.8 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 15809305 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-217067 0.748 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 10715136 t Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif. gcesareni A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) and p38 subs of map kinases, respectively. Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). SIGNOR-75792 0.733 IPO5 protein O00410 UNIPROT DSCAM protein O60469 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 30745319 t miannu DSCAM and DSCAML1 specifically interacted with the importin beta IPO5, whereas deletion of the identified NLSs abolished this specific interaction and suppressed nuclear translocation of the DSCAM/L1 ICDs in cell lines and cultured neurons. This suggests a direct role of IPO5 in the nuclear import of the DSCAM/L1 ICDs. SIGNOR-264273 0.2 NR3C1 protein P04150 UNIPROT IRAK3 protein Q9Y616 UNIPROT up-regulates quantity transcriptional regulation 9606 25585690 t We show that glucocorticoids and non-typeable Haemophilus influenzae synergistically upregulate IRAK-M expression via mutually and synergistically enhancing p65 and glucocorticoid receptor binding to the IRAK-M promoter SIGNOR-259287 0.368 LAT protein O43561 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 11368773 t lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. SIGNOR-252734 0.403 OLIG1 protein Q8TAK6 UNIPROT OLIG2 protein Q13516 UNIPROT up-regulates 9606 BTO:0000938 25206819 f miannu During central nervous system development, olig1 assists olig2 in formation of the motor neuron progenitor domain (pmn), the area responsible for generation of motor neurons and oligodendrocytes SIGNOR-205304 0.309 PPP5C protein P53041 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates activity dephosphorylation Ser667 SSLIRKRsTRRSVRG 9606 BTO:0000007 24333728 t Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp SIGNOR-272506 0.2 IGF1R protein P08069 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity binding -1 7541045 t lperfetto In our present work, we show that both IRS-1 and SHC interact directly with the juxtamembrane region of the IGFIR in a phosphotyrosine-dependent manner. |We propose a model in which IGFIR autophosphorylation of Tyr-950 forms a direct binding site for the amino-terminal receptor binding domains of SHC and IRS-1. This interaction is presumed to facilitate tyrosine phosphorylation of SHC on Tyr-317 leading to GRB2/SOS interaction SIGNOR-262587 0.726 SSTR2 protein P30874 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256963 0.36 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser283 RSVPEPLsPVSSLQA -1 16027724 t GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines) SIGNOR-251227 0.389 AURKB protein Q96GD4 UNIPROT SSU72 protein Q9NP77 UNIPROT down-regulates quantity by destabilization phosphorylation Ser19 CSSNQNRsMEAHNIL 24149858 t lperfetto Here we report that Aurora B kinase directly interacts with and phosphorylates Ssu72, a new cohesin-binding phosphatase, at Ser 19 in vitro and in vivo. The Aurora B-mediated phosphorylation of Ssu72 causes the structural modification of Ssu72 protein, downregulates phosphatase activity and triggers the ubiquitin-dependent degradation of Ssu72. SIGNOR-275529 0.256 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CELF6 protein Q96J87 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001109 31534127 t miannu CELF6 is degraded by ubiquitin-dependent proteasome pathway. The cell cycle-dependent expression of CELF6 is mediated through the ubiquitin-proteasome pathway, SCF-β-TrCP recognizes a nonphospho motif in CELF6 and regulates its proteasomal degradation. SIGNOR-269043 0.2 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser653 PSLSRHSsPHQSEDE -1 2117608 t llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. SIGNOR-250881 0.335 CUL3 protein Q13618 UNIPROT MAP1S protein Q66K74 UNIPROT down-regulates quantity ubiquitination 10090 BTO:0000142 18680552 t miannu Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. SIGNOR-268947 0.244 WWTR1 protein Q9GZV5 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates binding 9606 21084559 t gcesareni Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal. SIGNOR-169835 0.576 GABRA6 protein Q16445 UNIPROT GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263771 0.524 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:93369 ChEBI HTR1E protein P28566 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0000298 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258541 0.8 MAPK3 protein P27361 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser225 ARLGSQHsPGRTASL 9606 21419341 t gcesareni We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1. SIGNOR-172881 0.431 MIB1 protein Q86YT6 UNIPROT JAG1 protein P78504 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000938 12530964 t lperfetto Mib1 is essential for the generation of functional notch ligands and regulates the classical notch ligands dll1, dll4, jag1, and jag2 in vertebrates mib1 is an essential e3 ubiquitin ligase for jag1 in the developing cerebellum. SIGNOR-97388 0.68 CSF2RA protein P15509 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 9606 7716810 f gcesareni A major pathway which mediates the effects of gm-csf on macrophages involves activation of the latent transcription factor stat5a via a janus kinase 2 (jak2)-dependent pathway. SIGNOR-32220 0.575 PRKACA protein P17612 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 t miannu Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII). Incubation of Rad with PKA decreases GTP binding by 60-70%, but this effect seems to be independent of phosphorylation, as it is observed with the Ser273-->Ala mutant of Rad containing a mutation at the site of PKA phosphorylation. SIGNOR-250048 0.346 F2 protein P00734 UNIPROT F5 protein P12259 UNIPROT up-regulates activity cleavage Arg737 LAAALGIrSFRNSSL -1 10026263 t lperfetto Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 SIGNOR-263632 0.878 Glutaminolysis phenotype SIGNOR-PH119 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 22749528 f Luana Glutaminolysis Is Required for the Activation of mTORC1 by Leucine and Glutamine SIGNOR-268007 0.7 CAMK2A protein Q9UQM7 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser19 KGFRRAVsELDAKQA 9606 BTO:0000142 1680128 t llicata This increase in ser19 phosphorylation was associated with enhanced th activity and was due, in part, to glutamate-receptor-mediated calcium influx and possibly calcium/calmodulin-dependent protein kinase ii (camkii) activation. SIGNOR-20912 0.259 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser439 EPGTATGsGIKSHNS 9606 15574499 t amattioni Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility. SIGNOR-131447 0.255 TP53 protein P04637 UNIPROT SCO2 protein O43819 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 t miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. SIGNOR-267463 0.625 SCHEMBL14517914 chemical CID:10016910 PUBCHEM CHEK2 protein O96017 UNIPROT down-regulates chemical inhibition 9606 20068082 t gcesareni Xl844 (exelixis) a potent atp-competitive inhibitor of chk1 (ki, 2.2nm) and chk2 (ki, 0.07nm). SIGNOR-163234 0.8 HTR1D protein P28221 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257116 0.252 tolazoline chemical CHEBI:28502 ChEBI ADRA2C protein P18825 UNIPROT down-regulates activity chemical inhibition 9606 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258914 0.8 QRICH1 protein Q2TAL8 UNIPROT TARS2 protein Q9BW92 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269407 0.2 CSNK2A2 protein P19784 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser418 VEEDPLNsGDDVSEQ -1 12107178 t llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. SIGNOR-250993 0.424 RPLP1 protein P05386 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262450 0.82 SGK3 protein Q96BR1 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser664 GARQRALsAVSVLTS 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275768 0.279 RAB14 protein P61106 UNIPROT RUFY1 protein Q96T51 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 20534812 t Giulio Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn. SIGNOR-261279 0.615 DGC complex SIGNOR-C217 SIGNOR GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265437 0.2 KDM6A protein O15550 UNIPROT HOXC4 protein P09017 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260030 0.445 PRKCA protein P17252 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Ser518 VFRTNGVsDVPTSPT -1 27368100 t miannu These results suggest that PKC activates JAK2 and thereby STAT3 by directly phosphorylating T174 and S518.  SIGNOR-277261 0.262 SRC protein P12931 UNIPROT HNF4A protein P41235 UNIPROT down-regulates phosphorylation Tyr288 IDDNEYAyLKAIIFF 9606 22308320 t lperfetto Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function. SIGNOR-195900 0.373 OTX2 protein P32243 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 20530484 f miannu BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles. SIGNOR-255186 0.358 C8A protein P07357 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 t lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer SIGNOR-263445 0.58 XL765 chemical CHEBI:71958 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207869 0.8 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR MAP1LC3B protein Q9GZQ8 UNIPROT down-regulates activity phosphorylation Thr50 QLPVLDKtKFLVPDH -1 31857374 t done miannu LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1). SIGNOR-273905 0.2 AP2A2 protein O94973 UNIPROT AP-2 complex complex SIGNOR-C245 SIGNOR form complex binding 31671891 t lperfetto The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit SIGNOR-260423 0.851 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT down-regulates activity phosphorylation Ser30 EDLQEVLsSDENGGT 9606 BTO:0000567 12876286 t llicata CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites SIGNOR-250852 0.351 EEF1A1 protein P68104 UNIPROT Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269502 0.8 CDK6 protein Q00534 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 16160006 t gcesareni Phosphorylation on ser-10 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability.p27(kip1) was phosphorylated by v-cyclin-cdk6 predominantly on ser10, which enhances its cytoplasmic localization. SIGNOR-140401 0.85 CDK1 protein P06493 UNIPROT NDUFA12 protein Q9UI09 UNIPROT up-regulates activity phosphorylation Thr142 QEWIPPStPYK 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275587 0.2 diisononyl phthalate chemical CHEBI:35459 ChEBI OXER1 protein Q8TDS5 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR). SIGNOR-268773 0.8 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269334 0.719 MAPK14 protein Q16539 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 15879307 t gcesareni Conversely, constitutively active mkk6 induced p38 mapk activation that recapitulated the effects of polyphenols by inducing eralpha phosphorylation and downstream activation of akt, and enos. The key role of eralpha ser-118 phosphorylation was confirmed in enos-transfected cos-7 cells SIGNOR-136950 0.61 MAPK11 protein Q15759 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation 9606 20820849 t gcesareni Smads can also be phosphorylated in the linker region most prominently by the action of mitogen-activated protein (map) kinaseslinker region phosphorylation can prevent nuclear translocation of smads and inhibit tgf-_ signalling, potentially leading to oncogenesis. SIGNOR-167848 0.36 FZD8 protein Q9H461 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000971 21078818 t amattioni Ligands such as Wnt1, Wnt3a, and Wnt8 couple the seven-transmembrane domain receptor Frizzled (Fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (LRP5/6) to activate Wnt–Beta-catenin signaling. SIGNOR-169638 0.745 NR1D1 protein P20393 UNIPROT ARNTL protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20817722 t miannu In this study, we found that NPAS2, like BMAL1, is a direct target gene of RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding. SIGNOR-267983 0.658 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYB protein P10242 UNIPROT down-regulates phosphorylation Ser532 KIKQEVEsPTDKSGN 9606 BTO:0000661 8960373 t lperfetto Functional analysis of phosphorylation at serine 532 of human c-myb by map kinase. expression of a polypeptide containing the c-myb c-terminal domain stimulated c-myb activity. This effect is reduced upon mapk-dependent phosphorylation of serine 532. Our data suggest that the mapk-dependent state of phosphorylation modifies the cellular function of c-myb by modulating its interaction with a putative inhibitory factor SIGNOR-244569 0.2 EGFR protein P00533 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates phosphorylation Tyr199 AFLASPEyVNLPING 9606 BTO:0000150 19254954 t llicata Taken together, these results and those of the ms/ms analyses confirmed tyr-3, tyr-7, and tyr-198 to be primary residues phosphorylated by egfr in the gstp1 protein. The phosphorylation increased gstp1 enzymatic activity significantly, SIGNOR-184379 0.448 PTPN12 protein Q05209 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 BTO:0003892 11731619 t PTP-PEST-Containing Lysates from EGF-Treated HC11 Cells Dephosphorylate JAK2 More Efficiently than Lysates from Control Cells|phospho-JAK2-specific rabbit polyclonal antiserum (44-426, BioSource Technologies, Inc., Camarillo, CA) which recognizes Tyr1007/1008 in the activation site SIGNOR-248658 0.385 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000142 20308788 t The effect has been demonstrated using P10636-8 lperfetto Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro. SIGNOR-164663 0.2 WAS protein P42768 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000567 20498093 t lperfetto Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes. SIGNOR-261001 0.803 CEBPB protein P17676 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 7557387 t Andrea Cerquone Perpetuini  Induction of C/EBP beta DNA-binding activity in NIH-3T3 beta 2 cells exposed to dexamethasone in the presence of insulin and fetal bovine serum activates the expression of an adipocyte-specific nuclear hormone receptor, PPAR gamma, that stimulates the conversion of these fibroblasts into committed preadipocytes SIGNOR-255730 0.718 PRKCD protein Q05655 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 12464600 t gcesareni Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation. SIGNOR-96067 0.2 MYCT1 protein Q8N699 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30283340 f miannu MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. SIGNOR-261734 0.2 PTPN1 protein P18031 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates dephosphorylation Tyr42 DSMKDEEyEQMVKEL 9606 8940099 t gcesareni Ptp1b is able to dephosphorylate phosphorylated-tyr-42 on ikappabalpha SIGNOR-45004 0.36 sabcomeline chemical CHEBI:134846 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10116 9399977 t miannu SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes SIGNOR-258675 0.8 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001103 15829723 t apalma IGF-I binding to its receptor activates the kinase activity of the receptor, which then recruits the insulin response substrate-1, causing activation of phosphatidyl-inositol-3 kinase (PI3K) to phosphorylate Akt. SIGNOR-255106 0.784 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI GSN protein P06396 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000132 12788695 t lperfetto We further measured the ability of ppIs phosphorylated in positions D-3 and D-4 to release the F-actin capping proteins CapZ and gelsolin from OG-permeabilized platelets (Fig. 7A). Ten percent of platelet CapZ and gelsolin is found in the OG-insoluble fraction (4). PI3,4,5P3 and PI3,4P2 release both CapZ and gelsolin from these preparations. SIGNOR-261840 0.8 GADL1 protein Q6ZQY3 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 22718265 t miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. SIGNOR-267545 0.8 SMAD3 protein P84022 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 f miannu Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. SIGNOR-260432 0.7 PRKACA protein P17612 UNIPROT RGS10 protein O43665 UNIPROT down-regulates activity phosphorylation Ser176 QTAAKRAsRIYNT 9606 11443111 t lperfetto We report in this study the acute functional regulation of rgs10 thru the specific and inducible phosphorylation of rgs10 protein at serine 168 by camp-dependent kinase a. This phosphorylation nullifies the rgs10 activity at the plasma membrane, which controls the g protein-dependent activation of the inwardly rectifying potassium channel. SIGNOR-109173 0.34 MAPK1 protein P28482 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 20974802 t gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription. SIGNOR-169001 0.306 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser397 EQKFRMLsQDAPTVK 9606 10839545 t lperfetto We have identified two residues of nbs1, ser 278 and ser 343 that are phosphorylated in vitro by atm and whose modification in vivo is essential for the cellular response to dna damage. This response includes s-phase checkpoint activation, formation of the nbs1/mrel1/rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation. SIGNOR-78030 0.851 BRAF protein P15056 UNIPROT EEF1A1 protein P68104 UNIPROT down-regulates quantity by destabilization phosphorylation Ser21 GHVDSGKsTTTGHLI -1 22378069 t miannu Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.  SIGNOR-276404 0.265 Sincalide smallmolecule CID:9833444 PUBCHEM CCKBR protein P32239 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257467 0.8 TERF2 protein Q15554 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR down-regulates 10116 27117401 f miannu During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. SIGNOR-266805 0.7 NF1 protein P21359 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR up-regulates 9606 BTO:0000938 24431436 f miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-267847 0.408 PRKCD protein Q05655 UNIPROT ADD2 protein P35612 UNIPROT unknown phosphorylation Ser713 KKKFRTPsFLKKSKK -1 8810272 t lperfetto Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites for PKC. SIGNOR-248952 0.289 ATM protein Q13315 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser239 DPMTQDGsQPMDTNM 9606 22588298 t llicata On genotoxic stress, atm phosphorylates bmps-activated smad1 in the nucleus on s239, which disrupts smad1 interaction with protein phosphatase ppm1a, leading to enhanced activation and upregulation of smad1. SIGNOR-197533 0.2 CDK5 protein Q00535 UNIPROT CDK5R1 protein Q15078 UNIPROT down-regulates phosphorylation Thr138 PAVTSAGtPKRVIVQ 9606 18326489 t lperfetto P35 phosphorylation by cdk5 interferes with the microtubule-binding and polymerizing activities of p35. Using a mutational approach, we found that only phosphorylation at thr-138, one of the two residues primarily phosphorylated in vivo, inhibits the polymerizing activity SIGNOR-177967 0.942 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 19162178 t gcesareni The hgf-induced wave2 transport, lamellipodia formation, stathmin/op18 phosphorylation at ser38 and binding to kinesin-wave2 complex, but not stathmin/op18 phosphorylation at ser25 and microtubule growth, were abrogated by pak1 inhibitor ipa-3 SIGNOR-183503 0.382 NPTX1 protein Q15818 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity binding 10090 BTO:0000938 15115814 t inferred from family member lperfetto We found that NP1 colocalizes and physically associates with the fast excitatory GluR1 AMPA receptors and that hypoxia induces a time-dependent increase in the NP1-GluR1 interactions. Thus hypoxia recruits NP1 protein to GluR1 subunits concurrent with the hypoxic excitotoxic cascade.|Rather we propose that through interactions with GluR1 clusters, NP1 modulates the function of AMPA receptors in a manner whereby increased NP1-GluR1 interactions sensitize neurons to hypoxia-induced excitotoxic death. SIGNOR-270235 0.341 PRKACA protein P17612 UNIPROT CAPN2 protein P17655 UNIPROT down-regulates phosphorylation Thr370 GNWRRGStAGGCRNY 9606 11909964 t llicata Activation of m-calpain (calpain ii) by epidermal growth factor is limited by protein kinase a phosphorylation of m-calpain.These Data point to a novel mechanism of negative control of calpain activation, direct phosphorylation by pka. SIGNOR-116248 0.265 ABL1 protein P00519 UNIPROT DDB2 protein Q92466 UNIPROT down-regulates phosphorylation 9606 12107171 t miannu C-abl might act as a negative regulator of uv-ddb by phosphorylating ddb2 SIGNOR-90446 0.47 RUNX1 protein Q01196 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0002580 34902205 t lperfetto RUNX1 transactivates BCR-ABL1 expression in Philadelphia chromosome positive acute lymphoblastic leukemia. SIGNOR-272145 0.2 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 19914161 t lpetrilli Phosphorylation of the linker region of Smads mediated by ERK2, GSK3β, and CDK2/4 negatively regulates Smad activity SIGNOR-161609 0.736 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 BTO:0000938 12040039 t gcesareni Stress in primary cultured cns neurons induces phosphorylation of c-jun serines 63 and 73 and increased c-jun protein. Jnk2/3 activity selectively targets c-jun. SIGNOR-88212 0.881 BCR protein P11274 UNIPROT YWHAZ protein P63104 UNIPROT unknown phosphorylation Thr232 LTLWTSDtQGDEAEA -1 16045749 t llicata We show here that BCR interacts with at least five isoforms of 14-3-3 in vivo and phosphorylates 14-3-3tau on Ser233 and to a lesser extent 14-3-3zeta on Thr233 SIGNOR-250595 0.337 SMARCE1 protein Q969G3 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270691 0.833 CYP21A2 protein P08686 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity chemical modification 9606 BTO:0000050 25855791 t lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively SIGNOR-268643 0.8 FOXP1 protein Q9H334 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 18640093 f Notably, we demonstrate that FOXP1 directly interacts with AR and negatively regulates AR signaling ligand-dependently, as exemplified by the transcriptional repression of PSA gene regulated by androgen-dependent FOXP1 recruitment on its enhancer region. SIGNOR-253660 0.278 MLLT3 protein P42568 UNIPROT SCNN1A protein P37088 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005545 20159978 f Regulation miannu AF9/MLLT3 contributes to the regulation of the gene encoding the epithelial sodium channel alpha, ENaCalpha, in renal tubular cells. Specifically, increases in AF9 protein lead to a reduction in ENaCalpha expression and changes in AF9 activity appear to be an important component of aldosterone signaling in the kidney. SIGNOR-251944 0.275 CKM complex complex SIGNOR-C406 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo. SIGNOR-273172 0.2 MAPK15 protein Q8TD08 UNIPROT MAPK15 protein Q8TD08 UNIPROT up-regulates phosphorylation Tyr177 EDQAVTEyVATRWYR 9606 16336213 t lperfetto Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif.Our results suggest that the activity of erk8 in transfected hek-293 cells depends on the relative rates of erk8 autophosphorylation SIGNOR-142973 0.2 GPR34 protein Q9UPC5 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256688 0.252 Myog/SWI/SNF complex complex SIGNOR-C94 SIGNOR MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 17194702 t miannu Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle SIGNOR-151697 0.632 LCK protein P06239 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 BTO:0000782;BTO:0001271 8992971 t lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor SIGNOR-45524 0.745 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI SAICAR(4-) smallmolecule CHEBI:58443 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). SIGNOR-267320 0.8 DRAM2 protein Q6UX65 UNIPROT RHOA protein P61586 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30755245 f irozzo Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. SIGNOR-259142 0.2 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9823 BTO:0001840 SIGNOR-C3 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-219266 0.924 MAP2K1 protein Q02750 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000011 12270934 t lperfetto MEK1 as indicated by extensive phosphorylation of ERK1 and ERK2 during the initial 2 h of adipogenesis. SIGNOR-235352 0.742 ESR1 protein P03372 UNIPROT MYC protein P01106 UNIPROT unknown transcriptional regulation 9606 BTO:0000356 11517191 f ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression SIGNOR-253941 0.718 IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Ser376 GSSPSQSsMVARTQT -1 11960013 t In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4. SIGNOR-251328 0.673 CYP2D6 protein P10635 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬† SIGNOR-263996 0.8 CREB1 protein P16220 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity transcriptional regulation 9606 26652733 t inferred from family member miannu Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB SIGNOR-267786 0.2 GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263777 0.7 MLL3 complex complex SIGNOR-C446 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 34156443 t miannu MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. SIGNOR-268810 0.2 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR LASP1 protein Q14847 UNIPROT unknown phosphorylation Tyr171 IPTSAPVyQQPQQQP 9606 BTO:0000664 24913448 t phosphorylation blocks localization at focal adhesion sites and induces binding to CRLK lperfetto LASP1 is a novel BCR-ABL substrate and a phosphorylation-dependent binding partner of CRKL in chronic myeloid leukemia|We demonstrate that LASP1 is specifically phosphorylated by BCR-ABL at tyrosine-171 in CML patients SIGNOR-271703 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR CDCA7 protein Q9BWT1 UNIPROT down-regulates phosphorylation Thr163 SRRPRRRtFPGVASR 9606 23166294 t llicata The prosurvival kinase akt phosphorylates cdca7 at threonine 163, promoting binding to 14-3-3, dissociation from myc, and sequestration to the cytoplasm. we have mapped the domains of interaction and have discovered that akt phosphorylates cdca7 near this contact region, leading to loss of its association with myc, binding to 14-3-3 proteins, and exclusion from the nucleus. SIGNOR-199776 0.2 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 BTO:0000007 SIGNOR-C3 SIGNOR-C3 19864431 t lperfetto Our data that insulin-stimulated raptor ser863 phosphorylation requires kinase-active mtorc1 and displays rapamycin sensitivity in intact cells, together with the data of wang et al. (67) that mtor phosphorylates raptor ser863 in vitro, strongly suggest that mtor itself mediates raptor ser863 phosphorylation. / strikingly, raptor ser863 phosphorylation is absolutely required for raptor ser859 and ser855 phosphorylation. These data suggest that mtorc1 activation leads to raptor multisite phosphorylation and that raptor ser863 phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation SIGNOR-188924 0.989 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser19 SHGSSACsQPHGSVT 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir SIGNOR-81391 0.829 Shikonin chemical CHEBI:81068 ChEBI PKM protein P14618 UNIPROT down-regulates activity chemical inhibition 9606 21516121 t lperfetto Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2. SIGNOR-262008 0.8 TWIST1 protein Q15672 UNIPROT RAP1A protein P62834 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255533 0.2 UTS2R protein Q9UKP6 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256779 0.252 pimozide chemical CHEBI:8212 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258841 0.8 TGFBR2 protein P37173 UNIPROT USP2 protein O75604 UNIPROT up-regulates activity phosphorylation Ser225 SRVPEIIsPTYRPIG -1 29490279 t miannu Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1. SIGNOR-273603 0.2 ABL1 protein P00519 UNIPROT JUN protein P05412 UNIPROT unknown phosphorylation Tyr170 LHSEPPVyANLSNFN 9606 10637231 t gcesareni After phosphorylation of c-Jun by Abl on Tyr170, both proteins interacted via the SH2 domain of Abl SIGNOR-245370 0.541 GAS2L1 protein Q99501 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 24706950 f miannu Previous work has shown that members of the growth-arrest-specific 2 (GAS2) family mediate the crosstalk between filamentous actin (F-actin) and MTs, but the molecular basis of this process remained unclear. By using fluorescence microscopy, we demonstrate that three members of this family, GAS2-like 1, GAS2-like 2 and GAS2-like 3 (G2L1, G2L2 and G2L3, also known as GAS2L1, GAS2L2 and GAS2L3, respectively) are differentially involved in mediating the crosstalk between F-actin and MTs.  SIGNOR-273700 0.7 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser118 GEAAEPGsPTAAEGE -1 8034575 t lperfetto Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | We conclude that the primary phosphorylation site is Ser116 | SIGNOR-248907 0.719 clomipramine chemical CHEBI:47780 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 t miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. SIGNOR-258876 0.8 MAPK1 protein P28482 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 12050114 t gcesareni Tob is rapidly phosphorylated at ser 152, ser 154, and ser 164 by erk1 and erk2 upon growth-factor stimulation. SIGNOR-88724 0.361 PTPN9 protein P43378 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation 10029 BTO:0000246 12907755 t Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR SIGNOR-248505 0.319 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Tyr) smallmolecule CHEBI:29182 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269499 0.8 GRPR protein P30550 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256774 0.252 SMO protein Q99835 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 10090 BTO:0002572 16885213 t gcesareni We found that Smo, by virtue of what appears to be constitutive activity, activates all members of the G(i) family but does not activate members of the G(s), G(q), and G(12) families. The activation is suppressed by cyclopamine and other inhibitors of Hedgehog signaling and is enhanced by the Smo agonist purmorphamine. SIGNOR-148487 0.496 MAPK3 protein P27361 UNIPROT LAT protein O43561 UNIPROT down-regulates phosphorylation Thr184 PSAPALStPGIRDSA 9606 15192708 t The effect has been demonstrated using O43561-2 gcesareni Lat, an adapter protein essential for t-cell signaling, is phosphorylated at its thr 155 by erk in response to t-cell receptor stimulation. Thr 155 phosphorylation reduces the ability of lat to recruit plcgamma1 and slp76, leading to attenuation of subsequent downstream events such as [ca2+]i mobilization and activation of the erk pathway. SIGNOR-125770 0.309 BRAF protein P15056 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser467 GQRIGSGsFGTVYKG 9606 31929109 t miannu We previously identified that BRAFWT can autophosphorylate its P-loop (Ser-465/Ser-467) to inactivate itself in the absence of native substrate MEK SIGNOR-277499 0.2 EFNB1 protein P98172 UNIPROT EPHB4 protein P54760 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52580 0.744 SMC6 protein Q96SB8 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR form complex binding -1 27427983 t miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks SIGNOR-265482 0.897 ROCK2 protein O75116 UNIPROT LPP protein Q93052 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22886954 f miannu Inactivation of rho kinase (rok) with rok inhibitors significantly inhibited lpp mrna expression SIGNOR-191765 0.267 MAML1 protein Q92585 UNIPROT EP300 protein Q09472 UNIPROT up-regulates binding 9606 16530044 t gcesareni Maml-1 is preassociated with other components of the transcriptional machinery, such as p300 SIGNOR-145057 0.636 GRK2 protein P25098 UNIPROT OXTR protein P30559 UNIPROT down-regulates activity phosphorylation 9534 BTO:0000298 16179383 t miannu Recent experiments in COS-7 cells transfected with OTR have demonstrated that a rapid GRK2-mediated phosphorylation of the agonist-occupied OTR is a key first step leading to its desensitization, and that it precedes and is required for β-arrestin-dependent internalization SIGNOR-270329 0.2 SMC2 protein O95347 UNIPROT Condensin II complex SIGNOR-C342 SIGNOR form complex binding 9606 32445620 t miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263908 0.812 ACD protein Q96AP0 UNIPROT RPA3 protein P35244 UNIPROT down-regulates activity binding SIGNOR-C306 18680434 t lperfetto The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA SIGNOR-263329 0.2 ZIC1 protein Q15915 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 BTO:0002181 11238441 f fspada Moreover, gli proteins were translocated to cell nuclei by coexpressed zic proteins, and both proteins regulated each others transcriptional activity.In Nih3t3 and 293t cells, both gli1 and gli3 proteins were located predominantly in the cytoplasm (fig. 2, c, d, h, k, l, and p). Coexpression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels (fig. 2, e and m). SIGNOR-105494 0.385 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser345 PLVSDEKsSELIITD -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276198 0.388 PRKD1 protein Q15139 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP. SIGNOR-249260 0.2 PLK1 protein P53350 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity phosphorylation Thr406 AVYTKMMtKKPGMFF 9606 BTO:0000007 29138396 t lperfetto We find that Plk1 interacts with and directly phosphorylates glucose-6-phosphate dehydrogenase (G6PD). By activating G6PD through promoting the formation of its active dimer, Plk1 increases PPP flux and directs glucose to the synthesis of macromolecules.|the kinase domain of Plk1 phosphorylates T406, T466 of G6PD SIGNOR-267580 0.353 lidocaine chemical CHEBI:6456 ChEBI SCN2A protein Q99250 UNIPROT down-regulates activity chemical inhibition 10116 1658608 t miannu This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner. SIGNOR-258354 0.8 EP300 protein Q09472 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11796223 t lperfetto Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription. SIGNOR-232159 0.731 Factor VIIIa-IXa complex SIGNOR-C320 SIGNOR F10 protein P00742 UNIPROT up-regulates activity cleavage 10090 BTO:0000131 25769543 t lperfetto The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin. SIGNOR-263538 0.553 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9606 BTO:0000007 20048145 t lperfetto Herein, we demonstrate that the n-terminal kinase domain (ntk) of rsk1 is necessary for interactions with pkarialpha. Substitution of the activation loop phosphorylation site (ser-221) in the ntk with the negatively charged asp residue abrogated the association between rsk1 and pkarialpha. SIGNOR-252785 0.6 QRICH1 protein Q2TAL8 UNIPROT EARS2 protein Q5JPH6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269402 0.2 BLK protein P51451 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268208 0.633 RB1 protein P06400 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates activity binding 9606 8255752 t amattioni E2f binds rb. E2f activation domain is the target for rb-induced repression. Rb can silence the 57 residue e2f activation domain. Rb can mask e2f residues involved in the activation process, possibly by mimicking a component of the transcriptional machinery SIGNOR-37305 0.918 HRH1 protein P35367 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256778 0.2 PRKACA protein P17612 UNIPROT NOS1 protein P29475 UNIPROT unknown phosphorylation -1 1375933 t miannu NOS is stoichiometrically phosphorylated by PKA, PKC, and CaMK, with each enzyme predominantly phosphorylating a distinct serine. CPT-CAMP has no effect on NOS activity SIGNOR-250021 0.327 PI3K complex SIGNOR-C156 SIGNOR PIK3CB protein P42338 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-252719 0.623 Nalmefene chemical CHEBI:7457 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258812 0.8 phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI WASL protein O00401 UNIPROT up-regulates activity chemical activation 9606 10219243 t lperfetto In the presence of Cdc42 and PI(4,5)P2, the potency of N-WASP was increased to a level approaching that of GST-VCA, suggesting that N-WASP was fully activated by the two molecules. SIGNOR-261870 0.8 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2N protein P61088 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271354 0.753 miR-495 mirna URS000075C517_9606 RNAcentral Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 19219026 t Luana Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells.  SIGNOR-268044 0.4 DVL3 protein Q92997 UNIPROT CSNK1E protein P49674 UNIPROT up-regulates binding 9606 10535959 t gcesareni Ckiepsilon was in a complex with axin and other downstream components of the wnt pathway, including dishevelled. SIGNOR-71759 0.655 PKA proteinfamily SIGNOR-PF17 SIGNOR MYOM1 protein P52179 UNIPROT down-regulates activity phosphorylation Ser618 ARLKSRPsAPWTGQI -1 9029142 t miannu This interaction is regulated by phosphorylation of Ser482 in the linker between myomesin domains My4 and My5. Myomesin phosphorylation at this site by cAMP-dependent kinase and similar or identical activities in muscle extracts block the association with titin. SIGNOR-263156 0.2 MBTPS1 protein Q14703 UNIPROT CREB3L1 protein Q96BA8 UNIPROT up-regulates cleavage 9606 16417584 t miannu Cleavage of oasis by site-1 and site-2 proteases / oasis is cleaved at the membrane under er stress conditions and that its cleaved n-terminal domain translocates into the nucleus;and then activates transcription of target genes SIGNOR-143785 0.553 ETS1 protein P14921 UNIPROT GFI1 protein Q99684 UNIPROT down-regulates activity binding 9606 BTO:0002181 17213822 t miannu Co-immunoprecipitation analyses and glutathione-S-transferase pull-down assays revealed that ETS1 bound directly to GFI1 via its Ets domain, and GFI1 bound to ETS1 via its zinc-finger domain. Luciferase (Luc) assays using artificial reporters showed that GFI1 repressed ETS1-mediated transcriptional activation and ETS1 repressed GFI1-mediated transcriptional activation, in a dose-dependent manner. SIGNOR-254202 0.436 PCC complex SIGNOR-C414 SIGNOR propionyl-CoA(4-) smallmolecule CHEBI:57392 ChEBI down-regulates quantity chemical modification 9606 15890657 t miannu Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively. SIGNOR-267184 0.8 STAT2 protein P52630 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR form complex binding -1 8943351 t 2 miannu The first STAT-containing transcription factor to be studied, the alpha-interferon-induced ISGF3, is composed of a Stat1:2 heterodimer and a weak DNA-binding protein, p48. The p48 and Stat1:2 heterodimer do not associate stably in the absence of DNA, but we show that amino acids approximately 150 to 250 of Stat1 and a COOH-terminal portion of p48 exhibit physical interaction, implying contact that stabilizes ISGF3 SIGNOR-240603 0.727 ZNF503 protein Q96F45 UNIPROT GATA3 protein P23771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 28258171 f Monia Intriguingly, ZPO2/ZNF503 levels were higher in breast cancer samples with WT GATA3 than in those with mutated GATA3 (Fig. 1B). We found that Zpo2 down-regulated GATA3 levels, whereas shRNA-mediated Zpo2 knockdown enhanced GATA3 expression SIGNOR-261189 0.26 CDC14B protein O60729 UNIPROT SKP2 protein Q13309 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser64 SNLGHPEsPPRKRLK 9606 18239684 t The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1). SIGNOR-248333 0.364 SOX2 protein P48431 UNIPROT ABCC6 protein O95255 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21531766 f miannu ID4-mediated SOX2 induction enhanced ABCC3 and ABCC6 expression through direct transcriptional regulation, indicating that ID4 regulates the chemoresistance of iGSCs by promoting SOX2-mediated induction of ABC transporters. SIGNOR-255182 0.286 ERCC8 protein Q13216 UNIPROT RAD23B protein P54727 UNIPROT up-regulates activity 24086043 f lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275693 0.535 MAVS protein Q7Z434 UNIPROT IFNB1 protein P01574 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22588174 f Giorgia ECSIT enhances IPS-1-mediated IFN-Beta promoter activation SIGNOR-260372 0.501 clomipramine chemical CHEBI:47780 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 t miannu At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter.  SIGNOR-258874 0.8 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002882 15769897 t we observed constitutive activation of Erk-1 and Erk-2, Akt, and of Shc by both Flt3-ITD and Flt3-D835Y SIGNOR-261540 0.434 MAPK8 protein P45983 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr275 TTGTKSNtPTSSVPS 9606 15767678 t gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. SIGNOR-134545 0.715 CDH1 protein P12830 UNIPROT CTNNA1 protein P35221 UNIPROT up-regulates binding 9606 24336504 t milica Additionally, the E-cadherin associated protein _-catenin regulates YAP directly by sequestering YAP/14-3-3 complexes in the cytoplasm. SIGNOR-203468 0.673 SPOP protein O43791 UNIPROT PDX1 protein P52945 UNIPROT down-regulates quantity ubiquitination 10090 BTO:0000783 20811152 t Gianni Pdx1 C terminus-interacting factor-1 (Pcif1, also known as SPOP) is a nuclear protein that inhibits Pdx1 transactivation. Here, we show that Pcif1 targets Pdx1 for ubiquitination and proteasomal degradation. SIGNOR-268859 0.332 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr8 MSSILPFtPPIVKRL 9606 15241418 t lperfetto We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity, SIGNOR-217734 0.733 RET protein P07949 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 21454698 t gcesareni The identification of focal adhesion kinase (fak) as a direct substrate for ret kinase revealed (i) a ret-fak transactivation mechanism consisting of direct phosphorylation of fak tyr-576/577 by ret and a reciprocal phosphorylation of ret by fak, which crucially is able to rescue the kinase-impaired ret k758m mutant and (ii) that fak binds ret via its ferm domain. Interestingly, this interaction is abolished upon ret phosphorylation, indicating that ret binding to the ferm domain of fak is a priming step for ret-fak transactivation. SIGNOR-173013 0.623 LCK protein P06239 UNIPROT ITK protein Q08881 UNIPROT up-regulates phosphorylation Tyr512 RFVLDDQyTSSTGTK -1 9312162 t Lck phosphorylates the activation loop tyrosine of the Itk kinase domain and activates Itk kinase activity. The major site of Lck phosphorylation on Itk was mapped to the conserved tyrosine (Tyr511) in the activation loop of the Itk kinase domain. SIGNOR-251380 0.535 AKT2 protein P31751 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-217463 0.439 RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000848 18246127 t lperfetto To understand the mechanisms underlying B-RAF effects on cell survival we initially analysed the Bcl-2 family protein, Bad, that is phosphorylated by RSK1 at the inhibitory serine-75 residue in a MEK-dependent manner in melanoma cells SIGNOR-160635 0.404 IL1B protein P01584 UNIPROT CTSK protein P43235 UNIPROT up-regulates quantity by expression transcriptional regulation 11920402 f lperfetto This is supported by our finding that inflammatory cytokines such as IL-1b and TNFa increase the expres- sion of cathepsin K mRNA 􏰌6–8-fold and increase the secretion of the mature enzyme. SIGNOR-253316 0.339 CHUK protein O15111 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 SIGNOR-C14 15084260 t gcesareni Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation. SIGNOR-124203 0.554 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914161 t lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 SIGNOR-161613 0.736 IL1RN protein P18510 UNIPROT IL1R1 protein P14778 UNIPROT down-regulates activity binding 9606 2876877 t Gianni Homozygous truncating mutations result in lack of secreted interleukin-1–receptor antagonist protein, which inhibits the proinflammatory cytokines interleukin-1α and interleukin-1β SIGNOR-262302 0.894 RAC1 protein P63000 UNIPROT PAK proteinfamily SIGNOR-PF13 SIGNOR up-regulates activity binding 10090 BTO:0000142 8107774 t gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. SIGNOR-248256 0.782 BAD protein Q92934 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203 23725574 f irozzo Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions. SIGNOR-256260 0.7 MYCBP2 protein O75592 UNIPROT TSC complex SIGNOR-C101 SIGNOR down-regulates ubiquitination 10116 BTO:0001009 14559897 t Monia Pam Interacts with the Tuberin-Hamartin Complex—To examine the in vivo association of tuberin and Pam, we performed co-immunoprecipitation experiments in PC12 cells and rat embryonic brain. Immunoprecipitation of tuberin using an anti-tuberin antibody followed by immunoblot analysis showed that endogenous Pam co-immunoprecipitates with tuberin in PC12 cells and embryonic rat brain. Pam Homolog HIW Modulates Tsc1Tsc2 Activity in Drosophila. The enhancement of Tsc1Tsc2 phenotype by the removal of the hiw gene indicates that hiw negatively regulates Tsc1Tsc2 activity in Drosophila eye. Taken together, it is probable that Pam may function as an E3 ligase for tuberin and regulate the ubiquitination and proteasomal degradation of the tuberinhamartin complex particularly in the CNS SIGNOR-261202 0.32 CCNO protein P22674 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity binding 9606 BTO:0000007 25364462 t lperfetto Phosphorylation of cyclin O, a novel cyclin family protein containing a cyclin-like domain, is involved in the activation of cyclin-dependent kinase 2|This activity was reduced in cells overexpressing cyclin O, in which the 81st serine had been replaced with alanine (S81A). These results suggest that cyclin O is a novel cyclin family protein that regulates CDK2 kinase activity, which is mediated by the phosphorylation of the 81st serine residue of cyclin O SIGNOR-275616 0.465 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity phosphorylation Tyr424 GQVGTARyMAPEVLE -1 9169454 t lperfetto Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor. SIGNOR-48867 0.2 CDK5 protein Q00535 UNIPROT DLC1 protein Q96QB1 UNIPROT up-regulates activity phosphorylation Ser642 DSFGSLPsPKELSSF 9606 BTO:0002181 25452387 t miannu The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin.  SIGNOR-276444 0.2 PDXP protein Q96GD0 UNIPROT CFL1 protein P23528 UNIPROT down-regulates activity dephosphorylation Ser3 sGVAVSDG -1 15580268 t Chronophin, a novel HAD-type serine protein phosphatase, regulates cofilin-dependent actin dynamics|Cofilin is a key regulator of actin cytoskeletal dynamics whose activity is controlled by phosphorylation of a single serine residue. We report the biochemical isolation of chronophin (CIN), a unique cofilin-activating phosphatase of the haloacid dehalogenase (HAD) superfamily. SIGNOR-248764 0.458 serotonin smallmolecule CHEBI:28790 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258846 0.8 EEF1A2 protein Q05639 UNIPROT Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269538 0.8 TIGIT protein Q495A1 UNIPROT ARRB2 protein P32121 UNIPROT up-regulates activity binding 9606 BTO:0000914 24817116 t lperfetto With TIGIT/PVR engagement, cytoplasmic TIGIT was phosphorylated at Tyr-225 and Tyr-231 residues. Phosphorylated Tyr-225 recruits adaptor protein beta arrestin 2|TIGIT/PVR signaling mediates suppression of IFN- gamma production via the NF-kappaB pathway. We identified a new adaptor β-arrestin 2 that associates with phosphorylated TIGIT and mediates recruitment of inositol phosphatase SHIP1 through the ITT-like motif (Fig. 7). Finally, SHIP1 impairs TRAF6 autoubiquitination to abolish NF-kappaB activation, leading to inhibition of IFN- gamma production in NK cells. SIGNOR-261482 0.2 ARID1A protein O14497 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 t miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270611 0.801 idelalisib chemical CHEBI:82701 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190813 0.8 SRMS protein Q9H3Y6 UNIPROT DOK1 protein Q99704 UNIPROT unknown phosphorylation 9606 BTO:0000007 23822091 t lperfetto These data indicate that ectopically‐expressed GFP‐SRMS interacts with and mediates the phosphorylation of overexpressed GFP‐Dok1. SIGNOR-264569 0.424 MED16 protein Q9Y2X0 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266671 0.783 GOT1 protein P17174 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-267506 0.8 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser723 VITIDPAsPQSPESV 9606 11604491 t llicata Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728. SIGNOR-111039 0.553 MAPK3 protein P27361 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation Ser432 NQNVLLMsPPASDSG 9606 14988395 t lperfetto Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity. SIGNOR-123049 0.4 ECM stimulus SIGNOR-ST20 SIGNOR A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259047 0.7 NEK6 protein Q9HC98 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser377 PPFNPNVsGPNDLRH -1 12023960 t miannu The present study is the first report of a protein kinase (NEK6) capable of phosphorylating the hydrophobic motif of SGK1, although our data suggest that NEK6 may not mediate this reaction in cells. Nevertheless, the phosphorylation of the hydrophobic motif of SGK1in vitro, coupled with the phosphorylation of the T-loop with PDK1, may be a useful way of generating fully active wild type SGK1. Ser377 and Ser422of SGK1, and the CDK7 T-loop peptide, which are phosphorylated by NEK6. SIGNOR-250296 0.344 SLC34A1 protein Q06495 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI up-regulates quantity relocalization 9606 BTO:0000671 20335586 t lperfetto Genetic analysis revealed a homozygous in-frame duplication of 21 bp in SLC34A1, which encodes the renal sodium-inorganic phosphate cotransporter NaPi-IIa, SIGNOR-270576 0.8 AMHR2 protein Q16671 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates binding 9606 14746809 t gcesareni See table2 SIGNOR-121596 0.44 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74831 0.783 ALPL protein P05186 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity dephosphorylation 9606 24646911 t miannu TNAP dephosphorylates overphosphorylated tau once it is released upon neuronal death. SIGNOR-277097 0.2 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Ser4523 GSRHSLAsTDEKREL 9606 15272003 t lperfetto Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc. SIGNOR-127211 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ARHGAP26 protein Q9UNA1 UNIPROT unknown phosphorylation -1 9525907 t inferred from 70% family members miannu In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling. SIGNOR-270170 0.2 MDM4 protein O15151 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization 9606 15735705 f lperfetto Mdm2 and mdmx function as cellular regulators of the p53 tumor suppressor protein. Intriguingly, the activities of these proteins are interdependent;mdmx stabilizes mdm2, enabling its activities towards p53 SIGNOR-134391 0.722 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH20 protein Q9HBT6 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265837 0.8 mTORC1 complex SIGNOR-C3 SIGNOR EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser74 ERYSSSGsPANSFHF 9606 BTO:0000093 35513296 t miannu Our phosphoproteomics analysis add to this body of knowledge as it indicates that mTORC1 modulates additional phosphorylation sites in eEF2K, such as Y69, S70, S72, and S74, which is consistent with our previous findings SIGNOR-277907 0.348 mTORC1 complex SIGNOR-C3 SIGNOR EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser70 LTKSERYsSSGSPAN 9606 BTO:0000093 35513296 t miannu Our phosphoproteomics analysis add to this body of knowledge as it indicates that mTORC1 modulates additional phosphorylation sites in eEF2K, such as Y69, S70, S72, and S74, which is consistent with our previous findings SIGNOR-277908 0.348 mTORC1 complex SIGNOR-C3 SIGNOR EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Tyr69 NLTKSERySSSGSPA 9606 BTO:0000093 35513296 t miannu Our phosphoproteomics analysis add to this body of knowledge as it indicates that mTORC1 modulates additional phosphorylation sites in eEF2K, such as Y69, S70, S72, and S74, which is consistent with our previous findings SIGNOR-277909 0.348 PTK2B protein Q14289 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity phosphorylation Tyr591 KFDKQKLyYHATKAM 9606 BTO:0002181 37989995 t miannu  Mechanistically, we demonstrate that PTK2B directly phosphorylates residue Tyr591 of TBK1, which increases TBK1 oligomerization and activation. SIGNOR-277910 0.269 PRKDC protein P78527 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates quantity by destabilization phosphorylation Ser636 SRRPRYDsYEEYQHE 9606 BTO:0005949 36696363 t miannu Mechanistically, PGC1α was phosphorylated at serine (S) 636 by DNA-dependent protein kinase in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC1α by facilitating its binding to the E3 ligase RNF34.  SIGNOR-277911 0.2 RNF34 protein Q969K3 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0005949 36696363 t miannu Mechanistically, PGC1α was phosphorylated at serine (S) 636 by DNA-dependent protein kinase in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC1α by facilitating its binding to the E3 ligase RNF34.  SIGNOR-277912 0.325 atomoxetine chemical CHEBI:127342 ChEBI SLC6A3 protein Q01959 UNIPROT down-regulates activity chemical inhibition -1 9871604 t miannu The gamma-amino alcohol/ether unit contained in venlafaxine, 2 fluoxetine, 3 and tomoxetine 3 has been prepared by a sequence of nitrile aldol reaction and nitrile reduction. Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. SIGNOR-259070 0.8 CHEK1 protein O14757 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates quantity by destabilization phosphorylation Ser20 QLKRWIGsETDLEPP 9606 BTO:0000567 29262732 t miannu  MYPT1 is phosphorylated by CDK1, thus recruiting protein phosphatase 1β (PP1cβ) to dephosphorylate and inactivate Plk1. Here we identified that Chk1 directly interacts with MYPT1 and preferentially phosphorylates MYPT1 at Ser20, which is essential for MYPT1-PP1cβ interaction and subsequent Plk1 dephosphorylation. SIGNOR-277870 0.2 PLK1 protein P53350 UNIPROT ARHGDIA protein P52565 UNIPROT up-regulates activity phosphorylation Thr91 GPLELDLtGDLESFK 9606 BTO:0000567 38355643 t miannu PLK1 phosphorylates RhoGDI1 at Thr7/91 residue in vitro and in vivo. Collectively, we demonstrate that the phosphorylation of RhoGDI1 by PLK1 promotes cancer cell migration and invasion through RhoA activation. SIGNOR-277882 0.2 PLK1 protein P53350 UNIPROT ARHGDIA protein P52565 UNIPROT up-regulates activity phosphorylation Thr7 tAEQLAQI 9606 BTO:0000567 38355643 t miannu PLK1 phosphorylates RhoGDI1 at Thr7/91 residue in vitro and in vivo. Collectively, we demonstrate that the phosphorylation of RhoGDI1 by PLK1 promotes cancer cell migration and invasion through RhoA activation. SIGNOR-277883 0.2 GSK3B protein P49841 UNIPROT ATP2A2 protein P16615 UNIPROT down-regulates activity phosphorylation Ser663 EFDELNPsAQRDACL 9606 BTO:0000562 37291092 t miannu GSK3β-dependent phosphorylation of SERCA2 at serine 663 in human and mouse hearts. Phosphorylation of SERCA2 at serine 663 regulates SERCA2 activity.  SIGNOR-277886 0.287 MAP3K7 protein O43318 UNIPROT STING1 protein Q86WV6 UNIPROT up-regulates activity phosphorylation Ser355 TSAVPSTsTMSQEPE -1 37832545 t miannu Activated TAK1 directly mediates STING phosphorylation on serine 355, which facilitates its interaction with STING ER exit protein (STEEP) and thereby promotes its oligomerization and translocation to the ERGIC for subsequent activation SIGNOR-277887 0.2 CSNK2A1 protein P68400 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity phosphorylation Thr145 FYLALPPtVYEAVTK 9606 BTO:0002923 37478541 t miannu CK2 phosphorylates G6PD T145 under ionizing radiation  SIGNOR-277890 0.2 CSNK1A1 protein P48729 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Ser269 QVRVGGSsVDLHRFH 9606 24412065 t miannu Moreover, CK1α phosphorylates p120-catenin on Ser268 and Ser269, releasing this protein from the signalosome and facilitating the subsequent phosphorylation of cadherin and the disruption of this cadherin interaction with LRP5/6 SIGNOR-277893 0.2 AMPK complex SIGNOR-C15 SIGNOR PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser314 IQEVRSKsDPIMLLK -1 33022274 t miannu AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively.  SIGNOR-277894 0.257 AKT proteinfamily SIGNOR-PF24 SIGNOR PALLD protein Q8WX93 UNIPROT unknown phosphorylation Ser1118 VRRPRSRsRDSGDEN 9606 20471940 t llicata Akt1, but not akt2, phosphorylates palladin at ser507 in a domain that is critical for f-actin bundling. SIGNOR-165497 0.2 SNS-314 Mesylate chemical CID:24995523 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207099 0.8 AMPK complex SIGNOR-C15 SIGNOR PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser295 RYHGHSMsDPGVSYR -1 33022274 t miannu AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively.  SIGNOR-277895 0.257 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates activity phosphorylation Tyr191 SRLLHSDyMNMTPRR 8992971 t EMT can phosphorylate all four tyrosines of the CD28 tail. in vivo, tyrosines other than tyrosine 173 become phosphorylated following CD28 stimulation, this finding suggests that, like LCK, one function of EMT during CD28 signaling is phosphorylation of the receptor. SIGNOR-251336 0.677 SNAI2 protein O43623 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 20509143 f miannu SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness. SIGNOR-255154 0.432 ABL1 protein P00519 UNIPROT PSMA7 protein O14818 UNIPROT down-regulates phosphorylation Tyr153 QTDPSGTyHAWKANA 9606 16678104 t lperfetto Proteasome-mediated proteolysis is a primary protein degradation pathway in cells. The present study demonstrates that c-abl and arg (abl-related gene) tyrosine kinases associate with and phosphorylate the proteasome psma7 (alpha4) subunit at tyr-153. Consequently, proteasome-dependent proteolysis is compromised SIGNOR-146585 0.406 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr252 HDGTVTHtFCGTIEY 9606 9445476 t gcesareni A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-55306 0.716 ABL2 protein P42684 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Tyr78 RAIDFSPyLEPLGAP 9606 BTO:0000007 19563810 t gcesareni The y79 amino acid residue of c/ebpbeta was phosphorylated by c-abl or arg. The phosphorylation of c/ebpbeta resulted in an increased c/ebpbeta stability and a potentiation of c/ebpbeta transcription activation activity in cells SIGNOR-186427 0.278 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A9/b1 integrin complex SIGNOR-C166 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259020 0.408 HTR4 protein Q13639 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257309 0.252 CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity binding 9606 23151663 t gcesareni Upon wnt activation, cytoplasmic beta-catenin is stabilized and enters the nucleus, where it associates with transcription factors, notably tcf (t cell factor) and lef (lymphoid enhancer-binding factor), to regulate the transcription of target genes. Thus beta-catenin regulates gene expression by direct interaction with transcription factors such as lef-1, providing a molecular mechanism for the transmission of signals, from cell-adhesion components or wnt protein to the nucleus. SIGNOR-199378 0.914 ROCK1 protein Q13464 UNIPROT RDX protein P35241 UNIPROT unknown phosphorylation Thr573 RQIRQGNtKQRIDEF -1 9456324 t lperfetto  A peak of the phosphopeptide, in which only T573 was phosphorylated, was not detected. Quantitative analyses revealed that _100% of T564, but at most _40% of T573, was phosphorylated when C-rad was incubated with Rho-Kc for 1 h. Then we concluded that the major and primary phosphorylation site of radixin by Rho-kinase was T564 and referred to the Rho-Kc€“phosphorylated C-rad as T564-phosphorylated C-rad. SIGNOR-248995 0.666 NPTX1 protein Q15818 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity relocalization 10090 23069675 t lperfetto Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4 h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential SIGNOR-261439 0.2 PLK2 protein Q9NYY3 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates phosphorylation Ser589 EQAADEIsFSSNSSF 9606 20531387 t lperfetto Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. SIGNOR-165999 0.561 DDX21 protein Q9NR30 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 t miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription SIGNOR-268824 0.422 CDK5 protein Q00535 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Thr509 PVFDLTTtPKGGTPA 9606 16611631 t lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro SIGNOR-145967 0.587 POLR2K protein P53803 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266150 0.856 CCKAR protein P32238 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256906 0.267 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPC5 protein Q9UL62 UNIPROT down-regulates activity phosphorylation Ser794 SGGARAKsKSVSFNL 9606 BTO:0000007 21734191 t miannu We show that TRPC5 channels may become directly phosphorylated by PKA at serine residues 794 and 796, and that this phosphorylation abolishes the receptor-operated nonselective cation current mediated by TRPC5 channels in HEK-293 cells. SIGNOR-276340 0.2 CCND1 protein P24385 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR form complex binding 9606 7736585 t gcesareni D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb, SIGNOR-32298 0.964 CAMK2A protein Q9UQM7 UNIPROT CLCN3 protein P51790 UNIPROT up-regulates activity phosphorylation Ser109 ERHRRINsKKKESAW 14754994 t lperfetto Identification of an N-terminal amino acid of the CLC-3 chloride channel critical in phosphorylation-dependent activation of a CaMKII-activated chloride current|The N-terminus of CLC-3, which contains a CaMKII consensus sequence, was phosphorylated by CaMKII in vitro, and mutation of the serine at position 109 (S109A) abolished the CaMKII-dependent Cl(-) conductance, indicating that this residue is important in the gating of CLC-3 at the plasma membrane. SIGNOR-275863 0.343 CDK1 protein P06493 UNIPROT NUP210 protein Q8TEM1 UNIPROT up-regulates activity phosphorylation Ser1881 SPPSGLWsPAYASH -1 8672508 t miannu In vitro phosphorylation of GST fusion protein containing the carboxyl-terminal domain of gp210 by cyclin B-p34cdc2 protein kinase generates a phosphopeptide that comigrates with a mitosis-specific phosphopeptide. Ser1880 Is the Mitotic Phosphorylation Site of Gp210. SIGNOR-262699 0.53 DLK1 protein P80370 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 22640926 f fspada We conclude that DLK1(PREF1) is well expressed in human ASC and acts as a negative regulator of adipogenesis. SIGNOR-197634 0.7 PTPRA protein P18433 UNIPROT VPS33B protein Q9H267 UNIPROT down-regulates activity dephosphorylation 9606 18474358 t lperfetto Here, we report that VPS33B, a host protein involved in vesicle trafficking, is dephosphorylated by PtpA leading to a block of phagosome maturation by M. tuberculosis.|These data suggest that M. tuberculosis PtpA inhibits phagosome maturation.To assess the role of VPS33B in phagosome maturation, we attenuated the expression of endogenous VPS33B expression in THP-1 cells using a siRNA based approach. SIGNOR-277015 0.2 resveratrol chemical CHEBI:27881 ChEBI SIRT1 protein Q96EB6 UNIPROT up-regulates activity chemical activation -1 12939617 t gcesareni We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53 SIGNOR-238786 0.8 SH3RF1 protein Q7Z6J0 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 t gcesareni We confirmed that posh binds activated rac1 and find that it also binds all mlk family members tested and interacts with mkk4/7 as well as jnk1 and jnk2. SIGNOR-96952 0.315 CSNK2A1 protein P68400 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser92 VAELTSLsDEDSGKG 9606 19923321 t lperfetto Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively. SIGNOR-161775 0.355 P2RY4 protein P51582 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257122 0.2 venlafaxine chemical CHEBI:9943 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 20378347 t Luana The cycloalkanol ethylamine scaffold was successfully utilized in the discovery and development of dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitors (SNRIs).1 Drugs such as venlafaxine (1) and duloxetine (2) possessing norepinephrine reuptake inhibition, either selectively or in combination with serotonin reuptake inhibition were approved for major depressive disorder (MDD). SIGNOR-257836 0.8 WWP2 protein O00308 UNIPROT EGR2 protein P11161 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 19651900 t lperfetto The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-induced T-cell death by catalyzing EGR2 ubiquitination|AIP2 interacts with and promotes ubiquitin-mediated degradation of EGR2, a zinc finger transcription factor that has been found to regulate Fas ligand (FasL) expression during activation-induced T-cell death. SIGNOR-268849 0.38 MAP1LC3A protein Q9H492 UNIPROT ATG3 protein Q9NT62 UNIPROT up-regulates binding 9606 22170151 t gcesareni Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe. SIGNOR-191543 0.85 MAPK3 protein P27361 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 28646232 t Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels SIGNOR-262520 0.355 CSNK2A1 protein P68400 UNIPROT ANP32B protein Q92688 UNIPROT up-regulates phosphorylation Thr244 GEKRKREtDDEGEDD 9606 19130553 t gcesareni Here, we are able to report that casein kinase 2 (ck2) phosphorylates april on residue threonine244 (thr(244)) and demonstrate that the ck2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes cd83 expression in activated jurkat t cells by interfering with the nucleocytoplasmic translocation of cd83 mrna SIGNOR-183158 0.235 AHSA1 protein O95433 UNIPROT GCH1 protein P30793 UNIPROT up-regulates activity binding 9606 BTO:0001519 16696853 t miannu The interaction of GCH1 with Aha1 may recruit GCH1 into the eNOS/Hsp90 complex so as to support local changes in nitric oxide production by endothelial cells. SIGNOR-252213 0.301 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser266 FGYGGRAsDYKSAHK -1 2413024 t miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-163 SIGNOR-250013 0.353 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates phosphorylation Ser359 SALSYLQsPITTSPS 9606 10617468 t lperfetto Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein. SIGNOR-73621 0.798 RPS6KA1 protein Q15418 UNIPROT CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser173 PGKRRTQsLSALPKE 9606 BTO:0000848 21087211 t gcesareni Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3) SIGNOR-169883 0.2 FCRL3 protein Q96P31 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding -1 12051764 t miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. SIGNOR-274012 0.372 F12 protein P00748 UNIPROT F11 protein P03951 UNIPROT up-regulates activity cleavage 9606 BTO:0000131 8427954 t lperfetto Activation of factor XI in plasma is dependent on factor XII | Similar kinetics of factor XI cleavage are seen when 40 nmol/L factor XIIa (equal to 10% of factor XII activation) is added to factor XII-deficient plasma if an activating surface is provided. SIGNOR-263519 0.472 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269383 0.719 SMARCC1 protein Q92922 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 t miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. SIGNOR-132933 0.858 APEX1 protein P27695 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto An essential role of BER has been documented by inactivating functions of proteins in the common steps of BER. Thus, the major AP-endonuclease in mammalian cells, APE1, is essential for survival, as shown using knockout mice (Friedberg and Meira 2006). APE1 (also called HAP1 and Apex) carries both an AP-endonuclease activity and a redox function required for activation of several transcription factors SIGNOR-275721 0.7 PAK1 protein Q13153 UNIPROT DYNLL1 protein P63167 UNIPROT down-regulates phosphorylation Ser88 VAILLFKsG 9606 BTO:0000149 18084006 t lperfetto Dlc1 phosphorylation on ser(88) by p21-activated kinase 1 (pak1), a signaling nodule, promotes mammalian cell survival by regulating its interaction with bim and the stability of bim. Here we discovered that phosphorylation of ser(88), which juxtapose each other at the interface of the dlc dimer, disrupts dlc1 dimer formation and consequently impairs its interaction with bim SIGNOR-159995 0.386 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Thr346 TGENAGQtPMNINPQ 26375055 t lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity SIGNOR-276525 0.265 STX11 protein O75558 UNIPROT STX11-SNAP23 SNARE complex complex SIGNOR-C272 SIGNOR form complex binding 9606 BTO:0000132 22767500 t lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23.  SIGNOR-261894 0.735 MAST3 protein O60307 UNIPROT PTEN protein P60484 UNIPROT up-regulates binding 9606 15951562 t miannu Pten binds to and is phosphorylated by mast kinases./ Pdz domain-mediated binding to pten facilitates its phosphorylation by mast kinases / pdz domain binding increases pten protein stability. SIGNOR-138077 0.585 PTGER2 protein P43116 UNIPROT GNAS protein P63092 UNIPROT up-regulates binding 9606 16293724 t gcesareni Pge2 receptors are coupled to the g protein gs, which causes accumulation of cyclic adenosine monophosphate (camp) and activates protein kinase a (pka), we confirmed that pge2 treatment or transfection of cells with the active catalytic subunit of pka also stimulated the activity of a camp-responsive-elementdriven reporter gene (cre-luc). SIGNOR-141597 0.41 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation 9606 21419341 t inferred from 70% family members gcesareni We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1. SIGNOR-270048 0.2 IL17A protein Q16552 UNIPROT IL17R complex complex SIGNOR-C260 SIGNOR up-regulates activity binding 9606 BTO:0001946 32024054 t lperfetto Importantly, IL-17 was involved in increased collagen production in cardiac fibroblasts in response to HG, with both subunits of the IL-17RA and IL-17RC heterodimer complex being important to mediating this response. SIGNOR-261337 0.799 ESR1 protein P03372 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 BTO:0001264 22169964 f miannu 17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice SIGNOR-253471 0.2 CAMK2A protein Q9UQM7 UNIPROT HOMER3 protein Q9NSC5 UNIPROT down-regulates activity phosphorylation Ser120 ARLAREKsQDGGELT -1 18480293 t miannu Homer3 is phosphorylated at Ser120, Ser159, and Ser176 by CaMKII in vitro. Homer3 phosphorylation reduces its affinity for target molecules and modulates the Ca2+ signaling patterns induced by mGluR1α activation SIGNOR-262684 0.2 SMG1 protein Q96Q15 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates phosphorylation Ser1107 SQIDVALsQDSTYQG 9606 23356578 t lperfetto Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively SIGNOR-200789 0.971 PTPN1 protein P18031 UNIPROT IGF1R protein P08069 UNIPROT down-regulates activity dephosphorylation 9606 11884589 t lperfetto Ptp-1b can regulate igf-ir kinase activity and function and that loss of ptp-1b can enhance igf-i-mediated cell survival, growth, and motility in transformed cells. SIGNOR-115709 0.856 TYMS protein P04818 UNIPROT dTMP(2-) smallmolecule CHEBI:63528 ChEBI up-regulates quantity chemical modification 9606 21876188 t lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. SIGNOR-268235 0.8 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide chemical CHEBI:94504 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191433 0.8 MAP2K4 protein P45985 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Tyr185 TNFMMTPyVVTRYYR 9606 BTO:0000149;BTO:0001129 22730327 t gcesareni Mkk4, which activates p38gamma, p38delta, and jnk2 to phosphorylate p53 on ser-33 and cause a transient g(1) arrest. A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1) SIGNOR-197998 0.718 BCL2L1 protein Q07817 UNIPROT VDAC1 protein P21796 UNIPROT down-regulates activity binding 10365962 t lperfetto The anti-apoptotic protein Bcl-x(L) closes VDAC by binding to it directly SIGNOR-249614 0.583 NOTCH1 protein P46531 UNIPROT BCL11B protein Q9C0K0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 22577461 f miannu E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r. SIGNOR-197449 0.402 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT up-regulates activity phosphorylation Tyr28 SLNQSSGyRYGTDPT -1 9425276 t Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn. SIGNOR-251168 0.2 GSK3B protein P49841 UNIPROT ARHGAP31 protein Q2M1Z3 UNIPROT up-regulates activity phosphorylation Thr789 PPAPPPPtPLEESTP 10090 BTO:0000944 17158447 t miannu We show that GSK-3alpha and -beta interact with CdGAP in mammalian cells. We also demonstrate that GSK-3 phosphorylates CdGAP both in vitro and in vivo on Thr-776, which we have previously shown to be an ERK 1/2 phosphorylation site involved in CdGAP regulation. SIGNOR-262879 0.307 STAT3 protein P40763 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 18177723 f andrea cerquone perpetuini We identified cyclin D1 as a STAT3 target gene product downregulated in satellite cells from IL-6-deficient muscle in vitro and in vivo. SIGNOR-255411 0.78 carfilzomib chemical CHEBI:65347 ChEBI PSMB1 protein P20618 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 17591945 t miannu Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM. SIGNOR-259307 0.8 PRKG1 protein Q13976 UNIPROT ENAH protein Q8N8S7 UNIPROT down-regulates activity phosphorylation 9606 15066263 t miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts. PKG may preferentially phosphorylate sites of Ena/VASP proteins that reduce or inactivate these proteins. Inactivated Ena/VASP proteins dissociate from actin filaments, allowing capping proteins to bind and block monomer addition to plus ends, resulting in filament retraction. SIGNOR-268288 0.307 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR E2F1 protein Q01094 UNIPROT up-regulates activity phosphorylation 9606 23616010 t lperfetto Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1. SIGNOR-233526 0.2 FLT3 protein P36888 UNIPROT ACAT1 protein P24752 UNIPROT up-regulates activity phosphorylation Tyr407 HALKQGEyGLASICN 9606 BTO:0001545 34289383 t in mitochondria lperfetto We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1)  SIGNOR-267628 0.2 PDHX protein O00330 UNIPROT PDH complex SIGNOR-C402 SIGNOR form complex binding 9606 20160912 t miannu The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. SIGNOR-266543 0.809 TNF protein P01375 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253484 0.28 STK10 protein O94804 UNIPROT MSN protein P26038 UNIPROT up-regulates activity phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 19255442 t llicata Evidence in jurkat cells that lok phosphorylates erm and that erm phosphorylation impedes migration. SIGNOR-184433 0.394 Caspase 3 complex complex SIGNOR-C221 SIGNOR IKBKB protein O14920 UNIPROT down-regulates cleavage Asp78 PNVVAARdVPEGMQN 9606 11741536 t gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. SIGNOR-256434 0.372 ADRB1 protein P08588 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256758 0.507 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser188 RKRHKSDsISLSFDE 9606 BTO:0000671 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188) SIGNOR-124953 0.804 DVL1P1 protein P54792 UNIPROT PRKCB protein P05771 UNIPROT up-regulates binding 9606 23151663 t gcesareni Taken together, these results suggest that site-specific dvl2 phosphorylation is required for dvl2 association with pkc_. This interaction is likely to be one of the mechanisms essential for wnt3a-dependent neurite outgrowth. SIGNOR-199457 0.2 FOXS1 protein O43638 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates quantity by repression transcriptional regulation 9913 BTO:0004577 18288644 t Luana Fkhl18 suppressed the transcriptional activity of FoxO3a and FoxO4. SIGNOR-261611 0.2 SMURF2 protein Q9HAU4 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity ubiquitination 9606 17317136 t lperfetto Recruitment of ww and hect domain e3-ubiquitin ligases smurf1 and 2 to induce type i receptor ubiquitination and subsequent receptor degradation; SIGNOR-153423 0.698 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1185 FGMTRDIyETDYYRK -1 2449432 t lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106510 0.2 FBXO44 protein Q9H4M3 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates quantity by destabilization binding -1 23086937 t miannu The F-box protein FBXO44 mediates BRCA1 ubiquitination and degradation. The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro. SIGNOR-272037 0.376 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity phosphorylation Ser327 SEEDEMDsGTMVRAV 9534 12223493 t lperfetto Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationwas also highly autophosphorylated at the newly identified Thr(177) and Thr(387) residues SIGNOR-247569 0.2 SGK2 protein Q9HBY8 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000007 11154281 t lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. SIGNOR-252991 0.514 SYK protein P43405 UNIPROT FCGR2A protein P12318 UNIPROT up-regulates activity phosphorylation Tyr281 LEETNNDyETADGGY -1 8756631 t lperfetto To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and pointFyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation. SIGNOR-247590 0.659 UDP-D-galactose smallmolecule CHEBI:18307 ChEBI lactose smallmolecule CHEBI:17716 ChEBI up-regulates quantity precursor of 9606 16157350 t miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. SIGNOR-268471 0.8 XCL1 protein P47992 UNIPROT XCR1 protein P46094 UNIPROT up-regulates binding 9606 BTO:0000763 10518929 t gcesareni Scm-1 showed a high-affinity binding to xcr1 with a kd of 10 nm and induced vigorous chemotaxis and calcium mobilization in xcr1-transfected murine l1.2 cells. SIGNOR-71164 0.778 CAMK2A protein Q9UQM7 UNIPROT ETS1 protein P14921 UNIPROT down-regulates phosphorylation Ser257 DSFESIEsYDSCDRL 9606 BTO:0000782 12475968 t lperfetto Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition SIGNOR-96334 0.314 CSNK1A1 protein P48729 UNIPROT ERG protein P11308 UNIPROT down-regulates quantity by destabilization phosphorylation Ser38 TEMTASSsSDYGQTS -1 26344095 t miannu Using in vitro kinase assays, we further demonstrated that deletion of degron 1 largely abolished CKI-mediated phosphorylation of ERG (Figure S5B), indicating that serine residues within degron 1 are the major CKI phosphorylation sites. SIGNOR-276936 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 BTO:0000938 10529400 t lperfetto Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9BAD phosphorylation by Akt is an essential step for growth factor-mediated inhibition of caspase activation SIGNOR-71480 0.2 D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates activity 9606 31108873 f De novo biosynthesis of both purines and pyrimidines has been observed to be altered in cancer and requires the generation of 5-phosphoribose-1-pyrophosphate (PRPP), the activated form of ribose derived from ribose 5-phosphate, which is produced through the oxidative and nonoxidative arms of the pentose phosphate pathway (PPP) parallel to glycolysis. SIGNOR-267387 0.7 SCN3A protein Q9NY46 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 t miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. SIGNOR-253409 0.8 DLGAP2 protein Q9P1A6 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264589 0.746 CAV1 protein Q03135 UNIPROT SLC1A1 protein P43005 UNIPROT down-regulates activity binding 9606 BTO:0000938 26690923 t miannu EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers. SIGNOR-264807 0.2 Ribonucleotide reductase complex SIGNOR-C233 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 14583450 f miannu Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2. SIGNOR-259365 0.7 CDK7 protein P50613 UNIPROT AR protein P10275 UNIPROT down-regulates phosphorylation Ser516 VSRVPYPsPTCVKSE 9606 21157430 t acerquone Here, we show that the transcription factor tfiih, via its cdk7 kinase, phosphorylates the androgen receptor (ar) at position ar/s515. Strikingly, this phosphorylation is a key step for an accurate transactivation that includes the cyclic recruitment of the transcription machinery, the mdm2 e3 ligase, the subsequent ubiquitination of ar at the promoter of target genes and its degradation by the proteasome machinery SIGNOR-170599 0.385 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 phosphorylation:Ser473 RPHFPQFsYSASGTA 12167717 t gcesareni Together, these results suggest a mechanism in which 3' phosphoinositide lipid-dependent translocation of pkb to the plasma membrane promotes serine 473 phosphorylation, which is, in turn, necessary for pdk1-mediated phosphorylation of threonine 308 and, consequentially, full pkb activation. SIGNOR-91354 0.737 Gbeta proteinfamily SIGNOR-PF4 SIGNOR THRB protein P10828 UNIPROT down-regulates activity phosphorylation 9606 12809513 t inferred from 70% family members llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. SIGNOR-270016 0.2 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 8119945 t gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. SIGNOR-36271 0.852 AMPK complex SIGNOR-C15 SIGNOR FH protein P07954 UNIPROT up-regulates activity phosphorylation Ser75 YGAQTVRsTMNFKIG -1 28628081 t miannu Glucose deficiency induces AMPK activation, which phosphorylates FH at Ser75 and promotes its binding to ATF2 and the enrichment of the FH–ATF2 complex on the promoter regions of ATF2-targeted genes. SIGNOR-266313 0.2 MET protein P08581 UNIPROT GLMN protein Q92990 UNIPROT down-regulates relocalization 9606 11571281 t gcesareni Significantly, nonphosphorylated hgf receptor prevents fap68 from stimulating p70s6k. fap68 binding to met requires the last 30 amino acids of the c-terminal tail, which are unique to the hgf receptor. SIGNOR-110726 0.336 EIF5 protein P55010 UNIPROT EIF5B protein O60841 UNIPROT up-regulates activity relocalization 9606 30211544 t lperfetto eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC. SIGNOR-269122 0.74 ADARB1 protein P78563 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity binding 9606 BTO:0000661 19605474 t miannu Both forms of ADAR1 show enhanced interactions with PKR at the peak of HIV infection, suggesting a role for this protein in the regulation of PKR activation. SIGNOR-266359 0.471 LPAR2 protein Q9HBW0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257056 0.61 glutamine smallmolecule CHEBI:28300 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 27126896 f Luana  Importantly, asparagine/glutamine pre-load only results in mTOR activation following amino acid stimulation (Fig. 5a), indicating that it is their exchange factor roles that elicit mTORC1 activation. SIGNOR-268012 0.8 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser280 RSPSPQPsSHVAPQD 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248522 0.387 GUCY1A2-B2 complex SIGNOR-C137 SIGNOR 3',5'-cyclic GMP smallmolecule CHEBI:16356 ChEBI up-regulates quantity chemical modification 9606 10977868 t gcesareni Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types SIGNOR-244090 0.8 BIRC2 protein Q13490 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation. SIGNOR-272712 0.638 BTK protein Q06187 UNIPROT BTK protein Q06187 UNIPROT up-regulates phosphorylation Tyr551 RYVLDDEyTSSVGSK 9606 BTO:0000776 8630736 t lperfetto Overexpression of btk with a src family kinase increases tyrosine phosphorylation and catalytic activity of btk. This occurs by transphosphorylation at y551 in the btk catalytic domain and the enhancement of btk autophosphorylation at a second site. We mapped the major btk autophosphorylation site to y223 within the sh3 domain SIGNOR-41480 0.2 FOXN3 protein O00409 UNIPROT PIM2 protein Q9P1W9 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002552 24403608 t Luana CHES1/FOXN3 regulates cell proliferation by repressing PIM2 and protein biosynthesis. SIGNOR-261607 0.301 SMAD3 protein P84022 UNIPROT BCL2 protein P10415 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16766264 f irozzo This protection is conferred by Smad3’s ability to promote apoptosis by repressing Bcl-2 transcription in vivo through a GC-rich element in the Bcl-2 promoter. SIGNOR-256294 0.2 GABA-A proteinfamily SIGNOR-PF61 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f miannu Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-264970 0.7 belinostat chemical CHEBI:61076 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257956 0.8 NDUFB9 protein Q9Y6M9 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 SIGNOR-262172 0.804 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser226 ATGKDVEsYLQPKAK 9606 20573420 t lperfetto Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation. SIGNOR-166325 0.369 CDC25B protein P30305 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity dephosphorylation 9606 26474275 t miannu CDC25B is also able to dephosphorylate and activate CDK2-Cyclin A and CDK2-Cyclin E complexes [ xref \u2013 xref ]. SIGNOR-277140 0.757 CSNK2A1 protein P68400 UNIPROT PPP1R8 protein Q12972 UNIPROT up-regulates activity phosphorylation Thr161 LGLPEEEtELDNLTE -1 9407077 t llicata Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2. SIGNOR-250931 0.483 PRKG2 protein Q13237 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Ser556 HAKASRTsSKHKEDV 9606 BTO:0002181 21177494 t miannu  PKGII directly phosphorylated and stimulated SHP-1 activity SIGNOR-276286 0.2 IL21R protein Q9HBE5 UNIPROT JAK3 protein P52333 UNIPROT up-regulates binding 9606 BTO:0000776 12093291 t gcesareni Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5 SIGNOR-90269 0.54 PRKCD protein Q05655 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t lperfetto In addition, we found a protein kinase C-dependent phosphorylation of Ser(346) that was mutually exclusive with the basal phosphorylation at Ser(348) and therefore may be implicated in differential regulation of B2 receptor activation. Functional analysis of receptor mutants revealed that a low phosphorylation stoichiometry is sufficient to initiate receptor sequestration while a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation. SIGNOR-249108 0.305 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CD274 protein Q9NZQ7 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002548 27572267 t miannu We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP. SIGNOR-277277 0.2 AKT1 protein P31749 UNIPROT MITF protein O75030 UNIPROT down-regulates quantity by destabilization phosphorylation Ser516 KTSSRRSsMSMEETE 9606 BTO:0002181 27702651 t miannu We found that AKT phosphorylates MITF at S510. Phosphorylated MITF S510 enhances its affinity to TP53 and promotes CDKN1A expression. Phosphorylation of MITF by AKT induces its degradation SIGNOR-277281 0.451 JAK2 protein O60674 UNIPROT ARHGEF1 protein Q92888 UNIPROT up-regulates phosphorylation Tyr738 WDQEAQIyELVAQTV 9606 20098430 t gcesareni We found that angiotensin ii activates arhgef1 through a previously undescribed mechanism in which jak2 phosphorylates tyr738 of arhgef1 SIGNOR-163557 0.331 GNAI1 protein P63096 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates -1 10224115 f G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics. SIGNOR-256523 0.7 SCF-FBW7 complex SIGNOR-C135 SIGNOR NCOA3 protein Q9Y6Q9 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000093 17574025 t miannu We identified SCFFbw7α as an E3 ligase that binds to SRC-3 in an S505 phosphorylation-dependent manner (Figure 4Ci) and that is responsible for the further ubiquitination of SRC-3 (Figure 4A).  SIGNOR-276066 0.3 CSNK2A1 protein P68400 UNIPROT SEC63 protein Q9UGP8 UNIPROT up-regulates activity phosphorylation Ser576 VSDKGSDsEEEETNR 9606 BTO:0000599 23287549 t lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. SIGNOR-265267 0.295 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser274 RSKSQSSsNCSNPIS -1 12351658 t IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. SIGNOR-251291 0.644 MARCHF5 protein Q9NX47 UNIPROT FIS1 protein Q9Y3D6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 16874301 t Barakat MITOL associates with and ubiquitinates mitochondrial fission protein hFis1. (A) Ubiquitination of hFis1 by MITOL. Thus, MITOL may control the protein expression level of hFis1 through the ubiquitin‚Äìproteasome pathway. SIGNOR-274141 0.2 ERBB4 protein Q15303 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 18793634 t gcesareni Erbb4 might not be able to directly recruit cbl, and therefore downregulation of this receptor is slow. SIGNOR-180895 0.589 LRRFIP1 protein Q32MZ4 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 14522076 t Luana GC-binding factor 2 (GCF2) is a transcriptional repressor that decreases activity of the epidermal growth factor receptor (EGFR) and other genes. |Deletion mutants of GCF2 revealed that amino acids 429–528 are required for both DNA binding and repression of the EGFR promoter. SIGNOR-266057 0.297 SMO protein Q99835 UNIPROT GNAT1 protein P11488 UNIPROT up-regulates binding 9606 16885213 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-148496 0.264 SEC61 complex complex SIGNOR-C368 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 33925740 t lperfetto The Sec61 complex in the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER and provides a conduit for Ca2+ ions from the ER lumen to the cytosol.  SIGNOR-265284 0.8 MMP20 protein O60882 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage -1 10922468 t lperfetto Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|It has been suggested that MMPs play a role in the hydrolysis of COMP and, therefore, compromise the integrity of the cartilage ECM structure leading to the ultimate loss of joint function SIGNOR-266981 0.49 BACE2 protein Q9Y5Z0 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe634 VHHQKLVfFAEDVGS 9606 10931940 t lperfetto BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Aβ is produced from the Aβ precursor protein (APP) by two proteolytic events. A β-secretase activity cleaves APP at the N terminus of Aβ (β site) between amino acids Met-671 and Asp-672 |We show here that BACE2 cleaves APP at its β site and more efficiently at sites within the Aβ region of APP, after Phe-19 and Phe-20 of Aβ. SIGNOR-261772 0.56 CSMD1 protein Q96PZ7 UNIPROT C4B protein P0C0L5 UNIPROT down-regulates quantity binding 9606 28345259 t miannu CUB and sushi multiple domains 1 (CSMD1) is a relatively poorly studied large transmembrane protein of 390 kDa composed of 14 N-terminal CUB domains interspersed with complement control protein (CCP) domains followed by 15 consecutive CCP domains. The active domains of CSMD1 were then identified in CCP17-21, which were shown to interact with C4b and C3b and present these complement proteins for degradation by factor SIGNOR-265149 0.2 DLX5 protein P56178 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 f gcesareni Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme , indicat-ing that dlx5 can work as an upstream gene of runx2. SIGNOR-195576 0.498 EDNRA protein P25101 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 BTO:0000671 10199825 t gcesareni We studied the ability of et receptors to activate galfa13 using an assay for g protein alfa-chain activation that is based on the fact that an activated (gtp-bound) alfa-chain is resistant to trypsinization compared with an inactive (gdp-bound) alfa-chain. SIGNOR-66856 0.543 PAK4 protein O96013 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by stabilization phosphorylation Ser254 SKTFSRMsLLHKHEE -1 29849120 t miannu PAK4 bound and directly phosphorylated Slug at two previously unknown sites, S158 and S254, which resulted in its stabilization.  SIGNOR-277394 0.2 CDKN2C protein P42773 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 8891723 t miannu The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-44598 0.867 ARHGEF25 protein Q86VW2 UNIPROT CDC42 protein P60953 UNIPROT up-regulates guanine nucleotide exchange factor 10090 BTO:0000165;BTO:0000222 16314529 t lperfetto Exogenous expression of geft promotes myogenesis of c2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process. SIGNOR-235391 0.656 TSPAN12 protein O95859 UNIPROT NDP protein Q00604 UNIPROT up-regulates 9606 19837033 f Genetic Interaction gcesareni Tspan12 genetically interacts with norrin or lrp5 SIGNOR-188661 0.578 MMP8 protein P22894 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Ala20 VVGTAWTaDSGEGDF -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-8 20ADSGEGD a-chain | 442LRTGKEKV a-chain SIGNOR-263625 0.2 CASP7 protein P55210 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261751 0.323 EEF1A2 protein Q05639 UNIPROT Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269525 0.8 PLCE1 protein Q9P212 UNIPROT HRAS protein P01112 UNIPROT up-regulates guanine nucleotide exchange factor 9606 11022047 t gcesareni The presence of a rasgef motif in the n terminus of plcepsilon suggests that plcepsilon can activate ras by acting as an exchange factor by promoting the exchange of gtp for bound gdp. SIGNOR-82859 0.561 ATOH1 protein Q92858 UNIPROT HES6 protein Q96HZ4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17826772 f miannu Electrophoretic mobility shift assays and luciferase assays show that ATOH1 activates HES6 transcription through binding to three clustered E boxes of its promoter. SIGNOR-253754 0.451 CAY10505 chemical CID:1204893 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190859 0.8 metoprolol chemical CHEBI:6904 ChEBI ADRB1 protein P08588 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 10079020 t Luana In our CHO cells transfected with the human β1- and β2-adrenoceptors, the binding affinities of atenolol, metoprolol, betaxolol and practolol correlate with previously published β1- (P=0.03) and β2-adrenoceptor (P=0.03) binding affinities in human lung tissue SIGNOR-258337 0.8 FLT3 protein P36888 UNIPROT STAT5A protein P42229 UNIPROT up-regulates activity phosphorylation 10090 BTO:0001516 12796379 t FLT3-ITDs induced a strong activation of STAT5. FLT3-ITD mutants induce an autophosphorylation of the receptor, interleukin 3-independent growth in Ba/F3 cells, and a strong STAT5 and mitogen-activated protein kinase (MAPK) activation. SIGNOR-261516 0.593 EEF1A1 protein P68104 UNIPROT Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269510 0.8 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 17289999 t lperfetto Contrary to the direct-activation model, we show that Bax and Bak can mediate apoptosis without discernable association with the putative BH3-only activators (Bim, Bid, and Puma), even in cells with no Bim or Bid and reduced Puma. Our results indicate that BH3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding Bax and Bak SIGNOR-152986 0.826 CCR4-NOT complex complex SIGNOR-C439 SIGNOR NANOS2 protein P60321 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 t lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins SIGNOR-268349 0.492 SP1 protein P08047 UNIPROT CD34 protein P28906 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 10989198 t lperfetto Activation of the CD34 promoter by Sp1 requires the presence of a binding domain at -48 bp as well as the 5' untranslated region, which also binds Sp1 SIGNOR-241481 0.266 TOMM20 protein Q15388 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 t lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. SIGNOR-267678 0.692 MASP1 protein P48740 UNIPROT C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Arg756 KGQAGLQrALEILQE -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263435 0.59 STAT1 protein P42224 UNIPROT MMP13 protein P45452 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000249 17179173 f miannu IFNgamma, through its receptor, activates STAT1, which binds with CBP/p300 coactivator, sequesters it from the cell system, and thus inhibits transcriptional induction of the MMP13 gene in chondrocytes. SIGNOR-255235 0.294 ATIC protein P31939 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267326 0.8 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR MTA1 protein Q13330 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24089055 t lperfetto Here we provide genetic and biochemical evidence that metastasis-associated protein 1 (MTA1), a widely upregulated gene product in human cancers, is an integral component of the circadian molecular machinery. | The CLOCK-BMAL1 heterodimer activates MTA1 transcription through a conserved E-box element at its promoter. MTA1, in turn, interacts with and recruits CLOCK-BMAL1 at its own and CRY1 promoters and promotes their transcription. SIGNOR-253718 0.2 Dynorphin A smallmolecule CHEBI:4727 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258795 0.8 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH18 protein Q13634 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265835 0.8 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-260126 0.2 IRAK4 protein Q9NWZ3 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity phosphorylation Thr342 ASEKFAQtVMTSRIV 9606 BTO:0000007 17141195 t lperfetto The present data indicate that the kinase activity of irak-4 is dependent on the autophosphorylations at t342 SIGNOR-151006 0.2 RPL30 protein P62888 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262470 0.874 PBX1 protein P40424 UNIPROT MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR form complex binding 9606 BTO:0001103 17194702 t miannu Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes SIGNOR-151700 0.419 FLT1 protein P17948 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr154 QLNDSAAyYLNDLDR -1 33139573 t miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. SIGNOR-277230 0.26 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser9 LTFMASDsEEEVCDE -1 8972483 t llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  SIGNOR-250937 0.312 AURKA protein O14965 UNIPROT TACC3 protein Q9Y6A5 UNIPROT unknown phosphorylation Ser34 PEVTGRSsVLRVSQK -1 26134678 t lperfetto To address whether the phosphorylation state of TACC3 influenced Aurora-A binding and activation, we generated TACC3 variants in which all three Aurora-A phosphorylation sites (S34, S552 and S558)| The SA mutant had strongly reduced levels of phosphorylation compared to the individual mutations| SIGNOR-263697 0.934 PRKACA protein P17612 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 9534 1545828 t miannu Human c-Fos protein is phosphorylated in vitro by PKA. phosphorylation of Fos occurs at serine residue 362. Modification of the Fos protein by phosphorylation with PKA then allows it to act as a regulator of its own synthesis by downregulating fos gene expression at a transcriptional level SIGNOR-250356 0.502 KDM6B protein O15054 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR down-regulates 9606 22378047 f lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249563 0.7 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu69 CSYEEAReVFEDSDK -1 9538022 t lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). SIGNOR-263672 0.598 ASIP protein P42127 UNIPROT MC1R protein Q01726 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268698 0.733 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Asp683 HHGVVEVdAAVTPEE -1 8943232 t lperfetto The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261765 0.502 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 9315650 t llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase. SIGNOR-51292 0.47 Calprotectin complex complex SIGNOR-C293 SIGNOR AGER protein Q15109 UNIPROT up-regulates activity binding 9606 28137827 t miannu RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33 SIGNOR-262825 0.338 SL-327 chemical CHEBI:92211 ChEBI MAP2K5 protein Q13163 UNIPROT down-regulates chemical inhibition 9606 BTO:0000938 BTO:0000142 11160424 t gcesareni The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. SIGNOR-104933 0.8 RGMA protein Q96B86 UNIPROT NEO1 protein Q92859 UNIPROT down-regulates activity binding 10090 18485097 t miannu Netrin-1-neogenin interactions mediate chemoattractive axon guidance, while RGMa-neogenin interactions repel axons.  SIGNOR-268388 0.779 imatinib chemical CHEBI:45783 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258226 0.8 CTDSPL protein O15194 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser213 NLSPNPMsPAHNNLD 9606 BTO:0000007 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248308 0.399 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252853 0.908 17beta-estradiol smallmolecule CHEBI:16469 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258591 0.8 DNAJC3 protein Q13217 UNIPROT EIF2AK4 protein Q9P2K8 UNIPROT down-regulates activity binding 9606 BTO:0000567 25329545 t gcesareni € we show that p58IPK is a general inhibitor of the eIF2 kinases in that it also interacts with GCN2 SIGNOR-246204 0.56 BRCA2 protein P51587 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity binding 9606 17515904 t We suggest that interactions of the BRCA2 C-terminal region with RAD51 may facilitate efficient nucleation of RAD51 multimers on DNA and thereby stimulate recombination-mediated repair. SIGNOR-259905 0.945 F2 protein P00734 UNIPROT F5 protein P12259 UNIPROT up-regulates activity 9606 BTO:0000131 29880919 t lperfetto Thrombin also activates the cofactors FVIII (to FVIIIa) and FV (to FVa) and activates platelets such that they provide a procoagulant membrane surface to which these proteins then bind SIGNOR-263530 0.878 MAPK14 protein Q16539 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation 9606 19528229 t gcesareni P38 mapk phosphorylates the mrna binding protein hur on thr118, which results in cytoplasmic accumulation of hur and its enhanced binding to the p21cip1 mrna. SIGNOR-186138 0.538 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Thr676 NQMQPDTtSVVKDSQ 9606 19120698 t llicata Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity SIGNOR-183026 0.2 SRSF11 protein Q05519 UNIPROT LRP8 protein Q14114 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 10090 31269452 t miannu We demonstrate that SFRS11 directly binds to the 3' UTR of LRP8 mRNA, as well as to the third exon of apoE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling. SIGNOR-269670 0.2 MET protein P08581 UNIPROT MET protein P08581 UNIPROT up-regulates phosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 8302603 t lperfetto Previous work has shown that autophosphorylation of p190met enhances its enzymatic activity and that the major phosphorylation site is tyr1235, located in the catalytic domainonly the replacement of both tyr1234 and tyr1235 yielded a mutant which completely lost the ability to be activated by autophosphorylation SIGNOR-37723 0.2 SLC12A2 protein P55011 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 26951057 t miannu As shown in Fig. 2, the intracellular Cl− concentration is regulated mainly by two cation-chloride cotransporters, NKCC1 and KCC2 [32]. NKCC1 imports Cl− whereas KCC2 extrudes intracellular Cl−. SIGNOR-264986 0.8 EPHA3 protein P29320 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 BTO:0000007 11870224 t lperfetto Our results suggest that recruitment of crkii and activation of rho signalling are responsible for epha3-mediated cell rounding, blebbing and de-adhesion, and that ephrin-a5-mediated receptor clustering and epha3 tyrosine kinase activity are essential for this response SIGNOR-115335 0.61 MAPK3 protein P27361 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates phosphorylation Ser159 DGSCSSSsPPLPVLG 9606 15632084 t amattioni Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3 SIGNOR-132975 0.849 GSK3B protein P49841 UNIPROT XIAP protein P98170 UNIPROT up-regulates activity phosphorylation Thr180 WPDYAHLtPRELASA 9606 BTO:0002181 29678905 t miannu  We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAPT180A) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in Xenopus embryos.  SIGNOR-277390 0.403 KAT2A protein Q92830 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates binding 9606 BTO:0000150 SIGNOR-C7 15009097 t gcesareni Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo. SIGNOR-123315 0.343 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000938 9346240 f lperfetto Growth factors can promote cell survival by activating the phosphatidylinositide-3'-OH kinase and its downstream target, the serine-threonine kinase Akt SIGNOR-236428 0.81 UBR4 protein Q5T4S7 UNIPROT TRPV5 protein Q9NQA5 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0003913 23747339 t miannu Cytomix induced interaction between TRPV5 and UBR4 (Ubiquitin recoginition 4), an E3 ubiquitin ligase; knockdown of UBR4 with small interfering RNAs prevented cytomix-induced degradation of TRPV5.  UBR4/p600 ubiquitin ligase is responsible for TRPV5 ubiquitination and proteasomal degradation in response to cytomix SIGNOR-272117 0.248 MAPK3 protein P27361 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates phosphorylation Ser294 DPRQAQSsPPWSYDQ 9606 19801668 t llicata In this study, we identified two phosphorylation sites in runx2 at ser301 and ser319 that are required for mapk-dependent activation of runx2 transcriptional activity and osteoblast differentiation. SIGNOR-188343 0.547 PAX7 protein P23759 UNIPROT MLL1 complex complex SIGNOR-C89 SIGNOR up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t lperfetto Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-217716 0.2 CYCS protein P99999 UNIPROT Oxidative_phosphorylation phenotype SIGNOR-PH78 SIGNOR up-regulates 10090 23021218 f lperfetto PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). SIGNOR-253100 0.7 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Ser323 RMGQLRGsATRALPP 9606 BTO:0000007 10542239 t llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T SIGNOR-250807 0.2 CTDP1 protein Q9Y5B0 UNIPROT MASTL protein Q96GX5 UNIPROT down-regulates activity dephosphorylation Ser90 DALALSKsPFIVHLY 9606 26653855 t lperfetto Taken together, these data suggest that Fcp1 bound and dephosphorylated Gwl at S90 and S453, and possibly at other Cdk1 dependent sites, during mitosis exit and that Fcp1 catalyzed dephosphorylation lowered Gwl activity towards Ensa and ARPP19, allowing PP2A-B55 to autoactivate.|Together, these data indicate that Fcp1 dependent dephosphorylation greatly reduces S67-Ensa kinase activity of Gwl and that, downstream inactivation of Cdk1, Fcp1 deficit substantially blunts inactivation of Gwl. SIGNOR-276972 0.444 CAMK2A protein Q9UQM7 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser656 RAEFLNKsVQKSSGV 9606 2170388 t gcesareni Smooth muscle caldesmon was phosphorylated by smooth muscle calmodulin-dependent protein kinase. Ii SIGNOR-22635 0.2 PIAS4 protein Q8N2W9 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Ser4 sGFESYGS 9606 20016603 t gcesareni Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair furthermore, phosphorylation of the 34 kda subunit of rpa on ser-4 and ser-8 (ps4/ps8) in response to ir or camptothecin treatment was diminished by pias4 depletion, while pias1 depletion impaired ir-induced but not camptothecin-induced rpa phosphorylation SIGNOR-162160 0.2 PPM1D protein O15297 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 18265945 t lperfetto Because Chk1 phosphorylates and activates p53, the inhibition of Chk1 by Wip1 also places Wip1 in a negative feedback regulatory loop for p53 .|In vitro phosphatase assays showed that Wip1 dephosphorylated Chk1 at Ser345, but not Ser317. SIGNOR-276986 0.486 PPM1F protein P49593 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity dephosphorylation Ser317 ENVKYSSsQPEPRTG 9606 31944151 t lperfetto As a result, inactivation of Chk1 by POPX2 leads to impaired G1S checkpoint activation and cells are able to proceed from G1 to S phase despite DNA damage.|We also determined that POPX2 can dephosphorylate Chk1Ser317 and -Ser345 and is a potential regulator of Chk1 function in the cell. SIGNOR-276987 0.2 embelin chemical CHEBI:4778 ChEBI XIAP protein P98170 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001271 28704451 t lperfetto Targeting of X-linked inhibitor of apoptosis protein and PI3-kinase/AKT signaling by embelin suppresses growth of leukemic cells. SIGNOR-262013 0.8 CSNK2A2 protein P19784 UNIPROT KIF1C protein O43896 UNIPROT unknown phosphorylation Ser1092 PRMRRQRsAPDLKES -1 10559254 t llicata Serine 1092 was a substrate for the protein kinase casein kinase II in vitro, and inhibition of casein kinase II in cells diminished the association of KIF1C with 14-3-3gamma. Our data thus suggest that KIF1C can form dimers and is associated with proteins of the 14-3-3 family. SIGNOR-251010 0.315 CD3G protein P09693 UNIPROT CD3 complex SIGNOR-C432 SIGNOR form complex binding 9606 12507424 t miannu The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules. SIGNOR-255296 0.634 CDK4 protein P11802 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 t gcesareni In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-176524 0.283 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 23151663 t lperfetto Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells. SIGNOR-227866 0.891 PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR RAF1 protein P04049 UNIPROT up-regulates activity dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000007 16239230 t gcesareni ... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259. SIGNOR-243538 0.497 TGFBR1 protein P36897 UNIPROT SERPINE1 protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28520219 f miannu The transforming growth factor-β pathway is the major driver of fibrotic response. Plasminogen activator inhibitor-1 (PAI-1) is a crucial downstream target of this pathway. Transforming growth factor-β positively regulates PAI-1 gene expression via two main pathways including Smad-mediated canonical and non-canonical pathways. SIGNOR-260590 0.443 CDK1 protein P06493 UNIPROT USP24 protein Q9UPU5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2047 QRVSDQNsPVLPKKS 9606 BTO:0000018 27991932 t lperfetto Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. SIGNOR-275604 0.2 HNRNPH2 protein P55795 UNIPROT TERF2 protein Q15554 UNIPROT down-regulates quantity post transcriptional regulation 10116 BTO:0001009 27117401 t miannu During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels. SIGNOR-266806 0.339 DAB2IP protein Q5VWQ8 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates activity binding 9606 27858941 t miannu DAB2IP binds the p85 subunit of PI3K through its PR domain and prevents PI3K-p85 relocation from the cytoplasm to the membrane, a necessary step for PI3K activation and signaling to AKT. Notably, DAB2IP reinforces this inhibitory effect by directly binding AKT.2 SIGNOR-254757 0.286 RRAGC protein Q9HB90 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates binding 9606 SIGNOR-C3 20006481 t gcesareni Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor. SIGNOR-162054 0.94 RRAGB protein Q5VZM2 UNIPROT RAGBC complex SIGNOR-C115 SIGNOR form complex binding 9606 20381137 t gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant SIGNOR-228176 0.784 HNF1B protein P35680 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity binding 9606 BTO:0000007 9671480 t 2 miannu The mammalian two-hybrid system showed that the region aa 393 to 476 of LFB3 is involved in the interaction with CREB or ATF1. The importance of this region for mediating cAMP induction was confirmed in transient transfection assays. SIGNOR-241320 0.312 A8/b1 integrin complex SIGNOR-C165 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269014 0.7 RNF41 protein Q9H4P4 UNIPROT ERBB3 protein P21860 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 12411582 t miannu Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3 SIGNOR-272599 0.678 RASGEF1C protein Q8N431 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-161505 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates phosphorylation 9606 BTO:0001950 21561061 t Luana 3b Augments c-Fos Levels by Activating the ERK Pathway. | Higher c-Fos levels were observed in 3b-expressing cells than in GFP-expressing control cells SIGNOR-260762 0.2 ECM stimulus SIGNOR-ST20 SIGNOR A3/b1 integrin complex SIGNOR-C161 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259044 0.7 TRAF6 protein Q9Y4K3 UNIPROT ULK1 protein O75385 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 BTO:0000007 23524951 t lperfetto AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. SIGNOR-273000 0.533 OXTR protein P30559 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 30739093 t miannu OT binds to its cognate G protein–coupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi), and activation of phospholipase C (Gq). SIGNOR-270332 0.533 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Ser230 PEGATPTsPVGHFAK 9606 BTO:0000848 BTO:0001253 20959475 t lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). SIGNOR-168754 0.2 MAP4K3 protein Q8IVH8 UNIPROT MAP4K3 protein Q8IVH8 UNIPROT up-regulates phosphorylation Ser170 ATIAKRKsFIGTPYW 9606 20227368 t gcesareni We identify a transautophosphorylation site in the map4k3 kinase activation segment (ser170) that is required for map4k3 activity and its activation of mtorc1 signaling. SIGNOR-164103 0.2 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR ID2 protein Q02363 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 f Also comparable with ID1, RARα, RXR, PML, PLZF-RARα, and RARα/RXR did not transactivate the ID2 promoter, whereas PML-RARα did. Together, these data show that like ID1, ID2 may also be transactivated by PML-RARα without direct DNA binding of the fusion protein. SIGNOR-255727 0.2 PPM1F protein P49593 UNIPROT PAK2 protein Q13177 UNIPROT down-regulates dephosphorylation 9606 BTO:0000150;BTO:0000093 20016286 t gcesareni Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity. SIGNOR-162149 0.264 DIAPH1 protein O60610 UNIPROT CDH4 protein P55283 UNIPROT up-regulates activity 9606 BTO:0000815 22820501 t lperfetto Taken together, data obtained from MCF10A cells were consistent with the idea that Rho signaling to Dia1 and profilin-1 was essential for R-cadherin adherens junction formation. SIGNOR-253110 0.2 UBE3A protein Q05086 UNIPROT SIPA1L1 protein O43166 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 12036950 t miannu  the purified E6AP enhanced the ubiquitination and degradation of E6TP1 in the presence of E6 in vitro. Additionally, the expression of a dominant-negative E6AP mutant (C833A) in cells inhibited the E6-induced degradation of E6TP1. These findings demonstrate that the E6-induced decrease in the levels of E6TP1 protein involves the E6AP-mediated ubiquitination followed by proteasome-dependent degradation. SIGNOR-272608 0.373 SP1 protein P08047 UNIPROT SLC9A3 protein P48764 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 16464174 f Co-transfection of Sp1 or Sp3 into SL2 cells activated the NHE3-reporter constructs, suggesting that Sp1 and Sp3 act as positive regulators of the NHE3 expression. In addition, overexpression of EGR-1 was sufficient to transactivate the NHE3-reporter gene activity SIGNOR-254270 0.2 AMPK complex SIGNOR-C15 SIGNOR Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 20640476 f lperfetto The decreased glycogen synthesis rates upon acute AMPK activation are generally coupled to an increase in the glycolytic flux, thanks to the activation of 6-phosphofructo-2-kinase (PFK-2) through direct phosphorylation on Ser466 [35]. PFK-2 catalyzes the synthesis of fructose 2,6-bisphosphate, a potent stimulator of glycolysis. Therefore, activation of AMPK rapidly mobilizes glucose into ATP-generating processes. SIGNOR-209929 0.7 MAPK14 protein Q16539 UNIPROT JUNB protein P17275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10330170 f gcesareni Moreover, in addition to jnk, erk5, p38alpha, and p38gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements. SIGNOR-67535 0.492 PRKACA protein P17612 UNIPROT AANAT protein Q16613 UNIPROT up-regulates activity phosphorylation Thr31 PSCQRRHtLPASEFR -1 11336675 t miannu AANAT1201 is phosphorylated at Thr-31 by PKA, it binds to 14-3-3. regulation is achieved by binding to 14-3-3, which structurally modulates the substrate binding sites, leading to measurable effects on the affinity of AANAT for its substrates with an accompanying increase in activity at low substrate concentrations.  SIGNOR-250325 0.326 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT down-regulates quantity by destabilization cleavage Asp317 VSGISLLdNSNASVW 9606 BTO:0000567 11815631 t Giulio Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage SIGNOR-260602 0.405 RAC1 protein P63000 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates activity 23290138 f Simone Vumbaca This result strongly supports the assertion that Wnt7a and FN stimulate PCP signaling to drive the symmetric expansion of satellite stem cells during regenerative myogenesis. SIGNOR-255648 0.7 PDPK1 protein O15530 UNIPROT SGK2 protein Q9HBY8 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni One of the most studiedevents controlled by ptdins(3,4,5)p3, comprises the activation of aof agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-126177 0.582 PPP1R1B protein Q9UD71 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates activity binding 9606 BTO:0000938 10604473 t inferred from 70% of family members miannu DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.√¢‚Ǩ≈°√Ǭ† SIGNOR-269869 0.674 nintedanib chemical CHEBI:85164 ChEBI FGFR2 protein P21802 UNIPROT down-regulates activity chemical inhibition -1 18559524 t Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. SIGNOR-257806 0.8 ASTN2 protein O75129 UNIPROT ASTN1 protein O14525 UNIPROT down-regulates quantity binding 9606 BTO:0000007 20573900 t miannu Biochemical and flow cytometry experiments show that ASTN2 forms a complex with ASTN1 and regulates surface expression of ASTN1. Coexpression with ASTN2 reduces the cell surface localization of ASTN1. SIGNOR-269813 0.2 AKT1 protein P31749 UNIPROT TERT protein O14746 UNIPROT up-regulates phosphorylation Ser227 GARRRGGsASRSLPL 9606 10224060 t gcesareni Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins. SIGNOR-67313 0.721 ENSA protein O43768 UNIPROT PPP2R2D protein Q66LE6 UNIPROT down-regulates activity binding -1 phosphorylation:Ser67 KGQKYFDsGDYNMAK 21164014 t gcesareni We identified cyclic adenosine monophosphate€“regulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry. SIGNOR-243735 0.76 CSNK2A1 protein P68400 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 BTO:0000661 15818404 t lperfetto Akt/pkb ser129 is phosphorylated by ck2 in vitro and in vivo;(4) such a phosphorylation of activated akt/pkb correlates with a further increase in catalytic activity. SIGNOR-244400 0.379 MYC protein P01106 UNIPROT ST3GAL1 protein Q11201 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22547830 f We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. SIGNOR-253961 0.2 PLEKHG4B protein Q96PX9 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260565 0.289 GEMIN7 protein Q9H840 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 t lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. SIGNOR-253121 0.813 U50488 chemical CHEBI:73358 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258826 0.8 5-(1H-indol-3-ylmethyl)-3-methyl-2-sulfanylidene-4-imidazolidinone chemical CHEBI:91658 ChEBI RIPK1 protein Q13546 UNIPROT down-regulates chemical inhibition 9606 19524513 t gcesareni The interaction between rip1 and rip3 is abolished by the rip1 kinase inhibitor necrostatin-1. SIGNOR-186075 0.8 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Thr509 PVFDLTTtPKGGTPA 10116 16611631 t lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro SIGNOR-146011 0.452 Melanin-concentrating hormone smallmolecule CHEBI:80254 ChEBI MCHR1 protein Q99705 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257540 0.8 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Ser742 GEKSFRRsVVGTPAY -1 10867018 t lperfetto The last two autophosphorylation sites (Ser(744) and Ser(748)) are located in the activation loop but are only phosphorylated in the isolated PKD-catalytic domain and not in the full-length PKD; they may affect enzyme catalysis but are not involved in the activation of wild-type PKD by phorbol ester. | These results indicate that neither of the activation loop serines is involved in PDBu-induced activation but that they may be involved in catalysis or in maintaining the conformation of the enzyme prot SIGNOR-249047 0.2 Guanabenz chemical CHEBI:5553 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258911 0.8 HNuRF complex SIGNOR-C448 SIGNOR EN1 protein Q05925 UNIPROT up-regulates quantity by expression 9606 14609955 f miannu Human NURF (hNURF) is enriched in brain, and we demonstrate that it regulates human Engrailed, a homeodomain protein that regulates neuronal development in the mid-hindbrain. Furthermore, we show that hNURF potentiates neurite outgrowth in cell culture. Taken together, our data suggess a role for an ISWI complex in neuronal growth. ) ChIP assays localize hNURF specifically to engrailed-1 (en-1) and engrailed-2 (en-2) promoters. SIGNOR-268839 0.323 GSK3B protein P49841 UNIPROT CTPS1 protein P17812 UNIPROT down-regulates activity phosphorylation Ser575 SDRSGSSsPDSEITE 9606 BTO:0000007 17681942 t miannu We found that low serum conditions increased phosphorylation of endogenous CTPS1 and this phosphorylation was inhibited by the glycogen synthase kinase 3 (GSK3) inhibitor indirubin-3'-monoxime and GSK3beta short interfering RNAs, demonstrating the involvement of GSK3 in phosphorylation of endogenous human CTPS1. Separating tryptic peptides from [(32)P]orthophosphate-labeled cells and analyzing the phosphopeptides by mass spectrometry identified Ser-574 and Ser-575 as phosphorylated residues. Incubation with an alkaline phosphatase increased CTPS1 activity in a time-dependent manner, demonstrating that phosphorylation inhibits CTPS1 activity. SIGNOR-276069 0.2 CDK1 protein P06493 UNIPROT UBXN2B protein Q14CS0 UNIPROT down-regulates activity phosphorylation Ser56 PKATVFKsPRTPPQR 23500464 t lperfetto At mitosis, Cdc2 kinase phosphorylates p47 on Serine-140 and p37 on Serine-56 and Threonine-59, respectively. The phosphorylated p47 and p37 are unable to bind to Golgi membranes, resulting in mitotic inhibition of the p97/p47 and the p97/p37 pathways, respectively. SIGNOR-265040 0.2 PDK4 protein Q16654 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 BTO:0000887;BTO:0001103 14966024 t gcesareni Pyruvate dehydrogenase (pdh) activity (pdha) controls the entry of carbohydrate into the tricarboxylic cycle and is regulated by pdh kinase (pdk), which phosphorylates and inactivates the enzyme, and pdh phosphatase, which dephosphorylates the enzyme to the active form SIGNOR-121936 0.528 FGFR3 protein P22607 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000007 10918587 t Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3. SIGNOR-251138 0.657 ACOT4 protein Q8N9L9 UNIPROT glutaryl-CoA(5-) smallmolecule CHEBI:57378 ChEBI down-regulates quantity chemical modification 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271818 0.8 PRKAB1 protein Q9Y478 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 16054041 t gcesareni Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. SIGNOR-139164 0.866 NOD2 protein Q9HC29 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates activity binding 9606 17355968 t miannu The function of NOD2 could be to recruit RICK at the plasma membrane to form an active complex able to activate part of the NF-κB pathway. NOD2 induces a membrane recruitment of RICK that is dependent on a CARD-CARD interaction. SIGNOR-252402 0.756 ESR1 protein P03372 UNIPROT ESR2 protein Q92731 UNIPROT up-regulates binding 9606 10022879 t tpavlidou It was recently shown that er? And er? Could form a heterodimer complex both in vitro and in vivo SIGNOR-64427 0.507 CDC42BPA protein Q5VT25 UNIPROT MYL2 protein P10916 UNIPROT up-regulates activity phosphorylation Ser19 GANSNVFsMFEQTQI BTO:0000567 9418861 t llicata These approximately 190-kDa myotonic dystrophy kinase-related Cdc42-binding kinases (MRCKs) preferentially phosphorylate nonmuscle myosin light chain at serine 19, which is known to be crucial for activating actin-myosin contractility. SIGNOR-250723 0.635 SMARCD1 protein Q96GM5 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 t miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. SIGNOR-132939 0.882 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser530 DGPPSPRsPVIGSEV 9606 BTO:0001271 15093545 t The effect has been demonstrated using P29590-4 gcesareni We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3). SIGNOR-124056 0.366 FZD5 protein Q13467 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates activity binding 9606 23151663 t areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  SIGNOR-258963 0.626 PPP2R5C protein Q13362 UNIPROT RPS6KB1 protein P23443 UNIPROT down-regulates binding 9606 20444422 t gcesareni The human homolog of pp2a-b', ppp2r5c, also counteracts s6k1 phosphorylation, indicating a conserved mechanism in mammals SIGNOR-165224 0.347 atomoxetine chemical CHEBI:127342 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition -1 9871604 t miannu The gamma-amino alcohol/ether unit contained in venlafaxine, 2 fluoxetine, 3 and tomoxetine 3 has been prepared by a sequence of nitrile aldol reaction and nitrile reduction. Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. SIGNOR-259071 0.8 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2E3 protein Q969T4 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271364 0.594 CRKL protein P46109 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates binding 9606 BTO:0000782 9891069 t HPK1 phosphorylated CrkL mainly on serine and weakly on threonine gcesareni We found that hpk1 interacted with crk and crkl adaptor proteins in vitro and in vivo and that the proline-rich motifs within hpk1 were involved in the differential interaction of hpk1 with the crk proteins and grb2. Crk and crkl not only activated hpk1 but also synergized with hpk1 in the activation of jnk. SIGNOR-63991 0.57 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Glu637 QKLVFFAeDVGSNKG -1 8943232 t lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261768 0.502 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH8 protein P55286 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265848 0.8 RBPJ protein Q06330 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000165 10066785 t gcesareni ligand-induced Notch signaling up-regulated HES1 mRNA expression within 1h and subsequently reduced expression of MyoD mRNA SIGNOR-243178 0.583 PRKCA protein P17252 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser595 GLMQQQKsFR 9606 11781100 t lperfetto  In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta. SIGNOR-249138 0.329 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr236 FYDETYDyGGFTMMF 9606 12052863 t lperfetto We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown). SIGNOR-88911 0.608 BIRC3 protein Q13489 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 18997794 t lperfetto Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3. SIGNOR-182131 0.888 RBP4 protein P02753 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI up-regulates quantity relocalization 9606 31963453 t lperfetto In the blood, serum retinol travels in association with Retinol-binding protein 4 (RBP4) SIGNOR-265106 0.8 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid chemical CHEBI:91366 ChEBI AURKA protein O14965 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258250 0.8 MAPK8 protein P45983 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0002923 23255093 t lperfetto Transfection of the cells with sirna specific for jnk1 revealed that jnk silencing reduced serine727 phosphorylation of stat3, SIGNOR-235704 0.584 RAD18 protein Q9NS91 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination 9606 19706603 t gcesareni Rad5 interacts with the e3 ligase rad18, which is initially required to monoubiquitinate pcna SIGNOR-187705 0.84 GSK3B protein P49841 UNIPROT MUC1 protein P15941 UNIPROT down-regulates activity phosphorylation Ser1227 PPSSTDRsPYEKVSA BTO:0000567 9819408 t lperfetto GSK3beta binds directly to an STDRSPYE site in MUC1 and phosphorylates the serine adjacent to proline. Phosphorylation of MUC1 by GSK3beta decreases binding of MUC1 to beta-catenin in vitro and in vivo. SIGNOR-249356 0.468 CDK1 protein P06493 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Thr360 SGISSVPtPSPLGPL 9606 BTO:0000527 19941816 t gcesareni It has been shown that the c-terminal domains of ck2? Are phosphorylated by cdc2 and interact with the peptidyl-prolyl isomerase pin1 in a cell cycle-dependent manner SIGNOR-161843 0.361 SERPINE1 protein P05121 UNIPROT F12 protein P00748 UNIPROT down-regulates activity binding 9606 BTO:0000131 26707513 t lperfetto C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1). SIGNOR-263516 0.31 3-(4-quinolinylmethylamino)-N-[4-(trifluoromethoxy)phenyl]-2-thiophenecarboxamide chemical CHEBI:91433 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-195675 0.8 sunitinib chemical CHEBI:38940 ChEBI PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 20185585 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-163956 0.8 PRKDC protein P78527 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Thr5 tQTQDQPM 9606 BTO:0000567 2507541 t lperfetto Here we show that the dsDNA-activated protein kinase from human HeLa cells phosphorylates 2 threonine residues in the sequence PEETQTQDQPME at the amino terminus of human hsp90 alpha. SIGNOR-248887 0.437 MAPK1 protein P28482 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser225 ARLGSQHsPGRTASL 9606 21419341 t gcesareni We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1. SIGNOR-172877 0.421 RARB protein P10826 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. SIGNOR-16519 0.668 MBOAT7 protein Q96N66 UNIPROT acyl-CoA smallmolecule CHEBI:17984 ChEBI down-regulates quantity chemical modification -1 18772128 t miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. SIGNOR-267244 0.8 TEK protein Q02763 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9534 BTO:0004055 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-252728 0.484 CDK1 protein P06493 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser251 MIQFAINsTERKRMT 9606 SIGNOR-C17 19737929 t lperfetto A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1the phosphorylation at ser-251 is critical for the activation of foxm1. SIGNOR-187876 0.751 (2S)-2-[[2-(2,3-dihydro-1H-inden-5-yloxy)-9-[(4-phenylphenyl)methyl]-6-purinyl]amino]-3-phenyl-1-propanol chemical CHEBI:94469 ChEBI ARFGAP3 protein Q9NP61 UNIPROT down-regulates activity chemical inhibition -1 26152429 t lperfetto Here we present structure-activity relationship (SAR) studies of QS11 analogs in two assays: direct inhibition of enzymatic activity of purified ARFGAP1 protein and cellular activation of the Wnt/β-catenin pathway. The results confirm the direct inhibition of ARFGAP1 by QS11, and also suggest the presence of other potential cellular targets of QS11 SIGNOR-261980 0.8 Protocadherin_alpha proteinfamily SIGNOR-PF100 SIGNOR Protocadherin_beta proteinfamily SIGNOR-PF102 SIGNOR up-regulates activity binding 9606 BTO:0000007 15347688 t miannu We analyzed the expression of CNR/Pcdhalpha and Pcdhgamma in HEK293T cells and found that they formed a protein complex and that Pcdhgamma enhanced the surface expression of CNR/Pcdhalpha. This enhanced surface expression was confirmed by flow cytometry analysis and by marking cell surface proteins with biotin. The enhancement was observed using different combinations of CNR/Pcdhalpha and Pcdhgamma proteins. The surface expression activity was enhanced by the extracellular domains of the proteins, which could bind each other. Their cytoplasmic domains also had binding activity and influenced their localization. Their protein-protein interaction was also detected in extracts of mouse brain and two neuroblastoma cell lines. Thus, interactions between CNR/Pcdhalpha and Pcdhgamma regulate their surface expression and contribute to the combinatorial diversity of cell recognition proteins in the brain. SIGNOR-269036 0.2 PRMT1 protein Q99873 UNIPROT CNBP protein P62633 UNIPROT down-regulates methylation Arg25 ECPTGGGrGRGMRSR 9606 24726729 t miannu Cnbp interacts with protein arginine methyltransferase prmt1 / r25 or r27 appear to be the major methylation sites in cnbp /arginine methylation of cnbp impedes rna binding SIGNOR-204958 0.376 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser721 TPRLRSVsSYGNIRA 9606 SIGNOR-C3 18722121 t llicata Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity SIGNOR-252774 0.2 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273037 0.556 PCSK7 protein Q16549 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 14767066 f lperfetto The levels of ikb_? Where reduced in cells overexpressing mkk6 [] these results indicated that mkk6 was able to promote the degradation of the NF-kappaB inhibitor, in a p38-dependent manner. SIGNOR-235837 0.2 PMPCB protein O75439 UNIPROT PINK1 protein Q9BXM7 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0000007 22354088 t miannu Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy. SIGNOR-261363 0.345 vorinostat chemical CHEBI:45716 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257918 0.8 ARHGEF10 protein O15013 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260535 0.505 LLGL2 protein Q6P1M3 UNIPROT Scribble_complex_DLG2-LLGL2_variant complex SIGNOR-C503 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270879 0.548 AMPD1 protein P23109 UNIPROT adenosine 5'-monophosphate smallmolecule CHEBI:16027 ChEBI down-regulates quantity chemical modification 9606 BTO:0001103 1631143 t miannu AMP deaminase (AMPD; EC 3.5.4.6) is encoded by a multigene family in mammals. The AMPD1 gene is expressed at high levels in skeletal muscle, where this enzyme is thought to play an important role in energy metabolism. AMP deaminase (AMPD; EC 3.5.4.6), an enzyme that catalyzes deamination of AMP to IMP, and the purine nucleotide cycle, of which AMPD is one component, play a central role in purine nucleotide interconversion in eukaryotic cells. SIGNOR-269772 0.8 AMPK complex SIGNOR-C15 SIGNOR DNMT1 protein P26358 UNIPROT down-regulates activity phosphorylation Ser714 DNIPEMPsPKKMHQG -1 28143904 t lperfetto Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK decreased DNMT1 activity SIGNOR-264788 0.292 BIRC2 protein Q13490 UNIPROT RIPK4 protein P57078 UNIPROT up-regulates activity polyubiquitination lys145 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation. SIGNOR-272708 0.362 PTPN1 protein P18031 UNIPROT STAT6 protein P42226 UNIPROT down-regulates activity dephosphorylation 9606 22156494 t miannu Phosphorylated STAT6 may also serve as a cytoplasmic substrate for PTP1B since overexpression of PTP1B leads to STAT6 dephosphorylation and the suppression of STAT6 transcriptional activity, whereas PTP1B deficiency increases IL-4-induced STAT6 signaling in B-cells. SIGNOR-277122 0.333 MMP7 protein P09237 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272374 0.7 CAMK2A protein Q9UQM7 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2426 ASGDRPPsVSSVHSE 9606 22888005 t lperfetto We demonstrated that camkii directly bound and phosphorylated smrt at ser-1407, thereby facilitating smrt translocation from the nucleus to the cytoplasm and proteasome-dependent degradation. SIGNOR-191773 0.2 KCNB2 protein Q92953 UNIPROT VAPB protein O95292 UNIPROT up-regulates quantity relocalization 9606 BTO:0000007 29941597 t lperfetto Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions. SIGNOR-262123 0.2 3-(4-Methylphenyl)-5-(1-propyl-3,6-dihydro-2H-pyridin-5-yl)-1,2-oxazole chemical CID:9817231 PUBCHEM SIGMAR1 protein Q99720 UNIPROT down-regulates activity chemical inhibition 10090 9144641 t Federica PD144418 exhibited an affinity for ơ1 of 0.08nM(Ki) versusa Ki of 1377nM for ơ2 site. SIGNOR-261114 0.8 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser455 HFGSTSSsPPISPAS 9606 BTO:0000007 16141410 t In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity SIGNOR-251244 0.406 RARS1 protein P54136 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 t miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). SIGNOR-270357 0.2 PRKCA protein P17252 UNIPROT VCL protein P18206 UNIPROT unknown phosphorylation Ser1101 NAQNLMQsVKETVRE -1 11741957 t lperfetto PKC Phosphorylates Serines 1033 and 1045 in Helix H5 SIGNOR-249128 0.399 PPP2R5C protein Q13362 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates binding 9606 16456541 t inferred from 70% of family members gcesareni B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk SIGNOR-269900 0.2 PI3K complex SIGNOR-C156 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 19436055 f apalma Low pM concentrations of GM-CSF mediate βc Ser585 phosphorylation, leading to 14-3-3 binding, PI-3 kinase activation, and hemopoietic cell survival, whereas at concentrations of 10 pM or more, GM-CSF mediates βc Tyr577 phosphorylation, Shc recruitment, and PI-3 kinase activation, thereby promoting both survival and proliferation. SIGNOR-255576 0.7 THBS1 protein P07996 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 SIGNOR-252271 0.7 MAPK1 protein P28482 UNIPROT PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation Ser12 ESPLCPLsPLEAGDL 9606 BTO:0000599 10187842 t lperfetto We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution. SIGNOR-249433 0.56 CSF2RB protein P32927 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR form complex binding 9606 BTO:0000876 BTO:0001103 9680354 t apalma The high-affinity GMR is known to be composed of a specific ligand-binding alpha subunit (GMRα) and a common beta subunit (βc), which is also a component of the interleukins-3 (IL-3) and -5 (IL-5) receptors. SIGNOR-255583 0.865 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR USP9X protein Q93008 UNIPROT up-regulates activity phosphorylation Ser2547 YEGSEEVsPPQTKDQ 32152317 t Phosphosites were derived from Figure S1 lperfetto Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis. SIGNOR-275612 0.273 PER2 protein O15055 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001939 23836662 f miannu PER2 Suppresses TWIST1 and SLUG Transcription by Recruiting EZH2, SUZ12, and HDAC2. SIGNOR-254147 0.2 MAD2L1BP protein Q15013 UNIPROT TRIP13 protein Q15645 UNIPROT up-regulates activity binding 9606 BTO:0000567 25092294 t miannu We have indeed showed that TRIP13 action to disassemble the Cdc20–Mad2 complex requires the presence of p31comet (Fig. 3A). We furthermore found that the joint action of TRIP13 and p31comet is also required for the release of Mad2 from MCC, for the complete disassembly of MCC and for relieving APC/C from checkpoint inhibition (Figs. 3 and ​and4).4). SIGNOR-265971 0.482 CAMK2G protein Q13555 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1071 SFLQRYSsDPTGALT 9606 BTO:0000017 1309762 t llicata The mechanism of desensitization of kinase activity can be accounted for, in part, by the EGF-stimulated phosphorylation of the receptor at Ser1046/7, a substrate for the multifunctional calmodulin-dependent protein kinase II in vitro. Mutation of Ser1046/7 by replacement with Ala residues blocks desensitization of the EGF receptor protein-tyrosine kinase activity.  SIGNOR-250695 0.369 HSP90AB1 protein P08238 UNIPROT NOD2 protein Q9HC29 UNIPROT up-regulates quantity by stabilization binding 9606 23019338 t miannu Nod2 is constitutively associated with a chaperone protein, Hsp90, which is required for Nod2 stability and protects Nod2 from degradation. SIGNOR-252415 0.326 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo. SIGNOR-101119 0.924 XIAP protein P98170 UNIPROT RIPK4 protein P57078 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 t miannu In this study, we report that in addition to RIP1 and RIP2, also RIP3 and RIP4 directly interact with XIAP, cIAP1 and cIAP2. When comparing the ability of these IAPs to directly conjugate RIP1–RIP4 with ubiquitin chains, we found that cIAP1 was the most effective E3 and was capable of ubiquitinating all four RIPs in the presence of the E2 component UbcH5a. On the contrary, XIAP was only capable of inducing weak ubiquitination of RIP4. SIGNOR-272716 0.339 PRKG1 protein Q13976 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser444 QRKSQRSsYVSMRID -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The 1 IC-loop does not have consensus sequences for PKG, but we found that this enzyme phosphorylated the same sites as PKA: S422, S423 (Fig. 5A).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262757 0.322 CLTC protein Q00610 UNIPROT AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 t lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-260670 0.735 RNF5 protein Q99942 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization ubiquitination Lys362 RAGMVPSkVPTSMVL 9606 BTO:0000007 20483786 t miannu In this study, we showed that the E3 ubiquitin ligase RING-finger protein 5 (RNF5) interacted with VISA at mitochondria in a viral infection-dependent manner. Domain mapping experiments indicated that the C-terminal transmembrane domain of VISA was required for its interaction with RNF5. RNF5 targeted VISA at K362 and K461 for K48-linked ubiquitination and degradation after viral infection, whereas knockdown of RNF5 reversed virus-induced downregulation of VISA at the early phase.  SIGNOR-271488 0.467 GSK3B protein P49841 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates activity phosphorylation Ser303 RVKEEPPsPPQSPRV -1 8940068 t Ser-303 is phosphorylated by glycogen synthase kinase 3 (GSK3) through a mechanism dependent on primary phosphorylation of Ser-307 by MAPK. Secondary phosphorylation of Ser-303 by GSK3 may thus repress the activity of HSF-1, and its requirement for priming by MAPK phosphorylation of Ser-307 provides a potential link between the MAPK cascade and HSF-1. SIGNOR-251216 0.539 dexmedetomidine chemical CHEBI:4466 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258906 0.8 LARP7 protein Q4G0J3 UNIPROT HEXIM1 protein O94992 UNIPROT down-regulates activity binding 9606 BTO:0000567 30824372 t Monia To investigate whether LARP7 is part of the known 7SK RNP implicated in the regulation of transcription, co‐immunoprecipitation studies were performed using the nuclear extracts of HeLa cells (Fig 3A, lanes 1–4). Antibodies against LARP7, CDK9 and HEXIM1 efficiently precipitated 7SK RNA, whereas no RNA was found in the control (Fig 3A, lower panel, lanes 1–4). Interestingly, HEXIM1, CDK9, CYCT1 and LARP7 were present in all immunopurifications, as determined by mass spectrometry of silver‐stained gels (Fig 3A; data not shown) and western blotting. In conclusion, these experiments show that LARP7 negatively regulates not only viral but also cellular POLII class genes through the 7SK P‐TEFb system. SIGNOR-261183 0.708 CD79A protein P11912 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268188 0.641 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 18997794 t gcesareni A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution. SIGNOR-182137 0.888 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR DYSF protein O75923 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136497 0.35 PRKACA protein P17612 UNIPROT SPTBN1 protein Q01082 UNIPROT down-regulates activity phosphorylation Thr2159 NGATEQRtSSKESSP -1 17088250 t miannu Short C-terminal splice variant of betaII-spectrin (betaIISigma2) is a substrate for phosphorylation. protein kinase A phosphorylates Thr-2159. Mammalian alphaII- and betaII-spectrin subunits form dimers that associate head to head with high affinity to form tetramers In vitro, protein kinase A phosphorylation of an active fragment of betaIISigma2 greatly reduced its interaction with alphaII-spectrin at the tetramerization site. SIGNOR-250054 0.336 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates activity phosphorylation Ser336 PGPQPPKsPGPHSEE 9606 BTO:0000567 12734188 t lperfetto Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9. SIGNOR-101051 0.369 RORA protein P35398 UNIPROT PCP4 protein P48539 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001011 19381306 t miannu RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice. SIGNOR-266848 0.2 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRB protein P10828 UNIPROT up-regulates activity chemical activation 10116 BTO:0000759 2158622 t miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. SIGNOR-258384 0.8 MAPK3 protein P27361 UNIPROT NUP50 protein Q9UKX7 UNIPROT down-regulates activity phosphorylation Ser315 TQSKPVSsPFPTKPL 9606 19767751 t llicata Erk phosphorylates nup50 at ser221 and ser315 phosphorylation of nup50 reduces affinity for importin-beta SIGNOR-187378 0.2 PIK-294 chemical CID:24905149 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206202 0.8 GSK3B protein P49841 UNIPROT PSEN1 protein P49768 UNIPROT down-regulates activity phosphorylation Ser357 PHRSTPEsRAAVQEL 9606 BTO:0000007 SIGNOR-C110 17360711 t gcesareni We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin. SIGNOR-153631 0.604 Caspase 1 complex complex SIGNOR-C220 SIGNOR IL1B protein P01584 UNIPROT up-regulates activity cleavage Asp116 DNEAYVHdAPVRSLN -1 1919001 t lperfetto IL-1 converting enzyme (ICE) specifically cleaves the human IL-1 beta precursor at two sequence-related sites: Asp27-Gly28 (site 1) and Asp116-Ala117 (site 2). Cleavage at Asp116-Ala117 results in the generation of mature, biologically active IL-1 beta.  SIGNOR-256376 0.795 perfluorodecanoic acid chemical CHEBI:35546 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation -1 31332417 t miannu In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group. SIGNOR-268758 0.8 sapitinib chemical CHEBI:132986 ChEBI ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates chemical inhibition 9606 BTO:0000551 20145185 t AZD8931 has a unique pharmacologic profile providing equipotent EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. gcesareni In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. SIGNOR-269874 0.8 MAPK3 protein P27361 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 10090 15060146 t miannu Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation. SIGNOR-123656 0.323 COL6A1 protein P12109 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. SIGNOR-254673 0.7 CEBPB protein P17676 UNIPROT C3 protein P01024 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 25617152 t Gianni CCAAT/enhancer binding protein β directly regulates the expression of the complement component 3 gene in neural cells: implications for the pro-inflammatory effects of this transcription factor SIGNOR-261927 0.262 APH1B protein Q8WW43 UNIPROT NCSTN protein Q92542 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t gcesareni By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.These data indicate that maph-1 is probably a functional component of the gamma-secretase complex SIGNOR-93307 0.939 IRAK1 protein P51617 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 8837778 t lperfetto Il-1 treatment of 293 cells induces the association of traf6 with irak. SIGNOR-44234 0.911 BTC protein P35070 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 10209155 t gcesareni Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4. SIGNOR-67003 0.737 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIK3 protein Q13003 UNIPROT up-regulates activity chemical activation 9606 27586965 t miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors SIGNOR-264472 0.8 SMARCE1 protein Q969G3 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270704 0.833 UTS2R protein Q9UKP6 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257051 0.268 MAPK1 protein P28482 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser65 PCSSVPSsPSFCAPS 9606 BTO:0000567 11416124 t miannu In the present study, we provide the first evidence that MafA is phosphorylated and that its biological properties strongly rely upon phosphorylation of serines 14 and 65, two residues located in the transcriptional activating domain within a consensus for phosphorylation by mitogen-activated protein kinases and which are conserved among Maf proteins. These residues are phosphorylated by ERK2 but not by p38, JNK, and ERK5 in vitro.  SIGNOR-275977 0.34 F2R protein P25116 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254848 0.2 TNKS protein O95271 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 BTO:0000007 19759537 t lperfetto Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin. SIGNOR-263381 0.764 Frizzled proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates binding 19279717 t apalma After binding of Wnt to the receptor complex, the signal is transduced to cytoplasmic phosphoprotein Dishevelled (Dsh/Dvl), and studies have uncovered that Dsh can directly interact with Fz SIGNOR-255892 0.2 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser204 DSRPRSQsSKAAIPP 9534 BTO:0001538 23519612 t miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. SIGNOR-262706 0.323 SGK3 protein Q96BR1 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 16543730 t lperfetto Phosphorylation of GSK3 by PKB or SGK1 inhibits GSK3 activity|estern blotting using an antibody specific for the PKB/SGK1 consensus phosphorylation site in GSK3a/beta (serine 21 and 9 respectively) revealed an increase in GSK3a/beta phosphorylation in human embryonic kidney 293 (HEK293) cells overexpressing wild type SGK1, constitutively active SGK1, but not catalytically inactive SGK1.|The effect of SGK1 was mimicked by PKB and SGK3. SIGNOR-249167 0.453 TRAF6 protein Q9Y4K3 UNIPROT HK2 protein P52789 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 28980855 t The Lys63-linked ubiquitination of HK2 catalyzed by the E3 ligase TRAF6 was critical for the subsequent recognition of HK2 by the autophagy receptor protein SQSTM1/p62 for the process of selective autophagic degradation. SIGNOR-260003 0.2 OPRK1 protein P41145 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257105 0.319 ABL2 protein P42684 UNIPROT ABL2 protein P42684 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr261 GLVTTLHyPAPKCNK -1 15735735 t miannu The results show that Arg is stabilized in response to 0.1 mM H2O2 by autophosphorylation of Y-261, consistent with involvement of the Arg kinase function in regulating Arg levels. The results further demonstrate that c-Abl-mediated phosphorylation of Arg on Y-261 similarly confers Arg stabilization.. These findings indicate that abrogation of the Arg kinase function by the Y261F mutation is dependent on phosphorylation of the Y-439 site. SIGNOR-276033 0.2 NVP-BSK805 dihydrochloride chemical CID:57339395 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194934 0.8 ANKRD11 protein Q6UB99 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10090 BTO:0000142 29274743 f miannu We showed that ANKRD11 regulates dendrite outgrowth, arborization, and spine formation via Trkb transcription and activation of its downstream effectors in the developing mouse brain. SIGNOR-266733 0.7 RNF139 protein Q8WU17 UNIPROT INSIG2 protein Q9Y5U4 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 20068067 t miannu Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner  SIGNOR-271956 0.447 TNKS protein O95271 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 19759537 t lperfetto Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin. SIGNOR-263379 0.765 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIA3 protein P42263 UNIPROT up-regulates activity chemical activation 9606 30825796 t miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by Œ±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses SIGNOR-264610 0.8 PRKCA protein P17252 UNIPROT PLEK protein P08567 UNIPROT up-regulates phosphorylation Ser117 ARKSTRRsIRLPETI 9606 7559487 t gcesareni To determine the role of pkc-dependent phosphorylation in pleckstrin function, we mapped the phosphorylation sites in vivo of wild-type and site-directed mutants of pleckstrin expressed in cos cells. Phosphorylation was found to occur almost exclusively on ser-113 and ser-117. Replacing all these sites with glycine decreased phosphorylation by > 90% and reduced pleckstrin's ability to inhibit phosphoinositide hydrolysis by as much as 80%. SIGNOR-28884 0.284 RPGR protein Q92834 UNIPROT RAB8A protein P61006 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 20631154 t miannu PGR interacts with the small GTPase RAB8A, which participates in cilia biogenesis and maintenance. We show that RPGR primarily associates with the GDP-bound form of RAB8A and stimulates GDP/GTP nucleotide exchange. RPGR functions as a GEF for RAB8A and RPGR–RAB8A association may facilitate ciliary trafficking. SIGNOR-253030 0.438 PRKCB protein P05771 UNIPROT NOX1 protein Q9Y5S8 UNIPROT up-regulates activity phosphorylation Thr430 CADHNLKtKKIYFYW -1 25228390 t lperfetto Site-directed mutagenesis and isothermal titration calorimetry indicated that protein kinase C-beta1 phosphorylates Nox1 at threonine 429. Moreover, Nox1 threonine 429 phosphorylation facilitated the association of Nox1 with the NoxA1 activation domain and was necessary for NADPH oxidase complex assembly SIGNOR-264729 0.2 RPS6KA3 protein P51812 UNIPROT KCNK3 protein O14649 UNIPROT up-regulates activity phosphorylation Ser393 GLMKRRSsV 9606 21357689 t gcesareni The chaperone protein, 14-3-3, binds to a critical phosphorylated serine in the channel c termini of k2p3.1 and k2p9.1 (ser(393) and ser(373), respectively) and overcomes retention in the endoplasmic reticulum by ?COP. We sought to identify the kinase responsible for phosphorylation of the terminal serine in human and rat variants of k2p3.1 and k2p9.1. Adopting a bioinformatic approach, three candidate protein kinases were identified: camp-dependent protein kinase, ribosomal s6 kinase, and protein kinase c. SIGNOR-172470 0.2 RPS6KB1 protein P23443 UNIPROT EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 15071500 t gcesareni S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function. SIGNOR-123997 0.768 SCNN1G protein P51170 UNIPROT CACNA1H protein O95180 UNIPROT up-regulates activity binding 9606 BTO:0000142 30736831 t miannu This study describes the functional interaction between Cav3.2 calcium channels and the Epithelial Sodium Channel (ENaC). β- and γ-ENaC subunits could be co-immunoprecipitated with Cav3.2 calcium channels from brain lysates, dorsal horn and lumbar dorsal root ganglia. Αβγ-ENaC channels enhanced Cav3.2 calcium channel trafficking to the plasma membrane in tsA-201 cells. This effect was reciprocal such that Cav3.2 channel expression also enhanced β-ENaC trafficking to the cell surface. these findings reveal ENaC as an interactor and potential regulator of Cav3.2 calcium channels expressed in neuronal tissues. SIGNOR-269274 0.2 Substance P smallmolecule CHEBI:80308 ChEBI TACR1 protein P25103 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257586 0.8 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr187 CDIQTHMtNNKGSAA -1 20538596 t lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-227540 0.2 CBX3 protein Q13185 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-264495 0.2 IKBKG protein Q9Y6K9 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity binding 9606 SIGNOR-C14 SIGNOR-C14 20300203 t lperfetto The n-terminal domain of ikkgamma is required both for the binding of ikkalfa and ikkbeta and their assembly into a high-molecular-weight complex essential for activation SIGNOR-164512 0.962 SRC protein P12931 UNIPROT ARHGAP5 protein Q13017 UNIPROT up-regulates activity phosphorylation Tyr1109 KGYSDEIyVVPDDSQ -1 9819392 t miannu Phosphotyrosine (p-Tyr)-dependent and -independent mechanisms of p190 RhoGAP-p120 RasGAP interaction: Tyr 1105 of p190, a substrate for c-Src, is the sole p-Tyr mediator of complex formation. Phosphorylation of Y1105, but not the minor site, was modulated in vivo to a greater extent by overexpression of c-Src than by the EGF receptor and was efficiently catalyzed by c-Src in vitro, indicating that Y1105 is a selective and preferential target of c-Src both in vitro and in vivo. SIGNOR-276170 0.591 FLT1 protein P17948 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). SIGNOR-276190 0.2 Nucleosome_H2A.Z.2 variant complex SIGNOR-C323 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 24311584 f miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. SIGNOR-263714 0.7 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser214 TVLTAQEsFSGSLGH -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276217 0.2 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr46 NKISADTtDNSGTVN -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276218 0.388 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser168 YREPLCLsPASSGSS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248364 0.598 Camostat mesylate chemical CID:5284360 PUBCHEM TMPRSS2 protein O15393 UNIPROT down-regulates activity chemical inhibition 9606 32142651 t Monia Ndeed, the clinically proven serine protease inhibitor camostat mesylate, which is active against TMPRSS2 (Kawase et al., 2012), partially blocked SARS-2-S-driven entry into Caco-2 (Figure S3 B) and Vero-TMPRSS2 cells, efficiently blocked 2019-nCoV-S-driven entry into Caco-2 (TMPRSS2+) but not 293T (TMPRSS2- 110 ) cells while the CatB/L inhibitor E64d had the opposite effect SIGNOR-261098 0.8 VKORC1 protein Q9BQB6 UNIPROT Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI up-regulates quantity chemical modification 9606 31226734 t lperfetto This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR) SIGNOR-265905 0.8 BAZ2B protein Q9UIF8 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity binding 9606 acetylation:Lys15 ARKSTGGkAPRKQLA 31999386 t miannu The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation. SIGNOR-266622 0.2 ARHGEF19 protein Q8IW93 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260543 0.62 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu53 RYNSGKLeEFVQGNL 10090 BTO:0001103 11133752 t lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. SIGNOR-263686 0.67 STIP1 protein P31948 UNIPROT HSP90AB1 protein P08238 UNIPROT down-regulates activity binding 9606 BTO:0000007 27353360 t miannu Hsp90 chaperone cycle is tightly regulated by another group of proteins referred to as ‘co-chaperones'. Their stability does not depend on Hsp90 function but they interact with distinct Hsp90 conformational states, providing directionality to the Hsp90 cycle4. Furthermore, certain co-chaperones, such as HOP and Cdc37p50 inhibit the Hsp90 chaperone cycle, assisting in delivery of distinct sets of client proteins (steroid hormone receptors and kinases, respectively) to the Hsp90 chaperone machine. SIGNOR-261412 0.848 NLGN4Y protein Q8NFZ3 UNIPROT NRXN2 protein P58401 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264158 0.2 CAPN2 protein P17655 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Thr45 LIGKVDGtSHVTGKG -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263582 0.302 Telatinib chemical CID:9808844 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207230 0.8 SRC protein P12931 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr42 DSMKDEEyEQMVKEL 9606 9792645 t llicata C-src phosphorylates IkappaB On tyrosine 42|NF-kappaB is sequestered in the cytosol by IkappaBalpha and, in most cells, released upon serine phosphorylation of this inhibitory protein which then undergoes rapid, ubiquitin-dependent degradation. SIGNOR-60879 0.675 CCNK protein O75909 UNIPROT CyclinK/CDK12 complex SIGNOR-C37 SIGNOR form complex binding 9606 22012619 t miannu We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells SIGNOR-176783 0.941 REST protein Q13127 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 10449787 f miannu We show here that CoREST, a newly identified human protein, functions as a corepressor for REST. A single zinc finger motif in REST is required for CoREST interaction. Together, REST and CoREST mediate repression of the type II sodium channel promoter in nonneural cells, and the REST/CoREST complex may mediate long-term repression essential to maintenance of cell identity. SIGNOR-220698 0.297 SNAP91 protein O60641 UNIPROT SYT1 protein P21579 UNIPROT up-regulates quantity binding 9606 BTO:0000938 26903854 t miannu  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively .Stonin-2 and AP-2 are also Required for Efficient Synaptotagmin-1 Retrieval.  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. SIGNOR-264114 0.617 CDK5 protein Q00535 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown phosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 t lperfetto In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. SIGNOR-249194 0.38 MAPK14 protein Q16539 UNIPROT EEA1 protein Q15075 UNIPROT up-regulates activity phosphorylation Thr1392 CSAKNALtPSSKKPV 10090 BTO:0002572 16138080 t lperfetto We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes SIGNOR-140082 0.47 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BIRC3 protein Q13489 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9916987 f gcesareni The iaps have been shown to be induced by nf-kappab or v-rel in multiple cell lines and conversely, hiap1 and hiap2 have been shown to activate nf-kappab possibly forming a positive feed-back loop. SIGNOR-64103 0.672 FYN protein P06241 UNIPROT FYB1 protein O15117 UNIPROT up-regulates activity phosphorylation Tyr595 IEDDQEVyDDVAEQD 9606 10570256 t  two tyrosines, Tyr595 and Tyr651, of FYB are major sites of phosphorylation by FYN-T and mediate binding to SLP-76 in Jurkat T cells. We further demonstrate that the loss of SLP-76 binding by mutation of these sites markedly reduced the ability of FYN-T-FYB-SLP-76 to up-regulate IL-2 transcription. SIGNOR-251163 0.2 adenosine smallmolecule CHEBI:16335 ChEBI ADORA1 protein P30542 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257446 0.8 RBM10 protein P98175 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0001938 30403180 f irozzo Cell apoptosis is an important event in cancer progression. Overexpression of RBM10 dramatically induced U2OS cell apoptosis compared with negative control cells. SIGNOR-259150 0.7 MRAP protein Q8TCY5 UNIPROT MC2R protein Q01718 UNIPROT up-regulates activity binding 10029 BTO:0000246 19329486 t miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor. SIGNOR-252360 0.755 NAE complex SIGNOR-C131 SIGNOR CUL5 protein Q93034 UNIPROT up-regulates activity neddylation 9606 25504797 t lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. SIGNOR-243166 0.622 saxagliptin chemical CHEBI:71272 ChEBI DPP4 protein P27487 UNIPROT down-regulates activity chemical inhibition 9606 19149538 t Luana Various classes of structurally different DPP IV inhibitors are currently being explored and few of them such as Sitagliptin and Vildagliptin were successfully launched. SIGNOR-257813 0.8 PFDN6 protein O15212 UNIPROT URI1 prefoldin co-chaperone complex SIGNOR-C514 SIGNOR form complex binding 9606 30484151 t miannu In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR95 SIGNOR-270918 0.628 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT unknown phosphorylation Ser440 SPLLMILsQLLPQQR -1 10608806 t llicata Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself. SIGNOR-250576 0.2 PTPRS protein Q13332 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 27225731 f miannu LAR (for leukocyte common antigen-related) is a family of receptor protein tyrosine phosphatases (LAR-RPTPs) with three known members: LAR/PTPRF, PTPδ/PTPRD, and PTPσ/PTPRS. In mammals, LAR-RPTPs have been shown to regulate dendrite and excitatory synapse development and maintenance SIGNOR-264091 0.7 SSTR4 protein P31391 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256680 0.483 CDK4 protein P11802 UNIPROT KAT2A protein Q92830 UNIPROT up-regulates activity phosphorylation Ser372 EEIYGANsPIWESGF 24870244 t lperfetto Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT) SIGNOR-275494 0.367 DYRK2 protein Q92630 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Thr509 PVFDLTTtPKGGTPA 9606 16611631 t lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro SIGNOR-145979 0.371 STAT6 protein P42226 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17093501 t lperfetto We found that IL-4, like IFN-gamma, induces rapid de novo expression of SOCS-1 in primary macrophages. Induction of SOCS-1 gene expression by IL-4 is STAT6-dependent. SIGNOR-249570 0.623 AURKB protein Q96GD4 UNIPROT VIM protein P08670 UNIPROT down-regulates phosphorylation Ser73 SAVRLRSsVPGVRLL 9606 12458200 t llicata By identifying eight aurora-b phosphorylation sites on vimentin in vitro, we have demonstrated that vimentin-ser-72 is an in vitrophosphorylation site of aurora-b. in vitro analyses revealed that aurora-b phosphorylates vimentin at approximately 2 mol phosphate/mol of substrate for 30 min and that this phosphorylation dramatically inhibits vimentin filament formation. SIGNOR-96057 0.398 SRC protein P12931 UNIPROT MPZL1 protein O95297 UNIPROT up-regulates phosphorylation Tyr263 NKSESVVyADIRKN 9606 11751924 t lperfetto Indeed, our studies indicated that cross-linking of pzr by cona lead to activation of c-src, which may be responsible for phosphorylation of pzr and possibly other proteins. Phosphorylation of pzr in turn recruits shp-2, which by itself is an essential signal transducertyrosine residues 241 and 263 embedded in the itims are responsible for the tyrosine phosphorylation of pzr SIGNOR-113410 0.48 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Ser371 VRRVPGSsGHLHKTE 9606 BTO:0000007 BTO:0000671 18270262 t gcesareni Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1). SIGNOR-160842 0.457 FLT3 protein P36888 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity binding 10090 BTO:0002882 phosphorylation:Tyr599 VDFREYEyDLKWEFP 16684964 t gcesareni Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation. SIGNOR-245057 0.54 NT5E protein P21589 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI down-regulates quantity chemical modification -1 31461341 t Luana Ecto-5'-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5'-monophosphate to adenosine. SIGNOR-269743 0.8 CRYGS protein P22914 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 10521291 f The γ-crystallin proteins are tightly folded in two domains with no free loops. It is possible that the R58H mutation destabilizes the contact between lens-fiber cells, which is critical for the maintenance of lens transparency. Improper folding of CRYGD, the most abundantly expressed γ-crystallin in the lens, could well cause protein aggregation and lens opacification. SIGNOR-253625 0.7 PPM1A protein P35813 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates dephosphorylation 9606 16751101 t lpetrilli Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads. SIGNOR-146919 0.655 tRNA(Asn) smallmolecule CHEBI:29172 ChEBI Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity precursor of 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270459 0.8 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206139 0.8 CIITA protein P33076 UNIPROT MYOG protein P15173 UNIPROT down-regulates binding 9606 BTO:0001103 28163303 t apalma During early stages of myogenesis, CIITA binds directly to myogenin (MYOG) and inactivates it, preventing MYOG-mediated induction of myogenic genes that are required for muscle differentiation and function SIGNOR-255111 0.2 AATK protein Q6ZMQ8 UNIPROT STK39 protein Q9UEW8 UNIPROT down-regulates 9606 17267545 f gcesareni Taken together, our data are consistent with aatyk1 indirectly inhibiting the spak/wnk4 activation of the cotransporter by scaffolding an inhibitory phosphatase in proximity to a stimulatory kinase. SIGNOR-152921 0.349 DUX4 protein Q9UBX2 UNIPROT HEY1 protein Q9Y5J3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24278031 f miannu HEY1, a repressor of myogenesis, is activated by DUX4 through a MaLR promoter. SIGNOR-253840 0.277 Urotensin II smallmolecule CHEBI:80244 ChEBI UTS2R protein Q9UKP6 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257590 0.8 Vincristine sulfate chemical CHEBI:79401 ChEBI FN1 protein P02751 UNIPROT down-regulates activity chemical inhibition 9606 30599272 t miannu Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. SIGNOR-259252 0.8 PRKCD protein Q05655 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS -1 8422248 t lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. SIGNOR-248927 0.468 KAT6A/KAT6B complex SIGNOR-C54 SIGNOR TP53 protein P04637 UNIPROT up-regulates acetylation Lys120 FLHSGTAkSVTCTYS 9606 BTO:0001271 23431171 t lperfetto We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression SIGNOR-217194 0.491 ATM protein Q13315 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT down-regulates phosphorylation Ser19 GTSKCPPsQRVPALT 9606 18536714 t llicata Disruption of the hipk2-siah-1 complex is mediated by the atm/atr pathway and involves atm/atr-dependent phosphorylation of siah-1 at ser 19. SIGNOR-177945 0.313 maraviroc chemical CHEBI:63608 ChEBI CCL3 protein P10147 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193928 0.8 MAP3K5 protein Q99683 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation 9606 11959862 t amattioni Activation of mkk7 by ask1 SIGNOR-117264 0.577 AAAS protein Q9NRG9 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262067 0.528 lysophosphatidylserine 14:0(1-) chemical CHEBI:72402 ChEBI GPR34 protein Q9UPC5 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257505 0.8 WDFY3 protein Q8IZQ1 UNIPROT GABARAP protein O95166 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000567 24668264 t miannu Here, we show that ALFY binds selectively to LC3C and the GABARAPs through a LIR in its WD40 domain. Binding of ALFY to GABARAP is indispensable for its recruitment to LC3B-positive structures and, thus, for the clearance of certain p62 structures by autophagy. SIGNOR-266796 0.682 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 17078951 t The effect has been demonstrated using P10636-8 lperfetto Here, we found that prephosphorylation by pka promotes gsk-3beta-catalyzed tau phosphorylation at thr181, ser199, ser202, thr205, thr217, thr231, ser396 and ser422 SIGNOR-150360 0.728 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr67 LSILSGGtPKRCLDL 9606 SIGNOR-C17 10864927 t gcesareni Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-78432 0.852 D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR RAD51 protein Q06609 UNIPROT up-regulates activity relocalization 9606 23438602 t lperfetto We examined the effect of XRCC3 depletion on redistribution of RAD51 upon IR damage|Interestingly, cells expressing the XRCC3 S225A phosphomutant showed compromised chromatin loading of RAD51 upon IR damage (Fig. 4G) while the nuclear and cytosolic fractions of RAD51 were largely unchanged|It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation. SIGNOR-263259 0.681 ADRA2A protein P08913 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257093 0.482 CSNK2A1 protein P68400 UNIPROT DDHD1 protein Q8NEL9 UNIPROT down-regulates activity phosphorylation Ser92 SDENYDFsSAESGSS -1 11328814 t miannu Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity SIGNOR-262973 0.2 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation 9606 24252238 t miannu Src homology-2 (SH2) containing tyrosine phosphatase and CD45 tyrosine phosphatase play a major role in modulating JAK-STAT pathway. SH2 containing tyrosine phosphatases include SHP1 and SHP2 (shatterproof 1 & 2). Their SH2 domains allow attachment to the phospho-tyrosine residues present on activated receptors, JAKs or STAT proteins, leading to dephosphorylation of the substrates. SIGNOR-255679 0.484 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1924 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273063 0.635 PRKAA1 protein Q13131 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser155 GRLKRERsMSENAVR 9606 26816379 t gcesareni A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission. SIGNOR-245953 0.2 Tosedostat chemical CID:15547703 PUBCHEM LAP3 protein P28838 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207417 0.8 LYN protein P07948 UNIPROT PAG1 protein Q9NWQ8 UNIPROT up-regulates activity phosphorylation Tyr317 EEEISAMySSVNKPG 9534 16920712 t miannu Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn. SIGNOR-262898 0.714 KDM5B protein Q9UGL1 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-265335 0.2 MAPK1 protein P28482 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser255 HATSGALsPAKDCGS 9606 BTO:0000567 9535909 t lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. SIGNOR-249401 0.596 FGF6 protein P10767 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates binding 9606 1385111 t gcesareni Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides. SIGNOR-18570 0.722 CTNNB1 protein P35222 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887 18316399 t gcesareni We showed that beta-catenin interacts directly with myod, a basic helix-loop-helix transcription factor essential for muscle differentiation and enhances its binding to e box elements and transcriptional activity. SIGNOR-161113 0.416 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Ser503 KENIFGEsRASTFCG 9606 19366211 t llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. SIGNOR-185299 0.2 ibuprofen chemical CHEBI:5855 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition -1 9544212 t miannu The IC50 values for two benchmark compounds were determined for comparison. The marketed NSAID ibuprofen was a modestly selective COX-1 inhibitor, while Searle's SC-5766614 was a highly selective (>100-fold) COX-2 inhibitor, results consistent with literature reports. SIGNOR-258883 0.8 EFNA5 protein P52803 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9330863 t gcesareni Highly promiscuous for ephrin-a ligands it binds preferentially efna5 and became active. SIGNOR-52470 0.942 HIPK2 protein Q9H2X6 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Thr53 KEPSEVPtPKRPRGR 9606 17960875 t gcesareni Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation. SIGNOR-158620 0.507 RIPK1 protein Q13546 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 21525013 t amattioni Degradation of ciaps triggers the release of receptor interacting protein kinase (ripk1) from tnf receptor i (tnfr1) to form a caspase-8 activating complex SIGNOR-173432 0.907 EDNRB protein P24530 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257053 0.426 MAPK1 protein P28482 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 16282323 t lperfetto Erk phosphorylation serves as a signal for bim ubiquitination and proteasomal degradation SIGNOR-141584 0.704 BRAF protein P15056 UNIPROT EEF1A1 protein P68104 UNIPROT down-regulates quantity by destabilization phosphorylation Thr88 ETSKYYVtIIDAPGH -1 22378069 t miannu Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.  SIGNOR-276405 0.265 SGK1 protein O00141 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity phosphorylation Ser203 DLEFSSGsPGKETNE 9606 23650397 t gcesareni SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation|Having demonstrated that SGK1 mediates the cortisol-induced increase in GR phosphorylation at the S203 and S211 phospho-sites, which enhance GR nuclear translocation, but not at the S226 site, which inhibits nuclear translocation SIGNOR-251669 0.473 EGR1 protein P18146 UNIPROT SLC4A2 protein P04920 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000269 22228178 f Cellular and molecular experiments indicated that AE2 expression promoted proliferation of colon cancer cells. In addition, we found that transcription factor EGR1 underlies AE2 upregulation and the AE2 sequester p16INK4a (P16) in the cytoplasm of colon cancer cells SIGNOR-254250 0.2 HCRTR1 protein O43613 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256733 0.252 D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI up-regulates quantity precursor of 9606 11724794 t miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion SIGNOR-266493 0.8 PAK3 protein O75914 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser714 EGVRNIKsMWEKGNV 9606 BTO:0000887;BTO:0001260 20858431 t gcesareni We investigated the effects of phosphorylation by p(21)-activated kinase 3 (pak) and calmodulin on the 22 kda c-terminal fragment of caldesmon (cad22). We substituted the major pak sites, ser-672 and ser-702, with either alanine or aspartic acid to mimic nonphosphorylated and constitutively phosphorylated states of caldesmon, respectively. Phosphorylation at these sites weakened ca(2+)-calmodulin binding further and reduced the inhibitory activity of cad22 in the absence of ca(2+)-calmodulin. SIGNOR-167976 0.2 KANSL1 protein Q7Z3B3 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 26243146 f miannu Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. SIGNOR-267172 0.7 ziprasidone chemical CHEBI:10119 ChEBI HTR1E protein P28566 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258503 0.8 SMURF2 protein Q9HAU4 UNIPROT STAMBP protein O95630 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 14755250 t miannu RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome. SIGNOR-272951 0.545 MAPK1 protein P28482 UNIPROT NCOA6 protein Q14686 UNIPROT up-regulates activity phosphorylation Ser884 NKDVTLTsPLLVNLL -1 11773444 t miannu In vitro phosphorylation studies with His-tagged TRBP (795–931) suggested that S884 can be phosphorylated by MAPK (ERK2) in vitro (Fig. 10A).Analysis of in vitro and in vivo receptor interactions with TRBP suggested that S884 allowed selective interactions for ERβ, TR, and RXR vs. ERα. SIGNOR-265882 0.2 PERP protein Q96FX8 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity ubiquitination 9606 25860612 t We identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling SIGNOR-255843 0.2 PKN1 protein Q16512 UNIPROT MEFV protein O15553 UNIPROT down-regulates activity phosphorylation Ser208 VRLRRNAsSAGRLQG 10090 BTO:0004732 27270401 t no miannu PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. SIGNOR-275462 0.392 PAX3-FOXO1 fusion protein SIGNOR-FP12 SIGNOR IGF2 protein P01344 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 t miannu Insulin-like growth factor is required for RMS cell growth and IGF2 is expressed in an autocrine manner by the tumour cells. The IGF2 locus shows a loss of imprinting in both ERMS and ARMS tumours and expression of PAX3-FOXO1 can induce the upregulation of IGF2, thus enhancing the activation of IGF signalling pathway in ARMS SIGNOR-251573 0.2 NCAPG protein Q9BPX3 UNIPROT Condensin I complex SIGNOR-C341 SIGNOR form complex binding 9606 32445620 t miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263902 0.961 MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 9712898 t lperfetto The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1 SIGNOR-236380 0.718 MAPK3 protein P27361 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 BTO:0000599 10915800 t lperfetto Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo. SIGNOR-80096 0.454 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation 9606 20708156 t gcesareni Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase. SIGNOR-167520 0.352 ARID1A protein O14497 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270729 0.781 ethanol chemical CHEBI:16236 ChEBI SLC44A2 protein Q8IWA5 UNIPROT up-regulates quantity 9606 BTO:0003065 21367571 f lperfetto Among these, SLC44A2 (a putative choline transporter) was strikingly upregulated by ethanol (three fold), and GCN5 silencing downregulated it SIGNOR-260407 0.8 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser511 DSPFYRDsLPGSQRK 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression. SIGNOR-183692 0.627 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates phosphorylation 9606 10212258 t gcesareni C-abl phosphorylates rad51 in vitro and in vivo. In assays using purified components, phosphorylation of rad51 by c-abl enhances complex formation between rad51 and rad52, which cooperates with rad51 in recombination and repair SIGNOR-67069 0.764 WWTR1 protein Q9GZV5 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 21084559 t lperfetto Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal. SIGNOR-232098 0.536 ZDHHC2 protein Q9UIJ5 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity palmitoylation Cys5 cIVTTKKY 9606 23836932 t Plasma membrane targeting of DHHC2 palmitoyltransferase rapidly recruited PSD-95 to the plasma membrane and proved essential for postsynaptic nanodomain formation. SIGNOR-261290 0.388 PTK6 protein Q13882 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr165 PSPATDLyQVPPGPG 9606 22084245 t lperfetto Protein-tyrosine kinase 6 promotes peripheral adhesion complex formation and cell migration by phosphorylating p130 crk-associated substrate. Tyrosine residues 165 and 664 of p130cas were both phosphorylated by ptk6 in vitro SIGNOR-177238 0.583 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr680 RDIYSTDyYRVGGRT 9606 9099755 t gcesareni In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785 SIGNOR-47175 0.2 moclobemide chemical CHEBI:83531 ChEBI MAOB protein P27338 UNIPROT down-regulates activity chemical inhibition -1 21680183 t Luana Twenty-two pyrazoline derivatives were synthesized and tested for their human MAO (hMAO) inhibitory activity. Twelve molecules with unsubstituted ring A and substituted ring C (5–16) were found to be potent inhibitors of hMAO-A isoform with SIMAO-A in the order 103 and 104.  SIGNOR-258315 0.8 PRKCD protein Q05655 UNIPROT SMPD1 protein P17405 UNIPROT up-regulates phosphorylation Ser510 DGNYSGSsHVVLDHE 9606 17303575 t lperfetto Activation of acid sphingomyelinase by protein kinase cdelta-mediated phosphorylation. Phosphorylation of ser(508) proved to be an indispensable step for asmase activation and membrane translocation in response to pma SIGNOR-153276 0.259 FLCN protein Q8NFG4 UNIPROT RRAGD protein Q9NQL2 UNIPROT up-regulates activity gtpase-activating protein 9606 BTO:0000007 24095279 t The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur SIGNOR-256504 0.674 PPP3CA protein Q08209 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity dephosphorylation Ser637 VPVARKLsAREQRDC 9606 18838687 t When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. SIGNOR-248676 0.28 EPHB1 protein P54762 UNIPROT NRCAM protein Q92823 UNIPROT up-regulates activity phosphorylation Tyr1276 DGSFIGQySGKKEKE 9606 BTO:0000007 24023801 t miannu EphB receptors were found to induce phosphorylation of NrCAM on the tyrosine residue within the FIGQY ankyrin binding motif, inhibiting ankyrin recruitment. Furthermore, NrCAM phospho-FIGQY levels in the SC were decreased in EphB1/3 and EphB1/2/3 null mice and increased in mutant mice overexpressing constitutively active EphB2 kinase. SIGNOR-262862 0.421 SMARCB1 protein Q12824 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270725 0.757 antigen smallmolecule CHEBI:59132 ChEBI BCR-Ml complex SIGNOR-C434 SIGNOR up-regulates activity binding 9606 BTO:0000776 32323266 t scontino The recognition of antigen by the BCR initiates BCR signaling cascade. SIGNOR-268203 0.8 FASLG protein P48023 UNIPROT FAS protein P25445 UNIPROT up-regulates activity binding 9606 BTO:0000007 BTO:0000671 9228058 t lperfetto The death-inducing receptor fas is activated when cross-linked by the type ii membrane protein faslg (fasl) SIGNOR-49688 0.9 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser249 GLSLSRFsWGAEGQR -1 2413024 t lperfetto MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. SIGNOR-248872 0.502 rRNA_transcription phenotype SIGNOR-PH145 SIGNOR 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR up-regulates 25901680 f lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262602 0.7 IL1B protein P01584 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates binding 9606 BTO:0001253 9625767 t gcesareni Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab). SIGNOR-58122 0.903 STOM protein P27105 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 BTO:0000424 33187473 t lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] SIGNOR-266040 0.356 CTDSP1 protein Q9GZU7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000007 17035229 t SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248794 0.494 MAPK3 protein P27361 UNIPROT ADAM17 protein P78536 UNIPROT up-regulates phosphorylation Thr735 KPFPAPQtPGRLQPA 9606 12058067 t gcesareni Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated sheddingwe show that extracellular signal-regulated kinase (erk) acts as an intermediate in protein kinase c-regulated trka cleavage. We report that the cytosolic tail of the tumor necrosis factor alpha-converting enzyme (tace) is phosphorylated by erk at threonine 735. In addition, we show that erk and tace associate. This association is favored by erk activation and by the presence of threonine 735. In contrast to the erk route, the p38 mapk was able to stimulate trka cleavage in cells devoid of tace activity, indicating that other proteases are also involved in trka shedding. SIGNOR-89625 0.369 aminoglutethimide chemical CHEBI:2654 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates activity chemical inhibition -1 19470632 t Luana  A new naturally occurring relatively common alteration of enzyme structure at T201M increases enzyme activity and reduces the inhibitory effect of aminoglutethimide. SIGNOR-257824 0.8 FOXO3 protein O43524 UNIPROT FASLG protein P48023 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10102273 f gcesareni Within the nucleus, fkhrl1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the fas ligand gene. SIGNOR-66035 0.697 PLK1 protein P53350 UNIPROT TNKS protein O95271 UNIPROT up-regulates quantity by stabilization phosphorylation Thr839 DTQGRNStPLHLAAG 9606 BTO:0000567 21818122 t miannu Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends.  SIGNOR-276245 0.438 AKT1 protein P31749 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser652 LERPFRPsVTSVGHV -1 24548923 t miannu Here we show that Akt-mediated NF-κB activation is mediated at least in part through direct phosphorylation of the adaptor protein Carma1, which we previously demonstrated could interact with Akt in a TCR ligation-dependent manner. The putative Akt phosphorylation sites in Carma1 are distinct from known PKC consensus sites. Mutation of S551, S637 and S645 in Carma1 to non-phosphorylatable residues decreased phosphorylation of GST-Carma1-linker construct by Akt in vitro.  SIGNOR-276256 0.537 MRPL21 protein Q7Z2W9 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262372 0.701 CSNK2A1 protein P68400 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates activity phosphorylation Ser324 PFRPQIRsELDVGNF 9606 BTO:0002181 19933278 t miannu Here we report that the CK2 protein kinase, which contributes to NF-kappaB activation following UV radiation in a p38-dependent manner, physically interacts with MSK2 but not MSK1 and that CK2 inhibition specifically impairs UV-induced MSK2 kinase activation. A putative site of CK2 phosphorylation was mapped to MSK2 residue Ser(324) and when substituted to alanine (S324A) also compromised MSK2 activity.Serine 324 is required for UV-induced MSK2 activation and for autophosphorylation at MSK2-Ser196. SIGNOR-276268 0.284 IFNAR1 protein P17181 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation 9606 21631354 t miannu These results indicate that NF-κB activation by IFN via the PI3K pathway is distinct from the ISRE-driven mechanism in regulating gene expression. Activation of PI3K/AKT by IFN has also been described through the insulin receptor substrate 1 (Uddin and others 1997) and through the direct interaction of PI3K with IFNAR1, which also leads to induction of NF-κB activity SIGNOR-260435 0.331 AKT2 protein P31751 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 17386266 t lperfetto Insulin-stimulated phosphorylation of pras40 by akt/pkb suppresses its mtorc1 inhibitory activity. SIGNOR-236705 0.568 APC-c complex SIGNOR-C150 SIGNOR USP37 protein Q86T82 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 21596315 t lperfetto USP37 is ubiquitinated by APCCDH1 in late mitosis and early G1 phase||Inactive USP37 now becomes a substrate for APCCDH1, undergoing K11-linked polyubiquitination and proteasomal degradation. Elimination of USP37 ensures that it does not antagonize APC/C substrate degradation during mitosis. SIGNOR-265048 0.294 HIF-1 complex complex SIGNOR-C418 SIGNOR LDHB protein P07195 UNIPROT up-regulates quantity transcriptional regulation 9606 7673128 t lperfetto Deletional and mutational analysis of the function of mouse LDH-reporter fusion gene constructs in transient transfection assays defined three domains, between -41 and -84 base pairs upstream of the transcription initiation site, which were crucial for oxygen-regulated expression. The most important of these, although not capable of driving hypoxic induction in isolation, had the consensus of a hypoxia-inducible factor 1 (HIF-1) site, and cross-competed for the binding of HIF-1 with functionally active Epo and phosphoglycerate kinase-1 sequences SIGNOR-267653 0.36 PARD6/SMURF1 complex SIGNOR-C112 SIGNOR RHOA protein P61586 UNIPROT down-regulates ubiquitination 9606 15761148 t lperfetto The Par6-Smurf1 complex then mediates the localized ubiquitination of RhoA to enable the TGF_-dependent dissolution of tight junctions during EMT. SIGNOR-227492 0.662 CRHR1 protein P34998 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 22869609 t lperfetto Previous studies have indicated that CRHR could couple to multiple Galpha proteins including Gs, Gi, and Gq/11 and then go on to induce changes in AC activity and activation of PLC-beta3 SIGNOR-268619 0.29 MYOG protein P15173 UNIPROT ITGA7 protein Q13683 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 8798472 t lperfetto Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development. SIGNOR-241521 0.287 SCN9A protein Q15858 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. SIGNOR-253449 0.7 ZMIZ1 protein Q9ULJ6 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 26522984 t miannu The N-terminal domain (NTD) of Zmiz1 is important for driving Myc transcription and proliferation […] Zmiz1 directly interacted with Notch1 via a tetratricopeptide repeat domain at a special class of Notch-regulatory sites. SIGNOR-263939 0.37 PAK2 protein Q13177 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Ser618 APTPPKRsSSFREMD 9606 18161990 t lperfetto The interaction of c-abl with the abl interactor protein abi2 is shown to be negatively regulated by phosphorylation of serines 637 and 638. These serines are adjacent to the pxxp motif (ptppkrs637s638sfr) that binds the sh3 domain of abi. phosphorylation of c-abl by pak2 inhibits the interaction between the sh3 domain of abi2 and the pxxp motif of c-abl. SIGNOR-160215 0.424 CDK1 protein P06493 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT down-regulates phosphorylation Ser368 PNPSTSAsPKKSPPP 9606 17488717 t gcesareni Here, we demonstrate that sirt2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1. Overexpression of sirt2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation. SIGNOR-154681 0.422 (-)-anisomycin chemical CHEBI:338412 ChEBI JUNB protein P17275 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling;phospho-JunB (Thr102/Thr104) (D3C6) Rabbit mAb #8053 gcesareni SIGNOR-189644 0.8 regorafenib chemical CHEBI:68647 ChEBI ABL1 protein P00519 UNIPROT down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259209 0.8 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Tyr185 TSFMMTPyVVTRYYR -1 11062067 t Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1). SIGNOR-251419 0.741 UBAP2L protein Q14157 UNIPROT RNF2 protein Q99496 UNIPROT up-regulates activity binding 9606 BTO:0000007 25185265 t Sara UBAP2L associates with BMI1 and RNF2. UBAP2L, BMI1, RNF2, and PHC1 define a novel Polycomb subcomplex SIGNOR-261316 0.358 HTR4 protein Q13639 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257242 0.255 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity precursor of 9606 11381136 t miannu The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR. SIGNOR-267302 0.8 SLC4A3 protein P48751 UNIPROT hydrogencarbonate smallmolecule CHEBI:17544 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 26136660 t miannu Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. In neurons, bicarbonate transport is mainly mediated by members of the SLC4A family of proteins. While the Na+-independent anion-exchanger SLC4A3 lowers the intraneuronal bicarbonate concentration, the Na+-dependent anion exchangers SLC4A8 (NDCBE) and SLC4A10 (NCBE) use the sodium gradient to accumulate bicarbonate in exchange of chloride SIGNOR-264917 0.8 calcium(2+) smallmolecule CHEBI:29108 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR up-regulates activity chemical activation 9606 21880741 t miannu Except for nfat5, nfatc1c4 are activated upon a rise in intracellular ca2+, which stimulates the serine/threonine phosphatase activity of calcineurin the ca2+-calcineurin signal is the most important signal for regulating nfat activation, but the signal that leads to ca2+ influx during neural tube differentiation is still unclear. SIGNOR-255462 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Ser362 ISSVPTPsPLGPLAG 9606 BTO:0000527 19941816 t lperfetto Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity SIGNOR-244521 0.2 PRKACA protein P17612 UNIPROT ITGA4 protein P13612 UNIPROT up-regulates activity phosphorylation Ser1021 QEENRRDsWSYINSK 9606 BTO:0000782 11533025 t lperfetto PKA phosphorylationin vitro blocks the binding of the alpha4 tail to paxillin. A mutation that mimics alpha4 phosphorylation disrupts paxillin binding and promotes cell spreading SIGNOR-110119 0.472 MDGA2 protein Q7Z553 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 26206665 f miannu MDGA2 acts as a novel tumour suppressor in gastric cancer through inhibiting cell proliferation, suppressing G1–S cell cycle transition and inducing cell apoptosis. SIGNOR-264239 0.7 TP53INP1 protein Q96A56 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates binding 9606 22421968 t gcesareni In this work, we show that tp53inp1 is also able to interact with atg8-family proteins and to induce autophagy-dependent cell death. mammalian cells contain multiple atg8 orthologs belonging to three subfamilies: microtubule-associated protein 1 light chain 3, -aminobutyric acid receptor-associated protein (gabarap) and -aminobutyric acid receptor-associated protein like 2 (gabarapl2). SIGNOR-196667 0.388 ITCH protein Q96J02 UNIPROT CFLAR protein O15519 UNIPROT down-regulates quantity ubiquitination 10090 16469705 t gcesareni Depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation. SIGNOR-245307 0.601 CDK2 protein P24941 UNIPROT CCDC6 protein Q16204 UNIPROT up-regulates phosphorylation Ser244 QPVSAPPsPRDISME 9606 14712216 t amattioni Serine 244 phosphorylation is required for h4 apoptotic function. SIGNOR-121198 0.2 RAC1 protein P63000 UNIPROT GIT1 protein Q9Y2X7 UNIPROT up-regulates activity binding 9606 39000072 t miannu Activated RAC1 interacts with GIT1, a GAP protein of ARF6, and causes the inactivation of ARF6 [78]. As ARF6 plays a role in the promotion of the recycling of macropinosomes to the plasma membrane [78], the inactivation of ARF6 by RAC1 reduces the recycling of macropinosomes. SIGNOR-277783 0.642 GIT1 protein Q9Y2X7 UNIPROT ARF6 protein P62330 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 39000072 t miannu Activated RAC1 interacts with GIT1, a GAP protein of ARF6, and causes the inactivation of ARF6 [78]. As ARF6 plays a role in the promotion of the recycling of macropinosomes to the plasma membrane, the inactivation of ARF6 by RAC1 reduces the recycling of macropinosomes. SIGNOR-277784 0.703 mTORC1 complex SIGNOR-C3 SIGNOR Lysosome fusion phenotype SIGNOR-PH231 SIGNOR down-regulates activity 9606 39000072 f miannu The fusion of matured macropinosomes with lysosomes is promoted by TRPML1, and degradation of macropinosomes is inhibited by mTORC1. SIGNOR-277786 0.7 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu65 MEETCSYeEAREVFE -1 9538022 t lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). SIGNOR-263670 0.598 MTHFR protein P42898 UNIPROT (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI up-regulates quantity chemical modification 9606 10720211 t lperfetto Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine. SIGNOR-268229 0.8 MAPK13 protein O15264 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 10581258 t gcesareni In mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-72687 0.443 SRC protein P12931 UNIPROT SOCS1 protein O15524 UNIPROT down-regulates activity phosphorylation Tyr80 LLDACGFyWGPLSVH -1 31101761 t miannu SOCS1 is phosphorylated on Y80 by SRC family kinase members SRC and YES1. SIGNOR-276857 0.462 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR TRIM71 protein Q2Q1W2 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269239 0.298 APC-c complex SIGNOR-C150 SIGNOR AURKA protein O14965 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0004055 12023018 t miannu We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity. SIGNOR-272612 0.421 MCOLN1 protein Q9GZU1 UNIPROT Lysosome fusion phenotype SIGNOR-PH231 SIGNOR up-regulates 9606 39000072 f miannu The fusion of matured macropinosomes with lysosomes is promoted by TRPML1, and degradation of macropinosomes is inhibited by mTORC1. SIGNOR-277788 0.7 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 8940173 t miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246244 0.2 HIPK2 protein Q9H2X6 UNIPROT ZBTB4 protein Q9P1Z0 UNIPROT down-regulates activity phosphorylation Thr983 AAPPAPPtPPPPTLP -1 19448668 t miannu The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4. SIGNOR-262882 0.387 DYRK1A protein Q13627 UNIPROT PLK2 protein Q9NYY3 UNIPROT up-regulates quantity by stabilization phosphorylation Ser358 VPDFHLSsPAKNFFK 9606 BTO:0000007 37387444 t miannu  In the present study, it was demonstrated that dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) interacts with and phosphorylates PLK2 at Ser358. DYRK1A-mediated phosphorylation of PLK2 increases its protein stability.  SIGNOR-277791 0.317 AMPK complex SIGNOR-C15 SIGNOR ARMC10 protein Q8N2F6 UNIPROT up-regulates activity phosphorylation Ser45 LGIRSSKsAGALEEG 9606 BTO:0002524 30631047 t miannu Further analysis using an AMPK consensus phosphorylation motif indicated that 32 of these sites are likely direct AMPK phosphorylation sites. We validated one uncharacterized protein, ARMC10, and demonstrated that the S45 site of ARMC10 can be phosphorylated by AMPK both in vitro and in vivo. Function assay of ARMC10 and ARMC10 phosphorylation at S45. SIGNOR-277792 0.2 MAPK9 protein P45984 UNIPROT KLF13 protein Q9Y2Y9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser119 GAAAAPPsPAWSEPE 10090 37029927 t miannu TGF-β-mediated downregulation of KLF13 by HDAC-mediated epigenetic silencing and JNK-induced phosphorylation abrogates the latter’s inhibitory effect on TGF-β signaling. SIGNOR-277796 0.2 CSNK2A2 protein P19784 UNIPROT SUZ12 protein Q15022 UNIPROT up-regulates activity phosphorylation Ser583 PQEMEVDsEDEKDPE 9606 BTO:0002181 36351927 t miannu CK2 is the kinase for the phosphorylation of S583 of SUZ12. SIGNOR-277797 0.2 PRKAA1 protein Q13131 UNIPROT KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser559 VQRKVSGsRGSFCKA 9606 BTO:0000007 30279167 t miannu Thus, AMPK directly phosphorylates the  subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser559 SIGNOR-277799 0.2 PRKAA1 protein Q13131 UNIPROT KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser592 KCNVKAKsNVDLRRS 9606 BTO:0000007 30279167 t miannu Thus, AMPK directly phosphorylates the  subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser560 SIGNOR-277800 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DHPS protein P49366 UNIPROT up-regulates activity phosphorylation Ser233 KNHIPVFsPALTDGS 9606 BTO:0002524 32989218 t miannu The Ser-233 phosphorylation of DHPS by ERK1/2 is important for its function in cell proliferation. SIGNOR-277801 0.2 AKT1 protein P31749 UNIPROT RAB3IP protein Q96QF0 UNIPROT up-regulates activity phosphorylation Ser165 LSRLRSPsVLEVREK 9606 BTO:0001950 36797475 t miannu Rabin8 is phosphorylated and activated by Akt in cells grown on stiff ECM. SIGNOR-277802 0.2 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR AIIB/b3 integrin complex SIGNOR-C173 SIGNOR down-regulates activity relocalization 9606 27871158 t lperfetto Integrin αIIbβ3 is retained by the actin cytoskeleton in resting platelets but is released to the cell surface during platelet activation.  SIGNOR-261864 0.7 ULK2 protein Q8IYT8 UNIPROT AMPK complex SIGNOR-C15 SIGNOR down-regulates phosphorylation 9606 21460634 t lperfetto We could prove that ulk1-mediated phosphorylation of ampk reduced its level of phosphorylation at t172 of the _-subunit and hence interferes with its catalytic activity. I SIGNOR-217487 0.306 PRKCZ protein Q05513 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 8810272 t gcesareni These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc. SIGNOR-43834 0.2 CHEK2 protein O96017 UNIPROT TRIM32 protein Q13049 UNIPROT up-regulates activity phosphorylation Ser55 LEKLLASsINGVRCP 9606 BTO:0000007 37943659 t miannu We show that CHK2 binds and phosphorylates TRIM32 at the S55 site, which then mediates K63-linked ubiquitination of ATG7 at the K45 site to initiate autophagy.  SIGNOR-277804 0.2 DYRK1A protein Q13627 UNIPROT PLK2 protein Q9NYY3 UNIPROT up-regulates quantity by stabilization phosphorylation Ser358 VPDFHLSsPAKNFFK 9606 BTO:0000007 37387444 t miannu  In the present study, it was demonstrated that dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) interacts with and phosphorylates PLK2 at Ser358. DYRK1A-mediated phosphorylation of PLK2 increases its protein stability.  SIGNOR-277805 0.317 AMPK complex SIGNOR-C15 SIGNOR ARMC10 protein Q8N2F6 UNIPROT up-regulates activity phosphorylation Ser45 LGIRSSKsAGALEEG 9606 BTO:0002524 30631047 t miannu Further analysis using an AMPK consensus phosphorylation motif indicated that 32 of these sites are likely direct AMPK phosphorylation sites. We validated one uncharacterized protein, ARMC10, and demonstrated that the S45 site of ARMC10 can be phosphorylated by AMPK both in vitro and in vivo. Function assay of ARMC10 and ARMC10 phosphorylation at S45. SIGNOR-277806 0.2 MAPK9 protein P45984 UNIPROT KLF13 protein Q9Y2Y9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser119 GAAAAPPsPAWSEPE 10090 37029927 t miannu TGF-β-mediated downregulation of KLF13 by HDAC-mediated epigenetic silencing and JNK-induced phosphorylation abrogates the latter’s inhibitory effect on TGF-β signaling. SIGNOR-277810 0.2 CSNK2A2 protein P19784 UNIPROT SUZ12 protein Q15022 UNIPROT up-regulates activity phosphorylation Ser583 PQEMEVDsEDEKDPE 9606 BTO:0002181 36351927 t miannu CK2 is the kinase for the phosphorylation of S583 of SUZ12. SIGNOR-277811 0.2 PRKAA1 protein Q13131 UNIPROT KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser559 VQRKVSGsRGSFCKA 9606 BTO:0000007 30279167 t miannu Thus, AMPK directly phosphorylates the  subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser559 SIGNOR-277813 0.2 PRKAA1 protein Q13131 UNIPROT KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser592 KCNVKAKsNVDLRRS 9606 BTO:0000007 30279167 t miannu Thus, AMPK directly phosphorylates the  subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser560 SIGNOR-277814 0.2 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI TAL2 protein Q16559 UNIPROT up-regulates quantity by expression 10090 24816818 f irozzo These results demonstrate for the first time that atRA induces Tal2 expression in P19 cells, and suggest that TAL2 commits to the acquisition of neural fate in brain development. SIGNOR-259087 0.8 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr875 GLITTLHyPAPKRNK 9606 16912036 t Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. SIGNOR-260816 0.2 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM6B protein O15054 UNIPROT up-regulates activity chemical activation 29981745 t lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. SIGNOR-273461 0.8 DDIT3 protein P35638 UNIPROT TRIB3 protein Q96RU7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002183 18940792 f miannu Exogenous CHOP expression enhanced the TRB3 gene induction by amino acid deprivation. SIGNOR-253839 0.59 STAT3 protein P40763 UNIPROT HSPA1B protein P0DMV9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19754877 f miannu Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress. SIGNOR-255241 0.2 KAT2B protein Q92831 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates acetylation Lys19 VKRLLGWkKSAGGSG 9606 SIGNOR-C7 17074756 t gcesareni We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfbeta-dependent manner. Smad2 is also acetylated by p/caf. The acetylation of smad2 was significantly higher than that of smad3. Lys(19) in the mh1 domain was identified as the major acetylated residue in both the long and short isoform of smad2.....acetylation of the short isoform of smad2 improves its dna binding activity in vitro and enhances its association with target promoters in vivo, thereby augmenting its transcriptional activity SIGNOR-150273 0.56 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DHPS protein P49366 UNIPROT up-regulates activity phosphorylation Ser233 KNHIPVFsPALTDGS 9606 BTO:0002524 32989218 t miannu The Ser-233 phosphorylation of DHPS by ERK1/2 is important for its function in cell proliferation. SIGNOR-277815 0.2 BTRC protein Q9Y297 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 10835356 t miannu Here we demonstrate that following IkappaB kinase (IkappaK)-mediated phosphorylation, the C-terminal domain of p105 (residues 918-934) serves as a recognition motif for the SCF(beta)(-TrCP) ubiquitin ligase.In vitro, SCF(beta)(-TrCP) specifically conjugates and promotes processing of phosphorylated p105. SIGNOR-272570 0.572 MAPK3 protein P27361 UNIPROT PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation Ser21 LEAGDLEsPLSEEFL 9606 BTO:0000599 10187842 t lperfetto We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution. SIGNOR-249474 0.585 HSP90AA1 protein P07900 UNIPROT FER protein P16591 UNIPROT down-regulates activity phosphorylation Tyr714 RQEDGGVySSSGLKQ 9606 BTO:0002181 19159681 t miannu Hsp90 and tyrosine616 are required for Fer tyrosine kinase activity.Taken together, our findings underscore the importance of Hsp90 and the residue, tyrosine616, which resides in the Hsp90 recognition loop, in maintaining Fer tyrosine kinase activity. SIGNOR-277818 0.304 RARA protein P10276 UNIPROT RXRG protein P48443 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-16466 0.655 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX10 protein P56693 UNIPROT down-regulates activity phosphorylation Thr244 GPPTPPTtPKTELQS 9606 BTO:0002806 29295999 t miannu Phosphorylation of SOX10 by ERK inhibits its transcription activity toward multiple target genes by interfering with the sumoylation of SOX10 at K55, which is essential for its transcription activity.ERK2 directly phosphorylates SOX10 at T240 and T244. SIGNOR-277820 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX10 protein P56693 UNIPROT down-regulates activity phosphorylation Thr240 GQSHGPPtPPTTPKT 9606 BTO:0002806 29295999 t miannu Phosphorylation of SOX10 by ERK inhibits its transcription activity toward multiple target genes by interfering with the sumoylation of SOX10 at K55, which is essential for its transcription activity.ERK2 directly phosphorylates SOX10 at T240 and T244. SIGNOR-277821 0.2 PRKACA protein P17612 UNIPROT TRPC5 protein Q9UL62 UNIPROT down-regulates quantity phosphorylation Ser794 SGGARAKsKSVSFNL 9606 BTO:0000007 21734191 t miannu Together, these results suggest that TRPC5 is directly phosphorylated by G(s)/cAMP/PKA at positions S794 and S796. These inhibitory effects were blocked by the protein kinase A (PKA) inhibitors, KT-5720 and H-89, as well as by two point mutations at consensus PKA phosphorylation sites on TRPC5 (S794A and S796A). SIGNOR-277823 0.2 RRN3 protein Q9NYV6 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR up-regulates activity relocalization 9606 BTO:0000567 11250903 t lperfetto HRRN3 is essential in the SL1-mediated recruitment of RNA Polymerase I to rRNA gene promoters|We conclude that hRRN3 functions to recruit initiation-competent Pol I to rRNA gene promoters. The essential role for hRRN3 in linking Pol I to SL1 suggests a mechanism for growth control of Pol I transcription. SIGNOR-269648 0.772 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPC5 protein Q9UL62 UNIPROT down-regulates quantity phosphorylation Ser796 GARAKSKsVSFNLGC 9606 BTO:0000007 21734191 t miannu Together, these results suggest that TRPC5 is directly phosphorylated by G(s)/cAMP/PKA at positions S794 and S796. These inhibitory effects were blocked by the protein kinase A (PKA) inhibitors, KT-5720 and H-89, as well as by two point mutations at consensus PKA phosphorylation sites on TRPC5 (S794A and S796A). SIGNOR-277824 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR PPM1B protein O75688 UNIPROT down-regulates quantity by destabilization phosphorylation Ser195 MIQRVNGsLAVSRAL 9606 BTO:0000007 23756813 t miannu Collectively, these data suggest that PKA destabilizes PP2Cβ upon inflammatory stimuli via phosphorylation of Ser-195 in PP2Cβ. SIGNOR-277825 0.2 ZBTB14 protein O43829 UNIPROT ZBTB14 protein O43829 UNIPROT up-regulates activity binding 9606 10080939 t miannu ZF5, which we have cloned as a transcriptional repressor on the mouse c-myc promoter, has the POZ domain at the amino-terminus and the Kruppel-type zinc finger domain at the carboxy-terminus. We demonstrated that the POZ domain has a function mediating homomeric protein-protein interaction and this interaction requires the zinc finger domain. SIGNOR-220534 0.2 CCL11 protein P51671 UNIPROT CCR3 protein P51677 UNIPROT up-regulates activity binding 9606 BTO:0000399 10706854 t Eotaxin and other CC chemokines acting via CC chemokine receptor-3 (CCR3) are believed to play an integral role in the development of eosinophilic inflammation in asthma and allergic inflammatory diseases. SIGNOR-256091 0.934 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation. SIGNOR-236206 0.866 RXRA protein P19793 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity binding 9606 10976919 t inferred from family member gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr). SIGNOR-267800 0.715 monoisononyl phthalate chemical CHEBI:132593 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. SIGNOR-268781 0.8 α-D-glucose smallmolecule CHEBI:17925 ChEBI alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266450 0.8 CAMK2B protein Q13554 UNIPROT PLCB3 protein Q01970 UNIPROT unknown phosphorylation Ser537 PSLEPQKsLGDEGLN 11325525 t llicata CaMK II phosphorylated PLCbeta3 but not PLCbeta1 in vitro. Phosphorylation occurred exclusively on 537Ser in the X-Y linker region of PLCbeta3. 537Ser was also phosphorylated in the basal state in cells and phosphorylation was enhanced by ionomycin treatment SIGNOR-250689 0.509 EPB41 protein P11171 UNIPROT DLG1 protein Q12959 UNIPROT up-regulates activity relocalization 9615 BTO:0000837 12807908 t lperfetto Together, our results demonstrate that in addition to the N-terminal targeting domain, the alternatively spliced I3 insertion plays a critical role in recruiting hDlg to the lateral membrane in epithelial cells via its interaction with protein 4.1R. SIGNOR-266011 0.485 BMP7 protein P18075 UNIPROT ACVR2A protein P27037 UNIPROT up-regulates binding 9606 9748228 t fspada We show that bmp7 and activin bind to the same type ii receptors, actrii and iib, but recruit distinct type i receptors into heteromeric receptor complexes SIGNOR-60237 0.759 bisindolylmaleimide i chemical CID:2396 PUBCHEM PRKCB protein P05771 UNIPROT down-regulates chemical inhibition 9606 Other t CellSignaling gcesareni SIGNOR-190347 0.8 ANGPT1 protein Q15389 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 f lperfetto Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. SIGNOR-241529 0.268 HDAC11 protein Q96DB2 UNIPROT BRD2 protein P25440 UNIPROT down-regulates activity binding 9606 BTO:0000007 30089714 t lperfetto Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to β-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone-binding protein. SIGNOR-262058 0.345 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr1253 EGSFESRyQQPFEDF 9606 BTO:0000142 1689310 t llicata We have identified the sites phosphorylated in vitro by epidermal growth factor (egf) receptor kinase in bovine brain phospholipase c-gamma (plc-gamma). They are tyrosine residues 472, 771, 783, and 1254. we propose, therefore, that the phosphorylation of plc-gamma by egf receptor kinase alters its interaction with putative inhibitory proteins and leads to its activation. SIGNOR-20976 0.835 MARK4 protein Q96L34 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser420 KHPTPGSsDPLIQPS -1 21204788 t miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). SIGNOR-273936 0.429 ATM protein Q13315 UNIPROT RAD17 protein O75943 UNIPROT unknown phosphorylation Ser656 SASELPAsQPQPFSA 9606 10608806 t lperfetto We determined a general phosphorylation consensus sequence for atm and identified putative in vitro targets by using glutathione s-transferase peptides as substrates. Putative atm in vitro targets include p95/nibrin, mre11, brca1, rad17, pts, wrn, and atm (s440) itself. SIGNOR-73524 0.841 GCG protein P01275 UNIPROT GLP1R protein P43220 UNIPROT up-regulates binding 9606 BTO:0000776 7937318 t gcesareni In the present study we stably expressed the rat b-cell glp-i receptor in cho cells and studied binding characteristics and receptor activation utilizing the naturally occurring receptor agonist glp-i(7-36)-amide (glp-i), the proglucagon-derived glp-i-related peptide oxyntomodulin, the glp-i receptor agonist exendin-4, and the specific antagonist exendin SIGNOR-34855 0.774 CDK5 protein Q00535 UNIPROT NES protein P48681 UNIPROT unknown phosphorylation Thr1299 GETLPDStPLGFYLR 10090 12832492 t llicata We identify nestin as a novel in vivo target for cdk5 and p35 kinase, a critical signaling determinant in development. Two cdk5-specific phosphorylation sites on nestin, Thr-1495 and Thr-316, were established, the latter of which was used as a marker for cdk5-specific phosphorylation in vivo. | Cdk5 activity is necessary for differentiation and the concomitant nestin reorganization in C2C12 myoblasts. SIGNOR-250669 0.563 PRKACA protein P17612 UNIPROT PSEN1 protein P49768 UNIPROT unknown phosphorylation Ser310 PEAQRRVsKNSKYNA -1 14576165 t miannu PKA-mediated phosphorylation of PS1 is completely inhibited by mutation of Ser310.phosphorylation of Ser310 does not inhibit the caspase-mediated cleavage of PS1, and the biological function of this phosphorylation event remains to be determined in further experiments. SIGNOR-250036 0.473 RAB5A protein P20339 UNIPROT RAB7A protein P51149 UNIPROT down-regulates activity binding 9606 BTO:0000567 30485418 t miannu The absence of active Rab7 prolongs ALS2presence and Rab5 activation on macropinosomes, indicating that activeRab7 is necessary for Rab5 inactivation through ALS2 dissociation and playskey roles in the Rab switch on macropinosomes. Taken together, active Rab7is necessary for Rab5 down-regulation through ALS2dissociation, thereby acting as a central component inthe Rab5-to-Rab7 switch in macropinocytosis SIGNOR-277780 0.685 RPS6KB1 protein P23443 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Ser1859 PPRIHRAsDPGLPAE 9606 23429703 t lperfetto Mtorc1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein s6 kinase 1 (s6k1), which directly phosphorylates s1859 on cad, the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. Growth signaling through mtorc1 thus stimulates the production of new nucleotides to accommodate an increase in rna and dna synthesis. SIGNOR-201117 0.38 RPS6K proteinfamily SIGNOR-PF26 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 t gcesareni We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling. SIGNOR-252789 0.2 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr373 TVLVKDStNRDSLDM 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. SIGNOR-129296 0.29 FCER1 complex SIGNOR-C200 SIGNOR SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates 9606 BTO:0000830 16470226 f Alessandro Palma It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits SIGNOR-254963 0.593 PLCG1 protein P19174 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation 9606 12645577 t gcesareni Tnf-alfa binds to tnfr1 and activates pc-plc to induce pkcalfa and c-src activation, leading to tyrosine phosphorylation of ikkbeta at tyr188 and tyr199. SIGNOR-99310 0.537 SMO protein Q99835 UNIPROT MBP protein P02686 UNIPROT up-regulates quantity transcriptional regulation 10090 35082605 f Non-canonical pathway (Gli1-indipendent): SMO/AMPK SimoneGraziosi We show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMPactivated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell. SIGNOR-269226 0.2 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT up-regulates activity phosphorylation Thr471 PIKPLIStPPVSSQP 9606 BTO:0000567 30021153 t lperfetto Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. SIGNOR-265034 0.2 MEF2D protein Q14814 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0000222 7739551 t lperfetto Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. SIGNOR-238715 0.555 ERC1 protein Q8IUD2 UNIPROT CHUK protein O15111 UNIPROT up-regulates binding 9606 SIGNOR-C14 15218148 t miannu Elks likely functions by recruiting ikappabalpha to the ikk complex and thus serves a regulatory function for ikk activation. SIGNOR-126430 0.573 lisinopril chemical CHEBI:43755 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition -1 9187274 t miannu We analyzed the inhibition of angiotensin I and AcSDKP hydrolysis as well as that of three synthetic ACE substrates by wild-type ACE and the N and C domains by using a range of specific ACE inhibitors. We demonstrate that captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, with K(i) values in the subnanomolar range. SIGNOR-258611 0.8 BRAP protein Q7Z569 UNIPROT BRAP protein Q7Z569 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 23105109 t miannu Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. SIGNOR-272027 0.2 RASGEF1C protein Q8N431 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-161508 0.2 STUB1 protein Q9UNE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 14701756 t miannu CHIP mediates the ubiquitination of Smad1. we demonstrate that the coexpression of Smad1 and Smad4 with the CHIP protein results in the degradation of the Smad proteins through a ubiquitin-mediated process.  SIGNOR-272948 0.334 NUP214 protein P35658 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 SIGNOR-C9 12917407 t gcesareni We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import. SIGNOR-117644 0.531 coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI acyl-CoA(4-) chemical CHEBI:58342 ChEBI up-regulates quantity precursor of 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272769 0.8 SGK1 protein O00141 UNIPROT GLI1 protein P08151 UNIPROT down-regulates binding 9606 25790864 t gcesareni SGK1 is known to inhibit another intrinsic pathway, the Hedgehog pathway, through downregulation of SMO and the GLI transcription factor family SIGNOR-251672 0.2 AKT2 protein P31751 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t gcesareni We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-78685 0.275 NLGN1 protein Q8N2Q7 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264144 0.834 IFNL1 protein Q8IU54 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 12469119 t gcesareni Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha. SIGNOR-96177 0.599 reserpine chemical CHEBI:28487 ChEBI SLC18A2 protein Q05940 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000318 8643547 t miannu Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2. SIGNOR-258490 0.8 TRPV4 protein Q9HBA0 UNIPROT UCP1 protein P25874 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000443 23021218 f lperfetto TRPV4 negatively regulated the expression of PGC1α, UCP1, and cellular respiration. Additionally, it potently controlled the expression of multiple proinflammatory genes involved in the development of insulin resistance. SIGNOR-253096 0.291 SKP2 protein Q13309 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27858941 t miannu DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1 SIGNOR-254775 0.27 LRRK2 protein Q5S007 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000938 21658387 t lperfetto A knockdown experiment using intact cells also demonstrated LRRK2-mediated phosphorylation of Akt1 (Ser473), suggesting that Akt1 is a convincing candidate for the physiological substrate of LRRK2. SIGNOR-174044 0.387 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TSC1 protein Q92574 UNIPROT down-regulates phosphorylation 9606 15851026 t lperfetto Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin. SIGNOR-244761 0.2 NDUFB5 protein O43674 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 SIGNOR-262168 0.823 dibutyl phthalate chemical CHEBI:535597 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 10116 33508418 t miannu Both in vitro and in vivo experiments have proved that DBP is a real activator of PPARα. he current study proves that plasticizer DBP has severe hepatotoxicity and could induce liver dysfunction even at normal doses after prolonged exposure. DBP might accumulate in the liver for a long time to activate PPARα/SREBP-1c/FAS/GPAT/AMPK and result in the accumulation of triglycerides and cholesterol in the liver. SIGNOR-268748 0.8 SRC protein P12931 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr126 AKSVTCTySPALNKM 9606 BTO:0002181 25071020 t miannu We recently found that ISGylation of the p53 tumor suppressor is an important novel mechanism to control its stability. Here we identified that Isg15-dependent regulation of p53 can be enhanced by different oncogenes. We further show that the Src-mediated phosphorylation of p53 on Tyr126 and Tyr220 has a positive effect on p53 ISGylation by enhancing Herc5 binding. SIGNOR-276668 0.539 JAK2 protein O60674 UNIPROT CTLA4 protein P16410 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 10842319 t Janus Kinase 2 (Jak2) was directly associated with a box 1-like motif in the cytoplasmic tail of CTLA-4 molecule. Jak2 phosphorylated Y-165 residue in the cytoplasmic region of CTLA-4. It has been reported that phosphorylation and dephosphorylation of tyrosine residue Y-165 in the cytoplasmic region of CTLA-4 play an important role in its negative signaling and cell surface expression. Some signaling molecules such as Src homology 2 protein tyrosine phosphatase 2 (SHP-2) and the p85 subunit of phosphatidylinositol 3 kinase (PI3 kinase) associate with phosphorylated tyrosine residue Y-165, through Src homology 2 (SH2) domains. On the other hand, the adapter complex proteins, AP-2 and AP-50 interact with the same tyrosine residue when unphosphorylated, resulting in clathrin-mediated endocytosis of CTLA-4 molecules. SIGNOR-251346 0.456 TLN1 protein Q9Y490 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257609 0.603 CSNK2A1 protein P68400 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT down-regulates activity phosphorylation Ser575 AGESLDQsMEEEEEE 9606 BTO:0000567 12591939 t llicata We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified SIGNOR-250844 0.381 DEK protein P35659 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 t miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription SIGNOR-268823 0.43 BRDT protein Q58F21 UNIPROT EIF4EBP1 protein Q13541 UNIPROT up-regulates quantity binding 9606 33125143 t lperfetto It was revealed that eIF4EBP1 interacted with BRDT, a novel interacting protein. In addition, the present study further demonstrated that BRDT inhibitors PLX51107 and INCB054329 blocked the progression of RCC cells, along with suppressing eIF4EBP1 and c‑myc expression. SIGNOR-262049 0.2 NR0B2 protein Q15466 UNIPROT ESR1 protein P03372 UNIPROT down-regulates binding 9606 BTO:0000975 11861507 t gcesareni Our results identify shp as an inhibitor of 4-oht agonist activity in rl95-2 human endometrial carcinoma cells that express endogenous er?. We conclude that shp does not decrease er expression, but rather it is the direct interaction of shp with er that inhibits er transcriptional activity. SIGNOR-115033 0.634 WNT5A protein P41221 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. SIGNOR-141434 0.696 AKT proteinfamily SIGNOR-PF24 SIGNOR AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Thr246 LPRPRLNtSDFQKLK 9606 BTO:0000007 12524439 t gcesareni Treatment of these cells with 4-hydroxytamoxifen stimulated the phosphorylation of wt PRAS40 but not the mutant PRAS40 in which Thr-246 was mutated. These results demonstrate that activation of Akt alone is sufficient to induce phosphorylation of PRAS40 SIGNOR-236929 0.2 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr1217 LNNQLFLyDTHQNLR 9606 11507089 t lperfetto These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2. SIGNOR-109750 0.769 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation Thr40 DAESYTFtVPRRHLE 23972993 t For phosphorylated residues see Figure 7 lperfetto Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP SIGNOR-274052 0.419 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation 9606 14967450 t inferred from 70% family members gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-270206 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252828 0.908 PI4KB protein Q9UBF8 UNIPROT Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 9534 BTO:0001444 22253445 f lperfetto PI4KB knockdown inhibits SARS-CoV S-mediated entry, whereas PI3KR1 knockdown increases SARS-CoV S-mediated entry SIGNOR-260734 0.7 NFIA protein Q12857 UNIPROT GAS6 protein Q14393 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268876 0.2 vandetanib chemical CHEBI:49960 ChEBI EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258306 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR CHUK protein O15111 UNIPROT up-regulates phosphorylation Thr23 EMRERLGtGGFGNVC 9606 SIGNOR-C14 19609947 t lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-244210 0.2 PDP1 protein Q9P0J1 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16510868 t lpetrilli We show that the mammalian pdps are important in dephosphorylation of bmp-activated smad1 but not tgf-beta-activated smad2 or smad3. Thus, pdps specifically inactivate smads in the bmp/dpp pathway. [...] These observations suggest that pdp1 and pdp2 are important for dephosphorylation of smad1. SIGNOR-144876 0.245 WNT10B protein O00744 UNIPROT FZD5 protein Q13467 UNIPROT up-regulates binding 9606 12055200 t fspada Inhibition of adipogenesis by wnt10b is likely mediated by‚ wnt‚ receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 8 SIGNOR-210164 0.604 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 9657565 t allergic rhinitis gcesareni SIGNOR-251689 0.8 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT up-regulates activity phosphorylation Ser44 GLKFMQAsEDLLKEH 9606 BTO:0000093 8245015 t miannu An acid-stable (nonhistidine) phosphorylation was identified on autophosphorylated purified recombinant Nm23 proteins and [32P]orthophosphate-labeled human breast carcinoma and murine melanoma Nm23. Phosphoamino acid analysis identified serine as the acid-stable phosphorylation and serine 44 as the major site of phosphorylation. The biological relevance of the novel phosphorylation identified herein is suggested by the direct correlation of in vivo Nm23 acid-stable phosphorylation levels, but not Nm23 NDPK activity, with suppression of tumor metastatic potential among control and nm23-1 transfected murine melanoma cells. SIGNOR-250303 0.2 (+)-pilocarpine chemical CHEBI:8207 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258628 0.8 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates activity phosphorylation Thr404 SSMSTEQtLASDTDS -1 11062067 t MKK7 also phosphorylates JNK2 alpha 2 at Thr-404 and Ser-407 in vitro. Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. SIGNOR-251418 0.622 SRC protein P12931 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT up-regulates phosphorylation Tyr1105 RNEEENIySVPHDST 9606 9819392 t lperfetto Phosphorylation of y1105, but not the minor site, was modulated in vivo to a greater extent by overexpression of c-src than by the egf receptor and was efficiently catalyzed by c-src in vitro. Mutation of y1105 from tyr to phe resulted in complete loss of p-tyr-dependent complex formation, indicating that p-y1105 was the sole p-tyr residue mediating binding to p120 SIGNOR-61670 0.763 FBN1 protein P35555 UNIPROT EFEMP2 protein O95967 UNIPROT down-regulates activity binding 9606 19570982 t Regulation of binding miannu Fibulin-4 and -5 are extracellular glycoproteins with essential non-compensatory roles in elastic fiber assembly. Both fibulins differentially bound N-terminal fibrillin-1, which strongly inhibited their binding to lysyl oxidase and tropoelastin. SIGNOR-251860 0.402 EGR1 protein P18146 UNIPROT FAS protein P25445 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 9300687 f Thus, Egr-1 seems to control the expression of downstream target genes not only as a transcriptional activator, but also as a repressor molecule. In B cells, Egr-1 therefore plays a critical role in integrating the short-lived signal delivered by triggering of the Ag receptor into phenotypic changes, including repression of CD95 and CD23 transcription. SIGNOR-254278 0.277 PPM1D protein O15297 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity dephosphorylation Ser367 DTRSLEIsQSYTTTQ 9606 18265945 t lperfetto More recently, Shreeram et al.  have also shown that Wip1 dephosphorylates human ATM at Ser367 as well as Ser1981.|Thus, overexpression of Wip1 in an oncogenic context could contribute to tumor promotion by inhibiting both p53 and ATM functions. SIGNOR-276955 0.501 PRKAA1 protein Q13131 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 SIGNOR-C15 11069105 t gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. SIGNOR-84061 0.453 NONO protein Q15233 UNIPROT NONO/SFPQ complex SIGNOR-C62 SIGNOR form complex binding 9606 BTO:0000017 9756848 t miannu We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i SIGNOR-60475 0.698 PTPN11 protein Q06124 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t miannu Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. SIGNOR-255754 0.66 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity by destabilization ubiquitination Lys779 TKWMEHVkLERLKQV 9606 BTO:0000938 17283082 t lperfetto Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage. SIGNOR-249576 0.657 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248747 0.727 SLITRK5 protein O94991 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity binding 10090 BTO:0001593 34326333 t miannu SLITRK5 interacts with SHH and PTCH1. Mechanistically, SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain. SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation. Thus, SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts that may be attractive as a therapeutic target to enhance bone formation. SIGNOR-268438 0.2 RFX1 protein P22670 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 9583676 t gcesareni We show that rfxi and c-abl are in direct interaction, in vitro and in cell extracts, through the rfxi proline rich (pxxp) motif and the c-abl sh3 domain. Remarkably, this interaction significantly potentiates c-abl but not v-abl auto-kinase activity SIGNOR-57516 0.2 naltrexone chemical CHEBI:7465 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258936 0.8 BCL2 protein P10415 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates binding 9606 17643073 t gcesareni In mammalian cells, the antiapoptotic protein, bcl-2, binds to beclin 1 during nonstarvation conditions and inhibits its autophagy function. SIGNOR-156941 0.732 SMARCC1 protein Q92922 UNIPROT SMARCE1 protein Q969G3 UNIPROT up-regulates quantity by stabilization 9606 20829358 f miannu We show that the mechanism of baf155-mediated stabilization of baf57 involves blocking its ubiquitination by preventing interaction with trip12, an e3 ubiquitin ligase. SIGNOR-167869 0.894 JAK1 protein P23458 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 19041276 t lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249488 0.691 NUP98 protein P52948 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262074 0.692 PHACTR1 protein Q9C0D0 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR up-regulates activity binding 9606 BTO:0001949 21939755 t lperfetto Phactr-1 was previously identified as protein phosphatase 1 (PP1) Œ±-interacting protein that possesses actin-binding domains. We showed that Phactr-1 depletion decreased PP1 activity, disrupted the fine-tuning of actin polymerization and impaired lamellipodial dynamics. Taken together our results strongly suggest that Phactr-1 is a key component in the angiogenic process. SIGNOR-264656 0.552 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000150 12167717 f lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-236353 0.81 PPP1CC protein P36873 UNIPROT AHCYL1 protein O43865 UNIPROT unknown dephosphorylation Ser68 RSLSRSIsQSSTDSY 10090 17635105 t Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1. SIGNOR-248498 0.2 BKM120 chemical CHEBI:71954 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252656 0.8 RPL6 protein Q02878 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262456 0.87 CAMK4 protein Q16566 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 BTO:0000887;BTO:0001103 12058061 t lperfetto Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs. SIGNOR-236575 0.489 ATF4 protein P18848 UNIPROT NLRP1 inflammasome complex SIGNOR-C224 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 26086088 t miannu Transcription Factor ATF4 Induces NLRP1 Inflammasome Expression During Endoplasmic Reticulum Stress. Here we report that expression of NLRP1, a core inflammasome component, is specifically up-regulated during severe ER stress conditions in human cell lines. Both IRE1α and PERK, but not the ATF6 pathway, modulate NLRP1 gene expression. Furthermore, using mutagenesis, chromatin immunoprecipitation and CRISPR-Cas9-mediated genome editing technology, we demonstrate that ATF4 transcription factor directly binds to NLRP1 promoter during ER stress. SIGNOR-260354 0.285 EGFR protein P00533 UNIPROT CALM3 protein P0DP25 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t miannu Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. SIGNOR-266335 0.39 masitinib chemical CHEBI:63450 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258246 0.8 RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 11369754 t gcesareni These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994. SIGNOR-108260 0.432 ACADM protein P11310 UNIPROT Fatty_acid_oxidation phenotype SIGNOR-PH129 SIGNOR up-regulates 9606 BTO:0001370 28974683 f lperfetto This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation SIGNOR-261265 0.7 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000773 11278964 t lperfetto Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion. SIGNOR-106436 0.793 THOC1 protein Q96FV9 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 t miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. SIGNOR-268508 0.913 GSK3B protein P49841 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 phosphorylation:Ser9 SGRPRTTsFAESCKP 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245432 0.606 IRAK1 protein P51617 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 15465816 t gcesareni Irak1 can directly use stat3 as a substrate and cause stat3 serine 727 phosphorylation. SIGNOR-129685 0.566 POMC protein P01189 UNIPROT MC3R protein P41968 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268705 0.75 FLT3 protein P36888 UNIPROT IDH2 protein P48735 UNIPROT down-regulates activity phosphorylation Tyr107 SALATQKySVAVKCA 9606 BTO:0001545 34289383 t lperfetto FLT3 promotes mIDH2 acetylation through Y107 phosphorylation of mIDH2 that enhances ACAT1 recruitment, SIGNOR-267632 0.431 PTPN6 protein P29350 UNIPROT LCK protein P06239 UNIPROT down-regulates activity dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 11294838 t lperfetto We demonstrate that shp-1 dephosphorylates the lymphoid-specific src family kinase lck at tyr-394. Because phosphorylation of tyr-394 activates lck, the fact that shp-1 specifically dephosphorylates this site suggests that shp-1 is a negative regulator of lck. SIGNOR-106604 0.597 SRR protein Q9GZT4 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity chemical modification 10090 BTO:0000142 12393813 t lperfetto High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media. SIGNOR-268268 0.8 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 15241418 t lperfetto We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity SIGNOR-232146 0.748 CSNK2A1 protein P68400 UNIPROT WASF2 protein Q9Y6W5 UNIPROT down-regulates phosphorylation Ser497 EFDEDDWsD 9606 19012317 t gcesareni Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo. SIGNOR-182362 0.2 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIK4 protein Q16099 UNIPROT up-regulates activity chemical activation 9606 27586965 t miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors SIGNOR-264473 0.8 PPP1CA protein P62136 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity dephosphorylation 9606 32585168 t miannu The current study assessed whether PP1\u03b1 can stimulate GR function and tested two different hypotheses: First, that PP1\u03b1 regulates GR activity through suppression of MDM2 activity by dephosphorylating it at Ser166, thereby reducing the MDM2-mediated ubiquitination of GR and the subsequent proteasomal degradation of the receptor, as shown for the MR and AR ( xref ; xref ); and second, that PP1\u03b1 directly dephosphorylates the GR at a particular site to relieve functional repression as demonstrated for PP2A and PP5 ( xref ; xref ; xref ).|The involvement of GR-Ser211 phosphorylation supports the assumption that altered subcellular trafficking is a mechanism less likely contributing to the PP1\u03b1-dependent GR activation. SIGNOR-277161 0.295 PTPN11 protein Q06124 UNIPROT GRB7 protein Q14451 UNIPROT up-regulates activity dephosphorylation 9606 20142421 t miannu Dephosphorylation of Grb7 was blocked by the SHP inhibitor NSC-87877 (Zhan et al., 2009), supporting the specificity of SHP-2 in dephosphorylating Grb7.|Nuclear SHP-2 mediates the formation of an EGF induced complex of Grb7, HuR, and CRM1.|Using the \u03ba\u2013opioid receptor (OR [KOR]) as a model, we demonstrate that EGF activates nuclear SHP-2 (Src homology region 2\u2013containing tyrosine phosphatase), which dephosphorylates Grb7 in the nucleus. SIGNOR-277169 0.446 MAPK8 protein P45983 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates phosphorylation Ser95 TSSSSATsPASASFK 9606 17023523 t llicata We also identified the exact phosphorylation site of jnk to be serine 95 at the n terminus of tr3, around which a classical jnk phosphorylation motif exists. Furthermore, we demonstrated that tr3 phosphorylation by jnk coincided with its ubiquitination and degradation, resulting in the loss of its mitogenic activity. SIGNOR-149998 0.514 AKT1 protein P31749 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Thr1462 GLRPRGYtISDSAPS 10090 BTO:0000944 12150915 t lperfetto We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines. SIGNOR-235515 0.81 LTF protein P02788 UNIPROT iron(3+) smallmolecule CHEBI:29034 ChEBI up-regulates quantity relocalization 9606 11747454 t Lactoferrin (Lf), a major iron-binding protein in human milk, has been suggested to have multiple biological roles such as facilitating iron absorption, modulating the immune system, embryonic development, and cell proliferation. SIGNOR-272473 0.8 Survival Factors stimulus SIGNOR-ST8 SIGNOR BAD protein Q92934 UNIPROT down-regulates 9606 BTO:0000938 9346240 f lperfetto Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death MachineryAkt phosphorylates BAD in vitro and in vivo, and blocks the BAD-induced death of primary neurons in a site-specific manner. SIGNOR-209693 0.7 IMMT protein Q16891 UNIPROT PINK1 protein Q9BXM7 UNIPROT up-regulates activity binding -1 27153535 t miannu MIC60 Is Crucial for Parkin Recruitment and Transiently Interacts with PINK1 SIGNOR-266301 0.409 PRKACA protein P17612 UNIPROT HMGCR protein P04035 UNIPROT down-regulates activity phosphorylation Ser872 SHMIHNRsKINLQDL 10116 2369897 t miannu The intact, 100 kd microsomal enzyme and the 53 kd catalytic fragment of rat HMG-CoA reductase are both phosphorylated and inactivated by the AMP-activated protein kinase. this site is highly phosphorylated in intact liver under these conditions (Ser872 in the human enzyme). SIGNOR-249992 0.339 GAK protein O14976 UNIPROT CLTC protein Q00610 UNIPROT up-regulates activity phosphorylation Thr606 ILGNQMFtHYDRAHI 10090 31272276 t miannu Clathrin heavy chain (CHC) was phosphorylated at T606 by its association partner cyclin G-associated kinase (GAK). This phosphorylation was required for proper cell proliferation and tumor growth of cells implanted into nude mice.  SIGNOR-275448 0.852 NLGN4Y protein Q8NFZ3 UNIPROT NRXN1 protein P58400 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264148 0.2 SYK protein P43405 UNIPROT HCLS1 protein P14317 UNIPROT up-regulates phosphorylation Tyr397 EDEPEGDyEEVLEPE 9606 BTO:0000776 9104825 t llicata Here, we show that bcr-associated tyrosine kinases lyn and syk synergistically phosphorylate hs1, and that tyr-378 and tyr-397 of hs1 are the critical residues for its bcr-induced phosphorylation. once the two tyrosine residues are both phosphorylated, processive phosphorylation of hs1 by lyn and the other src family kinases would take place, producing hyperphosphorylated form of hs1. Finally, it is this hyperphosphorylated form of hs1 that translocates to the nucleus and activates b cell apoptosis. SIGNOR-47342 0.653 EIF4E protein P06730 UNIPROT Translational_regulation phenotype SIGNOR-PH202 SIGNOR up-regulates 9606 30459806 f gianni The mRNA cap-binding protein, eukaryotic translation initiation factor 4E (eIF4E), is involved in the recruitment of the ribosome to the mRNA cap structure, playing a central role in the regulation of translation initiation SIGNOR-268529 0.7 PRKCD protein Q05655 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates activity phosphorylation Ser40 SREVFDFsQRRKEYE -1 12198130 t lperfetto Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription. SIGNOR-249161 0.378 EID2 protein Q8N6I1 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR down-regulates activity binding 9606 14612439 t lperfetto Stable expression of eid-2 in the tgf-beta1-responsive cell line inhibits endogenous smad3-smad4 complex formation and tgf-beta1-induced expression of p21 and p15. These results suggest that eid-2 may function as an endogenous suppressor of tgf-beta signaling. SIGNOR-119174 0.408 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1C protein Q8TCG5 UNIPROT down-regulates activity binding 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267116 0.8 AURKA protein O14965 UNIPROT ALDH1A1 protein P00352 UNIPROT up-regulates activity phosphorylation Thr493 YTEVKTVtVKISQKN -1 28193222 t miannu AURKA phosphorylates ALDH1A1 at three critical residues which exert a multifaceted regulation over its level, enzymatic activity, and quaternary structure. While all three phosphorylation sites contribute to its increased stability, T267 phosphorylation primarily regulates ALDH1A1 activity. AURKA-mediated phosphorylation rapidly dissociates tetrameric ALDH1A1 into a highly active monomeric species.  SIGNOR-276749 0.38 TFIIH complex SIGNOR-C457 SIGNOR NR5A1 protein Q13285 UNIPROT up-regulates phosphorylation Ser203 EYPEPYAsPPQPGLP 9606 17901130 t llicata In conclusion, our results indicate that cdk7, as part of the cak complex and tfiih, phosphorylates sf1 at s203 followed by increased transcriptional activity of sf1 SIGNOR-269355 0.2 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr465 VPVPTNLyGDFFTGD -1 10210201 t llicata Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624. SIGNOR-250784 0.575 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates phosphorylation Thr531 NTTGSDNtDTEGS 9606 17936701 t lperfetto Pvhl acts as an adaptor to promote the inhibitory phosphorylation of the nf-kappab agonist card9 by ck2. The card9 c terminus contains multiple serine and threonine residues that resemble ck2 phosphorylation sites. Mass spectrometry analysis of myc-card9 recovered from hela cells revealed that these sites, including t531 and t533, were phosphorylated in vivo SIGNOR-158414 0.352 MAPK8IP3 protein Q9UPT6 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 10629060 t gcesareni These data demonstrate that jip3 interacts with proteins that can form a mapk signaling module, including jnk, mkk7, and mlk3jip3 increases mlk3-stimulated jnk activity. SIGNOR-73909 0.537 GNGT1 protein P63211 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 17419683 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-252686 0.401 AMPK complex SIGNOR-C15 SIGNOR TXNIP protein Q9H3M7 UNIPROT down-regulates quantity by destabilization phosphorylation Ser308 GLSSRTSsMASRTSS 10116 BTO:0000575 23453806 t miannu AMPK phosphorylation of TXNIP on S308 accelerates its degradation SIGNOR-276489 0.285 PTK2B protein Q14289 UNIPROT ASAP1 protein Q9ULH1 UNIPROT down-regulates activity phosphorylation Tyr323 QLQGNKEyGSEKKGY 9606 BTO:0000007 12771146 t miannu The tyrosine kinase Pyk2 regulates Arf1 activity by phosphorylation and inhibition of the Arf-GTPase-activating protein ASAP1. Pyk2 directly phosphorylates ASAP1 on tyrosine residues in vitro and increases ASAP1 tyrosine phosphorylation when co-expressed in HEK293T cells.Phosphorylation of tyrosine 308 and 782 affects the phosphoinositide binding profile of ASAP1, and fluorimetric Arf-GTPase assays with purified proteins revealed an inhibition of ASAP1 GTPase-activating protein activity by Pyk2-mediated tyrosine phosphorylation. SIGNOR-263186 0.469 IRF3 protein Q14653 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 27337441 t lperfetto Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation SIGNOR-251721 0.416 SLBP protein Q14493 UNIPROT H2AC1 protein Q96QV6 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265401 0.2 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Ser689 SQEFPYKsEMDSMPY 9606 BTO:0000567 34198826 t miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. SIGNOR-276660 0.252 PRKAR2B protein P31323 UNIPROT PRKACB protein P22694 UNIPROT down-regulates activity binding 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258758 0.89 CSNK2A1 protein P68400 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Ser102 NLNENQAsEEEDELG -1 2557337 t llicata Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase SIGNOR-250927 0.347 DDAH2 protein O95865 UNIPROT nitric oxide smallmolecule CHEBI:16480 ChEBI up-regulates quantity 33850055 f lperfetto Upon viral infection, DDAH2 relocated to mitochondria, where it induced the production of nitric oxide (NO) and the activation of dynamin-related protein 1 (Drp1) SIGNOR-275649 0.8 CDK1 protein P06493 UNIPROT DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr323 GCHLLVAtPGRLVDM 9606 SIGNOR-C17 16280325 t lperfetto Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis. SIGNOR-141569 0.301 CSNK2A1 protein P68400 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates phosphorylation 9606 15747065 t gcesareni Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex. Ck1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays. SIGNOR-134500 0.308 UBE2D2 protein P62837 UNIPROT PDZRN3 protein Q9UPQ7 UNIPROT up-regulates activity binding 9534 BTO:0000298 17576800 t miannu Our initial tests of various E2s showed that the RING domain of PDZRN3 exhibits ubiquitin ligase activity in the presence of E1 and the UbcH5 family of E2 enzymes (Fig. 3 A). Consistent with this finding, GST pull-down assays showed that PDZRN3 directly interacts with the UbcH5B ubiquitin conjugating enzyme (Fig. 3 B).  SIGNOR-271663 0.394 INTS3 protein Q68E01 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261485 0.891 HOXA9 protein P31269 UNIPROT IGF1 protein P05019 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25252870 f miannu Hoxa9bound directly to the putative promoter and a dnase-hypersensitive region in the first intron of the igf1 gene. Transcription rates of the igf1 gene paralleledhoxa9activity SIGNOR-205308 0.2 HRH3 protein Q9Y5N1 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256689 0.413 CSNK2A1 protein P68400 UNIPROT RGS19 protein P49795 UNIPROT unknown phosphorylation Ser24 ADRPPSMsSHDTASP -1 10760275 t llicata Phosphorylation was Mn(2+)-dependent, using both purified CK2 and CCVs. Ser-24 was identified as one of the phosphorylation sites. Our results establish that GAIP is phosphorylated and that only the membrane pool is phosphorylated, suggesting that GAIP can be regulated by phosphorylation events taking place at the level of clathrin-coated pits and vesicles. SIGNOR-250943 0.335 CDK20 protein Q8IZL9 UNIPROT CILK1 protein Q9UPZ9 UNIPROT up-regulates phosphorylation Thr157 IRSKPPYtDYVSTRW 9606 15988018 t lperfetto Recombinant cak1p phosphorylates thr-157 in the tdy motif of recombinant ick and activates its activity in vitro. SIGNOR-138420 0.2 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA12 protein O60330 UNIPROT up-regulates activity binding 9606 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265676 0.2 OS9 protein Q13438 UNIPROT TRPV4 protein Q9HBA0 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 17932042 t miannu Here we report that OS-9, a ubiquitously expressed endoplasmic reticulum (ER)-associated protein, interacts with the cytosolic N-terminal tail of TRPV4.Thus, OS-9 regulates the secretory transport of TRPV4 and appears to protect TRPV4 subunits from the precocious ubiquitination and ER-associated degradation. Our data suggest that OS-9 functions as an auxiliary protein for TRPV4 maturation. SIGNOR-261064 0.382 clonidine chemical CHEBI:46631 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258905 0.8 MED21 protein Q13503 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266678 0.807 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates 10090 BTO:0002572 22863277 f inferred from 70% of family members milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. SIGNOR-269868 0.8 TP53 protein P04637 UNIPROT FNTA protein P49354 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26469958 f lperfetto In this study, we provided evidence that p53 induces the expression of a group of enzymes of the MVA pathway including 3'-hydroxy-3'-methylglutaryl-coenzyme A reductase, MVA kinase, farnesyl diphosphate synthase and farnesyl diphosphate farnesyl transferase 1, in the human glioblastoma multiforme cell line, U343 cells, and in normal human astrocytes, NHAs. SIGNOR-242408 0.2 MAX protein P61244 UNIPROT MXD3 protein Q9BW11 UNIPROT up-regulates activity binding 9606 7954804 t 2 miannu the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. SIGNOR-240393 0.479 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr611 ETLPISStPSKSVLP 9606 19737929 t lperfetto A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1further analysis reveals that the leu-641 residue within an lxl motif is required for the recruitment of the cyclin-cdk complex, and the thr-596 residue is a critical cdk1 phosphorylation site within the activation domain of foxm1b. Cdk-dependent phosphorylation stimulates the foxm1b transcriptional activity SIGNOR-216837 0.752 YWHAE protein P62258 UNIPROT TBP protein P20226 UNIPROT up-regulates activity binding 10449590 t lperfetto The in vitro binding with general transcription factors TBP and TFIIB together with its nuclear location provide evidence supporting a role for 14-3-3 proteins as transcriptional activators or coactivators when part of a DNA binding complex. SIGNOR-262834 0.354 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248735 0.727 CASP6 protein P55212 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261745 0.37 TNFRSF1B protein P20333 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 20887952 f These results indicate that TNF-a-activated p38 pathway negatively controls the expansion of PAX7-positive SCs SIGNOR-253603 0.305 sirolimus chemical CHEBI:9168 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR down-regulates chemical inhibition -1 17350953 t lperfetto Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kDa FK506- and rapamycin-binding protein (FKBP12, or FKBP) and the FKBP-rapamycin binding (FRB) domain of the mammalian target of rapamycin (mTOR) kinase. The resulting ternary complex has been used to conditionally perturb protein function, and one such method involves perturbation of a protein of interest through its mislocalization. SIGNOR-219385 0.8 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Ser214 AVDQGNEsIVAKTTV 9606 19468302 t llicata Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex. SIGNOR-185754 0.657 ECM stimulus SIGNOR-ST20 SIGNOR AL/b2 integrin complex SIGNOR-C169 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259051 0.7 GPHA2 protein Q96T91 UNIPROT TSHR protein P16473 UNIPROT up-regulates binding 9606 12045258 t gcesareni Recombinant a2/b5 heterodimeric glycoproteins, purified using cation exchange and size fractionation chromatography, activated human tsh receptors, but not lh and fsh receptors, and showed high affinity to tsh receptors in a radioligand receptor assay SIGNOR-88614 0.527 SLC6A4 protein P31645 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI up-regulates quantity relocalization 9606 BTO:0000132 17506858 t miannu Serotonin (5HT) is a platelet-stored vasoconstrictor. Altered concentrations of circulating 5HT are implicated in several pathologic conditions, including hypertension. The actions of 5HT are mediated by different types of receptors and terminated by a single 5HT transporter (SERT). Therefore, SERT is a major mechanism that regulates plasma 5HT levels to prevent vasoconstriction and thereby secure a stable blood flow. SIGNOR-263952 0.8 MYOD1 protein P15172 UNIPROT PJA1 protein Q8NG27 UNIPROT up-regulates quantity transcriptional regulation 10090 28067271 t ... chromatin immunoprecipitation (ChIP) analysis showed MYOD binds to a site upstream the Pja1 promoter preferentially in C2C12 cells induced to differentiate (Fig. 2c). In addition, over-expression of MyoD in human fibroblasts is sufficient to up-regulate Pja1 expression SIGNOR-255718 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 14640983 t lperfetto We used non-radioactive electrophoretic mobility shift assays to show that c-terminal phosphorylation of p53 protein by cdk2/cyclin a on ser315 or by pkc on ser378 can efficiently stimulate p53 binding to dna in vitro. SIGNOR-217300 0.803 AKT1 protein P31749 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 9373175 t gcesareni Evidence that the inhibition of glycogen synthase kinase-3beta by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9 SIGNOR-252546 0.784 SRGAP3 protein O43295 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260518 0.547 JAG2 protein Q9Y219 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 10090 BTO:0000165;BTO:0000222 9315665 t gcesareni Immunohistochemistry revealed coexpression of jagged2 and notch1 within thymus and other fetal murine tissues, consistent with interaction of the two proteins in vivo. Coculture of fibroblasts expressing human jagged2 with murine c2c12 myoblasts inhibited myogenic differentiation, accompanied by increased notch1 and the appearance of a novel 115-kda notch1 fragment. Exposure of c2c12 cells to jagged2 led to increased amounts of notch mrna as well as mrnas for a second notch receptor, notch3, and a second notch ligand, jagged1. Constitutively active forms of notchl in c2c12 cells also induced increased levels of the same set of mrnas, suggesting positive feedback control of these genes initiated by binding of jagged2 to notch1. SIGNOR-236922 0.609 DIP2A protein Q14689 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI up-regulates quantity chemical modification -1 30672040 t miannu In this paper, we summarized the conservation of gene sequences and protein domains of DIP2 family members and predicted that they may have a similar functional role in acetyl-coenzyme A (acetyl-CoA) synthesis. We then used the most characterized member, disconnected interacting protein 2 homolog A (DIP2A), for further study. DIP2A is a cytoplasmic protein that is preferentially localized to mitochondria, and its acetyl-CoA synthetase activity has been demonstrated in vitro. Furthermore, the level of acetyl-CoA in HEK293 cells overexpressing DIP2A was increased, which is consistent with its metabolically related function. SIGNOR-266590 0.8 serotonin smallmolecule CHEBI:28790 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264287 0.8 FOXO3 protein O43524 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260089 0.25 CSNK1A1 protein P48729 UNIPROT RHOB protein P62745 UNIPROT down-regulates phosphorylation Ser185 ALQKRYGsQNGCINC 9606 BTO:0000567 18590726 t llicata Mass spectrometry analysis demonstrates that rhob is monophosphorylated by ck1, in its c-terminal end, on serine 185. lastly we show that the inhibition of ck1 activates rhob and promotes rhob dependent actin fiber formation and egf-r level. SIGNOR-179255 0.2 F2RL2 protein O00254 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257146 0.2 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914168 t lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 SIGNOR-161706 0.736 CSNK2B protein P67870 UNIPROT CDC34 protein P49427 UNIPROT unknown phosphorylation Ser222 EVEEEADsCFGDDED 9606 BTO:0000567 11546811 t llicata CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm.  SIGNOR-251058 0.358 MECOM protein Q03112 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates activity binding 21695170 t lperfetto The oncoprotein EVI1 and the DNA methyltransferase Dnmt3 co-operate in binding and de novo methylation of target DNA|Here we show that EVI1 physically interacts with DNA methyltransferases 3a and 3b (Dnmt3a/b), which are the only de novo DNA methyltransferases identified to date in mouse and man, and that it forms an enzymatically active protein complex that induces de novo DNA methylation in vitro. SIGNOR-273432 0.298 INPP5D protein Q92835 UNIPROT PLCG2 protein P16885 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000776 32323266 t scontino An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling. SIGNOR-268455 0.317 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser622 KHVPGGGsVQIVYKP -1 8999860 t miannu Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules SIGNOR-250286 0.318 Apoptosome complex SIGNOR-C230 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000567 9390557 t lperfetto Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade. SIGNOR-256472 0.73 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR CBFB protein Q13951 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f irozzo However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins. SIGNOR-255856 0.2 Naltriben chemical CID:5486827 PUBCHEM OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258426 0.8 SIRT5 protein Q9NXA8 UNIPROT GLS protein O94925 UNIPROT up-regulates activity binding 9606 BTO:0006301 30910998 t Monia Immunoprecipitation assays of interaction between GLS and SIRT5 in HepG2 cells infected with lentivirus containing empty or BAG3 construct. Ectopic BAG3 expression decreases the interaction between GLS and SIRT5. It has been reported that SIRT5 is responsible for desuccinylation of GLS35, immunoprecipitation (IP) was then performed. SIGNOR-261207 0.46 levomethadone chemical CHEBI:136003 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258807 0.8 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser573 ENSNSCRsSTTTCPE 9606 BTO:0000007 16862148 t lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). SIGNOR-249302 0.444 ATP13A1 protein Q9HD20 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004093 29650961 f doi.org/10.1101/185272 francesca Loss of ATP13A3 led to marked inhibition of serum-stimulated proliferation of BOECs, and increased apoptosis in serum-deprived conditions SIGNOR-261216 0.7 CTDSP1 protein Q9GZU7 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser213 NLSPNPMsPAHNNLD 9606 BTO:0000007 17035229 t SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248793 0.409 SMARCC1 protein Q92922 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 t miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270617 0.82 RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser153 SWTRVFQsWWDRNLG 9606 BTO:0000007 10837486 t lperfetto We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites. SIGNOR-249045 0.404 FADD protein Q13158 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 11717445 t amattioni Fadd recruits caspase-8 through homotypic interactions of death-effector domains (deds), leading to caspase-8 activation and apoptosis. In turn, fadd recruits the zymogen form of the apoptosis-initiating protease caspase-8, through homophilic interaction of death effector domains. SIGNOR-112061 0.929 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser531 GSRSRTPsLPTPPTR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251589 0.695 PRKCD protein Q05655 UNIPROT IL6ST protein P40189 UNIPROT up-regulates phosphorylation Thr890 GQVERFEtVGMEAAT 9606 12361954 t fspada This interaction, which does not seem to involve a classical phosphotyrosine sh2-mediated binding, however, significantly enhances the interaction of stat3 and the il-6 receptor subunit glycoprotein (gp) 130, which is the initial step for stat3 activation by il-6. Expression of a dominant negative pkcdelta or depletion of the endogenous pkcdelta by phorbol 12-myristate 3-acetate treatment abrogates the association of stat3 with gp130. At the same time, pkcdelta is recruited to gp130 via association with stat3, which may facilitate its phosphorylation on the gp130 receptor. Finally, we identified thr-890, a putative pkc phosphorylation site on gp130, to be critical for the effect of pkcdelta. Our data indicate that pkcdelta plays important regulatory roles in il-6 signaling. SIGNOR-94012 0.34 HCK protein P08631 UNIPROT RAPGEF1 protein Q13905 UNIPROT up-regulates phosphorylation Tyr504 APIPSVPyAPFAAIL 9606 24396067 t llicata We also showed that ctla-4 receptor signaling mediates tyrosine phosphorylation in the c3g protein, and that this is required for augmented activation of rap1 and increased adhesion mediated by leukocyte function-associated antigen type 1 (lfa-1). ctla-4 signaling leads to phosphorylation of c3g tyrosine 504. the src family member hck phosphorylates c3g downstream of ctla-4. SIGNOR-203613 0.512 LAMA4 protein Q16363 UNIPROT Laminin-9 complex SIGNOR-C180 SIGNOR form complex binding 10809728 t lperfetto Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. SIGNOR-253223 0.485 MMP15 protein P51511 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272383 0.7 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Thr4460 GFQHQRMtNGAMNVE 9606 15272003 t lperfetto Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc. SIGNOR-127215 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates activity dephosphorylation Ser671 RKRSTRRsVRGSQAQ 9606 BTO:0000007 24333728 t Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp SIGNOR-272509 0.2 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT down-regulates activity phosphorylation Ser410 RKDSLDDsGSCLSGS 9534 BTO:0000298 9353340 t lperfetto  Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response.  SIGNOR-248988 0.399 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1672 SPTSPSYsPTSPSYS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248820 0.849 GGCX protein P38435 UNIPROT PROC protein P04070 UNIPROT up-regulates activity carboxylation 9606 28125048 t lperfetto Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z SIGNOR-265925 0.554 MRPL46 protein Q9H2W6 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262350 0.635 CXCL10 protein P02778 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection SIGNOR-261031 0.7 SIRT7 protein Q9NRC8 UNIPROT H3C15 protein Q71DI3 UNIPROT up-regulates activity deacetylation Lys38 PATGGVKkPHRYRPG 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275887 0.2 TGFB1 protein P01137 UNIPROT ACTA2 protein P62736 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000452 11988769 t miannu A TGF-β1 response element that has a sequence different to that known for Smad binding has been identified in the α- SM actin promoter and seems to be essential for expression of α-SM actin in both SM cells 72 and myofibroblasts73 . How TGF-β1 activates expression of α-SM actin through this TGF-β1 control element is, as yet, unknown SIGNOR-277681 0.429 PTPN2 protein P17706 UNIPROT EGFR protein P00533 UNIPROT down-regulates dephosphorylation 9606 BTO:0000527 11514572 t gcesareni Tc45 dephosphorylated delta egfr in u87mg glioblastoma cells and inhibited mitogen-activated protein kinase erk2 and phosphatidylinositol 3-kinase signaling. In contrast, the substrate-trapping tc45-d182a mutant, which is capable of forming stable complexes with tc45 substrates, suppressed the activation of erk2 but not phosphatidylinositol 3-kinase. The activation results in reduced egfr phosphorylation after egf stimulation. Introduction of the alpha(1) cytoplasmic domain peptide into cells induces phosphatase activation and inhibits egf-induced cell proliferation and anchorage-independent growth of malignant cells. SIGNOR-109804 0.62 NPC2 protein P61916 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity 9606 21084287 f Giorgia Here we show that NPC2 deficiency in human fibroblasts confers their activation. The activation phenomenon was not limited to fibroblasts as it was also observed in aortic smooth muscle cells upon silencing NPC2 gene by siRNA. The molecular mechanism responsible for activation of NPC2-null cells was shown to be a sustained phosphorylation of ERK 1/2 mitogen-activated protein kinase (MAPK), which fulfills both the sufficient and necessary fibroblast activation criteria. All of these findings highlight a novel mechanism where NPC2 by negatively regulating ERK 1/2 MAPK phosphorylation may efficiently suppress development of maladaptive tissue remodeling and inflammation. SIGNOR-260660 0.358 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1166 QKGSHQIsLDNPDYQ 9606 BTO:0000007 10347170 t llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  SIGNOR-250624 0.378 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM5D protein Q9BY66 UNIPROT up-regulates activity chemical activation 29981745 t lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. SIGNOR-273473 0.8 PPP1CB protein P62140 UNIPROT NF2 protein P35240 UNIPROT up-regulates dephosphorylation Ser518 DTDMKRLsMEIEKEK 9606 18071304 t lperfetto When serine 518 is dephosphorylated by the myosin phosphatase mypt-1-pp1?, The tumor suppressor function of merlin is activated, inhibiting the ras signaling pathway and leading to growth arrest SIGNOR-159836 0.386 TOPBP1 protein Q92547 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates binding 9606 20068082 t gcesareni Topbp1 directly activates atr/atrip and promotes atr-mediated chk1 phosphorylation. SIGNOR-163214 0.788 SRC protein P12931 UNIPROT RASA1 protein P20936 UNIPROT down-regulates phosphorylation 9606 11389730 t lperfetto The phosphorylation of p120-gap by p60c-src inhibited its ability to stimulate the ha-ras-gtpase activity SIGNOR-86008 0.599 DZIP3 protein Q86Y13 UNIPROT H2AJ protein Q9BTM1 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESQKT 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271763 0.2 SMAD3 protein P84022 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 22740686 f lperfetto PD-1 also inhibited phosphorylation of the transcription factor Smad3, which increased its activity. These events induced additional inhibitory checkpoints in the cell cycle by increasing the abundance of the G(1) phase inhibitor p15(INK4) and repressing the Cdk-activating phosphatase Cdc25A SIGNOR-245445 0.55 phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI CAPZA1 protein P52907 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000132 12788695 t lperfetto We further measured the ability of ppIs phosphorylated in positions D-3 and D-4 to release the F-actin capping proteins CapZ and gelsolin from OG-permeabilized platelets (Fig. 7A). Ten percent of platelet CapZ and gelsolin is found in the OG-insoluble fraction (4). PI3,4,5P3 and PI3,4P2 release both CapZ and gelsolin from these preparations. SIGNOR-261843 0.8 NFATC1 protein O95644 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8668213 t lperfetto Recombinant NFAT1 can mediate transcription of the interleukin-2, interleukin-4, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor promoters in T cells, suggesting that NFAT1 contributes to the CsA-sensitive transcription of these genes during the immune response. SIGNOR-254498 0.531 SRC protein P12931 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Tyr86 VADIDGQyAMTRAQR 9606 BTO:0000038 11279024 t lperfetto beta-catenin is a good substrate of pp60c- srctyrosine kinase in vitro;this kinase modifies specifically tyr-86 and tyr-654although consistently detected, this negative effect of tyr-86 phosphorylation on tbp binding was clearly less important than the positive effect observed after tyr-654 phosphorylation. SIGNOR-106458 0.752 HNRNPA1 protein P09651 UNIPROT TRA2B protein P62995 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000586 31311954 t lperfetto HnRNPA1 interacts with G-quadruplex in the TRA2B promoter and stimulates its transcription in human colon cancer cells. SIGNOR-262280 0.685 LSM-1231 chemical CHEBI:91471 ChEBI NTRK2 protein Q16620 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258239 0.8 PRKACA protein P17612 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity phosphorylation YES 9606 12536214 t inferred from family member gcesareni We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus. SIGNOR-267784 0.488 HTR2C protein P28335 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257013 0.301 GSK3B protein P49841 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates phosphorylation Ser59 FPPSPTGsLTQDPAR 9606 16484495 t llicata We show here that gsk3beta phosphorylates and stabilizes the orphan nuclear receptor rev-erbalpha, a negative component of the circadian clock. SIGNOR-144570 0.285 FGB protein P02675 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 16418530 f lperfetto In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. SIGNOR-253374 0.7 calcium(2+) smallmolecule CHEBI:29108 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR up-regulates chemical activation 9606 22944199 t lperfetto Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell). SIGNOR-252320 0.8 CACNA1E protein Q15878 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 30849329 f miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. SIGNOR-264327 0.7 DSCAML1 protein Q8TD84 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity binding 9606 BTO:0000938 30745319 t miannu Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels. SIGNOR-264278 0.2 NFE2L2 protein Q16236 UNIPROT TBXAS1 protein P24557 UNIPROT up-regulates quantity by expression transcriptional regulation 14565864 f lperfetto Ecotopic expression of NF-E2 related factors showed that Nrf2, but not Nrf1, Nrf3, or Bach1, activated TXAS promoter in a dose-dependent manner. SIGNOR-268993 0.248 JNK proteinfamily SIGNOR-PF15 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 24315690 t miannu In addition to the possible regulation of the transcription factor c-Jun by phosphorylation via the c-Jun N-terminal kinase (JNK) or the kinases ERK1, ERK2 and GSK3β, further signaling pathways lead to an up-regulation of c-Jun protein and thus AP-1 activity SIGNOR-253340 0.811 ADSL protein P30566 UNIPROT fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity chemical modification 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-266606 0.8 PAF1C complex SIGNOR-C471 SIGNOR RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity binding 9606 BTO:0000567 20178742 t miannu HPAF1C Independently and Cooperatively (with SII) Stimulates Transcription Elongation. Direct Interactions of hPAF1C with Pol II and SII Are Required for Its Intrinsic and Synergistic Effects on Chromatin Transcription. SIGNOR-269837 0.439 NUAK2 protein Q9H093 UNIPROT WDR45 protein Q9Y484 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001938 28561066 t miannu WIPI4 is stimulated by AMPK, NUAK2 and BRSK2. This finding is supported by the results of our kinome screening, which identified AMPK and the AMKP-related kinases NUAK2 and BRSK2, all of which function downstream of LKB1 (ref. 69) and stimulate the localization of WIPI4 to nascent autophagosomes. SIGNOR-268481 0.265 AKT1 protein P31749 UNIPROT MDM4 protein O15151 UNIPROT up-regulates quantity by stabilization phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 18356162 t lperfetto We demonstrate that the serine/threonine kinase akt mediates phosphorylation of mdmx at ser367. This phosphorylation leads to stabilization of mdmx and consequent stabilization of mdm2. SIGNOR-252517 0.523 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser768 DEAYVMAsVDNPHVC 9606 BTO:0000007 10347170 t llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  SIGNOR-250625 0.378 Hexocyclium chemical CHEBI:5707 ChEBI CHRM4 protein P08173 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258398 0.8 NADPH(4-) smallmolecule CHEBI:57783 ChEBI FASN protein P49327 UNIPROT up-regulates activity binding 9606 34765544 t miannu We determined that FASN inhibitor treatment resulted in NADPH accumulation and inhibition of PGDH enzyme activity. NADPH is a cofactor utilized by FASN, also a known allosteric inhibitor of PGDH. SIGNOR-267371 0.8 PIK-90 chemical CID:6857685 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252653 0.8 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269370 0.719 CSF1 protein P09603 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 16492764 t gcesareni A crystal structure of the signaling complex between human granulocyte colony-stimulating factor (gcsf) and a ligand binding region of gcsf receptor (gcsf-r), has been determined to 2.8 a resolution SIGNOR-144737 0.326 PRKCD protein Q05655 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251631 0.55 MAPK12 protein P53778 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation 9606 10085140 t gcesareni Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target SIGNOR-65589 0.523 DIP2A protein Q14689 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity acetylation 10090 BTO:0000142 31600191 t miannu DIP2A binds to cortactin and modulates cortactin acetylation. Autism candidate gene disconnected-interacting protein homolog 2 A (DIP2A) is known to be involved in acetylated coenzyme A (Ac-CoA) synthesis and is primarily expressed in the brain regions with abundant pyramidal neurons. We further identified that DIP2A interacted with cortactin, an activity-dependent spine remodeling protein. The binding activity of DIP2A-PXXP motifs (P, proline; X, any residue) with the cortactin-Src homology 3 (SH3) domain was critical for maintaining the level of acetylated cortactin. SIGNOR-266589 0.2 IRF5 protein Q13568 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21240265 f miannu Among the genes with differences in expression in the M1 and M2 subsets are those regulated by IRF5, including IL12A, IL12B, IL23A, IL1B, TNF, CCL3(encoding MIP-1Œ±), RANTES, CD1A, CD40, CD86 and CCR7 SIGNOR-254518 0.464 BTK protein Q06187 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr216 SSTSLAQyDSNSKKI 9606 12573241 t lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. SIGNOR-98028 0.341 ULK2 protein Q8IYT8 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t miannu We could prove that ulk1-mediated phosphorylation of ampk reduced its level of phosphorylation at t172 of the _-subunit and hence interferes with its catalytic activity. I SIGNOR-173089 0.309 RELA protein Q04206 UNIPROT SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR form complex binding 9606 BTO:0000452;BTO:0002625 22223884 t alessandro Therefore, we conclude that the endogenous proteins PARP1, p65NF-κB and Snail1 form a ternary complex in the nuclei of cells that are actively expressing fibronectin SIGNOR-254527 0.453 PTK2B protein Q14289 UNIPROT NOS3 protein P29474 UNIPROT down-regulates phosphorylation Tyr657 FGLGSRAyPHFCAFA 9606 BTO:0000007 18483407 t gcesareni We found that fluid shear stress induces the association of enos with the proline-rich tyrosine kinase 2 (pyk2) in endothelial cells and that the enos immunoprecipitated from enos- and pyk2-overexpressing hek293 cells was tyrosine-phosphorylated on tyr657. SIGNOR-178648 0.314 PAX3-FOXO1 fusion protein SIGNOR-FP12 SIGNOR FGFR4 protein P22455 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 t miannu Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA. SIGNOR-251569 0.2 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide chemical CHEBI:95082 ChEBI BRD2 protein P25440 UNIPROT down-regulates activity chemical inhibition -1 24015967 t Gianni This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation SIGNOR-262202 0.8 CARD11 protein Q9BXL7 UNIPROT MALT1 protein Q9UDY8 UNIPROT up-regulates binding 9606 BTO:0000785 20685844 t gcesareni The carboxy-terminal part of the bcl10 card and a short stretch of 13 amino acids following the card are required for constitutive binding to malt1. SIGNOR-167393 0.798 trimethyl-[(5-methyl-2-furanyl)methyl]ammonium chemical CHEBI:94038 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258649 0.8 ABRAXAS1 protein Q6UWZ7 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates binding 9606 17525340 t gcesareni Full length abraxas binds the brct-repeats of brca1the rap80-abraxas complex may help recruit brca1 to dna damage sites in part through recognition of ubiquitinated proteins SIGNOR-155144 0.2 TBX21 protein Q9UL17 UNIPROT IL4 protein P05112 UNIPROT down-regulates transcriptional regulation 9606 BTO:0000782 17541280 f IL-4 gene transcription is inhibited by T-bet via the suppression of its promoter activity, independently of IFN-gamma. T-bet facilitates Th1 differentiation through not only upregulation of IFN-gamma, but also downregulation of IL-4 gene transcription SIGNOR-254496 0.491 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI GNB3 protein P16520 UNIPROT up-regulates chemical activation 9606 17251915 t gcesareni Lpa through galfai and gbetagamma subunits also activates phosphatidylinositol 3-kinase (pi3k), which results in the stimulation of the akt survival pathway and increased protein translation by the activation of the mammalian target of rapamycin (mtor) pathway. SIGNOR-152759 0.8 STOM protein P27105 UNIPROT SLC2A1 protein P11166 UNIPROT down-regulates activity binding 9606 10562431 t Giulio Similar to the results obtained in the RBC, Glut1 and stomatin immunoprecipitated with each other in lysates of Clone 9 cells. The above results suggest that stomatin is closely associated with Glut1 in the plasma membrane and that overexpression of stomatin results in a depression in the basal rate of glucose transport. SIGNOR-261278 0.542 MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation 9606 BTO:0005787 BTO:0001103 23612709 t miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion SIGNOR-255453 0.691 DHODH protein Q02127 UNIPROT (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI down-regulates quantity chemical modification 9606 30449682 t miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway SIGNOR-267430 0.8 SHC1 protein P29353 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 BTO:0000944 17673906 f lperfetto We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. SIGNOR-242628 0.708 FGR protein P09769 UNIPROT SDHA protein P31040 UNIPROT unknown phosphorylation Tyr604 YKVRIDEyDYSKPIQ -1 17997986 t miannu Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are "in vitro" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations. SIGNOR-262873 0.2 FZR1 protein Q9UM11 UNIPROT PFKFB3 protein Q16875 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000793 20080744 t miannu We have recently discovered that the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3), is degraded by the E3 ubiquitin ligase APC/C-Cdh1, which also degrades cell-cycle proteins. Cdh1 promotes PFKFB3 degradation in the nucleus. SIGNOR-271436 0.265 Inflammation phenotype SIGNOR-PH12 SIGNOR ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. SIGNOR-261036 0.7 TRIM23 protein P36406 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 BTO:0000007 28871090 t miannu TRIM23 interacts with TBK1 and p62. TRIM23 GTPase activates TBK1 to phosphorylate p62. Biochemical characterization showed that TRIM23 binds with its C-terminal ARF domain to the N-terminal KD of TBK1, and that GTP hydrolysis activity of the ARF stimulates TBK1-mediated phosphorylation of p62 at S403 in its ubiquitin-associated (UBA) domain, which was shown to promote cargo recruitment and autophagic flux SIGNOR-266654 0.534 DLG5 protein Q8TDM6 UNIPROT Scribble_complex_DLG5-LLGL1_variant complex SIGNOR-C508 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270901 0.314 ARHGAP39 protein Q9C0H5 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260494 0.48 CTNNB1 protein P35222 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity 9606 16510874 f Luana Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro. Chromatin immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp. SIGNOR-260448 0.2 PPP2CA protein P67775 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates dephosphorylation 9606 19061640 t gcesareni In the absence of the wt apc protein, phosphorylated beta-catenin is rapidly dephosphorylated by serine/threonine protein phosphatase 2a (pp2a). phosphorylated beta-catenin associated with the wild-type apc protein is recruited to the scf(beta-trcp) complex, ubiquitin conjugated, and degraded. SIGNOR-182637 0.439 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000150 10550055 t lperfetto Phosphorylation of serine 1387 in brca1 is specifically required for the atm-mediated s-phase checkpoint after ionizing irradiation.We recently reported that brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the s-phase and the g2 phase of the cell cycle. We also found that mutation of serine 1423 in brca1, a target of atm phosphorylation, abrogates the g2-m checkpoint but not the ionizing irradiation-induced s-phase checkpoint. Here we demonstrate that mutation of serine 1387 in brca1, another target of atm phosphorylation, conversely abrogates the radiation-induced s-phase arrest but does not affect the g2-m checkpoint. SIGNOR-72052 0.813 BMP4 protein P12644 UNIPROT MRTFA protein Q969V6 UNIPROT up-regulates 9606 21673106 f gcesareni These results demonstrate that mrtf-a is essential for the bmp4-mediated induction of pri-mir-143/145 and mature mir-143/145, whereas tgf- -mediated induction of mir-143/145 requires myocd. Mrtf-a is primarily localized in the cytoplasm in unstimulated cells;upon stimulation with bmp4, mrtf-a translocates into the nucleus to promote changes in gene expression. SIGNOR-174124 0.2 PFN1 protein P07737 UNIPROT CDH4 protein P55283 UNIPROT up-regulates activity 9606 BTO:0000815 22820501 t lperfetto Taken together, data obtained from MCF10A cells were consistent with the idea that Rho signaling to Dia1 and profilin-1 was essential for R-cadherin adherens junction formation. SIGNOR-253111 0.342 ERBB2 protein P04626 UNIPROT BBC3 protein Q9BXH1 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr152 ADDLNAQyERRRQEE 9606 BTO:0000093 24236056 t miannu HER2 phosphorylates and destabilizes pro-apoptotic PUMA. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life. SIGNOR-276472 0.285 PRKACA protein P17612 UNIPROT AKAP13 protein Q12802 UNIPROT down-regulates phosphorylation Ser1565 LSPFRRHsWGPGKNA 9606 15229649 t llicata Elevation of the cellular concentration of camp activates the pka holoenzyme anchored to akap-lbc, which phosphorylates the anchoring protein on the serine 1565. This phosphorylation event induces the recruitment of 14-3-3, which inhibits the rho-gef activity of akap-lbc. SIGNOR-126723 0.337 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe709 ENPTYKFfEQMQN -1 8943232 t lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261777 0.502 GSK3B protein P49841 UNIPROT OGT protein O15294 UNIPROT up-regulates activity phosphorylation Ser4 sVGNVADS 10090 BTO:0000142 23395175 t miannu We employed a circadian proteomic approach to demonstrate that circadian timing of phosphorylation is a critical factor in regulating complex GSK3β-dependent pathways and identified O-GlcNAc transferase (OGT) as a substrate of GSK3β. Interestingly, OGT activity is regulated by GSK3β; hence, OGT and GSK3β exhibit reciprocal regulation. SIGNOR-276481 0.501 PPP1CB protein P62140 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser217 YTRTGSEsPKVCSDQ 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248569 0.2 NEUROG1 protein Q92886 UNIPROT NEUROD2 protein Q15784 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000596 10814830 t Luana Based on these results, we concluded that the transactivation of the NDRF gene by ngn1 is mediated through the E4 box, suggesting that the E4 box and its binding bHLH protein(s) may play an important role in the transcriptional regulation of the NDRF gene. SIGNOR-266235 0.282 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr821 KISEGLPtPTKMTPR 9606 9139732 t lperfetto We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein. SIGNOR-217324 0.799 L-cystathionine dizwitterion smallmolecule CHEBI:58161 ChEBI L-cysteine zwitterion smallmolecule CHEBI:35235 ChEBI up-regulates quantity precursor of 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. SIGNOR-275813 0.8 BRCA1 protein P38398 UNIPROT HSPA5 protein P11021 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 18776923 f miannu We report here that glucose-regulated protein (GRP)-78, a critical regulator of the unfolded protein response (UPR), is a novel downstream target of BRCA1. We showed that overexpression of wild-type BRCA1 suppressed the expression of GRP78, whereas expression of mutant BRCA1 gene or targeted inhibition of endogenous BRCA1 using small-interfering RNA (siRNA) enhanced GRP78 expression. SIGNOR-253761 0.2 CDK5 protein Q00535 UNIPROT HTT protein P42858 UNIPROT up-regulates phosphorylation Ser1179 LTNPPSLsPIRRKGK 9606 BTO:0000938 17611284 t lperfetto Huntingtin is an antiapoptotic proteinwe show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (cdk5) at serines 1181 and 1201. Phosphorylation can be induced by dna damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by dna damage. SIGNOR-156836 0.458 DNMT3B protein Q9UBC3 UNIPROT IL32 protein P24001 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000018 20889550 f lperfetto A virus or dsRNA in human PBMCs from healthy volunteers. We demonstrate that the NF-κB and CREB pathways play key roles in the activation of IL-32 production in response to influenza virus infection in A549 human lung epithelial cells.|Overexpression assays combined with RNA interference show that DNA methyltransferases DNMT1 and DNMT3b are critical for IL32 promoter methylation and gene silencing before viral infection. SIGNOR-254127 0.2 NatA complex SIGNOR-C415 SIGNOR CHEK2 protein O96017 UNIPROT down-regulates activity acetylation 9606 BTO:0001109 21351257 t miannu The human protein N(α)-terminal acetyltransferase A complex (hNatA), composed of the catalytic hNaa10p (hArd1) and auxiliary hNaa15p (hNat1/NATH/Tubedown) subunits, was reported to be important for cell survival and growth of various types of cancer.  lack of acetylation by hNatA activated H2A.X and Chk2 in both HCT116 cell lines independent of TP53 status (Fig. 6). SIGNOR-267228 0.2 DLAT protein P10515 UNIPROT PDH complex SIGNOR-C402 SIGNOR form complex binding 9606 20160912 t miannu The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. SIGNOR-266546 0.85 EPHA3 protein P29320 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates activity phosphorylation Tyr779 EDDPEAAyTTRGGKI 9606 11870224 t Eph receptor activation leads to tyrosine phosphorylation of three major autophosphorylation sites. these residues function to regulate kinase activity, their phosphorylation being required for full intrinsic enzyme activity. these tyrosines (EphA3 Y596, Y602 and Y779) as the prominent autophosphorylation sites of EphA3 SIGNOR-251117 0.2 NF1 protein P21359 UNIPROT ADCY6 protein O43306 UNIPROT up-regulates 9606 BTO:0000938 24431436 f miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-204195 0.266 O-phosphoethanolamine smallmolecule CHEBI:17553 ChEBI GABARAP protein O95166 UNIPROT up-regulates chemical activation 9606 16303767 t gcesareni Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme) SIGNOR-142011 0.8 SNRPD2 protein P62316 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270636 0.831 PLK1 protein P53350 UNIPROT LRRK1 protein Q38SD2 UNIPROT up-regulates activity phosphorylation Ser1817 GDSIADVsIMYSEEL 9606 BTO:0000567 26192437 t phosphosite is derived from Fig 2 lperfetto Here we show that LRRK1 is a PLK1 substrate that is phosphorylated on Ser 1790. PLK1 phosphorylation is required for CDK1-mediated activation of LRRK1 at the centrosomes SIGNOR-275467 0.352 PTPN11 protein Q06124 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr740 TGESDGGyMDMSKDE -1 7545675 t Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides SIGNOR-248667 0.739 DRAP1 protein Q14919 UNIPROT NC2 complex complex SIGNOR-C108 SIGNOR form complex binding 9606 BTO:0000567 18838386 t miannu NC2_ co-fractionated with NC2_ only in the low molecular weight complex (fractions 86–94) and an NC2_ antibody co-immunoprecipitated NC2_ (but not GCN5) in these fractions, which thus contain the classical NC2 complex SIGNOR-226402 0.774 EGFR protein P00533 UNIPROT SPRED1 protein Q7Z699 UNIPROT down-regulates activity phosphorylation Ser105 KFGLTFQsPADARAF 9606 BTO:0000007 32697994 t miannu We show that oncogenic EGFR(L858R) signaling leads to the phosphorylation of SPRED1 on serine 105, disrupting the SPRED1-neurofibromin complex. The structural, biochemical, and biological results provide new mechanistic insights about how SPRED1 interacts with neurofibromin and regulates active KRAS levels in normal and pathologic conditions. SIGNOR-273638 0.275 CDK1 protein P06493 UNIPROT CDC23 protein Q9UJX2 UNIPROT up-regulates phosphorylation Thr565 NQGETPTtEVPAPFF 9606 14657031 t lperfetto Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation SIGNOR-119821 0.621 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Tyr188 SFVGTLQyLAPELLE 9606 SIGNOR-C14 12707358 t lperfetto These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation. SIGNOR-100784 0.37 TACR3 protein P29371 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257438 0.287 ASTN2 protein O75129 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000142 28506896 f miannu The role of astrotactin and Brinp proteins has been partially characterized, with ASTN1 and ASTN2 demonstrated to facilitate glial-guided neuronal migration during brain development SIGNOR-269814 0.7 RPS6KA1 protein Q15418 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 t lperfetto In this study, we showed that mad1 is a substrate of p90 ribosomal kinase (rsk) and p70 s6 kinase (s6k). Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway SIGNOR-178586 0.32 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser706 ARIIGEKsFRRSVVG 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275958 0.2 Caspase 8 complex complex SIGNOR-C231 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 f amattioni Downstream of caspase-8 activation, apoptosis induction takes place SIGNOR-256641 0.7 PRLHR protein P49683 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257089 0.278 PGD protein P52209 UNIPROT 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI down-regulates quantity chemical modification 9606 34775382 t miannu 6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule. SIGNOR-267060 0.8 RNF2 protein Q99496 UNIPROT Noncanonical PRC1 complex SIGNOR-C151 SIGNOR form complex binding 10090 25533466 t miannu inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. SIGNOR-255277 0.573 CSNK2A1 protein P68400 UNIPROT HOXB7 protein P09629 UNIPROT down-regulates activity phosphorylation Ser133 IYPWMRSsGTDRKRG 10090 BTO:0002882 11290787 t llicata Thus, we concluded that CKII can phosphorylate HOXB7 in vitro and that this phosphorylation occurs at both of the CKII target sites, S133 and T204. | Wild-type HOXB7 inhibited the differentiation of 32D cells, whereas mutations in the Pbx-binding pentapeptide motif or the DNA-binding homeodomain, as well as internal deletions of the N-terminal unique region, blocked this effect. Interestingly, mutations eliminating two target sites for casein kinase II, the glutamate-rich C terminus, or the first 14 amino acids of HOXB7, led to enhanced 32D differentiation. SIGNOR-250896 0.351 PPM1A protein P35813 UNIPROT CDK2 protein P24941 UNIPROT down-regulates activity dephosphorylation -1 10934208 t miannu Moreover, purified recombinant PP2C alpha and PP2C beta 2 proteins efficiently dephosphorylated monomeric Cdk2/Cdk6 in vitro. SIGNOR-277107 0.296 P4HB protein P07237 UNIPROT ERN1 protein O75460 UNIPROT down-regulates activity binding 32149426 t lperfetto The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity. SIGNOR-275573 0.438 PRKACA protein P17612 UNIPROT THOP1 protein P52888 UNIPROT up-regulates activity phosphorylation Ser643 KVGMDYRsCILRPGG -1 10969067 t miannu PKA phosphorylation is suggested to play a regulatory role in EP24.15 enzyme activity. Mutation analysis of each putative PKA site, in vitro phosphorylation, and phosphopeptide mapping indicated serine 644 as the phosphorylation site. The most dramatic change upon PKA phosphorylation was a substrate-specific, 7-fold increase in both K(m) and k(cat) for GnRH. SIGNOR-250060 0.312 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 15735019 t miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates SIGNOR-150476 0.634 HAX1 protein O00165 UNIPROT ATP2A2 protein P16615 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18971376 f miannu HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels. SIGNOR-254222 0.378 PRKCA protein P17252 UNIPROT APLP2 protein Q06481 UNIPROT unknown phosphorylation Thr723 LRKRQYGtISHGIVE -1 9109675 t lperfetto We report here that a cytoplasmic domain peptide from APLP1 is phosphorylated in vitro by protein kinase C and that a cytoplasmic domain peptide from APLP2 is phosphorylated in vitro by protein kinase C and cdc2 kinase. SIGNOR-248970 0.347 PRKCZ protein Q05513 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249284 0.378 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser527 RFRKRTHsAGTSPTI 9606 BTO:0000007 16914728 t lperfetto Turnover of the active fraction of irs1 involves raptor-mtor- and s6k1-dependent serine phosphorylation in cell culture models of tuberous sclerosiss6k1 phosphorylates irs1 in vitro on multiple residues showing strong preference for rxrxxs/t over s/t,p sites. SIGNOR-148903 0.78 TWIST1 protein Q15672 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255511 0.293 Dinaciclib chemical CID:46926350 PUBCHEM CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191331 0.8 7alpha,25-dihydroxycholesterol smallmolecule CHEBI:37623 ChEBI GPR183 protein P32249 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257504 0.8 HBB protein P68871 UNIPROT APOB protein P04114 UNIPROT up-regulates quantity by stabilization 9606 8611031 f Regulation of binding miannu Hemoglobin induced apolipoprotein B crosslinking in low-density lipoprotein peroxidation. Crosslinked apo B was shown to resist lysosomal degradation, thereby causing accumulation of oxidized LDL in macrophages SIGNOR-251754 0.278 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11035810 t gcesareni In response to insulin, gsk3a inhibited by phosphorylation at ser-21 by pkb/akt1;phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. SIGNOR-83217 0.2 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR JUP protein P14923 UNIPROT up-regulates quantity relocalization 9606 BTO:0000586 21598020 t miannu Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14 SIGNOR-265819 0.2 CARM1 protein Q86X55 UNIPROT PAX7 protein P23759 UNIPROT up-regulates methylation 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-198617 0.432 CDK5 protein Q00535 UNIPROT NES protein P48681 UNIPROT unknown phosphorylation Thr315 AENSRLQtPGGGSKT 10090 BTO:0000165 12832492 t llicata We identify nestin as a novel in vivo target for cdk5 and p35 kinase, a critical signaling determinant in development. Two cdk5-specific phosphorylation sites on nestin, Thr-1495 and Thr-316, were established, the latter of which was used as a marker for cdk5-specific phosphorylation in vivo. | Cdk5 activity is necessary for differentiation and the concomitant nestin reorganization in C2C12 myoblasts. SIGNOR-250670 0.563 RNF146 protein Q9NTX7 UNIPROT CASC3 protein O15234 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 21478859 t lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. SIGNOR-263339 0.265 TANC1 protein Q9C0D5 UNIPROT Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 10116 21068316 t miannu In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses. SIGNOR-266896 0.7 SHANK1 protein Q9Y566 UNIPROT ACTN1 protein P12814 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264583 0.277 PRKCE protein Q02156 UNIPROT RAB11A protein P62491 UNIPROT unknown phosphorylation Ser177 TEIYRIVsQKQMSDR -1 22188018 t miannu This report shows for the first time that Rab11 is differentially phosphorylated by distinct PKC isoenzymes and that this post-translational modification might be a regulatory mechanism of intracellular trafficking.Our results demonstrate that classical PKC (PKCα and PKCβII but not PKCβI) directly phosphorylate Rab11 in vitro. In addition, novel PKCε and PKCη but not PKCδ isoenzymes also phosphorylate Rab11. Mass spectrometry analysis revealed that Ser 177 is the Rab11 residue to be phosphorylated in vitro by either PKCβII or PKCε. SIGNOR-263170 0.273 CUL9 protein Q8IWT3 UNIPROT FERMT1 protein Q9BQL6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 35469017 t miannu M-phase-specific CDK1–cyclin B1 complex directly binds KIND1 and KIND2 and phosphorylates a conserved proline-directed CDK1 consensus motif in the flexible and intrinsically disordered loop of the F1 domain. This then results in the recruitment of the CUL9–FBXL10 complex, modification with K48-linked polyubiquitin chains and proteasomal degradation of KIND1 and KIND2. SIGNOR-276718 0.2 CKM complex complex SIGNOR-C406 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation -1 25344755 t lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues SIGNOR-273158 0.378 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 8335191 t Crohn's Disease gcesareni SIGNOR-251701 0.8 HLA-G protein P17693 UNIPROT KLRC1 protein P26715 UNIPROT up-regulates binding 9606 9560253 t gcesareni Current models of nk cell function have supposed that the cd94/nkg2a heterodimer is interacting with an epitope common to classical hla class i SIGNOR-56714 0.627 PRKCA protein P17252 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 8810272 t gcesareni These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc. SIGNOR-43744 0.2 TIP-LINK complex complex SIGNOR-C291 SIGNOR LHFPL5 protein Q8TAF8 UNIPROT up-regulates activity binding 10090 BTO:0000630 23217710 t lperfetto We conclude that the transmembrane and membrane proximal CR domain of PCDH15 mediate interaction with TMHS.|Based on the interdependence of PCDH15 and TMHS for their efficient localization to stereocilia, we reasoned that interaction between the two proteins might regulate their effective cell surface transport. SIGNOR-262580 0.416 RET protein P07949 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by destabilization phosphorylation Thr115 MPDDLLTtLDDTCDL 9606 BTO:0002181 25795775 t miannu We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA.  SIGNOR-276447 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates activity dephosphorylation Ser683 QAQDRKLsTKEALDE 9606 BTO:0000007 24333728 t Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp SIGNOR-272510 0.2 GPT2 protein Q8TD30 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity chemical modification 9606 11863375 t Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate, and thereby has a key role in the intermediary metabolism of glucose and amino acids. Two ALT isoenzymes are known to exist, but only one ALT gene has been cloned, GPT. In this study, we cloned a homolog of GPT and named it GPT2, and the corresponding protein ALT2 SIGNOR-266926 0.8 CAMK2A protein Q9UQM7 UNIPROT SYNGAP1 protein Q96PV0 UNIPROT up-regulates activity phosphorylation Ser780 MARGLNSsMDMARLP -1 14970204 t miannu Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. We identify four major sites of phosphorylation, serines 1123, 1058, 750/751/756, and 764/765. SIGNOR-262690 0.439 IFNAR1 protein P17181 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR form complex binding 9606 11278538 t miannu The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex. SIGNOR-260332 0.903 DVL1 protein O14640 UNIPROT DAAM1 protein Q9Y4D1 UNIPROT up-regulates activity binding 9606 19365405 t gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. SIGNOR-185271 0.724 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Thr17 RVSSYRRtFGGAPGF -1 12686604 t lperfetto The sites phosphorylated by Aurora-B; Thr-7/Ser-13/Ser-38 of GFAP, and Thr-16 of desmin are common with those related to Rho-associated kinase (Rho-kinase), which has been reported to phosphorylate GFAP and desmin at cleavage furrow during cytokinesis. Rho-kinase was found to phosphorylate desmin at Thr-16, Thr-75, and Thr-76 SIGNOR-100177 0.322 CSNK1A1 protein P48729 UNIPROT EIF2B5 protein Q13144 UNIPROT unknown phosphorylation Ser469 DGEFSDDsGADQEKD 9606 BTO:0000007 11500362 t llicata The fifth site, which lies outside the catalytic domain of eIF2Bepsilon, can be phosphorylated by casein kinase 1. All five sites are phosphorylated in the eIF2B complex in vivo. | A phosphopeptide corresponding to this region was identified in Asp‐N digests of eIF2Bϵ phosphorylated in vitro by CK1, suggesting that Ser461 or Ser464 may be phosphorylated by this kinase in vivo. SIGNOR-250788 0.329 MAPK8IP3 protein Q9UPT6 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates binding 9606 15767678 t gcesareni The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk. SIGNOR-134555 0.738 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2I protein P63279 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271346 0.45 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser15 GLGGGAAsPPAASPF 9534 BTO:0000298 12756254 t miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. SIGNOR-250123 0.879 HRH1 protein P35367 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257163 0.2 PRKCA protein P17252 UNIPROT DNM1 protein Q05193 UNIPROT unknown phosphorylation Ser795 VPPARPGsRGPAPGP -1 10766777 t lperfetto Phosphorylation of dynamin I on Ser-795 by protein kinase C blocks its association with phospholipids. SIGNOR-249039 0.34 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000938 8387505 t inferred from 70% family members lperfetto The pp90rsk phosphothreonine content paralleled the ERK1 activity more closely than the phosphoserine level. These results provide compelling evidence that in fibroblasts and PC12 cells ERK1 plays a direct role in the phosphorylation of pp90rsk and that pp90rsk represents a physiologically relevant substrate of extracellular-regulated kinases SIGNOR-270002 0.2 CDR2 protein Q01850 UNIPROT NUF2 protein Q9BZD4 UNIPROT up-regulates quantity by expression transcriptional regulation 20383333 f lperfetto Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology SIGNOR-252022 0.2 MAPK3 protein P27361 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 11904294 t gcesareni We report here that the important proangiogenic stimulus hypoxia stimulates phosphorylation, ubiquitination, and proteasomal breakdown of tal1 in endothelial cells. A specific serine in the putative transactivation domain of the protein, ser122, is preferentially phosphorylated by mapk in vitro. SIGNOR-116153 0.364 TNF protein P01375 UNIPROT SCN11A protein Q9UI33 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253483 0.2 IL5RA protein Q01344 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 21106848 f Human blood eosinophils exhibit a hyperactive phenotype in response to chemotactic factors after cell priming with IL-5 family cytokines. Earlier work has identified ERK1/2 as molecular markers for IL-5 priming SIGNOR-254350 0.2 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr869 LGAEEKEyHAEGGKV 9606 BTO:0000452 11983694 t lperfetto In summary, this study describes a novel mechanism for metal-induced egfr transactivation, which is likely to be mediated by src through the phosphorylation site of tyr-845 on egfr. emanating from a variety of growth factor receptors, including egfry845 (e-e-k-e-y845-h-a-e) SIGNOR-235921 0.609 GRP protein P07492 UNIPROT GRPR protein P30550 UNIPROT up-regulates binding 9606 17251915 t gcesareni Indeed, many potent mitogens such as thrombin, lysophosphatidic acid (lpa), gastrin-releasing peptide (grp), endothelin and prostaglandins stimulate cell proliferation by acting on their cognate gpcrs in various cell types. SIGNOR-152676 0.776 WNT16 protein Q9UBV4 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131677 0.534 ZDHHC9 protein Q9Y397 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity palmitoylation 9606 BTO:0000007 16000296 t miannu Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein. SIGNOR-261355 0.414 CSNK2A2 protein P19784 UNIPROT IL16 protein Q14005 UNIPROT up-regulates activity phosphorylation Ser743 MPLQPNAsLNEEEGT -1 12450396 t llicata We now show that N-terminal to the NLS domain of pro-IL-16 are protein kinase CK2 substrate and cdc2 kinase substrate sites which, along with the NLS, constitute a dual phosphorylation-regulated CcN motif which regulates nuclear localization of pro-IL-16. In addition, we demonstrate that mutation of either site is associated with impairment of the N-terminal domain's ability to induce G(0)/G(1) cell cycle arrest. | Thus, we confirm that the N-terminal (42SLNEE46) sequence of pro-IL-16 is in fact a site for protein kinase CK2 phosphorylation. SIGNOR-251009 0.331 TLK1 protein Q9UKI8 UNIPROT NEK1 protein Q96PY6 UNIPROT up-regulates activity phosphorylation Thr141 IFLTKDGtVQLGDFG 28426283 t lperfetto TLK1 phosphorylated NEK1 at T141, which lies in the kinase domain, and caused an increase in its activity.  SIGNOR-275840 0.295 TFE3 protein P19532 UNIPROT ATP6V0D2 protein Q8N8Y2 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276810 0.2 GH1 protein P01241 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15665309 f Luana Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells SIGNOR-261627 0.2 MCHR1 protein Q99705 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256762 0.272 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-267507 0.8 PKM protein P14618 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC -1 22306293 t PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor SIGNOR-267716 0.455 TGFB1 protein P01137 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 19114990 t lperfetto While association of the TGF_RI receptor with p85 requires TGF-_ stimulation. SIGNOR-252729 0.266 PTGFR protein P43088 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257082 0.426 CDK1 protein P06493 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT down-regulates activity phosphorylation Ser274 DPLPGPGsPSHSAPD 10116 BTO:0000951 15834132 t miannu Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. Phosphorylation of Ser-277 is also dramatically increased during mitosis, however this is mediated by Cdk1 and not by ERK. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events. SIGNOR-262840 0.704 PLK1 protein P53350 UNIPROT CENPU protein Q71F23 UNIPROT down-regulates phosphorylation Ser77 TFDPPLHsTAIYADE 9606 17081991 t lperfetto S77 and t78 of pbip1 are important for plk1-dependent pbip1 phosphorylation and degradation. Here, we demonstrate that a pbd-binding protein, pbip1, is crucial for recruiting plk1 to the interphase and mitotic kinetochores. Unprecedentedly, plk1 phosphorylated pbip1 at t78. Later in mitosis, plk1 also induced pbip1 degradation in a t78-dependent manner, thereby enabling itself to interact with other components critical for proper kinetochore functions SIGNOR-150453 0.73 SLN protein O00631 UNIPROT ATP2A1 protein O14983 UNIPROT down-regulates activity binding 9606 28487373 t lperfetto These results suggest that sAnk1 interacts with SLN both directly and in complex with SERCA1 and reduces SLN's inhibitory effect on SERCA1 activity. SIGNOR-265929 0.567 VAV1 protein P15498 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates 9606 9013873 f gcesareni Vav may link gp130 activation to downstream mapk activation in hematopoietic cells. SIGNOR-46064 0.523 USP5 protein P45974 UNIPROT UBB protein P0CG47 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270821 0.757 CD40LG protein P29965 UNIPROT IGSF6 protein O95976 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 9809579 f miannu CD40L activation of dendritic cells down-regulates DORA, a novel member of the immunoglobulin superfamily SIGNOR-261727 0.331 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 BTO:0000567 BTO:0000887;BTO:0001103 8454633 t gcesareni Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190. SIGNOR-39147 0.385 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation 9606 16023596 t gcesareni Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation. SIGNOR-138592 0.337 IQGAP1 protein P46940 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity binding 15695813 t lperfetto Although the name implies that it functions as a GTPase-activating protein, IQGAP1 actually stabilizes Cdc42 and Rac1 in the active, GTP-bound form (5, 8, 17). Thus, IQGAP1 acts as an “anti-GTPase-activating protein” for Cdc42 and Rac1, with marked effects on the cytoskeleton.  SIGNOR-261888 0.804 EGFR protein P00533 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 16829981 t Cbl binds directly to Tyr1045 receptors gcesareni Likewise, cbl is recruited to erbb1 either directly (tyr1045), or indirectly, trough grb2 SIGNOR-147826 0.883 Dynorphin A smallmolecule CHEBI:4727 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257552 0.8 GABRD protein O14764 UNIPROT GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263749 0.389 UBE3A protein Q05086 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR down-regulates activity ubiquitination 9606 BTO:0000007 28559284 t Through quantitative proteomics and reporter assays, we found that the UBE3AT485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A SIGNOR-270946 0.312 FGF5 protein P12034 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates binding 9606 8386828 t gcesareni Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2. SIGNOR-38704 0.699 BIK protein Q13323 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates binding 9606 7478623 t gcesareni We have identified a novel cellular protein, bik, that interacts with the cellular survival-promoting proteins, bcl-2 and bcl-xl in transient transfection assays, bik promotes cell death in a manner similar to the death-promoting members of the bcl-2 family, bax and bak. SIGNOR-26453 0.8 NFIA protein Q12857 UNIPROT ID3 protein Q02535 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268873 0.2 NMDA receptor_2A complex SIGNOR-C347 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30037851 t miannu NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS).  SIGNOR-264218 0.8 CDK1 protein P06493 UNIPROT CUX1 protein P39880 UNIPROT down-regulates phosphorylation Ser1237 TEYSQGAsPQPQHQL 9606 11584018 t lperfetto Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter. SIGNOR-110908 0.364 TNKS protein O95271 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization 9606 BTO:0000007 19759537 t Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. SIGNOR-261249 0.522 ZNF304 protein Q9HCX3 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000391 24623306 t Luana Finally, we show that ZNF304 also directs transcriptional silencing of INK4-ARF in human embryonic stem cells. SIGNOR-266098 0.307 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser464 QAIHQLRsVKMEQRK 9606 16513649 t llicata Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization SIGNOR-145028 0.2 CCL7 protein P80098 UNIPROT CCR1 protein P32246 UNIPROT up-regulates binding 9606 14991608 t For example, 11 chemokines are reported to bind to CC chemokine receptor (CCR) 1, including macrophage inflammatory protein (MIP)‐1α , MIP‐1β, MIP‐1δ, regulated upon activation, normal T cell‐expressed and secreted (RANTES), monocyte chemotactic peptide (MCP)‐1, MCP‐2, MCP‐3, MCP‐4, leukotactin‐1 (Lkn‐1), myeloid progenitor inhibitory factor (MPIF)‐1, and hemofiltrate CC chemokine (HCC)‐1 SIGNOR-254368 0.736 PRKG1 protein Q13976 UNIPROT PLCB3 protein Q01970 UNIPROT down-regulates activity phosphorylation Ser1105 LDRKRHNsISEAKMR 10116 BTO:0004576 11278298 t lperfetto PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG. SIGNOR-249077 0.523 cortisol smallmolecule CHEBI:17650 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258708 0.8 PTPRH protein Q9HD43 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 t gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase SIGNOR-76076 0.273 PSMB1 protein P20618 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263356 0.864 PPP5C protein P53041 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates activity dephosphorylation Ser661 SSNDSRSsLIRKRST 9606 BTO:0000007 24333728 t Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp SIGNOR-272505 0.2 MAPK1 protein P28482 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Ser780 DSLDSRLsPPAGLFT 9606 BTO:0000975 10194762 t lperfetto Gh treatment of chinese hamster ovary cells stably transfected with the gh receptor (choa cells) led to rapid and transient activation of both stat5a and erk1 and erk2. these observations show, for the first time, direct physical interaction between erk and stat5a and also clearly identify serine 780 as a target for erk. SIGNOR-66239 0.75 Scribble_complex_DLG5-LLGL1_variant complex SIGNOR-C508 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 f miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270902 0.7 CGAS protein Q8N884 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR down-regulates activity 9606 31544964 f Chromatin‐bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death SIGNOR-259951 0.7 STK11 protein Q15831 UNIPROT SIK1 protein P57059 UNIPROT up-regulates phosphorylation Thr182 KSGEPLStWCGSPPY 9606 14976552 t lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold SIGNOR-122784 0.567 CAMK2A protein Q9UQM7 UNIPROT SYNGAP1 protein Q96PV0 UNIPROT up-regulates activity phosphorylation Ser779 FMARGLNsSMDMARL -1 14970204 t miannu Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. The Major Phosphorylation Sites, Serines 764/765, 1058, and 1123, All Contribute to Regulation of GAP Activity of synGAP by CaMKII SIGNOR-262689 0.439 PRKCE protein Q02156 UNIPROT OCLN protein Q16625 UNIPROT up-regulates phosphorylation Thr404 HYETDYTtGGESCDE 9606 BTO:0000195 BTO:0000671 21545357 t lperfetto Thr403, thr404, thr424 and thr438 in the occludin c-terminal domain are the predominant sites of pkc_-dependent phosphorylation . The present study demonstrates that pkc_ phosphorylates occludin on specific threonine residues and promotes assembly of epithelial tight junctions. SIGNOR-173635 0.2 CDC42BPA protein Q5VT25 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 19851336 t lperfetto More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above. SIGNOR-188785 0.531 valine smallmolecule CHEBI:27266 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264747 0.7 CHIR-98014 chemical CID:53396311 PUBCHEM GSK3A protein P49840 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190985 0.8 FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 f �The present data provide a direct link between insulin signaling through Irs _ PI 3-kinase _ Akt and adipogenesis through Foxo1 phosphorylation. Inhibition of Foxo1 via phosphorylation appears to be required during the clonal expansion phase, and our data show that unrestrained Foxo1 activity prevents terminal differentiation. SIGNOR-254977 0.7 PRKACA protein P17612 UNIPROT STK38 protein Q15208 UNIPROT down-regulates activity phosphorylation Ser11 TGSTPCSsMSNHTKE -1 22142472 t miannu GSK-3β phosphorylated STK38 on residues S6 and T7 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively.  Our results indicate that that GSK-3β inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress. SIGNOR-276390 0.299 ANAPC2 protein Q9UJX6 UNIPROT DVL1 protein O14640 UNIPROT down-regulates binding 9606 19805045 t gcesareni We now report that the anaphase-promoting complex (apc/c) recognizes a d-box motif of dvl and ubiquitylates dvl on a highly conserved lysine residue.We now report that expression of the apc/c subunit anapc2 activates the apc/c-dependent degradation of dvl by disrupting canonical wnt signaling. SIGNOR-188393 0.24 C1QC protein P02747 UNIPROT Complement C1q complex SIGNOR-C308 SIGNOR form complex binding -1 29449492 t lperfetto C1q comprises 18 polypeptide chains; three chains of C1q-A, -B, and -C trimerize to form six collagen-like triple helices connected to six globular (trimeric) ligand-recognition (gC1q) modules (fig. S1B) (1). SIGNOR-263389 0.558 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270400 0.8 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 17804415 t gcesareni Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun. SIGNOR-157725 0.377 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser463 SPHNPISsVS 9606 9335504 t llicata The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. SIGNOR-52666 0.628 PPP2CA protein P67775 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser89 KQKQPSFsAKKMTEK 9606 BTO:0000567 24781523 t miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase SIGNOR-276380 0.3 CAMK2A protein Q9UQM7 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization phosphorylation Ser31 LKLGSGPsIKALDGR 9606 BTO:0000567 24781523 t miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase SIGNOR-276382 0.314 PYCARD protein Q9ULZ3 UNIPROT AIM2 inflammasome complex SIGNOR-C222 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256401 0.789 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SP3 protein Q02447 UNIPROT up-regulates phosphorylation 9606 17685427 t inferred from 70% family members gcesareni Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73. SIGNOR-270053 0.2 FGF11 protein Q92914 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253414 0.256 PPARGC1A protein Q9UBK2 UNIPROT COX5B protein P10606 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000443 23021218 f lperfetto PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). SIGNOR-253099 0.332 BRAF protein P15056 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser222 VSGQLIDsMANSFVG 9606 BTO:0000142 8668348 t gcesareni We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-42664 0.74 CSNK2A2 protein P19784 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates activity phosphorylation Ser122 RIQEQESsGEEDSDL -1 8288648 t llicata Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action. SIGNOR-251021 0.312 PPM1D protein O15297 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 18265945 t lperfetto Dephosphorylation of p53 at serine 15 by Wip1 also contributes to p53 degradation, as does dephosphorylation of Mdm2, which stabilizes Mdm2, an E3 ubiquitin ligase specific for p53 [ xref ]. SIGNOR-276943 0.575 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 24643073 t lperfetto At the onset of mitosis, the protein phosphatase Cdc25C activates the Cdc2 and cyclin B1 complex by removing the inhibitory phosphate groups from Thr 14 and Tyr 15 on Cdc2.|Dephosphorylation of Tyr15 of Cdc2 is catalyzed by Cdc25C phosphatases, and this reaction is believed to be the rate limited step for the entrance into mitosis . SIGNOR-276944 0.852 FOXL2 protein P58012 UNIPROT CYP11A1 protein P05108 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21862621 f miannu We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation. SIGNOR-254177 0.399 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191406 0.8 ceritinib chemical CHEBI:78432 ChEBI ALK protein Q9UM73 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 24670165 t miannu Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. SIGNOR-259263 0.8 PRKCA protein P17252 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates phosphorylation Ser591 DKEKSKGsLKRK 9606 15269224 t llicata Protein kinase calpha therefore critically and negatively regulates shp-1 function, forming part of a mechanism to retain shp-1 in a basal active state through interaction with its sh2 domains, and phosphorylating its c-terminal ser591 upon cellular activation SIGNOR-126876 0.371 RPS6KA5 protein O75582 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser29 ATKVARKsAPATGGV 10090 12773393 t lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 SIGNOR-249214 0.2 VRK3 protein Q8IV63 UNIPROT BANF1 protein O75531 UNIPROT down-regulates activity phosphorylation Ser4 sQKHRDFV -1 25899223 t lperfetto Although VRK3 has been regarded as a genuine pseudokinase from structural and biochemical studies, recent reports suggest that VRK3 acts as an active kinase as well as a signaling scaffold in cells. Here, we demonstrate that VRK3 phosphorylates the nuclear envelope protein barrier-to-autointegration factor (BAF) on Ser4.|Ectopic expression of VRK3 induces the translocation of BAF from the nucleus to the cytoplasm. I SIGNOR-264564 0.505 PPP2CA protein P67775 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates dephosphorylation Thr32 QSRPRSCtWPLQRPE 9606 20110348 t gcesareni Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a. SIGNOR-252974 0.412 PPM1D protein O15297 UNIPROT RBM38 protein Q9H0Z9 UNIPROT up-regulates activity dephosphorylation Ser195 DQYPYAAsPATAASF 9606 25823026 t lperfetto Interestingly, we showed that PPM1D directly interacts with and dephosphorylates RBM38 at serine 195. SIGNOR-277020 0.37 NDUFB8 protein O95169 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 SIGNOR-262171 0.815 OXTR protein P30559 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256936 0.252 FGFR1 protein P11362 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr446 GTEPEPVySMEAADY 9606 12601080 t lperfetto Cortactin, which is an actin-binding protein that also plays a role in actin cytoskeleton dynamics (45), was phosphorylated on tyr-446 in our assay (by fgfr1).Phosphorylation of these residues attenuates the f-actin cross-linking activity SIGNOR-98618 0.318 H4C1 protein P62805 UNIPROT BRD4 protein O60885 UNIPROT up-regulates activity relocalization 9606 acetylation:Lys21;Lys17 GGAKRHRkVLRDNIQ;GLGKGGAkRHRKVLR 27991587 t lperfetto BRD4 interacts with acetylated nucleosomes via both its BD1 and BD2 domains. Our results indicate that BRD4-BD1 binds to nucleosomes through the acetylated histone H4 tail and does not additionally interact with DNA. SIGNOR-262065 0.2 MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR up-regulates 17713585 f lperfetto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs).|Current emerging structural and biological evidence suggests that MRN has 3 coupled critical roles in DSB sensing, stabilization, signaling, and effector scaffolding: (1) expeditious establishment of protein--nucleic acid tethering scaffolds for the recognition and stabilization of DSBs; (2) initiation of DSB sensing, cell-cycle checkpoint signaling cascades, and establishment of epigenetic marks via the ATM kinase; and (3) functional regulation of chromatin remodeling in the vicinity of a DSB. SIGNOR-251503 0.7 FANCM protein Q8IYD8 UNIPROT FANCF protein Q9NPI8 UNIPROT up-regulates binding 9606 20064461 t gcesareni Protein interaction motifs in fancm, designated mm1 and mm2, were identified. Mm1 interacts with the fa core complex by binding to fancf, whereas mm2 interacts with rm1 and topoisomerase iiialpha, components of the bs complex. SIGNOR-163101 0.93 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates phosphorylation Tyr531 HEEDADSyENMDNPD 9606 10933394 t llicata Experiments with purified proteins demonstrated that cd19-y513 was lyn's initial phosphorylation and binding site. This led to processive phosphorylation of cd19-y482, which recruited a second lyn molecule, allowing for transphosphorylation and amplification of lyn activation. SIGNOR-80294 0.764 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI -1 7782287 t gcesareni Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase. SIGNOR-33201 0.674 CIITA protein P33076 UNIPROT HLA-DRB1 protein P01911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002417 10886240 f These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma. SIGNOR-253976 0.516 CIITA protein P33076 UNIPROT HLA-DMA protein P28067 UNIPROT up-regulates quantity by expression transcriptional regulation 9300700 f The class II transactivator (CIITA) is a highly specific transcription factor that activates only genes known to be involved in the class II MHC processing pathway, including class II MHC, invariant chain, and HLA-DMA/B genes. SIGNOR-254004 0.411 CDK2 protein P24941 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR form complex binding 9606 19665013 t lperfetto The eukaryotic cell cycle is controlled by different cyclins and their associated kinases (murray and hunt, 1993). In mammalian cells, levels of cycline and its associated kinase, cdk2, rise in late g1/early s-phase when dna replication is initiated SIGNOR-187457 0.932 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT down-regulates activity phosphorylation Ser193 AEVDPDMsWSSSLAT 9606 BTO:0001938 12815053 t lperfetto M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1 SIGNOR-102486 0.555 MECP2 protein P51608 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000452 19820693 f Luana We show that MeCP2 cooperates with HIPK2 in induction of apoptosis and that Ser 80 phosphorylation is required together with the DNA binding of MeCP2. | We found increased cell death in each of the tested cell lines not only, as expected, when HIPK2 was overexpressed but also with MeCP2 alone. When both proteins were expressed together, the number of dead cells increased in an additive manner. SIGNOR-264550 0.7 SGK2 protein Q9HBY8 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 11154281 t lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. SIGNOR-249132 0.512 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT unknown phosphorylation Thr17 PSEGEEStVRFARKG -1 2377895 t lperfetto Thus four peptides containing six major sites of intrapeptide autophosphorylation of protein kinase C have been identified. | Phosphoamino acid analyses indicated that only the NH2-terminal peptide contained phosphoserine. The modified residue was determined to be Ser16 SIGNOR-248868 0.2 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207941 0.8 RPL19 protein P84098 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262479 0.88 1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester chemical CHEBI:92418 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258636 0.8 CSNK2A2 protein P19784 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser103 EGISQESsEEEQ -1 2806554 t llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. SIGNOR-251005 0.334 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates activity phosphorylation Tyr177 ADAEKPFyVNVEFHH 9606 BTO:0000007 8955135 t Mutagenesis of BCR Tyr-177 to Phe completely abolished FES-induced BCR binding to the GRB2 SH2 domain, identifying Tyr-177 as an additional phosphorylation site for FES. Co-expression of BCR and FES in human 293T cells stimulated the tyrosine autophosphorylation of FES. By contrast, tyrosine phosphorylation of BCR by FES suppressed BCR serine/threonine kinase activity toward the 14-3-3 protein and BCR substrate, BAP-1. SIGNOR-251136 0.375 NFIA protein Q12857 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 32991581 t brain lperfetto NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog, SIGNOR-263982 0.248 RPS6KA5 protein O75582 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 10090 12773393 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 SIGNOR-249213 0.2 PDPK1 protein O15530 UNIPROT SGK2 protein Q9HBY8 UNIPROT up-regulates activity phosphorylation Thr193 EPEDTTStFCGTPEY 10548550 t miannu SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB. SIGNOR-250277 0.582 DIO1 protein P49895 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI down-regulates quantity chemical modification 9606 1400883 t scontino The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production. SIGNOR-266944 0.8 ESR1 protein P03372 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 BTO:0001264 22169964 f miannu 17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice SIGNOR-253470 0.293 NAE complex SIGNOR-C131 SIGNOR CUL3 protein Q13618 UNIPROT up-regulates activity neddylation 9606 25504797 t lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. SIGNOR-243157 0.59 AminoAcids stimulus SIGNOR-ST5 SIGNOR RAG2 protein P55895 UNIPROT up-regulates 9606 22790199 f gcesareni Rag gtpases, together with a multi-protein complex called ragulator, mediate amino acid-mediated mtor recruitment to the lysosome surface where mtor becomes activated. SIGNOR-198192 0.7 GSK690693 chemical CHEBI:90677 ChEBI AKT2 protein P31751 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193003 0.8 SLC4A8 protein Q2Y0W8 UNIPROT hydrogencarbonate smallmolecule CHEBI:17544 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 26136660 t miannu Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. In neurons, bicarbonate transport is mainly mediated by members of the SLC4A family of proteins. While the Na+-independent anion-exchanger SLC4A3 lowers the intraneuronal bicarbonate concentration, the Na+-dependent anion exchangers SLC4A8 (NDCBE) and SLC4A10 (NCBE) use the sodium gradient to accumulate bicarbonate in exchange of chloride SIGNOR-264918 0.8 HIF1A protein Q16665 UNIPROT KDM5A protein P29375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271565 0.276 DUSP4 protein Q13115 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Tyr204 HTGFLTEyVATRWYR 10116 7535768 t Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK SIGNOR-248716 0.697 SRC protein P12931 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr682 SRTTDGVyEGVAIGG 9606 BTO:0000007 32420483 t done miannu  We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. SIGNOR-274106 0.268 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT down-regulates activity phosphorylation Thr110 PRSGVRGtPVRQRPD 9606 BTO:0000567 SIGNOR-C83 12714602 t lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. SIGNOR-100889 0.757 POMC protein P01189 UNIPROT MC5R protein P33032 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268715 0.757 PLK1 protein P53350 UNIPROT SUGT1 protein Q9Y2Z0 UNIPROT up-regulates activity phosphorylation Ser331 VKRAMNKsFMESGGT 9606 22869522 t lperfetto Plk1 phosphorylates Sgt1 at the kinetochores to promote timely kinetochore-microtubule attachment|Plk1 is required for the kinetochore localization of Sgt1 and phosphorylates serine 331 of Sgt1 at the kinetochores. This phosphorylation event enhances the association of the Hsp90-Sgt1 chaperone SIGNOR-265222 0.448 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 4188963 t dermatitis gcesareni SIGNOR-251705 0.8 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr664 EGGWMEDyDYVHLQG 9606 11604500 t lperfetto The loss of activity in the cas-f668/f670 mutant is consistent with the notion that src, once initially bound by its sh3 domain, phosphorylates the tyr668/670 site to further stabilize its interaction by sh2 binding. SIGNOR-111056 0.796 AURKC protein Q9UQB9 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14583461 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. SIGNOR-118898 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-141424 0.2 ID1 protein P41134 UNIPROT TCF4 protein P15884 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C129 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241385 0.648 CBX3 protein Q13185 UNIPROT ChAHP complex SIGNOR-C407 SIGNOR form complex binding 10090 BTO:0002896 29795351 t miannu Here we show that ADNP interacts with the chromatin remodeller CHD4 and the chromatin architectural protein HP1 to form a stable complex, which we refer to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. In conclusion, CHD4, ADNP and HP1β/γ form a stable protein complex, which we refer to as ChAHP. SIGNOR-266753 0.416 LMO3 protein Q8TAP4 UNIPROT ASCL1 protein P50553 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21573214 f miannu Overexpression of both LMO3 and HEN2 induced expression of Mash1, suggesting that they might function as a transcriptional activator for Mash1. SIGNOR-254825 0.368 MAP3K20 protein Q9NYL2 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation Thr161 ASRFHNHtTHMSLVG 9606 15342622 t gcesareni Ionizing radiation induces mrk autophosphorylation and activation. Within the mrk kinase loop between the dfg (subdomain vii) and ape (subdomain viii) residues, there are three conserved threonine/serine residues (thr161, thr162, and ser165) that are important for activation. SIGNOR-128577 0.2 IRS2 protein Q9Y4H2 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0004087 24811175 t lperfetto Insulin receptor substrate 1 (IRS-1) and IRS-2 are cytoplasmic adaptor proteins that mediate the activation of signaling pathways in response to ligand stimulation of upstream cell surface receptors. Despite sharing a high level of homology and the ability to activate PI3K, only Irs-2 positively regulates aerobic glycolysis in mammary tumor cells. SIGNOR-252696 0.693 DCAF7 protein P61962 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates activity binding 9534 BTO:0000298 14593110 t miannu Two isoforms of DYRK, DYRK1A and DYRK1B, co-immunoprecipitate with HAN11 when coexpressed in COS cells indicating that the proteins interact in mammalian cells. HAN11 might target DYRKs to cytosolic locations for regulation of specific cellular functions. SIGNOR-260631 0.752 TNFSF10 protein P50591 UNIPROT TNFRSF10B protein O14763 UNIPROT up-regulates binding 9606 15766588 t gcesareni Tumour necrosis factor-related apoptosis inducing ligand (trail) receptor 2 (trail-r2) also known as tnfrsf10b (tumour necrosis factor receptor (tnfr) super family 10b) or killer/dr5, a member of the tnfr family, is a promising candidate tumour suppressor gene at 8p21-22. SIGNOR-134524 0.932 NEFL protein P07196 UNIPROT Neurofilament bundle assembly phenotype SIGNOR-PH72 SIGNOR up-regulates 9606 8376466 f miannu Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons. SIGNOR-252392 0.7 cyclosporin A chemical CHEBI:4031 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR down-regulates chemical inhibition 10116 BTO:0001103 15829723 t apalma On one hand, inhibition of calcineurin with cyclosporin A (CsA) significantly reduced the growth of both the slow/type I soleus muscle and fast/type II plantaris muscle in normal, ambulatory rats SIGNOR-255102 0.8 MAPK1 protein P28482 UNIPROT RORA protein P35398 UNIPROT down-regulates phosphorylation Thr183 PGEAEPLtPTYNISA 9606 17512500 t The effect has been demonstrated using P35398-4 gcesareni We identified the extracellular signal-regulated kinase 2 (erk-2) as roralpha4 phosphorylating kinase in vitro. The primary sequence of roralpha4 contains an erk-2 recognition motif (p-l-t(128)-p) within the hinge domain, and mutation of thr-128 to ala prevents roralpha4 phosphorylation by erk. The roralpha4-t128a mutant exhibits an increased dna-binding affinity, an increased transcriptional activity SIGNOR-154914 0.263 O-phosphonato-L-serine(2-) smallmolecule CHEBI:57524 ChEBI 3-phosphonatooxypyruvate(3-) smallmolecule CHEBI:18110 ChEBI up-regulates quantity precursor of 3702 30034403 t lperfetto Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction. SIGNOR-268564 0.8 CDC42 protein P60953 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT up-regulates activity binding 9606 BTO:0000452 11696321 t miannu We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia. SIGNOR-268424 0.858 SESN3 protein P58005 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR down-regulates activity binding 10090 BTO:0002572 25457612 t We describe AMPK-independent mechanism of mTORC1 regulation by the Sestrins, in which the Sestrins inhibit mTORC1 localization to the lysosomes in a Rag-dependent manner through an interaction with GATOR2 SIGNOR-253561 0.448 PTGER1 protein P34995 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257194 0.41 CDK1 protein P06493 UNIPROT EPN1 protein Q9Y6I3 UNIPROT down-regulates activity phosphorylation Ser382 FSDPWGGsPAKPSTN 10029 BTO:0000246 10764745 t miannu Phosphorylation of POB1 and Epsin by p34cdc2 kinase. Their phosphorylation sites (Ser411 of POB1 and Ser357 of Epsin) were determined. Phosphorylated Epsin and EpsinS357D formed a complex with α-adaptin less efficiently than wild type Epsin. SIGNOR-262723 0.328 Diprenorphine chemical CHEBI:4650 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9262330 t miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. SIGNOR-258662 0.8 CDK9 protein P50750 UNIPROT NCOA2 protein Q15596 UNIPROT up-regulates activity phosphorylation Ser487 GQPTSMLsPRHRMSP 9606 BTO:0000801 29170386 t Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties. SIGNOR-256097 0.248 MED4 protein Q9NPJ6 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266675 0.812 LHX4 protein Q969G2 UNIPROT POU1F1 protein P28069 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15998782 f miannu We show that normal LHX4 binds to a human-specific element and subsequently activates transcription from the proximal upstream regulatory sequence of POUIF1, a gene encoding a POU homeodomain transcription factor known as the main regulator of GH expression. SIGNOR-254558 0.528 AKT1 protein P31749 UNIPROT YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 15806160 t lperfetto Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102 SIGNOR-252475 0.575 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser733 TVREQDQsFTALDWS 9606 SIGNOR-C14 SIGNOR-C14 10195894 t lperfetto Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response SIGNOR-66344 0.2 PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization 10090 17548510 f Simone Vumbaca Previously, we showed that Pax7 overexpression in adult primary myoblasts down-regulates MyoD and prevents myogenin induction, inhibiting myogenesis. We show that Pax7 prevents muscle differentiation independently of its transcriptional activity, affecting MyoD function. [...] Pax7 expression affects MyoD protein stability SIGNOR-255637 0.616 furtrethonium chemical CHEBI:134764 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258644 0.8 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser196 EEKERTFsFCGTIEY 9606 BTO:0000567 10806207 t llicata Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity. SIGNOR-77204 0.587 CDKN2A protein P42771 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 SIGNOR-C18 8891723 t miannu The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks, cdk4 and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-44554 0.902 MYOD1 protein P15172 UNIPROT SMARCA4 protein P51532 UNIPROT up-regulates binding 9606 SIGNOR-C92 17194702 t miannu Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes SIGNOR-151685 0.544 PIM1 protein P11309 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation 9606 25280219 t FLT3-ITD kinase may regulate c-MYC through STAT5-induced enhancement of PIM kinases (Choudhary et al., 2009), which can modulate c-MYC stability and activity via phosphorylation (van der Lugt et al., 1995s). This is supported by the observation that FLT3-ITD CD34+ cells showed higher PIM activity compared to cells expressing FLT3-WT, indicated by increased expression of the PIM targets including p-BAD (Ser112), p-4EBP1 (Thr37/46), and p-c-MYC (Ser62) (Figure 6C); and by the observation that siRNA-mediated inhibition of PIM1, but not PIM2, expression resulted in significantly decreased p-c-MYC (Ser62), c-MYC, and SIRT1 expression in MV4-11 cells SIGNOR-261557 0.684 GSK3A protein P49840 UNIPROT PKD2 protein Q13563 UNIPROT unknown phosphorylation Ser76 AGAAASPsPPLSSCS 9606 BTO:0000007 BTO:0000671 16551655 t llicata We report the identification of a new phosphorylation site for pc2 within its n-terminal domain (ser(76)) and demonstrate that this residue is phosphorylated by glycogen synthase kinase 3 (gsk3). SIGNOR-145306 0.2 Sin3B_complex complex SIGNOR-C409 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity binding 9606 21041485 t miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. SIGNOR-266973 0.2 KHSRP protein Q92945 UNIPROT SRC protein P12931 UNIPROT up-regulates quantity by expression post transcriptional regulation -1 9858532 t lperfetto We show here that this component of the DCS complex is hnRNP H and that, like hnRNP F and KSRP, hnRNP H is needed for src N1 splicing in vitro. SIGNOR-261274 0.274 CACNA1H protein O95180 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 BTO:0000142 30736831 t miannu Certain types of sensory neurons express Cav3.2 calcium channels [12, 13] These channels belong to the family of low-voltage gated T-type calcium channels SIGNOR-269278 0.8 NR3C1 protein P04150 UNIPROT TDO2 protein P48775 UNIPROT down-regulates quantity by repression transcriptional regulation 16272140 t lperfetto Repression of GR-mediated expression of the tryptophan oxygenase gene by the SWI/SNF complex during liver development. SIGNOR-268995 0.344 AKT1 protein P31749 UNIPROT TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto  In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-235340 0.777 CFH protein P08603 UNIPROT CFI protein P05156 UNIPROT up-regulates activity binding 9606 26806831 t lperfetto FH also serves as cofactor for the serine protease factor I (FI) that cleaves C3b into iC3b, unable to form C3 convertase (Fig 1B). SIGNOR-263490 0.918 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr257 APSRQDVyGPQPQVR -1 11382764 t lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 SIGNOR-246488 0.92 MCHR2 protein Q969V1 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257334 0.41 SNCA protein P37840 UNIPROT VAMP2 protein P63027 UNIPROT down-regulates quantity binding 9606 BTO:0000938 31110017 t miannu The normal function of the small presynaptic protein α-synuclein (α-syn) is of exceptional interest, not only in the context of neurodegeneration, but also as a cytosolic regulator of neurotransmission. we show that α-syn-VAMP2 interactions are necessary for α-syn-induced synaptic attenuation. Our data connect divergent views and suggest a unified model of α-syn function. the data indicate that α-syn–VAMP2 binding is essential for α-syn function and advocate an “interlocking model” where α-syn multimers on the SV surface interact with VAMP2 on adjacent SVs, helping to maintain physiologic SV clustering. SIGNOR-264104 0.41 HCRTR1 protein O43613 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257128 0.252 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr69 PVPNQPVyNQPVYNQ 9606 11390389 t Manara Our data establish that the Abl SH3 domain binds to the N-terminal proline-rich segment of PLSCR1 and that ABL1 phosphorylates Tyr residues of the PLSCR1 polypeptide, most likely Tyr69 and Tyr74 within the tandem repeat sequence SIGNOR-260807 0.393 ULK2 protein Q8IYT8 UNIPROT PFKM protein P08237 UNIPROT down-regulates activity phosphorylation Ser74 EATWESVsMMLQLGG 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274043 0.2 bortezomib chemical CHEBI:52717 ChEBI PSMB1 protein P20618 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 21504411 t miannu Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma. SIGNOR-259306 0.8 UBA2 protein Q9UBT2 UNIPROT SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR form complex binding -1 15660128 t lperfetto E1 enzymes facilitate conjugation of ubiquitin and ubiquitin-like proteins through adenylation, thioester transfer within E1, and thioester transfer from E1 to E2 conjugating proteins. Structures of human heterodimeric Sae1/Sae2-Mg.ATP and Sae1/Sae2-SUMO-1-Mg.ATP complexes were determined at 2.2 and 2.75 A resolution, respectively. SIGNOR-263004 0.816 EEF1A1P5 protein Q5VTE0 UNIPROT Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269557 0.8 CDKN2B protein P42772 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0001056 14681685 f The Ink4b gene (Cdkn2b) encodes p15Ink4b, a cyclin-dependent kinase inhibitor. It has been implicated in playing a role in the development of acute myeloid leukemia (AML) in man, since it is hypermethylated with high frequency. We provide evidence that the gene is a tumor suppressor for myeloid leukemia in mice. SIGNOR-259407 0.7 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT unknown phosphorylation Tyr726 KEHNFSFyPTFQSHP 10090 BTO:0001516 16627759 t lperfetto In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated. SIGNOR-271922 0.2 AKT1 protein P31749 UNIPROT SH3RF1 protein Q7Z6J0 UNIPROT down-regulates phosphorylation Ser304 KNTKKRHsFTSLTMA 9606 17535800 t miannu We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac, as does phosphomimetic s304d and s304e mutation of posh. SIGNOR-252501 0.403 everolimus chemical CHEBI:68478 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 BTO:0000848 20689758 t gcesareni M14, m288, and skmel28 (sensitive and resistant) were exposed to rad001, an mtor inhibitor, and to ly294002, a pi3k inhibitor. SIGNOR-167402 0.8 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates phosphorylation Tyr500 TSLGSQSyEDMRGIL 9606 10933394 t llicata Experiments with purified proteins demonstrated that cd19-y513 was lyn's initial phosphorylation and binding site. This led to processive phosphorylation of cd19-y482, which recruited a second lyn molecule, allowing for transphosphorylation and amplification of lyn activation. SIGNOR-80290 0.764 SOSTDC1 protein Q6X4U4 UNIPROT WNT3 protein P56703 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242730 0.282 SIN3A protein Q96ST3 UNIPROT MECP2/SIN3A/HDAC complex complex SIGNOR-C360 SIGNOR form complex binding 9606 BTO:0000567 9620804 t Luana We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases. SIGNOR-267737 0.825 DUSP5 protein Q16690 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 10224087 t inferred from 70% of family members gcesareni Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway SIGNOR-269932 0.773 PGAM2 protein P15259 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity chemical modification 9606 24786789 t miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. SIGNOR-266515 0.8 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 t gcesareni Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion. SIGNOR-181327 0.622 GRK5 protein P34947 UNIPROT SNCB protein Q16143 UNIPROT down-regulates activity phosphorylation Ser118 LMEPEGEsYEDPPQE -1 10852916 t GRK5 prefers alpha-synuclein as a substrate. GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. Mutation of Ser118 practically abolishes Œ≤-synuclein phosphorylation by both GRK2 and GRK5 SIGNOR-251203 0.327 PLK1 protein P53350 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Thr382 PRSINTDtLSKETDS 9606 BTO:0000567 19509060 t lperfetto Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation. SIGNOR-272993 0.603 PLEKHG3 protein A1L390 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260585 0.361 PPP4C protein P60510 UNIPROT NDEL1 protein Q9GZM8 UNIPROT down-regulates activity dephosphorylation Thr219 ASLSLPAtPVGKGTE 9606 18347064 t Protein phosphatase 4 catalytic subunit regulates Cdk1 activity and microtubule organization via NDEL1 dephosphorylation|PP4c selectively dephosphorylates NDEL1 at Cdk1 sites. We also demonstrate that PP4c negatively regulates Cdk1 activity at the centrosome.|We next examined the ability of PP4c to dephosphorylate a Cdk1 phosphorylation site, phospho-T219 SIGNOR-248550 0.404 SARS1 protein P49591 UNIPROT MYC protein P01106 UNIPROT down-regulates activity binding 9606 BTO:0000007 24940000 t Using in vitro, cell and animal experiments, we show here that SerRS intervenes by antagonizing c-Myc, the major transcription factor promoting VEGFA expression, through a tandem mechanism. First, by direct head-to-head competition, nuclear-localized SerRS blocks c-Myc from binding to the VEGFA promoter. Second, DNA-bound SerRS recruits the SIRT2 histone deacetylase to erase prior c-Myc-promoted histone acetylation. SIGNOR-259368 0.2 CHUK protein O15111 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR form complex binding 9606 20300203 t gcesareni The kinase(s) responsible for the phosphorylation of the ikb inhibitors remained elusive for many years, until the biochemical purification of a cytoplasmic high-molecular weight complex migrating around 700900 kda and containing two related catalytic subunits, ikkalfa and ikkbeta. SIGNOR-164506 0.775 SRC protein P12931 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000763 14978237 t lperfetto The tyr701 phosphorylation of signal transducer and activator of transcription 1 (stat1) induced by interferon-gamma (ifn-gamma) and 12-o-tetradecanoylphorbol 13-acetate (tpa) was inhibited by the protein kinase c (pkc) inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin, or the src kinase inhibitor pp2. An association between c-src and stat1 was increased by ifn-gamma and tpa, indicating the direct phosphorylation of stat1 by pkc-dependent c-src activation. SIGNOR-235696 0.576 ANO6 protein Q4KMQ2 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 24663380 f francesca Ano6 deficiency significantly reduces ERK/AKT phosphorylation. Our data have also shown that Ano6-KD significantly attenuates ERK phosphorylation, which is implicated in the regulation of cancer cell proliferation by Ano1, suggesting that Ano6 is potentially involved in regulating myoblast proliferation through the ERK signaling pathway. SIGNOR-261214 0.2 APC-c complex SIGNOR-C150 SIGNOR CCNB1 protein P14635 UNIPROT down-regulates quantity by destabilization ubiquitination 21596315 t lperfetto Complexed with the activator proteins CDC20 or CDH1 (Fang et al., 1998, Visintin et al., 1997), the APC/C recognizes, ubiquitinates, and targets for proteasomal degradation a multitude of cell cycle regulators containing KEN or D box degrons, including securin, cyclin A, and cyclin B. SIGNOR-265051 0.608 AKT proteinfamily SIGNOR-PF24 SIGNOR S1PR1 protein P21453 UNIPROT up-regulates activity phosphorylation Thr236 RTRSRRLtFRKNISK 9606 11583630 t lperfetto Activated akt binds to edg-1 and phosphorylates the third intracellular loop at the t(236) residue. Transactivation of edg-1 by akt is not required for g(i)-dependent signaling but is indispensable for rac activation, cortical actin assembly, and chemotaxis SIGNOR-110845 0.2 panobinostat chemical CHEBI:85990 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257751 0.8 NEU1 protein Q99519 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity 9606 19151752 f Giorgia One of the major molecular changes by NEU1 was decreased sialylation of integrin beta4, assessed by PNA- and MAL-II-lectin blotting of immunoprecipitates with anti-integrin beta4 antibody. The desialylation was accompanied by decreased phosphorylation of the integrin followed by attenuation of focal adhesion kinase and Erk1/2 pathway. SIGNOR-260656 0.252 RAB5A protein P20339 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 t lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 SIGNOR-260616 0.535 Tiospirone chemical CID:55752 PUBCHEM HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258863 0.8 IL6R protein P08887 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 23663276 t milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. SIGNOR-202033 0.741 UMPS protein P11172 UNIPROT orotate smallmolecule CHEBI:30839 ChEBI down-regulates quantity chemical modification 9606 2912371 t miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). SIGNOR-267436 0.8 ITPR1 protein Q14643 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity chemical modification 9606 24646566 t miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256238 0.8 FBXW7 protein Q969H0 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27858941 t miannu DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1 SIGNOR-254774 0.333 SCN3A protein Q9NY46 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. SIGNOR-253455 0.7 ELOC protein Q15369 UNIPROT H1-1 protein Q02539 UNIPROT up-regulates phosphorylation Ser183 KPKKVAKsPAKAKAV 9606 BTO:0000567 20551309 t lperfetto Our results also show the potential function of p-tefb phosphorylation of h1, namely, to increase h1 dissociation from actively transcribed dna. P-tefb preferentially phosphorylates the ser-183 phosphorylation site of histone h1.1 SIGNOR-166120 0.2 TAB1 protein Q15750 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates binding 9606 25290089 t lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205437 0.392 SP1 protein P08047 UNIPROT MAOB protein P27338 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11259630 f miannu Cotransfection experiments show that Sp1 and its closely related family member Sp4 can trans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2. SIGNOR-253868 0.277 AURKB protein Q96GD4 UNIPROT NINL protein Q9Y2I6 UNIPROT up-regulates phosphorylation Ser448 QGYRERLsLLRSEVE 9606 20864540 t lperfetto Importantly, nlp is characterized as a novel substrate of aurora b and can be phosphorylated by aurora b. The specific phosphorylation sites are mapped at ser-185, ser-448, and ser-585. The phosphorylation at ser-448 and ser-585 is likely required for nlp association with aurora b and localization at midbody. Meanwhile, the phosphorylation at ser-185 is vital to nlp protein stability. Disruptions of these phosphorylation sites abolish cytokinesis and lead to chromosomal instability. SIGNOR-168049 0.254 P2RY2 protein P41231 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257145 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser23 ARKRHAPsPEPAVQG 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276092 0.274 GSK3B protein P49841 UNIPROT DPYSL5 protein Q9BPU6 UNIPROT up-regulates activity phosphorylation Thr516 TPLADTPtRPVTRHG 9606 BTO:0000938 25040932 t lperfetto The T516 phosphorylation was achieved by the glycogen synthase kinase-3beta (GSK-3beta), which can phosphorylate the wildtype protein but not the non-phosphorylatable mutant. Furthermore, we have shown that T516 phosphorylation is essential for the tubulin-binding property of CRMP5. Therefore, CRMP5-induced growth inhibition is dependent on T516 phosphorylation through the GSK-3beta pathway. SIGNOR-264835 0.407 BDKRB2 protein P30411 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256695 0.358 PCSK5 protein Q92824 UNIPROT Neurophysin 1 protein P01178-PRO_0000020496 UNIPROT up-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270336 0.2 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT up-regulates activity phosphorylation Thr244 AETHSSStPVQHPIK 9606 BTO:0000567 30021153 t lperfetto Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. SIGNOR-265032 0.2 copper(1+) smallmolecule CHEBI:49552 ChEBI SOD1 protein P00441 UNIPROT up-regulates activity chemical activation 1542024 t lperfetto Copper as a cofactor and regulator of copper,zinc superoxide dismutase SIGNOR-272299 0.8 MC3R protein P41968 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257298 0.252 UCK2 protein Q9BZX2 UNIPROT cytidine 5'-monophosphate(2-) smallmolecule CHEBI:60377 ChEBI up-regulates quantity chemical modification 11306702 t lperfetto Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. SIGNOR-275861 0.8 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser268 VALPPGAsPQRSRSP 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248519 0.387 CDK2 protein P24941 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Thr491 PQQRNALtPTTIPDG 9606 18769144 t lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively SIGNOR-180767 0.248 SIRT7 protein Q9NRC8 UNIPROT H3-5 protein Q6NXT2 UNIPROT up-regulates activity deacetylation Lys19 TGGKAPRkQLATKAA 22722849 t lperfetto SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. SIGNOR-275873 0.2 sunitinib chemical CHEBI:38940 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 BTO:0000776 20185585 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-163938 0.8 FYN protein P06241 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268216 0.619 bromocriptine chemical CHEBI:3181 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258722 0.8 NGF protein P01138 UNIPROT NGFR protein P08138 UNIPROT up-regulates binding 9606 14699954 t amattioni Neurotrophin binding to p75ntrhas also been shown to induce apoptosis SIGNOR-120555 0.83 LLGL2 protein Q6P1M3 UNIPROT Scribble_complex_DLG5-LLGL2_variant complex SIGNOR-C506 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270891 0.47 FYN protein P06241 UNIPROT PTPRF protein P10586 UNIPROT up-regulates activity phosphorylation 9534 12496362 t LAR PTPase domain 2 was tyrosine phosphorylated by Fyn tyrosine kinase. we confirmed that LAR dephosphorylated the phosphorylated tyrosine residues of Lck and Fyn, and tyrosine residue(s) in LAR PTPase D2 was phosphorylated by Fyn to supply Fyn SH2 binding site. SIGNOR-251180 0.405 RBM15 protein Q96T37 UNIPROT SON protein P18583 UNIPROT up-regulates binding 9606 19786495 t miannu Here we report that the human nxf1-binding protein rbm15 binds specifically to human dbp5 and facilitates its direct contact with mrna in vivo. SIGNOR-188264 0.241 GPAA1 protein O43292 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32432756 f miannu GPAA1 may contribute to the malignant progression of childhood ALL via activating c-myc. Luciferase reporter gene assay demonstrated that overexpression of c-myc remarkably attenuated the Luciferase activity of the wild-type GPAA1 vector without attenuating that of the mutant vector or empty vector, further demonstrating that GPAA1 can be targeted by c-myc. SIGNOR-261240 0.2 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser7 sDSEEEVC -1 8972483 t llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  SIGNOR-250803 0.371 GRM4 protein Q14833 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. SIGNOR-264935 0.8 P2RY1 protein P47900 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256943 0.2 PIK-93 chemical CID:6852167 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206241 0.8 NRG1 protein Q02297 UNIPROT ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR up-regulates binding 9606 14967450 t inferred from 70% of family members gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. SIGNOR-269870 0.903 MAPK1 protein P28482 UNIPROT DYNC1LI1 protein Q9Y6G9 UNIPROT unknown phosphorylation Ser516 VSPTTPTsPTEGEAS 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262773 0.257 ROCK1 protein Q13464 UNIPROT RDX protein P35241 UNIPROT up-regulates activity phosphorylation Thr564 AGRDKYKtLRQIRQG 10090 BTO:0005065 9456324 t lperfetto  A peak of the phosphopeptide, in which only T573 was phosphorylated, was not detected. Quantitative analyses revealed that _100% of T564, but at most _40% of T573, was phosphorylated when C-rad was incubated with Rho-Kc for 1 h. Then we concluded that the major and primary phosphorylation site of radixin by Rho-kinase was T564 and referred to the Rho-Kc€“phosphorylated C-rad as T564-phosphorylated C-rad. | In this study, we found that the T564 phosphorylation of radixin markedly suppressed its head-to-tail association. This suggests that the T564-phosphorylation of radixin (and probably also the phosphorylation of ezrin T567 and moesin T558) keeps them open and active. SIGNOR-248994 0.666 OPRD1 protein P41143 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256962 0.279 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser780 STRPPTLsPIPHIPR 9606 SIGNOR-C18 23336272 t gcesareni Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. SIGNOR-200483 0.928 AMPK complex SIGNOR-C15 SIGNOR ARMC10 protein Q8N2F6 UNIPROT up-regulates activity phosphorylation Ser45 LGIRSSKsAGALEEG 9606 30631047 t miannu We validated one uncharacterized protein, ARMC10, and demonstrated that the S45 site of ARMC10 can be phosphorylated by AMPK both in vitro and in vivo. Moreover, ARMC10 overexpression was sufficient to promote mitochondrial fission, whereas ARMC10 knockout prevented AMPK-mediated mitochondrial fission. These results demonstrate that ARMC10 is an effector of AMPK that participates in dynamic regulation of mitochondrial fission and fusion. SIGNOR-266413 0.2 zaleplon chemical CHEBI:10102 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t brain lperfetto The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005). SIGNOR-263804 0.8 IRF9 protein Q00978 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR form complex binding -1 8943351 t 2 miannu The first STAT-containing transcription factor to be studied, the alpha-interferon-induced ISGF3, is composed of a Stat1:2 heterodimer and a weak DNA-binding protein, p48. The p48 and Stat1:2 heterodimer do not associate stably in the absence of DNA, but we show that amino acids approximately 150 to 250 of Stat1 and a COOH-terminal portion of p48 exhibit physical interaction, implying contact that stabilizes ISGF3 SIGNOR-240600 0.865 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNAI1 protein P63096 UNIPROT up-regulates binding 9606 12393875 t inferred from 70% family members gcesareni We conclude that lpa(1) receptors couple to a g(i)-phosphoinositide 3-kinase-tiam1 pathway to activate rac. SIGNOR-269964 0.2 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT up-regulates activity phosphorylation Ser1004 SEHDSDEsSDDDSDS 9606 BTO:0000661 10066810 t llicata Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment.  SIGNOR-251029 0.445 doxorubicin chemical CHEBI:28748 ChEBI ABCC1 protein P33527 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002206 9647783 t Simone Vumbaca Unconjugated Dox and Dau failed to inhibit the transport of LTC4, whereas 30 microM GS-Dox or GS-Dau conjugates completely inhibited the transport. SIGNOR-261085 0.8 GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263781 0.7 G6PD protein P11413 UNIPROT NADP(3-) smallmolecule CHEBI:58349 ChEBI down-regulates quantity chemical modification 9606 24769394 t miannu G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress SIGNOR-268125 0.8 ADRA2A protein P08913 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256977 0.406 POU2F1 protein P14859 UNIPROT MYH2 protein Q9UKX2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 t lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation SIGNOR-238757 0.2 ATM protein Q13315 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser516 SSTVAGGsQSPKLFS 9606 16874298 t lperfetto The artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced dna double-strand breaks (dsbs) in an atm and dna-pk dependent process. Here, we show that artemis phosphorylation by atm and dna-pk in vitro is primarily attributable to s503, s516 and s645 and demonstrate atm dependent phosphorylation at serine 645 in vivo SIGNOR-148319 0.603 CEBPB protein P17676 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12493739 f miannu The C/EBP5 motif, which is located between the TATA-box and the translation start point, is essential for the C/EBP-mediated constitutive and most of the cAMP-stimulated expression as its mutation nearly abolished IL-10 promoter activity. Our results suggest a dominant role of C/EBP transcription factors relative to CREB/ATF in tissue-specific and differentiation-dependent IL-10 transcription SIGNOR-254523 0.363 SQSTM1 protein Q13501 UNIPROT WDFY3 protein Q8IZQ1 UNIPROT up-regulates quantity binding 9606 BTO:0000452 20168092 t miannu  We show here that p62 is required to recruit the large phosphoinositide-binding protein ALFY to cytoplasmic p62 bodies generated upon amino acid starvation or puromycin-treatment. ALFY, as well as p62, is required for formation and autophagic degradation of cytoplasmic ubiquitin-positive inclusions.  SIGNOR-266792 0.579 GATA4 protein P43694 UNIPROT HAMP protein P81172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 21609320 f miannu Co-transfection of a GATA-4 expression vector with a hepcidin promoter reporter construct enhanced hepcidin promoter transcriptional activity. SIGNOR-254196 0.2 MAPKAPK2 protein P49137 UNIPROT ETV1 protein P50549 UNIPROT down-regulates activity phosphorylation Ser216 PMYQRQMsEPNIPFP 452646 11551945 t miannu MK2 phosphorylates ER81 in vitro within its central inhibitory domain, and overexpression of MK2 leads to increased in vivo phosphorylation of ER81. Two serine residues, ER81 amino acids 191 and 216, were identified as MK2 phosphorylation sites. MK2 suppresses basal ER81-dependent transcription SIGNOR-250146 0.596 SMARCD3 protein Q6STE5 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270705 0.752 PRKCA protein P17252 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser187 DLGERKPsSAAYQKA -1 9244383 t lperfetto We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198. SIGNOR-248973 0.378 RPL29 protein P47914 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262471 0.856 TNF protein P01375 UNIPROT NOD2 protein Q9HC29 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18647246 f miannu NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B. SIGNOR-252407 0.426 PPARA protein Q07869 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16556735 t miannu We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression. SIGNOR-268024 0.579 TLK1 protein Q9UKI8 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates phosphorylation Ser328 VLPSISLsPGPQPPK 9606 18940270 t llicata Tlk1b phosphorylates hrad9 at s328 after the induction of dsb, occupancy of rad9 adjacent to the break increased during repair while that of asf1 decreased, and the effect was more pronounced in tlk1b-overexpressing cells. We propose that following genotoxic stress, tlk1/1b is first recruited to the dsb in a complex with rad9. It then exchanges with asf1 to promote nucleosomes eviction at the dsb and access of the repair machinery to unencumbered dna. SIGNOR-181748 0.46 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser151 VLPSSKRsPSTATLS 9606 BTO:0001061 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276779 0.629 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR KHSRP protein Q92945 UNIPROT down-regulates binding 9606 17177604 t gcesareni Akt phosphorylates ksrp at a unique serine residue, creating a functional binding site for the molecular chaperone 14-3-3. As a consequence, akt activation impairs ksrp ability to interact with the exoribonucleolytic complex exosome and, in turn, to promote rapid mrna decay. SIGNOR-151212 0.2 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI 3-phosphonatooxypyruvate(3-) smallmolecule CHEBI:18110 ChEBI up-regulates quantity precursor of 9606 25406093 t lperfetto PHDGH catalyzes the first reaction of de novo serine biosynthesis, producing 3-phosphohydroxypyruvate by NAD+-coupled oxidation of 3-phosphoglycerate (3PG).|The PHGDH reaction is reversible and, under standard conditions, thermodynamically favors the direction from 3-phosphohydroxypyruvate to 3PG. SIGNOR-268565 0.8 PRKACG protein P22612 UNIPROT PHKA2 protein P46019 UNIPROT down-regulates activity phosphorylation 9606 10487978 t Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. SIGNOR-267414 0.307 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 BTO:0001271 7637391 t gcesareni Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation. SIGNOR-30357 0.2 CSNK2A1 protein P68400 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates phosphorylation Ser421 IACEEEFsDSEEEGE 9606 11602581 t gcesareni Human hdac1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, ser(421) and ser(423), were unambiguously identified. Loss of phosphorylation at ser(421) and ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of hdac1. SIGNOR-111011 0.611 CDK1 protein P06493 UNIPROT TERT protein O14746 UNIPROT up-regulates activity phosphorylation Thr249 AAPEPERtPVGQGSW 9606 BTO:0000567 32214089 t miannu Here we report that hTERT is phosphorylated at threonine 249 during mitosis by the serine/threonine kinase CDK1.These observations indicate that phosphorylation at threonine 249 regulates hTERT RdRP and contributes to cancer progression in a telomere independent manner. SIGNOR-277517 0.329 TWIST1 protein Q15672 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003879 20646316 f miannu Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. SIGNOR-255522 0.331 DCC protein P43146 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity binding 9606 15494734 t miannu Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling. SIGNOR-268371 0.708 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG -1 11955436 t β-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC) SIGNOR-260015 0.891 CALM2 protein P0DP24 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates binding 9606 11796223 t miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-266322 0.524 SRC protein P12931 UNIPROT EMD protein P50402 UNIPROT down-regulates phosphorylation Tyr59 SSSAASSySFSDLNS 9606 BTO:0000567 BTO:0000887 19789182 t llicata Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf SIGNOR-188308 0.463 NEB protein P20929 UNIPROT WASL protein O00401 UNIPROT up-regulates binding 9606 21798082 t gcesareni Igf1-akt signaling, by inhibiting gsk3b, allows the interaction of n-wasp with the unphosphorylated nebulin;the consequent recruitment of n-wasp to the z-disk promotes actin nucleation and elongation of actin filaments. SIGNOR-175671 0.359 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1644 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273067 0.635 CASP8 protein Q14790 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261752 0.338 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT up-regulates activity phosphorylation Ser464 DKEGLSEsVRSSCTL 9606 20643644 t Manara We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase. SIGNOR-260796 0.2 PDCD1 protein Q15116 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity 9606 BTO:0000782 22740686 f Barakat MEK1/2 was phosphorylated and activated upon activation of T cells through TCR-CD3 and CD28, which resulted in phosphorylation of its downstream target ERK1/2, as determined by Western blotting analysis with an antibody specific for ERK1/2 phosphorylated at Thr202 and Tyr204, markers of activation. PD-1 substantially inhibited the activation of MEK1/2 and ERK1/2 SIGNOR-275411 0.265 MCHR1 protein Q99705 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257235 0.277 MDN1 protein Q9NU22 UNIPROT PELP1 protein Q8IZL8 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 27814492 t miannu MDN1 Is Physically and Functionally Associated with the Mammalian PELP1 Complex. To more specifically determine a function of mammalian MDN1 in the subnuclear distribution of PELP1-containing pre-60S-particles, we examined PELP1 localization in control cells or cells depleted from MDN1. Importantly, in the absence of MDN1, PELP1 became sequestered in enlarged nucleoli, indicating that MDN1 is involved in the nucleolar release of PELP1-containing pre-60S ribosomes SIGNOR-261357 0.385 PTPRC protein P08575 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation 9606 11124968 t lperfetto Taken together, these data indicate that CD45 inhibits PMA dependent PKCdelta activation by impeding PMA dependent PKCdelta tyrosine phosphorylation.|reduction in CD45 expression caused the duration of peak PMA-induced MEK and extracellular signal-regulated kinase (ERK) 1/2 activity to increase from 5 min to 30 min while leading to a 4-fold increase in PMA-dependent PKCdelta activation. SIGNOR-277028 0.301 CSNK1D protein P48730 UNIPROT ZNF322 protein Q6U7Q0 UNIPROT down-regulates quantity by destabilization phosphorylation Ser396 ELSPPHAsEASQMS 9606 BTO:0002552 28581525 t lperfetto CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction. SIGNOR-264892 0.2 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr612 TLHTDDGyMPMSPGV 9606 17827393 t gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157742 0.864 PRKD1 protein Q15139 UNIPROT CFL1 protein P23528 UNIPROT down-regulates activity phosphorylation Ser3 sGVAVSDG 19329994 t lperfetto PKD1 regulates cofilin S3-phosphorylation|Both, oxidative stress as well as RhoA activation enhanced cofilin phosphorylation at S3, implicating an increased inhibition due to PKD1-mediated signalling events SIGNOR-275944 0.34 Caspase 1 complex complex SIGNOR-C220 SIGNOR GSDMD protein P57764 UNIPROT up-regulates activity cleavage Asp275 CLHNFLTdGVPAEGA 9606 BTO:0000007 26375003 t lperfetto Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence | SIGNOR-256415 0.633 PLK1 protein P53350 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates phosphorylation Ser195 LTKTASEsISNLSEA 9606 20664522 t gcesareni Furthermore, we provide evidence that plk1 phosphorylation of clip-170 at s195 enhances its association with ck2 SIGNOR-167172 0.691 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR up-regulates activity chemical activation 9606 18790874 t brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-263791 0.8 STAT1 protein P42224 UNIPROT TAP1 protein Q03518 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15778351 f miannu We also show that this cytokine-dependent expression of TAP1 transcripts depends on STAT1 and IFN regulatory factor-2 (IRF-2), but not on IRF-1, and provide evidence that IRF-2 constitutively binds to the TAP1 gene promoter and enhances TAP1 promoter activity. We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-gamma target cells tested. SIGNOR-254531 0.276 RET protein P07949 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000944 15994200 t lperfetto The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity SIGNOR-252619 0.328 PTPN12 protein Q05209 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK 10090 18482983 t we identify SHP-2 and PTP-PEST as negative regulators of c-Src kinase | Inactivation of catalytically active c-Src kinase by the phosphatases SHP-2 or PTP-PEST by dephosphorylation of the tyrosine residue Tyr-416 within the c-Src kinase domain prevents the phosphorylation of villin SIGNOR-248659 0.543 CASP3 protein P42574 UNIPROT Caspase 3 complex complex SIGNOR-C221 SIGNOR form complex binding cleavage:Asp28 IHGSESMdSGISLDN 15115390 t lperfetto Caspases are expressed as inactive proenzymes of 30−50 kDa that include an amino-terminal domain of variable length and sequence that is followed by two domains of conserved sequences:  a large subunit (approximately 20 kDa, designated p17 in caspase-3) and a small carboxy-terminal subunit (approximately 10 kDa, designated p12 in caspase-3). Activation is accomplished by proteolytic cleavage between these domains and subsequent assembly of heterotetramers that contain two copies each of the large and small subunits but lack the amino-terminal domains. SIGNOR-256387 0.2 SOD1 protein P00441 UNIPROT DERL1 protein Q9BUN8 UNIPROT down-regulates activity binding 9606 BTO:0000007 18519638 t P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction) Various proteins involved in ERAD have been identified recently (Meusser et al. 2005). Among them, components of the retro-translocation machinery including ATPase p97, its cofactors Ufd1 and Npl4, and the ER membrane proteins Derlin-1 and VIMP are of key importance to ERAD function |Here we show that SOD1(mut) specifically interacted with Derlin-1, a component of endoplasmic reticulum (ER)-associated degradation (ERAD) machinery and triggered ER stress through dysfunction of ERAD. SIGNOR-262785 0.438 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser214 LVRSREVsVDEGRAC -1 9677319 t lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. SIGNOR-249000 0.292 DVL1 protein O14640 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 17569865 t amattioni The scaffold protein dishevelled (dvl) is required for lrp6 phosphorylation and aggregation. We propose that wnts induce coclustering of receptors and dvl in lrp6-signalosomes, which in turn triggers lrp6 phosphorylation to promote axin recruitment and beta-catenin stabilization. SIGNOR-156072 0.695 SMAD7 protein O15105 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity binding 9606 20663871 t lperfetto The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-_ (TGF-_) family signaling. I-Smads inhibit TGF-_ family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation. SIGNOR-167163 0.781 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser78 NKDQHSIsYTLSRAQ -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276126 0.644 LHFPL5 protein Q8TAF8 UNIPROT Hair cells mechanotransduction channel complex SIGNOR-C290 SIGNOR up-regulates activity binding 10090 BTO:0000630 23217710 t lperfetto Here we show that TMHS is an auxiliary subunit of the hair cells mechanotransduction channel.|TMHS belongs to the tetraspan family. It binds to PCDH15, controls the assembly of the hair cells mechanotransduction machinery, regulates the properties of their mechanotransduction channels, and is required for adaptation. SIGNOR-262574 0.424 5-aza-2'-deoxycytidine chemical CHEBI:50131 ChEBI DNMT1 protein P26358 UNIPROT down-regulates activity chemical inhibition 9606 14585280 t miannu Both Azacitidine and Decitabine may also exert antitumor activity through induction of DNA hypomethylation, by forming a covalent complex with the major DNA methyltransferase (now termed DNMT1).Azacitidine and Decitabine effectively deplete the cell of functional DNA methylating activity, which results in profound hypomethylation after several rounds of DNA replication (Fig. 2). DNMT1 is considered a bona fide anticancer target at different levels SIGNOR-259294 0.8 regorafenib chemical CHEBI:68647 ChEBI TEK protein Q02763 UNIPROT down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259213 0.8 NEUROD1 protein Q13562 UNIPROT MGAT5B protein Q3V5L5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001976 21771782 f miannu By EMSA and ChIP analyses we identified two regulatory proteins, NeuroD1 and CTCF that bind to and activate the GnT-IX promoter. We also revealed that GnT-IX expression was suppressed in CTCF- and NeuroD1-depleted cells, indicating that a NeuroD1- and CTCF-dependent epigenetic mechanism governs brain-specific GnT-IX expression. SIGNOR-253825 0.253 NBEAL2 protein Q6ZNJ1 UNIPROT VWF protein P04275 UNIPROT up-regulates 9606 BTO:0000132 28082341 f lperfetto Recent in vitro megakaryopoiesis studies using HSCs from GPS patients with NBEAL2 mutations showed normal MK differentiation with defective proplatelet formation and reduced α-granule proteins such as von Willebrand factor (VWF), thrombospondin and P-selectin. SIGNOR-261884 0.276 MRPS15 protein P82914 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261455 0.731 EREG protein O14944 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0001253 20513444 t Epiregulin may be a mediator of localized cell proliferation gcesareni Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling. SIGNOR-165782 0.889 CD38 protein P28907 UNIPROT nicotinic acid-adenine dinucleotide phosphate smallmolecule CHEBI:76072 ChEBI up-regulates quantity chemical modification 9606 18626062 t miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. SIGNOR-264245 0.8 ATP smallmolecule CHEBI:15422 ChEBI P2RX7 protein Q99572 UNIPROT up-regulates chemical activation 9606 18827222 t mrosina Pericellular ATP activates P2XRs on the T cell in an autocrine fashion (step 4) and perhaps also P2X7 receptors on the APC in a paracrine fashion resulting in IL-1beta processing and release (step 5). SIGNOR-254965 0.8 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Thr501 QMDSGYNtQNCGSNI 9606 18521620 t gcesareni Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp). SIGNOR-178807 0.779 XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 9545235 t lperfetto IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspasesThese findings demonstrate that IAPs can suppress different apoptotic pathways by inhibiting distinct caspases and identify pro-caspase-9 as a new target for IAP-mediated inhibition of apoptosis SIGNOR-56484 0.92 GSK3B protein P49841 UNIPROT STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization phosphorylation Thr385 ILTSNQKtLTPEKGQ 9606 BTO:0002181 31843895 t miannu GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation. SIGNOR-276765 0.293 tiagabine chemical CHEBI:9586 ChEBI SLC6A1 protein P30531 UNIPROT down-regulates activity chemical inhibition -1 7851497 t miannu Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1. SIGNOR-258477 0.8 DGC complex SIGNOR-C217 SIGNOR GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR up-regulates quantity binding 9606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265441 0.2 PAX7/MLL2 complex complex SIGNOR-C91 SIGNOR MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 f miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-198641 0.506 TBP protein P20226 UNIPROT LIN28B protein Q6ZN17 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 23494474 f miannu We conclude that the oncoprotein HBXIP as a co-activator of TF II D transactivates Lin28B promoter via directly binding to TBP to upregulate the expression of Lin28B in promotion of proliferation of breast cancer cells, in which Lin28B maintains the high level of HBXIP through suppressing miR-520b in a feedback manner. SIGNOR-255252 0.252 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr8 MTAKMETtFYDDALN 9606 BTO:0000848 21177766 t lperfetto P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286) SIGNOR-170768 0.271 CSNK2A1 protein P68400 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation Ser146 FYKRRGAsDLSSEEG -1 8954982 t llicata Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149. SIGNOR-250949 0.331 FGF2 protein P09038 UNIPROT ALPL protein P05186 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004473 19049325 f miannu FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2. SIGNOR-252194 0.383 MK-2461 chemical CID:44137946 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194378 0.8 DIABLO protein Q9NR28 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates binding 9606 17546047 t gcesareni Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. mitochondrial survivin associated with smac/diablo, delaying its release. SIGNOR-155364 0.586 PDX1 protein P52945 UNIPROT NKX6-1 protein P78426 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11309388 t In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1. SIGNOR-255542 0.481 CACNA1A protein O00555 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30849329 t miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). SIGNOR-264323 0.8 TGFB1 protein P01137 UNIPROT LPL protein P06858 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 11742878 f Regulation of expression miannu TGF-β1 inhibited gene expression and cell surface activity of LPL. TGF-β1 did not have an effect on LPL activity when it was added directly to the LPL activity assay (data not shown); however, as shown in the Table, TGF-β1 significantly reduced LPL mRNA by 55.0% SIGNOR-251847 0.268 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 16679294 t gcesareni Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action SIGNOR-146672 0.263 CSNK2A1 protein P68400 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates phosphorylation Ser122 RIQEQESsGEEDSDL 9606 9405437 t gcesareni Recombinant inh2 was phosphorylated by kinases in cytosols prepared from g1 and s phase cells. The amount of inh2 kinase attributed to casein kinase 2, based on inhibition by heparin, increased 2.6-fold from g1 to s phase SIGNOR-53861 0.312 TSC2 protein P49815 UNIPROT TSC complex SIGNOR-C101 SIGNOR form complex binding 9606 12172553 t lperfetto TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR). SIGNOR-217913 0.933 L-thyroxine smallmolecule CHEBI:18332 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 34674502 t scontino Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule.¬† SIGNOR-267042 0.8 LEPR protein P48357 UNIPROT AGRP protein O00253 UNIPROT down-regulates quantity 27154742 f lperfetto Leptin binding inhibits the neuropeptide Y/agouti-related protein (NPY/AgRP) production and stimulates pro-opiomelanocortin (POMC) production SIGNOR-253076 0.463 POLR2J2 protein Q9GZM3 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266174 0.2 HLX protein Q14774 UNIPROT EGR1 protein P18146 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003980 20008130 t Luana In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells. SIGNOR-261621 0.265 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 9335504 t llicata In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1 SIGNOR-52691 0.591 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser78 NKDQHSIsYTLSRAQ -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276133 0.758 TGFB2 protein P61812 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 1310899 t gcesareni A cdna encoding the tgf-beta type ii receptor protein has been isolated by an expression cloning strategy. The cloned cdna, when transfected into cos cells, leads to overexpression of an approximately 80 kd protein that specifically binds radioiodinated tgf-beta 1. Excess tgf-beta 1 competes for binding of radioiodinated tgf-beta 1 in a dose-dependent manner and is more effective than tgf-beta 2. SIGNOR-16690 0.744 NUCKS1 protein Q9H1E3 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 26323318 f miannu From these results, we can conclude that NUCKS1 plays a role in HR DNA repair, as does its paralog RAD51AP1. we have tested and uncovered a role for NUCKS1 in HR and in maintaining DNA replication integrity and genome stability. SIGNOR-261960 0.7 Raltegravir chemical CID:54671008 PUBCHEM UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258162 0.8 CHKA protein P35790 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity binding 9606 BTO:0000093 21822308 t miannu We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333. CHKA is required for maximum EGF-dependent cell growth in mammary epithelium-derived cell lines SIGNOR-266352 0.411 PRKAA2 protein P54646 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Ser505 GSVKRVTsGPSLGSL 9606 BTO:0000887;BTO:0001103 SIGNOR-C15 20231899 t gcesareni Ampk-wild type (wt) stimulates pld activity, while ampk-dominant negative (dn) inhibits it. Ampk regulates pld1 activity through phosphorylation of the ser-505 and this phosphorylation is increased by the presence of amp. SIGNOR-164293 0.2 CKB protein P12277 UNIPROT N-phosphocreatine smallmolecule CHEBI:17287 ChEBI up-regulates quantity chemical modification 9606 18502307 t miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. SIGNOR-265787 0.8 MYOF protein Q9NZM1 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 10090 16280346 f These data support a role for myoferlin in the maturation of myotubes and the formation of large myotubes that arise from the fusion of myoblasts to multinucleate myotubes SIGNOR-255973 0.7 STAT5A protein P42229 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000574 9168989 f Regulation miannu We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin. SIGNOR-251787 0.2 NUAK1 protein O60285 UNIPROT LATS1 protein O95835 UNIPROT down-regulates phosphorylation Ser464 NIPVRSNsFNNPLGN 9606 19927127 t lperfetto Moreover, we show that nuak1 phosphorylates lats1 at s464 and this has a role in controlling its stabilitycells that constitutively express nuak1 suffer gross aneuploidies and show diminished expression of the genomic stability regulator lats1 SIGNOR-161792 0.397 CSNK2A1 protein P68400 UNIPROT CASP2 protein P42575 UNIPROT down-regulates phosphorylation Ser157 LYKKLRLsTDTVEHS 9606 16193064 t gcesareni Here we show that protein kinase (pk) ck2 phosphorylates procaspase-2 directly at serine-157. When intracellular pkck2 activity is low or downregulated by specific inhibitors, procaspase-2 is dephosphorylated, dimerized, and activated in a piddosome-independent manner. SIGNOR-140836 0.314 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS -1 12383858 t gcesareni Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation. SIGNOR-94268 0.746 AHCYL1 protein O43865 UNIPROT PAPOLB protein Q9NRJ5 UNIPROT down-regulates activity binding 9606 BTO:0000007 19224921 t lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. SIGNOR-268331 0.2 SOD1 protein P00441 UNIPROT ER stress stimulus SIGNOR-ST9 SIGNOR up-regulates 10090 18519638 f P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction) SOD1mut-induced ER stress |we first examined whether SOD1mut induces ER stress in NSC34 motor neurons, as assessed by band-shift analyses of the ER transmembrane kinase receptors IRE1 and PERK. Adenovirus (Ad)-mediated expression of ALS-linked SOD1mut (SOD1G93A) was detectable within 48 h of infection (Supplemental Fig. S1A). SOD1mut (SOD1A4V, SOD1G85R, and SOD1G93A) but not wild-type SOD1 (SOD1wt) activated IRE1 and PERK SIGNOR-262788 0.7 BMP2 protein P12643 UNIPROT BMP2 protein P12643 UNIPROT up-regulates binding 9606 BTO:0000887 11178121 t lperfetto Bmps are dimeric proteins with a single interchain disulfide bond. The dimeric conformation is an absolute requirement for the biological action and interaction with receptors SIGNOR-236166 0.2 p38 proteinfamily SIGNOR-PF16 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation 9606 10085140 t inferred from 70% family members gcesareni Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target SIGNOR-270124 0.2 CSNK2A1 protein P68400 UNIPROT STX1A protein Q16623 UNIPROT up-regulates phosphorylation Ser14 ELRTAKDsDDDDDVA 9606 11846792 t lperfetto In this report, we show that syntaxin-1a is phosphorylated in vitro by cki on thr21. Casein kinase ii (ckii) has been shown previously to phosphorylate syntaxin-1a in vitro and we have identified ser14 as the ckii phosphorylation site. the phosphorylation of syntaxin-1a by ckii enhances its capacity to associate with synaptotagmin [21]. Therefore, phosphorylation of ser14 by ckii suggests an important role for this residue in regulating the interaction between syntaxin-1a and synaptotagmin SIGNOR-114840 0.374 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation -1 16326050 t miannu Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast SIGNOR-268751 0.8 creatine smallmolecule CHEBI:16919 ChEBI CKB protein P12277 UNIPROT up-regulates activity chemical activation 9606 18502307 t miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. SIGNOR-265783 0.8 IL9 protein P15248 UNIPROT IL9R protein Q01113 UNIPROT up-regulates binding 9606 10642536 t fspada Interleukin 9 (il-9) exerts its pleiotropic effects through the il-9 receptor (il-9r) complex, which consists of the il-9r alpha-chain, which determines the cytokine specificity, and the il-2 receptor gamma-chain SIGNOR-73601 0.742 ethanol chemical CHEBI:16236 ChEBI GLRA1 protein P23415 UNIPROT up-regulates activity chemical activation 8355 BTO:0000964 8700149 t miannu Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations. SIGNOR-258495 0.8 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr230 QPYDPNFyDETYDYG 9606 12052863 t lperfetto We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown). SIGNOR-88903 0.608 PTPN6 protein P29350 UNIPROT CTTN protein Q14247 UNIPROT down-regulates activity dephosphorylation Tyr421 RLPSSPVyEDAASFK 9606 34088320 t lperfetto Shp1 interacts with cortactin and reduces cortactin phosphorylation at tyrosine 421; 3.|induction of Shp1-cortactin complex formation impairs cortactin scaffolding-activity and negatively affects invadopodia behaviour; 4. SIGNOR-277003 0.2 HIF1A protein Q16665 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0001033 27476001 f miannu Our present study reveals that DAB2IP prevents EMT and metastasis of prostate cancer through targeting PROX1 gene transcription and destabilizing HIF1α protein, which provides a new insight into mechanism that DAB2IP regulates EMT and PCa metastasis. SIGNOR-254768 0.7 SP1 protein P08047 UNIPROT CACNA1G protein O43497 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 23868804 t miannu Consistent with this, Sp1 over-expression enhanced promoter activity while siRNA-mediated Sp1 silencing significantly decreased the level of CaV 3.1 protein and reduced the amplitude of whole-cell T-type Ca(2+) currents expressed in the N1E-115 cells. These results provide new insights into the molecular mechanisms that control CaV 3.1 channel expression. SIGNOR-264034 0.264 PPP1R9B protein Q96SB3 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 10090 BTO:0001976 15996550 f miannu Neurabin and spinophilin are preferentially expressed in neurons, where they are highly localized to dendritic spines via an interaction with F-actin. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc SIGNOR-269179 0.7 LAT protein O43561 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. SIGNOR-246050 0.416 LATS1 protein O95835 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 22658639 t Together,the YAP/TAZ-TEAD complex promotes proliferative and survival programs. milica In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. SIGNOR-197643 0.783 motesanib chemical CHEBI:51098 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258252 0.8 dopamine smallmolecule CHEBI:18243 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258717 0.8 KIF19 protein Q2TAC6 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272532 0.7 HARS1 protein P12081 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 10430027 t miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. SIGNOR-270488 0.8 POU2F1 protein P14859 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 t lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation SIGNOR-238760 0.2 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 t gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation SIGNOR-252444 0.634 N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide chemical CHEBI:63082 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 20590599 t Luana Thus, overall, salmeterol is a highly selective β2-adrenoceptor agonist because of its higher β2-affinity and not because of higher β2-intrinsic efficacy. A similar reasoning can be applied to formoterol, although this agonist has higher intrinsic efficacy at all three receptors (rank 6, 8 and 5 at β1, β2 and β3). SIGNOR-257855 0.8 PTPN1 protein P18031 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates activity dephosphorylation 9606 23521888 t lperfetto Since Gab1 is negatively regulated by PTP1B, a part of the retinal neuroprotective effect we have observed previously in PTP1B deficient mice could be contributed by Gab1 as well.|The results indicate that PTP1B completely dephosphorylated Gab1 and the mutant protein failed to dephosphorylate Gab1 (Figure\u00a0 xref C). SIGNOR-276965 0.388 POLR2M protein Q6EEV4 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266175 0.464 GSK3B protein P49841 UNIPROT USF1 protein P22415 UNIPROT up-regulates activity phosphorylation Thr153 EALLGQAtPPGTGQF 9606 21873430 t miannu  Both MITF and USF1 were activated by glycogen synthase kinase (GSK) 3, with GSK3 phosphorylation sites on USF1 identified as the previously described activating site threonine 153 as well as serine 186. SIGNOR-276355 0.291 RBBP7 protein Q16576 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263848 0.832 MAPK3 protein P27361 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 19237534 t lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309. SIGNOR-184180 0.2 ITGB2 protein P05107 UNIPROT Av/b2 integrin complex SIGNOR-C176 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253204 0.651 SCF-betaTRCP complex SIGNOR-C5 SIGNOR YBX1 protein P67809 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 16797541 t miannu Here we identify FBX33 as a component of an SCF E3-ubiquitin ligase that targets the multifunctional regulator Y-box binding protein 1 (YB-1)/dbpB/p50 for polyubiquitination and destruction by the proteasome. By targeting YB-1 for proteasomal degradation, FBX33 negatively interferes with YB-1 mediated functions.  FBX33 recruits Skp-1/Cul1 to YB-1 SIGNOR-271606 0.328 RAF1 protein P04049 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser218 VSGQLIDsMANSFVG 9606 10359597 t lperfetto Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 active raf phosphorylates mek phospholpeptide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-235987 0.738 EEF1A1 protein P68104 UNIPROT Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269505 0.8 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction SIGNOR-259921 0.63 YWHAH protein Q04917 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates binding 9606 12042314 t miannu 14-3-3_, 14-3-3_, and 14-3-3_ (but not 14-3-3_ and 14-3-3_) could form a complex with p27kip1 / we discovered that akt-mediated p27kip1phosphorylation directly induces p27kip1binding to 14-3-3 and cytoplasmic localization through phosphorylating the newly identified thr198residue. SIGNOR-109771 0.48 AKT1 protein P31749 UNIPROT PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 15896703 t gcesareni We also found that AMP activated protein kinase and protein kinases A, B, and C catalyzed the phosphorylation of Ser-460 of HBP1, and that in addition both isoforms are phosphorylated at a second, as yet undetermined site by protein kinase C. However, none of the phosphorylations had any effect on the intrinsic kinetic characteristics of either enzymatic activity, and neither did point mutation (mimicking phosphorylation), deletion, and alternative-splice modification of the HBP1 carboxy-terminal region. Instead, these phosphorylations and mutations decreased the sensitivity of the 6PF2K to a potent allosteric inhibitor, phosphoenolpyruvate, which appears to be the major regulatory mechanism. SIGNOR-252477 0.438 JUN protein P05412 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16149046 f miannu Constitutively active mutants of activating transcription factor 2 (ATF2) and c-Jun additionally stimulated GTP cyclohydrolase I promoter activity, but to a lesser extent than the constitutively active CREB mutant. Enzymatic reactions that require tetrahydrobiopterin as cofactor are therefore indirectly controlled by signaling cascades involving the signal-responsive transcription factors CREB, c-Jun, and ATF2. SIGNOR-252225 0.2 vitamin K epoxide smallmolecule CHEBI:28371 ChEBI VKORC1L1 protein Q8N0U8 UNIPROT up-regulates activity chemical activation 9606 31226734 t lperfetto The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form SIGNOR-265914 0.8 ACE2 protein Q9BYF1 UNIPROT APLN protein Q9ULZ1 UNIPROT up-regulates activity cleavage -1 11815627 t miannu ACE2 hydrolyzes the hormone apelin-13 with high catalytic efficiency and cleaves apelin-36, whose C-terminal 13 amino acids are identical to those of apelin-13. SIGNOR-256316 0.433 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-251524 0.2 TOPBP1 protein Q92547 UNIPROT BRCA1-B complex complex SIGNOR-C298 SIGNOR form complex binding 25400280 t lperfetto Another BRCA1 complex, the BRCA1–B complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‐phase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‐phase checkpoint activation SIGNOR-263218 0.661 DIP2A protein Q14689 UNIPROT SOD1 protein P00441 UNIPROT up-regulates activity binding 10090 BTO:0000142 33781892 t miannu DIP2a is associated with SOD in the mitochondria of mouse brain. DIP2a knockout inhibited SOD activity. In this paper, we analyzed the interacting proteins of DIP2A by mass spectrum analysis and found that DIP2A was correlated with superoxide dismutase (SOD), SOD1 and SOD2. Knockout of DIP2A decreased SOD activity and increased the level of ROS in the mouse brain. SIGNOR-266591 0.2 CTNNA1 protein P35221 UNIPROT YAP1 protein P46937 UNIPROT down-regulates binding 9606 23431053 t milica The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation. SIGNOR-201173 0.36 CAMK2A protein Q9UQM7 UNIPROT ITPKA protein P23677 UNIPROT up-regulates phosphorylation Thr311 EHAQRAVtKPRYMQW 9606 BTO:0000938 BTO:0000975;BTO:0000142 9155020 t lperfetto D-myo-inositol 1,4,5-trisphosphate 3-kinase a is activated by receptor activation through a calcium:calmodulin-dependent protein kinase ii phosphorylation mechanism. the phosphorylated residue was thr311. SIGNOR-48387 0.335 KIT protein P10721 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS -1 21135090 t KIT is responsible for the permanent phosphorylation of all three STAT proteins. STAT1, -3, and -5 were phosphorylated on their activation-specific Tyr701, Tyr704, and Tyr694, respectively, following KIT stimulation. SIGNOR-251365 0.714 IL22RA1 protein Q8N6P7 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15120645 t gcesareni Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain. SIGNOR-124489 0.503 UBE2I protein P63279 UNIPROT SOX6 protein P35712 UNIPROT down-regulates activity sumoylation Lys404 VSPTGIkNEKRGTS 9606 16442531 t We show that SOX6 is modified in vitro and in vivo by small ubiquitin‐related modifier (SUMO) on two distinct sites. Mutation of both sites abolished SOX6 sumoylation and increased SOX6 transcriptional activity. SUMO dependent repression of SOX6 transcription was promoted by UBC9 whereas siRNA to UBC9, cotransfection of inactive UBC9 or a SUMO protease increased SOX6 transcriptional activity. SIGNOR-256129 0.374 SMURF2 protein Q9HAU4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 11016919 t lperfetto The ability of smurf2 to promote smad2 destruction required the hect catalytic activity of smurf2 and depended on the proteasome-dependent pathway. SIGNOR-236133 0.77 GSK3B protein P49841 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by repression phosphorylation Ser76 SNLQRMGsSESTDSG 9606 BTO:0000567 20348946 t lperfetto Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a SIGNOR-164742 0.318 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1D protein P25100 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258457 0.8 ATM protein Q13315 UNIPROT XPA protein P23025 UNIPROT unknown phosphorylation Ser173 VKKNPHHsQWGDMKL -1 16540648 t llicata Kinase phosphorylation assays were done with synthesized short peptides (20-mer) with the sequences at Ser173 and Ser196 of XPA, respectively. Both peptides seemed to be good substrates for DNA-PK, ATR ( Fig. 2D), and ATM (data not shown). SIGNOR-250579 0.609 PSPH protein P78330 UNIPROT O-phosphonato-L-serine(2-) smallmolecule CHEBI:57524 ChEBI down-regulates quantity chemical modification 9606 BTO:0000142 12213811 t lperfetto Human phosphoserine phosphatase (HPSP) regulates the levels of glycine and d-serine, the putative co-agonists for the glycine site of the NMDA receptor in the brain. |Phosphoserine phosphatase (PSP)1 is an important enzyme in the phosphorylated pathway of serine biosynthesis, which contributes a major portion of the endogenous l-serine|he enzymatic reaction of PSP is Mg2+-dependent and results in the dephosphorylation of phospho-l-serine with the formation of a phosphoenzyme intermediate, which is subsequently autodephosphorylated. The resulting product, l-serine, is not only a precursor for the biosynthesis of glycine but also an uncompetitive inhibitor for the enzymatic reaction of PSP SIGNOR-268570 0.8 CILK1 protein Q9UPZ9 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 22356909 t lperfetto Our findings demonstrate an important role for ick in modulating the activity of mtorc1 through phosphorylation of raptor thr-908 and thus implicate a potential signaling mechanism by which ick regulates cell proliferation and division. SIGNOR-217562 0.2 NMUR2 protein Q9GZQ4 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257126 0.271 SMAD2 protein Q15796 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity binding 9606 11389444 t lperfetto We show that in the presence of TGF-beta signalling, Smad2 interacts through its proline-rich PPXY motif with the tryptophan-rich WW domains of Smurf2, a recently identified E3 ubiquitin ligases.Thus, stimulation by TGF-beta can induce the assembly of a Smad2-Smurf2 ubiquitin ligase complex that functions to target substrates for degradation. SIGNOR-108490 0.77 PPARGC1A protein Q9UBK2 UNIPROT APOA5 protein Q6Q788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255058 0.285 BECN1 protein Q14457 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001623 20921139 f miannu Autophagy initiation signaling requires both the ULK1 kinase and the BECLIN 1–VPS34 core complex to generate autophagosomes, double-membraned vesicles that transfer cellular contents to lysosomes. SIGNOR-219545 0.7 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr248 GSETPGAtPGSKIWD 9606 12105215 t lperfetto To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptides. Three phosphorylation sites were identified as thr244, thr248, and thr313 SIGNOR-216666 0.353 ACTB protein P60709 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269826 0.489 NAE1 protein Q13564 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000938 25568892 f lperfetto Overexpression of AppBp1 in primary neurons induces apoptosis through the neddylation pathway SIGNOR-251579 0.7 CSNK1A1 protein P48729 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser97 TIAESEDsQESVDSV 9606 9931297 t lperfetto Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement. SIGNOR-64254 0.317 LAT protein O43561 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 23150273 t Phosphorylated tyrosines 171, 191, and 226 [in LAT] bind to the SH2 domains of the Grb2 family of adaptor proteins and must be present for optimal signalling SIGNOR-251520 0.797 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation 9606 24714526 t miannu HRI is an intracellular heme sensor that coordinates heme and globin synthesis in erythropoiesis by inhibiting protein synthesis of globins and heme biosynthetic enzymes during heme deficiency. HRI is a heme-regulated kinase that phosphorylates the α-subunit of eIF2 in heme deficiency, impairing another round of translational initiation and thereby inhibiting translation. SIGNOR-251817 0.886 UMPS protein P11172 UNIPROT 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI down-regulates quantity chemical modification 9606 2912371 t miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). SIGNOR-267437 0.8 BIRC2 protein Q13490 UNIPROT BIRC2 protein Q13490 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 14960576 t lperfetto Ciap1 and ciap2 undergo autoubiquitination and degradation upon binding to the iap antagonist second mitochondrial activator of caspases (smac)/direct iap-binding protein with low pi (diablo), which is released from the mitochondria. SIGNOR-121877 0.2 SOCS1 protein O15524 UNIPROT STAT1 protein P42224 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16628196 f miannu SOCS1, which is another inducible gene, not only blocks STAT1 activation but also inhibits STAT1-dependent TLR3, IRF-7, and MIP-1α. SIGNOR-255229 0.622 RFPL4A protein A6NLU0 UNIPROT CCNB1 protein P14635 UNIPROT down-regulates quantity by destabilization ubiquitination 10029 BTO:0000246 12525704 t miannu We conclude that, like many RING-finger containing proteins, RFPL4 is an E3 ubiquitin ligase. The specificity of its expression and these interactions suggest that RFPL4 targets cyclin B1 for proteasomal degradation, a key aspect of oocyte cell cycle control during meiosis and the crucial oocyte-to-embryo transition to mitosis. SIGNOR-271476 0.325 RICTOR protein Q6R327 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-205624 0.828 DYRK2 protein Q92630 UNIPROT PSMC4 protein P43686 UNIPROT down-regulates quantity by destabilization phosphorylation Thr25 LSVSRPQtGLSFLGP 26655835 t lperfetto Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation. SIGNOR-275845 0.288 MEF2C protein Q06413 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates -1 23001426 f Luana  In brain, MEF2C is essential for early neurogenesis, neuronal migration, and differentiation.  SIGNOR-265800 0.7 Immune complexes stimulus SIGNOR-ST15 SIGNOR FCGR3A protein P08637 UNIPROT up-regulates activity 9606 BTO:0000801 17558411 f lperfetto After binding their antibody ligands, FcgRI and FcgRIII deliver activating signals through an association with the FcRg-chain (FcRg), a transmembrane adaptor protein with an immuno-receptor tyrosine-based activation motif in its cytoplasmic domain. SIGNOR-249523 0.7 SKI protein P12755 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR down-regulates activity binding 9606 BTO:0000848 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-253300 0.773 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser213 SGAPVKPsPQAAAVE 9606 11110801 t llicata In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676). SIGNOR-84984 0.453 METTL3 protein Q86U44 UNIPROT WWTR1 protein Q9GZV5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007;BTO:0000567 27117702 t miannu Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells.  SIGNOR-265955 0.2 FBXO21 protein O94952 UNIPROT EID1 protein Q9Y6B2 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 26085330 t miannu SCFFBXO21 ubiquitylates and thereby targets EID1 for degradation.We have now applied this approach to an uncharacterized human F-box protein, FBXO21, which serves as the substrate-recognition subunit of a SKP1-CUL1-F-box protein (SCF)-type E3, thereby identifying EID1 (EP300-interacting inhibitor of differentiation 1) as a candidate substrate.Over-expression of FBXO21 resulted in the down-regulation of EID1, whereas disruption of the FBXO21 gene with the CRISPR/Cas9 system stabilized EID1 and led to its accumulation in both the cytoplasm and nucleus. An in vitro ubiquitylation assay showed that EID1 is a direct substrate of SCF(FBXO) SIGNOR-272429 0.422 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr18 AIEWPGAyPKLMEID 9606 15952790 t llicata We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts. SIGNOR-138142 0.59 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser269 SEEGQELsDEDDEVY 9606 12167711 t gcesareni Hypophosphorylation of mdm2 augments p53 stability. SIGNOR-91191 0.352 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 17015473 t The effect has been demonstrated using Q01196-8 lperfetto Previous studies have shown that phosphorylation of aml1, particularly at serines 276 and 303, affects its transcriptional activation. Here, we report that phosphorylation of aml1 serines 276 and 303 can be blocked in vivo by inhibitors of the cyclin-dependent kinases (cdks) cdk1 and cdk2. Furthermore, these residues can be phosphorylated in vitro by purified cdk1/cyclin b and cdk2/cyclin a. SIGNOR-217340 0.2 CSNK2B protein P67870 UNIPROT SORT1 protein Q99523 UNIPROT up-regulates quantity by stabilization phosphorylation Ser825 KSGYHDDsDEDLLE 10090 BTO:0003449 25805502 t miannu  Phosphorylation of Ser-825 is required for insulin to induce Sort1 in AML12 cells. LC-MS/MS analysis further revealed that serine phosphorylation of Sort1 protein was required for insulin induction of Sort1 in a casein kinase 2-dependent manner and that inhibition of PI3K signaling or prevention of Sort1 phosphorylation accelerated proteasome-dependent Sort1 degradation.  SIGNOR-273636 0.2 WNT7A protein O00755 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131900 0.585 PPP1CA protein P62136 UNIPROT PREX2 protein Q70Z35 UNIPROT up-regulates activity dephosphorylation Ser1107 DTISNRDsYSDCNSN 9606 BTO:0000007 26438819 t miannu PREX2 is dephosphorylated by PP1α and PP2A.PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. SIGNOR-277183 0.2 clobetasol chemical CHEBI:205919 ChEBI SMO protein Q99835 UNIPROT up-regulates activity chemical activation 10090 20439738 t gcesareni We identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling. SIGNOR-248212 0.8 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH23 protein Q9H251 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265839 0.8 Hypoxia stimulus SIGNOR-ST25 SIGNOR NPTX1 protein Q15818 UNIPROT up-regulates 10090 BTO:0000938 15115814 f lperfetto We found that NP1 colocalizes and physically associates with the fast excitatory GluR1 AMPA receptors and that hypoxia induces a time-dependent increase in the NP1-GluR1 interactions. Thus hypoxia recruits NP1 protein to GluR1 subunits concurrent with the hypoxic excitotoxic cascade.|Rather we propose that through interactions with GluR1 clusters, NP1 modulates the function of AMPA receptors in a manner whereby increased NP1-GluR1 interactions sensitize neurons to hypoxia-induced excitotoxic death. SIGNOR-261431 0.7 GAPDHS protein O14556 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI down-regulates quantity chemical modification 9606 11724794 t miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion SIGNOR-266498 0.8 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249346 0.728 Gbeta proteinfamily SIGNOR-PF4 SIGNOR POLR2A protein P24928 UNIPROT down-regulates phosphorylation 9606 14662762 t inferred from 70% family members lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-270039 0.2 PRKACA protein P17612 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation 10116 BTO:0001593 18981475 t gcesareni These results suggest that camppka activation is involved in activation of lrp6(...) our results demonstrate that lrp6 can be directly phosphorylated by pka catalytic subunit. SIGNOR-181979 0.2 STK11 protein Q15831 UNIPROT SIK3 protein Q9Y2K2 UNIPROT up-regulates phosphorylation Thr221 TPGQLLKtWCGSPPY 9606 14976552 t lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold SIGNOR-122835 0.467 ITGB1 protein P05556 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253176 0.802 SRP54 protein P61011 UNIPROT SRPRB protein Q9Y5M8 UNIPROT up-regulates activity binding -1 30649417 t miannu The multi-domain SRP GTPase SRP54 recognizes the signal with its M domain and establishes the targeting complex consisting of its NG domain bound to the homologous NG domain of the SRP receptor SRα at a proximal ribosome binding site. SIGNOR-261165 0.812 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Tyr612 TLHTDDGyMPMSPGV 9606 14579029 t gcesareni Map kinases and mtor mediate insulin-induced phosphorylation of insulin receptor substrate-1 on serine residues 307, 612 and 632 SIGNOR-118873 0.698 CSK protein P41240 UNIPROT SRC protein P12931 UNIPROT down-regulates phosphorylation Tyr530 FTSTEPQyQPGENL 9606 18614016 t gcesareni The catalytic activity of the src family of tyrosine kinases is suppressed by phosphorylation on a tyrosine residue located near the c terminus (tyr 527 in c-src), which is catalyzed by c-terminal src kinase (csk). SIGNOR-179417 0.551 DIABLO protein Q9NR28 UNIPROT BIRC2 protein Q13490 UNIPROT down-regulates quantity binding 9606 BTO:0000567 14960576 t amattioni Smac/DIABLO selectively reduces the levels of c-IAP1 and c-IAP2 but not that of XIAP and livin in HeLa cells. SIGNOR-121883 0.891 CACNA2D3 protein Q8IZS8 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 31746409 f miannu Overexpression of CACNA2D3 reduced proliferation and migration, but increased apoptosis and Ca2+ influx in Ishikawa and RL95-2 cells. SIGNOR-266854 0.7 CD79A protein P11912 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268192 0.641 TFEB protein P19484 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Notably, TFEB regulates genes involved in several steps of lipid catabolism, which occur in different cellular compartments, such as the transport of fatty acid chains across the plasma membrane (for example, Cd36 and Fabps), and the β-oxidation of FFA in mitochondria (for example, Cpt1, Crat, Acadl, Acads and Hdad) and in peroxisomes (Cyp4a genes). SIGNOR-276707 0.286 STAT5A protein P42229 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 25506346 t lperfetto The GM-CSF receptor forms a dodecamer structure and recruits JAK2, leading to the activation of STAT5, extracellular signal-regulated kinase (ERK), V-Akt murine thymoma viral oncogene homolog 1 (AKT), and the nuclear translocation of NF-kappaB and IRF5 SIGNOR-249508 0.291 WNK1 protein Q9H4A3 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Ser382 KRASFAKsVIGTPEF 9606 BTO:0000007 BTO:0000671 18270262 t gcesareni We demonstrate that wnk1 is rapidly activated and phosphorylated at multiple residues after exposure of cells to hyperosmotic conditions and that activation is mediated by the phosphorylation of its t-loop ser382 residue, possibly triggered by a transautophosphorylation reaction. SIGNOR-160850 0.2 PRKCQ protein Q04759 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates activity phosphorylation Ser591 DKEKSKGsLKRK 9606 BTO:0000914 35258455 t miannu SHP-1 phosphorylation is mediated through PKC-θ. Here, we show that phosphorylation of SHP-1 in NK cells on the S591 residue by PKC-θ promotes the inhibited SHP-1 'folded' state. Silencing PKC-θ maintains SHP-1 in the active conformation, reduces NK cell activation and cytotoxicity, and promotes tumor progression in vivo. SIGNOR-277590 0.2 MAPK3 protein P27361 UNIPROT STMN1 protein P16949 UNIPROT down-regulates activity phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 9731215 t lperfetto Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs. SIGNOR-249483 0.563 PCDHA10 protein Q9Y5I2 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265664 0.2 ULK1 protein O75385 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation 9606 SIGNOR-C15 21460634 t lperfetto Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. SIGNOR-173047 0.553 SIK1 protein P57059 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates activity phosphorylation Ser348 PSLQSSLsNPNLQAS 9606 BTO:0000567 16306228 t lperfetto We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression SIGNOR-249168 0.63 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 11865049 t miannu We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. SIGNOR-267996 0.734 MRPL4 protein Q9BYD3 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262357 0.732 TOX2 protein Q96NM4 UNIPROT TBX21 protein Q9UL17 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002181 25352127 t Luana We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET). SIGNOR-266097 0.299 AKT1 protein P31749 UNIPROT MAP3K11 protein Q16584 UNIPROT down-regulates phosphorylation Ser674 PGRERGEsPTTPPTP 9606 BTO:0000938 12458207 t lperfetto Negative regulation of mixed lineage kinase 3 by protein kinase b/akt leads to cell survivalthe expression of activated akt1 inhibits mlk3-mediated cell death in a manner dependent on serine 674 phosphorylation. SIGNOR-252592 0.409 GNB1 protein P62873 UNIPROT SRC protein P12931 UNIPROT up-regulates activity 15345719 f In this study, we investigated the possible role of the Gβγ heterodimer in signaling Gi-induced Src activation SIGNOR-251107 0.459 4-(2,4,5-tripyridin-4-yl-3-thiophenyl)pyridine smallmolecule CHEBI:94284 ChEBI GLI2 protein P10070 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150;BTO:0000551 19860666 t gcesareni Both molecules gant58 and gant61 were capable of interfering with gli1 as well as gli2-mediated transcription in a dose-dependent manner SIGNOR-188866 0.8 AMP smallmolecule CHEBI:456215 ChEBI ETF complex SIGNOR-C463 SIGNOR form complex binding 9606 33450351 t miannu Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors. SIGNOR-269468 0.8 UBE2E2 protein Q96LR5 UNIPROT RNF19B protein Q6ZMZ0 UNIPROT up-regulates activity binding 9606 BTO:0000914 16709802 t miannu We demonstrated that both UbcH7 and UbcH8 bind to full-length NKLAM.  We demonstrated decreased protein expression and enhanced ubiquitination of URKL-1 in the presence of NKLAM. These data indicate that NKLAM is a RING finger protein that binds Ubcs and SIGNOR-271592 0.485 PRKCA protein P17252 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates activity phosphorylation Ser153 SMTDFYHsKRRLIFS 9606 16055744 t lperfetto Binding of calmodulin to the carboxy-terminal region of p21 induces nuclear accumulation via inhibition of protein kinase c-mediated phosphorylation of ser153| When phosphorylated at Ser153, p21 is located at the cytoplasm and disrupts stress fibers. SIGNOR-139302 0.384 KAT2A protein Q92830 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269602 0.2 SCF-FBW7 complex SIGNOR-C135 SIGNOR STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 31843895 t miannu  These results demonstrate that the interaction between STAT2 and FBXW7 is involved in the SCF complex containing cullin 1 and RBX1. SIGNOR-276766 0.29 PTPRA protein P18433 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 10090 BTO:0000944 10698938 t Protein tyrosine phosphatase alpha (PTPalpha) is believed to dephosphorylate physiologically the Src proto-oncogene at phosphotyrosine (pTyr)527, a critical negative-regulatory residue. It thereby activates Src, and PTPalpha overexpression neoplastically transforms NIH 3T3 cells. SIGNOR-248438 0.732 INCENP protein Q9NQS7 UNIPROT CPC complex SIGNOR-C554 SIGNOR form complex binding 9606 23175282 t miannu It is now known that the chromosomal passenger complex (CPC) is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin (also known as Dasra)5–7 (Figure 1A). SIGNOR-275425 0.873 CSNK2A1 protein P68400 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser228 PGVTPSKsTSASAIM 9606 BTO:0000938 26917740 t lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. SIGNOR-275738 0.272 S1PR1 protein P21453 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256856 0.483 CDK8 protein P49336 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser375 PVDEDRLsPLVAADS 9606 22945643 t lperfetto Cdk8 regulates e2f1 transcriptional activity through s375 phosphorylation. SIGNOR-198934 0.496 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR MASTL protein Q96GX5 UNIPROT down-regulates activity dephosphorylation Thr194 NMMDILTtPSMAKPR 9606 BTO:0002181 24391510 t miannu We demonstrate that PP2A/B55 is required for Gwl dephosphorylation at the essential Cdk site Thr194.Gwl phosphorylation by CycA/Cdk2 in vitro. Flag WT and Thr194A Gwl was transiently expressed and purified from asynchronous HEK 293T cells and incubated with recombinant CycA/Cdk2, following treatment with alkaline phosphatase (aPh) in the indicated samples. The proteins were analysed by immuno-blotting with anti-Gwl and Gwl pThr194 antibodies SIGNOR-276615 0.481 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR PPME1 protein Q9Y570 UNIPROT up-regulates activity dephosphorylation Ser15 MHLGRLPsRPPLPGS 9606 BTO:0000007 24841198 t lperfetto The results subsequently revealed that phosphorylated PME-1/Ser15 is dephosphorylated by SIK2·PP2A (Fig. 5G). |Our results also demonstrated that the phosphorylated levels of PME-1/Ser15 and CaMKI/Thr177 are inversely correlated with the phosphatase activity of SIK2·PP2A complex, further implying that the demethylase activity of phosphorylated PME-1/Ser15 may be higher than that of its unphosphorylated state. SIGNOR-265752 0.816 ATM protein Q13315 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Ser502 FSTDNSGsQPKQKSD 9606 22123827 t lperfetto Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication. SIGNOR-177793 0.384 TNKS protein O95271 UNIPROT PSMF1 protein Q92530 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 BTO:0000007 23622245 t lperfetto We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31. SIGNOR-263387 0.48 NDUFA6 protein P56556 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. SIGNOR-262157 0.829 GPER1 protein Q99527 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0000150 11897506 t gcesareni Gpcr-mediated transactivation of egfrs by estrogen provides a previously unappreciated mechanism of cross-talk between estrogen and serum growth factors, and explains prior data reporting the egf-like effects of estrogen SIGNOR-115988 0.398 PRKAA2 protein P54646 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates activity phosphorylation Ser792 LTQSAPAsPTNKGVH 10090 SIGNOR-C15 SIGNOR-C3 18439900 t lperfetto These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK SIGNOR-163463 0.681 S3I-201 chemical CHEBI:91224 ChEBI STAT3 protein P40763 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194847 0.8 SKP2 protein Q13309 UNIPROT MYBL2 protein P10244 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 10871850 t miannu P19Skp1 and Cul-1 bind to the F-box protein p45Skp2 to form a complex (SCF) that functions as E3 ubiquitin ligase.We show that B-Myb physically and functionally interacts with components of the Cdc34-SCFp45Skp2 ubiquitin pathway and propose that B-Myb degradation may be required for controlling the correct alternation of events during progression through the cell division cycle. SIGNOR-272572 0.386 BUB3 protein O43684 UNIPROT MCC complex SIGNOR-C382 SIGNOR form complex binding 9606 BTO:0000567 25092294 t miannu The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. SIGNOR-265975 0.966 MDM2 protein Q00987 UNIPROT KAT5 protein Q92993 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 11927554 t miannu Furthermore, we provide evidence that Mdm2, the ubiquitin ligase of the p53 tumour suppressor, interacts physically with Tip60 and induces its ubiquitylation and proteasome-dependent degradation. SIGNOR-272613 0.639 Caspase 3 complex complex SIGNOR-C221 SIGNOR RAD51 protein Q06609 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0002882 11684015 t lperfetto The RAD51 protein has been shown to be a substrate for caspase-3|he activated caspase-3 fragments (19 kDa and 17 kDa) and caspase-3 cleaved RAD51 fragment (∼23 kDa) was detected by Western analysis (Figure 3E). Activation of caspase-3 and the signature proteolytic degradation product of RAD51 only occurred in parental 32Dcl3 cells after treatment with cisplatin SIGNOR-271708 0.478 PTEN protein P60484 UNIPROT CREB1 protein P16220 UNIPROT down-regulates activity dephosphorylation Ser119 EILSRRPsYRKILND 10090 BTO:0002572 21385900 t Our study demonstrates that PTEN can dephosphorylate CREB at Ser133 and that PTEN protein phosphatase activity is required for CREB dephosphoryation.|Moreover, we use both in vitro and in vivo experiments to show PTEN can dephosphorylate CREB in a phosphatase-dependent manner, suggesting that CREB is a substrate of PTEN nuclear phosphatase. Loss of Pten results in an elevated RNA level of multiple CREB transcriptional targets and increased cell proliferation, which can be reversed by a nonphosphorylatable CREB mutant or knockdown of CREB. These data reveal a mechanism for PTEN modulation of CREB-mediated gene transcription and cell growth. SIGNOR-248543 0.447 Mubritinib chemical CID:6444692 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194581 0.8 TRAF2 protein Q12933 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys158 ALIHRDLkPPNLLLV 9606 BTO:0000007 20038579 t lperfetto Tumor necrosis factor receptor-associated factors 2 and 6 (traf2 and -6) act as the ubiquitin e3 ligases to mediate lys63-linked tak1 polyubiquitination at the lys158 residue in vivo and in vitro. Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue is required for TAK1-mediated IKK complex recruitment. SIGNOR-162638 0.58 SMARCD3 protein Q6STE5 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding -1 22068056 t lperfetto We show that the muscle determination factor MyoD and the SWI/SNF subunit BAF60c interact on the regulatory elements of MyoD-target genes in myoblasts, prior to activation of transcription. BAF60c facilitates MyoD binding to target genes and marks the chromatin for signal-dependent recruitment of the SWI/SNF core to muscle genes. SIGNOR-238289 0.554 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA10 protein Q9Y5H3 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265682 0.2 SCNN1B protein P51168 UNIPROT CACNA1H protein O95180 UNIPROT up-regulates activity binding 9606 BTO:0000142 30736831 t miannu This study describes the functional interaction between Cav3.2 calcium channels and the Epithelial Sodium Channel (ENaC). β- and γ-ENaC subunits could be co-immunoprecipitated with Cav3.2 calcium channels from brain lysates, dorsal horn and lumbar dorsal root ganglia. Αβγ-ENaC channels enhanced Cav3.2 calcium channel trafficking to the plasma membrane in tsA-201 cells. This effect was reciprocal such that Cav3.2 channel expression also enhanced β-ENaC trafficking to the cell surface. these findings reveal ENaC as an interactor and potential regulator of Cav3.2 calcium channels expressed in neuronal tissues. SIGNOR-269273 0.2 CREB1 protein P16220 UNIPROT CEBPB protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 14593102 f lperfetto Expression of constitutively active CREB strongly activated C/EBPbeta promoter-reporter genes, induced expression of endogenous C/EBPbeta, and caused adipogenesis in the absence of the hormonal inducers normally required SIGNOR-250573 0.577 BAG5 protein Q9UL15 UNIPROT HSPA1A protein P0DMV8 UNIPROT down-regulates activity binding 9606 BTO:0000142 15603737 t Monia Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity; Thus, BAG5 interacts with Hsp70 in vitro and in vivo, and substitution of select residues within the BAG domains is sufficient to abolish this interaction. SIGNOR-261196 0.743 tiotropium chemical CHEBI:90960 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition -1 8441333 t miannu A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed "kinetic receptor subtype selectivity" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors. SIGNOR-258484 0.8 (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol chemical CHEBI:94701 ChEBI RRM1 protein P23921 UNIPROT down-regulates activity chemical inhibition -1 7048062 t miannu In vitro biological activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. 2-F-araATP was a potent inhibitor of ribonucleotide reductase SIGNOR-258404 0.8 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT up-regulates activity phosphorylation Ser1001 SKESEHDsDESSDDD 9606 BTO:0000661 10066810 t llicata Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment.  SIGNOR-251032 0.445 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser626 DQTNVLSsTFLSPQC 9606 BTO:0000007 16141410 t In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity SIGNOR-251247 0.406 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1714 SPTSPSYsPTSPSYS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248822 0.849 lysophosphatidic acid smallmolecule CHEBI:132742 ChEBI LPAR5 protein Q9H1C0 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257532 0.8 AURKA protein O14965 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser106 SQKTYQGsYGFRLGF 9606 23201157 t gcesareni Ser-106 phosphorylation of p53 decreases its interaction with mdm2 and prolongs the half-life of p53 SIGNOR-199939 0.77 NAA25 protein Q14CX7 UNIPROT NatB complex SIGNOR-C416 SIGNOR form complex binding 9606 18570629 t miannu In the present study we present the components of hNatB (human NatB complex). It consists of the Nat3p homologue hNAT3 (human N-acetyltransferase 3) and the Mdm20p homologue hMDM20 (human mitochondrial distribution and morphology 20). They form a stable complex and in vitro display sequence-specific N(alpha)-acetyltransferase activity on a peptide with the N-terminus Met-Asp-. SIGNOR-267231 0.9 MRE11 protein P49959 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR form complex binding 17713585 t lperfetto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50. SIGNOR-251504 0.2 SOST protein Q9BQB4 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 19874086 f Interacts with LRP4 (via the extracellular domain);the interaction facilitates the Wnt signaling. Interacts with LRP5 (via the first two YWTD-EGF repeat domains);the interaction inhibits Wnt-mediated signaling. gcesareni It has been shown that both sclerostin and dkk1 act physiologically as downstream mole-cules of bmp signaling to inhibit canonical wnt sig-naling and therefore negatively regulate bone mass SIGNOR-188964 0.567 CAMK1 protein Q14012 UNIPROT NUMB protein P49757 UNIPROT down-regulates phosphorylation Ser276 EQLARQGsFRGFPAL 9606 17022975 t esanto Based on experiments using numb mutants, both the initial phosphorylation of ser(264) and the subsequent phosphorylation of ser(283) are sufficient to abolish the binding of numb to ap-2. SIGNOR-149993 0.34 PDE6G protein P18545 UNIPROT PDE6A protein P16499 UNIPROT down-regulates activity binding 9606 20940301 t Both PDE6C-A and PDE6C-B were potently and similarly inhibited by both Pγ subunits, with Ki values ranging from 33 to 46 pm (Fig. 5). The inhibition analysis revealed no significant differences between PDE6C-A and PDE6C-B SIGNOR-260010 0.861 regorafenib chemical CHEBI:68647 ChEBI FRK protein P42685 UNIPROT down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259207 0.8 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001412 8394219 f We expressed the PML-RARa protein in U937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of different stimuli (vitamin Ds and transforming growth factor pl), acquired enhanced sensitivity to retinoic acid, and exhibited a higher growth rate consequent to diminished apoptotic cell death. SIGNOR-255722 0.7 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 13760840 t gcesareni SIGNOR-251700 0.8 MPG protein P29372 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 25207814 t miannu Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. SIGNOR-271930 0.2 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Trp) smallmolecule CHEBI:29181 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269498 0.8 MAPK14 protein Q16539 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15824134 f Andrea Inhibition of p38 / MAPKs (a) promotes exit from the cell cycle, (b) prevents differentiation, and (c) insulates the cell from most external stimuli allowing the satellite cell to maintain a quiescent state. Activation of satellite cells and p38 / MAPKs occurs concomitantly, providing further support that these MAPKs function as a molecular switch for satellite cell activation SIGNOR-255745 0.7 propionic acid chemical CHEBI:30768 ChEBI FFAR3 protein O14843 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257490 0.8 GPR17 protein Q13304 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256692 0.385 Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR down-regulates 9606 15623580 f lperfetto All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage. SIGNOR-273458 0.7 PIK3R1 protein P27986 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates activity binding 9534 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242643 0.822 MAPK1 protein P28482 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates activity phosphorylation Ser239 FRRGLDDsTGGTPLT 9606 BTO:0000007 12556484 t lperfetto Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro. In the case of Nudel, the phosphorylation sites were also located in the S/TP motifs. Detailed mutagenesis study indicated that T219, S242, and T245 were phosphorylated by Cdc2, while T219 and T245 were phosphorylated by Erk2.|Phosphorylation of Nudel in M phase appears to positively modulate dynein motor activity. Both phosphorylated and unphosphorylated forms of Nudel were transported by dynein (Fig. 7 and 9 and data not shown), indicating that neither of them inactivated the dynein motor. On the other hand, both phospho-Nudel and Nudelpmt5 bound Lis1 more strongly than Nudel or Nudelmt5 did SIGNOR-249421 0.382 AKT1 protein P31749 UNIPROT TARBP2 protein Q15633 UNIPROT up-regulates activity phosphorylation Ser283 ILSLRSCsLGSLGAL -1 27407113 t miannu We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells. In vitro kinase assays demonstrated that TRBP-D3 can be phosphorylated by S6K1, S6K2, but also AKT1 (Figure ​(Figure1C),1C), SIGNOR-274064 0.2 WNT5A protein P41221 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates 9606 SIGNOR-C110 21078818 f gcesareni We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3). SIGNOR-169663 0.487 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR TP73 protein O15350 UNIPROT down-regulates phosphorylation Thr86 AASASPYtPEHAASV 9606 12676926 t lperfetto Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86. SIGNOR-216702 0.515 Upadacitinib chemical CID:58557659 PUBCHEM JAK1 protein P23458 UNIPROT down-regulates activity binding 9606 33240390 t Upadacitinib (ABT-494) is another selective inhibitor of JAK1 undergoing clinical trials to determine its benefit for several inflammatory diseases SIGNOR-272504 0.8 HDAC1 protein Q13547 UNIPROT GLI1 protein P08151 UNIPROT up-regulates activity deacetylation 20081843 t Here, we identify a mechanism whereby Hh signalling is regulated, in which acetylation of Gli1 at Lys 518 represents a transcriptional inhibitory switch, while its HDAC1-mediated deacetylation is responsible for transcriptional activation. SIGNOR-253544 0.577 HNRNPU protein Q00839 UNIPROT HEXIM1 protein O94992 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 f lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. SIGNOR-262283 0.249 SLC27A5 protein Q9Y2P5 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264466 0.7 MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 21902831 t lperfetto Tak1 can phosphorylate and activate map kinase kinase 3/6 (mkk3/6), and numerous studies have demonstrated a requirement for mkk3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236145 0.755 oxymetazoline chemical CHEBI:7862 ChEBI ADRA1D protein P25100 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258460 0.8 dovitinib; bis(lactic acid) chemical CID:56973714 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191418 0.8 INS protein P01308 UNIPROT GATA2 protein P23769 UNIPROT down-regulates 9606 BTO:0000876 15837948 f fspada We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity SIGNOR-135617 0.32 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251596 0.695 MAPK3 protein P27361 UNIPROT IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation Ser317 TPQGSRTsPGAPPPA -1 15133517 t miannu To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291–356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target. SIGNOR-263060 0.2 STAT5A protein P42229 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 22025054 f lperfetto The activation of receptors for both GM-CSF and IFN-g stimulates the Jak kinaseSTAT transcription factor pathway, and an ISRE in the Irf5 promoter can bind STAT1 and STAT2, which suggests a possible mechanism for IRF5 expression induced by GM-CSF and IFN-g. Consequently, high expression of IRF5 results in polarization of the macrophage phenotype toward M1. SIGNOR-249510 0.7 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-189129 0.391 ERN1 protein O75460 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 18519638 t P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction) Activated IRE1 has been demonstrated to recruit TRAF2 and ASK1 on the ER membrane and thus to activate ASK1|ASK1 was found to associate with IRE1 only in the presence of TRAF2 and SOD1mut (Fig. 4B), suggesting that SOD1mut induces formation of an IRE1–TRAF2–ASK1 complex on the ER membrane and thus activates ASK1 by triggering ER stress-induced IRE1 activation. SIGNOR-262790 0.667 PPP1CC protein P36873 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-252605 0.391 ROCK1 protein Q13464 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Thr480 TKEDGHRtSTSAVPN 9606 BTO:0000671 10209029 t lperfetto Rho-associated kinase (rho- kinase), which is activated by the small guanosine triphosphatase rho, phosphorylates alpha-adducin and thereby enhances the f-actin-binding activity of alpha-adducin in vitro. Here we identified the sites of phosphorylation of alpha-adducin by rho-kinase as thr445 and thr480 SIGNOR-66996 0.384 STK11 protein Q15831 UNIPROT MARK3 protein P27448 UNIPROT up-regulates activity phosphorylation Thr211 TVGGKLDtFCGSPPY 9606 BTO:0000568 12879020 t lperfetto Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211. SIGNOR-104063 0.32 FFAR4 protein Q5NUL3 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257313 0.252 MAPK12 protein P53778 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 t lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK SIGNOR-264448 0.2 CAMK2B protein Q13554 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser571 PWPLRRTsAQGQPSP 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275774 0.394 PLK3 protein Q9H4B4 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 19889641 t lperfetto Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. SIGNOR-189053 0.324 RXRB protein P28702 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 10976919 t inferred from 70% of family members gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr SIGNOR-269880 0.642 atropine chemical CHEBI:16684 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258392 0.8 Wnt proteinfamily SIGNOR-PF40 SIGNOR Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 23290138 t miannu Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-256173 0.834 CSNK2A2 protein P19784 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1112 VPIAVGEsDFENLNT 9606 BTO:0000938 19064667 t lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. SIGNOR-275754 0.2 LMTK2 protein Q8IWU2 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12393858 t gcesareni Kpi-2 kinase domain phosphorylated protein phosphatase-1 (pp1c) at thr(320), which attenuated pp1c activity. SIGNOR-94631 0.588 NFATC1 protein O95644 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21871017 t miannu NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration SIGNOR-264026 0.322 IFNAR complex SIGNOR-C243 SIGNOR CCL2 protein P13500 UNIPROT up-regulates quantity by expression 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260851 0.321 WASHC3 protein Q9Y3C0 UNIPROT WASH complex complex SIGNOR-C258 SIGNOR form complex binding 23721880 t lperfetto The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53. SIGNOR-261017 0.2 ADORA1 protein P30542 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256976 0.398 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000007 19881549 t lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis SIGNOR-236302 0.692 ETS1 protein P14921 UNIPROT ATP2A3 protein Q93084 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000255 12119294 t Luana Ets-1 was able to transactivate the SERCA3 promoter in MoBr 204 as cotransfection of an Ets-1 expression vector increased the activity of the −97/+301-Luc construct by 6-fold. SIGNOR-261601 0.332 Core mediator complex complex SIGNOR-C405 SIGNOR RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity binding 9606 25693131 t miannu The RNA polymerase II (Pol II) enzyme transcribes all protein-coding and most non-coding RNA genes and is globally regulated by Mediator — a large, conformationally flexible protein complex with a variable subunit composition (for example, a four-subunit cyclin-dependent kinase 8 module can reversibly associate with it). Because of its direct and extensive interactions with Pol II, Mediator regulates multiple stages of Pol II transcription (for example, initiation and re-initiation). Mediator interactions with the super elongation complex (SEC) also seem to be important for its regulation of Pol II elongation. SIGNOR-266682 0.341 CD19 protein P15391 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0000776 25673924 t lperfetto CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades. SIGNOR-252670 0.502 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Thr334 DSTQTSDtATNSTLP -1 7836371 t Phosphorylation of the FPR carboxyl terminus by GRK2 is the result of a high affinity interaction and proceeds in a hierarchical manner. sequential mechanism of phosphorylation beginning with residues 328 and/or 329, followed by residues 331 and/or 332, and finally residues 334 through 339. Attenuation of receptor-mediated signal amplification in response to external stimuli, an essential step in the balance of cellular activation, may be mediated by receptor phosphorylation. SIGNOR-251451 0.2 WDR5 protein P61964 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. SIGNOR-267157 0.648 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr487 SQKVVVTtPLHRDKT 9606 9840932 t lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk2 SIGNOR-217260 0.707 NFE2L3 protein Q9Y4A8 UNIPROT NQO1 protein P15559 UNIPROT down-regulates quantity by repression transcriptional regulation 15385560 f lperfetto Nrf3 negatively regulates antioxidant-response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. SIGNOR-268975 0.345 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 21423276 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-172911 0.8 PAX2 protein Q02962 UNIPROT WT1 protein P19544 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16631587 t Cotransfection of Pax2 with the Wt1 reporter construct led to moderate activation of the Wt1 promoter. SIGNOR-252290 0.617 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser173 MLETLSQsPPKGVTI 9606 BTO:0000664 17475908 t miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). SIGNOR-262914 0.329 PAX2/TLE4 complex SIGNOR-C152 SIGNOR WT1 protein P19544 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0002295 16631587 t Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1. SIGNOR-252291 0.459 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Thr8 MSSILPFtPPIVKRL 9606 15241418 t gcesareni We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function SIGNOR-126740 0.733 REST protein Q13127 UNIPROT HCN1 protein O60741 UNIPROT down-regulates quantity by repression transcriptional regulation BTO:0000938 21905079 t lperfetto Levels of NRSF and its physical binding to the Hcn1 gene were augmented after SE, resulting in repression of HCN1 expression and HCN1-mediated currents (I(h) ), and reduced I(h) -dependent resonance in hippocampal CA1 pyramidal cell dendrites. SIGNOR-268970 0.2 CSNK1A1 protein P48729 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity. SIGNOR-183667 0.2 vorinostat chemical CHEBI:45716 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257949 0.8 DRD3 protein P35462 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256845 0.431 WNT8B protein Q93098 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-132024 0.609 DOT1L protein Q8TEK3 UNIPROT H3-4 protein Q16695 UNIPROT unknown methylation Lys80 REIAQDFkTDLRFQS 9606 12123582 t miannu HDOT1L Is a Nucleosomal H3-K79-Specific HMTase. We identified a human DOT1-like (DOT1L) protein and demonstrated that this protein possesses intrinsic H3-K79-specific histone methyltransferase (HMTase) activity in vitro and in vivo. Furthermore, we found that K79 methylation level is regulated throughout the cell cycle. By using two different methods, we demonstrate that the K79 methylation level decreases during S phase, reaches its lowest level in G2, increases during M phase, and maintains at a high level during G1 phase. SIGNOR-267142 0.2 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser14 LYSFFSPsPARKRHA 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276085 0.282 GRIA3 protein P42263 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 30825796 f miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses SIGNOR-264613 0.7 ATF3 protein P18847 UNIPROT GDF15 protein Q99988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15670751 t lperfetto In addition, DIM increased the expression of NAG-1 as well as activating transcription factor 3 (ATF3), and the induction of ATF3 was earlier than that of NAG-1. The DIM treatment increased luciferase activity of NAG-1 in HCT-116 cells transfected with NAG-1 promoter construct. The results suggest that I3C represses cell proliferation through up-regulation of NAG-1 and that ATF3 may play a pivotal role in DIM-induced NAG-1 expression in human colorectal cancer cells. SIGNOR-253725 0.437 NUP98 Fusion fusion protein SIGNOR-FP16 SIGNOR CDK6 protein Q00534 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32344427 f miannu NUP98-fusion proteins directly regulate leukemia-associated gene expression programs in AML. CDK6 expression is under direct transcriptional control of NUP98-fusions and NUP98-fusion AML is particularly sensitive to CDK6 inhibition. SIGNOR-261505 0.2 Naloxone benzoylhydrazone chemical CID:9601084 PUBCHEM OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258423 0.8 NMBR protein P28336 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257248 0.271 MAP3K5 protein Q99683 UNIPROT ZNF622 protein Q969S3 UNIPROT up-regulates phosphorylation Ser314 WCNEKGKsFYSTEAV 9606 21771788 t gcesareni Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis. SIGNOR-175113 0.501 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser64 EPGTPPSsPLSAEQL 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276090 0.292 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr12 DLSGRELtIDSIMNK -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276202 0.388 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252524 0.907 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr12 DLSGRELtIDSIMNK -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276203 0.2 ATM protein Q13315 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Ser539 GLITINSsQEHLTVQ 9606 22123827 t lperfetto Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication. SIGNOR-177797 0.384 GPR183 protein P32249 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256994 0.2 ICAM1 protein P05362 UNIPROT ITGAX protein P20702 UNIPROT up-regulates binding 9606 7679388 t gcesareni Using assays to quantify cd11c-mediated cell adhesion, we demonstrate that cd11c recognizes icam-2 and vcam-1. The cd11c-binding site on vcam-1 appears to be different from that used by the integrin alpha4. SIGNOR-31388 0.666 ITGA6 protein P23229 UNIPROT A6/b4 integrin complex SIGNOR-C174 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253199 0.761 CAPN2 protein P17655 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR up-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain SIGNOR-251608 0.551 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM JAK3 protein P52333 UNIPROT down-regulates activity chemical inhibition -1 24556163 t miannu This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine SIGNOR-262234 0.8 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT up-regulates activity phosphorylation Ser99 KNKGKGFsVVADTPE -1 12432067 t miannu Lasp-1 binds to non-muscle filamentous (F) actin in vitro in a phosphorylation-dependent manner. Phosphorylation of recombinant lasp-1 with recombinant PKA increased the Kd and decreased the Bmax for lasp-1 binding to F-actin. PKA-dependent phosphorylation sites in rabbit lasp-1 to S99 and S146 SIGNOR-250075 0.311 STK3 protein Q13188 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser909 HQRCLAHsLVGTPNY 9606 BTO:0000007 15688006 t Two of these, S909 and T1079, were required for Lats1 activation. milica Since the N-terminal half of Lats1 (residues 1–588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1. SIGNOR-133544 0.604 MIB2 protein Q96AX9 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates activity polyubiquitination Lys634 KVYQMLQkWVMREGI 9606 BTO:0000815 29642005 t miannu Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2) regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation.  We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD association. MIB2 Ubiquitylates RIPK1 at Lysines K377 and K634 SIGNOR-272663 0.299 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 21798082 t lperfetto Positive feedback involves mtorc2, which phosphorylates akt at serine 473, a phosphorylation required for maximum activation of akt in addition to phosphorylation at threonine 308 by pdk1. SIGNOR-244396 0.737 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL 10116 BTO:0000575 15738637 t In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver. SIGNOR-248446 0.289 KARS1 protein Q15046 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 t miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). SIGNOR-270353 0.2 GSK3B protein P49841 UNIPROT NEFH protein P12036 UNIPROT down-regulates phosphorylation Ser503 GGEEETKsPPAEEAA 9606 12130654 t lperfetto Gsk3beta was shown to phosphorylate at ser-493 in vitro by phosphopeptide mapping and site-directed mutagenesis, and in vivo in hek293 cells. The role of ser-493 phosphorylation is also a question to be addressed in the future. Because the e-segment appears to be involved in filament formation (27, 42), phosphorylation in that region may also play a regulatory role in filament formation. Secondary structure prediction suggests that phosphorylation of ser-493 in combination with following the pro residue interrupts _-helix of the e-segment SIGNOR-90668 0.307 WWTR1 protein Q9GZV5 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001615 22470139 f miannu Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation. SIGNOR-255606 0.2 PAS complex complex SIGNOR-C190 SIGNOR Multivesicular_body_assembly phenotype SIGNOR-PH83 SIGNOR up-regulates 9606 17556371 f miannu Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. We further demonstrate a key function for each of the three proteins in the biogenesis of ECV/MVB transport intermediates from early endosomes. SIGNOR-253532 0.7 PRKCA protein P17252 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Ser87 AARARFEsKVPSFYY -1 12893243 t lperfetto The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚  SIGNOR-249223 0.322 manganese(2+) chemical CHEBI:29035 ChEBI BRCA1-C complex complex SIGNOR-C299 SIGNOR form complex binding 25400280 t lperfetto The BRCA1‚ÄìC complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2 SIGNOR-269476 0.8 APC protein P25054 UNIPROT ODC1 protein P11926 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12112318 t APC-dependent regulation of ornithine decarboxylase in human colon tumor cells|Upon induction of APC expression, ODC promoter activity and RNA levels were suppressed SIGNOR-253670 0.271 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Ser105 TGAGAAGsPAQQHAH 26375055 t lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity SIGNOR-276524 0.265 ADRA2C protein P18825 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256978 0.403 AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR oligopeptide smallmolecule CHEBI:25676 ChEBI up-regulates quantity relocalization 9606 25720354 t scontino APCs cell surface receptors facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. It is in these compartments that internalized antigen proteolysis and peptide–MHC class II complex formation takes place. SIGNOR-267862 0.8 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser12 KTLYSFFsPSPARKR 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276098 0.267 TSC22D3 protein Q99576 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity relocalization 9606 BTO:0000738 20018851 t inferred from 70% of family members GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells. SIGNOR-269854 0.407 MAP1LC3A protein Q9H492 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 19250911 t gcesareni Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation. SIGNOR-184198 0.784 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1242 ATSMFDDyQGDSSTL 9606 9722576 t lperfetto Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for src homology 2 domain-containing molecules. By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor. SIGNOR-59754 0.2 AMOT protein Q4VCS5 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates relocalization 9606 23431053 t AMOT proteins, a family of proteins including AMOT, AMOTL1, and AMOTL2, interact extensively with multiple TJ components and are important for maintaining TJ integrity and epithelial cell polarity. gcesareni Yap/taz and angiomotin (amot) family proteins were shown to interact, resulting in yap/taz localization to tight junctions and inhibition through phosphorylation-dependent and -independent mechanisms. SIGNOR-201132 0.669 AKT proteinfamily SIGNOR-PF24 SIGNOR TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Thr1462 GLRPRGYtISDSAPS 10090 BTO:0000944 12150915 t lperfetto We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines. SIGNOR-244365 0.2 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA6 protein Q9Y5G7 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265694 0.2 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7780739 t Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines|Protein phosphatase-2A was the only vanadate-insensitive phosphatase acting on Thr 183 of p42mapk or on MAPKK to be detected in PC12 cell extracts. SIGNOR-248625 0.605 PKNOX1 protein P55347 UNIPROT PBX1 protein P40424 UNIPROT up-regulates activity binding -1 9482740 t 2 miannu we show that Pbx proteins exist as stable heterodimers with a novel homeodomain protein, Prep1. Here we show that Prep1-Pbx interaction presents novel structural features: it is independent of DNA binding and of the integrity of their respective homeodomains, and requires sequences in the N-terminal portions of both proteins. The Prep1-Pbx protein-protein interaction is essential for DNA-binding activity. SIGNOR-241212 0.735 MYO3A protein Q8NEV4 UNIPROT MYO3A protein Q8NEV4 UNIPROT down-regulates activity phosphorylation Thr908 INLAKGDtGEATRHA 9534 24214986 t Manara We demonstrate by mass spectrometry that Thr-178 and Thr-184 in the kinase domain activation loop and two threonines in the loop 2 region of the motor domain are autophosphorylated (Thr-908 and Thr-919) | Thus, the phosphorylation sites in loop 2 (Thr-908 and Thr-919) are likely responsible for the down-regulation of MYO3A motor activity observed in our current and previous work SIGNOR-260923 0.2 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser172 LCLSPASsGSSASFI 9606 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248366 0.598 SMURF1 protein Q9HCE7 UNIPROT PADI4 protein Q9UM07 UNIPROT unknown ubiquitination -1 20804422 t miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. SIGNOR-272689 0.2 FYN protein P06241 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation Tyr731 QQIDSCTyEAMYNIQ 9606 9890970 t lperfetto Fyn associates with cbl and phosphorylates tyrosine 731 in cbl, a binding site for phosphatidylinositol 3-kinasecbl represents a substrate for src-like kinases that are activated in response to the engagement of cell surface receptors, and that src-like kinases are responsible for the phosphorylation of a tyrosine residue in cbl that may regulate activation of phosphatidylinositol 3-kinase SIGNOR-63968 0.805 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation 9606 12801888 t inferred from 70% family members llicata Our results suggest that map kinase can phosphorylate thr276 of smad4 and that phosphorylation can lead to enhanced tgf-beta-induced nuclear accumulation and, as a consequence, enhanced transcriptional activity of smad4. SIGNOR-270107 0.2 tacrolimus (anhydrous) chemical CHEBI:61049 ChEBI PP2B proteinfamily SIGNOR-PF18 SIGNOR down-regulates chemical inhibition 9606 15276472 t inferred from 70% of family members gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. SIGNOR-269893 0.8 RAB1A protein P62820 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity binding 9606 BTO:0000007 27479033 t Giulio Hemagglutinin (HA)-Rab1A is associated with mTOR and Raptor, not Rictor (Figure S2A), and is bound more with Myc-Raptor than Myc-mTOR (Figures S2B and S2C).|Rab1A Is an mTORC1 Activator and a Colorectal Oncogene SIGNOR-261286 0.321 NMDA proteinfamily SIGNOR-PF56 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor SIGNOR-264704 0.2 ATP(4-) smallmolecule CHEBI:30616 ChEBI ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity precursor of 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-268084 0.8 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser394 TRQTPVDsPDDSTLS 9606 9271440 t gcesareni Interestingly, phosphorylation at several ser/thr residues within the c-terminal autoinhibitory tail appears to either activate or inhibit s6k1, depending on the cell cycle phase. phosphorylation of those residues (featured by the thr-421/ser-424 site) during mitosis pursued by cdk1 inactivates s6k1 we then assessed the phosphorylation status of the mitosis-specific inhibitory residue of s6k1, thr-421/ser-424, which is targeted by mitotic cdk1. SIGNOR-50603 0.392 BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR CRY1 protein Q16526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. SIGNOR-267967 0.891 RPS6KA1 protein Q15418 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-262999 0.544 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser120 GRNIIHGsDSVESAE -1 8810265 t miannu For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown. SIGNOR-250300 0.2 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR TSC2 protein P49815 UNIPROT up-regulates activity phosphorylation Ser1452 LPSSSPRsPSGLRPR 9606 BTO:0000007 32294430 t done miannu We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452.  SIGNOR-274100 0.481 glutaryl-CoA(5-) smallmolecule CHEBI:57378 ChEBI glutarate(2-) smallmolecule CHEBI:30921 ChEBI up-regulates quantity precursor of 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271815 0.8 CDK5 protein Q00535 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Ser1232 SGHFTMRsPFKCDAC 10116 BTO:0000938 11675505 t llicata Here, we demonstrate that cyclin dependent kinase-5 (Cdk5) associates with and phosphorylates NR2A subunits at Ser-1232 in vitro and in intact cells. Moreover, we show that roscovitine, a selective Cdk5 inhibitor, blocks both long-term potentiation induction and NMDA-evoked currents in rat CA1 hippocampal neurons. These results suggest that Cdk5 plays a key role in synaptic transmission and plasticity through its up-regulation of NMDARs. SIGNOR-250666 0.54 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI LATS2 protein Q9NRM7 UNIPROT up-regulates 9606 23075495 f gcesareni On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz. SIGNOR-199199 0.8 RUVBL2 protein Q9Y230 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270854 0.688 ZNF804A protein Q7Z570 UNIPROT PIK3AP1 protein Q6ZUJ8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 23434502 t miannu ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). SIGNOR-269463 0.2 NFIB protein O00712 UNIPROT NFIX protein Q14938 UNIPROT up-regulates quantity transcriptional regulation 10090 29106906 t Gianni We report that, in the absence of Nfia or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord. SIGNOR-268870 0.43 SLC6A3 protein Q01959 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30465801 t miannu Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. SIGNOR-269189 0.8 PKC proteinfamily SIGNOR-PF53 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser162 FDIVSRGsTADLDGL -1 19661060 t miannu Activation of the TRPV4 ion channel is enhanced by phosphorylation. TRPV4 is phosphorylated in response to activation of PKC. We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-276229 0.2 Pac-1 chemical CID:135421197 PUBCHEM CASP3 protein P42574 UNIPROT up-regulates activity chemical activation -1 16936720 t lperfetto Here we report the identification of a small molecule (PAC-1) that directly activates procaspase-3 to caspase-3 in vitro and induces apoptosis in cancerous cells isolated from primary colon tumors in a manner directly proportional to the concentration of procaspase-3 inside these cells. W SIGNOR-262016 0.8 PTPN2 protein P17706 UNIPROT FYN protein P06241 UNIPROT down-regulates dephosphorylation Tyr420 RLIEDNEyTARQGAK 9606 BTO:0000782 22080863 t lperfetto Previously, we reported that sfks can serve as bona fide substrates for tcptp and that tcptp dephosphorylates the y418 activation loop autophosphorylation site (corresponding to y394 in lck and y417 in fyn) to inactivate sfks SIGNOR-177113 0.33 MAPK1 protein P28482 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 10915800 t llicata Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo. SIGNOR-80092 0.415 JAK2 protein O60674 UNIPROT PRMT5 protein O14744 UNIPROT down-regulates phosphorylation Tyr297 NRPPPNAyELFAKGY 9606 21316606 t llicata Oncogenic jak2 kinases phosphorylate prmt5 in_vivo phosphorylation of prmt5 by jak2v617f greatly impairs its methyltransferase activity SIGNOR-171994 0.68 MAPK7 protein Q13164 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Ser355 SALQGFNsPGMLSLG 9606 BTO:0000567 10849446 t lperfetto We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo. SIGNOR-236587 0.699 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR PIM2 protein Q9P1W9 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269249 0.2 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 t Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. SIGNOR-248334 0.553 DEAF1 protein O75398 UNIPROT HTR1A protein P08908 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14507979 f lperfetto Our data indicate that NUDR is a repressor of the 5-HT1A receptor in raphe cells the function of which is abrogated by a promoter polymorphism. SIGNOR-254124 0.448 MYC protein P01106 UNIPROT Enolase proteinfamily SIGNOR-PF74 SIGNOR up-regulates quantity transcriptional regulation 10116 10823814 t inferred from family member C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway. SIGNOR-270247 0.421 TFAP4 protein Q01664 UNIPROT NFIA protein Q12857 UNIPROT up-regulates activity binding 9606 BTO:0001109 19505873 t miannu We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads. SIGNOR-226586 0.27 26S Proteasome complex SIGNOR-C307 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates quantity destabilization 10090 BTO:0003569 9233789 t Here we show that the ubiquitin-dependent proteolysis system is involved in the regulation of beta-catenin turnover. beta-catenin, but not E-cadherin, p120(cas) or alpha-catenin, becomes stabilized when proteasome-mediated proteolysis is inhibited and this leads to the accumulation of multi-ubiquitinated forms of beta-catenin. SIGNOR-270340 0.391 AMPK complex SIGNOR-C15 SIGNOR EPM2A protein O95278 UNIPROT up-regulates activity phosphorylation Ser25 PELLVVGsRPELGRW 9606 BTO:0000007 21728993 t miannu We demonstrate that laforin is a phosphoprotein, as indicated by two-dimensional electrophoresis, and we identify Ser(25) as the residue involved in this modification. We also show that Ser(25) is phosphorylated both in vitro and in vivo by AMPK. Lastly, we demonstrate that this residue plays a critical role for both the phosphatase activity and the ability of laforin to interact with itself and with previously established binding partners. SIGNOR-277830 0.357 CDK2 protein P24941 UNIPROT RNF138 protein Q8WVD3 UNIPROT up-regulates activity phosphorylation Thr27 VCQEVLKtPVRTTAC 9606 BTO:0000007 38309501 t miannu Altogether, our results suggest RNF138 is phosphorylated at position T27 in a CDK1- and CDK2-dependent manner.Altogether, our results suggest RNF138 is phosphorylated at position T27 in a CDK1- and CDK2-dependent manner. SIGNOR-277831 0.2 CDK1 protein P06493 UNIPROT RNF138 protein Q8WVD3 UNIPROT up-regulates activity phosphorylation Thr27 VCQEVLKtPVRTTAC 9606 BTO:0000007 38309501 t miannu Altogether, our results suggest RNF138 is phosphorylated at position T27 in a CDK1- and CDK2-dependent manner.Altogether, our results suggest RNF138 is phosphorylated at position T27 in a CDK1- and CDK2-dependent manner. SIGNOR-277832 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MARS1 protein P56192 UNIPROT up-regulates activity phosphorylation Ser825 GGGQAKTsPKPAVVE 9606 BTO:0000567 25097229 t miannu Here, we report that methionyl-tRNA synthetase (MRS) is phosphorylated at Ser209 and Ser825 by extracellular signal-related kinase (ERK1/2) under conditions of stress caused by reactive oxygen species (ROS), and that this phosphorylated MRS shows increased affinity for non-cognate tRNAs with lower affinity for tRNA(Met), leading to an increase in Met residues in cellular proteins. SIGNOR-277833 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MARS1 protein P56192 UNIPROT up-regulates activity phosphorylation Ser209 LQKQPQPsPAEGRAV 9606 BTO:0000567 25097229 t miannu Here, we report that methionyl-tRNA synthetase (MRS) is phosphorylated at Ser209 and Ser825 by extracellular signal-related kinase (ERK1/2) under conditions of stress caused by reactive oxygen species (ROS), and that this phosphorylated MRS shows increased affinity for non-cognate tRNAs with lower affinity for tRNA(Met), leading to an increase in Met residues in cellular proteins. SIGNOR-277834 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR SIK1 protein P57059 UNIPROT down-regulates activity phosphorylation Ser435 VFRPRPVsPSSLLDT 9606 BTO:0000007 36806887 t miannu  Mass spectrometry-based analyses demonstrated that salt-inducible kinase 1 (SIK1) binds AKT and undergoes AKT-mediated phosphorylation, which compromises SIK1 tumor-suppressive functions.  SIGNOR-277835 0.2 VRK2 protein Q86Y07 UNIPROT TKT protein P29401 UNIPROT up-regulates activity phosphorylation Thr287 SKKKILAtPPQEDAP 9606 BTO:0001950 37653031 t miannu Mechanistically, VRK2 promoted Thr287 phosphorylation of TKT and then recruited FBXL6 to promote TKT ubiquitination and activation.  SIGNOR-277842 0.2 NR3C1 protein P04150 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates activity 10090 11742987 f gcesareni GR-mediated inhibition of c-Jun N-terminal kinase (JNK) activity SIGNOR-251676 0.623 SYK protein P43405 UNIPROT CGAS protein Q8N884 UNIPROT up-regulates activity phosphorylation Tyr214 GLLNTGSyYEHVKIS 10090 BTO:0003292 36252040 t miannu Mechanistically, viral infection or foreign DNA transfection triggers recruitment of the spleen tyrosine kinase (SYK) and cGAS to the endosomal vacuolar H+ pump (V-ATPase), where SYK is activated and then phosphorylates human cGASY214/215 (mouse cGasY200/201) to prime its activation. SIGNOR-277844 0.2 SYK protein P43405 UNIPROT CGAS protein Q8N884 UNIPROT up-regulates activity phosphorylation Tyr215 LLNTGSYyEHVKISA 10090 BTO:0003292 36252040 t miannu Mechanistically, viral infection or foreign DNA transfection triggers recruitment of the spleen tyrosine kinase (SYK) and cGAS to the endosomal vacuolar H+ pump (V-ATPase), where SYK is activated and then phosphorylates human cGASY214/215 (mouse cGasY200/201) to prime its activation. SIGNOR-277845 0.2 FGFR4 protein P22455 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000007 10918587 t Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3. SIGNOR-251141 0.355 CHEK1 protein O14757 UNIPROT MAP4 protein P27816 UNIPROT down-regulates quantity by destabilization phosphorylation Thr521 MALGKDVtPPPETEV 9606 36991467 t miannu MAP4 is a novel target of FBXW7 via the phosphorylated threonine T521 modified by CHEK1 in ESCC. The threonine T521 of MAP4, which was phosphorylated by CHEK1, played a key role in the FBXW7-related degradation system. SIGNOR-277846 0.2 CDK1 protein P06493 UNIPROT VHL protein P40337 UNIPROT down-regulates quantity by destabilization phosphorylation Ser80 QVIFCNRsPRVVLPV 9606 BTO:0000815 36813923 t miannu  Mechanistically, CDK1 directly phosphorylates pVHL at Ser80, which primes the recognition of pVHL by PIN1. PIN1 then binds to phosphorylated pVHL and facilitates the recruitment of the E3 ligase WSB1, therefore targeting pVHL for ubiquitination and degradation.  SIGNOR-277836 0.2 PRKACA protein P17612 UNIPROT CAST protein P20810 UNIPROT up-regulates activity phosphorylation Ser133 DKKKEKKsLTPAVPV -1 36984009 t miannu  The results showed that PKA promoted the phosphorylation of calpastatin, and a high phosphorylation level was maintained during incubation. Phosphorylation at serine 133 of calpastatin enhanced its inhibition on calpain activity by maintaining its structural stability, thus inhibiting the tenderization of meat. SIGNOR-277839 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR SLC9A3 protein P48764 UNIPROT down-regulates activity phosphorylation Ser555 AEGERRGsLAFIRSP 9606 BTO:0000195 38047302 t miannu AMPK activation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) phosphorylated NHE3 at S555. S555 is the primary site of phosphorylation by protein kinase A (PKA), but AMPK phosphorylated S555 independently of PKA. We conclude that AMPK activation inhibits NHE3 activity and NHE3 inhibition is associated with phosphorylation of NHE3 at S555 and S563. SIGNOR-277847 0.2 S100A9 protein P06702 UNIPROT Calprotectin complex complex SIGNOR-C293 SIGNOR form complex binding 9867828 t Using the two-hybrid system we analyzed the dimerization of MRP8 (S100A8) and MRP14 (S100A9), two S100 proteins expressed in myeloid cells. It is reported that the MRP8-MRP14 heteromer is the clearly preferred complex in both man and mouse. SIGNOR-262828 0.718 AMPK complex SIGNOR-C15 SIGNOR SLC9A3 protein P48764 UNIPROT down-regulates activity phosphorylation Ser563 LAFIRSPsTDNVVNV 9606 BTO:0000195 38047302 t miannu AMPK activation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) phosphorylated NHE3 at S555. S555 is the primary site of phosphorylation by protein kinase A (PKA), but AMPK phosphorylated S555 independently of PKA. We conclude that AMPK activation inhibits NHE3 activity and NHE3 inhibition is associated with phosphorylation of NHE3 at S555 and S563. SIGNOR-277848 0.2 AMPK complex SIGNOR-C15 SIGNOR SLC9A3 protein P48764 UNIPROT down-regulates activity phosphorylation Ser555 AEGERRGsLAFIRSP 9606 BTO:0000195 38047302 t miannu AMPK activation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) phosphorylated NHE3 at S555. S555 is the primary site of phosphorylation by protein kinase A (PKA), but AMPK phosphorylated S555 independently of PKA. We conclude that AMPK activation inhibits NHE3 activity and NHE3 inhibition is associated with phosphorylation of NHE3 at S555 and S563. SIGNOR-277849 0.2 CAMK2B protein Q13554 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr873 WQSEAQDtMKTGSST 9606 BTO:0000007 37686242 t miannu ERK1/2 and CaMKIIβ mediated phosphorylation of GABAB1 at serine 867 (S867) and threonine 872 (T872). We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. SIGNOR-277850 0.2 FOXS1 protein O43638 UNIPROT FASLG protein P48023 UNIPROT down-regulates quantity by repression transcriptional regulation 9913 BTO:0004577 18288644 t Luana As we expected, Fkhl18 suppressed, dose-dependently,human and mouseFasLpromoter in bovine vascularsmooth muscle cells SIGNOR-261612 0.2 CAMK2B protein Q13554 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser868 ITRGEWQsEAQDTMK 9606 BTO:0000007 37686242 t miannu ERK1/2 and CaMKIIβ mediated phosphorylation of GABAB1 at serine 867 (S867) and threonine 872 (T872). We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. SIGNOR-277851 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr873 WQSEAQDtMKTGSST 9606 BTO:0000007 37686242 t miannu We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. SIGNOR-277852 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser868 ITRGEWQsEAQDTMK 9606 BTO:0000007 37686242 t miannu We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. SIGNOR-277853 0.2 GSK3B protein P49841 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization phosphorylation Ser159 NNTSTDGsLPSTPPP 10090 BTO:0003328 16543145 t MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). S159 phosphorylation of MCL-1 was induced by IL-3 withdrawal or PI3K inhibition and prevented by AKT or inhibition of GSK-3, and it led to increased ubiquitinylation and degradation of MCL-1. SIGNOR-251242 0.514 PAX7 protein P23759 UNIPROT PAX7/MLL1 complex complex SIGNOR-C90 SIGNOR form complex binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-198632 0.2 CCNB1 protein P14635 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR form complex binding 9606 25603287 t lperfetto The central mitotic kinase, cyclin-dependent kinase-1 (human cdk1 is present through all stages of the cell cycle, but its activity is cell-cycle regulated by phosphorylation/dephosphorylation and cyclin binding.Cdk1-cyclin b phosphorylates ser/thr residues directly preceding pro; thus, it is classified as a proline-directed kinase. SIGNOR-205590 1 CHEK2 protein O96017 UNIPROT TRIM32 protein Q13049 UNIPROT up-regulates activity phosphorylation Ser55 LEKLLASsINGVRCP 9606 BTO:0000007 37943659 t miannu We show that CHK2 binds and phosphorylates TRIM32 at the S55 site, which then mediates K63-linked ubiquitination of ATG7 at the K45 site to initiate autophagy.  SIGNOR-277790 0.2 WNK1 protein Q9H4A3 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates activity phosphorylation Thr1023 QKKQGKNtIDVWWLF 9606 BTO:0000007 36318922 t miannu Combining these biochemical studies with the live cell imaging data, these results collectively suggest that the entire CTD is necessary for WNK1 to drive optimal SPAK/OSR1 activation and downstream NKCC1/KCC phosphorylation via PS. SIGNOR-277859 0.505 IKBKB protein O14920 UNIPROT TARDBP protein Q13148 UNIPROT down-regulates quantity by destabilization phosphorylation Ser92 MDETDASsAVKVKRA 9606 BTO:0002181 38197897 t miannu IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation. Furthermore, we identified IKKβ-induced phosphorylation sites of TDP-43 and found that phosphorylation at Thr8 and Ser92 is important for the reduction of TDP-43 by IKK. SIGNOR-277860 0.2 IKBKB protein O14920 UNIPROT TARDBP protein Q13148 UNIPROT down-regulates quantity by destabilization phosphorylation Thr8 MSEYIRVtEDENDEP 9606 BTO:0002181 38197897 t miannu IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation. Furthermore, we identified IKKβ-induced phosphorylation sites of TDP-43 and found that phosphorylation at Thr8 and Ser92 is important for the reduction of TDP-43 by IKK. SIGNOR-277861 0.2 ARP2/3 complex SIGNOR-C146 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 12479800 f lperfetto The Arp2/3 complex concentrates at leading edges, where it catalyzes the growth of branched actin networks that are believed to provide the protrusive force for leading edge extension. SIGNOR-251511 0.7 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Tyr68 DPPLESKyECPICLM 9606 BTO:0002181 37977223 t miannu  To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. SIGNOR-277862 0.582 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Tyr326 KMETQSMyVSELKRT 9606 BTO:0002181 37977223 t miannu  To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. SIGNOR-277863 0.582 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Tyr353 AQQCNGIyIWKIGNF 9606 BTO:0002181 37977223 t miannu  To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. SIGNOR-277864 0.582 SRC protein P12931 UNIPROT TRIM25 protein Q14258 UNIPROT up-regulates activity phosphorylation Tyr278 NSKFDTIyQILLKKK 9606 BTO:0002181 30100205 t miannu Here, we demonstrated that TRIM25 interacted with c-Src and underwent tyrosine phosphorylation by c-Src kinase upon viral infection and the phosphorylation is required for the complete activation of RIG-I signaling. Analysis using a c-Src inhibitor and TRIM25 mutant, in which tyrosine 278 is substituted by phenylalanine (Y278F), suggested that the phosphorylation positively regulates K63-linked polyubiquitination of RIG-I and subsequent antiviral signaling.  SIGNOR-277405 0.274 Endothelin-1 smallmolecule CHEBI:80240 ChEBI EDNRB protein P24530 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257483 0.8 WT1 protein P19544 UNIPROT PAX2 protein Q02962 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000671 7720589 t A marked increase in WT1 protein levels coincided precisely with down-regulation of the Pax-2 gene in the individual precursor cells of the visceral glomerular epithelium, suggesting a direct effect of the WT1 repressor protein on Pax-2 regulatory elements. To examine whether WT1 could directly repress Pax-2 transcription, binding of WT1 to three high affinity sites in the 5' untranslated Pax-2 leader sequence was demonstrated by DNAseI footprinting analysis SIGNOR-252298 0.617 STK16 protein O75716 UNIPROT STK16 protein O75716 UNIPROT unknown phosphorylation Tyr198 AQRCTISyRAPELFS -1 18184589 t Manara Indeed, our kinetic analysis of MPSK1 autophosphorylation showed that autophosphorylation is a slow process and that two of the three identified sites are largely buried in unphosphorylated MPSK1. However, two autophosphorylation sites are located in the P + 1 loop and phosphorylation at these locations might affect substrate recognition. SIGNOR-260805 0.2 CDK10 protein Q15131 UNIPROT ETS2 protein P15036 UNIPROT down-regulates quantity by destabilization phosphorylation Ser225 LDSMCPAsTPSVLSS 9606 24218572 t Manara Altogether, these results suggest that CDK10/cyclin M directly controls ETS2 degradation through the phosphorylation of these two serines. SIGNOR-260914 0.543 DGCR8 protein Q8WYQ5 UNIPROT RNF168 protein Q8IYW5 UNIPROT up-regulates activity binding 9606 BTO:0002181 34188037 t miannu  Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8's binding partner RNF168 to MDC1 and RNF8 at DSBs.  SIGNOR-277309 0.2 GSK3A protein P49840 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser509 GVHSPMAsSGNTGNH 9606 BTO:0000093 17574025 t miannu GSK3 Phosphorylates SRC-3 on S505.In this report, we identified GSK3 as a kinase that phosphorylates SRC-3 on S505 and demonstrated that this phosphorylation modulates SRC-3 transcriptional function and turnover. SIGNOR-276067 0.2 PRKAA1 protein Q13131 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates activity phosphorylation 9606 SIGNOR-C15 SIGNOR-C3 21460634 t lperfetto Ampk in turn inactivates mtorc1 directly by phosphorylating raptor and indirectly by phosphorylating tsc2. SIGNOR-173035 0.674 DNM2 protein P50570 UNIPROT GJB2 protein P29033 UNIPROT down-regulates binding 9606 25263585 t miannu This study identifies dynamin 2 (dyn2) as a cx26 interactor in yeast and mammalian cells / we demonstrate that dyn2 regulates cx26 endocytosis and ubiquitination SIGNOR-205372 0.334 EGFR protein P00533 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates phosphorylation Tyr1276 GGGPGGDyAAMGACP 9606 BTO:0000150 7929151 t lperfetto The erbb3 protein which possesses little or no intrinsic protein tyrosine kinase activiity is phosphorylated by the activated egf receptor protein tyrosine kinase on tyrosine residues within the yxxm sequence motif. These phosphorylated tyrosine residues interact with the p85 regulatory subunit of pi 3-kinase, which could result in the activation of the p110 catalytic subunit via a conformational mechanism. SIGNOR-34748 0.656 PLK1 protein P53350 UNIPROT IKBKB protein O14920 UNIPROT down-regulates phosphorylation Ser740 SFTALDWsWLQTEEE 9606 18957422 t lperfetto Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma SIGNOR-181802 0.349 RAB6C protein Q9H0N0 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 25492866 f miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons SIGNOR-266875 0.7 AKT1 protein P31749 UNIPROT RAB3IP protein Q96QF0 UNIPROT up-regulates activity phosphorylation Ser165 LSRLRSPsVLEVREK 9606 BTO:0001950 36797475 t miannu Rabin8 is phosphorylated and activated by Akt in cells grown on stiff ECM. SIGNOR-277816 0.2 NEK1 protein Q96PY6 UNIPROT VHL protein P40337 UNIPROT down-regulates quantity by destabilization phosphorylation Ser168 RCLQVVRsLVKPENY 9606 BTO:0000007 23255108 t miannu Nek1 phosphorylates Von Hippel-Lindau tumor suppressor to promote its proteasomal degradation and ciliary destabilization. Mutation of pVHL at S-168 increases protein stability. SIGNOR-276434 0.26 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK3 protein Q00526 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189987 0.8 CSNK2A2 protein P19784 UNIPROT AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser316 EKKGKDQsGEVLSSV 9615 11742978 t llicata We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4‐Cter proteins in which only one out of the three C‐terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. SIGNOR-250976 0.344 POLR2C protein P19387 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266163 0.878 NFIB protein O00712 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268901 0.2 oxotremorine M chemical CHEBI:38322 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258657 0.8 CAMK2A protein Q9UQM7 UNIPROT CACNA1H protein O95180 UNIPROT down-regulates activity phosphorylation Ser2137 RDLRRLYsVDAQGFL 10090 BTO:0003695 38001892 t miannu  we also discovered that a novel CaMKII-phosphorylated site, S2137, underwent dephosphorylation by calcineurin.  SIGNOR-277871 0.276 Calcineurin complex SIGNOR-C155 SIGNOR CACNA1H protein O95180 UNIPROT up-regulates activity dephosphorylation Ser2137 RDLRRLYsVDAQGFL 10090 BTO:0003695 38001892 t miannu  we also discovered that a novel CaMKII-phosphorylated site, S2137, underwent dephosphorylation by calcineurin.  SIGNOR-277872 0.272 SRC protein P12931 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity phosphorylation Tyr251 LQFPGAVyGTDGCPV 29844931 t lperfetto As a result, we established that Src was able to directly phosphorylate caspase-9 at tyrosine 251, leading to elevated caspase-9 activity. SIGNOR-272998 0.382 EGFR protein P00533 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Tyr154 PPFTARIyAAGFDSS 9606 BTO:0000815 36841821 t miannu EGFR is positively correlated with PELI1 expression in breast cancers, and its activation led to the phosphorylation of PELI1 at Tyr154 and Thr264, which subsequently activated its E3 ubiquitin ligase.  EGFR phosphorylated PELI1 leading to its K63-linked auto-ubiquitination. SIGNOR-277873 0.2 EGFR protein P00533 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr264 EGLSHTPtVKHLEAL 9606 BTO:0000815 36841821 t miannu EGFR is positively correlated with PELI1 expression in breast cancers, and its activation led to the phosphorylation of PELI1 at Tyr154 and Thr264, which subsequently activated its E3 ubiquitin ligase.  SIGNOR-277874 0.2 PELI1 protein Q96FA3 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by stabilization polyubiquitination 9606 BTO:0000815 36841821 t miannu EGFR is positively correlated with PELI1 expression in breast cancers, and its activation led to the phosphorylation of PELI1 at Tyr154 and Thr264, which subsequently activated its E3 ubiquitin ligase. Simultaneously, PELI1 physically interacted with and enhanced the stability of EGFR via the K63-linked polyubiquitination in reverse. SIGNOR-277875 0.2 PTPRJ protein Q12913 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Tyr1320 Y>1319 9606 BTO:0002181 24583284 t miannu CK2-dependent phosphorylation of DEP-1 T1318 promotes Y1320 phosphorylation and Src activation upon VEGF stimulation. SIGNOR-277877 0.621 PPP2CA protein P67775 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser122 PKPPPAAsPGVRAGH -1 29945972 t miannu MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation. SIGNOR-277878 0.2 PPP2CA protein P67775 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser211 LVGVTSSsCPADLTQ -1 29945972 t miannu MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation. SIGNOR-277879 0.2 PPP2CA protein P67775 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser114 HISPAQGsPKPPPAA -1 29945972 t miannu MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation. SIGNOR-277880 0.2 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCNA2 protein P20248 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189966 0.8 PPP2CA protein P67775 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser109 NKFAAHIsPAQGSPK -1 29945972 t miannu MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation. SIGNOR-277881 0.2 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI CYP26A1 protein O43174 UNIPROT up-regulates activity chemical activation 9606 31963453 t lperfetto Cytochrome P450 (CYP) subfamily 26 of enzymes degrade the excess of RA to avoid detrimental effects [17]. Among the three subtypes (CYP26A1, CYP26B1, and CYP26C1), CYP26A1 is particularly important during embryonic development SIGNOR-265138 0.8 LYN protein P07948 UNIPROT SOCS1 protein O15524 UNIPROT down-regulates activity phosphorylation Tyr80 LLDACGFyWGPLSVH -1 31101761 t miannu These findings show that SOCS1 phosphorylation by the SRC family inhibits its tumor-suppressive activity, indicating that patients with increased SOCS1 phosphorylation may benefit from SRC family kinase inhibitors. SIGNOR-277888 0.306 BLK protein P51451 UNIPROT SOCS1 protein O15524 UNIPROT down-regulates activity phosphorylation Tyr80 LLDACGFyWGPLSVH -1 31101761 t miannu These findings show that SOCS1 phosphorylation by the SRC family inhibits its tumor-suppressive activity, indicating that patients with increased SOCS1 phosphorylation may benefit from SRC family kinase inhibitors. SIGNOR-277889 0.2 MAP2K1 protein Q02750 UNIPROT TET2 protein Q6N021 UNIPROT up-regulates quantity by stabilization phosphorylation Ser1107 VLNNFIEsPSKLLDT 9606 BTO:0004082 38461173 t miannu TET2 was stabilized by MEK1 phosphorylation at Ser 1107, while MEK1 inactivation promoted its proteasome degradation by enhancing the recruitment of CUL7FBXW11. SIGNOR-277891 0.249 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRA protein P10827 UNIPROT up-regulates activity chemical activation 10116 BTO:0000759 2158622 t miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. SIGNOR-258385 0.8 ARAF protein P10398 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser222 LIDSMANsFVGTRSY 9606 BTO:0000567 8621729 t lperfetto Our data demonstrated that a-raf is, indeed, a mek1 activator and may play a role in growth factor signaling|The immunoprecipitates were assayed for GST-MEK1 activation. D, activation of MEK1 by A-Raf requires the presence of serine residue 218 and 222. SIGNOR-235944 0.729 tacedinaline chemical CHEBI:90195 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258007 0.8 PEA15 protein Q15121 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates 9606 11702783 f inferred from 70% of family members gcesareni Here, we report that pea-15, a protein variably expressed in multiple cell types, blocks erk-dependent transcription and proliferation by binding erks and preventing their localization in the nucleus._ Pea-15 can redirect the biological outcome of map kinase signaling by regulating the subcellular localization of erk map kinase. SIGNOR-269904 0.2 FOXO3 protein O43524 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14981546 f Induction of Foxo3a phosphorylation by FLT3-ITD receptors in Ba/F3 cells correlates with the suppression of Foxo-target genes p27Kip1 and the proapoptotic Bcl-2 family member Bim SIGNOR-261528 0.762 PAK1 protein Q13153 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation 9606 15037762 t gcesareni Kinases targeted sequentially to the neck, cla4/pak and cdc5/polo, are responsible for stepwise phosphorylation and down-regulation of swe1. SIGNOR-123528 0.304 PRKACA protein P17612 UNIPROT HAND1 protein O96004 UNIPROT down-regulates activity phosphorylation Ser109 KERRRTEsINSAFAE 10116 BTO:0001556 14636580 t miannu In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function. SIGNOR-249989 0.3 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 10090 BTO:0000944 15367694 t Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes SIGNOR-252606 0.89 PLCG1 protein P19174 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates chemical modification 9606 21918248 t gcesareni Phospholypase c is an enzyme which catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (p(4,5)p(2)) into second messangers inositol-1,4,5-triphosphate (ins(1,4,5)p3) and dag. SIGNOR-176606 0.8 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257518 0.8 4,4'-sulfonyldiphenol chemical CHEBI:34372 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 31995776 t miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . SIGNOR-268730 0.8 PTK2B protein Q14289 UNIPROT TGFB1I1 protein O43294 UNIPROT up-regulates activity phosphorylation Tyr60 SGDKDHLySTVCKPR 9534 10838081 t miannu Hic-5 is a CAKbeta-binding protein localized at focal adhesions. Here we show that overexpression of CAKbeta or Fyn, but not FAK, enhanced the tyrosine phosphorylation of coexpressed Hic-5 in COS-7 cells. The Y60F mutant of Hic-5 was not phosphorylated, and Hic-5 phosphorylated on tyrosine 60 was bound specifically to the SH2 domain of Csk. Specific phosphorylation of Hic-5 by CAKbeta and Fyn may activate a signaling pathway mediated by Hic-5. SIGNOR-262876 0.733 MAPK3 protein P27361 UNIPROT STMN2 protein Q93045 UNIPROT down-regulates activity phosphorylation Ser62 ELILKPPsPISEAPR 10116 BTO:0000142 9525956 t lperfetto SCG10, a growth cone-enriched MT-destabilizing protein, has been recently characterized as an in vitro substrate for various serine/threonine kinases including PKA, MAP kinase, and CDK (19). We have found that SCG10 is phosphorylated in vivo in developing rat brain.| The sites for MAP kinase phosphorylation were identified as Ser-62 and Ser-73 of SCG10|By expressing a series of phosphorylation site mutants, we showed that the MT-destabilizing effect of SCG10 could be modulated. While the nonphosphorylatable mutant showed higher activity than the wild-type protein, the activity of the mutant in which phosphorylation on all four sites was mimicked by an aspartate residue was greatly reduced. These data suggest that the nonphosphorylated state of SCG10 represents the most active form of the protein. SIGNOR-249115 0.359 SLC35A1 protein P78382 UNIPROT sialic acid smallmolecule CHEBI:26667 ChEBI up-regulates quantity relocalization 9606 34384782 t miannu The CMP-sialic acid transporter SLC35A1 and UDP-galactose transporter SLC35A2 are two well-characterized nucleotide sugar transporters with distinctive substrate specificities. Nucleotide sugar transporters (NSTs) transport nucleotide sugars from the cytosol into the lumen of the endoplasmic reticulum or the Golgi apparatus, where the nucleotide sugars serve as substrates for protein glycosylation and glycosphingolipid synthesis. SIGNOR-268466 0.8 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR EPCAM protein P16422 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11505407 f miannu The current results provide the first insights into the regulation of EpCAM expression, which is regulated negatively by TNFalpha and TPA through the activation of NF-kappaB. The repression may rely on the competition of NF-kappaB for p300/CBP histone acetyl transferase activity, because the overexpression of p300 reverts TNFalpha effects. SIGNOR-254790 0.287 H2AC4 protein P04908 UNIPROT Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR form complex binding 9606 15776021 t miannu Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes. SIGNOR-263874 0.2 PRKCB protein P05771 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1323 ALAPRSVsLKDKGRF -1 11306676 t lperfetto These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. SIGNOR-249087 0.371 APC-c complex SIGNOR-C150 SIGNOR CCNA2 protein P20248 UNIPROT down-regulates quantity by destabilization ubiquitination 21596315 t lperfetto Complexed with the activator proteins CDC20 or CDH1 (Fang et al., 1998, Visintin et al., 1997), the APC/C recognizes, ubiquitinates, and targets for proteasomal degradation a multitude of cell cycle regulators containing KEN or D box degrons, including securin, cyclin A, and cyclin B. SIGNOR-265050 0.539 TNF protein P01375 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection SIGNOR-261034 0.7 PRKCI protein P41743 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0000195 18270268 t llicata Pkciota phosphorylated ezrin on t567 in vitro, and in sf9 cells that do not activate human ezrin. we conclude that, although other molecular mechanisms contribute to ezrin activation, apically localized phosphorylation by pkciota is essential for the activation and normal distribution of ezrin at the early stages of intestinal epithelial cell differentiation. SIGNOR-160855 0.349 TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7566157 t gcesareni The p21 gene is under the transcriptional control of p53 (ref. 5), suggesting that p21 might promote p53-dependent cell cycle arrest or apoptosis. p21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage. p53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting g1/s entry. SIGNOR-29248 0.872 SPRY4 protein Q9C004 UNIPROT CD82 protein P27701 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002058 20501643 f miannu When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. SIGNOR-253039 0.2 GABRD protein O14764 UNIPROT GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263770 0.399 NEDD4L protein Q96PU5 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 t miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). SIGNOR-253458 0.341 ETF1 protein P62495 UNIPROT Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR form complex binding 9606 29735640 t miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3-guanosine triphosphate (GTP) complex. SIGNOR-270813 0.972 ADNP protein Q9H2P0 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates activity binding 10116 BTO:0000601 24365867 t miannu Here, we show for the first time that hippocampal ADNP deficiency paralleled reduced beclin1 expression which, in turn, parallels increased tauopathy and cell death. We now show that ADNP directly interacts with LC3B, implicating the requirement of a healthy ADNP system for the apoptotic/autophagy processes. SIGNOR-266759 0.377 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 BTO:0001412 8692915 t The SH3 domain of c-Abl interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that c-Abl phosphorylates C terminal Y536 and Y564 sites. The functional significance of the c-Abl-SHPTP1 interaction is supported by the demonstration that, like c-Abl, SHPTP1 regulates the induction of Jun kinase activity following DNA damage. SIGNOR-251433 0.423 POU5F1 protein Q01860 UNIPROT BMP4 protein P12644 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254932 0.484 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser75 LGYEPEGsASPTPPY 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248494 0.272 linifanib chemical CHEBI:91435 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition -1 16648571 t Gianni ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families SIGNOR-262207 0.8 E2F1 protein Q01094 UNIPROT SMAD7/HDAC1/E2F-1 complex SIGNOR-C12 SIGNOR form complex binding 9606 23213415 t gcesareni Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes SIGNOR-199955 0.445 CDK5 protein Q00535 UNIPROT CORO1A protein P31146 UNIPROT up-regulates activity phosphorylation Thr424 AAPEASGtPSSDAVS 9606 BTO:0001588 26823173 t lperfetto We here show that phosphorylation of coronin 1 on Thr(418/424) by cyclin-dependent kinase (CDK) 5 activity was responsible for coronin 1-G_s association and the modulation of cAMP production. Together these results show an essential role for CDK5 activity in promoting the coronin 1-dependent cAMP/PKA pathway. SIGNOR-245187 0.292 NTNG2 protein Q96CW9 UNIPROT LRRC4 protein Q9HBW1 UNIPROT up-regulates activity binding 9606 BTO:0000938 19467332 t miannu The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively. SIGNOR-264048 0.724 CBP/p300 complex SIGNOR-C6 SIGNOR RELA protein Q04206 UNIPROT up-regulates acetylation 9606 16382138 t lperfetto Rela is also acetylated at several sites by p300 and cbp SIGNOR-217210 0.845 clenbuterol chemical CHEBI:174690 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  SIGNOR-257861 0.8 MAPKAPK2 protein P49137 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser179 RRFRRSQsDCGELGD -1 15850461 t miannu Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. SIGNOR-263079 0.49 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT up-regulates activity phosphorylation Ser534 KSQHRSSsSAPHHNH 10441130 t miannu Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation SIGNOR-250341 0.417 N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-(2,6-dimethoxyphenoxy)ethanamine chemical CHEBI:64098 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258467 0.8 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates activity phosphorylation Ser535 ESEQSMDsEEPDSRG -1 12133000 t The largest (epsilon) subunit of eIF2B is a substrate for glycogen synthase kinase (GSK)-3 in vitro, and phosphorylation by GSK3 inhibits the activity of eIF2B. The site of phosphorylation has previously been identified as Ser(535). SIGNOR-251236 0.561 SMC5/6 complex SIGNOR-C374 SIGNOR Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 27427983 f miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks SIGNOR-265488 0.7 NDUFB1 protein O75438 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 SIGNOR-262162 0.768 CTBP1 protein Q13363 UNIPROT UBE2D3 protein P61077 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 21044962 f miannu knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene. SIGNOR-255174 0.2 1-phospho-alpha-D-glucuronic acid smallmolecule CHEBI:681 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation -1 7576010 t miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1.Similarly, the affinities of D3 receptors for quinpirole and dopamine were much higher than the affinities of D:! receptors for the agonists in the presence of Gpp(NH)p and NaCl when [1251]-NCQ-298 was used to label receptors; however, when Gpp(NH)p and NaCl were not present, and when [12sI]-7-OH-PIPAT was used, receptors bound quinpirole and dopamine with nearly equal affinities (Table 1). SIGNOR-258434 0.8 HDAC6 protein Q9UBN7 UNIPROT SRSF2 protein Q01130 UNIPROT up-regulates deacetylation Lys52 IPRDRYTkESRGFAF 9606 21157427 t miannu Our data support a model in which hdac6 has a key role in the maintenance of srsf2 protein level by inhibiting tip60_mediated acetylation and proteasomal degradation. SIGNOR-170590 0.363 DDIT3 protein P35638 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260173 0.466 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 12270934 f lperfetto We further show that activation of mek1 significantly enhances the transactivation of the c/ebpalpha minimal promoter during the early phase of the differentiation process. SIGNOR-244773 0.2 GDNF protein P39905 UNIPROT GCH1 protein P30793 UNIPROT up-regulates activity 9606 12358777 f miannu GDNF can support the function of primary dopaminergic neurones by triggering activation of GTP-cyclohydrolase I (GTPCH I), a key enzyme in catecholamine biosynthesis. GTPCH I mRNA levels in primary dopaminergic neurones were not altered by GDNF treatment, suggesting that the mode of action for that up-regulation is not directly connected to the regulation of GTPCH I transcription SIGNOR-252221 0.281 RAD50 protein Q92878 UNIPROT RINT1 protein Q6NUQ1 UNIPROT up-regulates activity binding 9606 BTO:0004784 16600870 t lperfetto We propose that p130, forming a complex with Rad50 through RINT-1, blocks telomerase-independent telomere lengthening in normal cells.  SIGNOR-265030 0.483 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Ser241 SKQARANsFVGTAQY 9606 11481331 t miannu In terms of the modulation of PDK1 activity by reversible phosphorylation, five pS sites have been identified on PDK1 in vivo, but only one of these sites, Ser-241 in the activation loop of PDK1, is essential for activity. It seems likely that PDK1 autophosphorylates itself on this residue. SIGNOR-250268 0.2 MTOR protein P42345 UNIPROT DAP protein P51397 UNIPROT down-regulates activity phosphorylation Ser3 DQEWESPsPPKPTVF 9606 20537536 t miannu A critical step in autophagy induction comprises the inactivation of a key negative regulator of the process, the Ser/Thr kinase mammalian target of rapamycin (mTOR). Here we identify death-associated protein 1 (DAP1) as a novel substrate of mTOR that negatively regulates autophagy. Mapping of the phosphorylation sites and analysis of phosphorylation mutants indicated that DAP1 is functionally silenced in growing cells through mTOR-dependent phosphorylations on Ser3 and Ser51. SIGNOR-259813 0.404 CDK1 protein P06493 UNIPROT PAPOLA protein P51003 UNIPROT up-regulates activity phosphorylation Ser537 DNSMSVPsPTSATKT 10090 BTO:0000964 34048556 t lperfetto Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity. SIGNOR-268338 0.261 CSNK1A1 protein P48729 UNIPROT AGO2 protein Q9UKV8 UNIPROT down-regulates activity phosphorylation Ser834 GSHTSGQsNGRDHQA 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276509 0.377 DAB1 protein O75553 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000142 22394407 t lperfetto The induction of disabled-1 (dab-1) tyrosine phosphorylation, and the subsequent activation of src family kinases, were found to be essential steps for the activation of notch-1 signaling by reelin SIGNOR-196438 0.387 MEF2A protein Q02078 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 9418854 t lperfetto Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis. SIGNOR-54086 0.732 DRAM2 protein Q6UX65 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30755245 f irozzo DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression. SIGNOR-259147 0.2 POLR2A protein P24928 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266160 0.864 Cap-binding complex complex SIGNOR-C440 SIGNOR PUM3 protein Q15397 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320643 t lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins SIGNOR-268352 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Ser175 SFVTPPQsHFVRVST 9606 BTO:0002181 26028025 t miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. SIGNOR-276910 0.422 MST1 protein P26927 UNIPROT MST1R protein Q04912 UNIPROT up-regulates binding 9606 8062829 t gcesareni P185ron is a tyrosine kinase activated by msp SIGNOR-31107 0.893 TGFB1 protein P01137 UNIPROT ANKH protein Q9HCJ1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20930330 f miannu TGF-β1 was shown to stimulate ANK and PC-1 expression in articular chondrocytes, and subsequent ePPi level, as well as to increase ePi uptake by inducing PiT-1 expression in a chondrogenic cell line. SIGNOR-252201 0.2 CSNK2A1 protein P68400 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser101 GSHRDQGsSALSGVG 9606 21750978 t miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo SIGNOR-174820 0.294 FGFR1 protein P11362 UNIPROT ACAT1 protein P24752 UNIPROT up-regulates activity phosphorylation Tyr407 HALKQGEyGLASICN 9606 BTO:0002552 27867011 t lperfetto Treatment with the FGFR1 inhibitor TKI258 in FGFR1-expressing H1299 cells led to decreased Y407 phosphorylation of ACAT1 in the mitochondrial fraction, where both ACAT1 and a fraction of FGFR1 were detected|Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity, SIGNOR-264423 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270367 0.8 ketanserin chemical CHEBI:6123 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258685 0.8 TIMP2 protein P16035 UNIPROT LRP2 protein P98164 UNIPROT up-regulates quantity binding 10116 BTO:0001860 28659595 t miannu We show that megalin/LRP-2 acts as an endocytic receptor for proMMP-2:TIMP-2 complex. We found that RAP, an antagonist of the LDL receptor family18, competed with binding of proMMP-2:TIMP-2 complex onto rat BN16 epithelial cells. SIGNOR-265254 0.2 RPIA protein P49247 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity chemical modification 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267070 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CALD1 protein Q05682 UNIPROT down-regulates phosphorylation 9606 BTO:0001260 10514499 t inferred from 70% family members lperfetto Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin. SIGNOR-270162 0.2 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser206 SSSTYPHsPTSSDPG 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248302 0.479 EIF3_complex complex SIGNOR-C401 SIGNOR 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269162 0.677 SYDE2 protein Q5VT97 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260522 0.376 cabazitaxel chemical CHEBI:63584 ChEBI TUBA4A protein P68366 UNIPROT down-regulates activity chemical inhibition 9606 21770474 t miannu Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization SIGNOR-259340 0.8 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto Tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process SIGNOR-171042 0.728 NEK6 protein Q9HC98 UNIPROT ACD protein Q96AP0 UNIPROT up-regulates activity phosphorylation Ser169 SNAGLSLsQLLDEMR 9606 BTO:0000007 27396482 t lperfetto NEK6-mediated phosphorylation of human TPP1 regulates telomere length through telomerase recruitment|Shelterin component TPP1 plays critical roles in chromosome end protection and telomere length regulation. Specifically, TPP1 contains an OB-fold domain that provides an interface to recruit telomerase.| SIGNOR-264424 0.2 RNF152 protein Q8N8N0 UNIPROT RRAGA protein Q7L523 UNIPROT down-regulates activity polyubiquitination 9606 BTO:0000007 25936802 t miannu  Here, we identified the lysosome-anchored E3 ubiquitin ligase RNF152 as an essential negative regulator of the mTORC1 pathway by targeting RagA for K63-linked ubiquitination. RNF152 interacts with and ubiquitinates RagA in an amino-acid-sensitive manner. The mutation of RagA ubiquitination sites abolishes this effect of RNF152 and enhances the RagA-mediated activation of mTORC1. Ubiquitination by RNF152 generates an anchor on RagA to recruit its inhibitor GATOR1, a GAP complex for Rag GTPases.  SIGNOR-272222 0.73 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Thr57 NFDFVTEtPLEGDFA 9606 19364816 t lperfetto We have shown that erk2 interacts with and phosphorylates p21cip1, promoting p21cip1_ubiquitination. We identified two erk2 phosphorylation sites, thr57 and ser130, in p21cip1_and showed that phosphorylation of these residues increases p21cip1_cytoplasmic distribution and proteasome-dependent degradation. SIGNOR-244513 0.2 DOK1 protein Q99704 UNIPROT Av/b8 integrin complex SIGNOR-C185 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257699 0.2 RPL41 protein P62945 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262458 0.2 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 24632615 t miannu Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine. SIGNOR-266555 0.8 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys64 RAGCCLGkAVRGAKG 9606 15831498 t gcesareni Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300 SIGNOR-135469 0.476 KDM4C protein Q9H3R0 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 BTO:0001033 29207681 t miannu JMJD2C was found to be co-localized with AR and LSD1 in the epithelium of prostate carcinoma and normal prostate cells. For the detailed mechanism, JMJD2C, AR and LSD1 assembled on the chromatin to remove the methyl groups from mono-, di- and trimethylated H3K9. Importantly, JMJD2C specifically removed the demethylation of the trimethyl H3K9 marks and modulated the transcriptional activity of AR. Moreover, JMJD2C cooperated with LSD1 and activated AR-mediated gene expression via decreasing H3K9me3 at the promoter of AR targeting genes KLK2 and PSA. SIGNOR-263879 0.2 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Ser14 PFSCHYPsRLRRDPF 9606 22721717 t lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation SIGNOR-197940 0.312 CSNK2A1 protein P68400 UNIPROT VAMP4 protein O75379 UNIPROT up-regulates phosphorylation Ser30 RNLLEDDsDEEEDFF 9606 14608369 t gcesareni The r-snare vamp4, which contains a dileucine motif, binds to the ap-1 or the ggas. Serine 20 and leucines 25,26 are essential for this binding. Ap-1 association with vamp4 is enhanced when serine 30 is phosphorylated by casein kinase 2. This phosphorylation-dependent modulation of ap-1 binding is mediated by pacs-1 (phosphofurin acidic cluster sorting protein). Ablation of both the dileucine motif and serine 30 results in a dramatic mislocalization of vamp4 in the regulated secretory pathway. SIGNOR-119090 0.457 DYRK1B protein Q9Y463 UNIPROT HDAC9 protein Q9UKV0 UNIPROT down-regulates phosphorylation Ser240 KVAERRSsPLLRRKD 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 15546868 t lperfetto Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner SIGNOR-235813 0.2 PTGER2 protein P43116 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256899 0.252 NELFE protein P18615 UNIPROT NELF complex SIGNOR-C521 SIGNOR form complex binding 9606 18628398 t miannu The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. SIGNOR-271400 0.901 PI3K complex SIGNOR-C156 SIGNOR MTOR protein P42345 UNIPROT up-regulates 9606 18721898 f lperfetto Phosphoinositide 3-kinase (pi3k)-dependent activation of the rheb-mtor pathway triggers the simultaneous local synthesis of tc10 and par3. SIGNOR-252705 0.562 PLG protein P00747 UNIPROT Fibrinolysis phenotype SIGNOR-PH6 SIGNOR up-regulates 9606 1447176 f lperfetto The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme SIGNOR-263535 0.7 LMO2 protein P25791 UNIPROT ANGPT2 protein O15123 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22792348 f miannu Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation. SIGNOR-198249 0.337 CDK2 protein P24941 UNIPROT ID3 protein Q02535 UNIPROT down-regulates phosphorylation Ser5 sPVRGCYE 9606 9372912 t lperfetto We now show that an analogous cell-cycle-regulated phosphorylation of id3 alters the specificity of id3 for abrogating both e-box-dependent bhlh homo- or heterodimer complex formation in vitro and e-box-dependent reporter gene function in vivo._ SIGNOR-53306 0.348 NEU1 protein Q99519 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0003554 32164705 f miannu Our data showed that NEU1 inhibited cancer cell proliferation, induced apoptosis, and suppressed tumor formation both in vitro and in vivo, by disrupting interaction of FN and integrin β1 and inhibiting the Akt signaling pathway. SIGNOR-260657 0.7 E2F1 protein Q01094 UNIPROT TLR3 protein O15455 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 22310660 f lperfetto Together, these data indicated that E2F1 suppresses TLR3 transcription, but during immune stimulation, Rb is upregulated to block the inhibitory effect of E2F1 on TLR3, highlighting a role of Rb-E2F1 axis in the innate immune response in epithelial cells. SIGNOR-254136 0.2 UFD1 protein Q92890 UNIPROT AMFR protein Q9UKV5 UNIPROT up-regulates activity binding 17681147 t miannu Here we show that Ufd1 directly interacts with gp78 and functions as a cofactor. Ufd1 enhances the E3 activity of gp78, accelerates the ubiquitination and degradation of reductase, and eventually promotes receptor-mediated uptake of low-density lipoprotein. SIGNOR-252425 0.2 KDM5B protein Q9UGL1 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-264304 0.2 CAMK4 protein Q16566 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates activity phosphorylation Ser467 RPLGRTQsAPLPQNA BTO:0001938 11470791 t llicata CaMKIV phosphorylates HDAC4 in vitro and promotes its nuclear-cytoplasmic shuttling in vivo. | Thus, CaMKIV can phosphorylate HDAC4 at Ser-467 and/or Ser-632 in vitro. | Collectively, our results suggest that CaMKIV reverses the transcriptional repression activity of HDAC4 by stimulating the mobilization of HDAC4 out of the nucleus. SIGNOR-250711 0.604 CBL protein P22681 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates ubiquitination 9606 BTO:0000782 11526404 t lperfetto Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner. SIGNOR-110060 0.682 TGFB1 protein P01137 UNIPROT CDK2 protein P24941 UNIPROT down-regulates 9606 SIGNOR-C16 10611320 f gcesareni Tgf-beta treatment resulted in the specific inactivation of cyclin cdk2 complexes caused by absence of the activating thr(160) phosphorylation on cdk2. SIGNOR-73537 0.285 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser66 GVYATRSsAVRLRSS -1 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248884 0.288 dehydroepiandrosterone chemical CHEBI:28689 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 9489820 t systemic lupus erythematosus gcesareni SIGNOR-251707 0.8 CYCS protein P99999 UNIPROT Apoptosome complex SIGNOR-C230 SIGNOR form complex binding -1 10206961 t lperfetto  APAF-1 binds and hydrolyzes ATP or dATP to ADP or dADP, respectively. The hydrolysis of ATP/dATP and the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9.  SIGNOR-256430 0.83 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser2996 QECKRNLsDIDQSFN 9606 21149446 t gcesareni In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible. SIGNOR-170473 0.2 PRKCZ protein Q05513 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 17183360 t lperfetto Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) SIGNOR-217370 0.477 PRKCD protein Q05655 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation Ser318 GDKILQVsFKTNKSH 9606 20086103 t lperfetto Tandem phosphorylation of serines 221 and 318 by protein kinase cdelta coordinates mrna binding and nucleocytoplasmic shuttling of hurstabilization of mrna by the ubiquitous rna binding protein human antigen r (hur), a member of the embryonic lethal abnormal vision (elav) protein family, requires canonical binding to au-rich element (are)-bearing target mrna and export of nuclear hur-mrna complexes to the cytoplasm. In human mesangial cells (hmc) both processes are induced by angiotensin ii (angii) via protein kinase cdelta (pkcdelta)-triggered serine phosphorylation of hur. SIGNOR-163528 0.622 DUSP23 protein Q9BVJ7 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation 9606 27281782 t miannu In particular, DUSP23 can dephosphorylate and inactivate MAPK3 ( xref ).|In particular, DUSP23 can dephosphorylate and inactivate MAPK3. SIGNOR-277103 0.315 MAPK3 protein P27361 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser255 HATSGALsPAKDCGS 9606 9535909 t lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. SIGNOR-249465 0.626 ESR2 protein Q92731 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 BTO:0001264 22169964 f miannu 17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice SIGNOR-253475 0.2 FXN protein Q16595 UNIPROT Mitochondrial Fe-S Cluster Assembly Complex complex SIGNOR-C276 SIGNOR form complex binding -1 27519411 t lperfetto As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry. SIGNOR-262125 0.782 CSNK2A1 protein P68400 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Ser608 ENTEDQYsLVEDDED -1 14729945 t miannu Protein kinase CK2 phosphorylates p85α on Ser608 when p85α is free but not when it is complexed with p110α.  SIGNOR-276005 0.248 MAPK1 protein P28482 UNIPROT PPARG protein P37231 UNIPROT down-regulates phosphorylation 9606 18596912 t lbriganti The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform SIGNOR-210182 0.469 USF2 protein Q15853 UNIPROT MYH9 protein P35579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 11467950 f miannu we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies. SIGNOR-222608 0.2 ANKRD11 protein Q6UB99 UNIPROT GAP43 protein P17677 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 29274743 t miannu Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.  SIGNOR-266736 0.2 FLT3 protein P36888 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 9606 26049753 f SIRT1 protein but not mRNA expression is increased in CD34+ cells from FLT3-ITD positive AML patients compared to FLT3 wild-type AML patients SIGNOR-261555 0.357 IL12A protein P29459 UNIPROT IL12B protein P29460 UNIPROT up-regulates binding 9606 7527811 t fspada However, a proper conformation required for high affinity binding is achieved only when p40 is associated with a p35 subunit or another p40 subunit. When p40 is associated with a p35 subunit, the heterodimer acts as an agonist mediating biologic activity. However, when p40 associates with another p40, the homodimer behaves as an antagonist in vitro SIGNOR-27619 0.843 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257981 0.8 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159381 0.2 BRD4 protein O60885 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR up-regulates activity binding 9606 16109377 t miannu Binding of Brd4 to Core P-TEFb Is Essential for Transcription. SIGNOR-266411 0.618 PTPN12 protein Q05209 UNIPROT WAS protein P42768 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 14707117 t gcesareni Furthermore, we demonstrate that pstpip serves as a scaffold protein between ptp-pest and wasp and allows ptp-pest to dephosphorylate wasp. This finding suggests a possible mechanism for ptp-pest to directly modulate actin remodeling through the pstpip-wasp interaction. SIGNOR-121136 0.455 TSC complex SIGNOR-C101 SIGNOR RHEB protein Q15382 UNIPROT down-regulates activity gtpase-activating protein 9606 15340059 t lperfetto Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb. SIGNOR-235895 0.914 PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18854138 f lperfetto Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. SIGNOR-181624 0.616 TRPC6 protein Q9Y210 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 12032305 t Members of the transient receptor potential channel (TRPC) family have been characterized as molecular substrates mediating receptor-activated cation influx SIGNOR-253339 0.8 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR SOX2 protein P48431 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269253 0.834 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr612 TLHTDDGyMPMSPGV 10116 11416002 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells SIGNOR-235971 0.912 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Thr2035 GIKTSEGtPGFRAPE 9606 BTO:0000938 20595391 t lperfetto Three putative autophosphorylation sites (thr-2031, ser-2032, and thr-2035) have been identified within the activation segment of the lrrk2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of lrrk2. SIGNOR-166474 0.2 LEF1 protein Q9UJU2 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19620402 f miannu We have identified LEF-1 as a decisive transcription factor in granulopoiesis controlling proliferation and granulocytic differentiation by direct activation of its target gene, C/EBPalpha. SIGNOR-254551 0.355 DUSP1 protein P28562 UNIPROT MAPK9 protein P45984 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 8626452 t fstefani We assayed the relative ability of mkp-2, pac1, and mkp-1 to dephosphorylate erk2 and the other related map kinases, jnk2 and p38. the dual specific phosphatases pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively. SIGNOR-40879 0.671 MAPK1 protein P28482 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 BTO:0000567 9628874 t gcesareni Activated following phosphorylation at thr-182 by p38-alpha/mapk14, p38-beta/mapk11, erk2/mapk1, erk3/mapk6, and erk4/mapk4. SIGNOR-58127 0.492 ABL1 protein P00519 UNIPROT BTK protein Q06187 UNIPROT unknown phosphorylation Tyr223 LKKVVALyDYMPMNA 9606 BTO:0000567 12445832 t gcesareni In this report we describe for the first time that c-Abl and Btk physically interact and that c-Abl can phosphorylate tyrosine 223 in the SH3 domain of Btk SIGNOR-245278 0.342 ATF3 protein P18847 UNIPROT PCLAF protein Q15004 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23593430 f gcesareni P15(paf) is a direct transcriptional target of atf3 SIGNOR-201850 0.2 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Ser272 SNHGLAIsPGMKTRI 9606 BTO:0000130 14499342 t lperfetto Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils. SIGNOR-118036 0.76 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 22123909 t gcesareni In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943) SIGNOR-177818 0.347 PPARGC1A protein Q9UBK2 UNIPROT ESRRA protein P11474 UNIPROT up-regulates activity 10090 18074631 f lperfetto The PGC1 transcriptional coactivators are major regulators of several crucial aspects of energy metabolism. PGC1alpha controls many aspects of oxidative metabolism, including mitochondrial biogenesis and respiration through the coactivation of many nuclear receptors, and factors outside the nuclear receptor family. ERRalpha, NRF1 and NRF2 are key targets of the PGC1s in mitochondrial biogenesis. SIGNOR-253392 0.921 PAX3 protein P23760 UNIPROT MEOX2 protein P50222 UNIPROT up-regulates activity binding -1 11423130 t miannu We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family. SIGNOR-222238 0.414 RET protein P07949 UNIPROT DOK4 protein Q8TEW6 UNIPROT up-regulates binding 9606 BTO:0000938 11470823 t gcesareni We identified two new family members, dok-4 and dok-5, that can directly associate with y1062 of c-ret dok-4 and dok-5 enhance c-ret-dependent activation of mitogen-activated protein kinase SIGNOR-109513 0.557 U0126.EtOH chemical CHEBI:90692 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207603 0.8 IL4R protein P24394 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 18852293 t lperfetto Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6. SIGNOR-249530 0.608 ACTB protein P60709 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR up-regulates 9606 BTO:0000007 19121306 f lperfetto However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin. SIGNOR-260610 0.31 MTHFD1 protein P11586 UNIPROT (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI up-regulates quantity chemical modification -1 18767138 t lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate SIGNOR-268249 0.8 SMARCC2 protein Q8TAQ2 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270708 0.83 LCK protein P06239 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr537 CKNVVPLyDLLLEML 9606 BTO:0000150;BTO:0000567 9500442 t gcesareni On the basis of these data and other reports describing the structure and activity of y537 mutations, as well as knowledge of the three-dimensional structure of the her ligand binding domain, we propose an alternate model wherein y537f mutation favors an open pocket conformation, affecting the estrogen binding kinetics and stability of the hormone-bound, transcriptionally active closed pocket conformation. SIGNOR-55853 0.391 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Thr8 MSSILPFtPPIVKRL 9606 19114991 t lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity SIGNOR-182975 0.733 ATM protein Q13315 UNIPROT RIF1 protein Q5UIP0 UNIPROT up-regulates activity binding 9606 15342490 t miannu Human Rif1, ortholog of a yeast telomeric protein, is regulated by ATM and 53BP1 and functions in the S-phase checkpoint. After induction of double-strand breaks (DSBs), Rif1 formed foci that colocalized with other DNA-damage-response factors. This response was strictly dependent on ATM (ataxia telangiectasia mutated) and 53BP1, but not affected by diminished function of ATR (ATM- and Rad3-related kinase), BRCA1, Chk2, Nbs1, and Mre11. SIGNOR-259059 0.476 ACVR2A protein P27037 UNIPROT ACVR1B protein P36896 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 12682303 t acerquone In this complex, the actrii??/Iib kinase phosphorylates alk4 within a glycine- and serine-rich region called the gs domain, and this phosphorylation event activates the alk4 kinase SIGNOR-99995 0.674 RPL10 protein P27635 UNIPROT YES1 protein P07947 UNIPROT down-regulates binding 9606 12138090 t miannu Several c-yes kinase activity assays indicated that the qm protein reduced c-yes kinase activity by 70% SIGNOR-90805 0.396 FFAR4 protein Q5NUL3 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256773 0.252 CDK1 protein P06493 UNIPROT PAPOLA protein P51003 UNIPROT up-regulates activity phosphorylation Ser545 PTSATKTsPLNSSGS 10090 BTO:0000964 34048556 t lperfetto Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity. SIGNOR-268339 0.261 IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Ser661 NVPDPSKsHIAQWSP -1 8511589 t lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238625 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252347 0.2 MCM7 protein P33993 UNIPROT MCM complex SIGNOR-C268 SIGNOR form complex binding 9606 19946136 t The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. SIGNOR-261677 0.76 PTPRC protein P08575 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity dephosphorylation Tyr1035 IETDKEYyTVKDDRD 10090 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells SIGNOR-248356 0.466 IL6 protein P05231 UNIPROT GCH1 protein P30793 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12859689 f miannu CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA. SIGNOR-252220 0.268 CDK1 protein P06493 UNIPROT PPP1R13L protein Q8WUF5 UNIPROT up-regulates activity phosphorylation Ser84 EPFGSRGsPRKAATD 9606 30105797 t done miannu Cyclin B/cyclin-dependent kinase 1 (CDK1) phosphorylates inhibitor of apoptosis stimulating protein of P53 (iASPP) to promote iASPP nucleus localization and its inhibitory effect on p53.  SIGNOR-273585 0.519 lysophosphatidic acid smallmolecule CHEBI:132742 ChEBI LPAR1 protein Q92633 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257528 0.8 PSMA6 protein P60900 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263368 0.826 MEF2D protein Q14814 UNIPROT DES protein P17661 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 25653159 t lperfetto Ectopic expression of myogenin and a specific Mef2 isoform induced myogenic differentiation without activating endogenous MyoD expression. Under these conditions, the regulatory sequences of late gene loci were not in close proximity, and these genes were prematurely activated. SIGNOR-241504 0.2 torkinib chemical CHEBI:90679 ChEBI PIK3CA protein P42336 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258269 0.8 GSK3B protein P49841 UNIPROT BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Ser175 SFVTPPQsHFVRVST 9606 BTO:0002181 26028025 t miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. SIGNOR-276911 0.262 HCK protein P08631 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr1253 EGSFESRyQQPFEDF -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249360 0.668 alvocidib hydrochloride chemical CHEBI:90998 ChEBI CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192467 0.8 AMPK complex SIGNOR-C15 SIGNOR CFTR protein P13569 UNIPROT down-regulates activity phosphorylation Ser768 LQARRRQsVLNLMTH 9606 19095655 t Luana AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites.|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions SIGNOR-72708 0.397 NOS1 protein P29475 UNIPROT nitric oxide smallmolecule CHEBI:16480 ChEBI up-regulates quantity chemical modification 9606 21890489 t gcesareni Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). They all utilize l-arginine and molecular oxygen as substrates SIGNOR-243957 0.8 CREB1 protein P16220 UNIPROT SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001379 34751390 t scontino CREB recognized and bound to the promoter of SLC5A5 to facilitate its transcription. SIGNOR-267137 0.27 SMARCB1 protein Q12824 UNIPROT SMARCA4 protein P51532 UNIPROT up-regulates activity binding 9606 10078207 t miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. SIGNOR-65438 0.942 PXDN protein Q92626 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0000567 29305973 f miannu Our findings show that Snai1 mediates repression of PXDN and consolidate a role for this ECM-modifier during EMT. SIGNOR-265253 0.7 PRKCA protein P17252 UNIPROT HMGN2 protein P05204 UNIPROT down-regulates phosphorylation Ser25 KDEPQRRsARLSAKP 9606 10739259 t lperfetto Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools. SIGNOR-76320 0.294 IKZF4 protein Q9H2S9 UNIPROT LNPEP protein Q9UIQ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003420 15894523 f miannu Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. SIGNOR-255406 0.2 HDAC1 protein Q13547 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity deacetylation -1 11486036 t miannu Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs. SIGNOR-268835 0.79 ERBB2 protein P04626 UNIPROT BBC3 protein Q9BXH1 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr58 PTLLPAAyLCAPTAP 9606 BTO:0000093 24236056 t miannu HER2 phosphorylates and destabilizes pro-apoptotic PUMA. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life. SIGNOR-276473 0.285 FASN protein P49327 UNIPROT long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity chemical modification 9606 15507492 t Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-267208 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NME1 protein P15531 UNIPROT up-regulates phosphorylation Ser120 GRNIIHGsDSVESAE 9606 18234856 t lperfetto Application of this approach to the discovery of cdk1-cyclin b substrates yielded identification of >70 substrates and phosphorylation sites. Many of these sites are known to be phosphorylated in vivo, but most of the proteins have not been characterized as cdk1-cyclin b substrates. SIGNOR-216825 0.274 SP1 protein P08047 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 10669635 f lperfetto These results suggest that PMA stimulates transcription of the Mn-SOD gene through an increase in Sp1 expression and thus implicate Sp1 as an effector mediating the PKC-signaling pathway elicited by extracellular signals. SIGNOR-271693 0.408 FOXL2 protein P58012 UNIPROT CYP19A1 protein P11511 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21862621 f miannu We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation. SIGNOR-254179 0.513 HDAC1 protein Q13547 UNIPROT MECP2/SIN3A/HDAC complex complex SIGNOR-C360 SIGNOR form complex binding 9606 BTO:0000567 9620804 t Luana We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases. SIGNOR-267738 0.743 CDK1 protein P06493 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates phosphorylation 9606 8114697 t lperfetto P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well SIGNOR-244847 0.474 HRAS protein P01112 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 9727023 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k we show here, however, that in vivo there are marked quantitative differences in the ability of ki- and ha-ras to activate raf-1 and phosphoinositide 3 kinase. the mechanism of raf-1 activation is complex, but it is clear that one important role of ras is to recruit raf-1 to the plasma membrane where a series of events is initiated that ultimately leads to full raf-1 activation. These events include tyrosine, serine, and threonine phosphorylation plus interactions with ras, phospholipids, 14-3-3 proteins and their associated proteins, and possibly dimerization. SIGNOR-59816 0.814 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM BTK protein Q06187 UNIPROT down-regulates activity chemical inhibition -1 24556163 t miannu BTK is a member of the TEC family of non-receptor tyrosine kinases whose deregulation has been implicated in a variety of B-cell-related diseases. We have used structure-based drug design in conjunction with kinome profiling and cellular assays to develop a potent, selective, and irreversible BTK kinase inhibitor, QL47, which covalently modifies Cys481. QL47 inhibits BTK kinase activity with an IC50 of 7 nM, inhibits autophosphorylation of BTK on Tyr223 in cells with an EC50 of 475 nM, and inhibits phosphorylation of a downstream effector PLCγ2 (Tyr759) with an EC50 of 318 nM. SIGNOR-262238 0.8 LRRK2 protein Q5S007 UNIPROT SH3GL2 protein Q99962 UNIPROT down-regulates phosphorylation 9606 22998870 t miannu We show that lrrk2 affects synaptic endocytosis by phosphorylating endoa at s75, a residue in the bar domain / our work uncovers a regulatory mechanism that indicates that reduced lrrk2 kinase activity facilitates endoa membrane association, while increased kinase activity inhibits membrane association. SIGNOR-192075 0.484 F2R protein P25116 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256875 0.375 MECP2 protein P51608 UNIPROT MECP2/SIN3A/HDAC complex complex SIGNOR-C360 SIGNOR form complex binding 10116 9620804 t Luana We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases. SIGNOR-265070 0.689 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT unknown phosphorylation Thr76 LRASRLGtTRTPSSY 9606 BTO:0000971 10574968 t lperfetto We developed antibodies specifically recognizing the kinase-dependent phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies, phosphorylation of desmin was observed specifically at the cleavage furrow in late mitotic Saos-2 cells. We then found that treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin SIGNOR-249031 0.322 BTG2 protein P78543 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22493435 f miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 SIGNOR-254649 0.376 AKT2 protein P31751 UNIPROT ACLY protein P53396 UNIPROT unknown phosphorylation Ser455 PAPSRTAsFSESRAD 10116 BTO:0000443 12107176 t gcesareni Taken together, these results demonstrate that serine 454 of ATP-citrate lyase is a novel and major in vivo substrate for protein kinase B. SIGNOR-245263 0.291 GSK3B protein P49841 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates quantity by destabilization phosphorylation Thr1363 HVQSVLLtPQDEFFI 9606 BTO:0002181 19797085 t miannu We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity.  SIGNOR-276264 0.36 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr383 GETSLMRtLCGTPTY 9606 BTO:0000007 11901158 t gcesareni Phosphorylation of thr-68 by the ataxia telangiectasia-mutated is necessary for efficient activation of chk2 when cells are exposed to ionizing radiation. By an unknown mechanism, this initial event promotes additional autophosphorylation events including modifications of thr-383 and thr-387 SIGNOR-116127 0.2 DOK1 protein Q99704 UNIPROT Av/b6 integrin complex SIGNOR-C179 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257694 0.2 DOCK4 protein Q8N1I0 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 BTO:0001976 32009906 t miannu DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia.  SIGNOR-266823 0.568 SGK3 protein Q96BR1 UNIPROT GSK3A protein P49840 UNIPROT down-regulates activity phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000007 16543730 t lperfetto Phosphorylation of GSK3 by PKB or SGK1 inhibits GSK3 activity|estern blotting using an antibody specific for the PKB/SGK1 consensus phosphorylation site in GSK3a/beta (serine 21 and 9 respectively) revealed an increase in GSK3a/beta phosphorylation in human embryonic kidney 293 (HEK293) cells overexpressing wild type SGK1, constitutively active SGK1, but not catalytically inactive SGK1.|The effect of SGK1 was mimicked by PKB and SGK3. SIGNOR-249165 0.361 Scribble_complex_DLG2-LLGL1_variant complex SIGNOR-C510 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 f miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270910 0.7 PBK protein Q96KB5 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation Ser495 GVLARKMsLGGGRPY 9606 BTO:0002181 31378785 t miannu We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1.  SIGNOR-277473 0.2 PLK1 protein P53350 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity phosphorylation Thr680 SKMQLLEtEFSHTVG -1 18922800 t miannu These findings indicate mechanistic roles contributed by protein phosphorylation and Plk1 to the SAC activity of Mad1.Here, we have studied the phosphorylation of Mad1 and mapped using liquid chromatography-tandem mass spectrometry several phosphorylated amino acids in this protein. One phosphorylated residue, Thr680, was characterized to be important for the kinetochore localization of Mad1 and its SAC function. SIGNOR-276173 0.441 CDK2 protein P24941 UNIPROT WEE1 protein P30291 UNIPROT down-regulates quantity by destabilization Ser123 EEGFGSSsPVKSPAA 9606 BTO:0000567 16085715 t miannu PS123 primes CK2 to phosphorylate S121, resulting in creation of a β-TrCP phosphodegron (EEGFGpS121) that is responsible for the instability of Wee1A during interphase.  SIGNOR-276039 0.652 CTSG protein P08311 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Phe43 ATLDPRSfLLRNPND -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. SIGNOR-263562 0.577 Telatinib chemical CID:9808844 PUBCHEM KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207224 0.8 TFEB protein P19484 UNIPROT HEXA protein P06865 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276541 0.311 PRKCQ protein Q04759 UNIPROT CARD11 protein Q9BXL7 UNIPROT down-regulates activity phosphorylation Ser893 SPRLSRAsFLFGQLL -1 35230873 t miannu PKCθ-catalyzed CARD11 Ser893 phosphorylation impairs CBM complex formation SIGNOR-276298 0.766 NFX1 protein Q12986 UNIPROT HLA-DRA protein P01903 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 7964459 t Luana A novel cysteine-rich sequence-specific DNA-binding protein interacts with the conserved X-box motif of the human major histocompatibility complex class II genes via a repeated Cys-His domain and functions as a transcriptional repressor SIGNOR-266224 0.405 CASP6 protein P55212 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp333 DTVAENDdGGFSEEW -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261753 0.379 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1023 DLVDAEEyLVPQQGF 9606 1706616 t Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. SIGNOR-251129 0.2 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2H protein P62256 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271328 0.747 diisononyl phthalate chemical CHEBI:35459 ChEBI monoisononyl phthalate chemical CHEBI:132593 ChEBI up-regulates quantity precursor of -1 33125036 t miannu The primary metabolite of DiNP is monoisononyl-phthalate (MiNP) and the secondary metabolites include three oxidative derivatives of DiNP, which have been identified mainly in urine: mono-oxoisononyl phthalate (MOINP or oxo-MiNP), mono-carboxyisooctyl phthalate (MCIOP, MCOP or cx-MiNP), and mono-hydroxyisononyl phthalate (MHINP or OH-MiNP). SIGNOR-268771 0.8 ACAT1 protein P24752 UNIPROT IDH2 protein P48735 UNIPROT down-regulates activity acetylation Lys413 VESGAMTkDLAGCIH 9606 BTO:0001545 34289383 t lperfetto Mitochondrial acetyltransferase ACAT1 and deacetylase SIRT3 are responsible for acetylation and deacetylation, respectively, at K413 of mIDH2|K413 acetylation inhibits mIDH2 by simultaneously attenuating dimer formation from monomers and destabilizing dimers for conversion to monomers SIGNOR-267627 0.291 SMO protein Q99835 UNIPROT GNG2 protein P59768 UNIPROT up-regulates binding 9606 16885213 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-148595 0.358 GSK3B protein P49841 UNIPROT H1-5 protein P16401 UNIPROT up-regulates phosphorylation Thr11 TAPAETAtPAPVEKS 9606 BTO:0000567 19136008 t lperfetto We found that threonine 10 of h1.5 can be phosphorylated by glycogen synthase kinase-3 in vitro. We have generated an antiserum specific for human h1.5 phosphorylated at threonine 10. Immunofluorescence labeling of hela cells with this antiserum revealed that the phosphorylation at this site appears in prometaphase and disappears in telophase, and that this hyperphosphorylated form of h1.5 is mainly chromatin-bound in metaphase when chromatin condensation is maximal. SIGNOR-183325 0.2 GARS1 protein P41250 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 24898252 t miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. SIGNOR-270480 0.8 ALK protein Q9UM73 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 9606 BTO:0000785 12185581 t gcesareni Anaplastic lymphoma kinase (alk), which turned out to be one of these phosphoproteins, was constitutively activated and associated with the ptb domain of shcc in three neuroblastoma cells. In vitro kinase assay revealed that shcc is a potent substrate of the activated alk kinase. The alk gene locus was significantly amplified in both of these cell lines, suggesting that gene amplification leads to constitutive activation of the alk kinase, which results in hyperphosphorylation of shcc. SIGNOR-91534 0.467 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS -1 8422248 t lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. SIGNOR-248928 0.719 EIF3A protein Q14152 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266400 0.918 PASK protein Q96RG2 UNIPROT EEF1A1 protein P68104 UNIPROT unknown phosphorylation 9606 BTO:0000567 17595531 t gcesareni Kinase assays, mass spectrometry and site-directed mutagenesis revealed PASKIN auto-phosphorylation as well as eEF1A1 target phosphorylation mainly but not exclusively at Thr432. SIGNOR-245862 0.381 PTGS2 protein P35354 UNIPROT prostaglandin G2(1-) smallmolecule CHEBI:82629 ChEBI up-regulates quantity chemical modification -1 7592599 t Luana [14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2, SIGNOR-269770 0.8 RPS6KA2 protein Q15349 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 20385620 t gcesareni Rsk2 is activated by treatment with tumor necrosis factor-alfa (tnf-alfa) and directly phosphorylates ikbalfa at ser-32, leading to ikbalfa degradation. SIGNOR-164790 0.27 PPP2CA protein P67775 UNIPROT EEF2 protein P13639 UNIPROT up-regulates dephosphorylation Thr57 RAGETRFtDTRKDEQ 9606 phosphorylation:Thr57 RAGETRFtDTRKDEQ 8386634 t gcesareni Protein phosphatases-2a and -2c (pp-2a and pp-2c) can each efficiently dephosphorylate phosphorylated eef-2 SIGNOR-38561 0.413 PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 BTO:0001130 23633519 t lperfetto Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. SIGNOR-236490 0.8 D-serine smallmolecule CHEBI:16523 ChEBI NMDA receptor_2B complex SIGNOR-C348 SIGNOR up-regulates activity chemical activation 9606 BTO:0002609 12393813 t lperfetto D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically SIGNOR-268278 0.8 PRKDC protein P78527 UNIPROT NR3C1 protein P04150 UNIPROT unknown phosphorylation Ser508 QQATTGVsQETSENP -1 9038175 t lperfetto Phosphorylation of the GR fusion protein by DNA-PK mapped to a single site, Ser-527. This site occurs adjacent the GR nuclear localization sequence between the DNA and ligand binding domains of GR, and thus its phosphorylation, if confirmed, has the potential to affect receptor function in vivo. SIGNOR-248965 0.356 IKBKB protein O14920 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 11815618 t lperfetto Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. The phosphorylation of I_Balpha on Ser32 and Ser36 is initiated by an IkapapB kinase (IKK) complex that includes a catalytic heterodimer composed of I_B kinase 1 (IKK-1) and IkapapB kinase 2 (IKK-2) as well as a regulatory adaptor subunit, NF-kappaB essential modulator. SIGNOR-249366 0.92 PRKCD protein Q05655 UNIPROT PTPRA protein P18433 UNIPROT up-regulates activity phosphorylation Ser213 PLLARSPsTNRKYPP 9606 11676480 t lperfetto In this process, PTPalpha Ser-180 and Ser-204 phosphorylation is critical for the induction of phosphatase activity, which is required for dephosphorylation of pp60(c-src). Taken together, we demonstrate the physical and functional association between PI 3-kinase, PKCdelta and PTPalpha in a signaling complex that mediates the antitumor activity of the somatostatin analogue TT-232. SIGNOR-249114 0.334 DAB2IP protein Q5VWQ8 UNIPROT ERN1 protein O75460 UNIPROT up-regulates activity binding 9606 BTO:0001176 27858941 t miannu DAB2IP binds IRE1α, and was shown to be required for activation of this signaling cascade in endothelial cells. IRE1α can trigger pro-apoptotic JNK signaling through recruitment of the TRAF2–ASK1 complex. DAB2IP facilitates IRE1α activation, and participates in a signaling complex required to induce TRAF2-dependent ASK1 activation and JNK phosphorylation. SIGNOR-254749 0.376 calcium(2+) smallmolecule CHEBI:29108 ChEBI Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 29953871 f miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. SIGNOR-264955 0.7 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser83 PTIPGVTsPSSDEPP 9606 9204908 t miannu MTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E. SIGNOR-250292 0.924 SLC36A1 protein Q7Z2H8 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI up-regulates quantity relocalization 9606 12748860 t lperfetto Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut. SIGNOR-264737 0.8 PML protein P29590 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates binding 9606 15356634 t gcesareni Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome. SIGNOR-128735 0.53 TMC2 protein Q8TDI7 UNIPROT Hair cells mechanotransduction channel complex SIGNOR-C290 SIGNOR form complex binding 10090 BTO:0000630 23217710 t lperfetto The pore forming subunits of the hair cells mechanotransduction channel still need to be identified, but some candidates have emerged including TMC-1,TMC-2 (Kawashima et al., 2011), Piezo1 and Piezo2 (Coste et al., 2010; Coste et al., 2012). SIGNOR-262570 0.403 ENPP1 protein P22413 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI down-regulates quantity chemical modification 20923972 t Phosphodiesterases Catalyze Hydrolysis of cAMP-bound to Regulatory Subunit of Protein Kinase A and Mediate Signal Termination SIGNOR-253018 0.8 GPR84 protein Q9NQS5 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257099 0.252 MFNG protein O00587 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 11346656 t gcesareni These observations indicate that the fringe proteins directly modify notch2, which is consistent with the recent finding that fringe is a glycosyltransferase that directly modifies notch (30, 31). It was further indicated that lfng does this at a site from the n terminus through the 15th egf repeat of notch2, and mfng does so at a site from the 23rd through the 29th egf repeat of notch2. SIGNOR-107708 0.674 CCKAR protein P32238 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257035 0.254 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr798 VSRNAAEyLLSSGIN 9606 16912036 t Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. SIGNOR-260812 0.2 GRK3 protein P35626 UNIPROT CCR5 protein P51681 UNIPROT down-regulates activity phosphorylation Ser336 QEAPERAsSVYTRST 9534 BTO:0000298 10085131 t Serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. CCR5 phosphorylation and desensitization through a GRK-mediated mechanism SIGNOR-251463 0.2 MYO10 protein Q9HD67 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 27580874 f miannu Myosin X is required for filopodia formation and extension. myosin X functions as an antiparallel dimer in cells with a unique geometry optimized for movement on actin bundles. Myosin X facilitates initiation and elongation of filopodia, which implies favouring formation of parallel bundled F-actin filaments. SIGNOR-268284 0.7 CAMK2A protein Q9UQM7 UNIPROT RIMS1 protein Q86UR5 UNIPROT up-regulates phosphorylation Ser242 PSAPPDRsKGAEPSQ 9606 BTO:0000938 BTO:0000142 12871946 t gcesareni Two serine residues in rim1 (ser-241 and ser-287) and one serine residue in rim2 (ser-335) were required for 14-3-3 binding. Incubation with ca2+/calmodulin-dependent protein kinase ii greatly stimulated the interaction of recombinant n-terminal rim but not the s241/287a mutant with 14-3-3, SIGNOR-103886 0.353 DAGLB protein Q8NCG7 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI down-regulates quantity chemical modification 9606 26787883 t miannu Diacylglycerol lipases (DAGL√鬱 and DAGL√é¬≤) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. SIGNOR-264263 0.8 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser29 ATKAARKsAPSTGGV 9606 18508628 t Ser 27 (29) phosphorylation of H3 isinhibitory as induces transcription. gcesareni In addition to ser10, msk was also found to phosphorylate a second site on h3, ser28 (75). It should be noted that while both ser10 and ser28 in h3 are extensively phosphorylated during mitosis, this is independent of msks and is catalysed by aurora kinases. In contrast, msks only phosphorylate a small proportion of the total cellular histone h3 in response to mitogens or stress. The spatial distribution of ser10 and ser28 phosphorylation is very tightly regulated in cells. In vitro, msk1 will phosphorylate one histone h3 molecule on both ser10 and ser28. Surprisingly it has been shown that in cells msk phosphorylates either ser10 or ser28 but not both on individual nucleosomes. SIGNOR-178708 0.2 3-isobutyl-1-methylxanthine chemical CHEBI:48518 ChEBI CEBPA protein P49715 UNIPROT up-regulates 9606 11279134 f fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin SIGNOR-106478 0.8 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 9606 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89268 0.402 MARCHF9 protein Q86YJ5 UNIPROT HLA-DQA1 protein P01909 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271538 0.2 ABL1 protein P00519 UNIPROT TP63 protein Q9H3D4 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr171 AIPSNTDyPGPHSFD 9606 19783996 t Manara In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. SIGNOR-260932 0.524 RPS3 protein P23396 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262421 0.89 CCND1 protein P24385 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates binding 9606 15713663 t gcesareni Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5. SIGNOR-134053 0.481 GDF5 protein P43026 UNIPROT ID1 protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004291 16716349 f Regulation miannu GDF5 induces ID1 and ID3 in HUVSMC by a smad-dependent, MAPK-independent pathway. GDF5 binds to specific receptors, thereby inducing phosphorylation and translocation of smad1 to the nucleus where it is involved in the regulation of transcription. SIGNOR-251871 0.285 beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI PFKM protein P08237 UNIPROT up-regulates activity binding 9606 19454274 t The PFKFB enzymes synthesize fructose-2,6-bisphosphate (F2,6BP) which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. PFK-1 is inhibited by ATP when energy stores are abundant and F2,6BP can override this inhibition and enhance glucose uptake and glycolytic flux SIGNOR-267267 0.8 CDK2 protein P24941 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates activity phosphorylation Ser163 KSQKLLRsPRKPTRK 12560341 t llicata  A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus.  SIGNOR-250733 0.734 CHRM3 protein P20309 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257018 0.561 Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 20223217 t miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. SIGNOR-270440 0.8 paliperidone chemical CHEBI:82978 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258564 0.8 PPP1R9B protein Q96SB3 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR up-regulates activity binding 9606 BTO:0000938 10194355 t miannu In the present study, the interaction between PP1 and spinophilin, a neuronal protein that targets PP1 to dendritic spines, has been characterized. . These studies support the notion that spinophilin functions in vivo as a neuronal PP1 targeting subunit by directing the enzyme to postsynaptic densities and regulating its activity toward physiological substrates. SIGNOR-269178 0.765 PINK1 protein Q9BXM7 UNIPROT UBA52 protein P62987 UNIPROT up-regulates phosphorylation Ser65 DYNIQKEsTLHLVLR 10090 BTO:0002572 24784582 t Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential. SIGNOR-270342 0.358 NLGN2 protein Q8NFZ4 UNIPROT NRXN3 protein Q9HDB5 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264171 0.819 TAGAP protein Q8N103 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260524 0.376 N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide chemical CHEBI:63082 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Thus, overall, salmeterol is a highly selective β2-adrenoceptor agonist because of its higher β2-affinity and not because of higher β2-intrinsic efficacy. A similar reasoning can be applied to formoterol, although this agonist has higher intrinsic efficacy at all three receptors (rank 6, 8 and 5 at β1, β2 and β3). SIGNOR-257854 0.8 taurine smallmolecule CHEBI:15891 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 9606 BTO:0000007 9009272 t inferred from family member miannu For each mutant GlyR we examined the agonist efficacies of taurine and beta-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where beta-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human alpha-1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and beta-alanine act as full agonists of huma nalpha-1 GlyRs when expressed in this system. SIGNOR-267793 0.8 MLNR protein O43193 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257222 0.252 TNPO1 protein Q92973 UNIPROT NUP153 protein P49790 UNIPROT up-regulates activity relocalization 29970603 t lperfetto TNPO1 only mediates the nuclear import of a subset of proteins.|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import SIGNOR-262100 0.513 C8G protein P07360 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 t lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer SIGNOR-263446 0.588 CDK1 protein P06493 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 BTO:0001130 18408765 t gcesareni Overexpression of cdk1 inhibits the transcriptional activity of foxo1 in pca cells through s249 phosphorylation on foxo1. SIGNOR-252890 0.525 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu61 EFVQGNLeRECMEEK 10090 BTO:0001103 11133752 t lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. SIGNOR-263688 0.67 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR MLLT3 protein P42568 UNIPROT down-regulates quantity relocalization 9606 BTO:0000567 14603337 t irozzo The AF4–AF9 interaction is maintained by the MLL–AF4 fusion protein, and expression of the MLL–AF4 fusion can alter the subnuclear localization of AF9. This fusion does, however, contain the AF9 interaction domain we have identified. These findings imply that the interaction that we have characterized plays an important role in MLL leukemogenesis. Furthermore, we show that MLL–AF4 does interact with AF9 and has the ability to misdirect AF9 expression from the AF4 body to alternative foci within the nucleolus. SIGNOR-255857 0.2 CSNK2A2 protein P19784 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates activity phosphorylation Ser394 EDAVHEDsGDEDGED 9606 BTO:0000567 12082111 t llicata HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2. SIGNOR-251001 0.398 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Thr384 LCEDLPGtEDFVGHQ -1 8662852 t we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). SIGNOR-251199 0.682 ENY2 protein Q9NPA8 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269577 0.575 PRKCA protein P17252 UNIPROT VCL protein P18206 UNIPROT unknown phosphorylation Ser1113 VREAEAAsIKIRTDA -1 11741957 t lperfetto PKC Phosphorylates Serines 1033 and 1045 in Helix H5 SIGNOR-249129 0.399 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser487 AQLAGSDsDLDSDDE 9606 23263282 t lperfetto Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. ere, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2) SIGNOR-200202 0.2 Complement C1 complex complex SIGNOR-C309 SIGNOR C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Arg756 KGQAGLQrALEILQE -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263436 0.629 KLF1 protein Q13351 UNIPROT CDKN2C protein P42773 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 17442339 t Luana Thus, EKLF is a direct regulator of p18INK4c gene expression, and much of EKLF's role in driving erythroid cell differentiation may occur via p18INK4c. SIGNOR-266046 0.269 POLR2L protein P62875 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266142 0.831 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2Q1 protein Q7Z7E8 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271338 0.436 AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. SIGNOR-244292 0.2 ITGB1BP1 protein O14713 UNIPROT Av/b5 integrin complex SIGNOR-C178 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257661 0.288 CEP152 protein O94986 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 t lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. SIGNOR-271724 0.282 TUBA3C protein P0DPH7 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. SIGNOR-269724 0.7 WNT1 protein P04628 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity 9606 BTO:0001103 21902831 f gcesareni Wnt1 and wnt7a stimulation of precursor cells activates protein kinase a (pka), which, through the phosphorylation of creb, induces the expression of the myogenic transcription factors myf5, myod and pax3, resulting in the myogenic commitment of embryonic precursors. SIGNOR-176572 0.27 capecitabine chemical CHEBI:31348 ChEBI TYMS protein P04818 UNIPROT down-regulates activity chemical inhibition 9606 15866500 t miannu These findings suggest that the mechanism of antiproliferative toxicity of capecitabine is at least partly due to TS inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). SIGNOR-259354 0.8 U2 snRNP complex complex SIGNOR-C479 SIGNOR RNA_splicing phenotype SIGNOR-PH201 SIGNOR up-regulates 9606 30765414 f lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270676 0.7 MAPK7 protein Q13164 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation 9606 BTO:0001271 20832753 t gcesareni We found that bmk1 interacted with promyelocytic leukemia protein (pml), and inhibited its tumor-suppressor function through phosphorylation. SIGNOR-167947 0.487 ADSS2 protein P30520 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI down-regulates quantity chemical modification 9606 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267343 0.8 BMS 794833 chemical CID:44155856 PUBCHEM KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190419 0.8 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser358 WPLSRTRsEPLPPSA 9606 18339811 t Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. SIGNOR-248648 0.322 MAPK14 protein Q16539 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 BTO:0000150 BTO:0000975 11145955 t tpavlidou Subsequent studies with dominant negative elk-1, wild type, and variant gal4-elk-1 fusion proteins confirmed that phosphorylation of elk-1 at serines 383 and 389 in the c-terminal region of elk-1 is an important downstream target associated with activation of an sre by e2. Both e2 (er?-Dependent) and growth factors (er?-Independent) activated the sre in breast cancer cells via the ras/mapk pathway SIGNOR-85510 0.506 BIRC3 protein Q13489 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 16603398 t amattioni In this report, we show that ciap1 and ciap2 promote cancer cell survival by functioning as e3 ubiquitin ligases that maintain constitutive ubiquitination of the rip1 adaptor protein. SIGNOR-145855 0.737 MAPK8 protein P45983 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 20630875 t gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress. SIGNOR-166694 0.322 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation 9606 22094256 t tpavlidou We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1, thereby maintain expression of g1/s phase genes, suppress the levels of reactive oxygen species (ros), and protect cancer cells from senescence. SIGNOR-177266 0.608 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation Tyr525 ALRADENyYKAQTHG 9606 9820500 t lperfetto These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520 SIGNOR-246617 0.2 E2F5 protein Q15329 UNIPROT CBX5 protein P45973 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000815 21374739 t Luana We identified for E2F5 a repressor function for HP1a expression. SIGNOR-261591 0.2 PAK4 protein O96013 UNIPROT PAK4 protein O96013 UNIPROT up-regulates activity phosphorylation Ser474 KEVPRRKsLVGTPYW 10090 BTO:0000944 11668177 t lperfetto Here we demonstrate that PAK4 is frequently overexpressed in human tumor cell lines of various tissue origins. We also have identified serine (Ser-474) as the likely autophosphorylation site in the kinase domain of PAK4 in vivo. Mutation of this serine to glutamic acid (S474E) results in constitutive activation of the kinase. SIGNOR-235867 0.2 abiraterone acetate chemical CHEBI:68639 ChEBI CYP17A1 protein P05093 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205573 0.8 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates 9502314 f lperfetto Inclusion body formation and other aggregates formed during protein folding have been assumed to arise from hydrophobic aggregation of the unfolded or denatured states SIGNOR-262268 0.7 HOXB8 protein P17481 UNIPROT PBX3 protein P40426 UNIPROT up-regulates activity binding 9606 BTO:0001545 11571641 t miannu the ability of HoxB8 to heterodimerizes with endogenous Pbx proteins on DNA alters gene transcription in a manner that prevents progression through an intrinsic genetic differentiation program. In conjunction with Pbx, HoxB8 could alter transcription of Pbx target genes by direct or indirect mechanisms. SIGNOR-223149 0.497 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr312 ISYDIPPtPGNTYQI 9606 15379552 t lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) SIGNOR-129196 0.2 TRIM38 protein O00635 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 22323536 t miannu As an E3 ligase, TRIM38 bound to TRAF6 and promoted K48-linked polyubiquitination, which led to the proteasomal degradation of TRAF6.  SIGNOR-272009 0.44 KIF4A protein O95239 UNIPROT PRC1 protein O43663 UNIPROT up-regulates activity binding 9606 15297875 t miannu These results suggest that KIF4 and its binding partner PRC1 play essential roles in the organization of central spindles and midzone formation. KIF4 deficiency leads to mislocalization of PRC1, MKLP1, CENP-E and chromosomal passenger proteins SIGNOR-265988 0.584 PTPN2 protein P17706 UNIPROT WASL protein O00401 UNIPROT down-regulates dephosphorylation Tyr256 RETSKVIyDFIEKTG 9606 16293614 t gcesareni Similarly, the t cell phosphatase has a 30-fold lower kcat/km toward autoinhibited p-n-wasp than toward the isolated p-gbd, and again this effect is largely reversed by that cdc42 SIGNOR-141652 0.294 HIF-1 complex complex SIGNOR-C418 SIGNOR BID protein P55957 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27692180 t miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. SIGNOR-267457 0.2 OST-B complex complex SIGNOR-C536 SIGNOR Protein_glycosylation phenotype SIGNOR-PH144 SIGNOR up-regulates 9606 31831667 t miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  SIGNOR-272056 0.7 ESR1 protein P03372 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 BTO:0001264 24493753 f miannu The effects of β-oestradiol (E2), the biologically active form of oestrogen, are classically mediated by two types of oestrogen receptor (ER): ERα and ERβ. E2 has both non-genomic and genomic effects upon VGSC expression/activity; and (ii) transcriptionally, E2 (via ERα) downregulates functional VGSC (nNav1.5) expression in BCa cells. SIGNOR-253467 0.2 CYP19A1 protein P11511 UNIPROT androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI down-regulates quantity chemical modification 9606 BTO:0000975 27702664 t lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively SIGNOR-268672 0.8 ATM protein Q13315 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates phosphorylation Thr643 EELNKRQtQKDLEHA 9606 17396146 t gcesareni The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells. SIGNOR-154171 0.394 MZF1 protein P28698 UNIPROT CCN3 protein P48745 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25899830 f miannu we report the regulation of the CTGF and NOV genes by Myeloid Zinc Finger-1 (MZF-1), a hematopoietic transcription factor. We show the interaction of MZF-1 with the CTGF and NOV promoters in several cell types. Up-regulation of MZF-1 via calcitriol and vitamin A induces expression of CTGF and NOV, implicating a role for these vitamins in the functions of these two genes. Lastly, knockdown of MZF1 reduces levels of CTGF and NOV. SIGNOR-226356 0.2 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 10581258 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-72699 0.764 TRIP12 protein Q14669 UNIPROT NAE1 protein Q13564 UNIPROT down-regulates quantity by destabilization ubiquitination -1 SIGNOR-C131 18627766 t miannu Our data suggest that that TRIP12 promotes degradation of APP-BP1 by catalyzing its ubiquitination, which in turn modulates the neddylation pathway. SIGNOR-266780 0.443 CDK1 protein P06493 UNIPROT MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr194 NMMDILTtPSMAKPR 8355 22354989 t gcesareni We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop SIGNOR-243414 0.492 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1924 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273038 0.556 PRC1 protein O43663 UNIPROT Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 9606 15297875 f miannu These results suggest that KIF4 and its binding partner PRC1 play essential roles in the organization of central spindles and midzone formation. KIF4 deficiency leads to mislocalization of PRC1, MKLP1, CENP-E and chromosomal passenger proteins SIGNOR-265987 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244580 0.2 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT up-regulates activity phosphorylation Ser661 QNEFAGFsYTNPEFV 9606 17115692 t lperfetto The catalytic or kinase domain requires phosphorylation at three sites for full activation (24, 25): ? Phosphorylation of threonine 500 (thr-500) in the activation loop by the upstream kinase pdk-1 is a prerequisite for the maturation of the enzyme (26), which subsequently leads to autophosphorylation at threonine 641 (thr-641) in the turn motif and serine 660 (ser-660) in the hydrophobic motif SIGNOR-150861 0.2 SDC4 protein P31431 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity binding 9606 BTO:0002314 BTO:0001103 23290138 t apalma Rac1 is associated with Sdc4 and is activated by FN binding […] We observed that over-expression of Fzd7, or stimulation with FN resulted in increased levels of active Rac1 in primary myoblasts SIGNOR-255849 0.482 pravastatin chemical CHEBI:63618 ChEBI HMGCR protein P04035 UNIPROT down-regulates activity chemical inhibition -1 1597859 t miannu A series of N-heteroaryl-substituted mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and in vivo, and to lower plasma cholesterol in a hypercholesterolemic dog model. The goal of the strategy employed was to design an inhibitor which possessed the pharmacological properties of lovastatin (1), and the physicochemical properties (increased hydrophilicity) of pravastatin (2). SIGNOR-258350 0.8 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity precursor of 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267123 0.8 CENPP protein Q6IPU0 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265208 0.728 MAPK8 protein P45983 UNIPROT CDC25B protein P30305 UNIPROT down-regulates quantity by destabilization phosphorylation Ser103 ESSLSSEsSESSDAG 9606 BTO:0000567 21807946 t miannu  Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104). SIGNOR-276351 0.288 ABL2 protein P42684 UNIPROT LGALS3 protein P17931 UNIPROT up-regulates phosphorylation Tyr118 AGPLIVPyNLPLPGG 9606 20150913 t llicata The sh (src homology)3 domains of c-abl/arg bind to a p(80)gppsgp motif of gal3, and tyr79 and tyr118 are the major tyrosine phosphorylation sites. A consequence of this interaction and phosphorylation is the significant impairment of chaperone-mediated autophagy of gal3. SIGNOR-163743 0.2 ABCA1 protein O95477 UNIPROT MEGF10 protein Q96KG7 UNIPROT up-regulates activity binding 9606 BTO:0000567 17205124 t miannu ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level. SIGNOR-265164 0.338 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Thr308 KDGATMKtFCGTPEY 10090 BTO:0000944 18042541 t gcesareni Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural subunit (A), catalytic subunit (C), and a variable regulatory subunit (B). SIGNOR-252613 0.671 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Ser16 PSANKPCsKQPPPQP 9606 22878263 t llicata In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis. SIGNOR-198721 0.42 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Thr451 KRTRSKGtLRYMSPE 9606 BTO:0000567 11337501 t lperfetto Taken together, our findings support the idea that binding of pkr to dsrna increases autophosphorylation in the activation loop of the kinase domain (fig. 9). Because dsrna binding promotes dimerization, this would facilitate trans-autophosphorylation of thr-446 and thr-451 by the two kinase moieties in a pkr dimer SIGNOR-107511 0.2 PPP1CC protein P36873 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity dephosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001176 19036824 t The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation SIGNOR-248501 0.2 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr659 VADERVDyVVVDQQK 9606 10068651 t lperfetto Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro. SIGNOR-236254 0.952 PF-2545920 chemical CID:11581936 PUBCHEM PDE10A protein Q9Y233 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206001 0.8 PLK1 protein P53350 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser198 SDELMEFsLKDQEAK 9606 11897663 t lperfetto The nuclear accumulation of active m-phase promoting factor (mpf) during prophase is thought to be essential for coordinating m-phase events in vertebrate cells. The protein phosphatase cdc25c, an activator of mpf, enters the nucleus to keep mpf active in the nucleus during prophase. these results suggest that plk1 phosphorylates cdc25c on ser198 and regulates nuclear translocation of cdc25c during prophase. SIGNOR-115993 0.796 MAPK13 protein O15264 UNIPROT CDC25B protein P30305 UNIPROT down-regulates 9606 11333986 f gcesareni P38 map k can also induce a g2/m checkpoint through the phosphorylation and the phosphatase cdc25b. SIGNOR-85999 0.461 AURKB protein Q96GD4 UNIPROT KNL1 protein Q8NG31 UNIPROT down-regulates phosphorylation Ser60 KKNSRRVsFADTIKV 9606 20471944 t lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). SIGNOR-165506 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 26194464 t MARCO ROSINA Taken together, ERK-mediated Smad2 linker phosphorylation is responsible for TH17 differentiation SIGNOR-255020 0.2 SMARCD3 protein Q6STE5 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269820 0.749 NR1D1 protein P20393 UNIPROT ARNTL protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21881539 f lperfetto Concomitant attenuation of NR1D1 downregulation (-2.4-fold compared with -4.1-fold in placebo; P=0.04), a transcriptional repressor of ARNTL, supported the view that ramipril might modulate glucose homeostasis pathways involving the NR1D1 ARNTL axis. SIGNOR-253719 0.658 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Thr53 PPGSLSStPLSTPCS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159394 0.2 CENPA protein P49450 UNIPROT CENP-A nucleosome complex SIGNOR-C321 SIGNOR form complex binding -1 23324462 t miannu In vitro assembly of both yeast and human CENP-A nucleosomes yields standard octameric structures containing two copies each of CENP-A, H2A, H2B and H4 histones. Human CENP-A also produces rigidified homotypic CENP-A/H4 tetramers in vitro. SIGNOR-263702 0.2 pazopanib hydrochloride chemical CHEBI:71217 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-201250 0.8 HK1 protein P19367 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266445 0.8 Fibrinogen complex SIGNOR-C311 SIGNOR Fibrin complex SIGNOR-C317 SIGNOR form complex cleavage 9606 BTO:0000131 18544683 t lperfetto A fibrin clot is the final product of the blood clotting cascade. Thrombin catalyzes release of fibrinopeptide A from fibrinogen to create fibrin monomers, which then aggregate to protofibrils. Proteolytic release of fibrinopeptide B by thrombin permits lateral protofibril aggregation, resulting in a three-dimensional fibrin gel.|Fibrin clots were formed as described for turbidity experiments, in which the fibrinogen, calcium, and polyP (when included) were preincubated for 15 minutes before adding thrombin. SIGNOR-263551 0.756 CSNK1D protein P48730 UNIPROT DCK protein P27707 UNIPROT up-regulates activity phosphorylation Ser74 EFEELTMsQKNGGNV 20637175 t lperfetto We showed that recombinant CKI delta phosphorylated several residues of bacterially overexpressed dCK: Ser-74, but also Ser-11, Ser-15, and Thr-72. Phosphorylation of dCK by CKI delta correlated with increased activity reaching at least 4-fold. Site-directed mutagenesis demonstrated that only Ser-74 phosphorylation was involved in dCK activation by CKI delta, SIGNOR-275799 0.345 PCBD1 protein P61457 UNIPROT HNF1B protein P35680 UNIPROT up-regulates activity binding 9606 BTO:0000482 24204001 t miannu Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg(2+) reabsorption in the DCT. SIGNOR-254910 0.598 ELF1 protein P32519 UNIPROT CD68 protein P34810 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 12676954 f Band shift experiments show that PU.1 associates with the -89 site whereas, Elf-1 preferentially binds the -106 Ets binding site and enhances CD68 activity in vitro. SIGNOR-254282 0.2 PRKACA protein P17612 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 15383283 t gcesareni Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites. SIGNOR-129349 0.341 TPI1 protein P60174 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Triosephosphate isomerase (TPI) is the glycolytic enzyme with the highest activity in vitro. TPI catalyzes the interconversion of glyceraldehyde-3-phosphate and DHAP (Figure 1). It consists of a dimer with 2 identical subunits of 248 amino acids (27 kDa). SIGNOR-266492 0.8 UBE2D2 protein P62837 UNIPROT TRIM5 protein Q9C035 UNIPROT up-regulates activity binding 9606 BTO:0000567 18312418 t miannu Here, we show that TRIM5alpha functions as a RING-finger-type E3 ubiquitin ligase both in vitro and in vivo and ubiquitinates itself in cooperation with the E2 ubiquitin-conjugating enzyme UbcH5B.  SIGNOR-271670 0.469 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser13 ITSAARRsYVSSGEM -1 7822264 t llicata On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II. SIGNOR-250626 0.437 PRKCB protein P05771 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser497 ATVKSRWsGSQQVEQ 9606 8288587 t gcesareni Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. the sites of pkc-mediated raf-1 phosphorylation are deduced to be ser497 and ser619. SIGNOR-37474 0.421 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Thr185 HDHTGFLtEYVATRW 9606 BTO:0004419 12840032 t lperfetto P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).Mapk activity is tightly regulated by phosphorylation and dephosphorylation. The activation of the mapk activity requires the dual phosphorylation of the ser/thr and tyr residues in the txy kinase activation motif (1113), and deactivation occurs through the action of either ser/thr protein phosphatase SIGNOR-103159 0.605 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) smallmolecule CHEBI:57795 ChEBI SPOP protein O43791 UNIPROT up-regulates activity binding 9606 BTO:0000007 18218622 t Gianni Taken together, these data define a novel mechanism whereby the phosphoinositide PI5P leads to stimulation of Cul3-SPOP ubiquitin ligase activity and also implicate PIPKIIbeta as a key regulator of this signaling pathway through its association with the Cul3-SPOP complex. SIGNOR-268863 0.8 Factor Va-Xa complex SIGNOR-C318 SIGNOR F2 protein P00734 UNIPROT up-regulates activity cleavage 11983337 t lperfetto This activation is accomplished at a physiologically relevant rate by the prothrombinase complex, a macromolecular association of the serine protease factor Xa (fXa) with its cognate cofactor, factor Va (fVa), and substrate, prothrombin|Factor Va Increases the Affinity of Factor Xa for Prothrombin SIGNOR-263546 0.657 PCM1 protein Q15154 UNIPROT CETN2 protein P41208 UNIPROT up-regulates relocalization 9606 12403812 t miannu Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome SIGNOR-94990 0.511 P2RY12 protein Q9H244 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256855 0.378 ADRB3 protein P13945 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256753 0.606 SLC18A2 protein Q05940 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30465801 t miannu Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. SIGNOR-269197 0.8 creatine smallmolecule CHEBI:16919 ChEBI CKB protein P12277 UNIPROT up-regulates activity chemical activation 9606 18502307 t miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. SIGNOR-265809 0.8 entinostat chemical CHEBI:132082 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257903 0.8 AKT1 protein P31749 UNIPROT ATG4B protein Q9Y4P1 UNIPROT up-regulates activity phosphorylation Ser34 WILGRKYsIFTEKDE 9606 BTO:0000586 29165041 t lperfetto In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells.| In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F1Fo-ATP synthase activity. SIGNOR-275834 0.315 FBXW8 protein Q8N3Y1 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002572 23142081 t miannu Defective IRS-1 degradation was due to attenuated expression and phosphorylation of the ubiquitin ligase substrate-targeting subunit, Fbw8. mTORC2 stabilizes Fbw8 by phosphorylation at Ser86, allowing the insulin-induced translocation of Fbw8 to the cytosol where it mediates IRS-1 degradation.  SIGNOR-271939 0.472 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr951 RFRQGKDyVGAIPVD 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. SIGNOR-157097 0.2 GPSM3 protein Q9Y4H4 UNIPROT GNAI1 protein P63096 UNIPROT down-regulates activity binding 9606 BTO:0000007 22843681 t lperfetto GPSM3 acts through its two GoLoco motifs to exert GDP dissociation inhibitor activity over Galpha(i) subunits|interactions between GPSM3 and Galphai1 or Gbeta1 (20) was assayed by BRET. SIGNOR-264864 0.47 PTPN6 protein P29350 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity dephosphorylation Tyr448 TILTEVNyEVSNKDD 9606 18086677 t Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis. SIGNOR-248478 0.361 ACSL1 protein P33121 UNIPROT hexadecanoic acid smallmolecule CHEBI:15756 ChEBI down-regulates quantity chemical modification 9606 21242590 t miannu Long-chain acyl-CoA synthetases (ACSLs) catalyze the thioesterification of long-chain FAs into their acyl-CoA derivatives. On the other hand, overexpression of ACSL1 resulted in large increases in oleoyl-CoA synthesis and palmitoyl-CoA synthesis in SMC lysates (Fig. 4A). SIGNOR-267878 0.8 GAP43 protein P17677 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10090 21938722 f miannu Growth associated protein 43 (Gap43) is a neuron-specific phosphoprotein, which plays critical role in axon growth and synapses functions during neurogenesis.  SIGNOR-266769 0.7 LYN protein P07948 UNIPROT HCLS1 protein P14317 UNIPROT up-regulates activity phosphorylation Tyr397 EDEPEGDyEEVLEPE 9606 9104825 t Lyn and Syk synergistically phosphorylate HS1, and that Tyr-378 and Tyr-397 of HS1 are the critical residues for its BCR-induced phosphorylation. tyrosine phosphorylation of HS1 is required for BCR-induced apoptosis and nuclear translocation of HS1 may be a prerequisite for B cell apoptosis. PMID: 9104825 PMCID: PMC2196252 SIGNOR-251401 0.702 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu49 RRANTFLeEVRKGNL -1 10556651 t lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. SIGNOR-263675 0.655 AKT proteinfamily SIGNOR-PF24 SIGNOR VCP protein P55072 UNIPROT up-regulates phosphorylation Ser352 AATNRPNsIDPALRR 9606 BTO:0000150 16551632 t llicata Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I SIGNOR-145284 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183612 0.2 ATF4 protein P18848 UNIPROT GARS1 protein P41250 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269426 0.2 Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 30397315 f miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270713 0.7 PLK1 protein P53350 UNIPROT STK38 protein Q15208 UNIPROT down-regulates activity phosphorylation Thr183 TLLMKKDtLTEEETQ 9606 BTO:0000567 26057687 t miannu Here, we identified a conserved signaling axis in which NDR1 kinase activity is regulated by PLK1 in mitosis. PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1-dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis.  SIGNOR-276913 0.321 PPP1CA protein P62136 UNIPROT PREX1 protein Q8TCU6 UNIPROT up-regulates activity dephosphorylation Ser1165 DSGHDTMsYRDSYSE 9606 22242915 t lperfetto MS analysis of wild-type P-Rex1 and a PP1\u03b1-binding-deficient mutant revealed that endogenous PP1\u03b1 dephosphorylates P-Rex1 on at least three residues, Ser834, Ser1001 and Ser1165.|The phosphatase activity of PP1\u03b1 is required for P-Rex1 activation. SIGNOR-277023 0.2 CDK1 protein P06493 UNIPROT NDUFB6 protein O95139 UNIPROT up-regulates activity phosphorylation Ser55 NKFLENKsPWRKMVH 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275590 0.2 NOD2 protein Q9HC29 UNIPROT ATG16L1 protein Q676U5 UNIPROT up-regulates activity binding 9606 BTO:0000567 19898471 t miannu By a mechanism independent of the adaptor RIP2 and transcription factor NF-kappaB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease. SIGNOR-252405 0.75 NME1 protein P15531 UNIPROT CCN2 protein P29279 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17671192 f miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. SIGNOR-255160 0.2 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR CRY2 protein Q49AN0 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253680 0.927 GTF3A protein Q92664 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR up-regulates activity relocalization 9606 8907699 t lperfetto One of the major functions of TFIIIA is to program the 5S RNA gene for transcription by binding directly to the ICR, which subsequently directs an ordered assembly of general factors to form a functional transcription complex. SIGNOR-269309 0.522 FGFR1 protein P11362 UNIPROT Non-structural protein 2 protein P0C6X7-PRO_0000037310 UNIPROT down-regulates activity chemical inhibition 9606 18620382 t Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. SIGNOR-260150 0.2 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu54 YNSGKLEeFVQGNLE 10090 BTO:0001103 11133752 t lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. SIGNOR-263687 0.67 JUN protein P05412 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 10090 BTO:0000725 17041602 f miannu These results show that restoration of c-Jun expression rescues the myelomonocytic differentiation block in preleukemic PU.1-knockdown bone marrow cells, suggesting that c-Jun is a critical downstream target in PU.1-knockdown HSCs. SIGNOR-256066 0.7 tiotropium chemical CHEBI:90960 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition -1 8441333 t miannu A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed "kinetic receptor subtype selectivity" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors. SIGNOR-258486 0.8 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203576 0.769 AMPK complex SIGNOR-C15 SIGNOR HIPK2 protein Q9H2X6 UNIPROT down-regulates activity phosphorylation Thr119 HNLMRRStVSLLDTY 23871434 t Phosphosite positions are derived from Figure S5 lperfetto AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro SIGNOR-275482 0.251 HOXC6 protein P09630 UNIPROT S100B protein P04271 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002253 17488478 t Luana HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells. SIGNOR-261646 0.2 PKM protein P14618 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity chemical modification 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266536 0.8 TGFA protein P01135 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252281 0.7 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFA12 protein Q9UI09 UNIPROT up-regulates activity phosphorylation Thr142 QEWIPPStPYK 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275595 0.2 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB5 protein Q9Y5G0 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265692 0.2 H3C1 protein P68431 UNIPROT CPC complex SIGNOR-C554 SIGNOR up-regulates quantity binding 9606 BTO:0000567 24413556 t miannu Histone modifications coordinate the chromatin localization of key regulatory factors in mitosis. For example, mitotic phosphorylation of Histone H3 threonine-3 (H3T3ph) by Haspin creates a binding site for the chromosomal passenger complex (CPC). SIGNOR-275422 0.2 KIT protein P10721 UNIPROT GRB7 protein Q14451 UNIPROT up-regulates activity binding 9606 BTO:0000567 phosphorylation:Tyr936 SESTNHIySNLANCS 10377264 t gcesareni We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936. SIGNOR-248291 0.566 daunorubicin chemical CHEBI:41977 ChEBI ABCC1 protein P33527 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002206 9647783 t Simone Vumbaca Unconjugated Dox and Dau failed to inhibit the transport of LTC4, whereas 30 microM GS-Dox or GS-Dau conjugates completely inhibited the transport. SIGNOR-261086 0.8 MYC protein P01106 UNIPROT PFKM protein P08237 UNIPROT up-regulates quantity transcriptional regulation 10116 10823814 t C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway. SIGNOR-259988 0.333 ITGB3BP protein Q13352 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265206 0.744 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT up-regulates activity phosphorylation Ser384 RLLAALEvASAAMAK 9606 20643644 t Manara We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase. SIGNOR-260795 0.2 lisuride chemical CHEBI:51164 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258886 0.8 LPAR2 protein Q9HBW0 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256784 0.373 PAK1 protein Q13153 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 BTO:0001033 29572236 f miannu  RAC1 activation induces the actin remodeling and membrane ruffling necessary to form macropinosomes by activating PAK kinases SIGNOR-277768 0.7 CREB1 protein P16220 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0001009 10753867 f lperfetto Creb activity by akt signaling leads to increased bcl-2 promoter activity and cell survival. SIGNOR-76558 0.438 IMPDH2 protein P12268 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity binding 9606 BTO:0001616 30518405 t miannu We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. There is evidence that IMPDH2 interacts with the pleckstrin homology domain of PKB/AKT in the regulation of GTP biosynthesis. SIGNOR-260961 0.394 PCDHA6 protein Q9UN73 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265666 0.2 TUBGCP2 protein Q9BSJ2 UNIPROT g-TuRC complex complex SIGNOR-C282 SIGNOR form complex binding -1 31862189 t lperfetto Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.” SIGNOR-262326 0.797 CSNK1D protein P48730 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 12000790 t gcesareni However, ckiepsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the -catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated cki as a candidate s45-kinase in several assays, both in vitro and in vivo. SIGNOR-87441 0.611 AR protein P10275 UNIPROT TMPRSS2 protein O15393 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20308527 t lperfetto We demonstrate that CHD8 directly associates with AR and that CHD8 and AR simultaneously localize to the TMPRSS2 enhancer after androgen treatment. In the LNCaP cell line, reduction of CHD8 levels by small interfering RNA treatment severely diminishes androgen-dependent activation of the TMPRSS2 gene. We demonstrate that the recruitment of AR to the TMPRSS2 promoter in response to androgen treatment requires CHD8 SIGNOR-253686 0.593 PI4KA protein P42356 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269096 0.8 TLX3 protein O43711 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity binding 9606 BTO:0002504 22516263 t irozzo We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement. SIGNOR-259098 0.372 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation 9606 21620960 t lperfetto Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. SIGNOR-252866 0.756 EPAS1 protein Q99814 UNIPROT CACNA1A protein O00555 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15833863 f miannu A second hypoxia-responsive factor, HIF-2, can activate many of the same genes as HIF-1. Ten genes were preferentially activated by HIF-2alpha, including two (CACNA1A and PTPRZ1) implicated in neurologic diseases. SIGNOR-264332 0.2 Collagen proteinfamily SIGNOR-PF103 SIGNOR ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 35268340 f miannu The extracellular matrix is a structure composed of many molecules, including fibrillar (types I, II, III, V, XI, XXIV, XXVII) and non-fibrillar collagens (mainly basement membrane collagens: types IV, VIII, X), non-collagenous glycoproteins (elastin, laminin, fibronectin, thrombospondin, tenascin, osteopontin, osteonectin, entactin, periostin) embedded in a gel of negatively charged water-retaining glycosaminoglycans (GAGs) such as non-sulfated hyaluronic acid (HA) and sulfated GAGs which are linked to a core protein to form proteoglycans (PGs). SIGNOR-269732 0.7 adenosine smallmolecule CHEBI:16335 ChEBI ADORA2B protein P29275 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257448 0.8 TGFBI protein Q15582 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR up-regulates activity 10090 BTO:0004093 25786978 t lperfetto First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs. SIGNOR-253283 0.339 AKT1 protein P31749 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 17130464 t Translocation from Cytoplasm to Nucleus lperfetto Phosphorylation of pras40-thr246 by pkb/akt, and pras40-ser183 and pras40-ser221 by mtorc1 results in dissociation from mtorc1, and its binding to 14-3-3 proteins. SIGNOR-252540 0.719 MAPK3 protein P27361 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser525 YGMIERLsPGTRKIE 9606 BTO:0000007 33217317 t miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. SIGNOR-265947 0.275 EGF protein P01133 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity binding 9606 12297050 t lperfetto Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase. SIGNOR-186159 0.948 tRNA(Trp) smallmolecule CHEBI:29181 ChEBI Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates quantity precursor of 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) SIGNOR-270515 0.8 PPP1CA protein P62136 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-252603 0.436 CSNK2A1 protein P68400 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates phosphorylation Ser123 EEEEESEsEDSEDSG 9606 16308564 t lperfetto Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting. SIGNOR-142347 0.2 UHRF2 protein Q96PU4 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0000298 21952639 t miannu We found that NIRF directly ubiquitinated cyclins D1 and E1, as evidenced by the appearance of the tail (Fig. 4B). In summary, the above findings suggest that NIRF tightly cooperates with the core cell cycle machinery and induces G1 arrest, which is accompanied by ubiquitination of cyclins D1 and E1. SIGNOR-271886 0.337 DPF2 protein Q92785 UNIPROT ESRRA protein P11474 UNIPROT down-regulates activity binding 10090 BTO:0000165 25713408 t 1 miannu DPF2 directly bound to ERRalpha and suppressed the transactivation function of nuclear receptors such as androgen receptor. DPF2 was recruited to ERR target gene promoters in myoblast cells, and knockdown of DPF2 derepressed the level of mRNA expressed by target genes of ERRalpha. These results show that DPF2 acts as a nuclear receptor-selective co-repressor for ERRalpha by associating with both acetylated histone H3 and HDAC1. SIGNOR-239539 0.2 CFII complex complex SIGNOR-C387 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity cleavage 9606 30139799 t lperfetto Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1. The heterodimer is active in partially reconstituted cleavage reactions SIGNOR-266121 0.8 GPI protein P06744 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Glucose 6-phosphate isomerase (GPI) catalyzes the interconversion of G6P into fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway (Figure 1). As a result of this reversible reaction, products of the hexose-monophosphate shunt can be recycled to G6P. SIGNOR-266462 0.8 dopamine smallmolecule CHEBI:18243 ChEBI DRD5 protein P21918 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257481 0.8 RPA4 protein Q13156 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 f lperfetto The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275708 0.7 NFE2L2 protein Q16236 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0000599 26194347 f irozzo Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes. SIGNOR-256652 0.7 CD28 protein P10747 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 7737275 t fspada In this study, we demonstrate that the co-stimulatory antigen cd28 binds to grb-2 by means of a cytoplasmic pymnm motif, which is the same motif bound by pi 3-kinase. SIGNOR-32509 0.69 ARHGAP22 protein Q7Z5H3 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260476 0.546 SMC1A protein Q14683 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR form complex binding 28430577 t lperfetto Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin SIGNOR-263313 0.878 HRAS protein P01112 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 8052307 t gcesareni In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-35878 0.922 COP1 protein Q8NHY2 UNIPROT ACACA protein Q13085 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16794074 t miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). SIGNOR-271598 0.2 NKRF protein O15226 UNIPROT IFNB1 protein P01574 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0005065 10562553 t Luana Constitutive silencing of IFN-beta promoter is mediated by NRF (NF-kappaB-repressing factor), a nuclear inhibitor of NF-kappaB SIGNOR-266227 0.366 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 9606 10212258 t Manara Tyrosine Phosphorylation of Rad51 by ABL1 Enhances the Interaction between Rad51 and Rad52 | our studies of Rad51·Rad52 complex formation in vitro and in vivo suggest that the ATM and ABL1-mediated signaling is likely to promote repair given the biochemical evidence that Rad51 acts in concert with Rad52 in homologous recombination SIGNOR-260777 0.764 GPR174 protein Q9BXC1 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257029 0.2 GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268607 0.263 WNK3 protein Q9BYP7 UNIPROT SLC12A7 protein Q9Y666 UNIPROT down-regulates activity phosphorylation 21613606 t lperfetto We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs SIGNOR-264630 0.463 MAPK8 protein P45983 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr451 PIPKALGtPVLTPPT 9606 15538382 t lperfetto Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment. SIGNOR-252964 0.703 ELAVL1 protein Q15717 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates quantity post transcriptional regulation 9606 19221430 t miannu Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure SIGNOR-266862 0.2 DAXX protein Q9UER7 UNIPROT AIRE protein O43918 UNIPROT down-regulates activity binding 9606 BTO:0000567 20185822 t 1 miannu The interaction between AIRE and DAXX has been validated by in vivo coimmunoprecipitation analysis and colocalization study in mammalian cells. The interaction has been further confirmed by showing in transactivation assays that DAXX exerts a strong repressive role on the transcriptional activity of AIRE. SIGNOR-239287 0.34 WIPI1 protein Q5MNZ9 UNIPROT ATG16L1 protein Q676U5 UNIPROT up-regulates quantity binding 9606 BTO:0001938 28561066 t miannu WIPI1 assists WIPI2 in recruiting ATG16L for LC3 lipidation. WIPI1-WIPI2 heterodimer may function more efficiently in ATG16L complex recruitment. SIGNOR-268477 0.594 BCL2L2 protein Q92843 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 17452531 t gcesareni Bcl-w may protect largely via its ability to associate with bax because it could efficiently protect xem from tbid and bid, bad, hrk, and bmf bh3 peptides SIGNOR-154518 0.47 LY294002 chemical CHEBI:65329 ChEBI PIK3C3 protein Q8NEB9 UNIPROT down-regulates chemical inhibition 9534 BTO:0001444 22253445 t lperfetto From these results, we conclude that LY294002 and wortmannin inhibit SARS pseudovirus entry by targeting PI4KB and that PI4KB is involved in SARS-CoV S-mediated entry into VeroE6 cells. SIGNOR-260731 0.8 AMPK complex SIGNOR-C15 SIGNOR NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 t lperfetto Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no. SIGNOR-216445 0.266 ABI1 protein Q8IZP0 UNIPROT WRC complex complex SIGNOR-C191 SIGNOR form complex binding 9606 21107423 t miannu WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems SIGNOR-253571 0.841 LSM-1231 chemical CHEBI:91471 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258236 0.8 DLGAP3 protein O95886 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264592 0.792 RPS6KA5 protein O75582 UNIPROT H2AC11 protein P0C0S8 UNIPROT up-regulates phosphorylation Ser2 sGRGKQGG 9606 15010469 t gcesareni We found that msk1 phosphorylated histone h2a on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by msk1. SIGNOR-123383 0.2 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii SIGNOR-203544 0.769 ERG protein P11308 UNIPROT EPB41L4B protein Q9H329 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20860828 f miannu EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression. SIGNOR-253919 0.2 PRKCG protein P05129 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Ser761 DSLGRRSsLSRLEPS 9606 25009260 t lperfetto Pkc_ directly phosphorylates _pix at ser583 and indirectly at ser340 in cells. herefore, we propose that pkc_ positively modulates dopamine release through _2pix phosphorylation. The pkc_-_pix-cdc42/rac1 phosphorylation axis may provide a new therapeutic target for the treatment of parkinsonian syndrome SIGNOR-205238 0.2 STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001103 9551976 f Federica Ferrentino A role for STAT1 in regulation of the CIITA promoter is shown by the rescue of IFN-gamma induction by expression of STAT1 in STAT1-defective U3A cells SIGNOR-255752 0.524 MMP21 protein Q8N119 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272366 0.7 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Thr326 TSSSQLStPKSKQSP 9606 14741103 t llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. SIGNOR-250659 0.415 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser784 GVEKCSDsQSWEDIA 9606 12697768 t llicata To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1 SIGNOR-100653 0.869 FER protein P16591 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation Tyr225 PTSSKDNyLGGTSTI 9606 BTO:0001130 23906537 t lperfetto Fer is required for il-6 mediated ar activation by phosphorylating ar tyrosine 223 and binding via its sh2 domain. SIGNOR-194749 0.262 ALDOC protein P09972 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266489 0.8 DRD1 protein P21728 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256796 0.476 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 9606 23431053 t milica MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation SIGNOR-201278 0.593 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR BIN1 protein O00499 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136399 0.281 (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one chemical CHEBI:125500 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258775 0.8 FOSL2 protein P15408 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004603 13679379 t Luana Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription.  SIGNOR-261602 0.381 IRX2 protein Q9BZI1 UNIPROT CXCL10 protein P02778 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003885 26560478 f Luana Our results imply that the IRX2 transcription factor might represent a novel metastasis associated protein that acts as a negative regulator of cellular motility and as a repressor of chemokine expression.  SIGNOR-266042 0.2 FCAR protein P24071 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 BTO:0000130;BTO:0000801;BTO:0000876;BTO:0000399 30766540 f lperfetto IgA-mediated immune effector responses such as phagocytosis, antibody-dependent cell-mediated cytotoxicity, respiratory burst and cytokine release are mediated through FcalphaRI (CD89), an IgA-specific receptor that is expressed on monocytes, eosinophils, neutrophils and macrophages SIGNOR-264862 0.7 CTSG protein P08311 UNIPROT C3 protein P01024 UNIPROT up-regulates activity cleavage Arg748 ASHLGLArSNLDEDI 9606 BTO:0001412 1861080 t miannu Plasma membrane elastase and cathepsin G from U937 cells cleave C3 into C3a- and C3b-like fragments; further incubation leads to C3c- and C3dg-like fragments, as judged from SDS-PAGE analysis of the digests. Sequencing of the C3b-like fragment purified by reverse phase chromatography indicates that initial cleavage of C3 by purified cathepsin G occurs at two positions in the amino-terminal part of the alpha-chain, at a Arg-Ser bond located between residues 748 and 749 and at a Leu-Asp bond between residues 751 and 752. These proteases are, thus, able to generate, on the U937 surface, active fragments of C3, which are likely to be involved in cell-protein and cell-cell interactions. SIGNOR-256347 0.582 TP53 protein P04637 UNIPROT HR protein O43593 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15489903 f miannu P53 may downregulate HR through multiple mechanisms including the reported associations with the Rad51 and Rad54 recombinases, and the BLM and WRN helicases. SIGNOR-255436 0.348 (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266282 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-262995 0.2 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 18550549 t gcesareni Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144. SIGNOR-178888 0.275 SSTR5 protein P35346 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256690 0.475 PRKCI protein P41743 UNIPROT NUMB protein P49757 UNIPROT down-regulates phosphorylation 9606 17609107 t esanto Numb is regulated by phosphorylation since the protein is released from ccss and no longer binds integrins when phosphorylated by atypical protein kinase c (apkc). SIGNOR-156765 0.762 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR DOCK6 protein Q96HP0 UNIPROT down-regulates activity phosphorylation Ser1194 GQRSRLAsMLDSDTE 23462102 t lperfetto Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching SIGNOR-275668 0.2 GNG3 protein P63215 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 23074268 t gcesareni Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance. SIGNOR-199141 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MBP protein P02686 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 16401070 t inferred from 70% family members lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. SIGNOR-270100 0.2 EGR1 protein P18146 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000574 7565762 f miannu TPA induced EGR1 binding to the -69/+20 promoter sequences over a time course which correlated with increased MDR1 promoter activity and increased steady-state MDR1 RNA levels. These data suggest a role for EGR1 in modulating MDR1 promoter activity in hematopoietic cells. SIGNOR-253871 0.373 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257927 0.8 TFAP2A protein P05549 UNIPROT CRYAB protein P02511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21556774 t miannu Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53 SIGNOR-253636 0.262 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000815 18570872 t miannu  In this report, we show that cIAP1 and cIAP2 promote cancer cell survival by functioning as E3 ubiquitin ligases that maintain constitutive ubiquitination of the RIP1 adaptor protein. We demonstrate that AEG40730, a compound modeled on BIR-binding tetrapeptides, binds to cIAP1 and cIAP2, facilitates their autoubiquitination and proteosomal degradation, and causes a dramatic reduction in RIP1 ubiquitination. We show that cIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1. SIGNOR-272638 0.759 TBK1 protein Q9UHD2 UNIPROT STAT6 protein P42226 UNIPROT up-regulates phosphorylation Ser407 PIQLQALsLPLVVIV 9606 22000020 t gcesareni We now show that stat6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger sting (also named mita/eris) to recruit stat6 to the endoplasmic reticulum, leading to stat6 phosphorylation on ser(407) by tbk1 and tyr(641), independent of jaks. Phosphorylated stat6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing. SIGNOR-176771 0.66 MDH2 protein P40926 UNIPROT NADH smallmolecule CHEBI:16908 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266288 0.8 TAOK3 protein Q9H2K8 UNIPROT TAOK3 protein Q9H2K8 UNIPROT up-regulates activity phosphorylation Thr181 PANSFVGtPYWMAPE 9534 BTO:0004055 10559204 t lperfetto These data indicate that JIK is indeed the protein kinase present in the immune complex responsible for autophosphorylation and for the phosphorylation of the exogenous substrate. Moreover, our observations suggest that JIK (A181F183) acts as the catalytically inactive mutant of JIK, which is no longer able to potently undergo autophosphorylation and dramatically phosphorylate MBP, as compared with the wild type JIK. SIGNOR-246298 0.2 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates activity phosphorylation Thr208 TFGNKLDtFCGSPPY -1 18424437 t miannu MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase. SIGNOR-276165 0.57 PPM1A protein P35813 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity dephosphorylation 9606 27419230 t miannu In contrast, coexpression of wild-type PPM1A, but not its D239N or R174G mutant, abolished IRF3 activation (XREF_FIG).|We found that PPM1A abolished the C-terminal phosphorylation of IRF3 (XREF_FIG), whereas depletion of PPM1A expression improved virus induced pIRF3 level (XREF_FIG and XREF_FIG). SIGNOR-277152 0.25 TNKS2 protein Q9H2K2 UNIPROT CASC3 protein O15234 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 21478859 t lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. SIGNOR-263382 0.2 haloperidol chemical CHEBI:5613 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258838 0.8 vilanterol chemical CHEBI:75037 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 20462258 t Luana A series of saligenin β2 adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for β2, β1, and β3 agonist activity in CHO cells. | Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo SIGNOR-257843 0.8 AEP complex complex SIGNOR-C117 SIGNOR HOXA9 protein P31269 UNIPROT up-regulates quantity by expression 9606 20854876 f irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. SIGNOR-255879 0.417 HOXA10 protein P31260 UNIPROT IGFBP1 protein P08833 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003697 17350963 f miannu The functional role of HOXA10 in IGFBP1 expression was further explored using human endometrial stromal cells (HSC). Overexpression of HOXA10 in HSC resulted in a decrease of IGFBP1 mRNA, whereas silencing HOXA10 caused an increase of IGFBP1 mRNA, even in the presence of H + dbcAMP. These data demonstrate that HOXA10 negatively influences IGFBP1 expression in decidualizing cells. SIGNOR-254467 0.419 TGFB2 protein P61812 UNIPROT KRT1 protein P04264 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16258965 f Regulation miannu Immunolocalization of the epithelial marker cytokeratin demonstrates decreased staining by 48 hr after the addition of TGFβ1 or TGFβ2 SIGNOR-251885 0.2 NFKBIE protein O00221 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 BTO:0001271 12835716 t lperfetto Nf-kb is normally sequestered in the cell cytoplasm by binding to ikbx, ikbb, ikbe SIGNOR-217361 0.572 SLBP protein Q14493 UNIPROT H2BE1 protein A0A2R8Y619 UNIPROT up-regulates quantity by expression translation regulation 9606 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265380 0.2 RAD23B protein P54727 UNIPROT ERCC5 protein P28715 UNIPROT up-regulates activity binding 24086043 t lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275702 0.624 IDH1 protein O75874 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 29090344 t miannu Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases. SIGNOR-253135 0.8 CHD8 protein Q9HCK8 UNIPROT MAP2 protein P11137 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 t Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells SIGNOR-268916 0.2 PPP2CA protein P67775 UNIPROT DOCK6 protein Q96HP0 UNIPROT down-regulates activity phosphorylation Ser1194 GQRSRLAsMLDSDTE 23462102 t lperfetto Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching SIGNOR-275669 0.2 SWI/SNF complex complex SIGNOR-C92 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16452181 f irozzo C-myc is a direct target of SWI/SNF complex–dependent promoter repression. These results indicate that repression of c-myc is indeed dependent on the activity of SWI/SNF–related complexes and specifically on complexes that contain ARID1A. SIGNOR-256292 0.407 Tubulin proteinfamily SIGNOR-PF46 SIGNOR Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 28347630 f miannu Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation SIGNOR-266827 0.7 CAMK2A protein Q9UQM7 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser142 RKILNDLsSDAPGVP 9606 11013247 t gcesareni Phosphorylation of creb1 at ser142 and ser143 is selectively activated by ca(2+) influx;phosphorylation of ser142 and ser143, disrupts the interaction of creb with its cofactor cbp. Phosphorylation of serine 142 in creb by camkii leads to dissociation of the creb dimer. SIGNOR-82501 0.577 AKT2 protein P31751 UNIPROT MYO5A protein Q9Y4I1 UNIPROT up-regulates activity phosphorylation Thr1650 PTGLRKRtSSIADEG 10090 BTO:0000944 17515613 t miannu Here we identify an Akt consensus phosphorylation motif in the actin-based motor protein myosin 5a and show that insulin stimulation leads to phosphorylation of myosin 5a at serine 1650. This Akt-mediated phosphorylation event enhances the ability of myosin 5a to interact with the actin cytoskeleton.Taken together, these data indicate that myosin 5a is a newly identified direct substrate of Akt2 and, upon insulin stimulation, phosphorylated myosin 5a facilitates anterograde movement of GLUT4 vesicles along actin to the cell surface. SIGNOR-262632 0.435 SGK1 protein O00141 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity phosphorylation Ser211 PGKETNEsPWRSDLL 9606 23650397 t gcesareni SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation|Having demonstrated that SGK1 mediates the cortisol-induced increase in GR phosphorylation at the S203 and S211 phospho-sites, which enhance GR nuclear translocation, but not at the S226 site, which inhibits nuclear translocation SIGNOR-251670 0.473 EGFR protein P00533 UNIPROT HGS protein O14964 UNIPROT up-regulates activity phosphorylation Tyr334 ARYLNRNyWEKKQEE 9606 12953068 t lperfetto We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation SIGNOR-100246 0.622 IL31RA protein Q8NI17 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000782 18926762 t gcesareni Il-31 can activate janus kinase (jak) 1 and jak2 signaling molecules after binding to its receptor complex. SIGNOR-161342 0.476 BTG2 protein P78543 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22493435 f miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 SIGNOR-254650 0.2 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI 9606 BTO:0000007;BTO:0000443 SIGNOR-C3 17510057 t lperfetto In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size. SIGNOR-154814 0.924 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258304 0.8 DAPK3 protein O43293 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH -1 15001356 t llicata ZIP kinase phosphorylates p21(WAF1) at Thr145 and alanine-substituted mutations in the p21(WAF1) phosphorylation site alter its ability to be phosphorylated by ZIP kinase. | Transfected ZIPK can promote the phosphorylation of p21(WAF1) at Thr145 in vivo and can increase the half-life of p21(WAF1) SIGNOR-251085 0.321 PRKCA protein P17252 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Ser536 GRGSKRLsRSVTMRK 9606 24505490 t llicata A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498. SIGNOR-204546 0.2 KDM1A protein O60341 UNIPROT BHC complex complex SIGNOR-C353 SIGNOR form complex binding 9606 BTO:0000567; BTO:0000007 15325272 t miannu BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells SIGNOR-264501 0.796 EPO protein P01588 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000574 9168989 f Regulation miannu We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin. SIGNOR-251786 0.325 PHLPP2 protein Q6ZVD8 UNIPROT PRKCA protein P17252 UNIPROT down-regulates quantity dephosphorylation Ser657 QSDFEGFsYVNPQFV 9606 BTO:0000067 18162466 t gcesareni In addition, knockdown of PHLPP expression reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif, but not turn motif, of PKC alpha SIGNOR-237051 0.256 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Thr179 SSPDKRLtLSQIYEW -1 17711846 t done miannu Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626). SIGNOR-274094 0.397 PRKD2 protein Q9BZL6 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity phosphorylation Ser358 WPLSRTRsEPLPPSA 18692497 t Conserved Phosphorylated residue Ser259 and Ser498 refer to HDAC5 sequence. Phospho-residues in HDAC7 were derived by aligning HDAC5 and HDAC7 lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. SIGNOR-275935 0.448 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates phosphorylation 9606 18756288 t lperfetto Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1. SIGNOR-217029 0.567 DNMT3A protein Q9Y6K1 UNIPROT CDKN2D protein P55273 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 26350239 f miannu Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family SIGNOR-261510 0.2 FBXW11 protein Q9UKB1 UNIPROT CHUK protein O15111 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 10321728 t miannu We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo.  SIGNOR-272545 0.417 NRAS protein P01111 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175219 0.849 JAK2 protein O60674 UNIPROT GTF2I protein P78347 UNIPROT up-regulates activity phosphorylation Tyr248 EESEDPDyYQYNIQA 10090 BTO:0000944 11313464 t lperfetto Jak2 activates tfii-i and regulates its interaction with extracellular signal-regulated kinase the interaction between tfii-i and erk, which is essential for its activity, can be regulated by jak2 through phosphorylation of tfii-i at tyrosine 248 SIGNOR-235313 0.334 EGR1 protein P18146 UNIPROT CYP2B6 protein P20813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18303024 f miannu The CYP2B6 enzyme metabolizes commonly used therapeutics and also activates pro-drugs. The CAR directly binds to the distal enhancer element of the CYP2B6 promoter, which is essential in converging to its drug-sensing function onto promoter activity. However, this binding alone is not sufficient to activate the CYP2B6 promoter; the promoter requires EGR1 to enable CAR to activate the CYP2B6 promoter. SIGNOR-253874 0.26 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000142 20308788 t The effect has been demonstrated using P10636-8 lperfetto Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro. SIGNOR-164659 0.2 CSNK2A2 protein P19784 UNIPROT MYF5 protein P13349 UNIPROT up-regulates activity phosphorylation Ser49 HKAELQGsDEDEHVR -1 9461343 t llicata Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity.  SIGNOR-251017 0.312 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr489 DGPYSNPyENSLIPA 12441334 t JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 SIGNOR-251354 0.805 TYK2 protein P29597 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates activity phosphorylation 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260148 0.719 TRIO protein O75962 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260579 0.679 MAP4K1 protein Q92918 UNIPROT LCP2 protein Q13094 UNIPROT down-regulates activity phosphorylation Ser376 PRKQLSESSDDDYDD 9606 BTO:0000661 17353368 t Barakat The serine/threonine kinase HPK-1 phosphorylates serine 376 of SLP-76 and induces the interaction with 14-3-3 proteins SIGNOR-274153 0.769 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser429 KEESVESsLPLNAIE 9606 BTO:0000007 19816404 t lperfetto These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination SIGNOR-188412 0.746 LMO1 protein P25800 UNIPROT TAL1 protein P17542 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 9020185 t miannu Transcriptional activity of tal1 in t cell acute lymphoblastic leukemia (t-all) requires rbtn1 or -2 SIGNOR-46114 0.725 PRKDC protein P78527 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser503 NDEITDEsLENFPSS 9606 16874298 t lperfetto Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin SIGNOR-148327 0.687 KCNJ11 protein Q14654 UNIPROT KATP channel complex SIGNOR-C274 SIGNOR form complex binding 9606 28842488 t lperfetto ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits. SIGNOR-262055 0.653 MCOLN1 protein Q9GZU1 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 26000950 t Induction of autophagy and lysosomal biogenesis via TFEB required MCOLN1-mediated calcineurin activation, linking lysosomal calcium signaling to both calcineurin regulation and autophagy induction. SIGNOR-255308 0.8 RNF8 protein O76064 UNIPROT H1-2 protein P16403 UNIPROT down-regulates polyubiquitination 9606 BTO:0000815 30517763 t miannu ITCH interacts with and ubiquitinates linker histone H1.2 at K46. ITCH biochemically competes with RNF168 and RNF8 to polyubiquitinate histone H1.2. SIGNOR-272928 0.2 PLK1 protein P53350 UNIPROT ZMYM2 protein Q9UBW7 UNIPROT down-regulates quantity by destabilization phosphorylation Ser303 QKQPGVDsLSPVASL 25855382 t lperfetto PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|Similar analyses with ZNF198 identified two clusters of putative Plk1 phosphorylation sites in vitro. A cluster of serine residues at the N-terminus of ZNF198, S303, S305, and S309, and a cluster at the C-terminus, S1056 and S1064. The triple Ser to Ala mutant, S303A/S305A/S309A, consistently exhibited the lowest level of phosphorylation in vitro, in comparison to the double S1056A/S1064A mutant SIGNOR-275559 0.384 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1069 EDSFLQRySSDPTGA 9606 10635327 t llicata Initially, an autophosphorylation reaction creates docking sites for several signaling proteins, including a Cbl binding site at tyrosine 1045 of EGFR. SIGNOR-251093 0.2 asparagine smallmolecule CHEBI:22653 ChEBI Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity precursor of 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270468 0.8 EGFR protein P00533 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 16729043 t gcesareni We identified stat5 as a direct binding partner to egfr and erbb4 and discovered new recognition motifs for shc and stat5.Egf stimulation and subsequent phosphorylation of egfr at tyrosine y978, y998 and y869 would then subsequently lead to recruitment and activation of stat5. SIGNOR-146852 0.818 IRF3 protein Q14653 UNIPROT IFNB1 protein P01574 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 16699525 t lperfetto Similarly, exogenous expression of wild-type Pin1 suppressed TLR3-mediated, IRF3-dependent activation of the IFN-beta promoter and reduced IFN-beta secretion in culture supernatants SIGNOR-252257 0.652 LAMC1 protein P11047 UNIPROT Laminin-9 complex SIGNOR-C180 SIGNOR form complex binding 10809728 t lperfetto Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. SIGNOR-253225 0.528 MAGOH protein P61326 UNIPROT Exon junction complex complex SIGNOR-C369 SIGNOR form complex binding -1 16923391 t miannu The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. SIGNOR-265243 0.95 MAPK1 protein P28482 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser14 MGAELPSsPLAIEYV 9606 BTO:0000567 11416124 t lperfetto These residues are phosphorylated by erk2 but not by p38, jnk, and erk5 in vitro. However, the contribution of the mek/erk pathway to mafa phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs mafa capacity to activate transcription. SIGNOR-108560 0.34 ACSS2 protein Q9NR19 UNIPROT acetate smallmolecule CHEBI:30089 ChEBI down-regulates quantity chemical modification 10843999 t lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. SIGNOR-271827 0.8 PAX7 protein P23759 UNIPROT KMT2D protein O14686 UNIPROT up-regulates binding 9606 SIGNOR-C88 22863532 t miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-198629 0.309 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser21 KSGNKPPsKTCLKEE 9606 9649584 t gcesareni This study investigated the molecular physiology of the nh2-terminal phosphorylation sites that regulate inactivation gating of an a-type k+ channel. The main results show that: (a) pkc acts on four phosphate acceptors (s8, s9, s15, and s21) within the inactivation domain because mutation of these residues to alanine is necessary and sufficient to remove the action of pkc on channel inactivation. SIGNOR-58502 0.2 GSK3A protein P49840 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates activity phosphorylation Ser540 MDSEEPDsRGGSPQM 9606 BTO:0000007 11500362 t We identify multiple phosphorylation sites in the largest, catalytic, subunit (epsilon) of mammalian eIF2B. Glycogen synthase kinase 3 (GSK3) is responsible for phosphorylating Ser535. This regulatory phosphorylation event requires both the fourth site (Ser539) and a distal region, which acts to recruit GSK3 to eIF2Bepsilon in vivo. eIF2Bϵ from mammals or insects is a substrate for glycogen synthase kinase 3 (GSK3), and this inhibits the activity of eIF2B SIGNOR-251215 0.375 PASK protein Q96RG2 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation -1 16275910 t gcesareni Recombinant human PASK (hPASK) phosphorylates purified muscle glycogen synthase, causing robust inactivation. Furthermore, hPASK interacts directly with glycogen synthase when expressed in cultured cells and this interaction and the phosphorylation of glycogen synthase by human PASK (hPASK) are inhibited by glycogen. SIGNOR-245866 0.522 S100A9 protein P06702 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001545 28137827 f miannu S100A9 induces differentiation of acute myeloid leukemia cells through TLR4. SIGNOR-261922 0.7 NCOA6 protein Q14686 UNIPROT GREB1 protein Q4ZG55 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003041 31744881 t miannu Herein, using growth-regulating estrogen receptor binding 1 (GREB1) as an ERα target gene in Ishikawa cells, we demonstrate that nuclear receptor co-activator 6 (NCOA6) is essential for estradiol (E2)/ERα-activated GREB1 transcription. We found that NCOA6 associates with the GREB1 promoter and enhancer in an E2-independent manner and that NCOA6 knockout reduces chromatin looping, enhancer-promoter interactions, and basal GREB1 expression in the absence of E2. SIGNOR-265883 0.2 KLF2 protein Q9Y5W3 UNIPROT NPNT protein Q6UXI9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0005787 BTO:0001103 23612709 f miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion SIGNOR-255456 0.268 ADNP protein Q9H2P0 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 32533114 t miannu Here, we show that ADNP is required for neural induction and differentiation by enhancing Wnt signaling. Mechanistically, ADNP functions to stabilize β-Catenin through binding to its armadillo domain which prevents its association with key components of the degradation complex: Axin and APC. SIGNOR-266756 0.252 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2. SIGNOR-236014 0.784 GATA1 protein P15976 UNIPROT GP6 protein Q9HCN6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12359731 f miannu Deletion analyses and site-directed mutagenesis identified Sp1(227), GATA(177), and Ets(48) sites as essential for GPVI expression. We show that transcription factors GATA-1, Fli-1, and Sp1 can bind to and activate this promoter. SIGNOR-254158 0.285 CDK3 protein Q00526 UNIPROT LIN9 protein Q5TKA1 UNIPROT up-regulates phosphorylation Thr96 KFTATMStPDKKASQ 9606 BTO:0002181 24475316 t lperfetto In this report, we demonstrate that cyclin e1/cdk3 phosphorylates lin-9 on thr-96. Mutating thr-96 to alanine inhibits activation of cyclins a2 and b1 promoters, whereas a phosphomimetic asp mutant strongly activates their promoters and triggers accelerated entry into g2/m phase in 293t cells. SIGNOR-204529 0.2 PKLR protein P30613 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity chemical modification 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266537 0.8 HIPK2 protein Q9H2X6 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates phosphorylation Ser422 AHPPHAPsPGQTVKP 9606 BTO:0002552 15708980 t lperfetto Homeodomain-interacting protein kinase-2 mediates ctbp phosphorylation and degradation in uv-triggered apoptosishipk2 phosphorylates ctbp at ser-422 SIGNOR-134040 0.483 HBEGF protein Q99075 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 10209155 t gcesareni It was concluded that her4 is a newly described receptor for hb-egf and that hb-egf can activate two egf receptor subtypes, her1 and her4, but with different biological response. SIGNOR-67009 0.74 MAPK1 protein P28482 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation 9606 15851026 t gcesareni Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin. SIGNOR-135692 0.469 diazepam chemical CHEBI:49575 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t brain lperfetto The traditional BZ site agonists (GABA-enhancing CNS depressants such as diazepam) are active on the GABAA-Rs containing a gamma2 subunit (Pritchett et al., 1989), a beta subunit, and one of the alpha subunits, alpha1, 2, 3, or 5. SIGNOR-263796 0.8 GSK3B protein P49841 UNIPROT PRKCE protein Q02156 UNIPROT up-regulates phosphorylation Ser346 SEEDRSKsAPTSPCD 9606 18604201 t llicata Specifically, we have identified three phosphorylation sites within pkcepsilon that control its association with 14-3-3.kinase (ser 350), gsk3 (ser 346) and pkc itself (ser 368) SIGNOR-179412 0.271 XAV939 chemical CHEBI:62878 ChEBI AXIN2 protein Q9Y2T1 UNIPROT up-regulates 9606 19759537 f gcesareni Using a quantitative chemical proteomic approach, we discovered that xav939 stabilizes axin by inhibiting the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2 SIGNOR-188048 0.8 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257928 0.8 STOML2 protein Q9UJZ1 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity binding 9606 18641330 t Giorgia In these studies, we also found that SLP-2 interacted with Lck, ZAP70, LAT, and PLC-gamma1 during the 30-min period following stimulation in vitro|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling. SIGNOR-260378 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation 9606 BTO:0001130 12163482 t inferred from 70% family members lperfetto Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein SIGNOR-270099 0.2 GAPDHS protein O14556 UNIPROT 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI up-regulates quantity chemical modification 9606 11724794 t miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion SIGNOR-266497 0.8 FOXQ1 protein Q9C009 UNIPROT MYLK protein Q15746 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002196 10896677 t Luana Results from this analysis revealed that the inhibitory activity of HFH-1 was contained within the forkhead DNA-binding domain. Truncated HFH-1 proteins that lack the entire forkhead domain were unable to repress telokin promoter activity, in contrast expression of the forkhead domain alone was able to repress promoter activity SIGNOR-261609 0.2 MEF2A protein Q02078 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates quantity by expression transcriptional regulation 14630949 f lperfetto Neither GEF nor MEF2A alone significantly activated GLUT4 promoter activity, but increased promoter activity 4- to 5-fold when expressed together. SIGNOR-271692 0.37 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161585 0.607 PIK3C2A protein O00443 UNIPROT PIPP smallmolecule CID:24755493 PUBCHEM up-regulates chemical modification 9606 23119004 t D3 position gcesareni Pi3ks phosphorylate the d3 position of membrane phosphatidylinositides to generate phosphatidylinositol 3,4,5-triphosphate (pip3); SIGNOR-199364 0.8 KCNJ8 protein Q15842 UNIPROT NLRP3 protein Q96P20 UNIPROT down-regulates activity binding 9606 31387986 t lperfetto We further show that Kir6.1 physically associates with NLRP3 and thus inhibits the interactions between the NLRP3 inflammasome subunits. Our results reveal a previously unrecognized function of Kir6.1 as a negative regulator of the NLRP3 inflammasome SIGNOR-262034 0.2 PPP1CC protein P36873 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 16501611 t Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. SIGNOR-248499 0.323 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr869 LGAEEKEyHAEGGKV 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-235956 0.2 Quazepam chemical CHEBI:8694 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t brain lperfetto The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005). SIGNOR-263800 0.8 EGFR protein P00533 UNIPROT LRRK1 protein Q38SD2 UNIPROT down-regulates activity phosphorylation Tyr971 TQQTEEQyFQFLAKF 9534 BTO:0000298 22337768 t miannu In this study, we demonstrate that EGFR regulates the kinase activity of LRRK1 via tyrosine phosphorylation and that this is required for proper endosomal trafficking of EGFR. Phosphorylation of LRRK1 at Tyr-944 results in reduced LRRK1 kinase activity. SIGNOR-262856 0.349 EIF2B3 protein Q9NR50 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269131 0.842 U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR RNA_splicing phenotype SIGNOR-PH201 SIGNOR up-regulates 9606 30765414 f lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270651 0.7 C3 protein P01024 UNIPROT C3 protein P01024 UNIPROT up-regulates activity cleavage Arg671 QPAARRRrSVQLTEK 9606 BTO:0000089 26806831 t lperfetto C3 autoactivates in a process known as “tick-over,” which is characterized by spontaneous hydrolysis of a reactive thiol-ester to generate C3(H2O). Although C3(H2O)Bb produces only relatively small amounts of C3b compared to the other C3 convertases, it nevertheless generates enough C3b to set the C3 convertase amplification loop in motion. SIGNOR-263483 0.2 CSF3 protein P09919 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252287 0.7 tRNA(Gly) smallmolecule CHEBI:29176 ChEBI Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates quantity precursor of 9606 24898252 t miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. SIGNOR-270483 0.8 UBTF protein P17480 UNIPROT rRNA_transcription phenotype SIGNOR-PH145 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0001412 7877691 t lperfetto Rb specifically inhibits the activity of the RNA polymerase I transcription factor UBF (upstream binding factor) in vitro. |These results indicate that there is an additional mechanism by which Rb suppresses cell growth, namely that Rb directly represses transcription of the rRNA genes. SIGNOR-262590 0.7 JAK2 protein O60674 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12370803 f irozzo In this study, we show that Jak2 is involved in c-Myc induction by inducing c-MYC mRNA and protecting c-Myc protein from 26S proteasome-dependent degradation. These results indicate that c-Myc is a downstream target of activated Jak2 in Bcr-Abl positive cells.  SIGNOR-255811 0.463 NAMPT protein P43490 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates 19299583 f lperfetto Using Per2:luciferase transcriptional reporter assays in HEK293 cells (Fig. 2C-E; S2), we show that inhibition of NAMPT by FK866 led to a significant increase in the CLOCK:BMAL1-driven transcription of the Per2:luciferase reporter (Fig. 2C), indicating that reduced NAMPT-mediated NAD+ biosynthesis released CLOCK:BMAL1 from the SIRT1-dependent suppression. SIGNOR-253721 0.596 PTPN1 protein P18031 UNIPROT MAPK15 protein Q8TD08 UNIPROT down-regulates dephosphorylation Tyr177 EDQAVTEyVATRWYR 9606 16336213 t lperfetto Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif. Dephosphorylation of the threonine residue by pp2a (protein serine/threonine phosphatase 2a) decreased erk8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by ptp1b (protein tyrosine phosphatase 1b) decreased activity by only 15-20% SIGNOR-142981 0.332 CASP3 protein P42574 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity cleavage 9606 BTO:0000938 15231831 t lperfetto Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant. SIGNOR-126727 0.516 MAPK7 protein Q13164 UNIPROT KLF2 protein Q9Y5W3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0005787 BTO:0001103 23612709 f miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion SIGNOR-255454 0.478 BCL2L11 protein O43521 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000007 18498746 t lperfetto Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly. SIGNOR-178679 0.955 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser24 GYLRKPKsMHKRFFV -1 8349691 t llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. SIGNOR-251072 0.325 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA -1 10949026 t gcesareni Survival factors, acting through kinases such as Akt and PKA, induce endogenous BAD phosphorylation at two evolutionarily conserved sites, Ser-112 and Ser-136, which leads to the translocation of BAD from the mitochondria to the cytoplasm and the inhibition of BAD-dependent death SIGNOR-67400 0.41 TACR3 protein P29371 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257066 0.2 PAR-1 (Protease-Activated Receptor) Selective Activating Peptide smallmolecule CID:71312048 PUBCHEM F2R protein P25116 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257484 0.8 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1248 PTAENPEyLGLDVPV 9606 BTO:0000149 1706616 t gcesareni However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2. SIGNOR-21203 0.2 ADORA2A protein P29274 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257038 0.276 diarsenic trioxide chemical CHEBI:30621 ChEBI PIN1 protein Q13526 UNIPROT down-regulates activity chemical inhibition 9606 30093655 t Here we show that ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1, and suppresses its oncogenic function by noncovalent binding to Pin1’s active site SIGNOR-259923 0.8 domperidone chemical CHEBI:31515 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258720 0.8 NFATC3 protein Q12968 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21871017 t miannu NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration SIGNOR-264028 0.282 PRKACA protein P17612 UNIPROT PTBP1 protein P26599 UNIPROT down-regulates activity phosphorylation Ser16 AVGTKRGsDELFSTC 10116 12851456 t miannu PKA directly phosphorylates PTB on conserved Ser-16, and PKA activation in PC12 cells induces Ser-16 phosphorylation. PTB carrying a Ser-16 to alanine mutation accumulates normally in the nucleus. However, export of this mutant protein from the nucleus is greatly reduced in heterokaryon shuttling assays. Conversely, hyperphosphorylation of PTB by coexpression with the catalytic subunit of PKA results in the accumulation of PTB in the cytoplasm. SIGNOR-263149 0.314 ADRA2B protein P18089 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256857 0.448 BRAF protein P15056 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0000797 27340238 f These alterations corresponded to mutant KRAS and BRAF-dependent increases in glucose uptake and lactate production. Metabolic reprogramming and glucose conversion to lactate in RKO cells were proportional to levels of BRAF V600E protein. SIGNOR-259373 0.7 BACH1 protein O14867 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity transcriptional regulation 9606 31257027 t inferred from family member BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells. SIGNOR-270266 0.2 AKT2 protein P31751 UNIPROT RALGAPA2 protein Q2PPJ7 UNIPROT down-regulates activity phosphorylation Ser486 SSWGRTYsFTSAMSR 10090 SIGNOR-C469 21148297 t miannu RGC2 is an endogenous substrate for Akt2 downstream of PI 3-kinase. kt2 directly phosphorylated all three sites on RGC2 (Figure 5A). SIGNOR-269797 0.43 ABL1 protein P00519 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Tyr405 STSSSIIySSQEDVK 9606 21081495 t lperfetto Mdm2 has three known c-abl phosphorylation sites (tyr276, tyr394, and tyr405)these data show that c-abl is important for reducing mdm2 and mdmx protein levels after genotoxic stress and suggest another cellular mechanism for the stabilization and activation of p53. SIGNOR-169703 0.704 PPP3CA protein Q08209 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 f gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-84035 0.487 CSNK2B protein P67870 UNIPROT CSNK2B protein P67870 UNIPROT unknown phosphorylation Ser2 sSSEEVSW 9606 1939094 t llicata Phosphorylation of the beta subunit of casein kinase II in human A431 cells. Identification of the autophosphorylation site | Cleavage of the beta subunit, that had been autophosphorylated in vitro, at tryptophan 9 and tryptophan 12 using N-chlorosuccinimide demonstrated that the autophosphorylation site is located near the amino terminus of the protein, most likely at serine 2 and serine 3. SIGNOR-251062 0.2 KANSL3 protein Q9P2N6 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. SIGNOR-267162 0.606 YARS1 protein P54577 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. SIGNOR-270798 0.8 GCC1 protein Q96CN9 UNIPROT ITSN1 protein Q15811 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 30540523 t Giulio GFP-GCC88 was immunoprecipitated by both the short and long form of ITSN-1 but not with FLAG-Rheb (Figure 4A). These data demonstrate that both GCC88 and ITSN-1 are part of a complex. We propose that GCC88 recruits ITSN-1-L to the TGN, which in turn activates Cdc42 at the trans-face of the Golgi (Figure 9A). SIGNOR-260600 0.2 PALB2 protein Q86YC2 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates binding 9606 24485656 t miannu Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates SIGNOR-204541 0.518 PRKCD protein Q05655 UNIPROT ITGB7 protein P26010 UNIPROT unknown phosphorylation Thr783 PLYKSAItTTINPRF 10090 BTO:0001825 12682249 t lperfetto Beta7 subunit is phosphorylated even in unstimulated TK-1 cells. Activation of TK-1 cells with anti-CD3 (Fig. 5_A) and PDBu (Fig. 5_B) increased the phosphorylation 15€“20%. | The result shows that the fourth amino acid of the tryptic peptide was phosphorylated. This phosphorylated threonine residue is most likely the first threonine (Thr782) of threonine triplet (Thr782€“784). SIGNOR-249205 0.311 IL21 protein Q9HBE4 UNIPROT PAX5 protein Q02548 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782;BTO:0000785 22486304 f miannu Interleukin-21 inhibits humoral response to an hiv dna vaccine by enhancing bcl-6 andpax-5expression. SIGNOR-196921 0.255 CSNK1A1L protein Q8N752 UNIPROT GLI3 protein P10071 UNIPROT up-regulates phosphorylation 9606 16481469 t gcesareni Ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed SIGNOR-144554 0.339 JAK2 protein O60674 UNIPROT STAM protein Q92783 UNIPROT up-regulates phosphorylation 9606 9133424 t gcesareni Stam is associated with jak3 and jak2 tyrosine kinases via its itam region and phosphorylated by jak3 and jak2 upon stimulation with il-2. SIGNOR-47834 0.605 FADD protein Q13158 UNIPROT CASP10 protein Q92851 UNIPROT up-regulates binding 9606 11717445 t gcesareni The death-effector domains ofcasp8and -10 bothinteractwith the death-effector domain offadd. Therefore, caspase-10 is recruited into the fas signaling complex and becomes activated like caspase-8 SIGNOR-112058 0.786 VEGFD protein O43915 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252278 0.7 NRG3 protein P56975 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 9275162 t gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. SIGNOR-50614 0.738 DLL1 protein O00548 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-254315 0.626 Mequitazine chemical CHEBI:31821 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 t Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells SIGNOR-257780 0.8 CSNK2A1 protein P68400 UNIPROT ACACA protein Q13085 UNIPROT unknown phosphorylation Ser29 GSVSEDNsEDEISNL -1 2900140 t llicata These results show that casein kinase-2 phosphorylates site 6 exclusively SIGNOR-250823 0.312 LCK protein P06239 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates activity phosphorylation Tyr688 FAEPYNLySSLKELV 9534 BTO:0004055 9461588 t The regulatory p85 subunit of phosphatidylinositol 3-kinase is phosphorylated on tyrosine residues. We report that this phosphorylation event is readily catalyzed by the Abl and Lck protein-tyrosine kinases in vitro, by Bcr-Abl or a catalytically activated Lck-Y505F in co-transfected COS cells. we have mapped a major phosphorylation site to Tyr-688 in the C-terminal SH2 domain of p85. Tyrosine phosphorylation of p85 in vitro or in vivo was not associated with detectable change in the enzymatic activity of the phosphatidylinositol 3-kinase heterodimer, but correlated with a strong reduction in the binding of some, but not all, phosphoproteins to the SH2 domains of p85. SIGNOR-252699 0.585 RBBP4 protein Q09028 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263849 0.826 BMP4 protein P12644 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 26330344 t fferrentino BMP interacts with specific receptors on the cell surface, BMP receptor types 1 and 2 (BMPr1 and BMPr2). SIGNOR-253548 0.887 MAPK14 protein Q16539 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates quantity by destabilization phosphorylation Thr367 NNSSRPStPTINVLE 10090 BTO:0000165 28067271 t Here, we show that p38α kinase promotes EZH2 degradation in differentiating muscle cells through phosphorylation of threonine 372 SIGNOR-255663 0.38 YWHAB protein P31946 UNIPROT SRPK2 protein P78362 UNIPROT down-regulates binding 9606 phosphorylation:Thr492 PSHDRSRtVSASSTG 19592491 t lperfetto 14-3-3 interacts with akt-phosphorylated srpk2 and blocks its nuclear translocation. kt phosphorylates SRPK2 on Thr-492 and promotes its nuclear translocation leading to cyclin D1 up-regulation, cell cycle reentry, and neuronal apoptosis. In addition, SRPK2 phosphorylates SC35 and, thus, inactivates p53, resulting in cyclin D1 up-regulation. 14-3-3 binding to SRPK2, regulated by Akt phosphorylation, inhibits these events. SIGNOR-186767 0.336 Caspase 9 complex complex SIGNOR-C229 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000567 9390557 t lperfetto Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade. SIGNOR-256462 0.623 CHEK2 protein O96017 UNIPROT AATF protein Q9NY61 UNIPROT up-regulates quantity by stabilization phosphorylation Ser477 ELIERKTsSLDPNDQ 9606 BTO:0001109 17157788 t lperfetto Three putative Chk2 phosphorylation sites (Stevens et al., 2003) are present in Che-1 at resides Ser141, Ser474, and Ser508. Thus, we performed in vitro Chk2 kinase assays utilizing the GST-Che-1 fusion peptides spanning these residues as substrates.| Taken together, these results indicate that Chk2 phosphorylates Che-1 and this phosphorylation contributes to increase Che-1 stability. SIGNOR-264417 0.365 FAS protein P25445 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates 9606 22830020 f gcesareni It was also shown that the fas active receptor induces rassf1a to compete with raf1 in binding to mst2, thus promoting the formation of a lats1 complex. SIGNOR-198435 0.259 SB 203580 chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258279 0.8 MAPK8 protein P45983 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr57 NFDFVTEtPLEGDFA -1 12058028 t miannu P38Œ± and JNK1 Phosphorylate p21 in Vitro at Thr57 and Ser130. These data suggest that phosphorylation at Thr57 is necessary for stabilization of p21. SIGNOR-250118 0.659 TP53 protein P04637 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 28073943 t miannu KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage. p53 directly regulates JMJD2B gene expression by binding to a canonical p53-consensus motif in the JMJD2B promoter. SIGNOR-263729 0.285 GART protein P22102 UNIPROT 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-267315 0.8 CDK2 protein P24941 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 17038621 t lperfetto Cdk2 specifically phosphorylated foxo1 at serine-249 (ser249) in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of foxo1. SIGNOR-150028 0.638 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Arg334 KNCPKKTrNLKKITR -1 7989361 t lperfetto The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994. SIGNOR-263628 0.584 LONP2 protein Q86WA8 UNIPROT TYSND1 protein Q2T9J0 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0000567 22002062 t miannu Self-cleavage of Tysnd1 in the active oligomer most likely inactivates its protease activity. Subsequently, the cleaved products are degraded by PsLon and removed from the Tysnd1 oligomer. SIGNOR-261054 0.646 DMTF1 protein Q9Y222 UNIPROT EGR1 protein P18146 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 t Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  SIGNOR-261584 0.2 PI4KA protein P42356 UNIPROT 1-phosphatidyl-1D-myo-inositol 4-phosphate smallmolecule CHEBI:17526 ChEBI up-regulates quantity chemical modification 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269103 0.8 PAPOLB protein Q9NRJ5 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 19224921 f lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. SIGNOR-268326 0.7 Caspase 3 complex complex SIGNOR-C221 SIGNOR ROCK1 protein Q13464 UNIPROT up-regulates cleavage 9606 11283607 t gcesareni Rock i is cleaved by casp3 at a conserved detd1113/g sequence and its carboxy-terminal inhibitory domain is removed, resulting in deregulated and constitutive kinase activity. SIGNOR-256460 0.724 NEK2 protein P51955 UNIPROT GAS2L1 protein Q99501 UNIPROT up-regulates activity phosphorylation Ser352 HPRSRRYsGDSDSSA 9606 32289147 t miannu Nek2A mediates G2/M phosphorylation of GAS2L1. GAS2L1 and its Ser352 phosphorylation are required for proper spindle organization and chromosome segregation.  SIGNOR-273683 0.2 R2SP co-chaperone complex SIGNOR-C517 SIGNOR PPFIA2 protein O75334 UNIPROT up-regulates quantity by stabilization binding 9606 29844425 t miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. Remarkably, R2SP is required for liprin-α2 expression and for the assembly of liprin-α2 complexes, indicating that R2SP functions in quaternary protein folding. SIGNOR-270942 0.2 SMARCD2 protein Q92925 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270603 0.716 ESR2 protein Q92731 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 f lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. SIGNOR-268547 0.489 MMP2 protein P08253 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272387 0.7 SRC protein P12931 UNIPROT PLSCR1 protein O15162 UNIPROT up-regulates activity phosphorylation Tyr74 PVYNQPVyNQPVGAA 9606 12871937 t lperfetto Plscr1 is phosphorylated by c-src, within the tandem repeat sequence 68vynqpvynqp77.|The EGF-mediated Interaction between PLSCR1 and Shc Requires Phosphorylation of Tyr69 and Tyr74 in PLSCR1 SIGNOR-103773 0.488 VPS13B protein Q7Z7G8 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 25492866 f miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons SIGNOR-266872 0.7 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000938 9771888 t The effect has been demonstrated using P10636-8 gcesareni Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase. SIGNOR-60655 0.728 BMP4 protein P12644 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates activity binding 10090 BTO:0000165 11282024 t lperfetto Bmp-4 and gdf-5 are known to bind to activin SIGNOR-235376 0.847 TP53 protein P04637 UNIPROT CRYAB protein P02511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21556774 t miannu Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53 SIGNOR-253638 0.483 REST protein Q13127 UNIPROT BDNF protein P23560 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21832040 f miannu HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK). SIGNOR-255075 0.431 ENAH protein Q8N8S7 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 18508258 f miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. SIGNOR-268392 0.7 PRKCA protein P17252 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1303 NKLRRQHsYDTFVDL -1 11306676 t lperfetto These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. SIGNOR-249083 0.481 PRKG2 protein Q13237 UNIPROT LASP1 protein Q14847 UNIPROT unknown phosphorylation Ser146 MEPERRDsQDGSSYR 9606 12571245 t lperfetto Recombinant human LASP was phosphorylated by cGMP- and cAMP-dependent protein kinase (cAK) in vitro. Cotransfection of PtK-2 cells with LASP and cGK confirmed phosphorylation of LASP in vivo. Studies with human LASP mutants identified serine 146 as a specific phosphorylation site for cGK and cAK in vivo. LASP is an actin-binding protein, and the phospho-LASP-mimicking mutant S146D showed reduced binding affinity for F-actin in cosedimentation experiments. SIGNOR-249197 0.348 NOTCH1 protein P46531 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 18342499 f flangone Genetic ablation or activation of the pathway reveals that Notch signalling promotes differentiation of the hair follicle, sebaceous gland and interfollicular epidermal lineages SIGNOR-241998 0.7 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage 9606 BTO:0000131 29880919 t lperfetto Activated protein C (APC), which cleaves and inactivates both FVIIIa and FVa, thereby shutting down both the tenase and prothrombinase complexes SIGNOR-263528 0.584 imatinib chemical CHEBI:45783 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition 9606 22045730 t Recently, imatinib, an inhibitor of several tyrosine kinases, including c-abl, c-kit and PDGFRs, was demonstrated to ameliorate dystrophic phenotypes in mdx mice by suppressing the phosphorylation of PDGFRa SIGNOR-254378 0.8 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu75 EEAFEALeSSTATDV -1 10556651 t lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. SIGNOR-263684 0.655 CSNK2A1 protein P68400 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation Ser565 VISSSEDsDAENSSS 9606 BTO:0000551 16873060 t llicata Here we show that ck2 regulates pml protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at ser517. SIGNOR-148310 0.348 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Thr141 EDEAKFPtMNRRGAI 9606 19366211 t llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. a t141d substitution markedly increases basal lipid-independent pkcdelta activity; SIGNOR-185279 0.2 NTF3 protein P20783 UNIPROT NTRK3 protein Q16288 UNIPROT up-regulates binding 9606 1653651 t gcesareni Trkc, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. SIGNOR-20699 0.844 SYVN1 protein Q86TM6 UNIPROT HMGCR protein P04035 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0000944 14593114 t miannu In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.Human HRD1 appears to be involved in the basal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase but not in the degradation that is regulated by sterols. SIGNOR-272594 0.578 CSNK2B protein P67870 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by destabilization phosphorylation Ser215 IKEEDTPsDNDSGIC 9606 BTO:0000567 23123191 t miannu By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form.  SIGNOR-276424 0.2 IFNG protein P01579 UNIPROT LPL protein P06858 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000801 2114181 f Regulation miannu Interferon-gamma inhibits lipoprotein lipase in human monocyte-derived macrophages. The data indicate that IFN-gamma is inhibiting macrophage LPL at least in part via a reduction of LPL synthesis SIGNOR-251848 0.362 P2RY2 protein P41231 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256759 0.358 MAML1 protein Q92585 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 16510869 t gcesareni Unexpectedly, however, emerging evidence implicate maml proteins as exciting key transcriptional co-activators in other signal transduction pathways including: muscle differentiation and myopathies (mef2c), tumor suppressor pathway (p53) and colon carcinoma survival (beta-catenin). SIGNOR-144913 0.402 SP1 protein P08047 UNIPROT ATP2C1 protein P98194 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 15955096 f miannu when Sp1 or YY1 was overexpressed in keratinocytes, an obvious increase in ATP2C1 promoter activity was observed, which was in contrast with the case where a mutant promoter lacking the binding sites for Sp1 and YY1 was used as the reporter. SIGNOR-255194 0.2 DYRK1A protein Q13627 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity SIGNOR-183680 0.31 GTF2I protein P78347 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity relocalization 9606 21282467 t lperfetto Moreover, the inhibitory effect of TFII-I on transcription is mediated by its ability to recruit corepressor complexes, including histone deacetylase 3 (HDAC3) (25, 133), histone H3K4-specific demethylase LSD1 (48), and components of the polycomb repressor complex SIGNOR-268540 0.414 2-[4-[3-(6-quinolinylmethyl)-5-triazolo[4,5-b]pyrazinyl]-1-pyrazolyl]ethanol chemical CHEBI:91425 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205968 0.8 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser53 LPPFEDEsEGLLGTE 9606 19647517 t lperfetto Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry SIGNOR-187400 0.961 OPTN protein Q96CV9 UNIPROT NEFL protein P07196 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22194658 f same result in PC12 cell miannu SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA. SIGNOR-259881 0.27 INSR protein P06213 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Tyr66 LHQEDNDyINASLIK -1 11506178 t lperfetto Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B SIGNOR-249370 0.78 EGFR protein P00533 UNIPROT SOX2 protein P48431 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19882665 f miannu We show that egfr-mediated signaling promotes sox2 expression, which in turn binds to the egfr promoter and directly upregulates egfr expression. SIGNOR-189033 0.493 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser139 DARDLEMsKKVRRSY -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276125 0.698 PAFAH1B1 protein P43034 UNIPROT Cerebral_cortex_development phenotype SIGNOR-PH66 SIGNOR up-regulates 9606 23973156 f miannu LIS1, the first gene to be identified as involved in a neuronal migration disease, is a dosage-sensitive gene whose proper levels are required for multiple aspects of cortical development. Deletions in LIS1 result in a severe brain malformation, known as lissencephaly, whereas duplications delay brain development. LIS1 affects the proliferation of progenitors, spindle orientation and interkinetic nuclear movement in the ventricular zone, as well as nucleokinesis and migration of neurons. SIGNOR-252165 0.7 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation Ser52 MILLSELsRRRIRSI 9606 25660019 t Manara We now demonstrate a major role for Rheb in inhibiting protein synthesis by enhancing the phosphorylation of eIF2α by protein kinase-like ER kinase (PERK). SIGNOR-260874 0.757 CSNK1D protein P48730 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates phosphorylation 9606 12000790 t lperfetto We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45 . This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/mscomplex of axin and casein kinase i (cki) induces betBeta-catenin phosphorylation at a single site: serine 45 (s45) SIGNOR-227970 0.519 STK4 protein Q13043 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 BTO:0000782 BTO:0001253 22898666 t gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1. SIGNOR-191847 0.582 ziprasidone chemical CHEBI:10119 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258502 0.8 PRSS2 protein P07478 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity cleavage Lys34 QGTNRSSkGRSLIGK -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263606 0.2 SMARCB1 protein Q12824 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270697 0.851 SIRT1 protein Q96EB6 UNIPROT XPA protein P23025 UNIPROT up-regulates activity deacetylation Lys63 TGGMANVkAAPKIID 9606 BTO:0002806 30327428 t miannu SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR SIGNOR-262293 0.525 UHMK1 protein Q8TAS1 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser438 GSHGQTPsPGALPLG 9606 10880969 t lperfetto We also identified a tryptic peptide of synapsin i phosphorylated by kis SIGNOR-78899 0.381 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249642 0.697 PTK6 protein Q13882 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000150 BTO:0001129 20606012 t gcesareni Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6. SIGNOR-166506 0.454 SLC9A2 protein Q9UBY0 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265592 0.8 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 18930133 t PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation. SIGNOR-248343 0.413 DAB2 protein P98082 UNIPROT LRP6 protein O75581 UNIPROT down-regulates binding 9606 22491013 t gcesareni Wnt stimulation induces the casein kinase 2 (ck2)-dependent phosphorylation of lrp6 at s1579, promoting its binding to dab2 and internalization with clathrin. SIGNOR-196925 0.508 BMPR1A protein P36894 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 10090 10712517 t gcesareni Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors SIGNOR-75652 0.616 FUBP1 protein Q96AE4 UNIPROT BIK protein Q13323 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19637194 f irozzo FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In particular, elevated expression of the Bcl-2 family members Bik and Noxa was detected. SIGNOR-259127 0.2 MYCT1 protein Q8N699 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity 9606 30283340 f miannu Herein, we observed that overexpression of MYCT1 induced apoptosis in HL-60 and KG-1a cells, and upregulated Bax, downregulated Bcl-2, and enhanced cleavage of caspase-3 and -9. Similar proapoptotic role of MYCT1 was also found in the AML cell xenografts. These results suggest that MYCT1 affects AML cell apoptosis by modulating the endogenous apoptotic pathways. SIGNOR-261943 0.2 NUMB protein P49757 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates BTO:0001103 12361602 t apalma Numb is an inhibitor of Notch signaling that interacts with the intracellular portion of Notch and antagonizes its activity by preventing nuclear translocation SIGNOR-255374 0.79 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCD protein Q05655 UNIPROT up-regulates activity binding 9606 14967450 t PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. SIGNOR-242587 0.8 PKC proteinfamily SIGNOR-PF53 SIGNOR KLHL3 protein Q9UH77 UNIPROT up-regulates quantity by stabilization phosphorylation Ser433 PMNTRRSsVGVGVVE 9534 BTO:0000298 25313067 t done miannu We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation. SIGNOR-273780 0.2 MMP2 protein P08253 UNIPROT A2M protein P01023 UNIPROT down-regulates quantity by destabilization cleavage Gly702 YEMHGPEgLRVGFYE -1 9344465 t lperfetto The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. SIGNOR-261780 0.62 CDK1 protein P06493 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Thr53 KEPSEVPtPKRPRGR 9606 17960875 t gcesareni Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation. SIGNOR-158608 0.392 TLN1 protein Q9Y490 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257612 0.744 NFATC2 protein Q13469 UNIPROT NF90-NF45 complex SIGNOR-C443 SIGNOR up-regulates activity binding 9606 BTO:0000782 33555115 t miannu Herein, we demonstrate that NFAT, a key regulator of the immune response, translocates from cytoplasm to nucleolus and interacts with NF45/NF90 complex to collaboratively promote rDNA transcription via triggering the directly binding of NF45/NF90 to the ARRE2-like sequences in rDNA promoter upon T-cell activation in vitro. NF45/NF90‐mediated rDNA transcription contributes to T‐cell activation by interacting with NFATc2 in the nucleolus SIGNOR-268492 0.254 P2RY2 protein P41231 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257233 0.2 3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid chemical CHEBI:91194 ChEBI LPAR3 protein Q9UBY5 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193564 0.8 SRC protein P12931 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Tyr54 YLKERRVyVTLTCAF 9606 17456551 t lperfetto Using fluorescently tagged proteins combined with resonance energy transfer and image cross-correlation spectroscopy approaches, we show in live cells that beta2-adaptin phosphorylation is an important regulatory process for the dissociation of beta-arrestin-AP-2 complexes in CCPs. Finally, we show that beta2-adaptin phosphorylation is involved in the early steps of receptor internalization. Our findings not only unveil beta2-adaptin as a new Src target during AT1R internalization, but also support the role of receptor-mediated signaling in the control of clathrin-dependent endocytosis of receptors. SIGNOR-154564 0.671 paliperidone chemical CHEBI:82978 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000601 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258565 0.8 WNK1 protein Q9H4A3 UNIPROT SYT2 protein Q8N9I0 UNIPROT up-regulates activity phosphorylation Thr199 ETKVHRKtLNPAFNE 9606 BTO:0000007 15350218 t miannu Endogenous WNK1 and Syt2 coimmunoprecipitate and colocalize on a subset of secretory granules in INS-1 cells. Phosphorylation by WNK1 increases the amount of Ca2+ required for Syt2 binding to phospholipid vesicles; mutation of threonine 202, a WNK1 phosphorylation site, partially prevents this change. These findings suggest that phosphorylation of Syts by WNK1 can regulate Ca2+ sensing and the subsequent Ca2+-dependent interactions mediated by Syt C2 domains. . In contrast, WNK1 phosphorylated Syt2 on T202 and T386 within the C2 domains (Figure 6B). SIGNOR-263049 0.621 NEUROG3 protein Q9Y4Z2 UNIPROT NEUROD1 protein Q13562 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19028584 f miannu Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. SIGNOR-254630 0.448 PRKDC protein P78527 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001949 18439899 t gcesareni DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform SIGNOR-252447 0.744 MAPK14 protein Q16539 UNIPROT MAPK10 protein P53779 UNIPROT down-regulates 9606 20626350 f gcesareni Jnk and p38 mapk activation have antagonistic effects in many cases. Froma a mechanicistic point of view, the p38 mapk pathway can negatively regulate jnk activity at the level of map3ks, either by phosphorylating mlk3 or the tak1 regulatory subunit tab1 SIGNOR-166608 0.402 AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR Early Endosome complex SIGNOR-C246 SIGNOR up-regulates activity relocalization 9606 23144738 t lperfetto Rabip4' colocalized with AP-3 on a tubular subdomain of early endosomes and the extent of colocalization was increased by a dominant negative rab4 mutant. Knock-down of AP-3 had an ever more dramatic effect and caused accumulation of lysosomes in protrusions at the plasma membrane. The most peripheral lysosomes were localized beyond microtubules, within the cortical actin network. Our results uncover a novel function for AP-3 and rabip4' in regulating lysosome positioning through an interorganellar pathway. SIGNOR-260712 0.2 Host translation inhibitor nsp1 protein P0DTD1-PRO_0000449619 UNIPROT RPS3 protein P23396 UNIPROT down-regulates activity binding -1 33188728 t miannu Nsp1 Locks the 40S in a Conformation Incompatible with mRNA Loading and Disrupts Initiation Factor Binding. Molecular interactions between C-Nsp1 and 40S ribosome components, including uS3, h18, and uS5. SIGNOR-262507 0.2 HPX protein P02790 UNIPROT HBB protein P68871 UNIPROT down-regulates activity 9606 20617898 f Regulation miannu The endogenous molecule hemoglobin and its derivative heme are often released into tissue compartments where there is infection in the presence of degrading blood. We found that hemoglobin synergizes with multiple TLR agonists to induce high levels of tumor necrosis factor and interleukin-6 from macrophages and that this synergy is independent of TLR4 and MyD88. In contrast, heme synergized with some but not all TLR agonists studied. Furthermore, the synergy of both hemoglobin and heme with lipopolysaccharide was suppressed by hemopexin, a plasma heme-binding protein. SIGNOR-251811 0.484 RNF4 protein P78317 UNIPROT KDM5C protein P41229 UNIPROT up-regulates activity sumoylation 9606 33859667 t SaraGualdi Hendriks and coworkers showed that, in response to alkylation damage by methyl methanesulfonate (MMS), SUMOylated JARID1B (KDM5B) is ubiquitylated by the SUMOtargeted ubiquitin ligase RNF4 and degraded by the proteasome, whereas JARID1C (KDM5C) is SUMOylated and recruited to the chromatin to demethylate histone H3K4 (Hendriks et al., 2015). SIGNOR-271576 0.2 PLK1 protein P53350 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1525 PIKYLEEsDEDDLF 9606 19098900 t gcesareni Here we report that when phosphorylated, ser 1524 of topo iialpha acts as a binding site for the brct domain of mdc1 (mediator of dna damage checkpoint protein-1), thereby recruiting mdc1 to chromatin SIGNOR-182844 0.492 MYD88 protein Q99836 UNIPROT DHX36 protein Q9H2U1 UNIPROT up-regulates activity binding 9606 BTO:0002042 20696886 t miannu We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. This study demonstrates that DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of pDCs and suggests a much broader role for DHX helicases in viral sensing. SIGNOR-260956 0.504 CSNK2A1 protein P68400 UNIPROT IGF2R protein P11717 UNIPROT unknown phosphorylation Ser2484 LVSFHDDsDEDLLHI 9606 8318012 t lperfetto The two sites phosphorylated by ck ii in vivo and in vitro are ser82 and ser157. SIGNOR-37835 0.485 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PAK1 protein Q13153 UNIPROT down-regulates phosphorylation 9606 14993270 t inferred from 70% family members gcesareni Activated erk can phosphorylate t292 in the prs, and this blocks the ability of pak to phosphorylate s298 and of rac-pak signaling to enhance mek1-erk complex formation. SIGNOR-270086 0.2 TNFRSF13C protein Q96RJ3 UNIPROT Lymphoma phenotype SIGNOR-PH14 SIGNOR up-regulates 9606 BTO:0000776 24432023 f lperfetto Non-canonical nf-kb signaling initiated by baff influences b cell biology at multiple junctures. SIGNOR-204364 0.7 TSC2 protein P49815 UNIPROT RHEB protein Q15382 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000142 15340059 t lperfetto Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb. SIGNOR-128432 0.92 SOHLH1 protein Q5JUK2 UNIPROT KIT protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0002181 22328502 t Luana Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression. SIGNOR-266205 0.353 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates activity dephosphorylation Tyr594 TYVDPHTyEDPNQAV -1 21538645 t gcesareni The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates SIGNOR-246039 0.646 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000671 9335553 t lperfetto These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling. SIGNOR-52700 0.757 SCN1A protein P35498 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 t miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. SIGNOR-253402 0.8 EGFR protein P00533 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 7925415 t lperfetto Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. SIGNOR-34691 0.414 neuropeptide FF receptor agonist smallmolecule CHEBI:141000 ChEBI NPFFR1 protein Q9GZQ6 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257549 0.8 ZBED1 protein O96006 UNIPROT RPS6 protein P62753 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 17220279 t Luana HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid. SIGNOR-266082 0.2 GTF2F1 protein P35269 UNIPROT GTF2F1 protein P35269 UNIPROT down-regulates phosphorylation Ser385 GGSSRGNsRPGTPSA 9606 10428810 t gcesareni We show that tfiifalpha possesses a serine/threonine kinase activity, allowing an autophosphorylation of the two residues at position serine 385 and threonine 389. Mutation analysis strongly suggests that autophosphorylation of both sites regulates the transcription elongation process. SIGNOR-69767 0.2 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser739 GSIDMVDsPQLATLA 9606 BTO:0000938 16923168 t The effect has been demonstrated using P10636-8 lperfetto Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation. SIGNOR-148978 0.462 ATR protein Q13535 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates phosphorylation Thr859 WEVGFPStQTCMERG 9606 23273981 t llicata Characterization of this site using phospho-specific antibodies and mutational analysis reveals that it is phosphorylated by atr and is required for binding of ctip to chromatin and subsequent processive resection. SIGNOR-200245 0.599 MLLT10 protein P55197 UNIPROT SS18/MLLT10 complex SIGNOR-C75 SIGNOR form complex binding 9606 11423977 t miannu Based on these results, a model is proposed in which the syt and af10 proteins act in concert as bipartite transcription factors SIGNOR-108924 0.436 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258098 0.8 MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation Ser271 ISGRLVDsKAKTRSA 9606 9312068 t lperfetto Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1 SIGNOR-51207 0.712 SYCP2 protein Q9BX26 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR form complex binding 9606 22394509 t miannu The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region. SIGNOR-264199 0.645 EFTUD2 protein Q15029 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270639 0.791 SRC protein P12931 UNIPROT FCRL3 protein Q96P31 UNIPROT up-regulates activity phosphorylation Tyr692 HEELTVLySELKKTH -1 12051764 t miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. SIGNOR-274007 0.2 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249325 0.754 MAP3K14 protein Q99558 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 9520446 t lperfetto Nf-kappab-inducing kinase activates ikk-alpha by phosphorylation of ser-176.Nik preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa. SIGNOR-217433 0.713 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser360 PRIFQGYsFVAPSIL 9606 BTO:0000567 10806207 t llicata Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity. SIGNOR-77216 0.587 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr771 ADIESSNyMAPYDNY 9606 18567737 t gcesareni Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr. SIGNOR-179080 0.679 EIF2B5 protein Q13144 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269123 0.834 TWIST2 protein Q8WVJ9 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002590 17487558 f miannu Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells SIGNOR-255514 0.2 GDF6 protein Q6KF10 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9606 16049014 t gcesareni We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10. SIGNOR-139090 0.59 PRKCB protein P05771 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser187 DLGERKPsSAAYQKA -1 9244383 t lperfetto We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198. SIGNOR-248974 0.334 pazopanib chemical CHEBI:71219 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 18620382 t Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. SIGNOR-257737 0.8 EIF2S2 protein P20042 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 t lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. SIGNOR-269115 0.954 FBXW7 protein Q969H0 UNIPROT NOTCH4 protein Q99466 UNIPROT down-regulates ubiquitination 9606 11585921 t gcesareni We show here that the f-box/wd40 repeat protein sel-10 negatively regulates notch receptor activity by targeting the intracellular domain of notch receptors for ubiquitin-mediated protein degradation. in conclusion, hsel-10 physically associates with mouse notch4(int-3) through the wd40 domain, whereas the f-box domain is not required for this interaction. SIGNOR-110955 0.513 chlorphenamine chemical CHEBI:52010 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 12781173 t Luana Identification of a dual histamine H1/H3 receptor ligand based on the H1 antagonist chlorpheniramine. SIGNOR-257896 0.8 LYN protein P07948 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Tyr52 VQKKPTMyPEWKSTF -1 9692543 t Lyn was found to phosphorylate Lyn-associated and recombinant PKC-delta in vitro and the tyrosine 52 phosphorylated PKC-delta was recruited to associate with the Lyn SH2 domain. SIGNOR-251408 0.538 CSNK1D protein P48730 UNIPROT PER1 protein O15534 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 11165242 t miannu Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2). SIGNOR-268001 0.8 PDPK1 protein O15530 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation Thr309 SDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of pkbbeta and pkbgamma by pdk1 was accompanied by the phosphorylation of the residues equivalent to thr308 in pkbalpha, namely thr309 (pkbbeta) and thr305 (pkbgamma) SIGNOR-236785 0.72 MMP2 protein P08253 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272364 0.7 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNJ2 protein P63252 UNIPROT down-regulates activity phosphorylation Ser425 PRPLRREsEI -1 19843922 t done miannu KCNJ2 encodes Kir2.1, a pore-forming subunit of the cardiac inward rectifier current, I(K1). This PKA-simulated catecholaminergic stimulation caused marked reduction of outward I(K1) compared with Kir2.1-WT. PKA-induced reduction in I(K1) was eliminated by mutating the phosphorylation site at serine 425 (S425N). SIGNOR-273779 0.2 CD3 complex SIGNOR-C432 SIGNOR NCK1 protein P16333 UNIPROT up-regulates activity relocalization 9606 12110186 t We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3ϵ and results in recruitment of the adaptor protein Nck. SIGNOR-259935 0.344 entinostat chemical CHEBI:132082 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257961 0.8 AKT1 protein P31749 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates activity phosphorylation Ser87 FIFMRRSsLLSRSSS 9606 16282323 t lperfetto Recombinant Akt could directly phosphorylate a GST-Bim(EL) fusion protein and identified the Akt phosphorylation site in the Bim(EL) domain as Ser(87). Further, we demonstrated that cytokine stimulation promotes Bim(EL) binding to 14-3-3 proteins. Finally, we show that mutation of Ser(87) dramatically increases the apoptotic potency of Bim(EL). SIGNOR-252487 0.584 FUS protein P35637 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates quantity post transcriptional regulation 10090 BTO:0000142 32118033 t lperfetto These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.|As seen in Figure 7 (top panel), both PSD-95 Q1-Q2 and Shank1a GQ probes pulled down endogenous FUS, whereas their M2 mutants did not, indicating that the GQ structure is sufficient for recognition. SIGNOR-262104 0.2 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation Thr185 HDHTGFLtEYVATRW 9606 BTO:0003807 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-236447 0.74 NRAS protein P01111 UNIPROT ARAF protein P10398 UNIPROT up-regulates binding 9606 21779497 t gcesareni The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175216 0.829 Macropinosomes formation phenotype SIGNOR-PH227 SIGNOR Early macropinosomes phenotype SIGNOR-PH228 SIGNOR up-regulates 9606 33722976 t miannu Completion of macropinosome formation requires membrane fusion and is followed by maturation of the resulting vacuole, which proceeds to merge with endosomes and, ultimately, lysosomes.  SIGNOR-277775 0.7 PRKD1 protein Q15139 UNIPROT RTKN protein Q9BST9 UNIPROT up-regulates activity phosphorylation Ser448 QALAKQGsLYHEMAI 22228765 t Phosphosite positions are derived from Figure 2 lperfetto Here, we show that rhotekin, an effector of RhoA GTPase, is a novel substrate of PKD. We identified Ser-435 in rhotekin as the potential site targeted by PKD in vivo. Expression of a phosphomimetic S435E rhotekin mutant resulted in an increase of endogenous active RhoA GTPase levels. Phosphorylation of rhotekin by PKD2 modulates the anchoring of the RhoA in the plasma membrane. SIGNOR-275511 0.362 mRNA_capping phenotype SIGNOR-PH178 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization chemical modification 9606 19224921 f lperfetto Because only mRNA molecules that have been correctly spliced, capped at the 5′ extremity, and processed at the 3′ extremity can be used as templates for translation, processing of mRNA precursors plays a critical role in the regulation of gene expression. 3′ processing of pre-mRNAs comprises two steps (reviewed in Ref. 4): cleavage and polyadenylation. SIGNOR-268317 0.7 CENPE protein Q02224 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates activity 10090 12925705 f lperfetto CENP-E is required for efficient recruitment of BubR1, Mad1, and Mad2 to attached and newly unattached kinetochores SIGNOR-252045 0.785 bortezomib chemical CHEBI:52717 ChEBI PSMD1 protein Q99460 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 21504411 t miannu Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma. SIGNOR-259312 0.8 CREB5 protein Q02930 UNIPROT STAT1 protein P42224 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002817 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253810 0.2 PRKCA protein P17252 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Thr478 CNENFKKtFKRILHI 9606 BTO:0000975 15107581 t Translocation from Endosome to Lysosome fspada The peptide p10-t478a (thr478 to alanine) was not phosphorylated by pkc, indicating that thr478 can be phosphorylated by pkc. SIGNOR-124356 0.2 CDK7 protein P50613 UNIPROT NR5A1 protein Q13285 UNIPROT up-regulates phosphorylation Ser203 EYPEPYAsPPQPGLP 9606 17901130 t llicata In conclusion, our results indicate that cdk7, as part of the cak complex and tfiih, phosphorylates sf1 at s203 followed by increased transcriptional activity of sf1 SIGNOR-157952 0.374 TUBE1 protein Q9UJT0 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 28347630 f miannu Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation SIGNOR-267178 0.7 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 12832467 t lperfetto Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. SIGNOR-252760 0.719 MLNR protein O43193 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257016 0.41 CCR3 protein P51677 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 BTO:0000399 10706854 t Activation of ERK2 and p38 by eotaxin is mediated through CCR3. SIGNOR-256093 0.3 SCN4A protein P35499 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 t miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. SIGNOR-253405 0.8 NEK9 protein Q8TD19 UNIPROT NEK9 protein Q8TD19 UNIPROT up-regulates phosphorylation Ser944 GQQVGMHsKGTQTAK 9606 21454704 t lperfetto We find that the interaction of lc8 with nek9 depends on a (k/r)xtqt motif adjacent to the nek9 c-terminal coiled coil motif, results in nek9 multimerization, and increases the rate of nek9 autoactivation. Lc8 binding to nek9 is regulated by nek9 activity through the autophosphorylation of ser(944), a residue immediately n-terminal to the (k/r)xtqt motif. SIGNOR-173026 0.2 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Ser105 TGAGAAGsPAQQHAH 26375055 t lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity SIGNOR-276520 0.261 PTAFR protein P25105 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257329 0.2 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:93369 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258538 0.8 YWHAE protein P62258 UNIPROT NEFL protein P07196 UNIPROT down-regulates activity binding 9606 23230147 t miannu These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments. SIGNOR-252398 0.28 RFX complex complex SIGNOR-C104 SIGNOR HLA-DQB1 protein P01920 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 f The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-253992 0.277 MAPK3 protein P27361 UNIPROT KRT8 protein P05787 UNIPROT unknown phosphorylation Ser432 SAYGGLTsPGLSYSL 16554440 t lperfetto Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002). SIGNOR-249468 0.429 SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-122075 0.821 PRKCA protein P17252 UNIPROT KCNQ2 protein O43526 UNIPROT up-regulates activity phosphorylation Ser551 CVMRFLVsKRKFKES 10029 BTO:0000246 12754513 t lperfetto Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(DeltaA) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. | These results suggest that Ser534 and 541 are key sites for PKC phosphorylation, although we have not ruled out the possibility that other PKC sites are involved in this process. SIGNOR-249209 0.33 CXCL11 protein O14625 UNIPROT CXCR3 protein P49682 UNIPROT up-regulates activity binding 9606 BTO:0000782 12750173 t miannu The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells. SIGNOR-260971 0.768 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248742 0.727 TAOK3 protein Q9H2K8 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2 SIGNOR-192762 0.287 LPAR5 protein Q9H1C0 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257284 0.333 MAPK1 protein P28482 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR up-regulates phosphorylation 9606 12359725 t lperfetto In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e. SIGNOR-217499 0.388 NKX2-1 protein P43699 UNIPROT TPO protein P07202 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 27347897 t scontino TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8. SIGNOR-267278 0.387 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser284 AGGGRRIsDSHEDTG 9606 BTO:0000887 20151718 t miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-163772 0.277 EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 24697349 t Adaptor protein Grb2 binds phosphotyrosines in the epidermal growth factor (EGF) receptor (EGFR) and thereby links receptor activation to intracellular signaling cascades. SIGNOR-267725 0.921 PIPP smallmolecule CID:24755493 PUBCHEM LRP6 protein O75581 UNIPROT up-regulates 9606 18772438 f gcesareni Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki. In turn, ptdins (4,5)p2 regulated phosphorylation of lrp6 at thr1479 and ser1490 SIGNOR-180797 0.8 RPS6KB1 protein P23443 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk. SIGNOR-186959 0.314 GFPT1 protein Q06210 UNIPROT 2-ammonio-2-deoxy-D-glucopyranose 6-phosphate(1-) smallmolecule CHEBI:58725 ChEBI up-regulates quantity chemical modification 9606 21310273 t miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans SIGNOR-267817 0.8 DSN1 protein Q9H410 UNIPROT MIS12 complex complex SIGNOR-C362 SIGNOR form complex binding -1 27881301 t lperfetto Human MIS12C (also known as MIND complex or Mtw1 complex in Saccharomyces cerevisiae) contains the MIS12, PMF1, NSL1, and DSN1 subunits SIGNOR-265189 0.898 A10/b1 integrin complex SIGNOR-C167 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257709 0.539 CDK1 protein P06493 UNIPROT NSFL1C protein Q9UNZ2 UNIPROT down-regulates activity phosphorylation Ser140 AVERVTKsPGETSKP 9606 12810701 t lperfetto Now, we have found that p47, which mainly localizes to the nucleus during interphase, is phosphorylated on serine-140 by cdc2 at mitosis. The phosphorylated p47 does not bind to golgi membranes. SIGNOR-102350 0.331 IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 7538655 f lperfetto We demonstrate that il4r triggering induced the tyrosine phosphorylation of jak3 SIGNOR-34756 0.705 TG101209 chemical CHEBI:90304 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207260 0.8 POLE3 protein Q9NRF9 UNIPROT DNA polymerase epsilon complex SIGNOR-C377 SIGNOR form complex binding 9606 BTO:0000567 10801849 t lperfetto Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon. SIGNOR-265522 0.902 etorphine chemical CHEBI:4912 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258802 0.8 Pyrin inflammasome complex SIGNOR-C226 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256383 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR HK1 protein P19367 UNIPROT up-regulates binding 9606 16892082 t gcesareni The glucose dependence of the antiapoptotic effects of growth factors and akt plus a strong correlation between akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects. SIGNOR-148675 0.2 CDS1 protein Q92903 UNIPROT CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI up-regulates chemical modification 9606 25375833 t lperfetto CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). SIGNOR-267017 0.8 ERAP1 protein Q9NZ08 UNIPROT peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity chemical modification 9606 31810556 t scontino While peptides loaded onto MHC class I molecules are 8‚Äì11 amino acid residues long (a restriction based on the size and conformation of the peptide-binding groove of MHC class I molecules), peptides translocated by TAP can be significantly longer. These peptides will be trimmed to the correct length by ERAP-1. SIGNOR-267772 0.8 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Thr180 RHADAEMtGYVVTRW -1 9218798 t SKK3 mediates the activation of SAPK4. Phosphorylation and activation of SAPK4 and SAPK2a by purified SKK3. SIGNOR-251424 0.646 CSNK2A1 protein P68400 UNIPROT YWHAQ protein P27348 UNIPROT down-regulates activity phosphorylation Ser232 LTLWTSDsAGEECDA 9606 25862939 t lperfetto The neuroprotective effect of 14-3-3theta against rotenone toxicity is dependent on the inhibition of the pro-apoptotic factor Bax|Phosphorylation at S232 induced by rotenone is reduced by casein kinase inhibitors, and is not dependent on alphasyn.| The S232D mutant partially reduced the ability of 14-3-3theta to inhibit Bax activation in response to rotenone. Based on these findings, we propose that phosphorylation of 14-3-3s at serine 232 contributes to the neurodegenerative process in PD. SIGNOR-264405 0.354 SLX4 protein Q8IY92 UNIPROT ERCC4 protein Q92889 UNIPROT up-regulates binding 9606 SIGNOR-C50 24726326 t miannu Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair. SIGNOR-204890 0.745 DNA_damage stimulus SIGNOR-ST1 SIGNOR TAOK2 protein Q9UL54 UNIPROT up-regulates 9606 17396146 f lperfetto These findings indicate that TAO kinases are regulators of p38-mediated responses to DNA damage and are intermediates in the activation of p38 by ATM. SIGNOR-226602 0.7 DLGAP3 protein O95886 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 9115257 t miannu SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area. SIGNOR-264211 0.748 PTPN6 protein P29350 UNIPROT PKM protein P14618 UNIPROT down-regulates activity dephosphorylation Tyr105 FASDPILyRPVAVAL 9606 26959741 t lperfetto SHP-1 dephosphorylates PKM2 at Y105 to inhibit nuclear function of PKM2 and determines the efficacy of targeted drugs.|SHP-1 directly dephosphorylated PKM2 at Y105 and further decreased the proliferative activity of PKM2; similar effects were found in sorafenib-treated hepatocellular carcinoma cells.|SHP-1 dephosphorylates p-PKM2Y105 and further affects the nucleus-related cell proliferation. SIGNOR-276997 0.2 CADPS2 protein Q86UW7 UNIPROT SNAP25 protein P60880 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 24363652 t miannu CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1 SIGNOR-264339 0.269 SGK3 protein Q96BR1 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser484 KRRKRMSsGTEECGE 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275767 0.279 SOX2 protein P48431 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 25126380 f flangone Sex determining region Y-box 2 (Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells (PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency.  SIGNOR-242002 0.7 DZIP3 protein Q86Y13 UNIPROT H2AW protein Q7L7L0 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271757 0.2 MAPK3 protein P27361 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates phosphorylation Thr292 YTAMDVAtGQEVAIK 9606 14993270 t gcesareni Activated erk can phosphorylate t292 in the prs, and this blocks the ability of pak to phosphorylate s298 and of rac-pak signaling to enhance mek1-erk complex formation. SIGNOR-123074 0.344 AMPK complex SIGNOR-C15 SIGNOR GBF1 protein Q92538 UNIPROT down-regulates phosphorylation Thr1337 GKIHRSAtDADVVNS 9606 18063581 t lperfetto These results indicate that gbf1 is a novel ampk substrate and that the ampk-mediated phosphorylation of gbf1 at thr(1337) has a critical role, presumably by attenuating the function of gbf1, in the disassembly of the golgi apparatus induced under stress conditions that lower the intracellular atp concentration. SIGNOR-216588 0.2 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227901 0.891 WWP1 protein Q9H0M0 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates ubiquitination 9606 15221015 t gcesareni Similar to smurfs, wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor. Consistent with these results, wwp1 inhibited phosphorylation of smad2 induced by tgf-beta. Wwp1 thus negatively regulates tgf-beta signaling in cooperation with smad7 SIGNOR-126581 0.513 PRKDC protein P78527 UNIPROT LIG4 protein P49917 UNIPROT down-regulates phosphorylation Ser672 CVMSGTDsQPKPDLE 9606 15194694 t lperfetto Using tandem mass spectrometry, we identified a dna-pk phosphorylation site at thr-650 in human lig4 and a potential second phosphorylation site at ser-668 or ser-672. Phosphorylation of lig4 per se was not required for lig4 dna end joining activity. Substitution of these amino acids with alanine, individually or in combination, led to changes in lig4 protein stability of mouse lig4. The phosphomimetic mutation s650d returned lig4 stability to that of the wild-type protein. Furthermore dna-pk was found to negatively regulate lig4 protein stability. SIGNOR-125873 0.8 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270428 0.8 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT up-regulates activity phosphorylation Tyr39 TDPTPQHyPSFGVTS -1 9425276 t Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn. SIGNOR-251166 0.2 CDK6 protein Q00534 UNIPROT CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR form complex binding 9606 8114739 t lperfetto Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells. SIGNOR-250681 0.951 KAR proteinfamily SIGNOR-PF57 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 15919192 f miannu Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1–4); five kainate receptor genes (GluR5–7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits. SIGNOR-264693 0.7 NAA30 protein Q147X3 UNIPROT NatC complex SIGNOR-C417 SIGNOR form complex binding 9606 19398576 t miannu We here identify and characterize the human NatC (hNatC) complex, containing the catalytic subunit hMak3 and the auxiliary subunits hMak10 and hMak31. This complex associates with ribosomes, and hMak3 acetylates Met-Leu protein N termini in vitro, suggesting a model in which the human NatC complex functions in cotranslational N-terminal acetylation. SIGNOR-267233 0.747 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT down-regulates activity phosphorylation Tyr731 PYDTLHIyGYEGSES 10029 BTO:0000246 16027153 t lperfetto cadherins also act to prevent epithelial cell motilityCadherin-cytoskeletal interactions occur through a number of adaptor proteins that interact with the C-terminal portion of the cadherin cytoplasmic tail, including the _-, _-, and _-catenin (6, 10). Additionally, VE-cadherin stability at the plasma membrane may be regulated by the binding of p120-catenin to the juxtamembrane region of the cytoplasmic tailWe show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and beta-catenin, respectively, to the cytoplasmic tail of VE-cadherinVE-cadherin becomes phosphorylated on Tyr-658 and/or Tyr-731 in response to Src kinase activity. SIGNOR-246466 0.584 MAPK8 protein P45983 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser68 GQNGEEKsPPNASHP -1 15850461 t miannu CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. SIGNOR-263085 0.29 CCNA1 protein P78396 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 15829981 f lperfetto Cyclin A1 contributes to G1 to S cell cycle progression in somatic cells. Cyclin A1 overexpression enhances S phase entry consistent with an oncogenic function. Finally, cyclin A1 might be a therapeutic target since its silencing inhibited leukemia cell growth. SIGNOR-252255 0.7 ADORA2B protein P29275 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256767 0.495 apixaban chemical CHEBI:72296 ChEBI F10 protein P00742 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189865 0.8 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257970 0.8 XL-647 chemical CID:10458325 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 22722787 t XL647 administered on an intermittent or daily-dosing schedule demonstrated antitumor activity in patients with EGFR-activating mutations. gcesareni Xl647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (egfr), vascular endothelial growth factor receptor 2, her2 and ephrin type-b receptor 4 (ephb4). SIGNOR-197959 0.8 MDFI protein Q99750 UNIPROT MYOG protein P15173 UNIPROT down-regulates activity binding 10090 BTO:0000944 8797820 t 2 miannu We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals. SIGNOR-240493 0.382 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 11839802 t gcesareni Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2a and dephosphorylation of akt and glycogen synthase kinase 3 beta SIGNOR-114767 0.89 motesanib chemical CHEBI:51098 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258251 0.8 PRKCQ protein Q04759 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity phosphorylation -1 15894802 t inferred from family member lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-270273 0.295 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Ser118 EPDNRRFsSYSQMEN -1 23444369 t miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. SIGNOR-273486 0.27 NFYB protein P25208 UNIPROT SOX18 protein P35713 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 18496767 f miannu co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells SIGNOR-254819 0.2 CD79B protein P40259 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268197 0.641 EXOSC8 protein Q96B26 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-261384 0.911 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFB6 protein O95139 UNIPROT up-regulates activity phosphorylation Thr5 tPDEKLRL 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275597 0.251 AURKB protein Q96GD4 UNIPROT PLEKHG6 protein Q3KR16 UNIPROT up-regulates phosphorylation Thr544 SPSTRPStPSLEGSQ 9606 24482237 t lperfetto In this study we report that aurora b-mediated phosphorylation of myogef at thr-544 creates a docking site for plk1, leading to the localization and activation of myogef at the central spindle. SIGNOR-204534 0.256 USP8 protein P40818 UNIPROT BACE1 protein P56817 UNIPROT up-regulates quantity deubiquitination 9606 BTO:0003704 27302062 t Here, we report that RNAi-mediated depletion of USP8 reduced levels of both ectopically expressed and endogenous BACE1 in H4 human neuroglioma cells. Moreover, USP8 depletion increased BACE1 ubiquitination, promoted BACE1 accumulation in the early endosomes and late endosomes/lysosomes, and decreased levels of BACE1 in the recycling endosomes. SIGNOR-266905 0.462 NME2 protein P22392 UNIPROT KCNN4 protein O15554 UNIPROT up-regulates phosphorylation His358 FRQVRLKhRKLREQV 9606 18796614 t gcesareni We previously showed that nucleoside diphosphate kinase beta (ndpk-b), a mammalian histidine kinase, is required for kca3.1 channel activation in human cd4 t lymphocytes. SIGNOR-181083 0.43 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1197 STAENAEyLRVAPQS 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-235951 0.2 FOXJ1 protein Q92949 UNIPROT SPAG6 protein O75602 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 t miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). SIGNOR-266935 0.458 PTPN13 protein Q12923 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates activity dephosphorylation 9606 19734941 t miannu Since a previous report showed PTPN13 may dephosphorylate ErbB2 directly, we also examined levels of phospho-ErbB2 (tyr 1248), and we also observed a small effect in the presence of wild-type PTPN13 (XREF_FIG).|The fact that both ErbB2 and H-RasV12 were potentiated by PTPN13 loss and PTPN13 inhibited MAP kinase signaling downstream of multiple oncogenes (ErbB2, EGFR, H-RasV12), suggest that the phosphatase target that inhibits MAP kinase signaling may not only be limited to ErbB2 tyrosine 1248. SIGNOR-277087 0.339 GRK2 protein P25098 UNIPROT PDE6G protein P18545 UNIPROT up-regulates activity phosphorylation Thr62 PGMEGLGtDITVICP 9606 BTO:0000007 12624098 t gcesareni Mutation of Thr-62 (to Ala) in PDEgamma produced a GRK2 phosphorylation-resistant mutant that was less effective in associating with GRK2 in response to epidermal growth factor and did not potentiate the stimulation of p42/p44 mitogen-activated protein kinase by this growth factor. SIGNOR-247823 0.2 AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000222 BTO:0000887;BTO:0001760 10576741 t gcesareni Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity. SIGNOR-252588 0.688 MAPK1 protein P28482 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 BTO:0000938 21079800 t gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. SIGNOR-169674 0.48 SNAI2 protein O43623 UNIPROT UBE2D3 protein P61077 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 21044962 f miannu knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene. SIGNOR-255173 0.2 KPNB1 protein Q14974 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates relocalization 9606 10846168 t gcesareni Here we show that the isolated smad 3 mh1 domain displays significant specific binding to importin beta. we propose that activation of all of the pathway-specific smad proteins (smads 1, 2, 3, 5, 8, and 9) exposes the conserved nls motif, which then binds directly to importin beta and triggers nuclear translocation. SIGNOR-78191 0.503 MYLK protein Q15746 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser744 GLKVGVSsRINEWLT 9606 20536391 t gcesareni Phosphorylation of caldesmon by myosin light chain kinase increases its binding affinity for phosphorylated myosin filaments. SIGNOR-166049 0.626 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Thr426 TEVEDTLtPPPSDAG 9606 BTO:0000007 19126544 t lperfetto Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1. SIGNOR-236667 0.498 TTK protein P33981 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates activity phosphorylation 18541701 t lperfetto Mps1 is an upstream component of the spindle assembly checkpoint, which, in human cells, is required for checkpoint activation in response to spindle damage but not apparently during an unperturbed mitosis. Mps1 also recruits Mad1 and Mad2 to kinetochores.|Thus, in human cells, Mps1 catalytic activity is required for spindle checkpoint function and recruitment of Mad2. SIGNOR-252036 0.735 AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR oligopeptide smallmolecule CHEBI:25676 ChEBI up-regulates quantity relocalization 9606 25720354 t scontino APCs cell surface receptors facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. It is in these compartments that internalized antigen proteolysis and peptide–MHC class II complex formation takes place. SIGNOR-267861 0.8 NMDA receptor_2D complex SIGNOR-C350 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30037851 t miannu NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS).  SIGNOR-264221 0.8 Vincristine sulfate chemical CHEBI:79401 ChEBI MMP10 protein P09238 UNIPROT down-regulates activity chemical inhibition 9606 30599272 t miannu Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. SIGNOR-259253 0.8 GSK3A protein P49840 UNIPROT BCL3 protein P20749 UNIPROT down-regulates quantity by destabilization phosphorylation Ser402 LSASPSSsPSQSPPR 9606 BTO:0000007 15469820 t miannu In this report, we show that BCL-3 is a substrate for the protein kinase GSK3 and that GSK3-mediated BCL-3 phosphorylation, which is inhibited by Akt activation, targets its degradation through the proteasome pathway. SIGNOR-276011 0.401 CLK1 protein P49759 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser243 DKRKDPSsVDIKKVL -1 10480872 t llicata The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site. SIGNOR-250774 0.353 ETNK2 protein Q9NVF9 UNIPROT O-phosphonatoethanaminium(1-) smallmolecule CHEBI:58190 ChEBI up-regulates quantity chemical modification 36866238 t lperfetto Ethanolamine kinase 2 (ETNK2) is a protein-coding gene. Spondylometaphyseal dysplasia with cone-rod dystrophy is one of the diseases linked to the ETNKT2 gene. Glycerophospholipid biosynthesis and nuclear receptor meta-pathways are two of the ETNK2-related pathways. SIGNOR-275643 0.8 GUCY1A2-B3 complex SIGNOR-C138 SIGNOR 3',5'-cyclic GMP smallmolecule CHEBI:16356 ChEBI up-regulates quantity chemical modification 9606 10977868 t gcesareni Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types SIGNOR-244093 0.8 frovatriptan chemical CHEBI:134991 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation -1 9986723 t miannu As far as the selectivity against the 5-HT1A receptor, compound 10 shows similar selectivity as VML-251 (4) but has slightly lower selectivity as compared to sumatriptan (1), naratriptan (2), and rizatriptan (3). Although none of the 5-HT1D receptor agonists in the current study demonstrate as good selectivity versus the 5-HT1B receptor, the N-methyl-5-tert-butyltryptamine (10) remains the most selective (4-fold). SIGNOR-259073 0.8 PRKCD protein Q05655 UNIPROT DAB2 protein P98082 UNIPROT unknown phosphorylation Ser24 QAAPKAPsKKEKKKG 9534 BTO:0004055 10542228 t lperfetto We have mapped the TPA-induced DOC-2/DAB2 protein phosphorylation site to Ser24, which appears to modulate the DOC-2/DAB2 inhibition of AP-1 transcription activity. Results indicate that phosphorylation of Ser24 is mediated by PKCbetaII, PKC_, and PKCdelta, but not CKII. This suggests that the PKC phosphorylation of Ser24 in DOC-2/DAB2 may be an underlying mechanisms for its tumor-suppressive function. SIGNOR-249028 0.3 CALM2 protein P0DP24 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates activity binding 9606 BTO:0000938 11807557 t miannu Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. SIGNOR-266330 0.461 FHIT protein P49789 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 9606 BTO:0000551 16407838 f miannu Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis SIGNOR-143700 0.381 TNKS2 protein Q9H2K2 UNIPROT RNF146 protein Q9NTX7 UNIPROT up-regulates activity 9606 BTO:0000007 21478859 f lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. SIGNOR-263337 0.598 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4A protein P27815 UNIPROT up-regulates activity phosphorylation Ser145 ATSQRREsFLYRSDS 9534 BTO:0001538 12023945 t miannu Phosphorylation of long PDE4 isoforms by PKA. COS1 cells were transfected to express various long PDE4 isoforms. SIGNOR-275985 0.2 PTPN1 protein P18031 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity dephosphorylation Tyr397 SVSETDDyAEIIDEE 9534 BTO:0004055 16291744 t The focal adhesion kinase (FAK) is a key regulator of cell migration. Phosphorylation at Tyr-397 activates FAK |The dephosphorylation at Tyr-397 in FAK triggered by wild-type alpha-actinin and PTP 1B caused a significant increase in cell migration. SIGNOR-248431 0.353 UBE2D1 protein P51668 UNIPROT MGRN1 protein O60291 UNIPROT up-regulates activity binding 9606 BTO:0000567 17229889 t miannu Our in vivo and in vitro ubiquitylation studies demonstrate that the binding of TSG101 to Mahogunin targets the substrate TSG101 for ubiquitylation by Mahogunin E3 ligase in cooperation with its cognate E2 enzyme Ubc5a SIGNOR-271637 0.474 PDGFB protein P01127 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates binding 9606 11331882 t miannu Pdgf-b activates both pdgfr-alpha and pdgfr-beta SIGNOR-107400 0.903 N-[5-[(2R)-2-methoxy-1-oxo-2-phenylethyl]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-1-piperazinyl)benzamide chemical CHEBI:94490 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191274 0.8 NDN protein Q99608 UNIPROT PIAS1 protein O75925 UNIPROT down-regulates quantity by destabilization binding 9606 24911587 t lperfetto Necdin bound to PIAS1 central domains that are highly conserved among PIAS family proteins and suppressed PIAS1-dependent sumoylation of the substrates STAT1 and PML (promyelocytic leukemia protein). Remarkably, necdin promoted degradation of PIAS1 via the ubiquitin-proteasome pathway. In transfected HEK293A cells, amino- and carboxyl-terminally truncated mutants of PIAS1 bound to necdin but failed to undergo necdin-dependent ubiquitination. SIGNOR-253387 0.301 MYC protein P01106 UNIPROT FUT3 protein P21217 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22547830 f miannu We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. SIGNOR-254612 0.256 17beta-estradiol smallmolecule CHEBI:16469 ChEBI 17beta-estradiol 3-sulfate(1-) smallmolecule CHEBI:136582 ChEBI up-regulates quantity precursor of -1 7779757 t Luana HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM. SIGNOR-269750 0.8 CSNK1D protein P48730 UNIPROT GJA1 protein P17302 UNIPROT up-regulates activity phosphorylation Ser328 GQAGSTIsNSHAQPF 10116 BTO:0000067 12270943 t lperfetto We have examined the role of casein kinase 1 (CK1) in connexin-43 (Cx43) gap junction assembly. Cellular co-immunoprecipitation experiments and in vitro CK1 phosphorylation reactions indicate that CK1 interacted with and phosphorylated Cx43, initially on serine(s) 325, 328, or 330.| To examine CK1 function, normal rat kidney cells were treated with CKI-7, and Cx43 content was analyzed by Triton X-100 extraction, cell-surface biotinylation, and immunofluorescence. Western blot analysis indicated a slight increase in total Cx43, whereas gap junctional (Triton-insoluble) Cx43 decreased, and non-junctional plasma membrane Cx43 increased (as detected by cell surface biotinylation). SIGNOR-249330 0.588 NR0B2 protein Q15466 UNIPROT NR1H2 protein P55055 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000195 12198243 f gcesareni Here we show that shp can interact with the liver x receptors lxr? (nr1h3) and lxr? (nr1h2), as demonstrated by glutathione-s-transferase pull-down assays, mammalian two-hybrid, and coimmunoprecipitation experiments. In transfection assays, shp inhibits the expression of an artificial reporter driven by an lxr-response element and represses the transcriptional activation by lxr of the human atp-binding cassette transporter 1 (abca1) promoter. T SIGNOR-91901 0.471 PPP2CA protein P67775 UNIPROT ELF1 protein P32519 UNIPROT down-regulates activity dephosphorylation Thr231 CPKYIKWtQREKGIF 9606 18714041 t Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response SIGNOR-248634 0.2 HCK protein P08631 UNIPROT ADAM15 protein Q13444 UNIPROT unknown phosphorylation Tyr715 LVMLGASyWYRARLH 9606 11741929 t llicata Hck, and to a lesser extent lck, phosphorylated the adam15 cytoplasmic domain in vitro in immune complex kinase assays. SIGNOR-112927 0.362 CREB1 protein P16220 UNIPROT PLAT protein P00750 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001282 8647095 f lperfetto We suggest that the mechanism for the transcriptional down-regulation of t-PA by PMA in HT-1080 cells requires CREB-1 binding to the t-PACRE while ATF-2, by associating with the same site, plays a role in PMA-mediated induction of t-PA in HeLa cells. SIGNOR-253732 0.267 CEBPA protein P49715 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 14592841 t Activation of C/EBPα induces PU.1 expression, cell cycle arrest, and differentiation in 32D cells expressing FLT3/ITD SIGNOR-261531 0.543 SYK protein P43405 UNIPROT SH3BP2 protein P78314 UNIPROT up-regulates activity phosphorylation Tyr183 HDDEDDSyLEPDSPE 9534 BTO:0004055 12709437 t lperfetto By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk SIGNOR-246592 0.568 AURKB protein Q96GD4 UNIPROT KIF20A protein O95235 UNIPROT down-regulates activity phosphorylation Ser878 RILRSRRsPLLKSGP 9606 BTO:0000567 27939310 t miannu We identify MKlp2 as an essential protein for promoting abscission, which may regulate tethering and stabilizing of the PM to the microtubule cytoskeleton. Aurora B phosphorylation of MKlp2 S878 in the LAM is a key inhibitory signal for abscission. Conversely, B56-PP2A promotes abscission by opposing Aurora B phosphorylation of MKlp2 S878. SIGNOR-262659 0.771 CADPS2 protein Q86UW7 UNIPROT STX1A protein Q16623 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 24363652 t miannu CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1 SIGNOR-264337 0.364 ANXA3 protein P12429 UNIPROT CASP3 protein P42574 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001109;BTO:0000038 30998268 f miannu ANXA3 depletion promoted cell apoptosis and upregulated c‐caspase 3 expression in HCT116/Ox and SW480/Ox cells with or without Ox, which is consistent with findings from a preliminary study by Yan et al SIGNOR-262209 0.265 MAPK1 protein P28482 UNIPROT AMPH protein P49418 UNIPROT down-regulates activity phosphorylation Ser293 PAPARPRsPSQTRKG 9606 15262992 t lperfetto Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2. SIGNOR-126859 0.268 FBLIM1 protein Q8WUP2 UNIPROT FLNA protein P21333 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 t miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. SIGNOR-266105 0.884 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser262 TFRPRSSsNASSVST 10090 10217147 t Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. SIGNOR-252839 0.908 CAMK2B protein Q13554 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Thr594 LHGKKNStVDCNGVV 9606 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275775 0.394 PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 7515062 t gcesareni The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. SIGNOR-27028 0.894 N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide chemical CHEBI:125619 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258887 0.8 SIRT1 protein Q96EB6 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates deacetylation Lys70 GKAVRGAkGHHHPHP 9606 17098745 t gcesareni Sirt1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (lys-64 and -70) on smad7. sirt1-mediated deacetylation of smad7 enhanced smad ubiquitination regulatory factor 1 (smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of smad7 in sirt1-overexpressing mesangial cells. SIGNOR-150599 0.452 GRIP1 protein Q9Y3R0 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11062529 t gcesareni The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis. SIGNOR-83883 0.377 PFDN2 protein Q9UHV9 UNIPROT URI1 prefoldin co-chaperone complex SIGNOR-C514 SIGNOR form complex binding 9606 30484151 t miannu In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR96 SIGNOR-270919 0.724 PIM1 protein P11309 UNIPROT RP9 protein Q8TA86 UNIPROT unknown phosphorylation Ser214 RKHKSSKsNEGSDSE -1 10931201 t miannu PAP-1 was phosphorylated in vitro by Pim-1, but not a kinase-negative Pim-1 mutant. The two serine residues of PAP-1 at amino acids 204 and 206 near the C-terminus were phosphorylated by Pim-1. PAP-1 is thus thought to be a target protein for Pim-1 kinase. SIGNOR-263030 0.2 JARID2 protein Q92833 UNIPROT MYOG protein P15173 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 23435416 t lperfetto JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells|Addition of Differentiation Media (DM) to human myoblasts was associated with the induction of MYOG, MYOD and MYL1 and a decrease in JARID2 RNA expression|Furthermore, we that showed JARID2 binds to and alters the methylation status of histone H3 lysine 27 in the promoter regions of MYOG and MYL1 and that the interaction of JARID2 at these promoters is dependent upon EED, a core component of the Polycomb Repressive Complex 2 (PRC2). Therefore JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS SIGNOR-249599 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR ETV1 protein P50549 UNIPROT up-regulates activity phosphorylation Ser191 HRFRRQLsEPCNSFP 9606 12213813 t lperfetto Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation. SIGNOR-252768 0.2 IL1B protein P01584 UNIPROT SCNN1A protein P37088 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005760 15755725 f Regulation of transcription miannu Interleukin-1beta decreases expression of the epithelial sodium channel alpha-subunit in alveolar epithelial cells via a p38 MAPK-dependent signaling pathway. SIGNOR-251947 0.2 EDNRA protein P25101 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257165 0.421 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT down-regulates activity phosphorylation Ser32 RSEDARSsPSQRRRG 9606 BTO:0000567 SIGNOR-C83 12714602 t lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. SIGNOR-100881 0.757 DLX2 protein Q07687 UNIPROT MSX2 protein P35548 UNIPROT down-regulates activity binding 10090 9111364 t 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. SIGNOR-240911 0.4 TGFB1 protein P01137 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252282 0.7 CDK2 protein P24941 UNIPROT HIRA protein P54198 UNIPROT up-regulates activity phosphorylation Thr555 LSPSVLTtPSKIEPM 9606 BTO:0001938 SIGNOR-C16 11238922 t lperfetto Hira bound to and was phosphorylated by cyclin a- and e-cdk2 in vitrohira became phosphorylated on threonine 555 in s phase when cyclin-cdk2 kinases are active.ectopic expression of hira in cells caused arrest in s phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle. SIGNOR-105548 0.331 CSNK2A1 protein P68400 UNIPROT TNFAIP1 protein Q13829 UNIPROT up-regulates phosphorylation Ser280 SRSQASPsEDEETFE 9606 BTO:0000567 19851886 t lperfetto It was demonstrated that ck2 could phosphorylate tnfaip1 in vitro and in vivo, which facilitated the distribution of tnfaip1 in nucleus and enhanced its interaction with pcna. It is suggested that the phosphorylation of tnfaip1 may be required for its functions. SIGNOR-188849 0.2 NFIB protein O00712 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268902 0.2 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2V1 protein Q13404 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271355 0.442 ITGB7 protein P26010 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257726 0.548 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation Tyr352 TEVYESPyADPEEIR 9606 9820500 t lperfetto These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520 SIGNOR-246613 0.2 EP300 protein Q09472 UNIPROT PLAGL2 protein Q9UPG8 UNIPROT up-regulates acetylation 9606 16207715 t miannu Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7. SIGNOR-140947 0.2 CENP-A nucleosome complex SIGNOR-C321 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000567 20566683 f miannu Centromeres contain specialized nucleosomes in which histone H3 is replaced by the histone variant centromere protein A (CENP-A). CENP-A nucleosomes are thought to act as an epigenetic mark that specifies centromere identity. SIGNOR-263703 0.7 PPARD protein Q03181 UNIPROT CAT protein P04040 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18048767 f miannu Activation of PPAR-delta upregulated the expression of antioxidant genes superoxide dismutase 1, catalase, and thioredoxin and decreased reactive oxygen species production in ECs. SIGNOR-255051 0.259 CENPE protein Q02224 UNIPROT BUB1B protein O60566 UNIPROT up-regulates activity binding -1 12925705 t miannu CENP-E binds to and directly stimulates the kinase activity of purified BubR1 in vitro. SIGNOR-266118 0.839 LMNA protein P02545 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000944 16415042 f Cleaved by CASP6 amattioni Nuclear lamin A inhibits adipocyte differentiation: implications for Dunnigan-type familial partial lipodystrophy.|We conclude that A-type lamins act as inhibitors of adipocyte differentiation, possibly by affecting PPARgamma2 and insulin signaling. SIGNOR-45455 0.7 CAMK2G protein Q13555 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Thr594 LHGKKNStVDCNGVV 9606 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275781 0.295 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser119 SFSSTSVsSLEAEAY 9606 15448698 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-129418 0.574 KSR2 protein Q6VAB6 UNIPROT ARAF protein P10398 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 t miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. SIGNOR-273875 0.534 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR2 protein P30874 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257582 0.8 SMAD3 protein P84022 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 19701891 t TGF-beta1-activated Smad3 plays a major role in the expression of Foxp3, since TGF-beta1-induced-Treg generation from Smad3(-/-) mice is markedly reduced and abolished by inactivating Smad2 SIGNOR-254362 0.538 CLOCK protein O15516 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21164265 t lperfetto We recently reported that the basic helix-loop- helix transcription factor Clock, which is a histone acetyltransferase and a central component of the self-oscillating transcription factor loop that generates circadian rhythms, represses GR transcriptional activity by acetylating lysine residues within the 'lysine cluster' located in the hinge region of the receptor. This Clock-mediated repression of GR transcriptional activity oscillates in inverse phase to the HPA axis, acting as a target tissue counter-regulatory mechanism to the diurnally fluctuating circulating glucocorticoids. SIGNOR-253699 0.42 RPS6KA1 protein Q15418 UNIPROT Translational_regulation phenotype SIGNOR-PH202 SIGNOR up-regulates 9606 17360704 f gianni Mutation of rpS6 at Ser(235/236) reveals that phosphorylation of these sites promotes its recruitment to the 7-methylguanosine cap complex, suggesting that Ras/ERK signaling regulates assembly of the translation preinitiation complex. These data demonstrate that RSK provides an mTOR-independent pathway linking the Ras/ERK signaling cascade to the translational machinery. SIGNOR-268528 0.7 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser23 PAPIRRRsSNYRAYA 9606 18550549 t gcesareni Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144. SIGNOR-178880 0.275 PRKCD protein Q05655 UNIPROT YWHAB protein P31946 UNIPROT down-regulates phosphorylation Ser60 VVGARRSsWRVISSI 9606 16024783 t gcesareni We provide a mechanism for these observations through the phosphorylation of 14-3-3 by ikk and pkc on serine residues ser132 and ser60, respectively, which interferes with its binding to ttp and hence the retention of ttp in the cytoplasm. SIGNOR-138612 0.506 KLF1 protein Q13351 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002731 9707565 f Regulation miannu EKLF is an acetylated transcription factor, and that it interacts in vivo with CBP, p300, and P/CAF. However, its interactions with these histone acetyltransferases are not equivalent, as CBP and p300, but not P/CAF, utilize EKLF as a substrate for in vitro acetylation within its trans-activation region. The functional effects of these interactions are that CBP and p300, but not P/CAF, enhance EKLF's transcriptional activation of the beta-globin promoter in erythroid cells. SIGNOR-251790 0.413 ERBB3 protein P21860 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 16729043 t gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. SIGNOR-252673 0.709 FOXJ1 protein Q92949 UNIPROT TUBA1A protein Q71U36 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 t miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). SIGNOR-266938 0.303 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser232 NRYGMGTsVERAAAS -1 7782287 t gcesareni Sites 1, 2, and 3 in the E1 mutants were phosphorylated either individually or in the presence of the other sites by the dihydrolipoamide acetyltransferase-protein X-E1 kinase indicating a site-independent mechanism of phosphorylation. SIGNOR-33040 0.666 PRKCA protein P17252 UNIPROT MBD4 protein O95243 UNIPROT up-regulates activity phosphorylation Ser165 CSMAALTsHLQNQSN 23195996 t lperfetto Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12] SIGNOR-275673 0.2 KDM4C protein Q9H3R0 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity demethylation 9606 29207681 t miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation SIGNOR-265333 0.2 PTK6 protein Q13882 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr326 EVLEDNDyGRAVDWW 9606 BTO:0000150 BTO:0001129 20606012 t gcesareni Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6. SIGNOR-166510 0.454 CCND1 protein P24385 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates activity 9606 15713663 f areggio Collectively, these studies suggest an important role of cyclin D1 in regulation of PPARgamma-mediated adipocyte differentiation through recruitment of HDACs to regulate PPAR response element local chromatin structure and PPARgamma function. SIGNOR-258981 0.7 INS protein P01308 UNIPROT TRIP10 protein Q15642 UNIPROT up-regulates 9606 12242347 f gcesareni The specific interaction of active tc10 with cip4 2 suggested thatinsulinmight induce a change in the subcellular localization of cip4 2 SIGNOR-93062 0.269 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser238 QGTPLTCsPNVENRG 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276101 0.29 STING1 protein Q86WV6 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 24622840 t miannu MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. SIGNOR-260153 0.2 Hexokinase proteinfamily SIGNOR-PF76 SIGNOR alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266449 0.8 GRIK3 protein Q13003 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264944 0.8 TP53 protein P04637 UNIPROT PMS2 protein P54278 UNIPROT up-regulates quantity transcriptional regulation 9606 15781865 t .... numerous potentially novel targets, including the DNA mismatch repair genes MLH1 and PMS2. Both of these genes were determined to be responsive to DNA damage and p53 activation in normal human fibroblasts, and have p53-response elements within their first intron. SIGNOR-257604 0.565 Gbeta proteinfamily SIGNOR-PF4 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 19282669 t inferred from 70% family members lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-270020 0.2 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1795 VASPRRLsNVSSSGS -1 8631898 t miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. SIGNOR-250166 0.428 VARLITINIB chemical CID:42642648 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189900 0.8 ASXL3 protein Q9C0F0 UNIPROT NR1H3 protein Q13133 UNIPROT down-regulates activity binding 9606 BTO:0000972 25450400 t miannu We determined that ASXL3 depletion augments the ligand-induced transcriptional activities of LXRα and TRβ, which were repressed by ASXL3 overexpression. The ligand-dependent interactions of ASXL3 with LXRα and TRβ were demonstrated by the GST pull-down and immunoprecipitation analyses. We confirmed that ASXL3 suppresses the expression of LXRα target genes through its recruitment to the LXR-response elements. SIGNOR-266765 0.2 PKC proteinfamily SIGNOR-PF53 SIGNOR NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation 9606 BTO:0001853 24379783 t inferred from 70% family members lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-269971 0.2 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 9922370 t gcesareni Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity. previous studies have shown that phosphorylation is required for raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated erk SIGNOR-64172 0.622 SMO protein Q99835 UNIPROT GNAT2 protein P19087 UNIPROT up-regulates binding 9606 23074268 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-199171 0.264 STAT3 protein P40763 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 10090 11426647 f Constitutive activation of Stat3 signaling is accompanied by upregulation of cyclin D1, c-Myc, and Bcl-x, changes consistent with subversion of normal cellular growth and survival control mechanisms. SIGNOR-252090 0.7 HTR2C protein P28335 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257129 0.255 CDC42 protein P60953 UNIPROT PAK proteinfamily SIGNOR-PF13 SIGNOR up-regulates activity binding 10090 BTO:0000142 8107774 t gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. SIGNOR-248259 0.941 PRKCA protein P17252 UNIPROT CDC42EP4 protein Q9H3Q1 UNIPROT down-regulates activity phosphorylation Ser18 SVHSKRRsRADLTAE 9606 BTO:0001939 25086031 t miannu Cdc42 effector protein-4 (CEP4) was recently identified by our laboratory to be a substrate of multiple PKC isoforms in non-transformed MCF-10A human breast cells. MS/MS analysis verified that Ser(18) and Ser(80) were directly phosphorylated by PKCα in vitro. Phosphorylation of CEP4 severely diminished its affinity for Cdc42 while promoting Rac activation and formation of filopodia (microspikes). SIGNOR-263160 0.2 GABRB1 protein P18505 UNIPROT GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263757 0.598 Gbeta proteinfamily SIGNOR-PF4 SIGNOR STMN1 protein P16949 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 9731215 t inferred from 70% family members lperfetto Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs. SIGNOR-270082 0.2 SACM1L protein Q9NTJ5 UNIPROT Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR down-regulates 9534 BTO:0001444 22253445 f lperfetto Ectopic Expression of Sac1 Phosphatase Inhibits SARS-CoV S-mediated Entry SIGNOR-260735 0.7 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. SIGNOR-164475 0.553 Galanin smallmolecule CHEBI:80161 ChEBI GALR2 protein O43603 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257495 0.8 CHEK1 protein O14757 UNIPROT CDC25B protein P30305 UNIPROT down-regulates activity phosphorylation Ser230 AFAQRPSsAPDLMCL 9606 17003105 t lperfetto Here, we show that cdc25b is phosphorylated by chk1 in vitro on multiple residues, including s230 and s563.We show that the s230-phosphorylated form of cdc25b is located at the centrosome from early s phase until mitosis. Furthermore, mutation of s230 to alanine increases the mitotic-inducing activity of cdc25b SIGNOR-149898 0.78 PCK2 protein Q16822 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI down-regulates quantity chemical modification 9606 24632615 t miannu Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine. SIGNOR-266556 0.8 CSNK2B protein P67870 UNIPROT SEC63 protein Q9UGP8 UNIPROT up-regulates activity phosphorylation Ser574 EEVSDKGsDSEEEET 9606 BTO:0000599 23287549 t lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. SIGNOR-265270 0.2 FURIN protein P09958 UNIPROT VWF protein P04275 UNIPROT up-regulates activity cleavage BTO:0001538 8218226 t Giorgia Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine SIGNOR-260368 0.494 CEP135 protein Q66GS9 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates activity binding 9606 23511974 t miannu In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation. SIGNOR-269677 0.801 PLK1 protein P53350 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser730 VLDTMNDsLSKILLD 9606 19737929 t lperfetto It has been reported that plk1 could directly phosphorylate foxm1 at ser-715 and ser-724 for full activation and proper mitotic progression SIGNOR-187888 0.692 CDS1 protein Q92903 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI down-regulates quantity chemical modification 9606 25375833 t lperfetto CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). SIGNOR-267018 0.8 NDUFA1 protein O15239 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. SIGNOR-262150 0.844 KLF11 protein O14901 UNIPROT HBE1 protein P02100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10207080 f Regulation miannu Transfection of K562 cells with FKLF cDNA enhanced the expression of the endogenous epsilon- and gamma-globin genes, suggesting an in vivo role of FKLF in fetal and embryonic globin gene expression. SIGNOR-251829 0.281 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR UBTF protein P17480 UNIPROT down-regulates phosphorylation 9606 11741541 t inferred from 70% family members lperfetto Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna SIGNOR-270181 0.2 CDC20 protein Q12834 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 9606 BTO:0000007 23979597 t miannu  We showed that PHF8 interacts with the CDC20-containing APC (APC(cdc20)) primarily during mitosis. we demonstrate that mutations of the LXPKXLF motif abrogate polyubiquitylation of PHF8 by the APC. APC substrates are typically cell cycle regulators, and consistent with this, the loss of PHF8 leads to prolonged G2 phase and defective mitosis. SIGNOR-272880 0.873 alvocidib hydrochloride chemical CHEBI:90998 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192461 0.8 ATG7 protein O95352 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates activity binding -1 16303767 t lperfetto Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme). SIGNOR-142002 0.903 TG protein P01266 UNIPROT Colloid phenotype SIGNOR-PH185 SIGNOR up-regulates 9606 24251883 f scontino The thyroid gland is unique among endocrine glands in storing its principle hormonal product—the two very small thyroid hormones (TH)—as components of a 1000-fold larger precursor—thyroglobulin (Tg)—that is secreted and stored in the colloid, outside of the thyroid cell. Moreover, the thyroid cell is part of a layer of similar cells—the thyroid follicular epithelium—that completely encloses the secreted Tg and segregates it from the circulation. SIGNOR-267135 0.7 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser155 GRLKRERsMSENAVR 9606 BTO:0002181 34010649 t miannu PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-277558 0.2 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT up-regulates phosphorylation Ser18 EKLQYYYsSSEDEDS 9606 16717095 t lperfetto Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2. SIGNOR-146825 0.36 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1346 SFDERQPyAHMNGGR -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246276 0.564 Neuropeptide W-30 smallmolecule CHEBI:80256 ChEBI NPBWR1 protein P48145 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257548 0.8 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser552 VVRTPPKsPSSAKSR 9606 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249319 0.754 PKN1 protein Q16512 UNIPROT PGM1 protein P36871 UNIPROT up-regulates phosphorylation Thr467 SANDKVYtVEKADNF 9606 BTO:0001271 15378030 t llicata Pak1-mediated phosphorylation of pgm selectively on threonine 466 significantly increased pgm enzymatic activity SIGNOR-128722 0.2 SLC34A3 protein Q8N130 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI up-regulates quantity relocalization 9606 BTO:0000671 11880379 t lperfetto Growth is critically dependent on the retention of a variety of nutrients. The kidney contributes to this positive external balance. In the present study, we isolated a cDNA from the human and rat kidney that encodes a growth-related Na(+)-dependent inorganic phosphate (P(i)) cotransporter (type IIc). SIGNOR-270577 0.8 MAPK1 protein P28482 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by stabilization phosphorylation Ser352 TRPTALTsPELSSWS 9606 BTO:0001109 28945223 t miannu In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation.  SIGNOR-276743 0.2 RUNX3 protein Q13761 UNIPROT TXN2 protein Q99757 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002384 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255093 0.2 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser38 QVSSLSEsEESQDSS 9606 20730097 t lperfetto We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf5 SIGNOR-167564 0.2 TNKS2 protein Q9H2K2 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19759537 t gcesareni Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. SIGNOR-188033 0.693 SKI protein P12755 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity binding 9606 10575014 t lperfetto Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling. SIGNOR-217658 0.731 PAMPs stimulus SIGNOR-ST11 SIGNOR TLRs proteinfamily SIGNOR-PF20 SIGNOR up-regulates 9606 20404851 f lperfetto the discovery of Toll-like receptors (TLRs) in the mid-1990s showed that pathogen recognition by the innate immune system is instead actually specific, relying on germline-encoded pattern-recognition receptors (PRRs) that have evolved to detect components of foreign pathogens referred to as pathogen-associated molecular patterns (PAMPs) SIGNOR-216295 0.7 OST-A complex complex SIGNOR-C535 SIGNOR Protein_glycosylation phenotype SIGNOR-PH144 SIGNOR up-regulates 9606 31831667 t miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  SIGNOR-272055 0.7 RPS6K proteinfamily SIGNOR-PF26 SIGNOR EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 15071500 t gcesareni S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function. SIGNOR-252783 0.2 CDK7 protein P50613 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity phosphorylation Thr160 GVPVRTYtHEVVTLW -1 10085115 t llicata Phosphorylation of monomeric human CDK2 by CAK1 is more efficient than phosphorylation of the binary CDK2-cyclin A complex. Phosphorylated CDK2 exhibits histone H1 kinase activity corresponding to approximately 0.3% of that observed with the fully activated phosphorylated CDK2-cyclin A complex. Fluorescence measurements have shown that Thr160 phosphorylation increases the affinity of CDK2 for both histone substrate and ATP and decreases its affinity for ADP. SIGNOR-250768 0.553 SRP54 protein P61011 UNIPROT SRPRA protein P08240 UNIPROT up-regulates activity binding -1 30649417 t miannu The multi-domain SRP GTPase SRP54 recognizes the signal with its M domain and establishes the targeting complex consisting of its NG domain bound to the homologous NG domain of the SRP receptor SRα at a proximal ribosome binding site. SIGNOR-261163 0.2 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002428 31908417 t miannu The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs. SIGNOR-262248 0.8 TRAF6 protein Q9Y4K3 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity binding 9606 10075662 t miannu RANK activates NF-κB by interacting with TRAF6 via a novel TRAF6 interaction motif and TRAF6 potentially activates NIK, leading to NF-κB activation. TRAF6 has been demonstrated to interact with NIK. SIGNOR-253048 0.619 RIMS2 protein Q9UQ26 UNIPROT CACNA1D protein Q01668 UNIPROT up-regulates activity binding 9606 BTO:0005822 28642685 t miannu Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells. SIGNOR-264356 0.354 CACNA2D3 protein Q8IZS8 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 31746409 f miannu The results indicated that the overexpression of CACNA2D3 induced an increase in intracellular Ca2+ and increased the levels of p-p38 MAPK. These data indicated that the p38 MAPK pathway is activated by overexpression of CACNA2D3 and P4 induction. SIGNOR-266857 0.2 CSNK2A2 protein P19784 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser385 RYSDTTDsDPENEPF -1 12297295 t llicata We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).  SIGNOR-251027 0.692 RAB14 protein P61106 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 t lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 SIGNOR-260619 0.414 CYSLTR2 protein Q9NS75 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257140 0.358 AR protein P10275 UNIPROT CYP7B1 protein O75881 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 16630558 f miannu DHT and overexpression of androgen receptor (AR) suppressed CYP7B1 promoter activity and CYP7B1-mediated catalysis in kidney-derived HEK293 cells. SIGNOR-253739 0.293 TGFB1 protein P01137 UNIPROT SALL2 protein Q9Y467 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000452 21228219 f miannu TGFβ effectively inhibits expression of SALL2 and its regulator AP4 when added to quiescent fibroblasts. SIGNOR-255427 0.2 SRC protein P12931 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 12707358 t lperfetto These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation. SIGNOR-217442 0.384 CEBPA protein P49715 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0004730 16319681 f lperfetto The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder. SIGNOR-249632 0.7 IFITM3 protein Q01628 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR up-regulates activity binding 10090 32879487 t miannu IFITM3 directly binds to γ-secretase. IFITM3 KO reduced γ-secretase activity for both Aβ40 and Aβ42 cleavages as compared to the EV (empty vector guide RNA) cell line by 36% and 27%, respectively (Fig. 2d, bar 1 and 3). SIGNOR-266303 0.2 S1PR2 protein O95136 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257215 0.51 COL6A3 protein P12111 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. SIGNOR-254675 0.7 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 BTO:0003807 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244788 0.2 phosphatidic acid smallmolecule CHEBI:16337 ChEBI PIP5K1A protein Q99755 UNIPROT up-regulates chemical activation 9606 17245604 t gcesareni All pip5k isoforms are stimulated by pa. SIGNOR-152542 0.8 RB1 protein P06400 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 21524151 f miannu Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time. SIGNOR-262533 0.7 EID1 protein Q9Y6B2 UNIPROT CREBBP protein Q92793 UNIPROT down-regulates activity binding 11073989 t lperfetto Here, we show that EID-1 is a potent inhibitor of differentiation and link this activity to its ability to inhibit p300 (and the highly related molecule, CREB-binding protein, or CBP) histone acetylation activity. SIGNOR-253380 0.415 STON2 protein Q8WXE9 UNIPROT SYT1 protein P21579 UNIPROT up-regulates quantity binding 9606 BTO:0000938 26903854 t miannu  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively .Stonin-2 and AP-2 are also Required for Efficient Synaptotagmin-1 Retrieval.  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. SIGNOR-264115 0.769 SUZ12 protein Q15022 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23836662 f miannu We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. SIGNOR-254150 0.469 CASP3 protein P42574 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 BTO:0000142 10200555 f amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation SIGNOR-66866 0.7 HBEGF protein Q99075 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 9135143 t gcesareni It was concluded that her4 is a newly described receptor for hb-egf and that hb-egf can activate two egf receptor subtypes, her1 and her4, but with different biological response. SIGNOR-47881 0.74 PIM proteinfamily SIGNOR-PF34 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 18593906 t fspada Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42). SIGNOR-259428 0.2 RIMBP3 protein Q9UFD9 UNIPROT RIMS1 protein Q86UR5 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264360 0.348 GSK3B protein P49841 UNIPROT PIAS1 protein O75925 UNIPROT down-regulates quantity by destabilization phosphorylation Ser17 MVMSLRVsELQVLLG 10090 BTO:0002268 26157031 t miannu We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model. We found that GSK3β phosphorylation of PIAS1 provided a phosphodegron for HECTD2 targeting.  SIGNOR-276923 0.338 GPR161 protein Q8N6U8 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 23332756 t Shh signaling directs Gpr161 to be internalized from cilia, preventing its activity. SIGNOR-259936 0.383 SEC23IP protein Q9Y6Y8 UNIPROT 1-acyl-sn-glycerol 3-phosphate smallmolecule CHEBI:16975 ChEBI up-regulates quantity chemical modification 9606 22922100 t miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. SIGNOR-269657 0.8 EDA protein Q92838 UNIPROT EDA2R protein Q9HAV5 UNIPROT up-regulates binding 9606 BTO:0001253 12084975 t gcesareni Identification of the major product of the eda gene (ectodysplasin a), a protein belonging to a group of tnf ligands, and molecular cloning of the cdna, encoding its receptor (edar), a member of the tnf receptor family, are presented. The role of an alternative eda receptor, localised on the x chromosome (xedar) in the developmental control of the differentiation of skin appendages, is discussed. SIGNOR-90040 0.669 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258305 0.8 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Ser5110 KAEAPLPsPKLEGEL 10090 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262764 0.259 ARAP1 protein Q96P48 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260451 0.431 FYN protein P06241 UNIPROT CD79B protein P40259 UNIPROT up-regulates activity phosphorylation Tyr196 GMEEDHTyEGLDIDQ -1 9531288 t CD79b cytoplasmic tail-containing GST fusion proteins were phosphorylated in vitro by baculovirus-produced Fyn, >80% of phosphorylation occurred on the N-terminal ITAM tyrosine. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM). pY195 and pY206 in CD79b SIGNOR-251154 0.658 PRKDC protein P78527 UNIPROT USF1 protein P22415 UNIPROT up-regulates phosphorylation 9606 19303849 t miannu Feeding induces the recruitment of dna-pk to usf-1 and its phosphorylation, which then allows recruitment of p/caf, resulting in usf-1 acetylation and fas promoter activation. SIGNOR-184849 0.297 PPM1A protein P35813 UNIPROT IKBKE protein Q14164 UNIPROT down-regulates activity dephosphorylation Ser172 DDDEKFVsVYGTEEY 9606 27419230 t miannu PPM1A directly dephosphorylates both MAVS and TBK1 and IKKepsilon.|In a similar in vitro phosphatase assay, incubation of PPM1A also eliminated TBK1 and IKKepsilon phosphorylation at Ser 172 residue, evidenced by phospho-S172 immunoblotting (XREF_FIG, F and G).|These observations suggest that PPM1A may block kinase activities of TBK1 and IKKepsilon. SIGNOR-277072 0.283 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR THRB protein P10828 UNIPROT down-regulates activity phosphorylation 9606 12809513 t inferred from 70% family members llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. SIGNOR-270143 0.2 sirolimus chemical CHEBI:9168 ChEBI AKT1 protein P31749 UNIPROT up-regulates 9606 16452206 f gcesareni We now show that mtor inhibition induces insulin receptor substrate-1 expression and abrogates feedback the pathway, resulting in akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, rad001. SIGNOR-252643 0.8 GABRA1 protein P14867 UNIPROT GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263750 0.641 BCORL1 protein Q5H9F3 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates activity binding 9606 BTO:0000567 17379597 t irozzo BCoR-L1 interacts with Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its function as transcriptional corepressor. SIGNOR-259113 0.45 PIM1 protein P11309 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0002552 19749799 t lperfetto Pim1 phosphorylates and negatively regulates ask1-mediated apoptosispim1 phosphorylation of ask1 on ser83 inhibited ask1-mediated c-jun n-terminal kinase phosphorylation SIGNOR-187905 0.284 RTKs proteinfamily SIGNOR-PF38 SIGNOR ITGB4 protein P16144 UNIPROT up-regulates activity phosphorylation 9606 30889378 t miannu The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs. SIGNOR-259031 0.2 NAA38 protein Q9BRA0 UNIPROT NatC complex SIGNOR-C417 SIGNOR form complex binding 9606 19398576 t miannu We here identify and characterize the human NatC (hNatC) complex, containing the catalytic subunit hMak3 and the auxiliary subunits hMak10 and hMak31. This complex associates with ribosomes, and hMak3 acetylates Met-Leu protein N termini in vitro, suggesting a model in which the human NatC complex functions in cotranslational N-terminal acetylation. SIGNOR-267235 0.672 THR proteinfamily SIGNOR-PF84 SIGNOR RARA protein P10276 UNIPROT up-regulates binding 9606 15650024 t inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. SIGNOR-270313 0.2 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT down-regulates activity phosphorylation Tyr658 GEMDTTSyDVSVLNS 10029 BTO:0000246 16027153 t lperfetto cadherins also act to prevent epithelial cell motilityCadherin-cytoskeletal interactions occur through a number of adaptor proteins that interact with the C-terminal portion of the cadherin cytoplasmic tail, including the _-, _-, and _-catenin (6, 10). Additionally, VE-cadherin stability at the plasma membrane may be regulated by the binding of p120-catenin to the juxtamembrane region of the cytoplasmic tailWe show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and beta-catenin, respectively, to the cytoplasmic tail of VE-cadherinVE-cadherin becomes phosphorylated on Tyr-658 and/or Tyr-731 in response to Src kinase activity. SIGNOR-246462 0.584 MAPK14 protein Q16539 UNIPROT MAX protein P61244 UNIPROT down-regulates phosphorylation 9606 7479834 t gcesareni Mxi2 phosphorylates max both in vitro and in vivo. Phosphorylation by mxi2 may affect the ability of max to oligomerize with itself and its partners, bind dna, or regulate gene expression. SIGNOR-26511 0.612 Hexokinase proteinfamily SIGNOR-PF76 SIGNOR α-D-glucose smallmolecule CHEBI:17925 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266459 0.8 MMP3 protein P08254 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage Asn360 DFVDIPEnFFGVGGE 9606 BTO:0000206 9202061 t lperfetto Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE374 SIGNOR-266986 0.728 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys21 EGPRDGLkKERLLDD 9606 9990853 t gcesareni We report here the identification of an ikappab-ubiquitin (ub) ligase complex containing the f-box/wd40-repeat protein, beta-trcp, a vertebrate homolog of drosophila slimb. beta-trcp binds to ikappabalpha only when the latter is specifically phosphorylated by an ikappab kinase complex. here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha. SIGNOR-64317 0.522 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr8 MEELQDDyEDMMEEN -1 10942405 t The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton SIGNOR-251413 0.462 NOTCH1 protein P46531 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000938 16554461 f gcesareni Notch1 activation by neuronal contact induces the glial expression of the brain lipid binding protein (blbp) and erbb2 genes. SIGNOR-145322 0.509 POU5F1 protein Q01860 UNIPROT TDGF1 protein P13385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254943 0.675 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation Tyr156 ADEDEDDyHNPGYLV 9606 BTO:0000782 11368773 t lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. SIGNOR-247018 0.761 CSNK2A2 protein P19784 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser11 DFGFFSSsESGAPEA -1 3128543 t llicata To date, the only evidence for a functional distinction of LCa and LCb is the preferential phosphorylation of LCb, which takes place at serine residues and is mediated by coated vesicle-associated casein kinase II. As a first step toward determining the function of light chain diversity, we have mapped the in vitro phosphorylation sites on LCb. We use [32P]ATP to phosphorylate LCb within coated vesicles, followed by sequencing of 32P-labeled chymotryptic peptides thereof, to identify serine residues at positions 11 and 13 as the phosphorylation sites. SIGNOR-250983 0.313 ZDHHC9 protein Q9Y397 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity palmitoylation 9606 BTO:0000007 16000296 t miannu Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein. SIGNOR-261352 0.447 OGT protein O15294 UNIPROT TET1 protein Q8NFU7 UNIPROT up-regulates activity glycosylation 9606 BTO:0002181 23729667 t irozzo The DNA demethylation enzyme Tet1 interacts with Ogt and is O-GlcNAcylated. Tet1 protein stability is positively regulated by O-GlcNAcylation, and its repression function on targeting genes is dependent on Ogt. SIGNOR-259184 0.451 POMC protein P01189 UNIPROT MC1R protein Q01726 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268700 0.757 LLGL1 protein Q15334 UNIPROT Scribble_complex_DLG2-LLGL1_variant complex SIGNOR-C510 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270907 0.544 MRPS18A protein Q9NVS2 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262334 0.709 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2J2 protein Q8N2K1 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271339 0.585 KDM4C protein Q9H3R0 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates activity binding 9606 29207681 t miannu In hypoxia, HIF-1α dimerizes with HIF-1β to form active HIF-1 complex. JMJD2C interacts with HIF-1α and promotes the transcriptional activation of HIF-1 targeting genes via demethylating di- and trimethylated H3K9. SIGNOR-263873 0.2 PLK1 protein P53350 UNIPROT TNKS protein O95271 UNIPROT up-regulates quantity by stabilization phosphorylation Thr982 SLISPAStPSCLSAA 9606 BTO:0000567 21818122 t miannu Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends.  SIGNOR-276241 0.438 SH3RF1 protein Q7Z6J0 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 9482736 t gcesareni Posh activates jnk1 in cos-1 cells. SIGNOR-55759 0.379 U0126 chemical CHEBI:90693 ChEBI MAPK7 protein Q13164 UNIPROT down-regulates 9606 11782488 f gcesareni Bmk1activation by h2o2 was inhibited by both pd98059 and u0126, which were reported to inhibit mek5 as well as mek1/2. SIGNOR-113782 0.8 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR YAP1 protein P46937 UNIPROT down-regulates binding 9534 BTO:0004055 12535517 t milica One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73. SIGNOR-97481 0.2 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1931 SPTSPTYsPTSPKGS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273099 0.745 SMC3 protein Q9UQE7 UNIPROT MXD4 protein Q14582 UNIPROT down-regulates activity binding 9534 BTO:0000318 9528857 t 2 miannu We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions. SIGNOR-241284 0.301 FOXO1 protein Q12778 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18805788 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-181195 0.2 AKT1 protein P31749 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Thr60 EYRRRRHtMDKDSRG 9606 16081417 t llicata Phosphorylation of wnk1 on thr-58 contributes to sgk1 activation. these data suggest that activation of sgk1 by wnk1 requires the catalytic activity of akt. SIGNOR-252481 0.402 DICER1 protein Q9UPY3 UNIPROT DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR form complex binding 9606 23661684 t miannu SIGNOR-143105 0.893 CDK1 protein P06493 UNIPROT MCM4 protein P33991 UNIPROT down-regulates activity phosphorylation Thr19 GSRRGRAtPAQTPRS 9606 BTO:0000567 12714602 t lperfetto We report here that human mcm4, a subunit of the putative dna replicative helicase, is extensively phosphorylated in hela cells when they are incubated in the presence of inhibitors of dna synthesis or are exposed to uv irradiation. The data presented here indicate that the consecutive actions of atr-chk1 and cdk2 kinases are involved in this phosphorylation in the presence of hydroxyurea. Phosphorylation of t19 correlates with lowered level of dna helicase activity of the purified mcm4,6,7 complex. SIGNOR-100877 0.608 ECM stimulus SIGNOR-ST20 SIGNOR AX/b2 integrin complex SIGNOR-C171 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259053 0.7 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH2 protein Q04721 UNIPROT up-regulates activity cleavage 9606 25610395 t lperfetto The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins. SIGNOR-209723 0.572 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 28370702 f lperfetto A specific subtype of non-small cell lung cancer (NSCLC) characterized with an EML4-ALK fusion gene, which drives constitutive oncogenic activation of ALK kinase. We demonstrated that exogenous introduction of EML4-ALK protein with the substitution of lysine 1610 to an alanine in these two cell lines reduced the phosphorylation levels of AKT, one of downstream oncogenic molecules in the EML4-ALK pathway, and suppressed the growth of the two cell lines. SIGNOR-253218 0.2 UDP-D-glucose smallmolecule CHEBI:18066 ChEBI P2RY14 protein Q15391 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257562 0.8 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser46 VKVNGDAsPAAAESG -1 8034575 t lperfetto Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites. SIGNOR-248908 0.719 FOXP1 protein Q9H334 UNIPROT HIP1R protein O75146 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000785 23884370 f miannu Hip1r was confirmed as a direct foxp1 target / hip1r repression by foxp1 SIGNOR-202370 0.298 PRKACA protein P17612 UNIPROT CCND1 protein P24385 UNIPROT unknown phosphorylation Ser234 YRLTRFLsRVIKCDP -1 8058338 t miannu PKA phosphorylates three distinct serine residues in cyclin D1 at positions 90, 197 and 234. SIGNOR-250346 0.339 FOXJ1 protein Q92949 UNIPROT CETN2 protein P41208 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 t miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). SIGNOR-266930 0.36 PTPN2 protein P17706 UNIPROT SRC protein P12931 UNIPROT down-regulates dephosphorylation 9606 22080863 t gcesareni We found that tcptp dephosphorylates and inactivates src family kinases to regulate t cell responses._ SIGNOR-177116 0.709 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser90 QHVRSHSsPASLQLG 9606 BTO:0000567 26183396 t miannu In this study, we found that Cdk1 (Cyclin-dependent kinase 1) directly phosphorylated TAZ on six novel sites independent of the Hippo pathway, which further resulted in TAZ degradation through proteasome system. SIGNOR-276926 0.261 UBE2D1 protein P51668 UNIPROT PEX5 protein P50542 UNIPROT up-regulates activity ubiquitination -1 19687296 t miannu Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. SIGNOR-253022 0.396 NEK11 protein Q8NG66 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser88 DSGFCLDsPGPLDSK 9606 19734889 t lperfetto Nek11 regulates cdc25a degradation and the ir-induced g2/m checkpointincubation of wild-type cdc25a with nek11 led to a marked increase in phosphorylation of ser 82 and 88 as detected with the phosphospecific antibody recognizing these sites SIGNOR-187871 0.428 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates activity phosphorylation Ser166 EPRSRHLsVSSQNPG 9606 12761204 t lperfetto Inhibition of mitogen-activated kinase kinase kinase 3 activity through phosphorylation by the serum- and glucocorticoid-induced kinase 1 SIGNOR-101211 0.2 TIMELESS protein Q9UNS1 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates activity binding 9534 23418588 t miannu We performed a detailed molecular characterization of TIM interactions with the core clock protein CRY1 and the DNA damage signal transducer CHK1, and found that the N-terminus of TIM is required for association with both proteins, as well as for homodimerization. SIGNOR-268054 0.787 HES1 protein Q14469 UNIPROT DTX1 protein Q86Y01 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000970 20208568 f gcesareni The notch target gene hes1 causes transcriptional inhibition of deltex1 by directly binding to the promoter of deltex1. SIGNOR-164071 0.317 biphenyl-4,4'-diol chemical CHEBI:34367 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9751507 t miannu Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings.  SIGNOR-268741 0.8 STK11 protein Q15831 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 17108107 t gcesareni We show that lkb1 physically associates with p53 in the nucleus and directly or indirectly phosphorylates p53 ser15 (previously shown to be phosphorylated by amp-dependent kinase) and p53 ser392 SIGNOR-150834 0.747 MUTYH protein Q9UIF7 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). SIGNOR-275716 0.7 PIAS1 protein O75925 UNIPROT PRDM1 protein O75626 UNIPROT up-regulates sumoylation Lys816 PLVPVKVkQETVEPM 9606 22555612 t miannu Blimp_1 is subjected to pias1_mediated sumoylation at lysine 816 / it appears that sumo_modified blimp_1 is a more potent transcriptional repressor. SIGNOR-197265 0.329 AKT proteinfamily SIGNOR-PF24 SIGNOR LTB4R2 protein Q9NPC1 UNIPROT unknown phosphorylation Thr324 GGRSREGtMELRTTP 9606 22044535 t llicata Blt2 phosphorylation at thr355 by akt is necessary for blt2-mediated chemotaxis. SIGNOR-177019 0.2 FPR2 protein P25090 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256745 0.41 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000938 17591690 t llicata We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 cdk5-stabilized p53 protein is transcriptionally active SIGNOR-156426 0.722 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000669 15568017 t gcesareni Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression. SIGNOR-131307 0.564 RRAGA protein Q7L523 UNIPROT RAGAC complex SIGNOR-C113 SIGNOR form complex binding 9606 20381137 t gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant SIGNOR-228164 0.772 CHN1 protein P15882 UNIPROT CDK5R1 protein Q15078 UNIPROT up-regulates binding 9606 15013773 t miannu _-chimaerin was identified to interact with the p35 activator of cdk5. The complex of _-chimaerin, cdk5 and p35 is enzymatically functional SIGNOR-123439 0.343 PSMF1 protein Q92530 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR down-regulates activity binding 9606 BTO:0000007 23622245 t lperfetto We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31. SIGNOR-263341 0.506 PTPN2 protein P17706 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr771 ADIESSNyMAPYDNY 10090 BTO:0002572 14966296 t The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP. SIGNOR-248389 0.546 MRPL34 protein Q9BQ48 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262363 0.654 HIPK2 protein Q9H2X6 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 17210684 t llicata Based on all these observations, it is legitimate to suggest that axin and daxx seem to adopt both parallel routes and a convergent means to activate p53. In either case, hipk2 seems to be the protein kinase that catalyzes the ser46 phosphorylation. SIGNOR-151930 0.79 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Ser434 PPPSDAGsPFQSSPL 9606 BTO:0000007 19126544 t lperfetto Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1. SIGNOR-235797 0.498 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 10090 BTO:0000759 34861291 t miannu Perfluorooctane sulfonate (PFOS) is a stable environmental contaminant that can activate peroxisome proliferator-activated receptor alpha (PPARα). These results indicate that mouse PPARα can be activated in the liver by PFOS causing increased expression of Acox1, Cyp4a10 and histopathological changes in the liver. SIGNOR-268754 0.8 ATF4 protein P18848 UNIPROT DDIT4 protein Q9NX09 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19439225 f lperfetto We additionally identified Redd1 as a downstream effector of C/EBP-beta stimulated by ATF4 activated under the stress conditions examined. RNA interference studies provided further evidence of the requirement of C/EBP-beta for Redd1 expression. We conclude that the Redd1 gene is transactivated by the ATF4 and C/EBP family of transcription factors, leading to mTOR inhibition in response to oxidative and ER stress. SIGNOR-253726 0.424 DOK4 protein Q8TEW6 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 t gcesareni Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells. SIGNOR-100996 0.472 CPS1 protein P31327 UNIPROT Pyrimidine biosynthesis phenotype SIGNOR-PH187 SIGNOR up-regulates activity 9606 15096496 f CPSase catalyzes the rate-limiting step in de novo pyrimidine biosynthesis and, as discussed below, controls the flux through the pathway SIGNOR-267195 0.7 FFAR3 protein O14843 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256957 0.2 MGluR proteinfamily SIGNOR-PF55 SIGNOR GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 t miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. SIGNOR-264689 0.2 CSNK2A1 protein P68400 UNIPROT FHOD3 protein Q2V2M9 UNIPROT down-regulates phosphorylation 9606 BTO:0000887 21149568 t tpavlidou We have identified a novel striated muscle-specific splice variant of the formin fhod3 that introduces a casein kinase 2 (ck2) phosphorylation site. The specific targeting of muscle fhod3 to the myofibrils in cardiomyocytes is abolished in phosphomutants or by the inhibition of ck2. Phosphorylation of muscle fhod3 also prevents its interaction with p62/sequestosome 1 and its recruitment to autophagosomes. SIGNOR-170525 0.314 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates activity phosphorylation Tyr842 DIMSDSNyVVRGNAR 10090 BTO:0001516 16627759 t lperfetto In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated. SIGNOR-271925 0.2 PTK6 protein Q13882 UNIPROT EPS8 protein Q12929 UNIPROT up-regulates activity phosphorylation Tyr525 NRHIDRNyEPLKTQP 9606 28214294 t miannu Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis. SIGNOR-263190 0.365 1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester chemical CHEBI:92418 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258637 0.8 SRC protein P12931 UNIPROT TNK2 protein Q07912 UNIPROT up-regulates activity phosphorylation Tyr860 KVSSTHYyLLPERPS -1 36178070 t miannu We identified two Src phosphorylation sites within the MHR (Y859, Y860). Addition of Src-phosphorylated MHR to the Ack1 KD enhanced enzymatic activity.  SIGNOR-276341 0.393 DHFR2 protein Q86XF0 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI down-regulates quantity chemical modification 9606 21876184 t lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. |We demonstrate that the DHFRP4, or dihydrofolate reductase-like 1 (DHFRL1), gene is expressed and shares some commonalities with DHFR. SIGNOR-268260 0.8 NFE2 protein Q16621 UNIPROT HBG2 protein P69892 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000426 16287851 f Regulation of expression miannu NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells. SIGNOR-251840 0.509 MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 10373569 t gcesareni Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator. SIGNOR-238529 0.41 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser463 SPHNPISsVS 9606 9136927 t lperfetto Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro SIGNOR-210079 0.651 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Ser360 RKTQTSMsLGTTREK 10090 24012422 t gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays SIGNOR-266428 0.743 EPHA2 protein P29317 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates 9606 BTO:0000782 7982920 f gcesareni In keeping with the above observations, activation of eck by its ligand, b61, increased phosphatidylinositol 3-kinase activity SIGNOR-35418 0.37 CAPZA1 protein P52907 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity binding 9606 BTO:0000132 27871158 t lperfetto Finally, the capZ protein recaps the barbed filament ends to complete the assembly and these actin cytoskeletons can be used for cellular contraction, resulting in the final activated platelet shape SIGNOR-261855 0.7 FANCM protein Q8IYD8 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 t lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263248 0.934 DAPK1 protein P53355 UNIPROT MYL12A protein P19105 UNIPROT up-regulates activity phosphorylation Thr18 KKRPQRAtSNVFAMF 9606 BTO:0000567 11485996 t miannu DAPK Phosphorylates Myosin II RLC in Vitro and in Vivo. Together these results show that similar to the conventional MLCKs, Ser-19 is the primary RLC residue phosphorylated by DAPK and that phosphorylation of Thr-18 is also possible. SIGNOR-262843 0.278 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. SIGNOR-33909 0.706 AGTR1 protein P30556 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256881 0.252 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Ser951 GFHPRRSsQGATQMP 10090 BTO:0000944 11581251 t lperfetto HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme SIGNOR-249204 0.585 CRYGC protein P07315 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 10521291 f The γ-crystallin proteins are tightly folded in two domains with no free loops. It is possible that the R58H mutation destabilizes the contact between lens-fiber cells, which is critical for the maintenance of lens transparency. Improper folding of CRYGD, the most abundantly expressed γ-crystallin in the lens, could well cause protein aggregation and lens opacification. SIGNOR-253624 0.7 IRF1 protein P10914 UNIPROT DST protein Q03001 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15560761 t miannu Transient transfection studies with BPAG1 promoter-luciferase reporter gene plasmids and IRF1 and IRF2 expression plasmids revealed that IRF1 and IRF2 directly down-regulated BPAG1 gene transcription in cultured normal human epidermal keratinocytes. SIGNOR-254492 0.2 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination 9606 18570872 t amattioni CIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1. In this way RIP1 functions as a prosurvival scaffold molecule instead of a proapoptotic adaptor protein SIGNOR-179100 0.759 SIRT5 protein Q9NXA8 UNIPROT LDHB protein P07195 UNIPROT up-regulates activity deacetylation Lys329 DTLWDIQkDLKDL 9606 BTO:0001615 34929314 t lperfetto In colorectal cancer, SIRT5 binds to lactate dehydrogenase B (LDHB) to deacetylate it at Lysine 329, thereby increasing its enzymatic activity. SIGNOR-267645 0.2 SP4 protein Q02446 UNIPROT RHO protein P08100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 15781457 f miannu Sp4 and Sp1 are activators of the rod opsin promoter SIGNOR-225382 0.2 CD40LG protein P29965 UNIPROT CD40 protein P25942 UNIPROT up-regulates activity binding 9606 BTO:0000782;BTO:0003076 19426221 t lperfetto Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated t cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner .cd40 binds its ligand cd40l. SIGNOR-185660 0.927 HSD17B2 protein P37059 UNIPROT estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity chemical modification -1 8099587 t Luana 17 beta-HSD type 2 was capable of catalyzing the interconversion of testosterone and androstenedione as well as estradiol and estrone.  SIGNOR-269762 0.8 CTDSPL protein O15194 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000007 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248312 0.476 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. SIGNOR-236671 0.741 IKBKB protein O14920 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates phosphorylation Ser8 MEPAAGSsMEPSADW 9606 20152798 t lperfetto Ikkbeta specifically binds to p16 and phosphorylates ser8 of p16 phosphorylation at ser8 of p16 brings about a significant loss of its cyclin-dependent kinase (cdk) 4-inhibitory activity SIGNOR-163801 0.405 SREBF1 protein P36956 UNIPROT VLDL_assembly phenotype SIGNOR-PH62 SIGNOR up-regulates 9606 11111091 f miannu SREBP1 increased the expression of MTP and increased the assembly and secretion of VLDL containing apo B100. SREBP1 induced the expression of the genes regulating the synthesis of all VLDL lipids SIGNOR-252112 0.7 PRKCA protein P17252 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser23 NDMKVRKsSTPEEVK 9606 BTO:0001271 22855535 t lperfetto Pkc_ phosphorylates cofilin at ser-23 and/or ser-24 during degranulationthese results indicate that a novel pkc_-mediated phosphorylation event regulates cofilin by inhibiting its ability to depolymerize f-actin and bind to 14-3-3_, thereby promoting f-actin polymerization SIGNOR-198478 0.2 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr471 YEDAGSHyLCLLKAR 9606 11113114 t gcesareni Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity. SIGNOR-85009 0.427 FUBP1 protein Q96AE4 UNIPROT TNF protein P01375 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19637194 f irozzo FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In addition, mRNA levels of the death ligands tumor necrosis factor (TNF) α and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) were significantly increased. SIGNOR-259130 0.2 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 26260587 t IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-253590 0.793 POU3F2 protein P20265 UNIPROT MITF protein O75030 UNIPROT up-regulates quantity by expression transcriptional regulation 18628967 t lperfetto We further demonstrate that BRN2 induces MITF transcription through a binding site located at ˆ’50/ˆ’36 of the MITF promoter SIGNOR-249616 0.449 LIPH protein Q8WWY8 UNIPROT LPAR2 protein Q9HBW0 UNIPROT up-regulates binding 9606 BTO:0000661 9525886 t gcesareni When overexpressed in jurkat t cells, the edg4 protein mediated lpa-induced activation of a serum response element reporter gene with lpa concentration dependence (ec50 of 10 nm) and specificity. SIGNOR-56093 0.298 PTEN protein P60484 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity dephosphorylation Ser97 LRLAEDRsKDPHDPH 9606 32394474 t lperfetto PTEN can dephosphorylate IRF-3 S97 residue and facilitate its nuclear import for the IFN signaling pathway (7).|PTEN expression directly increases activated IRF-3 nuclear import and subsequent interferon (IFN) synthesis. SIGNOR-277025 0.259 PKA proteinfamily SIGNOR-PF17 SIGNOR PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Ser83 YIGRKKIsPPTPKPR -1 21743495 t miannu in vitro kinase assays using purified protein kinase A (PKA) and either GST fused full length p85 (GST-p85) or GST fused p85 peptide spanning amino acids 50-109 (GST-p85Δ2) as substrate.  Serine 83 phosphorylation on p85 is necessary for PI3K activation and membrane translocation in 14-3-3ζ overexpressing cells  SIGNOR-276343 0.2 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1784 TPTSPNYsPTSPSYS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248757 0.727 letrozole chemical CHEBI:6413 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193651 0.8 UTS2R protein Q9UKP6 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256922 0.252 SOCS1 protein O15524 UNIPROT VAV1 protein P15498 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0000298 10747851 t miannu SOCS1 stimulates the polyubiquitination of VAV proteins in vivo, which was stabilized by proteasomal inhibitors. These results suggest that SOCS1 programs VAV degradation by acting as a substrate-specific recognition component of a VCB-like ubiquitin ligase complex. SIGNOR-272559 0.581 LCMT1 protein Q9UIC8 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates activity methylation Leu309 RRTPDYFl -1 18394995 t lperfetto Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |The PP2A core enzyme was methylated by a PP2A-specific leucine carboxyl methyltransferase (LCMT1) SIGNOR-265751 0.647 CXCL9 protein Q07325 UNIPROT CXCR3 protein P49682 UNIPROT up-regulates activity binding 9606 BTO:0000782 12750173 t miannu The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells. SIGNOR-260970 0.774 PRKACA protein P17612 UNIPROT ETV5 protein P41161 UNIPROT up-regulates activity phosphorylation Ser367 PPYQRRGsLQLWQFL 9606 BTO:0002909 11682477 t lperfetto We further show that the increase in erm transcriptional activity after pka phosphorylation is closely correlated with a drastic reduction in the dna binding of the transcription factor. These results indicate that the phosphorylation of erm by pka is involved in erm-mediated transcription and suggest that the activation of erm is probably related to conformational changes. SIGNOR-111239 0.2 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 f miannu YAP and TAZ are two main downstream effectors of the Hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-277640 0.7 NOTCH1 protein P46531 UNIPROT TCFL5 protein Q9UL49 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 16990763 f gcesareni Interestingly, in absence of delta signal, both hes-1 and tcfl5 decreased, and further decreased by incubation with dapt. (figure 4). This pharmacological approach therefore provides additional evidence that tcfl5, similar to hes1, is a true notch target gene. SIGNOR-149807 0.2 CDKN2A protein Q8N726 UNIPROT ATR protein Q13535 UNIPROT up-regulates activity phosphorylation 9606 15775976 t gcesareni Regulation of NF-kappaB and p53 through activation of ATR and Chk1 by the ARF tumour suppressorInduction of ATR activity in Hs68 E2F1ER cells by endogenous ARF. SIGNOR-134781 0.4 JUN protein P05412 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9615 9312063 t lperfetto Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter. SIGNOR-236139 0.663 EREG protein O14944 UNIPROT ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR up-regulates binding 9606 16829981 t inferred from 70% of family members gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4. SIGNOR-269873 0.891 TCOF1 protein Q13428 UNIPROT NBN protein O60934 UNIPROT up-regulates activity relocalization 9606 25064736 t lperfetto We further identify TCOF1 (also known as Treacle), a nucleolar factor implicated in ribosome biogenesis and mutated in Treacher Collins syndrome, as an interaction partner of NBS1, and demonstrate that NBS1 translocation and accumulation in the nucleoli is Treacle dependent. SIGNOR-265085 0.324 PML protein P29590 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 15093545 f gcesareni The promyelocytic leukemia (pml) protein is a potent growth suppressor and proapototic factor SIGNOR-124320 0.7 AGRP protein O00253 UNIPROT MC5R protein P33032 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268714 0.566 RAB3C protein Q96E17 UNIPROT Dense-core_vesicle_exocytosis phenotype SIGNOR-PH184 SIGNOR up-regulates 9606 31679900 f miannu Here, we identify the SEC4 ortholog RAB3 and its neuronal effector, RIM1, as essential molecules for neuropeptide and neurotrophin release from dense-core vesicles (DCVs) in mammalian neurons.  SIGNOR-264376 0.7 nilotinib chemical CHEBI:52172 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258257 0.8 PRKACA protein P17612 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser23 PAPIRRRsSNYRAYA 9606 15769444 t lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. SIGNOR-134605 0.398 GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263817 0.8 SIRT5 protein Q9NXA8 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31608237 f Monia In SIRT5 silenced Mero-14 cells, beclin-1 protein levels were downregulated upon rotenone and resveratrol treatment. In summary, in most cases, where significant effects were detected, SIRT1, SIRT3, and SIRT5 had positive effects on beclin1 and LC3II/LC3I ratio SIGNOR-261206 0.321 CDK1 protein P06493 UNIPROT NUSAP1 protein Q9BXS6 UNIPROT down-regulates phosphorylation Thr338 GNSAAVItPFKLTTE 9606 22101338 t llicata We report here that cdk1 phosphorylates nusap at threonine 300 and 338 in early mitosis. Phosphorylation of nusap inhibits its microtubule-binding activity in vitro and in vivo. SIGNOR-177549 0.441 SOD1 protein P00441 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity 9606 BTO:0000452 BTO:0001279 31623154 f P00441:p.Gly94Ala (mutation increasing interaction) We demonstrated the increased expression of S100A4 also in fibroblasts derived from amyotrophic lateral sclerosis (ALS) patients carrying SOD1 pathogenic variants. SIGNOR-262784 0.2 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine chemical CHEBI:91419 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190179 0.8 IGF1R protein P08069 UNIPROT PCNA protein P12004 UNIPROT up-regulates activity phosphorylation Tyr133 LGIPEQEySCVVKMP -1 28924044 t miannu In vitro MS analysis of PCNA co-incubated with the IGF-1R kinase indicated tyrosine residues 60, 133, and 250 in PCNA as IGF-1R targets, and PCNA phosphorylation was followed by mono- and polyubiquitination. SIGNOR-277254 0.2 NFATC3 protein Q12968 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16219765 f miannu Overexpression of NFAT3 enhanced both ERalpha and ERbeta transcriptional activities in a ligand-independent manner and up-regulated downstream estrogen-responsive genes including pS2 and cathepsin D. Reduction of endogenous NFAT3 with NFAT3 small interfering RNA or overexpression of NFAT3 deletion mutants that lack the ER-binding sites reduced the NFAT3 coactivation of ERalpha and ERbeta. SIGNOR-254640 0.2 GAMT protein Q14353 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates -1 26319512 f Luana GAMT enzyme (EC#2.1.1.2) deficiency caused by mutations in the GAMT gene (MIM# 601240) results in the depletion of creatine and accumulation of guanidinoacetate (GAA). Creatine has a buffering and transport function of high-energy phosphates in brain and muscle and is essential for growth cone migration, dendritic and axonal elongation, neurotransmitter release, and co-transmission on gamma amino butyric acid (GABA) postsynaptic receptors in the central nervous system SIGNOR-265795 0.7 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000552 20663147 t gcesareni DeltaNp63alpha depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of DeltaNp63alpha in p63-null tumour cells stimulates ATM transcription and p53 Serine-15 phosphorylation SIGNOR-167156 0.838 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HDAC6 protein Q9UBN7 UNIPROT up-regulates phosphorylation Thr1031 ASSTDHQtPPTSPVQ 9606 24089523 t lperfetto Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1 SIGNOR-244549 0.2 LSM-20934 chemical CHEBI:109533 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258727 0.8 ERG protein P11308 UNIPROT WNT11 protein O96014 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21242973 f miannu ERG transcriptional networks in leukemia converge on WNT signaling targets. Specifically, WNT11 emerged as a direct target of ERG. Small interfering RNA (siRNA)-mediated knockdown of ERG confirmed downregulation of WNT11 transcripts. SIGNOR-254071 0.2 NDUFA7 protein O95182 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. SIGNOR-262158 0.818 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Thr346 TGENAGQtPMNINPQ 26375055 t lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity SIGNOR-276521 0.261 MRGPRX1 protein Q96LB2 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257326 0.2 FRAT1 protein Q92837 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 9635432 t lperfetto The frat family consists of three members: frat-1, -2, and -3. It has been shown that different sites of frat-1 interact with gsk-3 and dvl-1 and that wnt-1 disintegrates the complex formation of frat-1, dvl-1, and axin, resulting in the activation of the wnt signaling pathway SIGNOR-227994 0.628 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation Thr221 AGTSFMMtPYVVTRY 9606 BTO:0000007 17761173 t lperfetto We next examined whether the phosphorylation of JNK at threonine 183 (Thr183) and tyrosine 185 (Tyr185) was enhanced by GRASP‐1 expression. Phosphorylation of Thr183 and Tyr185 by SEK1/MKK4, which is in turn phosphorylated and activated by several kinases including MEKK1, is known to activate JNK1/2/3 SIGNOR-260614 0.733 PTEN protein P60484 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates activity 9606 BTO:0000938 18794881 f lperfetto The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3)). SIGNOR-252725 0.706 ABL1 protein P00519 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Tyr213 PPTVPNDyMTSPARL 9606 21320496 t lperfetto Abi-1 is an adaptor protein for abelson kinase (c-abl). Here, we identified a new phosphorylation site (y398) in the sh3 domain of abi1, and disruption of y398, combined with the previously identified phosphorylation site y213, significantly weakens the binding of abi-1 to c-abl. Phosphorylation of abi-1 is dependent on c-abl kinase SIGNOR-172017 0.876 NR0B2 protein Q15466 UNIPROT NR1H3 protein Q13133 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000195 12198243 f gcesareni Here we show that shp can interact with the liver x receptors lxr? (nr1h3) and lxr? (nr1h2), as demonstrated by glutathione-s-transferase pull-down assays, mammalian two-hybrid, and coimmunoprecipitation experiments. In transfection assays, shp inhibits the expression of an artificial reporter driven by an lxr-response element and represses the transcriptional activation by lxr of the human atp-binding cassette transporter 1 (abca1) promoter. T SIGNOR-91996 0.49 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ZC3HC1 protein Q86WB0 UNIPROT down-regulates phosphorylation Ser395 PGLEVPSsPLRKAKR 9606 17389604 t lperfetto Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1 SIGNOR-216880 0.341 CSAD protein Q9Y600 UNIPROT beta-alanine zwitterion smallmolecule CHEBI:57966 ChEBI up-regulates quantity chemical modification 9606 22718265 t miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. SIGNOR-267549 0.8 RNF123 protein Q5XPI4 UNIPROT CBX1 protein P83916 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 23077635 t miannu In the present study, we report that HP1α and β undergo proteasomal degradation in lamin A/C knock-down cells and show by ectopic expression, RNAi and binding studies that the RING finger ubiquitin ligase RNF123 is directly involved in HP1 degradation. SIGNOR-272034 0.2 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser285 SSASPALsRRGSLGE 10090 17213202 t lperfetto Serines 281 and 285 of the nfat3 protein might be target amino acids of rsk2 phosphorylationrsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo. SIGNOR-234469 0.393 RNF5 protein Q99942 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization ubiquitination Lys461 GPEENEYkSEGTFGI 9606 BTO:0000007 20483786 t miannu In this study, we showed that the E3 ubiquitin ligase RING-finger protein 5 (RNF5) interacted with VISA at mitochondria in a viral infection-dependent manner. Domain mapping experiments indicated that the C-terminal transmembrane domain of VISA was required for its interaction with RNF5. RNF5 targeted VISA at K362 and K461 for K48-linked ubiquitination and degradation after viral infection, whereas knockdown of RNF5 reversed virus-induced downregulation of VISA at the early phase.  SIGNOR-271489 0.467 MET protein P08581 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates activity phosphorylation Tyr1510 LVKLQQTyAALNSKA 9606 BTO:0000815 33087447 t miannu IQGAP1 was phosphorylated exclusively on Tyr-1510 under conditions with enhanced MET or c-Src signaling, including in human lung cancer cell lines. This phosphorylation was significantly reduced by chemical inhibitors of MET or c-Src or by siRNA-mediated knockdown of MET. SIGNOR-277532 0.275 MINK1 protein Q8N4C8 UNIPROT PRICKLE1 protein Q96MT3 UNIPROT up-regulates activity phosphorylation Thr370 LSGNADDtLSRKLDD -1 22037766 t miannu We show that Mink1 phosphorylates Prickle on a conserved threonine residue and regulates its Rab5-dependent endosomal trafficking, a process required for the localized plasma membrane accumulation and function of Prickle. SIGNOR-263095 0.297 SRC protein P12931 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates activity phosphorylation Tyr1510 LVKLQQTyAALNSKA 9606 BTO:0000815 33087447 t miannu IQGAP1 was phosphorylated exclusively on Tyr-1510 under conditions with enhanced MET or c-Src signaling, including in human lung cancer cell lines. This phosphorylation was significantly reduced by chemical inhibitors of MET or c-Src or by siRNA-mediated knockdown of MET. SIGNOR-277533 0.683 ALK protein Q9UM73 UNIPROT CDK9 protein P50750 UNIPROT up-regulates activity phosphorylation Tyr19 FCDEVSKyEKLAKIG -1 36253486 t miannu We report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes. SIGNOR-277607 0.3 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1724 SPSYSPTsPSYSPTS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248776 0.442 CHEK1 protein O14757 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates activity phosphorylation Ser296 GFSKHIQsNLDFSPV 8355 15707391 t lperfetto This suggests that Ser296 is probably one of the sites autophosphorylated when Chk1 is fully activated [21], despite the sequence surrounding Ser296 (FSKHIQS296NL) being only weakly related to the optimal Chk1-recognition motif (M/I/L/V)-X-(R/K)-X-X-(S/T), where (S/T) is the phosphorylated residue SIGNOR-219240 0.2 TFAP2A protein P05549 UNIPROT DCC protein P43146 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19745029 f miannu Promoter analysis and transfection studies showed that the up-regulation of DCC in OA chondrocytes may be mediated by the transcription factors Sox9 and AP-2. SIGNOR-255189 0.2 GRM8 protein O00222 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. SIGNOR-264939 0.8 CSNK1E protein P49674 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser314 SREQSTDsGLGLGCY 9606 24715453 t milica LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP) SIGNOR-230747 0.342 SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-201703 0.821 ZNF322 protein Q6U7Q0 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24550733 t lperfetto Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays revealed that Zfp322a binds to Pou5f1 and Nanog promoters and regulates their transcription. SIGNOR-264899 0.2 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr398 SQFTKYWtESNGVES 9606 16216881 t lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. SIGNOR-141026 0.2 STAT5A protein P42229 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15626738 t FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells SIGNOR-261551 0.639 FGFR2 protein P21802 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates activity phosphorylation 10116 BTO:0002809 9182757 t fspada In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway. SIGNOR-236950 0.769 PRKCD protein Q05655 UNIPROT PLSCR1 protein O15162 UNIPROT up-regulates phosphorylation Thr161 CGPSRPFtLRIIDNM 9606 10770950 t lperfetto Following the induction of apoptosis, however, phosphorylation of serine residues decreased and it increased on threonine, consistent with the predicted pkc phosphorylation site at thr-161. Transfection of cho cells with scramblase and pkc_, but not scramblase or pkc_ alone, increased scramblase activity SIGNOR-76904 0.434 DNMT1 protein P26358 UNIPROT GAD1 protein Q99259 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 f miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. SIGNOR-254574 0.355 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARG protein P37231 UNIPROT up-regulates quantity by expression phosphorylation 10090 BTO:0000011 12270934 t lperfetto Our results suggest that activation of the MEK/ERK signaling pathway during the initial 12 h of adipogenesis enhances the activity of factors that regulate both C/EBPalpha and PPARgamma expression. SIGNOR-235334 0.2 MAPK3 protein P27361 UNIPROT ETS1 protein P14921 UNIPROT up-regulates phosphorylation Thr38 CADVPLLtPSSKEMM 9606 11948414 t gcesareni We found that hgf/sf activates the erk1 map kinase, leading to the phosphorylation of the threonine 38 residue of ets1 SIGNOR-116494 0.659 CDK2 protein P24941 UNIPROT LIG1 protein P18858 UNIPROT up-regulates activity phosphorylation Ser51 GVVSESDsPVKRPGR 9606 BTO:0000567 12851383 t lperfetto Thus, phosphorylation of serine 51 on hligi plays a critical role in regulating the interaction between hligi and rfc, which is required for efficient dna replication and repair. SIGNOR-103246 0.468 MYC protein P01106 UNIPROT PRPS2 protein P11908 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18677108 t miannu Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation. SIGNOR-267376 0.281 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser795 TASTRKVsLAPQANL 9606 1377674 t lperfetto Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function SIGNOR-18249 0.52 MAPKAPK2 protein P49137 UNIPROT UBE2J1 protein Q9Y385 UNIPROT down-regulates quantity by destabilization phosphorylation Ser184 KELARQIsFKAEVNS 9606 BTO:0000567 24020373 t miannu Endoplasmic reticulum-associated ubiquitin-conjugating enzyme Ube2j1 is a novel substrate of MK2 (MAPKAP kinase-2) involved in MK2-mediated TNFα production. These findings strongly suggest that MK2 directly phosphorylates Ube2j1 at Ser(184) upon p38-activating stress in vivo. SIGNOR-263091 0.34 ZMYND11 protein Q15326 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity binding methylation:Lys38 PSTGGVKkPHRYRPG 24675531 t miannu We found that full-length BS69 specifically interacted with H3K36me3 in native nucleosome co-immunoprecipitation (co-IP) experiments. We propose that BS69 specifically associates with H3K36me3-enriched chromatin through the PWWP domain, which facilitates the recruitment of MYND-bound transcription and chromatin remodeling factors including EZH2, HDAC1, Brg1 and E2F6 to target gene loci, thereby repressing target gene transcription. SIGNOR-263897 0.2 CLK2 protein P49760 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser242 MDKRKDPsSVDIKKV -1 10480872 t llicata The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site. SIGNOR-250775 0.328 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267883 0.8 2-[1-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1-pyrazolyl]-3-azetidinyl]acetonitrile chemical CHEBI:95341 ChEBI JAK1 protein P23458 UNIPROT down-regulates activity chemical inhibition 9606 20363976 t Luana INCB028050 is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM). SIGNOR-257833 0.8 NFYB protein P25208 UNIPROT PHGDH protein O43175 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18378410 f miannu Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y. SIGNOR-255210 0.2 SORBS1 protein Q9BX66 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0000887 11001060 t gcesareni Cbl is recruited to the insulin receptor by interaction with the adapter protein cap, through one of three adjacent sh3 domains in the carboxy terminus of cap SIGNOR-82283 0.675 FLI1 protein Q01543 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates activity 10090 BTO:0000725 23320737 f The transcription factor Fli-1 regulates monocyte, macrophage and dendritic cell development in mice SIGNOR-259972 0.7 bromocriptine chemical CHEBI:3181 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258723 0.8 TLK1 protein Q9UKI8 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR -1 11314006 t The effect has been demonstrated using Q9UKI8-2|Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto Purified tlk1b phosphorylated histone h3 at s(10) with high specificity both in a mix of core histones and in isolated chromatin, suggesting that histone h3 is a physiological substrate for tlk1b. Phosphorylation of H3 has been linked to the activation of the immediate-early genes upon mitogenic stimulation, and to chromatin condensation during mitotic/meiotic events. SIGNOR-107037 0.2 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269160 0.2 MAPK6 protein Q16659 UNIPROT TDP2 protein O95551 UNIPROT up-regulates activity phosphorylation Ser60 EMERALNsYFEPPVE -1 26701725 t miannu In the current study, we have found that ERK3, an atypical MAPK, phosphorylates TDP2 at S60 and regulates TDP2's phosphodiesterase activity, thereby cooperatively protecting lung cancer cells against Top2 inhibitors-induced DNA damage and growth inhibition.  SIGNOR-277188 0.385 ZFAT protein Q4KMQ4 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates quantity 10090 24663380 f francesca Ano6 deficiency significantly reduces ERK/AKT phosphorylation. In addition, Ano6-KD also affected levels of phosphorylated and total AKT levels. SIGNOR-261215 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR ATG4B protein Q9Y4P1 UNIPROT up-regulates activity phosphorylation Ser34 WILGRKYsIFTEKDE 9606 BTO:0000586 29165041 t lperfetto In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells.| In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F1Fo-ATP synthase activity. SIGNOR-275836 0.2 GRK6 protein P43250 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 t Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. SIGNOR-251206 0.292 AGT protein P01019 UNIPROT REN protein P00797 UNIPROT up-regulates activity binding 9606 32201502 t miannu Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10). SIGNOR-260224 0.926 AKT3 protein Q9Y243 UNIPROT ADARB1 protein P78563 UNIPROT down-regulates activity phosphorylation Thr553 LQGERLLtMSCSDKI -1 31095429 t miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively SIGNOR-276195 0.2 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR7 protein P34969 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257526 0.8 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser296 SPSALSSsPNNLSPT 10090 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-249442 0.616 RPS25 protein P62851 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262426 0.905 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 t gcesareni The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein. SIGNOR-105770 0.38 PCSK2 protein P16519 UNIPROT IAPP protein P10997 UNIPROT up-regulates activity cleavage Arg33 ESHQVEKrKCNTATC -1 10931181 t lperfetto The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule SIGNOR-261791 0.477 chloramphenicol chemical CHEBI:17698 ChEBI MT-CO1 protein P00395 UNIPROT down-regulates quantity chemical inhibition 9606 BTO:0002552 23148581 t Monia Chloramphenicol treatment suppressed mitochondria translation of mtDNA-encoded cytochrome c oxidase subunit I (Cox I) in H1299 cell. SIGNOR-261068 0.8 HOOK1 protein Q9UJC3 UNIPROT PTPN11 protein Q06124 UNIPROT down-regulates activity binding 9606 BTO:0000018 25331952 t miannu The protein-tyrosine phosphatase domain and N-terminal SH2 domain of SHP2 directly interacted with Hook1. Down-regulation of Hook1 increased SHP2 activity. These results suggested that Hook1 was an endogenous negative regulator of SHP2 phosphatase activity. SIGNOR-260642 0.36 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BU1 protein Q8N257 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRGRkESYSIYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271990 0.2 MAPK7 protein Q13164 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser255 HATSGALsPAKDCGS 9606 BTO:0000007 12637502 t miannu Activated BMK1 selectively phosphorylates Cx43 on Ser-255 in vitro and in vivo. These data demonstrate that BMK1 kinase activity alone is both a necessary and sufficient component in the mediation of EGF-induced Cx43 Ser-255 phosphorylation and subsequent inhibition of GJC. SIGNOR-250115 0.525 PPARGC1A protein Q9UBK2 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates 9606 19491292 f gcesareni Nuclear pgc-1alpha and foxo3a respond in a reciprocal manner following aicar treatment. SIGNOR-252970 0.567 PSMB3 protein P49720 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263359 0.86 ACTL6A protein O96019 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270699 0.821 GSK3A protein P49840 UNIPROT MAFB protein Q9Y5Q3 UNIPROT up-regulates phosphorylation 9606 18042454 t miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. SIGNOR-159429 0.2 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 20887952 f These results indicate that TNF-a-activated p38 pathway negatively controls the expansion of PAX7-positive SCs SIGNOR-253602 0.379 DPY30 protein Q9C005 UNIPROT MLL/SET subcomplex complex SIGNOR-C87 SIGNOR form complex binding 9606 24680668 t miannu Dimethylation of h3k4 requires a sub-complexincluding wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. SIGNOR-204747 0.886 LY294002 chemical CHEBI:65329 ChEBI PIK3R1 protein P27986 UNIPROT down-regulates chemical inhibition 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 t gcesareni Here we show that inhibition of pi3-k activity by the pharmacological agent ly294002 affects early processes of myoblast differentiation including the transcriptional activation of myogenin. SIGNOR-79347 0.8 NOTCH1 protein P46531 UNIPROT PAX7 protein P23759 UNIPROT up-regulates quantity by expression 9606 BTO:0001103;BTO:0002314 22493066 f lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells SIGNOR-219374 0.4 SAM complex complex SIGNOR-C422 SIGNOR Insertion into mitochondrial membrane phenotype SIGNOR-PH193 SIGNOR up-regulates 33408415 f lperfetto The mitochondrial outer membrane contains so-called β-barrel proteins, which allow communication between the cytosol and the mitochondrial interior1-3. Insertion of β-barrel proteins into the outer membrane is mediated by the multisubunit mitochondrial sorting and assembly machinery (SAM, also known as TOB) SIGNOR-267687 0.7 MAML1 protein Q92585 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity acetylation 9606 17300219 t gcesareni The n-terminal domain of maml1 directly interacts with both p300 and histones, and the p300-maml1 complex specifically acetylates histone h3 and h4 tails in chromatin. SIGNOR-265362 0.2 EXOSC4 protein Q9NPD3 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-261383 0.917 POU5F1 protein Q01860 UNIPROT ID2 protein Q02363 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254937 0.293 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC10 protein Q969S8 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002428 31908417 t miannu The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs. SIGNOR-262249 0.8 PPP6C protein O00743 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates dephosphorylation Thr187 CDIQTHMtNNKGSAA 9606 17079228 t gcesareni Our results demonstrate that pp6 specifically down-regulates tak1 through dephosphorylation of thr-187 in the activation loop, which is likely important for suppressing inflammatory responses via tak1 signaling pathways. SIGNOR-150408 0.38 CDK5 protein Q00535 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Ser732 SSEGFYPsPQHMVQT 9606 BTO:0000938 12941275 t gcesareni Here, we show that fak phosphorylation by cdk5 at s732 is important for microtubule organization, nuclear movement, and neuronal migration. In cultured neurons, s732-phosphorylated fak is enriched along a centrosome-associated microtubule fork that abuts the nucleus. Overexpression of the nonphosphorylatable mutant fak s732a results in disorganization of the microtubule fork and impairment of nuclear movement in vitro, and neuronal positioning defects in vivo. SIGNOR-86223 0.31 MAGEL2 protein Q9UJ55 UNIPROT TRIM27 protein P14373 UNIPROT up-regulates activity binding 9606 23452853 t miannu MAGE proteins are a family of proteins that contain a conserved domain known as the MAGE homology domain. Recently, we showed that MAGE proteins function biochemically to bind to and enhance the activity of E3 RING ubiquitin ligases. The E3 RING ubiquitin ligase TRIM27 was identified as a major binding partner of MAGE-L2. SIGNOR-253513 0.535 PAK1 protein Q13153 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12151336 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Histone h3 is a substrate of pak1 both in vitro and in vivo, and it specifically interacted with pak1 but not pak2 or pak3. Site-directed mutagenesis indicated that pak1 phosphorylates histone h3 on ser10. SIGNOR-91050 0.2 CCT365623 (hydrochloride) chemical CID:139266765 PUBCHEM LOX protein P28300 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000195 31070916 t Simone Vumbaca Further SAR optimization yielded the orally bioavailable LOX inhibitor CCT365623 with good anti-LOX potency, selectivity, pharmacokinetic properties, as well as anti-metastatic efficacy. SIGNOR-261121 0.8 TOP2B protein Q02880 UNIPROT CDH13 protein P55290 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24463367 f lperfetto While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development SIGNOR-242302 0.2 HHAT protein Q5VTY9 UNIPROT SHH protein Q15465 UNIPROT up-regulates palmitoylation 9606 18534984 t gcesareni Both the shh precursor and mature protein are n-palmitoylated by hhatn-palmitoylation of cys-24 by hhat is required for n-product multimerization and full activity SIGNOR-161548 0.67 betamethasone chemical CHEBI:3077 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 17561562 t dermatitis gcesareni SIGNOR-251686 0.8 MMP12 protein P39900 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272380 0.7 SPI1 protein P17947 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0004730 12130514 f lperfetto The transcription factor PU.1 is required for normal blood cell development. PU.1 regulates the expression of a number of crucial myeloid genes, such as the macrophage colony-stimulating factor (M-CSF) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. Myeloid cells derived from PU.1(-/-) mice are blocked at the earliest stage of myeloid differentiation, similar to the blast cells that are the hallmark of human acute myeloid leukemia (AML). These facts led us to hypothesize that molecular abnormalities involving the PU.1 gene could contribute to the development of AML. SIGNOR-249633 0.7 IL1R1 protein P14778 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 9625767 t lperfetto Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab SIGNOR-249513 0.388 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser366 SPQVRTLsGSRPPLL -1 14709557 t miannu AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase SIGNOR-250402 0.474 NMDA receptor_2B complex SIGNOR-C348 SIGNOR CTTN protein Q14247 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 14684878 t miannu Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors. SIGNOR-266600 0.304 MAPK11 protein Q15759 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 BTO:0000567 9628874 t gcesareni Prak activity was regulated by p38alpha and p38beta both in vitro and in vivo and thr182 was shown to be the regulatory phosphorylation site. SIGNOR-58131 0.603 SRC protein P12931 UNIPROT HNF4A protein P41235 UNIPROT down-regulates phosphorylation Tyr23 SAALDPAyTTLEFEN 9606 22308320 t lperfetto Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function. SIGNOR-195883 0.373 SMARCAD1 protein Q9H4L7 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates activity binding 9606 21549307 t 1 miannu SMARCAD1 interacts with HDAC1 and KAP1 and is required for their binding to heterochromatin SIGNOR-239835 0.324 MAP3K1 protein Q13233 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates phosphorylation Thr211 LVDSVAKtIDAGCKP 9606 9712898 t gcesareni Both wild type and kinase-inactive mutant rip immunoprecipitates can active mkk6 in vitrohe sapks are activated by at least two meks, sapk/erk kinase-1 (sek1, also called mapk-kinase (mkk)) and mkk7 SIGNOR-59679 0.431 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 9606 BTO:0000130 12056906 t esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. SIGNOR-89217 0.458 SRC protein P12931 UNIPROT GTF2I protein P78347 UNIPROT up-regulates activity phosphorylation Tyr652 KPELVISyLPPGMAS 9534 11934902 t lperfetto C-Src-dependent transcriptional activation of TFII-ITFII-I is a multifunctional transcription factor that is also involved in signal transduction. Here we show that TFII-I undergoes a c-Src-dependent tyrosine phosphorylation on tyrosine residues 248 and 611 and translocates to the nucleus in response to growth factor signaling SIGNOR-247189 0.465 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr884 SSGGEQDyDYLNDWG 9606 BTO:0000848 16371504 t lperfetto Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated. SIGNOR-143242 0.407 2-N,6-N-Bis(2,3-dihydroxy-N-benzoyl)-L-serine amide chemical CHEBI:1219 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation -1 7576010 t miannu D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole. SIGNOR-258436 0.8 P2RY2 protein P41231 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256902 0.2 KCNJ16 protein Q9NPI9 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 24561201 t miannu KCNJ10 encodes Kir4.1, a member of the K+ channel family known as inwardly rectifying K+ (Kir) channels. Kir4.1 channels may comprise either Kir4.1 homomers or Kir4.1/Kir5.1 heteromers SIGNOR-269447 0.8 UBE2C protein O00762 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR down-regulates 9606 19632176 f miannu The evolution of prostate cancer from an androgen-dependent state (ADPCa) to one that is androgen-independent (AIPCa) marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in AIPCa is poorly understood. We have defined the direct AR-dependent target genes in both AIPCa and ADPCa by generating AR-dependent gene expression profiles and AR cistromes. In contrast to ADPCa, AR selectively up-regulates M-phase cell cycle genes in AIPCa including UBE2C, a gene that inactivates the M-phase checkpoint. SIGNOR-251544 0.7 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI OXER1 protein Q8TDS5 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. SIGNOR-268776 0.8 SCN10A protein Q9Y5Y9 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. SIGNOR-253454 0.7 NMBR protein P28336 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256775 0.252 ARNT protein P27540 UNIPROT CDK2 protein P24941 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 21544813 f lperfetto Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC SIGNOR-253693 0.26 F2 protein P00734 UNIPROT Fibrinogen complex SIGNOR-C311 SIGNOR up-regulates activity cleavage 9606 BTO:0000131 29880919 t lperfetto Thrombin is a key enzyme in the pathway and cleaves fibrinogen to fibrin, which spontaneously forms the insoluble polymer that is the basis for the haemostatic plug. SIGNOR-263525 0.848 LPAR1 protein Q92633 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256696 0.537 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser249 LDILHNSsQMKSMST 9606 BTO:0000567 25670858 t lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. SIGNOR-265230 0.571 ATG5 protein Q9H1Y0 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR form complex binding 9606 BTO:0000007 18321988 t lperfetto Atg12 is conjugated to atg5 and forms an approximately 800-kda protein complex with atg16l (referred to as atg16l complex). SIGNOR-226693 0.948 PRDM1 protein O75626 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12626569 t miannu The positive regulatory domain i binding factor 1 (prdi-bf1 or blimp-1) protein represses the transcription of specific target genes, including c-myc, the mhc class ii trans-activator, pax-5, and cd23b SIGNOR-99119 0.447 CSNK1E protein P49674 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates activity phosphorylation Ser311 EINFENMsNDDAVRV -1 24993822 t miannu Co-expression of CK1ϵ with FLAG-Dvl3 retards electrophoretic migration and induces phosphorylation-dependent shift of Dvl (PS-Dvl3). mutations of Ser-280 and Ser-311 prevent efficient activation of Wnt/β-catenin by Dvl3. SIGNOR-276647 0.655 p38 proteinfamily SIGNOR-PF16 SIGNOR NFATC4 protein Q14934 UNIPROT down-regulates phosphorylation Ser168 QGGGAFFsPSPGSSS 9606 11997522 t lperfetto Phosphorylation of nfatc4 by p38 mitogen-activated protein kinasesthe p38 map kinase phosphorylates multiple residues, including ser(168) and ser(170), in the nfat homology domain of nfatc4. Replacement of ser(168,170) with ala promotes nuclear localization of nfatc4 and increases nfat-mediated transcription activity. SIGNOR-87393 0.2 P-TEFb complex SIGNOR-C238 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR form complex binding 9606 20153263 t miannu These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells. SIGNOR-239237 0.787 CDK1 protein P06493 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Ser272 RSRLTPVsPESSSTE 9606 SIGNOR-C17 20974803 t gcesareni Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis. SIGNOR-169012 0.35 HIPK2 protein Q9H2X6 UNIPROT ZBTB4 protein Q9P1Z0 UNIPROT down-regulates activity phosphorylation Thr797 ERPGGTPtPVIAYSK -1 19448668 t miannu The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4. SIGNOR-262881 0.387 DDX3X protein O00571 UNIPROT PABPC1 protein P11940 UNIPROT up-regulates activity binding 9606 21883093 t miannu In the present study, we indentified the SG marker PABP1 [poly(A)-binding protein 1] as another direct interaction partner of DDX3. Interestingly, down-regulation of DDX3 interfered with SG assembly, led to nuclear accumulation of PABP1 and reduced cell viability following stress. Conversely, supplementation with a shRNA (short hairpin RNA)-resistant DDX3 restored SG formation, the translocation of PABP1 into SGs and cell survival. SIGNOR-269194 0.587 CSNK2B protein P67870 UNIPROT CACNA1S protein Q13698 UNIPROT up-regulates activity phosphorylation Ser1575 PEICRTVsGDLAAEE -1 20937870 t miannu To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2. SIGNOR-263115 0.2 MARK3 protein P27448 UNIPROT CDC25C protein P30307 UNIPROT down-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR 9534 9543386 t miannu C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding. Phosphorylation of serine 21 6 promotes 1 4-3-3 binding to Cdc25C and is inhibitory to Cdc25C function. SIGNOR-250176 0.498 ETFA protein P13804 UNIPROT ETF complex SIGNOR-C463 SIGNOR form complex binding 9606 33450351 t miannu Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors. SIGNOR-269453 0.943 HCRTR1 protein O43613 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257220 0.443 940929-33-9 chemical CID:49867937 PUBCHEM KIF11 protein P52732 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206724 0.8 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19643666 t lperfetto Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways. SIGNOR-249566 0.399 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 9732876 t lperfetto Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos SIGNOR-253332 0.63 ALDH9A1 protein P49189 UNIPROT NADH(2-) smallmolecule CHEBI:57945 ChEBI up-regulates quantity chemical modification 9606 11802770 t miannu Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). SIGNOR-269695 0.8 ITGB2 protein P05107 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253190 0.912 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MKNK1 protein Q9BUB5 UNIPROT up-regulates activity phosphorylation Thr255 ITTPELTtPCGSAEY 9606 BTO:0000093 17130135 t We generated a phosphospecific antibody to Thr(P)-214 in the T-loop of MNKs and found that phosphorylations of both Thr-209 and Thr-214 in human MNK1 are required for activation SIGNOR-253015 0.2 MCC complex SIGNOR-C382 SIGNOR APC-c complex SIGNOR-C150 SIGNOR down-regulates activity binding 9606 BTO:0000567 25092294 t miannu The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. SIGNOR-265977 0.786 AIM2 protein O14862 UNIPROT AIM2 inflammasome complex SIGNOR-C222 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256399 0.739 MAPK3 protein P27361 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000150 21502402 t llicata Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro SIGNOR-173413 0.334 FOXO1 protein Q12778 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000304 30519351 t miannu To date , we have found that TNC regulates the transcriptional activity of FOXO1. And p27Kip1 is one of the transcriptional targets of FOXO1 (Fig. 5A). We speculated that TNC could regulate the binding of FOXO1 to the CDKN1B promoter. SIGNOR-277739 0.612 MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 t lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. SIGNOR-80528 0.968 PRKCA protein P17252 UNIPROT TRPV5 protein Q9NQA5 UNIPROT up-regulates activity phosphorylation Ser654 YVEVFKNsDKEDDQE 9606 17006539 t gcesareni A cell permeable analog of DAG increased TRPV5 activity within 30 min via protein kinase C activation of the channel since mutation of TRPV5 at the putative PKC phosphorylation sites S299 and S654 prevented the stimulatory effect of TK. SIGNOR-149952 0.2 PTPN1 protein P18031 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT down-regulates activity dephosphorylation 9606 22169477 t miannu Finally, we demonstrated that wild-type PTP1B directly dephosphorylated myc-tagged PERK that had been isolated from tunicamycin-treated HEK293T cells by immunoprecipitation ( xref ).|The ability of PTP1B to dephosphorylate Tyr619 and inactivate PERK is fine tuned by the production of H 2 S by CSE in response to ER stress. SIGNOR-277051 0.27 BARD1 protein Q99728 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates binding 9606 20029420 t gcesareni Brac1 dimerizes with brca1?associated Ring domain protein 1 (bard1) to yield a functional e3 ligase. SIGNOR-162499 0.786 AKT proteinfamily SIGNOR-PF24 SIGNOR SP7 protein Q8TDD2 UNIPROT up-regulates phosphorylation 9606 21777568 t gcesareni We found that Akt phosphorylates Osterix and that Akt activation increases protein stability, osteogenic activity and transcriptional activity of Osterix. We also found that BMP-2 increases the protein level of Osterix in an Akt activity-dependent manner. SIGNOR-174017 0.2 SMARCB1 protein Q12824 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269825 0.863 DEF6 protein Q9H4E7 UNIPROT RAP1A protein P62834 UNIPROT up-regulates activity binding 9606 BTO:0000782 26483383 t lperfetto Mechanistic studies revealed that SLAT interacts, through its PH domain, with a key component of inside-out signaling, namely the active form of the small GTPase Rap1 (which has two isoforms, Rap1A and Rap1B). This interaction has been further shown to facilitate the interdependent recruitment of Rap1 and SLAT to the T cell immunological synapse upon TCR engagement. Furthermore, a SLAT mutant lacking its PH domain drastically inhibited LFA-1 activation and CD4(+) T cell adhesion. SIGNOR-253365 0.26 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr198 PGLRRRQt 9606 12042314 t miannu Because Thr198-phosphorylated p27Kip1 was localized only in the cytoplasm, Akt might promote 14-3-3 binding to p27Kip1 by phosphorylation at Thr198, allowing its cytoplasmic localization and degradation. SIGNOR-88294 0.845 TGFB1 protein P01137 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity binding 9534 BTO:0004055 1310899 t lperfetto A cdna encoding the tgf-beta type ii receptor protein has been isolated by an expression cloning strategy. The cloned cdna, when transfected into cos cells, leads to overexpression of an approximately 80 kd protein that specifically binds radioiodinated tgf-beta 1. Excess tgf-beta 1 competes for binding of radioiodinated tgf-beta 1 in a dose-dependent manner and is more effective than tgf-beta 2. SIGNOR-236080 0.848 NMDA receptor_2C complex SIGNOR-C349 SIGNOR CAMK2A protein Q9UQM7 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu The most abundant signaling protein in the PSD fraction is Ca2+/calmodulin–dependent protein kinase II (CaMKII), which makes up 1 to 2% of the total protein in the forebrain (21). CaMKII is a target for Ca2+ flowing through the NMDA receptor and is necessary for normal synaptic plasticity in pyramidal neurons. The cytosolic tails of the NR2 subunits of the NMDA receptor bind to CaMKII and thus can serve as docking sites for it in the PSD SIGNOR-264216 0.584 GRK2 protein P25098 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates activity phosphorylation Ser357 REFCIPTsSNIEQQN 9606 12123746 t GRK2-mediated phosphorylation is involved in the development of agonist-induced μ-opioid receptor desensitization. two C-terminal amino acids, Ser355 and Thr357, are required for short-term homologous desensitization of μ-opioid receptors expressed in HEK 293 cells. SIGNOR-251458 0.2 acetyl-CoA smallmolecule CHEBI:15351 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 9606 15507492 t Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬¨‚Ćde novo¬¨‚Ćbiosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬¨‚Ć SIGNOR-267209 0.8 INTS13 protein Q9NVM9 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261469 0.2 MAST2 protein Q6P0Q8 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation 9606 15951562 t gcesareni We further demonstrate that binding of pten to specific pdz domains diminishes its degradation rate and facilitates its phosphorylation by mast kinases. Our results suggest a regulatory role of pdz domain binding on pten function by controlling its stability and phosphorylation status. SIGNOR-138051 0.687 PRKCG protein P05129 UNIPROT APTX protein Q7Z2E3 UNIPROT up-regulates phosphorylation Thr125 AKNPGLEtHRKRKRS 9606 19561170 t llicata We show the novel molecular consequences of increased kinase activities of mutants: aprataxin (aptx), a dna repair protein causative for autosomal recessive ataxia, was found to be a preferential substrate of mutant pkc gamma, and phosphorylation inhibited its nuclear entry. ollectively, phosphorylation occurred at thr111, reducing nuclear aptx. SIGNOR-186409 0.326 DAB2IP protein Q5VWQ8 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity binding 9606 BTO:0002195 27858941 t miannu In vascular smooth muscle cells (VSMCs) treated with IFN-γ, DAB2IP directly binds to JAK2 and inhibits its kinase activity, limiting JAK-dependent STAT1/3 and PI3K–AKT phosphorylation and activation SIGNOR-254760 0.356 CAMK2A protein Q9UQM7 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Ser843 DVRLSRGsIDREDGS 9606 15845548 t gcesareni Furthermore, activated camkii directly phosphorylated the recombinant cooh-terminal region of fak at a residue equivalent to ser-843. SIGNOR-135631 0.275 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR PRKN protein O60260 UNIPROT up-regulates activity binding 10090 BTO:0002572 phosphorylation: ser65 24784582 t The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator. SIGNOR-270343 0.2 NFKB1 protein P19838 UNIPROT KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001321 11909978 t NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer. SIGNOR-253668 0.2 ATM protein Q13315 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Ser1367 LVQGSPSsQEQQVTL 9606 15173573 t lperfetto Tonebp/orebp contains atm consensus phosphorylation sites at ser-1197, ser-1247, and ser-1367. In conclusion, signaling via atm is necessary for full activation of tonebp/orebp SIGNOR-125081 0.274 frovatriptan chemical CHEBI:134991 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation -1 9986723 t miannu As far as the selectivity against the 5-HT1A receptor, compound 10 shows similar selectivity as VML-251 (4) but has slightly lower selectivity as compared to sumatriptan (1), naratriptan (2), and rizatriptan (3). Although none of the 5-HT1D receptor agonists in the current study demonstrate as good selectivity versus the 5-HT1B receptor, the N-methyl-5-tert-butyltryptamine (10) remains the most selective (4-fold). SIGNOR-259075 0.8 EGFR protein P00533 UNIPROT PKM protein P14618 UNIPROT down-regulates activity phosphorylation Tyr148 KITLDNAyMEKCDEN 9606 BTO:0001570 26759242 t miannu EGFR binds to and phosphorylates PKM2 to inhibit its activity.  SIGNOR-277197 0.461 MCHR2 protein Q969V1 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256795 0.252 NUAK1 protein O60285 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Ser445 LGLRKTGsYGALAEI 9606 20354225 t gcesareni Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity. SIGNOR-164747 0.521 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates phosphorylation 9606 10469655 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-217400 0.865 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1623 SPTSPSYsPTSPSYS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248816 0.849 EPN1 protein Q9Y6I3 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates quantity by stabilization binding 24789820 t lperfetto Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth SIGNOR-260716 0.647 MIF protein P14174 UNIPROT SOD1 protein P00441 UNIPROT down-regulates quantity by destabilization relocalization 10090 BTO:0004488 29371591 t P00441:p.Gly94Ala (mutation causing interaction) Here, we show that MIF inhibits mutant SOD1 nuclear clearance when overexpressed in motor neuron-like NSC-34 cells|SOD1WT is evenly distributed between the cytoplasm and the nucleus while mutant SOD1G93A shows predominantly cytoplasmic distribution (Fig. 1a, b). Expression of MIF in cells expressing SOD1WT had no effect on the distribution of the SOD1WT–EGFP protein. However, expression of MIF together with the mutant SOD1G93A–EGFP, inhibited the nuclear clearance of misfolded SOD1 resulting in a more wild-type-like distribution of the mutant SOD1 protein SIGNOR-262797 0.311 PRKCA protein P17252 UNIPROT NR1H4 protein Q96RI1 UNIPROT up-regulates phosphorylation Ser145 VVCGDRAsGYHYNAL 9606 18755856 t llicata Phosphorylation of farnesoid x receptor by protein kinase c promotes its transcriptional activity. pkcalpha phosphorylates in vitro fxr in its dna-binding domain on s135 and s154. SIGNOR-180537 0.331 CNR2 protein P34972 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256843 0.429 LRRK2 protein Q5S007 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000938 24916379 t lperfetto Expression of wild-type LRRK2 promoted neuronal survival against apoptosis through activation of the downstream effector, Akt by phosphorylation of Ser473. Phosphorylated Akt in turn inhibited FOXO 1 signaling SIGNOR-252598 0.387 CIITA protein P33076 UNIPROT HLA-DRB3 protein P79483 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10886240 f These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma. SIGNOR-254011 0.2 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193612 0.8 RIOK3 protein O14730 UNIPROT IFIH1 protein Q9BYX4 UNIPROT down-regulates activity phosphorylation Ser828 GRARADEsTYVLVAH 9606 BTO:0000007 25865883 t lperfetto RIOK3 mediates phosphorylation of MDA5 Ser-828|RIOK3-mediated phosphorylation of MDA5 interferes with its assembly and attenuates the innate immune response SIGNOR-264576 0.48 calcitriol smallmolecule CHEBI:17823 ChEBI propan-2-ol smallmolecule CHEBI:17824 ChEBI up-regulates quantity precursor of 30080183 t lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). SIGNOR-270573 0.8 CDK6 protein Q00534 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates activity phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 16508017 t gcesareni Here, we show that p21cip1 is associated with k cyclin both in overexpression models and in primary effusion lymphoma cells and is a substrate of the k cyclin/cdk6 complex, resulting in phosphorylation of p21cip1 on serine 130. This phosphoform of p21cip1 appeared unable to associate with cdk2 in vivo. SIGNOR-144832 0.859 dactolisib chemical CHEBI:71952 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 BTO:0000848 21803746 t ATP-competitive inhibitor of PI3K and mTOR gcesareni While the pi3k inhibitors, ly294002 or wortmannin, in the presence of plx4032 were individually inactive against pprm cell lines (fig. S4), the dual pi3k and mtorc1/2 inhibitor bez235 was highly specific (vs. parental lines) and potent in growth-inhibiting pprm cell lines SIGNOR-175709 0.8 F2R protein P25116 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22318735 t milica The protease-activated receptors (PAR)2 are a class of G protein-coupled receptors (GPCR) that are activated by the proteolysis of the N-terminal exodomain. Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13). SIGNOR-196006 0.582 CSNK2A1 protein P68400 UNIPROT CREB3 protein O43889 UNIPROT down-regulates quantity by destabilization phosphorylation Ser46 LPLSEVPsDWEVDDL -1 31941600 t miannu Here, we found that human CREB3 is phosphorylated within its transcription activation domain on serine 46 by protein kinase CK2. However, phosphorylation at serine 46 reduced the stability of CREB3. SIGNOR-277501 0.2 MUL1 protein Q969V5 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity sumoylation Lys606 EELLAEEKSKPIPIM 9606 BTO:0000007 19638400 t Barakat Through detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms. SIGNOR-274129 0.549 CDC42 protein P60953 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity 9606 18976935 f lperfetto Furthermore, membrane targeting of the SLAT Dbl-homology (catalytic) domain was sufficient to trigger TCR-mediated NFAT activation and Th1 and Th2 differentiation in a Cdc42-dependent manner. SIGNOR-253370 0.279 CDK1 protein P06493 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates activity phosphorylation -1 12556484 t done miannu We found that Nudel and NudE were also phosphorylated in M phase (Fig. ​(Fig.22 and ​and3).3). First, Nudel and NudE were specifically phosphorylated in M phase. Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro.Due to conservation of the S/TP motifs, NudE may also be phosphorylated at similar sites by these kinases, though it contains an additional potential Cdk site at S282 (SPNR). SIGNOR-274077 0.64 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser157 EHIERRVsNAGGPPA 9606 12576312 t miannu Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro SIGNOR-250064 0.488 leucine smallmolecule CHEBI:25017 ChEBI Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270418 0.8 PRKAA1 protein Q13131 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 SIGNOR-C15 21892142 t gcesareni Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs) SIGNOR-176479 0.347 CTNNA3 protein Q9UI47 UNIPROT JUP protein P14923 UNIPROT up-regulates quantity relocalization 9606 BTO:0000586 21598020 t miannu Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14 SIGNOR-265494 0.497 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol chemical CHEBI:75722 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 19282177 t Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. SIGNOR-258150 0.8 CSF1R protein P07333 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 24890514 f apalma The Erk1/2 pathway has a central role in CSF-1R-regulated myeloid differentiation. CSF-1 induces early (peaking at ‚àº5 min) and persistent (starting at 1 h) waves of MEK/Erk1/2 phosphorylation SIGNOR-255572 0.29 SNTB1 protein Q13884 UNIPROT MAPK12 protein P53778 UNIPROT down-regulates 10090 BTO:0002314 BTO:0001103 29681515 t apalma [...] suggesting that, during an asymmetric cell division, p38gamma localization would be basally restricted by the DGC complex via its interaction with beta-1-syntrophin. SIGNOR-255903 0.376 FURIN protein P09958 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 22479394 t Cleavage in Golgi gcesareni The proteolytic activity of furin responsible for processing full length notch-1 (p300) plays a critical role in notch signaling. SIGNOR-196914 0.653 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252878 0.697 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR TNNI2 protein P48788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136786 0.351 SOHLH1 protein Q5JUK2 UNIPROT ZP3 protein P21754 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 16690745 t Luana Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters. SIGNOR-266078 0.386 PPP2CA protein P67775 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity dephosphorylation Ser59 GGQESQPsPLALLAA 9606 24382322 t gcesareni These results indicate that the signals from TCDD or OP caused PP2A-mediated dephosphorylation of Sp1 at Ser-59 and induced CYP1A1 transcription SIGNOR-248223 0.267 EEF1A2 protein Q05639 UNIPROT Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269529 0.8 triazolopyridazine chemical CHEBI:48384 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t brain lperfetto The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005). SIGNOR-263803 0.8 FOXO3 protein O43524 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260100 0.25 Exon junction complex complex SIGNOR-C369 SIGNOR Upf-EJC complex SIGNOR-C367 SIGNOR up-regulates activity binding -1 18066079 t miannu Nonsense-mediated mRNA decay (NMD) eliminates mRNAs containing a premature translation termination codon through the recruitment of the conserved NMD factors UPF1, UPF2 and UPF3. In humans, a dynamic assembly pathway allows UPF1 to join UPF2 and UPF3 recruited to the mRNA by the exon-junction complex (EJC).  SIGNOR-265244 0.859 CD19 protein P15391 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 10090 25673924 t lperfetto CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades. SIGNOR-242900 0.568 DTX1 protein Q86Y01 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16554461 f gcesareni Notch1-induced erbb2 expression in cerebellar astroglia occurs via dtx1 SIGNOR-145319 0.2 RORB protein Q92753 UNIPROT OPN1MW protein P04001 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001175 19381306 t miannu These observations indicate that RORβ is required for the induction of S opsin and support the conclusion that RORβ regulates Opn1sw transcription in a direct manner through ROREs within its proximal promoter region. In addition, they explain the greatly diminished expression of Opn1sw observed in the retina of RORβ-/- mice. SIGNOR-266851 0.2 clofarabine chemical CHEBI:681569 ChEBI PRIM1 protein P49642 UNIPROT down-regulates activity chemical inhibition 9606 1707752 t miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase. SIGNOR-258359 0.8 RUNX2 protein Q13950 UNIPROT ALPL protein P05186 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 f gcesareni In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast SIGNOR-107123 0.472 AKT1 protein P31749 UNIPROT ILF3 protein Q12906 UNIPROT up-regulates activity phosphorylation Ser647 RGRGRGGsIRGRGRG 9606 20870937 t llicata Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our previous work showed that CD28 costimulation of T cells activated AKT to phosphorylate NF90 at Ser647 and caused NF90 to undergo nuclear export and stabilize IL-2 mRNA. SIGNOR-252512 0.375 XIAP protein P98170 UNIPROT CASP7 protein P55210 UNIPROT down-regulates quantity by destabilization binding -1 11583623 t lperfetto Xiap is an endogenous inhibitor of caspase-7 SIGNOR-110840 0.854 Corticotropin protein P01189-PRO_0000024969 UNIPROT MC1R protein Q01726 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268701 0.2 JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 7888666 t apalma We found that IL-5 induced two GAS-binding proteins in the nuclear extract from eosinophils. One of them was identified as STAT1 (p91). SIGNOR-255071 0.799 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR up-regulates 9606 21529719 f milica In vertebrates, cell density information feeds into the Hpo pathway, which is transmitted, in part, through the Crumbs polarity complex. The Crumbs complex contains Angiomotin (AMOT), a protein that binds YAP/TAZ and SMAD to inhibit their nuclear activity. SIGNOR-230700 0.7 MED19 protein A0JLT2 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266663 0.846 WWTR1 protein Q9GZV5 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity binding 9606 21084559 t lperfetto Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal. SIGNOR-169838 0.576 AKT1 protein P31749 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Thr700 MESRRQAtVSWDSGG -1 23264741 t miannu  Here we show that soluble growth factors enhance integrin signaling through Akt phosphorylation of FAK at Ser695 and Thr700.  SIGNOR-276436 0.44 LLGL1 protein Q15334 UNIPROT Scribble_complex_DLG1-LLGL1_variant complex SIGNOR-C511 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270911 0.578 LARP7 protein Q4G0J3 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR down-regulates activity binding 9606 BTO:0000567 30824372 t Monia To investigate whether LARP7 is part of the known 7SK RNP implicated in the regulation of transcription, co‐immunoprecipitation studies were performed using the nuclear extracts of HeLa cells (Fig 3A, lanes 1–4). Antibodies against LARP7, CDK9 and HEXIM1 efficiently precipitated 7SK RNA, whereas no RNA was found in the control (Fig 3A, lower panel, lanes 1–4). Interestingly, HEXIM1, CDK9, CYCT1 and LARP7 were present in all immunopurifications, as determined by mass spectrometry of silver‐stained gels (Fig 3A; data not shown) and western blotting. In conclusion, these experiments show that LARP7 negatively regulates not only viral but also cellular POLII class genes through the 7SK P‐TEFb system. SIGNOR-261184 0.604 UHMK1 protein Q8TAS1 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 12093740 t lperfetto Hkis is a nuclear protein that binds the c-terminal domain of p27(kip1) and phosphorylates it on s10 in vitro and in vivo, promoting its nuclear export to the cytoplasm.Phosphorylation at serine 10, a major phosphorylation site of p27(kip1), increases its protein stability SIGNOR-90274 0.375 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000562 23457334 t lperfetto Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (pfkfb2) isoenzyme by amino acids. SIGNOR-252528 0.643 SPDYA protein Q5MJ70 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 33015044 t lperfetto Speedy/RINGO A, a noncanonical activator of CDK2, was recently identified as a key regulator for CDK2 recruitment to meiotic telomeres SIGNOR-263310 0.787 MAPK3 protein P27361 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates phosphorylation Ser312 SYLSQMTsPSIHSTT 9606 19801668 t llicata In this study, we identified two phosphorylation sites in runx2 at ser301 and ser319 that are required for mapk-dependent activation of runx2 transcriptional activity and osteoblast differentiation. SIGNOR-188347 0.547 ITCH protein Q96J02 UNIPROT TNFAIP3 protein P21580 UNIPROT up-regulates activity binding 9606 BTO:0000782;BTO:0001271 18246070 t lperfetto Here we demonstrate that the regulatory molecule tax1bp1 recruited the e3 ligase itch to a20 via two 'ppxy' motifs. Itch was essential for the termination of tumor necrosis factor receptor signaling by controlling a20-mediated recruitment and inactivation of rip1. (abstract) SIGNOR-160621 0.284 BCL3 protein P20749 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates activity binding 9606 BTO:0004298 21912613 t miannu In the present study, we report that regulation of CTCF by extracellular stress signals is dependent upon activations of an oxidative stress-regulated protein Bcl-3. We found that activated Bcl-3 was able to bind to the κB sites identified in the CTCF promoter region. Bcl-3 was activated by UV irradiation to interact with NF-κB p50 by forming a Bcl-3/p50 heterodimer complex. The Bcl-3/p50 complex suppressed CTCF promoter activity to down-regulate CTCF transcription. SIGNOR-254789 0.569 CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR Core Binding Factor complex complex SIGNOR-C214 SIGNOR down-regulates activity relocalization 9606 BTO:0000661 9632809 f The polyomavirus enhancer binding protein 2 (PEBP2)/core binding factor (CBF) is a transcription factor composed of two subunits, α and β. The gene encoding the β subunit is disrupted by inv(16), resulting in the formation of a chimeric protein, β-SMMHC, which is associated with acute myelogenous leukemia.Thus, the result suggess that β-SMMHC inhibits PEBP2-mediated transcription via cytoplasmic sequestration of the α subunit. SIGNOR-255741 0.2 glucose chemical CHEBI:17234 ChEBI AMPK complex SIGNOR-C15 SIGNOR down-regulates activity chemical inhibition 9606 32745890 t miannu Glucose deprivation, activates the glucose level–sensing kinase, AMPK, which in turn influences Rac1-dependent macropinocytosis. In this context macropinosomes take up necrotic cell debris as a rich nutrient source to fuel tumor cell growth SIGNOR-277765 0.8 MEF2D protein Q14814 UNIPROT ASH2L protein Q9UBL3 UNIPROT up-regulates 9606 BTO:0000887 18026121 f gcesareni Targeting of ash2l to specific genes is mediated by the transcriptional regulator mef2d. Furthermore, this interaction is modulated during differentiation through activation of the p38 mapk signaling pathway via phosphorylation of mef2d. SIGNOR-159334 0.478 LGALS3 protein P17931 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 9606 BTO:0000584 32745890 t miannu Oncogenic RAS requires a protein scaffold to induce downstream signaling and macropinocytosis, three separate studies have identified upstream and downstream regulators that help drive this process in cancer cells. Anchorage-independent growth of cancer cells is supported by avb3 integrins which can be clustered by the extracellular lectin, galectin-3 to drive mutant RAS-mediated macropinocytosis for nutrient supplementation and growth of anchorage-independent cells. Secreted galectin-3 was found to bind to the N-glycans on surface avb3 integrins, clustering the integrins on the surface of the nonadherent cells for the recruit- ment of mutant KRAS as a signaling platform for inducing macropinocytosis SIGNOR-277741 0.279 TNFSF10 protein P50591 UNIPROT TNFRSF10B protein O14763 UNIPROT up-regulates binding 9606 14585074 t amattioni Trail interacts with tril-r1 and trail-r2 and activetes them SIGNOR-101313 0.932 M2_polarization phenotype SIGNOR-PH55 SIGNOR IL10 protein P22301 UNIPROT up-regulates quantity by expression 22933625 f apalma P38 activation contributes to the macrophage phenotype switch in injured muscle, which could elevate production of IL-10 (63), creating positive feedback for the phenotype switch SIGNOR-255448 0.7 CSNK2A1 protein P68400 UNIPROT MECOM protein Q03112 UNIPROT up-regulates activity phosphorylation Ser1037 IGNSNHGsQSPRNVE 23858473 t phosphorylation site remapping based on Fig 5 lperfetto We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation. SIGNOR-273427 0.2 ATG2A protein Q2TAZ0 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001938 28561066 f miannu WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation. SIGNOR-268485 0.7 AKT1 protein P31749 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser496 ATPQRSGsVSNYRSC -1 27784766 t miannu Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle. SIGNOR-276461 0.296 MAPK1 protein P28482 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser643 KILIASPsPTHIHKE 9606 BTO:0000567 18519666 t lperfetto We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_ SIGNOR-178727 0.572 PP1 proteinfamily SIGNOR-PF54 SIGNOR SLC4A4 protein Q9Y6R1 UNIPROT up-regulates activity dephosphorylation 10090 BTO:0000988 21317537 t lperfetto WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, SIGNOR-264647 0.2 taurine smallmolecule CHEBI:15891 ChEBI GLRA1 protein P23415 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9009272 t miannu For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system. SIGNOR-258579 0.8 PFKFB4 protein Q16877 UNIPROT beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI down-regulates quantity chemical modification -1 30553771 t PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species SIGNOR-267272 0.8 Apoptosome complex SIGNOR-C230 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 15657060 t lperfetto Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3. SIGNOR-256471 0.73 Av/b3 integrin complex SIGNOR-C177 SIGNOR KRAS protein P01116 UNIPROT up-regulates activity binding 9606 BTO:0000584 32745890 t Oncogenic RAS miannu Oncogenic RAS requires a protein scaffold to induce downstream signaling and macropinocytosis, three separate studies have identified upstream and downstream regulators that help drive this process in cancer cells. Anchorage-independent growth of cancer cells is supported by avb3 integrins which can be clustered by the extracellular lectin, galectin-3 to drive mutant RAS-mediated macropinocytosis for nutrient supplementation and growth of anchorage-independent cells. Secreted galectin-3 was found to bind to the N-glycans on surface avb3 integrins, clustering the integrins on the surface of the nonadherent cells for the recruitment of mutant KRAS as a signaling platform for inducing macropinocytosis. SIGNOR-277742 0.346 ERBB4 protein Q15303 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 16729043 t gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. SIGNOR-252674 0.542 HCRT protein O43612 UNIPROT HCRTR2 protein O43614 UNIPROT up-regulates binding 9606 9491897 t gcesareni Identification and initial biological characterization of two orexins as well as their two receptors SIGNOR-55848 0.768 CREB1 protein P16220 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16205321 f gcesareni The results showed that the nuclear pkcalpha was significantly decreased in the liver during sepsis, which was accompanied by decreases in phospho-creb content, dna-binding activity of creb, and bcl-xl expression. SIGNOR-140911 0.368 PPP2CA protein P67775 UNIPROT PRKCB protein P05771-2 UNIPROT down-regulates activity dephosphorylation Ser660 QSEFEGFsFVNSEFL 10116 15880462 t Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform SIGNOR-248621 0.434 E2F1 protein Q01094 UNIPROT CDC25A protein P30304 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 11154267 f lperfetto Expression of Cdc25A is transcriptionally regulated by Myc and E2F-1 , both of which are expressed in MCF-7 cells in response to estrogen SIGNOR-245468 0.535 AMPK complex SIGNOR-C15 SIGNOR GAPDH protein P04406 UNIPROT up-regulates activity phosphorylation Ser122 GAKRVIIsAPSADAP 10090 26626483 t miannu Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated.  SIGNOR-267578 0.322 ACVR1 protein Q04771 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 18801898 f gcesareni Akt/mTOR signaling is a key target that accounts for myostatin function during muscle atrophy, uncovering a novel role for myostatin in protein metabolism and more specifically in the regulation of translation in skeletal muscle. SIGNOR-243185 0.25 PTGS2 protein P35354 UNIPROT prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI up-regulates quantity chemical modification 9606 16540375 t Arachidonic acid is transformed into PGE2 via cyclooxygenase (COX) enzymes and terminal prostaglandin E synthases (PGES) SIGNOR-255684 0.8 AKT1 protein P31749 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 20138985 t lperfetto Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1. SIGNOR-252539 0.719 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR PAX7 protein P23759 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 22493066 f svumbaca Both binding sites were enriched by more than 5-fold in the ChIP assay with RBP-Jk antibody, suggesting that RBP-Jk occupies these sequences in the Pax7 promoter region. SIGNOR-255365 0.385 ARAF protein P10398 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 BTO:0000567 8621729 t lperfetto Our data demonstrated that a-raf is, indeed, a mek1 activator and may play a role in growth factor signaling. SIGNOR-244813 0.744 propranolol chemical CHEBI:8499 ChEBI ADRB2 protein P07550 UNIPROT down-regulates activity chemical inhibition 10030 10079020 t Luana Similarly, the binding affinities of ICI 118–551, CGP 20712A, propranolol, bupranolol and CGP 12177 for human β1-, β2- and β3-adrenoceptors correlate with their affinities at human β1- (P=0.04), β2- (P=0.01) SIGNOR-258334 0.8 MECP2 protein P51608 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000614 18511691 t Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. SIGNOR-264680 0.353 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser342 SKLTHSLsTSDITAI 9606 16943424 t lperfetto Recently we showed that atm- and hdm2-dependent ubiquitination and subsequent degradation of hdmx following dsb induction are mediated by phosphorylation of hdmx on s403, s367, and s342, with s403 being targeted directly by atm. SIGNOR-149292 0.725 RPS6KA3 protein P51812 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 19112174 t gcesareni S6k1 regulates estrogen receptor alpha (eralpha) by phosphorylating it on serine 167, leading to transcriptional activation of eralpha. SIGNOR-182958 0.412 CSF1 protein P09603 UNIPROT CSF1R protein P07333 UNIPROT up-regulates activity binding 9606 BTO:0000801 39416792 t miannu CSF-1, derived from fibroblasts, tumor cells, etc., is produced in membrane-bound form, secreted glycoproteins and proteoglycans. Currently, CSF-1R is considered to be the sole receptor for CSF-1. These cells regulate macrophage growth, differentiation and function by secreting CSF1. Colony-stimulating factor receptor (CSF1R), a type I single-transmembrane protein, is ubiquitously expressed in myeloid cells such as monocytes, macrophages, neuroglia, and osteoblasts. CSF1R induces receptor homodimerization by binding to either CSF-1 or IL-34, followed by activation of receptor signaling and activation of extracellular pro-cell-survival kinase cascades, including PI3K, ERK1/2, and JNK SIGNOR-277713 0.937 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB3 protein Q9Y5G1 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265707 0.2 SELPLG protein Q14242 UNIPROT SELP protein P16109 UNIPROT up-regulates binding 9606 BTO:0000130 23994464 t apalma This steady-state rolling is primarily mediated by the interaction of endothelial P-selectins with their neutrophil glycoprotein counterreceptors, primarily PSGL-1. SIGNOR-255038 0.925 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252835 0.908 USP10 protein Q14694 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0003704 21962518 t lperfetto Since USP10 is known as a deubiquitinating protease of p53 (Yuan et al., 2010), inhibition of USP10 by spautin-1 may promote the degradation of p53.  SIGNOR-260297 0.648 PTEN protein P60484 UNIPROT SH2B2 protein O14492 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 f miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). SIGNOR-260051 0.2 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity phosphorylation Tyr336 AKGNLQEyLTRHVIS -1 9169454 t lperfetto Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor. SIGNOR-48863 0.2 CDK3 protein Q00526 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 15084261 t gcesareni The active form of prb is underphosphorylated. Cdk3/cyclin-c-mediated phosphorylation at ser-807 and ser-811 is required for g0-g1 transition. SIGNOR-124212 0.454 PTPRJ protein Q12913 UNIPROT LAT protein O43561 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 11259588 t flangone We propose that cd148 negatively regulates tcr signaling by interfering with the phosphorylation and function of plcgamma1 and lat SIGNOR-105787 0.36 TRIM63 protein Q969Q1 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys122 SPVEDNEkDLVKLAK -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). SIGNOR-272739 0.413 GGCX protein P38435 UNIPROT GAS6 protein Q14393 UNIPROT up-regulates activity carboxylation 9606 31226734 t lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. SIGNOR-265923 0.505 denileukin diftitox smallmolecule SID:125240988 ChEBI IL2RA protein P01589 UNIPROT up-regulates activity chemical activation 9606 15757436 t miannu Denileukin diftitox (DAB389IL-2; Ontak) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells.  SIGNOR-259392 0.8 CSNK2A1 protein P68400 UNIPROT MAX protein P61244 UNIPROT down-regulates phosphorylation Ser2 sDNDDIEV 9606 8018564 t gcesareni Here, we have mapped the nh2-terminal in vivo phosphorylation sites of max to ser2 and ser11[...] SIGNOR-35772 0.368 ATR protein Q13535 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT down-regulates activity phosphorylation Ser19 GTSKCPPsQRVPALT 9606 BTO:0002181 18536714 t miannu We have also demonstrated that DNA damage triggers disruption of the HIPK2-Siah-1 complex, resulting in HIPK2 stabilization and activation. Disruption of the HIPK2-Siah-1 complex is mediated by the ATM/ATR pathway and involves ATM/ATR-dependent phosphorylation of Siah-1 at Ser 19. SIGNOR-276167 0.2 GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268602 0.25 KAT2A protein Q92830 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269603 0.2 HNF1B protein P35680 UNIPROT FXYD2 protein P54710 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19389850 f Regulation miannu We analyzed genes associated with hypermagnesuria and detected highly conserved HNF1 recognition sites in FXYD2, a gene that can cause autosomal dominant hypomagnesemia and hypocalciuria when mutated. Using a luciferase reporter assay, we demonstrated HNF1B-mediated transactivation of FXYD2. SIGNOR-251927 0.297 CAST protein P20810 UNIPROT CAPN3 protein P20807 UNIPROT down-regulates activity binding 9606 BTO:0000590 25969760 t lperfetto In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain SIGNOR-251603 0.586 CHIR-124 chemical CID:11502647 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190976 0.8 Host translation inhibitor nsp1 protein P0DTD1-PRO_0000449619 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR down-regulates activity binding 9606 BTO:0002552 33188728 t miannu Our structure of the SARS-CoV-2 Nsp1 protein bound to the 40S ribosomal subunit establishes a mechanistic basis of the cellular effects of Nsp1, revealing a multifaceted mechanism of inhibition of the host protein synthesis at the initiation stage by the virusThis shows that Nsp1 not only plugs the mRNA entry channel but also keeps the 40S subunit in a conformation that is incompatible with mRNA loading. SIGNOR-262518 0.2 RANBP9 protein Q96S59 UNIPROT DYRK1B protein Q9Y463 UNIPROT down-regulates activity binding 9606 BTO:0000007 14500717 t llicata Serine/threonine kinase Mirk/Dyrk1B is an inhibitor of epithelial cell migration and is negatively regulated by the Met adaptor Ran-binding protein M. SIGNOR-238008 0.427 NFIA protein Q12857 UNIPROT NEUROD4 protein Q9HD90 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268891 0.2 ATF2 protein P15336 UNIPROT IL6 protein P05231 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 f JNK phosphorylates proteins that are part of AP-1, in particular c-Jun and activating transcription factor 2 (ATF-2). With dominant-negative mutants, antisense RNA, inhibitors, and genetic ablation, it has been shown that JNK and c-Jun play a major role in IL-1–induced expression of genes encoding IL-6 and IL-8 and other IL-1–responsive genes SIGNOR-254512 0.303 RAPGEF3 protein O95398 UNIPROT RAP1B protein P61224 UNIPROT up-regulates activity guanine nucleotide exchange factor 9534 BTO:0000298 10777494 t miannu Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well. SIGNOR-263957 0.707 bethanechol chemical CHEBI:3084 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258625 0.8 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 14585074 f amattioni Activation of the nf-kb pathway regulates a variety of ant-apoptotic factors SIGNOR-96834 0.7 SBF1 protein O95248 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 10090 20937701 f miannu Reduced sciatic nerve axons and normal myelination in the absence of Mtmr5. However, Mtmr5−/− mice had significantly fewer total myelinated axons in sciatic nerves than wild-type controls (Fig. 5G). SIGNOR-269812 0.7 DNA_damage stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates activity 9606 BTO:0000007 12556884 f miannu Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. Most ATM molecules in the cell are rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody is detectable after the introduction of only a few DNA double-strand breaks in the cell. Activation of the ATM kinase seems to be an initiating event in cellular responses to irradiation. SIGNOR-253376 0.7 PRKAB1 protein Q9Y478 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 SIGNOR-C3 21460634 t gcesareni Ampk in turn inactivates mtorc1 directly by phosphorylating raptor and indirectly by phosphorylating tsc2. SIGNOR-173041 0.443 mTORC1 complex SIGNOR-C3 SIGNOR Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 23863160 f lperfetto Cellular energy and nutrient status will dictate whether mTORC1 takes over and drives cell growth or conversely whether AMPK becomes active once again to drive consecutive waves of autophagy thorough ULK1. SIGNOR-209919 0.7 LYN protein P07948 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268212 0.696 ROS stimulus SIGNOR-ST2 SIGNOR Oxidative_stress phenotype SIGNOR-PH215 SIGNOR up-regulates 9606 22301329 f lperfetto Oxidative stress is defined by an imbalance between increased levels of reactive oxygen species (ROS) and a low activity of antioxidant mechanisms. An increased oxidative stress can induce damage to the cellular structure and potentially destroy tissues. SIGNOR-272275 0.7 CDK1 protein P06493 UNIPROT NME1 protein P15531 UNIPROT up-regulates phosphorylation Ser120 GRNIIHGsDSVESAE 9606 SIGNOR-C17 18234856 t gcesareni Application of this approach to the discovery of cdk1-cyclin b substrates yielded identification of >70 substrates and phosphorylation sites. Many of these sites are known to be phosphorylated in vivo, but most of the proteins have not been characterized as cdk1-cyclin b substrates. SIGNOR-160493 0.269 GSK3B protein P49841 UNIPROT JUNB protein P17275 UNIPROT down-regulates quantity by destabilization phosphorylation Thr255 EARSRDAtPPVSPIN 9606 BTO:0000567 22710716 t miannu  Thus, JunB phosphorylation at S251 and T255 by GSK3β is primed by phosphorylation at S259 by a yet to-be-identified kinase.Phosphorylation at S251, T255 and S259 is required for JunB degradation. SIGNOR-276417 0.2 N2,N4-Dibenzylquinazoline-2,4-diamine chemical CID:676352 PUBCHEM VCP protein P55072 UNIPROT down-regulates activity chemical inhibition -1 21383145 t Monia DBeQ (1) is a reversible and selective inhibitor of p97 SIGNOR-261100 0.8 PLK1 protein P53350 UNIPROT TOPORS protein Q9NS56 UNIPROT up-regulates activity phosphorylation Ser718 KDRDGYEsSYRRRTL 9606 19473992 t lperfetto Plk1-mediated phosphorylation of topors regulates p53 stabilityherein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. SIGNOR-185838 0.456 CSNK2A1 protein P68400 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Ser231 KERDKEVsDDEAEEK 9606 BTO:0000567 2492519 t llicata Both hsp 90 proteins are phosphorylated at two homologous sites. For the alpha protein, these sites correspond to serine 231 and serine 263. | Dephosphorylated hsp 90 is phosphorylated at both sites by casein kinase II from HeLa cells, calf thymus, or rabbit reticulocytes; no other hsp 90 residues were phosphorylated by casein kinase II in vitro. SIGNOR-250899 0.546 POLR2I protein P36954 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266166 0.847 NMBR protein P28336 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257160 0.271 NEFL protein P07196 UNIPROT Neurofilament L/H complex SIGNOR-C208 SIGNOR form complex binding 9606 BTO:0000938 19468066 t miannu Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H SIGNOR-255272 0.447 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19114991 t lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity SIGNOR-182822 0.748 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR FGB protein P02675 UNIPROT up-regulates activity binding 9606 BTO:0000132 16418530 t lperfetto In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. SIGNOR-253361 0.478 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser491 GSDSDLDsDDEFVPY 9606 20864032 t lperfetto Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. Here, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2) SIGNOR-168040 0.2 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12226093 t The effect has been demonstrated using P10636-8 lperfetto Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease. SIGNOR-251599 0.695 MED9 protein Q9NWA0 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266680 0.656 8-oxo-7-[(6-sulfo-2-naphthalenyl)hydrazinylidene]-5-quinolinesulfonic acid chemical CHEBI:95064 ChEBI PTPN6 protein P29350 UNIPROT down-regulates activity chemical inhibition 9606 20337577 t NSC-87877 (1, Fig. (7)) was identified as a Shp2 PTP inhibitor with an IC50 of 0.33 μM [83]. NSC-87877 inhibits Shp1 with the same potency. SIGNOR-261913 0.8 NFIB protein O00712 UNIPROT ANOS1 protein P23352 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268878 0.2 D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI up-regulates quantity precursor of 9606 16939420 t miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. SIGNOR-267077 0.8 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser446 SGIKSHNsALYSQVQ 9606 15574499 t amattioni Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility. SIGNOR-131455 0.255 PRKCZ protein Q05513 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr564 RGTASRStFHGQPRE 9606 15084291 t lperfetto Hpar-1a, t564, is phosphorylated in vivo and by apkc in vitro.This study establishes a novel functional link between two central determinants of cellular polarity, apkc and par-1, and suggests a model by which apkc may regulate par-1 in polarized cells SIGNOR-124221 0.2 MYO1C protein O00159 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 t miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription SIGNOR-268820 0.335 CCL5 protein P13501 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000584 38339310 f miannu This suggests CCL5 not only remodels the PDAC TME to benefit tumor cells, but can also enhance the tumor cell’s metastatic potential. SIGNOR-277729 0.7 BHLHE40 protein O14503 UNIPROT BHLHE40 protein O14503 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 14672706 f lperfetto We show here an autofeedback loop of Dec1 encoding a basic helix–loop–helix transcription factor: CLOCK/BMAL increased the promoter activity of Dec1, and DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression. SIGNOR-253715 0.2 PRKCA protein P17252 UNIPROT MYL9 protein P24844 UNIPROT down-regulates phosphorylation Ser2 sSKRAKAK 9606 22136066 t lperfetto Rlc can also be phosphorylated at ser1/ser2/thr9 by protein kinase c (pkc). Biophysical studies show that phosphorylation at these sites leads to an increase in the km of myosin light chain kinase (mlck) for rlc, thereby indirectly inhibiting myosin ii activity. SIGNOR-177940 0.282 CTNNB1 protein P35222 UNIPROT EP300 protein Q09472 UNIPROT up-regulates binding 9606 10775268 t gcesareni Ctnnb1 forms a ternary complex with lef1 and ep300 that is disrupted by ctnnbip1 binding SIGNOR-76987 0.693 CSNK1G1 protein Q9HCP0 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser325 SSNASTIsGRLSPIM -1 11980723 t llicata Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR SIGNOR-252902 0.473 PTPRJ protein Q12913 UNIPROT LAT protein O43561 UNIPROT down-regulates activity dephosphorylation 9606 11259588 t Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation SIGNOR-248696 0.36 ROS stimulus SIGNOR-ST2 SIGNOR GSTA4 protein O15217 UNIPROT up-regulates 9534 BTO:0004055 12646569 f lperfetto We have also provided evidence that the mitochondrial GSTA4-4 level markedly increases in COS cells under oxidative stress conditions, suggesting its critical role in maintaining the GSH homeostasis under conditions of chemical and oxidative stress SIGNOR-264797 0.7 AHR protein P35869 UNIPROT CYP1B1 protein Q16678 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 16115918 f miannu Expressions of CYP1B1 mRNA and protein were increased in prostate cancer. The aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) heterodimer complex activates gene transcription by binding to the DREs of CYP1B1. SIGNOR-253733 0.503 SP1 protein P08047 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 21854868 f miannu Doxorubixin-evoked β-TrCP up-regulation promoted Sp1 degradation, which subsequently suppressed ADAM10 expression in MCF-7 and MCF-7/Dox cells. SIGNOR-255192 0.2 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000586 SIGNOR-C110 16293724 t gcesareni This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. SIGNOR-141799 0.856 INS protein P01308 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 9606 BTO:0000887;BTO:0001103 8250835 f gcesareni The results suggest that ser-9 phosphorylation underlies the reported gsk3 beta inhibition by insulin and that gsk3 may represent a point of convergence of two major growth-factor-stimulated protein kinase cascades. SIGNOR-37220 0.469 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Ser302 TQRASRRsDSASSEP 9606 19366211 t llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. SIGNOR-185291 0.2 VEGFA protein P15692 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. SIGNOR-157100 0.814 PRKACA protein P17612 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by stabilization phosphorylation Ser937 ETSFRKLsFTESLTS 19531803 t lperfetto Ser940 of p105 was phosphorylated by PKA to a similar extent, whereas no phosphorylation of the same sequence occurred when Ser940 was substituted by Ala|Mechanistically, phosphorylation of p105 at Ser940 by PKA appeared to attenuate the extent of IKK-dependent phosphorylation of p105 at Ser935, which could in turn influence the rate of activation of NF-kappaB SIGNOR-260327 0.488 SCF-betaTRCP complex SIGNOR-C5 SIGNOR IKBKB protein O14920 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001321 20068069 t miannu CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation. SIGNOR-271431 0.56 RAB5A protein P20339 UNIPROT OCRL protein Q01968 UNIPROT up-regulates activity binding 9606 33722976 t miannu We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. Rab5 effectors Inpp5b, OCRL and APPL1 localize to macropinocytic cups and vesicles, and are required for macropinosome sealing. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis SIGNOR-277771 0.683 INPP5B protein P32019 UNIPROT 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI down-regulates quantity chemical modification 9606 33722976 t miannu We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. Rab5 effectors Inpp5b, OCRL and APPL1 localize to macropinocytic cups and vesicles, and are required for macropinosome sealing. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis SIGNOR-277772 0.8 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT up-regulates activity phosphorylation Ser514 SAPIRSAsQAEEEPS 10441130 t miannu Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation SIGNOR-249714 0.417 PTPRA protein P18433 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 17974954 t Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B SIGNOR-248437 0.732 GTP(4-) chemical CHEBI:37565 ChEBI 2'-3'-cGAMP(2-) smallmolecule CHEBI:143093 ChEBI up-regulates quantity precursor of 23258413 t lperfetto Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. SIGNOR-276595 0.8 MRPL48 protein Q96GC5 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262348 0.668 CDK2 protein P24941 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 SIGNOR-C16 21902831 t gcesareni Cyclin e/cdk2 can phosphorylate myod at serine 200, which causes ubiquitination and degradation of this transcription factor during g1, preventing its accumulation and a commitment to differentiation. SIGNOR-176509 0.537 ACSS2 protein Q9NR19 UNIPROT acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI up-regulates quantity chemical modification 10843999 t lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. SIGNOR-271826 0.8 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252879 0.697 LNX1 protein Q8TBB1 UNIPROT PBK protein Q96KB5 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 22889411 t miannu We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo. SIGNOR-272898 0.383 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR PI3K complex SIGNOR-C156 SIGNOR down-regulates 26721223 f Excessive accumulation of Aβ protein in the AD brain may lead to a decrease in the levels of phosphatidylinositol-3 kinase (PI3K) and the serine/threonine protein kinase B (Akt) activity. SIGNOR-255492 0.7 ketoprofen chemical CHEBI:6128 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001061 18667313 t Luana Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2.  SIGNOR-257810 0.8 PAK2 protein Q13177 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser9 NYLRRRLsDSNFMAN 10116 12237306 t miannu Recombinant PAK2 could also phosphorylate the Ser9 and Ser551 residues. SIGNOR-250236 0.332 LY2603618 chemical CID:11955855 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates activity chemical inhibition 9606 33261142 t miannu Here, using a panel of basal-like cancer cell lines, we explored the synergistic interactions of CHK1 inhibitors (rabusertib and SAR020106) with approved therapies in breast cancer and evaluated their potential to overcome resistance. SIGNOR-262538 0.8 ALDOA protein P04075 UNIPROT glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266483 0.8 OCRL protein Q01968 UNIPROT 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI down-regulates quantity chemical modification 9606 33722976 t miannu We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis. These observations raised the possibility that PtdIns(4,5)P2 depletion is in fact required for the completion of macropinocytosis or to prevent macropinosome back-fusion with the plasmalemma. SIGNOR-277773 0.8 CSMD1 protein Q96PZ7 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 9606 22538441 f miannu CSMD1 inhibits tumor growth, angiogenesis, and survival rate in vivo SIGNOR-265150 0.7 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI Early macropinosomes phenotype SIGNOR-PH228 SIGNOR down-regulates 9606 33722976 t miannu We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis. These observations raised the possibility that PtdIns(4,5)P2 depletion is in fact required for the completion of macropinocytosis or to prevent macropinosome back-fusion with the plasmalemma. SIGNOR-277774 0.7 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269340 0.719 GUCY1B1 protein Q02153 UNIPROT GUCY1A2-B3 complex SIGNOR-C138 SIGNOR form complex binding 9606 10977868 t gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity SIGNOR-243980 0.2 AKT1 protein P31749 UNIPROT NCOR1 protein O75376 UNIPROT down-regulates phosphorylation Ser1450 TVRSRHTsVVSSGPS 9606 BTO:0001271 23940660 t llicata Akt-induced phosphorylation of n-cor at serine 1450 contributes to its misfolded conformational dependent loss (mcdl) in acute myeloid leukemia of the m5 subtype. SIGNOR-198913 0.435 CDKL5 protein O76039 UNIPROT CDKL5 protein O76039 UNIPROT up-regulates activity phosphorylation Tyr171 NNANYTEyVATRWYR -1 16935860 t miannu Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif. SIGNOR-245876 0.2 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser621 PKINRSAsEPSLHRA 9606 11971957 t gcesareni We have mapped all camp-induced phosphorylation sites in raf-1, showing that serines 43, 259, and 621 are phosphorylated by pka in vitro and induced by camp in vivo SIGNOR-86137 0.482 CHKA protein P35790 UNIPROT choline smallmolecule CHEBI:15354 ChEBI down-regulates quantity chemical modification 27149373 t lperfetto Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes SIGNOR-275637 0.8 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 16782899 t llicata Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain SIGNOR-147199 0.476 GRPR protein P30550 UNIPROT PLA2G1B protein P04054 UNIPROT up-regulates binding 9606 17251915 t gcesareni Grpr stimulation activates phospholipase a2 (pla2) and cyclooxygenase 2 (cox2), which leads to prostaglandin e2 (pge2) production and ep receptor stimulation. SIGNOR-152756 0.257 TBX5 protein Q99593 UNIPROT SNCG protein O76070 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20802524 f miannu TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. SIGNOR-255255 0.2 SND1 protein Q7KZF4 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity binding -1 12234934 t irozzo STAT6 interacted with p100 in vitro and in vivo. Here, we show that the TAD of STAT6 is interacting with p100. p100 was found to enhance the STAT6-mediated transcription [.]. SIGNOR-259134 0.492 DEAF1 protein O75398 UNIPROT EN1 protein Q05925 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000375 31145909 t Gianni Deaf1 is the first transcription factor implicated in the regulation of En1, a critical determinant of eccrine fate, within keratinocytes. SIGNOR-269062 0.2 CXCL2 protein P19875 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates activity binding 9606 38309677 t miannu CXCL2/3, also known as macrophage inflammatory protein-2α/2β (MIP-2α/MIP-2β), share the same receptor CXCR2 with CXCL1 and are able to activate neutrophils effectively SIGNOR-277718 0.73 methylnaltrexone chemical CHEBI:136007 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 19282177 t Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. SIGNOR-258042 0.8 NOTCH3 protein Q9UM47 UNIPROT HEYL protein Q9NQ87 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 11044625 f gcesareni In the latter, heyl is coexpressed with notch3, so far the only notch pathway gene detected in vascular smooth muscles (fig. 2h,i;joutel et al., 2000). Both genes are also coexpressed during late thymus development and our own promoter studies further suggest a potential regulation of heyl transcription by notch3. SIGNOR-83402 0.593 FOXP1 protein Q9H334 UNIPROT CSF1R protein P07333 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000738 15286807 t Gianni Overexpression of MFH/Foxp1 markedly attenuated phorbol ester-induced expression of c-fms, which encodes the M-CSF receptor and is obligatory for macrophage differentiation. SIGNOR-269048 0.301 SPI1 protein P17947 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates activity 10090 BTO:0000725 8079170 f Mice carrying a mutation in the PU.1 locus were generated by gene targeting. Homozygous mutant embryos died at a late gestational stage. [...]An invariant consequence of the mutation was a multilineage defect in the generation of progenitors for B and T lymphocytes, monocytes, and granulocytes. Thus, the developmental programs of lymphoid and myeloid lineages require a common genetic function likely acting at the level of a multipotential progenitor. SIGNOR-259954 0.7 Corticotropin protein P01189-PRO_0000024969 UNIPROT MC2R protein Q01718 UNIPROT up-regulates activity binding 10029 BTO:0000047 20371771 t lperfetto Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP). SIGNOR-268616 0.2 IFNA2 protein P01563 UNIPROT HLA-B protein P01889 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 2507660 f Regulation miannu HLA-B (class I) and C13 gene expression was transcriptionally activated by IFN-gamma and IFN-alpha 2 SIGNOR-251925 0.261 CREBBP protein Q92793 UNIPROT DDX21 protein Q9NR30 UNIPROT down-regulates activity acetylation Lys137 PKKMKKEkEMNGETR 28790157 t lperfetto Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21. SIGNOR-275904 0.247 AKT1 protein P31749 UNIPROT FAS protein P25445 UNIPROT down-regulates 9606 15004527 f gcesareni Akt may serve to stimulate certain proteins (e.g., Ikk) involved in the prevention of apoptosis such as nf-kb as well as repress other proteins normally involved in the induction of apoptosis such as the forkhead transcription factors (fkhr, now know as foxo3), creb, glycogen synthetase-3 kinase-beta (gsk-3beta), fas, caspase-9 and cell cycle inhibitors such as p27 SIGNOR-252473 0.393 NRG1 protein Q02297 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 t gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. SIGNOR-122053 0.901 TLE5 protein Q08117 UNIPROT SIX6 protein O95475 UNIPROT down-regulates activity binding -1 12441302 t lperfetto Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. AES abrogates SIX3- and SIX6-induced phenotypes SIGNOR-234589 0.2 SREBF1 protein P36956 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity 10090 9539737 f gcesareni Finally, we demonstrate directly that cells expressing ADD1/SREBP1 produce and secrete lipid molecule(s) that bind directly to PPARgamma, displacing the binding of radioactive thiazolidinedione ligands SIGNOR-170607 0.459 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 24556163 t miannu This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine SIGNOR-262237 0.8 motesanib chemical CHEBI:51098 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194569 0.8 AKT1 protein P31749 UNIPROT NUAK1 protein O60285 UNIPROT up-regulates phosphorylation Ser600 PARQRIRsCVSAENF 9606 12409306 t esanto Ser(600) in ark5 was found to be phosphorylated by active akt resulting in the activation of kinase activity. SIGNOR-252591 0.265 SGK2 protein Q9HBY8 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000007 11154281 t lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. SIGNOR-252990 0.514 EEF1A1 protein P68104 UNIPROT Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269508 0.8 NFE2 protein Q16621 UNIPROT HBE1 protein P02100 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000426 16287851 f Regulation of expression miannu NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells. SIGNOR-251842 0.479 ALS2 protein Q96Q42 UNIPROT RAB5A protein P20339 UNIPROT up-regulates activity binding 9606 BTO:0000567 30485418 t miannu ALS2 activates Rab5 on macropinosomes. Rab5 is activated and concurrently recruited to macropinosomes during ruffle closure. ALS2 depletion abolishes transient Rab5 activation on macropinosomes, while ALS2 is recruited to macropinosomes simultaneously with Rab5 activation. Thus, we conclude ALS2 activates Rab5 on macropinosomes. SIGNOR-277776 0.725 LFNG protein Q8NES3 UNIPROT NOTCH2 protein Q04721 UNIPROT down-regulates binding 9606 11346656 t gcesareni Although both manic fringe (mfng) and lunatic fringe (lfng) decreased the binding of jagged1 to notch2 and not that of delta1, the decrease by mfng was greater in degree than that by lfng. We also found that both fringe proteins reduced jagged1-triggered notch2 signaling, whereas neither affected delta1-triggered notch2 signaling. SIGNOR-107705 0.685 ibuprofen chemical CHEBI:5855 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 9057869 t miannu Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). SIGNOR-258604 0.8 MAPK1 protein P28482 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser636 SGDYMPMsPKSVSAP 9606 12510059 t gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. SIGNOR-249407 0.667 pemetrexed chemical CHEBI:63616 ChEBI GART protein P22102 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205883 0.8 MLLT1 protein Q03111 UNIPROT AEP complex complex SIGNOR-C117 SIGNOR form complex binding 9606 BTO:0000664 20153263 t 1 miannu These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells. SIGNOR-239228 0.679 PTPRG protein P23470 UNIPROT ITGB2 protein P05107 UNIPROT down-regulates activity 9606 25624455 f miannu PTPRG activation inhibits chemoattractant induced LFA-1 affinity triggering and mediated adhesion in human primary monocytes.we show that PTPRG is a novel negative regulator of LFA-1 high-affinity-state triggering and mediated arrest by chemoattractants in human primary monocytes. Notably, PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role (37). In our context, SRC appears inhibited by PTPRG activation (Table I), thus making it unlikely that the antiadhesive effect of PTPRG is mediated by SRC activation. SIGNOR-254735 0.263 FLT3 protein P36888 UNIPROT FZD4 protein Q9ULV1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002882 15650056 f AML-typical Flt3 mutations induce the expression of Frizzled-4 on the mRNA and protein level, mimicking the effects of IL-3. SIGNOR-261533 0.2 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser295 FKLGGRDsRSGSPMA -1 2413024 t miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-164 SIGNOR-250014 0.353 RAC1 protein P63000 UNIPROT ALS2 protein Q96Q42 UNIPROT up-regulates activity binding 9606 BTO:0000567 30485418 t miannu Thus, in our system, activeRac1 may recruit ALS2 only at the very early stage ofmacropinocytosis including membrane ruffles, suggest-ing that ALS2 is retained by some other mechanismsuntil Rab conversion. SIGNOR-277777 0.516 FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 18423396 f fspada Akt1/Pkb-alpha was found to be the major regulator of phosphorylation and nuclear export of Foxo1, whose presence in the nucleus strongly attenuates adipocyte differentiation. SIGNOR-178281 0.7 MAPK12 protein P53778 UNIPROT SH3BP5 protein O60239 UNIPROT unknown phosphorylation Ser421 SKSQSSTsPEGQALE -1 15158451 t miannu Activated SAPK3 phosphorylates the mitochondrial protein Sab. we have identified serine 321 as the major site of phosphorylation by both SAPK3 and JNK2. SAPK3 but not JNK2 also phosphorylates serine 391 SIGNOR-250141 0.453 RAB7A protein P51149 UNIPROT ALS2 protein Q96Q42 UNIPROT down-regulates activity binding 9606 BTO:0000567 30485418 t miannu The absence of active Rab7 prolongs ALS2presence and Rab5 activation on macropinosomes, indicating that activeRab7 is necessary for Rab5 inactivation through ALS2 dissociation and playskey roles in the Rab switch on macropinosomes. Taken together, active Rab7is necessary for Rab5 down-regulation through ALS2dissociation, thereby acting as a central component inthe Rab5-to-Rab7 switch in macropinocytosis SIGNOR-277778 0.31 RAB7A protein P51149 UNIPROT Late macropinosomes phenotype SIGNOR-PH229 SIGNOR up-regulates 9606 19693279 f miannu Rab7 is localized on later macropinosomes. Rab21 is localized on macropinosomes at an intermediate stage partially overlapping with Rab5 and Rab7, and then dissociates from the macropinosomes prior to Lamp1 acquisition by fusing with lysosomes. SIGNOR-277779 0.7 TNC protein P24821 UNIPROT Av/b1 integrin complex SIGNOR-C175 SIGNOR up-regulates activity binding 9606 BTO:0001521 38058842 t miannu TNC is shown to bind to integrin receptors expressed in adjacent PAAD cells, thereby inducing EMT. In addition, TNC expression in CAFs had significant positive correlations with ITGαV, ITGβ1, or ITGβ3 expression in cancer cells, which supports our speculations that the TNC-integrin signaling axis promotes the EMT pathway in cancer cells. SIGNOR-277735 0.406 PRMT1 protein Q99873 UNIPROT CNBP protein P62633 UNIPROT down-regulates methylation Arg27 PTGGGRGrGMRSRGR 9606 24726729 t miannu Cnbp interacts with protein arginine methyltransferase prmt1 / r25 or r27 appear to be the major methylation sites in cnbp /arginine methylation of cnbp impedes rna binding SIGNOR-204962 0.376 AKT proteinfamily SIGNOR-PF24 SIGNOR HK2 protein P52789 UNIPROT up-regulates activity phosphorylation Thr473 QHRARQKtLEHLQLS 9606 BTO:0003324 25323588 t miannu Hexokinase II is phosphorylated by Akt leading to increased mitochondrial binding and mitochondrial protection.We found that Akt, activated by receptor agonists, translocates to mitochondria and phosphorylates HK-II at Thr473, a critical step in Akt-mediated mitoHK-II increase and protection in cardiomyocytes SIGNOR-267576 0.2 PITX1 protein P78337 UNIPROT GNRH1 protein P01148 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 19106114 f miannu Knockdown of PITX1 or PITX2 isoforms impaired GNRH1 induction, and endogenous PITX1 bound to the candidate PITX binding site on the LHB promoter. SIGNOR-254921 0.335 MAPK13 protein O15264 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 t lperfetto Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. SIGNOR-114075 0.2 regorafenib chemical CHEBI:68647 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition 9606 26254357 t miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF SIGNOR-259179 0.8 PAK1 protein Q13153 UNIPROT PGM1 protein P36871 UNIPROT up-regulates phosphorylation Thr467 SANDKVYtVEKADNF 9606 BTO:0001271 15378030 t gcesareni The signaling kinase p21-activated kinase 1 (pak1) binds to, phosphorylates and enhances the enzymatic activity of phosphoglucomutase 1 (pgm), SIGNOR-127135 0.35 PRKAA2 protein P54646 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0000876 21673972 t lperfetto These results demonstrate that the ikk is a direct substrate of ampk_2 and that its phosphorylation on ser177 and ser181no initiates the activation of the ampk_2 in endothelial cells which in turn phosphorylates and activates the _-subunit of the ikk. The latter also induces a higher rate of ikk auto-inactivation and thus attenuates the activation of nf_b and the expression of inflammatory genes SIGNOR-217457 0.259 RPS24 protein P62847 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262427 0.916 BAP1 protein Q92560 UNIPROT KEAP1 protein Q14145 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 35052618 t miannu BAP1 directly binds to and deubiquitinates KEAP1. BAP1 stabilizes KEAP1 by binding to the BTB domain. SIGNOR-268924 0.2 ASIP protein P42127 UNIPROT MC1R protein Q01726 UNIPROT down-regulates activity binding 9606 BTO:0000847 14500544 t miannu The antagonist agouti signal protein (ASP) interacts with the Mc1r and blocks its stimulation by MSH. SIGNOR-252378 0.733 TSC complex SIGNOR-C101 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity 9606 BTO:0000007;BTO:0001938 12271141 f lperfetto These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor SIGNOR-251527 0.613 SRPK1 protein Q96SB4 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 10196197 t gcesareni These results suggest that the formation of complexes between sf2/asf and srpks, which is influenced by the phosphorylation state of sf2/asf, may have regulatory roles in the assembly and localization of this splicing factor. SIGNOR-66465 0.795 CSNK1A1 protein P48729 UNIPROT AHCYL1 protein O43865 UNIPROT unknown phosphorylation Ser77 SSTDSYSsAASYTDS 9534 17635105 t lperfetto Residue 68 resides in a consensus phosphorylation site for PKD (Figure 1A) [22,23]. Interestingly, phosphorylation of Ser68 could allow for subsequent phosphorylation of Ser71, Ser74, Ser77 and Ser80 by CK1, for which the consensus phosphorylation site is pS/T-X-X-S/T SIGNOR-249185 0.2 MRPS7 protein Q9Y2R9 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-267730 0.755 STAT3 protein P40763 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates 9606 18156621 f Our results demonstrate that IL-27 inhibits the acquisition of the Treg phenotype at the level of Foxp3. The inhibitory effect of IL-27 on Treg generation was at least partially signal transducer and activator of transcription 3 (STAT3) dependent as examined by targeted STAT3 protein inhibition using small interfering RNA (siRNA) SIGNOR-254304 0.59 MEN1 protein O00255 UNIPROT KMT2A protein Q03164 UNIPROT up-regulates activity binding 9606 BTO:0000567 15640349 t irozzo However, menin dramatically increases the amount of MLL bound at the p27Kip1 and p18Ink4c loci, suggesting that it either directly or indirectly promotes MLL recruitment to these targets. Once recruited, MLL could enhance transcription by a number of mechanisms.Overall, the data suggest that transcriptional regulation by menin involves increasing MLL protein association with target loci. SIGNOR-255890 0.719 AURKB protein Q96GD4 UNIPROT CKAP2 protein Q8WWK9 UNIPROT up-regulates phosphorylation Ser628 FLTPVRRsRRLQEKT 9606 20458174 t lperfetto Here, we report that tmap is a novel substrate of the aurora b kinase. Ser627 of tmap was specifically phosphorylated by aurora b both in vitro and in vivo. Nearly all mutations at the phosphorylation motif had dramatic effects on the subcellular localization of tmap. SIGNOR-165410 0.299 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT unknown phosphorylation Thr417 SLPQATVtPPRKEER 9606 14551205 t llicata In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. SIGNOR-86696 0.502 CSNK2A1 protein P68400 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser316 VEEEPLNsEDDVSDE -1 11278496 t llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. SIGNOR-250876 0.387 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251598 0.695 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI RAB21 protein Q9UL25 UNIPROT down-regulates activity binding 9606 19693279 t miannu It was demonstrated that wild-type Rab21 was transiently associated with macropinosomes. Rab21 was recruited to the macropinosomes after a decrease in PI(4,5)P(2) and PI(3,4,5)P(3) levels. Although Rab21 was largely colocalized with Rab5, the recruitment of Rab21 to the macropinosomes lagged a minute behind that of Rab5, and preceded that of Rab7. SIGNOR-277781 0.8 KAT2B protein Q92831 UNIPROT H3-2 protein Q5TEC6 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269624 0.2 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates activity phosphorylation Ser927 DSDSVCDsGVETSFR 9606 BTO:0000007 SIGNOR-C13 11158290 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-104807 0.848 MAST3 protein O60307 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation 9606 15951562 t gcesareni Furthermore, binding of PTEN to the PDZ domains from microtubule-associated serine/threonine kinases facilitated PTEN phosphorylation at its C terminus by these kinases. SIGNOR-138080 0.585 JAK2 protein O60674 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Tyr158 Y-->S 9606 BTO:0000938 32599005 t lperfetto JAK2 regulates Nav1.6 channel function via FGF14Y158 phosphorylation|Patch-clamp electrophysiology revealed that through Y158, JAK2 controls FGF14-dependent modulation of Nav1.6 channels. In hippocampal CA1 pyramidal neurons, the JAK2 inhibitor Fedratinib reduced firing by a mechanism that is dependent upon expression of FGF14. SIGNOR-275747 0.2 TP53 protein P04637 UNIPROT NLRC4 protein Q9NPP4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15580302 f miannu Here we show that Ipaf, a human CED-4 homologue and an activator of caspase-1, is induced by p53. Overexpression of p53 by transfection in U2OS and A549 cells increased Ipaf mRNA levels. SIGNOR-255439 0.426 FASN protein P49327 UNIPROT WNT1 protein P04628 UNIPROT up-regulates activity 9606 18838960 f lperfetto Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer SIGNOR-242881 0.252 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267882 0.8 cholesterol smallmolecule CHEBI:16113 ChEBI RAC1 protein P63000 UNIPROT up-regulates quantity relocalization 9606 BTO:0000584 31827278 t miannu Accumulation of V-ATPase at the plasma membrane is necessary for the cholesterol-dependent plasma-membrane association of RAC1, a prerequisite for the stimulation of membrane ruffling and macropinocytosis. In line with these observations, immunohistochemical staining of V-ATPase in human pancreatic ductal adenocarcinoma (PDAC) specimens revealed prominent staining at the cell periphery in neoplastic lesions, in con- trast to the predominantly cytoplasmic staining observed in adjacent normal tissues (Fig. 2e). Thus, mutant RAS-dependent plasma mem- brane V-ATPase displayed preferential accumulation in membrane ruffles, consistent with patterns observed in invasive breast, melanoma and pancreatic cancer cells SIGNOR-277761 0.8 PTPN12 protein Q05209 UNIPROT WAS protein P42768 UNIPROT down-regulates dephosphorylation 9606 11711533 t gcesareni Furthermore, we demonstrate that pstpip serves as a scaffold protein between ptp-pest and wasp and allows ptp-pest to dephosphorylate wasp. This finding suggests a possible mechanism for ptp-pest to directly modulate actin remodeling through the pstpip-wasp interaction. SIGNOR-111688 0.455 UBE2G2 protein P60604 UNIPROT SYVN1 protein Q86TM6 UNIPROT up-regulates activity ubiquitination 10090 BTO:0000944 14593114 t miannu We show that human HRD1 is a non-glycosylated, stable ER protein with a cytosolic RING-H2 finger domain. In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation. SIGNOR-272593 0.68 TGFB1 protein P01137 UNIPROT DNAH10 protein Q8IVF4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000667 31836722 f miannu The protein expression of DNAH10 was assessed by Western blot analysis after stimulation of primary keratinocytes (P4) with inflammatory cytokine TNFα or growth factor TGF-β1 and their combination (Fig. 5C). Treatment with TNFα, TGF-β1, and their combination down regulated the expression of DNAH10 in keratinocytes after a 24-h-stimulation. SIGNOR-265552 0.2 BRCA1-C complex complex SIGNOR-C299 SIGNOR TP53BP1 protein Q12888 UNIPROT up-regulates activity relocalization 25400280 t lperfetto Additional to the role of the BRCA1–C complex in 53BP1 repositioning and initiation of resection, end resection is extended to facilitate RPA loading and subsequent RPA‐Rad51 exchange prior to sister strand invasion SIGNOR-263230 0.61 UBE4B protein O95155 UNIPROT ATXN3 protein P54252 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 14749733 t miannu Mammalian E4B (UFD2a), a ubiquitin chain assembly factor (E4), copurified with the polyubiquitylation activity for ataxin-3. E4B interacted with, and thereby mediated polyubiquitylation of, ataxin-3.  Collectively, these data suggest that E4B promotes the degradation of ataxin-3, and that this effect surmounts the stabilization of ataxin-3 conferred by expansion of the polyglutamine tract. SIGNOR-271502 0.595 ELMO2 protein Q96JJ3 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 BTO:0001909 25533347 t miannu We found in this study that AUTS2 is involved in Rac1 activation via P-Rex1 and the Elmo2/Dock180 complex, but not STEF or Tiam1, for the lamellipodia formation in N1E-115 cells. However, the enhancement of neurite elongation in primary neurons by AUTS2 expression is specifically mediated by the Elmo2/Dock180 complex. These results suggested that several Rac-GEFs differentially or cooperatively participate in Rac1 activation to promote neuronal migration and neurite outgrowth. SIGNOR-266821 0.566 KMT2E protein Q8IZD2 UNIPROT NCR2 protein O95944 UNIPROT up-regulates activity binding 9606 BTO:0000737 23958951 t miannu We identify natural cytotoxicity receptor NKp44 (NKp44L), a novel isoform of the mixed-lineage leukemia-5 protein, as a cellular ligand for NKp44. Unlike the other MLL family members, NKp44L is excluded from the nucleus, but expressed at the cell-surface level; its subcellular localization is being associated with the presence of a specific C-terminal motif. Strikingly, NKp44L has not been detected on circulating cells isolated from healthy individuals, but it is expressed on a large panel of the tumor and transformed cells. SIGNOR-260045 0.52 PRKCG protein P05129 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1323 ALAPRSVsLKDKGRF -1 11306676 t lperfetto These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. SIGNOR-249088 0.407 ARHGAP15 protein Q53QZ3 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260470 0.563 TFE3 protein P19532 UNIPROT HEXA protein P06865 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276824 0.2 POU1F1 protein P28069 UNIPROT GH1 protein P01241 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15998782 f miannu Such findings are consistent with the existence, in humans, of an LHX4-driven pathway leading to the expression of GH through transcriptional activation of POU1F1. SIGNOR-254559 0.365 RPS19 protein P39019 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262432 0.917 IKK-complex complex SIGNOR-C14 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 15084260 t lperfetto Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation. SIGNOR-216407 0.534 AKT proteinfamily SIGNOR-PF24 SIGNOR GAB2 protein Q9UQC2 UNIPROT down-regulates phosphorylation Ser159 LLRERKSsAPSHSSQ 9606 11782427 t lperfetto Pkb constitutively associates with gab2, phosphorylates gab2 on a consensus phosphorylation site, ser159, in vitro and inhibits gab2 tyrosine phosphorylation. SIGNOR-113669 0.2 PHKA2 protein P46019 UNIPROT PHKG1 protein Q16816 UNIPROT down-regulates activity binding 9606 10487978 t Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit. SIGNOR-267404 0.688 RAC1 protein P63000 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity binding 10090 BTO:0000142 8107774 t gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. SIGNOR-248250 0.74 TGFB1 protein P01137 UNIPROT TFAP4 protein Q01664 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000452 21228219 f miannu TGFβ effectively inhibits expression of SALL2 and its regulator AP4 when added to quiescent fibroblasts. SIGNOR-255428 0.2 MYCT1 protein Q8N699 UNIPROT BCL2 protein P10415 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30283340 f miannu MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. SIGNOR-261735 0.2 LPAR3 protein Q9UBY5 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22863277 t gcesareni Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2. SIGNOR-198547 0.385 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SP1 protein P08047 UNIPROT up-regulates phosphorylation 9606 11904305 t inferred from 70% family members gcesareni Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. sa-perk1/2 activates the transcription factor, sp1, via ser59 phosphorylation downstream of pkc_, leading to transcription of p21sdi1 and resulting in replicative senescence of hdf cells. SIGNOR-270104 0.2 ULK1 protein O75385 UNIPROT HK1 protein P19367 UNIPROT up-regulates activity phosphorylation Ser124 NIVHGSGsQLFDHVA 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274034 0.259 PPM1A protein P35813 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates dephosphorylation 9606 SIGNOR-C110 10644691 t acerquone Pp2c utilizes axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that pp2c is a positive regulator of wnt signal transduction and mediates its effects through the dephosphorylation of axin. SIGNOR-74231 0.445 UBE2T protein Q9NPD8 UNIPROT FANCL protein Q9NW38 UNIPROT up-regulates activity ubiquitination -1 24389026 t lperfetto Using the Fanconi Anemia pathway exclusive E3-E2 pair, FANCL-Ube2T, we report the atomic structure of the FANCL RING-Ube2T complex|Our structural and biochemical analyses suggest that, in a cellular environment with multiple E2s present, FANCL will preferentially select Ube2T. SIGNOR-263263 0.898 ATM protein Q13315 UNIPROT NHEJ1 protein Q9H9Q4 UNIPROT unknown phosphorylation Ser251 ASLQGIDsQCVNQPE 9606 18644470 t lperfetto Here, we have identified two major in vitro dna-pk phosphorylation sites in the c-terminal region of xlf, serines 245 and 251. We show that these represent the major phosphorylation sites in xlf in vivo and that serine 245 is phosphorylated in vivo by dna-pk, while serine 251 is phosphorylated by ataxia-telangiectasia mutated (atm). SIGNOR-179528 0.573 ADCY9 protein O60503 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 t miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. SIGNOR-265005 0.8 KDM5B protein Q9UGL1 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-264302 0.2 SMURF1 protein Q9HCE7 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity ubiquitination 9606 14701828 t lperfetto Recently we have found that smurf1 mediates the protein degradation of the osteoblast-specific transcription factor runx2/cbfa1. SIGNOR-95233 0.518 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT down-regulates activity phosphorylation Ser522 PAGSARGsPTRPNPP 10116 BTO:0000938 16611631 t lperfetto Primary rat cortical neurons were treated with purvalanol, a more potent inhibitor of cdk5 and dyrk2 than roscovitine (25). Phosphorylation was monitored using antibodies that specifically recognize crmp2 when phosphorylated at thr514/thr509, or crmp4 when phosphorylated at thr509. Loss of phosphorylation of ser522 will prevent subsequent phosphorylation of ser518/thr514/thr509 by gsk3. Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro SIGNOR-146007 0.452 (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one chemical CHEBI:125500 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258776 0.8 RNF216 protein Q9NWF9 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16968706 t miannu Triad3A promotes proteolytic degradation of adapter proteins. Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins. SIGNOR-271608 0.517 AURKA protein O14965 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser380 ATLARRDsLQKPGLE 9606 21822051 t lperfetto In the present study, aurora a was demonstrated to phosphorylate lats2 on serine 380 (s380) during mitosistogether, the results suggest that the aurora a-lats1/2-aurora b axis might be a novel pathway that regulates accurate mitotic progression by ensuring the proper mitotic localization of lats2. SIGNOR-175939 0.388 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 9271428 t gcesareni Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation. SIGNOR-50594 0.2 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT unknown phosphorylation Ser696 PNKELPPsPEKKTKP 9606 BTO:0000567 10791892 t miannu We have shown that MAP4 is phosphorylated in vivo in mitotic HeLa cells at eight sites. Five of these were phosphorylated by p34cdc2 kinase. Two of the five p34cdc2 kinase phosphorylation sites were shown to be Ser696 and Ser787 in the proline-rich region SIGNOR-277461 0.511 PAICS protein P22234 UNIPROT 5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-) smallmolecule CHEBI:77657 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). SIGNOR-267318 0.8 CBL protein P22681 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0000944 10347229 t miannu  Overexpression of wild type Cbl in NIH3T3 cells led to an enhancement of the ligand-dependent ubiquitination and subsequent degradation of the PDGFRbeta, as observed with PDGFRalpha. SIGNOR-272549 0.613 IL2 protein P60568 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 16477002 t miannu Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c). SIGNOR-144543 0.862 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates ubiquitination 9606 BTO:0001271 12835716 t lperfetto Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2 SIGNOR-217172 0.522 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB8 protein P26012 UNIPROT up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259012 0.2 SERPINE1 protein P05121 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 29474926 f miannu Plasminogen activator inhibitor-1 (PAI-1) formed in the injured alveolar epithelium also contributes to pulmonary fibrosis in a manner that involves vitronectin binding. SIGNOR-260588 0.7 ROCK2 protein O75116 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225]. SIGNOR-90832 0.423 CYP11A1 protein P05108 UNIPROT pregnenolone smallmolecule CHEBI:16581 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The steroidogenic acute regulatory protein (StAR) assists in the transport of cholesterol from the cytosol to the inner mitochondria membrane to be converted into pregnenolone using the P450 side-chain cleavage (P450scc) enzyme. SIGNOR-268632 0.8 AMPK complex SIGNOR-C15 SIGNOR PRPS1 protein P60891 UNIPROT down-regulates activity phosphorylation Ser180 GGAKRVTsIADRLNV 9606 BTO:0006038 29074724 t lperfetto We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. SIGNOR-265730 0.244 STAT3 protein P40763 UNIPROT STAT1/STAT3 complex SIGNOR-C118 SIGNOR form complex binding 10090 BTO:0000667 15284024 t lperfetto Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. SIGNOR-235664 0.598 NEK6 protein Q9HC98 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser53 EGGQLNEsMDHGGVG -1 12023960 t miannu Here we demonstrate that in addition to phosphorylating S6K1 and SGK1 at their hydrophobic motif, NEK6 also phosphorylates S6K1 at two other sites and phosphorylates SGK1 at one other site in vitro. Analysis of the peptides phosphorylated by NEK6 (Fig 2), performed in the present study has confirmed this, and identified two novel sites on S6K1 (Ser53 and Ser403) as major sites of NEK6 phosphorylation. SIGNOR-262952 0.375 KIT protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0000141 18179858 t irozzo KIT mutations within the carboxy-terminal region of the cytoplasmic tyrosine kinase domain (TK2), such as KITD816V, stabilize the KIT activation loop conformation in its active form.Previous studies have demonstrated hyperactivation of p85α regulatory subunit of class IA phosphatidylinositol-3-kinase (PI3K) in cell lines expressing the activation loop mutant of KIT. Although p85α is hyperphosphorylated and constitutively bound to KITD814V in cell-line models. SIGNOR-256121 0.709 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide chemical CHEBI:95082 ChEBI BRD3 protein Q15059 UNIPROT down-regulates activity chemical inhibition -1 24015967 t Gianni This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation SIGNOR-262203 0.8 ETS2 protein P15036 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 11175361 f miannu Ets1 and Ets2 seem to play opposing roles in apoptosis. While Ets1 seems to activate pro-apoptotic pathways, Ets2 seems to inhibit apoptosis SIGNOR-259870 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR FLNC protein Q14315 UNIPROT up-regulates quantity by stabilization phosphorylation Ser2233 LGRERLGsFGSITRQ 10090 BTO:0000165 32444788 t miannu We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells. In vitro kinase assays combined with LC-MS confirmed hFLNc-S2233 as a substrate of Akt, whereas PKCα preferentially targeted S2236. SIGNOR-262616 0.2 ACAT1 protein P24752 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity acetylation 34289383 t lperfetto We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1) SIGNOR-267633 0.402 EGLN3 protein Q9H6Z9 UNIPROT ADRB2 protein P07550 UNIPROT up-regulates quantity by stabilization hydroxylation Pro382 KLLCEDLpGTEDFVG 9606 BTO:0000007 19584355 t lperfetto We further show that the interaction of pVHL with beta(2)AR is dependent on proline hydroxylation (proline-382 and -395) and that the dioxygenase EGLN3 interacts directly with the beta(2)AR to serve as an endogenous beta(2)AR prolyl hydroxylase. Under hypoxic conditions, receptor hydroxylation and subsequent ubiquitylation decrease dramatically, thus attenuating receptor degradation and down-regulation. SIGNOR-262006 0.323 452342-67-5 chemical CID:10202642 PUBCHEM TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193018 0.8 PHIP protein Q8WWQ0 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR up-regulates activity binding 9606 BTO:0000664 30018425 t miannu One member of the CRL4 complex, the WD-40 containing protein RepID (DCAF14/PHIP), selectively binds and activates a group of replication origins. Here we show that RepID recruits the CRL4 complex to chromatin prior to DNA synthesis, thus playing a crucial architectural role in the proper licensing of chromosomes for replication. In the absence of RepID, cells rely on the alternative ubiquitin ligase, SKP2-containing SCF, to progress through the cell cycle. SIGNOR-266963 0.333 NR3C1 protein P04150 UNIPROT NR2F2 protein P24468 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14739255 f gcesareni Gralpha, but not grbeta, enhanced coup-tfii-induced transactivation of the simple coup-tfii-responsive 7alpha-hydroxylase promoter through the transcriptional activity of its activation function-1 domain, whereas coup-tfii repressed gralpha-induced transactivation of the glucocorticoid-responsive promoter by attracting the silencing mediator for retinoid and thyroid hormone receptors. SIGNOR-121422 0.358 POLG2 protein Q9UHN1 UNIPROT DNA polymerase gamma complex SIGNOR-C378 SIGNOR form complex binding -1 19837034 t lperfetto Here, we report a crystal structure of human DNA Pol gamma holoenzyme. The holoenzyme is a heterotrimer containing one Pol gammaA subunit and a dimeric Pol gammaB subunit. SIGNOR-265718 0.738 PIP3 smallmolecule CHEBI:16618 ChEBI AKT1 protein P31749 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositidedependent kinase 1 pdk1) and akt, and the subsequent phosphorylation of akt at serine 308 by pdk1, leading to akt activation. SIGNOR-236349 0.8 L-isoprenaline chemical CHEBI:6257 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257457 0.8 ARID1A protein O14497 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 t miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. SIGNOR-132919 0.787 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser171 HLQTCCGsLAYAAPE 9606 16216881 t gcesareni We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk. SIGNOR-140958 0.2 NKX3-1 protein Q99801 UNIPROT NKX3-1/SRF complex SIGNOR-C25 SIGNOR form complex binding 9606 BTO:0000887;BTO:0001260 10993896 t lperfetto A novel complex element containing a juxtaposed nkx-binding site (nke) and an srf-binding element (sre) in the proximal promoter region was found to be necessary for the nkx3-1/srf coactivation of smga transcription. SIGNOR-82087 0.405 DEAF1 protein O75398 UNIPROT RAC3 protein P60763 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001939 18826651 t Gianni Affymetrix gene profiling studies revealed Rac3 as a potential target gene and quantitative RT-PCR analysis confirmed that Rac3 was upregulated by Deaf-1 in immortalized mouse mammary epithelial cells. SIGNOR-269059 0.2 PRKAA1 protein Q13131 UNIPROT GSR protein P00390 UNIPROT up-regulates activity phosphorylation Thr507 TKADFDNtVAIHPTS 9606 BTO:0001890 31530934 t miannu Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity.  SIGNOR-273734 0.292 NMDA receptor_2C complex SIGNOR-C349 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor SIGNOR-264224 0.738 KLF14 protein Q8TD94 UNIPROT SPHK1 protein Q9NYA1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 24759103 t Luana KLF14 Is a Transcriptional Activator of SK1 Gene Expression in Endothelial Cells SIGNOR-266047 0.2 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 23431053 t milica MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation SIGNOR-201298 0.621 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide chemical CHEBI:131156 ChEBI CHEK2 protein O96017 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190206 0.8 haloperidol chemical CHEBI:5613 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000601 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258521 0.8 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 12050114 t gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk SIGNOR-88736 0.359 aloxistatin chemical CHEBI:101381 ChEBI CTSB protein P07858 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 32142651 t miannu Full inhibition was attained when camostat mesylate and E-64d, an inhibitor of CatB/L, were added (Figure 4A; Figure S3B), indicating that SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. SIGNOR-260281 0.8 ATR protein Q13535 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Ser502 FSTDNSGsQPKQKSD 9606 22123827 t lperfetto Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication. SIGNOR-177805 0.643 CERS1 protein P27544 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI up-regulates quantity chemical modification 9606 26887952 t done miannu  Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity.  SIGNOR-273993 0.8 ATR protein Q13535 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates phosphorylation Ser72 TLASQALsQCPAAAR 9606 15451423 t lperfetto When dna is damaged, the atr-atrip complex is recruited to chromatin and is activated to transduce the checkpoint signal, but the precise kinase activation mechanism remains unknown. Here, we show that atrip is phosphorylated in an atr-dependent manner after genotoxic stimuli. The serine 68 and 72 residues are important for the phosphorylation in vivo and are required exclusively for direct modification by atr in vitro. SIGNOR-129473 0.874 MLL/SET subcomplex complex SIGNOR-C87 SIGNOR MLL3 complex complex SIGNOR-C446 SIGNOR form complex binding 9606 34156443 t miannu MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. SIGNOR-268808 0.2 SERPINC1 protein P01008 UNIPROT F11 protein P03951 UNIPROT down-regulates activity cleavage 31030036 t lperfetto Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1 SIGNOR-264137 0.642 SIRT7 protein Q9NRC8 UNIPROT DDX21 protein Q9NR30 UNIPROT up-regulates activity deacetylation Lys137 PKKMKKEkEMNGETR 28790157 t lperfetto Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21. SIGNOR-275903 0.262 ZM447439 chemical CHEBI:91376 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207926 0.8 FZD5 protein Q13467 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 25902418 t areggio Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain. SIGNOR-258969 0.656 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1071 SFLQRYSsDPTGALT 9606 BTO:0000007 10347170 t llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  SIGNOR-250621 0.378 MAPK3 protein P27361 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 19153083 t gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation SIGNOR-183484 0.705 PGAM proteinfamily SIGNOR-PF78 SIGNOR 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI down-regulates quantity chemical modification 9606 24786789 t miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. SIGNOR-266513 0.8 dolichyl beta-D-mannosyl phosphate smallmolecule CHEBI:17624 ChEBI Protein_glycosylation phenotype SIGNOR-PH144 SIGNOR up-regulates 21384228 f lperfetto Dolichol has a well defined role as a lipid carrier for the glycan precursor in the early stages of N‐linked protein glycosylation, which is assembled in the endoplasmic reticulum of all eukaryotic cells. SIGNOR-262568 0.7 SPI1 protein P17947 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 9606 20861919 f irozzo In the myeloid compartment, Gfi1 is part of a regulatory network that determines lineage fate decision between granulocyte and monocyte/macrophage development. In this compartment, Gfi1 antagonizes the function of the transcription factor Pu.1. Pu.1 promotes monocytic differentiation, whereas Gfi1 enhances granulocytic differentiation. SIGNOR-256085 0.7 SLBP protein Q14493 UNIPROT H3-2 protein Q5TEC6 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265415 0.2 SCN5A protein Q14524 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. SIGNOR-253447 0.7 PLK3 protein Q9H4B4 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity phosphorylation Thr273 DAGALTTtFEELHFE 27325299 t lperfetto Furthermore, we identify caspase-8 as a new substrate for Plk3. Phosphorylation occurs on T273 and results in stimulation of caspase-8 proapoptotic function. SIGNOR-272995 0.345 PRKD2 protein Q9BZL6 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser275 DNVRYGIsNIDTTIE 34010649 t lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-275949 0.2 SMARCC1 protein Q92922 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269786 0.642 EEF1A2 protein Q05639 UNIPROT Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269523 0.8 AMPK complex SIGNOR-C15 SIGNOR RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation Ser792 LTQSAPAsPTNKGVH 10090 SIGNOR-C15 SIGNOR-C3 18439900 t lperfetto These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK SIGNOR-263044 0.501 HMOX1 protein P09601 UNIPROT STC2/HMOX1 complex SIGNOR-C244 SIGNOR form complex binding BTO:0000298 22503972 t Giorgia Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is a heat shock protein.|Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme. SIGNOR-260388 0.351 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193615 0.8 STAT6 protein P42226 UNIPROT KDM6B protein O15054 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19567879 f lperfetto We demonstrate that IL-4dependent Jmjd3 expression is mediated by STAT6, a major transcription factor of IL-4mediated signaling. After IL-4 stimulation, activated STAT6 is increased and binds to consensus sites at the Jmjd3 promoter. SIGNOR-249539 0.443 MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 BTO:0001939 15520018 t miannu Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways. SIGNOR-250113 0.552 MFGE8 protein Q08431 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 10116 31958465 t miannu Milk fat globule-EGF factor 8 (MFGE8), a protein known as lactadherin in humans, contains C domains interacting with extracellular matrices and epidermal growth factor–like domains with an RGD motif binding to integrins αvβ3 and αvβ5. SIGNOR-260644 0.505 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr325 TELEPLCtPVVTCTP phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-263011 0.784 MDGA2 protein Q7Z553 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26206665 f miannu Enhanced protein expression of p53 and p21 by MDGA2 was confirmed in MDGA2 overexpressed cells and xenograft tumours. SIGNOR-264242 0.2 mTORC1 complex SIGNOR-C3 SIGNOR NRBF2 protein Q96F24 UNIPROT up-regulates activity phosphorylation Ser120 SPLSQKYsPSTEKCL 9606 28059666 t miannu Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association. SIGNOR-265877 0.2 FOXO1 protein Q12778 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity binding 9606 BTO:0000007 25510553 t miannu FoxO1, which is up-regulated during early stages of diet-induced leptin resistance, directly interacts with STAT3 and prevents STAT3 from binding to specificity protein 1 (SP1)-pro-opiomelanocortin (POMC) promoter complex, and thereby inhibits STAT3-mediated regulation of POMC transcription. SIGNOR-263496 0.58 PKC proteinfamily SIGNOR-PF53 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates activity dephosphorylation Ser671 RKRSTRRsVRGSQAQ 9606 BTO:0000007 24333728 t Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp SIGNOR-272514 0.2 CDK1 protein P06493 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Ser382 DFIDAFAsPVEAEGT 9606 15125835 t lperfetto Here we show that, at the onset of mitosis, cdk1 phosphorylates the peripheral golgi protein nir2 at multiple sites;of these, s382 is the most prominent. Phosphorylation of nir2 by cdk1 facilitates its dissociation from the golgi apparatus, and phospho-nir2(ps382) is localized in the cleavage furrow and midbody during cytokinesis. SIGNOR-124638 0.477 UDP-D-galactose smallmolecule CHEBI:18307 ChEBI UDP(3-) smallmolecule CHEBI:58223 ChEBI up-regulates quantity precursor of 9606 16157350 t miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. SIGNOR-268473 0.8 FOXE1 protein O00358 UNIPROT MSX1 protein P28360 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 21177256 f miannu The MSX1 and TGF-β3 up-regulation in response to FOXE1 at both transcriptional and translational levels and the recruitment of FOXE1 to specific binding motifs, together with the transactivation of the promoters of these genes, indicate that MSX1 and TGF-β3 are direct FOXE1 targets. SIGNOR-254173 0.393 TCF4 protein P15884 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20459685 f miannu Cd2+ reduced the interaction of beta-catenin with AJ components (E-cadherin, alpha-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1) were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling. SIGNOR-255388 0.346 clobetasol chemical CHEBI:205919 ChEBI SMO protein Q99835 UNIPROT up-regulates activity chemical activation 9606 26658258 t Non-canonical SMO pathway SimoneGraziosi Two of the top ranking compounds, Halcinonide and Clobetasol, act as Smoothened (Smo) agonists to up-regulate myelin gene expression in the Oli-neuM cell line.  SIGNOR-269216 0.8 CSNK2A2 protein P19784 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser102 EEGISQEsSEEEQ -1 2806554 t llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. SIGNOR-251004 0.334 MEF2C protein Q06413 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0002320 21598020 t miannu GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter SIGNOR-265816 0.472 BBS4 protein Q96RK4 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 t lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome SIGNOR-262560 0.776 ESR2 protein Q92731 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 BTO:0001264 22169964 f miannu 17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice SIGNOR-253473 0.2 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser47 LGSALRPsTSRSLYA -1 2500966 t miannu Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure. SIGNOR-250070 0.313 KMN network complex SIGNOR-C366 SIGNOR Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 9606 18007590 f lperfetto Based on our results, we propose that the cooperative action of CENP-A NAC/CAD subunits and the KMN network drives efficient chromosome segregation and bipolar spindle assembly during mitosis. SIGNOR-265215 0.7 A9/b1 integrin complex SIGNOR-C166 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257708 0.562 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser312 TESITATsPASMVGG 9606 18728222 t gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. SIGNOR-180532 0.767 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 14711813 t lperfetto Mass spectrometric analysis revealed that ret tyr806, tyr809, tyr900, tyr905, tyr981, tyr1062, tyr1090, and tyr1096 were autophosphorylation sitesret short and middle isoforms contain 16 tyrosine residues in their intracellular domains, and ret long isoforms have two additional tyrosines in the c-terminal tail. Among these tyrosines, tyr905, tyr1015, tyr1062, and tyr1096 are thought to be phosphorylated to become binding sites for grb7/grb10, phospholipase c_, shc/snt(frs2)/enigma, and grb2, respectively. SIGNOR-121141 0.2 PRKAA1 protein Q13131 UNIPROT PRKAB1 protein Q9Y478 UNIPROT up-regulates phosphorylation Ser108 SKLPLTRsHNNFVAI 9606 SIGNOR-C15 SIGNOR-C15 17728241 t gcesareni Mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the beta1 subunit, almost completely abolishes activation of ampk by a-769662 in cells and in vitro, while only partially reducing activation by amp SIGNOR-157553 0.923 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 t gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. SIGNOR-40497 0.338 MK-2461 chemical CID:44137946 PUBCHEM MST1R protein Q04912 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194387 0.8 BTK protein Q06187 UNIPROT DAPP1 protein Q9UN19 UNIPROT up-regulates activity phosphorylation Tyr139 KVEEPSIyESVRVHT -1 11524430 t llicata We present a number of lines of evidence that in vivo, Src-type tyrosine kinases are responsible for the phosphorylation of tyrosine 139 in DAPP-1. | Although Btk appears to phosphorylate DAPP-1 relatively efficiently both in Sf9 cells and in vitro, we find no evidence that in either B cells or PAE cells Btk family kinases phosphorylate DAPP-1. SIGNOR-250602 0.658 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 19808903 t lperfetto We report a Notch signal-induced pathway that leads to transcriptional activation of HIF1-alpha gene. SIGNOR-209720 0.454 ERN1 protein O75460 UNIPROT JUN protein P05412 UNIPROT up-regulates 9606 BTO:0001976 18065414 f lperfetto The induction of MTHFR was also observed after overexpression of inositol-requiring enzyme-1 (IRE1) and was inhibited by a dominant-negative mutant of IRE1. Because IRE1 triggers c-Jun signaling, we examined the possible involvement of c-Jun in up-regulation of MTHFR. Transfection of c-Jun and two activators of c-Jun (LiCl and sodium valproate) increased MTHFR expression SIGNOR-253146 0.393 ADL-5859 chemical CID:46931003 PUBCHEM OPRD1 protein P41143 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-189278 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CALD1 protein Q05682 UNIPROT down-regulates phosphorylation 9606 BTO:0001260 10514499 t inferred from 70% family members lperfetto Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin. SIGNOR-270049 0.2 SOSTDC1 protein Q6X4U4 UNIPROT WNT16 protein Q9UBV4 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242718 0.268 CSNK2A1 protein P68400 UNIPROT CBX5 protein P45973 UNIPROT up-regulates phosphorylation Ser14 RTADSSSsEDEEEYV 9606 21245376 t gcesareni Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability. SIGNOR-171707 0.354 ARG1 protein P05089 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI up-regulates quantity chemical modification 9606 14617280 t miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-255545 0.8 RAD21 protein O60216 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 10090 20711430 f Rad21-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice SIGNOR-259975 0.7 LAMTOR1 protein Q6IAA8 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR form complex binding 9606 20381137 t lperfetto Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant SIGNOR-164769 0.923 CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 10090 BTO:0002572 10988287 t amattioni The temporal pattern of caspase-8 cleavage is consistent with the possibility that it may function upstream of caspase-3 during p53-dependent apoptosis. SIGNOR-81808 0.715 RAD23B protein P54727 UNIPROT RPA3 protein P35244 UNIPROT up-regulates activity binding 24086043 t lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275700 0.502 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[(3-methyl-4-oxo-6-quinazolinyl)amino]phenyl]benzamide chemical CHEBI:91354 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190146 0.8 NEDD4 protein P46934 UNIPROT AP1G2 protein O75843 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0001950 18772139 t miannu Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination. SIGNOR-272635 0.41 ADK protein P55263 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5‚Ä≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-267840 0.8 GFPT1 protein Q06210 UNIPROT Hexosamine_biosynthesis phenotype SIGNOR-PH194 SIGNOR up-regulates 9606 21310273 f miannu GFPT1 is the key enzyme of the hexosamine pathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation. SIGNOR-267819 0.7 MYOD1 protein P15172 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR up-regulates binding 9606 BTO:0001103 17194702 t lperfetto Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes SIGNOR-217737 0.341 MAPK1 protein P28482 UNIPROT PGR protein P06401 UNIPROT down-regulates phosphorylation Ser294 APMAPGRsPLATTVM 9606 BTO:0000150 10655479 t miannu Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26s proteasome SIGNOR-74712 0.588 SRF protein P11831 UNIPROT SERPINE1 protein P05121 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000161 15514113 f miannu We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1. SIGNOR-255228 0.267 CASP1 protein P29466 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates activity binding 9606 BTO:0000007 20197547 t Our data so far indicated colocalization of SphK2 with caspase-1 at the plasma membrane after induction of apoptosis.These observations supported caspase-1–dependent cleavage of SphK2 at its N-terminus as a prerequisite for its release. SIGNOR-268831 0.251 GTP smallmolecule CHEBI:15996 ChEBI GNAS protein Q5JWF2 UNIPROT up-regulates chemical activation 9606 17095603 t gcesareni Galfa subunits cycle between inactive (gdp-bound) and active (gtp-bound) states, and the lifetime of the active state is limited by gtp hydrolysis. SIGNOR-253071 0.8 MTOR protein P42345 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser299 SSPTLSSsPPVLCNP 9606 22017875 t llicata Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome. SIGNOR-176853 0.746 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 t lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. SIGNOR-109613 0.866 EP300 protein Q09472 UNIPROT KPNA2 protein P52292 UNIPROT up-regulates acetylation Lys22 HRFKNKGkDSTEMRR 9606 15342649 t lperfetto Ampk triggered the acetylation of importin alpha1 on lys(22), a process dependent on the acetylase activity of p300 SIGNOR-128625 0.364 MMP14 protein P50281 UNIPROT FGG protein P02679 UNIPROT down-regulates quantity by destabilization cleavage Tyr27 LSSTCVAyVATRDNC -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain SIGNOR-263616 0.2 ERBB2 protein P04626 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 12049736 t lperfetto Phosphorylation on tyrosine-15 of p34(cdc2) by erbb2 inhibits p34(cdc2) activation and is involved in resistance to taxol-induced apoptosis SIGNOR-88671 0.277 TNFRSF1B protein P20333 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates 9606 8069916 f gcesareni Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2. SIGNOR-33843 0.709 RIPK1 protein Q13546 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity phosphorylation Ser161 IADLGLAsFKMWSKL -1 18408713 t miannu These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1) SIGNOR-276158 0.2 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR LARP7 protein Q4G0J3 UNIPROT down-regulates quantity by destabilization ubiquitination 32726637 t lperfetto Here, we demonstrate that upon genotoxic stress, BRCA1 together with BARD1 catalyzes the K48 polyubiquitination on LARP7, a 7SK RNA binding protein known to control RNAPII pausing, and thereby degrades it through the 26S ubiquitin-proteasome pathway. SIGNOR-275581 0.2 PTGS2 protein P35354 UNIPROT prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI up-regulates chemical modification 9606 11751058 t gcesareni Cox catalyzes two enzymatic activities;namely, the conversion of aa to the hydroperoxy endoperoxide pgg2, followed by its subsequent reduction to the labile product pgh2. Pgh2_ is the common substrate for a number of different cell-specific synthases, which convert pgh2_ to the individual pgs or tx, including pge2, pgi2_ (prostacyclin), pgd2, pgf2alfa, and txa2. SIGNOR-113291 0.8 OPTN protein Q96CV9 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 BTO:0000007 20174559 t lperfetto Using biochemical experiments we showed that optineurin interacts with the protein kinase TBK1 and the ubiquitin ligase TRAF3. Furthermore, a mutation in optineurin that prevents the interaction with the small protein modifier ubiquitin (D474N) ablated the negative regulatory function of optineurin. SIGNOR-262276 0.785 SMAD7 protein O15105 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity binding 9534 BTO:0001538 11163210 t miannu Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.  SIGNOR-272937 0.865 quinpirole chemical CHEBI:75401 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation -1 7576010 t miannu D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole. SIGNOR-258441 0.8 MAPK1 protein P28482 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser295 PARPRSPsQTRKGPP 9606 BTO:0000142 15262992 t lperfetto Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2. SIGNOR-126863 0.268 DNMT3B protein Q9UBC3 UNIPROT BAG4 protein O95429 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 18413740 f lperfetto In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+) SIGNOR-254113 0.2 GRM7 protein Q14831 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264350 0.7 NRAS protein P01111 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. It was also described that ras interacts with pi3k in a direct manner.llysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-175228 0.71 GSK3B protein P49841 UNIPROT PDX1 protein P52945 UNIPROT down-regulates quantity phosphorylation Ser66 QGSPPDIsPYEVPPL 10090 BTO:0000783;BTO:0002284 16407209 t Here we show that a minor portion of IPF1/PDX1 is phosphorylated on serine 61 and/or serine 66 in pancreatic beta-cells. This phosphorylated form of IPF1/PDX1 preferentially accumulates following proteasome inhibition, an effect that is prevented by inhibition of glycogen synthase kinase 3 (GSK3) activity. SIGNOR-255544 0.2 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser177 ASSGSSAsFISDTFS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248369 0.598 DGC complex SIGNOR-C217 SIGNOR NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9606 BTO:0000142 11470830 t miannu In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan. SIGNOR-265446 0.351 C5 convertase complex complex SIGNOR-C312 SIGNOR C5 protein P01031 UNIPROT up-regulates activity cleavage Arg751 HKDMQLGrLHMKTLL 31331124 t lperfetto Association of C3b with C3 convertases (C3bBb or C4b2a) results in formation of C5 convertases, C3bBbC3b and C4b2aC3b, which initiate the lytic pathway by cleavage of C5 to C5a and C5b SIGNOR-263453 0.539 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Ser502 YFLQRRPsMKTLFVD 9606 BTO:0000007 11884385 t lperfetto Direct phosphorylation of capsaicin receptor VR1 by protein kinase Cepsilon and identification of two target serine residues. | Patch clamp analysis of the point mutants where Ser or Thr residues were replaced with Ala in the total 16 putative phosphorylation sites showed that two Ser residues, Ser(502) and Ser(800) were involved in the potentiation of the capsaicin-evoked currents by either PMA or ATP. SIGNOR-249141 0.2 BTF3 protein P20290 UNIPROT RRAS2 protein P62070 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17312387 f miannu BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. SIGNOR-253766 0.261 ATF2 protein P15336 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16149046 f miannu Constitutively active mutants of activating transcription factor 2 (ATF2) and c-Jun additionally stimulated GTP cyclohydrolase I promoter activity, but to a lesser extent than the constitutively active CREB mutant. Enzymatic reactions that require tetrahydrobiopterin as cofactor are therefore indirectly controlled by signaling cascades involving the signal-responsive transcription factors CREB, c-Jun, and ATF2. SIGNOR-252226 0.2 adenosine smallmolecule CHEBI:16335 ChEBI ADORA2A protein P29274 UNIPROT up-regulates activity binding -1 14662005 t Luana Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A1, A2A, A2B and A3. SIGNOR-268420 0.8 ACLY protein P53396 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI down-regulates quantity by destabilization chemical modification 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-268081 0.8 C3AR1 protein Q16581 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 BTO:0001669 9108406 f lperfetto  In summary, these findings indicate that C3a and C5a serve as chemotaxins for human mast cells. Anaphylatoxin-mediated recruitment of mast cells might play an important role in hypersensitivity and inflammatory processes. SIGNOR-263472 0.7 caffeine chemical CHEBI:27732 ChEBI PDE2A protein O00408 UNIPROT down-regulates activity chemical inhibition 36476859 t lperfetto We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice.  SIGNOR-275729 0.8 BRAF protein P15056 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29731393 f miannu Oncogenic proteins that regulate proliferation, such as KRAS, BRAF, and MYC increase the transcription of NRF2 SIGNOR-267362 0.2 NUMB protein P49757 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 12682059 t lperfetto Mammalian numb proteins promote notch1 receptor ubiquitination and degradation of the notch1 intracellular domain SIGNOR-99762 0.79 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR IKZF1 protein Q13422 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0003933 24292625 t miannu We found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. SIGNOR-272083 0.379 ERGIC1 protein Q969X5 UNIPROT ERGIC3 protein Q9Y282 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000599 15308636 t Giorgia Among novel cycling proteins we have characterized ERGIC-32, a new ERGIC protein that interacts with human Erv46, a protein previously characterized in yeast and functioning in ER to Golgi protein trafficking. ERGIC-32 interacts with human Erv46 (hErv46) as revealed by covalent cross-linking and mistargeting experiments, and silencing of ERGIC-32 by small interfering RNAs increases the turnover of hErv46. We propose that ERGIC-32 functions as a modulator of the hErv41-hErv46 complex by stabilizing hErv46. SIGNOR-260637 0.381 SMAD3 protein P84022 UNIPROT PAX6 protein P26367 UNIPROT down-regulates activity binding 9606 BTO:0001874 17251190 t Regulation miannu The paired domain of Pax6 interacts with the MH1 domain of Smad3. Smad3 prevents Pax6 paired domain from binding DNA SIGNOR-251875 0.408 PTPRG protein P23470 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr716 RPPSAELySNALPVG -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254715 0.344 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH17 protein Q12864 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265834 0.8 AT-406 chemical CID:25022340 PUBCHEM BIRC3 protein Q13489 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189957 0.8 AGTR1 protein P30556 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257017 0.628 PINK1 protein Q9BXM7 UNIPROT MFN2 protein O95140 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000793 20871098 f Barakat Ubiquitination of MFN-1 or MFN-2 was induced in untransfected cells and cells transfected with control siRNA. However, ubiquitination of MFN-1 and MFN-2 was significantly reduced when treated with either PINK1 siRNA combination. These results suggest that PINK1 is required for the ubiquitination of MFN-1 and MFN-2. SIGNOR-274136 0.803 POU5F1 protein Q01860 UNIPROT SOX2 protein P48431 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254942 0.834 FGF12 protein P61328 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253412 0.322 AKT1 protein P31749 UNIPROT CDKN1C protein P49918 UNIPROT down-regulates phosphorylation Ser282 FFAKRKRsAPEKSSG 9606 BTO:0000150 23421998 t lperfetto Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination SIGNOR-252535 0.459 RAB6A protein P20340 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 25492866 f miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons SIGNOR-266873 0.7 MAL protein P21145 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 15337780 f SimoneGraziosi Our results demonstrate a critical role for MAL in the maintenance of central nervous system paranodes SIGNOR-269228 0.7 LATS1 protein O95835 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Ser397 TYHSRDEsTDSGLSM 9606 BTO:0000007 20048001 t lperfetto We show that YAP is phosphorylated by Lats on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1delta/epsilon to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits beta-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition SIGNOR-218034 0.834 romidepsin chemical CHEBI:61080 ChEBI HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257989 0.8 EEF1A1P5 protein Q5VTE0 UNIPROT Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269559 0.8 AKT1 protein P31749 UNIPROT HTT protein P42858 UNIPROT unknown phosphorylation Ser419 GGRSRSGsIVELIAG 9606 BTO:0000938 12062094 t llicata We demonstrate that huntingtin is a substrate of akt and that phosphorylation of huntingtin by akt is crucial to mediate the neuroprotective effects of igf-1. SIGNOR-252590 0.568 CASP6 protein P55212 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates cleavage 9606 11455969 t gcesareni This pathway can either be ampli?ed By caspase- 8-mediated cleavage of bid and by the downstream, caspase-6- mediated cleavage of caspase-8. SIGNOR-109411 0.724 YWHAE protein P62258 UNIPROT GRIN2C protein Q14957 UNIPROT up-regulates quantity by stabilization binding 10090 19477150 t miannu Here, we demonstrate that PKB/Akt directly phosphorylates NR2C on serine 1096 (S1096). In addition, we identify 14-3-3epsilon as an NR2C interactor, whose binding is dependent on S1096 phosphorylation. These data are all consistent with a model in which NR1 and NR2C oligomerize, PKB phosphorylates S1096, and 14-3-3ε binds to phosphorylated NR2C thereby promoting NR2C-containing NMDA receptor surface expression in cerebellar granule cells. SIGNOR-262622 0.323 SIX1 protein Q15475 UNIPROT Six1/Dach complex SIGNOR-C122 SIGNOR form complex binding 10090 14628042 t llicata The phosphatase function of Eya switches the function of Six1-Dach from repression to activation, SIGNOR-238029 0.614 RXRB protein P28702 UNIPROT NR4A2 protein P43354 UNIPROT up-regulates binding 9606 BTO:0000938 9636132 t lperfetto The recent discovery that the nuclear transcription factor, nurr1, in heterodimeric tandem with rxr, is unequivocally necessary for the expression of dopaminergic neurons SIGNOR-58309 0.427 MAPK1 protein P28482 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity toward a substrate, eukaryotic initiation factor-4e (eif-4e). SIGNOR-48298 0.577 alvimopan chemical CHEBI:135686 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition -1 18313920 t Luana A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, l opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective l opioid receptor antagonist, which interacts selectively with l peripheral receptors. SIGNOR-257772 0.8 PRKACA protein P17612 UNIPROT RAP1A protein P62834 UNIPROT down-regulates activity phosphorylation Ser180 KKKPKKKsCLLL 9534 9867809 t miannu Phosphorylation of Rap1A by PKA abolished its binding activity to CRR. a mutant Rap1A(S180E), whose sole PKA phosphorylation residue, Ser-180, was substituted by an acidic residue, Glu, to mimic its phosphorylated form, failed to suppress Ras-dependent Raf-1 activation in COS-7 cells. SIGNOR-250042 0.504 TGM2 protein P21980 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 9606 16407273 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Tg2 is able to phosphorylate purified histone proteins, and h3 and h1 in chromatin preparations, and it is associated with chromatin in breast cancer cells. SIGNOR-143642 0.2 JAG2 protein Q9Y219 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 11006133 t gcesareni These results suggest that delta1, jagged1, and jagged2 are ligands for notch1 and notch3 receptors. SIGNOR-82401 0.609 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 BTO:0000782 12151396 t gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk SIGNOR-91063 0.359 UBE3A protein Q05086 UNIPROT RAD23A protein P54725 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 10373495 t miannu  Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP.  E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B. SIGNOR-272550 0.499 DIABLO protein Q9NR28 UNIPROT XIAP protein P98170 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000567 11583623 t Smac/DIABLO released from mitochondria amattioni Smac/diablo, an inhibitor of xiap, is released from mitochondria upon receiving apoptotic stimuli and binds to the bir2 and bir3 domains of xiap, thereby inhibiting its caspase-inhibitory activity SIGNOR-110831 0.912 CCL21 protein O00585 UNIPROT CCR7 protein P32248 UNIPROT up-regulates binding 9606 BTO:0000671 11970971 t gcesareni The regulated expression of the chemokine secondary lymphoid tissue chemokine (slc/ccl21) and its corresponding receptor, ccr7. SIGNOR-117566 0.778 PTPN1 protein P18031 UNIPROT NTRK2 protein Q16620 UNIPROT down-regulates activity dephosphorylation Tyr706 RDVYSTDyYRVGGHT 9606 BTO:0000793 26214522 t Luana Collectively, these data establish a direct enzyme-substrate interaction between PTP1B and phosphorylated Y705/706 (p-Y705/706) TRKB, the critical autophosphorylation sites that mediate BDNF-induced signaling.| Therefore, the data are consistent with a role of PTP1B as an inhibitor of BDNF/TRKB signaling SIGNOR-264554 0.388 BDNF protein P23560 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000142 32603820 f miannu BDNF is a central driver of synaptic plasticity and memory formation and its decreased levels may contribute to the degeneration of specific neuronal populations and progressive atrophy of neurons in the AD-affected brain SIGNOR-265063 0.7 TP53 protein P04637 UNIPROT TNFRSF10B protein O14763 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14585074 f Nuclear p53 amattioni Cd95l, cd95, and the trail death receptors are induced by the tumour suppressor p53 SIGNOR-113707 0.634 YWHAQ protein P27348 UNIPROT CDC25C protein P30307 UNIPROT down-regulates relocalization 9606 20068082 t gcesareni Cdc25c: nuclear exclusion/cytoplasmic sequestration via binding to 14-3-3 proteins. SIGNOR-163237 0.556 MMP3 protein P08254 UNIPROT DCN protein P07585 UNIPROT down-regulates quantity by destabilization cleavage Ser240 ISRVDAAsLKGLNNL -1 9148753 t miannu Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues. SIGNOR-256353 0.659 STAT1 protein P42224 UNIPROT TBX21 protein Q9UL17 UNIPROT up-regulates 9606 16386358 f T-bet is a transcription factor detected in Th1, but not in Th0 or Th2 cells. Its expression is up-regulated by IFN-gamma, through a STAT-1-dependent mechanism SIGNOR-254293 0.504 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser213 QNIPAHYsPRTSPIM 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252329 0.635 CRH protein P06850 UNIPROT CRHR1 protein P34998 UNIPROT up-regulates binding 9606 11416224 t gcesareni Crf and ucn bind and activate crf-r1 with similarly high affinities. SIGNOR-108713 0.957 CDK9 protein P50750 UNIPROT NCOA2 protein Q15596 UNIPROT up-regulates activity phosphorylation Ser499 MSPGVAGsPRIPPSQ 9606 BTO:0000801 29170386 t Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties. SIGNOR-256099 0.248 NKX3-1 protein Q99801 UNIPROT HDAC1 protein Q13547 UNIPROT down-regulates activity binding 9606 16697957 t miannu NKX3.1 also binds HDAC1 and releases p53 from p53-MDM2-HDAC1 complex, promoting p53 acetylation and activity. SIGNOR-251549 0.377 MAPK3 protein P27361 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 20068231 t gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. SIGNOR-163258 0.728 WNK1 protein Q9H4A3 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates activity phosphorylation Ser382 LKRASFAkSVIGTPE 9606 12374799 t Manara Activation of WNKs requires autophosphorylation of at least one serine residue, serine 382 in WNK1, within the WNK activation loop. SIGNOR-260826 0.2 EP300 protein Q09472 UNIPROT RELA protein Q04206 UNIPROT up-regulates acetylation 9606 SIGNOR-C6 16382138 t gcesareni Rela is also acetylated at several sites by p300 and cbp SIGNOR-143399 0.815 ANK3 protein Q12955 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates quantity relocalization 10090 BTO:0001103 19109891 t miannu We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4. SIGNOR-266714 0.262 COL18A1 protein P39060 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates binding 9606 12682293 t gcesareni The activity of human endostatin is mediated by alpha 5 beta 1 integrin. SIGNOR-99871 0.538 PTK6 protein Q13882 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr326 EVLEDNDyGRAVDWW 9606 BTO:0000150 BTO:0001129 20606012 t gcesareni Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6. SIGNOR-252622 0.454 BRCA1 protein P38398 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001130 22832221 f gcesareni Brca1/e2f1/ctipbinding to atm promoter activates atm transcription. SIGNOR-198467 0.813 PRKCA protein P17252 UNIPROT GRIA1 protein P42261 UNIPROT unknown phosphorylation Ser832 LIEFCYKsRSESKRM 9606 8663994 t lperfetto In addition, protein kinase C specifically phosphorylates Ser-831 of GluR1 in HEK-293 cells and in cultured neurons. SIGNOR-248950 0.704 SOSTDC1 protein Q6X4U4 UNIPROT WNT2 protein P09544 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242724 0.308 ERC1 protein Q8IUD2 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates binding 9606 15218148 t lperfetto Elks likely functions by recruiting ikappabalpha to the ikk complex and thus serves a regulatory function for ikk activation. SIGNOR-217448 0.595 SIRT7 protein Q9NRC8 UNIPROT TP53 protein P04637 UNIPROT down-regulates deacetylation 9606 18239138 t gcesareni We found that sirt7 interacts with p53 and efficiently deacetylates p53 in vitro, which corresponds to hyperacetylation of p53 in vivo. SIGNOR-160539 0.513 NR4A1 protein P22736 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15591535 f gcesareni Our data suggest a mechanism for transrepression between two nuclear receptors, gr and ngfi-b. SIGNOR-132312 0.329 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Thr21 YGGAGGYtQSPGGFG -1 9139719 t lperfetto In this study, we show that efficient phosphorylation of HSSB-p34 by DNA-PK requires Ku as well as DNA. The DNA-PK phosphorylation sites in HSSB-p34 have been mapped at Thr-21 and Ser-33. Kinetic studies demonstrated that a phosphate residue is first incorporated at Thr-21 followed by the incorporation of a second phosphate residue at Ser-33. SIGNOR-248972 0.597 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser288 DATEKDAsKKSDSNP 9534 BTO:0001538 23519612 t miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. SIGNOR-262709 0.323 CBX1 protein P83916 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-264492 0.2 PTPRJ protein Q12913 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates dephosphorylation 9606 18348712 t gcesareni As reduction of pi3k activity by cd148 or shp-1 [32] is not large (2540%), it is likely that these ptps may function as modulators of the pi3k pathway rather than suppressors. SIGNOR-252727 0.264 PRKCG protein P05129 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 t lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation SIGNOR-249249 0.297 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr498 KTPPAPKtPPSSGEP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251597 0.695 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249327 0.754 ASF1A protein Q9Y294 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates activity binding 9606 BTO:0002181 33503415 t miannu Chk1 activated by ataxia telangiectasia mutated (ATM) kinase on DNA breaks in G1 promotes NHEJ through direct phosphorylation of ASF1A at Ser-166. ASF1A phosphorylated at Ser-166 interacts with the repair protein MDC1 and thus enhances MDC1's interaction with ATM and the stable localization of ATM at DNA breaks. SIGNOR-277621 0.316 MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000887 8288123 f lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enancers. SIGNOR-37461 0.7 PKNOX1 protein P55347 UNIPROT HOXA1 protein P49639 UNIPROT up-regulates activity binding 9606 BTO:0000007 9582372 t miannu Our results are consistent with a primary interaction of the YPWM motif of HOXA1 with the homeodomain of PBX. HOX proteins are dependent upon cofactors of the PBX family for specificity of DNA binding. SIGNOR-220242 0.571 KMT5B protein Q4FZB7 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity methylation Lys21 GGAKRHRkVLRDNIQ -1 24396869 t miannu SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation. SIGNOR-266651 0.2 ETS1 protein P14921 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20392592 f miannu High ETS1 expression levels in all resistant MCF-7 sublines may lead to the upregulation of the transcription of MDR1 gene. SIGNOR-254077 0.2 TRAF2 protein Q12933 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 18635759 t gcesareni Traf2, ubc13, and ikkgamma were required for complex assembly and activation of mekk1 and mapk cascades. SIGNOR-179476 0.706 pazopanib hydrochloride chemical CHEBI:71217 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-201037 0.8 sunitinib chemical CHEBI:38940 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition 9606 20570526 t Luana Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors], SIGNOR-257851 0.8 MYC protein P01106 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29731393 f miannu Oncogenic proteins that regulate proliferation, such as KRAS, BRAF, and MYC increase the transcription of NRF2 SIGNOR-267363 0.534 MECP2 protein P51608 UNIPROT TFF1 protein P04155 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 15870696 f miannu Valproate (VPA) induces silencing of the ERalpha, cyclin D1 and pS2 promoters. Chromatin immunoprecipitation (ChIP) analysis demonstrates that VPA induces recruitment of the 5-MeCpG binding protein MeCP2 to the ERalpha A promoter and also to the pS2 and cyclin D1 promoters SIGNOR-254572 0.2 BAG1 protein Q99933 UNIPROT STUB1 protein Q9UNE7 UNIPROT up-regulates activity binding 9534 BTO:0001538 11676916 t miannu BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association SIGNOR-272587 0.555 PIGS protein Q96S52 UNIPROT GPAA1 protein O43292 UNIPROT up-regulates activity binding 10090 11483512 t miannu To determine roles for PIG-S and PIG-T, we disrupted these genes in mouse F9 cells by homologous recombination. PIG-S and PIG-T knockout cells were defective in transfer of GPI to proteins, particularly in formation of the carbonyl intermediates. We also demonstrate that PIG-S and PIG-T form a protein complex with GAA1 and GPI8, and that PIG-T maintains the complex by stabilizing the expression of GAA1 and GPI8. SIGNOR-261361 0.892 DYRK1A protein Q13627 UNIPROT SF3B1 protein O75533 UNIPROT unknown phosphorylation Thr434 PARKLTAtPTPLGGM 9606 BTO:0000007 16512921 t llicata The present data show that the splicing factor sf3b1 is a substrate of the protein kinase dyrk1a and suggest that dyrk1a may be involved in the regulation of pre mrna-splicing. by mass spectrometry and mutational analysis of sf3b1, thr434 was identified as the major phosphorylation site for dyrk1a. SIGNOR-144975 0.514 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation 9606 29920310 t lperfetto It has been reported that the protein tyrosine phosphatase PTP1B could inactivate MET by direct dephosphorylation of Tyr 1234 and 1235 in its activation loop, and that this dephosphorylation takes place in peri-nuclear region of the cell [ xref ]. SIGNOR-277001 0.622 NFIX protein Q14938 UNIPROT GAS6 protein Q14393 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268888 0.205 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 11901158 t lperfetto Thus, activation of chk2 in irradiated cells may occur through oligomerization of chk2 via binding of the thr-68-phosphorylated region of one chk2 to the fha domain of another. Oligomerization of chk2 may therefore increase the efficiency of trans-autophosphorylation resulting in the release of active chk2 monomers that proceed to enforce checkpoint control in irradiated cells. SIGNOR-116135 0.2 TNF protein P01375 UNIPROT BMP4 protein P12644 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000018 17350185 f Luana TNF-alpha represses the activity of a human Bmp4 promoter-luciferase construct, transfected into A549 and H441 cells. SIGNOR-266085 0.32 LCK protein P06239 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr323 DEPVADPyDQSFESR 10090 BTO:0000782 15735648 t miannu Lck, Fyn, and Zap70 activate p38 even in the absence of Tyr182 phosphorylation.p38 is a substrate for Fyn, Lck and Zap70.Thus, T cell Src family kinases and Zap70 activate p38 by phosphorylating Tyr323. SIGNOR-276029 0.452 CNTN6 protein Q9UQ52 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 BTO:0000938 15082708 t gcesareni Here, we establish that nb-3, a member of the f3/contactin family, acts as a novel notch ligand to participate in oligodendrocyte generation. Nb-3 triggers nuclear translocation of the notch intracellular domain and promotes oligodendrogliogenesis from progenitor cells and differentiation of oligodendrocyte precursor cells via deltex1. SIGNOR-254318 0.571 3-phenanthryl hydrogen sulfate chemical CHEBI:37459 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition -1 7576010 t miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. SIGNOR-258439 0.8 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227905 0.891 IKZF1 protein Q13422 UNIPROT LNPEP protein Q9UIQ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003420 15894523 f miannu Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. SIGNOR-255403 0.279 PYCARD protein Q9ULZ3 UNIPROT NLRC4 inflammasome complex SIGNOR-C223 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256405 0.65 NRP2 protein O60462 UNIPROT VEGFC protein P49767 UNIPROT up-regulates binding 9606 BTO:0000938 16816121 t gcesareni By in vitro binding studies we found that both vegf-c and vegf-d interact with np2, vegf-c in a heparin-independent and vegf-d in a heparin-dependent manner. SIGNOR-147530 0.738 CSNK1A1 protein P48729 UNIPROT RAPGEF2 protein Q9Y4G8 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1248 AADSGRGsWTSCSSG 9606 BTO:0002181 24290981 t miannu Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-β and casein kinase-1α and consequently degraded by the proteasome via the SCF(βTrCP) ubiquitin ligase. SIGNOR-276604 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244743 0.2 N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-268067 0.8 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity cleavage 9606 25610395 t lperfetto The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins. SIGNOR-254328 0.665 MAP4K4 protein O95819 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates activity phosphorylation Thr738 EEEPRGGtVSPPPGT 9606 BTO:0000007 34511598 t miannu The MAP4K4 and MLK3 associates with each other, and MAP4K4 phosphorylates MLK3 on Thr738 and increases MLK3 kinase activity and downstream signaling. SIGNOR-277571 0.309 HOPX protein Q9BPY8 UNIPROT FLG protein P20930 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 21256618 f miannu In the present study, we performed transcriptional profiling of cultured primary human keratinocytes and noted a robust induction of HOP upon calcium-induced cell differentiation. Overexpression of HOP using a lentiviral vector up-regulated FLG and LOR expression during keratinocyte differentiation. SIGNOR-254463 0.2 PRDM1 protein O75626 UNIPROT PAX5 protein Q02548 UNIPROT down-regulates quantity transcriptional regulation 10090 12052884 t Gianni Blimp-1 binds a site on the Pax-5 promoter in vitro and in vivo and represses the Pax-5 promoter in a binding-site-dependent manner. SIGNOR-269089 0.516 RPS18 protein P62269 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262433 0.882 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21440011 t lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252348 0.2 PRPF19 protein Q9UMS4 UNIPROT PRPF3 protein O43395 UNIPROT up-regulates activity polyubiquitination 9606 20595234 t k63 miannu Here, we report that the spliceosomal Prp19 complex modifies Prp3, a component of the U4 snRNP, with nonproteolytic K63-linked ubiquitin chains. The K63-linked chains increase the affinity of Prp3 for the U5 snRNP component Prp8, thereby allowing for the stabilization of the U4/U6.U5 snRNP.  SIGNOR-271966 0.744 CSNK1A1 protein P48729 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 16611981 t gcesareni Gli2 can also be phosphorylated directly by ck-1 at the non-optimal sites SIGNOR-146112 0.55 GATA1 protein P15976 UNIPROT CBFB protein Q13951 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004475 19825991 f miannu Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein alpha (Cebpa) and core-binding factor, beta subunit (Cbfb), which encode two key hematopoietic transcription factors. SIGNOR-254190 0.491 ADAM10 protein O14672 UNIPROT CD44 protein P16070 UNIPROT up-regulates activity cleavage 9606 26284334 t miannu The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin. SIGNOR-259847 0.353 PELI3 protein Q8N2H9 UNIPROT ELK1 protein P19419 UNIPROT up-regulates 9606 12874243 f gcesareni Pellino3 leads to activation of c-jun and elk-1, but not nf-kappab. SIGNOR-103986 0.2 RPL34 protein P49207 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262467 0.832 TLX1 protein P31314 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates activity binding 9606 BTO:0000661 15897879 t 2 miannu HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade. SIGNOR-240719 0.313 GSK690693 chemical CHEBI:90677 ChEBI AKT1 protein P31749 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252462 0.8 MUC12 protein Q9UKN1 UNIPROT JUN protein P05412 UNIPROT up-regulates activity binding 9606 BTO:0000037 32596961 t miannu MUC12 promoted the recruitment of c-Jun on the promoter of TGF-β1, leading to its transcription. SIGNOR-265474 0.259 HECW2 protein Q9P2P5 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity binding 9606 BTO:0000093 27119228 t miannu NEDL2 acts as a scaffold protein to promote GDNF-stimulated Akt activation. biochemical analysis indicated that NEDL2 appears to act like a scaffold protein to recruit SHC, Grb2, PI3K (p110 and p85), PDK1 and Akt together to promote the signaling transduction. NEDL2 binds p85, p110 and Akt with different domains SIGNOR-269459 0.2 HIF3A protein Q9Y2N7 UNIPROT EPAS1 protein Q99814 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000972 21479871 t Luana None of the long HIF-3α variants was capable of efficient induction of an HRE reporter in overexpression experiments, but instead inhibited the transcriptional activation of the reporter by HIF-1 and HIF-2.  SIGNOR-261616 0.509 TIMM29 protein Q9BSF4 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 t lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). SIGNOR-267707 0.2 PGR protein P06401 UNIPROT ESR1 protein P03372 UNIPROT up-regulates binding 9606 BTO:0000150 12612073 t gcesareni Here we identify two domains of prb, erid-i and -ii, mediating a direct interaction with the ligand-binding domain of eralpha. SIGNOR-98807 0.608 NR0B2 protein Q15466 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 17909097 f inferred from family member gcesareni As shown in fig. 3a, metformin (0.5 to 2 mmol/l) induced shp gene expression and repressed the camp/dex-induced expression of pepck and g6pase in a dose-dependent manner in h4iie cells SIGNOR-267791 0.2 ETS1 protein P14921 UNIPROT ECE1 protein P42892 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000396 9595399 f miannu Endothelial expression of endothelin-converting enzyme-1 beta mRNA is regulated by the transcription factor Ets-1. We conclude that Ets-1 is involved in transcriptional upregulation of ECE-1 beta mRNA in E.A. hy 926 cells induced by phorbol ester. SIGNOR-254080 0.265 TIMP1 protein P01033 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 SIGNOR-252272 0.7 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-217141 0.753 ADX-47273 chemical CID:11383075 PUBCHEM MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates chemical activation 9606 Other t Selleck|inferred from family member gcesareni SIGNOR-270276 0.8 PRKACA protein P17612 UNIPROT TENT2 protein Q6PIY7 UNIPROT down-regulates activity phosphorylation Ser116 LSGERRYsMPPLFHT 9606 31057087 t miannu We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. SIGNOR-259402 0.2 Caspase 3 complex complex SIGNOR-C221 SIGNOR DFFA protein O00273 UNIPROT up-regulates activity cleavage 9606 9108473 t lperfetto DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3. SIGNOR-256464 0.746 BDP1 protein A6H8Y1 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR form complex binding 29378333 t lperfetto Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1). SIGNOR-266189 0.879 ANKRD11 protein Q6UB99 UNIPROT RAB13 protein P51153 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 29274743 t miannu Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.  SIGNOR-266738 0.2 ILK protein Q13418 UNIPROT NACA protein Q13765 UNIPROT up-regulates phosphorylation Ser43 PELEEQDsTQATTQQ 9606 15299025 t lperfetto Ilk phosphorylated alpha-nac on residue ser-43. Ilk-dependent phosphorylation of alpha-nac induced the nuclear accumulation of the coactivator and that phosphorylation of alpha-nac by ilk is required for the potentiation of c-jun-mediated responses by the kinase. SIGNOR-127694 0.402 MTOR protein P42345 UNIPROT DAP protein P51397 UNIPROT down-regulates activity phosphorylation Ser51 DQEWESPsPPKPTVF 9606 20537536 t miannu A critical step in autophagy induction comprises the inactivation of a key negative regulator of the process, the Ser/Thr kinase mammalian target of rapamycin (mTOR). Here we identify death-associated protein 1 (DAP1) as a novel substrate of mTOR that negatively regulates autophagy. Mapping of the phosphorylation sites and analysis of phosphorylation mutants indicated that DAP1 is functionally silenced in growing cells through mTOR-dependent phosphorylations on Ser3 and Ser51. SIGNOR-259812 0.404 GRK5 protein P34947 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. SIGNOR-251208 0.467 WNT6 protein Q9Y6F9 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131894 0.575 AURKC protein Q9UQB9 UNIPROT TACC1 protein O75410 UNIPROT up-regulates activity phosphorylation Ser228 ELVPSRRsKLRKPKP -1 21531210 t miannu Aurora-C interacts with and phosphorylates the transforming acidic coiled-coil 1 protein. The results demonstrated that TACC1 is phosphorylated by Aurora-C on a serine at position 228. although the patho-physiological meaning of TACC1 phosphorylation by Aurora-C in normal and in malignant somatic cells remains to be fully investigated, our observations suggest that Aurora-C has a role in the later stage of mitosis, when an interaction with TACC1 may be relevant for the correct progression of the cell cycle. SIGNOR-262663 0.408 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 23431053 t milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity SIGNOR-201294 0.81 GATA3 protein P23771 UNIPROT GLS2 protein Q9UI32 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 31577957 t Luana Thus, GATA3 contributes to the elevated expression of GLS2 in luminal-subtype breast cancers. SIGNOR-268034 0.338 EGR1 protein P18146 UNIPROT COL11A1 protein P12107 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21931594 f Regulation miannu Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1) SIGNOR-251919 0.2 PTPN14 protein Q15678 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation 9534 35259601 t miannu Moreover, dephosphorylation of STAT3 by PTPN14 might occur in the cytoplasm but not in nucleus.|The tyrosine phosphatase PTPN14 inhibits the activation of STAT3 in PEDV infected Vero cells. SIGNOR-277088 0.275 OXGR1 protein Q96P68 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256913 0.2 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT down-regulates phosphorylation Thr3950 GHAFGSAtQFLPVPE 9606 17189255 t gcesareni Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, we have reported here that atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster. SIGNOR-151453 0.2 AKT1 protein P31749 UNIPROT YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 t lperfetto Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102 SIGNOR-252521 0.575 Degranulation phenotype SIGNOR-PH92 SIGNOR IL5 protein P05113 UNIPROT up-regulates quantity 9606 BTO:0000830 17259966 f apalma The array of mediators released by human mast cells is enormous and explains how mast cells can be involved in so many different physiological and pathophysiological functions. Of particular relevance [...] cytokines, such as IL-3 -basophil recruitment and activation-, IL-5 -eosinophil recruitment and activation- and IL-13 -induction of IgE synthesis by B cells. SIGNOR-255346 0.7 Vps34 Complex I complex SIGNOR-C242 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 30397185 f lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260325 0.7 MAPK1 protein P28482 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Thr345 GADSDVEtPSNFGKY 9606 BTO:0000007 27846390 t lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  SIGNOR-262984 0.306 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Thr119 PTCRGALtPSIRNLA 9606 22878263 t llicata In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis. SIGNOR-198733 0.42 PRKCD protein Q05655 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Thr566 FIQRWNFtKTTKAKY 9606 20733000 t Translocation from Cytoplasm to the Edge of Lamellipodia gcesareni Finally, we show that thr566 of pld2 is directly phosphorylated by pkc and that pld2 mutation in this region prevents pld2 activation, pld2 translocation to the edge of lamellipodia, rac translocation, and cell spreading after integrin activation SIGNOR-167577 0.475 CIC protein Q96RK0 UNIPROT Sin3B_complex complex SIGNOR-C409 SIGNOR up-regulates activity binding 10090 BTO:0000142 32229723 t miannu Mechanistically, we demonstrated that CIC represses VGF expression by tethering SIN3-HDAC to form a transcriptional corepressor complex. Mass spectrometry analysis of CIC-interacting proteins further identified the BRG1-containing mSWI/SNF complex whose function is necessary for transcriptional repression by CIC. CIC interacts with mSWI/SNF complex during neurogenesis. CIC tethers SIN3-HDAC corepressor complex and mSWI/SNF complex to VGF promoter during neurogenesis. SIGNOR-269206 0.342 PAK5 protein Q9P286 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000150 29041983 t lperfetto PAK5-mediated phosphorylation and nuclear translocation of NF-κB-p65 promotes breast cancer cell proliferation in vitro and in vivo|We characterized that PAK5 could promote the phosphorylation and the nuclear translocation of p65 subunit of nuclear factor-kappaB, and demonstrated that p65 could directly bind to the promoter of Cyclin D1 SIGNOR-275657 0.2 CAMK2A protein Q9UQM7 UNIPROT NOX5 protein Q96PH1 UNIPROT unknown phosphorylation Ser547 TMRKSQRsSKGSEIL -1 21642394 t miannu In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475. SIGNOR-276332 0.2 CXCL5 protein P42830 UNIPROT Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR up-regulates 9606 BTO:0000130 34237033 f miannu  We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs), and subsequent cancer cell invasion and metastasis. SIGNOR-277732 0.7 IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding 9606 12704343 t milica IL-4R Is a 140-kd protein that binds il-4 with high affinity SIGNOR-100762 0.941 CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser178 LFTQRQNsAPARMLS 9606 20068082 t gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts); SIGNOR-163138 0.851 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR down-regulates 15549093 f lperfetto The critical target of the G2 checkpoint is the mitosis-promoting activity of the cyclin B/CDK1 kinase, whose activation after various stresses is inhibited by ATM/ATR, CHK1/CHK2 and/or p38-kinase-mediated subcellular sequestration, degradation and/or inhibition of the CDC25 family of phosphatases that normally activate CDK1 at the G2/M boundary SIGNOR-251496 0.7 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120092 0.316 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR TIAM1 protein Q13009 UNIPROT down-regulates quantity by destabilization phosphorylation Ser329 DVNAGEGsEFADSGI 9606 BTO:0002181 25124033 t miannu Phosphorylation of Ser329, Ser334, and Thr340 in Tiam1 is required for its interaction with βTrCP1. The proteolysis of Tiam1 is prevented by βTrCP silencing, inhibition of CK1 and MEK, or mutation of the Tiam1 degron site. SIGNOR-276674 0.2 INSR protein P06213 UNIPROT PIK3R3 protein Q92569 UNIPROT unknown phosphorylation Tyr341 NEDADENyFINEEDE 9606 BTO:0000142;BTO:0000671 7542745 t llicata This pattern of 32p-tyr release unambiguously identified tyr-341 in p55pik as a major in vitro phosphorylation site. SIGNOR-28791 0.61 WKYMVm chemical CID:457933 PUBCHEM FPR2 protein P25090 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257493 0.8 DNAAF10 protein Q96MX6 UNIPROT PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR form complex binding 9606 30484152 t miannu The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92.  SIGNOR-270921 0.2 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL 9823 BTO:0004712 23486913 t lperfetto Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway SIGNOR-201538 0.96 CDK1 protein P06493 UNIPROT BUB1 protein O43683 UNIPROT up-regulates phosphorylation Thr609 SAAQLAStPFHKLPV 9606 16760428 t gcesareni The plk1-bub1 interaction requires the polo-box domain (pbd) of plk1 and is enhanced by cyclin-dependent kinase 1 (cdk1)-mediated phosphorylation of bub1 at t609 SIGNOR-147065 0.855 MAP2K1 protein Q02750 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258992 0.742 AMPK complex SIGNOR-C15 SIGNOR RAC1 protein P63000 UNIPROT up-regulates activity 9606 BTO:0000584 29572236 f miannu The discovery that AMPK activation is a general requirement for macropinosome formation in cancer cells dramatically extends our understanding of the regulation of this process. By increasing RAC1-GTP levels, AMPK activation stimulates macropinosome formation (Fig. 2I–K; Supplementary Fig. S5).  SIGNOR-277766 0.266 TRIM5 protein Q9C035 UNIPROT TRIM5 protein Q9C035 UNIPROT up-regulates quantity monoubiquitination 9606 BTO:0000567 18312418 t miannu Here, we show that TRIM5alpha functions as a RING-finger-type E3 ubiquitin ligase both in vitro and in vivo and ubiquitinates itself in cooperation with the E2 ubiquitin-conjugating enzyme UbcH5B. Thus, the ubiquitination of TRIM5alpha is catalyzed by itself and Ro52. Unexpectedly, although TRIM5alpha is ubiquitinated, our results have revealed that the proteasome inhibitors MG115 and MG132 do not stabilize it in HeLa cells, suggesting that the ubiquitination of TRIM5alpha does not lead to proteasomal degradation. Importantly, TRIM5alpha is clearly conjugated by a single ubiquitin molecule (monoubiquitination). Our monoubiquitin-fusion assay suggests that monoubiquitination is a signal for TRIM5alpha to translocate from cytoplasmic bodies to the cytoplasm. SIGNOR-271671 0.2 MAPK1 protein P28482 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser257 ESHPKPSsPRQESTR 10090 BTO:0000944 15060146 t miannu Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation. SIGNOR-260087 0.323 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation 9606 16508002 t inferred from 70% family members gcesareni Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity. SIGNOR-270043 0.2 PLK1 protein P53350 UNIPROT USP16 protein Q9Y5T5 UNIPROT up-regulates activity phosphorylation Ser386 HESFLDLsLPVLDDQ -1 26323689 t done miannu Plk1 phosphorylates and activates Usp16. In vitro phosphorylation of Usp16 with single (S330A, S386A, or S486A) or collective 3A (S330A/S386A/S486A) mutation showed that Plk1 phosphorylated Usp16 at all three sites (Fig. S2 D). SIGNOR-274015 0.35 RIPK1 protein Q13546 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates activity binding 9606 BTO:0000007 15327770 t lperfetto TNF_ induced the polyubiquitination of RIP and the association of polyubiquitinated RIP with TAB2. SIGNOR-128406 0.859 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Thr273 SPSVHPAtPISPGRA 9606 16046550 t The effect has been demonstrated using Q01196-8. gcesareni Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction. SIGNOR-138920 0.348 SETD5 protein Q9C0A6 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity methylation Lys37 APSTGGVkKPHRYRP -1 31515109 t miannu SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription. SIGNOR-264622 0.2 LAMTOR5 protein O43504 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 22740693 f miannu It suggests that HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4. SIGNOR-255248 0.371 LRRC4 protein Q9HBW1 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000142 25526788 f miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. SIGNOR-264057 0.2 MSH2 protein P43246 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 10090 9500552 f Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer SIGNOR-257594 0.7 CAMP protein P49913 UNIPROT FPR2 protein P25090 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 11015447 t gcesareni Ll-37 may contribute to innate and adaptive immunity by recruiting neutrophils, monocytes, and t cells to sites of microbial invasion by interacting with fprl1. SIGNOR-82701 0.549 BRCA1 protein P38398 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR up-regulates activity binding 10426999 t lperfetto BRCA1 encodes a tumor suppressor that is mutated in familial breast and ovarian cancers. Here, it is shown that BRCA1 interacts in vitro and in vivo with hRad50, which forms a complex with hMre11 and p95/nibrin. Upon irradiation, BRCA1 was detected in discrete foci in the nucleus, which colocalize with hRad50.| These data suggest that BRCA1 is important for the cellular responses to DNA damage that are mediated by the hRad50-hMre11-p95 complex. SIGNOR-251501 0.768 CSF2 protein P04141 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates activity binding 9606 BTO:0000801 18551128 t lperfetto The GM-CSF receptor (CSF2R) is a heterodimer composed of a specific ligand-binding subunit (CSF2Ralpha) and a common signal-transduction subunit (CSF2Rbeta) SIGNOR-249501 0.852 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:93369 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000601 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258540 0.8 D-ribofuranose smallmolecule CHEBI:47013 ChEBI D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity precursor of 9606 25749547 t miannu Human ribokinase (RK) is a member of the ribokinase family, and is the first enzyme responsible for D-ribose metabolism, since D-ribose must first be converted into D-ribose-5-phosphate to be further metabolized and incorporated into ATP or other high energy phosphorylated compounds. SIGNOR-267071 0.8 SUN1 protein O94901 UNIPROT TERB1 protein Q8NA31 UNIPROT up-regulates activity binding 9606 BTO:0000007 SIGNOR-C303 SIGNOR-C305 33015044 t lperfetto In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | It will be of great interest to test this hypothesis to fully understand the mechanisms of stable telomere–NE connection and telomere movement along the NE driven by the LINC complex. SIGNOR-263299 0.2 SRC protein P12931 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Tyr333 NIMRTYTyEKLLWTT 9606 22056988 t lperfetto Egfr activation induces translocation of pkm2 into the nucleus, where k433 of pkm2 binds to c-src-phosphorylated y333 of _-cateninthese findings reveal that egf induces _-catenin transactivation via a mechanism distinct from that induced by wnt/wingless and highlight the essential non-metabolic functions of pkm2 in egfr-promoted _-catenin transactivation, cell proliferation and tumorigenesis SIGNOR-177086 0.752 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr88 AVSPLLLtTTNSSEG 9606 11152499 t tpavlidou Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites. SIGNOR-85781 0.2 AIFM1 protein O95831 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 21210296 f gcesareni Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c, (diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore. SIGNOR-170960 0.413 RNF13 protein O43567 UNIPROT SNAPIN protein O95295 UNIPROT up-regulates activity polyubiquitination 9534 BTO:0000298 22890573 t miannu  RNF13 directly interacted with snapin, a SNAP-25-interacting protein. Interestingly, snapin was ubiquitinated by RNF13 via the lysine-29 conjugated polyubiquitin chain, which in turn promoted the association of snapin with SNAP-25. Consistently, we found an attenuated interaction between snapin and SNAP-25 in the RNF13-null mice. Therefore, these results suggest that RNF13 is involved in the regulation of the SNARE complex, which thereby controls synaptic function. SIGNOR-272044 0.536 Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT JUN protein P05412 UNIPROT down-regulates activity 9606 BTO:0000007 17715225 f miannu SARS-CoV nsp1 inhibits c-Jun expression and phosphorylation. SIGNOR-262505 0.2 USF1 protein P22415 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 9731700 f miannu Overexpression of cathepsin D (CD), a ubiquitous lysosomal protease, is closely associated with a poor clinical outcome for patients with breast cancer. Estrogen greatly induces transcription of the CD gene in estrogen receptor (ER)-positive breast cancer cells. These experiments suggest a model for ER stimulation of the CD promoter in which recruitment of USF-1/2 to the promoter is required for activation of transcription. SIGNOR-255595 0.386 MYCBP2 protein O75592 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001321 32814769 t miannu We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. SIGNOR-267149 0.2 TNF protein P01375 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253482 0.2 TWIST2 protein Q8WVJ9 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255503 0.2 CHEK1 protein O14757 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Thr12 KQTARKStGGKAPRK 9606 18243098 t gcesareni We identify chk1 as the kinase responsible for h3-t11 phosphorylation. H3-t11 phosphorylation occurs throughout the cell cycle and is chk1 dependent in vivo.Phosphorylation at thr-12 (h3t11ph) by pkn1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of lys-10 (h3k9me) by kdm4c/jmjd2c. SIGNOR-160557 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 t gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation SIGNOR-252453 0.426 MRPS21 protein P82921 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261486 0.658 TFEB protein P19484 UNIPROT NDUFB10 protein O96000 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). SIGNOR-276704 0.2 TSC complex SIGNOR-C101 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity 9606 BTO:0000007;BTO:0001938 12271141 f lperfetto These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor SIGNOR-217907 0.769 CLTC protein Q00610 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR form complex binding 9606 24789820 t lperfetto AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly.  SIGNOR-260665 0.735 BMP7 protein P18075 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates binding 10090 BTO:0000165 SIGNOR-C30 11282024 t gcesareni Bmp-4 and gdf-5 are known to bind to activin receptor-like kinase 3 (alk-3) and/or alk-6 (also termed bmp type ia and type ib receptors, respectively), whereas bmp-6 and bmp-7 preferentially bind to alk-2 SIGNOR-236913 0.8 calcium(2+) smallmolecule CHEBI:29108 ChEBI S100A9 protein P06702 UNIPROT up-regulates activity chemical activation 9606 BTO:0001044 16690079 t miannu S100 proteins comprise the largest family of calcium-binding proteins. Members of this family usually form homo- or heterodimers, which may associate to higher-order oligomers in a calcium-dependent manner. The heterodimers of S100A8 and S100A9 represent the major calcium-binding proteins in phagocytes. Both proteins regulate migration of these cells via modulation of tubulin polymerization. SIGNOR-261934 0.8 GNAQ protein P50148 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 9235901 t gcesareni Galfaq/11 subunits also activate p21ras SIGNOR-50104 0.63 MBD2 protein Q9UBB5 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263835 0.725 GP9 protein P14770 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR form complex binding 9606 16293600 t lperfetto The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbalpha, disulfide-linked to GPIbbeta, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1. SIGNOR-261848 0.683 TUBA1B protein P68363 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. SIGNOR-269727 0.7 HIF1A protein Q16665 UNIPROT KDM3A protein Q9Y4C1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271568 0.425 TP53INP1 protein Q96A56 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates binding 9606 22421968 t gcesareni Tp53inp1-lc3 interaction occurs via a functional lc3-interacting region (lir) SIGNOR-196673 0.301 COLGALT1 protein Q8NBJ5 UNIPROT ADIPOQ protein Q15848 UNIPROT up-regulates activity palmitoylation 9606 BTO:0000007 28428430 t We conclude that GLT25D1 regulates HMW adiponectin secretion and lipid accumulation, consistent with changes in mice after high-fat feeding. These results suggest a novel function of GLT25D1 leading to decreased HMW adiponectin secretion in early obesity. SIGNOR-261149 0.2 SRC protein P12931 UNIPROT VCL protein P18206 UNIPROT down-regulates activity phosphorylation Tyr100 QMLQSDPySVPARDY 9534 15229287 t lperfetto The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreadingWhen phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail. SIGNOR-247424 0.751 ARAP1 protein Q96P48 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260452 0.511 PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ARHGEF2 protein Q92974 UNIPROT down-regulates activity phosphorylation Ser960 SRLSPPHsPRDFTRM 9606 BTO:0000567 17488622 t miannu The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity. SIGNOR-276060 0.4 IYD protein Q6PHW0 UNIPROT 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI down-regulates quantity chemical modification 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-267036 0.8 PRKCB protein P05771 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 11700305 t lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | SIGNOR-249122 0.359 WDR83 protein Q9BRX9 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates binding 9606 15118098 t gcesareni Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex. SIGNOR-124473 0.487 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Thr444 DWVFINYtYKRFEGL 9606 12493777 t lperfetto We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo SIGNOR-96683 0.2 PAX3-FOXO1 fusion protein SIGNOR-FP12 SIGNOR IGF1R protein P08069 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 t miannu Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA. SIGNOR-251568 0.2 ATP7A protein Q04656 UNIPROT copper(1+) smallmolecule CHEBI:49552 ChEBI up-regulates quantity relocalization 28389643 t lperfetto Menkes disease (MD) is caused by mutations in ATP7A, encoding a copper- transporting P-type ATPase which exhibits copper-dependent trafficking. ATP7A is found in the Trans-Golgi Network (TGN) at low copper concentrations, and in the post-Golgi compartments and the plasma membrane at higher concentrations.  SIGNOR-272298 0.8 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR GATA2 protein P23769 UNIPROT up-regulates activity binding 10090 BTO:0001516 10938104 t We provide evidence that GATA-2 can physically associate with PML-RARα. Functional experiments further demonstrated that this interaction has the capacity to render GATA-dependent transcription inducible by retinoic acid, raising the possibility that GATA target genes may be involved in the molecular pathogenesis of APL. SIGNOR-259941 0.2 MAPK1 protein P28482 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation Thr72 PLLPPSAtGPDATVG 9606 12478298 t lperfetto In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites SIGNOR-96414 0.652 DMTF1 protein Q9Y222 UNIPROT JUNB protein P17275 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 t Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  SIGNOR-261585 0.268 STK4 protein Q13043 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser909 HQRCLAHsLVGTPNY 9606 BTO:0000007 15688006 t milica We show that Mst2 and hWW45 interact with each other in human cells and that both Mst2 and Mst1 are able to phosphorylate Lats1 and Lats2, thereby stimulating Lats kinase activity. SIGNOR-133551 0.607 1-(2,4-difluorophenyl)-3-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-fluorophenyl]urea chemical CHEBI:92822 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193573 0.8 ACVR1 protein Q04771 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity 9606 18801898 f gcesareni Akt/mTOR signaling is a key target that accounts for myostatin function during muscle atrophy, uncovering a novel role for myostatin in protein metabolism and more specifically in the regulation of translation in skeletal muscle. SIGNOR-252463 0.25 NR3C1/STAT5A complex SIGNOR-C84 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 9606 12540601 f fspada We have shown that stat5a is associated with the glucocorticoid receptor during adipogenesis in a highly regulated manner. SIGNOR-97562 0.7 INPPL1 protein O15357 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates 9606 18486448 f gcesareni Ship2 positively modulated the mlk3/jip1-mediated jnk1 activation SIGNOR-178652 0.2 PPP1CB protein P62140 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser77 YEPEGSAsPTPPYLK 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248568 0.2 VKORC1 protein Q9BQB6 UNIPROT Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI up-regulates quantity chemical modification 9606 31226734 t lperfetto The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form SIGNOR-265901 0.8 XAV939 chemical CHEBI:62878 ChEBI TNKS2 protein Q9H2K2 UNIPROT down-regulates chemical inhibition 9606 19759537 t gcesareni Xav939 inhibits the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2. SIGNOR-188057 0.8 AMPK complex SIGNOR-C15 SIGNOR PPP1R12C protein Q9BZL4 UNIPROT down-regulates phosphorylation Ser452 AGLQRSAsSSWLEGT 9606 22137581 t lperfetto Ampk-induced phosphorylation is necessary for ppp1r12c interaction with 14-3-3 and phosphorylation of myosin regulatory light chain. Both ampk activity and ppp1r12c phosphorylation are increased in mitotic cells and are important for mitosis completion. The interaction between ppp1r12c and 14-3-3_ may inactivate the ppp1r12c-containing phosphatase complex in vivo. SIGNOR-216600 0.259 BRCA1 protein P38398 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 15549093 f lperfetto The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination SIGNOR-267282 0.7 GAN protein Q9H2C0 UNIPROT ATG16L1 protein Q676U5 UNIPROT down-regulates quantity ubiquitination 9534 BTO:0000298 30770803 t miannu Here we identify Gigaxonin24, an E3 ligase mutated in a fatal neurodegenerative disease called giant axonal neuropathy (GAN)25, as the first regulator of ATG16L1. Gigaxonin poly-ubiquitinates and controls the degradation of ATG16L1, and is essential to activate autophagy. SIGNOR-268948 0.2 SCF-FBW7 complex SIGNOR-C135 SIGNOR BLM protein P54132 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 26028025 t miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. SIGNOR-276912 0.278 RIMBP3B protein A6NNM3 UNIPROT RIMS2 protein Q9UQ26 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264369 0.365 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273064 0.635 PRKACA protein P17612 UNIPROT RGS14 protein O43566 UNIPROT up-regulates activity phosphorylation Ser260 NAALRREsQGSLNSS -1 12534294 t miannu RGS14 is phosphorylated in vitro at Ser258 and Thr494 by PKA. cAMP-induced phosphorylation as an important modulator of RGS14 function since phosphorylation could enhance RGS14 binding to Galpha(i)-GDP SIGNOR-250045 0.344 ME1 protein P48163 UNIPROT NADP(3-) smallmolecule CHEBI:58349 ChEBI down-regulates quantity chemical modification 9606 33064660 t miannu Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. SIGNOR-267722 0.8 CLIP1 protein P30622 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates binding 17889670 t lperfetto Microtubule plus end binding proteins (+TIPs) localize to the dynamic plus ends of microtubules, where they stimulate microtubule growth and recruit signaling molecules. Three main +TIP classes have been identified (XMAP215, EB1, and CLIP-170) SIGNOR-264832 0.7 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser660 FSAERRNsILTETLH 9606 1716180 t lperfetto Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response. SIGNOR-21312 0.467 CAMK1 protein Q14012 UNIPROT NOS1 protein P29475 UNIPROT down-regulates activity phosphorylation Ser852 SYKVRFNsVSSYSDS -1 10400690 t llicata It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation. SIGNOR-250614 0.337 RPS6KB1 protein P23443 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 BTO:0000007 BTO:0001253 18296647 t gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. SIGNOR-160989 0.598 NCBP1 protein Q09161 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates activity relocalization 9606 26382858 t lperfetto The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. SIGNOR-268363 0.8 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr88 QALEEAAtADLDITE 9606 19530738 t lperfetto First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form. SIGNOR-186151 0.471 PKA proteinfamily SIGNOR-PF17 SIGNOR PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 t done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  SIGNOR-273898 0.2 ZFP91 protein Q96JP5 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates ubiquitination 9606 20682767 t gcesareni Zfp91 interacts with and promotes the lys(63)-linked ubiquitination of nik and subsequent processing of p100 to p52. SIGNOR-167331 0.514 ERBB4 protein Q15303 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 16829981 t gcesareni Erbb4 might not be able to directly recruit cbl, and therefore downregulation of this receptor is slow. SIGNOR-147841 0.589 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser438 PGLLRRVsSTWTTTT 9606 19261611 t llicata Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding. SIGNOR-184456 0.2 CAMK2G protein Q13555 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR down-regulates activity phosphorylation Ser1076 NVASRMEsTGVMGNI 9606 BTO:0000007 8798667 t llicata Phosphorylation and inhibition of type III adenylyl cyclase by calmodulin-dependent protein kinase II in vivo. | Site-directed mutagenesis of a CaM kinase II consensus site (Ser-1076 to Ala-1076) in III-AC greatly reduced Ca2+-stimulated phosphorylation and inhibition of III-AC in vivo. SIGNOR-267845 0.57 GBE1 protein Q04446 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI up-regulates quantity chemical modification 9606 26199317 t miannu Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis by generating Œ±-1,6-glucosidic branches from Œ±-1,4-linked glucose chains, to increase solubility of the glycogen polymer. In eukaryotes, glycogenin (EC 2.4.1.186) initiates the synthesis of the linear glucan chain (2), which is elongated by glycogen synthase (GYS, EC 2.4.1.11) (3), functioning in concert with glycogen branching enzyme (GBE, EC 2.4.1.18) to introduce side chains SIGNOR-267942 0.8 CXCL11 protein O14625 UNIPROT ACKR3 protein P25106 UNIPROT up-regulates activity binding 9606 BTO:0000093 16940167 t Luana This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell alpha chemoattractant (I-TAC; also known as CXCL11) SIGNOR-268415 0.623 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 19279133 t flangone Here, we show that Smad2/3, the downstream effectors of Activin/Nodal signalling, bind and directly control the activity of the Nanog gene in hESCs. SIGNOR-242049 0.535 NEK2 protein P51955 UNIPROT PPP1CC protein P36873 UNIPROT down-regulates phosphorylation Thr307 EKKKPNAtRPVTPPR 9606 10880350 t miannu Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity. / threonine-307 and -318 appear to be equally well phosphorylated by nek2 SIGNOR-78306 0.501 HRAS protein P01112 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 10090 BTO:0000944 12169099 t lperfetto c-Jun was first shown to be phosphorylated in its transactivation domain (Ser-63 and Ser-73) by ERKs and p54-JNK. This is consistent with other studies which show that PD98059 inhibits up-regulation of c-Jun protein in Ras-transformed NIH-3T3 cells SIGNOR-235526 0.514 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258567 0.8 FGF4 protein P08620 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 t gcesareni The nine known fgf ligands and the four signaling fgf receptors (and their alternatively spliced variants) are expressed in specific spatial and temporal patterns. The activity of this signaling pathway is regulated by ligand binding specificity, heparan sulfate proteoglycans, and the differential signaling capacity of individual fgf receptors. SIGNOR-42377 0.749 MAPK8 protein P45983 UNIPROT SARM1 protein Q6SZW1 UNIPROT down-regulates activity phosphorylation Ser548 AAREMLHsPLPCTGG 30333228 t lperfetto C-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD+ cleavage activity to inhibit mitochondrial respiration|Here, we report that NAD+ cleavage activity of SARM1 is regulated by its own phosphorylation at serine 548. The phosphorylation of SARM1 was mediated by c-jun N-terminal kinase (JNK) under oxidative stress conditions, resulting in inhibition of mitochondrial respiration concomitant with enhanced activity of NAD+ cleavage. Nonphosphorylatable mutation of Ser-548 or treatment with a JNK inhibitor decreased SARM1 activity. SIGNOR-275554 0.433 TNF protein P01375 UNIPROT SCN9A protein Q15858 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253479 0.254 VRK2 protein Q86Y07 UNIPROT DTNBP1 protein Q96EV8 UNIPROT down-regulates quantity by destabilization phosphorylation Ser297 ELRAKPPsSSSTCTD -1 30062698 t miannu  We show that VRK2 phosphorylates Ser 297 and Ser 299 of dysbindin using in vitro kinase assay. In addition, we found that VRK2-mediated phosphorylation of dysbindin enhanced ubiquitination of dysbindin and consequently resulted in the decrease in its protein stability through western blotting.  SIGNOR-277403 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR HTT protein P42858 UNIPROT unknown phosphorylation Ser419 GGRSRSGsIVELIAG 9606 BTO:0000938 12062094 t llicata We demonstrate that huntingtin is a substrate of akt and that phosphorylation of huntingtin by akt is crucial to mediate the neuroprotective effects of igf-1. SIGNOR-89696 0.2 CUL4A protein Q13619 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR form complex binding 9606 22649780 t gcesareni The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors SIGNOR-234793 0.899 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Thr451 PIPKALGtPVLTPPT 9606 BTO:0000848 BTO:0001253 20959475 t lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). SIGNOR-168762 0.2 F2R protein P25116 UNIPROT LATS1 protein O95835 UNIPROT down-regulates 9606 BTO:0000007 22972936 f Here we report that stimulation of protease-activated receptors (PARs) activates YAP/TAZ by decreasing phosphorylation and increasing nuclear localization. milica Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase. SIGNOR-192045 0.2 SSTR1 protein P30872 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256679 0.503 MYC protein P01106 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates 9606 11804592 f in cancer lperfetto Oncogenic c-myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of smads SIGNOR-114281 0.671 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR XBP1 protein P17861 UNIPROT down-regulates quantity by destabilization phosphorylation Ser68 RQRLTHLsPEEKALR 9606 BTO:0001109 23277279 t miannu Phosphorylation of XBP-1u by ERK is critical for the increased interaction of XBP-1u and FoxO1. SIGNOR-276438 0.2 AMG 458 chemical CID:24764449 PUBCHEM MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189516 0.8 4.1 complex complex SIGNOR-C386 SIGNOR SPTB protein P11277 UNIPROT up-regulates activity binding 9606 BTO:0000424 22465511 t lperfetto The junctional complex is focused around a hub or ‘junction’ arising from lateral connections between protein 4.1, actin and beta spectrin (the first of which stabilises the actin spectrin association via direct binding to both proteins [8]). SIGNOR-266041 0.361 quetiapine chemical CHEBI:8707 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9760039 t miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). SIGNOR-258842 0.8 AKT2 protein P31751 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C3 17386266 t gcesareni Insulin-stimulated phosphorylation of pras40 by akt/pkb suppresses its mtorc1 inhibitory activity. SIGNOR-153931 0.66 PDCD1 protein Q15116 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity 9606 BTO:0000782 22740686 f Barakat MEK1/2 was phosphorylated and activated upon activation of T cells through TCR-CD3 and CD28, which resulted in phosphorylation of its downstream target ERK1/2, as determined by Western blotting analysis with an antibody specific for ERK1/2 phosphorylated at Thr202 and Tyr204, markers of activation. PD-1 substantially inhibited the activation of MEK1/2 and ERK1/2 SIGNOR-275410 0.268 HCK protein P08631 UNIPROT ADAM15 protein Q13444 UNIPROT up-regulates phosphorylation Tyr715 LVMLGASyWYRARLH 9606 11741929 t lperfetto Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling. SIGNOR-112919 0.362 PRKACA protein P17612 UNIPROT CACNA1D protein Q01668 UNIPROT up-regulates activity phosphorylation Ser1700 VNSDRRDsLQQTNTT -1 19074150 t miannu We recently demonstrated that PKA activation led to increased alpha(1D) Ca(2+) channel activity in tsA201 cells by phosphorylation of the channel protein. Western blotting showed that the N terminus and C terminus were phosphorylated. Serines 1743 and 1816, two PKA consensus sites, were phosphorylated by PKA and identified by mass spectrometry. SIGNOR-263108 0.374 RXRA protein P19793 UNIPROT RARG protein P13631 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-16671 0.673 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 24692351 f scontino Skeletal muscle has been recognized as a key TH target for contractile function, regeneration, and transport as well as for metabolism and glucose disposal (237, 238). TH stimulation favors transition to fast-twitch fibers and transition to a faster myosin heavy chain (MHC) form. SIGNOR-267619 0.7 MMP10 protein P09238 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272378 0.7 RPS6KA1 protein Q15418 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 7838153 t gcesareni Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii. SIGNOR-34113 0.507 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0001271 BTO:0000671 14551213 t gcesareni The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases these include epidermal growth factor receptor (egfr) kinase,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1 SIGNOR-118596 0.709 TGFb proteinfamily SIGNOR-PF5 SIGNOR SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 30017632 f miannu Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. SIGNOR-260428 0.615 F2RL1 protein P55085 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257359 0.438 A2M protein P01023 UNIPROT MMP2 protein P08253 UNIPROT down-regulates activity binding -1 9344465 t lperfetto Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. SIGNOR-261803 0.62 ETS1 protein P14921 UNIPROT ITGA11 protein Q9UKX5 UNIPROT up-regulates quantity by expression 9606 BTO:0001282 16300938 t lperfetto We speculate that the "mesenchymal signature" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors. SIGNOR-253352 0.285 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 17827393 t gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157750 0.864 CDK5 protein Q00535 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Thr514 TTTPKGGtPAGSARG 9606 16611631 t lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro SIGNOR-145971 0.587 IL33 protein O95760 UNIPROT IL1RL1 protein Q01638 UNIPROT up-regulates activity binding 9606 BTO:0001679 16286016 t miannu We report a member of the IL-1 family, IL-33, which mediates its biological effects via IL-1 receptor ST 2, activates NF-kappaB and MAP kinases, and drives production of T(H)2-associated cytokines from in vitro polarized T(H)2 cells. In vivo, IL-33 induces the expression of IL-4, IL-5, and IL-13 and leads to severe pathological changes in mucosal organs.The binding of IL-33 to cells that express ST2 results in the activation of NF-κB and MAP kinases. Administration of purified IL-33 either in vitro or in vivo leads to the production of TH2-associated cytokines. SIGNOR-277711 0.923 CKM complex complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-273145 0.346 MAPK10 protein P53779 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates activity phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 BTO:0000007 11259409 t miannu JNK Phosphorylation of HnRNP K Increases Its Transcriptional Activity. the primary site for JNK phosphorylation consists of serines 216 and 353 on the K protein. SIGNOR-250083 0.345 MAP2K4 protein P45985 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Thr183 ACTNFMMtPYVVTRY 9606 BTO:0000007 17761173 t lperfetto We next examined whether the phosphorylation of JNK at threonine 183 (Thr183) and tyrosine 185 (Tyr185) was enhanced by GRASP‐1 expression. Phosphorylation of Thr183 and Tyr185 by SEK1/MKK4, which is in turn phosphorylated and activated by several kinases including MEKK1, is known to activate JNK1/2/3 SIGNOR-260615 0.718 AURKB protein Q96GD4 UNIPROT KNL1 protein Q8NG31 UNIPROT down-regulates phosphorylation Ser24 RPVRRRHsSILKPPR 9606 20471944 t lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). SIGNOR-165502 0.2 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR MLXIPL protein Q9NP71 UNIPROT down-regulates activity relocalization 10116 26984404 t AMP inhibits the nuclear localization of ChREBP through an allosteric activation of ChREBP/14-3-3 interactions SIGNOR-255667 0.2 MT-CO1 protein P00395 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267746 0.662 OXTR protein P30559 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 30739093 t miannu OT binds to its cognate G protein–coupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi), and activation of phospholipase C (Gq). SIGNOR-270331 0.409 BMP7 protein P18075 UNIPROT UCP1 protein P25874 UNIPROT up-regulates transcriptional regulation 9606 18719589 f fspada Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16; ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha; ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways SIGNOR-210059 0.439 PTPRC protein P08575 UNIPROT LYN protein P07948 UNIPROT down-regulates activity dephosphorylation Tyr508 YTATEGQyQQQP 10090 BTO:0000776 10415030 t CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508) SIGNOR-248354 0.652 NEK6 protein Q9HC98 UNIPROT KIF20A protein O95235 UNIPROT down-regulates activity phosphorylation Ser244 LSTSLKRsVYIESRI 9606 BTO:0000567 28630147 t done miannu We show that Nek9, Nek6, and the kinesin Mklp2 form a signaling module, which is required for Mklp2 to localize to the central spindle in anaphase. Nek6 also phosphorylates Mklp2 at Ser244, inhibiting its bundling activity until anaphase onset. SIGNOR-273891 0.354 MTHFD2 protein P13995 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI up-regulates quantity chemical modification 9606 16100107 t lperfetto Magnesium and phosphate ions enable NAD binding to methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase|One of the enzymes in this pathway, the NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase (NMDMC),5 catalyzes the interconversion of 5,10-methylenetetrahydrofolate (methylene-THF) and 10-formyltetrahydrofolate (formyl-THF) in mammalian mitochondria. SIGNOR-268256 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR SMN1 protein Q16637 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 BTO:0000007 19103745 t lperfetto PKA increases SMN complex formation and SMN stability.|As expected, SMN was phosphorylated by PKA (Fig. ​(Fig.6D).6D). SIGNOR-253114 0.2 TBX3 protein O15119 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 25211658 t lperfetto TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS SIGNOR-249602 0.308 PRKG1 protein Q13976 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Ser1131 AARERKRsRGNRKSL 9606 BTO:0000887;BTO:0001260 21106951 t lperfetto Pkgi also directly phosphorylates fhod1, and studies with wild-type and mutant fhod1-derived peptides identify ser-1131 in the fhod1 c terminus as the unique pkgi phosphorylation site in fhod1. phosphorylation of three conserved residues within the dad domain activates fhod1 while binding to rac regulates fhod1 subcellular localization SIGNOR-170094 0.361 RPS6KA4 protein O75676 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000782 17668895 t gcesareni Msk1 and msk2 directly phosphorilate and activete transcription factors such as creb1, atf1 msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. SIGNOR-157158 0.589 COP1 protein Q8NHY2 UNIPROT CEBPB protein P17676 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000078 32795415 t Gianni We show expression of c/EBPβ in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). In the absence of COP1, c/EBPβ accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures. SIGNOR-261924 0.2 LEF1 protein Q9UJU2 UNIPROT DSG4 protein Q86SJ6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000552 19683850 f miannu we studied the transcriptional regulation of DSG4 by transcription factors/pathways that are known regulators of hair keratin or KAP expression. We show that HOXC13, LEF1 and FOXN1 repress DSG4 transcription and provide in vitro and in vivo evidence correlating the Notch pathway with the activation and/or maintenance of DSG4 expression in the hair follicle. SIGNOR-254183 0.292 calcium(2+) smallmolecule CHEBI:29108 ChEBI SYT1 protein P21579 UNIPROT up-regulates activity chemical activation 9606 16679567 t miannu Because synaptotagmins bind SNAP-25 and Ca2+, SNAP-25 has also been linked to the Ca2+ dependence of exocytosis (42). One model suggests that synaptotagmin blocks full SNARE fusion pore formation by binding to t-SNAREs.This interaction prevents fusion from occurring in the absence of calcium. When Ca2+ is present, synaptotagmin releases the t-SNAREs so they can fully zipper with the v-SNARE, leading to fusion SIGNOR-263976 0.8 Caspase 3 complex complex SIGNOR-C221 SIGNOR DFFB protein O76075 UNIPROT up-regulates cleavage 9606 9108473 t gcesareni Casp3_ cleaves the 45 kda subunit at two sites to generate an active factor that produces_ dna_ fragmentation SIGNOR-256463 0.672 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 18394876 t gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. SIGNOR-253001 0.673 SNRNP70 protein P08621 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270677 0.907 DLD protein P09622 UNIPROT PDH complex SIGNOR-C402 SIGNOR form complex binding 9606 20160912 t miannu The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. SIGNOR-266545 0.851 CLK4 protein Q9HAZ1 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates activity phosphorylation -1 8617202 t miannu In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors. SIGNOR-273860 0.364 MAF protein O75444 UNIPROT MYB protein P10242 UNIPROT down-regulates binding 9606 9566892 t miannu Full-length c-maf binds to the c-myb and ets-1. / c-maf inhibits c-myb and ets-1 transcriptional activity. SIGNOR-56811 0.646 PKN3 protein Q6P5Z2 UNIPROT ARHGAP18 protein Q8N392 UNIPROT up-regulates activity phosphorylation Thr158 RVETVSQtLRKKNKQ -1 33092266 t lperfetto We present strong evidence that PKN3-ARHGAP18 interaction is increased upon ARHGAP18 phosphorylation and that the phosphorylation of ARHGAP18 by PKN3 enhances its GAP domain activity and contributes to negative regulation of active RhoA.|These results support our data from phosphoproteomic screen and suggest that ARHGAP18 can be phosphorylated by PKN3 on Thr154, Ser156 and Thr158. SIGNOR-264572 0.2 NOTCH1 protein P46531 UNIPROT HEYL protein Q9NQ87 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 11044625 f gcesareni These data confirm heyl as a notch1 target gene that is likely involved in somite formation and patterning. SIGNOR-83399 0.594 CSNK2A2 protein P19784 UNIPROT PPP1R8 protein Q12972 UNIPROT up-regulates activity phosphorylation Ser204 KNSRVTFsEDDEIIN -1 9407077 t llicata Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2. SIGNOR-251023 0.485 STK39 protein Q9UEW8 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates binding 9606 14563843 t gcesareni Spak, a ste20/sps1-related kinase that activates the p38 pathway. p38, one of the three major mapks, can be coimmunoprecipitated with spak and with nkcc1 in an activity-dependent manner. The amount of p38 coimmunoprecipitated with the kinase and the cotransporter significantly decreases upon cellular stress, SIGNOR-118848 0.369 AD/b2 integrin complex SIGNOR-C172 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257716 0.442 ADIPOQ protein Q15848 UNIPROT ADIPOR2 protein Q86V24 UNIPROT up-regulates binding 9606 16622416 t milica Two adiponectin receptors, adipor1 and adipor2, have recently been identified. SIGNOR-146173 0.764 Gbeta proteinfamily SIGNOR-PF4 SIGNOR AMPH protein P49418 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 15262992 t inferred from 70% family members lperfetto Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2. SIGNOR-270102 0.2 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269359 0.719 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. SIGNOR-129268 0.392 AURKA protein O14965 UNIPROT TPX2 protein Q9ULW0 UNIPROT up-regulates activity phosphorylation Ser125 QRRSLRLsAQKDLEQ 9606 BTO:0000567 26240182 t lperfetto Here we show that TPX2, a microtubule-bundling protein and activator of Aurora A, plays an important role. TPX2 was phosphorylated by Aurora A during mitosis. Its phospho-null mutant caused short metaphase spindles coupled with low microtubule flux rate. Interestingly, phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a.|This suggests that TPX2 phosphorylation positively regulates the function of CLASP1.| This is in accord with a phosphoproteomics study that identified S121 and S125 as potential phosphorylation sites for Aurora A in mitotic HeLa cells SIGNOR-265088 0.963 SP3 protein Q02447 UNIPROT SOX18 protein P35713 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 18496767 f miannu co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells SIGNOR-254820 0.287 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. SIGNOR-157085 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR POU5F1 protein Q01860 UNIPROT down-regulates phosphorylation 9606 23024368 t inferred from 70% family members gcesareni Phosphorylation of this site downregulates nanog, sox2, rex1 and upregulates bmp4, gata6, ddlx5. SIGNOR-270085 0.2 UBE3A protein Q05086 UNIPROT TSC2 protein P49815 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 18298802 t miannu  An in vivo ubiquitination assay was done to reveal that E6AP promoted the ubiquitination of TSC2 independent of HPV16 E6. We further found that TSC2 bound E6AP in the presence as well as in the absence of HPV16 E6. The binding regions on E6AP and TSC2 have been identified as amino acid (aa) 260-316, aa 428-500 and aa 1-175, aa 1251-1807, respectively. Taken together, degradation of TSC2 is mediated by E6AP ubiquitin ligase. SIGNOR-271396 0.617 BTRC protein Q9Y297 UNIPROT ATF2 protein P15336 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0002572 33861966 t miannu Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). SIGNOR-267830 0.2 MAPK3 protein P27361 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation Thr207 FLTEYVAtRWYRAPE 9606 BTO:0000562 19060905 t lperfetto Here we show that autophosphorylation of erk1/2 on thr188 directs erk1/2 to phosphorylate nuclear targets known to cause cardiac hypertrophy. SIGNOR-182628 0.2 DOK1 protein Q99704 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257677 0.321 UBAP2L protein Q14157 UNIPROT BMI1 protein P35226 UNIPROT up-regulates activity binding 9606 BTO:0000007 25185265 t Sara We identified UBAP2L as a novel BMI1-interacting protein. UBAP2L, BMI1, RNF2, and PHC1 define a novel Polycomb subcomplex SIGNOR-261315 0.494 EEF1E1 protein O43324 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 t miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). SIGNOR-270360 0.907 Delta(9)-tetrahydrocannabinol smallmolecule CHEBI:66964 ChEBI CNR2 protein P34972 UNIPROT up-regulates activity chemical activation 9606 BTO:0000142 29751001 t miannu Endocannabinoids (eCBs) are the body’s natural agonists for cannabinoid receptors (G protein-coupled CB1 and CB2) that also recognize Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana. SIGNOR-264268 0.8 RPS6KA3 protein P51812 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-138471 0.2 FFAR3 protein O14843 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256821 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR BORA protein Q6PGQ7 UNIPROT up-regulates activity phosphorylation 9606 18521620 t gcesareni Our data additionally identify the cdk1 site s252 as critical for the recruitment of plk1 to hbora. collectively, our findings lead us to propose that hbora contributes to integrate the functions of three major mitotic kinases, cdk1, plk1, and aurora a. SIGNOR-178799 0.556 SCN2A protein Q99250 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. SIGNOR-253450 0.7 FOXO proteinfamily SIGNOR-PF27 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222 18854138 f gcesareni Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. SIGNOR-252937 0.2 JAK2 protein O60674 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by stabilization binding 10090 12370803 t irozzo In this study, we show that Jak2 is involved in c-Myc induction by inducing c-MYC mRNA and protecting c-Myc protein from 26S proteasome-dependent degradation. These results indicate that c-Myc is a downstream target of activated Jak2 in Bcr-Abl positive cells.  SIGNOR-255810 0.463 GSK3B protein P49841 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation 9606 18045539 t gcesareni Phosphorylation at the gsk3 sites represses the transcriptional activity of smad1 by enhancing proteasomal degradation of psmad1cter SIGNOR-159484 0.517 HIPK2 protein Q9H2X6 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser257 PGVVMASsPALPTQP 9606 20573984 t lperfetto Ere we found that homeodomain-interacting protein kinase 2 (hipk2), a dna-damage responsive nuclear kinase, is a new creb kinase for phosphorylation at ser-271 but not ser-133, and activates creb transactivation function SIGNOR-166338 0.398 FADS2 protein O95864 UNIPROT arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity chemical modification 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267912 0.8 PRKACA protein P17612 UNIPROT SYN1 protein P17600 UNIPROT down-regulates activity phosphorylation Ser9 NYLRRRLsDSNFMAN -1 10571231 t miannu Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I SIGNOR-250058 0.344 QRICH1 protein Q2TAL8 UNIPROT YARS1 protein P54577 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269412 0.2 SRC protein P12931 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates activity phosphorylation 9606 30889378 t miannu SRC can directly phosphorylate and inhibit LATS SIGNOR-259056 0.391 RSPO2 protein Q6UXX9 UNIPROT SDC4 protein P31431 UNIPROT up-regulates binding 9606 21397842 t Thrombospondin domains gcesareni We show that rspo3 binds syndecan 4 (sdc4) and that together they activate wnt/pcp signaling. SIGNOR-172719 0.268 AR protein P10275 UNIPROT UBE2C protein O00762 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19632176 t miannu The evolution of prostate cancer from an androgen-dependent state (ADPCa) to one that is androgen-independent (AIPCa) marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in AIPCa is poorly understood. We have defined the direct AR-dependent target genes in both AIPCa and ADPCa by generating AR-dependent gene expression profiles and AR cistromes. In contrast to ADPCa, AR selectively up-regulates M-phase cell cycle genes in AIPCa including UBE2C, a gene that inactivates the M-phase checkpoint. SIGNOR-251543 0.406 DNMT1 protein P26358 UNIPROT BAG1 protein Q99933 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18413740 f lperfetto DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation SIGNOR-254108 0.2 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser729 ASPQSPEsVDLVNEE 9606 11604491 t llicata Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728. SIGNOR-111047 0.553 PPP3CA protein Q08209 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser75 EIRSRHSsYPAGTED -1 10195903 t lperfetto Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.| Bcl-xL did not coimmunoprecipitate with BAD(S75E, S99E) protein (Fig. 2A), regardless of whether it was coexpressed with DCnA/B¬† SIGNOR-263739 0.452 PPP2CA protein P67775 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity dephosphorylation Ser129 NEAYEMPsEEGYQDY 9606 21562258 t α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129 SIGNOR-248635 0.338 RPS6KA1 protein Q15418 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Thr929 STIIRSKtFSPGPQS 9606 BTO:0000149 24269383 t llicata Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2. SIGNOR-203298 0.341 IKBKE protein Q14164 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity phosphorylation Thr501 ELRSRLRtLAEVLSR 9606 BTO:0000018 24882218 t miannu As previously reported, IKKε underwent rapid activation by auto-phosphorylation on T501 upon IFNβ treatment of control A549 cells, which was impaired by TRIM6si (Figure 4D) SIGNOR-276637 0.2 PTMS protein P20962 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 16150697 t miannu Macromolecular translocation inhibitor II (MTI-II), which was first identified as an in vitro inhibitor of binding between the highly purified glucocorticoid receptor (GR) and isolated nuclei, is an 11.5-kDa Zn2+-binding protein that is also known as ZnBP or parathymosin. MTI-II Enhances GR-dependent Transcription through Its Acidic Domain. MTI-II Enhances GR-dependent Transcription in Cooperation with SRC-1 and p300 in Vivo. CBP and p300 Coprecipitate with MTI-II in a Glucocorticoid Hormone-dependent Manner SIGNOR-268460 0.334 SPOP protein O43791 UNIPROT GMNN protein O75496 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 34599168 t miannu SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127. This poly-ubiquitination of Geminin prevents DNA replication over-firing by indirectly blocking the association of Cdt1 with the MCM protein complex, an interaction required for DNA unwinding and replication. SIGNOR-268926 0.2 UBR1 protein Q8IWV7 UNIPROT RECQL4 protein O94761 UNIPROT up-regulates binding 9606 BTO:0000567 15317757 t miannu The isolated recql4, assayed as a complex with ubr1 and ubr2, exhibited dna-stimulated atpase activity but was inactive as either dna helicase or dna translocase / the discovery, in the present work, that these ub ligases, ubr1 and ubr2, interact with the putative helicase recql4 (fig. 2), and that recql4 is a long-lived, non-ubiquitylated protein in hela cells SIGNOR-128169 0.505 PSMA1 protein P25786 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263363 0.854 ALDH2 protein P05091 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity binding -1 phosphorylation:Thr429 MQILKFKtIEEVVGR 28056995 t lperfetto Consistent with previous data, HDAC3 only bound to the ATP6V0E2 promoter in the presence of ALDH2.|Taken together, our data demonstrate that in the macrophages of LDLR-KO or ALDH2 rs671 mutant, AMPK phosphorylates ALDH2 at T356, which enables its nuclear translocation. Once in the nucleus, ALDH2 binds to HDAC3 and suppresses the transcription and protein expression of ATP6V0E2. SIGNOR-271867 0.2 DNMT3B protein Q9UBC3 UNIPROT DNMT1/DNMT3B complex SIGNOR-C43 SIGNOR form complex binding 9606 12145218 t miannu We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation SIGNOR-90845 0.782 PTAFR protein P25105 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257174 0.2 DLX5 protein P56178 UNIPROT MSX1 protein P28360 UNIPROT down-regulates activity binding 10090 BTO:0000946 9111364 t 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. SIGNOR-240921 0.398 CXCL2 protein P19875 UNIPROT Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR up-regulates 9606 BTO:0000130 35022267 f miannu Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth.Taken together, these results show that the neutrophil attracting cytokines Cxcl1 and 2 are highly expressed in metastatic livers in response to gemcitabine withdrawal and this favours CXCR2-dependent recruitment of neutrophils at the hepatic metastatic site. SIGNOR-277722 0.7 Yellow AB chemical CHEBI:82554 ChEBI PTCH1 protein Q13635 UNIPROT down-regulates chemical inhibition 9606 17970037 t gcesareni Anti-patched-1 antibodies suppress hedgehog signaling pathway and pancreatic cancer proliferation. SIGNOR-158650 0.8 ARAP2 protein Q8WZ64 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260454 0.44 PRKCZ protein Q05513 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251637 0.379 ATM protein Q13315 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser106 GPGQVMAsQAQQSSP 9606 20471956 t lperfetto Atm mediates phosphorylation of p300 in response to dna damageexpression of nonphosphorylatable serine to alanine form of p300 (s106a) destabilized both p300 and nbs1 proteins, after dna damage SIGNOR-165567 0.409 CAMK2G protein Q13555 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2407 AKVSGRPsSRKAKSP 9606 22888005 t gcesareni The kinase activity of camkii was essential for the activation of notch signaling. We also determined that camkii could enhance the association between notch1-ic and rbp-jk. Furthermore, the physical association between rbp-jk and smrt was substantially suppressed by camkii. We demonstrated that camkii directly bound and phosphorylated smrt at ser-1407, thereby facilitating smrt translocation from the nucleus to the cytoplasm and proteasome-dependent degradation. SIGNOR-191777 0.2 COL4A4 protein P53420 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 t Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6) SIGNOR-254668 0.7 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 25901680 f lperfetto Ribosomes are translational machineries that catalyse protein synthesis. SIGNOR-262413 0.7 CUDC-101 chemical CID:24756910 PUBCHEM HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20143778 t miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. SIGNOR-262264 0.8 NFIA protein Q12857 UNIPROT SLIT1 protein O75093 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268892 0.259 MAPK3 protein P27361 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser333 KGLVSPQsPQKSDCQ 9606 BTO:0000782;BTO:0000785 9649500 t gcesareni Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway. SIGNOR-58489 0.415 HIF1A protein Q16665 UNIPROT STC2 protein O76061 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18394600 t Giorgia With the ChIP assay, we demonstrated the direct binding of HIF-1alpha to STC2 promoter. These findings support the notion that HIF-1 is a potent stimulator of STC2 expression. Collectively, this is the first report to show that STC2 was aberrantly hypermethylated in human cancer cells. The findings demonstrated that STC2 epigenetic inactivation may interfere with HIF-1 mediated activation of STC2 expression. SIGNOR-260389 0.302 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A1 protein P30531 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206960 0.8 MAP2K4 protein P45985 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 7839144 t lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-34121 0.574 C3 protein P01024 UNIPROT C3 convertase complex (C3bBb) complex SIGNOR-C314 SIGNOR form complex binding 9606 BTO:0000089 cleavage:Arg748 ASHLGLArSNLDEDI 26489954 t complement C3b fragment: PRO_0000005911 lperfetto Surface‐associated C3b recruits FB, which leads to FB activation and the formation of C3bBb, the AP C3 convertase, which cleaves more C3 and amplifies complement activation. In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over) SIGNOR-263485 0.903 FOXP3 protein Q9BZS1 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 38339310 t miannu FOXP3 expression additionally increased programmed death ligand 1 (PD-L1) expression, which, when inhibited with CCL5, decreased the tumor burden and Treg infiltration in orthotopic murine, Pan-02 PDAC tumors SIGNOR-277728 0.481 S1PR1 protein P21453 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257108 0.358 MRPL44 protein Q9H9J2 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262352 0.689 LCMT1 protein Q9UIC8 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity methylation Leu309 RRTPDYFl -1 18394995 t lperfetto Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |The PP2A core enzyme was methylated by a PP2A-specific leucine carboxyl methyltransferase (LCMT1) SIGNOR-265749 0.906 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr80 DQHSISYtLSRAQTV -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276138 0.758 bosutinib chemical CHEBI:39112 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190699 0.8 oxybutynin chemical CHEBI:7856 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 22243489 t Luana  Compared to the reference compound oxybutynin, an antagonist used for the treatment of OAB,(5) the newly synthesized 1,4-dioxane derivatives exhibit a higher potency. SIGNOR-258329 0.8 SREBF2 protein Q12772 UNIPROT PCSK9 protein Q8NBP7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17921436 t miannu Expression of nuclear forms of sterol-regulatory element binding protein-1 (SREBP-1) and SREBP-2 dramatically increased the promoter activity of PCSK9. SIGNOR-255223 0.478 TFEB protein P19484 UNIPROT CYP7A1 protein P22680 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) SIGNOR-276787 0.2 LYN protein P07948 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr783 EGRNPGFyVEANPMP -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249382 0.642 ABL1 protein P00519 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity phosphorylation Tyr102 YDLKLQEyQSAIKVE 10090 BTO:0000007;BTO:0000011 25368164 t We show that the tyrosine kinase Abelson murine leukemia viral oncogene (cAbl) is an adipogenic key regulator. c-Abl promotes adipogenesis by phosphorylation and subsequent stabilization of PPARγ. SIGNOR-262297 0.347 NR3C1 protein P04150 UNIPROT ATP1B1 protein P05026 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 9694812 t miannu Together these data indicate that the 21-base pair sequence represents a true MRE/GRE and that optimal activation of the human Na/K-ATPase beta1 promoter is controlled by mineralocorticoid and glucocorticoid hormones. It appears that an interaction of MR with GR on the beta1 promoter effectively down-regulates transcription. SIGNOR-254864 0.2 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser413 VRYIKENsPCVTPVS 9606 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. SIGNOR-104675 0.844 ADRA2B protein P18089 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257109 0.413 MC5R protein P33032 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257271 0.252 METTL3 protein Q86U44 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007;BTO:0000567 27117702 t miannu Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells.  SIGNOR-265954 0.338 ALDOC protein P09972 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266481 0.8 HCK protein P08631 UNIPROT CBL protein P22681 UNIPROT unknown phosphorylation 10090 10092522 t Hck is one member of the Src-family PTKs that is able to phosphorylate Cbl. Upon enzymatic activation of Hck either by pharmacological agents or genetic mutation, Cbl becomes tyrosine phosphorylated. SIGNOR-251262 0.654 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 20083114 t lperfetto A recent study revealed that ampk can inhibit mtorc1 independently of tsc2 by phosphorylating raptor at ser863. SIGNOR-216422 0.449 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI ITPR1 protein Q14643 UNIPROT up-regulates activity chemical activation 9606 24646566 t miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256239 0.8 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity 9606 BTO:0000007 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-252995 0.909 MRPL57 protein Q9BQC6 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262341 0.62 SRC protein P12931 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Tyr92 FYEEIKKyEKLETEE 9606 BTO:0000007 16725308 t miannu Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq.  SIGNOR-266305 0.2 CUDC-101 chemical CID:24756910 PUBCHEM HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20143778 t miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. SIGNOR-262265 0.8 GATAD2A protein Q86YP4 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263846 0.827 AKT1 protein P31749 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates activity phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 11274386 t lperfetto We show that akt interacts with nur77 and inactivates nur77 by phosphorylation at ser-350 SIGNOR-252466 0.718 AURKA protein O14965 UNIPROT ALDH1A1 protein P00352 UNIPROT up-regulates activity phosphorylation Thr267 KSNLKRVtLELGGKS -1 28193222 t miannu AURKA phosphorylates ALDH1A1 at three critical residues which exert a multifaceted regulation over its level, enzymatic activity, and quaternary structure. While all three phosphorylation sites contribute to its increased stability, T267 phosphorylation primarily regulates ALDH1A1 activity. AURKA-mediated phosphorylation rapidly dissociates tetrameric ALDH1A1 into a highly active monomeric species.  SIGNOR-276750 0.38 PTTG1 protein O95997 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002430 19351864 f miannu PTTG induced S100A4 and galectin-1 mRNA and protein expression as assessed by Western blot and reverse transcription-PCR. SIGNOR-255070 0.274 IRAK1 protein P51617 UNIPROT PELI3 protein Q8N2H9 UNIPROT up-regulates phosphorylation 9606 12874243 t gcesareni Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity. SIGNOR-103983 0.718 GNG2 protein P59768 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 17419683 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt. SIGNOR-252682 0.426 EIF4EBP1 protein Q13541 UNIPROT EIF4E protein P06730 UNIPROT down-regulates activity binding 9606 23584478 t lperfetto The rate-limiting factor for translation is eukaryotic translation initiation factor 4E (eIF4E), which is negatively regulated by eIF4E-binding protein 1 (4E-BP1). SIGNOR-167176 0.938 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Tyr317 TEQDLQLyCDFPNII 9606 BTO:0000007 19364823 t 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2. SIGNOR-236502 0.2 PTGS2 protein P35354 UNIPROT prostaglandin D2 smallmolecule CHEBI:15555 ChEBI up-regulates chemical modification 9606 11751058 t gcesareni Cox catalyzes two enzymatic activities;namely, the conversion of aa to the hydroperoxy endoperoxide pgg2, followed by its subsequent reduction to the labile product pgh2. Pgh2_ is the common substrate for a number of different cell-specific synthases, which convert pgh2_ to the individual pgs or tx, including pge2, pgi2_ (prostacyclin), pgd2, pgf2alfa, and txa2 SIGNOR-113282 0.8 BAZ2B protein Q9UIF8 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity binding 9606 acetylation:Lys15 ARKSTGGkAPRKQLA 31999386 t miannu The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation. SIGNOR-266620 0.2 NLGN1 protein Q8N2Q7 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 18923512 t brain lperfetto Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions. SIGNOR-264191 0.767 MTHFD2 protein P13995 UNIPROT (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI up-regulates quantity chemical modification 9606 16100107 t lperfetto Magnesium and phosphate ions enable NAD binding to methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase|One of the enzymes in this pathway, the NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase (NMDMC),5 catalyzes the interconversion of 5,10-methylenetetrahydrofolate (methylene-THF) and 10-formyltetrahydrofolate (formyl-THF) in mammalian mitochondria. SIGNOR-268255 0.8 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1189 QKGELSRsPSPFTHT 9606 BTO:0000551 19683496 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-187595 0.51 SGK1 protein O00141 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates phosphorylation Thr356 GTRSRSHtSEGTRSR 9606 18787837 t llicata Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1. SIGNOR-180825 0.586 DERA protein Q9Y315 UNIPROT acetaldehyde smallmolecule CHEBI:15343 ChEBI up-regulates quantity chemical modification 9606 25229427 t miannu Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase. SIGNOR-267099 0.8 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation Ser385 RYSDTTDsDPENEPF 9606 BTO:0001938 15987703 t lperfetto We provide evidence suggesting that LKB1 phosphorylates PTEN at residue S385 in combination either with S380, T382 or T383 SIGNOR-247446 0.622 ATP1A3 protein P13637 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 22797008 t miannu The sodium/potassium transporting ATPase subunit alpha-3 (AT1A3; syn.: sodium pump subunit alpha-3; E.C. 3.6.3.9; UniProtKB ID: Q6PIC6) belongs to the cation transport ATPase (P-type) 3.A.3 family catalyzing hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action generates the electrochemical gradient of sodium and potassium ions thus providing energy for active transport of various nutrients. Three sodium/potassium transporting ATPase isoforms are expressed in the brain but AT1A3 is detectable in neurons exclusively. SIGNOR-265793 0.8 LCK protein P06239 UNIPROT CCDC50 protein Q8IVM0 UNIPROT down-regulates activity phosphorylation Tyr279 TDGEDADyTHFTNQQ 9606 BTO:0000567 19059208 t miannu We found that Ymer was considerably phosphorylated on tyrosine residues also via Src family kinases such as Lck. A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling. SIGNOR-262854 0.2 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser139 RRGLLYDsDEEDEER 9606 BTO:0000567 16899510 t gcesareni In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells. SIGNOR-148709 0.961 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser397 SMVGGERsPPRILPP 9606 BTO:0000007 SIGNOR-C17 21059642 t The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). SIGNOR-169322 0.348 NTRK1 protein P04629 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates binding 9606 10092678 t gcesareni The signaling adapter frs-2 competes with shc for binding to the nerve growth factor receptor trka:a model for discriminating proliferation and differentiation SIGNOR-65955 0.77 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation Thr207 FLTEYVAtRWYRAPE 9606 BTO:0000562 19060905 t lperfetto Here we show that autophosphorylation of erk1/2 on thr188 directs erk1/2 to phosphorylate nuclear targets known to cause cardiac hypertrophy. SIGNOR-244565 0.2 SLC36A1 protein Q7Z2H8 UNIPROT proline smallmolecule CHEBI:26271 ChEBI up-regulates quantity relocalization 9606 12748860 t lperfetto Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut. SIGNOR-264741 0.8 SMO protein Q99835 UNIPROT GNAI2 protein P04899 UNIPROT up-regulates activity binding 10090 BTO:0002572 16885213 t lperfetto Using this assay we determined that mouse Smo couples to all members of the Gi family but does not couple to those of other G protein families. SIGNOR-148490 0.404 CCR5 protein P51681 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 20219869 t areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. SIGNOR-255119 0.328 CDH15 protein P55291 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265854 0.62 SMARCE1 protein Q969G3 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269819 0.839 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser664 KKTSGPLsPPTGPPG 9606 15851026 t lperfetto Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. s664 is the primary erk phosphorylation site on tsc2 in vitro and in vivo SIGNOR-244765 0.2 SLC2A4 protein P14672 UNIPROT glucose chemical CHEBI:17234 ChEBI up-regulates quantity relocalization 9606 17403369 t Skeletal muscle both stores glucose as glycogen and oxidizes it to produce energy following the transport step. The principal glucose transporter protein that mediates this uptake is GLUT4, which plays a key role in regulating whole body glucose homeostasis SIGNOR-267288 0.8 CAMK2G protein Q13555 UNIPROT GRIA1 protein P42261 UNIPROT up-regulates activity phosphorylation Ser645 LTVERMVsPIESAED BTO:0000007 7877986 t llicata In this study, CaM-kinase II enhanced kainate currents of expressed glutamate receptor 6 in 293 cells and of wild-type glutamate receptor 1, but not the Ser-627 to Ala mutant, in Xenopus oocytes. | This CaM-kinase II regulatory phosphorylation site is conserved in all AMPA/kainate-type glutamate receptors, and its phosphorylation may be important in enhancing postsynaptic responsiveness as occurs during synaptic plasticity. SIGNOR-250697 0.615 entinostat chemical CHEBI:132082 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191478 0.8 SPAG5 protein Q96R06 UNIPROT CENPE protein Q02224 UNIPROT up-regulates activity 9606 BTO:0000567 17664331 f lperfetto Furthermore, although both the core kinetochore protein Hec1 and the spindle checkpoint kinase Bub1 were unaffected (Fig. 3 C), the kinetochore resident motor protein CENP-E (Yen et al., 1992) and its interaction partner CENP-F (Chan et al., 1998) were delocalized from the kinetochore in the absence of astrin. These cells remained cyclin B1 positive (unpublished data), confirming that they were still in mitosis. These data suggest that the presence of astrin is required for the kinetochore recruitment or maintenance of CENP-E and CENP-F. SIGNOR-252041 0.386 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269378 0.719 ponatinib chemical CHEBI:78543 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition 9606 23468082 t miannu Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family. SIGNOR-259277 0.8 MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 21408055 f andrea cerquone perpetuini We have demonstrated that following muscle damage, phosphorylated STAT3 (p-STAT3) in SCs increases early (within one hour), inducing downstream target genes (i.e. GP130 and SOCS3), which further regulate the increase in STAT3 production and response (as induced via IL-6), leading to increased cMyc expression, which drives cell proliferation SIGNOR-255414 0.7 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser162 FDIVSRGsTADLDGL -1 19661060 t miannu We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-276232 0.2 CHMP7 protein Q8WUX9 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 t miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. SIGNOR-265525 0.604 CSNK1A1 protein P48729 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates quantity by destabilization phosphorylation Ser268 SSNASSVsTRLSPLR 9606 BTO:0001109 28945225 t miannu Here we report that CK1α similarly destabilizes FOXO4 in RAS-mutant cells by phosphorylation at serines 265/268.  SIGNOR-277326 0.2 PRKCA protein P17252 UNIPROT ADD2 protein P35612 UNIPROT down-regulates phosphorylation Ser713 KKKFRTPsFLKKSKK 9606 16116087 t gcesareni We now demonstrate that ptn stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (pk) c substrate domain of beta-adducin through activation of either pkc alpha or beta. SIGNOR-139870 0.2 FNIP2 protein Q9P278 UNIPROT HSP90AB1 protein P08238 UNIPROT down-regulates activity binding 9606 BTO:0000007 27353360 t miannu FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle. SIGNOR-261416 0.266 PRKDC protein P78527 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates phosphorylation Thr135 GGGSTSDtQEDILDE 9606 11867762 t lperfetto Phosphorylation of irf-3 by dna-pk after virus infection results in its nuclear retention and delayed proteolysis SIGNOR-115331 0.406 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser291 PVSSLQAsVPGSVPG -1 16027724 t GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines) SIGNOR-251229 0.389 ACE protein P12821 UNIPROT Angiotensin-2 protein P01019-PRO_0000032458 UNIPROT up-regulates quantity cleavage 9606 32201502 t MIANNU Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I SIGNOR-260236 0.2 Noncanonical PRC1 complex SIGNOR-C151 SIGNOR PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000011 25533466 f miannu We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis. SIGNOR-252251 0.326 QRICH1 protein Q2TAL8 UNIPROT YARS2 protein Q9Y2Z4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269413 0.2 taurine smallmolecule CHEBI:15891 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 9606 BTO:0000007 9009272 t inferred from family member miannu For each mutant GlyR we examined the agonist efficacies of taurine and Œ≤-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where Œ≤-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human Œ±1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and Œ≤-alanine act as full agonists of human Œ±1 GlyRs when expressed in this system. SIGNOR-270259 0.8 ANKRD1 protein Q15327 UNIPROT NPPA protein P01160 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 18273862 t In vitro calpain-mediated degradation assays, coupled to reporter gene analysis in transfected HeLa cells, strongly suggested that this mutation enhances both the stability of the ANKRD1/CARP protein and its transcriptional repression activity upon the cardiac-specific atrial natriuretic factor (ANF) promoter. SIGNOR-253647 0.332 CSNK2A1 protein P68400 UNIPROT PKD2 protein Q13563 UNIPROT up-regulates phosphorylation Ser812 FPRSLDDsEEDDDED 9606 14742446 t gcesareni Ser(812) can be phosphorylated by ck2 in vitro and substitution s812a results in failure to incorporate phosphate in cultured epithelial cells. SIGNOR-121572 0.431 methoxamine chemical CHEBI:6839 ChEBI ADRA1B protein P35368 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258447 0.8 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR1 protein P21453 UNIPROT up-regulates chemical activation 9606 16794003 t gcesareni The evidence suggests that s1p acting on s1p receptors coupled to gq SIGNOR-147227 0.8 POLR2M protein P0CAP2 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266169 0.464 RXRB protein P28702 UNIPROT RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates binding 9606 1310351 t inferred from 70% of family members gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-269852 0.71 MAP4 protein P27816 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 10791892 f miannu We have shown that MAP4 is phosphorylated in vivo in mitotic HeLa cells at eight sites. Five of these were phosphorylated by p34cdc2 kinase. Two of the five p34cdc2 kinase phosphorylation sites were shown to be Ser696 and Ser787 in the proline-rich region. Mutation of Ser787 to Glu strikingly reduced the MAP4's MT-polymerization activity, while Glu-mutation at Ser696 did not. These results suggest that Ser787 could be the critical phosphorylation site causing MTs to be dynamic at mitosis. SIGNOR-277460 0.7 FGFR1 protein P11362 UNIPROT SYNCRIP protein O60506 UNIPROT down-regulates phosphorylation Tyr373 RVKKLKDyAFIHFDE 9606 12601080 t lperfetto Novel in vivo tyrosine phosphorylation sites were found in the fgfr-1, phospholipase cgamma, p90 ribosomal s6 kinase, cortactin, and ns-1-associated protein-1. Syncrip, was very recently found to be phosphorylated in response to insulin treatment of 3t3-l1 adipocytes (32). Phosphorylation of syncrip was accommodated by the insulin receptor tyrosine kinase in vitro but was inhibited upon binding of rna. Tyrosine phosphorylation at tyr-373 in the third rna recognition motif domain of nsap1/syncrip can possibly influence its rna binding properties and thus link fgfr-1 signaling to mrna metabolism. SIGNOR-98704 0.2 DRD4 protein P21917 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257098 0.282 TCF12 protein Q99081 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 22577461 f miannu Hebalt positively regulates t-cell genes, such as pt_ and notch3 SIGNOR-197517 0.26 ZMYND8 protein Q9ULU4 UNIPROT ZMYND8 protein Q9ULU4 UNIPROT up-regulates activity binding 9606 BTO:0000007 27477906 t lperfetto We identified ZMYND8 as a transcriptional corepressor of the H3K4 demethylase JARID1D|Co-immunoprecipitation between ectopically expressed FLAG-tagged JARID1D and endogenous ZMYND8 protein. SIGNOR-262037 0.2 fingolimod chemical CHEBI:63115 ChEBI S1PR1 protein P21453 UNIPROT down-regulates chemical inhibition 9606 22225501 t gcesareni Sphingosine-1-phosphate (s1p(1)) receptor agonists such as fingolimod (fty-720) are a novel class of immunomodulators that have clinical utility in the treatment of remitting relapsing multiples sclerosis. SIGNOR-195343 0.8 DPP3 protein Q9NY33 UNIPROT KEAP1 protein Q14145 UNIPROT down-regulates quantity by destabilization cleavage 9606 35278345 t miannu The influence of DPP3 on the Keap1-Nrf2/ARE signal pathway suggest a direct involvement of DPP3 in the oxidative stress response [8,14,31,53,99,100]. It was shown that DPP3 competes with Nrf2 through the ETGE motif to bind to Keap1 and consequently enhances the translocation of Nrf2 to the nucleus, thereby driving the expression of an array of genes encoding antioxidative enzymes [99]. More specifically, binding of DPP3 to Keap1 releases Nrf2, and thus, prevents its degradation through the 26S proteasome SIGNOR-268464 0.617 CSNK2A1 protein P68400 UNIPROT IFI16 protein Q16666 UNIPROT up-regulates activity phosphorylation Ser132 GAQKRKKsTKEKAGP 9606 BTO:0000567 11115400 t llicata Here we examine the functionality of the interferon-induced factor 16 (IFI 16) CcN motif, demonstrating its ability to target a heterologous protein to the nucleus, and to be phosphorylated specifically by the CcN-motif-phosphorylating protein kinase CK2 (CK2). | Specific phosphorylation of IFI 16 Ser132 in HeLa cell extracts and by purified CK2 in vitro SIGNOR-250902 0.327 SOX17 protein Q9H6I2 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10549281 t gcesareni Two additional sox proteins, xsox17alfa and xsox3 , likewise bind to beta-catenin and inhibit its tcf-mediated signaling activity SIGNOR-72006 0.673 SCF-SKP2 complex SIGNOR-C136 SIGNOR MEF2D protein Q14814 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000944 25733682 t miannu  MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitin-proteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding.  SIGNOR-276889 0.292 PTCH1 protein Q13635 UNIPROT SMO protein Q99835 UNIPROT down-regulates activity binding 9606 14556242 t lperfetto In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling.Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other. SIGNOR-118609 0.778 dexamethasone chemical CHEBI:41879 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 27660409 t diabetic macular edema gcesareni They differ according to their glucocorticoid-receptor binding affinities (dexamethasone > triamcinolone > fluocinolone) and their lipophilicity (triamcinolone > fluocinolone > dexamethasone), characteristics that may partially explain their relative potencies SIGNOR-251694 0.8 RORA protein P35398 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20817722 t miannu Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding. SIGNOR-267982 0.676 CUL5 protein Q93034 UNIPROT ARIH2 protein O95376 UNIPROT up-regulates activity binding 9606 BTO:0000007 24076655 t miannu Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin. SIGNOR-268843 0.515 PRKCA protein P17252 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Thr147 PIPTRRHtFRRQNVR 9606 BTO:0000142 10441128 t gcesareni Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells. SIGNOR-69938 0.702 CD226 protein Q15762 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR up-regulates 9606 BTO:0000914 15039383 f lperfetto CD226 and LFA-1 cooperate in cytotoxicity and cytokine secretion mediated by T and NK cells|These results were consistent with our observation that cross-linking CD226 with anti- CD226 mAb did not induce re-directed cytotoxicity against P815 by LFA-1-deficient LAD NK clones (Fig. 4D), suggesting a requirement for LFA-1 for CD226-mediated cytotoxicity. SIGNOR-261427 0.527 HCK protein P08631 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC -1 12244095 t Activation of STAT3 by the Src family kinase Hck requires a functional SH3 domain. Direct Phosphorylation of STAT3 on Tyr-705 by Src Family Kinases SIGNOR-251267 0.602 PPARA protein Q07869 UNIPROT Fatty_acid_oxidation phenotype SIGNOR-PH129 SIGNOR up-regulates 9606 BTO:0001103;BTO:0000671 18836859 f miannu PPAR-α is predominantly expressed in the liver and skeletal muscles, participating in fatty-acids catabolism. PPAR-α also activates fatty-acid oxidation in the kidney, skeletal muscles, and heart SIGNOR-268027 0.7 WNT5A protein P41221 UNIPROT FZD6 protein O60353 UNIPROT up-regulates activity binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. SIGNOR-141437 0.685 F2R protein P25116 UNIPROT RAB3A protein P20336 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254845 0.2 KIT protein P10721 UNIPROT STAP1 protein Q9ULZ2 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10679268 t miannu STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells. SIGNOR-261820 0.486 HNF4G protein Q14541 UNIPROT AFP protein P02771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 9792724 f miannu AFP promoter-chloramphenicol acetyltransferase transient transfection assays demonstrated that the level of HNF1 had a direct impact on basal transcription as well as RA-mediated down-regulation of the AFP gene, and that co-transfection of HNF1 and HNF4, but not transfection of either factor alone, reversed the RA-mediated inhibition. Taken together these data point to an interaction among the RA, HNF1, and HNF4 signals, which is reflected in decreased expression of AFP. SIGNOR-254442 0.2 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 10482988 t miannu Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. SIGNOR-251146 0.434 OGT protein O15294 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. SIGNOR-267158 0.539 MET protein P08581 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0001033 22035268 f miannu C-Met expression and activation appears to be one of the common mechanisms of resistance to other targeted therapies. Given these multiple roles of c-Met in prostate cancer, several c-Met inhibitors have been developed. Evidence to date suggests that aberrant activation of the HGF/c-Met axis in prostate cancer epithelial cells appears to be a relatively late event in tumor progression. C-Met expression increases in advanced stages of the disease, with the highest expression observed in bone metastases. SIGNOR-263658 0.7 SMAD1/4 complex SIGNOR-C85 SIGNOR CEBPB protein P17676 UNIPROT up-regulates activity binding 9606 18854943 t fferrentino This Smad1/4 complex can directly interact with Shn-2 and C/EBP a on the PPAR g promoter thus, resulting in the transcriptional activation of PPAR g SIGNOR-253552 0.542 indometacin chemical CHEBI:49662 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition -1 9057869 t miannu Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). SIGNOR-258607 0.8 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser157 EHIERRVsNAGGPPA 9606 14679200 t lperfetto Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro SIGNOR-120347 0.729 UVRAG protein Q9P2Y5 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates activity binding 9606 18843052 t lperfetto Although both human atg14 and uvrag interact with beclin 1 and vps34. SIGNOR-181554 0.802 AKT1 protein P31749 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates phosphorylation Ser346 LLCLRRSsLKAYGNG 9606 11809767 t lperfetto Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation. SIGNOR-252470 0.362 UVB radiation stimulus SIGNOR-ST17 SIGNOR IL1B protein P01584 UNIPROT up-regulates 9606 9767234 f miannu UVB can stimulate the synthesis of IL-1, TNF-a and ET-1, and other cytokines by keratinocytes. SIGNOR-252382 0.7 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PTTG1 protein O95997 UNIPROT up-regulates phosphorylation 9606 10906323 t inferred from 70% family members gcesareni Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function. SIGNOR-270038 0.2 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 16076840 t gcesareni The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex. SIGNOR-139324 0.346 MAPK14 protein Q16539 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser396 TFDSLPSsPSSATPH -1 12171600 t miannu Inhibition of eEF2 kinase resulting from phosphorylation of Ser-396 by SAPK2a p38 was approx.25%. SIGNOR-249707 0.34 CDK1 protein P06493 UNIPROT CEP55 protein Q53EZ4 UNIPROT down-regulates phosphorylation Ser428 KVAASPKsPTAALNE 9606 16198290 t lperfetto Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis. SIGNOR-140886 0.46 perfluorooctanoic acid chemical CHEBI:35549 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 10090 BTO:0000011 16731579 t miannu Human, mouse, and rat PPARα were activated by PFOA isomers and PFOS. SIGNOR-268790 0.8 DAB2IP protein Q5VWQ8 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization 9606 27476001 f miannu DAB2IP destabilizes HIF1Œ± protein to inhibit EMT in PCa cells. DAB2IP may destabilize HIF1Œ± protein in PCa cells via an ubiquitin-proteasome system. SIGNOR-254765 0.2 TPH2 protein Q8IWU9 UNIPROT tryptophan smallmolecule CHEBI:27897 ChEBI down-regulates quantity chemical modification 9606 31024440 t brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. SIGNOR-264011 0.8 MAPK1 protein P28482 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation Ser455 SIDSEPGsPLLDDAK 9606 14988395 t lperfetto Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity. SIGNOR-123045 0.365 UIMC1 protein Q96RL1 UNIPROT BRCA1-A complex complex SIGNOR-C296 SIGNOR form complex binding 9606 BTO:0000007 20656690 t lperfetto We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1.  SIGNOR-263211 0.923 KRAS protein P01116 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 7744823 t fstefani Mitogen-activated protein kinase kinase kinase (mekk1) is a serine-threonine kinase that regulates sequential protein kinase pathways involving stress-activated protein kinases and mitogen-activated protein kinases. Mekk1 is activated in response to growth factor stimulation of cells and by expression of activated ras. mekk1 directly binds ras.GTP. Thus, ras interacts with protein kinases of both the raf and mekk families. SIGNOR-32620 0.373 BZW2 protein Q9Y6E2 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 BTO:0003897 30805927 f francesca Overexpression (or silence) of BZW2 in HCC cells significantly stimulates (or decreases) the activation of the PI3K/AKT/mTOR signaling pathway SIGNOR-261218 0.2 PRKDC protein P78527 UNIPROT PNPT1 protein Q8TCS8 UNIPROT up-regulates activity phosphorylation Ser776 IVMGEPIsQSSSNSQ 9606 22815474 t miannu We also demonstrated that DNAPK phosphorylates PNPase at Ser-776, which is critical for its ribonuclease activity. SIGNOR-263182 0.2 ZAP70 protein P43403 UNIPROT MUC1 protein P15941 UNIPROT up-regulates activity phosphorylation Tyr1203 IFPARDTyHPMSEYP 9606 BTO:0000661 14766232 t lperfetto Indeed, the present results demonstrate that ZAP-70 phosphorylates MUC1-CD and that the MUC1-CD Y-20 site functions, at least in part, as a ZAP-70 substrate (Fig. 4C). In this regard, the in vivo phosphorylation data indicate that ZAP-70 may also contribute to phosphorylation of MUC1-CD Y-46.The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 andBeta-catenin. SIGNOR-247039 0.459 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser208 DAGSPNLsPNPMSPA -1 15241418 t llicata Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. | Thr 8 and the four sites in the linker (Thr 178, Ser 203, Ser 207 and Ser 212). Each of the five sites was phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo. SIGNOR-250767 0.748 Caspase 3 complex complex SIGNOR-C221 SIGNOR PSIP1 protein O75475 UNIPROT down-regulates cleavage 9606 BTO:0001130 18708362 t miannu Ledgf/ p75 has a cooh-terminally truncated splice variant, p52 / during apoptosis, caspase-3 cleaved p52 to generate a p38 fragment that lacked the nh2-terminal pwwp domain and failed to transactivate the hsp27 promoter in reporter assays. However, p38 retained chromatin association properties and repressed the transactivation potential of ledgf/p75 SIGNOR-256469 0.355 AKT2 protein P31751 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C3 17277771 t gcesareni Furthermore, pras40 phosphorylation by akt and association with 14-3-3, a cytosolic anchor protein, are crucial for insulin to stimulate mtor. These findings identify pras40 as an important regulator of insulin sensitivity of the akt-mtor pathway and a potential target for the treatment of cancers, insulin resistance and hamartoma syndromes. SIGNOR-152936 0.66 LPAR2 protein Q9HBW0 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 15856019 t gcesareni Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. lpa2 also can couple to the gi/o, g12/13, and gqfamilies. SIGNOR-135834 0.47 NR3C1 protein P04150 UNIPROT HNF4A protein P41235 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17978169 t gcesareni Electrophoretic mobility shift, chromatin immunoprecipitation (ChIP), and streptavidin DNA binding assays revealed that DEX increased binding of HNF4alpha to the HNF4-RE and that an interaction of GR and HNF4alpha occurred at this site. SIGNOR-251684 0.377 DPF2 protein Q92785 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR up-regulates activity binding 9606 BTO:0000007 20460684 t miannu Our current findings indicate that REQ is a novel adaptor protein that links the Brm-type SWI/SNF complex and RelB/p52 and operates at the most downstream stages of the noncanonical NF-κB pathway. SIGNOR-261963 0.626 PKC proteinfamily SIGNOR-PF53 SIGNOR GNE protein Q9Y223 UNIPROT up-regulates activity phosphorylation 10116 BTO:0000759 10745088 t lperfetto Protein kinase C phosphorylates and regulates UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase|Furthermore, PKC phosphorylates UDP-GlcNAc 2-epimerase and this phosphorylation results in an upregulation of the UDP-GlcNAc 2-epimerase enzyme activity. SIGNOR-266072 0.2 MECP2 protein P51608 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0002881 19427855 f Luana Neuronal differentiation of neural precursor cells is promoted by the methyl-CpG-binding protein MeCP2 SIGNOR-264966 0.7 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219312 0.749 UHMK1 protein Q8TAS1 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Ser299 GRDSRSGsPMARR 9606 10880969 t lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. Mass spectrometry and peptide sequencing allowed us to identify serine 164 of mbp as the unique site phosphorylated by kis. Phosphorylation of synthetic peptides indicated the importance of the proline residue at position +1. SIGNOR-78895 0.2 ALDOB protein P05062 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266480 0.8 C1QBP protein Q07021 UNIPROT Complement C1q complex SIGNOR-C308 SIGNOR down-regulates activity binding 28018340 t lperfetto Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping. SIGNOR-263401 0.382 XAV939 chemical CHEBI:62878 ChEBI TNKS protein O95271 UNIPROT down-regulates activity chemical inhibition -1 19759537 t In biochemical activity assays, XAV939 strongly inhibited TNKS1 and TNKS2, with half-maximal inhibitory concentration values of 0.011 and 0.004 μM, respectively, but displayed much weaker effects on PARP1 and PARP2 SIGNOR-259994 0.8 ETS1 protein P14921 UNIPROT MUC4 protein Q99102 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001861 19757157 t lperfetto Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level. SIGNOR-254098 0.2 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Ser283 CASVRRAsSADDIEA 9606 10488078 t lperfetto Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a) SIGNOR-70722 0.312 tamoxifen citrate chemical CHEBI:9397 ChEBI ESR1 protein P03372 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000150 20512796 t miannu Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth. SIGNOR-259301 0.8 DUSP26 protein Q9BV47 UNIPROT TP53 protein P04637 UNIPROT down-regulates dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 20562916 t miannu We found that dusp26 promotes the resistance of human neuroblastoma to doxorubicin-induced apoptosis by acting as a p53 phosphatase to downregulate p53 tumor suppressor function in neuroblastoma cells. / we found that dusp26 binds to p53 and dephosphorylates p53 at ser20 and ser37. SIGNOR-166262 0.374 LCK protein P06239 UNIPROT MUC1 protein P15941 UNIPROT up-regulates activity phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 14766232 t lperfetto The present results demonstrate that Lck phosphorylation of MUC1 on Y-46 also increases binding of MUC1 and _-catenin. The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 and _-catenin SIGNOR-247058 0.472 CALM3 protein P0DP25 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity binding 9606 BTO:0001853 24379783 t miannu Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer SIGNOR-266339 0.582 CNR2 protein P34972 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257095 0.252 CHUK protein O15111 UNIPROT TAX1BP1 protein Q86VP1 UNIPROT up-regulates activity phosphorylation Ser666 RPPVRVPsWGLEDNV 10090 BTO:0002572 21765415 t The effect has been demonstrated using Q86VP1-2 lperfetto Here we demonstrate that tax1bp1 was inducibly phosphorylated on ser593 and ser624 in response to proinflammatory stimuli. The kinase ikkalpha, but not ikkbeta, was required for phosphorylation of tax1bp1 and directly phosphorylated tax1bp1 in response to stimulation with tumor necrosis factor (tnf) or interleukin 1 (il-1). SIGNOR-175062 0.391 CSNK2A1 protein P68400 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Ser482 SSMQPDNsSDSDYDL 9606 9834084 t lperfetto In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461) SIGNOR-62303 0.349 FYN protein P06241 UNIPROT CNN3 protein Q15417 UNIPROT down-regulates activity phosphorylation Tyr261 SQKGMSVyGLGRQVY 9534 BTO:0000298 15206927 t We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin SIGNOR-251159 0.339 DOK4 protein Q8TEW6 UNIPROT SRC protein P12931 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 t gcesareni Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells. SIGNOR-101002 0.429 PAX3 protein P23760 UNIPROT PITX2 protein Q99697 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21143873 f gcesareni Pitx genes, such as pitx2, which is positively regulated by pax3, have been implicated in myogenesis. SIGNOR-170343 0.28 CDK5 protein Q00535 UNIPROT PLD2 protein O14939 UNIPROT down-regulates activity phosphorylation Ser134 ARFAVAYsPARDAGN 9606 BTO:0000007 18625302 t miannu In this study, we suggest that the phosphorylation and activation of PLD2 by cyclin-dependent kinase 5 (Cdk5) is critical for EGF-dependent insulin secretion. We determined that the phosphorylation site of PLD2 was located at Ser(134). SIGNOR-276168 0.376 ARHGAP30 protein Q7Z6I6 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260485 0.425 CUL3 protein Q13618 UNIPROT HSF2 protein Q03933 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0002572 19768582 t 1 miannu Here we show that the PEST sequences of a short-lived protein called HSF2 interact with Cullin3, a subunit of a Cullin-RING E3 ubiquitin ligase, and that this interaction mediates the Cul3-dependent ubiquitination and degradation of HSF2 SIGNOR-239129 0.332 CCND3 protein P30281 UNIPROT CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR form complex binding 8114739 t lperfetto Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells. SIGNOR-273027 0.934 A9/b1 integrin complex SIGNOR-C166 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269015 0.7 CSNK2A1 protein P68400 UNIPROT CERS6 protein Q6ZMG9 UNIPROT up-regulates activity phosphorylation Ser345 DDRSDIEsSSDEEDS 9606 BTO:0000007 26887952 t miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  SIGNOR-273991 0.2 ponatinib chemical CHEBI:78543 ChEBI RET protein P07949 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001271;BTO:0000184 23526464 t miannu The RET tyrosine kinase encoding gene acts as a dominantly transforming oncogene in thyroid carcinoma and other malignancies. Ponatinib (AP24534) is an oral ATP-competitive tyrosine kinase inhibitor that is in advanced clinical experimentation in leukemia.Ponatinib is a potent inhibitor of RET kinase and has promising preclinical activity in models of RET-driven medullary thyroid carcinoma. SIGNOR-259275 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR JUND protein P17535 UNIPROT up-regulates phosphorylation 9606 22327296 t inferred from 70% family members gcesareni Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase. SIGNOR-270083 0.2 CDK1 protein P06493 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser86 TKNGLPGsRPGSPER 9606 16103124 t gcesareni Moreover, app stabilized tip60 through cdk-dependent phosphorylation SIGNOR-139649 0.491 AMFR protein Q9UKV5 UNIPROT MFN2 protein O95140 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 23427266 t miannu Gp78 induces ubiquitylation and proteasomal degradation of Mfn1 and Mfn2. SIGNOR-272887 0.304 MSH6 protein P52701 UNIPROT MSH2/MSH6 complex SIGNOR-C60 SIGNOR form complex binding 9606 15064730 t miannu The human msh2/6 complex is essential for mismatch recognition during the repair of replication errors. SIGNOR-123708 0.805 FGF9 protein P31371 UNIPROT BMP2 protein P12643 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 f FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1. gcesareni Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts. SIGNOR-195591 0.383 SRPK2 protein P78362 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19592491 f lperfetto Compared with control, srpk2 wild type evidently elevated cyclin d1 transcription, and the catalytic activity was lost in srpk2 kd, suggesting that kinase activity of srpk2 is required for this effect. SIGNOR-186763 0.2 MAPK1 protein P28482 UNIPROT PDXDC1 protein Q6P996 UNIPROT unknown phosphorylation Thr691 AGVTLPPtPSGSRTK 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262759 0.2 LPAR1 protein Q92633 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257091 0.524 YES1 protein P07947 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). SIGNOR-276185 0.2 prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI prostaglandin H2(1-) smallmolecule CHEBI:57405 ChEBI up-regulates quantity precursor of -1 10922363 t Luana Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently. SIGNOR-269767 0.8 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT down-regulates activity phosphorylation Ser768 EPLERRLsLVPDSEQ 9606 19095655 t Luana AMPK phosphorylates CFTR in vitro at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites. SIGNOR-18141 0.467 PPP1R1B protein Q9UD71 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity binding 9606 BTO:0000938 10604473 t miannu DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚  SIGNOR-264957 0.583 RNF111 protein Q6ZNA4 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates ubiquitination 9606 14657019 t gcesareni Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia SIGNOR-119666 0.725 amitriptyline chemical CHEBI:2666 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8100134 t miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. SIGNOR-258703 0.8 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser289 RSHSESAsPSALSSS 10090 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-143688 0.622 ITCH protein Q96J02 UNIPROT ERBB4 protein Q15303 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0000298 18334649 t miannu  Itch catalyzed ubiquitination of ErbB4 CYT-1, promoted its localization into intracellular vesicles, and stimulated degradation of ErbB4 CYT-1 SIGNOR-271416 0.59 FER protein P16591 UNIPROT FER protein P16591 UNIPROT up-regulates activity phosphorylation Tyr714 RQEDGGVySSSGLKQ -1 19159681 t miannu  Mutation analysis unveiled a tyrosine (Tyr(616)) embedded in the Hsp90 recognition loop, which is required for the kinase activity of Fer. Replacement of this tyrosine by phenylalanine (Y616F) disabled the auto-phosphorylation activity of Fer and abolished its ability to phosphorylate Stat3.  SIGNOR-276236 0.2 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser376 PPAPAYLsSPLALPS 9606 SIGNOR-C14 SIGNOR-C14 12657630 t IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376. IKK≈í‚⧠mediates IKK≈í‚â• phosphorylation under physiologic signaling conditions. IKK≈í‚â• is chronically phosphorylated in cells expressing the HTLV1 Tax oncoprotein, which interfaces directly with the I≈í‚à´B kinase complex.both Tax and TNF induce phosphorylation of human IKK≈í‚â• at Ser-31, Ser-43, and Ser-376. SIGNOR-251286 0.962 LCK protein P06239 UNIPROT CTLA4 protein P16410 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 9973379 t Lck and Fyn, but not ZAP70, induce tyrosine phosphorylation of CTLA-4 in the cell line HEK293. Phosphorylation of CTLA-4 occurs on both Y201 and Y218. Phosphorylation of Y201 correlated with accumulation of CTLA-4 on the cell surface. SIGNOR-251370 0.739 4-[4-(6-methoxy-2-naphthalenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine chemical CHEBI:91442 ChEBI TEK protein Q02763 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207287 0.8 BLK protein P51451 UNIPROT FCGR2A protein P12318 UNIPROT up-regulates activity phosphorylation Tyr304 TDDDKNIyLTLPPND -1 8756631 t lperfetto To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation. SIGNOR-249312 0.447 PAK2 protein Q13177 UNIPROT MYLK protein Q15746 UNIPROT down-regulates activity phosphorylation Ser1760 RAIGRLSsMAMISGL -1 10748018 t miannu PAK2 can directly phosphorylate MLCK, inhibiting its activity and limiting the development of isometric tension. PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991. SIGNOR-250223 0.513 AURKB protein Q96GD4 UNIPROT CDCA2 protein Q69YH5 UNIPROT down-regulates activity phosphorylation Ser542 KKINRRKsQETKCTK 9606 BTO:0000567 32938714 t done miannu This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin. SIGNOR-274002 0.457 POLA2 protein Q14181 UNIPROT DNA polymerase alpha:primase complex complex SIGNOR-C262 SIGNOR form complex binding -1 24043831 t lperfetto At the replication fork, primase is present in a constitutive complex with DNA polymerase α (Pol α), which extends the RNA primer with deoxynucleotides and makes the resulting RNA–DNA primer available to the leading- and lagging-strand polymerases, Pols ε and δ, for processive elongation  SIGNOR-261342 0.979 FASTKD5 protein Q7L8L6 UNIPROT COX4I1 protein P13073 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25683715 f miannu FASTKD5 is required for maturing precursor mRNAs that are not flanked by tRNAs and that therefore cannot be processed by the canonical mRNA maturation pathway. Silencing FASTKD5 rendered mature COX I mRNA almost undetectable, which severely reduced the synthesis of COX I, resulting in a complex IV assembly defect. SIGNOR-261223 0.2 GDNF protein P39905 UNIPROT ID1 protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252179 0.2 D-glucopyranose smallmolecule CHEBI:4167 ChEBI UDP(3-) smallmolecule CHEBI:58223 ChEBI up-regulates quantity precursor of 9606 16157350 t miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. SIGNOR-268472 0.8 CALM1 protein P0DP23 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT up-regulates binding 9606 10770941 t lperfetto The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases SIGNOR-232178 0.756 COL1A1 protein P02452 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253247 0.55 RCOR1 protein Q9UKL0 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 10449787 f miannu We show here that CoREST, a newly identified human protein, functions as a corepressor for REST. A single zinc finger motif in REST is required for CoREST interaction. Together, REST and CoREST mediate repression of the type II sodium channel promoter in nonneural cells, and the REST/CoREST complex may mediate long-term repression essential to maintenance of cell identity. SIGNOR-220695 0.273 PCK1 protein P35558 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 30193097 t miannu ¬†PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP).¬† SIGNOR-266587 0.8 MEN1 protein O00255 UNIPROT TERT protein O14746 UNIPROT down-regulates 9606 12837246 f miannu The tumor suppressor menin, is a direct repressor of htert SIGNOR-102874 0.311 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120028 0.781 CUL2 protein Q13617 UNIPROT APOBEC3A protein P31941 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 29367246 t lperfetto Human Papillomavirus 16 E7 Stabilizes APOBEC3A Protein by Inhibiting Cullin 2-Dependent Protein Degradation|Here, we report that the HPV oncoprotein E7 stabilizes the APOBEC3A (A3A) protein in human keratinocytes by inhibiting ubiquitin-dependent protein degradation in a cullin-dependent manner. SIGNOR-261325 0.253 PRKDC protein P78527 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 9363941 t gcesareni We demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of mdm2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by dna-pk (or other protein kinases with similar specificity) in response to dna damage. SIGNOR-53030 0.785 ATP5F1C protein P36542 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261405 0.2 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser239 GAKLRKVsKQEEASG 9606 14679200 t lperfetto Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro SIGNOR-120351 0.729 PRKACA protein P17612 UNIPROT VTN protein P04004 UNIPROT unknown phosphorylation Ser397 NQNSRRPsRATWLSL -1 1706595 t miannu Phosphorylation of vitronectin by protein kinase A is stoichiometric (approx. 1 mol/mol), that it is targeted to one site (Ser-378) at the C-terminal edge of the heparin-binding domain. gh the role of phosphorylation by PKA remains to be established, the identification of Ser-378 as the sole site for PKA action, and the proximity of the phosphorylation site to the point of cleavage that converts V75 into V65 10' focuses attention on a putative role for PKA in the modulation of this cleavage. SIGNOR-250072 0.312 PRKCE protein Q02156 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP. SIGNOR-249258 0.263 RAF1 protein P04049 UNIPROT KLF10 protein Q13118 UNIPROT down-regulates quantity by destabilization phosphorylation Thr93 TIPAFCLtPPYSPSD 9606 BTO:0000018 23994618 t miannu RAF1 phosphorylates the Thr93 site of KLF10 in vivo. Since the phosphorylation of Thr93 enables KLF10 and PIN1 to bind, it seems likely that RAF-1 will have an effect on KLF10 stability that is similar to that of PIN1.PIN1 facilitates KLF10 protein degradation. ( SIGNOR-276502 0.2 MAPKAPK2 protein P49137 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates phosphorylation Ser323 KDLGRSEsLRVVCRP 9606 16456544 t lperfetto Mk2 activated limk1 by phosphorylation at ser-323. SIGNOR-144333 0.367 RSPO2 protein Q6UXX9 UNIPROT LGR5 protein O75473 UNIPROT up-regulates binding 9606 21693646 t Furin domain gcesareni Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation SIGNOR-174532 0.681 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 18593525 f gcesareni Dag and ip3 initiate further signal transduction pathways through activation of protein kinase c (pkc) and intracellular calcium release. SIGNOR-179288 0.8 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10611223 t lperfetto Pak phosphorylates bad in vitro and in vivo on ser112 and ser136, resulting in a markedly reduced interaction between bad and bcl-2 or bcl-x(l) and the increased association of bad with 14-3-3tau. SIGNOR-73533 0.341 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 10428798 t lperfetto Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity. SIGNOR-217284 0.429 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Ser6 sKKRKFVA 9606 15950189 t lperfetto It has been shown previously that ribosomal protein s3 (rps3) SIGNOR-137967 0.2 PPARA protein Q07869 UNIPROT LPL protein P06858 UNIPROT up-regulates activity 9606 16511610 f Regulation miannu The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to a PPAR-alpha-dependent stimulation of lipoprotein lipase and of apolipoprotein (apo)A-V and to an inhibition of apoC-III expression, whereas the increase in plasma HDL-cholesterol depends partly on an overexpression of apoA-I and apoA-II.  SIGNOR-251849 0.575 RERE protein Q9P2R6 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000932 28144959 t miannu In mammalian cells, RERE co‐immunoprecipitates with CBF1 and Notch intracellular domain (NICD), and is recruited to nuclear foci formed by over‐expressed NICD1. RERE is also necessary for NICD to activate the expression of Notch target genes. SIGNOR-264486 0.323 PRKCA protein P17252 UNIPROT OPRD1 protein P41143 UNIPROT unknown phosphorylation Ser344 CGRPDPSsFSRAREA 9606 BTO:0000007 11085981 t lperfetto In the current study, we identified a PKC-mediated phosphorylation site in the delta-opioid receptor (DOR) and demonstrated that activation of PKC by stimulation of other types of GPCR or increase in intracellular Ca2+concentration in HEK 293 cells induces heterologous phosphorylation of DOR. Our results further established that DOR phosphorylation at Ser-344 by PKC results in internalization of DOR in HEK 293 cells through a beta-arrestin- and clathrin-mediated mechanism. SIGNOR-249062 0.355 STK3 protein Q13188 UNIPROT SAV1 protein Q9H4B6 UNIPROT up-regulates phosphorylation -1 BTO:0000007 16930133 t milica In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. The stabilizing effect of Mst was much greater on N-terminally truncated hSav mutants, as long as they retained the ability to bind Mst. Mst mutants that lacked the C-terminal coiled-coil domain and were unable to bind to hSav, also failed to stabilize or phosphorylate hSav SIGNOR-230716 0.827 AURKB protein Q96GD4 UNIPROT SKA1 protein Q96BD8 UNIPROT up-regulates activity phosphorylation -1 22371557 t miannu Aurora B directly phosphorylated Ska1 and Ska3 in vitro, and expression of phosphomimetic mutants of Ska1 and Ska3 impaired Ska KT recruitment and formation of stable KT-MT fibers (K-fibers), disrupting mitotic progression. We propose that Aurora B phosphorylation antagonizes the interaction between the Ska complex and the KMN network, thereby controlling Ska recruitment to KTs and stabilization of KT-MT attachments. SIGNOR-262662 0.725 ESR1 protein P03372 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates binding 9606 16169518 t gcesareni Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k. SIGNOR-140473 0.526 CHL1 protein O00533 UNIPROT ANK3 protein Q12955 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 t miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. SIGNOR-266723 0.422 IGF1 protein P05019 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates 10090 BTO:0000165;BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 10448861 f lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. SIGNOR-235645 0.278 H3C1 protein P68431 UNIPROT Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR up-regulates activity 9606 22266761 f Gianni Widely described to be associated with active chromatin, H3K36 methylation has also been implicated in transcriptional repression, alternative splicing, dosage compensation, DNA replication and repair SIGNOR-269072 0.7 UNC80 protein Q8N2C7 UNIPROT UNC79 protein Q9P2D8 UNIPROT up-regulates activity binding 9606 BTO:0000142 22196327 t miannu The NALCN complex in the brain consists of NALCN, UNC80 and UNC79. UNC80 directly associates with NALCN and UNC79 forms part of the complex by its interaction with UNC80. SIGNOR-265183 0.796 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr534 NFLMDNAyFCEADAK 10029 BTO:0000246 12907755 t PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates SIGNOR-248393 0.299 rivaroxaban chemical CHEBI:68579 ChEBI F10 protein P00742 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206550 0.8 HBB protein P68871 UNIPROT CD163 protein Q86VB7 UNIPROT up-regulates activity binding 9606 16522161 t Regulation miannu These data suggest that hemoglobin may mediate a stimulatory effect on erythropoiesis through the activation of CD163 on hematopoietic progenitor cells. SIGNOR-251746 0.418 HOXD10 protein P28358 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates activity binding -1 9343407 t 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. SIGNOR-241226 0.383 HEXIM1 protein O94992 UNIPROT KDM5B protein Q9UGL1 UNIPROT up-regulates activity relocalization 9606 BTO:0000815 31776402 t lperfetto We previously reported that the tumor suppressor HEXIM1 is a mediator of KDM5B recruitment to its target genes, and HEXIM1 is required for the inhibition of nuclear hormone receptor activity by KDM5B.  SIGNOR-273439 0.2 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR EDC3 protein Q96F86 UNIPROT down-regulates activity binding 10029 BTO:0000246 20051463 t miannu 14-3-3 binding to EDC3 resulted in a significant decrease in the binding of several key mRNA regulatory factors such as PABP and Y-box-binding protein 1 to EDC3. SIGNOR-262630 0.2 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT up-regulates activity phosphorylation Tyr1048 GMTCAELyEKLPQGY -1 11513602 t lperfetto Isoelectric focusing electrophoresis and mass spectrometric analysis of a tie2 autophosphorylation time course showed that tyr992 on the putative activation loop was phosphorylated first followed by tyr1108 in the c-terminal tail autophosphorylation of tie2 to produce ptie2 resulted in a 100-fold increase in kcat and a 460-fold increase in kcat/km. SIGNOR-109786 0.2 GATA1 protein P15976 UNIPROT GP9 protein P14770 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002581 15466856 f miannu Both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. SIGNOR-254161 0.362 TBXA2R protein P21731 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256887 0.64 FYN protein P06241 UNIPROT VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 11005864 t lperfetto Study of t cells from a fyn-deficient tcr transgenic mouse also showed that fyn was required for tyrosine phosphorylation and activation of vav induced by both antagonist and agonist peptides. SIGNOR-82287 0.621 RUNX2 protein Q13950 UNIPROT BMP2 protein P12643 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15765505 f gcesareni Runx2 is an important mediator of the expression of bmp-2 in response to fgf stimulation in cranial bone development SIGNOR-134515 0.508 TUT7 protein Q5VYS8 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR down-regulates 25480299 f lperfetto Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells. Consistently, purified TUT4/7 selectively recognize and uridylate RNAs with short A-tails (less than ∼ 25 nt) in vitro. PABPC1 antagonizes uridylation of polyadenylated mRNAs, contributing to the specificity for short A-tails. SIGNOR-268354 0.7 CSNK2A1 protein P68400 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates activity phosphorylation Ser424 CDEEFSDsEDEGEGG 9606 BTO:0000567 12082111 t llicata HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2. SIGNOR-250888 0.61 SRC protein P12931 UNIPROT KCNB1 protein Q14721 UNIPROT up-regulates phosphorylation Tyr128 YWGIDEIyLESCCQA 9606 BTO:0000938 19622611 t flangone In the present study we show that an n-terminal tyrosine of kv2.1 (y124), which is a known target of src kinase, is critical for the apoptotic current surge..Kv2.1-mediated k+ currents are also enhanced during non-injurious conditions through direct phosphorylation of intracellular n-terminal residue tyrosine 124 (y124) by src kinase SIGNOR-187201 0.492 PIP5K1A protein Q99755 UNIPROT LRP6 protein O75581 UNIPROT up-regulates 9606 18772438 f gcesareni Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki. In turn, ptdins (4,5)p2 regulated phosphorylation of lrp6 at thr1479 and ser1490 SIGNOR-180800 0.276 TBK1 protein Q9UHD2 UNIPROT HTT protein P42858 UNIPROT up-regulates activity phosphorylation Ser13 KLMKAFEsLKSFQQQ 9606 BTO:0000007 32757223 t Herein, we report the discovery and validation of a kinase, TANK-binding kinase 1 (TBK1), that efficiently phosphorylates full-length and N-terminal HTT fragments in vitro (at S13/S16), in cells (at S13) and in vivo. TBK1 expression in HD models (cells, primary neurons, and Caenorhabditis elegans) increases mutant HTT exon 1 phosphorylation and reduces its aggregation and cytotoxicity. SIGNOR-270350 0.293 JUN protein P05412 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 10369069 f miannu Co-transfection of WT cells with a c-jun expression vector and either of the AP-1 luciferase constructs demonstrated that c-jun could activate gene expression from both the consensus and the MDR1 AP-1 sites in a dose dependent manner. SIGNOR-254534 0.35 serotonin smallmolecule CHEBI:28790 ChEBI HTR3D protein Q70Z44 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264292 0.8 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates activity phosphorylation Ser337 DPRGRLRsADSENAL 9534 BTO:0001538 12392720 t miannu It was shown that the recombinant MEKK3 protein and fluorescein-labeled MEKK3 peptides (FITC-(159)epRsRhlSVi(168) and FITC-(330)dpRgRlpSAd(339)) are phosphorylated by SGK1 in vitro. It was also observed that the intrinsic kinase activity of MEKK3 on Ser(189) of MKK3 (equivalent to Ser(207) of MKK6) decreased along with phosphorylation of Ser(166) and Ser(337) in MEKK3 in vitro and in vivo. Therefore, it is suggested that SGK1 inhibits MEKK3-MKK3/6 signal transduction by phosphorylation of MEKK3. SIGNOR-250005 0.2 heme smallmolecule CHEBI:30413 ChEBI HBB protein P68871 UNIPROT up-regulates activity chemical activation 9606 26557657 t miannu Heme is a prosthetic group comprising ferrous iron (Fe2+) and protoporphyrin IX and is an essential cofactor in various biological processes such as oxygen transport (hemoglobin) and storage (myoglobin) and electron transfer (respiratory cytochromes) in addition to its role as a structural component of hemoproteins. SIGNOR-251908 0.8 PLIN3 protein O60664 UNIPROT M6PR protein P20645 UNIPROT up-regulates activity relocalization 9534 BTO:0004055 9590177 t lperfetto TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi. SIGNOR-253093 0.719 PK proteinfamily SIGNOR-PF80 SIGNOR STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation -1 22306293 t PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In¬†vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor SIGNOR-268149 0.2 PTPN6 protein P29350 UNIPROT CD72 protein P21854 UNIPROT down-regulates dephosphorylation 9606 BTO:0000776 9740800 t gcesareni Our work clearly identifies cd72 as both an shp-1 binding protein (figure 1,figure 2) and a direct substrate for shp-1 in vivo (figure 3). As tyrosine phosphorylation of cd72 strongly correlates with the ability of the bcr to deliver growth-inhibitory/apoptosis-inducing signals (figure 4), our results suggest that shp-1-catalyzed dephosphorylation of cd72 may antagonize these signals. SIGNOR-60155 0.608 MEF2C protein Q06413 UNIPROT MYH10 protein P35580 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 t lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation SIGNOR-238769 0.351 PRKCG protein P05129 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 11123317 t amattioni Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation. SIGNOR-85183 0.348 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr204 VQRTIARtIVLQESI 452646 7774578 t lperfetto The TGF-beta type II receptor (T beta R-II) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, T beta R-I, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling. SIGNOR-32748 0.711 MAPK3 protein P27361 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Ser416 GFPSKTDsPSCEYSR 9606 BTO:0000007 27846390 t lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  SIGNOR-262979 0.317 MAPK11 protein Q15759 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20162623 f Indirect:regulation miannu Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6). SIGNOR-251834 0.2 PRLR protein P16471 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 17975019 f miannu We also show that activation of RS represses the expression of the transcription factor Forkhead box O3 (FOXO3) and that of the enzyme galactose-1-phosphate uridyltransferase (Galt), two proteins known to be essential for normal follicular development. SIGNOR-254187 0.2 PRKG1 protein Q13976 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser23 PAPIRRRsSNYRAYA 9606 15769444 t lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. SIGNOR-134640 0.365 M2_polarization phenotype SIGNOR-PH55 SIGNOR IL4 protein P05112 UNIPROT up-regulates 9606 BTO:0000801 32454942 f miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. M2 polarized cells express a variety of anti-inflammatory mediators, such as IL-4, IL-10, and transforming growth factor-β (TGF-β), and contribute to immunoregulation SIGNOR-263822 0.7 Camostat chemical CID:2536 PUBCHEM TMPRSS2 protein O15393 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000195 32142651 t miannu Indeed, the clinically proven serine protease inhibitor camostat mesylate, which is active against TMPRSS2 (Kawase et al., 2012), partially blocked SARS-2-S-driven entry into Caco-2 (Figure S3 B) and Vero-TMPRSS2 cells (Figure 4 A). Full inhibition was attained when camostat mesylate and E-64d, an inhibitor of CatB/L, were added (Figure 4A; Figure S3B), indicating that SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. SIGNOR-260284 0.8 MTMR2 protein Q13614 UNIPROT 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI up-regulates quantity chemical modification 9606 18429927 t miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns SIGNOR-269808 0.8 NOTCH4 protein Q99466 UNIPROT MAML2 protein Q8IZL2 UNIPROT up-regulates binding 9606 12386158 t gcesareni We show here identification of two new members of human mam family (human mastermind-2 (hmam-2) and human mastermind-3 (hmam-3)), which retain characteristics similar to human mastermind-1 (hmam-1) and drosophila mastermind. Both hmam-2 and hmam-3 stabilize and participate in the dna-binding complex rbp-j/cbf-1 protein and the notch intracellular domains that serve as intermediates of the signaling. Both hmam-2 and hmam-3 enhanced the activation of transcription from a target promoter by notch signaling. However, we also show evidence that the activation of the target promoter by notch3 and notch4 is more efficiently potentiated by hmam-2 than by hmam-1 or -3. SIGNOR-94279 0.855 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120140 0.316 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20921405 f gcesareni Nf-kb activation following t-cell receptor engagement induces the expression of mdm2 through interaction with nf-kb sites in its p1 promoter SIGNOR-168296 0.38 EXT1 protein Q16394 UNIPROT BMP4 protein P12644 UNIPROT up-regulates activity 9606 24860992 f miannu Decreased Ext1 was shown to reduce the level of Wnt8 and BMP4 signaling and disrupt ventral-specific gene expression. Ext1 function is required for maintenance of normal levels of BMP and wnt, as well as their target genes. In addition, expression of xbra and the establishment of ventral mesoderm depend upon normal levels of Ext1. These findings suggest that ext1-dependent synthesis of HSPG is critical for wnt and BMP signaling, mesodermal identity, and ventral pattern. SIGNOR-264018 0.364 HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 21779497 t lperfetto The first RAS effector pathway to be identified was the RAF-MEK-ERK pathway. This pathway is an essential, shared element of mitogenic signaling involving tyrosine kinase receptors, leading to a wide range of cellular responses, including growth, differentiation, inflammation, and apoptosis.23 The RAF family of proteins (Raf-1, A-Raf, and B-Raf) is serine/threonine kinases that bind to the effector region of RAS-GTP, thus inducing translocation of the protein to the plasma membrane. SIGNOR-236656 0.934 BCL7A protein Q4VC05 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269784 0.503 EEF1A2 protein Q05639 UNIPROT Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269532 0.8 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 21697284 t gcesareni Exel-2880 (xl880, gsk1363089) is a small-molecule kinase inhibitor that targets members of the hgf and vegf receptor tyrosine kinase families, with additional inhibitory activity toward kit, flt-3, platelet-derived growth factor receptor _, and tie-2. SIGNOR-174552 0.8 CALM3 protein P0DP25 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates binding 9606 11796223 t miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-266338 0.593 CDK7 protein P50613 UNIPROT MCM2 protein P49736 UNIPROT up-regulates activity phosphorylation Ser27 GNDPLTSsPGRSSRR 9606 16899510 t Luana Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. | Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2. SIGNOR-259848 0.304 NLGN2 protein Q8NFZ4 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264166 0.819 GRK2 protein P25098 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. SIGNOR-251444 0.2 RNF170 protein Q96K19 UNIPROT ITPR2 protein Q14571 UNIPROT down-regulates activity polyubiquitination 9606 BTO:0000567 21610068 t miannu In summary, here we present evidence that RNF170 is an E3 ligase that mediates IP3 receptor ubiquitination and processing by the UPP and that it is recruited to activated IP3 receptors by the erlin1/2 complex to which it is constitutively bound. SIGNOR-271914 0.338 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 11359934 f gcesareni The nuclear factor-kappaB (NF-kappaB) family of transcription factors has been shown to regulate proliferation in several cell types. SIGNOR-245043 0.7 vatalanib chemical CHEBI:90620 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258309 0.8 AURKA protein O14965 UNIPROT SKI protein P12755 UNIPROT down-regulates quantity by destabilization phosphorylation Ser383 LSAFRPWsPAVSASE -1 26138431 t miannu Here we show that AURKA phosphorylates in vitro the transcripcional co-repressor Ski on aminoacids Ser326 and Ser383. Phosphorylations on these aminoacids decreased Ski protein half-life SIGNOR-276917 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PGR protein P06401 UNIPROT down-regulates phosphorylation 9606 BTO:0000150 10655479 t inferred from 70% family members gcesareni Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation. SIGNOR-270040 0.2 RCOR1 protein Q9UKL0 UNIPROT REST-CoREST complex SIGNOR-C111 SIGNOR form complex binding 9606 20080105 t 1 miannu Transcriptional repression of neural-specific genes in nonneuronal cells is dependent on the REST (RE1-silencing transcription factor)–CoREST complex. SIGNOR-239220 0.76 SMURF1 protein Q9HCE7 UNIPROT TPM4 protein P67936 UNIPROT unknown ubiquitination -1 20804422 t miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. SIGNOR-272684 0.2 PPP3CC protein P48454 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Ser313 TALHRSKsHEFQLGH 10090 19560418 t These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 SIGNOR-248527 0.262 IGF1R protein P08069 UNIPROT PCNA protein P12004 UNIPROT up-regulates activity phosphorylation Tyr250 DMGHLKYyLAPKIED -1 28924044 t miannu In vitro MS analysis of PCNA co-incubated with the IGF-1R kinase indicated tyrosine residues 60, 133, and 250 in PCNA as IGF-1R targets, and PCNA phosphorylation was followed by mono- and polyubiquitination. SIGNOR-277252 0.2 Nitrendipine chemical CID:4507 PUBCHEM NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition -1 18250364 t Luana Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression.  SIGNOR-257767 0.8 JAK2 protein O60674 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 8977526 t lperfetto JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation. SIGNOR-249503 0.513 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT down-regulates activity phosphorylation Ser313 LDLEESSsSDHAERP 10029 BTO:0000246 7876239 t The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization. SIGNOR-251442 0.2 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates activity phosphorylation Tyr531 HEEDADSyENMDNPD 10090 BTO:0000776 10933394 t lperfetto Experiments with purified proteins demonstrated that CD19-Y513 was Lyn's initial phosphorylation and binding site. This led to processive phosphorylation of CD19-Y482, which recruited a second Lyn molecule, allowing for transphosphorylation and amplification of Lyn activation|Tyrosine phosphorylation of CD19 following BCR and/or CD19 ligation provides Src homology 2 (SH2) recognition motifs that recruit regulatory molecules to the cell surface. CD19 dually phosphorylated at CD19€“Y482 and CD19€“Y513 binds the tandem SH2 domains of phosphatidylinositol 3-kinase (PI 3-kinase) p85 subuni SIGNOR-249377 0.764 SUN2 protein Q9UH99 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 t lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. SIGNOR-263286 0.534 alanine smallmolecule CHEBI:16449 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264746 0.7 D-glucopyranose smallmolecule CHEBI:4167 ChEBI AMP smallmolecule CHEBI:456215 ChEBI down-regulates 9606 10409121 f gcesareni The activation in response to glucose removal appeared to be due to changes in the concentration of the known regulators of the cascade, i.e. Amp and atp, since ampk activation was associated with a large increase in the cellular amp. SIGNOR-69249 0.8 panobinostat chemical CHEBI:85990 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257756 0.8 ILK protein Q13418 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 9736715 t acerquone Ilk can phosphorylate pkb-akt on serine-473, whereas kinase-deficient ilk severely inhibits endogenous phosphorylation of pkb-akt on serine-473, demonstrating that ilk is involved in agonist stimulated, pi(3)k-dependent, pkb-akt activation. SIGNOR-60115 0.771 HDAC1 protein Q13547 UNIPROT CEBPA protein P49715 UNIPROT down-regulates transcriptional regulation 9606 16431920 t fspada These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome SIGNOR-210013 0.446 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 SIGNOR-C110 11955436 t gcesareni Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-116528 0.856 LRIG1 protein Q96JA1 UNIPROT CBLC protein Q9ULV8 UNIPROT up-regulates binding 9606 BTO:0001253 15282549 t gcesareni Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation SIGNOR-127301 0.2 SOHLH1 protein Q5JUK2 UNIPROT LHX8 protein Q68G74 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 16690745 t Luana Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters. SIGNOR-266076 0.5 CEBPB protein P17676 UNIPROT CSRP1 protein P21291 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14522018 t We conclude that c-Rel regulates CRP expression without the requirement of binding to a kappaB site, and binds directly to C/EBPbeta to facilitate the binding of C/EBPbeta to the CRP promoter SIGNOR-254049 0.2 PPP1CA protein P62136 UNIPROT NMDA proteinfamily SIGNOR-PF56 SIGNOR down-regulates activity dephosphorylation 9606 BTO:0000142 14751588 t miannu DARPP-32/PP1 cascade modulates the physiological properties of NMDA and AMPA receptors, and activation of the DARPP-32/PP1 signaling leads to parallel increase in the phosphorylation of NMDA receptor subunits and intracellular Ca2+ levels SIGNOR-265061 0.2 TAOK2 protein Q9UL54 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity binding 9606 BTO:0001130 10660600 t lperfetto Immunoprecipitated psk phosphorylates myelin basic protein and transfected psk stimulates mkk4 and mkk7 and activates the c-jun n-terminal kinase mitogen-activated protein kinase pathway. SIGNOR-74864 0.262 IL1R1 protein P14778 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 21304099 f lperfetto The Il-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. SIGNOR-171876 0.7 MAS1 protein P04201 UNIPROT FLNA protein P21333 UNIPROT up-regulates activity binding 9606 26460884 t miannu We further determined that GPCRs, AT1R, and MAS directly recruited FLNa and promoted its phosphorylation by cellular S/T kinases in an agonist-dependent manner. Our studies thus provide a structural framework for filamin in GPCR signaling, potentially regulating a variety of cellular responses. MAS likely binds filamin constitutively and hence leads to constitutive filamin phosphorylation. These results emphasize that it is the active receptor that mediates filamin phosphorylation by PKA or other cellular S/T kinases SIGNOR-260627 0.2 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 15381704 t The effect has been demonstrated using P28329-3 gcesareni Protein kinase c isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity. SIGNOR-129288 0.29 ATM protein Q13315 UNIPROT MCM3 protein P25205 UNIPROT unknown phosphorylation Ser535 ATDDPNFsQEDQQDT 9606 15210935 t lperfetto Atm phosphorylates mcm3 on s535 in response to ionizing radiation. Second, atr phosphorylates mcm2 on s108 in response to multiple forms of dna damage and stalling of replication forksthe functional consequences of mcm2 s108 and mcm3 s535 phosphorylation are not clear SIGNOR-126308 0.457 GAL protein P22466 UNIPROT GALR2 protein O43603 UNIPROT up-regulates binding 9606 10601261 t gcesareni Galanin showed high affinity for the galr1 (ic(50) = 0.097 nm) and galr2 receptors (ic(50) = 0.48 nm). SIGNOR-73125 0.858 PKA proteinfamily SIGNOR-PF17 SIGNOR NOXA1 protein Q86UR1 UNIPROT down-regulates activity phosphorylation Ser172 DQVQRRGsLPPRQVP 9606 BTO:0003250 20943948 t lperfetto On the other hand, our group has shown that protein kinase A (PKA) inhibits Nox1 activity in colon epithelial cells by phosphorylating NoxA1 at two distinct sites, Ser172 and Ser461 SIGNOR-264712 0.2 ZFHX3 protein Q15911 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14654895 f miannu these results corroborated the previous reports that ATBF1 regulated AFP expression and inhibited transcription. SIGNOR-255625 0.426 LIMS3 protein P0CW19 UNIPROT IPP complex complex SIGNOR-C380 SIGNOR form complex binding 16493410 t lperfetto Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton. SIGNOR-265765 0.579 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT up-regulates phosphorylation Ser1782 GAEIITQsPGRSSVA 9606 BTO:0000567;BTO:0000938 BTO:0000142 11029056 t gcesareni Specific phosphorylation states may enhance the interaction of map2 with the actin cytoskeleton, thereby providing a regulated mechanism for map2 function within distinct cytoskeletal domains SIGNOR-83100 0.367 azelastine chemical CHEBI:2950 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 t Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells SIGNOR-257790 0.8 PP1 proteinfamily SIGNOR-PF54 SIGNOR AHCYL1 protein O43865 UNIPROT unknown dephosphorylation Ser68 RSLSRSIsQSSTDSY 10090 17635105 t lperfetto Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1. SIGNOR-264657 0.2 RANBP2 protein P49792 UNIPROT BICD2 protein Q8TD16 UNIPROT up-regulates quantity relocalization 9606 BTO:0000567 20386726 t irozzo We show that the dynein/dynactin adaptor BICD2 is specifically recruited to the NPC in G2phase through a direct interaction with the NPC componentRanBP2. SIGNOR-259122 0.519 GRID2 protein O43424 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264952 0.8 PPP1CA protein P62136 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser370 KKTIVNDsRESCVEE 9606 BTO:0001938 23277204 t Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity. SIGNOR-248566 0.363 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR NRARP protein Q7Z6K4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222;BTO:0000782 11783997 t gcesareni These observations demonstrate that the nrarp gene is an evolutionarily conserved transcriptional target of the notch signaling pathway. SIGNOR-113786 0.418 CAMK2B protein Q13554 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Thr332 VNIMRTYtYEKLLWT 9606 BTO:0000938 24117889 t lperfetto Camkii represses transcriptionally active _-catenin to mediate acute ethanol neurodegeneration and can phosphorylate _-catenincamkii can directly phosphorylate _-catenin. Using targeted mutagenesis we identified camkii phosphorylation sites within human _-catenin at t332, t472, and s552. SIGNOR-202829 0.293 CBP/p300 complex SIGNOR-C6 SIGNOR EPCAM protein P16422 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11505407 f miannu The current results provide the first insights into the regulation of EpCAM expression, which is regulated negatively by TNFalpha and TPA through the activation of NF-kappaB. The repression may rely on the competition of NF-kappaB for p300/CBP histone acetyl transferase activity, because the overexpression of p300 reverts TNFalpha effects. SIGNOR-254791 0.256 AURKC protein Q9UQB9 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates phosphorylation 9606 12588998 t gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. SIGNOR-265357 0.2 CDK2 protein P24941 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser301 IQSNLDFsPVNSASS 9606 21765472 t lperfetto Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency SIGNOR-175083 0.535 PTPRG protein P23470 UNIPROT CTTN protein Q14247 UNIPROT down-regulates activity dephosphorylation Tyr470 AYATEAVyESAEAPG -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254696 0.2 PRKACA protein P17612 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser24 APIRRRSsNYRAYAT 9606 15769444 t lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. SIGNOR-134609 0.398 SLC2A1 protein P11166 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 t lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  SIGNOR-266017 0.305 BMPR1A protein P36894 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates phosphorylation 9606 19620713 t gcesareni Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. SIGNOR-187184 0.675 OGT protein O15294 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity glycosylation Ser109 KSHSRQAsTDAGTAG 34155345 t lperfetto Mass spectrometry analysis showed that YAP was the effector protein modified by OGT. In details, YAP Ser109 O-GlcNAcylation promoted the malignant phenotypes in PTC cells by inducing YAP Ser127 dephosphorylation and activation. SIGNOR-276942 0.286 POLR3D protein P05423 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266130 0.872 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR RAE1 protein P78406 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16036565 f miannu Nup98/Nup96 (41) and Rae1 (17)are up regulated by interferons, which revert the mRNAexport block induced by VSV M protein SIGNOR-260869 0.2 ACD protein Q96AP0 UNIPROT TERT protein O14746 UNIPROT up-regulates binding 9606 17237768 t miannu We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme. SIGNOR-152321 0.553 T_cell_activation phenotype SIGNOR-PH73 SIGNOR ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. SIGNOR-261022 0.7 PLEKHF2 protein Q9H8W4 UNIPROT EEA1 protein Q15075 UNIPROT up-regulates activity binding -1 22816767 t Giulio In yeast two-hybrid analysis we identified Phafin2 as a novel interactor of the endosomal-tethering protein EEA1, and Phafin2 colocalized strongly with EEA1 in microdomains of the endosome membrane. Our results suggest that Phafin2 controls receptor trafficking and fluid-phase transport through early endosomes by facilitating endosome fusion in concert with EEA1. SIGNOR-261276 0.25 UHRF2 protein Q96PU4 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0000298 21952639 t miannu We found that NIRF directly ubiquitinated cyclins D1 and E1, as evidenced by the appearance of the tail (Fig. 4B). In summary, the above findings suggest that NIRF tightly cooperates with the core cell cycle machinery and induces G1 arrest, which is accompanied by ubiquitination of cyclins D1 and E1. SIGNOR-271885 0.298 CALM3 protein P0DP25 UNIPROT GEM protein P55040 UNIPROT up-regulates activity binding 10116 BTO:0001009 14701738 t miannu Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells. SIGNOR-266342 0.2 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Thr154 SSKRSPStATLSLPS 9606 BTO:0001061 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276777 0.629 SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-141647 0.821 TGFBR1 protein P36897 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0001660 9435577 t lperfetto These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells. SIGNOR-252730 0.354 DNMT3A protein Q9Y6K1 UNIPROT DPP6 protein P42658 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000596 23409053 t lperfetto In the absence of Dnmt3b, Dnmt3a was associated with Dpp6 gene promoter and regulated its expression and methylation in P19 cells. SIGNOR-268962 0.2 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser333 NLKSVQNsHFKEPLV -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276197 0.388 RBBP7 protein Q16576 UNIPROT HAT1 protein O14929 UNIPROT up-regulates activity binding -1 28143904 t lperfetto AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314| interaction between RBBP7 and HAT1 is required for acetyltransferase activity SIGNOR-264786 0.894 SATB1 protein Q01826 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000725 23563689 f miannu Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc SIGNOR-224831 0.405 UBA6 protein A0AVT1 UNIPROT Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR form complex binding 9606 24816100 t miannu The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin. SIGNOR-270835 0.2 NIPBL protein Q6KC79 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR up-regulates activity binding 9606 28914604 t miannu Scc2 (Nipbl) stimulates cohesin’s ABC-like ATPase and is essential for loading cohesin onto chromosomes. However, it is possible that the stimulation of cohesin’s ATPase by Scc2 also has a post-loading function, for example driving loop extrusion. Using fluorescence recovery after photobleaching (FRAP) and single-molecule tracking in human cells, we show that Scc2 binds dynamically to chromatin, principally through an association with cohesin. SIGNOR-264522 0.841 SSTR2 protein P30874 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256827 0.426 CSNK2A1 protein P68400 UNIPROT HCLS1 protein P14317 UNIPROT unknown phosphorylation Thr23 TQGDDWDtDPDFVND 9606 10806407 t llicata The in vivo Ser/Thr phosphorylation of HS1 is enhanced by okadaic acid and reduced by specific inhibitors of casein kinase (CK)2. In vitro, HS1 is an excellent substrate for either CK2 alpha subunit alone (Km = 47 nM) or CK2 holoenzyme | It is likely therefore that Thr16 and/or Thr23 account for the phosphate incorporated into HS1 threonyl residue(s) upon incubation with CK2. SIGNOR-250886 0.312 SUPT3H protein O75486 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269590 0.758 WNT1 protein P04628 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 18697834 t Simone Vumbaca Wnt1, Wnt3a and Wnt5a all induced a statistically greater degree of proliferation than control cells SIGNOR-255649 0.758 CSNK1A1L protein Q8N752 UNIPROT GLI2 protein P10070 UNIPROT up-regulates phosphorylation 9606 18698484 t gcesareni Gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed SIGNOR-179972 0.339 MAP3K12 protein Q12852 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 11781833 t gcesareni Zip kinase (hzipk) phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. In this study, we demonstrate that hzipk also induces the diphosphorylation of mrlc in nonmuscle cells. SIGNOR-113664 0.2 BAZ2B protein Q9UIF8 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity binding 9606 31999386 t inferred from 70% of family members miannu The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation. SIGNOR-269843 0.2 SMAD7 protein O15105 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 9606 BTO:0001130 15684397 f gcesareni In the current study, our data indicate that both smad7 and p38 map kinase positively contributed to the accumulation of -catenin SIGNOR-133447 0.688 ACTN1 protein P12814 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity binding 9534 16291744 t lperfetto Consistent with the results obtained with COS-7 cells, coexpression of wild-type Œ±-actinin with PTP 1B in PTP 1B-null cells resulted in Src/Œ±-actinin binding and limited the interaction between FAK and Src SIGNOR-261799 0.556 BMPR1B protein O00238 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates phosphorylation 9606 19620713 t gcesareni Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. SIGNOR-187193 0.667 ARHGAP31 protein Q2M1Z3 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260488 0.509 LRRC4 protein Q9HBW1 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 9606 BTO:0000142 25526788 f miannu The overexpression of LRRC4/NGL-2 suppresses glioma cell growth, angiogenesis and invasion through complicated signaling regulation networks. SIGNOR-264060 0.7 JUN protein P05412 UNIPROT TNFAIP6 protein P98066 UNIPROT up-regulates quantity by expression transcriptional regulation 8454627 t Tumor necrosis factor (TNF)-stimulated gene 6 (TSG-6) encodes a protein expressed during inflammation. We have previously shown that transcription factors of the NF-IL6 and AP-1 families cooperatively modulate activation of the TSG-6 gene by TNF or interleukin 1 (IL-1) through a promoter region that contains an NF-IL6 site (-106 to -114) and an AP-1 element SIGNOR-254052 0.313 TRIM3 protein O75382 UNIPROT GKAP1 protein Q5VSY0 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 20352094 t miannu Here we identify the RING finger-containing protein TRIM3 as a specific E3 ubiquitin ligase for the PSD scaffold GKAP/SAPAP1. Present in PSD fractions from rat brain, TRIM3 stimulates ubiquitination and proteasome-dependent degradation of GKAP, and induces the loss of GKAP and associated scaffold Shank1 from postsynaptic sites. SIGNOR-271959 0.25 PLK1 protein P53350 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser739 SKILLDIsFPGLDED 9606 19737929 t lperfetto It has been reported that plk1 could directly phosphorylate foxm1 at ser-715 and ser-724 for full activation and proper mitotic progression SIGNOR-187892 0.692 PRKACA protein P17612 UNIPROT AKAP13 protein Q12802 UNIPROT up-regulates phosphorylation Ser2733 SVSPKRNsISRTHKD 9606 15383279 t llicata Using a combination of biochemical, enzymatic, and immunofluorescence techniques, we show that the anchoring protein contributes to pkd activation in two ways: it recruits an upstream kinase pkceta and coordinates pka phosphorylation events that release activated protein kinase d. Thus, akap-lbc synchronizes pka and pkc activities in a manner that leads to the activation of a third kinase. SIGNOR-129345 0.337 MAPK3 protein P27361 UNIPROT TRPV3 protein Q8NET8 UNIPROT up-regulates activity phosphorylation Thr264 EGFYFGEtPLALAAC 9606 BTO:0000552 29084846 t done miannu We observed that ERK-mediated phosphorylation of TRPV3 alters its responsiveness to repeated chemical stimuli. Among several putative ERK phosphorylation sites, we identified threonine 264 in the N-terminal ankyrin repeat domain as the most critical site for the ERK-dependent modulation of TRPV3 channel activity. Of note, Thr264 is in close vicinity to a structurally and functionally important TRPV3 region comprising an atypical finger 3 and oxygen-dependent hydroxylation site. In summary, our findings indicate that Thr264 in TRPV3 is a key ERK phosphorylation site mediating EGFR-induced sensitization of the channel to stimulate signaling pathways involved in regulating skin homeostasis. SIGNOR-273672 0.2 YES1 protein P07947 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Tyr391 PFLNSGTyHSRDEST 9606 BTO:0000578 35041461 t miannu Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C). SIGNOR-277652 0.71 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1038 STSATQSsPAPGQSK 9606 BTO:0000551 24530506 t miannu In this study, we found that p300 was highly phosphorylated and its level was decreased during mitosis and tumorigenesis. In vitro and in vivo experiments aimed showed that cyclin-dependent kinase 1 (CDK1) and ERK1/2 phosphorylated p300 on Ser1038 and Ser2039. Mutations of Ser1038 and Ser2039 increased p300 protein stability and levels.  SIGNOR-276455 0.2 FGFR2 protein P21802 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation Tyr240 RREDKFMyFEFPQPL 9606 22891331 t llicata Fgfrs phosphorylate pten at tyrosine 240 SIGNOR-191793 0.438 sorafenib tosylate chemical CHEBI:50928 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. SIGNOR-259221 0.8 KIF5B protein P33176 UNIPROT JAKMIP1 protein Q96N16 UNIPROT up-regulates activity relocalization 10090 17532644 t SARA Marlin-1 is associated with kinesin-I and suggest that the movement of Marlin-1 is mediated by plus end microtubuledependent molecular motors SIGNOR-260989 0.2 COLGALT2 protein Q8IYK4 UNIPROT COL4A1 protein P02462 UNIPROT up-regulates activity glycosylation -1 19075007 t Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. SIGNOR-261159 0.428 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding 9606 1904542 t irozzo The proteins encoded by the proto-oncogenes c-fos and c-jun (Fos and Jun, respectively) form a heterodimeric complex that regulates transcription by interacting with the DNA-regulatory element known as the activator protein 1 (AP-1) binding site. SIGNOR-256364 0.951 RF-C complex complex SIGNOR-C375 SIGNOR PCNA protein P12004 UNIPROT up-regulates activity binding 9534 BTO:0004055 12930972 t lperfetto Replication factor C (RF-C) complex binds to DNA primers and loads PCNA onto DNA, thereby increasing the processivity of DNA polymerases. SIGNOR-265510 0.81 ETV4 protein P43268 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24983502 f miannu Transcriptional activation of oct4 by the ets transcription factor pea3 in nccit human embryonic carcinoma cells SIGNOR-205173 0.386 JAK1 protein P23458 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates activity phosphorylation Tyr619 NKVDDCNyAIKRIRL 10090 BTO:0000099 25113558 t miannu JAK1 interacts with and phosphorylates PERK. PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum stress-induced inflammation. Similarly, PERK is associated with and phosphorylated by JAK1 at Y585 and Y619 (and possibly other JAKs) during ER stress, resulting in PERK- and JAK1-dependent activation of STAT3. SIGNOR-276677 0.2 STK39 protein Q9UEW8 UNIPROT SLC12A3 protein P55017 UNIPROT down-regulates activity phosphorylation Thr55 SSTFCMRtFGYNTID 10090 25651566 t lperfetto SPAK directly phosphorylates NCC and its effects on NCC are universally associated with phosphorylation|This adds to the evidence that SPAK-mediated phosphorylation acts primarily to increase activity of individual cotransporters without affecting the amount of NCC on the surface| the kinase (SPAK) that phosphorylates NCC at T53 SIGNOR-264623 0.498 MMP3 protein P08254 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272373 0.7 RHOA protein P61586 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates binding 9606 11102529 t gcesareni Our results demonstrate that direct stimulation of pld1 in vivo by rhoa SIGNOR-84953 0.685 HPS4 protein Q9NQG7 UNIPROT BLOC-3 complex SIGNOR-C253 SIGNOR form complex binding 9606 20048159 t lperfetto Two of these genes, HPS1 and HPS4, encode components of the biogenesis of lysosome-related organelles complex-3 (BLOC-3). Herein we show that recombinant HPS1-HPS4 produced in insect cells can be efficiently isolated as a 1:1 heterodimer. SIGNOR-260692 0.743 isoleucine smallmolecule CHEBI:24898 ChEBI Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270426 0.8 NPLOC4 protein Q8TAT6 UNIPROT UFD1 protein Q92890 UNIPROT up-regulates activity binding 9606 20442859 t miannu These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes. SIGNOR-252422 0.2 Ast-487 chemical CID:11409972 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258173 0.8 PLK1 protein P53350 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation 23972993 t For phosphorylated residues see Figure 7 lperfetto Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP SIGNOR-274053 0.301 KSR2 protein Q6VAB6 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 t miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. SIGNOR-273877 0.601 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR up-regulates 9606 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268581 0.2 MTA2 protein O94776 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263841 0.812 IL10 protein P22301 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0000938 BTO:0001264 23357618 f miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. SIGNOR-253496 0.2 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192901 0.8 CASP7 protein P55210 UNIPROT PARP1 protein P09874 UNIPROT down-regulates cleavage 9606 11058599 t amattioni Caspase-7 cleaves parp;redundancy exists between the caspase-3 and -7 at the level of parp proteolysis. SIGNOR-83703 0.708 YWHAG protein P61981 UNIPROT GEM protein P55040 UNIPROT up-regulates quantity by stabilization binding 9534 BTO:0000298 14701738 t miannu In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase SIGNOR-261723 0.269 HDAC4 protein P56524 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 25726523 t lperfetto GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. SIGNOR-275663 0.291 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser660 FSAERRNsILTETLH 9606 1377674 t lperfetto Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function SIGNOR-18237 0.52 AP3S2 protein P59780 UNIPROT Neuronal AP-3 complex SIGNOR-C445 SIGNOR form complex binding 9606 BTO:0000938 19497727 t miannu Mammals contain more than one AP-3 complex owing to the existence of pairs of genes encoding β3, μ3, and σ3 subunits (A and B isoforms). While both σ3A and σ3B are expressed ubiquitously and seem to be functionally equivalent, the B isoforms of β3 and μ3 display rather restricted expression patterns, mostly in cells of neuronal origin. This has led to the notion of the existence of two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising δ, β3A, μ3A, and σ3(A or B) subunits, and a brain-specific AP-3 complex containing δ, β3B, μ3B, and σ3(A or B) SIGNOR-268518 0.701 AREL1 protein O15033 UNIPROT HTRA2 protein O43464 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23479728 t lperfetto Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists SIGNOR-267669 0.415 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT up-regulates activity phosphorylation Tyr30 NQSSGYRyGTDPTPQ -1 9425276 t Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn. SIGNOR-251165 0.2 PURA protein Q00577 UNIPROT MYH6 protein P13533 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12933792 f miannu In functional assays, PURalpha and PURbeta repressed alpha-myosin heavy chain (alpha-MHC) gene expression in the presence of upstream regulatory sequences of the gene. SIGNOR-253902 0.2 PRKCB protein P05771 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 t llicata Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm. SIGNOR-97283 0.2 PCDH19 protein Q8TAB3 UNIPROT GABRA6 protein Q16445 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C334,SIGNOR-C328,SIGNOR-C329 29360992 t miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  SIGNOR-267221 0.2 STRN4 protein Q9NRL3 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates activity binding 10090 BTO:0000938 29802198 t miannu The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms SIGNOR-261699 0.605 WDFY3 protein Q8IZQ1 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates quantity by destabilization relocalization 9606 BTO:0000793 27008544 t miannu Our data taken together with the known role of ALFY in autophagy, demonstrate specific targeting and autophagy-mediated removal of DVL3 by hALFY. SIGNOR-266793 0.253 FYN protein P06241 UNIPROT TOM1L1 protein O75674 UNIPROT up-regulates activity phosphorylation Tyr460 AVTTEAIyEEIDAHQ -1 11711534 t Tyr-457, located in the presumed Src SH2 binding site, is the predominant tyrosine residue that is phosphorylated by Fyn.Fyn can phosphorylate Srcasm, and association of these molecules relies on cooperative binding between the SH2 and SH3 domains of Fyn and corresponding canonical binding sites in Srcasm. Srcasm is capable of interacting with Grb2 and the regulatory subunit of phosphoinositide 3-kinase, p85, in a phosphorylation-dependent manner. The evidence suggests that Srcasm may help promote Src family kinase signaling in cells. SIGNOR-251185 0.444 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Macropinosomes formation phenotype SIGNOR-PH227 SIGNOR up-regulates 9606 39000072 f miannu The signaling for the regulation of macropinocytosis normally starts with the activation of RAS protein by macropinocytic stimulators, which in turn initiate signaling cascades involving RAC1 and phosphatidylinositol kinases and their downstream effectors or product that lead to actin cytoskeleton remodeling for plasma membrane ruffle and macropinocytic cup formation. Macropinosomes are further matured by regulation of the small GTPases RAC1 and CDC42 as well as phosphatidylinositol lipids, and matured macropinosomes undergo recycling or degradation processes. SIGNOR-277767 0.7 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR isoleucine smallmolecule CHEBI:24898 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270421 0.8 MCL1 protein Q07820 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 t gcesareni Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax SIGNOR-149774 0.609 KDM4C protein Q9H3R0 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity binding 9606 BTO:0001033 29207681 t miannu JMJD2C was found to be co-localized with AR and LSD1 in the epithelium of prostate carcinoma and normal prostate cells. For the detailed mechanism, JMJD2C, AR and LSD1 assembled on the chromatin to remove the methyl groups from mono-, di- and trimethylated H3K9. Importantly, JMJD2C specifically removed the demethylation of the trimethyl H3K9 marks and modulated the transcriptional activity of AR. Moreover, JMJD2C cooperated with LSD1 and activated AR-mediated gene expression via decreasing H3K9me3 at the promoter of AR targeting genes KLK2 and PSA. SIGNOR-263880 0.2 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI ADCY10 protein Q96PN6 UNIPROT up-regulates activity chemical activation 9606 BTO:0000567 31827278 t miannu In these cells, trafficking of V-ATPase to the plasma membrane has been shown to be mediated by activation of bicarbonate-dependent soluble adenylate cyclase (sAC), which increases cAMP levels, thereby activating protein kinase A (PKA) SIGNOR-277762 0.8 RAB21 protein Q9UL25 UNIPROT Early macropinosomes phenotype SIGNOR-PH228 SIGNOR up-regulates binding 9606 19693279 f miannu It was demonstrated that wild-type Rab21 was transiently associated with macropinosomes. Rab21 was recruited to the macropinosomes after a decrease in PI(4,5)P(2) and PI(3,4,5)P(3) levels. Although Rab21 was largely colocalized with Rab5, the recruitment of Rab21 to the macropinosomes lagged a minute behind that of Rab5, and preceded that of Rab7. SIGNOR-277782 0.7 MIB1 protein Q86YT6 UNIPROT SMN1 protein Q16637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23615451 t lperfetto The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein SIGNOR-253112 0.329 HES1 protein Q14469 UNIPROT NOC3L protein Q8WTT2 UNIPROT down-regulates quantity transcriptional regulation 9823 BTO:0003298 23611667 t The expression level of FAD24 is inversely associated with that of HES1 in porcine MSCs after adipogenic induction. Enforced overexpression of HES1 in MSCs during the early stage of adipogenesis significantly repressed the transcription of FAD24 (P < 0.01) and the other pro-adipogenic genes SIGNOR-253059 0.2 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding BTO:0001103 7566092 t svumbaca Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-Jk and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. SIGNOR-255363 0.95 ESR1 protein P03372 UNIPROT PGR protein P06401 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11000528 f gcesareni We observed the transcriptional inhibition of the progesterone and glucocorticoid receptors when eralpha was cotransfected SIGNOR-82161 0.608 Uridylate-specific endoribonuclease protein P0C6X7-PRO_0000037321 UNIPROT EIF2AK2 protein P19525 UNIPROT down-regulates activity 9606 28158275 f miannu Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation. SIGNOR-260348 0.2 PCNT protein O95613 UNIPROT CDK5RAP2 protein Q96SN8 UNIPROT up-regulates activity binding 9606 BTO:0001938 18042621 t Giulio Our observation that Cep215 may function downstream of pericentrin suggests that the two proteins affect centrosome cohesion through a common mechanism. |Finally, depletion of pericentrin caused an almost complete loss of Cep215 from centrosomes, a detectable reduction in centrosomal levels of Cep68 and rootletin, but no significant effect on C-Nap1 (Fig. 6C and Table 1). Taken together, these results point to functional (and perhaps molecular) interactions between (1) Cep68 and rootletin and (2) Cep215 and pericentrin. SIGNOR-260309 0.812 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr373 TVLVKDStNRDSLDM 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. SIGNOR-129332 0.327 CRK protein P46108 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 8524328 t gcesareni These results indicate that crk binds to c-cbl in a tyrosine phosphorylation-dependent manner. SIGNOR-39241 0.817 GABRB1 protein P18505 UNIPROT GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263754 0.604 VCP protein P55072 UNIPROT AURKA protein O14965 UNIPROT down-regulates activity binding 6239 23649807 t lperfetto The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A.|We found that UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 from embryonic extracts SIGNOR-265044 0.319 TP73 protein O15350 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 17700533 f miannu Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death. SIGNOR-256665 0.7 MAPK10 protein P53779 UNIPROT SFN protein P31947 UNIPROT down-regulates phosphorylation Ser186 FHYEIANsPEEAISL 9606 15071501 t Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons gcesareni Here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein.Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-191 SIGNOR-124005 0.2 dabrafenib chemical CHEBI:75045 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 24720932 t miannu Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations SIGNOR-259215 0.8 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr2 tAKMETTF 9606 BTO:0000848 21177766 t lperfetto P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286) SIGNOR-170760 0.271 CAMK2B protein Q13554 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates phosphorylation Thr183 SDGEFLRtSCGSPNY 9606 BTO:0000567 SIGNOR-C15 15980064 t gcesareni These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo. SIGNOR-138360 0.2 TNFRSF17 protein Q02223 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 10903733 f miannu Overexpression of bcma activates jnk SIGNOR-79489 0.295 TEC protein P42680 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr224 DSNSKKIyGSQPNFN 9606 12573241 t lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. For bmx, we obtained two phosphorylated sites, y215 and y223 (fig. 6c). The bmx-y215 is a conserved tyrosine, which is homologous to btk-y223 and itk-y180 SIGNOR-98094 0.338 PRKCA protein P17252 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser444 QRKSQRSsYVSMRID -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262755 0.342 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11485553 t lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. SIGNOR-109609 0.866 FGD2 protein Q7Z6J4 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260552 0.461 SETD2 protein Q9BYW2 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18158893 f gcesareni In response to hypoxia, foxo3a transcript levels accumulate in an hif1-dependent way, resulting in enhanced foxo3a activity. SIGNOR-160201 0.2 SOX5 protein P35711 UNIPROT COL2A1 protein P02458 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10980415 f miannu Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Two other members of the Sox family, L-Sox5 and Sox6, also bind to the 48-bp Col2a1 enhancer and together with Sox9 activate this enhancer as well as the endogenous Col2a1 SIGNOR-251759 0.438 GATA1 protein P15976 UNIPROT GATA1 protein P15976 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12432220 f irozzo Furthermore, GATA-1 has been shown to auto-regulate its own gene expression. SIGNOR-256057 0.2 SLBP protein Q14493 UNIPROT H2BW1 protein Q7Z2G1 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265387 0.2 veliparib chemical CHEBI:62880 ChEBI PARP1 protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189183 0.8 CPT1C protein Q8TCG5 UNIPROT palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI down-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267128 0.8 PRKCD protein Q05655 UNIPROT PTPN22 protein Q9Y2R2 UNIPROT down-regulates phosphorylation Ser35 FLKLKRQsTKYKADK 9606 BTO:0000782 18056643 t llicata We show that lyp is phosphorylated exclusively at ser-35 by pkc both in vitro and in vivo. our data establish a mechanism by which pkc could attenuate the cellular function of lyp, thereby augmenting t cell activation. SIGNOR-159591 0.319 RPS6K proteinfamily SIGNOR-PF26 SIGNOR STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 BTO:0001271 25846811 t lperfetto Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK. SIGNOR-252805 0.2 CREB1 protein P16220 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776;BTO:0003076 8816467 f lperfetto Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis SIGNOR-43927 0.438 TNFRSF6B protein O95407 UNIPROT TNFSF15 protein O95150 UNIPROT down-regulates binding 9606 BTO:0000782 11911831 t amattioni Tl1a, is a ligand for dr3 and decoy receptor tr6/dcr3. Tr6-fc protein antagonizes nf-kappab activation and apoptosis induced by tl1a SIGNOR-116256 0.732 LCK protein P06239 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 BTO:0000782 17998336 t inferred from 70% of family members gcesareni The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1. SIGNOR-269921 0.57 TKT protein P29401 UNIPROT D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI down-regulates quantity chemical modification 9606 24929114 t miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. SIGNOR-267085 0.8 estrone smallmolecule CHEBI:17263 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258583 0.8 SNRNP27 protein Q8WVK2 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270642 0.425 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr96 EENADDSyEPPPVEQ 9606 12456653 t llicata The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex. SIGNOR-96052 0.798 PPP1CC protein P36873 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates dephosphorylation 9606 14718519 t lpetrilli We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI. SIGNOR-121277 0.446 TACR3 protein P29371 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256937 0.2 NCBP2 protein P52298 UNIPROT Cap-binding complex complex SIGNOR-C440 SIGNOR form complex binding 9606 26382858 t lperfetto The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. SIGNOR-268358 0.969 UNC5B protein Q8IZJ1 UNIPROT DCC protein P43146 UNIPROT down-regulates activity binding 9606 BTO:0001484 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268166 0.644 SRC protein P12931 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000007 12600984 t lperfetto We also showed that phosphorylation of Tyr-315 in Akt induced by Src or EGF is dependent on the integrity of this proline-rich motif. Furthermore, the Akt mutant lacking this proline motif fails to block the transcription activity of Forkhead in 293 cells and poorly stimulates the proliferation of Madin-Darby canine kidney cells. Taken together, our data suggest that the interaction between the SH3 domain of Src family kinases and the proline-rich motif in the C-terminal regulatory region of Akt is required for tyrosine phosphorylation of Akt and its subsequent activation. SIGNOR-252621 0.664 Caspase 3 complex complex SIGNOR-C221 SIGNOR Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 BTO:0000142 10200555 f amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation SIGNOR-256481 0.7 DUSP1 protein P28562 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Tyr204 HTGFLTEyVATRWYR 10116 7535768 t We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively SIGNOR-248463 0.778 ETV6 protein P41212 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15958056 f Regulation of expression miannu Upon erythropoietin exposure, overexpressed TEL stimulated hemoglobin synthesis SIGNOR-251794 0.2 TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 t lperfetto Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. SIGNOR-236071 0.889 MEF2C protein Q06413 UNIPROT CTNNA3 protein Q9UI47 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002320 21598020 t miannu GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter SIGNOR-265491 0.243 MAPK1 protein P28482 UNIPROT ARHGAP26 protein Q9UNA1 UNIPROT unknown phosphorylation Ser685 PMFSAPSsPMPTSST -1 9525907 t miannu In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling. SIGNOR-262944 0.2 IFNA1 protein P01562 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates quantity by stabilization 9606 22171011 f 2 miannu IFN-I (IFN-_ and IFN-_) induces the assembly of IFN-stimulated gene factor 3 (ISGF3), a multimeric transcriptional activation complex composed of STAT1, STAT2, and IFN regulatory factor 9. SIGNOR-240610 0.462 CAMK2G protein Q13555 UNIPROT MYLK protein Q15746 UNIPROT down-regulates activity phosphorylation Ser1760 RAIGRLSsMAMISGL 2160950 t llicata Phosphorylation of MLC kinase by CaM protein kinase II increased the dissociation constant of MLC kinase for calmodulin about 10 times without changing the Vmax. The location of the phosphorylation sites was identified by isolating and sequencing the tryptic phosphopeptides of MLC kinase. The preferred site was identified as serine 512 and the second site as serine 525. These sites are the same as the sites phosphorylated by cAMP-dependent protein kinase. SIGNOR-250700 0.336 HIF-1 complex complex SIGNOR-C418 SIGNOR BNIP3L protein O60238 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 t miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. SIGNOR-267455 0.305 JNK proteinfamily SIGNOR-PF15 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser138 SLQLGAVsPGTLTPT 9606 BTO:0001938 21364637 t miannu JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells SIGNOR-277642 0.2 CSNK1A1 protein P48729 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser7 sDSEEEVC -1 8972483 t llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  SIGNOR-250791 0.4 SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR MBD4 protein O95243 UNIPROT up-regulates activity sumoylation Lys377 HLHTDILkRGSEMDN 31476572 t lperfetto MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro. SIGNOR-275681 0.2 LYN protein P07948 UNIPROT PDIA3 protein P30101 UNIPROT unknown phosphorylation Tyr454 VRGFPTIyFSPANKK -1 8631326 t miannu Lyn phosphorylates tyrosine residues Y444, Y453 and Y466 which are located in a highly acidic region of the protein at the C-terminus. Upon phosphorylation, p57 forms a complex with Lyn which can be immunoprecipitated with anti-Lyn IgG. The association which occurs between the phosphorylated substrate and the SH2 domain of the kinase is consistent with the suggested 'processive phosphorylation' model, which implies that a primary phosphorylation site of the substrate binds to the SH2 domain of the enzyme and triggers the phosphorylation at secondary site(s). SIGNOR-262895 0.2 MCU_MICU1_variant complex SIGNOR-C500 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270868 0.8 LEF1 protein Q9UJU2 UNIPROT NCAM1 protein P13591 UNIPROT up-regulates activity transcriptional regulation 10090 BTO:0003952 11696550 f miannu Consistent with our observation that expression of exogenous LEF-1 causes transactivation of the N-CAM promoter, a recent study demonstrated that noggin-dependent induction of LEF-1 coincidentally increased N-CAM expression (50). Ectopic noggin added to skin cultures up-regulates LEF-1 expression and stimulates hair induction. Based on promoter assays and EMSAs, our results further support the notion that N-CAM is a direct target of LEF-1. SIGNOR-254549 0.278 JUNB protein P17275 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 21799768 f Our results suggest that the prolonged IL-4 expression in NFAT1 deficient Th2 cells is mediated by preferential binding of JUNB/SATB1 to the IL-4 promoter with permissive chromatin architecture SIGNOR-254503 0.47 HBP1 protein O60381 UNIPROT NCF1 protein P14598 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 15024088 t Luana Together, these results indicate that HBP1 may contribute to the regulation of NADPH oxidase-dependent superoxide production through transcriptional repression of the p47phox gene.  SIGNOR-261614 0.268 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation 9606 15657420 t inferred from 70% family members lperfetto The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity. SIGNOR-270047 0.2 TFAP2C protein Q92754 UNIPROT SULT1E1 protein P49888 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002828 17187826 f miannu Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. SIGNOR-255399 0.2 PF-3845 chemical CID:25154867 PUBCHEM FAAH protein O00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206049 0.8 DSCAM protein O60469 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 10116 BTO:0000938 18585357 f miannu DSCAM is required for commissural axon guidance in vivo. DSCAM promotes axonal growth but is dispensable for cell body migration and for axon turning toward a local source of netrin-1 in whole spinal cord turning assays. SIGNOR-268401 0.7 PRKCD protein Q05655 UNIPROT G6PD protein P11413 UNIPROT up-regulates phosphorylation Ser180 FGRDLQSsDRLSNHI 9606 BTO:0001260 20649491 t lperfetto A pkc activator, significantly increased g6pd phosphorylation and activity, whereas single (s210a, t266a) and double (s210a/t266a) mutations at sites flanking the g6pd active site significantly inhibited phosphorylation, shifted the isoelectric point, and reduced enzyme activity. SIGNOR-167049 0.2 COL4A2 protein P08572 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 35267698 t lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. SIGNOR-272348 0.467 RNF11 protein Q9Y3C5 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity binding 9606 BTO:0000007 14755250 t miannu RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome. SIGNOR-272952 0.556 MYC protein P01106 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 23175188 f miannu Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. SIGNOR-255146 0.478 ATM protein Q13315 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser126 PPGTPLVsQDEKRDA 9606 21824916 t lperfetto We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro. SIGNOR-176012 0.474 PRKCG protein P05129 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser368 QRPSSRAsSRASSRP 10116 10871288 t lperfetto Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication. SIGNOR-249050 0.585 SDC4 protein P31431 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 23151663 t gcesareni Like other wnt co receptors, syndecan 4 directly interacts with dvl during pcp. SIGNOR-199635 0.259 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation 9606 17900900 t lperfetto We have recently found that AMPK phosphorylates human FOXO3 in mammalian cells at novel regulatory sites that are distinct from the AKT sites SIGNOR-216481 0.397 HIF1A protein Q16665 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001248 20682797 f miannu Here, we show the histone demethylase JMJD2B is regulated by both ERalpha and HIF-1alpha, drives breast cancer cell proliferation in normoxia and hypoxia, and epigenetically regulates the expression of cell cycle genes such as CCND1, CCNA1, and WEE1. SIGNOR-263738 0.264 NOS1 protein P29475 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255996 0.369 KEAP1 protein Q14145 UNIPROT CUL3 protein Q13618 UNIPROT up-regulates activity binding 9534 BTO:0001538 15983046 t miannu Keap1 is a BTB-Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. Keap1 targets its substrate, the Nrf2 transcription factor, for ubiquitination and subsequent degradation by the 26 S proteasome.  The N-terminal BTB domain and central linker region of Keap1 bind Cul3, whereas the C-terminal Kelch domain of Keap1 binds Nrf2 via residues located within loops that extend out from the bottom of the Kelch domain SIGNOR-268925 0.949 FN1 protein P02751 UNIPROT Av/b6 integrin complex SIGNOR-C179 SIGNOR up-regulates binding 9606 1532572 t gcesareni Integrin alpha v beta 6 binds to fibronectin, but not to vitronectin or collagen i. cell adhesion assays show that fg-2 cell attachment to fibronectin is only partially inhibited by anti-beta 1 integrin antibodies, implying that other fibronectin receptors may be involved. SIGNOR-19793 0.725 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 9381178 t Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival. SIGNOR-251469 0.2 LPAR1 protein Q92633 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257282 0.433 SIRT7 protein Q9NRC8 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity deacetylation Lys19 TGGKAPRkQLATKVA 22722849 t lperfetto SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. SIGNOR-275870 0.2 ECM stimulus SIGNOR-ST20 SIGNOR A4/b7 integrin complex SIGNOR-C187 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259041 0.7 MAPK3 protein P27361 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR down-regulates activity phosphorylation 9606 12809513 t inferred from family member llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. SIGNOR-270301 0.424 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates activity phosphorylation Ser813 DIYSRRLsQETGLEI -1 1377674 t miannu CFTR is phosphorylated directly by PKA and PKC in vivo. phosphorylation by PKA is necessary to allow ATP hydrolysis by CFTR and that ATP hydrolysis is necessary for channel opening. CF-2 was phosphorylated by PKA in vitro on serines 660,700, 737, 813 and most likely on both serines 768 and 795. SIGNOR-250351 0.467 PAK3 protein O75914 UNIPROT SORT1 protein Q99523 UNIPROT down-regulates activity phosphorylation Ser793 RFLVHRYsVLQQHAE 9606 BTO:0000007 31767632 t miannu PAKs specifically phosphorylate Ser15 of the sortilin-cd and alter its trafficking. It can be concluded that PAK1-3 may indeed instigate the phosphorylation of sortilin and that they target a single serine residue (Ser15) located in the kinase domain-binding site of the sortilin-cd. Full-length sortilins with the serine at position 793 (residue 15 in the cytoplasmic domain) (for the sequence, see Fig. 2). Phosphorylation (Ser15) downregulates the sortilin–AP-1 interaction. SIGNOR-273719 0.2 PRKCA protein P17252 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 9606 BTO:0001271 9738012 t gcesareni Purified pkca can efficiently and directly phosphorylate bcl2 at serine 70 SIGNOR-60120 0.356 PKN3 protein Q6P5Z2 UNIPROT BCAR1 protein P56945 UNIPROT unknown phosphorylation Ser428 PAEGKRLsASSTGST -1 30422386 t lperfetto These results verified the presence of a PKN3 phosphorylation motif in the sequence surrounding Ser432 and indicated that PKN3 phosphorylates p130Cas on Ser432 in vitro.|Human Ser428 of p130Cas corresponds to mouse p130Cas Ser432| SIGNOR-264574 0.2 MRGPRX1 protein Q96LB2 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257384 0.349 CERK protein Q8TCT0 UNIPROT ceramide 1-phosphate(2-) smallmolecule CHEBI:84404 ChEBI up-regulates quantity chemical modification 9606 34202192 t miannu Another relevant enzyme is Ceramide kinase (CerK), which phosphorylates Cer to produce Ceramide 1-phosphate (C1P). SIGNOR-268499 0.8 DR1 protein Q01658 UNIPROT NC2 complex complex SIGNOR-C108 SIGNOR form complex binding 9606 BTO:0000567 18838386 t miannu NC2_ co-fractionated with NC2_ only in the low molecular weight complex (fractions 86–94) and an NC2_ antibody co-immunoprecipitated NC2_ (but not GCN5) in these fractions, which thus contain the classical NC2 complex SIGNOR-226405 0.774 TFIID complex SIGNOR-C343 SIGNOR TFIIA complex SIGNOR-C395 SIGNOR up-regulates activity relocalization 9606 8990153 t lperfetto PIC assembly begins with TFIID recognizing the TATA element, followed by coordinated accretion of TFIIB, the nonphosphorylated form of pol II (pol IIA) plus TFIIF, TFIIE, and TFIIH. SIGNOR-269307 0.601 PRKCD protein Q05655 UNIPROT SDC4 protein P31431 UNIPROT up-regulates activity phosphorylation Ser179 MKKKDEGsYDLGKKP 10116 11916978 t lperfetto The phosphorylation state of Ser(183) in the cytoplasmic tail of syndecan-4 determines the binding affinity of the cytoplasmic tail to phosphatidylinositol 4,5-bisphosphate (PIP(2)), the capacity of the tail to multimerize, and its ability to activate protein kinase C (PKC) alpha. We sought to identify the kinase responsible for this phosphorylation and to determine its downstream effects on PKCalpha activity and on endothelial cell function. Among several PKC isoenzymes tested, only PKCalpha and -delta were able to specifically phosphorylate Ser(183) in vitro. However, studies in cultured endothelial cells showed that the phosphorylation level of syndecan-4 was significantly reduced in endothelial cells expressing a dominant negative (DN) PKCdelta but not a DN PKCalpha mutant. SIGNOR-116265 0.508 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr146 KEVHKSGyLSSERLI 9606 15647376 t llicata N this study we have demonstrated that ezrin y145 is a direct target for phosphorylation by the tyrosine kinase src evidence from this study suggests that a positive feedback loop exists whereby src-mediated ezrin y145 phosphorylation sustains src activity._ SIGNOR-133227 0.634 BTC protein P35070 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 16829981 t gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4 SIGNOR-147823 0.712 CASP3 protein P42574 UNIPROT GRIPAP1 protein Q4V328 UNIPROT up-regulates activity cleavage 9606 17761173 t Giorgia These results suggest that the region of GRASP‐1 downstream of the Caspase‐3‐cleavage site is capable of activating the JNK signaling pathway by enhancing the phosphorylation of JNK. these results suggest that full length GRASP‐1 does not enhance JNK pathway activity, possibly due to the inhibitory effect of the N‐terminal fragment on the C‐terminal fragment. In contrast, Caspase‐3 cleavage of GRASP‐1 releases the C‐terminal fragment, which in turn activates JNK signaling by serving as a scaffold protein. SIGNOR-260641 0.423 GSTA1 protein P08263 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000018 29928434 f irozzo In addition, the downregulation of GSTA1 in A549 cells significantly induced cell apoptosis in vitro. In conclusion, GSTA1 plays an important role in regulation of cell proliferation and cell apoptosis in A549 cell line. SIGNOR-256297 0.7 POU5F1 protein Q01860 UNIPROT SOX2/POU5F1 complex SIGNOR-C73 SIGNOR form complex binding 9606 7590241 t miannu Sox2 can form a ternary complex with either the ubiquitous oct-1 or the embryonic-specific oct-3 protein on fgf-4 enhancer dna sequences. However, only the sox2/oct-3 complex is able to promote transcriptional activation. SIGNOR-29509 0.834 DVL1P1 protein P54792 UNIPROT DAAM1 protein Q9Y4D1 UNIPROT up-regulates binding 9606 23151663 t gcesareni Importantly, daam1 binds to disheveled (dvl) and thus functions downstream of the frizzled receptors. Little is known of how daam1 is localized and functions in mammalian cells. SIGNOR-199451 0.2 MAP4K5 protein Q9Y4K4 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000776 16914735 t lperfetto Gckr can phosphorylate an n-terminal recombinant fusion protein of gsk3_ and enhance the in vivo phosphorylation of gsk3_ on serine 9reduction of gckr expression inhibits wnt3a-induced phosphorylation of gsk3_ at serine 9 and decreases the accumulation of cytosolic _-catenin. SIGNOR-148908 0.2 MMP2 protein P08253 UNIPROT HAPLN1 protein P10915 UNIPROT down-regulates quantity by destabilization cleavage Leu40 QAENGPHlLVEAEQA -1 7694569 t miannu Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix. SIGNOR-256333 0.345 PRKCB protein P05771 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL -1 8422248 t lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. SIGNOR-248923 0.663 XAV939 chemical CHEBI:62878 ChEBI TNKS2 protein Q9H2K2 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207833 0.8 CAMK2A protein Q9UQM7 UNIPROT CAMK2A protein Q9UQM7 UNIPROT down-regulates phosphorylation Thr305 KLKGAILtTMLATRN 9606 1324926 t lperfetto After removal of ca2+/calmodulin, the autonomous kinase undergoes a burst of inhibitory autophosphorylation at sites distinct from the autonomy site. Ca(2+)-independent autophosphorylation occurs within the calmodulin binding domain at thr305, thr306, and ser314 SIGNOR-17312 0.2 PREX2 protein Q70Z35 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity binding 9606 BTO:0000007 24367090 t irozzo Here, we report that P-REX2 interacts with PTEN via two interfaces. In summary, P-REX2 docks to the PDZ-BD of PTEN through its C-terminal domain, reads the phosphorylation state of the PTEN tail via the DH domain, and inhibits PTEN activity by unleashing the PH domain SIGNOR-259189 0.605 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr886 GGEQDYDyLNDWGPR 9606 BTO:0000848 16371504 t lperfetto Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated. SIGNOR-143246 0.407 RNF115 protein Q9Y4L5 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 23418353 t miannu RNF126 and Rabring7 associate with the EGFR through a ubiquitin-binding zinc finger domain and both E3 ubiquitin ligases promote ubiquitylation of EGFR. In HeLa cells depleted of either RNF126 or Rabring7 the EGFR is retained in a late endocytic compartment and is inefficiently degraded. SIGNOR-272104 0.383 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 1715686 t gcesareni Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta. SIGNOR-21303 0.309 NPFFR1 protein Q9GZQ6 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256851 0.252 CAMK2A protein Q9UQM7 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates phosphorylation Thr372 STRIRQNtRDHPSTA 9606 BTO:0000671 10908300 t gcesareni The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microm [d-ala(2),n-mephe(4),gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative ca(2+)/calmodulin-dependent protein kinase ii (camk ii) phosphorylation sites, s261 and s266, by alanines in the third intracellular loop of the rat mu-opioid receptor (rmor1) confers resistance to camk ii-induced receptor desensitization. SIGNOR-79686 0.2 ITGB3 protein P05106 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253198 0.947 IFI30 protein P13284 UNIPROT peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity chemical modification 9606 31810556 t scontino Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol. SIGNOR-267864 0.8 PRKCA protein P17252 UNIPROT RALBP1 protein Q15311 UNIPROT up-regulates activity phosphorylation Thr297 ACGRTTEtEKVQEFQ -1 16087181 t miannu In deletion mutant analyses of potential phosphorylation sites in RLIP76, we identified T297 and S509 as targets for phosphorylation by PKCalpha. Phosphorylation at T297 increased doxorubicin (DOX)-transport activity approximately 2-fold for RLIP76 purified from recombinant source SIGNOR-263164 0.398 ATRX protein P46100 UNIPROT ZBED1 protein O96006 UNIPROT up-regulates activity binding 7227 BTO:0001138 22021382 t 1 miannu XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression. SIGNOR-239729 0.422 CDC25A protein P30304 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 10454565 t Phosphatase activity of Cdc25A is critical for its activating capacity (data not shown). In this context, it should also be mentioned that Cdc25A is able to activate cyclin B-Cdk1 in vitro SIGNOR-248479 0.836 GPR84 protein Q9NQS5 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256847 0.28 HNF1A protein P20823 UNIPROT AKR1C4 protein P17516 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 2044952 f 2 miannu Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene. HNF-1_ binds to the target element in the rat DBP gene in the liver, while vHNF-1 recognizes a target element in extrahepatic tissues. The ability of vHNF-1-A to activate the rat DBP gene is much higher than that of vHNF-1-C. SIGNOR-239964 0.248 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 21248841 f lperfetto The importance of polycomb function for stem cells is best illustrated by various PcG-knockout mice. Deletion of any of the PRC2 members results in embryonic lethality. In vitro studies with ES cells demonstrated that cells lacking EED or Suz12 could not maintain their pluripotency and were prone to differentiation. SIGNOR-241910 0.7 CNOT3 protein O75175 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268301 0.813 SP7 protein Q8TDD2 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004058; BTO:0000165 11792318 f Giulio Giuliani To test whether Osx could activate typical osteoblast genes, we transfected an Osx expressing vector into both C2C12 and C3H10T1/2 cells. Our results showed that Osx produced an induction of osteocalcin RNA in both cell types. SIGNOR-255409 0.505 MYOG protein P15173 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25211658 t P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells SIGNOR-251575 0.337 CTDSPL protein O15194 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity dephosphorylation Ser807 PGGNIYIsPLKSPYK 9606 15051889 t ppRB (RB phosphorylated at Ser-807/811|Possible Mechanisms of HYA22 Action in Tumorigenesis: Dephosphorylation of RB by Transient Expression of HYA22 Isoforms. SIGNOR-248304 0.302 PARP1 protein P09874 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity relocalization 9606 19629035 t PARP1 collaborates with Mre11 to promote replication fork restart after release from replication blocks, most likely by recruiting Mre11 to the replication fork to promote resection of DNA. SIGNOR-272478 0.2 Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates activity deubiquitination 9606 31226023 t miannu Overexpressing PLPro of SARS-CoV or MERS-CoV significantly reduced the expression of IFN-β and proinflammatory cytokines in MDA5-stimulated 293T cells (83).Also, SARS-CoVPLPro catalyzed deubiquitination of TNF-receptor-associated factor3 (TRAF3) and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist (63). The deubiquitinating activity of SARS-CoV PLPro also suppressed a constitutively active phosphomimetic IRF3, suggesting its involvement in the postactivation signaling of IRF3 SIGNOR-260246 0.2 retinol smallmolecule CHEBI:50211 ChEBI all-trans-retinyl ester smallmolecule CHEBI:63410 ChEBI up-regulates quantity precursor of 10090 18093970 t lperfetto We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis SIGNOR-265109 0.8 CSNK1A1 protein P48729 UNIPROT EIF2B5 protein Q13144 UNIPROT unknown phosphorylation Ser466 DEDDGEFsDDSGADQ 9606 BTO:0000007 11500362 t llicata The fifth site, which lies outside the catalytic domain of eIF2Bepsilon, can be phosphorylated by casein kinase 1. All five sites are phosphorylated in the eIF2B complex in vivo. | A phosphopeptide corresponding to this region was identified in Asp‐N digests of eIF2Bϵ phosphorylated in vitro by CK1, suggesting that Ser461 or Ser464 may be phosphorylated by this kinase in vivo. SIGNOR-250787 0.329 TWIST2 protein Q8WVJ9 UNIPROT CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002590 17487558 f miannu Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells SIGNOR-255517 0.454 gemcitabine chemical CHEBI:175901 ChEBI TYMS protein P04818 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0003207 25562513 t miannu 2',2'-Difluoro-2'-deoxycytidine (dFdC, gemcitabine) is a cytidine analogue active against several solid tumor types, such as ovarian, pancreatic and non-small cell lung cancer. The compound has a complex mechanism of action. Because of the structural similarity of one metabolite of dFdC, dFdUMP, with the natural substrate for thymidylate synthase (TS) dUMP, we investigated whether dFdC and its deamination product 2',2'-difluoro-2'-deoxyuridine (dFdU) would inhibit TS. This study was performed using two solid tumor cell lines: the human ovarian carcinoma cell line A2780 and its dFdC-resistant variant AG6000. The specific TS inhibitor Raltitrexed (RTX) was included as a positive control. Using the in situ TS activity assay measuring the intracellular conversion of [5-(3)H]-2'-deoxyuridine or [5-(3)H]-2'-deoxycytidine to dTMP and tritiated water, it was observed that dFdC and dFdU inhibited TS. SIGNOR-259350 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR JAK2 protein O60674 UNIPROT down-regulates phosphorylation 9606 16705159 t 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner SIGNOR-270046 0.2 MLLT11 protein Q13015 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0003295 21715312 f irozzo Our results indicate that AF1q cooperates with the Notch signaling pathway to foster the emergence of BM prothymocytes and drive subsequent intrathymic specification toward the T-cell lineage. SIGNOR-259201 0.7 ABL1 protein P00519 UNIPROT RAPGEF1 protein Q13905 UNIPROT unknown phosphorylation Tyr504 APIPSVPyAPFAAIL 9606 20581864 t llicata Activation of endogenous c-abl by oxidative stress was associated with phosphorylation of cellular c3g on y504. Inhibition of c3g expression and function using rnai or dominant-negative approaches inhibited c-abl-mediated cell death. SIGNOR-166422 0.551 HIPK1 protein Q86Z02 UNIPROT DAXX protein Q9UER7 UNIPROT down-regulates activity phosphorylation Ser668 KKICTLPsPPSPLAS 9606 12529400 t Manara HIPK1 phosphorylates Daxx on Ser 669, and phosphorylation of this site is important in modulating the ability of Daxx to function as a transcriptional repressor. | Therefore, phosphorylation at Ser 669 by HIPK1 diminishes the ability of Daxx to repress transcription. SIGNOR-260842 0.63 chelerythrine chemical CHEBI:78373 ChEBI MAPK8 protein P45983 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling gcesareni SIGNOR-190964 0.8 RUNX2 protein Q13950 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001610 22641097 f miannu Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells. SIGNOR-255085 0.46 FLT3 protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 30552988 f miannu Oncogenic, constitutively active mutants of FLT3 are known to be expressed in acute myeloid leukemia and to correlate with poor prognosis. Activation of the receptor mediates cell survival, cell proliferation and differentiation of cells. Several of the signal transduction pathways downstream of FLT3 have been shown to include various members of the SRC family of kinases (SFKs). They are involved in regulating the activity of RAS/ERK pathways through the scaffolding protein GAB2 and the adaptor protein SHC. SIGNOR-260132 0.296 MK-2461 chemical CID:44137946 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194390 0.8 FBXW8 protein Q8N3Y1 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001109 phosphorylation:Thr286 EEVDLACtPTDVRDV 17205132 t miannu We next investigated whether in vitro ubiquitination of cyclin D1 through the SCF-like (SCFL) complex FBXW8 (SKP1-CUL7-FBXW8-RBX1/SCFLFBXW8) requires phosphorylation of cyclin D1 at Thr286 (Fig. 3F). Polyubiquitination through SCFLFBXW8 was dramatically reduced by the depletion of ERK2 (lane 2). Furthermore, cyclin D1 polyubiquitination was largely prevented by the alanine-for-Thr286 substitution (T286A, lane 3), suggesting that phosphorylation of cyclin D1 at Thr286 is necessary for ubiquitination by SCFLFBXW8. SIGNOR-271624 0.525 USP28 protein Q96RU2 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by stabilization deubiquitination 18662541 t lperfetto Usp28 deubiquitylates and consequently stabilizes Claspin in response to DNA damage SIGNOR-274057 0.2 SMO protein Q99835 UNIPROT SUFU protein Q9UMX1 UNIPROT down-regulates activity binding 9606 BTO:0000452 22114142 t lperfetto In addition to activating g(i), smo signals through its c-terminal tail to inhibit suppressor of fused, resulting in stabilization and activation of the gli family of transcription factors, which execute a transcriptional response to so-called canonical hh signaling. SIGNOR-177656 0.625 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser293 TYRYHGHsMSDPGVS -1 7782287 t gcesareni Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase. SIGNOR-33197 0.674 GSK3B protein P49841 UNIPROT MAP1B protein P46821 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 25040932 t lperfetto GSK-3beta phosphorylates MAP1B and the adenomatous polyposis coil gene product (APC; Grimes and Jope 2001; Frame and Cohen 2001). The phosphorylation of MAP1B by GSK-3beta suppresses detyrosination of microtubules and decreases the numbers of stable microtubules SIGNOR-264843 0.542 CYC1 protein P08574 UNIPROT Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 t lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits SIGNOR-262192 0.927 PRKCD protein Q05655 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser742 GEKSFRRsVVGTPAY 9606 15024053 t llicata Here we show that activation of pkd in response to oxidative stress requires two sequential signaling events, i.e., phosphorylation of tyr463 by abl, which in turn promotes a second step, phosphorylation of the pkd activation loop (ser738/ser742). We show that this is mediated by pkcdelta (protein kinase cdelta) SIGNOR-123453 0.273 AKT1 protein P31749 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Thr509 LKRKRRPtSGLHPED 9606 BTO:0000150 17428466 t lperfetto Phosphatidylinositol 3-kinase/akt signaling enhances nuclear localization and transcriptional activity of brca1. mutation of threonine 509 in brca1, the site of akt phosphorylation, to an alanine, attenuates the ability of heregulin to induce brca1 nuclear accumulation SIGNOR-154312 0.52 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation 9606 12832467 t lperfetto Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. SIGNOR-102648 0.707 SKP2 protein Q13309 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0003725 11439327 t miannu We show that SK-UT-1B cells express a novel splice variant of Skp2 that localizes to the cytoplasm and that cyclin D1 ubiquitination takes place in the nucleus. We propose that the translocation of Skp2 into the nucleus is required for the ubiquitination of cyclin D1 and that the absence of the SCF(Skp2) complex in the nucleus of SK-UT-1B cells is the mechanism underlying the ubiquitination defect observed in this cell line. SIGNOR-272575 0.577 KISS1R protein Q969F8 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256750 0.478 RIMS3 protein Q9UJD0 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 31679900 t miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle SIGNOR-264379 0.286 SNAI1 protein O95863 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 19055748 f lperfetto Taken together these results suggest that SNAI1 functional blockade is leading to partial re-expression of E-cadherin (i.e. at the level of transcription), to a decrease in PAI-1 and to a more collective migration, while the parental cells expressing SNAI1 have less E-cadherin, more PAI 1, and migrate individually. We suggest that the present study establishes a relation between SNAI1 function, PAI-1 distribution and EMT status. SIGNOR-252259 0.7 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser187 NSHPFPHsPNSSYPN 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248300 0.479 CASP8 protein Q14790 UNIPROT CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9727491 t gcesareni Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them. SIGNOR-59857 0.724 EFNA1 protein P20827 UNIPROT EPHA6 protein Q9UF33 UNIPROT up-regulates binding 9606 9576626 t tpavlidou Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity SIGNOR-56962 0.804 RPS6KA1 protein Q15418 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser291 CGSSGYFsSSPTLSS 9606 22017877 t lperfetto We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1 SIGNOR-176891 0.506 TTC8 protein Q8TAM2 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 t lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome SIGNOR-262554 0.751 HLX protein Q14774 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003980 20008130 t Luana In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells. SIGNOR-261619 0.2 IL17A protein Q16552 UNIPROT KLF3 protein P57682 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23332504 f fspada Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic. SIGNOR-192610 0.2 SPI1 protein P17947 UNIPROT Lymphopoiesis phenotype SIGNOR-PH111 SIGNOR up-regulates activity 10090 BTO:0000725 8079170 f Mice carrying a mutation in the PU.1 locus were generated by gene targeting. Homozygous mutant embryos died at a late gestational stage. [...]An invariant consequence of the mutation was a multilineage defect in the generation of progenitors for B and T lymphocytes, monocytes, and granulocytes. Thus, the developmental programs of lymphoid and myeloid lineages require a common genetic function likely acting at the level of a multipotential progenitor. SIGNOR-259956 0.7 SEH1L protein Q96EE3 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262092 0.633 CAMK4 protein Q16566 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0001271 12835716 t lperfetto Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. All these kinases target CREB on S133 to activate CREB. SIGNOR-102722 0.697 RB1 protein P06400 UNIPROT ANP32A protein P39687 UNIPROT down-regulates activity binding 9606 phosphorylation:Thr826 LPTPTKMtPRSRILV 15716273 t We further demonstrate that pp32-Rb interaction inhibits the apoptotic activity of pp32 and stimulates proliferation. SIGNOR-259083 0.2 PRKCA protein P17252 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000782 19836308 t lperfetto Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka). SIGNOR-188581 0.364 RXRA protein P19793 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 11237216 t gcesareni Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology SIGNOR-105445 0.732 CBFA2T3/ZNF651 complex SIGNOR-C197 SIGNOR ZNF652 protein Q9Y2D9 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 20116376 t Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex. SIGNOR-253955 0.524 SIRT1 protein Q96EB6 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-217884 0.7 EIF3L protein Q9Y262 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266389 0.921 Host translation inhibitor nsp1 protein P0DTD1-PRO_0000449619 UNIPROT RPS2 protein P15880 UNIPROT down-regulates activity binding -1 33188728 t miannu Nsp1 Locks the 40S in a Conformation Incompatible with mRNA Loading and Disrupts Initiation Factor Binding. Molecular interactions between C-Nsp1 and 40S ribosome components, including uS3, h18, and uS5. SIGNOR-262508 0.2 SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Tyr315 TFCGTPEyLAPEVLE 9534 BTO:0004055 11445557 t lperfetto Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity. SIGNOR-246368 0.664 HNF4A protein P41235 UNIPROT AKR1C4 protein P17516 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003846 2044952 f 2 miannu Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene. HNF-4_ is a necessary factor for the activation of the human DD4 gene. is much higher than that of vHNF-1-C. SIGNOR-240016 0.258 PORCN protein Q9H237 UNIPROT WNT3A protein P56704 UNIPROT up-regulates activity palmitoylation Ser209 KCKCHGLsGSCEVKTC 9606 BTO:0000007 20826466 t And WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A-WLS complex both in cells and at the plasma membrane. SIGNOR-256598 0.688 HIF1A protein Q16665 UNIPROT VEGFA protein P15692 UNIPROT up-regulates quantity transcriptional regulation 9606 8387214 t Transcription of the human erythropoietin (EPO) gene is activated in Hep3B cells exposed to hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a nuclear factor whose DNA binding activity is induced by hypoxia in Hep3B cells, and HIF-1 binds at a site in the EPO gene enhancer that is required for hypoxic activation of transcription. SIGNOR-256592 0.765 GDF5 protein P43026 UNIPROT Cartilage_development phenotype SIGNOR-PH75 SIGNOR up-regulates 9606 21976273 f miannu Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. SIGNOR-252418 0.7 RET protein P07949 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 16153436 t inferred from 70% of family members gcesareni We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1). SIGNOR-269894 0.2 PPM1D protein O15297 UNIPROT RPS6KA3 protein P51812 UNIPROT down-regulates activity dephosphorylation Thr577 AENGLLMtPCYTANF 10090 15206906 t RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity SIGNOR-248323 0.368 SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 30397315 f miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270609 0.7 GSK3B protein P49841 UNIPROT BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Thr171 ETSKSFVtPPQSHFV 9606 BTO:0002181 26028025 t miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. SIGNOR-276906 0.262 CYP11A1 protein P05108 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI down-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The steroidogenic acute regulatory protein (StAR) assists in the transport of cholesterol from the cytosol to the inner mitochondria membrane to be converted into pregnenolone using the P450 side-chain cleavage (P450scc) enzyme. SIGNOR-268633 0.8 STK3 protein Q13188 UNIPROT RCC1 protein P18754 UNIPROT up-regulates phosphorylation Ser2 sPKRIAKR 9606 BTO:0000007 19559616 t miannu MST2 Phosphorylates RCC1 In Vitro and In Vivo. Using an antibody generated against phospho-S2/11 in RCC1 [18], we found that these two residues were also efficiently phosphorylated by MST1 and MST2 (Figure 2D), further supporting that S2 and/or S11 are genuine MST2 phosphorylation targets. SIGNOR-263146 0.2 ABL1 protein P00519 UNIPROT DGCR8 protein Q8WYQ5 UNIPROT up-regulates activity phosphorylation Tyr267 KRRTEEKyGGDSDHP 9606 BTO:0000007 26126715 t miannu The kinase ABL phosphorylates the microprocessor subunit DGCR8 to stimulate primary microRNA processing in response to DNA damage. When coexpressed in HEK293T cells, ABL phosphorylated DGCR8 at Tyr(267). SIGNOR-262604 0.2 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH6 protein P55285 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265846 0.8 MRGPRX2 protein Q96LB1 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257385 0.2 SREBF2 protein Q12772 UNIPROT SQLE protein Q14534 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000759 31848472 t miannu The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription SIGNOR-265162 0.578 P2RY6 protein Q15077 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257076 0.2 RPS6KA1 protein Q15418 UNIPROT STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 BTO:0001271 25846811 t lperfetto Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK. SIGNOR-209871 0.292 CEBPE protein Q15744 UNIPROT CEBPG protein P53567 UNIPROT up-regulates activity binding 9606 BTO:0000007 15588942 t miannu C/EBP-epsilon interacts with C/EBP-gamma through the leucine-zipper containing domain. C/EBP-epsilon and C/EBP-gamma synergistically activate transcription of lactoferrin promoter SIGNOR-224900 0.381 SRC protein P12931 UNIPROT EMD protein P50402 UNIPROT down-regulates phosphorylation Tyr74 TRGDADMyDLPKKED 9606 BTO:0000567 BTO:0000887 19789182 t llicata Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf SIGNOR-188312 0.463 PIM1 protein P11309 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT up-regulates activity phosphorylation Thr362 GEKKKKItVFKEISY 9606 BTO:0001130 18056989 t lperfetto Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells|This is further corroborated by our finding that the plasma membrane localization and drug-resistant activity of BCRP were compromised by T362A mutation. SIGNOR-264420 0.367 SLC36A4 protein Q6YBV0 UNIPROT tryptophan smallmolecule CHEBI:27897 ChEBI up-regulates quantity relocalization 8355 21097500 t lperfetto HPAT4 in Xenopus oocytes mediated sodium-independent, electroneutral uptake of [(3)H]proline, with the highest rate of uptake when the uptake medium pH was 7.4 and an affinity of 3.13 μM. Tryptophan was also an excellently transported substrate with a similarly high affinity (1.72 μM). SIGNOR-264735 0.8 INTS7 protein Q9NVH2 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261464 0.781 alvocidib hydrochloride chemical CHEBI:90998 ChEBI CDK6 protein Q00534 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192470 0.8 TLN1 protein Q9Y490 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257607 0.79 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 BTO:0000150 18372406 t gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-178137 0.657 MAP2K7 protein O14733 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser312 TESITATsPASMVGG 9606 BTO:0000975 17360977 t lperfetto Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 Ser312 can be phosphorylated by kinases, such as c-jun NH2-terminal kinase and inhibitor of _B kinase SIGNOR-217920 0.377 EGR2 protein P11161 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 11494141 f miannu Flow cytometry suggested that over-expression of BPOZ inhibited progression of the cell cycle at the G1/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated. SIGNOR-260048 0.7 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Thr709 PKRLGAHtP 9606 14697653 t lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. SIGNOR-120483 0.271 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser1101 GCRRRHSsETFSSTP 10090 15306821 t lperfetto Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulates insulin. SIGNOR-127904 0.78 MMP19 protein Q99542 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage Asn360 DFVDIPEnFFGVGGE -1 10922468 t lperfetto Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|In this study we investigated the ability of MMP-19 and MMP-20 to cleave two of the macromolecules characterising the cartilage ECM, namely aggrecan and the cartilage oligomeric matrix protein (COMP). Both MMPs hydrolysed aggrecan efficiently at the well-described MMP cleavage site between residues Asn(341) and Phe(342), as shown by Western blotting using neo-epitope antibodies. Furthermore, the two enzymes cleaved COMP in a distinctive manner, generating a major proteolytic product of 60 kDa. Our results suggest that MMP-19 may participate in the degradation of aggrecan and COMP in arthritic disease, whereas MMP-20, due to its unique expression pattern, may primarily be involved in the turnover of these molecules during tooth development. SIGNOR-266978 0.409 SCF-SKP2 complex SIGNOR-C136 SIGNOR RBL2 protein Q08999 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 phosphorylation:Ser672 TLYDRYSsPPASTTR 12435635 t miannu  The activity of the ubiquitin ligase complex Skp1-Cul1/Cdc53-F-box protein Skp2 (SCF(Skp2)) and the proteasome were necessary for p130 degradation. In vitro, recombinant Skp2 was able to bind hyperphosphorylated but not dephosphorylated p130. Furthermore, in vitro polyubiquitination of p130 by SCF(Skp2) was specifically dependent on phosphorylation of p130 on Serine 672.  SIGNOR-272598 0.546 CEBPB protein P17676 UNIPROT SLC19A1 protein P41440 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15652157 t Collectively, these results identify transcriptionally important regions in the hRFC-C minimal promoter that include a GC-box and CCAAT-box, and suggest that cooperative interactions between Sp1 and C/EBP beta are essential for hRFC-C transactivation. SIGNOR-254053 0.2 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 11242034 t Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif. gcesareni A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) and p38 subs of map kinases, respectively. Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). SIGNOR-105692 0.733 HTR1B protein P28222 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256720 0.444 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Thr426 TEVEDTLtPPPSDAG 9606 BTO:0000567 16825193 t lperfetto The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding SIGNOR-236649 0.498 CD70 protein P32970 UNIPROT CD27 protein P26842 UNIPROT up-regulates binding 9606 BTO:0000776 12324477 t gcesareni The molecule defining the cd70 ag is identical to the recently defined ligand for cd27. Bioassays demonstrated that the cd70 cdna clone expressed in african green monkey kidney cells would induce the proliferation of pha-costimulated t cells. Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated t cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner. SIGNOR-93435 0.764 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR Core Binding Factor complex complex SIGNOR-C214 SIGNOR down-regulates activity binding 9606 15829516 t irozzo Two classes of models can describe how AML1-ETO could interfere with normal AML1 activity. First, because AML1-ETO has the potential to interact with AML1 co-factors (such as CBFβ) through its RD, it could act as a dominant-negative molecule by competing with AML1 for these co-factors. Although AML1-ETO has been shown to interact with CBFβ and repress the expression of AML1-regulated genes in vitro and in cell culture, the available data do not distinguish between these two models. SIGNOR-256100 0.2 AHSA1 protein O95433 UNIPROT HSP90AA1 protein P07900 UNIPROT up-regulates activity binding 9606 16696853 t miannu The N-terminal region of Aha1 interacts with the central domain of Hsp90 and stimulates Hsp90 ATPase activity SIGNOR-252211 0.766 ETV6 protein P41212 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000960;BTO:0002062 15958056 f irozzo We thus conclude that TEL is also an accelerator for erythroid differentiation upon cytokine stimulation in human hematopoietic cells. We demonstrated in the present study that TEL accelerates erythroid differentiation induced by a physiological cytokine EPO in human leukemia cell line UT-7/GM. SIGNOR-256017 0.7 arecoline chemical CHEBI:2814 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258641 0.8 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Pro54 NPNDKYEpFWEDEEK -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. SIGNOR-263578 0.43 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 18621737 t lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-179456 0.891 PRKACA protein P17612 UNIPROT CACNA1C protein Q13936 UNIPROT up-regulates activity phosphorylation Ser1897 LLRKANPsRCHSRES 10090 28119464 t These findings reveal an essential role for _1C phosphorylation at Ser1928 in stimulating CaV1.2 channel activity and vasoconstriction by AKAP-targeted PKA upon exposure to increased glucose and in diabetes SIGNOR-251709 0.48 CASP8 protein Q14790 UNIPROT RNF31 protein Q96EP0 UNIPROT down-regulates activity cleavage Asp348 GTGGLEPdLARGRWA 9606 BTO:0005111 32122970 t miannu We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death. SIGNOR-272194 0.32 MDM2 protein Q00987 UNIPROT NOTCH4 protein Q99466 UNIPROT down-regulates ubiquitination 9606 BTO:0000149 21402876 t gcesareni We demonstrate that the intracellular domain of notch 4 is targeted for ubiquitylation and hence degradation by the ubiquitin ligase mdm2. SIGNOR-172826 0.378 MARCHF9 protein Q86YJ5 UNIPROT LILRB1 protein Q8NHL6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271534 0.2 BAG1 protein Q99933 UNIPROT HSPA8 protein P11142 UNIPROT up-regulates activity binding -1 27474739 t lperfetto Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co-chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70. SIGNOR-254115 0.891 PRKG1 protein Q13976 UNIPROT TRPC6 protein Q9Y210 UNIPROT down-regulates activity phosphorylation Ser322 KNDYKKLsMQCKDFV -1 19961855 t miannu PKG phosphorylated TRPC6, and both T70 and S322 were targeted. Both sites were functionally relevant, as 8Br-cGMP strongly suppressed current in wild-type TRPC6 channels, but not in those with phospho-silencing mutations (T70A, S322A or S322Q).  SIGNOR-276271 0.473 NCL protein P19338 UNIPROT MYB protein P10242 UNIPROT down-regulates activity binding 9606 BTO:0000007 10660576 t miannu We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity. SIGNOR-221236 0.41 KAT2B protein Q92831 UNIPROT H3C15 protein Q71DI3 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269626 0.2 SPDEF protein O95238 UNIPROT MMP13 protein P45452 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003160 22761428 f miannu Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells. SIGNOR-255219 0.2 CYP1B1 protein Q16678 UNIPROT 4-hydroxy-17beta-estradiol smallmolecule CHEBI:62845 ChEBI up-regulates quantity chemical modification 9606 BTO:0000093 8790407 t Luana These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens. SIGNOR-269754 0.8 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCG protein P05129 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191499 0.8 BCL9 protein O00512 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 15208637 t amattioni The transcriptional activity of beta-catenin depends on bcl-9. Bcl-9 functions in targeting beta-catenin to the nucleus and thus increases the transcriptional activity of beta-catenin SIGNOR-126059 0.937 KIF2A protein O00139 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272533 0.7 BRD7 protein Q9NPI1 UNIPROT BRD3 protein Q15059 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000192 12600283 f miannu BRD7 protein could respectively interact with proteins, BRD2 and BRD3, and BRD7 could up-regulate the expression levels of BRD2 and BRD3 genes in mRNA level to some extent. SIGNOR-253764 0.391 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser717 VYKSPVVsGDTSPRH 9606 BTO:0000590 12387894 t lperfetto Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. SIGNOR-249355 0.728 SPOP protein O43791 UNIPROT CUL3 protein Q13618 UNIPROT up-regulates activity binding 9606 BTO:0000007 34599168 t miannu Here we show that the CULLIN3 E3 ubiquitin ligase adaptor protein SPOP binds Geminin at endogenous level and regulates DNA replication. SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127. SIGNOR-268927 0.919 EEF1A1P5 protein Q5VTE0 UNIPROT Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269545 0.8 Pituitary adenylate cyclase-activating peptide-27 smallmolecule CHEBI:80303 ChEBI ADCYAP1R1 protein P41586 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257445 0.8 NEDD4L protein Q96PU5 UNIPROT SCN4A protein P35499 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 t miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). SIGNOR-253460 0.283 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. SIGNOR-75922 0.606 STIP1 protein P31948 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates activity binding 9606 BTO:0000007 27353360 t miannu Hsp90 chaperone cycle is tightly regulated by another group of proteins referred to as ‘co-chaperones'. Their stability does not depend on Hsp90 function but they interact with distinct Hsp90 conformational states, providing directionality to the Hsp90 cycle. Furthermore, certain co-chaperones, such as HOP and Cdc37p50 inhibit the Hsp90 chaperone cycle, assisting in delivery of distinct sets of client proteins (steroid hormone receptors and kinases, respectively) to the Hsp90 chaperone machine. SIGNOR-261411 0.932 TLN1 protein Q9Y490 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257626 0.678 (R)-5-Fluoro-8-hydroxy-2-(dipropylamino)tetralin chemical CID:11957727 PUBCHEM HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258867 0.8 DYRK1A protein Q13627 UNIPROT SRSF1 protein Q07955 UNIPROT unknown phosphorylation Ser238 SRGSPRYsPRHSRSR 9606 BTO:0000142 18658135 t gcesareni Here, we demonstrate that dyrk1a, a kinase encoded by a gene in the ds critical region, phosphorylates alternative splicing factor (asf) at ser-227, ser-234, and ser-238, driving it into nuclear speckles and preventing it from facilitating tau exon 10 inclusion. SIGNOR-179615 0.4 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914161 t lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 SIGNOR-161601 0.591 MMP14 protein P50281 UNIPROT FGG protein P02679 UNIPROT down-regulates quantity by destabilization cleavage Ile105 ESSKPNMiDAATLKS -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain SIGNOR-263618 0.2 RAP1GDS1 protein P52306 UNIPROT RHOB protein P62745 UNIPROT up-regulates binding 9606 21242305 t miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob SIGNOR-171615 0.282 GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268605 0.254 CASP3 protein P42574 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates cleavage 9606 11283607 t gcesareni Rock i is cleaved by casp3 at a conserved detd1113/g sequence and its carboxy-terminal inhibitory domain is removed, resulting in deregulated and constitutive kinase activity. SIGNOR-106546 0.724 desipramine chemical CHEBI:47781 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition -1 9400006 t miannu In the SERT, the TCAs amitriptyline, nortriptyline, imipramine, desipramine and chloroimipramine were 4.5 to 10 times more potent (table 3) at the human SERT.in the SERT, the TCAs amitriptyline, nortriptyline, imipramine, desipramine and chloroimipramine were 4.5 to 10 times more potent (table 3) at the human SERT.Thus, amitriptyline, imipramine, nortriptyline and desipramine showed high affinity for the SERT, particularly the human version, and for the NET in which the secondary amines were more potent. SIGNOR-258679 0.8 ATM protein Q13315 UNIPROT RBBP8 protein Q99708 UNIPROT down-regulates phosphorylation Ser745 SCLADSFsQAADEEE 9606 BTO:0000150 10910365 t llicata Atm phosphorylates ctip at serine residues 664 and 745 our study suggests another dna damage-response pathway in which the signal is transmitted through phosphorylation of ctip by atm, leading to dissociation of the ctip_ctbp repressor complex from brca1, which in turn, activate transcription of gadd45 SIGNOR-79876 0.822 PRKACA protein P17612 UNIPROT PDE4D protein Q08499 UNIPROT up-regulates phosphorylation 9606 8663227 t llicata Phosphorylation and activation of a camp-specific phosphodiesterase by the camp-dependent protein kinase. SIGNOR-42515 0.563 DRD5 protein P21918 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257043 0.293 GRK3 protein P35626 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t gcesareni ...expression of GRK4Ž drastically increased the basal level of32P incorporation into B2R.[€]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation. SIGNOR-249658 0.2 ZNRF3 protein Q9ULT6 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates relocalization 9606 23151663 t gcesareni Znrf3 is associated with the wnt receptor complex, and inhibits wntby promoting the turnover of frizzled and lrp6. SIGNOR-199650 0.296 bisindolylmaleimide i chemical CID:2396 PUBCHEM PRKCE protein Q02156 UNIPROT down-regulates chemical inhibition 9606 Other t CellSignaling gcesareni SIGNOR-190353 0.8 sunitinib chemical CHEBI:38940 ChEBI PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 21423276 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-172926 0.8 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Gln) smallmolecule CHEBI:29168 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270387 0.8 ZNF804A protein Q7Z570 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 23434502 t miannu ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). SIGNOR-269464 0.2 BIRC2 protein Q13490 UNIPROT RIPK4 protein P57078 UNIPROT up-regulates activity polyubiquitination lys51 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation. SIGNOR-272706 0.362 MAPK1 protein P28482 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates activity phosphorylation Thr386 IGLNQPStPTHAAGV 9606 10567369 t lperfetto An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2 SIGNOR-236498 0.74 DGC complex SIGNOR-C217 SIGNOR GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265433 0.2 HCK protein P08631 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates activity phosphorylation Tyr752 GTSDQVLyGQLLGSP -1 9790917 t Hck becomes activated upon G-CSF treatment and is, in turn, able to phosphorylate the G-CSF-R, indicating a clear functional and physical involvement in G-CSF signaling. the ability of Hck to phosphorylate the G-CSF-R in vitro, both Y728 and Y763 fit the Src consensus phosphorylation site SIGNOR-251263 0.393 AGRP protein O00253 UNIPROT MC4R protein P32245 UNIPROT down-regulates binding 9606 9311920 t gcesareni Recombinant agouti-related protein was a potent, selective antagonist of mc3r and mc4r,. SIGNOR-51104 0.766 GSK3B protein P49841 UNIPROT JUN protein P05412 UNIPROT down-regulates activity phosphorylation Thr239 VPEMPGEtPPLSPID 9606 BTO:0000007 16023596 t lperfetto The c-jun and c-myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.Phosphorylation of Thr-239 and Ser-243 is required for Fbw7-mediated c-Jun disappearance SIGNOR-236717 0.7 BCL2L2 protein Q92843 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 t gcesareni Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax. SIGNOR-152989 0.458 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Ser485 QDNGAEDsGDTEDEL 9606 20471329 t lperfetto Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair SIGNOR-165419 0.404 VRK1 protein Q99986 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000567 10951572 t gcesareni Vrk1 phosphorylates murine p53 in threonine 18. This threonine is within the p53 hydrophobic loop (residues 13-23) required for the interaction of p53 with the cleft of its inhibitor mdm-2. SIGNOR-81222 0.538 CARS1 protein P49589 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 11347887 t miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. SIGNOR-270472 0.8 UBQLN2 protein Q9UHD9 UNIPROT TARDBP protein Q13148 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0003704 23541532 t lperfetto Here, we describe a high affinity interaction between UBQLN2 and TDP-43 and demonstrate that overexpression of both UBQLN2 and TDP-43 reduces levels of both exogenous and endogenous TDP-43 in human H4 cells.|Consequently, these data suggest that UBQLN2 enhances the clearance of TDP-43 SIGNOR-262112 0.601 dasatinib (anhydrous) chemical CHEBI:49375 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001056 23409026 t miannu Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. SIGNOR-259270 0.8 PLK1 protein P53350 UNIPROT STK38 protein Q15208 UNIPROT down-regulates activity phosphorylation Thr407 EIKSIDDtSNFDEFP 9606 BTO:0000567 26057687 t miannu Here, we identified a conserved signaling axis in which NDR1 kinase activity is regulated by PLK1 in mitosis. PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1-dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis.  SIGNOR-276915 0.321 entacapone chemical CHEBI:4798 ChEBI COMT protein P21964 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000759 9681662 t Simone Vumbaca Entacapone and tolcapone were powerful inhibitors of COMT and their IC50 estimates were 151 and 773 nM (P=0.008), respectively, in the liver; consistent results were obtained with the other tissues. SIGNOR-261088 0.8 ABT-737 chemical CID:11228183 PUBCHEM BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271;BTO:0000776;BTO:0000785 17200714 t gcesareni A cell-permeant compound, abt-737, binds with high affinity to bcl2, bcl2l1, and bcl2l2, antagonizes their antiapoptotic function, and induces apoptosis in select human tumor cell lines, primary patient-derived cells. SIGNOR-151781 0.8 ATF4 protein P18848 UNIPROT LARS2 protein Q15031 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269421 0.254 POLR2D protein O15514 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266164 0.836 CAMK2A protein Q9UQM7 UNIPROT CACNA1S protein Q13698 UNIPROT up-regulates activity phosphorylation Ser1575 PEICRTVsGDLAAEE -1 20937870 t miannu To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2. SIGNOR-263113 0.437 DEPDC5 protein O75140 UNIPROT GATOR1 complex SIGNOR-C192 SIGNOR form complex binding 9606 23723238 t miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 SIGNOR-255280 0.949 LPCAT4 protein Q643R3 UNIPROT 1-O-acyl-sn-glycero-3-phosphocholine chemical CHEBI:58168 ChEBI down-regulates quantity chemical modification 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272772 0.8 CDK1 protein P06493 UNIPROT UBXN2B protein Q14CS0 UNIPROT down-regulates activity phosphorylation Thr59 TVFKSPRtPPQRFYS 23500464 t lperfetto At mitosis, Cdc2 kinase phosphorylates p47 on Serine-140 and p37 on Serine-56 and Threonine-59, respectively. The phosphorylated p47 and p37 are unable to bind to Golgi membranes, resulting in mitotic inhibition of the p97/p47 and the p97/p37 pathways, respectively. SIGNOR-265041 0.2 GDF5 protein P43026 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates activity binding 10090 15890363 t In contrast to other members of the TGF-beta superfamily, GDF-5 shows a pronounced specificity in type I receptor interaction in cross-link experiments binding only to BMP receptor IB (BMPR-IB). In mice, deletion of either GDF-5 or BMPR-IB results in a similar phenotype, indicating that GDF-5 signaling is highly dependent on BMPR-IB. SIGNOR-256483 0.777 CDK7 protein P50613 UNIPROT MCM2 protein P49736 UNIPROT up-regulates activity phosphorylation Ser139 RRGLLYDsDEEDEER 9606 16899510 t Luana Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. | Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2. SIGNOR-259850 0.304 CASP3 protein P42574 UNIPROT GAS2 protein O43903 UNIPROT up-regulates cleavage Asp278 MLQISRVdGKTSPIQ 9606 10564664 t gcesareni We now demonstrate that gas2 is a substrate of caspase-3 but not of caspase-6. Proteolytic processing both in vitro and in vivo is dependent on aspartic residue 279. SIGNOR-72347 0.428 nilotinib chemical CHEBI:52172 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194640 0.8 UBE2D2 protein P62837 UNIPROT PEX5 protein P50542 UNIPROT down-regulates quantity by destabilization ubiquitination -1 19687296 t miannu Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. SIGNOR-253023 0.426 SMAD1 protein Q15797 UNIPROT SATB2 protein Q9UPW6 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 t Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation SIGNOR-268934 0.2 SRC protein P12931 UNIPROT Enolase proteinfamily SIGNOR-PF74 SIGNOR up-regulates phosphorylation 9606 24841372 t inferred from family member lperfetto The present finding suggested that the tyrosine residue at position 44 in chicken alpha-enolase is the phosphorylation site by the tyrosine kinase. Our data suggest that eno1 was upregulated by caga protein through activating the src and mek/erk signal pathways SIGNOR-270248 0.422 ATR protein Q13535 UNIPROT MCM4 protein P33991 UNIPROT up-regulates phosphorylation 9606 21070963 t gcesareni Together these data strongly support the conclusion that mec1 directly targets the s/tq sites in mcm4 and mcm6, although it is formally possible that mec1 and mrc1 activate a different s/tq-directed kinase to target mcm4 and mcm6. SIGNOR-169412 0.714 C5 convertase complex (C3bBbC3b) complex SIGNOR-C315 SIGNOR C5 protein P01031 UNIPROT up-regulates activity cleavage Arg677 KEILRPRrTLQKKIE 9606 BTO:0000089 26489954 t lperfetto In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC). SIGNOR-263481 0.539 PRKDC protein P78527 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser126 PPGTPLVsQDEKRDA 9606 21824916 t lperfetto We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro. SIGNOR-176020 0.635 pictrelisib chemical CHEBI:65326 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 BTO:0000149 21876152 t gcesareni Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed SIGNOR-252664 0.8 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser230 PEGATPTsPVGHFAK 9606 BTO:0000848 BTO:0001253 20959475 t lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). SIGNOR-252953 0.703 leukotriene D4(1-) smallmolecule CHEBI:63166 ChEBI CYSLTR1 protein Q9Y271 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257475 0.8 GSK3A protein P49840 UNIPROT OSBP2 protein Q969R2 UNIPROT up-regulates activity phosphorylation 30925160 t lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. SIGNOR-264875 0.2 MRPS34 protein P82930 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261443 0.653 EEF1D protein P29692 UNIPROT EEF1B complex complex SIGNOR-C460 SIGNOR form complex binding 9606 23699257 t lperfetto An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. The requirement for a guanine nucleotide exchange factor, the eEF1B complex, which in metazoans is composed of the subunits α, δ, and γ (also called eEF1B, eEF1D, and eEF1G, respectively) SIGNOR-269392 0.815 MITF protein O75030 UNIPROT DCT protein P40126 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22371403 f miannu MITF transcription factor regulates melanogenesis by activation of tyrosinase, TRP1 and TRP2 transcription. SIGNOR-254592 0.473 P2RY4 protein P51582 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256870 0.358 paliperidone chemical CHEBI:82978 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258563 0.8 PPM1D protein O15297 UNIPROT KDM1A protein O60341 UNIPROT down-regulates activity dephosphorylation Ser131 DESLANLsEDEYYSE 9606 BTO:0002181 25999347 t miannu We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites. SIGNOR-276904 0.477 MAPKAPK2 protein P49137 UNIPROT TCF3 protein P15923 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2 SIGNOR-166643 0.5 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR2 protein P30518 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257463 0.8 PTPRF protein P10586 UNIPROT RET protein P07949 UNIPROT down-regulates dephosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 11121408 t gcesareni Lar expression significantly reduced tyrosine-1062 phosphorylation in ret-men2a but not in ret-men2b SIGNOR-85170 0.436 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1355 SLGFKRSyEEHIPYT -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-22577 0.2 herbimycin chemical CHEBI:5674 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 BTO:0000142 11782488 t gcesareni Herbimycin a and pp2, specific inhibitors of src family kinases, both inhibited h2o2-mediated c-src and bmk1 activation. SIGNOR-113767 0.8 PRKACA protein P17612 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser305 IKRSKKNsLALSLTA 9606 15193262 t lperfetto We show that phosphorylation of serine-305 in the hinge region of er_ by protein kinase a (pka) induced resistance to tamoxifenactivation of pka prevents tamoxifen-mediated inhibition of er transactivation SIGNOR-125779 0.467 SGK1 protein O00141 UNIPROT SMO protein Q99835 UNIPROT down-regulates binding 9606 25790864 t gcesareni SGK1 is known to inhibit another intrinsic pathway, the Hedgehog pathway, through downregulation of SMO and the GLI transcription factor family SIGNOR-251673 0.2 S1PR5 protein Q9H228 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256819 0.358 CUDC-101 chemical CID:24756910 PUBCHEM HDAC10 protein Q969S8 UNIPROT down-regulates activity chemical inhibition -1 20143778 t miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. SIGNOR-262257 0.8 MAPK14 protein Q16539 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates activity phosphorylation Thr66 EPICSVNtPREVTLH -1 10206983 t miannu The noncatalytic N terminus of HePTP binds Erk and p38 and is phosphorylated at Ser-72 and Thr-45 by these kinases. the N terminus of HePTP binds Erk and p38 but may release them upon phosphorylation.it is clear that phosphorylation of HePTP at Thr-45 and/or Ser-72 is not required for inhibition of MAP kinase. Rather, it seems that phosphorylation has the opposite effect, namely to lessen the inhibitory effect of HePTP. SIGNOR-250110 0.585 NatC complex SIGNOR-C417 SIGNOR Protein_acetylation phenotype SIGNOR-PH189 SIGNOR up-regulates 9606 21351257 f miannu About 80% of soluble human proteins are N-terminally acetylated by 1 of 3 major Nα-terminal acetyltransferase complexes, hNatA, hNatB and hNatC, which differ in their subunit composition and substrate specificity. SIGNOR-267236 0.7 LCK protein P06239 UNIPROT PRDX2 protein P32119 UNIPROT down-regulates activity phosphorylation Tyr193 NVDDSKEyFSKHN -1 20178744 t miannu Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation. SIGNOR-276279 0.2 USF1 protein P22415 UNIPROT B2M protein P61769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12480693 f miannu Here we show that upstream stimulatory factor 1 (USF1) and USF2 bind to the E box and regulate beta(2)m transactivation. SIGNOR-254655 0.2 Unii-2ewn8Z05CN chemical CID:129138801 PUBCHEM EIF4A1 protein P60842 UNIPROT down-regulates activity chemical inhibition 9606 32470302 t Simone Vumbaca Design of Development Candidate eFT226, a First in Class Inhibitor of Eukaryotic Initiation Factor 4A RNA Helicase SIGNOR-261120 0.8 FLT3 protein P36888 UNIPROT STAT5A protein P42229 UNIPROT up-regulates activity phosphorylation Tyr694 LAKAVDGyVKPQIKQ 10090 BTO:0002882 17356133 t gcesareni in vitro kinase assays revealed that STAT5 is a direct target of Flt3 SIGNOR-245069 0.593 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr387 LMRTLCGtPTYLAPE 9606 BTO:0000007 11901158 t gcesareni Phosphorylation of thr-68 by the ataxia telangiectasia-mutated is necessary for efficient activation of chk2 when cells are exposed to ionizing radiation. By an unknown mechanism, this initial event promotes additional autophosphorylation events including modifications of thr-383 and thr-387 SIGNOR-116131 0.2 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Ser676 LSPIIEDsREATHSS 9606 17785528 t lperfetto We identify s676 as a plk1-specific phosphorylation site on bubr1. These findings describe the first in vivo verified phosphorylation site for human bubr1, identify plk1 as the kinase responsible for causing the characteristic mitotic bubr1 upshift, and attribute a kt-specific function to the hyperphosphorylated form of bubr1 in the stabilization of kt-mt interactions. SIGNOR-157646 0.834 FOXO proteinfamily SIGNOR-PF27 SIGNOR CDKN2D protein P55273 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17873901 f gcesareni Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity SIGNOR-252918 0.2 KIF5B protein P33176 UNIPROT GABBR1 protein Q9UBS5 UNIPROT up-regulates activity relocalization 10090 17532644 t SARA GABABR1 co-immunoprecipitated with Marlin-1 and kinesin-I, providing evidence for the existence of a complex between these proteins. Kinesin-I modulates GABAB receptor transport. SIGNOR-260990 0.258 1-acyl-sn-glycerol 3-phosphate(2-) smallmolecule CHEBI:57970 ChEBI phosphatidic acid smallmolecule CHEBI:16337 ChEBI up-regulates quantity precursor of 9606 21173190 t lperfetto The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬† SIGNOR-267010 0.8 DUSP8 protein Q13202 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 23159405 t gcesareni M3/6 (dusp8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of jnk and, to a lesser extent, p38 mapk SIGNOR-199695 0.574 ENO1 protein P06733 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI down-regulates quantity chemical modification 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266528 0.8 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT up-regulates activity binding 17151142 t These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling SIGNOR-253592 0.928 NMDA proteinfamily SIGNOR-PF56 SIGNOR CTTN protein Q14247 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 14684878 t miannu Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors. SIGNOR-266598 0.2 BRSK1 protein Q8TDC3 UNIPROT TUBG1 protein P23258 UNIPROT up-regulates phosphorylation Ser131 READGSDsLEGFVLC 9606 19648910 t The effect has been demonstrated using Q8TDC3-2 llicata Sadb kinases associate and phosphorylate gamma-tubulin on ser 131 s131d gamma-tubulin expression amplifies centrosome duplication SIGNOR-187405 0.25 MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Ser221 DLDRIAAsMRALVLR -1 SIGNOR-C3 SIGNOR-C3 18372248 t lperfetto We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competitionwe also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1. SIGNOR-178128 0.901 TANC2 protein Q9HCD6 UNIPROT Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 10116 21068316 t miannu In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses. SIGNOR-266897 0.7 CAST protein P20810 UNIPROT CAPN1 protein P07384 UNIPROT down-regulates activity binding 9606 BTO:0000590 25969760 t lperfetto In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain SIGNOR-251582 0.913 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK2 protein P24941 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258176 0.8 GLI1 protein P08151 UNIPROT GLI1/GLI2 complex SIGNOR-C450 SIGNOR form complex binding 9606 BTO:0000304 32766732 t GLI2 and GLI1 heterodimerize via the Zn-finger domain SimoneGraziosi GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. SIGNOR-269209 0.434 VBP1 protein P61758 UNIPROT Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR form complex binding 9606 32699605 t miannu The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6) SIGNOR-270935 0.952 PAK4 protein O96013 UNIPROT FH protein P07954 UNIPROT down-regulates quantity phosphorylation Ser46 PNAARMAsQNSFRIE 9606 BTO:0002058 30683654 t miannu  FH is massively phosphorylated at the Ser 46 by PAK4 in non-small cell lung cancer (NSCLC) cells, and PAK4-phosphorylated FH binds to 14-3-3, resulting in cytosolic detention of FH and prohibition of FH/CSL/p53 complex formation.  SIGNOR-266315 0.2 SMAD7 protein O15105 UNIPROT PPP1CA protein P62136 UNIPROT up-regulates binding 9606 16571110 t gcesareni Smad7, induced by alk1 activation, recruits pp1? To alk1 and thereby inhibits tgf-?/Alk1-induced smad1/5 phosphorylation in ecs SIGNOR-145389 0.405 LAMA3 protein Q16787 UNIPROT Laminin-5 complex SIGNOR-C184 SIGNOR form complex binding 9211848 t lperfetto Like the other laminins (3), Ln-5 comprises three disul- fide-bonded subunits: a3, b3, and g2. SIGNOR-253235 0.559 BTK protein Q06187 UNIPROT GTF2I protein P78347 UNIPROT up-regulates activity phosphorylation Tyr503 EAHPNDLyVEGLPEN 9534 11373296 t lperfetto These residues, tyr248, tyr357, and tyr462, were also found to be the major sites for btk-dependent phosphorylation of bap/tfii-i in vivo. Residues tyr357 and tyr462 are contained within the loop regions of adjacent helix-loop-helix-like repeats within bap/tfii-i. Mutation of either tyr248, tyr357, or tyr462 to phenylalanine reduced transcription from a c-fos promoter relative to wild-type bap/tfii-i in transfected cos-7 cells, consistent with the interpretation that phosphorylation at these sites contributes to transcriptional activation. SIGNOR-108346 0.531 Hypoxia stimulus SIGNOR-ST25 SIGNOR EGLN2 protein Q96KS0 UNIPROT down-regulates 9606 24990963 f lperfetto There are three EglN family members in humans and mice (EglN1, EglN2, and EglN3). Their enzymatic activity requires oxygen, ascorbic acid, iron, and α-ketoglutarate (α-KG). Under hypoxic conditions, EglNs lose their activity and fail to hydroxylate HIFα, which leads to HIFα stabilization SIGNOR-262001 0.7 PIGBOS1 protein A0A0B4J2F0 UNIPROT DDIT3 protein P35638 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 31653868 f miannu We then confirmed via Western blot that TM treatment of PIGBOS-KD cells led to higher ATF4 and CHOP protein levels (Supplementary Fig. 13h). These data identified PIGBOS as a heretofore unknown mitochondrial regulator of UPR, and the only known microprotein linked to the regulation of cell stress or inter-organelle signaling. Upon UPR induction with TM, the loss of PIGBOS led to dramatic increases in the levels of all UPR target genes measured, indicating increased UPR signaling across all the branches (IRE1, PERK, and ATF6) (Fig. 6d and Supplementary Fig. 14a). Meanwhile, PIGBOS overexpressing cells showed the opposite effect, in which the UPR target genes showed less UPR activation, indicating a tunable modulation of ER stress by PIGBOS microprotein levels SIGNOR-261043 0.2 NEUROG2 protein Q9H2A3 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 BTO:0000142 18400164 f lperfetto While the mechanisms by which Ngn2 promotes neurogenesis have been characterized, little is known about how Ngn2 confers neuronal cell-type identity during spinal cord development. Ngn1 and Ngn2, two mammalian orthologs of the Drosophila proneural bHLH gene atonal, are expressed in overlapping patterns throughout the developing nervous system and act as important regulators of developmental neurogenesis SIGNOR-265173 0.7 EP300 protein Q09472 UNIPROT RUNX2/EP300 complex SIGNOR-C211 SIGNOR form complex binding 10116 BTO:0002648 12697832 t Giulio Giuliani More interestingly, the bone-specific transcriptionfactor Runx2/Cbfa1 is present in the immunoprecipitated material, strongly indicating that in osteoblastic cells expressing OC, p300 and Runx2/Cbfa1 are components of the same nuclear protein complex. SIGNOR-255418 0.464 N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide chemical CHEBI:91409 ChEBI MST1R protein Q04912 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190407 0.8 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser465 HNPISSVs 9606 9136927 t fspada Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro SIGNOR-249649 0.721 MTCH2 protein Q9Y6C9 UNIPROT BID protein P55957 UNIPROT up-regulates binding 9606 21295084 t gcesareni Mtch2/mimp and its role in bid recruitment may synergise with cl-induced mitosome formation to facilitate momp. SIGNOR-171773 0.308 KLHL3 protein Q9UH77 UNIPROT WNK4 protein Q96J92 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23453970 t miannu Here, we found that KLHL3 interacted with Cullin3 and WNK4, induced WNK4 ubiquitination, and reduced the WNK4 protein level. The reduced interaction of KLHL3 and WNK4 by PHAII-causing mutations in either protein reduced the ubiquitination of WNK4, resulting in an increased level of WNK4 protein. SIGNOR-272105 0.603 SYK protein P43405 UNIPROT LCK protein P06239 UNIPROT down-regulates activity phosphorylation Tyr192 NLDNGGFyISPRITF 9606 BTO:0000782 8798764 t lperfetto Our experiments indicate that the TCR-induced activation of Erk2 depends on the function of SH2 domain of Lck and is reduced by phosphorylation of wild type Lck at Tyr192 or by mutation of this site to a negatively charged amino acid. Such dependence on the SH2 domain has also been reported for the bulk of TCR-induced tyrosine phosphorylation and activation of the interleukin 2 gene (26). Thus, phosphorylation of Lck at Tyr192 may represent a negative feedback mechanism in the interplay between Src and Syk family PTKs in TCR signaling SIGNOR-246562 0.574 MECP2 protein P51608 UNIPROT DLL1 protein O00548 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 25420914 t Luana As the first step to reveal how MeCP2 phosphorylation may regulate Notch signaling, we conducted chromatin immunoprecipitation (ChIP) experiment to determine whether the phosphor-mutant MeCP2 protein has altered promoter occupancy at the promoters of Dll1 and Notch1. We found increased binding of the phosphor-mutant protein at the promoters of both Dll1 and Notch1  SIGNOR-264674 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARG protein P37231 UNIPROT up-regulates activity phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 11733495 t gcesareni Moreover, the inhibition of erks 1 and 2 with a mek inhibitor, u1026, lead to an inhibition in the decay of ppargamma proteins, indicating that serine phosphorylation influences the degradation of ppargamma in fat cells. SIGNOR-232236 0.2 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition 9606 31908417 t miannu The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs. SIGNOR-262250 0.8 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Thr978 AEMSIMTtELQSLCS 9606 18055457 t lperfetto Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta SIGNOR-159586 0.275 GNRH1 protein P01148 UNIPROT EGR1 protein P18146 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19106114 f miannu GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity. SIGNOR-254917 0.454 SFXN1 protein Q9H9B4 UNIPROT L-serine chemical CHEBI:17115 ChEBI up-regulates quantity relocalization 9606 30442778 t lperfetto SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism. SIGNOR-268245 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 17287208 t lperfetto Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo. SIGNOR-244222 0.2 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser876 QGLAERIsVL 9606 12058027 t gcesareni Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs. SIGNOR-89431 0.2 WDHD1 protein O75717 UNIPROT CLSPN protein Q9HAW4 UNIPROT up-regulates activity binding 9606 BTO:0001109 26082189 t miannu And-1 is phosphorylated at T826 by ATR following replication stress, and this phosphorylation is required for And-1 to accumulate at the damage sites, where And-1 promotes the interaction between Claspin and Chk1, thereby stimulating efficient Chk1 activation by ATR. Significantly, And-1 binds directly to ssDNA and facilitates the association of Claspin with ssDNA. SIGNOR-262665 0.4 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys262 DSDDALLkMTISQQE -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. SIGNOR-272744 0.475 TP53 protein P04637 UNIPROT FAS protein P25445 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 9841917 t Nuclear p53 amattioni In an attempt to understand how CD95 expression is regulated by p53, we identified a p53-responsive element within the first intron of the CD95 gene, as well as three putative elements within the promoter. The intronic element conferred transcriptional activation by p53 and cooperated with p53-responsive elements in the promoter of the CD95 gene. wt p53 bound to and transactivated the CD95 gene, SIGNOR-62376 0.588 GSK3A protein P49840 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity phosphorylation Thr312 TMKTFCGtPEYLAPE 10090 BTO:0005655 23142783 t gcesareni GSK3_ negatively regulates AKT activation by phosphorylating AKT at T312 in the substrate binding site, which inhibited IL-1-induced AKT activation and function. SIGNOR-252434 0.621 CD38 protein P28907 UNIPROT nicotinamide smallmolecule CHEBI:17154 ChEBI up-regulates quantity chemical modification 9606 18626062 t miannu CD38 is also able to catalyze the degradation of the NAD precursor nicotinamide mono-nucleotide (NMN) into nicotinamide SIGNOR-264253 0.8 ABL1 protein P00519 UNIPROT STX17 protein P56962 UNIPROT down-regulates activity phosphorylation Tyr157 SQSLTQIyALPEIPQ 9534 BTO:0001538 23006999 t miannu C-Abl was identified as one of the kinases, which phosphorylates syntaxin 17.Western blot shows phosphorylation of syntaxin 17 on Tyr-156 by overexpression and activation of c-Abl. A phospho-mimicking mutant (Y156E) of syntaxin 17 showed reduced interaction with COPI vesicles. These results suggest that tyrosine phosphorylation of syntaxin 17 is likely to have a role in regulating syntaxin 17 dependent membrane trafficking in the early secretory pathway. SIGNOR-273538 0.2 NFIX protein Q14938 UNIPROT NEUROD1 protein Q13562 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268904 0.268 SARM1 protein Q6SZW1 UNIPROT TICAM1 protein Q8IUC6 UNIPROT down-regulates binding 10090 17667936 t gcesareni SARM utilizes its TIR domain to negatively regulate TRIF SIGNOR-252068 0.545 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser63 NVKVETQsDEENGRA 9606 21750978 t miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo SIGNOR-174852 0.2 PTK2B protein Q14289 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 16760434 t gcesareni Activated rock phosphorylates fak on ser732, which is essential for phosphorylation of tyr407 and for cell migration. We further show that pyk2 is activated by vegf-induced clustering of integrin v 3 and is responsible for the phosphorylation of tyr407. SIGNOR-147070 0.504 clozapine chemical CHEBI:3766 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 10116 BTO:0001311 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258519 0.8 IGF1 protein P05019 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 9606 2689937 f fspada Preadipocytes converted to adipocytes when insulin-like growth factor-1 or insulin was added to a medium depleted of those compounds SIGNOR-23166 0.7 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser9 LTFMASDsEEEVCDE -1 8972483 t llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  SIGNOR-250804 0.371 KAT6A protein Q92794 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates binding 9606 SIGNOR-C54 11742995 t miannu The activation domain of aml1 is required for its interaction with moz / moz activates aml1_mediated transcription SIGNOR-113056 0.477 GPR35 protein Q9HC97 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257283 0.2 AKT1 protein P31749 UNIPROT TTC3 protein P53804 UNIPROT up-regulates phosphorylation Ser378 AYTPRSLsAPIFTTS 9606 20059950 t llicata Phosphorylation of ttc3 at ser378 is required for efficient biological function together, these observations support that ttc3 is a phosphorylation target of akt both in an in vitro and in a cellular context SIGNOR-252508 0.404 PIM1 protein P11309 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 18593906 t fspada Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42). SIGNOR-179308 0.396 SPTAN1 protein Q13813 UNIPROT ERCC4 protein Q92889 UNIPROT up-regulates activity 19102630 f lperfetto We have shown that in the nucleus alphaRIISp is involved in repair of DNA interstrand cross-links (13,14). It binds to purified DNA containing an interstrand crosslink; it colocalizes with the cross-link repair protein, XPF, in damage-induced nuclear foci after treatment of cells with a DNA interstrand cross-linking agent, and it is needed for the production of incisions by XPF at the site of an interstrand cross-link SIGNOR-263276 0.29 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser335 YDSFGEPsYPEVFEP -1 9558331 t llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. SIGNOR-250802 0.371 PTPRH protein Q9HD43 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation 9606 28065597 t miannu We further found that PTPRH and PTPRB directly dephosphorylate EGFR and repress its downstream signaling. SIGNOR-277090 0.292 NR3C1 protein P04150 UNIPROT KLF15 protein Q9UIH9 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 20956975 f lperfetto We identified glucocorticoid response element sites in the first intron of KLF15 by bioinformatical promoter analysis and confirmed their functional relevance by demonstrating GR interaction by chromatin immunoprecipitation SIGNOR-236212 0.384 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1457 SEKAVLTsQKSSEYP 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks SIGNOR-72056 0.813 CXCL1 protein P09341 UNIPROT PLCE1 protein Q9P212 UNIPROT up-regulates binding 9606 17251915 t gcesareni In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor. SIGNOR-152591 0.2 CEBPB protein P17676 UNIPROT PCK2 protein Q16822 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000608 8093246 f miannu C/EBP beta can regulate PEPCK gene transcription by acting through the CRE and that C/EBP beta, together with CREB, may contribute to the cAMP responsiveness of the PEPCK promoter. SIGNOR-253773 0.333 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC10 protein Q969S8 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002428 31908417 t miannu The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs. SIGNOR-262252 0.8 CKM complex complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914168 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-273143 0.346 MAPK1 protein P28482 UNIPROT DAZAP1 protein Q96EP5 UNIPROT down-regulates activity phosphorylation Thr315 GVPPPPAtPGAAPLA 9606 BTO:0000007 16848763 t miannu Further experiments showed that DAZAP1 was phosphorylated stoichiometrically in vitro by ERK2 (extracellular-signal-regulated protein kinase 2) at two Thr-Pro sequences (Thr269 and Thr315), and that both sites became phosphorylated in HEK-293 (human embryonic kidney 293) cells in response to PMA or EGF (epidermal growth factor), or RAW 264.7 macrophages in response to LPS. Phosphorylation of the ARE-binding protein DAZAP1 by ERK2 induces its dissociation from DAZ SIGNOR-262971 0.2 hexadecanoic acid smallmolecule CHEBI:15756 ChEBI palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI up-regulates quantity precursor of 9606 21242590 t miannu Long-chain acyl-CoA synthetases (ACSLs) catalyze the thioesterification of long-chain FAs into their acyl-CoA derivatives. On the other hand, overexpression of ACSL1 resulted in large increases in oleoyl-CoA synthesis and palmitoyl-CoA synthesis in SMC lysates (Fig. 4A). SIGNOR-267876 0.8 CHD8 protein Q9HCK8 UNIPROT MLL/SET subcomplex complex SIGNOR-C87 SIGNOR up-regulates activity binding 9606 BTO:0000946 20085832 t miannu Chromodomain, helicase, DNA-binding protein 8 (CHD8) is an ATP-dependent chromatin remodeling enzyme that has been demonstrated to exist within a large protein complex which includes WDR5, Ash2L, and RbBP5, members of the Mixed Lineage Leukemia (MLL) histone modifying complexes. CHD8 forms a complex with the core WDR5/Ash2L/RbBP5 complex. CHD8 is required for recruitment of the WAR complex SIGNOR-268807 0.427 CBL protein P22681 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 10514377 t miannu Ubiquitination of the PDGF β-receptor (Rβ) by the c-Cbl RING in an SH2-dependent manner. SIGNOR-272553 0.613 APLNR protein P35414 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256681 0.413 CSNK1G2 protein P78368 UNIPROT LYN protein P07948 UNIPROT up-regulates quantity by stabilization phosphorylation Ser13 SKGKDSLsDDGVDLK 9606 BTO:0000007 33004926 t miannu Although there have been more than 40 reports of mass spectrometric studies on phosphorylation at Lyn-S13, the kinase responsible remained unclear. We succeeded in identifying casein kinase 1γ (CK1γ) as the kinase responsible for phosphorylation of Lyn-S13. In HEK293 cells co-expressing Lyn and CK1γ, the phosphorylation level of Lyn-S13 increased significantly. we concluded that S-palmitoylated CK1γ encounters N-myristoylated Lyn and specifically phosphorylates the Ser-13 residue at the Golgi during intracellular protein traffic, as shown schematically in Fig. 8. Phosphorylated dual-lipid-modified Lyn and S-palmitoylated CK1γ are then transported from the Golgi to the plasma membrane. SIGNOR-275397 0.2 PPP1CC protein P36873 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 16501611 t Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. SIGNOR-248500 0.323 MAPK14 protein Q16539 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates transcriptional regulation 10116 11904165 f ggiuliani These data indicate that TGF-beta1-induced p38 activation is involved in TGF-beta1-stimulated collagen synthesis. SIGNOR-255958 0.7 GDF11 protein O95390 UNIPROT ACTR2 protein P61160 UNIPROT up-regulates binding 9606 16446785 t gcesareni Here we demonstrate using genetic and biochemical studies that actriib and its subfamily receptor, actriia, cooperatively mediate the gdf11 signal in patterning the axial vertebrae, and that gdf11 binds to both actriia and actriib, and induces phosphorylation of smad2. SIGNOR-144147 0.2 ITGA2B protein P08514 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253197 0.947 RACK1 protein P63244 UNIPROT PTK7 protein Q13308 UNIPROT up-regulates binding 9606 21350015 t gcesareni Here, we identify rack1 as a novel interaction partner of ptk7. Mechanistically, rack1 is necessary for the ptk7-mediated membrane localization of dishevelled (dsh). Rack1 facilitates the ptk7-dsh interaction by recruiting pkcdelta1, a known effector of dsh membrane translocation. SIGNOR-172322 0.2 PRKACA protein P17612 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Thr34 MIRRRRPtPAMLFRL 10604473 t miannu DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚  SIGNOR-250031 0.483 glutamine smallmolecule CHEBI:28300 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 22749528 f Luana Leucine and Glutamine Activate Glutaminolysis and mTORC1 SIGNOR-268008 0.8 superoxide smallmolecule CHEBI:18421 ChEBI Oxidative_stress phenotype SIGNOR-PH215 SIGNOR up-regulates 9606 29301787 f lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272276 0.7 beta-carboline chemical CHEBI:109895 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t brain lperfetto The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005). SIGNOR-263805 0.8 FOXO1 protein Q12778 UNIPROT NPY protein P01303 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000614 28270795 f miannu Foxo1 (when activated) stimulates the transcription of AgRP and NPY, but suppresses the transcription of POMC; thereby antagonizing the transcriptional action of STAT3 in these hypothalamic subpopulations. SIGNOR-263502 0.41 GABA-B receptor complex SIGNOR-C336 SIGNOR GNB/GNG complex SIGNOR-C202 SIGNOR up-regulates activity binding 9606 BTO:0000938 20655485 t miannu The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release. SIGNOR-265068 0.386 gamma-secretase complex SIGNOR-C98 SIGNOR DSCAML1 protein Q8TD84 UNIPROT down-regulates quantity cleavage 9606 BTO:0000938 30745319 t miannu γ‐secretase‐mediated intra‐membrane cleavage of DSCAM receptors results in the release of the DSCAM ICD, which is likely proceeded by shedding of the DSCAM ectodomain. Interaction of IPO5 with the NLS of DSCAM then leads to importin‐mediated nuclear import of the DSCAM ICD. In the nucleus, the DSCAM ICD may regulate the transcription of genes involved in neuronal development and function, thereby regulating processes such as neurite outgrowth, branching, and repulsion, as well as synapse formation, axon guidance, and neuronal cell death and survival. SIGNOR-264272 0.2 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F8 protein P00451 UNIPROT down-regulates activity cleavage Arg355 CPEEPQLrMKNNEEA -1 10350471 t lperfetto N-Terminal sequencing along with time courses of proteolysis indicated that VIIa-TF/PL cleaved factor VIII first at R740, followed by concomitant cleavage at R336 and R372. |hus, heavy chain cleavage of factor VIII by VIIa-TF/PL produces an inactive factor VIII cofactor no longer capable of activation by thrombin. SIGNOR-263643 0.466 ADSS2 protein P30520 UNIPROT Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates 9606 10496970 f miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267834 0.7 serine smallmolecule CHEBI:17822 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264760 0.7 ritonavir chemical CHEBI:45409 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258154 0.8 apraclonidine chemical CHEBI:2788 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation -1 8784451 t miannu we describe full details of our studies with 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline (AGN 193080, 3), a potent, selective α2 adrenoceptor agonist that does not cross the blood−brain barrier. SIGNOR-258497 0.8 Stress_granules phenotype SIGNOR-PH124 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 27920254 f miannu Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis. SIGNOR-260867 0.7 trichostatin A chemical CHEBI:46024 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258015 0.8 COPS4 protein Q9BT78 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270762 0.937 PRKACA protein P17612 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Thr90 NKQDRTLtIVDTGIG 9606 21919888 t lperfetto Thr90 phosphorylation of hsp90_ by protein kinase a regulates its chaperone machinery SIGNOR-176614 0.459 ESRRB protein O95718 UNIPROT NR0B1 protein P51843 UNIPROT down-regulates 9606 12482977 f lperfetto When dax-1 was cotransfected, it exerted efficient repression on transcription of the reporter gene activated by gal4-ad4bp-lbd, gal4-lrh-1-lbd, gal4-err2-lbd SIGNOR-96533 0.35 trichostatin A chemical CHEBI:46024 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258013 0.8 ziprasidone chemical CHEBI:10119 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 10116 BTO:0001311 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258501 0.8 CASP3 protein P42574 UNIPROT MYL3 protein P08590 UNIPROT down-regulates quantity by destabilization cleavage Glu135 GTYEDFVeGLRVFDK 9986 BTO:0003324 12186978 t lperfetto By sequencing and site-directed mutagenesis, a noncanonical cleavage site for caspase-3 was mapped to the C-terminal DFVE(135)G motif. We demonstrated that vMLC1 cleavage in failing myocardium in vivo is associated with a morphological disruption of the organized vMLC1 staining of sarcomeres, and with a reduction in myocyte contractile performance. SIGNOR-270593 0.386 hexestrol chemical CHEBI:31669 ChEBI ESR1 protein P03372 UNIPROT down-regulates activity chemical inhibition -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258593 0.8 MECP2 protein P51608 UNIPROT MET protein P08581 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000007 24150225 t Luana MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2 SIGNOR-264683 0.273 GSK3B protein P49841 UNIPROT GPHN protein Q9NQX3 UNIPROT down-regulates phosphorylation Ser270 LSTTPSEsPRAQATS 9606 BTO:0000142 23408424 t miannu Identification of gsk3_ as the kinase targeting ser-270 /phosphorylation at ser-270 promotes gephyrin processing by calpain SIGNOR-200957 0.287 RBP1 protein P09455 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI up-regulates quantity relocalization 31963453 t lperfetto Once in the cytosol, retinol molecules are sequestered by membrane systems and bind to Cellular retinol-binding protein 1 (CRBP1), which plays a role in vitamin A cytoplasmic trafficking SIGNOR-265108 0.8 SNAI2 protein O43623 UNIPROT MMP9 protein P14780 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 22074556 f miannu We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. Furthermore, ectopic expression of SLUG increased MMP9 expression and activity in PC3, 22RV1, and DU-145 cells, and SLUG knockdown by shRNA downregulated MMP9 expression. SIGNOR-255170 0.464 MYC protein P01106 UNIPROT VEGFA protein P15692 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12368264 f These defects are intrinsic to c-Myc, and are in part associated with a requirement for c-Myc for the expression of vascular endothelial growth factor (VEGF), as VEGF can partially rescue these defects. SIGNOR-259369 0.473 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Thr308 KDGATMKtFCGTPEY 9606 18160256 t Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248626 0.89 ACTR3 protein P61158 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 t The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc SIGNOR-251513 0.916 MAPK8 protein P45983 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 7824938 t gcesareni Activating transcription factor-2 (atf2) was found to be a target of the jnk signal transduction pathway. Atf2 was phosphorylated by jnk on two closely spaced threonine residues within the nh2-terminal activation domain. SIGNOR-33918 0.771 BACH1 protein O14867 UNIPROT MAFK protein O60675 UNIPROT up-regulates activity binding 10090 BTO:0004475 19011633 t miannu Bach1 forms a heterodimer with the small Maf oncoproteins and binds to the Maf-recognition element (MARE) to inhibit target genes SIGNOR-226409 0.486 PAMPs stimulus SIGNOR-ST11 SIGNOR Pr3-ANCA complex SIGNOR-C475 SIGNOR up-regulates quantity 9606 BTO:0000133 15972951 f lperfetto In the early phase, LPS enhanced anti-MPO IgG-induced glomerular neutrophil accumulation. |using bacterial lipopolysaccharide (LPS) as the proinflammatory stimulus. SIGNOR-270587 0.7 CHEK2 protein O96017 UNIPROT VHL protein P40337 UNIPROT up-regulates phosphorylation Ser111 GTGRRIHsYRGHLWL 9606 BTO:0000680 22071692 t llicata We demonstrated that checkpoint kinase-2 (chk2) binds to the beta-domain of pvhl and phosphorylates ser 111 on dna damage. Notably, this modification enhances pvhl-mediated transactivation of p53 by recruiting p300 and tip60 to the chromatin of p53 target gene SIGNOR-177091 0.466 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT up-regulates activity phosphorylation Ser245 KPGALSNsESIPTID 9534 BTO:0000298 11483516 t llicata BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads. SIGNOR-250598 0.294 Fe2S2 iron-sulfur cluster chemical CHEBI:49601 ChEBI SDH complex SIGNOR-C400 SIGNOR form complex binding 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. SIGNOR-267735 0.8 ILK protein Q13418 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 9736715 t acerquone Ilk can phosphorylate pkb-akt on serine-473, whereas kinase-deficient ilk severely inhibits endogenous phosphorylation of pkb-akt on serine-473, demonstrating that ilk is involved in agonist stimulated, pi(3)k-dependent, pkb-akt activation. SIGNOR-252597 0.771 CDK1 protein P06493 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Thr245 GFGTSPLtPSARISA -1 12556484 t done miannu In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites SIGNOR-274072 0.646 MAPK1 protein P28482 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Thr245 GFGTSPLtPSARISA -1 12556484 t done miannu In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites SIGNOR-274075 0.291 GNGT1 protein P63211 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 16537363 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-145128 0.408 cabozantinib chemical CHEBI:72317 ChEBI AXL protein P30530 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000184 26536165 t miannu Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. SIGNOR-262241 0.8 MEF2C protein Q06413 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15728583 t lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation SIGNOR-238754 0.391 AMPK complex SIGNOR-C15 SIGNOR ACACA protein Q13085 UNIPROT down-regulates activity phosphorylation Ser80 LHIRSSMsGLHLVKQ 9606 29899443 t Human ACC1 is inactivated by phosphorylation at Ser80, Ser1201 and Ser1216 by AMP-activated protein kinase (AMPK) SIGNOR-267475 0.541 GNAS protein Q5JWF2 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR up-regulates activity binding 9606 12145344 t lperfetto HETEROTRIMERIC G PROTEINS are essential for cell signaling throughout the body. The stimulatory G protein, Gs, couples activation of a host of different transmembrane receptors to adenylyl cyclase stimulation, leading to intracellular generation of cAMP SIGNOR-268693 0.731 AKT1 protein P31749 UNIPROT LONP1 protein P36776 UNIPROT up-regulates activity phosphorylation Ser181 NESDVVEsLDEIYHT 9606 BTO:0001061 31406245 t lperfetto In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity. SIGNOR-265725 0.255 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB4 protein Q9UN71 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265701 0.2 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1931 SPTSPTYsPTSPKGS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203600 0.769 URI1 protein O94763 UNIPROT URI1 prefoldin co-chaperone complex SIGNOR-C514 SIGNOR form complex binding 9606 30484151 t miannu In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR94 SIGNOR-270917 0.565 PRKACA protein P17612 UNIPROT FYN protein P06241 UNIPROT up-regulates phosphorylation Ser21 LTEERDGsLNQSSGY 9606 20658524 t lperfetto The serine 21 (s21) residue of fyn is a protein kinase a (pka) recognition site within an rxxs motif of the amino terminal sh4 domain of fyn. In addition, s21 is critical for fyn kinase-linked cellular signaling. Mutation of s21a blocks pka phosphorylation of fyn and alters its tyrosine kinase activity. SIGNOR-167147 0.435 DDX5 protein P17844 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 18829551 t miannu P68 is a nuclear protein and interacts with ar / p68 co-occupies the active psa promoter at are regions and enhances ar transcriptional activity SIGNOR-181456 0.325 L-arginine chemical CHEBI:16467 ChEBI SLC38A9 protein Q8NBW4 UNIPROT up-regulates activity chemical activation 9606 29053970 t SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins SIGNOR-254895 0.8 MFGE8 protein Q08431 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR down-regulates 10116 31958465 f miannu We demonstrated that Milk fat globule-EGF factor8 (MFGE8) is protective against Ang-II-induced atrial fibrosis and atrial fibrillation. In vitro, silencing of MFGE8 by small interfering RNA significantly increased Ang-II-induced atrial fibrosis, whereas administration of recombinant human MFGE8 (rhMFGE8) attenuated the atrial fibrosis. SIGNOR-260646 0.7 regorafenib chemical CHEBI:68647 ChEBI NTRK1 protein P04629 UNIPROT down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259212 0.8 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270431 0.8 NMDA receptor_2C complex SIGNOR-C349 SIGNOR CTTN protein Q14247 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 14684878 t miannu Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors. SIGNOR-266601 0.292 FLT3 protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 14981546 f These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation. SIGNOR-261521 0.296 HDAC3 protein O15379 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates binding 9606 23213415 t gcesareni Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes. SIGNOR-199961 0.475 CUDC-101 chemical CID:24756910 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates activity chemical inhibition -1 20143778 t miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. SIGNOR-262255 0.8 Netrin proteinfamily SIGNOR-PF97 SIGNOR DSCAM protein O60469 UNIPROT up-regulates activity binding 10090 BTO:0001279 18585357 t miannu Here, we report that the Down's syndrome Cell Adhesion Molecule (DSCAM), a candidate gene implicated in the mental retardation phenotype of Down's syndrome, is expressed on spinal commissural axons, binds netrin-1, and is necessary for commissural axons to grow toward and across the midline. DSCAM and DCC can each mediate a turning response of these neurons to netrin-1. SIGNOR-268173 0.2 YARS1 protein P54577 UNIPROT tRNA(Tyr) smallmolecule CHEBI:29182 ChEBI down-regulates quantity chemical modification 9606 16429158 t miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr SIGNOR-270517 0.8 TWIST2 protein Q8WVJ9 UNIPROT CTPS1 protein P17812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255500 0.2 RET protein P07949 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr925 DRSNDKVyENVTGLV 9606 21454698 t gcesareni Strikingly, when fak and ret kinases were co-incubated in the presence of atp, a marked increased in fak tyr-576/577 and tyr-925 phosphorylation was observed together with a shift in mobility of fak, indicating conversion to an activated state SIGNOR-173021 0.623 GATA6 protein Q92908 UNIPROT CDX2 protein Q99626 UNIPROT up-regulates quantity by expression 9606 BTO:0000195 24317510 f lperfetto Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2. SIGNOR-253155 0.469 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203560 0.769 GARS1 protein P41250 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. SIGNOR-270804 0.8 DPP6 protein P42658 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity relocalization 8355 BTO:0000964 17130523 t Luisa DPPX-S reduced energy barriers of the voltage-dependent transitions; therefore, this auxiliary subunit may exert a catalytic effect on voltage-dependent gating of Kv4.2 channels. DPPX-S may also accelerate coupled inactivation indirectly SIGNOR-269005 0.564 PAH protein P00439 UNIPROT phenylalanine smallmolecule CHEBI:28044 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors SIGNOR-263988 0.8 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB3 protein P05106 UNIPROT up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259002 0.2 CAMK2A protein Q9UQM7 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser362 FYTLNGSsVDSQPQS 9606 BTO:0004553 24614225 t gianni NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity. SIGNOR-266434 0.312 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 t flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. SIGNOR-75930 0.366 SMURF2 protein Q9HAU4 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps SIGNOR-153417 0.714 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser283 NLQMLPEsEDEESYD 9606 BTO:0000782 8622692 t llicata Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation. SIGNOR-40502 0.567 dopamine smallmolecule CHEBI:18243 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257478 0.8 FADD protein Q13158 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 21525013 t lperfetto Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8 SIGNOR-173429 0.783 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser551 ELQAPVRsPITRSFA 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249461 0.618 4-(trimethylammonio)butanoate smallmolecule CHEBI:16244 ChEBI carnitine smallmolecule CHEBI:17126 ChEBI up-regulates quantity precursor of 9606 11802770 t miannu In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. SIGNOR-269701 0.8 TRIM62 protein Q9BVG3 UNIPROT CARD9 protein Q9H257 UNIPROT up-regulates activity polyubiquitination Lys125 LLMTEVMkLQKKVQD 9606 BTO:0000007 26488816 t miannu We identified TRIM62 as a CARD9 binding partner and showed that TRIM62 facilitated K27-linked poly-ubiquitination of CARD9. We identified K125 as the ubiquitinated residue on CARD9 and demonstrated that this ubiquitination was essential for CARD9 activity.  SIGNOR-272420 0.524 SUV39H1 protein O43463 UNIPROT MYOG protein P15173 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 23435416 f lperfetto The methyl marks H3K9me3 on the myoD promoter and H3K27me3 on the myogenin promoter have been shown to be under the control of the histone methyl transferase KMT1A and the HDM KDM4A, respectively, during normal myogenesis. In addition, KMT1A has recently been shown to play a role in ARMS by inhibiting myogenic differentiation SIGNOR-249601 0.414 P2RY12 protein Q9H244 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257107 0.2 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 9753485 t Crohn's Disease gcesareni SIGNOR-251690 0.8 GDNF protein P39905 UNIPROT GFRA1 protein P56159 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9182803 t gcesareni A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling SIGNOR-49091 0.792 RARA protein P10276 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-16433 0.713 STAT6 protein P42226 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity binding 9606 BTO:0000801 10982806 t lperfetto STAT6 mediates suppression of STAT1 and NF-kB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site SIGNOR-249552 0.466 ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 22863277 t milica To further explore the role of camp signaling in the hippo pathway, we treated cells with forskolin, an activator of adenylyl cyclase that results in cAMP production. SIGNOR-198486 0.8 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Thr326 GCYSVPTtPEDFLSN 26375055 t lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity SIGNOR-276519 0.261 GTF2H3 protein Q13889 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 t lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269314 0.902 RBM10 protein P98175 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30403180 f irozzo These data indicated that RBM10 overexpression induced osteosarcoma cell apoptosis via promoting the production of TNF-α that appear to act as an autocrine factor regulating osteosarcoma programmed cell death. SIGNOR-259153 0.2 SMAD6 protein O43541 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates activity binding 9606 BTO:0000007 19561075 t miannu Smad6 mediates Tbx6 ubiquitination and proteasomal degradation. Tbx6 forms a ternary complex with Smad6 and Smurf1. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase. SIGNOR-272786 0.824 NPFFR2 protein Q9Y5X5 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257104 0.255 MECP2 protein P51608 UNIPROT BDNF protein P23560 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 18599437 f MeCP2 is involved in gene silencing and known to affect the activity of brain-derived neurotrophic factor (BDNF) SIGNOR-254023 0.484 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT up-regulates activity phosphorylation Thr2153 LDIPLQThrPHKLVD -1 26051540 t irozzo Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment. SIGNOR-259117 0.452 BIRC3 protein Q13489 UNIPROT RIPK4 protein P57078 UNIPROT up-regulates activity polyubiquitination lys145 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation. SIGNOR-272709 0.362 PIM2 protein Q9P1W9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by stabilization phosphorylation 9606 24142698 t inferred from family member Manara Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. SIGNOR-270287 0.378 NOS1 protein P29475 UNIPROT HDAC2 protein Q92769 UNIPROT down-regulates activity s-nitrosylation 10090 BTO:0001103 19047631 t gcesareni we found that restoration of NO signaling in vivo, by adenoviral-mediated expression of a constitutively active endothelial NOS mutant in MDX muscles, and in vitro, by exposing MDX-derived satellite cells to NO donors, resulted in HDAC2 blockade by cysteine S-nitrosylation SIGNOR-236919 0.268 GH1 protein P01241 UNIPROT GHR protein P10912 UNIPROT up-regulates activity binding 9606 7862673 t miannu Although growth hormone (GH) receptors (GHRs) in many species bind human (h) GH as well as their own GH, the hGHR only binds primate GH. SIGNOR-255451 0.854 PRKCA protein P17252 UNIPROT EWSR1 protein Q01844 UNIPROT down-regulates activity phosphorylation Ser266 SSYGQQSsFRQDHPS 9606 9341188 t miannu Here we report thatews, a nuclearrna-bindingprooncoprotein, contains an iq domain, is phosphorylated byproteinkinase c, and interacts with calmodulin. Interestingly, pkc phosphorylation of ews inhibits its binding to rna homopolymers, and conversely,rna binding to ews interferes with pkc phosphorylation./ these data indicate that ews contains an iq domain with ser266 acting as the primary site for pkc phosphorylation. SIGNOR-52850 0.337 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser584 ETSIFTPsPCKIPPP 9606 BTO:0000680;BTO:0001573;BTO:0001286 14551205 t lperfetto Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex SIGNOR-216944 0.426 sorafenib tosylate chemical CHEBI:50928 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. SIGNOR-259223 0.8 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Thr731 FEPSPYPtTSSLEDF 9606 BTO:0000567 34198826 t miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. SIGNOR-276665 0.252 SPTA1 protein P02549 UNIPROT Erythrocytic spectrin complex SIGNOR-C384 SIGNOR form complex binding 9606 BTO:0000424 24302288 t lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell SIGNOR-266025 0.731 EIF2B5 protein Q13144 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269138 0.81 STYK1 protein Q6J9G0 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation Ser90 IPPARMMsTESANSF 9606 BTO:0000007 31696776 t lperfetto We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. |The results indicated that the level of BECN1 S90 phosphorylation significantly increased after STYK1 overexpression, but not STYK1K147R mutant.|STYK1 promotes autophagy through enhancing the assembly of autophagy-specific class III phosphatidylinositol 3-kinase complex I SIGNOR-264568 0.2 WNK3 protein Q9BYP7 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates activity phosphorylation 21613606 t lperfetto We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs SIGNOR-264625 0.541 ATM protein Q13315 UNIPROT DAXX protein Q9UER7 UNIPROT down-regulates phosphorylation Ser564 LEEESPVsQLFELEI 9606 23405218 t gcesareni The main phosphorylation site of daxx is identified to be ser564, which is a direct target of atm. Phosphorylation of endogenous daxx at ser564 occurs rapidly during the dna damage response and precedes p53 activation. Blockage of this phosphorylation event prevents the separation of daxx from mdm2, stabilizes mdm2, and inhibits dna damage-induced p53 activation. SIGNOR-200889 0.513 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr81 APAPAAPtPAAPAPA 9606 BTO:0000007 11283254 t lperfetto Jnk phosphorylated p53 at t81 in response to dna damage and stress-inducing agents, as determined by phospho-specific antibodies to t81 . Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress. SIGNOR-106542 0.789 COL4A3 protein Q01955 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253244 0.431 PRKAA1 protein Q13131 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Ser385 RRRKKRTsIETNIRV 9606 1684878 t lperfetto Mitosis-specific phosphorylation site in the homeodomain of oct-1 was phosphorylated in vitro by protein kinase a. Pka-mediated phosphorylation event was identified in the cns-specific pou domain protein brn-2/n-oct-3/pou3f2 (nieto et al. 2007). In this case, the modification, at a position homologous to oct1 s385, was found to alter binding specificity for complex dimeric sites. SIGNOR-20971 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser43 RNPEAALsPTFRSDS 9606 BTO:0000007 33217317 t miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. SIGNOR-265953 0.2 GLI1/GLI2 complex SIGNOR-C450 SIGNOR MYCN protein P04198 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000304 32766732 t GLI2 and GLI1 heterodimerize via the Zn-finger domain SimoneGraziosi GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. | RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells SIGNOR-269212 0.408 SLBP protein Q14493 UNIPROT H2BC12 protein O60814 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265383 0.2 UBE2I protein P63279 UNIPROT ETV5 protein P41161 UNIPROT down-regulates sumoylation 9606 15857832 t miannu Here we show that erm interacts with the sumo-conjugating enzyme ubc9 and is modified by sumo. We further show that sumo modification of this ets transcription factor affects its ability to activate transcription. SIGNOR-135850 0.269 ETV6 protein P41212 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002883 16828711 f miannu Forced expression of TEL stimulated transcription via the p53-responsive element and increased the expression of cellular target genes for p53 such as cell cycle regulator p21 and apoptosis inducer Puma. SIGNOR-254138 0.344 ATM protein Q13315 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Thr491 PQQRNALtPTTIPDG 9606 18769144 t lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively SIGNOR-180755 0.412 RPS6KB1 protein P23443 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser291 CGSSGYFsSSPTLSS 9606 22017876 t llicata Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation. SIGNOR-176866 0.658 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser859 DTSSLTQsAPASPTN 9606 BTO:0000007 19864431 t lperfetto Strikingly, raptor Ser(863) phosphorylation is absolutely required for raptor Ser(859) and Ser(855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser(863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser(859) and Ser(855)) SIGNOR-188920 0.989 MYOD1 protein P15172 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15130492 f lperfetto MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA SIGNOR-251727 0.397 PRKCA protein P17252 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation Ser657 QSDFEGFsYVNPQFV 9606 15277524 t lperfetto Pkc is frequently autophosphorylated on two c-terminal sites, the turn motif (thr- 638 in human pkc) and the hydrophobic site (ser-657 in human pkc). Thus, it is becoming clear that autophosphorylation of pkc can be a regulated event and that it has significant impact on pkc function SIGNOR-127253 0.2 P2RY10 protein O00398 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256869 0.2 AKT1 protein P31749 UNIPROT DLX5 protein P56178 UNIPROT up-regulates phosphorylation 9606 21619873 t gcesareni Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5. SIGNOR-252513 0.267 RPS6KA4 protein O75676 UNIPROT TP53 protein P04637 UNIPROT down-regulates 9606 19797274 f gcesareni Mitogen- and stress-activated kinase 2 (msk2) inhibits the transcription factor p53, and we investigate here the mechanisms underlying this inhibition. In the absence of stress stimuli, msk2 selectively suppressed the expression of a subset of p53 target genes.Msk2 can also control the the transcriptional activity of p53 in a kinase-indipendent mannermsk2 can also control the the transcriptional activity of p53 in a kinase-indipendent manner SIGNOR-188334 0.252 PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 12040186 t lperfetto The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. SIGNOR-252713 0.8 MUSK protein O15146 UNIPROT WNT11 protein O96014 UNIPROT up-regulates binding 9606 23151663 t gcesareni Like ror, musk has an extracellular region with homolgogy to the frizzled crd, binding of which by wnt11 stimulates a pcp-like pathway during neuromuscular development SIGNOR-199518 0.468 AZD1480 chemical CID:16659841 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190167 0.8 DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 9606 23151663 f gcesareni In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl associated activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. SIGNOR-199384 0.566 Ile(5)-angiotensin II smallmolecule CHEBI:2719 ChEBI AGTR1 protein P30556 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257459 0.8 SMAD3 protein P84022 UNIPROT PAX8 protein Q06710 UNIPROT down-regulates activity binding 9606 14623893 t miannu DNA Binding Activity of Pax8 to the NIS Promoter Is Reduced by Smad3. TGF-β decreases Pax8 DNA binding to the NIS promoter and also found a physical interaction between Pax8 and Smad3. SIGNOR-251992 0.373 RAP1GDS1 protein P52306 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 21242305 t miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob SIGNOR-171418 0.463 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR3 protein Q99500 UNIPROT up-regulates activity chemical activation 10116 10617617 t We observed that S1P treatment significantly increased proliferation of HTC4 hepatoma cells stably transfected with human S1P receptor Edg3 or Edg5, which was attributable to stimulation of cell growth and inhibition of apoptosis caused by serum starvation. SIGNOR-261142 0.8 PRLHR protein P49683 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256694 0.281 GSK3A protein P49840 UNIPROT STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization phosphorylation Ser381 RKFNILTsNQKTLTP 9606 BTO:0002181 31843895 t miannu GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation. SIGNOR-276760 0.266 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Phe) smallmolecule CHEBI:29184 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269492 0.8 PD318088 chemical CID:10231331 PUBCHEM MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck lperfetto SIGNOR-244927 0.8 CREB1 protein P16220 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11557984 t CREB was found to induce expression of the gluconeogenic programme through the nuclear receptor coactivator PGC-1, which is shown here to be a direct target for CREB regulation in vivo SIGNOR-256150 0.535 PTPN12 protein Q05209 UNIPROT GIT2 protein Q14161 UNIPROT down-regulates dephosphorylation Tyr392 QDNDQPDyDSVASDE 9606 16317044 t fspada Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest. SIGNOR-142715 0.351 PRSS3 protein P35030 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity cleavage Arg36 TNRSSKGrSLIGKVD -1 10978167 t lperfetto Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3. SIGNOR-263604 0.373 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252742 0.756 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159365 0.2 AHCYL2 protein Q96HN2 UNIPROT PAPOLA protein P51003 UNIPROT down-regulates activity binding 9606 BTO:0000007 19224921 t lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. SIGNOR-268330 0.2 ODAD4 protein Q96NG3 UNIPROT Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR up-regulates activity binding 10090 BTO:0000379 33347437 t miannu CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B). It also interacts with ODA proteins including dynein heavy chains such as DNAH11 and possibly DNAH5/9. CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. SIGNOR-265546 0.2 SKP2 protein Q13309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates ubiquitination 9606 17409098 t gcesareni Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. ;the recognition of p27 by skp2/cks1 of the scfskp2 complex is dictated by cycline/cdk2, providing a high affinity binding site and the phosphorylation of p27 at t187, serving here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3). SIGNOR-154194 0.757 dopamine smallmolecule CHEBI:18243 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258376 0.8 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0002181 SIGNOR-C3 10942774 t lperfetto PHAS-I in adipocytes and HEK293 cells is phosphorylated in the following five sites, all of which conform to a (S/T)P motif (9, 10): Thr-36, Thr-45, Ser-64, Thr-69, and Ser-82. Thr-45 and Ser-64 flank the eIF4E-binding motif (7, 8), and phosphorylation of either site blocks eIF4E binding in vitro (10, 11). Insulin stimulates the phosphorylation of Thr-36, Thr-45, Ser-64, and Thr-69 in both fat cells and HEK293 cells, and incubating cells with rapamycin decreases the phosphorylation of these sites.Immunoprecipitated epitope-tagged mammalian target of rapamycin (mTOR) phosphorylated Thr-36/45. mTOR also phosphorylated Thr-69 and Ser-64 but only when purified immune complexes were incubated with the activating antibody, mTAb1. SIGNOR-226714 0.924 CCL3 protein P10147 UNIPROT CCR1 protein P32246 UNIPROT up-regulates activity binding 9606 20219869 t areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.  SIGNOR-255114 0.71 LNX1 protein Q8TBB1 UNIPROT BCR protein P11274 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 22889411 t miannu We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo. SIGNOR-272903 0.27 PRKCA protein P17252 UNIPROT TRPV5 protein Q9NQA5 UNIPROT up-regulates activity phosphorylation Ser299 FLELVVSsDKREARQ 9606 17006539 t gcesareni A cell permeable analog of DAG increased TRPV5 activity within 30 min via protein kinase C activation of the channel since mutation of TRPV5 at the putative PKC phosphorylation sites S299 and S654 prevented the stimulatory effect of TK. SIGNOR-149948 0.2 PRKG1 protein Q13976 UNIPROT EVL protein Q9UI08 UNIPROT down-regulates activity phosphorylation 9606 15066263 t miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts SIGNOR-268290 0.2 AKT2 protein P31751 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates activity phosphorylation Ser571 RMRSRSRsFSRHRSC 10090 17554339 t miannu Here we describe a mechanism by which insulin, through the intermediary protein kinase Akt2/protein kinase B (PKB)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (PGC-1alpha), a global regulator of hepatic metabolism during fasting.  Akt phosphorylates PGC-1α at Ser 570. SIGNOR-262626 0.355 CDK12 protein Q9NYV4 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Thr169 TEAPAVVtEEEDDDE 9606 BTO:0004828 32483448 t lperfetto Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway SIGNOR-273110 0.2 AP-2 complex complex SIGNOR-C245 SIGNOR EPS15 protein P42566 UNIPROT up-regulates activity binding 10116 BTO:0000142 15496985 t Giorgia Some of the more minor interactors are very strongly enriched (AAK, auxilin, Dab2, eps15, epsin1 and synaptojanin170). All these enriched proteins have multiple copies of short alpha‐appendage interaction motifs SIGNOR-260394 0.655 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 20937773 t lperfetto In this study, we demonstrate that procaspase-8 is phosphorylated in mitotic cells by cdk1na interference-mediated silencing of cyclin b1 or treatment with the cdk1 inhibitor ro-3306 enhances the fas-mediated activation and processing of procaspase-8 in mitotic cells/cyclin b1 on ser-387 SIGNOR-216737 0.379 ACAN protein P16112 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 9606 BTO:0003858 16051604 t lperfetto Cartilage Oligomeric Matrix Protein/Thrombospondin 5 Supports Chondrocyte Attachment through Interaction with Integrins|We show that COMP/TSP5 can support chondrocyte attachment and that the RGD sequence in COMP/TSP5 and the integrin receptors alpha5beta1 and alphaVbeta3 on the chondrocytes are involved in mediating this attachment. The interactions of COMP/TSP5 with the integrins are dependent on COMP/TSP5 conformation. SIGNOR-266987 0.267 SP1 protein P08047 UNIPROT NDUFV2 protein P19404 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000931 17786189 f miannu Sp1 role in the regulation of complex I subunits, was demonstrated by the ability of the Sp1/DNA binding inhibitor, mithramycin, to inhibit the transcription of NDUFV1 and NDUFV2, in neuroblastoma cells. In addition, Sp1 activated NDUFV2 promoter by binding to its three GC-boxes. Both activation and binding were inhibited by mithramycin. SIGNOR-255207 0.351 IRX1 protein P78414 UNIPROT CELF2 protein O95319 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. SIGNOR-261657 0.2 MAPK3 protein P27361 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser226 IDENCLLsPLAGEDD -1 9199329 t lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. SIGNOR-154409 0.522 NCOR1 protein O75376 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18588516 f miannu The down-regulation of slug in the ERalpha-positive MCF-7 cell line was mediated by direct repression of slug transcription by the formation of a co-repressor complex involving ligand-activated ERalpha protein, HDAC1 (histone deacetylase 1) and N-CoR (nuclear receptor co-repressor). SIGNOR-254229 0.361 PTPN12 protein Q05209 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 BTO:0003892 11731619 t PTP-PEST-Containing Lysates from EGF-Treated HC11 Cells Dephosphorylate JAK2 More Efficiently than Lysates from Control Cells|phospho-JAK2-specific rabbit polyclonal antiserum (44-426, BioSource Technologies, Inc., Camarillo, CA) which recognizes Tyr1007/1008 in the activation site SIGNOR-248657 0.385 AURKB protein Q96GD4 UNIPROT ATM protein Q13315 UNIPROT up-regulates phosphorylation Ser1403 CHKTKLKsILEILSK 9606 22099307 t lperfetto Aurora-b mediated atm serine 1403 phosphorylation is required for mitotic atm activation and the spindle checkpoint SIGNOR-177280 0.442 linifanib chemical CHEBI:91435 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 16648571 t Gianni ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families SIGNOR-262206 0.8 EEF1A1P5 protein Q5VTE0 UNIPROT Translational_elongation phenotype SIGNOR-PH210 SIGNOR up-regulates 9606 23699257 f lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269395 0.7 FKBP5 protein Q13451 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by expression catalytic activity 9606 BTO:0002035 28978117 t Barakat FKBP51s upregulated PD-L1 expression on the plasma membrane by catalysing the protein folding required for subsequent glycosylation. Inhibition of FKBP51s isomerase activity by SAFit decreased PD-L1 levels SIGNOR-274973 0.2 MAPK1 protein P28482 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation Tyr187 HTGFLTEyVATRWYR 1712480 t lperfetto Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.| SIGNOR-249415 0.2 INSIG2 protein Q9Y5U4 UNIPROT SCAP protein Q12770 UNIPROT down-regulates activity binding 10029 BTO:0000246 12242332 t insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. SIGNOR-256209 0.705 TNKS2 protein Q9H2K2 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates ubiquitination 9606 19759537 t gcesareni Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. SIGNOR-188036 0.685 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Ala) smallmolecule CHEBI:29170 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269480 0.8 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR MAGEA3 protein P43357 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002806 31267705 t miannu  The CRL4‐DCAF12 E3 ubiquitin ligase degrades MAGE‐A3/6 SIGNOR-272265 0.2 TNKS2 protein Q9H2K2 UNIPROT TARDBP protein Q13148 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0000142 32409565 t lperfetto Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation. SIGNOR-262116 0.2 CRX protein O43186 UNIPROT RBP3 protein P10745 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 f miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. SIGNOR-253821 0.389 CDK8 protein P49336 UNIPROT CKM complex complex SIGNOR-C406 SIGNOR form complex binding 9606 23563140 t miannu The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation. SIGNOR-266686 0.899 ERG protein P11308 UNIPROT NKX3-1 protein Q99801 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25277175 f miannu Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3. SIGNOR-251556 0.341 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr487 SQKVVVTtPLHRDKT 9606 SIGNOR-C83 9840932 t lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk2 SIGNOR-62361 0.711 TGFB1 protein P01137 UNIPROT COL1A2 protein P08123 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8182090 f gcesareni Tgf-beta stimulates transcription of the human alpha 2(i) collagen gene (col1a2) promoter by increasing the affinity of an sp1-containing protein complex for its cognate dna-binding site SIGNOR-36783 0.404 MYT1L protein Q9UL68 UNIPROT Demyelination phenotype SIGNOR-PH155 SIGNOR down-regulates 9606 29397565 f miannu Myt1L (myelin transcription factor 1-like), mainly expressed in neurons, has been associated with intellectual disability, schizophrenia, and depression. In the present study, we found that Myt1L was expressed in oligodendrocyte lineage cells during myelination and remyelination. SIGNOR-266779 0.7 SNRPA protein P09012 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270627 0.667 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270381 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Thr326 GCYSVPTtPEDFLSN 26375055 t lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity SIGNOR-276523 0.265 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser13 GQDMSQVsGKESPPV 9606 BTO:0001271 21750978 t miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway SIGNOR-174844 0.2 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser752 PSADRDSsPTTNSKL 9606 22966201 t llicata Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress. SIGNOR-199004 0.328 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Thr207 TPPTLSStVLIVRNE 9606 BTO:0001938 12815053 t lperfetto Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation. SIGNOR-249221 0.555 Nalorphine chemical CHEBI:7458 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258813 0.8 S100A8 protein P05109 UNIPROT TLR4 protein O00206 UNIPROT down-regulates activity binding 9606 28137827 t miannu Interestingly, in the present study, we report that extracellular S100A9 induces terminal differentiation of myeloid leukemia cells in human and murine AMLs after TLR4 activation, which is highly expressed by primary myelomonocytic and monocytic leukemia cells. In contrast, anti-S100A8 induced the differentiation of AML cells, suggesting that the differentiation-promoting effect of S100A9 is inhibited by S100A8. ) S100A8 could bind to TLR4 and activate different signaling pathways, leading to the inhibition of cellular differentiation induced by S100A9. SIGNOR-261921 0.515 PRDM16 protein Q9HAZ2 UNIPROT Brown_adipogenesis phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 BTO:0000222 BTO:0000887;BTO:0001103 18719582 f fspada Loss of prdm16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of prdm16 in myoblasts induces their differentiation into brown fat cells. SIGNOR-180295 0.7 MMP20 protein O60882 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272388 0.7 DPYSL2 protein Q16555 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 25040932 f lperfetto In the non-phosphorylated state, CRMP2 binding to tubulin induces the promotion of tubulin polymerisation leading to dendrite outgrowth while SIGNOR-264842 0.7 RAPGEF3 protein O95398 UNIPROT RAP1A protein P62834 UNIPROT up-regulates activity guanine nucleotide exchange factor 9534 BTO:0000298 10777494 t miannu Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well. SIGNOR-263956 0.699 GNAI1 protein P63096 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI down-regulates 9606 23994464 f apalma The G alpha I subunit inhibits adenylyl cyclase activity and therefore reduces cytoplasmic cAMP levels SIGNOR-255008 0.8 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser330 RLSPIMAsTELDEVQ 9606 19188143 t lperfetto Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition. SIGNOR-252906 0.52 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr451 TDPEALHyDYIDVEM 9534 BTO:0004055 9655255 t lperfetto In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110. SIGNOR-246351 0.589 oxotremorine M chemical CHEBI:38322 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258655 0.8 POLR2E protein P19388 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266167 0.889 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2S protein Q16763 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271343 0.63 SOX11 protein P35716 UNIPROT SPAST protein Q9UBP0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22574173 f miannu we demonstrate that SPAST transcription is positively regulated by NRF1 and SOX11. SIGNOR-254886 0.37 H2AX protein P16104 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 15635255 t esanto Nbs1 physically interacts with ?-H2ax to form nuclear foci at dna damage sites. The inhibition of this interaction by introduction of anti-?-H2ax antibody into cells abolishes nbs1 foci formation in response to dna damage. SIGNOR-133020 0.2 RRAGD protein Q9NQL2 UNIPROT RAGAD complex SIGNOR-C114 SIGNOR form complex binding 9606 20381137 t gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant SIGNOR-228170 0.769 GDNF protein P39905 UNIPROT CLU protein P10909 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252187 0.264 FBXW11 protein Q9UKB1 UNIPROT EEF2K protein O00418 UNIPROT down-regulates ubiquitination 9606 phosphorylation:Ser441;Ser445 ESENSGDsGYPSEKR;SGDSGYPsEKRGELD 22669845 t gcesareni Eef2k was degraded by the ubiquitin-proteasome system through the ubiquitin ligase scf(__trcp) (skp1-cul1-f-box protein, __-transducin repeat-containing protein) to enable rapid resumption of translation elongation. This event required autophosphorylation of eef2k on a canonical __trcp-binding domain SIGNOR-197730 0.447 CREB1 protein P16220 UNIPROT GDA protein Q9Y2T3 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0000938 BTO:0000142 21715638 t lperfetto In addition, exposure of the neurons to BDNF increased CREB binding to the cypin promoter and, in line with these data, expression of a dominant negative form of CREB blocked BDNF-promoted increases in cypin protein levels and proximal dendrite branches. SIGNOR-268968 0.2 RAP1GDS1 protein P52306 UNIPROT RAC2 protein P15153 UNIPROT up-regulates binding 9606 21242305 t miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob SIGNOR-171421 0.513 antigen smallmolecule CHEBI:59132 ChEBI BCR-Dk complex SIGNOR-C435 SIGNOR up-regulates activity binding 9606 BTO:0000776 32323266 t scontino The recognition of antigen by the BCR initiates BCR signaling cascade. SIGNOR-268204 0.8 MAPK7 protein Q13164 UNIPROT ETS1 protein P14921 UNIPROT up-regulates phosphorylation Thr38 CADVPLLtPSSKEMM 9606 12048211 t gcesareni 9-cis retinoid x receptor alpha (rxr alpha) interacted with erk2 but not erk5 in intact cells, whereas ets-1 interacted preferentially with erk5. Increased phosphorylation of rxr alpha and ets-1 was detected in response to 1,25d. Activated erk2 and erk5 specifically phosphorylated rxr alpha and ets-1, respectively.Mutagenesis of ets-1 (t38a) reduced cyp24 promoter activity to levels observed with the dominant-negative mek5(a) and inhibited erk5-directed phosphorylation. Mutated rxr alpha (s260a) inhibited 1,25d-induced cyp24 promoter activity and abolished phosphorylation by activated erk2. SIGNOR-88666 0.43 DLG4 protein P78352 UNIPROT TANC2 protein Q9HCD6 UNIPROT up-regulates activity binding 10116 BTO:0000142 21068316 t miannu In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses. SIGNOR-266895 0.317 MRGPRD protein Q8TDS7 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR down-regulates 10116 23446738 f Luana Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. SIGNOR-262309 0.7 G3BP1 protein Q13283 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 BTO:0002181 23279204 f SARA G3BP1 and G3BP2 form homo‐ and hetero‐multimers to induce SGs SIGNOR-260984 0.7 DIO proteinfamily SIGNOR-PF83 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20978344 f inferred from family member miannu The active thyroid hormone 3,5,3' triiodothyronine (T3) is a major regulator of skeletal muscle function. The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4). Here we show that type 2 deiodinase (D2) is essential for normal mouse myogenesis and muscle regeneration. Indeed, D2-mediated increases in T3 were essential for the enhanced transcription of myogenic differentiation 1 (MyoD) and for execution of the myogenic program. SIGNOR-270306 0.2 CDK5 protein Q00535 UNIPROT TPPP protein O94811 UNIPROT down-regulates activity phosphorylation Ser18 ANRTPPKsPGDPSKD -1 17693641 t miannu Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP. SIGNOR-262932 0.413 MAP3K7 protein O43318 UNIPROT TAB1 protein Q15750 UNIPROT up-regulates activity phosphorylation Ser452 STNTHTQsSSSSSDG 9606 BTO:0000007 22216226 t miannu We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro.  SIGNOR-276364 0.927 MAPK3 protein P27361 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 19327116 t gcesareni Thr235 phosphorylation occurs in nuclei of differentiated macrophages, but not in monocytes. SIGNOR-184917 0.654 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259708 0.8 RELA protein Q04206 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates activity relocalization 10090 14982881 t Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. This indicates that shuttling of p65 was necessary for Flt3-ITD-mediated SMRT nuclear export. SIGNOR-261539 0.413 NOTCH1 protein P46531 UNIPROT IL7R protein P16871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 22577461 f miannu E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r. SIGNOR-197452 0.327 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252837 0.908 OXGR1 protein Q96P68 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257155 0.358 SOX9 protein P48436 UNIPROT COL2A1 protein P02458 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10980415 f miannu Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan. SIGNOR-251756 0.517 NOTCH3 protein Q9UM47 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21743488 f gcesareni We demonstrate that her2 overexpression in this cellular model of dcis drives transcriptional upregulation of multiple components of the notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising notch3, its cleaved intracellular domain and the transcriptional regulator hes1. SIGNOR-174750 0.595 IL1B protein P01584 UNIPROT SERPINA3 protein P01011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002600 11027208 f miannu We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. SIGNOR-254806 0.2 TRHR protein P34981 UNIPROT GNA11 protein P29992 UNIPROT up-regulates activity binding 9606 BTO:0001379 27515033 t scontino Binding of TRH to TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C. SIGNOR-267201 0.462 NFIB protein O00712 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24553933 f miannu Nfibbinds to the ezh2 promoter and overexpression ofnfibrepresses ezh2 transcription. SIGNOR-204643 0.383 MAPK3 protein P27361 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 12110590 t gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. SIGNOR-90529 0.728 GSK1059615 chemical CHEBI:71955 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192777 0.8 TACR1 protein P25103 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257161 0.2 IMPDH2 protein P12268 UNIPROT MKI67 protein P46013 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30518405 f miannu We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. SIGNOR-260958 0.2 CDK1 protein P06493 UNIPROT BCL2 protein P10415 UNIPROT up-regulates activity phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10766756 t gcesareni Using synthetic peptides and mutant cell lines, we identified threonine 56, one of two consensus sites for cdc2 within the bcl-2 sequence, as a residue phosphorylated by cdc2. Mutation at threonine 56 abrogated the cell cycle inhibitory effect of bcl-2 without affecting anti-apoptotic function.Taken together, our present findings indicate that phosphorylation of bcl-2 at threonine 56 by cdc2 is required for bcl-2-mediated cell cycle inhibition, which may have some roles during mitosis in the normal cell cycle. SIGNOR-76837 0.352 UNC80 protein Q8N2C7 UNIPROT NALCN protein Q8IZF0 UNIPROT up-regulates activity binding 9606 BTO:0000142 22196327 t miannu The NALCN complex in the brain consists of NALCN, UNC80 and UNC79. UNC80 directly associates with NALCN and UNC79 forms part of the complex by its interaction with UNC80. SIGNOR-265184 0.802 H3C1 protein P68431 UNIPROT Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR form complex binding -1 21812398 t miannu The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. SIGNOR-263721 0.2 MAPK8 protein P45983 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates activity phosphorylation Ser363 DTEGRPPsPPPTSTP 9606 BTO:0000567 10747973 t miannu JNK is activated by heat shock and phosphorylates HSF-1 on serine 363. JNK Phosphorylation of HSF-1 Leads to Reduction in Its Transcriptional Activity SIGNOR-250119 0.511 TFEB protein P19484 UNIPROT FGF21 protein Q9NSA1 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 f lperfetto On the contrary, proteins increasing the most included those degraded by autophagy (e.g., SQSTM1/p62 and GABARAPL2 SIGNOR-276791 0.278 FOXO3 protein O43524 UNIPROT TSC22D3 protein Q99576 UNIPROT up-regulates activity transcriptional regulation 10090 15031210 t We then characterized the human gilz promoter and showed that FoxO3 (Forkhead box class O3) binding to the Forkhead responsive elements identified in the promoter is necessary for induction of gilz expression upon IL-2 withdrawal SIGNOR-256094 0.404 PTGER1 protein P34995 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000586 17251915 t gcesareni Ep1 is a galfaq-coupled receptor that promotes calcium mobilization and pkc activation, whereas ep2 and ep4, which have a more prominent role in colon cancer, are coupled to galfas and stimulate camp accumulation SIGNOR-152802 0.425 RAF1 protein P04049 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 8157000 t Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. gcesareni To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1. SIGNOR-36553 0.722 PLK1 protein P53350 UNIPROT STAG2 protein Q8N3U4 UNIPROT down-regulates activity dephosphorylation Ser1137 KRLRPEDsFMSVYPM 9606 BTO:0000567 15737063 t lperfetto Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase SIGNOR-275534 0.727 PAX7-FOXO1 fusion protein SIGNOR-FP11 SIGNOR IGF1R protein P08069 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20663909 t lperfetto We also provide the first direct evidence that FGFR4 and IGF1R are the targets for PAX3-FKHR. The map of PAX3-FKHR binding sites provides a framework for understanding the pathogenic roles of PAX3-FKHR, as well as its molecular targets to allow a systematic evaluation of agents against this aggressive rhabdomyosarcoma. SIGNOR-249595 0.2 arginine smallmolecule CHEBI:29016 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264756 0.7 RB1 protein P06400 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates 9606 14560017 f gcesareni We find that active rb mediates histone deacetylation on cyclin a, cdc2, topoisomerase iialfa, and thymidylate synthase promoters. We also demonstrate that this deacetylation is hdac dependent, since the hdac inhibitor trichostatin a (tsa) prevented histone deacetylation at each promoter. SIGNOR-118839 0.609 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000599 10187842 t inferred from 70% family members lperfetto We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution. SIGNOR-270079 0.2 MAPK3 protein P27361 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 19282669 t lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-252963 0.582 EEF1A1 protein P68104 UNIPROT Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269504 0.8 DRD4 protein P21917 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256703 0.44 JAK2 protein O60674 UNIPROT CCR2 protein P41597 UNIPROT up-regulates activity phosphorylation Tyr139 ILLTIDRyLAIVHAV 9606 9670957 t JAK2 phosphorylates CCR2 at the Tyr139 position and promotes JAK2/STAT3 complex association to the receptor.  SIGNOR-251345 0.601 CSNK2A1 protein P68400 UNIPROT TOP1 protein P11387 UNIPROT up-regulates activity phosphorylation Ser10 GDHLHNDsQIEADFR -1 18408216 t miannu In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells. SIGNOR-276155 0.391 AKT1 protein P31749 UNIPROT S1PR1 protein P21453 UNIPROT up-regulates activity phosphorylation Thr236 RTRSRRLtFRKNISK 9606 11583630 t lperfetto Activated akt binds to edg-1 and phosphorylates the third intracellular loop at the t(236) residue. Transactivation of edg-1 by akt is not required for g(i)-dependent signaling but is indispensable for rac activation, cortical actin assembly, and chemotaxis SIGNOR-252467 0.692 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI -1 11777913 t lperfetto Here, using mass spectrometry, we identify the serum-responsive, rapamycin-sensitive sites as Ser 65 and Thr 70. | Phosphorylation of Thr 37/Thr 46 is followed by Thr 70 phosphorylation, and Ser 65 is phosphorylated last. Finally, we show that phosphorylation of Ser 65 and Thr 70 alone is insufficient to block binding to eIF4E, indicating that a combination of phosphorylation events is necessary to dissociate 4E-BP1 from eIF4E. SIGNOR-249131 0.658 FUS protein P35637 UNIPROT DUSP22 protein Q9NRW4 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 28515487 f This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease SIGNOR-262803 0.2 NFIL3 protein Q16649 UNIPROT CYP3A4 protein P08684 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 18004209 f miannu The oscillation in the expression of the CYP3A4 gene seemed to be the underlying cause of the rhythmic change in its metabolic activity. Luciferase reporter gene analysis and electrophoretic mobility shift assay revealed that the circadian transcriptional factor, D-site-binding protein (DBP), activated the transcription of the CYP3A4 gene by binding to the DNA sequence near the upstream of the transcriptional start site. The transactivation of the CYP3A4 gene by DBP was repressed by the E4 promoter-binding protein-4 (E4BP4), a negative component of the circadian clock. SIGNOR-253836 0.2 ERBB3 protein P21860 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 14967450 t gcesareni All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor. In this study, we identify grb2 as a specific binding partner to tyrosines y1199 and y1268 of erbb3. SIGNOR-121971 0.833 CHUK protein O15111 UNIPROT TRAF4 protein Q9BUZ4 UNIPROT down-regulates phosphorylation Ser426 KPGTWRGsLDESSLG 9606 22547678 t llicata Traf4 is atypical within its family because it is the only traf family member to negatively regulate innate immune signaling. Ikk_'s phosphorylation of serine-426 on traf4 was required for this negative regulation. SIGNOR-197253 0.392 PRKAA1 protein Q13131 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser355 EADLPEPsEKQPAAA -1 10090741 t miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. SIGNOR-275440 0.2 MAPK1 protein P28482 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 18676833 t gcesareni We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage. SIGNOR-179808 0.542 NR0B2 protein Q15466 UNIPROT THRA protein P10827 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11368516 f gcesareni Shp (short heterodimer partner) is an orphan nuclear receptor lacking a dna binding domain that interacts with nuclear receptors (nr) including thyroid receptor (tr), retinoic acid receptors (rar and rxr), and estrogen receptors alpha and beta (eralpha and erbeta). Shp acts as a negative regulator of these receptors by inhibiting dna binding and transcriptional activation. SIGNOR-108248 0.378 DLG4 protein P78352 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 19075115 f miannu Postsynaptic density 95 (PSD-95) is an important regulator of synaptic structure and plasticity. SIGNOR-264053 0.7 NLRX1 protein Q86UT6 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity binding 9606 21703539 t Giorgia Immunoprecipitation experiments showed that NLRX1 interacted with TRAF6 and TRAF3, but not with TRAF2 or TRAF5. These results further suggest that NLRX1 specifically inhibits TLR-induced TRAF6-dependent NF-kB signaling through targeting TRAF6. SIGNOR-260364 0.484 CSNK2A1 protein P68400 UNIPROT VTN protein P04004 UNIPROT up-regulates activity phosphorylation Thr69 VTRGDVFtMPEDEYT 10090 BTO:0000944 9733784 t llicata  Therefore, we expressed Vn in a baculovirus system and show (i) that the CKII phosphorylation of wt-Vn enhances the adhesion of bovine aorta endothelial cells; (ii) that the double mutant T50E/T57E (in which the neutral Thr residues are replaced by the negatively charged Glu residues considered analogs of Thr-P) has a significantly enhanced capacity to promote cell adhesion and to accelerate cell spreading when compared with either wild-type Vn or to the neutral T50A/T57A mutant SIGNOR-250970 0.334 BCL7A protein Q4VC05 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270723 0.515 CDK5 protein Q00535 UNIPROT DLC1 protein Q96QB1 UNIPROT up-regulates activity phosphorylation Ser859 RRENSSDsPKELKRR 9606 BTO:0002181 25452387 t miannu The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin.  SIGNOR-276445 0.2 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI LATS2 protein Q9NRM7 UNIPROT down-regulates 9606 BTO:0000007 22863277 f milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. SIGNOR-198553 0.8 HTR1B protein P28222 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256863 0.412 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 9606 21808241 t MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction. SIGNOR-175829 0.897 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MEF2A protein Q02078 UNIPROT down-regulates binding 9606 21902831 t lperfetto In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-216960 0.271 MAPK14 protein Q16539 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser283 RSVPEPLsPVSSLQA 9606 16027724 t miannu ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation SIGNOR-250092 0.424 SNAI1 protein O95863 UNIPROT SERPINE1 protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19055748 f lperfetto We demonstrated by both cDNA microarrays and real-time quantitative RT-PCR that the functional blockade of SNAI1 induces a significant decrease of PAI-1 and uPA transcripts. SIGNOR-252262 0.427 NOD1 protein Q9Y239 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 18079694 f miannu Nod1 and Nod2 stimulation activates NF-kappaB through RICK, a caspase-recruitment domain-containing kinase. SIGNOR-252411 0.298 MAP2K4 protein P45985 UNIPROT RXRA protein P19793 UNIPROT down-regulates phosphorylation Tyr249 VEPKTETyVEANMGL 9606 10938283 t miannu Phosphorylation by mkk4/sek1 had profound effects on the biochemical properties of rxr, inhibiting the expression of genes activated by rxr-retinoic acid receptor complexes. Tyr-249 in the rxr de region was required for the inhibitory effect of mkk4/sek1. SIGNOR-80619 0.2 PSENEN protein Q9NZ42 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates cleavage 9606 12522139 t gcesareni Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex. SIGNOR-97113 0.959 NFAT5 protein O94916 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000815 22266867 t done miannu  As expected, the depletion of NFAT5 decreased the S100A4 and LCN2 mRNA levels (Figure 3a). In addition, chromatin immunoprecipitation (ChIP) assay using NFAT5 antibody indicated that NFAT5 was bound to the S100A4 and LCN2 promoters (Figure 3b, Supplementary Figure S3), as expected (Chen et al., 2009). SIGNOR-274115 0.491 TIMP3 protein P35625 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 SIGNOR-252274 0.7 EGFR protein P00533 UNIPROT SQSTM1 protein Q13501 UNIPROT down-regulates activity phosphorylation Tyr433 AALDTIQySKHPPPL 9606 31931029 t miannu Here we found that EGFR-stimulated phosphorylation of SQSTM1 at tyrosine 433 induces dimerization of its UBA domain, which disturbs the sequestration function of SQSTM1 and causes autophagic flux blocking. SIGNOR-277500 0.336 SRC protein P12931 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr226 KRNKPTVyGVSPNYD 9606 11847100 t lperfetto c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function. SIGNOR-246307 0.518 CDC20 protein Q12834 UNIPROT FBXO31 protein Q5XUX0 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002181 29343641 t miannu Here we show that the low levels of FBXO31 are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (APC/C). We find that the APC/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in FBXO31 to promote its polyubiquitination and degradation in a cell-cycle-regulated manner, which requires phosphorylation of FBXO31 on serine-33 by the prosurvival kinase AKT. SIGNOR-277378 0.372 ceramide smallmolecule CHEBI:17761 ChEBI glycosphingolipid smallmolecule CHEBI:24402 ChEBI up-regulates quantity precursor of 9606 18184806 t miannu Ceramide is a common precursor for both sphingomyelin and glycosphingolipids, which are ubiquitous components of membranes in mammalian cells and play important roles in cell growth, differentiation, and apoptosis SIGNOR-268498 0.8 CHUK protein O15111 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 SIGNOR-C14 15084260 t gcesareni Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation. SIGNOR-252893 0.554 CDKN1A protein P38936 UNIPROT CCNB1 protein P14635 UNIPROT down-regulates binding 9606 19158493 t gcesareni P21-mediated degradation of cyclin b1 in response to dna damage is necessary for the maintenance of g2 cell cycle arrest. SIGNOR-183498 0.823 aspartic acid smallmolecule CHEBI:22660 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264754 0.7 PTPRG protein P23470 UNIPROT VCL protein P18206 UNIPROT down-regulates activity dephosphorylation Tyr822 KSFLDSGyRILGAVA -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254731 0.2 CHEK1 protein O14757 UNIPROT RASSF1 protein Q9NS23 UNIPROT unknown phosphorylation Ser188 PSSKKPPsLQDARRG 9606 24197116 t llicata This study reveals that chk1-mediated phosphorylation of rassf1a, at serine 184, plays an important role in cell-cycle regulation SIGNOR-203144 0.359 RAB32 protein Q13637 UNIPROT AP-3 complex complex SIGNOR-C247 SIGNOR up-regulates activity relocalization 9606 23247405 t lperfetto Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. SIGNOR-260698 0.29 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT unknown phosphorylation Thr77 RASRLGTtRTPSSYG 9606 BTO:0000971 10574968 t lperfetto We developed antibodies specifically recognizing the kinase-dependent phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies, phosphorylation of desmin was observed specifically at the cleavage furrow in late mitotic Saos-2 cells. We then found that treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin SIGNOR-249033 0.322 MAPK3 protein P27361 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr117 DFPKKPLtPYFRFFM 9606 11741541 t lperfetto Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna SIGNOR-112813 0.561 Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity 9606 17715225 f miannu SARS-CoV nsp1 inhibits virus-dependent activation of IRF3 and IRF7. SIGNOR-262503 0.2 FYN protein P06241 UNIPROT MAG protein P20916 UNIPROT up-regulates activity phosphorylation Tyr620 LTEELAEyAEIRVK 10090 BTO:0000142 7525550 t Fyn constitutively binds to MAG in a latent form. Ligand stimulation of L-MAG would result in activation of Fyn kinase and phosphorylation of Tyr-620. Binding and activation of PLC y through this phosphotyrosine residue would contribute to the signaling pathway involved in the regulation of myelination. SIGNOR-251178 0.436 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 24168260 f miannu NF-κB, which can be activated by mitogen-activated protein kinases (MAPKs) (12), is responsible for the transcription of inflammatory factors and profibrotic cytokines, which promote an inflammatory response and fibrosis SIGNOR-260445 0.7 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 9712898 t lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-59689 0.891 SRC protein P12931 UNIPROT CAV2 protein P51636 UNIPROT down-regulates phosphorylation Tyr19 LFMDDDSySHHSGLE 9606 12091389 t lperfetto We show that caveolin-2 undergoes src-induced phosphorylation on tyrosine 19. we conclude that the tyrosine phosphorylation of caveolin-2 (tyr(p)(19)) may function as a signal that is recognized by the cellular machinery to induce the dissociation of caveolin-2 from caveolin-1 oligomers SIGNOR-90225 0.667 NSD1 protein Q96L73 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates methylation 9606 20080798 t lperfetto Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. SIGNOR-217388 0.475 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr830 PLEEQCEyLSYDASQ 9606 20431062 t lperfetto Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk. SIGNOR-165047 0.492 SPOP protein O43791 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates quantity by destabilization binding 9606 24239470 t miannu Mutations in SPOP represent the most common point mutations in primary prostate cancer,with recurrent mutations in SPOP in 6% to 15% of multiple independent cohorts. Wild-type SPOP will bind and promote the degradation of SRC-3,whereas prostate cancer–derived SPOP mutants lose this ability,leading to increased androgen signaling in certain model systems. SIGNOR-251529 0.492 SDHC protein Q99643 UNIPROT SDH complex SIGNOR-C400 SIGNOR form complex binding 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. SIGNOR-266273 0.953 MAPK1 protein P28482 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser770 MMRSKETsSPGTDDV 9606 17209041 t miannu We have demonstrated that the map kinases extracellular signal-regulated kinases 1 and 2 (erk1/2) are implicated in growth factor activation of nhe1. / our results suggest that amino acids ser770 and ser771 mediate erk-dependent activation of the na+/h+ exchanger in vivo. SIGNOR-151925 0.659 SMOC1 protein Q9H4F8 UNIPROT COL1A1 protein P02452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20359165 f lperfetto The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells SIGNOR-260402 0.2 CHRM1 protein P11229 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256878 0.326 g-TuRC complex complex SIGNOR-C282 SIGNOR TUBG1 protein P23258 UNIPROT up-regulates activity binding -1 31862189 t lperfetto Despite its asymmetric architecture, the γ-TuRC arranges γ-tubulins into a helical geometry poised to nucleate microtubules. SIGNOR-262325 0.865 PIM1 protein P11309 UNIPROT HBP1 protein O60381 UNIPROT up-regulates activity phosphorylation Ser372 SAVYVLSsMARQRRA 9606 BTO:0002181 28348080 t miannu  Pim-1 binds to and phosphorylates the transcription factor high mobility group box transcription factor 1 (HBP1), activating it. SIGNOR-277346 0.2 CSNK2A1 protein P68400 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates activity phosphorylation Ser82 RKMKDTDsEEEIREA -1 26675311 t miannu Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third. We found that in the complex between CaM and CaMKII, residue E115 of CaM is strongly interacting with K299 of the kinase through forming a salt-bridge (PDB entry 1WEL), it is quite likely that the phosphorylation induced structural change can disrupt this interaction and negatively affect the binding between the two proteins SIGNOR-266353 0.432 CUDC-101 chemical CID:24756910 PUBCHEM HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20143778 t miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. SIGNOR-262261 0.8 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser705 TPSAMKSsPQIPHQT 9606 20236090 t Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. SIGNOR-248833 0.626 CASP6 protein P55212 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Asp616 EISEVKMdAEFRHDS -1 10438520 t lperfetto Inhibition of caspase-6 activity prevents serum deprivation-mediated increase of Ab. Caspase-6 directly cleaves APP at the C terminus and generates a C-terminal fragment of 3 kDa (Capp3) and an Ab-containing 6.5-kDa fragment, Capp6.5, that increases in serum-deprived neurons SIGNOR-261762 0.713 MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr838 GINPCTEtFTGTLQY 9606 17937911 t lperfetto Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling. SIGNOR-158427 0.2 ABL1 protein P00519 UNIPROT ABL2 protein P42684 UNIPROT up-regulates phosphorylation Tyr261 GLVTTLHyPAPKCNK 9606 15735735 t lperfetto The results show that arg is stabilized in response to 0.1 mm h2o2 by autophosphorylation of y-261, consistent with involvement of the arg kinase function in regulating arg levels. The results further demonstrate that c-abl-mediated phosphorylation of arg on y-261 similarly confers arg stabilization SIGNOR-134396 0.496 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 12777400 t Manara These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386 SIGNOR-260771 0.346 CTCF protein P49711 UNIPROT TERT protein O14746 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16326864 t miannu CTCF binds the proximal exonic region of hTERT and inhibits its transcription SIGNOR-253832 0.334 chloroquine chemical CHEBI:3638 ChEBI ACE2 protein Q9BYF1 UNIPROT down-regulates activity chemical inhibition 9534 32020029 t miannu Chloroquine is known to block virus infection by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV. Our time-of-addition assay demonstrated that chloroquine functioned at both entry, and at post-entry stages of the 2019-nCoV infection in Vero E6 cells SIGNOR-260223 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser251 MIQFAINsTERKRMT 9606 19737929 t lperfetto A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1the phosphorylation at ser-251 is critical for the activation of foxm1. SIGNOR-216833 0.752 MLL1 complex complex SIGNOR-C89 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 24680668 t miannu Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. SIGNOR-268802 0.2 hexestrol chemical CHEBI:31669 ChEBI AKR1C1 protein Q04828 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193230 0.8 WNK2 protein Q9Y3S1 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates activity phosphorylation Ser382 KRASFAKsVIGTPEF 9606 22032326 t Manara WNK1, which is activated in response to osmotic stress by phosphorylation of its T-loop residue (Ser382). | We found that wild-type WNK2 (Figure 8A) or WNK3 (Figure 8B) phosphorylated kinase-inactive WNK1 (1–667, D368A) at Ser382 in vitro. SIGNOR-260790 0.561 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 11123317 t amattioni Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation. SIGNOR-85179 0.346 TP53 protein P04637 UNIPROT ANKRD11 protein Q6UB99 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 18840648 t miannu Ankyrin repeat domain 11, ANKRD11 (also known as ANR11 or ANCO1), was found to be a novel p53-interacting protein that enhanced the transcriptional activity of p53. In addition, ANKRD11 itself was found to be a novel p53 target gene. These findings demonstrate a role for ANKRD11 as a p53 coactivator and suggest the involvement of ANKRD11 in a regulatory feedback loop with p53. SIGNOR-266735 0.313 PBK protein Q96KB5 UNIPROT GPSM2 protein P81274 UNIPROT up-regulates phosphorylation Thr457 LKGKKYKtNSSTKVL 9606 BTO:0000150 20589935 t lperfetto We found that the 450th threonine (thr450) of lgn/gpsm2 was phosphorylated by the serine/threonine kinase pbk/topk during mitosis. Western blot analysis indicated the highest expression and the phosphorylated form of lgn/gpsm2 protein in g2/m phase. SIGNOR-166461 0.273 CDK5 protein Q00535 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000938 BTO:0000887;BTO:0001760;BTO:0000142 15096606 t gcesareni We report here that the cdk5/p35 complex associates with stat3 and phosphorylates stat3 on the ser-727 residue in vitro and in vivo. Ser phosphorylation of stat3 and transcription of stat3 target genes, such as c-fos and junb, in a cdk5-dependent manner. SIGNOR-124325 0.411 ANGPTL1 protein O95841 UNIPROT TEK protein Q02763 UNIPROT up-regulates binding 9606 10051567 t gcesareni Ang3 and ang4 are agonists of tie2, but mouse ang3 has strong activity only on endothelial cells of its own species. SIGNOR-65110 0.52 KNG1 protein P01042 UNIPROT BDKRB2 protein P30411 UNIPROT up-regulates activity binding 9606 cleavage:Arg381;Arg389 GMISLMKrPPGFSPF;PPGFSPFrSSRIGEI 28966616 t lperfetto BK binds receptor B2 (B2R) and triggers inflammation, edema, and symptoms of anaphylaxis. SIGNOR-263554 0.852 HRAS protein P01112 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 10090 BTO:0000944 12169099 t lperfetto c-Jun was first shown to be phosphorylated in its transactivation domain (Ser-63 and Ser-73) by ERKs and p54-JNK. This is consistent with other studies which show that PD98059 inhibits up-regulation of c-Jun protein in Ras-transformed NIH-3T3 cells SIGNOR-235522 0.514 MECP2 protein P51608 UNIPROT ALOX5 protein P09917 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001412 19781662 f Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation.|Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene. SIGNOR-254062 0.2 CEBPA protein P49715 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001056 11283671 t apalma Here, we demonstrate that C/EBPα indeed activates its promoter in transient transfection assays in myeloid cells. SIGNOR-255673 0.2 KMT5C protein Q86Y97 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity methylation Lys21 GGAKRHRkVLRDNIQ -1 24396869 t miannu SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation. SIGNOR-266650 0.2 ROCK1 protein Q13464 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Thr696 ARQSRRStQGVTLTD 9606 8662509 t Rho-associated kinase (Rho-kinase) is activated by GTP-RhoA gcesareni Rho-associated kinase (rho-kinase) phosphorylated mbs and consequently inactivated myosin phosphatase. Rho appears to inhibit myosin phosphatase through the action of rho-kinase. SIGNOR-42354 0.765 ELOVL3 protein Q9HB03 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267886 0.8 SOD3 protein P08294 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI down-regulates quantity chemical modification 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272271 0.8 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120232 0.321 nifedipine chemical CHEBI:7565 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9606 9770465 t miannu In addition to rifampicin, other known inducers of human CYP3A4 expression, including nifedipine and clotrimazole, also activated hPAR. SIGNOR-259066 0.8 Sin3B_complex complex SIGNOR-C409 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity binding 9606 21041482 t miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. SIGNOR-266970 0.2 ANKRD6 protein Q9Y2G4 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 20006983 t gcesareni Our data thus demonstrate that diversin and dishevelled function together in a mutually dependent fashion in zebrafish gastrulation and organ formation SIGNOR-162142 0.486 AMPK complex SIGNOR-C15 SIGNOR HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 21892142 t lperfetto Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs) SIGNOR-216550 0.317 KIRREL3 protein Q8IZU9 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000142 32503885 f miannu We demonstrate that ectopic Kirrel3 expression in CA1 neurons specifically induces ectopic DG synapse formation, providing direct evidence that Kirrel3 plays an instructive role in synapse development. SIGNOR-269077 0.7 CDK1 protein P06493 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Thr550 PPINGSStPNPKIAS 9606 BTO:0000567 19509060 t lperfetto Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation. SIGNOR-272973 0.567 SRC protein P12931 UNIPROT RAPGEF1 protein Q13905 UNIPROT up-regulates phosphorylation Tyr504 APIPSVPyAPFAAIL 9606 15320955 t llicata C3g is activated upon phosphorylation at tyrosine 504 c3g is phosphorylated in vivo on y504 upon coexpression with src or hck, two members of the src family tyrosine kinases. SIGNOR-128273 0.658 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270392 0.8 PRKACA protein P17612 UNIPROT GMFB protein P60983 UNIPROT up-regulates activity phosphorylation Thr27 KFRFRKEtNNAAIIM -1 9030586 t miannu Protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor of extracellular signal-regulated kinase (ERK) and enhancer of p38; both are subfamilies of mitogen-activated protein (MAP) kinase, suggesting GMF as a bifunctional regulator of the MAP kinase cascades. PKA is capable of phosphorylating threonine 26 and serine 82. SIGNOR-249984 0.312 BKM120 chemical CHEBI:71954 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190389 0.8 STAT5A protein P42229 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 19436055 f miannu The alternative survival and proliferation pathway triggered by higher concentrations of GM-CSF is dependent on the dodecamer assembly and involves the Jak/STAT, Ras/mitogen-activated protein kinase, and PI-3 kinase pathways SIGNOR-255578 0.7 ZBP1 protein Q9H171 UNIPROT RIPK3 protein Q9Y572 UNIPROT up-regulates activity binding 10090 BTO:0002572 32200799 t gianni ZBP1 initiates RIPK3-driven cell death by sensing IAV RNA and activating RIPK3. Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis. SIGNOR-266430 0.622 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 t gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation SIGNOR-252451 0.634 PRKACA protein P17612 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 SIGNOR-C13 9660950 t llicata The transcriptional activity of nf-kappa b is stimulated upon phosphorylation of its p65 subunit on serine 276 by protein kinase a (pka). SIGNOR-58972 0.495 AR protein P10275 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 16281084 f After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. SIGNOR-253675 0.363 ELOC protein Q15369 UNIPROT BAF250b E3 ligase complex SIGNOR-C522 SIGNOR form complex binding 9606 BTO:0000567 20086098 t miannu In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro SIGNOR-271438 0.2 GGCX protein P38435 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 31539109 f miannu GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05). SIGNOR-261230 0.304 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194340 0.8 PPP1CA protein P62136 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation 9606 20186153 t lperfetto Several stps have been reported to negatively regulate akt pathway. It has been shown that pp1 dephosphorylates akt and regulates cell survival. SIGNOR-244436 0.436 FERMT2 protein Q96AC1 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding 9606 BTO:0000007 26037143 t miannu Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration. SIGNOR-266101 0.378 DAPK3 protein O43293 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000776 17339337 t gcesareni A cell-free ser(20) phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser(20) kinases.Evaluation of these calcium calmodulin kinase superfamily members as candidate ser(20) kinases in vivo has shown that only chk1 or dapk-1 can stimulate p53 transactivation and induce ser(20) phosphorylation of p53. SIGNOR-153495 0.415 KAT2A protein Q92830 UNIPROT H3C15 protein Q71DI3 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269609 0.2 CSNK1A1 protein P48729 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1359 VPRPHVQsVLLTPQD 9606 BTO:0002181 19797085 t miannu We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity.  SIGNOR-276261 0.314 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Ser216 PSGSGAAsPTGSAVD 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262762 0.259 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1672 SPTSPSYsPTSPSYS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248784 0.442 cabozantinib chemical CHEBI:72317 ChEBI RET protein P07949 UNIPROT down-regulates activity chemical inhibition 9606 21606412 t miannu XL184 (cabozantinib) is a potent inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2), and RET, with robust antiangiogenic, antitumor, and anti-invasive effects in preclinical models. SIGNOR-259321 0.8 thalidomide chemical CHEBI:9513 ChEBI CRBN protein Q96SW2 UNIPROT down-regulates activity chemical inhibition 9606 20223979 t miannu  Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity.  SIGNOR-272207 0.8 PRKACA protein P17612 UNIPROT POLD3 protein Q15054 UNIPROT down-regulates phosphorylation Ser458 GKANRQVsITGFFQR 9606 22148433 t llicata In this study, we identified s458, located in the pcna-interacting protein (pip-box) motif of p68, as a phosphorylation site for pka. Phosphomimetic mutation of s458 resulted in a decrease in p68 affinity for pcna as well as the processivity of pol _. SIGNOR-195203 0.2 SP1 protein P08047 UNIPROT GFER protein P55789 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 18513187 f miannu We also confirmed that activation and repression of hHSS transcription induced by Sp1 and HNF4alpha resulted from binding of these factors to these two cis-elements respectively. Overexpression of HNF4alpha led to a dramatic repression of the promoter activity and, in contrast, the activity was markedly elevated by overexpression of Sp1. SIGNOR-254450 0.2 E2F1 protein Q01094 UNIPROT RASGRP1 protein O95267 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18396012 f miannu We demonstrate that E2F1 induces ERK activation via a transcriptional mechanism and upregulates the expression of two guanine nucleotide exchange factors, RASGRP1 and RASGEF1B, which promote Ras activation. SIGNOR-253850 0.2 DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity ubiquitination 10090 BTO:0000165 11226752 t gcesareni Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis SIGNOR-236870 0.772 TP53 protein P04637 UNIPROT MGMT protein P16455 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000711 17564708 f miannu we observed that IFN-beta sensitized TMZ-resistant glioma cells with the unmethylated MGMT promoter and that the mechanism of action was possibly due to attenuation of MGMT expression via induction of TP53. In this context, IFN-beta inactivates MGMT via p53 gene induction and enhances the therapeutic efficacy to TMZ. SIGNOR-255437 0.487 TUBA3D protein P0DPH8 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. SIGNOR-269723 0.7 VRK3 protein Q8IV63 UNIPROT DUSP3 protein P51452 UNIPROT up-regulates activity binding 27346674 t lperfetto Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding SIGNOR-275546 0.693 MMP7 protein P09237 UNIPROT HAPLN1 protein P10915 UNIPROT down-regulates quantity by destabilization cleavage Leu40 QAENGPHlLVEAEQA -1 7694569 t miannu Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix. SIGNOR-256329 0.327 [5-[5-[5-(hydroxymethyl)-2-thiophenyl]-2-furanyl]-2-thiophenyl]methanol chemical CHEBI:94980 ChEBI TP53 protein P04637 UNIPROT up-regulates chemical activation 9606 19223463 t gcesareni Rita has been proposed to stabilize p53 by inhibiting the p53-hdm2 interaction. SIGNOR-184062 0.8 TRIM27 protein P14373 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000671 12807881 f miannu Here we show that ectopic expression of rfp in human embryonic kidney 293 cells causes extensive apoptosis, as assessed by multiple criteria. SIGNOR-256667 0.7 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257517 0.8 MAPK3 protein P27361 UNIPROT PAX5 protein Q02548 UNIPROT down-regulates activity phosphorylation Ser189; Ser283 SGILGITsPSADTNK;DMKANLAsPTPADIG 9606 BTO:0003079 22593617 t Gianni In this study, we demonstrated that PAX5 was phosphorylated by ERK1/2 in vitro and in vivo at serines 189 and 283. This phosphorylation attenuated the transcriptional repression of BLIMP1 by PAX5. SIGNOR-269086 0.249 OPRL1 protein P41146 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256865 0.435 TWIST1 protein Q15672 UNIPROT NR2F1 protein P10589 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255531 0.252 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH19 protein Q9H159 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265836 0.8 KCNE3 protein Q9Y6H6 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 11506885 t miannu Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height SIGNOR-265589 0.8 A3/b1 integrin complex SIGNOR-C161 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269010 0.7 Gbeta proteinfamily SIGNOR-PF4 SIGNOR TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 21502402 t inferred from 70% family members llicata Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro SIGNOR-270122 0.2 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT unknown phosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Atm resides in a complex with brca1 and phosphorylated brca1 in vivo and in vitro in a region that contains clusters of serine-glutamine residues. Phosphorylation of this domain appears to be functionally important because a mutated brca1 protein lacking two phosphorylation sites failed to rescue the radiation hypersensitivity of a brca1-deficient cell line.Atm-dependent phosphorylation of ser1423 or ser1524 also occurred in vivo, SIGNOR-72079 0.813 NOTCH1 protein P46531 UNIPROT HEY1 protein Q9Y5J3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11486044 t lperfetto These data establish that HERP2 is a novel primary target gene of Notch that, together with HES, may effect diverse biological activities of Notch SIGNOR-235397 0.765 PPM1A protein P35813 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 18586681 t Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. SIGNOR-248493 0.343 CSNK2A3 protein Q8NEV1 UNIPROT F8 protein P00451 UNIPROT down-regulates activity phosphorylation Ser1656 GRTERLCsQNPPVLK -1 8427963 t lperfetto Our findings suggest that phosphorylation of factors Va and VIIIa by a platelet casein kinase II-like kinase may downregulate the activity of the two cofactors.| Recombinant human factor VIII also showed incorporation of radioactivity in the presence of purified casein kinase II at the acidic NH2-terminal portion of factor VIII light chain (residues 1648 through 1689). Based on all the considerations reported above Se1657 is the most likely candidate within this region capable of incorporation of radioactivity SIGNOR-263649 0.2 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR CREB3L2 protein Q70SY1 UNIPROT up-regulates 9606 17178827 f miannu Although bbf2h7 protein is not expressed under normal conditions, it is markedly induced at the translational level during er stress, suggesting that bbf2h7 might contribute to only the late phase of unfolded protein response signaling. SIGNOR-151312 0.7 TRIM33 protein Q9UPN9 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization binding 9606 25639486 t Luana Tumour suppressor TRIM33 targets nuclear β-catenin degradation SIGNOR-260896 0.468 TLR4 protein O00206 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 9606 BTO:0000801 7635431 f lperfetto The activation of NF-kB is triggered by different stimuli, eg., lipopolysaccharides (LPSs), muramyl peptides, viruses,e inflammatory cytokines tumor necrosis factor-alpha(TNF-a) and interleukin (IL)-1b, irradiation, and reactive xygen intermediates (H2O2). SIGNOR-249517 0.563 TP53 protein P04637 UNIPROT RLIM protein Q9NVW2 UNIPROT down-regulates quantity by repression transcriptional regulation 23650532 f lperfetto In the present study, we identified RLIM as a novel target of p53 and demonstrated that p53 repressed both mRNA and protein levels of RLIM. SIGNOR-268981 0.2 AKT1 protein P31749 UNIPROT USP14 protein P54578 UNIPROT up-regulates activity phosphorylation Ser432 THQGRSSsSGHYVSW 9606 26523394 t lperfetto Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system|These results suggested S432 as a major and S143 as a minor phosphorylation site of Akt. SIGNOR-265056 0.434 ABL1 protein P00519 UNIPROT CKMT1A protein P12532 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr153 ASKIRSGyFDERYVL 9606 BTO:0001932 30174304 t miannu Here, we show that oncogenic HER2 tyrosine kinase signaling induces phosphorylation of mitochondrial creatine kinase 1 (MtCK1) on tyrosine 153 (Y153) in an ABL-dependent manner in breast cancer cells. Y153 phosphorylation, which is commonly upregulated in HER2+ breast cancers, stabilizes MtCK1 to increase the phosphocreatine energy shuttle and promote proliferation.  SIGNOR-277406 0.2 GATA6 protein Q92908 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression 9606 BTO:0000195 24317510 f lperfetto Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2. SIGNOR-253152 0.375 CUDC-101 chemical CID:24756910 PUBCHEM EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 20143778 t miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. SIGNOR-262254 0.8 WNT3A protein P56704 UNIPROT ALPL protein P05186 UNIPROT up-regulates 9606 19175684 f gcesareni Wnt3a and bmp-9 enhanced each other's ability to induce alp in mscs. SIGNOR-183538 0.347 BMP7 protein P18075 UNIPROT BMP7 protein P18075 UNIPROT up-regulates binding 9606 BTO:0000887 11178121 t lperfetto Bmps are dimeric proteins with a single inter-chain disulfide bond. The dimeric conformation is an absolute requirement for the biological action and interac- tion with receptors SIGNOR-236172 0.2 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189981 0.8 motesanib chemical CHEBI:51098 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194566 0.8 DHFR2 protein Q86XF0 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity chemical modification 9606 21876184 t lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. |We demonstrate that the DHFRP4, or dihydrofolate reductase-like 1 (DHFRL1), gene is expressed and shares some commonalities with DHFR. SIGNOR-268261 0.8 CREB5 protein Q02930 UNIPROT CREB5 protein Q02930 UNIPROT up-regulates activity binding 9534 BTO:0000318 8378084 t miannu CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription SIGNOR-219602 0.2 SMARCA2 protein P51531 UNIPROT SMARCC2 protein Q8TAQ2 UNIPROT up-regulates binding 9606 10078207 t miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. SIGNOR-65435 0.897 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1616 TPQSPSYsPTSPSYS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248803 0.849 PRKCE protein Q02156 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 15695813 t gcesareni Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth. SIGNOR-133865 0.2 PPAT protein Q06203 UNIPROT 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI down-regulates quantity chemical modification 9606 9914248 t miannu Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine. SIGNOR-267293 0.8 ESR2 protein Q92731 UNIPROT TFF1 protein P04155 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 11517191 f ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression SIGNOR-253939 0.358 SRC protein P12931 UNIPROT HRAS protein P01112 UNIPROT down-regulates activity phosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 25157176 t Src binds to and phosphorylates GTP-, but not GDP-, loaded Ras on a conserved Y32 residue within the switch I region in vitro and that in vivo, Ras-Y32 phosphorylation markedly reduces the binding to effector Raf and concomitantly increases binding to GTPase-activating proteins and the rate of GTP hydrolysis SIGNOR-252093 0.767 TGFB1 protein P01137 UNIPROT SFTPB protein P07988 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004299 18003659 f miannu TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. SIGNOR-254170 0.285 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. SIGNOR-129328 0.327 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244588 0.2 PP121 chemical CHEBI:50915 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206301 0.8 MAPK3 protein P27361 UNIPROT LIFR protein P42702 UNIPROT down-regulates phosphorylation Ser1044 WNLVSPDsPRSIDSN 9606 7777512 t gcesareni Thus, our results identify the human lifr as a substrate for mapk and suggest a mechanism of heterologous receptor regulation of lifr signaling occurring at ser-1044. SIGNOR-32757 0.304 WWP1 protein Q9H0M0 UNIPROT AMOT protein Q4VCS5 UNIPROT up-regulates quantity by stabilization ubiquitination 24101513 t lperfetto Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130 SIGNOR-275847 0.278 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2M protein P61081 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271332 0.715 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0002181 11726515 t irozzo However, direct binding of Grb2 to Bcr/Abl also facilitates its tyrosine phosphorylation, which we propose reflects activation of a physiological negative regulatory mechanism by this oncogenic tyrosine kinase.Direct binding of Grb2 to Bcr/Abl facilitates Grb2 phosphorylation. SIGNOR-255820 0.2 EGFR protein P00533 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 24212772 t GRB2 recruit indirectly through PTB domain-mediated binding of the Shc adaptor gcesareni Several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc). SIGNOR-55861 0.605 SKP2 protein Q13309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates ubiquitination 9606 15998794 t gcesareni Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. ;the recognition of p27 by skp2/cks1 of the scfskp2 complex is dictated by cycline/cdk2, providing a high affinity binding site and the phosphorylation of p27 at t187, serving here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3). SIGNOR-138493 0.757 lapatinib chemical CHEBI:49603 ChEBI RET protein P07949 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 21443688 t Luana YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ. SIGNOR-257899 0.8 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI L-tyrosine zwitterion smallmolecule CHEBI:58315 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-267035 0.8 FLT3 protein P36888 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12468433 f We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling SIGNOR-261546 0.285 SH3GLB1 protein Q9Y371 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates binding 9606 21311563 t gcesareni Bif-1 forms a complex with beclin1 through uvrag and promotes the activation of the class iii pi3 kinase, vps34, in mammalian cells. SIGNOR-171899 0.559 FOXP1 protein Q9H334 UNIPROT SEMA5B protein Q9P283 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001176 24023716 t Gianni FoxP1 stimulates angiogenesis by repressing the inhibitory guidance protein semaphorin 5B in endothelial cells. SIGNOR-269050 0.336 NEK2 protein P51955 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates phosphorylation Ser14 LKKSFQDsLEDIKKR 9606 17621308 t lperfetto Here we show that nek2a phosphorylates human sgo1 and such phosphorylation is essential for faithful chromosome congression in mitosis. phosphorylation sites were mapped to ser(14) and ser(507) SIGNOR-156878 0.2 IKK-complex complex SIGNOR-C14 SIGNOR IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser376 PPAPAYLsSPLALPS 9606 SIGNOR-C14 12657630 t lperfetto Phosphopeptide-mapping experiments with metabolically radiolabeled cells indicate that ikkbeta phosphorylates human ikkgamma at ser-31, ser-43, and ser-376 SIGNOR-209792 0.929 PRKCZ protein Q05513 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT down-regulates activity phosphorylation Thr50 QLPVLDKtKFLVPDH -1 31857374 t done miannu LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1). SIGNOR-273906 0.2 RPA2 protein P15927 UNIPROT MRE11 protein P49959 UNIPROT up-regulates binding 9606 19586055 t fstefani The response to replication stress requires the recruitment of rpa and the mre11-rad50-nbs1 (mrn) complex. SIGNOR-186648 0.2 MLL2 complex complex SIGNOR-C88 SIGNOR CBP/p300 complex SIGNOR-C6 SIGNOR up-regulates activity binding 9606 28669924 t miannu KMT2D associates with WRAD (WDR5, RbBP5, ASH2L, and DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX in one protein complex. It acts as a scaffold protein within the complex and is responsible for maintaining the stability of UTX. KMT2D is a major mammalian H3K4 mono-methyltransferase and co-localizes with lineage determining transcription factors on transcriptional enhancers. It is required for the binding of histone H3K27 acetyltransferases CBP and p300 on enhancers, enhancer activation and cell-type specific gene expression during differentiation. SIGNOR-268814 0.2 PIAS3 protein Q9Y6X2 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 SIGNOR-C9 14691252 t gcesareni Taken together, our studies indicate that on tgf-beta treatment, pias3 can form a complex with smads and p300/cbp and activate smad transcriptional activity. SIGNOR-120359 0.58 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ARHGAP26 protein Q9UNA1 UNIPROT unknown phosphorylation -1 9525907 t inferred from 70% family members miannu In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling. SIGNOR-270058 0.2 PPARG protein P37231 UNIPROT FABP4 protein P15090 UNIPROT up-regulates transcriptional regulation 10116 8943212 f fspada We report that insulin and a ppargamma ligand (thiazolidinedione (tzd)) stimulate in a synergistic manner the expression of an adipocyte-specific gene (ap2) in rat adipocytes and 3t3-l1 cells SIGNOR-210149 0.672 AKT1 protein P31749 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates phosphorylation Ser280 AKRPRVTsGGVSESP 9606 15107605 t gcesareni The chk1 protein phosphorylated by pkb on serine 280 does not enter into protein complexes after replication arrest. Moreover, chk1 phosphorylated by pkb fails to undergo activating phosphorylation on serine 345 by atm/atr. Phosphorylation by atm/atr and association with other checkpoint proteins are essential steps in activation of chk1. SIGNOR-124365 0.441 FASN protein P49327 UNIPROT Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates 9606 9356448 f miannu Our model of the native fatty acid synthase (FAS) depicts it as a dimer of two identical multifunctional proteins (Mr approximately 272,000) arranged in an antiparallel configuration so that the active Cys-SH of the beta-ketoacyl synthase of one subunit (where the acyl group is attached) is juxtaposed within 2 A of the pantetheinyl-SH of the second subunit (where the malonyl group is bound). This arrangement generates two active centers for fatty acid synthesis and predicts that if we have two appropriate halves of the monomer, we should be able to reconstitute an active fatty acid-synthesizing site SIGNOR-270536 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser92 RFRDRSFsEGGERLL 9606 15538381 t lperfetto Here we report that protein kinase b (pkb/akt) stabilizes are transcripts by phosphorylating brf1 at serine 92 (s92). Recombinant brf1 promoted in vitro decay of are-containing mrna (are-mrna), yet phosphorylation by pkb impaired this activity. SIGNOR-244385 0.2 GLI1 protein P08151 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin SIGNOR-188875 0.707 EEA1 protein Q15075 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 t lperfetto Early endosomal antigen-1 (EEA1) is a well-characterized effector of Rab5 and one of the most widely used markers for EE due to its specific localization to this compartment. EEA1, in coordination with members of the SNARE family, is essential for EE fusion in vivo SIGNOR-260623 0.536 risperidone chemical CHEBI:8871 ChEBI HTR1E protein P28566 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0000298 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258528 0.8 ECM stimulus SIGNOR-ST20 SIGNOR A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259035 0.7 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 10521487 t gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. SIGNOR-252584 0.643 INHBA protein P08476 UNIPROT ACVR2A protein P27037 UNIPROT up-regulates activity binding 9606 1646080 t gcesareni A protein of 494 amino acids comprising a ligand-binding extracellular domain, a single membrane-spanning domain, and an intracellular kinase domain with predicted serine/threonine specificity. 125I-activin A binds to transfected COS cells with an affinity of 180 pM and can be competed by activin A, activin B, and inhibin A, but not by transforming growth factor beta 1. SIGNOR-235138 0.808 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates quantity by stabilization 9606 27141364 f irozzo EML4-ALK enhanced HIF-1Œ± expression through increasing transcription and decreasing ubiquitination of HIF-1Œ±. SIGNOR-259173 0.2 MAML1 protein Q92585 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 BTO:0000887 17875709 t gcesareni Unexpectedly, however, emerging evidence implicate maml proteins as exciting key transcriptional co-activators in other signal transduction pathways including: muscle differentiation and myopathies (mef2c), tumor suppressor pathway (p53) and colon carcinoma survival (beta-catenin). SIGNOR-157843 0.279 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity phosphorylation Thr363 IEDDIIYtQDFTVPG 9606 BTO:0000007;BTO:0000567 12805220 t lperfetto It was shown that thr336 and thr366 are the major autophosphorylation sites of mouse lkb1 (sapkota et al., 2002). We confirmed these data on the human orthologues thr336 and thr363. Moreover, the enhanced stoichiometry of lkb1 autophosphorylation by strad enabled us to identify two novel sites: thr185 and thr402. We show that increased lkb1 autophosphorylation of all sites correlates with the activation of its catalytic activity. SIGNOR-101848 0.2 MAP2K4 protein P45985 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Thr180 RHADAEMtGYVVTRW 9606 BTO:0000007 10066767 t done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. SIGNOR-273956 0.436 LINC complex complex SIGNOR-C303 SIGNOR NXF1 protein Q9UBU9 UNIPROT up-regulates activity binding 9606 BTO:0000567 28831067 t lperfetto SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1. SIGNOR-263297 0.306 CDK2 protein P24941 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 SIGNOR-C16 19237534 t lperfetto In vitro, lsf is phosphorylated by cyclin e/cyclin-dependent kinase 2 (cdk2), cyclin c/cdk2, and cyclin c/cdk3, predominantly on s309. Phosphorylation by cyclin c/cyclin-dependent kinase 2 following mitogenic stimulation of murine fibroblasts inhibits transcriptional activity of lsf during g1 progression SIGNOR-184160 0.2 LARP4B protein Q92615 UNIPROT PABPC1 protein P11940 UNIPROT up-regulates activity binding 9606 20573744 t miannu Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. Biochemical studies further show that the protein interacts with two key factors of the translational machinery, namely, the cytoplasmic poly(A) binding protein (PABPC1) and the receptor for activated C Kinase (RACK1). The biochemical and functional data of LARP4B presented in this study suggest a possible mode of action of LARP4B in translation. Assuming that LARP4B interacts with mRNA-associated PABPC1 and RACK1 simultaneously, it may form a bridge between the 3′ end of mRNAs and the initiating ribosome. This process would lead to mRNA circularization, possibly in an analogous way as it has been described for PABPC1 and eIF4G, the scaffold protein of the cap-binding complex. SIGNOR-260940 0.572 SP1 protein P08047 UNIPROT CHGA protein P10645 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12456801 t Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation. SIGNOR-254273 0.2 AKT1 protein P31749 UNIPROT PHF20 protein Q9BVI0 UNIPROT down-regulates phosphorylation Ser291 ELRRRKIsKGCEVPL 9606 22334668 t llicata Akt phosphorylates phf20 at ser(291) in vitro and in vivo, which results in its translocation from the nucleus to the cytoplasm and attenuation of phf20 function. SIGNOR-252529 0.533 NOTCH proteinfamily SIGNOR-PF30 SIGNOR LFNG protein Q8NES3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 f gcesareni Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta. SIGNOR-254336 0.2 1-(4,4-diphenylbut-3-enyl)-3-piperidinecarboxylic acid chemical CHEBI:91734 ChEBI SLC6A1 protein P30531 UNIPROT down-regulates activity chemical inhibition -1 7851497 t miannu Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1. SIGNOR-258478 0.8 nintedanib chemical CHEBI:85164 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190299 0.8 2-[4-[3-[2-(trifluoromethyl)-9-thioxanthenylidene]propyl]-1-piperazinyl]ethanol chemical CHEBI:93235 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258728 0.8 CIITA protein P33076 UNIPROT RFX5 protein P48382 UNIPROT up-regulates activity binding 9606 BTO:0000776 9177217 t 2 miannu RFX5 can activate transcription only in cooperation with CIITA. RFX5 and CIITA associate to form a complex capable of activating transcription from class II major histocompatibility complex promoters. In this complex, promoter specificity is determined by the DNA binding domain of RFX5 and the general transcription apparatus is recruited by the acidic activation domain of CIITA. SIGNOR-240980 0.754 LPAR6 protein P43657 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256868 0.2 TGFBR2 protein P37173 UNIPROT VPS39 protein Q96JC1 UNIPROT up-regulates activity binding 9534 12941698 t miannu TLP interacts with TGF-β and activin receptors in vivo. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling. SIGNOR-261374 0.33 PTPRG protein P23470 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity dephosphorylation Tyr742 KQADTTQyVPMLERK -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254713 0.251 (-)-anisomycin chemical CHEBI:338412 ChEBI MAPK14 protein Q16539 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb gcesareni SIGNOR-189699 0.8 CSNK2A1 protein P68400 UNIPROT APEX1 protein P27695 UNIPROT up-regulates activity phosphorylation Ser123 HQYWSAPsDKEGYSG 9534 BTO:0004055 10023679 t llicata Here we demonstrate that APE/Ref-1 is phosphorylated by casein kinase II (CKII). This was shown for both the recombinant APE/Ref-1 protein (Km=0.55 mM) and for APE/Ref-1 expressed in COS cells. Phosphorylation of APE/Ref-1 did not alter the repair activity of the enzyme, whereas it stimulated its redox capability towards AP-1, thus promoting DNA binding activity of AP-1. SIGNOR-250825 0.498 USP8 protein P40818 UNIPROT RNF41 protein Q9H4P4 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0002181 23750007 t irozzo Ubiquitin-specific protease 8 (USP8), an RNF41-interacting deubiquitylating enzyme (DUB) stabilizes RNF41 and is involved in trafficking of various transmembrane proteins. SIGNOR-259105 0.876 NKX2-5 protein P52952 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003265 19479054 f Using antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased beta-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the beta-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5. SIGNOR-253653 0.352 tRNA(Ala) smallmolecule CHEBI:29170 ChEBI Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI up-regulates quantity precursor of 9606 32314272 t miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). SIGNOR-270451 0.8 MAPK1 protein P28482 UNIPROT TPPP protein O94811 UNIPROT down-regulates activity phosphorylation Ser18 ANRTPPKsPGDPSKD -1 17693641 t miannu Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP. SIGNOR-262929 0.362 PTPRJ protein Q12913 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1365 NVKCVAPyPSLLSSE 9606 BTO:0000150;BTO:0000551 12475979 t gcesareni Hepatocyte growth factor receptor tyrosine kinase met is a substrate of the receptor protein-tyrosine phosphatase dep-1 SIGNOR-96347 0.592 AKT2 protein P31751 UNIPROT ATP7A protein Q04656 UNIPROT up-regulates quantity by stabilization phosphorylation Ser1466 YSRASINsLLSDKRS 10090 29301787 t lperfetto Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus|Immunoprecipitation, in vitro kinase assay, and mass spectrometry analysis reveal that insulin stimulates Akt2 binding to ATP7A to induce phosphorylation at Ser1424/1463/1466 SIGNOR-272270 0.263 NFATC1 protein O95644 UNIPROT PLAUR protein Q03405 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23015147 t Inducible podocyte-specific expression of constitutively active NFATc1 increased podocyte uPAR expression by binding to the Plaur gene promoter (encoding uPAR) in chromatin immunoprecipitation assays. SIGNOR-253336 0.2 GSK3B protein P49841 UNIPROT ARNTL protein O00327 UNIPROT down-regulates phosphorylation Ser17 STISDFMsPGPTDLL 9606 20049328 t lperfetto Gsk3beta phosphorylates bmal1 specifically on ser 17 and thr 21 and primes it for ubiquitylation. In the absence of gsk3beta-mediated phosphorylation, bmal1 becomes stabilized and bmal1 dependent circadian gene expression is dampened. SIGNOR-162786 0.391 seliciclib chemical CHEBI:45307 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206571 0.8 TGFB1 protein P01137 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8142649 f Regulation miannu Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production. SIGNOR-251798 0.2 KDM4C protein Q9H3R0 UNIPROT H2AC4 protein P04908 UNIPROT down-regulates activity demethylation Lys 37 RVHRLLRkGNYSERV 9606 29207681 t miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation SIGNOR-263862 0.2 wortmannin chemical CHEBI:52289 ChEBI MYLK protein Q15746 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207791 0.8 axitinib chemical CHEBI:66910 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 21297102 t gcesareni Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (rcc) after failure of prior treatment with sunitinib or a cytokine. SIGNOR-171860 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR PIK3CG protein P48736 UNIPROT down-regulates activity phosphorylation Thr1024 YLALRHHtNLLIILF 9606 BTO:0002181 21474070 t miannu Anchored PKA activates PDE3B to enhance cAMP degradation and phosphorylates p110γ to inhibit PIP(3) production.  SIGNOR-276321 0.2 FOXO proteinfamily SIGNOR-PF27 SIGNOR FASLG protein P48023 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10102273 f gcesareni Within the nucleus, fkhrl1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the fas ligand gene. SIGNOR-252942 0.2 DNM1 protein Q05193 UNIPROT Synaptic_vesicle_recycling phenotype SIGNOR-PH161 SIGNOR up-regulates 9606 BTO:0000938 10823955 f miannu The GTPase dynamin I is required for synaptic vesicle (SV) endocytosis. Our observation that dynamin binds to the SV protein synaptophysin in a Ca2+-dependent fashion suggested the possibility that a dynamin/synaptophysin complex functions in SV recycling. SIGNOR-264118 0.7 FYN protein P06241 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Tyr453 ASHVDNEySQPPRNS -1 11298344 t Tyrosine-mutated CD5 molecules have been used to show that residues Y429 and Y463 are targeted in vivo by protein tyrosine kinases following cell stimulation with anti-CD3 mAb or pervanadate. This is in agreement with data from direct in vitro kinase assays using purified recombinant Lck and Fyn protein tyrosine kinases. SIGNOR-251151 0.504 MAT2B protein Q9NZL9 UNIPROT GIT1 protein Q9Y2X7 UNIPROT up-regulates activity binding 9606 BTO:0000599 23325601 t miannu We found both MAT2B variants interact with GIT1. MAT2B directly promoted binding of GIT1 and ERK2 to MEK1. MAT2B and GIT1 interact and are overexpressed in most human liver and colon cancer specimens. MAT2B and GIT1 require each other to activate MEK1/ERK and increase growth. SIGNOR-261244 0.407 AVPR1A protein P37288 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256948 0.274 NUP62 protein P37198 UNIPROT SASS6 protein Q6UVJ0 UNIPROT up-regulates activity binding 9606 BTO:0000567 24107630 t Simone Furthermore, we found interactions and co-localization with γ-tubulin and SAS-6. Our results also point to a potential role of Nup62 in targeting gamma-tubulin and SAS-6 to the centrioles. SIGNOR-261256 0.2 IL11 protein P20809 UNIPROT IL11RA protein Q14626 UNIPROT up-regulates binding 9606 10948192 t gcesareni Il-11 has been shown to induce gp130-dependent signaling through the formation of a high affinity complex with the il-11 receptor (il-11r) and gp130 SIGNOR-81102 0.727 PRKCA protein P17252 UNIPROT CTPS1 protein P17812 UNIPROT down-regulates phosphorylation Thr455 MRLGKRRtLFQTKNS 9606 17463002 t llicata These data indicated that protein kinase c phosphorylation at ser(462) stimulates human ctp synthetase 1 activity, whereas phosphorylation at thr(455) inhibits activity. SIGNOR-154621 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR Translational_regulation phenotype SIGNOR-PH202 SIGNOR up-regulates 9606 17360704 f gianni Mutation of rpS6 at Ser(235/236) reveals that phosphorylation of these sites promotes its recruitment to the 7-methylguanosine cap complex, suggesting that Ras/ERK signaling regulates assembly of the translation preinitiation complex. These data demonstrate that RSK provides an mTOR-independent pathway linking the Ras/ERK signaling cascade to the translational machinery. SIGNOR-268527 0.7 MZF1 protein P28698 UNIPROT PRKCA protein P17252 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16297876 f irozzo We demonstrated that both Elk-1 and MZF-1 were highly expressed in human poor differentiated HCC cells and involved in the up-regulation of PKCa, which was essential for cell migration and invasion. Over-expression assay confirmed that the PKCa expression may be modulated by these two factors at the transcriptional level. SIGNOR-256283 0.393 PRKDC protein P78527 UNIPROT WRN protein Q14191 UNIPROT up-regulates phosphorylation Ser440 DTSYVIEsDEDLEME 9606 BTO:0000007 24429382 t llicata Here, we identify ser-440 and -467 in wrn as major phosphorylation sites mediated by dna-pk our findings indicate that phosphorylation of ser-440 and -467 in wrn are important for relocalization of wrn to nucleoli, and that it is required for efficient dsb repair. SIGNOR-203737 0.661 BBS9 protein Q3SYG4 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 t lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome SIGNOR-262555 0.785 8-hydroxy-5-[1-hydroxy-2-(propan-2-ylamino)butyl]-1H-quinolin-2-one chemical CHEBI:91585 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 20590599 t Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  SIGNOR-257857 0.8 SMARCA4 protein P51532 UNIPROT Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270756 0.857 LAMC2 protein Q13753 UNIPROT Laminin-5 complex SIGNOR-C184 SIGNOR form complex binding 9211848 t lperfetto Like the other laminins (3), Ln-5 comprises three disul- fide-bonded subunits: a3, b3, and g2. SIGNOR-253237 0.567 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 17615152 t inferred from 70% family members gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-270023 0.2 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1654 SPSYSPTsPSYSPTS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248807 0.849 WNT11 protein O96014 UNIPROT FZD7 protein O75084 UNIPROT up-regulates activity binding 7227 10862746 t gcesareni Consistent with this, xfz7 biochemically and functionally interacts with xwnt11 SIGNOR-78406 0.7 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCE protein Q02156 UNIPROT up-regulates activity binding 9606 14967450 t PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. SIGNOR-242590 0.8 STAT3 protein P40763 UNIPROT HSPA1A protein P0DMV8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19754877 f miannu Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress. SIGNOR-255240 0.322 DDR1 protein Q08345 UNIPROT CXCL5 protein P42830 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003303 34237033 f miannu  We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs), and subsequent cancer cell invasion and metastasis. SIGNOR-277731 0.2 AKT2 protein P31751 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 11504915 t lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.. Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. SIGNOR-109732 0.542 RNF7 protein Q9UBF6 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR down-regulates 9606 23136067 f miannu We examined potential role of SAG in conferring cellular radioresistance, based upon two pieces of evidence. First, SAG is an antioxidant protein that scavenges ROS. R SIGNOR-271445 0.7 ATM protein Q13315 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Ser498 QIVMAPSsQSQPSGS 9606 15916964 t lperfetto Here, we demonstrate that the protein kinase atm phosphorylates atf2 on serines 490 and 498 following ionizing radiation (ir). dose- and time-dependent phosphorylation of atf2 by atm that results in its rapid colocalization with gamma-h2ax and mrn components into ir-induced foci (irif) SIGNOR-137623 0.583 PIK3CA protein P42336 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity 9606 11160134 f lperfetto Ly294002 or wortmannin were used to determine whether pi 3-kinasedependent pathways mediate ser307 phosphorylation during insulin/igf-1 or TNF-alpha Stimulation. As expected, the pi-3 kinase inhibitors ly294002 or wortmannin inhibited activation of pkb/akt in insulin or igf-1 stimulated 3t3-l1 preadipocytes, but were without effect on erk1/2. these results suggest that elements of the pi 3-kinase cascade mediate insulin/igf-1stimulated phosphorylation of ser307 SIGNOR-104911 0.711 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1799 RRLSNVSsSGSINLL -1 8631898 t miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. SIGNOR-250167 0.428 clotrimazole chemical CHEBI:3764 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9606 9770465 t miannu In addition to rifampicin, other known inducers of human CYP3A4 expression, including nifedipine and clotrimazole, also activated hPAR. SIGNOR-259065 0.8 TBX5 protein Q99593 UNIPROT NPPA protein P01160 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000562 18451335 f miannu TBX5 is expressed, among others, in the embryonic heart and forelimbs.8 In the heart, it regulates transcription of downstream genes such as the atrial natriuretic factor (NPPA) and fibroblast growth factor 10 (FGF10) by the binding to T-box binding elements (TBEs),11 often in combination with the NKX2-5 transcription factor. SIGNOR-255384 0.574 glutaryl-CoA(5-) smallmolecule CHEBI:57378 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271816 0.8 AAK1 protein Q2M2I8 UNIPROT NUMB protein P49757 UNIPROT up-regulates phosphorylation Thr102 LRVVDEKtKDLIVDQ 9606 18657069 t llicata Collectively, these observations demonstrate that numb endocytic activity is regulated by aak1 and that phosphorylation may be a critical step in promoting coated pit maturation. SIGNOR-179606 0.471 ATM protein Q13315 UNIPROT RAD50 protein Q92878 UNIPROT unknown phosphorylation Ser635 KLFDVCGsQDFESDL 9606 17570479 t llicata The ms/ms fragmentation spectra (figure s7) confirmed the phosphorylation of rad50 at the predicted atm substrate site, s635, in agreement with published data SIGNOR-156077 0.806 PRKD1 protein Q15139 UNIPROT PI4KB protein Q9UBF8 UNIPROT up-regulates phosphorylation Ser294 SNLKRTAsNPKVENE 9606 16912074 t The effect has been demonstrated using Q9UBF8-2 gcesareni Binding of 14-3-3 proteins to pi4kiiibeta involved the pkd phosphorylation site ser294, evident from reduced 14-3-3 binding to a s294a pi4kiiibeta mutant. Phospho-specific binding of 14-3-3 proteins to phosphatidylinositol 4-kinase iii beta protects from dephosphorylation and stabilizes lipid kinase activity. SIGNOR-148876 0.414 EP300 protein Q09472 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates acetylation Lys57 TIVRRRAkGAMGLEH 9606 BTO:0000801 20626350 t gcesareni A recent report shows that mkp1 may also be regulated by acetylation. When raw macrophages are stimulated with lps, mkp1 becomes acetylated on lys57 by p300 SIGNOR-166581 0.314 AKT proteinfamily SIGNOR-PF24 SIGNOR CFLAR protein O15519 UNIPROT down-regulates quantity phosphorylation Ser273 LLRDTFTsLGYEVQK 9606 19339247 t gcesareni TNFalpha enhanced FLIP(L) serine phosphorylation, which was increased by activated Akt-1. Serine 273, a putative Akt-1 phosphorylation site in FLIP(L), was critical for the activation-induced reduction of FLIP(L). Thus, these observations document a novel mechanism where by TNFalpha facilitates the reduction of FLIP(L) protein, which is dependent on the phosphatidylinositol 3-kinase/Akt signaling. SIGNOR-245304 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR HK2 protein P52789 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000192 31435020 t K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization SIGNOR-259985 0.2 VCP protein P55072 UNIPROT NPLOC4 protein Q8TAT6 UNIPROT up-regulates activity binding 9606 20442859 t miannu These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes. SIGNOR-252423 0.945 FOXO proteinfamily SIGNOR-PF27 SIGNOR IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260088 0.2 BDKRB1 protein P46663 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257237 0.252 FAM83G protein A6ND36 UNIPROT CD2AP protein Q9Y5K6 UNIPROT up-regulates activity binding 9606 BTO:0001938 29175910 t lperfetto PAWS1 interacts in a dynamic fashion with the actin/cytoskeletal regulator CD2AP at lamellae|Loss of PAWS1 causes severe defects in F-actin organization and distribution as well as in lamellipodial organization, resulting in impaired cell migration. SIGNOR-264768 0.353 TFE3 protein P19532 UNIPROT UVRAG protein Q9P2Y5 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells SIGNOR-276829 0.267 KIFC1 protein Q9BW19 UNIPROT CENPE protein Q02224 UNIPROT up-regulates activity binding 9606 BTO:0000948 33361741 t miannu We found that KIFC1 could directly bind to CENPE in SKOV3 cells (Figure 4C, 4D). SIGNOR-266116 0.554 ESRRA protein P11474 UNIPROT RNF208 protein Q9H0X6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 31862882 t Gianni Furthermore, RNF208 was induced by 17β-estradiol (E2) treatment in an estrogen receptor alpha (ΕRα)-dependent manner SIGNOR-269052 0.2 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269173 0.7 buspirone chemical CHEBI:3223 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258837 0.8 NLRP3 inflammasome complex SIGNOR-C225 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256381 0.2 ABL1 protein P00519 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Tyr88 KGSLPEFyYRPPRPP -1 17254966 t Lyn and Abl phosphorylate Y88 of p27 in vitro. phosphorylation of Y88 in p27 impaired its ability to inhibit the bound kinase complex SIGNOR-251426 0.578 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser474 HFPQFSYsASGRE 9606 18160256 t Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248609 0.473 SLC4A1 protein P02730 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 BTO:0000424 33187473 t lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] SIGNOR-266036 0.385 Caspase 3 complex complex SIGNOR-C221 SIGNOR CASP9 protein P55211 UNIPROT up-regulates activity cleavage 9606 14585074 t lperfetto Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation SIGNOR-256453 0.623 BMP2 protein P12643 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 26330344 t fferrentino BMP interacts with specific receptors on the cell surface, BMP receptor types 1 and 2 (BMPr1 and BMPr2). SIGNOR-253547 0.927 Ethylketocyclazocine chemical CHEBI:4901 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258782 0.8 SIRT6 protein Q8N6T7 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR up-regulates activity binding 9606 BTO:0000007 25083875 t miannu SIRT6 is involved in circadian control of gene expression and metabolism. SIRT6 Interacts with CLOCK:BMAL1 and Controls Their Chromatin Recruitment. SIRT6 physically interacts with CLOCK and BMAL1, individually or together, as shown by coimmunoprecipitation (co-IP) (Figures 4A and 4B). SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1. SIGNOR-268157 0.376 MCU protein Q8NE86 UNIPROT MCU_MICUB_variant complex SIGNOR-C499 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270862 0.695 FLT4 protein P35916 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). SIGNOR-276180 0.2 PRKCH protein P24723 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser576 CAEMREDsARVYENV 9606 11781100 t lperfetto  In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta SIGNOR-249137 0.313 SH2B1 protein Q9NRF2 UNIPROT BLNK protein Q8WV28 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000776 32323266 t scontino SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK. SIGNOR-268446 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation 9606 14988395 t inferred from 70% family members lperfetto Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity. SIGNOR-270141 0.2 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR CDT1 protein Q9H211 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 14578910 t miannu We show that radiation-mediated CDT1 proteolysis is independent of ATM and CHK2 and can occur in G1-phase cells. Loss of the COP9-signalosome (CSN) or CUL4-ROC1 complexes completely suppresses CDT1 proteolysis. CDT1 is specifically polyubiquitinated by CUL4 complexes and the interaction between CDT1 and CUL4 is regulated in part by gamma-irradiation. Our study reveals an evolutionarily conserved and uncharacterized G1 checkpoint that induces CDT1 proteolysis by the CUL4-ROC1 ubiquitin E3 ligase and CSN complexes in response to DNA damage. SIGNOR-272810 0.531 TP63 protein Q9H3D4 UNIPROT PLEC protein Q15149 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 28595999 t lperfetto Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by a marked decrease in expression of several nuclear envelope-associated components (Lamin B1, Lamin A/C, Sun1, Nesprin-3, Plectin) compared with controls. Furthermore, chromatin immunoprecipitation-quantitative PCR assay showed enrichment of p63 on Sun1, Syne3, and Plec promoters, suggesting them as p63 targets. SIGNOR-263279 0.2 androsta-1,4,6-triene-3,17-dione chemical CHEBI:131190 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates activity chemical inhibition -1 7083195 t miannu Recently, it was discovered that 4-hydroxy-4-androstene-3,17-dione, 4-androstene-3,6,17-trione, and 1,4,6-androstatriene-3,17-dione, compounds previously reported to be competitive inhibitors of aromatase, cause a time-dependent loss of aromatase activity in human placental microsomes. SIGNOR-258408 0.8 CDK5 protein Q00535 UNIPROT AMFR protein Q9UKV5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser516 SIRPALNsPVERPSS 9606 BTO:0000007 28528366 t miannu We found that GP78 expression is decreased in MPTP-based cellular and animal PD models, and CDK5 directly phosphorylated GP78 at Ser516, which promoted the ubiquitination and degradation of GP78.  SIGNOR-277356 0.25 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267426 0.8 XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates activity binding 9606 10548111 t amattioni The linker region located adjacent to the bir2 domain also participates in the binding of xiap to the effector caspases (-3 and -7). SIGNOR-71954 0.938 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120200 0.321 INS protein P01308 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity 9606 10358076 f lperfetto Insulin disrupts irs-dependent transactivation by fkhr, and phosphorylation of ser-256 by pkb is necessary and sufficient to mediate this effect. SIGNOR-68155 0.492 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation Tyr310 YVGVWKKySLTVAVK -1 34144039 t miannu  PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. SIGNOR-277300 0.308 4,4'-sulfonyldiphenol chemical CHEBI:34372 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 31995776 t miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . SIGNOR-268733 0.8 BPTF protein Q12830 UNIPROT HNuRF complex SIGNOR-C448 SIGNOR form complex binding 9606 BTO:0000007 14609955 t miannu hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays. SIGNOR-268817 0.689 HOXD3 protein P31249 UNIPROT ITGA5 protein P08648 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14610084 t Luana The homeobox transcription factor Hox D3 promotes integrin alpha5beta1 expression and function during angiogenesis. SIGNOR-261649 0.253 MAPK8 protein P45983 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation Ser82 SIMQQCDsPHVVKYY 9606 20028971 t llicata C-jun n-terminal kinase enhances mst1-mediated pro-apoptotic signaling through phosphorylation at serine 82. SIGNOR-162327 0.271 TLR2 protein O60603 UNIPROT TIRAP protein P58753 UNIPROT up-regulates activity binding 10090 22664090 t scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266745 0.716 4-[6-[4-(methoxycarbonylamino)phenyl]-4-(4-morpholinyl)-1-pyrazolo[3,4-d]pyrimidinyl]-1-piperidinecarboxylic acid methyl ester chemical CHEBI:94742 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck;ATP-competitive inhibitor mTOR gcesareni SIGNOR-207809 0.8 BGJ-398 chemical CHEBI:63451 ChEBI FGFR3 protein P22607 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190269 0.8 androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity precursor of 9606 BTO:0000975 27702664 t lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively SIGNOR-268668 0.8 MAP3K20 protein Q9NYL2 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 11416147 t gcesareni We show here that members of the mixed-lineage kinase (MLK) family (including MLK1, MLK2, MLK3, and dual leucine zipper kinase [DLK]) are expressed in neuronal cells and are likely to act between Rac1/Cdc42 and MKK4 and -7 in death signaling. SIGNOR-243348 0.2 SAGA complex complex SIGNOR-C465 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269630 0.2 STAT1 protein P42224 UNIPROT IRF2 protein P14316 UNIPROT up-regulates activity binding 9606 15778351 t miannu We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-gamma target cells tested. Interaction of IRF-2 and STAT1 on the promoter depends on the DNA-binding domain of IRF-2. SIGNOR-254532 0.563 MAPK9 protein P45984 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 15071501 f JNK-mediated phosphorylation of 14-3-3 at Ser184 reduces its affinity for Bax. gcesareni Demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria;these results strongly indicate that jnk regulates the activity of bax by phosphorylating 14-3-3 proteins. SIGNOR-124023 0.302 spiperone chemical CHEBI:9233 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258692 0.8 PHLPP1 protein O60346 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001544 19261608 t The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. SIGNOR-248327 0.751 GRK2 protein P25098 UNIPROT RPLP2 protein P05387 UNIPROT up-regulates phosphorylation Ser105 KKEESEEsDDDMGFG 9606 12379128 t gcesareni The phosphorylation sites in grk2-phosphorylated p2 are identified (s102 and s105) and are identical to the sites known to regulate p2 activity. SIGNOR-94258 0.2 Nalorphine chemical CHEBI:7458 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9262330 t miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. SIGNOR-258664 0.8 CBP/p300 complex SIGNOR-C6 SIGNOR ALOX15 protein P16050 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 12517954 f lperfetto IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300. SIGNOR-254100 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR IDH2 protein P48735 UNIPROT down-regulates quantity by destabilization phosphorylation Thr197 GTFKMVFtPKDGSGV 34929314 t lperfetto During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome SIGNOR-267622 0.268 PINK1 protein Q9BXM7 UNIPROT PRKN protein O60260 UNIPROT up-regulates phosphorylation Ser65 NCDLDQQsIVHIVQR 9606 22724072 t llicata We show that human pink1 is specifically activated by mitochondrial membrane potential (??m) depolarization, enabling it to phosphorylate parkin at ser(65). We further show that phosphorylation of parkin at ser(65) leads to marked activation of its e3 ligase activity that is prevented by mutation of ser(65) or inactivation of pink1. SIGNOR-197976 0.2 NFKB1 protein P19838 UNIPROT NPPB protein P16860 UNIPROT unknown transcriptional regulation 15837525 f In comparison to the ANF gene, less is known about BNP promoter consensus elements that regulate gene expression by mechanical or neurohumoral agonists. A number of cis-acting elements for GATA, Nkx2.5, NF-kappaB and TEF transcription factors have recently been identified within the BNP promoter that regulate BNP expression in response to specific agonists. This review focuses on the information available regarding cis-acting determinants responsible for inducible BNP transcription. SIGNOR-253648 0.2 CDK2 protein P24941 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 10090 SIGNOR-C16 11278991 t lperfetto We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication. Upon phosphorylation by CDK2-cyclin E, NPM/B23 dissociates from centrosomes, which is a prerequisite step for centrosomes to initiate duplication. SIGNOR-235725 0.578 AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT unknown phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 10910062 t lperfetto AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a repressor domain that negatively regulates the catalytic activity of mTOR.¬† SIGNOR-244311 0.2 EEF1A1 protein P68104 UNIPROT Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269519 0.8 SRPK1 protein Q96SB4 UNIPROT RBM8A protein Q9Y5S9 UNIPROT down-regulates phosphorylation Ser166 RRGGRRRsRSPDRRR 9606 16100109 t gcesareni We demonstrate that y14 is phosphorylated at its repeated arginine/serine (rs) dipeptides, likely by sr protein-specific kinases. Phosphorylation of y14 abolished its interaction with ejc components as well as factors that function downstream of the ejc. SIGNOR-139551 0.264 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 BTO:0000763;BTO:0000149 10197981 t llicata Oncogenically activated ras inhibits the tgfbeta-induced nuclear accumulation of smad2 and smad3 and smad-dependent transcription. Ras acting via erk map kinases causes phosphorylation of smad2 and smad3 at specific sites in the region linking the dna-binding domain and the transcriptional activation domain. SIGNOR-66742 0.736 SNTB1 protein Q13884 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255992 0.497 NUP62 protein P37198 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262079 0.696 TRIM59 protein Q8IWR1 UNIPROT MACROH2A1 protein O75367 UNIPROT down-regulates quantity by destabilization polyubiquitination 31488827 t miannu Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity.  SIGNOR-272931 0.2 adenosine smallmolecule CHEBI:16335 ChEBI ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity precursor of 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5‚Ä≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-267836 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization phosphorylation Thr92 EVPDVTAtPARLLFF 9606 18676833 t gcesareni Mcl-1 is phosphorylated at two sites in mitosis, ser64 and thr92. Phosphorylation of thr92 by cyclin-dependent kinase 1 (cdk1)-cyclin b1 initiates degradation of mcl-1 in cells arrested in mitosis by microtubule poisons. SIGNOR-216900 0.43 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252357 0.783 NBR1 protein Q14596 UNIPROT GABARAP protein O95166 UNIPROT up-regulates binding 9606 BTO:0000007 19250911 t gcesareni We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family SIGNOR-184261 0.751 CSNK2A1 protein P68400 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates phosphorylation Ser467 IDLTIDSsSDEEEEE 9606 19217413 t llicata Ck2 phosphorylates serine residues adjacent to the sim of pias1 these findings show that the phosphosim module mediates binding to free sumo and sumo conjugates in a phosphorylation-dependent mode, with ck2 being the critical kinase involvedin this process. SIGNOR-184043 0.338 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269338 0.719 axitinib chemical CHEBI:66910 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 21297102 t gcesareni Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (rcc) after failure of prior treatment with sunitinib or a cytokine. SIGNOR-171863 0.8 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9606 17132853 t miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. SIGNOR-256196 0.8 CTSL protein P07711 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Gly58 RYLYQWLgAPVPYPD -1 9076588 t miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. SIGNOR-256321 0.2 DICER1 protein Q9UPY3 UNIPROT RISC(DICER1/AGO2/TARBP2) complex SIGNOR-C32 SIGNOR form complex binding 9606 16142218 t lperfetto Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si_ or mi_riscs in mammalian cells, but it may also facilitate the cleavage of pre_mirnas by dicer. SIGNOR-140223 0.939 SMURF2 protein Q9HAU4 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 11158580 t miannu Here, we report the identification of Smurf2, a new member of the Hect family of E3 ubiquitin ligases. Smurf2 selectively interacts with receptor-regulated Smads and preferentially targets Smad1 for ubiquitination and proteasome-mediated degradation. At higher expression levels, Smurf2 also decreases the protein levels of Smad2, but not Smad3.  SIGNOR-272936 0.714 FLI1 protein Q01543 UNIPROT HOXA10 protein P31260 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001549 17688409 f miannu Transcription factors GATA-1 and Fli-1 regulate human HOXA10 expression in megakaryocytic cells. Mutation of the GATA-1 and the Ets-1 motifs amplified the expression of HOXA10 in HEL and K562 cells, confirming the importance of these cis-acting elements in regulating HOXA10 expression in megakaryocytic cells. Chromatin immunoprecipitation (ChIP) and chloramphenicol acetyl transferase (CAT) assays confirm that HOXA11 binds to the putative binding site, resulting in repression of HOXA10 expression. SIGNOR-254471 0.2 EZH2 protein Q15910 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 23239736 t miannu This study demonstrates that phosphorylation of EZH2 at Ser21, mediated directly or indirectly by the PI3K-Akt pathway, can switch its function from a Polycomb repressor to a transcriptional coactivator of AR (and potentially other factors). SIGNOR-251542 0.556 PBRM1 protein Q86U86 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 18339845 f miannu Endogenous wild-type baf180 bound to the p21 promoter and was required for proper p21 expression and g(1) arrest after transforming growth factor-beta and gamma-radiation treatment. SIGNOR-178022 0.265 UCHL3 protein P15374 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity deubiquitination Lys57 EAVAYAPkKELINIK 27941124 t lperfetto Here we report that ubiquitination of RAD51 hinders RAD51-BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51-BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. | UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2.|Our results suggested that three lysine sites (56, 57, and 63) on RAD51 that are close to E59 are deubiquitinated by UCHL3. SIGNOR-275907 0.331 PHF1 protein O43189 UNIPROT HOXA10 protein P31260 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20565746 t miannu These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression. SIGNOR-260071 0.289 SLBP protein Q14493 UNIPROT H2BC20P protein Q6DN03 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265382 0.2 lysophosphatidic acid smallmolecule CHEBI:132742 ChEBI LPAR4 protein Q99677 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257531 0.8 DLG5 protein Q8TDM6 UNIPROT Scribble_complex_DLG5-LLGL2_variant complex SIGNOR-C506 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270893 0.319 AMPK complex SIGNOR-C15 SIGNOR SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser122 YRNTGSIsGPKVNRP 10090 BTO:0003946 17341212 t miannu In the present study, we demonstrate that the metabolic sensing kinase AMPK (AMP-activated protein kinase) phosphorylates NKCC2 on Ser126 in vitro. Activation of AMPK in the MMDD1 (mouse macula densa-derived 1) cell line resulted in an increase in Ser126 phosphorylation in situ, suggesting that AMPK may phosphorylate NKCC2 in vivo. The functional significance of Ser126 phosphorylation was examined by mutating the serine residue to an alanine residue resulting in a marked reduction in co-transporter activity when exogenously expressed in Xenopus laevis oocytes under isotonic conditions. SIGNOR-263103 0.2 SYN1 protein P17600 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR down-regulates 9606 BTO:0000938 33809712 f miannu Synapsins are a family of peripheral proteins that bind to the SV membrane. Synapsins Maintain the SV Reserve Pool. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet. SIGNOR-264105 0.7 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT up-regulates activity phosphorylation Ser2251 ASPLASSerPVRKNL -1 26051540 t irozzo Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment. SIGNOR-259119 0.452 RUVBL1 protein Q9Y265 UNIPROT R2TP core co-chaperone complex SIGNOR-C515 SIGNOR form complex binding 9606 29662061 t miannu  Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90.  SIGNOR-270928 0.805 VAV2 protein P52735 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260583 0.752 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Thr501 QMDSGYNtQNCGSNI 9606 18378770 t gcesareni Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp). SIGNOR-178154 0.779 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PARP1 protein P09874 UNIPROT up-regulates phosphorylation Thr373 AATPPPStASAPAAV 9606 BTO:0000938 BTO:0000142 16627622 t lperfetto Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation. SIGNOR-244673 0.2 LAMTOR3 protein Q9UHA4 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR form complex binding 9606 20381137 t lperfetto Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant SIGNOR-164775 0.929 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 9606 22703233 t lperfetto TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. SIGNOR-249548 0.84 PHKG1 protein Q16816 UNIPROT PYGL protein P06737 UNIPROT up-regulates activity phosphorylation Ser15 QEKRRQIsIRGIVGV 9606 BTO:0002049 22225877 t It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15 SIGNOR-267399 0.532 HTR1E protein P28566 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256984 0.363 tandutinib chemical CHEBI:90237 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258296 0.8 PRKCD protein Q05655 UNIPROT HAX1 protein O00165 UNIPROT down-regulates quantity by destabilization phosphorylation Ser210 QPKSYFKsISVTKIT 10090 BTO:0002572 25419709 t lperfetto FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cdelta (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1.|Accordingly, PRKCD-induced phosphorylation of Hax-1 at Ser210 and Fbxo25 at Ser178 was associated with decreased expression of Hax-1 in control cells, SIGNOR-275562 0.2 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser807 PGGNIYIsPLKSPYK 9606 1756735 t lperfetto The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2. SIGNOR-21552 0.675 GSK3B protein P49841 UNIPROT MNX1 protein P50219 UNIPROT down-regulates phosphorylation Ser79 RLRAESPsPPRLLAA 9606 24425879 t miannu Here we show that gsk-3_ inactivates the proapoptotic activity of hlxb9 by phosphorylating hlxb9 at ser-78/ser-80 (phlxb9). SIGNOR-203661 0.3 HECTD3 protein Q5T447 UNIPROT TRIOBP protein Q9H2D6 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18194665 t miannu Here, we identify a novel Tara-binding protein HECTD3, a putative member of HECT E3 ubiquitin ligases. HECTD3 directly binds Tara in vitro and forms a complex with Tara in vivo. Overexpression of HECTD3 enhances the ubiquitination of Tara in vivo and promotes the turnover of Tara, whereas depletion of HECTD3 by small interfering RNA decreases Tara degradation. SIGNOR-271770 0.449 GCG protein P01275 UNIPROT GCGR protein P47871 UNIPROT up-regulates binding 9606 12529935 t fspada Mutation of a highly conserved d64 residue in the n-terminal portion of the rat glucagon receptor completely eliminates glucagon binding. This residue corresponds to a mutated asp residue at amino acid 60 in the growth hormone releasing hormone receptor that gives rise to the little mouse phenotype (lin et al.1993). Antisera directed against amino acid sequences 126_137 of the n-terminal region, and agai residues 206_219 of the first extracellular loop block [125i]-glucagon binding and interfere with glucagon-induced adenylyl cyclase generation in rat liver membranes. SIGNOR-97338 0.768 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1172 ISLDNPDyQQDFFPK 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236467 0.2 sorafenib tosylate chemical CHEBI:50928 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. SIGNOR-259225 0.8 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT up-regulates sumoylation Lys160 EAHQWFLkHEARPLA 9534 9756909 t lperfetto We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation. SIGNOR-261786 0.771 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT up-regulates quantity by stabilization phosphorylation Thr228 GPSSSLNtPGSFRRG 9606 BTO:0000007 16682949 t done miannu Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. SIGNOR-274085 0.525 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273035 0.556 adenosine smallmolecule CHEBI:16335 ChEBI ADORA1 protein P30542 UNIPROT up-regulates activity binding -1 14662005 t Luana Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A1, A2A, A2B and A3. SIGNOR-268419 0.8 diisononyl phthalate chemical CHEBI:35459 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR). SIGNOR-268775 0.8 PIK3C3 protein Q8NEB9 UNIPROT Vps34 Complex I complex SIGNOR-C242 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260316 0.916 P2RY1 protein P47900 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257442 0.2 TP53 protein P04637 UNIPROT TNFRSF10B protein O14763 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15964798 f gcesareni Reduction in p53 expression also blocks p65 binding to the intronic region of the dr5 gene, indicating cooperation between p53 and p65 in dr5 expression. (articolo-abstract) SIGNOR-138293 0.634 USP13 protein Q92995 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0006155 27923907 t done miannu  In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation. SIGNOR-274124 0.36 KDM6A protein O15550 UNIPROT HOXA13 protein P31271 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260022 0.289 PRKACA protein P17612 UNIPROT NEFL protein P07196 UNIPROT down-regulates activity phosphorylation 9606 8019002 t miannu Phosphorylation of neurofilament-L protein (NF-L) by the catalytic subunit of cAMP-dependent protein kinase (A-kinase) inhibits the reassembly of NF-L and disassembles filamentous NF-L. SIGNOR-252401 0.2 CYP11B2 protein P19099 UNIPROT 18-hydroxycorticosterone smallmolecule CHEBI:16485 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268684 0.8 PTPRJ protein Q12913 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by stabilization dephosphorylation Tyr1069 EDSFLQRySSDPTGA 9606 BTO:0000567 19836242 t We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex|By employing commercially available antibodies, which are supposed to recognize specific tyrosine phosphorylation sites of EGFR, we found that depletion of endogenous DEP-1 nonselectively increased receptor phosphorylation, affecting all three sites we analyzed (tyrosines 1045, 1068, and 1173 SIGNOR-248697 0.504 MAP3K7 protein O43318 UNIPROT IKBKG protein Q9Y6K9 UNIPROT up-regulates activity binding 9606 SIGNOR-C14 20038579 t lperfetto This result suggests that ikkgamma/nemo binds to the polyubiquitinated tak1. SIGNOR-162634 0.808 MAPK11 protein Q15759 UNIPROT MAPK11 protein Q15759 UNIPROT down-regulates activity phosphorylation Ser261 HARTYIQsLPPMPQK -1 26976637 t miannu P38β Mitogen-Activated Protein Kinase Modulates Its Own Basal Activity by Autophosphorylation of the Activating Residue Thr180 and the Inhibitory Residues Thr241 and Ser261 SIGNOR-277214 0.2 MAPK3 protein P27361 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser50 SPTFRSDsPVPTAPT 9606 BTO:0000007 33217317 t miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. SIGNOR-265945 0.275 PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 12167717 t lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-244429 0.81 PRKAA1 protein Q13131 UNIPROT HAT1 protein O14929 UNIPROT up-regulates activity phosphorylation Ser190 MWFIETAsFIDVDDE -1 28143904 t lperfetto Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314 SIGNOR-264782 0.2 CXCL12 protein P48061 UNIPROT ACKR3 protein P25106 UNIPROT up-regulates binding 9606 BTO:0000782 16107333 t gcesareni Here we show that cxcl12, the only known natural ligand for cxcr4, binds to and signals through rdc1. SIGNOR-139709 0.709 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr72 SDDFDSDyENPDEHS 9606 BTO:0000776 12456653 t llicata The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex. SIGNOR-96044 0.798 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 15048722 f We demonstrate that NF-kappa B binds to the IL-4 promoter in vivo upon T cell activation. Inhibition of NF-kappa B nuclear translocation in living cells blocked binding of NF-kappa B to the IL-4 promoter. The data provide first evidence that NF-kappa B is directly involved in IL-4 transcription SIGNOR-254497 0.417 KAT2A protein Q92830 UNIPROT H3-2 protein Q5TEC6 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269607 0.2 HSPA1A protein P0DMV8 UNIPROT PACRG protein Q96M98 UNIPROT up-regulates quantity by stabilization binding -1 12150907 t miannu Our in vitro data suggest that CHIP competes with Hsp70 in binding to Parkin, probably via suppression of the ATPase activity of Hsc/Hsp70 (Figure 4E).In fact, it acts as an inhibitory factor that suppresses the ubiquitination of Pael-R mediated by Parkin in vitro, and Hsp70 enhances the efficiency of folding of overexpressed Pael-R in vivo. SIGNOR-272890 0.2 HDAC1 protein Q13547 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 11994312 f To define a mechanism for repression of AR function, we demonstrate that AR activity is specifically down-regulated by the histone deacetylase activity of HDAC1. Furthermore, using both mammalian two-hybrid and immunoprecipitation experiments, we show that AR and HDAC1 interact, suggestive of a direct role for down-regulation of AR activity by HDAC1. In chromatin immunoprecipitation assays, we provide evidence that AR, Tip60, and HDAC1 form a trimeric complex upon the endogenous AR-responsive PSA promoter, suggesting that acetylation and deacetylation of the AR is an important mechanism for regulating transcriptional activity. SIGNOR-253666 0.302 PRKCD protein Q05655 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser738 ARIIGEKsFRRSVVG 9606 15024053 t llicata Here we show that activation of pkd in response to oxidative stress requires two sequential signaling events, i.e., phosphorylation of tyr463 by abl, which in turn promotes a second step, phosphorylation of the pkd activation loop (ser738/ser742). We show that this is mediated by pkcdelta (protein kinase cdelta) SIGNOR-123449 0.273 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser124 PALKRSHsDSLDHDI 9606 12676583 t Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. SIGNOR-99721 0.837 ROR1 protein Q01973 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation 9606 BTO:0000551 22439932 t miannu Ror1 binds to and phosphorylates c-src / ror1 kinase-dependent c-src activation SIGNOR-196751 0.324 CIITA protein P33076 UNIPROT S100A4 protein P26447 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17143014 f miannu IFN-gamma represses S100A4 promoter activity through induction of the class II transactivator (CIITA). SIGNOR-253776 0.329 (2S)-N1-[5-(2-tert-butyl-4-thiazolyl)-4-methyl-2-thiazolyl]pyrrolidine-1,2-dicarboxamide chemical CHEBI:91449 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-204490 0.8 MAPK3 protein P27361 UNIPROT EPS8 protein Q12929 UNIPROT down-regulates activity phosphorylation Ser625 ADTPPAPsPPPTPAP -1 19564905 t miannu We further show that the actin barbed-end capping activity of Eps8 is inhibited by brain-derived neurotrophic factor (BDNF) treatment through MAPK-dependent phosphorylation of Eps8 residues S624 and T628. Additionally, an Eps8 mutant, impaired in the MAPK target sites (S624A/T628A), displays increased association to actin-rich structures, is resistant to BDNF-mediated release from microfilaments, and inhibits BDNF-induced filopodia. The opposite is observed for a phosphomimetic Eps8 (S624E/T628E) mutant. Thus, collectively, our data identify Eps8 as a critical capping protein in the regulation of axonal filopodia and delineate a molecular pathway by which BDNF, through MAPK-dependent phosphorylation of Eps8, stimulates axonal filopodia formation, a process with crucial impacts on neuronal development and synapse formation. SIGNOR-263058 0.329 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR BAD protein Q92934 UNIPROT down-regulates binding 9606 8929531 t gcesareni 14-3-3 blocks bad activity by promoting ser-155 phosphorylation, which induces the dissociation of bad and bcl-xl. in the presence of survival factor il-3, cells phosphorylated bad on two serine residues embedded in 14-3-3 consensus binding sites. Only the nonphosphorylated bad heterodimerized with bcl-x(l) at membrane sites to promote cell death. SIGNOR-44855 0.2 SRC protein P12931 UNIPROT DNM1 protein Q05193 UNIPROT up-regulates activity phosphorylation Tyr597 NTEQRNVyKDYRQLE 9534 BTO:0004055 12011079 t lperfetto Endocytosis of ligand-activated receptors requires dynamin-mediated GTP hydrolysis, which is regulated by dynamin self-assembly. Here, we demonstrate that phosphorylation of dynamin I by c-Src induces its self-assembly and increases its GTPase activity. Electron microscopic analyses reveal that tyrosine-phosphorylated dynamin I spontaneously self-assembles into large stacks of rings. Tyrosine 597 was identified as being phosphorylated both in vitro and in cultured cells following epidermal growth factor receptor stimulation. SIGNOR-247129 0.621 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser280 RSPSPQPsSHVAPQD 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248691 0.613 Immunoglobulin kappa light chain protein P0DOX7 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR form complex binding 9606 BTO:0000776 32323265 t scontino An antibody is composed of two identical HCs and two identical LCs (either kappa or lambda ), consisting of variable (V) and constant (C) regions linked by disulfide bonds. Pro- genitor B cells rearrange their Ig heavy chain (HC) genes to differentiate into precursor B (pre- B) cells that express μ HCs. SIGNOR-268186 0.2 2-methylpropanethioic acid S-[2-[[[1-(2-ethylbutyl)cyclohexyl]-oxomethyl]amino]phenyl] ester chemical CHEBI:95001 ChEBI CETP protein P11597 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191265 0.8 Prolactin-releasing peptide-20 smallmolecule CHEBI:80301 ChEBI PRLHR protein P49683 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257566 0.8 NR3C2 protein P08235 UNIPROT ATP1B1 protein P05026 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000318 9694812 f miannu Together these data indicate that the 21-base pair sequence represents a true MRE/GRE and that optimal activation of the human Na/K-ATPase beta1 promoter is controlled by mineralocorticoid and glucocorticoid hormones. It appears that an interaction of MR with GR on the beta1 promoter effectively down-regulates transcription. SIGNOR-254865 0.239 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t gcesareni FOXO4 transcription factor, also referred to AFX, contains three putative phosphorylation motif sites for protein kinase B (PKB), Thr32, Ser197, and Ser262, and it is proposed that phosphorylated FOXO4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression.[...]These results indicate that phosphorylation at Thr32 and Ser197 is indispensable, whereas that at Ser262 is not critical, for regulation of the nuclear localization and transcriptional activity of FOXO4 SIGNOR-252870 0.756 PRKACA protein P17612 UNIPROT RYR1 protein P21817 UNIPROT up-regulates activity phosphorylation Ser2843 KKKTRKIsQSAQTYD -1 14532276 t miannu PKA-mediated hyperphosphorylation of a conserved serine, Ser-2843 in skeletal RyR and Ser-2809 in cardiac RyR, results in an aberrant SR function during heart failure. hyperphosphorylated RyRs are leaky and therefore lead to a reduced SR Ca2+ load and impaired contractile function in heart failure SIGNOR-250078 0.331 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser175 SPASSGSsASFISDT 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248513 0.387 5-carboxamidotryptamine chemical CHEBI:48292 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258845 0.8 DVL2 protein O14641 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates binding 9606 23151663 t gcesareni In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl-associated activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. SIGNOR-199500 0.628 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser706 ARIIGEKsFRRSVVG 9606 12058027 t gcesareni Furthermore, we show that pkd2 can be activated by classical and novel members of the protein kinase c (pkc) family such as pkc alpha, pkc epsilon, and pkc eta. These pkcs are activated by gastrin in ags-b cells. Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. SIGNOR-89411 0.2 FGF2 protein P09038 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 11390973 t lperfetto we determined the crystal structures of these two FGFR2 mutants in complex with fibroblast growth factor 2 (FGF2).These structures demonstrate that both mutations introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity. SIGNOR-86121 0.894 GSK3B protein P49841 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates phosphorylation 9606 18042454 t miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. SIGNOR-159476 0.2 LCK protein P06239 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates phosphorylation Tyr342 NMRPPFTyATLIRWA 9606 24155921 t llicata Lck phosphorylated tyr-342 of foxp3 by immunoprecipitation and in vitro kinase assay, and the replacement of tyr-342 with phenylalanine (y342f) abolished the ability to suppress mmp9 expression. SIGNOR-203089 0.41 Guanfacine chemical CHEBI:5558 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258919 0.8 NDUFS3 protein O75489 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. SIGNOR-262177 0.864 PRKCA protein P17252 UNIPROT AQP1 protein P29972 UNIPROT up-regulates phosphorylation Thr239 APRSSDLtDRVKVWT 9606 BTO:0000671 17522053 t llicata Activation of protein kinase c (pkc) by 1-oleoyl-2-acetyl-sn-glycerol (oag) induced a marked increase of aqp1-dependent water permeability. This regulation was abolished in mutated aqp1 channels lacking both consensus pkc phosphorylation sites thr(157) and thr(239) (termed aqp1 deltapkc). SIGNOR-155106 0.2 DBP protein Q10586 UNIPROT CYP3A4 protein P08684 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 18004209 f miannu The oscillation in the expression of the CYP3A4 gene seemed to be the underlying cause of the rhythmic change in its metabolic activity. Luciferase reporter gene analysis and electrophoretic mobility shift assay revealed that the circadian transcriptional factor, D-site-binding protein (DBP), activated the transcription of the CYP3A4 gene by binding to the DNA sequence near the upstream of the transcriptional start site. The transactivation of the CYP3A4 gene by DBP was repressed by the E4 promoter-binding protein-4 (E4BP4), a negative component of the circadian clock. SIGNOR-253835 0.2 WWTR1 protein Q9GZV5 UNIPROT ASNS protein P08243 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001615 22470139 f miannu Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation. SIGNOR-255608 0.2 GSK3B protein P49841 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Thr514 PATPKYAtPAPSAKS 9606 BTO:0000938 16611631 t lperfetto Using in vitro kinase assays and pharmacological inhibition of gsk3 as described above for crmp2 and crmp4, it was found that thr509 (and presumably ser518 and thr514) of human crmp1 is phosphorylated by gsk3, following priming of ser522 by cdk5 SIGNOR-145999 0.448 SIRT7 protein Q9NRC8 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity deacetylation Lys37 APATGGVkKPHRYRP 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275880 0.2 MAPK1 protein P28482 UNIPROT CIITA protein P33076 UNIPROT down-regulates phosphorylation Ser288 PDRPGSTsPFAPSAT 9606 15210796 t gcesareni Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation. SIGNOR-126254 0.442 RBPJ protein Q06330 UNIPROT MAML2 protein Q8IZL2 UNIPROT up-regulates binding 9606 21873209 t gcesareni When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects SIGNOR-176197 0.866 PITX2 protein Q99697 UNIPROT GNRH1 protein P01148 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004467 19106114 f miannu Knockdown of PITX1 or PITX2 isoforms impaired GNRH1 induction, and endogenous PITX1 bound to the candidate PITX binding site on the LHB promoter. SIGNOR-254922 0.264 SMURF2 protein Q9HAU4 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 11163210 t miannu Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.  SIGNOR-272938 0.698 MAPK3 protein P27361 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation Thr614 AFRLEPLtPRGVLTV 9606 BTO:0000150 17311928 t llicata Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1 SIGNOR-153391 0.505 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1644 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273042 0.556 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser726 IDPASPQsPESVDLV 9606 18701649 t gcesareni Such results suggest that during apoptosis, oxidative stress could activate p38 mapk, phosphorylating nhe1 at s726 and s729. SIGNOR-180044 0.553 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser670 SKVRGPVsGSPDSMN 9606 BTO:0000007 10195894 t Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. SIGNOR-251274 0.2 VRK1 protein Q99986 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr2 tTSQKHRD 9606 16495336 t lperfetto Herein, we demonstrate that b1, vrk1, and vrk2 efficiently phosphorylate the extreme n' terminus of the baf protein. We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain SIGNOR-144787 0.873 SIRT6 protein Q8N6T7 UNIPROT ME1 protein P48163 UNIPROT down-regulates activity deacetylation Lys337 KIWLVDSkGLIVKGR 31735643 t lperfetto PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation. SIGNOR-275572 0.252 PLK1 protein P53350 UNIPROT ANAPC1 protein Q9H1A4 UNIPROT up-regulates phosphorylation Ser355 AALSRAHsPALGVHS 9606 14657031 t gcesareni Our analysis revealed an unexpected and unprecedented complexity of mitotic phosphorylation sites and suggests that other kinases than cdk1 and plk1 also contribute to apc phosphorylation. SIGNOR-119881 0.504 PIM proteinfamily SIGNOR-PF34 SIGNOR MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr95 DKTQLNPtSLQKLFR 9606 15319445 t gcesareni Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1. SIGNOR-259430 0.2 ATF6 protein P18850 UNIPROT ATF6 protein P18850 UNIPROT up-regulates activity binding -1 12805554 t miannu E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins SIGNOR-224202 0.2 TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 14585074 t lperfetto Tradd mediates recruitment of the traf2 adaptor protein SIGNOR-118770 0.866 RAB38 protein P57729 UNIPROT Neuronal AP-3 complex SIGNOR-C445 SIGNOR up-regulates activity relocalization 9606 23247405 t miannu Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. SIGNOR-268526 0.282 CSK protein P41240 UNIPROT FGR protein P09769 UNIPROT down-regulates activity phosphorylation Tyr523 FTSAEPQyQPGDQT -1 7515063 t llicata CSK catalyzed phosphorylation affects Tyr-511 of c-Fgr, homologous to Tyr-527 of c-Src and it prevents the autophosphorylation normally occurring at c-Fgr Tyr-400, homologous to c-Src Tyr-416. | Once phosphorylated at Tyr-511 and down-regulated by CSK, c-Fgr is no more susceptible to polylysine stimulation. SIGNOR-250779 0.517 GNAO1 protein P09471 UNIPROT TAOK2 protein Q9UL54 UNIPROT up-regulates 9606 BTO:0000007 12665513 f lperfetto These results suggest that go alpha q205l activates p38 through taos and mek3/6. SIGNOR-235542 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PBK protein Q96KB5 UNIPROT up-regulates activity phosphorylation Thr9 EGISNFKtPSKLSEK 15541388 t llicata During mitosis, TOPK-Thr-9 was phosphorylated by cdk1/cyclin B and TOPK significantly associates with mitotic spindles. When TOPK expression was suppressed, formation of spindle midzone was thinned and dimmed and cytokinesis was disturbed. SIGNOR-250720 0.567 MAOB protein P27338 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI down-regulates quantity chemical modification 9606 31024440 t brain lperfetto Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA). SIGNOR-264015 0.8 CSNK2A2 protein P19784 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-250978 0.29 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT down-regulates activity phosphorylation Ser518 KTVTPASsAKTSPAK 10116 BTO:0000938 15652488 t lperfetto Ser-518 is also a potential phosphorylation site of CRMP-2 by GSK-3_. SIGNOR-133251 0.713 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser613 EKKQITTsPITVRKN 9606 12372621 t lperfetto Warts is a serine/threonine kinase and a dynamic component of the mitotic apparatus. We have found that cdc2/cyclin b forms a complex with a fraction of warts in the centrosome and phosphorylates the ser613 site of warts during mitosisit can be speculated that phosphorylation of warts by cdc2/cyclin b promotes a protein complex formation on the mitotic apparatus at early mitosis, which may be required for subsequent activation of warts kinase at the metaphase-anaphase transition. SIGNOR-216757 0.358 PKA proteinfamily SIGNOR-PF17 SIGNOR PRKD3 protein O94806 UNIPROT up-regulates activity phosphorylation Ser731 ARIIGEKsFRRSVVG 18692497 t lperfetto The results presented in this study indicate that during mitosis, PKD3 and PKD are phosphorylated at Ser(731) and Ser(744) within their activation loop by a mechanism that requires protein kinase C. Mitosis-associated PKD3 Ser(731) and PKD Ser(744) phosphorylation is related to the catalytic activation of these kinases as evidenced by in vivo phosphorylation of histone deacetylase 5, a substrate of PKD and PKD3. SIGNOR-275924 0.2 PMS2 protein P54278 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 10090 9500552 f Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer SIGNOR-257596 0.7 ELK1 protein P19419 UNIPROT PRKCA protein P17252 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26010542 t irozzo The luciferase reporter assay results revealed that the presence of both MZF-1 and Elk-1 significantly contributed to the upregulation of PKCα gene transcription activity. SIGNOR-256336 0.418 CDC42 protein P60953 UNIPROT WASL protein O00401 UNIPROT up-regulates activity binding 9606 10219243 t lperfetto In the presence of Cdc42 and PI(4,5)P2, the potency of N-WASP was increased to a level approaching that of GST-VCA, suggesting that N-WASP was fully activated by the two molecules. SIGNOR-261868 0.917 phosphatidic acid smallmolecule CHEBI:16337 ChEBI SOS1 protein Q07889 UNIPROT up-regulates chemical activation 9606 17486115 t gcesareni Phosphatidic acid interacts with a defined site in the sos ph domain with high affinity and specificity SIGNOR-154676 0.8 DMTF1 protein Q9Y222 UNIPROT ADM protein P35318 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 f Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  SIGNOR-261581 0.2 PI4KA protein P42356 UNIPROT 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI down-regulates quantity chemical modification 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269095 0.8 EXOSC10 protein Q01780 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-261390 0.944 FZR1 protein Q9UM11 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 16896351 t lperfetto In addition to E2 enzymes, APC/C activity is also strictly dependent on one of several co-activator proteins that associate with APC/C during specific periods of the cell cycle. The best studied of these are Cdc20 and Cdh1 SIGNOR-252015 0.846 Uridylate-specific endoribonuclease protein P0C6X7-PRO_0000037321 UNIPROT IFIH1 protein Q9BYX4 UNIPROT down-regulates activity 9606 28158275 f miannu Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation. SIGNOR-260245 0.2 CMA1 protein P23946 UNIPROT EDN3 protein P14138 UNIPROT up-regulates activity cleavage Tyr127 TPEQTVPyGLSNYRG 9606 BTO:0000830 9257865 t miannu Chymase from human mast cells selectively cleaved big endothelins (ETs) at the Tyr31-Gly32 bond and produced novel trachea-constricting 31-amino acid-length endothelins, ETs(1-31), without any further degradation products. SIGNOR-256355 0.382 FANCC protein Q00597 UNIPROT STAT1 protein P42224 UNIPROT up-regulates 9606 11520787 f miannu Fancc is also required for optimal activation of stat1 in response to cytokine and growth factors SIGNOR-110043 0.478 TOP2A protein P11388 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 20562910 f lperfetto Topoisomerase IIalpha (topoIIalpha) is an essential mammalian enzyme that topologically modifies DNA and is required for chromosome segregation during mitosis. SIGNOR-242530 0.7 MYC protein P01106 UNIPROT SHMT1 protein P34896 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 t miannu Myc regulates the de novo purine and pyrimidine synthetic genes in multiple biological systems. Intriguingly, MYC was found to directly activate the expression of SHMT1, and SHMT2, which are enzymes involved in single carbon metabolism and are essential for dNTP synthesis SIGNOR-267379 0.28 MAPK9 protein P45984 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates activity phosphorylation Ser77 PGPFATRsPLFIFMR 12818176 t miannu JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity. SIGNOR-250135 0.622 ERBB2 protein P04626 UNIPROT ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR up-regulates activity phosphorylation -1 1706616 t inferred from 70% of family members ¬†Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. SIGNOR-269875 0.611 EGFR protein P00533 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 20802513 t llicata In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases. SIGNOR-167646 0.582 lenalidomide chemical CHEBI:63791 ChEBI CSNK1A1 protein P48729 UNIPROT down-regulates quantity by destabilization 9606 BTO:0000670 26131937 f gcesareni We demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1a) by the E3 ubiquitin ligase CUL4€“RBX1€“DDB1€“CRBN (known as CRL4CRBN) SIGNOR-236895 0.8 MAPK3 protein P27361 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000176 14967450 t lperfetto Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-121997 0.591 PSMA3 protein P25788 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263362 0.847 LAMB1 protein P07942 UNIPROT Laminin-1 complex SIGNOR-C183 SIGNOR form complex binding 7496033 t lperfetto Laminin-1 is an extracellular matrix protein composed of three polypeptide chains that are designated alpha 1, beta 1, and gamma 1. SIGNOR-253233 0.613 SLC9A3R1 protein O14745 UNIPROT ADRB2 protein P07550 UNIPROT up-regulates activity binding -1 9671706 t lperfetto The Na+/H+ exchanger regulatory factor (NHERF) binds to the tail of the beta2-adrenergic receptor and plays a role in adrenergic regulation of Na+/H+ exchange. NHERF contains two PDZ domains, the first of which is required for its interaction with the beta2 receptor. SIGNOR-262598 0.581 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser214 LVRSREVsVDEGRAC -1 9677319 t lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. SIGNOR-249001 0.309 PRKACA protein P17612 UNIPROT GJB1 protein P08034 UNIPROT unknown phosphorylation Ser233 NPPSRKGsGFGHRLS -1 8390988 t miannu connexin- 32 is proteolyzed by pcalpain and mcalpain. phosphorylation of connexin-32 by protein kinase C, but not by protein kinase A, efficiently prevents its proteolysis by both calpain isoforms. major phosphorylation sites: Ser233(for protein kinase A). Phosphorylation of connexin-32 by protein kinase C,but not by protein kinase A, prevents the proteolytic attack of p-calpain and m-calpain. Phosphorylation of connexin-32 by protein kinase A and protein kinase C does not prevent its proteolysis by papain, a-chymotrypsin, proteinase K, and trypsin SIGNOR-249715 0.312 MAP4K1 protein Q92918 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser558 MQPPRSRsSIMSITA -1 19706536 t miannu HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKC consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro. SIGNOR-276257 0.506 CSNK2A1 protein P68400 UNIPROT DEK protein P35659 UNIPROT up-regulates phosphorylation Ser32 MPGPREEsEEEEDED 9606 16809543 t amattioni Dek phosphorylated at serines 19 and 32. Dek and its phosphorylation are required for intron removal SIGNOR-147365 0.356 SWI/SNF complex complex SIGNOR-C92 SIGNOR TP53 protein P04637 UNIPROT up-regulates activity binding 9606 BTO:0002181 11950834 t irozzo Using genetic and biochemical approaches, we show that several subunits of the human SWI/SNF complex bind to the tumor suppressor protein p53 in vivo and in vitro.Molecular connection between p53 and the SWI/SNF complex implicates that (i) the SWI/SNF complex is necessary for p53-driven transcriptional activation, and (ii) the SWI/SNF complex plays an important role in p53-mediated cell cycle control. SIGNOR-256285 0.443 MLL1 complex complex SIGNOR-C89 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 24680668 t miannu Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. SIGNOR-268803 0.2 DUSP16 protein Q9BY84 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 11359773 t gcesareni Mkp-7 binds to and inactivates p38 mapk and jnk/sapk, but not erk inhibited by dual specificity phosphatases, such as dusp1, dusp10, and dusp16(uniprot) SIGNOR-108233 0.798 EIF2AK2 protein P19525 UNIPROT PPP2R5A protein Q15172 UNIPROT up-regulates phosphorylation Ser28 VDGFTRKsVRKAQRQ 9606 18957415 t llicata Phosphorylation of serine 28 by pkr promotes mitochondrial localization of b56alpha, because wild-type but not mutant s28a b56alpha promoted mitochondrial pp2a activity. SIGNOR-181793 0.333 PEX1 protein O43933 UNIPROT Protein_localization_to_peroxisome phenotype SIGNOR-PH86 SIGNOR up-regulates 9606 26476099 f The Pex1 and Pex6 proteins are members of the AAA family of ATPases and are involved in peroxisome biogenesis. SIGNOR-253616 0.7 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1193 QPTSKAYsPRYSISD 9606 8816480 t gcesareni In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1 SIGNOR-43951 0.621 PRKD3 protein O94806 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates activity phosphorylation Ser978 SPLKRSHsLAKLGSL 21832093 t lperfetto Active PKD Isoforms Phosphorylate and Inactivate SSH1L|Here, we show that active PKD3 also mediates SSH1L phosphorylation at Ser-978 and binding to 14-3-3, further confirming the involvement of all three PKD isoforms in negatively regulating this phosphatase SIGNOR-275938 0.29 MAP2K3 protein P46734 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates phosphorylation 9606 11062067 t fstefani Mkk3, mkk4 and mkk6 all show a strong preference for phosphorylation of the tyrosine residue of the thr-gly-tyr motifs in their known substrates sapk2a/p38, sapk3/p38 gamma and sapk4/p38 delta. we therefore examined the phosphorylation of sapk2a/p38, sapk3/p38? And sapk4/p38? By mkk3, mkk4 and mkk6, which are all known to be capable of activating these enzymes in vitro. SIGNOR-83718 0.634 P2RY1 protein P47900 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256800 0.305 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates activity phosphorylation Tyr223 TSFMMTPyVVTRYYR -1 10715136 t Activation of JNK3 alpha 1 requires both MKK4 and MKK7. both MKK4 and MKK7 were required for bisphosphorylation and maximal enzyme activity. a processive mechanism for JNK3R1 activation that requires phosphorylation of Thr 221 by MKK7 prior to phosphorylation of Tyr 223 by MKK4 SIGNOR-251423 0.733 EIF4G1 protein Q04637 UNIPROT eIF4F_complex complex SIGNOR-C44 SIGNOR form complex binding 9606 BTO:0000671 11408474 t miannu Eif4a interacts with a scaffold protein, eif4g, to form complexes that also contain the cap-binding protein eif4e, which binds the cap structure (m7gpppn_) at the 5_-end of the mrna. These complexes are termed eif4f. SIGNOR-108518 0.925 PRKCB protein P05771 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity phosphorylation -1 15894802 t inferred from family member lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-270277 0.384 EIF4E protein P06730 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 15094766 f lperfetto A key player in the regulation of translation is the mRNA 5' cap-binding protein eIF4E, which is the rate-limiting member of the eIF4F complex SIGNOR-236806 0.7 HOPX protein Q9BPY8 UNIPROT LORICRIN protein P23490 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 21256618 f miannu In the present study, we performed transcriptional profiling of cultured primary human keratinocytes and noted a robust induction of HOP upon calcium-induced cell differentiation. Overexpression of HOP using a lentiviral vector up-regulated FLG and LOR expression during keratinocyte differentiation. SIGNOR-254464 0.2 PFKFB3 protein Q16875 UNIPROT beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI up-regulates quantity chemical modification 9606 9404080 t A full-length cDNA, which encodes a human placental fructose-6-phosphate,2-kinase/ fructose-2,6-bisphosphatase, was constructed and expressed in¬†Escherichia coli. [...]The expressed enzyme was bifunctional with¬†Vmax¬†values of 142 and 0.2 milliunits/mg for the kinase and phosphatase activities, respectively. SIGNOR-267260 0.8 LCK protein P06239 UNIPROT LCK protein P06239 UNIPROT up-regulates activity phosphorylation Tyr394 RLIEDNEyTAREGAK 9606 2250907 t lperfetto They also demonstrate that replacement of the major site of autophosphorylation of p56lck (tyrosine 394) by a phenylalanine residue abolishes the ability to activate p56lck by CD4 cross-linking, implying that this residue is critical for the positive regulation of the Lck tyrosine kinase activity by CD4. SIGNOR-81372 0.2 NRCAM protein Q92823 UNIPROT ANK1 protein P16157 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 t miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. SIGNOR-266721 0.525 Galanin smallmolecule CHEBI:80161 ChEBI GALR3 protein O60755 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257496 0.8 F2R protein P25116 UNIPROT CORO1C protein Q9ULV4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254847 0.2 RBBP7 protein Q16576 UNIPROT DNMT1 protein P26358 UNIPROT down-regulates activity binding -1 28143904 t lperfetto AMPK inhibited DNMT1 through phosphorylation of Ser730 in DNMT1 and Ser314 in RBBP7|association with RBBP7 could inhibit DNMT1 SIGNOR-264785 0.553 NCOR1 protein O75376 UNIPROT BCL6 protein P41182 UNIPROT up-regulates activity binding 9606 BTO:0000007 10898795 t miannu The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT. SIGNOR-252239 0.586 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1948 SPTSPGYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273061 0.635 EYA3 protein Q99504 UNIPROT Six1/Dach complex SIGNOR-C122 SIGNOR up-regulates activity dephosphorylation 10090 14628042 t llicata The phosphatase function of Eya switches the function of Six1-Dach from repression to activation, SIGNOR-238032 0.582 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1197 STAENAEyLRVAPQS 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236471 0.2 AKT1 protein P31749 UNIPROT SH2B2 protein O14492 UNIPROT up-regulates activity phosphorylation Ser598 SARSRSNsAERLLEA 10090 16141217 t gcesareni This study identifies APS as a novel physiological substrate for PKB and the first serine phosphorylation site on APS SIGNOR-252557 0.409 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser486 RPLSRAQsSPAAPAS -1 15738054 t lperfetto We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro. SIGNOR-249276 0.491 FCGR2B protein P31994 UNIPROT TLR4 protein O00206 UNIPROT down-regulates activity 9606 24445665 f lperfetto Triggering of FcgammaRIIB also subverted the normal activation of DCs by the TLR4 agonist lipopolysaccharide. In addition, triggering of FcgammaRIIB by immune complexes might affect the differentiation of moDCs. When moDCs develop from monocytes invitro in the presence of immune complexes, their differentiation is hampered and they no longer produce IL-12 in response to TLR4 agonists. SIGNOR-249525 0.39 SUFU protein Q9UMX1 UNIPROT SAP18 protein O00422 UNIPROT up-regulates binding 9606 11960000 t gcesareni Here we report that the mouse homolog of su(fu) [msu(fu)] specifically interacts with sap18, a component of the msin3 and histone deacetylase complex. In addition, we demonstrate that msu(fu) functionally cooperates with sap18 to repress transcription by recruiting the sap18-msin3 complex to promoters containing the gli-binding element. SIGNOR-117311 0.66 MAPK1 protein P28482 UNIPROT BMF protein Q96LC9 UNIPROT up-regulates phosphorylation Ser77 TQTLSPAsPSQGVML 9606 BTO:0000785 22258404 t llicata Phosphomimetic mutation of this site (s74d) moderately enhanced bmf apoptotic activity in vivo.22 here, we demonstrate a previously unrecognized mode of regulation of bmf. We show that b-raf-mek-erk2 signaling regulates bmf phosphorylation at serine 74 and serine 77. Phosphorylation of serine 77 downregulates the pro-apoptotic activity of bmf. SIGNOR-195475 0.255 PIM1 protein P11309 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 16146838 f lperfetto The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. SIGNOR-249623 0.7 IL10 protein P22301 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 23357618 f miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. SIGNOR-253498 0.2 SHH protein Q15465 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity binding 9606 BTO:0001253 9811851 t lperfetto Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH. SIGNOR-61552 0.941 NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity binding 10090 BTO:0000011 11279134 t lperfetto The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin SIGNOR-250566 0.472 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr932 IRRESSVyDISEHRR -1 11024032 t Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro. SIGNOR-251174 0.759 BAG4 protein O95429 UNIPROT TNFRSF1A protein P19438 UNIPROT down-regulates activity binding 10090 BTO:0000801 12748303 t gcesareni It was suggested that the silencer of death domains (SODD) protein constitutively associates intracellularly with TNFR1 and inhibits the recruitment of cytoplasmic signaling proteins to TNFR1 to prevent spontaneous aggregation of the cytoplasmic death domains of TNFR1 molecules that are juxtaposed in the absence of ligand stimulation SIGNOR-245022 0.632 LCK protein P06239 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates phosphorylation Tyr753 ERDINSLyDVSRMYV 9606 12181444 t gcesareni In vitro phosphorylation experiments with recombinant plcgamma2 and recombinant lck, fyn, and lyn tyrosine kinases showed that phosphorylation of plcgamma2 led to activation of the recombinant enzyme. SIGNOR-91473 0.539 SMAD1 protein Q15797 UNIPROT GADD45G protein O95257 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 t Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation SIGNOR-268937 0.2 PRKAA1 protein Q13131 UNIPROT CFTR protein P13569 UNIPROT down-regulates activity phosphorylation Ser768 LQARRRQsVLNLMTH 9606 19095655 t Luana AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites.|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions SIGNOR-259867 0.475 SIRT1 protein Q96EB6 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity deacetylation 10090 BTO:0002572 27776347 t SIRT1 deacetylates β-catenin to promote its accumulation in the nucleus and thus induces the transcription of genes that block MSC adipogenesis. SIGNOR-256208 0.52 SCAND1 protein P57086 UNIPROT MZF1 protein P28698 UNIPROT up-regulates activity binding -1 10777584 t miannu Co-immunoprecipitation and yeast two-hybrid analyses demonstrate that MZF1B and RAZ1 associate in vitro via a SCAN box-dependent mechanism. The interaction between MZF1B and RAZ1 might be necessary for mediating MZF1B function SIGNOR-221561 0.372 ZFPM2 protein Q8WW38 UNIPROT GATA4 protein P43694 UNIPROT down-regulates activity binding 10090 BTO:0000944 9927675 t miannu FOG-2 associates physically with the N-terminal zinc finger of GATA-4 both in vitro and in vivo. This interaction appears to modulate specifically the transcriptional activity of GATA-4 because overexpression of FOG-2 in both NIH 3T3 cells and primary rat cardiomyocytes represses GATA-4-dependent transcription from multiple cardiac-restricted promoters. SIGNOR-236959 0.774 MAPK8 protein P45983 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11781324 t lperfetto Kinase assays showed that c-jun n-terminal kinase (jnk) was also activated with activation kinetics corresponding to that of k8 phosphorylation. Furthermore, k8 was also phosphorylated on ser-73 by jnk in vitro. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. SIGNOR-113645 0.383 SRC protein P12931 UNIPROT PIP5K1C protein O60331 UNIPROT up-regulates phosphorylation Tyr649 TDERSWVySPLHYSA 9606 15738269 t lperfetto Phosphorylation by src of the tyrosine adjacent to s650 (y649 in human pipki gamma) was shown to enhance pipki gamma targeting to focal adhesions. We find that y649 phosphorylation does not stimulate directly pipki gamma binding to talin, but may do so indirectly by inhibiting s650 phosphorylation. SIGNOR-134459 0.289 rauwolscine chemical CHEBI:48562 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 9459568 t miannu These studies display the usefulness of [3H]rauwolscine as an antagonist radioligand for the cloned human 5-HT2B receptor. The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor SIGNOR-258690 0.8 CSNK2A1 protein P68400 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation -1 8954982 t llicata Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149. SIGNOR-250951 0.331 TYMS protein P04818 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI up-regulates quantity chemical modification 9606 21876188 t lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. SIGNOR-268232 0.8 A4/b1 integrin complex SIGNOR-C162 SIGNOR DLL1 protein O00548 UNIPROT up-regulates quantity by expression 10090 25786978 f lperfetto First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs. SIGNOR-253285 0.27 MFN1 protein Q8IWA4 UNIPROT Mitochondrial_fusion phenotype SIGNOR-PH218 SIGNOR up-regulates 9606 25486875 f lperfetto OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria SIGNOR-272984 0.7 MAP4K1 protein Q92918 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Ser376 SSFPQSAsLPPYFSQ 9606 BTO:0000782 17353368 t lperfetto The serine/threonine kinase hpk-1 phosphorylates serine 376 of slp-76 and induces the interaction with 14-3-3 proteins SIGNOR-153613 0.769 AVPR1B protein P47901 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257176 0.271 MRPL55 protein Q7Z7F7 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262335 0.596 EFNA1 protein P20827 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates binding 9606 9576626 t gcesareni The best known function is their role in the guidance of migration of axons and cells in the nervous system through repulsive interactions SIGNOR-56965 0.805 RAB9A protein P51151 UNIPROT RABEPK protein Q7Z6M1 UNIPROT up-regulates activity 9230071 t lperfetto P40 is a very potent transport factor in that the pure, recombinant protein can stimulate, significantly, an in vitro transport assay that measures transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network. The functional importance of p40 is confirmed by the finding that anti-p40 antibodies inhibit in vitro transport. Finally, p40 shows synergy with Rab9 in terms of its ability to stimulate mannose 6-phosphate receptor transport. These data are consistent with a model in which p40 and Rab9 act together to drive the process of transport vesicle docking. SIGNOR-253088 0.564 BRCA1 protein P38398 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates ubiquitination 9606 16818604 t gcesareni In conclusion, our data show that ctip is a physiological substrate of the brca1 e3 ligase. Brca1 recruits ctip through its c-terminal brct domains and promotes ctip ubiquitination through its n-terminal ring domain. The ubiquitinated ctip is not targeted for degradation. Instead, ubiquitinated ctip binds to chromatin following dna damage and is likely to be involved in dna damage checkpoint control. SIGNOR-147711 0.836 SCF-betaTRCP complex SIGNOR-C5 SIGNOR YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23431053 t lperfetto This cascade of phosphorylation allows the binding of scfbetatrcp that promotes the ubiquitination and degradation of yap. SIGNOR-217187 0.373 SEC24A protein O95486 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 t lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat SIGNOR-265295 0.707 PRKACA protein P17612 UNIPROT ITPKA protein P23677 UNIPROT up-regulates activity phosphorylation Ser121 LQQPRRLsTSSVSST -1 9374536 t miannu Two isoforms of the inositol 1,4,5-trisphosphate 3-kinase have been identified, the A form and the B form. phosphorylation of isoform A by the cyclic AMP-dependent protein kinase increased activity 1.5-fold, whereas phosphorylation of isoform B decreased activity by 45%. major phosphorylation sites in the protein are Ser119 for PKA. Ser119 in the A isoform is conserved in the B isoform as Ser328 SIGNOR-249994 0.332 SLC44A2 protein Q8IWA5 UNIPROT choline smallmolecule CHEBI:15354 ChEBI up-regulates activity relocalization 9606 21367571 t lperfetto Among these, SLC44A2 (a putative choline transporter) was strikingly upregulated by ethanol (three fold), and GCN5 silencing downregulated it SIGNOR-260409 0.8 PLK3 protein Q9H4B4 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr366 ASSSTSVtPDVSDNE 9606 20940307 t gcesareni Plk3 phosphorylates pten on thr-366 and ser-370. Plk3-mediated phosphorylation facilitates pten stabilization, thereby negatively regulating the pi3k/pdk1/akt1 signaling axis SIGNOR-168473 0.341 IL1RL1 protein Q01638 UNIPROT IL1RAP protein Q9NPH3 UNIPROT up-regulates activity binding 9606 35238669 t miannu The initial step in IL-33 signal transduction is ligand-induced conformational changes in IL-33R, which facilitate recruitment of interleukin-1 receptor accessory protein (IL-1RAP). SIGNOR-277715 0.517 Caspase 3 complex complex SIGNOR-C221 SIGNOR GAS2 protein O43903 UNIPROT up-regulates cleavage Asp278 MLQISRVdGKTSPIQ 9606 10564664 t gcesareni We now demonstrate that gas2 is a substrate of caspase-3 but not of caspase-6. Proteolytic processing both in vitro and in vivo is dependent on aspartic residue 279. SIGNOR-256439 0.428 BORA protein Q6PGQ7 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation 9606 18615013 t gcesareni Bora/aurora-a-dependent phosphorylation is a prerequisite for plk1 to promote mitotic entry after a checkpoint-dependent arrest. SIGNOR-179425 0.779 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates activity binding 9606 12244043 t areggio Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes SIGNOR-254986 0.624 zotepine chemical CHEBI:32316 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258551 0.8 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 SIGNOR-C83 10428798 t gcesareni Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity. SIGNOR-69710 0.49 APC-c complex SIGNOR-C150 SIGNOR KIF4A protein O95239 UNIPROT down-regulates quantity by destabilization ubiquitination -1 24510915 t miannu Biochemical studies on the kinesins confirmed KIFC1, KIF18A, KIF2C, and KIF4A as APC/C substrates. Furthermore, we showed that the APC/CCDH1-dependent degradation of KIFC1 regulates the bipolar spindle formation and proper cell division. Our in vitro degradation assays showed a time-dependent degradation for four of the five potential substrates tested: KIF18A, KIF2C, KIFC1 and KIF4A were readily degraded in vitro, however remained stable in the presence of either APC/C inhibitor (Fig​(Fig4A4A and Supplementary Fig S3A). SIGNOR-266112 0.29 TFAP2A protein P05549 UNIPROT SULT1E1 protein P49888 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17187826 f miannu Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. SIGNOR-255397 0.2 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 t gcesareni The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein. SIGNOR-105766 0.38 PTPRB protein P23467 UNIPROT CDH5 protein P33151 UNIPROT up-regulates activity dephosphorylation 9606 19015309 t miannu Because we had shown previously that VE-PTP supports VE-cadherin function when exogenously expressed in transfected cells, we expected it to be expressed at endothelial cell contacts.|Indeed, tyrosine phosphorylation of VE-cadherin is reduced by VE-PTP in COS-7 and CHO cells. SIGNOR-277131 0.599 AKT1 protein P31749 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity phosphorylation Ser71 YDRLRPLsYPQTDVF 9606 BTO:0000848 10617634 t Akt protein kinase inhibits Rac1-GTP binding through phosphorylation at serine 71 of Rac1 SIGNOR-252576 0.714 SMAD3 protein P84022 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9534 9670020 t lperfetto Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGF-beta type I receptor, and this oligomerization does not require Smad4 SIGNOR-217227 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr325 TELEPLCtPVVTCTP phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-263010 0.2 SOCS3 protein O14543 UNIPROT JAK3 protein P52333 UNIPROT down-regulates activity binding 9606 21508344 t lperfetto SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity directly through their kinase inhibitory regions (KIR). SIGNOR-238645 0.687 CDK8 protein P49336 UNIPROT CCNH protein P51946 UNIPROT down-regulates phosphorylation Ser5 sSQKRHWT 9606 10993082 t gcesareni Here we show that cdk8/cyclin c can regulate transcription by targeting the cdk7/cyclin h subunits of the general transcription initiation factor iih (tfiih). cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity. In addition, mimicking cdk8 phosphorylation of cyclin h in vivo has a dominant-negative effect on cell growth. SIGNOR-82037 0.665 PPP2R1A protein P30153 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR form complex binding 9606 23454242 t gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. SIGNOR-243445 0.883 JNK proteinfamily SIGNOR-PF15 SIGNOR KIF5C protein O60282 UNIPROT up-regulates activity phosphorylation Ser176 CTERFVSsPEEVMDV 9606 BTO:0000142 27013971 t miannu JNK phosphorylates KIF5C on S176 in the motor domain; a site that we show is phosphorylated in brain. In the peroxisome cargo-bound state, S176 phosphorylated KIF5C(1-560) transports to microtubule plus ends, whereas dephosphorylated KIF5C(1-560) is bound tightly to microtubules resulting in an immobile state. As a consequence, phosphorylation of S176 can facilitate plus-end cargo transport by KIF5C(1-560). SIGNOR-264063 0.2 ITGB3 protein P05106 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257718 0.653 SRC protein P12931 UNIPROT GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000938 BTO:0000142;BTO:0000671 11882681 t inferred from family member gcesareni These findings indicate that glyr function is upregulated by ptks and this modulation is dependent on the tyrosine-413 residue of the beta subunit. SIGNOR-267796 0.273 CAMK2D protein Q13557 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates phosphorylation Ser210 YGKTQHSsLDQSSPP 9606 17179159 t lperfetto These results demonstrate that camkiideltab preferentially targets hdac4, and this involves serine 210overexpression of camkiideltab in primary neonatal cardiomyocytes increases the activity of the mef2 transcription factor and completely rescues hdac4-mediated repression of mef2 SIGNOR-151418 0.365 glycogen smallmolecule CHEBI:28087 ChEBI alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity precursor of 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [‚Ķ] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267394 0.8 SMARCA2 protein P51531 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270701 0.825 RNF7 protein Q9UBF6 UNIPROT CASP3 protein P42574 UNIPROT down-regulates activity ubiquitination 9606 23136067 t miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. SIGNOR-271448 0.2 PRKD3 protein O94806 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity phosphorylation Ser358 WPLSRTRsEPLPPSA 18692497 t Conserved Phosphorylated residue Ser259 and Ser498 refer to HDAC5 sequence. Phospho-residues in HDAC7 were derived by aligning HDAC5 and HDAC7 lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. SIGNOR-275934 0.2 PRKG1 protein Q13976 UNIPROT ITPR1 protein Q14643 UNIPROT unknown phosphorylation Ser1764 RPSGRREsLTSFGNG 10116 BTO:0004578 8132598 t lperfetto Phosphorylation of the inositol 1,4,5-trisphosphate receptor by cyclic GMP-dependent protein kinase. | The synthetic peptide corresponding to serine 1755 (GRRESLTSFG) was phosphorylated with aKm in the range of 30-40 microM by both kinases. The kinetic analysis revealed that this peptide substrate is the best substrate described for cGMP kinase to date. Vascular smooth muscle cells prelabeled with [32P]orthophosphate and treated with atrial natriuretic peptide or sodium nitroprusside to elevate cGMP also resulted in increased labeling of the IP3 receptor. Phosphorylation of IP3 receptor by cGMP kinase may regulate the function of IP3 receptor in vascular smooth muscle cells and contribute to the effect of cGMP to regulate intracellular calcium levels. SIGNOR-248916 0.472 VXJPSOQJNUZHDN-YJFQKBDPSA-N smallmolecule CID:118708139 PUBCHEM NMUR2 protein Q9GZQ4 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257592 0.8 26S Proteasome complex SIGNOR-C307 SIGNOR Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 9606 29636472 f lperfetto The proteasome is a sophisticated ATP-dependent molecular machine responsible for protein degradation in all known eukaryotic cells.  SIGNOR-263375 0.7 NTRK2 protein Q16620 UNIPROT NCK2 protein O43639 UNIPROT up-regulates binding 9606 12074588 t gcesareni We identified the nck2 adaptor protein as a novel interaction partner of the active form of trkb. Additionally, we identified three tyrosines in icd-trkb (y694, y695, and y771) that are crucial for this interaction. SIGNOR-89764 0.342 FLI1 protein Q01543 UNIPROT GATA1 protein P15976 UNIPROT up-regulates activity binding 10090 BTO:0000944 12556498 t irozzo On the other hand, our data demonstrate that FLI-1 also interacts with GATA-1. However, FLI-1 does not repress but enhances GATA-1 activity. SIGNOR-256045 0.533 ZC3HAV1 protein Q7Z2W4 UNIPROT PARN protein O95453 UNIPROT up-regulates activity binding 9606 BTO:0000007 21876179 t We provide evidence indicating that ZAP selectively recruits cellular poly(A)-specific ribonuclease (PARN) to shorten the poly(A) tail of target viral mRNA and recruits the RNA exosome to degrade the RNA body from the 3′ end. SIGNOR-261296 0.424 MRPL52 protein Q86TS9 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262346 0.669 SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-59472 0.888 DAPK1 protein P53355 UNIPROT MCM3 protein P25205 UNIPROT unknown phosphorylation Ser160 KTIERRYsDLTTLVA 9606 18283219 t lperfetto Mcm3 was efficiently and specifically phosphorylated by dapk on a unique site, ser160 / the functional effects of dapk-mediated phosphorylation and any connection to these functions remain to be determined SIGNOR-160958 0.336 CALM2 protein P0DP24 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT up-regulates binding 9606 10770941 t miannu The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases SIGNOR-266328 0.501 NELFA protein Q9H3P2 UNIPROT NELF complex SIGNOR-C521 SIGNOR form complex binding 9606 18628398 t miannu The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. SIGNOR-271401 0.882 FAD smallmolecule CHEBI:16238 ChEBI FADH2 smallmolecule CHEBI:17877 ChEBI up-regulates quantity precursor of 9606 33450351 t miannu ETF is a two-electron and two-proton transporter as its FAD undergoes successive reduction via two-consecutive one-electron transfer steps, with the formation of an intermediate one-electron red flavin semiquinone species (FAD•−), which is then fully reduced to FADH2 with the uptake of one additional electron and two protons (Fig. 4a). SIGNOR-269456 0.8 FGF2 protein P09038 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates binding 9606 22298955 t gcesareni Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts. SIGNOR-195588 0.814 JAK1 protein P23458 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002882 9305869 t Janus kinase-dependent activation of insulin receptor substrate 1 SIGNOR-251343 0.697 Flesinoxan chemical CID:57347 PUBCHEM HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). SIGNOR-258950 0.8 LPAR4 protein Q99677 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257057 0.2 ZEB1 protein P37275 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15311212 f miannu known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT. SIGNOR-255158 0.672 PPP2CA protein P67775 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates dephosphorylation 9606 BTO:0000848 11591705 t lperfetto Rela was dephosphorylated by a purified pp2a core enzyme, a heterodimer formed by the catalytic subunit of pp2a (pp2ac) and pr65, in a concentration-dependent manner.These data suggest that the constitutive activation of rela in melanoma cells could be due, at least in part, to the deficiency of pp2a, which exhibits decreased dephosphorylation of nf-kappa b/rela. SIGNOR-217421 0.439 NPFF protein O15130 UNIPROT NPFFR2 protein Q9Y5X5 UNIPROT up-regulates binding 9606 11024015 t gcesareni Npff specifically bound to npff1 (k(d) = 1.13 nm) and npff2 (k(d) = 0.37 nm), and both receptors were activated by npff in a variety of heterologous expression systems SIGNOR-82961 0.763 MAPK1 protein P28482 UNIPROT SCNN1B protein P51168 UNIPROT down-regulates quantity by destabilization phosphorylation Thr615 QALPIPGtPPPNYDS -1 11805112 t lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. SIGNOR-249446 0.294 CD79B protein P40259 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268193 0.641 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser20 PLSQETFsDLWKLLP 9606 17339337 t Manara Evaluation of these calcium calmodulin kinase superfamily members as candidate Ser(20) kinases in vivo has shown that only CHK1 or DAPK-1 can stimulate p53 transactivation and induce Ser(20) phosphorylation of p53.| Thus, endogenous CHK1 is required for the majority of Ser20 site phosphorylation of ectopically expressed p53 in H1299 cells. SIGNOR-260776 0.783 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr51 SRKLQLKtLLLQIAK 9606 BTO:0000671 18986304 t llicata Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143). SIGNOR-182061 0.2 SORT1 protein Q99523 UNIPROT APOA1 protein P02647 UNIPROT up-regulates quantity binding 10029 BTO:0000246 23283348 t miannu Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Sortilin interacts with all human APOE isoforms. SIGNOR-273722 0.337 MECOM protein Q03112 UNIPROT PBX1 protein P40424 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001271 19767769 f miannu In this study, we identified pbx1, a proto-oncogene in hematopoietic malignancy, as a target gene of evi-1. Overexpression of evi-1 increased pbx1 expression in hematopoietic stem/progenitor cells SIGNOR-188155 0.434 OPRM1 protein P35372 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256854 0.492 NPM1 protein P06748 UNIPROT HEXIM1 protein O94992 UNIPROT down-regulates activity binding 9606 BTO:0001545 18371977 t miannu We identified NPM as a novel HEXIM1-binding protein. NPM functioned as a negative regulator of HEXIM1. cytoplasmic localization of endogenous HEXIM1 is detected in an acute myeloid leukemia (AML) cell line containing the NPMc+ mutation, suggesting the physiological importance of HEXIM1-NPMc+ interaction. SIGNOR-260134 0.394 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser251 KNDYRKLsMQCKDFV 9606 16331690 t The effect has been demonstrated using Q13507-3 llicata The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263. SIGNOR-142961 0.417 CSNK2A1 protein P68400 UNIPROT SLK protein Q9H2G2 UNIPROT down-regulates phosphorylation Ser347 SSDLSIAsSEEDKLS 9606 16837460 t gcesareni Slk down-regulation by v-src is indirect and is accompanied by slk hyperphosphorylation on serine residues. Deletion analysis revealed that casein kinase ii (ck2) sites at position 347/348 are critical for v-src-dependent modulation of slk activity. SIGNOR-147879 0.2 SMO protein Q99835 UNIPROT ARRB1 protein P49407 UNIPROT up-regulates binding 9606 15618519 t The binding occours if Smo is phosphorylated gcesareni Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2 SIGNOR-132678 0.62 CSNK2A1 protein P68400 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser81 TQDQQSLsDVEGAYS -1 7983041 t llicata Although human PR contains 11 potential CKII consensus sequences, CKII in vitro phosphorylated purified PR-B only at Ser81 suggesting that this may be an authentic site for CKII in vivo. SIGNOR-250926 0.359 SAR1A protein Q9NR31 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR up-regulates quantity binding 30605680 t lperfetto Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. SIGNOR-265304 0.711 PRKD1 protein Q15139 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser246 QYQEERRsVKHILFS -1 16479000 t miannu HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. SIGNOR-276046 0.2 GFAP protein P14136 UNIPROT ACTB protein P60709 UNIPROT up-regulates quantity binding 9606 BTO:0000099 31626364 t miannu GFAP is the major cytoskeletal element and scaffold of astrocytes In astrocytes, GFAP has close interaction with F-actin molecularly and functionally. SIGNOR-269271 0.383 RNF7 protein Q9UBF6 UNIPROT CDC34 protein P49427 UNIPROT down-regulates activity polyubiquitination 9606 10851089 t miannu SAG was found to be the second family member of Rbx (RING box protein) or ROC (Regulator of cullins) or Hrt that is a component of SCF E3 ubiquitin ligase. Indeed, like ROC1/Rbx1/Hrt1, SAG binds to Cul1 and SAG-Cul1 complex has ubiquitin ligase activity to promote poly-ubiquitination of E2/Cdc34.  SIGNOR-271443 0.738 NR1I2 protein O75469 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 11706036 t gcesareni The constitutive androstane receptor (car, nr1i4), like fxr and pxr, binds dna as a heterodimer with rxr? SIGNOR-111624 0.547 CSNK1E protein P49674 UNIPROT PER1 protein O15534 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 11865049 t miannu We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. SIGNOR-267997 0.836 (S)-methylmalonyl-CoA(5-) smallmolecule CHEBI:57327 ChEBI succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI up-regulates quantity precursor of 9606 1978672 t miannu Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme that catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA). SIGNOR-269110 0.8 GATA2 protein P23769 UNIPROT TSHB protein P01222 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 9305891 t scontino Pit-1, is necessary but not sufficient to allow basal transcription of the mTSHβ gene.The analysis of the mTSHβ gene described in this report provides evidence for the participation of a zinc finger factor, GATA-2, with a POU homeodomain partner, Pit-1, on a such a composite element.In summary, we have shown the requirement for at least two different classes of transcription factors to regulate mTSHβ gene expression. Both GATA-2 and Pit-1 can bind independently to the P1 region of the promoter, form a heteromeric complex with DNA, and functionally synergize to activate TSHβ promoter activity. SIGNOR-267253 0.399 CTNNB1 protein P35222 UNIPROT TCF7 protein P36402 UNIPROT up-regulates binding 9606 BTO:0000782 15735151 t gcesareni Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation (fig 2?2),), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1 SIGNOR-134282 0.749 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser324 RDLELPLsPSLLGGP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-34653 0.584 MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 9312068 t gcesareni Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues. SIGNOR-51199 0.687 PLAT protein P00750 UNIPROT PLG protein P00747 UNIPROT up-regulates activity binding 9606 BTO:0000131 1447176 t lperfetto The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme SIGNOR-263533 0.555 MKNK1 protein Q9BUB5 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 9606 17724079 t lperfetto Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes. SIGNOR-157533 0.77 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates phosphorylation 9606 11242034 t gcesareni Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily. SIGNOR-105698 0.646 PRKCQ protein Q04759 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr354 RKPANDItSQLEINF 9606 14699138 t lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation SIGNOR-249250 0.307 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120032 0.781 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1280 QVILAKAsQEHHLSE 9606 BTO:0002181 11114888 t llicata Of the four potential phosphoacceptor sites in the BRCA1 (1005–1313) fragment (Ser 1143, Ser 1239, Ser 1280, Ser 1298), Ala substitutions at two sites, Ser 1143 and Ser 1280, reduced the in vitro phosphorylation of GST–BRCA1 (1005–1313) by ATR, whereas substitution of Ser 1239 or Ser 1298 with Ala had little or no effect (Fig. 2C; data not shown). A Ser 1143/Ser 1280 double mutant was a poor substrate for ATR, suggesting that these are the two major in vitro phosphorylation sites on this BRCA1 fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication. SIGNOR-250582 0.793 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT unknown phosphorylation Tyr842 DIMSDSNyVVRGNAR 10090 BTO:0001516 28271164 t lperfetto Tyrosine 842 in the activation loop is required for full transformation by the oncogenic mutant FLT3-ITD|Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. Among these tyrosine residues, Y842 is located in the so-called activation loop. SIGNOR-271924 0.2 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation Ser715 YQSTIPQsPSPAPDD 9606 BTO:0000801 16973330 t The effect has been demonstrated using Q08499-2 gcesareni These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro. SIGNOR-149570 0.36 RELA protein Q04206 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR form complex binding 9606 9450761 t gcesareni Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna SIGNOR-55381 0.701 MSL1 protein Q68DK7 UNIPROT MSL acetyltransferase complex SIGNOR-C344 SIGNOR form complex binding 9606 BTO:0000567 16227571 t miannu We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. SIGNOR-263942 0.851 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR methionine smallmolecule CHEBI:16811 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270397 0.8 CYP2D6 protein P10635 UNIPROT tyramine smallmolecule CHEBI:15760 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬† SIGNOR-263995 0.8 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Ser241 SKQARANsFVGTAQY 9606 10455013 t lperfetto Pdk1 is itself phosphorylated in vivo and whether phosphorylation plays a role in regulating its activity/ phosphorylation of ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1 SIGNOR-236789 0.2 YWHAE protein P62258 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity binding 9606 BTO:0000938 17202468 t miannu 14-3-3epsilon is involved in the proper localization of NUDEL and LIS1 in axons. 14-3-3ε binds to NUDEL phosphorylated by cyclin-dependent kinase (cdk5) and maintains NUDEL phosphorylation. Deficiency of 14-3-3ε causes mislocalization of the NUDEL/LIS1 complex from axons, suggesting that 14-3-3ε regulates the axonal targeting of the NUDEL/LIS1 complex by sustaining NUDEL phosphorylation SIGNOR-252160 0.653 KIF11 protein P52732 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272521 0.7 TERF2 protein Q15554 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity binding SIGNOR-C306 18680434 t lperfetto It is not yet clear how the presence of TRF2 at telomeres averts the activation of the ATM kinase.> In this regard, overexpression of TRF2can dampen the activation of the ATM kinase, even at nontelomeric sites of DNA damage (95). Furthermore, TRF2 can interact with the ATM kinase as well as with the Mre11 complex SIGNOR-263323 0.672 PRKACA protein P17612 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates phosphorylation Ser1364 PSGSQRPsVSDDTGC 9606 17615294 t lperfetto Additionally, we show that s1360 and s1364 of beta4 are the only residues phosphorylated by pkc and pka in cells, respectivelywe have defined three regions on beta4 that together harbor all the serine and threonine phosphorylation sites and show that three serines (s1356, s1360, and s1364), previously implicated in hd regulation, prevent the interaction of beta4 with the plectin actin-binding domain when phosphorylated SIGNOR-156873 0.2 Fluocinonide chemical CHEBI:5109 ChEBI SMO protein Q99835 UNIPROT up-regulates activity chemical activation 10090 20439738 t gcesareni We identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling. SIGNOR-248218 0.8 THOC3 protein Q96J01 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 t miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. SIGNOR-268513 0.921 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Tyr570 VRREVGDyGQLHETE 9606 BTO:0000007 15143187 t JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251359 0.2 CAMK4 protein Q16566 UNIPROT HNRNPL protein P14866 UNIPROT up-regulates phosphorylation Ser544 GKSERSSsGLLEWES 9606 22570490 t lperfetto Here we show that the regulation of the stress axis-regulated exon of the slo1 potassium channel transcripts by membrane depolarization requires a highly conserved camkiv target serine (ser-513) of the heterogeneous ribonucleoprotein l. Ser-513 phosphorylation within the rna recognition motif 4 enhanced heterogeneous ribonucleoprotein l interaction with the camkiv-responsive rna element 1 of stress axis-regulated exon and inhibited binding of the large subunit of the u2 auxiliary factor u2af65. SIGNOR-197367 0.388 CHEK1 protein O14757 UNIPROT PABIR1 protein Q96E09 UNIPROT down-regulates activity phosphorylation Ser37 GGLRRSNsAPLIHGL 9606 BTO:0000018 33108758 t miannu Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression. SIGNOR-266380 0.2 DZIP3 protein Q86Y13 UNIPROT H2AX protein P16104 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTSATVG 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271752 0.2 CDK5 protein Q00535 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Ser518 KGGTPAGsARGSPTR 9606 16611631 t lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro SIGNOR-145963 0.587 EGR1 protein P18146 UNIPROT PCSK2 protein P16519 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9359835 f miannu we show that the transcription factor EGR-1 interacts with two distinct elements within the proximal human PC2 promoter region. Transfection experiments also demonstrate that EGR-1 is able to enhance PC2 promoter activity. SIGNOR-253896 0.2 MAP3K7 protein O43318 UNIPROT TAB1 protein Q15750 UNIPROT up-regulates activity phosphorylation Ser453 TNTHTQSsSSSSDGG 9606 BTO:0000007 22216226 t miannu We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro.  SIGNOR-276366 0.927 RNF7 protein Q9UBF6 UNIPROT JUN protein P05412 UNIPROT down-regulates activity ubiquitination 9606 23136067 t miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. SIGNOR-271452 0.33 KSR2 protein Q6VAB6 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 t miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. SIGNOR-273879 0.589 HTR2B protein P41595 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256743 0.28 NFE2L2 protein Q16236 UNIPROT PXDN protein Q92626 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567; BTO:0000007 29953917 t miannu PXDN expression in response to H2O2 and the Nrf2-specific inducers, tert-butylhydroquinone (tBHQ) and sulforaphane (SFN), was determined by western blotting and immunofluorescence microscopy, in HeLa and HEK293 cells.We found that Nrf2 binds to and increases luciferase reporter gene expression from the PXDN promoter via a putative Nrf2-binding site. In summary, we show that PXDN is a novel target of the redox sensitive transcription factor Nrf2. SIGNOR-265248 0.2 SH2B1 protein Q9NRF2 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 27154742 t lperfetto The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex SIGNOR-253078 0.679 MAPK8 protein P45983 UNIPROT SYT4 protein Q9H2B2 UNIPROT up-regulates activity phosphorylation Ser135 EGEKESVsPESLKSS 10116 BTO:0001009 18046461 t done miannu JNK phosphorylates Syt 4 at Ser135 in vitro and in vivo. SIGNOR-273673 0.42 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270364 0.8 SKP1 protein P63208 UNIPROT Noncanonical PRC1 complex SIGNOR-C151 SIGNOR form complex binding 10090 25533466 t miannu inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. SIGNOR-255278 0.453 GXYLT2 protein A0PJZ3 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 22117070 t Xylosylation in ER membrane gcesareni We have previously identified two human genes, gxylt1 and gxylt2, encoding glucoside xylosyltransferases responsible for the transfer of xylose to o-linked glucose. The identity of the enzyme further elongating the glycan to generate the final trisaccharide xylose-xylose-glucose, however, remained unknown. Here, we describe that the human gene c3orf21 encodes a udp-xylose:alfa-xyloside alfa1,3-xylosyltransferase, acting on xylose-alfa1,3-glucosebeta1-containing acceptor structures. We have, therefore, renamed it xxylt1 (xyloside xylosyltransferase 1). Xxylt1 cannot act on a synthetic acceptor containing an alfa-linked xylose alone, but requires the presence of the underlying glucose. Activity on notch egf repeats was proven by in vitro xylosylation of a mouse notch1 fragment recombinantly produced in sf9 insect cells, a bacterially expressed egf repeat from mouse notch2 modified in vitro by rumi and gxylt2 and in vivo by co-expression of the enzyme with the notch1 fragment. The enzyme was shown to be a typical type ii membrane-bound glycosyltransferase localized in the endoplasmic reticulum. SIGNOR-177717 0.328 MIB1 protein Q86YT6 UNIPROT SMN1 protein Q16637 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23615451 t miannu In this study, we show that the E3 ubiquitin ligase, mind bomb 1 (Mib1), interacts with and ubiquitinates SMN and facilitates its degradation. Knocking down Mib1 levels increases SMN protein levels in cultured cells.  SIGNOR-272664 0.329 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273084 0.745 GABRG2 protein P18507 UNIPROT GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263764 0.626 CAMK4 protein Q16566 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation 9606 11062529 t gcesareni Mckinsey et al. report that calcium/calmodulin-dependent kinase (camk), stimulates myogenesis and prevents formation of mef2/hdac complexes by inducing phosphorylation and nuclear export of hdacs 4 and 5. SIGNOR-83837 0.604 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 9020188 t lperfetto The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-g they become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases. SIGNOR-236239 0.782 ATF4 protein P18848 UNIPROT SARS2 protein Q9NP81 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269425 0.2 DPH5 protein Q9H2P9 UNIPROT EEF2 protein P13639 UNIPROT down-regulates activity methylation His715 TLHADAIhRGGGQII 9606 23486472 t Analysis of EF2 in the mutant cells revealed a novel form of diphthamide with an additional methyl group that prevented ADP-ribosylation and inactivation of EF2. The abnormal methylation appeared to be catalyzed by DPH5. SIGNOR-261146 0.738 MAVS protein Q7Z434 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 25636800 t miannu After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively. SIGNOR-260145 0.91 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol chemical CHEBI:75722 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 19282177 t Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. SIGNOR-258149 0.8 2'-3'-cGAMP(2-) smallmolecule CHEBI:143093 ChEBI STING1 protein Q86WV6 UNIPROT up-regulates activity binding 23258413 t lperfetto Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. SIGNOR-276596 0.8 HIF1A protein Q16665 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003123 12067980 f miannu Examination of the MDR1 gene identified a binding site for hypoxia inducible factor-1 (HIF-1), and inhibition of HIF-1 expression by antisense oligonucleotides resulted in significant inhibition of hypoxia-inducible MDR1 expression and a nearly complete loss of basal MDR1 expression. SIGNOR-254420 0.306 CASP8 protein Q14790 UNIPROT RNF31 protein Q96EP0 UNIPROT down-regulates activity cleavage Asp387 QPPSLVVdSRDAGIC 9606 BTO:0005111 32122970 t miannu We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death. SIGNOR-272195 0.32 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser215 DRNTFRHsVVVPYEP 9606 22611192 t gcesareni We show that aurora b phosphorylates p53 at s183, t211, and s215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and puma). SIGNOR-197602 0.708 SCF-SKP2 complex SIGNOR-C136 SIGNOR CCNE2 protein O96020 UNIPROT down-regulates quantity by destabilization ubiquitination -1 phosphorylation:Ser383;Thr392 FRKGGQLsPVCNGGI;VCNGGIMtPPKSTEK 11533444 t lperfetto The amount of cyclin E protein present in the cell is tightly controlled by ubiquitin-mediated proteolysis. Here we identify the ubiquitin ligase responsible for cyclin E ubiquitination as SCFFbw7 and demonstrate that it is functionally conserved in yeast, flies, and mammals. Fbw7 associates specifically with phosphorylated cyclin E, and SCFFbw7 catalyzes cyclin E ubiquitination in vitro SIGNOR-267559 0.558 NGFR protein P08138 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates 9606 14699954 f amattioni Jnk3 is expressed exclusively in the nervous system and recent evidence indicates that this jnk isoform may be required for p75ntr-mediated cell death SIGNOR-120561 0.426 ADSL protein P30566 UNIPROT 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58475 ChEBI up-regulates quantity chemical modification 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-266608 0.8 PTPN1 protein P18031 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 23639442 t lperfetto This led to increased PTPN1 (PTP1b)-mediated dephosphorylation of VEGFR2 at Y 1175 , the site involved in activating ERK signaling. SIGNOR-277011 0.429 SMC2 protein O95347 UNIPROT Condensin I complex SIGNOR-C341 SIGNOR form complex binding 9606 32445620 t miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263903 0.923 RPS6KB2 protein Q9UBS0 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 t lperfetto In this study, we showed that mad1 is a substrate of p90 ribosomal kinase (rsk) and p70 s6 kinase (s6k). Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway SIGNOR-178594 0.2 LPCAT1 protein Q8NF37 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272761 0.8 GCM2 protein O75603 UNIPROT CASR protein P41180 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004712 BTO:0000975 18712808 f miannu we show that both promoters (P1 and P2) of the calcium-sensing receptor (CASR) gene, a differentiation marker for the parathyroid gland, are transactivated by wild-type GCM2. SIGNOR-254199 0.47 GSK3B protein P49841 UNIPROT PDX1 protein P52945 UNIPROT down-regulates quantity phosphorylation Ser268 LPPGLSAsPQPSSVA 10090 BTO:0002284 19833727 t We show that glucose levels modulate PDX1 protein phosphorylation at a novel C-terminal GSK3 consensus that maps to serines 268 and 272. A decrease in glucose levels triggers increased turnover of the PDX1 protein in a GSK3-dependent manner, such that PDX1 phosphomutants are refractory to the destabilizing effect of low glucose SIGNOR-255566 0.2 DYRK2 protein Q92630 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Thr514 TTTPKGGtPAGSARG 9606 16611631 t lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro SIGNOR-145987 0.371 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273045 0.556 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HECTD3 protein Q5T447 UNIPROT up-regulates activity phosphorylation Thr157 ARLVPIDtPNHLQRQ 9606 BTO:0004461 28716524 t miannu HECTD3 binds and ubiquitinates caspase-9.Phosphorylation of HECTD3 by ERK is required for the association of HECTD3 and caspase-9. HECTD3 suppressing caspase-9 activation is dependent on T157 phosphorylation by ERK. SIGNOR-272330 0.2 CBP/p300 complex SIGNOR-C6 SIGNOR KLF1 protein Q13351 UNIPROT up-regulates activity acetylation 9606 BTO:0002731 9707565 t Regulation miannu CBP and p300, but Not P/CAF, Enhance EKLF Trans-activation in Erythroid Cells. We find that EKLF is an acetylated transcription factor, and that it interacts in vivo with CBP, p300, and P/CAF. However, its interactions with these histone acetyltransferases are not equivalent, as CBP and p300, but not P/CAF, utilize EKLF as a substrate for in vitro acetylation within its trans-activation region. SIGNOR-251789 0.472 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 23431053 t milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity SIGNOR-201286 0.845 SRC protein P12931 UNIPROT CHRNA7 protein P36544 UNIPROT down-regulates phosphorylation Tyr386 ASNGNLLyIGFRGLD 9606 16251431 t gcesareni ?7 Neuronal nicotinic acetylcholine receptors are negatively regulated by tyrosine phosphorylation and src-family kinases SIGNOR-141307 0.2 AKT1 protein P31749 UNIPROT NHEJ1 protein Q9H9Q4 UNIPROT down-regulates quantity by destabilization phosphorylation Thr181 LIRDRLKtEPFEENS 9606 BTO:0000567 25661488 t miannu Akt1 phosphorylates XLF at T181 Here, we report that Akt phosphorylates XLF at Thr181 to trigger its dissociation from the DNA ligase IV/XRCC4 complex, and promotes its interaction with 14-3-3β leading to XLF cytoplasmic retention, where cytosolic XLF is subsequently degraded by SCF(β-TRCP) in a CKI-dependent manner.  SIGNOR-276881 0.365 CNR1 protein P21554 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257119 0.255 GFI1 protein Q99684 UNIPROT SPI1 protein P17947 UNIPROT down-regulates activity binding 10090 BTO:0000725 17197705 t miannu Our data demonstrate that GFI-1 physically interacts with PU.1, repressing PU.1-dependent transcription. This repression is functionally significant, as GFI-1 blocked PU.1-induced macrophage differentiation of a multipotential hematopoietic progenitor cell line. SIGNOR-256043 0.612 KATP channel complex SIGNOR-C274 SIGNOR potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 28842488 t lperfetto ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits. SIGNOR-262053 0.8 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273077 0.635 CHUK protein O15111 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser181 DQGSLCTsFVGTLQY -1 10022904 t llicata Our data indicate that IKKα stimulates IKKβ kinase activity for the IκBα substrate. Finally, we demonstrate that IKKα can phosphorylate IKKβ in in vitro kinase assays. SIGNOR-250772 0.656 TRiC complex SIGNOR-C539 SIGNOR KRAS protein P01116 UNIPROT up-regulates quantity by stabilization binding 9606 36185250 t miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). SIGNOR-272871 0.269 ABL1 protein P00519 UNIPROT CRK protein P46108 UNIPROT down-regulates activity phosphorylation Tyr221 GGPEPGPyAQPSVNT 9606 21602891 t lperfetto Abl induces phosphorylation at y251 in vivo, and that the kinetics of phosphorylation at y251 and the negative regulatory y221 site in vitro are similar. SIGNOR-173845 0.754 PLCG2 protein P16885 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates quantity chemical modification 9606 23000145 t scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). SIGNOR-268453 0.8 MAPK3 protein P27361 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation 9606 19188143 t lperfetto Phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression SIGNOR-183695 0.681 CNR1 protein P21554 UNIPROT HCRTR1 protein O43613 UNIPROT up-regulates activity binding 9606 29751001 t miannu Another example is the heteromer between CB1 and orexin 1 receptor (OX1R). The CB1 activation potentiated the OX1R signaling (218), suggesting the interaction of these two receptors. Interaction of their surface distribution was also reported.  SIGNOR-264269 0.397 MAPK3 protein P27361 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 t lperfetto Erk phosphorylates threonine 42 residue of ribosomal protein s3. SIGNOR-137175 0.358 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI ALK protein Q9UM73 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258219 0.8 SCF-betaTRCP complex SIGNOR-C5 SIGNOR NFKB1 protein P19838 UNIPROT up-regulates activity ubiquitination 9534 BTO:0004055 11295495 t lperfetto The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk. SIGNOR-217190 0.502 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.737 SLC4A10 protein Q6U841 UNIPROT hydrogencarbonate smallmolecule CHEBI:17544 ChEBI up-regulates quantity relocalization 9606 26136660 t miannu Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. In neurons, bicarbonate transport is mainly mediated by members of the SLC4A family of proteins. While the Na+-independent anion-exchanger SLC4A3 lowers the intraneuronal bicarbonate concentration, the Na+-dependent anion exchangers SLC4A8 (NDCBE) and SLC4A10 (NCBE) use the sodium gradient to accumulate bicarbonate in exchange of chloride SIGNOR-264919 0.8 Obatoclax mesylate chemical CID:46930996 PUBCHEM BCL2L1 protein Q07817 UNIPROT down-regulates activity chemical inhibition -1 23515850 t lperfetto Obatoclax and its predecessor analogs bind to BCL-2, BCL-XL, BCL-w, BCL-B, BFL-1, and MCL-1 in vitro SIGNOR-262023 0.8 BAD protein Q92934 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 t lperfetto Bad, however, bound tightly to bcl-2, bcl2l1, and bcl2l2 SIGNOR-133759 0.842 PPP2CA protein P67775 UNIPROT RPS6KB1 protein P23443 UNIPROT down-regulates dephosphorylation 9606 2826472 t gcesareni Protein phosphatase 2a inactivates the mitogen-stimulated s6 kinase from swiss mouse 3t3 cells SIGNOR-23575 0.709 MICU1 protein Q9BPX6 UNIPROT MCU_MICUB_variant complex SIGNOR-C499 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270859 0.678 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser262 DSEDYSLsEEGQELS 9606 20708156 t gcesareni Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination SIGNOR-167517 0.352 MC5R protein P33032 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257393 0.271 CTDSPL2 protein Q05D32 UNIPROT HBG2 protein P69892 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 20932329 f Indirect:regulation of transcription miannu CTD small phosphatase like 2 (CTDSPL2) can increase ε- and γ-globin gene expression in K562 cells and CD34+ cells derived from umbilical cord blood. SIGNOR-251777 0.2 TMLHE protein Q9NVH6 UNIPROT succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity chemical modification 9606 11431483 t miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. SIGNOR-269683 0.8 PKN1 protein Q16512 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Thr678 RHIVRKRtLRRLLQE 9606 21749319 t lperfetto This identified thr654 in egfr as the pkn1 phosphorylation siteit has been shown that the phosphorylation of egfr at thr654 by pkc reduces the tyrosine kinase activity of the receptor SIGNOR-174755 0.2 RAI1 protein Q7Z5J4 UNIPROT CRY1 protein Q16526 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000614 22578325 f miannu Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. SIGNOR-266842 0.349 lofepramine chemical CHEBI:47782 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 t miannu At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter.  SIGNOR-258881 0.8 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 10090 BTO:0002572;BTO:0000801 21232017 t gcesareni Rip1 is known to directly interact with traf2 SIGNOR-245032 0.891 calcidiol smallmolecule CHEBI:17933 ChEBI calcitriol smallmolecule CHEBI:17823 ChEBI up-regulates quantity precursor of 9606 BTO:0000671 12050193 t lperfetto The rate-limiting, hormonally regulated step in the biological activation of vitamin D is its 1alpha-hydroxylation to 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] in the kidney, catalyzed by the mitochondrial cytochrome P450 enzyme, P450c1alpha. SIGNOR-270558 0.8 GSK3B protein P49841 UNIPROT MITF protein O75030 UNIPROT up-regulates activity phosphorylation Ser405 QARAHGLsLIPSTGL -1 10587587 t miannu Here, we show that Ser298, which locates downstream of the bHLHZip and was previously found to be mutated in individuals with WS2, plays an important role in MITF function. Glycogen synthase kinase 3 (GSK3) was found to phosphorylate Ser298 in vitro, thereby enhancing the binding of MITF to the tyrosinase promoter.  SIGNOR-275967 0.446 ADCYAP1 protein P18509 UNIPROT ADCYAP1R1 protein P41586 UNIPROT up-regulates binding 9606 8703026 t gcesareni Type i pacap receptors bind pacap-27 and -38. the potencies of the two forms of pacap are similar for adenylate cyclase stimulation, whereas pacap-38 is more potent than pacap-27 in phospholipase c activation. SIGNOR-43225 0.873 TGFB2 protein P61812 UNIPROT TGFBR3 protein Q03167 UNIPROT up-regulates binding 9606 10746731 t gcesareni Betaglycan binds tgf-b isoforms with high affinity and increases the functional interaction between tgf-b and its type ii and type i signalling receptors. SIGNOR-76473 0.532 carbachol chemical CHEBI:3385 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258619 0.8 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1787 SPNYSPTsPSYSPTS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248815 0.849 SOX9 protein P48436 UNIPROT DCC protein P43146 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003858 19745029 f miannu Promoter analysis and transfection studies showed that the up-regulation of DCC in OA chondrocytes may be mediated by the transcription factors Sox9 and AP-2. SIGNOR-255188 0.2 IL1B protein P01584 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 f miannu High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity. SIGNOR-261026 0.7 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR AMPK complex SIGNOR-C15 SIGNOR down-regulates activity phosphorylation 9606 21460634 t lperfetto Here we report that ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. Thus, we propose that ulk1 is not only involved in the induction of autophagy, but also in terminating signaling events that trigger autophagy. In our model, phosphorylation of ampk by ulk1 represents a negative feedback circuit. SIGNOR-209916 0.409 AMPK complex SIGNOR-C15 SIGNOR GYS2 protein P54840 UNIPROT down-regulates activity phosphorylation Ser8 MLRGRSLsVTSLGGL -1 22233421 t miannu Recombinant muscle GYS1 (glycogen synthase 1) and recombinant liver GYS2 were phosphorylated by recombinant AMPK (AMP-activated protein kinase) in a time-dependent manner and to a similar stoichiometry. The phosphorylation site in GYS2 was identified as Ser7, which lies in a favourable consensus for phosphorylation by AMPK. Phosphorylation of GYS1 or GYS2 by AMPK led to enzyme inactivation by decreasing the affinity for both UDP-Glc (UDP-glucose) [assayed in the absence of Glc-6-P (glucose-6-phosphate)] and Glc-6-P (assayed at low UDP-Glc concentrations). SIGNOR-263101 0.397 CDK3 protein Q00526 UNIPROT MECOM protein Q03112 UNIPROT up-regulates activity phosphorylation Ser624 KMFKDKVsPLQNLAS 33082307 t lperfetto The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A. SIGNOR-273431 0.2 17beta-estradiol smallmolecule CHEBI:16469 ChEBI GPER1 protein Q99527 UNIPROT up-regulates chemical activation 9534 BTO:0000298 15705806 t Luana Competition binding assays of E2-Alexa 633 binding with 17β-estradiol demonstrated a Ki for 17β-estradiol of approximately 6.6 nM for GPR30 (Fig. 2F). These results demonstrate that a classic GPCR superfamily member directly binds a sex steroid hormone and that GPR30 is an estrogen-binding receptor. |Activating GPR30 by estrogen resulted in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus. SIGNOR-269752 0.8 ERP44 protein Q9BS26 UNIPROT ITPR1 protein Q14643 UNIPROT down-regulates activity binding 9606 BTO:0000567 15652484 t Simone In this study, we found that ERp44, an ER lumenal protein of the thioredoxin family, directly interacts with the third lumenal loop of IP(3)R type 1 (IP(3)R1) and that the interaction is dependent on pH, Ca(2+) concentration, and redox state. In this study we demonstrated that ERp44 directly interacts with the L3V domain of IP3R1, thereby inhibiting its channel activity. SIGNOR-261046 0.597 PAK5 protein Q9P286 UNIPROT GATA1 protein P15976 UNIPROT up-regulates activity phosphorylation Ser187 LNSAAYSsPKLRGTL 9606 BTO:0000150 25726523 t lperfetto GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. SIGNOR-275656 0.2 IRAK4 protein Q9NWZ3 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity phosphorylation Ser346 FAQTVMTsRIVGTTA 9606 BTO:0000876 24567333 t lperfetto We show irak4 autophosphorylation occurs by an intermolecular reaction and that autophosphorylation is required for full catalytic activity of the kinase. Phosphorylation of any two of the residues thr-342, thr-345, and ser-346 is required for full activity SIGNOR-204653 0.2 SHANK3 protein Q9BYB0 UNIPROT GRIA1 protein P42261 UNIPROT up-regulates quantity binding 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264601 0.2 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARB protein P10826 UNIPROT up-regulates activity chemical activation 9606 17132853 t miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. SIGNOR-256195 0.8 E2F2 protein Q14209 UNIPROT TFDP1 protein Q14186 UNIPROT up-regulates activity binding 10029 BTO:0000246 8832394 t 2 miannu The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3. SIGNOR-240550 0.727 CAMK2A protein Q9UQM7 UNIPROT LIPE protein Q05469 UNIPROT down-regulates phosphorylation Ser855 EPMRRSVsEAALAQP 9606 9636039 t gcesareni Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase. SIGNOR-58251 0.2 CLTA protein P09496 UNIPROT AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 t lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-260672 0.756 SLBP protein Q14493 UNIPROT H2BC21 protein Q16778 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265386 0.2 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI JNK proteinfamily SIGNOR-PF15 SIGNOR down-regulates chemical inhibition 9606 11717429 t inferred from 70% of family members gcesareni We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm). To determine whether jnk activity is required for stress-induced translocation of bax to the mitochondria, we examined the effect of sp600125, a jnk inhibitor. SIGNOR-269885 0.8 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr1063 FGLARDIyKDPDYVR 9606 20431062 t lperfetto Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk. SIGNOR-165035 0.492 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258631 0.8 PRKCA protein P17252 UNIPROT DGKD protein Q16760 UNIPROT down-regulates activity phosphorylation Ser70 QNNSFQRsKRRYFKL 9534 15228384 t lperfetto The plasma membrane translocation of diacylglycerol kinase delta1 is negatively regulated by conventional protein kinase C-dependent phosphorylation at Ser-22 and Ser-26 within the pleckstrin homology domain. SIGNOR-249266 0.373 MAPK3 protein P27361 UNIPROT AMPH protein P49418 UNIPROT down-regulates activity phosphorylation Ser293 PAPARPRsPSQTRKG 9606 15262992 t lperfetto Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2. SIGNOR-126867 0.277 AKT proteinfamily SIGNOR-PF24 SIGNOR PDE3B protein Q13370 UNIPROT up-regulates phosphorylation Ser295 VIRPRRRsSCVSLGE 9606 10454575 t esanto Pde3b is a physiological substrate of akt and that akt-mediated phosphorylation of pde3b on serine-273 is important for insulin-induced activation of pde3b. SIGNOR-70205 0.2 RAB1A protein P62820 UNIPROT GOLGA2 protein Q08379 UNIPROT up-regulates activity relocalization 10116 11285137 t Giulio Here, we demonstrate that the cis ‐Golgi tethering protein GM130, complexed with GRASP65 and other proteins, forms a novel Rab1 effector complex that interacts with activated Rab1‐GTP in a p115‐independent manner and is required for coat protein II vesicle targeting/fusion with the cis ‐Golgi SIGNOR-261285 0.706 Ast-487 chemical CID:11409972 PUBCHEM KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258070 0.8 (8R)-7-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-13,14-diol chemical CHEBI:92234 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258731 0.8 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr12 FGSRSSKtFKPKKNI 9606 21808241 t The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction. SIGNOR-175813 0.81 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT unknown phosphorylation Thr17 RVSSYRRtFGGAPGF 9606 BTO:0000971 10574968 t lperfetto We developed antibodies specifically recognizing the kinase-dependent phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies, phosphorylation of desmin was observed specifically at the cleavage furrow in late mitotic Saos-2 cells. We then found that treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin SIGNOR-249032 0.322 STK26 protein Q9P289 UNIPROT ATG4B protein Q9Y4P1 UNIPROT up-regulates activity phosphorylation Ser383 RLERFFDsEDEDFEI 29232556 t lperfetto ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. SIGNOR-275833 0.2 lenalidomide chemical CHEBI:63791 ChEBI CRBN protein Q96SW2 UNIPROT down-regulates activity chemical inhibition 9606 22552008 t miannu Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide. SIGNOR-259284 0.8 PTPRJ protein Q12913 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1365 NVKCVAPyPSLLSSE 9606 BTO:0000007 12475979 t When co-expressed in 293 cells, the full-length substrate-trapping mutant form of DEP-1 formed a stable complex with the chimeric receptor colony stimulating factor 1 (CSF)-Met and wild type DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1 preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr(1365)), SIGNOR-248703 0.592 PIK-90 chemical CID:6857685 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206223 0.8 AMPK complex SIGNOR-C15 SIGNOR VASP protein P50552 UNIPROT down-regulates phosphorylation Ser322 TTLPRMKsSSSVTTS 9606 21945940 t lperfetto Here we show that phosphorylation of vasp by ampk occurs at a novel site, serine 322, and that phosphorylation at this site alters actin filament binding. We also show that inhibition of ampk activity results in the accumulation of vasp at cell-cell adhesions and a concomitant increase in cell-cell adhesion. SIGNOR-216568 0.2 OXSR1 protein O95747 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser91 ASFHAYDsHTNTYYL 9606 BTO:0000007 21321328 t miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). SIGNOR-276312 0.516 IFNG protein P01579 UNIPROT Demyelination phenotype SIGNOR-PH155 SIGNOR up-regulates 10090 BTO:0000227 24507514 f miannu Beside its wellknown antiviral and proinflammatory action, overexpression of IFN-g in the CNS could participate in demyelination. Transgenic overexpression of IFN-g in the mouse by CNS oligodendrocytes led to chronic demyelination that may be severe SIGNOR-263833 0.7 SMAD5 protein Q99717 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR form complex binding 9606 20957627 t lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. SIGNOR-255266 0.661 trametinib chemical CHEBI:75998 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates activity chemical inhibition 9606 26347206 t miannu Trametinib (Mekinist™) is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 with anticancer activity against metastatic melanoma carrying the BRAF V600 mutation. SIGNOR-259447 0.8 DHRS9 protein Q9BPW9 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI down-regulates quantity chemical modification 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS10 SIGNOR-265116 0.8 DAPK3 protein O43293 UNIPROT RPL13A protein P40429 UNIPROT up-regulates phosphorylation Ser77 PYHFRAPsRIFWRTV 9606 BTO:0000801 18995835 t lperfetto Zipk phosphorylates l13a in vitro / l13a is phosphorylated on ser77 in vitro SIGNOR-182117 0.411 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu72 MEEKCSFeEAREVFE 10090 BTO:0001103 11133752 t lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. SIGNOR-263692 0.67 THBS1 protein P07996 UNIPROT NGF protein P01138 UNIPROT up-regulates binding 9606 10708953 t lpetrilli We have identified a mechanism for the activation of latent tgf-beta that involves binding of the secreted and extracellular matrix protein, thrombospondin-1 (tsp-1), to the latent precursor. SIGNOR-75624 0.281 CDX2/PAX6/P300 complex SIGNOR-C33 SIGNOR GCG protein P01275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10506141 f miannu Pax-6 and cdx-2 also directly interacted with one another at the protein level. pax-6, bound to its dna recognition site in the glucagon g1 promoter element, tethered cdx-2 to the molecular complex of pax-6 and p300. Further, we found that the presence of cdx-2 enhanced the interaction of pax-6 with p300, thus establishing a molecular complex of transcription factors implicated in tissue-specific glucagon gene expression with the basal transcriptional machinery. SIGNOR-70957 0.452 MAPK9 protein P45984 UNIPROT ATN1 protein P54259 UNIPROT down-regulates activity phosphorylation Ser739 EEYETPEsPVPPARS 9606 BTO:0000142 12812981 t lperfetto Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment, SIGNOR-102402 0.2 PRSS21 protein Q9Y6M0 UNIPROT RAD21 protein O60216 UNIPROT up-regulates cleavage 9606 11875078 t miannu Rad21 is a component of the cohesin complex that holds sister chromatids together during mitosis and repairs double-strand dna breaks. Interestingly, rad21 is cleaved by a caspase-like esp1/separase at the onset of anaphase to trigger sister chromatid separation. SIGNOR-115426 0.2 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000142 20308788 t The effect has been demonstrated using P10636-8 lperfetto Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro. SIGNOR-164667 0.2 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI up-regulates quantity precursor of 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267423 0.8 SLC12A5 protein Q9H2X9 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates quantity relocalization 21613606 t lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  SIGNOR-264637 0.8 NEK2 protein P51955 UNIPROT NDC80 protein O14777 UNIPROT up-regulates phosphorylation Ser165 LGYPFALsKSSMYTV 9606 12386167 t lperfetto Phosphorylation of the mitotic regulator protein hec1 by nek2 kinase is essential for faithful chromosome segregation.Hec1 (highly expressed in cancer) plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the g(2)/m phase.Nek2 phosphorylates hec1 on serine residue 165, both in vitro and in vivo. SIGNOR-94322 0.609 FANCC protein Q00597 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 t lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263246 0.921 KAT2A protein Q92830 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 BTO:0000150 SIGNOR-C7 15009097 t gcesareni Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo. SIGNOR-123318 0.506 GSK3A protein P49840 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser641 KVTSKCGsLGNIHHK 9606 BTO:0000590 7706316 t lperfetto Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262. SIGNOR-249342 0.44 glycogen smallmolecule CHEBI:28087 ChEBI PYGB protein P11216 UNIPROT up-regulates activity chemical activation 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267951 0.8 ATR protein Q13535 UNIPROT WRN protein Q14191 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1141 PEKAYSSsQPVISAQ 9606 BTO:0000567 26695548 t miannu A serine residue, S1141, in WRN is phosphorylated in vivo by the ATR kinase in response to replication stress. ATR-mediated WRN S1141 phosphorylation leads to ubiquitination of WRN, facilitating the reversible interaction of WRN with perturbed replication forks and subsequent degradation of WRN. SIGNOR-277187 0.786 CAMK2D protein Q13557 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates 9606 19725819 f areggio In response toincreases in intracellular Ca2+ levels, activated CaMKII translocates into the nucleus where it phosphorylates and deactivates HDAC4 which, as a result, dissociates from theDNA-binding domain of MEF2. This dissociation allows MEF2 to bind to its DNA-binding domain to activate transcription of the MEF2-dependent target gene products MyoD and myogenin SIGNOR-255956 0.43 GSK3B protein P49841 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 9606 14563837 t gcesareni Conversely, overexpression of gsk-3 alpha or gsk-3 beta enhances thr-58 phosphorylation and ubiquitination of c-myc SIGNOR-118844 0.709 CNR1 protein P21554 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256867 0.521 PRKCZ protein Q05513 UNIPROT PARD3 protein Q8TEW0 UNIPROT up-regulates phosphorylation Ser827 REGFGRQsMSEKRTK 9606 12390250 t gcesareni These results imply that serine 827 in the apkc binding site of par-3 is a target of apkc and that the regulated interaction between a protein kinase, apkc, and its substrate, par-3, plays an essential role in the establishment of cell polarity SIGNOR-94523 0.699 PPP1CA protein P62136 UNIPROT AHCYL1 protein O43865 UNIPROT unknown dephosphorylation Ser68 RSLSRSIsQSSTDSY 10090 17635105 t Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1. SIGNOR-248555 0.2 SMAD5 protein Q99717 UNIPROT GADD45G protein O95257 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 t Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation SIGNOR-268942 0.2 IL15RA protein Q13261 UNIPROT JAK3 protein P52333 UNIPROT up-regulates 9606 30029643 t Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated SIGNOR-256226 0.48 IFNA1 protein P01562 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates binding 9606 8181059 t fspada The present study describes a novel type i ifn receptor having the ability to bind and respond to several subtypes of ifn-a as well as to ifn-8. This 102 kda-51 kda receptor is essential for the activity of many type i ifns, as demonstrated with anti-receptor antibodies. SIGNOR-36622 0.648 GCC2 protein Q8IWJ2 UNIPROT M6PR protein P20645 UNIPROT up-regulates activity relocalization 18195106 t lperfetto Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector SIGNOR-253086 0.512 FOXL2 protein P58012 UNIPROT STAR protein P49675 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21862621 f miannu We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation. SIGNOR-254180 0.367 SMARCE1 protein Q969G3 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270602 0.818 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser168 YREPLCLsPASSGSS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252319 0.635 GTF2I protein P78347 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR up-regulates activity relocalization 17970752 t lperfetto We demonstrate that Suz12, a component of the polycomb repressor complex 2, is recruited to the beta-globin gene.| Our data suggest that TFII-I contributes to the recruitment of the polycomb repressor complex 2 complex to the beta-globin gene. SIGNOR-268543 0.369 SAR1A protein Q9NR31 UNIPROT SEC24D protein O94855 UNIPROT up-regulates quantity binding SIGNOR-C370 30605680 t lperfetto Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. SIGNOR-265301 0.702 MAPK3 protein P27361 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates phosphorylation Thr679 PGVELLLtPREPALP 9606 BTO:0000567 18211802 t gcesareni Activates rhoa and as a result regulates actin assembly. SIGNOR-160420 0.294 CHD4 protein Q14839 UNIPROT ChAHP complex SIGNOR-C407 SIGNOR form complex binding 10090 BTO:0002896 29795351 t miannu Here we show that ADNP interacts with the chromatin remodeller CHD4 and the chromatin architectural protein HP1 to form a stable complex, which we refer to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. In conclusion, CHD4, ADNP and HP1β/γ form a stable protein complex, which we refer to as ChAHP. SIGNOR-266752 0.421 NBR1 protein Q14596 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 BTO:0000007 19250911 t gcesareni We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. SIGNOR-184270 0.576 IL4R protein P24394 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica The type i il-4 receptors result from association of IL-4R With the common ? Chain (?c), which is also a component of the receptors for il-2, il-7, il-9, and il-15. SIGNOR-100765 0.823 CDK1 protein P06493 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Thr219 ASLSLPAtPVGKGTE -1 12556484 t done miannu In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites SIGNOR-274074 0.646 PAX3-FOXO1 fusion protein SIGNOR-FP12 SIGNOR PDGFA protein P04085 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 t miannu Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA. SIGNOR-251571 0.2 HIC1 protein Q14526 UNIPROT VEGFA protein P15692 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000815 24067369 f miannu HIC1 suppressing the VEGF and c-Myc promoter activity and the colony formation of MDA-MB 231 cells were STAT3-dependent. SIGNOR-254247 0.2 CYP11B2 protein P19099 UNIPROT corticosterone smallmolecule CHEBI:16827 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268680 0.8 LTF protein P02788 UNIPROT ITLN1 protein Q8WWA0 UNIPROT up-regulates activity binding 9606 23921499 t Intelectin 1 (IntL) is known as a lectin expressed in intestinal epithelia and also as a receptor for an iron-binding protein, lactoferrin (LF).  SIGNOR-272500 0.369 NOD1 protein Q9Y239 UNIPROT ATG16L1 protein Q676U5 UNIPROT up-regulates activity binding 9606 BTO:0000567 19898471 t miannu By a mechanism independent of the adaptor RIP2 and transcription factor NF-kappaB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease. SIGNOR-252406 0.672 PSMB7 protein Q99436 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263360 0.856 STOML2 protein Q9UJZ1 UNIPROT MFN2 protein O95140 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20359165 f Giorgia Of interest, induction of SLP-2 expression also resulted in significant increases in the levels of OPA-1 and mitofusin-2 (P < 0.05), both integral mitochondrial membrane proteins associated with mitochondrial fusion. SIGNOR-260380 0.342 GC protein P02774 UNIPROT vitamin D smallmolecule CHEBI:27300 ChEBI up-regulates quantity relocalization 9606 BTO:0000759 30080183 t lperfetto Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. SIGNOR-270566 0.8 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates 9606 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268578 0.2 vincaleukoblastine sulfate chemical CHEBI:9984 ChEBI TUBG1 protein P23258 UNIPROT down-regulates activity chemical inhibition 9606 15579115 t miannu Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. SIGNOR-259259 0.8 LATS2 protein Q9NRM7 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22863277 t miannu Lats1/2 inhibit yap by direct phosphorylation at s127, which results in yap binding to 14-3-3 and cytoplasmic sequestration SIGNOR-198514 0.815 DUSP1 protein P28562 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7535768 t We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively SIGNOR-248464 0.798 etanercept chemical CHEBI:4875 ChEBI TNF protein P01375 UNIPROT down-regulates activity binding 9606 25455504 t Etanercept is a recombinant human TNF receptor p75Fc fusion protein that binds with high affinity to the soluble and transmembrane forms of TNF, thereby acting as a decoy receptor for TNF and, prevents TNF-mediated inflammatory cellular responses by competitive inhibition SIGNOR-272490 0.8 MAPK14 protein Q16539 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates 9606 17003045 f gcesareni The ring finger ubiquitin ligase siah2 controls the stability of various substrates involved in stress and hypoxia responses, including the phd3, which controls the stability of hif-1alpha. In the present study we determined the role of siah2 phosphorylation in the regulation of its activity toward phd3. We show that siah2 is subject to phosphorylation by p38 mapk, which increases siah2-mediated degradation of phd3. SIGNOR-149887 0.312 PRKCB protein P05771 UNIPROT ORAI1 protein Q96D31 UNIPROT down-regulates phosphorylation Ser27 GGSTTSGsRRSRRRS 9606 20534587 t llicata We propose that pkc suppresses soce and crac channel function by phosphorylation of orai1 at n-terminal serine residues ser-27 and ser-30. SIGNOR-166040 0.2 oxybutynin chemical CHEBI:7856 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 22243489 t Luana  Interestingly, unlike the methiodide 5, the tertiary amine 17 and to a lesser extent its (S)-eutomer preferentially block the M3 receptor subtype with respect to the M2, with an M3/M2 selectivity ratio slightly higher than those of oxybutynin and the conventional M3selective antagonist 4-DAMP.  SIGNOR-258327 0.8 NCKAP1 protein Q9Y2A7 UNIPROT WAVE complex complex SIGNOR-C271 SIGNOR form complex binding 9606 BTO:0000567 15070726 t lperfetto Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex.  SIGNOR-261874 0.926 AMPK complex SIGNOR-C15 SIGNOR KLC2 protein Q9H0B6 UNIPROT up-regulates phosphorylation Ser582 PRMKRASsLNFLNKS 9606 21725060 t lperfetto Consistent with phosphorylation of both ser545 and ser582 of klc2 contributing to its 14-3-3 binding, a ser545ala mutant of klc2 could be phosphorylated in vitro by ampk on ser582 SIGNOR-216468 0.291 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser497 ATVKSRWsGSQQVEQ 9606 8288587 t gcesareni Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. SIGNOR-37470 0.539 POLR3A protein O14802 UNIPROT Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR up-regulates 9606 19631370 t miannu Here we show that the cytosolic poly(dA-dT) DNA is converted into 5′-ppp RNA to induce IFN-β through the RIG-I pathway. Biochemical purification led to the identification of DNA-dependent RNA polymerase III (Pol-III) as the enzyme responsible for synthesizing 5′-ppp RNA from the poly(dA-dT) template. Inhibition of RNA Pol-III prevents IFN-β induction by transfection of DNA or infection with DNA viruses. SIGNOR-265563 0.7 prostaglandin G2(1-) smallmolecule CHEBI:82629 ChEBI prostaglandin H2(1-) smallmolecule CHEBI:57405 ChEBI up-regulates quantity precursor of -1 7592599 t Luana [14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2, SIGNOR-269777 0.8 P2RY10 protein O00398 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257213 0.358 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR up-regulates 9606 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268588 0.2 SAV1 protein Q9H4B6 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity binding 9606 21084559 t miannu Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst. SIGNOR-256183 0.892 CSNK1G1 protein Q9HCP0 UNIPROT LYN protein P07948 UNIPROT up-regulates quantity by stabilization phosphorylation Ser13 SKGKDSLsDDGVDLK 9606 BTO:0000007 33004926 t miannu Although there have been more than 40 reports of mass spectrometric studies on phosphorylation at Lyn-S13, the kinase responsible remained unclear. We succeeded in identifying casein kinase 1γ (CK1γ) as the kinase responsible for phosphorylation of Lyn-S13. In HEK293 cells co-expressing Lyn and CK1γ, the phosphorylation level of Lyn-S13 increased significantly. we concluded that S-palmitoylated CK1γ encounters N-myristoylated Lyn and specifically phosphorylates the Ser-13 residue at the Golgi during intracellular protein traffic, as shown schematically in Fig. 8. Phosphorylated dual-lipid-modified Lyn and S-palmitoylated CK1γ are then transported from the Golgi to the plasma membrane. SIGNOR-275396 0.2 FYN protein P06241 UNIPROT FCGR2A protein P12318 UNIPROT up-regulates activity phosphorylation Tyr304 TDDDKNIyLTLPPND -1 8756631 t lperfetto To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation. SIGNOR-249337 0.514 NFIX protein Q14938 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268909 0.2 TWIST2 protein Q8WVJ9 UNIPROT NF1 protein P21359 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255505 0.2 ZNHIT1 protein O43257 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20473270 t gcesareni We show that the srcap subunit named znhit1 or p18hamlet, which is a substrate of p38 mapk, is recruited to the myogenin promoter at the onset of muscle differentiation, in a p38 mapk-dependent manner. We also show that p18hamlet is required for h2a.z accumulation into this genomic region and for subsequent muscle gene transcriptional activation. SIGNOR-165613 0.262 PTGS2 protein P35354 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 9606 BTO:0000586 16293724 f lperfetto We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway. SIGNOR-141783 0.418 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 10090 15856019 t milica Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. SIGNOR-236988 0.437 CDC42 protein P60953 UNIPROT CDC42BPA protein Q5VT25 UNIPROT up-regulates activity binding 9606 BTO:0000567 9418861 t lperfetto Myotonic dystrophy kinase-related Cdc42-binding kinase acts as a Cdc42 effector in promoting cytoskeletal reorganization|MRCK alpha and Cdc42V12 colocalize, particularly at the cell periphery in transfected HeLa cells. Microinjection of plasmid encoding MRCK alpha resulted in actin and myosin reorganization. SIGNOR-262593 0.784 USP7 protein Q93009 UNIPROT MDM4 protein O15151 UNIPROT up-regulates deubiquitination 9606 16082221 t gcesareni Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins. SIGNOR-139453 0.747 EGLN3 protein Q9H6Z9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates activity hydroxylation 9606 BTO:0000567 21620138 t Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1Œ± and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. SIGNOR-268147 0.447 PTGES2 protein Q9H7Z7 UNIPROT prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI up-regulates quantity chemical modification -1 10922363 t Luana Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently. SIGNOR-269766 0.8 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser129 PYPSPVLsEEEDLPL 9606 10618498 t lperfetto Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability SIGNOR-73879 0.439 YY1 protein P25490 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates activity binding 9606 BTO:0000664 12913000 t Taken together, these results indicate that transcription factor YY1 may modulate Notch signaling via association with the high molecular weight Notch complex [..] both YY1 and N1IC were present in a large complex of the nucleus to suppress the luciferase reporter activity transactivated by Notch signaling. SIGNOR-251654 0.607 PAK proteinfamily SIGNOR-PF13 SIGNOR SYN1 protein P17600 UNIPROT unknown phosphorylation 10116 12237306 t inferred from 70% family members miannu Recombinant PAK2 could also phosphorylate the Ser9 and Ser551 residues. SIGNOR-269974 0.2 LRP1B protein Q9NZR2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002940 27626682 f irozzo Conversely, in Calu-1 cells, which express higher endogenous levels of the receptor, siRNA-mediated LRP1B knockdown significantly enhanced cellular proliferation. Taken together, these findings demonstrate that, consistent with the postulated tumor suppressor function, overexpression of full-length Lrp1b leads to impaired cellular proliferation, while LRP1B knockdown has the opposite effect. SIGNOR-259089 0.7 PRKCA protein P17252 UNIPROT TOP1 protein P11387 UNIPROT up-regulates activity phosphorylation Ser21 ADFRLNDsHKHKDKH -1 18408216 t miannu In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells. SIGNOR-276154 0.2 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19914161 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161561 0.547 RHOA protein P61586 UNIPROT RDX protein P35241 UNIPROT up-regulates activity phosphorylation Thr564 AGRDKYKtLRQIRQG 9606 BTO:0000132 35267019 t miannu Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. SIGNOR-268430 0.483 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 12110590 t gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. SIGNOR-90521 0.786 AXIN2 protein Q9Y2T1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates 9606 BTO:0000149 11940574 f gcesareni Although wnts act to stabilize _-catenin levels in the cytosol and nucleus, a multiprotein complex containing adenomatous polyposis coli, glycogen synthase kinase 3_, and axin1 or its homolog axin2/axil/conductin promotes _-catenin phosphorylation and subsequent proteasomal degradation. SIGNOR-116480 0.843 WNT6 protein Q9Y6F9 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 22944199 f gcesareni In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod. Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. SIGNOR-198916 0.329 GPER1 protein Q99527 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 10696571 t GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; the activated receptor induces a conformational change in the associated G protein α-subunit leading to release of GDP followed by binding of GTP and α-subunit dissociation from the receptor. SIGNOR-251102 0.354 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val48 KVDGTSHvTGKGVTV -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263598 0.381 STAP1 protein Q9ULZ2 UNIPROT KIT protein P10721 UNIPROT up-regulates activity binding 9606 BTO:0000007 10679268 t miannu STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells. SIGNOR-261822 0.486 ADGRG1 protein Q9Y653 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 24949629 t Like many other adhesion GPCRs, GPR56 is cleaved via a GPCR autoproteolysis-inducing (GAIN) domain into N- and C-terminal fragments (GPR56N and GPR56C); | We demonstrate that ligand binding releases GPR56N from the membrane-bound GPR56C and triggers the association of GPR56C with lipid rafts and RhoA activation. SIGNOR-253981 0.2 GATA3 protein P23771 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 15632071 f fspada Constitutive expression of both gata-2 and gata-3 suppressed adipocyte differentiation, partially through direct binding to the peroxisome proliferator-activated receptor gamma (ppargamma) promoter and suppression of its basal activity SIGNOR-132955 0.355 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258187 0.8 CDK6 protein Q00534 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 BTO:0000776;BTO:0000785 16160006 t gcesareni Phosphorylation on thr-187, by cdk2 leads to protein ubiquitination and proteasomal degradationp27(kip1) was phosphorylated by v-cyclin-cdk6 predominantly on ser10, which enhances its cytoplasmic localization. Interestingly, upon reactivation of kshv lytic cycle, v-cyclin-cdk6 phosphorylated p27(kip1) on thr187, which resulted in down-regulation of p27(kip1) protein levels. SIGNOR-140405 0.85 PRKCB protein P05771 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS -1 8422248 t lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III SIGNOR-248926 0.663 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr383 HYRYSDTtDSDPENE 9606 21779440 t gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity SIGNOR-89830 0.667 AAK1 protein Q2M2I8 UNIPROT AP2M1 protein Q96CW1 UNIPROT up-regulates phosphorylation Thr156 SQITSQVtGQIGWRR 9606 BTO:0000938 11877461 t lperfetto Aak1 is enriched at presynaptic terminals, whereas in nonneuronal cells it colocalizes with clathrin and ap2 in clathrin-coated pits and at the leading edge of migrating cells. Aak1 specifically phosphorylates the mu subunit in vitro, and stage-specific assays for endocytosis show that mu phosphorylation by aak1 results in a decrease in ap2-stimulated transferrin internalization. Together, these results provide strong evidence that aak1 is the endogenous mu 2 kinase and plays a regulatory role in clathrin-mediated endocytosis. SIGNOR-115657 0.782 SRP19 protein P09132 UNIPROT SRP72 protein O76094 UNIPROT up-regulates activity binding -1 30649418 t miannu Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54. SIGNOR-261166 0.941 WNT4 protein P56705 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131832 0.635 HIF1A protein Q16665 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27141364 f irozzo STAT3 and HIF-1α cooperatively enhance PD-L1 expression in EML4-ALK-translocated pADC cells under hypoxia. Taken together, these findings suggest that EML4-ALK might increase HIF-1α expression under hypoxia by enhancing transcription and inhibiting ubiquitination of HIF-1α, resulting in the stabilization of HIF-1α, consequently contributing to HIF-1α-mediated upregulation of PD-L1 under hypoxia. SIGNOR-259092 0.285 RAD23B protein P54727 UNIPROT RPA2 protein P15927 UNIPROT up-regulates activity binding 24086043 t lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275699 0.502 CSNK2A1 protein P68400 UNIPROT MAPK9 protein P45984 UNIPROT unknown phosphorylation Thr404 SSMSTEQtLASDTDS 9606 11062067 t lperfetto The phosphorylation of thr-404 and ser-407 is not increased in response to other agonists that activate mkk7 and sapk1/jnk, suggesting that phosphorylation of these residues is catalysed by another protein kinase, such as ck2, which also phosphorylates thr-404 and ser-407 in vitro. SIGNOR-83715 0.222 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR2 protein O95136 UNIPROT up-regulates activity chemical activation 10116 10617617 t We observed that S1P treatment significantly increased proliferation of HTC4 hepatoma cells stably transfected with human S1P receptor Edg3 or Edg5, which was attributable to stimulation of cell growth and inhibition of apoptosis caused by serum starvation. SIGNOR-261141 0.8 MMP13 protein P45452 UNIPROT F12 protein P00748 UNIPROT down-regulates quantity by destabilization cleavage Gly376 SMTRVVGgLVALRGA -1 10930399 t lperfetto The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage. SIGNOR-263609 0.318 rRNA_transcription phenotype SIGNOR-PH145 SIGNOR 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR up-regulates 25838379 f lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by means of single-particle electron cryogenic microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three ribosomal RNA molecules. SIGNOR-262600 0.7 RPA1 protein P27694 UNIPROT POLA1 protein P09884 UNIPROT up-regulates activity binding -1 9214288 t Federica In our studies, we have shown that T antigen, DNA polymerase R, and the activation domain of VP16 all interact with overlapping regions of the 70-kDa subunit of RPA.| In the latter, both the direct protein-protein interaction and ssDNA-binding activities of RPA were needed for RPA to modulate polymerase processivity. We also found that SV40 T antigen inhibited the ability of RPA to increase processivity of DNA polymerase alpha, suggesting that this activity of RPA may be important for elongation but not during the initiation of DNA replication. SIGNOR-261272 0.674 PTPN18 protein Q99952 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr1112 DPSPLQRySEDPTVP 9606 BTO:0000007 25081058 t lperfetto PTPN18 knockdown selectively enhances the EGF-induced tyrosine phosphorylation of the HER2 Y1112, Y1196 and Y1248 sites. |Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop. SIGNOR-262595 0.658 AGT protein P01019 UNIPROT AGTR1 protein P30556 UNIPROT up-regulates binding 9606 BTO:0001130 16597412 t gcesareni Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors. SIGNOR-145677 0.847 PLK3 protein Q9H4B4 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates phosphorylation Ser49 ESEMETPsAINGNPS 9606 21336504 t lperfetto Polo kinase 3 (plk3) was implicated in bcl-xl(ser49) phosphorylation. These data indicate that, during g2 checkpoint, phospho-bcl-xl(ser49) is another downstream target of plk3, acting to stabilize g2 arrest. SIGNOR-172230 0.399 CyclinC/CDK3 complex SIGNOR-C545 SIGNOR G0/G1_transition phenotype SIGNOR-PH219 SIGNOR up-regulates 37104883 f lperfetto Among them, CDK3 is critically important because it triggers the transitions of G0 to G1 and G1 to S phase through binding to cyclin C and cyclin E1, respectively. SIGNOR-273190 0.7 CDK2 protein P24941 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 SIGNOR-C83 17601773 t fspada Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity. SIGNOR-156509 0.404 CAMK1 protein Q14012 UNIPROT KRT18 protein P05783 UNIPROT unknown phosphorylation Ser53 ISVSRSTsFRGGMGS 9606 7523419 t flangone Ser-52 in k18 is not glycosylated and matches consensus sequences for phosphorylation by cam kinase..these kinases can phosphorylate k18 in vitro predominantly at that site SIGNOR-27398 0.2 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser61 PLSTPCSsVPSSPSF 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159390 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR UHRF1 protein Q96T88 UNIPROT down-regulates quantity by destabilization phosphorylation Ser639 QQEGGFAsPRTGKGK -1 22411829 t miannu Importantly, the S652ph antibody identifies phosphorylated UHRF1 in mitotic cells and consistently S652 can be phosphorylated by the M phase-specific kinase CDK1-cyclin B in vitro. UHRF1 S652 phosphorylation significantly reduces UHRF1 interaction with USP7 in vitro and in vivo, which is correlated with a decreased UHRF1 stability in the M phase of the cell cycle. In contrast, UHRF1 carrying the S652A mutation, which renders UHRF1 resistant to phosphorylation at S652, is more stable.  SIGNOR-276408 0.322 CDKN2A protein Q8N726 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity relocalization 9606 23416275 t fstefani We propose that p14(arf) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53. SIGNOR-192697 0.756 PTK2 protein Q05397 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates activity phosphorylation Tyr174 QKASAPTyPSLYSSY 9606 BTO:0000007 22493428 t miannu  In addition, FAK directly phosphorylates Nanog in a dose-dependent manner by in vitro kinase assay and in cancer cells in vivo. The site-directed mutagenesis of Nanog tyrosines, Y35F and Y174F, blocked phosphorylation and binding by FAK. SIGNOR-276410 0.278 NUMA1 protein Q14980 UNIPROT TUBB3 protein Q13509 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-116979 0.2 BAIAP2 protein Q9UQB8 UNIPROT WASF1 protein Q92558 UNIPROT up-regulates binding 9606 11130076 t gcesareni Here we demonstrate that irsp53, a substrate forinsulinreceptor with unknown function, is the 'missing link' between rac and wave. Activated rac binds to the amino terminus of irsp53, and carboxy-terminal src-homology-3 domain of irsp53 binds to wave to form a trimolecular complex. SIGNOR-85299 0.613 PTH1R protein Q03431 UNIPROT CYP24A1 protein Q07973 UNIPROT up-regulates quantity 28363951 f lperfetto These PTH actions are mainly mediated by Gsalpha signaling, which induces the expression of the gene encoding 25-hydroxyvitamin D 1alpha-hydroxylase (Cyp27b1) and destabilizes the transcript encoding vitamin D 24-hydroxylase (Cyp24a1) SIGNOR-270555 0.292 IRX1 protein P78414 UNIPROT COL9A3 protein Q14050 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. SIGNOR-261653 0.2 PRKAA1 protein Q13131 UNIPROT STIM1 protein Q13586 UNIPROT down-regulates activity phosphorylation Ser257 GLHRAEQsLHDLQER 10090 BTO:0000452 31381180 t miannu STIM1 is a novel exercise‐regulated AMPK substrate. Phosphorylation of STIM1 by AMPK suppresses SOCE SIGNOR-277299 0.2 ILK protein Q13418 UNIPROT MYL12B protein O14950 UNIPROT up-regulates activity phosphorylation Ser20 KRPQRATsNVFAMFD 9606 11278951 t lperfetto Integrin-linked kinase cdna was cloned, sequenced, expressed in e. coli, and shown to phosphorylate myosin light chain in the absence of ca(2+) at ser(19) and thr(18). Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activation of myosin light chain kinase, and phosphorylation of the 20-kDa light chain of myosin at Ser(19). SIGNOR-106423 0.319 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser21 TPPSTALsPGKMSEA 9606 21059642 t The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). SIGNOR-169326 0.599 AMPK complex SIGNOR-C15 SIGNOR TET2 protein Q6N021 UNIPROT up-regulates quantity by stabilization phosphorylation Ser99 GGIKRTVsEPSLSGLL 9606 BTO:0001025 30022161 t We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo SIGNOR-256135 0.2 Alkannin chemical CHEBI:2578 ChEBI PKM protein P14618 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000093;BTO:0000018 21516121 t lperfetto Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2. SIGNOR-262009 0.8 CFD protein P00746 UNIPROT CFB protein P00751 UNIPROT up-regulates activity cleavage Thr25 LLSGGVTtTPWSLAR 9606 BTO:0000089 26489954 t lperfetto The resulting proconvertase C3bB is subsequently cleaved by factor D (FD), generating the AP C3 convertase C3bBb SIGNOR-263488 0.797 G6PC2 protein Q9NQR9 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity chemical modification 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-266565 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR RNF11 protein Q9Y3C5 UNIPROT down-regulates quantity phosphorylation Thr135 DWLMRSFtCPSCMEP 9606 BTO:0003474 16123141 t gcesareni Upon inhibition of the AKT pathway or mutation of T135, the phosphorylation at one of these sites is virtually eliminated, suggesting that AKT may phosphorylate RNF11 at T135. Moreover, RNF11 is phosphorylated by AKT in vitro and is recognized by phospho-AKT substrate antibodies. RNF11 shows enhanced binding to 14-3-3 in WM239 cells compared with that seen in the parental WM35 cells which have low AKT activity SIGNOR-248085 0.2 POU2F1 protein P14859 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23836662 f miannu This PER2-OCT1 interaction effectively converted OCT1 sites, which normally activate expression, into repressor sites by recruitment of a polycomb repressor complex including EZH2 and SUZ12, as well as HDAC2. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. SIGNOR-254149 0.27 POMC protein P01189 UNIPROT MC5R protein P33032 UNIPROT up-regulates binding 9606 BTO:0000007 11785979 t gcesareni The purpose of this study was to identify the peptide that functions as a natural ligand at the mc5r in the skin. alpha-msh, acth1-39, acth1-17, acth1-10, and acth4-10 all increased the production of camp in hek293 cells transfected with the mouse mc5r. alpha-msh and acth1-17 were the most potent in this respect. In addition, all peptides stimulated a rapid and transient increase in [ca(2+)](i). SIGNOR-114058 0.757 DPF3 protein Q92784 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270730 0.742 PRKCA protein P17252 UNIPROT GJA1 protein P17302 UNIPROT down-regulates phosphorylation Ser262 SPAKDCGsQKYAYFN 9606 14702389 t gcesareni Using immunoblotting and phosphospecific antibodies we were able to show that serine-262 (s262) on cx43 becomes phosphorylated in response to growth factor or pkc stimulation of cardiomyocytes.In cell-cell contact forming cultures, the s262d mutation reversed while the s262a mutation increased the inhibitory effect of cx43.Phosphorylation at s262, a pkc site that becomes phosphorylated in the cell environment in response to growth factor stimulation, cancels cx43 inhibition only in contact-forming myocytes. SIGNOR-120907 0.55 PRKCD protein Q05655 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 9606 BTO:0000562 17075052 t gcesareni The triple aspartic acid mutation shows greater distance between the two thick myosin filaments (affects the steric arrangement of the filament distances) in heart tissue. Mutation is cardioprotective during stress (ischemia-reprofusion injury) against apoptosis similar to isoproterenol treatment. SIGNOR-150355 0.2 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249677 0.509 dactolisib chemical CHEBI:71952 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 BTO:0000848 21803746 t ATP-competitive inhibitor of PI3K and mTOR gcesareni The dual pi3k and mtorc1/2 inhibitor bez235 was highly specific SIGNOR-252665 0.8 S1PR2 protein O95136 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257007 0.358 CSNK1D protein P48730 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser601 SDKESKEsSVEGAEN 9606 BTO:0000150 19339517 t lperfetto In this study, we show that both eralpha and aib1 are substrates for ck1delta in vitro, and identify a novel aib1 phosphorylation site (s601) targeted by ck1delta, significant for the co-activator function of aib1. SIGNOR-184946 0.288 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RXR proteinfamily SIGNOR-PF44 SIGNOR up-regulates activity chemical activation 9606 17132853 t miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. SIGNOR-256190 0.8 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR up-regulates 9606 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268582 0.2 sertindole chemical CHEBI:9122 ChEBI HTR1D protein P28221 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000529 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258546 0.8 NFIA protein Q12857 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268895 0.2 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257516 0.8 COPS5 protein Q92905 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270775 0.941 ASNS protein P08243 UNIPROT L-asparagine zwitterion smallmolecule CHEBI:58048 ChEBI up-regulates quantity chemical modification 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267533 0.8 etoposide chemical CHEBI:4911 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 16101488 t miannu Etoposide is an important chemotherapeutic agent that is used to treat a wide spectrum of human cancers. It has been in clinical use for more than two decades and remains one of the most highly prescribed anticancer drugs in the world. The primary cytotoxic target for etoposide is topoisomerase II. SIGNOR-259325 0.8 Terfenadine chemical CHEBI:9453 ChEBI KCNH2 protein Q12809 UNIPROT down-regulates activity chemical inhibition -1 19660947 t Luana  hERG activity was initially determined in a high throughput patch clamp screening assay (Ionworks)5 while a human H1 binding assay was used to determine H1 binding affinity.6 Selected results were confirmed in vitro using an IonWorks Quattro patch clamp assay and in vivo in the guinea pig.7, 8 Histamine H1activity was confirmed in vivo in the guinea pig.7 SIGNOR-257826 0.8 aclidinium chemical CHEBI:65346 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000131 19653626 t Luana This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. SIGNOR-258152 0.8 ASMT protein P46597 UNIPROT melatonin smallmolecule CHEBI:16796 ChEBI up-regulates quantity chemical modification -1 22775292 t miannu Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. Melatonin synthesis requires serotonin, which is first acetylated by the arylalkylamine N-acetyltransferase (AA-NAT) to produce N-acetyl serotonin (NAS) (Fig. 1A). Then, acetyl serotonin methyltransferase (ASMT, also known as hydroxyindole O-methyltransferase or HIOMT) produces melatonin by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to NAS SIGNOR-265475 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 12676795 f Luana Activation of the Ras-MAPK/Erk signaling cascade is essential for neurotrophin-promoted differentiation of neurons and PC12 cells. SIGNOR-264978 0.7 PTPN6 protein P29350 UNIPROT STAT6 protein P42226 UNIPROT down-regulates 9606 BTO:0000801 9852037 f gcesareni Expression of an shp-1 transgene in nih 3t3 cells markedly reduces both il-4-dependent stat6 activation and stat6-mediated transcription of il-4-responsive genes SIGNOR-62578 0.604 PTEN protein P60484 UNIPROT MAPT protein P10636 UNIPROT up-regulates activity dephosphorylation 9606 27221467 t miannu Reduced phosphorylation of PTEN can dramatically increase tau phosphorylation and impair the ability of tau to bind to microtubules . SIGNOR-277079 0.391 CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 16977332 t lperfetto Apaf-1 exists in an inactive conformation in cells and is activated through binding to cytochrome c and dATP. SIGNOR-149574 0.785 TBX21 protein Q9UL17 UNIPROT TBX21 protein Q9UL17 UNIPROT up-regulates 9606 16386358 t In turn, T-bet is an IFN-gamma activator (Szabo et al., 2000), thus creating an indirect positive feedback. Furthermore, it has been shown that ectopic T-bet is able to induce the transcription of its own gene SIGNOR-254294 0.2 PRKCA protein P17252 UNIPROT KCNJ4 protein P48050 UNIPROT down-regulates activity phosphorylation Thr53 IFTTCVDtRWRYMLM -1 10206975 t miannu These results therefore indicate that Kir2.3 is directly modulated by PKC phosphorylation of its channel protein and threonine 53 is the PKC phosphorylation site in Kir2.3. SIGNOR-275965 0.2 N-tert-butyl-3-[[5-methyl-2-[4-[2-(1-pyrrolidinyl)ethoxy]anilino]-4-pyrimidinyl]amino]benzenesulfonamide chemical CHEBI:91408 ChEBI JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207239 0.8 HTR6 protein P50406 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257274 0.252 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRNB3 protein Q05901 UNIPROT up-regulates activity chemical activation 9606 BTO:0000227 28901280 t miannu Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a super-family of Cysloop ligand-gated ion channels that respond to endogenous acetylcholine (ACh) or other cholinergic ligands. These receptors are also the targets of drugs such as nicotine (the main addictive agent delivered by cigarette smoke) and are involved in a variety of physiological and pathophysiological processes. SIGNOR-264258 0.8 PRKACA protein P17612 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser396 FTWKRLRsHSRQYVS 9606 15328002 t gcesareni Two amino acid residues (ser396, ser398) on hr1 were determined to be pkc phosphorylation sites by in vitro phosphorylation studies.Site-directed mutagenesis studies suggests that the ser398 residue was primarily involved in pkc-mediated desensitization. Possibly, phosphorylation of the residues is required for receptor transport from endosomes to lysosomes. SIGNOR-128411 0.2 RIPK1 protein Q13546 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity phosphorylation Ser20 KSSDFLEsAELDSGG -1 18408713 t miannu These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1) SIGNOR-276160 0.2 PRKCA protein P17252 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 t lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization. SIGNOR-202780 0.2 SMC5 protein Q8IY18 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR form complex binding -1 27427983 t miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks SIGNOR-265481 0.891 ARHGAP20 protein Q9P2F6 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260472 0.697 FOXJ1 protein Q92949 UNIPROT TEKT2 protein Q9UIF3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 t miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). SIGNOR-266937 0.33 UBC protein P0CG48 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity binding 9606 BTO:0000938 26161729 t lperfetto Mechanism of phospho-ubiquitin-induced PARKIN activation|PhosphoUb binding leads to straightening of a helix in the RING1 domain, and the resulting conformational changes release the Ubl domain from the PARKIN core; this activates PARKIN|Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator. SIGNOR-249692 0.2 tRNA(Lys) smallmolecule CHEBI:29185 ChEBI Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270409 0.8 pyruvate smallmolecule CHEBI:15361 ChEBI Citric_Acid_Cycle phenotype SIGNOR-PH191 SIGNOR up-regulates activity 9606 18613815 f Pyruvate carboxylase (PC) is a biotin-containing enzyme that catalyses the HCO3−- and MgATP-dependent carboxylation of pyruvate to form oxaloacetate. This is a very important anaplerotic reaction, replenishing oxaloacetate withdrawn from the Krebs cycle for various pivotal biochemical pathways. SIGNOR-267384 0.7 EGFR protein P00533 UNIPROT VAV2 protein P52735 UNIPROT up-regulates phosphorylation Tyr172 EDGGDDIyEDIIKVE 9606 12454019 t miannu To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor. SIGNOR-95980 0.61 TFIIH complex SIGNOR-C457 SIGNOR E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser403 PEEFISLsPPHEALD 9606 10428966 t lperfetto These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase.  here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain. SIGNOR-269353 0.324 CDK4 protein P11802 UNIPROT RBL1 protein P28749 UNIPROT up-regulates activity phosphorylation Ser650 SVHERYSsPTAGSAK 9606 12006580 t llicata Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression.  SIGNOR-250763 0.8 MAPK1 protein P28482 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 19153083 t gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation SIGNOR-183480 0.716 EIF1AX protein P47813 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity relocalization 9606 12514125 t lperfetto Translation initiation factor 1A (eIF1A) is predicted to bind in the decoding site of the 40S ribosome and has been implicated in recruitment of the eIF2-GTP-Met-tRNA i Met ternary complex (TC) and ribosomal scanning.  SIGNOR-269147 0.713 SPAG9 protein O60271 UNIPROT CDON/SPAG9 complex SIGNOR-C21 SIGNOR form complex binding 9606 BTO:0000222 17074887 t gcesareni In this study, we report that the cdo intracellular region interacts with jlp, a scaffold protein for the p38alpha/beta mapk pathway. SIGNOR-149178 0.477 (-)-anisomycin chemical CHEBI:338412 ChEBI JUN protein P05412 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling gcesareni SIGNOR-189632 0.8 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 BTO:0000782 14722106 t gcesareni Once activated, calcineurin directly dephosphorylates NFAT proteins that are present in a hyperphosphorylated latent form in the cytoplasm and induces their rapid translocation into the nucleus, where in concert with nuclear partner proteins such as the AP-1 transcription factor complex, they are able to bind cooperatively to their target promoter elements and activate the transcription of specific NFAT target genes SIGNOR-84038 0.818 PRKCA protein P17252 UNIPROT ITPKB protein P27987 UNIPROT down-regulates activity -1 9374536 t lperfetto However, when assayed in the presence of calcium/calmodulin, the activity of the B isoform was decreased following phosphorylation by either protein kinase. SIGNOR-248990 0.367 SMARCD3 protein Q6STE5 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270692 0.752 dopamine smallmolecule CHEBI:18243 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257479 0.8 IL34 protein Q6ZMJ4 UNIPROT CSF1R protein P07333 UNIPROT up-regulates activity binding 9606 BTO:0000801 39416792 t miannu CSF-1, derived from fibroblasts, tumor cells, etc., is produced in membrane-bound form, secreted glycoproteins and proteoglycans. Currently, CSF-1R is considered to be the sole receptor for CSF-1. These cells regulate macrophage growth, differentiation and function by secreting CSF1. Colony-stimulating factor receptor (CSF1R), a type I single-transmembrane protein, is ubiquitously expressed in myeloid cells such as monocytes, macrophages, neuroglia, and osteoblasts. CSF1R induces receptor homodimerization by binding to either CSF-1 or IL-34, followed by activation of receptor signaling and activation of extracellular pro-cell-survival kinase cascades, including PI3K, ERK1/2, and JNK SIGNOR-277714 0.909 ABL1 protein P00519 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Tyr292 RLGHCHTyWAVSEEL 9606 BTO:0000007 30842273 t miannu The data in this study show that IRF3 is physically associated with c-Abl in vivo and directly binds to c-Abl in vitro. IRF3 is phosphorylated by c-Abl and c-Abl-related kinase, Arg, mainly at Y292. SIGNOR-277440 0.2 PRKACA protein P17612 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity phosphorylation Thr312 RSQELRKtFKEIICC 9606 12639913 t miannu Activation of MC4R by agonist is associated with protein kinase A (PKA) and GRK phosphorylation of serine/threonine residues in the C-terminal tail of MC4R, followed by -arrestin and dynamin-dependent internalization of the receptor. Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA SIGNOR-250017 0.313 PDPK1 protein O15530 UNIPROT PGK1 protein P00558 UNIPROT up-regulates activity phosphorylation Thr243 IGGGMAFtFLKVLNN 9606 BTO:0002036 30029001 t miannu PDPK1 Phosphorylates PGK1 T243. Macrophages increase PGK1 pT243 to reduce the 3-PG affinity of PGK1, which alters the equilibrium of the PGK1-catalyzed reaction toward glycolysis, promoting tumor cell proliferation. SIGNOR-277402 0.2 KLF4 protein O43474 UNIPROT NPNT protein Q6UXI9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0005787 BTO:0001103 23612709 f miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion SIGNOR-255457 0.2 F10 protein P00742 UNIPROT Factor Va-Xa complex SIGNOR-C318 SIGNOR form complex binding -1 2026608 t lperfetto The binding of factor Xa to factor Va in the presence of Ca2+ ions and phospholipid is fundamental for the activation of prothrombin to thrombin. |Regardless of which protein was labeled, a factor Xa-Va complex (s20,w = 9.8) was formed. The interaction is specific and reversible. I SIGNOR-263557 0.766 PKN1 protein Q16512 UNIPROT MEFV protein O15553 UNIPROT down-regulates activity phosphorylation Ser242 SGKMRPRsLEVTIST 10090 BTO:0004732 27270401 t no miannu PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. SIGNOR-275461 0.392 Av/b1 integrin complex SIGNOR-C175 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-277737 0.693 NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys9 SGRGKGGkGLGKGGA 9606 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. by comparing the substrate specificities of the MSL and NSL complexes, we obtain evidence that MOF HAT activity is differentially regulated by assembly into the MSL complex, where it acetylates nucleosomal histone H4 on lysine 16, and the NSL complex, where it also acetylates nucleosomal histone H4 on lysines 5 and 8. SIGNOR-267168 0.2 TYK2 protein P29597 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates activity phosphorylation Tyr466 VFLRCINyVFFPSLK -1 8605876 t lperfetto We demonstrate that, in vitro, p135tyk2 phosphorylates two tyrosines on IFNaR1. A phosphopeptide corresponding to the major phosphorylation site (Tyr466) binds STAT2, but not STAT1, in an SH-2-dependent manner. Furthermore, only latent, non-phosphorylated STAT2 interacts with this phosphopeptide. When this phosphopeptide is introduced into permeabilized cells, the IFN alpha-dependent tyrosine phosphorylation of both STATs is blocked. Finally, mutant versions of IFNaR1, in which Tyr466 is changed to phenylalanine, can act in a dominant negative manner to inhibit phosphorylation of STAT2. SIGNOR-246934 0.908 GSK3B protein P49841 UNIPROT ZNF281 protein Q9Y2X9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser638 PRVDLHTsGEHSELV 9606 BTO:0001615 29179460 t lperfetto GSK-3beta phosphorylation-dependent degradation of ZNF281 by beta-TrCP2 suppresses colorectal cancer progression| SIGNOR-264890 0.2 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR KDM5B protein Q9UGL1 UNIPROT down-regulates activity 9606 35217626 t SaraGualdi Our transcriptomic profiling in AML further identified Kdm5b (also known as Jarid1b, Plu-1, or RBP2-H1), a multifunctional demethylase that can remove histone H3 lysine 4 tri/di-methylation (H3K4me3/2), to be a critical downstream target repressed by PRC2. SIGNOR-271577 0.37 PRKCG protein P05129 UNIPROT GRIN1 protein Q05586 UNIPROT up-regulates activity phosphorylation Ser890 ITSTLASsFKRRRSS 10116 BTO:0000938 15936117 t miannu Serines 890 and 896 of the NMDA receptor subunit NR1 are differentially phosphorylated by protein kinase C isoforms. The results show that PKC alpha phosphorylates preferentially S896 and PKC gamma preferentially S890. SIGNOR-263176 0.358 STAT6 protein P42226 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 20508200 f lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. SIGNOR-249533 0.528 HES1 protein Q14469 UNIPROT NEUROG1 protein Q92886 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 f lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production SIGNOR-265140 0.353 EEF1A2 protein Q05639 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269526 0.8 LFNG protein Q8NES3 UNIPROT DLL1 protein O00548 UNIPROT up-regulates binding 9606 11346656 t gcesareni The modification of notch by fringe would influence binding between the notch receptor and its ligand. It was reported previously that mfng and lfng inhibited notch1-mediated signaling triggered by jagged1 and enhanced that triggered by delta1, and either jagged1- or delta1-triggered notch2 signaling was enhanced by lfng SIGNOR-107699 0.458 NTRK2 protein Q16620 UNIPROT KCNA3 protein P22001 UNIPROT down-regulates phosphorylation Tyr161 PSFDAILyYYQSGGR 9606 BTO:0000938 BTO:0000671 19166614 t gcesareni Previously we have shown that acute brain-derived neurotrophic factor (bdnf) activation of neurotrophin receptor tyrosine kinase b (trkb) suppresses the shaker voltage-gated potassium channel (kv1.3) via phosphorylation of multiple tyrosine residues in the n and c terminal aspects of the channel protein. SIGNOR-183515 0.386 PLCD4 protein Q9BRC7 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates chemical modification 9606 9125218 t gcesareni A key pathway is the hydrolysis of PIP2 . This is mediated by PLC, and yields the two second messengers 1,4,5-IP3 and DAG SIGNOR-195516 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR NIBAN1 protein Q9BZQ8 UNIPROT unknown phosphorylation Ser602 ASPARRAsAILPGVL 9606 22510990 t llicata We demonstrate here that ultraviolet irradiation induces phosphorylation of niban at s602 by akt, which increases the association of niban with nucleophosmin and disassociation of nucleophosmin from the mdm2 complex. SIGNOR-197053 0.2 IL1RL1 protein Q01638 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 35238669 t miannu The activated heterodimer complex recruits downstream signaling components, including myeloid differentiation primary response protein 88 (MyD88), IL-1 receptor (IL-1R)–associated kinase, tumor necrosis factor (TNF) receptor–associated factor 6 (TRAF6), and transforming growth factor (TGF)-β–activated kinase 1 (TAK1) complex, resulting in TAK1 activation. TAK1 subsequently activates downstream kinases inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKα) and IKKβ, which phosphorylate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor (IκB) proteins. These events ultimately lead to activation of the transcription factor NF-κB and induction of downstream effector genes SIGNOR-277716 0.2 INPP4B protein O15327 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity dephosphorylation 9606 26411369 t lperfetto In support, the increase in PTEN caused by INPP4B knockdown was associated with increased phosphorylation of the Ser380, Thr382, Thr383 and Ser385 cluster of the protein (XREF_FIG), which is known to increase PTEN half-life, in colon cancer cells.|Exogenous INPP4B could pull down and dephosphorylate endogenous PTEN, suggesting that effect of INPP4B on PTEN in colon cancer cells is not due to cell-type-specific characteristics of INPP4B per se.|INPP4B downregulates PTEN in colon cancer cells. SIGNOR-277018 0.617 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 9606 17126298 t gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. SIGNOR-150875 0.338 FAM162A protein Q96A26 UNIPROT VDAC1 protein P21796 UNIPROT up-regulates activity binding 9606 BTO:0001061 15082785 t Giulio HGTD-P was coprecipitated with VDAC but not with ANT or cyclophilin D (Fig. 7A, left upper panel).|However, it is not clear at present whether HGTD-P participates directly in channel formation in association with VDAC or modulates its channel-forming activity. SIGNOR-260293 0.2 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI MST1R protein Q04912 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194346 0.8 NLGN4Y protein Q8NFZ3 UNIPROT NRXN2 protein Q9P2S2 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264153 0.2 HTR1A protein P08908 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256836 0.551 CRYGD protein P07320 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 10521291 f The γ-crystallin proteins are tightly folded in two domains with no free loops. It is possible that the R58H mutation destabilizes the contact between lens-fiber cells, which is critical for the maintenance of lens transparency. Improper folding of CRYGD, the most abundantly expressed γ-crystallin in the lens, could well cause protein aggregation and lens opacification. SIGNOR-253620 0.7 FGF10 protein O15520 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 t gcesareni Fgf3, fgf7, fgf10 and fgf22 are ligands that activate fgfr2b. SIGNOR-42362 0.89 CTNNB1 protein P35222 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000304 30519351 t miannu One of the most well studied activators of CCND1 transcription is β-catenin, which could be actived by AKT signalling to inducing G1/S transition. When β-catenin is translocated from the cytoplasm to the nucleus, it forms a complex with the ternary complex factor (TCF) and/or lymphoid enhancer-binding factor (LEF) and stimulates cyclin D1 gene transcription (Fig. 4C).In agreement with the data described above, a chromatin immunoprecipitation (ChIP) assay confirmed that TNC regulates the binding of β-catenin to the TCF/LEF-binding site in the CCND1 promoter (Fig. 4C). Additionally, the β-cateninbinding activity with respect to the CCND1 promoter was much higher in TNC-overexpression PANC-1 cells than in the vector controls. SIGNOR-277738 0.794 AHI1 protein Q8N157 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 BTO:0000452 23532844 f miannu Mutations in AHI1 cause Joubert syndrome (JBTS), a neurodevelopmental ciliopathy, characterized by midbrain-hindbrain malformations and motor/cognitive deficits. Here, we show that primary cilia (PC) formation is decreased in fibroblasts from individuals with JBTS and AHI1 mutations. SIGNOR-269080 0.7 RARG protein P13631 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. SIGNOR-16659 0.673 SPRY4 protein Q9C004 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity binding 9606 12717443 t miannu Here we show that mammalian Sprouty4 suppresses vascular epithelial growth factor (VEGF)-induced, Ras-independent activation of Raf1 but does not affect epidermal growth factor (EGF)-induced, Ras-dependent activation of Raf1. Sprouty4 binds to Raf1 through its carboxy-terminal cysteine-rich domain, and this binding is necessary for the inhibitory activity of Sprouty4. SIGNOR-253033 0.443 mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization chemical modification 9606 19224921 f lperfetto Because only mRNA molecules that have been correctly spliced, capped at the 5′ extremity, and processed at the 3′ extremity can be used as templates for translation, processing of mRNA precursors plays a critical role in the regulation of gene expression. 3′ processing of pre-mRNAs comprises two steps (reviewed in Ref. 4): cleavage and polyadenylation. SIGNOR-268322 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000304 30519351 t miannu The results showed that TNC induced the cytoplasmic translocation of pFOXO1 via regulation of AKT activation. As shown in Fig. 3C, stimulation of PANC-1 cells with exogenous TNC markedly increased the phosphorylation of AKT and FOXO1. Our study showed that pFOXO1 translocates from the nucleus to the cell cytoplasm after exogenous TNC treatment, which indicates that its transcriptional activity was inhibited. SIGNOR-277740 0.2 CXCL1 protein P09341 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates activity binding 9606 38309677 t miannu CXCL1 produces cellular chemotactic activity by binding to the CXC chemokine receptor 2 (CXCR2). In PC, this chemokine has been associated with a variety of carcinogenic mechanisms, including oncogene-induced senescence (OIS), angiogenesis, cancer metastasis, and immunosuppressive microenvironments  SIGNOR-277717 0.768 CXCL3 protein P19876 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates activity binding 9606 38309677 t miannu CXCL2/3, also known as macrophage inflammatory protein-2α/2β (MIP-2α/MIP-2β), share the same receptor CXCR2 with CXCL1 and are able to activate neutrophils effectively SIGNOR-277719 0.712 HBA1 protein P69905 UNIPROT APOB protein P04114 UNIPROT up-regulates quantity by stabilization 9606 8611031 f Regulation of binding miannu Hemoglobin induced apolipoprotein B crosslinking in low-density lipoprotein peroxidation. Crosslinked apo B was shown to resist lysosomal degradation, thereby causing accumulation of oxidized LDL in macrophages SIGNOR-251755 0.325 GAS6 protein Q14393 UNIPROT AXL protein P30530 UNIPROT up-regulates activity binding 9606 BTO:0000130 35022267 t miannu Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth.Taken together, these results show that the neutrophil attracting cytokines Cxcl1 and 2 are highly expressed in metastatic livers in response to gemcitabine withdrawal and this favours CXCR2-dependent recruitment of neutrophils at the hepatic metastatic site. SIGNOR-277720 0.906 EVL protein Q9UI08 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 18508258 f miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. SIGNOR-268391 0.7 ribosomal RNA smallmolecule CHEBI:18111 ChEBI B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 t miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription SIGNOR-269470 0.8 PYCARD protein Q9ULZ3 UNIPROT NLRP1 inflammasome complex SIGNOR-C224 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256408 0.673 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM5B protein Q9UGL1 UNIPROT up-regulates activity chemical activation 29981745 t lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. SIGNOR-273476 0.8 MC2R protein Q01718 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268694 0.496 FCRL3 protein Q96P31 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity binding -1 12051764 t miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. SIGNOR-274014 0.392 PTPN2 protein P17706 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 12138178 t gcesareni The nuclear isoform of protein-tyrosine phosphatase tc-ptp regulates interleukin-6-mediated signaling pathway through stat3 dephosphorylation. SIGNOR-90818 0.725 MTOR protein P42345 UNIPROT EIF4EBP3 protein O60516 UNIPROT up-regulates phosphorylation 9606 14967450 t gcesareni While promoting initiation of protein translation through mtor, eukaryoticinitiation factor 4e, and the ribosomal p70-s6 kinase. SIGNOR-122035 0.365 NCOR2 protein Q9Y618 UNIPROT BCL6 protein P41182 UNIPROT up-regulates activity binding 9606 BTO:0000007 10898795 t miannu The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT. SIGNOR-252240 0.651 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75641 0.783 AX/b2 integrin complex SIGNOR-C171 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257714 0.44 SENP1 protein Q9P0U3 UNIPROT GCM1 protein Q9NP62 UNIPROT up-regulates activity desumoylation 9606 BTO:0000007 21791615 t miannu We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation. SIGNOR-262681 0.481 CTCF protein P49711 UNIPROT RARRES1 protein P49788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 22615834 f miannu Epigenetic repression of RARRES1 is mediated by methylation of a proximal promoter and a loss of CTCF binding. knocking-down CTCF expression hampered RARRES1 expression, suggesting CTCF positively regulated RARRES1 transcription presumably by binding to unmethylated promoter poised at transcription-ready state. SIGNOR-253831 0.353 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 10090 15367694 t Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes SIGNOR-248652 0.727 BIRC2 protein Q13490 UNIPROT UBE2J1 protein Q9Y385 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 28321712 t miannu We also found that ubiquitin-ligase (E3), c-IAP1 preferentially interacts with phosphorylated Ube2j1. Moreover, we noticed that phosphorylated Ube2j1 is rapidly degraded by the proteasome during ER stress cell recovery. Taken together, these data suggest that Ube2j1 and its phosphorylation is important for transient ER stress cell recovery and the phosphorylated Ube2j1 is degraded by the proteasome. SIGNOR-263092 0.377 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser83 PRRSPRIsFFLEKEN -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276118 0.698 KIF5B protein P33176 UNIPROT SYBU protein Q9NX95 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 15459722 t miannu Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes. SIGNOR-264811 0.577 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 8106516 t Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed√¢‚Ǩ¬ù SIGNOR-267189 0.8 HP protein P00738 UNIPROT APOA1 protein P02647 UNIPROT up-regulates quantity by stabilization binding 9606 17824618 t miannu Haptoglobin binding to apolipoprotein A-I prevents damage from hydroxyl radicals on its stimulatory activity of the enzyme lecithin-cholesterol acyl-transferase. haptoglobin, when circulating at enhanced levels with free Hb during the acute phase of inflammation, might protect ApoA-I structure and function against hydroxyl radicals. SIGNOR-252106 0.722 TNC protein P24821 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 9606 BTO:0001521 38058842 t miannu TNC is shown to bind to integrin receptors expressed in adjacent PAAD cells, thereby inducing EMT. In addition, TNC expression in CAFs had significant positive correlations with ITGαV, ITGβ1, or ITGβ3 expression in cancer cells, which supports our speculations that the TNC-integrin signaling axis promotes the EMT pathway in cancer cells. SIGNOR-277736 0.406 CCL5 protein P13501 UNIPROT CCR5 protein P51681 UNIPROT up-regulates activity binding 9606 BTO:0000584 38339310 t miannu CCL5, also known RANTES (regulated on activation, normal T cell expressed and secreted), is a potent chemoattractant for a variety of leukocytes, including T cells, mono- cytes, NK cells, and basophils, signaling via the CCR1, CCR3, and CCR5 cell surface receptors [59]. Among these receptors, CCL5 has the highest affinity for CCR5. SIGNOR-277726 0.936 FOXP3 protein Q9BZS1 UNIPROT CCL5 protein P13501 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 38339310 t miannu Given its role as a potent chemoattractant for T cells, CCL5 can be utilized to attract Tregs to malignant epithelial cells. Wang et al. demonstrated that Forkheadbox protein 3 (FOXP3), a key transcription factor for Tregs, was highly ex- pressed in pancreatic cancer cell lines, which, in turn, upregulated CCL5 expression SIGNOR-277727 0.445 SMURF1 protein Q9HCE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 22298955 t Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps SIGNOR-195660 0.696 naltrexone chemical CHEBI:7465 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258767 0.8 MTOR protein P42345 UNIPROT MKNK2 protein Q9HBH9 UNIPROT down-regulates activity phosphorylation Ser74 KRGRATDsFSGRFED 9606 BTO:0000007 32170339 t miannu MTOR phosphorylates MNK2a on Ser74. Here, we show that mTORC1, a key regulator of mRNA translation and oncogenesis, directly phosphorylates MNK2 on Ser74. This suppresses MNK2 activity and impairs binding of MNK2 to eIF4G. SIGNOR-277516 0.277 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr126 RDAMVRDyVRQTWKL 9606 BTO:0000661 7961936 t lperfetto We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. By comparative two-dimensional phosphopeptide mapping, we show that ZAP-70 isolated from Jurkat T cells also autophosphorylates at Tyr-292 and Tyr-126 SIGNOR-247044 0.2 ATM protein Q13315 UNIPROT DYRK2 protein Q92630 UNIPROT up-regulates quantity by stabilization phosphorylation Thr106 NKRTVLTtQPNGLTT 19965871 t Phosphosites were derived from Figure 3 lperfetto ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus. SIGNOR-275576 0.539 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro. SIGNOR-131391 0.2 V-ATPase complex SIGNOR-C560 SIGNOR cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates quantity relocalization 9606 BTO:0000584 31827278 t miannu Accumulation of V-ATPase at the plasma membrane is necessary for the cholesterol-dependent plasma-membrane association of RAC1, a prerequisite for the stimulation of membrane ruffling and macropinocytosis. In line with these observations, immunohistochemical staining of V-ATPase in human pancreatic ductal adenocarcinoma (PDAC) specimens revealed prominent staining at the cell periphery in neoplastic lesions, in con- trast to the predominantly cytoplasmic staining observed in adjacent normal tissues (Fig. 2e). Thus, mutant RAS-dependent plasma mem- brane V-ATPase displayed preferential accumulation in membrane ruffles, consistent with patterns observed in invasive breast, melanoma and pancreatic cancer cells SIGNOR-277760 0.8 CXCL5 protein P42830 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates activity binding 9606 BTO:0000584 38339310 t miannu CXCL5 is another ELR+ CXC chemokine and, thus, also potently attracts neutrophils. Just like CXCL1, CXCL5 also signals through CXCR2, explaining why, often, CXCL5 and CXCL1 are seen to function in parallel in PDAC. CXCL5 was increased in human pancreatic tissue compared to the normal pancreas, and the knockdown of CXCL5 in pancreatic cancer cell lines reduced the proliferation and migration ability of cells SIGNOR-277730 0.743 SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR IL17A protein Q16552 UNIPROT up-regulates transcriptional regulation 9606 26194464 t MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. SIGNOR-255027 0.479 BMPR1A protein P36894 UNIPROT SOST protein Q9BQB4 UNIPROT up-regulates 9606 19874086 f gcesareni These results demonstrate that bmpria in osteoblasts negatively regulates endogenous bone mass and wnt/beta-catenin signaling and that this regulation may be mediated by the activities of sost and dkk1. SIGNOR-188958 0.336 GABRG2 protein P18507 UNIPROT GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263758 0.622 NEXMIF protein Q5QGS0 UNIPROT CDH2 protein P19022 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0000938 27822498 f miannu Xpn regulates N-cadherin and β1-integrin expression at the transcriptional level in PC12 cells SIGNOR-269660 0.2 SEC23IP protein Q9Y6Y8 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI down-regulates quantity chemical modification 9606 22922100 t miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. SIGNOR-269651 0.8 IQSEC2 protein Q5JU85 UNIPROT GRIA3 protein P42263 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 27009485 t miannu BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors. SIGNOR-264914 0.2 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT up-regulates activity binding 14732063 t [...] two distinct types of TNF-Rs have been identified and molecularly cloned: TNF-R55 (also referred to as TNFR1, p55 or CD120a) and TNF-R75 (also called TNFR2, p75 or CD120b) SIGNOR-253594 0.928 PRKCZ protein Q05513 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1101 GCRRRHSsETFSSTP 9606 BTO:0000975 17360977 t lperfetto Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 SIGNOR-236022 0.716 DOT1L protein Q8TEK3 UNIPROT MYC protein P01106 UNIPROT up-regulates activity binding 9606 BTO:0001939 26199140 t 1 miannu Our data suggest that the c-Myc-dependent transcriptional switch is modulated by DOT1L, as in the presence of DOT1L c-Myc preferentially forms an active complex with p300 rather than a repressive complex containing HDAC1 and DNMT1 SIGNOR-239362 0.341 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB1 protein Q9Y5G3 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265681 0.2 SLC2A2 protein P11168 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity relocalization 9606 25421524 t The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion. SIGNOR-267385 0.8 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT down-regulates activity phosphorylation 9606 15066263 t miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts SIGNOR-268289 0.729 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9534 12387817 t lperfetto Thus, it was suggested that NHERF2 mediates the activation and phosphorylation of SGK1 by PDK1 through its first PDZ domain and PIF motif, as a novel SGK1 activation mechanism. SIGNOR-236800 0.635 ETS2 protein P15036 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11175361 t miannu We demonstrated that Ets2 is capable of binding to and transactivating the OPN promoter using gel shift and transient transfection assays SIGNOR-259872 0.254 PAK4 protein O96013 UNIPROT SYNJ1 protein O43426 UNIPROT up-regulates activity phosphorylation -1 22371566 t miannu We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. SIGNOR-263024 0.2 ANGPT1 protein Q15389 UNIPROT TEK protein Q02763 UNIPROT up-regulates binding 9606 9204896 t gcesareni Angiopoietin-1 (ang1) is an angiogenic factor that signals through the endothelial cell-specific tie2 receptor tyrosine kinase. SIGNOR-49355 0.789 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257965 0.8 Riluzole chemical CHEBI:8863 ChEBI KCNN2 protein Q9H2S1 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 18955585 t Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  SIGNOR-258020 0.8 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser180 GSSASFIsDTFSPYT 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248684 0.613 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000763;BTO:0000149 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244591 0.2 PBK protein Q96KB5 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 16982762 t gcesareni Pbk/topk could phosphorylate histone h3 at ser10 in vitro and in vivo, and mediated its growth-promoting effect through histone h3 modification. SIGNOR-265364 0.2 SNRNP40 protein Q96DI7 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270644 0.701 tyrphostin B42 chemical CHEBI:131968 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity 9606 11368440 t gcesareni The Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Ralpha mRNA and protein expression in parallel SIGNOR-238293 0.8 GNB/GNG complex SIGNOR-C202 SIGNOR CACNA1B protein Q00975 UNIPROT down-regulates activity binding 9606 BTO:0000938 20655485 t miannu The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release. SIGNOR-265067 0.4 GNAI1 protein P63096 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates activity binding 9606 15922020 t Activation of receptors coupled to inhibitory G proteins (Galpha i/o) has opposing consequences for cyclic AMP accumulation and the activity of cyclic AMP-dependent protein kinase, depending on the duration of stimulation. Acute activation inhibits the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation; in contrast, persistent activation of Galpha i/o-coupled receptors produces a paradoxical enhancement of adenylate cyclase activity, thus increasing cyclic AMP accumulation when the action of the inhibitory receptor is terminated. SIGNOR-256532 0.533 CAD protein P27708 UNIPROT carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI down-regulates quantity chemical modification 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-268092 0.8 PICK1 protein Q9NRD5 UNIPROT GRIA2 protein P42262 UNIPROT up-regulates activity binding 9534 BTO:0000298 25784538 t miannu RAB39B directs GluA2 trafficking in neurons. GTP-bound RAB39B interacts with PICK1. In line with evidence that PICK1 can dimerize, the structural model suggests that dimerization of PICK1 is a prerequisite for simultaneous recognition of both RAB39B and GluA2 each by one of the PICK1 molecules in the PICK1 dimer (Fig. 6a–c). The existence of such complex is supported by our co-immunoprecipitation experiments shown above. SIGNOR-264046 0.8 MAPKAPK2 protein P49137 UNIPROT TH protein P07101 UNIPROT up-regulates activity phosphorylation Ser19 KGFRRAVsELDAKQA -1 11359875 t miannu MAPKAP-K2 phosphorylates both Ser19 and Ser40 of TH. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation. SIGNOR-250149 0.499 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser937 SNLTRSSsSDSIHSV 9606 21525957 t gcesareni Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1. SIGNOR-173437 0.492 D-glucopyranose smallmolecule CHEBI:4167 ChEBI lactose smallmolecule CHEBI:17716 ChEBI up-regulates quantity precursor of 9606 16157350 t miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. SIGNOR-268474 0.8 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BS1 protein P57053 UNIPROT down-regulates activity monoubiquitination Lys35 RKRKRSRkESYSVYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271984 0.2 TAGAP protein Q8N103 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260523 0.424 PRKCA protein P17252 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser38 LGPGTRLsLARMPPP -1 2155236 t lperfetto Glial fibrillary acidic protein (GFAP), the intermediate filament component of astroglial cells, can serve as an excellent substrate for both cAMP-dependent protein kinase and protein kinase C, in vitro. GFAP phosphorylated by each protein kinase does not polymerize, and the filaments that do polymerize tend to depolymerize after phosphorylation. Dephosphorylation of phospho-GFAP by phosphatase led to a recovery of the polymerization competence of GFAP. Most of the phosphorylation sites for cAMP-dependent protein kinase and protein kinase C on GFAP are the same, Ser-8, Ser-13, and Ser-34. cAMP-dependent protein kinase has one additional phosphorylation site, Thr-7. SIGNOR-248862 0.374 PLK1 protein P53350 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates phosphorylation Ser30 EADSPSDsGQGSYET 9606 16885022 t gcesareni We show that claspin, an adaptor protein required for chk1 activation, becomes degraded at the onset of mitosis. Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbtrcp ubiquitin ligase. This interaction was phosphorylation dependent and required the activity of the plk1 kinase SIGNOR-148447 0.764 MAPK1 protein P28482 UNIPROT RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 17604322 t lperfetto In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE SIGNOR-88658 0.514 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr556 LNGQPIQyARSTCEA 9606 BTO:0000763 20861316 t lperfetto Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity SIGNOR-167997 0.304 FUS protein P35637 UNIPROT SNRNP70 protein P08621 UNIPROT up-regulates activity binding 9606 26124092 t FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP SIGNOR-262823 0.446 CSNK2A2 protein P19784 UNIPROT DDX58 protein O95786 UNIPROT down-regulates activity phosphorylation Thr770 DSILRLQtWDEAVFR 9606 BTO:0000007 21068236 t miannu Phosphorylation of RIG-I by casein kinase II inhibits its antiviral response.Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of RIG-I are phosphorylated by casein kinase II (CK2) in the resting state of the cell and dephosphorylated when cells are infected by RNA virus. SIGNOR-276285 0.2 TRIM28 protein Q13263 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity binding 9606 BTO:0000007 16107876 t 2 miannu we present evidence that MDM2 interacts with the nuclear corepressor KAP1. MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation. SIGNOR-240405 0.582 ITGA4 protein P13612 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253175 0.802 KAT2B protein Q92831 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269619 0.2 PRKAA1 protein Q13131 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 19262508 f gcesareni The acute actions of ampk on lipid oxidation alter the balance between cellular nad+ and nadh, which acts as a messenger to activate sirt1 SIGNOR-184473 0.404 PRC1 protein O43663 UNIPROT CENPE protein Q02224 UNIPROT up-regulates activity binding 9606 15297875 t miannu These data indicate that PRC1 binds to KIF4, MKLP1 and CENP-E during late mitosis; however, it apparently does not interact simultaneously with more than one of these motor proteins. SIGNOR-265990 0.6 bisphenol F chemical CHEBI:34575 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 31995776 t miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . SIGNOR-268731 0.8 PTPRF protein P10586 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 15896785 t 10226025:Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. acerquone Knock-down of lar by the l3 sirna probe markedly inhibited the insulin-stimulated increase in the phosphorylation of protein kinase b (pkb, also called akt) on serine 473 by >90% SIGNOR-137246 0.348 ATM protein Q13315 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Thr21 YGGAGGYtQSPGGFG 9606 14872059 t llicata Atm and dna?PK Phosphorylate rpa32 thr21in vitro and in vivo SIGNOR-121865 0.802 PBX2 protein P40425 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription SIGNOR-265778 0.253 NEDD4L protein Q96PU5 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity ubiquitination 9606 19917253 t lperfetto Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation SIGNOR-232104 0.797 CASP3 protein P42574 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25787076 f miannu The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice SIGNOR-255336 0.7 H1-2 protein P16403 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity binding 9606 BTO:0001938 22249259 t done miannu Similarly, DNA-PK-mediated phosphorylation of H1.2 at T146 enhances p53 transcriptional activity by impeding H1.2 binding to p53 and thereby attenuating its suppressive effects on p53 transactivation.  SIGNOR-273833 0.2 TP53 protein P04637 UNIPROT HK2 protein P52789 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27692180 t miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. SIGNOR-267466 0.422 MYOM1 protein P52179 UNIPROT OBSCN protein Q5VST9 UNIPROT up-regulates quantity relocalization 9606 BTO:0003324 19840192 t miannu Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins. SIGNOR-266727 0.304 MAML1 protein Q92585 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity acetylation 9606 17300219 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 gcesareni The n-terminal domain of maml1 directly interacts with both p300 and histones, and the p300-maml1 complex specifically acetylates histone h3 and h4 tails in chromatin. SIGNOR-153038 0.2 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser876 QGLAERIsVL 9606 12058027 t gcesareni Furthermore, we show that pkd2 can be activated by classical and novel members of the protein kinase c (pkc) family such as pkc alpha, pkc epsilon, and pkc eta. These pkcs are activated by gastrin in ags-b cells. Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. SIGNOR-89419 0.2 SWI/SNF complex complex SIGNOR-C92 SIGNOR MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR form complex binding 9606 BTO:0001103 17194702 t miannu Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes SIGNOR-151703 0.2 PRKCA protein P17252 UNIPROT LRRK1 protein Q38SD2 UNIPROT up-regulates activity phosphorylation Ser1074 GNQRNRCsTFRVKRN -1 36040231 t miannu PKCα unexpectedly does not activate LRRK1 by phosphorylating the kinase domain, but instead phosphorylates a cluster of conserved residues (Ser1064, Ser1074 and Thr1075) located within a region of the CORB domain of the GTPase domain. we postulate that phosphorylation of Ser1064, Ser1074 and Thr1075 activates LRRK1 by promoting interaction and stabilization of the αC-helix on the kinase domain. SIGNOR-276867 0.2 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 18997792 t gcesareni A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution. SIGNOR-182124 0.888 2'-deoxyadenosine smallmolecule CHEBI:17256 ChEBI 2'-deoxyadenosine 5'-monophosphate(2-) smallmolecule CHEBI:58245 ChEBI up-regulates quantity precursor of 20637175 t lperfetto Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis SIGNOR-275811 0.8 ITCH protein Q96J02 UNIPROT LAPTM5 protein Q13571 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 22009753 t miannu Here, we found that the level of LAPTM5 protein is regulated negatively by the degradation through ubiquitination by ITCH, an E3 ubiquitin ligase. ITCH directly binds to the PPxY motif of LAPTM5 via its WW domains and promotes ubiquitination through a HECT-type ligase domain. SIGNOR-272721 0.421 AKT2 protein P31751 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity 9606 16293724 f gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway. SIGNOR-141655 0.552 NUMA1 protein Q14980 UNIPROT TUBB4A protein P04350 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-117025 0.376 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr980 YASVNPEyFSAADVY -1 8940173 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-247197 0.564 sabcomeline chemical CHEBI:134846 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10116 9399977 t miannu SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes SIGNOR-258677 0.8 CSNK2A1 protein P68400 UNIPROT F5 protein P12259 UNIPROT down-regulates activity phosphorylation Ser692 IPDDDEDsYEIFEPP -1 9525959 t llicata Factor Va, the essential cofactor for prothrombinase, is phosphorylated on the acidic COOH terminus of the heavy chain of the cofactor, at Ser692, by a platelet membrane-associated casein kinase II (CKII). | The phosphorylated cofactor has increased susceptibility to inactivation by activated protein C, since phosphorylated factor Va was found to be inactivated approximately 3-fold faster than its native counterpart. SIGNOR-250862 0.312 SH3RF1 protein Q7Z6J0 UNIPROT MAP3K12 protein Q12852 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 t gcesareni One explanation as provided by our model is that mlk3 and dlk interact indirectly via posh with mutual activation when both are wild-type the multidomain protein posh binds to the constitutively active form of rac1, which is known to regulate the activity of mlks, while jip1 binds to mlks and additional components of the jnk pathway and appears to be capable of activating mlks SIGNOR-97060 0.384 dexamethasone chemical CHEBI:41879 ChEBI GLUL protein P15104 UNIPROT up-regulates quantity by expression 10090 8099704 f miannu GS transcripts were measured by laser densitometry and normalized to actin, and GS specific activity was also determined. Following a single injection of dexamethasone (0.5 mg/kg), lung GS activity increased by 40% at 4 hours and by 75% at 8 hours. The dexamethasone-mediated increase in GS activity was associated with a marked increase in GS mRNA levels, which preceded the increase in enzyme activity by approximately 2 hours. SIGNOR-267827 0.8 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser27 GNDPLTSsPGRSSRR 9606 16446360 t gcesareni In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells. SIGNOR-143992 0.961 RDH5 protein Q92781 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity chemical modification 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS11 SIGNOR-265114 0.8 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257982 0.8 NDFIP2 protein Q9NV92 UNIPROT NEDD4 protein P46934 UNIPROT down-regulates activity relocalization 9606 BTO:0002181 26363003 t SARA Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2. SIGNOR-260995 0.585 MAT2B protein Q9NZL9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000599 23325603 f miannu MAT2B and GIT1 regulate cell growth and increase ERK activity.GIT1 and MAT2B (V1 and V2) require one another to regulate growth and activate ERK SIGNOR-261246 0.7 DCTPP1 protein Q9H773 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 BTO:0001033 29874556 f miannu Autophagy Induced by Overexpression of DCTPP1 Promotes Tumor Progression and Predicts Poor Clinical Outcome in Prostate Cancer SIGNOR-261177 0.7 HOOK2 protein Q96ED9 UNIPROT CNTRL protein Q7Z7A1 UNIPROT up-regulates binding 9606 17140400 t miannu Hook2 localizes to the centrosome, binds directly to centriolin/cep110 and contributes to centrosomal function SIGNOR-150956 0.36 LEP protein P41159 UNIPROT LEPR protein P48357 UNIPROT up-regulates binding 9606 9463481 t gcesareni Both ob-ra and ob-rb bind leptin with the same affinity, whereas only ob-rb can elicit intracellular response SIGNOR-55656 0.807 NME1 protein P15531 UNIPROT MET protein P08581 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001567 17671192 f miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. SIGNOR-255164 0.336 STAT5A protein P42229 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001096 14530308 f apalma Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells SIGNOR-256583 0.7 Avagacestat chemical CID:46883536 PUBCHEM APP protein P05067 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190479 0.8 MAPK3 protein P27361 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser674 QSPKRPRsPGSNSKV 9606 10648599 t lperfetto Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation. SIGNOR-74308 0.382 POLR3F protein Q9H1D9 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266128 0.881 SPART protein Q8N0X7 UNIPROT WWP1 protein Q9H0M0 UNIPROT up-regulates activity binding 9606 19580544 t miannu Cytosolic endogenous spartin is mono-ubiquitinated and we demonstrate that it interacts via a PPXY motif with the ubiquitin E3 ligases AIP4 [atrophin-interacting protein 4; ITCH (itchy E3 ubiquitin protein ligase homologue] [corrected] and AIP5 (WWP1). Surprisingly, the PPXY motif, AIP4 and AIP5 are not required for spartin's ubiquitination, and so we propose that spartin acts as an adaptor for these proteins. SIGNOR-261307 0.2 PRKAA1 protein Q13131 UNIPROT NAMPT protein P43490 UNIPROT up-regulates quantity transcriptional regulation 10090 18477450 f gcesareni Activated AMPK was required to promote GR-induced transcription of the NAD+ biosynthetic enzyme Nampt SIGNOR-238598 0.302 HSPH1 protein Q92598 UNIPROT HSPA1B protein P0DMV9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19754877 f miannu Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress. SIGNOR-255243 0.455 AGTR1 protein P30556 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257133 0.468 cyproheptadine chemical CHEBI:4046 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7925364 t miannu The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum. SIGNOR-258869 0.8 maraviroc chemical CHEBI:63608 ChEBI CCL5 protein P13501 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194127 0.8 TP53BP2 protein Q13625 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 11839776 t gcesareni 53bp2 interacts with the tumour suppressor p53 and enhances p53-mediated activation of transcription, possibly by facilitating the dephosphorylation of one or more sites on p53 SIGNOR-114762 0.895 BTK protein Q06187 UNIPROT GTF2I protein P78347 UNIPROT up-regulates activity phosphorylation Tyr398 QSHVEDLyVEGLPEG 9534 11373296 t lperfetto These residues, tyr248, tyr357, and tyr462, were also found to be the major sites for btk-dependent phosphorylation of bap/tfii-i in vivo. Residues tyr357 and tyr462 are contained within the loop regions of adjacent helix-loop-helix-like repeats within bap/tfii-i. Mutation of either tyr248, tyr357, or tyr462 to phenylalanine reduced transcription from a c-fos promoter relative to wild-type bap/tfii-i in transfected cos-7 cells, consistent with the interpretation that phosphorylation at these sites contributes to transcriptional activation. SIGNOR-108342 0.531 WNT11 protein O96014 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates 9606 BTO:0000938 BTO:0000887 22309736 f gcesareni We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles. SIGNOR-195963 0.2 RXR proteinfamily SIGNOR-PF44 SIGNOR RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates activity binding 9606 1310351 t miannu Cellular responsiveness to retinoic acid and its metabolites is conferred through two structurally and pharmacologically distinct families of receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Here we report that the transcriptional activity of RAR and RXR can be reciprocally modulated by direct interactions between the two proteins. SIGNOR-256199 0.714 NR0B2 protein Q15466 UNIPROT PPARA protein Q07869 UNIPROT up-regulates binding 9606 11369442 t gcesareni Surprisingly, shp potentiated transcription by pparalpha/rxralpha heterodimers from the hd-ppre. This is the first demonstration of positive transcriptional activity attributable to shp. Together, these results suggest that shp can modulate pparalpha/rxralpha-mediated transcription in a response element-specific manner. SIGNOR-108252 0.514 okadaic acid chemical CHEBI:44658 ChEBI STK3 protein Q13188 UNIPROT up-regulates 9606 23493077 f gcesareni Okadaic acid has been frequently used to enhance the phosphorylation of mst1 and mst2 and to trigger the activation of the hippo pathway. SIGNOR-201551 0.8 PTPRG protein P23470 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity dephosphorylation Tyr292 DTLNSDGyTPEPARI -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254732 0.263 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR2 protein O95136 UNIPROT up-regulates chemical activation 9606 16794003 t gcesareni The evidence suggests that s1p acting on s1p receptors coupled to gq. SIGNOR-147230 0.8 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Thr256 EHNSTTStFCGTPEY -1 10191262 t miannu PDK1 activates SGK in vitro by phosphorylating Thr256. SIGNOR-250275 0.635 SARS1 protein P49591 UNIPROT Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates quantity chemical modification 9606 24095058 t miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis SIGNOR-270498 0.8 KCTD10 protein Q9H3F6 UNIPROT RHOA protein P61586 UNIPROT down-regulates quantity binding 9606 19782033 t miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. SIGNOR-264237 0.272 STAG3 protein Q9UJ98 UNIPROT RAD21L Cohesin complex complex SIGNOR-C355 SIGNOR form complex binding 10090 BTO:0000534 21242291 t miannu RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21. SIGNOR-264536 0.799 NFY complex SIGNOR-C1 SIGNOR CCNB2 protein O95067 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10086339 f gcesareni In this study, we analysed the mechanisms leading to activation of the cyclin b2 ccaat boxes: a combination of (i) genomic footprinting, (ii) transfections with single, double and triple mutants, (iii) emsas with nuclear extracts, antibodies and nf-y recombinant proteins and (iv) transfections with an nf-ya dominant negative mutant established the positive role of the three ccaat sequences and proved that nf-y plays a crucial role in their activation. SIGNOR-65638 0.368 ITK protein Q08881 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr597 RHSTILDyINVVPTA 9606 11733002 t lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling SIGNOR-112471 0.2 COPS8 protein Q99627 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270763 0.919 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 12777400 t Manara These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386 SIGNOR-260769 0.412 coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI up-regulates quantity precursor of 10843999 t lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. SIGNOR-271825 0.8 MAPK3 protein P27361 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser294 QLSKWPGsPTSRSSD 9606 19282669 t lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-184569 0.582 PRKCA protein P17252 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP. SIGNOR-249259 0.503 GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268593 0.2 HSPA9 protein P38646 UNIPROT iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI up-regulates activity relocalization 27714045 t lperfetto Cluster transfer from ISCU to recipient apoproteins is assisted by a dedicated chaperone/cochaperone (HSPA9/HSC20) system that facilitates cluster release from the primary scaffold ISCU and transfer to recipient apoproteins or to intermediate carriers SIGNOR-262131 0.8 HOXB7 protein P09629 UNIPROT FGF2 protein P09038 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 8756643 t Luana Band shift and cotransfection experiments showed that HOXB7 directly transactivates the hFGF gene through one out of five putative homeodomain binding sites present in its promoter. SIGNOR-261639 0.405 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser528 KPRSSRGsIFTFRRR -1 12242273 t miannu These results demonstrate that the effect of PKA stimulation to increase cardiac INa requires at least 2 processes: phosphorylation of consensus sites in the I-II interdomain linker, and one or more additional molecular events mediated by the kinase, that could include phosphorylation of other substrates/proteins. SIGNOR-275992 0.2 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Thr357 FELRKTQtSMSLGTT -1 24012422 t gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays SIGNOR-266438 0.743 axitinib chemical CHEBI:66910 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 21297102 t gcesareni The inhibitory effect of four tkis (axitinib, imatinib, masitinib, and vatalanib) for proliferation and phosphorylation of c-kit receptor as well as the expression and function of abcb1 were investigated in three cmct cell lines (hrmc, vimc1, and cmmc1). SIGNOR-171866 0.8 LRFN2 protein Q9ULH4 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments. SIGNOR-264099 0.7 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000586 16293724 f lperfetto We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein;G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt SIGNOR-235914 0.81 FGF13 protein Q92913 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253439 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser240 RLSSLRAsTSKSESS 9606 21233202 t lperfetto In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity SIGNOR-252765 0.2 AKT1 protein P31749 UNIPROT RPS6KA3 protein P51812 UNIPROT down-regulates activity phosphorylation Ser19 KMAVESPsDSAENGQ 9606 BTO:0000815 33574926 t miannu Akt interacts with and phosphorylates RSK2 at S19. SIGNOR-277548 0.267 CDK5 protein Q00535 UNIPROT DNM1 protein Q05193 UNIPROT up-regulates activity phosphorylation Ser774 SVPAGRRsPTSSPTP -1 12855954 t llicata Here, we show that cyclin-dependent kinase 5 (Cdk5) phosphorylates dynamin I on Ser 774 and Ser 778 in vitro, which are identical to its endogenous phosphorylation sites in vivo. Cdk5 antagonists and expression of dominant-negative Cdk5 block phosphorylation of dynamin I, but not of amphiphysin or AP180, in nerve terminals and inhibit SVE.  SIGNOR-250661 0.531 AR protein P10275 UNIPROT KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 20069563 t TH1 also associates with AR at the active androgen-responsive prostate-specific antigen (PSA) promoter in the nucleus of LNCaP cells. Decrease of endogenous AR protein by TH1 interferes with androgen-induced luciferase reporter expression and reduces endogenous PSA expression. SIGNOR-253657 0.816 PAX8 protein Q06710 UNIPROT SLC3A1 protein Q07837 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000671 15673291 f miannu Expression of SLC3A1 mRNA was found to be tenfold higher in postnatal vs. fetal kidney; SLC3A1 expression is doubled by the proximal tubule transcription factor, PAX8. rBAT is expressed in the proximal convoluted and straight tubules in both fetal and adult kidney. SIGNOR-254907 0.253 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates activity phosphorylation Thr355 EPSTVPGtPPPKKFR 9606 12734188 t lperfetto Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9. SIGNOR-101059 0.369 KDM5C protein P41229 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30921702 f miannu KDM5C performs its oncogenic function by suppressing PTEN epigenetically. SIGNOR-264312 0.342 ITGAL protein P20701 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253189 0.912 N-[3-[[5-iodo-4-[3-[[oxo(thiophen-2-yl)methyl]amino]propylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide chemical CHEBI:91439 ChEBI TBK1 protein Q9UHD2 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190795 0.8 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser177 ASSGSSAsFISDTFS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248514 0.387 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Thr293 QSAQSLAtPVVSVAT 9606 9858528 t The effect has been demonstrated using Q06413-3 lperfetto Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain SIGNOR-62792 0.683 CHEVI complex complex SIGNOR-C269 SIGNOR Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 9606 27319744 f lperfetto VPS33B association with VIPAS39, α-tubulin, and SEC22B was identified by co-immunoprecipitation, mass spectra, and immunoblotting in human embryonic kidney 293T (HEK293T) cells. Also, pull-down experiments revealed that VIPAS39 bound to intact VPS33B; in contrast, α-tubulin and SEC22B separately interacted with the sec1-like domains of VPS33B. Vps33b deficiency in megakaryocytes disturbs the redistribution of Vipas39 and Sec22b to proplatelets, and interrupted the co-localization of Sec22b with Vwf-positive vesicles SIGNOR-261833 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP3K8 protein P41279 UNIPROT up-regulates activity phosphorylation Ser413 LERKRLLsRKELELP 9606 BTO:0000007 12138205 t Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator. SIGNOR-251481 0.2 zotepine chemical CHEBI:32316 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258553 0.8 GSK3B protein P49841 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000782 16407239 t lperfetto Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) . SIGNOR-217430 0.38 PRKAA1 protein Q13131 UNIPROT NR2C2 protein P49116 UNIPROT down-regulates phosphorylation Ser351 HVISRDQsTPIIEVE 9606 SIGNOR-C15 21478464 t gcesareni Tr4 transactivation is inhibited via phosphorylation bymetformin-induced amp-activated protein kinase (ampk) at the amino acid serine 351, which results in the suppression of scd1 gene expression SIGNOR-173118 0.2 ROCK1 protein Q13464 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates activity phosphorylation Thr853 PREKRRStGVSFWTQ 10090 10601309 t lperfetto Phosphorylation by Rho-kinase inhibited MP activity and this reflected a decrease in V(max). Activity of MP with different substrates also was inhibited by phosphorylation. Two major sites of phosphorylation on MYPT1 were Thr(695) and Thr(850). SIGNOR-249034 0.765 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120024 0.781 FGF2 protein P09038 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 11781339 f gcesareni In these collagen gel cultures, p38 activation was induced more potently by fgf-2 treatment compared with that in proliferating cultures SIGNOR-113649 0.4 ATM protein Q13315 UNIPROT CREB1 protein P16220 UNIPROT down-regulates activity phosphorylation Ser97 TIAESEDsQESVDSV 9606 15073328 t lperfetto Individual ala substitutions at thr-100, ser-111, or ser-121 inhibited atm-catalyzed phosphate incorporationatm phosphorylated creb in vitro and in vivophosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp) SIGNOR-124043 0.537 MAP2K4 protein P45985 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Tyr182 ADAEMTGyVVTRWYR 9606 BTO:0000007 10066767 t done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. SIGNOR-273955 0.436 CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI PGS1 protein Q32NB8 UNIPROT up-regulates activity chemical activation 9606 29034233 t lperfetto After activation of PA by the CDP-DAG synthase TAMM41 (Kutik et al., 2008), the phosphatidylglycerol phosphate synthase (PGS1) catalyzes the committed step by converting CDP-DAG to phosphatidylglycerol phosphate (PGP) SIGNOR-267024 0.8 STAT3 protein P40763 UNIPROT CASP3 protein P42574 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 25787076 f miannu We determined that Stat3 activation increases caspase-3 expression in C2C12 cells. SIGNOR-255335 0.474 PTGFR protein P43088 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256953 0.252 SUFU protein Q9UMX1 UNIPROT GLI2 protein P10070 UNIPROT down-regulates activity relocalization 10090 16316410 t lperfetto We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms SIGNOR-129065 0.906 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates phosphorylation 9606 8663074 t gcesareni Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily. SIGNOR-42390 0.646 CDK2 protein P24941 UNIPROT RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser44 LENDFFNsPPRKTVR 9606 SIGNOR-C16 15004009 t miannu Cdk2/cyclin e-mediated phosphorylation at ser 44 activates tif-ia SIGNOR-123231 0.486 CDK1 protein P06493 UNIPROT APLP2 protein Q06481 UNIPROT unknown phosphorylation Thr736 VEVDPMLtPEERHLN 9606 BTO:0000142 9109675 t lperfetto A cytoplasmic domain peptide from aplp2 is phosphorylated in vitro by protein kinase c and cdc2 kinase. Aplp2 is phosphorylated by cdc2 kinase at a site homologous to the cdc2 kinase site phosphorylated in app. SIGNOR-47483 0.339 PTGS1 protein P23219 UNIPROT prostaglandin G2(1-) smallmolecule CHEBI:82629 ChEBI up-regulates quantity chemical modification -1 7592599 t Luana [14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2, SIGNOR-269771 0.8 SHANK3 protein Q9BYB0 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates quantity binding 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264604 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 t llicata Akt regulates ranbp3 phosphorylation in vitro and in vivo SIGNOR-160900 0.2 MARCHF9 protein Q86YJ5 UNIPROT PVR protein P15151 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271530 0.2 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser293 EESYDTEsEFTEFTE 9606 BTO:0000782 8622692 t llicata Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation. SIGNOR-40510 0.567 NLK protein Q9UBE8 UNIPROT SETDB1/NLK/CHD7 complex SIGNOR-C189 SIGNOR form complex binding 10090 21952300 t FFerrentino The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1)42. SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3‑L1 cells42,43. SIGNOR-253525 0.424 PSMC5 protein P62195 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263372 0.878 doxorubicin chemical CHEBI:28748 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 19377506 t An important reason why Top2 has held the interest of researchers studying cancer was the discovery that active anti-cancer drugs, notably etoposide and doxorubicin target Top2 SIGNOR-261911 0.8 XBP1 protein P17861 UNIPROT XBP1 protein P17861 UNIPROT up-regulates activity binding -1 12805554 t miannu E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins SIGNOR-224199 0.2 ZBTB20 protein Q9HC78 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 23776228 t miannu ChIP and next generation high-throughput DNA sequencing assay showed that ZBTB20 specifically bound to IκBα gene promoter (+1 to +60 region) after TLR activation. ZBTB20 could inhibit IκBα gene transcription, govern IκBα protein expression, and then promote NF-κB activation. Therefore, transcriptional repressor ZBTB20 is needed to promote full activation of TLR signaling and TLR-triggered innate immune response by selectively suppressing the suppressor IκBα gene transcription. SIGNOR-266868 0.261 CDK5 protein Q00535 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates activity phosphorylation Thr873 LLYSEAKtPIKWMAL 10116 BTO:0004102 12824184 t llicata We demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival.  SIGNOR-250664 0.347 ATP5MG protein O75964 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261408 0.2 CDK1 protein P06493 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser439 AGSPFQSsPLSLGSR 9606 SIGNOR-C17 16880739 t llicata Cdk1/cyclin b-mediated phosphorylation stabilizes srebp1 during mitosis. SIGNOR-148354 0.291 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser171 PLCLSPAsSGSSASF 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248365 0.598 INTS2 protein Q9H0H0 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261466 0.745 HK3 protein P52790 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266457 0.8 MAPK1 protein P28482 UNIPROT ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser272 CSLERQLsLEQEVQQ 9606 BTO:0000567 12670876 t lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. SIGNOR-264439 0.39 CHEK1 protein O14757 UNIPROT CDC7 protein O00311 UNIPROT up-regulates phosphorylation 9606 20068082 t gcesareni Chk1 directly phosphorylates essential s-phase kinases cdc7. SIGNOR-163161 0.723 CSNK2A1 protein P68400 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1525 PIKYLEEsDEDDLF 9606 19098900 t gcesareni Here we report that when phosphorylated, ser 1524 of topo iialpha acts as a binding site for the brct domain of mdc1 (mediator of dna damage checkpoint protein-1), thereby recruiting mdc1 to chromatin SIGNOR-182840 0.613 FBXW7 protein Q969H0 UNIPROT JUN protein P05412 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 14739463 t miannu  We report that in neurons the stability of c-Jun is regulated by the E3 ligase SCF(Fbw7), which ubiquitinates phosphorylated c-Jun and facilitates c-Jun degradation.  SIGNOR-272950 0.509 CHFR protein Q96EP1 UNIPROT HDAC1 protein Q13547 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 19182791 t miannu Histone deacetylase 1 (HDAC1), which represses transcription by deacetylating histones, was newly isolated as a Chfr-interacting protein. Chfr binds and downregulates HDAC1 by inducing its polyubiquitylation, both in vitro and in vivo. Together, these results suggest that the ubiquitin ligase activity of Chfr targets HDAC1 for degradation. SIGNOR-271465 0.403 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 10090 BTO:0002572 28646232 t Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels SIGNOR-262522 0.2 PRKDC protein P78527 UNIPROT PDX1 protein P52945 UNIPROT down-regulates quantity by destabilization phosphorylation Thr11 EEQYYAAtQLYKDPC 10090 16166097 t miannu The interaction of PDX-1 with Ku subunits and its phosphorylation on threonine 11 by the DNA-PK appear to be implicated in its degradation by the proteosome. SIGNOR-225542 0.312 PAX8 protein Q06710 UNIPROT SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14623893 t miannu Pax8 has an essential role in thyroid organogenesis and differentiation, being the main mediator of thyroid gene transcription, including the NIS gene. SIGNOR-251990 0.418 TFIIA complex SIGNOR-C395 SIGNOR RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity relocalization 9606 7724559 t lperfetto The human general transcription factor TFIIA is one of several factors involved in specific transcription by RNA polymerase II SIGNOR-266200 0.653 RAP1A protein P62834 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 BTO:0002181 24290981 t miannu Our data are consistent with a pathway involving the cAMP-mediated activation of Rapgef2, which then stimulates Rap1, leading to increases in B-Raf, MEK, and ERK activity.Increased intracellular concentrations of cAMP enhanced the Rapgef2-dependent activation of Rap1, which in turn associated with B-Raf to enable the activation of ERK and subsequent neuronal- and endocrine-specific cellular outcomes, such as induction of neuroendocrine-specific genes and extension of neuritic processes (neuritogenesis). SIGNOR-276608 0.679 TFEB protein P19484 UNIPROT CYP17A1 protein P05093 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) SIGNOR-276786 0.2 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates activity phosphorylation Ser90 GLFNELAsPFENEFK 9606 BTO:0000599 10085140 t miannu P38 directly phosphorylates ATF-2 at Thr-69, Thr-71, and Ser-90, resulting in stimulation of its trans-activating capacity. SIGNOR-250090 0.786 CSNK1A1 protein P48729 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates quantity by destabilization phosphorylation Ser265 PRSSSNAsSVSTRLS 9606 BTO:0001109 28945225 t miannu Here we report that CK1α similarly destabilizes FOXO4 in RAS-mutant cells by phosphorylation at serines 265/268.  SIGNOR-277325 0.2 ATF4 protein P18848 UNIPROT FGF21 protein Q9NSA1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22233381 f miannu These results add FGF21 gene induction to the transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation. SIGNOR-253748 0.439 PTPRF protein P10586 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation 9606 12018405 t lperfetto Some 10 years ago, Hashimoto et al. (87) had shown that the LAR catalytic domain can dephosphorylate the EGFR receptor in vitro, and more recently, Kulas and colleagues (88) have demonstrated that the antisense mediated suppression of LAR can enhance the growth factor induced activation of EGFR in rat hepatoma cells.|These data indicate that LAR and RPTPsigma may have a significant role in GPCR induced EGFR signalling.Whereas in A431 cells LAR and RPTPsigma may act to suppress the EGFR in response to GPCR activation, it is possible that the converse may also be true in other cell types. SIGNOR-277029 0.342 TNF protein P01375 UNIPROT SCNN1A protein P37088 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005760 16877633 f Regulation of expression miannu TNF, a proinflammatory cytokine present in several lung pathologies, decreases the expression and activity of the epithelial Na(+) channel (ENaC) by approximately 70% in alveolar epithelial cells. SIGNOR-251954 0.31 PPP1CA protein P62136 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 20186153 t gcesareni Several stps have been reported to negatively regulate akt pathway. It has been shown that pp1 dephosphorylates akt and regulates cell survival. SIGNOR-163961 0.436 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation 9606 14988395 t inferred from 70% family members lperfetto Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity. SIGNOR-270012 0.2 UBQLN4 protein Q9NRR5 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity binding 9606 BTO:0001938 30612738 t lperfetto These data suggest that MRE11 is one of probably many UBQLN4 interaction partners. >Particularly HRR is dependent on ATM activity (Dietlein et al., 2014). Here, we showed that UBQLN4 is an ATM substrate and that DSB sealing is markedly impaired in UBQLN4-depleted cells. HRR depends on a 5′-3′ DSB end resection, which is initiated by the MRE11 nuclease SIGNOR-265077 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr194 NMMDILTtPSMAKPR 9606 BTO:0002181 24391510 t miannu We demonstrate that PP2A/B55 is required for Gwl dephosphorylation at the essential Cdk site Thr194.Gwl phosphorylation by CycA/Cdk2 in vitro. Flag WT and Thr194A Gwl was transiently expressed and purified from asynchronous HEK 293T cells and incubated with recombinant CycA/Cdk2, following treatment with alkaline phosphatase (aPh) in the indicated samples. The proteins were analysed by immuno-blotting with anti-Gwl and Gwl pThr194 antibodies SIGNOR-276614 0.278 EIF3E protein P60228 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266396 0.94 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR up-regulates activity chemical activation 26083061 t lperfetto Respiratory chain complexes I–III depend on Fe-S clusters for function SIGNOR-262135 0.8 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB6 protein Q9Y5F9 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265684 0.2 ATM protein Q13315 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates activity phosphorylation Ser43 RNPEAALsPTFRSDS 32615088 t miannu Here, we report that, in response to DSBs, the RNA methyltransferase METTL3 is activated by ATM-mediated phosphorylation at S43. SIGNOR-265969 0.2 NR0B2 protein Q15466 UNIPROT AR protein P10275 UNIPROT down-regulates binding 9606 11735420 t gcesareni We demonstrated that shp inhibited both ar-lbd and ntd-dependent transactivation, which evidenced for the first time a protein capable of inhibiting a steroid receptor amino-terminal-dependent transactivation. We further characterized the shp mechanism of action by showing that shp reversed ar coactivator-mediated activation SIGNOR-112589 0.425 UCHL5 protein Q9Y5K5 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270852 0.598 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120096 0.316 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDK7 protein P50613 UNIPROT up-regulates activity phosphorylation Ser164 GLAKSFGsPNRAYTH -1 11113184 t lperfetto Activating phosphorylation of CDK7 by CDC2 and CDK2. The ability of pure CDK2-cyclin A to activate CDK7 in T170-dependent fashion (Fig. ​(Fig.3C,3C, lane 2) strongly suggested a direct phosphorylation mechanism. Tryptic phosphopeptide mapping confirmed that both CDK2-cyclin A (Fig. ​(Fig.4A)4A) and CDC2-cyclin B (Fig. ​(Fig.4D)4D) phosphorylated CDK7 on both S164 and T170. SIGNOR-270807 0.63 SHMT1 protein P34896 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI up-regulates quantity chemical modification 9606 32439610 t lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. SIGNOR-268223 0.8 PAMPs stimulus SIGNOR-ST11 SIGNOR NLRP1 protein Q9C000 UNIPROT up-regulates activity 16037825 f lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-256425 0.7 erlotinib hydrochloride chemical CHEBI:53509 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 17178722 t JAK2(V617F), a mutant of tyrosine kinase JAK2. Erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor. gcesareni This study shows that the anti-cancer drug erlotinib (tarceva) is a potent inhibitor of jak2(v617f) activity. SIGNOR-151271 0.8 ZBTB20 protein Q9HC78 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 29748916 f miannu The transcription factor (TF) Zbtb20 is important for the hippocampal specification and the regulation of neurogenesis of neocortical projection neurons. Herein, we show a critical involvement of the TF Zbtb20 in the neurogenesis of both projection neurons and interneurons of the olfactory bulb during embryonic stages SIGNOR-266866 0.7 TFDP1 protein Q14186 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates activity binding 9606 14618416 t miannu DP-1 is a heterodimerization partner for members of the E2F family of transcription factors; E2F/DP-1 regulates the expression of various cellular promoters, particularly gene products that are involved in the cell cycle. SIGNOR-253865 0.807 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-264179 0.8 AGTR1 protein P30556 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 11313903 t gcesareni These neuropeptide gpcrs are coupled to the activation of phospholipase c, and therefore to calcium ele- vation and protein kinase c (pkc) activation, through g proteins of the alfaq family. SIGNOR-106932 0.628 PPP1R14A protein Q96A00 UNIPROT PPP1CB protein P62140 UNIPROT down-regulates activity binding -1 12144526 t lperfetto We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin SIGNOR-265742 0.484 WNK3 protein Q9BYP7 UNIPROT SLC12A3 protein P55017 UNIPROT up-regulates activity phosphorylation 21613606 t lperfetto We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs SIGNOR-264624 0.467 CD28 protein P10747 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 24098653 t fspada Binding of the py site in cd28 (py-m-n-m) by pi3k and grb2 through their sh2 domains is a key step that triggers the cd28 signal transduction for t cell activation and differentiation SIGNOR-202706 0.69 EGR1 protein P18146 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22431919 f miannu Overexpression or short interfering RNA (siRNA)-mediated down-regulation of EGR1 or NAB2, and chromatin immunoprecipitations indicated that EGR1 and NAB2 act in concert to positively regulate p130(Cas)/BCAR1 expression in breast cancer cells. SIGNOR-253890 0.2 SH3PXD2A protein Q5TCZ1 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates activity binding 9606 BTO:0000007 20943948 t lperfetto Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation SIGNOR-264708 0.419 GTP smallmolecule CHEBI:15996 ChEBI GNAI1 protein P63096 UNIPROT up-regulates chemical activation 9606 12040175 t gcesareni Agonist binding triggers a conformational change in the receptor, which catalyses the dissociation of gdp from the alfa subunit followed by gtp-binding to galfa and the dissociation of galfa from gbetagamma subunits1. The alfa subunits of g proteins are divided into four subfamilies: galfas, galfai, galfaq and galfa12, and a single gpcr can couple to either one or more families of galfa proteins. SIGNOR-88238 0.8 VARS1 protein P26640 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. SIGNOR-270797 0.8 TYMS protein P04818 UNIPROT Purine biosynthesis phenotype SIGNOR-PH186 SIGNOR up-regulates 9606 21876188 t lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. SIGNOR-253139 0.7 SRC protein P12931 UNIPROT PROM1 protein O43490 UNIPROT unknown phosphorylation Tyr852 GYHKDHVyGIHNPVM 9606 19296573 t llicata Cd133 (prominin-1) is phosphorylated on cytoplasmic tyrosine-828 and tyrosine-852 by src SIGNOR-184776 0.514 PPM1D protein O15297 UNIPROT RPS6KA3 protein P51812 UNIPROT down-regulates activity dephosphorylation Ser369 TAKTPKDsPGIPPSA 10090 15206906 t RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity SIGNOR-248321 0.368 USP9X protein Q93008 UNIPROT EPS15 protein P42566 UNIPROT down-regulates activity deubiquitination 9606 26748853 t gcesareni We identify the endocytic protein Eps15 as one of the critical substrates of USP9X SIGNOR-245052 0.275 CREBBP protein Q92793 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity acetylation Lys390 QKTLTPEkGQSQGLI 9606 BTO:0000007 17923090 t lperfetto STAT2 is another important component of ISGF3 complex, and its acetylation was similar to IFNaR2 and IRF9 acetylation in many respects: CBP downregulation largely abolished STAT2 acetylation induction by IFNa (Figure 6A), and CBP was more potent than transferases tested in catalyzing STAT2 acetylation (Figure 6B). [...] Figure 6 (I) STAT2-K390R substitution has reduced activity in ISGF3 complex formation. SIGNOR-217891 0.549 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA2 protein Q9Y5H1 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265713 0.2 SP1 protein P08047 UNIPROT SCNN1A protein P37088 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004299 12684058 f Regulation of expression miannu Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression. SIGNOR-251950 0.2 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity phosphorylation Ser102 LQTVIRTsPSSLVAF 9606 26190112 t Luana AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. SIGNOR-259861 0.339 MAGED1 protein Q9Y5V3 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates 9606 BTO:0001760 20646279 f gcesareni By comparing in vitro differentiation of myoblasts derived from wild-type or maged1 knockout mice, we observed that maged1 deficiency results in reduced levels of p21cip1/waf1, defective cell cycle exit and impaired myotube maturation. SIGNOR-166893 0.2 YWHAQ protein P27348 UNIPROT NEFL protein P07196 UNIPROT down-regulates activity binding 9606 23230147 t miannu These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments. SIGNOR-252399 0.303 paracetamol chemical CHEBI:46195 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000876 17884974 t Luana Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man SIGNOR-257757 0.8 FBXW11 protein Q9UKB1 UNIPROT AICDA protein Q9GZX7 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 31092637 t miannu  Further analysis indicated that CUL7 mediated AID ubiquitination by forming a complex with FBXW11. In a CUL7 fl/fl CD19 cre+ mouse model, we demonstrated that CUL7 knockout significantly enhanced AID protein levels in B cells in the germinal center and increased both the IgG1 and IgA class switching. Collectively, our results reveal a subtle regulation mechanism for tightly controlling AID protein levels. F-box proteins are components of SCF ubiquitin-ligase complexes that contain Skp1, CUL1, or CUL7, and an F-box protein SIGNOR-272024 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR FTH1 protein P02794 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003212 19258503 f miannu We show that inhibition of constitutively active NF-kappaB causes down-regulation of ferritin heavy chain (FHC) that leads to an increase of free intracellular iron, which, in turn, induces massive generation of ROS. SIGNOR-254792 0.343 C3 convertase complex (C3bBb) complex SIGNOR-C314 SIGNOR C3 protein P01024 UNIPROT up-regulates activity cleavage Arg748 ASHLGLArSNLDEDI 9606 BTO:0000089 26489954 t lperfetto In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC). SIGNOR-263478 0.903 CRCP protein O75575 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266134 0.793 RARB protein P10826 UNIPROT RXRB protein P28702 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. SIGNOR-16581 0.651 MRPL43 protein Q8N983 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262353 0.686 COL4A3 protein Q01955 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 t Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6) SIGNOR-254667 0.7 PPY protein P01298 UNIPROT NPY4R protein P50391 UNIPROT up-regulates binding 9606 BTO:0000142 7592911 t gcesareni Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid. SIGNOR-24230 0.637 RNF111 protein Q6ZNA4 UNIPROT PML protein P29590 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23530056 t miannu Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4. SIGNOR-272883 0.361 CDK1 protein P06493 UNIPROT LBR protein Q14739 UNIPROT down-regulates phosphorylation Ser71 KGGSTSSsPSRRRGS 9606 14718546 t lperfetto The binding of the nk fragment to chromatin pretreated with an s-phase extract was suppressed by incubation with an m-phase extract. Enzyme inhibitor experiments revealed that multiple kinases participate in the suppression. One of these kinases was shown to be cdc2 experiments involving a mutant nk fragment showed that the phosphorylation of serine 71 by cdc2 kinase is responsible for the suppression. SIGNOR-121335 0.405 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu82 REVFENTeRTTEFWK 10090 BTO:0001103 11133752 t lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. SIGNOR-263695 0.67 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 17126298 t gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. SIGNOR-150879 0.338 PRKCA protein P17252 UNIPROT FERMT3 protein Q86UX7 UNIPROT up-regulates activity phosphorylation Ser484 LSLQRTGsGGPGNHP 9606 BTO:0000565 25609252 t miannu  PKC-induced phosphorylation events, as we have shown kindlin-3 to be a PKC phosphorylation target (Fig. 6C), are often followed by rapid activation of phosphatases (38).  SIGNOR-266415 0.2 PDGFRB protein P09619 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 9606 8195171 t gcesareni In this study, we have characterized the interaction between the pdgf beta-receptor and shc. multiple autophosphorylation sites in the pdgf beta-receptor are responsible for the binding of shc. SIGNOR-36906 0.645 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1724 SPSYSPTsPSYSPTS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248812 0.849 SDHA protein P31040 UNIPROT Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 30030361 t lperfetto Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites SIGNOR-262188 0.95 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser40 RRTDALTsSPGRDLP 9606 19647517 t lperfetto Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry SIGNOR-187392 0.961 A-966492 chemical CID:16666333 PUBCHEM PARP2 protein Q9UGN5 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-203622 0.8 PHF5A protein Q7RTV0 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270670 0.764 SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR form complex binding 9606 20957627 t lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. SIGNOR-255838 0.672 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 18160256 t Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248628 0.89 EIF3K protein Q9UBQ5 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266390 0.921 glycogen smallmolecule CHEBI:28087 ChEBI alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity precursor of 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267955 0.8 MAPK10 protein P53779 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 14699954 t amattioni The targets of jnk include the transcription factors p53. P75ntr-mediated apoptosis was shown to be dependent of p53 SIGNOR-120552 0.617 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 BTO:0000938 12367505 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. gcesareni Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27. SIGNOR-94025 0.802 Nucleosome_H2A.Z.2 variant complex SIGNOR-C323 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR down-regulates 9606 15623580 f lperfetto All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage. SIGNOR-273456 0.7 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr723 SSQGVDTyVEMRPVS 9606 BTO:0001271 15297464 t lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins. SIGNOR-127614 0.2 RFX complex complex SIGNOR-C104 SIGNOR HLA-DRB3 protein P79483 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 f The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-254001 0.2 SMARCD3 protein Q6STE5 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15870273 f lperfetto We observed that the homeodomain factor pbx1, which cooperates with myod to stimulate myogenin expression, is constitutively bound to the myogenin promoter in a swi/snf-independent manner, suggesting a two-step mechanism in which myod initially interacts indirectly with the myogenin promoter and attracts chromatin-remodeling enzymes, which then facilitate direct binding by MyoD and other regulatory proteins. SIGNOR-136945 0.36 CNOT3 protein O75175 UNIPROT CAND2 protein O75155 UNIPROT unknown binding 10090 12207886 t lperfetto Hnot3l is associated with tip120b / tip120b presumably affects tissue-specific transcriptional regulation via interaction with not3. SIGNOR-235593 0.337 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 12213813 t lperfetto In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E SIGNOR-262994 0.658 MED10 protein Q9BTT4 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266656 0.844 RNF8 protein O76064 UNIPROT UBE2N protein P61088 UNIPROT up-regulates binding 9606 18678647 t gcesareni The rnf8 ring domain signals ubc13 to sites of damage, which is sufficient for dna damage signal transduction. SIGNOR-179823 0.74 CDK9 protein P50750 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15546612 f gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. SIGNOR-130703 0.2 Scribble_complex_DLG2-LLGL2_variant complex SIGNOR-C503 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 f miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270882 0.7 PRKAA1 protein Q13131 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates phosphorylation Ser158 REGTRVQsVEQIREV 9606 SIGNOR-C15 23291169 t lperfetto We found that an activated amp-activated protein kinase (ampk) phosphorylates ctbp1 on ser-158 upon metabolic stresses. Moreover, ampk-mediated phosphorylation of ctbp1 (s158) attenuates the repressive function of ctbp1 SIGNOR-200250 0.2 IRAK1 protein P51617 UNIPROT PELI3 protein Q8N2H9 UNIPROT up-regulates phosphorylation 9606 17997719 t gcesareni Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity. SIGNOR-159052 0.718 PTPRC protein P08575 UNIPROT LCK protein P06239 UNIPROT up-regulates activity dephosphorylation Tyr505 FTATEGQyQPQP 9606 11259588 t Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr505 and Tyr394, the net effect in normal thymocytes being a decrease in enzymatic activity SIGNOR-248350 0.789 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21071439 t lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-174878 0.2 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCH protein P24723 UNIPROT up-regulates activity binding 9606 14967450 t PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. SIGNOR-242593 0.8 NFKB1 protein P19838 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity binding 9606 9450761 t lperfetto Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna SIGNOR-55378 0.701 AR protein P10275 UNIPROT ARG1 protein P05089 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001321 20711410 f miannu The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression. SIGNOR-253738 0.2 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr90 SPLLLTTtNSSEGLS 9606 11152499 t tpavlidou Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites. SIGNOR-85789 0.2 TNFRSF10B protein O14763 UNIPROT FADD protein Q13158 UNIPROT up-regulates binding 9606 14585074 t amattioni Fadd binds to ligated trailr1 or trail-r2 SIGNOR-98565 0.844 TNK2 protein Q07912 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Tyr176 EKATGRYyAMKILKK 10090 BTO:0002021 20333297 t gcesareni Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation. SIGNOR-252457 0.437 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-70444 0.2 IL10 protein P22301 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0000938 BTO:0001264 23357618 f miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. SIGNOR-253501 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser597 VPMNPNLsSEDPNLF 9606 15379552 t lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) SIGNOR-129192 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR ACAP1 protein Q15027 UNIPROT unknown phosphorylation Ser554 SIRPRPGsLRSKPEP 9606 16256741 t llicata Akt phosphorylates s554 in acap1 SIGNOR-141343 0.2 ADAM10 protein O14672 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity cleavage 9606 26284334 t miannu The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin. SIGNOR-259846 0.529 MRPL27 protein Q9P0M9 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262368 0.694 RHCE protein P18577 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 t lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  SIGNOR-266022 0.327 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser121 ESSDSGTsVSENRCH 9606 20708156 t gcesareni Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase. SIGNOR-167501 0.352 ABL1 protein P00519 UNIPROT ERCC6 protein Q03468 UNIPROT up-regulates activity phosphorylation Tyr932 GANRVVIyDPDWNPS 9606 17626041 t Regulation miannu N-terminal region of CSB interacts with the SH3 domain of c-Abl in vitro and in vivo. In addition, c-Abl kinase phosphorylates CSB at Tyr932. our results suggest that c-Abl interacts with and tyrosine phosphorylates CSB. This interaction may play an important role in the response to oxidative stress, resulting in activation of c-Abl, tyrosine phosphorylation of CSB and more efficient BER of oxidative DNA damage. Tyrosine-phosphorylated CSB may serve as a signal for repair proteins to localize to DNA damage and may help maintain active transcription in the nucleolus. SIGNOR-251933 0.274 HOMER proteinfamily SIGNOR-PF59 SIGNOR SHANK3 protein Q9BYB0 UNIPROT up-regulates activity binding 9606 BTO:0000938 17243894 t miannu It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD SIGNOR-264697 0.2 RNF38 protein Q9H0F5 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 23973461 t miannu Here we demonstrate that RNF38 is a functional ubiquitin protein ligase (E3). We show that RNF38 isoform 1 is localized to the nucleus by a bipartite nuclear localization sequence (NLS). We confirm that RNF38 is a binding partner of p53 and demonstrate that RNF38 can ubiquitinate p53 in vitro and in vivo. Finally, we show that overexpression of RNF38 in HEK293T cells results in relocalization of p53 to discrete foci associated with PML nuclear bodies.  SIGNOR-272130 0.371 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Platelet_degranulation phenotype SIGNOR-PH138 SIGNOR down-regulates 9606 BTO:0000132 23805129 f lperfetto Inhibition of actin polymerization also augments the kinetics and degree of alpha-granule release (Flaumenhaft et al., 2005). These results suggest that F-actin disassembly might actually be required for normal granule secretion and that activation-mediated granule release is related to actin. SIGNOR-266000 0.7 UVB radiation stimulus SIGNOR-ST17 SIGNOR GCH1 protein P30793 UNIPROT up-regulates 9606 9204951 f miannu UVB light induces GTP-CH.-1 to increase the de novo synthesis of 6-BH4 in association with a concomitant increase in PAH activities, thus providing more L-tyrosine. SIGNOR-252206 0.7 SNARE_complex complex SIGNOR-C346 SIGNOR Exocytosis phenotype SIGNOR-PH157 SIGNOR up-regulates 9606 BTO:0000938 30267828 f miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. SIGNOR-263969 0.7 KAT2B protein Q92831 UNIPROT H3C15 protein Q71DI3 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269618 0.2 SGK3 protein Q96BR1 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000007 11154281 t lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. SIGNOR-252992 0.448 IRF4 protein Q15306 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 20729857 f lperfetto We found Irf4 to be one of the direct targets of Jmjd3-mediated demethylation. Finally, we found that Irf4 is a transcription factor crucial for the induction of M2 macrophage responses. SIGNOR-249543 0.7 MAPK14 protein Q16539 UNIPROT H3-3A protein P84243 UNIPROT unknown phosphorylation 9606 10806218 t gcesareni More importantly, incubation of active erk2 or p38 kinase with h3 protein resulted in phosphorylation of h3 at serine 10 in vitro. These results suggest that erk and p38 kinase are at least two important mediators of phosphorylation of h3 at serine 10. SIGNOR-77224 0.2 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258632 0.8 FOXO3 protein O43524 UNIPROT STK11 protein Q15831 UNIPROT down-regulates quantity transcriptional regulation 22848740 t SGK-1 Negatively Regulates LKB1 Expression via FOXO3 Transcription Factor SIGNOR-255758 0.623 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR HYAL1 protein Q12794 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004796 18718911 f miannu In 253J-Lung and HT1376 bladder cancer cell lines, which show high HYAL-1 expression, transcription factors Egr-1, AP-2, and NFκB bind the HYAL-1 promoter. Because both SP1 and Egr-1 have two overlapping binding sites within the promoter (Fig. 5), it appears that although SP1 binding to the methylated HYAL-1 promoter turns off transcription, binding of Erg-1 (and also AP-2) to the unmethylated promoter turns on transcription. SIGNOR-253880 0.2 DAPK1 protein P53355 UNIPROT DDX58 protein O95786 UNIPROT down-regulates activity phosphorylation Thr667 ILTGRGKtNQNTGMT 9606 BTO:0002181 28132841 t miannu DAPK1 phosphorylates RIG-I in vitro at previously reported as well as other sites that limit 5'ppp-dsRNA sensing and virtually abrogate RIG-I activation. SIGNOR-277336 0.336 ITGB1 protein P05556 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253188 0.694 RPS6KB1 protein P23443 UNIPROT CCT2 protein P78371 UNIPROT unknown phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 19332537 t llicata Mass spectrometry and mutagenesis analysis revealed that rsk and s6k1 phosphorylate cct_ ser-260 in vitro and in intact cells SIGNOR-184926 0.2 SPAG5 protein Q96R06 UNIPROT CDK5RAP2 protein Q96SN8 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 t lperfetto By bringing CDK5RAP2 to the centrosome, the centriolar satellite proteins CEP72 and SPAG5 are required for the centrosomal localization of the other three MCPH proteins despite not interacting with them biochemically. SIGNOR-271719 0.477 MYOG protein P15173 UNIPROT Myog/SWI/SNF complex complex SIGNOR-C94 SIGNOR form complex binding 9606 BTO:0001103 17194702 t miannu Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle SIGNOR-151691 0.632 ODAD4 protein Q96NG3 UNIPROT Cilium_movement phenotype SIGNOR-PH171 SIGNOR up-regulates 10090 27486780 f miannu Our results in mice suggest that TTC25 plays an essential role in the correct function of motile cilia at the ventral node and is therefore important for the development of left-right body asymmetry. SIGNOR-265548 0.7 MAPK8 protein P45983 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 7651411 t lperfetto However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity. SIGNOR-236432 0.495 ATM protein Q13315 UNIPROT CDC25C protein P30307 UNIPROT down-regulates 9606 10097108 f gcesareni Atm also contributes to the cdc25c activity, particularly in ir-damaged cells, by activating chk2. SIGNOR-65966 0.509 OSI-420 chemical CID:18924996 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-195248 0.8 NTN1 protein O95631 UNIPROT DSCAM protein O60469 UNIPROT up-regulates activity binding 10090 BTO:0001279 18585357 t miannu Here, we report that the Down's syndrome Cell Adhesion Molecule (DSCAM), a candidate gene implicated in the mental retardation phenotype of Down's syndrome, is expressed on spinal commissural axons, binds netrin-1, and is necessary for commissural axons to grow toward and across the midline. DSCAM and DCC can each mediate a turning response of these neurons to netrin-1. SIGNOR-268376 0.723 LEF1 protein Q9UJU2 UNIPROT PITX2 protein Q99697 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 19850024 f gcesareni These results suggest that wnt/lef1 signaling regulates epaxial myogenesis via pitx2 but that this link is uncoupled in other regions of the body, emphasizing the unique molecular networks that control the development of various muscles in vertebrates. The pitx2 promoter contains tcf/lef binding sites and expression can be induced by licl, which activates the canonical wnt signaling pathway SIGNOR-188730 0.708 MPHOSPH10 protein O00566 UNIPROT IMP3 protein Q9NV31 UNIPROT up-regulates activity binding -1 28813493 t miannu Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome. In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA. SIGNOR-261173 0.876 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT down-regulates activity phosphorylation Ser186 PVLRQSIsFSGLPSG -1 14688255 t miannu We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated. SIGNOR-250152 0.686 HTR7 protein P34969 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256926 0.432 NBR1 protein Q14596 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates binding 9606 BTO:0000007 19250911 t gcesareni We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. SIGNOR-184267 0.735 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 15241418 t lperfetto We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity SIGNOR-232142 0.748 AKT2 protein P31751 UNIPROT BMI1 protein P35226 UNIPROT up-regulates activity phosphorylation Ser316 ANRPRKSsVNGSSAT 22505453 t lperfetto the polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate SIGNOR-249582 0.297 CDK5 protein Q00535 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Thr135 TVQQHPStPKRHTVL 9606 BTO:0000007 21209322 t lperfetto High nacl-induced activation of cdk5 increases phosphorylation of the osmoprotective transcription factor tonebp/orebp at threonine 135, which contributes to its rapid nuclear localization. n hek293 cells, mass spectrometry shows phosphorylation of tonebp/orebp-s120, -s134, -t135, and -s155. SIGNOR-170886 0.2 SF3A3 protein Q12874 UNIPROT SF3a complex SIGNOR-C345 SIGNOR form complex binding 9606 BTO:0000567 8349644 t miannu Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. SIGNOR-263949 0.974 PAK proteinfamily SIGNOR-PF13 SIGNOR VIM protein P08670 UNIPROT down-regulates activity phosphorylation -1 11895474 t inferred from 70% family members miannu In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK.¬† SIGNOR-269975 0.2 SRC protein P12931 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr1006 PATPLLDyALEVEKI 9606 BTO:0000007 32420483 t done miannu  We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. SIGNOR-274107 0.268 NSD3 protein Q9BZ95 UNIPROT MYC protein P01106 UNIPROT up-regulates activity binding 9606 BTO:0002181 28205554 t irozzo Indeed, dose-dependent TR-FRET and affinity pull-down assay confirmed the interaction of NSD3-s with MYC. Supporting functional significance of the interaction, co-expression of NSD3-s, but not the MYC-binding defective fragment of NSD3-s (1–347), stabilized MYC protein and increased MYC transcriptional activity as revealed by a MYC-driven reporter assay. SIGNOR-259200 0.2 INSR protein P06213 UNIPROT IRS4 protein O14654 UNIPROT up-regulates activity phosphorylation 10090 25905389 t lperfetto The binding of insulin to the subunit of IR not only concentrates insulin at its site of action, but also induces conformational changes in the receptor, which in turn stimulates the tyrosine kinase activity intrinsic to the _ subunit of the IR and triggers the signaling cascades (Fig. 3). Insulin receptors trans phosphorylate several immediate substrates (on Tyr residues) including IRS1-4, Shc, and Gab 1, Cbl, APS, and P60dok. SIGNOR-217897 0.502 PASK protein Q96RG2 UNIPROT PASK protein Q96RG2 UNIPROT up-regulates activity phosphorylation Thr1161 ERGKLFYtFCGTIEY -1 11459942 t lperfetto We present evidence that the activity of pask is regulated by two mechanisms. Autophosphorylation at two threonine residues located within the activation loop significantly increases catalytic activity. SIGNOR-109481 0.2 KRAS protein P01116 UNIPROT MINK1 protein Q8N4C8 UNIPROT up-regulates 9606 16337592 f gcesareni Mink is activated after ras induction via a mechanism involving reactive oxygen species and mediates stimulation of the stress-activated protein kinase p38 mapk downstream of the raf/erk pathway. SIGNOR-142985 0.2 SH3RF1 protein Q7Z6J0 UNIPROT RAC2 protein P15153 UNIPROT up-regulates binding 9606 9482736 t gcesareni Posh interacts with the gtp form of rac but not the gdp form SIGNOR-55811 0.266 CHEVI complex complex SIGNOR-C269 SIGNOR SEC22B protein O75396 UNIPROT up-regulates activity relocalization 9606 27319744 t lperfetto VPS33B association with VIPAS39, α-tubulin, and SEC22B was identified by co-immunoprecipitation, mass spectra, and immunoblotting in human embryonic kidney 293T (HEK293T) cells. Also, pull-down experiments revealed that VIPAS39 bound to intact VPS33B; in contrast, α-tubulin and SEC22B separately interacted with the sec1-like domains of VPS33B. Vps33b deficiency in megakaryocytes disturbs the redistribution of Vipas39 and Sec22b to proplatelets, and interrupted the co-localization of Sec22b with Vwf-positive vesicles SIGNOR-261832 0.384 TDGF1 protein P13385 UNIPROT ACVR1B protein P36896 UNIPROT up-regulates activity binding 9606 19874624 t Regulation miannu Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors. SIGNOR-251938 0.717 EGFR protein P00533 UNIPROT HDAC6 protein Q9UBN7 UNIPROT down-regulates phosphorylation Tyr570 SSNFDSIyICPSTFA 9606 20029029 t gcesareni A negative feedback loop consisting of egfr-mediated phosphorylation of hdac6 tyr(570) resulted in reduced deacetylase activity and increased acetylation of alpha-tubulin. SIGNOR-162431 0.452 CD3 complex SIGNOR-C432 SIGNOR ZAP70 protein P43403 UNIPROT up-regulates activity binding 9534 1423621 t We have recently identified a 70 kd tyrosine phosphoprotein (ZAP-70) that associates with zeta and undergoes tyrosine phosphorylation following TCR stimulation|Moreover, tyrosine phosphorylation and association of ZAP-70 with zeta require the presence of src family PTKs and provide a potential mechanism by which the src family PTKs and ZAP-70 may interact to mediate TCR signal transduction. SIGNOR-252304 0.683 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 16782899 t llicata Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain SIGNOR-147183 0.476 CTH protein P32929 UNIPROT L-cysteine zwitterion smallmolecule CHEBI:35235 ChEBI down-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. SIGNOR-275824 0.8 MAPK11 protein Q15759 UNIPROT EWSR1 protein Q01844 UNIPROT unknown phosphorylation Thr79 QPPTGYTtPTAPQAY 9606 19076070 t lperfetto Here we report that ews and ews-fli1 become phosphorylated at thr79 . but the p38_/p38_ mapks were the major kinases phosphorylating ews-fli1. It will be important to investigate how the p38_/p38_-stimulated phosphorylation of ews-fusion proteins affects their ability to transactivate and their oncogenic potential. SIGNOR-182774 0.2 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr620 SKSVLPRtPESWRLT 9606 22094256 t lperfetto We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627) SIGNOR-177259 0.608 ARAP2 protein Q8WZ64 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260455 0.473 SRC protein P12931 UNIPROT VAV3 protein Q9UKW4 UNIPROT up-regulates phosphorylation Tyr173 EDEGGEVyEDLMKAE 9606 BTO:0000785 17998938 t gcesareni Activation of rac1 and the exchange factor vav3 are involved in npm-alk signaling in anaplastic large cell lymphomas. SIGNOR-159240 0.331 PLK1 protein P53350 UNIPROT SUZ12 protein Q15022 UNIPROT down-regulates quantity by destabilization phosphorylation Ser539 RPKRTKAsMSEFLES 25855382 t lperfetto PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|In SUZ12, residues 539, 541 and 546 phosphorylated by Plk1 in vitro SIGNOR-275557 0.37 MTHFD1 protein P11586 UNIPROT formate smallmolecule CHEBI:15740 ChEBI up-regulates quantity chemical modification -1 18767138 t lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate SIGNOR-268251 0.8 TIAM2 protein Q8IVF5 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260578 0.572 PGM2 protein Q96G03 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267934 0.8 MAPK8 protein P45983 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates phosphorylation Ser422 AHPPHAPsPGQTVKP 9606 BTO:0000551 16984892 t lperfetto In this study, we found that c-jun nh2-terminal kinase 1 activation triggered ctbp phosphorylation on ser-422 and subsequent degradation, SIGNOR-149721 0.365 PAK2 protein Q13177 UNIPROT RPS6 protein P62753 UNIPROT unknown phosphorylation Ser235 IAKRRRLsSLRASTS -1 1985906 t miannu The synthetic peptide AKRRRLSSLRASTSKSESSQK (S6-21) which corresponds to the carboxyl-terminal 21 amino acids of human ribosomal protein S6 was synthesized and tested as a substrate for S6/H4 kinase purified from human placenta. The principal phosphorylation sites were serines in the acidic carboxyl-terminal domain of the peptide. SIGNOR-250231 0.314 BTRC protein Q9Y297 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates ubiquitination 9606 10228155 t gcesareni Here we show that fwd1 (the mouse homologue of slimb/betatrcp), an f-box/wd40-repeat protein, specifically formed a multi-molecular complex with beta-catenin, axin, gsk-3beta and apc. Mutations at the signal-induced phosphorylation site of beta-catenin inhibited its association with fwd1. Fwd1 facilitated ubiquitination and promoted degradation of beta-catenin, resulting in reduced cytoplasmic beta-catenin levels. SIGNOR-67374 0.868 DRAM2 protein Q6UX65 UNIPROT RHOB protein P62745 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30755245 f irozzo Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. SIGNOR-259145 0.2 ARMC10 protein Q8N2F6 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity binding 9606 BTO:0000971;BTO:0005814 17904127 t miannu Co-immunoprecipitation and GST pull-down assays have demonstrated that SVH-B directly interacts with p53. In both BEL-7404 cells and p53-null Saos-2 cells transfected with a temperature-sensitive mutant of p53, V143A, ectopically expressed SVH-B suppresses the transcriptional activity of p53, and suppression of SVH by RNA interference increases the transcriptional activity of p53. Our results suggested the function of SVH-B in accelerating growth and inhibition of apoptosis is related to its inhibitory binding to p53. SIGNOR-266414 0.2 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC4 protein P62807 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271986 0.2 CDK2 protein P24941 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12202491 t gcesareni Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity SIGNOR-92265 0.385 NDUFB3 protein O43676 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 SIGNOR-262166 0.801 BGJ-398 chemical CHEBI:63451 ChEBI FGFR2 protein P21802 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190266 0.8 RFC1 protein P35251 UNIPROT RF-C complex complex SIGNOR-C375 SIGNOR form complex binding 12930972 t lperfetto RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned SIGNOR-265505 0.859 VARS1 protein P26640 UNIPROT valine smallmolecule CHEBI:27266 ChEBI down-regulates quantity chemical modification 9606 30755602 t miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. SIGNOR-270526 0.8 EIF4E2 protein O60573 UNIPROT EIF4E2/GIGYF2 complex complex SIGNOR-C257 SIGNOR form complex binding 9606 BTO:0000568 22751931 t SARA A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development|GIGYF2 interacts specifically with m4EHP. The stabilities of m4EHP and GIGYF2 proteins are coregulated. SIGNOR-261008 0.714 FOXJ1 protein Q92949 UNIPROT Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 t miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). SIGNOR-266939 0.2 DRD5 protein P21918 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257244 0.363 MAPK1 protein P28482 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser525 YGMIERLsPGTRKIE 9606 BTO:0000007 33217317 t miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. SIGNOR-265948 0.276 MAPK11 protein Q15759 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 17254968 t gcesareni We show that prak activates p53 by direct phosphorylation. SIGNOR-152843 0.594 PRKACA protein P17612 UNIPROT GLI2 protein P10070 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 19056373 t gcesareni These results indicate that phosphorylation of Gli2 by PKA induces Gli2 processing and destabilization SIGNOR-182573 0.445 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 12050114 t gcesareni Tob is rapidly phosphorylated at Ser 152, Ser 154, and Ser 164 by Erk1 and Erk2 upon growth-factor stimulation. SIGNOR-88732 0.359 PPM1A protein P35813 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity dephosphorylation Ser172 EDDEQFVsLYGTEEY 9606 27419230 t lperfetto Furthermore, PPM1A, but not PPM1B, serves as an efficient phosphatase to dephosphorylate Ser 172 residue of both TBK1 and IKKepsilon kinases, which is critical for their kinase activities.|In a similar in vitro phosphatase assay, incubation of PPM1A also eliminated TBK1 and IKKepsilon phosphorylation at Ser 172 residue, evidenced by phospho-S172 immunoblotting (XREF_FIG, F and G).|These observations suggest that PPM1A may block kinase activities of TBK1 and IKKepsilon. SIGNOR-276966 0.42 KDM5B protein Q9UGL1 UNIPROT NANOG protein Q9H9S0 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000815 31776402 t lperfetto Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes. SIGNOR-273451 0.313 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser295 LQASVPGsVPGVLGP -1 16027724 t GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines) SIGNOR-251230 0.389 GNA12 protein Q03113 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 23450633 t gcesareni Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism. SIGNOR-192108 0.54 AKAP12 protein Q02952 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates activity relocalization 14657015 t lperfetto A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. SIGNOR-271837 0.2 TNF protein P01375 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004914 22190977 f Exposure of RA FLSs to TNF-α (10 ng/ml) led to increase of Hes-1, a target gene of Notch signaling, and a marked upregulation of Notch 2, Delta-like 1, and Delta-like 3 mRNA levels. SIGNOR-253605 0.2 ADSS1 protein Q8N142 UNIPROT GDP smallmolecule CHEBI:17552 ChEBI up-regulates quantity chemical modification 9606 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267350 0.8 MLLT11 protein Q13015 UNIPROT TCF7 protein P36402 UNIPROT up-regulates activity binding -1 26079538 t irozzo Here, we show that AF1q specifically binds to T-cell-factor-7 (TCF7) in the Wnt signaling pathway and results in transcriptional activation of CD44 as well as multiple downstream targets of the TCF7/LEF1. Super-shift and electrophoretic mobility shift assay (EMSA) further confirmed that AF1q directly interacted with TCF7 and enhanced the binding affinity of the complex SIGNOR-259108 0.475 MTTP protein P55157 UNIPROT APOB protein P04114 UNIPROT up-regulates activity lipidation 9606 23721961 t miannu As ApoB is translated, it is lipidated by microsomal triglyceride transfer protein (MTP). MTP adds triglycerides to the nascent ApoB during its co-translational translocation into the lumen of the endoplasmic reticulum. SIGNOR-252118 0.785 UBE2K protein P61086 UNIPROT RNF138 protein Q8WVD3 UNIPROT up-regulates activity binding 9606 BTO:0000007 16714285 t miannu NARF exhibits E3 ubiquitin-ligase activity in cooperation with the ubiquitin conjugating enzyme, E2-25K. These data show that the auto-ubiquitylating activity of NARF is coordinated with E2-25K, and that the RING finger domain of NARF is indispensable for this reaction. SIGNOR-271594 0.516 SUN3 protein Q8TAQ9 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 t lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. SIGNOR-263291 0.413 CSNK2A1 protein P68400 UNIPROT MYCN protein P04198 UNIPROT unknown phosphorylation Ser261 TSGEDTLsDSDDEDD -1 1425701 t llicata Analysis of phosphorylation sites in synthetic peptides of this acidic region identified the major sites phosphorylated by CKII as Ser261 and Ser263. SIGNOR-250920 0.458 CSNK1A1 protein P48729 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser321 NSNASTVsGRLSPIM 9606 20110348 t lperfetto Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export SIGNOR-163676 0.2 GNG3 protein P63215 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 16537363 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-145125 0.358 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120064 0.781 SENP3 protein Q9H4L4 UNIPROT Rix1 complex complex SIGNOR-C373 SIGNOR form complex binding 9606 BTO:0000007 22190735 t miannu LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes. SIGNOR-265468 0.797 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RGCC protein Q9H4X1 UNIPROT up-regulates activity phosphorylation Thr111 ALLSATVtPQKAKLG 9606 BTO:0001685 11687586 t miannu RGC-32 was physically associated with cyclin-dependent kinase p34CDC2 and increased the kinase activity in vivo and in vitro. In addition, RGC-32 was phosphorylated by p34CDC2-cyclin B1 in vitro. Mutation of RGC-32 protein at Thr-91 prevented the p34CDC2-mediated phosphorylation and resulted in loss of p34CDC2 kinase enhancing activity. SIGNOR-262725 0.456 CAK complex complex SIGNOR-C456 SIGNOR RARG protein P13631 UNIPROT up-regulates activity phosphorylation Ser77 SEEMVPSsPSPPPPP 9534 BTO:0000298 10748061 t miannu Retinoic acid receptor gamma (RARgamma) is phosphorylated in COS-1 cells at two conserved serine residues located in the N-terminal region (serines 77 and 79 in RARgamma1 and serines 66 and 68 in RARgamma2) that contains the activation function AF-1. These serines are phosphorylated in vitro by cdk7, a cyclin-dependent kinase associated to cyclin H and MAT1 in the CAK complex (cdk7.cyclin H. MAT1), that is found either free or as a component of the transcription/DNA repair factor TFIIH.  SIGNOR-275969 0.394 DLX5 protein P56178 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity transcriptional regulation 9606 19497851 t gcesareni Here we demonstrate by luciferase assay that the MYC promoter is specifically activated by overexpression of DLX5 and that two DLX5 binding sites in the MYC promoter are important for transcriptional activation of MYC. We also show that DLX5 binds to the MYC promoter both in vitro and in vivo and that transfection of a DLX5 expression plasmid promotes the expression of MYC in a dose-dependent manner in mammalian cells SIGNOR-241914 0.278 FKBP5 protein Q13451 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates binding 9606 25790864 t gcesareni When not associated with glucocorticoids, glucocorticoid receptors are predominantly found in the cytoplasm as part of a multimeric molecular chaperone complex that includes several heat shock proteins (HSPs), such as HSP70 and HSP90, the HSP90_binding protein p23 (also known as PTGES3) and proteins that help to bind HSP90 such as FK506_binding protein 5 (FKBP5). SIGNOR-251666 0.735 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Ser161 QKATPGSsRKTCRYI 9606 BTO:0000567 15525512 t llicata Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.  SIGNOR-250605 0.992 vandetanib chemical CHEBI:49960 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207624 0.8 nilotinib chemical CHEBI:52172 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001056 23409026 t miannu Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. SIGNOR-259269 0.8 TFIIH complex SIGNOR-C457 SIGNOR E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Thr433 DCDFGDLtPLDF 9606 10428966 t lperfetto These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase.  here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain. SIGNOR-269354 0.324 trichostatin A chemical CHEBI:46024 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258017 0.8 TIAM1 protein Q13009 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 BTO:0000938 BTO:0000142 20654717 f gcesareni This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1. SIGNOR-167073 0.74 TRIB3 protein Q96RU7 UNIPROT ACACA protein Q13085 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 16794074 t miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). SIGNOR-271600 0.277 LARS1 protein Q9P2J5 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 t miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). SIGNOR-270355 0.2 BTK protein Q06187 UNIPROT DDX41 protein Q9UJV9 UNIPROT up-regulates activity phosphorylation Tyr414 DVIQEVEyVKEEAKM 10090 BTO:0002572 25704810 t miannu The kinase and SH3/SH2 interaction domains of BTK bind, respectively, the DEAD-box domain of DDX41 and transmembrane region of STING. BTK phosphorylates DDX41, and its kinase activities are critical for STING-mediated IFN-β production. We show that Tyr364 and Tyr414 of DDX41 are critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identifies Tyr414 as the BTK phosphorylation site. SIGNOR-266404 0.415 SMAD7 protein O15105 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates binding 9606 BTO:0001253 17384642 t lperfetto The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling SIGNOR-153917 0.551 PPP2CA protein P67775 UNIPROT EEF2 protein P13639 UNIPROT up-regulates dephosphorylation Thr59 GETRFTDtRKDEQER 9606 phosphorylation:Thr59 GETRFTDtRKDEQER 8386634 t gcesareni Protein phosphatases-2a and -2c (pp-2a and pp-2c) can each efficiently dephosphorylate phosphorylated eef-2 SIGNOR-38566 0.413 ATR protein Q13535 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Ser33 GFGSPAPsQAEKKSR 9606 19843584 t llicata Atr phosphorylates s33 in response to replication stress SIGNOR-188666 0.747 ERBB2 protein P04626 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 15173068 t gcesareni The results presented here show for the first time that er redistribution to the cytoplasm and its interaction with her2 are important downstream effects of her2 overexpression, that erk1/2 is important for er cytoplasmic localization, and that subcellular localization of er may play a mechanistic role in determining the responsiveness of breast cancer cells to tamoxifen. SIGNOR-124962 0.59 5-[6-[(4-methyl-1-piperazinyl)methyl]-1-benzimidazolyl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]-2-thiophenecarboxamide chemical CHEBI:91333 ChEBI PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192991 0.8 PRKACA protein P17612 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates phosphorylation Ser119 YGPPSRRsENRVVVS 9606 22393468 t llicata Here, we show that pka phosphorylates srsf1 on serine 119 in vitro. Phosphorylation of srsf1 on this site enhanced the rna binding capacity of srsf1 in vivo SIGNOR-196397 0.2 NR1I3 protein Q14994 UNIPROT CYP2B6 protein P20813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18303024 f miannu The CYP2B6 enzyme metabolizes commonly used therapeutics and also activates pro-drugs. The CAR directly binds to the distal enhancer element of the CYP2B6 promoter, which is essential in converging to its drug-sensing function onto promoter activity. However, this binding alone is not sufficient to activate the CYP2B6 promoter; the promoter requires EGR1 to enable CAR to activate the CYP2B6 promoter. SIGNOR-253875 0.483 STK11 protein Q15831 UNIPROT STRADA protein Q7RTN6 UNIPROT up-regulates activity phosphorylation Thr419 SGIFGLVtNLEELEV 9606 BTO:0000007 12805220 t lperfetto Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners.LKB1 phosphorylates STRAD at Thr329 and Thr419 SIGNOR-247564 0.938 ICOSLG protein O75144 UNIPROT ICOS protein Q9Y6W8 UNIPROT up-regulates activity binding 9606 27559335 t ICOSL expression is largely restricted to professional antigen-presenting cells (APCs), including B cells [in which ICOSL is regulated by BAFFR and non-canonical NFκB signaling (20)], macrophages, and dendritic cells (DCs) (12, 17, 21, 22), but is also expressed by certain endothelial cells (23) and lung epithelium SIGNOR-272497 0.2 ROBO2 protein Q9HCK4 UNIPROT CFL1 protein P23528 UNIPROT up-regulates quantity by expression post transcriptional regulation -1 16226035 t miannu Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. SIGNOR-268378 0.26 CASC3 protein O15234 UNIPROT Exon junction complex complex SIGNOR-C369 SIGNOR form complex binding -1 16923391 t miannu The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. SIGNOR-265241 0.922 MTOR protein P42345 UNIPROT ISCU protein Q9H1K1 UNIPROT up-regulates phosphorylation Ser14 FRLRRAAsALLLRSP 9606 SIGNOR-C3 23508953 t llicata Here, we demonstrate that mtorc1 associates with iscu and phosphorylates iscu at serine 14. This phosphorylation stabilized iscu protein. SIGNOR-201595 0.2 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG4-LLGL2_variant complex SIGNOR-C505 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270888 0.529 AMP smallmolecule CHEBI:456215 ChEBI adenosine smallmolecule CHEBI:16335 ChEBI up-regulates quantity precursor of -1 31461341 t Luana Ecto-5'-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5'-monophosphate to adenosine. SIGNOR-269741 0.8 SB 505124 chemical CHEBI:100922 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 14978253 t gcesareni Sb-505124 is a selective inhibitor of transforming growth factor-beta type i receptors alk4, alk5, and alk7. SIGNOR-122910 0.8 ivacaftor chemical CHEBI:66901 ChEBI CFTR protein P13569 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck;potentiator gcesareni SIGNOR-193495 0.8 estrone smallmolecule CHEBI:17263 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258584 0.8 CEBPA protein P49715 UNIPROT S100A9 protein P06702 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001370 9706399 t Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells. SIGNOR-254041 0.228 sonidegib chemical CHEBI:90863 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 21041712 t gcesareni Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date. SIGNOR-169203 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 10864927 t lperfetto Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-216773 0.839 CDR2 protein Q01850 UNIPROT AURKA protein O14965 UNIPROT up-regulates quantity by expression transcriptional regulation 20383333 f lperfetto Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology SIGNOR-252023 0.2 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL 10090 BTO:0000944 11579209 t lperfetto Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor. SIGNOR-235503 0.78 SRC protein P12931 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 9606 11641791 t gcesareni Src can thus directly tyrosine-phosphorylate the activation site of stat5 (tyr 694 in stat5a), and src may contribute to epo-induced signal transduction via stat5. SIGNOR-111078 0.741 RPS6KA1 protein Q15418 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 9606 22017877 t lperfetto We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1 SIGNOR-176883 0.506 AKT proteinfamily SIGNOR-PF24 SIGNOR RGCC protein Q9H4X1-2 UNIPROT up-regulates activity phosphorylation Ser47 MKRRSSAsVSDSSGF 9606 BTO:0000567 19162005 t miannu Akt phosphorylated GST-RGC-32 in vitro, and CDC2 was also able to phosphorylate RGC-32.  Akt failed to phosphorylate RGC-32 S45A-S47A mutant. These data indicate that Ser 45 and Ser 47 may be the RGC-32 phosphorylation sites for Akt kinase. SIGNOR-262628 0.2 CABIN1 protein Q9Y6J0 UNIPROT HIRA complex 2 complex SIGNOR-C462 SIGNOR form complex binding 9606 30285846 t miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. SIGNOR-269438 0.518 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-176373 0.613 MYD88 protein Q99836 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity binding 10090 BTO:0003432 10217414 t lperfetto Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88. Myd88 binds to both irak (il-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of irak with the receptor. SIGNOR-67143 0.843 MAPK9 protein P45984 UNIPROT JUNB protein P17275 UNIPROT down-regulates binding 9606 9405416 t gcesareni Jnk targets junb ubiquitination SIGNOR-53827 0.671 leucine smallmolecule CHEBI:25017 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 22749528 f Luana Leucine and Glutamine Activate Glutaminolysis and mTORC1 SIGNOR-268010 0.8 IL26 protein Q9NPH9 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 17208301 t gcesareni See table 2 SIGNOR-151917 0.585 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR TNNT2 protein P45379 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136870 0.339 Monobutylphthalate chemical CHEBI:88522 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9606 BTO:0000816 16326050 t miannu Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast SIGNOR-268752 0.8 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Ser239 LIRGVKSsGKVVYFT 9823 21864610 t miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. SIGNOR-262918 0.337 WNT7A protein O00755 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-253130 0.76 PLAU protein P00749 UNIPROT PLAUR protein Q03405 UNIPROT up-regulates binding 9606 16456079 t gcesareni The urokinase plasminogen activator binds to its cellular receptor with high affinity and initiates signaling cascades that are implicated in pathological processes including tumor growth, metastasis, and inflammation. SIGNOR-144306 0.887 C25H27N5O4S chemical CID:66577011 PUBCHEM KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189711 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CTTN protein Q14247 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 20444238 t inferred from 70% family members gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. SIGNOR-270164 0.2 DNMBP protein Q6XZF7 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260547 0.554 REL protein Q04864 UNIPROT CSRP1 protein P21291 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14522018 f We conclude that c-Rel regulates CRP expression without the requirement of binding to a kappaB site, and binds directly to C/EBPbeta to facilitate the binding of C/EBPbeta to the CRP promoter SIGNOR-254063 0.2 PRKCZ protein Q05513 UNIPROT AQP9 protein O43315 UNIPROT up-regulates phosphorylation Ser11 EGAEKGKsFKQRLVL 9606 21873454 t lperfetto Wt-pkc_-mediated phosphorylation of wt aqp9 in vitro. In the experiments, substitution of ser11 to ala markedly inhibited phosphorylation. the s11a mutation in fibroblasts caused a smoother cell periphery with fewer aqp9-induced filopodia SIGNOR-176278 0.2 FFAR2 protein O15552 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257342 0.2 MCU protein Q8NE86 UNIPROT MCU_MICU1_variant complex SIGNOR-C500 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270865 0.715 SRC protein P12931 UNIPROT BCKDK protein O14874 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr246 RRLCEHKyGNAPRVR 9606 BTO:0001615 32238881 t lperfetto Src phosphorylated BCKDK at the tyrosine 246 (Y246) site in vitro and ex vivo. Knockdown and knockout of Src downregulated the phosphorylation of BCKDK. Importantly, phosphorylation of BCKDK by Src enhanced the activity and stability of BCKDK, thereby promoting the migration, invasion, and EMT of CRC cells. SIGNOR-275584 0.2 DOK1 protein Q99704 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257678 0.321 PHKA1 protein P46020 UNIPROT PHKG2 protein P15735 UNIPROT down-regulates activity binding 9606 10487978 t Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit. SIGNOR-267407 0.85 UBR5 protein O95071 UNIPROT TOPBP1 protein Q92547 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 11714696 t miannu Using an in vitro reconstitution, specific E2 (ubiquitin-conjugating) enzymes (human UbcH4, UbcH5B, and UbcH5C) transferred ubiquitin molecules to hHYD, leading to the ubiquitination of TopBP1. TopBP1 was usually ubiquitinated and degraded by the proteosome, whereas X-irradiation diminished the ubiquitination of TopBP1 probably via the phosphorylation, resulting in the stable colocalization of up-regulated TopBP1 with gamma-H2AX nuclear foci in DNA breaks. SIGNOR-272667 0.473 ATR protein Q13535 UNIPROT PARP1 protein P09874 UNIPROT down-regulates activity phosphorylation Ser179 FRPEYSAsQLKGFSL 9606 BTO:0000018 33811702 t miannu Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments. This site-specific phosphorylation inactivates PARP1, inhibiting ionophore-induced necrosis. SIGNOR-277551 0.364 NEK7 protein Q8TDX7 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity phosphorylation Ser1217 PIKNLHSsHSSGLMD 9606 BTO:0000565 28630147 t miannu Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C). SIGNOR-266420 0.379 PRKN protein O60260 UNIPROT PHGDH protein O43175 UNIPROT down-regulates quantity by destabilization ubiquitination Lys330 SAFSPHTkPWIGLAE 9606 BTO:0000018;BTO:0003885 32478681 t Luisa Parkin binds to PHGDH and degrades it through ubiquitination to inhibit serine synthesis, which contributes greatly to the tumor-suppressive function of Parkin. SIGNOR-269075 0.2 SLC12A6 protein Q9UHW9 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates quantity relocalization 21613606 t lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  SIGNOR-264638 0.8 CDK1 protein P06493 UNIPROT AKAP12 protein Q02952 UNIPROT up-regulates activity phosphorylation Thr767 ESFKRLVtPRKKSKS 9606 BTO:0000007 23063527 t lperfetto Mass spectrometry, molecular, and cellular approaches show that CDK1/Cyclin B1 phosphorylates Gravin on threonine 766 to prime the recruitment of the polo-like kinase Plk1 at defined phases of mitosis. SIGNOR-271839 0.328 SHMT1 protein P34896 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity chemical modification 9606 32439610 t lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. SIGNOR-268226 0.8 GNAT1 protein P11488 UNIPROT PDE6G protein P18545 UNIPROT down-regulates activity binding 10090 30962282 t In the dark, PDE6 activity is suppressed by its inhibitory γ-subunit (Pγ). Rhodopsin-catalyzed activation of the G protein, transducin, relieves this inhibition and enhances PDE6 catalysis. SIGNOR-260008 0.755 FOXO3 protein O43524 UNIPROT TSC1 protein Q92574 UNIPROT up-regulates quantity transcriptional regulation 10090 20371605 t FoxO3a binds to and transactivates the TSC1 promoter, indicating a key role for FoxO3a in regulating TSC1 expression. Together, these data demonstrate that FoxO3a regulates glycolysis downstream of Akt through transcriptional control of Tsc1 SIGNOR-259382 0.46 PTPRF protein P10586 UNIPROT LCK protein P06239 UNIPROT up-regulates dephosphorylation 9606 12496362 t flangone We confirmed that lar dephosphorylated the phosphorylated tyrosine residues of lck..Activation Of lck and fyn involves tyrosine dephosphorylation of the cooh-terminal regulatory domain of kinases, followed by autophosphorylation of the kinase domain. SIGNOR-96771 0.371 PRKCG protein P05129 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251633 0.2 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation 9606 17510057 t lperfetto In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-217074 0.586 AKT1 protein P31749 UNIPROT ALYREF protein Q86V81 UNIPROT up-regulates phosphorylation Thr219 GGGTRRGtRGGARGR 9606 18562279 t llicata Nuclear akt directly binds aly and phosphorylates it on the t219 residue. gfp-aly t219d displayed comparable activity to gfp control and wild-type aly, indicating that aly phosphorylation by akt is sufficient to enhance mrna export. SIGNOR-252518 0.461 MAPK1 protein P28482 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Thr456 KVYFLPItPHYVTQV 9606 15890648 t lperfetto Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol SIGNOR-137171 0.391 NFIA protein Q12857 UNIPROT ETV5 protein P41161 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268874 0.2 NCK1 protein P16333 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9606 11157752 t lperfetto Both nck and grb4 proteins could associate with receptor tyrosine kinases and the sh3-binding proteins pak, sos1, and prk2, and they synergized with v-abl and sos to induce gene expression via the transcription factor elk-1. Association of nck with pak1 may serve to link this important regulatory kinase to cell activation by growth factor receptors. SIGNOR-235947 0.697 SOSTDC1 protein Q6X4U4 UNIPROT BMP7 protein P18075 UNIPROT down-regulates activity 10090 18032587 f lperfetto SOSTDC1 is orthologous to a recently characterized murine antagonist of BMPs-2, -4, and -7 SIGNOR-242752 0.76 GSK3A protein P49840 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation Thr687 PRGMGPGtPAGYGRG 9606 20932480 t miannu Here we demonstrate that in resting tcells psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. Upon tcell activation, reduced gsk3 activity leads to reduced psf phosphorylation, releasing psf from trap150 and allowing it to bind cd45 splicing regulatory elements and repress exon inclusion. SIGNOR-168382 0.2 PTPN7 protein P35236 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation Tyr182 TDDEMTGyVATRWYR 9606 BTO:0000661 10206983 t In Jurkat cells, LC-PTP suppressed the ERK and p38 mitogen-activated protein kinase cascades SIGNOR-248485 0.585 HGS protein O14964 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates 9606 11094085 f gcesareni Hgs and sara, are prerequisites for receptor-mediated activation of smad2 SIGNOR-84616 0.37 CXCL1 protein P09341 UNIPROT Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR up-regulates 9606 BTO:0000130 35022267 f miannu Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth.Taken together, these results show that the neutrophil attracting cytokines Cxcl1 and 2 are highly expressed in metastatic livers in response to gemcitabine withdrawal and this favours CXCR2-dependent recruitment of neutrophils at the hepatic metastatic site. SIGNOR-277721 0.7 AXL protein P30530 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates activity binding 9606 BTO:0000130 35022267 t miannu Gas6 and its main receptor AXL are overexpressed in pancreatic cancer and their expression correlates with poor prognosis.Gas6/AXL signalling in cancer cells is associated with tumour cell proliferation, epithelial mesenchymal transition and metastases. SIGNOR-277723 0.7 Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR GAS6 protein Q14393 UNIPROT up-regulates 9606 BTO:0000130 35022267 f miannu Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth.Taken together, these results show that the neutrophil attracting cytokines Cxcl1 and 2 are highly expressed in metastatic livers in response to gemcitabine withdrawal and this favours CXCR2-dependent recruitment of neutrophils at the hepatic metastatic site. SIGNOR-277724 0.7 AXL protein P30530 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 35022267 f miannu Gas6 and its main receptor AXL are overexpressed in pancreatic cancer and their expression correlates with poor prognosis.Gas6/AXL signalling in cancer cells is associated with tumour cell proliferation, epithelial mesenchymal transition and metastases. SIGNOR-277725 0.7 EID1 protein Q9Y6B2 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates 11073990 f lperfetto Thus, EID-1 binds both Rb and p300 and is a novel repressor of MyoD function. SIGNOR-253378 0.35 PRKAA2 protein P54646 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 SIGNOR-C15 16308421 t gcesareni Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2 SIGNOR-142211 0.472 CNOT9 protein Q92600 UNIPROT GIGYF2 protein Q6Y7W6 UNIPROT up-regulates activity binding 9606 BTO:0000007 20878056 t miannu Through interaction analysis of RQCD1 with full-length or partial proteins of GIGYF1 and GIGYF2, segments corresponding to 620-665th and 667-712th amino acids were identified as potential interacting regions on GIGYF1 and GIGYF2, respectively, with RQCD1. we found that RQCD1 was required for enhancement of the interaction of Grb10 with GIGYF1 and GIGYF2 SIGNOR-260058 0.2 RPS6KA1 protein Q15418 UNIPROT MAGI1 protein Q96QZ7 UNIPROT up-regulates activity phosphorylation Ser741 QPLERKDsQNSSQHS 9606 BTO:0001949 30944250 t done miannu  We report herein that p90RSK associates with MAGI1 in ECs and executes 2 independently regulated PTMs of MAGI1: S741 phosphorylation and K931 deSUMOylation. MAGI1-S741 phosphorylation is vital for Rap1 activation. SIGNOR-273837 0.29 ADSL protein P30566 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression 9606 31729379 f miannu An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. ADSL regulates cMYC protein level through adenosine levels SIGNOR-266614 0.2 NCAPG2 protein Q86XI2 UNIPROT Condensin II complex SIGNOR-C342 SIGNOR form complex binding 9606 32445620 t miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263911 0.857 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 20219869 f apalma ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation SIGNOR-256216 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser289 RSHSESAsPSALSSS 10090 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-244677 0.2 ECT2 protein Q9H8V3 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260550 0.701 PKA proteinfamily SIGNOR-PF17 SIGNOR SYN2 protein Q92777 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 10571231 t miannu Synapsins are exclusively localized to synaptic vesicles, which they coat as peripheral membrane proteins; they probably constitute one of the most abundant neuronal PKA substrates. Our study reveals an unexpectedly dynamic state of synapsins in nerve terminals: any changes in PKA or CaM Kinase I activity will modulate the amount of synapsin on synaptic vesicles. PKA Activation Triggers Synapsin Dissociation SIGNOR-264109 0.2 PHB2 protein Q99623 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates binding 10090 BTO:0000165 BTO:0000887 15173318 t lperfetto Phb2 interacts with both myod and mef2, and represses both myod- and mef2-dependent gene transcription. Furthermore, binding of phb2 to both myod and mef2 significantly decreases upon myogenic differentiation. SIGNOR-235840 0.315 AAK1 protein Q2M2I8 UNIPROT AP1M1 protein Q9BXS5 UNIPROT up-regulates phosphorylation Thr144 QEGHKLEtGAPRPPA 9606 BTO:0000938 11877461 t lperfetto Aak1 is enriched at presynaptic terminals, whereas in nonneuronal cells it colocalizes with clathrin and ap2 in clathrin-coated pits and at the leading edge of migrating cells. Aak1 specifically phosphorylates the mu subunit in vitro, and stage-specific assays for endocytosis show that mu phosphorylation by aak1 results in a decrease in ap2-stimulated transferrin internalization. Together, these results provide strong evidence that aak1 is the endogenous mu 2 kinase and plays a regulatory role in clathrin-mediated endocytosis. SIGNOR-115589 0.2 TM9SF4 protein Q92544 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity binding 9606 BTO:0000007 29125601 t miannu TM9SF4 inhibited mTOR activity in HEK293 cells. Under nutrient starvation, TM9SF4 functions to facilitate mTOR inactivation, resulting in an enhanced autophagic flux, which serves to protect cells from apoptotic cell death. SIGNOR-266703 0.2 BID protein P55957 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000093 22464442 t lperfetto Overexpression of antiapoptotic proteins including Bcl-XL and/or Bcl-2 contributes to tumor initiation, progression, and resistance to therapy by direct interactions with proapoptotic BH3 proteins. Release of BH3 proteins from antiapoptotic proteins kills some cancer cells and sensitizes others to chemotherapy. Binding of Bcl-XL and Bcl-2 to the BH3 proteins Bad, Bid, and the three major isoforms of Bim was measured for fluorescent protein fusions in live cells using fluorescence lifetime imaging microscopy and fluorescence resonance energy transfer. SIGNOR-209675 0.854 SNAI1 protein O95863 UNIPROT PXDN protein Q92626 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 29305973 t miannu TGF-β1 induced Snai1 binding to the PXDN promoter (as assessed by chromatin immunoprecipitation-PCR) and significantly repressed luciferase reporter gene expression, as did Snai1 overexpression. SIGNOR-265249 0.2 IKBKB protein O14920 UNIPROT COMT protein P21964 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000100 19291302 f Regulation of expression miannu TNFα-dependent COMT downregulation was indeed mediated by the NF-κB pathway. Transient expression of p65, the essential component of NF-κB complexes, or IKKβ, the major positive regulator of NF-κB activition, significantly decreased P2-COMT reporter expression. SIGNOR-251965 0.2 HDAC1 protein Q13547 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity deacetylation 10090 24463822 t The ability of HDAC1 to cause muscle atrophy required its deacetylase activity and was linked to the induction of several atrophy genes by HDAC1, including atrogin-1, which required deacetylation of FoxO3a SIGNOR-256486 0.376 IGF1 protein P05019 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates 10090 BTO:0000165;BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 10448861 f inferred from 70% of family members lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. SIGNOR-269890 0.278 HDAC4 protein P56524 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates deacetylation 9606 22298955 t gcesareni Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation. SIGNOR-195603 0.539 LATS2 protein Q9NRM7 UNIPROT MTF1 protein Q14872 UNIPROT down-regulates activity phosphorylation Ser152 EGCPRTYsTAGNLRT 35027733 t lperfetto The Hippo pathway kinases LATS1 and LATS2 attenuate cellular responses to heavy metals through phosphorylating MTF1|the Hippo pathway kinase LATS phosphorylates and inhibits MTF1|LATS phosphorylates MTF1 at S152 and disrupts its association with the promoters of heavy metal response genes, resulting in the loss of heavy metal response gene expression SIGNOR-275475 0.2 EGR1 protein P18146 UNIPROT LHB protein P01229 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19106114 f miannu EGR1 bound to two binding sites on the LHB promoter and this binding was increased by GNRH1. Mutation of either site or knockdown of endogenous EGR1 decreased basal and/or GNRH1-regulated promoter activity. SIGNOR-254919 0.405 CDC42BPA protein Q5VT25 UNIPROT CDC42BPA protein Q5VT25 UNIPROT up-regulates activity phosphorylation Ser234 MEDGTVQsSVAVGTP 9534 BTO:0000298 11283256 t miannu N terminus-mediated dimerization and transautophosphorylation are essential for MRCKα catalytic activity. Three mutations, S234A, T240A, and T403A, strongly affected the in vitro autophosphorylation activity of FLAG-MRCKα-CAT1–473 (Fig. ​(Fig.5D).5D). SIGNOR-275974 0.2 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1221 SPAFDNLyYWDQDPP 9606 BTO:0000149 1706616 t gcesareni However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2. SIGNOR-21199 0.2 HTR1D protein P28221 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256864 0.41 CDK2 protein P24941 UNIPROT TOB2 protein Q14106 UNIPROT up-regulates activity phosphorylation Ser254 PAPQSQLsPNAKEFV -1 32404348 t miannu Taken together, these observations strongly support the notion that several different CDK-cyclin complexes are involved in the phosphorylation of Tob2 at S254.A more detailed regulatory context of Tob2 phosphorylation at S254 is provided by our findings from mass-spec and in vitro kinase analyses that suggest connections to PP2B and PP2C phosphatases and CDK-cyclin complexes, particularly CDK1, CDK2, and CDK4 (Table 1; Supplemental Table S2).One possibility is that the phosphorylation of S254 helps stabilize the interaction of Tob2 with the Ccr4–Not complex, which could contribute to Tob2's ability to recruit the entire Ccr4–Not complex and thus further enhances deadenylation. SIGNOR-273601 0.248 CSNK2A1 protein P68400 UNIPROT IP6K2 protein Q9UHH9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser356 AEDLEDLsEESADES 9606 BTO:0000007 21262846 t miannu CK2 physiologically phosphorylates IP6K2 at amino acid residues S347 and S356 contained within a PEST sequence, a consensus site for ubiquitination. HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of IP6K2 enhances its ubiquitination and subsequent degradation. SIGNOR-273625 0.257 tibolone chemical CHEBI:32223 ChEBI PGR protein P06401 UNIPROT up-regulates activity chemical activation 9606 19464167 t Luana In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1). SIGNOR-257822 0.8 POGLUT1 protein Q8NBL1 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 22872643 t gcesareni O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. O-glucose can be elongated by xylose to the trisaccharide, xylalfa1-3xylalfa1-3glcbeta1-o-ser, whose synthesis is catalyzed by the consecutive action of three glycosyltransferases. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus. SIGNOR-198716 0.557 MAPK1 protein P28482 UNIPROT BMF protein Q96LC9 UNIPROT up-regulates phosphorylation Ser74 DKATQTLsPASPSQG 9606 BTO:0000785 22258404 t llicata Phosphomimetic mutation of this site (s74d) moderately enhanced bmf apoptotic activity in vivo.22 here, we demonstrate a previously unrecognized mode of regulation of bmf. We show that b-raf-mek-erk2 signaling regulates bmf phosphorylation at serine 74 and serine 77. Phosphorylation of serine 77 downregulates the pro-apoptotic activity of bmf. SIGNOR-195471 0.255 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1A protein P35348 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258456 0.8 PRKG2 protein Q13237 UNIPROT PLCB3 protein Q01970 UNIPROT down-regulates activity phosphorylation Ser1105 LDRKRHNsISEAKMR 10116 11278298 t lperfetto PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG. SIGNOR-249078 0.509 MYO10 protein Q9HD67 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 27580874 f miannu Myosin X is required for filopodia formation and extension. myosin X functions as an antiparallel dimer in cells with a unique geometry optimized for movement on actin bundles. Myosin X facilitates initiation and elongation of filopodia, which implies favouring formation of parallel bundled F-actin filaments. SIGNOR-268283 0.7 KIF18B protein Q86Y91 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272525 0.7 DAPK3 protein O43293 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 1178183 t gcesareni Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge. SIGNOR-16047 0.526 PTPRJ protein Q12913 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR -1 19494114 t llicata Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the RAS pathway by direct dephosphorylation of ERK1/2 kinases.|Pulldown and in vitro dephosphorylation assays confirmed our prediction and demonstrated an overall specificity of DEP-1 in targeting the phosphorylated tyrosine 204 of ERK1/2. SIGNOR-248708 0.416 PTPRA protein P18433 UNIPROT KCNB1 protein Q14721 UNIPROT down-regulates dephosphorylation 9606 16870705 t gcesareni Ptpalpha inhibits kv channels more strongly than ptpepsilon;this correlates with constitutive association of ptpalpha with kv2.1, driven by membranal localization of ptpalpha. SIGNOR-148301 0.2 PRKCG protein P05129 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity phosphorylation -1 15894802 t inferred from family member lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-270279 0.462 TARS1 protein P26639 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 25824639 t miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. SIGNOR-270503 0.8 CDK4 protein P11802 UNIPROT PELP1 protein Q8IZL8 UNIPROT up-regulates phosphorylation Ser477 ADALKLRsPRGSPDG 9606 BTO:0000150 20807815 t llicata Using site-directed mutagenesis and in vitro kinase assays, we identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we identified pelp1 as a novel substrate of cdks and found that cdk phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function. SIGNOR-167770 0.358 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1110 GSVQNPVyHNQPLNP 9606 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236483 0.2 SPI1 protein P17947 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 20861919 f apalma In the myeloid compartment, Gfi1 is part of a regulatory network that determines lineage fate decision between granulocyte and monocyte/macrophage development. In this compartment, Gfi1 antagonizes the function of the transcription factor Pu.1. Pu.1 promotes monocytic differentiation, whereas Gfi1 enhances granulocytic differentiation. SIGNOR-256372 0.7 CSNK2A1 protein P68400 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates activity phosphorylation Ser87 GDDEDACsDTEATEA -1 8288648 t llicata Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action. SIGNOR-250929 0.312 TARBP2 protein Q15633 UNIPROT DICER1 protein Q9UPY3 UNIPROT up-regulates binding 9606 16142218 t miannu Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si? Or mi?RISCs In mammalian cells, but it may also facilitate the cleavage of pre?miRNAs By dicer. SIGNOR-140226 0.939 SIRT5 protein Q9NXA8 UNIPROT ACOX1 protein Q15067 UNIPROT down-regulates activity catalytic activity 9606 BTO:0000007 29491006 t Monia SIRT5‐mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation. SIGNOR-261210 0.263 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI PHF2 protein O75151 UNIPROT up-regulates activity chemical activation 29981745 t lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. SIGNOR-273464 0.8 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr373 TVLVKDStNRDSLDM 9606 BTO:0000938 BTO:0000142 12486117 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. SIGNOR-96632 0.29 GSK3B protein P49841 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by stabilization phosphorylation Ser907 QAHSLPLsPASTRQQ 10090 BTO:0000452 12871932 t GSK-3 beta forms an in vivo complex with and specifically phosphorylates NF-kappa B1/p105 at Ser-903 and Ser-907 in vitro. GSK-3 beta has a dual effect on p105: it stabilizes p105 under resting conditions and primes p105 for degradation upon tumor necrosis factor (TNF)-alpha treatment. Indeed, constitutive processing of p105 to p50 occurs at a higher rate in cells lacking GSK-3 beta with respect to wild-type cells and can be reduced upon reintroduction of GSK-3 beta by transfection. S903A and S907A point mutations impair p105 proteolysis in response to TNF-α. SIGNOR-251252 0.396 TNF protein P01375 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 21514273 f via a ?-catenin-dependent pathway fspada Tumor necrosis factor-? (TNF-alpha) Is known to suppress adipocyte differentiation via a Beta-catenin-dependent pathway. SIGNOR-173421 0.7 PTPN11 protein Q06124 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9534 BTO:0004055 14560030 t Inhibition is achieved through the dephosphorylation of RasGAP binding sites at the level of the plasma membrane. We have identified Tyr992 of the epidermal growth factor receptor (EGFR) to be one such site, since its mutation to Phe renders the EGFR refractory to the effect of dominant-negative SHP2. To our knowledge, this is the first report to outline the site and molecular mechanism of action of SHP2 in EGFR signaling, SIGNOR-248666 0.865 BBIP1 protein A8MTZ0 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 t lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome SIGNOR-262561 0.653 CSNK2A1 protein P68400 UNIPROT KIF1C protein O43896 UNIPROT unknown phosphorylation Ser1092 PRMRRQRsAPDLKES -1 10559254 t llicata Serine 1092 was a substrate for the protein kinase casein kinase II in vitro, and inhibition of casein kinase II in cells diminished the association of KIF1C with 14-3-3gamma. Our data thus suggest that KIF1C can form dimers and is associated with proteins of the 14-3-3 family. SIGNOR-250912 0.315 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2D3 protein P61077 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271314 0.833 EGFR protein P00533 UNIPROT ABCA1 protein O95477 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2054 GGNKRKLsTAMALIG 9606 BTO:0000567 12196520 t lperfetto We further provide in vitro evidence that epidermal growth factor receptor (EGFR)-mediated phosphorylation regulated ABCA1 ubiquitination |The EGFR selective inhibitor PD168393 blocked the EGFR-ABCA1 interaction and abolished ABCA1Ser2054 phosphorylation| SIGNOR-264419 0.299 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 15141161 t gcesareni The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus SIGNOR-124727 0.879 CSNK2B protein P67870 UNIPROT CDC34 protein P49427 UNIPROT unknown phosphorylation Ser203 APAPDEGsDLFYDDY 9606 BTO:0000567 11546811 t llicata CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm.  SIGNOR-251057 0.358 MARK1 protein Q9P0L2 UNIPROT MAP4 protein P27816 UNIPROT down-regulates activity phosphorylation Ser1073 KAQAKVGsLDNVGHL -1 8631898 t miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. SIGNOR-250169 0.448 CDK5 protein Q00535 UNIPROT EZR protein P15311 UNIPROT up-regulates activity phosphorylation Thr235 YEKDDKLtPKIGFPW 9606 BTO:0000971 12769842 t llicata Increased ezrin expression and activation by CDK5 coincident with acquisition of the senescent phenotype. SIGNOR-250665 0.476 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM6A protein O15550 UNIPROT up-regulates activity chemical activation 29981745 t lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. SIGNOR-273462 0.8 ACOX1 protein Q15067 UNIPROT TP73 protein O15350 UNIPROT down-regulates quantity by destabilization binding 9606 31401980 t miannu Downregulation of ACOX1 increased p73, but not p53, expression. p73 expression was critical for apoptosis induction induced by ACOX1 downregulation. ACOX1 reduced p73 expression by destabilizing p73 protein. We also found that ACOX1 interacted with p73 protein SIGNOR-261056 0.2 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates activity phosphorylation Ser634 ISQCGYSsTIVHVPP 9534 BTO:0000298 11865049 t llicata The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly.  SIGNOR-250819 0.734 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 10197981 t llicata Oncogenically activated ras inhibits the tgfbeta-induced nuclear accumulation of smad2 and smad3 and smad-dependent transcription. Ras acting via erk map kinases causes phosphorylation of smad2 and smad3 at specific sites in the region linking the dna-binding domain and the transcriptional activation domain. SIGNOR-66746 0.736 SRC protein P12931 UNIPROT DLG4 protein P78352 UNIPROT up-regulates phosphorylation Tyr523 REDSVLSyETVTQME 9606 24981431 t llicata These results indicate that psd-95 phosphorylation by src facilitates the integration of pyk2 to psd-95 signal complex, the activation of pyk2/src, as well as the subsequent tyrosine phosphorylation of nr2a, which ultimately results in the upregulation of nmda receptor function and synaptic transmission. SIGNOR-205120 0.582 CDK1 protein P06493 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 24173284 t lperfetto The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A SIGNOR-84256 0.596 RHOH protein Q15669 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity relocalization 10090 BTO:0004850 18089848 t irozzo Therefore, RhoH functions as a Rac1 antagonist by inhibiting Rac1 translocation to the cell plasma membrane in the regulation of cell migration and F-actin assembly of HPCs SIGNOR-259085 0.385 COX5B protein P10606 UNIPROT Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR down-regulates 10090 BTO:0000165 18701479 f lperfetto Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS.|R-cadherin expression inhibits myoblast cell cycle exit SIGNOR-253105 0.7 PTPN1 protein P18031 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity dephosphorylation Tyr421 RLPSSPVyEDAASFK 9606 27824079 t lperfetto We conclude that Mena INV promotes invadopodium maturation by inhibiting normal dephosphorylation of cortactin at tyrosine 421 by the phosphatase PTP1B. SIGNOR-277027 0.531 MAP4K1 protein Q92918 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 8824585 f gcesareni These results demonstrated that the observed jnk1 activation was from hpk1 and not from other hpkl-associated kinases or from cross-reactive kinases precipitated by anti-hpk1 antibody. SIGNOR-43999 0.324 KAT2A protein Q92830 UNIPROT SLC44A2 protein Q8IWA5 UNIPROT up-regulates quantity 9606 BTO:0003065 21367571 f lperfetto Among these, SLC44A2 (a putative choline transporter) was strikingly upregulated by ethanol (three fold), and GCN5 silencing downregulated it SIGNOR-260408 0.2 CSNK2A1 protein P68400 UNIPROT FOSB protein P53539 UNIPROT up-regulates phosphorylation Ser27 SAESQYLsSVDSFGS 9606 17241283 t lperfetto Our findings indicate that ck2 activation increases deltafosb's transactivation potential, while ck2 inhibition decreases it. Further, we show that preventing ser27 phosphorylation by mutating the site to ala results in a significant decrease in deltafosb transactivation SIGNOR-152403 0.2 GSK3B protein P49841 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates activity phosphorylation Thr1966 TPEKTDMtPSTTSPP 9606 BTO:0000938 32599005 t lperfetto Glycogen synthase kinase 3β (GSK3beta) phosphorylates the Nav1.2C-terminal tail at T1966, suppressing Na+ currents and channel trafficking to the plasma membrane SIGNOR-275748 0.2 COL4A2 protein P08572 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253243 0.468 TSPO2 protein Q5TGU0 UNIPROT SLC25A4 protein P12235 UNIPROT up-regulates activity binding 9606 BTO:0000424 30061676 t miannu Our results demonstrate the existence of a VDAC-TSPO2-ANT complex that mediates ATP release from RBCs. We previously demonstrated that the translocase protein TSPO2 together with the voltage-dependent anion channel (VDAC) and adenine nucleotide transporter (ANT) were involved in a membrane transport complex in human red blood cells (RBCs). . The present results show that TSPO ligands induce polymerization of VDAC, coupled to activation of ATP release by a supramolecular complex involving VDAC, TSPO2 and ANT. SIGNOR-261825 0.281 PP1 proteinfamily SIGNOR-PF54 SIGNOR SP1 protein P08047 UNIPROT down-regulates activity dephosphorylation 9606 12684058 t lperfetto Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression. SIGNOR-264669 0.2 CSF1 protein P09603 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 10572088 t gcesareni Granulocyte-macrophage colony-stimulating factor (gm-csf) is an important hematopoietic cytokine that exerts its effects by interaction with the gm-csf receptor (gmr) on the surface of responsive cells. The gm-csf receptor consists of two subunits: gmralpha, which binds gm-csf with low affinity, and gmrbeta, which lacks intrinsic ligand-binding capability but complexes with gmralpha to form a high-affinity receptor (gmralpha/beta). SIGNOR-72455 0.343 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1A protein P50416 UNIPROT down-regulates activity binding 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267114 0.8 EEF1A1P5 protein Q5VTE0 UNIPROT Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269561 0.8 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr487 SLSNIDFyAQVSDIT 10029 12907755 t PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates SIGNOR-248419 0.48 SLC46A1 protein Q96NT5 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI up-regulates quantity relocalization 9606 BTO:0000575 17129779 t lperfetto However, the current study establishes that a major function of this gene product is proton-coupled folate transport required for folate homeostasis in man, and we have thus amended the name to PCFT/HCP1. SIGNOR-268264 0.8 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192601 0.8 LYN protein P07948 UNIPROT HCLS1 protein P14317 UNIPROT up-regulates activity phosphorylation Tyr378 EPEPENDyEDVEEMD 9606 9104825 t Lyn and Syk synergistically phosphorylate HS1, and that Tyr-378 and Tyr-397 of HS1 are the critical residues for its BCR-induced phosphorylation. tyrosine phosphorylation of HS1 is required for BCR-induced apoptosis and nuclear translocation of HS1 may be a prerequisite for B cell apoptosis. PMID: 9104825 PMCID: PMC2196252 SIGNOR-251400 0.702 AURKA protein O14965 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser98 RSSSGYFsFDTDRSP 9606 BTO:0002181 23912711 t miannu  We observed that BimEL is phosphorylated by Aurora A early in mitosis and reversed by PP2A after mitotic exit. Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL.  SIGNOR-276246 0.384 MTF1 protein Q14872 UNIPROT MCAT protein Q8IVS2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15378601 f miannu MRE-binding transcription factor-1 (MTF-1) is a highly conserved heavy metal-induced transcriptional activator. MTF-1 also activates transcription in response to oxidative stress and regulates the expression of several cytoprotective factor genes, including MT, gamma-glutamylcysteine synthetase, and Cu/Zn-superoxide dismutase. SIGNOR-254600 0.2 USP37 protein Q86T82 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 21596315 t lperfetto USP37 Binds, Deubiquitinates, and Stabilizes Cyclin A SIGNOR-265052 0.563 metaproterenol chemical CHEBI:6792 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) SIGNOR-257874 0.8 ABL1 protein P00519 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates phosphorylation 9606 BTO:0000938 22590567 t inferred from 70% of family members llicata We demonstrate that c-abl kinase phosphorylates mst2 at an evolutionarily conserved site, y81, within the kinase domain. We further show that the phosphorylation of mst2 by c-abl leads to the disruption of the interaction with raf-1 proteins and the enhancement of homodimerization of mst2 proteins. It thereby enhances the mst2 activation and induces neuronal cell death. SIGNOR-269946 0.349 PTGER1 protein P34995 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257278 0.265 TIMM17A protein Q99595 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 t lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. SIGNOR-267695 0.701 GPR183 protein P32249 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256858 0.406 CHEK1 protein O14757 UNIPROT TP73 protein O15350 UNIPROT up-regulates phosphorylation Ser47 EVVGGTDsSMDVFHL 9606 14585975 t llicata We found that endogenous p73alpha is serine phosphorylated by endogenous chk1 upon dna damage, which is a mechanism required for the apoptotic-inducing function of p73alpha. SIGNOR-118913 0.517 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1120 QPLNPAPsRDPHYQD 9606 BTO:0000007 10347170 t llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  SIGNOR-250623 0.378 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 9606 BTO:0000887 20151718 t miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-163792 0.278 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4C protein Q08493 UNIPROT up-regulates activity phosphorylation Ser14 GEGAEACsRLSRSRG 9534 12023945 t miannu Phosphorylation of long PDE4 isoforms by PKA. COS1 cells were transfected to express various long PDE4 isoforms. SIGNOR-275987 0.2 romidepsin chemical CHEBI:61080 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257993 0.8 PRKCA protein P17252 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 15355962 t gcesareni Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth. SIGNOR-128714 0.261 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 7545671 t gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-28800 0.579 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM4 protein Q14833 UNIPROT up-regulates activity chemical activation 9606 25042998 t miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate SIGNOR-264074 0.8 NCF1 protein P14598 UNIPROT CYBA protein P13498 UNIPROT up-regulates activity binding 9606 12672956 t miannu Stimulus-induced phosphorylation of p47phox causes a conformational change, by which both PX and SH3 domains become accessible to their membranous targets, phosphoinositides and p22phox, respectively. Cooperation of these two interactions, each being indispensable, enables p47phox to form a stable complex with cytochrome b558 (composed of the two subunit gp91phox and p22phox), leading to activation of the phagocyte NADPH oxidase. SIGNOR-276625 0.782 PRKDC protein P78527 UNIPROT MCC protein P23508 UNIPROT up-regulates activity phosphorylation Ser118 SELRSELsQSQHEVN 9606 BTO:0001109 21779472 t miannu MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity. SIGNOR-273530 0.2 POU4F2 protein Q12837 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity binding 9606 BTO:0000093 9448000 t 2 miannu the POU domain of Brn-3a and Brn-3b was shown to interact with the DNA-binding domain of the ER. Brn-3-ER interactions also affect transcriptional activity of an ERE-containing promoter, such that in estradiol-stimulated cells, Brn-3b strongly activated the promoter via the ERE, while Brn-3a had a mild inhibitory effect. SIGNOR-241208 0.553 MMP25 protein Q9NPA2 UNIPROT MMP2 protein P08253 UNIPROT up-regulates activity cleavage Asn109 CGNPDVAnYNFFPRK -1 14583471 t miannu Direct activation of pro-matrix metalloproteinase-2 by leukolysin/membrane-type 6 matrix metalloproteinase/matrix metalloproteinase 25 at the asn(109)-Tyr bond. Leukolysin Cleaves ProMMP-2 at Asn66-Leu and Asn109-Tyr. SIGNOR-256345 0.383 RHOA protein P61586 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates activity binding 9606 23151663 t gcesareni Planar cell polarity (pcp) signalling triggers activation of the small gtpases rhoa and rac1, which in turn activate rho kinase (rock) and jun-n-terminal kinase (jnk), respectively, leading to actin polymerization and microtubule stabilization. SIGNOR-199542 0.803 GSK3B protein P49841 UNIPROT CTNND1 protein O60716 UNIPROT unknown phosphorylation Thr310 GTARRTGtPSDPRRR -1 12885254 t GSK3beta selectively phosphorylates p120 on S252 and T310 in Vitro SIGNOR-251235 0.396 NR3C1 protein P04150 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity transcriptional regulation 9606 26652733 t inferred from family member Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB SIGNOR-267792 0.2 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258899 0.8 RIMS1 protein Q86UR5 UNIPROT UNC13B protein O14795 UNIPROT up-regulates activity relocalization 9606 31679900 t miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle SIGNOR-264385 0.79 LPAR1 protein Q92633 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 12393875 t gcesareni We conclude that lpa(1) receptors couple to a g(i)-phosphoinositide 3-kinase-tiam1 pathway to activate rac. SIGNOR-94635 0.537 IRX3 protein P78415 UNIPROT GJA1 protein P17302 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003324 21825130 t Luana Irx3 directly represses Cx43 transcription  SIGNOR-266044 0.282 SP1 protein P08047 UNIPROT CRX protein O43186 UNIPROT up-regulates activity binding 9606 15781457 t miannu Zinc finger DNA-binding domains of both Sp1 and Sp3 interact with Crx. Sp4 and Sp1 produce much higher levels of transcriptional activation when co-transfected with Crx, they may additionally act by directly increasing the rate of transcriptional initiation by the general transcriptional apparatus through their activation domains. SIGNOR-225336 0.329 FLT4 protein P35916 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 9927207 t llicata We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites. SIGNOR-64186 0.575 SP3 protein Q02447 UNIPROT IFITM5 protein A6NNB3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23530031 f miannu Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation. SIGNOR-254220 0.2 NEUROG3 protein Q9Y4Z2 UNIPROT INSM1 protein Q01101 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000944 17300785 f miannu The ngn3/E47 heterodimer selectively binds and activates the E-box3 of the INSM1 promoter. The endogenous ngn3 and CREB-binding protein (CBP) co-activator occupy the INSM1 promoter, resulting in hyper-acetylation of histone H3/H4 chromatin in a human neuroblastoma cell line, IMR-32. SIGNOR-253814 0.579 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM4C protein Q9H3R0 UNIPROT up-regulates activity chemical activation 29981745 t lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. SIGNOR-273474 0.8 UNC80 protein Q8N2C7 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding 9606 BTO:0000007 19535918 t miannu UNC80 is a protein that is associated with the NALCN Na(+) leak cation channel, and is required for the activation of this channel by the neuropeptide substance P through GPCRs in a G-protein-independent fashion. Here, we show that UNC80 binds Src kinases and recruits Src into the channel complex.  SIGNOR-265179 0.358 PAK5 protein Q9P286 UNIPROT PACSIN1 protein Q9BY11 UNIPROT up-regulates activity phosphorylation Ser346 SQAGDRGsVSSYDRG -1 22371566 t miannu We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. SIGNOR-263025 0.2 PD173074 chemical CHEBI:63448 ChEBI FGFR1 protein P11362 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205725 0.8 HIPK2 protein Q9H2X6 UNIPROT PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization phosphorylation Ser54 QPLPPRPsPAALPGG 23871434 t lperfetto WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation|Analysis of the phosphoamino acids of WIP1 revealed that both Ser85 and Ser54 are phosphorylation sites, confirming that HIPK2 is a protein kinase for WIP1 phosphorylation at Ser54 as well as Ser85 SIGNOR-275480 0.43 CUDC-101 chemical CID:24756910 PUBCHEM HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20143778 t miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. SIGNOR-262260 0.8 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser358 WPLSRTRsEPLPPSA -1 15738054 t lperfetto We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro. SIGNOR-249274 0.491 PRKAR1A protein P10644 UNIPROT PRKACB protein P22694 UNIPROT down-regulates activity binding 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258755 0.858 DISC1 protein Q9NRI5 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity binding 9606 BTO:0000938 17202468 t miannu Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3ε. 14-3-3ε is involved in the proper localization of NUDEL and LIS1 in axons. the association with NUDEL and LIS1 supports the notion that DISC1 contributes to the neuronal development and morphology  SIGNOR-252162 0.598 CDH11 protein P55287 UNIPROT CTNNB1 protein P35222 UNIPROT unknown binding 9606 BTO:0000150 10029089 t miannu Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin SIGNOR-64862 0.639 MAX protein P61244 UNIPROT MXI1 protein P50539 UNIPROT up-regulates activity binding 9606 7954804 t 2 miannu The role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. SIGNOR-240314 0.575 PPP2CB protein P62714 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 14712210 t miannu Phosphorylation of p53 at serine 37 is important for transcriptional activity and regulation in response to DNA damage| Furthermore, in vitro phosphatase assays show that PP2A dephosphorylates p53 at S37. SIGNOR-248584 0.412 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR EIF4B protein P23588 UNIPROT up-regulates activity phosphorylation Ser422 RERSRTGsESSQTGT 9606 BTO:0001109 36882522 t lperfetto CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. SIGNOR-273116 0.279 PRKCB protein P05771 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Ser625 PIVGSNGsSRLQDSR 9823 21864610 t miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. SIGNOR-262924 0.2 CCR4-NOT complex complex SIGNOR-C439 SIGNOR RC3H2 protein Q9HBD1 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 t lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins SIGNOR-268353 0.32 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Thr291 EDEESYDtESEFTEF 9606 BTO:0000782 8622692 t llicata Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation. SIGNOR-40514 0.567 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr199 VKKSIRDtPAKNAQK 9606 SIGNOR-C17 12058066 t llicata However, under the experimental conditions used here, the t199 residue was the most likely candidate to be phosphorylated by cyclin b/cdc2 these results strongly support the concept that the rna binding activity of b23.1 is inactivated by cyclin b/cdc2-mediated phosphorylation. SIGNOR-89605 0.533 KLF15 protein Q9UIH9 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates transcriptional regulation 10090 BTO:0002572 20956975 f lperfetto Our results provide a new mechanism for understanding glucocorticoids-dependent adipogenesis and that GR promotes adipogenesis via KLF15 gene expression as a transcriptional direct target. SIGNOR-236230 0.7 CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000007 16964285 t amattioni Casp8 induces apoptosis by directly activating casp3. SIGNOR-149420 0.715 2-[[2-[[2-[[2-[[2-amino-3-(4-hydroxyphenyl)-1-oxopropyl]amino]-1-oxoethyl]amino]-1-oxoethyl]amino]-1-oxo-3-phenylpropyl]amino]-4-methylpentanoic acid chemical CHEBI:91634 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258805 0.8 tazarotene chemical CHEBI:32184 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9534 19058965 t Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  SIGNOR-258029 0.8 β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI up-regulates quantity precursor of 9606 15170386 t Fru-2,6-P2 (fructose 2,6-bisphosphate) is a signal molecule that controls glycolysis. Since its discovery more than 20 years ago, inroads have been made towards the understanding of the structure‚Äì function relationships in PFK-2 (6-phosphofructo-2-kinase)/ FBPase-2 (fructose-2,6-bisphosphatase), the homodimeric bifunctional enzyme that catalyses the synthesis and degradation of Fru-2,6-P2 SIGNOR-267265 0.8 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser415 HKLDVSRsPPLMVKK 9606 16862148 t lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS‚‚PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573‚‚577 (see Supplementary Information, Table S2). SIGNOR-249307 0.444 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI TET2 protein Q6N021 UNIPROT up-regulates activity binding 9606 25699704 t irozzo A second group of AML patients (15%–33% of all cases) harbor mutations in either the isocitrate dehydrogenase (IDH) 1 or 2 gene (Shih et al., 2012). These enzymes produce α-ketoglutarate (α-KG), which is required for TET activity. SIGNOR-255706 0.8 MYF5 protein P13349 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates activity BTO:0001103 17495111 f Simone Vumbaca In summary, the absence of Myf5 clearly reduced the initial expansion of satellite cell-derived transient amplifying cells and resulted in a shift of the ratio of satellite cell subpopulations but did not affect the specification and generation of specific subpopulations of satellite cell-derived cells such as reserve cells, amplifying cells, and differentiating mature myogenic cells. SIGNOR-255643 0.7 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser122 DQHLMKCsPAQLLCS 9606 10864927 t lperfetto Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-216741 0.839 APC-c complex SIGNOR-C150 SIGNOR CDR2 protein Q01850 UNIPROT down-regulates quantity by destabilization ubiquitination 20383333 t lperfetto Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis. SIGNOR-252024 0.2 N-(2-(4-(7-Methoxy-1-naphthalenyl)-1-piperazinyl)ethyl)-2-thiophenecarboxamide chemical CID:131907 PUBCHEM HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258866 0.8 alvocidib chemical CHEBI:47344 ChEBI CDK2 protein P24941 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258171 0.8 GALR3 protein O60755 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256719 0.426 GSK2126458 chemical CID:25167777 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252645 0.8 CDK1 protein P06493 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser5 sPPLRDVD 9606 SIGNOR-C17 14749395 t lperfetto Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21. SIGNOR-121605 0.372 CD40 protein P25942 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000776 18635759 t lperfetto Cd40, a tumor necrosis factor receptor (tnfr) family member, forms a complex containing adaptor molecules traf2 and traf3. SIGNOR-179473 0.838 SLBP protein Q14493 UNIPROT H3-3A protein P84243 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265418 0.2 tyramine smallmolecule CHEBI:15760 ChEBI dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬† SIGNOR-264176 0.8 CSNK2A1 protein P68400 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Thr387 LPWDLWTtSTDLVQP 9606 BTO:0000567 16945112 t lperfetto Amphiphysins interact directly with clathrin and have a function in clathrin-mediated synaptic vesicle recycling and clathrin-mediated endocytosis. The n-terminal domain of clathrin bound to unphosphorylated amphiphysin-1, but not to the phosphorylated protein. The assumption that casein kinase 2 phosphorylates amphiphysin-1 at t350 and t387 was corroborated by experiments showing that: casein kinase 2 phosphorylated these residues directly in vitro,. upon activation by nerve growth factor, casein kinase 2 phosphorylates amphiphysin-1 and thereby regulates the endocytosis of clathrin-coated vesicles via the interaction between clathrin and amphiphysin. SIGNOR-149318 0.2 NDUFS7 protein O75251 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. SIGNOR-262181 0.858 ADSS1 protein Q8N142 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI down-regulates quantity chemical modification 9606 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267344 0.8 PTBP1 protein P26599 UNIPROT Alternative_Splicing_Regulation phenotype SIGNOR-PH204 SIGNOR up-regulates 9606 20010808 f We show that three heterogeneous nuclear ribonucleoprotein (hnRNP) proteins, polypyrimidine tract binding protein (PTB, also known as hnRNPI), hnRNPA1 and hnRNPA2, bind repressively to sequences flanking exon 9, resulting in exon 10 inclusion. SIGNOR-268688 0.7 UVRAG protein Q9P2Y5 UNIPROT Vps34 Complex II complex SIGNOR-C241 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260322 0.814 PRKD1 protein Q15139 UNIPROT PIP4K2A protein P48426 UNIPROT down-regulates phosphorylation Thr376 KAAHAAKtVKHGAGA 9606 16563698 t lperfetto We conclude that the type ii pip kinases are physiological targets for pkd phosphorylation, and that this modification is likely to regulate inositol lipid turnover by inhibition of these lipid kinases. SIGNOR-145370 0.2 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT down-regulates phosphorylation Thr675 ANQMQPDtTSVVKDS 9606 18680479 t miannu We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / mutation of thr675 to alanine increased mps1 catalytic domain activity, and this was reduced to wt levels by mutation to aspartate SIGNOR-179904 0.2 CDK1 protein P06493 UNIPROT RFC1 protein P35251 UNIPROT down-regulates activity phosphorylation Thr506 KESKLERtPQKNVQG 9534 BTO:0004055 12930972 t lperfetto Phosphorylation of the PCNA binding domain of the large subunit of replication factor C on Thr506 by cyclin-dependent kinases regulates binding to PCNA|Replication factor C (RF-C) complex binds to DNA primers and loads PCNA onto DNA, thereby increasing the processivity of DNA polymerases. |Phosphorylation of either RF-Cp145 as a part of the RF-C complex or RF-Cp145 domain B by cdk-cyclin kinases inhibits their ability to bind PCNA. SIGNOR-265504 0.247 atropine chemical CHEBI:16684 ChEBI CHRM5 protein P08912 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258393 0.8 CDK2 protein P24941 UNIPROT LIG1 protein P18858 UNIPROT up-regulates activity phosphorylation Ser76 EEEDEALsPAKGQKP 9606 BTO:0000567 12851383 t lperfetto We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner. SIGNOR-103250 0.468 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2279 PVQPNPMsPQQHMLP 9606 17623675 t lperfetto Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo. SIGNOR-244533 0.2 PHF3 protein Q92576 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR down-regulates activity binding 9606 BTO:0000007 34667177 t miannu PHF3 interacts with RNA polymerase II through the SPOC domain. PHF3 negatively regulates mRNA levels. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. Our data suggest that PHF3 acts as a prominent effector of neuronal gene regulation by bridging transcription with mRNA decay. PHF3 SPOC preferentially binds RNA Pol II CTD phosphorylated on Serine-2 SIGNOR-266964 0.346 RPS6KA1 protein Q15418 UNIPROT MITF protein O75030 UNIPROT down-regulates phosphorylation Ser409 HGLSLIPsTGLCSPD 9606 21749389 t The effect has been demonstrated using O75030-9 gcesareni The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73, whereas serine 409 serves as a substrate for p90 rsk-1. An unphosphorylatable double mutant at these two residues is at once profoundly stable and transcriptionally inert. SIGNOR-174760 0.419 CSNK2A1 protein P68400 UNIPROT EIF5 protein P55010 UNIPROT up-regulates phosphorylation Ser389 LKEAEEEsSGGEEED 9606 18649047 t gcesareni We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2. SIGNOR-179542 0.402 SMARCC2 protein Q8TAQ2 UNIPROT Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270754 0.843 KDM4B protein O94953 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 30759871 t miannu The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. The majority of studies regarding its function describe it as an activator that removes repressive H3K9me3 and H3K9me2 at or near regulated promoters in order to facilitate expression of the indicated pathways. SIGNOR-263734 0.2 PRKCD protein Q05655 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser715 GYRQDDPsYRSFHSG 9606 25639486 t Manara Moreover, protein kinase Cδ, which directly phosphorylates β-catenin at Ser715, is required for the TRIM33–β-catenin interaction. | Phosphorylation of β-catenin Ser715 is critical for TRIM33-induced β-catenin degradation SIGNOR-260897 0.272 BRCA1 protein P38398 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates quantity by destabilization ubiquitination 10090 BTO:0002572 19074868 t gcesareni The BRCA1-BRCT domains bind to phosphorylated AKT (pAKT) and lead to its ubiquitination toward protein degradation SIGNOR-252458 0.52 PKA proteinfamily SIGNOR-PF17 SIGNOR CHKB protein Q9Y259 UNIPROT up-regulates activity phosphorylation Ser39 TPKRRRAsSLSRDAE 27149373 t lperfetto Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. | This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar. SIGNOR-275632 0.2 LAMA1 protein P25391 UNIPROT Laminin-1 complex SIGNOR-C183 SIGNOR form complex binding 7496033 t lperfetto Laminin-1 is an extracellular matrix protein composed of three polypeptide chains that are designated alpha 1, beta 1, and gamma 1. SIGNOR-253232 0.55 RPS6KA5 protein O75582 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 12213813 t lperfetto Phosphorylation of Bad at Ser112 in response to growth factors or cytokines is generally linked to cell survival. Knockdown of MSK1 suppressed Bad phosphorylation after calcium ionophore A23187 treatment in neuronal cells SIGNOR-262990 0.35 KAT2B protein Q92831 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity acetylation 9606 SIGNOR-C465 34811519 t lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269610 0.2 NOTCH1 protein P46531 UNIPROT FABP7 protein O15540 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16554461 f gcesareni Here we demonstrate that neuronal induction of radial glia formation is the result of sequential signaling through notch1 and erbb receptors. First, notch1 activation by neuronal contact induces the glial expression of the brain lipid binding protein (blbp) and erbb2 genes. SIGNOR-145365 0.528 RUNX3 protein Q13761 UNIPROT CASP2 protein P42575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002384 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255094 0.2 CHD8 protein Q9HCK8 UNIPROT SOX3 protein P41225 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 t Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells SIGNOR-268920 0.2 mTORC1 complex SIGNOR-C3 SIGNOR PPARG protein P37231 UNIPROT up-regulates quantity by expression 10090 19593385 f lperfetto Activation of mTORC1 causes a robust increase in the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARgamma), which is the master transcriptional regulator of adipocyte differentiation. SIGNOR-235343 0.427 CDK5 protein Q00535 UNIPROT AMPH protein P49418 UNIPROT unknown phosphorylation Ser276 PLPSPTAsPNHTLAP -1 11113134 t llicata Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells.  SIGNOR-250649 0.536 KRAS protein P01116 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. SIGNOR-252698 0.728 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-119366 0.316 LCK protein P06239 UNIPROT CCDC50 protein Q8IVM0 UNIPROT down-regulates activity phosphorylation Tyr217 MAEEKKAyKKAKERE 9606 19059208 t miannu We found that Ymer was considerably phosphorylated on tyrosine residues also via Src family kinases such as Lck. A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling. SIGNOR-262853 0.2 EGFR protein P00533 UNIPROT NCK1 protein P16333 UNIPROT up-regulates 9606 9362449 f Nck interacts witn ErbB1 through SH2 and SH3 domains gcesareni We found that nck does not directly bind to egf receptor, instead it binds via its sh2 domain to a 62 kda phosphotyrosine protein SIGNOR-52954 0.593 naloxone chemical CHEBI:7459 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258942 0.8 ATG7 protein O95352 UNIPROT ATG12 protein O94817 UNIPROT up-regulates binding 9606 18704115 t gcesareni Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein. SIGNOR-180132 0.935 TRIP13 protein Q15645 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 32860853 t lperfetto Mechanistically, TRIP13 enhanced EGFR protein abundance in part by preventing Cbl-mediated ubiquitination and proteasomal degradation. SIGNOR-265084 0.2 CREBBP protein Q92793 UNIPROT ALOX15 protein P16050 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 12517954 f lperfetto In A549 cells activation of 15-LOX by IL-4 required the coactivation of histone acetyltransferases CREB-binding protein/p300 and led to a sizable production of 15(S)-HETE SIGNOR-254093 0.2 ELOVL5 protein Q9NYP7 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267891 0.8 ACP1 protein P24666 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Ser474 RTHFPQFsYSASIRE 10090 17353188 t Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3 SIGNOR-248456 0.2 PPP2CB protein P62714 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 17015476 t Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo. SIGNOR-248578 0.269 LAMB1 protein P07942 UNIPROT Laminin-8 complex SIGNOR-C181 SIGNOR form complex binding 10809728 t lperfetto Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. SIGNOR-253227 0.601 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258990 0.2 mepyramine chemical CHEBI:6762 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7925364 t miannu The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum. SIGNOR-258748 0.8 TRIM9 protein Q9C026 UNIPROT TRIM9 protein Q9C026 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000142 20085810 t miannu Collectively, these results indicated that TRIM9 is an E3 ligase for its self-ubiquitination and that the ubiquitination of TRIM9 likely serves as a signal for proteasomal degradation. As shown in Fig. 1A, TRIM9 was ubiquitinated by itself when incubated with UbcH5b. In contrast, ubiquitination was observed when incubated with other E2 enzymes. These results suggest that TRIM9 cooperates with UbcH5b for its self-ubiquitination. N SIGNOR-271419 0.2 CCKBR protein P32239 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257238 0.257 TOP2B protein Q02880 UNIPROT DAB1 protein O75553 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24463367 f lperfetto While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development SIGNOR-242210 0.2 CDK9 protein P50750 UNIPROT NCOA2 protein Q15596 UNIPROT up-regulates activity phosphorylation Ser469 NYALKMNsPSQSSPG 9606 BTO:0000801 29170386 t Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties. SIGNOR-256096 0.248 lenalidomide chemical CHEBI:63791 ChEBI IKZF3 protein Q9UKT9 UNIPROT down-regulates quantity by destabilization chemical inhibition 9606 24328678 t gcesareni Members of the Ikaros family of transcription factors, specifically Ikaros and Aiolos (encoded by the genes IKZF1 and IKZF3 respectively), are recruited as protein substrates for CRL4CRBN in T cells in response to lenalidomide or pomalidomide treatment. SIGNOR-236925 0.8 WEE1 protein P30291 UNIPROT ERG protein P11308 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr183 FQRLTPSyNADILLS 9606 BTO:0001033 32871104 t miannu Here, we demonstrate that DNA damage induces proteasomal degradation of wild-type ERG and TMPRSS2-ERG oncoprotein through ERG threonine-187 and tyrosine-190 phosphorylation mediated by GSK3β and WEE1, respectively. SIGNOR-277529 0.2 PTPN7 protein P35236 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR 9606 16226275 t First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185 SIGNOR-248483 0.805 Olopatadine chemical CHEBI:7769 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 t Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells SIGNOR-257782 0.8 LYPLA2 protein O95372 UNIPROT GAP43 protein P17677 UNIPROT down-regulates quantity by destabilization deacetylation Cys4 cMRRTKQV 9606 BTO:0000567 21152083 t miannu Acyl-protein thioesterase 2 catalyzes the deacylation of peripheral membrane-associated GAP-43. In this work, we investigated the deacylation of growth-associated protein-43 (GAP-43), a dually acylated protein at cysteine residues 3 and 4. Thus, the results demonstrate that APT-2 is the protein thioesterase involved in the acylation/deacylation cycle operating in GAP-43 subcellular distribution.we demonstrated that the reduction in the protein level was abrogated when cells were also treated with proteasome inhibitors (chloroquine, MG132 and lactacystin) which strongly suggest that GAP-43 deacylation is an early and necessary step for its later ubiquitination and degradation by the proteasome. In addition, it also suggests that acyl-protein thioesterase levels not only regulate palmitate turnover but also global protein turnover of GAP-43. SIGNOR-266768 0.455 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258991 0.2 PP2B proteinfamily SIGNOR-PF18 SIGNOR JUN protein P05412 UNIPROT up-regulates dephosphorylation Ser243 PGETPPLsPIDMESQ 9606 BTO:0000938;BTO:0000017 17215518 t lperfetto Importantly, pp2b not only dephosphorylates the c-jun at ser-243 but also interacts with c-jun in pma-treated cells. Pma stimulates the association of the pp2b/c-jun/sp1 complex with the promoter. These findings indicate the dephosphorylation of c-jun c terminus is required for the c-jun/sp1 interaction SIGNOR-152006 0.2 bremazocine chemical CHEBI:3171 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258777 0.8 DLGAP1 protein O14490 UNIPROT SHANK2 protein Q9UPX8 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264587 0.82 ESRRA protein P11474 UNIPROT NR2F1 protein P10589 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000155 15955695 f miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. SIGNOR-253795 0.248 MARCHF9 protein Q86YJ5 UNIPROT PLXNC1 protein O60486 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271532 0.2 CSNK1D protein P48730 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 23431053 t milica Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ SIGNOR-201154 0.4 CYP27B1 protein O15528 UNIPROT calcidiol smallmolecule CHEBI:17933 ChEBI down-regulates quantity chemical modification 9606 BTO:0000671 12050193 t lperfetto The rate-limiting, hormonally regulated step in the biological activation of vitamin D is its 1alpha-hydroxylation to 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] in the kidney, catalyzed by the mitochondrial cytochrome P450 enzyme, P450c1alpha. SIGNOR-270560 0.8 CSNK2A1 protein P68400 UNIPROT CORO1C protein Q9ULV4 UNIPROT up-regulates phosphorylation Ser463 CNQDERIsKLEQQMA 9606 22355754 t lperfetto We demonstrate that crn2 is a binding partner and substrate of protein kinase ck2, which phosphorylates crn2 at s463 in its c-terminal coiled coil domain SIGNOR-196193 0.2 SLBP protein Q14493 UNIPROT H2BC9 protein Q93079 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265391 0.2 MYLK protein Q15746 UNIPROT MYL6B protein P14649 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 BTO:0000671 10092231 t gcesareni Cytoskeletal dynamics are primarily modulated by interactions of actin and myosin ii that are regulated by myosin light chain kinase (mlck)-mediated phosphorylation of the regulatory myosin light chain (mlc). SIGNOR-65865 0.709 BMX protein P51813 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 23716717 t llicata Bmx phosphorylated focal adhesion kinase (fak) at tyr577 subsequent to its src-mediated phosphorylation at tyr576. Loss of bmx by rna interference or by genetic deletion in mouse embryonic fibroblasts (mefs) markedly impaired fak activity. SIGNOR-202139 0.531 KANSL3 protein Q9P2N6 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 26243146 f miannu Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. SIGNOR-267171 0.7 SMARCB1 protein Q12824 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270607 0.814 CASP6 protein P55212 UNIPROT Caspase 6 complex complex SIGNOR-C228 SIGNOR form complex binding cleavage:Asp193 DTNITEVdAASVYTL 21621544 t lperfetto It is generally recognized that effector caspases undergo proteolytic cleavage of the inactive zymogen at a specific aspartate residue, resulting in a large N-terminal p20 polypeptide chain and a small C-terminal p10 polypeptide chain, leading to a p202/p102 tetramer. SIGNOR-256392 0.2 calcium(2+) smallmolecule CHEBI:29108 ChEBI Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 11988172 f miannu Ca(2+) influx through voltage-gated channels initiates the exocytotic fusion of synaptic vesicles to the plasma membrane. SIGNOR-264355 0.7 SGK1 protein O00141 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates phosphorylation Thr346 GTRSRSHtSEGTRSR 9606 18787837 t llicata Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1. SIGNOR-180821 0.586 FGFR3 protein P22607 UNIPROT TET2 protein Q6N021 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr1902 TRISLVFyQHKSMNE 9606 BTO:0000976 33097695 t miannu FGFR3∆7-9, but not wild-type FGFR3, directly interacts with TET2 and phosphorylates TET2 at Y1902 site, leading to the ubiquitination and proteasome-mediated degradation of TET2. SIGNOR-277535 0.253 ZMYND8 protein Q9ULU4 UNIPROT NAV2 protein Q8IVL1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 21620140 t Luana We also confirmed transcriptional coactivator functions of ZMYND8 in ERα-driven reporter assays and on endogenous E2-dependent genes (Figure 5F,G). siRNA knockdown of ZMYND8 showed markedly decreased transcription at the presumptive ERα/Z3 target genes ADORA1 and NAV2, while the classical ERα targets pS2/TFF1 and GREB1 appear to be less affected (Figure 5G), suggesting likely gene-specificity of ZMYND8.  SIGNOR-266209 0.2 SOSTDC1 protein Q6X4U4 UNIPROT WNT10A protein Q9GZT5 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242695 0.337 RIMBP3C protein A6NJZ7 UNIPROT RIMS3 protein Q9UJD0 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264372 0.268 CSNK2B protein P67870 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1124 LNTEEFSsESDMEES 9606 BTO:0000938 19064667 t lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. SIGNOR-275756 0.2 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.737 PRL protein P01236 UNIPROT PRLR protein P16471 UNIPROT up-regulates binding 9606 10585417 t gcesareni Prolactin-dependent signaling occurs as the result of ligand-induced dimerization of the prolactin receptor (prlr). SIGNOR-72810 0.922 INO80C protein Q6PI98 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270851 0.641 CDK1 protein P06493 UNIPROT NDUFS2 protein O75306 UNIPROT up-regulates activity phosphorylation Ser364 KVDDAKVsPPKRAEM 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275592 0.2 LRFN4 protein Q6PJG9 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 21736948 t miannu SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. One possibility is that SALM3, which is capable of inducing presynaptic differentiation in contacting axons [19], recruits PSD-95 or SAP102 to the sites of early synaptic adhesion. SIGNOR-264096 0.669 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273080 0.635 HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-147327 0.874 BIRC3 protein Q13489 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 9545235 t gcesareni Xiap, birc2 and birc3 were shown to bind pro-casp9. Iaps may suppress casp9 by direct auto-activation of pro-caspase-11 SIGNOR-56481 0.75 IGF1R protein P08069 UNIPROT SIRPA protein P78324 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001260 11779860 f gcesareni These studies indicate that igf-ir stimulates phosphorylation of shps-1 which is critical for shp-2 recruitment to the plasma membrane and for its recruitment to the igf-ir SIGNOR-113640 0.372 TP53 protein P04637 UNIPROT FASLG protein P48023 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9841917 f Nuclear p53 amattioni Cd95l, cd95, and the trail death receptors are induced by the tumour suppressor p53 SIGNOR-62379 0.414 JAK1 protein P23458 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity phosphorylation 9606 9020188 t lperfetto The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-?, They become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases. SIGNOR-88285 0.759 VX-745 chemical CHEBI:90528 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258310 0.8 TP53 protein P04637 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR down-regulates 9606 27692180 f miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. SIGNOR-267467 0.7 LBX1 protein P52954 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002181 19651985 t Luana Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively  SIGNOR-266053 0.325 SETD1B protein Q9UPS6 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 32546566 t miannu SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks. SIGNOR-265576 0.2 SYN3 protein O14994 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates activity binding 9606 BTO:0000938 15265865 t miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. SIGNOR-269186 0.7 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 10649448 f gcesareni The dose of DEX required to promote maximal expression of PPARg mRNA is approximately 10 nM, which is within the range of the Kd for the association of DEX with the glucocorticoid receptor in 3T3-L1 cells SIGNOR-255753 0.401 HDAC5 protein Q9UQL6 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates binding 9606 11062529 t gcesareni The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis. SIGNOR-84023 0.694 MASP2 protein O00187 UNIPROT C2 protein P06681 UNIPROT up-regulates activity cleavage Arg243 KTKESLGrKIQIQRS 9606 BTO:0000392 11907111 t lperfetto The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase SIGNOR-263416 0.415 MAP3K14 protein Q99558 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates activity phosphorylation Ser870 KEDSAYGsQSVEQEA 9606 BTO:0000007 11239468 t lperfetto NIK-induced p100 processing requires phosphorylation of p100 at serines 866 and 870 SIGNOR-105557 0.664 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo. SIGNOR-101115 0.924 ADSL protein P30566 UNIPROT N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI down-regulates quantity chemical modification 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-266612 0.8 PGAM2 protein P15259 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI down-regulates quantity chemical modification 9606 24786789 t miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. SIGNOR-266512 0.8 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr465 GEEELSNyICMGGKG 10116 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-236713 0.912 CAMKK2 protein Q96RR4 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation 9606 BTO:0000567 15980064 t lperfetto These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo. SIGNOR-217496 0.59 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation Ser143 PPFPSRDsGRLSPDL 9606 BTO:0000567 21658950 t miannu Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis. SIGNOR-263138 0.2 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1784 TPTSPNYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273082 0.635 JMJD1C protein Q15652 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 32034158 t miannu We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state. SIGNOR-265170 0.2 PRKCE protein Q02156 UNIPROT GABRG2 protein P18507 UNIPROT down-regulates activity phosphorylation Ser366 FVSNRKPsKDKDKKK -1 17875639 t miannu Protein kinase C epsilon regulates gamma-aminobutyrate type A receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma2 subunits. Our findings indicate that PKCepsilon phosphorylation of gamma2 regulates the response of GABA(A) receptors to specific allosteric modulators, and, in particular, PKCepsilon inhibition renders these receptors sensitive to low intoxicating concentrations of ethanol. SIGNOR-263174 0.235 PRKCB protein P05771 UNIPROT TYR protein P14679 UNIPROT up-regulates phosphorylation Ser523 MEKEDYHsLYQSHL 9606 10347209 t llicata We conclude that pkc-beta activates tyrosinase directly by phosphorylating serine residues at positions 505 and 509 in the cytoplasmic domain of this melanosome-associated protein. our results strongly suggest that direct phosphorylation of tyrosinase by pkc-_ leads to its activation. SIGNOR-67866 0.421 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT up-regulates dephosphorylation Thr14 VEKIGEGtYGVVYKA 9606 22263797 t gcesareni Cell division cycle 25 a (cdc25a), a dual-specificity protein phosphatase, is one of the most crucial cell cycle regulators, which removes the inhibitory phosphorylation in cyclin-dependent kinases (cdks), such as cdk2, cdk4, and cdk6, and positively regulates the activities of cdks that lead to cell cycle progression. SIGNOR-195521 0.824 GRM3 protein Q14832 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264353 0.7 EGFR protein P00533 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates binding 9606 11279155 t gcesareni These results demonstrate that egfr-erbb2 oligomers are potent activators of mapk and akt, and this signaling does not require egfr kinase activity SIGNOR-106500 0.597 CSNK2A1 protein P68400 UNIPROT ESR1 protein P03372 UNIPROT down-regulates phosphorylation Ser559 PTSRGGAsVEETDQS 9606 BTO:0000150;BTO:0000567 20043841 t lperfetto Additionally protein kinase ck2 was identified as a kinase that phosphorylated eralpha at s282 and s559 s282 and s559 represent the second and third sites of er_ regulation by ck2. Remarkably, mutation of s282 or s559 to alanine resulted in near opposite functional effects on er_ as compared to mutation of s167 to alanine. Er_ ligand independent transcriptional activity was markedly enhanced upon mutation of s282 and s559 to alanine SIGNOR-162657 0.248 PTPN22 protein Q9Y2R2 UNIPROT CD247 protein P20963 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000007 16461343 t In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22. SIGNOR-248837 0.458 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252745 0.756 MED7 protein O43513 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266657 0.847 UNC5A protein Q6ZN44 UNIPROT PICK1 protein Q9NRD5 UNIPROT up-regulates activity binding 10116 BTO:0003036 16554470 t miannu Recently, our laboratory showed that UNC5A is coimmunoprecipitated with PICK1 and PKCα. Moreover, we demonstrated that the association of PKCα with UNC5A depends on the activation of PKCα and the ability of UNC5A to bind PICK1 SIGNOR-268181 0.292 MOV10 protein Q9HCE1 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity binding 9606 BTO:0000007 27016603 t miannu MOV10 enhances IRF3 activation and IRF3-mediated gene induction. This indicated that MOV10-mediated antiviral activity is most likely mediated through IKKε and not through TBK1. Involvement of IKKε was further established by examining the physical interaction of MOV10 and IKKε. SIGNOR-261138 0.2 ELP6 protein Q0PNE2 UNIPROT Elongator complex complex SIGNOR-C466 SIGNOR form complex binding 9606 28601220 t miannu Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer. SIGNOR-269713 0.761 PTPN1 protein P18031 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates dephosphorylation 9606 phosphorylation:Tyr177 9566916 t gcesareni We have observed association and dephosphorylation of p210 bcr-abl, but not v-abl, by ptp1b in vivo. SIGNOR-56822 0.2 HOXB6 protein P17509 UNIPROT HBA1 protein P69905 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000664 15269212 t Luana HOXB6 protein represses globin transcript levels in stably transfected K562 cells in a DNA-binding dependent fashion. SIGNOR-261637 0.2 OXSR1 protein O95747 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Thr100 TNTYYLQtFGHNTMD 9606 BTO:0000007 21321328 t miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). SIGNOR-276311 0.516 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR -1 15486195 t miannu Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. SIGNOR-250080 0.677 NFIA protein Q12857 UNIPROT RBFOX3 protein A6NFN3 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268911 0.263 SYK protein P43405 UNIPROT LAT2 protein Q9GZY6 UNIPROT up-regulates activity phosphorylation Tyr193 EDEESEDyQNSASIH 10090 BTO:0001930 14722116 t miannu Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases. SIGNOR-273575 0.576 MARCHF9 protein Q86YJ5 UNIPROT PTPRF protein P10586 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271536 0.2 PTPN1 protein P18031 UNIPROT LAT protein O43561 UNIPROT down-regulates activity dephosphorylation 9606 12857726 t Using a pharmacological inhibitor, we provide evidence that PTP1B activation and LAT dephosphorylation processes were required for irreversible platelet aggregation.|In collagen-stimulated platelets, the signaling complexes recruited by tyrosine-phosphorylated LAT are essential for PLCgamma2 activation SIGNOR-248403 0.483 SMDT1 protein Q9H4I9 UNIPROT MCU_MICUB_variant complex SIGNOR-C499 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270861 0.618 NR2E3 protein Q9Y5X4 UNIPROT ESR1 protein P03372 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22174013 t Luana NR2E3 directly regulates expression of ESR1 | Furthermore, overexpression of exogenous NR2E3 further increased expression of ESR1 and its downstream targets as well as its transcriptional activity in MCF-7 cells (Fig S1 of Supporting Information), strongly demonstrating that NR2E3 regulates ESR1 expression and subsequent ESR1-mediated induction of target genes. SIGNOR-266207 0.253 SEPTIN9 protein Q9UHD8 UNIPROT ARHGEF18 protein Q6ZSZ5 UNIPROT down-regulates binding 9606 15558029 t miannu In transient expression analyses, sept9b inhibited sa-rhogef-dependent rho activation in cos7 and hela cells. SIGNOR-131184 0.2 STX11 protein O75558 UNIPROT STX11-VAMP8 SNARE complex complex SIGNOR-C273 SIGNOR form complex binding 9606 BTO:0000132 22767500 t lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23.  SIGNOR-261897 0.658 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0001321 15659650 t lperfetto CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37 SIGNOR-217791 0.771 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr751 SKDESVDyVPMLDMK -1 7545675 t Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides SIGNOR-248414 0.679 PRKCE protein Q02156 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser185 SAYVGRLsARPKLKA -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276021 0.2 SRC protein P12931 UNIPROT HK1 protein P19367 UNIPROT up-regulates activity phosphorylation Tyr732 YDRLVDEySLNAGKQ 9606 BTO:0002181 28054552 t miannu Mechanistically, c-Src phosphorylation of HK1 at Tyr732 robustly decreases its Km and increases its Vmax by disrupting its dimer formation.  SIGNOR-277335 0.505 MC5R protein P33032 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256798 0.436 MTOR protein P42345 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-255944 0.7 Rigosertib sodium chemical CID:23696523 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-195028 0.8 PRKACA protein P17612 UNIPROT LRRK2 protein Q5S007 UNIPROT down-regulates activity phosphorylation Ser1444 NIKARASsSPVILVG -1 24351927 t gcesareni Furthermore, our work establishes S1444 as a PKA-regulated 14-3-3 docking site€.Strikingly, 14-3-3 binding to phospho-S1444 decreased LRRK2 kinase activity in vitro. SIGNOR-237444 0.415 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203564 0.769 CDK2 protein P24941 UNIPROT ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr226 SAPVGKEtPSKRMKR 9606 22334659 t gcesareni Phosphorylation at thr-116 and thr-226 of orc2 occurs by cyclin-dependent kinase during the s phase and is maintained until the m phase. Phosphorylation of orc2 at thr-116 and thr-226 dissociated the orc2-5 from chromatin. SIGNOR-196048 0.745 ANXA3 protein P12429 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001109;BTO:0000038 30998268 f miannu ANXA3 downregulation evidently increased the apoptosis of HCT116 (Figure 2C) and SW480 (Figure 2D) cells, and Ox‐induced cell apoptosis was further aggravated by ANXA3 suppression. SIGNOR-262208 0.7 CHGA protein P10645 UNIPROT Peptide_hormone_processing phenotype SIGNOR-PH88 SIGNOR up-regulates 10090 12456801 f CgA was initially identified as the major soluble matrix protein of secretory vesicles formed in neuroendocrine cells. Its functions include modulation of secretory granule stability, prohormone processing, and regulation of peptide sorting into secretory pathways SIGNOR-254275 0.7 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr325 TELEPLCtPVVTCTP phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-263012 0.706 MASP1 protein P48740 UNIPROT C2 protein P06681 UNIPROT up-regulates activity cleavage Ser20 LYPGLADsAPSCPQN 9606 BTO:0000392 11907111 t lperfetto The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase SIGNOR-263420 0.517 HTR1D protein P28221 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256721 0.41 FES protein P07332 UNIPROT PECAM1 protein P16284 UNIPROT up-regulates activity phosphorylation Tyr713 KKDTETVySEVRKAV 9606 BTO:0000007 12972546 t miannu PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1. SIGNOR-262868 0.28 VXJPSOQJNUZHDN-YJFQKBDPSA-N smallmolecule CID:118708139 PUBCHEM NMUR1 protein Q9HB89 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257591 0.8 EEF1A1P5 protein Q5VTE0 UNIPROT Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269550 0.8 INS protein P01308 UNIPROT CEBPB protein P17676 UNIPROT up-regulates 10090 BTO:0000011 11279134 f lperfetto The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin SIGNOR-250565 0.437 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation 10090 BTO:0003620 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling SIGNOR-248347 0.484 CSNK1D protein P48730 UNIPROT GJA1 protein P17302 UNIPROT up-regulates activity phosphorylation Ser325 NRMGQAGsTISNSHA 10116 BTO:0000067 12270943 t lperfetto We have examined the role of casein kinase 1 (CK1) in connexin-43 (Cx43) gap junction assembly. Cellular co-immunoprecipitation experiments and in vitro CK1 phosphorylation reactions indicate that CK1 interacted with and phosphorylated Cx43, initially on serine(s) 325, 328, or 330.| To examine CK1 function, normal rat kidney cells were treated with CKI-7, and Cx43 content was analyzed by Triton X-100 extraction, cell-surface biotinylation, and immunofluorescence. Western blot analysis indicated a slight increase in total Cx43, whereas gap junctional (Triton-insoluble) Cx43 decreased, and non-junctional plasma membrane Cx43 increased (as detected by cell surface biotinylation). SIGNOR-249329 0.588 IL5 protein P05113 UNIPROT IL5RA protein Q01344 UNIPROT up-regulates binding -1 8567620 t fspada Single chain and wt il5 also had similar binding affinity for soluble il5 receptor alpha chain, the specificity subunit of the il5 receptor, as measured kinetically with an optical biosensor. SIGNOR-40039 0.88 CS protein O75390 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI down-regulates quantity chemical modification 9606 3013232 t miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. SIGNOR-266549 0.8 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR1 protein Q92633 UNIPROT up-regulates chemical activation 9606 22863277 t gcesareni Lpa binds to a family of gpcrs known as lpa receptors (lpa1-6) to initiate intracellular signaling. Lpa1 was highly expressed and lpa3 was detectable in hek293a cells compared to other lpa receptors. SIGNOR-198523 0.8 MAPK14 protein Q16539 UNIPROT ZNHIT1 protein O43257 UNIPROT up-regulates phosphorylation 9606 20473270 t gcesareni We show that the srcap subunit named znhit1 or p18(hamlet), which is a substrate of p38 mapk, is recruited to the myogenin promoter at the onset of muscle differentiation, in a p38 mapk-dependent manner. Furthermore, p18hamlet was phosphorylated during myoblast differentiation in a p38 mapk-dependent manner (dal testo pmc) SIGNOR-165571 0.319 EGR1 protein P18146 UNIPROT PITX1 protein P78337 UNIPROT up-regulates activity binding 10090 19106114 t miannu GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity. SIGNOR-254916 0.528 GLS2 protein Q9UI32 UNIPROT glutamine smallmolecule CHEBI:28300 ChEBI down-regulates quantity chemical modification 9606 22049910 t Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. SIGNOR-266909 0.8 sertindole chemical CHEBI:9122 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258548 0.8 MAP3K6 protein O95382 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr838 GINPCTEtFTGTLQY 9606 17210579 t Manara These results suggested that ASK2 activates ASK1 by direct phosphorylation of Thr838 of ASK1. SIGNOR-260773 0.531 ITGB2 protein P05107 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257711 0.552 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1763 TPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248756 0.727 yohimbine chemical CHEBI:10093 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258682 0.8 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT down-regulates activity phosphorylation Ser88 RPSDEDSsSLESAAS -1 12852856 t lperfetto Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction SIGNOR-103356 0.688 SYNGAP1 protein Q96PV0 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 26356309 t miannu The reversible removal of AIDA-1 from the PSD core under excitatory conditions is similar to the redistribution of another abundant PSD protein, SynGAP. Both SynGAP-alpha1 and AIDA-1 are known to bind PSD-95. SIGNOR-264229 0.614 HIPK2 protein Q9H2X6 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser8 MEPAPARsPRPQQDP 9606 19015637 t llicata In response to dna damage, hipk2 phosphorylates pml at serines 8 and 38. he n-terminal phosphorylation sites contribute to the dna damage-induced pml sumoylation and are required for the ability of pml to cooperate with hipk2 for the induction of cell death. SIGNOR-182432 0.449 TLE4 protein Q04727 UNIPROT PAX2 protein Q02962 UNIPROT down-regulates activity binding 9606 BTO:0000007 25631048 t In cell culture, Grg4 suppresses Pax2-mediated transcriptional activation and inhibits phosphorylation of the Pax2 activation domain by WNT signaling and JNK SIGNOR-251710 0.468 USF1 protein P22415 UNIPROT JMJD1C protein Q15652 UNIPROT up-regulates activity binding 9606 BTO:0000759 32034158 t miannu We show that, by direct interaction with USF-1, JMJD1C is recruited to lipogenic promoters. We also show that JMJD1C is phosphorylated at T505 by mammalian target of rapamyci (mTOR) to be recruited to lipogenic genes in response to insulin/feeding. SIGNOR-265167 0.2 TP53INP2 protein Q8IXH6 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates binding 9606 19056683 t gcesareni Tp53inp2 binds to lc3 as well as to lc3-related proteins gabarap and gabarap-like2. SIGNOR-182611 0.589 PTPN11 protein Q06124 UNIPROT NEDD9 protein Q14511 UNIPROT down-regulates activity dephosphorylation 9606 19275884 t miannu In this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L.|These results show that both SH2 domains of SHP-2 are necessary for the interaction with Cas-L.\nIn this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L. Furthermore, our data raise the possibility that Cas-L is a direct substrate for SHP-2, although SHP-2 may inhibit Cas-L phosphorylation indirectly by regulating kinase activity. SIGNOR-277083 0.502 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI glycine zwitterion smallmolecule CHEBI:57305 ChEBI up-regulates quantity precursor of 9606 11802770 t miannu HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. SIGNOR-269691 0.8 EXOSC3 protein Q9NQT5 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-261382 0.967 PAK1 protein Q13153 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser298 RTPGRPLsSYGMDSR 9606 BTO:0001955 12876277 t lperfetto We find that adhesion to fibronectin induces pak1-dependent phosphorylation of mek1 on s298 and that this phosphorylation is necessary for efficient activation of mek1 and subsequent mapk activation. SIGNOR-236002 0.564 TGFBR1 protein P36897 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0001660 9435577 t lperfetto These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells. SIGNOR-227525 0.389 MMP8 protein P22894 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272398 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FGFR1 protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 23405013 t lperfetto Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling SIGNOR-244541 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251628 0.2 MMP3 protein P08254 UNIPROT HAPLN1 protein P10915 UNIPROT down-regulates quantity by destabilization cleavage His31 LDHDRAIhIQAENGP -1 7694569 t miannu Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix. SIGNOR-256330 0.392 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr74 PVYNQPVyNQPVGAA 9606 11390389 t lperfetto C-abl tyrosine kinase binds and phosphorylates phospholipid scramblase 1. Phosphorylation was abolished by mutation of tyr residues tyr(69)/tyr(74) within the tandem repeat sequence (68)vynqpvynqp(77) of plscr1 SIGNOR-86017 0.393 denileukin diftitox smallmolecule SID:125240988 ChEBI IL2RB protein P14784 UNIPROT up-regulates activity chemical activation 9606 15757436 t miannu Denileukin diftitox (DAB389IL-2; Ontak) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells.  SIGNOR-259393 0.8 ABL1 protein P00519 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates activity phosphorylation Tyr194 DVQKSKEyFSKQK -1 20178744 t miannu Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation. SIGNOR-276278 0.395 STON2 protein Q8WXE9 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates quantity binding 9606 26903854 t miannu  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. Furthermore, recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. SIGNOR-264113 0.546 vorinostat chemical CHEBI:45716 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257919 0.8 PAK2 protein Q13177 UNIPROT RPS6 protein P62753 UNIPROT unknown phosphorylation Ser240 RLSSLRAsTSKSESS -1 1985906 t miannu The synthetic peptide AKRRRLSSLRASTSKSESSQK (S6-21) which corresponds to the carboxyl-terminal 21 amino acids of human ribosomal protein S6 was synthesized and tested as a substrate for S6/H4 kinase purified from human placenta. The principal phosphorylation sites were serines in the acidic carboxyl-terminal domain of the peptide. SIGNOR-250233 0.314 MKRN1 protein Q9UHC7 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys291 TEEENLRkKGEPHHE 9606 BTO:0002552 19536131 t miannu Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. K291 and K292 of p53 are required for MKRN1-mediated degradation and ubiquitination of p53 SIGNOR-271846 0.442 IDH complex SIGNOR-C396 SIGNOR NADH smallmolecule CHEBI:16908 ChEBI down-regulates quantity chemical modification 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-268114 0.8 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257908 0.8 PB28 dihydrochloride chemical CID:46861545 PUBCHEM SIGMAR1 protein Q99720 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000093 16891467 t Federica Cyclohexylpiperazine derivative PB28, a σ2 agonist and σ1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer SIGNOR-261111 0.8 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 24877152 f Conversely, a reduced amount of IGF-1R diminished the levels of P-AKT, allowing dissociation and nuclear translocation of Smad3 and enhancement of the TGFŒ≤1 signaling pathway and fibrosis SIGNOR-254375 0.7 ASXL1 protein Q8IXJ9 UNIPROT RXRA protein P19793 UNIPROT up-regulates activity binding 9606 BTO:0000567 16606617 t irozzo In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells. SIGNOR-255911 0.288 CDK5 protein Q00535 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity phosphorylation Ser211 PGKETNEsPWRSDLL 9606 17440046 t llicata Cdk5 phosphorylated gr at multiple serines, including ser203 and ser211 of its n-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to dna.| the effect of CDK5 on GR-induced transcriptional activity is specific to gene promoter, and possibly, to tissue SIGNOR-154405 0.459 SNCA protein P37840 UNIPROT Lewy_body_formation phenotype SIGNOR-PH56 SIGNOR up-regulates 9606 12666095 f lperfetto A key observation linking alpha-synuclein to PD was the demonstration that it is one of the principal components of Lewy bodies. Furthermore, mutant isoforms of alpha-synuclein more readily oligomerize, and it has been suggested that its tendency to aggregate into misfolded structures may confer toxic properties to the protein. SIGNOR-249700 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR RANBP3 protein Q9H6Z4 UNIPROT up-regulates quantity phosphorylation Ser57 HGTGHPEsAGEHALE 9606 BTO:0000007 18280241 t miannu Akt phosphorylates RanBP3 at Serine 58 residue in vitro and in vivo. RanBP3 phosphorylation increases its affinity towards Ran SIGNOR-276150 0.2 JAK2 protein O60674 UNIPROT LEPR protein P48357 UNIPROT up-regulates activity phosphorylation Tyr986 QRQPFVKyATLISNS 9606 BTO:0000007 11018044 t miannu LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2. SIGNOR-263493 0.765 HOXB4 protein P17483 UNIPROT IGFBP1 protein P08833 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12489992 t Luana These data showed that Hox genes selectively activate the transcription of theIGFBP-1 SIGNOR-261636 0.2 PPM1E protein Q8WY54 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 11864573 t The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX. SIGNOR-248760 0.307 PRKD1 protein Q15139 UNIPROT RIN1 protein Q13671 UNIPROT unknown phosphorylation Ser351 RPLLRSMsAAFCSLL 9606 11784866 t llicata Serine 351 is a substrate for protein kinase d (pkd [also known as pkcmu]) in vitro and in vivo. These data suggest that the normal localization and function of rin1, as well as its ability to compete with raf, are regulated in part by 14-3-3 binding, which in turn is controlled by pkd phosphorylation. SIGNOR-113964 0.412 AMPK complex SIGNOR-C15 SIGNOR MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser155 GRLKRERsMSENAVR 9606 BTO:0001938 26816379 t gcesareni A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission. SIGNOR-245948 0.2 CAMKK2 protein Q96RR4 UNIPROT CAMK1 protein Q14012 UNIPROT up-regulates activity phosphorylation Thr177 DPGSVLStACGTPGY 7641687 t llicata Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase. SIGNOR-250716 0.422 vorinostat chemical CHEBI:45716 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257921 0.8 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1015 MMVKRRDyLDLAAST 9606 14981541 t llicata Opn upregulation depended on the integrity of the ret/ptc kinase and tyrosines y1015 and y1062, two major ret/ptc autophosphorylation sites. ret signalling mainly depends on three key tyrosine residues: tyrosine 905, in the activation loop, whose phosphorylation stabilizes the active conformation of the catalytic domain , tyrosine 1015, a docking site for phospholipase citalic gamma and tyrosine 1062. SIGNOR-122915 0.2 CUDC-907 chemical CID:54575456 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252661 0.8 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Ser287 ATAGPKAsPTPQKTS 9606 BTO:0000007 14741103 t llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. SIGNOR-250655 0.415 mTORC1 complex SIGNOR-C3 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates 9606 20670887 f gcesareni Hif1alfa is the transcription factor downstream of mtorc1 in the control of glycolytic genes. SIGNOR-167187 0.368 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation 9606 12591950 t gcesareni Jnk phosphorylates two members of the bh3-only sub of bcl2-related proteins (bim and bmf). SIGNOR-98399 0.75 EZH2 protein Q15910 UNIPROT TWIST1 protein Q15672 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001939 23836662 f miannu We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. SIGNOR-254151 0.336 HNF1A protein P20823 UNIPROT UGT1A1 protein P22309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18172616 f miannu This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities. SIGNOR-254437 0.284 MAPK8 protein P45983 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Ser62 PSWHLADsPAVNGAT 9606 BTO:0001130 12633850 t gcesareni By site-directed mutagenesis studies, we have identified that serine 62 is the necessary site for taxol- or 2-me-induced bcl-xl phosphorylation in prostate cancer cells. Further studies with the inhibitor of jun kinase (jnk) and phosphorylation mutant of bcl-xl reveal the augmentative role of jnk-mediated bcl-xl phosphorylation in apoptosis of prostate cancer cells. In summary, our studies suggest that the phosphorylation of bcl-xl by stress response kinase signaling might oppose the anti-apoptotic function of bcl-xl to permit prostate cancer cells to die by apoptosis SIGNOR-99219 0.771 TRIM13 protein O60858 UNIPROT TRIM13 protein O60858 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 31744379 t miannu  In this study, we showed that the N-degron pathway mediates ubiquitin (Ub)-dependent reticulophagy. During this 2-step process, the ER transmembrane E3 ligase TRIM13 undergoes auto-ubiquitination via lysine 63 (K63) linkage chains and acts as a ligand for the autophagic receptor SQSTM1/p62 (sequestosome 1).  SIGNOR-272219 0.2 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 20966922 f APL cells closely resemble normal promyelocytes, a specific stage of the granulocytic differentiation pathway, suggesting that PML–RARα blocks the normal myeloid differentiation programme. SIGNOR-255724 0.7 gefitinib chemical CHEBI:49668 ChEBI EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258218 0.8 OXGR1 protein Q96P68 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257243 0.2 DNMT3A protein Q9Y6K1 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19786833 f irozzo Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. SIGNOR-255808 0.485 lapatinib chemical CHEBI:49603 ChEBI ERBB2 protein P04626 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258131 0.8 DUSP23 protein Q9BVJ7 UNIPROT GCM1 protein Q9NP62 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser322 NYPFPLTsWPCSFSP 9606 20855292 t lperfetto DUSP23 prevents GCM1 from ubiquitination and prolongs the half-life of GCM1.|Second, DUSP23 is able to dephosphorylate Ser322 in GCM1 in vitro and in a stable cell line expressing HA-GCM1. SIGNOR-276982 0.476 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser465 LKHVTQSsRKLIRAD 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. SIGNOR-129320 0.327 Laminin-8 complex SIGNOR-C181 SIGNOR A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates activity binding 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253220 0.519 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMBRA1 protein Q9C0C7 UNIPROT up-regulates activity phosphorylation Thr1238 ASWDQPGtPGREPTQ 9606 BTO:0000567 37584777 t phosphorylation site remapping based on mass spec table lperfetto CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects. SIGNOR-272967 0.259 H2AC4 protein P04908 UNIPROT Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR form complex binding -1 20498094 t miannu A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. SIGNOR-263724 0.2 NOTCH1 protein P46531 UNIPROT LFNG protein Q8NES3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 f gcesareni Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta. SIGNOR-195621 0.747 CAMK2A protein Q9UQM7 UNIPROT ETS1 protein P14921 UNIPROT down-regulates phosphorylation Ser285 QRVPSYDsFDSEDYP 9606 BTO:0000782 12475968 t lperfetto Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition SIGNOR-96342 0.314 GRK2 protein P25098 UNIPROT ADIPOR1 protein Q96A54 UNIPROT down-regulates quantity by destabilization phosphorylation Ser205 EKVSRTFsKLDYSGI 10090 BTO:0003324 35611695 t miannu . GRK2-induced AdipoR1 endocytosis and degradation were blocked by AdipoR1S205A overexpression. Moreover, AdipoR1S205E (pseudophosphorylation) phenocopied GRK2 effects, promoted AdipoR1 endocytosis and degradation, and inhibited AdipoR1 biological function. SIGNOR-277594 0.2 AVPR1B protein P47901 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256791 0.428 EIF3E protein P60228 UNIPROT MAD2L1 protein Q13257 UNIPROT down-regulates quantity translation regulation 9606 BTO:0000815; BTO:0001938 20453879 f irozzo Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression. SIGNOR-259157 0.265 FUS protein P35637 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates activity sumoylation Lys298 MGVVECAkHELLQPF 9606 BTO:0000007 19946338 t gcesareni Here, we show that Ebp1 p42 isoform can be sumoylated on both K93 and K298 residues, which mediate its nuclear translocation and are required for its anti-proliferative activity €.. Hence, TLS-mediated sumoylation is required for Ebp1 transcriptional repressive activity. SIGNOR-249657 0.342 BMP7 protein P18075 UNIPROT PRDM16 protein Q9HAZ2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18719589 f fspada Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways SIGNOR-180317 0.413 CDKN2A protein P42771 UNIPROT CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR down-regulates binding 9606 8891723 t luana The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-259810 0.803 ROCK1 protein Q13464 UNIPROT MSN protein P26038 UNIPROT up-regulates activity phosphorylation Thr558 LGRDKYKtLRQIRQG 9534 BTO:0000298 9856983 t lperfetto Rho-associated kinase (Rho-kinase), which is activated by the small GTPase Rho, phosphorylates moesin at Thr558 in vitro. Here, using a site- and phosphorylation state-specific antibody, we found that the expression of dominant active RhoA in COS7 cells induced moesin phosphorylation and the formation of microvilli-like structures at apical membranes where the Thr558-phosphorylated moesin accumulated, whereas the expression of dominant negative Rho-kinase inhibited both of these processes. SIGNOR-249014 0.675 TARS1 protein P26639 UNIPROT threonine smallmolecule CHEBI:26986 ChEBI down-regulates quantity chemical modification 9606 25824639 t miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. SIGNOR-270502 0.8 MAPK10 protein P53779 UNIPROT STMN2 protein Q93045 UNIPROT down-regulates phosphorylation Ser73 EAPRTLAsPKKKDLS 9606 11718727 t gcesareni We demonstrate that purified scg10 can be phosphorylated by two subclasses of mitogen-activated protein (map) kinases, c-jun n-terminal/stress-activated protein kinase (jnk/sapk) and p38 map kinase;jnk3/sapkbeta phosphorylation occurs at ser-62 and ser-73, residues that result in reduced microtubule-destabilizing activity for scg10. SIGNOR-112114 0.455 M2_polarization phenotype SIGNOR-PH55 SIGNOR TGFb proteinfamily SIGNOR-PF5 SIGNOR up-regulates 9606 BTO:0000801 32454942 f miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. M2 polarized cells express a variety of anti-inflammatory mediators, such as IL-4, IL-10, and transforming growth factor-β (TGF-β), and contribute to immunoregulation SIGNOR-263824 0.7 ZNRF3 protein Q9ULT6 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates ubiquitination 9606 22575959 t gcesareni Znrf3 is associated with the wnt receptor complex, and inhibits wntby promoting the turnover of frizzled and lrp6. SIGNOR-197417 0.296 GNA12 protein Q03113 UNIPROT ARHGEF11 protein O15085 UNIPROT up-regulates activity binding 9606 11799111 t This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho SIGNOR-256516 0.62 metyrapone chemical CHEBI:44241 ChEBI CYP11B1 protein P15538 UNIPROT down-regulates activity chemical inhibition -1 21129965 t Luana In an effort to develop and evaluate new classes of compounds as CYP inhibitors, we based our investigations on the structure of the well-known CYP inhibitor Metyrapone 2, which has been used for the treatment of hypercortisolism and Cushing’ssyndrome for several decades. SIGNOR-257884 0.8 GCK protein P35557 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266458 0.8 PRKAA2 protein P54646 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Ser181 DQGSLCTsFVGTLQY 9606 SIGNOR-C14 21673972 t lperfetto These results demonstrate that the ikk is a direct substrate of ampk_2 and that its phosphorylation on ser177 and ser181no initiates the activation of the ampk_2 in endothelial cells which in turn phosphorylates and activates the _-subunit of the ikk. The latter also induces a higher rate of ikk auto-inactivation and thus attenuates the activation of nf_b and the expression of inflammatory genes SIGNOR-174405 0.259 ESCRT-III complex SIGNOR-C379 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 26775243 f miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. SIGNOR-265536 0.7 ENG protein P17813 UNIPROT BMP10 protein O95393 UNIPROT up-regulates activity binding 9606 BTO:0003767 21737454 t miannu Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. We found that mouse and human endoglin ECD-Fc bound directly, specifically, and with high affinity to bone morphogenetic proteins 9 and 10 (BMP9 and BMP10) in surface plasmon resonance (Biacore) and cell-based assays. SIGNOR-276657 0.37 ERCC2 protein P18074 UNIPROT ERCC3 protein P19447 UNIPROT up-regulates binding 9606 10024882 t miannu Xpd helps xpb in promoter opening and as such participates in the transcription reaction. SIGNOR-64672 0.954 WNK3 protein Q9BYP7 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates activity phosphorylation Ser382 KRASFAKsVIGTPEF 9606 22032326 t Manara We found that wild-type WNK2 (Figure 8A) or WNK3 (Figure 8B) phosphorylated kinase-inactive WNK1 (1–667, D368A) at Ser382 in vitro. SIGNOR-260789 0.286 MRPL51 protein Q4U2R6 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262337 0.65 TP53 protein P04637 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 15077116 t gcesareni P53 interacts with the pro-apoptotic mitochondrial membrane protein bak SIGNOR-124122 0.678 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MARS1 protein P56192 UNIPROT up-regulates activity phosphorylation Ser209 LQKQPQPsPAEGRAV 9606 BTO:0000567 25097229 t miannu Here, we report that methionyl-tRNA synthetase (MRS) is phosphorylated at Ser209 and Ser825 by extracellular signal-related kinase (ERK1/2) under conditions of stress caused by reactive oxygen species (ROS), and that this phosphorylated MRS shows increased affinity for non-cognate tRNAs with lower affinity for tRNA(Met), leading to an increase in Met residues in cellular proteins.  SIGNOR-276671 0.2 BCR-Ml complex SIGNOR-C434 SIGNOR SYK protein P43405 UNIPROT up-regulates activity binding 9606 32323266 t scontino The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK). SIGNOR-268440 0.703 P2RY11 protein Q96G91 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257261 0.2 CHAF1A protein Q13111 UNIPROT MGMT protein P16455 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 15657354 f miannu Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT. SIGNOR-254569 0.2 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr286 RLEEKVKtLKAQNSE 9606 BTO:0000848 21177766 t lperfetto P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286) SIGNOR-170764 0.271 PPM1F protein P49593 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 31944151 t lperfetto As a result, inactivation of Chk1 by POPX2 leads to impaired G1S checkpoint activation and cells are able to proceed from G1 to S phase despite DNA damage.|We also determined that POPX2 can dephosphorylate Chk1Ser317 and -Ser345 and is a potential regulator of Chk1 function in the cell. SIGNOR-276988 0.2 TFIIH complex SIGNOR-C457 SIGNOR RARA protein P10276 UNIPROT unknown phosphorylation Ser77 EIVPSPPsPPPLPRI 9606 11955452 t llicata Thus, we demonstrate that the cdk7 kinase of tfiih phosphorylates the nuclear receptor, then allowing ligand-dependent control of the activation of the hormone-responsive genes. SIGNOR-269332 0.272 DOCK1 protein Q14185 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 BTO:0001909 25533347 t miannu We found in this study that AUTS2 is involved in Rac1 activation via P-Rex1 and the Elmo2/Dock180 complex, but not STEF or Tiam1, for the lamellipodia formation in N1E-115 cells. However, the enhancement of neurite elongation in primary neurons by AUTS2 expression is specifically mediated by the Elmo2/Dock180 complex. These results suggested that several Rac-GEFs differentially or cooperatively participate in Rac1 activation to promote neuronal migration and neurite outgrowth. SIGNOR-266822 0.724 SCF-SKP2 complex SIGNOR-C136 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000552 9736735 t lperfetto Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21CIP1/WAF1 and cyclin D proteins|These data suggest that the human p19(SKP1)/p45(SKP2)/CUL-1 complex is likely to function as an E3 ligase to selectively target cyclin D and p21 for the ubiquitin-dependent protein degradation. SIGNOR-267556 0.668 TP53 protein P04637 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19879762 t lperfetto As a transcription factor, p53 induces several pro-apoptotic Bcl-2 members including Bax, Puma, Noxa and Bid, and represses the transcription of certain anti-apoptotic genes, including those encoding Bcl-2, Bcl-xL and survivin 3_and_5. SIGNOR-209687 0.263 5-(2-propoxyphenyl)-2,3-dihydrotriazolo[4,5-d]pyrimidin-7-one chemical CHEBI:92215 ChEBI GPR35 protein Q9HC97 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257506 0.8 vandetanib chemical CHEBI:49960 ChEBI RET protein P07949 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258307 0.8 GATA3 protein P23771 UNIPROT CD8A protein P01732 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8413295 f miannu Taken together, these results suggest that the human CD8 alpha gene is regulated by the interaction of multiple T-cell nuclear proteins with a transcriptional enhancer located in the last intron of the gene. Site-directed mutation of the Ets-1 and GATA-3 sites dramatically reduced enhancer activity. SIGNOR-254079 0.311 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269339 0.719 PRKCB protein P05771 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser368 QRPSSRAsSRASSRP 10116 10871288 t lperfetto Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication. SIGNOR-249049 0.396 SIRT2 protein Q8IXJ6 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by stabilization deacetylation Lys594 KEVEDIEkYLEDQVN 9606 BTO:0000007 21726808 t lperfetto Conversely, SIRT2 deacetylates and stabilizes PEPCK1.|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 SIGNOR-267602 0.436 MAPK1 protein P28482 UNIPROT POU5F1 protein Q01860 UNIPROT down-regulates phosphorylation Ser111 ESNSDGAsPEPCTVT 9606 23024368 t miannu We demonstrate that oct4a interacts with erk1/2 by using both in vitro gst pulldown and in vivo co-immunoprecipitation assays. Ms analysis identified phosphorylation of oct4a at ser-111. / serine 111 phosphorylation regulates oct4a protein subcellular distribution and degradation. SIGNOR-192097 0.389 H4C1 protein P62805 UNIPROT BRDT protein Q58F21 UNIPROT up-regulates activity relocalization 9606 acetylation:Lys6;Lys9 kGGKGLGK;SGRGKGGkGLGKGGA 27991587 t lperfetto BRDT interacts with acetylated nucleosomes via its BD1 domain. Binding may be initiated through non-specific interactions with DNA, which allow BRDT to localize to chromatin. Specificity is generated through recognition of tandem acetylated lysine residues (K5ac/K8ac) on the histone H4 tail, SIGNOR-262066 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser824 AVRIRGKsYVQCQGI 9606 10224060 t lperfetto Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins. SIGNOR-244357 0.2 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser323 HCSAEAGsPAMAVLD 9606 16286470 t lperfetto The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain SIGNOR-141601 0.798 SUCLG2 protein Q96I99 UNIPROT Succinyl-CoA GTP variant complex SIGNOR-C399 SIGNOR form complex binding 9606 32627745 t miannu Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS). SIGNOR-266264 0.927 CXCL8 protein P10145 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates binding 9606 11350788 t gcesareni Il-8 activates both the cxcr1 and the cxcr2 on microvascular endothelial cells, using different signal transduction cascades. SIGNOR-107983 0.856 ACP1 protein P24666 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 10090 17353188 t Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3 SIGNOR-248457 0.2 PRKACA protein P17612 UNIPROT PDE3B protein Q13370 UNIPROT unknown phosphorylation Ser442 TPQLRRSsGTSGLLP -1 8163498 t miannu Serine 427 is the target for cAMP-PK phosphorylation of the rat adipocyte cGI-PDE in vitro SIGNOR-250023 0.463 ZNF384 protein Q8TF68 UNIPROT MMP1 protein P03956 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000944 10669742 t Luana Luciferase activity driven by the MMP-1 promoter also increased by 2.5- to 3-fold. In contrast, CIZ had no effect on the luciferase activity from the MMP-1 promoter that was mutated at the CIZ binding consensus sequence. These results show that the CIZ transactivates the MMP-1 promoter through this sequence. SIGNOR-266229 0.312 PRKCA protein P17252 UNIPROT SRF protein P11831 UNIPROT down-regulates phosphorylation Ser162 LRRYTTFsKRKTGIM 10090 16537394 t lperfetto Mimicking phosphorylation of serine-162, a target of protein kinase c-alpha, with an aspartic acid substitution (srf-s162d) completely inhibited srf-dna binding and blocked alpha-actin gene transcription pkc? Highly phosphorylated serine-162. SIGNOR-234461 0.248 ZBTB7A protein O95365 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15662416 f miannu Pokemon can specifically repress the transcription of the tumour suppressor gene ARF through direct binding. SIGNOR-225900 0.374 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 12056906 t esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. SIGNOR-89233 0.458 PPP4C protein P60510 UNIPROT BANF1 protein O75531 UNIPROT up-regulates dephosphorylation Ser4 sQKHRDFV 9606 16495336 t lperfetto Herein, we demonstrate we demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. We have identified the major phosphatase responsible for dephosphorylation of ser-4 to be protein phosphatase 4 catalytic subunit. SIGNOR-144779 0.2 D-glucitol smallmolecule CHEBI:17924 ChEBI HNRNPA1 protein P09651 UNIPROT down-regulates activity relocalization 9606 BTO:0000312 33172210 f We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne SIGNOR-262814 0.8 FBXW7 protein Q969H0 UNIPROT CCDC6 protein Q16204 UNIPROT down-regulates binding 9606 BTO:0000551 23108047 t miannu Fbxw7 interacts with and targets ccdc6 for ubiquitin-mediated proteasomal degradation SIGNOR-199279 0.374 FGFR1 protein P11362 UNIPROT LDHA protein P00338 UNIPROT up-regulates phosphorylation Tyr83 KIVSGKDyNVTANSK 9606 21969607 t gcesareni We found that the oncogenic receptor tyrosine kinase fgfr1 directly phosphorylates ldh-a. Phosphorylation at y10 and y83 enhances ldh-a activity by enhancing the formation of active, tetrameric ldh-a and the binding of ldh-a substrate nadh, respectively. SIGNOR-176734 0.374 ULK1 protein O75385 UNIPROT ENO1 protein P06733 UNIPROT down-regulates activity phosphorylation Ser115 ANAILGVsLAVCKAG 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274030 0.2 MAPK1 protein P28482 UNIPROT TNFRSF1A protein P19438 UNIPROT down-regulates activity phosphorylation Ser274 LAPNPSFsPTPGFTP -1 11606045 t lperfetto Phosphorylation of murine CD120a by p42(mapk/erk2) has been shown to inhibit its ability to initiate apoptosis while preserving signaling events such as NF-kappaB activation.|Additionally, we demonstrated that (i) the p42(mapk/erk2)-dependent phosphorylation of CD120a and DR3 occurred on Ser and Thr residues, (ii) p42(mapk/erk2) phosphorylated residues located in the membrane proximal regions but not the death domains of CD120a and DR3, (iii) Ser 253 is a preferred site of phosphorylation on CD120a SIGNOR-249452 0.514 BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT down-regulates binding 9606 15694340 t gcesareni Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.. Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1 SIGNOR-133823 0.812 CDK2 protein P24941 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates activity phosphorylation Thr611 ETLPISStPSKSVLP BTO:0001938 15024056 t llicata We demonstrated that FoxM1B transcriptional activity requires binding of either S-phase or M-phase Cdk-cyclin complexes to mediate efficient Cdk phosphorylation of the FoxM1B Thr 596 residue, which is essential for recruitment of p300/CBP coactivator proteins. SIGNOR-250731 0.74 FGF2 protein P09038 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates 9606 20974802 f gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription. SIGNOR-168995 0.586 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176793 0.775 PAK2 protein Q13177 UNIPROT MYLK protein Q15746 UNIPROT down-regulates activity phosphorylation Ser1208 MKSRRPKsSLPPVLG -1 10748018 t miannu PAK2 can directly phosphorylate MLCK, inhibiting its activity and limiting the development of isometric tension. PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991. SIGNOR-250222 0.513 CSNK1A1 protein P48729 UNIPROT RAPGEF2 protein Q9Y4G8 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1244 ASLDAADsGRGSWTS 9606 BTO:0002181 24290981 t miannu Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-β and casein kinase-1α and consequently degraded by the proteasome via the SCF(βTrCP) ubiquitin ligase. SIGNOR-276605 0.2 SHMT1 protein P34896 UNIPROT 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI up-regulates quantity chemical modification 9606 11802770 t miannu HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. SIGNOR-269688 0.8 EEF2K protein O00418 UNIPROT EEF2 protein P13639 UNIPROT down-regulates phosphorylation Thr57 RAGETRFtDTRKDEQ 9606 BTO:0000007 12194824 t gcesareni The activation of eef2 kinase by ampk, resulting in the phosphorylation and inactivation of eef2, provides a novel mechanism for the inhibition of protein synthesis. SIGNOR-91751 0.78 ALOX5 protein P09917 UNIPROT leukotriene A4 smallmolecule CHEBI:15651 ChEBI up-regulates chemical modification 9606 11751058 t gcesareni 5-lipoxygenase catalyzes the production of leukotriene (lt) a4, from 5- hydroperoxyeicosatetraenoic acid (5-hpete) as well as the nitial oxidation of arachidonic acid to this hydroperoxy in-termediate SIGNOR-113198 0.8 Scribble_complex_DLG4-LLGL2_variant complex SIGNOR-C505 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 f miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270890 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation 9606 20230789 t inferred from 70% family members lperfetto Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity SIGNOR-270203 0.2 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-252704 0.784 TBK1 protein Q9UHD2 UNIPROT REL protein Q04864 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C68 16888014 t miannu The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel. SIGNOR-148623 0.565 SRC protein P12931 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity phosphorylation Tyr325 AISEELPySEYFEYF -1 30317579 t miannu C-Src also phosphorylated three tyrosine sites of HDAC3 at tyrosine 325, 328, and 331. Importantly, wild-type c-Src increases HDAC3 activity, but not mutant c-SrcK298M (kinase inactive form).  SIGNOR-277484 0.394 MAP3K11 protein Q16584 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates phosphorylation Thr277 LAREWHKtTQMSAAG 9606 11053428 t gcesareni These residues within the activation loop are critical for mlk-3 autophosphorylation and activation. In addition, when the thr277 and ser281 residues were mutated to negatively charged glutamic acid to mimic phosphorylated serine/threonine residues, the resulting mutants were fully functional, implying that these two residues may serve as the autophosphorylation sites. SIGNOR-83411 0.2 INS protein P01308 UNIPROT APOB protein P04114 UNIPROT down-regulates quantity by destabilization 9606 23721961 f miannu Insulin decreases ApoB secretion by promoting ApoB degradation in the hepatocyte. Though insulin does not alter ApoB mRNA levels, it inhibits ApoB translation by promoting the trafficking of ApoB mRNA into P-bodies, aggregates of translationally repressed mRNAs SIGNOR-252114 0.487 CDX2 protein Q99626 UNIPROT VIL1 protein P09327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19371634 f miannu We concluded that cdx2 regulates intestinal villin expression through recruiting brm-type swi/snf complex to the villin promoter. SIGNOR-185486 0.347 GSN protein P06396 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR down-regulates quantity binding 9606 BTO:0000132 27871158 t lperfetto Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step. SIGNOR-261835 0.7 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MITF protein O75030 UNIPROT down-regulates phosphorylation Ser409 HGLSLIPsTGLCSPD 9606 21749389 t The effect has been demonstrated using O75030-9 gcesareni The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73, whereas serine 409 serves as a substrate for p90 rsk-1. An unphosphorylatable double mutant at these two residues is at once profoundly stable and transcriptionally inert. SIGNOR-252795 0.2 MMP23B protein O75900 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272390 0.7 PTPN2 protein P17706 UNIPROT STAT5B protein P51692 UNIPROT down-regulates activity dephosphorylation 9606 12359225 t miannu In the previous study, we demonstrated that the nuclear isoform of T-cell protein-tyrosine phosphatase (TC-PTP) dephosphorylated and deactivated signal transducer and activator of transcription 5a (STAT5a) and STAT5b, thereby negatively regulating prolactin (PRL)-mediated signaling pathway. SIGNOR-277126 0.722 PRKACA protein P17612 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 17959673 t lperfetto In this study, we demonstrate that the phosphorylation of p50 and p65 by the catalytic subunit of protein kinase a (pkac) is essential for nf-kappab dna binding and transactivation activity. treatment with h89 and knockdown of pkac in cells led to the inhibition of phosphorylation at p50 ser(337) and p65 ser(276) and loss of dna binding by nf-kappab. SIGNOR-217391 0.492 CARM1 protein Q86X55 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates methylation 10090 BTO:0001103 29163212 t FFerrentino The first evidence alluding to a role of PRMTs in mediating skeletal muscle plasticity, specifically myogenesis, arose from the identification of CARM1 as a glucocorticoid receptor-interacting protein 1 (GRIP1) binding protein. (Chen et al., 2000). Here, GRIP1 and MEF2 were co-expressed in the nucleus during skeletal muscle differentiation. These initial findings led to an investigation that revealed that this methyltransferase was responsible for coactivating the transcription of myocyte enhancer factor-2C (MEF2C) via GRIP1  SIGNOR-255964 0.396 SKOR1 protein P84550 UNIPROT LBX1 protein P52954 UNIPROT down-regulates activity binding 9606 BTO:0000007 15528197 t llicata Furthermore, Corl1 interacted with Lbx1 and cooperatively repressed transcription, suggesting that it acts as a transcriptional corepressor for Lbx1 in regulating cell fate determination in the dorsal spinal cord. SIGNOR-238004 0.574 RAF1 protein P04049 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser222 LIDSMANsFVGTRSY 9606 BTO:0000975 10359597 t lperfetto Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 ras activation leads to raf and subsequently mek activation. Phospholipide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-235991 0.738 AMPK complex SIGNOR-C15 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 20640476 t lperfetto The decreased glycogen synthesis rates upon acute AMPK activation are generally coupled to an increase in the glycolytic flux, thanks to the activation of 6-phosphofructo-2-kinase (PFK-2) through direct phosphorylation on Ser466 [35]. PFK-2 catalyzes the synthesis of fructose 2,6-bisphosphate, a potent stimulator of glycolysis. Therefore, activation of AMPK rapidly mobilizes glucose into ATP-generating processes. SIGNOR-209947 0.392 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000007 14761950 t The effect has been demonstrated using P10636-8 lperfetto Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells. SIGNOR-121713 0.381 PDPK1 protein O15530 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates activity phosphorylation Thr779 LYKEATStFTNITYR -1 10896934 t miannu PDK1 specifically phosphorylates Thr-753 in 3. Our data argue that phosphorylation of Thr-753, which is conserved in many subunits, reduces the ability of PTB-containing proteins to bind the NXX(pY) motif in 3. SIGNOR-250266 0.45 GAMT protein Q14353 UNIPROT Neuron_maturation phenotype SIGNOR-PH169 SIGNOR up-regulates -1 26319512 f Luana GAMT enzyme (EC#2.1.1.2) deficiency caused by mutations in the GAMT gene (MIM# 601240) results in the depletion of creatine and accumulation of guanidinoacetate (GAA). Creatine has a buffering and transport function of high-energy phosphates in brain and muscle and is essential for growth cone migration, dendritic and axonal elongation, neurotransmitter release, and co-transmission on gamma amino butyric acid (GABA) postsynaptic receptors in the central nervous system SIGNOR-265794 0.7 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MCM4 protein P33991 UNIPROT down-regulates phosphorylation Ser32 RSEDARSsPSQRRRG 9606 BTO:0000567 12714602 t lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. SIGNOR-217344 0.686 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000944 21415216 t irozzo We also found that phosphorylation of both the mitogen-activated proteinkinase (MAPK) ERK and STAT3 was markedly increased inthe cells expressing either variant of EML4-ALK[.]. Oncogenic EML4-ALK tyrosine kinase activates ERKand STAT3 signaling pathways SIGNOR-259174 0.2 MAPK1 protein P28482 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates activity phosphorylation -1 12556484 t done miannu We found that Nudel and NudE were also phosphorylated in M phase (Fig. ​(Fig.22 and ​and3).3). First, Nudel and NudE were specifically phosphorylated in M phase. Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro.Due to conservation of the S/TP motifs, NudE may also be phosphorylated at similar sites by these kinases, though it contains an additional potential Cdk site at S282 (SPNR). SIGNOR-274078 0.382 PTPRO protein Q16827 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr1248 PTAENPEyLGLDVPV 9606 27345410 t lperfetto In this study, our co-immunoprecipitation experiment along with the results derived from in vivo , cultured cells and clinical specimen confirm that PTPRO dephosphorylates ERBB2 at Y1248.|PTPRO overexpression remarkably accelerated degradation of ERBB2 (XREF_FIG). SIGNOR-276979 0.412 PPP2R2A protein P63151 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates activity binding 9606 19114990 t lperfetto Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity SIGNOR-217875 0.91 ANAPC2 protein Q9UJX6 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 t lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. SIGNOR-252002 0.871 YAP1 protein P46937 UNIPROT TOP2A protein P11388 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 f lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. SIGNOR-276570 0.2 AURKA protein O14965 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 10090 12234980 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni In the present study, chromosome number instability and increased tumor invasiveness were noted in constitutively AIM-1-overexpressing cells in vivo. Increased mitotic Ser-10 phosphorylation was also observed in various colorectal tumor cells with high AIM-1 expression levels. These data suggest that increased H3 histone phosphorylation as a result of AIM-1 overexpression is a major precipitating factor of chromosome instability and, thus, may play a role in carcinogenesis. SIGNOR-118886 0.2 SRGAP3 protein O43295 UNIPROT RAC3 protein P60763 UNIPROT down-regulates 9606 12447388 f miannu Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo. SIGNOR-95964 0.539 TNF protein P01375 UNIPROT SCN1A protein P35498 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253487 0.26 PRKCA protein P17252 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser21 KEEPKRRsARLSAKP 9606 10739259 t lperfetto Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools. SIGNOR-76282 0.312 Calcineurin complex SIGNOR-C155 SIGNOR DNM2 protein P50570 UNIPROT unknown dephosphorylation Ser764 LQSASSHsPTPQRRP 10116 20496096 t CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII). SIGNOR-252317 0.269 CDK14 protein O94921 UNIPROT CCNY protein Q8ND76 UNIPROT down-regulates quantity by destabilization phosphorylation Ser71 RASTIFLsKSQTDVR 9606 BTO:0000599 24794231 t lperfetto Phosphorylation of cyclin Y by CDK14 induces its ubiquitination and degradation|Phosphorylation of CCNY at Serines 71 and 73 creates a putative phospho-degron that controls its association with an SCF complex SIGNOR-273008 0.824 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser386 DDKITQAsQSQESED 9606 BTO:0000007 19816404 t lperfetto These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination SIGNOR-188408 0.746 AMPK complex SIGNOR-C15 SIGNOR PIKFYVE protein Q9Y2I7 UNIPROT up-regulates activity phosphorylation Ser307 PARNRSAsITNLSLD -1 23905686 t miannu AMPK phosphorylated PIKfyve at Ser307 both in vitro and in intact cells. We propose that PIKfyve activity is required for the stimulation of skeletal muscle glucose uptake by contraction/AMPK activation. PIKfyve is a new AMPK substrate whose phosphorylation at Ser307 could promote PIKfyve translocation to endosomes for PtdIns(3,5)P2 synthesis to facilitate GLUT4 (glucose transporter 4) translocation. SIGNOR-263031 0.2 COPS5 protein Q92905 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 27866850 t Barakat The results suggested that TNF-α upregulates expression of CSN5, which interacts and deubiquitinates PD-L1 for protein stabilization. SIGNOR-274977 0.2 IDH2 protein P48735 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI down-regulates quantity 9606 26178471 t lperfetto Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG) SIGNOR-253136 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 BTO:0000567 17615152 t lperfetto In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo. SIGNOR-244655 0.2 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269348 0.719 linifanib chemical CHEBI:91435 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258243 0.8 AURKA protein O14965 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 10090 12234980 t gcesareni In the present study, chromosome number instability and increased tumor invasiveness were noted in constitutively AIM-1-overexpressing cells in vivo. Increased mitotic Ser-10 phosphorylation was also observed in various colorectal tumor cells with high AIM-1 expression levels. These data suggest that increased H3 histone phosphorylation as a result of AIM-1 overexpression is a major precipitating factor of chromosome instability and, thus, may play a role in carcinogenesis. SIGNOR-265356 0.2 TAF1 protein P21675 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263932 0.877 RAB6B protein Q9NRW1 UNIPROT VPS13B protein Q7Z7G8 UNIPROT down-regulates activity binding 9606 BTO:0000007 25492866 t miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 Golgi Localization Is Mediated by Active RAB6 . COH1 Interacts with All Three Mammalian RAB6 Homologues SIGNOR-269205 0.2 mTORC2 complex SIGNOR-C2 SIGNOR FUS protein P35637 UNIPROT down-regulates activity 9606 BTO:0000007 33082139 f When mTORC2 is inhibited, FUS is recruited to polyribosomes to promote translation inhibition and polyribosome stalling. Panel iv, ALS-FUS R521G and P525L mutants that localize more prominently to the cytoplasm also associate more abundantly with polyribosomes to inhibit translation and protein synthesis. SIGNOR-262819 0.298 SYP protein P08247 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates quantity binding 9606 17331077 t miannu Synaptophysin I interacts with VAMP2 and controls its subcellular distribution. On the SV membrane, VAMP2 is engaged in a complex with synaptophysin I, which is mutually exclusive with the formation of fusogenic SNARE complexes. This model implicates synaptophysin I in escorting VAMP2 to the sites where exocytosis must take place exclusively after the arrival of the appropriate stimulus. We show that, at early stages along the secretory pathway, synaptophysin I directs sorting of VAMP2 to vesicles exhibiting limited availability for constitutive exocytosis. SIGNOR-264102 0.618 INSR protein P06213 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation Tyr371 TQEQYELyCEMGSTF 10090 BTO:0000944 11997497 t Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation. SIGNOR-251304 0.507 SIRT6 protein Q8N6T7 UNIPROT TNF protein P01375 UNIPROT up-regulates deacetylation Lys19 LAEEALPkKTGGPQG 9606 23552949 t gcesareni Sirt6 regulates tnf-alfa secretion through hydrolysis of long-chain fatty acyl lysine SIGNOR-201658 0.32 Laminin-10 complex SIGNOR-C182 SIGNOR Laminin-10 complex SIGNOR-C182 SIGNOR up-regulates activity binding 10090 BTO:0001086 18757303 t lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. SIGNOR-253277 0.715 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates activity phosphorylation Ser700 FGEKRKNsILNPINS -1 1377674 t miannu CFTR is phosphorylated directly by PKA and PKC in vivo. phosphorylation by PKA is necessary to allow ATP hydrolysis by CFTR and that ATP hydrolysis is necessary for channel opening. CF-2 was phosphorylated by PKA in vitro on serines 660,700, 737, 813 and most likely on both serines 768 and 795. SIGNOR-250348 0.467 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 8702662 t lperfetto A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function SIGNOR-42968 0.797 phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266533 0.8 ALDOC protein P09972 UNIPROT glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266485 0.8 N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-(2,6-dimethoxyphenoxy)ethanamine chemical CHEBI:64098 ChEBI ADRA1B protein P35368 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258466 0.8 PIM2 protein Q9P1W9 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10837473 t gcesareni Similar to pim1, pim2 phosphorylates bad, which antagonizes the pro-apoptotic function of bax SIGNOR-78015 0.4 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216389 0.885 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266477 0.8 RPL8 protein P62917 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262453 0.853 CSDE1 protein O75534 UNIPROT FOS protein P01100 UNIPROT down-regulates quantity post transcriptional regulation 10090 BTO:0000944 15314026 t By testing different classes of mammalian poly(A) nucleases, we identified CCR4 as a poly(A) nuclease involved in the mCRD-mediated rapid deadenylation in viv SIGNOR-261145 0.299 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Thr357 FELRKTQtSMSLGTT 10090 24012422 t gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays SIGNOR-266429 0.743 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD2 protein Q15796 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 11016919 t lperfetto The ability of smurf2 to promote smad2 destruction required the hect catalytic activity of smurf2 and depended on the proteasome-dependent pathway. SIGNOR-253263 0.2 L-isoprenaline chemical CHEBI:6257 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257456 0.8 Helicase protein P0DTD1-PRO_0000449630 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 9606 BTO:0000007 32979938 t miannu We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F). SIGNOR-262511 0.2 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr474 VLLVNRHyAKISDFG 9606 BTO:0000661 9685404 t lperfetto We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck SIGNOR-249375 0.602 PRKCD protein Q05655 UNIPROT CYBA protein P13498 UNIPROT up-regulates phosphorylation Thr147 ERPQIGGtIKQPPSN -1 19948736 t Manara Phosphorylation of p22phox on threonine 147 enhances NADPH oxidase activity by promoting p47phox binding. | Threonine 147 of p22phox Is Phosphorylated by PKC-α and PKC-δ in Vitro SIGNOR-260892 0.2 GSK3A protein P49840 UNIPROT UNG protein P13051 UNIPROT down-regulates quantity by destabilization phosphorylation Ser64 EPGTPPSsPLSAEQL 9606 BTO:0000812 27875297 t lperfetto Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation SIGNOR-264886 0.2 GSK3B protein P49841 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization phosphorylation Thr286 EEVDLACtPTDVRDV 9606 phosphorylation:Ser9 SGRPRTTsFAESCKP 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245437 0.775 MKX protein Q8IYA7 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001592 33115953 t miannu MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2). SIGNOR-267215 0.306 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 t miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. SIGNOR-264925 0.8 MAD2L1 protein Q13257 UNIPROT MCC complex SIGNOR-C382 SIGNOR form complex binding 9606 BTO:0000567 25092294 t miannu The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. SIGNOR-265973 0.963 GlyR proteinfamily SIGNOR-PF62 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18721822 t miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. SIGNOR-264984 0.8 NR2F2 protein P24468 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14739255 f gcesareni Gralpha, but not grbeta, enhanced coup-tfii-induced transactivation of the simple coup-tfii-responsive 7alpha-hydroxylase promoter through the transcriptional activity of its activation function-1 domain, whereas coup-tfii repressed gralpha-induced transactivation of the glucocorticoid-responsive promoter by attracting the silencing mediator for retinoid and thyroid hormone receptors. SIGNOR-121419 0.358 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1D protein P25100 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257452 0.8 MAPK1 protein P28482 UNIPROT IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation Ser64 QAATGFGsPLQYSAD -1 15133517 t miannu We tested the transcriptional properties of Irx2 by dividing it into amino- and carboxy terminal parts and found that Mek1-mediated phosphorylation activates and derepresses the amino and carboxyl parts, respectively. When Ser46 and Ser65 were mutated to alanine (S46A and S65A), phosphorylation was reduced, whereas substitution of Ser83 and Ser103 (S83A and S103A) did not affect phosphorylation. SIGNOR-263053 0.2 metformin chemical CHEBI:6801 ChEBI PCK1 protein P35558 UNIPROT down-regulates quantity 9606 17909097 f gcesareni In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp. SIGNOR-158062 0.8 PPM1D protein O15297 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates dephosphorylation Ser395 SQESEDYsQPSTSSS 9606 17936559 t gcesareni Wip1 interacts with and dephosphorylates mdm2 at serine 395, a site phosphorylated by the atm kinase. Dephosphorylated mdm2 has increased stability and affinity for p53, facilitating p53 ubiquitination and degradation. SIGNOR-158328 0.668 NFIA protein Q12857 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268896 0.2 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI up-regulates quantity precursor of 9606 15953811 t miannu The Œ±-ketoglutarate‚Äìdehydrogenase complex is a complex including multiple copies of three proteins: E1k (Œ±-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. SIGNOR-266253 0.8 GRK6 protein P43250 UNIPROT GRK6 protein P43250 UNIPROT unknown phosphorylation Ser484 VLDIEQFsTVKGVEL 9534 BTO:0000298 10334944 t GRK6 Is Autophosphorylated in COS-7 Cells. GRK6, like GRK5, is autophosphorylated on Ser484 and Thr485. Whether the autophosphorylation of GRK6 modulates its activity remains however to be established. SIGNOR-251211 0.2 FIZ1 protein Q96SL8 UNIPROT NRL protein P54845 UNIPROT up-regulates activity binding 9913 12566383 t miannu Interaction of Fiz1 and NRL-leucine zipper was validated by GST pulldown assays and co-immunoprecipitation from bovine retinal nuclear extracts. Fiz1 suppressed NRL- but not CRX-mediated transactivation of rhodopsin promoter activity in transiently transfected CV1 cells. SIGNOR-223796 0.566 PASK protein Q96RG2 UNIPROT PASK protein Q96RG2 UNIPROT up-regulates activity phosphorylation Thr1165 LFYTFCGtIEYCAPE -1 11459942 t lperfetto We present evidence that the activity of pask is regulated by two mechanisms. Autophosphorylation at two threonine residues located within the activation loop significantly increases catalytic activity. SIGNOR-109485 0.2 GLI3 protein P10071 UNIPROT MED12 protein Q93074 UNIPROT down-regulates binding 9606 17000779 t gcesareni We propose that activated gli3 physically targets med12 in mediator to reverse mediator-dependent suppression of shh target gene (i.e., Gli1 or cyclin d1) transcription. SIGNOR-149876 0.519 TCL1B protein O95988 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t lperfetto In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation. SIGNOR-244452 0.662 TNFRSF17 protein Q02223 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 10903733 f miannu Overexpression of bcma activates the p38 mapk SIGNOR-79504 0.268 BACH1 protein O14867 UNIPROT HMOX1 protein P09601 UNIPROT down-regulates quantity transcriptional regulation 9606 14747657 t These results indicate that ho-1 regulation involves a competition between the activator Nrf2 and the Bach1 repressor for interactions with the small Maf proteins. SIGNOR-259336 0.369 GGCX protein P38435 UNIPROT PROS1 protein P07225 UNIPROT up-regulates activity carboxylation 9606 28125048 t lperfetto Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z SIGNOR-265924 0.598 PLK1 protein P53350 UNIPROT TP73 protein O15350 UNIPROT down-regulates phosphorylation Thr27 SSLEPDStYFDLPQS 9606 18418051 t llicata P73-mediated transcriptional activity is negatively regulated by polo-like kinase 1. tap73 is phosphorylated by this kinase on threonine-27 (thr-27) within the ta domain. SIGNOR-178253 0.489 LMX1A protein Q8TE12 UNIPROT CUX2 protein O14529 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 30770393 t miannu Lmx1a drives Cux2 expression in the cortical hem through activation of a conserved intronic enhancer. Lmx1a knockdown abolishes activation of the Cux2 enhancer in the cortical hem SIGNOR-263961 0.289 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr784 MYGSGSRtPMYGSQT 9606 16427012 t lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif SIGNOR-143927 0.768 Elongator complex complex SIGNOR-C466 SIGNOR TUBA1C protein Q9BQE3 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 t miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. SIGNOR-269720 0.257 MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 SIGNOR-C2 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-134185 0.928 dabrafenib chemical CHEBI:75045 ChEBI CDK16 protein Q00536 UNIPROT down-regulates activity chemical inhibition 9606 29112787 t Monia We have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and our studies suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations. We confirmed NEK9 to be a potent target of dabrafenib by in vitro kinase assays, with inhibition of NEK9 observed in the single-digit nanomolar range. SIGNOR-261073 0.8 DYRK1A protein Q13627 UNIPROT CCNL2 protein Q96S94 UNIPROT unknown phosphorylation Ser369 AKKAKADsPVNGLPK 9534 BTO:0000298 14623875 t llicata DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. | Three phosphoserines were identified in the slower migrating bands (Fig. 9; Ser-330, Ser-338, and Ser-369). All of these serine residues are located N-terminal of proline residues, consistent with our previous classification of DYRK1A as a “proline-directed” kinase. SIGNOR-251089 0.589 RAPGEF6 protein Q8TEU7 UNIPROT HRAS protein P01112 UNIPROT up-regulates guanine nucleotide exchange factor 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-183796 0.342 p38 proteinfamily SIGNOR-PF16 SIGNOR DDIT3 protein P35638 UNIPROT up-regulates activity phosphorylation -1 8650547 t Luana Stress-Induced Phosphorylation and Activation of the Transcription Factor CHOP (GADD153) by p38 MAP Kinase SIGNOR-260724 0.2 TACR3 protein P29371 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257179 0.2 NMBR protein P28336 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257315 0.252 RAD21 protein O60216 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates activity relocalization 9606 BTO:0001545 26607380 t miannu Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity. SIGNOR-261514 0.287 CIITA protein P33076 UNIPROT HLA-DOA protein P06340 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11823510 f Class II transactivator is required for maximal expression of HLA-DOB in B cells|HLA-DO, encoded by the HLA-DOA and HLA-DOB genes, has been shown to function as a modulator of Ag presentation. DNA microarray comparisons between B cells wild-type and mutant for the master regulator of MHC class II transcription, class II transactivator (CIITA), identified HLA-DOA and HLA-DOB as being up-regulated by CIITA. SIGNOR-254005 0.341 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation 9606 22621922 t gcesareni The kinase vrk1 is activated by dna double strand breaks induced by ionizing radiation (ir) and specifically phosphorylates 53bp1 in serum-starved cells. SIGNOR-197622 0.869 MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 SIGNOR-C2 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-252599 0.928 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser676 SNGRRKRsPTQSFRF 9606 15657420 t esanto We demonstrate that p90 ribosomal s6 kinase (rsk) is recruited to the nfat-dna transcription complex upon activation.Bound Rsk phosphorylates ser(676) and potentiates nfatc4 dna binding. Ser(676) is also targeted by the erk map kinase. SIGNOR-133283 0.393 CDK1 protein P06493 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Thr287 SAASNTGtPDGPEAP 9606 15125835 t lperfetto T287 is phosphorylated by cdk1 during mitosis. Phosphorylation of nir2 by cdk1 facilitates its dissociation from the golgi apparatus, and phospho-nir2(ps382) is localized in the cleavage furrow and midbody during cytokinesis. SIGNOR-124642 0.477 ATM protein Q13315 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Ser140 GKKATQAsQEY 9606 18158901 t gcesareni H2ax interacts with numerous proteins required for dna damage signaling and repair when phosphorylated on ser-140. Phosphorylation of ser-140 (h2ax139ph) in response to ionizing radiation is mediated by both atm and prkdc. Our data showed that h2ax is phosphorylated by uva-activated jnk. SIGNOR-160206 0.2 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0003316 11777913 t miannu 4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E. SIGNOR-250099 0.444 LCK protein P06239 UNIPROT ADAM15 protein Q13444 UNIPROT up-regulates phosphorylation Tyr715 LVMLGASyWYRARLH 9606 BTO:0000661 11741929 t lperfetto Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling. SIGNOR-112931 0.356 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 BTO:0000007 9724739 t gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 SIGNOR-244982 0.741 serotonin smallmolecule CHEBI:28790 ChEBI HTR3E protein A5X5Y0 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264291 0.8 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1626 SPSYSPTsPSYSPTS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248805 0.849 PRKCG protein P05129 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 11123317 t lperfetto Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5.  SIGNOR-249074 0.348 PPP1R3A protein Q16821 UNIPROT GYS1 protein P13807 UNIPROT up-regulates dephosphorylation 9606 BTO:0000887;BTO:0001103 8250835 t gcesareni In skeletal muscle, the activation of glycogen synthase by insulin involves the dephosphorylation of serine residues that are phosphorylated by gsk3 and dephosphorylated by the glycogen-associated form of protein phosphatase-l (pp1g). SIGNOR-37301 0.492 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 BTO:0000938 21106647 f miannu Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. SIGNOR-268387 0.7 CSNK1E protein P49674 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 12000790 t gcesareni However, ck1epsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the beta-catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated ck1epsilon as a candidate s45-kinase in several assays, both in vitro and in vivo. SIGNOR-87448 0.643 MAPK1 protein P28482 UNIPROT MYB protein P10242 UNIPROT unknown phosphorylation Ser532 KIKQEVEsPTDKSGN -1 8960373 t lperfetto Functional analysis of phosphorylation at serine 532 of human c-Myb by MAP kinase| Expression of a constitutively active form of Ras together with c-Myb in transient transfection experiments had no effect on the transcriptional activity of c-Myb, while expression of a polypeptide containing the c-Myb C-terminal domain stimulated c-Myb activity. This effect is reduced upon MAPK-dependent phosphorylation of serine 532. SIGNOR-249420 0.491 YAP1 protein P46937 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates binding 9606 22153608 t Regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation. gcesareni Here we show that the endogenous yes-associated protein (yap), a mediator of src/yes signaling, interacts with the native runx2 protein, an osteoblast-related transcription factor, and suppresses runx2 transcriptional activity in a dose-dependent manner. SIGNOR-195221 0.461 BECN1 protein Q14457 UNIPROT USP13 protein Q92995 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0003704 21962518 t Giulio We found that endogenous Beclin1 can interact with USP13 and the interaction was reduced in the presence of spautin-1 (Figure 5C). Interestingly, the DUB activities were significantly increased when USP13 and USP10 coincubated together or with Beclin1 or all 3 proteins together, suggesting the DUB activity can be significantly enhanced when USP13 interacts with its substrate Beclin1 or USP10. SIGNOR-260296 0.511 AKT1 protein P31749 UNIPROT IMPDH2 protein P12268 UNIPROT up-regulates activity phosphorylation 9534 BTO:0004055 10930578 t Federica Further, we have demonstrated an in vivo association of IMPDH and PKB/Akt by co‐immunoprecipitation from COS cells expressing a constitutively active form of PKB/Akt. Finally, we were able to show that this constitutively active PKB/Akt could phosphorylate IMPDH in vitro. Thus, the interplay between PKB/Akt and IMPDH reported here could suggest that PKB/Akt activation leads to IMPDH type II activation which in turn prepares the cell for entry into S phase. SIGNOR-261262 0.394 KCNC4 protein Q03721 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 11506885 t miannu Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height SIGNOR-265588 0.8 PRKCQ protein Q04759 UNIPROT RASGRP3 protein Q8IV61 UNIPROT up-regulates phosphorylation Thr133 YDWMRRVtQRKKVSK 9606 BTO:0000776 15545601 t lperfetto Activation of rasgrp3 by phosphorylation of thr-133 is required for b cell receptor-mediated ras activation. our data suggest that pkc, after being activated by diacylglycerol, phosphorylates rasgrp3, thereby contributing to its full activation. SIGNOR-130490 0.334 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SCNN1B protein P51168 UNIPROT down-regulates quantity by destabilization phosphorylation -1 11805112 t inferred from 70% family members lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. SIGNOR-270163 0.2 MTMR1 protein Q13613 UNIPROT 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate(5-) smallmolecule CHEBI:57923 ChEBI down-regulates quantity chemical modification 9606 18429927 t miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns SIGNOR-269804 0.8 FBXO11 protein Q86XK2 UNIPROT BCL6 protein P41182 UNIPROT down-regulates binding 9606 BTO:0000785 22113614 t miannu Fbxo11 targets bcl6 for degradation SIGNOR-177652 0.504 WASL protein O00401 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000567 20498093 t lperfetto Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes. SIGNOR-261003 0.781 SOCS1 protein O15524 UNIPROT IFNGR1 protein P15260 UNIPROT down-regulates binding 9606 18708154 t gcesareni Suppressor of cytokine signaling (socs)-1, the key negative regulator of interferon (ifn)-gamma-dependent signaling, is induced in response to ifngamma. Socs-1 binds to and inhibits the ifngamma receptor-associated kinase janus-activated kinase (jak) 2 and inhibits its function in vitrothe binding of socs-1 to tyr441 also blocks the access of stat1 to tyr419 and that this effect may be the principal mechanism of inhibition of downstream signaling SIGNOR-180140 0.661 ANXA3 protein P12429 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates activity 9606 BTO:0000018 27995049 f miannu We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells. SIGNOR-262213 0.2 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser44 KKSKISAsRKLQLKT 9606 15769444 t lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. SIGNOR-134617 0.349 Y-27632 chemical CHEBI:75393 ChEBI ROCK2 protein O75116 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207893 0.8 ELANE protein P08246 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Ala86 PLQKQLPaFISEDAS -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. SIGNOR-263566 0.441 TM9SF4 protein Q92544 UNIPROT ATP6V1H protein Q9UI12 UNIPROT up-regulates activity binding 9606 BTO:0001109;BTO:0000038 25659576 t miannu Here, we demonstrate that TM9SF4 represents a novel V-ATPase-associated protein involved in V-ATPase activation. We have observed in HCT116 and SW480 colon cancer cell lines that TM9SF4 interacts with the ATP6V1H subunit of the V-ATPase V1 sector. Suppression of TM9SF4 with small interfering RNAs strongly reduces assembly of V-ATPase V0/V1 sectors, thus reversing tumor pH gradient with a decrease of cytosolic pH, alkalization of intracellular vesicles and a reduction of extracellular acidity. SIGNOR-266885 0.274 CBX4 protein O00257 UNIPROT ZEB2 protein O60315 UNIPROT down-regulates activity sumoylation 9606 BTO:0000007 16061479 t miannu Polycomb protein Pc2 acts as an SUMO E3 ligase for SIP1. SIP1 is an active transcription repressor for many transcription factors and target genes. SIP1 Sumoylation Disrupts the Recruitment of the Corepressor CtBP SIGNOR-225481 0.337 CAMK2G protein Q13555 UNIPROT SPR protein P35270 UNIPROT unknown phosphorylation Ser213 QQLARETsVDPDMRK 11825621 t llicata Phosphorylation sites of rat sepiapterin reductase (rSPR) by Ca2+/calmodulin-dependent protein kinase II were determined in the present study. Using specific monoclonal anti-phospho-Ser and -Thr antibodies, we found that only Ser residues of rSPR were phosphorylated. We constructed several point mutants of SPR by systematically replacing the three Ser residues by Ala ones. These mutants showed that all three Ser residues, i.e. S46, S196, and S214, of rSPR were phosphorylated. We also recognized that only Ser-213 of human SPR was phosphorylated.  SIGNOR-250705 0.312 NOG protein Q13253 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates activity binding 9606 BTO:0001593 BTO:0000140 22298955 t lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptorsNoggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors (pmid 12478285) SIGNOR-192799 0.595 HMOX2 protein P30519 UNIPROT heme smallmolecule CHEBI:30413 ChEBI down-regulates quantity chemical modification 9606 10490932 t Regulation miannu Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme SIGNOR-251912 0.8 EIF2S1 protein P05198 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 31226023 f miannu Activated PERK phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α), which inhibits the conversion of inactive GDP-bound eIF2α back to the active GTP-bound form, thereby suppressing translation initiation.The resulting global attenuation of protein synthesis reduces the ER protein influx and allows the ER to reprogram for preferential expression of UPR genes. SIGNOR-260166 0.7 CDK1 protein P06493 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Ser533 ATGTGTFsPGASPGS 9606 BTO:0000567 31981797 t miannu CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines. SIGNOR-276834 0.412 SP3 protein Q02447 UNIPROT FMR1 protein Q06787 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15479157 f miannu we show that Sp1 (specificity protein 1) and Sp3 are also strong positive regulators of FMR1 promoter activity. SIGNOR-255203 0.2 USP15 protein Q9Y4E8 UNIPROT SQSTM1 protein Q13501 UNIPROT down-regulates activity deubiquitination 9606 BTO:0000567 27368102 t miannu SQSTM1 Is a Substrate for RNF26 and the DUB USP15. Catalytically competent RNF26 (light red) recruits SQSTM1 (blue) and mediates ubiquitin ligation (red), which serves to attract UBDs of specific vesicle-associated adaptors. Dissociation of the RNF26/SQSTM1 complex, promoted by the DUB USP15 (yellow), releases target vesicles for (4) fast transport into the cell periphery. SIGNOR-269829 0.262 RAPH1 protein Q70E73 UNIPROT ENAH protein Q8N8S7 UNIPROT up-regulates activity binding 9606 20417104 t miannu Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins. SIGNOR-268425 0.559 adenosine smallmolecule CHEBI:16335 ChEBI Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000142 18957298 t miannu Adenosine is an endogenous inhibitor of excitatory synaptic transmission with potent anticonvulsant properties in the mammalian brain. SIGNOR-265464 0.7 MAP2K7 protein O14733 UNIPROT FADD protein Q13158 UNIPROT down-regulates activity phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 15001534 t gcesareni The results clearly show that fadd phosphorylation at ser194 affects functions both upstream and downstream of the mekk1/mkk7/jnk1 pathway and is closely associated with chemosensitivity in prostate cancer cells SIGNOR-123164 0.476 CHD1 protein O14646 UNIPROT SF3a complex SIGNOR-C345 SIGNOR up-regulates activity binding 9606 BTO:0000567 18042460 t miannu CHD1 was found to bridge core spliceosomal components to H3K4me3 via specific interactions with the SF3a sub-complex of U2 snRNP. The recruitment of SF3a and the efficiency of pre-mRNA splicing were perturbed upon reduction of CHD1 and H3K4me3. SIGNOR-263951 0.25 GNAI1 protein P63096 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity binding 10090 BTO:0000944 11099498 t These findings indicate that both G alpha(i) and G beta gamma stimulate Rac and Cdc42 pathways with lysophosphatidic acid-induced cell spreading on fibronectin SIGNOR-256531 0.502 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 25728771 t inferred from 70% family members lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation SIGNOR-270188 0.2 TFEB protein P19484 UNIPROT ATP6V0E1 protein O15342 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276534 0.315 CASP3 protein P42574 UNIPROT ACIN1 protein Q9UKV3 UNIPROT up-regulates cleavage 9606 10490026 t amattioni Induces apoptotic chromatin condensation after activation by casp3 SIGNOR-70800 0.613 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT down-regulates activity phosphorylation Ser23 YLQARKPsDCDSKEL 9606 15946941 t Luana Phosphorylation of GRK1 and GRK7 by cAMP-dependent Protein Kinase Attenuates Their Enzymatic Activities | We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA. SIGNOR-260839 0.2 STOML2 protein Q9UJZ1 UNIPROT SDHD protein O14521 UNIPROT up-regulates activity 9606 20359165 f Giorgia We found that SLP-2hi cells had significantly higher activities of NADH dehydrogenase and succinate dehydrogenase (P < 0.05), complexes I and II of the electron transport chain. SIGNOR-260383 0.21 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity phosphorylation Ser279 VLKRPERsQEESPPG 9606 12676583 t Manara Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A SIGNOR-260834 0.837 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates phosphorylation Tyr588 QLKPLKTyVDPHTYE 9606 18387945 t lperfetto The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells. SIGNOR-178169 0.2 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 21159646 t gcesareni In comparison, in the same assay conditions, the previously reported mps1 inhibitor sp600125 (13) was 10-fold less potent than nms-p715 on mps1 and, in addition, it was highly unspecific, being more active on at least 12 kinases including mitotic kinases with ic50 values well below 1 ?mol/l SIGNOR-170614 0.8 IGF1 protein P05019 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 BTO:0000150;BTO:0000680 16039586 t lperfetto Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin. This pathway is a general signal, as it was also observed in cell lines in which erk-primed inactivation of gsk-3beta was regulated by igf-1, tgf-beta, and receptor tyrosine kinase her2 SIGNOR-227948 0.342 CSNK2A1 protein P68400 UNIPROT VTN protein P04004 UNIPROT up-regulates activity phosphorylation Thr76 TMPEDEYtVYDDGEE 10090 9733784 t llicata  Therefore, we expressed Vn in a baculovirus system and show (i) that the CKII phosphorylation of wt-Vn enhances the adhesion of bovine aorta endothelial cells; (ii) that the double mutant T50E/T57E (in which the neutral Thr residues are replaced by the negatively charged Glu residues considered analogs of Thr-P) has a significantly enhanced capacity to promote cell adhesion and to accelerate cell spreading when compared with either wild-type Vn or to the neutral T50A/T57A mutant SIGNOR-250971 0.334 VCP protein P55072 UNIPROT NGLY1 protein Q96IV0 UNIPROT up-regulates activity binding 9606 15362974 t simone PNGase is directed to polyubiquitinated MGPs via VCP and the adaptor protein SAKS1, allowing PNGase to deglycosylate MGPs, which can then be degraded by the proteasome. PNGase itself is reported to bind to the S4 component of the 19 S proteasome. SIGNOR-261058 0.683 PPP2CB protein P62714 UNIPROT BCL2 protein P10415 UNIPROT up-regulates activity dephosphorylation Ser87 AAAGPALsPVPPVVH 9606 15225643 t The phosphorylation of Bcl-2 resulted in a reduction in anti-apoptotic function, implying that dephosphorylation promoted the anti-apoptotic activity of Bcl-2 protein in human tumor cell lines. Thus, the present findings suggest that ERK and PP2A are physiological regulators of Bcl-2 phosphorylation, and these enzymes exert an influence on the anti-apoptotic function of Bcl-2.phosphorylation of Bcl2 at Ser70 is proposed to be a dynamic process regulated by the sequential action of an agonist-activated Bcl2 kinase and PP2A. SIGNOR-248589 0.37 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI up-regulates quantity precursor of 9606 11802770 t miannu HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. SIGNOR-269690 0.8 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser527 RFRKRTHsAGTSPTI 10090 BTO:0002572 18498745 t lperfetto In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8 SIGNOR-236595 0.78 FH protein P07954 UNIPROT fumarate(2-) smallmolecule CHEBI:29806 ChEBI down-regulates quantity chemical modification 9606 30761759 t miannu Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors. SIGNOR-266279 0.8 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2A protein Q9UQM7 UNIPROT up-regulates activity chemical activation 15621017 t It has been reported that Aβ can result in an increase in intracellular Ca2+, which in turn can activates CaMK. SIGNOR-255491 0.8 PRKAA1 protein Q13131 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by stabilization phosphorylation Thr198 PGLRRRQt 10090 30033086 t Luana P27Kip1-Mediated Cell Survival Is Dependent on AMPK-Specific Thr198 Phosphorylation|AMPK-dependent phosphorylation of p27Kip1 on Thr198 promotes p27Kip1 protein stability, resulting in more autophagy and less apoptosis. SIGNOR-259859 0.27 PRKAA2 protein P54646 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 16054041 t gcesareni Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. SIGNOR-139161 0.824 prostaglandin F2alpha(1-) smallmolecule CHEBI:57404 ChEBI PTGFR protein P43088 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257573 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000567 9535909 t inferred from 70% family members lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. SIGNOR-270025 0.2 AMPK complex SIGNOR-C15 SIGNOR TSC2 protein P49815 UNIPROT up-regulates phosphorylation Ser1387 QPLSKSSsSPELQTL 9606 16959574 t lperfetto We have observed that ampk directly phosphorylates tsc2, and the ampk-dependent phosphorylation of tsc2 is critical for the coordination between cell growth and cellular energy levels. Phosphorylation of tsc2 by ampk is required for translation regulation and cell size control in response to energy deprivation. SIGNOR-216438 0.516 ARF4 protein P18085 UNIPROT Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 14973189 f lperfetto ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface SIGNOR-272151 0.7 GNAO1 protein P09471 UNIPROT NDN protein Q99608 UNIPROT up-regulates activity 9606 BTO:0002036 25012566 f lperfetto We subsequently analyzed whether Gαo modulates the cellular activities of Necdin. Notably, expression of Gαo significantly augmented Necdin-mediated cellular responses, such as proliferation and differentiation. Moreover, activation of type 1 cannabinoid receptor (CB1R), a Gi/oα-coupled receptor, augmented cell growth suppression, which was mediated by Gαo and Necdin in U87MG cells containing CB1R, Gαo, and Necdin as normal components. SIGNOR-253388 0.241 AMPK complex SIGNOR-C15 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser214 GGKERPGsKEEVDED -1 21204788 t done miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). SIGNOR-273926 0.257 CNR1 protein P21554 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257285 0.365 LSM8 protein O95777 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270626 0.823 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Val) smallmolecule CHEBI:29183 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269500 0.8 DZIP3 protein Q86Y13 UNIPROT H2AC12 protein Q96KK5 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271760 0.2 adrenaline smallmolecule CHEBI:33568 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) SIGNOR-257876 0.8 COX7C protein P15954 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267754 0.772 BMPR1A protein P36894 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR up-regulates activity phosphorylation 9606 8893010 t ggiuliani Conversely, Smad1 and DPC4 formed a complex when the cells were stimulated with BMP4 but not with activin of TGF-beta. SIGNOR-255778 0.701 TP73 protein O15350 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17700533 f miannu Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis. SIGNOR-255468 0.378 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276095 0.274 17beta-hydroxy-5alpha-androstan-3-one smallmolecule CHEBI:16330 ChEBI AR protein P10275 UNIPROT up-regulates chemical activation 9606 15861399 t miannu Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions. SIGNOR-251533 0.8 CDK11A protein Q9UQ88 UNIPROT SPDEF protein O95238 UNIPROT down-regulates quantity by destabilization phosphorylation Ser238 SEESWTDsEVDSSCS 9606 BTO:0000007 26885618 t lperfetto In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.| SIGNOR-273020 0.363 ABL1 protein P00519 UNIPROT RBM39 protein Q14498 UNIPROT up-regulates activity phosphorylation Tyr95 DRRFRGRyRSPYSGP 9606 BTO:0000007 27018250 t miannu In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner. SIGNOR-262609 0.328 TERB2 protein Q8NHR7 UNIPROT TTM complex complex SIGNOR-C305 SIGNOR form complex binding 9606 BTO:0000007 30718482 t lperfetto Meiotic specific proteins TERB1, TERB2, and MAJIN form a stable complex that plays a critical role in regulating the recruitment of telomeres to the NE SIGNOR-263304 0.2 PRKACA protein P17612 UNIPROT TRPM8 protein Q7Z2W7 UNIPROT up-regulates activity phosphorylation Ser9 SFRAARLsMRNRRND 9606 BTO:0000007 20110357 t done miannu Using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. the intracellular serine/threonine protein phosphatase 2A (PP2A) dephosphorylates TRPM8 Ser-9 and Thr-17 inhibiting the channel activity. SIGNOR-273792 0.2 PTEN protein P60484 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity 9606 BTO:0001271 20596030 f lperfetto Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfralpha was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib. SIGNOR-252638 0.654 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser111 SPPSPAPsSFSSTSV 9606 20305697 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-164625 0.574 EPO protein P01588 UNIPROT EPOR protein P19235 UNIPROT up-regulates binding -1 9774108 t gcesareni Human erythropoietin is a haematopoietic cytokine required for the differentiation and proliferation of precursor cells into red blood cells. It activates cells by binding and orientating two cell-surface erythropoietin receptors (EPORs) which trigger an intracellular phosphorylation cascade. SIGNOR-60663 0.872 EXOSC6 protein Q5RKV6 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-261389 0.914 Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI vitamin K epoxide smallmolecule CHEBI:28371 ChEBI up-regulates quantity precursor of 9606 31226734 t lperfetto GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form. SIGNOR-265909 0.8 NANOG protein Q9H9S0 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 f miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. SIGNOR-254626 0.453 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269386 0.719 PITX1 protein P78337 UNIPROT LHB protein P01229 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19106114 f miannu GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity. SIGNOR-254920 0.356 PFKL protein P17858 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. SIGNOR-266472 0.8 SREBF2 protein Q12772 UNIPROT SND1 protein Q7KZF4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29296233 t irozzo These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression. SIGNOR-259136 0.348 PRKAA1 protein Q13131 UNIPROT GFPT1 protein Q06210 UNIPROT down-regulates phosphorylation Ser242 SKFTRWGsQGERGKD 9606 19170765 t lperfetto Amp-activated protein kinase phosphorylates glutamine : fructose-6-phosphate amidotransferase 1 at ser243 to modulate its enzymatic activityhe 2-dg induced phosphorylation of gfat1 . The assay of the gfat enzymatic activity in the cell lysates indicated that the 2-dg-treatment inhibited the enzymatic activity SIGNOR-183528 0.2 CYCS protein P99999 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 BTO:0000567 9390557 t lperfetto Caspase-9 and apaf-1 bind to each other via their respective nh2-terminal ced-3 homologous domains in the presence of cytochrome c and datp, an event that leads to caspase-9 activation. SIGNOR-53585 0.876 TPR protein P12270 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262070 0.591 PPP3R1 protein P63098 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR form complex binding 9606 14623295 t miannu Calcineurin is a heterodimer consisting of a catalytic subunit with a molecular mass of about 59 kDa (calcienurin A or CNA) and a regulatory subunit with a molecular mass of 19 kDa (calcineurin B or CNB). SIGNOR-255289 0.953 UBA3 protein Q8TBC4 UNIPROT NAE complex SIGNOR-C131 SIGNOR form complex binding 9606 25504797 t lperfetto the NEDD8 E1-activating enzyme (NAE) is a heterodimer of APPBP1 and UBA3 corresponding to the N-terminal and C-terminal of the single polypeptide of the ubiquitin E1 respectively SIGNOR-242904 0.965 HCK protein P08631 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr783 EGRNPGFyVEANPMP -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249362 0.668 CAMK2B protein Q13554 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser561 PFLSRHNsKSSIFSF 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275787 0.275 CD40 protein P25942 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity binding 9606 18635759 t lperfetto Cd40, a tumor necrosis factor receptor (tnfr) family member, forms a complex containing adaptor molecules traf2 and traf3. SIGNOR-250560 0.916 SMARCA1 protein P28370 UNIPROT ST7 protein Q9NRC1 UNIPROT down-regulates quantity by repression transcriptional regulation 15485929 t lperfetto Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes. SIGNOR-268991 0.2 GATAD2A protein Q86YP4 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. SIGNOR-263858 0.825 PGAM1 protein P18669 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity chemical modification 9606 24786789 t miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. SIGNOR-266514 0.8 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr67 LSILSGGtPKRCLDL 9606 8119945 t gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. SIGNOR-36275 0.852 DUSP22 protein Q9NRW4 UNIPROT ESR1 protein P03372 UNIPROT down-regulates activity dephosphorylation Ser118 LHPPPQLsPFLQPHG 9606 17384676 t These results strongly suggest that DUSP22 acts as a negative regulator of the ERalpha-mediated signaling pathway|whereas E2-induced phosphorylation and activation of ERalpha was suppressed by overexpression of DUSP22 but not catalytically inactive mutants. SIGNOR-248827 0.264 PINK1 protein Q9BXM7 UNIPROT RAB8A protein P61006 UNIPROT down-regulates activity phosphorylation Ser111 RNIEEHAsADVEKMI -1 31361120 t lperfetto For Rab8a, it was shown that serine 111 phosphorylation (pS111) is dependent on the protein kinase PINK1 and that mimicking the phosphorylation at S111 by a serine/glutamate substitution (S111E) impaired Rab8a activation by its cognate nucleotide exchange factor (GEF) Rabin8. SIGNOR-260268 0.275 spiperone chemical CHEBI:9233 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258859 0.8 NFASC protein O94856 UNIPROT ANK2 protein Q01484 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 t miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. SIGNOR-266716 0.681 RFWD3 protein Q6PCD5 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 BTO:0002552 20173098 t miannu RFWD3 is a positive regulator of p53 abundance and regulates the G1 checkpoint in response to IR. We found that an E3 ubiquitin ligase RFWD3 (RNF201/FLJ10520) forms a complex with Mdm2 and p53 to synergistically ubiquitinate p53 and is required to stabilize p53 in the late response to DNA damage.  SIGNOR-271944 0.368 indometacin chemical CHEBI:49662 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000135 15770365 t Simone Vumbaca Indomethacin, a nonselective cyclooxygenase inhibitor, may prevent AAA formation by inhibiting cyclooxygenase-2 (COX-2) activity. SIGNOR-261089 0.8 MAPKAPK2 protein P49137 UNIPROT HNRNPA0 protein Q13151 UNIPROT up-regulates activity phosphorylation Ser84 VELKRAVsREDSARP 10090 BTO:0000801 12456657 t miannu MAPKAP-K2 phosphorylated hnRNP A0 at Ser84 in vitro and this residue became phosphorylated in LPS-stimulated cells. The simplest explanation for these findings is that the phosphorylation of hnRNP A0 at Ser84 by MAPKAP-K2 enhances binding to the AREs of these mRNAs or allows hnRNP A0 to displace another protein(s) from the AREs. SIGNOR-262951 0.547 SRC protein P12931 UNIPROT KLF16 protein Q9BXK1 UNIPROT up-regulates activity phosphorylation Tyr10 AAVACVDyFAADVLM 9606 BTO:0003041 22203677 t miannu We further confirmed that the Tyr-10 residue of KLF16 is phosphorylated in uterine cells (Fig. 7c). Additional experiments using both pharmacological and dominant negative inhibitors of Src further supported a role for this tyrosine kinase in modulating the activity of KLF16 (Fig. 7, d and f).  SIGNOR-276398 0.246 BIRC3 protein Q13489 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation. SIGNOR-272715 0.779 SOD3 protein P08294 UNIPROT dioxygen smallmolecule CHEBI:15379 ChEBI up-regulates quantity chemical modification 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272272 0.8 AKT1 protein P31749 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251622 0.873 TNF protein P01375 UNIPROT SCN1A protein P35498 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253478 0.26 FHIT protein P49789 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 18077326 t miannu Fhit interacts with _-catenin in vitro and in vivo / the tumor suppressor fhit acts as a repressor of _-catenin transcriptional activity SIGNOR-159873 0.524 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser177 ASSGSSAsFISDTFS 9606 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248683 0.613 FASN protein P49327 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI down-regulates quantity chemical modification 9606 15507492 t Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-267211 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 18519666 t inferred from 70% family members lperfetto We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_ SIGNOR-270095 0.2 KRAS protein P01116 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 16293107 t gcesareni Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2. the raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade. SIGNOR-141641 0.841 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 9841871 t lperfetto When truncated mapkkk4 (deltamapkkk4) was overexpressed in hek293 cells, it was constitutively activeco-expressed map kinase kinase (mkk)-1, mkk-4, mkk-3 and mkk-6 were activated in vivo by deltamapkkk4. All of the above mkks purified from escherichia coli were phosphorylated and activated by deltamapkkk4 immunoprecipitates in vitro. SIGNOR-62372 0.642 GAS6 protein Q14393 UNIPROT AXL protein P30530 UNIPROT up-regulates binding 9606 7867073 t gcesareni Receptor tyrosine kinases of the axl family are activated by the vitamin k-dependent protein gas6. We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function. SIGNOR-34339 0.906 GATA2 protein P23769 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 11021798 f fspada Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage. SIGNOR-78659 0.7 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr334 QSTKVPQtPLHTSRV 9606 BTO:0000130 14499342 t lperfetto Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils. SIGNOR-118044 0.76 CSNK2A1 protein P68400 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1377 KPQKSVVsDLEADDV 9606 BTO:0000567 7961967 t llicata Tryptic phosphopeptide mapping revealed that casein kinase II phosphorylated the C-terminal domain primarily on 2 serine residues in vitro, which were shown to be sites of modification in vivo. Site-directed mutagenesis studies identified these casein kinase II-specific phosphorylation sites as serine 1524 and serine 1376. SIGNOR-250965 0.613 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MED1 protein Q15648 UNIPROT up-regulates phosphorylation 9606 12356758 t inferred from 70% family members lperfetto Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase SIGNOR-270199 0.2 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser463 PPISPASsDLSVAGS 9606 BTO:0000007 16141410 t In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity SIGNOR-251246 0.406 VEGFA protein P15692 UNIPROT FLT1 protein P17948 UNIPROT up-regulates binding 9606 BTO:0004980 14704231 t gcesareni Vegf exerts its action by binding to vegfr-1 and vegfr-2. SIGNOR-121132 0.838 CDK2 protein P24941 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates phosphorylation Ser373 SSRSAPAsPNHAGVL 9606 20810654 t gcesareni We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis. SIGNOR-167830 0.376 PTPRG protein P23470 UNIPROT INSR protein P06213 UNIPROT up-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254704 0.373 2-deoxy-D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:62877 ChEBI acetaldehyde smallmolecule CHEBI:15343 ChEBI up-regulates quantity precursor of 9606 25229427 t miannu Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase. SIGNOR-268076 0.8 GRK6 protein P43250 UNIPROT IGF1R protein P08069 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1321 LPLPDRHsGHKAENG -1 22509025 t miannu GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting β-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated β-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation SIGNOR-276412 0.311 gefitinib chemical CHEBI:49668 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0000551 15329413 t gcesareni Egfr is a tk of the erbb family that is the presumptive target of the tk inhibitor (tki) gefitinib. SIGNOR-126976 0.8 MAPK10 protein P53779 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates phosphorylation Ser184 FYYEILNsPEKACSL 9606 15071501 t Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons gcesareni Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-190 SIGNOR-124009 0.2 PTEN protein P60484 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity dephosphorylation 9606 BTO:0001544 31374292 t miannu PTEN targets the protein phosphatase activity of BCR-ABL. PTEN has the same function as PTP1B, which can regulate BCR-ABL dephosphorylation [13]. However, whether PTEN can mediate BCR-ABL dephosphorylation remains unknown. We found that under-expression of PTEN significantly upregulated phosphorylation level of BCR-ABL. In order to verify the mechanisms, co-IP assays were applied, demonstrating the ways in which PTEN and BCR-ABL interact with each other. SIGNOR-260080 0.2 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Gly) smallmolecule CHEBI:29176 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269487 0.8 PPP3CB protein P16298 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Ser198 IRTHLSQsPRVPSKC 10090 19560418 t These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 SIGNOR-248380 0.262 G3BP2 protein Q9UN86 UNIPROT G3BP1 protein Q13283 UNIPROT up-regulates activity binding 9606 BTO:0000007 23279204 t miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. SIGNOR-260863 0.47 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-189137 0.391 BCL7B protein Q9BQE9 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269783 0.435 PAK1 protein Q13153 UNIPROT ITGB3BP protein Q13352 UNIPROT up-regulates phosphorylation Ser28 SKITRKKsVITYSPT 9606 BTO:0000150 18521086 t lperfetto Serine 28 phosphorylation of nrif3 confers its co-activator function for estrogen receptor-alpha transactivation. p21-activated protein kinase 1 (pak1) phosphorylates eralpha at ser305 and this modification is important in eralpha transactivation function. SIGNOR-178795 0.2 FASN protein P49327 UNIPROT Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates 9606 9356448 f miannu Our model of the native fatty acid synthase (FAS) depicts it as a dimer of two identical multifunctional proteins (Mr approximately 272,000) arranged in an antiparallel configuration so that the active Cys-SH of the beta-ketoacyl synthase of one subunit (where the acyl group is attached) is juxtaposed within 2 A of the pantetheinyl-SH of the second subunit (where the malonyl group is bound). This arrangement generates two active centers for fatty acid synthesis and predicts that if we have two appropriate halves of the monomer, we should be able to reconstitute an active fatty acid-synthesizing site SIGNOR-268159 0.7 4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-[4-methyl-6-(4-morpholinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-pyridinone chemical CHEBI:91454 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190443 0.8 CDK1 protein P06493 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1393 GSVPLSSsPPATHFP 9606 7635160 t llicata We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. phosphopeptide 1 was eliminated by replacement of ser1392 SIGNOR-30256 0.539 1-acyl-sn-glycerol 3-phosphate(2-) smallmolecule CHEBI:57970 ChEBI phosphatidic acid smallmolecule CHEBI:16337 ChEBI up-regulates quantity precursor of 9606 21173190 t lperfetto The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬† SIGNOR-267013 0.8 AKT1 protein P31749 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser457 RGRKRFVsEGDGGRL 9606 16357133 t gcesareni Our results show that akt specifically phosphorylates ser(67) and ser(457) residues of pdcd4 in vitro and in vivo. We further show that phosphorylation of pdcd4 by akt causes nuclear translocation of pdcd4. SIGNOR-252488 0.446 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser102 LQTVIRTsPSSLVAF 26190112 t Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. SIGNOR-253542 0.301 MBD3/NuRD complex complex SIGNOR-C338 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 27098840 f miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. SIGNOR-263860 0.7 PTPN1 protein P18031 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 17974954 t Overexpression of PTP1B increased Src specific activity in colon cancer cells by reducing phosphorylation at Y530 of Src. SIGNOR-248422 0.772 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation Ser93 RVPKDRPsLTVTPKR 9606 BTO:0000567 21658950 t miannu Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis. SIGNOR-263139 0.2 dUMP(2-) smallmolecule CHEBI:246422 ChEBI dTMP(2-) smallmolecule CHEBI:63528 ChEBI up-regulates quantity precursor of 9606 21876188 t lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. SIGNOR-268236 0.8 SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR DLX5 protein P56178 UNIPROT up-regulates transcriptional regulation 10090 BTO:0000165 12815054 f ggiuliani Over-expression of Smad1 or Smad5, mediators of BMP-signaling, also induced Dlx5 expression even in the absence of BMP-2 treatment concomitant with positive ALP staining SIGNOR-255790 0.325 GATA1 protein P15976 UNIPROT ZFPM1 protein Q8IX07 UNIPROT up-regulates activity binding 9606 21853041 t miannu GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1. SIGNOR-256059 0.791 PRKACA protein P17612 UNIPROT CACNA1D protein Q01668 UNIPROT up-regulates activity phosphorylation Ser1773 AAHGKRPsIGNLEHV -1 19074150 t miannu We recently demonstrated that PKA activation led to increased alpha(1D) Ca(2+) channel activity in tsA201 cells by phosphorylation of the channel protein. Western blotting showed that the N terminus and C terminus were phosphorylated. Serines 1743 and 1816, two PKA consensus sites, were phosphorylated by PKA and identified by mass spectrometry. SIGNOR-263109 0.374 SIK2 protein Q9H0K1 UNIPROT SIK2 protein Q9H0K1 UNIPROT up-regulates activity phosphorylation Ser343 RLKSHRSsFPVEQRL -1 27478041 t miannu SIK2 S358 Autophosphorylation Is a Marker of SIK2 Activity SIGNOR-277268 0.2 FLT3 protein P36888 UNIPROT USP22 protein Q9UPT9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26049753 f USP22 deubiquitinase was overexpressed in FLT3-ITD positive AML CD34+ cells.USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells. SIGNOR-261559 0.2 FGF13 protein Q92913 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253411 0.416 PPP2CA protein P67775 UNIPROT TFCP2 protein Q12800 UNIPROT up-regulates dephosphorylation Ser309 SLGEGNGsPNHQPEP 9606 20682773 t lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. This predominant cis conformation would also limit dephosphorylation of ser-291 and ser-309 by phosphatases such as pp2a SIGNOR-167389 0.2 NDUFS1 protein P28331 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. SIGNOR-262175 0.852 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser100 HLSGRKLsLQERSQG 9606 22778263 t lperfetto Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity SIGNOR-198146 0.2 NR2F6 protein P10588 UNIPROT LHCGR protein P22888 UNIPROT down-regulates quantity by repression transcriptional regulation 9534 BTO:0000318 10644740 t Luana Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription. SIGNOR-266216 0.307 COL1A1 protein P02452 UNIPROT DDR1 protein Q08345 UNIPROT up-regulates activity binding 9606 BTO:0001282 17318226 t lperfetto The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75.  SIGNOR-272340 0.342 NUP205 protein Q92621 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262083 0.672 MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 f lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252746 0.756 FOXO1 protein Q12778 UNIPROT TCF4 protein P15884 UNIPROT down-regulates activity binding 9606 BTO:0000797 18250171 t Gianni Here we show that the beta-catenin binding to FOXO serves a dual effect. beta-catenin, through binding, enhances FOXO transcriptional activity. In addition, FOXO competes with TCF for interaction with beta-catenin, thereby inhibiting TCF transcriptional activity. SIGNOR-262529 0.27 RAPGEF5 protein Q92565 UNIPROT HRAS protein P01112 UNIPROT up-regulates guanine nucleotide exchange factor 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-183732 0.491 WNT5A protein P41221 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates 9606 21078818 f lperfetto We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3). SIGNOR-227958 0.433 SRC protein P12931 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Tyr529 TITKTVEyLHAQGVV 9606 BTO:0000007 18156174 t llicata Together, our findings suggest that src-dependent phosphorylation at tyr-529 facilitates inactive erk binding to rsk2, which might be a general requirement for rsk2 activation by egf through the mek/erk pathway. SIGNOR-160052 0.362 FOXO1 protein Q12778 UNIPROT CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17873901 f gcesareni Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity SIGNOR-157794 0.307 CX3CL1 protein P78423 UNIPROT CX3CR1 protein P49238 UNIPROT up-regulates binding 9606 11432858 t gcesareni Fractalkine/cx3cl1 is a membrane-tethered chemokine that functions as a chemoattractant and adhesion protein by interacting with the receptor cx3cr1. SIGNOR-109135 0.777 GUCY1B2 protein O75343 UNIPROT GUCY1A2-B2 complex SIGNOR-C137 SIGNOR form complex binding 9606 10977868 t gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity SIGNOR-243974 0.2 LEF1 protein Q9UJU2 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19653274 f gcesareni Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation SIGNOR-245351 0.62 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI (R)-2-hydroxyglutarate(2-) smallmolecule CHEBI:15801 ChEBI up-regulates quantity precursor of 25406093 t lperfetto Here we show that, in addition to catalyzing oxidation of 3-phosphoglycerate, PHGDH catalyzes NADH-dependent reduction of alpha-ketoglutarate (AKG) to the oncometabolite d-2-hydroxyglutarate (d-2HG). SIGNOR-268573 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000007 9829964 t gcesareni When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner. SIGNOR-247992 0.2 N-[2-(4-bromocinnamylamino)ethyl]isoquinoline-5-sulfonamide chemical CHEBI:47495 ChEBI PRKACA protein P17612 UNIPROT down-regulates activity chemical inhibition 10116 2156866 t Simone Vumbaca Kinetic analysis indicated that H-89 inhibits protein kinase A, in competitive fashion against ATP. SIGNOR-261087 0.8 PTPRG protein P23470 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254729 0.262 PRKACA protein P17612 UNIPROT MCOLN1 protein Q9GZU1 UNIPROT down-regulates phosphorylation Ser557 SGKFRRGsGSACSLL 9606 17988215 t llicata The stimulatory effect of h89 on mcoln1 function was not observed when ser(557) and ser(559) were mutated to alanine residues, indicating that these two residues are essential for pka-mediated negative regulation of mcoln1. SIGNOR-158946 0.2 reserpine chemical CHEBI:28487 ChEBI SLC18A1 protein P54219 UNIPROT down-regulates activity chemical inhibition 9606 8643547 t miannu Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2. SIGNOR-258492 0.8 CASP3 protein P42574 UNIPROT GSN protein P06396 UNIPROT down-regulates cleavage 9606 BTO:0000130 9323209 t amattioni Caspase-3 mediates cleavage of gelsolin, generating a fragment that severs actin filaments in an unregulated fashion. The cleavage of gelsolin causes cells to round up, detach and undergo nuclear fragmentation. SIGNOR-51652 0.624 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1B protein P35368 UNIPROT up-regulates activity chemical activation -1 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258442 0.8 GADD45A protein P24522 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR down-regulates binding 9606 10362260 t lperfetto Gadd45 has now been found to directly inhibit the activity of cdc2/cyclin b1 complex SIGNOR-217508 0.678 ATM protein Q13315 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Ser490 QSTEPALsQIVMAPS 9606 15916964 t lperfetto Here, we demonstrate that the protein kinase atm phosphorylates atf2 on serines 490 and 498 following ionizing radiation (ir). dose- and time-dependent phosphorylation of atf2 by atm that results in its rapid colocalization with gamma-h2ax and mrn components into ir-induced foci (irif) SIGNOR-137619 0.583 SLA2 protein Q9H6Q3 UNIPROT FLT3 protein P36888 UNIPROT down-regulates activity binding 10090 BTO:0000740 27458164 t miannu We screened a panel of SH2 domain-containing proteins and identified SLAP2 as a potent interacting partner of FLT3. We demonstrated that interaction occurs when FLT3 is activated, and also, an intact SH2 domain of SLAP2 is required for binding. Expression of SLAP2 blocked FLT3 downstream signaling cascades including AKT, ERK, p38 and STAT5. SIGNOR-256155 0.251 NLGN1 protein Q8N2Q7 UNIPROT NRXN2 protein Q9P2S2 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264154 0.823 dexmedetomidine chemical CHEBI:4466 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258907 0.8 N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide chemical CHEBI:47322 ChEBI CSNK1E protein P49674 UNIPROT down-regulates chemical inhibition 9606 11524435 t amattioni Cki-7, an inhibitor of ck1epsilon SIGNOR-110053 0.8 TP53 protein P04637 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates binding 9606 11714700 t gcesareni This study identifies the anti-apoptotic survivin gene as a p53-repressed gene;notably, survivin repression by p53 is shown to be distinct from p53-dependent growth arrest. SIGNOR-111971 0.543 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252865 0.756 SMC5/6 complex SIGNOR-C374 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 27427983 f miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks SIGNOR-265487 0.7 RPS6K proteinfamily SIGNOR-PF26 SIGNOR WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Ser947 CRLNRSDsDSSTLSK 9606 BTO:0000149 24269383 t llicata Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. erk_rsk phosphorylation of kibra is required for proper cell proliferation and rsk-mediated phosphorylation also positively modulates kibra's migratory activity. SIGNOR-252809 0.2 TTC19 protein Q6DKK2 UNIPROT CHMP4B protein Q9H444 UNIPROT up-regulates activity binding 9606 BTO:0000567 SIGNOR-C379 20208530 t miannu We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B. SIGNOR-265541 0.428 SRC protein P12931 UNIPROT SDHA protein P31040 UNIPROT up-regulates activity phosphorylation Tyr215 SLRYDTSyFVEYFAL 9606 BTO:0001583 22823520 t miannu Phosphorylation-site analysis selects c-Src targets, including NDUFV2 (NADH dehydrogenase [ubiquinone] flavoprotein 2) at Tyr(193) of respiratory complex I and SDHA (succinate dehydrogenase A) at Tyr(215) of complex II. The phosphorylation of these sites by c-Src is supported by an in vivo assay using cells expressing their phosphorylation-defective mutants.  SIGNOR-276420 0.27 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9823 BTO:0001840 SIGNOR-C3 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-219257 0.924 GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268609 0.275 SRC protein P12931 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates phosphorylation Tyr361 KVMENFIyESMRYQP 9606 BTO:0000150 19556341 t amattioni Phosphorylation of the 361-tyrosine residue is crucial in the up-regulation of aromatase activity. c-src protein directly phosphorylates aromatase on tyrosine 361. SIGNOR-186284 0.357 CDK1 protein P06493 UNIPROT ORC1 protein Q13415 UNIPROT up-regulates phosphorylation Ser258 TSCASLDsPGRIKRK 9606 11931757 t lperfetto Horc1p contains three (s/t)px(k/r) consensus sites for cdk phosphorylation (ser258, ser273, and thr375). These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability. SIGNOR-116321 0.621 TPO protein P07202 UNIPROT TG protein P01266 UNIPROT up-regulates activity catalytic activity 9606 23349248 t miannu After transport through the apical membrane, I− is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO). SIGNOR-259914 0.519 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9606 18321241 t miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). SIGNOR-259236 0.8 SGK1 protein O00141 UNIPROT HTT protein P42858 UNIPROT down-regulates phosphorylation Ser419 GGRSRSGsIVELIAG 9606 14725621 t llicata The serum- and glucocorticoid-induced kinase sgk inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin. SIGNOR-121349 0.381 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Ser346 LLCLRRSsLKAYGNG -1 1848190 t lperfetto We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling. SIGNOR-248856 0.358 GNAS protein P63092 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates activity binding -1 10224115 t G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics. SIGNOR-256539 0.2 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR DPPA4 protein Q7L190 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269243 0.47 KAT2B protein Q92831 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates acetylation 9606 BTO:0000782;BTO:0001271 23029358 t gcesareni In earlier studies, we demonstrated that maml1 enhanced p300 acetyltransferase activity, which increased the acetylation of notch by p300.Acetylation controls notch stability and function in t-cell leukemia. SIGNOR-199024 0.585 DVL3 protein Q92997 UNIPROT PIP5K1A protein Q99755 UNIPROT up-regulates binding 9606 18772438 t gcesareni Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki. SIGNOR-180788 0.2 SRPK1 protein Q96SB4 UNIPROT SRPK1 protein Q96SB4 UNIPROT up-regulates phosphorylation Ser33 SETQHRGsAPHSESD 9606 22727668 t llicata We found that activated akt binds and induces srpk1 autophosphorylation because akt-mediated phosphorylation depends on the kinase activity of srpk1 SIGNOR-197989 0.2 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val42 GRSLIGKvDGTSHVT -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263588 0.404 FZD3 protein Q9NPG1 UNIPROT GNB1 protein P62873 UNIPROT up-regulates binding 9606 17251915 t gcesareni In the non-canonical wnt signalling pathway, frizzled uses galphaq or galphai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat. SIGNOR-152600 0.358 GABBR2 protein O75899 UNIPROT GABA-B receptor complex SIGNOR-C336 SIGNOR form complex binding 9606 BTO:0000007 9872316 t brain lperfetto Heterodimerization is required for the formation of a functional GABA(B) receptor.|These results indicate that, in vivo, functional brain GABA(B) receptors may be heterodimers composed of GABA(B)R1 and GABA(B)R2. SIGNOR-263743 0.68 GNAI1 protein P63096 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates activity binding -1 10224115 t G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics. SIGNOR-256538 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6KA2 protein Q15349 UNIPROT up-regulates phosphorylation 9606 8939914 t inferred from 70% family members gcesareni Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms SIGNOR-270018 0.2 RALA protein P11233 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Thr455 ALGTPVLtPPTEAAS 10090 BTO:0000944 11689711 t gcesareni We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT. SIGNOR-252985 0.2 DNA_damage stimulus SIGNOR-ST1 SIGNOR Fanconi anemia core complex complex SIGNOR-C300 SIGNOR up-regulates 9606 BTO:0000567 17396147 f lperfetto The Fanconi anemia (FA) core complex plays a central role in the DNA damage response network involving breast cancer susceptibility gene products, BRCA1 and BRCA2. The complex consists of eight FA proteins, including a ubiquitin ligase (FANCL) and a DNA translocase (FANCM), and is essential for monoubiquitination of FANCD2 in response to DNA damage. SIGNOR-263251 0.7 RANBP17 protein Q9H2T7 UNIPROT TCF3 protein P15923 UNIPROT up-regulates binding 9606 20503194 t miannu Yeast two-hybrid, mammalian two-hybrid, and co-immunoprecipitation analyses demonstrate specific interaction of e12 with ranbp17, a novel member of the importin-beta superfamily;this interaction maps to the crm1 homology region of ranbp17. Ectopic expression of ranbp17 leads to a approximately 3-fold increase in e2a/myod mediated transactivation of an e-box regulated luciferase reporter gene. SIGNOR-165655 0.2 HDAC1 protein Q13547 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005192 20037778 f miannu we find UHRF1 plays an important role in inhibiting MDR1 promoter activity by directly binding to the MDR1 promoter. Overexpression of UHRF1 in NCI/ADR-RES cells can induce deacetylation of histones H3 and H4 on the MDR1 promoter, which is facilitated by recruitment of HDAC1 to the MDR1 promoter. SIGNOR-254223 0.291 PTPN9 protein P43378 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates activity dephosphorylation 9606 20335174 t miannu Conversely, increasing expression of PTPN9 wild type (WT) inhibits tyrosyl phosphorylation of ErbB2 and EGFR.|Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells. SIGNOR-277170 0.309 ATM protein Q13315 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity 9606 BTO:0000887 18534819 f gcesareni The decreased atm expression suggests that atm is involved in the development of insulin resistance through down-regulation of akt activity. SIGNOR-161434 0.46 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser421 DNCASVSsPYESAIG 9534 BTO:0000298 12756254 t miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. SIGNOR-250126 0.879 CAV1 protein Q03135 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264454 0.7 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252848 0.908 Angiotensin 1-7 protein P01019-PRO_0000420660 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity 9606 24168260 f miannu We hypothesized that the ACE2/Ang-(1-7)/Mas axis protects against pulmonary fibrosis by inhibiting the MAPK/NF-κB pathway.In summary, our study demonstrate that exogenous Ang-(1-7) and ACE2 overexpression protect against BLM- or AngII-induced pulmonary fibrosis by down-regulating the MAPK/NF-κB pathway. However, constant infusion of Ang-(1-7) paradoxically initiates an inflammatory response in the lungs. The antifibrotic effects of Ang-(1-7) noted here make the heptapeptide a strong candidate for a therapeutic target in humans with pulmonary fibrosis. SIGNOR-260447 0.2 SRF protein P11831 UNIPROT ACTA2 protein P62736 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 15269336 f gcesareni The primary goal of the present study was to directly assess the role of the degeneracy of sm ?-Actin cargs in the regulation of smc-selective gene expression in vivo. in addition, our present studies address the possible role of this carg degeneracy, and the smc-selective srf coactivator myocardin, in regulating differential expression of carg-dependent smc genes and growth regulatory genes. SIGNOR-126923 0.434 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT down-regulates activity phosphorylation Ser205 LATPPTLsSTVLIVR 9606 BTO:0001938 12815053 t lperfetto M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1 SIGNOR-102490 0.555 ACSS1 protein Q9NUB1 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI down-regulates quantity chemical modification 10843999 t lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. SIGNOR-271831 0.8 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Thr95 AYDSHTNtYYLQTFG 9606 BTO:0000007 21321328 t miannu We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity. SIGNOR-263132 0.595 PRKCA protein P17252 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates activity phosphorylation Ser294 PHGSPRVsVTDDSWL 9606 12351631 t lperfetto Protein kinase A negatively modulates the nuclear accumulation of NF-ATc1. | Here we show that overexpression of PKA causes phosphorylation and cytoplasmic accumulation of NF-ATc1 in direct opposition to calcineurin by phosphorylating Ser-245, Ser-269, and Ser-294 in the conserved serine-proline repeat domain, and that mutation of these serines blocks the effect of PKA. Activation of endogenous PKA is similarly able to promote phosphorylation of these sites on NF-ATc1 in two lymphoid cell lines. SIGNOR-249175 0.392 SCAP protein Q12770 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates activity relocalization 10029 BTO:0000246 12202038 t SCAP contains two domains: an NH2-terminal membrane attachment domain with eight membrane-spanning helices (Nohturfft et al., 1998b) and a long COOH-terminal extension that contains multiple copies of a WD40 repeat sequence, which forms a propeller-like structure that binds to the COOH-terminal domains of the SREBPs, thereby permitting the escort function SIGNOR-267502 0.898 PPARG protein P37231 UNIPROT HDAC1 protein Q13547 UNIPROT down-regulates relocalization 9606 16431920 t fspada These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome SIGNOR-143961 0.601 DNA polymerase gamma complex SIGNOR-C378 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 19837034 f lperfetto DNA Pol gamma, in contrast to the many nuclear DNA polymerases (DNAPs) that have specialized functions, is solely responsible for DNA replication and repair in mitochondria.  SIGNOR-265723 0.7 BMPR2 protein Q13873 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates activity binding 9534 10712517 t lperfetto Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii). SIGNOR-219291 0.609 MAPK9 protein P45984 UNIPROT PPM1J protein Q5JR12 UNIPROT down-regulates phosphorylation Ser93 HAGRAVQsPPDTGRR 9606 18553930 t gcesareni Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells. SIGNOR-178934 0.2 CUX2 protein O14529 UNIPROT OGG1 protein O15527 UNIPROT up-regulates activity binding 10090 26221032 t miannu CUX2 Interacts Directly with OGG1 and Stimulate Its Binding to DNA Containing 8-OxoG SIGNOR-263960 0.2 Blood vessel damage stimulus SIGNOR-ST26 SIGNOR F12 protein P00748 UNIPROT up-regulates NBK482253 f lperfetto It begins with the activation of Factor XII (a zymogen, inactivated serine protease) which becomes Factor XIIA (activated serine protease) after exposure to endothelial collagen. Endothelial collagen is only exposed when endothelial damage occurs. SIGNOR-263514 0.7 NLGN4Y protein Q8NFZ3 UNIPROT NRXN3 protein Q9HDB5 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264168 0.2 FZD4 protein Q9ULV1 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 27096005 t areggio Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin. SIGNOR-258955 0.593 RBMX2 protein Q9Y388 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270674 0.563 acetyl-CoA smallmolecule CHEBI:15351 ChEBI citrate(3-) smallmolecule CHEBI:16947 ChEBI up-regulates quantity precursor of 9606 3013232 t miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. SIGNOR-266236 0.8 CDK5 protein Q00535 UNIPROT AGAP2 protein Q99490 UNIPROT up-regulates phosphorylation Ser279 KSKTLDNsDLHPGPP 9606 BTO:0000938;BTO:0000527 18487454 t lperfetto Here, we demonstrate that cyclin dependent kinase 5 (cdk5), a protein known to function mainly in postmitotic neurons, directly phosphorylates pike-a at ser-279 in its gtpase domain in glioblastoma cells. This phosphorylation event stimulates pike-a gtpase activity and the activity of its downstream effector akt. SIGNOR-178660 0.265 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser17 ARRSYVSsGEMMVGG -1 7822264 t llicata On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II. SIGNOR-250627 0.437 PRKCA protein P17252 UNIPROT EIF6 protein P56537 UNIPROT unknown phosphorylation Ser235 QPSTIATsMRDSLID 9606 14654845 t llicata Pkc stimulation led to eif6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eif6 impaired rack1/pkc-mediated translational rescue. SIGNOR-119600 0.322 Av/b2 integrin complex SIGNOR-C176 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269025 0.7 CAMK2A protein Q9UQM7 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000590 10090741 t lperfetto We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II. SIGNOR-249314 0.579 PIAS4 protein Q8N2W9 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 SIGNOR-C9 12904571 t gcesareni Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity. SIGNOR-104538 0.633 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser293 FNTLAFPsMKRKDVV -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276137 0.758 NRF1 protein Q16656 UNIPROT FMR1 protein Q06787 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001363; BTO:0000142 11058604 f miannu We have also shown that USF1, USF2, and alpha-Pal/Nrf-1 are the major transcription factors that bind the promoter in brain and testis extracts and suggest that elevated levels of these factors account in part for elevated FMR1 expression in these organs. SIGNOR-254881 0.293 SEPTIN4 protein O43236 UNIPROT XIAP protein P98170 UNIPROT down-regulates quantity binding 9534 BTO:0004055 15029247 t lperfetto The mitochondrial ARTS protein promotes apoptosis through targeting XIAP.|Binding of ARTS to XIAP is direct, as recombinant ARTS and XIAP proteins can bind to each other in vitro. ARTS binding to XIAP is specific and related to its pro-apoptotic function, as mutant forms of ARTS (or related septins) that fail to bind XIAP failed to induce apoptosis. ARTS leads to decreased XIAP protein levels and caspase activation. Our data suggest that ARTS induces apoptosis by antagonizing IAPs. SIGNOR-267671 0.2 AMPK complex SIGNOR-C15 SIGNOR HNF4A protein P41235 UNIPROT down-regulates activity phosphorylation Ser303 DPDAKGLsDPGKIKR -1 12740371 t miannu Here we demonstrate that AMPK directly phosphorylates HNF4alpha and represses its transcriptional activity. AMPK-mediated phosphorylation of HNF4alpha on serine 304 had a 2-fold effect, reducing the ability of the transcription factor to form homodimers and bind DNA and increasing its degradation rate in vivo. SIGNOR-263106 0.311 SCNN1A protein P37088 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 26772908 t miannu The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na(+) ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na(+) in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity. SIGNOR-269275 0.8 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273039 0.556 MYC protein P01106 UNIPROT ST3GAL4 protein Q11206 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22547830 f We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. SIGNOR-253959 0.2 CTBP1 protein Q13363 UNIPROT BHLHE41 protein Q9C0J9 UNIPROT up-regulates binding 9606 16287852 t gcesareni We identify the ctip and ctbp corepressors as novel components of the human rbp-jkappa/sharp-corepressor complex and show that ctip binds directly to the sharp repression domain. Functionally, ctip and ctbp augment sharp-mediated repression. SIGNOR-141613 0.268 PIM1 protein P11309 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser186 RQRKRHKsDSISLSF 9606 BTO:0000785 18467333 t gcesareni Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt. SIGNOR-178619 0.397 calcium(2+) smallmolecule CHEBI:29108 ChEBI Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 29953871 f miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. SIGNOR-264954 0.7 HOOK1 protein Q9UJC3 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR down-regulates 9606 BTO:0000018 25331952 f miannu The epithelial-mesenchymal transition (EMT) is an essential process for embryogenesis. It also plays a critical role in the initiation of tumor metastasis.Overexpression of Hook1 inhibited EMT while knockdown of Hook1 promoted EMT. SIGNOR-260643 0.7 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1172 ISLDNPDyQQDFFPK 9606 8845374 t lperfetto Revealed that peptides derived from egfr residues y992, y1086, y1101, and y1148 bound directly to the sh2 domain of c-src (figure 8c). These experiments demonstrate that a specific subset of egfr receptor c-src phosphorylation sites are also ligands for the sh2 domain of c-src.Cellular src functions as a co-transducer of transmembrane signals emanating from a variety of growth factor receptors, including egfr SIGNOR-44251 0.609 ADIPOQ protein Q15848 UNIPROT ADIPOR2 protein Q86V24 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 12802337 t acerquone Expression of adipor1/r2 or suppression of adipor1/r2 expression by small-interfering rna supports our conclusion that they serve as receptors for globular and full-length adiponectin, SIGNOR-101809 0.764 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Phe619 EVKMDAEfRHDSGYE -1 8943232 t lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261769 0.502 tamoxifen chemical CHEBI:41774 ChEBI ESR2 protein Q92731 UNIPROT down-regulates activity chemical inhibition 9606 20512796 t miannu Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth. SIGNOR-258588 0.8 FHIT protein P49789 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates 9606 BTO:0000551 15313915 f miannu We found that this synergistic inhibition of tumor cell growth corresponded with the fhit-mediated inactivation of mdm2, which thereby blocked the association of mdm2 with p53, thus stabilizing the p53 protein. SIGNOR-127610 0.439 GSK3B protein P49841 UNIPROT IL17RA protein Q96F46 UNIPROT down-regulates quantity by destabilization phosphorylation Thr780 MVLTDPHtPYEEEQR 9606 BTO:0000007 26871944 t miannu Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation.  SIGNOR-277205 0.2 GREB1 protein Q4ZG55 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 BTO:0000599 31462641 t miannu GREB1 is localized to the nucleus where it binds Smad2/3 in a competitive manner with p300 and inhibits TGFβ signaling, thereby promoting HepG2 HB cell proliferation. Binding of GREB1 to Smad2/3 inhibits transcription SIGNOR-265885 0.2 CC2D1B protein Q5T0F9 UNIPROT HTR1A protein P08908 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007;BTO:0000938 19423080 t nucleus lperfetto Human Freud-2/CC2D1B: a novel repressor of postsynaptic serotonin-1A receptor expression|Human Freud-2 showed strong repressor activity at the human 5-HT1A or heterologous promoter in human HEK-293 5-HT1A-negative cells and neuronal SK-N-SH cells, a model of postsynaptic 5-HT1A receptor-positive cells. SIGNOR-268298 0.341 pralatrexate chemical CHEBI:71223 ChEBI DHFR protein P00374 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002207 19221750 t Luana This study reports a head-to-head comparison of in vitro and in vivo activities of three antifolates: pralatrexate, methotrexate, and pemetrexed. A clear difference was demonstrated among the antifolates in regulation of enzymatic activity. Pralatrexate demonstrated a unique activity profile relative to methotrexate and pemetrexed SIGNOR-257815 0.8 FLT3 protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 16266983 f gcesareni We show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway. SIGNOR-245064 0.442 bis(2-ethylhexyl) phthalate chemical CHEBI:17747 ChEBI SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression 10116 16257484 f miannu DIDP, BBP and DOP stimulate NIS mRNA expression. Here, hNIS promoter construct (N3) was up-regulated 2.5-fold by DIDP, 2.6-fold by BBP and 2.4-fold by DOP in the presence of TSH. Likewise, these phthalates also enhanced rNIS endogenous mRNA expression, which increased ca. 2-fold after 48 h of treatment compared with the expression level generated by TSH only. At 72 h, mRNA content was unchanged. SIGNOR-268744 0.8 L-selenocystathionine zwitterion smallmolecule CHEBI:62226 ChEBI L-selenocysteine zwitterion smallmolecule CHEBI:57843 ChEBI up-regulates quantity precursor of 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. SIGNOR-275817 0.8 PIGF protein Q07326 UNIPROT PIGO protein Q8TEQ8 UNIPROT down-regulates quantity by destabilization 10029 BTO:0000246 15632136 f miannu We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O. SIGNOR-261360 0.698 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR PSEN1 protein P49768 UNIPROT down-regulates activity phosphorylation Ser353 SHLGPHRsTPESRAA 9606 BTO:0000007 17360711 t gcesareni We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin. SIGNOR-228018 0.404 POU5F1 protein Q01860 UNIPROT THY1 protein P04216 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254931 0.431 tRNA(Asp) smallmolecule CHEBI:29186 ChEBI Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270377 0.8 SOSTDC1 protein Q6X4U4 UNIPROT WNT5A protein P41221 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242736 0.307 vincaleukoblastine sulfate chemical CHEBI:9984 ChEBI TUBE1 protein Q9UJT0 UNIPROT down-regulates activity chemical inhibition 9606 15579115 t miannu Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. SIGNOR-259258 0.8 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser172 LCLSPASsGSSASFI 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248680 0.613 MAP2K1 protein Q02750 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 11904294 t gcesareni We found that hypoxia greatly accelerated tal1 turnover in these cells through mitogen-activated protein kinase (mapk)2-mediated phosphorylation, ubiquitination, and proteasomal degradation. SIGNOR-116149 0.2 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1265 FPMTPTTyKGSVDNQ 9606 BTO:0000394 12881528 t lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. SIGNOR-104080 0.2 CDKN1A protein P38936 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR down-regulates activity binding 9606 BTO:0000093 11154267 t lperfetto Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity SIGNOR-245462 0.887 isoprenaline chemical CHEBI:64317 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8982677 t miannu K i values of the agonists for [~25I]iodocyanopindolol binding to the COS-7 cell membranes are shown in Table 1. In the membranes expressing one of the 13-adrenoceptor subtypes, both isoproterenol and T-0509 caused monophasic dis- placement of [~25I]iodocyanopindolol, suggesting a single binding site of the agonists. SIGNOR-258576 0.8 Hair cells mechanotransduction channel complex SIGNOR-C290 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 10090 23217710 t lperfetto Despite this progress, it is not known which genes encode subunits of the mechanotransduction channel of hair cells. Ca2+ enters stereocilia upon mechanical stimulation near the lower tip-link insertion site, indicating that transduction channels are present in proximity to PCDH15 SIGNOR-262573 0.8 MSL3 protein Q8N5Y2 UNIPROT MSL acetyltransferase complex SIGNOR-C344 SIGNOR form complex binding 9606 BTO:0000567 16227571 t miannu We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. SIGNOR-263940 0.816 MYC protein P01106 UNIPROT HLA-A protein P04439 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8206526 f miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. SIGNOR-254603 0.272 PTPRG protein P23470 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity dephosphorylation Tyr1474 GSSNGHVyEKLSSIE -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254702 0.28 LRRK2 protein Q5S007 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 19576176 t lperfetto Here we show that full-length Lrrk2 or fragments containing its kinase domain have a significant capacity to phosphorylate recombinant alpha synuclein (Asyn) at serine 129. Such phosphorylated Asyn is the major component of pathological deposits in PD. SIGNOR-249690 0.643 CDK1 protein P06493 UNIPROT ERCC6L protein Q2NKX8 UNIPROT up-regulates phosphorylation Thr1063 VKQFDAStPKNDISP 9606 17218258 t lperfetto Following phosphorylation of pich on the cdk1 site t1063, plk1 is recruited to pich and controls its localization. Starting in prometaphase, pich accumulates at kinetochores and inner centromeres. SIGNOR-152133 0.56 GSK3B protein P49841 UNIPROT CABYR protein O75952 UNIPROT unknown phosphorylation Ser155 KTTTPPSsPPPTAVS -1 15752768 t GSK3β interacts with and phosphorylates CABYR in vitro. GSK3β interacts with and phosphorylates CABYR in vitro. the functional extent of the CABYR phosphorylation sites to participate in cellular processes through GSK3β remains to be investigated. SIGNOR-251223 0.41 TACR1 protein P25103 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257316 0.293 CSNK2A1 protein P68400 UNIPROT WEE1 protein P30291 UNIPROT down-regulates quantity by destabilization phosphorylation Ser121 WEEEGFGsSSPVKSP 9606 BTO:0000567 16085715 t miannu  In the present study, we show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms.  S123 phosphorylation creates a PBD-binding motif and accelerates S53 phosphorylation by Plk1. SIGNOR-276038 0.418 GSK3B protein P49841 UNIPROT APP protein P05067 UNIPROT unknown phosphorylation Thr743 VEVDAAVtPEERHLS -1 8764598 t The sole site of phosphorylation in APPcyt by GSK-3beta was determined by phosphoamino acid analysis and phosphorylation of APPcyt mutant peptides to be Thr743 (numbering as for APP770). SIGNOR-251220 0.557 KTN1 protein Q86UP2 UNIPROT KIF5B protein P33176 UNIPROT up-regulates binding 9606 15316074 t miannu This study demonstrated the effect of kinectin-kinesin interaction on lysosome dynamics and observed that the kinesin-binding domain of kinectin can significantly enhance the mt-stimulated atpase activity of kinesin. SIGNOR-128092 0.592 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Ala369 DYAPVIPaNMDKKYR -1 9242537 t lperfetto Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.Va treated with HNE indicated cleavage at Ala341, Ile508, and Thr1767 under conditions, which the cofactor became inactivated, as measured by prothrombinase activity. SIGNOR-263635 0.373 FCGR3A protein P08637 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression 9606 BTO:0000801 10728755 f lperfetto This study suggests a dominant role for FcgammaRIIIA in the induction of both TNFalpha and IL-1alpha production by human macrophages in rheumatoid arthritis following receptor ligation by small immune complexes. The signaling of TNFalpha production may require the ligation of either 3 FcgammaRIIIA receptors or only 2 FcgammaRIIIA receptors, where one interaction must involve binding via an Fc domain. SIGNOR-249526 0.338 ANKRD11 protein Q6UB99 UNIPROT Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 10090 BTO:0000142 29274743 f miannu We found that Ankrd11 knockdown disrupted dendrite and spine formation in developing pyramidal neurons. SIGNOR-266730 0.7 Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity deubiquitination 9606 31226023 t miannu Also, SARS-CoVPLPro catalyzed deubiquitination ofTNF-receptor-associatedfactor3(TRAF3)and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist SIGNOR-260248 0.2 A1/b1 integrin complex SIGNOR-C159 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257701 0.561 AXIN2 protein Q9Y2T1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 BTO:0000142;BTO:0000671;BTO:0000763 10911903 t gcesareni It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains. SIGNOR-79947 0.843 MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR UFL1 protein O94874 UNIPROT up-regulates activity relocalization 9606 BTO:0001938 30886146 t lperfetto UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation. UFL1 is recruited to double strand breaks by the MRE11/RAD50/NBS1 complex, and monoufmylates histone H4 following DNA damage. SIGNOR-265074 0.2 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1696 SPSYSPTsPSYSPTS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248810 0.849 MMP27 protein Q9H306 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272394 0.7 nilotinib chemical CHEBI:52172 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258258 0.8 FRZB protein Q92765 UNIPROT WNT8A protein Q9H1J5 UNIPROT down-regulates binding 9606 BTO:0000671 9326585 t gcesareni We and others demonstrated that fzb-1 blocks wnt-1 and xwnt-8 signaling in xenopus embryos, SIGNOR-51798 0.497 SGK1 protein O00141 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation Ser29 GPRYTNLsYIGEGAY 9606 BTO:0000599 19447520 t miannu SGK1 was found to physically interact with ERK1/2 as well as MEK1/2. Furthermore, SGK1 mediated the phosphorylation of ERK2 on Ser(29) in a serum-dependent manner. Replacement of Ser(29) to aspartic acid, which mimics the phosphorylation of Ser(29), enhanced the ERK2 activity as well as the MEK/ERK complexes formation. SIGNOR-276223 0.314 EFNA1 protein P20827 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52087 0.816 SMO protein Q99835 UNIPROT GNB2 protein P62879 UNIPROT up-regulates binding 9606 23074268 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-199177 0.2 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 BTO:0000093 12777400 t lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases SIGNOR-101306 0.346 INSR protein P06213 UNIPROT IRS2 protein Q9Y4H2 UNIPROT up-regulates binding 9534 7629118 t Tyrosine phosphorylation of insulin receptor substrate-1 in vivo depends upon the presence of its pleckstrin homology region. SIGNOR-253604 0.748 IKBKB protein O14920 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity phosphorylation Ser134 DGATNNLsRSNSDES 9606 BTO:0000007 16818229 t miannu Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling. SIGNOR-276291 0.764 RPS6K proteinfamily SIGNOR-PF26 SIGNOR PPP1R3A protein Q16821 UNIPROT up-regulates activity phosphorylation Ser46 PQPSRRGsDSSEDIY -1 10648825 t lperfetto The protein G(M), which targets protein phosphatase 1 (PP1) to the glycogen particles and sarcoplasmic reticulum (SR) of striated muscles, is known to be phosphorylated at Ser48 and Ser67 in vitro by adenosine 3',5' cyclic monophosphate-dependent protein kinase (PKA) and at Ser48 by MAP kinase-activated protein kinase-1 (MAPKAP-K1, also called p90 RSK). The phosphorylation of Ser48 increases the rate at which the glycogen-associated PP1.G(M) complex dephosphorylates (activates) glycogen synthase, but the phosphorylation of Ser67 has the opposite effect, suppressing the activity of PP1 toward glycogen-bound substrates. SIGNOR-252777 0.2 COL1A1 protein P02452 UNIPROT DDR1 protein Q08345 UNIPROT up-regulates binding 9606 9659900 t gcesareni We report that the collagens serve as ligands for the previously orphan family of discoidin domain-containing receptor-like tyrosine kinases. SIGNOR-58779 0.342 RALGAPA2 protein Q2PPJ7 UNIPROT RalGAP2 complex SIGNOR-C469 SIGNOR form complex binding 10090 21148297 t miannu Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. SIGNOR-269793 0.589 RFX complex complex SIGNOR-C104 SIGNOR HLA-DRB4 protein P13762 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 f The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-254002 0.2 FGFR1 protein P11362 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates phosphorylation Tyr244 RRLCDLYyINSPELE 9606 22195962 t llicata Mitochondrial pdhk1 is tyrosine phosphorylated and activated by fgfr1 in cancer cells further mass spectrometric analysis identified three tyrosine residues of pdhk1, including y136, y243 and y244, that are phosphorylated by fgfr1 SIGNOR-193454 0.354 SNAI2 protein O43623 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 22074556 f miannu We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. SIGNOR-255171 0.413 CAMK2A protein Q9UQM7 UNIPROT SYNGAP1 protein Q96PV0 UNIPROT up-regulates activity phosphorylation Ser1138 PSITKQHsQTPSTLN -1 14970204 t miannu Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. We identify four major sites of phosphorylation, serines 1123, 1058, 750/751/756, and 764/765. SIGNOR-262688 0.439 adenosine smallmolecule CHEBI:16335 ChEBI inosine smallmolecule CHEBI:17596 ChEBI up-regulates quantity precursor of -1 15926889 t Luana Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates SIGNOR-269736 0.8 PRPS2 protein P11908 UNIPROT Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates 9606 BTO:0006038 29074724 f lperfetto We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. SIGNOR-265734 0.7 BAK1 protein Q16611 UNIPROT CYCS protein P99999 UNIPROT up-regulates relocalization 9606 11175253 t Translocation from Mitochondria to Cytosol amattioni Allosteric activation of bak induces its intramembranous oligomerization into a proposed pore for cytochrome c efflux SIGNOR-105206 0.548 MAP1LC3A protein Q9H492 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 17580304 t gcesareni Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation. SIGNOR-156353 0.784 prostaglandin E2 smallmolecule CHEBI:15551 ChEBI PTGER4 protein P35408 UNIPROT up-regulates chemical activation 9606 15299086 t gcesareni Pge2 is the ligand for four ep receptor subtypes termed ep1 to ep4. SIGNOR-127789 0.8 CBL protein P22681 UNIPROT ABL1 protein P00519 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001271 20675402 t lperfetto We found that while c-cbl e3 ligase induced ubiquitin-dependent degradation of mature and phosphorylated bcr-abl proteins SIGNOR-167194 0.609 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates activity phosphorylation Thr388 NQAFLGFtYVAPSVL -1 11733037 t miannu In vitro phosphorylation and activation of p70β by mTOR and PDK1. We observed that the replacement of either Thr241 or Thr401 to Ala in p70β1(T241A, T401A) severely decreased the kinase activity. SIGNOR-250295 0.832 AMPK complex SIGNOR-C15 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 15866171 t lperfetto Ampk activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate ampk-dependent cell-cycle arrest SIGNOR-216475 0.421 APBA1 protein Q02410 UNIPROT Exocytosis phenotype SIGNOR-PH157 SIGNOR up-regulates 9606 BTO:0000938 11036064 f miannu As neurexins have been proposed to function in neuronal cell adhesion, it is possible that they define specific sites at the plasma membrane and that Mint complexes and Mint1-CASK complexes on neurexin are involved in the localized recruitment of Munc18 to the sites of exocytosis. In support of this hypothesis, both CASK and Mint1 have been reported to be localized at synapses SIGNOR-264043 0.7 GSK3B protein P49841 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Ser451 STSTPAPsRTASFSE 10653665 t Thr 446 and Ser 450, which are phosphorylated by glycogen synthase kinase-3 (GSK-3) SIGNOR-251218 0.371 PSEN1 protein P49768 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR form complex binding 9606 25610395 t lperfetto -Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2) SIGNOR-209705 0.956 SIX1 protein Q15475 UNIPROT EZR protein P15311 UNIPROT up-regulates quantity transcriptional regulation 9606 16488997 t We now show that the gene encoding Ezrin is a direct transcriptional target of Six1. SIGNOR-259374 0.349 HTR4 protein Q13639 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257154 0.252 CSF2 protein P04141 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 BTO:0000130 16492764 t gcesareni A g-csfr expression plasmid was introduced into interleukin-3 (il-3)-dependent mouse myeloid precursor fdc-p1 cells that normally do not respond to g-csf. G-csf stimulated proliferation of the transformants. These results suggested that the g-csfr, but not the il-3/gm-csf receptors, transduced the neutrophilic differentiation signal into cells SIGNOR-144740 0.586 PTEN protein P60484 UNIPROT RPS6KB1 protein P23443 UNIPROT down-regulates activity dephosphorylation 9606 19436944 f miannu Expression of WT-PTEN also caused decreased activation of Akt, p70 S6K, and Erk signaling pathways.|This may potentially be a result of PTEN inhibition of p70 S6K phosphorylation and may explain the mechanism by which PTEN inhibits proliferation of HSCs. SIGNOR-277080 0.547 PLK2 protein Q9NYY3 UNIPROT NPM1 protein P06748 UNIPROT up-regulates phosphorylation Ser4 sMDMDMSP 9606 BTO:0000567 15190079 t gcesareni Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis. SIGNOR-125720 0.517 DYRK1A protein Q13627 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity. SIGNOR-183670 0.52 PTK2 protein Q05397 UNIPROT BCAR1 protein P56945 UNIPROT unknown phosphorylation Tyr666 GWMEDYDyVHLQGKE 11604500 t lperfetto FAK phosphorylates CAS-SBD tyrosines 668 and/or 670, driving an SH2-mediated recruitment of Src which then phosphorylates CAS-SD. SIGNOR-249112 0.804 dimethyloxalylglycine chemical CHEBI:102218 ChEBI EGLN2 protein Q96KS0 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000018 28900510 t lperfetto We treated the A549 cells with the following EGLN/PHD inhibitors: dimethyloxalyglycine (DMOG), CoCl2, inhibitors of dioxygenases, and BAY 85-3494 (BAY), a specific inhibitor of EGLNs with highest potency against EGLN1. SIGNOR-261992 0.8 CREB5 protein Q02930 UNIPROT JUN protein P05412 UNIPROT up-regulates activity binding -1 8440710 t 2 miannu CRE-BPa binds to CRE with higher affinity than to the 12-O-tetradecanoylphorbol-13-acetate response element as a homodimer or a CRE-BPa/c-Jun or CRE-BPa/CRE-BP1 heterodimer. SIGNOR-240397 0.523 CPT1C protein Q8TCG5 UNIPROT O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267131 0.8 CSNK2A1 protein P68400 UNIPROT CFTR protein P13569 UNIPROT down-regulates phosphorylation Ser511 ENIIFGVsYDEYRYR 9606 21930781 t lperfetto Serine 511 has been previously implicated in the regulation of cftr by ck2, as the mutant s511d was found to be insensitive to tbb in xenopus oocytes but to have no major impact on the single-channel behavior of cftr SIGNOR-176623 0.281 DAAM1 protein Q9Y4D1 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 9606 23151663 f gcesareni In pcp, dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. SIGNOR-199381 0.417 EGFR protein P00533 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000093 BTO:0000150 26918608 t lperfetto p85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation. SIGNOR-33633 0.803 L-serine chemical CHEBI:17115 ChEBI PKM protein P14618 UNIPROT up-regulates activity chemical activation 9606 23064226 t We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation. SIGNOR-251557 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GTF2I protein P78347 UNIPROT up-regulates phosphorylation 9606 10648599 t inferred from 70% family members lperfetto Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation. SIGNOR-270057 0.2 GTF2I protein P78347 UNIPROT PRRX1 protein P54821 UNIPROT up-regulates binding 9606 9334314 t miannu Spin binds specifically to multiple sequences in the c-fos promoter and interacts cooperatively withphox1to promote serum-inducible transcription of a reporter gene driven by the c-fos serum response element (sre). SIGNOR-52654 0.351 MAP3K11 protein Q16584 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Ser257 ISGQLVDsIAKTRDA 9606 BTO:0001538 9003778 t lperfetto These data suggest that mlk-3 phosphorylates sek1 directly and that it does so specifically on those residues known to activate sek1 in vivo. SIGNOR-48574 0.609 AKAP12 protein Q02952 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity relocalization 14657015 t lperfetto A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. SIGNOR-271835 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MKNK1 protein Q9BUB5 UNIPROT up-regulates activity phosphorylation Thr250 NSCTPITtPELTTPC 9606 BTO:0000093 17130135 t We generated a phosphospecific antibody to Thr(P)-214 in the T-loop of MNKs and found that phosphorylations of both Thr-209 and Thr-214 in human MNK1 are required for activation SIGNOR-253014 0.2 NR0B2 protein Q15466 UNIPROT NR1I3 protein Q14994 UNIPROT down-regulates binding 9606 15000748 t gcesareni The short heterodimer partner (shp), an orphan nuclear receptor that lacks a conventional dna binding domain, was initially identified by its interaction with car. We have examined the role of shp in car-mediated transactivation of the cyp2b gene. Coexpression of shp inhibited the transactivation of the cyp2b gene by car in cultured hepatoma cells and the p160 coactivator grip1 reversed the inhibition. SIGNOR-123154 0.522 pimozide chemical CHEBI:8212 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258378 0.8 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser443 ATGSGIKsHNSALYS 9606 15574499 t amattioni Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility. SIGNOR-131451 0.255 PRKCZ protein Q05513 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni Finally, basal chat phosphorylation in neurons is mediated predominantly by pkc at ser-476, with pkc activation increasing phosphorylation at ser-440 and enhancing chat activity. SIGNOR-129336 0.292 PPM1A protein P35813 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity dephosphorylation 9606 16751101 t lperfetto Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads. SIGNOR-232110 0.607 RDH10 protein Q8IZV5 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity chemical modification 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS11 SIGNOR-265120 0.8 IMPDH2 protein P12268 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI down-regulates quantity chemical modification 9606 19480389 t miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). SIGNOR-267334 0.8 MUC1 protein P15941 UNIPROT KLF4 protein O43474 UNIPROT up-regulates activity binding 17308127 t lperfetto Previous work has shown that the Kruppel-like factor 4 (KLF4) transcription factor represses p53 transcription by binding to the PE21 element. Our results show that MUC1-C binds constitutively to KLF4, occupies PE21 with KLF4, and enhances the KLF4 occupancy of PE21.  SIGNOR-270543 0.285 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Thr336 SKQSPIStPTSPGSL 9606 14741103 t llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. SIGNOR-250660 0.415 CDK1 protein P06493 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity phosphorylation 9606 BTO:0003918 19917720 t lperfetto Cyclin-Dependent Kinase 1-Mediated Bcl-xL/Bcl-2 Phosphorylation Acts as a Functional Link Coupling Mitotic Arrest and Apoptosis|These findings suggest a model whereby a switch in the duration of CDK1 activation, from transient during mitosis to sustained during mitotic arrest, dramatically increases the extent of Bcl-xL/Bcl-2 phosphorylation, resulting in inactivation of their antiapoptotic function. Thus, phosphorylation of antiapoptotic Bcl-2 proteins acts as a sensor for CDK1 signal duration and as a functional link coupling mitotic arrest to apoptosis. SIGNOR-267987 0.352 SUCLG1 protein P53597 UNIPROT Succinyl-CoA GTP variant complex SIGNOR-C399 SIGNOR form complex binding 9606 32627745 t miannu Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS). SIGNOR-266263 0.927 RPS27 protein P42677 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262444 0.864 ERCC1 protein P07992 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 f lperfetto The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275710 0.7 ziprasidone chemical CHEBI:10119 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258504 0.8 RECQL4 protein O94761 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 9606 27287744 f RECQL4 is important for genome stability and DNA damage repair. SIGNOR-258951 0.7 MYC protein P01106 UNIPROT USP22 protein Q9UPT9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26049753 f USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells. SIGNOR-261560 0.508 PRKCA protein P17252 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser876 QGLAERIsVL 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275953 0.371 DUOX1 protein Q9NRD9 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity chemical modification 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264726 0.8 (-)-anisomycin chemical CHEBI:338412 ChEBI MAPK11 protein Q15759 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb gcesareni SIGNOR-189675 0.8 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR ATP2A1 protein O14983 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136300 0.316 CDC25A protein P30304 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates activity dephosphorylation 9606 16682204 t miannu Cdc25A dephosphorylates and activates CyclinE\u2013Cdk2, CyclinA\u2013Cdk2 and CyclinB\u2013Cdk1, whereas Cdc25B and Cdc25C primarily target CyclinB\u2013Cdk1  [4,5] . SIGNOR-277136 0.679 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1068 HKNETMLsPREKIFY 9606 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. SIGNOR-104667 0.844 NOX4 protein Q9NPH5 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity chemical modification 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264724 0.8 PLK1 protein P53350 UNIPROT RAN protein P62826 UNIPROT up-regulates phosphorylation Ser135 DRKVKAKsIVFHRKK 9606 16930555 t lperfetto Plk1 is capable of phosphorylating co-immunoprecipitated ran in vitro on serine-135 and ran is phosphorylated in vivo at the same site during mitosis when plk1 is normally activated. Deregulation of ran phosphorylation disrupts normal spindle structure and segregation of chromosomes. SIGNOR-149073 0.267 MECP2 protein P51608 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000601 25420914 f Luana Our current study highlights the phosphorylation, but not the overall expression level, of MeCP2 as a significant regulatory mechanism in regulating adult neurogenesis in the hippocampus.  SIGNOR-264967 0.7 L3MBTL2 protein Q969R5 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates activity binding 9606 31225475 t miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. SIGNOR-266786 0.2 NEK2 protein P51955 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates phosphorylation Ser2392 AGLHHSLsHSLLAVA 9606 24695856 t lperfetto Our data support a model in which centrosome disjunction is triggered by the hyperphosphorylation of c-nap1, a major linker component. This occurs in response to a shift in the balance of activities of the nek2?_Pp1 bi-stable switch. C-nap1 hyperphosphorylation triggers the loss of both oligomerization and, crucially, interaction with the core centriole proximal-end protein, cep135. All three of these sites were identified in our in vivo analysis but only two (s2234 and s2394) were identified as nek2 phosphorylation sites in vitro. SIGNOR-204833 0.765 PRKACA protein P17612 UNIPROT RET protein P07949 UNIPROT down-regulates phosphorylation Ser696 SSGARRPsLDSMENQ 9606 BTO:0000938 20682772 t llicata Furthermore, we find that activation of protein kinase a (pka) by forskolin reduces the recruitment of shp2 to ret and negatively affects ligand-mediated neurite outgrowth. In agreement with this, mutation of ser(696), a known pka phosphorylation site in ret, enhances shp2 binding to the receptor and eliminates the effect of forskolin on ligand-induced outgrowth. SIGNOR-167349 0.374 RFX complex complex SIGNOR-C104 SIGNOR HLA-DRB1 protein P01911 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 t The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-253977 0.287 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Thr404 NSHPLSLtSDQYKAY -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178387 0.731 CUL3 protein Q13618 UNIPROT MAP1B protein P46821 UNIPROT down-regulates quantity ubiquitination 10090 BTO:0000142 18680552 t miannu Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. SIGNOR-268946 0.256 CDK3 protein Q00526 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 19118012 t gcesareni Egf-induced cdk3 activation caused c-jun phosphorylation at ser63 and ser73, resulting in increased ap-1 transactivation. SIGNOR-183009 0.455 perfluorooctanoic acid chemical CHEBI:35549 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 23764977 t miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  SIGNOR-268768 0.8 FZD4 protein Q9ULV1 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity binding 9606 27096005 t areggio Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin. SIGNOR-258958 0.741 IRX1 protein P78414 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. SIGNOR-261662 0.2 adenosine smallmolecule CHEBI:16335 ChEBI ADORA2A protein P29274 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257447 0.8 PTPRD protein P23468 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000551;BTO:0000527 BTO:0000142 19478061 t miannu Transfection of wild-type ptprd resulted in the specific dephosphorylation of stat3 at tyrosine 705, a residue that must be phosphorylated for stat3 to be active SIGNOR-185933 0.532 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser227 FGSFPVHsPITQGTP 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276103 0.29 RAB4A protein P20338 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 t lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 SIGNOR-260617 0.436 NPPA protein P01160 UNIPROT NPR1 protein P16066 UNIPROT up-regulates binding 9606 15911069 t gcesareni Natriuretic peptide receptor-a (npra) is the biological receptor of the peptide hormones atrial natriuretic peptide (anp) and brain natriuretic peptide (bnp) SIGNOR-137600 0.883 NKX6-3 protein A6NJ46 UNIPROT GKN1 protein Q9NS71 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001007 26314965 t Luana  In particular, NKX6.3 transcriptional factor was found to bind specifically to the upstream sequences of GKN1, a gastric-specific tumor suppressor, and dramatically increase expression of the latter.  SIGNOR-266096 0.379 PFK proteinfamily SIGNOR-PF79 SIGNOR beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. SIGNOR-266474 0.8 WAC protein Q9BTA9 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity binding 9606 BTO:0000567 30021153 t lperfetto Here, we report that the activation of Plk1 requires WAC, a WW domain-containing adaptor protein with a coiled-coil region that predominantly localizes to the nucleus in interphase. Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1.  SIGNOR-265036 0.2 JAK1 protein P23458 UNIPROT JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR form complex binding 10090 15284024 t lperfetto Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. SIGNOR-235608 0.2 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates 9606 10795740 t We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-256252 0.891 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Ser376 GSSPSQSsMVARTQT -1 11960013 t In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4. SIGNOR-251326 0.2 PRKD3 protein O94806 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates activity phosphorylation Ser259 FPLRKTAsEPNLKVR 18692497 t lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. SIGNOR-275926 0.268 PKA proteinfamily SIGNOR-PF17 SIGNOR EVL protein Q9UI08 UNIPROT up-regulates activity phosphorylation 9606 15066263 t miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts SIGNOR-268287 0.2 GRK2 protein P25098 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity phosphorylation Ser329 LGGLCDLsSRY 9606 12639913 t Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA and GRK phosphorylation and the subsequent recruitment of β-arrestin to the activated receptor. Replacement by alanine(s) of Thr312 and Ser329/330 in the C-terminal tail resulted in an impaired sequestration of mutated receptors to agonist, whereas mutations of Thr232 or Ser306 did not. This indicates that phosphorylation of these residues by kinases is critical for the internalization of MC4R. SIGNOR-251453 0.2 PA2G4 protein Q9UQ80 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 16254079 t Ectopic expression of ebp1, a member of the PA2G4 family, inhibits the proliferation and induces the differentiation of human breast and prostate cancer cell lines. Ebp1 inhibits transcription of E2F1 and androgen receptor regulated genes such as prostate specific antigen (PSA) through its interactions with histone deacetylases (HDACs) SIGNOR-253662 0.2 MAPK3 protein P27361 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser664 KKTSGPLsPPTGPPG 10090 BTO:0000944 15851026 t lperfetto Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation. SIGNOR-249457 0.681 SPOP protein O43791 UNIPROT HDAC6 protein Q9UBN7 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 28599312 t Gianni Cullin3 SPOP ubiquitin E3 ligase promotes the poly-ubiquitination and degradation of HDAC6 SIGNOR-268862 0.2 AKT2 protein P31751 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251624 0.483 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000567 12853467 t gcesareni These findings suggest that PKB-dependent binding of 14-3-3s to phospho-Ser483 of cardiac PFK-2 mediates the stimulation of glycolysis by growth factor. SIGNOR-252555 0.643 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 t gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase. SIGNOR-76088 0.309 FYN protein P06241 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates activity phosphorylation Tyr15 EKIGEGTyGTVFKAK 9606 14757045 t Constitutively active Fyn phosphorylated Tyr15 of Cdk5. Fyn Facilitates Kinase Activity of Cdk5 Via Tyr15 Phosphorylation SIGNOR-251156 0.591 HSP90AA1 protein P07900 UNIPROT CBLL1 protein Q75N03 UNIPROT up-regulates quantity binding 9606 BTO:0000007 31952268 t miannu By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity. SIGNOR-271474 0.2 FIG4 protein Q92562 UNIPROT 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate)(5-) smallmolecule CHEBI:85342 ChEBI down-regulates quantity chemical modification -1 23165282 t miannu Fig4/Sac3 can decrease PI(3,5)P2 levels via its phosphatase function and also promote PI3,5P2 synthesis by acting as a secondary scaffold for the Fab1/Vac14 interaction. However, the later function appears dominant. SIGNOR-253535 0.8 IRF8 protein Q02556 UNIPROT CD68 protein P34810 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000801 12676954 f However, our data show that PU.1/IRF-4 and IRF-8 heterocomplexes down-regulate CD68 promoter activity in macrophages and repression is dependent on the integrity of both the IRF and PU.1 half-sites of this composite element. SIGNOR-254285 0.284 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT unknown phosphorylation Tyr857 DIMRDSNyISKGSTF 9606 2550144 t llicata We have identified two platelet-derived growth factor (pdgf)-dependent autophosphorylation sites in the beta subunit of the human pdgf receptor (pdgf-r). The major site of phosphorylation (tyr-857) corresponds to the major autophosphorylation site in many other tyrosine kinases. Tyr-751, which lies within the kinase insert region, is a second in vivo site and the major in vitro site. SIGNOR-22997 0.2 NOTCH1 protein P46531 UNIPROT LFNG protein Q8NES3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15207708 f gcesareni Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta. SIGNOR-236845 0.747 vorinostat chemical CHEBI:45716 ChEBI HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257947 0.8 PRKCA protein P17252 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1323 ALAPRSVsLKDKGRF -1 11306676 t lperfetto These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. SIGNOR-249086 0.481 RASGRF2 protein O14827 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260574 0.476 RFX3 protein P48380 UNIPROT FOXJ1 protein Q92949 UNIPROT up-regulates activity binding 9606 BTO:0000939 23822649 t miannu RFX3 acts as a transcriptional co-activator to FOXJ1 that enhances the expression of cilia-associated genes. FOXJ1 is an important regulator of cilia gene expression during ciliated cell differentiation, with RFX3 as a transcriptional co-activator to FOXJ1, helping to induce the expression of cilia genes in the process of ciliated cell differentiation of basal/progenitor cells. SIGNOR-266929 0.565 SRC protein P12931 UNIPROT FBXO5 protein Q9UKT4 UNIPROT up-regulates phosphorylation Tyr142 ALETSRLyEDSGYSS 9606 20717963 t lperfetto We found that emi1 stability was regulated by phosphorylation and mutation of tyrosine 142 reduced the stability. Our data suggested bcr-abl-induced emi1 phosphorylation might be mediated by src kinase. SIGNOR-167529 0.33 RIMS2 protein Q9UQ26 UNIPROT UNC13B protein O14795 UNIPROT up-regulates activity relocalization 9606 31679900 t miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle SIGNOR-264383 0.365 DUSP22 protein Q9NRW4 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation 9606 16636663 f miannu IL-6 and LIF-induced LMW-DSP2 expression in murine testicular or hepatoma cell lines, while LMW-DSP2 overexpression in 293T cells suppressed IL-6-induced phosphorylation and activation of STAT3.|These results strongly suggest that LMW-DSP2 acts as a negative regulator of the IL-6/LIF/STAT3-mediated signaling pathway. SIGNOR-277149 0.365 CLASP1 protein Q7Z460 UNIPROT CLIP2 protein Q9UDT6 UNIPROT up-regulates activity binding 9606 BTO:0000567 15631994 t lperfetto CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. SIGNOR-265092 0.612 2-(6-Bromo-1,3-benzodioxol-5-yl)-N-(4-cyanophenyl)-1-[(1S)-1-cyclohexylethyl]benzimidazole-5-carboxamide chemical CID:126961335 PUBCHEM F2RL1 protein P55085 UNIPROT down-regulates activity chemical inhibition -1 28445455 t Simone Vumbaca The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. | Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. SIGNOR-261119 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 12670876 t inferred from 70% family members lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. SIGNOR-270088 0.2 CBL protein P22681 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates ubiquitination 9606 BTO:0000782 11526404 t lperfetto Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner. SIGNOR-252668 0.595 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT up-regulates binding 9606 9405416 t Inactive c-Jun NH2-terminal kinase (JNK). gcesareni C-jun is targeted for ubiquitination by its association with inactive c-jun nh2-terminal kinase (jnk).Phosphorylation By activated jnk protects c-jun from ubiquitination. SIGNOR-53791 0.881 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 t gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase. SIGNOR-76092 0.309 Av/b5 integrin complex SIGNOR-C178 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257723 0.634 MTMR2 protein Q13614 UNIPROT 1-phosphatidyl-1D-myo-inositol 3-phosphate(3-) smallmolecule CHEBI:58088 ChEBI down-regulates quantity chemical modification 9606 18429927 t miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns SIGNOR-269807 0.8 RPS6KA3 protein P51812 UNIPROT RANBP3 protein Q9H6Z4 UNIPROT up-regulates quantity phosphorylation Ser57 HGTGHPEsAGEHALE 9606 BTO:0000007 18280241 t miannu RSK phosphorylates RanBP3 at Serine 58 residue in vitro and in vivo.RanBP3 phosphorylation increases its affinity towards Ran SIGNOR-276148 0.335 BBOX1 protein O75936 UNIPROT carnitine smallmolecule CHEBI:17126 ChEBI up-regulates quantity chemical modification 9606 11802770 t miannu In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. SIGNOR-269699 0.8 NEFH protein P12036 UNIPROT Neurofilament bundle assembly phenotype SIGNOR-PH72 SIGNOR up-regulates 9606 8376466 f miannu Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons. SIGNOR-252390 0.7 SYK protein P43405 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 BTO:0000782 9710204 t gcesareni The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2). SIGNOR-59635 0.753 ABL1 protein P00519 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Tyr79 GAPAPGVyPGPPSGP 9606 20600357 t llicata In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at positions 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-abl kinase. our results demonstrate that cells expressing galectin-3 y107f variant showed reduced migration in wound healing assay ( fig. 5). This result confirms the role of galectin-3 tyrosine phosphorylation in cell motility. SIGNOR-166501 0.362 CSNK1A1 protein P48729 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser19 EVCDERTsLMSAESP -1 8972483 t llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  SIGNOR-250790 0.4 MRAP protein Q8TCY5 UNIPROT MC1R protein Q01726 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 t miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. SIGNOR-252364 0.356 P2RY6 protein Q15077 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257343 0.2 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A3/b1 integrin complex SIGNOR-C161 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259015 0.409 MAPK1 protein P28482 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation Ser623 ALDFQPSsPSPHRKP 9606 15356145 t lperfetto Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623. SIGNOR-128727 0.667 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser153 PSSKRSPsTATLSLP 9606 BTO:0001061 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276774 0.629 ABL1 protein P00519 UNIPROT YAP1 protein P46937 UNIPROT up-regulates phosphorylation Tyr407 SGLSMSSySVPRTPD 9606 18280240 t llicata In this study, we show that c-abl directly phosphorylates yap1 at position y357 in response to dna damage. Tyrosine-phosphorylated yap1 is a more stable protein that displays higher affinity to p73 and selectively coactivates p73 proapoptotic target genes. SIGNOR-160860 0.707 FOXA1 protein P55317 UNIPROT HSPA1A protein P0DMV8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19486887 f miannu The results showed overexpression of Foxa1 promoted the expression of HSP72, while Foxa1 depletion, induced by antisense oligonucleotides, decreased the expression of HSP72 in MCF-7 cells under normal and heat stress condition. SIGNOR-254164 0.2 TRRAP protein Q9Y4A5 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269589 0.73 CDKAL1 protein Q5VV42 UNIPROT tRNA(Lys) smallmolecule CHEBI:29185 ChEBI up-regulates quantity chemical modification 9606 21841312 t We show that Cdkal1 is a mammalian methylthiotransferase that biosynthesizes 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A) in tRNA(Lys)(UUU) and that it is required for the accurate translation of AAA and AAG codons SIGNOR-272474 0.8 PAX7 protein P23759 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates BTO:0001103 15501225 f svumbaca We found that ectopic expression of Pax-7 prevented myogenic differentiation and the induction of myogenin protein. SIGNOR-255367 0.7 WNT11 protein O96014 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. SIGNOR-253127 0.701 MAPK3 protein P27361 UNIPROT SCNN1G protein P51170 UNIPROT down-regulates quantity by destabilization phosphorylation Thr622 LGTQVPGtPPPKYNT -1 11805112 t lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. SIGNOR-249449 0.284 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MYB protein P10242 UNIPROT down-regulates phosphorylation 9606 8798443 t inferred from 70% family members llicata Here we describe that human c-myb can be phosphorylated by mitogen-activated protein kinases (mapk's) at serine 532 of the carboxy (c-) terminal regulatory domain in vitro. expression of a constitutively active form of ras together with c-myb in transient transfection experiments had no effect on the transcriptional activity of c-myb, while expression of a polypeptide containing the c-myb c-terminal domain stimulated c-myb activity. This effect is reduced upon mapk-dependent phosphorylation of serine 532. SIGNOR-270089 0.2 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252978 0.509 CTNND1 protein O60716 UNIPROT VAV2 protein P52735 UNIPROT up-regulates binding 9606 22946057 t gcesareni We demonstrate that p120-catenin participates in the stimulation of rac1 activity, binding directly to this protein. In addition we show that vav2 also binds to p120-catenin and is required for rac1 activation and for beta-catenin translocation to the nucleus.Vav2 And rac1 association with p120-catenin was modulated by phosphorylation of this protein, which was stimulated upon serine/threonine phosphorylation by ck1 and inhibited by tyrosine phosphorylation by src or fyn SIGNOR-198941 0.594 DLX2 protein Q07687 UNIPROT MSX1 protein P28360 UNIPROT down-regulates activity binding 10090 BTO:0000944 9111364 t 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. SIGNOR-240918 0.408 MTOR protein P42345 UNIPROT TFEB protein P19484 UNIPROT down-regulates activity phosphorylation Ser211 LVGVTSSsCPADLTQ 9606 BTO:0000567 SIGNOR-C3 22692423 t gcesareni Our data points to the lysosome as the site where mTORC1-dependent phosphorylation of TFEB occurs. [...]Our study has revealed a specific role for phosphorylation of TFEB S211 in the negative regulation of the nuclear abundance of TFEB. This occurs through the promotion of 14-3-3 binding and the masking of the nearby NLS on TFEB. SIGNOR-248270 0.49 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity by destabilization ubiquitination Lys773 RRNPAGTkWMEHVKL 9606 BTO:0000938 17283082 t lperfetto Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage. SIGNOR-145116 0.657 JNK proteinfamily SIGNOR-PF15 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 14699954 t inferred from 70% family members amattioni The targets of jnk include the transcription factors p53. P75ntr-mediated apoptosis was shown to be dependent of p53 SIGNOR-269985 0.2 OTUB1 protein Q96FW1 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization deubiquitination 34785775 t lperfetto Furthermore, although OTUB1 dramatically induced p53 deubiquitination, its mutant (S16A) and deletion mutant did not have this effec SIGNOR-276528 0.547 MAPK1 protein P28482 UNIPROT DAPK1 protein P53355 UNIPROT up-regulates phosphorylation Ser734 NSSRFPPsPLASKPT 9606 15616583 t gcesareni Dapk interacts with erk through a docking sequence within its death domain and is a substrate of erk. Phosphorylation of dapk at ser 735 by erk increases the catalytic activity of dapk both in vitro and in vivo SIGNOR-132614 0.551 TP53 protein P04637 UNIPROT GLS2 protein Q9UI32 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22307140 t Luana Glutaminase 2 (GLS2) can be directly transactivated by p53 and can therefore mediate p53-dependent regulation of cellular energy metabolism. G SIGNOR-268041 0.616 GATA1 protein P15976 UNIPROT HBG1 protein P69891 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004911 20395365 f Regulation miannu BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. SIGNOR-251806 0.384 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 SIGNOR-C17 10864927 t gcesareni Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-78420 0.852 CDK1 protein P06493 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization phosphorylation Thr92 EVPDVTAtPARLLFF 9606 SIGNOR-C17 20526282 t gcesareni Mcl-1 is phosphorylated at two sites in mitosis, ser64 and thr92. Phosphorylation of thr92 by cyclin-dependent kinase 1 (cdk1)-cyclin b1 initiates degradation of mcl-1 in cells arrested in mitosis by microtubule poisons. SIGNOR-165867 0.473 HTR7 protein P34969 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257323 0.252 MDM4 protein O15151 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination -1 12393902 t miannu Here we demonstrate that MdmX acts as a ubiquitin ligase in vitro, being capable of autoubiquitination, as well as mediating the ubiquitination of p53.  SIGNOR-271389 0.947 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR S100A6 protein P06703 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12859951 f miannu NF-kappaB transcription factor contributes to the activation of S100A6 gene expression in response to TNFalpha in HepG2 cells. SIGNOR-254803 0.2 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t lperfetto The transcription factor, forkhead in rhabdomyosarcoma (FKHR), is phosphorylated at three amino acid residues (Thr-24, Ser-256 and Ser-319) by protein kinase b (PKB)alpha. FKHR (forkhead in rhabdomyosarcoma), AFX (all1 fused gene from chromosome x) and FKHRL1 (FKHR-like 1) are phosphorylated directly by PKB in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus. SIGNOR-105459 0.866 PGM1 protein P36871 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267932 0.8 PTPRA protein P18433 UNIPROT FYN protein P06241 UNIPROT up-regulates dephosphorylation Tyr531 FTATEPQyQPGENL 9606 BTO:0000782 17507376 t gcesareni Ptpalpha is a more widely expressed transmembrane ptp that has been shown to regulate the src family kinases, src and fyn, and is also present in t cells. SIGNOR-154796 0.644 B4GALT1 protein P15291 UNIPROT UDP(3-) smallmolecule CHEBI:58223 ChEBI up-regulates quantity chemical modification 9606 16157350 t miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. SIGNOR-268470 0.8 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267884 0.8 LHX3 protein Q9UBR4 UNIPROT ISL2 protein Q96A47 UNIPROT up-regulates activity binding 9606 BTO:0000007 9452425 t lperfetto a direct NLI-independent interaction between Lhx3 and the related proteins Isl1 and Isl2 was observed. The combinatorial expression of the LIM homeodomain proteins Isl1, Isl2, Lhx1, and Lhx3 in subsets of developing motor neurons correlates with the future organization of these neurons into motor columns with distinct innervation targets, implying a functional role for LIM homeodomain protein combinations in the specification of neuronal identity SIGNOR-236836 0.444 F2RL3 protein Q96RI0 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257370 0.358 GATA6 protein Q92908 UNIPROT CYP17A1 protein P05093 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002850 BTO:0000975 15284005 f miannu The transcription factor GATA6, which regulates the promoter activity of CYP17 and CYP11A, was increased in the PCOS compared to normal theca cells. SIGNOR-254198 0.352 AURKA protein O14965 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser83 ALREIRYsLLPFANE 9606 15147269 t lperfetto On the basis of these observations, we conclude that s83 of lats2 is a phosphorylation target of aurora-a and this phosphorylation plays a role of the centrosomal localization of lats2. SIGNOR-124830 0.388 LRRC4 protein Q9HBW1 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000142 25526788 f miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. SIGNOR-264056 0.2 CPT1A protein P50416 UNIPROT O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267129 0.8 CSNK2B protein P67870 UNIPROT EIF5 protein P55010 UNIPROT up-regulates activity phosphorylation Ser389 LKEAEEEsSGGEEED 9606 BTO:0001938 11861906 t llicata Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis. SIGNOR-251069 0.387 FOXP1 protein Q9H334 UNIPROT PITX3 protein O75364 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000596 20175877 t Gianni We identified FoxP1 as a novel marker for midbrain dopamine neurons. Enforced expression of FoxP1 in embryonic stem cells actuates the expression of Pitx3, a homeobox protein that is exclusively expressed in midbrain dopaminergic neurons and is required for their differentiation and survival during development and from embryonic stem cells in vitro. We show that FoxP1 can be recruited to the Pitx3 locus in embryonic stem cells and regulate Pitx3 promoter activity in a dual-luciferase assay. SIGNOR-269049 0.296 PPFIA1 protein Q13136 UNIPROT PTPRF protein P10586 UNIPROT up-regulates activity relocalization 9606 BTO:0000093 7796809 t brain lperfetto We have identified a novel cytoplasmic 160 kDa phosphoserine protein termed LAR-interacting protein 1 (LIP.1), which binds to the LAR membrane-distal D2 protein tyrosine phosphatase domain and appears to localize LAR to focal adhesions. SIGNOR-264141 0.793 NPRL3 protein Q12980 UNIPROT GATOR1 complex SIGNOR-C192 SIGNOR form complex binding 9606 23723238 t miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 SIGNOR-255282 0.952 BBOX1 protein O75936 UNIPROT 4-(trimethylammonio)butanoate smallmolecule CHEBI:16244 ChEBI down-regulates quantity chemical modification 9606 11802770 t miannu In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. SIGNOR-269697 0.8 PPARD protein Q03181 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001951 18048767 f miannu Activation of PPAR-delta upregulated the expression of antioxidant genes superoxide dismutase 1, catalase, and thioredoxin and decreased reactive oxygen species production in ECs. SIGNOR-255053 0.269 GHR protein P10912 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates 9606 23612709 f miannu Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin. Possible stimuli for NFATc2 activation are PGF2α and GH. SIGNOR-255459 0.2 WNT5A protein P41221 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity 9606 21078818 f gcesareni Common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3). SIGNOR-169666 0.705 MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 15870273 t Simone Vumbaca We suggest that the interaction between MyoD and Pbx is necessary to initially target MyoD to the myogenin promoter SIGNOR-255639 0.437 ERO1A protein Q96HE7 UNIPROT ERP44 protein Q9BS26 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 11847130 t Simone Here, we report the functional characterization of a novel UPR-induced ER resident protein (ERp44) that forms mixed disulfides with both hEROs, as well as with partially unfolded Ig subunits. SIGNOR-261049 0.2 RPA1 protein P27694 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 f lperfetto The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275705 0.7 FOXO proteinfamily SIGNOR-PF27 SIGNOR PCK1 protein P35558 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22521266 t gcesareni Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase). SIGNOR-252924 0.2 GSK3B protein P49841 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 20331603 t lperfetto Phosphorylation of the residue Tyrosine in 216 position results in the constitutive activity of GSK-3beta and believed to be important target for signal transduction. SIGNOR-217865 0.2 NEUROG3 protein Q9Y4Z2 UNIPROT ASH1L protein Q9NR48 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19028584 f miannu Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. SIGNOR-254629 0.2 RPS6KA5 protein O75582 UNIPROT ETV1 protein P50549 UNIPROT up-regulates activity phosphorylation Ser216 PMYQRQMsEPNIPFP 9606 BTO:0002181 12213813 t lperfetto Activated, overexpressed MSK1 was able to phosphorylate ER81 at Ser191 and Ser216. Mutation of these residues strongly impairs ER81-responsive promoter activity. SIGNOR-262987 0.476 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120052 0.781 FZR1 protein Q9UM11 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 12234927 t miannu We found that Cdc25 A degradation during mitotic exit and in early G(1) is mediated by the anaphase-promoting complex or cyclosome (APC/C)(Cdh1) ligase, and that a KEN-box motif in the N-terminus of the protein is required for its targeted degradation. SIGNOR-271388 0.476 RPS6KA1 protein Q15418 UNIPROT RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 t llicata Rsk phosphorylates serine 58 of ranbp3 in vitro and in vivo SIGNOR-160904 0.325 glucose chemical CHEBI:17234 ChEBI AMPK complex SIGNOR-C15 SIGNOR down-regulates activity 10090 BTO:0000222 18477450 f Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK). SIGNOR-256137 0.8 RRAGB protein Q5VZM2 UNIPROT RAGBD complex SIGNOR-C116 SIGNOR form complex binding 9606 20381137 t gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant SIGNOR-228179 0.772 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser495 KTMIRKRsFGNPFEG 9606 22778263 t lperfetto Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity SIGNOR-198150 0.2 SULT1E1 protein P49888 UNIPROT 17beta-estradiol 3-sulfate(1-) smallmolecule CHEBI:136582 ChEBI up-regulates quantity chemical modification -1 7779757 t Luana HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM. SIGNOR-269751 0.8 17beta-estradiol smallmolecule CHEBI:16469 ChEBI estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity precursor of -1 8994190 t Luana Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues.  SIGNOR-269757 0.8 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR TDGF1 protein P13385 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269244 0.518 DLL1 protein O00548 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209732 0.611 BAZ1B protein Q9UIG0 UNIPROT MDC1 protein Q14676 UNIPROT down-regulates 9606 20965415 f gcesareni H2ax tyr142 is constitutively phosphorylated by the kinase wstf, a member of the baz/wal family of chromatin remodelling enzymes, and blocks mdc1 recruitment SIGNOR-168831 0.37 DIO2 protein Q92813 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 34674502 t scontino Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3. SIGNOR-266953 0.8 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity dephosphorylation Ser232 NRYGMGTsVERAAAS -1 7782287 t Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism SIGNOR-252055 0.722 UQCRC1 protein P31930 UNIPROT Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 t lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits SIGNOR-262198 0.889 MAPK3 protein P27361 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 9606 15486195 t lperfetto In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel SIGNOR-129878 0.72 DOK1 protein Q99704 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257686 0.34 F2R protein P25116 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256732 0.376 EPAS1 protein Q99814 UNIPROT KDM5B protein Q9UGL1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271578 0.287 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser705 LPEPAKKsEELVAEA 9606 10195894 t Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. SIGNOR-251283 0.2 FLT3 protein P36888 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity 10090 BTO:0001516 23246379 f miannu Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation. These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells. SIGNOR-260083 0.54 BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. SIGNOR-267969 0.74 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser174 LSPASSGsSASFISD 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248367 0.598 A6/b4 integrin complex SIGNOR-C174 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257721 0.497 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr285 AVNPPTMtPDMRSIT 9606 BTO:0000567 26183396 t miannu In this study, we found that Cdk1 (Cyclin-dependent kinase 1) directly phosphorylated TAZ on six novel sites independent of the Hippo pathway, which further resulted in TAZ degradation through proteasome system. SIGNOR-276925 0.261 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR PKM protein P14618 UNIPROT down-regulates activity phosphorylation Ser37 MCRLDIDsPPITARN 9606 28607489 t miannu We show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. Phosphomimicking mutants of PFKP (S679E) or PKM2 (S37E) displayed decreased catalytic activity, which was not further affected by pre-incubation with cyclin D3-CDK6 (Extended Data Fig. 3a, b). SIGNOR-276454 0.262 CASP8 protein Q14790 UNIPROT CASP8AP2 protein Q9UKL3 UNIPROT up-regulates binding 9606 17245429 t gcesareni The caspase-8-binding protein flice-associated huge protein (flash) would form a molecular complex with caspase-8, thereby presumably activating the mitochondrial apoptosis pathway by regulating caspase-8 activity. SIGNOR-152473 0.459 E4F1 protein Q66K89 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity ubiquitination Lys319 TSSSPQPkKKPLDGE 9606 BTO:0001938 17110336 t miannu E4F1 Has an Intrinsic Ubiquitin E3 Ligase Activity that Drives K48-type Ubiquitylation of p53. These data demonstrate that E4F1 stimulates the ubiquitylation of p53 on the lysine cluster K319–K321, i.e., at sites distinct from those targeted by Hdm2. p53 forms Ubiquitylated by E4F1 Are Localized on Chromatin. In striking contrast with Ub-p53 forms stimulated by Hdm2, which are mainly cytosoluble and targeted to the proteasome, we found that E4F1-stimulated Ub-p53 forms are tightly associated with chromatin, suggesting that they could be involved in transcription. SIGNOR-271394 0.592 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 9155018 t inferred from 70% family members lperfetto Mnk1 was phosphorylated and activated in vitro by erk1 and p38 map kinasespreliminary results showed that thr344 at least was one of the major sites phosphorylated by erk1 SIGNOR-270022 0.2 VDR protein P11473 UNIPROT CYP24A1 protein Q07973 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000067 9687155 f miannu Repression of basal transcription of a 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) responsive 25-hydroxyvitamin D3-24-hydroxylase (CYP24) promoter construct as observed in kidney cells in the absence of ligand and this repression was dependent on a functional vitamin D response element (VDRE). Basal repression was also seen with a construct where a consensus DR-3-type VDRE was fused to the thymidine kinase promoter. Expression of a dominant negative vitamin D receptor (VDR) isoform that strongly bound to the VDRE motif in the CYP24 promoter ablated basal repression. SIGNOR-255599 0.583 PPM1A protein P35813 UNIPROT RELA protein Q04206 UNIPROT down-regulates activity dephosphorylation Ser536 SGDEDFSsIADMDFS 9606 23812431 t lperfetto We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited NF-kappaB transcriptional activity, resulting in decreased expression of monocyte chemotactic protein-1 and chemokine (C-C motif) ligand 2 and interleukin-6, cytokines implicated in cancer metastasis.|18 Wild-type, but not phosphatase-dead, PPM1A dephosphorylated the pS536 peptide with equivalent efficacy as the known RelA S536 phosphatase, Wip1 (XREF_FIG, compare lanes 4 and 7).|Taken together, these data suggest that dephosphorylation of S276 by PPM1A may contribute to inhibit RelA transcriptional activity, but the majority of PPM1A activity to inhibit RelA transcription relies on dephos phorylation of S536 of RelA. SIGNOR-276964 0.36 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Thr171 ETSKSFVtPPQSHFV 9606 BTO:0002181 26028025 t miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. SIGNOR-276907 0.422 SMO protein Q99835 UNIPROT GNG3 protein P63215 UNIPROT up-regulates binding 9606 23074268 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-199186 0.2 MAPK3 protein P27361 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 15001544 t lperfetto Rin beta-cells exposed to high glucose exhibited increased c-jun n-terminal kinase (jnk) and erk1/2 activity, which was associated with increased irs-1 phosphorylation at serine (ser)(307) and ser(612), respectively, that inhibits coupling of irs-1 to the insulin receptor and is upstream of the inhibition of irs-1 tyrosine phosphorylation. SIGNOR-123177 0.696 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 18930133 t PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation. SIGNOR-248487 0.313 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR BRCA1-C complex complex SIGNOR-C299 SIGNOR form complex binding 25400280 t lperfetto The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2 SIGNOR-263222 0.808 FFAR2 protein O15552 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257397 0.2 SND1 protein Q7KZF4 UNIPROT MGLL protein Q99685 UNIPROT down-regulates quantity by destabilization binding 9606 26997225 t irozzo Interaction of SND1 with MGLL resulted in ubiquitination and proteosomal degradation of MGLL. We demonstrate that interaction of SND1 with MGLL results in increased ubiquitination and subsequent proteosomal degradation of MGLL. This down-regulation of MGLL is required for SND1 to exert its pro-tumorigenic activity because forced overexpression of MGLL markedly abrogates cell proliferation. SIGNOR-259138 0.2 ITGAV protein P06756 UNIPROT Av/b8 integrin complex SIGNOR-C185 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253289 0.829 HMGA1 protein P17096 UNIPROT SLC2A3 protein P11169 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22706202 f miannu CAV1 was shown to stimulate GLUT3 transcription via an HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization. SIGNOR-254427 0.2 LY-2157299 chemical CHEBI:137064 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193775 0.8 Scribble_complex_DLG3-LLGL2_variant complex SIGNOR-C504 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 f miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270886 0.7 MC1R protein Q01726 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257085 0.252 CSNK1G2 protein P78368 UNIPROT PER1 protein O15534 UNIPROT down-regulates phosphorylation 9606 15917222 t miannu Ck1_ and ck1_2 can promote proteasome-dependent per1 degradation in mammalian tissue culture cells, and their removal by rnai leads to an increased abundance of per1. SIGNOR-137751 0.402 monoisononyl phthalate chemical CHEBI:132593 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. SIGNOR-268782 0.8 CSNK1E protein P49674 UNIPROT PER1 protein O15534 UNIPROT down-regulates phosphorylation 9606 15917222 t miannu Ck1_ and ck1_2 can promote proteasome-dependent per1 degradation in mammalian tissue culture cells, and their removal by rnai leads to an increased abundance of per1. SIGNOR-137706 0.836 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser26 GTASRPSsSRSYVTT -1 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248882 0.288 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser394 TRQTPVDsPDDSTLS 9823 BTO:0004712 23486913 t lperfetto Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway SIGNOR-201530 0.96 AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT unknown phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 10910062 t AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a repressor domain that negatively regulates the catalytic activity of mTOR.¬† SIGNOR-251482 0.2 PRKACB protein P22694 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. SIGNOR-81149 0.404 EZR protein P15311 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0001802 16488997 f Ezrin is indispensable for Six1-induced metastasis and highly expressed in a panel of representative pediatric cancers. SIGNOR-259375 0.7 BCR-Dk complex SIGNOR-C435 SIGNOR SYK protein P43405 UNIPROT up-regulates activity binding 9606 32323266 t scontino The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK). SIGNOR-268441 0.703 CSNK2A1 protein P68400 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Ser231 KSNIVLLsAEEKKEQ 9606 7678037 t llicata These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells. SIGNOR-250915 0.312 TLK1 protein Q9UKI8 UNIPROT RAD9A protein Q99638 UNIPROT unknown phosphorylation Thr355 EPSTVPGtPPPKKFR 9606 24376897 t The effect has been demonstrated using Q9UKI8-2 llicata Here we show that rad9 is phosphorylated in a tlk-dependent manner in vitro and in vivo, and that t355 within the c-terminal tail is the primary targeted residue. SIGNOR-203503 0.46 PRKAA1 protein Q13131 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 SIGNOR-C15 19217427 t gcesareni Amp-activated protein kinase phosphorylates retinoblastoma protein. Rb phosphorylation sites, ser804 (ser811 in human), resembled the ampk consensus phosphorylation site. SIGNOR-184052 0.2 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr472 EPIQEANyVPMTPGT 10090 10978177 t HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin SIGNOR-251314 0.492 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 SIGNOR-C110 11955436 t gcesareni Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-116524 0.856 NQO1 protein P15559 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0003934 28599455 f irozzo The results demonstrated that NQO1 siRNA-mediated knockdown effectively impaired colony formation capacity, induced cell cycle arrest at the G1 phase and suppressed migration of KKU-100 cells. SIGNOR-256265 0.7 AMPK complex SIGNOR-C15 SIGNOR MTOR protein P42345 UNIPROT up-regulates activity phosphorylation Ser1261 PMKKLHVsTINLQKA 10090 BTO:0002572 31186373 t miannu AMPK directly activates mTORC2 to promote cell survival during acute energetic stress. AMPK associates with and phosphorylates mTOR within mTORC2., these data indicate that AMPK phosphorylates mTOR on Ser1261 within mTORC2, an event that correlates with increased mTORC2 autophosphorylation and downstream signaling. SIGNOR-262535 0.549 STOML2 protein Q9UJZ1 UNIPROT LCK protein P06239 UNIPROT up-regulates activity binding 9606 18641330 t Giorgia In these studies, we also found that SLP-2 interacted with Lck, ZAP70, LAT, and PLC-gamma1 during the 30-min period following stimulation in vitro|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling. SIGNOR-260376 0.2 RET protein P07949 UNIPROT GRB7 protein Q14451 UNIPROT up-regulates binding 9606 8631863 t gcesareni Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell SIGNOR-41765 0.552 USP45 protein Q70EL2 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR up-regulates activity deubiquitination 9606 BTO:0001938 25538220 t miannu USP45 associates with the ERCC1–XPF endonuclease. USP45 interacts specifically with ERCC1–XPF via its N-terminal 61 residues. USP45 deubiquitylates ERCC1. USP45 promotes survival of cells exposed to agents that induce DNA damage responses controlled by ERCC1–XPF endonuclease SIGNOR-268504 0.541 PRKCZ protein Q05513 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 BTO:0002181 25660024 t miannu  Yap and β-catenin are direct substrates of PKCζ. Similar MS/MS analysis to map the sites phosphorylated in β-catenin by PKCζ identified S45 and several sites of low abundance that included S552 and S675 (Figure S3C). SIGNOR-276879 0.582 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252860 0.908 MAPK1 protein P28482 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser14 MGAELPSsPLAIEYV 9606 BTO:0000567 11416124 t miannu In the present study, we provide the first evidence that MafA is phosphorylated and that its biological properties strongly rely upon phosphorylation of serines 14 and 65, two residues located in the transcriptional activating domain within a consensus for phosphorylation by mitogen-activated protein kinases and which are conserved among Maf proteins. These residues are phosphorylated by ERK2 but not by p38, JNK, and ERK5 in vitro.  SIGNOR-275976 0.34 TLN1 protein Q9Y490 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257615 0.638 CASP3 protein P42574 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity cleavage -1 10579725 t lperfetto P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro SIGNOR-72677 0.66 ATR protein Q13535 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser317 ENVKYSSsQPEPRTG 9606 15775976 t gcesareni Atr activation typically leads to chk1 phosphorylation and activation. In response to genotoxic stress, chk1 is phosphorylated on serines 317 (s317) and 345 (s345) by the ataxia-telangiectasia-related (atr) protein kinase. SIGNOR-134712 0.923 BRCC3 protein P46736 UNIPROT BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR form complex binding 9606 BTO:0000007 14636569 t lperfetto These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer SIGNOR-263205 0.559 CEBPB protein P17676 UNIPROT KLF5 protein Q13887 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16054042 f fspada Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter. SIGNOR-210004 0.691 exemestane chemical CHEBI:4953 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191520 0.8 NPBWR1 protein P48145 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256818 0.41 MAPK1 protein P28482 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity phosphorylation Thr607 IPTPPVTtPEGDDRP 10116 BTO:0000601 11080179 t miannu We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP. SIGNOR-262936 0.375 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr581 SDGHEYIyVDPMQLP 9606 BTO:0000599 9642269 t miannu We used two platelet-derived growth factor beta-receptor (beta-PDGFR) mutants to identify events that are required for full engagement (autophosphorylation and activation of the kinase activity) of the beta-PDGFR kinase. The F79/81 receptor (Tyr to Phe substitution at 579 and 581 in the juxtamembrane domain of the receptor) was capable of only very modest ligand-dependent autophosphorylation and also failed to associate with numerous SH2 domain-containing proteins. SIGNOR-250255 0.2 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10837473 t gcesareni Similar to pim1, pim2 phosphorylates bad, which antagonizes the pro-apoptotic function of bax SIGNOR-259418 0.2 Immune complexes stimulus SIGNOR-ST15 SIGNOR Complement C1q complex SIGNOR-C308 SIGNOR up-regulates activity binding -1 29449492 t lperfetto We used IgG monoclonal antibodies (mAbs) oligomerized through antigen-binding on liposomes or preformed antibody complexes in solution and applied tomography and single-particle cryo–electron microscopy (cryo-EM) to resolve the mechanisms of C1 binding and activation.|Binding of C1 through its gC1q modules to mediators of inflammation, such as immunoglobulin G (IgG) or IgM antibodies (fig. S1, C and D), on cell surfaces activates the associated proteases and initiates the proteolytic cascade of complement SIGNOR-263397 0.7 HRH1 protein P35367 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257050 0.2 GPER1 protein Q99527 UNIPROT GNB1 protein P62873 UNIPROT up-regulates activity binding 10696571 t GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; GNB1 stands for the subunit β, which dissociates from the receptor after the binding of GTP on α-subunit. SIGNOR-251103 0.358 H2AC11 protein P0C0S8 UNIPROT RNF168 protein Q8IYW5 UNIPROT up-regulates binding 9606 19203578 t gcesareni Rnf168 is recruited to sites of dna damage by binding to ubiquitylated histone h2a. SIGNOR-183890 0.2 pazopanib hydrochloride chemical CHEBI:71217 ChEBI ITK protein Q08881 UNIPROT down-regulates activity chemical inhibition -1 17620431 t miannu Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases.  SIGNOR-259164 0.8 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser141 MASQKRPsQRHGSKY -1 2413024 t miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 SIGNOR-250010 0.353 PPARG protein P37231 UNIPROT UCP1 protein P25874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 32991581 t brain lperfetto NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog, SIGNOR-263985 0.549 MITF protein O75030 UNIPROT SERPINF1 protein P36955 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001177 22115973 f miannu Here we show that the basic-helix-loop-helix-leucine zipper microphthalmia-associated transcription factor (MITF), which plays central roles in the development and function of a variety of cell types including RPE cells, upregulates the expression of a multifunctional factor PEDF in RPE cells. SIGNOR-254587 0.311 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation 9606 BTO:0001130 12163482 t inferred from 70% family members lperfetto Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein SIGNOR-270194 0.2 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr201 DQTPLAIyNSISYKT 9534 BTO:0000298 17027227 t Site of Jak2 tyrosine autophosphorylation; namely, tyrosine 201. Jak2 tyrosine residue 201 was the principal mediator of SHP-2 binding as conversion of this tyrosine residue to phenylalanine abolished this interaction SIGNOR-251360 0.2 PAK1 protein Q13153 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Ser192 VNSVRRKsCLVKEVE 9606 23055517 t lperfetto Here we found that mcak is a cognate substrate of pak1 wherein pak1 phosphorylates mcak on serines 192 and 111 both in vivo and in vitro. Furthermore, we found that pak1 phosphorylation of mcak on serines 192 and 111 preferentially regulates its microtubule depolymerization activity and localization to centrosomes SIGNOR-199084 0.394 NCS1 protein P62166 UNIPROT GRK2 protein P25098 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000938 12351722 t miannu Here we show that the neuronal calcium sensor-1 (NCS-1) can mediate desensitization of D2 dopamine receptors. Analysis of D2 receptors expressed in human embryonic kidney 293 cells indicates that NCS-1 attenuates agonist-induced receptor internalization via a mechanism that involves a reduction in D2 receptor phosphorylation. Coimmunoprecipitation experiments from striatal neurons reveal that NCS-1 is found in association with both the D2 receptor and G-protein-coupled receptor kinase 2, a regulator of D2 receptor desensitization. SIGNOR-263965 0.2 PRKACA protein P17612 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser183 GLRTRTGsNIDCEKL 9606 15703181 t lperfetto We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195. SIGNOR-133880 0.2 FOXO1 protein Q12778 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates 9606 20577053 f gcesareni Foxo1 antagonized ppargamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner. SIGNOR-166352 0.567 lysophosphatidylserine 14:0(1-) chemical CHEBI:72402 ChEBI P2RY10 protein O00398 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257558 0.8 RRAGA protein Q7L523 UNIPROT RAGAD complex SIGNOR-C114 SIGNOR form complex binding 9606 20381137 t gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant SIGNOR-228167 0.769 RPS6KA1 protein Q15418 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser703 MSRARIGsDPLAYEP 9606 10400637 t gcesareni The results indicate that p90rsk phosphorylates serine 703 of nhe-1, and this phosphorylation is required for growth factor stimulation of na+/h+ exchange. SIGNOR-69171 0.464 p38 proteinfamily SIGNOR-PF16 SIGNOR BCL2 protein P10415 UNIPROT down-regulates activity phosphorylation Ser87 AAAGPALsPVPPVVH 9606 19336399 t gcesareni The protein's reduced antiapoptotic capacity was related to phosphorylation of its threonine 56 and serine 87 residues by virally activated p38mapk SIGNOR-260450 0.2 NFYB protein P25208 UNIPROT NFY complex SIGNOR-C1 SIGNOR form complex binding 9606 9885213 t lperfetto Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding. SIGNOR-63016 0.963 ULK1 protein O75385 UNIPROT ATG9A protein Q7Z3C6 UNIPROT up-regulates activity phosphorylation Ser761 QSIPRSAsYPCAAPR 9606 25266655 t miannu Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK. SIGNOR-266366 0.599 CASP6 protein P55212 UNIPROT Caspase 6 complex complex SIGNOR-C228 SIGNOR form complex binding cleavage:Asp23 EENMTETdAFYKREM 21621544 t lperfetto It is generally recognized that effector caspases undergo proteolytic cleavage of the inactive zymogen at a specific aspartate residue, resulting in a large N-terminal p20 polypeptide chain and a small C-terminal p10 polypeptide chain, leading to a p202/p102 tetramer. SIGNOR-256391 0.2 GPSM3 protein Q9Y4H4 UNIPROT GNB1 protein P62873 UNIPROT down-regulates quantity by destabilization binding 22843681 t lperfetto GPSM3 was found not only to modulate heterotrimeric G-protein subunit signaling through its two active GoLoco motifs, but also to affect monomeric Gbeta subunit biosynthesis and stability|interactions between GPSM3 and Galphai1 or Gbeta1 (20) was assayed by BRET. SIGNOR-264865 0.358 FABP4 protein P15090 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264458 0.7 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH4 protein Q99466 UNIPROT up-regulates activity cleavage 9606 25610395 t lperfetto The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins. SIGNOR-209729 0.516 CTNNB1 protein P35222 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 22298955 f gcesareni In-teractions between beta-catenin and runx2 play an im-portant role in bmp-9-induced osteogenic differentia-tion of mscs. SIGNOR-195570 0.453 ACP1 protein P24666 UNIPROT PKM protein P14618 UNIPROT up-regulates activity dephosphorylation 9606 30251652 t miannu Indeed, it is evident that LMW-PTP, hydrolyzing phosphotyrosine residues, contributes to maintain PKM2 in its active form.|We speculate that this effect is in large part due to LMW-PTP inhibition, which leads a fast PKM2 phosphorylation and inactivation.|we demonstrate that in melanoma cells the overexpression of LMW-PTP is functional to maintain PKM2 in its dephosphorylate status – the tetrameric, “full active” form - which is retained in the cytoplasm SIGNOR-277134 0.282 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252875 0.697 P2RY13 protein Q9BPV8 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257027 0.2 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr852 NDPTAPPyDSLLVFD 9606 16371504 t lperfetto Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated. SIGNOR-143234 0.407 PIM proteinfamily SIGNOR-PF34 SIGNOR MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr90 AIKIIDKtQLNPTSL 9606 15319445 t gcesareni Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1. SIGNOR-259431 0.2 TSSK1B protein Q9BXA7 UNIPROT TSSK1B protein Q9BXA7 UNIPROT up-regulates activity phosphorylation Thr174 GRMALSKtFCGSPAY -1 15733851 t Manara Electrospray Q‐TOF2 mass spectroscopy analysis of a trypsin digested TSSK1 purified from E. coli, revealed that it was phosphorylated at its T‐loop residue (Fig. 2D), indicating that TSSK1 as was previously shown for MELK [18], can autophosphorylate its T‐loop Thr residue. SIGNOR-260823 0.2 PRKCA protein P17252 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser440 RSSPQRKsQRSSYVS -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262753 0.342 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 18930133 t lperfetto Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation SIGNOR-181655 0.313 APC-c complex SIGNOR-C150 SIGNOR TK1 protein P04183 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 14701726 t miannu We show that hTK1 is degraded via a ubiquitin-proteasome pathway in mammalian cells and that anaphase-promoting complex/cyclosome (APC/C) activator Cdh1 is not only a necessary but also a rate-limiting factor for mitotic degradation of hTK1. By in vitro ubiquitinylation assays, we demonstrated that hTK1 is targeted for degradation by the APC/C-Cdh1 ubiquitin ligase dependent on this KEN box motif. SIGNOR-272946 0.25 CCKBR protein P32239 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257363 0.429 ETS1 protein P14921 UNIPROT VWF protein P04275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9444957 f miannu Cotransfection of Ets-1 and Erg expression plasmids is sufficient to induce the -60/+19 vWF promoter activity in HeLa cells. SIGNOR-253915 0.298 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252975 0.509 USF1 protein P22415 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 9677331 f inferred from family member miannu Cotransfection of an expression plasmid encoding USF1 into HepG2 hepatoma cells resulted in the activation of the glucokinase promoter, dependent on the integrity of the P2 element SIGNOR-270263 0.293 MAPK8 protein P45983 UNIPROT JUNB protein P17275 UNIPROT up-regulates activity phosphorylation Thr102 SNGVITTtPTPPGQY 10090 9889198 t miannu JunB-control of IL-4 expression is mediated by the phosphorylation of JunB at Thr102 and -104 by JNK MAP kinase. The synergy between c-Maf and JunB can be attributed to cooperative DNA binding, which is facilitated by JunB phosphorylation. SIGNOR-250120 0.72 KISS1 protein Q15726 UNIPROT KISS1R protein Q969F8 UNIPROT up-regulates binding 9606 11385580 t gcesareni Here we show that kiss-1 (refs 1, 4) encodes a carboxy-terminally amidated peptide with 54 amino-acid residues, which we have isolated from human placenta as the endogenous ligand of an orphan g-protein-coupled receptor (hot7t175) and have named 'metastin' SIGNOR-108480 0.799 PTMS protein P20962 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity binding 9606 BTO:0000567 16150697 t miannu Macromolecular translocation inhibitor II (MTI-II), which was first identified as an in vitro inhibitor of binding between the highly purified glucocorticoid receptor (GR) and isolated nuclei, is an 11.5-kDa Zn2+-binding protein that is also known as ZnBP or parathymosin. MTI-II Enhances GR-dependent Transcription through Its Acidic Domain. MTI-II Enhances GR-dependent Transcription in Cooperation with SRC-1 and p300 in Vivo. CBP and p300 Coprecipitate with MTI-II in a Glucocorticoid Hormone-dependent Manner. Immunoprecipitation analysis showed that in the presence of glucocorticoid hormone, p300 and CREB-binding protein are coprecipitated with MTI-II. Furthermore, the knockdown of endogenous MTI-II by RNAi reduces the transcriptional activity of GR in cells. SIGNOR-268461 0.327 PRKAR2A protein P13861 UNIPROT PRKACA protein P17612 UNIPROT down-regulates activity binding 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258752 0.871 CAMKK1 protein Q8N5S9 UNIPROT CAMK4 protein Q16566 UNIPROT up-regulates phosphorylation 9606 10770941 t lperfetto Ca(2+)/calmodulin-dependent protein kinase kinase (CaM-KK) is a novel member of the CaM kinase family, which specifically phosphorylates and activates CaM kinase I and IV SIGNOR-232181 0.604 CIB2 protein O75838 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity binding 10090 34162842 t miannu Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to 'nucleotide empty' or inactive GDP-loaded Rheb.  SIGNOR-269663 0.266 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000150 18372406 t gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-178133 0.657 IKBKE protein Q14164 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 11815618 t lperfetto Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. |TBK-1 and IKK-i phosphorylate Ser36 of IkappaBalpha. SIGNOR-249367 0.497 PAK6 protein Q9NQU5 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Thr158 HLVSRPStSSRRRAI 9606 BTO:0000007 23132866 t miannu We also showed that PAK6 phosphorylates Mdm2 on Thr-158 and Ser-186, which is critical for AR ubiquitin-mediated degradation. SIGNOR-276428 0.2 chlorpromazine chemical CHEBI:3647 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258836 0.8 long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity precursor of 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267906 0.8 DAPK3 protein O43293 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 1178183 t lperfetto Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge. SIGNOR-16043 0.526 MAPK3 protein P27361 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates phosphorylation 9606 14967450 t gcesareni Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1 SIGNOR-121991 0.296 MAPK1 protein P28482 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 20630875 t gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. The kinases involved in phosphorylating stmn ser-16 and ser-63 include camp-dependent protein kinase (pka) and pak1, whereas stmn ser-25 and ser-38 have been shown to be targets for proline-directed serine/threonine kinases such as cyclin-dependent kinases, erk1/2, and members of the p38 mapk subfamily. SIGNOR-166686 0.432 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser641 YRYPRPAsVPPSPSL 9606 BTO:0000887;BTO:0001103 14593110 t lperfetto Glycogen synthase kinase-3 (gsk-3) phosphorylates four serine residues in the cooh terminus of glycogen synthase. Phosphorylation of one of these residues, ser640 (site 3a), causes strong inactivation of glycogen synthase SIGNOR-235793 0.673 LCK protein P06239 UNIPROT PRKCQ protein Q04759 UNIPROT unknown phosphorylation Tyr90 SETTVELySLAERCR 9606 10652356 t llicata Tyrosine 90 (tyr-90) in the regulatory domain of pkctheta was identified as the major phosphorylation site by lck. SIGNOR-74574 0.549 CAMKK1 protein Q8N5S9 UNIPROT CAMK4 protein Q16566 UNIPROT up-regulates phosphorylation Thr200 EHQVLMKtVCGTPGY 9606 15769749 t gcesareni Phosphorylation of ca(2+)/cam-bound camkiv on its activation loop threonine (residue thr(200) in human camkiv) by ca(2+)/calmodulin-dependent kinase kinase leads to increased camkiv kinase activity. SIGNOR-134649 0.604 PRKCZ protein Q05513 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity phosphorylation Ser346 EWEAQRDsHLGPHRS 9606 14576165 t lperfetto A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis. SIGNOR-249239 0.343 FYN protein P06241 UNIPROT PTPRJ protein Q12913 UNIPROT up-regulates activity phosphorylation Tyr1311 DSKVDLIyQNTTAMT 9606 BTO:0000007 22898603 t miannu  We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin. SIGNOR-276372 0.373 Corticotropin protein P01189-PRO_0000024969 UNIPROT MC3R protein P41968 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268706 0.2 BCL2L11 protein O43521 UNIPROT BCL2L2 protein Q92843 UNIPROT down-regulates binding 9606 15694340 t gcesareni Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1. SIGNOR-133832 0.789 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.78 ponatinib chemical CHEBI:78543 ChEBI RIPK1 protein Q13546 UNIPROT down-regulates activity chemical inhibition 9606 25801024 t Federica Discovery of ponatinib as the first-in-class dual inhibitor of RIPK1 and RIPK3 SIGNOR-261082 0.8 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2C protein O00762 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271322 0.716 ABCC4 protein O15439 UNIPROT sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI up-regulates quantity relocalization 9606 29304533 t lperfetto Release of Platelet-Derived Sphingosine-1-Phosphate Involves Multidrug Resistance Protein 4 (MRP4/ABCC4) and Is Inhibited by Statins SIGNOR-265912 0.8 PRKD1 protein Q15139 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225]. SIGNOR-123226 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR TP53RK protein Q96S44 UNIPROT up-regulates phosphorylation Ser250 RLRGRKRsMVG 9606 17712528 t gcesareni Here we show that such an activation of prpk is mediated by another kinase, akt/pkb, which phosphorylates prpk at ser250. SIGNOR-157467 0.2 SETD5 protein Q9C0A6 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity methylation -1 31515109 t miannu SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription. SIGNOR-265350 0.2 YES1 protein P07947 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr80 LLDACGFyWGPLSVH 9606 BTO:0000104 31101761 t miannu  Samples from human lymphomas that often overexpress SOCS1 also displayed SRC family kinase activation, constitutive phosphorylation of SOCS1 on Y80, and SOCS1 cytoplasmic localization.  SIGNOR-277453 0.2 YAP1 protein P46937 UNIPROT TEAD4 protein Q15561 UNIPROT up-regulates binding 9606 23431053 t Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4 gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14. SIGNOR-201474 0.925 MAPK14 protein Q16539 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates activity phosphorylation 10090 20551513 t ggiuliani Mechanistic analysis revealed that the TAK1–MKK3/6–p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38β and establish that MAPK signaling is essential for bone formation in vivo. SIGNOR-255777 0.375 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR H3C1 protein P68431 UNIPROT up-regulates activity methylation Lys28 LATKAARkSAPATGG 9606 24987060 t miannu The presence of trimethylation of H3K27 (H3K27me3) at promoter regions is associated with gene repression. This modification is generated by the Polycomb repressive complex 2 (PRC2), composed of the SET domain-containing histone methyltransferase (HMT) EZH2 (enhancer of zeste homolog 2) or its functional homologue EZH1, and core accessory proteins (EED, SUZ12, and RbAp48) (Fig. 1A). SIGNOR-260449 0.2 SDHB protein P21912 UNIPROT Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 30030361 t lperfetto Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites SIGNOR-262189 0.965 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-264178 0.8 PPARGC1A protein Q9UBK2 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001103 17609368 f gcesareni Pgc-1alpha protein is required for ampk action on glut4 gene expression and mitochondrial function. SIGNOR-156769 0.611 YAP1 protein P46937 UNIPROT TP73 protein O15350 UNIPROT up-regulates binding 9606 21808241 t The WW domain of YAP binds to PPXY-containing p73 family members. gcesareni Yap also interacts with p73, a p53 family pro-apoptotic transcription factor, to induce expression of genes such as bax, puma and pml. SIGNOR-175934 0.704 CEBPA protein P49715 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates activity 10090 BTO:0000725 19706798 f Conditional cebpa deficiency in adult mice blocks the transition from common myeloid progenitors (CMP) to granulocyte monocyte progenitors (GMP) resulting in the accumulation of myeloid blasts SIGNOR-259965 0.7 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser217 AHYSPRTsPIMSPRT 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248372 0.598 progesterone smallmolecule CHEBI:17026 ChEBI CACNA2D3 protein Q8IZS8 UNIPROT up-regulates quantity 9606 31746409 f miannu In vivo and in vitro, the addition of P4 upregulated the expression of CACNA2D3 and silencing of CACNA2D3 impaired the function of P4 on cell apoptosis and proliferation. SIGNOR-266856 0.8 canertinib chemical CHEBI:61399 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258094 0.8 ZFX protein P17010 UNIPROT FBP1 protein P09467 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003081;BTO:0000849 30616754 t lperfetto For instance, nucleophosmin (NPM1) and zinc-finger protein X-linked (ZFX) bind to the E-box and ZFX binding site on the FBP1 promoter, respectively, and restrain FBP1 expression to facilitate aerobic glycolysis in PDAC and melanoma SIGNOR-267595 0.2 COL4A1 protein P02462 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 35267698 t lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. SIGNOR-272353 0.512 CDK2 protein P24941 UNIPROT COIL protein P38432 UNIPROT up-regulates phosphorylation Ser184 NEEAKRKsPKKKEKC 9606 SIGNOR-C16 11102515 t lperfetto In particular, we have recently found that the cdk2/cyclin e complex can phosphorylate coilin in vitro . there is but a single consensus cdk2/cyclin e phosphorylation site in coilin, located at serine 184. when serine 184 was mutated to an alanine (s184a), mimicking a dephosphorylated state, a nucleolar mislocalization similar to that of gfp-coilin(1_248) was observed SIGNOR-84949 0.389 IDE protein P14735 UNIPROT INS protein P01308 UNIPROT down-regulates quantity by destabilization cleavage -1 29596046 t SARA IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds SIGNOR-260986 0.743 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 12950161 t lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitro.catalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases SIGNOR-86581 0.412 IKBKB protein O14920 UNIPROT YWHAB protein P31946 UNIPROT down-regulates phosphorylation Ser132 GDYFRYLsEVASGDN 9606 16024783 t gcesareni We provide a mechanism for these observations through the phosphorylation of 14-3-3beta by ikkbeta and pkcdelta on serine residues ser132 and ser60, respectively, which interferes with its binding to ttp and hence the retention of ttp in the cytoplasm. SIGNOR-138608 0.377 ZMIZ1 protein Q9ULJ6 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 10090 BTO:0001825 26522984 f miannu Our data suggest that Zmiz1 and Notch1 cooperatively recruit each other to chromatin through direct interaction via the TPR resulting in a slight increase in activating histone marks and decrease of repressive histone marks. SIGNOR-263938 0.7 TWIST2 protein Q8WVJ9 UNIPROT MYB protein P10242 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255495 0.2 CAMK2G protein Q13555 UNIPROT PLCB3 protein Q01970 UNIPROT unknown phosphorylation Ser537 PSLEPQKsLGDEGLN 11325525 t llicata CaMK II phosphorylated PLCbeta3 but not PLCbeta1 in vitro. Phosphorylation occurred exclusively on 537Ser in the X-Y linker region of PLCbeta3. 537Ser was also phosphorylated in the basal state in cells and phosphorylation was enhanced by ionomycin treatment SIGNOR-250702 0.385 RHOA protein P61586 UNIPROT MSN protein P26038 UNIPROT up-regulates activity phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 BTO:0000132 35267019 t miannu Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. SIGNOR-268431 0.629 MAPK3 protein P27361 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser540 KVMARSLsPPPELEE 10090 15851026 t lperfetto Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation. SIGNOR-249458 0.681 trametinib chemical CHEBI:75998 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192826 0.8 WNT10B protein O00744 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131625 0.601 CNKSR1 protein Q969H4 UNIPROT EPHB1 protein P54762 UNIPROT up-regulates activity binding 26319181 t lperfetto The phosphorylated CNK1 interacts with ephrinB1. The binding of ephrinB1 to CNK1 connects RhoA and p115RhoGEF with ephrinB1-associated MKK4, promoting JNK activation and cell migration. SIGNOR-275921 0.297 NUMA1 protein Q14980 UNIPROT TUBA1C protein Q9BQE3 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-116677 0.261 DNA_damage stimulus SIGNOR-ST1 SIGNOR RAD23A protein P54725 UNIPROT up-regulates 24086043 f lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). SIGNOR-275686 0.7 KIT protein P10721 UNIPROT SLA protein Q13239 UNIPROT down-regulates activity phosphorylation Tyr273 SFFSSPPyFED 9534 BTO:0001538 24284075 t miannu Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity SIGNOR-263142 0.2 DAPK1 protein P53355 UNIPROT STX1A protein Q16623 UNIPROT down-regulates activity phosphorylation Ser188 IIMDSSIsKQALSEI 9606 BTO:0000007;BTO:0000356 12730201 t llicata Syntaxin-1A phosphorylation by DAP kinase or its S188D mutant, which mimics a state of complete phosphorylation, significantly decreases syntaxin binding to Munc18-1, a syntaxin-binding protein that regulates SNARE complex formation and is required for synaptic vesicle docking. SIGNOR-251083 0.346 INSR protein P06213 UNIPROT BLVRA protein P53004 UNIPROT up-regulates activity phosphorylation Tyr228 PGLKRNRyLSFHFKS 15870194 t lperfetto Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK).|in addition to Y198 in the YMKM motif, 2 other tyrosines, Y228 in the YLSF motif and Y291 in the C-terminus of the protein, are directly phosphorylated by IRK SIGNOR-275515 0.492 NAE complex SIGNOR-C131 SIGNOR CUL4A protein Q13619 UNIPROT up-regulates activity neddylation 9606 25504797 t lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. SIGNOR-243160 0.61 TMC1 protein Q8TDI8 UNIPROT Hair cells mechanotransduction channel complex SIGNOR-C290 SIGNOR form complex binding 10090 BTO:0000630 23217710 t lperfetto The pore forming subunits of the hair cells mechanotransduction channel still need to be identified, but some candidates have emerged including TMC-1,TMC-2 (Kawashima et al., 2011), Piezo1 and Piezo2 (Coste et al., 2010; Coste et al., 2012). SIGNOR-262569 0.4 DYRK1A protein Q13627 UNIPROT SPRY2 protein O43597 UNIPROT down-regulates phosphorylation Thr75 KPAPRPStQHKHERL 9606 18678649 t gcesareni We identify dyrk1a as one of the protein kinases of sprouty2. We show that dyrk1a interacts with and regulates the phosphorylation status of sprouty2. Moreover, we identify thr75 on sprouty2 as a dyrk1a phosphorylation site in vitro and in vivo. SIGNOR-179828 0.309 CHD8 protein Q9HCK8 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 t Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells SIGNOR-268914 0.2 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1173 QDTSKFWyKADISRE 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t llicata Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate SIGNOR-187843 0.417 WT1 protein P19544 UNIPROT SRY protein Q05066 UNIPROT up-regulates binding 9606 12970737 t miannu Here we report that wt1 binds to and acts synergistically with sry to activate transcription from a promoter containing sry-binding sites SIGNOR-100345 0.2 CENPX protein A8MT69 UNIPROT FANCM protein Q8IYD8 UNIPROT up-regulates binding 9606 20347429 t gcesareni We also provide biochemical evidence that mhf1 and mhf2 assemble into a heterodimer that binds dna and enhances the dna branch migration activity of fancm. These findings reveal critical roles of the mhf1-mhf2 dimer in dna damage repair and genome maintenance through fancm. SIGNOR-164729 0.2 MAPK1 protein P28482 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Thr360 SGISSVPtPSPLGPL 9606 BTO:0000527 19941816 t lperfetto Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity SIGNOR-161855 0.376 SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000007 12600984 t lperfetto We also showed that phosphorylation of Tyr-315 in Akt induced by Src or EGF is dependent on the integrity of this proline-rich motif. Furthermore, the Akt mutant lacking this proline motif fails to block the transcription activity of Forkhead in 293 cells and poorly stimulates the proliferation of Madin-Darby canine kidney cells. Taken together, our data suggest that the interaction between the SH3 domain of Src family kinases and the proline-rich motif in the C-terminal regulatory region of Akt is required for tyrosine phosphorylation of Akt and its subsequent activation. SIGNOR-246373 0.664 erlotinib chemical CHEBI:114785 ChEBI EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258212 0.8 GTF2I protein P78347 UNIPROT USF1 protein P22415 UNIPROT up-regulates activity binding 9606 21282467 t lperfetto TFII-I has been shown to interact with USF and to associate with either E-box elements or initiator sequences to activate gene transcription SIGNOR-268538 0.503 SLC9A8 protein Q9Y2E8 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265598 0.8 vorinostat chemical CHEBI:45716 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257920 0.8 PTPRF protein P10586 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates dephosphorylation 9606 11121408 t gcesareni Here we show that lar reduces the constitutive tyrosine autophosphorylation and kinase activity of ret-men2a but not ret-men2b, accompanying a significant decrease of phosphorylation of phospholipase cgamma, akt, and erk1/2. SIGNOR-85166 0.2 RAN protein P62826 UNIPROT XPOT protein O43592 UNIPROT up-regulates activity binding 9606 9660920 t miannu The first step in export appears to be the formation of a trimeric tRNA/exportin-t/RanGTP complex. tRNA and RanGTP bind to exportin-t in a highly cooperative manner: tRNA increases the affinity of exportin-t for RanGTP apparently 300-fold (Figure 5A); conversely, RanGTP has to increase the affinity of exportin-t for tRNA by the same factor. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus SIGNOR-261392 0.808 TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus SIGNOR-235380 0.805 HTR2B protein P41595 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257022 0.252 COX5B protein P10606 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 10090 BTO:0000165 18701479 f lperfetto Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS. SIGNOR-253104 0.7 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr536 QKGQESEyGNITYPP 9606 BTO:0001412 8692915 t gcesareni Treatment with ionizing radiation is associated with c-Abl-dependent tyrosine phosphorylation of SHPTP1. The results demonstrate that the SH3 domain of c-Abl interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that c-Abl phosphorylates C terminal Y536 and Y564 sites. SIGNOR-246227 0.423 SRC protein P12931 UNIPROT PTPRJ protein Q12913 UNIPROT up-regulates activity phosphorylation Tyr1320 NTTAMTIyENLAPVT 9606 BTO:0000007 22898603 t miannu  We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin. SIGNOR-276375 0.621 MAPK8 protein P45983 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Ser140 GKKATQAsQEY 9606 BTO:0000671 19234442 t gcesareni The stress-response kinase jnk1, activated by dna damage and initiating a pro-apoptotic program, has been recently shown to translocate into the nucleus upon activation where it phosphorylates substrates including h2ax s139, an event critical for dna degradation mediated by caspase-activated dnase (cad) in apoptotic cells SIGNOR-184146 0.2 RPS5 protein P46782 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262419 0.884 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Lys72 SASVLTGkLTTVFLP -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263594 0.381 ARRB2 protein P32121 UNIPROT KIF3A protein Q9Y496 UNIPROT up-regulates binding 9606 23074268 t gcesareni Betaarrestin 2 was subsequentialy shown to bridge smo to the kinestesin motor kif3 to promote ciliary accumulation of smo in mammalian cells SIGNOR-199107 0.623 CDC14B protein O60729 UNIPROT TAF1C protein Q15572 UNIPROT up-regulates activity dephosphorylation 9606 26023773 t miannu Consistent with prior studies showing that the phosphatase hCdc14B regulates progression through mitosis by counteracting mitotic phosphorylation by Cdk1/cyclin B [ ], hCdc14B dephosphorylates TAFI110, thus promoting its reactivation as cells exit mitosis.|Here we show that hCdc14B, the phosphatase that regulates Cdk1/cyclin B activity and progression through mitosis, promotes reactivation of rDNA transcription by dephosphorylating TAFI110. SIGNOR-277135 0.2 PTGS1 protein P23219 UNIPROT prostaglandin H2(1-) smallmolecule CHEBI:57405 ChEBI up-regulates quantity chemical modification -1 7592599 t Luana [14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2, SIGNOR-269778 0.8 ASXL1 protein Q8IXJ9 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 29967380 t miannu Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification. These results indicated that loss of protein interaction between Asxl1 mutant and Bmi1 affected the activity of PRC1, and subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in Asxl1G643fs/+ mice. SIGNOR-260119 0.305 UBE2I protein P63279 UNIPROT IRF7 protein Q92985 UNIPROT down-regulates activity sumoylation Lys452 EKSLVLVkLEPWLCR 9606 BTO:0002181 22951831 t scontino One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses. We recently documented that LMP1 induces a third major protein modification by physically interacting with the SUMO-conjugating enzyme Ubc9 through CTAR3 and inducing the sumoylation of cellular proteins in latently infected cells. we identified that IRF7 is sumoylated at lysine 452. SIGNOR-266837 0.291 GPIb-IX-V complex complex SIGNOR-C270 SIGNOR Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 9606 32644488 f lperfetto Therefore, VWF cannot bind to the GpIb receptors on platelets via the A1 domain to induce platelet aggregation and further hemostasis.  SIGNOR-261866 0.7 nilotinib chemical CHEBI:52172 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258259 0.8 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 21098032 t gcesareni Kinase activity of plk3 was significantly activated by hyperosmotic stimulation. Further downstream, active plk3 phosphorylated atf-2 at the thr-71 site in vivo and in vitro. SIGNOR-170008 0.2 SIRT5 protein Q9NXA8 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity catalytic activity 9606 27113762 t Monia Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose-6-phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH-producing enzymes. SIGNOR-261211 0.281 AVPR1B protein P47901 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256934 0.252 GHITM protein Q9H3K2 UNIPROT CYCS protein P99999 UNIPROT down-regulates quantity relocalization 9606 BTO:0000567 18417609 t Giulio MICS1 was clearly coprecipitated with cytochrome c-3FLAG and the amount was DSP concentration-dependent (Figure 6A). Together with the finding that overexpression of exogenous MICS1 delayed the apoptotic release of cytochrome c in normal-serum level medium (Figure 4A), these results suggest that MICS1 helps to retain cytochrome c in the inner membrane, apart from the morphological changes. SIGNOR-260294 0.257 ATG16L1 protein Q676U5 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR form complex binding 9606 BTO:0000007 18321988 t lperfetto Atg12 is conjugated to atg5 and forms an approximately 800-kda protein complex with atg16l (referred to as atg16l complex). SIGNOR-226696 0.882 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19114991 t lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity SIGNOR-182967 0.733 LPAR2 protein Q9HBW0 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257431 0.461 TNF protein P01375 UNIPROT AKT2 protein P31751 UNIPROT up-regulates 9606 11287630 f lperfetto Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase SIGNOR-106596 0.323 CD27 protein P26842 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 12324477 f gcesareni Cd40 ligation up-regulated bcl-2 and bcl-xl as much as 9.7- (p < 0.01) and 6.8-fold (p < 0.01), respectively (fig. 2, b and c). Under similar conditions, cd27 ligation also up-regulated bcl-2 and bcl-xl as much as 5.0- (p < 0.01) and 3.9-fold (p < 0.01), respectively. SIGNOR-93320 0.327 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. SIGNOR-216797 0.373 SRC protein P12931 UNIPROT RACK1 protein P63244 UNIPROT up-regulates phosphorylation Tyr246 LCFSPNRyWLCAATG 9606 12400005 t gcesareni We found that rack1 is a src substrate. Moreover, src activity is necessary for both the tyrosine phosphorylation of rack1 and the binding of rack1 to src's sh2 domain that occur following pkc activation. To identify the tyrosine(s) on rack1 that is phosphorylated by src, we generated and tested a series of rack1 mutants. We found that src phosphorylates rack1 on tyr 228 and/or tyr 246 SIGNOR-94800 0.2 MAPK1 protein P28482 UNIPROT RSPH3 protein Q86UC2 UNIPROT up-regulates activity phosphorylation Thr243 QEQLRPQtPEPVEGR 9606 19684019 t miannu ERK1/2 phosphorylate RSPH3. the extent of radiolabeled phosphate incorporation into RSPH3 T286A was much less than that into wild-type RSPH3, suggesting that threonine 286 is the major ERK1/2 phosphorylation site in cells. ERK2 also phosphorylates RSPH3 on threonine 243 to a lesser extent. Phosphorylation of the double mutant T243V/T286A RSPH3 was no more than 20% that of wild-type RSPH3 (Fig. 4, C and D). inhibiting ERK1/2 activity appears to negatively regulate the AKAP function of RSPH3. SIGNOR-262839 0.2 RNF8 protein O76064 UNIPROT RAD18 protein Q9NS91 UNIPROT up-regulates binding 9606 19396164 t gcesareni Rnf8 depletion also significantly reduced the accumulation of rad18 to chromatin fraction after ir SIGNOR-185593 0.425 NFYA protein P23511 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity binding 9606 12427542 t miannu Our results further confirm the important transactivating role for NF-Y for the CBS-1b promoter, via its synergism with Sp1. While differential phosphorylation of Sp1 likely contributes to binding to multiple GC-/GT-boxes in the CBS-1b and promoter activation [16], NF-Y is clearly necessary for a maximal activation response. SIGNOR-254816 0.6 RPS6K proteinfamily SIGNOR-PF26 SIGNOR DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 9606 22017877 t lperfetto We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1 SIGNOR-252797 0.2 SRCAP protein Q6ZRS2 UNIPROT KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003160 20432434 f miannu ShRNA mediated knockdown of SRCAP resulted in decreased H2A.Z binding at the enhancer region of the PSA promoter and decreased expression of PSA in prostate cancer cells. SIGNOR-255220 0.2 CEBPD protein P49716 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000792 20385105 f miannu Expression of CEBPD reduced cisplatin-induced reactive oxygen species (ROS) and apoptosis in NTUB1 cells by inducing the expression of Cu/Zn-superoxide dismutase (SOD1) via direct promoter transactivation. SIGNOR-253774 0.2 SRC protein P12931 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Tyr92 FYEEIKKyEKLETEE 16725308 t miannu Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq.  SIGNOR-266293 0.2 MAP2K2 protein P36507 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244637 0.736 RAGAC complex SIGNOR-C113 SIGNOR MTOR protein P42345 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 SIGNOR-C3 20381137 t lperfetto The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb SIGNOR-228657 0.804 MAPKAPK5 protein Q8IW41 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates activity phosphorylation Ser727 RQNPSRCsVSLSNVE 9606 BTO:0000007;BTO:0000567 10978317 t miannu The p38-activated protein kinases MNK1, MSK1, and PRAK1 phosphorylate cPLA2 in vitro uniquely on Ser-727. By using Chinese hamster ovary, HeLa, and HEK293 cells stably transfected with wild type and phosphorylation site mutant forms of cPLA2, we show that phosphorylation of cPLA2 at both Ser-505 and Ser-727 and elevation of Ca(2+) leads to its activation in agonist-stimulated cells. SIGNOR-250162 0.34 PSMA4 protein P25789 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263366 0.836 TNFRSF17 protein Q02223 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates 9606 10903733 f miannu Overexpression of bcma activates the p38 mapk SIGNOR-79501 0.2 MAPK1 protein P28482 UNIPROT RPS3 protein P23396 UNIPROT unknown phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 t llicata Erk phosphorylates threonine 42 residue of ribosomal protein s3. SIGNOR-136075 0.2 GRM4 protein Q14833 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264352 0.7 PAK1 protein Q13153 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 12198493 t gcesareni In flna, the pak1-binding site involves tandem repeat 23 in the carboxyl terminus and phosphorylation takes place on serine 2152. SIGNOR-92065 0.782 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 9606 20151718 t miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-163776 0.277 ZBED1 protein O96006 UNIPROT RPS12 protein P25398 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 17220279 t Luana HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid. SIGNOR-266084 0.2 imatinib chemical CHEBI:45783 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193375 0.8 RAB7A protein P51149 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates activity guanine nucleotide exchange factor BTO:0001131 14617358 t Sara The p150 adapter protein is in a complex with rab7. The hVPS34/p150 complex colocalized with rab7 on late endosomes and hVPS34 activity was dependent on nucleotide cycling of rab7 SIGNOR-261302 0.498 NFE2L2 protein Q16236 UNIPROT TXN protein P10599 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000552 18629308 f miannu When overexpressed in HaCaT cells, NRF2 was also directly involved in not only the up-regulation of the detoxification gene thioredoxin but also K16 gene expression. SIGNOR-254646 0.413 SEC23IP protein Q9Y6Y8 UNIPROT SEC23A protein Q15436 UNIPROT up-regulates activity binding 10090 BTO:0000142 10400679 t lperfetto The results showed that the N-terminal region of p125 is important for the interaction with Sec23p. We confirmed the interaction between the two proteins by a yeast two-hybrid assay. Overexpression of p125, like that of mammalian Sec23p, caused disorganization of the endoplasmic reticulum-Golgi intermediate compartment and Golgi apparatus, suggesting its role in the early secretory pathway. SIGNOR-265307 0.554 MAPK1 protein P28482 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Thr125 PEVLRPEtPRPVDIG 10090 BTO:0000782 16888006 t lperfetto ERK/MAPK phosphorylates caspase-9 at Thr(125), and this phosphorylation is crucial for caspase-9 inhibition SIGNOR-148616 0.549 DKK1 protein O94907 UNIPROT LRP6 protein O75581 UNIPROT down-regulates binding 9606 11448771 t gcesareni We report that dkk-1 is a high-affinity ligand for lrp6 and inhibits wnt signaling by preventing fz-lrp6 complex formation induced by wnt. Dkk1 has been shown to inhibit wnt by binding to and antagonizing lrp5/6. SIGNOR-109247 0.901 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1132 TLPHGPRsASVSSIS 9606 8816480 t lperfetto In this report, we describe the identification of five MAP kinase sites (S-1137, S-1167, S-1178, S-1193, and S-1197) on hSos1.Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-43939 0.621 ITGB4 protein P16144 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 9428518 t gcesareni Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation. SIGNOR-252697 0.4 WSB1 protein Q9Y6I7 UNIPROT HIPK2 protein Q9H2X6 UNIPROT down-regulates ubiquitination 9606 18093972 t lperfetto Ubiquitination and degradation of homeodomain-interacting protein kinase 2 by wd40 repeat/socs box protein wsb-1 SIGNOR-160032 0.585 MTHFD1L protein Q6UB35 UNIPROT formate smallmolecule CHEBI:15740 ChEBI up-regulates quantity chemical modification 9606 16171773 t lperfetto A human mitochondrial isozyme of C1-tetrahydrofolate (THF) synthase was previously identified by its similarity to the human cytoplasmic C1-THF synthase. All C1-THF synthases characterized to date, from yeast to human, are trifunctional, containing the activities of 5,10-methylene-THF dehydrogenase, 5,10-methenyl-THF cyclohydrolase, and 10-formyl-THF synthetase. Here we report on the enzymatic characterization of the recombinant human mitochondrial isozyme. Enzyme assays of purified human mitochondrial C1-THF synthase protein revealed only the presence of 10-formyl-THF synthetase activity. SIGNOR-268254 0.8 PRKACA protein P17612 UNIPROT PPP2R5D protein Q14738 UNIPROT up-regulates phosphorylation Ser573 KVLLRRKsELPQDVY 9606 17301223 t gcesareni Protein kinase a activates protein phosphatase 2a by phosphorylation of the b56delta subunit. SIGNOR-153218 0.2 DDX3X protein O00571 UNIPROT EIF4E protein P06730 UNIPROT down-regulates activity binding 9606 BTO:0001950 17667941 t miannu DDX3 is a human RNA helicase with plethoric functions. we identified translation initiation factor eukaryotic initiation factor 4E (eIF4E) as a DDX3-binding partner. Interestingly, DDX3 utilizes a consensus eIF4E-binding sequence YIPPHLR to interact with the functionally important dorsal surface of eIF4E in a similar manner to other eIF4E-binding proteins. Furthermore, cap affinity chromatography analysis suggests that DDX3 traps eIF4E in a translationally inactive complex by blocking interaction with eIF4G. SIGNOR-269193 0.648 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 12612081 t In this study, we investigated the downregulation of insulin receptor (IR) signaling by TCPTP. In response to insulin stimulation, the TC48-D182A and TC45-D182A substrate-trapping mutants formed stable complexes with the endogenous tyrosine-phosphorylated IR beta-subunit in 293 cells.|IR β-subunit phosphorylated on tyrosine and specifically on tyrosines 1162 and 1163 could be coimmunoprecipitated with the TC48-D182A and TC45-D182A mutants but not the wild-type TC48 or TC45 in response to insulin SIGNOR-248386 0.606 vorinostat chemical CHEBI:45716 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257951 0.8 CDK2 protein P24941 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity SIGNOR-252891 0.638 EIF2B1 protein Q14232 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269129 0.771 carvedilol chemical CHEBI:3441 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258165 0.8 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI guanosine 5'-monophosphate smallmolecule CHEBI:17345 ChEBI up-regulates quantity precursor of 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267336 0.8 CDK2 protein P24941 UNIPROT ZC3HC1 protein Q86WB0 UNIPROT down-regulates phosphorylation Ser395 PGLEVPSsPLRKAKR 9606 17389604 t gcesareni Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1 SIGNOR-154051 0.2 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CD4 protein P01730 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 11893391 t miannu Degradation of the HIV receptor CD4 by the proteasome, mediated by the HIV-1 protein Vpu, is crucial for the release of fully infectious virions. To promote CD4 degradation Vpu has to be phosphorylated on a motif DSGXXS, which is conserved in several signalling proteins known to be degraded by the proteasome upon phosphorylation. Such phosphorylation is required for the interaction of Vpu with the ubiquitin ligase SCF-beta-TrCP that triggers CD4 degradation by the proteasome. SIGNOR-272615 0.255 pazopanib hydrochloride chemical CHEBI:71217 ChEBI FGFR3 protein P22607 UNIPROT down-regulates activity chemical inhibition -1 17620431 t miannu Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases.  SIGNOR-259165 0.8 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI CEBPB protein P17676 UNIPROT up-regulates 9606 11279134 f fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin SIGNOR-209986 0.8 CASP8 protein Q14790 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates activity cleavage Asp324 RMQSLQLdCVAVPSS 9606 BTO:0000007;BTO:0000093;BTO:0000567 10521396 t amattioni These results suggested that the aspartic acid at position 324 is the cleavage site of ripk1. In this study we found that receptor-interacting protein (ripk1) is cleaved by casp8 when cells undergo tnf-induced apoptosis. The cleavage of ripk1 abolished its nf-kb inducing ability. SIGNOR-71265 0.907 CSNK2A1 protein P68400 UNIPROT BRMS1 protein Q9HCU9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser30 MNGEEEEsEEERSGS -1 26980766 t miannu We show that BRMS1 is posttranslationally regulated by TNF-induced casein kinase 2 catalytic subunit (CK2α') phosphorylation of nuclear BRMS1 on serine 30 (S30), resulting in 14-3-3ε-mediated nuclear exportation, increased BRMS1 cytosolic expression, and ubiquitin-proteasome-induced BRMS1 degradation. SIGNOR-266407 0.464 SHH protein Q15465 UNIPROT MYF5 protein P13349 UNIPROT up-regulates 9606 BTO:0002314 18662193 f gcesareni Shh reactivation plays a regulatory role on myogenesis, as its inhibition impairs the activation of the myogenic regulatory factors myf-5 and myod, decreases the up-regulation of insulin-like growth factor (igf)-1 and reduces the number of myogenic satellite cells at injured site. SIGNOR-179629 0.418 SIRT1 protein Q96EB6 UNIPROT COL10A1 protein Q03692 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21337390 f miannu The inhibition of SIRT1 by siRNA induced OA-like gene expression changes, namely the significant down-regulation of aggrecan and up-regulation of COL10A1 and ADAMTS-5. SIGNOR-255141 0.2 TADA3 protein O75528 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269584 0.751 CHD8 protein Q9HCK8 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity binding 9606 BTO:0000567 19255092 t miannu We also show that CHD8 associates with the elongating form of RNAPII, which is phosphorylated in its carboxy-terminal domain (CTD). Furthermore, CHD8-depleted cells are hypersensitive to drugs that inhibit RNAPII phosphorylation at serine 2, suggesting that CHD8 is required for an early step of the RNAPII transcription cycle. SIGNOR-268806 0.28 RNGTT protein O60942 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity chemical modification 9606 9512541 t lperfetto The human mRNA 5'-capping enzyme cDNA was identified. Three highly related cDNAs, HCE1 (human mRNAcappingenzyme1), HCE1A and HCE1B , were isolated from a HeLa cDNA library. The HCE1 cDNA has the longest ORF, which can encode a 69 kDa protein. A short region of 69 bp in the 3'-half of the HCE1 ORF was missing in HCE1A and HCE1B , and, additionally, HCE1B has an early translation termi SIGNOR-268357 0.8 STX17-VAMP8 SNARE complex complex SIGNOR-C551 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates activity 9606 BTO:0000007 23217709 f miannu Here, we identify syntaxin 17 (Stx17) as the autophagosomal SNARE required for fusion with the endosome/lysosome. Stx17 localizes to the outer membrane of completed autophagosomes but not to the isolation membrane (unclosed intermediate structures); for this reason, the lysosome does not fuse with the isolation membrane. Stx17 interacts with SNAP-29 and the endosomal/lysosomal SNARE VAMP8. SIGNOR-273712 0.7 GNB1 protein P62873 UNIPROT GNG2 protein P59768 UNIPROT up-regulates activity binding 10696571 t GNB1 dissociates from the receptor, bound with GNG2 as stable dimer SIGNOR-251105 0.939 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity phosphorylation Ser486 LRTPGRQsPGPGHRS 9606 10581160 t Axin residues T609 and S614 are physiological GSK3beta targets. Axin phosphorylation in the regulation of b-catenin stability. When active (left), GSK3b phosphorylates Axin as well as APC and b-catenin. The phosphorylated form of Axin binds strongly to b-catenin and promotes the phosphorylation of b-catenin by GSK3b, leading to strong interaction with b-TrCP SIGNOR-251221 0.918 ARHGEF9 protein O43307 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 25882190 f miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. SIGNOR-264976 0.7 anastrozole chemical CHEBI:2704 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189614 0.8 CDH1 protein P12830 UNIPROT FBXO31 protein Q5XUX0 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002181 29343641 t miannu Here we show that the low levels of FBXO31 are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (APC/C). We find that the APC/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in FBXO31 to promote its polyubiquitination and degradation in a cell-cycle-regulated manner, which requires phosphorylation of FBXO31 on serine-33 by the prosurvival kinase AKT. SIGNOR-277377 0.2 LEF1 protein Q9UJU2 UNIPROT CLDN2 protein P57739 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0003569 14751232 f lperfetto Activity of the claudin-2 promoter was elevated in mouse mammary epithelial C57 cells expressing Wnt-1. LEF-1, a nuclear effector of the Wnt signaling pathway which is involved in the regulation of cell differentiation and polarization, was found to bind directly to the claudin-2 promoter as revealed by electrophoretic mobility shift assays. Expression of LEF-1 and beta-catenin both enhanced claudin-2 promoter activity. SIGNOR-254120 0.2 17beta-estradiol smallmolecule CHEBI:16469 ChEBI ESR2 protein Q92731 UNIPROT up-regulates chemical activation 9606 BTO:0000150 17478088 t gcesareni Oestrogen receptors (er)alpha and beta modify the expression of genes involved in cell growth, proliferation and differentiation through binding to oestrogen response elements (eres) located in a number of gene promoters. SIGNOR-154663 0.8 TACR1 protein P25103 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257249 0.2 Stress_granules phenotype SIGNOR-PH124 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 27920254 f miannu Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis. SIGNOR-260866 0.7 IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR STAT1 protein P42224 UNIPROT up-regulates activity binding 9606 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249494 0.665 MRE11 protein P49959 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 17713585 t esanto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50. SIGNOR-157475 0.2 serotonin smallmolecule CHEBI:28790 ChEBI HTR3B protein O95264 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264290 0.8 ATM protein Q13315 UNIPROT DYRK2 protein Q92630 UNIPROT up-regulates quantity by stabilization phosphorylation Ser442 IELLGMPsQKLLDAS 19965871 t Phosphosites were derived from Figure 3 lperfetto ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus. SIGNOR-275577 0.539 PTPN2 protein P17706 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates activity dephosphorylation 9606 21984578 f miannu Moreover, it indicates that PTPN2 modulates the apoptotic activity of Bim via regulation of the protein kinase JNK1.|PTPN2 inhibition increased Bim phosphorylation at residue 65 in untreated INS-1E cells, and this effect was prolonged until 4 h of treatment with IFNalpha or 8 h after treatment with IFNgamma (XREF_FIG). SIGNOR-277055 0.271 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser23 PAPIRRRsSNYRAYA -1 11121119 t lperfetto In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation. SIGNOR-249066 0.349 VCPIP1 protein Q96JH7 UNIPROT VCP protein P55072 UNIPROT up-regulates activity binding 23500464 t lperfetto Golgi biogenesis requires two distinct p97ATPase-mediated membrane fusion, the p97/p47 and p97/p37 pathways. |We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97. SIGNOR-265039 0.567 PK proteinfamily SIGNOR-PF80 SIGNOR HIF-1 complex complex SIGNOR-C418 SIGNOR up-regulates activity binding 9606 BTO:0000567 21620138 t PKM2 interacts directly with the HIF-1Œ± subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, SIGNOR-268150 0.398 regorafenib chemical CHEBI:68647 ChEBI ABCB1 protein P08183 UNIPROT down-regulates activity chemical inhibition 9606 26254357 t miannu It is suggested that in vitro, regorafenib is an inhibitor of ABCB1 and ABCG2, but not a substrate, and that its active metabolites, M2 (N-Oxide metabolite) and M5 (N-Oxide/N-desmethyl metabolite), are substrates of ABCB1 and ABCG2 SIGNOR-259182 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR DIAPH1 protein O60610 UNIPROT up-regulates quantity by stabilization phosphorylation Thr768 PVLPFGLtPKKLYKP 9606 BTO:0002588 23325789 t miannu  DIAPH1 is phosphorylated in response to dibutyryl cAMP (Bt2cAMP) at Thr-759 via a pathway that requires extracellular signal-related kinase (ERK).We also show that Bt2cAMP promotes the PKA- and ERK-dependent phosphorylation of DIAPH1 at T759 and that mutation of this site alters the stability of the protein and the rate of cAMP-stimulated mitochondrial movement. SIGNOR-276484 0.2 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser307 TRRSRTEsITATSPA 10090 15306821 t lperfetto Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin. SIGNOR-127908 0.78 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr860 DSLLVFDyEGSGSTA 9606 BTO:0000848 16371504 t lperfetto Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated. SIGNOR-143238 0.407 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser245 NQSMDTGsPAELSPT 9606 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248297 0.422 HASPIN protein Q8TF76 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity binding 9606 BTO:0000567 24413556 t miannu Phosphorylation by Cyclin B-Cdk1 allows Haspin to bind Plk1-PBD. Phosphorylation of Haspin at T128 and Plk1 target sites is required for full H3T3ph generation and normal Aurora B localization in mitosis. SIGNOR-275420 0.2 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation 12792650 t inferred from 70% family members lperfetto Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK|The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2 SIGNOR-270222 0.2 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000007 14761950 t The effect has been demonstrated using P10636-8 lperfetto Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells. SIGNOR-121705 0.381 Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 20223217 t miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. SIGNOR-270441 0.8 CSNK1A1 protein P48729 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 21695114 t gcesareni We demonstrate that mammalian Smo (mSmo) is activated through multi-site phosphorylation of its carboxyl-terminal tail by CK1α and GRK2. Phosphorylation of mSmo induces its active conformation and simultaneously promotes its ciliary accumulation. SIGNOR-174542 0.5 ASCL1 protein P50553 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 BTO:0000142 24243019 f lperfetto Here we reveal a hierarchical mechanism in the direct conversion of fibroblasts into induced neuronal (iN) cells mediated by the transcription factors Ascl1|Accordingly, Ascl1-mutant mice show severe defects in neurogenesis SIGNOR-265174 0.7 CDK2 protein P24941 UNIPROT ARID4A protein P29374 UNIPROT down-regulates phosphorylation Ser1007 QHNFSVAsPLTLSQD 9606 21148318 t lperfetto We identified rbp1 as a novel cdk substrate. Rbp1 is phosphorylated by cdk2 on serines 864 and 1007, which are n- and c-terminal to the lxcxe motif, respectively. Cdk2-mediated phosphorylation of rbp1 or prb destabilizes their interaction in vitro, with concurrent phosphorylation of both proteins leading to their dissociation SIGNOR-170451 0.437 sedoheptulose smallmolecule CHEBI:16802 ChEBI sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI up-regulates quantity precursor of 9606 22682222 t miannu The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. CARKL bridges glycolysis and PPP by catalyzing the formation of S7P from sedoheptulose SIGNOR-268137 0.8 TRAF6 protein Q9Y4K3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity ubiquitination Lys134 AEAWSPRkLPSSAST 9606 BTO:0000007 18347055 t K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-_B SIGNOR-262298 0.911 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates activity phosphorylation Ser39 EPHAKKKsKISASRK -1 11121119 t lperfetto In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Overphosphorylation of troponin I reduced its affinity for troponin C, as measured by isothermal titration microcalorimetry. Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation. SIGNOR-249068 0.349 CSNK1D protein P48730 UNIPROT UHRF1 protein Q96T88 UNIPROT up-regulates phosphorylation Ser95 SELSDTDsGCCLGQS 9606 23297342 t llicata We further show that uhrf1 physically interacts with _-trcp1 in a manner dependent on phosphorylation of serine 108 (s108(uhrf1)) within the dsg degron. Furthermore, we demonstrate that s108(uhrf1) phosphorylation is catalyzed by casein kinase 1 delta (ck1_) and is important for the recognition of uhrf1 by scf(_-trcp). SIGNOR-200349 0.247 DTX3L protein Q8TDB6 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity monoubiquitination Lys92 MDVVYALkRQGRTLY 9606 BTO:0000007 19818714 t miannu Herein, we demonstrate that BBAP selectively monoubiquitylates histone H4 lysine 91 and protects cells exposed to DNA-damaging agents. Disruption of BBAP-mediated monoubiquitylation of histone H4K91 is associated with the loss of chromatin-associated H4K20 methylase, mono- and dimethyl H4K20, and a delay in the kinetics of 53BP1 foci formation at sites of DNA damage.  In response to DNA damage, BBAP expression increases and the E3 ligase selectively monoubiquitylates H4K91. Disruption of BBAP-mediated monoubiquitylation of H4K91 is associated with loss of chromatin-associated PR-Set7/Set8 and mono- and dimethyl H4K20, delayed kinetics of 53BP1 foci formation and increased sensitivity to DNA damage. SIGNOR-271897 0.2 STAT3 protein P40763 UNIPROT BIRC5 protein O15392 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26512963 f miannu DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells. SIGNOR-254762 0.61 CARS1 protein P49589 UNIPROT cysteine smallmolecule CHEBI:15356 ChEBI down-regulates quantity chemical modification 9606 11347887 t miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. SIGNOR-270470 0.8 ITGAV protein P06756 UNIPROT Av/b2 integrin complex SIGNOR-C176 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253203 0.651 GOT1 protein P17174 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-267510 0.8 CTSG protein P08311 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Phe64 TVFSVDEfSASVLTG -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263586 0.518 GMPS protein P49915 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267340 0.8 CDK1 protein P06493 UNIPROT TOP1 protein P11387 UNIPROT up-regulates activity phosphorylation Ser112 EKENGFSsPPQIKDE -1 18408216 t miannu In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells. SIGNOR-276156 0.356 GRK5 protein P34947 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 2787365 t gcesareni we found that g protein-coupled receptor kinases 5 and 6 (grk5/6), traditionally known to phosphorylate and desensitize 7tm g protein-coupled receptors, directly phosphorylate the pppsp motifs on single transmembrane lrp6 and regulate wnt/lrp6 signaling SIGNOR-23330 0.529 EPHA5 protein P54756 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). SIGNOR-276183 0.2 PTEN protein P60484 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity 9606 BTO:0001332 19903340 f lperfetto PTEN-mediated suppression of the PI3K/AKT pathway is well established, accumulating evidence suggests that nuclear PTEN also plays a critical role in tumor suppression SIGNOR-189105 0.654 COL1A1 protein P02452 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR up-regulates activity binding 10090 BTO:0000165 12496264 t lperfetto Modeling of the alpha I domain-collagen peptide complexes could partially explain the observed preference of different I domains for certain GFOGER sequence variations. In summary, our data indicate that the GFOGER sequence in fibrillar collagens is a common recognition motif used by alpha(1)beta(1), alpha(2)beta(1), and also alpha(11)beta(1) integrins. SIGNOR-253345 0.565 MAPK1 protein P28482 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates activity phosphorylation Thr215 ATGSVPStPIAHRGP 9606 BTO:0000007 12556484 t lperfetto Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro. In the case of Nudel, the phosphorylation sites were also located in the S/TP motifs. Detailed mutagenesis study indicated that T219, S242, and T245 were phosphorylated by Cdc2, while T219 and T245 were phosphorylated by Erk2.|Phosphorylation of Nudel in M phase appears to positively modulate dynein motor activity. Both phosphorylated and unphosphorylated forms of Nudel were transported by dynein (Fig. 7 and 9 and data not shown), indicating that neither of them inactivated the dynein motor. On the other hand, both phospho-Nudel and Nudelpmt5 bound Lis1 more strongly than Nudel or Nudelmt5 did SIGNOR-249422 0.382 WNT7B protein P56706 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131981 0.66 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 12637538 t llicata By using a phospho-specific antibody, we show that abl directly phosphorylates pkd at tyr(463) in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of pkd SIGNOR-99255 0.345 TSPOAP1 protein O95153 UNIPROT RIMS1 protein Q86UR5 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264363 0.2 MAPK1 protein P28482 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser540 KVMARSLsPPPELEE 10090 BTO:0000944 15851026 t lperfetto Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation. SIGNOR-249454 0.668 NR5A1 protein Q13285 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 f miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254871 0.492 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 8702756 t miannu Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase. SIGNOR-261708 0.633 diphenhydramine chemical CHEBI:4636 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 t Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells SIGNOR-257787 0.8 PPAT protein Q06203 UNIPROT 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI up-regulates quantity chemical modification 9606 9914248 t miannu Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine. SIGNOR-267295 0.8 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM FGFR2 protein P21802 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258080 0.8 MAPK14 protein Q16539 UNIPROT HBP1 protein O60381 UNIPROT up-regulates phosphorylation Ser402 GFSKNCGsPGSSQLS 9606 14612426 t lperfetto A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression. SIGNOR-119138 0.405 TAF12 protein Q16514 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263924 0.885 CDK11A protein Q9UQ88 UNIPROT SPDEF protein O95238 UNIPROT down-regulates quantity by destabilization phosphorylation Ser243 TDSEVDSsCSGQPIH 9606 BTO:0000007 26885618 t lperfetto In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.| SIGNOR-273022 0.363 MYC protein P01106 UNIPROT ITGA7 protein Q13683 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14525975 f lperfetto This report provides evidence that alpha7 gene expression during muscle differentiation is regulated by the c-Myc transcription factor. In myoblasts, alpha7 is expressed at basal levels, but following conversion to myotubes the expression of the integrin is strongly elevated. The increased alpha7 mRNA and protein levels following myogenic differentiation are inversely correlated with c-Myc expression. Transfection of myoblasts with the c-Myc transcription factor down-regulated alpha7 expression SIGNOR-241769 0.2 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 9606 19433246 t miannu Phthalates are true ligands of PPARs. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARgamma identified MEHP as a selective PPARgamma modulator, and thus a possible contributor to the obesity epidemic. SIGNOR-268745 0.8 GDNF protein P39905 UNIPROT ID3 protein Q02535 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252181 0.2 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser221 PRTSPIMsPRTSLAE 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252331 0.635 DRD5 protein P21918 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256914 0.492 hexadecanoic acid smallmolecule CHEBI:15756 ChEBI FFAR1 protein O14842 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257488 0.8 RIMBP2 protein O15034 UNIPROT RIMS3 protein Q9UJD0 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264371 0.285 COL1A1 protein P02452 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates binding 9606 7688313 t gcesareni Both a2b1- and a1b1- inegrins are implicated in chondrocyte adhesion to native collagene i and ii SIGNOR-31787 0.623 SGK1 protein O00141 UNIPROT NDRG2 protein Q9UN36 UNIPROT up-regulates phosphorylation Thr330 TRLSRSRtASLTSAA 9606 BTO:0000567 BTO:0000887;BTO:0001103;BTO:0000763 15461589 t llicata Sgk1 phosphorylated ndrg2 at thr330, ser332 and thr348 in vitro. for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, the phosphorylation of thr348 by sgk1 may prime for phosphorylation at ser344 SIGNOR-129676 0.404 Cyclopamine chemical CHEBI:4021 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191227 0.8 clofarabine chemical CHEBI:681569 ChEBI PRIM2 protein P49643 UNIPROT down-regulates activity chemical inhibition 9606 1707752 t miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase. SIGNOR-258360 0.8 ASXL3 protein Q9C0F0 UNIPROT THRB protein P10828 UNIPROT down-regulates activity binding 9606 BTO:0000972 25450400 t miannu We determined that ASXL3 depletion augments the ligand-induced transcriptional activities of LXRα and TRβ, which were repressed by ASXL3 overexpression. The ligand-dependent interactions of ASXL3 with LXRα and TRβ were demonstrated by the GST pull-down and immunoprecipitation analyses. We confirmed that ASXL3 suppresses the expression of LXRα target genes through its recruitment to the LXR-response elements. SIGNOR-266766 0.2 TCF4 protein P15884 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18852287 t Association of c-Jun, β-catenin, and TCF4 specifically with the downstream enhancer underlies mitogen stimulation of c-Myc transcription. SIGNOR-253324 0.379 (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol chemical CHEBI:94562 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258091 0.8 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270372 0.8 ACE protein P12821 UNIPROT bradykinin smallmolecule CHEBI:3165 ChEBI down-regulates quantity by destabilization binding 9606 16219810 t The angiotensin-converting enzyme (ACE) is a membrane-bound peptidyl dipeptidase known to act on a variety of peptide substrates in the extracellular space. Its most notable functions are the formation of angiotensin II and the degradation of bradykinin. SIGNOR-253341 0.8 RTKN protein Q9BST9 UNIPROT SEPTIN9 protein Q9UHD8 UNIPROT down-regulates 9606 16007136 f miannu We identified rhotekin, a downstream effector for rho, as a candidate regulator organizing septin structures through filament disruption. SIGNOR-138578 0.2 PTPRB protein P23467 UNIPROT TEK protein Q02763 UNIPROT down-regulates activity dephosphorylation 9606 34417472 t miannu Simultaneous inhibition of Tie2 cleavage and VE-PTP synergistically enhances Tie2 activation by up to 10-fold (Fig. 7A).|Tie2 activation is also importantly regulated by vascular endothelial protein tyrosine phosphatase (VE-PTP), which dephosphorylates Tie2 to inhibit its vascular stabilizing effects  .|Tie2 activation is also importantly regulated by vascular endothelial protein tyrosine phosphatase (VE-PTP), which dephosphorylates Tie2 to inhibit its vascular stabilizing effects. SIGNOR-277059 0.571 FOLR1 protein P15328 UNIPROT (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI up-regulates quantity relocalization 9606 10787414 t lperfetto The differential polarized distribution of the reduced-folate transporter (RFT-1) and folate receptor alpha (FRalpha), the two proteins involved in the transport of folate, has been characterized in normal mouse retinal pigment epithelium (RPE) and in cultured human RPE cells. SIGNOR-268267 0.8 SACM1L protein Q9NTJ5 UNIPROT phosphatidylinositol 4-phosphate smallmolecule CHEBI:37530 ChEBI down-regulates quantity chemical modification 9534 22253445 t lperfetto To investigate whether kinase activity could account for the different effects of the PI kinases on SARS-CoV S-mediated entry and to test whether PI4P lipids directly regulate viral entry independent of PI4KB, VeroE6 cells were transiently transfected with the SAC1 gene, a PI phosphatase that specifically converts PI4P lipids back to PI (27).|These results indicate that PI4P is indispensable for SARS-CoV S-mediated entry and suggest that PI4KB mediates SARS-CoV S entry by regulating the level of cellular PI4P. SIGNOR-260733 0.8 GLI2 protein P10070 UNIPROT FOXF1 protein Q12946 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0005738 23034409 f miannu we propose that chromatin looping between SDR and FOXF1 allows GLI2 to increase FOXF1 activity specifically in lung endothelium. SIGNOR-254216 0.402 ACTL6B protein O94805 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270749 0.672 PRKCA protein P17252 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser443 PQRKSQRsSYVSMRI -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262752 0.342 CREB1 protein P16220 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by expression transcriptional regulation 8355 10775268 f lperfetto Here we demonstrate that the closely related acetyltransferases p300 and cbp potentiate beta-catenin-mediated activation of the siamois promoter SIGNOR-76984 0.467 TAF13 protein Q15543 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263923 0.869 CPN1 protein P15169 UNIPROT HBA1 protein P69905 UNIPROT down-regulates activity cleavage Tyr141 STVLTSKyR -1 8635221 t miannu Both human plasma carboxypeptidase N (CPN) and membrane-bound carboxypeptidase M (CPM) released the C-terminal arginine (alpha-Arg141) of the alpha chain of human adult hemoglobin. Thus, the hydrolysis of hemoglobin by CPM and CPN demonstrated the contribution of the alpha-Arg141 residue to sustaining the tetrameric structure of hemoglobin and its normal oxygen affinity and vasoactivity. SIGNOR-256508 0.2 HES1 protein Q14469 UNIPROT FLT3 protein P36888 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 25234168 t We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity. SIGNOR-261563 0.2 IGF2BP1 protein Q9NZI8 UNIPROT ACTB protein P60709 UNIPROT up-regulates quantity post transcriptional regulation 10116 BTO:0004102 21734271 t miannu We found that ZBP1 is necessary for netrin-1 stimulated local translation of β-actin mRNA in axonal growth cones. ZBP1 binds to β-actin mRNA in the soma and transports it to the growth cone on microtubules. SIGNOR-268160 0.347 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI CEBPB protein P17676 UNIPROT up-regulates 9606 8754811 f fspada The differentiation of 3t3 preadipocytes into adipocytes is accompanied by a transient induction of c/ebpbeta and c/ebpdelta expression in response to treatment of the cells with methylisobutylxanthine (mix) and dexamethasone (dex), respectively SIGNOR-210068 0.8 GRK3 protein P35626 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 t Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. SIGNOR-251462 0.2 DENR protein O43583 UNIPROT JAK2 protein O60674 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004163 35440133 t miannu DENR directly regulates JAK2 expression. SIGNOR-269675 0.2 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates activity phosphorylation Thr292 PQLQAHStPHPDDFA 9606 12734188 t lperfetto Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9. SIGNOR-101055 0.369 ATM protein Q13315 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Ser140 GKKATQAsQEY 9606 21690091 t gcesareni Upon dna damage, h2ax is phosphorylated by ataxia telangiectasia mutated (atm) and atm-related kinases at serine 139, known as ?_?_?_-H2ax, which serves as a docking site to recruit the mediator of dna damage checkpoint protein 1 (mdc1) to sites of dna damage, named dna damage foci SIGNOR-174442 0.2 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BW2 protein P0C1H6 UNIPROT down-regulates activity monoubiquitination Lys35 ANSTKAQkQKRRGCR 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271981 0.2 GNRHR protein P30968 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257177 0.252 LPAR3 protein Q9UBY5 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 15856019 t gcesareni Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. SIGNOR-135846 0.385 NLRC4 inflammasome complex SIGNOR-C223 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256384 0.2 PRKCG protein P05129 UNIPROT NRGN protein Q92686 UNIPROT up-regulates activity phosphorylation Ser36 AAAKIQAsFRGHMAR -1 8080473 t lperfetto Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM. SIGNOR-248915 0.44 DTNBP1 protein Q96EV8 UNIPROT WASF2 protein Q9Y6W5 UNIPROT up-regulates activity binding 10116 BTO:0000601 20531346 t miannu Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation. Although dysbindin-1, WAVE2 and Abi-1 form a ternary complex, dysbindin-1 promoted the binding of WAVE2 to Abi-1. SIGNOR-265659 0.35 VX-765 chemical CID:53245642 PUBCHEM CASP1 protein P29466 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207770 0.8 COL14A1 protein Q05707 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t Types XII and XIV collagen are fibril-associated collagens with interrupted triple helices (FACITs) localized primarily to perimysium.23 While they appear to link fibrillar collagen to other ECM components, their precise function is not known SIGNOR-254672 0.7 fumarate(2-) smallmolecule CHEBI:29806 ChEBI Citric_Acid_Cycle phenotype SIGNOR-PH191 SIGNOR up-regulates 9606 30090811 f miannu Fumarase is a TCA cycle enzyme which catalyzes the conversion of fumarate to L-malate in the mitochondria. Upon DNA damage the cytosolic echoform of fumarase is localized to the nucleus, there, its enzymatic activity catalyzes the reverse conversion of malate to fumarate, so causing local accumulation of fumarate. SIGNOR-267989 0.7 ABL1 protein P00519 UNIPROT EGFR protein P00533 UNIPROT up-regulates phosphorylation Tyr1172 ISLDNPDyQQDFFPK 9606 16943190 t gcesareni We show that activated abl phosphorylates the egfr primarily on tyrosine 1173. SIGNOR-149273 0.429 ITGB1BP1 protein O14713 UNIPROT A4/b7 integrin complex SIGNOR-C187 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257666 0.291 TPI1 protein P60174 UNIPROT glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Triosephosphate isomerase (TPI) is the glycolytic enzyme with the highest activity in vitro. TPI catalyzes the interconversion of glyceraldehyde-3-phosphate and DHAP (Figure 1). It consists of a dimer with 2 identical subunits of 248 amino acids (27 kDa). SIGNOR-266491 0.8 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT up-regulates activity phosphorylation Ser2276 SFKSALSerPSKSPA -1 26051540 t irozzo Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment. SIGNOR-259120 0.452 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269022 0.7 PI3K complex SIGNOR-C156 SIGNOR AKT2 protein P31751 UNIPROT up-regulates 9606 BTO:0000586 16293724 f gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. SIGNOR-252716 0.63 SIRT1 protein Q96EB6 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21633182 t miannu Interestingly, SIRT1 suppresses PPARγ but activates PGC-1α , and thus affects the clock network through multiple mechanisms. SIGNOR-268033 0.792 PABPC1 protein P11940 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization binding 9606 25480299 t lperfetto As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length. SIGNOR-268318 0.8 PICK1 protein Q9NRD5 UNIPROT BNC1 protein Q01954 UNIPROT up-regulates activity relocalization 10116 BTO:0000938 11802773 t miannu we found that the PDZ domain-containing protein PICK1 (protein interacting with C kinase) interacts specifically with the C-termini of BNC1 and ASIC. Our studies showing association of recombinant PICK1 with ASIC and BNC1, and the presence of both PICK1 and ASIC in the synaptosomal fraction SIGNOR-223414 0.312 MAPK3 protein P27361 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser291 TYVNNSPsPGFNSSH 9606 19237534 t lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309. SIGNOR-184176 0.2 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates binding 9606 20006481 t lperfetto Akt can phosphorylate pras40, a raptor binding protein that also acts as an inhibitor of torc1. Akt-mediated phosphorylation of pras40 again promotes 14-3-3 binding, in this case leading to relief from pras40-mediated inhibition. SIGNOR-217565 0.511 SPI1 protein P17947 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10523830 f irozzo Our results suggest that Spi-1 and GATA-1 might play a key role in the regulation of Fli-1. Most notably, we observed that the GATA/EBS dual element near the Fli-1 CAP sites had an enhancer activity in HEL cells. Spi-1 and GATA-1 were both found to bind to this sequence and hence both factors could represent potential regulators of Fli-1 expression. SIGNOR-256054 0.271 GFPT1 protein Q06210 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 21310273 t miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans SIGNOR-267818 0.8 GATA1 protein P15976 UNIPROT ITGA2B protein P08514 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17725493 f miannu We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. SIGNOR-254192 0.579 HTR2A protein P28223 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256885 0.271 SERPINC1 protein P01008 UNIPROT F9 protein P00740 UNIPROT down-regulates activity cleavage 31030036 t lperfetto Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1 SIGNOR-264140 0.893 LRRK2 protein Q5S007 UNIPROT LARS1 protein Q9P2J5 UNIPROT down-regulates activity phosphorylation Thr293 NIFLVAAtLRPETMF -1 30411383 t miannu In this study, we elucidated that leucyl-tRNA synthetase (LRS) was an LRRK2 kinase substrate and identified T293 as an LRRK2 phosphorylation site. LRRK2-meidated LRS phosphorylation or G2019S can lead to impairment of LRS editing, increased ER stress, and accumulation of autophagy markers. SIGNOR-277417 0.2 dopamine smallmolecule CHEBI:18243 ChEBI DRD4 protein P21917 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257480 0.8 MAPK3 protein P27361 UNIPROT MYB protein P10242 UNIPROT down-regulates phosphorylation Ser532 KIKQEVEsPTDKSGN 9606 BTO:0000661 8960373 t lperfetto Functional analysis of phosphorylation at serine 532 of human c-myb by map kinase. expression of a polypeptide containing the c-myb c-terminal domain stimulated c-myb activity. This effect is reduced upon mapk-dependent phosphorylation of serine 532. Our data suggest that the mapk-dependent state of phosphorylation modifies the cellular function of c-myb by modulating its interaction with a putative inhibitory factor SIGNOR-45348 0.306 MAP2K6 protein P52564 UNIPROT HSF4 protein Q9ULV5 UNIPROT up-regulates activity phosphorylation Thr471 LGLPGALtIYSTPES 24361130 t lperfetto Regulation of Hsf4b nuclear translocation and transcription activity by phosphorylation at threonine 472| At the upstream, MEK6 was found to interact with Hsf4b and enhance Hsf4b's nuclear translocation and transcription activity, probably by phosphorylation at sites such as T472. Taken together, our results suggest that phosphotylation of Hsf4b at T472 by protein kinases such as MEI SIGNOR-275493 0.2 ADD1 protein P35611 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 BTO:0000424 33187473 t lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] SIGNOR-266037 0.341 WWTR1 protein Q9GZV5 UNIPROT TEAD2 protein Q15562 UNIPROT up-regulates binding 9606 23431053 t YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death. gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14. SIGNOR-201382 0.801 BAK1 protein Q16611 UNIPROT CYCS protein P99999 UNIPROT up-regulates 9606 18097445 f gcesareni This process of mitochondrial outer membrane permeabilization (momp) results in the release of cycs. It is commonly thought that bax and bak form pores in membranes SIGNOR-160036 0.548 PPP1CA protein P62136 UNIPROT SP1 protein P08047 UNIPROT down-regulates activity dephosphorylation 9606 12684058 t miannu Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression. SIGNOR-251952 0.269 TGFB1 protein P01137 UNIPROT OMD protein Q99983 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16970923 f miannu We found tgf-beta1 to down regulate osad SIGNOR-149565 0.272 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates activity phosphorylation Ser6 sKKRKFVA 9606 19059439 t Manara Here we show that PKCδ phosphorylates rpS3 resulting in its mobilization in the nucleus to repair damaged DNA SIGNOR-260894 0.2 p38 proteinfamily SIGNOR-PF16 SIGNOR BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 10116 15486195 t miannu Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. SIGNOR-260443 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252744 0.756 KAT5 protein Q92993 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269297 0.776 TRIM13 protein O60858 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21333377 t miannu Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT.  We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro. SIGNOR-271851 0.381 PTCRA protein Q6ISU1 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 BTO:0000782 1717999 t lperfetto Stimulation of the T-cell antigen receptor (TCR) leads to tyrosine phosphorylation of a number of cellular proteins, including phospholipase C (PLC) gamma 1 and the TCR zeta chain. We describe here a 70-kDa tyrosine phosphoprotein (ZAP-70) that associates with zeta within 15 sec following TCR stimulation. The phosphorylation of ZAP-70 and its association with zeta is independent of the other TCR chains SIGNOR-134325 0.289 ITK protein Q08881 UNIPROT ITK protein Q08881 UNIPROT up-regulates activity phosphorylation Tyr180 ETVVIALyDYQTNDP 9606 BTO:0000782 12842872 t lperfetto In this study, we present evidence for another mode of regulation for itk, the autophosphorylation of tyr-180 in the src homology 3 (sh3) domain. SIGNOR-103170 0.2 EXOC8 protein Q8IYI6 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270783 0.914 LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Ser397 TYHSRDEsTDSGLSM 9606 BTO:0000007 20048001 t miannu We show that YAP is phosphorylated by Lats on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1delta/epsilon to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits beta-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition SIGNOR-277636 0.2 hydromorphone chemical CHEBI:5790 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 19282177 t Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. SIGNOR-258037 0.8 PPAT protein Q06203 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 9914248 t miannu Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine. SIGNOR-267294 0.8 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser181 NPLLRKEsAPPSLRR 9606 18339811 t Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. SIGNOR-248647 0.322 Frizzled proteinfamily SIGNOR-PF11 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates BTO:0001103 23209147 f apalma The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization. SIGNOR-255687 0.2 G3BP2 protein Q9UN86 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates activity relocalization 9606 BTO:0000567 10969074 t SARA IkappaBalpha interacts with G3BP2 both in vivo and in vitrothrough the IkappaBalpha CRS. Overexpression of G3BP2 directly promotes retention of IkappaBalpha in the cytoplasm. SIGNOR-260985 0.349 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252086 0.2 ATM protein Q13315 UNIPROT NABP2 protein Q9BQ15 UNIPROT up-regulates activity phosphorylation Thr117 EPNPEYStQQAPNKA 10090 BTO:0002245 18449195 t miannu Ataxia telangiectasia mutated (ATM) kinase phosphorylates hSSB1 in response to DNA double-strand breaks (DSBs). This phosphorylation event is required for DNA damage-induced stabilization of hSSB1. SIGNOR-262639 0.515 HES1 protein Q14469 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 16282371 f Notch signaling blocks differentiation of 3T3-L1 preadipocytes, and this can be mimicked by constitutive expression of the Notch target gene Hes-1 SIGNOR-253058 0.7 PLCG1 protein P19174 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 31575057 t gcesareni Phosphorylation at Ser-146 by PKCδ increases p21 stability SIGNOR-262962 0.265 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269367 0.719 UNC13B protein O14795 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity transcriptional regulation 9606 BTO:0000938 30267828 t miannu In neuronal exocytosis, Munc18-1 (aSM-protein) and Munc13-1/2 (similar to CATCHRs) arethe relevant proteins responsible for SNARE-complex formation. Munc18-1 associates with syntaxin-1 in its‘closed’ conformation, i.e. with the regulatory Habc-domain folded against the SNARE (H3-)-domain. Opening-up of syntaxin is catalyzed by the Mun-domainwithin Munc13-1/2 and allows assembly with the partnerSNARE SNAP-25 and possibly VAMP2. SIGNOR-263972 0.707 NCSTN protein Q92542 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 12603837 t Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation gcesareni Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. SIGNOR-98724 0.965 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MARS1 protein P56192 UNIPROT up-regulates activity phosphorylation Ser825 GGGQAKTsPKPAVVE 9606 BTO:0000567 25097229 t miannu Here, we report that methionyl-tRNA synthetase (MRS) is phosphorylated at Ser209 and Ser825 by extracellular signal-related kinase (ERK1/2) under conditions of stress caused by reactive oxygen species (ROS), and that this phosphorylated MRS shows increased affinity for non-cognate tRNAs with lower affinity for tRNA(Met), leading to an increase in Met residues in cellular proteins.  SIGNOR-276670 0.2 CDK2 protein P24941 UNIPROT MECOM protein Q03112 UNIPROT up-regulates activity phosphorylation Ser624 KMFKDKVsPLQNLAS 33082307 t lperfetto The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A. SIGNOR-273426 0.3 ALK protein Q9UM73 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation Tyr293 RRPGEKTyTQRCRLF 9606 BTO:0000785 17537995 t lperfetto Furthermore, psf was shown to be a direct substrate of purified alk kinase domain in vitro, and psf tyr293 was identified as the site of phosphorylation. Psf phosphorylation also increased its binding to rna and decreased the psf-mediated suppression of gage6 expression. SIGNOR-155298 0.2 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT down-regulates quantity by destabilization cleavage Asp390 LPQLTLPdSLTSAAS 9606 11815631 t Giulio Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage SIGNOR-260604 0.405 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT down-regulates activity phosphorylation Ser2093 GPNRSFLsLKHTPMG 9606 BTO:0000007 12794074 t Ser-2093 is efficiently phosphorylated by GSK-3β and, to a minor extent, residues Thr-2068 and/or Ser-2070 and Thr-2074 of Notch2 are also targets for GSK-3β-dependent phosphorylation. We also find that GSK-3β-dependent phosphorylation of Notch2 is inhibiting transcriptional activation of different Notch target genes. SIGNOR-251253 0.494 ATM protein Q13315 UNIPROT USP10 protein Q14694 UNIPROT up-regulates quantity by stabilization phosphorylation Thr42 SGTVLCGtQAVDKLP 9606 BTO:0001109 20096447 t miannu The translocation and stabilization of USP10 is regulated by ATM -mediated phosphorylation of USP10 at Thr42 and Ser337.  SIGNOR-276275 0.254 PSPN protein O60542 UNIPROT GFRA4 protein Q9GZZ7 UNIPROT up-regulates binding 9606 BTO:0000938 11116144 t gcesareni Glial cell line-derived neurotrophic factor (gdnf) family ligands signal through receptor complex consisting of a glycosylphosphatidylinositol-linked gdnf family receptor (gfr) alpha subunit and the transmembrane receptor tyrosine kinase ret. SIGNOR-85162 0.737 CSF2RA protein P15509 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR form complex binding 9606 9680354 t apalma The high-affinity GMR is known to be composed of a specific ligand-binding alpha subunit (GMRα) and a common beta subunit (βc), which is also a component of the interleukins-3 (IL-3) and -5 (IL-5) receptors. SIGNOR-255582 0.865 PTPN1 protein P18031 UNIPROT STAT5A protein P42229 UNIPROT down-regulates activity dephosphorylation Tyr694 LAKAVDGyVKPQIKQ 9534 10993888 t A Cytosolic Protein-tyrosine Phosphatase PTP1B Specifically Dephosphorylates and Deactivates Prolactin-activated STAT5a and STAT5b SIGNOR-248428 0.662 ACTB protein P60709 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 BTO:0000007 19121306 f lperfetto However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin. SIGNOR-260608 0.7 YAP1 protein P46937 UNIPROT KIF23 protein Q02241 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 f lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. SIGNOR-276567 0.2 SMAD9 protein O15198 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR form complex binding 10116 9371779 t ggiuliani As shown in Fig. 2, immunoprecipitation of Smad8 with an anti-myc antibody could bring down the Flag-tagged Smad4 only in the presence of CA-ALK-2, indicating that only activation of ALK-2 but not ALK-4 could induce the heteromerization of Smad8 with Smad4. SIGNOR-255776 0.672 HOXC11 protein O43248 UNIPROT HNF1A protein P20823 UNIPROT up-regulates 9606 9582375 f miannu The observed stimulatory effect of hoxc11 on hnf1_ may be due to a similar stabilizing effect on hnf1_ dna binding and/or an increase in transcriptional activity of hnf1_. SIGNOR-57484 0.312 ITGB2 protein P05107 UNIPROT AD/b2 integrin complex SIGNOR-C172 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253196 0.731 afatinib chemical CHEBI:61390 ChEBI ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0000551 22452896 t Like lapatinib and neratinib, afatinib is a next generation tyrosine kinase inhibitor (TKI) that irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases. gcesareni Afatinib, an irreversible erbb-family blocker, has shown preclinical activity when tested in egfr mutant models with mutations that confer resistance to egfr tyrosine-kinase inhibitors. SIGNOR-259440 0.8 KIT protein P10721 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002882 22806893 t irozzo SHP2 can be phosphorylated at 2 C-terminal tyrosyl residues by receptor tyrosine kinases, including KIT as well as cytosolic tyrosine kinases, including Src and Abl. The level of tyrosyl phosphorylation of SHP2 has been associated with its recruitment to the receptor.Thus, pharmacologic inhibition of SHP2 phosphatase function might permit SHP2 to return to its inactive conformation resulting in reduced tyrosine phosphorylation. SIGNOR-256140 0.671 TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus SIGNOR-235385 0.805 CYP19A1 protein P11511 UNIPROT estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity chemical modification 9606 BTO:0000975 27702664 t lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively SIGNOR-268670 0.8 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000017 28192398 t miannu We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation.  SIGNOR-277344 0.492 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000007 14761950 t The effect has been demonstrated using P10636-8 lperfetto Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells. SIGNOR-121717 0.381 ESR1 protein P03372 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18588516 f miannu The down-regulation of slug in the ERalpha-positive MCF-7 cell line was mediated by direct repression of slug transcription by the formation of a co-repressor complex involving ligand-activated ERalpha protein, HDAC1 (histone deacetylase 1) and N-CoR (nuclear receptor co-repressor). SIGNOR-254230 0.432 PIK3R4 protein Q99570 UNIPROT Vps34 Complex I complex SIGNOR-C242 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260317 0.917 arformoterol chemical CHEBI:408174 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation -1 20655218 t Luana Table 1. Human β2- and β1-adrenoceptor binding and calculated log D7.4 values for formoterol, indacaterol, salmeterol, S1319 and the representative library members 11–41 SIGNOR-257881 0.8 NME1 protein P15531 UNIPROT PTN protein P21246 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001567 17671192 f miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. SIGNOR-255167 0.2 SREBF1 protein P36956 UNIPROT PCSK9 protein Q8NBP7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17921436 t miannu Expression of nuclear forms of sterol-regulatory element binding protein-1 (SREBP-1) and SREBP-2 dramatically increased the promoter activity of PCSK9. SIGNOR-255222 0.438 AMPK complex SIGNOR-C15 SIGNOR PRPS2 protein P11908 UNIPROT down-regulates activity phosphorylation Ser180 GGAKRVTsIADRLNV 9606 BTO:0006038 29074724 t lperfetto We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. SIGNOR-265732 0.243 KRAS protein P01116 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner. SIGNOR-175213 0.769 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 18394876 t gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1. SIGNOR-252999 0.673 RALGDS protein Q12967 UNIPROT RIT1 protein Q92963 UNIPROT up-regulates activity binding 9606 10545207 t miannu Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors. SIGNOR-220859 0.55 SEC62 protein Q99442 UNIPROT Protein_translocation phenotype SIGNOR-PH176 SIGNOR up-regulates 22375059 f lperfetto We demonstrated, with a similar knockdown approach, a precursor-specific involvement of mammalian Sec63 in the initial phase of co-translational protein transport into the ER. SIGNOR-265281 0.7 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 12151396 t gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. SIGNOR-91071 0.346 Fibrin complex SIGNOR-C317 SIGNOR Fibrin_clot_formation phenotype SIGNOR-PH153 SIGNOR up-regulates binding 9606 BTO:0000131 18544683 t lperfetto A fibrin clot is the final product of the blood clotting cascade. Thrombin catalyzes release of fibrinopeptide A from fibrinogen to create fibrin monomers, which then aggregate to protofibrils. Proteolytic release of fibrinopeptide B by thrombin permits lateral protofibril aggregation, resulting in a three-dimensional fibrin gel.|Fibrin clots were formed as described for turbidity experiments, in which the fibrinogen, calcium, and polyP (when included) were preincubated for 15 minutes before adding thrombin. SIGNOR-263531 0.7 CDH9 protein Q9ULB4 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265871 0.569 estrone smallmolecule CHEBI:17263 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of -1 8994190 t Luana Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues.  SIGNOR-269759 0.8 KDM6A protein O15550 UNIPROT ETS2 protein P15036 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29736013 t miannu Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase SIGNOR-260035 0.2 PBX2 protein P40425 UNIPROT EMX2 protein Q04743 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15494461 f miannu EMSA demonstrated HOXA10-Pbx2 binding as a heterodimer to an enhancer of the EMX2 gene, a known target of HOXA10 regulation. SIGNOR-254466 0.399 CDK1 protein P06493 UNIPROT SUN1 protein O94901 UNIPROT down-regulates activity phosphorylation Ser334 FLLLAGLsLRGQGNF 9606 25482198 t miannu Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions. SIGNOR-263100 0.365 SYK protein P43405 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr771 IGTAEPDyGALYEGR 9606 BTO:0000776 8657103 t lperfetto Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771. SIGNOR-246572 0.765 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT up-regulates activity phosphorylation Ser297 PQKTSAKsPGPMRRS 9606 14741103 t llicata We identified that Ser297 is the major phosphorylation site by Cdk5. Phosphorylation of this site occurs in human. | Mutation of Ser297 blocks the effect of Dcx on migration in a fashion similar to pharmacological inhibition of Cdk5 activity. SIGNOR-250657 0.415 SHANK3 protein Q9BYB0 UNIPROT ACTN1 protein P12814 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264585 0.2 WNT8A protein Q9H1J5 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131987 0.618 CASP8 protein Q14790 UNIPROT CYCS protein P99999 UNIPROT up-regulates activity 9606 BTO:0000661 10364179 f Translocation from Mitochondria to Cytosol lperfetto Caspase-8 triggered rapid cytochrome c release from mitochondria. The effect was indirect. SIGNOR-68225 0.493 ATR protein Q13535 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser1981 SLAFEEGsQSTTISS 9606 17124492 t lperfetto Atr-dependent phosphorylation and activation of atm in response to uv treatment or replication fork stalling. Here, we show that atm phosphorylation at ser1981, a characterised autophosphorylation site, is atr-dependent and atm-independent following replication fork stalling or uv treatment SIGNOR-150870 0.736 NUP214 protein P35658 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262075 0.654 ADRB2 protein P07550 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257081 0.342 RAD9A protein Q99638 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates binding 9606 18594563 t gcesareni The 9-1-1 complex functions as a clamp, encircling the dna, and recruits the brct domain-containing protein topbp1 in a phospho-dependent manner SIGNOR-179382 0.82 PP1 proteinfamily SIGNOR-PF54 SIGNOR PYGM protein P11217 UNIPROT down-regulates activity dephosphorylation Ser15 QEKRKQIsVRGLAGV 9606 BTO:0002049 22225877 t GP is the first protein whose function was discovered to be regulated by reversible protein phosphorylation, which is controlled by phosphorylase kinase (PhK) and protein phosphatase 1 (PP1). Here we report that lysine acetylation negatively regulates GP activity by both inhibiting enzyme activity directly and promoting dephosphorylation SIGNOR-267402 0.2 MAPK3 protein P27361 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 15568999 t lperfetto In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 SIGNOR-249479 0.568 JAK1 protein P23458 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates activity phosphorylation 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260149 0.714 AKT1 protein P31749 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 BTO:0000007 BTO:0001253 18296647 t gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. SIGNOR-252505 0.446 TWIST1 protein Q15672 UNIPROT MMP2 protein P08253 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003879 20646316 f miannu Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. SIGNOR-255525 0.383 SEMA3C protein Q99985 UNIPROT PLXNA2 protein O75051 UNIPROT up-regulates activity binding 19666519 t lperfetto Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes. SIGNOR-253151 0.501 NEUROG3 protein Q9Y4Z2 UNIPROT NEUROG1 protein Q92886 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19028584 f miannu Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. SIGNOR-254632 0.252 MASTL protein Q96GX5 UNIPROT ARPP19 protein P56211 UNIPROT up-regulates activity phosphorylation Ser62 KGQKYFDsGDYNMAK -1 21164014 t gcesareni We identified cyclic adenosine monophosphate€“regulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry. SIGNOR-243611 0.72 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser218 VSGQLIDsMANSFVG 9606 BTO:0000007 15466476 t lperfetto Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases. SIGNOR-129690 0.556 PLK1 protein P53350 UNIPROT KIF2C protein Q99661 UNIPROT up-regulates activity phosphorylation Ser633 ELSSQMSsFNEAMTQ 9606 BTO:0000567 25504441 t miannu Our studies suggest new mechanisms by which Plk1 regulates MCAK: the degradation of MCAK is controlled by Plk1 phosphorylation on S621, whereas its activity is modulated by Plk1 phosphorylation on S632/S633 in mitosis.We have recently shown that S621 in MCAK is the major phosphorylation site of Plk1, which is responsible for regulating MCAK's degradation by promoting the association of MCAK with APC/CCdc20.  In the present study, we have addressed another two residues phosphorylated by Plk1, namely S632/S633 in the C-terminus of MCAK. Our data suggest that Plk1 phosphorylates S632/S633 and regulates its catalytic activity in mitosis. This phosphorylation is required for proper spindle assembly during early phases of mitosis. SIGNOR-276861 0.804 SRC protein P12931 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000944 9566874 t lperfetto Previous studies have demonstrated that one STAT family member, Stat3, possesses constitutively elevated tyrosine phosphorylation and DNA-binding activity in fibroblasts stably transformed by the Src oncoprotein.We conclude that Stat3 activation by the Src oncoprotein leads to specific gene regulation and that Stat3 is one of the critical signaling pathways involved in Src oncogenesis. SIGNOR-235445 0.781 CAMK2A protein Q9UQM7 UNIPROT ITGB1BP1 protein O14713 UNIPROT up-regulates activity phosphorylation Thr38 GGLSRSStVASLDTD 9813144 t llicata The point mutation T38D localized within the optimal CaMKII recognition motif of ICAP-1alpha results in a strong defect in cell spreading which cannot be overcome by the inhibition of the endogenous CaMKII. This fact strongly suggests that the phosphorylation of Threonine 38 by CaMKII modulates the alpha5beta1 integrin function. Conversely, the mutation T38A produces an analog of ICAP-1alpha that cannot be phosphorylated and that stimulates cell spreading on fibronectin to a similar extent when CaMKII is inhibited. SIGNOR-250632 0.312 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser531 GSRSRTPsLPTPPTR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249318 0.754 ATM protein Q13315 UNIPROT KHDC3L protein Q587J8 UNIPROT up-regulates activity phosphorylation Thr145 IEVREAGtQRSVEVR 9606 BTO:0001086 31609975 t miannu Notably, we identified two critical residues, Thr145 and Thr156, whose phosphorylation by Ataxia-telangiectasia mutated (ATM) is essential for KHDC3L's functions.  SIGNOR-273505 0.2 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT unknown phosphorylation Thr1404 GREEFYStHPHFMTQ 9606 BTO:0000938 19824698 t lperfetto We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. SIGNOR-188433 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR JUN protein P05412 UNIPROT up-regulates phosphorylation 9606 12169099 t inferred from 70% family members gcesareni Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. SIGNOR-270033 0.2 nintedanib chemical CHEBI:85164 ChEBI FGFR3 protein P22607 UNIPROT down-regulates activity chemical inhibition -1 18559524 t Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. SIGNOR-257798 0.8 HSP90AB1 protein P08238 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity binding 9606 9580552 t miannu Here we show that Hsp90 associates with endothelial nitric oxide synthase (eNOS) and is rapidly recruited to the eNOS complex by agonists that stimulate production of nitric oxide, namely vascular endothelial growth factor, histamine and fluid shear stress. Moreover, the binding of Hsp90 to eNOS enhances the activation of eNOS. SIGNOR-252214 0.528 NR0B2 protein Q15466 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17909097 f gcesareni As shown in fig. 3a, metformin (0.5 to 2 mmol/l) induced shp gene expression and repressed the camp/dex-induced expression of pepck and g6pase in a dose-dependent manner in h4iie cells SIGNOR-158065 0.2 GATA1 protein P15976 UNIPROT MPL protein P40238 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15466856 f miannu Both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. SIGNOR-254162 0.452 PRKAA2 protein P54646 UNIPROT ACACB protein O00763 UNIPROT down-regulates activity phosphorylation Ser222 PTMRPSMsGLHLVKR 9606 9148944 t miannu The results suggest that the decrease in ACC activity during muscle contraction is caused by an increase in its phosphorylation, most probably due, at least in part, to activation of the alpha2 isoform of AMPK. SIGNOR-250318 0.638 HIRA protein P54198 UNIPROT HIRA complex 2 complex SIGNOR-C462 SIGNOR form complex binding 9606 30285846 t miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. SIGNOR-269437 0.52 ABL1 protein P00519 UNIPROT BTK protein Q06187 UNIPROT down-regulates activity phosphorylation Tyr223 LKKVVALyDYMPMNA 9606 12445832 t Manara In this report we describe for the first time that ABL1 and Btk physically interact and that ABL1 can phosphorylate tyrosine 223 in the SH3 domain of Btk. | This is presumably due to the negative regulatory effectof Btk SH3 domain phosphorylation caused by ABL1,which would result in a decreased catalytic activity ofBtk resulting in impaired autophosphorylation. SIGNOR-260801 0.342 POU2F1 protein P14859 UNIPROT MYH10 protein P35580 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15728583 t lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation SIGNOR-238772 0.2 MAPK1 protein P28482 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 t gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. SIGNOR-163242 0.723 AGTR2 protein P50052 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 32201502 f MIANNU AT2 receptor stimulation has been associated, for instance, with protection of the brain against ischemia [94]. In essence, AT2 receptors are linked to vasodilatation, release of nitric oxide, tissue development and remodeling, by stimulating apoptosis and inhibition of cell growth SIGNOR-260232 0.7 AKT2 protein P31751 UNIPROT RALGAPA2 protein Q2PPJ7 UNIPROT down-regulates activity phosphorylation Thr715 PMRFRSAtTSGAPGV 10090 SIGNOR-C469 21148297 t miannu RGC2 is an endogenous substrate for Akt2 downstream of PI 3-kinase SIGNOR-269799 0.43 PCDH19 protein Q8TAB3 UNIPROT GABRA3 protein P34903 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C334 29360992 t miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  SIGNOR-267222 0.2 HNRNPU protein Q00839 UNIPROT IER3 protein P46695 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 f lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. SIGNOR-262285 0.2 MTCH2 protein Q9Y6C9 UNIPROT BID protein P55957 UNIPROT up-regulates relocalization 9606 20436477 t In the experiment they use a truncated BID (tBID)-interacting protein. gcesareni Mtch2/mimp (mitochondrial carrier homologue 2/met-induced mitochondrial protein), a novel truncated bid (tbid)-interacting protein, is a surface-exposed outer mitochondrial membrane protein that facilitates the recruitment of tbid to mitochondria SIGNOR-165081 0.308 FIG4 protein Q92562 UNIPROT MCOLN1 protein Q9GZU1 UNIPROT up-regulates activity 9606 23165282 f miannu PI(3,5)P2 begins to be synthesized on endosomal membranes and is additionally required for the activation of lysosomal TRPML1/MCOLN1 channels. Thus, a deficiency of FIG4/PI(3,5)P2 would impair TRPML1/MCOLN1 channel function, leading to the accumulation of calcium in the lysosomes. SIGNOR-253536 0.362 TWIST2 protein Q8WVJ9 UNIPROT ERBB3 protein P21860 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255501 0.2 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11486031 t lperfetto Using this inducible system, we show that Notchic activates transcription of the cyclin D1 gene with rapid kinetics. SIGNOR-209753 0.595 NTRK1 protein P04629 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 8384556 t gcesareni The nerve growth factor (ngf) receptor/trk associated with and phosphorylated phospholipase c gamma (plc gamma) SIGNOR-38538 0.637 long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI up-regulates quantity precursor of 9606 24269233 t ACSs catalyze the conversion of FAs to their active form acyl-CoAs. The human genome codes for 26 ACS isozymes, which are classified into six subfamilies based on their substrate specificities toward the chain length of FAs and on sequence similarity SIGNOR-267711 0.8 USP6 protein P35125 UNIPROT ARF6 protein P62330 UNIPROT up-regulates relocalization 9606 15509780 t miannu Here we show that tre17 (also called tre-2 and usp6), a founding member of the tbc family, targets the arf family gtpase arf6, which regulates plasma membrane-endosome trafficking. Surprisingly, tre17 does not function as a gap for arf6 but rather promotes its activation in vivo. Forced expression of tre17 promotes the localization of arf6 to the plasma membrane, leading to arf6 activation, presumably due to facilitated access to membrane-associated guanine nucleotide exchange factors (gefs). SIGNOR-130019 0.646 TAB3 protein Q8N5C8 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates binding 9606 25290089 t lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205452 0.439 CDK1 protein P06493 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Thr143 AVSPGTLtPTGVVSG 26933062 t lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. SIGNOR-276588 0.435 PRKCH protein P24723 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000751 11700305 t lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | SIGNOR-249123 0.351 SRC protein P12931 UNIPROT HCN2 protein Q9UL51 UNIPROT up-regulates activity phosphorylation Tyr476 LDSSRRQyQEKYKQV 9606 BTO:0000007 26280531 t miannu We identified a highly conserved tyrosine residue in the C-linker of HCN channels (Tyr476 in HCN2) that confers modulation by Src. Replacement of this tyrosine by phenylalanine in HCN2 or HCN4 abolished sensitivity to Src inhibitors. Mass spectrometry confirmed that Tyr476 is phosphorylated by Src. Our results have functional implications for HCN channel gating. Furthermore, they indicate that tyrosine phosphorylation contributes in vivo to the fine tuning of HCN channel activity. SIGNOR-263199 0.27 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT up-regulates phosphorylation Tyr1125 APSRDPHyQDPHSTA 9606 8845374 t lperfetto The c-terminal autophosphorylation domain of egfr was extensively phosphorylated by c-src./These studies revealed that y1086 was phosphorylated to a significantly higher extent by c-src than by egfr. Additionally, y1101 was identified as a unique c-src phosphorylation site SIGNOR-44247 0.609 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR EIF4EBP1 protein Q13541 UNIPROT up-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0001109 36882522 t lperfetto CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. SIGNOR-273114 0.2 RNF167 protein Q9H6Y7 UNIPROT VAMP3 protein Q15836 UNIPROT down-regulates quantity by destabilization ubiquitination Lys68 ETSAAKLkRKYWWKN 9606 BTO:0000007 23353890 t miannu Here, we show that Godzilla/RNF167 regulates endosome recycling by the ubiquitylation of VAMP3 on Lys66, Lys68 and Lys77; namely, two adjacent Lys residues on the both sides of the critical interface of SNARE complex are ubiquitylated. In agreement with VAMP3 being a target for Goliath family ubiquitin ligases, we show that recycling endosome trafficking is abrogated in response to their activity. While we observed ubiquitylation of VAMP3 by Godzilla, we are unable to describe the nature of this ubiquitination, be it mono-ubiquitin or extended ubiquitin chains. SIGNOR-272094 0.334 ZMYND8 protein Q9ULU4 UNIPROT MMP3 protein P08254 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 27477906 t lperfetto Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported SIGNOR-262043 0.2 IFNAR2 protein P48551 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR form complex binding 9606 11278538 t miannu The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex. SIGNOR-260333 0.903 CDK1 protein P06493 UNIPROT PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization phosphorylation Ser40 PTAEEKPsPRRSLSQ 33309518 t lperfetto Phosphorylation of multiple residues in the catalytic domain of PPM1D during mitosis, including Ser40 by Cyclin-dependent kinase 1 (CDK1), leads to ubiquitination of PPM1D and subsequent proteasomal degradation by Adenomatous polyposis coli (APC) and cell-division cycle protein 20 (CDC20) SIGNOR-275489 0.354 OPTN protein Q96CV9 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates 27181519 f lperfetto Optineurin and TBK1 have also been discovered co-localizing in protein aggregates, and the phosphorylation of optineurin at serine 177 has been shown to be critical to its function in mediating clearance of aggregated proteins via autophagy SIGNOR-262275 0.7 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR up-regulates activity chemical activation 26083061 t lperfetto Respiratory chain complexes I–III depend on Fe-S clusters for function SIGNOR-262136 0.8 AURKB protein Q96GD4 UNIPROT ZWINT protein O95229 UNIPROT up-regulates activity phosphorylation Thr251 TRPQEQStGDTMGRD -1 21775627 t lperfetto Zwint-1 is a novel Aurora B substrate required for the assembly of a dynein-binding platform on kinetochores|During prometaphase, AurB phosphorylation of zwint-1 is required for recruitment of ZW10-, pT89 dynein-, and RZZ-dependent proteins to kinetochores. This is defective after AurB inhibition or after expression of the triple-A zwint-1 mutant. Triple-E mutant zwint-1 mimics phospho–zwint-1 in RZZ recruitment, even after AurB inhibition SIGNOR-265010 0.636 PML protein P29590 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity binding 9606 15356634 t lperfetto Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome. SIGNOR-128738 0.53 RNF128 protein Q8TEB7 UNIPROT CD83 protein Q01151 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys177 SIFPDFSkAGMERAF 9606 BTO:0000007 19542455 t miannu In this study, we show that GRAIL can down-modulate the expression of CD83 (previously described as a cell surface marker for mature dendritic cells) on CD4 T cells. GRAIL-mediated down-modulation of CD83 is dependent on an intact GRAIL extracellular protease-associated domain and an enzymatically active cytosolic RING domain, and proceeds via the ubiquitin-dependent 26S proteosome pathway. Ubiquitin modification of lysine residues K168 and K183, but not K192, in the cytoplasmic domain of CD83 was shown to be necessary for GRAIL-mediated degradation of CD83. SIGNOR-271850 0.359 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 16046550 t The effect has been demonstrated using Q01196-8 gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-138928 0.2 TGFBR2 protein P37173 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates phosphorylation Ser345 RGDGSGFsL 9606 BTO:0000551 23249950 t lpetrilli Transforming growth factor ? (tgf-?) Has been shown to regulate cell plasticity through the phosphorylation of par6 on a conserved serine residue (s345) by the type ii tgf-? Receptor. SIGNOR-200193 0.443 FGF11 protein Q92914 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253442 0.2 AIM2 inflammasome complex SIGNOR-C222 SIGNOR Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 f miannu Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. SIGNOR-263123 0.7 nintedanib chemical CHEBI:85164 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 18559524 t Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. SIGNOR-257802 0.8 TLR2 protein O60603 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity 9606 BTO:0001025 19185596 f miannu S protein is a ligand for human TLR2. S protein utilizes toll-like receptor 2(TLR 2) to increase IL-8 production.Our results show that SARS S protein in a soluble form increased IL-8 production through hTLR2 ligand interaction. we have provided evidence that S protein induces IL-8 in PBMC in vitro and in THP-1 cells. The ability of S protein to increase IL-8 mRNA was mediated by activation of NF-κB possibly via TLR2 ligand and could be inhibited by the NF-κB inhibitor TPCK. The ability to detect elevated NF-κB transcription factor activity in the nucleus in response to S protein suggests that this most likely occurs by the mechanism of induction. Moreover increased secretion of IL-8 and IL-6 cytokines indicated that levels of proinflammatory mediators could be enhanced by S protein interaction with monocyte macrophages and could stimulate NK, neutrophil and monocyte migration to the site of infection. SIGNOR-260973 0.546 GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268591 0.2 ALDH9A1 protein P49189 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI down-regulates quantity chemical modification 9606 11802770 t miannu Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). SIGNOR-269694 0.8 PRIM2 protein P49643 UNIPROT DNA primase complex complex SIGNOR-C261 SIGNOR form complex binding -1 24043831 t lperfetto Here, we describe the crystal structure of human primase in heterodimeric form consisting of full-length catalytic subunit and a C-terminally truncated large subunit. SIGNOR-261340 0.99 PD318088 chemical CID:10231331 PUBCHEM MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205740 0.8 CSNK1E protein P49674 UNIPROT APC protein P25054 UNIPROT up-regulates activity phosphorylation Ser1392 SRCTSVSsLDSFESR 9606 BTO:0000038 11487578 t lperfetto Apc can be phosphorylated by ck1epsilon at ser1279 and ser1392. Mutation of conserved serine residues in the beta-catenin regulatory motifs of APC interfered with both axin-dependent phosphorylation and phosphorylation by CKIepsilon and impaired the ability of APC to regulate beta-catenin. SIGNOR-109664 0.597 RINT1 protein Q6NUQ1 UNIPROT Telomere_maintenance phenotype SIGNOR-PH148 SIGNOR down-regulates 9606 BTO:0004784 16600870 f lperfetto We propose that p130, forming a complex with Rad50 through RINT-1, blocks telomerase-independent telomere lengthening in normal cells.  SIGNOR-265031 0.7 axitinib chemical CHEBI:66910 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 21297102 t gcesareni Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (rcc) after failure of prior treatment with sunitinib or a cytokine. SIGNOR-171857 0.8 PRKCA protein P17252 UNIPROT CFTR protein P13569 UNIPROT up-regulates activity phosphorylation Ser790 IHRKTTAsTRKVSLA -1 1377674 t lperfetto Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC. SIGNOR-248851 0.408 PRKCQ protein Q04759 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser644 NLMFRKFsLERPFRP 9606 BTO:0000782 21157432 t lperfetto NF-kappaB activation is triggered by PKCteta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCteta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCteta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation. SIGNOR-249193 0.766 CSNK2A2 protein P19784 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser321 LNSEDDVsDEEGQEL -1 11278496 t llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. SIGNOR-250998 0.382 GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268594 0.2 TAL1 protein P17542 UNIPROT ANGPT2 protein O15123 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22792348 f miannu Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation. SIGNOR-198279 0.2 1-(4-fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]-1-butanol chemical CHEBI:91549 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). SIGNOR-258849 0.8 MRPL47 protein Q9HD33 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262349 0.716 CDKN1A protein P38936 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 24470334 f The cell cycle regulator p21 is induced early in myoblast differentiation and functions to block cell cycle progression SIGNOR-267286 0.7 EIF6 protein P56537 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates activity binding 9606 14654845 t lperfetto The assembly of 80S ribosomes requires joining of the 40S and 60S subunits, which is triggered by the formation of an initiation complex on the 40S subunit. This event is rate-limiting for translation, and depends on external stimuli and the status of the cell. Here we show that 60S subunits are activated by release of eIF6 (also termed p27BBP). | Loading 60S subunits with eIF6 caused a dose-dependent translational block and impairment of 80S formation, which were reversed by expression of RACK1 and stimulation of PKC in vivo and in vitro. PKC stimulation led to eIF6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eIF6 impaired RACK1/PKC-mediated translational rescue. SIGNOR-269150 0.505 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser124 PALKRSHsDSLDHDI 9606 11298456 t Phosphorylation is the signal for ubiquitination lperfetto We show that IR-induced destruction of Cdc25A requires both ATM and the Chk2-mediated phosphorylation of Cdc25A on serine 123. SIGNOR-106808 0.837 PTPRJ protein Q12913 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates dephosphorylation 9606 18348712 t gcesareni As reduction of pi3k activity by cd148 or shp-1 [32] is not large (2540%), it is likely that these ptps may function as modulators of the pi3k pathway rather than suppressors. SIGNOR-178049 0.264 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 23764977 t miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  SIGNOR-268760 0.8 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2R2 protein Q712K3 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271324 0.756 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 9606 22326956 t giulio giuliani In Tgfbr2fl/fl control MEPM cells, radioactive TGF-β2 ligands (12.5 kDa) bind to TβRI (53 kDa), TβRII (70 kDa), and TβRIII (100–200 kDa, highly glycosylated molecule) and form the ligand-receptor complexes of TβRI::TGF-β2 (65.5 kDa), TβRII::TGF-β2 (82.5 kDa), and TβRIII::TGF-β2 (112.5–212.5 kDa) SIGNOR-255960 0.84 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr813 NSLFTPDyELLTEND 9606 BTO:0000007 15121872 t 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Tyrosine 813 is a site of jak2 autophosphorylation critical for activation of jak2 by sh2-b betawe show that phosphorylation of tyrosine 813 is required for the sh2 domain-containing adapter protein sh2-b beta to bind jak2 and to enhance the activity of jak2 and stat5b. SIGNOR-235910 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser442 STFLAFPsPEKLLRL 9606 15037602 t lperfetto Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain. SIGNOR-216785 0.447 CALM3 protein P0DP25 UNIPROT GEM protein P55040 UNIPROT up-regulates activity binding 10116 BTO:0001009 14701738 t miannu Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells. SIGNOR-266341 0.2 HTR2C protein P28335 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257405 0.28 methionine smallmolecule CHEBI:16811 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264750 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR MDM4 protein O15151 UNIPROT up-regulates activity phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 18356162 t lperfetto We demonstrate that the serine/threonine kinase akt mediates phosphorylation of mdmx at ser367. This phosphorylation leads to stabilization of mdmx and consequent stabilization of mdm2. SIGNOR-178063 0.2 Vps34 Complex II complex SIGNOR-C241 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 30397185 f lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260326 0.7 MAPKAPK2 protein P49137 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates phosphorylation Ser387 SKLMRSAsFNTDPYV 9606 20626350 t gcesareni Mk2 was found to phopsphorylate in vitro the ago2 protein in ser387, which was identified as the major ago2 phosphorylation site in cells.and mutation of ser387 to alanineimpairsago2 localization to therna-containing granules termedprocessing bodies SIGNOR-166615 0.447 PTPRG protein P23470 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1003 VSNESVDyRATFPED -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254712 0.322 SB 431542 chemical CHEBI:91108 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206706 0.8 CCL2 protein P13500 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection SIGNOR-261032 0.7 MAPK14 protein Q16539 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates quantity by destabilization phosphorylation Thr339 STDKAEYtFYEGMGP 9606 BTO:0000007 22302987 t miannu P38 MAPK phosphorylates RBP-Jk at Thr339 by physical binding, which subsequently induces the degradation and ubiquitylation of the RBP-Jk protein.  SIGNOR-276403 0.25 PRKCD protein Q05655 UNIPROT PEBP1 protein P30086 UNIPROT up-regulates phosphorylation Ser153 RGKFKVAsFRKKYEL 9606 14654844 t miannu Here we show that the raf kinase inhibitor protein (rkip) is a physiological inhibitor of grk-2. After stimulation of gpcr, rkip dissociates from its known target, raf-1 (refs 6-8), to associate with grk-2 and block its activity. This switch is triggered by protein kinase c (pkc)-dependent phosphorylation of the rkip on serine 153. SIGNOR-119551 0.305 IL6ST protein P40189 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 9716487 t lperfetto All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59]. SIGNOR-238630 0.624 XRCC3 protein O43542 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity 9606 BTO:0000567 23438602 f lperfetto Interestingly, as with ATM (40, 41), XRCC3-deficient cells exhibited RDS and impaired CHK2 activation|Notably, early activation of CHK2 in S/G2 phase was downstream of XRCC3 recruitment as well as its phosphorylation at the sites of DSBs. NBS1 also has been shown to be involved in the early activation of CHK2 in response to IR (42). It is likely that NBS1-dependent CHK2 phosphorylation is mediated through XRCC3 activation. SIGNOR-263261 0.526 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Ser950 EGFHPRRsSQGATQM 10090 BTO:0000944 11581251 t lperfetto HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme SIGNOR-249203 0.585 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRA protein P10827 UNIPROT up-regulates activity binding 9606 BTO:0001073 29407449 t scontino T3 binds its receptor (TR) in the nucleus. TRs are ligand-dependent transcription factors belonging to the type II group of NHRs. TRs are encoded by two genes, Thra and Thrb. SIGNOR-267255 0.8 CTSS protein P25774 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI down-regulates quantity chemical modification 9606 31810556 t scontino Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol. SIGNOR-267868 0.8 MAPK8 protein P45983 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 t miannu JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain. SIGNOR-250122 0.904 dexamethasone chemical CHEBI:41879 ChEBI PPARG protein P37231 UNIPROT up-regulates 9606 11279134 f fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin SIGNOR-106475 0.8 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC10 protein Q969S8 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-202108 0.8 ITCH protein Q96J02 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates ubiquitination 9606 15946939 t gcesareni We identified atrophin 1-interacting protein 4 (aip4) as an e3 ubiquitin ligase that specifically targets smad7 for ubiquitin-dependent degradation without affecting the turnover of the activated tbetari. Surprisingly, we found that despite the ability to degrade smad7, aip4 can inhibit tgf-beta signaling, presumably by enhancing the association of smad7 with the activated tbetari. SIGNOR-137951 0.52 regorafenib chemical CHEBI:68647 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206412 0.8 PPP1CB protein P62140 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity dephosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001176 19036824 t The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation SIGNOR-248574 0.2 IKBKE protein Q14164 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser536 SGDEDFSsIADMDFS 9606 SIGNOR-C13 15489227 t gcesareni Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro. SIGNOR-129943 0.449 SRC protein P12931 UNIPROT PRMT5 protein O14744 UNIPROT down-regulates activity phosphorylation Tyr324 DNLESQTyEVFEKDP 9606 BTO:0002181 32759981 t miannu Here, we demonstrate that PRMT5 is phosphorylated at residue Y324 by Src kinase, a negative regulator of its activity. SIGNOR-277523 0.264 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR OTX2 protein P32243 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269248 0.438 MIF protein P14174 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates activity binding 10090 17435771 t gcesareni We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF [] By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. SIGNOR-252061 0.391 PPM1F protein P49593 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 11864573 t The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX. SIGNOR-248531 0.399 MAPK14 protein Q16539 UNIPROT PPARG protein P37231 UNIPROT up-regulates 9606 12589053 f fspada Specific inhibitors for p38 kinase inhibited bmp2-induced adipocytic differentiation and transcriptional activation of ppargamma, whereas overexpression of smad6 had no effect on transcriptional activity of ppargamma.  SIGNOR-210090 0.404 MAPK3 protein P27361 UNIPROT NUP50 protein Q9UKX7 UNIPROT down-regulates phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 t gcesareni Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. SIGNOR-188151 0.2 PTPN2 protein P17706 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity dephosphorylation Tyr1035 IETDKEYyTVKDDRD 10090 11909529 t The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3|We have identified JAK1 and JAK3 as physiological substrates of TCPTP.| Using a site-specific antibody directed against the activation loop phosphotyrosines in JAK1 (pY1022/pY1023), we found that these sites were in fact dephosphorylated by TCPTP SIGNOR-248396 0.758 HHIP protein Q96QV1 UNIPROT IHH protein Q14623 UNIPROT down-regulates activity binding 10090 10050855 t lperfetto Hip encodes a membrane glycoprotein that binds to all three mammalian hedgehog proteins with an affinity comparable to that of ptc-1. our findings support a model in which hip attenuates hedgehog signalling as a result of binding to hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any hedgehog signal. SIGNOR-65075 0.702 MOB1B protein Q7L9L4 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates binding 9606 21084559 t Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. SIGNOR-169798 0.872 Hexocyclium chemical CHEBI:5707 ChEBI CHRM5 protein P08912 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258399 0.8 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 11970898 t Immunoblots with phospho-specific antibodies confirmed that PTP1B suppresses phosphorylation of the Jak2 activation site tyrosines (Y1007/Y1008) and Stat3 in a dose-dependent manner SIGNOR-248405 0.789 CTDSP1 protein Q9GZU7 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser204 NHSMDAGsPNLSPNP 9606 17035229 t SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248791 0.409 AKT1 protein P31749 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 BTO:0000938 10529400 t lperfetto Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9BAD phosphorylation by Akt is an essential step for growth factor-mediated inhibition of caspase activation SIGNOR-252585 0.767 OXTR protein P30559 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257065 0.429 LLGL2 protein Q6P1M3 UNIPROT Scribble_complex_DLG4-LLGL2_variant complex SIGNOR-C505 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270887 0.526 SIK2 protein Q9H0K1 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Ser154 STLYRTQsSSNLAEL -1 27478041 t miannu The Regulatory Subunit of PI3K Is a Direct Catalytic Target of SIK2. These data confirm that p85α is a direct catalytic substrate of SIK2 and that SIK2 S154 phosphorylation significantly increases the activity of the PI3K/AKT pathway in ovarian cancer cells. SIGNOR-277269 0.327 TAF6 protein P49848 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263922 0.909 PRKAA1 protein Q13131 UNIPROT GAPDH protein P04406 UNIPROT up-regulates activity phosphorylation Ser122 GAKRVIIsAPSADAP 10090 26626483 t Luana  Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated.  SIGNOR-259857 0.297 EXOC4 protein Q96A65 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270787 0.959 RBBP8 protein Q99708 UNIPROT SPEN protein Q96T58 UNIPROT down-regulates binding 9606 16287852 t gcesareni We identify the ctip and ctbp corepressors as novel components of the human rbp-jk/sharp-corepressor complex and show that ctip binds directly to the sharp repression domain. SIGNOR-141616 0.523 CTDSP2 protein O14595 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser204 NHSMDAGsPNLSPNP 9606 BTO:0000007 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248293 0.399 COX6B1 protein P14854 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267742 0.748 C9 protein P02748 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 t lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer SIGNOR-263441 0.468 RELA protein Q04206 UNIPROT CITED1 protein Q99966 UNIPROT up-regulates binding 9606 SIGNOR-C13 9660950 t gcesareni The transcriptional coactivator cpb/p300 associates with nf-kappa b p65 through two sites, an n-terminal domain that interacts with the c-terminal region of unphosphorylated p65, and a second domain that only interacts with p65 phosphorylated on serine 276. SIGNOR-59054 0.2 MC1R protein Q01726 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268697 0.458 CDK1 protein P06493 UNIPROT RPA2 protein P15927 UNIPROT up-regulates activity phosphorylation Ser29 QSPGGFGsPAPSQAE 9606 1318195 t llicata Cdc2 family kinases phosphorylate a human cell dna replication factor, rpa, and activate dna replication. therefore, the serines on rpa p34 that were necessary for phosphorylation by cdc2 kinase were also necessary for phosphorylation in the cell SIGNOR-16975 0.52 MTMR4 protein Q9NYA4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates dephosphorylation 9606 20061380 t gcesareni Here we demonstrate that myotubularin-related protein 4 (mtmr4), a fyve domain-containing dual-specificity protein phosphatase (dsp), attenuates tgfbeta signaling by reducing the phosphorylation level of r-smads in early endosomes. SIGNOR-163031 0.51 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG5-LLGL2_variant complex SIGNOR-C506 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270892 0.45 NARS1 protein O43776 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270455 0.8 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 8702756 t miannu Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase. SIGNOR-261718 0.633 CDC42BPA protein Q5VT25 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates activity phosphorylation Thr508 PDRKKRYtVVGNPYW BTO:0000567 11340065 t llicata Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha. \ In vitro, MRCKalpha phosphorylated the protein kinase domain of LIM kinases, and the site in LIMK2 phosphorylated by MRCKalpha proved to be threonine 505 within the activation segment. SIGNOR-250721 0.413 CBP/p300 complex SIGNOR-C6 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates binding 9606 BTO:0000887 10944526 t gcesareni Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo. SIGNOR-81047 0.634 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252523 0.907 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr86 YTLSRAQtVVVEYTH -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276135 0.758 mTORC1 complex SIGNOR-C3 SIGNOR SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser422 AEAFLGFsYAPPTDS -1 18570873 t lperfetto Mtor phosphorylated sgk1, but not sgk1-s422a, in vitro. Sgk1 phosphorylated p27 in vitro. These data implicate sgk1 as an mtorc1 (mtor-raptor) substrate. mtor may promote g1 progression in part through sgk1 activation SIGNOR-217078 0.607 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT down-regulates activity phosphorylation Ser31 DLQEVLSsDENGGTY 9606 BTO:0000567 12876286 t llicata CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites SIGNOR-250853 0.351 CYP26A1 protein O43174 UNIPROT all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI down-regulates quantity chemical modification 9606 31963453 t lperfetto Cytochrome P450 (CYP) subfamily 26 of enzymes degrade the excess of RA to avoid detrimental effects [17]. Among the three subtypes (CYP26A1, CYP26B1, and CYP26C1), CYP26A1 is particularly important during embryonic development SIGNOR-265139 0.8 DUSP3 protein P51452 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Tyr204 HTGFLTEyVATRWYR 9606 BTO:0004419 12840032 t lperfetto The activation of the mapk activity requires the dual phosphorylation of the ser/thr and tyr residues in the txy kinase activation motif (1113), and deactivation occurs through the action of either ser/thr protein phosphatase (14), protein-tyrosine phosphatase (ptp) (14, 15), or dual specificity phosphatases SIGNOR-103035 0.651 ATM protein Q13315 UNIPROT HNF1A protein P20823 UNIPROT up-regulates phosphorylation Ser249 IQRGVSPsQAQGLGS 9606 24821553 t lperfetto Serine 249 phosphorylation by atm protein kinase regulates hepatocyte nuclear factor-1_ transactivation SIGNOR-205087 0.259 AKT proteinfamily SIGNOR-PF24 SIGNOR NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 t lperfetto Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no. SIGNOR-244322 0.2 TTK protein P33981 UNIPROT MAP4 protein P27816 UNIPROT down-regulates quantity by destabilization phosphorylation Ser928 SRLATNTsAPDLKNV 9606 BTO:0000567 31253867 t miannu We further uncovered that Mps1 is a kinase of MAP4, and E7-MAP4 binding blocks Mps1 phosphorylation of MAP4, thereby interrupting phosphorylation-dependent MAP4 degradation.  SIGNOR-277458 0.2 PPM1D protein O15297 UNIPROT TP53 protein P04637 UNIPROT down-regulates dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 15870257 t lperfetto PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair. SIGNOR-135980 0.575 PPM1D protein O15297 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 15870257 t Here we show that the oncogenic p53-induced serine/threonine phosphatase, PPM1D (or Wip1), dephosphorylates two ATM/ATR targets, Chk1 and p53. PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. SIGNOR-248317 0.486 KCNMA1 protein Q12791 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31152168 t miannu The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. SIGNOR-269198 0.8 PLK1 protein P53350 UNIPROT KLF4 protein O43474 UNIPROT up-regulates quantity by stabilization phosphorylation Ser234 GKFVLKAsLSAPGSE 9606 BTO:0002181 31281496 t miannu We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization. SIGNOR-277463 0.252 B2M protein P61769 UNIPROT Class I MHC complex SIGNOR-C425 SIGNOR form complex binding -1 28367149 t scontino One Ig domain is present in each chain of MHC class II, while the second Ig-type domain of MHC class I is provided by non-covalent association of the invariant light chain beta-2 microglobulin (beta2m) with the HC.|The MHC class I HC folds and assembles with beta2m in the lumen of the endoplasmic reticulum (ER) SIGNOR-267777 0.2 GNA12 protein Q03113 UNIPROT ARHGEF12 protein Q9NZN5 UNIPROT up-regulates activity binding 10090 12024019 t P115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G alpha 12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation. SIGNOR-256522 0.756 SP1 protein P08047 UNIPROT PDGFC protein Q9NRA1 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0001685 15247255 f The PDGF family of ligands is comprised of A, B, C, and D chains. Here, we provide the first functional characterization of the PDGF-C promoter. We examined 797 bp of the human PDGF-C promoter and identified several putative recognition elements for Sp1, Ets Egr-1, and Smad.|These findings thus demonstrate that PDGF-C transcription, activated by FGF-2, is mediated by Egr-1 and its upstream kinase ERK.|Egr-1 and Sp1 specifically bind the PDGF-C promoter SIGNOR-254272 0.2 PRKCB protein P05771 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Ser239 LIRGVKSsGKVVYFT 9823 21864610 t miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. SIGNOR-262922 0.2 GPHN protein Q9NQX3 UNIPROT ARHGEF9 protein O43307 UNIPROT up-regulates activity binding 9606 25882190 t miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. SIGNOR-264973 0.623 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR USP7 protein Q93009 UNIPROT up-regulates activity phosphorylation Tyr243 NQLRKAVyMMPTEGD 24317448 t lperfetto In this study, we show that BCR-ABL enhances HAUSP-induced de-ubiquitination of PTEN in turn favoring its nuclear exclusion. We further demonstrate that BCR-ABL physically interacts with and phosphorylates HAUSP on tyrosine residues to trigger its activity.|The HAUSP Y243F mutant showed significantly reduced BCR-ABL-induced HAUSP phosphorylation, which in turn was completely abrogated by imatinib treatment SIGNOR-276532 0.2 AHR protein P35869 UNIPROT CYP1A1 protein P04798 UNIPROT up-regulates quantity by expression transcriptional regulation -1 9865727 t Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor|These data demonstrate that resveratrol inhibits CYP1A1 expression in vitro, and that it does this by preventing the binding of the AHR to promoter sequences that regulate CYP1A1 transcription. SIGNOR-253639 0.671 PPARG protein P37231 UNIPROT CEBPA protein P49715 UNIPROT up-regulates activity transcriptional regulation 10090 BTO:0002572;BTO:0000011;BTO:0005065 16431920 f Dislodging hdac1 from the promoter lperfetto These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome SIGNOR-235358 0.64 MAD2L2 protein Q9UI95 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates activity binding -1 11459826 t miannu The APC is activated in mitosis and G1 by CDC20 and CDH1, and inhibited by the checkpoint protein MAD2, a specific inhibitor of CDC20. We show here that a MAD2 homolog MAD2B also inhibits APC. MAD2B directly inhibits activation of APC by CDC20 and CDH1 SIGNOR-264902 0.528 CAMK2B protein Q13554 UNIPROT CAMK2B protein Q13554 UNIPROT up-regulates activity phosphorylation Thr287 SMMHRQEtVECLKKF 2842767 t llicata Ca2+/calmodulin-dependent protein kinase II: identification of threonine-286 as the autophosphorylation site in the alpha subunit associated with the generation of Ca2+-independent activity. SIGNOR-250640 0.2 RPS16 protein P62249 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262435 0.871 ARHGAP44 protein Q17R89 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260498 0.572 AKT3 protein Q9Y243 UNIPROT TBX3 protein O15119 UNIPROT up-regulates activity phosphorylation Ser719 AEKEAATsELQSIQR 9606 25595898 t miannu We have identified TBX3 as a key substrate of AKT3 in melanomagenesis. we have identified the AKT3 target site at serine residue 720 in the TBX3 protein and show that this site is phosphorylated in vivo. the phosphorylation at S720 promotes TBX3 protein stability, nuclear localization, transcriptional repression of E-cadherin, and its role in cell migration and invasion. SIGNOR-223534 0.362 MFGE8 protein Q08431 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR down-regulates activity 10116 19020771 f Giorgia In our current study, we have shown that after LPS-stimulation, MFG-E8-mediated apoptotic cell phagocytosis suppresses various ERK1/2, p38, JNK, and NFκB activation, resulting in a lower TNF-α release. We also explored whether MFG-E8 helps to suppress the proinflammatory pathway within RPMs. We hence incubated the macrophages with apoptotic cells and stimulated them with LPS and examined the activation of MAP kinase and NFkB pathways after the exogenous addition of recombinant MFG-E8 (rMFG-E8). While apoptotic cells alone had no effect on these pathways, the addition of rMFG-E8 to apoptotic cells prior to phagocytosis and LPS stimulation had a marked suppressive effect on all of the investigated pathways, particularly on the p38 and NFκB pathways that play a key role in the cytokine response of macrophages SIGNOR-260651 0.248 RPS6KB2 protein Q9UBS0 UNIPROT TARBP2 protein Q15633 UNIPROT up-regulates activity phosphorylation Ser283 ILSLRSCsLGSLGAL -1 27407113 t miannu We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells.  SIGNOR-274066 0.34 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT unknown phosphorylation Ser1403 AGREEFYsTHPHFMT 9606 BTO:0000938 19824698 t lperfetto We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. SIGNOR-188429 0.2 CSNK2A1 protein P68400 UNIPROT SERINC3 protein Q13530 UNIPROT up-regulates activity phosphorylation Ser380 ILGDTTTsGASDEED -1 30135209 t miannu The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the μ subunits in vitro. SIGNOR-273631 0.2 PAK1 protein Q13153 UNIPROT PGAM1 protein P18669 UNIPROT down-regulates phosphorylation Ser23 WNLENRFsGWYDADL 9606 BTO:0000130 12189148 t Activated pak1 gcesareni Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity. SIGNOR-91598 0.2 GSK3B protein P49841 UNIPROT RXRA protein P19793 UNIPROT up-regulates activity phosphorylation Ser49 GSPGQLHsPISTLSS 9606 BTO:0000007 29137318 t miannu GSK3β-induced RXRα phosphorylation decreased for RXRα-S49A, RXRα-S66A and RXRα-S78A in HEK293 cells compared with RXRα WT by western blot analysis.  SIGNOR-277372 0.278 JNK proteinfamily SIGNOR-PF15 SIGNOR YWHAZ protein P63104 UNIPROT down-regulates phosphorylation 9606 15071501 t Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons gcesareni Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-190 SIGNOR-269980 0.2 ETS1 protein P14921 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000948 22270366 f miannu VEGF-induced MMP-9 and MMP-13 promoter activities were down-regulated in ETS-1 siRNA-transfected cells. it is hypothesized that the activation of PI3K/AKT and p38 MAPK by VEGF results in ETS-1 gene expression, which activates MMP-9 and MMP-13, leading to the invasion and scattering of SKOV-3 cells. SIGNOR-254084 0.311 GGCX protein P38435 UNIPROT BGLAP protein P02818 UNIPROT up-regulates activity carboxylation 9606 31226734 t lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. SIGNOR-265922 0.674 SRC protein P12931 UNIPROT DNM2 protein P50570 UNIPROT down-regulates activity phosphorylation Tyr597 NTEQRNVyKDLRQIE 10090 BTO:0000944 33113375 t miannu We used cSrc-transformed NIH 3T3 fibroblasts to examine the effect of mutant Dyn2Y597. Similar to its effect in myotubes, Dyn2Y597F presented reduced enrichment at podosomes, whereas Dyn2Y597E clearly targeted podosome rosettes (Figures S9B and S9C). Moreover, Dyn2Y597F significantly reduced the podosome area, ECM degradation ability, and lifespan of the podosome in cSrc-transformed NIH 3T3 fibroblasts, whereas Dyn2Y597E displayed contradictory effects (Figures S9D–S9G). SIGNOR-277539 0.574 GSK3B protein P49841 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 BTO:0000150 16504004 t gcesareni Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover. SIGNOR-144818 0.775 SRC protein P12931 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity phosphorylation Tyr240 RREDKFMyFEFPQPL 9606 BTO:0002035 11948419 t miannu MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e). SIGNOR-275982 0.552 CDK8 protein P49336 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser289 PPPLAPQsPQGGVMG -1 29967145 t miannu CDK8 phosphorylates YAP and promotes its activation. Of interest, mutating four amino acid positions (T119, S128, S289, and S367) to alanines (YAP-4A) completely blocked phosphorylation (Fig. 6J), suggesting that CDK8 phosphorylates these sites in YAP in vitro. SIGNOR-277650 0.327 PRKG1 protein Q13976 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser412 GIPFRRPsTYGIPRL 9606 BTO:0000671 12082086 t lperfetto G-kinase phosphorylated tfii-i in vitro and in vivo on ser(371) and ser(743) outside of the interaction domain. G-kinase strongly enhanced tfii-i transactivation of a serum-response element-containing promoter in cos7 cells SIGNOR-89849 0.555 KCNQ4 protein P56696 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 19298256 t miannu KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. SIGNOR-265985 0.8 PRKAA1 protein Q13131 UNIPROT FANCA protein O15360 UNIPROT up-regulates activity phosphorylation Ser347 VQMQREWsFARTHPL 9606 BTO:0001938 27449087 t miannu FANCA was phosphorylated by AMPK at S347 and phosphorylation increased with MMC treatment. MMC-induced FANCD2 monoubiquitination and nuclear foci formation were compromised in a U2OS cell line that stably overexpressed the S347A mutant form of FANCA compared to wild-type FANCA-overexpressing cells, indicating a requirement for FANCA phosphorylation at S347 for proper activation of the FA/BRCA pathway.  SIGNOR-277264 0.338 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFB6 protein O95139 UNIPROT up-regulates activity phosphorylation Ser55 NKFLENKsPWRKMVH 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275598 0.251 CNTRL protein Q7Z7A1 UNIPROT CEP290 protein O15078 UNIPROT down-regulates activity binding 9606 18694559 t miannu CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110. CP110 in this complex is to keep CEP290 inactive in growing cells until cells are ready to undergo ciliogenesis as they transit into the quiescent state SIGNOR-252149 0.447 tacrolimus (anhydrous) chemical CHEBI:61049 ChEBI PPP3CC protein P48454 UNIPROT down-regulates chemical inhibition 9606 15276472 t gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. SIGNOR-127245 0.8 F2 protein P00734 UNIPROT F8 protein P00451 UNIPROT up-regulates activity cleavage Arg1708 EDENQSPrSFQKKTR -1 10350471 t lperfetto Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689. SIGNOR-263639 0.746 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9534 BTO:0000298 10880354 t miannu Ser(155) is phosphorylated preferentially by PKA in vitro and is the only residue in BAD that becomes phosphorylated when cells are exposed to cAMP-elevating agents. The phosphorylation of BAD at Ser(155) prevents it from binding to Bcl-X(L) and promotes its interaction with 14-3-3 proteins. SIGNOR-250338 0.523 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 t irozzo Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. SIGNOR-255876 0.2 Microprocessor complex complex SIGNOR-C356 SIGNOR NcRNA_processing phenotype SIGNOR-PH95 SIGNOR up-regulates 24581491 f lperfetto Microprocessor minimally comprises the ribonuclease DROSHA and its double-stranded RNA-binding partner DGCR8 (Denli et al., 2004; Gregory et al., 2004). Microprocessor recognizes pri-miRNA through the stem-loop (Zeng et al., 2005) and the stem-loop-ssRNA junction (Han et al., 2006), and cleaves both the 5′ and 3′ flanking segments to generate pre-miRNA. SIGNOR-264850 0.7 UBE2I protein P63279 UNIPROT MBD4 protein O95243 UNIPROT up-regulates activity sumoylation Lys137 KNGETSLkPEDFDFT 31476572 t lperfetto MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro. SIGNOR-275676 0.2 PRKCD protein Q05655 UNIPROT MUC1 protein P15941 UNIPROT up-regulates phosphorylation Thr1224 RYVPPSStDRSPYEK 9606 11877440 t gcesareni We show that phosphorylation of muc1 by pkcdelta increases binding of muc1 and beta-catenin in vitro and in vivo. The functional significance of the muc1-pkcdelta interaction is further supported by the demonstration that mutation of the pkcdelta phosphorylation site abrogates muc1-mediated decreases in binding of beta-catenin to e-cadherin SIGNOR-115501 0.342 CDK5 protein Q00535 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Thr509 PVYEVPAtPKYATPA 9606 BTO:0000938 16611631 t lperfetto In summary, phosphorylation of thr509 of human crmp1 appears to be regulated by two mechanisms; direct phosphorylation by cdk5, or by priming of ser522 by cdk5 followed by sequential phosphorylation of ser518, thr514, and thr509 by gsk3. SIGNOR-145912 0.607 CPSF2 protein Q9P2I0 UNIPROT CPSF complex complex SIGNOR-C53 SIGNOR form complex binding 9606 BTO:0000007 19224921 t lperfetto The CPSF complex consists of five subunits, named CPSF160, CPSF100, Fip1, CPSF73, and CPSF30. SIGNOR-268335 0.894 ADAM10 protein O14672 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity cleavage 9606 BTO:0000782 28624438 t miannu ADAM10-mediated Notch1 cleavage is the rate limiting-step for release of the NICD and subsequent activation of Notch1 signaling. In T cells ADAM10-mediated Notch1 shedding controls T cell development SIGNOR-259838 0.773 LY2940680 chemical CID:49848070 PUBCHEM SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193805 0.8 SMURF2 protein Q9HAU4 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 11163210 t miannu Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.  SIGNOR-272940 0.865 PRKACA protein P17612 UNIPROT PTPRR protein Q15256 UNIPROT down-regulates activity phosphorylation Ser339 GLQERRGsNVSLTLD 9534 10601328 t miannu The PKA phosphorylation site on PTP-SL was identified as the Ser(231) residue. treatment of COS-7 cells with PKA activators, or overexpression of the Calpha catalytic subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38alpha by wild-type PTP-SL, but not by a PTP-SL S231A mutant.‚  SIGNOR-250038 0.349 PRKN protein O60260 UNIPROT EPS15 protein P42566 UNIPROT down-regulates activity ubiquitination 10090 16862145 t gcesareni Treatment of cells with EGF stimulates parkin binding to both Eps15 and the EGFR and promotes parkin-mediated ubiquitination of Eps15. SIGNOR-243282 0.2 EGLN2 protein Q96KS0 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization hydroxylation 9606 24990963 t lperfetto There are three EglN family members in humans and mice (EglN1, EglN2, and EglN3). Their enzymatic activity requires oxygen, ascorbic acid, iron, and α-ketoglutarate (α-KG). Under hypoxic conditions, EglNs lose their activity and fail to hydroxylate HIFα, which leads to HIFα stabilization SIGNOR-261999 0.851 WDR61 protein Q9GZS3 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR form complex binding 9606 BTO:0000567 20178742 t miannu Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A).  SIGNOR-269831 0.845 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252863 0.756 PICK1 protein Q9NRD5 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity binding 10116 BTO:0003036 16554470 t miannu We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis. SIGNOR-268178 0.795 PTPN2 protein P17706 UNIPROT STAT1 protein P42224 UNIPROT down-regulates dephosphorylation Tyr701 DGPKGTGyIKTELIS 9606 12138178 t miannu Stat1 becomes tyrosine phosphorylated and translocates into the nucleus, where it binds to dna to activate transcription. The activity of stat1 is dependent on tyrosine phosphorylation, and its inactivation in the nucleus is accomplished by a previously unknown protein tyrosine phosphatase (ptp). We have now purified a stat1 ptp activity from hela cell nuclear extract and identified it as tc45, the nuclear isoform of the t-cell ptp (tc-ptp). Tc45 can dephosphorylate stat1 both in vitro and in vivo. SIGNOR-90814 0.723 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Thr1969 DKASLTRtLQHRIAL 9606 BTO:0000938 19824698 t lperfetto We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. Substitution of thr1967, an autophosphorylation site located within the kinase domain, to ala caused a significant decrease in the kinase activity SIGNOR-188421 0.2 RAB2A protein P61019 UNIPROT PRKCI protein P41743 UNIPROT down-regulates activity binding 9606 BTO:0000567 14570876 t Sara Rab2 Binds to the PKCι/λ Regulatory Domain and Inhibits PKCι/λ-dependent GAPDH Phosphorylation SIGNOR-261301 0.468 MAPK3 protein P27361 UNIPROT THRB protein P10828 UNIPROT down-regulates activity phosphorylation Ser142 IQKNLHPsYSCKYEG 9606 12809513 t llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. SIGNOR-102224 0.408 Sound_vibration stimulus SIGNOR-ST27 SIGNOR TIP-LINK complex complex SIGNOR-C291 SIGNOR up-regulates 10090 BTO:0000630 23217710 f lperfetto Sound induced vibrations or motion lead to deflection of the stereociliary bundles, which directly control the activity of the mechanotransduction channels in stereocilia. It is thought that tip links, fine extracellular filaments that connect the tips of neighboring stereocilia, transmit tension force onto the transduction channels SIGNOR-262581 0.7 SMO protein Q99835 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates binding 9606 16885213 t gcesareni We found that smo, by virtue of what appears to be constitutive activity, activates all members of the g(i) family but does not activate members of the g(s), g(q), and g(12) families. SIGNOR-148484 0.2 ITGAV protein P06756 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253205 0.913 GSK3B protein P49841 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity 10090 24260231 f miannu Involvement of GSK3 Inhibition by the PI3K/Akt Pathway in Regulation of Etoposide-induced Chk1 Activation. GSK3ß regulates etoposide-induced Chk1 activation. GSK3 inhibitors, including LiCl and SB216763, restored the sustained Chk1 activation and mitigated apoptosis in cells treated with etoposide and the inhibitors for aberrant kinases, PI3K, or Akt. Thus, proteasomal degradation of Chk1 as well as GSK3 activation may be involved in negative regulation of etoposide-induced Chk1 by imatinib in these cells. SIGNOR-263050 0.302 DGC complex SIGNOR-C217 SIGNOR NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000142 11470830 t miannu In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan. SIGNOR-265451 0.305 MAX protein P61244 UNIPROT MXD4 protein Q14582 UNIPROT up-regulates activity binding 9606 7954804 t 2 miannu the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. SIGNOR-240224 0.495 L-serine chemical CHEBI:17115 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 10090 BTO:0000142 12393813 t lperfetto High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media. SIGNOR-268269 0.8 GDNF protein P39905 UNIPROT NCAM1 protein P13591 UNIPROT up-regulates activity binding 10116 BTO:0002881 15212950 t miannu Recently, NCAM was identified as an alternative receptor for GDNF. These new results may explain the findings that, in several regions, the GDNF receptor (GFRa1) is highly expressed, while RET is undetectable. SIGNOR-252189 0.688 SNRPG protein P62308 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270632 0.789 NTRK1 protein P04629 UNIPROT SH2B2 protein O14492 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9856458 t lperfetto Two substrates of trk kinases, raps and sh2-b. raps and sh2-b mediate trk signaling in developing neurons SIGNOR-62619 0.532 MYC protein P01106 UNIPROT IMPDH2 protein P12268 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18677108 t miannu Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation. SIGNOR-267375 0.298 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM3A protein Q9Y4C1 UNIPROT up-regulates activity chemical activation 29981745 t lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. SIGNOR-273479 0.8 GNAS protein P63092 UNIPROT HCK protein P08631 UNIPROT up-regulates activity binding -1 11007482 t Galphas and Galphai similarly modulate Hck, another member of Src-family tyrosine kinases. SIGNOR-256529 0.2 MAPK3 protein P27361 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation Ser455 SIDSEPGsPLLDDAK 9606 14988395 t lperfetto Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity. SIGNOR-123053 0.4 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr312 ISYDIPPtPGNTYQI 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249399 0.585 SOX9 protein P48436 UNIPROT CEBPB protein P17676 UNIPROT down-regulates transcriptional regulation 9606 19254573 f fspada Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation SIGNOR-210037 0.331 SHOC2 protein Q9UQ13 UNIPROT PPP1CA protein P62136 UNIPROT up-regulates activity binding 9606 BTO:0000007 16630891 t Using a proteomics approach, we have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site SIGNOR-251647 0.579 SEC13 protein P55735 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 30605680 t lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat SIGNOR-265296 0.842 ATR protein Q13535 UNIPROT MCM2 protein P49736 UNIPROT unknown phosphorylation Ser108 DVEELTAsQREAAER 9606 15210935 t lperfetto Atm phosphorylates mcm3 on s535 in response to ionizing radiation. Second, atr phosphorylates mcm2 on s108 in response to multiple forms of dna damage and stalling of replication forksthe functional consequences of mcm2 s108 and mcm3 s535 phosphorylation are not clear SIGNOR-126363 0.697 WNK1 protein Q9H4A3 UNIPROT OXSR1 protein O95747 UNIPROT up-regulates phosphorylation Ser325 VRRVPGSsGRLHKTE 9606 17190791 t gcesareni Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1) SIGNOR-151659 0.497 PIM2 protein Q9P1W9 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 16403219 t lperfetto All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death. SIGNOR-249604 0.4 GATA1 protein P15976 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10523830 f irozzo Our results suggest that Spi-1 and GATA-1 might play a key role in the regulation of Fli-1. Most notably, we observed that the GATA/EBS dual element near the Fli-1 CAP sites had an enhancer activity in HEL cells. Spi-1 and GATA-1 were both found to bind to this sequence and hence both factors could represent potential regulators of Fli-1 expression. SIGNOR-256053 0.533 Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR phenylalanine smallmolecule CHEBI:28044 ChEBI down-regulates quantity chemical modification 9606 20223217 t miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. SIGNOR-270439 0.8 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser181 NPLLRKEsAPPSLRR 9606 18339811 t Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs. SIGNOR-248604 0.2 IKBKE protein Q14164 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 19940156 t lperfetto Here, we show that ikkepsilon interacts with and phosphorylates estrogen receptor alpha (eralpha) on serine 167 in vitro and in vivo. As a result, ikkepsilon induces eralpha transactivation activity and enhances eralpha binding to dna. SIGNOR-161834 0.347 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273075 0.635 Aldolase proteinfamily SIGNOR-PF75 SIGNOR glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266486 0.8 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation Tyr161 DDYHNPGyLVVLPDS 9606 11368773 t lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. SIGNOR-247022 0.761 ZNF165 protein P49910 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 26567849 t Luana ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1. SIGNOR-266093 0.2 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR LEFTY2 protein O00292 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269251 0.429 long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity precursor of 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267904 0.8 GOLPH3 protein Q9H4A6 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR up-regulates activity 9606 BTO:0000018;BTO:0005011 19553991 f Mechanistically, GOLPH3 regulates cell size, enhances growth factor-induced mTOR signaling in human cancer cells and alters response to mTOR inhibitor in vivo. SIGNOR-253556 0.296 CYTH2 protein Q99418 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 BTO:0003102 14565977 f miannu ARNO and ARF6 regulate axonal elongation and branching through downstream activation of phosphatidylinositol 4-phosphate 5-kinase alpha SIGNOR-264909 0.7 RWDD3 protein Q9Y3V2 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates sumoylation 9606 17956732 t lperfetto Rsume,_a small_rwd-containing protein, enhances sumo conjugation and stabilizes hif-1alpha during hypoxia SIGNOR-158590 0.469 ASNS protein P08243 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267534 0.8 CAD protein P27708 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267424 0.8 POU5F1 protein Q01860 UNIPROT SOX17/POU5F1 complex SIGNOR-C451 SIGNOR form complex binding 23474895 t SimoneGraziosi Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm|We show that Sox17 partners with Oct4 and binds to a unique ‘compressed' Sox/Oct motif that earmarks endodermal genes. This is in contrast to the pluripotent state where Oct4 selectively partners with Sox2 at ‘canonical' binding sites. SIGNOR-269221 0.627 MYCL protein P12524 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0000724 7882978 f irozzo These observations indicate that continued late-stage expression of L-myc affected differentiation processes directly, rather than indirectly through deregulated growth control, whereas constitutive c-myc expression inhibited proliferative arrest, but did not appear to disturb differentiation. SIGNOR-259202 0.7 TNFRSF10C protein O14798 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates binding 9606 BTO:0000671 20103630 t amattioni Albeit on binding the ligand, dcr1 and dcr2 do not transduce the apoptogenic signal, SIGNOR-163611 0.895 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Glu) smallmolecule CHEBI:29175 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269486 0.8 IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding -1 10219247 t gcesareni Nterleukin-4 (il-4) is a principal regulatory cytokine during an immune response and a crucial determinant for allergy and asthma. Il-4 binds with high affinity and specificity to the ectodomain of the il-4 receptor alpha chain (il4-bp). SIGNOR-67217 0.941 EGFR protein P00533 UNIPROT EZR protein P15311 UNIPROT unknown phosphorylation Tyr146 KEVHKSGyLSSERLI 9606 BTO:0000017 15647376 t lperfetto Here we report the identification of the tyrosine phosphorylation sites in ezrin using bacterially expressed protein as a substrate for in vitro phosphorylation with the egf receptor. tyrosines 145 and 353 were identified as the sites of phosphorylation. but as of yet the role of ezrin phosphorylation at y145 is unknown. SIGNOR-133219 0.545 MALT1 protein Q9UDY8 UNIPROT CBM complex SIGNOR-C555 SIGNOR form complex binding 9606 15122200 t miannu CARMA1, the adaptor protein BCL-10 (B-cell lymphoma 10) and the caspase-like protein MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) form a signalling complex that has a key role in antigen-receptor-mediated activation of the nuclear factor-κB (NF-κB) and JUN N-terminal kinase (JNK) pathways. SIGNOR-276295 0.805 GLI3 protein P10071 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17419683 f gcesareni Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin. SIGNOR-154234 0.574 SATB1 protein Q01826 UNIPROT IGFBP2 protein P18065 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 17343824 f miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. SIGNOR-255129 0.2 GATA2 protein P23769 UNIPROT CYBB protein P04839 UNIPROT down-regulates quantity transcriptional regulation 9606 10734088 t These results suggest that GATA-1 is an activator and that GATA-2 is a relative competitive inhibitor of GATA-1 in the expression of the gp91(phox) gene in human eosinophils. SIGNOR-259948 0.253 Calcineurin complex SIGNOR-C155 SIGNOR IL6 protein P05231 UNIPROT up-regulates quantity by expression 10090 18177723 f lperfetto Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy SIGNOR-252340 0.256 SMURF1 protein Q9HCE7 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates activity monoubiquitination 9615 BTO:0000837 32010791 t miannu  Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation. SIGNOR-277507 0.2 CCND1 protein P24385 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000575 11731443 f Cyclin D1 regulates mitogen-dependent progression through G1 phase in cultured cells, and its overexpression in malignant cells is thought to contribute to autonomous proliferation in vivo. SIGNOR-260014 0.7 ARPP19 protein P56211 UNIPROT PPP2R2D protein Q66LE6 UNIPROT down-regulates activity binding -1 phosphorylation:Ser62 KGQKYFDsGDYNMAK 21164014 t gcesareni We identified cyclic adenosine monophosphate€“regulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry. SIGNOR-243731 0.682 NOG protein Q13253 UNIPROT GDF5 protein P43026 UNIPROT down-regulates activity binding 9606 19956691 t Regulation miannu We identified two mutations (N445K,T) in patients with multiple synostosis syndrome (SYM1) in the BMP–related ligand GDF5. Residue N445, situated within overlapping receptor and antagonist interfaces, is highly conserved among the BMP family with the exception of BMP9 and BMP10, in which it is substituted with lysine. Like the mutant GDF5, both BMPs are insensitive to NOGGIN and show a high chondrogenic activity. SIGNOR-251865 0.687 Diprenorphine chemical CHEBI:4650 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258789 0.8 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 15905173 t lperfetto Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain SIGNOR-137255 0.2 TBK1 protein Q9UHD2 UNIPROT DDAH2 protein O95865 UNIPROT down-regulates activity phosphorylation Thr203 VRAMAVLtDHPYASL 33850055 t lperfetto TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o SIGNOR-275645 0.2 RIPK3 protein Q9Y572 UNIPROT DLD protein P09622 UNIPROT up-regulates activity phosphorylation Thr135 STAVKALtGGIAHLF -1 29358703 t miannu Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135. SIGNOR-266372 0.2 CHUK protein O15111 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates phosphorylation 9606 16612387 t gcesareni Ikkalfa associated with and phosphorylated and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production. SIGNOR-146116 0.68 Frizzled proteinfamily SIGNOR-PF11 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates activity 18697834 f Simone Vumbaca […] we suggest that Wnt1, Wnt3a and Wnt5a result in the accumulation of Act-β-Cat SIGNOR-255652 0.2 PTPN6 protein P29350 UNIPROT SH3BP2 protein P78314 UNIPROT down-regulates activity dephosphorylation Tyr448 GDDSDEDyEKVPLPN 9606 16649996 t miannu Shp-1 dephosphorylates 3bp2 and potentially downregulates 3bp2-mediated t cell antigen receptor signaling|adaptor protein 3BP2 serves as a binding protein and a physiological substrate of SHP-1. 3BP2 is phosphorylated on tyrosyl residue 448 in response to TCR activation, and the phosphorylation is required for T c SIGNOR-277172 0.552 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t gcesareni Although sh2 domains have not been reported previously to be phosphorylated, the tensin-3 sh2 domain is a physiologic substrate for src. Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. SIGNOR-187854 0.417 RPLP2 protein P05387 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262449 0.81 IRS1 protein P35568 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0000156 11259577 t lperfetto Association ofinsulinreceptor substrate 1 (irs-1) y895 with grb-2 mediates theinsulinsignaling involved in irs-1-deficient brown adipocyte mitogenesis. SIGNOR-236614 0.796 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates phosphorylation Ser696 PNKELPPsPEKKTKP 9606 BTO:0000567 9398320 t lperfetto Map4 is phosphorylated by cdc2 kinase in mitotic hela/ phosphorylation by cdc2 kinase decreased the microtubule-stabilizing ability of map4, suggesting that there are critical phosphorylation sites among the five major cdc2 kinase-dependent phosphorylation sites [spots 4 (ser-696), 5, 6, 9, and 10 (ser-787)]. SIGNOR-53735 0.511 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr775 QGWVPSNyITPVNSL 9606 16912036 t Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. SIGNOR-260811 0.2 CAMK4 protein Q16566 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates activity phosphorylation Ser302 PQLASKQsMVNSLPT BTO:0000938 11970865 t llicata Ser301 of CBP was identified as a major target of CaMKIV phosphorylation in vitro and in vivo. CaM kinase inhibitors attenuated phosphorylation at Ser301 and blocked CBP-dependent transcription. Additionally, mutation of Ser301 impaired NMDA- and CaMKIV-stimulated transcription. These findings demonstrate that activity-induced CaMKIV signaling contributes to CREB/CBP-dependent transcription by phosphorylating CBP at Ser301. SIGNOR-250710 0.624 DEF6 protein Q9H4E7 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 18976935 t lperfetto Furthermore, membrane targeting of the SLAT Dbl-homology (catalytic) domain was sufficient to trigger TCR-mediated NFAT activation and Th1 and Th2 differentiation in a Cdc42-dependent manner. SIGNOR-253369 0.401 PRKACA protein P17612 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser99 NRQAAKLsKPTLENL 9606 15703181 t lperfetto We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195. SIGNOR-133888 0.2 IRX1 protein P78414 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. SIGNOR-261651 0.2 DDIT3 protein P35638 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 31226023 f miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260171 0.7 ATR protein Q13535 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser407 SSSIIYSsQEDVKEF 9606 BTO:0002552 14654783 t lperfetto We found that a major kinase responsible for s407 phosphorylation is atrs407 phosphorylation of mdm2 by atr reduces mdm2-dependent export of p53 from nuclei to cytoplasm. SIGNOR-119546 0.502 LRP6 protein O75581 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 23209147 t Gianni The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization. SIGNOR-262526 0.695 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates activity phosphorylation Ser860 NRAVSLDsPVSVGSS 9606 BTO:0000093 15383283 t miannu P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators. SIGNOR-250105 0.506 CKM complex complex SIGNOR-C406 SIGNOR STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Ser727 TDNLLPMsPEEFDEV 29239838 t lperfetto We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727. Here we report that phosphorylation of STAT1 S727 promotes the proliferation of AML cells with JAK-STAT pathway activation. SIGNOR-273182 0.299 CC2D1A protein Q6P1N0 UNIPROT HTR1A protein P08908 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 20171170 t nucleus lperfetto Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A is localized in the cytosol, nucleus, and centrosome. Aki1 plays distinct roles depending on its localization. In the cytosol, it acts as a scaffold protein in the phosphoinositide 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathway. In the nucleus, it is a transcriptional repressor of the serotonin-1A (5-HT1A) receptor. SIGNOR-268295 0.379 MAPK1 protein P28482 UNIPROT CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser1409 SAPEDPTsPKRKMRR 9606 BTO:0000848 21087211 t gcesareni Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3))[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3 SIGNOR-169875 0.38 ZNF804A protein Q7Z570 UNIPROT ANKRD1 protein Q15327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 23434502 t miannu ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). SIGNOR-269461 0.2 SFN protein P31947 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates relocalization 9606 20940406 t lperfetto Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding SIGNOR-168540 0.2 ANXA3 protein P12429 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 27995049 f miannu We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells. SIGNOR-262212 0.285 DVL3 protein Q92997 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 12533515 t gcesareni Wnt/fz activation of rac and rho is inhibited by rac-n17 and rho-n19, respectively (figs. _(figs.1d,1d, _d,5c,d;5c,d;habas et al. 2001), and requires different dvl domains wnt signaling induces complex formation between dvl and rac. SIGNOR-97409 0.444 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-267313 0.8 PRKN protein O60260 UNIPROT MFN1 protein Q8IWA4 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000793 20871098 t miannu Parkin and PINK1 are required for ubiquitination of MFN-1 and MFN-2.  Decreases in MFN-1 and MFN-2 protein levels seen at later timepoints are difficult to interpret as it is unclear whether this is due to degradation by the proteasome and/or loss of whole mitochondria by mitophagy. SIGNOR-272779 0.2 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257979 0.8 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr548 KKVAVVRtPPKSPSS -1 9199504 t miannu Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective. SIGNOR-250088 0.505 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI SDHB protein P21912 UNIPROT up-regulates activity chemical activation 26083061 t lperfetto Succinate dehydrogenase subunit B contains three Fe-S clusters |The enzymatic activity of both proteins depends on the presence of intact Fe-S clusters SIGNOR-262133 0.8 CXCL10 protein P02778 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 f miannu High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity. SIGNOR-261025 0.7 adenosine smallmolecule CHEBI:16335 ChEBI ADORA2B protein P29275 UNIPROT up-regulates activity binding -1 14662005 t Luana Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A1, A2A, A2B and A3. SIGNOR-268421 0.8 ZFYVE26 protein Q68DK2 UNIPROT TTC19 protein Q6DKK2 UNIPROT up-regulates activity binding 9606 BTO:0000567 20208530 t miannu We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. FYVE-CENT interacts with KIF13A and TTC19 SIGNOR-265538 0.474 CSNK1A1 protein P48729 UNIPROT AGO2 protein Q9UKV8 UNIPROT down-regulates activity phosphorylation Ser828 EHDSAEGsHTSGQSN 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276512 0.377 DLL4 protein Q9NR61 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000574 11739188 t lperfetto Expression analysis of known notch ligands suggests that dll4 is the only ligand that exhibits spatial and temporal expression consistent with the activation of notch1 and notch4 during vascular development. The identification of dll4 reveals a candidate ligand for notch receptors involved in blood vessel biology SIGNOR-112649 0.629 SIRT5 protein Q9NXA8 UNIPROT HMGCS2 protein P54868 UNIPROT up-regulates activity post translational modification Lys310 PFCKMVQkSLARLMF 9606 BTO:0000007 24315375 t desuccinylation lperfetto We demonstrate that SIRT5 regu-lates succinylation of the rate-limiting ketogenicenzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(HMGCS2) both in vivo and in vitro.|Succinylation of Lysine Residues within the SubstrateBinding Pocket Inhibits HMGCS2 Activity|Here, we use a label-freequantitative proteomic approach to characterizethe lysine succinylome in liver mitochondria and itsregulation by the desuccinylase SIRT5 SIGNOR-267642 0.35 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 9606 22326956 t lperfetto TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-196022 0.84 YAP1 protein P46937 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21233212 f miannu We also found that KIBRA mRNA is induced by YAP overexpression in both murine and human cells, suggesting the evolutionary conservation of KIBRA as a transcriptional target of the Hippo signaling pathway. Thus, our study revealed a new connection between KIBRA and mammalian Hippo signaling. SIGNOR-263660 0.373 AKT1 protein P31749 UNIPROT BLVRA protein P53004 UNIPROT up-regulates activity phosphorylation Ser230 LKRNRYLsFHFKSGS 15870194 t lperfetto Site-directed mutagenesis, mass spectrometry, and kinetic analyses identified S(230) in hBVR (225)RNRYLSF sequence as the Akt1 target. SIGNOR-275517 0.301 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG -1 17711846 t done miannu Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626). SIGNOR-274095 0.397 SLC9A7 protein Q96T83 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265606 0.8 DYRK2 protein Q92630 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Ser518 KGGTPAGsARGSPTR 9606 16611631 t lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro SIGNOR-145975 0.371 AKT1 protein P31749 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0000007 11154276 t lperfetto Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 akt decreased ask1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus akt site at serine 83 of ask1. SIGNOR-252465 0.718 CTSL protein P07711 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Arg94 IGFQEAYrRFYGPV -1 9076588 t miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. SIGNOR-256322 0.2 EN1 protein Q05925 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription SIGNOR-265776 0.464 clozapine chemical CHEBI:3766 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258516 0.8 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2. SIGNOR-235671 0.784 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120156 0.316 ZRSR2/U2AF2 complex SIGNOR-C81 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 11739736 f miannu The essential splicing factor U2AF (U2 auxiliary factor) is a heterodimer composed of 65-kDa (U2AF(65)) and 35-kDa (U2AF(35)) subunits. U2AF(35) has multiple functions in pre-mRNA splicing. First, U2AF(35) has been shown to function by directly interacting with the AG at the 3' splice site. Second, U2AF(35) is thought to play a role in the recruitment of U2AF(65) by serine-arginine-rich (SR) proteins in enhancer-dependent splicing. SIGNOR-263946 0.7 PKN1 protein Q16512 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser338 RPRGQRDsSYYWEIE 9606 11733498 t lperfetto Interaction between active pak1 and raf-1 is necessary for phosphorylation and activation of raf-1. SIGNOR-112549 0.2 AMPK complex SIGNOR-C15 SIGNOR AMPK complex SIGNOR-C15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 17728241 t lperfetto Mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the beta1 subunit, almost completely abolishes activation of ampk by a-769662 in cells and in vitro, while only partially reducing activation by ampk SIGNOR-216411 0.795 PRPF19 protein Q9UMS4 UNIPROT RPA1 protein P27694 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000567 24332808 t miannu PRP19 is a ubiquitin ligase involved in pre-mRNA splicing and the DNA damage response (DDR). PRP19 ubiquitylates RPA and promotes ATRIP recruitment. SIGNOR-272076 0.487 RPS6KA1 protein Q15418 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser719 PCTPRLRsVSSYGNI 9606 SIGNOR-C3 18722121 t llicata Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity SIGNOR-180458 0.562 SOSTDC1 protein Q6X4U4 UNIPROT BMP2 protein P12643 UNIPROT down-regulates activity 10090 18032587 f lperfetto SOSTDC1 is orthologous to a recently characterized murine antagonist of BMPs-2, -4, and -7 SIGNOR-242746 0.583 BAZ1B protein Q9UIG0 UNIPROT WICH complex SIGNOR-C449 SIGNOR form complex binding 9606 16603771 t miannu We show here that the WICH complex (WSTF-SNF2h) interacts with several nuclear proteins as follows: Sf3b155/SAP155, RNA helicase II/Gualpha, Myb-binding protein 1a, CSB, the proto-oncogene Dek, and nuclear myosin 1 in a large 3-MDa assembly, B-WICH, during active transcription. Our results show that a WSTF-SNF2h assembly is involved in RNA polymerase III transcription, and we suggest that WSTF-SNF2h-NM1 forms a platform in transcription while providing chromatin remodeling. SIGNOR-268828 0.923 FOXO1 protein Q12778 UNIPROT IGFBP1 protein P08833 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10358076 f miannu Reporter gene studies in hepg2 hepatoma cells show that fkhr stimulates insulin-like growth factor-binding protein-1 promoter activity through an irs SIGNOR-68152 0.386 RAD21 protein O60216 UNIPROT GATA2 protein P23769 UNIPROT down-regulates activity relocalization 9606 BTO:0001545 26607380 t miannu Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity. SIGNOR-261513 0.331 PSMB5 protein P28074 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263357 0.854 F2 protein P00734 UNIPROT F8 protein P00451 UNIPROT up-regulates activity cleavage Arg759 KNNAIEPrSFSQNSR -1 10350471 t lperfetto Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689. SIGNOR-263641 0.746 GFs stimulus SIGNOR-ST12 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity 9606 23300340 f lperfetto Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation SIGNOR-245402 0.7 MAPK1 protein P28482 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Thr388 VYFKPSLtPSGEFRK 9606 19767751 t llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. SIGNOR-188127 0.397 CDK2 protein P24941 UNIPROT CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR form complex binding 9606 19056339 t lperfetto We therefore compared human cyclin a1- and cyclin a2-containing cdk complexes in vitro by determining kinetic constants and by examining the complexes for their ability to phosphorylate prb and p53. Differences in biochemical activity were observed in cdk2 but not cdk1 when complexed with cyclin a1 versus cyclin a2. Further, cdk1/cyclin a1 is a better kinase complex for phosphorylating potentially physiologically relevant substrates prb and p53 than cdk2/cyclin a2. SIGNOR-182569 0.977 SEPTIN2 protein Q15019 UNIPROT SEPT6/SEPT2 complex SIGNOR-C71 SIGNOR form complex binding 9606 16914550 t miannu We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains. SIGNOR-148889 0.2 SEPTIN7 protein Q16181 UNIPROT SEPT6/SEPT7 complex SIGNOR-C72 SIGNOR form complex binding 9606 16914550 t miannu We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains. SIGNOR-148898 0.2 ESR2 protein Q92731 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 11517191 f ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression SIGNOR-253943 0.295 EPAS1 protein Q99814 UNIPROT KDM5C protein P41229 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271579 0.281 C5 protein P01031 UNIPROT C5AR2 protein Q9P296 UNIPROT up-regulates binding 9606 cleavage:Arg751;Arg677 HKDMQLGrLHMKTLL;KEILRPRrTLQKKIE 11773063 t complement C5a (anaphylatoxin) fragment: PRO_0000005988 gcesareni Here we report that the orphan receptor c5l2/gpr77, which shares 35% amino acid identity with cd88, binds c5a with high affinity. SIGNOR-113558 0.648 TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd. SIGNOR-109719 0.798 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT up-regulates activity phosphorylation Tyr198 EDVEDPVyQYIVFEA 10090 BTO:0000938 11279201 t lperfetto Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons. SIGNOR-247076 0.43 PRKCB protein P05771 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser44 KKSKISAsRKLQLKT 9606 15769444 t lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. SIGNOR-134628 0.2 U0126 chemical CHEBI:90693 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 11160424 t gcesareni The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2. SIGNOR-104939 0.8 LPAR5 protein Q9H1C0 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256997 0.2 DDX5 protein P17844 UNIPROT RNA helicases DDX5/DDX17 complex SIGNOR-C34 SIGNOR form complex binding 9606 BTO:0000887;BTO:0001103 17011493 t lperfetto We have found that the rna helicases p68/p72 are myod-associated proteins and that the noncoding rna sra also immunoprecipitates with myod. In vitro and in vivo experiments indicated that both p68/p72 and sra are coactivators of myod. SIGNOR-149964 0.435 ITCH protein Q96J02 UNIPROT BCL10 protein O95999 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000661 15082780 t miannu The HECT domain ubiquitin ligases NEDD4 and Itch promote ubiquitination and degradation of Bcl10, thus downmodulating NF-kappa B activation.  SIGNOR-271413 0.28 GTF2I protein P78347 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19097122 f miannu Transcription factor TFII-I causes transcriptional upregulation of GRP78 synthesis in prostate cancer cells. SIGNOR-254221 0.379 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1193 QPTSKAYsPRYSISD 9606 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244747 0.2 RARA protein P10276 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 15650024 t inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. SIGNOR-270293 0.517 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Ser440 NGTSGKDsATTSTLS 9606 BTO:0000567 34198826 t miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. SIGNOR-276662 0.252 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 17389598 t lperfetto Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2. SIGNOR-153944 0.679 PDGFRB protein P09619 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr5 yLDPNLNH 9606 20802513 t llicata In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases. SIGNOR-167662 0.538 PAX7 protein P23759 UNIPROT PAX7/MLL2 complex complex SIGNOR-C91 SIGNOR form complex binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-198635 0.309 AP1 complex SIGNOR-C154 SIGNOR SPI1 protein P17947 UNIPROT up-regulates activity binding 9606 BTO:0004136 12393465 t miannu These results indicate that AML1-ETO competes c-Jun away from binding to the β3β4 domain of PU.1. Thus, the c-Jun coactivation function of PU.1 is down-regulated and this in turn down-regulates transcriptional activity of PU.1. SIGNOR-260098 0.524 CSNK2A1 protein P68400 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity phosphorylation Ser688 SKGVDFEsSEDDDDD -1 28436950 t miannu Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. SIGNOR-265893 0.2 IGF1 protein P05019 UNIPROT FBN1 protein P35555 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 17200203 f Regulation of expression miannu Decorin and IGF-I induce fibrillin-1 protein synthesis in normal rat kidney fibroblasts SIGNOR-251862 0.295 CENPH protein Q9H3R5 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265198 0.756 JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 15322115 t lperfetto Phosphorylation at tyr701 by the janus family of tyrosine kinases (jak) leads to stat1 dimerization via its src homology 2 domains, exposure of a dimer-specific nuclear localization signal, and subsequent nuclear translocation. SIGNOR-235709 0.799 Macrophage_activation phenotype SIGNOR-PH126 SIGNOR CCL7 protein P80098 UNIPROT up-regulates quantity 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260963 0.7 PRKCB protein P05771 UNIPROT TOP2A protein P11388 UNIPROT up-regulates activity phosphorylation Ser29 EDAKKRLsVERIYQK 9606 BTO:0000567 12569090 t lperfetto Here, we have shown that the enzymatic activity of topoisomerase II alpha protein purified from HeLa cell nuclei was strongly enhanced following phosphorylation by protein kinase C. | Site-directed mutagenesis studies indicated that phosphorylation of serine 29 generated both of these phosphopeptides. SIGNOR-249195 0.366 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 15664191 t gcesareni Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity. previous studies have shown that phosphorylation is required for raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated erk SIGNOR-133345 0.622 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-118027 0.706 AKT1 protein P31749 UNIPROT AR protein P10275 UNIPROT down-regulates activity phosphorylation Ser215 SGRAREAsGAPTSSK 9534 BTO:0001538 11404460 t lperfetto Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Here, we demonstrate that akt phosphorylates the androgen receptor (ar) at ser-210 and ser-790 SIGNOR-108504 0.604 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe709 ENPTYKFfEQMQN -1 10605825 t lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. SIGNOR-261778 0.502 RNF139 protein Q8WU17 UNIPROT INSIG1 protein O15503 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 20068067 t miannu TRC8/RNF139 encodes an endoplasmic reticulum-resident E3 ubiquitin ligase that inhibits growth in a RING- and ubiquitylation-dependent manner. TRC8 also contains a predicted sterol-sensing domain. Here, we report that TRC8 protein levels are sterol responsive and that it binds and stimulates ubiquitylation of the endoplasmic reticulum anchor protein INSIG. Thus, we conclude that INSIG-1 and 2 physically interact with TRC8, and that TRC8 enhances ubiquitylation of INSIG-1 in a RING-dependent manner SIGNOR-271955 0.49 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT down-regulates activity phosphorylation Ser231 FGDDEDDsGTEES 9606 BTO:0000567 11546811 t lperfetto The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm. SIGNOR-110399 0.403 PTPRJ protein Q12913 UNIPROT FLT1 protein P17948 UNIPROT down-regulates dephosphorylation 9606 12771128 t gcesareni Vegf acts by binding to two high affinity receptor tyrosine kinases: vegf receptor (vegfr)* 1 also called flt-1, and vegfr-2, also called flk-1/kdr a dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation. SIGNOR-101272 0.369 GSK3B protein P49841 UNIPROT FCAR protein P24071 UNIPROT down-regulates activity phosphorylation Ser284 LTFARTPsVCK 10090 BTO:0001516 30766540 t lperfetto GSK-3 is constitutively active in the absence of cytokine stimulation and can phosphorylate S263, keeping FcalphaRI in the inactive state. SIGNOR-264857 0.2 SARS1 protein P49591 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. SIGNOR-270800 0.8 MTARC1 protein Q5VT66 UNIPROT nitric oxide smallmolecule CHEBI:16480 ChEBI up-regulates quantity chemical modification 9606 24500710 t miannu our results indicate that mARC can generate nitric oxide (NO) from nitrite when forming an electron transfer chain with NADH, cytochrome b5, and NADH-dependent cytochrome b5 reductase. expression of mARC-1 in HEK cells using a lentivirus vector was used to confirm cellular nitrite reduction to NO. SIGNOR-261419 0.8 CSNK2A1 protein P68400 UNIPROT OTUB1 protein Q96FW1 UNIPROT up-regulates activity phosphorylation Ser16 QKQEPLGsDSEGVNC 34785775 t lperfetto Casein kinase 2 (CK2)-dependent phosphorylation of OTUB1 at Ser16 played a critical role in ODN- and cathepsin K siRNA-mediated p53 stabilization. |Furthermore, although OTUB1 dramatically induced p53 deubiquitination, its mutant (S16A) and deletion mutant did not have this effec SIGNOR-276527 0.324 PURB protein Q96QR8 UNIPROT MYH6 protein P13533 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12933792 f miannu In functional assays, PURalpha and PURbeta repressed alpha-myosin heavy chain (alpha-MHC) gene expression in the presence of upstream regulatory sequences of the gene. SIGNOR-253901 0.372 INS protein P01308 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates 9606 15209375 f gcesareni The interaction ofinsulin and growth factors with their receptors on the outside surface of a cell, leads to the activation of phosphatidylinositol 3-kinase (pi 3-kinase) and generation of the phosphatidylinositol 3,4,5-trisphosphate (ptdins(3,4,5)p3) second messenger at the inner surface of the cell membrane. SIGNOR-126063 0.341 GSK3B protein P49841 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates quantity by destabilization phosphorylation Thr265 ATYHHNStTTWTGSR 10090 BTO:0000944 25373906 t miannu In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region.  SIGNOR-276442 0.407 CDK1 protein P06493 UNIPROT DCTN6 protein O00399 UNIPROT up-regulates activity phosphorylation Thr186 KTMKGSStPVKN -1 23455152 t lperfetto Here, we show that the p27/p25 heterodimer undergoes mitotic phosphorylation by cyclin‐dependent kinase 1 (Cdk1) at a single site, p27 Thr186, to generate an anchoring site for polo‐like kinase 1 (Plk1) at kinetochores. SIGNOR-264777 0.312 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr94 SSLPEGYyEEAVPLS 9534 9655255 t lperfetto In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110. SIGNOR-246363 0.589 PRKACA protein P17612 UNIPROT ALOX5 protein P09917 UNIPROT down-regulates activity phosphorylation Ser524 GMRGRKSsGFPKSVK -1 15280375 t lperfetto These results indicate that PKA phosphorylates 5-LO on Ser-523, which inhibits the catalytic activity of 5-LO and reduces cellular LT generation. SIGNOR-264410 0.341 S100A9 protein P06702 UNIPROT AGER protein Q15109 UNIPROT up-regulates activity binding 9606 BTO:0001545 28137827 t miannu RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33 SIGNOR-261920 0.353 KDM1A protein O60341 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR down-regulates 9606 28720390 f gianni The Lysine-specific demethylase 1, KDM1A/LSD1, plays a central role in the regulation of Pol II transcription through the removal of the activation mark (mono- and dimethyl lysine 4 of histone H3). LSD1 is often deregulated in human cancers, and it is frequently overexpressed in human solid cancers and leukemia. SIGNOR-268728 0.7 SB-202190 chemical CHEBI:79090 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206694 0.8 ATM protein Q13315 UNIPROT PPP1R2 protein P41236 UNIPROT down-regulates phosphorylation Ser44 DEELSKKsQKWDEMN 9606 18250156 t gcesareni Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1. SIGNOR-160648 0.2 SNIP1 protein Q8TAD8 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR down-regulates binding 9606 10887155 t lperfetto In this study, we characterize a novel nuclear protein, termed snip1 its principal mechanism of action appears to be through transcription by binding to cbp/p300 and interfering with the ability of these coactivators to interact with smad4 SIGNOR-217661 0.59 MAPK8 protein P45983 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates phosphorylation Ser184 FYYEILNsPEKACSL 9606 15071501 t JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8. gcesareni Jnk phosphorylated 14-3-3 at ser-184 and 14-3-3 at ser-186 both in vitro and in vivo, and such phosphorylation reduced the affinity of 14-3-3 proteins for bax SIGNOR-124020 0.379 MMP19 protein Q99542 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272386 0.7 SPAG1 protein Q07617 UNIPROT R2SP co-chaperone complex SIGNOR-C517 SIGNOR form complex binding 9606 29844425 t miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. SIGNOR-270938 0.392 ANGPT1 protein Q15389 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 f lperfetto Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. SIGNOR-241560 0.2 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT up-regulates activity phosphorylation Ser661 QNEFAGFsYTNPEFV 9606 10828076 t The effect has been demonstrated using P05771-2 llicata We found in preliminary studies that autophosphorylation at ser660 was enhanced in response to angiotensin ii and phorbol esters|However, it was apparent that the return of the mutant GFP-S660A from the membrane to the cytoplasm was impaired, suggesting a specific role for this autophosphorylation site in the regulation of reverse translocation. SIGNOR-77583 0.2 MSH release-inhibiting hormone smallmolecule CID:56842142 PUBCHEM MC1R protein Q01726 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257536 0.8 RLF protein Q13129 UNIPROT RIN1 protein Q13671 UNIPROT up-regulates activity binding 9606 10545207 t miannu Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors. SIGNOR-220920 0.2 NTN1 protein O95631 UNIPROT UNC5C protein O95185 UNIPROT up-regulates binding 9606 10399920 t gcesareni We provide evidence that netrin-1 triggers the formation of a receptor complex of dcc and unc5 proteins and simultaneously derepresses the interaction between their cytoplasmic domains, thereby converting dcc-mediated attraction to unc5/dcc-mediated repulsion. SIGNOR-69047 0.826 CAMK2G protein Q13555 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser561 PFLSRHNsKSSIFSF 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275793 0.274 DVL2 protein O14641 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity binding 9606 17529994 t amattioni Dishevelled (dvl) transduces the wnt signal by interacting with the cytoplasmic axin complex. SIGNOR-155221 0.655 apomorphine chemical CHEBI:48538 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258375 0.8 TYMS protein P04818 UNIPROT dUMP(2-) smallmolecule CHEBI:246422 ChEBI down-regulates quantity chemical modification 9606 21876188 t lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. SIGNOR-268234 0.8 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1623 SPTSPSYsPTSPSYS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248780 0.442 EIF2B4 protein Q9UI10 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269142 0.765 PTPN11 protein Q06124 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9534 BTO:0004055 12582165 t lperfetto Given that substrate trapping occurred in intact cells and that the interaction was very specific, it is highly likely that egfr and gab1 represent physiological shp2 substrates.To further confirm that phosphotyrosyl proteins trapped by SHP2 are target substrates, we carried out an immunocomplex in vitrophosphatase assay.The WT protein partially dephosphorylated both the EGFR and Gab1, whereas the DM protein did not SIGNOR-236424 0.865 PELI1 protein Q96FA3 UNIPROT HPD protein P32754 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0003036 31537781 t lperfetto Decreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia. However, the regulation of HPD expression remains largely unknown. Here, we demonstrate that molecular chaperone TTC36, which is highly expressed in liver, is associated with HPD and reduces the binding of protein kinase STK33 to HPD, thereby inhibiting STK33-mediated HPD T382 phosphorylation. The reduction of HPD T382 phosphorylation results in impaired recruitment of FHA domain-containing PELI1 and PELI1-mediated HPD polyubiquitylation and degradation. SIGNOR-272959 0.2 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17442773 f miannu Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. CD44 is also upregulated by NUP98‐HOXA9. SIGNOR-261502 0.2 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 10090 SIGNOR-C17 11278991 t lperfetto CDK1-cyclin B phosphorylates NPM/B23 on Thr234. SIGNOR-235530 0.533 GTF2E2 protein P29084 UNIPROT TFIIE complex SIGNOR-C458 SIGNOR form complex binding 9606 31064989 t lperfetto The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur. SIGNOR-269361 0.94 NFATC1 protein O95644 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates activity 10358178 f The transcription factor NF-ATc that controls gene expression in T lymphocytes and embryonic cardiac cells is expressed in three prominent isoforms. SIGNOR-252344 0.7 SMOC1 protein Q9H4F8 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20359165 f Giorgia The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells SIGNOR-260385 0.2 LPAR6 protein P43657 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257286 0.343 PCSK2 protein P16519 UNIPROT OXT protein P01178 UNIPROT down-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270328 0.268 LAMC1 protein P11047 UNIPROT Laminin-10 complex SIGNOR-C182 SIGNOR form complex binding 11821406 t lperfetto The laminin (LN) family of large heterotrimeric extracellular matrix glycoproteins has multiple functions: LNs take part in the regulation of processes such as cell migration, differentiation, and proliferation, in addition to contributing to the structure of basement membranes. LN-10, composed of alpha5, beta1, and gamma1 chains, is widely distributed in most basement membranes of both epithelia and endothelia. SIGNOR-253231 0.695 RPS21 protein P63220 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262429 0.851 E4F1 protein Q66K89 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity ubiquitination Lys321 SSPQPKKkPLDGEYF 9606 BTO:0001938 17110336 t miannu E4F1 Has an Intrinsic Ubiquitin E3 Ligase Activity that Drives K48-type Ubiquitylation of p53. These data demonstrate that E4F1 stimulates the ubiquitylation of p53 on the lysine cluster K319–K321, i.e., at sites distinct from those targeted by Hdm2. p53 forms Ubiquitylated by E4F1 Are Localized on Chromatin. In striking contrast with Ub-p53 forms stimulated by Hdm2, which are mainly cytosoluble and targeted to the proteasome, we found that E4F1-stimulated Ub-p53 forms are tightly associated with chromatin, suggesting that they could be involved in transcription. SIGNOR-271395 0.592 MAML1 protein Q92585 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 11101851 t inferred from 70% of family members gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes4 SIGNOR-269934 0.921 MAPK1 protein P28482 UNIPROT NEFH protein P12036 UNIPROT up-regulates activity phosphorylation Ser532 KSPAEAKsPEKEEAK 10116 9592082 t lperfetto The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation. SIGNOR-249425 0.375 SRC protein P12931 UNIPROT RRAS protein P10301 UNIPROT down-regulates activity phosphorylation Tyr66 DPTIEDSyTKICSVD 9606 BTO:0000007 11682467 t lperfetto The small gtpase, r-ras, affects cell adhesion by maintaining integrin activity. Activated src oncogene phosphorylates r-ras and suppresses integrin activity. the src phosphorylation site in r-ras was tyrosine 66 SIGNOR-111189 0.562 PRKCB protein P05771 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser496 ATPQRSGsVSNYRSC -1 27784766 t miannu Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle. SIGNOR-276460 0.2 EFNB2 protein P52799 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 8559144 t gcesareni Lerk-5 is a ligand for both elk and hek and induces receptor phosphorylation SIGNOR-39862 0.879 MTA1 protein Q13330 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263842 0.801 POLD2 protein P49005 UNIPROT DNA polymerase delta complex SIGNOR-C376 SIGNOR form complex binding -1 12403614 t lperfetto Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme. SIGNOR-265516 0.921 TAOK3 protein Q9H2K8 UNIPROT TAOK3 protein Q9H2K8 UNIPROT up-regulates activity phosphorylation Tyr183 NSFVGTPyWMAPEVI 9534 BTO:0004055 10559204 t lperfetto These data indicate that JIK is indeed the protein kinase present in the immune complex responsible for autophosphorylation and for the phosphorylation of the exogenous substrate. Moreover, our observations suggest that JIK (A181F183) acts as the catalytically inactive mutant of JIK, which is no longer able to potently undergo autophosphorylation and dramatically phosphorylate MBP, as compared with the wild type JIK. SIGNOR-246302 0.2 GALR2 protein O43603 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257226 0.292 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser272 FSGIESSsPEVKGYW 9606 17475908 t miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). SIGNOR-262916 0.329 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252358 0.783 SGK1 protein O00141 UNIPROT KMT2D protein O14686 UNIPROT down-regulates activity phosphorylation Ser1331 RGRARLKsTASSIET 9606 BTO:0002181 30943409 t miannu  Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function, leading to a loss of methylation of lysine 4 on histone H3 (H3K4) and a repressive chromatin state at ER loci to attenuate ER activity.  SIGNOR-277447 0.287 ITGB1BP1 protein O14713 UNIPROT AE/b7 integrin complex SIGNOR-C186 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257665 0.291 NMDA receptor_2D complex SIGNOR-C350 SIGNOR CAMK2A protein Q9UQM7 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu The most abundant signaling protein in the PSD fraction is Ca2+/calmodulin–dependent protein kinase II (CaMKII), which makes up 1 to 2% of the total protein in the forebrain (21). CaMKII is a target for Ca2+ flowing through the NMDA receptor and is necessary for normal synaptic plasticity in pyramidal neurons. The cytosolic tails of the NR2 subunits of the NMDA receptor bind to CaMKII and thus can serve as docking sites for it in the PSD SIGNOR-264217 0.566 UV stress stimulus SIGNOR-ST7 SIGNOR RRM2B protein Q7LG56 UNIPROT up-regulates 9606 BTO:0001061 14583450 f miannu Taken together, we conclude that UV-induced activation of p53R2 transcription and binding of p53R2 to hRRM1 to form RR holoenzyme are impaired in the p53-mutant cell line PC3. SIGNOR-259362 0.7 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr204 LTRYTRPtPVQKHAI 9606 16280325 t lperfetto Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis. SIGNOR-216868 0.345 LRIG1 protein Q96JA1 UNIPROT ERBB4 protein Q15303 UNIPROT down-regulates ubiquitination 9606 16123311 t gcesareni We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation. SIGNOR-139954 0.592 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser515 SGDRSGYsSPGSPGT 9606 BTO:0000590 9832145 t lperfetto Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. SIGNOR-249354 0.728 TAB2 protein Q9NYJ8 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates binding 9606 25290089 t lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205443 0.425 PRKAA2 protein P54646 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 SIGNOR-C15 22137581 t lperfetto Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction SIGNOR-195102 0.2 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity precursor of 9606 24786789 t miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. SIGNOR-266510 0.8 DYRK1A protein Q13627 UNIPROT DYRK1A protein Q13627 UNIPROT up-regulates phosphorylation Tyr321 LGQRIYQyIQSRFYR 9606 10910078 t lperfetto Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site SIGNOR-79764 0.2 WHAMM protein Q8TF30 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000567 20498093 t lperfetto Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes. SIGNOR-261004 0.356 PPP1R2 protein P41236 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates binding 9606 18250156 t lperfetto Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1. SIGNOR-264672 0.808 ATF4 protein P18848 UNIPROT NUPR1 protein O60356 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 19946894 f lperfetto Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4. SIGNOR-253730 0.394 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK4 protein P11802 UNIPROT down-regulates activity chemical inhibition -1 29901072 t miannu AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9. SIGNOR-262220 0.8 isoprenaline chemical CHEBI:64317 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8982677 t miannu K i values of the agonists for [~25I]iodocyanopindolol binding to the COS-7 cell membranes are shown in Table 1. In the membranes expressing one of the 13-adrenoceptor subtypes, both isoproterenol and T-0509 caused monophasic dis- placement of [~25I]iodocyanopindolol, suggesting a single binding site of the agonists. SIGNOR-258578 0.8 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 9606 23431053 t milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity SIGNOR-201282 0.845 CDK1 protein P06493 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 SIGNOR-C17 20937773 t lperfetto In this study, we demonstrate that procaspase-8 is phosphorylated in mitotic cells by cdk1na interference-mediated silencing of cyclin b1 or treatment with the cdk1 inhibitor ro-3306 enhances the fas-mediated activation and processing of procaspase-8 in mitotic cells/cyclin b1 on ser-387 SIGNOR-168446 0.369 LMO3 protein Q8TAP4 UNIPROT HES1 protein Q14469 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21573214 f miannu Luciferase reporter assay demonstrated that the co-expression of LMO3 and HEN2 attenuates HES1 (a negative regulator for Mash1)-dependent reduction of luciferase activity driven by the Mash1 promoter. SIGNOR-254826 0.348 ICAM1 protein P05362 UNIPROT Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 23994464 f apalma Before leaving the vessel lumen, neutrophils crawl on the endothelium, primarily using cell surface Mac-1 integrins binding to endothelial ICAM-1. After finding the place for transmigration, neutrophils migrate to the interstitium through transcellular or paracellular routes and begin chemotaxing towards the site of infection/inflammation within the perivascular and interstitial space. SIGNOR-255042 0.7 MAS1 protein P04201 UNIPROT AGTR1 protein P30556 UNIPROT down-regulates activity binding 9606 BTO:0000007 15809376 t miannu our findings demonstrate that the protein encoded by the Mas proto-oncogene exhibits direct antagonistic properties on the AT1 receptor in vitro and that this oligomeric interaction may represent a natural state for these receptors in vivo in some tissues. the present findings in native tissues suggest that the Mas receptor can act as an in vivo functional antagonist of the AT1 receptor owing to formation of a hetero-oligomeric complex SIGNOR-260626 0.279 AP3B1 protein O00203 UNIPROT KIF3A protein Q9Y496 UNIPROT up-regulates activity binding 10090 BTO:0002572 19934039 t Giorgia Here, we show that the beta subunit of AP-3, a clathrin-associated protein complex required for HIV-1 release, is a target of IP(7)-mediated pyrophosphorylation. We have identified Kif3A, a motor protein of the kinesin superfamily, as an AP3B1-binding partner and demonstrate that Kif3A, like the AP-3 complex, is involved in an intracellular process required for HIV-1 Gag release. SIGNOR-260398 0.379 YAP1 protein P46937 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-256669 0.7 SIL1 protein Q9H173 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates activity binding 9534 BTO:0001538 12356756 t Simone BAP, a Mammalian BiP-associated Protein, Is a Nucleotide Exchange Factor That Regulates the ATPase Activity of BiP. In addition,BAP was associated with BiP in mammalian cells and inter-acted with BiP functionallyin vitro. BAP stimulated the ATPase activity of BiP when added alone or together with the ER DnaJ protein, ERdj4, by promoting the release of ADP from BiP. Together, these data demonstrate that BAP serves as a nucleotide exchange factor for BiP and provide insights into the mechanisms that control protein folding in the mammalian ER. SIGNOR-261045 0.594 ADAM17 protein P78536 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity cleavage 9606 10882063 t gcesareni ... here we show that an additional processing event occurs in the extracellular part of the receptor, preceding cleavage by the gamma-secretase-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to tace (tnfalpha-converting enzyme), a member of the adam (a disintegrin and metalloprotease domain) family of metalloproteases. SIGNOR-78903 0.729 CSNK2A1 protein P68400 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Ser1005 EHDSDESsDDDSDSE 9606 10066810 t gcesareni Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein, SIGNOR-65273 0.453 MAPK14 protein Q16539 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 20626350 t gcesareni Fgfr1 translocation requires p38 mapk activation which phosphorylates the c-term tail of fgfr1 on ser777 SIGNOR-166598 0.278 NFATC1 protein O95644 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001260 17079331 t lperfetto The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries. SIGNOR-251730 0.425 FCRL3 protein Q96P31 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity binding -1 12051764 t miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. SIGNOR-274013 0.399 RNF26 protein Q9BY78 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000567 27368102 t miannu SQSTM1 Is a Substrate for RNF26 and the DUB USP15. Catalytically competent RNF26 (light red) recruits SQSTM1 (blue) and mediates ubiquitin ligation (red), which serves to attract UBDs of specific vesicle-associated adaptors. SIGNOR-269830 0.365 GSK3B protein P49841 UNIPROT PPIF protein P30405 UNIPROT up-regulates activity phosphorylation Ser191 IESFGSKsGRTSKKI 9606 BTO:0000007 32814770 t lperfetto Phosphorylation of cyclophilin D at serine 191 regulates mitochondrial permeability transition pore opening and cell death after ischemia-reperfusion|We conclude that CypD phosphorylation at S191 residue leads to its binding to OSCP and thus sensitizes mPTP opening for the subsequent cell death.|Under baseline condition (WT group), the phosphorylation of CypD by a kinase (e.g. GSK3beta) at S191 induces its translocation to the OSCP, to favor mPTP opening and subsequent cell death at reperfusion. SIGNOR-264880 0.386 AKT1 protein P31749 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates quantity phosphorylation Ser257 PSRPPRPsRPPPPTP 9606 BTO:0000815 30517763 t miannu AKT1-mediated phosphorylation of ITCH at Ser257 drives its nuclear translocation SIGNOR-272922 0.324 4-fluoro-N-{2-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]ethyl}benzamide chemical CHEBI:64101 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258893 0.8 BECN1 protein Q14457 UNIPROT Vps34 Complex II complex SIGNOR-C241 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260319 0.903 OPRK1 protein P41145 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256710 0.453 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser139 RRGLLYDsDEEDEER 9606 16446360 t gcesareni In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells. SIGNOR-143988 0.961 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates quantity by destabilization phosphorylation Ser276 VHPATPIsPGRASGM 9606 17015473 t The effect has been demonstrated using Q01196-8. gcesareni Aml1/runx1 phosphorylation by cyclin-dependent kinases regulates the degradation of aml1/runx1 by the anaphase-promoting complex. SIGNOR-149972 0.348 KAT2B protein Q92831 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity acetylation 32917954 t SimoneGraziosi NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase SIGNOR-269270 0.481 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser155 FPLRKTVsEPNLKLR 9606 18339811 t Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. SIGNOR-248646 0.322 MYC protein P01106 UNIPROT ST3GAL3 protein Q11203 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22547830 f We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. SIGNOR-253962 0.2 GRPR protein P30550 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256917 0.252 IFNW1 protein P05000 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR up-regulates activity binding 9606 11278538 t miannu Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. SIGNOR-260336 0.736 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. SIGNOR-252869 0.756 FOXA1 protein P55317 UNIPROT SFTPB protein P07988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004299 18003659 f miannu TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. SIGNOR-254171 0.287 F2RL1 protein P55085 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256895 0.2 FGF14 protein Q92915 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253445 0.245 VRK1 protein Q99986 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Ser62 FGPARNDsVIVADQT 9606 15105425 t gcesareni Vrk1 phosphorylates atf2 mainly on thr-73, stabilizing the atf2 protein and increasing its intracellular level. SIGNOR-124330 0.379 CCL3 protein P10147 UNIPROT CCR1 protein P32246 UNIPROT up-regulates binding 9606 10734056 t CCR1 is also activated by MIP-1α, MCP-2, and MCP-3, although maximum responses are only obtained with RANTES and MIP-1α. SIGNOR-254366 0.71 ATM protein Q13315 UNIPROT MECOM protein Q03112 UNIPROT up-regulates activity phosphorylation Ser1039 NSNHGSQsPRNVEER 29939287 t phosphorylation site remapping based on Fig 1 lperfetto To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif. SIGNOR-273434 0.2 TBCK protein Q8TEA7 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23977024 f miannu Depletion of TBCK significantly inhibits cell proliferation, reduces cell size, and disrupts the organization of actin, but not microtubule. SIGNOR-266700 0.7 CDK1 protein P06493 UNIPROT RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Thr409 GQGEKSAtPSRKILD 9606 SIGNOR-C17 15037602 t lperfetto Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis. The m-phase kinase cyclin b/cdk1 phosphorylates rangap1 efficiently in vitro, and t409 phosphorylation correlates with nuclear accumulation of cyclin b1 in vivo. SIGNOR-123524 0.472 EPHB2 protein P29323 UNIPROT SRC protein P12931 UNIPROT up-regulates binding 9606 9632142 t lperfetto We propose src kinase as a downstream effector that mediates the neuron's response to eph receptor activation SIGNOR-58142 0.547 HSF1 protein Q00613 UNIPROT HSPA6 protein P17066 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12813038 f miannu These experiments suggest that HSF2 is involved in the stress response, but unlike the ubiquitous HSF1 operates in a cell-line specific manner through differential expression of alternatively spliced isoforms. Curiously, HSF2A could not be activated by heat shock in cells deficient in functional HSF1 and required the expression of HSF1 for heat induction of the hsp70B gene in cells. SIGNOR-254477 0.44 SB 505124 chemical CHEBI:100922 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206742 0.8 AD/b2 integrin complex SIGNOR-C172 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269021 0.7 CTNNB1 protein P35222 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity 9606 16510874 f Luana Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro. Chromatin immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp. SIGNOR-265358 0.2 SCF-betaTRCP complex SIGNOR-C5 SIGNOR RAPGEF2 protein Q9Y4G8 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 24290981 t miannu Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-β and casein kinase-1α and consequently degraded by the proteasome via the SCF(βTrCP) ubiquitin ligase. SIGNOR-276607 0.2 NOTCH1 protein P46531 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 16256737 t lperfetto The notch intracellular domain interacts with hif-1alpha and hif-1alpha is recruited to notch-responsive promoters upon notch activation under hypoxic conditions. SIGNOR-141315 0.635 PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity phosphorylation Tyr988 RVDSDNAyIGVTYKN 9823 BTO:0004007 7535778 t miannu We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF α-receptor carboxyl-terminal tail bind PLC-γ, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-γ. SIGNOR-250252 0.2 SRC protein P12931 UNIPROT KCNA3 protein P22001 UNIPROT up-regulates phosphorylation Tyr187 FSEEIRFyQLGEEAM 9606 11812778 t gcesareni The shaker family k+ channel protein, kv1.3, is tyrosine phosphorylated by v-src kinase at tyr137 and tyr449 to modulate current magnitude and kinetic properties. SIGNOR-114641 0.315 AMPK complex SIGNOR-C15 SIGNOR MLXIPL protein Q9NP71 UNIPROT down-regulates phosphorylation Ser556 LLRSPGsPQETVPE 10116 11724780 t lperfetto These results strongly suggested that the fatty acid inhibition of glucose-induced l-PK transcription resulted from AMPK phosphorylation of ChREBP at Ser568, which inactivated the DNA binding activity. SIGNOR-216526 0.406 CRTC2 protein Q53ET0 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity transcriptional regulation 9606 26652733 t These results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/GR- and glucagon/CREB-signaling pathways on the key genes G6P and PEPCK. SIGNOR-256106 0.395 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR BCL2L11 protein O43521 UNIPROT down-regulates binding 9606 16282323 t gcesareni Cytokine stimulation promotes bim(el) binding to 14-3-3 proteins. Akt could directly phosphorylate a gst-bim(el) fusion protein and identified the akt phosphorylation site in the bim(el) domain as ser(87). we propose that ser87 of bimel is an important regulatory site that is targeted byakt to attenuate thepro-apoptotic function of bim el, thereby promoting cell survival. SIGNOR-141577 0.2 PIM proteinfamily SIGNOR-PF34 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 t tpavlidou Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene. SIGNOR-259429 0.2 PCSK7 protein Q16549 UNIPROT ELK4 protein P28324 UNIPROT up-regulates phosphorylation 9606 9130707 t gcesareni In contrast, the tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387 SIGNOR-47771 0.2 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Thr658 VGGVVIAtVIVITLV -1 10605825 t lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. SIGNOR-261792 0.502 INS protein P01308 UNIPROT IGF1R protein P08069 UNIPROT up-regulates binding 9606 BTO:0000887 1851182 t fspada Because of the sequence homology and tertiary structure similarities between proinsulin (pi) and insulin-like growth factor-i (igf-i), it is possible that pi interacts with the igf-i receptor with higher affinity than insulin. SIGNOR-22083 0.891 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 18362890 t inferred from 70% family members gcesareni These findings indicate that the phosphorylation of mob1 at thr74 by mst2 is essential to make a complex of mob1, mst2 and ndr1, and to fully activate ndr1 SIGNOR-270220 0.2 KLF2 protein Q9Y5W3 UNIPROT PPARG protein P37231 UNIPROT down-regulates transcriptional regulation 9606 12426306 f fspada Constitutive overexpression of klf2 but not klf15 potently inhibits peroxisome proliferator-activated receptor-gamma (ppargamma) expression with no effect on the upstream regulators c/ebpbeta and c/ebpdelta. SIGNOR-210019 0.428 PRKAA1 protein Q13131 UNIPROT ULK1 protein O75385 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 SIGNOR-C15 21460634 t lperfetto Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition. SIGNOR-173038 0.553 PHF12 protein Q96QT6 UNIPROT TLE1 protein Q04724 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 t miannu We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE. SIGNOR-266994 0.2 SOSTDC1 protein Q6X4U4 UNIPROT WNT7A protein O00755 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242710 0.273 TP53 protein P04637 UNIPROT SLC2A1 protein P11166 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27692180 t miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. SIGNOR-267464 0.584 (8R)-7-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-13,14-diol chemical CHEBI:92234 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258730 0.8 MAP4K3 protein Q8IVH8 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates activity phosphorylation Ser480 NTVWKQLsSSVTGLT -1 31431460 t miannu GLK directly phosphorylated IQGAP1 at Ser-480 enhancing Cdc42 activation and subsequent cell migration.  SIGNOR-277479 0.2 p38 proteinfamily SIGNOR-PF16 SIGNOR CDT1 protein Q9H211 UNIPROT up-regulates quantity by stabilization phosphorylation Ser391 LRSAAPSsPGSPRPA 9606 BTO:0000567 21930785 t miannu  We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2.  SIGNOR-276362 0.2 AKT1 protein P31749 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser558 MQPPRSRsSIMSITA -1 24548923 t miannu Here we show that Akt-mediated NF-κB activation is mediated at least in part through direct phosphorylation of the adaptor protein Carma1, which we previously demonstrated could interact with Akt in a TCR ligation-dependent manner. The putative Akt phosphorylation sites in Carma1 are distinct from known PKC consensus sites. Mutation of S551, S637 and S645 in Carma1 to non-phosphorylatable residues decreased phosphorylation of GST-Carma1-linker construct by Akt in vitro.  SIGNOR-276254 0.537 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT down-regulates phosphorylation Tyr54 HTVEAVAyAPKKELI 9606 9461559 t llicata Here we demonstrate that c-abl interacts constitutively with rad51. We show that c-abl phosphorylates rad51 on tyr-54 in vitro. The results also show that treatment of cells with ionizing radiation induces c-abl-dependent phosphorylation of rad51. Phosphorylation of rad51 by c-abl inhibits the binding of rad51 to dna and the function of rad51 in atp-dependent dna strand exchange reactions. SIGNOR-55482 0.764 NPTX1 protein Q15818 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity 9606 BTO:0004168;BTO:0003227 31113871 f lperfetto We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control SIGNOR-260413 0.2 IL1B protein P01584 UNIPROT ITGA2 protein P17301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001596 1744142 f lperfetto TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way. SIGNOR-253356 0.277 TNFSF13B protein Q9Y275 UNIPROT TNFRSF13C protein Q96RJ3 UNIPROT up-regulates activity binding 9606 BTO:0000776 15644327 t lperfetto Baff interacts with baff receptor (baffr). SIGNOR-133210 0.777 MAPK14 protein Q16539 UNIPROT MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity SIGNOR-48349 0.424 AP3D1 protein O14617 UNIPROT AP-3 complex complex SIGNOR-C247 SIGNOR form complex binding 9606 21097499 t lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) SIGNOR-260683 0.931 CIITA protein P33076 UNIPROT HLA-DRB4 protein P13762 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002417 10886240 f These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma. SIGNOR-254012 0.2 FBXO21 protein O94952 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by destabilization binding -1 26299618 t miannu Here we demonstrate that a ubiquitin E3-ligase, FBXO21, targets the multidrug resistance transporter, ABCB1, also known as P-glycoprotein (P-gp), for proteasomal degradation.Purified in vitro translated FLAG-tagged P-gp along with E2 (UbcH5c), E3 ligase FBXO21, Cul1, Skp1, Roc1 purified from Sf-9 insect cells were incubated in vitro. SIGNOR-272422 0.331 DBP protein Q10586 UNIPROT Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR up-regulates 9606 21633182 f miannu In addition to NHRs, Dbp, a known clock target gene, regulates expression of key metabolic genes involved in gluconeogenesis and lipogenesis (60). Because DBP levels change 100-fold in response to CLOCK/BMAL1 activation, it is conceivable that DBP generates circadian oscillation in metabolic processes such as gluconeogenesis. SIGNOR-268028 0.7 Jervine chemical CHEBI:6088 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 BTO:0000149 16112412 t gcesareni Here, we demonstrate that cyclopamine and jervine, two structurally related inhibitors of smo, force ciliary translocation of smo. SIGNOR-139865 0.8 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 20610653 f miannu Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-260329 0.2 Caspase 1 complex complex SIGNOR-C220 SIGNOR IL18 protein Q14116 UNIPROT up-regulates activity cleavage Asp36 DDENLESdYFGKLES 9606 BTO:0001370 9334240 t lperfetto We also found two precursor hIL-18 (prohIL-18)-processing activities in the cytosol of THP.1 cells. These activities were blocked separately by the caspase inhibitors Ac-YVAD-CHO and Ac-DEVD-CHO. Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products. SIGNOR-256377 0.783 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 18936167 t These results therefore suggest that the autoactivation residues Y1054 and Y1059 are targeted by DEP-1 and that this results in the inhibition of kinase activity and the consequent general dephosphorylation of VEGFR2. SIGNOR-248710 0.687 MLKL protein Q8NB16 UNIPROT CNR2 protein P34972 UNIPROT down-regulates quantity by destabilization phosphorylation Ser352 KITPWPDsRDLDLSD 9606 BTO:0000007 10400664; 36448459 t done miannu Under hyperglycemic conditions, high glucose induced CB2R internalization in a β-arrestin 2-dependent manner; thereafter, MLKL (mixed lineage kinase domain-like), but not receptor-interacting protein kinase 1 or 3, phosphorylated CB2R at serine 352 and promoted CB2R degradation by ubiquitin modification. CB2R transcriptionally repressed necroptosis through interaction with BACH2; in turn, MLKL formed a negative feedback to phosphorylate CB2R. SIGNOR-274121 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser36 AEKQARGsTTLQESR 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275765 0.2 AKT1 protein P31749 UNIPROT COPS6 protein Q7L5N1 UNIPROT up-regulates phosphorylation Ser60 DHWIRMRsQEGRPVQ 9606 23095642 t llicata Mechanistic studies show that akt causes csn6 phosphorylation at ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of csn6. SIGNOR-252532 0.286 DYRK1B protein Q9Y463 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser641 YRYPRPAsVPPSPSL 9534 BTO:0000298 14593110 t miannu DYRK Family Protein Kinases Phosphorylate and Inactivate Glycogen Synthase. both protein kinases phosphorylate site 3a but no other sites that affect glycogen synthase activity. SIGNOR-260633 0.261 PLK1 protein P53350 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser260 SLDSEDYsLSEEGQE 9606 19833129 t gcesareni Polo-like kinase-1 phosphorylates mdm2 at ser260 and stimulates mdm2-mediated p53 turnover. SIGNOR-188471 0.477 GNRHR protein P30968 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257265 0.452 PRKAA2 protein P54646 UNIPROT EEF2K protein O00418 UNIPROT up-regulates activity phosphorylation Ser398 DSLPSSPsSATPHSQ -1 14709557 t miannu Stimulation of the AMP-activated Protein Kinase Leads to Activation of Eukaryotic Elongation Factor 2 Kinase and to Its Phosphorylation at a Novel Site, Serine 398. phosphorylation of eEF2 kinase at Ser-398 leads to an increase in its activity. SIGNOR-250158 0.48 SDH complex SIGNOR-C400 SIGNOR succinate(2-) smallmolecule CHEBI:30031 ChEBI down-regulates quantity chemical modification 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions. SIGNOR-266276 0.8 POU2F1 protein P14859 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001939 23836662 f miannu This PER2-OCT1 interaction effectively converted OCT1 sites, which normally activate expression, into repressor sites by recruitment of a polycomb repressor complex including EZH2 and SUZ12, as well as HDAC2. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. SIGNOR-254152 0.26 MAP3K11 protein Q16584 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates phosphorylation Ser281 WHKTTQMsAAGTYAW 9606 11053428 t gcesareni These residues within the activation loop are critical for mlk-3 autophosphorylation and activation. In addition, when the thr277 and ser281 residues were mutated to negatively charged glutamic acid to mimic phosphorylated serine/threonine residues, the resulting mutants were fully functional, implying that these two residues may serve as the autophosphorylation sites. SIGNOR-83407 0.2 SPAG9 protein O60271 UNIPROT MAP3K7 protein O43318 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 SIGNOR-C21 22337877 t lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts SIGNOR-235548 0.2 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Ser452 PVKTLPFsPSQFLNF BTO:0000007 10593981 t llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. SIGNOR-250735 0.711 NTRK1 protein P04629 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000938 10708759 t esanto Autophosphorylated trka binds directly to plc?, Abl, and shc. SIGNOR-75405 0.637 CDK1 protein P06493 UNIPROT DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr204 LTRYTRPtPVQKHAI 9606 SIGNOR-C17 16280325 t lperfetto Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis. SIGNOR-141565 0.301 sertindole chemical CHEBI:9122 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258542 0.8 AMPK complex SIGNOR-C15 SIGNOR CTBP1 protein Q13363 UNIPROT down-regulates phosphorylation Ser158 REGTRVQsVEQIREV 9606 23291169 t lperfetto We found that an activated amp-activated protein kinase (ampk) phosphorylates ctbp1 on ser-158 upon metabolic stresses. Moreover, ampk-mediated phosphorylation of ctbp1 (s158) attenuates the repressive function of ctbp1 SIGNOR-216604 0.2 PPP2CB protein P62714 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization dephosphorylation Thr55 DDIEQWFtEDPGPDE 9606 17245430 t A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55| In this study, we reported that the specific B regulatory subunits of PP2A B56gamma1 and B56gamma3 mediate dephosphorylation of p53 at Thr55. Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis SIGNOR-248583 0.412 HAP1 protein P54257 UNIPROT NEUROD1 protein Q13562 UNIPROT up-regulates activity binding -1 12881483 t lperfetto We identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2). Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2 SIGNOR-234602 0.333 NFE2L2 protein Q16236 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22493435 t miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 SIGNOR-254652 0.462 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr252 HDGTVTHtFCGTIEY -1 9445476 t gcesareni The results presented here are consistent with PDK1 as the in vivo kinase responsible for mediating Thr252 phosphorylation in the catalytic domain of p70s6k. SIGNOR-243338 0.716 RFXANK protein O14593 UNIPROT RFX complex complex SIGNOR-C104 SIGNOR form complex binding -1 10825209 t miannu RFXANK and RFXAP bind to each other and form a heterodimer (step 1) that subsequently interacts with RFX5 Upon binding, the conformation of RFX5 changes (step 2) in a way that enables the RFX complex to bind to DNA (step 3) and to recruit other proteins that are required for the transcription of MHC II genes SIGNOR-221571 0.809 PTPRJ protein Q12913 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12771128 t inferred from 70% of family members gcesareni A dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation. SIGNOR-269897 0.2 NFIA protein Q12857 UNIPROT ANOS1 protein P23352 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268872 0.2 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 15774499 t gcesareni The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. SIGNOR-134658 0.579 CSNK2A1 protein P68400 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates phosphorylation Ser423 CEEEFSDsEEEGEGG 9606 11602581 t gcesareni Human hdac1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, ser(421) and ser(423), were unambiguously identified. Loss of phosphorylation at ser(421) and ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of hdac1. SIGNOR-111015 0.611 BIRC5 protein O15392 UNIPROT CASP3 protein P42574 UNIPROT down-regulates binding 9606 10587640 t gcesareni Use of a dominant-negative survivin mutant or antisense survivin complementary dna disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21waf1/cip1 within centrosomes, and results in caspase-dependent cleavage of p21. SIGNOR-72882 0.502 SYK protein P43405 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Tyr18 MEDHAGTyGLGDRKD 9606 BTO:0000938 18070606 t lperfetto We established that tyrosine 18 was the primary residue in tau phosphorylated by sykphosphorylation of tau by syk could be involved in neurite outgrowth. SIGNOR-159648 0.479 pemetrexed disodium chemical CHEBI:63722 ChEBI TYMS protein P04818 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 14596699 t miannu Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT). SIGNOR-259289 0.8 CSNK2A1 protein P68400 UNIPROT EXOSC9 protein Q06265 UNIPROT up-regulates phosphorylation Ser394 APIILSDsEEEEMII 9606 19217413 t lperfetto Indeed recombinant pmscl1 undergoes ck2-mediated phosphorylation in vitro at various serine residues, including serines 409 and 411, which reside within the phosphosim region. the exchange of hydrophobic core residues or serines 409 and 411 to alanine attenuates binding of sumo to the phosphosim-containing fragment of pmscl1 in a yeast two-hybrid assay SIGNOR-184035 0.2 PRKAA2 protein P54646 UNIPROT TSC2 protein P49815 UNIPROT up-regulates phosphorylation Ser1387 QPLSKSSsSPELQTL 9606 SIGNOR-C15 16959574 t gcesareni We have observed that ampk directly phosphorylates tsc2, and the ampk-dependent phosphorylation of tsc2 is critical for the coordination between cell growth and cellular energy levels. SIGNOR-149388 0.559 CSNK2A1 protein P68400 UNIPROT SLC29A1 protein Q99808 UNIPROT up-regulates activity phosphorylation Ser254 ETKLDLIsKGEEPRA -1 17520485 t miannu These data suggest that inhibition of CK2-mediated phosphorylation at Ser254 had the same effect on transporter function as the actual loss of Ser254 in mENT1a, implying that this site is constitutively phosphorylated by CK2.  SIGNOR-276063 0.2 WICH complex SIGNOR-C449 SIGNOR RNA Polymerase I complex SIGNOR-C390 SIGNOR up-regulates activity binding 9606 16514417 t miannu Here, we show by biochemical fractionation of nuclear extracts, protein-protein interaction studies and chromatin immunoprecipitation assays that NM1 is part of a multiprotein complex that contains WICH, a chromatin remodelling complex containing WSTF (Williams syndrome transcription factor) and SNF2h. NM1, WSTF and SNF2h were found to be associated with RNA polymerase I (Pol I) and ribosomal RNA genes (rDNA). RNA interference-mediated knockdown of NM1 and WSTF reduced pre-rRNA synthesis in vivo, and antibodies to WSTF inhibited Pol I transcription on pre-assembled chromatin templates but not on naked DNA. The results indicate that NM1 cooperates with WICH to facilitate transcription on chromatin. SIGNOR-268830 0.441 CAMK2A protein Q9UQM7 UNIPROT DLG1 protein Q12959 UNIPROT down-regulates activity phosphorylation Ser232 ITLERGNsGLGFSIA 9534 BTO:0000298 12933808 t llicata Synapse-associated protein 97 (SAP97), a member of membrane-associated guanylate kinase protein family, has been implicated in the processes of targeting ionotropic glutamate receptors at postsynaptic sites. | We show here that SAP97 is directly associated with NR2A through its PDZ1 domain, and CaMKII-dependent phosphorylation of SAP97-Ser-232 disrupts NR2A interaction both in an in vitro pull-out assay and in transfected COS-7 cells. Moreover, expression of SAP97(S232D) mutant has effects similar to those observed upon constitutively activating CaMKII. SIGNOR-250618 0.634 NMDA receptor_2D complex SIGNOR-C350 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor SIGNOR-264225 0.731 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12777400 t Manara These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386 SIGNOR-260772 0.346 SNAI2 protein O43623 UNIPROT JAG1 protein P78504 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 20509143 f miannu SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness. SIGNOR-255151 0.427 CSNK2A2 protein P19784 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT down-regulates activity phosphorylation Ser740 TKAQRENsPAAFPDR 9606 BTO:0000567 12591939 t llicata We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified SIGNOR-250986 0.381 2-cyclopentyl-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid chemical CHEBI:95066 ChEBI SGK3 protein Q96BR1 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0003136 25458846 t lperfetto A catalytic small molecule pan-SGK inhibitor, GSK650394 (Sherk et al., 2008) also significantly blocks MCF7, ZR-75-1, and T47D cell migration (Figure 5C, Figures S4B–C). Finally, ectopic expression of SGK3 also promotes invasive migration through Matrigel (Figure 5D). Therefore, SGK3 protein kinase activity promotes migration of breast cancer cells that display elevated levels of INPP4B. SIGNOR-262019 0.8 BTG1 protein P62324 UNIPROT HOXB9 protein P17482 UNIPROT up-regulates activity binding 9606 BTO:0000567 10617598 t miannu The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation. SIGNOR-221019 0.453 TP53 protein P04637 UNIPROT OGG1 protein O15527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16293709 t miannu Using gel-shift assays, we showed that p53 binds to its putative cis-elements within the hOGG1 promoter. In addition we demonstrated that supplementing p53 in HCT116p53-/- cells enhanced the transcription of hOGG1. SIGNOR-255440 0.44 AMPK complex SIGNOR-C15 SIGNOR BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 22137581 t lperfetto Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction SIGNOR-216608 0.2 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Ser742 QQIINQIsKLHAIID 9606 18680479 t gcesareni We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity after expression in bacteria or in cultured human cells. SIGNOR-179900 0.2 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR LIN28A protein Q9H9Z2 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269238 0.703 RASSF1 protein Q9NS23 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates binding 9606 21808241 t Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage milica Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization. SIGNOR-269950 0.802 UBIAD1 protein Q9Y5Z9 UNIPROT HRAS protein P01112 UNIPROT down-regulates activity binding 9606 BTO:0000362 30518913 t miannu This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells. SIGNOR-256206 0.2 PRKCQ protein Q04759 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000782 26284074 t Barakat PKC-θ-mediated phosphorylation of serine and tyrosine residues of c-Cbl prevents its inhibitory effect. Phosphorylation of c-Cbl by PKC-θ inhibits the recruitment of Sh2-containing proteins and subsequent association of cbl E3 ubiquitin ligase with its target proteins SIGNOR-274144 0.362 JNK proteinfamily SIGNOR-PF15 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 18931691 f miannu JNKs activate apoptotic signaling by the upregulation pro-apoptotic genes via the transactivation of specific transcription factors or by directly modulating the activities of mitochondrial pro- and anti-apoptotic proteins through distinct phosphorylation events. SIGNOR-260178 0.7 PPARG protein P37231 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002042 16785230 f miannu these results uncovered a mechanism by which up-regulation of functional ABCG2 expression can be achieved via exogenous or endogenous activation of the lipid-activated transcription factor, PPARgamma. SIGNOR-255054 0.405 ROCK1 protein Q13464 UNIPROT MYLK protein Q15746 UNIPROT up-regulates binding 9606 11283607 t gcesareni Rock proteins are known to regulate mlc-phosphorylation, and apoptotic cells exhibit a gradual increase in levels of phosphorylated mlc concomitant with rock i cleavage. SIGNOR-106552 0.321 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr154 NRMPVAPyWTSPEKM 9606 8443592 t lperfetto Tyrosine residues 154 and 307, which are in the extracellular domain of transmembrane receptor isoforms and are in an unusual sequence context for tyrosine phosphorylation, were also phosphorylated. SIGNOR-98622 0.2 PTPRG protein P23470 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 BTO:0000876 25624455 t miannu Deeper examination shows that JAKs are critically involved in integrin-mediated monocyte adhesion and that PTPRG activation leads to JAK2 dephosphorylation on the critical 1007–1008 phosphotyrosine residues, implying JAK2 inhibition and thus explaining the antiadhesive role of PTPRG. SIGNOR-254689 0.291 BMPR1B protein O00238 UNIPROT SMAD9 protein O15198 UNIPROT up-regulates phosphorylation 9606 19620713 t gcesareni Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. SIGNOR-187196 0.696 AKT1 protein P31749 UNIPROT PDE3B protein Q13370 UNIPROT up-regulates activity phosphorylation Ser295 VIRPRRRsSCVSLGE 10090 BTO:0000944 10454575 t PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B SIGNOR-252573 0.679 HNF4A protein P41235 UNIPROT PCSK9 protein Q8NBP7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000398 21123766 f miannu Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes. SIGNOR-254451 0.271 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276099 0.267 PPARG protein P37231 UNIPROT ACADM protein P11310 UNIPROT down-regulates activity binding 9606 BTO:0001370 28974683 t Federica This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation SIGNOR-261264 0.353 TRIM41 protein Q8WV44 UNIPROT PRKCB protein P05771 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 17893151 t miannu RINCK induces the ubiquitination of PKC both in vitro and in cells. Overexpression of RINCK reduces the levels of PKC in cells, whereas genetic knockdown of endogenous RINCK increases the levels of PKC. The RINCK-mediated ubiquitination is likely to be polyubiquitination, because the ubiquitinated PKCβII was detected as a high molecular weight smear. SIGNOR-271667 0.323 CDH2 protein P19022 UNIPROT CDON/SPAG9 complex SIGNOR-C21 SIGNOR up-regulates binding 9606 20160094 t lperfetto We report here that n-cadherin ligation activates p38alpha/beta in myoblasts in a cdo-, bnip-2-, and jlp-dependent manner SIGNOR-217517 0.529 STAT3 protein P40763 UNIPROT SP1/STAT3 complex SIGNOR-C74 SIGNOR form complex binding 9606 19723038 t miannu Sp1 and stat3 seem to synergistically augment renalase transcription. SIGNOR-187793 0.467 HCFC1 protein P51610 UNIPROT CREB3 protein O43889 UNIPROT up-regulates activity binding -1 9658067 t 2 miannu We also show that while interaction with HCF is not required for the ability of Luman to activate transcription when tethered to the GAL4 promoter, it appears to be essential for Luman to activate transcription through CRE sites. SIGNOR-241372 0.583 RDH5 protein Q92781 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI down-regulates quantity chemical modification 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS10 SIGNOR-265113 0.8 EGFR protein P00533 UNIPROT STAT5B protein P51692 UNIPROT up-regulates activity phosphorylation Tyr699 TAKAVDGyVKPQIKQ 9606 BTO:0000007;BTO:0000356 11751923 t llicata We have shown that EGF activates STAT5b not only in a HEK293 cell model in which the EGFR is stably overexpressed but also in the MDA-MB468 breast cancer cell line. Furthermore, EGF (but not GH) is able to activate tyrosine phosphorylation of a Tyr-699 mutant of STAT5b. | Fig. 2 A (bottom panels) demonstrates that EGF-induced phosphorylation of tyrosine 699 (the well-described site of STAT5b phosphorylation) is detected only in the EGFR-overexpressing MDA-MB468 cells and not the MCF-7 cells. SIGNOR-251098 0.827 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TH protein P07101 UNIPROT up-regulates phosphorylation 9606 7901013 t inferred from 70% family members gcesareni In this paper we have studied the phosphorylation and activation of alternatively spliced forms of human th by mapkap kinase-1 , mapkap kinase-2, map kinase, and cam kinase-11 SIGNOR-270167 0.2 TWIST2 protein Q8WVJ9 UNIPROT RBL2 protein Q08999 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255509 0.2 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser367 DTRSLEIsQSYTTTQ 9606 21149446 t gcesareni In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible. SIGNOR-170477 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 10230396 t inferred from 70% family members gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-270129 0.2 EZH2 protein Q15910 UNIPROT HOXA10 protein P31260 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20565746 t miannu These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression. SIGNOR-260070 0.449 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr740 TGESDGGyMDMSKDE -1 8195171 t miannu Synthetic peptide analysis revealed that certain autophosphorylation sites in the PDGF beta-receptor (Tyr-579, Tyr-740, Tyr-751, and Tyr-771) were able to mediate the specific binding of the Shc SH2 domain as well as intact Shc proteins. SIGNOR-250257 0.2 ramipril chemical CHEBI:8774 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition -1 6097265 t miannu 2-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl] - (1S,3S,5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid (Hoe 498) is a new, very effective and long lasting, nonsulfhydryl angiotensin I converting enzyme inhibitor. SIGNOR-258400 0.8 AURKA protein O14965 UNIPROT FANCA protein O15360 UNIPROT up-regulates activity phosphorylation Ser165 HSMFSRLsFCQELWK 9606 BTO:0002181 27398318 t miannu E detected interactions between Aurora A kinase and FANCA protein, one of the components of the FA nuclear core complex. These results suggest that S165 phosphorylation by Aurora A kinase is required for proper activation of the FA/BRCA pathway in response to DNA damage. SIGNOR-277263 0.479 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4D protein Q08499 UNIPROT up-regulates activity phosphorylation Ser125 CRAMDRTsYAVETGH 9534 12023945 t miannu Phosphorylation of long PDE4 isoforms by PKA. COS1 cells were transfected to express various long PDE4 isoforms. SIGNOR-275988 0.2 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr371 LLAKLEEtKEYQEPE -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276211 0.2 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2A protein P49459 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271361 0.66 STAT5A protein P42229 UNIPROT PIM2 protein Q9P1W9 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15769897 t The serine-threonine kinase Pim-2 is a functionally relevant downstream target of STAT5. Here, we observed only a weak induction of Pim-2 by Flt3-D835Y compared to the effects of Flt3-ITD. SIGNOR-261543 0.42 STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT up-regulates transcriptional regulation 9606 BTO:0001103 21576360 t When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita SIGNOR-256249 0.524 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Ser775 EGVKRTLsFSLRSSR 9534 BTO:0000298 14523239 t lperfetto We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. SIGNOR-249231 0.2 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000938 9771888 t The effect has been demonstrated using P10636-8 gcesareni Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase. SIGNOR-60659 0.443 PPM1A protein P35813 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation 9606 25026293 t miannu All of these results lead to the conclusion that PPM1A inhibits the TGF-\u03b2-induced the activity of Smad2, Smad3 and transcriotional responses, whereas depletion of PPM1A enhances the activation of TGF-\u03b2/Smads signaling in bladder cancer cells.|Protein phosphatase PPM1A has been reported to dephosphorylate TGF-\u03b2-activated Smad2/3, thus inhibiting the TGF-\u03b2 signaling pathway. SIGNOR-277034 0.655 MTOR protein P42345 UNIPROT ULK2 protein Q8IYT8 UNIPROT down-regulates phosphorylation 9606 19211836 t gcesareni Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2 SIGNOR-183961 0.768 NOTCH1 protein P46531 UNIPROT ADAM19 protein Q9H013 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782;BTO:0001454 10933396 f gcesareni Deltex, meltrin beta, ifi-202, and ifi-204 were also upregulated by notchic in the 2b4.11 t cell hybridoma, whereas ifi-d3 was expressed constitutively at relatively high levels and slightly upregulated by notchic, and pre-talfa was not expressed. Deltex, meltrin beta, pre-talfa, ifi-202, and ifi-204 were upregulated by notchic expression in the akr1 dp thymoma cell line, whereas ifi-d3 was not expressed SIGNOR-80330 0.316 metformin chemical CHEBI:6801 ChEBI G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression 9606 17909097 f inferred from family member gcesareni In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp. SIGNOR-270254 0.8 SLC6A8 protein P48029 UNIPROT creatine smallmolecule CHEBI:16919 ChEBI up-regulates quantity relocalization 9606 18652074 t miannu CRT is essential for normal brain function as mutations in the CRT gene (SLC6A8) result in X-linked mental retardation, associated with the almost complete lack of creatine in the brain, severe speech and language delay, epilepsy, and autistic behaviour. SIGNOR-265808 0.8 CDK2 protein P24941 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates activity phosphorylation Ser770 LISRPRPsPLRSRID -1 35843311 t miannu Using in vitro kinase assays and phosphomutants, we determined that CDK1 phosphorylates MLK3 on Ser548 and decreases MLK3 activity during mitosis, whereas CDK2 phosphorylates MLK3 on Ser770 and increases MLK3 activity during G1/S and G2 phases. SIGNOR-277604 0.2 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7566092 t lperfetto Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-J kappa (refs 8,9) and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. SIGNOR-209590 0.673 GATA2 protein P23769 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24583263 f irozzo We also identify Spi1 as a common downstream target gene of Etv2 and Gata2. We provide evidence that Etv2 and Gata2 bind to the Spi1 promoter in vitro and in vivo. Etv2 and Gata2 synergistically transactivate Spi1 gene expression. SIGNOR-256007 0.595 Immunoglobulin mu heavy chain protein P0DOX6 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR form complex binding 9606 BTO:0000776 32323265 t scontino An antibody is composed of two identical HCs and two identical LCs (either kappa or lambda ), consisting of variable (V) and constant (C) regions linked by disulfide bonds. Pro- genitor B cells rearrange their Ig heavy chain (HC) genes to differentiate into precursor B (pre- B) cells that express μ HCs. SIGNOR-268191 0.2 JAK2 protein O60674 UNIPROT ITGAL protein P20701 UNIPROT up-regulates activity phosphorylation 9606 25624455 t miannu PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role. SIGNOR-254739 0.271 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH13 protein P55290 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265831 0.8 WNT7A protein O00755 UNIPROT FZD7 protein O75084 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni Analysis of the expression of the fzd receptors during somitogenesis demonstrated that fzd7 is expressed in the hypaxial region of the somite, suggesting an interaction with wnt7a. SIGNOR-198919 0.665 NCAPH2 protein Q6IBW4 UNIPROT TERF1 protein P54274 UNIPROT up-regulates activity binding 9606 BTO:0000567 31026066 t miannu Taken together these observations suggest that NCAPH2 promotes telomere stability, possibly through a direct interaction with the TRF1 shelterin component, and prevents telomere dysfunction resulting from impaired DNA replication. SIGNOR-263914 0.2 KAT2B protein Q92831 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates acetylation 9606 BTO:0000782;BTO:0001271 22120716 t gcesareni In earlier studies, we demonstrated that maml1 enhanced p300 acetyltransferase activity, which increased the acetylation of notch by p300.Acetylation controls notch stability and function in t-cell leukemia. SIGNOR-177749 0.585 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120260 0.321 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates activity phosphorylation Tyr432 KEGWMVHyTSKDTLR 9606 BTO:0000567 12637538 t lperfetto Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr(432), Tyr(463), and Tyr(502)), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr(463)) leads to PKD activation. SIGNOR-247320 0.42 AMPK complex SIGNOR-C15 SIGNOR CRY1 protein Q16526 UNIPROT down-regulates quantity by destabilization phosphorylation Ser280 YKKVKKNsSPPLSLY 9606 19833968 t miannu We demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Phosphorylation of S71 or S280 by AMPK destabilizes CRY1 SIGNOR-268047 0.349 MLL Fusion fusion protein SIGNOR-FP14 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 9606 BTO:0001133 18977325 t miannu Recent studies have identified association of multiple MLL-fusion partners including AF4, AF9, and AF10 with DOT1L, a histone H3K79 methyltransferase.This leads to a model where MLL-AF4 recruits DOT1L to MLL target genes, and promotes methylation of H3K79 at loci with existing H3K4 methylation (i.e., by wildtype MLL or other H3K4 methyltransferases) thus stimulating transcriptional elongation of genes that are normally primed but not fully transcribed. SIGNOR-260095 0.2 WNT3A protein P56704 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have SIGNOR-169657 0.688 TLE1 protein Q04724 UNIPROT SIX6 protein O95475 UNIPROT up-regulates activity binding -1 12441302 t lperfetto Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. TLE1 over-expression induces an enlargement of the eye field and reinforcesSIX3/SIX6 capability of initiating retina formation SIGNOR-234592 0.405 PRKACA protein P17612 UNIPROT ACACA protein Q13085 UNIPROT down-regulates activity phosphorylation Ser1201 IPTLNRMsFSSNLNH -1 2900138 t TC1 = Ser-2Ser(P)-Met-3Ser(P)-Gly-Leu; TC2 = Arg-Met-1Ser(P)-Phe- Cyclic-AMP-dependent protein kinase phosphorylates sites 1 and 2 exclusively, whereas the AMP-activated protein kinase phosphorylates sites 1 and 3, plus at least one other minor site.[…]The results suggest that phosphorylation of site 3 is primarily responsible for the large decrease in Vmax produced by the AMP-activated protein kinase, while phosphorylation of site 1 may be primarily responsible for the increase in A0.5 for citrate and more modest depression of Vmax produced by cyclic-AMP-dependent protein kinase and ACK2 SIGNOR-267714 0.2 DRD4 protein P21917 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256846 0.424 CDK8 protein P49336 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2513 EHPFLTPsPESPDQW -1 25344755 t lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues SIGNOR-273176 0.534 AKT1 protein P31749 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser52 TRRTRTFsATVRASQ 9606 BTO:0000671 15910284 t lperfetto These and other results demonstrate that crhsp24 is phosphorylated at ser52 by pkbalpha in response to igf-1, at ser52 by pkbalpha and rsk in response to egf SIGNOR-252478 0.353 KAT2A protein Q92830 UNIPROT H3-5 protein Q6NXT2 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269600 0.2 ibrutinib chemical CHEBI:76612 ChEBI BTK protein Q06187 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189641 0.8 CTNNB1 protein P35222 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23645839 f apalma For example, prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion SIGNOR-255695 0.7 MAPK3 protein P27361 UNIPROT CREM protein Q03060 UNIPROT down-regulates quantity by destabilization phosphorylation Ser277 ASPGSLHsPQQLAEE 10090 BTO:0001077 11466319 t miannu  The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway.  SIGNOR-275978 0.419 GLI1 protein P08151 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 3563490 f gcesareni The gli gene is a member of a select group of cellular genes that are genetically altered in primary human tumors. SIGNOR-235196 0.7 MYC protein P01106 UNIPROT SLC2A1 protein P11166 UNIPROT up-regulates quantity transcriptional regulation 10116 10823814 t C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway. SIGNOR-259987 0.441 Integrator complex complex SIGNOR-C265 SIGNOR H4C1 protein P62805 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 25675981 f lperfetto Integrator-dependent function at promoter proximal sites that is unrelated to NELF-regulated pausing. Given its termination function at both the U2 snRNA and Histone H4 genes, we favor a model in which Integrator also has a termination function at promoter proximal sites. SIGNOR-261481 0.2 CSNK1A1 protein P48729 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser318 SRTNSNAsTVSGRLS 9606 20110348 t lperfetto Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export SIGNOR-163672 0.2 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser927 DSDSVCDsGVETSFR 10090 BTO:0000944 SIGNOR-C14 SIGNOR-C13 11297557 t lperfetto The i b kinase (ikk) complex rapidly phosphorylates nf- b1 p105 on serine 927 in the pest region romashkova et al. demonstrated that akt binds to and activates inhibitor of kappa b kinase-alfa (ikkalfa), which in turn phosphorylates and thereby promotes the degradation of the inhibitory cofactor of nf-kb, i-kb the scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk. SIGNOR-235438 0.737 CAMK2A protein Q9UQM7 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization phosphorylation Thr66 ATRKALGtVNRATEK 9606 BTO:0000567 24781523 t miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase SIGNOR-276377 0.314 RPS6KA1 protein Q15418 UNIPROT NR4A3 protein Q92570 UNIPROT unknown phosphorylation Ser376 GRRGRLPsKPKSPLQ 9606 BTO:0000007 16223362 t lperfetto We have established that two related proteins, Nurr1 and Nor1, are also phosphorylated on the equivalent site by RSK in cells in response to mitogenic stimulation. | Similar to Nur77, when FLAG€“Nor1 was expressed in HEK-293 cells, its phosphorylation on Ser377 was stimulated by both PMA and EGF SIGNOR-249297 0.32 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG 9606 8940173 t lperfetto Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor SIGNOR-45126 0.564 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates activity phosphorylation Thr635 SQCGYSStIVHVPPP 9534 BTO:0000298 11865049 t llicata The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly.  SIGNOR-250820 0.734 PTEN protein P60484 UNIPROT DVL2 protein O14641 UNIPROT down-regulates activity dephosphorylation Ser143 FHPNVSSsHENLEPE 9606 26399523 t miannu This showed that while both PTEN WT and the lipid phosphatase-inactive G129E mutant suppressed phosphorylation of DVL2 on serine 143 that accumulated upon PTEN knockdown, the C124S and Y138L mutants did not .|Finally, it is important to point out that while our studies show that PTEN can directly dephosphorylate DVL2 in vitro, it is possible that regulation of serine 143 phosphorylation of DVL2 by PTEN in cells may require additional protein factors, or post-translational modifications. SIGNOR-277035 0.323 JARID2 protein Q92833 UNIPROT NPPA protein P01160 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0003324 15542826 f miannu JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4. SIGNOR-224790 0.2 metaproterenol chemical CHEBI:6792 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation -1 19168263 t Luana Synthesis, pharmacological and in silico evaluation of 1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo[4.4.0]deca-7,9,11-trien-9-yl)-2-(tert-butylamino)ethanol, a compound designed to act as a β2 adrenoceptor agonist | After that, in vitro assays were carried out and the Kd value obtained for BR-AEA was compared with reported in vitro data for salbutamol and other well-known ligands. SIGNOR-257814 0.8 KAT2B protein Q92831 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269620 0.2 GNG12 protein Q9UBI6 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000586 16293724 t gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. SIGNOR-252681 0.374 CHKB protein Q9Y259 UNIPROT choline smallmolecule CHEBI:15354 ChEBI down-regulates quantity chemical modification 27149373 t lperfetto Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes SIGNOR-275635 0.8 BKM120 chemical CHEBI:71954 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190383 0.8 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates quantity relocalization 9606 BTO:0000586 21598020 t miannu Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14 SIGNOR-265818 0.2 HNF1B protein P35680 UNIPROT ALB protein P02768 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 1673926 f Regulation miannu VHNF1 transactivated the albumin promoter in transfection experiments SIGNOR-251930 0.297 MYLIP protein Q8WY64 UNIPROT LDLR protein P01130 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 30896554 t miannu The RING E3 ubiquitin ligase inducible degrader of the LDL receptor (IDOL, also known as MYLIP) promotes ubiquitylation and subsequent lysosomal degradation of the LDL receptor (LDLR), thus acting to limit uptake of lipoprotein-derived cholesterol into cells.  SIGNOR-271485 0.716 PRKCZ protein Q05513 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation Thr309 SDGATMKtFCGTPEY -1 9512493 t lperfetto The activation of PKBbeta and PKBgamma by PDK1 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma). PKBgamma which had been activated by PDK1 possessed a substrate specificity identical with that of PKBalpha and PKBbeta towards a range of peptides. The activation of PKBgamma and its phosphorylation at Thr305 was triggered by insulin-like growth factor-1 in 293 cells. SIGNOR-248997 0.48 Gbeta proteinfamily SIGNOR-PF4 SIGNOR EGFR protein P00533 UNIPROT down-regulates phosphorylation 9606 1651322 t inferred from 70% family members lperfetto It is likely that the map2 and ert kinases account for the phosphorylation of the egf receptor at thr669 (egf receptor (krel veplt669psgeapnqallr)) observed in cultured cells.Phosphorylation at ser-695 is partial and occurs only if thr-693 is phosphorylated. Phosphorylation at thr-678 and thr-693 by prkd1 inhibits egf-induced mapk8/jnk1 activation. SIGNOR-270017 0.2 PRKCG protein P05129 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser44 KKSKISAsRKLQLKT 9606 BTO:0000887 15769444 t lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. SIGNOR-134636 0.2 MTOR protein P42345 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 BTO:0000661 34535949 t Barakat Furthermore, we confirmed also in Jurkat cells that the specific silencing of both ERK1/2 and mTOR by siRNA downregulates Drp1 phosphorylation on Ser616 SIGNOR-275430 0.352 CCL2 protein P13500 UNIPROT Macrophage_activation phenotype SIGNOR-PH126 SIGNOR up-regulates 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260849 0.7 FBXO32 protein Q969P5 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001103 19319192 t gcesareni Here we present evidence that mafbx targets myod for degradation in several models of skeletal muscle atrophy. SIGNOR-184861 0.577 CBFA2T3 protein O75081 UNIPROT ZNF652 protein Q9Y2D9 UNIPROT down-regulates activity binding 9606 BTO:0000007 20116376 t Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. SIGNOR-253954 0.524 CCNH protein P51946 UNIPROT CAK complex complex SIGNOR-C456 SIGNOR form complex binding 9606 30860024 t lperfetto CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269321 0.96 CSNK1A1 protein P48729 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser316 FKSIMKKsPFSGPTD -1 26082493 t miannu These data strongly suggested that CKI phosphorylated Ser-316 of p65. Our data suggested that phosphorylation of p65 on Ser-316 controls the activity and function of NF-κB. Importantly, we found that phosphorylation at the novel Ser-316 site and other two known phosphorylation sites, Ser-529 and Ser-536, either individually or cooperatively, regulated distinct groups of NF-κB-dependent genes, suggesting the unique role of each individual phosphorylation site on NF-κB-dependent gene regulation.  SIGNOR-276916 0.2 SMARCC2 protein Q8TAQ2 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270695 0.83 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Ser272 RSRLTPVsPESSSTE 9606 BTO:0000551 20974803 t lperfetto Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis. SIGNOR-216932 0.355 EIF3E protein P60228 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity translation regulation 9606 BTO:0000815; BTO:0001938 20453879 f irozzo Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression. SIGNOR-259156 0.2 CCKAR protein P32238 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways. SIGNOR-106998 0.442 NPTX1 protein Q15818 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity 9606 BTO:0004168;BTO:0003227 31113871 f lperfetto We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control SIGNOR-260411 0.2 NCOR2 protein Q9Y618 UNIPROT SPEN protein Q96T58 UNIPROT up-regulates binding 9606 11331609 t gcesareni Sharp is a potent transcriptional repressor whose repression domain (rd) interacts directly with smrt SIGNOR-107260 0.479 BIRC2 protein Q13490 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 18997794 t lperfetto Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3. SIGNOR-182128 0.868 NR1D1 protein P20393 UNIPROT ARNTL protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24577401 t miannu A retinoic acid receptor-related orphan receptor (ROR) response element within the BMAL1 promoter is responsive to both ROR and REV-ERB (encoded by the genes NR1D1 and NR1D2); ROR activates the transcription of BMAL1, whereas REV-ERB suppresses its transcription. SIGNOR-268005 0.658 PSENEN protein Q9NZ42 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR form complex binding 9606 25610395 t lperfetto -Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2) SIGNOR-209708 0.96 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR down-regulates 9606 22303254 f Polycomb group (PcG) and Trithorax group (TrxG) proteins are epigenetic regulators that control gene expression through modulating chromatin structure and addition of posttranslational modifications (PTMs) on histones SIGNOR-268625 0.7 PAMPs stimulus SIGNOR-ST11 SIGNOR NAIP protein Q13075 UNIPROT up-regulates activity 16037825 f lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-256424 0.7 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269349 0.719 SMARCD2 protein Q92925 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270745 0.771 EGR1 protein P18146 UNIPROT PTGES protein O14684 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21983014 f In conclusion we demonstrated that treatment of HeLa cells with DMC leads to an enhanced formation of a complex consisting of NF-κB and HDAC1 that binds to the EGR1 promoter resulting in downregulation of EGR1 expression which plays a major role for transcriptional inhibition of mGPES-1 expression.|EGR1 downregulation seems to be the major effect of DMC leading to transcriptional inhibition of mPGES-1 SIGNOR-254249 0.342 IKBKB protein O14920 UNIPROT COPS5 protein Q92905 UNIPROT down-regulates activity phosphorylation Thr205 EGPSEYQtIPLNKIE -1 31950832 t lperfetto Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. SIGNOR-275519 0.336 PRKCA protein P17252 UNIPROT TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Thr175 GLLPFLLtHKKRLTD 9606 19661060 t Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-260882 0.357 SMARCA2 protein P51531 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269779 0.639 GABRA6 protein Q16445 UNIPROT GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263762 0.595 CDK1 protein P06493 UNIPROT BIRC5 protein O15392 UNIPROT up-regulates phosphorylation Thr34 FLEGCACtPERMAEA 9606 11861764 t gcesareni Survivin is a member of the inhibitor of apoptosis gene family that has been implicated in both apoptosis inhibition and regulation of mitosisin synchronized cultures, cytosolic survivin abruptly increased at mitosis, physically associated with p34(cdc2), and was phosphorylated by p34(cdc2) on thr(34), in vivo SIGNOR-115129 0.672 HTR6 protein P50406 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257073 0.252 LYN protein P07948 UNIPROT RGS16 protein O15492 UNIPROT up-regulates activity phosphorylation Tyr168 TLMEKDSyPRFLKSP -1 12588871 t Lyn kinase phosphorylated recombinant RGS16 in vitro. Induction of RGS16 tyrosine phosphorylation was associated with increased RGS16 protein levels and enhanced GAP activity in cell membranes. SIGNOR-251410 0.353 WNT5A protein P41221 UNIPROT FZD4 protein Q9ULV1 UNIPROT up-regulates activity binding 9606 16602827 t areggio We show that in addition to its inhibitory function, Wnt5a can also activate beta-catenin signaling in the presence of the appropriate Frizzled receptor, Frizzled 4. SIGNOR-258954 0.728 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR PECAM1 protein P16284 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17442773 f miannu Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. The platelet endothelial cell adhesion molecule PECAM1 is also downregulated by NUP98‐HOXA9. SIGNOR-261500 0.2 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR PRDM14 protein Q9GZV8 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269242 0.512 CHRM3 protein P20309 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256739 0.281 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT down-regulates activity phosphorylation Ser436 TCSPLRHsFQKQQRE -1 8810272 t miannu Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin. SIGNOR-250330 0.316 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F5 protein P12259 UNIPROT down-regulates activity cleavage Arg1220 LSPELIQrNLSPALG -1 10026263 t lperfetto Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 SIGNOR-263648 0.496 PRKCA protein P17252 UNIPROT EGLN2 protein Q96KS0 UNIPROT down-regulates phosphorylation Ser234 QRAIPPRsIRGDQIA 9606 18710826 t tpavlidou Thus, recombinant phd1 was examined for in vitro phosphorylation using protein kinase a, protein kinase calpha, casein kinase i and ii and erk2. The protein was most strongly phosphorylated by protein kinase calpha, and the phosphorylation sites were found to be ser-132, ser-226 and ser-234.Mutation Of ser-132 or ser-234 to asp or glu diminished the enzymatic activity to 25-60%, while mutation of ser-226 scarcely influenced the activity. SIGNOR-180203 0.341 ABL1 protein P00519 UNIPROT WASL protein O00401 UNIPROT up-regulates activity phosphorylation Tyr256 RETSKVIyDFIEKTG -1 16199863 t Abl phosphorylates N-WASP on tyrosines 175 and 256. Phosphorylation at this site stabilizes the active conformation of N-WASP, resulting in comet tail elongation. SIGNOR-251437 0.566 GRK5 protein P34947 UNIPROT GRK5 protein P34947 UNIPROT up-regulates activity phosphorylation Thr485 LDIEQFStVKGVNLD -1 8144599 t Autophosphorylation of GRK5 occurs primarily at residues Ser-484 and Thr-485. Phospholipid-stimulated autophosphorylation activates the G protein-coupled receptor kinase GRK5. SIGNOR-251202 0.2 heme smallmolecule CHEBI:30413 ChEBI HBA1 protein P69905 UNIPROT up-regulates activity chemical activation 9606 26557657 t miannu Heme is a prosthetic group comprising ferrous iron (Fe2+) and protoporphyrin IX and is an essential cofactor in various biological processes such as oxygen transport (hemoglobin) and storage (myoglobin) and electron transfer (respiratory cytochromes) in addition to its role as a structural component of hemoproteins. SIGNOR-251909 0.8 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu62 NLERECVeETCSYEE -1 10556651 t lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. SIGNOR-263679 0.655 3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea chemical CHEBI:91362 ChEBI AURKA protein O14965 UNIPROT down-regulates activity chemical inhibition 9606 19567821 t miannu The protein kinases, Aurora A, B, and C have critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. GSK1070916, is a novel ATP competitive inhibitor that is highly potent and selective for Aurora B/C kinases. SIGNOR-262225 0.8 BCL9 protein O00512 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 BTO:0000776 11955446 t amattioni Bcl9 exert its function by physically linking pygo to beta-catenin. The recruitment of pygo permits beta-catenin to transcriptionally activate wnt target genes. SIGNOR-116552 0.937 SMARCB1 protein Q12824 UNIPROT CCNA1 protein P78396 UNIPROT down-regulates 9606 12226744 f miannu We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6. SIGNOR-92779 0.342 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR JUN protein P05412 UNIPROT up-regulates binding 9606 18174238 t lperfetto Chromatin immunoprecipitation (chip) analysis confirmed the serum-induced recruitment of jund to the promoter in vivo and showed that the presence of jund was dependent on the presence of p65 and p50, indicating a protein-protein-dependent mechanism of jund recruitment SIGNOR-216337 0.577 NUDT21 protein O43809 UNIPROT CFI complex complex SIGNOR-C388 SIGNOR form complex binding 9606 8626397 t lperfetto We report here the purification of CF Im from HeLa cell nuclear extracts. Three polypeptides of 68, 59, and 25 kDa copurified with CF Im activity. SIGNOR-266122 0.947 R547 chemical CID:6918852 PUBCHEM CCNE1 protein P24864 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206355 0.8 YAP1 protein P46937 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199217 0.7 MAPK14 protein Q16539 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates activity phosphorylation Ser438 TPTLTNQsPTLTLQS 9606 BTO:0000801 14592977 t lperfetto Tab1, a subunit of the kinase tak1, was phosphorylated by sapk2a/p38alpha at ser423, thr431 and ser438 in vitro. the results presented here also show that sapk2a/p38? Suppresses the activity of tak1 in cells, because the activation of tak1 by proinflammatory cytokines and lps is enhanced if cells are first pre?incubated With sb 203580 or in cells that do not express sapk2a/p38?. SIGNOR-118922 0.817 P2RY4 protein P51582 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256727 0.358 NRBF2 protein Q96F24 UNIPROT Vps34 Complex I complex SIGNOR-C242 SIGNOR down-regulates activity binding 9606 BTO:0001938 phosphorylation:Ser113;Ser120 AEDAEGQsPLSQKYS;SPLSQKYsPSTEKCL 24785657 t miannu We have now identified NRBF2 (nuclear receptor-binding factor 2) as a new member of Vps34 Complex I. NRBF2 binds to complexes that include Vps34, Vps15, Beclin-1 and ATG-14L, but not the Vps34 Complex II component UVRAG (UV radiation resistance-associated gene). NRBF2 directly interacts with Vps15 via the Vps15 WD40 domain as well as other regions of Vps15. Thus NRBF2 plays a critical role in the induction of starvation-induced autophagy as a specific member of Vps34 Complex I. SIGNOR-265880 0.708 WNT3A protein P56704 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000568 16890161 t gcesareni Here, we present evidence that lrp6 is internalized with caveolin and that the components of this endocytic pathway are required not only for wnt-3a-induced internalization of lrp6 but also for accumulation of beta-catenin. SIGNOR-148671 0.782 CDK1 protein P06493 UNIPROT KMT5A protein Q9NQR1 UNIPROT up-regulates quantity by stabilization phosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 t miannu We found that PR-Set7 is phosphorylated at Ser 29 (S29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinB complex, primarily from prophase through early anaphase, subsequent to global accumulation of H4K20me1. While S29 phosphorylation did not affect PR-Set7 methyltransferase activity, this event resulted in the removal of PR-Set7 from mitotic chromosomes. S29 phosphorylation also functions to stabilize PR-Set7 by directly inhibiting its interaction with the anaphase-promoting complex (APC), an E3 ubiquitin ligase. SIGNOR-259832 0.2 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates chemical activation 10090 10448861 t lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. SIGNOR-235590 0.8 Obatoclax mesylate chemical CID:46930996 PUBCHEM BCL2 protein P10415 UNIPROT down-regulates activity chemical inhibition -1 23515850 t lperfetto Obatoclax and its predecessor analogs bind to BCL-2, BCL-XL, BCL-w, BCL-B, BFL-1, and MCL-1 in vitro SIGNOR-262022 0.8 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 9335504 t llicata In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1 SIGNOR-52687 0.591 IGF1R protein P08069 UNIPROT IRS4 protein O14654 UNIPROT up-regulates phosphorylation 9606 9553137 t gcesareni Insulin-like growth factor i acting through its receptor was as effective as insulin in eliciting tyrosine phosphorylation of irs-4. SIGNOR-56604 0.643 SRC protein P12931 UNIPROT FERMT2 protein Q96AC1 UNIPROT up-regulates activity phosphorylation Tyr193 SKTMTPTyDAHDGSP 9606 BTO:0000007 26037143 t miannu Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration. SIGNOR-266100 0.378 Goserelin chemical CHEBI:5523 ChEBI GNRHR protein P30968 UNIPROT up-regulates activity chemical activation 9606 BTO:0001033 22416801 t miannu The efficacy of degarelix compared with a GnRH agonist (goserelin, plus flare protection with bicalutamide) was evaluated in a 12‐week trial in men with lower urinary tract symptoms secondary to prostate cancer. SIGNOR-259161 0.8 MARK2 protein Q7KZI7 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 16980613 t lperfetto We further show that emk and c-tak1 phosphorylate class iia hdacs on one of their multiple 14-3-3 binding sites and alter their subcellular localization and repressive function SIGNOR-149583 0.35 MAPK3 protein P27361 UNIPROT IL16 protein Q14005 UNIPROT up-regulates phosphorylation Ser845 SIRQRISsFETFGSS 9606 14768064 t lperfetto The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 in antigen receptor-, sdf1alpha- and il-2-activated t cells. Genetic and pharmacological-inhibitor experiments showed that the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response. SIGNOR-121856 0.269 CEBPB protein P17676 UNIPROT ADM protein P35318 UNIPROT up-regulates quantity by expression transcriptional regulation 9480831 t These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells. SIGNOR-254047 0.247 VEGFC protein P49767 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252277 0.7 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252485 0.754 5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-) smallmolecule CHEBI:77657 ChEBI SAICAR(4-) smallmolecule CHEBI:58443 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). SIGNOR-268109 0.8 CELF4 protein Q9BZC1 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 23209433 f miannu CELF4 (CUGBP, ELAV-like family member 4) is one of six mammalian CELF proteins that function in mRNA metabolism. CELF4 is expressed predominantly in excitatory neurons, with highest expression in pyramidal neurons of the hippocampus and the cerebral cortex. we suggest that CELF4 deficiency leads to abnormal neuronal function by combining a specific effect on neuronal excitation with a general impairment of synaptic transmission. SIGNOR-264257 0.7 PRKDC protein P78527 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates phosphorylation Thr68 SSLETVStQELYSIP 9606 15668230 t gcesareni We have found that dna-pk is the major constituent of an activity present in extracts of mammalian cells that phosphorylates chk2. Our results suggest that hypophosphorylated chk2 can be phosphorylated at thr68 by dna-pk in vitro. SIGNOR-133384 0.608 SETD2 protein Q9BYW2 UNIPROT TUBA1B protein P68363 UNIPROT up-regulates activity methylation Lys40 DGQMPSDkTIGGGDD 9606 BTO:0000007 27518565 t Gianni The histone methyltransferase SET-domain-containing 2 (SETD2), which is responsible for H3 lysine 36 trimethylation (H3K36me3) of histones, also methylates α-tubulin at lysine 40, the same lysine that is marked by acetylation on microtubules. Methylation of microtubules occurs during mitosis and cytokinesis and can be ablated by SETD2 deletion, which causes mitotic spindle and cytokinesis defects, micronuclei, and polyploidy SIGNOR-269090 0.246 EPHA2 protein P29317 UNIPROT CLDN4 protein O14493 UNIPROT down-regulates activity phosphorylation Tyr208 RSAAASNyV 9534 16236711 t miannu EphA2 associates with claudin-4 via their extracellular domains. This association, in turn, leads to phosphorylation of the cytoplasmic carboxyl terminus of claudin-4 at Tyr-208. The tyrosine phosphorylation of claudin-4 attenuates association of claudin-4 with ZO-1, decreasing integration of claudin-4 into sites of cell-cell contact and enhancing paracellular permeability. These results indicate that EphA2 moderates the function of tight junctions via phosphorylation of claudin-4. SIGNOR-262859 0.49 CDK2 protein P24941 UNIPROT CDK7 protein P50613 UNIPROT unknown phosphorylation Ser164 GLAKSFGsPNRAYTH 9606 11113184 t amattioni Cdk2 phosphorylates serine-164 in the cdk7 t loop. SIGNOR-84832 0.553 NCS1 protein P62166 UNIPROT PI4KB protein Q9UBF8 UNIPROT up-regulates activity 10116 21104311 f miannu In chromaffin and PC12 cells, NCS-1 can enhance secretion via its activation of PI4 kinaseIIIb with the subsequent increase in PIP2 levels. PIP2 has been shown to be an important requirement for exocytosis SIGNOR-263963 0.669 CDK1 protein P06493 UNIPROT NEK9 protein Q8TD19 UNIPROT up-regulates activity phosphorylation Thr210 SEYSMAEtLVGTPYY 9606 BTO:0000567 21642957 t done miannu We now identify Plk1 as Nek9 direct activator and propose a two-step activation mechanism that involves Nek9 sequential phosphorylation by CDK1 and Plk1. while CDK1 activity is necessary for Nek9 phosphorylation in mitosis and the resulting change in electrophoretical mobility, Nek9 Thr210 phosphorylation and mitotic activation requires both CDK1 and Plk1. SIGNOR-273889 0.46 DAMPS stimulus SIGNOR-ST18 SIGNOR NLRP1 protein Q9C000 UNIPROT up-regulates activity 16037825 f lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-256421 0.7 Caspase 3 complex complex SIGNOR-C221 SIGNOR KDM4C protein Q9H3R0 UNIPROT down-regulates activity cleavage 9606 29207681 t miannu JMJD2C as a novel substrate for caspase-3 (cysteine-aspartic acid protease-3), and cleavage of JMJD2C by caspase-3 led to inactivation of JMJD2C demethylase activity and elevation of H3K9 methylation levels. SIGNOR-263871 0.2 G6PD protein P11413 UNIPROT 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI up-regulates quantity chemical modification 9606 24769394 t miannu G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress SIGNOR-267051 0.8 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Thr179 LGSKGQKtTQNRYSF -1 23444369 t miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. SIGNOR-273489 0.27 CWC27 protein Q6UX04 UNIPROT Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 11991638 f Purification and characterization of native pliceosomes suitable for three-dimensional structural analysis SIGNOR-261148 0.7 PDIA6 protein Q15084 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT down-regulates activity 10116 BTO:0003318 26487694 t Protein disulfide isomerase A6 (PDIA6) interacts with protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme (IRE)-1 and inhibits their unfolded protein response signaling. SIGNOR-256537 0.2 DLX5 protein P56178 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17335796 f gcesareni Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme. SIGNOR-153454 0.498 MAP1LC3B protein Q9GZQ8 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 20921139 f lperfetto We assessed both conversion of LC3-I to its cleaved and lipidated form LC3-II and its translocation to autophagic structures, two steps in autophagosome formation SIGNOR-219403 0.7 MAPK1 protein P28482 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation 9606 23616010 t lperfetto Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1. SIGNOR-201943 0.783 (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI orotate smallmolecule CHEBI:30839 ChEBI up-regulates quantity precursor of 9606 30449682 t miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway SIGNOR-267428 0.8 CDC25A protein P30304 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates activity dephosphorylation 9606 16682204 t miannu Cdc25A dephosphorylates and activates CyclinE\u2013Cdk2, CyclinA\u2013Cdk2 and CyclinB\u2013Cdk1, whereas Cdc25B and Cdc25C primarily target CyclinB\u2013Cdk1  [4,5] . SIGNOR-277137 0.849 PRKACA protein P17612 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser443 PQRKSQRsSYVSMRI -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). These data, indicate that S422 and/or S423 are the major sites of PKA-mediated phosphorylation of the 1 GABA receptor.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262751 0.29 SLC30A9 protein Q6PML9 UNIPROT NUMB protein P49757 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 11782429 t lperfetto Lnx functions as a ring type e3 ubiquitin ligase that targets the cell fate determinant numb for ubiquitin-dependent degradation. SIGNOR-113704 0.2 TACR1 protein P25103 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257374 0.477 PCDH15 protein Q96QU1 UNIPROT TIP-LINK complex complex SIGNOR-C291 SIGNOR form complex binding 10090 BTO:0000630 23217710 t lperfetto The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction. SIGNOR-262575 0.565 ELOVL2 protein Q9NXB9 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267897 0.8 PRKACA protein P17612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser311 SFRTPRDsKLEAPAE 9606 BTO:0000887 20151718 t miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-163764 0.278 MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 10090 17299140 t lperfetto Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK. SIGNOR-42402 0.484 HECW1 protein Q76N89 UNIPROT DVL1 protein O14640 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0001976 14684739 t miannu We have also found that NEDL1 targets Dishevelled-1 (Dvl1) for ubiquitination-mediated degradation and that mutant (but not wild-type) SOD1 affects the function of Dvl1.  SIGNOR-271499 0.626 PLK1 protein P53350 UNIPROT STAG2 protein Q8N3U4 UNIPROT down-regulates activity dephosphorylation Ser1224 PASIMDEsVLGVSMF 9606 BTO:0000567 15737063 t lperfetto Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase SIGNOR-275532 0.727 TTL protein Q8NG68 UNIPROT TUBA1B protein P68363 UNIPROT down-regulates tyrosination 9606 22020298 t miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization SIGNOR-176915 0.436 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD40 protein P25942 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19164127 f miannu We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40. SIGNOR-254785 0.555 PK proteinfamily SIGNOR-PF80 SIGNOR pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity chemical modification 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266540 0.8 ATM protein Q13315 UNIPROT MRE11 protein P49959 UNIPROT up-regulates phosphorylation Ser264 EQQLFYIsQPGSSVV 9606 10608806 t lperfetto In this report, we showed that atm phosphorylates a p95 peptide (ser-343) and a mre11 peptide (ser-264) in vitro, suggesting that atm may regulate the function of p95?Mre11? Rad50 repair complex in response to dna damage. SIGNOR-73366 0.2 MAPK3 protein P27361 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser43 RNPEAALsPTFRSDS 9606 BTO:0000007 33217317 t miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. SIGNOR-265949 0.275 NEK1 protein Q96PY6 UNIPROT ME1 protein P48163 UNIPROT down-regulates activity phosphorylation Ser336 KKIWLVDsKGLIVKG 31735643 t lperfetto PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation. SIGNOR-275570 0.2 ID1 protein P41134 UNIPROT TCF3 protein P15923 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C127 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241107 0.653 CCR4-NOT complex complex SIGNOR-C439 SIGNOR NANOS1 protein Q8WY41 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 t lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins SIGNOR-268346 0.355 HEY1 protein Q9Y5J3 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 19917614 f lperfetto Our results indicate instead that hey1 is recruited to the promoter regions of myogenin and mef2c, two genes whose induction is critical for myogenesis. SIGNOR-235819 0.312 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH4 protein P55283 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265844 0.8 PRKACA protein P17612 UNIPROT ASIC1 protein P78348 UNIPROT unknown phosphorylation Ser479 QKEAKRSsADKGVAL 9606 BTO:0000142 12578970 t llicata We found that protein kinase a phosphorylation of ser-479 in the asic1 c terminus interfered with pick1 binding. SIGNOR-98196 0.332 CSNK1D protein P48730 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates activity phosphorylation Ser159 GIPVRCYsAEVVTLW -1 10500146 t llicata We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro. SIGNOR-250798 0.536 glycine smallmolecule CHEBI:15428 ChEBI Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates quantity precursor of 9606 24898252 t miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. SIGNOR-270484 0.8 PTK2 protein Q05397 UNIPROT ACTN4 protein O43707 UNIPROT down-regulates phosphorylation Tyr4 yHAANQSY 9606 23454549 t lperfetto Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin SIGNOR-192199 0.54 AKT proteinfamily SIGNOR-PF24 SIGNOR CCNF protein P41002 UNIPROT up-regulates activity phosphorylation Thr31 RRRPRNLtILSLPED 9606 BTO:0001938 28954236 t miannu AKT phosphorylation of cyclin F enhances its stability and promotes assembly into productive E3 ligase complexes. SIGNOR-266360 0.2 NPC complex SIGNOR-C263 SIGNOR Nuclear_pore_function phenotype SIGNOR-PH130 SIGNOR up-regulates 9606 BTO:0000007 9660920 f miannu Exportin-t Is Predominantly Nuclear, Binds NPCs, and Shuttles Rapidly between Nucleus and Cytoplasm. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus . RanGTP causing a conformational change in exportin-t, which increases the affinity for export sites at the NPC. Exportin-t probably makes a direct contact to the NPC and accounts for the interactions that drive translocation of the tRNA/exportin-t/RanGTP complex out of the nucleus. SIGNOR-261395 0.7 PP2B proteinfamily SIGNOR-PF18 SIGNOR MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 f inferred from 70% family members gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-269993 0.2 FOS protein P01100 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19022561 t miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254879 0.353 RXRA protein P19793 UNIPROT NR1H2 protein P55055 UNIPROT up-regulates binding 9606 14993927 t lperfetto We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active. SIGNOR-123091 0.681 CDK8 protein P49336 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser128 QHVRAHSsPASLQLG -1 29967145 t miannu CDK8 phosphorylates YAP and promotes its activation. Of interest, mutating four amino acid positions (T119, S128, S289, and S367) to alanines (YAP-4A) completely blocked phosphorylation (Fig. 6J), suggesting that CDK8 phosphorylates these sites in YAP in vitro. SIGNOR-277649 0.327 CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR G0/G1_transition phenotype SIGNOR-PH219 SIGNOR up-regulates 12640120 f lperfetto Transition through this point requires cdk6/4-cyclin D, since inhibition with TAT-p16INK4A during the first 3 to 5 h prevents cell cycle entry and maintains both naive and memory T cells in G0. SIGNOR-273192 0.7 MRE11 protein P49959 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 21763684 t gcesareni One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase. SIGNOR-175006 0.2 SDHA protein P31040 UNIPROT SDH complex SIGNOR-C400 SIGNOR form complex binding 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. SIGNOR-266271 0.95 ELOVL4 protein Q9GZR5 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267899 0.8 NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys17 GLGKGGAkRHRKVLR 9606 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. by comparing the substrate specificities of the MSL and NSL complexes, we obtain evidence that MOF HAT activity is differentially regulated by assembly into the MSL complex, where it acetylates nucleosomal histone H4 on lysine 16, and the NSL complex, where it also acetylates nucleosomal histone H4 on lysines 5 and 8. SIGNOR-267166 0.2 PRKACA protein P17612 UNIPROT STK24 protein Q9Y6E0 UNIPROT unknown phosphorylation Thr18 ALNKRRAtLPHPGGS 9606 BTO:0000007 BTO:0000142;BTO:0000671 10644707 t llicata Further experiments demonstrated that mst3b, but not mst3, was effectively phosphorylated by activation of cyclic amp-dependent protein kinase (pka) in both in vivo and in vitro assays. The mutation of thr-18 into ala in mst3b (t18a), a putative pka phosphorylation site that is absent in mst3, abolished its phosphorylation by pka. SIGNOR-74284 0.218 TLN1 protein Q9Y490 UNIPROT AD/b2 integrin complex SIGNOR-C172 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257623 0.485 ARID1A protein O14497 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270689 0.8 STAT3 protein P40763 UNIPROT CD46 protein P15529 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17699108 f miannu The CD46 promoter contains two binding sites for activated STAT3 and mutations introduced into the major site abolished STAT3 binding. Chromatin immunoprecipitation confirms binding of STAT3 to the CD46 promoter. CD46 promoter activity is induced by activation of STAT3 and blocked by a dominant-negative form of STAT3 in luciferase reporter assays. SIGNOR-255238 0.271 MCM10 protein Q7L590 UNIPROT RECQL4 protein O94761 UNIPROT down-regulates binding 9606 19696745 t miannu Mcm10 inhibits recq4 helicase activity. SIGNOR-187701 0.523 RAB23 protein Q9ULC3 UNIPROT GLI3 protein P10071 UNIPROT down-regulates 9606 16364285 f gcesareni Based on su(fu) function, we predict that rab23 can interact with all gli1 molecules including gli1, gli2 and gli3, and inhibit their transcriptional activities and nuclear localization. SIGNOR-143160 0.561 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr37 EECDQNWyKAELNGK 9606 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246289 0.2 LPAR3 protein Q9UBY5 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257229 0.252 HTR6 protein P50406 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257186 0.255 TBK1 protein Q9UHD2 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 21329883 t lperfetto Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, tbk1 is recruited to the exocyst, where it activates akt. Akt is a direct tbk1 substrate that connects tbk1 to prosurvival signaling. SIGNOR-172132 0.417 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT down-regulates quantity by destabilization phosphorylation Ser37 KHSSYPDsEGAPDSL 9606 BTO:0000567 10618498 t llicata Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo SIGNOR-251042 0.312 asparagine smallmolecule CHEBI:22653 ChEBI Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity precursor of 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270460 0.8 TLK2 protein Q86UE8 UNIPROT ASF1A protein Q9Y294 UNIPROT up-regulates quantity by stabilization phosphorylation Ser192 GWSTSENsLNVMLES 9606 20016786 t Manara We found that only S192A in hASF1a and S198A in hASF1b significantly affected phosphorylation by hTLK2 | Consistent SIGNOR-260787 0.689 ROBO proteinfamily SIGNOR-PF14 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 15916964 t lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities SIGNOR-137639 0.2 ARHGAP40 protein Q5TG30 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260496 0.407 TCF12 protein Q99081 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR form complex binding 9606 16847330 t 2 miannu The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation. SIGNOR-241119 0.66 PRKDC protein P78527 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001949 18439899 t gcesareni DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform SIGNOR-252431 0.744 GRK2 protein P25098 UNIPROT PDE6G protein P18545 UNIPROT up-regulates activity phosphorylation Thr62 PGMEGLGtDITVICP 9606 BTO:0000007 11502744 t Rod PDEγ is predominantly phosphorylated by GRK2 at the Thr-62. GRK2 is required for the stimulatory effect of rod PDEγ on both the EGF- and thrombin-dependent activation of p42/p44 MAPK SIGNOR-251459 0.2 4,4'-sulfonyldiphenol chemical CHEBI:34372 ChEBI AHR protein P35869 UNIPROT up-regulates activity chemical activation -1 31995776 t miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity.In our study, BPs showed AhR agonist activity only at the highest concentrations, and the mixture did not differ from the single BPs. SIGNOR-268736 0.8 SCF-betaTRCP complex SIGNOR-C5 SIGNOR MTSS1 protein O43312 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 24318128 t miannu Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation.  SIGNOR-276610 0.324 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates activity phosphorylation Tyr206 PGPTRKHyQPYAPPR 8992971 t EMT can phosphorylate all four tyrosines of the CD28 tail. in vivo, tyrosines other than tyrosine 173 become phosphorylated following CD28 stimulation, this finding suggests that, like LCK, one function of EMT during CD28 signaling is phosphorylation of the receptor. SIGNOR-251334 0.677 PRKDC protein P78527 UNIPROT XRCC4 protein Q13426 UNIPROT up-regulates activity phosphorylation Ser328 LETLRNSsPEDLFDE 9606 BTO:0002137 26774286 t miannu In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair.  SIGNOR-277199 0.905 D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity precursor of 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267064 0.8 AR protein P10275 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 15861399 f miannu AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation SIGNOR-251538 0.7 TUBD1 protein Q9UJT1 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 28347630 f miannu Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation SIGNOR-267177 0.7 Mob1 proteinfamily SIGNOR-PF42 SIGNOR LATS1 protein O95835 UNIPROT up-regulates binding 9606 21084559 t Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. SIGNOR-269958 0.2 CSNK2A1 protein P68400 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Ser118 EVVGGDDsDGLRAED 9606 23226345 t lperfetto More recently, we identified and mapped multiple phosphorylation sites in yy1, including, threonine 39, serine 118, serine 247, threonine 348 and threonine 378. The first kinase proven to phosphorylate yy1 in vivo was plk1, which phosphorylates threonine 39 during g2/m stage of the cell cycle [25]. Ck2_ is another kinase identified as constitutively phosphorylating yy1 at serine 118. This modification protects yy1 cleavage by caspase 7 during apoptosis SIGNOR-200083 0.29 BMP4 protein P12644 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 8006002 t fspada Bmp-4 bound to alk-3 and alk-6 efficiently SIGNOR-35763 0.772 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 9315650 t llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase. SIGNOR-51288 0.47 IRS1 protein P35568 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 10090 BTO:0000944 11416002 t lperfetto To examine contributions of specific YXXM motifs in human insulin receptor substrate-1 (IRS-1) to mediating the metabolic actions of insulin, we studied IRS-1 mutants containing various substitutions of Phe for Tyr. In transfected NIH-3T3(IR) cells, insulin stimulation caused a 5-fold increase in phosphatidylinositol 3-kinase (PI3K) activity coimmunoprecipitated with wild-type IRS-1 SIGNOR-235487 0.712 E2F1 protein Q01094 UNIPROT PPARG protein P37231 UNIPROT up-regulates transcriptional regulation 9606 12110166 f During clonal expansion fspada We show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation SIGNOR-210047 0.472 IFNG protein P01579 UNIPROT IFNGR2 protein P38484 UNIPROT up-regulates binding 9606 7673114 t gcesareni Ifn-g Binds to the ifn-g Receptor binding subunit (ifn-gR1;receptor chain 1), a species-specific cell surface transmembrane receptor chain (41, 42). A second transmembrane protein (ifn-gR2) (43 45) is required for signal transduction SIGNOR-31013 0.634 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser23 ARKRHAPsPEPAVQG 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276084 0.282 CHFR protein Q96EP1 UNIPROT SMARCD1 protein Q96GM5 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 22285184 t miannu Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination. SIGNOR-271459 0.312 IRX1 protein P78414 UNIPROT INHBA protein P08476 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. SIGNOR-261666 0.2 SMARCA4 protein P51532 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18234970 f miannu An increased association of the chromatin remodeling factor, Brg-1, to the ABCG2 promoter was observed consistently in S1 and H460 cells where ABCG2 expression was activated by romidepsin treatment SIGNOR-255150 0.309 CALM2 protein P0DP24 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates binding 9606 11796223 t inferred from 70% of family members miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-269888 0.604 HNF4A protein P41235 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-142153 0.2 MUL1 protein Q969V5 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity sumoylation Lys608 LLAEEKSKPIPIMPA 9606 BTO:0000007 19638400 t Barakat Through detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms. SIGNOR-274130 0.549 1-phosphatidyl-1D-myo-inositol 3-phosphate(3-) smallmolecule CHEBI:58088 ChEBI 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI up-regulates quantity precursor of 9606 18429927 t miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns SIGNOR-269809 0.8 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser352 SSNNFSSsPSTPVGS 9606 19801649 t llicata Mlk2 inhibits e47 transactivation activity on the trkb promote SIGNOR-161527 0.2 CHUK protein O15111 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates activity phosphorylation Ser866 TAEVKEDsAYGSQSV 10090 BTO:0000785 15084608 t lperfetto Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52. SIGNOR-124226 0.784 LCK protein P06239 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr537 CKNVVPLyDLLLEML 9606 10571988 t gcesareni On the basis of these data and other reports describing the structure and activity of y537 mutations, as well as knowledge of the three-dimensional structure of the her ligand binding domain, we propose an alternate model wherein y537f mutation favors an open pocket conformation, affecting the estrogen binding kinetics and stability of the hormone-bound, transcriptionally active closed pocket conformation. SIGNOR-72373 0.391 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr534 SRTPSLPtPPTREPK 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251595 0.695 PAC-1 chemical CID:6851947 PUBCHEM CASP3 protein P42574 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-198535 0.8 S1PR3 protein Q99500 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 10488065 t gcesareni Edg-3 and edg-5 couple not only to gibut also to gqand g13 SIGNOR-70713 0.472 SNRPF protein P62306 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270682 0.918 SIRT1 protein Q96EB6 UNIPROT nicotinamide smallmolecule CHEBI:17154 ChEBI up-regulates quantity chemical modification 9606 18662546 t miannu The SIRT1 catalytic reaction involves the breakdown of one NAD+ molecule for each deacetylated acetyl lysine and the generation of nicotinamide and O-acetyl-ADP-ribose. SIGNOR-267964 0.8 TAF1B protein Q53T94 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR form complex binding 9606 30693017 t lperfetto SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation. SIGNOR-269565 0.838 DIABLO protein Q9NR28 UNIPROT BIRC2 protein Q13490 UNIPROT down-regulates quantity binding -1 10929711 t amattioni Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, IAPs, and removing their inhibitory activity. Smac is normally a mitochondrial protein but is released into the cytosol when cells undergo apoptosis. SIGNOR-80206 0.891 IRAK4 protein Q9NWZ3 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Thr356 PLEEERQtQRSKPQP 9606 BTO:0000130 17217339 t lperfetto Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.We found that thr133, ser288 and thr356, targets for irak-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after lps stimulation. We conclude that irak-4 phosphorylates p47phox and regulates nadph oxidase activation after lps stimulation. SIGNOR-152027 0.389 AR protein P10275 UNIPROT CRH protein P06850 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000931 16446741 t lperfetto A direct androgenic involvement in the expression of human corticotropin-releasing hormone|A potential androgen-responsive element (ARE) in the human CRH promoter was subsequently analyzed with bandshifts and cotransfections in neuroblastoma cells. In the presence of testosterone, recombinant human AR bound specifically to the CRH-ARE. SIGNOR-268723 0.31 MECP2 protein P51608 UNIPROT Neuron_maturation phenotype SIGNOR-PH169 SIGNOR up-regulates 10090 BTO:0000601 17532643 f Luana Our studies suggest that MeCP2 plays a central role in neuronal maturation, which might be mediated through epigenetic control of expression pathways that are instrumental in both dendritic development and synaptogenesis. SIGNOR-264968 0.7 PTPN6 protein P29350 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 18377662 t Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175 SIGNOR-248475 0.654 SRC protein P12931 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 8939605 t lperfetto Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway. SIGNOR-44866 0.652 SOX6 protein P35712 UNIPROT MEST protein Q5EB52 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003298 26893351 f We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST. SIGNOR-255823 0.2 GSK3B protein P49841 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser133 LPYSPVSsPQSSPRL 9606 22778263 t lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. SIGNOR-198138 0.276 GABRA4 protein P48169 UNIPROT GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263748 0.508 VRK2 protein Q86Y07 UNIPROT TRiC complex SIGNOR-C539 SIGNOR down-regulates quantity by destabilization binding 9606 BTO:0000007 24298020 t miannu Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not.The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.COP1 functions as an E3 ligase by forming a supercomplex that also includes heterodimeric substrate receptor DET1, adaptor DDB1, scaffold Cul4A, and RBX1 to recruit the E2 enzyme.The results suggest that VRK2 enables the COP1 complex to efficiently attach ubiquitin on the CCT4 by providing a close interaction between CCT4 and the COP1 complex. SIGNOR-272875 0.305 PINK1 protein Q9BXM7 UNIPROT UBC protein P0CG48 UNIPROT up-regulates activity phosphorylation Ser65 DYNIQKEsTLHLVLR 9606 BTO:0000938 24784582 t lperfetto Ubiquitin is phosphorylated by PINK1 to activate parkin|PINK1 phosphorylated ubiquitin at Ser65 both in vitro and in cells SIGNOR-249691 0.587 4-(2,4,5-tripyridin-4-yl-3-thiophenyl)pyridine smallmolecule CHEBI:94284 ChEBI GLI1 protein P08151 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150;BTO:0000551 19860666 t gcesareni Gant58 is a gli antagonist that inhibits gli1-induced transcription SIGNOR-188863 0.8 RAC1 protein P63000 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity binding 10090 BTO:0000142 8107774 t gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. SIGNOR-248236 0.782 CDK1 protein P06493 UNIPROT ZC3HC1 protein Q86WB0 UNIPROT down-regulates phosphorylation Ser395 PGLEVPSsPLRKAKR 9606 SIGNOR-C17 17389604 t gcesareni Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1 SIGNOR-154047 0.255 MATK protein P42679 UNIPROT LYN protein P07948 UNIPROT down-regulates activity phosphorylation Tyr508 YTATEGQyQQQP -1 9171348 t miannu In vitro phosphorylation assays showed that Chk suppressed Lyn activity by phosphorylating its C-terminal negative regulatory tyrosine. SIGNOR-250177 0.339 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248744 0.727 AMPK complex SIGNOR-C15 SIGNOR HIPK2 protein Q9H2X6 UNIPROT down-regulates activity phosphorylation Ser121 LMRRSTVsLLDTYQK 23871434 t Phosphosite positions are derived from Figure S5 lperfetto AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro SIGNOR-275483 0.251 PABPC4 protein Q13310 UNIPROT NFX1 protein Q12986 UNIPROT up-regulates activity binding 9606 BTO:0000008 17267499 t Simone We identifiednew protein partners of NFX1-123, including several cytoplasmic poly(A) binding proteins (PABPCs) thatinteracted with NFX1-123 through its N-terminal PAM2 motif. Central to our findings were our observations that PABPCs copurify with NFX1-123, that a PAM2 motif is present in NFX1, and this motif and the PABPCs are important in the enhancement of hTERT activity by NFX1-123. SIGNOR-261051 0.248 CDK9 protein P50750 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Thr217 PSEYQNMtVDILCND 9606 23603988 t lperfetto We showed that cdk9 phosphorylates pirh2 on ser-211 and thr-217 residues through their physical interaction. Phosphorylation of pirh2 renders it inactive and may contribute to p53-inhibition of transcriptional elongation of the hiv-1 ltr. SIGNOR-201927 0.472 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr539 RGLDKVItVLTRSKR 9606 16216881 t lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. SIGNOR-141034 0.2 MAPK1 protein P28482 UNIPROT NUP50 protein Q9UKX7 UNIPROT down-regulates activity phosphorylation Ser315 TQSKPVSsPFPTKPL 9606 19767751 t llicata Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. SIGNOR-188135 0.2 MAP4K4 protein O95819 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity phosphorylation Thr322 SNVNRNStIENTRRH 9606 BTO:0002181 21690388 t miannu Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.  SIGNOR-276335 0.2 KDM6A protein O15550 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity demethylation 9606 24561908 t This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions. miannu Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation. SIGNOR-265360 0.2 histidine smallmolecule CHEBI:27570 ChEBI His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates quantity precursor of 9606 10430027 t miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. SIGNOR-270492 0.8 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 27418133 f The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-?-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-? skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-?/SNAIL signaling restores the production of pro-inflammatory cytokines SIGNOR-253588 0.7 CDK1 protein P06493 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates activity phosphorylation 9606 12202491 t lperfetto Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity. SIGNOR-264648 0.557 SP1 protein P08047 UNIPROT FMR1 protein Q06787 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15479157 f miannu we show that Sp1 (specificity protein 1) and Sp3 are also strong positive regulators of FMR1 promoter activity. SIGNOR-255204 0.2 CDK5 protein Q00535 UNIPROT LMTK2 protein Q8IWU2 UNIPROT down-regulates phosphorylation 9606 12832520 t gcesareni Cprk displays catalytic activity in in vitro kinase assays and is itself phosphorylated by cdk5/p35. Cdk5/p35 inhibits cprk activity. SIGNOR-102652 0.511 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000742 15568017 t gcesareni We demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for Wnt-directed myogenic gene expression. SIGNOR-255799 0.564 CREB5 protein Q02930 UNIPROT MX1 protein P20591 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002807 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253800 0.2 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-118031 0.706 glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Triosephosphate isomerase (TPI) is the glycolytic enzyme with the highest activity in vitro. TPI catalyzes the interconversion of glyceraldehyde-3-phosphate and DHAP (Figure 1). It consists of a dimer with 2 identical subunits of 248 amino acids (27 kDa). SIGNOR-268136 0.8 IRX1 protein P78414 UNIPROT SPON1 protein Q9HCB6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. SIGNOR-261669 0.2 EIF5B protein O60841 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR down-regulates activity binding 9606 30211544 t lperfetto eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC. SIGNOR-269120 0.662 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser10 LNRTLSMsSLPGLED -1 2117608 t llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. | From analysis of 32P release during Edman degradation, no radioactively labeled phosphate was associated with Thr3 or Ser7, but could be accounted for by phosphorylation at Ser10 SIGNOR-250878 0.335 panobinostat chemical CHEBI:85990 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257755 0.8 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser100 DEDSGKGsQPPSPPS 9606 15448698 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-129398 0.574 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SIRT3 protein Q9NTG7 UNIPROT up-regulates activity phosphorylation Ser159 SGIPDFRsPGSGLYS 9606 BTO:0001109 26141949 t miannu  Posttranscriptionally, SIRT3 enzymatic activity is further enhanced via Thr150/Ser159 phosphorylation by cyclin B1-CDK1, which is also induced by radiation and relocated to mitochondria together with SIRT3.  SIGNOR-276921 0.294 INPP4B protein O15327 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation 9606 24070612 t miannu Further, we show that INPP4B but not PTEN is able to reduce tyrosine phosphorylation of Akt1 and both the lipid and PTP activity of INPP4B likely contribute to the reduction of Akt1 phosphorylation.|Further, we show that INPP4B but not PTEN is able to reduce tyrosine phosphorylation of Akt1 and both the lipid and protein tyrosine phosphatase activity of INPP4B likely contribute to the reduction of Akt1 phosphorylation. SIGNOR-277106 0.382 RPL13 protein P26373 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262486 0.785 SMO protein Q99835 UNIPROT MAL protein P21145 UNIPROT up-regulates quantity transcriptional regulation 10090 35082605 f Non-canonical pathway (Gli1-indipendent): SMO/AMPK SimoneGraziosi We show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMPactivated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell. SIGNOR-269224 0.2 GABRB2 protein P47870 UNIPROT GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263769 0.464 RBM10 protein P98175 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0001938 30403180 f irozzo Osteosarcoma is the most common malignant bone tumor with high incidence in adolescence and poor prognosis. RBM10, a member of RBPs, was reported to be a tumor suppressor in many kinds of cancers. The results showed that U2OS cell growth was significantly inhibited when RBM10 is overexpressed as compared with negative control cells. SIGNOR-259149 0.7 VEZF1 protein Q14119 UNIPROT CITED2 protein Q99967 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001086 29794136 t miannu The transcription factor Vezf1 represses the expression of the antiangiogenic factor Cited2 in endothelial cells SIGNOR-266883 0.2 NFYA protein P23511 UNIPROT CBS protein P35520 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12427542 f miannu Our results further confirm the important transactivating role for NF-Y for the CBS-1b promoter, via its synergism with Sp1. While differential phosphorylation of Sp1 likely contributes to binding to multiple GC-/GT-boxes in the CBS-1b and promoter activation [16], NF-Y is clearly necessary for a maximal activation response. SIGNOR-254815 0.2 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269372 0.719 MICU1 protein Q9BPX6 UNIPROT MCU_MICU2_variant complex SIGNOR-C502 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270876 0.678 ATF6 protein P18850 UNIPROT NUCB1 protein Q02818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17686766 f miannu we identified nucleobindin 1 (NUCB1) as a novel repressor of the S1P-mediated ATF6 activation. NUCB1 is an ER stress-inducible gene with the promoter region having functional cis-elements for transcriptional activation by ATF6. SIGNOR-253753 0.36 IL1A protein P01583 UNIPROT SERPINA3 protein P01011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002600 11027208 f miannu We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. SIGNOR-254807 0.2 CRK protein P46108 UNIPROT RAPGEF1 protein Q13905 UNIPROT up-regulates binding 9606 7806500 t gcesareni The endogenous c3g could be coprecipitated with crk from cell lysates of cells expressing high levels of c-crk or v-crk, suggesting high binding affinity and a possible interaction in vivo. SIGNOR-33732 0.898 ponatinib chemical CHEBI:78543 ChEBI FGFR3 protein P22607 UNIPROT down-regulates activity chemical inhibition 9606 23468082 t miannu Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family. SIGNOR-259279 0.8 PRSS3 protein P35030 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity cleavage Lys34 QGTNRSSkGRSLIGK -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263607 0.373 RAB32 protein Q13637 UNIPROT Neuronal AP-3 complex SIGNOR-C445 SIGNOR up-regulates activity relocalization 9606 23247405 t miannu Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. SIGNOR-268524 0.276 carfilzomib chemical CHEBI:65347 ChEBI PSMB9 protein P28065 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 17591945 t miannu Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM. SIGNOR-259311 0.8 CSNK2A1 protein P68400 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Ser112 KRAGGEEsQFEMDI 9606 12588975 t gcesareni Phosphorylation at s112 directly affects binding of 4e-bp1 to eif4e without influencing phosphorylation of other sites. SIGNOR-98280 0.347 ATP smallmolecule CHEBI:15422 ChEBI 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity precursor of 9606 11376933 t miannu To date, ten different mammalian isoforms of adenylyl cyclase (AC) have been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for different cells to respond diversely to similar stimuli. The product of the enzymatic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a crucial role for a variety of fundamental physiological cell functions ranging from cell growth and differentiation, to transcriptional regulation and apoptosis. SIGNOR-267842 0.8 CLOCK/BMAL2 complex SIGNOR-C196 SIGNOR SERPINE1 protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001615 22198637 t lperfetto Both CLOCK:ARNTL and CLOCK:ARNTL2 heterodimers powerfully activate the promoter of the PAI-1 gene, officially called SERPINE1 and located on the seventh chromosome (7q21.3-q22), underlying the circadian variation in circulating PAI-1 SIGNOR-253713 0.497 PRKCD protein Q05655 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249287 0.354 ELAVL2 protein Q12926 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates quantity post transcriptional regulation 9606 19221430 t miannu Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure SIGNOR-266863 0.2 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 20802513 t gcesareni In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain (band 4.1 and ezrin/radixin/moesin homology domain). SIGNOR-167654 0.476 YARS1 protein P54577 UNIPROT tyrosine smallmolecule CHEBI:18186 ChEBI down-regulates quantity chemical modification 9606 16429158 t miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr SIGNOR-270518 0.8 ROCK1 protein Q13464 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Ser229 VKIYSSNsGPTRRED 9606 BTO:0000672 15793569 t llicata In addition, active rhoa is able to stimulate the phospholipid phosphatase activity of pten in human embryonic kidney cells and leukocytes, and this regulation seems to require rhoa's downstream effector, rhoa-associated kinase (rock). together with the observation that individual substitution of ser 229 and thr 223 restored some of the rescuing ability (fig. 4b), we conclude that effective regulation of pten by sdf-1 may require more than one of these residues. SIGNOR-134851 0.642 RBBP8 protein Q99708 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001130 22832221 f gcesareni Brca1/e2f1/ctipbinding to atm promoter activates atm transcription. SIGNOR-198473 0.822 PRKACA protein P17612 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser38 LGPGTRLsLARMPPP -1 2155236 t miannu GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments. SIGNOR-249713 0.286 LY2784544 chemical CID:46213929 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193796 0.8 SMAD4 protein Q13485 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity 9606 BTO:0000599 10890911 f lperfetto Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity SIGNOR-229311 0.677 phenobarbital chemical CHEBI:8069 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0000318 9727070 t miannu The antihypercholesterolemic drug lovastatin also activated hPXR as did phenobarbital and the organochlorine pesticide transnonachlor (Fig. 4 A). Thus, hPXR is activated by a remarkably diverse group of synthetic compounds that are known to induce CYP3A4 gene expression (Fig. 4 C). SIGNOR-258830 0.8 AURKB protein Q96GD4 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. SIGNOR-98297 0.2 MDM2 protein Q00987 UNIPROT EP300 protein Q09472 UNIPROT down-regulates binding 9606 BTO:0000567 11070080 t gcesareni Mdm2, a negative-feedback regulator of p53, inhibited p300-mediated p53 acetylation by complexing with these two proteins. SIGNOR-84077 0.675 PIK3C3 protein Q8NEB9 UNIPROT Vps34 Complex II complex SIGNOR-C241 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260320 0.891 FGF13 protein Q92913 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253443 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 10464286 t gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-265345 0.2 Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR BMI1 protein P35226 UNIPROT up-regulates activity phosphorylation Ser316 ANRPRKSsVNGSSAT 22505453 t lperfetto The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate SIGNOR-249584 0.7 SRC protein P12931 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates 9606 BTO:0000142 11782488 f gcesareni C-src was suggested to be involved in bmk1 activation from the experiments with herbimycin a and pp2, specific inhibitors of src family kinases. SIGNOR-113779 0.351 CSNK2A1 protein P68400 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Thr142 DSVTKLLtDVQLMKG -1 12659875 t llicata Transcriptional activity and DNA binding of heat shock factor-1 involve phosphorylation on threonine 142 by CK2. SIGNOR-250898 0.378 PAK2 protein Q13177 UNIPROT SORT1 protein Q99523 UNIPROT down-regulates activity phosphorylation Ser793 RFLVHRYsVLQQHAE 9606 BTO:0000007 31767632 t miannu PAKs specifically phosphorylate Ser15 of the sortilin-cd and alter its trafficking. It can be concluded that PAK1-3 may indeed instigate the phosphorylation of sortilin and that they target a single serine residue (Ser15) located in the kinase domain-binding site of the sortilin-cd. Full-length sortilins with the serine at position 793 (residue 15 in the cytoplasmic domain) (for the sequence, see Fig. 2). Phosphorylation (Ser15) downregulates the sortilin–AP-1 interaction. SIGNOR-273717 0.2 PLAGL2 protein Q9UPG8 UNIPROT SFTPC protein P11686 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000353 17618602 f miannu nuclear PLAGL2 occupied and transactivated the endogenous SP-C promoter in lung cells. SIGNOR-254927 0.303 MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Ser183 PTQQYAKsLPVSVPV -1 SIGNOR-C3 SIGNOR-C3 18372248 t lperfetto Pras40 functions as a negative regulator when bound to mtorc1, and it dissociates from mtorc1 in response to insulin. Pras40 has been demonstrated to be a substrate of mtorc1, and one phosphorylation site, ser-183, has been identified. SIGNOR-178120 0.901 PIM proteinfamily SIGNOR-PF34 SIGNOR MAP3K5 protein Q99683 UNIPROT down-regulates phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0002552 19749799 t lperfetto Pim1 phosphorylates and negatively regulates ask1-mediated apoptosispim1 phosphorylation of ask1 on ser83 inhibited ask1-mediated c-jun n-terminal kinase phosphorylation SIGNOR-259410 0.2 CAMK2A protein Q9UQM7 UNIPROT HOMER3 protein Q9NSC5 UNIPROT down-regulates activity phosphorylation Ser159 EKLFRSQsADAPGPT -1 18480293 t miannu Homer3 is phosphorylated at Ser120, Ser159, and Ser176 by CaMKII in vitro. Homer3 phosphorylation reduces its affinity for target molecules and modulates the Ca2+ signaling patterns induced by mGluR1α activation SIGNOR-262685 0.2 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates phosphorylation Ser746 RRSVRIGsYIERDVT 9606 7539802 t miannu Phosphorylation of kit/scfr by pkc-_ in vitro: identification of ser-741 and ser-746 as the major phosphorylation sites for pkc / pkc, which acts in an scf-stimulated feedback loop, that negatively controls kit/scfr kinase activity SIGNOR-28605 0.511 SOX2 protein P48431 UNIPROT ABCC3 protein O15438 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21531766 f miannu ID4-mediated SOX2 induction enhanced ABCC3 and ABCC6 expression through direct transcriptional regulation, indicating that ID4 regulates the chemoresistance of iGSCs by promoting SOX2-mediated induction of ABC transporters. SIGNOR-255181 0.298 AKT2 protein P31751 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 17287208 t lperfetto Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activitywe have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo. SIGNOR-152958 0.552 S1PR2 protein O95136 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257289 0.358 FGR protein P09769 UNIPROT ACO2 protein Q99798 UNIPROT unknown phosphorylation Tyr665 VVIGDENyGEGSSRE -1 17997986 t miannu Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are "in vitro" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations. SIGNOR-262870 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser703 MSRARIGsDPLAYEP 9606 10400637 t gcesareni The results indicate that p90rsk phosphorylates serine 703 of nhe-1, and this phosphorylation is required for growth factor stimulation of na+/h+ exchange. SIGNOR-252792 0.2 ACE protein P12821 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage 9606 11076943 t gcesareni Angiotensin I-converting enzyme is a zinc metallopeptidase that plays an important role in blood pressure regulation by cleaving the inactive decapeptide angiotensin I to angiotensin II, a potent vasopressor octapeptide. SIGNOR-253326 0.774 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser159 KKKKKRFsFKKSFKL -1 1560845 t gcesareni Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin SIGNOR-243192 0.719 CIB2 protein O75838 UNIPROT a7/b1 integrin complex SIGNOR-C126 SIGNOR up-regulates activity binding 9606 35408910 t miannu So far, two integrins have been found to interact with CIB2: αIIbβ3 is expressed by platelets and megakaryocytes and, apparently, a common target for all CIB family members, at odds with α7Bβ1D, which seems to be CIB2-specific and is expressed in skeletal muscles. SIGNOR-269668 0.2 NDUFA10 protein O95299 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. SIGNOR-262151 0.819 IRF2BP1 protein Q8IU81 UNIPROT IRF2 protein P14316 UNIPROT up-regulates activity binding 9606 BTO:0000567 12799427 t miannu We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation. SIGNOR-224045 0.714 KAT2B protein Q92831 UNIPROT H3Y2 protein P0DPK5 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkATAWQAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269615 0.2 POU2F1 protein P14859 UNIPROT HOXD10 protein P28358 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25301728 f miannu Knockdown of pou2f1 significantly reduced expression of hoxd10 and d11 SIGNOR-205540 0.2 NHEJ1 protein Q9H9Q4 UNIPROT Lig4-Xrcc4 complex complex SIGNOR-C354 SIGNOR up-regulates activity binding 9606 BTO:0000567 25661488 t miannu Here we report that Akt phosphorylates XLF (XRCC4 like factor, also called NHEJ1) at T181, to dissociate XLF from the XRCC4 (X-ray repair cross-complementing protein 4)/DNA ligase IV (LIG4) complex and subsequently triggers XLF cytoplasmic translocation, leading to XLF ubiquitination by SCFβ-TRCP in a CKI-dependent manner. SIGNOR-276883 0.826 PTPRT protein O14522 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation 9606 17360477 t miannu Here, we report identification of signal transducer and activator of transcription 3 (STAT3) as a substrate of PTPRT. Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position. Accordingly, overexpression of normal PTPRT in colorectal cancer cells reduced the expression of STAT3 target genes.|Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position. SIGNOR-277043 0.53 ANXA3 protein P12429 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity 9606 26095609 f miannu ANXA3 Induces a Feed-Forward Loop that Is Mediated by the MKK4/JNK Signaling Cascade. To substantiate the importance of the JNK/AP-1 pathway in ANXA3-driven HCC, we performed rescue experiments using the JNK-specific inhibitor (JNKi) SP600125. JNKi suppressed the oncogenic properties conferred by ANXA3 overexpression, as evidenced by the diminished abilities of HCC cells to form colonies, migrate, invade, induce angiogenesis, form hepatospheres, and resist apoptosis and chemotherapy (Figures 6F–6J). Interestingly, treatment of parental HCC cells or HCC cells overexpressing ANXA3 with JNKi resulted in not only a reduction in JNK activity and modulation of downstream target genes (c-MYC and p21) but also a marked decrease in ANXA3 expression, suggesting that ANXA3 induces a feed-forward loop that is mediated by MKK4/JNK signaling (Figures 6K–6L). SIGNOR-262214 0.281 PRRX1 protein P54821 UNIPROT MAFF protein Q9ULX9 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221890 0.36 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR BAD protein Q92934 UNIPROT down-regulates binding 9606 10949026 t gcesareni 14-3-3 blocks bad activity by promoting ser-155 phosphorylation, which induces the dissociation of bad and bcl-xl. in the presence of survival factor il-3, cells phosphorylated bad on two serine residues embedded in 14-3-3 consensus binding sites. Only the nonphosphorylated bad heterodimerized with bcl-x(l) at membrane sites to promote cell death. SIGNOR-81106 0.2 RIPK1 protein Q13546 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT up-regulates activity phosphorylation Ser728 PSPARSSsYSEANEP 9606 27858941 t miannu Upon TNF stimulation, RIP1 phosphorylates DAB2IP on Serine 604, inducing a conformational switch that allows formation of the complex. SIGNOR-254763 0.436 CDH11 protein P55287 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR up-regulates activity binding 9606 10029089 t miannu Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin SIGNOR-265825 0.498 FCER1 complex SIGNOR-C200 SIGNOR SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates 9606 BTO:0000830 16470226 f Alessandro Palma It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits SIGNOR-254955 0.593 arginine smallmolecule CHEBI:29016 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 27126896 f Luana  Importantly, asparagine/glutamine pre-load only results in mTOR activation following amino acid stimulation (Fig. 5a), indicating that it is their exchange factor roles that elicit mTORC1 activation. SIGNOR-268013 0.8 TNFRSF10D protein Q9UBN6 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates binding 9606 9382840 t amattioni One function of trail-r4 may be inhibition of trail cytotoxicy. Dcr2 functions as an inhibitory apo2l receptor. SIGNOR-53447 0.717 Oxotremorine chemical CHEBI:7851 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258650 0.8 PRKCQ protein Q04759 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249290 0.295 sorafenib tosylate chemical CHEBI:50928 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu This effort culminated in the identification of the clinical candidate BAY 43-9006 (Sorafenib, Nexavar), which has recently been approved by the FDA for advanced renal cell carcinoma in phase III clinical trials. Sorafenib inhibited the kinase activity of both C-RAF and B-RAF (wild type and V600E mutant). SIGNOR-259220 0.8 CDK1 protein P06493 UNIPROT EEF2K protein O00418 UNIPROT down-regulates phosphorylation Ser359 GTEEKCGsPQVRTLS 9606 18337751 t gcesareni Phosphorylation at ser359 inhibits eef2k activity even at high calcium concentrations. we demonstrate that cdc2 contributes to controlling eef2 phosphorylation in cells. inactivation of eef2k by cdc2 may serve to keep eef2 active during mitosis SIGNOR-177982 0.375 ECM stimulus SIGNOR-ST20 SIGNOR Av/b5 integrin complex SIGNOR-C178 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259038 0.7 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser660 FSAERRNsILTETLH 9606 10581361 t lperfetto Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function SIGNOR-72712 0.52 MFNG protein O00587 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 10935626 t Fucosylation gcesareni Manic fringe elongates the o-linked fucose saccharides on full-length notch1 and notch1 egf repeats 1923. SIGNOR-80555 0.709 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2G1 protein P62253 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271315 0.753 JAK1 protein P23458 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates activity phosphorylation Tyr585 NDIKNSGyISRYLTD 10090 BTO:0000099 25113558 t miannu JAK1 interacts with and phosphorylates PERK. PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum stress-induced inflammation. Similarly, PERK is associated with and phosphorylated by JAK1 at Y585 and Y619 (and possibly other JAKs) during ER stress, resulting in PERK- and JAK1-dependent activation of STAT3. SIGNOR-276676 0.2 GTF2F2 protein P13984 UNIPROT POLR2E protein P19388 UNIPROT up-regulates activity binding 9534 11278533 t miannu Direct Interaction Between the Subunit RAP30 of Transcription Factor IIF (TFIIF) and RNA Polymerase Subunit 5, Which Contributes to the Association Between TFIIF and RNA Polymerase II. we showed that RPB5 binds RAP30 but not RAP74 and associates to TFIIF through the binding to RAP30. SIGNOR-261179 0.919 TAF6L protein Q9Y6J9 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269587 0.711 ACP1 protein P24666 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity dephosphorylation 9606 12815062 t miannu Lymphocyte function-associated antigen-1-mediated T cell adhesion is impaired by low molecular weight phosphotyrosine phosphatase-dependent inhibition of FAK activity.  4000254={CellProcess=4107155 CellType=10000184}}|Moreover, in these conditions LMW-PTP causes FAK dephosphorylation, thus preventing the activation of FAK downstream pathways. SIGNOR-277064 0.28 GSDMD protein P57764 UNIPROT Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates cleavage:Asp275 CLHNFLTdGVPAEGA 26375003 f lperfetto These results establish that proteolytic cleavage at Asp275 in GSDMDis sufficient to instructmammalian cells to undergo pyroptosis SIGNOR-256416 0.7 GATA4 protein P43694 UNIPROT CTNNA3 protein Q9UI47 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002320 21598020 t miannu GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter SIGNOR-265490 0.253 PTPRJ protein Q12913 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by stabilization dephosphorylation Tyr1197 STAENAEyLRVAPQS 9606 BTO:0000567 19836242 t We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex|By employing commercially available antibodies, which are supposed to recognize specific tyrosine phosphorylation sites of EGFR, we found that depletion of endogenous DEP-1 nonselectively increased receptor phosphorylation, affecting all three sites we analyzed (tyrosines 1045, 1068, and 1173 SIGNOR-248699 0.504 CSNK2A1 protein P68400 UNIPROT PACS1 protein Q6VY07 UNIPROT up-regulates activity phosphorylation Ser278 SPDIDNYsEEEEESF 10090 BTO:0003532 14633983 t llicata Phosphorylation of Ser278 by CK2 or a Ser278-->Asp mutation increased the interaction between PACS-1 and cargo, whereas a Ser278-->Ala substitution decreased this interaction. Moreover, the Ser278-->Ala mutation yields a dominant-negative PACS-1 molecule that selectively blocks retrieval of PACS-1-regulated cargo molecules to the TGN. SIGNOR-250925 0.561 SGK1 protein O00141 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser1130 GARDRVRsMSGGHGL -1 27451907 t miannu SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2.  SIGNOR-277266 0.596 CKM complex complex SIGNOR-C406 SIGNOR NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 15546612 t gcesareni Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. SIGNOR-273153 0.378 FASN protein P49327 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization 9606 BTO:0001130 18838960 f lperfetto Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer SIGNOR-242878 0.271 POU5F1 protein Q01860 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22795133 t lperfetto Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation SIGNOR-253158 0.448 MYBBP1A protein Q9BQG0 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 t miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription SIGNOR-268821 0.468 MTMR3 protein Q13615 UNIPROT 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI up-regulates quantity chemical modification 9606 18429927 t miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns SIGNOR-269811 0.8 MDM2 protein Q00987 UNIPROT POLQ protein O75417 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001890 22056306 t miannu DNA polymerase eta is targeted by Mdm2 for polyubiquitination and proteasomal degradation in response to ultraviolet irradiation SIGNOR-272729 0.2 CAMK2D protein Q13557 UNIPROT ANKRD28 protein O15084 UNIPROT down-regulates activity phosphorylation Ser1011 TNTSKTVsFEALPIM -1 17023142 t lperfetto We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K SIGNOR-264793 0.2 SCAF11 protein Q99590 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261758 0.298 JNK proteinfamily SIGNOR-PF15 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Thr41 GIHSGATtTAPSLSG 9606 19667122 t lperfetto Specifically, we provide evidence that jnk binds to e-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by gsk-3beta. SIGNOR-187582 0.2 CDK2 protein P24941 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C16 21902831 t gcesareni Cycline/cdk2 blocks myod-induced gene expression through the phosphorylation of rb, preventing rb from binding and transactivating myod, and triggering s phase entry instead of differentiation. SIGNOR-176512 0.88 LYN protein P07948 UNIPROT PDIA3 protein P30101 UNIPROT unknown phosphorylation Tyr445 ANDVPSPyEVRGFPT -1 8631326 t miannu Lyn phosphorylates tyrosine residues Y444, Y453 and Y466 which are located in a highly acidic region of the protein at the C-terminus. Upon phosphorylation, p57 forms a complex with Lyn which can be immunoprecipitated with anti-Lyn IgG. The association which occurs between the phosphorylated substrate and the SH2 domain of the kinase is consistent with the suggested 'processive phosphorylation' model, which implies that a primary phosphorylation site of the substrate binds to the SH2 domain of the enzyme and triggers the phosphorylation at secondary site(s). SIGNOR-262894 0.2 MITF protein O75030 UNIPROT TYRP1 protein P17643 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000847 22371403 f miannu MITF transcription factor regulates melanogenesis by activation of tyrosinase, TRP1 and TRP2 transcription. SIGNOR-254591 0.5 GZMA protein P12544 UNIPROT SET protein Q01105 UNIPROT down-regulates cleavage 9606 11555662 t miannu Gzma cleaved the nucleosome assembly protein set after lys176 and disrupted its nucleosome assembly activity. SIGNOR-110462 0.699 KDM1A protein O60341 UNIPROT CoREST-HDAC complex complex SIGNOR-C105 SIGNOR form complex binding 9606 BTO:0000567 11171972 t miannu Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function. SIGNOR-222121 0.739 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser7 sSSSYRRM -1 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248886 0.288 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270368 0.8 CAMK2B protein Q13554 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity phosphorylation Ser282 NSLQRVPsYDSFDSE BTO:0003637 12475968 t llicata Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1  SIGNOR-250686 0.314 SRC protein P12931 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Tyr374 PLPPAPAyLSSPLAL 9606 BTO:0000007 23131831 t miannu Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.  SIGNOR-276370 0.426 mTORC1 complex SIGNOR-C3 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 19593385 f lperfetto Activation of mTORC1 causes a robust increase in the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARgamma), which is the master transcriptional regulator of adipocyte differentiation. SIGNOR-235349 0.7 TSH complex SIGNOR-C412 SIGNOR TSHR protein P16473 UNIPROT up-regulates activity binding 9606 BTO:0001379 25905363 t scontino The thyroid-stimulating hormone (TSH) receptor (TSHR) is a member of the glycoprotein hormone receptors (GPHRs), a sub-group of class A G protein-coupled receptors (GPCRs). TSHR and its ligand thyrotropin are of essential importance for growth and function of the thyroid gland. SIGNOR-267048 0.56 PFKFB2 protein O60825 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 20640476 f lperfetto The decreased glycogen synthesis rates upon acute AMPK activation are generally coupled to an increase in the glycolytic flux, thanks to the activation of 6-phosphofructo-2-kinase (PFK-2) through direct phosphorylation on Ser466 [35]. PFK-2 catalyzes the synthesis of fructose 2,6-bisphosphate, a potent stimulator of glycolysis. Therefore, activation of AMPK rapidly mobilizes glucose into ATP-generating processes. SIGNOR-209950 0.7 SRC protein P12931 UNIPROT VIL1 protein P09327 UNIPROT up-regulates activity phosphorylation Tyr81 EQGAAAIyTTQMDDF 9606 BTO:0000567 15342783 t lperfetto These data suggest that phosphorylation of villin by c-src is involved in the actin cytoskeleton remodeling necessary for cell migration.To further investigate the role of tyrosine phosphorylated villin in cell migration, we used phosphorylation site mutants (tyrosine to phenylalanine or tyrosine to glutamic acid) in HeLa cells. We determined that tyrosine phosphorylation at residues 60, 81, and 256 of human villin played an essential role in cell migration as well as in the reorganization of the actin cytoskeleton SIGNOR-247441 0.371 PRKCA protein P17252 UNIPROT RAB37 protein Q96AX2 UNIPROT down-regulates activity phosphorylation Thr172 YGVPFLEtSAKTGMN 9606 BTO:0002877 29312551 t done miannu We also show that Rab37 is phosphorylated by protein kinase Cα (PKCα) at threonine 172 (T172), leading to attenuation of its GTP-bound state, and impairment of the Rab37-mediated exocytosis of TIMP1, and thus reduces its suppression activity on lung cancer cell motility.  SIGNOR-273803 0.2 SMO protein Q99835 UNIPROT GNG2 protein P59768 UNIPROT up-regulates binding 9606 23074268 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-199183 0.358 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser439 AGSPFQSsPLSLGSR 9606 16880739 t lperfetto Cdk1/cyclin b-mediated phosphorylation stabilizes srebp1 during mitosis. SIGNOR-216821 0.28 FASTKD5 protein Q7L8L6 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25683715 f miannu DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU. SIGNOR-261226 0.7 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-217110 0.753 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser381 CIPTAGMsPSRSNTI 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249395 0.585 FBXO22 protein Q8NEZ5 UNIPROT KLF4 protein O43474 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000594 26087183 t lperfetto F-box protein FBXO22 mediates polyubiquitination and degradation of KLF4 to promote hepatocellular carcinoma progression SIGNOR-273444 0.372 PRKCB protein P05771 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 BTO:0000661 11123317 t lperfetto Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5.  SIGNOR-249075 0.364 NMBR protein P28336 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256918 0.281 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 BTO:0000782 BTO:0001253 22898666 t gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. SIGNOR-253000 0.673 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270384 0.8 veliparib chemical CHEBI:62880 ChEBI PARP2 protein Q9UGN5 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189224 0.8 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT down-regulates phosphorylation Ser38 QVSSLSEsEESQDSS 9606 20730097 t lperfetto These data suggested that atf1 is always hyperphosphorylated on the ck sites in vivo. Also, the antibody reactivity suggested that in addition to ser-36 and ser-41, ser-38 and ser-44 were phosphorylated in vivo. To accommodate these findings, we propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. SIGNOR-167548 0.301 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16882717 t lpetrilli In human cells, rnai-mediated depletion of scp1 and scp2 increases the extent and duration of smad1 phosphorylation in response to bmp, the transcriptional action of smad1, and the strength of endogenous bmp gene responses. The present identification of the scp family as smad c-terminal phosphatases sheds light on the events that attenuate smad signaling and reveals unexpected links to the essential phosphatases that control rna polymerase ii in eukaryotes. SIGNOR-148434 0.479 TFDP1 protein Q14186 UNIPROT PCNA protein P12004 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253858 0.462 LYN protein P07948 UNIPROT PDIA3 protein P30101 UNIPROT unknown phosphorylation Tyr467 KKLNPKKyEGGRELS -1 8631326 t miannu Lyn phosphorylates tyrosine residues Y444, Y453 and Y466 which are located in a highly acidic region of the protein at the C-terminus. Upon phosphorylation, p57 forms a complex with Lyn which can be immunoprecipitated with anti-Lyn IgG. The association which occurs between the phosphorylated substrate and the SH2 domain of the kinase is consistent with the suggested 'processive phosphorylation' model, which implies that a primary phosphorylation site of the substrate binds to the SH2 domain of the enzyme and triggers the phosphorylation at secondary site(s). SIGNOR-262896 0.2 UVB radiation stimulus SIGNOR-ST17 SIGNOR TNF protein P01375 UNIPROT up-regulates 9606 19005488 f miannu UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription. UVB and IL-1alpha treatment synergistically enhanced TNF-alpha secretion and mRNA levels in human keratinocytes, similar to the findings reported previously in human fibroblasts. SIGNOR-252208 0.7 KIF2B protein Q8N4N8 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR down-regulates 9606 22535524 f lperfetto The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation. SIGNOR-252051 0.7 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT down-regulates activity phosphorylation Ser406 RSQSRKDsLDDSGSC 9534 BTO:0000298 9353340 t lperfetto  Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response.  SIGNOR-248987 0.399 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1672 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273046 0.556 WNT5B protein Q9H1J7 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131888 0.621 AP-1 complex complex SIGNOR-C248 SIGNOR AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR form complex binding 9606 23103167 t lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-260674 0.529 PTPN11 protein Q06124 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates activity dephosphorylation Tyr1474 GSSNGHVyEKLSSIE 9606 32140036 t lperfetto In addition, surface expression of GluN2B was not reduced in mutant mice and it remains to be investigated how the direct dephosphorylation of GluN2B Y1252 by Shp2 reduces GluN2B function.|The increased GluN2B Y1472 phosphorylation was reversed by a Src family kinase inhibitor, suggesting that Shp2 may negatively regulate GluN2B Y1472 phosphorylation through suppressing Src activity . SIGNOR-276950 0.481 CDK1 protein P06493 UNIPROT RRM2 protein P31350 UNIPROT unknown phosphorylation Ser20 DPQQLQLsPLKGLSL 9606 9990288 t llicata Ribonucleotide reductase r2 protein is phosphorylated at serine-20 by p34cdc2 kinase. comparison of ribonucleotide reductase activities between wild type and mutated forms of the r2 proteins suggested that mutation at serine-20 did not significantly affect enzyme activity. SIGNOR-64312 0.517 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP2K4 protein P45985 UNIPROT down-regulates phosphorylation Ser80 IERLRTHsIESSGKL 9606 BTO:0000007 11707464 t lperfetto Akt phosphorylated sek1 on serine 78. SIGNOR-244285 0.2 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser190 RGAPKRGsGKDSHHP -1 2413024 t miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-162 SIGNOR-250012 0.353 ADAM17 protein P78536 UNIPROT AREG protein P15514 UNIPROT up-regulates activity cleavage 9606 26284334 t miannu ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF SIGNOR-259842 0.459 PCGF2 protein P35227 UNIPROT HSF2 protein Q03933 UNIPROT down-regulates activity sumoylation 9606 BTO:0000007 18211895 t miannu MEL-18, in contrast to the polycomb protein PC2/CBX4, in which SUMO E3 activity stimulates sumoylation of certain proteins, actually functions like an anti-SUMO E3 protein, interacting with both HSF2 and the SUMO E2 UBC9 but acting to inhibit UBC9 activity and thereby decreasing sumoylation of a target protein, in this case that of HSF2. sumoylation of HSF2 is up-regulated during mitosis and is important for the interaction of this factor with a subunit of the condensin complex during the bookmarking process SIGNOR-226245 0.33 CDKN1B protein P46527 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 18423396 f fspada Moreover, expression of p27(kip1), an inhibitor of the cell cycle, was down regulated in an akt1/pkbalpha-specific manner during adipocytedifferentiation. SIGNOR-178278 0.7 EGLN3 protein Q9H6Z9 UNIPROT BCL2L11 protein O43521-1 UNIPROT up-regulates quantity by stabilization hydroxylation Pro70 PLAPPASpGPFATRS 9606 31375625 t lperfetto EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance|EglN3 Hydroxylates BIM-EL at the Proline67/70 Residues SIGNOR-262004 0.256 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-235929 0.702 NRG1 protein Q02297 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 BTO:0000150 7514177 t gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4 direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3. SIGNOR-26878 0.868 GNG2 protein P59768 UNIPROT GNB/GNG complex SIGNOR-C202 SIGNOR form complex binding 9606 23994464 t apalma Instead, our current understanding is that the majority of GPCR signal transduction in neutrophils occurs through the GŒ≤Œ≥ subunit SIGNOR-255005 0.939 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser181 NPLLRKEsAPPSLRR -1 15738054 t lperfetto We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro. SIGNOR-249273 0.491 PRKCD protein Q05655 UNIPROT SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization phosphorylation Thr71 VAFSVDNtIKRPNPA 29383184 t lperfetto PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8. SIGNOR-275564 0.2 WNT5B protein Q9H1J7 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131885 0.582 Corticotropin protein P01189-PRO_0000024969 UNIPROT MC4R protein P32245 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268711 0.2 N-(6-Chloro-7-methoxy-9H-pyrido[3,4-b]indol-8-yl)-2-methylnicotinamide chemical CID:9929127 PUBCHEM IKBKB protein O14920 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258249 0.8 sirolimus chemical CHEBI:9168 ChEBI CD86 protein P42081 UNIPROT down-regulates quantity by repression 9606 18652845 f miannu Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells. SIGNOR-255479 0.8 SRC protein P12931 UNIPROT GJA1 protein P17302 UNIPROT down-regulates phosphorylation Tyr265 KDCGSQKyAYFNGCS 9606 16916748 t lperfetto The oncogenic tyrosine kinase, v-src, phosphorylates connexin43 (cx43) on y247 and y265 and inhibits cx43 gap junctional communication (gjc), the process of intercellular exchange of ions and metabolites. SIGNOR-148917 0.606 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ARRB2 protein P32121 UNIPROT up-regulates activity phosphorylation Ser14 TRVFKKSsPNCKLTV 10090 BTO:0002572 26324936 t done miannu ERK1/2-dependent βarr2 phosphorylation on S14 and T276 induces CXCR4 intracellular sequestration. SIGNOR-274018 0.2 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-202807 0.8 DAB2IP protein Q5VWQ8 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity binding 9606 BTO:0001033 26512963 t miannu DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells. SIGNOR-254761 0.353 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 t miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. SIGNOR-264923 0.8 GSK3B protein P49841 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 25309941 f Following GSK3β activation, NF-κB is translocated from the cytoplasm to the nucleus and binds transcriptional sites with CBP leading to an increase in the transcription of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6). SIGNOR-255485 0.38 AS-605240 chemical CID:5289247 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189921 0.8 RPS6KA3 protein P51812 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Thr1326 VNGADEDtISRFLAE 9606 BTO:0002181 23608533 t miannu We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding. SIGNOR-276462 0.2 PIK3AP1 protein Q6ZUJ8 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 BTO:0000801 22187458 t gcesareni This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Therefore, bcap is an essential activator of the pi3k pathway downstream of tlr signaling, providing a brake to limit potentially pathogenic excessive tlr responses. SIGNOR-191670 0.245 tolazoline chemical CHEBI:28502 ChEBI ADRA2A protein P08913 UNIPROT down-regulates activity chemical inhibition 9606 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258912 0.8 ROCK1 protein Q13464 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates activity phosphorylation Thr1226 LRSLRRNtKKPKPKP 9534 BTO:0000298 19103606 t miannu these results indicate that Rho-kinase can phosphorylate p190A RhoGAP at Ser1150 in COS7 cells. Similarly, the immunoblot analysis, through the use of the anti-p190A RhoGAP-pT1226 and -pS1236 antibodies, revealed that Rho-kinase can phosphorylate p190A RhoGAP at Thr1226 and Ser1236 in COS7 cells SIGNOR-276178 0.424 A5/b1 integrin complex SIGNOR-C163 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257705 0.595 TFEB protein P19484 UNIPROT NDUFA8 protein P51970 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). SIGNOR-276702 0.2 CREB5 protein Q02930 UNIPROT MAPKAPK3 protein Q16644 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002814 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253807 0.253 PPP1CA protein P62136 UNIPROT MECOM protein Q03112 UNIPROT down-regulates activity dephosphorylation Ser1037 IGNSNHGsQSPRNVE 23858473 t phosphorylation site remapping based on Fig 5 lperfetto We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation. SIGNOR-273429 0.2 serotonin smallmolecule CHEBI:28790 ChEBI AANAT protein Q16613 UNIPROT up-regulates activity chemical activation -1 22775292 t miannu Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. Melatonin synthesis requires serotonin, which is first acetylated by the arylalkylamine N-acetyltransferase (AA-NAT) to produce N-acetyl serotonin (NAS) (Fig. 1A). Then, acetyl serotonin methyltransferase (ASMT, also known as hydroxyindole O-methyltransferase or HIOMT) produces melatonin by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to NAS. SIGNOR-265477 0.8 RET protein P07949 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 15994200 t lperfetto The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity SIGNOR-166514 0.328 GSK3B protein P49841 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 BTO:0000782 SIGNOR-C13 16407239 t gcesareni Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) . SIGNOR-143581 0.364 JUN protein P05412 UNIPROT Brown_adipogenesis phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103 22944199 f gcesareni Other g protein-mediated pathways are the planar cell polarity (pcp) pathway (shown in blue) leading to the activation of rac/rho, c-jun n-terminal kinase (jnk), and/or rho-associated kinase (rock). Jnk can induce jun, which, together with fos, forms the ap-1 early response transcription factor. Both pcp pathways have been implicated in cytoskeletal rearrangements SIGNOR-198834 0.7 PRKDC protein P78527 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser114 EETRTPEsQPDTPPG 9606 21824916 t lperfetto We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro. SIGNOR-176016 0.635 HARS1 protein P12081 UNIPROT tRNA(His) smallmolecule CHEBI:29178 ChEBI down-regulates quantity chemical modification 9606 10430027 t miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. SIGNOR-270485 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2366 MEQGHFAsPDQNSML 9606 17623675 t lperfetto Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo. SIGNOR-244537 0.2 FPR2 protein P25090 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256888 0.41 Ionizing radiation stimulus SIGNOR-ST16 SIGNOR TRIM13 protein O60858 UNIPROT up-regulates 9606 BTO:0000007 21333377 f miannu These data suggest that irradiation causes RFP2 overexpression, which enhances ionizing radiation-induced apoptosis by increasing p53 stability and decreasing AKT kinase activity through MDM2 and AKT degradation. SIGNOR-271854 0.7 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser222 LIDSMANsFVGTRSY 9606 8131746 t gcesareni Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf SIGNOR-36449 0.556 MAPK1 protein P28482 UNIPROT PARVA protein Q9NVD7 UNIPROT up-regulates activity phosphorylation Ser8 MATSPQKsPSVPKSP 9606 BTO:0001938 22955285 t lperfetto Actopaxin (alpha-parvin) is a paxillin, integrin-linked kinase, and F-actin binding focal adhesion protein with several serine phosphorylation sites in the amino terminus that contribute to the regulation of cell spreading and migration.|Actopaxin phosphorylation of Ser4/8 enhances cell migration whereas a nonphosphorylatable (Quint) mutant suppresses migration in U2OS osteosarcoma cells (7). SIGNOR-265759 0.262 MARK3 protein P27448 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates activity phosphorylation Ser151 LSLAKSVsTTNIAGH 9606 BTO:0002181 29089450 t miannu Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates Ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state through binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that liver kinase B1 (LKB1) activated the microtubule affinity-regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at Ser151 This modification disrupted the interaction between ARHGEF2 and DYNLT1 by generating a 14-3-3 binding site in ARHGEF2, thus causing ARHGEF2 to dissociate from microtubules. SIGNOR-277368 0.39 RXRB protein P28702 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 10976919 t inferred from family member gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr SIGNOR-270297 0.642 (1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid chemical CHEBI:94640 ChEBI MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates chemical activation 9606 Other t Selleck|inferred from family member gcesareni SIGNOR-270281 0.8 FBP2 protein O00757 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity chemical modification 9606 30616754 t lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle SIGNOR-267613 0.8 AR protein P10275 UNIPROT AKR1C3 protein P42330 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 22971343 f miannu Both AR antagonism and androgen deprivation can upregulate AKR1C3. SIGNOR-253737 0.46 PPP3CB protein P16298 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Thr290 NKLKPPGtPPPSSRK 10090 19560418 t These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 SIGNOR-248381 0.262 CUL9 protein Q8IWT3 UNIPROT FERMT2 protein Q96AC1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 35469017 t miannu M-phase-specific CDK1–cyclin B1 complex directly binds KIND1 and KIND2 and phosphorylates a conserved proline-directed CDK1 consensus motif in the flexible and intrinsically disordered loop of the F1 domain. This then results in the recruitment of the CUL9–FBXL10 complex, modification with K48-linked polyubiquitin chains and proteasomal degradation of KIND1 and KIND2. SIGNOR-276717 0.2 NFE2L2 protein Q16236 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000599 26194347 f irozzo Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes. SIGNOR-256263 0.7 POLD4 protein Q9HCU8 UNIPROT DNA polymerase delta complex SIGNOR-C376 SIGNOR form complex binding -1 12403614 t lperfetto Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme. SIGNOR-265517 0.873 DDX3X protein O00571 UNIPROT PABPC1 protein P11940 UNIPROT up-regulates activity binding 9606 21883093 t miannu In the present study, we indentified the SG marker PABP1 [poly(A)-binding protein 1] as another direct interaction partner of DDX3. Interestingly, down-regulation of DDX3 interfered with SG assembly, led to nuclear accumulation of PABP1 and reduced cell viability following stress. Conversely, supplementation with a shRNA (short hairpin RNA)-resistant DDX3 restored SG formation, the translocation of PABP1 into SGs and cell survival. SIGNOR-269201 0.587 HOXA9 protein P31269 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates activity binding -1 9343407 t 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. SIGNOR-241162 0.639 ADAM10 protein O14672 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity cleavage 9606 28624438 t miannu One of the most important and best characterized ADAM10 substrates is the Notch receptor [16]. After ligand binding to the Notch receptor, ADAM10 liberates the ectodomain and the membrane remaining part is processed by the γ-secretase complex, which releases a Notch Intracellular Domain (NICD). SIGNOR-259836 0.773 DISC1 protein Q9NRI5 UNIPROT PAFAH1B1 protein P43034 UNIPROT up-regulates activity binding 9606 BTO:0000938 17202468 t miannu Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3ε. 14-3-3ε is involved in the proper localization of NUDEL and LIS1 in axons. the association with NUDEL and LIS1 supports the notion that DISC1 contributes to the neuronal development and morphology  SIGNOR-252163 0.489 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser49 REQQEQLsLQQTIID 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262722 0.733 MAPK3 protein P27361 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 15568999 t gcesareni In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. SIGNOR-131379 0.568 SOX6 protein P35712 UNIPROT COL2A1 protein P02458 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10980415 f miannu Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Two other members of the Sox family, L-Sox5 and Sox6, also bind to the 48-bp Col2a1 enhancer and together with Sox9 activate this enhancer as well as the endogenous Col2a1 SIGNOR-251760 0.429 KLF3 protein P57682 UNIPROT KLF8 protein O95600 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000759 18687676 t Luana Here we report that Klf8 is repressed by Klf3 in vivo and is up-regulated by Klf1. Transcript analysis indicates that Klf8 has two promoters, both containing multiple CACCC elements. Transactivation assays and chromatin immunoprecipitation experiments indicate that Klf3 represses Klf8 directly and that Klf1 activates Klf8 directly.  SIGNOR-266049 0.258 UBA52 protein P62987 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity binding 10090 BTO:0002572 phosphorylation: ser65 DYNIQKEsTLHLVLR 24784582 t The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator. SIGNOR-270344 0.2 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1766 SPSYSPTsPSYSPTS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248814 0.849 NOX5 protein Q96PH1 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity chemical modification 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264725 0.8 FGF9 protein P31371 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 f FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1 gcesareni Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts SIGNOR-195594 0.312 PSMD12 protein O00232 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263352 0.915 KAT2A protein Q92830 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269604 0.2 CIITA protein P33076 UNIPROT HLA-F protein P30511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11137213 f HLA-E is inducible by CIITA through the SXY regulatory module. HLA-F is inducible by NF-kappaB through the kappaB1 site of enhancer A, is responsive to IFN-gamma through the ISRE, and is inducible by CIITA SIGNOR-254018 0.453 MAPK15 protein Q8TD08 UNIPROT MAPK15 protein Q8TD08 UNIPROT up-regulates phosphorylation Thr175 GPEDQAVtEYVATRW 9606 16336213 t lperfetto Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif.Our results suggest that the activity of erk8 in transfected hek-293 cells depends on the relative rates of erk8 autophosphorylation SIGNOR-142969 0.2 PTPRF protein P10586 UNIPROT FYN protein P06241 UNIPROT up-regulates dephosphorylation Tyr531 FTATEPQyQPGENL 9606 12496362 t gcesareni Regulation of lck and fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule. SIGNOR-96764 0.405 entinostat chemical CHEBI:132082 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257905 0.8 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120104 0.316 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT up-regulates activity phosphorylation Thr316 GTASSRKtLWNQELY 21880142 t miannu Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2.PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites. SIGNOR-266298 0.312 FGR protein P09769 UNIPROT ACO2 protein Q99798 UNIPROT unknown phosphorylation Tyr544 FDPGQDTyQHPPKDS -1 17997986 t miannu Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are "in vitro" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations. SIGNOR-262869 0.2 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr989 VPSSRGDyMTMQMSC 9606 17827393 t gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157758 0.864 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser386 ARVGGASsLENTVDL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178395 0.816 TRIM31 protein Q9BZY9 UNIPROT KIF21B protein O75037 UNIPROT up-regulates activity binding 24086586 t Here we show that the ubiquitin E3 ligase TRIM3, also known as BERP, interacts with KIF21B via its RBCC domain ||he E3-ligase function of TRIM3 is not involved in KIF21B degradation, however TRIM3 depletion reduces the motility of the motor. Together, our data suggest that TRIM3 is a regulator in the modulation of KIF21B motor function SIGNOR-272479 0.2 PRKACA protein P17612 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000782 19836308 t lperfetto Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3alpha or ser9 in gsk3beta. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka). SIGNOR-188577 0.542 NIN protein Q8N4C6 UNIPROT JAK2 protein O60674 UNIPROT down-regulates binding 9606 25332239 t miannu We showed that jak2 directly phosphorylates the n-terminus ofnineinwhile the c-terminus ofnineininhibits jak2 kinase activity in vitro. SIGNOR-205581 0.244 RRM1 protein P23921 UNIPROT Ribonucleotide reductase complex SIGNOR-C233 SIGNOR form complex binding 9606 14583450 t miannu Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2. SIGNOR-259363 0.93 BAK1 protein Q16611 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates relocalization 9606 14585074 t Translocation from Mitochondria to Cytosol amattioni Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi SIGNOR-118908 0.3 MAST1 protein Q9Y2H9 UNIPROT PTEN protein P60484 UNIPROT down-regulates phosphorylation 9606 15951562 t gcesareni Mast1 was found to associate to pten. SIGNOR-138003 0.53 docetaxel anhydrous chemical CHEBI:4672 ChEBI TUBA4A protein P68366 UNIPROT down-regulates activity chemical inhibition 9606 23337758 t miannu Tubulin exists in the cell as dimers of α and β subunits, which complexes with a variety of regulatory proteins. There is a dynamic equilibrium between free and polymerized tubulin causing a state called "dynamic instability," which is a target of anticancer drugs, which inhibit tubulin through polymerization (taxanes, epothilones) or depolymerization (vinca alkaloids). Docetaxel-based therapy was the first such treatment to demonstrate a survival benefit in men with castration-resistant prostate cancer. SIGNOR-259342 0.8 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258994 0.742 MED24 protein O75448 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266666 0.773 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 9606 SIGNOR-C3 18722121 t llicata Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity SIGNOR-252773 0.2 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257455 0.8 RPS20 protein P60866 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262430 0.873 M2_polarization phenotype SIGNOR-PH55 SIGNOR IL10 protein P22301 UNIPROT up-regulates 9606 BTO:0000801 32454942 f miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. M2 polarized cells express a variety of anti-inflammatory mediators, such as IL-4, IL-10, and transforming growth factor-β (TGF-β), and contribute to immunoregulation SIGNOR-263823 0.7 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Tyr199 ELLEQQKyTVTVDYW 9606 SIGNOR-C14 12645577 t gcesareni These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation. SIGNOR-99318 0.37 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 BTO:0000887;BTO:0001103 11705993 t gcesareni The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. SIGNOR-111511 0.579 SRC protein P12931 UNIPROT ARHGDIB protein P52566 UNIPROT unknown phosphorylation Tyr153 YGPRPEEyEFLTPVE 9606 19321744 t llicata Studies confirmed that activated src kinase binds and phosphorylates rhogdi2 in vitro and vivo. Mutagenesis revealed that tyr-153 and, to a lesser degree, tyr-24 were the primary src phosphorylation sites. Phosphorylation decreased the amount of rac1 in rhogdi2 complexes and increased rhogdi2 association with cell membranes. SIGNOR-184908 0.404 AREL1 protein O15033 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination Lys191 RNHIQLVkLQVEEVH 9606 BTO:0002552 31732561 t lperfetto AREL1 ubiquitinated SMAC, primarily on Lys62 and Lys191 |E701A substitution in the AREL1 HECT domain substantially increased its autopolyubiquitination and SMAC ubiquitination activity, whereas deletion of the last three amino acids at the C terminus completely abrogated AREL1 autoubiquitination and reduced SMAC ubiquitination. SIGNOR-267672 0.385 ASIP protein P42127 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268708 0.514 FZD7 protein O75084 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 23290138 f Simone Vumbaca We observed that overexpression of Fzd7 or stimulation with FN resulted in increased levels of active Rac1 in primary myoblasts SIGNOR-255647 0.431 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Ser1490 AILNPPPsPATERSH 10090 BTO:0002572 16341017 t gcesareni Glycogen synthase kinase 3 (gsk3), which is known for its inhibitory role in wnt through the promotion of beta-catenin phosphorylation and degradation, mediates the phosphorylation and activation of lrp6. We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin. SIGNOR-228014 0.722 AKT2 protein P31751 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 17277771 t lperfetto Furthermore, pras40 phosphorylation by akt and association with 14-3-3, a cytosolic anchor protein, are crucial for insulin to stimulate mtor. These findings identify pras40 as an important regulator of insulin sensitivity of the akt-mtor pathway and a potential target for the treatment of cancers, insulin resistance and hamartoma syndromes. SIGNOR-235967 0.568 GPHN protein Q9NQX3 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000938 25882190 t miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. SIGNOR-264974 0.486 MAPKAPK2 protein P49137 UNIPROT ETV1 protein P50549 UNIPROT down-regulates activity phosphorylation Ser191 HRFRRQLsEPCNSFP 452646 11551945 t miannu MK2 phosphorylates ER81 in vitro within its central inhibitory domain, and overexpression of MK2 leads to increased in vivo phosphorylation of ER81. Two serine residues, ER81 amino acids 191 and 216, were identified as MK2 phosphorylation sites. MK2 suppresses basal ER81-dependent transcription SIGNOR-250145 0.596 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser706 ARIIGEKsFRRSVVG 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275961 0.2 PAK5 protein Q9P286 UNIPROT TCF3 protein P15923 UNIPROT up-regulates activity phosphorylation Ser39 NGKGRPAsLAGAQFG 9606 BTO:0000150 26212009 t lperfetto The p21-activated kinase 5 (PAK5) is overexpressed in advanced cancer and the transcription factor E47 is a direct repressor of E-cadherin and inducer of epithelial-mesenchymal transition (EMT). |In this study, we found that PAK5-mediated E47 phosphorylation promoted EMT in advanced colon cancer. PAK5 interacted with E47 and phosphorylated E47 on Ser39 under hepatocyte growth factor (HGF) stimulation SIGNOR-275653 0.2 MRGPRX2 protein Q96LB1 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257172 0.2 RGCC protein Q9H4X1 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity binding 9606 BTO:0001685 11687586 t miannu RGC-32 was physically associated with cyclin-dependent kinase p34CDC2 and increased the kinase activity in vivo and in vitro. In addition, RGC-32 was phosphorylated by p34CDC2-cyclin B1 in vitro. Mutation of RGC-32 protein at Thr-91 prevented the p34CDC2-mediated phosphorylation and resulted in loss of p34CDC2 kinase enhancing activity. SIGNOR-262726 0.545 MAPK3 protein P27361 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3. SIGNOR-66781 0.608 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR PFKM protein P08237 UNIPROT down-regulates activity phosphorylation -1 28607489 t miannu In vitro kinase reactions revealed that all three PFK1 isoforms (PFKP, PFKL, PFKM) and PKM2 were phosphorylated by cyclin D3-CDK6 (Extended Data Fig. 2a–d, Supplementary Table 4). SIGNOR-276452 0.2 RPL14 protein P50914 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262484 0.867 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr267 SQYGQEVyDTPPMAV 10090 12972425 t lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs SIGNOR-246401 0.796 RANBP3 protein Q9H6Z4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity relocalization 9606 19289081 t lperfetto RanBP3 directly recognizes dephosphorylated Smad2/3, which results from the activity of nuclear Smad phosphatases, and mediates nuclear export of Smad2/3 in a Ran-dependent manner. SIGNOR-217634 0.446 SCF-FBW7 complex SIGNOR-C135 SIGNOR DLGAP5 protein Q15398 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 15145941 t miannu We show here that Fbx7, an F-box protein without WD repeats and leucine-rich repeats, is required for the proteasome-mediated proteolysis of the hepatoma up-regulated protein (HURP).Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module. Depletion of Fbx7 by small interfering RNA leads to depression of HURP ubiquitination and accumulation of HURP abundance. In the SCFFbx7 complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner. SIGNOR-271508 0.276 CBL protein P22681 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20332299 t lperfetto Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface. SIGNOR-30794 0.619 DPF2 protein Q92785 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 24332853 f miannu Here, DPF2 appears to be another important regulator of myeloid differentiation that can cooperate with PRMT4 to maintain the “stemness” of HSPCs. SIGNOR-261969 0.7 PRKAA2 protein P54646 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 SIGNOR-C15 20577053 t gcesareni Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2 SIGNOR-166365 0.472 TRAC protein P01848 UNIPROT TCR complex SIGNOR-C153 SIGNOR form complex binding 9606 12507424 t miannu The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules.the TCRα-CD3δε and TCRβ-CD3γε interactions are similar since both require a lysine in the TM region of the respective TCR chain and both acidic TM residues in the relevant CD3 heterodimer. Nevertheless, formation of fully assembled αβ TCR-CD3 complexes containing the ζ-chain strictly required both CD3γ and δ SIGNOR-255297 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 t lperfetto Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102 SIGNOR-182493 0.2 SPOP protein O43791 UNIPROT TRIM24 protein O15164 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25278611 t miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. SIGNOR-272825 0.344 HOXD3 protein P31249 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0002828 14610084 t Luana The homeobox transcription factor Hox D3 promotes integrin alpha5beta1 expression and function during angiogenesis. SIGNOR-261650 0.253 MARCHF9 protein Q86YJ5 UNIPROT HLA-DQB1 protein P01920 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271539 0.2 precursor messenger RNA smallmolecule CHEBI:139356 ChEBI SF3b complex SIGNOR-C442 SIGNOR up-regulates activity relocalization 9606 32140746 t lperfetto The SF3b complex is an intrinsic component of the functional U2 small nuclear ribonucleoprotein (snRNP). As U2 snRNP enters nuclear pre-mRNA splicing, SF3b plays key roles in recognizing the branch point sequence (BPS) and facilitating spliceosome assembly and activation. SIGNOR-268413 0.8 PRKACA protein P17612 UNIPROT GRIA1 protein P42261 UNIPROT up-regulates activity phosphorylation Ser863 TSTLPRNsGAGASSG 9606 8663994 t miannu Phosphorylation of Ser-845 on GluR1 by PKA potentiates its response to glutamate. SIGNOR-249987 0.476 CDK1 protein P06493 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr611 ETLPISStPSKSVLP 9606 SIGNOR-C17 19737929 t lperfetto A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1further analysis reveals that the leu-641 residue within an lxl motif is required for the recruitment of the cyclin-cdk complex, and the thr-596 residue is a critical cdk1 phosphorylation site within the activation domain of foxm1b. Cdk-dependent phosphorylation stimulates the foxm1b transcriptional activity SIGNOR-187880 0.751 EFNA2 protein O43921 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52203 0.921 CDK1 protein P06493 UNIPROT MPLKIP protein Q8TAP9 UNIPROT up-regulates phosphorylation Ser104 SQQQFGYsPGQQQTH 9606 17310276 t lperfetto Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1 SIGNOR-153300 0.347 PRKD1 protein Q15139 UNIPROT ATP7B protein P35670 UNIPROT up-regulates activity phosphorylation Ser478 APDILAKsPQSTRAV 9606 BTO:0000599 21189263 t lperfetto ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking. SIGNOR-272296 0.301 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Leu664 ATVIVITlVMLKKKQ -1 8943232 t lperfetto The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261784 0.502 Z-RNA stimulus SIGNOR-ST29 SIGNOR ZBP1 protein Q9H171 UNIPROT up-regulates activity binding 10090 32200799 t gianni Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis. SIGNOR-266432 0.7 AMPA proteinfamily SIGNOR-PF58 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 15919192 f miannu Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1–4); five kainate receptor genes (GluR5–7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits. SIGNOR-264695 0.7 CSNK1D protein P48730 UNIPROT CDH1 protein P12830 UNIPROT down-regulates activity phosphorylation Ser844 GSGSEAAsLSSLNSS 17353278 t lperfetto Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846 SIGNOR-274046 0.273 IRAK4 protein Q9NWZ3 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity phosphorylation Thr342 ASEKFAQtVMTSRIV 9606 BTO:0000876 24567333 t lperfetto We show irak4 autophosphorylation occurs by an intermolecular reaction and that autophosphorylation is required for full catalytic activity of the kinase. Phosphorylation of any two of the residues thr-342, thr-345, and ser-346 is required for full activity SIGNOR-204657 0.2 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser696 EKNYALPsPATTEGG 9606 SIGNOR-C3 21071439 t llicata We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-169514 0.532 PCSK7 protein Q16549 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates phosphorylation 9606 11259586 t gcesareni This together with the rapid kinetics of pp1-pp2a activation following p38 activation suggests that pp1 and/or pp2a complexes are direct targets for p38-mediated phosphorylation SIGNOR-105783 0.2 CAMK2A protein Q9UQM7 UNIPROT FBXO43 protein Q4G163 UNIPROT up-regulates activity phosphorylation Ser192 NLEKNIPsSASGFSR -1 16407128 t Manara CaMKII and polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit. | these results implicate the 192RSST motif of Emi2 as a critical molecular target of CaMKII during CSF release SIGNOR-260907 0.381 PIM1 protein P11309 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 t done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  SIGNOR-273895 0.2 CDK1 protein P06493 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser123 EEGFGSSsPVKSPAA 9606 15070733 t gcesareni We have found also that the major M-phase kinases polo-like kinase 1 (Plk1) and Cdc2 are responsible for the phosphorylation of S53 and S123, respectively, and that in each case phosphorylation generates an unconventional phospho-degron (signal for degradation) that can be recognized by beta-TrCP SIGNOR-123824 0.853 phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI CADPS2 protein Q86UW7 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 24363652 t miannu CAPS exhibits low affinity but functionally significant interactions with plasma membrane PIP2 via its central PH (pleckstrin homology) domain (82, 111). PIP2 enhanced CAPS stimulation of SNARE-dependent liposome fusion with wild-type but not with mutant PH domain CAPS proteins SIGNOR-264335 0.8 DAB2 protein P98082 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT up-regulates activity binding 9606 27858941 t miannu In prostate cancer cells, DAB2IP was shown to be recruited by the adaptor protein DAB2/DOC2 to promote Ras inactivation and inhibition of MAPK signaling upon receptor stimulation. SIGNOR-254744 0.536 TAF10 protein Q12962 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263926 0.893 PRKCD protein Q05655 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation 9606 17183360 t gcesareni By contrast, after uv stimulation, rela directly induces the expression of pkcdelta, which in turn activates jnk. SIGNOR-151428 0.483 HDAC2 protein Q92769 UNIPROT CIITA protein P33076 UNIPROT down-regulates quantity by repression deacetylation 9606 BTO:0000801;BTO:0004576 19041327 t miannu We report that CIITA and histone deacetylase 2 (HDAC2) interact in smooth muscle cells and macrophages as assayed by co-immunoprecipitations. HDAC2 deacetylates CIITA whereas both the HDAC inhibitor trichostatin A (TSA) and over-expression of HDAC2 interfering RNA increase CIITA acetylation. HDAC2 down-regulates CIITA recruitment to target promoters as evidenced by chromatin immunoprecipitation assays, and suppresses MHC II activation and collagen repression mediated by CIITA in luciferase reporter assays. SIGNOR-254231 0.423 L-thyroxine smallmolecule CHEBI:18332 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity chemical activation 10116 BTO:0000759 2158622 t inferred from family member miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. SIGNOR-270300 0.8 MEST protein Q5EB52 UNIPROT LRP6 protein O75581 UNIPROT down-regulates activity 9606 21375506 f Mest/Peg1 inhibited maturation of LRP6 by controlling the glycosylation of LRP6. Knockdown of Mest/Peg1, which might enhance Wnt signalling, blocked adipogenic differentiation of 3T3-L1 cells SIGNOR-255826 0.2 NLGN4X protein Q8N0W4 UNIPROT NRXN3 protein Q9HDB5 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264170 0.759 CDKL5 protein O76039 UNIPROT CDKL5 protein O76039 UNIPROT up-regulates activity phosphorylation Thr169 EGNNANYtEYVATRW -1 16935860 t gcesareni Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif. SIGNOR-262289 0.2 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity phosphorylation Thr739 SEGSGTAtPSALITT 9606 14744793 t lperfetto Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1.|this activation promotes the phosphorylation of Sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased Sp1 binding and enhanced p21(waf1/cip1) transcription. SIGNOR-249481 0.639 AKT1 protein P31749 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser939 SFRARSTsLNERPKS 10090 BTO:0000944 12150915 t lperfetto We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines. SIGNOR-235511 0.81 RPL10 protein P27635 UNIPROT JUN protein P05412 UNIPROT down-regulates binding 9606 12138090 t miannu The qm gene encodes a 24.5 kda ribosomal protein l10 known to be highly homologous to a jun-binding protein (jif-1), which inhibits the formation of jun-jun dimers. SIGNOR-90750 0.396 A9/b1 integrin complex SIGNOR-C166 SIGNOR TNF protein P01375 UNIPROT up-regulates quantity by expression 9606 24241034 f lperfetto Importantly, autocrine and paracrine interactions of alpha9beta1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-alpha± and IL-1beta in synovial macrophages. SIGNOR-253315 0.316 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Ser539 SLFNVSPsCSSFNSP 9606 BTO:0000887;BTO:0001103 17609368 t lperfetto Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538. SIGNOR-216647 0.483 STK11 protein Q15831 UNIPROT MARK1 protein Q9P0L2 UNIPROT up-regulates phosphorylation Thr215 TVGNKLDtFCGSPPY 9606 14976552 t lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold SIGNOR-122545 0.42 NR3C1 protein P04150 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9590696 t gcesareni Transactivation of these templates depends on the association of the GR with co-activators such as SRC-1/NcoA1, GRIP-1/TIF-2/NcoA2 and p300/CBP. SIGNOR-251682 0.76 NEUROG3 protein Q9Y4Z2 UNIPROT VSX2 protein P58304 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19028584 f miannu Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. SIGNOR-254635 0.277 RB1 protein P06400 UNIPROT E2F2 protein Q14209 UNIPROT down-regulates binding 9606 22569856 t gcesareni Cyclin-dependent kinase (cdk) phosphorylation of the retinoblastoma protein (rb) drives cell proliferation through rb complexes with e2f transcription factors and other regulatory proteins. SIGNOR-197328 0.912 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo. SIGNOR-101127 0.924 FLT3 protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 10090 BTO:0001516 14981546 t These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation. SIGNOR-261522 0.442 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Thr53 PPGSLSStPLSTPCS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159450 0.259 PRKD3 protein O94806 UNIPROT PAK4 protein O96013 UNIPROT up-regulates activity phosphorylation Ser474 KEVPRRKsLVGTPYW 23841590 t lperfetto PAK4 activity is regulated by an autoinhibitory domain that is released upon RhoGTPase binding as well as phosphorylation at Ser474 in the activation loop of the kinase domain. In the present study, we add another level of complexity to PAK4 regulation by showing that phosphorylation at Ser99 is required for its targeting to the leading edge. This phosphorylation is mediated by PKD1 (protein kinase D1) SIGNOR-275931 0.255 SLC24A3 protein Q9HC58 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264391 0.8 ADRA1B protein P35368 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256807 0.484 YY1 protein P25490 UNIPROT COX7C protein P15954 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9092564 f miannu Mutation of both YY1 sites eliminates most of the promoter activity. Mutation at the upstream YY1 site significantly reduces the efficiency of transcript initiation at the major start site and thus plays the dominant role in COX7C regulation. SIGNOR-255617 0.259 FFAR2 protein O15552 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256946 0.2 SIRT1 protein Q96EB6 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 20713551 f miannu Overexpression of SIRT1 enhanced both FoxO reporter activity and nuclear levels of FoxO1. Protein expression of MDR1 and gene transcriptional activity were also up-regulated by SIRT1 overexpression. SIGNOR-255139 0.26 PAK2 protein Q13177 UNIPROT PREX2 protein Q70Z35 UNIPROT down-regulates activity phosphorylation Ser1107 DTISNRDsYSDCNSN 9606 BTO:0000007 26438819 t miannu P21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase. PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. SIGNOR-277182 0.366 COP1 protein Q8NHY2 UNIPROT MTA1 protein Q13330 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 19805145 t miannu Here we report that MTA1 is an ubiquitinated protein and targeted by the RING-finger E3 ubiquitin-protein ligase constitutive photomorphogenesis protein 1 (COP1) for degradation via the ubiquitin-proteasome pathway. SIGNOR-271891 0.2 regorafenib chemical CHEBI:68647 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition 9606 26254357 t miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF SIGNOR-259180 0.8 MAPK1 protein P28482 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser189 YRPKPSSsPVIFAGG 9606 BTO:0000664 17475908 t miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). SIGNOR-262911 0.324 CHD2 protein O14647 UNIPROT XRCC4 protein Q13426 UNIPROT up-regulates quantity relocalization 9606 BTO:0001938 26895424 t miannu CHD2 Promotes the Recruitment of Core NHEJ Factors. overexpression of ATPase-dead CHD2 (K515R; Figure S5F), but not wild-type CHD2, also reduced the recruitment of XRCC4 (Figure 5E). Together, these findings suggest that the chromatin remodeling activity of CHD2 promotes the efficient assembly of NHEJ complexes at DSBs. SIGNOR-264528 0.2 PRKACG protein P22612 UNIPROT PHKA1 protein P46020 UNIPROT down-regulates activity phosphorylation 9606 10487978 t Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. SIGNOR-267415 0.307 PRKN protein O60260 UNIPROT HSD17B10 protein Q99714 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0000298 25591737 t miannu  This study identifies the multifunctional PD-related mitochondrial matrix enzyme 17-β hydroxysteroid dehydrogenase type 10 (HSD17B10) as a new Parkin substrate. SIGNOR-272823 0.2 CCN2 protein P29279 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 33358571 f miannu As a matricellular protein, connective tissue growth factor (CTGF) functions beyond its classical role in extracellular matrix (ECM) remolding. Increasing evidence emphasizes the notion that CTGF is pivotal in cancer initiation and progression. SIGNOR-277683 0.7 RAD51 protein Q06609 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 27660832 f lperfetto Rad51 is a key component of homologous recombination (HR) to repair DNA double-strand breaks and it forms Rad51 recombinase filaments of broken single-stranded DNA to promote HR. In addition to its role in DNA repair and cell cycle progression, Rad51 contributes to the reprogramming process during the generation of induced pluripotent stem cells SIGNOR-251508 0.7 IL10 protein P22301 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 23357618 f miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. SIGNOR-253499 0.273 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 28531279 f miannu The activation of NLRP3 inflammasomes in macrophages requires two stimuli. The first signal, called priming, is provided by an inflammatory stimulus such as TLRs and TNF-α receptor (TNFR) that leads to NF-κB-mediated NLRP3 expression and post-translational modifications of NLRP3 SIGNOR-260328 0.361 HK2 protein P52789 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates activity 9606 18350175 f The first step in metabolism of glucose (Glc) is usually phosphorylation, catalyzed by hexokinase. SIGNOR-259980 0.7 JMJD1C protein Q15652 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity demethylation 9606 BTO:0000007 32034158 t miannu We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state. SIGNOR-265331 0.2 RAPGEF2 protein Q9Y4G8 UNIPROT RAP1A protein P62834 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0002181 24290981 t miannu Our data are consistent with a pathway involving the cAMP-mediated activation of Rapgef2, which then stimulates Rap1, leading to increases in B-Raf, MEK, and ERK activity.Increased intracellular concentrations of cAMP enhanced the Rapgef2-dependent activation of Rap1, which in turn associated with B-Raf to enable the activation of ERK and subsequent neuronal- and endocrine-specific cellular outcomes, such as induction of neuroendocrine-specific genes and extension of neuritic processes (neuritogenesis). SIGNOR-276609 0.785 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SP3 protein Q02447 UNIPROT up-regulates phosphorylation 9606 17685427 t inferred from 70% family members gcesareni Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73. SIGNOR-270165 0.2 SNTB2 protein Q13425 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255993 0.474 CDC25B protein P30305 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 25384584 t lperfetto CDC25B facilitates dephosphorylation of the key cell cycle regulator CDC2 (also called CDK1) at Tyr15 or Thr14, thereby initiating the G 2 /M transition ( xref ).|CDC25B facilitates dephosphorylation of the key cell cycle regulator CDC2 (also called CDK1) at Tyr15 or Thr14, thereby initiating the G2/M transition ( ). SIGNOR-276969 0.823 WNT1 protein P04628 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 15454084 t lperfetto Mammalian ryk is a wnt coreceptor required for stimulation of neurite outgrowth SIGNOR-129577 0.697 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr283 YQPYQSIyVGGMMEG 9606 BTO:0001271 8622703 t lperfetto We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrose 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr. SIGNOR-40615 0.2 USP22 protein Q9UPT9 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 26049753 t USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells. SIGNOR-261561 0.55 MT-CO3 protein P00414 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267743 0.673 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 18971378 t gcesareni In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943) SIGNOR-181811 0.347 FLT3 protein P36888 UNIPROT PIM2 protein Q9P1W9 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15769897 f The serine-threonine kinase Pim-2 is a functionally relevant downstream target of STAT5.24 Here, we observed only a weak induction of Pim-2 by Flt3-D835Y compared to the effects of Flt3-ITD. SIGNOR-261541 0.343 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser160 PVRLLGHsPVLRNIT 9606 12107172 t lperfetto We demonstrate that serine 146 is required for two crucial features of cdc25b1. It is essential for cdc25b1 to function as a mitotic inducer and to prevent cdc25b1 export from the nucleus. We also show that serine 146 is phosphorylated in vitro by cdk1-cyclin b. Serine 146 phosphorylation is proposed to be a key event in the regulation of the cdc25b function SIGNOR-216753 0.758 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT up-regulates activity phosphorylation Ser48 VEIIRMAsIYSEEGN 9534 BTO:0000298 11483516 t llicata BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads. SIGNOR-250600 0.294 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI HNF4A protein P41235 UNIPROT down-regulates quantity by repression 9606 9792724 f miannu Retinoic acid mediates down-regulation of the alpha-fetoprotein gene through decreased expression of hepatocyte nuclear factors. The levels of HNF1 and HNF4 mRNA were also decreased following RA treatment. SIGNOR-254445 0.8 SIRT2 protein Q8IXJ6 UNIPROT MYCN protein P04198 UNIPROT up-regulates quantity by stabilization 9606 23175188 f miannu Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. SIGNOR-255147 0.384 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1096 RYPNDSVyANWMLSP 9606 14711813 t llicata Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. SIGNOR-121149 0.2 LCK protein P06239 UNIPROT ADAM15 protein Q13444 UNIPROT up-regulates phosphorylation Tyr735 LKGPTCQyRAAQSGP 9606 11741929 t lperfetto Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling. SIGNOR-112935 0.356 PRKG1 protein Q13976 UNIPROT RGS2 protein P41220 UNIPROT up-regulates activity phosphorylation Ser46 KDWKTRLsYFLQNSS -1 14608379 t lperfetto Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction.  SIGNOR-249240 0.671 COX5B protein P10606 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267749 0.788 PRKACA protein P17612 UNIPROT CDK18 protein Q07002 UNIPROT up-regulates activity phosphorylation Ser14 KNFKRRFsLSVPRTE 28361970 t lperfetto We previously revealed that PCTK3 is activated by two pathways: interaction with cytoplasmic cyclin A and phosphorylation at Ser-12 by protein kinase A (PKA)12. Activated PCTK3 phosphorylates retinoblastoma protein (Rb) in vitro.  SIGNOR-264560 0.226 ATG12 protein O94817 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR form complex binding 9606 BTO:0000007 18321988 t lperfetto Atg12 is conjugated to atg5 and forms an approximately 800-kda protein complex with atg16l (referred to as atg16l complex). SIGNOR-226689 0.864 TSPOAP1 protein O95153 UNIPROT RIMS3 protein Q9UJD0 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264373 0.2 DUSP9 protein Q99956 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates binding 9606 21908610 t gcesareni Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein. SIGNOR-176583 0.687 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. SIGNOR-252359 0.783 SNRPD3 protein P62318 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270637 0.821 IRAK4 protein Q9NWZ3 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser288 QKSGQDVsQAQRQIK 9606 BTO:0000130 17217339 t lperfetto Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.We found that thr133, ser288 and thr356, targets for irak-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after lps stimulation. We conclude that irak-4 phosphorylates p47phox and regulates nadph oxidase activation after lps stimulation. SIGNOR-152011 0.389 SRC protein P12931 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Tyr13 AVLADVSyLMAMEKS 9606 BTO:0000007 16725308 t miannu Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq.  SIGNOR-266307 0.2 PLAG1 protein Q6DJT9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 11888928 f miannu Plagl1 has been shown to prevent the proliferation of tumor cells by inducing cell cycle arrest and apoptosis SIGNOR-115772 0.7 CASP8 protein Q14790 UNIPROT CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 18073771 t amattioni Active caspase-8 then proteolytically processes and activates caspase-7 SIGNOR-159853 0.731 NLGN1 protein Q8N2Q7 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264164 0.823 H4C1 protein P62805 UNIPROT Nucleosome_H2A.Z.1 variant complex SIGNOR-C322 SIGNOR form complex binding -1 24311584 t miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. SIGNOR-263718 0.2 PRPS1 protein P60891 UNIPROT Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates 9606 BTO:0006038 29074724 f lperfetto We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. SIGNOR-265733 0.7 GOLGB1 protein Q14789 UNIPROT GOLGA2 protein Q08379 UNIPROT up-regulates activity binding 9606 23555793 t miannu The “cis-golgin tether” is one of the most well-characterized golgin tether complexes. It is composed of the COPI vesicle-associated golgin giantin linked to Golgi membrane-associated GM130 via p115. GM130 is in turn linked to GRASP65 via a PDZ-like domain. GRASP65 is anchored to the Golgi membrane through N-terminal myristoylation as well as through binding to other Golgi proteins [10]. Together, these proteins appear to mediate vesicle tethering at the cis-Golgi membrane. SIGNOR-261238 0.76 TP53 protein P04637 UNIPROT CYCS protein P99999 UNIPROT up-regulates 9606 19007744 f Translocation from Mitochondria to Cytosol lperfetto P53 translocation precedes changes of mitochondrial membrane potential, cytochrome c release and caspase activation SIGNOR-140251 0.468 GABPB1 protein Q06547 UNIPROT HCFC1 protein P51610 UNIPROT down-regulates activity binding 9606 BTO:0000567 10675337 t miannu The C1 factor interacts with the GABP_ transactivation domain.The domain of the C1 factor required for C1–GABP interaction can inhibit GABP_dependent transcriptional activation SIGNOR-221377 0.334 FYN protein P06241 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268210 0.619 PPP3CA protein Q08209 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 t In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. SIGNOR-248693 0.392 quizartinib chemical CHEBI:90217 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258271 0.8 MELK protein Q14680 UNIPROT CDC25B protein P30305 UNIPROT down-regulates activity phosphorylation Ser219 HALAEWAsRREAFAQ 9606 BTO:0001938 12400006 t In the present study we show that the human pEg3 kinase is able to specifically phosphorylate CDC25B in vitro. One phosphorylation site was identified and corresponded to serine 323[Ä] Taken together these results suggest that pEg3 is a potential regulator of the G2/M progression and may act antagonistically to the CDC25B phosphatase SIGNOR-255655 0.548 IYD protein Q6PHW0 UNIPROT L-tyrosine zwitterion smallmolecule CHEBI:58315 ChEBI up-regulates quantity chemical modification 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-267033 0.8 PRKCA protein P17252 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 BTO:0000150;BTO:0000938 15695813 t gcesareni Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth. SIGNOR-133861 0.261 CP-91149 chemical CID:9843900 PUBCHEM PYGL protein P06737 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191112 0.8 PTPRF protein P10586 UNIPROT BCAR1 protein P56945 UNIPROT down-regulates quantity by destabilization dephosphorylation 9606 10320483 t lperfetto LAR specifically dephosphorylates and destabilizes p130Cas and may play a role in regulating cell adhesion-mediated cell survival.|Transmembrane tyrosine phosphatase LAR induces apoptosis by dephosphorylating and destabilizing p130Cas. SIGNOR-276998 0.344 A6/b1 integrin complex SIGNOR-C164 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression 10090 18757303 f lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. SIGNOR-253282 0.386 INPPL1 protein O15357 UNIPROT CBLC protein Q9ULV8 UNIPROT down-regulates binding 9606 BTO:0000567 15668240 t gcesareni This association between ship2 and cbl could sequester cbl from the egfr, thereby regulating the kinetics of egfr-cbl association and subsequent internalization and degradation of the receptor. SIGNOR-133388 0.2 FBN1 protein P35555 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity binding 9606 17242066 t Regulation of localization miannu We have discovered that fibrillin-1, which forms extracellular microfibrils, can regulate the bioavailability of transforming growth factor (TGF) beta1, a powerful cytokine that modulates cell survival and phenotype. Altered TGFbeta signaling is a major contributor to the pathology of Marfan syndrome (MFS) and related diseases. In the presence of cell layer extracellular matrix, a fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling. SIGNOR-251888 0.502 CARD9 protein Q9H257 UNIPROT BCL10 protein O95999 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 11053425 t To identify upstream signaling partners of BCL10, we performed a mammalian two-hybrid analysis and identified CARD9 as a novel CARD-containing protein that interacts selectively with the CARD activation domain of BCL10. When expressed in cells, CARD9 binds to BCL10 and activates NF-kappaB. SIGNOR-257602 0.751 SRC protein P12931 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr679 DRPKDEVySKYYTPV 9606 12621061 t llicata Stat5 is activated by a broad spectrum of cytokines, as well as non-receptor tyrosine kinases, such as src. these conformational differences may in part be due to differential effects of prl and src on stat5b tyrosine phosphorylation, since src induced several additional sites of tyrosine phosphorylation of stat5b at residues other than tyr-699, including tyr-724 and tyr-679. SIGNOR-99002 0.596 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CAPN2 protein P17655 UNIPROT up-regulates phosphorylation 9606 14993287 t inferred from 70% family members lperfetto Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo. SIGNOR-270078 0.2 MAPK8IP2 protein Q13387 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 10490659 t gcesareni Both jip1 and jip2 selectively bind the mapkk isoform mkk7. SIGNOR-70857 0.668 APP protein P05067 UNIPROT GSK3A protein P49840 UNIPROT up-regulates 9606 BTO:0000938 16446437 f gcesareni These results suggest a direct relationship between app proteolytic processing, but not amyloid-_, in gsk-3_ activation and tau phosphorylation in human neurons. SIGNOR-144057 0.419 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser38 LGPGTRLsLARMPPP -1 7822264 t llicata On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II. SIGNOR-250628 0.437 PPP2CB protein P62714 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7780739 t Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines|Protein phosphatase-2A was the only vanadate-insensitive phosphatase acting on Thr 183 of p42mapk or on MAPKK to be detected in PC12 cell extracts. SIGNOR-248590 0.457 MYC protein P01106 UNIPROT LDHA protein P00338 UNIPROT up-regulates quantity transcriptional regulation 10116 9192621 f Our studies have linked c-Myc to the induction of LDH-A, whose expression increases lactate production and is necessary for c-Myc-mediated transformation SIGNOR-259367 0.576 CRK protein P46108 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates binding 9606 BTO:0000782 9891069 t HPK1 phosphorylated Crk mainly on threonine and weakly on serine gcesareni We found that hpk1 interacted with crk and crkl adaptor proteins in vitro and in vivo and that the proline-rich motifs within hpk1 were involved in the differential interaction of hpk1 with the crk proteins and grb2. Crk and crkl not only activated hpk1 but also synergized with hpk1 in the activation of jnk. SIGNOR-63988 0.674 LYN protein P07948 UNIPROT FCGR2C protein P31995 UNIPROT up-regulates activity phosphorylation Tyr310 TDDDKNIyLTLPPND -1 8756631 t miannu Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation SIGNOR-262676 0.2 EEF1A2 protein Q05639 UNIPROT Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269528 0.8 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273104 0.745 HMG20B protein Q9P0W2 UNIPROT BHC complex complex SIGNOR-C353 SIGNOR form complex binding 9606 BTO:0000567; BTO:0000007 15325272 t miannu BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells SIGNOR-264503 0.765 PRKCA protein P17252 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity phosphorylation Ser346 EWEAQRDsHLGPHRS 9606 14576165 t lperfetto A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis. SIGNOR-249236 0.267 RPS6K proteinfamily SIGNOR-PF26 SIGNOR DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser291 CGSSGYFsSSPTLSS 9606 22017877 t lperfetto We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1 SIGNOR-252799 0.2 GSK1016790A chemical CID:23630211 PUBCHEM TRPV4 protein Q9HBA0 UNIPROT up-regulates activity binding 23021218 t lperfetto We next examined whether chemical activation of TRPV4 would have the opposite impact on these pathways. When added to 3T3-F442A adipocytes, the TRPV4 agonist GSK1016790A repressed the expression of mRNAs encoding Pgc1a, Ucp1, and Cox8b in a TRPV4-dependent manner (Fig- ure 2I). Taken together, these data strongly suggest that TRPV4 functions as a negative regulator of PGC1a and oxidative metabolism in white adipocytes. SIGNOR-253094 0.8 STAT3 protein P40763 UNIPROT CEBPD protein P49716 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24011072 f miannu To assess whether Stat3 affects C/EBPŒ¥ expression, we co-transfected C2C12 myoblasts with a plasmid expressing a C/EBPŒ¥promoter-driven luciferase plus a lentivirus expressing the constitutively active Stat3C-GFP. Overexpression of Stat3C increased C/EBPŒ¥promoter activity compared to that in lentivirus expressing GFP control SIGNOR-255333 0.595 mTORC2 complex SIGNOR-C2 SIGNOR mTORC2 complex SIGNOR-C2 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000782 10702316 t lperfetto We report here the identification of a FRAP autophosphorylation site. This site, Ser-2481, is located in a hydrophobic region near the conserved carboxyl-terminal FRAP tail. We demonstrate that the COOH-terminal tail is required for FRAP kinase activity and for signaling to the translational regulator p70(s6k) (ribosomal subunit S6 kinase). SIGNOR-217000 0.677 MAPK14 protein Q16539 UNIPROT USF1 protein P22415 UNIPROT up-regulates activity phosphorylation Thr153 EALLGQAtPPGTGQF 9606 19389701 t lperfetto Following uv irradiation, usf-1 is phosphorylated by the p38 stress-activated kinase on threonine 153 and directly up-regulates expression of the pomc, mc1r, tyr, tyrp-1 and dct genes SIGNOR-185572 0.533 SMC3 protein Q9UQE7 UNIPROT MXI1 protein P50539 UNIPROT down-regulates activity binding 9534 BTO:0000318 9528857 t 2 miannu We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions. SIGNOR-241223 0.413 N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-6-quinazolinyl]-2-propenamide chemical CHEBI:91467 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189942 0.8 LYN protein P07948 UNIPROT BTK protein Q06187 UNIPROT up-regulates phosphorylation Tyr551 RYVLDDEyTSSVGSK 9606 BTO:0000776 8630736 t lperfetto Phosphorylation at y551 requires lyn kinase activity, indicating that y551 is a transphosphorylation site \ this transphosphorylation at y551 is followed by phosphorylation at a second site, which is dependent on btk catalytic activity. SIGNOR-41607 0.525 CAMKK1 protein Q8N5S9 UNIPROT CAMK1D protein Q8IU85 UNIPROT up-regulates activity phosphorylation Thr180 GKGDVMStACGTPGY BTO:0000567 12935886 t llicata CaM-KIdelta exhibits Ca(2+)/CaM-dependent activity that is enhanced (approximately 30-fold) in vitro by phosphorylation of its Thr180 by CaM-K kinase (CaM-KK)alpha, consistent with detection of CaM-KIdelta-activating activity in HeLa cells. | This sustained activation of CaM-KIdelta was completely abolished by Thr180Ala mutation and inhibited by CaM-KK inhibitor, STO-609, indicating a functional CaM-KK/CaM-KIdelta cascade in HeLa cells. SIGNOR-250715 0.426 PIK3C2A protein O00443 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates chemical modification 9606 23119004 t gcesareni Pi3ks phosphorylate the d3 position of membrane phosphatidylinositides to generate phosphatidylinositol 3,4,5-triphosphate (pip3). SIGNOR-199367 0.8 RELA protein Q04206 UNIPROT BMP4 protein P12644 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000018 17350185 t Luana Co-transfection with pCMV4-RelA alone or in combination with pCMV4p50 repressed pSLA4.1 EX-Lux activity by approximately 75 percent in both H441 and A549 cells  SIGNOR-266087 0.2 PRKCD protein Q05655 UNIPROT KCNE3 protein Q9Y6H6 UNIPROT up-regulates activity phosphorylation Ser82 LILGYTRsRKVDKRS 21911611 t lperfetto Currents mediated by the complex formed by KCNQ1 and the mutant KCNE3-S82A β-subunit (mutation of the site for PKCdelta-promoted phosphorylation and modulation of the activity of KCNE3) showed rapid run-down and insensitivity to E2.  SIGNOR-275964 0.2 DDIT3 protein P35638 UNIPROT CEBPB protein P17676 UNIPROT down-regulates quantity transcriptional regulation 10090 7588595 t We find that expression of CHOP, a nuclear protein that dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process. SIGNOR-255914 0.668 MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 9312068 t gcesareni Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues. SIGNOR-51203 0.687 USP5 protein P45974 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270830 0.841 FASN protein P49327 UNIPROT hexadecanoic acid smallmolecule CHEBI:15756 ChEBI up-regulates quantity chemical modification 9606 12689621 t An organizational model for animal FAS was proposed in which the two subunits depicted in domains I, II, and III were arranged in an antiparallel fashion, thereby generating two sites for palmitate synthesis. Initiation of the series of condensation reactions leading to the production of palmitic acid requires the translocation of one acetyl and seven malonyl moieties, from CoA thioester to the phosphopantetheine thiol of the ACP domain. SIGNOR-267373 0.8 ITGAE protein P38570 UNIPROT AE/b7 integrin complex SIGNOR-C186 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253291 0.676 SIRT1 protein Q96EB6 UNIPROT NCOR2 protein Q9Y618 UNIPROT up-regulates 9606 22395773 t FFerrentino In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription. SIGNOR-253506 0.507 GABA-A proteinfamily SIGNOR-PF61 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268610 0.2 CBP/p300 complex SIGNOR-C6 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates activity acetylation Lys19 VKRLLGWkKSAGGSG 9606 BTO:0000567;BTO:0002181;BTO:0000552 17074756 t lperfetto We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfbeta-dependent manner. To identify the specific lysine residue acetylated by p300, lys19, and lys20 in smad2(fl) were mutated individually and subjected to p300-mediated acetylation following expression in 293t cells. Mutation of lys19 blocked the p300-mediated acetylation of smad2(fl), whereas mutation of lys20 had no effect (fig. 2b), suggesting that lys19 is the preferred site for p300-mediated acetylation of smad2(fl). SIGNOR-235899 0.647 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser695 MSQPSTAsNSLPEPA 9606 10195894 t Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. SIGNOR-251281 0.2 CSNK1A1 protein P48729 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity. SIGNOR-252898 0.393 URI1 prefoldin co-chaperone complex SIGNOR-C514 SIGNOR PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR form complex binding 9606 30484152 t miannu The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92.  SIGNOR-270924 0.564 NRAS protein P01111 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-175225 0.654 PFKP protein Q01813 UNIPROT ATG4B protein Q9Y4P1 UNIPROT up-regulates activity phosphorylation Ser34 WILGRKYsIFTEKDE 9606 BTO:0000007 33607258 t lperfetto In vitro kinase assay validated that PFKP functioning as a protein kinase phosphorylated ATG4B at S34. This phosphorylation could enhance ATG4B activity and p62 degradation. In addition, PFKP S386 phosphorylation was important to ATG4B S34 phosphorylation and autophagy in HEK293T cells. SIGNOR-275832 0.2 ruxolitinib chemical CHEBI:66919 ChEBI JAK3 protein P52333 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206673 0.8 PTEN protein P60484 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 f miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). SIGNOR-260054 0.402 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates phosphorylation Ser184 QSPRTRGsRRQIQRL 9606 19789335 t gcesareni Our data demonstrated that ask1 controls the cytoplasmic localization of daxx (fig.1). our results indicate that daxx not only activates ask1 but also is a downstream target of ask1 and that accumulated daxx further activates ask1. Thus, the daxx-ask1 positive feedback loop amplifying jnk/p38 signaling plays an important role in the cell-killing effects of stressors, such as tnfalpha. SIGNOR-188325 0.835 GATA3 protein P23771 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 16386358 t Experimental data indeed supports the existence of a positive circuit involvingGATA-3 that excludes IL-4 and STAT-6, specifically in mouse cells SIGNOR-254300 0.2 TNFSF10 protein P50591 UNIPROT TNFRSF10A protein O00220 UNIPROT up-regulates binding 9606 14585074 t amattioni Trail interacts with tril-r1 and trail-r2 and activetes them SIGNOR-101082 0.932 OPRD1 protein P41143 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256826 0.438 TNFRSF1A protein P19438 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization 10090 BTO:0002572;BTO:0000801 21232017 f lperfetto Tnfr1-induced phosforylation and degradarionn of ikb are almost completely abolished in tradd-deficient mefs,these hallmarks of classical nf-kn signaling are only attenuated in tradd-deficient macrophage. SIGNOR-235789 0.539 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation -1 9793625 t Mometasone furoate (MF, CAS 83919-23-7, Sch 32088), budesonide (BUD, CAS 51372-29-3), fluticasone propionate (FP, CAS 80474-14-2), and triamcinolone acetonide (TA, CAS-76-25-5) are corticosteroids. All of the test compounds had a higher affinity for the recombinant glucocorticoid receptor than the reference glucocorticoid receptor ligand, dexamethasone (DEX, CAS 50-02-2). All compounds showed greater potency than dexamethasone in stimulating transcription of a synthetic target gene regulated by a glucocorticoid response element. SIGNOR-253053 0.8 EGFR protein P00533 UNIPROT ERRFI1 protein Q9UJM3 UNIPROT up-regulates activity phosphorylation Tyr394 KKVSSTHyYLLPERP 10090 BTO:0000944 phosphorylation:Tyr395 KVSSTHYyLLPERPP 26280531 t "here we found that the epidermal growth factor receptor (EGFR) phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, by Src." SIGNOR-252091 0.661 CHEK1 protein O14757 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates phosphorylation Ser328 INITKPAsVFVQLRR 9606 22152481 t llicata Taken together, the above findings suggest that chk1 phosphorylates p50 at s329 and further, that this phosphorylation blocks p50 dna binding. SIGNOR-195208 0.278 TDGF1 protein P13385 UNIPROT MSTN protein O14793 UNIPROT down-regulates 9606 23129614 f fstefani We provide evidence that cripto modulates myogenic cell determination and promotes proliferation by antagonizing the tgf-beta ligand myostatin. SIGNOR-192436 0.318 CHRM3 protein P20309 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257134 0.385 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr21 ENLEQEEyEDPDIPE -1 10942405 t The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton SIGNOR-251411 0.462 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser100 QPQDKVIsGIAREKL 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262713 0.733 RBBP4 protein Q09028 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR form complex binding 9606 23110252 t lperfetto The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48). SIGNOR-241906 0.887 DNA_damage stimulus SIGNOR-ST1 SIGNOR PARP1 protein P09874 UNIPROT up-regulates 9606 17891139 f miannu We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus. SIGNOR-260065 0.7 TFEB protein P19484 UNIPROT GLA protein P06280 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276539 0.289 LMO2 protein P25791 UNIPROT ERG protein P11308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001106 21536859 f miannu We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. SIGNOR-253922 0.39 FZD2 protein Q14332 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates activity binding 9606 23151663 t areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  SIGNOR-258962 0.626 ITK protein Q08881 UNIPROT BMX protein P51813 UNIPROT up-regulates activity phosphorylation Tyr216 SSTSLAQyDSNSKKI -1 12573241 t Itk phosphorylated Bmx-SH3 to a low extent. pY positions correspond to the residues Y215 and Y223 in Bmx. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. SIGNOR-251331 0.34 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 10816598 t miannu Fak autophosphorylation site, tyr397. / extracellular matrix (ecm)-induced autophosphorylation of fak on tyr397 creates a high affinity binding site for the sh2 domain of c-src, and mutation (tyr to phe) of this residue inhibits association SIGNOR-77434 0.2 NFE2L2 protein Q16236 UNIPROT GCLC protein P48506 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22459801 f miannu Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed. SIGNOR-254643 0.483 KIT protein P10721 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9534 7509796 t Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells SIGNOR-255948 0.716 TESK2 protein Q96S53 UNIPROT CFL2 protein Q9Y281 UNIPROT down-regulates activity phosphorylation Ser3 sGVTVNDE 9606 BTO:0001363 11418599 t lperfetto Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin SIGNOR-246711 0.326 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 20185585 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-163941 0.8 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257925 0.8 RHEB protein Q15382 UNIPROT FKBP8 protein Q14318 UNIPROT down-regulates activity gtpase-activating protein 9606 19222999 t lperfetto Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1. SIGNOR-233568 0.55 XRCC5 protein P13010 UNIPROT PDX1 protein P52945 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002284 16166097 t miannu The interaction of PDX-1 with Ku subunits and its phosphorylation on threonine 11 by the DNA-PK appear to be implicated in its degradation by the proteosome. SIGNOR-225537 0.312 CDK8 protein P49336 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo. SIGNOR-273171 0.2 ANK3 protein Q12955 UNIPROT SPTBN1 protein Q01082 UNIPROT up-regulates activity binding 9606 BTO:0000007 17620337 t miannu Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. Ankyrin-G also recruits beta-2-spectrin to E-cadherin-beta-catenin complexes, thus providing a direct connection between E-cadherin and the spectrin/actin skeleton. SIGNOR-266711 0.629 CHEK1 protein O14757 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates activity phosphorylation Ser331 KSKGRASsSGNQESS 9606 BTO:0000567 19861535 t lperfetto In vitro and in vivo experiments show that phosphorylation of s331 is mediated by chk1, the s-phase checkpoint kinase implicated in the fanconi anemia dna repair pathway. phosphorylation at this site is dependent on chk1, signifying the importance of the s-phase checkpoint in the activation of fanconi anemia pathway. SIGNOR-107042 0.603 SCHEMBL14517914 chemical CID:10016910 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 20068082 t gcesareni Xl844 (exelixis) a potent atp-competitive inhibitor of chk1 (ki, 2.2nm) and chk2 (ki, 0.07nm). SIGNOR-163231 0.8 CCAR2 protein Q8N163 UNIPROT SIRT1 protein Q96EB6 UNIPROT down-regulates activity binding 9606 22735644 t lperfetto  Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death.  SIGNOR-267663 0.735 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity phosphorylation Ser293 GSTKRRKsMSGASPK 9606 12676583 t Manara Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A SIGNOR-260836 0.837 PPM1D protein O15297 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity dephosphorylation Thr543 IDEDGENtQIEDTEP 9606 31619012 t miannu In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. SIGNOR-277046 0.401 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1193 QPTSKAYsPRYSISD 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-236440 0.702 CSNK2A1 protein P68400 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates phosphorylation Ser126 EESESEDsEDSGGEE 9606 16308564 t lperfetto Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting. SIGNOR-142351 0.2 RCHY1 protein Q96PM5 UNIPROT POLH protein Q9Y253 UNIPROT down-regulates activity monoubiquitination Lys709 QTLESFFkPLTH 9606 21791603 t miannu Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709). SIGNOR-272733 0.563 ERG protein P11308 UNIPROT VIM protein P08670 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093;BTO:0000815 8895512 f miannu Our results suggest that PEA3 specifically transactivates vimentin promoter through PEA3 site. Among members of the ETS transcription factor family only Erg showed ability to transactivate vimentin promoter besides PEA3. SIGNOR-254069 0.2 DLL4 protein Q9NR61 UNIPROT NRP1 protein O14786 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18339870 f gcesareni Dll4 down-regulates vascular endothelial growth factor (vegf)_ receptor_ 2 and nrp1 expression and inhibits vegf function SIGNOR-178029 0.369 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR MYL4 protein P12829 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136697 0.304 BMP7 protein P18075 UNIPROT Brown_adipogenesis phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 18719589 f fspada Here we demonstrate that whereas some members of the family of bone morphogenetic proteins (bmps) support white adipocyte differentiation, bmp7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail. SIGNOR-180305 0.7 UNG protein P13051 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). SIGNOR-275711 0.7 VEGFC protein P49767 UNIPROT NRP2 protein O60462 UNIPROT up-regulates binding 9606 BTO:0000938 16816121 t gcesareni The functional importance of the interaction of np2 with the lymphangiogenic growth factors was demonstrated by cointernalization of np2 along with vegfr-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with vegf-c or vegf-d. SIGNOR-147611 0.738 oligopeptide smallmolecule CHEBI:25676 ChEBI peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity precursor of 9606 31810556 t scontino Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol. SIGNOR-267866 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR FRAT1 protein Q92837 UNIPROT down-regulates activity phosphorylation Ser188 RLQQRRGsQPETRTG 9606 BTO:0002181 16982607 t miannu Protein kinase A (PKA) was found to phosphorylate Ser188 in vitro as well as in intact cells. Importantly, activation of endogenous cAMP-coupled beta-adrenergic receptors with norepinephrine stimulated the phosphorylation of FRAT1 at Ser188. GSK-3 was also able to phosphorylate FRAT1 at Ser188 and other residues in vitro or when overexpressed in intact cells.  Phosphorylation of Ser188 by PKA inhibited the ability of FRAT1 to activate beta-catenin-dependent transcription. SIGNOR-276058 0.2 EGFR protein P00533 UNIPROT KCND3 protein Q9UK17 UNIPROT up-regulates activity phosphorylation Tyr136 GDCCYEEyKDRKREN 22198508 t lperfetto Our results demonstrate that human atrial I(to) and cloned hKv4.3 channels are modulated by EGFR kinase via phosphorylation of the Y136 residue and by Src-family kinases via phosphorylation of the Y108 residue|We found that human atrial I(to) was inhibited by the broad-spectrum PTK inhibitor genistein, the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556, and the Src-family kinases inhibitor PP2. SIGNOR-275549 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Thr273 SPSVHPAtPISPGRA 9606 BTO:0002181 16046550 t The effect has been demonstrated using Q01196-8 lperfetto We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-244715 0.2 STAT3 protein P40763 UNIPROT HAMP protein P81172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001950 18671304 f miannu HCV-induced ROS stabilized the expression of two negative hepcidin regulators, HIF1alpha and HIF2alpha, and its expression was decreased by a HDAC inhibitor or an anti-oxidant. HCV-induced ROS also caused hypoacetylation of histones and inhibited binding of two positive regulators, C/EBPalpha and STAT3, to the hepcidin promoter, whereas anti-oxidant treatment of cells recovered C/EBPalpha and STAT3 binding to the hepcidin promoter. SIGNOR-255239 0.437 NOTCH1 protein P46531 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR down-regulates 10090 9601631 f Luana Signalling through activated Notch is known both to control multiple cell fate determinations (in both invertebrates and vertebrates) and to inhibit developmental processes, such as neurogenesis SIGNOR-265769 0.7 FYN protein P06241 UNIPROT CTLA4 protein P16410 UNIPROT unknown phosphorylation Tyr218 CEKQFQPyFIPIN 9606 9973379 t CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218.  Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4. SIGNOR-251160 0.761 NFYC protein Q13952 UNIPROT SOX18 protein P35713 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 18496767 f miannu co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells SIGNOR-254822 0.2 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK9 protein P45984 UNIPROT down-regulates binding 9606 10490659 t JNK bound to an NH2-terminal reagion of JIP1 (residues 283 to 660) gcesareni These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins. SIGNOR-70854 0.764 ULK1 protein O75385 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT up-regulates phosphorylation 9606 20921139 t gcesareni When autophagy is induced, ulk1 phosphorylates ambra1, releasing the autophagy core complex from dynein. Its subsequent relocalization to the endoplasmic reticulum enables autophagosome nucleation. Ambra1-dlc1 dissociates from the dynein complex upon ulk1-dependent ambra1 phosphorylation. SIGNOR-168292 0.683 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89178 0.538 S1PR3 protein Q99500 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257175 0.4 N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 17194761 t miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. SIGNOR-267525 0.8 IFNG protein P01579 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 f lperfetto Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS SIGNOR-260259 0.7 CDK1 protein P06493 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser123 EEGFGSSsPVKSPAA 9606 16085715 t gcesareni We show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms. The pS123 not only directly interacted with basic residues in the WD40 repeat domain of beta-TrCP but also primed phosphorylation by two independent protein kinases, Plk1 and CK2 (formerly casein kinase 2) SIGNOR-139465 0.853 CLASP2 protein O75122 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates activity binding 9534 BTO:0004055 19638411 t lperfetto CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells|the C-terminal region of CLASP2 is known to interact with CLIP-170 SIGNOR-264827 0.763 JAK1 protein P23458 UNIPROT IL2RB protein P14784 UNIPROT up-regulates activity phosphorylation Tyr364 SCFTNQGyFFFHLPD 9534 8700888 t In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc. SIGNOR-251342 0.616 NBEA protein Q8NFP9 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates activity binding 9606 BTO:0000007 BTO:0000227 26999814 t lperfetto Yeast two-hybrid identified the Notch1 intracellular domain as a physical interactor of the PBW domain and a role for NBEA as a negative regulator in Notch-mediated transcription was demonstrated.|Defining novel interaction partners of conserved NBEA domain modules identified a role for NBEA as transcriptional regulator in the nucleus. The physical interaction of NBEA with NOTCH1 is most relevant for ASD pathogenesis because NOTCH signaling is essential for neural development. SIGNOR-266010 0.31 PLK1 protein P53350 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser397 GKNQDFSsFDDTGKS 9606 BTO:0000567 19509060 t lperfetto Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation. SIGNOR-272994 0.603 PRKACA protein P17612 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 10116 11297520 t miannu Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell growth. SIGNOR-250055 0.48 Integrator complex complex SIGNOR-C265 SIGNOR SDC4 protein P31431 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 25675981 f lperfetto The Integrator complex controls the termination of transcription at diverse classes of gene targets.|Following INTS3 or INTS9 knockdown, the levels of SDC4, JUNB, FOSL1, and GADD45B increased, suggesting that the Integrator complex negatively regulates the transcription of these genes. SIGNOR-261480 0.2 SMAD5 protein Q99717 UNIPROT SMAD6 protein O43541 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 t Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation SIGNOR-268940 0.582 TARDBP protein Q13148 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates quantity 9606 BTO:0000312 22051914 f lperfetto Pathological protein aggregates, identified as compact or skein-like ubiquitinated inclusions, are a cardinal feature of ALS.4–6 The identification of TDP-43 as the major protein constituent of these inclusions initi- ated a major shift in our understanding of the patho- biology of ALS SIGNOR-262278 0.7 PRKCZ protein Q05513 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser307 TRRSRTEsITATSPA 10029 15069075 t lperfetto Extensive studies have provided evidence that phosphorylation of Ser307 in IRS-1 inhibits IR/IRS-1 complex formation and IRS-1 tyrosine phosphorylation after prolonged insulin-stimulation similar to our results. SIGNOR-236760 0.716 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide chemical CHEBI:94504 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191436 0.8 RASSF1 protein Q9NS23 UNIPROT STK3 protein Q13188 UNIPROT up-regulates binding 9606 21808241 t Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage milica Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization. SIGNOR-175790 0.688 PRKACA protein P17612 UNIPROT HSPB6 protein O14558 UNIPROT down-regulates phosphorylation Ser16 PSWLRRAsAPLPGLS 9606 10196226 t llicata Hosphorylation of hsp20 at ser16 is not only associated with cyclic nucleotide-dependent vasorelaxation but also inhibits agonist-induced contractile responses. SIGNOR-66493 0.2 KAT2B protein Q92831 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269613 0.2 FRAT1 protein Q92837 UNIPROT GSK3B protein P49841 UNIPROT up-regulates binding 9606 SIGNOR-C110 9635432 t gcesareni The frat family consists of three members: frat-1, -2, and -3. It has been shown that different sites of frat-1 interact with gsk-3 and dvl-1 and that wnt-1 disintegrates the complex formation of frat-1, dvl-1, and axin, resulting in the activation of the wnt signaling pathway SIGNOR-58219 0.767 CSNK1D protein P48730 UNIPROT SMARCA4 protein P51532 UNIPROT down-regulates quantity by destabilization phosphorylation Ser31 PGAMLGPsPGPSPGS 9606 BTO:0001225 30177679 t miannu  We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation.  SIGNOR-277408 0.2 SYVN1 protein Q86TM6 UNIPROT HERPUD1 protein Q15011 UNIPROT up-regulates activity binding 9606 BTO:0000007 28827405 t miannu FAM8A1 enhances binding of Herp to Hrd1, an interaction that is required for ERAD. Our findings support a model of Hrd1 complex formation, where the Hrd1 cytoplasmic domain and FAM8A1 have a central role in the assembly and activity of this ERAD machinery. A conserved Hrd1 cytoplasmic domain interacts with FAM8A1 and Herp SIGNOR-261349 0.591 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203540 0.769 AKT1 protein P31749 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 11108261 t lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. SIGNOR-84975 0.756 XPO1 protein O14980 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity relocalization 9606 17891139 t miannu We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus. SIGNOR-260067 0.565 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914161 t lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 SIGNOR-161605 0.591 FCRL3 protein Q96P31 UNIPROT SYK protein P43405 UNIPROT up-regulates activity binding -1 12051764 t miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. SIGNOR-274011 0.359 NEDD4 protein P46934 UNIPROT SYK protein P43405 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 11046148 t miannu The latent membrane protein (LMP) 2A of Epstein-Barr virus (EBV) is implicated in the maintenance of viral latency and appears to function in part by inhibiting B-cell receptor (BCR) signaling. LMP2A enhances Lyn and Syk ubiquitination in vivo in a fashion that depends on the activity of Nedd4 family members and correlates with destabilization of the Lyn tyrosine kinase. These results suggest that LMP2A serves as a molecular scaffold to recruit both B-cell tyrosine kinases and C2/WW/Hect domain E3 protein-ubiquitin ligases.  SIGNOR-272581 0.296 NOD1 protein Q9Y239 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 BTO:0000567 19898471 f miannu Autophagy is emerging as a crucial defense mechanism against bacteria, but the host intracellular sensors responsible for inducing autophagy in response to bacterial infection remain unknown. Here we demonstrated that the intracellular sensors Nod1 and Nod2 are critical for the autophagic response to invasive bacteria. SIGNOR-252404 0.7 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser217 AHYSPRTsPIMSPRT 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248686 0.613 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257968 0.8 EEF2 protein P13639 UNIPROT Translational_elongation phenotype SIGNOR-PH210 SIGNOR up-regulates 9606 14709557 f lperfetto In mammalian cells, peptide chain elongation requires two main elongation factors, eEF1A and eEF2. SIGNOR-269396 0.7 ACVR1 protein Q04771 UNIPROT VPS39 protein Q96JC1 UNIPROT up-regulates activity binding 9534 12941698 t miannu TLP interacts with TGF-β and activin receptors in vivo. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling. SIGNOR-261376 0.2 CBL protein P22681 UNIPROT INSR protein P06213 UNIPROT down-regulates ubiquitination 9606 11498022 t gcesareni Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor SIGNOR-109688 0.507 FADS1 protein O60427 UNIPROT long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI down-regulates quantity chemical modification 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267907 0.8 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 SIGNOR-C110 SIGNOR-C110 10318824 t lperfetto From the binding experiments, we defined the domains of Axin that bind glycogen synthase kinase-3beta (GSK-3beta) and beta-catenin. We also examined the ability of each Axin mutant to inhibit lymphoid enhancer factor-1 (Lef-1) reporter activity in a cell line expressing high levels of beta-catenin. SIGNOR-67438 0.918 TFE3 protein P19532 UNIPROT CD63 protein P08962 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276812 0.2 CSNK2A1 protein P68400 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity phosphorylation Ser59 SETNQNSsSDSEAER -1 11711551 t llicata We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. SIGNOR-250963 0.365 TCF3 protein P15923 UNIPROT BBC3 protein Q96PG8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23684607 f miannu The transcription factor TCF3, also known as E2A, drives p21 expression while repressing PUMA across cancer cell types of multiple origins. SIGNOR-255386 0.275 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249647 0.2 APEX1 protein P27695 UNIPROT TG protein P01266 UNIPROT up-regulates quantity by expression transcriptional regulation 9813166 t lperfetto In co-transfection experiments, Ref-1 increases the Pax-8 activating effect on thyroglobulin promoter. SIGNOR-271694 0.2 KRAS protein P01116 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates 10090 BTO:0003104 10082541 f lperfetto A constitutively active Ras protein [Ras(G12V)] regulates the stable expression of the NFIL3 transcription factor through both the Raf-MAPK and PI3-K pathways. SIGNOR-242757 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression SIGNOR-244602 0.2 QRICH1 protein Q2TAL8 UNIPROT VARS1 protein P26640 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269408 0.2 MARK2 protein Q7KZI7 UNIPROT UTRN protein P46939 UNIPROT up-regulates phosphorylation Ser1258 TLEERMKsTEVLPEK 9606 BTO:0000887;BTO:0001103 19945424 t lperfetto Par-1b, interacts with the utrophin-dg complex, and positively regulates the interaction between utrophin and dg. Ser1258 within r9 is specifically phosphorylated by par-1b. SIGNOR-161915 0.434 EPAS1 protein Q99814 UNIPROT KDM1A protein O60341 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271588 0.283 CTTNBP2 protein Q8WZ74 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity binding 9606 BTO:0000938 35562389 t miannu Synaptopathy, a key feature of autism spectrum disorders (ASD), is likely relevant to the impaired phase separation and/or transition of ASD-linked synaptic proteins. Here, we report that LLPS and zinc-induced liquid-to-gel phase transition regulate the synaptic distribution and protein-protein interaction of cortactin-binding protein 2 (CTTNBP2), an ASD-linked protein. CTTNBP2 forms self-assembled condensates through its C-terminal intrinsically disordered region and facilitates SHANK3 co-condensation at dendritic spines. SIGNOR-269702 0.2 NARS1 protein O43776 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270456 0.8 SIRT5 protein Q9NXA8 UNIPROT CPS1 protein P31327 UNIPROT up-regulates activity post translational modification 9606 BTO:0000567 24703693 t deglutarylation lperfetto Glutarylation suppresses CPS1 activity, which is targeted by SIRT5 for removal|SIRT5 can catalyze the enzymatic removal of lysine glutarylation SIGNOR-267643 0.522 MAPK9 protein P45984 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr275 TTGTKSNtPTSSVPS 9606 15767678 t gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. SIGNOR-134572 0.653 YWHAQ protein P27348 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates binding 9606 11433030 t gcesareni 14-3-3tau associates with and activates the mef2d transcription factor during muscle cell differentiation. SIGNOR-109139 0.565 SRC protein P12931 UNIPROT CAV2 protein P51636 UNIPROT down-regulates phosphorylation Tyr27 SHHSGLEyADPEKFA 9606 15504032 t lperfetto Here, we show that cav-2 is phosphorylated at both tyrosines 19 and 27. We reconstituted this phosphorylation event by recombinantly coexpressing c-src and cav-2.Further functional analysis revealed that tyrosine phosphorylation of cav-2 has no effect on its targeting to lipid rafts, but clearly disrupts the hetero-oligomerization of cav-2 with cav-1. SIGNOR-129961 0.667 TNFRSF11A protein Q9Y6Q6 UNIPROT Osteoclast_differentiation phenotype SIGNOR-PH76 SIGNOR up-regulates 9606 17572386 f miannu Osteoclasts are fully differentiated, multi-nucleated cells originating from the hematopoietic monocyte-macrophage linage. RANKL, a member of the tumor necrosis factor (TNF) superfamily, and its receptor RANK are essential regulators of osteoclast maturation and activation SIGNOR-253043 0.7 RPL18 protein Q07020 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262481 0.847 PRKAA1 protein Q13131 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates quantity by stabilization phosphorylation Ser92 SFLVRKPsDPNRKPN 9606 19923321 t lperfetto Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively. SIGNOR-161779 0.2 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT up-regulates activity phosphorylation Ser2 sDHGDVSL 9534 BTO:0000298 11483516 t llicata BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads. SIGNOR-250596 0.294 Bafetinib chemical CID:24853523 PUBCHEM LYN protein P07948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190227 0.8 NMBR protein P28336 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways. SIGNOR-107025 0.286 DAB2IP protein Q5VWQ8 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity binding 9606 27858941 t miannu DAB2IP inhibits the PI3K–AKT axis by directly interacting with both proteins, reducing phosphorylation and activation of AKT. The GAP activity of DAB2IP can further enforce inhibition of the PI3K–AKT axis by reducing Ras-dependent activation of PI3K p110α subunit. SIGNOR-254750 0.2 NMDA receptor_2D complex SIGNOR-C350 SIGNOR CTTN protein Q14247 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 14684878 t miannu Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors. SIGNOR-266602 0.292 HBB protein P68871 UNIPROT AHSP protein Q9NZD4 UNIPROT down-regulates activity 9606 2545495 f Regulation miannu EDRF is rapidly inactivated by hemoglobin and superoxide. SIGNOR-251750 0.545 BDKRB2 protein P30411 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256974 0.2 PPP2R5C protein Q13362 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates binding 9606 16456541 t inferred from 70% of family members gcesareni B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk SIGNOR-269922 0.499 SNRPB protein P14678 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270680 0.918 U0126 chemical CHEBI:90693 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 9873633 t gcesareni The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2. SIGNOR-62892 0.8 TLN1 protein Q9Y490 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257619 0.589 USP9X protein Q93008 UNIPROT UBA52 protein P62987 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270825 0.594 Histone H3 proteinfamily SIGNOR-PF69 SIGNOR Nucleosome complex SIGNOR-C371 SIGNOR form complex binding -1 21812398 t lperfetto The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. SIGNOR-265308 0.2 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr36 LPPGDYStTPGGTLF 9606 BTO:0000007 SIGNOR-C3 9465032 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-55697 0.924 G6P proteinfamily SIGNOR-PF81 SIGNOR α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity chemical modification 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-266567 0.8 BACH1 protein O14867 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000150 22875853 f Transcriptional network analysis identifies BACH1 as a master regulator of breast cancer bone metastasis SIGNOR-259337 0.7 chloroquine chemical CHEBI:3638 ChEBI TNF protein P01375 UNIPROT down-regulates quantity 9606 32283152 f miannu Chloroquine inhibits the production and release of TNF and IL-6, which indicates that chloroquine may suppress the cytokine storm in patients infected with COVID-19. SIGNOR-260853 0.8 NCS1 protein P62166 UNIPROT DRD2 protein P14416 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000938 12351722 t miannu Here we show that the neuronal calcium sensor-1 (NCS-1) can mediate desensitization of D2 dopamine receptors. Analysis of D2 receptors expressed in human embryonic kidney 293 cells indicates that NCS-1 attenuates agonist-induced receptor internalization via a mechanism that involves a reduction in D2 receptor phosphorylation. Coimmunoprecipitation experiments from striatal neurons reveal that NCS-1 is found in association with both the D2 receptor and G-protein-coupled receptor kinase 2, a regulator of D2 receptor desensitization. SIGNOR-263964 0.667 NFIA protein Q12857 UNIPROT ROBO1 protein Q9Y6N7 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268893 0.2 JNK proteinfamily SIGNOR-PF15 SIGNOR HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 t lperfetto Using modified jnk and its atp analogue enables the detection of novel jnk substrates. Among substrates identified using this approach is heterogeneous nuclear ribonucleoprotein k, which is involved in transcription and post-transcriptional mrna metabolism. The newly identified substrate can be phosphorylated by jnk on amino acids 216 and 353, which contribute to heterogeneous nuclear ribonucleoprotein k mediated transcriptional activities. SIGNOR-105762 0.2 PAX7 protein P23759 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 18066051 t Simone Vumbaca Together, these experiments indicate that Pax7 enforces satellite cell commitment by recruiting a HMT complex to Myf5, resulting in transcriptional activation. SIGNOR-255641 0.506 CSNK2A3 protein Q8NEV1 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1126 TEEFSSEsDMEESKE 9606 BTO:0000938 19064667 t lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. SIGNOR-275759 0.2 CCT129202 chemical CID:16202152 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190883 0.8 precursor messenger RNA smallmolecule CHEBI:139356 ChEBI messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity precursor of 9606 19224921 t lperfetto Because only mRNA molecules that have been correctly spliced, capped at the 5′ extremity, and processed at the 3′ extremity can be used as templates for translation, processing of mRNA precursors plays a critical role in the regulation of gene expression. 3′ processing of pre-mRNAs comprises two steps (reviewed in Ref. 4): cleavage and polyadenylation. SIGNOR-268314 0.8 NUP210 protein Q8TEM1 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262072 0.584 PSTPIP1 protein O43586 UNIPROT DNM2 protein P50570 UNIPROT down-regulates binding 9606 18480402 t miannu We show that pstpip1 associates with the regulator of endocytosis, dynamin 2, and pstpip1 expression impairs transferrin uptake and endocytosis SIGNOR-178628 0.382 ROCK1 protein Q13464 UNIPROT LIMK2 protein P53671 UNIPROT up-regulates phosphorylation Thr505 NDRKKRYtVVGNPYW 9606 11018042 t lperfetto Specific activation of lim kinase 2 via phosphorylation of threonine 505 by rock, a rho-dependent protein kinase SIGNOR-82755 0.617 MAPK1 protein P28482 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation Thr185 HDHTGFLtEYVATRW 1712480 t lperfetto Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.| SIGNOR-249414 0.2 EPHA3 protein P29320 UNIPROT SRC protein P12931 UNIPROT up-regulates binding 9606 BTO:0000938 9632142 t gcesareni We propose src kinase as a downstream effector that mediates the neuron's response to eph receptor activation. SIGNOR-58139 0.508 HTR1B protein P28222 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256999 0.469 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser41 RTDALTSsPGRDLPP 9606 16446360 t gcesareni In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells. SIGNOR-143996 0.961 HAP1 protein P54257 UNIPROT AHI1 protein Q8N157 UNIPROT up-regulates activity binding 9606 BTO:0000452 23532844 t miannu Huntingtin-associated protein-1 (Hap1) is a regulatory protein that binds Ahi1, and Hap1 knock-out mice have been reported to have JBTS-like phenotypes, suggesting a role for Hap1 in ciliogenesis. SIGNOR-269081 0.565 MCU protein Q8NE86 UNIPROT MCU_MICU2_variant complex SIGNOR-C502 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270874 0.695 RNF208 protein Q9H0X6 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization ubiquitination Lys97 DAINTEFkNTRTNEK 9606 BTO:0000815 31862882 t Gianni Here, we show that RING finger protein 208 (RNF208) decreases the stability of soluble Vimentin protein through a polyubiquitin-mediated proteasomal degradation pathway, thereby suppressing metastasis of TNBC cells SIGNOR-269051 0.2 PRKAA1 protein Q13131 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Thr119 HNLMRRStVSLLDTY -1 23871434 t miannu These results indicate that HIPK2 is a substrate of AMPKα2 in vitro and in vivo. Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKα2 in vitro (Figure S5J). SIGNOR-276468 0.2 CSNK1A1 protein P48729 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates quantity by destabilization phosphorylation Thr1363 HVQSVLLtPQDEFFI 9606 BTO:0002181 19797085 t miannu We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity.  SIGNOR-276262 0.314 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t inferred from 70% family members gcesareni Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity. SIGNOR-270115 0.2 FUS protein P35637 UNIPROT DDX3X protein O00571 UNIPROT down-regulates activity relocalization 9606 27460707 t P35637:p.Pro525Leu (mutation causing interaction) We found that ALS mutants of FUS co-localized with Caprin-1, DDX3X, and DHX9 in cytoplasmic inclusions that could lead to the mis-regulation of their respective pathways, providing further clues to the mechanism of ALS pathogenesis.|FUS interacting proteins were sequestered into the cytoplasmic mutant FUS inclusions that could lead to their mis-regulation or loss of function, contributing to ALS pathogenesis. | We also demonstrated the co-localization of DHX9, DDX3X and Caprin-1 with cytoplasmic EGFP-P525L mutant FUS inclusions in primary cortical neurons SIGNOR-262811 0.259 SYK protein P43405 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 t gcesareni The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2). SIGNOR-59643 0.753 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BHMT protein Q93088 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16953798 f miannu SAM and MTA down-regulate BHMT expression in HepG2 cells in part by inducing NF-kappaB, which acts as a repressor for the human BHMT gene. While SAM's mechanism is NF-kappaB-dependent, MTA has both NF-kappaB-dependent and -independent mechanisms. SIGNOR-254659 0.2 ELF4 protein Q99607 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19380490 f miannu We found that elf4/mef activates mdm2 expression SIGNOR-185490 0.391 CYSLTR2 protein Q9NS75 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257024 0.496 histamine smallmolecule CHEBI:18295 ChEBI HRH2 protein P25021 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257513 0.8 CyclinA2/CDK1 complex SIGNOR-C420 SIGNOR BORA protein Q6PGQ7 UNIPROT up-regulates activity phosphorylation 9606 29870721 t lperfetto The active cyclin A/cdk1 complex phosphorylates Bora and promotes Plx1 activation SIGNOR-267573 0.437 SMAD7 protein O15105 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates binding 9606 14718519 t lpetrilli We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI. SIGNOR-121280 0.666 NYYJKMXNVNFOFQ-MHZLTWQESA-N chemical CID:9829836 PUBCHEM ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana There were several β3-selective compounds (e.g. AZ 40140d, L 755507, L 748337 and TAK 677) SIGNOR-257856 0.8 EDNRB protein P24530 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256924 0.27 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 20626350 t lperfetto Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2. SIGNOR-166619 0.679 FLI1 protein Q01543 UNIPROT ERG protein P11308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001106 21536859 f miannu We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. SIGNOR-253921 0.317 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2E2 protein Q96LR5 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271317 0.702 MED1 protein Q15648 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266667 0.804 FBXO22 protein Q8NEZ5 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0003031 26868148 t methylated tp53 lperfetto We demonstrate here that SCFFbxo22-KDM4A is a senescence-associated E3 ligase targeting methylated p53 for degradation. We find that Fbxo22 is highly expressed in senescent cells in a p53-dependent manner, and that SCFFbxo22 ubiquitylated p53 and formed a complex with a lysine demethylase, KDM4A. |SCFFbxo22 forms a ternary complex with p53 and KDM4A that targets methylated p53 for degradation. SIGNOR-273448 0.345 GNAS protein P63092 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR up-regulates activity binding 9606 17652154 t gcesareni Because adenylyl cyclases are directly activated by G(s)alpha and the carboxyl termini of the various Galpha proteins determine their receptor coupling specificity, we proposed a set of chimeric G(s)alpha where the COOH-terminal five amino acids are replaced by those of other Galpha proteins and used these to dissect the potential Galpha linked to a given GPCR SIGNOR-267848 0.731 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser311 SFRTPRDsKLEAPAE 9606 BTO:0000887 20151718 t miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-163796 0.278 LNX1 protein Q8TBB1 UNIPROT NUMB protein P49757 UNIPROT down-regulates ubiquitination 9606 11782429 t esanto Lnx functions as a ring type e3 ubiquitin ligase that targets the cell fate determinant numb for ubiquitin-dependent degradation. SIGNOR-112201 0.73 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser702 AVILTVEsEEEEEES 21296876 t lperfetto Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2. SIGNOR-275503 0.2 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser139 EDLTNVSsLLNMERA 9606 25670858 t lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. SIGNOR-265233 0.571 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000590 11578751 f lperfetto Alzheimer's disease, the cause of one of the most common types of dementia, is a brain disorder affecting the elderly and is characterized by the formation of two main protein aggregates: senile plaques and neurofibrillary tangles, which are involved in the process leading to progressive neuronal degeneration and death SIGNOR-251640 0.7 PKA proteinfamily SIGNOR-PF17 SIGNOR LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Ser950 EGFHPRRsSQGATQM 19018281 t miannu  Our results demonstrate that PKA activates human HSL against lipid substrates in vitro primarily through phosphorylation of Ser649 and Ser650.  SIGNOR-276174 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR GADD45B protein O75293 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11713530 f gcesareni Here we report that nf-kappab complexes downregulate the c-jun amino-terminal kinase (jnk) cascade, thus establishing a link between the nf-kappab and the jnk pathways. This link involves the transcriptional upregulation of gadd45beta/myd118, which downregulates jnk induced by the tnf receptor (tnf-r). SIGNOR-111963 0.295 PTPRA protein P18433 UNIPROT FYN protein P06241 UNIPROT up-regulates activity dephosphorylation Tyr531 FTATEPQyQPGENL 10090 BTO:0000255 9535845 t In a coexpression system, PTPalpha effected a dose-dependent tyrosine dephosphorylation and activation of p59(fyn), where maximal dephosphorylation correlated with a 5-fold increase in kinase activity.|the increased p59fyn catalytic activity and SH2 availability for binding are consistent with a PTPα-mediated dephosphorylation of the C-terminal Tyr-531 of p59fyn. SIGNOR-248435 0.644 RAD50 protein Q92878 UNIPROT MRE11 protein P49959 UNIPROT up-regulates binding 9606 17713585 t fstefani To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50. SIGNOR-157478 0.2 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19797526 f We therefore conclude that PML-RARα–mediated repression of C/EBPα is driven through a DNA methylation pathway. In accordance with this finding, a recent study in human APL samples described increased C/EBPα promoter methylation, consistent with the ability of PML-RARα to recruit corepressor complexes. Moreover, the PML-RARα effect on C/EBPα repression does not seem to be mediated via direct binding. SIGNOR-255726 0.2 Obatoclax mesylate chemical CID:46930996 PUBCHEM MCL1 protein Q07820 UNIPROT down-regulates activity chemical inhibition -1 23515850 t lperfetto Obatoclax and its predecessor analogs bind to BCL-2, BCL-XL, BCL-w, BCL-B, BFL-1, and MCL-1 in vitro|The ability of obatoclax to inhibit MCL-1 may be particularly important, given that several hematological malignancies appear to depend on this protein for survival, such as acute lymphoblastic leukemia (ALL),44 CLL,44 multiple myeloma,45 and diffuse large B-cell lymphoma (DLBCL) SIGNOR-262025 0.8 FGF14 protein Q92915 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates activity binding 9606 BTO:0000199 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253417 0.286 NR3C1 protein P04150 UNIPROT NR4A2 protein P43354 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15591535 f gcesareni We now show that the other nur factors, nurr1 and nor-1, are also subject to antagonism by gr and that this transrepression appears to involve direct protein-protein interactions between the dbds of gr and nur factors. SIGNOR-132254 0.311 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 16679294 t gcesareni Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action SIGNOR-146676 0.263 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr583 RRPPGLEyCYNPSHN 10116 BTO:0003293 19224897 t lperfetto Autophosphorylation of Y653 is followed by the ordered autophosphorylation of several key tyrosine residues within binding sites for the SH2 or PTB domains of signaling proteins that bind to and are phosphorylated by activated FGFR1. This second-stage autophosphorylation occurs on Y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of Y463 in the juxtamembrane region, Y766 in the C-terminal tail, and Y585 in the kinase insert region SIGNOR-235906 0.2 CDK5 protein Q00535 UNIPROT CABLES1 protein Q8TDN4 UNIPROT unknown phosphorylation Ser313 RCRTLSGsPRPKNFK 9534 11733001 t miannu P70ik3-1 is phosphorylated by either cyclin A/cdk3 or cyclin E/cdk3 reconstituted in COS7 cells. Accordingly, we can conclude that in COS7 cells, Ser274 in p70ik3-1 is phosphorylated by endogenous kinases other than cdk5 (Fig. 4), at least one of which is cdk3 as shown in this work. Currently, however, the question of how ik3-1 function is modified by its cdk3-mediated phosphorylation of Ser274 remains to be adressed. SIGNOR-112418 0.731 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:93369 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258537 0.8 MAPK4 protein P31152 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0001109 30688659 t miannu  Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308.  SIGNOR-275450 0.274 AURKB protein Q96GD4 UNIPROT CHMP4C protein Q96CF2 UNIPROT up-regulates phosphorylation Ser215 RRSRAASsQRAEEED 9606 22422861 t lperfetto Chmp4c functioned in the aurora b-dependent abscission checkpoint to prevent both premature resolution of intercellular chromosome bridges and accumulation of dna damage. Chmp4c engaged the chromosomal passenger complex (cpc) via interaction with borealin, which suggested a model whereby chmp4c inhibits abscission upon phosphorylation by aurora b SIGNOR-196728 0.482 DAB2IP protein Q5VWQ8 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity binding 9606 BTO:0000007 20080667 t miannu DAB2IP activates GSK-3β and antagonizes Wnt-mediated EMT. GSK-3β appears to directly associate with DAB2IP. Because DAB2IP is not a phosphatase, the mechanism of GSK-3β activation by DAB2IP is likely mediated by a separate phosphatase associated within this complex. PP2A is critical for DAB2IP-mediated GSK-3β activation and MET responses. SIGNOR-254752 0.316 CDKN2AIP protein Q9NXV6 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18292944 f fstefani Carf interacts with hdm2 and undergoes degradation by an hdm2-dependent proteasome pathway, and ii) it acts as a transcriptional repressor of hdm2. SIGNOR-160971 0.378 PAR-1 (Protease-Activated Receptor) Selective Activating Peptide smallmolecule CID:71312048 PUBCHEM F2RL1 protein P55085 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257485 0.8 IC-87114 chemical CHEBI:90686 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 BTO:0000848 21048785 t gcesareni Ic87114 is a selective pi3kinhibitor. SIGNOR-169213 0.8 double-stranded DNA chemical CHEBI:4705 ChEBI BRCA1-C complex complex SIGNOR-C299 SIGNOR form complex binding 25400280 t lperfetto The BRCA1‚ÄìC complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2 SIGNOR-269477 0.8 CDK1 protein P06493 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates phosphorylation Thr487 APAEDVDtPPRKKKR 9606 21659531 t lperfetto Cdk1, which phosphorylates ezh2 at threonines 345 and 487.Phosphorylation of thr-345 and thr-487 promotes ezh2 ubiquitination and subsequent degradation by the proteasome SIGNOR-174058 0.591 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 16982699 t gcesareni Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation.[...] We next investigated if phosphorylation of p21-t145 interfered with akt2 binding. As shown in fig. ?Fig.8e8e (right lane), phosphorylation of p21 on t145 effectively prevented akt2 interaction. SIGNOR-244180 0.2 OGA protein O60502 UNIPROT G6PD protein P11413 UNIPROT down-regulates activity deglycosylation Ser84 VADIRKQsEPFFKAT 9606 26399441 t lperfetto O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth|O-GlcNAcylation of G6PD activates enzyme activity|G6PD is dynamically modified by O-GlcNAc at serine 84|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. SIGNOR-267605 0.2 MAPK8IP1 protein Q9UQF2 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 20508646 t Interferes with binding to RBP-J gcesareni Here, we show that jip1 suppresses notch1 activity. Jip1 was found to physically associate with either intracellular domain of notch1 or rbp-jk and interfere with the interaction between them. SIGNOR-165710 0.269 MAPK1 protein P28482 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 SIGNOR-C16 12359725 t gcesareni In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e. SIGNOR-94003 0.476 SF3A2 protein Q15428 UNIPROT SF3a complex SIGNOR-C345 SIGNOR form complex binding 9606 BTO:0000567 8349644 t miannu Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. SIGNOR-263947 0.96 PIK3CG protein P48736 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Ser70 LFGGFNSsDTVTSPQ 9606 BTO:0000007 27169346 t miannu PI3Kγ mediated phosphorylation of Src enhances Src activity protein kinase activity of PI3K phosphorylates serine residue 70 on Src to enhance its activity and induce EGFR transactivation following βAR stimulation.  SIGNOR-277225 0.372 GBAF complex SIGNOR-C467 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 30397315 f miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269790 0.7 PTK2 protein Q05397 UNIPROT BCAR1 protein P56945 UNIPROT unknown phosphorylation Tyr664 EGGWMEDyDYVHLQG 11604500 t lperfetto FAK phosphorylates CAS-SBD tyrosines 668 and/or 670, driving an SH2-mediated recruitment of Src which then phosphorylates CAS-SD. SIGNOR-249111 0.804 CDC23 protein Q9UJX2 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 t lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. SIGNOR-252008 0.913 STAT5A protein P42229 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 f Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression SIGNOR-254302 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NUP50 protein Q9UKX7 UNIPROT down-regulates activity phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 t llicata Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. SIGNOR-188131 0.2 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 21524151 f miannu In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-262532 0.7 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Ser803 QREIQMDsPMLLADL 9606 BTO:0000567 20667468 t miannu Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803. SIGNOR-259826 0.2 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 21993628 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-176757 0.8 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile chemical CHEBI:77397 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 18487050 t Luana For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428.  SIGNOR-257794 0.8 USF1 protein P22415 UNIPROT GATA5 protein Q9BWX5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22625849 f miannu The present study provides the first evidence that USF1 activates GATA5 gene expression through the E-box motif and suggests a potential mechanism (disruption of the E-box) by which GATA5 promoter methylation reduces GATA5 expression in cancer. SIGNOR-255596 0.341 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI MAPK10 protein P53779 UNIPROT down-regulates chemical inhibition 9606 15071501 t gcesareni We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm). To determine whether jnk activity is required for stress-induced translocation of bax to the mitochondria, we examined the effect of sp600125, a jnk inhibitor. SIGNOR-124034 0.8 MEIS1 protein O00470 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001271 19109563 f irozzo To discern the mechanisms by which Meis1 inhibition leads to reduced cell growth, we performed cell-cycle and apoptosis analyses.Meis1 knockdown also resulted in increased apoptosis, as evidenced by increased uptake of PI and a stain for activated caspases (CaspaTag) by M26-transduced cells compared with control cells. These results indicate that Meis1 is required for proliferation and survival of 4166 leukemia cells. SIGNOR-255860 0.7 GSK3B protein P49841 UNIPROT ETS1 protein P14921 UNIPROT up-regulates quantity by stabilization phosphorylation Ser269 DRLTQSWsSQSSFNS 9606 BTO:0000007 34023818 t miannu Here, we show that ETS1 forms a complex with glycogen synthase kinase-3β (GSK3β). Specifically, GSK3β-mediated phosphorylation of ETS1 at threonine 265 and serine 269 promoted protein stability, induced the transcriptional activation of matrix metalloproteinase (MMP)-9, and increased cell migration. SIGNOR-277561 0.2 CSNK1E protein P49674 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity phosphorylation Ser139 DNETGTEsMVSHRRE 9606 16965538 t lperfetto Phenotypic analysis of mutant mDvl-1 indicates that phosphorylation of these sites stimulates the Dvl-activated beta-catenin-dependent Wnt signaling pathway in both cell culture and in Xenopus development. SIGNOR-217845 0.622 LATS2 protein Q9NRM7 UNIPROT YWHAG protein P61981 UNIPROT up-regulates phosphorylation Ser59 VVGARRSsWRVISSI 9606 25086053 t lperfetto Phosphorylation of 14-3-3_ on s59 by lats2. Ser(58) phosphorylation and lys(49) acetylation of 14-3-3_ occur in a coordinated time-dependent manner to regulate 14-3-3_ homodimerization. 14-3-3_ ser(58) phosphorylation is required for star interactions under control conditions, SIGNOR-205247 0.337 STK24 protein Q9Y6E0 UNIPROT STK38L protein Q9Y2H1 UNIPROT up-regulates phosphorylation Thr442 DWVFLNYtYKRFEGL 9606 BTO:0000007 16314523 t lperfetto Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity. SIGNOR-142510 0.451 LHX3 protein Q9UBR4 UNIPROT FSHB protein P01225 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23766128 f miannu we also demonstrated that LHX3 bound with greater affinity to the wild-type human FSHB promoter compared with the -211 G/T mutation and that LHX3 binding was more effectively competed with excess wild-type oligonucleotide than with the SNP. Finally, we showed that FSHB transcription was decreased in gonadotrope cells with the -211 G/T mutation compared with the wild-type FSHB promoter. SIGNOR-254557 0.376 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser555 RALSNSVsNMGLSES 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252882 0.398 EPHA2 protein P29317 UNIPROT YES1 protein P07947 UNIPROT up-regulates activity phosphorylation Tyr426 RLIEDNEyTARQGAK 9606 BTO:0001007 33941853 t miannu EphA2 interacts with YES1 and phosphorylates YES1 at Tyr426 site. SIGNOR-277556 0.398 SAGA complex complex SIGNOR-C465 SIGNOR H3Y1 protein P0DPK2 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkATAWQAP 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269631 0.2 SLBP protein Q14493 UNIPROT H2AC18 protein Q6FI13 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265396 0.2 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75017 0.783 PRKCA protein P17252 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000599 15730925 f irozzo PKC-alpha asODN (antisense oligonucleotides) could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC. SIGNOR-256266 0.7 SRC protein P12931 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr783 EGRNPGFyVEANPMP -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-247316 0.621 MLH1 protein P40692 UNIPROT MLH1/PMS1 complex SIGNOR-C58 SIGNOR form complex binding 9606 10542278 t miannu We now show that hpms1 is expressed in human cells and that it interacts with hmlh1 with high affinity to form the heterodimer hmutl_. SIGNOR-71768 0.695 XBP1 protein P17861 UNIPROT B-Lymphocyte_diff phenotype SIGNOR-PH113 SIGNOR up-regulates activity 9606 BTO:0000392 11460154 f XBP-1 is the only transcription factor known to be selectively and specifically required for the terminal differentiation of B lymphocytes to plasma cells. SIGNOR-259957 0.7 RXRB protein P28702 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 11237216 t lperfetto Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology SIGNOR-105454 0.654 Kallidin smallmolecule CHEBI:6102 ChEBI BDKRB2 protein P30411 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257465 0.8 MTOR protein P42345 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT down-regulates activity phosphorylation Ser52 KRVELPDsPRSTFLL 23524951 t lperfetto We show that under non-autophagic conditions, mTOR inhibits AMBRA1 by phosphorylation, whereas on autophagy induction, AMBRA1 is dephosphorylated. In this condition, AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. As ULK1 has been shown to activate AMBRA1 by phosphorylation, the proposed pathway may act as a positive regulation loop, which may be targeted in human disorders linked to impaired autophagy.|mTOR phosphorylates AMBRA1 at Ser 52, inhibiting its role in ULK1 modification SIGNOR-272986 0.484 GLI2 protein P10070 UNIPROT GLI1 protein P08151 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 f lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. SIGNOR-209629 0.434 pazopanib hydrochloride chemical CHEBI:71217 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR down-regulates activity chemical inhibition -1 17620431 t miannu The present study describes an orally bioavailable, ATP-competitive, multitargeted kinase inhibitor, pazopanib (GW786034), and the drug concentration requirement for maximal in vivo activity. Pazopanib is a low nanomolar inhibitor of VEGFR, PDGFR, and c-Kit tyrosine kinases. Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. SIGNOR-259451 0.8 IDH3G protein P51553 UNIPROT IDH complex SIGNOR-C396 SIGNOR form complex binding 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-266247 0.689 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser422 AEAFLGFsYAPPTDS -1 10191262 t miannu The activation of SGK by PDK1 in vitro is unaffected by PtdIns(3,4,5)P3, abolished by the mutation of Ser422 to Ala, and greatly potentiated by mutation of Ser422 to Asp SIGNOR-250274 0.635 AREL1 protein O15033 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination Lys62 CAVPIAQkSEPHSLS 9606 BTO:0002552 31732561 t lperfetto AREL1 ubiquitinated SMAC, primarily on Lys62 and Lys191 |E701A substitution in the AREL1 HECT domain substantially increased its autopolyubiquitination and SMAC ubiquitination activity, whereas deletion of the last three amino acids at the C terminus completely abrogated AREL1 autoubiquitination and reduced SMAC ubiquitination. SIGNOR-267673 0.385 AMPK complex SIGNOR-C15 SIGNOR BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 19933840 t lperfetto Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction SIGNOR-216572 0.2 mTORC2 complex SIGNOR-C2 SIGNOR SLC7A11 protein Q9UPY5 UNIPROT down-regulates activity phosphorylation Ser26 NVNGRLPsLGNKEPP 9606 BTO:0002036 28648777 t miannu MTORC2 phosphorylates serine 26 at the cytosolic N terminus of xCT, inhibiting its activity.  SIGNOR-273682 0.278 LCK protein P06239 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates activity phosphorylation 9606 10799545 t Phosphorylation of p56 dok and p62 dok is increased following CD2 stimulation and requires Lck. Phosphorylation of Dok proteins by Lck might provide a mechanism by which SH2-containing proteins can be recruited and co-localized with their substrates. SIGNOR-251373 0.583 MECP2 protein P51608 UNIPROT OPRK1 protein P41145 UNIPROT up-regulates quantity by expression post transcriptional regulation 10090 BTO:0000614 18511691 t Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. SIGNOR-264677 0.276 BUD13 protein Q9BRD0 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270672 0.535 PTPRJ protein Q12913 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr205 IMLNSKGyTKSIDIW 9606 BTO:0000007 19494114 t lperfetto In this study we show that one of these potential targets, the erk1/2, is indeed a direct dep-1 substrate in vivo. SIGNOR-101276 0.416 AKT2 protein P31751 UNIPROT JAG1 protein P78504 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 38402584 f miannu Jagged1 is upregulated by Akt upon activation by R-Ras. All three Akt isoforms influence Jagged1 expression in ECs, but Akt3 is the most prominent Akt isoform in this role, despite its low expression level compared with Akt1. Jagged1 then activates Notch to upregulate Hey1, Hes1, p21, p53, and Unc5b in adjacent cells.  SIGNOR-277223 0.312 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267124 0.8 PLK1 protein P53350 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation Ser146 LLTFPNSsPGLRRQK phosphorylation:Ser36;Thr40 HPGFDAEsYTFTVPR;DAESYTFtVPRRHLE 23972993 t For phosphorylated residues see Figure 7 lperfetto Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP SIGNOR-274054 0.301 UBA1 protein P22314 UNIPROT Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR form complex binding 9606 24816100 t miannu The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin. SIGNOR-270833 0.2 CDK1 protein P06493 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates phosphorylation Ser465 MVPGGDRsPSRMLPP 9606 BTO:0000150;BTO:0001130 16407259 t llicata In vitro kinase assays using recombinant cdc2 kinase showed that runx2 was phosphorylated at ser(451) the cdc2 inhibitor roscovitine dose dependently inhibited in vivo runx2 dna-binding activity during mitosis and the runx2 mutant s451a exhibited lower dna-binding activity and reduced stimulation of anchorage-independent growth relative to wild type runx2. SIGNOR-143586 0.491 RPS6KA1 protein Q15418 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 10558990 t lperfetto The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival. SIGNOR-72117 0.738 Gbeta proteinfamily SIGNOR-PF4 SIGNOR IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation 9606 12510059 t inferred from 70% family members gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. SIGNOR-269997 0.2 UBE2L3 protein P68036 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity ubiquitination -1 19240029 t miannu Only UbcH5 and Related Class I E2s Support Ubiquitination of S5a—UbcH5 belongs to the Class I family of E2s which contains a catalytic core (UBC domain) without a distinct Ub binding domain (38). To test whether other Class I E2s can also support ubiquitination of S5a, we assayed the ubiquitination of S5a with UbcH7 and the E3s, Nedd4, or Parkin. With either of these E3s, UbcH7 supported ubiquitination of S5a (Fig. 8, A and B). In addition, another Class I E2, Ubc4, a close homolog of UbcH5, supported ubiquitination of S5a by the APC, a multimeric Ring finger E3 responsible for cell cycle progression through mitosis (39) (Fig. 8C). Thus, multiple Class I E2s can support ubiquitination of S5a by various types of E3s (Table 1). SIGNOR-272734 0.2 PLK1 protein P53350 UNIPROT TRIOBP protein Q9H2D6 UNIPROT up-regulates phosphorylation Thr2229 QAEEREHtLRRCQQE 9606 22820163 t lperfetto Here we show that tara is a novel polo-like kinase 1 (plk1) target protein. Plk1 interacts with and phosphorylates tara in vivo and in vitro. Actually, the thr-457 in tara was a bona fide in vivo phosphorylation site for plk1. Interestingly, we found that the centrosomal localization of tara depended on the thr-457 phosphorylation and the kinase activity of plk1 SIGNOR-198353 0.341 AFDN protein P55196 UNIPROT RIT1 protein Q92963 UNIPROT up-regulates activity binding 9606 10545207 t miannu Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors. SIGNOR-220917 0.2 SREBF2 protein Q12772 UNIPROT LDLR protein P01130 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21123766 t miannu Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes. SIGNOR-254453 0.764 CSNK2A1 protein P68400 UNIPROT IGFBP3 protein P17936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser138 PPAPGNAsESEEDRS 9606 BTO:0000093 10650937 t llicata The importance of Ser111 and Ser113 as targets for CK2 has also been shown in our laboratory, as mutation of either residue to alanine caused a major decrease in IGFBP-3 phosphorylation by this enzyme in vitro | These results indicate that IGFBP-3 interaction with acid-labile subunit and with the cell surface, both of which involve basic carboxyl-terminal residues, may be modulated by phosphorylation. Relative resistance to proteolysis and poor binding to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF activity in the extracellular environment. SIGNOR-250903 0.345 NARS1 protein O43776 UNIPROT asparagine smallmolecule CHEBI:22653 ChEBI down-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270454 0.8 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2Q2 protein Q8WVN8 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271363 0.401 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser641 GKVYGKTsHLRAHLR 9606 19464346 t gcesareni The hdac inhibitor tsa-induced cell-specific phosphatase release from the promoter, which serves as an 'on' mechanism for sp1 phosphorylation by phosphatidylinositol 3-kinase/protein kinase czeta (pi3k/pkczeta) at ser641, leading to p107 repressor derecruitment and lhr transcriptional activation. SIGNOR-185741 0.497 TNKS2 protein Q9H2K2 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization 9606 BTO:0000007 19759537 t Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. SIGNOR-261248 0.451 AKT2 protein P31751 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation 9606 21620960 t lperfetto Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. SIGNOR-233529 0.593 SMURF1 protein Q9HCE7 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. SIGNOR-195651 0.646 VAV2 protein P52735 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 10618391 t tpavlidou Oligomerization of receptor protein tyrosine kinases such as the epidermal growth factor receptor (egfr) by their cognate ligands leads to activation of the receptor.We Demonstrate that vav-2 is phosphorylated on tyrosine residues in response to egf and associates with the egfr in vivo. SIGNOR-73874 0.61 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr788 SLEKHSWyHGPVSRN 9606 16912036 t Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. SIGNOR-260813 0.2 NHP2 protein Q9NX24 UNIPROT TERT protein O14746 UNIPROT up-regulates activity binding 18680434 t lperfetto A complex of four proteins (GAR1, NHP2, NOP10, and the putative pseudouridine synthase dyskerin) associates with snoRNAs to form small nucleolar ribonucleoprotein particles (snoRNPs), and the binding of this complex to the H/ACA domain of TERC may have a role in the biogenesis of the telomerase RNP SIGNOR-263330 0.642 NOTCH proteinfamily SIGNOR-PF30 SIGNOR ADAM19 protein Q9H013 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10933396 f gcesareni Interestingly, in absence of delta signal, both hes-1 and tcfl5 decreased, and further decreased by incubation with dapt. (figure 4). This pharmacological approach therefore provides additional evidence that tcfl5, similar to hes1, is a true notch target gene. SIGNOR-254340 0.2 SPI1 protein P17947 UNIPROT GATA2 protein P23769 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12433372 f irozzo Using these progenitors and a conditionally activatable PU.1 protein, we show that PU.1 can negatively regulate expression of the GATA-2 gene.The above experiments suggested that PU.1 may physiologically downregulate the expression of the GATA-2 gene during the differentiation of myeloid progenitors into macrophages. SIGNOR-256069 0.595 UBE2N protein P61088 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000785 14713952 t lperfetto Intact ring and zinc finger domains are required for tnfalfa-induced traf2 ubiquitination, which is also dependent on ubc13. Traf2 ubiquitination coincides with its translocation to the insoluble cellular fraction, resulting in selective activation of jnk. Ubc13 expression by rnai resulted in tnfalfa-induced traf2 translocation and impaired activation of jnk but not of ikk or p38. SIGNOR-121274 0.439 SRC protein P12931 UNIPROT SLC6A4 protein P31645 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr142 MELALGQyHRNGCIS 10116 BTO:0000132 21992875 t miannu We found that 1) SERT exists in a tyrosine-phosphorylated form, 2) inhibition of tyrosine kinase(s) reduces SERT expression levels by facilitating SERT protein degradation, 3) Src-kinase activity up-regulates SERT protein expression with a concomitant increase in 5-HT uptake and tyrosine phosphorylation, and 4) mutation of Tyr47 or Tyr142 abolishes src-induced increases in transport function and phosphorylation of SERT.  SIGNOR-276386 0.261 EDNRB protein P24530 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257321 0.41 MICU3 protein Q86XE3 UNIPROT MCU_MICU3_variant complex SIGNOR-C501 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270872 0.632 PTPN11 protein Q06124 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 17974954 t Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B SIGNOR-248671 0.639 AURKA protein O14965 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates activity phosphorylation Ser960 SRLSPPHsPRDFTRM 9606 BTO:0000567 17488622 t miannu The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity. SIGNOR-276061 0.338 PRKCZ protein Q05513 UNIPROT ADARB1 protein P78563 UNIPROT up-regulates activity phosphorylation Ser211 GDLSLSAsPVPASLA 9606 BTO:0001615 29694894 t miannu  Here, we identified ADAR2 as a direct substrate of PKCζ in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKCζ/ADAR2 axis regulates miR-200 secretion through RNA editing.  SIGNOR-277392 0.2 AURKB protein Q96GD4 UNIPROT DSN1 protein Q9H410 UNIPROT down-regulates phosphorylation Ser109 KETNRRKsLHPIHQG 9606 20471944 t lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). SIGNOR-165550 0.639 MT-ATP8 protein P03928 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261406 0.2 TXNL4A protein P83876 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270638 0.742 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR GPSM3 protein Q9Y4H4 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000876 phosphorylation:Ser35 STTRPWRsAPPSPPP 22843681 t lperfetto Mutation of serine 35 completely abrogates the 14-3-3 interaction (e.g. Fig. 2, B–F), suggesting that phosphorylation of serine 35 is obligatory for 14-3-3 binding|The GPSM3/14-3-3 interaction is seen to stabilize GPSM3 from degradation and also support the nuclear exclusion of both proteins. SIGNOR-264866 0.2 CHMP4B protein Q9H444 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 t miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. SIGNOR-265533 0.722 GRID2IP protein A4D2P6 UNIPROT GRID2 protein O43424 UNIPROT up-regulates quantity binding 9606 11826110 t miannu We identified a novel GluRdelta2-interacting protein, named Delphilin, that contains a single PDZ domain and formin homology (FH) domains FH1 and FH2 plus coiled-coil structure. Delphilin is selectively localized at the postsynaptic junction site of the parallel fiber-Purkinje cell synapse and colocalized with GluRdelta2. Thus, Delphilin is a postsynaptic scaffolding protein at the parallel fiber-Purkinje cell synapse, where it may serve to link GluRdelta2 with actin cytoskeleton and various signaling molecules. SIGNOR-264475 0.628 PDZD8 protein Q8NEN9 UNIPROT MSN/PDZD8 complex SIGNOR-C61 SIGNOR form complex binding 9606 21549406 t miannu These results demonstrated that both human moesin and its newly identified binding partner, pdzd8 had similar effects on host mt networks, suggesting that they are likely to function as part of a stable mt regulatory complex. SIGNOR-173650 0.323 PRKCE protein Q02156 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates phosphorylation Ser782 PLEQYSPsYPDTRSS 9606 BTO:0000938 23564461 t lperfetto Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiation SIGNOR-201675 0.2 Cadherins proteinfamily SIGNOR-PF71 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265812 0.2 CSNK2A2 protein P19784 UNIPROT ACACA protein Q13085 UNIPROT unknown phosphorylation Ser29 GSVSEDNsEDEISNL -1 2900140 t llicata Phosphorylation at site 6 by casein kinase-2 is in good agreement with previous studies on the specificity of this kinase, which is known to phosphorylate serine residues followed by an acidic cluster SIGNOR-250973 0.312 DERA protein Q9Y315 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 25229427 t miannu Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase. SIGNOR-267098 0.8 WNT9B protein O14905 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000887 22309736 t gcesareni We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles. SIGNOR-195978 0.2 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT down-regulates activity phosphorylation Ser2070 DEYNVTPsPPGTVLT 9606 BTO:0000007 12794074 t Ser-2093 is efficiently phosphorylated by GSK-3β and, to a minor extent, residues Thr-2068 and/or Ser-2070 and Thr-2074 of Notch2 are also targets for GSK-3β-dependent phosphorylation. We also find that GSK-3β-dependent phosphorylation of Notch2 is inhibiting transcriptional activation of different Notch target genes. SIGNOR-251254 0.494 PP121 chemical CHEBI:50915 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206289 0.8 PITRM1 protein Q5JRX3 UNIPROT APP protein P05067 UNIPROT down-regulates activity cleavage 9606 BTO:0000142 16849325 t Giorgia In the present study we have identified and characterized the human PreP homologue, hPreP, in brain mitochondria, and we show its capacity to degrade the amyloid beta-protein (Abeta). PreP belongs to the pitrilysin oligopeptidase family M16C containing an inverted zinc-binding motif. We show that hPreP is localized to the mitochondrial matrix. In situ immuno-inactivation studies in human brain mitochondria using anti-hPreP antibodies showed complete inhibition of proteolytic activity against Abeta. SIGNOR-260661 0.381 CASP3 protein P42574 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates quantity by destabilization cleavage Asp1155 ETPDDLLdDGEIKED 9606 12149654 t miannu We demonstrate the cleavage and the consequential downregulation of full-length BRCA1 by caspase-3 during UV-induced apoptosis. Finally, mutation of a caspase-3 specific cleavage site (D/A1154) rendered BRCA1 non-cleavable. SIGNOR-256326 0.485 AKT2 protein P31751 UNIPROT SH3RF1 protein Q7Z6J0 UNIPROT down-regulates phosphorylation Ser304 KNTKKRHsFTSLTMA 9606 17535800 t gcesareni Overexpression of posh induces apoptosis in a variety of cell types, but apoptosis can be prevented by co-expressing the pro-survival protein kinase akt. We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac SIGNOR-155233 0.397 PLK1 protein P53350 UNIPROT KAT7 protein O95251 UNIPROT up-regulates phosphorylation Ser57 SQSSQDSsPVRNLQS 9606 18250300 t lperfetto Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate. SIGNOR-160751 0.517 SRC protein P12931 UNIPROT RPS6KA3 protein P51812 UNIPROT unknown phosphorylation Tyr488 DVYDDGKyVYVVTEL 9606 BTO:0000007 18156174 t llicata The results showed that tyr-488 is a major site of src but mutations at tyr-529 or tyr-707 did not significantly decrease src-dependent tyrosine phosphorylation of rsk2 (fig. 4c). However, we have previously characterized the tyr-488 site that is also phosphorylated by fgfr3 (14), and substitution of tyr-488 did not affect rsk2 activation. SIGNOR-160056 0.362 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser315 ITATSPAsMVGGKPG 10116 BTO:0000452 11287630 t lperfetto Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten SIGNOR-106578 0.757 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1738 SPSYSPTsPSYSPTS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248777 0.442 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity phosphorylation Thr1074 QRGSSGHtPPPSGPP 9606 26190112 t Luana AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. SIGNOR-259862 0.339 CDC25A protein P30304 UNIPROT CDK4 protein P11802 UNIPROT up-regulates activity dephosphorylation Tyr17 AEIGVGAyGTVYKAR 9606 BTO:0000007 23429262 t lperfetto Invalidation of CDK4 has no impact by itself on the cell proliferation, but invalidation of CDC25A prevents the dephosphorylation of CDK6 (Y24) and CDK4 (Y17) residues, and impedes their association with CCNDs. SIGNOR-267568 0.693 metyrapone chemical CHEBI:44241 ChEBI CYP11B2 protein P19099 UNIPROT down-regulates activity chemical inhibition -1 21129965 t Luana In an effort to develop and evaluate new classes of compounds as CYP inhibitors, we based our investigations on the structure of the well-known CYP inhibitor Metyrapone 2, which has been used for the treatment of hypercortisolism and Cushing’ssyndrome for several decades. SIGNOR-257885 0.8 MLKL protein Q8NB16 UNIPROT Necroptosis phenotype SIGNOR-PH174 SIGNOR up-regulates activity 9606 24316671 t gianni Here, we report that MLKL forms a homotrimer through its amino-terminal coiled-coil domain and locates to the cell plasma membrane during TNF-induced necroptosis. By generating different MLKL mutants, we demonstrated that the plasma membrane localization of trimerized MLKL is critical for mediating necroptosis. Importantly, we found that the membrane localization of MLKL is essential for Ca(2+) influx, which is an early event of TNF-induced necroptosis. SIGNOR-266431 0.7 SMURF1 protein Q9HCE7 UNIPROT SLAIN2 protein Q9P270 UNIPROT unknown ubiquitination -1 20804422 t miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. SIGNOR-272696 0.2 IKBKB protein O14920 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 t gcesareni Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway SIGNOR-124207 0.679 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXA2 protein Q9Y261 UNIPROT down-regulates phosphorylation 9606 14500912 t �Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins. This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects. Mutant Foxa-2T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression. SIGNOR-254978 0.2 FGF2 protein P09038 UNIPROT BMP2 protein P12643 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15780951 f lperfetto Furthermore, FGF-2 and FGF-9 increased expression of other osteogenic factors BMP-2 and TGFbeta-1. Meanwhile, blocking endogenous FGF signaling, using a virally transduced dominant-negative FGF receptor (FgfR), resulted in drastically reduced expression of the BMP-2 gene, demonstrating for the first time that endogenous FGF/FgfR signaling is a positive upstream regulator of the BMP-2 gene in calvarial osteoblasts SIGNOR-134785 0.484 ITGB1BP1 protein O14713 UNIPROT ITGB5 protein P18084 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257660 0.323 TPR protein P12270 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates binding 9606 BTO:0000567 18981471 t miannu Tpr directly binds to mad1 and mad2. / depletion of tpr decreases the levels of mad1 at kinetochores during prometaphase, correlating with the inability of mad1 to activate mad2, which is required for inhibiting apc(cdc20). SIGNOR-181918 0.499 GRK5 protein P34947 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Thr55 DDIEQWFtEDPGPDE 9606 20124405 t llicata Grk5, but not grk2 or grk6, phosphorylates p53 at thr-55, which promotes the degradation of p53, leading to inhibition of p53-dependent apoptotic response to genotoxic damage. SIGNOR-163707 0.378 ATF1 protein P18846 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10540320 f miannu Our data suggest that intracellular cAMP may directly affect expression of the immunoregulatory cytokine IL-10 in monocytic cells via activation of the eukaryotic transcription factors CREB-1 and ATF-1 and their binding to CRE1 and CRE4 in the upstream enhancer of the IL-10 promoter SIGNOR-254521 0.251 CTNNB1 protein P35222 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates activity binding 10090 BTO:0001086 21295277 t flangone We provide evidence suggesting that Beta-catenin’s interaction with the pluripotency regulator Oct-4 at least partially underlies its effects on sustaining pluripotency. SIGNOR-241981 0.592 BMX protein P51813 UNIPROT RUFY1 protein Q96T51 UNIPROT up-regulates activity phosphorylation Tyr400 RQGLDEMySDVWKQL 9534 11877430 t miannu Etk interacts with RUFY1 through its SH3 and SH2 domains. RUFY1 is tyrosine-phosphorylated and appears to be a substrate of Etk. Phosphorylation of the two tyrosine residues, Tyr-281 and Tyr-292, located in the linker region of the two coiled-coil domains by Etk seems to be critical for RUFY1 targeting to the endosomes. SIGNOR-262679 0.619 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates chemical activation 9606 22863277 t gcesareni Lpa binds to a family of gpcrs known as lpa receptors (lpa1-6) to initiate intracellular signaling. Lpa1 was highly expressed and lpa3 was detectable in hek293a cells compared to other lpa receptors. SIGNOR-198526 0.8 AKAP11 protein Q9UKA4 UNIPROT IQGAP2 protein Q13576 UNIPROT up-regulates activity binding 9606 21776420 t miannu We show that IQGAP2 is regulated by an interaction with the A-kinase anchoring protein AKAP220. Phosphorylation of IQGAP2 via AKAP220-anchored PKA leads to enhanced Rac binding. Since AKAPs function to direct PKA toward specific substrates, we proposed that the formation of an IQGAP2/AKAP220/PKA ternary complex sharpens the response to cAMP. SIGNOR-273740 0.448 GLI1 protein P08151 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 f lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. SIGNOR-209620 0.707 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Ser92 AAQMEVAsFLLSKEN 9606 BTO:0000567 15525512 t llicata Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.  SIGNOR-250608 0.992 BTF3 protein P20290 UNIPROT ABL2 protein P42684 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 17312387 f In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. SIGNOR-253947 0.2 WNT16 protein Q9UBV4 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates 9606 BTO:0000938 BTO:0000887 22309736 f gcesareni We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles. SIGNOR-195969 0.2 GSK3B protein P49841 UNIPROT CLASP2 protein O75122 UNIPROT down-regulates activity phosphorylation Ser537 REASRESsRDTSPVR 9534 BTO:0004055 19638411 t lperfetto GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells SIGNOR-264826 0.529 sunitinib chemical CHEBI:38940 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 21993628 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-176754 0.8 HTR2C protein P28335 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257221 0.55 NEDD4L protein Q96PU5 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 t miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). SIGNOR-253461 0.33 ACO1 protein P21399 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI down-regulates quantity chemical modification 9606 24068518 t miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. SIGNOR-266242 0.8 RNGTT protein O60942 UNIPROT mRNA_capping phenotype SIGNOR-PH178 SIGNOR up-regulates quantity chemical modification 9606 9512541 f lperfetto The human mRNA 5'-capping enzyme cDNA was identified. Three highly related cDNAs, HCE1 (human mRNAcappingenzyme1), HCE1A and HCE1B , were isolated from a HeLa cDNA library. The HCE1 cDNA has the longest ORF, which can encode a 69 kDa protein. A short region of 69 bp in the 3'-half of the HCE1 ORF was missing in HCE1A and HCE1B , and, additionally, HCE1B has an early translation termi SIGNOR-268356 0.7 CASP2 protein P42575 UNIPROT Caspase 2 complex complex SIGNOR-C227 SIGNOR form complex binding cleavage:Asp347 SPGCEESdAGKEKLP 21828056 t lperfetto Like other caspases, caspase-2 is synthesized as an inactive zymogen. The zymogen sequence includes a long prodomain containing a CARD followed by a large domain, a linker, and a small domain. Caspase-2 undergoes autocatalytic activation to remove the prodomain and linker region to generate a stable dimer consisting of the large subunit (p19) and the small subunit (p12). This p19/p12 dimer self-associates to form the active caspase-2 SIGNOR-256389 0.2 SYK protein P43405 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 BTO:0000782 9710204 t gcesareni The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2). SIGNOR-59639 0.753 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120072 0.781 PRKACA protein P17612 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 t gcesareni We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus. SIGNOR-97550 0.416 MAPK1 protein P28482 UNIPROT IER3 protein P46695 UNIPROT up-regulates phosphorylation Thr18 MTILQAPtPAPSTIP 9606 12356731 t lperfetto Upon phosphorylation by erks, iex-1 acquires the ability to inhibit cell death induced by various stimuli. In turn, iex-1 potentiates erk activation in response to various growth factors. SIGNOR-93740 0.533 CIITA protein P33076 UNIPROT IL4 protein P05112 UNIPROT down-regulates transcriptional regulation 9606 BTO:0000782 10946277 f We identified two domains of CIITA that interact with two distinct domains of CBP/p300 that are also recognized by NF-AT. CIITA mutants that retain the ability to interact with CBP/p300 are sufficient to inhibit NF-AT-mediated IL-4 gene expression SIGNOR-254499 0.415 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 35318320 t miannu Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT. SIGNOR-273843 0.748 FOXO proteinfamily SIGNOR-PF27 SIGNOR Metabolism phenotype SIGNOR-PH77 SIGNOR up-regulates 18391974 f Forkhead proteins, and FoxO1 in particular, play a significant role in regulating whole body energy metabolism. SIGNOR-253016 0.7 PRKACA protein P17612 UNIPROT CHCHD3 protein Q9NX63 UNIPROT unknown phosphorylation Thr11 TTSTRRVtFEADENE -1 17242405 t miannu Identification of ChChd3 as a novel substrate of the cAMP-dependent protein kinase (PKA) using an analog-sensitive catalytic subunit. we used the recombinant GST-ChChd3 for an in vitro kinase assays to determine whether in vitro phosphorylation by PKA was direct. Fig. 6 demonstrates that PKA directly phosphorylates recombinant Chchd3 with a stoichiometry of 0.3 mol of phosphate incorporated per mol of ChChd3. Although three potential PKA phosphorylation sites exist in ChChd3, Thr10 represents the most likely site to be phosphorylated. SIGNOR-263116 0.2 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 9606 21808241 t gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. SIGNOR-175825 0.621 MAPK1 protein P28482 UNIPROT RAI14 protein Q9P0K7 UNIPROT unknown phosphorylation Thr249 SQDADLKtPTKPKQH 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262760 0.269 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser40 PTAEEKPsPRRSLSQ 33309518 t lperfetto Phosphorylation of multiple residues in the catalytic domain of PPM1D during mitosis, including Ser40 by Cyclin-dependent kinase 1 (CDK1), leads to ubiquitination of PPM1D and subsequent proteasomal degradation by Adenomatous polyposis coli (APC) and cell-division cycle protein 20 (CDC20) SIGNOR-275490 0.34 PP1 proteinfamily SIGNOR-PF54 SIGNOR IKZF1 protein Q13422 UNIPROT up-regulates dephosphorylation 9606 21750978 t lperfetto Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway SIGNOR-264663 0.2 2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide chemical CHEBI:91426 ChEBI SYK protein P43405 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000793 30744170 t lperfetto The Selective SYK Inhibitor BAY 61-3606 Enhances the Effect of Chemotherapeutic Drugs on Neuroblastoma Cells SIGNOR-262020 0.8 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser363 LKNKTESsLLAKLEE -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276208 0.388 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 BTO:0000007 9724739 t gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 SIGNOR-249654 0.741 PRKACA protein P17612 UNIPROT RXRA protein P19793 UNIPROT down-regulates phosphorylation Ser27 TSPTGRGsMAAPSLH 9606 11162439 t llicata Serine 27, a human retinoid x receptor alpha residue, phosphorylated by protein kinase a is essential for cyclicamp-mediated downregulation of rxralpha function. SIGNOR-104954 0.2 CENPC protein Q03188 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265200 0.65 HTR7 protein P34969 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257055 0.284 C3AR1 protein Q16581 UNIPROT Vascular_Permeability phenotype SIGNOR-PH140 SIGNOR up-regulates 10984054 f lperfetto The anaphylatoxins C3a and C5a are liberated as activation byproducts and are potent pro-inflammatory mediators that bind to specific cell surface receptors and cause leukocyte activation, smooth muscle contraction and vascular permeability SIGNOR-263458 0.7 PLK4 protein O00444 UNIPROT PLK4 protein O00444 UNIPROT up-regulates phosphorylation Ser305 SSTSISGsLFDKRRL 9606 20032307 t llicata Autophosphorylation probably plays a role in the process of centriole duplication, because mimicking s305 phosphorylation enhances the ability of overexpressed plk4 to induce centriole amplification. Importantly, we show that s305-phosphorylated plk4 is specifically sequestered at the centrosome contrary to the nonphosphorylated form. SIGNOR-162559 0.2 ponatinib chemical CHEBI:78543 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001056 23409026 t miannu Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. SIGNOR-259268 0.8 3-methyladenine chemical CHEBI:38635 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205639 0.8 PRKCB protein P05771 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser619 SLPKINRsASEPSLH 9606 8288587 t gcesareni Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. the sites of pkc-mediated raf-1 phosphorylation are deduced to be ser497 and ser619. SIGNOR-37478 0.421 RPL22 protein P35268 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262499 0.85 HCRTR1 protein O43613 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257354 0.426 HBA1 protein P69905 UNIPROT EDN1 protein P05305 UNIPROT down-regulates activity 9606 8573884 f Regulation of localization miannu Hb inhibitory activity toward ET-1 production might be related to Hb mediated endothelial oxidative injury. SIGNOR-251767 0.264 SARS1 protein P49591 UNIPROT tRNA(Ser) smallmolecule CHEBI:29179 ChEBI down-regulates quantity chemical modification 9606 24095058 t miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis SIGNOR-270493 0.8 LRRK2 protein Q5S007 UNIPROT SNAPIN protein O95295 UNIPROT down-regulates phosphorylation Thr117 NHSVAKEtARRRAML 9606 BTO:0000938 BTO:0000142 23949442 t lperfetto Lrrk2 phosphorylates snapin and inhibits interaction of snapin with snap-25. these data suggest that lrrk2 may regulate neurotransmitter release via control of snapin function by inhibitory phosphorylation. hreonine 117 of snapin is one of the sites phosphorylated by lrrk2 SIGNOR-202436 0.529 EIF2B1 protein Q14232 UNIPROT EIF2S3 protein P41091 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269134 0.681 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-217114 0.753 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates activity phosphorylation Tyr577 RRPPGLDySFDTCKP 9606 BTO:0000007 11294897 t lperfetto Ligand stimulation leads to autophosphorylation of fgfr3 the absence of y577 (3y-577f) or y760 (3y-760f) resulted in a modest decrease in activity. SIGNOR-106726 0.2 STK4 protein Q13043 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates phosphorylation 9606 18394876 t gcesareni The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1 SIGNOR-178193 0.406 BRCA1 protein P38398 UNIPROT FOXC2 protein Q99958 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 22120723 f miannu We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. SIGNOR-253760 0.263 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser408 GPLPRAPsISTVEPK 26843621 t Indeed we show that AMPK phosphorylates Gli1 at the unique residue Ser408, which is conserved only in primates but not in other species. Once phosphorylated, Gli1 is targeted for proteasomal degradation. SIGNOR-253540 0.301 PTPRA protein P18433 UNIPROT LYN protein P07948 UNIPROT down-regulates activity dephosphorylation Tyr397 RVIEDNEyTAREGAK 10116 15537644 t We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397|Lyn expressed in CHO cells has a substantially higher specific activity than Lyn in RBL cells because of high levels of phosphorylation at its active site Tyr-397 (Fig. 1). Enhanced Lyn kinase activity in the CHO cells leads to spontaneous phosphorylation of multiple cellular proteins, including FcϵRI SIGNOR-248436 0.304 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 18519666 t inferred from 70% family members lperfetto We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_ SIGNOR-270191 0.2 sorafenib tosylate chemical CHEBI:50928 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. SIGNOR-259222 0.8 CSNK2A1 protein P68400 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Ser53 DEELEGIsPDELKDE -1 7598724 t llicata We report that recombinant glia maturation factor (GMF), a 17-kD brain protein, can be phosphorylated in vitro at the serine residue by protein kinase C (PKC), protein kinase A (PKA), and casein kinase II (CKII), and at the threonine residue by p90 ribosomal S6 kinase (RSK).  SIGNOR-250868 0.337 phenformin chemical CHEBI:8064 ChEBI KCNJ11 protein Q14654 UNIPROT down-regulates activity chemical inhibition 9606 20188727 t lperfetto Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel |Phenformin but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). SIGNOR-262031 0.8 ATM protein Q13315 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates phosphorylation Ser990 SRSTSVTsQISNGSH 9606 17396146 t gcesareni The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells. SIGNOR-154167 0.394 FANCG protein O15287 UNIPROT D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR form complex binding 9606 BTO:0000567 18212739 t lperfetto These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3).  SIGNOR-263254 0.726 PRKACA protein P17612 UNIPROT SCRIB protein Q14160 UNIPROT unknown phosphorylation Ser1445 PSPTSRQsPASPPPL 9606 BTO:0000007 20622900 t miannu HScrib is a substrate of ERK and PKA. Under normal growth conditions, hScrib is phosphorylated at S853, most likely by ERK, and at S1445 by PKA. Interestingly, stimulation of MAPK by osmotic stress results in a marked loss of phosphorylation at the PKA site S1445, but a concomitant increase in phosphorylation at S1448, presumably also by ERK. At present, we have no information as to what are the functional consequences of ERK or PKA phosphorylation of hScrib. However, we can speculate that this will most likely affect the ability of hScrib to interact with some of its cellular partners, and studies are currently in progress to investigate these aspects further. SIGNOR-263066 0.252 GRK2 protein P25098 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 15618519 t gcesareni We find that two molecules interact with mammalian smo in an activation-dependent manner: g protein-coupled receptor kinase 2 (grk2) leads to phosphorylation of smo, and beta-arrestin 2 fused to green fluorescent protein interacts with smo. Ck1a, grk2, and another still-unidentified protein kinase phosphorylate the c-tail of mammalian smo in the presence of hh proteins SIGNOR-132669 0.2 ARID5B protein Q14865 UNIPROT TAL1 protein P17542 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29326336 f miannu ARID5B positively regulates the expression of TAL1 and its regulatory partners. we also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F). SIGNOR-256157 0.268 HMOX1 protein P09601 UNIPROT heme smallmolecule CHEBI:30413 ChEBI down-regulates quantity chemical modification 9606 10490932 t Regulation miannu Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme SIGNOR-251911 0.8 OGT protein O15294 UNIPROT PFKM protein P08237 UNIPROT down-regulates activity glycosylation Ser530 VVIPATVsNNVPGSD 9606 26399441 t lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. SIGNOR-267584 0.353 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 21205641 t lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-216453 0.469 GSK3B protein P49841 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser226 PKPGVTPsKSTSASA 9606 BTO:0000938 32599005 t lperfetto Our laboratory has also demonstrated that FGF14 is a key accessory protein that binds to the intracellular Nav1.6 C-terminal tail, and that GSK3β can phosphorylate FGF14 both in vitro and in vivo at S226 [20] in an experimental model of Alzheimer's disease SIGNOR-275746 0.262 SNRPE protein P62304 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270681 0.941 AKT proteinfamily SIGNOR-PF24 SIGNOR HTRA2 protein O43464 UNIPROT down-regulates phosphorylation Ser212 RVRVRLLsGDTYEAV 9606 17311912 t lperfetto Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212 SIGNOR-153323 0.2 CCL3 protein P10147 UNIPROT CCR2 protein P41597 UNIPROT up-regulates activity binding 10090 15075201 t lperfetto The purpose of this study was to determine whether certain chemokines, which are highly expressed in injured skeletal muscle, are involved in the repair and functional recovery of the muscle after traumatic injury. In wild-type control mice, mRNA transcripts of macrophage inflammatory protein (MIP)-1􏰂, MIP-1􏰃, and monocyte chemoattractant protein (MCP)-1 as well as their major receptors, CCR5 and CCR2, increased after freeze injury and gradu- ally returned to control (uninjured) levels by 14 days. SIGNOR-251723 0.548 ABL1 protein P00519 UNIPROT CASP9 protein P55211 UNIPROT up-regulates phosphorylation Tyr153 RGNADLAyILSMEPC 9606 15657060 t gcesareni C-abl phosphorylates casp9 on tyr-153 in vitro and in vivo in response to dna damage.The Present results demonstrate that c-abl binds directly to casp9. SIGNOR-133260 0.527 INTS1 protein Q8N201 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261468 0.89 C5AR2 protein Q9P296 UNIPROT Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 9108406 f lperfetto We report here that the anaphylatoxins C3a and C5a are chemotactic factors for the human mast cell line HMC-1, human cord blood-derived mast cells (CBMC) and cutaneous mast cells in vitro. SIGNOR-263459 0.7 CTDSP1 protein Q9GZU7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000007 17035229 t SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248796 0.494 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG2-LLGL2_variant complex SIGNOR-C503 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270880 0.537 TNF protein P01375 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity 10090 10485710 f lperfetto Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k). SIGNOR-252733 0.323 LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR VEPH1 protein Q14D04 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 22055343 f In the neuronal differentiation lperfetto Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r9 SIGNOR-269959 0.2 PAK1 protein Q13153 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Ser57 KKDRFYRsILPGDKT 9534 BTO:0000298 9032240 t miannu Cdc42 and Rac1 cause alpha-PAK autophosphorylation and kinase activation. SIGNOR-250219 0.2 CSNK2A2 protein P19784 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser356 VDGSGDTsSNEEIGS -1 12107178 t llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. SIGNOR-250991 0.424 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Thr317 EDATLEEtLVKKKKK 9606 20573420 t lperfetto Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation. SIGNOR-166333 0.369 CDK5 protein Q00535 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Thr75 RPNPCAYtPPSLKAV 10116 BTO:0000142 10604473 t llicata We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism. SIGNOR-250671 0.768 PPP2CB protein P62714 UNIPROT PRKCB protein P05771-2 UNIPROT down-regulates activity dephosphorylation Ser660 QSEFEGFsFVNSEFL 10116 15880462 t Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform SIGNOR-248586 0.458 CSNK2A1 protein P68400 UNIPROT EIF2B5 protein Q13144 UNIPROT up-regulates activity phosphorylation Ser718 KEAEEESsEDD 9606 BTO:0000007 11500362 t llicata Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.  SIGNOR-250860 0.394 SAMM50 protein Q9Y512 UNIPROT SAM complex complex SIGNOR-C422 SIGNOR form complex binding 31387448 t lperfetto The SAM complex of the outer membrane mediates insertion of β-barrel proteins into the outer membrane. hSam50 associates with MTX1 and MTX2. SIGNOR-267683 0.799 NEFM protein P07197 UNIPROT Neurofilament bundle assembly phenotype SIGNOR-PH72 SIGNOR up-regulates 9606 8376466 f miannu Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons. SIGNOR-252391 0.7 glycine smallmolecule CHEBI:15428 ChEBI GLRA1 protein P23415 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9009272 t miannu For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system. SIGNOR-258580 0.8 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr450 TAQMITItPPDQDDS 10090 BTO:0002572 18566586 t gcesareni MTORC2 phosphorylates newly synthesized Akt at the TM (Thr450) site to facilitate carboxyl-terminal folding and to stabilize Akt SIGNOR-252448 0.634 BZW2 protein Q9Y6E2 UNIPROT EIF3A protein Q14152 UNIPROT up-regulates activity binding 9606 31643092 t miannu BZW2, as an evolutionary highly conserved protein, interacts with eIF2 and eIF3 and promotes ternary complex formation in vitro SIGNOR-261221 0.329 TRIM27 protein P14373 UNIPROT PIK3C2B protein O00750 UNIPROT down-regulates ubiquitination 9606 22128329 t miannu We now show that trim27 functions as an e3 ligase and mediates lysine 48 polyubiquitination of pi3kc2_, leading to a decrease in pi3k enzyme activity. SIGNOR-177935 0.411 MAPK8 protein P45983 UNIPROT AP1 complex SIGNOR-C154 SIGNOR up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 t lperfetto The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity. SIGNOR-252354 0.811 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR G2/M_transition phenotype SIGNOR-PH52 SIGNOR up-regulates 15549093 f lperfetto The critical target of the G2 checkpoint is the mitosis-promoting activity of the cyclin B/CDK1 kinase, whose activation after various stresses is inhibited by ATM/ATR, CHK1/CHK2 and/or p38-kinase-mediated subcellular sequestration, degradation and/or inhibition of the CDC25 family of phosphatases that normally activate CDK1 at the G2/M boundary SIGNOR-251497 0.7 LEF1 protein Q9UJU2 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 17081971 f amattioni The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells. SIGNOR-229770 0.7 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Thr102 RAAMFPEtLDEGMQI 9606 BTO:0000007 12432063 t llicata We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin SIGNOR-250847 0.541 CCKAR protein P32238 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257236 0.254 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation 9606 19620713 t lperfetto Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. SIGNOR-255265 0.628 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1A protein P54750 UNIPROT down-regulates activity chemical inhibition 9606 22014080 t Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors. SIGNOR-256274 0.8 RXRB protein P28702 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-16674 0.71 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A4/b7 integrin complex SIGNOR-C187 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259011 0.324 DCX DET1-COP1 complex SIGNOR-C24 SIGNOR JUN protein P05412 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 14739464 t miannu We report that human DET1 (hDET1) promotes ubiquitination and degradation of the proto-oncogenic transcription factor c-Jun by assembling a multisubunit ubiquitin ligase containing DNA Damage Binding Protein-1 (DDB1), cullin 4A (CUL4A), Regulator of Cullins-1 (ROC1), and constitutively photomorphogenic-1.  Ablation of any subunit by RNA interference stabilized c-Jun and increased c-Jun-activated transcription. SIGNOR-271500 0.378 CDK1 protein P06493 UNIPROT NDUFV1 protein P49821 UNIPROT up-regulates activity phosphorylation Thr383 HESCGQCtPCREGVD 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275594 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Thr175 GLLPFLLtHKKRLTD 9606 19661060 t Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-260881 0.2 PCNA protein P12004 UNIPROT DNA polymerase epsilon complex SIGNOR-C377 SIGNOR up-regulates activity binding 9534 BTO:0004055 12930972 t lperfetto Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA). SIGNOR-265512 0.557 TLK2 protein Q86UE8 UNIPROT ASF1B protein Q9NVP2 UNIPROT unknown phosphorylation Ser198 PGLLPENsMDCI 9606 20016786 t Manara We found that only S192A in hASF1a and S198A in hASF1b significantly affected phosphorylation by hTLK2 | hASF1b stability does not appear to depend on phosphorylation by TLKs, but recently it has been shown that hASF1b transcription is controlled by the cell-cycle regulated E2F transcription factors SIGNOR-260788 0.72 CSNK2A1 protein P68400 UNIPROT CFTR protein P13569 UNIPROT down-regulates phosphorylation Thr1471 IAALKEEtEEEVQDT 9606 21930781 t lperfetto Cftr possesses two ck2 phosphorylation sites (s422 and t1471) the t1471 residue, previously described as a site for cftr phosphorylation by ck2 (25), seems to be critical for cftr turnover and processing. SIGNOR-176627 0.281 GATA1 protein P15976 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates activity 10090 BTO:0004911 12032775 f The zinc finger transcription factor GATA-1, a central mediator of erythroid gene expression, interacts with multiple proteins including FOG-1, EKLF, SP1, CBP/p300 and PU.1. SIGNOR-259962 0.7 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser876 QGLAERIsVL 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275956 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT1 protein Q9BQL6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser176 SSPTASGsSVSPGLY 9606 BTO:0000567 35469017 t miannu  CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry. SIGNOR-276720 0.2 MICU1 protein Q9BPX6 UNIPROT MCU_MICU1_variant complex SIGNOR-C500 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270867 0.685 CLOCK protein O15516 UNIPROT CRY2 protein Q49AN0 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253632 0.923 FBLIM1 protein Q8WUP2 UNIPROT FLNB protein O75369 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 t miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. SIGNOR-266106 0.745 PPARG protein P37231 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 32991581 t brain lperfetto NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog, SIGNOR-263984 0.9 methionine smallmolecule CHEBI:16811 ChEBI Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270402 0.8 BRCA1-C complex complex SIGNOR-C299 SIGNOR G2/M_transition-checkpoint phenotype SIGNOR-PH146 SIGNOR up-regulates 9606 BTO:0000567 16391231 f lperfetto This result implies that the BRCA1/BARD1–RMN–CtIP complex is required for activation of the G2/M checkpoint. SIGNOR-263229 0.7 NFIA protein Q12857 UNIPROT NFIX protein Q14938 UNIPROT up-regulates quantity transcriptional regulation 10090 29106906 t Gianni We report that, in the absence of Nfia or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord. SIGNOR-268871 0.2 GLS protein O94925 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 22049910 t miannu Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. SIGNOR-266910 0.8 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 22369944 t lperfetto Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity. SIGNOR-217316 0.344 ASH2L protein Q9UBL3 UNIPROT TBX1 protein O43435 UNIPROT up-regulates activity binding 9606 20463296 t Regulation miannu Tbx1 interacts with Ash2l in both yeast and mammalian cells and Ash2l acts as a transcriptional co-activator in luciferase reporter assays. SIGNOR-251868 0.313 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR USP24 protein Q9UPU5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1616 NSHSPAGsAAISQQD 9606 BTO:0000018 27991932 t lperfetto Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. SIGNOR-275611 0.26 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 15621017 f It has been reported that Aβ can result in an increase in intracellular Ca2+, which in turn can activates CaMK. SIGNOR-255481 0.7 APOC2 protein P02655 UNIPROT LPL protein P06858 UNIPROT up-regulates activity 9606 19956660 f Regulation miannu Triglycerides in VLDL are hydrolyzed by lipoprotein lipase, which in turn is activated by apolipoprotein CII on the surface but inhibited by apolipoprotein CIII. SIGNOR-251846 0.755 FH protein P07954 UNIPROT (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI up-regulates quantity chemical modification 9606 30761759 t miannu Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors. SIGNOR-266280 0.8 acetyl-CoA smallmolecule CHEBI:15351 ChEBI (3S)-3-hydroxy-3-methylglutaryl-CoA(5-) smallmolecule CHEBI:43074 ChEBI up-regulates quantity precursor of 29597274 t lperfetto Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis SIGNOR-267651 0.8 7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-2-ol chemical CHEBI:111176 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258724 0.8 AKT1 protein P31749 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser92 RFRDRSFsEGGERLL 9606 15538381 t llicata Here we report that protein kinase b (pkb/akt) stabilizes are transcripts by phosphorylating brf1 at serine 92 (s92). Recombinant brf1 promoted in vitro decay of are-containing mrna (are-mrna), yet phosphorylation by pkb impaired this activity. SIGNOR-130376 0.643 DYRK1A protein Q13627 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna SIGNOR-171030 0.438 SALL4 protein Q9UJQ4 UNIPROT SALL1 protein Q9NSC2 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19440552 f miannu Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex. SIGNOR-255127 0.432 OXGR1 protein Q96P68 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257368 0.2 DGC complex SIGNOR-C217 SIGNOR AQP4 protein P55087 UNIPROT up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626543 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265443 0.312 PIAS3 protein Q9Y6X2 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity binding 9606 9388184 t lperfetto PIAS3 blocked the DNA- binding activity of Stat3 and inhibited Stat3-mediated gene activation. Although Stat1 is also phosphorylated in response to IL-6, PIAS3 did not interact with Stat1 or affect its DNA-binding or transcriptional activity. The results indicate that PIAS3 is a specific inhibitor of Stat3. SIGNOR-238648 0.72 AKT proteinfamily SIGNOR-PF24 SIGNOR CCT2 protein P78371 UNIPROT unknown phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 19332537 t lperfetto Furthermore, ha-tagged akt can phosphorylate gst-cct_ protein in vitro SIGNOR-244172 0.2 SRC protein P12931 UNIPROT WNK4 protein Q96J92 UNIPROT down-regulates activity phosphorylation Tyr1164 KKEIEDLySRLGKQP 9606 BTO:0002181 25805816 t miannu Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c-Src: Tyr(1092), Tyr(1094), and Tyr(1143), and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4.  SIGNOR-276896 0.2 SLBP protein Q14493 UNIPROT H2BC18 protein Q5QNW6 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265394 0.2 WWTR1 protein Q9GZV5 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 22153608 t Runx family members play key roles in regulating mesenchymal stem cell differentiation during bone formation, and therefore the regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation. gcesareni Taz binding to the transcription factor runx2 promotes osteoblast lineage specification, whereas taz binding to the transcription factor ppargamma inhibits adipogenesis. SIGNOR-195218 0.52 TALDO1 protein P37837 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI down-regulates quantity chemical modification 9606 19401148 t miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. SIGNOR-267090 0.8 CAD protein P27708 UNIPROT carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity chemical modification 9606 24332717 t In animals, the first three reactions of the pathway are catalyzed by CAD, an 240 kDa multifunctional protein that combines glutamine-dependent carbamyl phosphate synthetase (GLNCPSase), aspartate transcarbamylase (ATCase), and dihydroorotase (DHOase) activities SIGNOR-267194 0.8 SOCS5 protein O75159 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity binding 9606 BTO:0000007 15590694 t miannu SOCS5 Can Physically Associate with the EGFR. The complex recruited by SOCS proteins is composed of ElonginBC, Cullin, and Roc1 (15, 16). Together, this complex has E3 ubiquitin ligase activity. We suspect that the role of the SB domain is to mediate coupling of EGFR with the Elongin-Cullin-Roc E3 ubiquitin ligase complex, resulting in enhanced EGFR degradation. SIGNOR-271516 0.458 LATS2 protein Q9NRM7 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates quantity by stabilization phosphorylation -1 24157836 t miannu FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 is ubiquitinated by the SCFFBXL5 complex. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination. SIGNOR-272138 0.543 CDH1 protein P12830 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265863 0.96 PPP2CB protein P62714 UNIPROT AKT2 protein P31751 UNIPROT down-regulates dephosphorylation 9606 8650155 t gcesareni These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity SIGNOR-42123 0.458 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser276 PQRSRSPsPQPSSHV 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248690 0.613 BTRC protein Q9Y297 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000944 16421275 t lperfetto Here we show that Gli is rapidly destroyed by the proteasome and that mouse basal cell carcinoma induction correlates with Gli protein accumulation. We identify two independent destruction signals in Gli1, D(N) and D(C), and show that removal of these signals stabilizes Gli1 protein and rapidly accelerates tumor formation in transgenic animals.Levels of _TrCP appeared to be limiting for Gli1 degradation, as increasing the levels of _TrCP protein significantly decreased steady-state levels of Gli1 protein SIGNOR-235631 0.65 AURKB protein Q96GD4 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Ser192 VNSVRRKsCLVKEVE 9606 17567953 t lperfetto Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres. SIGNOR-155898 0.719 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Ser738 ARIIGEKsFRRSVVG -1 10867018 t lperfetto The last two autophosphorylation sites (Ser(744) and Ser(748)) are located in the activation loop but are only phosphorylated in the isolated PKD-catalytic domain and not in the full-length PKD; they may affect enzyme catalysis but are not involved in the activation of wild-type PKD by phorbol ester. | These results indicate that neither of the activation loop serines is involved in PDBu-induced activation but that they may be involved in catalysis or in maintaining the conformation of the enzyme prot SIGNOR-249046 0.2 S1PR2 protein O95136 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 10488065 t gcesareni Edg-3 and edg-5 couple not only to gibut also to gqand g13. SIGNOR-70664 0.452 GAS6 protein Q14393 UNIPROT MERTK protein Q12866 UNIPROT up-regulates binding 9606 BTO:0000975 8939948 t gcesareni We also found that gas6 stimulated tyrosine phosphorylation of axl, sky, and mer receptors ectopically expressed in chinese hamster ovary cells. Taken together, these findings suggest that gas6 is a common ligand for axl, sky, and mer, all known members of an axl/sky receptor subfamily. SIGNOR-44953 0.753 MYO9B protein Q13459 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260510 0.521 CNOT8 protein Q9UFF9 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268310 0.784 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser126 RKETSARsLGSPLLH 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262715 0.733 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR up-regulates activity chemical activation 9606 18790874 t brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-263788 0.8 8-oxo-7-[(6-sulfo-2-naphthalenyl)hydrazinylidene]-5-quinolinesulfonic acid chemical CHEBI:95064 ChEBI PTPN11 protein Q06124 UNIPROT down-regulates activity chemical inhibition 9606 16717135 t These results identified NSC-87877 as the first PTP inhibitor capable of inhibiting Shp2 PTP in cell cultures without a detectable off-target effect. SIGNOR-261912 0.8 KDM4B protein O94953 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001109 28073943 f miannu JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. SIGNOR-263730 0.2 BMP7 protein P18075 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18719589 f induction of mitochondrial biogenesis fspada Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways SIGNOR-180314 0.293 DAG1 protein Q14118 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255983 0.573 EEF1A1 protein P68104 UNIPROT Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269513 0.8 DNA_damage stimulus SIGNOR-ST1 SIGNOR ERCC8 protein Q13216 UNIPROT up-regulates 24086043 f lperfetto TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. SIGNOR-275690 0.7 CNP protein P09543 UNIPROT MBP protein P02686 UNIPROT down-regulates activity 28076777 t SimoneGraziosi We provide evidence that CNP directly associates with and organizes the actin cytoskeleton, thereby providing an intracellular strut that counteracts membrane compaction by myelin basic protein (MBP). SIGNOR-269269 0.467 JAK3 protein P52333 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr597 RHSTILDyINVVPTA 9606 11733002 t lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling SIGNOR-112479 0.2 ITK protein Q08881 UNIPROT BTK protein Q06187 UNIPROT down-regulates activity phosphorylation Tyr223 LKKVVALyDYMPMNA -1 12573241 t Btk-SH3 mutant Y223A was not phosphorylated by Itk. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.|In Btk, the SH3 domain mutation Y223F results in enhanced fibroblast transformation, implying that the SH3 domain may play a negative regulatory role SIGNOR-251333 0.475 CSNK2A1 protein P68400 UNIPROT KLF1 protein Q13351 UNIPROT up-regulates activity phosphorylation Thr23 ALGPFPDtQDDFLKW 10090 BTO:0004475 9722526 t 2 miannu Regulation of erythroid Krƒppel-like factor (EKLF) transcriptional activity by phosphorylation of a protein kinase casein kinase II site within its interaction domain. the transactivation capability of EKLF is augmented by co-transfection of CKIIalpha. in vitro assays demonstrate that CKIIalpha interacts with EKLF, and that the EKLF interaction domain is phosphorylated by CKII only at Thr-41 SIGNOR-241361 0.35 AURKB protein Q96GD4 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Ser184 GKKSGKKsYLSGGAG 9606 23226345 t lperfetto Aurora b kinase phosphorylates yy1 on serine 184 and to a lesser extent serine 180 at the g2/m stage of the cell cycle (fig. 7). We show that yy1 is rapidly dephosphorylated as the cells exit mitosis, likely by pp1. Also, our data indicates that phosphorylation at serine 180 and serine 184 can affect the dna binding activity of yy1 SIGNOR-200079 0.376 CAMK2A protein Q9UQM7 UNIPROT NOX5 protein Q96PH1 UNIPROT unknown phosphorylation Ser548 MRKSQRSsKGSEILL -1 21642394 t miannu In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475. SIGNOR-276333 0.2 IGFBP3 protein P17936 UNIPROT Neuron_maturation phenotype SIGNOR-PH169 SIGNOR down-regulates 10090 BTO:0000142 17278996 f Luana IGFBP3 overexpression due to lack of MeCP2 may lead to delayed brain maturation. SIGNOR-265774 0.7 DDR2 protein Q16832 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 16186108 t gcesareni Collectively, our findings are consistent with the following mechanism for src-dependent ddr2 activation and signaling: 1) ligand binding promotes phosphorylation of tyr-740 in the ddr2 activation loop by src;2) tyr-740 phosphorylation stimulates intramolecular autophosphorylation of ddr2;3) ddr2 autophosphorylation generates cytosolic domain phosphotyrosines that promote the formation of ddr2 cytosolic domain-shc signaling complexes. SIGNOR-140724 0.402 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of 9606 30616754 t lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle SIGNOR-267589 0.8 RUNX3 protein Q13761 UNIPROT IKBKB protein O14920 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255089 0.2 BAK1 protein Q16611 UNIPROT ENDOG protein Q14249 UNIPROT up-regulates 9606 12941691 f gcesareni We show that the mitochondrial outer-membrane permeabilization induced by bax-, tbid- or bax/bak-dependent pro-apoptotic drugs results in the release of cytochrome c, smac/diablo and htra2/omi, but that subsequent caspase activation is required to induce the translocation of endog in addition to aif into the cytosol. SIGNOR-86406 0.296 CHUK protein O15111 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity phosphorylation Ser1415 PTPAILEsLISINNK 9606 BTO:0002181 24990947 t miannu  Importantly, IKKα is shown to phosphorylate mTOR at serine 1415 in a manner dependent on Akt to promote mTORC1 activity. These results demonstrate that IKKα is an effector of Akt in promoting mTORC1 activity. SIGNOR-276646 0.524 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser197 DRVSRSSsPLKTGEQ 9534 BTO:0000298 12756254 t miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. SIGNOR-250124 0.879 PRKCA protein P17252 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 t lperfetto Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway. SIGNOR-115714 0.352 LAMTOR2 protein Q9Y2Q5 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR form complex binding 9606 20381137 t lperfetto Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant SIGNOR-164772 0.924 PRKAA1 protein Q13131 UNIPROT SYN1 protein P17600 UNIPROT down-regulates activity phosphorylation Ser9 NYLRRRLsDSNFMAN 9606 10880969 t lperfetto It has been reported that site 1 of syn i can be phosphorylated by pka. Pka-mediated synapsin i ser9 phosphorylation occurs in response to cgs 21680 treatment. Results show that the adenosine a2a receptor agonist, cgs 21680, increases neurotransmitter release, in particular, glutamate and noradrenaline and such response is mediated by protein kinase a activation, which in turn increased synapsin i phosphorylation SIGNOR-78891 0.2 FLT3 protein P36888 UNIPROT PTPRJ protein Q12913 UNIPROT down-regulates activity 10090 22438257 f Taken together, the described findings supported the notion that FLT3 ITD causes reduced DEP-1 activity compared with cells expressing WT FLT3 rather than alterations in mRNA or protein levels. SIGNOR-261553 0.503 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20565746 f irozzo These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression. SIGNOR-256126 0.349 regorafenib chemical CHEBI:68647 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259205 0.8 F2R protein P25116 UNIPROT KLF6 protein Q99612 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254849 0.2 KSR1 protein Q8IVT5 UNIPROT ARAF protein P10398 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 t miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. SIGNOR-273876 0.549 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Asp) smallmolecule CHEBI:29186 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270371 0.8 MAFA protein Q8NHW3 UNIPROT PDX1 protein P52945 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17149590 f miannu the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. SIGNOR-254562 0.737 FLT3 protein P36888 UNIPROT PARP1 protein P09874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 21228325 f Interestingly, quantitative RT-PCR analysis demonstrated a 2-fold increase in PARP-1 expression. Western blotting analysis of protein nuclear extracts from FLT3/ITD B-cells confirmed that PARP1 was up-regulated, compared with wild-type controls  SIGNOR-261554 0.252 SPTB proteinfamily SIGNOR-PF73 SIGNOR Non-erythrocytic spectrin complex SIGNOR-C385 SIGNOR form complex binding 9606 24302288 t lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell SIGNOR-266027 0.2 metformin chemical CHEBI:6801 ChEBI PRKAA2 protein P54646 UNIPROT up-regulates 9606 11602624 f gcesareni Here we report that metformin activates ampk in hepatocytes. SIGNOR-111034 0.8 IRAK1 protein P51617 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 12242293 t lperfetto We now find that the phosphorylated IRAK in turn recruits TRAF6 to the receptor complex (complex I), which differs from the previous concept that IRAK interacts with TRAF6 after it leaves the receptor. IRAK then brings TRAF6 to TAK1 SIGNOR-92994 0.911 NMUR2 protein Q9GZQ4 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257218 0.441 TGFB2 protein P61812 UNIPROT TGFB2 protein P61812 UNIPROT up-regulates binding 9606 16885528 t gcesareni The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge SIGNOR-148608 0.2 PLCB3 protein Q01970 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity 23994464 f apalma The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release SIGNOR-255014 0.8 HOXD13 protein P35453 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16314414 f miannu We show that hoxd13 andhoxa13activate transcription from the epha7 promoter and that a mutation of thehoxa13/hoxd13 binding site was sufficient to abolish activation. SIGNOR-142453 0.275 MAPK8IP1 protein Q9UQF2 UNIPROT MAP3K10 protein Q02779 UNIPROT up-regulates binding 9606 15767678 t gcesareni The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk. SIGNOR-134552 0.518 FANCI protein Q9NVI1 UNIPROT Fanconi anemia ID complex complex SIGNOR-C302 SIGNOR form complex binding 9606 BTO:0000007 17412408 t lperfetto Immunoprecipitation of HA-FLAG-tagged FANCI expressed in 293T cells with antibodies against either HA or FLAG, but not MYC, resulted in coimmunoprecipitation of endogenous FANCD2|The FANCI protein associates with FANCD2 and, together, as the FANCI-FANCD2 (ID) complex, localize to chromatin in response to DNA damage. SIGNOR-263269 0.955 HTR1E protein P28566 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257100 0.255 AKT1 protein P31749 UNIPROT CABLES1 protein Q8TDN4 UNIPROT down-regulates activity phosphorylation Thr415 AFGARRNtIDSTSSF -1 25361894 t miannu Here, we report that Cables1 levels are controlled by a phosphorylation and 14-3-3-dependent mechanism. Mutagenic analyses identified two residues, T44 and T150, that are specifically critical for 14-3-3 binding and that serve as substrates for phosphorylation by the cell survival kinase Akt, which by binding directly to Cables1 recruits 14-3-3 to the complex.Ectopic expression of activated Akt (AKT1) prevented Cables1-induced apoptosis. SIGNOR-276757 0.346 CDKN1A protein P38936 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 7626805 t gcesareni P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage.We Have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases. SIGNOR-29957 0.939 DAPK1 protein P53355 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000776 17339337 t gcesareni Dna damage-activated protein kinases like chk1/2 modify the box-i domain of p53 at thr18 and ser20 (46) by an allosteric mechanism (10). SIGNOR-153491 0.574 MAPK1 protein P28482 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 12110590 t gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. SIGNOR-90517 0.723 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr384 ACQVYFTyDPYSEED -1 10214954 t Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510. SIGNOR-251376 0.629 SKI protein P12755 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 BTO:0000848 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-236077 0.717 KIF5B protein P33176 UNIPROT Organelle_transport phenotype SIGNOR-PH159 SIGNOR up-regulates 9606 BTO:0000938 9438838 f miannu The kinesin superfamily of proteins plays a major role in this complex organelle transport. Kinesin is primarily associated with anterogradely transported membranous organelles in nerve axons. KIF5B and HsuKHC are expressed ubiquitously in many tissues, whereas KIF5A, KIF5C, and HsnKHC are specific to nerve tissue. SIGNOR-264068 0.7 EID1 protein Q9Y6B2 UNIPROT EP300 protein Q09472 UNIPROT down-regulates activity binding 11073990 t lperfetto Inhibition of MyoD may be explained by EID-1's ability to bind and inhibit p300's histone acetylase activity, an essential MyoD coactivator. SIGNOR-253377 0.431 NCK1 protein P16333 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9534 8824201 t lperfetto We describe here a specific interaction of the Nck adapter molecule with PAK1 both in vitro and in vivo. Association of Nck with PAK1 may serve to link this important regulatory kinase to cell activation by growth factor receptors. SIGNOR-236324 0.697 PRKCA protein P17252 UNIPROT UNC5A protein Q6ZN44 UNIPROT down-regulates quantity phosphorylation Ser352 TSGFQPVsIKPSKAD 10116 BTO:0003036 16554470 t miannu We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis. SIGNOR-268180 0.2 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation 9606 12270934 t lbriganti Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. SIGNOR-210176 0.742 FZD2 protein Q14332 UNIPROT CEBPA protein P49715 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma) SIGNOR-80601 0.2 BDKRB1 protein P46663 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257304 0.572 NOTCH1 protein P46531 UNIPROT IL2RA protein P01589 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001454 10933396 f gcesareni Activation of notch1 signaling in dp thymocytes and thymoma cell lines results in the upregulation of cd25 and cd44 expression. SIGNOR-80336 0.299 HMOX1 protein P09601 UNIPROT HBA1 protein P69905 UNIPROT down-regulates activity 9606 10490932 t Regulation miannu Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme SIGNOR-251813 0.255 SKIL protein P12757 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity binding 9606 10531062 t lperfetto Thus, SnoN can interact with Smad4 and Smad2 and inhibit their abilities to activate transcription. SIGNOR-71633 0.882 DYRK2 protein Q92630 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser41 LRGNVVPsPLPTRRT 9606 21177848 t gcesareni Ser41 is known to be phosphorylated by a dyrk isoform in serum-fed or -starved cells (21). A phosphomimetic mutation of ser41 to asp resulted in complete loss of human crhsp-24 binding ability whether in the oxidative state or not SIGNOR-170781 0.263 NOS2 protein P35228 UNIPROT nitric oxide smallmolecule CHEBI:16480 ChEBI up-regulates 9606 7537672 f apalma Activation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the ammino acid L-arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline SIGNOR-255381 0.8 AD/b2 integrin complex SIGNOR-C172 SIGNOR VCAM1 protein P19320 UNIPROT up-regulates activity binding 9606 BTO:0000751 10438935 t lperfetto These results indicate that VCAM-1 can bind to an I domain and that the binding of alpha D beta 2 to VCAM-1 may contribute to the trafficking of a subpopulation of leukocytes that express alpha D beta 2. SIGNOR-253375 0.573 Pyridostigmine chemical CHEBI:8665 ChEBI BCHE protein P06276 UNIPROT down-regulates activity chemical inhibition -1 20627738 t Luana The compounds 3-[(dimethylamino)carboxyl]oxy]-N,N,N-trimethylammonium methyl sulfate, better known as neostigmine methyl sulfate (3),1 and 3-[(dimethylcarbamoyl)oxy]-1-methylpyridinium bromide, pyridostigmine bromide (4)2 (Figure 1) are well known peripheral cholinesterase inhibitors  SIGNOR-257880 0.8 MBTPS2 protein O43462 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity cleavage 10029 BTO:0000246 10419520 t In order to activate transcription, the NH2-terminal domain of the SREBP must be released from the membrane so that it can enter the nucleus. This release has been studied most extensively for one of the SREBPs, namely, SREBP-2. However, the mechanism appears to be similar for the other SREBPs (SREBP-1a and -1c) (1). Release of the NH2-terminal domain is accomplished by a two-step proteolytic event that is regulated by sterols (3). In sterol-depleted mammalian cells, this proteolysis is initiated by the Site-1 protease (S1P), which cleaves human SREBP-2 between the Leu522-Ser523 bond in the sequence RSVL S (4). This cleavage requires formation of a complex between SREBP and SCAP, a polytopic membrane protein of the ER, and it is prevented when this complex is disrupted SIGNOR-267499 0.637 ACO2 protein Q99798 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI down-regulates quantity chemical modification 9606 24068518 t miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. SIGNOR-266244 0.8 AKAP13 protein Q12802 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260527 0.734 TUBB protein P07437 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity binding 9606 17429065 t lperfetto Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin. SIGNOR-217631 0.2 Caspase 3 complex complex SIGNOR-C221 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000142 10200555 f amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation SIGNOR-256477 0.7 PRKDC protein P78527 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Ser43 PAMLHLPsEQGAPET -1 31932854 t miannu Here, we show that DNA-dependent protein kinase (DNA-PK), an enzyme involved in DNA double-strand break (DSB) repair, triggers the phosphorylation of NEMO by genotoxic stress, thereby enabling shuttling of NEMO through the nucleus with subsequent NF-κB activation. We identified serine 43 of NEMO as a DNA-PK phosphorylation site and point mutation of this serine to alanine led to a complete block of NF-κB activation by ionizing radiation (IR). SIGNOR-277508 0.301 MAP2K2 protein P36507 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 11971971 t gcesareni Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-86713 0.734 LIMS4 protein P0CW20 UNIPROT IPP complex complex SIGNOR-C380 SIGNOR form complex binding 16493410 t lperfetto Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton. SIGNOR-265766 0.2 NFY complex SIGNOR-C1 SIGNOR ZDHHC5 protein Q9C0B5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28775165 t Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y SIGNOR-261151 0.2 ATM protein Q13315 UNIPROT BLM protein P54132 UNIPROT up-regulates phosphorylation Thr99 NAPAGQEtQRGGSKS 9606 12034743 t lperfetto Mitotic phosphorylation of blm was partially dependent on atm, and phosphorylation sites on blm were identified. A phosphospecific antibody against one of these sites (thr-99) revealed radiation-induced phosphorylation, which was defective in ataxia-telangiectasia cells. These data suggest that atm and blm function together in recognizing abnormal dna structures by direct interaction and that these phosphorylation sites in blm are important for radiosensitivity status but not for sce frequency. SIGNOR-88010 0.767 PPP2CB protein P62714 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation 9606 8650155 t gcesareni These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity SIGNOR-42050 0.487 HES1 protein Q14469 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000759 14614508 t CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo SIGNOR-253584 0.25 STOML2 protein Q9UJZ1 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 18641330 t Giorgia In these studies, we also found that SLP-2 interacted with Lck, ZAP70, LAT, and PLC-gamma1 during the 30-min period following stimulation in vitro|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling. SIGNOR-260377 0.2 GDNF protein P39905 UNIPROT TUBA1A protein Q71U36 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization. SIGNOR-252174 0.2 Degranulation phenotype SIGNOR-PH92 SIGNOR IL6 protein P05231 UNIPROT up-regulates quantity 9606 BTO:0000830 24232182 f apalma Particularly, damage-activated mast cells almost instantly begin to secrete TNFa, histamine and tryptase and then initiate the de novo synthesis of other cytokines, such as interleukin (IL)6 SIGNOR-255349 0.7 PPP1CC protein P36873 UNIPROT CDK9 protein P50750 UNIPROT up-regulates dephosphorylation Thr186 NSQPNRYtNRVVTLW 9606 21533037 t amattioni Pp1 is an activator of cdk9. Pp1 dephosphorylates cdk9 thr186. SIGNOR-173454 0.2 TNFRSF17 protein Q02223 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates 9606 10903733 f inferred from 70% of family members miannu Overexpression of bcma activates the p38 mapk SIGNOR-269917 0.268 PLK1 protein P53350 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser286 KFIMGDSsVQDQWKE 9606 BTO:0000567 phosphorylation:Ser386 LRGAQAAsPAKGEPS 23348582 t lperfetto Cdk1-cyclin B1 directly phosphorylates PTP1B at serine 386 in a kinase assay. Recombinant Plk1 phosphorylates PTP1B on serine 286 and 393 in vitro, however, it requires a priming phosphorylation by Cdk1 at serine 386 highlighting a novel co-operation between Cdk1 and Plk1 in the regulation of PTP1B.|Finally, phosphorylation on serine 286 enhanced PTP1B phosphatase activity. SIGNOR-272990 0.361 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser649 VPPSPSLsRHSSPHQ 11427888 t Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. SIGNOR-251240 0.673 MRTFA protein Q969V6 UNIPROT SRF protein P11831 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 21673106 t gcesareni Similarly, the myocd-related transcription factor (mrtf) family of proteins, mrtf-a and mrtf-b, are also involved in the transcriptional regulation of contractile gene markers as coactivators of srf. SIGNOR-174264 0.2 DNAJC15 protein Q9Y5T4 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 t lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. SIGNOR-267692 0.445 TGFB2 protein P61812 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 22326956 t miannu Tgf-? Signaling mediates a wide range of biological activities in development and disease. Tgf-? Ligands signal through heterodimeric type i and type ii receptors (tgf-? Receptor type i [t?RI, also known as alk5 and tgfbr1] and t?RII) that are members of the serine/threonine kinase family. SIGNOR-196025 0.735 RGS6 protein P49758 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates binding 9606 17609107 t flangone Numb binds to integrin-betas and localizes to clathrin-coated structures SIGNOR-156762 0.2 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000938 BTO:0000142 SIGNOR-C110 19303846 t gcesareni DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin. SIGNOR-184785 0.856 PRKAG2 protein Q9UGJ0 UNIPROT STIM1 protein Q13586 UNIPROT down-regulates activity phosphorylation Ser257 GLHRAEQsLHDLQER 10090 BTO:0000452 31381180 t miannu STIM1 is a novel exercise‐regulated AMPK substrate. Phosphorylation of STIM1 by AMPK suppresses SOCE SIGNOR-277297 0.2 SGK1 protein O00141 UNIPROT MKNK1 protein Q9BUB5 UNIPROT down-regulates activity phosphorylation Ser352 SEAKDLIsKLLVRDA -1 28545025 t miannu We show that SGK1 phosphorylates MNK1 at a conserved site, which represses its activity.  SIGNOR-277357  0.2 diarsenic trioxide chemical CHEBI:30621 ChEBI PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR down-regulates quantity by destabilization chemical inhibition 9606 24344243 t ATO was shown to degrade PML-RARa via its PML moiety further reinforcing the idea that APL is addicted to the PML-RARa oncoprotein SIGNOR-259924 0.8 CDK2 protein P24941 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser560 LARLGCSsCLDYFTT 9606 18769144 t lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively SIGNOR-180763 0.248 RALA protein P11233 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates activity phosphorylation Thr455 ALGTPVLtPPTEAAS 10090 11689711 t gcesareni We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT. SIGNOR-249665 0.2 PRKCG protein P05129 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser188 LGERKPSsAAYQKAP -1 9244383 t lperfetto We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198. SIGNOR-248978 0.36 4'-((2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile chemical CID:9843116 PUBCHEM ACHE protein P22303 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001239 17888667 t Luana AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE. SIGNOR-257759 0.8 EFR3B protein Q9Y2G0 UNIPROT PI4KA protein P42356 UNIPROT up-regulates quantity binding 9606 BTO:0000007 34504076 t miannu PI4KA is recruited to plasma membrane by the adapter protein EFR3, which has two isoforms, EFR3A and EFR3B SIGNOR-269093 0.524 AKT1 protein P31749 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr72 TERPRPNtFIIRCLQ -1 16549426 t miannu Autophosphorylation of Akt on Thr-72 and Ser-246 appeared to require prior phosphorylation of Akt on Thr-308 and Ser-473. Compared with wild-type Akt, Akt/T72A/S246A mutant exhibited markedly reduced basal Akt kinase activity and response to cellular stimulation by insulin-like growth factor-1, and also conferred less cellular resistance to doxorubicin-induced apoptosis. SIGNOR-276054 0.2 MYLK3 protein Q32MK0 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Thr80 NEPHESRtNSDIVET 9606 BTO:0000007 21556048 t lperfetto Here, we show that phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis.|Here, we show that skMLCK directly phosphorylates MEF2C, leading to p300/PCAF recruitment, increased acetylation of skeletal muscle-specific genes, and enhanced skeletal myogenesis SIGNOR-264565 0.272 CAMK4 protein Q16566 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 BTO:0000887 11114197 t gcesareni Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs. SIGNOR-85106 0.489 UBE2I protein P63279 UNIPROT MBD4 protein O95243 UNIPROT up-regulates activity sumoylation Lys215 TSTHLLLkEDEGVDD 31476572 t lperfetto MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro. SIGNOR-275677 0.2 ITCH protein Q96J02 UNIPROT BID protein P55957 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 20392206 t miannu The ubiquitin ligase Itch mediates the antiapoptotic activity of epidermal growth factor by promoting the ubiquitylation and degradation of the truncated C-terminal portion of Bid SIGNOR-271415 0.359 CPSF1 protein Q10570 UNIPROT CPSF complex complex SIGNOR-C53 SIGNOR form complex binding 9606 14749727 t miannu Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna. SIGNOR-121646 0.94 PRKACA protein P17612 UNIPROT NF2 protein P35240 UNIPROT up-regulates phosphorylation Ser10 GAIASRMsFSSLKRK 9606 18071304 t lperfetto Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth, SIGNOR-159840 0.379 DIDO1 protein Q9BTC0 UNIPROT ITGA5 protein P08648 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001673 22469980 t Luana Dido1 upregulates the expression of Integrin αV, thereby influencing the attachment, apoptosis and migration of melanoma cells. SIGNOR-261580 0.2 JUN protein P05412 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 23936544 t lperfetto MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-beta mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-beta production SIGNOR-251713 0.523 RARG protein P13631 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 15650024 t inferred from family member lperfetto We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs SIGNOR-270296 0.394 RARB protein P10826 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 15650024 t inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs SIGNOR-270299 0.398 CDX2 protein Q99626 UNIPROT INS protein P01308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000120 12783165 f miannu In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3. SIGNOR-254906 0.313 PKA proteinfamily SIGNOR-PF17 SIGNOR PHF2 protein O75151 UNIPROT up-regulates activity phosphorylation Ser1056 FLTQRRPsASSPNNN 9606 BTO:0000007 21532585 t miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. Replacement of all of four serine residues by alanines (4SA: Ser 757/Ser 899/Ser 954/Ser 1056) fully abrogated PKA phosphorylation of PHF2 (Fig. 2h). SIGNOR-264513 0.2 GRIA2 protein P42262 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264948 0.8 PAK1 protein Q13153 UNIPROT SORT1 protein Q99523 UNIPROT down-regulates activity phosphorylation Ser793 RFLVHRYsVLQQHAE 9606 BTO:0000007 31767632 t miannu PAKs specifically phosphorylate Ser15 of the sortilin-cd and alter its trafficking. It can be concluded that PAK1-3 may indeed instigate the phosphorylation of sortilin and that they target a single serine residue (Ser15) located in the kinase domain-binding site of the sortilin-cd. Full-length sortilins with the serine at position 793 (residue 15 in the cytoplasmic domain) (for the sequence, see Fig. 2). Phosphorylation (Ser15) downregulates the sortilin–AP-1 interaction. SIGNOR-273718 0.2 GNRHR protein P30968 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256935 0.277 XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 11447297 t lperfetto Xiap promotes the degradation of active-form caspase-3, but not procaspase-3, in living cells. Both the association of XIAP with caspase-3 and the RING finger domain of XIAP were essential for ubiquitination. XIAP promotes the degradation of caspase-3, which enhances its anti-apoptotic effect. SIGNOR-109243 0.938 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248741 0.727 CTSG protein P08311 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Tyr69 NESGLTEyRLVSINK -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. SIGNOR-263564 0.577 NF1 protein P21359 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 7549116 f miannu Our results pointed to a key role that NF1 might play in the functioning of the AFP promoter. Indeed, overexpression of NF1 induced a specific decrease in the activity of the AFP promoter. Competition between NF1 and HNF-1 for binding to their overlapping binding sites on the AFP promoter would be critical for modulating its activity. SIGNOR-254636 0.275 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120068 0.781 TBX21 protein Q9UL17 UNIPROT IFNG protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0003432 10761931 t Luana T-bet Transactivates the IFNγ Gene and Represses the IL-2 Gene in EL4 Cells SIGNOR-266234 0.488 STAT1 protein P42224 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19482358 f miannu Socs1 expression is induced in the human keratinocytes HaCaT cell line through sequential activation of STAT1 and IRF-1 SIGNOR-226484 0.622 CAMK2G protein Q13555 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1070 DSFLQRYsSDPTGAL BTO:0000017 1309762 t llicata The mechanism of desensitization of kinase activity can be accounted for, in part, by the EGF-stimulated phosphorylation of the receptor at Ser1046/7, a substrate for the multifunctional calmodulin-dependent protein kinase II in vitro. Mutation of Ser1046/7 by replacement with Ala residues blocks desensitization of the EGF receptor protein-tyrosine kinase activity.  SIGNOR-250694 0.369 MMP1 protein P03956 UNIPROT COL1A1 protein P02452 UNIPROT down-regulates quantity by destabilization cleavage Gly776 IGPPGPAgAPGDKGE -1 17318226 t lperfetto In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4.  SIGNOR-272336 0.386 PPP3CA protein Q08209 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10195903 t Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. SIGNOR-248694 0.452 AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000887;BTO:0001103;BTO:0001760 20138985 t lperfetto Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1. SIGNOR-217586 0.719 CDK1 protein P06493 UNIPROT NUP98 protein P52948 UNIPROT down-regulates activity phosphorylation Ser623 RDSENLAsPSEYPEN 9606 21335236 t gcesareni We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks. SIGNOR-172221 0.407 MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser47 DGPGLERsPGEPGGA 9606 20027304 t This phosphorylation increased sirt1 nuclear localization gcesareni Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53. SIGNOR-162318 0.62 AKT proteinfamily SIGNOR-PF24 SIGNOR EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 18836482 t gcesareni Using an in vitro kinase assay, we found that pkb can directly phosphorylate eif4b on serine 422 (ser422). This was prevented by pretreatment of cells with the phosphatidylinositol 3-kinase (pi3k) inhibitor ly294002 or pharmacological inhibition of pkb. Phosphorylation regultes the activation of eukaryotic translation initiation factor 4b. SIGNOR-181536 0.2 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr72 IKALRTDyNASVSVP 9606 12052863 t lperfetto We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown). SIGNOR-88919 0.608 EMSY protein Q7Z589 UNIPROT CBX1 protein P83916 UNIPROT up-regulates activity binding 9606 BTO:0000567 14651845 t miannu The binding sites for HP1β and BS69 with EMSY abut each other, and are found directly adjacent to the ENT domain of EMSY. This demonstrates that EMSY has the capacity to contact directly at least two proteins which contain a Royal Family domain. Since this domain is found in proteins with a chromatin connection, we assume that EMSY functions, at least partly, in the regulation of chromatin. SIGNOR-263917 0.2 BBC3 protein Q9BXH1 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 17289999 t gcesareni Bh3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding bax and bak enabler bh3-only proteins such as puma promote momp more indirectly. They activate bax and bak by forming inhibitory complexes with the anti-apoptotic bh1-4 proteins such as bcl2, bclxl and mcl1 that normally stabilize the outer membrane. SIGNOR-152974 0.391 F2R protein P25116 UNIPROT LATS2 protein Q9NRM7 UNIPROT down-regulates 9606 BTO:0000007 22972936 f milica Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase. SIGNOR-192048 0.2 PRKD1 protein Q15139 UNIPROT PKD2 protein Q13563 UNIPROT up-regulates activity phosphorylation Ser801 SSLPRPMsSRSFPRS 9606 BTO:0000007 20881056 t miannu Here, we report the identification of a previously unrecognized phosphorylation site within the polycystin-2 C terminus (Ser801), and we demonstrate that it is phosphorylated by protein kinase D. Phosphorylation at this site was significantly increased in response to serum and epidermal growth factor stimulation.We confirmed previous studies showing that PC2 mediated Ca2+ release from the ER can be stimulated by ATP.Phosphorylation at Ser801 seems to be permissive for this activity without altering the subcellular localization nor homophilic and heterophilic (with PC1) interactions of wild-type PC2. SIGNOR-259829 0.47 PPP2CB protein P62714 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity dephosphorylation Ser317 ENVKYSSsQPEPRTG 9606 17015476 t Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo. SIGNOR-248579 0.269 BLM protein P54132 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 28912125 f miannu The BLM gene product, BLM, is a RECQ helicase that is involved in DNA replication and repair of DNA double-strand breaks by the homologous recombination (HR) pathway. During HR, BLM has both pro- and anti-recombinogenic activities, either of which may contribute to maintenance of genomic integrity. SIGNOR-261824 0.7 PPP1R9B protein Q96SB3 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates activity binding 10090 BTO:0001976 15996550 t miannu The Rho Family GEF Lfc Interacts with Neurabin and Spinophilin. Neurabin and spinophilin are homologous protein phosphatase 1 and actin binding proteins that regulate dendritic spine function. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc SIGNOR-269176 0.405 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates phosphorylation Tyr1325 RLLEGNFyGSLFSVP 9606 19834457 t lperfetto The nr2a subunit of the nmda receptor is tyrosine-phosphorylated, with tyr 1325 as its one of the major phosphorylation sitewe also show that the tyr 1325 phosphorylation site is required for src-induced potentiation of the nmda receptor channel in the striatum. SIGNOR-188531 0.584 CSNK2A1 protein P68400 UNIPROT LIG1 protein P18858 UNIPROT up-regulates activity phosphorylation Ser66 KAARVLGsEGEEEDE 9606 BTO:0000567 12851383 t lperfetto Moreover, these data confirmed the occurrence of Ser66 phosphorylation, which was previously studied with a specific monoclonal antibody (23). SIGNOR-103258 0.346 CEBPB protein P17676 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 16431920 t fspada These data suggest that c/CEBP beta activates a single unified pathway of adipogenesis involving its stimulation of PPARgamma expression, which then activates C/EBP alpha expression by dislodging HDAC1 from the promoter for degradation in the proteasome SIGNOR-143952 0.718 TNFRSF17 protein Q02223 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 10903733 f miannu Bcma overexpression induces nf-kb activation SIGNOR-79510 0.285 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A13 protein Q9NSD5 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207066 0.8 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2E1 protein P51965 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271325 0.709 CAMK2A protein Q9UQM7 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Thr107 ELTHNWGtEDDETQS -1 32966793 t miannu This study is able to show that a phosphorylation of threonine-107 (T107) in the (rate-limiting) Glyoxalase 1 (Glo1) protein, mediated by Ca2+/calmodulin-dependent kinase II delta (CamKIIδ), is associated with elevated catalytic efficiency of Glo1 (lower KM; higher Vmax). SIGNOR-273553 0.2 PCDHA2 protein Q9Y5H9 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265661 0.2 PDP2 protein Q9P2J9 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16510868 t lpetrilli We show that the mammalian pdps are important in dephosphorylation of bmp-activated smad1 but not tgf-beta-activated smad2 or smad3. Thus, pdps specifically inactivate smads in the bmp/dpp pathway. [...] These observations suggest that pdp1 and pdp2 are important for dephosphorylation of smad1. SIGNOR-144909 0.245 RHOQ protein P17081 UNIPROT EXOC7 protein Q9UPT5 UNIPROT up-regulates binding 9606 12687004 t gcesareni Here we show that tc10 interacts with one of the components of the exocyst complex, exo70. SIGNOR-100486 0.621 SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 11154281 t lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. SIGNOR-249133 0.787 TFE3 protein P19532 UNIPROT GABARAPL1 protein Q9H0R8 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells SIGNOR-276821 0.33 RPS6KA1 protein Q15418 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 t gcesareni We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling. SIGNOR-37154 0.544 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR up-regulates 9606 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268586 0.2 CDK1 protein P06493 UNIPROT ATAD5 protein Q96QE3 UNIPROT down-regulates activity phosphorylation Ser653 TVPFDSEsPIRMKFT 9606 BTO:0000007 31875566 t miannu To determine whether mitotic CDK phosphorylates ATAD5, a CDK1 inhibitor (RO3306) was applied to nocodazole-arrested cells (Figure S3F). CDK1 inhibition resulted in a loss of S653 phosphorylation (Figure S3F). These data meant that the S653 residue in the BET BD of ATAD5 is phosphorylated by mitotic CDK. This result suggested that the BRD4-ATAD5 interaction is inhibited during mitosis. SIGNOR-266410 0.241 PRKACA protein P17612 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates phosphorylation Ser44 RLQERRGsNVALMLD 9606 10559944 t llicata Here we show that cyclic-amp-dependent protein kinase (pka) phosphorylates serine residue 23 in the kim of heptp in vitro and in intact cells. This modification reduces binding of map kinases to the kim, an effect that is prevented by mutation of serine 23 to alanine. SIGNOR-72147 0.368 KAT6A protein Q92794 UNIPROT KAT6A/PML complex SIGNOR-C55 SIGNOR form complex binding 9606 BTO:0001271 23431171 t miannu We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression SIGNOR-201478 0.503 CSNK2A1 protein P68400 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity phosphorylation Ser60 ETNQNSSsDSEAERR -1 11711551 t llicata We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. SIGNOR-250964 0.365 CPSF4 protein O95639 UNIPROT CPSF complex complex SIGNOR-C53 SIGNOR form complex binding 9606 BTO:0000007 19224921 t lperfetto The CPSF complex consists of five subunits, named CPSF160, CPSF100, Fip1, CPSF73, and CPSF30. SIGNOR-268334 0.915 STAT6 protein P42226 UNIPROT PPARA protein Q07869 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 20508200 f lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. SIGNOR-249534 0.358 SMARCB1 protein Q12824 UNIPROT CSF1 protein P09603 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 16267391 f miannu Ini1/hsnf5/baf47 is involved in activation of the csf1 promoter. SIGNOR-141047 0.2 PRKACA protein P17612 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser195 EKLRRRFsSLHFMVE 9606 15703181 t lperfetto We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195. SIGNOR-133884 0.2 MBTPS2 protein O43462 UNIPROT CREB3L1 protein Q96BA8 UNIPROT up-regulates cleavage 9606 16417584 t miannu Cleavage of oasis by site-1 and site-2 proteases / oasis is cleaved at the membrane under er stress conditions and that its cleaved n-terminal domain translocates into the nucleus;and then activates transcription of target genes SIGNOR-143820 0.55 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates activity phosphorylation Ser144 NAGNKRLsTIDESGS 9606 BTO:0000567 14744859 t llicata It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1 SIGNOR-250586 0.771 CREBBP protein Q92793 UNIPROT KLF1 protein Q13351 UNIPROT up-regulates activity acetylation Lys288 CAHPGCGkSYTKSSH 9606 11259590 t Regulation miannu EKLF residues acetylated by CREB binding protein (CBP) in vitro map to Lys-288 in its transactivation domain and Lys-302 in its zinc finger domain. SIGNOR-251826 0.504 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr476 EANYVPMtPGTFDFS 9606 15379552 t lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) SIGNOR-129200 0.2 IL6 protein P05231 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity -1 8511589 f lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238617 0.864 LATS1 protein O95835 UNIPROT MTF1 protein Q14872 UNIPROT down-regulates activity phosphorylation Ser152 EGCPRTYsTAGNLRT 35027733 t lperfetto The Hippo pathway kinases LATS1 and LATS2 attenuate cellular responses to heavy metals through phosphorylating MTF1|the Hippo pathway kinase LATS phosphorylates and inhibits MTF1|LATS phosphorylates MTF1 at S152 and disrupts its association with the promoters of heavy metal response genes, resulting in the loss of heavy metal response gene expression SIGNOR-275473 0.2 RUNX1 protein Q01196 UNIPROT CCL3 protein P10147 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 12771199 t lperfetto We show that RUNX1 can specifically bind to both RUNX sites but that only the proximal RUNX site is essential for PMA/ PHA stimulation of the MIP-1a promoter in Jurkat T-cells. We also show that the endogenous MIP-1a promoter is constitutively bound by RUNX1. SIGNOR-251738 0.2 IL23A protein Q9NPF7 UNIPROT IL23R protein Q5VWK5 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 t gcesareni We identify a novel member of the hemopoietin receptor family as a subunit of the receptor for il-23, il-23r. SIGNOR-87805 0.857 STX11-SNAP23 SNARE complex complex SIGNOR-C272 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 BTO:0000782 22767500 f lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. |The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release. SIGNOR-261899 0.7 ZNF143 protein P52747 UNIPROT TCP1 protein P17987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10893243 t Luana The transcription from the minimalCcta promoter was up-regulated 3-fold by ZNF143 and 6-fold by ZNF76 when full-length proteins were co-expressed, indicating that both ZNF143 and ZNF76 can enhance Ccta transcription. SIGNOR-266220 0.282 GSK3B protein P49841 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Thr77 DPCSLIPtPDKEDDD 9606 14536078 t gcesareni Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380 SIGNOR-118563 0.456 5-chloro-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine chemical CHEBI:91338 ChEBI ALK protein Q9UM73 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258293 0.8 SYK protein P43405 UNIPROT DUSP3 protein P51452 UNIPROT up-regulates activity phosphorylation Tyr138 SPTLVIAyLMMRQKM 9534 BTO:0001538 12447358 t miannu ZAP-70 and Syk also tyrosine-phosphorylated VHR in COS-1 cells (Fig. 2d), whereas other kinases (Csk, Lck, Fyn, Jak2, Bcr-Abl and Itk) had little effect. Finally, recombinant ZAP-70 readily phosphorylated VHR in vitro (Fig. 2f).  SIGNOR-275999 0.37 BIRC2 protein Q13490 UNIPROT RIPK3 protein Q9Y572 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation. SIGNOR-272711 0.664 FBP1 protein P09467 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity chemical modification 9606 30616754 t lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle SIGNOR-267611 0.8 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser23 ARKRHAPsPEPAVQG 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276097 0.267 CGAS protein Q8N884 UNIPROT 2'-3'-cGAMP(2-) smallmolecule CHEBI:143093 ChEBI up-regulates quantity chemical modification 23258413 t lperfetto Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. SIGNOR-276593 0.8 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. SIGNOR-164408 0.626 EXOC3 protein O60645 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270786 0.959 CSN1S1 protein P47710 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser529 GLPNGLLsGDEDFSS 9606 21232017 t gcesareni Phosphorylation of serine 529 of p65 is mediated by casein kinase ii, but is prevented in nonstimulated cells by the interaction with ikba SIGNOR-171222 0.2 CDK1 protein P06493 UNIPROT CyclinA2/CDK1 complex SIGNOR-C420 SIGNOR form complex binding 9606 29870721 t lperfetto Here we show that cyclin A/cdk1 kinase is the factor triggering mitosis. SIGNOR-267570 0.919 FLI1 protein Q01543 UNIPROT COL1A2 protein P08123 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24058639 f miannu Fli1 functions as a potent transcriptional repressor of the col1a2 gene SIGNOR-202685 0.248 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr249 APGPQDIyDVPPVRG 9606 12972425 t lperfetto We tested synthetic peptides modeled on cas phosphorylation sites, and found that the sequence containing tyrosine 253 was phosphorylated by src most efficiently. Using cells derived from cas-deficient mice, we confirmed that cas greatly enhanced the ability of src to transform cells. SIGNOR-100363 0.796 PRKCQ protein Q04759 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249283 0.295 TLR4 protein O00206 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 28137827 t miannu Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation. SIGNOR-261929 0.499 MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 10116 14512875 t lperfetto P38 mapk mediates fibrogenic signal through smad3 phosphorylation in rat myofibroblasts. the phosphorylation promoted hetero-complex formation and nuclear translocation of smad3 and smad4. SIGNOR-236136 0.552 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR up-regulates activity chemical activation 9606 18790874 t brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-263790 0.8 MELK protein Q14680 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser169 VLRNITNsQAPDGRR 9606 15908796 t lperfetto We demonstrate that cdc25b is phosphorylated in vitro by peg3 on serine 169this phosphorylated form of cdc25b accumulates during mitosis, and is localized to the centrosomes SIGNOR-137378 0.548 MPO-ANCA complex SIGNOR-C474 SIGNOR Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR up-regulates 9606 BTO:0000133 2161532 f lperfetto ANCA cause normal human neutrophils to undergo an oxidative burst and degranulate. Both ANCA phenotypes (i.e., cytoplasmic-pattern ANCA and myeloperoxidase-specific ANCA) induce neutrophil activation. SIGNOR-270583 0.7 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT up-regulates activity phosphorylation Tyr439 VVIPPPDyLECLSMG -1 21840312 t miannu Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility. SIGNOR-263042 0.398 STAT3 protein P40763 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates 9606 18156621 f Our results demonstrate that IL-27 inhibits the acquisition of the Treg phenotype at the level of Foxp3. The inhibitory effect of IL-27 on Treg generation was at least partially signal transducer and activator of transcription 3 (STAT3) dependent as examined by targeted STAT3 protein inhibition using small interfering RNA (siRNA) SIGNOR-254364 0.59 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 9606 BTO:0005014 27856324 t irozzo Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4. SIGNOR-255882 0.2 TBL1XR1 protein Q9BZK7 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001130 24243687 t miannu We showed that tblr1 physically interacts with ar and directly occupies the androgen-response elements of the affected ar target genes in an androgen-dependent manner. / we characterized tblr1 as a coactivator of ar SIGNOR-203235 0.402 HSPA1B protein P0DMV9 UNIPROT GSTA4 protein O15217 UNIPROT up-regulates activity relocalization phosphorylation:Thr193;Ser189 VKLSNIPtIKRFLEP;QEYTVKLsNIPTIKR 21929724 t lperfetto Model showing Ser189/Thr193 protein kinase dependent phosphorylation of GST A4‐4 has increased affinity for chaperone Hsp70 which activates mitochondrial competent import signals for GSTA4‐4. |Protein kinase A mediated phosphorylation of serine residues of CYPs increases the affinity of proteins for binding to cytoplasmic chaperones such as heat shock proteins (Hsp), Hsp70/Hsp90, resulting in increased mitochondrial translocation SIGNOR-264800 0.2 OXSR1 protein O95747 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Thr105 LQTFGHNtMDAVPKI 9606 BTO:0000007 21321328 t miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). SIGNOR-276310 0.516 TNKS2 protein Q9H2K2 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 BTO:0000007 19759537 t lperfetto Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin. SIGNOR-263380 0.685 LLGL1 protein Q15334 UNIPROT Scribble_complex_DLG5-LLGL1_variant complex SIGNOR-C508 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270899 0.46 RPS15 protein P62841 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262437 0.9 ATM protein Q13315 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates phosphorylation Thr785 SINEMLStQALRLDE 9606 17396146 t gcesareni The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells. SIGNOR-154175 0.394 MMUT protein P22033 UNIPROT (S)-methylmalonyl-CoA(5-) smallmolecule CHEBI:57327 ChEBI down-regulates quantity chemical modification 9606 1978672 t miannu Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme that catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA). SIGNOR-269108 0.8 CDK5 protein Q00535 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser137 PVSSPQSsPRLPRRP 9606 22778263 t lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. SIGNOR-197945 0.2 eIF4F_complex complex SIGNOR-C44 SIGNOR 48S_initiation_complex complex SIGNOR-C454 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269166 0.845 PROX1 protein Q92786 UNIPROT RORC protein P51449 UNIPROT down-regulates 23723244 f azuccotti In this study, we identify Prospero-related homeobox 1 (Prox1) as a novel co-repressor of the retinoic acid-related orphan receptors, RORgamma and RORalpha. Prox1 interacts directly with RORgamma and RORalpha and negatively regulates their transcriptional activity. SIGNOR-254507 0.274 F2RL3 protein Q96RI0 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257419 0.404 ASXL1 protein Q8IXJ9 UNIPROT RARA protein P10276 UNIPROT up-regulates activity binding 9606 BTO:0000567 16606617 t irozzo Therefore, ASXL1, a vertebrate PcG/TrxG protein, may mediate RA-regulated cell growth by modulating RAR activity.Finally, the ASXL1-induced accumulation of acetylated H3 may enhance the RAR-mediated transcriptional activity. In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells. SIGNOR-255910 0.455 conivaptan chemical CHEBI:681850 ChEBI AVPR2 protein P30518 UNIPROT down-regulates activity chemical inhibition -1 20471258 t Luana One of the targets, 13d, demonstrated improved V2-receptor binding and was further profiled for comparison with conivaptan, the program’s mixed V1a/V2 standard (Table 4). Compound 13d displayed similar V1a-receptor affinity, albeit with a 30-fold weaker V2-receptor affinity when compared to conivaptan. SIGNOR-257844 0.8 IL1R1 protein P14778 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 BTO:0003432 10217414 t lperfetto Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88. SIGNOR-67140 0.944 NOG protein Q13253 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR down-regulates binding 9606 BTO:0000142 12478285 t Create trimers (2 typeII and 1 typeI) with serine/threonine kinase function lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors.Noggin Inhibits bmpby blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors SIGNOR-217541 0.583 RELA protein Q04206 UNIPROT SP1 protein P08047 UNIPROT up-regulates binding 9606 SIGNOR-C13 10671503 t gcesareni Rela (p65) nf-kappab subunit interacts with the zinc finger dna-binding domain of sp1. SIGNOR-75004 0.615 DLL4 protein Q9NR61 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000574 10837024 t lperfetto Expression analysis of known notch ligands suggests that dll4 is the only ligand that exhibits spatial and temporal expression consistent with the activation of notch1 and notch4 during vascular development. The identification of dll4 reveals a candidate ligand for notch receptors involved in blood vessel biology SIGNOR-77973 0.629 TTK protein P33981 UNIPROT USP16 protein Q9Y5T5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser415 VEDEDQDsEEEKDND 9606 BTO:0002181 28380042 t miannu  Usp16 is a TTK phosphorylation substrate.  SIGNOR-277350 0.378 HTR4 protein Q13639 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256769 0.476 PP2B proteinfamily SIGNOR-PF18 SIGNOR BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation 9606 BTO:0000007 10195903 t inferred from 70% family members Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. SIGNOR-269992 0.2 FUS protein P35637 UNIPROT GRIA4 protein P48058 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0001279 28515487 f This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease SIGNOR-262806 0.2 SIRT1 protein Q96EB6 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity deacetylation 9606 20640476 t lperfetto AMPK can directly phosphorylate PGC-1a at Thr177 and Ser538 in in vitro assays PGC-1a phosphorylation might not directly affect its intrinsic coactivation activity, but, rather, release it from its repressor protein p160myb [79] and/or allow deacetylation and subsequent activation by SIRT1 SIGNOR-209962 0.792 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Thr1462 GLRPRGYtISDSAPS 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex. SIGNOR-183640 0.719 CPC complex SIGNOR-C554 SIGNOR Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 37292983 f miannu Here, we focus on the chromosome passenger complex (CPC), that forms a chromatin body that regulates chromosome segregation in mitosis. SIGNOR-275427 0.7 CDK1 protein P06493 UNIPROT PRPS1 protein P60891 UNIPROT up-regulates activity phosphorylation Ser103 RQDKKDKsRAPISAK 31253668 t lperfetto CDK1 contributes to upregulation of PRPS1 activity by phosphorylating PRPS1 at S103|In conclusion, compared with upregulation of PRPS1 expression levels, increased PRPS1 activity, which is marked by S103 phosphorylation SIGNOR-265728 0.257 RFX2 protein P48378 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 10090 32725242 f miannu RFX2 and RFX3 are key regulators of ependymal cell ciliogenesis in vitro and in vivo. We show here that RFX2 and RFX3 have both redundant and specific functions in the biogenesis of motile cilia on mouse ependymal cells, whereas RFX1 does not seem to play a key regulatory role in this process. SIGNOR-266928 0.7 PRKCA protein P17252 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates phosphorylation Ser76 VQDTSGTsPVHDAAR 9606 22558186 t lperfetto Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively. Nuclear translocation of p19ink4d induced by dna damage was shown to be dependent on serine 76 phosphorylation. SIGNOR-197285 0.2 GRB10 protein Q13322 UNIPROT INSR protein P06213 UNIPROT down-regulates binding 9606 21659604 t gcesareni Grb10 negatively regulates growth factor signaling. It binds the insulin and insulin-like growth factor 1 (igf-1) receptors;mice without grb10 are larger and exhibit enhanced insulin sensitivity. SIGNOR-174065 0.646 TMOD1 protein P28289 UNIPROT TPM3 protein P06753 UNIPROT down-regulates activity binding 9606 8002995 t irozzo Tropomodulin is a 40.6-kDa protein that binds to one end of the rod-like tropomyosin and inhibits its cooperativity and binding to actin. [.] we demonstrate that it is the N-terminus of tropomyosin that interacts with tropomodulin. Among several tropomyosin isoforms tested, hTM5 encoded by the human gamma-tropomyosin gene has the highest affinity toward human erythrocyte tropomodulin. SIGNOR-259111 0.72 SEC31A protein O94979 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 t lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat SIGNOR-265292 0.755 FOXO1 protein Q12778 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 16670091 f lperfetto FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. SIGNOR-218013 0.56 TARS1 protein P26639 UNIPROT tRNA(Thr) smallmolecule CHEBI:29180 ChEBI down-regulates quantity chemical modification 9606 25824639 t miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. SIGNOR-270501 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDCA5 protein Q96FF9 UNIPROT up-regulates activity phosphorylation Ser209 DMTLPGIsPPPEKQK 9606 BTO:0000567 20551060 t miannu Phosphorylation and activation of cell division cycle associated 5 by mitogen-activated protein kinase play a crucial role in human lung carcinogenesis. Our data suggest that transactivation of CDCA5 and its phosphorylation at Ser209 by ERK play an important role in lung cancer proliferation, and that the selective suppression of the ERK-CDCA5 pathway could be a promising strategy for cancer therapy. SIGNOR-262968 0.2 NRXN2 protein P58401 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626545 t miannu The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites SIGNOR-265455 0.823 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. MKK3 is therefore a specific activator of p38 MAP kinase that is independent of the JNK and ERK signaling pathways. SIGNOR-40356 0.716 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr681 QRHKRTHtGEKKFAC 9606 BTO:0000887;BTO:0001260 18258854 t llicata Here we have used a variety of approaches to identify 3 amino acids (thr668, ser670, and thr681) in the zinc finger domain of sp1 that are modified by pkc-zeta angiotensin ii, which activates pkc-? Phosphorylation (at thr410) via the angiotensin ii type 1 receptor, stimulates sp1 phosphorylation and increases sp1 binding to the platelet-derived growth factor-d promoter. SIGNOR-160774 0.497 SMO protein Q99835 UNIPROT GNGT1 protein P63211 UNIPROT up-regulates binding 9606 16885213 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-148601 0.2 TRIB2 protein Q92519 UNIPROT PKM protein P14618 UNIPROT up-regulates activity phosphorylation Ser37 MCRLDIDsPPITARN 9606 BTO:0000018 35790734 t miannu  This study demonstrated that TRIB2, not a "pseudokinase", has the kinase activity to directly phosphorylate PKM2 at serine 37 in cancer cells.  SIGNOR-275431 0.2 KDM5D protein Q9BY66 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-264310 0.2 CDC25C protein P30307 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates activity dephosphorylation 9606 25949173 t miannu Cdc25C is an activator of Cdc2 kinase and dephosphorylates and activates the CyclinB-Cdc2 complex shortly before the entry into the mitosis. SIGNOR-277099 0.825 PTAFR protein P25105 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257387 0.413 RalGAP2 complex SIGNOR-C469 SIGNOR RALA protein P11233 UNIPROT down-regulates activity guanine nucleotide exchange factor 10090 BTO:0000011 21148297 t miannu Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. RGC2 negatively regulates RalA activity in adipocytes. When immunoprecipitated from cell lysates of 3T3-L1 adipocytes by an anti-RGC2 antibody, RGC proteins efficiently enhanced GTP hydrolysis of recombinant RalA in vitro, compared with RalA alone or RalA incubated with various control immunoprecipitates (Figure 2C). SIGNOR-269796 0.497 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser396 DDKKAKTsTRSSAKT 9606 BTO:0000590 20679343 t lperfetto Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3? SIGNOR-167286 0.728 WAPL protein Q7Z5K2 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR down-regulates activity 9606 BTO:0000567 17113138 t lperfetto We show that human Wapl interacts with cohesin throughout the cell cycle via cohesin's Scc1 and SA1/SA2 subunits and that Wapl forms a subcomplex with Pds5A|These results indicate that Wapl is required for the release of cohesin from both interphase chromatin and mitotic chromosomes, perhaps by facilitating opening of the cohesin ring or by modulating direct interactions between cohesin and DNA. SIGNOR-265265 0.2 PTK6 protein Q13882 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates activity phosphorylation Tyr250 PFLLDEDyEKVLGYV 9606 19393627 t lperfetto Our previous studies revealed that STAP-2 binds to signal transducer and activator of transcription 3 (STAT3) and STAT5, and regulates the signaling pathways downstream of them. In the present study, we identified tyrosine-250 (Tyr250) in STAP-2 as a major site of phosphorylation by Brk, using a series of STAP-2 YF mutants and anti-phospho-STAP-2 Tyr250 antibody. Furthermore, overexpression of the STAP-2 Y250F mutant protein affected Brk-mediated STAT3 activation. SIGNOR-247067 0.713 MAPK14 protein Q16539 UNIPROT PIAS2 protein O75928 UNIPROT up-regulates activity phosphorylation Ser116 VTPHSPSsPVGSVLL 9606 BTO:0000007 16713578 t miannu The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles SIGNOR-262949 0.322 HARS1 protein P12081 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 10430027 t miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. SIGNOR-270489 0.8 Chaperone-mediated autophagy phenotype SIGNOR-PH118 SIGNOR HK2 protein P52789 UNIPROT down-regulates quantity by destabilization 9606 BTO:0004424 26323688 t Our proteome analysis revealed that HK2 is a CMA substrate and that its degradation by CMA is regulated by glucose availability. SIGNOR-261247 0.7 PDRG1 protein Q9NUG6 UNIPROT URI1 prefoldin co-chaperone complex SIGNOR-C514 SIGNOR form complex binding 9606 30484151 t miannu In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR92 SIGNOR-270915 0.577 RIN1 protein Q13671 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 12783862 t gcesareni The interaction between egfr and rin1 delineates a novel signal transduction pathway between egfr and its effectors, rin1, rab5a, and ras, which together coordinate and regulate both signaling and membrane trafficking. SIGNOR-101530 0.412 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR form complex binding 9606 24816100 t miannu The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin. SIGNOR-270836 0.729 gemcitabine chemical CHEBI:175901 ChEBI RRM1 protein P23921 UNIPROT down-regulates activity chemical inhibition -1 2233693 t miannu Direct assays of partially purified ribonucleoside diphosphate reductase (EC 1.17.4.1) demonstrated 50% inhibition by 4 microM dFdC 5'-diphosphate; dFdC 5'-triphosphate was much less inhibitory. We conclude that dFdC 5'-diphosphate acts as an inhibitor of ribonucleoside diphosphate reductase. SIGNOR-258386 0.8 CSNK1E protein P49674 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 15767683 t miannu The mammalian circadian regulatory proteins PER1 and PER2 undergo a daily cycle of accumulation followed by phosphorylation and degradation. CKIepsilon-mediated phosphorylation of PER2 recruits the ubiquitin ligase adapter protein beta-TrCP to a specific site, and dominant negative beta-TrCP blocks phosphorylation-dependent degradation of mPER2. These results provide a biochemical mechanism and functional relevance for the observed phosphorylation-degradation cycle of mammalian PER2. SIGNOR-267995 0.898 MLL Fusion fusion protein SIGNOR-FP14 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-260129 0.2 WWC1 protein Q8IX03 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates activity binding 9606 BTO:0000007 21233212 t miannu Here, we show that KIBRA associates with and activates Lats (large tumor suppressor) 1 and 2 kinases by stimulating their phosphorylation on the hydrophobic motif. KIBRA overexpression stimulates the phosphorylation of Yes-associated protein (YAP), the Hippo pathway effector. SIGNOR-263659 0.782 PKA proteinfamily SIGNOR-PF17 SIGNOR SYN1 protein P17600 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 10571231 t miannu Synapsins are exclusively localized to synaptic vesicles, which they coat as peripheral membrane proteins; they probably constitute one of the most abundant neuronal PKA substrates. Our study reveals an unexpectedly dynamic state of synapsins in nerve terminals: any changes in PKA or CaM Kinase I activity will modulate the amount of synapsin on synaptic vesicles. PKA Activation Triggers Synapsin Dissociation SIGNOR-264108 0.2 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Thr339 PVKSRKTtLEQPPSV 9606 BTO:0001061 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276771 0.629 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI up-regulates quantity precursor of 9606 11381136 t miannu The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR. SIGNOR-268104 0.8 GTF2B protein Q00403 UNIPROT TFIIF complex SIGNOR-C394 SIGNOR up-regulates activity relocalization 9606 27096372 t lperfetto Our structures suggest that a primary function of TFIID during PIC assembly is the proper positioning of TBP on the upstream promoter, which ultimately determines the placement of Pol II relative to the TSS. The structures presented here offer a structural framework for understanding the complex mechanism underlying TFIID function, shedding new light into the overlapping roles of TFIID as both a coactivator and a general platform for PIC assembly in the coordination of transcription initiation. SIGNOR-266193 0.929 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates phosphorylation Thr208 TFGNKLDtFCGSPPY 9606 14976552 t lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold SIGNOR-122628 0.57 PKA proteinfamily SIGNOR-PF17 SIGNOR VASP protein P50552 UNIPROT up-regulates activity phosphorylation 9606 15066263 t miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts SIGNOR-268286 0.2 CDK18 protein Q07002 UNIPROT AQP2 protein P41181 UNIPROT down-regulates quantity by destabilization phosphorylation Ser261 RQSVELHsPQSLPRG 9606 BTO:0000007 32164329 t lperfetto CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. |We had previously observed that a decrease in the phosphorylation of AQP2 at S261 is associated with a decrease in its poly-ubiquitination and an increase in its abundance SIGNOR-264562 0.262 DIO3 protein P55073 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 12746313 t scontino Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. SIGNOR-266942 0.8 HDAC1 protein Q13547 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263851 0.818 Immunoglobulin delta heavy chain protein P0DOX3 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR form complex binding 9606 BTO:0000776 20176268 t scontino Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes. SIGNOR-268195 0.2 Tomivosertib chemical CID:118598754 PUBCHEM MKNK1 protein Q9BUB5 UNIPROT down-regulates activity chemical inhibition 9606 29526098 t Simone Vumbaca Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. SIGNOR-261116 0.8 PRKACA protein P17612 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates phosphorylation 9606 10464286 t gcesareni Identification of a novel phosphorylation site on histone h3 coupled with mitotic chromosome condensation. SIGNOR-265344 0.2 DIO proteinfamily SIGNOR-PF83 SIGNOR 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 34674502 t scontino Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule.¬† SIGNOR-267044 0.8 MAPK14 protein Q16539 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates activity phosphorylation Ser423 QMVNGAHsASTLDEA 9606 19393267 t lperfetto Egfr-mediated phosphorylation of tab1 was completely inhibited by a chemical inhibitor and sirna of p38alpha. The phosphorylation of tab1 was occurred at ser-423 and thr-431, the residues underlying the p38-mediated feedback inhibition of tak1. SIGNOR-185580 0.817 midostaurin chemical CHEBI:63452 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258248 0.8 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Ser539 SLFNVSPsCSSFNSP 10090 BTO:0001103 17609368 t gcesareni AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter SIGNOR-228646 0.483 HDAC1 protein Q13547 UNIPROT CoREST-HDAC complex complex SIGNOR-C105 SIGNOR form complex binding 9606 11171972 t miannu Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function. SIGNOR-222124 0.7 MAP3K5 protein Q99683 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 17110930 t Barakat Upon TNFα stimulation, MEKK1, ASK1, and TAK1 phosphorylate and activate MKK7, which in turn activates JNK SIGNOR-274148 0.577 NLGN1 protein Q8N2Q7 UNIPROT NRXN1 protein P58400 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264149 0.834 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC7 protein O00311 UNIPROT up-regulates activity phosphorylation Thr376 QVAPRAGtPGFRAPE -1 10846177 t llicata Among four possible Cdk phosphorylation sites of huCdc7, replacement of Thr-376, corresponding to the activating threonine of Cdk, with alanine (T376A mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue. In vitro, Cdk2-Cyclin E, Cdk2-Cyclin A, and Cdc2-Cyclin B, but not Cdk4-Cyclin D1, phosphorylates the Thr-376 residue of huCdc7, suggesting possible regulation of huCdc7 by Cdks. SIGNOR-250643 0.479 ELOC protein Q15369 UNIPROT NOTCH4 protein Q99466 UNIPROT down-regulates ubiquitination 9606 BTO:0000672 22001063 t gcesareni Using proteomic techniques, several components of the elongin c complex were identified as candidate notch4(icd) interactors. Elongin c complexes can function as ubiquitin ligases capable of regulating proteasomal degradation of specific protein substrates. Our studies indicate that ectopic elongin c expression stimulates notch4(icd) degradation and inhibits its transcriptional activity in human kidney tubule hk11 cells. SIGNOR-176779 0.2 DDR1 protein Q08345 UNIPROT DDR1 protein Q08345 UNIPROT up-regulates activity phosphorylation Tyr513 LLLSNPAyRLLLATY 9606 BTO:0000007;BTO:0000356 9659899 t llicata The discoidin domain receptor tyrosine kinases are activated by collagen | Here, we present evidence that stimulating DDR1- and DDR2-expressing cells with various types of collagen induces receptor autophosphorylation. SIGNOR-251086 0.2 WNT9A protein O14904 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-132070 0.607 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu66 NLERECMeEKCSFEE 10090 BTO:0001103 11133752 t lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. SIGNOR-263690 0.67 MYC protein P01106 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity binding 10090 BTO:0000944 8266081 t miannu Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc.Yin-Yang-1 (YY1) regulates the transcription of many genes, including the oncogenes c-fos and c-myc. Depending on the context, YY1 acts as a transcriptional repressor, a transcriptional activator, or a transcriptional initiator. In cotransfections, c-Myc inhibits both the repressor and the activator functions of YY1, which suggests that one way c-Myc acts is by modulating the activity of YY1. SIGNOR-268795 0.56 EGFR protein P00533 UNIPROT TRIP13 protein Q15645 UNIPROT up-regulates quantity phosphorylation Tyr56 HNIVFGDyTWTEFDE 9606 BTO:0000007 32860853 t lperfetto Reciprocally, TRIP13 was phosphorylated at tyrosine(Y) 56 by EGFRvIII and EGF-activated EGFR. Abrogating TRIP13 Y56 phosphorylation dramatically attenuated TRIP13 expression-enhanced EGFR signaling and GBM cell growth. SIGNOR-265083 0.2 LRRC4 protein Q9HBW1 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 25526788 f miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. SIGNOR-264055 0.2 EXOSC9 protein Q06265 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-261388 0.918 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser269 PCNKRKYsLNGRQPP 9606 BTO:0001061 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276769 0.629 PP121 chemical CHEBI:50915 ChEBI PRKDC protein P78527 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206304 0.8 MAPK1 protein P28482 UNIPROT PCYT1A protein P49585 UNIPROT down-regulates phosphorylation Ser315 GRMLQAIsPKQSPSS 9606 BTO:0000763 15788406 t gcesareni Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis. SIGNOR-134837 0.43 ITGB1 protein P05556 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257700 0.698 GLI3 protein P10071 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 f lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. SIGNOR-209641 0.697 RFNG protein Q9Y644 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000975 12486116 t gcesareni We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1. SIGNOR-96561 0.633 KLKB1 protein P03952 UNIPROT F12 protein P00748 UNIPROT up-regulates activity cleavage Arg353 EQPPSLTrNGPLSCG 9606 BTO:0000131 28966616 t lperfetto FXIIa converts PK to the active protease PKa, which reciprocally activates more FXII|In addition, PKa can initiate a further proteolysis of FXIIa into a ~30 kDa light chain fragment, termed β-FXIIa. The cleavage takes place at the peptide bond Arg353–Val354 and consequently, the active site released from the heavy chain and thus from surfaces. SIGNOR-263520 0.589 FYN protein P06241 UNIPROT ITPR1 protein Q14643 UNIPROT up-regulates phosphorylation Tyr353 NAQEKMVySLVSVPE 9606 14761954 t lperfetto We have identified tyrosine 353 (tyr353) in the ip3-binding domain of type 1 ip3r (ip3r1) as a phosphorylation site for fyntyrosine phosphorylation of ip3r1 increased ip3 binding at low ip3 concentrations (<10 nm). SIGNOR-121795 0.5 C5 protein P01031 UNIPROT C5AR1 protein P21730 UNIPROT up-regulates activity binding 9606 cleavage:Arg751;Arg677 HKDMQLGrLHMKTLL;KEILRPRrTLQKKIE 1847994 t complement C5a (anaphylatoxin) fragment: PRO_0000005988 lperfetto The chemotactic receptor for human C5a anaphylatoxin|The human C5a receptor was cloned from U937 and HL-60 cells and identified by high affinity binding when expressed in COS-7 cells. SIGNOR-263457 0.747 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr312 ISYDIPPtPGNTYQI 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249463 0.618 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates activity phosphorylation Ser277 SHSQDLGsPERHQPV 9606 BTO:0000567 12734188 t lperfetto Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9. SIGNOR-101043 0.369 NEK6 protein Q9HC98 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser422 AEAFLGFsYAPPTDS -1 12023960 t miannu The present study is the first report of a protein kinase (NEK6) capable of phosphorylating the hydrophobic motif of SGK1, although our data suggest that NEK6 may not mediate this reaction in cells. Nevertheless, the phosphorylation of the hydrophobic motif of SGK1in vitro, coupled with the phosphorylation of the T-loop with PDK1, may be a useful way of generating fully active wild type SGK1. Ser377 and Ser422of SGK1, and the CDK7 T-loop peptide, which are phosphorylated by NEK6. SIGNOR-250297 0.344 PEX2 protein P28328 UNIPROT PEX5 protein P50542 UNIPROT down-regulates quantity by destabilization ubiquitination -1 19687296 t miannu Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. SIGNOR-253021 0.597 AVPR1A protein P37288 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257077 0.44 JNJ-28312141 free base chemical CID:11676971 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259749 0.8 ID2 protein Q02363 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR down-regulates activity binding 10090 BTO:0004058 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241149 0.579 1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester chemical CHEBI:92418 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258635 0.8 PRKCA protein P17252 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser656 RAEFLNKsVQKSSGV 9606 BTO:0000887;BTO:0001260 8182108 t gcesareni Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase. SIGNOR-36792 0.364 RPS6KA1 protein Q15418 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser295 TKRRKSMsGASPKES 9606 23708659 t lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. SIGNOR-202117 0.373 CDK5 protein Q00535 UNIPROT PARP1 protein P09874 UNIPROT down-regulates activity phosphorylation Ser786 RGGSDDSsKDPIDVN -1 21922195 t miannu These results would suggest that the phosphorylation of PARP-1 via Cdk5's kinase activity is necessary for its persistence at damage sites.Based on these results and the recruitment data, we hypothesize that the phosphorylation of the PARP-1 protein by Cdk5 on one or more of the serines 782, 785, and 786 results in an attenuation of its ribosylating activity facilitating its persistence at the sites of DNA damage. SIGNOR-276359 0.261 AP1 complex SIGNOR-C154 SIGNOR CCND1 protein P24385 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000762 12509763 f lperfetto Substrates for ERK1/2 include nuclear proteins such as C-JUN, this leads to activation of the AP-1 transcription factor, which is made up of FOS-JUN heterodimers.|As a result of stimulating these transcriptional regulators, key cell-cycle regulatory proteins, such as D-type cyclins, are expressed, which enables the cell to progress through the G1 phase of the cell-cycle. SIGNOR-253215 0.605 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr169 KRSSRANtVTPAVGR 9606 19530738 t lperfetto First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form. SIGNOR-186143 0.471 GATA2 protein P23769 UNIPROT ETV2 protein O00321 UNIPROT up-regulates activity binding 10090 24583263 t irozzo Transcriptional assays with the Spi1 promoter-reporter demonstrated that Gata2 cooperates with Etv2 and augments the transcriptional activity of Etv2.The protein-protein interaction between Etv2 and Gata2 is mediated by the Ets and Gata domains. Using the embryoid body differentiation system, we demonstrate that co-expression of Gata2 augments the activity of Etv2 in promoting endothelial and hematopoietic lineage differentiation. SIGNOR-256008 0.441 CDKN1A protein P38936 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR down-regulates activity binding 10913154 t lperfetto P21 Inhibits Thr161 Phosphorylation of Cdc2 to Enforce the G2 DNA Damage Checkpoint|The cyclin-dependent kinase inhibitor p21 is required for a sustained G2 arrest after activation of the DNA damage checkpoint. Here we have addressed the mechanism by which p21 can contribute to this arrest in G2. We show that p21 blocks the activating phosphorylation of Cdc2 on Thr161 SIGNOR-251498 0.85 PRL protein P01236 UNIPROT KRT15 protein P19012 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 20103718 f Regulation miannu PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes. SIGNOR-251904 0.2 CAMK2B protein Q13554 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser641 RRSVKRNsTVDCNGV 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275788 0.275 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 11041858 t lperfetto The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases . The ser-51 mutant showed little covalent modification by the endogenous enzymes. Phosphorylation of the serine 51 residue in the alpha-subunit of translational initiation factor 2 in eukaryotes (eif2 alpha) impairs protein synthesis presumably by sequestering eif2b, a rate-limiting pentameric guanine nucleotide exchange protein which catalyzes the exchange of gtp for gdp in the eif2-gdp binary complex SIGNOR-83226 0.886 ULK1 protein O75385 UNIPROT DENND3 protein A2RUS2 UNIPROT up-regulates activity phosphorylation Ser472 THRRMVVsMPNLQDI 9606 25925668 t lperfetto ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. SIGNOR-264730 0.411 FAD(3-) chemical CHEBI:57692 ChEBI ETF complex SIGNOR-C463 SIGNOR form complex binding 9606 33450351 t miannu Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors. SIGNOR-269469 0.8 PRKCA protein P17252 UNIPROT PPP2R5A protein Q15172 UNIPROT down-regulates activity phosphorylation Ser41 RQKRSQGsSQFRSQG -1 24225947 t miannu  In this study, we identified a novel phosphorylation site at Ser(41) of B56α. This phosphoamino acid residue was efficiently phosphorylated in vitro by PKCα.  SIGNOR-276603 0.347 MAPK14 protein Q16539 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates activity phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 BTO:0000567 9628874 t lperfetto In hela cells, prak was activated in response to cellular stress and proinflammatory cytokines. Prak activity was regulated by p38alpha and p38beta both in vitro and in vivo and thr182 was shown to be the regulatory phosphorylation site. SIGNOR-58135 0.622 TCF3 protein P15923 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887 1649701 t E12/E47-like proteins interact in vivo with the myogenic HLH proteins MyoD and myogenin lperfetto In addition we demonstrate that myod, in conjunction with e12/e47-like proteins, is functioning as a regulatory nodal point for activation of several other downstream muscle regulators. SIGNOR-20540 0.799 ADORA3 protein P0DMS8 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256671 0.438 CCAR2 protein Q8N163 UNIPROT HDAC3 protein O15379 UNIPROT down-regulates activity binding 26158765 t lperfetto Besides SIRT1, CCAR2 inhibits the activity of the histone-modifying enzymes SUV39H1 and HDAC3 [9, 10], thus playing an important role in chromatin structure regulation. SIGNOR-267665 0.256 PEX12 protein O00623 UNIPROT UBE2D1 protein P51668 UNIPROT up-regulates activity binding -1 19687296 t miannu Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. SIGNOR-253024 0.611 NAALAD2 protein Q9Y3Q0 UNIPROT Ac-Asp-Glu(3-) smallmolecule CHEBI:76931 ChEBI down-regulates quantity chemical modification 9606 10085079 t miannu The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. SIGNOR-267541 0.8 PPP2CA protein P67775 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser31 LKLGSGPsIKALDGR 9606 BTO:0000567 24781523 t miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase SIGNOR-276379 0.3 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Thr2137 EDRTVPStPTLVVPH 9606 18794356 t miannu Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore. SIGNOR-181022 0.382 GSK3B protein P49841 UNIPROT NEB protein P20929 UNIPROT down-regulates phosphorylation 9606 21798082 t gcesareni Gsk3b is able to phosphorylate nebulin at two ser sites in the c-terminal region of nebulin localized to the z-disk, thus preventing the interaction of nebulin with neuronal wiscott-aldrich syndrome protein (nwasp), a ubiquitously expressed member of the wasp family, which is involved in actin assembly. SIGNOR-175659 0.311 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity dephosphorylation Tyr576 RYMEDSTyYKASKGK -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254719 0.245 YAP1 protein P46937 UNIPROT SLC2A1 protein P11166 UNIPROT up-regulates quantity by expression transcriptional regulation 30348863 f lperfetto Transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap-/- mutants, and impaired glucose tolerance in adults. SIGNOR-276584 0.262 pemetrexed chemical CHEBI:63616 ChEBI TYMS protein P04818 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205933 0.8 PRKACA protein P17612 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates activity phosphorylation Ser364 PLLSRMGsLRAPVDE 9606 BTO:0000007 33110360 t miannu We confirmed the phosphorylation of T130, S235, and S364 by developing monoclonal antibodies against phospho-specific forms of these sites and showed that their phosphorylation is cell cycle-dependent. According to our results, PKA-mediated phosphorylation of E2F1 by PKA inhibits proliferation and glucose uptake and induces caspase-3 activation and senescence. SIGNOR-277537 0.2 DLK1 protein P80370 UNIPROT SOX9 protein P48436 UNIPROT up-regulates transcriptional regulation 9606 19254573 f fspada Pref-1 inhibits adipocyte differentiation through upregulating sox9 expression. SIGNOR-209968 0.401 GRB7 protein Q14451 UNIPROT RND1 protein Q92730 UNIPROT up-regulates binding 9606 BTO:0000150 10664463 t gcesareni We would like to propose that when cells are driven to divide by growth factor stimulation, grb7 relocalizes at the membrane, in the same subcellular compartment as rnd1, where they could interact in vivo. SIGNOR-74914 0.611 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-252815 0.2 MRGPRX2 protein Q96LB1 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256930 0.2 (+)-pilocarpine chemical CHEBI:8207 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258626 0.8 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2H protein P62256 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271362 0.49 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 BTO:0000222 14749395 t lperfetto Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21. SIGNOR-216920 0.325 THRA protein P10827 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 15650024 t gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. SIGNOR-133240 0.407 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SCNN1G protein P51170 UNIPROT down-regulates quantity by destabilization phosphorylation -1 11805112 t inferred from 70% family members lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. SIGNOR-270171 0.2 MAPK3 protein P27361 UNIPROT SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation Ser225 VGSKTPAsPVVVQQG 9606 14532121 t gcesareni Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation. SIGNOR-118550 0.589 PRKCE protein Q02156 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates phosphorylation Ser268 PQVRVGGsSVDLHRF 9606 BTO:0000150;BTO:0001130;BTO:0000551 23542175 t lperfetto We find that ctnnd1/p120ctn phosphorylation at serine 268 (p-s268) occurs in a strictly pkc_-dependent manner,serine/threonine phosphorylation of p120-ctn has been reported to affect the integrity of ajs [12], [24] and [25]. Xia et al. (2003) reported that several residues (ser122, ser252, ser268, ser288, thr310, ser312, ser873, and thr910) in p120ctn can be either phosphorylated or dephosphorylated upon pkc activation SIGNOR-201600 0.2 E2F1 protein Q01094 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12110166 f fspada We show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation SIGNOR-90459 0.472 SMO protein Q99835 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 17251915 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling as pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp SIGNOR-152814 0.2 DLX5 protein P56178 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 12000792 f Giulio Giuliani In conclusion, Dlx5 and Dlx6 are dynamic regulators of mammalian development, which are absolutely required for proper craniofacial and skeletal development and which display overlapping genetic functions in all tissues in which they are expressed. In addition, they appear to act as essential regulators of chondrogenesis and osteogenesis. SIGNOR-255450 0.7 Alamandine chemical CID:44192273 PUBCHEM MRGPRD protein Q8TDS7 UNIPROT up-regulates activity binding 10029 BTO:0000246 23446738 t Luana Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. SIGNOR-262308 0.8 CDK2 protein P24941 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser154 AKPEPSPsPRITRKS 9606 21565170 t gcesareni We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5 SIGNOR-173681 0.349 FNTB protein P49356 UNIPROT KRAS protein P01116 UNIPROT up-regulates activity 9606 24294527 t lperfetto Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. SIGNOR-242556 0.429 NME1 protein P15531 UNIPROT NETO2 protein Q8NC67 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17671192 f miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. SIGNOR-255166 0.26 ADRB2 protein P07550 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257192 0.319 PCSK2 protein P16519 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270335 0.2 SMARCB1 protein Q12824 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates 9606 12226744 f miannu We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6. SIGNOR-92785 0.319 EGR1 protein P18146 UNIPROT HSD11B2 protein P80365 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15659537 f miannu Overexpression of p50 inhibited HSD11B2 promoter activity and overexpression of Egr-1 inhibited transactivation of the HSD11B2 promoter by p65/p50. SIGNOR-253876 0.28 CHD8 protein Q9HCK8 UNIPROT SOX7 protein Q9BT81 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 t Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells SIGNOR-268922 0.2 Hemoglobin complex SIGNOR-C209 SIGNOR hb:hp complex SIGNOR-C149 SIGNOR form complex binding 9606 11854029 t miannu CD163 was identified as the endocytic receptor binding hemoglobin (Hb) in complex with the plasma protein haptoglobin (Hp). This specific receptor-ligand interaction leading to removal from plasma of the Hp-Hb complex-but not free Hp or Hb-now explains the depletion of circulating Hp in individuals with increased intravascular hemolysis. SIGNOR-255284 0.741 Diprenorphine chemical CHEBI:4650 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258791 0.8 CDK1 protein P06493 UNIPROT MPLKIP protein Q8TAP9 UNIPROT up-regulates phosphorylation Thr120 QGSPRTStPFGSGRV 9606 17310276 t lperfetto Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1 SIGNOR-153308 0.347 PLK1 protein P53350 UNIPROT ZMYM2 protein Q9UBW7 UNIPROT down-regulates quantity by destabilization phosphorylation Ser305 QPGVDSLsPVASLPK 25855382 t lperfetto PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|Similar analyses with ZNF198 identified two clusters of putative Plk1 phosphorylation sites in vitro. A cluster of serine residues at the N-terminus of ZNF198, S303, S305, and S309, and a cluster at the C-terminus, S1056 and S1064. The triple Ser to Ala mutant, S303A/S305A/S309A, consistently exhibited the lowest level of phosphorylation in vitro, in comparison to the double S1056A/S1064A mutant SIGNOR-275558 0.384 PRKCZ protein Q05513 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Thr110 SHSRQAStDAGTAGA 9606 BTO:0002181 25660024 t miannu  Yap and β-catenin are direct substrates of PKCζ.We show here that PKCζ suppresses intestinal stem cell function by promoting the downregulation of β-catenin and Yap through direct phosphorylation.Consistent with MS/MS analysis, mutation to alanine of these two sites completely abolished Yap phosphorylation by PKCζ. Interestingly, S109 and T110 sites were highly conserved among species (Figure S3B), which suggested an important role in Yap regulation. SIGNOR-276877 0.28 ELOVL5 protein Q9NYP7 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267898 0.8 (-)-anisomycin chemical CHEBI:338412 ChEBI FOSB protein P53539 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling gcesareni SIGNOR-189629 0.8 TGFA protein P01135 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity binding 9606 BTO:0000584 16585207 t Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines gcesareni Our data indicate that a subset of cell lines is dependent on TGF-_-mediated activation of the EGFR for cell proliferation and strongly suggest that pancreatic tumors expressing high levels of TGF-_ and phosphorylated (activated) EGFR are EGFR-dependent in vitro and in vivo. SIGNOR-93199 0.896 CDK1 protein P06493 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser460 STSVLHSsPLNVFMG 21690413 t lperfetto Mechanistically, we demonstrated that Cdc2-dependent phosphorylation on a γ-tubulin ring complex (γ-TuRC) recruitment protein, Nedd1/GCP-WD, at the previously uncharacterized S460 residue induces the Nedd1-Plk1 interaction SIGNOR-272972 0.567 PARP1 protein P09874 UNIPROT THBD protein P07204 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002423 21489980 f miannu Silencing of PARP1 resulted in a strong down-regulation of TM expression in Met-5A cells, while restoring TM expression in H28 cells. SIGNOR-254892 0.2 PRKCB protein P05771 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates phosphorylation Ser40 SREVFDFsQRRKEYE 9606 12198130 t miannu Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress SIGNOR-91830 0.393 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0001538 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252759 0.719 ZDHHC2 protein Q9UIJ5 UNIPROT AKAP5 protein P24588 UNIPROT up-regulates activity palmitoylation Cys129 KSRLKIPcIKFPRGP 10116 25589740 t Here, we report that the recycling endosome-resident palmitoyl acyltransferase DHHC2 interacts with and palmitoylates AKAP79/150 to regulate these plasticity signaling mechanisms SIGNOR-261289 0.337 DYRK1B protein Q9Y463 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0000165;BTO:0000222;BTO:0001946 BTO:0000887;BTO:0001760 15851482 f lperfetto Mirk diminishes the extent of myoblast apoptosis during the differentiation process, at least in part by direct modulation of p21cip1 localization. SIGNOR-235731 0.7 MASP1 protein P48740 UNIPROT C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263423 0.663 imatinib chemical CHEBI:45783 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258227 0.8 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC12 protein O60814 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271979 0.2 alvocidib chemical CHEBI:47344 ChEBI CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192449 0.8 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257453 0.8 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Ser62 PSWHLADsPAVNGAT 9606 BTO:0001130 12633850 t lperfetto We have identified that serine 62 is the necessary site for taxol- or 2-me-induced bcl-xl phosphorylation in summary, our studies suggest that the phosphorylation of bcl-xl by stress response kinase signaling might oppose the anti-apoptotic function of bcl-xl SIGNOR-99215 0.2 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000093 10581258 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-72695 0.764 KDM5A protein P29375 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-265334 0.2 HIF-1 complex complex SIGNOR-C418 SIGNOR LDHA protein P00338 UNIPROT up-regulates quantity transcriptional regulation 9606 7673128 t Deletional and mutational analysis of the function of mouse LDH-reporter fusion gene constructs in transient transfection assays defined three domains, between -41 and -84 base pairs upstream of the transcription initiation site, which were crucial for oxygen-regulated expression. The most important of these, although not capable of driving hypoxic induction in isolation, had the consensus of a hypoxia-inducible factor 1 (HIF-1) site, and cross-competed for the binding of HIF-1 with functionally active Epo and phosphoglycerate kinase-1 sequences SIGNOR-267479 0.643 FGFR4 protein P22455 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates phosphorylation Tyr643 GVHHIDYyKKTSNGR 9606 BTO:0001130 18670643 t lperfetto Binding of fgf to fgf receptors leads to receptor dimerization and subsequent tyrosine autophosphorylation and phosphorylation of target substrates. Autophosphorylation on tyrosine is considered to have at least two functions. One such function is the stimulation of the intrinsic protein tyrosine kinase activity by an allosteric mechanismthis antibody specifically recognizes tyr642/643 in fgfr-4. SIGNOR-179780 0.2 SMARCC1 protein Q92922 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270606 0.792 SATB2 protein Q9UPW6 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates activity binding 9606 21965674 t miannu SATB2 attenuates p63-mediated gene expression of perp (p53 apoptosis effector related to PMP-22), a critical downstream target gene during development, and specifically decreases p63 perp promoter binding. SIGNOR-255149 0.379 CSNK2A1 protein P68400 UNIPROT FANCD2 protein Q9BXW9 UNIPROT down-regulates activity phosphorylation Ser898 SECDPTPsHRGQLNK 9606 BTO:0000567 31167143 t miannu Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations.  SIGNOR-276729 0.2 CDK11B protein P21127 UNIPROT EIF3F protein O00303 UNIPROT up-regulates activity phosphorylation Thr119 GAARVIGtLLGTVDK 19245811 t lperfetto Here, we identified a second eIF3f phosphorylation site (Thr119) by CDK11(p46) during apoptosis. We demonstrated that eIF3f is directly phosphorylated by CDK11(p46) in vivo. Phosphorylation of eIF3f plays an important role in regulating its function in translation and apoptosis. Phosphorylation of eIF3f enhances the association of eIF3f with the core eIF3 subunits during apoptosis.  SIGNOR-273131 0.529 PTEN protein P60484 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0001271 20596030 f lperfetto Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfralpha was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib. SIGNOR-166478 0.654 PFDN2 protein Q9UHV9 UNIPROT Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR form complex binding 9606 32699605 t miannu The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6) SIGNOR-270931 0.949 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 10090 15486195 t miannu Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. SIGNOR-250132 0.75 TAB1 protein Q15750 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates binding 9606 25290089 t lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205440 0.821 FGF2 protein P09038 UNIPROT ENPP1 protein P22413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004473 19049325 f miannu FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2. SIGNOR-252191 0.259 MRAP protein Q8TCY5 UNIPROT MC5R protein P33032 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 t miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. SIGNOR-252368 0.405 SSH1 protein Q8WYL5 UNIPROT LIMK1 protein P53667 UNIPROT down-regulates activity dephosphorylation 9606 23153585 t miannu In addition to its cofilin\u2013phosphatase activity, SSH1 can also dephosphorylate LIMK1 and LIMK2, although LIMK1 is a better substrate than LIMK2  [63] .|SSH1 suppresses the kinase activity of LIMK1 toward cofilin by dephosphorylation at Thr 508 in the kinase catalytic domain and other autophosphorylated residues [63]. SIGNOR-277096 0.615 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MEF2C protein Q06413 UNIPROT down-regulates binding 9606 21902831 t lperfetto In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-216963 0.292 COL1A2 protein P08123 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR up-regulates activity binding 10090 BTO:0000165 12496264 t lperfetto Modeling of the alpha I domain-collagen peptide complexes could partially explain the observed preference of different I domains for certain GFOGER sequence variations. In summary, our data indicate that the GFOGER sequence in fibrillar collagens is a common recognition motif used by alpha(1)beta(1), alpha(2)beta(1), and also alpha(11)beta(1) integrins. SIGNOR-253346 0.455 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Ser745 FEKEKLKsQWNNDNP 9606 BTO:0000751 11700305 t lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | SIGNOR-249120 0.335 tyrphostin B42 chemical CHEBI:131968 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189386 0.8 baicalein chemical CHEBI:2979 ChEBI CYP2C9 protein P11712 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190236 0.8 TOP1 protein P11387 UNIPROT ARNTL protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 22904072 t miannu We examined the mechanism of topoisomerase I (Top1) to understand the role of the unique chromatin structure in Bmal1 gene regulation.  Promoter assays showed that the Top1-binding site is required for transcriptional suppression and that it functions cooperatively with the distal RORE, supporting that Bmal1 transcription is upregulated by Top1 inhibition.  SIGNOR-277354 0.348 AGTR1 protein P30556 UNIPROT NPHS1 protein O60500 UNIPROT down-regulates activity 10116 21982880 f miannu Ang II-receiving rats displayed diminished phosphorylation of nephrin but enhanced glomerular/podocyte injury and proteinuria when compared to control rats. These findings indicate that Ang II induces nephrin dephosphorylation and podocyte injury through a caveolin-1-dependent mechanism. SIGNOR-253342 0.371 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr981 DNCSEEMyRLMLQCW 9606 14711813 t lperfetto Mass spectrometric analysis revealed that ret tyr806, tyr809, tyr900, tyr905, tyr981, tyr1062, tyr1090, and tyr1096 were autophosphorylation sitesthe results suggest that phosphorylation of tyr981 is not obligatorily required for the catalytic activity but plays a supplementary role in initiating autophosphorylation of tyr905, which brings about the overall kinase activity. SIGNOR-121169 0.2 TUBG1 protein P23258 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 19029337 f miannu It has been reported that NEDD1 directly interacts with and recruits the γ-tubulin ring complex to centrosomes and to spindle MTs to promote MT nucleation and spindle assembly SIGNOR-261423 0.7 KLK3 protein P07288 UNIPROT PTHLH protein P12272 UNIPROT down-regulates activity cleavage Pro21 FLLSYAVpSCGRSVE -1 8753751 t lperfetto Our study demonstrates that PTHrP is a substrate for PSA. The cleavage of the amino-terminal portion of PTHrP completely disrupts its ability to interact with the PTH/PTHrP receptor and thus inhibits its PTH-like activity. | Our data show that PSA proteolytically cleaves PTHrP (1-34) after either residue 22 or 23, generating three peptide fragments. SIGNOR-270546 0.432 CDK6 protein Q00534 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1035 NMDAPPLsPYPFVRT 9606 BTO:0001938 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. all three residues selectively targeted by cdk4(6), t401 (n-terminus), s672 (spacer region) and s1035 (c-terminus) SIGNOR-104711 0.667 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Ser161 ENLTQVGsILGNLKD 9606 12930825 t lperfetto Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion. SIGNOR-249227 0.335 Non-structural protein 6 protein P0DTD1-PRO_0000449624 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 9606 32979938 t miannu We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F). SIGNOR-262510 0.2 AKT1 protein P31749 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 18483217 f PDGF signaling has been implicated in several fibrotic conditions and is assumed to play a role in driving proliferation of cells with a myofibroblast phenotype. SIGNOR-254371 0.7 RXRB protein P28702 UNIPROT NR2F1 protein P10589 UNIPROT up-regulates binding 9606 10900149 t gcesareni Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site SIGNOR-79449 0.277 TSC2 protein P49815 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT down-regulates 9606 12172553 f gcesareni Here, we show that tsc1-tsc2 inhibits the p70 ribosomal protein s6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4e binding protein 1 (4e-bp1, an inhibitor of translational initiation). SIGNOR-91395 0.541 TNF protein P01375 UNIPROT REL protein Q04864 UNIPROT up-regulates 9606 BTO:0000782 10823840 f miannu C-rel emerges as the main nf-kb family member stimulated by tnf_ in the context of physiologic activation of resting t cells. SIGNOR-77547 0.423 BMI1 protein P35226 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20551323 f gcesareni One important pathway in which bmi-1 acts to promote the overall growth of mice and cellular proliferation includes cdkn2a;bmi-1 represses the expression of cdkn2a, which encodes two cyclin-dependent kinase inhibitors, p16ink4a (p16) and p19arf SIGNOR-166163 0.468 DRD5 protein P21918 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257418 0.267 PP1 proteinfamily SIGNOR-PF54 SIGNOR CFTR protein P13569 UNIPROT up-regulates activity dephosphorylation 10090 BTO:0000988 21317537 t lperfetto WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, SIGNOR-264646 0.2 F2RL1 protein P55085 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu PAR2 expression is up-regulated following PAR2 activation. This is logical for PAR2, as endogenous activators for the receptor are serine proteases, which irreversibly activate PAR2 through N-terminal cleavage. SIGNOR-254840 0.2 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT down-regulates phosphorylation Ser448 IRRPRSLsSPTVTLS 9606 15677482 t gcesareni Nedd4-2 function is negatively regulated by phosphorylation via a serum- and glucocorticoid-inducible protein kinase (sgk1), which serves as a mechanism to inhibit the ubiquitination-dependent degradation of enac. Sgk1 catalyzed phosphorylation of hnedd4-2 at ser-468 maintaining hnedd4-2 in an inactive phosphorylated state. SIGNOR-133438 0.779 EDN1 protein P05305 UNIPROT MYH7 protein P12883 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12847114 f Regulation of expression miannu βMHC expression was markedly augmented by PE and ET, suggesting the transformation of myosin. endothelin-1 (ET) SIGNOR-251955 0.284 IL13 protein P35225 UNIPROT IL4R protein P24394 UNIPROT up-regulates activity binding 9606 19880493 t lperfetto IL-4 and IL-13 have overlapping but distinct effects on MFs, dependent on a common IL-4R, with profound changes in the expression of a range of cellular proteins and functions broadly implicated in the regulation of inflammation and repair. SIGNOR-249528 0.893 APH1B protein Q8WW43 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 12522139 t gcesareni Biochemical and genetic studies have recently identified nicastrin, aph-1, and pen-2 as essential cofactors that physically interact with ps1 and are necessary for the gamma-secretase activity. SIGNOR-97107 0.908 SRC protein P12931 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Tyr380 TDSEEQPyLEMDLSS 9606 16619028 t lperfetto Src kinase phosphorylates caspase-8 on tyr380: a novel mechanism of apoptosis suppressionwe identified caspase-8 as a new substrate for src kinase. Phosphorylation occurs on tyr380, situated in the linker region between the large and the small subunits of human procaspase-8, and results in downregulation of caspase-8 proapoptotic function SIGNOR-146127 0.465 PPBP protein P02775 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258413 0.358 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RRAS protein P10301 UNIPROT up-regulates activity phosphorylation Ser201 QEQELPPsPPSAPRK 9606 BTO:0002181 27086924 t miannu  In this study, we report that TC21 and R-Ras are phosphorylated on a conserved serine, Ser186 and Ser201, respectively, in intact cells. This residue is located in the C-terminal hypervariable region of the proteins and is not conserved in M-Ras. We show that the MAP kinases ERK1/2 phosphorylate TC21 and R-Ras on this C-terminal serine residue both in vitro and in vivo.  SIGNOR-277219 0.2 MAPK12 protein P53778 UNIPROT NUP62 protein P37198 UNIPROT down-regulates quantity by destabilization phosphorylation Thr269 GAASGTStTTSTAAT 9606 BTO:0000007 30401435 t miannu We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1).  SIGNOR-277415 0.2 PRKD2 protein Q9BZL6 UNIPROT PI4KB protein Q9UBF8 UNIPROT up-regulates phosphorylation Ser294 SNLKRTAsNPKVENE 9606 16912074 t The effect has been demonstrated using Q9UBF8-2 gcesareni Binding of 14-3-3 proteins to pi4kiiibeta involved the pkd phosphorylation site ser294, evident from reduced 14-3-3 binding to a s294a pi4kiiibeta mutant. Phospho-specific binding of 14-3-3 proteins to phosphatidylinositol 4-kinase iii beta protects from dephosphorylation and stabilizes lipid kinase activity. SIGNOR-148880 0.2 DUSP5 protein Q16690 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 10224087 t gcesareni Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway SIGNOR-67355 0.773 ABL1 protein P00519 UNIPROT AHSA1 protein O95433 UNIPROT up-regulates activity phosphorylation Tyr223 LTSPEELyRVFTTQE 9606 26235616 t Manara Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1), promoting its interaction with Hsp90. This, consequently, results in an increased Hsp90 ATPase activity SIGNOR-260938 0.254 WDR62 protein O43379 UNIPROT MAP3K3 protein Q99759 UNIPROT up-regulates activity relocalization 10090 30566428 t lperfetto In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis SIGNOR-271717 0.2 MAPK8IP3 protein Q9UPT6 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates binding 9606 10523642 t gcesareni Overexpression of full-length jsap1 in cos-7 cells led to a considerable enhancement of jnk3 activation, and modest enhancement of jnk1 and jnk2 activation, by the mekk1-sek1 pathwaythe regions of jsap1 that bound jnk, sek1, and mekk1 were distinct from one another. Jnk and mekk1 also bound jsap1 in vitro, suggesting that these interactions are direct. SIGNOR-71468 0.617 CELF6 protein Q96J87 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 9606 BTO:0001109 31534127 t miannu CELF6 binds to the 3'UTR of p21 transcript and increases its mRNA stability. Depletion of CELF6 promotes cell cycle progression, cell proliferation and colony formation whereas overexpression of CELF6 induces G1 phase arrest. SIGNOR-269044 0.2 GRIK3 protein Q13003 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264344 0.7 PIM1 protein P11309 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr95 DKTQLNPtSLQKLFR 9606 15319445 t gcesareni Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1. SIGNOR-128268 0.428 MEGF10 protein Q96KG7 UNIPROT ABCA1 protein O95477 UNIPROT up-regulates activity binding 9606 BTO:0000567 17205124 t miannu ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level. SIGNOR-265165 0.338 AURKB protein Q96GD4 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser13 ITSAARRsYVSSGEM -1 12686604 t lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro. SIGNOR-100165 0.449 CSNK2A1 protein P68400 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Thr231 ALKEEPQtVPEMPGE 9606 1516134 t lperfetto Casein kinase ii is a negative regulator of c-jun dna binding and ap-1 activitywe show that two of these sites, thr-231 and ser-249, are phosphorylated by casein kinase ii (ckii). SIGNOR-19607 0.575 CHEK1 protein O14757 UNIPROT SNCB protein Q16143 UNIPROT unknown phosphorylation Tyr127 EDPPQEEyQEYEPEA 9606 21699177 t llicata Chk preferentially phosphorylates recombinant _-synuclein at tyrosine-127 SIGNOR-174590 0.2 S1RA chemical CID:44247568 PUBCHEM SIGMAR1 protein Q99720 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000195 22784008 t Simone Vumbaca The most selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862) emerged as the most interesting candidate. Compound 28 is a highly selective σ1R antagonist and has successfully completed phase I safety and pharmacokinetic evaluation in humans. SIGNOR-261122 0.8 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259809 0.8 NDRG1 protein Q92597 UNIPROT RAB4A protein P20338 UNIPROT up-regulates binding 9606 BTO:0000150;BTO:0001130 17786215 t miannu In this report evidence is provided that ndrg1 is a rab4a effector protein that localizes to perinuclear recycling/sorting vesicles in the trans golgi network by binding to phophatidylinositol 4-phosphate and is involved in recycling of e-cadherin. This is the first demonstration providing evidence that ndrg1 is a rab4a effector recruiting to recycling/sorting endosomes. SIGNOR-157697 0.328 PTGER3 protein P43115 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256995 0.283 DNMT3B protein Q9UBC3 UNIPROT HOXB13 protein Q92826 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 22808286 f miannu EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex. SIGNOR-254145 0.259 RAC3 protein P60763 UNIPROT CIB1 protein Q99828 UNIPROT up-regulates activity binding 10029 BTO:0000246 11756406 t Gianni We here report that CIB, a protein that binds to the alpha(IIb)beta(3) fibrinogen receptor, interacts exclusively with activated (V12) Rac3 but not Rac1 or Rac2. Binding of V12Rac3 to CIB was mediated by the C-terminal end of Rac3 and by Rac3 membrane localization SIGNOR-269060 0.355 PRKCG protein P05129 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates phosphorylation 9606 12536214 t inferred from family member gcesareni We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus. SIGNOR-270233 0.693 DDX17 protein Q92841 UNIPROT Microprocessor complex complex SIGNOR-C356 SIGNOR up-regulates activity binding 9606 26045258 t miannu In addition, nuclear YAP has also been found to regulate miRNA processing. Nuclear YAP/TAZ bind and sequester DEAD box helicase 17 (DDX17) (also known as p72) to repress its association with Microprocessor, a complex that regulates miRNA processing (Figure 3B). SIGNOR-277660 0.57 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NR3C1 protein P04150 UNIPROT down-regulates phosphorylation -1 9199329 t inferred from 70% family members lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. SIGNOR-270098 0.2 PTK2 protein Q05397 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 15688067 t miannu Src-mediated phosphorylation of FAK at Tyr925 creates an SH2 binding site for the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which leads to the activation of Ras and the extracellular signal-regulated kinase-2 (ERK2) cascade. SIGNOR-257733 0.694 TRIB3 protein Q96RU7 UNIPROT COP1 protein Q8NHY2 UNIPROT up-regulates activity binding 9606 BTO:0000007 16794074 t miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). SIGNOR-271602 0.2 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser272 RPRSKSQsSSNCSNP -1 12351658 t IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. SIGNOR-251290 0.644 NR3C1 protein P04150 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 11279134 f lperfetto The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin SIGNOR-235346 0.467 RRN3 protein Q9NYV6 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR up-regulates activity relocalization 9606 BTO:0000567 11250903 t lperfetto HRRN3 is essential in the SL1-mediated recruitment of RNA Polymerase I to rRNA gene promoters|We conclude that hRRN3 functions to recruit initiation-competent Pol I to rRNA gene promoters. The essential role for hRRN3 in linking Pol I to SL1 suggests a mechanism for growth control of Pol I transcription. SIGNOR-269647 0.648 RNF125 protein Q96EQ8 UNIPROT DDX58 protein O95786 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0005029 17460044 t miannu Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production. SIGNOR-271647 0.658 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251588 0.695 SMAD2 protein Q15796 UNIPROT CREB1 protein P16220 UNIPROT up-regulates binding 9606 SIGNOR-C8 9689110 t gcesareni We demonstrate that human smad2 and smad4, two essential smad proteins involved in mediating tgf-beta transcriptional responses in endothelial and other cell types, can functionally interact with the transcriptional coactivator creb binding protein (cbp). This interaction is specific in that it requires ligand (tgf-beta) activation and is mediated by the transcriptional activation domains of the smad proteins. SIGNOR-59462 0.331 UBE2S protein Q16763 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 9606 BTO:0000567 19822757 t lperfetto Here, we identify the highly conserved Ube2S as a regulator of human and Drosophila APC/C. Ube2S functions as a K11-specific chain elongating E2 of APC/C, which depends on chain initiation by UbcH10. Together, UbcH10 and Ube2S are required for the degradation of all APC/C substrates tested so far, spindle formation, and progression of cells through mitosis. SIGNOR-265080 0.656 CBL protein P22681 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20332299 t lperfetto Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface. SIGNOR-65642 0.883 MGLL protein Q99685 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 26997225 f irozzo Overexpression of MGLL inhibits proliferation and delays cell cycle progression in QGY-7703 cells. Forced overexpression of MGLL in human HCC cells resulted in marked inhibition in cell proliferation with a significant delay in cell cycle progression [.] SIGNOR-259139 0.7 CPSF complex complex SIGNOR-C53 SIGNOR PAPOLB protein Q9NRJ5 UNIPROT up-regulates activity relocalization 9606 14749727 t lperfetto Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna. SIGNOR-268324 0.565 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PML protein P29590 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 15093545 t The effect has been demonstrated using P29590-4 gcesareni Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis. SIGNOR-270034 0.2 GATA1 protein P15976 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity binding 9606 17725493 t miannu We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. In particular, we will elaborate on recent data which suggest that GATA-1 targets RUNX1 for modification, in particular phosphorylation by cyclin-dependent kinases. Furthermore, targeting of RUNX1 by GATA-1 for phosphorylation may convert RUNX1 from a repressor to an activator. This is a potential mechanism of transcriptional cooperation and may be an essential step in megakaryocytic differentiation. SIGNOR-254194 0.628 POT1 protein Q9NUX5 UNIPROT RPA3 protein P35244 UNIPROT down-regulates activity binding SIGNOR-C306 18680434 t lperfetto The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA SIGNOR-263326 0.266 BMPR1A protein P36894 UNIPROT FAM83G protein A6ND36 UNIPROT up-regulates activity phosphorylation Ser614 RRPSVASsVSEEYFE -1 24554596 t lperfetto These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway. SIGNOR-264766 0.382 GCG protein P01275 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates 9606 23075495 f inferred from 70% of family members gcesareni On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz. SIGNOR-269857 0.276 PTK6 protein Q13882 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 15994200 t gcesareni These observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis. SIGNOR-138437 0.454 AKT proteinfamily SIGNOR-PF24 SIGNOR PRPH protein P41219 UNIPROT up-regulates activity phosphorylation Ser59 SSSVRLGsFRSPRAG 9606 BTO:0000007 17569669 t miannu Here we demonstrate that peripherin, which is a peripheral nervous system neuron-specific intermediate filament protein, is a novel Akt substrate, and that Ser66 of peripherin is the phosphorylation site. Peripherin phosphorylation is apparently induced in motor neurons after nerve injury, suggesting that the Akt-mediated peripherin phosphorylation may play a role in motor nerve regeneration. SIGNOR-262627 0.2 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR3 protein Q99500 UNIPROT up-regulates chemical activation 9606 16794003 t gcesareni The evidence suggests that s1p acting on s1p receptors coupled to gq SIGNOR-147233 0.8 HRAS protein P01112 UNIPROT ARAF protein P10398 UNIPROT up-regulates binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175183 0.832 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 24342355 t lperfetto We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity SIGNOR-244509 0.2 TAOK proteinfamily SIGNOR-PF21 SIGNOR STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity phosphorylation 9606 23431053 t miannu The thousand-and-one (TAO) amino acids kinase or TAOK1 – 3 has been shown to directly phosphorylate and activate Hpo or MST1/2. SIGNOR-256182 0.378 MAPK9 protein P45984 UNIPROT MYC protein P01106 UNIPROT up-regulates phosphorylation Ser71 SRRSGLCsPSYVAVT 9606 10551811 t gcesareni The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71. SIGNOR-72108 0.366 PPP3CB protein P16298 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser211 LVGVTSSsCPADLTQ 9606 BTO:0000007 26000950 t Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation. SIGNOR-255306 0.385 DLGAP1 protein O14490 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264586 0.852 TYSND1 protein Q2T9J0 UNIPROT SCP2 protein P22307 UNIPROT up-regulates activity cleavage -1 17255948 t miannu Here, we demonstrate that Tysnd1, a previously uncharacterized protein, is responsible both for the removal of the leader peptide from PTS2 proteins and for the specific processing of PTS1 proteins. All of the identified Tysnd1 substrates catalyze peroxisomal β-oxidation. In vitro cleavage of Acox1, Scp2 and prethiolase by recombinant Tysnd1. SIGNOR-261055 0.482 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition 9606 17868033 t Simone Vumbaca Apicidin inhibited rhHDACs 2 and 3 in the nanomolar range. SIGNOR-261128 0.8 FCER1G/FCER1G complex SIGNOR-C199 SIGNOR FCER1 complex SIGNOR-C200 SIGNOR form complex binding 9606 BTO:0000830 16470226 t Alessandro Palma FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling. SIGNOR-254962 0.595 SS18 protein Q15532 UNIPROT SS18/MLLT10 complex SIGNOR-C75 SIGNOR form complex binding 9606 BTO:0001271 11423977 t miannu Based on these results, a model is proposed in which the syt and af10 proteins act in concert as bipartite transcription factors SIGNOR-108927 0.436 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser361 TLRDVVPsPDTQEKG 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276106 0.357 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR LIN28A protein Q9H9Z2 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269246 0.528 NANOG protein Q9H9S0 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 f miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. SIGNOR-254621 0.451 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17442773 f miannu Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. Runx1 is also upregulated in the NUP98‐HOXA9 transcriptosome and is a critical regulator of hematopoietic development and a frequent target for chromosomal translocation in leukemia SIGNOR-261499 0.2 PPP1CA protein P62136 UNIPROT WWTR1 protein Q9GZV5 UNIPROT up-regulates activity dephosphorylation Ser311 PYHSREQsTDSGLGL 9606 21189257 t miannu PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase. SIGNOR-277115 0.526 BKM120 chemical CHEBI:71954 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190392 0.8 SOX9 protein P48436 UNIPROT OTX2 protein P32243 UNIPROT up-regulates activity binding 10090 20530484 t miannu BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles. SIGNOR-255184 0.356 PRKACA protein P17612 UNIPROT CBX3 protein Q13185 UNIPROT up-regulates phosphorylation Ser93 KDGTKRKsLSDSESD 9606 16531993 t gcesareni We demonstrate that p-ser 83-hp1gamma has an exclusively euchromatic localization, interacts with ku70 (a regulatory protein involved in multiple nuclear procesess), has impaired silencing activity and serves as a marker for transcription elongation. SIGNOR-145109 0.2 N-(6-fluoro-1H-indazol-5-yl)-6-methyl-2-oxo-4-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-pyridine-5-carboxamide chemical CHEBI:91332 ChEBI ROCK1 protein Q13464 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 19740074 t miannu We also observed that several ROCK (Rho kinase) inhibitors such as Y-27632 and H-1152, suppressed LRRK2 with similar potency to which they inhibited ROCK2. In contrast, GSK429286A, a selective ROCK inhibitor, did not significantly inhibit LRRK2. SIGNOR-262229 0.8 IL23R protein Q5VWK5 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 t gcesareni Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12. SIGNOR-87808 0.689 SMO protein Q99835 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 16885213 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling as pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp SIGNOR-148592 0.2 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Tyr350 RRSSLKAyGNGYSSN 10029 BTO:0000246 8557631 t Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors. SIGNOR-251301 0.385 FYN protein P06241 UNIPROT CD300LB protein A8K4G0 UNIPROT up-regulates activity phosphorylation Tyr188 EPGEQPIyMNFSEPL 9534 16920917 t lperfetto As CD300b phosphorylation was occurring only in the presence of both c-Fyn and DAP-12, we addressed whether tyrosine phosphorylation was required for association of CD300b and DAP-12. For this purpose, we generated a set of HA-tagged CD300b mutants affecting the transmembrane lysine (K158L), the cytoplasmic tyrosine (Y188F) or both residues.|As expected, the CD300b double mutant could neither recruit DAP-12 nor become phosphorylated in the presence of c-Fyn kinase (Fig. 5⇑C). Association between CD300b and DAP-12 was maintained in absence of the c-Fyn kinase, indicating that phosphorylation of the adaptor was not essential for the formation of the complex (data not shown) SIGNOR-264771 0.313 PCDH19 protein Q8TAB3 UNIPROT GABRA1 protein P14867 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C330 29360992 t miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  SIGNOR-267217 0.371 PRKG1 protein Q13976 UNIPROT PRKAR1A protein P10644 UNIPROT up-regulates activity phosphorylation Ser101 RRRRGAIsAEVYTEE 9606 BTO:0002181 29378851 t miannu  In this study, we further examined the potential of RIα phosphorylation to regulate physiologically relevant "desensitization" of PKAc activity. First, the serine 101 site of RIα was validated as a target of PKGIα phosphorylation both in vitro and in cells.These findings suggest that RIα phosphorylation may be a novel mechanism to circumvent the requirement of cAMP stimulus to activate type I PKA in cells. SIGNOR-277383 0.236 MEF2C protein Q06413 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 9418854 t lperfetto Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis. SIGNOR-54089 0.732 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C110 SIGNOR-C110 23579495 t lperfetto Phosphorylation by GSK3 kept Axin activated (open) for _-catenin interaction and poised for engagement of LRP6. SIGNOR-201683 0.918 C4A protein P0C0L4 UNIPROT C3 convertase complex complex SIGNOR-C310 SIGNOR form complex binding -1 cleavage:Arg756;Gly1446 KGQAGLQrALEILQE;TPLQLFEgRRNRRRR 17204478 t complement C4b fragment: PRO_0000005970 lperfetto However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex SIGNOR-263400 0.607 MAP3K14 protein Q99558 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates activity phosphorylation Ser866 TAEVKEDsAYGSQSV 9606 BTO:0000007 11239468 t lperfetto NIK-induced p100 processing requires phosphorylation of p100 at serines 866 and 870 SIGNOR-105553 0.664 CDK5 protein Q00535 UNIPROT APEX1 protein P27695 UNIPROT up-regulates activity phosphorylation Thr233 NKKNAGFtPQERQGF 9606 21727086 t miannu Apurinic/apyrimidinic endonuclease-1 (APE1) is a multifunctional DNA repair/gene regulatory protein in mammalian cells, and was recently reported to be phosphorylated at Thr233 by CDK5. SIGNOR-276337 0.385 PPP5C protein P53041 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates activity dephosphorylation Ser671 RKRSTRRsVRGSQAQ 9606 BTO:0000007 24333728 t Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp SIGNOR-272507 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR CLK2 protein P49760 UNIPROT up-regulates phosphorylation Ser34 HKRRRSRsWSSSSDR 9606 BTO:0000567 20682768 t lperfetto Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva SIGNOR-244214 0.2 serotonin smallmolecule CHEBI:28790 ChEBI HTR1E protein P28566 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264288 0.8 pyridoxal 5'-phosphate(2-) smallmolecule CHEBI:597326 ChEBI PSAT1 protein Q9Y617 UNIPROT up-regulates activity chemical activation 3702 30034403 t lperfetto Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction. SIGNOR-268561 0.8 MAPK14 protein Q16539 UNIPROT ZAP70 protein P43403 UNIPROT down-regulates activity phosphorylation Thr293 TLNSDGYtPEPARIT 9606 BTO:0000782 29440413 t miannu We have found that T cell p38 MAP kinase (MAPK), which is directly phosphorylated and activated by ZAP-70 downstream of the TCR, in turn phosphorylates Thr-293 in the interdomain B region of ZAP-70. These results identify a tight negative feedback loop in which ZAP-70-activated p38 reciprocally phosphorylates ZAP-70 and destabilizes the signaling complex. SIGNOR-277384 0.457 ZWINT protein O95229 UNIPROT RZZ complex complex SIGNOR-C357 SIGNOR form complex binding 9606 BTO:0000567 20462495 t lperfetto The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico. SIGNOR-265013 0.638 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. SIGNOR-268783 0.8 PPP2CB protein P62714 UNIPROT CARD11 protein Q9BXL7 UNIPROT down-regulates activity dephosphorylation Ser644 NLMFRKFsLERPFRP 9606 21157432 t NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation. SIGNOR-248607 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR TENT2 protein Q6PIY7 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 31057087 t inferred from 70% family members miannu We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. SIGNOR-270130 0.2 CCND1 protein P24385 UNIPROT MSI1 protein O43347 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20443831 f gcesareni We hypothesized that cyclin d1 may induce notch1 activity either by repressing numb or by inducing musashi 1 expression SIGNOR-165186 0.287 PTPRG protein P23470 UNIPROT ITGB1 protein P05556 UNIPROT down-regulates activity dephosphorylation Tyr783 DTGENPIyKSAVTTV -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254706 0.268 SUPT20H protein Q8NEM7 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269575 0.74 PDPK1 protein O15530 UNIPROT PRKCZ protein Q05513 UNIPROT up-regulates phosphorylation Thr410 GPGDTTStFCGTPNY 9606 11141077 t gcesareni Our findings suggest that insulin, via pip(3), provokes increases in pkc-zeta enzyme activity through (a) pdk-1-dependent t410 loop phosphorylation, (b) t560 autophosphorylationcytoskeletal reorganization;tnni1(induces);desmin(induces);tpm1(induces);myo1c(induces);tnnt1(induces); SIGNOR-85501 0.559 Delta(9)-tetrahydrocannabinol smallmolecule CHEBI:66964 ChEBI CNR1 protein P21554 UNIPROT up-regulates activity chemical activation 9606 BTO:0000142 29751001 t miannu Endocannabinoids (eCBs) are the body’s natural agonists for cannabinoid receptors (G protein-coupled CB1 and CB2) that also recognize Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana. SIGNOR-264267 0.8 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000018 10734310 t miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. SIGNOR-250289 0.661 P2RY2 protein P41231 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-264307 0.2 TFEB protein P19484 UNIPROT GALNS protein P34059 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276538 0.293 metformin chemical CHEBI:6801 ChEBI NR0B2 protein Q15466 UNIPROT up-regulates quantity by expression 9606 17909097 f gcesareni In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp. SIGNOR-158059 0.8 PHKA2 protein P46019 UNIPROT PHKG2 protein P15735 UNIPROT down-regulates activity binding 9606 10487978 t Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit. SIGNOR-267406 0.914 SOCS3 protein O14543 UNIPROT IL6ST protein P40189 UNIPROT down-regulates activity binding 9606 BTO:0000887;BTO:0001103 19620279 t miannu We now show that SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by specifically inhibiting the LIF-induced JAK1/STAT1/STAT3 pathway via distinct targets; whereas SOCS1 and SOCS3 selectively bind and inhibit JAK1 and gp130, respectively, PIAS1 targets mainly the activated STAT1 and prevents its binding to DNA. SIGNOR-202045 0.637 AP2M1 protein Q96CW1 UNIPROT AP-2 complex complex SIGNOR-C245 SIGNOR form complex binding 31671891 t lperfetto The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit SIGNOR-260420 0.915 MAP3K8 protein P41279 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf SIGNOR-244892 0.556 STOML2 protein Q9UJZ1 UNIPROT NDUFV1 protein P49821 UNIPROT up-regulates activity 9606 BTO:0000782 20359165 f Giorgia We found that SLP-2hi cells had significantly higher activities of NADH dehydrogenase and succinate dehydrogenase (P < 0.05), complexes I and II of the electron transport chain. SIGNOR-260382 0.289 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Thr2116 VGRGLQLtPGIGGMQ 9606 18794356 t miannu Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore. SIGNOR-181018 0.382 RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10558990 t lperfetto The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival. SIGNOR-180910 0.404 MAPK3 protein P27361 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser323 HCSAEAGsPAMAVLD 9606 16286470 t lperfetto The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain SIGNOR-141609 0.778 MAP3K13 protein O43283 UNIPROT TRIM25 protein Q14258 UNIPROT up-regulates quantity by stabilization phosphorylation Ser12 CPLAEELsCSICLEP 9606 BTO:0002181 31186535 t miannu Mechanistically, MAP3K13 phosphorylates the E3 ubiquitin ligase TRIM25 at Ser12 to decrease its polyubiquitination and proteasomal degradation. SIGNOR-277456 0.2 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1070 DSFLQRYsSDPTGAL 9606 BTO:0000007 10347170 t llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  SIGNOR-250620 0.378 LAMC1 protein P11047 UNIPROT Laminin-8 complex SIGNOR-C181 SIGNOR form complex binding 10809728 t lperfetto Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. SIGNOR-253228 0.569 NDEL1 protein Q9GZM8 UNIPROT DYNC1H1 protein Q14204 UNIPROT up-regulates activity binding 10090 BTO:0000938 11163259 t miannu LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex SIGNOR-252159 0.709 belinostat chemical CHEBI:61076 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257742 0.8 TSSK4 protein Q6SA08 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000007 15964553 t gcesareni Tssk5, a novel member of the testis-specific serine/threonine kinase family, phosphorylates creb at ser-133, and stimulates the cre/creb responsive pathway. SIGNOR-138289 0.595 PRKCA protein P17252 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 t lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation SIGNOR-249246 0.294 HNF1A protein P20823 UNIPROT SLC22A10 protein Q63ZE4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 20829431 t lperfetto Luciferase reporter gene constructs containing the OAT5 (SLC22A10) and OAT7 (SLC22A9) promoter regions were transactivated by HNF-1 in HepG2 cells. SIGNOR-268983 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244505 0.2 JUNB protein P17275 UNIPROT LORICRIN protein P23490 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000667 12200429 f miannu Loricrin expression is suppressed by Jun B, Sp3, and KSR-1 proteins. SIGNOR-254535 0.2 RPS6KA3 protein P51812 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0002181 23608533 t miannu We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding. SIGNOR-276464 0.2 CAMK2A protein Q9UQM7 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Ser155 CLEDIHTsRVVAHVL 9606 17568776 t lperfetto Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53 SIGNOR-156064 0.301 GSK3B protein P49841 UNIPROT UNG protein P13051 UNIPROT down-regulates quantity by destabilization phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000812 phosphorylation:Ser64 EPGTPPSsPLSAEQL 27875297 t lperfetto Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation SIGNOR-264885 0.2 PTPRG protein P23470 UNIPROT PXN protein P49023 UNIPROT up-regulates activity dephosphorylation -1 25624455 t miannu a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254722 0.262 RUNX2 protein Q13950 UNIPROT SNAI3 protein Q3KNW1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001610 22641097 f miannu Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells. SIGNOR-255083 0.2 SHC3 protein Q92529 UNIPROT GRB2 protein P62993 UNIPROT up-regulates relocalization 9606 16729043 t gcesareni In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation. SIGNOR-146897 0.812 SYK protein P43405 UNIPROT VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 11331248 t gcesareni Vav interacts with the tyrosine kinase syk. inhibition of syk kinase activity prevents tyrosine phosphorylation of vav and its interaction with pi 3-k. SIGNOR-107046 0.918 CHEK1 protein O14757 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity 9606 28138032 f miannu Mechanistically, Ras-MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras-MEK signaling, thereby limiting DNA damage. Ras–MEK signaling transcriptionally activates Chk1, which appears to sustain cancer cell growth by maintaining DNA damage levels below a threshold that would otherwise drive apoptosis. SIGNOR-263059 0.329 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219349 0.707 SOX9 protein P48436 UNIPROT COL11A2 protein P13942 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10980415 f miannu Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan. SIGNOR-251758 0.397 DUSP4 protein Q13115 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 9020184 t lperfetto Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2 SIGNOR-27756 0.703 CD47 protein Q08722 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 t lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  SIGNOR-266016 0.375 CPSF3 protein Q9UKF6 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 30507380 f lperfetto Replication-dependent (RD) core histone mRNA produced during S-phase is the only known metazoan protein-coding mRNA presenting a 3' stem-loop instead of the otherwise universal polyA tail. A metallo β-lactamase (MBL) fold enzyme, cleavage and polyadenylation specificity factor 73 (CPSF73), is proposed to be the sole endonuclease responsible for 3' end processing of both mRNA classes. SIGNOR-268336 0.7 FBXO11 protein Q86XK2 UNIPROT TP53 protein P04637 UNIPROT down-regulates neddylation Lys321 SSPQPKKkPLDGEYF 9606 17098746 t miannu Fbxo11 promotes the neddylation of p53 and inhibits its transcriptional activity / we found that fbxo11 also neddylates p53 on two lysines, lys-320 and lys-321 SIGNOR-150673 0.657 LYN protein P07948 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 BTO:0000007 10574931 t Lyn phosphorylates SHPTP1 at the C-terminal Tyr-564 site. Lyn-mediated phosphorylation of SHPTP1 stimulates SHPTP1 tyrosine phosphatase activity. SIGNOR-251409 0.724 AKT1 protein P31749 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr39 LKKIRLDtETEGVPS 9606 18354084 t lperfetto Akt phosphorylates cdk2 at threonine 39 residue both in vitro and in vivo. Although cdk2 threonine 39 phosphorylation mediated by akt enhances cyclin-a binding, it is dispensable for its basal binding and the kinase activity. SIGNOR-178058 0.335 AHCYL1 protein O43865 UNIPROT PAPOLA protein P51003 UNIPROT down-regulates activity binding 9606 BTO:0000007 19224921 t lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. SIGNOR-268329 0.248 alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI EEF1A:GTP:aa-tRNA complex SIGNOR-C493 SIGNOR form complex binding 9606 8722040 t miannu The mechanism of elongation factor Tu (EF-Tu) catalyzed aminoacyl-tRNA (aa-tRNA) binding to the A site of the ribosome was studied. Two types of complexes of EF-Tu with GTP and aa-tRNA, EF-Tu.GTP-aa-tRNA (ternary) and (EF-Tu.GTP)2.aa-tRNA (quinternary), can be formed in vitro depending on the conditions. SIGNOR-270808 0.8 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT up-regulates activity phosphorylation Tyr293 PAPSGRAyTSPLIDM -1 21840312 t miannu Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility. SIGNOR-263040 0.398 ABL1 protein P00519 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Tyr118 AGPLIVPyNLPLPGG 9606 20600357 t llicata In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at positions 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-abl kinase. our results demonstrate that cells expressing galectin-3 y107f variant showed reduced migration in wound healing assay ( fig. 5). This result confirms the role of galectin-3 tyrosine phosphorylation in cell motility. SIGNOR-166497 0.362 SCF-betaTRCP complex SIGNOR-C5 SIGNOR GBF1 protein Q92538 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 29898406 t miannu We show that, in mitosis, GBF1 is phosphorylated on Ser292 and Ser297 by casein kinase-2 allowing recognition by the F-box protein βTrCP. GBF1 interaction with βTrCP recruits GBF1 to the SCFβTrCP ubiquitin ligase complex, triggering its degradation. SIGNOR-277399 0.253 KATNA1 protein O75449 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates 9606 19287380 f miannu Katanin, one of the best-characterized microtubule (MT) severing proteins, is composed of two subunits: catalytic p60-katanin, and regulatory p80-katanin. p60-katanin triggers MT reorganization by severing them. MT reorganization is essential for both mitotic cells and post-mitotic neurons in numerous vital processes such as intracellular transport, mitosis, cellular differentiation and apoptosis.  SIGNOR-271794 0.7 GTF3C2 protein Q8WUA4 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR form complex binding 9606 29378333 t lperfetto Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains SIGNOR-266187 0.868 QOCYWLABLBUJOR-UHFFFAOYSA-N chemical CID:53299324 PUBCHEM SLC6A3 protein Q01959 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 18487050 t Luana For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428.  SIGNOR-257796 0.8 AKT3 protein Q9Y243 UNIPROT CYCS protein P99999 UNIPROT down-regulates activity phosphorylation Tyr47 KTGQAPGySYTAANK -1 32781572 t miannu Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain. SIGNOR-277235 0.268 TPR protein P12270 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates binding 9606 18981471 t miannu Tpr directly binds to mad1 and mad2. / depletion of tpr decreases the levels of mad1 at kinetochores during prometaphase, correlating with the inability of mad1 to activate mad2, which is required for inhibiting apc(cdc20). SIGNOR-181975 0.314 DPM2 protein O94777 UNIPROT DPM complex complex SIGNOR-C289 SIGNOR form complex binding 9606 10835346 t lperfetto Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3. SIGNOR-262564 0.778 LYN protein P07948 UNIPROT IRF5 protein Q13568 UNIPROT down-regulates activity phosphorylation Tyr313 PSDKQRFyTNQLLDV 9606 BTO:0002181 27521268 t miannu Lyn Kinase Suppresses the Transcriptional Activity of IRF5. Here, we found that Lyn physically interacted with IRF5 to inhibit ubiquitination and phosphorylation of IRF5 in the TLR-MyD88 pathway, thereby suppressing the transcriptional activity of IRF5 in a manner independent of Lyn's kinase activity. SIGNOR-277247 0.335 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273060 0.635 PAMPs stimulus SIGNOR-ST11 SIGNOR NLRP1 inflammasome complex SIGNOR-C224 SIGNOR up-regulates activity 16037825 f miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-263125 0.7 EIF3_complex complex SIGNOR-C401 SIGNOR EIF5 protein P55010 UNIPROT up-regulates activity stabilization 9606 17581632 t lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit SIGNOR-269153 0.684 MAP4K1 protein Q92918 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates phosphorylation Thr165 ISAQIGAtLARRLSF 9606 BTO:0000782 15743830 t gcesareni Activation of hematopoietic progenitor kinase 1 involves relocation, autophosphorylation, and transphosphorylation by protein kinase d1. SIGNOR-134490 0.2 PYGL protein P06737 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI down-regulates quantity chemical modification 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267949 0.8 IGF1R protein P08069 UNIPROT PCNA protein P12004 UNIPROT up-regulates activity phosphorylation Tyr60 RSEGFDTyRCDRNLA -1 28924044 t miannu In vitro MS analysis of PCNA co-incubated with the IGF-1R kinase indicated tyrosine residues 60, 133, and 250 in PCNA as IGF-1R targets, and PCNA phosphorylation was followed by mono- and polyubiquitination. SIGNOR-277253 0.2 SRC protein P12931 UNIPROT MUC1 protein P15941 UNIPROT up-regulates phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 11152665 t lperfetto The c-src tyrosine kinase regulates signaling of the human df3/muc1 carcinoma-associated antigen with gsk3 beta and betBeta-catenin c-src phosphorylates the muc1 cytoplasmic domain at a yekv motif c-src-mediated phosphorylation of muc1 increases binding of muc1 and betBeta-catenin SIGNOR-85938 0.455 PRKCD protein Q05655 UNIPROT FLI1 protein Q01543 UNIPROT down-regulates phosphorylation Thr312 TNGEFKMtDPDEVAR 9606 21321929 t lperfetto We have previously demonstrated that in response to transforming growth factor _ (tgf_), fli-1 activity is repressed through a series of sequential posttranslational modifications, consisting of protein kinase c_ (pkc_)-induced thr312 phosphorylation, acetylation by p300/creb binding protein-associated factor, and detachment from the collagen promoter. SIGNOR-172113 0.353 MLF1 protein P58340 UNIPROT COP1 protein Q8NHY2 UNIPROT up-regulates 9606 15861129 f miannu As downstream elements of mlf1 leading to cell growth arrest due to p53 accumulation, we identified two factors, csn3, the third component of the cop9 signalosome (csn), and cop1, a recently characterized e3 ubiquitin ligase for p53 SIGNOR-135940 0.2 FIG4 protein Q92562 UNIPROT PAS complex complex SIGNOR-C190 SIGNOR form complex binding 9606 BTO:0000007 17556371 t miannu Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. SIGNOR-253528 0.929 FSTL3 protein O95633 UNIPROT MSTN protein O14793 UNIPROT down-regulates binding 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 t gcesareni Fstl3 inhibits myostatin via its n-terminal domain. SIGNOR-199063 0.696 AMOT protein Q4VCS5 UNIPROT YAP1 protein P46937 UNIPROT down-regulates relocalization 9606 21808241 t gcesareni Yap/taz and angiomotin (amot) family proteins were shown to interact, resulting in yap/taz localization to tight junctions and inhibition through phosphorylation-dependent and -independent mechanisms. SIGNOR-175779 0.727 CAST protein P20810 UNIPROT CAPN2 protein P17655 UNIPROT down-regulates activity binding 9606 BTO:0000590 25969760 t lperfetto In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain SIGNOR-251609 0.901 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 t lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-75633 0.783 MYC protein P01106 UNIPROT CDK6 protein Q00534 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001271 12835716 f gcesareni The degradation of c-myc protein decreases the expression of the cell cycle regulators cdk4 and cdk6, which reversibly slows down the cell cycle. SIGNOR-102737 0.465 pomalidomide chemical CHEBI:72690 ChEBI CRBN protein Q96SW2 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 22552008 t miannu Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide. SIGNOR-259283 0.8 FLI1 protein Q01543 UNIPROT GP9 protein P14770 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002581 15466856 f miannu Both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. SIGNOR-254160 0.25 cyclosporin A chemical CHEBI:4031 ChEBI PPP3CC protein P48454 UNIPROT down-regulates chemical inhibition 9606 15276472 t gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. SIGNOR-127231 0.8 retinol smallmolecule CHEBI:50211 ChEBI retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity precursor of 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS9 SIGNOR-265115 0.8 ABL2 protein P42684 UNIPROT CRK protein P46108 UNIPROT down-regulates phosphorylation Tyr221 GGPEPGPyAQPSVNT 10090 15886098 t gcesareni Rin1 binds to the abl sh3 and sh2 domains, and these interactions stimulate abl2 catalytic activity. This leads to increased phosphorylation of crk and crkl, inhibiting these cytoskeletal regulators by promoting intramolecular over intermolecular associations. the ability of crk to function as an adaptor protein is negatively regulated and terminated by phosphorylation on y221, which results in an intramolecular sh2-ptyr clamp, thereby resulting in the disassembly of crk-mediated signaling complexes SIGNOR-136955 0.686 RRAGC protein Q9HB90 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates binding 9606 20006481 t lperfetto Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor. SIGNOR-217547 0.687 ESCRT-III complex SIGNOR-C379 SIGNOR Viral_budding phenotype SIGNOR-PH125 SIGNOR up-regulates 9606 26775243 f miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. SIGNOR-265534 0.7 CSNK1E protein P49674 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation Ser480 PVPHSGSsGYGSLGS -1 30425162 t miannu Priming-independent clusters located in the C-terminal portion of PER2’s PAS domains are targeted by CK1ε/δ and are required for ubiquitin ligase–mediated degradation of PER2 SIGNOR-277419 0.898 CSNK1D protein P48730 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation Ser480 PVPHSGSsGYGSLGS -1 30425162 t miannu Priming-independent clusters located in the C-terminal portion of PER2’s PAS domains are targeted by CK1ε/δ and are required for ubiquitin ligase–mediated degradation of PER2 SIGNOR-277420 0.865 SPI1 protein P17947 UNIPROT FCER1A protein P12319 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11971001 f Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1. The alpha-chain promoter activity was up-regulated approximately 2-fold by exogenously expressed YY1 or PU.1 and approximately 7-fold by GATA-1, respectively, in KU812 cells SIGNOR-254289 0.278 FLT4 protein P35916 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 9927207 t llicata We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites. SIGNOR-64076 0.575 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr791 TPMYGSQtPLQDGSR 9606 16427012 t lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif SIGNOR-143931 0.768 morphine chemical CHEBI:17303 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258765 0.8 P2RY4 protein P51582 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257214 0.2 PRKCD protein Q05655 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser932 DDTPEKDsFRARSTS 9606 BTO:0002181 30684133 t miannu In vivo kinase analysis further indicated that both S932 and S939 are phosphorylated in response to translation inhibitors. Finally, phosphorylation defective TSC2 mutants (S932A and S939A single mutants and a S932A/S939A double mutant) failed to upregulate mTORC1 activity in the presence of translation inhibitors, suggesting that activation of mTORC1 by translation inhibitors is mediated by PKC-δ phosphorylation of TSC2 at S932/S939, which inactivates TSC. SIGNOR-277426 0.2 NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT up-regulates quantity transcriptional regulation 9606 31257023 f Nrf2 accumulation in lung cancers causes the stabilization of Bach1 by inducing Ho1, the enzyme catabolizing heme. SIGNOR-259334 0.667 tacedinaline chemical CHEBI:90195 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258009 0.8 CKM complex complex SIGNOR-C406 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates quantity by destabilization phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914168 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-273146 0.421 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2L3 protein P68036 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271360 0.486 PRKCD protein Q05655 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser939 SFRARSTsLNERPKS 9606 BTO:0002181 30684133 t miannu In vivo kinase analysis further indicated that both S932 and S939 are phosphorylated in response to translation inhibitors. Finally, phosphorylation defective TSC2 mutants (S932A and S939A single mutants and a S932A/S939A double mutant) failed to upregulate mTORC1 activity in the presence of translation inhibitors, suggesting that activation of mTORC1 by translation inhibitors is mediated by PKC-δ phosphorylation of TSC2 at S932/S939, which inactivates TSC. SIGNOR-277427 0.2 PRKCA protein P17252 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates quantity by stabilization phosphorylation Ser144 TLPSDKLsKIQTLKL 9606 BTO:0002181 30733340 t miannu Because most of these sites were predicted to be phosphorylated by protein kinase C (PKC), we overexpressed PKCα in several cell lines and found that it phosphorylates Twist1 on Ser-144. we observed that PKCα-mediated Twist1 phosphorylation at Ser-144 inhibits Twist1 ubiquitination and consequently stabilizes it. SIGNOR-277429 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPP2R5C protein Q13362 UNIPROT down-regulates phosphorylation 9606 16456541 t inferred from 70% family members gcesareni Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit. SIGNOR-270196 0.2 WASF1 protein Q92558 UNIPROT WRC complex complex SIGNOR-C191 SIGNOR form complex binding 9606 21107423 t miannu WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems. SIGNOR-253572 0.893 COL6A2 protein P12110 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. SIGNOR-254674 0.7 ATM protein Q13315 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser222 LPEILGDsQHADVGK 9606 12086603 t lperfetto Atm phosphorylates fancd2 on serine 222 in vitro. This site is also phosphorylated in vivo in an atm-dependent manner following ir. Phosphorylation of fancd2 is required for activation of an s phase checkpoint. The atm-dependent phosphorylation of fancd2 on s222 and the fa pathway-dependent monoubiquitination of fancd2 on k561 are independent posttranslational modifications regulating discrete cellular signaling pathways. SIGNOR-90121 0.781 TESK1 protein Q15569 UNIPROT CFL1 protein P23528 UNIPROT down-regulates activity phosphorylation Ser3 sGVAVSDG 9606 BTO:0001363 11418599 t lperfetto Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin SIGNOR-246723 0.544 ATR protein Q13535 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser717 KDGGPVTsQESGQKL 9606 16943440 t lperfetto In the present study, we identify two novel dna damage-inducible phosphorylation sites on fancd2, threonine 691 and serine 717. Atr phosphorylates fancd2 on these two sites, thereby promoting fancd2 monoubiquitination and enhancing cellular resistance to dna cross-linking agents SIGNOR-149305 0.66 MAPK8 protein P45983 UNIPROT GRB7 protein Q14451 UNIPROT down-regulates quantity by destabilization phosphorylation Ser194 KYELFKSsPHSLFPE 9606 BTO:0000017 27658202 t miannu Our data show that phosphorylation of Grb7 protein on the Ser194-Pro motif by c-Jun N-terminal kinase facilitates its binding with the WW domain of Pin1. Subsequently, Grb7 is degraded by the ubiquitin- and proteasome-dependent proteolytic pathway. I SIGNOR-277280 0.265 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD80 protein P33681 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12860928 f miannu Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. SIGNOR-254783 0.301 AKT3 protein Q9Y243 UNIPROT JAG1 protein P78504 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 38402584 f miannu Jagged1 is upregulated by Akt upon activation by R-Ras. All three Akt isoforms influence Jagged1 expression in ECs, but Akt3 is the most prominent Akt isoform in this role, despite its low expression level compared with Akt1. Jagged1 then activates Notch to upregulate Hey1, Hes1, p21, p53, and Unc5b in adjacent cells.  SIGNOR-277224 0.292 Aldolase proteinfamily SIGNOR-PF75 SIGNOR beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266490 0.8 TUBA1A protein Q71U36 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. SIGNOR-269725 0.7 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1231 HSLAARYyNWVSFPG 9606 12881528 t lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. SIGNOR-104076 0.2 EZH2 protein Q15910 UNIPROT ALDH1A1 protein P00352 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004094 22144423 f miannu For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci. SIGNOR-254141 0.399 ITCH protein Q96J02 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization ubiquitination Lys420 GLGSELSkPGVLASQ 9606 BTO:0002181 19881509 t Giorgia These data collectively indicate that AIP4 is the E3 ligase for MAVS.|We generated single substitutions (K362A, K371A or K420A) and combined point substitutions of MAVS and tested their degradation. K371A or K420A MAVS showed partial resistance to PCBP2-induced degradation (data not shown), whereas MAVS with the combined substitutions K371A and K420A (KK-AA) completely withstood the degradation SIGNOR-260363 0.631 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser368 QRPSSRAsSRASSRP 10116 10871288 t lperfetto Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication. SIGNOR-144465 0.451 TNPO1 protein Q92973 UNIPROT HNRNPA1 protein P09651 UNIPROT up-regulates activity relocalization 29970603 t lperfetto TNPO1 only mediates the nuclear import of a subset of proteins.|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import SIGNOR-262099 0.589 DNA_damage stimulus SIGNOR-ST1 SIGNOR KDM4B protein O94953 UNIPROT up-regulates 9606 30759871 f miannu The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. KDM4 enzymes are generally over-expressed in cancers, making them compelling targets for study and therapeutic inhibition. One of these family members, KDM4B, is especially interesting due to its regulation by multiple cellular stimuli, including DNA damage, steroid hormones, and hypoxia. SIGNOR-263736 0.7 ENO1 protein P06733 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266524 0.8 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI TP53 protein P04637 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189999 0.8 JAK2 protein O60674 UNIPROT TET2 protein Q6N021 UNIPROT up-regulates activity phosphorylation Tyr1939 CEKYGPDyVPQKSHG -1 30944118 t miannu Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964. Phosphorylated TET2 interacts with the erythroid transcription factor KLF1, and this interaction with TET2 is increased upon exposure to erythropoietin.  SIGNOR-277290 0.428 SRC protein P12931 UNIPROT LPIN1 protein Q14693 UNIPROT up-regulates activity phosphorylation Tyr795 FPNTEPFyAAFGNRP 9606 BTO:0002181 33203880 t miannu Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride. SIGNOR-277291 0.2 SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR FN1 protein P02751 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000452;BTO:0002625 22223884 f alessandro Taken together, our results indicate that Snail1, p65NF-κB and PARP1 interact to activate the expression of fibronectin and other ECM genes involved in cell movement. This mechanism is functional not only in epithelial cells undergoing EMT but also in fibroblasts. SIGNOR-254529 0.42 SRC protein P12931 UNIPROT LPIN1 protein Q14693 UNIPROT up-regulates activity phosphorylation Tyr398 HLGADGVyLDDLTDM 9606 BTO:0002181 33203880 t miannu Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride. SIGNOR-277292 0.2 SNAI2 protein O43623 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15311212 f miannu known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT. SIGNOR-255155 0.667 PRKCA protein P17252 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates activity phosphorylation Ser181 TGTARYAsINTHLGI -1 31096047 t miannu In the present study we analyzed the CK1δ kinase domain for phosphorylation sites targeted by PKCα. Several phosphorylation sites were identified in vitro by initially using GST-CK1δ wild type and phosphorylation-site mutant protein fragments originating from the CK1δ kinase domain. Residues S53, T176, and S181 could finally be confirmed as targets for PKCα. Determination of kinetic parameters of full-length wild type and mutant GST-CK1δ-mediated substrate phosphorylation revealed that integrity of residue T176 is crucial for maintaining CK1δ kinase activity. SIGNOR-277452 0.2 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 10090 BTO:0000887 24145169 f The BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling SIGNOR-256487 0.2 UQCRH protein P07919 UNIPROT Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 t lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits SIGNOR-262195 0.907 TRIM13 protein O60858 UNIPROT AKT2 protein P31751 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21333377 t miannu Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT.  We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro. SIGNOR-271853 0.2 nalbuphine chemical CHEBI:7454 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 19282177 t Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. SIGNOR-258144 0.8 8-Hydroxy-7-(6-sulfo-naphthalen-2-ylazo)-quinoline-5-sulfonic acid chemical CID:92577 PUBCHEM PTPN11 protein Q06124 UNIPROT down-regulates activity chemical inhibition -1 19233143 t lperfetto In this study, we screened protein tyrosine phosphatases (PTPs) by in vitro phosphatase assays to identify PTPs that are inhibited by 8-hydroxy-7-(6-sulfonaphthalen-2-yl)diazenyl-quinoline-5-sulfonic acid (NSC-87877), a potent inhibitor of SHP-1 and SHP-2 PTPs. SIGNOR-261977 0.8 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 19914161 t lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 SIGNOR-161593 0.591 PPP2CA protein P67775 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 19951945 t gcesareni Accordingly, smad3-associated pp2a activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of tgf-beta-induced smad3 but did not affect smad2. Moreover, the influence of tgf-beta on a set of smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical pp2a inhibition. Our data demonstrate the existence of a smad3-specific phosphatase and identify a novel role for pp2a. SIGNOR-161919 0.2 MAPK9 protein P45984 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates phosphorylation Ser163 SYRESSLsPSPASSI 9606 BTO:0000782 9374467 t lperfetto Ser163 and ser165 represent the major sites of in vitro phosphorylation of nfat4 by jnk. / the negative regulation of nfat4 nuclear accumulation caused by jnk provides a mechanism for cell type?specific Responses to extracellular stimulation SIGNOR-53364 0.699 Obatoclax mesylate chemical CID:46930996 PUBCHEM BCL2L2 protein Q92843 UNIPROT down-regulates activity chemical inhibition -1 23515850 t lperfetto Obatoclax and its predecessor analogs bind to BCL-2, BCL-XL, BCL-w, BCL-B, BFL-1, and MCL-1 in vitro SIGNOR-262024 0.8 cyclosporin A chemical CHEBI:4031 ChEBI PP2B proteinfamily SIGNOR-PF18 SIGNOR down-regulates chemical inhibition 9606 15276472 t inferred from 70% of family members gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. SIGNOR-269889 0.8 USP9X protein Q93008 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates deubiquitination Lys519 DYPRQSIkETPCWIE 10090 BTO:0000165 20016939 t gcesareni Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4. SIGNOR-236855 0.633 PTPRG protein P23470 UNIPROT SHC1 protein P29353 UNIPROT down-regulates activity dephosphorylation Tyr350 EPPDHQYyNDFPGKE -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254724 0.2 KDM5A protein P29375 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by destabilization transcriptional regulation 9606 31374292 t miannu The retinoblastoma binding protein 2 (RBP2) belongs to the KDM5 family, and is also known as JARID1A or KDM5A. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL. SIGNOR-260079 0.293 XL765 chemical CHEBI:71958 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252660 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ADAM17 protein P78536 UNIPROT up-regulates phosphorylation Thr735 KPFPAPQtPGRLQPA 9606 12058067 t lperfetto We report that the cytosolic tail of the tumor necrosis factor alpha-converting enzyme (tace) is phosphorylated by erk at threonine 735.These results demonstrate that secretases are able to discriminate between the different stimuli that trigger membrane protein ectodomain cleavage and indicate that phosphorylation by mapks may regulate the proteolytic function of membrane secretases. SIGNOR-89614 0.2 ABL2 protein P42684 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 10090 33622779 f miannu Here, using cultured hippocampal neurons pooled from both sexes of mice, we provide evidence that binding to cortactin tethers Abl2 in spines, where Abl2 and cortactin maintain the small pool of stable actin required for dendritic spine stability. SIGNOR-266594 0.7 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser516 PQVLAQPsTSRKRPR 9606 BTO:0002201 12855706 t lperfetto Chk2 is also autophosphorylated following dna damage. It is proposed that autophosphorylation of chk2 may contribute to chk2 activation. To fully understand the regulation of chk2, we mapped an in vitro chk2 autophosphorylation site at c-terminal serine 516 site (ser-516). Ser-516 of chk2 is phosphorylated following radiation in vivo, and this phosphorylation depends on the kinase activity of chk2. SIGNOR-103544 0.2 TRAM-34 chemical CHEBI:34990 ChEBI KCNN4 protein O15554 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-207426 0.8 RUNX3 protein Q13761 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 19800882 t gcesareni To investigate the possible mechanism of the down-regulation of hes-1 by runx3, we performed western blot and reporter assay and found that runx3 suppressed intracellular domain of notch1 (icn1)-mediated transactivation of notch signaling while it did not alter the expression of icn1 and recombination signal binding protein-j kappa (rbp-j) in smmc7721 cells. SIGNOR-188338 0.677 tyrosine smallmolecule CHEBI:18186 ChEBI L-dopa smallmolecule CHEBI:15765 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH). SIGNOR-264173 0.8 CDK5 protein Q00535 UNIPROT DNM1 protein Q05193 UNIPROT up-regulates activity phosphorylation Ser778 GRRSPTSsPTPQRRA -1 12855954 t llicata Here, we show that cyclin-dependent kinase 5 (Cdk5) phosphorylates dynamin I on Ser 774 and Ser 778 in vitro, which are identical to its endogenous phosphorylation sites in vivo. Cdk5 antagonists and expression of dominant-negative Cdk5 block phosphorylation of dynamin I, but not of amphiphysin or AP180, in nerve terminals and inhibit SVE.  SIGNOR-250662 0.531 MAPK1 protein P28482 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser175 EEEEDLSsPPGLPEP 9606 14697653 t lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. SIGNOR-120451 0.262 NFIB protein O00712 UNIPROT NFIX protein Q14938 UNIPROT down-regulates activity binding 9606 BTO:0000567 9099724 t 2 miannu Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function. SIGNOR-240915 0.43 MDGA2 protein Q7Z553 UNIPROT DMAP1 protein Q9NPF5 UNIPROT up-regulates quantity by stabilization binding 9606 26206665 t miannu The anti-tumorigenic effect of MDGA2 was mediated through direct stabilising of DNA methyltransferase 1 associated protein 1 (DMAP1), which played a tumour suppressive role in gastric cancer. MDGA2 expression and MG132 treatment increased the level of DMAP1, suggesting that the MDGA2–DMAP1 interaction stabilises DMAP1 by inhibiting its ubiquitin-mediated degradation. SIGNOR-264240 0.355 TBK1 protein Q9UHD2 UNIPROT PRPS1 protein P60891 UNIPROT up-regulates activity phosphorylation Thr228 DMADTCGtICHAADK -1 34343500 t miannu Here, we show that ionizing radiation results in TBK1-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase (PRPS)1/2 at T228, thereby enhancing PRPS1/2 catalytic activity and promoting deoxyribonucleotide synthesis.  SIGNOR-277316 0.2 UMPS protein P11172 UNIPROT Pyrimidine_nucleotide_metabolic_process phenotype SIGNOR-PH85 SIGNOR up-regulates 26059768 f miannu The bifunctional enzyme UMP synthase leads to the synthesis of uridine 5′-monophosphate (UMP). UMP could be considered one of the hub molecules in pyrimidine metabolism because it is the precursor of other pyrimidine nucleotides. SIGNOR-253582 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000150;BTO:0001130 16854453 t lperfetto Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity. SIGNOR-244337 0.2 NOTCH1 protein P46531 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 11404076 t gcesareni Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip. SIGNOR-86125 0.585 DRD5 protein P21918 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257369 0.484 CDK2 protein P24941 UNIPROT CDK7 protein P50613 UNIPROT up-regulates phosphorylation Thr170 GSPNRAYtHQVVTRW 9606 11113184 t amattioni Threonine-170 of cdk7 is phosphorylated in vitro by cdk2. Full activation of cdk7 requires phorylation of a conserved threonine residue at position 170 in its own t loop. SIGNOR-85013 0.553 PTGDR protein Q13258 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256755 0.576 NUP37 protein Q8NFH4 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262085 0.675 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR BCOR protein Q6W2J9 UNIPROT up-regulates activity binding 10090 BTO:0000944 12776190 t irozzo As BCoR binds the C-terminus of AF9, it seems likely that BCoR will also bind chimeric MLL–AF9 proteins. As transcriptional repressors, BCoR or Pc3 bound to MLL–AF9 might interfere with the expression of genes required for normal hematopoiesis. SIGNOR-256142 0.2 RRAGC protein Q9HB90 UNIPROT RAGAC complex SIGNOR-C113 SIGNOR form complex binding 9606 20381137 t gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant SIGNOR-228161 0.772 GRM7 protein Q14831 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 t miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. SIGNOR-264080 0.341 BMP7 protein P18075 UNIPROT ACVR1/BMPR2 complex SIGNOR-C30 SIGNOR up-regulates binding 10090 BTO:0000165 11282024 t lperfetto Bmp-4 and gdf-5 are known to bind to activin receptor-like kinase 3 (alk-3) and/or alk-6 (also termed bmp type ia and type ib receptors, respectively), whereas bmp-6 and bmp-7 preferentially bind to alk-2 SIGNOR-235364 0.798 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR peptide smallmolecule CHEBI:16670 ChEBI up-regulates quantity chemical modification 9606 20025795 t miannu In the initial binding state, referred to as A/T state, this aa-tRNA is in a ternary complex with the GTPase EF-Tu (eEF1A in eukaryotes) and GTP. When a Watson–Crick codon–anticodon match is recognized by the ribosome, a signal is transmitted to EF-Tu that triggers GTP hydrolysis and thereby causes the dissociation of EF-Tu from the ribosome. The subsequent accommodation of the 3′ acceptor arm of the tRNA in the PTC of the large subunit leads to a rapid peptide bond transfer SIGNOR-270811 0.8 SCRIB protein Q14160 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 19458197 f miannu Our data supports a model by which scribble functions downstream of beta-catenin to cluster synaptic vesicles at developing synapses. SIGNOR-265827 0.7 PIN4 protein Q9Y237 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity isomerization 9606 BTO:0000599 23720771 t lperfetto In this study, the association of Par14 with insulin receptor substrate 1 (IRS-1) was demonstrated in HepG2 cells|Therefore, although Pin1 and Par14 associate with different portions of IRS-1, the prolyl cis/trans isomerization in multiple sites of IRS-1 by these isomerases appears to be critical for efficient insulin receptor-induced IRS-1 phosphorylation|Par14 overexpression in HepG2 markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events SIGNOR-265756 0.2 ACLY protein P53396 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-267102 0.8 TRADD protein Q15628 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates binding 9606 10629108 t amattioni Tradd mediates recruitment of traf1/2 SIGNOR-73913 0.682 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR PFKL protein P17858 UNIPROT down-regulates activity phosphorylation -1 28607489 t miannu In vitro kinase reactions revealed that all three PFK1 isoforms (PFKP, PFKL, PFKM) and PKM2 were phosphorylated by cyclin D3-CDK6 (Extended Data Fig. 2a–d, Supplementary Table 4). SIGNOR-276451 0.2 Caspase 3 complex complex SIGNOR-C221 SIGNOR STX5 protein Q13190 UNIPROT down-regulates activity cleavage 9606 14970262 t miannu Giantin and syntaxin 5 are cleaved by caspase-3. Given that both giantin and syntaxin 5 are cleaved at an early stage during apoptosis, we anticipated that, at the very least, the delivery of ER-derived transport intermediates to the Golgi would be impaired in apoptotic cells. SIGNOR-261236 0.2 DDB1 protein Q16531 UNIPROT RAD23A protein P54725 UNIPROT up-regulates 24086044 f lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). SIGNOR-275687 0.586 PIAS4 protein Q8N2W9 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates sumoylation 9606 20016603 t gcesareni Pias1 and pias4 are recruited to dna-damage sites and mediate 53bp1 recruitment and sumoylation SIGNOR-162167 0.621 oxymetazoline chemical CHEBI:7862 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258916 0.8 RPS6KA4 protein O75676 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 22187936 t gcesareni Rsk1/2 stabilize c-fos and increases its activity. SIGNOR-191678 0.401 PRKCB protein P05771 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser170 SFKLSGFsFKKNKKE -1 8422248 t lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. SIGNOR-248929 0.663 MAPKAPK5 protein Q8IW41 UNIPROT KALRN protein O60229 UNIPROT up-regulates activity phosphorylation Ser487 DVLQRPLsPGNSESL -1 22508986 t miannu The brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. The MK5 substrate Kal7, a Rho GEF and known activator of Rac GTPases, further contributes to PAK activation and actin filament reorganization. Thus, the coordinated phosphorylation of Borg proteins and Kal7 by ERK3 and MK5 constitute a novel signaling cascade involving feed-forward circuits, multiple GTPases, and cytoskeletal elements. The fragment SR3-6, but not the mutated fragment SR3-6-S487A, is phosphorylated by MK5. SIGNOR-263093 0.358 SREBF2 protein Q12772 UNIPROT LRP1 protein Q07954 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20980003 f miannu In the present study we report that specific silencing of either SREBP-1 or SREBP-2 enhanced LRP1 whereas overexpression of the active SREBP isoforms decreased LRP1 expression. SIGNOR-254461 0.333 SLBP protein Q14493 UNIPROT H2AZ1 protein P0C0S5 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265408 0.2 PRKCG protein P05129 UNIPROT OCLN protein Q16625 UNIPROT up-regulates activity phosphorylation Ser340 DKRFYPEsSYKSTPV 9615 11502742 t lperfetto Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X. SIGNOR-249107 0.312 SF3B2 protein Q13435 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270664 0.779 lofexidine chemical CHEBI:51368 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 22341244 t Luana Lofexidine was selected because its scaffold is similar to that of the imidazolines of the present study and, as emerged from our functional study (Table 2), it displayed significant α2A- and α2C-AR agonism.  SIGNOR-258332 0.8 CHUK protein O15111 UNIPROT ELAVL1 protein Q15717 UNIPROT down-regulates quantity by destabilization phosphorylation Ser304 EAAMAIAsLNGYRLG 9606 BTO:0001321 23115237 t miannu Furthermore, mutational analysis indicates that IKKα-dependent phosphorylation at Ser-304 is crucial to the binding of HuR to β-TrCP1. Mechanistically, this HuR degradation pathway differs from that reported for heat shock and hypoxia, which underlies the complexity in the regulation of HuR turnover under different stress stimuli.  SIGNOR-276422 0.328 Gbeta proteinfamily SIGNOR-PF4 SIGNOR METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 BTO:0000007 33217317 t inferred from 70% family members miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. SIGNOR-270035 0.2 EFNA3 protein P52797 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9330863 t gcesareni The eph family of receptors. SIGNOR-52309 0.807 CREB5 protein Q02930 UNIPROT ATP6V0E1 protein O15342 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253801 0.2 PRKCA protein P17252 UNIPROT ARHGDIB protein P52566 UNIPROT down-regulates phosphorylation Ser31 YKPPPQKsLKELQEM 9606 22469974 t llicata These results reveal a mechanism of downregulation of rhogdi2 activity through pkc-mediated phosphorylation of ser31. SIGNOR-196765 0.2 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000938 24614225 t lperfetto Thus, serine 418 is phosphorylated in vivo. Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204688 0.524 BCOR protein Q6W2J9 UNIPROT RNF2 protein Q99496 UNIPROT up-regulates activity binding 9606 17296600 t miannu BcoR and Fbxl10/Jhdm1B are among the most abundant Ring1B/Rnf2 interactors identified with the highest confidence, and their association has been validated by coimmunoprecipitation studies; hence we call this the Fbxl10-BcoR complex. In summary, we have widened the set of multiprotein complexes containing the Polycomb group protein Ring1B/Rnf2. The new interactors contain protein motifs whose enzymatic activities and binding properties would expand the regulatory potential and gene target diversity of Ring1B/Rnf2 complexes in terms of recruitment to and modification of chromatin SIGNOR-252241 0.561 PRKCD protein Q05655 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates activity phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 18332134 t Manara In this report, we show that VEGF stimulates PKD-dependent phosphorylation of HDAC5 at Ser259/498residues in ECs, which leads to HDAC5 nuclear exclusion and myocyte enhancer factor-2 (MEF2) transcriptional activation. SIGNOR-260875 0.359 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser107 SQPPSPPsPAPSSFS 9606 20305697 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-164621 0.574 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1092 TFLPVPEyINQSVPK 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236479 0.2 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266478 0.8 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Ser281 NRRQLAFsTVGTPDY 9606 12493777 t lperfetto We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo SIGNOR-96679 0.2 cabozantinib chemical CHEBI:72317 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207845 0.8 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT up-regulates activity phosphorylation Ser243 SLKPGALsNSESIPT 9534 BTO:0000298 11483516 t llicata BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads. SIGNOR-250597 0.294 LAMB2 protein P55268 UNIPROT Laminin-9 complex SIGNOR-C180 SIGNOR form complex binding 10809728 t lperfetto Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. SIGNOR-253224 0.541 ABCA7 protein Q8IZY2 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 10090 14570867 f miannu Transfected ABCA7-GFP induced apolipoprotein-mediated assembly of cholesterol-containing HDL also in L929 cells, which otherwise generate only cholesterol-deficient HDL with their endogenous ABCA1. SIGNOR-265177 0.7 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 10090 18278053 f lperfetto Activated alphaIIbbeta3 integrins bind fibrinogen, vWF and fibronectin, thus allowing firm platelet adhesion and platelet aggregation. SIGNOR-266067 0.7 CSNK2A2 protein P19784 UNIPROT PTPN1 protein P18031 UNIPROT unknown phosphorylation -1 9600099 t llicata In this study, we demonstrate that HPTP1B are multiple phosphorylated on threonine and tyrosine as well as serine near its N-terminus by CKII and p60c-src in vitro. SIGNOR-251028 0.348 AURKB protein Q96GD4 UNIPROT MAPRE3 protein Q9UPY8 UNIPROT up-regulates phosphorylation Ser176 MQTSGRLsNVAPPCI 9606 23712260 t lperfetto Phosphorylation of eb3 at s176 by aurora b ensures successful cytokinesis completion by promoting midbody mt stability and midbody stabilization. SIGNOR-202130 0.484 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Asp) smallmolecule CHEBI:29186 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269483 0.8 STAT1 protein P42224 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 16628196 f miannu The activation of STAT1 by IFNs not only induces chemokine production, but also results in the expression of IRF-7 and TLR3, thus amplifying the dsRNA-provoked reaction in a positive-feedback manner during viral infection. SIGNOR-255231 0.495 regorafenib chemical CHEBI:68647 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition 9606 26254357 t miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF SIGNOR-259177 0.8 TIM23 complex complex SIGNOR-C423 SIGNOR Insertion into mitochondrial membrane phenotype SIGNOR-PH193 SIGNOR up-regulates 32074073 f lperfetto Mitochondrial precursor proteins with amino-terminal presequences are imported via the presequence pathway, utilizing the TIM23 complex for inner membrane translocation. Initially, the precursors pass the outer membrane through the TOM complex and are handed over to the TIM23 complex where they are sorted into the inner membrane or translocated into the matrix. SIGNOR-267709 0.7 CAMK2G protein Q13555 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser605 AGPTRQAsQAGPVPR 3118371 t llicata Sites 2 and 3 are serine residues phosphorylated by calcium/calmodulin-dependent protein kinase II. SIGNOR-250708 0.457 MMP20 protein O60882 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage Asn360 DFVDIPEnFFGVGGE -1 10922468 t lperfetto Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|In this study we investigated the ability of MMP-19 and MMP-20 to cleave two of the macromolecules characterising the cartilage ECM, namely aggrecan and the cartilage oligomeric matrix protein (COMP). Both MMPs hydrolysed aggrecan efficiently at the well-described MMP cleavage site between residues Asn(341) and Phe(342), as shown by Western blotting using neo-epitope antibodies. Furthermore, the two enzymes cleaved COMP in a distinctive manner, generating a major proteolytic product of 60 kDa. Our results suggest that MMP-19 may participate in the degradation of aggrecan and COMP in arthritic disease, whereas MMP-20, due to its unique expression pattern, may primarily be involved in the turnover of these molecules during tooth development. SIGNOR-266979 0.49 H3C1 protein P68431 UNIPROT Nucleosome_H2A.Z.2 variant complex SIGNOR-C323 SIGNOR form complex binding -1 24311584 t miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. SIGNOR-263711 0.2 CTNNB1 protein P35222 UNIPROT FOXA2 protein Q9Y261 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22945641 f gcesareni Our study indicates that beta-catenin regulates foxa2 expression, and this interaction is possibly essential to control cell cycle progression during endometrial hyperplasia formation SIGNOR-198929 0.455 WIPF1 protein O43516 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 19121306 f lperfetto However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin. SIGNOR-260609 0.7 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 21440011 t lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252858 0.908 STAT5A protein P42229 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates 9606 BTO:0004408 15353555 f miannu Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors. SIGNOR-256074 0.7 RFX complex complex SIGNOR-C104 SIGNOR HLA-DRA protein P01903 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 f The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-253998 0.424 BMI1 protein P35226 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24392140 t lperfetto In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, SIGNOR-253385 0.468 PRKACA protein P17612 UNIPROT PIM1 protein P11309 UNIPROT up-regulates activity phosphorylation Ser65 HSHSPRHsLRHSPGS 9606 30017192 t miannu In this study, we found that PKCα stabilized and activated PIM-1L by phosphorylation at Ser65. The PIM-1L phosphorylation suppressed sotrastaurin-induced apoptosis. These findings suggest that PKCα promotes cell survival and proliferation by upregulating PIM-1L in acute myeloid leukemia. SIGNOR-256153 0.269 BDKRB1 protein P46663 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256907 0.252 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269345 0.719 DIABLO protein Q9NR28 UNIPROT BIRC2 protein Q13490 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000891 10929712 t amattioni Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. ciap1 and ciap2 undergo autoubiquitination and degradation upon binding to the iap antagonist second mitochondrial activator of caspases (smac)/direct iap-binding protein with low pi (diablo), which is released from the mitochondria. SIGNOR-80222 0.891 LE-TGN SNARE complex SIGNOR-C157 SIGNOR M6PR protein P20645 UNIPROT up-regulates activity relocalization 9606 18195106 t lperfetto These findings place the retromer complex upstream of both STX10 function and the GCC185 tethering complex in MPR transport. Together, our data suggest that STX10, STX16, Vti1a, and VAMP3 are important for the trafficking of both CD- and CI-MPRs.|Thus, MPRs must pass through a compartment of pH ≤ 5.5 before returning to the Golgi to carry out their biological function. SIGNOR-253084 0.516 CAK complex complex SIGNOR-C456 SIGNOR RARG protein P13631 UNIPROT up-regulates activity phosphorylation Ser79 EMVPSSPsPPPPPRV 9534 BTO:0000298 10748061 t miannu Retinoic acid receptor gamma (RARgamma) is phosphorylated in COS-1 cells at two conserved serine residues located in the N-terminal region (serines 77 and 79 in RARgamma1 and serines 66 and 68 in RARgamma2) that contains the activation function AF-1. These serines are phosphorylated in vitro by cdk7, a cyclin-dependent kinase associated to cyclin H and MAT1 in the CAK complex (cdk7.cyclin H. MAT1), that is found either free or as a component of the transcription/DNA repair factor TFIIH.  SIGNOR-275968 0.394 CDR2 protein Q01850 UNIPROT MYC protein P01106 UNIPROT up-regulates activity binding 20383333 t lperfetto Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis. SIGNOR-252000 0.512 SIRT5 protein Q9NXA8 UNIPROT IDH2 protein P48735 UNIPROT up-regulates activity catalytic activity 9606 27113762 t Monia Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose-6-phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH-producing enzymes. SIGNOR-261212 0.419 IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 24710148 t milica The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-204841 0.663 Naltriben chemical CID:5486827 PUBCHEM OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258425 0.8 MED15 protein Q96RN5 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266660 0.793 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1735 SPTSPSYsPTSPSYS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248788 0.442 crizotinib chemical CHEBI:64310 ChEBI MET protein P08581 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258102 0.8 IFNB1 protein P01574 UNIPROT TYK2 protein P29597 UNIPROT up-regulates 9606 10918594 f gcesareni Early events in type i ifn signaling are tyrosine phosphorylation of the type i ifn receptor subunits (ifnar1 and ifnar2), and the activation of the receptor-associated tyk-2 and jak-1 janus kinases. SIGNOR-80103 0.535 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser61 PLSTPCSsVPSSPSF 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159462 0.259 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser156 KKPVRPVsRGCLHSH 9606 BTO:0002181 34363019 t miannu Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.  SIGNOR-276740 0.2 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR1B protein P47901 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257462 0.8 IKK-complex complex SIGNOR-C14 SIGNOR IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Ser68 LRDAIRQsNQILRER 9606 SIGNOR-C14 17977820 t lperfetto In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I SIGNOR-209788 0.929 VKORC1L1 protein Q8N0U8 UNIPROT vitamin K smallmolecule CHEBI:28384 ChEBI up-regulates quantity chemical modification 9606 31226734 t lperfetto The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form SIGNOR-265903 0.8 PTPRR protein Q15256 UNIPROT MAPK7 protein Q13164 UNIPROT down-regulates activity dephosphorylation Tyr221 HQYFMTEyVATRWYR 9534 12042304 t In this study we concentrated on whether and how PTP-SL, a kinase-interacting motif-containing PTP, might be involved in the down-regulation of the ERK5 signal|Whereas inactivation of ERK5 by PTP-SL monitored in vitro is most probably simply due to the dephosphorylation of tyrosine 220 in the activating TEY motif SIGNOR-248721 0.461 GATA1 protein P15976 UNIPROT CYBB protein P04839 UNIPROT up-regulates quantity transcriptional regulation 9606 10734088 t These results suggest that GATA-1 is an activator and that GATA-2 is a relative competitive inhibitor of GATA-1 in the expression of the gp91(phox) gene in human eosinophils. SIGNOR-259947 0.283 PAXIP1 protein Q6ZW49 UNIPROT PAX2 protein Q02962 UNIPROT up-regulates activity binding 10090 BTO:0000944 10908331 t miannu PTIP, a novel BRCT domain-containing protein interacts with Pax2 and is associated with active chromatin. The degree of interaction with the Pax2 C-terminal polypeptides correlates with their transcription transactivation potential and we have therefore designated this factor PTIP for Pax transactivation-domain interacting protein. SIGNOR-236965 0.588 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1C protein P49918 UNIPROT down-regulates phosphorylation Thr310 GVGSVEQtPRKRLR 9606 BTO:0000150 23421998 t lperfetto Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination SIGNOR-201046 0.2 PTH protein P01270 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17656568 f miannu Parathyroid hormone (PTH) functions as an essential regulator of calcium homeostasis and as a mediator of bone remodeling. We have already shown that PTH stimulates the expression of matrix metalloproteinase-13 (MMP-13), which is responsible for degrading components of extracellular matrix. SIGNOR-254234 0.458 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2J1 protein Q9Y385 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271342 0.571 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 10090 BTO:0000944 15060146 t miannu Leukemia-related transcription factor TEL is negatively regulated through extracellular signal-regulated kinase-induced phosphorylation. Overexpressed TEL becomes phosphorylated in vivo by activated ERK. TEL is also directly phosphorylated in vitro by ERK. The inducible phosphorylation sites are Ser(213) and Ser(257). SIGNOR-260084 0.2 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity precursor of 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267417 0.8 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr317 PTQRMTItEFMNHPW -1 7592979 t miannu In Vitro Activation of MAPKAP Kinase 2 by p38/40. the constitutively active mutant T205E,T317E shows no changes in activity after treatment with the p38/40 fraction SIGNOR-250102 0.76 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270404 0.8 TRAF6 protein Q9Y4K3 UNIPROT TNFRSF11A protein Q9Y6Q6 UNIPROT up-regulates activity binding 9606 10075662 t miannu TRAF6 interacts with a novel motif located between residues 340 and 358 of RANK. TRAF6-binding region (340-358), but not the TRAF2 or TRAF5-binding region, is necessary and sufficient for RANK-induced NF-kappaB activation. SIGNOR-253045 0.718 CDK8 protein P49336 UNIPROT CCNH protein P51946 UNIPROT down-regulates phosphorylation Ser304 YEDDDYVsKKSKHEE 9606 10993082 t lperfetto Cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity SIGNOR-82033 0.665 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR EGR1 protein P18146 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 21983014 f In conclusion we demonstrated that treatment of HeLa cells with DMC leads to an enhanced formation of a complex consisting of NF-κB and HDAC1 that binds to the EGR1 promoter resulting in downregulation of EGR1 expression which plays a major role for transcriptional inhibition of mGPES-1 expression. SIGNOR-254258 0.406 PRKACA protein P17612 UNIPROT LCP1 protein P13796 UNIPROT up-regulates phosphorylation Ser5 sVSDEEMM 9606 BTO:0000007 16636079 t gcesareni Phosphorylation on ser5 increases the f-actin-binding activity of l-plastin and promotes its targeting to sites of actin assembly in cells. L-plastin phosphorylation require protein kinase a. SIGNOR-146287 0.332 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Ser430 DTLTPPPsDAGSPFQ 9606 BTO:0000567 16825193 t lperfetto The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding SIGNOR-236645 0.498 PRKAA1 protein Q13131 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Ser539 SLFNVSPsCSSFNSP 10090 BTO:0001103 SIGNOR-C15 17609368 t lperfetto AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter SIGNOR-228654 0.561 calcium(2+) smallmolecule CHEBI:29108 ChEBI PPP3CA protein Q08209 UNIPROT up-regulates chemical activation 9606 21880741 t gcesareni Except for nfat5, nfatc1c4 are activated upon a rise in intracellular ca2+, which stimulates the serine/threonine phosphatase activity of calcineurin the ca2+-calcineurin signal is the most important signal for regulating nfat activation, but the signal that leads to ca2+ influx during neural tube differentiation is still unclear. SIGNOR-176367 0.8 MAPKAPK2 protein P49137 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Ser326 LTIPPRFsIAPSSLD 9606 18695677 t llicata Here, we have identified mk2 as a major plk1 kinase toward ser326, whose phosphorylation is critical to recruit ?-Tubulin to centrosomes and subsequent establishment of functional bipolar spindles. To our knowledge, this is the first direct evidence to demonstrate that the essential function of plk1 in centrosome maturation and bipolar spindle formation is controlled by its upstream kinase. SIGNOR-179968 0.356 ARHGEF1 protein Q92888 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260528 0.825 LRRC4 protein Q9HBW1 UNIPROT CDK2 protein P24941 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000142 25526788 f miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. SIGNOR-264058 0.354 RET protein P07949 UNIPROT GFRA1 protein P56159 UNIPROT up-regulates binding 9606 10829012 t gcesareni Gdnfr-alpha-ligand complex, together with the tyrosine kinase receptor (cret) forms a functional receptor that activates downstream signal transduction pathways SIGNOR-77587 0.745 TLX1 protein P31314 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity binding 9606 BTO:0002504 22516263 t irozzo We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement. SIGNOR-259097 0.479 ULK1 protein O75385 UNIPROT ATG9A protein Q7Z3C6 UNIPROT up-regulates activity phosphorylation Ser14 EYQRLEAsYSDSPPG 9606 27934868 t miannu Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation. SIGNOR-266369 0.599 PYHIN1 protein Q6K0P9 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001570 16479015 t miannu Here, we show that IFIXalpha1 downregulates HDM2, a principal negative regulator of p53, at the posttranslational level. IFIXalpha1 destabilizes HDM2 protein and promotes its ubiquitination. The E3 ligase activity of HDM2 appears to be required for this IFIXalpha1 effect. Importantly, HDM2 downregulation is required for the IFIXalpha1-mediated increase of p53 protein levels, transcriptional activity, and nuclear localization, suggesting that IFIXalpha1 positively regulates p53 by acting as a negative regulator of HDM2. SIGNOR-268493 0.423 NMDA receptor_2B complex SIGNOR-C348 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor SIGNOR-264223 0.8 SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 11154281 t lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. SIGNOR-249134 0.787 AURKB protein Q96GD4 UNIPROT DIAPH2 protein O60879 UNIPROT up-regulates phosphorylation Ser196 SLTSNPVsWVNNFGH 9606 21397845 t lperfetto The microtubule binding fh2 domain of mdia3 is phosphorylated by aurora b kinase in vitro, and cells expressing the nonphosphorylatable mdia3 mutant cannot position chromosomes at the metaphase plate SIGNOR-172803 0.292 PPP2CA protein P67775 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation Thr202 HDHTGFLtEYVATRW 9606 phosphorylation:Thr202 HDHTGFLtEYVATRW 16456541 t gcesareni B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk SIGNOR-144322 0.633 RAB8A protein P61006 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 18694559 f miannu CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110 SIGNOR-252148 0.7 Sin3B_complex complex SIGNOR-C409 SIGNOR H3Y2 protein P0DPK5 UNIPROT down-regulates activity binding 9606 21041488 t miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. SIGNOR-266976 0.2 RELA protein Q04206 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates binding 9606 SIGNOR-C6 10207072 t gcesareni Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo. SIGNOR-66953 0.874 ARHGAP22 protein Q7Z5H3 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260478 0.523 IKK-complex complex SIGNOR-C14 SIGNOR NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2407 AKVSGRPsSRKAKSP 9606 15494311 t Translocation from Nucleus to Cytoplasm lperfetto Nf-kappab transcription requires ikkalpha to phosphorylate smrt on chromatin, stimulating the exchange of corepressor for coactivator complexes. Ikk directly phosphorylates smrt to stimulate nuclear export. Ikkalpha orchestrates smrt derepression, a prerequisite for nf-kappab transcription and survival. SIGNOR-216393 0.419 INS protein P01308 UNIPROT LPL protein P06858 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001487 21966368 f Regulation miannu Insulin has a major effect on LPL regulation in adipose tissue since in mature adipocytes insulin not only increases the level of LPL mRNA but also regulates LPL activity through both posttranscriptional and posttranslational mechanisms SIGNOR-251857 0.476 N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI up-regulates quantity precursor of 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-268091 0.8 POLR3K protein Q9Y2Y1 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266135 0.819 CDK1 protein P06493 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser160 PVRLLGHsPVLRNIT 9606 SIGNOR-C17 12107172 t lperfetto We demonstrate that serine 146 is required for two crucial features of cdc25b1. It is essential for cdc25b1 to function as a mitotic inducer and to prevent cdc25b1 export from the nucleus. We also show that serine 146 is phosphorylated in vitro by cdk1-cyclin b. Serine 146 phosphorylation is proposed to be a key event in the regulation of the cdc25b function SIGNOR-90451 0.823 KRAS protein P01116 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 10882715 t gcesareni Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2. the raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade. SIGNOR-78911 0.841 CENPT protein Q96BT3 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265204 0.718 SH3PXD2B protein A1X283 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates activity binding 9606 BTO:0000007 20943948 t lperfetto Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation SIGNOR-264707 0.354 pimozide chemical CHEBI:8212 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258719 0.8 ATR protein Q13535 UNIPROT WDHD1 protein O75717 UNIPROT up-regulates activity phosphorylation Thr826 KAAELTAtQVEEEEE 9606 BTO:0001109 26082189 t miannu And-1 is phosphorylated at T826 by ATR following replication stress, and this phosphorylation is required for And-1 to accumulate at the damage sites, where And-1 promotes the interaction between Claspin and Chk1, thereby stimulating efficient Chk1 activation by ATR. SIGNOR-262664 0.554 TTK protein P33981 UNIPROT MAP4 protein P27816 UNIPROT down-regulates quantity by destabilization phosphorylation Thr927 LSRLATNtSAPDLKN 9606 BTO:0000567 31253867 t miannu We further uncovered that Mps1 is a kinase of MAP4, and E7-MAP4 binding blocks Mps1 phosphorylation of MAP4, thereby interrupting phosphorylation-dependent MAP4 degradation.  SIGNOR-277462 0.2 PTK6 protein Q13882 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr699 TAKAVDGyVKPQIKQ 9606 BTO:0000150 17997837 t llicata Phosphospecific antibodies, mutational analysis, and in vitro kinase assays demonstrated that brk specifically mediated stat5b phosphorylation at the activating tyrosine, y699. SIGNOR-159066 0.44 SERPINE1 protein P05121 UNIPROT Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 10368279 f gcesareni Pai-1 is now being identified as a key player in the link between coagulation and the cell adhesion pathways involved in tissue remodeling and metastasis. Active pai-1 (but not its latent or cleaved forms) binds tightly to the adhesive glycoprotein vitronectin in the extracellular matrix. SIGNOR-68478 0.7 ITGAL protein P20701 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates binding 9606 BTO:0000130 23994464 t apalma This leads to further neutrophil-endothelial cell interactions through the binding of LFA-1 to its endothelial counterreceptor ICAM-1 during the slow rolling phase SIGNOR-255040 0.92 NF2 protein P35240 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity binding 10090 BTO:0003324 27402866 t Hippo pathway Gianni NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart. SIGNOR-269948 0.421 PDPK1 protein O15530 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-126066 0.392 SREBF2 protein Q12772 UNIPROT PON2 protein Q15165 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19497963 f miannu UPA upregulated PON2 expression in a sterol regulatory binding protein-2 (SREBP-2)-dependent manner, since blocking SREBP-2 maturation by 4-(2-aminoethyl)-benzenesulfonyl fluoride abolished uPA-stimulation of PON2, whereas inhibition of SREBP-2 catabolism by N-acetyl-leucyl-norleucinal had an opposite effect. SIGNOR-255225 0.279 Macrophage_activation phenotype SIGNOR-PH126 SIGNOR CCL2 protein P13500 UNIPROT up-regulates quantity 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260962 0.7 IC-87114 chemical CHEBI:90686 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206193 0.8 CAMK2A protein Q9UQM7 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization phosphorylation Ser89 KQKQPSFsAKKMTEK 9606 BTO:0000567 24781523 t miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase SIGNOR-276383 0.314 FZD2 protein Q14332 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 23151663 t areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  SIGNOR-258956 0.653 SNAI2 protein O43623 UNIPROT CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 20509143 f miannu SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness. SIGNOR-255153 0.418 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252832 0.908 UBE3A protein Q05086 UNIPROT LAMTOR1 protein Q6IAA8 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 30020076 t Ube3a regulates mTORC1 signaling by targeting p18, a subunit of the Ragulator. Ube3a ubiquinates p18, resulting in its proteasomal degradation, and Ube3a deficiency in the hippocampus of AS mice induces increased lysosomal localization of p18 and other members of the Ragulator-Rag complex, and increased mTORC1 activity SIGNOR-256145 0.2 STRN protein O43815 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates activity binding 10090 BTO:0000938 29802198 t miannu The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms SIGNOR-261700 0.612 DLGAP4 protein Q9Y2H0 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 9115257 t miannu SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area. SIGNOR-264212 0.795 SUFU protein Q9UMX1 UNIPROT GLI3 protein P10071 UNIPROT down-regulates relocalization 9606 BTO:0001130;BTO:0000848;BTO:0000527 10564661 t gcesareni Su(fu) is a negative regulator of shh that interacts with all three gli proteins to retain them in the cytosol. SIGNOR-72308 0.885 PRKCA protein P17252 UNIPROT KCNE1 protein P15382 UNIPROT down-regulates activity phosphorylation Ser102 VQARVLEsYRSCYVV -1 1553557 t lperfetto Inhibition of the current was not seen in channels in which Ser103 was replaced by Ala, although other properties of the current were unchanged. These results indicate that inhibition of the potassium current results from direct phosphorylation of the channel subunit protein at Ser103. SIGNOR-248852 0.312 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser335 YDSFGEPsYPEVFEP -1 9558331 t llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. SIGNOR-250935 0.312 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CEP76 protein Q8TAP6 UNIPROT down-regulates activity phosphorylation Ser83 VEQELPSsPKQPICF 9606 BTO:0000007 27065328 t miannu Cep76 is phosphorylated by cyclin A/CDK2 at a single site S83. These data suggest that the phosphomimetic mutant is functional and that phosphorylation at S83 is critical for Cep76 to suppress centriole amplification. SIGNOR-262603 0.304 AR protein P10275 UNIPROT SEPTIN7 protein Q16181 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 16281084 f After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. SIGNOR-253677 0.2 NLRC4 protein Q9NPP4 UNIPROT NLRC4 inflammasome complex SIGNOR-C223 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256404 0.743 PPP1CA protein P62136 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity dephosphorylation Ser8 MTTEQRRsLQAFQDY 9606 BTO:0000007 23499489 t lperfetto We identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.|endogenous RIG-I and MDA5 that interacted with PP1 exhibited markedly decreased phosphorylation levels at S8 and S88, respectively  SIGNOR-264581 0.2 CREBL2 protein O60519 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 21728997 f Luana Accordingly, the results of QPCR and immunoblot analysis showed that during adipogenesis, both the mRNA (Figures 4D and 4E) and protein (Figure 4F) levels of PPARγ , as well as C/EBPα, in 3T3-L1 preadipocytes transfected with either siCREBL2-1 or siCREBL2-2 were significantly decreased compared with the control (P < 0.05), suggesting that knockdown of CREBL2 protein suppress 3T3-L1 preadipocyte differentiation via inhibition of PPARγ and C/EBPα expression. SIGNOR-261574 0.2 RPA2 protein P15927 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates binding 9606 20068082 t gcesareni Ssdna lesions are then coated by replication protein a (rpa), recruiting atr/atrip (atr-interacting protein) complexes via recognition and association of rpa-ssdna by atrip. SIGNOR-163176 0.673 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR LATS2 protein Q9NRM7 UNIPROT down-regulates 9606 23450633 f gcesareni Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism. SIGNOR-192783 0.7 SMO protein Q99835 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation 9606 18455992 t gcesareni Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion. SIGNOR-178610 0.415 PRKCA protein P17252 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 t gcesareni Receptor internalization, altered;intracellular localization SIGNOR-97554 0.551 DUSP26 protein Q9BV47 UNIPROT FADD protein Q13158 UNIPROT down-regulates activity dephosphorylation Ser194 QNRSGAMsPMSWNSD 9606 24548998 t lperfetto This multi-functionality of fadd may depend primarily on its subcellular location. Fadd shuttles between the cytosol and the nucleus and this signal is unclear;however, fadd trafficking requires phosphorylation of the protein on ser194dusp26 suppresses cell proliferation by fadd dephosphorylation SIGNOR-204559 0.374 PCDH19 protein Q8TAB3 UNIPROT GABRA2 protein P47869 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C331 29360992 t miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  SIGNOR-267218 0.2 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000567 17615152 t gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-156860 0.692 P2RY10 protein O00398 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257348 0.2 FBXW5 protein Q969U6 UNIPROT SEC23B protein Q15437 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 30596474 t lperfetto SCFFBXW5 interacts with SEC23B and targets it for ubiquitylation and proteasome-mediated degradation. SIGNOR-265286 0.2 SATB1 protein Q01826 UNIPROT HSPA6 protein P17066 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000664 17343824 f miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. SIGNOR-255134 0.2 NFIX protein Q14938 UNIPROT RBFOX3 protein A6NFN3 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268913 0.2 PRKACA protein P17612 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 30017192 t miannu In this study, we found that PKCα stabilized and activated PIM-1L by phosphorylation at Ser65. The PIM-1L phosphorylation suppressed sotrastaurin-induced apoptosis. These findings suggest that PKCα promotes cell survival and proliferation by upregulating PIM-1L in acute myeloid leukemia. SIGNOR-259413 0.269 PRKCB protein P05771 UNIPROT LMNB1 protein P20700 UNIPROT unknown phosphorylation Ser405 VTVSRASsSRSVRTT 9606 BTO:0001271 8034666 t lperfetto Beta II PKC-mediated phosphorylation of lamin B is confined to two sites, Ser395 and Ser405 | Comparative tryptic phosphopeptide mapping demonstrates that the beta II PKC site, Ser405, is a prominent target of mitotic lamin B phosphorylation in vivo. beta II PKC translocates to the nucleus during the G2/M phase of cell cycle concomitant with phosphorylation of Ser405, indicating a physiologic role for nuclear beta II PKC activation in mitotic lamin B phosphorylation in vivo. SIGNOR-248912 0.477 PTPRF protein P10586 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 27225731 f miannu LAR (for leukocyte common antigen-related) is a family of receptor protein tyrosine phosphatases (LAR-RPTPs) with three known members: LAR/PTPRF, PTPδ/PTPRD, and PTPσ/PTPRS. In mammals, LAR-RPTPs have been shown to regulate dendrite and excitatory synapse development and maintenance SIGNOR-264090 0.7 CASP9 protein P55211 UNIPROT Caspase 9 complex complex SIGNOR-C229 SIGNOR form complex binding 29500231 t lperfetto The caspase-9 CARD has been thought to be principally involved in recruitment to the apoptosome, but its roles outside this interaction have yet to be uncovered. In this work, we show that the CARD is involved in physical interactions with the catalytic core of caspase-9 in the absence of the apoptosome; this interaction requires a properly formed caspase-9 active site.  SIGNOR-256397 0.2 trimipramine chemical CHEBI:9738 ChEBI SLC6A3 protein Q01959 UNIPROT down-regulates activity chemical inhibition 9606 9537821 t miannu At the human dopamine transporter, sertraline and nomifensine were the most potent with KD's of 25±2 and 56±3, respectively. Except for these two compounds, most antidepressants were not potent at the human dopamine transporter. SIGNOR-258740 0.8 PHLPP2 protein Q6ZVD8 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 BTO:0001544 19261608 t The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. SIGNOR-248731 0.67 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58475 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267323 0.8 DVL1 protein O14640 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 15735151 t amattioni Activated DVL binds and inhibits the phosphorylation of beta-catenin by GSK3B, blocking beta-catenin degradation so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1. SIGNOR-134285 0.799 IGF1R protein P08069 UNIPROT CSK protein P41240 UNIPROT up-regulates 9606 10026153 f lperfetto The results suggest that c-src and csk are involved in igf-ir and ir signaling and that the interaction of csk with the igf-ir may play a role in the decrease in c-src activity following igf-i stimulation SIGNOR-64676 0.353 EP300 protein Q09472 UNIPROT SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR form complex binding 9606 26194464 t MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. SIGNOR-255025 0.674 CHRM3 protein P20309 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256882 0.2 UBE2I protein P63279 UNIPROT ZHX1 protein Q9UKY1 UNIPROT up-regulates quantity by stabilization sumoylation Lys454 VPTSQSVkHETALVN 9606 BTO:0000007 23686912 t miannu Here, we report that the SUMO-E2 conjugating enzyme Ubc9 was identified to interact with ZHX1 by an interaction screen using a yeast two-hybrid system. This interaction was confirmed by co-immunoprecipitation and co-localization assays. Further study showed that ZHX1 is SUMOylated by Ubc9 with SUMO1 at the sites K159, K454, and K626. Furthermore, we demonstrated that the SUMOylation of ZHX1 regulated the stability, ubiquitination and transcriptional activity of ZHX1. The sumoylation of zinc‐fingers and homeoboxes 1 (ZHX1) by ubc9 regulates its stability and transcriptional repression activity. However, in the current work, we demonstrated that ZHX1 was only SUMOylated by SUMO1. SIGNOR-263900 0.464 STK11 protein Q15831 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity phosphorylation Ser615 GEKNERTsVAGTVRK 9606 BTO:0002181 34216621 t miannu  Resveratrol promotes the binding between LKB1 and Sirt1, which we first reported, and this binding leads to LKB1-mediated phosphorylation of Sirt1 at three different serine residues in the C terminus of Sirt1. Mechanistically, LKB1-mediated phosphorylation increases intramolecular interactions in Sirt1, such as the binding of the C terminus to the deacetylase core domain, thereby eliminating DBC1 (Deleted in Breast Cancer 1, Sirt1 endogenous inhibitor) inhibition and promoting Sirt1-substrate interaction.  SIGNOR-277322 0.59 MAPK3 protein P27361 UNIPROT SOX9 protein P48436 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20457810 f fspada Soluble pref-1 inhibits adipocyte differentiation through the activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (erk/mapk) and the subsequent upregulation of sox9 expression. SIGNOR-165353 0.39 P2RY11 protein Q96G91 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256931 0.2 PLAG1 protein Q6DJT9 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 11888928 f miannu Plagl1 has been shown to prevent the proliferation of tumor cells by inducing cell cycle arrest and apoptosis SIGNOR-256658 0.7 TNF protein P01375 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 11287630 f lperfetto Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase SIGNOR-244458 0.494 NEK9 protein Q8TD19 UNIPROT NEK7 protein Q8TDX7 UNIPROT up-regulates activity phosphorylation Ser195 SKTTAAHsLVGTPYY 9606 BTO:0000007 12840024 t lperfetto Nercc1 catalyzes the phosphorylation of nek6 (ser206) and the equivalent site on nek7 (ser195), resulting in a 20-25-fold activation of nek6/7 kinase activity SIGNOR-103030 0.703 FABP2 protein P12104 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264456 0.7 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser492 MTLTKSRsFTSSYAI 9606 19261611 t llicata Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding. SIGNOR-184464 0.2 AKT1 protein P31749 UNIPROT MAP3K8 protein P41279 UNIPROT up-regulates activity phosphorylation Ser413 LERKRLLsRKELELP 9606 BTO:0000007 12138205 t Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator. SIGNOR-252572 0.539 citrate(3-) smallmolecule CHEBI:16947 ChEBI ACACA protein Q13085 UNIPROT up-regulates activity binding 9606 6138356 t miannu Citrate, an allosteric activator of acetyl-CoA carboxylase, induces polymerization of an inactive protomeric form of the enzyme into an active filamentous form composed of 10-20 protomers.  SIGNOR-267104 0.8 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Ser193 AEVDPDMsWSSSLAT 9606 BTO:0001938 12815053 t lperfetto Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation. SIGNOR-249217 0.555 ABL1 protein P00519 UNIPROT LASP1 protein Q14847 UNIPROT up-regulates phosphorylation Tyr171 IPTSAPVyQQPQQQP 9606 BTO:0000150 15138294 t llicata C-abl activation by apoptotic agents specifically promotes phosphorylation of lasp-1 at tyrosine 171, which is associated with the loss of lasp-1 localization to focal adhesions and induction of cell death. Thus, lasp-1 is a dynamic focal adhesion protein necessary for cell migration and survival in response to growth factors and ecm proteins. SIGNOR-124719 0.35 ZNF224 protein Q9NZL3 UNIPROT ALDOA protein P04075 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17900823 f miannu We previously reported that ZNF224, a novel Krüppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor. SIGNOR-255627 0.503 IMPDH2 protein P12268 UNIPROT 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI up-regulates quantity chemical modification 9606 19480389 t miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). SIGNOR-267335 0.8 GATA6 protein Q92908 UNIPROT SEMA3C protein Q99985 UNIPROT up-regulates quantity by expression transcriptional regulation 19666519 f lperfetto Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes. SIGNOR-253150 0.407 PPP1CA protein P62136 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser75 LGYEPEGsASPTPPY 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248551 0.339 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MYOG protein P15173 UNIPROT down-regulates binding 9606 21902831 t lperfetto In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-216972 0.345 SGK1 protein O00141 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates phosphorylation Ser227 QQRRRITsVQPPTGL 9606 BTO:0001271 21147854 t lperfetto Here, we report that the serum- and glucocorticoid-inducible protein kinase sgk1 remarkably reduced the protein stability of the active form of notch1 through fbw7activated sgk1 phosphorylated fbw7 at serine 227 SIGNOR-170404 0.295 OXTR protein P30559 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 30739093 t miannu OT binds to its cognate G protein–coupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi), and activation of phospholipase C (Gq). SIGNOR-270330 0.429 PTPN1 protein P18031 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 24590766 t miannu Here, we show that PTP1B regulates CD40 and BAFF-R signaling and dephosphorylates the mitogen-activated protein kinase p38.|Specifically, PTP1B counteracts p38 mitogen-activated protein kinase activation by directly dephosphorylating Tyr182 of this kinase. SIGNOR-277167 0.454 PIM1 protein P11309 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 16403219 t miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. SIGNOR-250392 0.379 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Thr218 TAANSRDtIFQKERF 9606 19366211 t llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. SIGNOR-185303 0.2 TXK protein P42681 UNIPROT CTLA4 protein P16410 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 9813138 t lperfetto We demonstrate that rlk (resting lymphocyte kinase) is capable of phosphorylating ctla-4 at the yvkm motif. Consistent with this finding, rlk is capable of providing conditions for the binding of the sh2 domains of pi 3-kinase to the receptor. Ctla-4 is therefore the first known substrate for rlk suggesting the possibility that this kinase may participate in ctla-4 function SIGNOR-61624 0.512 BTK protein Q06187 UNIPROT TEC protein P42680 UNIPROT up-regulates phosphorylation Tyr206 RLERGQEyLILEKND 9606 12573241 t lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated SIGNOR-98086 0.474 PRKCB protein P05771 UNIPROT EIF6 protein P56537 UNIPROT down-regulates activity phosphorylation Ser235 QPSTIATsMRDSLID 9606 14654845 t lperfetto Our results show that release of eIF6 from 60S subunits may operate, in mammalian cells, through a RACK1–PKC betaII pathway. |Loading 60S subunits with eIF6 caused a dose-dependent translational block and impairment of 80S formation, which were reversed by expression of RACK1 and stimulation of PKC in vivo and in vitro. PKC stimulation led to eIF6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eIF6 impaired RACK1/PKC-mediated translational rescue. |S235A eIF6 inhibits ribosomal joining in the presence of RACK1–PKCbetaII SIGNOR-249245 0.312 KDM6A protein O15550 UNIPROT HOXC8 protein P31273 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260029 0.312 RPS6KB1 protein P23443 UNIPROT MRE11 protein P49959 UNIPROT down-regulates quantity by destabilization phosphorylation Thr597 SQRGRADtGLETSTR -1 28967905 t miannu MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro. SIGNOR-265944 0.2 PPP2CB protein P62714 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity dephosphorylation Thr68 SSLETVStQELYSIP 9606 16596250 t Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation. SIGNOR-248582 0.314 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1B protein P35368 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257451 0.8 LATS2 protein Q9NRM7 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 21808241 t Together the YAP/TAZ-TEAD complex promotes proliferative and survival programs. gcesareni Activated lats1/2 in turn phosphorylate and inhibit yap/taz transcription co-activators SIGNOR-175787 0.686 NRXN1 protein P58400 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626543 t miannu The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites SIGNOR-265453 0.819 PPP2CA protein P67775 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity dephosphorylation Thr32 QSRPRSCtWPLQRPE 9606 20110348 t gcesareni Pp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a. SIGNOR-163688 0.412 ketanserin chemical CHEBI:6123 ChEBI SLC18A2 protein Q05940 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000318 8643547 t miannu Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2. SIGNOR-258494 0.8 CSNK2A1 protein P68400 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates phosphorylation Ser394 EDAVHEDsGDEDGED 9606 12082111 t gcesareni Protein kinase ck2-mediated phosphorylation of hdac2 regulates co-repressor formation, deacetylase activity and acetylation of hdac2 by cigarette smoke and aldehydesstudies using unfractionated cell extracts with ck2 inhibitors suggest that protein kinase ck2 is the major source of hdac2 kinase. Finally, and perhaps most interesting, hdac2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. Together, our data indicate that like many hdacs, hdac2 is regulated by post-translational modification, particularly phosphorylation. SIGNOR-89937 0.61 STARD8 protein Q92502 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260519 0.538 KLF4 protein O43474 UNIPROT SOD1 protein P00441 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002104 23370975 f miannu The expression of superoxide dismutase (SOD) 1 in both mRNA and protein levels was found to be decreased by overexpressing KLF4, while increased by knockdown of KLF4 SIGNOR-254545 0.295 LCK protein P06239 UNIPROT MUC1 protein P15941 UNIPROT up-regulates activity phosphorylation Tyr1229 SSTDRSPyEKVSAGN BTO:0000661 14766232 t lperfetto The present results demonstrate that Lck phosphorylation of MUC1 on Y-46 also increases binding of MUC1 and beta-catenin. The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 and beta-catenin SIGNOR-249358 0.472 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates activity phosphorylation Ser633 GISQCGYsSTIVHVP 9534 BTO:0000298 11865049 t llicata The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly.  SIGNOR-250818 0.734 LYN protein P07948 UNIPROT NMT1 protein P30419 UNIPROT unknown phosphorylation Tyr180 YTLLNENyVEDDDNM -1 11594778 t Human NMT was found to be phosphorylated by non-receptor tyrosine kinase family members of Lyn. a site-directed mutagenesis study indicated that substitution of tyrosine 100 with phenylalanine served NMT as a poor substrate for the Lyn kinase. SIGNOR-251404 0.354 SMURF1 protein Q9HCE7 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity ubiquitination 9606 17317136 t lperfetto Recruitment of WW and HECT domain E3-ubiquitin ligases Smurf1 and 2 to induce type I receptor ubiquitination and subsequent receptor degradation; SIGNOR-153414 0.681 TGFB1 protein P01137 UNIPROT TSHB protein P01222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14623893 t miannu TGF-β inhibits thyroid-stimulated hormone (TSH)-induced NIS mRNA and protein levels in a dose-dependent manner. This effect takes place at the transcriptional level, as TGF-β inhibits TSH-induced transcription SIGNOR-251991 0.2 ELOVL1 protein Q9BW60 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267889 0.8 CH5132799 chemical CID:49784945 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190946 0.8 1,2-diacyl-sn-glycero-3-phosphocholine chemical CHEBI:57643 ChEBI 1-O-acyl-sn-glycero-3-phosphocholine chemical CHEBI:58168 ChEBI up-regulates quantity precursor of 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272768 0.8 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270412 0.8 USP16 protein Q9Y5T5 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR down-regulates activity deubiquitination 9606 17914355 t miannu  Here we report the identification and functional characterization of the major deubiquitinase for histone H2A, Ubp-M (also called USP16). Ubp-M prefers nucleosomal substrates in vitro, and specifically deubiquitinates histone H2A but not H2B in vitro and in vivo.  This study identifies the major deubiquitinase for histone H2A and demonstrates that H2A deubiquitination is critically involved in cell cycle progression and gene expression. SIGNOR-277348 0.2 RCAN1 protein P53805 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR down-regulates activity binding 9606 12554096 t MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure SIGNOR-252341 0.623 MRPS18C protein Q9Y3D5 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261450 0.689 Oxytocin protein P01178-PRO_0000020495 UNIPROT OXTR protein P30559 UNIPROT up-regulates binding 9606 1313946 t gcesareni The oxytocin receptor, expressed in xenopus oocytes, specifically responds to oxytocin and induces an inward membrane current SIGNOR-16758 0.2 ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity relocalization 9606 9865696 t lperfetto We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor by controlling the subcellular localization of Smad2 and by interacting with the TGFbeta receptor complex. SIGNOR-232126 0.856 MYBL2 protein P10244 UNIPROT CLU protein P10909 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0000298 10770937 t miannu Here we show that the human ApoJ/Clusterin gene contains a Myb binding site in its 5' flanking region, which interacts with bacterially synthesized B-MYB protein and mediates B-MYB-dependent transactivation of the ApoJ/Clusterin promoter in transient transfection assays. Endogenous ApoJ/Clusterin expression is induced in mammalian cell lines following transient transfection of a B-MYB cDNA. SIGNOR-269800 0.278 CDK2 protein P24941 UNIPROT ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr226 SAPVGKEtPSKRMKR 9606 SIGNOR-C83 11931757 t lperfetto We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability. SIGNOR-116476 0.745 ABL1 protein P00519 UNIPROT SRCIN1 protein Q9C0H9 UNIPROT unknown phosphorylation Tyr396 LVKGEGLyADPYGLL 9606 BTO:0000142 23383002 t llicata Mapping of p140cap phosphorylation sites: the eplya and eglya motifs have a key role in tyrosine phosphorylation and csk binding, and are substrates of the abl kinase SIGNOR-200858 0.2 NLK protein Q9UBE8 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation Thr155 SHAVHPLtPLITYSD 9606 12556497 t gcesareni Regulation of lymphoid enhancer factor 1/t-cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in wnt/beta-catenin signaling.Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk. SIGNOR-97812 0.751 MECP2 protein P51608 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 25420914 t Luana As the first step to reveal how MeCP2 phosphorylation may regulate Notch signaling, we conducted chromatin immunoprecipitation (ChIP) experiment to determine whether the phosphor-mutant MeCP2 protein has altered promoter occupancy at the promoters of Dll1 and Notch1. We found increased binding of the phosphor-mutant protein at the promoters of both Dll1 and Notch1  SIGNOR-264675 0.294 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ID2 protein Q02363 UNIPROT down-regulates phosphorylation Ser5 sPVRSVRK 9606 9029153 t lperfetto Id2 acts by forming heterodimers that are unable to bind to specific (e-box) dna sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (cdks). In vitro, id2 can be phosphorylated by either cyclin e-cdk2 or cyclin a-cdk2_ SIGNOR-217320 0.37 PLK3 protein Q9H4B4 UNIPROT CDC25C protein P30307 UNIPROT unknown phosphorylation Ser216 SGLYRSPsMPENLNR -1 10557092 t lperfetto The physical association and phosphorylation of Cdc25C protein phosphatase by Prk. | Further studies reveal that His6-Prk phosphorylates Cdc25C on serine216, a residue also phosphorylated by Chk1 and Chk2. Together, these observations strongly suggest that Prk's role in mitosis is at least partly mediated through direct regulation of Cdc25C. SIGNOR-249030 0.72 teniposide chemical CHEBI:75988 ChEBI TOP2B protein Q02880 UNIPROT down-regulates activity chemical inhibition 9606 1329225 t miannu Recognition of transient DNA breaks induced by teniposide, etoposide, and other podophyllotoxin analogues established not only that their site of activity was DNA but also that their cytotoxic effect was dose-dependent. Extensive investigation has further indicated that a primary mechanism of action of these agents involves inhibition of the catalytic activity of eukaryote topoisomerase II and, more important, the consequent stabilization of the normally transient covalent intermediate formed between the DNA substrate and the enzyme. SIGNOR-259330 0.8 TNF protein P01375 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 9606 8530143 f andrea cerquone perpetuini Data from our laboratory demonstrate that the TNF signal transduction pathway-mediating NF-kappa B activation involves two phospholipases, a phosphatidylcholine-specific phospholipase C (PC-PLC) and an endosomal acidic sphingomyelinase (aSMase). The aSMase activation by TNF is secondary to the generation of 1,2-diacylglycerol (DAG) produced by a TNF-responsive PC-PLC. SMase and its product ceramide induce degradation of the NF-kappa B inhibitor I kappa B as well as NF-kappa B activation. SIGNOR-255689 0.666 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 SIGNOR-C3 21071439 t inferred from 70% family members lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-270032 0.2 ATM protein Q13315 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates activity phosphorylation Thr172 SDGEFLRtSCGSPNY 23871434 t lperfetto ATM phosphorylates AMPKalpha2 to induce inhibitory phosphorylation of HIPK2| SIGNOR-275488 0.267 KDM6A protein O15550 UNIPROT HOXA11 protein P31270 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260021 0.266 ICE2 protein Q659A1 UNIPROT ELL/ICE2 complex SIGNOR-C49 SIGNOR form complex binding 9606 BTO:0001271 22195968 t miannu The ell-ice complex is called lec for its proposed role in transcriptional regulation of the littlesnrna genes. SIGNOR-193603 0.63 PSMA6 protein P60900 UNIPROT XBP1 protein P17861 UNIPROT down-regulates quantity by destabilization binding -1 19941857 t 1 miannu We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination. SIGNOR-239039 0.308 SIRT1 protein Q96EB6 UNIPROT XPA protein P23025 UNIPROT up-regulates activity deacetylation Lys67 ANVKAAPkIIDTGGG 9606 BTO:0002806 30327428 t miannu SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR SIGNOR-262294 0.525 CSNK2A1 protein P68400 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser357 DGSGDTSsNEEIGST -1 12107178 t llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. SIGNOR-250871 0.435 PRKCZ protein Q05513 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity phosphorylation Ser184 VAGVLTAsLTIWKKM 9606 17525161 t lperfetto Protein kinase czeta abrogates the proapoptotic function of bax through phosphorylation. Overexpression of wild type or the constitutively active a119d but not the dominant negative k281w pkczeta mutant results in bax phosphorylation at serine 184. SIGNOR-155111 0.2 HTR6 protein P50406 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257395 0.252 NF2 protein P35240 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity binding 10090 BTO:0003324 27402866 t Hippo pathway Gianni NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart. SIGNOR-261956 0.421 NAA20 protein P61599 UNIPROT NatB complex SIGNOR-C416 SIGNOR form complex binding 9606 18570629 t miannu In the present study we present the components of hNatB (human NatB complex). It consists of the Nat3p homologue hNAT3 (human N-acetyltransferase 3) and the Mdm20p homologue hMDM20 (human mitochondrial distribution and morphology 20). They form a stable complex and in vitro display sequence-specific N(alpha)-acetyltransferase activity on a peptide with the N-terminus Met-Asp-. SIGNOR-267230 0.9 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 SIGNOR-C17 12058066 t gcesareni Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association. SIGNOR-89597 0.533 FBXL17 protein Q9UF56 UNIPROT SUFU protein Q9UMX1 UNIPROT down-regulates quantity by destabilization ubiquitination 27234298 t Here, we show that Fbxl17 (F-box and leucine-rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction SIGNOR-253545 0.429 MECP2 protein P51608 UNIPROT PRPF3 protein O43395 UNIPROT up-regulates activity binding 10090 BTO:0000142 21070191 t lperfetto MeCP2 interacts directly with Prpf3 and Sdccag1|Notably, Mecp2308/Y mice, which produce a truncated form of MeCP2 and reproduce many of the classical features of RTT [43], have been shown to have multiple genes that are abnormally spliced in the brain [23]. This suggests the C-terminal portion of MeCP2, which we have identified as the putative Sdccag1 interaction domain, plays a critical role in regulating alternative splicing. SIGNOR-277691 0.27 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser569 SRRRRSSsTAPPTSS 9606 16513649 t llicata Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization SIGNOR-145044 0.2 MUTYH protein Q9UIF7 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates 9606 21615992 f miannu Hmyh is involved in the activation mechanism of chk1 upon dna damage, but not in stability or inactivation. SIGNOR-173969 0.348 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 t lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. SIGNOR-249005 0.309 STUB1 protein Q9UNE7 UNIPROT TAL1 protein P17542 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000944 17962192 t miannu Ubiquitination and degradation of Tal1/SCL are induced by notch signaling and depend on Skp2 and CHIP. CHIP promoted Tal1 degradation with both chaperone binding and ubiquitin ligase activities, which are mediated by its TPR domain and U box, respectively. SIGNOR-271393 0.363 OXGR1 protein Q96P68 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256770 0.2 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR CABLES1 protein Q8TDN4 UNIPROT down-regulates activity binding -1 25361894 t miannu Here, we report that Cables1 levels are controlled by a phosphorylation and 14-3-3-dependent mechanism. Mutagenic analyses identified two residues, T44 and T150, that are specifically critical for 14-3-3 binding and that serve as substrates for phosphorylation by the cell survival kinase Akt, which by binding directly to Cables1 recruits 14-3-3 to the complex.Ectopic expression of activated Akt (AKT1) prevented Cables1-induced apoptosis. SIGNOR-276758 0.2 ID3 protein Q02535 UNIPROT TCF3 protein P15923 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C127 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241134 0.546 APC-c complex SIGNOR-C150 SIGNOR APC-c complex SIGNOR-C150 SIGNOR down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 22086178 t miannu Cdc20 is a co-activator of the anaphase-promoting complex/cyclosome (APC/C complex), which recruits substrates at particular phases of the cell cycle and mediates their degradation. Overexpression of Cdc20 resulted in decreased levels of both endogenous Sp100 protein and overexpressed Sp100 mRNA in HEK 293 cells. Our results suggested that sp100 is a novel substrate of Cdc20 and it is degraded by the ubiquitination pathway. The intact D-box of Sp100 was necessary for this process. SIGNOR-272725 0.881 SMARCD3 protein Q6STE5 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270732 0.742 PFKP protein Q01813 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. SIGNOR-266469 0.8 EIF2B2 protein P49770 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269130 0.74 STOX1 protein Q6ZVD7 UNIPROT CNTNAP2 protein Q9UHC6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000601 22728895 t Gianni In this study we performed chromatin immunoprecipitation coupled to shotgun cloning to discover novel STOX1A target genes. Our results show that CNTNAP2, a member of the neurexin family, is directly downregulated by STOX1A. SIGNOR-269065 0.2 CAMK2B protein Q13554 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000938 20841359 t gcesareni Inhibitory phosphorylation of gsk-3 by camkii couples depolarization to neuronal survival. SIGNOR-167962 0.295 FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 f lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-235715 0.449 KIF1C protein O43896 UNIPROT RAB6A protein P20340 UNIPROT up-regulates quantity relocalization -1 20360680 t miannu Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation. SIGNOR-266877 0.419 KMT2D protein O14686 UNIPROT HMT complex SIGNOR-C19 SIGNOR form complex binding 9606 17500065 t lperfetto The evolutionarily conserved hdpy-30, ash2l, rbbp5, and wdr5 likely constitute a subcomplex that is shared by all human set1-like hmt complexes. SIGNOR-154763 0.829 morphine chemical CHEBI:17303 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258931 0.8 SEPTIN6 protein Q14141 UNIPROT SEPT6/SEPT2 complex SIGNOR-C71 SIGNOR form complex binding 9606 16914550 t miannu We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains. SIGNOR-148892 0.2 STUB1 protein Q9UNE7 UNIPROT S100P protein P25815 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 23344957 t miannu S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway. SIGNOR-272919 0.297 JAK3 protein P52333 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 30029643 t Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated SIGNOR-256254 0.785 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CACNA1B protein Q00975 UNIPROT up-regulates activity phosphorylation Ser446 ADLCAVGsPFARASL 9534 16406008 t miannu Thus, Ser-447 on Ca(v)2.2 and Ser-161 and Ser-348 of Ca(v)beta1b appear to be both necessary and sufficient for ERK-dependent modulation of these channels. Together, our data strongly suggest that modulation of neuronal N-type VDCCs by ERK involves phosphorylation of Ca(v)2.2alpha1 and to a lesser extent possibly also Ca(v)beta subunits. On the basis of the evidence presented here, it is therefore suggested that ERK-dependent up-regulation of Cav2.2 channels is primarily mediated by phosphorylation of Ser-447 on the I–II loop of Cav2.2 and possibly also the two SP sites conserved on Cavβs. SIGNOR-262967 0.2 CERS6 protein Q6ZMG9 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI up-regulates quantity chemical modification 9606 26887952 t done miannu  Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity.  SIGNOR-273997 0.8 ARNTL protein O00327 UNIPROT PER3 protein P56645 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253630 0.588 STAT5A protein P42229 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15498859 t lperfetto Pim-1 is know to be up regulated by signal transducer and activator of transcription 5 (stat5) SIGNOR-249606 0.384 CCT6A protein P40227 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 t miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). SIGNOR-272865 0.751 WNT1 protein P04628 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni Distinctly, wnt1 signals through fzd receptors 1 and 6 in the epaxial domain of the somite, to regulate myf5 expression via the canonical _-catenin pathway SIGNOR-198843 0.689 NLRP1 inflammasome complex SIGNOR-C224 SIGNOR Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 f miannu Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. SIGNOR-260355 0.7 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser402 ISNSHPLsLTSDQYK -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178407 0.816 GSK3B protein P49841 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 17183360 t lperfetto Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) . SIGNOR-217367 0.38 NARS2 protein Q96I59 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270464 0.8 ARSA protein P15289 UNIPROT HBB protein P68871 UNIPROT up-regulates activity acetylation 9606 237937 t Regulation miannu ASA acetylates hemoglobin. Purified acetylated hemoglobin had a slightly increased oxygen affinity and decreased heme-heme interaction. SIGNOR-251772 0.2 PLG protein P00747 UNIPROT PLAT protein P00750 UNIPROT up-regulates activity cleavage Arg310 QYSQPQFrIKGGLFA 9606 BTO:0000131 1447176 t lperfetto The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme SIGNOR-263534 0.555 ATP5MC1 protein P05496 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261409 0.2 EGFR protein P00533 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Tyr21 IENEEQEyVQTVKSS 9606 24103589 t lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].Finally in 2013 caron et al. showed the relevance of y21 phosphorylation for the anxa1 stability. In fact the authors demonstrated that the tyrosine 21 phosphorylation is crucial for anxa1 sumoylation induced by egf SIGNOR-202776 0.523 ERN1 protein O75460 UNIPROT ERN1 protein O75460 UNIPROT up-regulates activity phosphorylation Tyr628 EHPNVIRyFCTEKDR -1 25968568 t miannu IRE1 transduces the unfolded protein response by splicing XBP1 through its C-terminal cytoplasmic kinase-RNase region. IRE1 autophosphorylation is coupled to RNase activity through formation of a back-to-back dimer, although the conservation of the underlying molecular mechanism is not clear from existing structures.  SIGNOR-275417 0.2 SRF protein P11831 UNIPROT PLAU protein P00749 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000161 15514113 f miannu We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1. SIGNOR-255227 0.26 ARHGAP23 protein Q9P227 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260480 0.405 (-)-anisomycin chemical CHEBI:338412 ChEBI MAPK8 protein P45983 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling gcesareni SIGNOR-189702 0.8 COL4A2 protein P08572 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 t Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6) SIGNOR-254666 0.7 FOXP2 protein O15409 UNIPROT RELN protein P78509 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 25232744 t miannu By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets. SIGNOR-266833 0.373 PER2 protein O15055 UNIPROT TWIST1 protein Q15672 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001939 23836662 f miannu We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. SIGNOR-254153 0.2 GRK2 protein P25098 UNIPROT OPRD1 protein P41143 UNIPROT down-regulates activity phosphorylation Thr358 ATARERVtACTPSDG 9606 BTO:0000007 11040053 t GRK2 strongly enhanced agonist-stimulated phosphorylation of the wild-type DOR (WT), but Delta15 or mutant DOR (T358A/T361A/S363G) failed to show any detectable phosphorylation under these conditions. agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus. GRKs are important mediators in agonist-induced opioid receptor phosphorylation and desensitization. SIGNOR-251457 0.2 USP10 protein Q14694 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0002181 SIGNOR-C242 21962518 t lperfetto Similarly, the overexpression of USP13 reduced the levels of ubiquitinated Beclin1 which was inhibited by spautin-1 (Figure 4E) SIGNOR-260299 0.488 FSTL1 protein Q12841 UNIPROT DIP2A protein Q14689 UNIPROT up-regulates activity binding 9606 BTO:0005562 20054002 t miannu We identified DIP2A as a novel FSTL1-binding partner from the membrane fraction of endothelial cells. Co-immunoprecipitation assays revealed a direct physical interaction between FSTL1 and DIP2A. The work in the current study identifies DIP2A as a novel receptor for FSTL1 that mediates Akt activation and cell survival and function in cardiovascular cells in vitro. SIGNOR-266603 0.493 PTMA protein P06454 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 BTO:0000567 12522243 t PHAP proteins promoted caspase-9 activation after apoptosome formation, whereas ProT negatively regulated caspase-9 activation by inhibiting apoptosome formation. SIGNOR-259079 0.372 IER3 protein P46695 UNIPROT PPP2R5C protein Q13362 UNIPROT down-regulates binding 9606 16456541 t gcesareni Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit. SIGNOR-144309 0.522 ZBED1 protein O96006 UNIPROT RPS10 protein P46783 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 17220279 t Luana HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid. SIGNOR-266083 0.2 MAPK1 protein P28482 UNIPROT PARP1 protein P09874 UNIPROT up-regulates phosphorylation Thr373 AATPPPStASAPAAV 9606 BTO:0000938 BTO:0000142 16627622 t esanto Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation. SIGNOR-146224 0.533 MAPK3 protein P27361 UNIPROT RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser633 SFDTHFRsPSSSVGS 9606 12620228 t llicata Erk-dependent phosphorylation of the transcription initiation factor tif-ia is required for rna polymerase i transcription and cell growth. phosphopeptide mapping and mutational analysis reveals two serine residues (s633 and s649) that are phosphorylated by erk and rsk kinases. Replacement of s649 by alanine inactivates tif-ia, inhibits pre-rrna synthesis, and retards cell growth. SIGNOR-98980 0.2 R547 chemical CID:6918852 PUBCHEM CDK4 protein P11802 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259794 0.8 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser697 QPSTASNsLPEPAKK 9606 10195894 t Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. SIGNOR-251282 0.2 KIT protein P10721 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 BTO:0000830 15526160 f miannu A number of studies have demonstrated the ability of SCF to activate the Ras-Erk pathway. The adapter protein Grb2 can directly associate with phosphorylated Y703 and Y936 in c-Kit SIGNOR-254947 0.309 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT down-regulates activity phosphorylation Thr207 TPPTLSStVLIVRNE 9606 BTO:0001938 12815053 t lperfetto M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1 SIGNOR-102502 0.555 lisuride chemical CHEBI:51164 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9205951 t miannu The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively. SIGNOR-258615 0.8 TGFBI protein Q15582 UNIPROT A3/b1 integrin complex SIGNOR-C161 SIGNOR up-regulates activity binding 26387839 t lperfetto BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers SIGNOR-253267 0.431 IL10RA protein Q13651 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 19837374 f apalma Treatment of monocytes with IL-10 as compared to IL-15 resulted in a two-fold greater level of phagocytosis and binding of latex beads. In summary, IL-10, in comparison to IL-15, induces greater macrophage endocytic function SIGNOR-255442 0.7 STAR protein P49675 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates quantity relocalization 17579211 t lperfetto StAR transfers cholesterol from the outer to the inner mitochondrial membranes, where the enzyme complex of cholesterol side chain cleavage cytochrome P450 (P450scc) converts it to the first steroid, pregnenolone SIGNOR-265727 0.8 INSR protein P06213 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Tyr174 TIPSQRRyVYYYSYL -1 23995781 t miannu Our results show that the kinase region of IRβ subunit physically binds to PTEN and phosphorylates on Y27 and Y174. In the current study, we discovered that IR also downregulates PTEN through tyrosine phosphorylation and suggest that Y27 and 174 are the two key tyrosines. SIGNOR-276471 0.454 D-glucitol smallmolecule CHEBI:17924 ChEBI FUS protein P35637 UNIPROT down-regulates activity relocalization 9606 BTO:0000312 33172210 f We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne SIGNOR-262813 0.8 ATG10 protein Q9H0Y0 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR up-regulates binding 9606 18704115 t lperfetto Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein. SIGNOR-226699 0.777 PTPN1 protein P18031 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 15821101 t PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTPalpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3. SIGNOR-248427 0.568 SMAD1 protein Q15797 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 9606 16621789 t gcesareni These results identify a potential mechanism whereby bmp-2 antagonizes wnt signaling in osteoblast progenitors by promoting an interaction between smad1 and dvl-1 that restricts beta-catenin activation. SIGNOR-146131 0.353 PIM2 protein Q9P1W9 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 16403219 t miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. SIGNOR-250395 0.4 DDX23 protein Q9BUQ8 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270646 0.718 FOXO1 protein Q12778 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15109499 f miannu The activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression. SIGNOR-252069 0.438 PPP3CA protein Q08209 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser99 PFRGRSRsAPPNLWA -1 10195903 t lperfetto Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.| Bcl-xL did not coimmunoprecipitate with BAD(S75E, S99E) protein (Fig. 2A), regardless of whether it was coexpressed with DCnA/B¬† SIGNOR-263740 0.452 SMARCC2 protein Q8TAQ2 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270735 0.83 CCN2 protein P29279 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates activity binding 9606 32928643 t miannu CTGF is highly expressed in PDAC tissues, especially in tumor stroma (as shown by immunohistochemistry, CTGF: brown stain). The tumor cell-secreted CTGF promotes pancreatic stellate cell (PSC) proliferation, adhesion, and migration via integrin α5β1, leading to extracellular matrix (ECM) deposition.Pancreatic cancer cells secrete high levels of CTGF that binds to integrin α5β1, promoting PSC proliferation, adhesion, and migration SIGNOR-277687 0.2 FZD5 protein Q13467 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity binding 9606 23151663 t areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  SIGNOR-258960 0.692 YY1 protein P25490 UNIPROT GDAP1 protein Q8TB36 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19720140 f miannu Overexpression of YY1 activated the GDAP1 promoter in a reporter gene system as well as increased the level of endogenous mRNA. SIGNOR-255618 0.2 NRG3 protein P56975 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 7477375 t gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. SIGNOR-26251 0.738 CHEK1 protein O14757 UNIPROT CDC25C protein P30307 UNIPROT down-regulates quantity by destabilization phosphorylation Ser216 SGLYRSPsMPENLNR 9606 20068082 t gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). SIGNOR-163158 0.845 ALPL protein P05186 UNIPROT Bone_mineralization phenotype SIGNOR-PH69 SIGNOR up-regulates 9606 19049325 f miannu PC-1 and Tnap work together to produce normally mineralized bone matrix through the generation and hydrolysis of pyrophosphate. SIGNOR-252196 0.7 UBXN1 protein Q04323 UNIPROT NGLY1 protein Q96IV0 UNIPROT up-regulates activity binding 9606 15362974 t miannu PNGase is directed to polyubiquitinated MGPs via VCP and the adaptor protein SAKS1, allowing PNGase to deglycosylate MGPs, which can then be degraded by the proteasome. PNGase itself is reported to bind to the S4 component of the 19 S proteasome. SIGNOR-261060 0.466 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser170 SFKLSGFsFKKNKKE -1 8422248 t lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. SIGNOR-248931 0.719 VAV1 protein P15498 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260580 0.74 DCC protein P43146 UNIPROT CACNA1D protein Q01668 UNIPROT up-regulates activity 9606 12827203 t miannu DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER. SIGNOR-268292 0.301 CTDSPL protein O15194 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000007 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248311 0.476 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 t gcesareni We have identified ptp1b and tcptp as negative regulators of the hepatocyte growth factor receptor, the met receptor-tyrosine kinase. In vivo, loss of ptp1b or tcptp enhances hepatocyte growth factor-mediated phosphorylation of met. SIGNOR-181335 0.48 AKT proteinfamily SIGNOR-PF24 SIGNOR BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Thr509 LKRKRRPtSGLHPED 9606 BTO:0000150 17428466 t lperfetto Phosphatidylinositol 3-kinase/akt signaling enhances nuclear localization and transcriptional activity of brca1. mutation of threonine 509 in brca1, the site of akt phosphorylation, to an alanine, attenuates the ability of heregulin to induce brca1 nuclear accumulation SIGNOR-244168 0.2 LETM1 protein O95202 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 10090 29123128 t lperfetto LETM1 is a mitochondrial inner membrane protein and several reports suggest that it mediates mitochondrial Ca2+ uptake and extrusion in a gradient-dependent manner SIGNOR-262541 0.8 SOCS4 protein Q8WXH5 UNIPROT CUL5 protein Q93034 UNIPROT up-regulates activity binding 9534 BTO:0000298 24210661 t miannu SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SIGNOR-272141 0.506 JAKMIP1 protein Q96N16 UNIPROT GABBR1 protein Q9UBS5 UNIPROT up-regulates quantity 9534 BTO:0004055 14718537 f SARA Reduction in the Marlin-1 protein levels interferes with the translation, assembly, or stability of GABAB receptors during the maturation of cortical neurons. SIGNOR-260988 0.535 FRZB protein Q92765 UNIPROT WNT1 protein P04628 UNIPROT down-regulates binding 9606 BTO:0000671 9326585 t gcesareni We and others demonstrated that fzb-1 blocks wnt-1 and xwnt-8 signaling in xenopus embryos, SIGNOR-51762 0.532 MT-ND4L protein P03901 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. SIGNOR-262147 0.693 MECOM protein Q03112 UNIPROT ANGPT1 protein Q15389 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15889140 t Luana We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2  SIGNOR-266059 0.2 CDKN1A protein P38936 UNIPROT Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR up-regulates 10090 BTO:0000222 9388774 f gcesareni The upregulation of the cyclin-dependent kinase inhibitor p21 and the dephosphorylation of retinoblastoma protein (pRb) appear to be critical regulatory events for the establishment ,,, the postmitotic ... states [in myoblasts differentiating into mature myotubes] SIGNOR-241956 0.7 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 11823427 t lperfetto The central event in cytokine_dependent transcriptional regulation is phosphorylation of STATs on a single tyrosine residue at their C_terminus (Darnell, 1997b). The reaction is catalyzed by cytokine receptor_associated tyrosine kinases of the Janus type (Jak) at the cell membrane and triggers the homo_ and heterodimerization of STAT molecules via reciprocal phosphotyrosine“SH2 domain interactions SIGNOR-236373 0.782 PAK proteinfamily SIGNOR-PF13 SIGNOR NF2 protein P35240 UNIPROT down-regulates phosphorylation 9606 18071304 t inferred from 70% family members lperfetto Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth, SIGNOR-269976 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser528 KPRSSRGsIFTFRRR 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275764 0.2 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM4B protein O94953 UNIPROT up-regulates activity chemical activation 29981745 t lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. SIGNOR-273466 0.8 EP300 protein Q09472 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR form complex binding 9606 11559745 t lperfetto P300/cbp proteins: hats for transcriptional bridges and scaffolds SIGNOR-110562 0.525 CBX5 protein P45973 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-264489 0.2 MAP4K4 protein O95819 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates binding 9606 10807933 t gcesareni The existence of an at least trimolecular complex consisting of nik, tak1, and ikk2, although the precise sequence of activation as well as the possible location of the kinases within the signalosome remains to be elucidated. SIGNOR-77404 0.564 Enolase proteinfamily SIGNOR-PF74 SIGNOR 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI down-regulates quantity chemical modification 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266531 0.8 PSMD14 protein O00487 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263346 0.895 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000782 14679297 t lperfetto We show that purified recombinant ikk-epsilon and tbk1 directly phosphorylate the critical serine residues in irf3 allowing its translocation into the nucleus and production of interferon type i. SIGNOR-120355 0.816 JNK proteinfamily SIGNOR-PF15 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser37 YLDSGIHsGATTTAP 9606 19667122 t lperfetto Specifically, we provide evidence that jnk binds to e-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by gsk-3beta. SIGNOR-187578 0.2 NPTX1 protein Q15818 UNIPROT BAD protein Q92934 UNIPROT up-regulates quantity 9606 BTO:0004168;BTO:0003227 31113871 f lperfetto We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control SIGNOR-260410 0.2 PPP2R5B protein Q15173 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr308 KDGATMKtFCGTPEY 9606 16495456 t gcesareni Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt. SIGNOR-252615 0.647 VASP protein P50552 UNIPROT ATIC protein P31939 UNIPROT up-regulates activity phosphorylation Tyr104 RVVACNLyPFVKTVA 9606 BTO:0002181 18845790 t miannu ATIC and VASP phosphorylation is dependent on NPM-ALK kinase activity.  SIGNOR-276172 0.349 PTPN11 protein Q06124 UNIPROT CTNNA1 protein P35221 UNIPROT down-regulates dephosphorylation Tyr148 LADMADVyKLLVQLK 9606 16767162 t gcesareni Tyr148 of beta-catenin is an shp2 target dephosphorylation site. Together, these results suggest that beta-catenin plays a suppressor role in cell transformation and that shp2, by dephosphorylating beta-catenin, promotes mitogenic, cell survival and transformation signals. SIGNOR-147075 0.41 SIRT7 protein Q9NRC8 UNIPROT H3-5 protein Q6NXT2 UNIPROT up-regulates activity deacetylation Lys38 K-->P 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275885 0.2 1,1-dioxo-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3-one chemical CHEBI:93578 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258891 0.8 CSNK2A2 protein P19784 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Thr250 KEEVVGLtETSSQPK 9606 BTO:0000776 7678037 t llicata These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells. SIGNOR-251013 0.312 ABCA1 protein O95477 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 23077142 f miannu Cholesterol efflux is the first step in the formation of HDL, which is initiated through the action of ATP binding cassette transporter (ABC) A1 on apolipoprotein (apo) A-I that produces nascent HDL (nHDL). SIGNOR-252109 0.7 GTF3C1 protein Q12789 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR form complex binding 9606 29378333 t lperfetto Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains SIGNOR-266188 0.877 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269347 0.719 NOTCH1 protein P46531 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001253 12107827 f gcesareni Addition of jag-1 peptide induced ikkalpha mediated nf-kappab activation, as well as increased ppargamma expression. SIGNOR-90455 0.346 MMP9 protein P14780 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272376 0.7 OXGR1 protein Q96P68 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257417 0.2 MEIS2 protein O14770 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 21746878 t miannu We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. SIGNOR-267240 0.2 olanzapine chemical CHEBI:7735 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). SIGNOR-258834 0.8 AKT1 protein P31749 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 SIGNOR-C7 17964260 t gcesareni Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. SIGNOR-158624 0.685 NODAL protein Q96S42 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0004094 15531507 f Regulation miannu Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7. SIGNOR-256656 0.7 DYRK2 protein Q92630 UNIPROT KATNA1 protein O75449 UNIPROT down-regulates quantity by destabilization phosphorylation Ser109 VPVERRPsPGPRKRQ 9606 BTO:0000007 19287380 t miannu DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d). SIGNOR-262847 0.523 MYOG protein P15173 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR up-regulates binding 9606 BTO:0001103 17194702 t lperfetto Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle SIGNOR-217740 0.326 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0002552 11331603 t lperfetto Atm phosphorylates mdm2 on s395 in vitro. Moreover, s395 appears to be phosphorylated in an atm-dependent manner in vivo the precise mechanism through which s395 phosphorylation attenuates mdm2 function is unclear. SIGNOR-107256 0.746 FURIN protein P09958 UNIPROT INSR protein P06213 UNIPROT up-regulates activity cleavage 9606 BTO:0000666 25527501 t Giorgia Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation. SIGNOR-260365 0.286 PTPRC protein P08575 UNIPROT TYK2 protein P29597 UNIPROT down-regulates activity dephosphorylation Tyr1055 VPEGHEYyRVREDGD 10090 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells SIGNOR-248358 0.416 ASH2L protein Q9UBL3 UNIPROT GATA3 protein P23771 UNIPROT up-regulates binding 9606 BTO:0000150 25258321 t miannu We identifiedgata3as the binding protein of ash2l. Ash2l was shown to potentiate the transcriptional activity ofgata3. SIGNOR-205312 0.252 MAFA protein Q8NHW3 UNIPROT PCSK1 protein P29120 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17149590 f miannu the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. SIGNOR-254566 0.291 IDH3B protein O43837 UNIPROT IDH complex SIGNOR-C396 SIGNOR form complex binding 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-266249 0.684 PHLPP2 protein Q6ZVD8 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity dephosphorylation Thr387 TMKRRDEtMQPAKPS 9606 20513427 t PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis. SIGNOR-248730 0.2 BAMBI protein Q13145 UNIPROT FZD5 protein Q13467 UNIPROT up-regulates binding 9606 BTO:0000763 2662247 t gcesareni These data together suggest that bambi may form a ternary coreceptor complex with fzd5 and lrp6 SIGNOR-23040 0.577 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Ser518 GEDPYAGsTDENTDS 9606 BTO:0000567 15367657 t lperfetto Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523 SIGNOR-128893 0.404 ROCK1 protein Q13464 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates phosphorylation Ser1236 PKPKPRPsITKATWE 9606 BTO:0000887;BTO:0001260 19103606 t acerquone Here we show that rho-kinase, an effector of rhoa, phosphorylated p190a rhogap at ser1150 and attenuated p190a rhogap activity in cos7 cells SIGNOR-182853 0.424 RPS6KA4 protein O75676 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates activity phosphorylation Ser196 EEKERTFsFCGTIEY 9606 BTO:0002181 19933278 t miannu Here we report that the CK2 protein kinase, which contributes to NF-kappaB activation following UV radiation in a p38-dependent manner, physically interacts with MSK2 but not MSK1 and that CK2 inhibition specifically impairs UV-induced MSK2 kinase activation. A putative site of CK2 phosphorylation was mapped to MSK2 residue Ser(324) and when substituted to alanine (S324A) also compromised MSK2 activity.Serine 324 is required for UV-induced MSK2 activation and for autophosphorylation at MSK2-Ser196. SIGNOR-276269 0.2 PRKCG protein P05129 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Ser518 LSASPRMsGFIYQGK 9606 25009260 t lperfetto Pkc_ directly phosphorylates _pix at ser583 and indirectly at ser340 in cells. herefore, we propose that pkc_ positively modulates dopamine release through _2pix phosphorylation. The pkc_-_pix-cdc42/rac1 phosphorylation axis may provide a new therapeutic target for the treatment of parkinsonian syndrome SIGNOR-205234 0.2 ACLY protein P53396 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-268080 0.8 OSBP2 protein Q969R2 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates quantity relocalization 30925160 t lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. SIGNOR-264879 0.8 Tomivosertib chemical CID:118598754 PUBCHEM MKNK2 protein Q9HBH9 UNIPROT down-regulates activity chemical inhibition 9606 29526098 t Simone Vumbaca Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. SIGNOR-261117 0.8 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT up-regulates binding 9606 BTO:0000150;BTO:0001130;BTO:0000848 23450633 t gcesareni Thrombin, actin through par1 promotes tumor cell proliferation, migration and contributes to the metastatic potenital of breast, prostate, gastrointestinal cancers and melanoma. SIGNOR-199788 0.883 MAPK3 protein P27361 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Ser284 RRDYDDMsPRRGPPP 9606 16564677 t gcesareni Erk phosphorylation drives cytoplasmic accumulation of hnrnp-k and inhibition of mrna translation mitogen-activated protein kinase/extracellular-signal-regulated kinase (mapk/erk) efficiently phosphorylates hnrnp-k both in vitro and in vivo at serines 284 and 353. SIGNOR-145375 0.351 PIK3R4 protein Q99570 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates binding 9606 8999962 t gcesareni Recombinant p150 associated with ptdins 3-kinase in vitro in a stable manner, resulting in a 2-fold increase in lipid kinase activity. SIGNOR-45664 0.938 GATA4 protein P43694 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001086 32376282 f miannu HYDIN promotes expression of Gata4 in cardiomyocyte differentiation. HYDIN functions as a positive regulator of human cardiomyocyte differentiation and promotes expression of cardiac contractile genes in hESC cells. This is mediated through GATA4, a critical transcription factor in heart development. Cardiac-specific Hydin knockdown in vivo leads to Gata4 downregulation and enhanced atrial septal defect (ASD) risk in mice. GATA4 is a fundamental TF in embryonic heart development and cardiac differentiation, and reduction in GATA4 function results in a diverse range of CHDs SIGNOR-265480 0.7 TXK protein P42681 UNIPROT TXK protein P42681 UNIPROT up-regulates phosphorylation Tyr91 KIQVKALyDFLPREP 9606 12081135 t lperfetto Evidence of autophosphorylation in txk: y91 is an autophosphorylation site. the results suggest that phosphorylated txk is an active form to promote ifn-gamma synthesis SIGNOR-89844 0.2 PRKACA protein P17612 UNIPROT AKAP12 protein Q02952 UNIPROT up-regulates activity phosphorylation Ser772 LVTPRKKsKSKLEEK -1 14657015 t lperfetto Following receptor activation, gravin binding to the receptor increases, a process dependent upon PKA-catalyzed phosphorylation of two canonical PKA sites (Ser696–698 and Ser772) located within the AKAP domain of gravin. SIGNOR-271842 0.2 AMHR2 protein Q16671 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates binding 9606 14746809 t gcesareni See table2 SIGNOR-121593 0.534 PIM1 protein P11309 UNIPROT SKP2 protein Q13309 UNIPROT up-regulates activity phosphorylation Thr417 WGIKCRLtLQKPSCL 9606 20663873 t miannu We found that expression of Pim-1 increases the level of Skp2 through direct binding and phosphorylation of multiple sites on this protein. Along with known Skp2 phosphorylation sites including Ser(64) and Ser(72), we have identified Thr(417) as a unique Pim-1 phosphorylation target. Phosphorylation of Thr(417) controls the stability of Skp2 and its ability to degrade p27. SIGNOR-259817 0.346 PAK1 protein Q13153 UNIPROT PREX2 protein Q70Z35 UNIPROT down-regulates activity phosphorylation Ser1107 DTISNRDsYSDCNSN 9606 BTO:0000007 26438819 t miannu P21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase. PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. SIGNOR-277181 0.374 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR DBP protein Q10586 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 30100984 t miannu The albumin D-box binding protein (DBP) is a member of the PAR bZip (proline and acidic amino acid-rich basic leucine zipper) transcription factor family and functions as important regulator of circadian core and output gene expression. Gene expression of DBP itself is under the control of E-box-dependent binding by the Bmal1-Clock heterodimer and CRE-dependent binding by the cAMP responsive element binding protein (CREB). SIGNOR-268029 0.7 CRY1 protein Q16526 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267971 0.891 MAPK8IP1 protein Q9UQF2 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 10490659 t gcesareni Both jip1 and jip2 selectively bind the mapkk isoform mkk7. SIGNOR-70848 0.715 PTPN11 protein Q06124 UNIPROT SPRY1 protein O43609 UNIPROT down-regulates dephosphorylation 9606 16481357 t gcesareni These results identify sprouty proteins as in vivo targets of corkscrew/shp-2 tyrosine phosphatases and show how corkscrew/shp-2 proteins can promote rtk signaling by inactivating a feedback inhibitor. SIGNOR-144547 0.418 gemfibrozil chemical CHEBI:5296 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 9606 21889235 t Luana  The combination of stilbene scaffold and gemfibrozil enhances the PPARα agonistic activity. SIGNOR-258318 0.8 PIK3CG protein P48736 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates chemical modification 9606 16847462 t gcesareni The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2) SIGNOR-147954 0.8 GNAI2 protein P04899 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates activity binding 9606 19703466 t Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma) SIGNOR-256499 0.58 PRKCA protein P17252 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates activity phosphorylation Ser498 RPLSRTQsSPLPQSP 10116 BTO:0002320 15367659 t lperfetto We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. | Finally, we assessed the ability of PKD to phosphorylate HDAC5 in cells by employing an antibody that specifically recognizes HDAC5 that has been phosphorylated at serine 259. HDAC5 was basally phosphorylated at serine 259, and phosphorylation at this site was dramatically increased by coexpression of constitutively active PKD S/E SIGNOR-249269 0.2 CDH2 protein P19022 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265864 0.811 AMPK complex SIGNOR-C15 SIGNOR KPNA2 protein P52292 UNIPROT up-regulates phosphorylation Ser105 QAARKLLsREKQPPI 9606 15342649 t lperfetto Ampk phosphorylated importin alpha1 on ser(105). Accordingly, expression of importin alpha1 proteins bearing k22r or s105a mutations failed to mediate the nuclear import of hur in intact cells. Our results point to importin alpha1 as a critical downstream target of ampk and key mediator of ampk-triggered hur nuclear import. SIGNOR-216449 0.2 PAX3-FOXO1 fusion protein SIGNOR-FP12 SIGNOR MET protein P08581 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 t miannu Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA. SIGNOR-251570 0.2 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000751 11700305 t lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | SIGNOR-249124 0.335 SRC protein P12931 UNIPROT INPPL1 protein O15357 UNIPROT up-regulates phosphorylation Tyr987 SFNNPAYyVLEGVPH 9606 12235291 t lperfetto Ship2 could be phosphorylated in vitro by recombinant src kinase and tyrosines 986-987 in the npxy motif of ship2 appear to be the major sites of phosphorylation for src both in vitro and in vivo. SIGNOR-92935 0.55 SMURF1 protein Q9HCE7 UNIPROT ILRUN protein Q9H6K1 UNIPROT unknown ubiquitination -1 20804422 t miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. SIGNOR-272697 0.2 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 8692915 t Manara The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites. SIGNOR-260821 0.423 PIK3CA protein P42336 UNIPROT PI3K complex SIGNOR-C156 SIGNOR form complex binding 9606 19805105 t miannu Phosphoinositol 3- kinase alpha (PI3Kα) is a heterodimeric enzyme formed by a catalytic subunit (p110α, encoded by PIK3CA) and one of several regulatory subunits (a major one being p85α, encoded by PI3KR1). SIGNOR-255299 0.934 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity chemical inhibition 25309440 t inferred from 70% of family members lperfetto Different agents were used to inhibit either the PI3K/Akt or MEK/ERK pathways. The PI3K inhibitor, LY294002, and the Akt inhibitor, Akt inhibitor VIII, were used to inhibit the PI3K/Akt pathway. SIGNOR-269849 0.8 NMUR2 protein Q9GZQ4 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257292 0.41 HDLBP protein Q00341 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 33941620 f miannu Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. SIGNOR-266695 0.7 MAPK14 protein Q16539 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser7 sPAPLSPL 9606 BTO:0000150 22128155 t gcesareni Ogether, our results suggest that p38 phosphorylation of foxo3a on ser-7 is essential for its nuclear relocalization in response to doxorubicin SIGNOR-252960 0.512 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT up-regulates phosphorylation Ser398 DSLPSSPsSATPHSQ 9606 SIGNOR-C15 22669845 t gcesareni In response to genotoxic stress, eef2k was activated by ampk (adenosine monophosphate-activated protein kinase)-mediated phosphorylation on serine 398. Activated eef2k phosphorylated eef2 and induced a temporary ribosomal slowdown at the stage of elongation SIGNOR-197734 0.474 P2RY14 protein Q15391 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257002 0.25 BCL2L11 protein O43521 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 22492984 t gcesareni Bim, and puma bind with high affinity to all pro-survival proteins SIGNOR-196932 0.831 DYRK1A protein Q13627 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser87 KTVEGAGsIAAATGF 9606 BTO:0000938 16959772 t lperfetto In vitro kinase assay of anti-dyrk1a immunocomplexes demonstrated that dyrk1a could phosphorylate alpha-synuclein at ser-87. Furthermore, aggregates formed by phosphorylated alpha-synuclein have a distinct morphology and are more neurotoxic compared with aggregates composed of unmodified wild type alpha-synuclein. These findings suggest alpha-synuclein inclusion formation regulated by dyrk1a, potentially affecting neuronal cell viability. SIGNOR-149393 0.578 AFF1 protein P51825 UNIPROT AEP complex complex SIGNOR-C117 SIGNOR form complex binding 9606 BTO:0000664 20153263 t 1 miannu These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells. SIGNOR-239231 0.47 LAS1L protein Q9Y4W2 UNIPROT Rix1 complex complex SIGNOR-C373 SIGNOR up-regulates activity binding 9606 BTO:0000007 22190735 t miannu LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes. SIGNOR-265467 0.844 E2F1 protein Q01094 UNIPROT USP37 protein Q86T82 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21596315 t lperfetto USP37 was induced by E2F transcription factors in G1|Ectopic E2F1 activated the wild-type promoter, but not the mutant promoter, 3-fold over basal levels in 293T cells (Figure 4F), confirming the functionality of the E2F binding sites in the USP37 promoter. SIGNOR-265047 0.2 NF1 protein P21359 UNIPROT ADCY7 protein P51828 UNIPROT up-regulates 9606 BTO:0000938 24431436 f miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-204246 0.29 AMPK complex SIGNOR-C15 SIGNOR HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 21892142 t lperfetto Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs). SIGNOR-216554 0.281 PBX1 protein P40424 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 21746878 t miannu We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. SIGNOR-267239 0.313 BVES protein Q8NE79 UNIPROT VAMP3 protein Q15836 UNIPROT up-regulates activity binding -1 20057356 t llicata Taken together, these data demonstrate that Bves interacts with VAMP3 and facilitates receptor recycling both in vitro and during early development. SIGNOR-237771 0.431 EGFR protein P00533 UNIPROT CRK protein P46108 UNIPROT down-regulates activity phosphorylation Tyr221 GGPEPGPyAQPSVNT 9606 BTO:0000007 9642287 t llicata To address these questions, we have developed an antibody that specifically recognizes the CrkII protein phosphorylated on Tyr221, and we found that the EGF receptor directly phosphorylates CrkII on Tyr221. Furthermore, we observed that the phosphorylation of Tyr221 of CrkII correlated with its dissociation from the EGF receptor, implicating the phosphorylation of Tyr221 in the negative feedback of binding to the EGF receptor. SIGNOR-251091 0.733 CAPN2 protein P17655 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val58 KGVTVETvFSVDEFS -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263583 0.302 BMS-554417 chemical CID:54754526 PUBCHEM IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190455 0.8 CBP/p300 complex SIGNOR-C6 SIGNOR FLI1 protein Q01543 UNIPROT down-regulates acetylation 9606 21321929 t lperfetto We have previously demonstrated that in response to transforming growth factor _ (tgf_), fli-1 activity is repressed through a series of sequential posttranslational modifications, consisting of protein kinase c_ (pkc_)-induced thr312 phosphorylation, acetylation by p300/creb binding protein-associated factor, and detachment from the collagen promoter. SIGNOR-172109 0.295 LATS2 protein Q9NRM7 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Ser397 TYHSRDEsTDSGLSM 9606 BTO:0000007 20048001 t lperfetto We show that YAP is phosphorylated by Lats on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1delta/epsilon to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits beta-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition SIGNOR-218038 0.815 PTPN6 protein P29350 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr654 RNEGVATyAAAVLFR 9606 20840866 t lperfetto Because SHP-1 can dephosphorylate residues Y86 and Y654 on the \u03b2-catenin protein, these residues were therefore mutated into phenylalanine and the transcriptional activity of the subsequent \u03b2-catenin mutants analyzed: \u03b2-catenin/Y86F, \u03b2-catenin/Y654F and \u03b2-catenin/Y86F/Y654F. As shown in  Fig.\u00a03 B, the mutants \u03b2-catenin/Y86F, \u03b2-catenin/Y654F and \u03b2-catenin/Y86F/Y654F had a significantly reduced transcriptional activity in comparison to wild-type \u03b2-catenin.|SHP-1 inhibits \u03b2-catenin function by inducing its degradation and interfering with its association with TATA-binding protein. SIGNOR-277014 0.539 STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation -1 14614828 t lperfetto We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli SIGNOR-217469 0.595 CSNK2A1 protein P68400 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates quantity by stabilization phosphorylation Ser11 SFLVRKPsDPNRKPN 9606 19923321 t lperfetto Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively. SIGNOR-161771 0.355 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Thr576 NSCRSSTtTCPEQDF 9606 BTO:0000007 16862148 t lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). SIGNOR-249300 0.444 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB2 protein Q9Y5G2 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265710 0.2 DHFR protein P00374 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity chemical modification 9606 21876184 t lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. SIGNOR-268258 0.8 TRIM27 protein P14373 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 BTO:0000671 12807881 f miannu Rfp expression in hek 293 cells activated jnk1 SIGNOR-102034 0.26 PLAG1 protein Q6DJT9 UNIPROT ABCC6 protein O95255 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007;BTO:0000599 18850323 f miannu We identified ABCC6 as a target gene for transcriptional induction by PLAG1 and PLAGL1, transcription factors from the PLAG family of cell cycle progression-related DNA-binding proteins. Both these factors are shown to bind to the same single consensus-binding element in the ABCC6 proximal promoter in cell lines of hepatic and renal origin by reporter gene assay, electrophoretic mobility shift assay and chromatin immunoprecipitation. PLAG-mediated ABCC6 transactivation may play an important role in determining the level of tissue-specific expression of this gene. The described mechanism can also find potential application in therapeutic interventions in forms of PXE related to impaired ABCC6 expression. SIGNOR-254925 0.388 IL6ST protein P40189 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 9716487 t lperfetto All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59]. SIGNOR-238634 0.624 TGFB1 protein P01137 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR down-regulates activity 9606 10611320 f lperfetto Tgf-beta treatment resulted in the specific inactivation of cyclin cdk2 complexes caused by absence of the activating thr(160) phosphorylation on cdk2. SIGNOR-217502 0.279 Calcineurin complex SIGNOR-C155 SIGNOR BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10195903 t Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. SIGNOR-252324 0.413 WNT7A protein O00755 UNIPROT SPRY4 protein Q9C004 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002058 15705594 f miannu In NSCLC cells, Wnt-7a and Fzd-9 induced both cadherin and Sprouty-4 expression and stimulated the JNK pathway, but not beta-catenin/T cell factor activity. SIGNOR-253034 0.279 UBE2J1 protein Q9Y385 UNIPROT DIO2 protein Q92813 UNIPROT down-regulates quantity by destabilization ubiquitination Lys244 KIAYLGGkGPFSYNL 9606 BTO:0001379 29892818 t scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. SIGNOR-267482 0.387 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr447 SEELDENyVPMNPNS 10090 10978177 t HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin SIGNOR-251313 0.492 CORT protein O00230 UNIPROT MRGPRX2 protein Q96LB1 UNIPROT up-regulates binding 9606 BTO:0000938 16111673 t gcesareni The mrgx2 receptor has been shown to be activated by the peptides cortistatin and proadrenomedullin n-terminal peptides (pamp) SIGNOR-139855 0.526 POLR1H protein Q9P1U0 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266156 0.2 STK11 protein Q15831 UNIPROT SIK2 protein Q9H0K1 UNIPROT up-regulates phosphorylation Thr175 KSGELLAtWCGSPPY 9606 14976552 t llicata A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold. SIGNOR-122788 0.459 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation Tyr904 SLRLVMEyLPSGCLR 9606 18250158 t lperfetto Y904 and y939 are required for optimal jak3 autophosphorylation and kinase activity in vitro SIGNOR-160664 0.2 CASP8 protein Q14790 UNIPROT Caspase 8 complex complex SIGNOR-C231 SIGNOR form complex binding cleavage:Asp216 SDSPREQdSESQTLD 10508785 t lperfetto Activated caspase-8 (an alpha2beta2 heterotetramer) activates other downstream caspases that are incapable of autocatalytic processing and activation. |The alphabeta dimeric protein associates further to form an alpha2beta2 heterotetramer that appears to be required for catalytic activity. SIGNOR-256395 0.2 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 23070005 t miannu For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. SIGNOR-199091 0.923 CDK5 protein Q00535 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates activity phosphorylation 9606 12202491 t lperfetto Pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity. Increasing doses of cdk2 resulted in increased phosphorylation of the thr-320 site. Phosphorylation of this site in pp1 corresponded to decreased pp1 activity. SIGNOR-264649 0.484 SMURF1 protein Q9HCE7 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates activity ubiquitination 9606 22298955 t lperfetto Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. SIGNOR-195672 0.599 MAPK8IP2 protein Q13387 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates binding 9606 10490659 t gcesareni Deletion analysis demonstrated that the cooh-terminal regions of jip1 and jip2 were sufficient for the formation of hetero-oligomeric complexes SIGNOR-70863 0.645 vismodegib chemical CHEBI:66903 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 21041712 t gcesareni Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date. SIGNOR-169194 0.8 KHK protein P50053 UNIPROT PRPS1 protein P60891 UNIPROT up-regulates activity phosphorylation Thr225 LVDDMADtCGTICHA 29074724 t lperfetto Ketohexokinase-A (KHK-A; also known as fructokinase-A) phosphorylates PRPS1 T225 and activates PRPS1 by blocking the binding of ADP, AMP, and GDP, which is required for hepatocellular carcinoma development SIGNOR-265735 0.355 alvocidib chemical CHEBI:47344 ChEBI CDK7 protein P50613 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192446 0.8 INS protein P01308 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates 9606 22521266 f gcesareni In conclusion,insulinlikely promotes mkp-3 protein degradation SIGNOR-197203 0.39 ABL1 protein P00519 UNIPROT RBM39 protein Q14498 UNIPROT up-regulates activity phosphorylation Tyr99 RGRYRSPySGPKFNS 9606 BTO:0000007 27018250 t miannu In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner. SIGNOR-262610 0.328 sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of 9606 19401148 t miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. SIGNOR-268133 0.8 haloperidol chemical CHEBI:5613 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258520 0.8 NUMB protein P49757 UNIPROT GLI1 protein P08151 UNIPROT down-regulates binding 9606 20818436 t gcesareni The consequent activation of_ itch, together with the recruitment of gli1 through direct binding with_ numb, allows gli1 to enter into the complex, resulting in gli1 ubiquitination and degradation. SIGNOR-167841 0.607 LPAR3 protein Q9UBY5 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 12531543 t gcesareni Lpa3couples to gq SIGNOR-97400 0.461 trimipramine chemical CHEBI:9738 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 9537821 t miannu At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter.  SIGNOR-258742 0.8 MALT1 protein Q9UDY8 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates binding 9606 BTO:0000782 17948050 t gcesareni Tab2/tak1 associate with ubiquitinated malt1 upon t-cell stimulation. SIGNOR-158551 0.59 PDGFRB protein P09619 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 20802513 t llicata In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases. SIGNOR-167658 0.538 NMDA proteinfamily SIGNOR-PF56 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). In contrast, group I mGluRs increase the intracellular Ca2+ concentration via a classical Gq-mediated mechanism that triggers release from intracellular stores through IP3 receptors SIGNOR-264931 0.8 SIK2 protein Q9H0K1 UNIPROT CEP250 protein Q9BV73 UNIPROT unknown phosphorylation Ser2394 LHHSLSHsLLAVAQA 9606 20708153 t lperfetto Remarkably, lc-ms confirmed that the predominant serine phosphorylation site of the recombinant carboxy-terminal domain of c-nap1 is s2392 at the predicted consensus phosphorylation sequence and to a lesser extent s2394. SIGNOR-167492 0.326 TERB1 protein Q8NA31 UNIPROT TERF1 protein P54274 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 SIGNOR-C305 SIGNOR-C306 33015044 t lperfetto The shelterin complex has six proteins, containing TRF1, TRF2, POT1, RAP1, TIN2, and TPP1. The shelterin complex is localized to the chromosome end and protects telomeric DNA (Palm and de Lange, 2008). The TTM complex acts as a “linker” and bridges the LINC and shelterin complexes together. The connection between TTM and shelterin complexes is well-known, which is mediated by TERB1 and TRF1 SIGNOR-263315 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR WEE1 protein P30291 UNIPROT down-regulates quantity by destabilization phosphorylation Ser123 EEGFGSSsPVKSPAA 23051732 t lperfetto Cdk1 phosphorylates Wee1 on Ser-123, which primes additional phosphorylation by other kinases, leading to the formation of phosphodegrons responsible for SCF (Skp1/cullin/F-box) ubiquitin-mediated degradation of Wee1 SIGNOR-267471 0.777 GSK3A protein P49840 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Thr254 RQVAIVFRtPPYADPS 10090 BTO:0000249 22761446 t Redundant functions of GSK-3_ and GSK-3_ through phosphorylation of RelA at Thr-254 play a crucial role in early stages of chondrocyte differentiation SIGNOR-255827 0.2 CSNK1G1 protein Q9HCP0 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Thr1479 SSSSTKGtYFPAILN 9606 16341016 t gcesareni Ck1gamma is associated with lrp6, which has multiple, modular ck1 phosphorylation sites. Wnt treatment induces the rapid ck1gamma-mediated phosphorylation of these sites within lrp6 SIGNOR-143029 0.526 BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 15574335 t gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma SIGNOR-131442 0.818 MMP2 protein P08253 UNIPROT LRP2 protein P98164 UNIPROT up-regulates quantity binding 10116 28659595 t miannu We show that megalin/LRP-2 acts as an endocytic receptor for proMMP-2:TIMP-2 complex. We found that RAP, an antagonist of the LDL receptor family18, competed with binding of proMMP-2:TIMP-2 complex onto rat BN16 epithelial cells. SIGNOR-265255 0.349 PRKCB protein P05771 UNIPROT KIR3DL1 protein P43629 UNIPROT down-regulates activity phosphorylation Ser415 QRKITRPsQRPKTPP -1 17911614 t miannu Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of Ser(394) by protein kinase C slightly suppresses KIR3DL1 inhibitory function, and reduces receptor internalization and turnover.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII. SIGNOR-276079 0.2 EPO protein P01588 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000574 9168989 f Regulation miannu We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin. SIGNOR-251783 0.357 bexarotene chemical CHEBI:50859 ChEBI RXRA protein P19793 UNIPROT up-regulates activity chemical activation 9606 BTO:0002058 17483357 t miannu Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification. SIGNOR-259230 0.8 ATP6AP1 protein Q15904 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization 9606 28296633 f miannu Depletion or inhibition of the V-ATPase stabilises HIF1α in aerobic conditions. SIGNOR-261347 0.2 NFS1 protein Q9Y697 UNIPROT Mitochondrial Fe-S Cluster Assembly Complex complex SIGNOR-C276 SIGNOR form complex binding -1 27519411 t lperfetto As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry. SIGNOR-262127 0.786 1038915-60-4 chemical CID:24958200 PUBCHEM PARP1 protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194399 0.8 PRKCB protein P05771 UNIPROT NRGN protein Q92686 UNIPROT up-regulates activity phosphorylation Ser36 AAAKIQAsFRGHMAR -1 8080473 t lperfetto Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM. SIGNOR-248914 0.368 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 15896703 t gcesareni We also found that AMP activated protein kinase and protein kinases A, B, and C catalyzed the phosphorylation of Ser-460 of HBP1, and that in addition both isoforms are phosphorylated at a second, as yet undetermined site by protein kinase C. However, none of the phosphorylations had any effect on the intrinsic kinetic characteristics of either enzymatic activity, and neither did point mutation (mimicking phosphorylation), deletion, and alternative-splice modification of the HBP1 carboxy-terminal region. Instead, these phosphorylations and mutations decreased the sensitivity of the 6PF2K to a potent allosteric inhibitor, phosphoenolpyruvate, which appears to be the major regulatory mechanism. SIGNOR-137241 0.2 DNMT1 protein P26358 UNIPROT DNMT1/DNMT3A complex SIGNOR-C42 SIGNOR form complex binding 9606 12145218 t miannu We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation SIGNOR-90836 0.774 SEC61G protein P60059 UNIPROT SEC61 complex complex SIGNOR-C368 SIGNOR form complex binding -1 33925740 t lperfetto The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER SIGNOR-265278 0.888 P2RY12 protein Q9H244 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256712 0.378 MAPKAPK3 protein Q16644 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser179 RRFRRSQsDCGELGD -1 15850461 t miannu Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. SIGNOR-263081 0.495 MVD protein P53602 UNIPROT HRAS protein P01112 UNIPROT up-regulates quantity by stabilization 9534 12646231 f miannu An overexpression of mot-2 resulted in reduced level of Ras and phosphorylated ERK2. These were rescued by co-expression of MPD from an exogenous promoter demonstrating a functional link between mot-2, MPD, and Ras. Ras and its oncogenic forms act as key players in controlling proliferation of normal and cancerous cells. Assigning mot-2 upstream of p21Ras offers an important mechanism for influence over cell proliferation. Therefore, we ra tionaled to investigate if overexpression of MPD could affect the steady state levels of Ras by affecting its prenylationTransient transfections of MPD-myc in COS 7 cells resulted in higher stable levels of Ras as compared to the untransfected cells (Fig. 3A, compare lanes 4 and 8 and Fig. 3B) SIGNOR-265888 0.2 ATM protein Q13315 UNIPROT FANCI protein Q9NVI1 UNIPROT unknown phosphorylation Ser730 LDKSADFsQSTSIGI 9606 BTO:0000007 17412408 t Three phosphorylation sites were detected in a human KIAA1794 protein: S730, T952, S1121, and two other sites in the mouse protein S555, T558. We renamed the KIAA1794 protein as FANCI, since, as shown below, the locus encoding this protein is mutated in an individual with Fanconi anemia complementation group I SIGNOR-255590 0.541 VRK1 protein Q99986 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Ser4 sQKHRDFV 9606 16495336 t gcesareni We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell SIGNOR-144783 0.873 SNTB1 protein Q13884 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding BTO:0001103 29681515 t apalma Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated SIGNOR-255979 0.497 FZD2 protein Q14332 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 25902418 t areggio Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain. SIGNOR-258968 0.675 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t miannu Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-264963 0.8 eprosartan chemical CHEBI:4814 ChEBI AGTR1 protein P30556 UNIPROT down-regulates activity chemical inhibition 9606 1309870 t miannu The angiotensin II (AII) antagonist activity of (E)-alpha-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5- yl]methylene]-2-thiophenepropanoic acid (SK&F 108566), was examined in a number of in vitro and in vivo assays. SIGNOR-258347 0.8 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Ser12 LASDFAFsPPPGGGG -1 31306665 t lperfetto Recent work found that CyclinE/CDK2 can phosphorylate OCT4 on serine 12 (S12), serine 355 (S355) and threonine 322 (T322) in vitro|Phosphorylation of OCT4 on S12 has been previously implicated to stabilize OCT4 by binding to PIN1, thereby preventing ubiquitinylation by WWP2. SIGNOR-264436 0.324 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 9606 8622669 t gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. SIGNOR-40493 0.338 RORA protein P35398 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates quantity by expression transcriptional regulation 28608249 t lperfetto Some genes which are directly regulated by RORA such as NLGN1 and NTRK2 have been shown to be associated with increased susceptibility to ASD (Correia et al. 2010; Ylisaukko-oja et al. 2005). SIGNOR-265137 0.269 CDK14 protein O94921 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Ser1490 AILNPPPsPATERSH 9606 20059949 t gcesareni Low-density lipoprotein receptor related proteins 5 and 6 (lrp5/6) are transmembrane receptors that initiate wnt/beta-catenin signaling. Phosphorylation of pppsp motifs in the lrp6 cytoplasmic domain is crucial for signal transduction. Using a kinome-wide rnai screen, we show that pppsp phosphorylation requires the drosophila cyclin-dependent kinase (cdk) l63. L63 and its vertebrate homolog pftk are regulated by the membrane tethered g2/m cyclin, cyclin y, which mediates binding to and phosphorylation of lrp6. SIGNOR-162924 0.339 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser192 PRPDHTKsIYTRSVI -1 10075701 t miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites SIGNOR-250225 0.2 HDAC4 protein P56524 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity deacetylation 9606 16613856 t lperfetto HDAC4 and HDAC5 deacetylate Runx2, allowing the protein to undergo Smurf-mediated degradation SIGNOR-227547 0.539 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002861 18682241 t flangone We also find that SMADs bind with the NANOG promoter and that SMAD2/3 activity enhances NANOG promoter activity. SIGNOR-242052 0.432 HNRNPU protein Q00839 UNIPROT GADD45A protein P24522 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 f lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. SIGNOR-262282 0.343 EIF3I protein Q13347 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266392 0.932 EGFR protein P00533 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 22693070 t lperfetto The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation SIGNOR-235689 0.728 ABL2 protein P42684 UNIPROT ABL2 protein P42684 UNIPROT up-regulates phosphorylation Tyr261 GLVTTLHyPAPKCNK 9606 15735735 t lperfetto The results show that arg is stabilized in response to 0.1 mm h2o2 by autophosphorylation of y-261, consistent with involvement of the arg kinase function in regulating arg levels. The results further demonstrate that c-abl-mediated phosphorylation of arg on y-261 similarly confers arg stabilization SIGNOR-134400 0.2 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 t Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases. SIGNOR-248388 0.48 BCL2L1 protein Q07817 UNIPROT APAF1 protein O14727 UNIPROT down-regulates activity binding 9606 9539746 t lperfetto These experiments demonstrate that bcl-xl associates with caspase-9 and apaf-1, and show that bcl-xl inhibits the maturation of caspase-9 mediated by apaf-1. SIGNOR-56399 0.836 SMAD4 protein Q13485 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR form complex binding 9606 11274206 t gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235178 0.709 PRKCE protein Q02156 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation SIGNOR-129312 0.317 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT up-regulates phosphorylation His118 QVGRNIIhGSDSVES 9606 BTO:0000763 22869372 t llicata Ndpk catalytic function requires autophosphorylation at the catalytic his-118 residue. the simplest interpretation of these data is that ampk does not directly phosphorylate ndpk-a at ser-120 or ser-122 (or at any other site) but rather enhances ndpk-a autophosphorylation at his-118. SIGNOR-198667 0.2 GSK3A protein P49840 UNIPROT STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization phosphorylation Thr385 ILTSNQKtLTPEKGQ 9606 BTO:0002181 31843895 t miannu GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation. SIGNOR-276761 0.266 IL1B protein P01584 UNIPROT KRT1 protein P04264 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17982242 f Regulation of expression miannu IL-1β alone decreased the expression of E-cadherin and cytokeratin SIGNOR-251883 0.251 ITK protein Q08881 UNIPROT TEC protein P42680 UNIPROT up-regulates phosphorylation Tyr206 RLERGQEyLILEKND 9606 12573241 t lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated SIGNOR-98090 0.382 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 11904305 t gcesareni Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1. SIGNOR-116166 0.629 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRNA7 protein P36544 UNIPROT up-regulates activity chemical activation 27167578 t Here, we demonstrate a role for α7 nAChR/G protein interaction in the activation of the small (monomeric) RhoA GTPase leading to cytoskeletal changes during neurite growth. Treatment of PC12 cells with the α7 nAChR agonist choline or PNU-282987 was associated with an increase in RhoA activity and an inhibition in neurite growth. SIGNOR-253984 0.8 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 17804415 t gcesareni Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun. SIGNOR-157721 0.377 PTPRB protein P23467 UNIPROT GHR protein P10912 UNIPROT down-regulates dephosphorylation 9606 12907755 t gcesareni Inally, mrna tissue distribution of these ptps by rt-pcr analysis and coexpression of the wild-type ptps to test their ability to dephosphorylate ligand-activated ghr suggest ptp-h1 and ptp1b as potential candidates involved in ghr signaling. SIGNOR-104580 0.299 BRSK1 protein Q8TDC3 UNIPROT CDC25B protein P30305 UNIPROT down-regulates phosphorylation Ser375 ARVLRSKsLCHDEIE 9606 BTO:0000567;BTO:0000938 BTO:0000142 15150265 t lperfetto Hssad1 specifically phosphorylated wee1a, cdc25-c, and -b on ser-642, ser-216, and ser-361 in vitro, respectivelyphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 SIGNOR-124839 0.52 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation 9606 19230643 t gcesareni Mdc1 also undergoes phosphorylation by ck2 after dna damage to generate a phospho-motif on mdc1, which binds directly to nbs1. SIGNOR-184130 0.353 MAPK3 protein P27361 UNIPROT PPP2R5C protein Q13362 UNIPROT down-regulates phosphorylation Ser337 QLAKCVSsPHFQVAE 9606 16456541 t gcesareni Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit. SIGNOR-144317 0.395 YWHAZ protein P63104 UNIPROT NEFL protein P07196 UNIPROT down-regulates activity binding 9606 23230147 t miannu These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments. SIGNOR-252397 0.281 DVL1 protein O14640 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity 9606 19279717 t areggio Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin SIGNOR-258978 0.278 SALL4 protein Q9UJQ4 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16840789 t Luana We conclude that the Nanog enhancer activity is regulated by both Sall4 and Nanog.  SIGNOR-266079 0.784 PIK3CA protein P42336 UNIPROT MTOR protein P42345 UNIPROT up-regulates 9606 18721898 f lperfetto Phosphoinositide 3-kinase (pi3k)-dependent activation of the rheb-mtor pathway triggers the simultaneous local synthesis of tc10 and par3. SIGNOR-180453 0.529 TNK2 protein Q07912 UNIPROT KDM3A protein Q9Y4C1 UNIPROT down-regulates activity phosphorylation Tyr1114 ITPEDRKyGTTNLHL 9606 BTO:0000093 25148682 t miannu We report that ACK1 phosphorylates the ER co-activator, KDM3A, a H3K9 demethylase, at an evolutionary conserved tyrosine 1114 site in a heregulin-dependent manner, even in the presence of tamoxifen. SIGNOR-276842 0.378 BDKRB2 protein P30411 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257281 0.402 D-thyroxine smallmolecule CHEBI:30659 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity chemical activation 9606 BTO:0003736 6777394 t inferred from family member miannu The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response. SIGNOR-270294 0.8 TAF11 protein Q15544 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263925 0.9 β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35 Three different subunits have been identified in humans: PFK-M (muscle), PFK-L (liver), and PFK-P (platelet).The subunits are expressed in a tissue-specific manner and, in erythrocytes, 5 isoenzymes of varying subunit composition (M4, M3L1, M2L2, ML3, and L4) can be identified. SIGNOR-266464 0.8 ACP1 protein P24666 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr857 DIMRDSNyISKGSTF 9606 12149261 t Insight into the role of low molecular weight phosphotyrosine phosphatase (LMW-PTP) on platelet-derived growth factor receptor (PDGF-r) signaling. LMW-PTP controls PDGF-r kinase activity through TYR-857 dephosphorylation|On the basis of these results, we propose a key role for LMW-PTP in PDGF-r down-regulation through the dephosphorylation of the activation loop Tyr-857, thus determining a general negative regulation of all downstream signals, with the exception of those elicited by internalized receptors. SIGNOR-248452 0.313 FLI1 protein Q01543 UNIPROT MPL protein P40238 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002581 15466856 f miannu Both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. SIGNOR-254163 0.248 PRKD1 protein Q15139 UNIPROT ATP7B protein P35670 UNIPROT up-regulates activity phosphorylation Ser1121 AHSERPLsAPASHLN 9606 BTO:0000599 21189263 t lperfetto ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking. SIGNOR-272295 0.301 MAPK3 protein P27361 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser696 EKNYALPsPATTEGG 9606 BTO:0000007 SIGNOR-C3 21071439 t lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-169526 0.481 GTF2A2 protein P52657 UNIPROT TFIIA complex SIGNOR-C395 SIGNOR form complex binding 9606 BTO:0000567 7724559 t lperfetto TFIIA purified from HeLa extracts consists of 35-, 19-, and 12-kDa subunits. Here we describe the isolation of a cDNA clone (hTFIIA gamma) encoding the 12-kDa subunit. SIGNOR-266196 0.938 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT unknown phosphorylation Tyr969 VSECPHTyQNRRPFS 10090 BTO:0001516 16627759 t lperfetto In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated. SIGNOR-271920 0.2 LDHB protein P07195 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI down-regulates quantity chemical modification 9606 24929216 t lperfetto Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. SIGNOR-267656 0.8 ITGB1BP1 protein O14713 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257647 0.756 IMPDH1 protein P20839 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI down-regulates quantity chemical modification 9606 19480389 t miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). SIGNOR-267331 0.8 SAGA complex complex SIGNOR-C465 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269637 0.2 MAPK1 protein P28482 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Thr1179 NYGTNPGtPPASTSP 9606 10660621 t lperfetto Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene. SIGNOR-74880 0.371 CPM protein P14384 UNIPROT HBA1 protein P69905 UNIPROT down-regulates activity cleavage Tyr141 STVLTSKyR -1 8635221 t miannu Both human plasma carboxypeptidase N (CPN) and membrane-bound carboxypeptidase M (CPM) released the C-terminal arginine (alpha-Arg141) of the alpha chain of human adult hemoglobin. Thus, the hydrolysis of hemoglobin by CPM and CPN demonstrated the contribution of the alpha-Arg141 residue to sustaining the tetrameric structure of hemoglobin and its normal oxygen affinity and vasoactivity. SIGNOR-256507 0.2 CYFIP1 protein Q7L576 UNIPROT NHS protein Q6T4R5 UNIPROT up-regulates activity binding 9606 20332100 t miannu We show that the WHD of NHS interacts with the Abi family of proteins, HSPC300, Nap1 and Sra1, and is important for the localization of NHS to the leading edge. SIGNOR-253575 0.2 3-[8-amino-1-(2-phenyl-7-quinolinyl)-3-imidazo[1,5-a]pyrazinyl]-1-methyl-1-cyclobutanol chemical CHEBI:91402 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193675 0.8 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t gcesareni Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190. SIGNOR-75906 0.385 BCL2L1 protein Q07817 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity binding -1 10949026 t lperfetto Bad dimerizes with bcl-xl at the mitochondrial membrane where it exert its killing effects. Phosphorylation of bad promotes its binding to 14-3-3 protein, which may sequester bad from bcl-xl, thus promoting cell cells survival. SIGNOR-81125 0.842 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT up-regulates activity phosphorylation Thr457 YVSPRIStPQTNTVP 9606 BTO:0000567 30021153 t lperfetto Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. SIGNOR-265035 0.2 PRKCA protein P17252 UNIPROT DLX3 protein O60479 UNIPROT unknown phosphorylation Ser138 KPRTIYSsYQLAALQ 10090 11343707 t lperfetto Dlx3 is primarily phosphorylated by PKCalpha. By deletion and mutational analysis, we show that the serine residue S138, located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3. | Since DNA binding may reveal only a part of Dlx3 protein function, we cannot rule out the influence of phosphorylation on other biological functions. Thus, the characterization of the full biological function of PKC phosphorylation of Dlx3 protein will require further studies. SIGNOR-249095 0.312 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LIMA1 protein Q9UHB6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser362 PVHPKPLsPDSRASS 9606 BTO:0001033 23188829 t miannu Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover. SIGNOR-263062 0.2 WARS1 protein P23381 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) SIGNOR-270512 0.8 MAP3K8 protein P41279 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates phosphorylation 9606 22435554 t gcesareni Furthermore, we found that immunoprecipitated tpl-2 could directly phosphorylate and activate both mek-1 and mkk4 (also known as sek-1) SIGNOR-196744 0.54 (R)-2-hydroxyglutarate(2-) smallmolecule CHEBI:15801 ChEBI TET2 protein Q6N021 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001883 29090344 t miannu Various studies have tried to investigate how the accumulation of R2-HG promotes leukemogenesis in cooperation with other frequently observed mutations in AML. An important role appears to be the ability of R2-HG to competitively inhibit multiple αKG-dependent dioxygenases. While TET2 normally catalyzes the conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), inhibition of TET2 by R2-HG has been found to result in a hypermethylated gene signature in HSPCs, which overlaps with the signatures of both IDH and TET2-mutated leukemic cells. SIGNOR-261829 0.8 USP2 protein O75604 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity deubiquitination Lys502 LSQQEGIkM -1 29490279 t miannu Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1. SIGNOR-273605 0.2 ITSN1 protein Q15811 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates quantity by stabilization binding 24789820 t lperfetto Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth SIGNOR-260714 0.562 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser77 YEPEGSAsPTPPYLK 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248495 0.272 SMAD3 protein P84022 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 15367216 t The TCR, IL-2R, and TbetaR must all be stimulated to induce Foxp3 + Tregs. Failure to engage any one of these receptors prevents the generation of Foxp3 + Tregs SIGNOR-254363 0.538 NR2E3 protein Q9Y5X4 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates binding 9606 15190009 t gcesareni All four proteins, nr2e3, nr1d1, nrl and crx, could be co-immunoprecipitated from the bovine retinal nuclear extract, suggesting their existence in a multi-protein transcriptional regulatory complex in vivo. SIGNOR-125661 0.408 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM FGFR3 protein P22607 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258081 0.8 CSNK1A1 protein P48729 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser321 NSNASTVsGRLSPIM 9606 20110348 t lperfetto Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export SIGNOR-252900 0.393 PRKCB protein P05771 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 t lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization. SIGNOR-202784 0.2 PCDHAC2 protein Q9Y5I4 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-269033 0.2 FZD3 protein Q9NPG1 UNIPROT GNGT1 protein P63211 UNIPROT up-regulates binding 9606 17251915 t gcesareni In the non-canonical wnt signalling pathway, frizzled uses galphaq or galphai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat. SIGNOR-152606 0.372 AKT proteinfamily SIGNOR-PF24 SIGNOR TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-251526 0.777 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. SIGNOR-235960 0.741 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 8940173 t lperfetto Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor SIGNOR-45130 0.564 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser295 LQASVPGsVPGVLGP 9606 16027724 t llicata Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo. SIGNOR-250730 0.488 GNG12 protein Q9UBI6 UNIPROT PRKACA protein P17612 UNIPROT down-regulates binding 9606 17251915 t gcesareni As pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp. SIGNOR-152615 0.385 PPP1CA protein P62136 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 16501611 t Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. SIGNOR-248557 0.319 MMP14 protein P50281 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 28709001 f MMP14 Promotes Adipogenesis Downstream of or in Parallel to TIMP3 SIGNOR-255909 0.7 COPS3 protein Q9UNS2 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates quantity by stabilization binding 9606 30631038 t miannu Our observations characterizing the interaction between CSN3 and the Sos1 HD suggest that this domain not only functions regulating Sos-GEF autoinhibition but is also involved in other functional roles, such as the control of Sos protein stability and homeostasis by modulating the degradation and intracellular levels of Sos1. SIGNOR-256217 0.2 CSNK1A1 protein P48729 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates activity phosphorylation Ser159 GIPVRCYsAEVVTLW -1 10500146 t miannu We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro. Ser(159) in cdk5 is homologous to the regulatory Thr(160) in cdk2. SIGNOR-275966 0.302 FGF1 protein P05230 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 10618369 t lperfetto We have crystallized a complex between human FGF1 and a two-domain extracellular fragment of human FGFR2. SIGNOR-73811 0.906 ATP(4-) smallmolecule CHEBI:30616 ChEBI P2RY2 protein P41231 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257563 0.8 SIK2 protein Q9H0K1 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 16308421 t gcesareni Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2 SIGNOR-142218 0.733 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser505 SPERRCRsVELDLNQ 9606 16216881 t lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. SIGNOR-141014 0.2 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR Core Binding Factor complex complex SIGNOR-C214 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-255972 0.2 CDC20 protein Q12834 UNIPROT UBE2S protein Q16763 UNIPROT up-regulates activity binding 9606 BTO:0000567 19822757 t lperfetto Ube2S depends on the cell cycle-dependent association with the APC/C activators Cdc20 and Cdh1 for its activity SIGNOR-265082 0.867 CAMK2D protein Q13557 UNIPROT TPD52 protein P55327 UNIPROT unknown phosphorylation Ser176 KNSPTFKsFEEKVEN 9606 20032513 t gcesareni Here we demonstrate, using site-specific mutations, that ca(2+)-sensitive phosphorylation at serine 136 modulates the accumulation of d52 at the plasma membrane within 2 min of cell stimulation SIGNOR-162630 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250555 0.2 IST1 protein P53990 UNIPROT SPAST protein Q9UBP0 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 23897888 t Gianni Our results suggest that inclusion of IST1 into the ESCRT complex allows recruitment of spastin to promote fission of recycling tubules from the endosome. Thus, we reveal a novel cellular role for MT severing and identify a mechanism by which endosomal recycling can be coordinated with the degradative machinery. SIGNOR-269047 0.534 ALDOB protein P05062 UNIPROT glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266484 0.8 dothiepin chemical CHEBI:36798 ChEBI CHRM4 protein P08173 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8100134 t miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. SIGNOR-258698 0.8 LSM-20934 chemical CHEBI:109533 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258726 0.8 ATR protein Q13535 UNIPROT ZDHHC13 protein Q8IUH4 UNIPROT up-regulates activity phosphorylation Ser8 MEGPGLGsQCRNHSH 10090 BTO:0000847 28869973 t miannu Collectively these results suggest that ZDHHC13 phosphorylation by ATR following UVB irradiation promotes its interaction with MC1R to stimulate MC1R palmitoylation. SIGNOR-273517 0.2 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 t The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction. SIGNOR-175817 0.81 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT up-regulates activity sumoylation Lys65 QQCQAEAkCPKLLPC 9534 BTO:0000298 9756909 t lperfetto We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins |We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites. The PML mutant with Lys to Arg substitutions in all three sites is expressed normally, but cannot be sentrinized|Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. SIGNOR-270542 0.771 STAT5A protein P42229 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15498859 t Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells. SIGNOR-261517 0.384 MBD3 protein O95983 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263847 0.801 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR PSEN1 protein P49768 UNIPROT down-regulates activity phosphorylation Ser357 PHRSTPEsRAAVQEL 9606 BTO:0000007 17360711 t gcesareni We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin. SIGNOR-228022 0.404 TFIIH complex SIGNOR-C457 SIGNOR AR protein P10275 UNIPROT down-regulates phosphorylation Ser516 VSRVPYPsPTCVKSE 9606 21157430 t acerquone Here, we show that the transcription factor tfiih, via its cdk7 kinase, phosphorylates the androgen receptor (ar) at position ar/s515. Strikingly, this phosphorylation is a key step for an accurate transactivation that includes the cyclic recruitment of the transcription machinery, the mdm2 e3 ligase, the subsequent ubiquitination of ar at the promoter of target genes and its degradation by the proteasome machinery SIGNOR-269331 0.324 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1016 DVVDADEyLIPQQGF 9606 8845374 t lperfetto The c-terminal autophosphorylation domain of egfr was extensively phosphorylated by c-src./These studies revealed that y1086 was phosphorylated to a significantly higher extent by c-src than by egfr. Additionally, y1101 was identified as a unique c-src phosphorylation site SIGNOR-44239 0.609 (S)-selisistat chemical CHEBI:90371 ChEBI SIRT1 protein Q96EB6 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191511 0.8 CSNK2A1 protein P68400 UNIPROT FANCD2 protein Q9BXW9 UNIPROT down-regulates activity phosphorylation Thr896 KNSECDPtPSHRGQL 9606 BTO:0000567 31167143 t miannu Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations.  SIGNOR-276733 0.2 BABAM1 protein Q9NWV8 UNIPROT BRCA1-A complex complex SIGNOR-C296 SIGNOR form complex binding 9606 BTO:0000007 20656690 t lperfetto We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1.  SIGNOR-263215 0.924 PPP1CA protein P62136 UNIPROT NEK2 protein P51955 UNIPROT down-regulates dephosphorylation 9606 17283141 t gcesareni Nek2 is activated by autophosphorylation, and its dephosphorylation is catalyzed by pp1 SIGNOR-152949 0.382 MAPK3 protein P27361 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates phosphorylation Ser307 EPPSPPQsPRVEEAS 9606 8940068 t gcesareni Sequential phosphorylation of hsf1 by mitogen-activated protein kinase and glycogen synthase kinase 3 at ser-303 and ser-307 represses transcriptional activation by heat shock factor-1. SIGNOR-44999 0.616 TFEB protein P19484 UNIPROT ATP6V1H protein Q9UI12 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276535 0.309 FLNA protein P21333 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity binding 9606 20156194 t miannu We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself SIGNOR-260629 0.507 MELK protein Q14680 UNIPROT PDPK1 protein O15530 UNIPROT down-regulates activity phosphorylation Thr354 WENLHQQtPPKLTAY 9606 BTO:0000007 22544756 t miannu The results showed that MPK38 interacted with and inhibited PDK1 activity via Thr(354) phosphorylation.  SIGNOR-276414 0.27 TBR1 protein Q16650 UNIPROT FEZF2 protein Q8TBJ5 UNIPROT down-regulates quantity by repression transcriptional regulation BTO:0000938 21228164 t lperfetto We found that TBR1 promotes the identity of corticothalamic neurons and represses subcerebral fates through reducing expression of Fezf2 and CTIP2.|(3) Chromatin immunoprecipitation analysis using TBR1 antibodies showed that TBR1 bound to a conserved region in the Fezf2 gene. SIGNOR-268967 0.499 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR RBPMS protein Q93062 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17442773 f miannu Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. The gene for the RNA‐binding protein with multiple splicing (RBPMS) was upregulated in NUP98‐HOXA9–transduced cord blood CD34+ cells and also in the transcriptosomes of normal CD34+ and CD133+ cells. SIGNOR-261503 0.2 FSCN1 protein Q16658 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 10090 BTO:0000526 21706053 f miannu Plexin-B3 interacts with the actin-binding protein fascin-1. The present finding suggests fascin-1 as a potential effector of plexin-B3 to mediate the signal of Sema5A in glioma cells.Sema5A and plexin-B3 remodel F-actin cytoskeleton and induce fascin-1 translocation in glioma cells. SIGNOR-268375 0.7 GRIK3 protein Q13003 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity relocalization 9606 BTO:0002609 12393813 t lperfetto Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine SIGNOR-268274 0.8 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249350 0.728 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr775 TPMYGSQtPMYGSGS 9606 16427012 t lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif SIGNOR-143923 0.768 CDC42BPA protein Q5VT25 UNIPROT PPP1R12C protein Q9BZL4 UNIPROT down-regulates activity phosphorylation Thr560 MRQSRRStQGVTLTD BTO:0000298 11399775 t llicata Identification of the Phosphorylation Site of p85 on Threonine 560 by MRCKα-CAT | Wild-type p85 but not the mutant p85AA, when phosphorylated in vitro with MRCKα-CAT, showed significant reduction in the rate of MLC2 dephosphorylation. These results confirm a similar observation with MBS130 where phosphorylation of a conserved threonine 695 within a highly conserved motif was essential for the inhibition of phosphatase catalytic activity SIGNOR-250724 0.575 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR USP24 protein Q9UPU5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2047 QRVSDQNsPVLPKKS 9606 BTO:0000018 27991932 t lperfetto Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. SIGNOR-275610 0.26 FOXO proteinfamily SIGNOR-PF27 SIGNOR FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15109499 t Constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers SIGNOR-252929 0.2 CSF2RA protein P15509 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 8977526 t lperfetto JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation. SIGNOR-249502 0.513 USF1 protein P22415 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28624438 t miannu The promoter region of ADAM10 contains several transcription factor binding sites that can stimulate its transcription. These include binding sites for transcription factors SP1 and USF, and the spliced form of the X-box binding protein (XBP)-1 as well as a retinoic acid-responsive element SIGNOR-259837 0.273 GNB/GNG complex SIGNOR-C202 SIGNOR PLCB2 protein Q00722 UNIPROT up-regulates 23994464 t apalma However, it was later shown that other PLCβ isoforms (particularly PLCβ2 and PLCβ3) can also be directly activated by Gβγ subunits SIGNOR-255015 0.528 QARS1 protein P47897 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 t miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). SIGNOR-270358 0.2 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1784 TPTSPNYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273107 0.745 POLE2 protein P56282 UNIPROT DNA polymerase epsilon complex SIGNOR-C377 SIGNOR form complex binding 9606 BTO:0000567 10801849 t lperfetto Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon. SIGNOR-265519 0.919 TLR7 protein Q9NYK1 UNIPROT IFNA1 protein P01562 UNIPROT up-regulates quantity 9606 BTO:0004625 15661881 f miannu TLR7 in pDC is functionally associated with the production of IFN-α- and IFN-regulated cytokines, similar to the role of TLR9. SIGNOR-259248 0.413 SIAH2 protein O43255 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates ubiquitination 9606 16174773 t lperfetto Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system SIGNOR-140651 0.604 TGFB1 protein P01137 UNIPROT ENPP1 protein P22413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000249 20930330 f miannu TGF-β1 was shown to stimulate ANK and PC-1 expression in articular chondrocytes, and subsequent ePPi level, as well as to increase ePi uptake by inducing PiT-1 expression in a chondrogenic cell line. SIGNOR-252200 0.271 FANCL protein Q9NW38 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates activity ubiquitination SIGNOR-C300 18985065 t lperfetto Phosphorylation of FANCD2 and Fanconi anemia core components (broken pink circles) affects the efficiency of, but is not essential for, ID ubiquitination by the FA core complex, together with E1 and UBE2T. Analogously, ubiquitination of FANCD2 (solid orange ovals) is essential for DNA repair, activating the ID complex for chromatin binding SIGNOR-263264 0.897 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation Tyr223 TSFMMTPyVVTRYYR 9606 15911620 t lperfetto Two mapkks, sek1 and mkk7, synergistically activate jnk. Sek1 prefers the tyr-185 residue, and mkk7 prefers the thr-183 residue (17, 19). SIGNOR-137605 0.733 PRKCB protein P05771 UNIPROT EWSR1 protein Q01844 UNIPROT down-regulates activity phosphorylation Ser266 SSYGQQSsFRQDHPS 9606 9341188 t miannu Here we report thatews, a nuclearrna-bindingprooncoprotein, contains an iq domain, is phosphorylated byproteinkinase c, and interacts with calmodulin. Interestingly, pkc phosphorylation of ews inhibits its binding to rna homopolymers, and conversely,rna binding to ews interferes with pkc phosphorylation./ these data indicate that ews contains an iq domain with ser266 acting as the primary site for pkc phosphorylation. SIGNOR-52854 0.279 TSC1 protein Q92574 UNIPROT TSC complex SIGNOR-C101 SIGNOR form complex binding 9606 12172553 t lperfetto TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR). SIGNOR-217910 0.933 PRKAR1B protein P31321 UNIPROT PRKACA protein P17612 UNIPROT down-regulates activity binding 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258753 0.851 CSNK1A1 protein P48729 UNIPROT HNRNPC protein P07910 UNIPROT down-regulates phosphorylation Ser253 ETNVKMEsEGGADDS 9606 15687492 t gcesareni A kinase activity was identified in mouse liver that phosphorylates the acd of hnrnp-c at ser(240) and at two sites at ser(225)-ser(228). The kinase was purified and identified by tandem mass spectrometry as protein kinase ck1alpha (formerly casein kinase 1alpha).hnrnp-c1 that was also modified at the ck1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that ck1alpha-mediated phosphorylation modulates the mrna binding ability of hnrnp-c. SIGNOR-133528 0.361 histamine smallmolecule CHEBI:18295 ChEBI HRH4 protein Q9H3N8 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257515 0.8 PPP2R5D protein Q14738 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR form complex binding 9606 23454242 t gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. SIGNOR-243439 0.852 RPL23A protein P62750 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262476 0.852 FRK protein P42685 UNIPROT PTEN protein P60484 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr336 NKDKANRyFSPNFKV 9606 BTO:0000093 19345329 t miannu Rak phosphorylates PTEN on Tyr 336 to prevent its protein degradation. In this study, we demonstrate that the Rak tyrosine kinase physically interacts with PTEN and phosphorylates PTEN on Tyr336. Knockdown of Rak enhanced the binding of PTEN to its E3 ligase NEDD4-1 and promoted PTEN polyubiquitination, leading to PTEN protein degradation.  SIGNOR-275458 0.582 NHLRC1 protein Q6VVB1 UNIPROT AGL protein P35573 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0000298 17908927 t miannu The E3 ubiquitin ligase Malin interacts with and promotes the ubiquitination of AGL. SIGNOR-271669 0.577 SIN3A protein Q96ST3 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 16254079 t Chromatin immunoprecipitation (ChIP) and DNA affinity precipitation analysis demonstrated that Ebp1 and Sin3A associate at the PSA and E2F1 promoters. Functionally, Sin3A enhanced the ability of Ebp1 to repress transcription of androgen receptor (AR) and E2F1 regulated genes. SIGNOR-253663 0.2 YAP1 protein P46937 UNIPROT TEAD1 protein P28347 UNIPROT up-regulates binding 9606 23431053 t Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4 gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14. SIGNOR-201465 0.902 FIS1 protein Q9Y3D6 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 25486875 f lperfetto During fission, DRP1 is recruited from the cytosol to the outer mitochondrial membrane, where it assembles with FIS1 to constrict the mitochondrial tubule (2) SIGNOR-272976 0.7 CAK complex complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 9315650 t llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase. SIGNOR-269324 0.446 MC4R protein P32245 UNIPROT Food intake phenotype SIGNOR-PH152 SIGNOR down-regulates 9606 BTO:0000614 33094623 f miannu Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. Adipose tissue derived hormone leptin induces negative energy balance by stimulating α-MSH and melanocortin-4 receptor (MC4R) (Friedman 1997, Kask et al. 1998). Increased melanocortin signaling in hypotalamus leads not only to decreased food intake but also increases sympathetic nervous system outflow to skeletal muscle, energy expenditure and physical activity SIGNOR-263504 0.7 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser705 TPSAMKSsPQIPHQT 9606 20236090 t Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. SIGNOR-248337 0.553 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr225 IKGRAQPyDPNFYDE 9606 12052863 t lperfetto We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown). SIGNOR-88899 0.608 PRCP protein P42785 UNIPROT POMC protein P01189 UNIPROT down-regulates activity 10090 20694162 f miannu Prolylcarboxypeptidase (PRCP) was found to be responsible for the control of food intake and energy expenditure at a central level. The molecular mechanisms underlying the suppression of food intake in PRCP-deficient mice or by the inhibitor of PRCP clearly provide physiological evidence that PRCP is an inactivator of α-MSH SIGNOR-252372 0.303 RPS6KA1 protein Q15418 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Ser947 CRLNRSDsDSSTLSK 9606 BTO:0000149 24269383 t llicata Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. erk_rsk phosphorylation of kibra is required for proper cell proliferation and rsk-mediated phosphorylation also positively modulates kibra's migratory activity. SIGNOR-203294 0.341 GATA2 protein P23769 UNIPROT Mast-Cell_diff phenotype SIGNOR-PH117 SIGNOR up-regulates activity 10090 BTO:0000830 25801432 f We have identified GATA2 as an essential transcription factor in differentiation of newly identified common basophil and mast cell progenitors into basophils and mast cells. ll differentiation and maintenance SIGNOR-259959 0.7 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RXRA protein P19793 UNIPROT up-regulates activity chemical activation 9606 18321241 t miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). SIGNOR-259237 0.8 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Ser77 GEKGRALsTRCQPLE -1 2584239 t lperfetto We have now determined that PKC phosphorylated serine 43 (and/or serine 45), serine 78, and threonine 144 in the free Tn-I subunit SIGNOR-248890 0.349 CNOT7 protein Q9UIV1 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268307 0.83 AKT proteinfamily SIGNOR-PF24 SIGNOR PHB2 protein Q99623 UNIPROT down-regulates binding 10090 15173318 t lperfetto Akt binds prohibitin 2 and relieves its repression of myod and muscle differentiation SIGNOR-234441 0.2 ARPC2 protein O15144 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 t The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc SIGNOR-251514 0.958 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser585 WRGMLKTSKAEELLA 9606 BTO:0000007 17301055 t Barakat Drp1 was specifically phosphorylated at Ser-585 by Cdk1/cyclin B, which stimulated the mitochondrial fission in mitosis. From these results, we concluded that mitochondrial morphology is regulated by Drp1-dependent mitochondrial fission in mitotic cells SIGNOR-274131 0.379 VKORC1L1 protein Q8N0U8 UNIPROT vitamin K epoxide smallmolecule CHEBI:28371 ChEBI down-regulates quantity chemical modification 9606 31226734 t lperfetto The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form SIGNOR-265902 0.8 KMT5B protein Q4FZB7 UNIPROT EID3 protein Q8N140 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 23720823 t miannu Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. The novel inhibitor of differentiation Eid3 is an FRG1/Suv4-20h1 target involved in the myogenic defects caused by FRG1 over-expression. Eid3 is down-regulated upon muscle differentiation and behaves as a myogenic inhibitor gene. SIGNOR-266640 0.2 WDR45B protein Q5MNZ6 UNIPROT TSC complex SIGNOR-C101 SIGNOR up-regulates quantity binding 9606 BTO:0001938 28561066 t miannu WIPI3 associates with the TSC complex and FIP200. The specific interaction between WIPI3 and the TSC complex was demonstrated by immunopurification of both endogenous TSC1 and TSC2 with GFP-WIPI3 (Fig. 5a). These data suggest that WIPI3 functions in association with the TSC complex to regulate mTOR activity in the lysosomal compartment. SIGNOR-268479 0.2 KIF16B protein Q96L93 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272527 0.7 BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR TP53 protein P04637 UNIPROT unknown ubiquitination 9606 BTO:0000007 14636569 t lperfetto However, since the same domain of p53 is also the target of ubiquitination by MDM2 protein, further in vivo experiments are required to demonstrate the biological relevance of p53 ubiquitination by BRCC.|The Extreme C Terminus of p53 Is Ubiquitinated by BRCC SIGNOR-263210 0.615 PIP3 smallmolecule CHEBI:16618 ChEBI ZFYVE26 protein Q68DK2 UNIPROT up-regulates quantity relocalization 9606 BTO:0000567 20208530 t miannu We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. SIGNOR-265537 0.8 MIB1 protein Q86YT6 UNIPROT DLL1 protein O00548 UNIPROT up-regulates activity ubiquitination 9606 16140393 t lperfetto Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity. SIGNOR-209750 0.732 Benzofuro(3,2-d)pyrimidin-4(3H)-one, 8-chloro-2-((2S)-2-pyrrolidinyl)- chemical CID:135564632 PUBCHEM CDC7 protein O00311 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000179 22560567 t Federica In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413. SIGNOR-261105 0.8 PDPK1 protein O15530 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation Thr500 WDGVTTKtFCGTPDY 9606 17115692 t lperfetto The catalytic or kinase domain requires phosphorylation at three sites for full activation (24, 25): ? Phosphorylation of threonine 500 (thr-500) in the activation loop by the upstream kinase pdk-1 is a prerequisite for the maturation of the enzyme (26), which subsequently leads to autophosphorylation at threonine 641 (thr-641) in the turn motif and serine 660 (ser-660) in the hydrophobic motif SIGNOR-150857 0.501 ROS stimulus SIGNOR-ST2 SIGNOR SNCA protein P37840 UNIPROT up-regulates quantity 9606 16000336 f lperfetto The increased concentration of neuronal alpha-synuclein and pigment in normal A9 neurons may already predispose these neurons to precipitate alpha-synuclein around pigment-associated lipid under oxidative conditions. SIGNOR-249699 0.7 MAPK9 protein P45984 UNIPROT MFN2 protein O95140 UNIPROT down-regulates phosphorylation Ser27 HMAEVNAsPLKHFVT 9606 22748923 t lperfetto Jnk phosphorylation of mitofusin 2 in response to cellular stress leads to recruitment of the ubiquitin ligase (e3) huwe1/mule/arf-bp1/hecth9/e3histone/lasu1 to mitofusin 2, with the bh3 domain of huwe1 implicated in this interaction. This results in ubiquitin-mediated proteasomal degradation of mitofusin 2these data establish that mfn2 is phosphorylated on ser27 in response to a variety of cellular stresses and implicate jnk in this process SIGNOR-198054 0.358 MAP2K6 protein P52564 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation 9606 8974401 t gcesareni A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) SIGNOR-45369 0.451 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120116 0.316 MAML1 protein Q92585 UNIPROT EP300 protein Q09472 UNIPROT up-regulates relocalization 9606 19304754 t gcesareni We show that maml1 potentiates p300 autoacetylation and p300 transcriptional activation. Maml1 directly enhances p300 hat activity, and this coincides with the translocation of maml1, p300 and acetylated histones to nuclear bodies. SIGNOR-184853 0.636 DUSP6 protein Q16828 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12840032 t gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). SIGNOR-103149 0.849 fluoxetine chemical CHEBI:5118 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 9537821 t miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. SIGNOR-258738 0.8 CDK1 protein P06493 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser688 QFHSPVGsPLKSIQA 9606 SIGNOR-C17 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. SIGNOR-164491 0.462 VRK1 protein Q99986 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Ser4 sQKHRDFV 9606 BTO:0000567 16371512 t gcesareni We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell SIGNOR-143285 0.873 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage -1 10978167 t lperfetto Thrombin selectively cleaves PAR1, PAR3, and PAR4 to induce activation of platelets and vascular cells, SIGNOR-263608 0.883 mTORC1 complex SIGNOR-C3 SIGNOR MYC protein P01106 UNIPROT up-regulates 9606 24856037 f miannu MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity SIGNOR-256172 0.348 FGR protein P09769 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr925 DRSNDKVyENVTGLV 9606 12387730 t gcesareni Phosphorylated on tyrosine residues upon activation. Phosphorylation at tyr-925 is important for interaction with grb2 and depends on the complex formation between fak and the src-kinase fgr. SIGNOR-94405 0.533 MAPK9 protein P45984 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 18691976 t The effect has been demonstrated using P45984-2 gcesareni Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. SIGNOR-179275 0.495 L-thyroxine smallmolecule CHEBI:18332 ChEBI iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity precursor of 9606 34674502 t scontino Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule.¬† SIGNOR-268126 0.8 PTEN protein P60484 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates quantity by stabilization dephosphorylation Thr179 FQNRRYKtKRKQLSS 9606 31213464 t lperfetto Loss of PTEN Accelerates NKX3.1 Degradation to Promote Prostate Cancer Progression.|PTEN was also able to dephosphorylate NKX3.1 at threonine 179, a target of protein kinase C, but not threonine residues 89 and 93, targeted by casein kinase 2 . SIGNOR-277026 0.453 DLG3 protein Q92796 UNIPROT NMDA receptor_2B complex SIGNOR-C348 SIGNOR up-regulates activity relocalization BTO:0000227 32904533 t lperfetto DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses. SIGNOR-266007 0.727 STK38 protein Q15208 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 BTO:0000007 21262772 t no lperfetto More importantly, with the direct regulation of p21 stability by phosphorylation on Ser 146, we define here the first downstream signaling mechanisms by which NDR kinases can control G1/S progression.|NDR kinases regulate p21 stability by phosphorylation of S146 on p21. | SIGNOR-272961 0.2 SKA complex complex SIGNOR-C364 SIGNOR Ndc80 complex complex SIGNOR-C361 SIGNOR up-regulates activity relocalization -1 22483620 t lperfetto The Ska complex is an essential mitotic component required for accurate cell division in human cells. It is composed of three subunits that function together to establish stable kinetochore-microtubule interactions in concert with the Ndc80 network. |We discuss how this symmetric architecture might complement and stabilize the Ndc80-microtubule attachments SIGNOR-265225 0.545 NSD2 protein O96028 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001130 19481544 t miannu In this study, we discovered that nsd2 specifically interacts with the dna-binding domain of androgen receptor (ar) via its hmg domain, and the nuclear translocation of both nsd2 and ar is enhanced in the presence of ligand / the histone methyltransferase, nsd2, enhances androgen receptor-mediated transcription. SIGNOR-186045 0.2 CDK5 protein Q00535 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12202491 t gcesareni Pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity. Increasing doses of cdk2 resulted in increased phosphorylation of the thr-320 site. Phosphorylation of this site in pp1 corresponded to decreased pp1 activity. SIGNOR-92269 0.403 NAE complex SIGNOR-C131 SIGNOR CUL1 protein Q13616 UNIPROT up-regulates activity neddylation 9606 25504797 t lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. SIGNOR-243151 0.736 NR3C1 protein P04150 UNIPROT NR3C1/STAT5A complex SIGNOR-C84 SIGNOR form complex binding 9606 8878484 t fspada We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter. SIGNOR-44373 0.545 AKT1 protein P31749 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 21798082 t gcesareni Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-175294 0.634 SPOP protein O43791 UNIPROT BMI1 protein P35226 UNIPROT up-regulates activity binding 9606 BTO:0000007 15897469 t miannu Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. To investigate whether BMI1 can form a complex with SPOP and CULLIN3 in vivo, we reconstituted the complex in 293HEK cells. We find that BMI1 readily immunoprecipitates both hemagglutinin (HA)-SPOP and CULLIN3, and, conversely, CULLIN3 immunoprecipitates BMI1 (Fig. 2a). Complex formation depends on the presence of SPOP, in accordance with BMI1 binding to the MATH domain of SPOP (Fig. 1b) and previously published data showing SPOP–CULLIN interaction by means of the BTB/POZ domain of SPOP (30). SIGNOR-272658 0.409 CRTC3 protein Q6UUV7 UNIPROT BCL3 protein P20749 UNIPROT up-regulates binding 9606 BTO:0001271;BTO:0000776;BTO:0000786 17644518 t miannu The ankyrin repeat domain of bcl3 interacted with torc3 / we determined that bcl3 inhibited transcription from the htlv-1 ltr in a manner dependent on torc3 SIGNOR-156950 0.368 PFKFB4 protein Q16877 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI down-regulates quantity chemical modification 9606 15170386 t miannu Fru-2,6-P2 (fructose 2,6-bisphosphate) is a signal molecule that controls glycolysis. Since its discovery more than 20 years ago, inroads have been made towards the understanding of the structure‚Äì function relationships in PFK-2 (6-phosphofructo-2-kinase)/ FBPase-2 (fructose-2,6-bisphosphatase), the homodimeric bifunctional enzyme that catalyses the synthesis and degradation of Fru-2,6-P2 SIGNOR-268117 0.8 452342-67-5 chemical CID:10202642 PUBCHEM TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 BTO:0000671 18075500 t gcesareni Gw788388 is a new tgf-beta type i receptor inhibitor with a much improved pharmacokinetic profile compared with sb431542. SIGNOR-159863 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SP1 protein P08047 UNIPROT up-regulates activity phosphorylation 9606 23616010 t lperfetto Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1. SIGNOR-233523 0.2 RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000975 11018021 t lperfetto The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins. SIGNOR-244945 0.738 PRKACA protein P17612 UNIPROT AQP5 protein P55064 UNIPROT up-regulates activity phosphorylation Ser156 STDSRRTsPVGSPAL 9606 BTO:0000007 26569106 t lperfetto AQP5 can be directly phosphorylated by PKA at Ser 156 |Our data hint at a mechanism whereby phosphorylation of Ser 156 in AQP5 increases its membrane localization, thereby enhancing cancer cell proliferation. SIGNOR-272088 0.2 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 16046550 t The effect has been demonstrated using Q01196-8 miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. SIGNOR-138973 0.2 PAMPs stimulus SIGNOR-ST11 SIGNOR AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR up-regulates 9606 25720354 f scontino APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. SIGNOR-267855 0.7 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser110 SDKKEKKsFSLEEKS 9606 20573420 t lperfetto Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation. SIGNOR-166317 0.369 AKT1 protein P31749 UNIPROT VCP protein P55072 UNIPROT up-regulates phosphorylation Ser352 AATNRPNsIDPALRR 9606 BTO:0000150 16551632 t llicata Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I SIGNOR-252491 0.523 CPT1B protein Q92523 UNIPROT (R)-carnitine smallmolecule CHEBI:16347 ChEBI down-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267121 0.8 DAGLA protein Q9Y4D2 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI down-regulates quantity chemical modification 9606 26787883 t miannu Diacylglycerol lipases (DAGL√鬱 and DAGL√é¬≤) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. SIGNOR-264262 0.8 NSD3 protein Q9BZ95 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0002181 28205554 t irozzo Indeed, dose-dependent TR-FRET and affinity pull-down assay confirmed the interaction of NSD3-s with MYC. Supporting functional significance of the interaction, co-expression of NSD3-s, but not the MYC-binding defective fragment of NSD3-s (1–347), stabilized MYC protein and increased MYC transcriptional activity as revealed by a MYC-driven reporter assay. SIGNOR-259199 0.2 MERTK protein Q12866 UNIPROT MERTK protein Q12866 UNIPROT up-regulates phosphorylation Tyr749 FGLSKKIySGDYYRQ 9606 8702477 t gcesareni By using a vaccinia virus expression system to express a constitutively activated form of nyk, we identified the major sites of nyk autophosphorylation in tryptic peptide iy749sgdy753y754r. Tyr-749, tyr-753, and tyr-754 in this peptide lie in the activation loop of the kinase domain. SIGNOR-42914 0.2 AURKB protein Q96GD4 UNIPROT CHMP4C protein Q96CF2 UNIPROT up-regulates phosphorylation Ser210 MSSTARRsRAASSQR 9606 22724069 t lperfetto Moreover, we find that the cpc's catalytic subunit, aurora b kinase, phosphorylates one of the three human snf7 paralogues-chmp4c-in its c-terminal tail, a region known to regulate its ability to form polymers and associate with membranes. Phosphorylation at these sites appears essential for chmp4c function because their mutation leads to cytokinesis defects. The introduction of the s214a and s215a mutations together with s210a almost completely abolished aurora b phosphorylation SIGNOR-197967 0.482 MTSS1 protein O43312 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates binding 9606 BTO:0001253 15545630 t miannu We found that in vitro translated gli1 and sufu bind to gst-mim, but not gst-mim?N399 Or gst columns (fig. 4f). Indicative of the importance of the mim/gli complex interactions, the mim?N399 Mutant that fails to interact with gli and sufu showed a markedly reduced capacity to potentiate gli-dependent transcription (fig. 4g). Although these results indicate that a mim/gli/sufu complex is important for mim-mediated transcriptional potentiation SIGNOR-130545 0.449 C5AR1 protein P21730 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity by expression 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263469 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4C protein Q08493 UNIPROT up-regulates activity phosphorylation Ser14 GEGAEACsRLSRSRG 9534 12023945 t miannu Long PDE4 isoforms from all four sub-families can be phosphorylated by protein kinase A (PKA). This leads to an increase in their activity and may thus contribute to cellular desensitization processes in cells where these isoforms are selectively expressed.These were Ser89Ala-PDE4A8, Ser133Ala-PDE4B1, Ser13Ala-PDE4C2 and Ser126Ala-PDE4D5. SIGNOR-273938 0.2 MAPK3 protein P27361 UNIPROT SYN3 protein O14994 UNIPROT up-regulates phosphorylation Ser470 PQGQQPLsPQSGSPQ 9606 14732590 t lperfetto A rare, missense polymorphism, s470n, was identified in the synapsin iii gene and appeared more frequently in individuals with schizophrenia than in controls. Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action. SIGNOR-121402 0.2 SNAI2 protein O43623 UNIPROT CXCL12 protein P48061 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 22074556 f miannu We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. SIGNOR-255169 0.418 ITCH protein Q96J02 UNIPROT DTX1 protein Q86Y01 UNIPROT down-regulates ubiquitination 9606 17028573 t gcesareni Itch/aip4 mediates deltex degradation through the formation of k29-linked polyubiquitin chains. SIGNOR-150002 0.688 PRKACA protein P17612 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser486 DDEITEAKsGTATPQRS 10116 BTO:0002135 17023420 t These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine. SIGNOR-256110 0.402 GNE protein Q9Y223 UNIPROT UDP-N-acetyl-alpha-D-glucosamine smallmolecule CHEBI:16264 ChEBI down-regulates quantity chemical modification 10745088 t lperfetto UDP-GlcNAc 2-epimerase is a bifunctional enzyme and catalyzes the first two steps of neuraminic acid synthesis in the cytosol, the conversion of UDP-N-acetylglucosamine to ManAc and the phosphorylation to ManAc-6-phosphate. SIGNOR-266073 0.8 CBX1 protein P83916 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-264493 0.2 HIC1 protein Q14526 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000452 19486893 f miannu HIC1 is also implicated in growth control since it recruits BRG1, one of the two alternative ATPases (BRM or BRG1) of SWI/SNF chromatin-remodeling complexes to repress transcription of E2F1 in quiescent fibroblasts. SIGNOR-254239 0.292 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR PROX1 protein Q92786 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002181 36433955 t miannu Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation. SIGNOR-277610 0.2 CYP11B2 protein P19099 UNIPROT 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI down-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268681 0.8 ZNF521 protein Q96K83 UNIPROT EBF1 protein Q9UH73 UNIPROT down-regulates binding 9606 BTO:0000776 14630787 t miannu Ehzf inhibits the transcriptional activity of early b-cell factor (ebf), a transcription factor essential for specification of the b-cell lineage /ability to interact with the neural and hematopoietic transcription factor olf1/ebf1 and inhibit its binding to dna SIGNOR-119300 0.514 CD38 protein P28907 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000078 18626062 f miannu CD38 knockdown was found to increase apoptosis in normal microglia, but played a protective role in LPS-stimulated microglia and reduced proinflammatory cytokine secretion (Figure 1) SIGNOR-264255 0.7 GABA-A proteinfamily SIGNOR-PF61 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t miannu GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-264988 0.8 MC3R protein P41968 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256891 0.252 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM2 protein Q14416 UNIPROT up-regulates activity chemical activation 9606 25042998 t miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate SIGNOR-264071 0.8 FYN protein P06241 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268213 0.619 SRC protein P12931 UNIPROT ENG protein P17813 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr614 TAALWYIySHTRSPS 9606 BTO:0002828 25070888 t miannu We identified epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) as Src-activators that induce endoglin turnover following (612)YIY(614) phosphorylation.  SIGNOR-276654 0.393 sirolimus chemical CHEBI:9168 ChEBI LILRB2 protein Q8N423 UNIPROT down-regulates quantity by repression 9606 18652845 f miannu Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells. SIGNOR-255477 0.8 DPM complex complex SIGNOR-C289 SIGNOR dolichyl beta-D-mannosyl phosphate smallmolecule CHEBI:17624 ChEBI up-regulates quantity chemical modification 9606 10835346 t lperfetto Dolichol-phosphate-mannose (DPM) synthase generates mannosyl donors for glycosylphosphatidylinositols, N-glycan and protein O- and C-mannosylation. SIGNOR-262566 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EGR1 protein P18146 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11085989 f miannu We also show for the first time that leptin rapidly stimulates the mRNA expression of the zinc finger transcription factor, Egr-1, in the hypothalamus of mice. Our transfection results suggest that this regulation by leptin occurs by activation of theegr-1 promoter via activation of SHP-2 and of the ERK pathway.  SIGNOR-263507 0.2 NF2 protein P35240 UNIPROT LATS1 protein O95835 UNIPROT up-regulates binding 9606 24012335 t The opposite changes in Lats/YAP and Mst1/2 phosphorylation upon loss of NF2 therefore argue against the generally assumed linear model in which NF2 signals through activation of Mst1/3 flangone As expected, the nf2-/- fc-912 cells were defective in lats1/2 phosphorylation (figure s2e-f). Subcellular fractionation revealed a significant increase of endogenous lats1/2 in the cytoplasmic relative to the membrane fraction in the nf2-/- fc-912 schwann cells compared to the nf2+/+ fh-912 schwann cells (figure 2e). This localization defect was rescued by re-expression of nf2 SIGNOR-202604 0.711 CSRP3 protein P50461 UNIPROT MYF6 protein P23409 UNIPROT up-regulates activity binding 10090 BTO:0004058 9234731 t 2 miannu we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements. SIGNOR-241096 0.457 RPS6KA1 protein Q15418 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 BTO:0000848 15024089 t gcesareni We show that the n-terminal kinase domain of rsk phosphorylates flna on ser(2152) in response to mitogens SIGNOR-123458 0.391 pyruvate smallmolecule CHEBI:15361 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 24363178 t miannu As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2) SIGNOR-266553 0.8 MYC protein P01106 UNIPROT HLA-E protein P13747 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000848 8206526 f miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. SIGNOR-254604 0.2 oxaprozin chemical CHEBI:7822 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000132;BTO:0003652 9650852 t miannu We used human platelets cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 for measuring cyclooxygenase selectivity. The presence of the enzymes was confirmed by immunoblotting and immunoprecipitation analysis, and by the reverse transcriptase-polymerase chain reaction. Mean IC50 values (microM) for human platelet cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 and cyclooxygenase-1/-2 IC50 ratio of various NSAIDs were as follows: aspirin, 3.2, 26, 0.12; diclofenac, 0.037, 0.00097, 38; etodolac, 122, 0.68, 179; ibuprofen, 3.0, 3.5, 0.86; indomethacin, 0.013, 0.044, 0.30; loxoprofen (active metabolite), 0.38, 0.12, 3.2; NS-398, 12, 0.0095, 1263; oxaprozin, 2.2, 36, 0.061; zaltoprofen, 1.3, 0.34, 3.8; respectively. SIGNOR-258929 0.8 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione chemical CHEBI:92539 ChEBI ADRA1A protein P35348 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190604 0.8 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253682 0.753 FARSA protein Q9Y285 UNIPROT Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR form complex binding 9606 20223217 t miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. SIGNOR-270436 0.994 APC2 protein O95996 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 SIGNOR-C110 9601641 t acerquone Human axin (haxin) binds directly to beta-catenin, gsk3 beta, and apc in vitro, and the endogenous proteins are found in a complex in cells. SIGNOR-57673 0.766 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191409 0.8 SNU13 protein P55769 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270629 0.2 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr89 VSPLLLTtTNSSEGL 9606 11152499 t tpavlidou Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites. SIGNOR-85785 0.2 S1PR3 protein Q99500 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 BTO:0000007 10488065 t gcesareni Edg-3 and edg-5 couple not only to gibut also to gqand g13. SIGNOR-70710 0.509 CEP72 protein Q9P209 UNIPROT CDK5RAP2 protein Q96SN8 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 t lperfetto By bringing CDK5RAP2 to the centrosome, the centriolar satellite proteins CEP72 and SPAG5 are required for the centrosomal localization of the other three MCPH proteins despite not interacting with them biochemically. SIGNOR-271720 0.649 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 17311928 t inferred from 70% family members llicata Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1 SIGNOR-270036 0.2 MCM2 protein P49736 UNIPROT MCM complex SIGNOR-C268 SIGNOR form complex binding 9606 19946136 t The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. SIGNOR-198428 0.768 PRKCG protein P05129 UNIPROT STK17B protein O94768 UNIPROT down-regulates activity phosphorylation Ser351 PEDSSMVsKRFRFDD 10090 BTO:0000944 18084041 t miannu These results suggest that phosphorylation of Ser350 plays an essential role in regulating translocation of DRAK2 to the nucleus from the cytoplasm, possibly by affecting the activity of the NLS. Ectopic expression of PKC-gamma induced cytoplasmic localization of DRAK2 and PKC-gamma phosphorylated Ser350 flanking the NLS. SIGNOR-263178 0.2 ADORA1 protein P30542 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256840 0.438 CTNND1 protein O60716 UNIPROT CDH5 protein P33151 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0003564 14610055 t miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. SIGNOR-252126 0.767 DEPTOR protein Q8TB45 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-205603 0.714 RNF5 protein Q99942 UNIPROT PXN protein P49023 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 12861019 t miannu Here we demonstrate that the human homologue of RNF5 associates with the amino-terminal domain of paxillin, resulting in its ubiquitination. RNF5 requires intact RING and C-terminal domains to mediate paxillin ubiquitination.  Concomitantly, RNF5 expression results in inhibition of cell motility. Via targeting of paxillin ubiquitination, which alters its localization, RNF5 emerges as a novel regulator of cell motility. SIGNOR-271479 0.416 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr1008 LNANDEAtVSVLGEL 9606 17376779 t gcesareni Bubr1 was phosphorylated by plk1 in vitro at two plk1 consensus sites in the kinase domain of bubr1 SIGNOR-153863 0.834 Dacinostat chemical CID:6445533 PUBCHEM HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 15171259 t lperfetto We have developed a cinnamic hydroxamic class of histone deacetylase inhibitors of which a prototype was designated as NVP-LAQ824. NVP-LAQ824, inhibits histone deacetylase enzymatic activities in vitro and transcriptionally activated the p21 promoter in reporter gene assays. SIGNOR-262032 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 21502402 t inferred from 70% family members llicata Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro SIGNOR-270209 0.2 HIPK2 protein Q9H2X6 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser38 EGRQPSPsPSPTERA 9606 19015637 t llicata In response to dna damage, hipk2 phosphorylates pml at serines 8 and 38. he n-terminal phosphorylation sites contribute to the dna damage-induced pml sumoylation and are required for the ability of pml to cooperate with hipk2 for the induction of cell death. SIGNOR-182428 0.449 LATS2 protein Q9NRM7 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 t Uninhibited YAP/TAZ localize to the nucleus where they serve as coactivators for the TEA-domain family member (TEAD) of DNA-binding transcription factors. milica In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. SIGNOR-197655 0.815 JNJ-28312141 free base chemical CID:11676971 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258125 0.8 CDK1 protein P06493 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation 9606 21840486 t gcesareni Here, we show that klhl20, a cullin3 (cul3) substrate adaptor induced by hif-1, coordinates with the actions of cdk1/2 and pin1 to mediate hypoxia-induced pml proteasomal degradation. SIGNOR-176033 0.351 MAPK1 protein P28482 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 19364816 t gcesareni Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21cip1.|Phosphopeptide analysis of in vitro ERK2-phosphorylated p21(Cip1) revealed two phosphorylation sites, Thr57 and Ser130. SIGNOR-185215 0.372 PAK1 protein Q13153 UNIPROT ILK protein Q13418 UNIPROT up-regulates phosphorylation Thr173 DTFWKGTtRTRPRNG 9606 17420447 t lperfetto We found that pak1 phosphorylates ilk at threonine-173 and serine-246 in vitro and in vivo. together, these results suggest that ilk is a pak1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin. SIGNOR-154307 0.42 Elongator complex complex SIGNOR-C466 SIGNOR TUBA1B protein P68363 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 t miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. SIGNOR-269719 0.256 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249639 0.741 FST protein P19883 UNIPROT MSTN protein O14793 UNIPROT down-regulates activity binding 10090 24627466 t lperfetto Follistatin (FST) is a member of the tissue growth factor beta family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. FST315-deltaHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function. SIGNOR-251717 0.75 EEF1A1 protein P68104 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-205606 0.302 BRF1 protein Q92994 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR form complex binding 29378333 t lperfetto Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1). SIGNOR-266190 0.703 SRC protein P12931 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr566 RYVLDDQyVSSVGTK 9606 10688651 t lperfetto Coexpression of v-src and etk led to a transphosphorylation on tyrosine 566 of etk and subsequent autophosphorylation. These events correlated with a substantial increase in the kinase activity of etk. SIGNOR-75330 0.516 CDK1 protein P06493 UNIPROT PLEC protein Q15149 UNIPROT down-regulates phosphorylation Thr4539 GGLIEPDtPGRVPLD 9606 SIGNOR-C17 19709076 t lperfetto Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane. SIGNOR-187766 0.396 MAPK1 protein P28482 UNIPROT PDE4C protein Q08493 UNIPROT down-regulates phosphorylation Ser641 YQSKIPRsPSDLTNP 9606 11030732 t The effect has been demonstrated using Q08493-2 gcesareni The short-form pde4b2 isoenzyme was activated by erk2 phosphorylation. sub-family selective actions in the ability of erk2 map kinase to phosphorylate and regulate the activity of pde4 cyclic amp-specific phosphodiesterases SIGNOR-83187 0.258 TDGF1 protein P13385 UNIPROT ACVR2A protein P27037 UNIPROT down-regulates binding 9606 BTO:0000007 12682303 t acerquone Here we show that cripto can form a complex with activin and actrii/iib cripto inhibited crosslinking of activin to alk4 and the association of alk4 with actrii/iib. SIGNOR-100052 0.627 ABL1 protein P00519 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 BTO:0001271 8441409 t lperfetto Sh1 domain autophosphorylation of p210 bcr/abl is required for transformation but not growth factor independence. SIGNOR-39142 0.2 AMER1 protein Q5JTC6 UNIPROT CSNK1G1 protein Q9HCP0 UNIPROT up-regulates binding 9606 21304492 t gcesareni Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6. SIGNOR-171889 0.2 HDLBP protein Q00341 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity binding 9606 BTO:0000150 33941620 t miannu We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites. SIGNOR-266697 0.2 AURKA protein O14965 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser539 TSLSPRSsLSSPSPP 9606 21878642 t llicata We identified the highly conserved ser(539) as the primary phosphorylation site for aurora kinases. SIGNOR-176359 0.253 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 BTO:0000567 17615152 t gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-156852 0.657 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC3 protein O15379 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-203476 0.8 MMP16 protein P51512 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272384 0.7 MCM4 protein P33991 UNIPROT MCM complex SIGNOR-C268 SIGNOR form complex binding 9606 19946136 t The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. SIGNOR-261674 0.767 oxymetazoline chemical CHEBI:7862 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 9913 BTO:0000142 9632357 t miannu Benzylimidazolines may represent a class of 5-HT1D ligands that has yet to be exploited. On the basis of a previous report that the 2-(substituted-benzyl)imidazoline alpha-adrenergic agonist oxymetazoline (8) binds with high affinity at calf brain 5-HT1D receptors, we explored the structure-affinity relationships of a series of related derivatives. SIGNOR-258928 0.8 ANAPC13 protein Q9BS18 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 t lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. SIGNOR-252012 0.829 SIRT1 protein Q96EB6 UNIPROT TP53 protein P04637 UNIPROT down-regulates deacetylation Lys382 QSTSRHKkLMFKTEG 9606 BTO:0000150 19047049 t gcesareni Sirt1 has been shown to regulate cell fate in part by deacetylating the p53 protein at lysine 382 and inhibiting p53-mediated transcriptional activation and apoptosis. SIGNOR-182515 0.796 LAMC1 protein P11047 UNIPROT Laminin-1 complex SIGNOR-C183 SIGNOR form complex binding 7496033 t lperfetto Laminin-1 is an extracellular matrix protein composed of three polypeptide chains that are designated alpha 1, beta 1, and gamma 1. SIGNOR-253234 0.602 SMAD7 protein O15105 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 9892110 t lperfetto Smad6 and smad7, can prevent tgfb signaling by interacting either with the receptor or with smad2 and smad3. SIGNOR-64085 0.597 estriol smallmolecule CHEBI:27974 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258586 0.8 PTPN11 protein Q06124 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity dephosphorylation Ser727 TDNLLPMsPEEFDEV 9606 BTO:0000007 12270932 t SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei|In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr(701) and the serine residue Ser(727) |Overexpression of SHP-2 in 293T cells inhibited IFNgamma-dependent Stat1 phosphorylation and suppressed Stat1-dependent induction of luciferase activity. SIGNOR-248673 0.733 ANAPC7 protein Q9UJX3 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 t lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. SIGNOR-252007 0.836 MARK1 protein Q9P0L2 UNIPROT MAP4 protein P27816 UNIPROT down-regulates activity phosphorylation Ser941 NVRSKVGsTENIKHQ -1 8631898 t miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. SIGNOR-250171 0.448 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide chemical CHEBI:91447 ChEBI EPHB4 protein P54760 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194916 0.8 CTBP1 protein Q13363 UNIPROT ZEB2 protein O60315 UNIPROT up-regulates activity binding 9606 16061479 t miannu Polycomb protein Pc2 acts as an SUMO E3 ligase for SIP1. SIP1 is an active transcription repressor for many transcription factors and target genes. SIP1 Sumoylation Disrupts the Recruitment of the Corepressor CtBP SIGNOR-225484 0.486 BCL3 protein P20749 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates 9606 16713561 f gcesareni The cyclin d1 elevation is caused not by increased p65/p50 action but rather by increased nuclear activity of bcl-3-associated nf-kappab p50 and p52 SIGNOR-146771 0.554 Ruboxistaurin chemical CID:153999 PUBCHEM PRKACB protein P22694 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258275 0.8 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser531 GSRSRTPsLPTPPTR -1 9614189 t miannu S214 can be rapidly and selectively phosphorylated in vitro by PKA, and this single site strongly affects tau's ability to bind and stabilize microtubules. SIGNOR-250006 0.443 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 12510059 t gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. SIGNOR-96944 0.767 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr832 LRYEGRVyHYRINTA 9606 16912036 t Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. SIGNOR-260814 0.2 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 11839802 t gcesareni Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2a and dephosphorylation of akt and glycogen synthase kinase 3 beta SIGNOR-252616 0.89 TRAF2 protein Q12933 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 10346818 t amattioni Oligomerization of the traf2 effector domain results in specific binding to mekk1, a protein kinase capable of jnk, p38, and ikk activation SIGNOR-67552 0.706 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 9741627 t lperfetto Shc is subsequently phosphorylated at tyrosine 317 and recruits grb2 SIGNOR-60160 0.721 PTPN3 protein P26045 UNIPROT VCP protein P55072 UNIPROT down-regulates activity dephosphorylation Tyr805 EDNDDDLyG 9606 BTO:0000007 10364224 t Identification of VCP as a substrate of PTPH1in vivo.|The tyrosines (Tyr796 and Tyr805) at the C terminus of VCP have been reported to be the major sites of phosphorylation, with Tyr805 accounting for more than 90% of the tyrosine phosphorylation on the protein |The Y796F/Y805F VCP mutant was not associated with any of the PTPH1 constructs. SIGNOR-248461 0.491 PKI-587 chemical CID:44516953 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252650 0.8 HOXA11 protein P31270 UNIPROT PRL protein P01236 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003697 19727442 t Luana HoxA-11 enhanced upregulation of PRL only in differentiated cells. SIGNOR-261630 0.358 PTPN12 protein Q05209 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates activity dephosphorylation Tyr1196 GAVENPEyLTPQGGA 9606 29330094 t miannu In MDA-MB-231 cells, a human triple negative breast cancer cell line, phosphorylation of PTPN12 on Ser 19 was increased in response to cyclin dependent kinase 2 (CDK2), and this impaired PTPN12 's ability to dephosphorylate HER2 on Y1196.|PTPN12 negatively regulates Her2, by dephosphorylation on Tyr 1196 on Her2. SIGNOR-277038 0.603 α-D-glucosyl-glycogenin complex SIGNOR-C430 SIGNOR glycogen smallmolecule CHEBI:28087 ChEBI up-regulates quantity precursor of 9606 26199317 t miannu Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis by generating α-1,6-glucosidic branches from α-1,4-linked glucose chains, to increase solubility of the glycogen polymer. In eukaryotes, glycogenin (EC 2.4.1.186) initiates the synthesis of the linear glucan chain (2), which is elongated by glycogen synthase (GYS, EC 2.4.1.11) (3), functioning in concert with glycogen branching enzyme (GBE, EC 2.4.1.18) to introduce side chains SIGNOR-268138 0.8 LHX1 protein P48742 UNIPROT OTX2 protein P32243 UNIPROT up-regulates activity binding 9606 BTO:0000567 10623575 t miannu Here we show that OTX2 directly associates with LIM1 and HNF-3beta. The luciferase assay with the P3C sequence, a specific DNA binding sequence for paired-class homeobox genes, has demonstrated that LIM1 enhances, but HNF-3beta represses, OTX2-directed gene expression. SIGNOR-221161 0.445 BCL7C protein Q8WUZ0 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270715 0.516 WNT5A protein P41221 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 16273260 t gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. SIGNOR-253129 0.828 FAM13A protein O94988 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260502 0.41 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates activity phosphorylation Ser211 TLGSPLTsPGGSPGG 9606 BTO:0001131 9630228 t lperfetto Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4. SIGNOR-109763 0.573 MYC protein P01106 UNIPROT ENO1 protein P06733 UNIPROT up-regulates quantity transcriptional regulation 10116 10823814 t C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway. SIGNOR-259989 0.421 RPL22 protein P35268 UNIPROT RPL22L1 protein Q6P5R6 UNIPROT down-regulates 9606 23990801 f miannu We find that rpl22 directly represses expression of rpl22l1 mrna by binding to an internal hairpin structure. SIGNOR-202600 0.387 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR TRIM71 protein Q2Q1W2 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269247 0.289 AMPK complex SIGNOR-C15 SIGNOR TET2 protein Q6N021 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001412 31900833 t miannu Inactivation of AMPK suppressed the expression of ten-eleven translocation methylcytosine dioxygenase 2 (TET2) in tumor cells. Compound C-induced AMPK suppression causes downregulation TET2 and FOXP3 expression, leading to death of parental and HQ-selected U937 cells. These results confirm the connection of AMPK with the TET2–FOXP3 axis in modulating the survival of AML cells and suggest that suppression of the AMPK–TET2–FOXP3 axis suppresses the progression of AML and HQ-induced malignant transformation of AML cells. SIGNOR-260097 0.2 PTEN protein P60484 UNIPROT HCLS1 protein P14317 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 f miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). SIGNOR-260052 0.2 TNF protein P01375 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by repression transcriptional regulation 10116 9397972 f inferred from family member scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells grown in TSH-containing medium. These include TNF-a, IL-lb and INF-g but not TGF-b. SIGNOR-267811 0.26 KIF3B protein O15066 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 28290984 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272516 0.7 NEUROG3 protein Q9Y4Z2 UNIPROT NEUROG2 protein Q9H2A3 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19028584 f miannu Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. SIGNOR-254633 0.2 PPP3CC protein P48454 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 f gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-83740 0.433 CFI protein P05156 UNIPROT C3 protein P01024 UNIPROT down-regulates activity cleavage 9606 BTO:0000089 26806831 t lperfetto FH also serves as cofactor for the serine protease factor I (FI) that cleaves C3b into iC3b, unable to form C3 convertase (Fig 1B). SIGNOR-263489 0.874 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser9 EEPQSDPsVEPPLSQ 9606 11875057 t gcesareni In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization. SIGNOR-115348 0.838 AKT proteinfamily SIGNOR-PF24 SIGNOR SRPK2 protein P78362 UNIPROT up-regulates phosphorylation Thr492 PSHDRSRtVSASSTG 9606 BTO:0000938 BTO:0000142 19592491 t lperfetto Here we show that srpk2, a protein kinase specific for the serine/arginine (sr) family of splicing factors, triggers cell cycle progression in neurons and induces apoptosis through regulation of nuclear cyclin d1. Akt phosphorylates srpk2 on thr-492 and promotes its nuclear translocation leading to cyclin d1 up-regulation, cell cycle reentry, and neuronal apoptosis. SIGNOR-244341 0.2 KRAS protein P01116 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation Ser67 RQLRKVRsVELDQLP 9606 BTO:0000776;BTO:0000785 8649450 t gcesareni Activation of ras may lead to two distinct ras-dependent pathways involving either a raf1/mek/mapk module or a mekk/sek/sapk module; jnk/sapk binds to the d domain near the nh2 terminus of mekk1 from approximately residues 6270 (9, 10). Pak1 can phosphorylate mekk1 on serine 67 within its jnk/sapk-binding d domain. Phosphorylation of mekk1 on serine 67 alters the state of the d domain, thereby decreasing its affinity for jnk/sapk. Under these conditions jnk/sapk is not recruited into the mekk1 signaling module. SIGNOR-41953 0.373 NCOA1 protein Q15788 UNIPROT APOC3 protein P02656 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255065 0.2 ERBB2 protein P04626 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 8816440 t gcesareni Most breast, skin, lung, ovary, and gastrointestinal tract tumors express erbb-4, and heterodimerization of this receptor with erbb-2, may be involved in some cancer SIGNOR-43844 0.509 CAMK2B protein Q13554 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1303 NKLRRQHsYDTFVDL BTO:0003036 8940188 t llicata By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons. SIGNOR-250688 0.589 WASF2 protein Q9Y6W5 UNIPROT WAVE complex complex SIGNOR-C271 SIGNOR form complex binding 9606 BTO:0000567 15070726 t lperfetto Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex.  SIGNOR-261871 0.907 E2F1 protein Q01094 UNIPROT ELF4 protein Q99607 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20805247 f miannu we determined that E2F1 specifically binds to MEF promoter and transactivates MEF. SIGNOR-253849 0.248 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 BTO:0002181 16046550 t The effect has been demonstrated using Q01196-8. gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-138953 0.599 AKT3 protein Q9Y243 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245424 0.726 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr280 VEFMCKVySDPQPHI 9606 12601080 t lperfetto Fgfr signaling is under the control of tyrosine phosphorylation to elicit activation of cellular signaling cascades. Ligand binding induces receptor dimerization and transphosphorylation. Fgfr1 contains eleven tyrosine residues (tyr154, tyr280, tyr307, tyr463, tyr585, tyr605, tyr653, tyr654, tyr730 and tyr766), some of which are directly involved regulating the activity of the receptor and others bind to activate substrates leading to the activation of various transduction pathways. SIGNOR-98626 0.2 A4/b1 integrin complex SIGNOR-C162 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257704 0.622 R2TP core co-chaperone complex SIGNOR-C515 SIGNOR PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR form complex binding 9606 30484152 t miannu The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92.  SIGNOR-270925 0.646 IKBKB protein O14920 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 11971985 t We demonstrated the in vitro phosphorylation of SRC-3 by the two catalytic subunits of the IKK complex, IKKα and IKKβ.  IKK kinase activity is required for synergistic activation with SRC-3 SIGNOR-251298 0.386 RPS6KA3 protein P51812 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Thr1109 DRKIIATtLSKLKLE 9606 BTO:0002181 23608533 t miannu We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding. SIGNOR-276463 0.2 CUDC-101 chemical CID:24756910 PUBCHEM HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20143778 t miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. SIGNOR-262262 0.8 NFE2L2 protein Q16236 UNIPROT TALDO1 protein P37837 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 f miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). SIGNOR-267357 0.375 CLK2 protein P49760 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser243 DKRKDPSsVDIKKVL -1 10480872 t llicata The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site. SIGNOR-250776 0.328 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA2 protein Q9Y5H1 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265691 0.2 clonidine chemical CHEBI:46631 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258903 0.8 RPS6KA3 protein P51812 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-70436 0.2 DSCAM protein O60469 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity binding 9606 BTO:0000938 30745319 t miannu Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels. SIGNOR-264277 0.2 TFIIE complex SIGNOR-C458 SIGNOR TFIIH complex SIGNOR-C457 SIGNOR up-regulates activity relocalization 9606 31064989 t lperfetto The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur. SIGNOR-269363 0.731 PELI1 protein Q96FA3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates quantity by expression ubiquitination 9606 17997719 t lperfetto These results were consistent with the observations made in vitro, namely that pellino isoforms are activated by irak1-catalysed phosphorylation and that, once activated, can ubiquitinate irak1 in cells. SIGNOR-159055 0.758 PIK3R1 protein P27986 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242637 0.934 BNIP3 protein Q12983 UNIPROT RHEB protein Q15382 UNIPROT down-regulates binding 9606 17928295 t gcesareni Bnip3, a hypoxia-inducible bcl-2 homology 3 domain-containing protein, directly binds rheb and inhibits the mtor pathway. Bnip3 decreases rheb gtp levels in a manner depending on the binding to rheb. SIGNOR-158274 0.741 BST1 protein Q10588 UNIPROT NAD(+) smallmolecule CHEBI:15846 ChEBI down-regulates quantity chemical modification 9606 18626062 t miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. SIGNOR-264250 0.8 TRIB3 protein Q96RU7 UNIPROT ACACB protein O00763 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 16794074 t miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). SIGNOR-271601 0.261 Lig4-Xrcc4 complex complex SIGNOR-C354 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates -1 19837014 t miannu The DNA ligase IV-Xrcc4 complex is responsible for the ligation of broken DNA ends in the non-homologous end-joining (NHEJ) pathway of DNA double strand break repair in mammals. SIGNOR-264534 0.7 PRKCE protein Q02156 UNIPROT KCNK3 protein O14649 UNIPROT down-regulates activity phosphorylation Thr383 TGLHSLStFRGLMKR -1 23229553 t miannu We have previously shown that carbamylated PAF-induced repolarization abnormalities result from the protein kinase C (PKC) ε-dependent phosphorylation of the two-pore domain potassium channel TASK-1. Further studies identified threonine 383 in the C terminus of human and canine TASK-1 as the phosphorylation site required for PAF-dependent inhibition of the channel. SIGNOR-276431 0.2 DOK1 protein Q99704 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257679 0.321 ALG11 protein Q2TAA5 UNIPROT alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc(PP-Dol) smallmolecule CHEBI:133994 ChEBI up-regulates quantity chemical modification 9606 28575298 t lperfetto The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in eukaryotic protein N-glycosylation starts on the cytoplasmic side of the endoplasmic reticulum and includes the sequential addition of five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by the Alg1, Alg2 and Alg11 gene products and yield Dol-PP-GlcNAc2Man5, an LLO intermediate that is subsequently flipped to the lumen of the endoplasmic reticulum. SIGNOR-260417 0.8 PAX8 protein Q06710 UNIPROT TPO protein P07202 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 27347897 t scontino TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8. SIGNOR-267277 0.409 Anacetrapib chemical CID:11556427 PUBCHEM CETP protein P11597 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189605 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR AGAP2 protein Q99490 UNIPROT up-regulates phosphorylation Ser985 THLSRVRsLDLDDWP 9606 BTO:0001130 19176382 t lperfetto In addition, we have found that activated akt can bind and phosphorylate ggap2 at serine 629, which enhances gtp binding by ggap2. SIGNOR-244132 0.2 SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 30397315 f miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269828 0.7 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 11904294 t lperfetto We found that hypoxia greatly accelerated tal1 turnover in these cells through mitogen-activated protein kinase (mapk)2-mediated phosphorylation, ubiquitination, and proteasomal degradation. SIGNOR-244975 0.2 DVL1 protein O14640 UNIPROT RND1 protein Q92730 UNIPROT up-regulates 9606 23151663 f gcesareni In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. SIGNOR-199387 0.276 EEF1A1 protein P68104 UNIPROT Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269507 0.8 PRKCD protein Q05655 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Ser12 KSKPKDAsQRRRSLE 9606 BTO:0001938 18069897 t gcesareni We conclude that treatment with either UV or PMA induces the phosphorylation of the PKC site Ser12 on c-SRC and that this specific phosphorylation event is significantly diminished in cells overexpressing PR55 SIGNOR-247974 0.585 NRXN2 protein Q9P2S2 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 t miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. SIGNOR-265460 0.265 MAPK3 protein P27361 UNIPROT RPS3 protein P23396 UNIPROT unknown phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 t llicata Erk phosphorylates threonine 42 residue of ribosomal protein s3. SIGNOR-137959 0.358 KIF14 protein Q15058 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272524 0.7 phosphatidic acid smallmolecule CHEBI:16337 ChEBI CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI up-regulates quantity precursor of 9606 25375833 t lperfetto CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). SIGNOR-267019 0.8 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr340 RGQRDSSyYWEIEAS 9606 12551923 t gcesareni We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain. SIGNOR-97635 0.588 acyl-CoA smallmolecule CHEBI:17984 ChEBI 1-phosphatidyl-1D-myo-inositol smallmolecule CHEBI:16749 ChEBI up-regulates quantity precursor of -1 18772128 t miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. SIGNOR-267243 0.8 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 18936167 t These results therefore suggest that the autoactivation residues Y1054 and Y1059 are targeted by DEP-1 and that this results in the inhibition of kinase activity and the consequent general dephosphorylation of VEGFR2. SIGNOR-248709 0.687 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Ser188 QNRYSFYsTCSGQKA -1 23444369 t miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. SIGNOR-273490 0.27 sapitinib chemical CHEBI:132986 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190152 0.8 RAF1 protein P04049 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity phosphorylation Ser621 PKINRSAsEPSLHRA 9534 19595761 t lperfetto We show that phosphorylation of s621 turns over rapidly and is enriched in the activated pool of endogenous raf-1. The phosphorylation on this site can be mediated by raf-1 itself but also by other kinase(s) SIGNOR-235770 0.2 EIF2B3 protein Q9NR50 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269141 0.798 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser83 YSGSEGDsESGEEEE -1 2046671 t llicata Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro. We report here that serine 83 appears to be the residue phosphorylated by CKII but that three other serines in this region can also be involved in phosphorylation and the enhancement of DNA-binding activity. SIGNOR-250958 0.533 CBL protein P22681 UNIPROT KIT protein P10721 UNIPROT down-regulates activity ubiquitination 9606 15315962 t miannu KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT. SIGNOR-260104 0.602 FLT3 protein P36888 UNIPROT IDH1 protein O75874 UNIPROT up-regulates activity phosphorylation Tyr391 PNVQRSDyLNTFEFM -1 34289383 t lperfetto Moreover, in an in vitro kinase assay, purified recombinant FLT3 (rFLT3) phosphorylated recombinant IDH2 R140Q mutant but did not alter its catalytic activity (Figure 1C), whereas rFLT3 phosphorylated mIDH1 protein and enhanced its catalytic activity SIGNOR-267630 0.435 ATP smallmolecule CHEBI:15422 ChEBI AMPK complex SIGNOR-C15 SIGNOR down-regulates chemical inhibition 9606 21399626 t lperfetto Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive SIGNOR-217481 0.8 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys64 RAGCCLGkAVRGAKG 9606 12408818 t gcesareni Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300 SIGNOR-95165 0.476 CDK1 protein P06493 UNIPROT RECQL4 protein O94761 UNIPROT up-regulates activity phosphorylation Ser251 EVSIRVGsPQPSSSG 9606 BTO:0002181 29229926 t miannu  During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs. SIGNOR-277375 0.362 creatine smallmolecule CHEBI:16919 ChEBI CKM protein P06732 UNIPROT up-regulates activity chemical activation 9606 18502307 t miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. SIGNOR-265784 0.8 TGFB1 protein P01137 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity 10090 BTO:0000944 17673906 f lperfetto We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. SIGNOR-242631 0.431 SAGA complex complex SIGNOR-C465 SIGNOR H3-5 protein Q6NXT2 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269642 0.2 PIM1 protein P11309 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 17643117 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation. SIGNOR-156946 0.2 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates activity phosphorylation Tyr218 PPRDFAAyRS 8992971 t EMT can phosphorylate all four tyrosines of the CD28 tail. in vivo, tyrosines other than tyrosine 173 become phosphorylated following CD28 stimulation, this finding suggests that, like LCK, one function of EMT during CD28 signaling is phosphorylation of the receptor. SIGNOR-251337 0.677 ERCC5 protein P28715 UNIPROT ERCC2 protein P18074 UNIPROT up-regulates quantity by stabilization binding 9606 20840796 t Regulation of binding The NER protein XPG was also found to associate with the TFIIH complex by interacting directly with XPD stabilizing the interaction between TFIIH and the CAK-XPD complex SIGNOR-251974 0.946 MAPK13 protein O15264 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 10581258 t gcesareni In mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-72691 0.443 NEK2 protein P51955 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization phosphorylation Thr210 TNEIFYCtFRRLDPE 10090 BTO:0000584 34315872 t miannu NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen.  SIGNOR-277314 0.2 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr799 PLQDGSRtPHYGSQT 9606 16427012 t lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif SIGNOR-143935 0.768 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 f gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 0.7 bisphenol F chemical CHEBI:34575 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 31995776 t miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . SIGNOR-268734 0.8 amisulpride chemical CHEBI:64045 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258364 0.8 carbachol chemical CHEBI:3385 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258618 0.8 PAM protein P19021 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates activity cleavage 9606 23084901 t lperfetto Nevertheless, overall the results of this study show that peptide sequence recognition is an important aspect of the interactions of the prohormone substrates prooxytocin (3d) and procalcitonin (7e) with PAM, which is mirrored in the potency of analogous peptidomimetic glycolate inhibitors of the enzyme. SIGNOR-268551 0.2 TERT protein O14746 UNIPROT Telomere_maintenance phenotype SIGNOR-PH148 SIGNOR up-regulates 18680434 t lperfetto Dyskerin was recently found to be associated with active human telomerase (34), and mutations in dyskerin or NOP10 or deletion of the H/ACA motif of hTERC result in diminished telomerase activity SIGNOR-263334 0.7 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation Tyr131 KENLIREyVKQTWNL 9606 BTO:0000776 9820500 t lperfetto These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520 SIGNOR-246601 0.2 NTRK1 protein P04629 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 10708759 t esanto Autophosphorylated trka binds directly to plc?, Abl, and shc. SIGNOR-75402 0.516 MCM10 protein Q7L590 UNIPROT POLA1 protein P09884 UNIPROT up-regulates quantity by stabilization relocalization -1 19608746 t Federica Mcm10 is an essential eukaryotic protein required for the initiation and elongation phases of chromosomal replication. Specifically, Mcm10 is required for the association of several replication proteins, including DNA polymerase alpha (pol alpha), with chromatin. SIGNOR-261271 0.857 DPF3 protein Q92784 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270703 0.74 MAPK14 protein Q16539 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 17502367 t gcesareni All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below). SIGNOR-154783 0.605 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr285 TEADGELyVFNTPSG 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236400 0.751 PRKACA protein P17612 UNIPROT CHKB protein Q9Y259 UNIPROT up-regulates activity phosphorylation Ser40 PKRRRASsLSRDAER 27149373 t lperfetto Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. | This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar. SIGNOR-275629 0.255 TAF1D protein Q9H5J8 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR form complex binding 9606 30693017 t lperfetto SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation. SIGNOR-269563 0.805 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation Tyr939 QICKGMEyLGSRRCV 9606 18250158 t lperfetto Y904 and y939 are required for optimal jak3 autophosphorylation and kinase activity in vitro SIGNOR-160668 0.2 LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 t miannu In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. SIGNOR-256188 0.2 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273106 0.745 USP7 protein Q93009 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270837 0.778 SRC protein P12931 UNIPROT PTPRJ protein Q12913 UNIPROT up-regulates activity phosphorylation Tyr1311 DSKVDLIyQNTTAMT 9606 BTO:0000007 22898603 t miannu  We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin. SIGNOR-276373 0.621 PRKACA protein P17612 UNIPROT EEF2K protein O00418 UNIPROT up-regulates activity phosphorylation Ser500 RLHLPRAsAVALEVQ -1 11171059 t miannu EEF-2K can be phosphorylated in vitro by cAMP-dependent protein kinase (PKA) and that this induces significant Ca(2+)/calmodulin (CaM)-independent eEF-2K activity. sites of phosphorylation were Ser-365 and Ser-499 SIGNOR-250444 0.31 MUSK protein O15146 UNIPROT DOK7 protein Q18PE1 UNIPROT up-regulates activity phosphorylation Tyr395 CLPGTVEyQVPTSLR 10090 20603078 t miannu Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes. SIGNOR-273845 0.745 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 20626350 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. gcesareni Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27. SIGNOR-166633 0.802 betrixaban chemical CHEBI:140421 ChEBI F10 protein P00742 UNIPROT down-regulates activity chemical inhibition -1 19297154 t Luana Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor. SIGNOR-257817 0.8 BBC3 protein Q9BXH1 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 t lperfetto Only bimbh3 and bbc3 had comparable strong affinitiesfor all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1. SIGNOR-133808 0.649 EIF2S1 protein P05198 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity transcriptional regulation 9606 27629041 t miannu ER stress, viral infection, and other cellular stress signals activate PERK, PKR, HRI, and GCN2 kinases that converge on phosphorylation of eIF2alpha, the core of ISR. This leads to global attenuation of Cap dependent translation while concomitantly initiates the preferential translation of ISR specific mRNAs, such as ATF4. ATF4 is the main effector of the ISR. eIF2alpha phosphorylation causes a reduction in global protein synthesis while allowing the translation of selected genes including activating transcription factor 4 (ATF4), aiding cell survival and recovery SIGNOR-260169 0.625 HACD4 protein Q5VWC8 UNIPROT FASN protein P49327 UNIPROT up-regulates activity chemical activation 9606 18554506 t Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases, SIGNOR-267763 0.2 PRKACG protein P22612 UNIPROT TENT2 protein Q6PIY7 UNIPROT down-regulates activity phosphorylation Ser116 LSGERRYsMPPLFHT 9606 BTO:0000007 31057087 t miannu We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. SIGNOR-259404 0.2 MINK1 protein Q8N4C8 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity phosphorylation Thr322 SNVNRNStIENTRRH 9606 BTO:0002181 21690388 t miannu Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.  SIGNOR-276336 0.2 BACE1 protein P56817 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Asp616 EISEVKMdAEFRHDS 9606 10931940 t lperfetto Figure 6 Preferred BACE1 and BACE2 cleavage sites. (A) Sequence of APP indicating α- and β-cleavage sites, BACE1- and BACE2-cleavage sites, and the location of mutations analyzed here. APP numbering is that of the 770-aa isoform. SIGNOR-261763 0.786 MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity phosphorylation 9606 21133840 t miannu RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of Œ∫B kinase) complex SIGNOR-256024 0.718 DAPK1 protein P53355 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser511 RREERSLsAPGNLLT 9606 BTO:0000938 BTO:0000142 15209507 t lperfetto Dapk phosphorylates camkk. S511 was identified as the phosphorylation site . a potential mechanism of action was identified on the basis of the location of s511 near the cam recognition domain of camkk and demonstrated by attenuation of cam-stimulated camkk autophosphorylation after dapk phosphorylation. SIGNOR-126241 0.287 PRKACA protein P17612 UNIPROT PJA2 protein O43164 UNIPROT up-regulates activity phosphorylation Ser342 RHEAKQRsVQRWREA -1 21423175 t miannu In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h). SIGNOR-276316 0.2 HIF3A protein Q9Y2N7 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000972 21479871 t Luana None of the long HIF-3α variants was capable of efficient induction of an HRE reporter in overexpression experiments, but instead inhibited the transcriptional activation of the reporter by HIF-1 and HIF-2.  SIGNOR-261615 0.504 AR protein P10275 UNIPROT WEE1 protein P30291 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16281084 f After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. SIGNOR-253678 0.263 AGRP protein O00253 UNIPROT MC3R protein P41968 UNIPROT down-regulates activity binding 9606 10318826 t miannu AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor. SIGNOR-252380 0.611 FGF14 protein Q92915 UNIPROT SCN4A protein P35499 UNIPROT down-regulates activity binding 9606 BTO:0001103 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253433 0.263 SYNE1 protein Q8NF91 UNIPROT MSH2/MSH6 complex SIGNOR-C60 SIGNOR up-regulates activity binding 9606 BTO:0001950 24781983 t miannu Nesprin-1 is involved in the DNA Damage Response network. The Nesprin-1 interaction with MSH2 and MSH6 (MutSα complex) is a constitutive cellular event required for proper DNA repair. SIGNOR-261823 0.254 ROS stimulus SIGNOR-ST2 SIGNOR NLRP3 protein Q96P20 UNIPROT up-regulates activity 28531279 f lperfetto Different mechanisms have been proposed for NLRP3 activation, including potassium efflux, calcium influx, reactive oxygen species (ROS), oxidized mitochondrial DNA, translocation of cardiolipin from the inner mitochondrial membrane, phagosome destabilization, perturbation in cell volume and pore-formation mechanisms driven by the host or bacteria SIGNOR-256427 0.7 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Thr123 RLLQQCEtLKVPPKK 9606 BTO:0000567 25670858 t lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. SIGNOR-265231 0.571 clonidine chemical CHEBI:46631 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258904 0.8 PAFAH1B1 protein P43034 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates activity binding 9606 BTO:0000567 11940666 t miannu Here we demonstrate colocalization and direct interaction between CLIP-170 and LIS1. In mammalian cells, LIS1 recruitment to kinetochores is dynein/dynactin dependent, and recruitment there of CLIP-170 is dependent on its site of binding to LIS1, located in the distal zinc finger motif. SIGNOR-252166 0.785 CAMK2G protein Q13555 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR 9677319 t llicata Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. By deletion and point mutation analysis we show that phosphorylation by CaMKII and PKA occurs on a single serine residue at position 273 SIGNOR-250703 0.342 GOT2 protein P00505 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI down-regulates quantity chemical modification 9606 31422819 t miannu This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-268059 0.8 MLN protein P12872 UNIPROT MLNR protein O43193 UNIPROT up-regulates binding 9606 BTO:0000938 10381885 t gcesareni A heterotrimeric guanosine triphosphate-binding protein (g protein)-coupled receptor for motilin was isolated from human stomach SIGNOR-68721 0.762 p38 proteinfamily SIGNOR-PF16 SIGNOR DROSHA protein Q9NRR4 UNIPROT down-regulates activity phosphorylation Ser300 RHRDNRRsPSLERSY 9606 BTO:0000007 25699712 t lperfetto Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes.  SIGNOR-264847 0.2 MIPOL1 protein Q8TD10 UNIPROT RHOB protein P62745 UNIPROT up-regulates activity binding 9606 31609475 t miannu MIPOL1 protein interacts with tumor suppressor RhoB and enhances its cellular activity SIGNOR-261134 0.2 SOD1 protein P00441 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates activity binding 10090 BTO:0004488 18519638 t P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction) SOD1mut-induced ER stress |we first examined whether SOD1mut induces ER stress in NSC34 motor neurons, as assessed by band-shift analyses of the ER transmembrane kinase receptors IRE1 and PERK. Adenovirus (Ad)-mediated expression of ALS-linked SOD1mut (SOD1G93A) was detectable within 48 h of infection (Supplemental Fig. S1A). SOD1mut (SOD1A4V, SOD1G85R, and SOD1G93A) but not wild-type SOD1 (SOD1wt) activated IRE1 and PERK SIGNOR-262787 0.277 RAE1 protein P78406 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262095 0.569 NLGN1 protein Q8N2Q7 UNIPROT NRXN3 protein Q9HDB5 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264169 0.823 TRIM59 protein Q8IWR1 UNIPROT ECSIT protein Q9BQ95 UNIPROT down-regulates activity binding 9606 BTO:0000567; BTO:0002181 22588174 t Giorgia In this study, we showed that one of the TRIM family ubiquitin ligases, TRIM59, interacts with ECSIT as an adaptor protein required for the TLR-mediated transduction pathway. The B-box and RING domains of TRIM59 are important for interaction with ECSIT.|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation.|Luciferase reporter assays using reporter plasmids including NF-kappaB responsive element, interferon beta (IFN-beta) promoter and interferon-sensitive response element (ISRE) showed that overexpression of TRIM59 repressed their transcriptional activities, whereas knockdown of TRIM59 enhanced their transcriptional activities. SIGNOR-260369 0.533 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser81 AAGSGAAsPSAAEKG -1 8034575 t lperfetto Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites. SIGNOR-248910 0.719 PRKCD protein Q05655 UNIPROT KLF5 protein Q13887 UNIPROT up-regulates activity phosphorylation Ser153 LRTGLYKsQRPCVTH 9606 BTO:0003038 12682370 t lperfetto Phosphorylation of Kruppel-like factor 5 (KLF5/IKLF) at the CBP interaction region enhances its transactivation function. | Inhibition of protein kinase activity by H7 or calphostin C blocked both full-length and N-terminal fragment (amino acids 1-238) KLF5 activities. Mutation at a potential protein kinase C phosphorylation site within the CBP interaction domain of KLF5 reduces its transactivation function. Furthermore, using the GST pull-down approach, we showed that phosphorylation of KLF5 enhances its interaction with CBP. The results of the present study provide a mechanism for KLF5 transactivation function. | We found that KLF5€™s activity was reduced to half when the serine in the potential PKC phosphorylation site was mutated to alanine (Fig. 6B, S153A) Nonetheless, the S153A mutant still retains significant transactivation activity. SIGNOR-249206 0.341 DVL2 protein O14641 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates activity binding 10029 BTO:0000457 23132247 t gcesareni Mechanistically, Dishevelled binds and directly inhibits CSL transcription factors downstream of Notch receptors, reducing their activity. Furthermore, our data suggest that this crosstalk mechanism is conserved between vertebrate and invertebrate homologues. Thus, we identify a dual function for Dishevelled as an inhibitor of Notch signalling and an activator of the Wnt pathway that sharpens the distinction between opposing Wnt and Notch responses, allowing for robust cell-fate decisions. SIGNOR-243999 0.272 PRMT1 protein Q99873 UNIPROT TAF15 protein Q92804 UNIPROT up-regulates methylation 9606 19124016 t miannu The methylation of taf15 by prmt1 is required for the ability of taf15 to positively regulate the expression of the studied endogenous taf15-target genes. SIGNOR-183137 0.441 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr502 TPGTGLGtSPALAGD -1 8349691 t llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. SIGNOR-251077 0.325 EP300 protein Q09472 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates binding 9606 11796223 t lperfetto Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription. SIGNOR-232162 0.733 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT up-regulates activity phosphorylation Ser287 RQRKGTLsVNFVDLY -1 27292631 t miannu We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment. SIGNOR-274062 0.308 SOSTDC1 protein Q6X4U4 UNIPROT WNT8A protein Q9H1J5 UNIPROT down-regulates activity 9606 BTO:0000815 21113658 f lperfetto For example, SOSTDC1 decreases Wnt signaling by impeding the binding of Wnt8 to the LRP6 receptor SIGNOR-242742 0.38 TNFRSF17 protein Q02223 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates 9606 10903733 f miannu Overexpression of bcma activates jnk SIGNOR-79507 0.2 PRKCG protein P05129 UNIPROT DAB2 protein P98082 UNIPROT unknown phosphorylation Ser24 QAAPKAPsKKEKKKG 9534 BTO:0004055 10542228 t lperfetto We have mapped the TPA-induced DOC-2/DAB2 protein phosphorylation site to Ser24, which appears to modulate the DOC-2/DAB2 inhibition of AP-1 transcription activity. Results indicate that phosphorylation of Ser24 is mediated by PKCbetaII, PKC_, and PKCdelta, but not CKII. This suggests that the PKC phosphorylation of Ser24 in DOC-2/DAB2 may be an underlying mechanisms for its tumor-suppressive function. SIGNOR-249027 0.304 A2M protein P01023 UNIPROT MMP9 protein P14780 UNIPROT down-regulates activity binding -1 9344465 t lperfetto Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. SIGNOR-261801 0.471 CDK1 protein P06493 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates phosphorylation Ser165 LFQLGPPsPVKMPSP 9606 10656688 t llicata Hpttg is phosphorylated by cdc2 at ser165 these results suggest that hpttg is induced by, and may have a role in, regulatory pathways involved in the control of cell proliferation. SIGNOR-74619 0.615 F11 protein P03951 UNIPROT HGF protein P14210 UNIPROT up-regulates activity cleavage Arg424 KNMEDLHrHIFWEPD -1 12372819 t miannu the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain. SIGNOR-256515 0.318 PRKACA protein P17612 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 10090 12809504 t llicata Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha.  SIGNOR-188177 0.259 CSNK2A2 protein P19784 UNIPROT AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser276 AAQQTKGsYMEVEDN 9615 BTO:0000837 11742978 t llicata We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4‐Cter proteins in which only one out of the three C‐terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. SIGNOR-250974 0.344 RNF144B protein Q7Z419 UNIPROT NPM1 protein P06748 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000772 20864535 t miannu NPMc degradation was mediated by the ubiquitin-proteasome pathway involving the IBR-type RING-finger E3 ubiquitin ligase IBRDC2, and genetic correction of FA-A or FA-C lymphoblasts prevented NPMc ubiquitination. As shown in Fig. 4C, knockdown of IBRDC2, an IBR-type RING-finger E3 ubiquitin ligase (21), significantly reduced NPMc ubiquitination and restored NPMc stability in FA-A cells SIGNOR-271490 0.2 PRKAA1 protein Q13131 UNIPROT MLXIPL protein Q9NP71 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21892142 t gcesareni Ampk has also been suggested to phosphorylate the glucose-sensitive transcription factor chrebpthe dna binding activity, as assayed in a gel-shift assay of the truncated chrebp, was gradually inactivated with time by treatment with ampk SIGNOR-176494 0.428 USP13 protein Q92995 UNIPROT ATG5 protein Q9H1Y0 UNIPROT up-regulates quantity by stabilization deubiquitination 36528756 t lperfetto Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells. SIGNOR-275838 0.278 SEMA7A protein O75326 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 10090 17377534 t lperfetto Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin. SIGNOR-253249 0.527 leucine smallmolecule CHEBI:25017 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264748 0.7 NCSTN protein Q92542 UNIPROT APH1A protein Q96BI3 UNIPROT up-regulates binding 9606 BTO:0000142 12857757 t gcesareni We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch). SIGNOR-103611 0.967 MMP14 protein P50281 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Phe117 MEILRGDfSSANNRD -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain SIGNOR-263621 0.2 ZC3H12A protein Q5D1E8 UNIPROT TAL1 protein P17542 UNIPROT up-regulates quantity post transcriptional regulation 9606 BTO:0000007 30842549 t Here, we show that Regnase-1 regulates self-renewal of HSPCs through modulating the stability of Gata2 and Tal1 mRNA SIGNOR-259944 0.2 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNAQ protein P50148 UNIPROT up-regulates binding 9606 20331961 t inferred from 70% family members gcesareni The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits) SIGNOR-269966 0.2 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR ENO3 protein P13929 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136550 0.269 MAP3K7 protein O43318 UNIPROT NLK protein Q9UBE8 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 12482967 t gcesareni The tak1-nlk-mapk-related pathway antagonizes signalling between beta-catenin and transcription factor tcf. SIGNOR-96425 0.636 FAM20C protein Q8IXL6 UNIPROT P4HB protein P07237 UNIPROT up-regulates activity phosphorylation Ser357 KIKPHLMsQELPEDW 32149426 t lperfetto The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity. SIGNOR-275574 0.36 PPARA protein Q07869 UNIPROT PLIN2 protein Q99541 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003204 17150915 f miannu To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA. SIGNOR-255046 0.528 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Thr663 IATVIVItLVMLKKK -1 10605825 t lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. SIGNOR-261793 0.502 LATS1 protein O95835 UNIPROT VEPH1 protein Q14D04 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 22055343 f In the neuronal differentiation lperfetto Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r8 SIGNOR-177068 0.2 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation. SIGNOR-272710 0.759 ARAF protein P10398 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser218 VSGQLIDsMANSFVG 9606 BTO:0000567 8621729 t lperfetto Our data demonstrated that a-raf is, indeed, a mek1 activator and may play a role in growth factor signaling|The immunoprecipitates were assayed for GST-MEK1 activation. D, activation of MEK1 by A-Raf requires the presence of serine residue 218 and 222. SIGNOR-236451 0.729 SNAI1 protein O95863 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity transcriptional regulation 9606 19055748 f lperfetto Taken together these results suggest that SNAI1 functional blockade is leading to partial re-expression of E-cadherin (i.e. at the level of transcription), to a decrease in PAI-1 and to a more collective migration, while the parental cells expressing SNAI1 have less E-cadherin, more PAI 1, and migrate individually. We suggest that the present study establishes a relation between SNAI1 function, PAI-1 distribution and EMT status. SIGNOR-252260 0.749 JUN protein P05412 UNIPROT LORICRIN protein P23490 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 12200429 f miannu Mutation and DNA-protein analyses show that Sp1, c-Jun, an unidentified regulator, and the co-activator p300/CREB-binding protein up-regulate whereas Sp3, CREB-1/CREMalpha/ATF-1, Jun B, and an AP2-like protein (termed the keratinocyte-specific repressor-1 (KSR-1)) suppress loricrin promoter activity. SIGNOR-254536 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 10837486 t lperfetto Rsk1, and survival factor signaling stimulate phosphorylation of bad at ser-155, blocking the binding of bad to bcl-xl. SIGNOR-252786 0.2 ATR protein Q13535 UNIPROT XPA protein P23025 UNIPROT up-regulates activity phosphorylation Ser173 VKKNPHHsQWGDMKL 9606 BTO:0000018 16540648 t llicata Defects in ATR-dependent XPA phosphorylation increases the cell sensitivity to UV irradiation. | The XPA-deficient cells complemented with XPA-S196A mutant, in which Ser196 was substituted with an alanine, displayed significantly higher UV sensitivity compared with the XPA cells complemented with wild-type XPA. Moreover, substitution of Ser196 with aspartic acid for mimicking the phosphorylation of XPA increased the cell survival to UV irradiation. SIGNOR-250584 0.505 PSMC3 protein P17980 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263369 0.872 CDK1 protein P06493 UNIPROT STIP1 protein P31948 UNIPROT down-regulates activity phosphorylation Thr332 KSLAEHRtPDVLKKC 10090 BTO:0000944 14754904 t miannu Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions. A lower level of phosphorylation was observed for the double mutant, suggesting that T332 might also be phosphorylated by cdc2 kinase. SIGNOR-262728 0.267 MRPL11 protein Q9Y3B7 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262382 0.75 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Thr145 QKSKKHLtDNEFKDP -1 14523239 t lperfetto We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. | Edman sequencing and scintillation counting delineated T144 as the in vitro PKC phosphorylation site SIGNOR-249234 0.2 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258570 0.8 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser626 SLECDMEsIIRSELM 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252979 0.509 KHSRP protein Q92945 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates binding 9606 BTO:0000130;BTO:0000876 2848118 t gcesareni Ksrp was shown to interact with the c-terminus of dvl3. We show that ksrp negatively regulates wnt/beta-catenin signaling at the level of post-transcriptional ctnnb1 (beta-catenin) mrna stability. SIGNOR-23800 0.2 TNKS protein O95271 UNIPROT TERF1 protein P54274 UNIPROT down-regulates activity ADP-ribosylation -1 11739745 t lperfetto Tankyrase 1 ADP-ribosylates TRF1, inhibiting its binding to telomeric DNA. SIGNOR-263377 0.796 PLK1 protein P53350 UNIPROT KIF2B protein Q8N4N8 UNIPROT up-regulates activity phosphorylation Thr125 MIPQKNQtASGDSLD 9606 BTO:0001938 22535524 t lperfetto We show that Plk1 directly phosphorylates Kif2b at threonine 125 (T125) and serine 204 (S204), and that these two sites differentially regulate Kif2b function. Phosphorylation of S204 is required for the kinetochore localization and activity of Kif2b in prometaphase, and phosphorylation of T125 is required for Kif2b activity in the correction of k-MT attachment errors. SIGNOR-252049 0.646 CTSK protein P43235 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 11920402 f lperfetto Cathepsins K and S have been implicated in various aspects of extracellular matrix degradation and inflammatory responses. SIGNOR-253318 0.7 GSK3B protein P49841 UNIPROT MITF protein O75030 UNIPROT up-regulates quantity by stabilization phosphorylation Ser419 S-->N 9606 25605940 t miannu We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here. SIGNOR-276476 0.446 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0001538 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219337 0.707 STUB1 protein Q9UNE7 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 19940151 t miannu the ubiquitin ligase activity of CHIP regulates HIF-1α degradation. SIGNOR-271426 0.384 PNPLA6 protein Q8IY17 UNIPROT Lysophosphatidylcholine smallmolecule CID:5311264 PUBCHEM down-regulates quantity chemical modification 9606 25033069 t PNPLA6 encodes NTE, a lysophospholipase that converts lysophosphatidylcholine (LPC) to glycerophosphocholine. PNPLA6 is expressed in neurons throughout the brain, particularly in the cortex, Purkinje cells of the cerebellum, and hippocampus SIGNOR-253610 0.8 PAMPs stimulus SIGNOR-ST11 SIGNOR NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates activity 16037825 f miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-263127 0.7 ODC1 protein P11926 UNIPROT spermidine smallmolecule CHEBI:16610 ChEBI up-regulates quantity chemical modification 9606 14617280 t miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256038 0.8 TJP2 protein Q9UDY2 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates binding 9606 21808241 t milica In addition, yap and taz interact with another tight junction protein zo-2, which was reported to increase nuclear localization of yap and tight-junction localization of taz. SIGNOR-175931 0.486 C1QBP protein Q07021 UNIPROT C1QA protein P02745 UNIPROT down-regulates activity binding SIGNOR-C308 28018340 t lperfetto Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping. SIGNOR-263402 0.392 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0001538 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252761 0.719 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC14 protein Q99879 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271994 0.2 MAPK1 protein P28482 UNIPROT ZFP36 protein P26651 UNIPROT unknown phosphorylation Ser228 PPGDLPLsPSAFSAA 10090 BTO:0000944 7768935 t lperfetto By a combination of protease digestion experiments and site-directed mutagenesis strategies, we found that serine 220 was phosphorylated by p42 MAP kinase in vitro. Expression of mutant TTP in fibroblasts confirmed that serine 220 was one of the major, mitogen-stimulated phosphorylation sites on the protein in intact cells. |It is not obvious how phosphorylation of TTP at serine 220 would alter DNA binding, since this residue lies well outside of the putative zinc finger region, which is between amino acids 95 to 159 in the mouse protein SIGNOR-249456 0.468 NAMPT protein P43490 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI up-regulates quantity chemical modification 9606 12555668 t gcesareni Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesi SIGNOR-238602 0.8 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity dephosphorylation Ser293 TYRYHGHsMSDPGVS -1 7782287 t Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism SIGNOR-252054 0.722 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1665 SPTSPSYsPTSPSYS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248819 0.849 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249641 0.741 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 9606 18570871 t gcesareni Together, our findings demonstrate that jnk1-mediated multisite phosphorylation of bcl-2 stimulates starvation-induced autophagy by disrupting the bcl-2/beclin 1 complex. SIGNOR-179088 0.564 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PLCB1 protein Q9NQ66 UNIPROT up-regulates activity phosphorylation -1 11287604 t inferred from 70% family members lperfetto Plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982 SIGNOR-270109 0.2 Kindlin proteinfamily SIGNOR-PF48 SIGNOR Av/b8 integrin complex SIGNOR-C185 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259013 0.332 SNAP91 protein O60641 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates quantity binding 9606 BTO:0000938 26903854 t miannu  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. Furthermore, recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. SIGNOR-264112 0.615 PRKACA protein P17612 UNIPROT CUL5 protein Q93034 UNIPROT up-regulates activity phosphorylation Ser730 MKMRKKIsNAQLQTE 9534 BTO:0000298 10898738 t miannu Elimination of the S730 but not the T325 PKA phosphorylation site of VACM-1 resulted in a complete inhibition of the VACM-1 activity, thus suggesting a direct effect of PKA on the VACM-1 receptor. SIGNOR-250352 0.327 FOXO6 protein A8MYZ6 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260092 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR Postsynaptic density assembly phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 BTO:0004249 23125836 f miannu PKA is activated by Group I mGluRs in ACC neurons. The cAMP signaling pathway contributes to the activity-dependent synaptic plasticity in the anterior cingulate cortex SIGNOR-264960 0.7 DUOX1 protein Q9NRD9 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264719 0.7 KPNA6 protein O60684 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 20454918 t gcesareni Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of nicd and thus are directly involved in notch signaling. SIGNOR-254332 0.2 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UBTF protein P17480 UNIPROT up-regulates activity phosphorylation Ser484 ERGKLPEsPKRAEEI 10090 BTO:0000944 10202152 t llicata We have identified Ser484 as a direct target for cyclin-dependent kinase 4 (cdk4)-cyclin D1- and cdk2-cyclin E-directed phosphorylation. Mutation of Ser484 impairs rDNA transcription in vivo and in vitro.  SIGNOR-250754 0.346 PRKAA2 protein P54646 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates phosphorylation Ser396 TAVHKSKsLKDLVSA 9606 SIGNOR-C15 21459323 t gcesareni Here we demonstrate that ampk interacts with and directly phosphorylates sterol regulatory element binding proteins (srebp-1c and -2). Ser372 SIGNOR-173031 0.334 PTPN6 protein P29350 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation 9534 8943354 t Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1 SIGNOR-248466 0.718 GLDC protein P23378 UNIPROT Glycine cleavage system complex SIGNOR-C437 SIGNOR form complex binding 9606 16051266 t lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. SIGNOR-268240 0.686 HDLBP protein Q00341 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity binding 9606 BTO:0000150 33941620 t miannu We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites. SIGNOR-266698 0.2 LRFN5 protein Q96NI6 UNIPROT PTPRS protein Q13332 UNIPROT up-regulates activity binding 9606 27225731 t miannu SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1). SIGNOR-264088 0.376 KLF10 protein Q13118 UNIPROT SIN3A protein Q96ST3 UNIPROT up-regulates activity binding 10029 BTO:0000246 11438660 t miannu detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A. SIGNOR-222394 0.458 imatinib methanesulfonate chemical CHEBI:31690 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0000740 15206509 t miannu Imatinib mesylate (Gleevec/Glivec, Novartis, Basel, Switzerland), formerly called STI571, is a specific and potent inhibitor of the BCR-ABL tyrosine kinase, the molecular hallmark of chronic myeloid leukaemia. SIGNOR-259357 0.8 BCORL1 protein Q5H9F3 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates activity binding 9606 BTO:0000567 17379597 t irozzo BCoR-L1 interacts with Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its function as transcriptional corepressor. SIGNOR-259112 0.438 S1PR2 protein O95136 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256871 0.36 TBX5 protein Q99593 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20802524 f miannu TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. SIGNOR-255253 0.27 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AKAP12 protein Q02952 UNIPROT up-regulates activity phosphorylation Thr767 ESFKRLVtPRKKSKS 9606 BTO:0000007 23063527 t lperfetto Mass spectrometry, molecular, and cellular approaches show that CDK1/Cyclin B1 phosphorylates Gravin on threonine 766 to prime the recruitment of the polo-like kinase Plk1 at defined phases of mitosis. SIGNOR-271840 0.289 CDK1 protein P06493 UNIPROT STIP1 protein P31948 UNIPROT down-regulates activity phosphorylation Ser189 LLGVDLGsMDEEEEI 10090 BTO:0000944 14754904 t miannu Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions. SIGNOR-262729 0.267 SMAD4 protein Q13485 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR form complex binding 9606 20957627 t lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. SIGNOR-255269 0.672 CHUK protein O15111 UNIPROT FOXA2 protein Q9Y261 UNIPROT down-regulates phosphorylation Ser111 PHLSPSLsPLGGQAA 9606 22196886 t lperfetto Here, we show that ikk_, an important downstream kinase of tnf_, interacts with and phosphorylates foxa2 at s107/s111, thereby suppressing foxa2 transactivation activity and leading to decreased numb expression SIGNOR-195316 0.2 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB3 protein Q9Y5G1 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265685 0.2 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR PDPK1 protein O15530 UNIPROT down-regulates activity dephosphorylation 9606 21075311 t gcesareni Here, we show that PPP2R2B, encoding the B55² regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. B55²-associated PP2A interacts with PDK1 and modulates its activity toward Myc phosphorylation. SIGNOR-243515 0.286 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246268 0.564 AHR protein P35869 UNIPROT CYP1B1 protein Q16678 UNIPROT up-regulates quantity by expression transcriptional regulation 17012224 t The formation of the AHR/ARNT dimerization complex converts the AHR into a high affinity DNA-binding form that recognizes specific DNA recognition sites termed DREs. In this manner, the agonist activated AHR upregulates a battery of target genes, including those involved in the metabolism of chemical carcinogens, such as CYP1A1 and CYP1B1 . SIGNOR-253642 0.503 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFS2 protein O75306 UNIPROT up-regulates activity phosphorylation Ser364 KVDDAKVsPPKRAEM 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275600 0.2 MAPK1 protein P28482 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser93 ALQRQPPsPKQLEEE -1 16226275 t lperfetto First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.| SIGNOR-249436 0.805 SMARCE1 protein Q969G3 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 t miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270612 0.83 HEXIM1 protein O94992 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR down-regulates activity binding 9606 18371977 t miannu Studies show that more than half of P-TEFb in cells is associated with HEXIM1, which results in the inactivation of P-TEFb. The mislocalization of HEXIM1 and the increased P-TEFb-dependent transcription caused by NPMc+ suggests that the misregulated activity of PTEFb may contribute to the tumorigenesis of NPMc+ AML. SIGNOR-260135 0.742 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser567 DSSRFPMsPRPDSVH 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249462 0.618 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 23603988 t gcesareni We recently demonstrated that through their physical interaction, cdk9 phosphorylates p53 on ser-392, leading to p53 stability and accumulation SIGNOR-201935 0.55 LPAR6 protein P43657 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 15856019 t gcesareni Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. SIGNOR-135822 0.385 RUNX2 protein Q13950 UNIPROT COL2A1 protein P02458 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 f gcesareni In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast SIGNOR-107169 0.451 AKT2 protein P31751 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates 9606 17604717 f gcesareni Several studies have demonstrated that akt signaling can activate the nf-kb transcription factor downstream of a variety of stimuli, such as tumor necrosis factor (tnfalfa) SIGNOR-156530 0.334 MC3R protein P41968 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268702 0.528 protriptyline chemical CHEBI:8597 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 9537821 t miannu At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter. SIGNOR-258736 0.8 PRKACA protein P17612 UNIPROT SNAP25 protein P60880 UNIPROT unknown phosphorylation Thr138 GGFIRRVtNDARENE 10116 BTO:0001009 12459461 t miannu Thr138 as the exclusive site of SNAP-25 phosphorylation by protein kinase A in vivo. PMA or forskolin treatment alone resulted in dramatic phosphorylation of SNAP-25 Ser187 and/or Thr138 without appreciable neurotransmitter release. SIGNOR-250052 0.331 coenzyme Q10 smallmolecule CHEBI:46245 ChEBI ubiquinol smallmolecule CHEBI:17976 ChEBI up-regulates quantity precursor of 9606 30449682 t miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway SIGNOR-267429 0.8 ACTL6A protein O96019 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270712 0.822 Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR Respiratory electron transport chain phenotype SIGNOR-PH141 SIGNOR up-regulates 30030361 f lperfetto The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA). SIGNOR-262138 0.7 E2F1 protein Q01094 UNIPROT PCNA protein P12004 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253856 0.474 TACR3 protein P29371 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257389 0.287 PPP2CB protein P62714 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser199 PRPEHTKsVYTRSVI 10116 18586681 t Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. SIGNOR-248599 0.2 TYSND1 protein Q2T9J0 UNIPROT TYSND1 protein Q2T9J0 UNIPROT down-regulates activity cleavage 9606 BTO:0000567 22002062 t miannu Self-cleavage of Tysnd1 in the active oligomer most likely inactivates its protease activity. Subsequently, the cleaved products are degraded by PsLon and removed from the Tysnd1 oligomer. SIGNOR-261053 0.2 CHEK1 protein O14757 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity phosphorylation Ser612 MYLSPVRsPKKKGST 9606 17380128 t llicata These results suggest that ser612 is phosphorylated by chk1/2 after dna damage, leading to the formation of prb-e2f-1. phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1 SIGNOR-153904 0.432 RPS6KA3 protein P51812 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-119225 0.2 nintedanib chemical CHEBI:85164 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190305 0.8 ERG protein P11308 UNIPROT WNT3A protein P56704 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001321 23913826 t Luana Interestingly, our data showed that ERG drastically induced Wnt ligand gene expression. SIGNOR-261598 0.2 GHR protein P10912 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates activity phosphorylation 9606 BTO:0005787 BTO:0001103 23612709 t miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion SIGNOR-255452 0.2 IRAK4 protein Q9NWZ3 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 9606 BTO:0000130 17217339 t lperfetto Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.These results strongly support the observation that irak-4 is a kinase for p47phox in vivo. We also detected the signature of phosphorylation at ser320 and ser345 SIGNOR-152015 0.389 L-cysteine zwitterion smallmolecule CHEBI:35235 ChEBI hydrosulfide smallmolecule CHEBI:29919 ChEBI up-regulates quantity precursor of 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. SIGNOR-275814 0.8 TGFB1 protein P01137 UNIPROT CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7592908 f gcesareni The steadystate level of p15ink4b mrna was induced 30-fold upon tgf-beta treatment, implicating p15ink4b as a primary effector of the tgf-beta-mediated cell cycle arrest SIGNOR-29582 0.285 SMAD6 protein O43541 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 9892110 t lperfetto Smad6 and smad7, can prevent tgfb signaling by interacting either with the receptor or with smad2 and smad3 SIGNOR-64071 0.479 CHEK2 protein O96017 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation Ser90 IPPARMMsTESANSF 9606 BTO:0002552 32187724 t lperfetto We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion.|CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, promoting autophagy via Beclin 1 release from Bcl‐2 sequestration SIGNOR-264557 0.303 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser347 PVYSPPGsPPPGDPR 9606 BTO:0000567 10806207 t llicata Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity. SIGNOR-77212 0.587 AMBRA1 protein Q9C0C7 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 9606 17589504 t lperfetto Here we show that Ambra1 (activating molecule in Beclin1-regulated autophagy), a large, previously unknown protein bearing a WD40 domain at its amino terminus, regulates autophagy and has a crucial role in embryogenesis. We found that Ambra1 is a positive regulator of the Becn1-dependent programme of autophagy SIGNOR-156409 0.778 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR DDX58 protein O95786 UNIPROT up-regulates 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260141 0.7 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr80 DQHSISYtLSRAQTV -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276131 0.644 CSNK2A1 protein P68400 UNIPROT EGR1 protein P18146 UNIPROT down-regulates activity phosphorylation Thr391 TTHIRTHtGEKPFAC 10090 BTO:0000944 8662759 t llicata Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10. SIGNOR-250857 0.477 AKT2 protein P31751 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue. SIGNOR-186776 0.293 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser172 GQLVRNDsLWHRSDS 34010649 t lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-275942 0.2 PRKACA protein P17612 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity phosphorylation Ser329 LGGLCDLsSRY 9606 12639913 t miannu Activation of MC4R by agonist is associated with protein kinase A (PKA) and GRK phosphorylation of serine/threonine residues in the C-terminal tail of MC4R, followed by -arrestin and dynamin-dependent internalization of the receptor. Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA SIGNOR-250016 0.313 NR3C1 protein P04150 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR down-regulates 9606 25910399 f Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases [.. }The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged. SIGNOR-257599 0.7 Caspase 3 complex complex SIGNOR-C221 SIGNOR PTCH1 protein Q13635 UNIPROT down-regulates cleavage Asp1405 CPGYPETdHGLFEDP 9606 23074268 t gcesareni Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain. SIGNOR-256437 0.326 YWHAZ protein P63104 UNIPROT GEM protein P55040 UNIPROT up-regulates quantity by stabilization binding 9534 BTO:0000298 14701738 t miannu In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase SIGNOR-261725 0.307 HRH1 protein P35367 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257318 0.2 SRC protein P12931 UNIPROT HSP90AB1 protein P08238 UNIPROT up-regulates phosphorylation Tyr301 DDITQEEyGEFYKSL 9606 17855507 t lperfetto C-src directly phosphorylates hsp90 on tyrosine 300 residue and that this event is essential for vegf-stimulated enos association to hsp90 and thus no release from endothelial cells. SIGNOR-157781 0.57 TOPBP1 protein Q92547 UNIPROT ATR protein Q13535 UNIPROT up-regulates activity binding 9606 BTO:0001938 SIGNOR-C298 16530042 t lperfetto These results establish that TopBP1 can activate both Xenopus and human ATR. Furthermore, these experiments provide conclusive evidence that the kinase activity that is induced by TopBP1 is intrinsic to the ATR protein itself and is not due to a kinase that associates with ATR. SIGNOR-263232 0.807 SOX2 protein P48431 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19882665 f miannu We show that egfr-mediated signaling promotes sox2 expression, which in turn binds to the egfr promoter and directly upregulates egfr expression. SIGNOR-189036 0.493 17beta-estradiol smallmolecule CHEBI:16469 ChEBI Corticotropin protein P01189-PRO_0000024969 UNIPROT up-regulates 24631756 f lperfetto ACTH and corticosterone responses to the same acute stress stimulus are higher in the pro-estrus phase of the cycle, when the serum concentrations of estrogen are the highest |Moreover, Kirschbaum et al. conducted a double blind study of 32 men, showing that 100 mcg of estradiol/day for two days was sufficient to produce statistically significant increases in ACTH SIGNOR-268726 0.8 NFKB1 protein P19838 UNIPROT MAP3K8 protein P41279 UNIPROT down-regulates binding 9606 SIGNOR-C13 22435554 t gcesareni Tpl-2 is stoichiometrically complexed with the nf-kb inhibitory protein, nf-kb1 p105, and the ubiquitin-binding protein abin-2, both of which are required to maintain tpl-2 protein stability. Binding to p105 also prevents tpl-2 from phosphorylating mek SIGNOR-196747 0.675 CSNK2A1 protein P68400 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity phosphorylation Ser137 LSEDEYYsEEERNAK 9606 BTO:0002181 25999347 t miannu We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites. SIGNOR-276903 0.323 CEBPB protein P17676 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 15044620 f miannu C/EBPbeta activates the endogenous MDR1 gene of MCF-7 cells, and this activation was associated with a novel C/EBPbeta interaction region within the proximal MDR1 promoter (-128 to -75). SIGNOR-253771 0.455 PRKACA protein P17612 UNIPROT AICDA protein Q9GZX7 UNIPROT unknown phosphorylation Ser38 YVVKRRDsATSFSLD 9606 BTO:0000776 18417471 t llicata We have found using sf9 insect cells to overexpress human gst-aid that a small fraction of the enzyme is phosphorylated at ser38 and thr27 and at two residues not reported previously, ser41 and ser43 SIGNOR-178244 0.33 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Glu612 IKTEEISeVKMDAEF -1 8943232 t lperfetto The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261766 0.502 PLCB2 protein Q00722 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate(6-) smallmolecule CHEBI:203600 ChEBI up-regulates quantity chemical modification 9606 23994464 t apalma The first phase of this signal is likely mediated by phospholipase C≈í‚⧠(PLC≈í‚â§) enzymes leading to the generation of IP3 and concomitant release of Ca2+ from intracellular stores SIGNOR-255017 0.8 LETM1 protein O95202 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 10090 29123128 t lperfetto Others have suggested that LETM1 plays an essential role in mitochondrial K+ homeostasis by mediating the mitochondrial K+/H+ exchange SIGNOR-262542 0.8 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser393 MQVSSSSsSHSLSAS 9606 10455013 t lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-235782 0.2 SERPINC1 protein P01008 UNIPROT F2 protein P00734 UNIPROT down-regulates activity cleavage 31030036 t lperfetto Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1 SIGNOR-264136 0.946 NR2F2 protein P24468 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 9606 9826778 t gcesareni The orphan nuclear receptor, coup-tf ii, inactivates myogenesis by post-transcriptional regulation of myod function: coup-tf ii directly interacts with p300 and myod. SIGNOR-62248 0.391 STAT6 protein P42226 UNIPROT RETN protein Q9HD89 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 20508200 f lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. SIGNOR-249536 0.318 SRC protein P12931 UNIPROT DAPP1 protein Q9UN19 UNIPROT up-regulates activity phosphorylation Tyr139 KVEEPSIyESVRVHT 9606 BTO:0000776 10880360 t lperfetto Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell linesyrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins. SIGNOR-247119 0.569 PTPN12 protein Q05209 UNIPROT BCAR1 protein P56945 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 11432829 t gcesareni Ptp-pest is an efficient negative regulator of lymphocyte activation. This function correlated with the ability of ptp-pest to induce dephosphorylation of shc, pyk2, fak and cas, and inactivate the ras pathway. SIGNOR-109032 0.562 ICOS protein Q9Y6W8 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 18641334 t ICOS ligation in concert with TCR stimulation results in strong PI3K activation in T lymphocytes. The ICOS cytoplasmic tail contains an YMFM motif that binds the p85alpha subunit of class IA PI3K, similar to the YMNM motif of CD28, suggesting a redundant function of the two receptors in PI3K signaling. SIGNOR-272539 0.479 PLK1 protein P53350 UNIPROT TP53 protein P04637 UNIPROT down-regulates 9606 19473992 f lperfetto Plk1-mediated phosphorylation of topors regulates p53 stability. Herein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. SIGNOR-185841 0.593 BCR-Dl complex SIGNOR-C436 SIGNOR SYK protein P43405 UNIPROT up-regulates activity binding 9606 32323266 t scontino The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK). SIGNOR-268442 0.703 1-phosphatidyl-1D-myo-inositol 4-phosphate smallmolecule CHEBI:17526 ChEBI AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR form complex binding 9606 23103167 t lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-260675 0.8 LAT protein O43561 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000661 10811803 t Our results showed that three distal tyrosines, Tyr(171), Tyr(191), and Tyr(226), are responsible for Grb2-binding; SIGNOR-251521 0.797 PRKCA protein P17252 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 10090 12809504 t llicata Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha.  SIGNOR-188181 0.248 PPP1R9A protein Q9ULJ8 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 10090 BTO:0001976 15996550 f miannu Neurabin and spinophilin are preferentially expressed in neurons, where they are highly localized to dendritic spines via an interaction with F-actin. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc SIGNOR-269180 0.7 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto Mark and pka phosphorylate several sites within the repeats (notably the kxgs motifs including ser262, ser324, and ser356, plus ser320)tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process SIGNOR-171050 0.44 VEGFC protein P49767 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000763 9435229 t gcesareni Vegf-c is also a ligand for vegfr-2 (12), but the functional significance of this potential interaction in vivo is unknown SIGNOR-55208 0.913 CIT protein O14578 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Ser20 KRPQRATsNVFAMFD -1 21457715 t Giulio Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation. SIGNOR-260305 0.542 TRAF3 protein Q13114 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 24622840 t miannu MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. SIGNOR-260156 0.9 PRKCD protein Q05655 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates activity phosphorylation Ser58 VVGARRSsWRVVSSI 9606 12861023 t lperfetto We confirmed that MAPKAPK2 interacted with and phosphorylated 14-3-3zeta in vitro and in HEK293 cells. | Experimentally, S58D mutation significantly impaired both 14-3-3zeta dimerization and binding to Raf-1. SIGNOR-249222 0.457 DNA_damage stimulus SIGNOR-ST1 SIGNOR TP53 protein P04637 UNIPROT up-regulates quantity 9606 19879762 f lperfetto In the case of DNA-damage, phosphorylation of both p53 and Mdm2 by the checkpoint kinases ATM, ATR, Chk1 and Chk2 contributes to the dissociation of the Mdm2-p53 complex, leading to enhanced cellular p53 levels that primarily accumulate in the nucleus. SIGNOR-209690 0.7 GSK3B protein P49841 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Thr1938 HREKKEStPSTASLP 10116 BTO:0000938 29642012 t lperfetto In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3β. A GSK3β-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity. SIGNOR-275763 0.2 NRXN1 protein Q9ULB1 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 t miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. SIGNOR-265458 0.401 CDK1 protein P06493 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates phosphorylation 9606 16682949 t gcesareni We found that nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative cdc2 phosphorylation sites in nde1 and found that alteration of these sites diminishes phosphorylation by cdc2 in vitro and affects the stability of su48-nde1 interactions and the centrosomal localization of nde1. SIGNOR-146734 0.64 YAP1 protein P46937 UNIPROT TEAD proteinfamily SIGNOR-PF22 SIGNOR up-regulates activity binding 9606 23431053 t miannu YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death SIGNOR-230719 0.94 sertindole chemical CHEBI:9122 ChEBI HTR1B protein P28222 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0001311 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258545 0.8 ABTB1 protein Q969K4 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 11494141 f miannu Flow cytometry suggested that over-expression of BPOZ inhibited progression of the cell cycle at the G1/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated. SIGNOR-260046 0.7 SPOP protein O43791 UNIPROT EGLN2 protein Q96KS0 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001033 28089830 t lperfetto Tumor suppressor SPOP ubiquitinates and degrades EglN2 to compromise growth of prostate cancer cells SIGNOR-261996 0.354 WIPF1 protein O43516 UNIPROT WASL protein O00401 UNIPROT up-regulates activity binding 9606 10878810 t lperfetto Recruitment of N-WASP to vaccinia is mediated by WASP-interacting protein (WIP), whereas in Shigella WIP is recruited by N-WASP. Our observations show that vaccinia and Shigella activate the Arp2/3 complex to achieve actin-based motility, by mimicking either the SH2/SH3-containing adaptor or Cdc42 signalling pathways to recruit the N-WASP-WIP complex. SIGNOR-261880 0.931 ERAP2 protein Q6P179 UNIPROT peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity chemical modification 9606 15908954 t The generation of many HLA class I peptides entails a final trimming step in the endoplasmic reticulum that, in humans, is accomplished by two 'candidate' aminopeptidases | We show here that one of these, ERAP1, was unable to remove several N-terminal amino acids that were trimmed efficiently by the second enzyme, ERAP2. SIGNOR-272496 0.8 vismodegib chemical CHEBI:66903 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 21679342 t gcesareni Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date. SIGNOR-174417 0.8 ACVR2B protein Q13705 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 10090 21966641 t areggio It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains SIGNOR-254984 0.767 PEX3 protein P56589 UNIPROT PEX19 protein P40855 UNIPROT up-regulates activity binding -1 15007061 t miannu PEX3 is required for PEX19 to dock at peroxisomes, interacts specifically with the docking domain of PEX19, and is required for recruitment of the PEX19 docking domain to peroxisomes. SIGNOR-253026 0.953 PRKCH protein P24723 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser742 GEKSFRRsVVGTPAY 9606 10197446 t llicata These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748. SIGNOR-66734 0.362 FERMT2 protein Q96AC1 UNIPROT FBLIM1 protein Q8WUP2 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 t miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. SIGNOR-266102 0.775 POU5F1 protein Q01860 UNIPROT DPPA4 protein Q7L190 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254941 0.614 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser454 YVPMNPNsPPRQHSS 9606 15379552 t lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) SIGNOR-129188 0.2 PRKDC protein P78527 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser446 STMQVSHsQVQEPGG -1 8407951 t lperfetto  The carboxyl-terminal transcription activation domain was mapped within a 71-amino acid region that contains both DNA-PK phosphorylation sites. Amino acid substitutions that interfered with phosphorylation by DNA-PK at Ser-435/446 in GAL4-SRF fusion proteins were reduced in transactivation potency. From these data we suggest that DNA-PK phosphorylation may modulate SRF activity in vivo. SIGNOR-248922 0.415 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR WWC1 protein Q8IX03 UNIPROT unknown phosphorylation 9606 BTO:0000149 24269383 t inferred from 70% family members llicata We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro. SIGNOR-270208 0.2 ULK1 protein O75385 UNIPROT FBP1 protein P09467 UNIPROT down-regulates activity phosphorylation Ser63 HLYGIAGsTNVTGDQ 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274032 0.2 F7 protein P08709 UNIPROT Factor FVIIa:TF complex SIGNOR-C319 SIGNOR form complex binding 9606 BTO:0000131 32665005 t lperfetto During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury. SIGNOR-263555 0.932 UBXN1 protein Q04323 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 9606 15362974 f miannu Our working hypothesis is that SAKS1 acts as scaffolding protein to enhance the unfolding and proteolytic destruction of a subset of proteins. PNGase removes high-mannose-containing oligosaccharides from MGPs [30], and our results suggest this may be facilitated by the formation of a complex between PNGase, VCP, SAKS1 and ubiquitinated MGPs, as illustrated schematically in Figure 7(B). PNGase has been reported to bind to the S4 component of the proteasome [30], so that the deglycosylation of MGPs by PNGase, followed by VCP-catalysed unfolding, may facilitate their destruction by the proteasome. SIGNOR-261059 0.7 NCAPD3 protein P42695 UNIPROT Condensin II complex SIGNOR-C342 SIGNOR form complex binding 9606 32445620 t miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263912 0.882 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR4 protein O95977 UNIPROT up-regulates activity chemical activation 9606 10753843 t These results indicate that EDG-6 is a high affinity receptor for SPP, which couples to a G(i/o) protein, resulting in the activation of growth-related signaling pathways SIGNOR-261143 0.8 PHLPP1 protein O60346 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 9606 BTO:0001544 19261608 t The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. SIGNOR-248331 0.751 TLN1 protein Q9Y490 UNIPROT A4/b7 integrin complex SIGNOR-C187 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257635 0.538 PRKCA protein P17252 UNIPROT RAB11A protein P62491 UNIPROT unknown phosphorylation Ser177 TEIYRIVsQKQMSDR -1 22188018 t miannu This report shows for the first time that Rab11 is differentially phosphorylated by distinct PKC isoenzymes and that this post-translational modification might be a regulatory mechanism of intracellular trafficking.Our results demonstrate that classical PKC (PKCα and PKCβII but not PKCβI) directly phosphorylate Rab11 in vitro. In addition, novel PKCε and PKCη but not PKCδ isoenzymes also phosphorylate Rab11. Mass spectrometry analysis revealed that Ser 177 is the Rab11 residue to be phosphorylated in vitro by either PKCβII or PKCε. SIGNOR-263168 0.2 S100A8 protein P05109 UNIPROT AGER protein Q15109 UNIPROT up-regulates activity binding 9606 28137827 t miannu RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33 SIGNOR-261919 0.323 FLT3 protein P36888 UNIPROT CEBPB protein P17676 UNIPROT down-regulates quantity by repression transcriptional regulation 16146838 f lperfetto Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1. SIGNOR-250563 0.301 PPP1CA protein P62136 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity dephosphorylation Ser127 PQHVRAHsSPASLQL 9606 21909427 t lperfetto In the present study, we demonstrate that PP1A (catalytic subunit of protein phosphatase-1) interacts with and dephosphorylates YAP2 in vitro and in vivo, and PP1A-mediated dephosphorylation induces the nuclear accumulation and transcriptional activation of YAP2.|PP1A dephosphorylates endogenous YAP2 at serine 127. SIGNOR-276999 0.658 MECP2 protein P51608 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 15870696 f miannu Valproate (VPA) induces silencing of the ERalpha, cyclin D1 and pS2 promoters. Chromatin immunoprecipitation (ChIP) analysis demonstrates that VPA induces recruitment of the 5-MeCpG binding protein MeCP2 to the ERalpha A promoter and also to the pS2 and cyclin D1 promoters SIGNOR-254573 0.399 PRKCD protein Q05655 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Ser29 ATPAARAsKKILLPE 9606 BTO:0000007 11042191 t lperfetto Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells. SIGNOR-249059 0.2 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 16537444 t gcesareni Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion. SIGNOR-145145 0.622 GSK3B protein P49841 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation 9606 20932480 t miannu Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687 SIGNOR-168392 0.351 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation 9606 14532121 t inferred from 70% family members gcesareni Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation. SIGNOR-270063 0.2 AP1 complex SIGNOR-C154 SIGNOR GLIS1 protein Q8NBF1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 24383088 t miannu Co-transfection experiments revealed that HIF-2α had greater potency on the GLIS1 promoter activation than HIF-1α. Subsequent studies using wild-type and mutant HIF-2α demonstrated that DNA binding activity was not necessary but TADs were critical for GLIS1 induction. Finally, co-transfection experiments indicated that HIF-2α cooperated with AP-1 family members in upregulating GLIS1 transcription. These results suggest that the hypoxic signaling pathway may play a pivotal role in regulating the reprogramming factor GLIS1, via non-canonical mechanisms involving partner transcription factor rather than by direct HIF transactivation. SIGNOR-269041 0.2 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1784 TPTSPNYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273057 0.556 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI 9606 BTO:0000007 SIGNOR-C3 9465032 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-55701 0.924 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PARP1 protein P09874 UNIPROT up-regulates phosphorylation Ser372 VAATPPPsTASAPAA 9606 BTO:0000938 BTO:0000142 16627622 t lperfetto Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation. SIGNOR-244669 0.2 SLC19A1 protein P41440 UNIPROT (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI up-regulates quantity relocalization 9606 10787414 t lperfetto The differential polarized distribution of the reduced-folate transporter (RFT-1) and folate receptor alpha (FRalpha), the two proteins involved in the transport of folate, has been characterized in normal mouse retinal pigment epithelium (RPE) and in cultured human RPE cells. SIGNOR-268266 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252830 0.908 CAMK2A protein Q9UQM7 UNIPROT CAMK2A protein Q9UQM7 UNIPROT up-regulates phosphorylation Thr286 SCMHRQEtVDCLKKF 9606 BTO:0000975 1849884 t lperfetto Role of threonine-286 as autophosphorylation site for appearance of ca2(+)-independent activity of calmodulin-dependent protein kinase ii alpha subunit SIGNOR-21797 0.2 GART protein P22102 UNIPROT N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI down-regulates quantity chemical modification 9606 34283828 t miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). SIGNOR-268101 0.8 PPP2CA protein P67775 UNIPROT STK3 protein Q13188 UNIPROT down-regulates dephosphorylation Thr180 DTMAKRNtVIGTPFW 9606 23431053 t gcesareni Rassf1a apparently protects mst1/2 against inactivation by pp2a, the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively. SIGNOR-201266 0.684 1-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-2-methoxyphenyl)-3-(1-(thiazol-2-yl)ethyl)urea chemical CID:9869779 PUBCHEM CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259750 0.8 F2RL1 protein P55085 UNIPROT DUSP6 protein Q16828 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). SIGNOR-254853 0.2 SP1 protein P08047 UNIPROT SLC19A3 protein Q9BZV2 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 15217784 f miannu In transiently transfected Drosophila SL2 cells, both SP1 and SP3 transactivated the SLC19A3 minimal promoter in a dose-dependent manner and in combination demonstrated an additive stimulatory effect. SIGNOR-255215 0.274 LRP4 protein O75096 UNIPROT MUSK protein O15146 UNIPROT up-regulates activity binding 9606 BTO:0000887 23458718 t miannu AGRN is released by the nerve and binds to LRP4, which then binds to MuSK. This interaction leads to MuSK autophosphorylation and activation of its kinase function, leading to anterograde signalling by subsequent phosphorylation of DOK7 (not shown), which binds MuSK as a dimer. SIGNOR-273850 0.719 RPS6KA1 protein Q15418 UNIPROT EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 15071500 t gcesareni S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function. SIGNOR-123993 0.545 HARS1 protein P12081 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 10430027 t miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. SIGNOR-270487 0.8 PRKD1 protein Q15139 UNIPROT CACNA1C protein Q13936 UNIPROT up-regulates phosphorylation Ser1981 ASLGRRAsFHLECLK 9606 22100296 t gcesareni Both the expression of a dominant-negative mutant of pkd and the mutation of serine 1884 but not serine 1930, putative targets of pkd, strongly reduced l-type calcium currents and single channel activity without affecting the channel's expression at the plasma membrane. Our results suggest that serine 1884 is essential for the regulation of hcav1.2 by pkd. SIGNOR-177481 0.257 PRKCB protein P05771 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Ser363 ALLQSSAsRKTQKKK 9606 BTO:0004737 11325528 t lperfetto We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC. SIGNOR-249090 0.286 MTNR1A protein P48039 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256706 0.454 POGZ protein Q7Z3K3 UNIPROT CBX5 protein P45973 UNIPROT down-regulates activity binding 9606 BTO:0000932 20562864 t miannu POGZ was found to bind to HP1alpha through a zinc-finger-like motif. Binding by POGZ, mediated through its zinc-finger-like motif, competed with PxVxL proteins and destabilized the HP1alpha-chromatin interaction. SIGNOR-264487 0.443 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR Mob1 proteinfamily SIGNOR-PF42 SIGNOR up-regulates activity phosphorylation 9606 23431053 t miannu Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity SIGNOR-256185 0.897 TLK1 protein Q9UKI8 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates activity phosphorylation Ser160 NLLFKDNsLDAPVKL 9606 BTO:0000007 35064619 t miannu We established that TLK1 phosphorylates MK5 on three residues (S160, S354 and S386), resulting in MK5 activation, and additionally, mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected HEK 293 cells. SIGNOR-276745 0.2 MYC protein P01106 UNIPROT TYMS protein P04818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18677108 t miannu Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation. SIGNOR-267374 0.344 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates phosphorylation Thr533 TGSDNTDtEGS 9606 17936701 t lperfetto Pvhl acts as an adaptor to promote the inhibitory phosphorylation of the nf-kappab agonist card9 by ck2. The card9 c terminus contains multiple serine and threonine residues that resemble ck2 phosphorylation sites. Mass spectrometry analysis of myc-card9 recovered from hela cells revealed that these sites, including t531 and t533, were phosphorylated in vivo SIGNOR-158418 0.352 IL10 protein P22301 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 BTO:0000671 11035029 t fspada The il-10r2 chain is ubiquitously expressed, whereas the il-10 activity is restricted mainly to cells of hematopoietic origin (35, 36). This raised the question of why the second chain of the il-10 receptor complex is widely expressed when its function was required only in limited cellular subsets. One hypothesis is that the il-10r2 chain is shared by receptors for ligands other than il-10 SIGNOR-83191 0.703 canertinib chemical CHEBI:61399 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258095 0.8 GNAS protein P63092 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 SIGNOR-C110 16293724 t gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. SIGNOR-141789 0.389 PRKACA protein P17612 UNIPROT NOLC1 protein Q14978 UNIPROT up-regulates activity phosphorylation Ser623 KGEKRASsPFRRVRE -1 12167624 t miannu PKA-dependent Nopp140 phosphorylation is important for its role in agp gene activation. both Ser627 and Ser628 are phosphorylated by PKA. SIGNOR-250020 0.312 TNF protein P01375 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004914 14586405 f We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues. SIGNOR-253606 0.488 DFFA protein O00273 UNIPROT DFFB protein O76075 UNIPROT down-regulates binding 9606 BTO:0000567 9108473 t amattioni Dff is a heterodimer of 40 kda and 45 kda subunits. SIGNOR-29729 0.927 SOSTDC1 protein Q6X4U4 UNIPROT WNT2B protein Q93097 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242701 0.294 FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15109499 f miannu Constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers SIGNOR-252070 0.449 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser42 AKKKSKIsASRKLQL 9606 BTO:0000887 15769444 t lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. SIGNOR-134613 0.349 BMP10 protein O95393 UNIPROT ACVRL1 protein P37023 UNIPROT up-regulates binding 9606 17068149 t acerquone Taken together, our results sug- gest that bmp9 and bmp10 are two spe- cific alk1 ligands that may physiologi- cally trigger the effects of alk1 on angiogenesis SIGNOR-150201 0.698 NCOA1 protein Q15788 UNIPROT PCK2 protein Q16822 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255066 0.285 P2RY14 protein Q15391 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256866 0.377 RIMS3 protein Q9UJD0 UNIPROT UNC13B protein O14795 UNIPROT up-regulates activity relocalization 9606 31679900 t miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle SIGNOR-264384 0.269 VDR protein P11473 UNIPROT HLA-DRB1 protein P01911 UNIPROT up-regulates quantity by expression transcriptional regulation -1 19956544 f The promoter sequence analysis of HLA-DRB1 0301 showed presence of VDRE involved in higher expression of HLA-DRB1 030, which was confirmed by flow cytometry and real time PCR analysis| The data shows an average of 1.79±0.28 (mean±S.D. of three independent experiments) fold increase in the HLA-DRB1 transcripts from B-LCL treated with calcitriol as compared to the vehicle control. SIGNOR-253978 0.309 KDM2A protein Q9Y2K7 UNIPROT RELA protein Q04206 UNIPROT down-regulates demethylation Lys218 EIFLLCDkVQKEDIE 9606 SIGNOR-C13 20080798 t miannu Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. SIGNOR-163384 0.471 EP300 protein Q09472 UNIPROT CAV3 protein P56539 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0001538 15199055 f Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. SIGNOR-254259 0.2 NRAS protein P01111 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 17845852 f gcesareni Ras and akt signaling enhances the nuclear localization of gli1, counteracting its suppression by other modifiers that retain it in the cytoplasm, such as suppressor of fused (sufu) SIGNOR-157773 0.29 MYC protein P01106 UNIPROT CDKN2B protein P42772 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001271 12835716 f gcesareni Miz1 is a zinc finger transcription factor with an n-terminal poz domain. Complexes with myc, bcl-6 or gfi-1 repress expression of genes like cdkn2b (p15(ink4)) or cdkn1a (p21(cip1)). SIGNOR-102746 0.587 SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 15526160 f apalma The SFK family of tyrosine kinases is named after its prototypic family member c-Src. SCF-induced chemotaxis of Mo7 cells was dependent on SFK activity SIGNOR-254996 0.7 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates cleavage 23729744 t apalma Receptor–ligand engagement triggers a second NECD cleavage (S2 cleavage) by a metalloproteinase ADAM (known as Kuzbanian in Drosophila melanogaster), which in turn facilitates a further crucial signaling cleavage within the Notch transmembrane domain by a γ-secretase complex that contains Presenilin (S3 cleavage) SIGNOR-255372 0.665 MDFI protein Q99750 UNIPROT MYF5 protein P13349 UNIPROT down-regulates activity binding 10090 BTO:0000944 8797820 t 2 miannu We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals. SIGNOR-240433 0.378 CTNND2 protein Q9UQB3 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 t miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. SIGNOR-252134 0.458 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227870 0.891 perfluorododecanoic acid chemical CHEBI:90633 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation -1 31332417 t miannu In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group. SIGNOR-268759 0.8 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates 9606 11777913 f gcesareni Phosphorylation of 4e-bp1 is mediated by the p38/msk1 pathway in response to uvb irradiation. In the present study we demonstrated that uvb induced 4e-bp1 phosphorylation at multiple sites, thr-36, thr-45, ser-64, and thr-69, leading to dissociation of 4e-bp1 from eif-4e. Uvb-induced phosphorylation of 4e-bp1 was blocked by p38 kinase inhibitors, pd169316 and sb202190, and msk1 inhibitor, h89, but not by mitogen-activated protein kinase kinase inhibitors, pd98059 or u0126. SIGNOR-113566 0.444 NR4A3 protein Q92570 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30455429 t miannu Over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax. SIGNOR-259397 0.2 IL26 protein Q9NPH9 UNIPROT IL20RA protein Q9UHF4 UNIPROT up-regulates binding 9606 BTO:0001253 17208301 t gcesareni The mrna expression level of il10, il19, il20, il22, il24, il26, il28b, il29 and their receptors il10ra, il10rb, il20ra, il20rb, il22ra1, il22ra2, il28ra was compared in skin biopsies of children and adults and in childrens' skin cells by quantitative real-time pcr (qrt-pcr). SIGNOR-151920 0.585 SIRT3 protein Q9NTG7 UNIPROT SOD2 protein P04179 UNIPROT up-regulates activity deacetylation 34929314 t lperfetto SOD2 is the key substrate of SIRT3 in mitochondria. The combination of SIRT3 and SOD2 leads to the deacetylation and activation of SOD2 SIGNOR-267646 0.64 KDM6A protein O15550 UNIPROT HOXA1 protein P49639 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260019 0.377 ELL protein P55199 UNIPROT ELL/ICE2 complex SIGNOR-C49 SIGNOR form complex binding 9606 BTO:0001271 22195968 t miannu The ell-ice complex is called lec for its proposed role in transcriptional regulation of the littlesnrna genes. SIGNOR-193461 0.63 CAMK1 protein Q14012 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates activity phosphorylation Thr198 PGLRRRQt 10090 23707388 t Monia We also demonstrate that i) CaMKI phosphorylates p27 at Thr157and Thr198 in human cells and at Thr170and Thr197in mouse cells to modulate its subcellular localization;|Collectively, these results suggest that CaMKI is involved in mediating G1 progression by promoting cyclin D1/cdk4 complex formation through site-specific p27 phosphorylation in human lung epithelia. SIGNOR-261194 0.309 ABL1 protein P00519 UNIPROT TP73 protein O15350 UNIPROT up-regulates phosphorylation Tyr99 SVPTHSPyAQPSSTF 9606 10391251 t gcesareni C-abl phosphorylates p73 on a tyrosine residue at position 99 both in vitro and in cells that have been exposed to ionizing radiation. Our results show that c-abl stimulates p73-mediated transactivation and apoptosis. SIGNOR-68931 0.745 ETS1 protein P14921 UNIPROT TNC protein P24821 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15001984 t Luana Sp1 and Ets1 are potent transactivators of the TN-C promoter. SIGNOR-261599 0.2 GSK3A protein P49840 UNIPROT GATA6 protein Q92908 UNIPROT down-regulates quantity by destabilization phosphorylation Ser37 REPSTPPsPISSSSS 9606 BTO:0000182 27273097 t lperfetto Through bioinformatics and cell-based experiments, we identified the AKT-repressed signal as glycogen synthase kinase 3 (GSK3)-catalyzed phosphorylation of Ser(37) on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser(37) promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin SIGNOR-253156 0.268 TARS1 protein P26639 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. SIGNOR-270799 0.8 PAK4 protein O96013 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by stabilization phosphorylation Ser158 CDAQSRKsFSCKYCD -1 29849120 t miannu PAK4 bound and directly phosphorylated Slug at two previously unknown sites, S158 and S254, which resulted in its stabilization.  SIGNOR-277393 0.2 GSK3B protein P49841 UNIPROT MITF protein O75030 UNIPROT up-regulates quantity by stabilization phosphorylation Ser405 QARAHGLsLIPSTGL 9606 BTO:0005451 25605940 t miannu We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here. SIGNOR-276477 0.446 PPP2CA protein P67775 UNIPROT STK4 protein Q13043 UNIPROT down-regulates dephosphorylation Thr183 DTMAKRNtVIGTPFW 9606 23431053 t gcesareni Rassf1a apparently protects mst1/2 against inactivation by pp2a , the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively. SIGNOR-201270 0.375 CCT128930 chemical CID:17751819 PUBCHEM AKT2 protein P31751 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck;ATP-competitive inhibitor of Akt2 gcesareni SIGNOR-190868 0.8 FYN protein P06241 UNIPROT SLAMF1 protein Q13291 UNIPROT up-regulates activity phosphorylation Tyr281 EKKSLTIyAQVQKPG 9534 BTO:0000298 11806999 t All 3 tyrosines of CD150 (Tyr281, Tyr307, Tyr327) are phosphorylated by the src kinase Fyn. CD150 is unique among its homologues in the immunoglobulin superfamily in that it is able to bind SAP, a floating SH2 domain, in the absence of tyrosine phosphorylation. In this study, using a detailed mutagenesis mapping approach we have shown that SAP binding to CD150 is in fact bimodal. Prior to tyrosine phosphorylation, SAP binds the membrane-proximal motif surrounding Tyr281. Following tyrosine phosphorylation by tyrosine kinases such as Fyn, SAP binds additionally to the distal motif surrounding Tyr327. SIGNOR-251181 0.647 bethanechol chemical CHEBI:3084 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258624 0.8 GRIK1 protein P39086 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264342 0.7 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates phosphorylation Ser364 LQSPITTsPSC 9606 10617468 t lperfetto Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein. SIGNOR-73625 0.798 CDK1 protein P06493 UNIPROT PIK3C2A protein O00443 UNIPROT down-regulates activity phosphorylation Ser259 KVSNLQVsPKSEDIS 9606 12719431 t lperfetto Mitotic and stress-induced phosphorylation of HsPI3K-C2alpha targets the protein for degradation. Stress-dependent and mitotic phosphorylation of hspik3-c2alpha occurs on the same serine residue (ser259) within a recognition motif for proline-directed kinases. Mitotic phosphorylation of hspik3-c2alpha can be attributed to cdc2 activity, and stress-induced phosphorylation of hspik3-c2alpha is mediated by jnk/sapk SIGNOR-100903 0.285 ATF4 protein P18848 UNIPROT DYRK3 protein O43781 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000578 31066068 t miannu Interestingly, the promoter activity of Dyrk3 was negatively regulated by ATF4, indicating a double-negative feedback loop. SIGNOR-275453 0.2 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1387 EDCSGLSsQSDILTT 9606 BTO:0000150 12183412 t gcesareni Phosphorylation of serine 1387 in brca1 is specifically required for the atm-mediated s-phase checkpoint after ionizing irradiation.We recently reported that brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the s-phase and the g2 phase of the cell cycle. We also found that mutation of serine 1423 in brca1, a target of atm phosphorylation, abrogates the g2-m checkpoint but not the ionizing irradiation-induced s-phase checkpoint. Here we demonstrate that mutation of serine 1387 in brca1, another target of atm phosphorylation, conversely abrogates the radiation-induced s-phase arrest but does not affect the g2-m checkpoint. SIGNOR-91482 0.813 clobetasol chemical CHEBI:205919 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation 9606 4594577 t SimoneGraziosi The clinical evaluation of a new topical corticosteroid, clobetasol propionate. An international controlled trial. SIGNOR-269217 0.8 AKT1 protein P31749 UNIPROT RPS3 protein P23396 UNIPROT up-regulates activity phosphorylation Thr70 GRRIRELtAVVQKRF 10116 BTO:0003060 20605787 t miannu Here, we show that human RPS3 is a physiological target of Akt kinase and a novel mediator of neuronal apoptosis. NGF stimulation resulted in phosphorylation of threonine 70 of RPS3 by Akt, and this phosphorylation was required for Akt binding to RPS3.our experiment demonstrated that Akt up-regulates the endonuclease activity of RPS3 via phosphorylation and led us to believe that Akt phosphorylation of RPS3 after DNA damage is an antiapoptotic signal or a molecular switch that extends the life of a cell after DNA damage. SIGNOR-259815 0.376 FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates activity 10090 25549588 f areggio Muscle-specific ubiq- uitin ligases, muscle-specific RING-finger 1 (MURF1; also known as TRIM63)12 and atrogin 1 (also known as MAFBX)8, are markedly induced in almost all types of atrophy. SIGNOR-254994 0.7 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr900 FGLSRDVyEEDSYVK 9606 14711813 t gcesareni Mass spectrometric analysis revealed that ret tyr(900) was autophosphorylation site. Tyr900 can partially replace the function of tyr905 as a local switch for kinase activation SIGNOR-121161 0.2 sunitinib chemical CHEBI:38940 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 21993628 t gcesareni The action of kit kinase inhibitors, especially imatinib, sunitinib, dasatinib and pkc412, on different primary and secondary mutants is discussed. SIGNOR-176760 0.8 TELO2 protein Q9Y4R8 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000007 20427287 t miannu MTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. Furthermore, using immunoprecipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. SIGNOR-272001 0.531 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT up-regulates activity phosphorylation Tyr232 SQKKEGVyDVPKSQP 10090 BTO:0000938 11279201 t lperfetto Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons. SIGNOR-247084 0.43 EXOC8 protein Q8IYI6 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270791 0.939 MAP2K2 protein P36507 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258996 0.734 HTR4 protein Q13639 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256912 0.36 CLK3 protein P49761 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates activity phosphorylation -1 8617202 t miannu In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors. SIGNOR-273859 0.545 PRKCA protein P17252 UNIPROT TRPM4 protein Q8TD43 UNIPROT up-regulates phosphorylation Ser1145 RDKRESDsERLKRTS 9606 15590641 t gcesareni Phorbol ester-induced activation of protein kinase c (pkc) increased the ca(2+) sensitivity of wild-type trpm4 but not of two mutants mutated at putative pkc phosphorylation sites. SIGNOR-132243 0.2 CDKN1B protein P46527 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002392 22343731 f fcortellessa The results of the MTT assay and growth curves revealed that the cells transfected with pEGFP-p27kip1 had a significant growth inhibition when compared with cells transfected with pEGFP-NC (Fig. 5B and D). These data indicated that overexpression of p27kip1 could arrest cell-cycle progression and decrease proliferation of SGC-7901 cells. SIGNOR-261687 0.7 TGFB1 protein P01137 UNIPROT Activated PSC phenotype SIGNOR-PH224 SIGNOR up-regulates 9606 BTO:0000988 38540204 t miannu Resident fibroblasts, especially PSC, have the ability to transdifferentiate from a “quiescent” retinoid/lipid storing phenotype in the normal pancreas to an “activated” α-smooth muscle-actin-producing myofibroblastic phenotype through tumor-derived stimuli such as cytokines (interleukin(IL)-1, IL-6, and IL-8 and tumor necrosis factor (TNF)-α), growth factors (platelet-derived growth factor (PDGF) and tumor growth factor (TGF)-β), and reactive oxygen species [33]. Activated PSCs can, in turn, produce autocrine factors such as PDGF, TGF-β, and cytokines, which may contribute to a looping mechanism promoting a desmoplastic reaction SIGNOR-277679 0.7 ROCK2 protein O75116 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225]. SIGNOR-96696 0.423 SUCLG1 protein P53597 UNIPROT Succinyl-CoA ATP variant complex SIGNOR-C398 SIGNOR form complex binding 9606 32627745 t miannu Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS). SIGNOR-266261 0.986 PTGES2 protein Q9H7Z7 UNIPROT prostaglandin H2(1-) smallmolecule CHEBI:57405 ChEBI up-regulates quantity chemical modification -1 10922363 t Luana Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently. SIGNOR-269768 0.8 orantinib chemical CHEBI:91088 ChEBI FGFR1 protein P11362 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207435 0.8 2,5-dichloro-N-(2-methyl-4-nitrophenyl)benzenesulfonamide chemical CHEBI:125569 ChEBI PPARG protein P37231 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001950 27489280 t lperfetto We performed reporter assays to examine the effect of NeoB on the transcriptional activity of specific nuclear hormone receptors, including PPARs, retinoic acid receptor (RAR), ER, and LXR, in uninfected Huh7-25 cells (Fig. 3A). NeoB did not have a significant effect [...] in contrast to the transcriptional repression by known antagonists as positive controls (GW6471, GSK0660, FH535, Ro41-5253, and 4-hydroxytamoxifen) (Fig. 3A) SIGNOR-262015 0.8 CSNK1D protein P48730 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser400 SRDESTDsGLSMSSY 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 23431053 t milica Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ SIGNOR-201143 0.4 SRPK1 protein Q96SB4 UNIPROT SRPK1 protein Q96SB4 UNIPROT up-regulates phosphorylation Thr326 ENPPNKMtQEKLEES 9606 22727668 t llicata We found that activated akt binds and induces srpk1 autophosphorylation because akt-mediated phosphorylation depends on the kinase activity of srpk1 SIGNOR-197993 0.2 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser41 RTDALTSsPGRDLPP 9606 16899510 t gcesareni In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells. SIGNOR-148717 0.961 SYK protein P43405 UNIPROT FCGR2C protein P31995 UNIPROT up-regulates activity phosphorylation Tyr310 TDDDKNIyLTLPPND -1 8756631 t miannu Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation SIGNOR-262675 0.2 FN1 protein P02751 UNIPROT FN1/SDC4 complex SIGNOR-C210 SIGNOR form complex binding 23290138 t apalma We found that binding of ECM glycoprotein Fibronectin (FN) to Sdc4 stimulates the ability of Wnt7a to induce the symmetric expansion of satellite stem cells SIGNOR-255285 0.7 SRC protein P12931 UNIPROT MPZL1 protein O95297 UNIPROT up-regulates phosphorylation Tyr241 SHQGPVIyAQLDHSG 9606 11751924 t lperfetto Indeed, our studies indicated that cross-linking of pzr by cona lead to activation of c-src, which may be responsible for phosphorylation of pzr and possibly other proteins. Phosphorylation of pzr in turn recruits shp-2, which by itself is an essential signal transducertyrosine residues 241 and 263 embedded in the itims are responsible for the tyrosine phosphorylation of pzr SIGNOR-113406 0.48 SREBF1 protein P36956 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 t inferred from family member gcesareni Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk) SIGNOR-267799 0.339 TFPT protein P0C1Z6 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270857 0.438 melatonin smallmolecule CHEBI:16796 ChEBI MTNR1A protein P48039 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257545 0.8 PRKCA protein P17252 UNIPROT CDC42EP4 protein Q9H3Q1 UNIPROT down-regulates activity phosphorylation Ser80 SSKRSLLsRKFRGSK 9606 BTO:0001939 25086031 t miannu Cdc42 effector protein-4 (CEP4) was recently identified by our laboratory to be a substrate of multiple PKC isoforms in non-transformed MCF-10A human breast cells. MS/MS analysis verified that Ser(18) and Ser(80) were directly phosphorylated by PKCα in vitro. Phosphorylation of CEP4 severely diminished its affinity for Cdc42 while promoting Rac activation and formation of filopodia (microspikes). SIGNOR-263161 0.2 MEN1 protein O00255 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15640349 f irozzo Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions. SIGNOR-255889 0.414 CEBPA protein P49715 UNIPROT GFI1 protein Q99684 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20924107 f irozzo We show here that C/EBPα interacts with a functional C/EBP binding site in the Gfi-1 5'-flanking region and enhances the promoter activity of Gfi-1. SIGNOR-256068 0.382 sunitinib chemical CHEBI:38940 ChEBI PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 21993628 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-176766 0.8 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Thr455 ALGTPVLtPPTEAAS 9606 BTO:0000848 BTO:0001253 20959475 t lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). SIGNOR-168766 0.2 ELF3 protein P78545 UNIPROT SPRR2A protein P35326 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 10773884 f Interestingly, ELF3 suppressed basal keratin 4 promoter activity in both esophageal and cervical epithelial cancer cell lines, a novel result, while simultaneously activating the late-differentiation linked SPRR2A promoter. SIGNOR-254292 0.407 LAMTOR4 protein Q0VGL1 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR form complex binding 9606 20381137 t lperfetto Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant SIGNOR-164778 0.924 MAPK1 protein P28482 UNIPROT IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation Ser46 SASGSAFsPYPGSAA -1 15133517 t miannu We tested the transcriptional properties of Irx2 by dividing it into amino- and carboxy terminal parts and found that Mek1-mediated phosphorylation activates and derepresses the amino and carboxyl parts, respectively. When Ser46 and Ser65 were mutated to alanine (S46A and S65A), phosphorylation was reduced, whereas substitution of Ser83 and Ser103 (S83A and S103A) did not affect phosphorylation. SIGNOR-263052 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPC5 protein Q9UL62 UNIPROT down-regulates activity phosphorylation Ser796 GARAKSKsVSFNLGC 9606 BTO:0000007 21734191 t miannu We show that TRPC5 channels may become directly phosphorylated by PKA at serine residues 794 and 796, and that this phosphorylation abolishes the receptor-operated nonselective cation current mediated by TRPC5 channels in HEK-293 cells. SIGNOR-276339 0.2 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1644 SPTSPSYsPTSPSYS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248817 0.849 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. SIGNOR-268777 0.8 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:93369 ChEBI HTR1D protein P28221 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000529 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258539 0.8 MAPK1 protein P28482 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser43 RNPEAALsPTFRSDS 9606 BTO:0000007 33217317 t miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. SIGNOR-265950 0.276 CLCC1 protein Q96S66 UNIPROT PIGBOS1 protein A0A0B4J2F0 UNIPROT up-regulates activity binding 9606 31653868 t Simone The PIGBOS microprotein interacts with the ER protein CLCC1. PIGBOS localizes to the mitochondrial outer membrane where itinteracts with the ER protein CLCC1 at ER–mitochondria contact sites. PIGBOS-CLCC1 interaction is necessary for PIGBOS function SIGNOR-261040 0.2 DCK protein P27707 UNIPROT 2'-deoxycytosine 5'-monophosphate(2-) smallmolecule CHEBI:57566 ChEBI up-regulates quantity chemical modification 20637175 t lperfetto Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis SIGNOR-275807 0.8 WNT3 protein P56703 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131820 0.616 GLI2 protein P10070 UNIPROT GLI1/GLI2 complex SIGNOR-C450 SIGNOR form complex binding 9606 BTO:0000304 32766732 t GLI2 and GLI1 heterodimerize via the Zn-finger domain SimoneGraziosi GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. SIGNOR-269210 0.434 AKT1 protein P31749 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 20086174 t llicata We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2. SIGNOR-163533 0.363 TARS1 protein P26639 UNIPROT Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates quantity chemical modification 9606 25824639 t miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. SIGNOR-270506 0.8 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 8376365 t gcesareni Phosphorylation at either ser(16) or ser(63) strongly reduced or abolished the ability of stathmin to bind to and sequester soluble tubulin and its ability to act as a catastrophe factor by directly binding to the microtubules. The known in vivo phosphorylation sites of stathmin are ser-16 and ser-63 for cyclic amp-dependent protein kinase (pka). SIGNOR-38318 0.314 KAT6A/KAT6B complex SIGNOR-C54 SIGNOR TP53 protein P04637 UNIPROT up-regulates acetylation Lys382 QSTSRHKkLMFKTEG 9606 BTO:0001271 23431171 t lperfetto We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression SIGNOR-217198 0.491 PTEN protein P60484 UNIPROT CFL1 protein P23528 UNIPROT up-regulates activity dephosphorylation 9606 22317922 t lperfetto Unexpectedly, cofilin-1 activation by PGE 2 was mediated by the protein phosphatase activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10), with which it directly associated.|Unexpectedly, cofilin-1 dephosphorylation and activation in our model was mediated by the protein phosphatase activity of PTEN. SIGNOR-276980 0.452 propionyl-CoA(4-) smallmolecule CHEBI:57392 ChEBI (S)-methylmalonyl-CoA(5-) smallmolecule CHEBI:57327 ChEBI up-regulates quantity precursor of 9606 15890657 t miannu Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively. SIGNOR-267185 0.8 HMGB2 protein P26583 UNIPROT POU3F1 protein Q03052 UNIPROT up-regulates activity binding 10090 BTO:0002910 7720710 t 2 miannu HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins SIGNOR-240148 0.312 NCOA3 protein Q9Y6Q9 UNIPROT ATF4 protein P18848 UNIPROT up-regulates activity binding 9606 BTO:0000578 31066068 t miannu Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity. SIGNOR-275452 0.2 BCL11A protein Q9H165 UNIPROT HBG1 protein P69891 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004408 29606353 t Gianni Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching. SIGNOR-269067 0.458 PPARGC1A protein Q9UBK2 UNIPROT Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR up-regulates 9606 20640476 f Gianni However, in contrast to the role of AMPK, most reports to date indicate that PGC-1a induces gluconeogenesis SIGNOR-209932 0.7 MITF protein O75030 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 12086670 t lperfetto MITF directly occupies the BCL2 promoter in vivo and this suggest that BCL2 may be a direct transcriptional target of MITF SIGNOR-249618 0.453 4'-epidoxorubicin chemical CHEBI:47898 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 17639997 t miannu The combinatory use of low concentrations of SM with low-toxic topoisomerase II inhibitor epirubicin accelerated apoptotic cell death. SIGNOR-259282 0.8 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Thr305 TDAATMKtFCGTPEY 9606 18160256 t Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248651 0.727 SDH complex SIGNOR-C400 SIGNOR fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity chemical modification 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions. SIGNOR-266277 0.8 LYN protein P07948 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity phosphorylation Tyr567 IRVDTPHyPRWITKE -1 11812791 t Src, Fyn, or Lyn are the essential kinases that tyrosine phosphorylate and inactivate PKC δ. Lyn phosphorylates tyrosine residue 565 in vitro SIGNOR-251407 0.538 NAB2 protein Q15742 UNIPROT GFI1 protein Q99684 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16923394 f miannu Impairing Egr-2 or Nab-2 induction resulted in sustained expression of Gfi-1, demonstrating that Egr-2 and Nab-2 negatively regulate Gfi-1 expression . Importantly, the Gfi-1 promoter was repressed via the Egr site by coexpression of Egr-2 and Nab-2. Thus, Egr-2 and Nab-2 directly repress the Gfi-1 gene. SIGNOR-256042 0.402 STK38 protein Q15208 UNIPROT PI4KB protein Q9UBF8 UNIPROT up-regulates activity phosphorylation Ser277 RTHQRSKsDATASIS 10090 BTO:0000142 22445341 t miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. SIGNOR-263033 0.27 LAG3 protein P18627 UNIPROT T cell exhaustion phenotype SIGNOR-PH221 SIGNOR up-regulates 9606 BTO:0000782 27192565 f Barakat Lag-3, Tim-3, and TIGIT are highly expressed on dysfunctional or exhausted T cells in chronic diseases such as chronic viral infection and cancer. SIGNOR-275414 0.7 TWIST1 protein Q15672 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 21931630 f miannu Using human MSCs, we discovered TWIST, a downstream target of HIF-1α, was induced under hypoxia and acted as a transcription repressor of RUNX2 through binding to the E-box located on the promoter of type 1 RUNX2. SIGNOR-255593 0.46 RPS6KA1 protein Q15418 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 BTO:0000669 11500364 t lperfetto We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity SIGNOR-109708 0.528 CyclinA2/CDK1 complex SIGNOR-C420 SIGNOR G2/M_transition phenotype SIGNOR-PH52 SIGNOR up-regulates 9606 29870721 f lperfetto Here we show that cyclin A/cdk1 kinase is the factor triggering mitosis. SIGNOR-267572 0.7 RET protein P07949 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Tyr9 ARTTSQLyDAVPIQS 10029 12738763 t lperfetto Ret/ptc (rearranged in transformation/papillary thyroid carcinomas) tyrosine kinase phosphorylates and activates phosphoinositide-dependent kinase 1 (pdk1) ret/ptc phosphorylates a specific tyrosine (y9) residue located in the n-terminal region of pdk1. SIGNOR-235863 0.2 LTC4S protein Q16873 UNIPROT glutathionate(1-) smallmolecule CHEBI:57925 ChEBI down-regulates quantity chemical modification 9606 27365393 t miannu Leukotriene C4 synthase (LTC4S) catalyzes the formation of the proinflammatory lipid mediator leukotriene C4 (LTC4). SIGNOR-277259 0.8 PLK1 protein P53350 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates phosphorylation Thr68 SSLETVStQELYSIP 9606 12493754 t gcesareni Plk1 overexpression enhances phosphorylation of chk2 at thr-68. SIGNOR-96637 0.504 ACTB protein P60709 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269788 0.425 AMPK complex SIGNOR-C15 SIGNOR NEDD4L protein Q96PU5 UNIPROT up-regulates activity phosphorylation Ser795 VDLKPNGsEIMVTNE -1 21501591 t miannu The AMP-activated protein kinase (AMPK) down-regulates the inward rectifier K+ channel Kir2.1. Expression of wild type Nedd4-2 or of Nedd4-2S795A lacking an AMPK phosphorylation consensus sequence downregulated Kir2.1 currents. The effect of wild type Nedd4-2 but not of Nedd4-2S795A was significantly augmented by additional coexpression of AMPK. SIGNOR-276324 0.258 GNAO1 protein P09471 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates activity binding -1 10224115 t G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics. SIGNOR-256540 0.2 MKRN1 protein Q9UHC7 UNIPROT RPS10 protein P46783 UNIPROT up-regulates activity ubiquitination Lys107 ETGRPRPkGLEGERP 9606 BTO:0000007 31640799 t miannu We show that MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1) and associates with polysomes. MKRN1 is positioned upstream of poly(A) tails in mRNAs in a PABPC1-dependent manner. Ubiquitin remnant profiling and in vitro ubiquitylation assays uncover PABPC1 and ribosomal protein RPS10 as direct ubiquitylation substrates of MKRN1.Our data show that MKRN1 associates with polysomes and ubiquitylates RPS10, indicating a role in translational control. We hypothesize that ribosomes encountering the MKRN1-PABPC1 complex are stalled, possibly via ubiquitylation of RPS10 on K107 and other MKRN1 substrates. SIGNOR-272216 0.2 TGFB2 protein P61812 UNIPROT Activated PSC phenotype SIGNOR-PH224 SIGNOR up-regulates 9606 BTO:0000988 38540204 t miannu Resident fibroblasts, especially PSC, have the ability to transdifferentiate from a “quiescent” retinoid/lipid storing phenotype in the normal pancreas to an “activated” α-smooth muscle-actin-producing myofibroblastic phenotype through tumor-derived stimuli such as cytokines (interleukin(IL)-1, IL-6, and IL-8 and tumor necrosis factor (TNF)-α), growth factors (platelet-derived growth factor (PDGF) and tumor growth factor (TGF)-β), and reactive oxygen species [33]. Activated PSCs can, in turn, produce autocrine factors such as PDGF, TGF-β, and cytokines, which may contribute to a looping mechanism promoting a desmoplastic reaction SIGNOR-277680 0.7 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT down-regulates activity phosphorylation Thr383 PSVAYVHtTPGLPSG -1 12911626 t miannu Site‐directed mutagenesis of the SGK1 phosphorylation sites in the Nedd4‐2 protein (S382A,S468ANedd4‐2) and in the EAAT1 protein (T482AEAAT1, T482DEAAT1) significantly blunts the effect of S422DSGK1. Introduction of a negative charge at the SGK phosphorylation site in the EAAT1 protein leads to a strong stimulation of the carrier, whereas replacement with alanine markedly decreases the EAAT1‐mediated current. These observations suggest that SGK1 exerts its effect not only by phosphorylation of Nedd4‐2 but also by phosphorylation of EAAT1. SIGNOR-263076 0.779 TSC22D3 protein Q99576 UNIPROT NFKB2 protein Q00653 UNIPROT down-regulates activity binding 9606 BTO:0000007 11468175 t GILZ inhibits NF-kappaB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-kappaB subunits. SIGNOR-253298 0.332 FGR protein P09769 UNIPROT FGR protein P09769 UNIPROT up-regulates activity phosphorylation Tyr412 RLIKDDEyNPCQGSK -1 8612628 t Autophosphorylation of c-Fgr under basal conditions involves Tyr-400 (homologous of c-Src Tyr-416) but not, to any appreciable extent, Tyr-511. Both Tyr-511 and Tyr-400, however, incorporate phosphate if autophosphorylation is performed in the presence of polycationic peptides, such as polylysine, histones H1 and protamines. Such a double phosphorylation induced by polylysine gives rise to an upshifted form of c-Fgr on SDS-PAGE and correlates with a stimulation of catalytic activity instead of a down-regulation SIGNOR-251143 0.2 CAMK4 protein Q16566 UNIPROT NOS1 protein P29475 UNIPROT down-regulates activity phosphorylation Ser852 SYKVRFNsVSSYSDS 10400690 t llicata It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation. SIGNOR-250713 0.364 PRKACA protein P17612 UNIPROT PIN1 protein Q13526 UNIPROT down-regulates activity phosphorylation Ser16 PGWEKRMsRSSGRVY 9606 11723108 t llicata Pka and pkc readily phosphorylated pin1 and its ww domain in summary, we have demonstrated that phosphorylation of the pin1 ww domain on ser16 regulates its ability to function as a pser/thr-binding module. |To examine the importance of Ser16 of Pin1, it was mutated to Glu to mimic pSer, and the mutant Pin1S16E failed to bind mitotic phosphoproteins SIGNOR-112164 0.2 GPS1 protein Q13098 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270765 0.921 ZNHIT1 protein O43257 UNIPROT H2AZ1 protein P0C0S5 UNIPROT unknown 9606 BTO:0000887 20473270 f gcesareni The chromatin-remodelling complex snf2-related cbp activator protein (srcap) regulates chromatin structure in yeast by modulating the exchange of histone h2a for the h2a.z variant. We also show that p18hamlet is required for h2a.z accumulation into this genomic region and for subsequent muscle gene transcriptional activation. SIGNOR-165610 0.2 PTP4A3 protein O75365 UNIPROT ITGB1 protein P05556 UNIPROT down-regulates activity dephosphorylation Tyr783 DTGENPIyKSAVTTV 9606 23092334 t miannu In this study, we demonstrate that PRL-3 directly binds to integrin \u03b21 and dephosphorylates integrin \u03b21-Y783, a key residue for integrin \u03b21 function [ ].|These results indicate that PRL-3 dephosphorylates integrin \u03b21 in vitro and in vivo. SIGNOR-277050 0.507 EIF2B4 protein Q9UI10 UNIPROT EIF2S3 protein P41091 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269137 0.686 EEF1A1P5 protein Q5VTE0 UNIPROT Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269552 0.8 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 20551172 t miannu We characterize a new Myc-interacting factor, TRPC4AP (transient receptor potential cation channel, subfamily C, member 4-associated protein)/TRUSS (tumor necrosis factor receptor-associated ubiquitous scaffolding and signaling protein), which is the receptor for a DDB1 (damage-specific DNA-binding protein 1)-CUL4 (Cullin 4) E3 ligase complex for selective Myc degradation through the proteasome. TRPC4AP/TRUSS binds specifically to the Myc C terminus and promotes its ubiquitination and destruction through the recognition of evolutionarily conserved domains in the Myc N terminus.  SIGNOR-271965 0.385 ATF3 protein P18847 UNIPROT ASNS protein P08243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12881527 f miannu Transcription from the ASNS (asparagine synthetase) gene is increased in response to either amino acid (amino acid response) or glucose (endoplasmic reticulum stress response) deprivation. the results provide evidence for a potential role of multiple predicted ATF3 isoforms in the transcriptional regulation of the ASNS gene in response to nutrient deprivation. SIGNOR-253746 0.418 ATM protein Q13315 UNIPROT MECOM protein Q03112 UNIPROT up-regulates activity phosphorylation Ser1037 IGNSNHGsQSPRNVE 29939287 t phosphorylation site remapping based on Fig 1 lperfetto To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif. SIGNOR-273433 0.2 OXTR protein P30559 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256793 0.409 FLT3 protein P36888 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 10090 18192505 f Inhibition of FLT3/ITD leads to a small decrease in RAC1 activity SIGNOR-261536 0.2 NEK2 protein P51955 UNIPROT YAP1 protein P46937 UNIPROT up-regulates quantity by stabilization phosphorylation Thr143 AVSPGTLtPTGVVSG 35705994 t lperfetto NEK2 promotes the migration and proliferation of ESCC via stabilization of YAP1 by phosphorylation at Thr-143 SIGNOR-276586 0.2 MAPK1 protein P28482 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser476 MNILGSQsPLHPSTL 9606 15952796 t lperfetto We show that grb10 is a direct substrate of the p42/44 mitogen-activated protein kinase (mapk)we identified ser(150), ser(418), and ser(476) of human grb10zeta as mapk-mediated in vitro phosphorylation sites. Replacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation. Taken together, our findings suggest that phosphorylation of the adaptor protein may provide a feedback inhibitory mechanism by which grb10 regulates insulin signaling. SIGNOR-138167 0.381 MRGPRX1 protein Q96LB2 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257433 0.2 A5/b1 integrin complex SIGNOR-C163 SIGNOR Activated PSC phenotype SIGNOR-PH224 SIGNOR up-regulates 9606 32928643 t miannu CTGF is highly expressed in PDAC tissues, especially in tumor stroma (as shown by immunohistochemistry, CTGF: brown stain). The tumor cell-secreted CTGF promotes pancreatic stellate cell (PSC) proliferation, adhesion, and migration via integrin α5β1, leading to extracellular matrix (ECM) deposition.Pancreatic cancer cells secrete high levels of CTGF that binds to integrin α5β1, promoting PSC proliferation, adhesion, and migration SIGNOR-277688 0.7 CSNK2A2 protein P19784 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates phosphorylation Thr142 DSVTKLLtDVQLMKG 9606 12659875 t lperfetto Transcriptional activity and dna binding of heat shock factor-1 involve phosphorylation on threonine 142 by ck2.As hsf1 is activated by heat shock simultaneously with the nuclear translocation of the protein kinase ck2, we have investigated the role of ck2 in hsf1 activatio SIGNOR-99606 0.355 GSK3B protein P49841 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Ser518 KYATPAPsAKSSPSK 9606 BTO:0000938 16611631 t lperfetto Using in vitro kinase assays and pharmacological inhibition of gsk3 as described above for crmp2 and crmp4, it was found that thr509 (and presumably ser518 and thr514) of human crmp1 is phosphorylated by gsk3, following priming of ser522 by cdk5 SIGNOR-145991 0.448 SGK1 protein O00141 UNIPROT NDRG2 protein Q9UN36 UNIPROT up-regulates phosphorylation Ser332 LSRSRTAsLTSAASV 9606 BTO:0000567 BTO:0000887;BTO:0001103;BTO:0000763 15461589 t llicata Sgk1 phosphorylated ndrg2 at thr330, ser332 and thr348 in vitro. for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, the phosphorylation of thr348 by sgk1 may prime for phosphorylation at ser344 SIGNOR-129672 0.404 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BGN protein P21810 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15536164 f miannu Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kappaB, a transcription factor that is activated in FAP nerves and SG. SIGNOR-254797 0.2 C1RL protein Q9NZP8 UNIPROT HP protein P00738 UNIPROT up-regulates activity cleavage Arg161 NPANPVQrILGGHLD 9534 BTO:0001538 15385675 t miannu We demonstrate that coexpression of the proform of Hp (proHp) and C1r-LP in COS-1 cells effected cleavage of proHp in the endoplasmic reticulum. This cleavage depended on proteolytic activity of C1r-LP because mutation of the putative active-site Ser residue abolished the reaction. Furthermore, incubation of affinity-purified C1r-LP and proHp led to the cleavage of the latter protein. ProHp appeared to be cleaved at the expected site because substitution of Gly for Arg-161 blocked the reaction. SIGNOR-256358 0.383 CDX2 protein Q99626 UNIPROT CDH17 protein Q12864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972;BTO:0004168 20568120 t The present study aims to identify the transcription factors which interact and regulate CDH17 promoter activity that might contribute to the up-regulation of CDH17 gene in human HCC|we identified hepatic nuclear factor 1α (HNF1α) and caudal-related homeobox 2 (CDX2) binding sites at the proximal promoter region which modulate the CDH17 promoter activities in two HCC cell lines (Hep3B and MHCC97L) SIGNOR-253963 0.415 SAGA complex complex SIGNOR-C465 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR up-regulates 9606 15970593 f lperfetto Transcription initiation is a major regulatory step in eukaryotic gene expression. Co-activators establish transcriptionally competent promoter architectures and chromatin signatures to allow the formation of the pre-initiation complex (PIC), comprising RNA polymerase II (Pol II) and general transcription factors (GTFs).|this observation appears remarkably prevalent for chromatin-modifying and remodeling complexes. Here, we use the modular organization of the evolutionary conserved Spt-Ada-Gcn5 acetyltransferase (SAGA) complex as a paradigm to illustrate how co-activators share and combine a relatively limited set of functional tools. SIGNOR-269570 0.7 SOX2 protein P48431 UNIPROT SOX2/POU5F1 complex SIGNOR-C73 SIGNOR form complex binding 9606 7590241 t miannu Sox2 can form a ternary complex with either the ubiquitous oct-1 or the embryonic-specific oct-3 protein on fgf-4 enhancer dna sequences. However, only the sox2/oct-3 complex is able to promote transcriptional activation. SIGNOR-29512 0.834 (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI methionine smallmolecule CHEBI:16811 ChEBI up-regulates quantity precursor of 9606 10720211 t lperfetto Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine. SIGNOR-253141 0.8 KRAS protein P01116 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 9727023 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner. SIGNOR-59819 0.769 PRKCG protein P05129 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser187 DLGERKPsSAAYQKA -1 9244383 t lperfetto We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198. SIGNOR-248975 0.36 WRC complex complex SIGNOR-C191 SIGNOR ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 20332100 t miannu The activated WAVE complex at the leading edge of lamellipodia promotes actin polymerization at the plasma membrane by activating the Arp2/3 complex SIGNOR-253573 0.525 HBA1 protein P69905 UNIPROT CD163 protein Q86VB7 UNIPROT up-regulates activity binding 9606 16522161 t Regulation miannu These data suggest that hemoglobin may mediate a stimulatory effect on erythropoiesis through the activation of CD163 on hematopoietic progenitor cells. SIGNOR-251747 0.262 HMOX2 protein P30519 UNIPROT HBA1 protein P69905 UNIPROT down-regulates activity 9606 10490932 t Regulation miannu Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme SIGNOR-251814 0.257 PDPK1 protein O15530 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0000298 10480933 t miannu Full-length RSK1, RSK2, and RSK3 Are Activated when Coexpressed with PDK1 in COS7 Cells. Ser221 phosphorylation is increased 2–3-fold during ERK-mediated activation of RSK1 in COS1 cells SIGNOR-250270 0.614 KIT protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000830 15526160 t miannu Activation of PI3-kinase by c-Kit has been linked to mitogenesis, differentiation, survival, adhesion, secretion and actin cytoskeletal reorganization. In c-Kit, Y721 has been found to directly interact with PI3-kinase SIGNOR-254949 0.709 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1087 HGHVSNAsISLGESV -1 22302995 t miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. SIGNOR-262901 0.69 serotonin smallmolecule CHEBI:28790 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258889 0.8 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser214 TVLTAQEsFSGSLGH -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276216 0.388 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates activity phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 t lperfetto The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein. SIGNOR-105247 0.38 ELF4 protein Q99607 UNIPROT CXCL8 protein P10145 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000130;BTO:0000782 14625302 f miannu Myeloid elf1-like factor is a potent activator of interleukin-8 expression in hematopoietic cells SIGNOR-119204 0.243 PPARG protein P37231 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 17681149 f lperfetto This mechanism is mainly operative in native monocytes that, in the presence of an appropriate M2 stimulus such as IL-4, can be primed by PPARg ligands to an enhanced M2 phenotype. SIGNOR-249542 0.7 PIM1 protein P11309 UNIPROT RPS19 protein P39019 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 16266891 t gcesareni The pim-1/rps19 interaction was demonstrated both in vitro and in living cells and led to phosphorylation of rps19 in an in vitro kinase assay. SIGNOR-141411 0.449 SAICAR(4-) smallmolecule CHEBI:58443 ChEBI fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity precursor of 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-268068 0.8 REN protein P00797 UNIPROT Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT up-regulates quantity cleavage 9606 32201502 t miannu Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10). SIGNOR-260225 0.2 HSPA9 protein P38646 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 t lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. SIGNOR-267693 0.678 FGFR1 protein P11362 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates 9606 12270934 f lperfetto  Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors SIGNOR-218010 0.315 FOXO1 protein Q12778 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates 9606 16308421 f gcesareni Foxo1 antagonized ppargamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner. SIGNOR-142150 0.567 NARS1 protein O43776 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270457 0.8 PRKCD protein Q05655 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser246 QYQEERRsVKHILFS -1 16479000 t miannu HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. SIGNOR-276048 0.2 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr115 QPQPDSVyLVPTPSK 10090 12972425 t lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs SIGNOR-246381 0.796 p38 proteinfamily SIGNOR-PF16 SIGNOR KRT8 protein P05787 UNIPROT up-regulates phosphorylation 9606 11788583 t inferred from 70% family members lperfetto Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. SIGNOR-270125 0.2 GUCY1A2-B2 complex SIGNOR-C137 SIGNOR IDH2 protein P48735 UNIPROT down-regulates quantity by destabilization ubiquitination phosphorylation:Thr197 GTFKMVFtPKDGSGV 34929314 t lperfetto During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome SIGNOR-267624 0.2 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR PRC1 protein O43663 UNIPROT unknown phosphorylation Thr470 LYGSAPRtPSKRRGL 9885575 t llicata We have shown that PRC1 is a good in vitro substrate for several CDKs, and that it is also phosphorylated in a cell cycle–dependent manner in vivo at Thr-481 (major mitosis. and Thr-470 (minor site), which are the in vitro phosphorylation sites. SIGNOR-250745 0.351 TSPO2 protein Q5TGU0 UNIPROT VDAC1 protein P21796 UNIPROT up-regulates activity binding 9606 BTO:0000424 30061676 t miannu Our results demonstrate the existence of a VDAC-TSPO2-ANT complex that mediates ATP release from RBCs. We previously demonstrated that the translocase protein TSPO2 together with the voltage-dependent anion channel (VDAC) and adenine nucleotide transporter (ANT) were involved in a membrane transport complex in human red blood cells (RBCs). . The present results show that TSPO ligands induce polymerization of VDAC, coupled to activation of ATP release by a supramolecular complex involving VDAC, TSPO2 and ANT. SIGNOR-261826 0.314 FYN protein P06241 UNIPROT KIRREL1 protein Q96J84 UNIPROT up-regulates activity phosphorylation Tyr606 KDPTNGYyNVRAHED 9606 BTO:0000007 18258597 t miannu Here we have characterized Neph1, another SD component, as a novel substrate of SFK. Fyn interacts with and phosphorylates the cytoplasmic domain of Neph1 in vitro and in intact cells. Both tyrosine 637 and 638 of Neph1 are crucial for Neph1-Grb2 binding. SIGNOR-262746 0.2 RORA protein P35398 UNIPROT SLC1A6 protein P48664 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001011 19381306 t miannu RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice. SIGNOR-266850 0.253 GSK3B protein P49841 UNIPROT OGT protein O15294 UNIPROT up-regulates activity phosphorylation Ser3 sSVGNVAD 10090 BTO:0000142 23395175 t miannu We employed a circadian proteomic approach to demonstrate that circadian timing of phosphorylation is a critical factor in regulating complex GSK3β-dependent pathways and identified O-GlcNAc transferase (OGT) as a substrate of GSK3β. Interestingly, OGT activity is regulated by GSK3β; hence, OGT and GSK3β exhibit reciprocal regulation. SIGNOR-276482 0.501 MAP1LC3A protein Q9H492 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001623 20921139 f lperfetto We assessed both conversion of LC3-I to its cleaved and lipidated form LC3-II and its translocation to autophagic structures, two steps in autophagosome formation SIGNOR-219406 0.7 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser233 VSSQHRYsTPHAFTF 9606 12551925 t gcesareni For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1. SIGNOR-37466 0.539 PRKCE protein Q02156 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Ser779 PLDQYSPsFPDTRSS 9606 BTO:0000938 23564461 t lperfetto Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiationour findings show that in addition to fgfr tyrosine phosphorylation, the phosphorylation of a conserved serine residue, ser(779), can quantitatively control ras/mapk signaling to promote specific cellular responses. SIGNOR-201671 0.2 FOXA1 protein P55317 UNIPROT NFIB protein O00712 UNIPROT up-regulates binding 9606 24801505 t miannu Androgen receptor (ar) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between ar and forkhead box (fox) transcription factors, particularly foxa1./ Foxa1 is capable of bringing ar and nfix into proximity, indicating that foxa1 facilitates the ar and nfi interaction by bridging the complex. SIGNOR-205027 0.319 PXDN protein Q92626 UNIPROT COL4A4 protein P53420 UNIPROT up-regulates quantity by stabilization catalytic activity 9606 BTO:0000567 29305973 t miannu Peroxidasin (PXDN), an ECM protein with peroxidase activity, is integral to basement membrane consolidation through catalysis of sulfilimine bonds in collagen IV. PXDN has been shown to form dityrosine crosslinks and also catalyses sulfilimine bonds, in the presence of hypohalous acids, to connect collagen IV protomers, which are an integral component of the basement membrane SIGNOR-265250 0.258 STAT3 protein P40763 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0000452 26738736 f miannu Collectively, the activation of IL-6/STAT3 pathway contributed to the PSCs-induced EMT i SIGNOR-277690 0.7 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189984 0.8 SATB1 protein Q01826 UNIPROT MYB protein P10242 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17343824 f miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. SIGNOR-255135 0.2 SLBP protein Q14493 UNIPROT H4C1 protein P62805 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265376 0.2 PAK1 protein Q13153 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Ser111 KESLRSRsTRMSTVS 9606 23055517 t lperfetto Here we found that mcak is a cognate substrate of pak1 wherein pak1 phosphorylates mcak on serines 192 and 111 both in vivo and in vitro. Furthermore, we found that pak1 phosphorylation of mcak on serines 192 and 111 preferentially regulates its microtubule depolymerization activity and localization to centrosomes SIGNOR-199080 0.394 HDAC2 protein Q92769 UNIPROT MECP2/SIN3A/HDAC complex complex SIGNOR-C360 SIGNOR form complex binding 9606 BTO:0000567 9620804 t Luana We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases. SIGNOR-267736 0.711 NDUFV2 protein P19404 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. SIGNOR-262184 0.854 ETV3 protein P41162 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 22028473 t miannu ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation. SIGNOR-262780 0.2 TAOK2 protein Q9UL54 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 10660600 t gcesareni Immunoprecipitated psk phosphorylates myelin basic protein and transfected psk stimulates mkk4 and mkk7 and activates the c-jun n-terminal kinase mitogen-activated protein kinase pathway. SIGNOR-74867 0.2 GSK3B protein P49841 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser58 SFFKEPDsGSHSRQS 9606 BTO:0002181 22692215 t miannu GSK3 destabilizes TAZ. TAZS58A/S62A but not the TAZ S66A mutant diminished phos- phorylation by GSK3 , suggesting that Ser-58 and Ser-62 are important for GSK3  phosphorylation, whereas the Ser-66 is not (Fig. 4D). SIGNOR-277646 0.2 Deltorphin B chemical CHEBI:81498 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258785 0.8 PRKACA protein P17612 UNIPROT MIP protein P30301 UNIPROT down-regulates activity phosphorylation Ser229 LLFPRLKsISERLSV -1 2176601 t miannu Phosphorylation at one of these sites (serine 243) could be increased by A kinase in vitro. phosphorylation of MIP reconstituted into single bilayers increased the voltage dependence and long-term closures of the channels observed. SIGNOR-250018 0.317 N'-(1,8-dimethyl-4-imidazo[1,2-a]quinoxalinyl)ethane-1,2-diamine chemical CHEBI:91340 ChEBI IKBKB protein O14920 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258190 0.8 WNT7B protein P56706 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131978 0.633 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates activity transcriptional regulation 9606 12244043 f areggio Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes SIGNOR-254987 0.624 CSNK2A1 protein P68400 UNIPROT PTGES3 protein Q15185 UNIPROT up-regulates phosphorylation Ser118 DDSDEDMsNFDRFSE 9606 15040786 t gcesareni Cpges-activating protein kinase is ck-ii (casein kinase ii). Mutations of either of two predicted ck-ii phosphorylation sites on cpges (ser113 and ser118) abrogated its phosphorylation and activation both in vitro and in vivo. Hypoxia induced the mitogen-activated protein kinase-mediated phosphorylation of a single serine residue, ser(122), in the protein, and site-directed mutagenesis demonstrated that ser(122) phosphorylation was necessary for hypoxic acceleration of tal1 turnover. SIGNOR-123598 0.36 RRAGD protein Q9NQL2 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates binding 9606 SIGNOR-C3 20006481 t gcesareni Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor SIGNOR-162093 0.902 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT unknown phosphorylation Thr495 LLSLFEDtLDPT 9606 12738781 t lperfetto These results suggest that Ser-426 is a major phosphorylation site by Plk1, and Thr-495 is a second major site.  SIGNOR-249208 0.709 HACD proteinfamily SIGNOR-PF86 SIGNOR very long-chain (R)-3-hydroxyacyl-CoA(4-) smallmolecule CHEBI:85440 ChEBI down-regulates quantity chemical modification 9606 18554507 t miannu Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle. SIGNOR-267917 0.8 SIRT1 protein Q96EB6 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress SIGNOR-217878 0.7 PPP2R2A protein P63151 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity binding 10090 18042541 t gcesareni Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural |Here we report the identification of the specific B regulatory subunit that targets the PP2A holoenzyme to Akt. We found endogenous association of PP2A AB55C holoenzymes with Akt by co-immunoprecipitation analyses in pro-lymphoid FL5.12 cells.subunit (A), catalytic subunit (C), and a variable regulatory subunit (B). SIGNOR-252637 0.474 AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-252817 0.719 DNM1 protein Q05193 UNIPROT MYO1E protein Q12965 UNIPROT up-regulates activity binding 10116 BTO:0000142 17257598 t miannu We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta. SIGNOR-265424 0.338 DYRK1A protein Q13627 UNIPROT GLI1 protein P08151 UNIPROT up-regulates phosphorylation 9606 12138125 t Dyrk1 acts synergistically with Shh to induce transcription of a Gli-promoter-driven luciferase reporter gene and of endogenous alkaline phosphatase. gcesareni Dyrk1 phosphorylates gli1 on more than one domain. SIGNOR-90809 0.528 PRKCA protein P17252 UNIPROT RPL10 protein P27635 UNIPROT unknown -1 9016777 t lperfetto QM is phosphorylated by PKC and the extent of phosphorylation by PKC is correlated with the extent of inhibition of binding of QM to c-Jun. SIGNOR-248957 0.312 SMARCA4 protein P51532 UNIPROT TERT protein O14746 UNIPROT up-regulates binding 9606 19571879 t miannu Tert activates wnt reporter plasmids in a brg1-dependent manner. SIGNOR-186607 0.767 SOSTDC1 protein Q6X4U4 UNIPROT WNT3A protein P56704 UNIPROT down-regulates activity 9606 BTO:0000815 21113658 f lperfetto In this context, SOSTDC1 leads to decreased cellular proliferation and inhibition of Wnt3a- and BMP-7-induced signaling SIGNOR-242714 0.301 aldosterone smallmolecule CHEBI:27584 ChEBI NR3C2 protein P08235 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258712 0.8 MARK1 protein Q9P0L2 UNIPROT MAP4 protein P27816 UNIPROT down-regulates activity phosphorylation Ser928 SRLATNTsAPDLKNV -1 8631898 t miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. SIGNOR-250170 0.448 PPME1 protein Q9Y570 UNIPROT PPP2CB protein P62714 UNIPROT down-regulates activity demethylation Leu309 RRTPDYFl -1 18394995 t lperfetto Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans. SIGNOR-265750 0.704 CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser76 SNLQRMGsSESTDSG 9606 20068082 t gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts); SIGNOR-163150 0.851 CRABP2 protein P29373 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000551 30696915 f Analysis of clinical samples revealed that high CRABP2 levels were correlated with lymph node metastases, poor overall survival, and increased recurrence. Knockdown of Crabp2 decreased migration, invasion, anoikis resistance, and in vivo metastasis. SIGNOR-259371 0.7 PTAFR protein P25105 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257061 0.2 MBOAT7 protein Q96N66 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification -1 18772128 t miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. SIGNOR-267247 0.8 GNAI1 protein P63096 UNIPROT HCK protein P08631 UNIPROT up-regulates activity binding -1 11007482 t Galphas and Galphai similarly modulate Hck, another member of Src-family tyrosine kinases. SIGNOR-256528 0.33 A11/b1 integrin complex SIGNOR-C168 SIGNOR Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 10090 BTO:0000165 11518510 f lperfetto In addition, alpha11beta1 mediated contraction of fibrillar collagen gels in a manner similar to alpha2beta1, and supported migration on collagen I in response to chemotactic stimuli. Our data support a role for alpha11beta1 as a receptor for interstitial collagens on mesenchymally derived cells and suggest a multifunctional role of alpha11beta1 in the recognition and organization of interstitial collagen matrices during development. SIGNOR-253349 0.7 TGFBR2 protein P37173 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates binding 9606 9435577 t lperfetto These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells. SIGNOR-227528 0.444 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr36 LPPGDYStTPGGTLF 9606 SIGNOR-C3 17510057 t lperfetto In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size. SIGNOR-154810 0.924 TP53 protein P04637 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11965534 f acerquone Further analyses suggested that the modification of chromatin within the survivin promoter could be a molecular explanation for silencing of survivin gene transcription by p53. SIGNOR-117328 0.543 PLCG2 protein P16885 UNIPROT 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI down-regulates quantity chemical modification 9606 23000145 t scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). SIGNOR-268452 0.8 MMP25 protein Q9NPA2 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272369 0.7 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269352 0.719 ADRA1D protein P25100 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256808 0.295 RPL35A protein P18077 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262465 0.849 IFNG protein P01579 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by repression transcriptional regulation 10116 9397972 f inferred from family member scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5‚Äô-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. SIGNOR-270238 0.2 F2RL1 protein P55085 UNIPROT MSC protein O60682 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21072196 f miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). SIGNOR-254861 0.2 ELK1 protein P19419 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 23426362 f lperfetto AR required ELK1 to up-regulate a major subset of its target genes that was strongly and primarily enriched for cell growth functions SIGNOR-233471 0.7 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-189133 0.391 JAK2 protein O60674 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr304 PNEPVSDyINANIIM 9534 BTO:0004055 8995399 t lperfetto Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2 SIGNOR-236266 0.786 PPP2CA protein P67775 UNIPROT RBL2 protein Q08999 UNIPROT up-regulates dephosphorylation 9606 15467457 t miannu Pocket protein family consists of the retinoblastoma tumor suppressor protein (prb) and the functionally and structurally related proteins p107 and p130./dephosphorylation of p130 and p107 in cell extracts is inhibited by concentrations of okadaic acid known to inhibit pp2a, but not pp1. Finally, the pp2a catalytic subunit pp2a/c) specifically interacts with both p130 and p107 / the cell cycle repressor activity of pocket proteins is inactivated by cdk mediated phosphorylation. SIGNOR-129752 0.563 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr1009 LDTSSVLyTAVQPNE 9606 18567737 t gcesareni Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr. SIGNOR-179064 0.679 AKT2 protein P31751 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0000150 12697749 t lperfetto Akt2 interacts with and phosphorylates ask1 at ser-83 resulting in inhibition of its kinase activity SIGNOR-100588 0.635 PLXNB3 protein Q9ULL4 UNIPROT ARHGDIA protein P52565 UNIPROT up-regulates activity binding 10116 BTO:0000526 20696765 t miannu Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays. SIGNOR-268435 0.253 PIK3R3 protein Q92569 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 9415396 t gcesareni The region between the src homology 2 (sh2) domains of p55pik bound to the nh2 terminus region of p110alpha SIGNOR-53597 0.841 Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR Respiratory electron transport chain phenotype SIGNOR-PH141 SIGNOR up-regulates 30030361 f lperfetto The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA). SIGNOR-262140 0.7 SHC1 protein P29353 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity 10090 BTO:0000944 17673906 f lperfetto We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. SIGNOR-242622 0.701 CSNK2A2 protein P19784 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser513 GEDEESEsD -1 9045708 t llicata Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells.  SIGNOR-251037 0.312 LYN protein P07948 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr359 AKPDSSFyKGLDLNG -1 10942405 t Lyn phosphorylates Y904 and Y359 of band 3. The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton movements, and anion transport. SIGNOR-251412 0.344 GDNF protein P39905 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252176 0.2 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273054 0.556 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273059 0.635 MACC1 protein Q6ZN28 UNIPROT MET protein P08581 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000038 19098908 t Luana Human colon carcinoma SW480 cells express virtually no MACC1. MACC1 cDNA transfection led not only to strong increases in MACC1 mRNA expression (Fig. 3a), but also to a 40-fold upregulation of the HGF receptor MET mRNA expression (Fig. 3b). This was confirmed on the protein level SIGNOR-266058 0.403 ERG protein P11308 UNIPROT VWF protein P04275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 9444957 f miannu Cotransfection of Ets-1 and Erg expression plasmids is sufficient to induce the -60/+19 vWF promoter activity in HeLa cells. SIGNOR-253914 0.25 DCX DET1-COP1 complex SIGNOR-C24 SIGNOR CRTC2 protein Q53ET0 UNIPROT down-regulates quantity by destabilization ubiquitination Lys212 LDGEMDPkVPAIEEN 9606 BTO:0000007 17805301 t miannu  In the presence of relevant cofactors (DDB1, DET1), COP1 promoted the ubiquitination of wild-type but not COP1-interaction defective VP/AA TORC2 (Fig. 3e). COP1 also stimulated the ubiquitination of TORC2(K213R) but had no effect on TORC2(K628R), suggesting an important role for Lys 628 in this regard (Fig. 3e). We performed mass spectrometry studies to characterize residues in TORC2 that undergo COP1-mediated ubiquitination. This analysis revealed one major (Lys 628) and one minor (Lys 213) site on TORC2 SIGNOR-271666 0.2 PTPN1 protein P18031 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 15821101 t gcesareni Mechanism of protein tyrosine phosphatase 1b-mediated inhibition of leptin signalling. Ptp1b plays a critical role in the down-regulation of activated-stat3 by dephosphorylating tyr705, that is the phosphorylation site of activation of stat3. SIGNOR-135211 0.568 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Thr1047 SSSSELStPEKPPHQ 9606 BTO:0000680;BTO:0001573;BTO:0001286 14551205 t lperfetto Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex SIGNOR-216949 0.426 MXI1 protein P50539 UNIPROT CCNB1 protein P14635 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002036 11875718 t Luana Mxi1 inhibits the proliferation of U87 glioma cells through down-regulation of cyclin B1 gene expression | Mxi1 inhibits the promoter activity of the cyclin B1 gene. SIGNOR-266064 0.269 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Asp638 KLVFFAEdVGSNKGA -1 8943232 t lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261764 0.502 ZNRF3 protein Q9ULT6 UNIPROT FZD4 protein Q9ULV1 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22575959 t Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. SIGNOR-260115 0.547 MIB1 protein Q86YT6 UNIPROT PCM1 protein Q15154 UNIPROT down-regulates ubiquitination 9606 BTO:0001938 24121310 t miannu  We demonstrate that the E3 ubiquitin ligase MIB1 is a new component of centriolar satellites, which interacts with and ubiquitylates AZI1 and PCM1 and suppresses primary cilium formation.  SIGNOR-272878 0.379 CDK5 protein Q00535 UNIPROT TPPP protein O94811 UNIPROT down-regulates activity phosphorylation Thr14 PAKAANRtPPKSPGD -1 17693641 t miannu Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP. SIGNOR-262933 0.413 STRN4 protein Q9NRL3 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 10090 BTO:0000938 29802198 t miannu The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms SIGNOR-261697 0.587 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A4/b1 integrin complex SIGNOR-C162 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259016 0.359 CDH2 protein P19022 UNIPROT CDON protein Q4KMG0 UNIPROT up-regulates binding 9606 SIGNOR-C21 20160094 t gcesareni We report here that n-cadherin ligation activates p38alpha/beta in myoblasts in a cdo-, bnip-2-, and jlp-dependent manner SIGNOR-163844 0.633 TELO2 protein Q9Y4R8 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000007 20427287 t miannu MTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. Furthermore, using immunoprecipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. SIGNOR-272003 0.568 TP53 protein P04637 UNIPROT VCAN protein P13611 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12438652 t miannu By using in vitro and in vivo assays, we showed CSPG2 to be directly transactivated by p53. SIGNOR-255441 0.294 PTPN1 protein P18031 UNIPROT KRT8 protein P05787 UNIPROT down-regulates activity dephosphorylation Tyr267 IAEVKAQyEDIANRS 9606 BTO:0000182 24003221 t lperfetto Keratin 8 phospho-Tyr-267 is dephosphorylated by PTP1B and promotes insolubility and filament organization, as does the paralogous GFAP tyrosine. SIGNOR-265495 0.2 PAMPs stimulus SIGNOR-ST11 SIGNOR MEFV protein O15553 UNIPROT up-regulates activity 16037825 f lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-256426 0.7 MAP2K6 protein P52564 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 8974401 t gcesareni A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subgroups of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) SIGNOR-45363 0.441 AP1 complex SIGNOR-C154 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates activity 9606 31340499 f Luana AP-1 Transcription Factors as Regulators of Immune Responses in Cancer SIGNOR-260766 0.7 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates phosphorylation Ser176 TNAENTAsQSPRTRG 9606 19789335 t gcesareni Our data demonstrated that ask1 controls the cytoplasmic localization of daxx (fig.1). our results indicate that daxx not only activates ask1 but also is a downstream target of ask1 and that accumulated daxx further activates ask1. Thus, the daxx-ask1 positive feedback loop amplifying jnk/p38 signaling plays an important role in the cell-killing effects of stressors, such as tnfalpha. SIGNOR-188321 0.835 NAA10 protein P41227 UNIPROT NatA complex SIGNOR-C415 SIGNOR form complex binding 9606 BTO:0000007 15496142 t miannu Protein acetyltransferases and deacetylases have been implicated in oncogenesis, apoptosis and cell cycle regulation. Most of the protein acetyltransferases described acetylate epsilon-amino groups of lysine residues within proteins. We now describe the human homologue of Nat1p, NATH (NAT human), as the partner of the hARD1 (human ARD1) protein. Included in the characterization of the NATH and hARD1 proteins is the following: (i) endogenous NATH and hARD1 proteins are expressed in human epithelial, glioma and promyelocytic cell lines; (ii) NATH and hARD1 form a stable complex, as investigated by reciprocal immunoprecipitations followed by MS analysis; (iii) NATH-hARD1 complex expresses N-terminal acetylation activity; (iv) NATH and hARD1 interact with ribosomal subunits, indicating a co-translational acetyltransferase function SIGNOR-267224 0.95 CXCL10 protein P02778 UNIPROT CXCR3 protein P49682 UNIPROT up-regulates activity binding 9606 BTO:0000782 12750173 t miannu The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells. SIGNOR-260969 0.779 GGNBP2 protein Q9H3C7 UNIPROT ESR1 protein P03372 UNIPROT down-regulates activity binding 9606 BTO:0001248 27357812 t miannu We further demonstrate that GGNBP2 protein physically interacts with ERα, inhibits E2-induced activation of estrogen response element-driven reporter activity, and attenuates ER target gene expression in T47D cells. SIGNOR-269076 0.2 MAPK3 protein P27361 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 t gcesareni Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both_ in vitro_ and_ in vivo. SIGNOR-74939 0.541 PRKDC protein P78527 UNIPROT H1-2 protein P16403 UNIPROT down-regulates activity phosphorylation Thr146 KKAAGGAtPKKSAKK 9606 BTO:0001938 22249259 t done miannu Similarly, DNA-PK-mediated phosphorylation of H1.2 at T146 enhances p53 transcriptional activity by impeding H1.2 binding to p53 and thereby attenuating its suppressive effects on p53 transactivation.  SIGNOR-273834 0.2 PGM2 protein Q96G03 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-268116 0.8 BMP10 protein O95393 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000562 16049014 t acerquone We showed that three orphan ligands known to be important for joint and cartilage formation (gdf6) (10), interneuron, sensory neurons, and seminal vesicle formation (gdf7) (11_13), and heart development (bmp10) (14) used the type i receptors alk3 or alk6 and the type ii receptors bmprii or actriia to activate the smad1/5/8 proteins. SIGNOR-139052 0.617 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Thr507 FGESRAStFCGTPDY 9606 19366211 t llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. studies reported herein show that a t505a substitution reduces pkcdelta-thr(295) autophosphorylation SIGNOR-185287 0.2 PRKCQ protein Q04759 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 26431586 f lperfetto It is known that the teta isoform of the PKC family promotes the fusion of myoblasts and regulates the expression of caveolin-3 and beta1D integrin [15]. Of note, it has also been demonstrated that PKCepsilon expression increases during insulin-induced myogenic differentiation of the C2C12 cells. SIGNOR-241525 0.2 ACE2 protein Q9BYF1 UNIPROT Angiotensin 1-7 protein P01019-PRO_0000420660 UNIPROT up-regulates quantity cleavage 9606 32201502 t miannu At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function. SIGNOR-260227 0.2 NEU1 protein Q99519 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0003554 32164705 f Giorgia Taken together, these findings indicate that NEU1 overexpression reduces cell proliferation and enhances cell apoptosis through by downregulation of FN-integrin β1-mediated Akt signaling pathway. SIGNOR-260659 0.2 PPM1A protein P35813 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser199 PRPEHTKsVYTRSVI 10116 18586681 t Purified PP2Cα protein efficiently dephosphorylated PAK1 in vitro (Fig. 1, D and E). We previously assessed the time course of phospho-PAK1 dephosphorylation assessed using specific antibodies against either Ser(P)198/203 or Thr(P)422 sites in the PAK1 activation loop. SIGNOR-248492 0.343 DMTF1 protein Q9Y222 UNIPROT MBD1 protein Q9UIS9 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 f Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  SIGNOR-261586 0.2 CUL2 protein Q13617 UNIPROT ARIH1 protein Q9Y4X5 UNIPROT up-regulates activity binding 9606 BTO:0000007 24076655 t miannu Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin. SIGNOR-268845 0.315 ELF4 protein Q99607 UNIPROT ELF4/RUNX1 complex SIGNOR-C47 SIGNOR form complex binding 9606 BTO:0001271 10207087 t miannu We readily detected an in vivo physical interaction between mef and aml1 proteins in kasumi-1 cells/ coexpression of mef and aml1b synergistically activates promoter function SIGNOR-66960 0.357 WARS1 protein P23381 UNIPROT Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) SIGNOR-270514 0.8 ERBB3 protein P21860 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 16729043 t gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. SIGNOR-146867 0.395 L-thyroxine smallmolecule CHEBI:18332 ChEBI THRB protein P10828 UNIPROT up-regulates activity chemical activation 10116 BTO:0000759 2158622 t miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. SIGNOR-258383 0.8 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 15659650 t lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. On activation, both of these kinases also phosphorylate multiple sites in the p53 N-terminal domain. These include Ser15, Thr18, Ser20, and Ser37, which are all DNA-damageinducible sites SIGNOR-153475 0.783 RDH10 protein Q8IZV5 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI down-regulates quantity chemical modification 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS10 SIGNOR-265119 0.8 CSNK2A1 protein P68400 UNIPROT IGF2R protein P11717 UNIPROT unknown phosphorylation Ser2409 LHGDDQDsEDEVLTI 9606 8318012 t lperfetto The two sites phosphorylated by ck ii in vivo and in vitro are ser82 and ser157. SIGNOR-37831 0.485 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser705 TPSAMKSsPQIPHQT 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. SIGNOR-216805 0.373 RFX5 protein P48382 UNIPROT RFX complex complex SIGNOR-C104 SIGNOR form complex binding -1 10825209 t miannu RFXANK and RFXAP bind to each other and form a heterodimer (step 1) that subsequently interacts with RFX5 Upon binding, the conformation of RFX5 changes (step 2) in a way that enables the RFX complex to bind to DNA (step 3) and to recruit other proteins that are required for the transcription of MHC II genes SIGNOR-221565 0.893 SP3 protein Q02447 UNIPROT MAOB protein P27338 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11259630 f miannu Cotransfection experiments show that Sp1 and its closely related family member Sp4 can trans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2. SIGNOR-253870 0.2 NUP42 protein O15504 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262097 0.2 SOCS3 protein O14543 UNIPROT STAT3 protein P40763 UNIPROT down-regulates 9606 BTO:0000801 21628332 f lperfetto SOCS3 attenuates IL-6-induced STAT3 anti-inflammatory effects, as well as IL-4-induced insulin receptor substrate-2/PI3K-mediated gene expression. SIGNOR-249567 0.697 PIM3 protein Q86V86 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation -1 31730483 t miannu In addition to PIM1, also PIM2 and PIM3 were able to phosphorylate WT, but not MM NFATC1 in vitro (Fig. ​(Fig.22c). SIGNOR-276773 0.248 DEAF1 protein O75398 UNIPROT HTR1A protein P08908 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000142 29636529 t Gianni The human 5-HT1A gene (HTR1A) rs6295 risk allele prevents Deaf1 binding to HTR1A, resulting in increased 5-HT1A autoreceptor transcription SIGNOR-269064 0.448 ZRSR2 protein Q15696 UNIPROT ZRSR2/U2AF2 complex SIGNOR-C81 SIGNOR form complex binding 9606 9237760 t miannu Recognition of a functional 3' splice site in pre-mrna splicing requires a heterodimer of the proteins u2af65/u2af35. SIGNOR-50176 0.771 NCOA1 protein Q15788 UNIPROT STAT5B protein P51692 UNIPROT up-regulates binding 9606 BTO:0000149 12954634 t miannu Ncoa-1/src-1 is an essential coactivator of stat5 that binds to the fdl motif in the alpha-helical region of the stat5 transactivation domain. SIGNOR-100261 0.329 RNA_splicing phenotype SIGNOR-PH201 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates 9606 32140746 f lperfetto The splicing of introns from nuclear precursors of message RNA (pre-mRNA) is executed by the spliceosome, a ribonucleoprotein (RNP) apparatus that first surfaced in the literature in 1985  SIGNOR-268402 0.7 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser78 NKDQHSIsYTLSRAQ 9606 BTO:0000007 12496252 t lperfetto In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation SIGNOR-96743 0.758 ASCL1 protein P50553 UNIPROT DKK1 protein O94907 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000527 23707066 t gcesareni We demonstrate that a critical factor in the set, ASCL1, activates Wnt signaling by repressing the negative regulator DKK1. SIGNOR-245885 0.311 Apelin smallmolecule CID:56841713 PUBCHEM APLNR protein P35414 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257460 0.8 JUN protein P05412 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 f miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254876 0.35 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10230396 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-67396 0.41 CEBPA protein P49715 UNIPROT ELANE protein P08246 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004408 19620402 f miannu The ELA2 gene promoter is positively regulated by the direct binding of LEF-1 or C/EBPalpha, documenting the role of LEF1 in the diminished ELA2 expression. SIGNOR-253769 0.313 AKT proteinfamily SIGNOR-PF24 SIGNOR STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr387 TMKRRDEtMQPAKPS 9606 23431053 t gcesareni Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt. SIGNOR-201121 0.2 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 18593525 t gcesareni The increases in the membrane levels of nacholeate itself and of dag induce a translocation and overexpression of protein kinase c (pkc) and subsequent reductions of cyclin d, cyclin-dependent kinases 4 and 6 (cdks 4 and 6), hypophosphorylation of the retinoblastoma protein, inhibition of e2f1 and knockdown of dihydrofolate reductase (dhfr) impairing dna synthesis. SIGNOR-179279 0.8 methylnaltrexone chemical CHEBI:136007 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 19282177 t Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. SIGNOR-258147 0.8 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation 6239 SIGNOR-C15 17900900 t lperfetto The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt. SIGNOR-219247 0.509 DDC protein P20711 UNIPROT tyrosine smallmolecule CHEBI:18186 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬¨‚Ć SIGNOR-263993 0.8 SMURF1 protein Q9HCE7 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR down-regulates ubiquitination 9606 22298955 t Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps SIGNOR-269847 0.76 MYC protein P01106 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12835716 t gcesareni C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a SIGNOR-102740 0.771 alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Glucose 6-phosphate isomerase (GPI) catalyzes the interconversion of G6P into fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway (Figure 1). As a result of this reversible reaction, products of the hexose-monophosphate shunt can be recycled to G6P. SIGNOR-266460 0.8 HBB protein P68871 UNIPROT CYP2E1 protein P05181 UNIPROT up-regulates activity 9606 BTO:0000575 19325051 f Regulation miannu Hemoglobin dramatically stimulated CYP 2E1 activity but not the protein expression in quercetin- and ethanol-cotreated hepatocytes. SIGNOR-251764 0.2 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser222 EEQDRPRsPTGPSNS 9534 BTO:0001538 23519612 t miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. SIGNOR-262707 0.323 MC5R protein P33032 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257070 0.252 FOXO1 protein Q12778 UNIPROT GK protein P32189 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18805788 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription foxo1 localizes to the nucleus, where it represses hnf-4-dependent activity of the gk promoter as a corepressor. SIGNOR-181268 0.253 ARNTL protein O00327 UNIPROT CRY1 protein Q16526 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253626 0.932 ETS1 protein P14921 UNIPROT GP6 protein Q9HCN6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12377757 f miannu We have determined that the GP6 sequence -191 to -39 represents the core promoter and that transcription is driven largely by GATA-1 (-176) and c-Ets-1 (-45) sites within this segment. SIGNOR-254082 0.2 GTF2I protein P78347 UNIPROT GSC protein P56915 UNIPROT up-regulates quantity by expression transcriptional regulation 16611241 f lperfetto For example, TFII-I binds to the Inr element of the T cell receptor Vbeta gene and activates its transcription in reporter gene assays (Cheriyath et al. 1998). TFII-I also activates transcription of c-fos and Goosecoid through binding to the serum response element and the distal element, respectively (Grueneberg et al. 1997; Ku et al. 2005). SIGNOR-268536 0.2 IL21 protein Q9HBE4 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 t gcesareni The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex SIGNOR-108858 0.594 STARD13 protein Q9Y3M8 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260521 0.63 P2RY11 protein Q96G91 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257173 0.2 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120076 0.781 CDK5 protein Q00535 UNIPROT PMAIP1 protein Q13794 UNIPROT down-regulates phosphorylation Ser13 ARKNAQPsPARAPAE 9606 BTO:0001271 21145489 t llicata We show that noxa is phosphorylated on a serine residue (s(13)) in the presence of glucose. Phosphorylation promotes its cytosolic sequestration and suppresses its apoptotic function. We identify cdk5 as the noxa kinase SIGNOR-170357 0.364 PLK1 protein P53350 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Thr206 MTSELEStSLGDSDE 9606 20823832 t lperfetto Dvl2 bound to and was phosphorylated at thr206 by a mitotic kinase, polo-like kinase 1 (plk1), and this phosphorylation was required for spindle orientation and stable microtubule (mt)-kt attachment SIGNOR-167858 0.477 MARCHF9 protein Q86YJ5 UNIPROT VAMP8 protein Q9BV40 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271531 0.2 HNF1A protein P20823 UNIPROT AFP protein P02771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 9792724 f miannu AFP promoter-chloramphenicol acetyltransferase transient transfection assays demonstrated that the level of HNF1 had a direct impact on basal transcription as well as RA-mediated down-regulation of the AFP gene, and that co-transfection of HNF1 and HNF4, but not transfection of either factor alone, reversed the RA-mediated inhibition. Taken together these data point to an interaction among the RA, HNF1, and HNF4 signals, which is reflected in decreased expression of AFP. SIGNOR-254447 0.335 CYSLTR1 protein Q9Y271 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257135 0.358 TNF protein P01375 UNIPROT LPL protein P06858 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 3063839 f Regulation of expression miannu Cytokines, notably TNF and IL-1, suppress synthesis of lipoprotein lipase which decreases the rate of TGFA clearance. SIGNOR-251853 0.4 MRPL9 protein Q9BYD2 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262343 0.734 MAPK1 protein P28482 UNIPROT TFEB protein P19484 UNIPROT down-regulates activity phosphorylation Ser142 AGNSAPNsPMAMLHI 9606 BTO:0000567 21617040 t gcesareni Evidence for ERK2-mediated TFEB phosphorylation came from ERK2-TFEB coimmuno-precipitation (fig. S12C) in normal but not in starved medium and from a peptide-based kinase assay showing that mutation of Ser142 to alanine abolished ERK2-mediated phosphorylation ( SIGNOR-248279 0.423 PLK2 protein Q9NYY3 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 19889641 t lperfetto Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. Pathological serine 129 phosphorylation regulates membrane accumulation of mutant alpha-synuclein. SIGNOR-182155 0.491 RPS17 protein P08708 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262434 0.899 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Ser207 TSVRRRTsFYLPKDA 9606 18071316 t llicata This skp2-dependent destruction of rassf1a requires phosphorylation of the latter on serine-203 by cyclin d-cyclin-dependent kinase 4. SIGNOR-216976 0.489 CBP/p300 complex SIGNOR-C6 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity acetylation 9606 21131905 t lperfetto These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription. SIGNOR-265322 0.2 CSNK2A1 protein P68400 UNIPROT MAX protein P61244 UNIPROT down-regulates phosphorylation Ser11 NDDIEVEsDEEQPRF 9606 8018564 t gcesareni Max activity is affected by phosphorylation at two nh2-terminal sites, ser2 and ser11. SIGNOR-35768 0.368 LIF protein P15018 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 24710148 t milica The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-204847 0.75 SOX9 protein P48436 UNIPROT COL9A2 protein Q14055 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10980415 f miannu Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan. SIGNOR-251757 0.362 DUSP10 protein Q9Y6W6 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 10391943 t gcesareni Mkp-5 directly dephosphorylates sapk/jnk and p38 in vitromkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk SIGNOR-68986 0.705 ATM protein Q13315 UNIPROT STK11 protein Q15831 UNIPROT unknown phosphorylation Thr363 IEDDIIYtQDFTVPG 9606 BTO:0000848 12234250 t llicata We demonstrate that both dna-pk and atm efficiently phosphorylate lkb1 at thr-366 in vitro and provide evidence that atm mediates this phosphorylation in vivo. however, phosphorylation of lkb1 at thr-366 may have some role in enabling lkb1 to suppress cell growth SIGNOR-92877 0.588 FBXW7 protein Q969H0 UNIPROT CCNE2 protein O96020 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002524 17298674 t miannu Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme SIGNOR-271642 0.447 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192604 0.8 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT up-regulates phosphorylation Ser20 LQYYYSSsEDEDSDH 9606 16717095 t lperfetto Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2. SIGNOR-146833 0.36 MAPK3 protein P27361 UNIPROT GRK2 protein P25098 UNIPROT down-regulates phosphorylation Ser670 KMKNKPRsPVVELSK 9606 BTO:0000007 10574913 t gcesareni Erk1 phosphorylates grk2 at ser(670). Inhibition of erk activity in hek293 cells potentiates grk2 activity, whereas, conversely, erk activation inhibits grk2 activity. SIGNOR-72582 0.2 EXT2 protein Q93063 UNIPROT EXT1/EXT2 complex SIGNOR-C51 SIGNOR form complex binding 9606 11518722 t miannu Biochemical analysis shows that ext1 and ext2 are type ii transmembrane glycoproteins and form a golgi-localized hetero-oligomeric complex that catalyzes the polymerization of hs SIGNOR-109941 0.564 GTP smallmolecule CHEBI:15996 ChEBI EEF1A:GTP:aa-tRNA complex SIGNOR-C493 SIGNOR form complex binding 9606 8722040 t miannu The mechanism of elongation factor Tu (EF-Tu) catalyzed aminoacyl-tRNA (aa-tRNA) binding to the A site of the ribosome was studied. Two types of complexes of EF-Tu with GTP and aa-tRNA, EF-Tu.GTP-aa-tRNA (ternary) and (EF-Tu.GTP)2.aa-tRNA (quinternary), can be formed in vitro depending on the conditions. SIGNOR-270812 0.8 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259706 0.8 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation 9606 31226023 t miannu Activated PERK phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α), which inhibits the conversion of inactive GDP-bound eIF2α back to the active GTP-bound form, thereby suppressing translation initiation. SIGNOR-260165 0.757 PHF2 protein O75151 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 BTO:0000007 21532585 t miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. SIGNOR-264518 0.2 CTBP2 protein P56545 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 21315774 t Luana Overexpression of the CtBP2 protein enhanced the repression activity of the E-cadherin promoter in a dose-dependent manner, whereas overexpression of ataxin-1 increased the activity of the E-cadherin promoter in a dose-dependent manner  SIGNOR-261578 0.39 ANAPC10 protein Q9UM13 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 t lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. SIGNOR-252009 0.917 TNFRSF21 protein O75509 UNIPROT Demyelination phenotype SIGNOR-PH155 SIGNOR down-regulates 9606 32454942 f miannu Next to inhibition of sTNF/TNFR1 signaling, specific activation of TNFR2 may hold promise as a new MS therapy. Indeed, TNF promotes proliferation of oligodendrocyte progenitors and remyelination via TNFR2 SIGNOR-263832 0.7 RAB5A protein P20339 UNIPROT PIK3R4 protein Q99570 UNIPROT up-regulates activity binding 10090 27411398 t lperfetto Vps34 PI 3-kinase activity18 is stimulated by complex formation with the protein kinase Vps15|Rab5GTP binds Vps15, enhancing Vps34 activity SIGNOR-260708 0.432 NKX3-1 protein Q99801 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization 9606 16697957 f miannu NKX3.1 stabilizes p53.NKX3.1 can physically associate with HDAC1 and promotes p53 acetylation by recruiting HDAC1 from p53-MDM2-HDAC1 complex SIGNOR-251548 0.363 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Thr329 RALTEDStQTSDTAT -1 7836371 t gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. SIGNOR-249664 0.2 PIK3R1 protein P27986 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242646 0.712 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity phosphorylation Thr235 SSSSPPGtPSPADAK 10090 BTO:0001169 22355693 t We found that expression of srebf1a depended on GSK3β activity and that GSK3β activity was necessary for C/EBPβ phosphorylation at Thr188 SIGNOR-251644 0.469 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR2A protein P28223 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257521 0.8 KAT2B protein Q92831 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269612 0.2 PPP6C protein O00743 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity dephosphorylation Ser824 LVDKEHDsAEGSHTS 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276516 0.334 CREBBP protein Q92793 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates activity acetylation Lys399 SGPCERRkSPLQDPF 9606 BTO:0000007 17923090 t lperfetto By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2. SIGNOR-217783 0.353 MAPK3 protein P27361 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 10090 BTO:0002572 28646232 t Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels SIGNOR-262523 0.298 CREB1 protein P16220 UNIPROT UXT protein Q9UBK9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 17761951 f lperfetto The DNA response elements that control the induction of ART-27 gene expression were also characterized. The major cis-acting element corresponds to a consensus cAMP-responsive element (CRE) and binds the CRE-binding protein (CREB) as shown by EMSA and chromatin immunoprecipitation assays. Furthermore, ART-27 promoter activity is induced upon CREB overexpression. Epidermal growth factor, which activates CREB via phosphorylation, also induces ART-27 expression, whereas a reduction in CREB phosphorylation or expression blocks this induction in prostate cells. SIGNOR-254092 0.2 FOXN1 protein O15353 UNIPROT DSG4 protein Q86SJ6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000552 19683850 f miannu we studied the transcriptional regulation of DSG4 by transcription factors/pathways that are known regulators of hair keratin or KAP expression. We show that HOXC13, LEF1 and FOXN1 repress DSG4 transcription and provide in vitro and in vivo evidence correlating the Notch pathway with the activation and/or maintenance of DSG4 expression in the hair follicle. SIGNOR-254182 0.389 MT-CYB protein P00156 UNIPROT Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 t lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits SIGNOR-262193 0.88 MLL2 complex complex SIGNOR-C88 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 24680668 t miannu Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. SIGNOR-268799 0.2 PAF1 protein Q8N7H5 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR form complex binding 9606 BTO:0000567 20178742 t miannu Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A).  SIGNOR-269833 0.879 SNIP1 protein Q8TAD8 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270671 0.444 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0001538 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219332 0.707 HASPIN protein Q8TF76 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Thr3 T-->R 9606 20705812 t miannu Here we show that phosphorylation of histone H3 threonine 3 (H3T3ph) by Haspin is necessary for CPC accumulation at centromeres and that the CPC subunit Survivin binds directly to H3T3ph. SIGNOR-275418 0.2 CTCFL protein Q8NI51 UNIPROT BAG1 protein Q99933 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0003293 18413740 t lperfetto DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation SIGNOR-254107 0.284 NANOG protein Q9H9S0 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16840789 t Luana We conclude that the Nanog enhancer activity is regulated by both Sall4 and Nanog.  SIGNOR-266080 0.2 GRIK4 protein Q16099 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity relocalization 9606 BTO:0002609 12393813 t lperfetto Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine SIGNOR-268275 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR PTPN1 protein P18031 UNIPROT down-regulates activity phosphorylation Ser50 RNRYRDVsPFDHSRI 10090 BTO:0000944 11579209 t lperfetto Phosphorylation of ptp1b at ser(50) by akt impairs its ability to dephosphorylate the insulin receptor. SIGNOR-235411 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD83 protein Q01151 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19164127 f miannu We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40. SIGNOR-254781 0.262 RAD23B protein P54727 UNIPROT ERCC1 protein P07992 UNIPROT up-regulates activity binding 24086043 t lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275703 0.636 NEK2 protein P51955 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates phosphorylation 9606 10880350 t lperfetto Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity. / threonine-307 and -318 appear to be equally well phosphorylated by nek2 SIGNOR-264655 0.502 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation 22848740 t When AMPK is stimulated, pre-existing FOXO3 becomes reverted toward an active form. SIGNOR-255755 0.509 TBX21 protein Q9UL17 UNIPROT IL2 protein P60568 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003432 10761931 t Luana T-bet Transactivates the IFNγ Gene and Represses the IL-2 Gene in EL4 Cells SIGNOR-266233 0.486 DDX3X protein O00571 UNIPROT EIF4E protein P06730 UNIPROT down-regulates activity binding 9606 BTO:0001950 17667941 t miannu DDX3 is a human RNA helicase with plethoric functions. we identified translation initiation factor eukaryotic initiation factor 4E (eIF4E) as a DDX3-binding partner. Interestingly, DDX3 utilizes a consensus eIF4E-binding sequence YIPPHLR to interact with the functionally important dorsal surface of eIF4E in a similar manner to other eIF4E-binding proteins. Furthermore, cap affinity chromatography analysis suggests that DDX3 traps eIF4E in a translationally inactive complex by blocking interaction with eIF4G. SIGNOR-269200 0.648 TWIST1 protein Q15672 UNIPROT FAP protein Q12884 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20646316 f miannu Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. SIGNOR-255523 0.244 BRD9 protein Q9H8M2 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269787 0.487 CFB protein P00751 UNIPROT C3 convertase complex (C3bBb) complex SIGNOR-C314 SIGNOR form complex binding 9606 BTO:0000089 cleavage:Arg259 GPGEQQKrKIVLDPS 26489954 t complement factor B, b fragment: PRO_0000027547 lperfetto Surface‐associated C3b recruits FB, which leads to FB activation and the formation of C3bBb, the AP C3 convertase, which cleaves more C3 and amplifies complement activation. In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over) SIGNOR-263486 0.903 PLK1 protein P53350 UNIPROT NEK9 protein Q8TD19 UNIPROT up-regulates activity phosphorylation Thr210 SEYSMAEtLVGTPYY 9606 BTO:0000567 21642957 t done miannu We now identify Plk1 as Nek9 direct activator and propose a two-step activation mechanism that involves Nek9 sequential phosphorylation by CDK1 and Plk1. while CDK1 activity is necessary for Nek9 phosphorylation in mitosis and the resulting change in electrophoretical mobility, Nek9 Thr210 phosphorylation and mitotic activation requires both CDK1 and Plk1. SIGNOR-273888 0.594 midostaurin chemical CHEBI:63452 ChEBI FGR protein P09769 UNIPROT down-regulates activity chemical inhibition -1 30069632 t Gianni Midostaurin (PKC412, Rydapt®) is an oral multiple tyrosine kinase inhibitor. Main targets are the kinase domain receptor, vascular endothelial-, platelet derived-, and fibroblast growth factor receptor, stem cell factor receptor c-KIT, as well as mutated and wild-type FLT3 kinase SIGNOR-261976 0.8 NCKAP1 protein Q9Y2A7 UNIPROT WRC complex complex SIGNOR-C191 SIGNOR form complex binding 9606 21107423 t miannu WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems SIGNOR-253569 0.912 KMT2A protein Q03164 UNIPROT MLL1 complex complex SIGNOR-C89 SIGNOR form complex binding 9606 24680668 t miannu The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation. SIGNOR-204813 0.2 KLF11 protein O14901 UNIPROT HBG2 protein P69892 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 10207080 f Regulation miannu Transfection of K562 cells with FKLF cDNA enhanced the expression of the endogenous epsilon- and gamma-globin genes, suggesting an in vivo role of FKLF in fetal and embryonic globin gene expression. SIGNOR-251827 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR ADRB2 protein P07550 UNIPROT down-regulates phosphorylation Ser345 ELLCLRRsSLKAYGN 9606 11809767 t lperfetto Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation. SIGNOR-114466 0.2 PRKACA protein P17612 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser294 PHGSPRVsVTDDSWL 9606 12351631 t lperfetto Here we show that overexpression of pka causes phosphorylation and cytoplasmic accumulation of nf-atc1 in direct opposition to calcineurin by phosphorylating ser-245, ser-269, and ser-294 in the conserved serine-proline repeat domainwe further show that a complete block of nf-atc1 nuclear localization by pka requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (gsk-3) SIGNOR-93539 0.358 corticosterone smallmolecule CHEBI:16827 ChEBI 18-hydroxycorticosterone smallmolecule CHEBI:16485 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268674 0.8 mTORC1 complex SIGNOR-C3 SIGNOR TFEB protein P19484 UNIPROT down-regulates activity phosphorylation Ser142 AGNSAPNsPMAMLHI 9606 BTO:0000007 22343943 t Here, we have used an mTORC1 in-vitro kinase assay and a phosphoantibody to demonstrate that serine S142, which we previously found to be phosphorylated by ERK2, is also phosphorylated by mTOR and that this phosphorylation has a crucial role in controlling TFEB subcellular localization and activity. SIGNOR-255309 0.37 oligopeptide smallmolecule CHEBI:25676 ChEBI peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity precursor of 9606 31810556 t scontino Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol. SIGNOR-267863 0.8 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR GSK3B protein P49841 UNIPROT up-regulates activity dephosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 20080667 t miannu DAB2IP interacts via its C2 domain with GSK3β, recruiting phosphatase PP2A for S9 de-phosphorylation and leading to GSK3β activation. SIGNOR-254754 0.422 tRNA(Val) smallmolecule CHEBI:29183 ChEBI Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates quantity precursor of 9606 30755602 t miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. SIGNOR-270531 0.8 CDK5 protein Q00535 UNIPROT CLOCK protein O15516 UNIPROT up-regulates phosphorylation Thr451 AVSDPSStPTKIPTD 9606 24235147 t lperfetto Cdk5 phosphorylates clock at the thr-451 and thr-461 residues in association with transcriptional activation of clock. SIGNOR-203227 0.334 ORC6 protein Q9Y5N6 UNIPROT ORC complex SIGNOR-C419 SIGNOR form complex binding 9606 32808929 t lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA SIGNOR-267562 0.943 USF1 protein P22415 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 9677331 f inferred from family member miannu Cotransfection of an expression plasmid encoding USF1 into HepG2 hepatoma cells resulted in the activation of the glucokinase promoter, dependent on the integrity of the P2 element SIGNOR-267797 0.293 TRIM17 protein Q9Y577 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0001976 22976837 t miannu Here, we identified Trim17 as a novel E3 ubiquitin-ligase for Mcl-1. Indeed, Trim17 co-immunoprecipitated with Mcl-1. Trim17 ubiquitinated Mcl-1 in vitro. Overexpression of Trim17 decreased the protein level of Mcl-1 in a phosphorylation- and proteasome-dependent manner. Finally, knock down of Trim17 expression reduced both ubiquitination and degradation of Mcl-1 in neurons. SIGNOR-272032 0.455 TP53 protein P04637 UNIPROT CCNG1 protein P51959 UNIPROT up-regulates quantity by expression transcriptional regulation 7957050 t lperfetto Using a DNA binding assay, a specific p53 binding site was identified upstream from the cyclin G gene, which functioned as a p53-dependent cis-acting element in a transient transfection assay. SIGNOR-268960 0.782 PRKAA1 protein Q13131 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 SIGNOR-C15 21892142 t gcesareni Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs) SIGNOR-176483 0.347 trichostatin A chemical CHEBI:46024 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257941 0.8 5-[(2,2-difluoro-1,3-benzodioxol-5-yl)methylidene]thiazolidine-2,4-dione chemical CHEBI:94690 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189912 0.8 MDM2 protein Q00987 UNIPROT NUMB protein P49757 UNIPROT down-regulates ubiquitination 9606 BTO:0001938 12646252 t gcesareni These data strongly suggest thatmdm2functions as the ubiquitin ligase toward hnumb and that it induces its degradation in intact cells. SIGNOR-99497 0.455 NOTCH4 protein Q99466 UNIPROT MAML3 protein Q96JK9 UNIPROT up-regulates binding 9606 12370315 t gcesareni Moreover, as determined by using coimmunoprecipitation assays, each maml protein was found to be capable of forming a multiprotein complex with the intracellular domain of each notch receptor (icn1 to -4) and csl in vivo SIGNOR-94109 0.862 CREBBP protein Q92793 UNIPROT LHX3 protein Q9UBR4 UNIPROT up-regulates activity binding 9606 10931853 t scontino Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). P-Lim and CBP Act Synergistically in TRH Stimulation of the Human α-GSU Promoter. SIGNOR-267206 0.2 IFNG protein P01579 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection SIGNOR-261033 0.7 ziprasidone chemical CHEBI:10119 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258505 0.8 TMPRSS2 protein O15393 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25122198 t miannu we identified pro-hepatocyte growth factor (HGF) as a TMPRSS2 substrate and confirmed that HGF and it’s cognate receptor c-Met are activated in prostate cancers expressing TMPRSS2, a finding that also associated with the acquisition of a pro-invasive mesenchymal gene expression program. SIGNOR-263657 0.2 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257924 0.8 PRKACA protein P17612 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 9660950 t lperfetto The transcriptional activity of nf-kappa b is stimulated upon phosphorylation of its p65 subunit on serine 276 by protein kinase a (pka). SIGNOR-217364 0.492 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Thr594 LHGKKNStVDCNGVV 9606 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275778 0.481 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Ser4 sQKHRDFV 9606 BTO:0000567 16371512 t gcesareni We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell SIGNOR-143368 0.516 CDCA2 protein Q69YH5 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates activity binding 9606 BTO:0000567 32938714 t done miannu This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin. SIGNOR-274003 0.379 Nutlin-3 smallmolecule CID:216345 PUBCHEM TP53 protein P04637 UNIPROT up-regulates 9606 17700533 t miannu Nutlin, a class of small molecule antagonist of HDM2, binds to the p53-binding pocket of HDM2, preventing p53 from binding to HDM2 and thus, resulting in stabilization and activation of p53 SIGNOR-255471 0.8 MAPK1 protein P28482 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity phosphorylation Ser616 EGDDRPEsPEYSGGN 10116 BTO:0000601 11080179 t miannu We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP. SIGNOR-262934 0.375 TNKS protein O95271 UNIPROT BLZF1 protein Q9H2G9 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 BTO:0000007 21478859 t lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. SIGNOR-263385 0.357 PRKAA1 protein Q13131 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 BTO:0000443 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000759 16054041 t lperfetto Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. SIGNOR-139158 0.823 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 23729744 t apalma The released NICD translocates directly to the nucleus, where it forms a transcriptional complex with the DNA-binding protein CSL (CBF1, Suppressor of Hairless, Lag1), Mastermind (Mam) and transcriptional co-activators to drive the expression of Notch target genes SIGNOR-255377 0.95 CSF3 protein P09919 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 10572088 t gcesareni Granulocyte-macrophage colony-stimulating factor (gm-csf) is an important hematopoietic cytokine that exerts its effects by interaction with the gm-csf receptor (gmr) on the surface of responsive cells. The gm-csf receptor consists of two subunits: gmralpha, which binds gm-csf with low affinity, and gmrbeta, which lacks intrinsic ligand-binding capability but complexes with gmralpha to form a high-affinity receptor (gmralpha/beta). SIGNOR-72511 0.455 EGR1 protein P18146 UNIPROT SLC9A3 protein P48764 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 16464174 f Transcriptional stimulation of the human NHE3 promoter activity by PMA: PKC independence and involvement of the transcription factor EGR-1|Co-transfection of Sp1 or Sp3 into SL2 cells activated the NHE3-reporter constructs, suggesting that Sp1 and Sp3 act as positive regulators of the NHE3 expression. In addition, overexpression of EGR-1 was sufficient to transactivate the NHE3-reporter gene activity SIGNOR-254269 0.248 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000599 10187842 t inferred from 70% family members lperfetto We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution. SIGNOR-270180 0.2 CCND1 protein P24385 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates 9606 BTO:0000150 BTO:0000149 20443831 f gcesareni The mechanism by which cyclin d1 enhances notch1 activity in different cell types remains to be determined;the current studies demonstrate for the first time that notch1 activity is induced by cyclin d1. The expression of cyclin d1 sirna reduced notch1 activity. SIGNOR-165189 0.623 SUFU protein Q9UMX1 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000848;BTO:0000527 10564661 t miannu Hsu(fu) associated with itself / homo- or heterodimers of hsu(fu) might function to bring together other effector proteins SIGNOR-72311 0.2 HPS3 protein Q969F9 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR form complex binding 9606 15030569 t lperfetto Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS6 SIGNOR-260688 0.704 NECAP1 protein Q8NC96 UNIPROT AP-2 complex complex SIGNOR-C245 SIGNOR up-regulates activity binding 9606 24130457 t lperfetto Knockdown and functional rescue studies demonstrate that through these interactions, NECAP 1 and AP-2 cooperate to increase the probability of clathrin-coated vesicle formation and to control the number, size, and cargo content of the vesicles. SIGNOR-260710 0.464 PAX7-FOXO1 fusion protein SIGNOR-FP11 SIGNOR FGFR4 protein P22455 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 f miannu Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA. SIGNOR-251565 0.2 methiothepin chemical CHEBI:64203 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258687 0.8 ACTN1 protein P12814 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 17243894 f miannu On most principal neurons in the mammalian brain (e.g., pyramidal neurons of cortex and hippocampus, Purkinje cells of cerebellum, medium spiny neurons of striatum), the postsynaptic specialization is housed on tiny actin rich protrusions called dendritic spines The size, shape, motility, and stability of dendritic spines depend largely on actin, the primary cytoskeleton within spines. SIGNOR-264618 0.7 ADORA2A protein P29274 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257364 0.304 PRKCA protein P17252 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser703 SLVPSPKsFVYFIMR 9606 16331690 t gcesareni There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712. SIGNOR-142945 0.354 LEPR protein P48357 UNIPROT POMC protein P01189 UNIPROT up-regulates quantity 27154742 f lperfetto Leptin binding inhibits the neuropeptide Y/agouti-related protein (NPY/AgRP) production and stimulates pro-opiomelanocortin (POMC) production SIGNOR-253074 0.477 HSPH1 protein Q92598 UNIPROT HSPA1A protein P0DMV8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19754877 f miannu Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress. SIGNOR-255242 0.479 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser36 AQQVSSLsESEESQD 9606 20730097 t lperfetto We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf1 SIGNOR-167560 0.2 MED13L protein Q71F56 UNIPROT CKM complex complex SIGNOR-C406 SIGNOR form complex binding 9606 23563140 t miannu The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation. SIGNOR-266702 0.762 CDK2 protein P24941 UNIPROT RECQL4 protein O94761 UNIPROT up-regulates activity phosphorylation Ser251 EVSIRVGsPQPSSSG 9606 BTO:0002181 29229926 t miannu  During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs. SIGNOR-277374 0.335 NCOA2 protein Q15596 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 18584035 t gcesareni Collectively, our data provide the first evidence that erbeta-deficiency protects against diet-induced ir and glucose intolerance which involves an augmented ppargamma signaling in adipose tissue. Moreover, our data suggest that the coactivators src1 and tif2 are involved in this interaction. SIGNOR-179175 0.76 STUB1 protein Q9UNE7 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 21454478 t gcesareni In addition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activities of smad1/5 by recruiting smad1/5 from the functional r/co-smad complex and further promoting the ubiquitination and degradation of smad1/5 in a chaperone-independent manner SIGNOR-172996 0.349 ADORA2B protein P29275 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257365 0.386 CD3G protein P09693 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates 9606 BTO:0000782 17668895 f gcesareni Tcr stimulation also activates the mitogen- and stress-activated kinases (msk) downstream of erk1/2. SIGNOR-157148 0.2 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr732 CSSAQAQyDTPKAGK -1 23770091 t done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. SIGNOR-273947 0.357 PRKAA1 protein Q13131 UNIPROT BTRC protein Q9Y297 UNIPROT down-regulates quantity by destabilization phosphorylation Ser82 SLRQTYNsCARLCLN 9606 BTO:0002419 31406304 t miannu Glucose deprivation activates AMPK kinase to phosphorylate β-TrCP1 and promotes the subsequent ubiquitination and degradation of β-TrCP1 by β-TrCP2, but does not promote β-TrCP2 degradation by β-TrCP1.  SIGNOR-277475 0.2 CREB1 protein P16220 UNIPROT POMC protein P01189 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 11081181 t lperfetto Transcriptional activation of the proopiomelanocortin gene by cyclic AMP-responsive element binding protein|Further, expression of a dominant inhibitory mutant of CREB reduced cAMP stimulated transcription of the full length POMC promoter and the PTRE. SIGNOR-268620 0.378 APH1A protein Q96BI3 UNIPROT NCSTN protein Q92542 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t gcesareni By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. SIGNOR-93259 0.967 TFIID complex SIGNOR-C343 SIGNOR GTF2B protein Q00403 UNIPROT up-regulates activity relocalization 9606 8990153 t lperfetto Early in PIC assembly, TFIIA can associate with and stabilize the TFIID–DNA or the TFIIB–TFIID–DNA complexes, allowing them to ward off the deleterious effects of inhibitory negative cofactors and enhance the stimulatory effects of transcriptional activators SIGNOR-269308 0.638 PTPN12 protein Q05209 UNIPROT ARHGDIA protein P52565 UNIPROT up-regulates activity dephosphorylation 9606 25666508 t miannu Integrin-bound PTP-PEST dephosphorylates RhoGDI1.|Translocation of Src phosphorylated RhoGDI1 to the cell 's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1 and Cdc42 in the cytoplasm.|Translocation of Src-phosphorylated RhoGDI1 to the cell's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin-bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1/Cdc42 in the cytoplasm. SIGNOR-277175 0.2 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr753 YACASPKtPIQAGGY 9606 16508002 t gcesareni Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity. SIGNOR-144827 0.63 PSMD11 protein O00231 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263351 0.9 CDON/SPAG9 complex SIGNOR-C21 SIGNOR MAP3K5 protein Q99683 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 22337877 t lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts SIGNOR-235557 0.363 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Ser332 TEDSTQTsDTATNST -1 7836371 t gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. SIGNOR-249680 0.2 FGFR2 protein P21802 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates activity phosphorylation Tyr769 TLTTNEEyLDLSQPL 9606 BTO:0000567 15629145 t miannu Our data also show that tyrosine 769 is not involved in the regulation of the endocytic process of KGFR.Following ligand binding, KGFR is rapidly autophosphorylated on specific tyrosine residues SIGNOR-276026 0.2 CSNK1A1 protein P48729 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity SIGNOR-183658 0.393 ITGB4 protein P16144 UNIPROT PMP22 protein Q01453 UNIPROT up-regulates activity binding 10090 16436605 t Regulation miannu PMP22 is in a complex with α6β4 integrin and laminin. PMP22 and β4 integrin are in a complex in a variety of cell types. The interaction with the integrins provides PMP22 with the ability to modulate the cell–ECM communications, as well as intracellular events. Signaling between the ECM and the intracellular compartment is essential for SC myelination, as well as cellular differentiation and motility, in general. The identification of PMP22 as a binding partner for an integrin signaling complex provides a major step toward understanding the role of this disease-linked molecule in the nervous system and in non-neural cell types. SIGNOR-251896 0.383 PPM1D protein O15297 UNIPROT MDM4 protein O15151 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser403 DLAHSSEsQETISSM 9606 19808970 t lperfetto Here, we present evidence that Wip1 specifically dephosphorylates MdmX at Ser403 and indirectly suppresses phosphorylation of MdmX at Ser342 and Ser376.|Thus, Wip1 may need to be inhibited in the early stage of DNA damage response to facilitate rapid MdmX degradation. SIGNOR-276951 0.442 SOD1 protein P00441 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity 10116 BTO:0000452;BTO:0000099 BTO:0001279 31623154 f P00441:p.Gly94Ala (mutation increasing interaction) We found that S100A4 was significantly up-regulated in astrocytes and microglia in the spinal cord of a transgenic rat SOD1-G93A model of amyotrophic lateral sclerosis SIGNOR-262783 0.2 4-aminopyridine smallmolecule CHEBI:34385 ChEBI KCNJ13 protein O60928 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9620703 t miannu Figure 4 shows the response of Kir7.1 to increasing [Ba2+]o. The EC50 for Ba2+ block was 1 mM (Figure 4C), independent of the type of cell in which the channel was expressed. Other known inward rectifier K+ channels are sensitive to inhibition at much lower concentrations SIGNOR-258924 0.8 FKBP5 protein Q13451 UNIPROT YY1 protein P25490 UNIPROT up-regulates activity 9606 BTO:0000848 34589486 f miannu FKBP51 Affects the Binding of YY1 Repressor to DR5 Gene. These results suggest that reduced YY1 DNA-binding activity in FKBP51-silenced cells corresponds to reduced YY1 acetylation. SIGNOR-268792 0.2 KDM6A protein O15550 UNIPROT HOXC11 protein O43248 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260026 0.307 SKP1 protein P63208 UNIPROT SCF-FBW7 complex SIGNOR-C135 SIGNOR form complex binding 9606 15340381 t gcesareni The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions. SIGNOR-243760 0.935 ATM protein Q13315 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser477 NSMNKLPsVSQLINP 9606 18769144 t lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively SIGNOR-180747 0.412 PSMB4 protein P28070 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263355 0.886 AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 11108261 t lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. SIGNOR-244251 0.2 EGFR protein P00533 UNIPROT CCDC50 protein Q8IVM0 UNIPROT down-regulates activity phosphorylation Tyr217 MAEEKKAyKKAKERE 9606 BTO:0000567 19059208 t miannu We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling. SIGNOR-262850 0.425 CSNK2A1 protein P68400 UNIPROT GBF1 protein Q92538 UNIPROT down-regulates quantity by destabilization phosphorylation Ser297 TDSGLEFsSQTTSKE 9606 BTO:0002181 29898406 t miannu We show that, in mitosis, GBF1 is phosphorylated on Ser292 and Ser297 by casein kinase-2 allowing recognition by the F-box protein βTrCP. GBF1 interaction with βTrCP recruits GBF1 to the SCFβTrCP ubiquitin ligase complex, triggering its degradation. SIGNOR-277398 0.2 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM5A protein P29375 UNIPROT up-regulates activity chemical activation 29981745 t lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. SIGNOR-273467 0.8 HMOX1 protein P09601 UNIPROT heme smallmolecule CHEBI:30413 ChEBI down-regulates quantity chemical modification 9606 16115609 t The microsomal heme oxygenase system consists of heme oxygenase (HO) and NADPH-cytochrome P450 reductase, and plays a key role in the physiological catabolism of heme which yields biliverdin, carbon monoxide, and iron as the final products. Heme degradation proceeds essentially as a series of autocatalytic oxidation reactions involving heme bound to HO SIGNOR-259333 0.8 EEF1A1 protein P68104 UNIPROT Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269521 0.8 CENPL protein Q8N0S6 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265199 0.652 PRDM1 protein O75626 UNIPROT CIITA protein P33076 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000776 12626569 f miannu The positive regulatory domain i binding factor 1 (prdi-bf1 or blimp-1) protein represses the transcription of specific target genes, including c-myc, the mhc class ii trans-activator, pax-5, and cd23b SIGNOR-99116 0.431 MMP7 protein P09237 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272397 0.7 RASGEF1A protein Q8N9B8 UNIPROT NRAS protein P01111 UNIPROT up-regulates binding 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-183829 0.358 INTS6 protein Q9UL03 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261463 0.843 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI 9606 17474719 t gcesareni Regulation of mammalian pdc activity is accomplished in large part by phosphorylation (resulting in inactivation) of the e1 component by a family of pyruvate dehydrogenase kinases (pdk 14 isozymes) and dephosphorylation (leading to activation) of phosphorylated e1 by a set of specific phosphatases (phosphopyruvate dehydrogenase phosphatase 12 isozymes) (1, 3-6). The subunit of the e1 component has three phosphorylation sites, named site 1 (ser-264), site 2 (ser-271), and site 3 (ser-203), and phosphorylation of any one of these three sites results in inactivation SIGNOR-154640 0.666 ATP synthase complex SIGNOR-C264 SIGNOR ATP smallmolecule CHEBI:15422 ChEBI up-regulates quantity chemical modification 9606 21874297 t miannu Human mitochondrial (mt) ATP synthase, or complex V consists of two functional domains: F(1), situated in the mitochondrial matrix, and F(o), located in the inner mitochondrial membrane. Complex V uses the energy created by the proton electrochemical gradient to phosphorylate ADP to ATP. SIGNOR-261410 0.8 GNAS protein Q5JWF2 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity 9606 12145344 f lperfetto HETEROTRIMERIC G PROTEINS are essential for cell signaling throughout the body. The stimulatory G protein, Gs, couples activation of a host of different transmembrane receptors to adenylyl cyclase stimulation, leading to intracellular generation of cAMP SIGNOR-268692 0.8 MC5R protein P33032 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257337 0.252 PTPRD protein P23468 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 19478061 t Transfection of wild-type PTPRD resulted in the specific dephosphorylation of STAT3 at tyrosine 705, a residue that must be phosphorylated for STAT3 to be active SIGNOR-248442 0.532 POLR2E protein P19388 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266138 0.886 CSNK2A2 protein P19784 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization phosphorylation Thr102 RAAMFPEtLDEGMQI -1 12432063 t miannu We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin.  SIGNOR-275993 0.453 CDK5 protein Q00535 UNIPROT NOS3 protein P29474 UNIPROT down-regulates phosphorylation Ser114 RKLQGRPsPGPPAPE 9606 BTO:0000938 20213743 t llicata Together, our data suggest that cdk5 can phosphorylate enos at the ser-113 site and down-regulate enos-derived no levels. SIGNOR-164080 0.379 DLST protein P36957 UNIPROT OGDC complex SIGNOR-C397 SIGNOR form complex binding 9606 15953811 t miannu The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. SIGNOR-266254 0.902 PLK1 protein P53350 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1337 LDSDEDFsDFDEKTD 9606 18171681 t llicata Plk1 phosphorylates ser(1337) and ser(1524) of topoiialpha plk1-associated phosphorylation is essential for the functions of topoiialpha in mitosis SIGNOR-160233 0.492 DCK protein P27707 UNIPROT CDK1 protein P06493 UNIPROT down-regulates activity binding 22850745 t lperfetto We demonstrate that dCK interacts with cyclin-dependent kinase 1 (Cdk1) after IR and that the interaction inhibits Cdk1 activity both in vitro and in vivo. SIGNOR-275805 0.386 NFIA protein Q12857 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 32991581 t brain lperfetto NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog, SIGNOR-263983 0.2 NFE2L2 protein Q16236 UNIPROT G6PD protein P11413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 f miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). SIGNOR-267354 0.333 PP1 proteinfamily SIGNOR-PF54 SIGNOR SP3 protein Q02447 UNIPROT down-regulates activity dephosphorylation 9606 12684058 t lperfetto Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression. SIGNOR-264652 0.2 CD40LG protein P29965 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates 9606 BTO:0000776 19047375 f gcesareni Coimmunoprecipitation and western blot analysis showed that heptp was phosphorylated in a pka-dependent manner, which inactivated heptp and allowed for increased free p38 mapk to be phosphorylated by the mapk cascade that was activated by cd40l SIGNOR-182519 0.2 AURKB protein Q96GD4 UNIPROT DSN1 protein Q9H410 UNIPROT down-regulates phosphorylation Ser100 RQSWRRAsMKETNRR 9606 20471944 t lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). SIGNOR-165546 0.639 sunitinib chemical CHEBI:38940 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 21993628 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-176748 0.8 IL1A protein P01583 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0000876 7964161 t lperfetto Interleukin-1 receptor (il-1r) is a cytokine receptor which binds interleukin 1. SIGNOR-35077 0.758 IL1RAPL2 protein Q9NP60 UNIPROT NCS1 protein P62166 UNIPROT up-regulates activity binding 10116 BTO:0001009 12783849 t miannu IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction. SIGNOR-264476 0.326 CREBBP protein Q92793 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 SIGNOR-C6 11062529 t gcesareni The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis. SIGNOR-83843 0.677 GAB1 protein Q13480 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 11043767 t lperfetto We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1. SIGNOR-83343 0.428 POM121 protein Q96HA1 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262071 0.465 C4B protein P0C0L5 UNIPROT C3 convertase complex complex SIGNOR-C310 SIGNOR form complex binding -1 cleavage:Arg756;Gly1446 KGQAGLQrALEILQE;TPLQLFEgRRNRRRR 17204478 t complement C4b fragment:PRO_0000042703 lperfetto However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex SIGNOR-263398 0.656 RNMT protein O43148 UNIPROT mRNA_capping phenotype SIGNOR-PH178 SIGNOR up-regulates 9606 BTO:0000567 26942677 f lperfetto The creation of translation-competent mRNA is dependent on RNA polymerase II transcripts being modified by addition of the 7-methylguanosine (m7G) cap. The factors that mediate splicing, nuclear export, and translation initiation are recruited to the transcript via the cap. The cap structure is formed by several activities and completed by RNMT (RNA guanine-7 methyltransferase), which catalyzes N7 methylation of the cap guanosine. SIGNOR-265503 0.7 (S)-verapamil chemical CHEBI:77736 ChEBI ABCC1 protein P33527 UNIPROT up-regulates activity chemical activation 10036 17646169 t Federica (S)-Verapamil acts as a “killer” by activation of MRP1-mediated GSH efflux, leading to the death of potentially resistant tumor cells. SIGNOR-261081 0.8 alvocidib chemical CHEBI:47344 ChEBI CDK6 protein Q00534 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192385 0.8 CSNK2A2 protein P19784 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Ser102 NLNENQAsEEEDELG -1 2557337 t llicata Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase SIGNOR-251018 0.383 DNA_damage stimulus SIGNOR-ST1 SIGNOR TTK protein P33981 UNIPROT up-regulates 9606 19151762 f lperfetto Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68 SIGNOR-242619 0.7 MEN1 protein O00255 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates binding 9606 12874027 t miannu Menin interacts with fancd2 / loss of menin expression in mouse embryonic fibroblasts leads to increased sensitivity to dna damage. Furthermore, menin is localized to chromatin and nuclear matrix, and the association with nuclear matrix is enhanced by gamma-irradiation. Together, these results suggest that menin plays a critical role in repair of dna damage in concert with fancd2. SIGNOR-103947 0.452 HMGA2 protein P52926 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 25300915 f miannu This study unraveled a novel function ofhmga2in induction of apoptosis in human primary cell lines SIGNOR-205465 0.7 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Thr577 SCRSSTTtCPEQDFF 9606 BTO:0000007 16862148 t lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). SIGNOR-249301 0.444 CSNK2A1 protein P68400 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates phosphorylation Ser1479 HVYEKLSsIESDV 9606 BTO:0000938 15537897 t gcesareni Here we show that casein kinase ii (ck2) phosphorylates the serine residue (ser1480) within the c-terminal pdz ligand (iesdv) of the nr2b subunit of nmdar in vitro and in vivo. Phosphorylation of ser1480 disrupts the interaction of nr2b with the pdz domains of psd-95 and sap102 and decreases surface nr2b expression in neurons. SIGNOR-130336 0.329 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR AKT1S1 protein Q96B36 UNIPROT down-regulates binding 9606 SIGNOR-C3 20006481 t gcesareni Akt can phosphorylate pras40, a raptor binding protein that also acts as an inhibitor of torc1. Akt-mediated phosphorylation of pras40 again promotes 14-3-3 binding, in this case leading to relief from pras40-mediated inhibition. SIGNOR-162003 0.2 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser157 EHIERRVsNAGGPPA 9606 16197368 t llicata We show that, in human platelets, vasp is phosphorylated by pkc on ser157, but not ser239, in response to phorbol ester stimulation, in a manner blocked by the pkc inhibitor bim i (bisindolylmaleimide i). SIGNOR-140841 0.488 SETD1B protein Q9UPS6 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 32546568 t miannu SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks. SIGNOR-265578 0.2 CSNK2A1 protein P68400 UNIPROT NR1H3 protein Q13133 UNIPROT down-regulates phosphorylation Ser198 SLPPRASsPPQILPQ 9606 BTO:0000801 18250151 t llicata Ck2? Also phosphorylated lxr? At s198 in vitro, suggesting that ck2 may be a bona fide s198 kinase. our results show that macrophage lxr? Phosphorylation at s198 affects the transcriptional activity of the receptor in a gene-specific manner (fig. ?(Fig.3a)3a) and restricts the repertoire of genes regulated by lxr? SIGNOR-160640 0.2 PBX3 protein P40426 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription SIGNOR-265779 0.2 MRGPRX1 protein Q96LB2 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257058 0.251 BACE2 protein Q9Y5Z0 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe709 ENPTYKFfEQMQN 9606 10931940 t lperfetto BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Figure 6 Preferred BACE1 and BACE2 cleavage sites. (A) Sequence of APP indicating α- and β-cleavage sites, BACE1- and BACE2-cleavage sites, and the location of mutations analyzed here. APP numbering is that of the 770-aa isoform. SIGNOR-261779 0.56 PPP1CC protein P36873 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-248502 0.391 PPP2CA protein P67775 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR form complex binding 9606 23454242 t gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. SIGNOR-243433 0.903 FGF12 protein P61328 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253444 0.237 RAB22A protein Q9UL26 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR up-regulates activity relocalization 9606 30404817 t lperfetto Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis. SIGNOR-260696 0.2 IGF1R protein P08069 UNIPROT PIK3R3 protein Q92569 UNIPROT up-regulates binding 9606 phosphorylation:Tyr1346 SFDERQPyAHMNGGR 9415396 t gcesareni Moreover, we found that the insulin-like growth factor-1 receptor (igf-ir) bound to p55pik;the interaction occurred at the receptor tyrosine 1316 and involved both p55pik sh2 domains. SIGNOR-52683 0.803 F2RL1 protein P55085 UNIPROT TNFRSF12A protein Q9NP84 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254837 0.2 TNF protein P01375 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 11287630 f lperfetto Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase SIGNOR-106593 0.494 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-252611 0.737 PRKCA protein P17252 UNIPROT SNAP25 protein P60880 UNIPROT unknown phosphorylation Thr138 GGFIRRVtNDARENE 9606 12459461 t lperfetto This study establishes that SNAP-25 is differentially phosphorylated by protein kinase C and protein kinase A in neuroendocrine PC12 cells. Using phosphopeptide mapping and site-directed mutagenesis we identified both Thr138 and Ser187 as the targets of SNAP-25 phosphorylation by protein kinase C SIGNOR-249179 0.359 JAK2 protein O60674 UNIPROT ATOH1 protein Q92858 UNIPROT up-regulates quantity phosphorylation Tyr80 CTARAAQyLLHSPEL 9606 BTO:0004328 29168692 t Gianni We discovered tyrosine 78 of Atoh1 is phosphorylated by a Jak2-mediated pathway only in tumor-initiating cells and in human SHH-type medulloblastoma. Phosphorylation of tyrosine 78 stabilizes Atoh1, increases Atoh1’s transcriptional activity, and is independent of canonical Jak2 signaling. SIGNOR-262201 0.346 CELF1 protein Q92879 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity binding 10090 BTO:0000759 16931514 t miannu These studies showed that both the increased levels of CUGBP1 and cdk4-mediated hyper-phosphorylation of CUGBP1 are involved in the age-associated induction of the CUGBP1-eIF2 complex. The CUGBP1-eIF2 complex is bound to C/EBPbeta mRNA in the liver of old animals, and this binding correlates with the increased amounts of liver-enriched activator protein and liver-enriched inhibitory protein. SIGNOR-262736 0.253 HACE1 protein Q8IYU2 UNIPROT RAC1 protein P63000 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 22036506 t The CNF1 toxin of pathogenic Escherichia coli addresses Rac1 to ubiquitin-proteasome system (UPS). We report the essential role of the tumor suppressor HACE1, a HECT-domain containing E3 ubiquitin-ligase, in the targeting of Rac1 to UPS. HACE1 binds preferentially GTP-bound Rac1 and catalyzes its polyubiquitylation SIGNOR-255538 0.375 CSNK2B protein P67870 UNIPROT CDC34 protein P49427 UNIPROT unknown phosphorylation Ser236 DDSGTEEs 9606 12037680 t llicata CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm.  SIGNOR-251060 0.358 MMP11 protein P24347 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272379 0.7 OPRK1 protein P41145 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256853 0.436 GPR132 protein Q9UNW8 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257444 0.376 PRKCE protein Q02156 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Thr276 GFRKRWFtMDDRRLM -1 12893243 t lperfetto The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚ | The phosphorylation site analysis was carried out twice after phosphorylation of centaurin-alpha1‚ with PKCalpha and once with PKC_. A similar pattern of phosphopeptides was obtained each time. SIGNOR-249226 0.318 CSNK2A1 protein P68400 UNIPROT CDK1 protein P06493 UNIPROT up-regulates phosphorylation Ser39 MKKIRLEsEEEGVPS 9606 15788687 t lperfetto Additionally, transfection of cdc2 with a mutation at ser(39) to ala, which is the ck2 phosphorylation site, partially inhibits cell cycle progression in g(1) to g(2) phase following 6-tg treatment. SIGNOR-134846 0.361 MAPK3 protein P27361 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2. SIGNOR-48352 0.557 motesanib chemical CHEBI:51098 ChEBI RET protein P07949 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194572 0.8 INSR protein P06213 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Tyr152 ISEDIKSyYTVRQLE -1 11506178 t lperfetto Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B SIGNOR-249368 0.78 INSR protein P06213 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation Tyr700 EGEEDTEyMTPSSRP 10090 11997497 t Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation. SIGNOR-251305 0.507 RIPK1 protein Q13546 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 12887920 t amattioni Tradd and rip1 associate with fadd and caspase-8, forming a cytoplasmic complex SIGNOR-104255 0.907 MSH2 protein P43246 UNIPROT BLM protein P54132 UNIPROT up-regulates binding 9606 SIGNOR-C60 15064730 t miannu We show that the recombinant hmsh2/6 protein complex stimulated the ability of the bloom's syndrome gene product, blm, to process holliday junctions in vitro SIGNOR-123699 0.6 sonidegib chemical CHEBI:90863 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193630 0.8 Av/b1 integrin complex SIGNOR-C175 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression 10090 18757303 f lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. SIGNOR-253276 0.327 SP3 protein Q02447 UNIPROT SCNN1A protein P37088 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004299 12684058 f Regulation of expression miannu Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression. SIGNOR-251951 0.2 CTDNEP1 protein O95476 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9606 17141153 t lperfetto We show that dullard promotes the ubiquitin-mediated proteosomal degradation of bmp receptors (bmprs). Dullard preferentially complexes with the bmp type ii receptor (bmprii) and partially colocalizes with the caveolin-1-positive compartment, suggesting that dullard promotes bmpr degradation via the lipid raft-caveolar pathway SIGNOR-150998 0.295 MYCBP2 protein O75592 UNIPROT RAN protein P62826 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 26304119 t Monia MYCBP2 Is a Nuclear GEF for Ran in DRG Neurons—Next, we studied whether or not MYCBP2 modulates the interaction between Ran/RanGAP1. MYCBP2 contains an N-terminal RCC1-like domain (Fig. 8C) (13), and RCC1 is a known GEF for Ran, indicating a potential functional interaction between MYCBP2 and Ran. SIGNOR-261204 0.3 DAXX protein Q9UER7 UNIPROT FAS protein P25445 UNIPROT down-regulates binding 9606 9215629 t gcesareni A c-terminal portion of daxx interacts with the fas death domain. The fas-binding domain of daxx is a dominant-negative inhibitor of both fas-induced apoptosis and jnk activation. SIGNOR-49473 0.691 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI -1 7782287 t gcesareni Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase. SIGNOR-33141 0.666 HIF1A protein Q16665 UNIPROT FAM162A protein Q96A26 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15082785 t Giulio In this work, we report the identification of an HIF-1 alpha-responsive proapoptotic molecule, HGTD-P. Its expression was directly regulated by HIF-1 alpha through a hypoxia-responsive element on the HGTD-P promoter region. SIGNOR-260292 0.285 SNX9 protein Q9Y5X1 UNIPROT EGFR protein P00533 UNIPROT down-regulates 9606 11799118 f gcesareni We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor.The cdc42 target ack2 interacts with sorting nexin 9 (sh3px1) to regulate epidermal growth factor receptor degradation. SIGNOR-114167 0.556 P2RY6 protein Q15077 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257277 0.375 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Ile) smallmolecule CHEBI:29174 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269501 0.8 NOTCH1 protein P46531 UNIPROT TCF12 protein Q99081 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22577461 f miannu E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r. SIGNOR-197514 0.373 H2BC11 protein P06899 UNIPROT Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR form complex binding 9606 15776021 t miannu Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes. SIGNOR-263875 0.2 AURKB protein Q96GD4 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Ser111 KESLRSRsTRMSTVS 9606 17567953 t lperfetto Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres. SIGNOR-155894 0.719 HMGB2 protein P26583 UNIPROT POU2F2 protein P09086 UNIPROT up-regulates activity binding 10090 7720710 t 2 miannu HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins SIGNOR-240108 0.325 MAP3K3 protein Q99759 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates 9606 10347227 f gcesareni However, the autocatalytic activities of both mkk6 and mkk7 were enhanced by their coexpression with either mekk3 or mekk2. SIGNOR-68020 0.408 mTORC1 complex SIGNOR-C3 SIGNOR APOB protein P04114 UNIPROT down-regulates quantity by repression translation regulation 9606 23721961 f miannu Activation of mTORC1 also has dual effects on ApoB synthesis: it inhibits ApoB secretion by decreasing ApoB translation, but promotes ApoB secretion by inhibiting sortilin. SIGNOR-252117 0.274 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1176 ISLGESVsDMAPARP -1 22302995 t miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. SIGNOR-262904 0.69 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MYC protein P01106 UNIPROT up-regulates activity phosphorylation -1 32482868 t inferred from 70% family members lperfetto ERK1 phosphorylates MYC Ser62 resulting in MYC stabilization and activation SIGNOR-270030 0.2 CALM2 protein P0DP24 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates binding 9606 11796223 t miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-266331 0.476 KEAP1 protein Q14145 UNIPROT NFE2L2 protein Q16236 UNIPROT down-regulates binding 9606 24997453 t miannu Keap1 is an oxidative stress-sensing protein and is a negative regulator of nuclear factor-erythroid-2-related factor 2 (nrf2). SIGNOR-205229 0.807 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-34657 0.584 TUBGCP4 protein Q9UGJ1 UNIPROT g-TuRC complex complex SIGNOR-C282 SIGNOR form complex binding -1 31862189 t lperfetto Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.” SIGNOR-262328 0.814 F2R protein P25116 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257219 0.565 AMPK complex SIGNOR-C15 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSSN 10116 11069105 t AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells. AMPK-mediated PFK-2 activation is likely to be involved in the stimulation of heart glycolysis during ischaemia. SIGNOR-260011 0.392 FN1 protein P02751 UNIPROT SDC4 protein P31431 UNIPROT up-regulates activity binding 9606 23290138 t apalma Sdc4 is a high affinity receptor for fibronectin (FN) […] Therefore, we conclude that Sdc4 binds FN on activated satellite cells. SIGNOR-255846 0.7 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser756 HSCLEQAs 9606 10195894 t Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. SIGNOR-251284 0.2 HSP90AA1 protein P07900 UNIPROT NOD2 protein Q9HC29 UNIPROT up-regulates quantity by stabilization binding 9606 23019338 t miannu Nod2 is constitutively associated with a chaperone protein, Hsp90, which is required for Nod2 stability and protects Nod2 from degradation. SIGNOR-252414 0.355 JARID2 protein Q92833 UNIPROT GATA4 protein P43694 UNIPROT down-regulates activity binding 10116 BTO:0003324 15542826 t miannu JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4. SIGNOR-224697 0.468 IRF3 protein Q14653 UNIPROT ABCC2 protein Q92887 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15185298 f miannu Expression of recombinant human IRF3 increased MRP2 promoter activity.  SIGNOR-254533 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SLC25A27 protein O95847 UNIPROT up-regulates quantity by expression transcriptional regulation 20385226 t lperfetto We present the first direct evidence that UCP4 is regulated by NF-kappaB, mediated via a functional NF-kappaB site in its promoter region, and that UCP4 has a significant role in NF-kappaB prosurvival signaling, mediating its protection against MPP(+) toxicity.|NF-kappaB inhibition significantly suppressed the MPP(+)-induced increase in UCP4 expression. SIGNOR-268984 0.2 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR NANOS3 protein P60323 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269259 0.357 F2RL1 protein P55085 UNIPROT CORO1C protein Q9ULV4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254838 0.2 DLC1 protein Q96QB1 UNIPROT MYH9 protein P35579 UNIPROT down-regulates activity binding 9606 BTO:0004006 phosphorylation:Ser1943 RKGAGDGsDEEVDGK 26977077 t miannu Our study has shown that Dlc1 interacts with non-muscle myosin heavy chain II-A (Myh9), plectin and spectrin proteins in different multiprotein complexes. Overexpression of Dlc1 led to increased phosphorylation of Myh9 protein and activation of Rac1 GTPase. Dlc1 interacts with phosphorylated Myh9 (Ser-1943). This association of Dlc1 with S1943 phosphorylated Myh9, suggests that Dlc1 may be involved in reduced Myh9 filament stability. SIGNOR-269283 0.2 PIP5K1C protein O60331 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 9367159 t miannu Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities SIGNOR-277287 0.8 NDUFA5 protein Q16718 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. SIGNOR-262156 0.822 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RXRG protein P48443 UNIPROT up-regulates activity chemical activation 9606 18321241 t miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). SIGNOR-259239 0.8 KDR protein P35968 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity relocalization 9825 BTO:0004007 phosphorylation:Tyr1175 AQQDGKDyIVLPISE 9405464 t VEGF pathway Gianni In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function. SIGNOR-261949 0.7 HES1 protein Q14469 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity 9606 BTO:0001938 24300895 t Altering the expression of HES1 did not obviously affect GR abundance (Figure 3A). However, genome-wide microarrays revealed that overexpression of HES1 resulted in inhibition of GR-mediated changes in the glucocorticoid regulated transcriptome, as compared to non-overexpressing controls SIGNOR-253064 0.2 PHF21A protein Q96BD5 UNIPROT BHC complex complex SIGNOR-C353 SIGNOR form complex binding 9606 BTO:0000567; BTO:0000007 15325272 t miannu BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells SIGNOR-264502 0.732 ITGB5 protein P18084 UNIPROT Av/b5 integrin complex SIGNOR-C178 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253208 0.763 GPR119 protein Q8TDV5 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257415 0.252 PPP1CB protein P62140 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 14633703 t Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-252604 0.394 GPHN protein Q9NQX3 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 25882190 f miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. SIGNOR-264975 0.7 GNAQ protein P50148 UNIPROT PLCE1 protein Q9P212 UNIPROT up-regulates binding 9606 17251915 t gcesareni Typically galfas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate manymolecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152609 0.286 Caspase 3 complex complex SIGNOR-C221 SIGNOR DNA_fragmentation phenotype SIGNOR-PH22 SIGNOR up-regulates 9606 10200555 f amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation SIGNOR-256478 0.7 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NUP50 protein Q9UKX7 UNIPROT down-regulates phosphorylation 9606 19767751 t inferred from 70% family members gcesareni Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. SIGNOR-270041 0.2 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 16537444 t gcesareni Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion. SIGNOR-145141 0.622 MEF2C protein Q06413 UNIPROT MYH2 protein Q9UKX2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 t lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation SIGNOR-238718 0.442 MRGPRX2 protein Q96LB1 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257059 0.2 PICK1 protein Q9NRD5 UNIPROT ASIC1 protein P78348 UNIPROT up-regulates activity relocalization 10116 BTO:0000938 11802773 t miannu we found that the PDZ domain-containing protein PICK1 (protein interacting with C kinase) interacts specifically with the C-termini of BNC1 and ASIC. Our studies showing association of recombinant PICK1 with ASIC and BNC1, and the presence of both PICK1 and ASIC in the synaptosomal fraction SIGNOR-223417 0.553 UBTF protein P17480 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR up-regulates activity binding 9606 15970593 t lperfetto Therefore, we propose that SL1 directs PIC formation, functioning in core promoter binding, RNA polymerase I recruitment, and UBF stabilization and that SL1-promoter complex formation is a necessary prerequisite to the assembly of functional and stable PICs that include the UBF activator in mammalian cells. SIGNOR-269568 0.485 PTGIR protein P43119 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257078 0.41 PIM1 protein P11309 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Ser96 KTQLNPTsLQKLFRE 9606 15319445 t gcesareni Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1. SIGNOR-128260 0.428 TRPS1 protein Q9UHF7 UNIPROT GDF5 protein P43026 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0005092 18363966 f Regulation of expression miannu Treatment of cells with Gdf5 enhanced Trps1 protein levels and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner. Nuclear translocation of Trps1 was also induced by Gdf5. These effects were blocked by a dominant negative form of activin-linked kinase 6 (dn-Alk6) and by SB203580, an inhibitor of the p38 MAPK pathway. Conversely, Gdf5 expression was suppressed by the over-expression of Trps1. SIGNOR-251866 0.311 PKA proteinfamily SIGNOR-PF17 SIGNOR LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Ser951 GFHPRRSsQGATQMP 19018281 t miannu  Our results demonstrate that PKA activates human HSL against lipid substrates in vitro primarily through phosphorylation of Ser649 and Ser650.  SIGNOR-276175 0.2 CDK1 protein P06493 UNIPROT NUMA1 protein Q14980 UNIPROT down-regulates phosphorylation Thr2055 MAFSILNtPKKLGNS 9606 23921553 t llicata Cdk1-mediated phosphorylation at t2055 negatively regulates numa cortical localization and that this phosphorylation is counteracted by ppp2ca phosphatase activity. SIGNOR-194825 0.57 APC-c complex SIGNOR-C150 SIGNOR KIF2C protein Q99661 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 25504441 t miannu Our studies suggest new mechanisms by which Plk1 regulates MCAK: the degradation of MCAK is controlled by Plk1 phosphorylation on S621, whereas its activity is modulated by Plk1 phosphorylation on S632/S633 in mitosis.We have recently shown that S621 in MCAK is the major phosphorylation site of Plk1, which is responsible for regulating MCAK's degradation by promoting the association of MCAK with APC/CCdc20.  In the present study, we have addressed another two residues phosphorylated by Plk1, namely S632/S633 in the C-terminus of MCAK. Our data suggest that Plk1 phosphorylates S632/S633 and regulates its catalytic activity in mitosis. This phosphorylation is required for proper spindle assembly during early phases of mitosis. SIGNOR-276864 0.281 FFAR1 protein O14842 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256799 0.2 ruxolitinib chemical CHEBI:66919 ChEBI JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206670 0.8 UPF2 protein Q9HAU5 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates activity binding -1 18066079 t miannu UPF2 and UPF3b increase UPF1 ATPase activity SIGNOR-265246 0.979 GATOR2 complex SIGNOR-C193 SIGNOR GATOR1 complex SIGNOR-C192 SIGNOR down-regulates activity binding 7227 23723238 t Thus, GATOR2 is an inhibitor of an inhibitor (GATOR1) of the amino acid sensing branch of the TORC1 pathway SIGNOR-253564 0.824 GOLGA2 protein Q08379 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT up-regulates activity binding 9606 23555793 t miannu The “cis-golgin tether” is one of the most well-characterized golgin tether complexes. It is composed of the COPI vesicle-associated golgin giantin linked to Golgi membrane-associated GM130 via p115. GM130 is in turn linked to GRASP65 via a PDZ-like domain. GRASP65 is anchored to the Golgi membrane through N-terminal myristoylation as well as through binding to other Golgi proteins [10]. Together, these proteins appear to mediate vesicle tethering at the cis-Golgi membrane. SIGNOR-261239 0.875 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 21808241 t gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. SIGNOR-175797 0.593 DUSP5 protein Q16690 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 10224087 t inferred from 70% of family members gcesareni Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway SIGNOR-269912 0.2 RIMS2 protein Q9UQ26 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 31679900 t miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle SIGNOR-264377 0.757 CPSF complex complex SIGNOR-C53 SIGNOR PAPOLA protein P51003 UNIPROT up-regulates activity relocalization 9606 14749727 t lperfetto Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna. SIGNOR-268323 0.788 POLR2F protein P61218 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266148 0.897 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules SIGNOR-171066 0.443 EXOC6 protein Q8TAG9 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270789 0.94 RPL13A protein P40429 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262485 0.831 TSHZ3 protein Q63HK5 UNIPROT CASP4 protein P49662 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 19343227 t miannu Chromatin immunoprecipitation showed a direct interaction of FE65 and Teashirt3 with the promoter region of CASP4. The results were consistent with a model in which reduced expression of Teashirt3, mediated by genetic or other causes, increases caspase-4 expression, leading to progression of AD. SIGNOR-264815 0.273 ARHGEF2 protein Q92974 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260529 0.799 MC3R protein P41968 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257026 0.252 EEF1A2 protein Q05639 UNIPROT Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269534 0.8 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR LEF1 protein Q9UJU2 UNIPROT up-regulates transcriptional regulation 9606 10890911 f lperfetto Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity SIGNOR-217169 0.603 NCOR2 protein Q9Y618 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22395773 t FFerrentino In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription. SIGNOR-253508 0.735 PRKCA protein P17252 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr760 LFKSATTtVMNPKFA 9606 BTO:0000751 11700305 t lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | SIGNOR-249125 0.347 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89260 0.402 SPI1 protein P17947 UNIPROT TAL2 protein Q16559 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24086757 f irozzo We show that Tal2 is a direct target gene of the myeloid transcription factor PU.1, which is a key transcription factor for osteoclast gene expression SIGNOR-259086 0.2 NOTCH1 protein P46531 UNIPROT TCF3 protein P15923 UNIPROT down-regulates binding 9606 BTO:0000776 9528794 t gcesareni We provide evidence that notch and deltex may act on e47 by inhibiting signaling through ras because (i) full e47 activity was found to be dependent on ras and (ii) both notch and deltex inhibited gal4-jun, a hybrid transcription factor whose activity is dependent on signaling from ras to sapk/jnk. SIGNOR-56150 0.437 IFNG protein P01579 UNIPROT S100A10 protein P60903 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567;BTO:0002923 12645529 f miannu The effect of interferon (IFN)-gamma on p11 expression was studied in two human epithelial cell lines (BEAS-2B and HeLa). Treatment with IFN-gamma resulted in increased steady-state levels of p11 mRNA and protein expression, with a time-dependent and dose-dependent effect. SIGNOR-255236 0.27 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr741 NLYSGDYyRIQGRAV 9606 16186108 t gcesareni Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues. SIGNOR-140767 0.388 MAPK3 protein P27361 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 19282669 t lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-252962 0.582 COPS4 protein Q9BT78 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270773 0.942 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser405 SHPLSLTsDQYKAYL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178411 0.816 NFATC4 protein Q14934 UNIPROT GPC6 protein Q9Y625 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21871017 t miannu NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype. SIGNOR-264023 0.2 FOXO1 protein Q12778 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21798082 f lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-236540 0.438 ZNF503 protein Q96F45 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 10090 25538248 f Monia Zpo2-overexpressing cells demonstrated high levels of pFAK compared with the control (Fig. 6A). Additionally, Western blot analysis indicated that, in response to Zpo2 expression, both EpH4.9 and PyMT cells increase FAK activity, as demonstrated by higher levels of pFAK staining (Fig. 6B). SIGNOR-261191 0.2 PAK5 protein Q9P286 UNIPROT GATA1 protein P15976 UNIPROT up-regulates activity phosphorylation Ser161 SSLPVPNsAYGGPDF 9606 BTO:0000150 25726523 t lperfetto GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. SIGNOR-275655 0.2 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT up-regulates activity cleavage Ile847 LQPDVTGiRLLSLGA -1 9242537 t lperfetto Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.V treated with HNE indicated cleavage at Ile819 and Ile1484 under conditions during which the procofactor expressed enhanced cofactor activity in the prothrombinase complex. SIGNOR-263637 0.373 EGFR protein P00533 UNIPROT PCNA protein P12004 UNIPROT up-regulates phosphorylation Tyr211 QLTFALRyLNFFTKA 9606 BTO:0000150 17115032 t lperfetto Here, we show that the chromatin-bound pcna protein is phosphorylated on tyr 211, which is required for maintaining its function on chromatin and is dependent on the tyrosine kinase activity of egf receptor (egfr) in the nucleus. Phosphorylation on tyr 211 by egfr stabilizes chromatin-bound pcna protein and associated functions. SIGNOR-150852 0.347 MYC protein P01106 UNIPROT SHMT2 protein P34897 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 t miannu Myc regulates the de novo purine and pyrimidine synthetic genes in multiple biological systems. Intriguingly, MYC was found to directly activate the expression of SHMT1, and SHMT2, which are enzymes involved in single carbon metabolism and are essential for dNTP synthesis SIGNOR-267380 0.295 glutamic acid smallmolecule CHEBI:18237 ChEBI GRID1 protein Q9ULK0 UNIPROT up-regulates activity chemical activation 9606 27586965 t miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors SIGNOR-264468 0.8 CSF2 protein P04141 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 BTO:0000130 7691413 t gcesareni A g-csfr expression plasmid was introduced into interleukin-3 (il-3)-dependent mouse myeloid precursor fdc-p1 cells that normally do not respond to g-csf. G-csf stimulated proliferation of the transformants these results suggested that the g-csfr, but not the il-3/gm-csf receptors, transduced the neutrophilic differentiation signal into cells. SIGNOR-31963 0.586 TBK1 protein Q9UHD2 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 11815618 t lperfetto Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. TBK-1 and IKK-i phosphorylate Ser36 of IkappaBalpha. SIGNOR-246643 0.467 CDK5 protein Q00535 UNIPROT PIP5K1C protein O60331 UNIPROT down-regulates phosphorylation Ser650 DERSWVYsPLHYSAQ 9606 15738269 t lperfetto The interaction of talin with phosphatidylinositol(4) phosphate 5 kinase type i gamma (pipki gamma) regulates pi(4,5)p2 synthesis at synapses and at focal adhesions. Here, we show that phosphorylation of serine 650 (s650) within the talin-binding sequence of human pipki gamma blocks this interaction. At synapses, s650 is phosphorylated by p35/cdk5 and mitogen-activated protein kinase at rest, and dephosphorylated by calcineurin upon stimulation. SIGNOR-134455 0.371 SMAD7 protein O15105 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity binding 9606 30017632 t miannu Smad7 inhibits both transforming growth factor β (TGF-β)- and BMP-induced Smad signaling. Smad7 can use both surfaces in its interaction with the ALK-2, -3, and -4 receptors, but only the basic groove is used in the interaction between Smad7 and the TGF-β type I receptor (TβRI, also known as ALK-5). SIGNOR-260438 0.781 PYY protein P10082 UNIPROT NPY4R protein P50391 UNIPROT up-regulates binding 9606 7592911 t gcesareni Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid. SIGNOR-29767 0.656 RUNX1 protein Q01196 UNIPROT ITGA2B protein P08514 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17725493 f miannu We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. SIGNOR-254193 0.472 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 16199882 t gcesareni Although pka did not affect the formation of a complex between glycogen synthase kinase 3beta (gsk-3beta), beta-catenin, and axin, phosphorylation of beta-catenin by pka inhibited ubiquitination of beta-catenin in intact cells and in vitro. SIGNOR-140902 0.46 MARK2 protein Q7KZI7 UNIPROT KIF13B protein Q9NQT8 UNIPROT down-regulates activity phosphorylation Ser1410 SNKGRWEsQQDVSQT 9534 BTO:0000298 20194617 t miannu We report here the identification of GAKIN/KIF13B as a novel in vivo substrate for Par1b and present evidence that GAKIN/KIF13B plays a critical role in axon formation in neurons, which is negatively regulated by Par1b-mediated phosphorylation. Par1b phosphorylates GAKIN/KIF13B at both Ser1381 and Ser1410. SIGNOR-262956 0.425 SMAD7 protein O15105 UNIPROT TAB3 protein Q8N5C8 UNIPROT up-regulates binding 9606 17384642 t gcesareni The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling. SIGNOR-153920 0.39 ROCK1 protein Q13464 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Thr445 QKQQREKtRWLNSGR 9606 BTO:0000671 10209029 t lperfetto Rho-associated kinase (rho- kinase), which is activated by the small guanosine triphosphatase rho, phosphorylates alpha-adducin and thereby enhances the f-actin-binding activity of alpha-adducin in vitro. Here we identified the sites of phosphorylation of alpha-adducin by rho-kinase as thr445 and thr480 SIGNOR-66992 0.384 NOTCH proteinfamily SIGNOR-PF30 SIGNOR CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11486031 f gcesareni Moreover, as determined by using coimmunoprecipitation assays, each maml protein was found to be capable of forming a multiprotein complex with the intracellular domain of each notch receptor (icn1 to -4) and csl in vivo SIGNOR-254349 0.2 CEBPA protein P49715 UNIPROT SOX4 protein Q06945 UNIPROT down-regulates transcriptional regulation 9606 24183681 t apalma In summary, our data demonstrate that C/EBPα negatively regulates Sox4 transcription via direct DNA-binding. SIGNOR-255675 0.39 MRPL37 protein Q9BZE1 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262360 0.685 PRPF8 protein Q6P2Q9 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270641 0.773 panobinostat chemical CHEBI:85990 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257749 0.8 INSR protein P06213 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr427 ELFDDPSyVNVQNLD 11075717 t Insulin predominantly phosphorylates the Shc Tyr-317 residue. Phosphorylated Shc binds to Grb2 which forms a complex with Sos guanine nucleotide exchange factor for p21ras.  SIGNOR-251325 0.698 MST1R protein Q04912 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation 35569509 t lperfetto This suggests that by interacting with Sdc4, either directly or indirectly, RON is activated via transphosphorylation when clustered, engages the ABL1 SH2 domain, and activates ABL1 by phosphorylation. SIGNOR-272999 0.276 SMURF2 protein Q9HAU4 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity ubiquitination 9606 11163210 t lperfetto Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways. SIGNOR-104999 0.698 TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14522900 f miannu  In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction SIGNOR-254484 0.872 NUP58 protein Q9BVL2 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262077 0.2 GABA-B receptor complex SIGNOR-C336 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 9872316 f brain lperfetto GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals. SIGNOR-263794 0.7 NR3C1 protein P04150 UNIPROT CAV1 protein Q03135 UNIPROT up-regulates binding 9606 23339905 t gcesareni He mGR appears to reside in caveolae and its association with caveolin-1 (Cav-1) was clearly detected in two of the four cell lines investigated using double recognition proximity ligation assay. SIGNOR-251683 0.388 ACTL6B protein O94805 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270740 0.7 SH3GLB1 protein Q9Y371 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 25517094 f miannu Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. SIGNOR-263886 0.7 PRKCA protein P17252 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser25 KRRSARLsAKPPAKV 9606 10739259 t lperfetto Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools. SIGNOR-76286 0.312 prostaglandin H2(1-) smallmolecule CHEBI:57405 ChEBI prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI up-regulates quantity precursor of -1 10922363 t Luana Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently. SIGNOR-269765 0.8 TNFRSF6B protein O95407 UNIPROT FASLG protein P48023 UNIPROT down-regulates binding 9606 BTO:0001271;BTO:0000661 BTO:0000763 10318773 t amattioni Tr6 specifically binds fas ligand. Tr6 may play a regulatory role for suppressing in fasl- mediated cell death. SIGNOR-67434 0.671 ISYNA1 protein Q9NPH2 UNIPROT 1D-myo-inositol 1-phosphate smallmolecule CHEBI:18297 ChEBI up-regulates quantity chemical modification 9606 15464731 t lperfetto Human myo-inositol 1-phosphate synthase (IP synthase; E.C. 5.5.1.4), encoded by ISYNA1, catalyzes the de novo synthesis of inositol 1-phosphate from glucose 6-phosphate. SIGNOR-254131 0.8 POLR1B protein Q9H9Y6 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266154 0.867 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249322 0.754 AKT2 protein P31751 UNIPROT CYCS protein P99999 UNIPROT down-regulates activity phosphorylation Tyr47 KTGQAPGySYTAANK -1 32781572 t miannu Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain. SIGNOR-277236 0.297 CREBBP protein Q92793 UNIPROT MYBL1 protein P10243 UNIPROT up-regulates activity binding 9534 9210395 t 2 miannu CBP co-operates functionally with A-Myb SIGNOR-240984 0.493 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT down-regulates activity phosphorylation Ser311 DALDLEEsSSSDHAE 10029 BTO:0000246 7876239 t The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization. SIGNOR-251440 0.2 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val61 TVETVFSvDEFSASV -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263600 0.381 GSK3B protein P49841 UNIPROT JUNB protein P17275 UNIPROT down-regulates quantity by destabilization phosphorylation Ser251 QTVPEARsRDATPPV 9606 BTO:0000567 22710716 t miannu  Thus, JunB phosphorylation at S251 and T255 by GSK3β is primed by phosphorylation at S259 by a yet to-be-identified kinase.Phosphorylation at S251, T255 and S259 is required for JunB degradation. SIGNOR-276418 0.2 PPM1D protein O15297 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser395 SQESEDYsQPSTSSS 9606 17936559 t Here we show that the wild-type p53-induced phosphatase 1 (Wip1), or PPM1D, downregulates p53 protein levels by stabilizing Mdm2 and facilitating its access to p53. Wip1 interacts with and dephosphorylates Mdm2 at serine 395, a site phosphorylated by the ATM kinase. SIGNOR-248324 0.668 CTNND2 protein Q9UQB3 UNIPROT CDH2 protein P19022 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 t miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. SIGNOR-252131 0.476 IRX1 protein P78414 UNIPROT ERMAP protein Q96PL5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. SIGNOR-261667 0.2 FBXL12 protein Q9NXK8 UNIPROT CAMK1 protein Q14012 UNIPROT down-regulates quantity ubiquitination 10090 BTO:0002268 23707388 t Monia Here, we show that a ubiquitin E3 ligase component, F-box protein Fbxl12, mediates CaMKI degradation via a proteasome-directed pathway leading to disruption of cyclin D1/cdk4 complex. Endogenous Fbxl12 and CaMKI interacted as demonstrated after Fbxl12 immuno-precipitation followed by immunoblot analysis with CaMKI antibodies assembly and resultantG1 arrest in lung epithelia. Fbxl12 targets CaMKI for ubiquitination. SIGNOR-261193 0.488 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR PPARG protein P37231 UNIPROT up-regulates binding 9606 18596912 t lperfetto The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform. SIGNOR-244971 0.2 TFAP2C protein Q92754 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 31583686 f SimoneGraziosi SOX17 regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and suppressing somatic differentiation. SIGNOR-269262 0.7 SMARCC2 protein Q8TAQ2 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270746 0.837 PPP1CA protein P62136 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-248559 0.436 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 21133840 t simone vumbaca TNF alpha and IFN gamma exhibit a cross-talk at the level of TNFR1 to induce activation of macrophages SIGNOR-256025 0.923 AMPK complex SIGNOR-C15 SIGNOR TSC complex SIGNOR-C101 SIGNOR up-regulates activity phosphorylation 10090 BTO:0002572 SIGNOR-C15 16959574 t lperfetto GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation SIGNOR-217749 0.463 PRKACA protein P17612 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates activity phosphorylation Thr130 GEKSRYEtSLNLTTK 9606 BTO:0000007 33110360 t miannu We confirmed the phosphorylation of T130, S235, and S364 by developing monoclonal antibodies against phospho-specific forms of these sites and showed that their phosphorylation is cell cycle-dependent. According to our results, PKA-mediated phosphorylation of E2F1 by PKA inhibits proliferation and glucose uptake and induces caspase-3 activation and senescence. SIGNOR-277536 0.2 RFC5 protein P40937 UNIPROT RF-C complex complex SIGNOR-C375 SIGNOR form complex binding 12930972 t lperfetto RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned SIGNOR-265509 0.759 CSNK1A1 protein P48729 UNIPROT YWHAQ protein P27348 UNIPROT down-regulates activity phosphorylation Ser232 LTLWTSDsAGEECDA -1 9360956 t llicata This protein kinase has been identified as casein kinase Ialpha (CKIalpha) by peptide mapping analysis and sequencing. Among mammalian 14-3-3, only 14-3-3 tau possesses a phosphorylatable residue at the same position (Ser-233), and we show that this residue is also phosphorylated by CKI. In addition, we show that 14-3-3 zeta is exclusively phosphorylated on Thr-233 in human embryonic kidney 293 cells. The residue 233 is located within a region shown to be important for the association of 14-3-3 to target proteins.  SIGNOR-250795 0.495 MMP24 protein Q9Y5R2 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272368 0.7 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252486 0.754 IL17A protein Q16552 UNIPROT KLF15 protein Q9UIH9 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23332504 f fspada Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic. SIGNOR-192474 0.2 PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity phosphorylation Tyr1018 RLSADSGyIIPLPDI 9823 BTO:0004007 7535778 t miannu We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF α-receptor carboxyl-terminal tail bind PLC-γ, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-γ. SIGNOR-250250 0.2 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219308 0.749 glycogen smallmolecule CHEBI:28087 ChEBI alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity precursor of 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267950 0.8 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 BTO:0000887;BTO:0001103 17609368 t lperfetto Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538. SIGNOR-216651 0.483 SLK protein Q9H2G2 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates phosphorylation 9606 BTO:0000671 16316999 t gcesareni Induction of apoptosis by the ste20-like kinase slk, a germinal center kinase that activates apoptosis signal-regulating kinase and p38 SIGNOR-142665 0.255 ATF4 protein P18848 UNIPROT YARS1 protein P54577 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269431 0.2 Integrator complex complex SIGNOR-C265 SIGNOR GADD45B protein O75293 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25675981 f lperfetto The Integrator complex controls the termination of transcription at diverse classes of gene targets.|Following INTS3 or INTS9 knockdown, the levels of SDC4, JUNB, FOSL1, and GADD45B increased, suggesting that the Integrator complex negatively regulates the transcription of these genes. SIGNOR-261478 0.2 PRKCD protein Q05655 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 15972820 t Manara The present study showed that shear stress, but not stretch, activates PKC delta and phosphorylates K8 Ser-73, which then mediates the disassembly/reorganization of keratin IF in AEC. SIGNOR-260887 0.328 PEX6 protein Q13608 UNIPROT PEX5 protein P50542 UNIPROT up-regulates activity binding 10029 16314507 t Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. ​(Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner. SIGNOR-253619 0.587 PIK3R1 protein P27986 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity 10116 21798082 f lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2). SIGNOR-175678 0.8 PPP1CA protein P62136 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser217 YTRTGSEsPKVCSDQ 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248553 0.339 CREB1 protein P16220 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 f inferred from family member gcesareni In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1 SIGNOR-270285 0.252 TET2 protein Q6N021 UNIPROT WT1 protein P19544 UNIPROT up-regulates activity binding 9606 BTO:0000670;BTO:0000738 25601757 t irozzo  In this study, we demonstrate that WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of WT1 target genes. SIGNOR-255703 0.459 CDC42 protein P60953 UNIPROT WAS protein P42768 UNIPROT up-regulates activity binding 9606 BTO:0000132 27871158 t lperfetto Cdc42 can induce Arp2/3-mediated filopodia formation through the activation of WASp (Wiskott-Aldrich syndrome proteins) and neuronal N-WASp (Rohatgi et al., 1999). Similarly, Rac1-enhanced lamellipodia formation is related to Arp2/3 activation by the WAVE (WASP-family verprolin-homologous) complex SIGNOR-261869 0.956 PPM1A protein P35813 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 16751101 t lpetrilli Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads. SIGNOR-146922 0.607 5,15-Diphenyl-21H,23H-porphine chemical CID:10895852 PUBCHEM STAT3 protein P40763 UNIPROT down-regulates activity chemical inhibition 9606 26260587 t gcesareni 15-DPP is an effective STAT3 inhibitor and blocks IL10-mediated signalling in macrophages leading to altered regulation of CNV SIGNOR-238549 0.8 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI formate smallmolecule CHEBI:15740 ChEBI up-regulates quantity precursor of 9606 18767138 t lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate SIGNOR-268248 0.8 PAX3 protein P23760 UNIPROT MEOX1 protein P50221 UNIPROT up-regulates activity binding -1 11423130 t miannu We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family. SIGNOR-222235 0.432 PRKCA protein P17252 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Thr366 QSSASRKtQKKKKKK 9606 BTO:0004737 11325528 t lperfetto We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC. SIGNOR-249092 0.441 INTS9 protein Q9NV88 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261471 0.788 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNK18 protein Q7Z418 UNIPROT down-regulates activity phosphorylation Ser252 QAMERSNsCPELVLG -1 18397886 t miannu Phosphorylation of serine 264 in mouse TRESK was required for the binding of 14-3-3η. PKA was used to phosphorylate serine 264 in our further in vitro experiments. SIGNOR-263154 0.2 NR3C1 protein P04150 UNIPROT SGK1 protein O00141 UNIPROT up-regulates quantity transcriptional regulation 10116 15793248 f We show here that dexamethasone upregulates transcription and expression of the serum- and glucocorticoid-inducible kinase 1 (SGK1) in insulin-secreting cells, an effect reversed by mifepristone (RU486), an antagonist of the nuclear glucocorticoid receptor. SIGNOR-255926 0.473 TRIM37 protein O94972 UNIPROT TRIM37 protein O94972 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 14561866 t miannu In this paper, we present data showing that TRIM37, a member of the TRIM subfamily of RING finger proteins, is autoubiquitinated in a RING domain-dependent manner.  However, we feel tempted to speculate that the most likely mechanism, in which TRIM37-mediated ubiquitination could be involved, is proteasomal degradation of a target protein and, possibly, its own turnover. SIGNOR-271503 0.2 PRKCB protein P05771 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 10090 8662663 t lperfetto Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins.[..] This suggests a two-step model for the phosphorylation (and activation) of eIF4E by growth factors and hormones: first, dissociation of eIF4E . SIGNOR-248946 0.355 MAPK9 protein P45984 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates quantity by stabilization phosphorylation Ser115 SQFSDCSsAKARGDL 9606 BTO:0002932 34048060 t miannu Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation. SIGNOR-277563 0.2 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGC4 protein Q9Y5F7 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265693 0.2 PALB2 protein Q86YC2 UNIPROT BRCA2 protein P51587 UNIPROT up-regulates binding 9606 BTO:0000150 16793542 t miannu Palb2 colocalizes with brca2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions. SIGNOR-147217 0.94 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates activity dephosphorylation Tyr575 RQSPEDVyFSKSEQL -1 21538645 t gcesareni The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates SIGNOR-246031 0.646 MAPK1 protein P28482 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser347 TFPAQSLsPEPLPQE 9606 14697653 t lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. SIGNOR-120459 0.262 olanzapine chemical CHEBI:7735 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 10116 BTO:0001311 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258507 0.8 MRPS24 protein Q96EL2 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261436 0.647 FERMT3 protein Q86UX7 UNIPROT FBLIM1 protein Q8WUP2 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 t miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. SIGNOR-266104 0.502 MAPK1 protein P28482 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser434 LTLASERsSPQRKSQ -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262748 0.29 VPS11 protein Q9H270 UNIPROT EZR protein P15311 UNIPROT up-regulates activity binding 9606 BTO:0000567 21148287 t Sara The interaction between the full-length Vps11 and ezrin was confirmed by immunoprecipitation and GST-pull down. ERM proteins and the HOPS complex are required for the transition from early to late endosomes SIGNOR-261311 0.357 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR VRK3 protein Q8IV63 UNIPROT up-regulates activity phosphorylation Ser108 RPPTPKSsPQKTRKS 27346674 t lperfetto Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding|Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation| SIGNOR-275545 0.363 (2S)-2-[[2-(2,3-dihydro-1H-inden-5-yloxy)-9-[(4-phenylphenyl)methyl]-6-purinyl]amino]-3-phenyl-1-propanol chemical CHEBI:94469 ChEBI ARFGAP1 protein Q8N6T3 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 17460038 t Through affinity chromatography and subsequent functional assays, we showed that QS11 binds and inhibits the GTPase activating protein of ADP-ribosylation factor 1 (ARFGAP1), suggesting that QS11 modulates Wnt/beta-catenin signaling through an effect on protein trafficking. Consistent with its function as an ARFGAP inhibitor, QS11 inhibits migration of ARFGAP overexpressing breast cancer cells SIGNOR-261914 0.8 FBXL7 protein Q9UJT9 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002268 25778398 t miannu Fbxl7 targets survivin for polyubiquitylation and proteasomal degradation.these data suggest that the Skp1·Cul1·F-box protein complex subunit Fbxl7 modulates mitochondrial function by controlling the cellular abundance of survivin. These results suggest that both Lys-90 and Lys-91 are critical for Fbxl7-mediated polyubiquitylation. SIGNOR-272436 0.312 MYD88 protein Q99836 UNIPROT DHX9 protein Q08211 UNIPROT up-regulates activity binding 9606 BTO:0002042 20696886 t miannu We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. This study demonstrates that DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of pDCs and suggests a much broader role for DHX helicases in viral sensing. SIGNOR-260955 0.469 adrenaline smallmolecule CHEBI:33568 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) SIGNOR-257877 0.8 PHLPP1 protein O60346 UNIPROT PRKCB protein P05771 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 18162466 t These data reveal that PHLPP controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation.|n contrast, results from siRNA depletion and overexpression experiments indicate that the hydrophobic motif site (Ser660) is regulated by PHLPP isoforms, SIGNOR-248326 0.347 SRSF1 protein Q07955 UNIPROT Alternative_Splicing_Regulation phenotype SIGNOR-PH204 SIGNOR up-regulates 9606 26273603 f miannu In particular, SRSF1 recognizes SREs in its own transcripts, leading to alternative splicing, with some transcript forms being degraded by nonsense-mediated mRNA decay (NMD). SIGNOR-273861 0.7 AKT1 protein P31749 UNIPROT MTOR protein P42345 UNIPROT unknown phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 10910062 t lperfetto Although AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. Transient transfection assays with mTOR mutants bearing Ala substitutions at Ser2448 and/or Thr2446 indicated that AKT-dependent mTOR phosphorylation was not essential for either PHAS-I phosphorylation or p70S6K activation in HEK cells. SIGNOR-251099 0.928 MMP10 protein P09238 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272355 0.7 IDH complex SIGNOR-C396 SIGNOR 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-266252 0.8 RPS6KA4 protein O75676 UNIPROT HMGN1 protein P05114 UNIPROT unknown phosphorylation Ser7 sSAEGAAK 10090 BTO:0000452 12773393 t lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 and HMG-14 at Ser6 after stimulation of primary embryonic fibroblasts by TPA or anisomycin. SIGNOR-249216 0.341 GRM6 protein O15303 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264354 0.7 ADAM17 protein P78536 UNIPROT HBEGF protein Q99075 UNIPROT up-regulates activity cleavage 9606 26284334 t miannu ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF SIGNOR-259844 0.574 SRC protein P12931 UNIPROT CAV1 protein Q03135 UNIPROT down-regulates activity phosphorylation Tyr14 VDSEGHLyTVPIREQ 9606 12921535 t lperfetto Caveolin-1 is phosphorylated on tyr(14) in response to both oxidative and hyperosmotic stress. In the present paper, we show that this phosphorylation requires activation of the src family kinase fyn SIGNOR-118007 0.755 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr285 TEADGELyVFNTPSG 10090 10978177 t HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin SIGNOR-251311 0.492 BMP2 protein P12643 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 10090 BTO:0001957 11714695 t lperfetto For this, bmp-2 binds first to the high affinity receptor bri and then recruits brii into the signaling complex. SIGNOR-237000 0.856 MYO3A protein Q8NEV4 UNIPROT MYO3A protein Q8NEV4 UNIPROT down-regulates activity phosphorylation Thr919 TRHARETtNMKTQTV 9534 24214986 t Manara We demonstrate by mass spectrometry that Thr-178 and Thr-184 in the kinase domain activation loop and two threonines in the loop 2 region of the motor domain are autophosphorylated (Thr-908 and Thr-919) | Thus, the phosphorylation sites in loop 2 (Thr-908 and Thr-919) are likely responsible for the down-regulation of MYO3A motor activity observed in our current and previous work SIGNOR-260924 0.2 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2L5 protein A0A1B0GUS4 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271331 0.2 AR protein P10275 UNIPROT SCN9A protein Q15858 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24493753 t miannu In neuroblastoma ND7 cells, a nuclear interaction between the developmentally regulated transcription factor Brn-3a and AR resulted in a complex which bound to multiple elements within the promoter region of SCN9A (Nav1.7) and upregulated channel expression. SIGNOR-253466 0.2 DNMT1 protein P26358 UNIPROT IL32 protein P24001 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000018 20889550 f lperfetto A virus or dsRNA in human PBMCs from healthy volunteers. We demonstrate that the NF-κB and CREB pathways play key roles in the activation of IL-32 production in response to influenza virus infection in A549 human lung epithelial cells.|Overexpression assays combined with RNA interference show that DNA methyltransferases DNMT1 and DNMT3b are critical for IL32 promoter methylation and gene silencing before viral infection. SIGNOR-254126 0.347 MARCHF9 protein Q86YJ5 UNIPROT SLAMF1 protein Q13291 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271537 0.2 HIC1 protein Q14526 UNIPROT EFNA1 protein P20827 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20154726 f miannu we show that HIC1 is a direct transcriptional repressor of the gene encoding ephrin-A1, a cell surface ligand implicated in the pathogenesis of epithelial cancers. SIGNOR-254240 0.367 C8B protein P07358 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 t lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer SIGNOR-263444 0.575 GNAS protein P63092 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding -1 11007482 t Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src SIGNOR-256527 0.49 TRAF6 protein Q9Y4K3 UNIPROT KLF4 protein O43474 UNIPROT up-regulates quantity by stabilization ubiquitination Lys32 SGPAGREkTLRQAGA 9606 BTO:0002181 31281496 t miannu We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization. SIGNOR-277464 0.289 PRKCB protein P05771 UNIPROT TRPV6 protein Q9H1D0 UNIPROT down-regulates activity phosphorylation Ser184 LARRASVsARATGTA -1 19805577 t miannu  This regulation requires PKC(betaII) and defined phosphorylation sites within the ARD and the C-terminus. Both regulatory sites act synergistically to constitute a novel mechanism by which ATP stabilizes channel activity and acts as a metabolic switch for Ca(2+) influx. Decreases in ATP concentration or activation of PKC(betaII) disable regulation of the channels by ATP, rendering them more susceptible to inactivation and rundown and preventing Ca(2+) overload. SIGNOR-276265 0.2 TFE3 protein P19532 UNIPROT GAA protein P10253 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276820 0.281 CCNC protein P24863 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 15546612 t Leads to a following ubiquitination and degradation gcesareni Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. SIGNOR-130592 0.458 Caspase 3 complex complex SIGNOR-C221 SIGNOR Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25787076 f miannu The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice SIGNOR-256475 0.7 PTPN22 protein Q9Y2R2 UNIPROT LCK protein P06239 UNIPROT down-regulates activity dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 16461343 t In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22. SIGNOR-248836 0.741 GRK3 protein P35626 UNIPROT CCR5 protein P51681 UNIPROT down-regulates activity phosphorylation Ser337 EAPERASsVYTRSTG 9534 BTO:0000298 10085131 t Serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. CCR5 phosphorylation and desensitization through a GRK-mediated mechanism SIGNOR-251464 0.2 CSNK2A1 protein P68400 UNIPROT HSP90AB1 protein P08238 UNIPROT down-regulates phosphorylation Ser255 PKIEDVGsDEEDDSG 9606 18591256 t gcesareni Although the kinase responsible for hsp90? Phosphorylation in vivo is not known, it has been reported that ck2 can phosphorylate these sites in vitro (24). Thus, we prephosphorylated recombinant hsp90? With ck2 before addition to the reaction. Remarkably, hsp90? Phosphorylation greatly reduced its ability to inhibit apaf-1 oligomerization and caspase-9 recruitment (fig. 5b). These results indicate that the phosphorylation status of hsp90? Significantly impacts its ability to inhibit apoptosome formation. SIGNOR-179264 0.339 CDK1 protein P06493 UNIPROT EIF4G2 protein P78344 UNIPROT up-regulates activity phosphorylation Thr508 AQPPRTQtPPLGQTP 9606 BTO:0000007 29530922 t miannu To test whether CDK1 phosphorylates T508, Flag-DAP5 was purified from dox-induced HEK293 cells and incubated with active recombinant JNK2 or CDK1 in the presence of ATP (Fig. 3G). DAP5(T508) was phosphorylated only upon incubation with CDK1 (Fig. 3G). SIGNOR-266387 0.345 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 10090 BTO:0004052 23996074 t irozzo In this work, we have identified and mapped the protein-protein interaction site between DOT1L and MLL fusion proteins, AF9 and ENL. The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). It is known that the recruitment of DOT1L results in hypermethylation of H3K79 on the prominent MLL fusion downstream target loci Hoxa9 and Meis1 SIGNOR-255870 0.2 RNF135 protein Q8IUD6 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity ubiquitination Lys907 GVQTLYSkWKDFHFE 9606 BTO:0000007 19017631 t miannu Our data suggest that Riplet/RNF135 is a novel factor of the RIG-I pathway that is involved in the evoking of human innate immunity against RNA virus infection, and activates RIG-I through ubiquitination of its C-terminal region. SIGNOR-265568 0.755 KSR1 protein Q8IVT5 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 t miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. SIGNOR-273880 0.639 PRKCD protein Q05655 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates phosphorylation Ser360 ELKALLQsSASRKTQ 9606 BTO:0000938 21145366 t gcesareni Trk receptor activation by both ngf and bdnf induced phosphorylation of ebp1 at the s360 upon the activation of protein kinase c (pkc ) and triggered dissociation of p48 from retinoblastoma (rb SIGNOR-170348 0.488 PRKCG protein P05129 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249282 0.425 CIITA protein P33076 UNIPROT HLA-E protein P13747 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11137213 f HLA-E is inducible by CIITA through the SXY regulatory module. HLA-F is inducible by NF-kappaB through the kappaB1 site of enhancer A, is responsive to IFN-gamma through the ISRE, and is inducible by CIITA SIGNOR-254019 0.475 959122-11-3 chemical CID:24768261 PUBCHEM DGAT1 protein O75907 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205695 0.8 lapatinib chemical CHEBI:49603 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 21443688 t Luana YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ. SIGNOR-257901 0.8 lysine smallmolecule CHEBI:25094 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264755 0.7 DRD5 protein P21918 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256771 0.46 MKX protein Q8IYA7 UNIPROT SCX protein Q7RTU7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001592 33115953 t miannu MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2). SIGNOR-267213 0.426 RUNX1 protein Q01196 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR down-regulates activity binding 9606 22021368 t apalma We found that AML1 inhibits NF-κB signaling through interaction with IκB kinase complex in the cytoplasm. Remarkably, AML1 mutants found in myeloid tumors lack the ability to inhibit NF-κB signaling, and human cases with AML1-related leukemia exhibits distinctly activated NF-κB signaling SIGNOR-255690 0.2 UNC5A protein Q6ZN44 UNIPROT DCC protein P43146 UNIPROT down-regulates activity binding 9606 BTO:0001484 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268164 0.647 GAD2 protein Q05329 UNIPROT gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI up-regulates quantity chemical modification 9606 32041144 t miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. SIGNOR-267555 0.8 ADORA3 protein P0DMS8 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256814 0.429 LCK protein P06239 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr667 ESQEELHyATLNFPG 9606 11733002 t lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Phosphorylation of the tyrosine located at position 667 in an itim motif appears to be necessary for the recruitment of shp-1 and partial recruitment of shp-2 SIGNOR-112495 0.262 PARP1 protein P09874 UNIPROT CHD2 protein O14647 UNIPROT up-regulates quantity binding 9606 26895424 t miannu Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in human cells, but our understanding of how it operates in chromatin is limited. Here, we define a mechanism that plays a crucial role in regulating NHEJ in chromatin. This mechanism is initiated by DNA damage-associated poly(ADP-ribose) polymerase 1 (PARP1), which recruits the chromatin remodeler CHD2 through a poly(ADP-ribose)-binding domain. CHD2 in turn triggers rapid chromatin expansion and the deposition of histone variant H3.3 at sites of DNA damage. SIGNOR-264526 0.2 TNFSF11 protein O14788 UNIPROT TNFRSF11A protein Q9Y6Q6 UNIPROT up-regulates activity binding 9606 12897775 t miannu RANKL, a member of the tumour necrosis factor superfamily, is most abundantly expressed as a cell-surface protein by bone-marrow stromal cells. It interacts with its receptor RANK (which is encoded by Tnfrsf11a) on macrophages and mature osteoclasts. SIGNOR-253042 0.892 CDK14 protein O94921 UNIPROT TAGLN2 protein P37802 UNIPROT down-regulates activity phosphorylation Ser163 KENPRNFsDNQLQEG 21577206 t lperfetto This newly identified oncogene–tumor suppressor cascade, where oncogenic PFTK1 inactivates a tumor suppressor gene TAGLN2 via phosphorylation|. Our data therefore underline much importance for S83 and S163 residues on TAGLN2 in its actin-binding capacity. SIGNOR-265105 0.32 CKM complex complex SIGNOR-C406 SIGNOR CCNH protein P51946 UNIPROT down-regulates activity phosphorylation Ser5 sSQKRHWT 9606 10993082 t gcesareni Here we show that cdk8/cyclin c can regulate transcription by targeting the cdk7/cyclin h subunits of the general transcription initiation factor iih (tfiih). cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity. In addition, mimicking cdk8 phosphorylation of cyclin h in vivo has a dominant-negative effect on cell growth. SIGNOR-273139 0.446 superoxide smallmolecule CHEBI:18421 ChEBI ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 35681445 f lperfetto The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment. SIGNOR-272277 0.7 CPT1A protein P50416 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267132 0.8 PRKACA protein P17612 UNIPROT FXYD1 protein O00168 UNIPROT up-regulates activity phosphorylation Ser83 EEGTFRSsIRRLSTR -1 15621037 t miannu PKA-dependent, alpha 1-specific NKA activation may be mediated through phosphorylation of the accessory protein PLM, rather than direct alpha1 subunit phosphorylation. we propose that phosphorylation of the small accessory protein phospholemman (PLM) by PKA at serine 68 is responsible for the observed isoform-specific activation of NKA. SIGNOR-263117 0.43 NFIL3 protein Q16649 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 10090 BTO:0003104 10082541 f lperfetto NFIL3 inhibits apoptosis without affecting Bcl-xL expression. SIGNOR-256653 0.7 SCN8A protein Q9UQD0 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 t miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. SIGNOR-253406 0.8 AKT3 protein Q9Y243 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t gcesareni We show that phosphorylation of b-raf by akt occurs at multiple residues within its aminoterminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity. SIGNOR-78693 0.293 NCOA1 protein Q15788 UNIPROT APOA5 protein Q6Q788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255064 0.381 zotepine chemical CHEBI:32316 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258552 0.8 IKBKG protein Q9Y6K9 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000007 14695475 t Barakat Here we show that Bcl10 targets NEMO for lysine-63-linked ubiquitination. Notably, a mutant form of NEMO that cannot be ubiquitinated inhibited Bcl10-induced NF-κB activation. SIGNOR-274149 0.821 MVD protein P53602 UNIPROT NRAS protein P01111 UNIPROT up-regulates quantity by stabilization 9534 12646231 f miannu An overexpression of mot-2 resulted in reduced level of Ras and phosphorylated ERK2. These were rescued by co-expression of MPD from an exogenous promoter demonstrating a functional link between mot-2, MPD, and Ras. Ras and its oncogenic forms act as key players in controlling proliferation of normal and cancerous cells. Assigning mot-2 upstream of p21Ras offers an important mechanism for influence over cell proliferation. Therefore, we ra tionaled to investigate if overexpression of MPD could affect the steady state levels of Ras by affecting its prenylationTransient transfections of MPD-myc in COS 7 cells resulted in higher stable levels of Ras as compared to the untransfected cells (Fig. 3A, compare lanes 4 and 8 and Fig. 3B) SIGNOR-265889 0.2 TGFB1 protein P01137 UNIPROT SLC5A5 protein Q92911 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14623893 f miannu The sodium/iodide symporter mediates the active transport of iodide in thyroid follicular cells. A number of agents regulate NIS expression; among these, TGF-β is a potent inhibitor of both iodide uptake and NIS gene expression SIGNOR-259912 0.2 Guanfacine chemical CHEBI:5558 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258920 0.8 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr249 APGPQDIyDVPPVRG 9606 12601080 t lperfetto Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas. SIGNOR-98492 0.259 TBX22 protein Q9Y458 UNIPROT MSX2 protein P35548 UNIPROT down-regulates quantity by repression transcriptional regulation 9031 BTO:0005956 20033915 t miannu the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22. SIGNOR-265567 0.314 TSHR protein P16473 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0001379 32698392 t scontino Activation of TSHR and the linked signaling cascades through binding of circulating TSH plays a pivotal role in controlling thyrocyte growth and in regulating thyroid hormone production/secretion. This is executed through switching on different subtypes of G proteins and signaling pathways. Among them, the Gαs- and Gαq-induced cascades are of the greatest importance, as they have been tightly linked to specific intracellular signal transductions downstream of TSHR in response to stimulations SIGNOR-267138 0.546 GPC6 protein Q9Y625 UNIPROT SHH protein Q15465 UNIPROT up-regulates activity binding 9606 31756413 t miannu Based on results from in vitro experiments, we had previously proposed that GPC6 stimulates Hh signaling by interacting with Hh and Patched1 (Ptc1), and facilitating/stabilizing their interaction. SIGNOR-264029 0.463 RUNX2 protein Q13950 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates transcriptional regulation 10090 16574347 f Giulio Giuliani Osx promoter activity was up-regulated by 2 fold after Runx2 over-expression in ATDC5 cells. Osx Is Phosphorylated by p38 at Ser-73 and Ser-77 SIGNOR-255410 0.524 NMBR protein P28336 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257047 0.271 PAK1 protein Q13153 UNIPROT ARAF protein P10398 UNIPROT up-regulates phosphorylation Ser299 KNLGYRDsGYYWEVP 9606 BTO:0000848 15710605 t lperfetto Phosphorylation of endogenous a-raf, b-raf and raf-1 on the homologous pak phosphorylation sites (serine 299, serine 445, or serine 338 respectively)we found that the phosphorylation of a-raf on serine 299 was also stimulated by egf, although the duration of phosphorylation on this site was much shorter than for raf-1. Thus, by analogy with raf-1, phosphorylation of this site may play an important role in the a-raf activation mechanism. SIGNOR-236342 0.27 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCZ protein Q05513 UNIPROT up-regulates activity binding 9606 14967450 t PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. SIGNOR-242599 0.8 PTPN1 protein P18031 UNIPROT LAT protein O43561 UNIPROT down-regulates dephosphorylation 9606 12857726 t gcesareni Our results demonstrate that ptp1b plays an important role in the integrin-mediated dephosphorylation of lat in human platelets and is involved in the control of irreversible aggregation upon fcgammariia stimulation. SIGNOR-103599 0.483 PRKACA protein P17612 UNIPROT APC protein P25054 UNIPROT down-regulates activity phosphorylation Ser2054 MPKKKKPsRLKGDNE 9606 11050185 t miannu Changing a serine residue (Ser(2054)) to aspartic acid mutated the potential protein kinase A site adjacent to NLS2(APC), resulting in both inhibition of the NLS2(APC)-mediated nuclear import of a chimeric beta-galactosidase fusion protein and a reduction of full-length APC nuclear localization. SIGNOR-250335 0.312 bethanechol chemical CHEBI:3084 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258623 0.8 PPP5C protein P53041 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity dephosphorylation Ser211 PGKETNEsPWRSDLL 9606 BTO:0000093 19586900 t Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation.|Inhibition of GR phosphorylation at Ser-211 is associated with decreased nuclear retention of GR and decreased gene transcription. SIGNOR-248538 0.521 PTPN6 protein P29350 UNIPROT NFAT5 protein O94916 UNIPROT down-regulates activity dephosphorylation Tyr143 PKRHTVLyISPPPED 9606 BTO:0000007 20351292 t We confirmed that SHP-1 is inhibitory by overexpressing it, which reduces TonEBP/OREBP transcriptional activity at 500 mosmol/kg. SHP-1 dephosphorylates TonEBP/OREBP at a known regulatory site, Y143, both in vivo and in vitro. It inhibits TonEBP/OREBP by both reducing TonEBP/OREBP nuclear localization, which is Y143 dependent, and by lowering high NaCl-induced TonEBP/OREBP transactivating activity SIGNOR-248467 0.349 NR0B2 protein Q15466 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 11368516 f inferred from family member gcesareni Shp (short heterodimer partner) is an orphan nuclear receptor lacking a dna binding domain that interacts with nuclear receptors (nr) including thyroid receptor (tr), retinoic acid receptors (rar and rxr), and estrogen receptors alpha and beta (eralpha and erbeta). Shp acts as a negative regulator of these receptors by inhibiting dna binding and transcriptional activation. SIGNOR-270298 0.378 PRKG1 protein Q13976 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Thr143 RCFTRKYtLPPGVDP 9606 19593530 t 11383510: to test the hypothesis that cGK could inhibit platelet aggregation by phosphorylating Hsp27 and interfering with the MAPKAP kinase phosphorylation of Hsp27, the known MAPKAP kinase 2-phosphorylation sites (Ser15, Ser78, and Ser82) as well as Thr143 were replaced by negatively charged amino acids, which are considered to mimic phosphate groups, and tested in actin polymerization experiments. Mimicry at the MAPKAP kinase 2 phosphorylation sites led to mutants with a stimulating effect on actin polymerization lperfetto Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization SIGNOR-186792 0.277 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. SIGNOR-236675 0.741 PRKACA protein P17612 UNIPROT ABCA1 protein O95477 UNIPROT up-regulates activity phosphorylation Ser1042 GGMQRKLsVALAFVG 10090 BTO:0000801 12196520 t miannu Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ABCA1 phosphorylation may affect ApoA-I-dependent phospholipid efflux by either altering the conformation of the protein to a more active state or by affecting the interaction between ABCA1 and its partner proteins. SIGNOR-250326 0.486 EPX protein P11678 UNIPROT RNASE3 protein P12724 UNIPROT up-regulates activity post translational modification 9606 BTO:0000399 18694936 t miannu Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism. SIGNOR-261705 0.49 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser710 GEKSFRRsVVGTPAY 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275957 0.2 MMP1 protein P03956 UNIPROT COL3A1 protein P02461 UNIPROT down-regulates quantity by destabilization cleavage Gly774 IGPPGPAgQPGDKGE -1 17318226 t lperfetto In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4.  SIGNOR-272339 0.357 MYC protein P01106 UNIPROT DHODH protein Q02127 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 t miannu PPAT, catalyzing the first step of purine synthesis, and DHODH, an enzyme generating uridine in the middle of the pyrimidine synthesis pathway, were validated as direct c-MYC target genes by all criteria. SIGNOR-267382 0.353 CSNK2A1 protein P68400 UNIPROT ESR1 protein P03372 UNIPROT down-regulates phosphorylation Ser282 EGRGEVGsAGDMRAA 9606 BTO:0000150;BTO:0000567 20043841 t lperfetto Additionally protein kinase ck2 was identified as a kinase that phosphorylated eralpha at s282 and s559 s282 and s559 represent the second and third sites of er_ regulation by ck2. Remarkably, mutation of s282 or s559 to alanine resulted in near opposite functional effects on er_ as compared to mutation of s167 to alanine. Er_ ligand independent transcriptional activity was markedly enhanced upon mutation of s282 and s559 to alanine SIGNOR-162653 0.248 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr373 VNVIPPHtPVRTVMN 9606 1756735 t lperfetto The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2. SIGNOR-21564 0.675 iodide smallmolecule CHEBI:16382 ChEBI 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI up-regulates quantity precursor of 9606 23349248 t miannu After transport through the apical membrane, I‚àí is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO). SIGNOR-259913 0.8 DUSP2 protein Q05923 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 8626452 t fstefani Pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively. SIGNOR-40915 0.735 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT down-regulates phosphorylation Thr526 GEAGGPLtPRRVSSD 9606 7588608 t lperfetto Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf SIGNOR-29505 0.579 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR MCM10 protein Q7L590 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 22570418 t miannu By screening the known DDB1 interacting proteins, we discovered that VprBP is the substrate recognition subunit that targets Mcm10 for degradation. Hence, these results establish that Cul4-DDB1-VprBP ubiquitin ligase mediates the stress-induced proteolysis of replication factor, Mcm10. SIGNOR-272045 0.392 ZM447439 chemical CHEBI:91376 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207923 0.8 WNT11 protein O96014 UNIPROT FZD6 protein O60353 UNIPROT up-regulates activity binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. SIGNOR-141431 0.659 1-(3-sn-phosphatidyl)-sn-glycerol 3-phosphate(3-) smallmolecule CHEBI:60110 ChEBI phosphatidylglycerol(1-) smallmolecule CHEBI:60523 ChEBI up-regulates quantity precursor of 10090 21641550 t lperfetto PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle. We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. Loss of PTPMT1 leads to dramatic diminution of cardiolipin, which can be partially reversed by the expression of catalytic active PTPMT1. Our study identifies PTPMT1 as the mammalian PGP phosphatase and points to its role as a regulator of cardiolipin biosynthesis. SIGNOR-267027 0.8 ALG1 protein Q9BT22 UNIPROT alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc(PP-Dol) smallmolecule CHEBI:133994 ChEBI up-regulates quantity chemical modification 9606 28575298 t lperfetto The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in eukaryotic protein N-glycosylation starts on the cytoplasmic side of the endoplasmic reticulum and includes the sequential addition of five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by the Alg1, Alg2 and Alg11 gene products and yield Dol-PP-GlcNAc2Man5, an LLO intermediate that is subsequently flipped to the lumen of the endoplasmic reticulum. SIGNOR-260418 0.8 CHEK2 protein O96017 UNIPROT CDC25C protein P30307 UNIPROT down-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR 9606 12835754 t lperfetto Activated chk2 in turn phosphorylates cdc25c at serine-216 contributing to the g2/m checkpoints. Cds1 phosphorylates and inactivates cdc25 in vitro|CDC25C is phosphorylated on Ser 216 throughout interphase, but not in mitosis. This creates a binding site for 14‐3‐3 proteins | It has been suggested that 14‐3‐3 protein binding is responsible for retaining Cdc25C in the cytoplasm during interphase, thereby contributing to the prevention of premature initiation of mitotic events SIGNOR-102779 0.851 NFE2 protein Q16621 UNIPROT HBG1 protein P69891 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000426 16287851 f Regulation of expression miannu NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells. SIGNOR-251841 0.508 regorafenib chemical CHEBI:68647 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR down-regulates activity chemical inhibition 9606 26254357 t miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF SIGNOR-259452 0.8 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 16403219 t miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. SIGNOR-259422 0.2 CSNK2A2 protein P19784 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser511 PIGEDEEsESD -1 9045708 t llicata Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells.  SIGNOR-251038 0.312 RUNX2 protein Q13950 UNIPROT VEGFC protein P49767 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001610 22641097 f miannu Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells. SIGNOR-255081 0.2 ADORA2A protein P29274 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257413 0.252 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr980 YASVNPEyFSAADVY -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase. We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246256 0.2 GNB1 protein P62873 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000938 16537363 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-252679 0.51 NANOG protein Q9H9S0 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 16153702 f flangone Our results suggest that OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal by activating their own genes and genes encoding components of key signaling pathways and by repressing genes that are key to developmental processes. SIGNOR-242076 0.7 FGG protein P02679 UNIPROT VWF protein P04275 UNIPROT down-regulates activity binding 9606 2243140 t Regulation miannu Fibrinogen y-chain carboxyterminal (GQQHHLGGAKQAGDV) peptides inhibit fibrinogen, fibronectin (Fn), vitronectin, and von Willebrand factor (vWF) binding to the platelet glycoprotein Ilb-Illa complex (GP lIbII1a). SIGNOR-251968 0.478 BLOC-1 complex SIGNOR-C381 SIGNOR Melanosome_assembly phenotype SIGNOR-PH180 SIGNOR up-regulates 9606 BTO:0000847 22203680 f lperfetto Lysosome-related organelles (LROs) 6 are present in a range of cells in multicellular eukaryotes and include lytic granules, lung lamellar bodies, platelet-dense granules, and melanosomes (1.). The melanosome of the pigment cells in the skin and eye is the best studied of the LROs (1., 2.). The biogenesis of the melanosome and other LROs requires the AP-3 adaptor complex, the class C Vps complex, and three BLOC (biogenesis of lysosome-related organelles complex) complexes SIGNOR-265939 0.7 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257966 0.8 ARAP3 protein Q8WWN8 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260457 0.5 Gbeta proteinfamily SIGNOR-PF4 SIGNOR IL16 protein Q14005 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 14768064 t inferred from 70% family members lperfetto The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 in antigen receptor-, sdf1alpha- and il-2-activated t cells. Genetic and pharmacological-inhibitor experiments showed that the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response. SIGNOR-270056 0.2 GNAI3 protein P08754 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 8327893 t gcesareni Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required SIGNOR-38032 0.578 HRH3 protein Q9Y5N1 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256832 0.413 SIRT5 protein Q9NXA8 UNIPROT SHMT2 protein P34897 UNIPROT down-regulates activity post translational modification Lys280 IVTTTTHkTLRGARS 34929314 t desuccinylation lperfetto Mitochondrial serine hydroxymethyl transferase (SHMT2) is a rate-limiting enzyme that catalyzes the catabolism of serine and drives the proliferation of osteosarcoma cells and colon cancer cells. SIRT5 directly mediates the desuccinylation of Lysine 280 on SHMT2. Therefore, SIRT5 is a candidate target to inhibit serine catabolism SIGNOR-267644 0.236 KLF11 protein O14901 UNIPROT SIN3A protein Q96ST3 UNIPROT up-regulates activity binding 10029 BTO:0000246 11438660 t miannu detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A. SIGNOR-222344 0.5 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR HDAC1 protein Q13547 UNIPROT up-regulates activity binding 9606 BTO:0000007 28630438 t miannu NUP98-HOXA9 has an activator-repressor role in transcriptional regulation driven by p300 and HDAC1 interactions. The chromosomal translocation t(7;11)(p15, p15), encoding the fusion protein NUP98-HOXA9 (NHA9), is a rare poor risk cytogenetic event in AML associated with a particularly poor prognosis.In summary, NHA9 deregulates the expression of key leukemic genes, including MEIS1-HOXA9-PBX3 complex, through the enhancer binding and the direct interaction of the fusion protein with HDAC and p300 transcriptional regulators. SIGNOR-261498 0.2 RPL27A protein P46776 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262473 0.853 GSK3B protein P49841 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1359 VPRPHVQsVLLTPQD 9606 BTO:0002181 19797085 t miannu We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity.  SIGNOR-276263 0.36 NFIB protein O00712 UNIPROT NEUROD4 protein Q9HD90 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268898 0.2 CHEK2 protein O96017 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser988 PPLFPIKsFVKTKCK 9606 BTO:0000150 14701743 t gcesareni In this study, we tested the hypothesis that the brca1-mediated regulation of recombination requires the chk2- and atm-dependent phosphorylation sites. SIGNOR-120575 0.779 EIF2B5 protein Q13144 UNIPROT EIF2S3 protein P41091 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269133 0.724 IRF1 protein P10914 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19482358 f miannu Socs1 expression is induced in the human keratinocytes HaCaT cell line through sequential activation of STAT1 and IRF-1 SIGNOR-226481 0.389 TNFRSF21 protein O75509 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR down-regulates 9606 32454942 f miannu Further, data from our laboratories indicate that selective agonism of TNFR2 rescues neurons from oxidative stress-induced cell death [160] and excitotoxic cell death [161, 162]. Similarly, TNFR2 activation induces expression of antiapoptotic and detoxifying proteins and protects OPCs against oxidative stress. SIGNOR-263831 0.7 MTA1 protein Q13330 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000812 18719363 f miannu Screening for the expression of angiogenic cytokines expressed by ovarian cancer cells revealed MTA1-mediated upregulation of the oncogenic and angiogenic cytokine GRO (growth-regulated oncogene, CXCL1). SIGNOR-254598 0.2 SRC protein P12931 UNIPROT GRB10 protein Q13322 UNIPROT down-regulates phosphorylation Tyr67 NASLESLySACSMQS 9606 10871840 t lperfetto Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir. SIGNOR-78706 0.458 SLX4 protein Q8IY92 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR up-regulates binding 9606 24726326 t lperfetto Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair. SIGNOR-217652 0.813 AKAP11 protein Q9UKA4 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates quantity binding 9606 21776420 t miannu We show that IQGAP2 is regulated by an interaction with the A-kinase anchoring protein AKAP220. Phosphorylation of IQGAP2 via AKAP220-anchored PKA leads to enhanced Rac binding. Since AKAPs function to direct PKA toward specific substrates, we proposed that the formation of an IQGAP2/AKAP220/PKA ternary complex sharpens the response to cAMP. SIGNOR-273741 0.435 SLBP protein Q14493 UNIPROT H2BC1 protein Q96A08 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265393 0.2 CDCA8 protein Q53HL2 UNIPROT CPC complex SIGNOR-C554 SIGNOR form complex binding 9606 23175282 t miannu It is now known that the chromosomal passenger complex (CPC) is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin (also known as Dasra)5–7 (Figure 1A). SIGNOR-275423 0.85 BMP2 protein P12643 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates 9606 22298955 f lperfetto Neogenin, a transmembranous protein, was reported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation. SIGNOR-195561 0.639 MAPK1 protein P28482 UNIPROT RBFOX2 protein O43251 UNIPROT unknown phosphorylation Thr7 tPGYHGFP 10090 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262761 0.2 BIRC3 protein Q13489 UNIPROT RIPK3 protein Q9Y572 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation. SIGNOR-272714 0.633 HLX protein Q14774 UNIPROT ELK1 protein P19419 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003980 20008130 t Luana In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells. SIGNOR-261622 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DUSP6 protein Q16828 UNIPROT down-regulates phosphorylation 9606 15632084 t inferred from 70% family members amattioni Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3 SIGNOR-270205 0.2 GNB5 protein O14775 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR down-regulates activity binding 9606 BTO:0004032 21303898 t miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC SIGNOR-267850 0.458 GRPR protein P30550 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257159 0.271 GRB2 protein P62993 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates binding 9606 12766170 t Grb2-associated binding (Gab) scaffolding/adapter proteins are a family of three members including mammalian Gab1, Gab2, and Gab3 that are highly conserved. lperfetto The gab1 docking protein forms a platform for the assembly of a multiprotein signaling complex downstream from receptor tyrosine kinases. In general, recruitment of gab1 occurs indirectly, via the adapter protein grb2 SIGNOR-235917 0.868 TSC22D1 protein Q15714 UNIPROT NPPC protein P23582 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 9022669 t Luana TSC-22 significantly enhanced CNP promoter activity in GH3 cells. SIGNOR-266226 0.26 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser289 PALSRRGsLGEEGSE 10090 17213202 t lperfetto The results indicated that rsk2 phosphorylated two additional sites at ser289 (peptide 2) and ser344 (peptide 3)rsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo. SIGNOR-234473 0.393 PPM1D protein O15297 UNIPROT ATM protein Q13315 UNIPROT down-regulates dephosphorylation 9606 19360021 t gcesareni The negative regulator wip1 plays an important role in inhibiting atm, resulting in a pulse of atm activity. SIGNOR-185135 0.501 Bombesin smallmolecule CHEBI:80229 ChEBI GRPR protein P30550 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257509 0.8 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIK2 protein Q13002 UNIPROT up-regulates activity chemical activation 9606 27586965 t miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors SIGNOR-264471 0.8 dexamethasone chemical CHEBI:41879 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258711 0.8 potassium(1+) smallmolecule CHEBI:29103 ChEBI Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 11506885 f miannu Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height SIGNOR-265590 0.7 SNAI2 protein O43623 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 21044962 f miannu knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene. SIGNOR-255176 0.47 DNAH10 protein Q8IVF4 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000667 31836722 f miannu Epidermal expression of axonemal dynein heavy chain 10 (DNAH10) was increased 20-fold in samples having had regenerating dermis vs control. Our results associate DNAH10 expression with cell proliferation and inflammation as well as with the epidermal memory resulting from the previous regenerative signals of dermis. SIGNOR-265550 0.7 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC3 protein P33778 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271983 0.2 EGFR protein P00533 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr5 yLDPNLNH 9606 20802513 t llicata In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases. SIGNOR-167650 0.582 Isoetharine chemical CHEBI:6005 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation -1 7576010 t miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. SIGNOR-258433 0.8 CDK1 protein P06493 UNIPROT TOB2 protein Q14106 UNIPROT up-regulates activity phosphorylation Ser254 PAPQSQLsPNAKEFV -1 32404348 t done miannu Taken together, these observations strongly support the notion that several different CDK-cyclin complexes are involved in the phosphorylation of Tob2 at S254.A more detailed regulatory context of Tob2 phosphorylation at S254 is provided by our findings from mass-spec and in vitro kinase analyses that suggest connections to PP2B and PP2C phosphatases and CDK-cyclin complexes, particularly CDK1, CDK2, and CDK4 (Table 1; Supplemental Table S2).One possibility is that the phosphorylation of S254 helps stabilize the interaction of Tob2 with the Ccr4–Not complex, which could contribute to Tob2's ability to recruit the entire Ccr4–Not complex and thus further enhances deadenylation. SIGNOR-273591 0.2 ASXL1 protein Q8IXJ9 UNIPROT HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22897849 f miannu ASXL1 siRNA in human primary CD34+ cells form cord blood results in upregulation of HOXA5 and HOXA9 with ASXL1 knockdown (KD) as revealed by quantitative real-time PCR SIGNOR-256127 0.446 WNK4 protein Q96J92 UNIPROT WNK4 protein Q96J92 UNIPROT down-regulates activity phosphorylation Ser335 KRASFAKsVIGTPEF -1 25542968 t miannu  Elimination of the catalytic activity (D321A or D321K-K186D) or the autophosphorylation site (S335A) in mutant WNK4-L322F abrogated the positive effect on NCC.  SIGNOR-276871 0.2 EAF2 protein Q96CJ1 UNIPROT ELL protein P55199 UNIPROT up-regulates binding 9606 16006523 t miannu The eaf1-related eaf2 protein is also a positive regulator of ell elongation activity SIGNOR-138540 0.736 PTK6 protein Q13882 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 15994200 t gcesareni These observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis. SIGNOR-252617 0.454 PRLHR protein P49683 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256973 0.311 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CEBPB protein P17676 UNIPROT up-regulates phosphorylation 9606 BTO:0000801 19327116 t inferred from 70% family members gcesareni Thr235 phosphorylation occurs in nuclei of differentiated macrophages, but not in monocytes. SIGNOR-270045 0.2 AXL protein P30530 UNIPROT YES1 protein P07947 UNIPROT up-regulates activity phosphorylation Tyr426 RLIEDNEyTARQGAK 9606 BTO:0001007 33941853 t miannu Here, we show that EphA2, YES1, and ANXA2 form a signal axis, in which YES1 activated by EphA2 phosphorylates ANXA2 at Tyr24 site, leading to ANXA2 activation and increased ANXA2 nuclear distribution in gastric cancer (GC) cells. SIGNOR-277555 0.2 3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol chemical CHEBI:94691 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207251 0.8 RNF138 protein Q8WVD3 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 16714285 t miannu Here, we show that NARF induces the ubiquitylation of TCF/LEF in vitro and in vivo, and functions as an E3 ubiquitin-ligase that specifically cooperates with the E2 conjugating enzyme E2-25K. We found that NLK augmented NARF binding and ubiquitylation of TCF/LEF, and this required NLK kinase activity. The ubiquitylated TCF/LEF was subsequently degraded by the proteasome. SIGNOR-271593 0.331 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR JUN protein P05412 UNIPROT up-regulates activity binding 9606 9732876 t lperfetto Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos SIGNOR-229545 0.702 TIMM9 protein Q9Y5J7 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 t lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). SIGNOR-267702 0.568 ACTL6A protein O96019 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269295 0.639 SRGAP2 protein O75044 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260517 0.587 DDHD1 protein Q8NEL9 UNIPROT long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity chemical modification 9606 22922100 t miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. SIGNOR-269653 0.8 RYBP protein Q8N488 UNIPROT ABL1 protein P00519 UNIPROT down-regulates binding 9606 8943360 t gcesareni We identified a novel protein, aap1 (abl-associated protein 1), that associates with these c-abl domains and fails to bind to the sh3 domain in the activated oncoprotein bcrabl. we conclude that aap1 inhibits c-abl tyrosine kinase activity SIGNOR-45325 0.339 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA8 protein Q9Y5G5 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265702 0.2 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR up-regulates activity chemical activation 9606 18790874 t brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-263789 0.8 MYC protein P01106 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates activity binding 9606 19786833 t irozzo Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. SIGNOR-255806 0.7 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide chemical CHEBI:91447 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194925 0.8 MAPK3 protein P27361 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Ser780 DSLDSRLsPPAGLFT 9606 BTO:0000975 10194762 t gcesareni Serine 780 is the only substrate in full-length stat5a for active erk SIGNOR-66247 0.694 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 16679294 t gcesareni Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action SIGNOR-146668 0.263 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Thr194 FPKTSSAtPQETLIS -1 12361598 t miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) SIGNOR-265961 0.53 calcitriol smallmolecule CHEBI:17823 ChEBI calcitetrol smallmolecule CHEBI:47799 ChEBI up-regulates quantity precursor of 30080183 t lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). SIGNOR-270570 0.8 SOD1 protein P00441 UNIPROT ERN1 protein O75460 UNIPROT up-regulates activity binding 10090 BTO:0004488 18519638 t P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction) SOD1mut-induced ER stress |we first examined whether SOD1mut induces ER stress in NSC34 motor neurons, as assessed by band-shift analyses of the ER transmembrane kinase receptors IRE1 and PERK. Adenovirus (Ad)-mediated expression of ALS-linked SOD1mut (SOD1G93A) was detectable within 48 h of infection (Supplemental Fig. S1A). SOD1mut (SOD1A4V, SOD1G85R, and SOD1G93A) but not wild-type SOD1 (SOD1wt) activated IRE1 and PERK SIGNOR-262786 0.321 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002417 15358865 t gcesareni Activation of the Jun amino-terminal kinase (JNK) mitogen-activated protein kinase cascade after T cell stimulation accelerated degradation of c-Jun and JunB through phosphorylation-dependent activation of the E3 ligase Itch. SIGNOR-245315 0.644 WNT11 protein O96014 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 23151663 t gcesareni Musk has an extracellular region with homology to the frizzled crd,binding of which by wnt11 stimulates a pcp-like pathway during neuromuscolar development. Here, we show that in vivo, wnt11r and wnt4a initiate musk translocation from muscle membranes to recycling endosomes we provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase SIGNOR-199641 0.468 ZAP70 protein P43403 UNIPROT DBNL protein Q9UJU6 UNIPROT up-regulates phosphorylation Tyr334 QAEEEAVyEEPPEQE 9606 BTO:0000782 14557276 t lperfetto We found an interaction between the tyrosine kinase zap-70 and hip-55, which was induced by tcr stimulation. Zap-70 phosphorylated hip-55 at tyr-334 and tyr-344, which were shown to be the tyrosine phosphorylation sites of hip-55 in stimulated t cells.Our results demonstrate for the first time that hip-55 is an important adaptor protein for the jnk kinase cascade in tcr signaling. SIGNOR-118691 0.625 prazosin chemical CHEBI:8364 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258473 0.8 Non-structural protein 10 protein P0C6X7-PRO_0000037317 UNIPROT MT-ND4L protein P03901 UNIPROT down-regulates activity binding 9606 BTO:0000764 16157265 t lperfetto This result suggests that the nsp10 protein could affect the activities of NADH and cytochrome oxidase II via a direct interaction while being involved in viral replication. SIGNOR-260253 0.2 BTRC protein Q9Y297 UNIPROT NFKBIB protein Q15653 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0004055 10514424 t miannu Interaction with beta-TrCP is also necessary for ubiquitination of IkappaBbeta upon stimulation of cells, and deletion of the F-box in beta-TrCP abolishes its ability to ubiquitinate IkappaBbeta. Therefore, these results indicate that beta-TrCP plays a critical role in the activation of NF-kappaB by assembling the ubiquitin ligase complex for both phosphorylated IkappaBalpha and IkappaBbeta.β-TrCP recognizes IκBα phosphorylated at Ser-32 and Ser-36 through its WD40 domain, whereas the F-box motif recruits additional proteins including Skp1 and Cullin to form the Skp1-cullin-F-box (SCF) ubiquitin ligase complex SIGNOR-272554 0.564 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR1 protein Q92633 UNIPROT up-regulates chemical activation 9606 16014605 t gcesareni Lpa exerts its downstream signaling by binding to the lpa(1), lpa(2), and lpa(3) (formerly edg-2, -4, and -7) family of seven-transmembrane, segmented, heterotrimeric guanine nucleotide-binding protein (g protein)-coupled receptors. SIGNOR-138582 0.8 Melanin-concentrating hormone smallmolecule CHEBI:80254 ChEBI MCHR2 protein Q969V1 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257541 0.8 Immune_response phenotype SIGNOR-PH17 SIGNOR ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. SIGNOR-261035 0.7 DOCK6 protein Q96HP0 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 23462102 t lperfetto Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton. SIGNOR-275670 0.508 F2RL2 protein O00254 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256904 0.2 LRP1B protein Q9NZR2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000038; BTO:0000675 28408316 f irozzo Forced expression of LRP1B in SW480 and SW620 cells inhibited the growth, migration and anchorage-independent growth of cancer cells. SIGNOR-259091 0.7 VHL protein P40337 UNIPROT HIF-1 complex complex SIGNOR-C418 SIGNOR down-regulates ubiquitination 9606 10944113 t miannu Here we show that the product of the von hippel-lindau (vhl) tumor suppressor gene mediated ubiquitylation and proteasomal degradation of hif-1 alpha under normoxic conditions via interaction with the core of the oxygen-dependent degradation domain of hif-1 alpha. SIGNOR-80969 0.682 OPRM1 protein P35372 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256990 0.625 PPM1B protein O75688 UNIPROT CDK2 protein P24941 UNIPROT down-regulates activity dephosphorylation 9606 20538721 t miannu CDK2 can be dephosphorylated and inactivated by protein phosphatase type 2C beta isoform long (PP2Cbetal), a unique phosphatase that was originally cloned from human liver. SIGNOR-277153 0.369 CDK9 protein P50750 UNIPROT XRN2 protein Q9H0D6 UNIPROT up-regulates activity phosphorylation Thr439 FTPSGILtPHALGSR -1 26728557 t miannu Among the RNA processing factors phosphorylated by Cdk9 was the 5'-to-3' "torpedo" exoribonuclease Xrn2, required in transcription termination by Pol II, which we validated as a bona fide P-TEFb substrate in vivo and in vitro. Phosphorylation by Cdk9 or phosphomimetic substitution of its target residue, Thr439, enhanced enzymatic activity of Xrn2 on synthetic substrates in vitro.  SIGNOR-277194 0.281 GIGYF2 protein Q6Y7W6 UNIPROT EIF4E2/GIGYF2 complex complex SIGNOR-C257 SIGNOR form complex binding 9606 BTO:0000568 22751931 t SARA A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development|GIGYF2 interacts specifically with m4EHP. The stabilities of m4EHP and GIGYF2 proteins are coregulated. SIGNOR-261009 0.714 MAPK9 protein P45984 UNIPROT SH3BP5 protein O60239 UNIPROT unknown phosphorylation Ser351 PGSLDLPsPVSLSEF -1 15158451 t miannu we have identified serine 321 as the major site of phosphorylation by both SAPK3 and JNK2. SAPK3 but not JNK2 also phosphorylates serine 391 SIGNOR-250142 0.377 PARP1 protein P09874 UNIPROT KDM5B protein Q9UGL1 UNIPROT up-regulates activity relocalization 9606 33859667 t SaraGualdi The mechanism of KDM5B recruitment is quite specific and requires the presence of nucleosomes containing histone variant MacroH2A1.1 and PARylation by PARP1. SIGNOR-271574 0.361 CDK2 protein P24941 UNIPROT UHRF1 protein Q96T88 UNIPROT down-regulates quantity by destabilization phosphorylation Ser675 KTKVEPYsLTAQQSS -1 26727879 t miannu UHRF1 is phosphorylated by CDK2/cyclin A. In vitro kinase assay was performed with CDK2/cyclin A using recombinant wild-type UHRF1 or UHRF1-S674A mutant  SIGNOR-277192 0.307 BMP7 protein P18075 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates binding 9606 9748228 t acerquone We show that bmp7 and activin bind to the same type ii receptors, actrii and iib, but recruit distinct type i receptors into heteromeric receptor complexes. SIGNOR-60240 0.56 UBIAD1 protein Q9Y5Z9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000362 30518913 f miannu This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells. SIGNOR-256205 0.7 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGC3 protein Q9UN70 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265674 0.2 AGRP protein O00253 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity binding 9606 10318826 t miannu AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor. SIGNOR-252379 0.766 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 12747827 t lperfetto Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e. SIGNOR-235964 0.753 ERBB2 protein P04626 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 8816440 t gcesareni Although erbb-2 binds neither ligand, even in a heterodimeric receptor complex, it is the preferred heterodimer partner of the three other members, and it favors interaction with erbb-3. SIGNOR-147838 0.597 CBP/p300 complex SIGNOR-C6 SIGNOR THBD protein P07204 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15677570 f miannu We further show evidence suggesting that NF-κB inhibits TM expression indirectly by competition for the coactivator p300/CBP. SIGNOR-253908 0.2 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 9606 SIGNOR-C15 19584320 t gcesareni In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-186641 0.483 GSK3B protein P49841 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser137 PVSSPQSsPRLPRRP 9606 22778263 t lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. SIGNOR-198142 0.276 AP1 complex SIGNOR-C154 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates activity 9606 21561061 f Luana AP-1 regulates transcription of many genes involved in viralpathogenesis, including pro-inflammatory and antiviral cytokineslike IL-6,33IL-8,34RANTES,35MCP-1,19interferons,9etc., thatare characteristic of an infection. SARS pathology is the result ofan exacerbated pro-inflammatory immune response by cytokinesin the lungs of patients and in infected animal models. SIGNOR-260765 0.7 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA1 protein Q9Y5H4 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265686 0.2 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Thr310 VPPLPKVtPTKELQQ 9606 BTO:0000142 16733250 t lperfetto Here we report that amphiphysin i (amph i) is also a mnb/dyrk1a substrate. This kinase phosphorylated native amph i in rodent brains and recombinant human amph i expressed in escherichia coli. Serine 293 (ser-293) was identified as the major site, whereas serine 295 and threonine 310 were found as minor kinase sitesamph i phosphorylated by mnb/dyrk1a decreased endophilin binding in vitro. From these results we conclude that amph i at ser-293 is phosphorylated by mnb/dyrk1a and that the phosphorylation has physiological significance in controlling the interaction of amphiphysin with endocytic accessory proteins. SIGNOR-146910 0.405 LRRK2 protein Q5S007 UNIPROT CADPS2 protein Q86UW7 UNIPROT up-regulates quantity transcriptional regulation 9606 28647363 f gianni This approach enabled us to disclose a differential effect of high levels of LRRK2 and aSyn on CADPS2 promoter activity. Specifically, CADPS2 transcriptional activity was enhanced by high cellular levels of LRRK2 and reduced by overexpression of aSyn. Consistently, CADPS2 mRNA levels were diminished in aSyn overexpressing cells. SIGNOR-268928 0.297 GSK3A protein P49840 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000938 9771888 t The effect has been demonstrated using P10636-8 gcesareni Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase. SIGNOR-60651 0.44 TBK1 protein Q9UHD2 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser158 QRMLPSLsLTEDVKW 9606 22412986 t lperfetto Activation of interferon regulatory factor 5 by site specific phosphorylation. Although the gene induction by irf5 in the presence of tbk-1 was modest, phosphorylation by tbk-1 produced a significant shift in the mobility of irf5 in sds-page. For this reason we identified the residues that are phosphorylated on irf5 by tbk-1 with mass spectrometry. Ser-158 and ser-309 were found to be phosphorylated SIGNOR-196528 0.557 MTHFD1 protein P11586 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI up-regulates quantity chemical modification -1 18767138 t lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate SIGNOR-268250 0.8 CSNK2A2 protein P19784 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates activity phosphorylation Thr523 AGSTDENtDSEEHQE 9606 BTO:0000567 15367657 t llicata XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on S518, T519, and T523 largely determines aprataxin binding to XRCC1 though its FHA domain | In addition, we present data to show that the acute loss of aprataxin by small interfering RNA (siRNA) renders HeLa cells sensitive to MMS through a mechanism that destabilizes XRCC1. SIGNOR-251052 0.472 CAMK2A protein Q9UQM7 UNIPROT ETS1 protein P14921 UNIPROT down-regulates phosphorylation Ser251 GKLGGQDsFESIESY 9606 BTO:0000782 12475968 t lperfetto Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition SIGNOR-96330 0.314 UBE2J1 protein Q9Y385 UNIPROT DIO2 protein Q92813 UNIPROT down-regulates quantity by destabilization ubiquitination Lys237 VCIVQRQkIAYLGGK 9606 BTO:0001379 29892818 t scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. SIGNOR-267481 0.387 KU-60019 chemical CID:15953870 PUBCHEM ATM protein Q13315 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193597 0.8 MITF protein O75030 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004595 14982938 f miannu These studies define the VMD2 promoter region sufficient to drive RPE-specific expression in the eye, identify positive regulatory regions in vitro, and suggest that MITF as well as other E-box binding factors may act as positive regulators of VMD2 expression. SIGNOR-254586 0.384 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARA protein P10276 UNIPROT up-regulates activity chemical activation 9606 17132853 t miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. SIGNOR-256194 0.8 PIAS1 protein O75925 UNIPROT DDX5 protein P17844 UNIPROT up-regulates sumoylation Lys53 WNLDELPkFEKNFYQ 9606 17369852 t miannu We demonstrate that the sumo e3 ligase pias1 interacts with p68 and enhances its sumo modification in vivo / sumo modification enhances p68 transcriptional repression activity and inhibits the ability of p68 to function as a coactivator of p53. SIGNOR-153719 0.527 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9606 9405416 t Phosphorylation of c-Jun on Ser73 by JNK is sufficient to protect c-Jun from ubiquitination. lperfetto Phosphorylation by activated jnk protects c-jun from ubiquitination. SIGNOR-53788 0.2 PREX2 protein Q70Z35 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260572 0.434 BTG2 protein P78543 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 21172304 f Androgen-induced promoter activation and expression of prostate-specific antigen (PSA) are significantly attenuated by BTG2. SIGNOR-253658 0.2 HTR1D protein P28221 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257000 0.36 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates phosphorylation 9606 16469705 t gcesareni Here we show that tnfalpha-mediated jnk activation accelerates turnover of the nf-kappab-induced antiapoptotic protein c-flip, an inhibitor of caspase-8. This is not due to direct c-flip phosphorylation but depends on jnk-mediated phosphorylation and activation of the e3 ubiquitin ligase itch, which specifically ubiquitinates c-flip and induces its proteasomal degradation. SIGNOR-144456 0.644 PLK1 protein P53350 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates quantity by destabilization phosphorylation Ser170 KTCRYIPsLPDRILD -1 23643811 t miannu Plk1 directly bound to Cdc20 and phosphorylates it on serine-170 located in CRY-box. Whereas wild-type Cdc20 was degraded according to progress cell cycle beyond mitosis, the phosphorylation-defective mutant, which serine-170 was changed into alanine, was not destroyed in early G1 phase.  SIGNOR-276493 0.976 NDUFB10 protein O96000 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 SIGNOR-262163 0.816 TNKS2 protein Q9H2K2 UNIPROT PSMF1 protein Q92530 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 BTO:0000007 23622245 t lperfetto We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31. SIGNOR-263386 0.474 trichostatin A chemical CHEBI:46024 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257936 0.8 EEF1A2 protein Q05639 UNIPROT Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269536 0.8 SYVN1 protein Q86TM6 UNIPROT SERPINI1 protein Q99574 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21507957 t miannu In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin. SIGNOR-272757 0.2 SOD1 protein P00441 UNIPROT BCL2 protein P10415 UNIPROT up-regulates activity binding 9606 BTO:0001279 15233914 t P00441:p.Gly94Ala (mutation disrupting interaction) Familial amyotrophic lateral sclerosis (ALS)-linked mutations in the copper-zinc superoxide dismutase (SOD1) gene cause motor neuron death in about 3% of ALS cases. While the wild-type (wt) protein is anti-apoptotic, mutant SOD1 promotes apoptosis.|We now demonstrate that both wt and mutant SOD1 bind the anti-apoptotic protein Bcl-2, providing evidence of a direct link between SOD1 and an apoptotic pathway. This interaction is evident in vitro and in vivo in mouse and human spinal cord.|These findings provide new insights into the anti-apoptotic function of SOD1 and suggest that entrapment of Bcl-2 by large SOD1 aggregates may deplete motor neurons of this anti-apoptotic protein. SIGNOR-262799 0.489 FOXO1 protein Q12778 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260090 0.261 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr130 PAQLLCStPNGLDRG 9606 10864927 t lperfetto Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-216769 0.839 DTX1 protein Q86Y01 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity ubiquitination 7227 22162134 t lperfetto The expression of dx, which physically interacts with notch, favors a mono-ubiquitinated state of the receptor, which leads to a ligand-independent intracellular activation of notch SIGNOR-254317 0.772 FBXW7 protein Q969H0 UNIPROT NFKB2 protein Q00653 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002572 22388891 t miannu Fbxw7α is a member of the F-box family of proteins, which function as the substrate-targeting subunits of SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complexes. Using differential purifications and mass spectrometry, we identified p100, an inhibitor of NF-κB signalling, as an interactor of Fbxw7α. p100 is constitutively targeted in the nucleus for proteasomal degradation by Fbxw7α SIGNOR-272907 0.405 FYN protein P06241 UNIPROT CTLA4 protein P16410 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 9973379 t CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218.¬† Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4. SIGNOR-251161 0.761 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser228 EEDTSFEsLSKFNVK 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262718 0.733 miR-495 mirna URS000075C517_9606 RNAcentral Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 26055960 f miannu Our results suggest that activating mutation of FLT3 in AML can lead, through the induction of JUN, to an increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently may causes block of myeloid differentiation. SIGNOR-255801 0.4 PKA proteinfamily SIGNOR-PF17 SIGNOR PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser710 GEKSFRRsVVGTPAY 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275951 0.2 BIRC5 protein O15392 UNIPROT CPC complex SIGNOR-C554 SIGNOR form complex binding 9606 23175282 t miannu It is now known that the chromosomal passenger complex (CPC) is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin (also known as Dasra)5–7 (Figure 1A). SIGNOR-275424 0.793 PTEN protein P60484 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK 9606 22482061 t lperfetto Antisense- or shRNA mediated downregulation of PTEN induced SRC Tyr416 phosphorylation, SRC activation, and ultimately elevated TZMB resistance, whereas induction of PTEN phosphatase activity directly dephosphorylated SRC Tyr416 residue and so abolished SRC activity .|These observations indicate that the loss of PTEN phosphatase activity induces SRC activation and so implicates SRC in shaping de novo TZMB resistance in PTEN deficient cells . SIGNOR-277009 0.552 PPM1F protein P49593 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity dephosphorylation 9606 28906490 t miannu However, our current work shows that POPX2 can downregulate TAK1 and affect the anti-apoptotic activities of TAK1, implying that silencing POPX2 could facilitate TAK1 activation and will lead to increased cell survival.|We have also demonstrated that POPX2 can directly dephosphorylate TAK1 (XREF_FIG). SIGNOR-277047 0.404 IL23R protein Q5VWK5 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 t gcesareni Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12. SIGNOR-87841 0.565 PINK1 protein Q9BXM7 UNIPROT TUFM protein P49411 UNIPROT down-regulates activity phosphorylation Ser219 ETPVIVGsALCALEG 9606 BTO:0000567 33113344 t miannu PINK1 interacts with the autophagy effector TUFm and phosphorylates TUFm at Ser222. These results indicated that p222-hTUFm sequestered more monomer Atg5 and reduced the conjugated Atg5-Atg12 complex to subdue mitophagy. SIGNOR-266382 0.2 FYN protein P06241 UNIPROT FYB1 protein O15117 UNIPROT up-regulates activity phosphorylation Tyr651 LDMGDEVyDDVDTSD 9606 10570256 t  two tyrosines, Tyr595 and Tyr651, of FYB are major sites of phosphorylation by FYN-T and mediate binding to SLP-76 in Jurkat T cells. We further demonstrate that the loss of SLP-76 binding by mutation of these sites markedly reduced the ability of FYN-T-FYB-SLP-76 to up-regulate IL-2 transcription. SIGNOR-251164 0.2 GSK3B protein P49841 UNIPROT CABYR protein O75952 UNIPROT unknown phosphorylation Thr151 PATPKTTtPPSSPPP -1 15752768 t GSK3β interacts with and phosphorylates CABYR in vitro. GSK3β interacts with and phosphorylates CABYR in vitro. the functional extent of the CABYR phosphorylation sites to participate in cellular processes through GSK3β remains to be investigated. SIGNOR-251224 0.41 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 t lperfetto Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes. SIGNOR-233435 0.613 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89272 0.402 CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 15907471 t lperfetto Cytochrome c (Cyt c) is then released from the intermembrane space of the mitochondrion into the cytosol, where it binds to apoptotic protease-activating factor 1 (Apaf-1) in the presence of ATP/dATP to form the apoptosome. SIGNOR-137295 0.785 IL5 protein P05113 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 21106848 f It has been reported that IL-5 family members and selected chemotactic factors can activate the PI3K-Akt pathway in human blood eosinophils SIGNOR-254351 0.405 FOXO proteinfamily SIGNOR-PF27 SIGNOR IGFBP1 protein P08833 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10358076 f miannu Reporter gene studies in hepg2 hepatoma cells show that fkhr stimulates insulin-like growth factor-binding protein-1 promoter activity through an irs SIGNOR-252925 0.2 SUFU protein Q9UMX1 UNIPROT GLIS3 protein Q8NEA6 UNIPROT down-regulates binding 9606 21543335 t fspada These data indicate that the inhibition of glis3-mediated transactivation by sufu appears to rely on the interaction with glis3 through the ygh motif and is not related to an effect on the general transcriptional machinery SIGNOR-173573 0.389 PPP6C protein O00743 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity dephosphorylation Ser828 EHDSAEGsHTSGQSN 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276517 0.334 IGF1R protein P08069 UNIPROT FBN1 protein P35555 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0000951 17200203 f Indirect:regulation of expression miannu Decorin and IGF-I induce fibrillin-1 protein synthesis in normal rat kidney fibroblasts SIGNOR-251863 0.298 Nucleosome_H2A.Z.1 variant complex SIGNOR-C322 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 24311584 f miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. SIGNOR-263713 0.7 ITCH protein Q96J02 UNIPROT H1-2 protein P16403 UNIPROT up-regulates activity polyubiquitination Lys46 PVSELITkAVAASKE 9606 BTO:0000815 30517763 t miannu ITCH interacts with and ubiquitinates linker histone H1.2 at K46. ITCH biochemically competes with RNF168 and RNF8 to polyubiquitinate histone H1.2. The results indicated that ITCH-mediated K46-Ubn is essential for the binding of histone H1.2 to chromatin. SIGNOR-272926 0.2 AKT1 protein P31749 UNIPROT GATA1 protein P15976 UNIPROT up-regulates phosphorylation Ser310 QTRNRKAsGKGKKKR 9606 16107690 t llicata We found that akt directly phosphorylates the transcription factor gata-1 at serine 310 and that this site-specific phosphorylation is required for the transcriptional activation of the timp-1 promoter. SIGNOR-139782 0.528 ABCC9 protein O60706 UNIPROT KATP channel complex SIGNOR-C274 SIGNOR form complex binding 9606 28842488 t lperfetto ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits. SIGNOR-262057 0.62 SNX5 protein Q9Y5X3 UNIPROT IGF2R protein P11717 UNIPROT down-regulates quantity binding 9606 BTO:0000567 32150533 t miannu Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures. SIGNOR-269442 0.551 Guanabenz chemical CHEBI:5553 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258910 0.8 ATM protein Q13315 UNIPROT NKX3-1 protein Q99801 UNIPROT down-regulates quantity by destabilization phosphorylation Thr134 SRAAFSHtQVIELER 9606 BTO:0002181 23890999 t miannu ATM phosphorylates NKX3.1 on T166 and then T134, resulting in NKX3.1 ubiquitination and degradation resulting from an apparent regulatory interaction. SIGNOR-276499 0.37 PAK1 protein Q13153 UNIPROT PXN protein P49023 UNIPROT unknown phosphorylation Ser272 ELDELMAsLSDFKIQ 9606 16717130 t llicata We show that p21-activated kinase (pak)-induced phosphorylation of serine 273 in paxillin is a critical regulator of this turnover. SIGNOR-146842 0.65 MAPK9 protein P45984 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates activity phosphorylation Thr103 LIDATGDtPGAEDDE 9606 BTO:0000298 12756254 t lperfetto Recruitment of jnk to jip1 and jnk-dependent jip1 phosphorylation regulates jnk module dynamics and activation it was observed that phosphorylation by jnk of jip1 on thr-103 and not other phosphorylated jip1 residues is necessary for the regulation of dlk association with jip1, dlk activation, and subsequent module activation. SIGNOR-101201 0.764 TP53 protein P04637 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 27692180 t inferred from family member miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. SIGNOR-270272 0.422 RORA protein P35398 UNIPROT CAV3 protein P56539 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15199055 f Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. SIGNOR-254255 0.2 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1110 GSVQNPVyHNQPLNP 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-236516 0.2 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser567 SSSRRRRsSSTAPPT 9606 16513649 t llicata Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization SIGNOR-145032 0.2 LLGL1 protein Q15334 UNIPROT Scribble_complex_DLG3-LLGL1_variant complex SIGNOR-C507 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270895 0.578 SLC9A3 protein P48764 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265602 0.8 BCL7B protein Q9BQE9 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270721 0.461 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR JUN protein P05412 UNIPROT down-regulates activity 9606 BTO:0000801 10973958 f lperfetto NF-kB-, AP-1-, and Smad3-driven promoters all require p300/CREB-binding protein for their transactivation. Previous studies have suggested that NF-kB- and AP-1-driven promoters can be inhibited by competitive recruitment of coactivators such as p300/CPB to other unrelated promoters. We hypothesized that NF-kB and AP-1 compete with Smad3 for limiting quantities of p300. This hypothesis predicts that added p300 should alleviate TGF-b1/Smad3-mediated inhibition of inflammatory genes. Conversely, increasing doses of TGF-b1/Smad3 would compete away even overexpressed p300 from NF-kB/AP- 1-driven promoters. SIGNOR-249557 0.702 dabrafenib chemical CHEBI:75045 ChEBI LIMK1 protein P53667 UNIPROT down-regulates activity chemical inhibition -1 24720932 t miannu Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations SIGNOR-259216 0.8 CRX protein O43186 UNIPROT RHO protein P08100 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 f miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. SIGNOR-253820 0.483 ETV4 protein P43268 UNIPROT VIM protein P08670 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093;BTO:0000815 8895512 f miannu Our results suggest that PEA3 specifically transactivates vimentin promoter through PEA3 site. Among members of the ETS transcription factor family only Erg showed ability to transactivate vimentin promoter besides PEA3. SIGNOR-254070 0.2 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation Ser463 SPHNPISsVS 9606 BTO:0000416 9136927 t lperfetto Here, we report that BMP receptors phosphorylate and activate Smad1 directly. Phosphorylation of Smad1 in vivo involves serines in the carboxy-terminal motif SSXS. These residues are phosphorylated directly by a BMP type I receptor in vitro SIGNOR-217985 0.651 PRKAA1 protein Q13131 UNIPROT INSIG1 protein O15503 UNIPROT up-regulates quantity by stabilization phosphorylation Thr222 ITIAFLAtLITQFLV 9606 BTO:0000007 30733434 t miannu Here we report that AMPK interacts with and mediates phosphorylation of Insig. Thr222 phosphorylation following AMPK activation is required for protein stabilization of Insig-1, inhibition of cleavage and processing of SREBP-1, and lipogenic gene expression in response to metformin or A769662. AMPKα1 subunit associates with Insig-1 in a dose-dependent manner. SIGNOR-277430 0.259 CHUK protein O15111 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser177 AKELDQGsLCTSFVG -1 10022904 t llicata Our data indicate that IKKα stimulates IKKβ kinase activity for the IκBα substrate. Finally, we demonstrate that IKKα can phosphorylate IKKβ in in vitro kinase assays. SIGNOR-250771 0.656 SLC12A3 protein P55017 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity phosphorylation 21613606 t lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  SIGNOR-264633 0.8 PRKCZ protein Q05513 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 BTO:0000938 BTO:0000671 9679146 t gcesareni These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc. SIGNOR-59303 0.2 MYC protein P01106 UNIPROT HECTD4 protein Q9Y4D8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 32814769 t miannu We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. SIGNOR-267144 0.2 IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 15864272 t gcesareni The only type ii ifn, ifn-, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2 SIGNOR-135955 0.703 ITGAM protein P11215 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 12393465 f apalma CD11b, another marker for differentiation, was also less expressed in patients with t(8;21) in comparison to patients without t(8;21) SIGNOR-255662 0.7 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI 5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-) smallmolecule CHEBI:77657 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). SIGNOR-267316 0.8 MAPK3 protein P27361 UNIPROT KARS1 protein Q15046 UNIPROT up-regulates phosphorylation Ser207 PYEITLLsPCLHMLP 9606 19524539 t gcesareni Lysrs serves as a key signaling molecule in the immune response by regulating gene expression. Lysrs was phosphorylated on serine 207 in a mapk-dependent manner, released from the multisynthetase complex, and translocated into the nucleus. SIGNOR-186125 0.2 N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI acetic acid smallmolecule CHEBI:15366 ChEBI up-regulates quantity precursor of 9606 17194761 t miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. SIGNOR-268085 0.8 ATM protein Q13315 UNIPROT SMC3 protein Q9UQE7 UNIPROT unknown phosphorylation Ser1083 ESERGSGsQSSVPSV 9606 18442975 t llicata Ser-1083 phosphorylation is ir-inducible, depends on atm and nijmegen breakage syndrome 1 (nbs1), and is required for intra-s phase checkpoint. SIGNOR-178479 0.731 HDAC5 protein Q9UQL6 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates binding 9606 11062529 t gcesareni The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis. SIGNOR-84029 0.698 POLR2G protein P62487 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266165 0.869 RIMBP3C protein A6NJZ7 UNIPROT RIMS2 protein Q9UQ26 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264367 0.268 MAPK3 protein P27361 UNIPROT NCKIPSD protein Q9NZQ3 UNIPROT up-regulates phosphorylation 9606 14559906 t gcesareni Spin90 was phosphorylated by erk1, which was, itself, activated by cell adhesion and platelet-derived growth factor. Such phosphorylation of spin90 likely promotes the interaction of the spin90.betapix.wasp complex and nck SIGNOR-118747 0.432 PPM1L protein Q5SGD2 UNIPROT CERT1 protein Q9Y5P4 UNIPROT up-regulates activity dephosphorylation 9606 18165232 t miannu The expression of PP2Cepsilon also enhanced the association between CERT and VAPA.|These results suggest that CERT is a physiological substrate of PP2Cepsilon and that dephosphorylation of CERT by PP2Cepsilon may play an important role in the regulation of ceramide trafficking from the ER to the Golgi apparatus. SIGNOR-277113 0.2 PPP1CA protein P62136 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser77 YEPEGSAsPTPPYLK 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248552 0.339 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 10980595 t lperfetto We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway SIGNOR-244692 0.2 AKAP12 protein Q02952 UNIPROT PKC proteinfamily SIGNOR-PF53 SIGNOR up-regulates activity relocalization 14657015 t lperfetto A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. SIGNOR-271838 0.471 DUSP6 protein Q16828 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates activity dephosphorylation Ser256 SPRRRAAsMDNNSKF 9606 22848439 t lperfetto It has been previously demonstrated that MKP-3 dephosphorylates FOXO1 on Ser256 and promotes nuclear translocation of FOXO1 , which subsequentially binds to the promoters of gluconeogenic genes and turns on the gluconeogenic program.|We also reported that MKP-3 can activate FOXO1 by at least dephosphorylating Ser 256, one of the Akt phosphorylation sites xref . SIGNOR-276983 0.439 UBE2I protein P63279 UNIPROT FOS protein P01100 UNIPROT down-regulates activity sumoylation Lys265 SISSMELkTEPFDDF 9606 SIGNOR-C154 16055711 t lperfetto We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. SIGNOR-263013 0.373 ENO1 protein P06733 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9534 BTO:0000318 2005901 t Luana This result suggests that MBP-1 in vivo acts as a sequence-specific repressor. SIGNOR-261594 0.421 PKA proteinfamily SIGNOR-PF17 SIGNOR DNM1L protein O00429 UNIPROT down-regulates activity phosphorylation Ser637 VPVARKLsAREQRDC -1 31063459 t lperfetto For example, protein kinase A (PKA) phosphorylation of Drp1S600 has been reported to decrease Drp1 GTPase activity in vitro (23, 24), whereas phosphorylation of the same conserved serine residue by Ca2+-calmodulin–dependent protein kinase Iα (CaMKIα) in Drp1 isoform 3 has been reported to cause a significant increase in mitochondrial fission SIGNOR-262551 0.2 CSNK2A1 protein P68400 UNIPROT TOP2A protein P11388 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1365 TKTSPKLsNKELKPQ 9606 BTO:0003492 21254166 t miannu  This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361. SIGNOR-276300 0.613 RUNX2 protein Q13950 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates binding 9606 20551513 t gcesareni Mechanistic analysis revealed that the tak1-mkk3/6-p38 mapk axis phosphory-lated runx2, promoting its association with the coac-tivator creb-binding protein (cbp), which is re-quired to regulate osteoblast genetic programs. SIGNOR-166170 0.416 NKX3-1 protein Q99801 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 16697957 t miannu NKX3.1 negatively regulates AKT activity in an AR-dependent manner SIGNOR-251552 0.502 DOK3 protein Q7L591 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0000776 32323266 t scontino An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling. SIGNOR-268448 0.57 RNF111 protein Q6ZNA4 UNIPROT AP2M1 protein Q96CW1 UNIPROT up-regulates ubiquitination 9606 20965945 t gcesareni Arkadia ubiquitylated the _?2 Subunit at lys130. In addition, arkadia interacted with the ap2 complex, and modified endocytosis of epidermal growth factor receptor (egfr) induced by egf. Arkadia thus appears to regulate egf signalling by modulating endocytosis of egfr through interaction with ap2 complex. SIGNOR-168931 0.2 JAG1 protein P78504 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 7227 18660822 t Binding Ca-dependent lperfetto We identify functional fragments of human notch-1 (n-1) and jagged-1 (j-1) which interact in a calcium-dependent manner. SIGNOR-219253 0.627 SAGA complex complex SIGNOR-C465 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity acetylation 9606 34811519 t lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269627 0.2 SMO protein Q99835 UNIPROT GNAI2 protein P04899 UNIPROT up-regulates activity binding 9606 23074268 t lperfetto it was proposed that Smo might signal through activation of Gi proteins to reduce PKA activity. SIGNOR-199162 0.404 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT1 protein P31749 UNIPROT down-regulates activity chemical inhibition 25309440 t lperfetto Different agents were used to inhibit either the PI3K/Akt or MEK/ERK pathways. The PI3K inhibitor, LY294002, and the Akt inhibitor, Akt inhibitor VIII, were used to inhibit the PI3K/Akt pathway. SIGNOR-262010 0.8 PAX7-FOXO1 fusion protein SIGNOR-FP11 SIGNOR MET protein P08581 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 t miannu Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA. SIGNOR-251566 0.2 sorafenib tosylate chemical CHEBI:50928 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. SIGNOR-259224 0.8 CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 15657060 t lperfetto Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3. SIGNOR-133267 0.623 DDIT3 protein P35638 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity transcriptional regulation 10090 7588595 t We find that expression of CHOP, a nuclear protein that dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process. SIGNOR-255913 0.533 PPP1CB protein P62140 UNIPROT CASP2 protein P42575 UNIPROT up-regulates activity dephosphorylation Ser164 STDTVEHsLDNKDGP -1 19531356 t llicata Nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2. SIGNOR-248576 0.2 SCF-betaTRCP complex SIGNOR-C5 SIGNOR NFKB2 protein Q00653 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000567 14676825 t lperfetto Mechanism of processing of the nf-kappa b2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of nedd8-modification on the scf(beta-trcp) ubiquitin ligase. SIGNOR-217175 0.534 MDM2 protein Q00987 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001061 14761977 t miannu  MDM2 facilitates p21 degradation independent of ubiquitination and the E3 ligase function of MDM2. Instead, MDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8 subunit. The physical interaction between p21 and MDM2 was demonstrated both in vitro and in vivo with the binding region in amino acids 180-298 of the MDM2 protein. SIGNOR-272954 0.663 MAPK9 protein P45984 UNIPROT MYC protein P01106 UNIPROT up-regulates phosphorylation Ser62 LLPTPPLsPSRRSGL 9606 10551811 t gcesareni The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71. SIGNOR-72104 0.366 CSNK2A1 protein P68400 UNIPROT EXOSC9 protein Q06265 UNIPROT up-regulates phosphorylation Ser392 QDAPIILsDSEEEEM 9606 19217413 t lperfetto Indeed recombinant pmscl1 undergoes ck2-mediated phosphorylation in vitro at various serine residues, including serines 409 and 411, which reside within the phosphosim region. the exchange of hydrophobic core residues or serines 409 and 411 to alanine attenuates binding of sumo to the phosphosim-containing fragment of pmscl1 in a yeast two-hybrid assay SIGNOR-184031 0.2 Caspase 3 complex complex SIGNOR-C221 SIGNOR IKBKB protein O14920 UNIPROT down-regulates cleavage Asp242 VRQKSEVdIVVSEDL 9606 11741536 t gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. SIGNOR-256441 0.372 ERG protein P11308 UNIPROT ENG protein P17813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22235125 f miannu It has been shown that ERG is a positive regulator of several EC-restricted genes including VE-cadherin, endoglin, and von Willebrand factor, and a negative regulator of other genes such as interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1. SIGNOR-253916 0.2 CROCC protein Q5TZA2 UNIPROT Centrosome_separation phenotype SIGNOR-PH177 SIGNOR down-regulates 9606 BTO:0000567 24035387 t miannu C-Nap1 and rootletin have been previously reported to be the important centrosome linker components involved in centrosome cohesion. SIGNOR-273706 0.7 AP-3 complex complex SIGNOR-C247 SIGNOR AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 t lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-260668 0.457 ponatinib chemical CHEBI:78543 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 23430109 t lperfetto AP24534 also inhibited SRC (IC50: 5.4 nM) and members of the VEGFR, FGFR, and PDGFR families of receptor tyrosine kinases (Table 1 and Table S1) SIGNOR-261985 0.8 DZIP3 protein Q86Y13 UNIPROT H2AC21 protein Q8IUE6 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHKP 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271758 0.2 CSNK1A1L protein Q8N752 UNIPROT GLI2 protein P10070 UNIPROT up-regulates phosphorylation 9606 16481469 t gcesareni Gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed SIGNOR-144551 0.339 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 17419683 t gcesareni Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms. SIGNOR-154285 0.2 H4C1 protein P62805 UNIPROT Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR form complex binding -1 21812398 t miannu The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. SIGNOR-263722 0.2 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 1303753 t gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. SIGNOR-16247 0.563 ATM protein Q13315 UNIPROT TDP1 protein Q9NUW8 UNIPROT up-regulates phosphorylation Ser81 PKRQKSGsQEDLGWC 9606 19851285 t lperfetto Optimal function of the dna repair enzyme tdp1 requires its phosphorylation by atm and/or dna-pk. Here we show that top1-associated dna double-stranded breaks (dsbs) induce the phosphorylation of tdp1 at s81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (atm) and dna-dependent protein kinase (dna-pk) SIGNOR-188772 0.558 phosphatidic acid smallmolecule CHEBI:16337 ChEBI CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI up-regulates quantity precursor of 9606 25375833 t lperfetto CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). SIGNOR-267022 0.8 EPAS1 protein Q99814 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271584 0.2 PRKCA protein P17252 UNIPROT GRIA4 protein P48058 UNIPROT unknown phosphorylation Thr850 EAKRMKLtFSEAIRN -1 10366608 t lperfetto In addition, we identified threonine 830 as a potential PKC phosphorylation site. SIGNOR-249017 0.551 PLK1 protein P53350 UNIPROT TERF1 protein P54274 UNIPROT up-regulates phosphorylation Ser435 KKLKLISsDSED 9606 18625707 t lperfetto Plk1 phosphorylation of trf1 is essential for its binding to telomeres SIGNOR-179461 0.381 HDAC1 protein Q13547 UNIPROT BHC complex complex SIGNOR-C353 SIGNOR form complex binding 9606 BTO:0000567; BTO:0000007 15325272 t miannu BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells SIGNOR-264500 0.716 CTDSPL protein O15194 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser208 DAGSPNLsPNPMSPA 9606 BTO:0000007 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248307 0.399 AURKB protein Q96GD4 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates phosphorylation Ser894 RYHKRTSsAVWNSPP 9606 12925766 t gcesareni Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites. SIGNOR-118015 0.973 MARK2 protein Q7KZI7 UNIPROT KIF13B protein Q9NQT8 UNIPROT down-regulates activity phosphorylation Ser1381 KLSRRSIsSPNVNRL 9534 BTO:0000298 20194617 t miannu We report here the identification of GAKIN/KIF13B as a novel in vivo substrate for Par1b and present evidence that GAKIN/KIF13B plays a critical role in axon formation in neurons, which is negatively regulated by Par1b-mediated phosphorylation. Par1b phosphorylates GAKIN/KIF13B at both Ser1381 and Ser1410. SIGNOR-262955 0.425 SYK protein P43405 UNIPROT BTK protein Q06187 UNIPROT up-regulates activity phosphorylation Tyr551 RYVLDDEyTSSVGSK 9606 11226282 t lperfetto We have demonstrated that BLNK mediates Syk-dependent Btk activation. In a reconstitution cell system, coexpression of BLNK allows Syk to phosphorylate Btk on its tyrosine 551, leading to the enhancement of Btk activity. SIGNOR-247586 0.571 PCCB protein P05166 UNIPROT PCC complex SIGNOR-C414 SIGNOR form complex binding 9606 15890657 t miannu Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively. SIGNOR-267183 0.887 PLK3 protein Q9H4B4 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser198 SDELMEFsLKDQEAK 9606 14968113 t lperfetto Cdc25c phosphorylation on serine 191 by plk3 promotes its nuclear translocation SIGNOR-122094 0.72 H4C1 protein P62805 UNIPROT Nucleosome_H2A.Z.2 variant complex SIGNOR-C323 SIGNOR form complex binding -1 24311584 t miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. SIGNOR-263712 0.2 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR IFNAR complex SIGNOR-C243 SIGNOR up-regulates activity binding 9606 11278538 t miannu Interferons have antiviral, antigrowth and immunomodulatory effects. The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex. SIGNOR-260331 0.2 LAMTOR3 protein Q9UHA4 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates binding 9606 15547943 t gcesareni We analyzed the ability of mp1 to bind to mek1, erk1, and to itself, and the regulation of these interactions. Gel filtration of cell lysates revealed two major mp1 peaks: a broad high molecular weight peak and a 28 kda complex. An mp1 mutant that lost mek1 binding no longer enhanced rasv12-stimulated erk1 activity, and functioned as a dominant negative, consistent with the concept that mp1 function depends on facilitating these oligomerizations. SIGNOR-130924 0.599 FGF13 protein Q92913 UNIPROT SCN1A protein P35498 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253419 0.281 6alpha-methylprednisolone chemical CHEBI:6888 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 9259419 t rheumatoid arthritis gcesareni SIGNOR-251695 0.8 ARHGEF1 protein Q92888 UNIPROT RHOA protein P61586 UNIPROT up-regulates guanine nucleotide exchange factor 9606 BTO:0000887;BTO:0001260 10836144 t gcesareni Rhogefs catalyze the exchange of gdp for gtp and thereby activate rho. SIGNOR-77914 0.825 ZDHHC2 protein Q9UIJ5 UNIPROT AKAP5 protein P24588 UNIPROT up-regulates activity palmitoylation Cys36 KEKASMLcFKRRKKA 10116 BTO:0004553 25589740 t Here, we report that the recycling endosome-resident palmitoyl acyltransferase DHHC2 interacts with and palmitoylates AKAP79/150 to regulate these plasticity signaling mechanisms SIGNOR-262295 0.337 PTK2 protein Q05397 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 21454698 t llicata Focal adhesion kinase (fak) binds ret kinase via its ferm domain, priming a direct and reciprocal ret-fak transactivation mechanism. following gdnf stimulation, increased phosphorylation of fak at tyr-576/577 as well as phosphorylation of ret at tyr-905 was observed. SIGNOR-173009 0.623 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 f miannu Smad4 interacted withSmad2/3 and participated in the transcription of downstream pro-fi-brotic target genes SIGNOR-260440 0.7 CDK1 protein P06493 UNIPROT KDM5B protein Q9UGL1 UNIPROT down-regulates activity phosphorylation Ser1456 FKLERERsYELVRSA 9606 BTO:0000815 31776402 t lperfetto Phosphorylation of the histone demethylase KDM5B and regulation of the phenotype of triple negative breast cancer|Here, we demonstrate that KDM5B is phosphorylated at Ser1456 by the cyclin-dependent kinase 1 (CDK1). Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes. SIGNOR-273435 0.261 AMPD1 protein P23109 UNIPROT ammonium smallmolecule CHEBI:28938 ChEBI up-regulates quantity chemical modification 9606 BTO:0001103 1631143 t miannu AMP deaminase (AMPD; EC 3.5.4.6) is encoded by a multigene family in mammals. The AMPD1 gene is expressed at high levels in skeletal muscle, where this enzyme is thought to play an important role in energy metabolism. AMP deaminase (AMPD; EC 3.5.4.6), an enzyme that catalyzes deamination of AMP to IMP, and the purine nucleotide cycle, of which AMPD is one component, play a central role in purine nucleotide interconversion in eukaryotic cells. SIGNOR-269775 0.8 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273048 0.556 CAMK2A protein Q9UQM7 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates activity phosphorylation Ser521 WTNRLYEsFKASDPL -1 21642394 t miannu In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475. SIGNOR-276329 0.2 POU5F1 protein Q01860 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254939 0.759 APLNR protein P35414 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256960 0.255 GADD45A protein P24522 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates binding 9606 20626350 t gcesareni Gadd45alfa appears to act as an endogenous inhibitor of the alternative p38alfa-activation pathway in t-cell, by binding to p38alfa and preventing tyr323 phosphorilation SIGNOR-166584 0.473 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 10428798 t lperfetto Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity. SIGNOR-217288 0.429 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates phosphorylation 9606 BTO:0000150 10931950 t inferred from 70% family members gcesareni These data suggest that increased signaling by erbb receptors up-regulates mapk activity, which, in turn, phosphorylates and destabilizes p27, thus contributing to dysregulated cell cycle progression. SIGNOR-270087 0.2 Noncanonical PRC1 complex SIGNOR-C151 SIGNOR CDK1 protein P06493 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000011 25533466 f miannu We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis. SIGNOR-252249 0.525 CBX5 protein P45973 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-264488 0.2 COPS6 protein Q7L5N1 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270767 0.925 BIRC3 protein Q13489 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 18570872 t amattioni In this report, we show that ciap1 and ciap2 promote cancer cell survival by functioning as e3 ubiquitin ligases that maintain constitutive ubiquitination of the rip1 adaptor protein. SIGNOR-179104 0.737 SMARCC2 protein Q8TAQ2 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 t miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270616 0.823 FOXO6 protein A8MYZ6 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260103 0.2 FGFR2 protein P21802 UNIPROT GRB2 protein P62993 UNIPROT up-regulates phosphorylation 9606 22726438 t gcesareni Inhibition of basal fgf receptor signaling by dimeric grb2. SIGNOR-197980 0.764 CDK11A protein Q9UQ88 UNIPROT CDK11B protein P21127 UNIPROT up-regulates phosphorylation Thr726 KHEYFREtPLPIDPS 9606 21078675 t lperfetto Overall, our data indicated that thr-370 is responsible for the autophosphorylation, dimerization, and kinase activity of cdk11(p58) SIGNOR-169628 0.31 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser343 TRLEPVYsPPGSPPP 9606 BTO:0000567 10806207 t llicata Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity. SIGNOR-77208 0.587 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity binding 9606 24710148 t lperfetto The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-236369 0.793 SLC16A3 protein O15427 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 26384349 f lperfetto Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival. SIGNOR-256581 0.7 CDK5 protein Q00535 UNIPROT DRD2 protein P14416 UNIPROT down-regulates activity phosphorylation Ser321 GLHSTPDsPAKPEKN 9606 24391960 t miannu These results indicate that Cdk5-mediated phosphorylation of S321 inhibits DRD2 function, providing a novel regulatory mechanism for dopamine signaling. SIGNOR-259401 0.392 SGK1 protein O00141 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates activity phosphorylation Ser274 LERERPLsLLQLLGS 8355 BTO:0000887 17382906 t lperfetto We evaluated the putative role of sgk1 in the modulation of glut4. Coexpression of the kinase along with glut4 in xenopus oocytes stimulated glucose transport. The enhanced glut4 activity was paralleled by increased transporter abundance in the plasma membrane. Disruption of the sgk1 phosphorylation site on glut4 ((s274a)glut4) abrogated the stimulating effect of sgk1. In summary, sgk1 promotes glucose transporter membrane abundance via glut4 phosphorylation at ser274. SIGNOR-236653 0.318 PRKG2 protein Q13237 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Ser557 AKASRTSsKHKEDVY 9606 BTO:0002181 21177494 t miannu  PKGII directly phosphorylated and stimulated SHP-1 activity SIGNOR-276287 0.2 Calcineurin complex SIGNOR-C155 SIGNOR PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 t In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. SIGNOR-252334 0.388 INO80B protein Q9C086 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270846 0.637 NFATC2 protein Q13469 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates binding 9606 11796223 t lperfetto Upon dephosphorylation by calcineurin, nfatc2, also referred to as nfatp/nfat1, translocates to the nucleus where it directly associates with mef2a and -d. Nfatc2 stimulates mef2-dependent transcription by facilitating recruitment of the p300 coactivator to mef2-response elements. SIGNOR-117586 0.395 BID protein P55957 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 17289999 t gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome c. these data support a two-class model for bh3 domains: bid-like domains that activate bax, bak and bad-like domains that sensitize by occupying the pocket of antiapoptotic members. SIGNOR-152992 0.816 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1647 SPSYSPTsPSYSPTS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248806 0.849 DUSP3 protein P51452 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR 9534 BTO:0004055 10224087 t Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2 SIGNOR-248536 0.659 (D-Ala(2)-mephe(4)-gly-ol(5))enkephalin chemical CHEBI:272 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258784 0.8 CSNK1A1 protein P48729 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates activity binding 9606 19293931 t lperfetto In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)] SIGNOR-227964 0.658 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-141420 0.2 MRE11 protein P49959 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 18854157 t gcesareni One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase. SIGNOR-181628 0.2 Non-erythrocytic spectrin complex SIGNOR-C385 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates binding 9606 24302288 t lperfetto Spectrin is a member of the F-actin-crosslinking protein superfamily. SIGNOR-266031 0.7 NMBR protein P28336 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 8026589 t fspada G-proteins of the q family have been implicated as mediators of bombesin receptors action. This suggests that nmb-r couples to g?q, and that grp-r and nmb-r show distinct g-protein coupling preferences in the xenopus oocyte. SIGNOR-35864 0.449 PHF2 protein O75151 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 BTO:0000007 21532585 t miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. SIGNOR-264516 0.2 IFNG protein P01579 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates 9606 BTO:0001760 11009425 f gcesareni In contrast, in differentiated myotubes, tnf plus interferon-gamma (ifn-gamma) signaling was required for nf-kappab-dependent down-regulation of myod and dysfunction of skeletal myofibers. SIGNOR-82467 0.294 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR JUNB protein P17275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9694870 f lperfetto Here we report the identification of Smad Binding Elements (SBEs) composed of the sequence CAGACA in the promoter of the JunB gene, an immediate early gene that is potently induced by TGF-beta, activin, and bone morphogenetic protein (BMP) 2. Two JunB SBEs are arranged as an inverted repeat that is transactivated in response to Smad3 and Smad4 co-overexpression and shows inducible binding of a Smad3- and Smad4-containing complex in nuclear extracts from TGF-beta-treated cells. SIGNOR-59476 0.56 SREBF1 protein P36956 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 t inferred from family member gcesareni Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk) SIGNOR-270288 0.339 MECP2 protein P51608 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by repression transcriptional regulation 11865062 f We have established that methyl-CpG binding protein 2 (MeCP2) is involved in methylation-dependent silencing of human MDR1 in cells that lack the known transcriptional repressors MBD2 and MBD3. In the repressed state the MDR1 promoter is methylated and assembled into chromatin enriched with MeCP2 and deacetylated histone. TSA induced significant acetylation of histones H3 and H4 but did not activate transcription. 5aC induced DNA demethylation, leading to the release of MeCP2, promoter acetylation, and partial relief of repression SIGNOR-254033 0.2 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 21620960 t gcesareni Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. SIGNOR-252515 0.754 ARPC3 protein O15145 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 t The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc SIGNOR-251516 0.963 YY1 protein P25490 UNIPROT POSTN protein Q15063 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21839814 f miannu In this study we demonstrate that the ability of the human POSTN promoter to drive transcription mostly depends on the activity of YingYang-1 (YY1) zinc finger transcription factor. YY1, whose regulatory role in biology includes, besides transcriptional control, also chromatin remodeling, DNA damage repair and tumorigenesis, acts as a strong negative modulator of the POSTN expression. SIGNOR-255621 0.2 BAZ2B protein Q9UIF8 UNIPROT H3-5 protein Q6NXT2 UNIPROT down-regulates activity binding 9606 acetylation:Lys15 ARKSTGGkAPRKQLA 31999386 t miannu The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation. SIGNOR-266621 0.2 STK24 protein Q9Y6E0 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Thr444 DWVFINYtYKRFEGL 9606 BTO:0000007 16314523 t lperfetto Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity. SIGNOR-142467 0.39 ATP6V1H protein Q9UI12 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 10090 BTO:0004122 29782852 t miannu ATP6V1H interacts with TGF-β receptor I and AP-2 complex to regulate the proliferation and differentiation of BMSCs. SIGNOR-266886 0.2 CHEK1 protein O14757 UNIPROT E2F3 protein O00716 UNIPROT up-regulates phosphorylation Ser124 PALGRGGsGGGGGPP 9606 19917728 t llicata These results suggest that e2f3a is directly phosphorylated by chk kinases and that the phosphorylation of serine 124 is required for the posttranslational induction of e2f3a protein by chemotherapy. SIGNOR-161758 0.334 Calcineurin complex SIGNOR-C155 SIGNOR Chemorepulsion_of_axon phenotype SIGNOR-PH198 SIGNOR up-regulates 9606 15363394 f miannu In this study, we have identified CaMKII and CaN-PP1 as the downstream effectors of localized Ca2+ signals in mediating attractive and repulsive turning responses of growth cones, respectively. Local Ca2+ elevation activates CaMKII and CaN-PP1 for attraction and repulsion, respectively. SIGNOR-268386 0.7 HOOK3 protein Q86VS8 UNIPROT MARCO protein Q9UEW3 UNIPROT down-regulates binding 9606 BTO:0000801 17237231 t miannu We have identified a microtubule-binding protein, hook3, as a novel interacting partner of sr-a. / by transfecting small interfering rna targeting hook3, total and surface expression, receptor-mediated ligand uptake and protein stability of sr-a were significantly promoted, whereas the protein synthesis and maturation were not altered. We propose for the first time that hook3 may participate in the turnover of the endocytosed scavenger receptor SIGNOR-152268 0.2 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 9606 BTO:0000130 12056906 t esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. SIGNOR-89241 0.458 PPP2CA protein P67775 UNIPROT RB1 protein P06400 UNIPROT up-regulates dephosphorylation 9606 10702384 t gcesareni This dephosphorylation returns prb to its active, growth suppressive state. SIGNOR-75398 0.484 MAPK1 protein P28482 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Thr753 YACASPKtPIQAGGY 10116 BTO:0001009 16508002 t lperfetto Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity. SIGNOR-236388 0.613 CCAN complex complex SIGNOR-C365 SIGNOR Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 9606 18007590 f lperfetto Based on our results, we propose that the cooperative action of CENP-A NAC/CAD subunits and the KMN network drives efficient chromosome segregation and bipolar spindle assembly during mitosis. SIGNOR-265214 0.7 HNF1A protein P20823 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 8383844 f inferred from family member miannu Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators SIGNOR-270224 0.316 MTA1 protein Q13330 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000812 18719363 f miannu MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG. SIGNOR-254594 0.423 HRH2 protein P25021 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257424 0.252 WNT10B protein O00744 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131631 0.605 protriptyline chemical CHEBI:8597 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 9537821 t miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. SIGNOR-258737 0.8 PAK1 protein Q13153 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser174 KGMLARGsYSIKSRF 9606 15225553 t lperfetto Pak1 binds and phosphorylates rhogdi both in vitro and in vivo at ser101 and ser174. This resulted in dissociation of rac1-rhogdi, but not rhoa-rhogdi, complexes, as determined by in vitro assays of complexation and in vivo by coimmunoprecipitation analysis. We observed that cdc42-induced rac1 activation is inhibited by expression of pak1 autoinhibitory domain. The dissociation of rac1 from rhogdi and its subsequent activation stimulated by pdgf or egf is also attenuated by pak1 autoinhibitory domain, and this is dependent on the ability of rhogdi to be phosphorylated at ser101/174. SIGNOR-126654 0.595 RNF167 protein Q9H6Y7 UNIPROT SLC22A18 protein Q96BI1 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 16314844 t miannu  Here, we present evidences indicating that RING105, a novel conserved RING-finger protein with a PA (protease-associated) domain and a PEST sequence, is a ubiquitin ligase for TSSC5 that can function in concert with the ubiquitin-conjugating enzyme UbcH6. The polyubiquitin target site on TSSC5 was mapped to a region in the 6th hydrophilic loop. SIGNOR-271551 0.54 AKT1 protein P31749 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 t gcesareni Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no. SIGNOR-112363 0.873 PRKD1 protein Q15139 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 22865920 t lperfetto When phosphorylated by camk/pkd, class iia hdacs bind 14-3-3 chaperone proteins, which facilitates their nuclear export, thereby relieving hdac-mediated transcriptional repression. SIGNOR-198662 0.531 E2F1 protein Q01094 UNIPROT CCNE1 protein P24864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8649818 f lperfetto We have found that cell cycle regulation of cyclin E transcription is mediated by E2F binding sites present in the promoter. The activity of this promoter can be regulated negatively by pRB. SIGNOR-245474 0.67 HIF-1 complex complex SIGNOR-C418 SIGNOR SLC2A3 protein P11169 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 t miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. SIGNOR-267451 0.366 BRD4 protein O60885 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 9606 32482868 t lperfetto We report that BRD4 phosphorylates MYC at Thr58, leading to MYC ubiquitination and degradation, thereby regulating MYC target genes. SIGNOR-262046 0.578 CSNK2B protein P67870 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser230 VTPSKSTsASAIMNG 9606 BTO:0000938 26917740 t lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. SIGNOR-275745 0.273 methotrexate chemical CHEBI:44185 ChEBI DHFR protein P00374 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0004254 23581023 t miannu Methotrexate, a structural analogue of folic acid, is one of the most frequently used chemotherapeutics, especially in haematological malignancies, various solid tumours and also inflammatory disorders. Methotrexate interferes with folate metabolism, mainly by inhibition of dihydrofolate reductase, resulting in the suppression of purine and pyrimidine precursor synthesis. SIGNOR-258481 0.8 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser155 FPLRKTVsEPNLKLR -1 15738054 t lperfetto We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro. SIGNOR-249275 0.491 PRKCD protein Q05655 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation Ser221 QAQRFRFsPMGVDHM 9606 20086103 t lperfetto Tandem phosphorylation of serines 221 and 318 by protein kinase cdelta coordinates mrna binding and nucleocytoplasmic shuttling of hurstabilization of mrna by the ubiquitous rna binding protein human antigen r (hur), a member of the embryonic lethal abnormal vision (elav) protein family, requires canonical binding to au-rich element (are)-bearing target mrna and export of nuclear hur-mrna complexes to the cytoplasm. In human mesangial cells (hmc) both processes are induced by angiotensin ii (angii) via protein kinase cdelta (pkcdelta)-triggered serine phosphorylation of hur. SIGNOR-163524 0.622 PPP2R5C protein Q13362 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 9606 7592815 t We have identified by two-hybrid interaction a new human gene family encoding PP2A B subunits. This family, denoted B56, contains three distinct genes, one of which is differentially spliced. SIGNOR-268155 0.859 afatinib chemical CHEBI:61390 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0000551 22452896 t Like lapatinib and neratinib, afatinib is a next generation tyrosine kinase inhibitor (TKI) that irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases. gcesareni Afatinib, an irreversible erbb-family blocker, has shown preclinical activity when tested in egfr mutant models with mutations that confer resistance to egfr tyrosine-kinase inhibitors. SIGNOR-196760 0.8 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser287 WEPPGRAsPSQGSSP 9606 14697653 t lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. SIGNOR-120475 0.271 MAPK3 protein P27361 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 24342355 t lperfetto We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity SIGNOR-203480 0.706 NHS protein Q6T4R5 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity relocalization 9606 20332100 t miannu NHS knockdown also resulted in the mislocalization of the Arp2/3 complex and disruption of the actin cytoskeleton. in the absence of NHS, Arp2/3 localization and F-actin distribution are disrupted, suggesting that Arp2/3 actin-nucleation activity is mediated, in part, by NHS providing an additional functional link between NHS and actin. SIGNOR-253566 0.2 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser932 CDSGVETsFRKLSFT 10090 BTO:0000944 SIGNOR-C14 SIGNOR-C13 11297557 t lperfetto The i b kinase (ikk) complex rapidly phosphorylates nf- b1 p105 on serine 927 in the pest region romashkova et al. demonstrated that akt binds to and activates inhibitor of kappa b kinase-alfa (ikkalfa), which in turn phosphorylates and thereby promotes the degradation of the inhibitory cofactor of nf-kb, i-kb the scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk. SIGNOR-235442 0.737 GH1 protein P01241 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001939 15665309 t Luana Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells SIGNOR-261628 0.2 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2T protein Q9NPD8 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271316 0.682 SCAP protein Q12770 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity relocalization 10029 BTO:0000246 12202038 t SCAP contains two domains: an NH2-terminal membrane attachment domain with eight membrane-spanning helices (Nohturfft et al., 1998b) and a long COOH-terminal extension that contains multiple copies of a WD40 repeat sequence, which forms a propeller-like structure that binds to the COOH-terminal domains of the SREBPs, thereby permitting the escort function SIGNOR-267501 0.715 CCR3 protein P51677 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates 9606 11591790 f We and others have recently found that eotaxin activates extracellular signal-regulated kinase (ERK)-1/2 and p38 mitogen-activated protein (MAP) kinases in eosinophils, and that these kinases are indispensable for eosinophil chemotaxis and degranulation SIGNOR-254358 0.25 ATR protein Q13535 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates phosphorylation Ser601 EMDLAHNsQSMHASS 9606 21242293 t lperfetto Atr-mediated phosphorylation of dna polymerase _ is needed for efficient recovery from uv damage. We show that, after uv irradiation, pol_ becomes phosphorylated at ser601 by the ataxia-telangiectasia mutated and rad3-related (atr) kinase. Atr-dependent phosphorylation of pol_ is necessary to restore normal survival and postreplication repair SIGNOR-171290 0.424 P-TEFb complex SIGNOR-C238 SIGNOR MLLT1 protein Q03111 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0000007 17135274 t miannu Phosphorylation of Af9 and Enl by P-TEFb promotes their proteolysis SIGNOR-266799 0.707 RalGAP1 complex SIGNOR-C468 SIGNOR RALA protein P11233 UNIPROT down-regulates activity guanine nucleotide exchange factor 10090 BTO:0000011 21148297 t miannu Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. SIGNOR-269795 0.43 cisapride chemical CHEBI:3720 ChEBI KCNH2 protein Q12809 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9395068 t miannu A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity blockade of the human cardiac potassium channel HERG. cisapride displays specific, high affinity block of the human cardiac K+ channel HERG. It is likely that this interaction underlies the proarrhythmic effects of the drug observed under certain clinical settings. SIGNOR-258672 0.8 YAP1 protein P46937 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199214 0.7 PRPF4B protein Q13523 UNIPROT KLF13 protein Q9Y2Y9 UNIPROT down-regulates phosphorylation 9606 17513757 t flangone Using yeast two-hybrid screening of a human thymus cdna library, prp4, a serine/threonine protein kinase, was identified as a klf13-binding protein...coexpression of prp4 and klf13 increases nuclear localization of klf13 and ccl5 transcription. SIGNOR-154951 0.349 JAK3 protein P52333 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 9606 19088846 t gcesareni For these assays, coexpression of wt jak3 with stat5a was found to result in tyrosine phosphorylation of stat5a (lane 2) mediated by jak3, since stat5a coexpressed with the kinase-inactive k855a mutant form of jak3 was not tyrosine phosphorylated. SIGNOR-182817 0.849 F2RL2 protein O00254 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257033 0.2 DAPT chemical CHEBI:86193 ChEBI PSEN1 protein P49768 UNIPROT down-regulates chemical inhibition 9606 16569643 t gcesareni The catalytic aspartates are necessary for binding of the transition state analogue inhibitor, l-685,458, to ps1. It is possible that these catalytic aspartates also contribute to the direct interaction of ps with dapt. SIGNOR-145385 0.8 ITGAV protein P06756 UNIPROT Av/b6 integrin complex SIGNOR-C179 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253209 0.865 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507-3 UNIPROT down-regulates phosphorylation Thr11 SPSLRRMtVMREKGR 9606 BTO:0000007 16331690 t The effect has been demonstrated using Q13507-3 llicata The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263. SIGNOR-142957 0.417 LAMB1 protein P07942 UNIPROT Laminin-10 complex SIGNOR-C182 SIGNOR form complex binding 11821406 t lperfetto The laminin (LN) family of large heterotrimeric extracellular matrix glycoproteins has multiple functions: LNs take part in the regulation of processes such as cell migration, differentiation, and proliferation, in addition to contributing to the structure of basement membranes. LN-10, composed of alpha5, beta1, and gamma1 chains, is widely distributed in most basement membranes of both epithelia and endothelia. SIGNOR-253230 0.71 USF1 protein P22415 UNIPROT GCK protein P35557 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9677331 f miannu Cotransfection of an expression plasmid encoding USF1 into HepG2 hepatoma cells resulted in the activation of the glucokinase promoter, dependent on the integrity of the P2 element SIGNOR-255597 0.293 VDAC1 protein P21796 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 10365962 f lperfetto Our results indicate that the Bcl-2 family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis. SIGNOR-249615 0.7 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 t flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. SIGNOR-75914 0.606 INTS5 protein Q6P9B9 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261465 0.902 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT up-regulates activity phosphorylation Ser300 KKDQEGDsAAALSLY 9606 20643644 t Manara We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase. SIGNOR-260793 0.2 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT down-regulates activity phosphorylation Tyr770 LSAPFEQySPGGQDT 9606 BTO:0000007 11294897 t lperfetto Ligand stimulation leads to autophosphorylation of fgfr3these results suggest that y770 may negatively regulate the activation of pi 3-kinase by constitutively activated fgfr3 SIGNOR-106746 0.2 KDM5A protein P29375 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-264301 0.2 NCOA1 protein Q15788 UNIPROT RARA protein P10276 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16606617 f irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. SIGNOR-255932 0.698 TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20651737 t lperfetto Under resting conditions cellular inhibitor of apoptosis (ciap) proteins target nuclear factor-kb (nf-kb)-inducing kinase (nik) for ubiquitylation and proteasomal degradation. SIGNOR-167066 0.569 NADPH(4-) smallmolecule CHEBI:57783 ChEBI PGD protein P52209 UNIPROT down-regulates activity binding 9606 34765544 t miannu We determined that FASN inhibitor treatment resulted in NADPH accumulation and inhibition of PGDH enzyme activity. NADPH is a cofactor utilized by FASN, also a known allosteric inhibitor of PGDH. PGDH is the onl yrate-limiting unidirectional enzyme susceptible to allosteric inhibition by NADPH SIGNOR-267372 0.8 Brivanib alaninate chemical CID:11154925 PUBCHEM KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190732 0.8 PPP1CA protein P62136 UNIPROT SP3 protein Q02447 UNIPROT down-regulates activity dephosphorylation 9606 12684058 t miannu Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression. SIGNOR-251953 0.2 AMPK complex SIGNOR-C15 SIGNOR CPS1 protein P31327 UNIPROT down-regulates quantity 9606 28538732 f Luana In KL cells, pharmacological activation of AMPK or expression of constitutively active AMPK reduced CPS1 mRNA and protein, and silencing AMPK increased CPS1 expression even in the presence of LKB1 SIGNOR-267920 0.274 LEF1 protein Q9UJU2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 17081971 f amattioni The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells. SIGNOR-229764 0.7 DYDC1 protein Q8WWB3 UNIPROT SH3GL3 protein Q99963 UNIPROT up-regulates activity binding 10029 BTO:0000246 19545932 t miannu DYDC1 and SH3P13 interact in vitro and in vivo. We recently demonstrated that SH3P13, a BAR domain-containing protein, assists in regulatingclathrin-coated vesicle traffic that is crucial for acrosome biogenesis during spermatogenesis SIGNOR-263882 0.313 RARG protein P13631 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity binding 9606 15650024 t inferred from family member lperfetto We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs SIGNOR-267804 0.394 MAPK3 protein P27361 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser530 DGPPSPRsPVIGSEV 9606 BTO:0001271 15093545 t The effect has been demonstrated using P29590-4 gcesareni Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis. SIGNOR-124317 0.345 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1330 QMRHQSEsQGVGLSD 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks SIGNOR-72048 0.813 FYN protein P06241 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates activity phosphorylation Tyr436 EWKVVNAyHLRVRRK 10090 BTO:0000944 27626315 t miannu Here we identified that Fyn phosphorylates the α subunit of AMPK on Y436 and inhibits AMPK enzymatic activity without altering the assembly state of the AMPK heterotrimeric complex.  SIGNOR-277279 0.26 ZEB2 protein O60315 UNIPROT CTBP1 protein Q13363 UNIPROT up-regulates activity binding 9606 BTO:0000007 12743039 t Luisa The two members of the ZEB family of zinc finger factors (ZEB-1/deltaEF1 and ZEB-2/SIP1) regulate TGFbeta/BMP signaling in opposite ways: ZEB-1/deltaEF1 synergizes with Smad-mediated transcriptional activation, while ZEB-2/SIP1 represses it. Here we report that these antagonistic effects by the ZEB proteins arise from the differential recruitment of transcriptional coactivators (p300 and P/CAF) and corepressors (CtBP) to the Smads. Thus, while ZEB-1/deltaEF1 binds to p300 and promotes the formation of a p300-Smad transcriptional complex, ZEB-2/SIP1 acts as a repressor by recruiting CtBP. SIGNOR-268953 0.486 PRKACA protein P17612 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates activity phosphorylation Ser58 VVGARRSsWRVVSSI 9606 16376338 t llicata Phosphorylation by pka leads to modulation of 14-3-3zeta dimerization and affect its interaction with partner proteins. Substitution of ser58 to ala completely abolished phosphorylation of 14-3-3zeta by pka. SIGNOR-143373 0.547 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR TSPYL2 protein Q9H2G4 UNIPROT up-regulates activity phosphorylation Thr340 GRLVSHStPIRWHRG 9606 BTO:0000567 11395479 t llicata We observed that a CDA1 mutant with the two consensus CDK phosphorylation sites abolished (S20A and T340A) disabled its capacity to inhibit cell growth, indicating that these sites are important for the function of this protein. Furthermore, we showed that these sites are phosphorylated by cyclin/CDKs in vitro, suggesting that these kinases may regulate CDA1 function in vivo.  SIGNOR-250753 0.344 SP1 protein P08047 UNIPROT PON1 protein P27169 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 15380450 f miannu These data suggest that Sp1 acts as a positive regulator of PON1 transcription, and that an interaction between Sp1 and PKC is a key mechanism for the effect of Sp1 on PON1 transcription. SIGNOR-255212 0.271 MTNR1B protein P49286 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256986 0.252 UBE2I protein P63279 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates sumoylation Lys159 APSSMMVkDEYVHDF 9606 12621041 t gcesareni The mh1 domain of smad4 was shown to associate physically with ubc9, the ubiquitin carrier protein (e2) conjugating enzyme in sumoylation. In cultured cells, smad4 is modified by sumo-1 at the endogenous level. The sumoylation sites were identified as two evolutionarily conserved lysine residues, lys-113 and lys-159, in the mh1 domain. We found that the mutations at lys-113 and lys-159 did not alter the ability of smad4 to form a complex with smad2 and fast on the mix.2 promoter. Importantly, sumo-1 overexpression enhanced tgf-beta-induced transcriptional responses. These findings identify sumoylation as a unique mechanism to modulate smad4-dependent cellular responses SIGNOR-98997 0.61 MAPK3 protein P27361 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 t gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. SIGNOR-163254 0.728 3-isobutyl-1-methylxanthine chemical CHEBI:48518 ChEBI CEBPB protein P17676 UNIPROT up-regulates 9606 11279134 f fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin SIGNOR-106481 0.8 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249321 0.754 ERG protein P11308 UNIPROT CXCL8 protein P10145 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001949 19359602 f miannu ERG can inhibit the activity of the IL-8 promoter in a dose dependent manner. SIGNOR-253912 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 RDPVARTsPLQTPAA 9534 BTO:0004055 10677502 t lperfetto Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70. SIGNOR-244501 0.2 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252849 0.908 RPS2 protein P15880 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262431 0.902 ODC1 protein P11926 UNIPROT spermine smallmolecule CHEBI:15746 ChEBI up-regulates quantity chemical modification 9606 14617280 t miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256035 0.8 GSK3A protein P49840 UNIPROT GSK3A protein P49840 UNIPROT up-regulates phosphorylation Tyr279 RGEPNVSyICSRYYR 9606 BTO:0000527 18701488 t gcesareni Gsk3a is activated by phosphorylation at tyr-279. SIGNOR-180035 0.2 SH3GLB1 protein Q9Y371 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 BTO:0000567 16227588 t gcesareni Here, we provide evidence that bif-1 plays a regulatory role in apoptotic activation of not only bax but also bak and appears to be involved in suppression of tumorigenesis. while bif-1 did not directly interact with bak, it heterodimerized with bax on mitochondria in intact cells, and this interaction was enhanced by apoptosis induction and preceded the bax conformational change. SIGNOR-141166 0.335 MAPK3 protein P27361 UNIPROT EGFR protein P00533 UNIPROT down-regulates phosphorylation Thr693 RELVEPLtPSGEAPN 9606 1651322 t lperfetto It is likely that the map2 and ert kinases account for the phosphorylation of the egf receptor at thr669 (egf receptor (krel veplt669psgeapnqallr)) observed in cultured cells.Phosphorylation at ser-695 is partial and occurs only if thr-693 is phosphorylated. Phosphorylation at thr-678 and thr-693 by prkd1 inhibits egf-induced mapk8/jnk1 activation. SIGNOR-20549 0.539 AKT proteinfamily SIGNOR-PF24 SIGNOR HJURP protein Q8NCD3 UNIPROT up-regulates activity phosphorylation Ser486 GLETRRLsLPSSKAK -1 17256767 t miannu These data define a new protein complex in mammalian cells where 14‐3‐3 associates with FAKTS through phosphorylated S479. Our research identifies a widely expressed eukaryotic protein FAKTS, as a new Akt/PKB substrate localized in the nucleus. Akt/PKB promotes FAKTS association with 14‐3‐3, placing FAKTS under the control of 14‐3‐3 proteins. FAKTS may play an important role in transmitting Akt/PKB‐mediated signals in the complex network of intracellular signal transduction. SIGNOR-262623 0.2 SB 203580 chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 BTO:0000567 15208625 t gcesareni Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme. SIGNOR-126055 0.8 TBX21 protein Q9UL17 UNIPROT IFNG protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 17541280 f T-bet is crucially implicated in Th1 differentiation due to its strong promoting activity for IFN-gamma gene transcription SIGNOR-254508 0.488 CLSPN protein Q9HAW4 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates binding 9606 11090622 t gcesareni Binding of claspin to xchk1 is highly elevated in the presence of dna templates that trigger a checkpoint arrest of the cell cycle in xenopus egg extracts SIGNOR-84474 0.786 CD3E protein P07766 UNIPROT NCK1 protein P16333 UNIPROT up-regulates activity relocalization 9606 BTO:0000661 12110186 t We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3ϵ and results in recruitment of the adaptor protein Nck. SIGNOR-259934 0.379 TPH1 protein P17752 UNIPROT tryptophan smallmolecule CHEBI:27897 ChEBI down-regulates quantity chemical modification 9606 31024440 t brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. SIGNOR-264009 0.8 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRB protein P10828 UNIPROT up-regulates activity binding 9606 BTO:0001073 29407449 t scontino T3 binds its receptor (TR) in the nucleus. TRs are ligand-dependent transcription factors belonging to the type II group of NHRs. TRs are encoded by two genes, Thra and Thrb. SIGNOR-267254 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ARRB2 protein P32121 UNIPROT up-regulates activity phosphorylation Thr276 FCKVYTItPLLSDNR 10090 BTO:0002572 26324936 t done miannu ERK1/2-dependent βarr2 phosphorylation on S14 and T276 induces CXCR4 intracellular sequestration. SIGNOR-274019 0.2 ITGB1BP1 protein O14713 UNIPROT A6/b4 integrin complex SIGNOR-C174 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257659 0.356 IC-87114 chemical CHEBI:90686 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252662 0.8 EFNA1 protein P20827 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 17420126 t gcesareni Ephrins are cell-surface tethered guidance cues that bind to eph receptor tyrosine kinases in trans on opposing cells. SIGNOR-154298 0.81 SCF-betaTRCP complex SIGNOR-C5 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity ubiquitination 9534 11295495 t lperfetto The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk. SIGNOR-235305 0.492 CHEK2 protein O96017 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser342 SKLTHSLsTSDITAI 9606 16163388 t lperfetto Phosphorylation of s342 and s367 in vivo require the chk2 kinase. Chk2 also stimulates mdmx ubiquitination and degradation by mdm2 SIGNOR-140417 0.712 PP1 proteinfamily SIGNOR-PF54 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 12840032 t inferred from 70% of family members lperfetto P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases SIGNOR-269923 0.505 WEE1 protein P30291 UNIPROT CDK2 protein P24941 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKAR 9606 BTO:0000567 11029659 t gcesareni Identification and characterization of human wee1b, a new member of the wee1 family of cdk-inhibitory kinases. SIGNOR-83139 0.652 EGFR protein P00533 UNIPROT NCK1 protein P16333 UNIPROT up-regulates activity binding 10090 BTO:0000944 1333047 t We show that epidermal growth factor or platelet-derived growth factor stimulation of intact human or murine cells leads to phosphorylation of Nck protein on tyrosine, serine, and threonine residues SIGNOR-252089 0.593 PTPRG protein P23470 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates activity dephosphorylation Tyr84 EHSDSEMyVMPAEEN -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254692 0.2 PVR protein P15151 UNIPROT CD226 protein Q15762 UNIPROT up-regulates activity binding 9606 BTO:0000914 30591568 t lperfetto We focused on receptor-ligand interactions between CAFs and NK cell and found that cell-surface poliovirus receptor (PVR/CD155), a ligand of activating NK receptor DNAM-1, was downregulated in the CAFs compared with NEFs. |Poliovirus receptor (PVR/CD155) is a ligand of the paired NK receptors, DNAM-1 (activating) and TIGIT (inhibiting). NK cells can kill cancer cells expressing PVR via the DNAM-1-mediated activating signaling (11,12). SIGNOR-261424 0.814 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AMPH protein P49418 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 15262992 t inferred from 70% family members lperfetto Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2. SIGNOR-270197 0.2 RPS13 protein P62277 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262439 0.89 SOCS1 protein O15524 UNIPROT JAK3 protein P52333 UNIPROT down-regulates activity binding 9606 21508344 t lperfetto SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity directly through their kinase inhibitory regions (KIR). SIGNOR-238642 0.697 ID3 protein Q02535 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR down-regulates activity binding 10090 BTO:0004058 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241158 0.495 PTBP2 protein Q9UKA9 UNIPROT KHSRP protein Q92945 UNIPROT up-regulates activity binding 9606 BTO:0000567 11003644 t lperfetto Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA. SIGNOR-261268 0.476 HOXB13 protein Q92826 UNIPROT TCF4 protein P15884 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 15928669 f miannu In prostate cancers, HOXB13 negatively regulates beta-catenin/TCF4-mediated transactivation and subsequently inhibits cell growth.  SIGNOR-254476 0.2 MAPK1 protein P28482 UNIPROT EXOC7 protein Q9UPT5 UNIPROT up-regulates phosphorylation Ser250 SSSGVPYsPAIPNKR 9606 22595671 t lperfetto Erk1/2 phosphorylation enhances the binding of exo70 to other exocyst components and promotes the assembly of the exocyst complex in response to epidermal growth factor (egf) signaling. SIGNOR-197543 0.337 CHEK2 protein O96017 UNIPROT PPP2R5C protein Q13362 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 15380617 t gcesareni Found that chk2 associated with the b' regulatory subunit of protein phosphatase pp2a. In vitro kinase assays showed that b'gamma3 was a potent chk2 substrate. This phosphorylation increased the catalytic phosphatase activity of pp2a. SIGNOR-129255 0.327 EEF1A1P5 protein Q5VTE0 UNIPROT Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269542 0.8 EREG protein O14944 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 16829981 t gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4. SIGNOR-147859 0.695 NFE2L2 protein Q16236 UNIPROT TFB2M protein Q9H5Q4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15684387 f lperfetto Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC SIGNOR-268998 0.252 MAPK11 protein Q15759 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21757713 t llicata Arsenite treatment of cells activates p38_ and induces interaction between p38_ and raptor, a regulatory component of mtorc1, resulting in phosphorylation of raptor on ser(863) and ser(771). The phosphorylation of raptor on these sites enhances mtorc1 activity, and contributes largely to arsenite-induced mtorc1 activation. SIGNOR-174874 0.359 DOK1 protein Q99704 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257687 0.34 MPG protein P29372 UNIPROT IGBP1 protein P78318 UNIPROT down-regulates quantity by destabilization monoubiquitination 9606 BTO:0000007 22613722 t miannu  We show MID1-dependent monoubiquitination of α4 triggers calpain-mediated cleavage and switches α4's activity from protective to destructive, resulting in increased Tau phosphorylation. MID1 serves as the E3 ligase for α4 (2B), leading to a conformational change in α4 whereby the UIM of α4 binds in cis to the covalently attached ubiquitin (Ub; 3). This structural rearrangement then leads to calpain-mediated cleavage of the C terminus of α4 (4), allowing for polyubiquitination of PP2Ac by a currently unknown E3 ligase (5) and subsequent degradation by the proteasome. SIGNOR-272040 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR PTGS2 protein P35354 UNIPROT up-regulates quantity by expression 9606 17705188 f lperfetto Inflammatory stimuli can activate IkappaB kinase (IKK) signalsome and subsequently the nuclear factor kappa B (NF-kappaB), which influences gene expression of cyclooxygenase-2 (Cox-2) along with other transcription factors. SIGNOR-260262 0.372 CDON protein Q4KMG0 UNIPROT MAP3K5 protein Q99683 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 SIGNOR-C21 22337877 t lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts SIGNOR-235551 0.2 PAICS protein P22234 UNIPROT 5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-) smallmolecule CHEBI:77657 ChEBI down-regulates quantity chemical modification 9606 33179964 t miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). SIGNOR-268110 0.8 SNRPA1 protein P09661 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270655 0.768 AKT1 protein P31749 UNIPROT PIKFYVE protein Q9Y2I7 UNIPROT up-regulates phosphorylation Ser307 PARNRSAsITNLSLD 9606 BTO:0000887 15546921 t gcesareni Here we report that serine318 on the fyve domain-containing ptdins3p 5-kinase (pikfyve) is a novel substrate for pkb, and show that phosphorylation stimulates the ptdins3p 5-kinase activity of the enzyme. SIGNOR-252474 0.505 CLASP2 protein O75122 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates activity binding 9534 BTO:0004055 19638411 t lperfetto IQGAP1 is a novel CLASP2-interacting protein| nonphosphorylated CLASP2 on microtubules is allowed to associate with IQGAP1 for the coupling of microtubules to actin filaments at the front of migrating cells. SIGNOR-264828 0.426 GARS1 protein P41250 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 24898252 t miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. SIGNOR-270481 0.8 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates phosphorylation 9606 10693759 t gcesareni In vertebrates,pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation SIGNOR-75362 0.445 MAP3K20 protein Q9NYL2 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation Thr162 SRFHNHTtHMSLVGT 9606 15342622 t gcesareni Ionizing radiation induces mrk autophosphorylation and activation. Within the mrk kinase loop between the dfg (subdomain vii) and ape (subdomain viii) residues, there are three conserved threonine/serine residues (thr161, thr162, and ser165) that are important for activation. SIGNOR-128581 0.2 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Thr151 RSYSRLEtLGSASTS -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276117 0.613 PTPN1 protein P18031 UNIPROT STAM2 protein O75886 UNIPROT up-regulates quantity by stabilization dephosphorylation Tyr291 KSEPEPVyIDEDKMD 9606 20504764 t Together, the results presented here demonstrate that PTP1B can influence RTK signaling in a previously unrecognized manner. We show that PTP1B directly targets STAM2, part of the ESCRT-0 endosomal sorting complex, and we provide the first evidence that tyrosine phosphorylation affects STAM localization and function. This regulatory mechanism could impact signaling downstream of numerous cell surface receptors that are ubiquitinated and recognized by this conserved sorting machinery. SIGNOR-248406 0.484 HIC1 protein Q14526 UNIPROT SIRT1 protein Q96EB6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21277938 f miannu HIC1, via its BTB/POZ domain, forms a transcriptional repressor complex with Sirt1 [8] that binds directly to Sirt1 promoter itself, repressing its transcription. SIGNOR-254419 0.606 CALM1 protein P0DP23 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates binding 9606 11796223 t gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-114101 0.695 KDM5B protein Q9UGL1 UNIPROT FOXG1 protein P55316 UNIPROT up-regulates activity binding 9606 BTO:0000007 12657635 t miannu Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9. In a reporter assay system, PLU-1 has potent transcriptional repression activity. BF-1 and PAX9 also represses transcription in the same assay, but co-expression of PLU-1 with BF-1 or PAX9 significantly enhances this repression SIGNOR-223878 0.412 RIPK1 protein Q13546 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates activity binding 9606 BTO:0000007;BTO:0000661 16603398 t lperfetto Taken together, these results indicate that polyubiquitination of RIP1 mediates the independent re- cruitment of TAB2 and NEMO, which in turn recruits TAK1 and IKK, respectively, to TNF-R1. SIGNOR-145861 0.859 ATF6 protein P18850 UNIPROT Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 9606 31226023 f miannu Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network SIGNOR-260182 0.7 PRC1 protein O43663 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity binding 9606 16431929 t miannu KIF14 interacts with PRC1 and citron kinase. We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. I SIGNOR-266423 0.618 IL20RB protein Q6UXL0 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 BTO:0000782;BTO:0000876 12941475 f gcesareni Il-20 induces cheratin proliferation and stat-3 signal transduction pathway SIGNOR-86305 0.49 UTP(4-) smallmolecule CHEBI:46398 ChEBI UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI up-regulates quantity precursor of 9606 8631325 t miannu UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. SIGNOR-267925 0.8 retinol smallmolecule CHEBI:50211 ChEBI retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity precursor of 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS9 SIGNOR-265112 0.8 GOT2 protein P00505 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267518 0.8 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates activity phosphorylation Ser126 PILVDTAsPSPMETS 9606 BTO:0000567 11242082 t lperfetto Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation. SIGNOR-105707 0.919 IKZF5 protein Q9H5V7 UNIPROT LNPEP protein Q9UIQ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003420 15894523 f miannu Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. SIGNOR-255407 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR AR protein P10275 UNIPROT down-regulates activity phosphorylation Ser792 CVRMRHLsQEFGWLQ 9534 BTO:0001538 11404460 t lperfetto Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Here, we demonstrate that akt phosphorylates the androgen receptor (ar) at ser-210 and ser-790 SIGNOR-244136 0.2 COX4I1 protein P13073 UNIPROT Oxidative_phosphorylation phenotype SIGNOR-PH78 SIGNOR up-regulates 10090 23021218 f lperfetto PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). SIGNOR-253101 0.7 FAU protein P62861 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262443 0.834 MAP3K5 protein Q99683 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 8974401 t lperfetto A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) SIGNOR-45373 0.616 Orexin A smallmolecule CHEBI:80319 ChEBI HCRTR1 protein O43613 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257510 0.8 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 18930133 t lperfetto Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation SIGNOR-181667 0.413 FUS protein P35637 UNIPROT ATXN2 protein Q99700 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0001279 28515487 f This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease SIGNOR-262809 0.466 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1011 DVFPCSVyVPDEWEV -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-233564 0.2 SRC protein P12931 UNIPROT AP2B1 protein P63010 UNIPROT down-regulates phosphorylation Tyr737 THRQGHIyMEMNFTN 9606 18938240 t gcesareni The phosphorylation of beta2-adaptin on tyrosine residue 737 (y737) negatively regulates its interaction with betaarrestin. SIGNOR-181743 0.275 GSK3B protein P49841 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity by destabilization phosphorylation 7227 11955435 t lperfetto We show that these phosphoserines prime further phosphorylation at adjacent Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase I (CK1) sites. Alteration of the GSK3 or CK1 sites prevents Ci-155 proteolysis and activates Ci in the absence of Hedgehog. SIGNOR-219231 0.517 MAPK3 protein P27361 UNIPROT MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation Ser454 TGSTPPVsPTPSERS 9606 18694962 t Translocation from Nuleus to Cytoplasm gcesareni Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. SIGNOR-179963 0.2 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser6 sQLDSDFS 9606 12697768 t llicata To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1 SIGNOR-100649 0.869 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity phosphorylation Ser907 TDASRRSsEASQSDG 9606 10693759 t lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. SIGNOR-75355 0.445 MKRN1 protein Q9UHC7 UNIPROT TERT protein O14746 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002552 15805468 t miannu MKRN1 functions as an E3 ubiquitin-ligase for hTERT in vitro and in vivo. Furthermore, we have used the yeast two-hybrid method to identify a novel RING finger gene (MKRN1) encoding an E3 ligase that mediates ubiquitination of hTERT. Overexpression of MKRN1 in telomerase-positive cells promotes the degradation of hTERT and decreases telomerase activity and subsequently telomere length.  SIGNOR-271529 0.488 CTDSPL protein O15194 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser187 NSHPFPHsPNSSYPN 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248313 0.477 PPP1R3B protein Q86XI6 UNIPROT GYS2 protein P54840 UNIPROT up-regulates binding 9606 BTO:0000759 36551183 t miannu In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2) SIGNOR-271732 0.771 NLGN4X protein Q8N0W4 UNIPROT NRXN2 protein Q9P2S2 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264155 0.759 PRKCG protein P05129 UNIPROT VTN protein P04004 UNIPROT up-regulates quantity by stabilization phosphorylation Ser381 RNRKGYRsQRGHSRG -1 9030777 t lperfetto Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin. SIGNOR-248964 0.289 HIPK2 protein Q9H2X6 UNIPROT PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization phosphorylation Ser85 PLPDAGAsPAPSRCC 23871434 t lperfetto WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation|Analysis of the phosphoamino acids of WIP1 revealed that both Ser85 and Ser54 are phosphorylation sites, confirming that HIPK2 is a protein kinase for WIP1 phosphorylation at Ser54 as well as Ser85 SIGNOR-275481 0.43 DLGAP5 protein Q15398 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264598 0.459 nitric oxide smallmolecule CHEBI:16480 ChEBI GUCY1A2-B2 complex SIGNOR-C137 SIGNOR up-regulates activity chemical activation 9606 15036565 t gcesareni One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP) SIGNOR-243961 0.8 Dynorphin A smallmolecule CHEBI:4727 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258793 0.8 CDC25A protein P30304 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR up-regulates activity dephosphorylation 9606 BTO:0000007 23429262 t lperfetto We show that the miRNA-induced silencing of CDC25A increases the tyrosine phosphorylation status of CDK4/6 cyclin-dependent kinases which, in turn, abolishes CDK4/6 capacity to associate with D-type cyclins. This prevents CDK4/6 kinases’ activation, impairs downstream events such as cyclin E stimulation and sequesters cells in early G1. SIGNOR-245456 0.638 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser29 FDGSSCIsPTIVQQF 10090 BTO:0000944 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-249441 0.616 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization ubiquitination phosphorylation:Ser146 LLTFPNSsPGLRRQK 23972993 t For phosphorylated residues see Figure 7 lperfetto Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP SIGNOR-274055 0.293 MC1R protein Q01726 UNIPROT Pigmentation phenotype SIGNOR-PH70 SIGNOR up-regulates 9606 19656324 f miannu Alpha-melanocyte stimulating hormone (alpha-MSH) binds to melanocortin-1 receptor (MC1R) on melanocytes to stimulate pigmentation and modulate various cutaneous inflammatory responses. SIGNOR-252374 0.7 SREBF2 protein Q12772 UNIPROT ABCG8 protein Q9H221 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21123766 f miannu these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α. SIGNOR-254456 0.431 TFAP2A protein P05549 UNIPROT LNPEP protein Q9UIQ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003420 15894523 f miannu Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. SIGNOR-255402 0.283 SMO protein Q99835 UNIPROT GNAT1 protein P11488 UNIPROT up-regulates binding 9606 23074268 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-199168 0.264 DYRK2 protein Q92630 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates quantity by destabilization phosphorylation Ser527 QDIDSRLsPGGSLAD 9606 BTO:0000007 26407194 t miannu  We further found that DYRK2 phosphorylated Ser527 of TBK1, which is essential for the recruitment of NLRP4 and for the E3 ubiquitin ligase DTX4 to degrade TBK1.  SIGNOR-276939 0.422 terbutaline chemical CHEBI:9449 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 20590599 t Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) SIGNOR-257872 0.8 PRKCZ protein Q05513 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser181 DQGSLCTsFVGTLQY 9606 10022904 t lperfetto Activation of IkappaB kinase beta by protein kinase C isoforms. | Interestingly, recombinant active zetaPKC and alphaPKC are able to stimulate in vitro the activity of IKKbeta but not that of IKKalpha. In addition, evidence is presented here that recombinant zetaPKC directly phosphorylates IKKbeta in vitro, involving Ser177 and Ser181. Collectively, these results demonstrate a critical role for the PKC isoforms in the NF-kappaB pathway at the level of IKKbeta activation and IkappaB degradation. SIGNOR-249016 0.496 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120196 0.321 MAPK8 protein P45983 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr278 SVSAATLtPSSQAVT 9606 19245816 t gcesareni In addition, for mutation of the jnk-1 phosphorylated residues of sp1, namely, sp1(t278/739a) and sp1(t278/739d), the effect of ga on sp1 stability was reversed. SIGNOR-184190 0.694 POLH protein Q9Y253 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 21242293 f miannu In this study we show that, in human cells, polη becomes phosphorylated by ATR at Ser601 after UV irradiation. Phosphorylation requires physical interaction of polη with Rad18 but is independent of PCNA monoubiquitination. We show that UV-induced phosphorylation of polη is required for normal survival and postreplication repair and is involved in checkpoint control. SIGNOR-259061 0.7 OTUD7B protein Q6GQQ9 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates activity deubiquitination 9606 BTO:0000007 18178551 t lperfetto NF-kappaB Suppression by the Deubiquitinating Enzyme Cezanne|Our study provides several lines of evidence to suggest that Cezanne suppresses TNFR signaling to NF-κB by targeting RIP1 for deubiquitination. SIGNOR-268411 0.519 DYRK2 protein Q92630 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser243 PGETPPLsPIDMESQ 9606 BTO:0000150 22307329 t lperfetto Degradation of c-jun/c-myc is a critical process for the g(1)/s transition, which is initiated upon phosphorylation by glycogen synthase kinase 3 ? (gsk3?). However, a specific kinase or kinases responsible for priming phosphorylation events that precede this gsk3? Modification has not been definitively identified. Here, we found that the dual-specificity tyrosine phosphorylation-regulated kinase dyrk2 functions as a priming kinase of c-jun and c-myc.The finding that kinase-active dyrk2 phosphorylated gst_c-jun210_310-wt by detection with an anti_phospho_c-jun(ser243) antibody demonstrated that dyrk2 is a ser243 kinase in vitro SIGNOR-195771 0.258 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG1-LLGL1_variant complex SIGNOR-C511 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270912 0.54 EDNRA protein P25101 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257378 0.523 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser343 TVSKTETsQVAPA -1 9099669 t lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. SIGNOR-248968 0.45 CDK1 protein P06493 UNIPROT NUSAP1 protein Q9BXS6 UNIPROT down-regulates phosphorylation Thr300 HKRSLTKtPARKSAH 9606 22101338 t llicata We report here that cdk1 phosphorylates nusap at threonine 300 and 338 in early mitosis. Phosphorylation of nusap inhibits its microtubule-binding activity in vitro and in vivo. SIGNOR-177545 0.441 CDK2 protein P24941 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates phosphorylation Ser154 PMDGSFEsPHTMDMS 9606 10652300 t lperfetto Here we present evidence from in vitro and in vivo assay systems that the degradation of human cyclin a can be inhibited by kinase-inactive mutants of cdk2 and cdc2cdk2 can phosphorylate cyclin a on ser-154 SIGNOR-74466 0.977 SMARCA2 protein P51531 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270688 0.822 AURKA protein O14965 UNIPROT AURKA protein O14965 UNIPROT up-regulates phosphorylation Thr288 APSSRRTtLCGTLDY 9606 24867643 t lperfetto The upstream pak1 kinase can phosphorylate aurora a at t288, autophosphorylation appears to be the essential mode of activation. Our experiments suggest that phosphorylation of t288 is important for regulation of the aurora2 kinase both for its activity and its stability SIGNOR-205106 0.2 DNA polymerase alpha:primase complex complex SIGNOR-C262 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 24043831 f lperfetto At the replication fork, primase is present in a constitutive complex with DNA polymerase α (Pol α), which extends the RNA primer with deoxynucleotides and makes the resulting RNA–DNA primer available to the leading- and lagging-strand polymerases, Pols ε and δ, for processive elongation  SIGNOR-261344 0.7 CDK1 protein P06493 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates phosphorylation Ser373 SSRSAPAsPNHAGVL 9606 20810654 t gcesareni We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis. SIGNOR-167822 0.38 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser51 LRPSTSRsLYASSPG -1 2500966 t miannu Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure. SIGNOR-250069 0.313 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 1715686 t gcesareni Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta. SIGNOR-21295 0.309 belinostat chemical CHEBI:61076 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257953 0.8 ID1 protein P41134 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR down-regulates activity binding 10090 BTO:0004058 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241110 0.545 CDC14B protein O60729 UNIPROT KMT5A protein Q9NQR1 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 t The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC(cdh1)-mediated ubiquitination of PR-Set7 and subsequent proteolysis. SIGNOR-248339 0.2 CAMK2A protein Q9UQM7 UNIPROT GFPT1 protein Q06210 UNIPROT up-regulates phosphorylation Ser261 CNLSRVDsTTCLFPV 9606 17941647 t gcesareni Amp-activated protein kinase and calcium/calmodulin-dependent kinase ii were identified to phosphorylate specifically ser243 in vitro. Phosphorylation by these two kinases results in an increase of enzymatic activity by 1.4-fold. These findings suggest for the first time that hgfat1 may be regulated by kinases other than pka. SIGNOR-158486 0.2 PRKAA1 protein Q13131 UNIPROT USP10 protein Q14694 UNIPROT up-regulates activity phosphorylation Ser76 DTLPRTPsYSISSTL 9606 BTO:0001109 26876938 t miannu Under energy stress, USP10 activity in turn is enhanced through AMPK-mediated phosphorylation of Ser76 of USP10.  SIGNOR-277207 0.314 STAT1 protein P42224 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 19029990 f lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. SIGNOR-249496 0.7 BLVRB protein P30043 UNIPROT biliverdin(2-) smallmolecule CHEBI:57991 ChEBI up-regulates quantity chemical modification 9606 BTO:0000759 7929092 t lperfetto This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. SIGNOR-275524 0.8 AHSP protein Q9NZD4 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by stabilization binding 9606 18179859 t Regulation miannu α-Hemoglobin stabilizing protein (AHSP) binds α-hemoglobin (Hb), avoiding its precipitation and its pro-oxidant activity. SIGNOR-251770 0.772 TP53 protein P04637 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7958853 f gcesareni The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop. SIGNOR-34962 0.968 PRKAA2 protein P54646 UNIPROT HNF4A protein P41235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser313 GKIKRLRsQVQVSLE 10029 BTO:0000246 12740371 t miannu AMPK directly phosphorylates HNF4alpha and represses its transcriptional activity. AMPK-mediated phosphorylation of HNF4alpha on serine 304 had a 2-fold effect, reducing the ability of the transcription factor to form homodimers and bind DNA and increasing its degradation rate in vivo. Phosphorylation of HNF4α on Ser-304 reduces protein stability. SIGNOR-250322 0.375 CTLA4 protein P16410 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0000782 16227604 f Barakat Akt phosphorylation in cells stimulated by CD3/CD28/CTLA-4 or CD3/CD28/PD-1 aAPCs did not have detectable phosphorylated Akt at any time point, indicating that CTLA-4 and PD-1 signaling blocked rather than delayed Akt activation. SIGNOR-275409 0.588 IFNG protein P01579 UNIPROT SLC11A1 protein P49279 UNIPROT up-regulates 9606 BTO:0000801 11909746 f Functional studies in Nramp1 transfected macrophages have demonstrated that the Nramp1 protein plays a vital role in early macrophage activation [10,29,30]. Nramp1 is constitutively expressed in macrophage cell lines of the myeloid lineage (isolated peritoneal, splenic, and liver resident macrophages), and can be induced by treatment of macrophages with IFN-γ, or IFN-γ plus lipopolysaccharide (LPS) SIGNOR-254038 0.354 SMO protein Q99835 UNIPROT GPR161 protein Q8N6U8 UNIPROT down-regulates activity relocalization 10090 23332756 f Constitutive Gpr161 activity increases cAMP levels, which is reduced upon knockdown of Gαs, suggesting it to be a Gαs-coupled receptor. SIGNOR-259937 0.323 ENO2 protein P09104 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266525 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR RPS3 protein P23396 UNIPROT up-regulates activity phosphorylation Thr70 GRRIRELtAVVQKRF 10116 BTO:0003060 20605787 t miannu Here, we show that human RPS3 is a physiological target of Akt kinase and a novel mediator of neuronal apoptosis. NGF stimulation resulted in phosphorylation of threonine 70 of RPS3 by Akt, and this phosphorylation was required for Akt binding to RPS3.our experiment demonstrated that Akt up-regulates the endonuclease activity of RPS3 via phosphorylation and led us to believe that Akt phosphorylation of RPS3 after DNA damage is an antiapoptotic signal or a molecular switch that extends the life of a cell after DNA damage. SIGNOR-259816 0.2 PLK1 protein P53350 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates phosphorylation Ser30 EADSPSDsGQGSYET 9606 16885021 t gcesareni We show that claspin, an adaptor protein required for chk1 activation, becomes degraded at the onset of mitosis. Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbtrcp ubiquitin ligase. This interaction was phosphorylation dependent and required the activity of the plk1 kinase SIGNOR-148442 0.764 PRKCA protein P17252 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249278 0.426 GCC2 protein Q8IWJ2 UNIPROT IGF2R protein P11717 UNIPROT up-regulates activity relocalization 18195106 t lperfetto Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector SIGNOR-253085 0.509 MAP3K6 protein O95382 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 t Manara These data indicate that MKK6 phosphorylates p38 MAP kinase on Thr-180 and Tyr-182, the sites of phosphorylation that activate p38 MAP kinase SIGNOR-260915 0.2 PRKACA protein P17612 UNIPROT GLI1 protein P08151 UNIPROT down-regulates phosphorylation 16293631 t We report that activation of PKA retains Gli1 in the cytoplasm. Conversely, inhibition of PKA activity promotes nuclear accumulation of Gli1.We provide direct evidence to support that the cAMP/PKA signaling axis regulates Gli1 protein localization primarily through a site at Thr374. .These data suggest that Thr374 is an important PKA site responsible for PKA phosphorylation and for the transcriptional activity of Gli1. SIGNOR-253539 0.532 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR PER1 protein O15534 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253681 0.722 NFKB1 protein P19838 UNIPROT CTCF protein P49711 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21912613 f miannu In the present study, we report that regulation of CTCF by extracellular stress signals is dependent upon activations of an oxidative stress-regulated protein Bcl-3. We found that activated Bcl-3 was able to bind to the κB sites identified in the CTCF promoter region. Bcl-3 was activated by UV irradiation to interact with NF-κB p50 by forming a Bcl-3/p50 heterodimer complex. The Bcl-3/p50 complex suppressed CTCF promoter activity to down-regulate CTCF transcription. SIGNOR-254788 0.309 SRC protein P12931 UNIPROT NELFCD protein Q8IXH7 UNIPROT down-regulates activity phosphorylation Tyr14 GAIMDEDyYGSAAEW 9534 22238675 t miannu  Here we show that c-Src interacts with TH1 by GST-pull down assay, coimmunoprecipitation and confocal microscopy assay. The interaction leads to phosphorylation of TH1 at Tyr-6 in vivo and in vitro. Phosphorylation of TH1 decreases its association with A-Raf and PAK1. SIGNOR-276402 0.343 PIKFYVE protein Q9Y2I7 UNIPROT PAS complex complex SIGNOR-C190 SIGNOR form complex binding 9606 BTO:0000007 17556371 t miannu Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. SIGNOR-253529 0.932 UBE2I protein P63279 UNIPROT JUN protein P05412 UNIPROT down-regulates activity sumoylation Lys226 HPRLQALkEEPQTVP 9606 SIGNOR-C154 16055711 t lperfetto We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. SIGNOR-263002 0.43 LPCAT2 protein Q7L5N7 UNIPROT 1-O-acyl-sn-glycero-3-phosphocholine chemical CHEBI:58168 ChEBI down-regulates quantity chemical modification 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272766 0.8 MAPK8 protein P45983 UNIPROT WDR62 protein O43379 UNIPROT down-regulates quantity by destabilization phosphorylation Thr1053 PSSSLPQtPEQEKFL 9606 BTO:0000007 30566428 t lperfetto WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. |JNK1 can induce the phosphorylation of WDR62 T1053 SIGNOR-271710 0.572 ARHGAP35 protein Q9NRY4 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260492 0.889 MTOR protein P42345 UNIPROT UVRAG protein Q9P2Y5 UNIPROT up-regulates activity phosphorylation Ser550 KITSLSSsLDTSLDF 9606 BTO:0001938 26139536 t miannu MTOR phosphorylates UVRAG at serine 550 and serine 571 SIGNOR-276920 0.418 SUZ12/EZH2/YY1 complex SIGNOR-C102 SIGNOR PAX7 protein P23759 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000165;BTO:0002314 20887952 t lperfetto TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter. SIGNOR-235583 0.33 KIF1B protein O60333 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272519 0.7 Kisspeptin-10 smallmolecule CHEBI:80307 ChEBI KISS1R protein Q969F8 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257527 0.8 EP300 protein Q09472 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates binding 9606 SIGNOR-C6 22298955 t gcesareni Ski and snon also prevent smads from binding to the transcriptional coactivator p300/cbp SIGNOR-195582 0.414 CDK3 protein Q00526 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2513 EHPFLTPsPESPDQW -1 25344755 t lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues SIGNOR-273169 0.245 PRKCE protein Q02156 UNIPROT SLC4A3 protein P48751 UNIPROT up-regulates activity phosphorylation Ser67 EKPSRSYsERDFEFH 9606 BTO:0000007 11739292 t lperfetto We conclude that following Ang II stimulation of cells, PKCepsilon phosphorylates serine 67 of the AE3 cytoplasmic domain, inducing the Ang II-induced increase in anion transport observed in the hypertrophic myocardium. SIGNOR-249127 0.314 AURKB protein Q96GD4 UNIPROT SSU72 protein Q9NP77 UNIPROT down-regulates activity phosphorylation Ser19 CSSNQNRsMEAHNIL 24149858 t lperfetto Here we report that Aurora B kinase directly interacts with and phosphorylates Ssu72, a new cohesin-binding phosphatase, at Ser 19 in vitro and in vivo. The Aurora B-mediated phosphorylation of Ssu72 causes the structural modification of Ssu72 protein, downregulates phosphatase activity and triggers the ubiquitin-dependent degradation of Ssu72. SIGNOR-275530 0.256 GSK3B protein P49841 UNIPROT CLOCK protein O15516 UNIPROT down-regulates quantity by destabilization phosphorylation Ser427 ALERFDHsPTPSASS 9606 BTO:0002181 19946213 t miannu We have identified a conserved cluster of serines that include, Ser431, which is a prerequisite phosphorylation site for the generation of BMAL dependent phospho-primed CLOCK and for the potential GSK-3 phosphorylation at Ser427.  SIGNOR-276270 0.347 FBXW7 protein Q969H0 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates quantity by destabilization ubiquitination 26971449 t lperfetto We then examined the effect of necdin on ubiquitin-dependent degradation of PGC-1α using Rnf34, a PGC-1α E3 ubiquitin ligase22. Rnf34 reduced the PGC-1α level, and necdin completely inhibited the reduction (Fig. 4i). In addition, necdin strongly suppressed Rnf34-mediated ubiquitination of PGC-1α (Fig. 4j). Necdin also protected PGC-1α against ubiquitination mediated by Fbxw7, another PGC-1α E3 ubiquitin ligase23 (Fig. 4k). These data indicate that necdin stabilizes PGC-1α by inhibiting its degradation in the ubiquitin-proteasomal system. SIGNOR-253394 0.407 RPS6KB1 protein P23443 UNIPROT LTC4S protein Q16873 UNIPROT down-regulates activity phosphorylation Ser36 ARRAFRVsPPLTTGP -1 27365393 t miannu Here, we identified Ser(36) as the major p70S6k phosphorylation site, along with a low frequency site at Thr(40), using an in vitro phosphorylation assay combined with mass spectrometry. Cellular LTC4S activity is suppressed by PKC-mediated phosphorylation, and recently a downstream p70S6k was shown to play an important role in this process. SIGNOR-277256 0.2 SGI-1776 chemical CID:24795070 PUBCHEM PIM proteinfamily SIGNOR-PF34 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-259435 0.8 HRH2 protein P25021 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257317 0.252 LPAR2 protein Q9HBW0 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257382 0.58 PAPOLA protein P51003 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization chemical modification 9606 19224921 t lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. SIGNOR-268327 0.8 CREB1 protein P16220 UNIPROT CHGA protein P10645 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001007 12456801 t Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation. SIGNOR-254276 0.268 Av/b1 integrin complex SIGNOR-C175 SIGNOR SOX2 protein P48431 UNIPROT up-regulates quantity by expression 10090 18757303 f lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. SIGNOR-253273 0.318 quinpirole chemical CHEBI:75401 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation -1 7576010 t miannu D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole. SIGNOR-258440 0.8 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity phosphorylation Thr177 VAGQLTDtMAKRNTV 9534 12223493 t lperfetto Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationwas also highly autophosphorylated at the newly identified Thr(177) and Thr(387) residues SIGNOR-247573 0.2 SH2B1 protein Q9NRF2 UNIPROT SYK protein P43405 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000776 32323266 t scontino SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK. SIGNOR-268445 0.2 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1466 KSSEYPIsQNPEGLS 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks SIGNOR-72060 0.813 PPARG protein P37231 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates quantity by expression transcriptional regulation 18292390 t lperfetto EMSA, ChIP, and transient transfection assays indicate that PPAR-gamma activates the CXCR2 promoter by binding to a PPAR response element (PPRE). SIGNOR-271682 0.267 FOXN4 protein Q96NZ1 UNIPROT PTF1A protein Q7RTS3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001175 17075007 f Luana  We conclude that Foxn4 functions upstream of Ptf1a to activate its expression, thereby regulating the generation of amacrine and horizontal cells during retinogenesis. SIGNOR-261608 0.473 CDK2 protein P24941 UNIPROT LIG1 protein P18858 UNIPROT up-regulates activity phosphorylation Ser91 ALDCSQVsPPRPATS 9606 BTO:0000567 12851383 t lperfetto We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner. SIGNOR-103254 0.468 HIF1A protein Q16665 UNIPROT KDM5B protein Q9UGL1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271563 0.274 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT up-regulates quantity by stabilization phosphorylation Thr246 STGGTPLtPAARISA 9606 BTO:0000007 16682949 t done miannu Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. SIGNOR-274086 0.525 hesperadin chemical CHEBI:70726 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193128 0.8 GDNF protein P39905 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252184 0.431 CDK1 protein P06493 UNIPROT USP24 protein Q9UPU5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2604 HLQQGSEsPMMIGEL 9606 BTO:0000018 27991932 t lperfetto Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. SIGNOR-275603 0.2 PRKCA protein P17252 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity phosphorylation -1 15894802 t inferred from family member lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-270278 0.568 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. SIGNOR-40353 0.716 UFL1 protein O94874 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000007 30886146 t lperfetto UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation. UFL1 is recruited to double strand breaks by the MRE11/RAD50/NBS1 complex, and monoufmylates histone H4 following DNA damage. SIGNOR-265073 0.2 1-(1-naphthalenyl)piperazine chemical CHEBI:108599 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258683 0.8 UBE3A protein Q05086 UNIPROT DLG4 protein P78352 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 17121805 t miannu E6-induced degradation of DLG4 depends on E6AP in vivo.  Our findings as a whole indicate that E6AP is involved in E6-mediated ubiquitination and degradation of DLG4 both in vivo and in vitro. SIGNOR-271397 0.356 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser175 SPASSGSsASFISDT 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248368 0.598 JAKMIP1 protein Q96N16 UNIPROT TUBB protein P07437 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000661 15277531 t SARA In Jamip1, the N-terminal region mediates the association with microtubules, when highly expressed, N-ter drastically affects the organization of microtubules that appear to be bundled, stabilized against the depolymerizing effect of nocodazole, and enriched in acetylated tubulin. SIGNOR-260987 0.2 F9 protein P00740 UNIPROT Factor VIIIa-IXa complex SIGNOR-C320 SIGNOR form complex binding 10090 BTO:0000131 25769543 t lperfetto The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin. SIGNOR-263552 0.757 TICAM2 protein Q86XR7 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 9606 BTO:0000801 14519765 t lperfetto Tram binds trif directly and recruits it to tlr4 SIGNOR-118367 0.569 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1363 TFFTDNSy 9606 BTO:0000394 12881528 t lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. SIGNOR-104092 0.2 SOSTDC1 protein Q6X4U4 UNIPROT WNT5B protein Q9H1J7 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242727 0.28 NELFCD protein Q8IXH7 UNIPROT NELF complex SIGNOR-C521 SIGNOR form complex binding 9606 18628398 t miannu The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. SIGNOR-271399 0.855 UBE3A protein Q05086 UNIPROT SCRIB protein Q14160 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 11027293 t miannu Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase SIGNOR-272573 0.537 CKM complex complex SIGNOR-C406 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates quantity by destabilization phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19914161 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-273142 0.421 TFPI protein P10646 UNIPROT VLDLR protein P98155 UNIPROT up-regulates binding 9606 11278667 t gcesareni Binding studies revealed that full-length tfpi, but not the truncated tfpi molecule, is recognized by the very low density lipoprotein receptor (vldl receptor) indicating that this receptor is a novel high affinity endothelial cell receptor for tfpi SIGNOR-106353 0.259 ITGB8 protein P26012 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257729 0.45 Succinyl-CoA ATP variant complex SIGNOR-C398 SIGNOR succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity chemical modification 9606 27487822 t miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. SIGNOR-266269 0.8 CSNK2A1 protein P68400 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser709 SEEEEEEsDSSETEK -1 21296876 t miannu CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis SIGNOR-276252 0.2 GPRIN1 protein Q7Z2K8 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 22956546 f Luana  GAP-43 and G protein regulated inducer of neurite outgrowth 1 (Gprin1) in differentiating cells. SIGNOR-265799 0.7 M1_polarization phenotype SIGNOR-PH54 SIGNOR IFNG protein P01579 UNIPROT up-regulates 9606 BTO:0000801 32454942 f miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. According to the M1/M2 model, M1 polarized cells are characterized by the release of proinflammatory mediators, such as TNF, IL-1β, and IFNγ SIGNOR-263827 0.7 QRICH1 protein Q2TAL8 UNIPROT GARS1 protein P41250 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269405 0.2 SKP2 protein Q13309 UNIPROT CYGB protein Q8WWM9 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 28948618 t miannu Skp2 induces ubiquitin-dependent degradation of Cygb. To this end, we performed an in vivo ubiquitination assay in HEK293T cells by transfecting relevant plasmids as indicated. The V5-Skp2DN was generated by deleting the N-terminal residues from 1 to 153 containing the F-box domain, which is involved in recruiting Skp2 to the SCF complex. SIGNOR-272792 0.2 cysteine smallmolecule CHEBI:15356 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264759 0.7 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation Ser715 YQSTIPQsPSPAPDD 9606 10828059 t The effect has been demonstrated using Q08499-5 gcesareni These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro. SIGNOR-77571 0.36 CTDSPL protein O15194 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser204 NHSMDAGsPNLSPNP 9606 BTO:0000007 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248306 0.399 GDNF protein P39905 UNIPROT DNM2 protein P50570 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization. SIGNOR-252173 0.2 PRKACA protein P17612 UNIPROT CD44 protein P16070 UNIPROT up-regulates phosphorylation Ser697 AVEDRKPsGLNGEAS 9606 16785995 t lperfetto Pka can phosphorylate ser316 directly cd44 s291a and s316a mutants may disrupt downstream signalling events by displacing endogenous cd44 from plasma membrane microdomains. SIGNOR-147208 0.2 STUB1 protein Q9UNE7 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity by destabilization destabilization 9606 BTO:0002806 28813410 t Barakat Deletion of STUB1 resulted in a more profound increase in PD-L1 levels in CMTM6 deficient than in CMTM6 proficient cells, identifying STUB1 as an E3 ligase that causes destabilization of PD-L1 (Fig. 4f,g), either by direct modification of one of the lysines in the PD-L1 cytoplasmic domain or indirectly SIGNOR-274979 0.2 PIP5K1C protein O60331 UNIPROT 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) smallmolecule CHEBI:58456 ChEBI up-regulates quantity chemical modification 9606 9367159 t miannu Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities SIGNOR-277286 0.8 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 t gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation SIGNOR-252443 0.426 PRKACA protein P17612 UNIPROT PLN protein P26678 UNIPROT up-regulates activity phosphorylation Ser16 RSAIRRAsTIEMPQQ 10090 10988285 t miannu Phospholamban (PLB) can be phosphorylated at Ser(16) by cyclic AMP-dependent protein kinase. phosphorylation of Ser(16) is sufficient for mediating the maximal cardiac responses to beta-adrenergic stimulation. SIGNOR-250030 0.47 GSK3B protein P49841 UNIPROT GLI2 protein P10070 UNIPROT down-regulates quantity by destabilization phosphorylation Ser863 DPISTDAsRRSSEAS 9606 BTO:0000007 16611981 t lperfetto The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3. SIGNOR-249590 0.544 UCK1 protein Q9HA47 UNIPROT uridine 5'-monophosphate(2-) smallmolecule CHEBI:57865 ChEBI up-regulates quantity chemical modification 11306702 t lperfetto Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. SIGNOR-275858 0.8 PRKCD protein Q05655 UNIPROT LIMK2 protein P53671 UNIPROT down-regulates phosphorylation Ser283 EGTLRRRsLRRSNSI 9606 15923181 t Translocation from Cytosol to Nucleus flangone Activation of pkc by phorbol ester treatment of endothelial cells stimulated limk2 phosphorylation at ser-283 and inhibited nuclear import of limk2 SIGNOR-137927 0.258 FZD3 protein Q9NPG1 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 14977528 t gcesareni Gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families. SIGNOR-122892 0.246 GABRG2 protein P18507 UNIPROT GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263761 0.627 AKT1 protein P31749 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser42 GGRKRRSsRRSAGGG 9606 20400976 t llicata Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis. SIGNOR-164884 0.449 CDK5 protein Q00535 UNIPROT HTT protein P42858 UNIPROT up-regulates phosphorylation Ser1199 EQASVPLsPKKGSEA 9606 BTO:0000938 17611284 t lperfetto Huntingtin is an antiapoptotic proteinwe show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (cdk5) at serines 1181 and 1201. Phosphorylation can be induced by dna damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by dna damage. SIGNOR-156840 0.458 HSD3B1 protein P14060 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity chemical modification 9606 BTO:0000050 2139411 t lperfetto The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione. SIGNOR-268636 0.8 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257913 0.8 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267900 0.8 SSH2 protein Q76I76 UNIPROT CFL1 protein P23528 UNIPROT up-regulates activity dephosphorylation Ser3 sGVAVSDG 9606 14531860 t Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH). SIGNOR-248733 0.725 G6PC1 protein P35575 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-266582 0.8 NDFIP2 protein Q9NV92 UNIPROT NEDD4 protein P46934 UNIPROT up-regulates activity relocalization 9606 BTO:0002181 26363003 t SARA Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2. SIGNOR-260996 0.585 RUNX3 protein Q13761 UNIPROT CHUK protein O15111 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255090 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation 9606 21419341 t inferred from 70% family members gcesareni We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1. SIGNOR-270161 0.2 ARNT protein P27540 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates activity binding 14764593 t lperfetto The functional transcription factor exists as a heterodimeric complex consisting of HIF-1alpha and the aryl hydrocarbon receptor nuclear translocator (ARNT). Association of HIF-1 with ARNT is required for its activity; however, no other role has been ascribed to this interaction. SIGNOR-253720 0.778 AMFR protein Q9UKV5 UNIPROT SERPINI1 protein Q99574 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21507957 t miannu In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin. SIGNOR-272756 0.3 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 BTO:0001271 7637391 t gcesareni Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation. SIGNOR-30353 0.2 BAG6 protein P46379 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by destabilization acetylation 9606 BTO:0000007 21726808 t lperfetto These results indicate that BAT3 and P300 can both exist in the PEPCK1 protein complex, suggesting the possibility that BAT3 could be an enhancer of PEPCK1 acetylation. | indicating a synergistic effect of BAT3 and P300 to promote PEPCK1 acetylation. SIGNOR-267598 0.347 ULK2 protein Q8IYT8 UNIPROT ATG13 protein O75143 UNIPROT up-regulates phosphorylation 9606 19225151 t gcesareni Ulks directly phosphorylates atg13. SIGNOR-184126 0.741 USP7 protein Q93009 UNIPROT TP53 protein P04637 UNIPROT up-regulates deubiquitination 9606 16082221 t gcesareni Hausp counteracts the destabilizing effect of mdm2 by direct deubiquitination of p53. SIGNOR-139456 0.731 SIRT2 protein Q8IXJ6 UNIPROT KAT2B protein Q92831 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 12887892 t gcesareni Sir2 forms a complex with the acetyltransferase pcaf and myod and, when overexpressed, retards muscle differentiation. SIGNOR-104248 0.546 FMR1 protein Q06787 UNIPROT DLG4 protein P78352 UNIPROT up-regulates quantity post transcriptional regulation 10090 BTO:0000142 32118033 t lperfetto These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets. SIGNOR-262108 0.486 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser371 AHSSHLKsKKGQSTS 9606 9315650 t llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase. SIGNOR-51280 0.47 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM6 protein O15303 UNIPROT up-regulates activity chemical activation 9606 25042998 t miannu Glutamate is the major excitatory neurotransmitter in the central nervous system. Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate. SIGNOR-264076 0.8 chloroquine chemical CHEBI:3638 ChEBI IL6 protein P05231 UNIPROT down-regulates quantity 9606 32283152 f miannu Chloroquine inhibits the production and release of TNF and IL-6, which indicates that chloroquine may suppress the cytokine storm in patients infected with COVID-19. SIGNOR-260854 0.8 GGCX protein P38435 UNIPROT Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI down-regulates quantity chemical modification 9606 31226734 t lperfetto GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form. SIGNOR-265908 0.8 RIPK1 protein Q13546 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity phosphorylation Ser166 LASFKMWsKLNNEEH -1 18408713 t miannu These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1) SIGNOR-276159 0.2 (R)-salbutamol chemical CHEBI:8746 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 20590599 t Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  SIGNOR-257865 0.8 TNKS protein O95271 UNIPROT CASC3 protein O15234 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 21478859 t lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. SIGNOR-263383 0.2 adenosine smallmolecule CHEBI:16335 ChEBI ADORA3 protein P0DMS8 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257449 0.8 MECP2 protein P51608 UNIPROT GAD1 protein Q99259 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 f miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. SIGNOR-254579 0.377 PPARG protein P37231 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity 9606 23128507 t PAX8-PPARγ fusion protein miannu The PAX8-PPARγ rearrangement leads to strong induction of the PPARγ protein and the consequent abrogation of the normal PPARγ function. PPARγ overexpression abolishes the PTEN-inhibitory effect on immunoactive AKT, which in turn induces the PI3K signaling pathway. SIGNOR-251997 0.468 GATA1 protein P15976 UNIPROT FCER1A protein P12319 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000732 11971001 f Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1. The alpha-chain promoter activity was up-regulated approximately 2-fold by exogenously expressed YY1 or PU.1 and approximately 7-fold by GATA-1, respectively, in KU812 cells SIGNOR-254288 0.315 ERBB3 protein P21860 UNIPROT AR protein P10275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001130 15542423 f gcesareni Suspected erbb receptor involvement in prostate cancer originates partly from the realization that these proteins are capable of promoting the transcriptional activity of the androgen receptor (ar), her2/her3 effects on ar included effects on protein stability and stimulation of dna binding to ar target genes. SIGNOR-130443 0.519 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Thr134 LKFYDSNtVKQKYLS 9606 BTO:0004828 32483448 t lperfetto Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway SIGNOR-273111 0.2 LYN protein P07948 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity phosphorylation Tyr383 IHTGDRPyVCPFDGC 9606 BTO:0002181 26198631 t miannu In the case of Lyn overexpression, single mutations at either tyrosine 8, 254, or 383 severely reduced Lyn-mediated YY1 phosphorylation, suggesting that these three sites may be targets of Lyn in vivo (Fig. 3, A and B). SIGNOR-276928 0.2 DDX3X protein O00571 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity binding 9606 33627125 t miannu DDX3X enhances transcription by interacting with transcription factors to promote their binding to the promoter of the target gene. The best characterized mechanism is its cooperation with the transcription factor SP1. The downstream genes of DDX3X-SP1-mediated transactivation include P21, KRAS, and MDM2 SIGNOR-269195 0.36 PTPN11 protein Q06124 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates dephosphorylation Tyr1023 DLVDAEEyLVPQQGF -1 32024694 t lperfetto ...which in turn suggests the importance SHP2 dephosphorylation of pTyr992 in EGFR and pTyr1023 in HER2 to mediate signaling.|More specifically, we show that acidic residues N-terminal to the substrate pTyr in EGFR and HER2 mediate specific binding by the SHP2 active site, leading to blockade of RasGAP binding and optimal signaling by the two receptors. SIGNOR-262957 0.832 MRPS18B protein Q9Y676 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261452 0.759 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Ser192 HMTNNKGsAAWMAPE 9606 10702308 t lperfetto A mutant of TAK1 that lacks kinase activity is not phosphorylated either following IL-1 treatment or when coexpressed with TAB1, indicating that TAK1 phosphorylation is due to autophosphorylation. Furthermore, mutation to alanine of a conserved serine residue (Ser-192) in the activation loop between kinase domains VII and VIII abolishes both phosphorylation and activation of TAK1. These results suggest that IL-1 and ectopic expression of TAB1 both activate TAK1 via autophosphorylation of Ser-192. SIGNOR-235758 0.2 KLF2 protein Q9Y5W3 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12426306 f fspada Constitutive overexpression of klf2 but not klf15 potently inhibits peroxisome proliferator-activated receptor-gamma (ppargamma) expression with no effect on the upstream regulators c/ebpbeta and c/ebpdelta. SIGNOR-95519 0.428 GPR183 protein P32249 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257110 0.252 IL22 protein Q9GZX6 UNIPROT IL22RA1 protein Q8N6P7 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 12941475 t fspada In addition, il-22 mediates inflammation and binds class ii cytokine receptor heterodimers il-22 ra1/crf2-4. SIGNOR-86340 0.89 bexarotene chemical CHEBI:50859 ChEBI RXRB protein P28702 UNIPROT up-regulates activity chemical activation 9606 BTO:0002058 17483357 t miannu Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification. SIGNOR-259231 0.8 CSNK2A1 protein P68400 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser129 SGSPSDNsGAEEMEV 9606 BTO:0000007 21735093 t gcesareni CK2 hyperactivates AKT by phosphorylation at Ser129 SIGNOR-252595 0.379 MAPK14 protein Q16539 UNIPROT PAK6 protein Q9NQU5 UNIPROT up-regulates phosphorylation Ser165 MPWPEPQsPRVLPNG 9606 15550393 t gcesareni The activation of pak6 by both p38 map kinase and mkk6 suggests that pak6 plays a role in the cellular response to stress-related signals. SIGNOR-130979 0.2 USF1 protein P22415 UNIPROT POMC protein P01189 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19389701 f gcesareni Following uv irradiation, usf-1 is phosphorylated by the p38 stress-activated kinase on threonine 153 and directly up-regulates expression of the pomc, mc1r, tyr, tyrp-1 and dct genes SIGNOR-185575 0.25 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MBP protein P02686 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 16401070 t inferred from 70% family members lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. SIGNOR-270195 0.2 PPM1D protein O15297 UNIPROT H2AX protein P16104 UNIPROT down-regulates dephosphorylation Ser140 GKKATQAsQEY 9606 20118229 t gcesareni Wild-type p53-induced phosphatase 1 dephosphorylates histone variant gamma-h2ax and suppresses dna double strand break repair. Here, we demonstrate that the wild-type p53-induced phosphatase 1 (wip1) also dephosphorylates gamma-h2ax at serine 139 in vitro and in vivo. SIGNOR-163693 0.2 ERCC6 protein Q03468 UNIPROT APEX1 protein P27695 UNIPROT down-regulates activity binding 9606 17567611 t Regulation miannu CSB stimulates the AP site incision activity of APE1 on normal (i.e. fully paired) and bubble AP-DNA substrates, with the latter being more pronounced (up to 6-fold). This activation is ATP-independent, and specific for the human CSB and full-length APE1 protein. CSB and APE1 were also found in a common protein complex in human cell extracts, and recombinant CSB, when added back to CSB-deficient whole cell extracts, resulted in increased total AP site incision capacity. SIGNOR-251932 0.428 PPP2R2B protein Q00005 UNIPROT PDPK1 protein O15530 UNIPROT down-regulates activity binding 9606 21075311 t gcesareni Here, we show that PPP2R2B, encoding the B55² regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. B55²-associated PP2A interacts with PDK1 and modulates its activity toward Myc phosphorylation. SIGNOR-243511 0.337 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr373 ASDTDSSyCIPTAGM 10090 10978177 t HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin SIGNOR-251312 0.492 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT down-regulates quantity by destabilization phosphorylation Ser241 SKQARANsFVGTAQY -1 12177059 t miannu PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241. PDK1 binds to 14-3-3 in vivo and in vitro through the residues surrounding the autophosphorylation site Ser-241 and that the association is achieved only when Ser-241 has been phosphorylated SIGNOR-250077 0.2 KPNA3 protein O00505 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 20454918 t gcesareni Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. SIGNOR-254321 0.33 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 BTO:0002181 16046550 t The effect has been demonstrated using Q01196-8 lperfetto We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-244707 0.2 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation Tyr272 KCNKPTVyGVSPIHD -1 34144039 t miannu  PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. SIGNOR-277305 0.308 EEF1A1P5 protein Q5VTE0 UNIPROT Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269556 0.8 COL18A1 protein P39060 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. Types XV and XVIII collagen are classified as multiplexins, which are heparan sulfate proteoglycans (HSPGs). The multiplexins can bind growth factors and also aid in linking the basement membrane to other basement membrane glycoproteins and endomysium SIGNOR-254679 0.7 monoisononyl phthalate chemical CHEBI:132593 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. SIGNOR-268779 0.8 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Thr74 SVLTGKLtTVFLPIV -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263587 0.404 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr970 GEGYKKKyQQVDEEF -1 19275932 t miannu C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis.  SIGNOR-276143 0.507 P2RY2 protein P41231 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257031 0.382 CNBP protein P62633 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 23774591 t Luana These data verified that the binding of CNBP with c-myc promoter G-quadruplex can indeed down-regulate its associated gene expression for a certain period of time. This result with human CNBP is somehow consistent with previous reports that c-myc G-quadruplex serves as a silencer of c-myc transcription [7] and CNBP promotes the formation of c-myc G-quadruplex. SIGNOR-261571 0.308 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser311 SFRTPRDsKLEAPAE 9606 20151718 t miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation./Phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-163780 0.277 MAPK1 protein P28482 UNIPROT ATP1A1 protein P05023 UNIPROT down-regulates activity phosphorylation Ser16 KYEPAAVsEQGDKKG 1792 BTO:0003069 14976217 t miannu Parathyroid hormone (PTH) inhibits Na+,K+-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the α1-subunit. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit. SIGNOR-262940 0.51 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates activity phosphorylation Ser700 FGEKRKNsILNPINS -1 1377674 t lperfetto Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC. SIGNOR-248850 0.52 PRKAA1 protein Q13131 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates activity phosphorylation Ser374 GDTLLGLsDSEVEEL -1 31805502 t miannu MS-based analysis of immunoprecipitated Nrf2 revealed serine 374, 408 and 433 in human Nrf2 to be hyperphosphorylated as a function of activated AMPK. A direct phosphate-transfer by AMPK to those sites was indicated by in vitro kinase assays with recombinant proteins as well as interaction of AMPK and Nrf2 in cells, evident by co-immunoprecipitation. Mutation of serine 374, 408 and 433 to alanine did not markedly affect half-life, nuclear accumulation or induction of reporter gene expression upon Nrf2 activation with sulforaphane. However, some selected endogenous Nrf2 target genes responded with decreased induction when the identified phosphosites were mutated, whereas others remained unaffected. SIGNOR-277494 0.2 prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 20219869 f apalma Prostaglandins are able to affect muscle cell proliferation (142), differentiation (96) and fusion (141), and can also modulate muscle fiber growth and the synthesis and degradation of proteins in muscle SIGNOR-255360 0.7 GSK3B protein P49841 UNIPROT DNM1L protein O00429 UNIPROT down-regulates activity phosphorylation Ser693 LVGQLYKsSLLDDLL -1 23185298 t miannu After identifying Ser693 as a GSK3beta phosphorylation site, we also determined that K679 is crucial for GSK3beta-binding, which strongly suggests that Drp1 is a novel substrate for GSK3beta. Our results suggest that GSK3beta-mediated phosphorylation at Ser693 does cause a dramatic decrease of GTPase activity; in contrast, GSK3beta-mediated phosphorylation at Ser693 appears not to affect Drp1 inter-/intra-molecular interactions. SIGNOR-276430 0.397 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 t lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. SIGNOR-249004 0.292 GTF2F1 protein P35269 UNIPROT TFIIF complex SIGNOR-C394 SIGNOR form complex binding -1 18218714 t lperfetto Human general transcription factor IIF (TFIIF), a component of the transcription pre-initiation complex (PIC) associated with RNA polymerase II (Pol II), was characterized by size-exclusion chromatography (SEC), electrospray ionization mass spectrometry (ESI-MS), and chemical cross-linking. Recombinant TFIIF, composed of an equimolar ratio of alpha and beta subunits, was bacterially expressed, purified to homogeneity, and found to have a transcription activity similar to a natural one in the human in vitro transcription system. SIGNOR-266194 0.962 CDK14 protein O94921 UNIPROT TAGLN2 protein P37802 UNIPROT down-regulates activity phosphorylation Ser83 PVKKIQAsTMAFKQM 21577206 t lperfetto This newly identified oncogene–tumor suppressor cascade, where oncogenic PFTK1 inactivates a tumor suppressor gene TAGLN2 via phosphorylation|. Our data therefore underline much importance for S83 and S163 residues on TAGLN2 in its actin-binding capacity. SIGNOR-265103 0.32 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates activity phosphorylation Tyr647 RDVHNLDyYKKTTNG 9606 BTO:0000007 11294897 t lperfetto Ligand stimulation leads to autophosphorylation of fgfr3 the two tyrosine residues in the YYKK Motif of the activation loop of fgfrs are required for kinase activity of fgfr1 and fgfr3. SIGNOR-106730 0.2 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Thr26 PPPQPQHtPSPAAPP 9606 22878263 t llicata In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis. SIGNOR-198737 0.42 SRC protein P12931 UNIPROT SH3PXD2B protein A1X283 UNIPROT up-regulates activity phosphorylation Tyr508 DMSASAGyEEISDPD 9606 20943948 t lperfetto C-Src-mediated phosphorylation of NoxA1 and Tks4 induces the reactive oxygen species (ROS)-dependent formation of functional invadopodia in human colon cancer cells|Here, we show that the interaction of noxa1 and tks proteins is dependent on src activity. Interestingly, the abolishment of src-mediated phosphorylation of tyr110 on noxa1 and of tyr508 on tks4 blocks their binding and decreases nox1-dependent ros generation. SIGNOR-264705 0.522 NR3C1 protein P04150 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity 10090 BTO:0000944 11742987 f inferred from 70% of family members gcesareni Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. SIGNOR-269920 0.618 SKI protein P12755 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity binding 9606 BTO:0000848 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-236155 0.731 ZMIZ1 protein Q9ULJ6 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 10090 BTO:0001825 26522984 t miannu The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions SIGNOR-263936 0.463 PRKDC protein P78527 UNIPROT PRKAG1 protein P54619 UNIPROT up-regulates activity phosphorylation Thr284 LKCYLHEtLETIINR -1 31983282 t miannu PRKDC interacted with the AMPK complex and phosphorylated its nucleotide-sensing γ1 subunit PRKAG1/AMPKγ1 at Ser192 and Thr284, both events being significantly reduced upon the activation of the AMPK complex. Alanine substitutions of PRKDC phosphorylation sites in PRKAG1 reduced AMPK complex activation without affecting its nucleotide sensing capacity.  SIGNOR-277504 0.2 SIRT7 protein Q9NRC8 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity deacetylation Lys19 TGGKAPRkQLATKAA 22722849 t lperfetto SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. SIGNOR-275872 0.2 NMI protein Q13287 UNIPROT SOX10 protein P56693 UNIPROT up-regulates activity binding 9606 BTO:0000007 16214168 t miannu we identify an association of Sox10 with the N-myc interactor Nmi. Nmi modulated the transcriptional activity of Sox10 in reporter gene assays. Nmi effects varied between different Sox10 target gene promoters, indicating that Nmi function in vivo may be promoter-specific. SIGNOR-225599 0.439 MAPK1 protein P28482 UNIPROT RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Thr82 HSMSVPTtPTLGFST 9606 17604322 t lperfetto In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE SIGNOR-262958 0.514 Exosome_Complex complex SIGNOR-C255 SIGNOR FUS protein P35637 UNIPROT up-regulates activity relocalization 9606 BTO:0000793 27460707 t P35637:p.Arg495_Tyr526del (mutation increasing interaction) We hypothesized that FUS could be secreted via the exosome pathway. We tested and confirmed that FUS was indeed present in exosomes in both SH-SY5Y and N2A cells (Fig. 6 and Supplemental Fig. 2). It is also noted that the level of the R495X mutant in exosomes was significantly higher than that of WT or the R521G mutant. |It raises the possibility that the exosome-mediated secretion of FUS may contribute to the cell-to-cell propagation of FUS pathology. SIGNOR-262812 0.233 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr632 GRKGSGDyMPMSPKS 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236741 0.912 AURKB protein Q96GD4 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Ser180 KKGGGKKsGKKSYLS 9606 23226345 t lperfetto Aurora b kinase phosphorylates yy1 on serine 184 and to a lesser extent serine 180 at the g2/m stage of the cell cycle (fig. 7). We show that yy1 is rapidly dephosphorylated as the cells exit mitosis, likely by pp1. Also, our data indicates that phosphorylation at serine 180 and serine 184 can affect the dna binding activity of yy1 SIGNOR-200075 0.376 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation 9606 8381049 t inferred from 70% family members gcesareni Activated map kinase phosphorylates cpla2 at ser-505, causing increased enzymatic activity of cpla2, which is only realized upon translocation of cpla2 to the membrane. SIGNOR-270192 0.2 SLC6A8 protein P48029 UNIPROT creatine smallmolecule CHEBI:16919 ChEBI up-regulates quantity relocalization 9606 18652074 t miannu CRT is essential for normal brain function as mutations in the CRT gene (SLC6A8) result in X-linked mental retardation, associated with the almost complete lack of creatine in the brain, severe speech and language delay, epilepsy, and autistic behaviour. SIGNOR-265782 0.8 SBF1 protein O95248 UNIPROT MTMR2 protein Q13614 UNIPROT up-regulates activity binding 9534 BTO:0001538 12668758 t miannu We also demonstrate that MTMR2 interacts with MTMR5 via its coiled-coil domain and that mutations in the coiled-coil domain of either MTMR2 or MTMR5 abrogate this interaction. Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization.  SIGNOR-269803 0.62 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2 protein P10415 UNIPROT up-regulates activity phosphorylation Ser70 RDPVARTsPLQTPAA -1 11323415 t Luana JNK1 directly phosphorylates Bcl2 at Ser70 in vitro and co-localizes with Bcl2 in mitochondrial membranes in vivo. SIGNOR-261133 0.2 PTGDR protein Q13258 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256898 0.252 WRC complex complex SIGNOR-C191 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 20332100 f miannu The activated WAVE complex at the leading edge of lamellipodia promotes actin polymerization at the plasma membrane by activating the Arp2/3 complex. SIGNOR-253578 0.7 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-209773 0.885 Crenolanib chemical CID:10366136 PUBCHEM PDGFRA protein P16234 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191121 0.8 MMP14 protein P50281 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Leu105 NNKDSHSlTTNIMEI -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain SIGNOR-263619 0.2 NRXN1 protein P58400 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 t miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. SIGNOR-265459 0.401 KLF1 protein Q13351 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates 9606 BTO:0000725 28026072 f irozzo Activation of KLF1 at day 10 of the differentiation process when hematopoietic progenitor cells were present, enhanced erythroid commitment and differentiation. SIGNOR-256086 0.7 Adechlorin chemical CID:125913 PUBCHEM ADA protein P00813 UNIPROT down-regulates activity chemical inhibition 9606 2433905 t miannu 2'-Chloropentostatin is a new inhibitor of adenosine deaminase isolated from the fermentation broth of an unidentified actinomycete, ATCC 39365. It contains the aglycone of coformycin, i.e. 3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-o1, coupled to the unusual carbohydrate, 2'-chloro-2'-deoxyribose. 2'-Chloropentostatin is a slightly weaker inhibitor of rat and human adenosine deaminases than coformycin, and considerably weaker than pentostatin. Unlike pentostatin, which appears to undergo a two-stage interaction with adenosine deaminase, 2'-chloropentostatin forms a single enzyme-inhibitor complex. The enzyme-inhibitor complex between adenosine deaminase and 2'-chloropentostatin was much more rapidly dissociable than the complex with pentostatin. SIGNOR-259262 0.8 DIP2A protein Q14689 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity binding 10090 BTO:0003102 33622779 t miannu Here, using cultured hippocampal neurons pooled from both sexes of mice, we provide evidence that binding to cortactin tethers Abl2 in spines, where Abl2 and cortactin maintain the small pool of stable actin required for dendritic spine stability. SIGNOR-266593 0.2 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT up-regulates phosphorylation Ser369 RPSSRASsRASSRPR 9606 16474210 t lperfetto We previously showed that follicle-stimulating hormone (fsh) promoted phosphorylation of cx43 in rat primary granulosa cells. We further identified ser365, ser368, ser369, and ser373 in the carboxy-terminal tail as the major sites of phosphorylation by fsh, and found that the phosphorylation of these residues was essential for channel activity. SIGNOR-144469 0.451 JAK2 protein O60674 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1069 EDSFLQRySSDPTGA 9534 9363897 t Tyrosine at residue 1,068 of the EGFR is proposed to be one of the principal phosphorylation sites and Grb2-binding sites stimulated by growth hormone via Jak2. Our results indicate that the role of EGFR in signalling by growth hormone is to be phosphorylated by Jak2, thereby providing docking sites for Grb2 and activating MAP kinases and gene expression, independently of the intrinsic tyrosine kinase activity of EGFR.¬† SIGNOR-251347 0.6 LDHA protein P00338 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI down-regulates quantity chemical modification 9606 24929216 t Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. SIGNOR-266918 0.8 EGFR protein P00533 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity binding 9606 11350724 t lperfetto Adaptors such as Shc, Grb2, Crk or the recently characterised Dok-R protein (Jones Dumont 1999) show a modular structure containing protein– protein interaction domains and putative phosphorylation sites and act as signalling platforms which extend the receptor’s repertoire of activated intracellular pathways. SIGNOR-107712 0.911 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT down-regulates activity phosphorylation Ser338 KGKRGGHsSVSTESE 9606 10521508 t Manara Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization. SIGNOR-260900 0.2 S1PR3 protein Q99500 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257330 0.358 LEF1 protein Q9UJU2 UNIPROT ELANE protein P08246 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004850 14594802 f miannu We find that LEF-1 and CBFalpha co-activate ELA2 expression. SIGNOR-254550 0.259 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR JUN protein P05412 UNIPROT up-regulates activity 9606 BTO:0000093 8415704 t PML-RAR alpha chimera cooperates with c-Jun and, strikingly, with c-Fos to stimulate the transcription of both synthetic and natural reporter genes containing an AP-1 site SIGNOR-259940 0.2 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Ser567 VLSDNDRsLLERWTR 9606 BTO:0000567 20667468 t miannu Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803. SIGNOR-259823 0.2 UTS2R protein Q9UKP6 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257164 0.268 olodaterol chemical CHEBI:82700 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation -1 20371707 t Luana In vitro, olodaterol showed a potent, nearly full agonistic response at the hbeta(2)-AR (EC(50) = 0.1 nM; intrinsic activity = 88% compared with isoprenaline) and a significant selectivity profile (241- and 2299-fold [corrected] against the hbeta(1)- and hbeta(3)-ARs, respectively).  SIGNOR-257834 0.8 MAPK8 protein P45983 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr450 TAQMITItPPDQDDS 10116 BTO:0003324 16306447 t gcesareni We report that JNKs are necessary for the reactivation of Akt after ischemic injury. We identified Thr450 of Akt as a residue that is phosphorylated by JNKs, and the phosphorylation status of Thr450 regulates reactivation of Akt after hypoxia, apparently by priming Akt for subsequent phosphorylation by 3-phosphoinositide-dependent protein kinase. SIGNOR-252426 0.438 HIPK2 protein Q9H2X6 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Ser882 IVIPDTPsPTVSVIT 9606 BTO:0002181 24145406 t miannu  Here, we deciphered the molecular mechanism of HIPK2 activation and show its relevance for DNA damage-induced apoptosis in cellulo and in vivo. HIPK2 autointeracts and site-specifically autophosphorylates upon DNA damage at Thr880/Ser882. Autophosphorylation regulates HIPK2 activity and mutation of the phosphorylation-acceptor sites deregulates p53 Ser46 phosphorylation and apoptosis in cellulo. SIGNOR-276600 0.2 VHL protein P40337 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity binding 9606 BTO:0000567 17936701 t We found that pVHL associates with the NF-kappaB agonist Card9 but does not target Card9 for destruction. Instead, pVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2. SIGNOR-266899 0.402 FOXO1 protein Q12778 UNIPROT POMC protein P01189 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000614 28270795 f miannu Foxo1 (when activated) stimulates the transcription of AgRP and NPY, but suppresses the transcription of POMC; thereby antagonizing the transcriptional action of STAT3 in these hypothalamic subpopulations. SIGNOR-263503 0.414 NANOG protein Q9H9S0 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 25126380 f flangone Sex determining region Y-box 2 (Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells (PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency.  SIGNOR-242073 0.7 MAP2K4 protein P45985 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9606 7535770 t lperfetto Recently, two MAP kinase kinases (MKK3 and MKK4) that activate p38 MAP kinase have been identified. The mechanism of p38 activation is mediated by dual phosphorylation on Thr-180 and Tyr-182 SIGNOR-27973 0.574 FGFR1 protein P11362 UNIPROT LDHA protein P00338 UNIPROT up-regulates phosphorylation Tyr10 TLKDQLIyNLLKEEQ 9606 21969607 t gcesareni We found that the oncogenic receptor tyrosine kinase fgfr1 directly phosphorylates ldh-a. Phosphorylation at y10 and y83 enhances ldh-a activity by enhancing the formation of active, tetrameric ldh-a and the binding of ldh-a substrate nadh, respectively. SIGNOR-176730 0.374 imiquimod chemical CHEBI:36704 ChEBI TLR7 protein Q9NYK1 UNIPROT up-regulates activity chemical activation 9606 15661881 t miannu Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively. SIGNOR-259244 0.8 PAK4 protein O96013 UNIPROT ITGB5 protein P18084 UNIPROT up-regulates phosphorylation Ser759 REFAKFQsERSRARY 9606 20507994 t llicata Pak4 specifically phosphorylated the integrin beta5 subunit at ser-759 and ser-762 within the beta5-sers-motif. Point mutation of these two serine residues abolished the pak4-induced cell migration, indicating a functional role for these phosphorylations in migration. SIGNOR-165702 0.462 SRC protein P12931 UNIPROT PBK protein Q96KB5 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr74 NPICNDHyRSVYQKR 9606 BTO:0000038 27016416 t miannu Phosphorylation of TOPK at Y74, Y272 by Src increases the stability of TOPK and promotes tumorigenesis of colon SIGNOR-277218 0.404 TAOK2 protein Q9UL54 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates phosphorylation 9606 23431053 t inferred from 70% of family members gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2. SIGNOR-269939 0.283 PTEN protein P60484 UNIPROT PTK6 protein Q13882 UNIPROT down-regulates activity dephosphorylation Tyr342 RLIKEDVyLSHDHNI -1 29142193 t lperfetto PTEN inhibits PTK6 activity and downstream signaling in prostate cancer cells.|Using an in vitro phosphatase assay, we observed that PTEN was able to dephosphorylate PTK6 at tyrosine residue 342 in a dose dependent manner. SIGNOR-276975 0.426 PRKCA protein P17252 UNIPROT PTPN12 protein Q05209 UNIPROT down-regulates phosphorylation Ser39 FMRLRRLsTKYRTEK 9606 7520867 t miannu Ptp-pest is phosphorylated in vitro by both cyclic amp-dependent protein kinase (pka) and protein kinase c (pkc) at two major sites, which we have identified as ser39 and ser435 / phosphorylation of ser39 in vitro decreases the activity of ptp-pest by reducing its affinity for substrate. SIGNOR-27300 0.327 NFIB protein O00712 UNIPROT ROBO1 protein Q9Y6N7 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268900 0.248 GSK3B protein P49841 UNIPROT SRC protein P12931 UNIPROT down-regulates activity phosphorylation Ser493 CPPECPEsLHDLMCQ 9606 BTO:0002181 33388549 t miannu Concurrently, ROCK1 was able to phosphorylate GSK-3β at Ser9, which phosphorylated Src at Ser51 and Ser492 residues, leading to Src inactivation SIGNOR-277544 0.391 bexarotene chemical CHEBI:50859 ChEBI RXR proteinfamily SIGNOR-PF44 SIGNOR up-regulates activity chemical activation 9606 BTO:0002058 17483357 t miannu Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification. SIGNOR-259233 0.8 MAPK14 protein Q16539 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 18691976 t gcesareni Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. SIGNOR-179912 0.605 PTPRG protein P23470 UNIPROT DAB1 protein O75553 UNIPROT down-regulates activity dephosphorylation Tyr198 EDVEDPVyQYIVFEA -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254697 0.2 Liprin-alpha proteinfamily SIGNOR-PF82 SIGNOR KIF1A protein Q12756 UNIPROT up-regulates activity binding 10116 BTO:0003102 30021165 t miannu Kinesin-3 Family Member KIF1A Interacts with Liprin-α and TANC2. TANC2 and Liprin-α Recruit KIF1A-Driven DCVs in Dendritic Spines. Upon Ca2+/CaM binding, KIF1A is activated, allowing for DCV loading and motility. KIF1A-driven DCVs are recruited in dendritic spines by liprin-α and TANC2, which ensure a precise mechanism of synaptic tagging for the vesicles. SIGNOR-266892 0.2 SLBP protein Q14493 UNIPROT H2AW protein Q7L7L0 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265409 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities. SIGNOR-170339 0.2 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates binding 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni In this study, we demonstrate that akt also regulates the activity of fkhrl1, a member of the forkhead family of transcription factors. In the presence of survival factors, akt phosphorylates fkhrl1, leading to fkhrl1's association with 14-3-3 proteins and fkhrl1's retention in the cytoplasm. Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252818 0.702 MC3R protein P41968 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257358 0.275 carfilzomib chemical CHEBI:65347 ChEBI PSMB10 protein P40306 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 17591945 t miannu Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM. SIGNOR-259308 0.8 ACVR1 protein Q04771 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 10090 BTO:0000165 10564272 f gcesareni We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2 SIGNOR-236848 0.749 SPATA13 protein Q96N96 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260576 0.707 UBE2D1 protein P51668 UNIPROT MPG protein P29372 UNIPROT up-regulates activity binding -1 25207814 t miannu Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. We observed that PP2Ac was ubiquitinated in the presence of UbcH5a-c and UbcH6, similar to results obtained with MID1-catalyzed ubiquitination of alpha4 (Figure 2E) SIGNOR-271927 0.2 SMAD3 protein P84022 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 14638857 t gcesareni Nicd and smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and smad3 could be recruited to csl-binding sites on dna in the presence of csl and nicd SIGNOR-254325 0.717 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT unknown phosphorylation Thr1410 STHPHFMtQRALYLA 9606 BTO:0000938 19824698 t lperfetto We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. SIGNOR-188437 0.2 CAMKK2 protein Q96RR4 UNIPROT CAMK4 protein Q16566 UNIPROT up-regulates activity phosphorylation Thr200 EHQVLMKtVCGTPGY 7615569 t llicata Phosphorylation and activation of Ca(2+)-calmodulin-dependent protein kinase IV by Ca(2+)-calmodulin-dependent protein kinase Ia kinase. Phosphorylation of threonine 196 is essential for activation. SIGNOR-250718 0.604 NOTCH1 protein P46531 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782;BTO:0001271;BTO:0000785 16847353 f gcesareni We identified c-myc as a direct target of notch1 SIGNOR-147944 0.656 NUP188 protein Q5SRE5 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262084 0.602 PINK1 protein Q9BXM7 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity phosphorylation Ser65 NCDLDQQsIVHIVQR 9606 BTO:0000007 22724072 t PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65 SIGNOR-270345 0.2 MAPK1 protein P28482 UNIPROT NUP50 protein Q9UKX7 UNIPROT down-regulates activity phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 t gcesareni Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. SIGNOR-188139 0.2 NRF1 protein Q16656 UNIPROT TFB2M protein Q9H5Q4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15684387 f lperfetto Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC SIGNOR-268999 0.54 PRKCQ protein Q04759 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates activity phosphorylation Ser323 LCLQKDPsKRPTAAE -1 14988727 t miannu Recombinant SPAK was phosphorylated on Ser-311 in its kinase domain by PKCtheta, but not by PKCalpha. This synergistic activity, as well as the receptor-induced SPAK activation, required the PKCtheta-interacting region of SPAK, and Ser-311 mutation greatly reduced these activities of SPAK. SIGNOR-276007 0.465 PSME2 protein Q9UL46 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR up-regulates activity binding 35932807 t lperfetto While PA28alpha beta is responsible for promoting peptidase activity of proteasome to facilitate MHC-I antigen processing, but unable to promote protein degradation, PA28gamma is well-known to not only promote peptidase activity but also proteolytic activity of proteasome. SIGNOR-275868 0.615 2-[2-Amino-5-(3,4-dimethoxyphenyl)pyrimidin-4-yl]-5-[(4-bromobenzyl)oxy]phenol smallmolecule CID:135651766 PUBCHEM GIPR protein P48546 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257498 0.8 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Thr515 QKYSMDNtPHTPTPF BTO:0000007 10593981 t llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. SIGNOR-250739 0.711 PTH protein P01270 UNIPROT PTH1R protein Q03431 UNIPROT up-regulates binding 9606 18981475 t gcesareni Here we show that binding of pth to its receptor pth1r induced association of lrp6, a coreceptor of wnt, with pth1r. The formation of the ternary complex containing pth, pth1r, and lrp6 promoted rapid phosphorylation of lrp6, which resulted in the recruitment of axin to lrp6, and stabilization of beta-catenin. SIGNOR-182039 0.763 IRAK3 protein Q9Y616 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT down-regulates binding 9606 25290089 t flangone Irak3 exerts negative regulatory effects through preventing (i) the dissociation of irak1 and irak4 from myd88 irak3 negatively regulates irak signalling through suppression of irak4 and irak1 activation SIGNOR-205434 0.701 MECP2 protein P51608 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR down-regulates quantity by repression transcriptional regulation 10116 BTO:0004102 22262897 t inferred from family member Luana Bicuculline treatment also leads to an increase in the levels of the transcriptional repressor MeCP2, which binds to the GluR2 promoter along with the corepressors HDAC1 and mSin3A. SIGNOR-270237 0.331 Guanfacine chemical CHEBI:5558 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258918 0.8 FYN protein P06241 UNIPROT CD79B protein P40259 UNIPROT up-regulates activity phosphorylation Tyr207 DIDQTATyEDIVTLR -1 9531288 t CD79b cytoplasmic tail-containing GST fusion proteins were phosphorylated in vitro by baculovirus-produced Fyn, >80% of phosphorylation occurred on the N-terminal ITAM tyrosine. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM). pY195 and pY206 in CD79b SIGNOR-251155 0.658 ATM protein Q13315 UNIPROT TERF1 protein P54274 UNIPROT up-regulates activity phosphorylation Ser219 SKLLMIIsQKDTFHS 9606 BTO:0000567 11375976 t lperfetto Telomeric protein pin2/trf1 as an important atm target in response to double strand dna breaks. activated atm directly phosphorylated pin2/trf1 preferentially on the conserved ser(219)-gln site in vitro and in vivo. SIGNOR-108419 0.588 UTS2R protein Q9UKP6 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257377 0.41 TP63 protein Q9H3D4 UNIPROT SUN1 protein O94901 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0005098 28595999 t lperfetto Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by a marked decrease in expression of several nuclear envelope-associated components (Lamin B1, Lamin A/C, Sun1, Nesprin-3, Plectin) compared with controls. Furthermore, chromatin immunoprecipitation-quantitative PCR assay showed enrichment of p63 on Sun1, Syne3, and Plec promoters, suggesting them as p63 targets. SIGNOR-263278 0.2 KAT6B protein Q8WYB5 UNIPROT KAT6A/KAT6B complex SIGNOR-C54 SIGNOR form complex binding 9606 17694082 t miannu Like gcn5/pcaf and p300/cbp, moz and morf are transcriptional co-activators with intrinsic hat activity. SIGNOR-157307 0.39 NatA complex SIGNOR-C415 SIGNOR Protein_acetylation phenotype SIGNOR-PH189 SIGNOR up-regulates 9606 21351257 f miannu About 80% of soluble human proteins are N-terminally acetylated by 1 of 3 major Nα-terminal acetyltransferase complexes, hNatA, hNatB and hNatC, which differ in their subunit composition and substrate specificity. SIGNOR-267229 0.7 PYCARD protein Q9ULZ3 UNIPROT Pyrin inflammasome complex SIGNOR-C226 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256414 0.705 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates phosphorylation Tyr753 ERDINSLyDVSRMYV 9606 11606584 t gcesareni By measuring the ability of human plcgamma2 to restore calcium responses to the b-cell receptor stimulation or oxidative stress in a b-cell line (dt40) deficient in plcgamma2, we have demonstrated that two tyrosine residues, tyr(753) and tyr(759), were important for the plcgamma2 signaling function.Of the two kinases that previously have been proposed to phosphorylate plcgamma2, btk, and syk, purified btk had much greater ability to phosphorylate recombinant plcgamma2 in vitro, whereas syk efficiently phosphorylated adapter protein blnk. SIGNOR-111069 0.769 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273076 0.635 RNF7 protein Q9UBF6 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates activity ubiquitination 9606 23136067 t miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. SIGNOR-271449 0.304 RNF6 protein Q9Y252 UNIPROT LIMK1 protein P53667 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 16204183 t miannu Consistent with a role in axonal growth, we found that Rnf6 binds to, polyubiquitinates, and targets LIMK1 for proteasomal degradation in growth cones of primary hippocampal neurons.  SIGNOR-271481 0.443 LAMP2 protein P13473 UNIPROT Chaperone-mediated autophagy phenotype SIGNOR-PH118 SIGNOR up-regulates activity 10029 BTO:0000977 8662539 f Here, the lysosomal membrane glycoprotein LGP96 was identified as a receptor for the selective import and degradation of proteins within lysosomes. Specific substrates of this proteolytic pathway bound to the cytosolic tail of a 96-kilodalton lysosomal membrane protein in two different binding assays. SIGNOR-259990 0.7 MAVS protein Q7Z434 UNIPROT STING1 protein Q86WV6 UNIPROT up-regulates activity binding 9606 24622840 t miannu MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. SIGNOR-260152 0.2 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser726 IDPASPQsPESVDLV 9606 11604491 t llicata Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728. SIGNOR-111043 0.553 DDX21 protein Q9NR30 UNIPROT JUN protein P05412 UNIPROT up-regulates activity binding 9606 BTO:0000007 ; BTO:0001282 11823437 t SARA C-Jun and RHII/Gu proteins interact in human cells at their endogenous level of expression. The helicase activity of RHII/Gu specifically facilitates c-Jun-mediated transcription. SIGNOR-260977 0.467 IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica IL-4Rα, γc, and IL-13Rα1 all contain proline-rich box-1 regions that bind jak1, jak3, and tyk2, respectively. Il-4 uses the type ii receptor, and IL-13R1 Binds tyk2. Il-13 results in activation of jak1 and tyk2 in hematopoietic and nonhematopoietic cells. SIGNOR-100774 0.705 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR leucine smallmolecule CHEBI:25017 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270413 0.8 TTN protein Q8WZ42 UNIPROT OBSCN protein Q5VST9 UNIPROT up-regulates quantity relocalization 9606 BTO:0003324 19840192 t miannu Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins. SIGNOR-266728 0.597 PRKACA protein P17612 UNIPROT CCND1 protein P24385 UNIPROT unknown phosphorylation Ser90 NYLDRFLsLEPVKKS -1 8058338 t miannu PKA phosphorylates three distinct serine residues in cyclin D1 at positions 90, 197 and 234. SIGNOR-250347 0.339 S100A9 protein P06702 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000876 16690079 t miannu Calcium-induced complexes of S100A8 and S100A9 have been shown to colocalize with microtubules (MTs) during activation of monocytes. Functional analyses demonstrated that the complexes are involved in cytoskeletal organization and that they directly bind to tubulin and promote tubulin polymerization in a calcium-dependent manner SIGNOR-261936 0.2 adrenaline smallmolecule CHEBI:33568 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) SIGNOR-257878 0.8 Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 30397315 f miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270700 0.7 WNT10B protein O00744 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 12055200 f fspada We have identified wnt10b as a potent inhibitor of adipogenesis that must be suppressed for preadipocytes to differentiate in vitro SIGNOR-89131 0.7 MAPK1 protein P28482 UNIPROT LIN28A protein Q9H9Z2 UNIPROT down-regulates activity phosphorylation Ser200 EEEEEIHsPTLLPEA 9606 BTO:0000567 28179426 t miannu Here we show that Lin28a is directly phosphorylated by ERK1/2 kinases at Ser-200.  SIGNOR-277338 0.265 SOD2 protein P04179 UNIPROT dioxygen smallmolecule CHEBI:15379 ChEBI up-regulates quantity chemical modification 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272282 0.8 L-thyroxine smallmolecule CHEBI:18332 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 8755651 t scontino Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5‚Äô-position) to yield T3 SIGNOR-268127 0.8 SLIT2 protein O94813 UNIPROT GPC1 protein P35052 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 10364234 t gcesareni Slit family proteins are functional ligands of glypican-1 in nervous tissue and suggest that their interactions may be critical for certain stages of central nervous system histogenesis. SIGNOR-68428 0.587 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 t esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. SIGNOR-89248 0.458 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 BTO:0000007 11970898 t Immunoblots with phospho-specific antibodies confirmed that PTP1B suppresses phosphorylation of the Jak2 activation site tyrosines (Y1007/Y1008) and Stat3 in a dose-dependent manner SIGNOR-248404 0.789 MIR9-1HG protein Q13536 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002874 10995546 t Luana CROC-4: a novel brain specific transcriptional activator of c-fos expressed from proliferation through to maturation of multiple neuronal cell types. SIGNOR-261569 0.2 EGFR protein P00533 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr177 RFLKSPAyRDLAAQA 9606 11602604 t lperfetto Rgs16 contains two conserved tyrosine residues in the rgs box, tyr(168) and tyr(177), which are predicted sites of phosphorylation. Rgs16 underwent phosphorylation in response to m2 muscarinic receptor or egfr stimulation in hek 293t or cos-7 cells, which required egfr kinase activity. Mutational analysis suggested that rgs16 was phosphorylated on both tyrosine residues (tyr(168) tyr(177)) after egf stimulation.Phosphorylated rgs16 demonstrated enhanced gtpase accelerating (gap) activity on galpha(i). Mutation of tyr(168) to phenylalanine resulted in a 30% diminution in rgs16 gap activity mutation of tyr(177) to phenylalanine had no effect on rgs16 gap activity but also abolished its regulation of g(i)-mediated signal transduction in these cells. SIGNOR-111024 0.425 SCF-FBW7 complex SIGNOR-C135 SIGNOR PDCD1 protein Q15116 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys233 LDFQWREkTPEPPVP 9606 BTO:0000007 36104103 t miannu We identified FBW7 as a E3 ubiquitin ligase for PD-1 protein, in which FBW7 promotes the K48-linked polyubiquitination of PD-1 protein at Lys233 residue. SIGNOR-277606 0.2 CREB1 protein P16220 UNIPROT PCSK1 protein P29120 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8999965 f miannu both CREB-1 and ATF-1 transactivate the human PC1 promoter in transient transfection experiments. SIGNOR-253789 0.2 HK2 protein P52789 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266456 0.8 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2Q2 protein Q8WVN8 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271329 0.492 ADCY1 protein Q08828 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity 9606 27065076 f Gianni Adenylate cyclases (AC) produce cAMP from adenosin-tri-phosphate (ATP). High levels of cytosolic cAMP lead to activation of protein kinase A (PKA) SIGNOR-262528 0.492 DRAM2 protein Q6UX65 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30755245 f irozzo DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression. SIGNOR-259146 0.311 AHCYL2 protein Q96HN2 UNIPROT PAPOLB protein Q9NRJ5 UNIPROT down-regulates activity binding 9606 BTO:0000007 19224921 t lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. SIGNOR-268332 0.2 4-oxobutanoate smallmolecule CHEBI:57706 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity precursor of 9606 19300440 t miannu Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix. SIGNOR-266615 0.8 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR RAD52 protein P43351 UNIPROT up-regulates activity phosphorylation Tyr104 DLNNGKFyVGVCAFV 9606 23836560 t Manara Have found that BCR-ABL1 interacts with the C-terminal portion of RAD52, resulting in tyrosine phosphorylation of Y104 located in RAD52 DNA II and enhanced nuclear foci formation SIGNOR-262531 0.2 MAPK8 protein P45983 UNIPROT BMF protein Q96LC9 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 12591950 t miannu Activated JNK causes BimL and Bmf phosphorylation in vivo. It is known that UV radiation causes the release of Bim and Bmf from dynein and myosin V motor complexes and that these proteins cause Bax/Bak-dependent apoptosis . The results of this study demonstrate that JNK can engage this apoptotic pathway by phosphorylation of BH3-only proteins, including Bim and Bmf. SIGNOR-250116 0.677 LRFN5 protein Q96NI6 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments. SIGNOR-264098 0.7 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 BTO:0000782 8892604 t lperfetto Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function SIGNOR-44665 0.717 Bafetinib chemical CID:24853523 PUBCHEM BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 21154127 t irozzo Bafetinib (NS-187, INNO-406) is a second-generation tyrosine kinase inhibitor in development by CytRx under license from Nippon Shinyaku for treating Bcr-Abl+ leukemia's, including chronic myelogenous leukemia (CML) and Philadelphia+ acute lymphoblastic leukemia. It is a rationally developed tyrosine kinase inhibitor based on the chemical structure of imatinib, with modifications added to improve binding and potency against Bcr-Abl kinase. SIGNOR-255819 0.8 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 t lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. SIGNOR-109559 0.666 TRIM11 protein Q96F44 UNIPROT PHOX2B protein Q99453 UNIPROT down-regulates ubiquitination 9606 22307522 t miannu The e3 ubiquitin ligasetrim11mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expandedphox2b. SIGNOR-195878 0.498 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFV3 protein P56181 UNIPROT up-regulates activity phosphorylation Ser105 QPSSGREsPRH 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275601 0.2 PRKDC protein P78527 UNIPROT FH protein P07954 UNIPROT up-regulates activity phosphorylation Thr236 IKIGRTHtQDAVPLT -1 26237645 t miannu We show that exposure to ionizing radiation induces DNA-PK-dependent phosphorylation of nuclear fumarase at Thr 236, which leads to an interaction between fumarase and the histone variant H2A.Z at DNA double-strand break (DSB) regions.  SIGNOR-266349 0.2 alvocidib chemical CHEBI:47344 ChEBI CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192104 0.8 USP15 protein Q9Y4E8 UNIPROT BRAP protein Q7Z569 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 23105109 t miannu Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. SIGNOR-272030 0.27 HLF protein Q16534 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23415677 f miannu Ectopic hlf expression inhibits apoptosis in murine and human cells, suggesting that hlf is regulating a conserved transcriptional program that inhibits cell death. SIGNOR-201034 0.7 KCNIP3 protein Q9Y2W7 UNIPROT PDYN protein P01213 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12667101 f miannu As a transcriptional repressor, DREAM may control the expression of the endogenous opioid gene prodynorphin amongst others, and itself is exquisitely regulated by second messenger molecules, protein kinases and other transcription factors. SIGNOR-254540 0.362 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation 10029 BTO:0000246 15379552 t inferred from 70% family members lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-270060 0.2 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Ser28 SRMNGLPsPTHSAHC -1 14741103 t llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. These were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35 (Figure 3D). However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. | Therefore, S28 residue may be a substrate in vitro, but our best efforts failed to detect phosphorylation of S28 in vivo. SIGNOR-250654 0.415 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252844 0.908 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120144 0.316 PTPN5 protein P54829 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates activity dephosphorylation Tyr1474 GSSNGHVyEKLSSIE 9606 19625523 t lperfetto In addition, STEP 61 dephosphorylates the tyr 1472 on the NR2B subunit of the NMDAR, which promotes internalization of the NMDAR complex. SIGNOR-276991 0.563 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser233 VSSQHRYsTPHAFTF 9534 12801936 t miannu Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. Cyclic AMP (cAMP) blocks Raf-1 activation by stimulating its phosphorylation on serine 43 (Ser43), serine 233 (Ser233), and serine 259 (Ser259). SIGNOR-250040 0.482 HSPA8 protein P11142 UNIPROT CFTR protein P13569 UNIPROT down-regulates quantity binding 9606 BTO:0000007 21148293 t miannu JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation. JB12 drives Hsc70 to associate with CFTR and the RMA1 E3 complex SIGNOR-271492 0.658 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr279 PPLEYQPyQSIYVGG 9606 BTO:0000007 8955135 t lperfetto In the present study, we demonstrate that bcr tyr-246 and at least one of the closely spaced tyrosine residues, tyr-279, tyr-283, and tyr- 289 (3y cluster), are phosphorylated by fes both in vitro and in 32p(i)- labeled cells. tyrosine phosphorylation of bcr by fes suppressed bcr serine/threonine kinase activity toward the 14-3-3 protein and bcr substrate, bap-1. SIGNOR-45334 0.375 DEPTOR protein Q8TB45 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity binding 9606 BTO:0000007 19446321 t DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival SIGNOR-251658 0.717 HSD3B1 protein P14060 UNIPROT androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI up-regulates quantity chemical modification 9606 BTO:0000056 2139411 t lperfetto The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione. SIGNOR-268638 0.8 NEXMIF protein Q5QGS0 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 BTO:0000938 27822498 f miannu The X-Linked Autism Protein KIAA2022/KIDLIA Regulates Neurite Outgrowth via N-Cadherin and δ-Catenin Signaling. We found that KIDLIA is distributed exclusively in the nucleus SIGNOR-269659 0.7 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser379 AGAPGALsPSYDGGL 9606 19801649 t llicata Mlk2 inhibits e47 transactivation activity on the trkb promote SIGNOR-161540 0.2 NatB complex SIGNOR-C416 SIGNOR Protein_acetylation phenotype SIGNOR-PH189 SIGNOR up-regulates 9606 21351257 f miannu About 80% of soluble human proteins are N-terminally acetylated by 1 of 3 major Nα-terminal acetyltransferase complexes, hNatA, hNatB and hNatC, which differ in their subunit composition and substrate specificity. SIGNOR-267232 0.7 BACH1 protein O14867 UNIPROT GAPDH protein P04406 UNIPROT up-regulates quantity transcriptional regulation 9606 31257027 t BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells. SIGNOR-259339 0.2 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser400 AKTSTRSsAKTLKNR 9606 BTO:0000590 20679343 t lperfetto Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3? SIGNOR-167290 0.728 MAPKAPK2 protein P49137 UNIPROT ARPC5 protein O15511 UNIPROT unknown phosphorylation Ser77 AVKDRAGsIVLKVLI -1 12829704 t miannu MAPKAPK2 also phosphorylated p16-Arc in intact Arp2/3 complexes precipitated from neutrophil lysates. Mutation of serine-77 to alanine on the A isoform prevented phosphorylation by MAPKAPK2. SIGNOR-250144 0.358 PRKACA protein P17612 UNIPROT HAND1 protein O96004 UNIPROT down-regulates activity phosphorylation Thr107 PKKERRRtESINSAF 10116 BTO:0001556 14636580 t miannu In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function. SIGNOR-249991 0.3 FYN protein P06241 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr200 SMESIDDyVNVPESG 9606 BTO:0000782 16938345 t gcesareni Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk. SIGNOR-149174 0.739 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR TP53 protein P04637 UNIPROT up-regulates quantity by expression 9606 15044535 f gcesareni These results indicate that nf-kb actions occur upstream of p53 to regulate both p53 levels and activity. SIGNOR-123602 0.499 HOOK3 protein Q86VS8 UNIPROT MSR1 protein P21757 UNIPROT down-regulates binding 9606 BTO:0000801 17237231 t miannu We have identified a microtubule-binding protein, hook3, as a novel interacting partner of sr-a. / by transfecting small interfering rna targeting hook3, total and surface expression, receptor-mediated ligand uptake and protein stability of sr-a were significantly promoted, whereas the protein synthesis and maturation were not altered. We propose for the first time that hook3 may participate in the turnover of the endocytosed scavenger receptor SIGNOR-152314 0.339 SIRT1 protein Q96EB6 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity deacetylation 10090 24003218 t lperfetto SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 SIGNOR-217972 0.909 FOXA2 protein Q9Y261 UNIPROT SLCO1B3 protein Q9NPD5 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14739090 f lperfetto The human organic anion transporting polypeptide 8 (SLCO1B3) gene is transcriptionally repressed by hepatocyte nuclear factor 3beta in hepatocellular carcinoma. SIGNOR-268987 0.2 CDK3 protein Q00526 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 19118012 t gcesareni Egf-induced cdk3 activation caused c-jun phosphorylation at ser63 and ser73, resulting in increased ap-1 transactivation. SIGNOR-183013 0.455 PKA proteinfamily SIGNOR-PF17 SIGNOR PRKD1 protein Q15139 UNIPROT up-regulates activity phosphorylation Ser742 GEKSFRRsVVGTPAY 18692497 t lperfetto The results presented in this study indicate that during mitosis, PKD3 and PKD are phosphorylated at Ser(731) and Ser(744) within their activation loop by a mechanism that requires protein kinase C. Mitosis-associated PKD3 Ser(731) and PKD Ser(744) phosphorylation is related to the catalytic activation of these kinases as evidenced by in vivo phosphorylation of histone deacetylase 5, a substrate of PKD and PKD3. SIGNOR-275925 0.2 Core Binding Factor complex complex SIGNOR-C214 SIGNOR SPI1 protein P17947 UNIPROT up-regulates quantity by expression methylation 10090 BTO:0002884 22012064 t irozzo Furthermore, we show that both MLL and AML1/CBFβ are required for maintaining the H3K4-me3 mark at the PU.1 upstream regulatory element (URE) and promoter region, and for full PU.1 gene expression. SIGNOR-255875 0.53 acetyl-CoA smallmolecule CHEBI:15351 ChEBI Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates activity 9606 10893421 f Acetyl-CoA carboxylase (ACC) catalyzes the first committed step of the fatty acid synthetic pathway. Although ACC has often been proposed to be a major rate-controlling enzyme of this pathway, no direct tests of this proposal in vivo SIGNOR-267383 0.7 cabozantinib chemical CHEBI:72317 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000184 26536165 t miannu Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. SIGNOR-262243 0.8 PFAS protein O15067 UNIPROT N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI down-regulates quantity chemical modification 9606 33179964 t miannu The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure. SIGNOR-267309 0.8 CSNK2A1 protein P68400 UNIPROT HSP90AB1 protein P08238 UNIPROT down-regulates phosphorylation Ser226 KEREKEIsDDEAEEE 9606 18591256 t gcesareni Although the kinase responsible for hsp90? Phosphorylation in vivo is not known, it has been reported that ck2 can phosphorylate these sites in vitro (24). Thus, we prephosphorylated recombinant hsp90? With ck2 before addition to the reaction. Remarkably, hsp90? Phosphorylation greatly reduced its ability to inhibit apaf-1 oligomerization and caspase-9 recruitment (fig. 5b). These results indicate that the phosphorylation status of hsp90? Significantly impacts its ability to inhibit apoptosome formation. SIGNOR-179260 0.339 GH1 protein P01241 UNIPROT PRLR protein P16471 UNIPROT up-regulates binding 9606 7984244 t gcesareni Hprl does not bind to the hgh receptor, but hgh binds to both the hghr and hprlr, and mutagenesis studies have shown that the receptor-binding sites on hgh overlap. SIGNOR-35575 0.768 FHIT protein P49789 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18077326 f miannu In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin. SIGNOR-159867 0.274 HMOX1 protein P09601 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000848 17148680 f irozzo Here we investigated the effects of HO-1 overexpression in murine and human melanoma cells. The most important findings of our study are that 1) overexpression of HO-1 augments the proliferation [.] SIGNOR-256295 0.7 glycine smallmolecule CHEBI:15428 ChEBI GLRA3 protein O75311 UNIPROT up-regulates activity chemical activation 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 t miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. SIGNOR-264982 0.8 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12950161 t lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases SIGNOR-86684 0.346 MAPK8IP1 protein Q9UQF2 UNIPROT MAP3K12 protein Q12852 UNIPROT down-regulates binding 9606 11432832 t gcesareni Jip inhibits dlk dimerization. SIGNOR-109046 0.53 WWTR1 protein Q9GZV5 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 21084559 t gcesareni Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal. SIGNOR-169841 0.536 EEF1A1P5 protein Q5VTE0 UNIPROT His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269551 0.8 PRKCD protein Q05655 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 16377624 t llicata Here, we show that the pro-apoptotic kinase, protein kinase c delta (pkcdelta), is involved in phosphorylation of p53 on ser(46). pkcdelta potentiates p53-dependent apoptosis by ser(46) phosphorylation in response to genotoxic stress. SIGNOR-143382 0.664 PRKAR2B protein P31323 UNIPROT PRKAR2B protein P31323 UNIPROT up-regulates activity phosphorylation Ser114 NRFTRRAsVCAEAYN 10090 15822905 t miannu Ser114 (the autophosphorylation site) of human RII beta. Point mutation of the autophosphorylation site or in the nuclear location signal causes protein kinase A RII beta regulatory subunit to lose its ability to revert transformed fibroblasts. SIGNOR-250076 0.2 STAT6 protein P42226 UNIPROT KLF4 protein O43474 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22378047 t lperfetto STAT6 coordinates and synergizes with both PPAR? and KrŸppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function. SIGNOR-249568 0.352 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Thr169 TEAPAVVtEEEDDDE 9606 BTO:0004828 32483448 t lperfetto Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway SIGNOR-273112 0.2 ZMYND8 protein Q9ULU4 UNIPROT ADORA1 protein P30542 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 21620140 t Luana We also confirmed transcriptional coactivator functions of ZMYND8 in ERα-driven reporter assays and on endogenous E2-dependent genes (Figure 5F,G). siRNA knockdown of ZMYND8 showed markedly decreased transcription at the presumptive ERα/Z3 target genes ADORA1 and NAV2, while the classical ERα targets pS2/TFF1 and GREB1 appear to be less affected (Figure 5G), suggesting likely gene-specificity of ZMYND8.  SIGNOR-266208 0.2 TFE3 protein P19532 UNIPROT CLCN7 protein P51798 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276814 0.288 MAPK1 protein P28482 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates phosphorylation Ser165 LFQLGPPsPVKMPSP 9606 10906323 t gcesareni Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function. SIGNOR-79515 0.36 ZMYM2 protein Q9UBW7 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity binding 9606 BTO:0000599 32439918 t miannu Here we have identified the zinc-finger proteins ZMYM2 and ZMYM4 as novel B-MYB binding proteins. B-MYB has been implicated in cell cycle progression at two steps, namely at the G1/S- and the G2/M-transition. ZMYM2 is required for the G1/S-transition in HepG2 cells. SIGNOR-269801 0.2 CSNK2A1 protein P68400 UNIPROT HCLS1 protein P14317 UNIPROT unknown phosphorylation Thr16 DVSVSVEtQGDDWDT 9606 10806407 t llicata The in vivo Ser/Thr phosphorylation of HS1 is enhanced by okadaic acid and reduced by specific inhibitors of casein kinase (CK)2. In vitro, HS1 is an excellent substrate for either CK2 alpha subunit alone (Km = 47 nM) or CK2 holoenzyme | It is likely therefore that Thr16 and/or Thr23 account for the phosphate incorporated into HS1 threonyl residue(s) upon incubation with CK2. SIGNOR-250885 0.312 NPY protein P01303 UNIPROT NPY4R protein P50391 UNIPROT up-regulates binding 9606 BTO:0000142 7592911 t gcesareni Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid. SIGNOR-29633 0.68 ARID1A protein O14497 UNIPROT Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270751 0.758 CDK4 protein P11802 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 t gcesareni In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-176515 0.287 MMP14 protein P50281 UNIPROT ADAM9 protein Q13443 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0000007 22632802 t Giulio Here we show that MT1-MMP forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9|Western blotting using antibodies against ectodomain of ADAM9 detected a fragment (around 26 kDa) of ADAM9 in the conditioned culture medium from cells cotransfected with wild-type MT1-MMP, but not in that with catalytic activity-dead MT1-MMP (Figure 6A, top). SIGNOR-260301 0.347 IL1B protein P01584 UNIPROT IL1R2 protein P27930 UNIPROT down-regulates binding 9606 BTO:0000876 8332913 t gcesareni Interleukin-1 (il-1) interacts with cells through two types of binding molecules, il-1 type i receptor (il-1r i) and il-1r ii. Il-1r ii inhibits il-1 activity by acting as a decoy target for il-1 SIGNOR-38302 0.874 CDH5 protein P33151 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265867 0.751 TP53 protein P04637 UNIPROT AIFM1 protein O95831 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23506862 t miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. SIGNOR-267462 0.359 VIPAS39 protein Q9H9C1 UNIPROT CHEVI complex complex SIGNOR-C269 SIGNOR form complex binding 9606 BTO:0000007 29778605 t lperfetto It has been recently suggested that VPS33B and VIPAR comprise two subunits of a novel multi-subunit tethering complex (named "CHEVI") SIGNOR-261831 0.781 belinostat chemical CHEBI:61076 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257744 0.8 MAPK13 protein O15264 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 t lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK SIGNOR-264449 0.2 RIMS1 protein Q86UR5 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 31679900 t miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle SIGNOR-264381 0.798 GCG protein P01275 UNIPROT GCGR protein P47871 UNIPROT up-regulates binding 9606 BTO:0000007 22863277 t milica In contrast, stimulation of gs-coupled receptors by glucagon or epinephrine activates lats1/2 kinase activity, thereby inhibiting yap function. SIGNOR-198504 0.768 STUB1 protein Q9UNE7 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity binding -1 12150907 t miannu In this study, we found that CHIP promotes Parkin-mediated Pael-R ubiquitination and subsequent degradation. In vitro ubiquitination assays suggested that only a combination of both Parkin and its cofactor CHIP function as a ubiquitin ligase, which is able to sufficiently ubiquitinate Pael-R in vivo (Figure 6).  SIGNOR-272888 0.2 EP300 protein Q09472 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates binding 9606 SIGNOR-C6 12419246 t gcesareni Thus, Ski/SnoN represses TGFβ signaling by multiple mechanisms. In addition to recruitment of a transcriptional repressor complex and dissociation of the transcriptional coactivator p300/CBP from the Smads SIGNOR-95462 0.414 NR0B1 protein P51843 UNIPROT NCOR2 protein Q9Y618 UNIPROT up-regulates activity binding 9606 BTO:0002588 19237537 t miannu The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes. SIGNOR-271785 0.401 CDK1 protein P06493 UNIPROT ERF protein P50548 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C17 7588608 t lperfetto Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf SIGNOR-29501 0.2 PPARGC1A protein Q9UBK2 UNIPROT IGF1 protein P05019 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 23217713 t miannu PGC-1 alpha specifically induces IGF1 and represses myostatin, and expression of PGC-1a 4 in vitro and in vivo induces robust skeletal muscle hypertrophy SIGNOR-256152 0.346 tyrosine smallmolecule CHEBI:18186 ChEBI Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates quantity precursor of 9606 16429158 t miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr SIGNOR-270524 0.8 SLBP protein Q14493 UNIPROT H2BC13 protein Q99880 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265389 0.2 PRKCI protein P41743 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000527 21419810 t lperfetto In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer SIGNOR-172890 0.325 pizotifen chemical CHEBI:50212 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9205951 t miannu The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively. SIGNOR-258617 0.8 ATP6AP1 protein Q15904 UNIPROT RAB7A protein P51149 UNIPROT up-regulates activity binding 22467241 t lperfetto We found that Ac45 colocalized with Rab7 in resorbing osteoclasts cultured on bone slices (Fig. 6A). In addition, a co-immunoprecipitation assay revealed that Ac45 directly interacted with Rab7| Therefore, Ac45’s role in extracellular acidification, lysosomal trafficking, and cathepsin K exocytosis may be through the Rab7 pathway. SIGNOR-261484 0.294 INO80E protein Q8NBZ0 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270845 0.637 LFNG protein Q8NES3 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000975 12486116 t gcesareni We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1. SIGNOR-96537 0.747 BIRC3 protein Q13489 UNIPROT BIRC3 protein Q13489 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000567 14960576 t amattioni Ciap1 and ciap2 undergo autoubiquitination and degradation upon binding to the iap antagonist second mitochondrial activator of caspases (smac)/direct iap-binding protein with low pi (diablo), which is released from the mitochondria. SIGNOR-121880 0.2 PRKCQ protein Q04759 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates activity phosphorylation Thr217 LEPEALHtPTLMTTP 9606 27816489 t Manara PKCθ-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors. SIGNOR-260878 0.2 ITGB1BP1 protein O14713 UNIPROT ITGB1 protein P05556 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257638 0.756 PRKACA protein P17612 UNIPROT GJA5 protein P36382 UNIPROT up-regulates activity phosphorylation Ser120 RAKEVRGsGSYEYPV 9606 BTO:0003477 10728420 t miannu Gap junction channels formed of Cx40 are modulated by protein-kinase-A-mediated phosphorylation. Macroscopic conductance and permeability of Cx40 gap junctions is strongly increased by cAMP. two serine residues that can be phosphorylated by PKA, S120 and S345 SIGNOR-250357 0.312 LRIG1 protein Q96JA1 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates ubiquitination 9606 16123311 t gcesareni We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation. SIGNOR-139948 0.412 FHIT protein P49789 UNIPROT MMP14 protein P50281 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18077326 f miannu In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin. SIGNOR-159876 0.281 TLR9 protein Q9NR96 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 10090 22664090 t miannu To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266742 0.7 GYS2 protein P54840 UNIPROT UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI down-regulates quantity chemical modification 9606 26882899 t miannu Glycogenin initiates the first step of glycogen synthesis by self glycosylation of a short 8–12 glucose oligosaccharide primer. Glycogen synthase (GYS) elongates the glucose oligossacharide primer, which utilises UDP-glucose as the glucosyl donor. SIGNOR-267937 0.8 CDK2 protein P24941 UNIPROT DLG1 protein Q12959 UNIPROT up-regulates phosphorylation Ser443 FLGQTPAsPARYSPV 9606 19066288 t llicata We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor. phosphorylation on ser158 and ser442 enhances nuclear expression of dlg1 SIGNOR-182765 0.286 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser301 SSSPNNLsPTGWSQP 9606 16407412 t lperfetto Using mass spectrometry, we identified raf-1 phosphorylation on three sp motif sites: s289/s296/s301. These sites were phosphorylated by extracellular signal-regulated kinase (erk)-1 in vitro, and their phosphorylation in vivo was dependent on endogenous erk activity. Functionally, erk-1 expression sustains raf-1 activation in a manner dependent on raf-1 phosphorylation on the identified sites, and s289/296/301a substitution markedly decreases the in vivo activity of raf-1 s259a. SIGNOR-244685 0.2 SOD2 protein P04179 UNIPROT hydrogen peroxide smallmolecule CHEBI:16240 ChEBI up-regulates quantity chemical modification 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272283 0.8 ATM protein Q13315 UNIPROT AVEN protein Q9NQS1 UNIPROT up-regulates activity phosphorylation Ser135 VNNESGEsQRGTDFS -1 18571408 t miannu Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM after DNA damage is enhanced by ATM-mediated Aven phosphorylation. We found that mutating S135 and S308 sites to Alanine largely dampened Aven’s phosphorylation by ATM (though some phosphorylation remained, due to either a contaminating kinase or an unidentified ATM phosphorylation site). SIGNOR-262636 0.39 ER stress stimulus SIGNOR-ST9 SIGNOR QRICH1 protein Q2TAL8 UNIPROT up-regulates 9606 33384352 f miannu QRICH1 promotes cell death under ER stress SIGNOR-269398 0.7 PAK5 protein Q9P286 UNIPROT PAK5 protein Q9P286 UNIPROT up-regulates activity phosphorylation His22 SNFEHRVhTGFDPQE -1 12860998 t miannu Active form of Cdc42, but not Rac1 and Rho, protein was able to activate the purified GST-Pak5 autophosphorylation and kinase activity. Mutations of Pak5, which disrupted the interaction of Cdc42 and Pak5, also abolished the induction of autophosphorylation.  The H19L/H22L mutant of Pak5 was insensitive to the Cdc42-induced autophosphorylation. SIGNOR-250249 0.2 vorinostat chemical CHEBI:45716 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257923 0.8 STAT3 protein P40763 UNIPROT S100A9 protein P06702 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18809714 f miannu Accumulation of myeloid-derived suppressor cells (MDSCs) associated with inhibition of dendritic cell (DC) differentiation is one of the major immunological abnormalities in cancer and leads to suppression of antitumor immune responses. The molecular mechanism of this phenomenon remains unclear. We report here that STAT3-inducible up-regulation of the myeloid-related protein S100A9 enhances MDSC production in cancer. SIGNOR-261931 0.381 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates 9606 23450633 f inferred from 70% of family members gcesareni Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism. SIGNOR-269861 0.7 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000130;BTO:0000801;BTO:0000876 7535770 t lperfetto Recently, two map kinase kinases (mkk3 and mkk4) that activate p38 map kinase have been identified. the mechanism of p38 activation is mediated by dual phosphorylation on thr-180 and tyr-182. SIGNOR-236103 0.716 N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester chemical CHEBI:94306 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000785 31016515 t Gianni We explored the anti-tumor effect and the molecular mechanism of cay10603, a potent HDAC6 inhibitor in Burkitt's lymphoma cells. SIGNOR-262205 0.8 NR1I2 protein O75469 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000003 18540626 f miannu Among approximately 40 kinds of phytochemicals, tangeretin and ginkgolides A and B markedly induced the PXR-dependent transcriptional activity and also the activity of the human MDR1 promoter. The expression levels of MDR1 mRNA as well as of CYP3A4 mRNA, another gene regulated by PXR, were significantly increased by these phytochemicals. SIGNOR-254834 0.47 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-235933 0.702 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation 21443865 t The MAPT H1 haplotype and subhaplotypes may be associated with sporadic tauopathies including AD. And that, tau's phosphorylation is regulated by many protein kinases, including glycogen synthase kinase 3beta (GSK3B). SIGNOR-255486 0.728 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 19188143 t gcesareni Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183652 0.697 PTPN2 protein P17706 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 9606 12612081 f acerquone We found that insulin-induced ir tyrosine phosphorylation and pkb/akt sig- naling were enhanced in tcptp- cells and suppressed upon tcptp reconstitution, providing persuasive evidence that tcptp can regulate ir activation and signaling. SIGNOR-98811 0.364 TLN1 protein Q9Y490 UNIPROT A3/b1 integrin complex SIGNOR-C161 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257610 0.641 TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser467 SVRCSSMs 9534 9346908 t lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-beta (TGF-beta) type I receptor, TbetaRI. Phosphorylation sites on Smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. SIGNOR-235995 0.818 TRIP12 protein Q14669 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 20208519 t miannu ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF. SIGNOR-266781 0.6 A6/b4 integrin complex SIGNOR-C174 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269023 0.7 PTPRF protein P10586 UNIPROT DAPK1 protein P53355 UNIPROT up-regulates dephosphorylation Tyr491 CAAWHGYySVAKALC 9606 17803936 t amattioni Lar tyrosine phosphatase dephosphorylates dapk at py491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of dapk SIGNOR-157706 0.2 CAK complex complex SIGNOR-C456 SIGNOR TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 t lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269318 0.851 HMOX1 protein P09601 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26722274 f irozzo The results of the present study indicated that knockdown of HMOX-1 significantly enhanced doxorubicin-induced apoptosis and downregulated the expression of Bcl-2 and Bcl-xL in breast cancer cells. SIGNOR-256303 0.252 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RHOA protein P61586 UNIPROT up-regulates activity phosphorylation Ser88 LMCFSIDsPDSLENI 9534 BTO:0000298 26816343 t miannu We have recently reported that Rac1 is phosphorylated on threonine 108 (108T) by extracellular signal-regulated kinases (ERK) in response to epidermal growth factor (EGF) stimulation. Here, we provide evidence that RhoA is phosphorylated by ERK on 88S and 100T in response to EGF stimulation. SIGNOR-277202 0.2 INPPL1 protein O15357 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 9606 BTO:0000776 10942391 f lperfetto Taken together, the data presented here demonstrate that ship inhibits akt primarily through regulation of akt membrane localization. SIGNOR-244406 0.635 ritanserin chemical CHEBI:64195 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258691 0.8 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT up-regulates activity phosphorylation Thr285 QMRQRKGtLSVNFVD -1 27292631 t miannu We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment. SIGNOR-274061 0.308 CDKL5 protein O76039 UNIPROT AMPH protein P49418 UNIPROT down-regulates activity phosphorylation Ser293 PAPARPRsPSQTRKG 10090 23651931 t gcesareni This 120-kDa protein was identified as amphiphysin 1 (Amph1) by LC-MS/MS analysis, and the site of phosphorylation by CDKL5 was determined to be Ser-293.| The phosphorylation mimic mutants, Amph1(S293E) and Amph1(S293D), showed significantly reduced affinity for endophilin, a protein involved in synaptic vesicle endocytosis SIGNOR-245881 0.368 MC1R protein Q01726 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256813 0.458 KAT2A protein Q92830 UNIPROT H3Y2 protein P0DPK5 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkATAWQAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269598 0.2 FBXW7 protein Q969H0 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 phosphorylation:Ser62 LLPTPPLsPSRRSGL 15103331 t lperfetto We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 SIGNOR-249638 0.753 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 14670079 t gcesareni We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication. SIGNOR-120330 0.533 HDAC1 protein Q13547 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263839 0.816 SB-705498 chemical CID:9910486 PUBCHEM TRPV1 protein Q8NER1 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206826 0.8 GZMB protein P10144 UNIPROT IGF2R protein P11717 UNIPROT up-regulates binding 9606 11081635 t gcesareni The serine proteinase granzyme b is crucial for the rapid induction of target cell apoptosis by cytotoxic t cells. We now present evidence that this receptor is the cation-independent mannose 6-phosphate/insulin-like growth factor receptor (ci-mpr). Inhibition of the granzyme b ci-mpr interaction prevented granzyme b cell surface binding, uptake, and the induction of apoptosis. SIGNOR-84314 0.417 INTS14 protein Q96SY0 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261474 0.2 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000567 12853467 t 14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling. SIGNOR-252574 0.643 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 BTO:0002181 16046550 t The effect has been demonstrated using Q01196-8 lperfetto We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-244703 0.2 MYC protein P01106 UNIPROT BCR protein P11274 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664;BTO:0004465 26179066 t lperfetto In the present study we demonstrate that MYC and its partner MAX bind to the BCR promoter, leading to up-regulation of BCR and BCR/ABL1 at both transcriptional and protein levels.|Here we describe a regulatory pathway modulating BCR and BCR/ABL1 expression, showing that the BCR promoter is under the transcriptional control of the MYC/MAX heterodimer. SIGNOR-272144 0.37 Netrin proteinfamily SIGNOR-PF97 SIGNOR NEO1 protein Q92859 UNIPROT up-regulates activity binding 9606 BTO:0001484 21558366 t miannu In mammals, three secreted netrins, netrin 1, 3 and 4, and two membrane-tethered glycophosphatidylinositol (GPI)-linked (see Glossary, Box 1) netrins, netrin G1 and G2, have been identified. In mammals, receptors for the secreted netrins include deleted in colorectal cancer (DCC), the DCC paralogue neogenin, the UNC-5 homologues UNC5A-D, and Down syndrome cell adhesion molecule (DSCAM). SIGNOR-268172 0.2 JAK2 protein O60674 UNIPROT STAT1/STAT3 complex SIGNOR-C118 SIGNOR up-regulates activity phosphorylation 9606 15526160 t miannu Downstream of JAKs are the signal transducers and activators of transcription (STATs), which are phosphorylated by JAKs. SIGNOR-254999 0.805 TRIM25 protein Q14258 UNIPROT KLF5 protein Q13887 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 21542805 t miannu  The oestrogen-inducible E3 ligase EFP (oestrogen-responsive finger protein) was identified as a key player in oestrogen-mediated degradation of KLF5, as knockdown and overexpression of EFP increased and decreased KLF5 protein levels respectively, and the decrease continued even when protein synthesis was blocked.  SIGNOR-271908 0.495 AKT proteinfamily SIGNOR-PF24 SIGNOR BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser694 QTSKRHDsDTFPELK 9606 BTO:0000150 20085797 t lperfetto We identify a novel akt phosphorylation site in brca1 at s694 which is responsive to activation of these signaling pathways. These data suggest akt phosphorylation of brca1 increases total protein expression by preventing proteasomal degradation SIGNOR-244164 0.2 BMI1 protein P35226 UNIPROT BMI1 protein P35226 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 23239878 t gcesareni Here, we report that BMI1 autoactivates its own promoter via an E-box present in its promoter. SIGNOR-245344 0.2 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys365 SLASQATkDGKKDKK -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. SIGNOR-272745 0.475 CEBPA protein P49715 UNIPROT Basophil_diff phenotype SIGNOR-PH116 SIGNOR up-regulates activity 10090 BTO:0000725 23990620 f Notably, enforced overexpression of C/EBP-α in BMCPs results in exclusive differentiation into basophils, whereas conditional deletion of C/EBP-α in these same cells promotes mast cell differentiation,1 suggesting that C/EBP-α is an essential “switch factor” for basophil lineage choice SIGNOR-259968 0.7 SIRT1 protein Q96EB6 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates quantity by destabilization deacetylation 10090 BTO:0001103 24003218 t lperfetto SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 SIGNOR-217975 0.803 RPS6KA4 protein O75676 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 SIGNOR-C13 17183360 t gcesareni Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) msk 1 and 2 can directly phosphorylate and activate transcription factors such as creb, atf1, the nf-kb isoform p65 and stat 1 and 3. SIGNOR-151436 0.275 FYN protein P06241 UNIPROT CAV1 protein Q03135 UNIPROT down-regulates activity phosphorylation Tyr14 VDSEGHLyTVPIREQ 9606 12921535 t lperfetto Caveolin-1 is phosphorylated on tyr(14) in response to both oxidative and hyperosmotic stress. In the present paper, we show that this phosphorylation requires activation of the src family kinase fyn.Therefore, SIGNOR-118003 0.71 ASXL1 protein Q8IXJ9 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR up-regulates activity binding 9606 BTO:0001271 22897849 t irozzo These data led us to hypothesize that ASXL1 interacts with the PRC2 complex; co-immunoprecipitation studies revealed that ASXL1 associates with members of the PRC2 complex including EZH2 and SUZ12 but not with the PRC1 repressive complex. Importantly, ASXL1 downregulation resulted in loss of EZH2 recruitment to the HOXA locus indicating a role of ASXL1 in recruiting the PRC2 complex to known leukemogenic loci. SIGNOR-255923 0.544 WARS1 protein P23381 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) SIGNOR-270513 0.8 PPP4C protein P60510 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates activity dephosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 t lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |Depletion of PP4C, or PP4R3beta, causes persistence of phospho-T1609 and phospho-S1618 SIGNOR-264450 0.364 tertatolol chemical CHEBI:135244 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258862 0.8 RORC protein P51449 UNIPROT Th17 phenotype SIGNOR-PH94 SIGNOR up-regulates 9606 16990136 f MARCO ROSINA Our results demonstrate that RORgt is the transcription factor that directs the differentiation of inflammatory Th17 cells SIGNOR-255028 0.7 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1C protein Q14123 UNIPROT down-regulates activity chemical inhibition 9606 22014080 t Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors. SIGNOR-253017 0.8 beta-alanine smallmolecule CHEBI:16958 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 9606 BTO:0000007 9009272 t inferred from family member miannu For each mutant GlyR we examined the agonist efficacies of taurine and Œ≤-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where Œ≤-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human Œ±1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and Œ≤-alanine act as full agonists of human Œ±1 GlyRs when expressed in this system. SIGNOR-270261 0.8 MAP2K7 protein O14733 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Tyr182 ADAEMTGyVVTRWYR 9606 BTO:0000007 10066767 t done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. SIGNOR-273953 0.412 AKT3 protein Q9Y243 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 9812896 t gcesareni Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity SIGNOR-61565 0.497 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation Ser63 GILARRPsYRKILKD 9606 8663317 t lperfetto Camk ii phosphorylates only ser63 (corresponding to ser133 of creb), which is essential for the activation, and not ser72 (corresponding to ser142 of creb), which is a negative regulation site SIGNOR-42565 0.301 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 BTO:0000782 15276472 t gcesareni Once activated, calcineurin directly dephosphorylates members of the nuclear factor of activated t-cells (nfat) transcription factor family in the cytoplasm, promoting their translocation into the nucleus. SIGNOR-127248 0.818 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 t Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  SIGNOR-258030 0.8 Neurokinin A smallmolecule CHEBI:80311 ChEBI TACR2 protein P21452 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257587 0.8 BTRC protein Q9Y297 UNIPROT WEE1 protein P30291 UNIPROT down-regulates binding 9606 SIGNOR-C5 15340381 t gcesareni Scfb-trcp continues to have a role in this phase, however, through its induced degradation of the cdk1 inhibitor, wee1. SIGNOR-128439 0.403 AIP protein O00170 UNIPROT GREB1 protein Q4ZG55 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 21984905 f miannu We show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells. SIGNOR-253735 0.2 PLK1 protein P53350 UNIPROT KIZ protein Q2M2Z5 UNIPROT up-regulates phosphorylation Thr379 WSTSSDLtISISEDD 9606 16980960 t lperfetto Here, we identify a novel centrosomal substrate of plk1, kizuna (kiz), depletion of which causes fragmentation and dissociation of the pericentriolar material from centrioles at prometaphase, resulting in multipolar spindles. Plk1 maintains the integrity of the spindle poles by phosphorylating kiz. SIGNOR-149630 0.499 CNTFR protein P26992 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 10582086 f gcesareni Clc/clf activates stat1 and stat3. SIGNOR-72774 0.345 CBL protein P22681 UNIPROT PDGFRA protein P16234 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10347229 t lperfetto Cbl overexpression in nih3t3 cells enhanced the ubiquitination and degradation of the platelet-derived growth factor receptor-alpha (pdgfralpha) SIGNOR-68024 0.468 AKT proteinfamily SIGNOR-PF24 SIGNOR ZNF322 protein Q6U7Q0 UNIPROT up-regulates activity phosphorylation Thr150 LVHQRSHtGEKPYLC 9606 BTO:0002552 31399647 t miannu We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A. SIGNOR-276754 0.2 SOX6 protein P35712 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity binding 10090 BTO:0000011 26893351 t SOX6 interacts with β-catenin in adipocytes, suggesting an inhibition of WNT/β-catenin signaling, thereby promoting adipogenesis. SIGNOR-256073 0.639 TRIM21 protein P19474 UNIPROT TRIM5 protein Q9C035 UNIPROT up-regulates quantity monoubiquitination 9606 BTO:0000567 18312418 t miannu Here, we show that TRIM5alpha functions as a RING-finger-type E3 ubiquitin ligase both in vitro and in vivo and ubiquitinates itself in cooperation with the E2 ubiquitin-conjugating enzyme UbcH5B. Thus, the ubiquitination of TRIM5alpha is catalyzed by itself and Ro52. Unexpectedly, although TRIM5alpha is ubiquitinated, our results have revealed that the proteasome inhibitors MG115 and MG132 do not stabilize it in HeLa cells, suggesting that the ubiquitination of TRIM5alpha does not lead to proteasomal degradation. Importantly, TRIM5alpha is clearly conjugated by a single ubiquitin molecule (monoubiquitination). Our monoubiquitin-fusion assay suggests that monoubiquitination is a signal for TRIM5alpha to translocate from cytoplasmic bodies to the cytoplasm. SIGNOR-271672 0.35 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Thr339 SDTATNStLPSAEVE -1 7836371 t Phosphorylation of the FPR carboxyl terminus by GRK2 is the result of a high affinity interaction and proceeds in a hierarchical manner. sequential mechanism of phosphorylation beginning with residues 328 and/or 329, followed by residues 331 and/or 332, and finally residues 334 through 339. Attenuation of receptor-mediated signal amplification in response to external stimuli, an essential step in the balance of cellular activation, may be mediated by receptor phosphorylation. SIGNOR-251452 0.2 ritonavir chemical CHEBI:45409 ChEBI CYP2B6 protein P20813 UNIPROT up-regulates activity chemical activation 9606 18285471 t Luana These results show that ritonavir induces human CYP2B6 activity.  SIGNOR-257770 0.8 KCND3 protein Q9UK17 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 10090 24762397 t miannu Kv4.3 belongs to voltage activated (Kv) K+ channel, mammalian Shal-related family. It is encoded by KCND3 gene and expressed in heart, brain and smooth muscle. Transient outward K+ current (I(to)) plays a crucial role in the early phase of cardiac action potential repolarization. Kv4.3 K(+) channel is an important component of I(to). The function and expression of Kv4.3 K(+) channel decrease in variety of heart diseases, especially in heart hypertrophy/heart failure. SIGNOR-265657 0.8 retinol smallmolecule CHEBI:50211 ChEBI retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity precursor of 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS9 SIGNOR-265118 0.8 PDGFRB protein P09619 UNIPROT NCK2 protein O43639 UNIPROT up-regulates binding 9606 10026169 t gcesareni The sh2 domains of grb2, nck, and grb4 all precipitated activated pdgf receptor with similar efficiency. SIGNOR-64740 0.599 tRNA(Tyr) smallmolecule CHEBI:29182 ChEBI Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates quantity precursor of 9606 16429158 t miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr SIGNOR-270523 0.8 ADGRG1 protein Q9Y653 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0000142 31515243 t lperfetto Binding of collagen III to ADGRG1 provides a canonical example of adhesion GPCR interactions with ECM proteins (Luo et al., 2011). Identified by an in vitro biotinylation/proteomics approach, extracellular interactions with collagen III were subsequently proven capable of activating ADGRG1-mediated signaling via Gα12/13 followed by RhoA activation to regulate corticogenesis SIGNOR-272345 0.2 canertinib chemical CHEBI:61399 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191009 0.8 BLOC-2 complex SIGNOR-C252 SIGNOR KIF13A protein Q9H1H9 UNIPROT up-regulates activity binding 9606 30404817 t lperfetto Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis. SIGNOR-260702 0.26 AURKA protein O14965 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser405 FDDTGKSsLGDMFSP 9606 BTO:0001938 31028180 t lperfetto Microtubule nucleation during central spindle assembly requires NEDD1 phosphorylation on serine 405 by Aurora A| In the absence of Aurora A, the HURP (also known as DLGAP5) and NEDD1 proteins that are involved in nucleation of microtubules fail to concentrate in the midzone. SIGNOR-272965 0.539 PRKCA protein P17252 UNIPROT INSR protein P06213 UNIPROT unknown phosphorylation Ser1064 KTVNESAsLRERIEF -1 7926007 t lperfetto Identification of serines-1035/1037 in the kinase domain of the insulin receptor as protein kinase C alpha mediated phosphorylation sites. SIGNOR-248906 0.354 MAPK1 protein P28482 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Thr213 SASFPHTtPSMCLNP 9606 BTO:0000664 17475908 t miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). SIGNOR-262913 0.324 NEK6 protein Q9HC98 UNIPROT BSG protein P35613 UNIPROT down-regulates activity phosphorylation Ser368 GSAPLKSsGQHQNDK 9606 31016558 t done miannu These results indicate that NEK6 directly interacts with CD147 and phosphorylates the protein at serine-252 in Huh-7 cells. SIGNOR-273882 0.2 NFE2L2 protein Q16236 UNIPROT GSTA1 protein P08263 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22459801 f miannu Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed. SIGNOR-254644 0.349 AKT1 protein P31749 UNIPROT CLK2 protein P49760 UNIPROT up-regulates phosphorylation Ser34 HKRRRSRsWSSSSDR 9606 BTO:0000567 20682768 t lperfetto Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva SIGNOR-167336 0.398 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89174 0.538 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000093 11258706 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-105737 0.764 Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269159 0.2 FOXA1 protein P55317 UNIPROT BCL2 protein P10415 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19127412 f miannu Foxa1 overexpression decreased the expression of bcl2, while foxa1 depletion increased the expression of bcl2 SIGNOR-161448 0.2 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser20 PLSQETFsDLWKLLP 10090 BTO:0004831 11896587 t lperfetto Serine 20 phosphorylation of p53 has been shown to be required for the activation of p53 following UV radiation. we determined the role of map kinases in uvb-induced phosphorylation and found that jnks are directly involved in the phosphorylation of p53 at serine 20 SIGNOR-106538 0.789 MBL2 protein P11226 UNIPROT MASP1 protein P48740 UNIPROT up-regulates activity binding 9606 BTO:0000392 9087411 t lperfetto The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5). SIGNOR-263414 0.741 RINT1 protein Q6NUQ1 UNIPROT NRZ complex complex SIGNOR-C358 SIGNOR form complex binding 25364732 t lperfetto NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay. SIGNOR-265025 0.868 PARP1 protein P09874 UNIPROT SERPINF1 protein P36955 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001949 18312852 f miannu Upregulation of PEDF expression by PARP inhibition contributes to the decrease in hyperglycemia-induced apoptosis in HUVECs. SIGNOR-254891 0.2 tibolone chemical CHEBI:32223 ChEBI AR protein P10275 UNIPROT up-regulates activity chemical activation 9606 19464167 t Luana In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1). SIGNOR-257823 0.8 CHEK1 protein O14757 UNIPROT FANCE protein Q9HB96 UNIPROT up-regulates phosphorylation Ser374 LFLGRILsLTSSASR 9606 17296736 t llicata Chk1 directly phosphorylates the fance subunit of the fa core complex on two conserved sites (threonine 346 and serine 374). chk1-mediated phosphorylation of fance is required for the fanconi anemia/brca pathway. SIGNOR-153023 0.705 GRM1 protein Q13255 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. SIGNOR-264932 0.8 PLK1 protein P53350 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates phosphorylation Ser216 IPLMLNDsGSAHSMP 9606 18794143 t lperfetto Hsf1 was phosphorylated by plk1 at ser(216) of the dsgxxs motif during the timing of mitosis and a phospho-defective mutant form of hsf1 inhibited mitotic progression. Phosphorylated hsf1 during spindle pole localization underwent ubiquitin degradation through the scf(beta-trcp) pathway. SIGNOR-180915 0.455 CIITA protein P33076 UNIPROT HLA-DOB protein P13765 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11823510 f Class II transactivator is required for maximal expression of HLA-DOB in B cells|HLA-DO, encoded by the HLA-DOA and HLA-DOB genes, has been shown to function as a modulator of Ag presentation. DNA microarray comparisons between B cells wild-type and mutant for the master regulator of MHC class II transcription, class II transactivator (CIITA), identified HLA-DOA and HLA-DOB as being up-regulated by CIITA. SIGNOR-254015 0.316 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser101 GSHRDQGsSALSGVG 9606 BTO:0001271 21750978 t miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway SIGNOR-174840 0.2 CDK1 protein P06493 UNIPROT PPP1R13L protein Q8WUF5 UNIPROT up-regulates activity phosphorylation Ser113 LHPYSPLsPKGRPSS 9606 30105797 t done miannu Cyclin B/cyclin-dependent kinase 1 (CDK1) phosphorylates inhibitor of apoptosis stimulating protein of P53 (iASPP) to promote iASPP nucleus localization and its inhibitory effect on p53.  SIGNOR-273586 0.519 TBK1 protein Q9UHD2 UNIPROT DDAH2 protein O95865 UNIPROT down-regulates activity phosphorylation Ser253 QEALQKLsDVTLVPV 33850055 t lperfetto TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o SIGNOR-275646 0.2 DZIP3 protein Q86Y13 UNIPROT H2AC1 protein Q96QV6 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHH 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271761 0.2 CCR3 protein P51677 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 11591790 f We and others have recently found that eotaxin activates extracellular signal-regulated kinase (ERK)-1/2 and p38 mitogen-activated protein (MAP) kinases in eosinophils, and that these kinases are indispensable for eosinophil chemotaxis and degranulation SIGNOR-254357 0.3 DDX20 protein Q9UHI6 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 t lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. SIGNOR-253117 0.853 BTG2 protein P78543 UNIPROT CAT protein P04040 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22493435 f miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 SIGNOR-254648 0.2 RUNX1 protein Q01196 UNIPROT ANKRD26 protein Q9UPS8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000843 24430186 t lperfetto In healthy individual, RUNX1/FLI1 complex negatively regulates ANKRD26 gene expression in MKs. SIGNOR-266069 0.2 TFEB protein P19484 UNIPROT WDFY3 protein Q8IZQ1 UNIPROT up-regulates quantity by expression transcriptional regulation 30145926 f lperfetto Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB SIGNOR-276804 0.273 JAK2 protein O60674 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 9852261 t gcesareni Stat6 activation is mediated through jak1 and jak2 tyrosine kinases. SIGNOR-62585 0.657 ERCC2 protein P18074 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 t lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269312 0.866 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR CSNK1A1 protein P48729 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000670 26131937 t gcesareni We demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1a) by the E3 ubiquitin ligase CUL4€“RBX1€“DDB1€“CRBN (known as CRL4CRBN) SIGNOR-236907 0.384 PRKCG protein P05129 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser42 AKKKSKIsASRKLQL 9606 BTO:0000887 15769444 t lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. SIGNOR-134632 0.2 HDAC1 protein Q13547 UNIPROT EGR1 protein P18146 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21983014 f In conclusion we demonstrated that treatment of HeLa cells with DMC leads to an enhanced formation of a complex consisting of NF-κB and HDAC1 that binds to the EGR1 promoter resulting in downregulation of EGR1 expression which plays a major role for transcriptional inhibition of mGPES-1 expression. SIGNOR-254257 0.555 FOXO1 protein Q12778 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0001103 21798082 t FoxO factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy F-box (MAFbx) and muscle ring finger 1 (MuRF1), leading to the ubiquitylation of myosin and other muscle proteins (see below), and their degradation via the proteasome SIGNOR-256268 0.251 3-[(4-Bromophenyl)methyl]-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one chemical CID:10248127 PUBCHEM ACHE protein P22303 UNIPROT down-regulates activity chemical inhibition 9606 17888667 t Luana AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE. SIGNOR-257761 0.8 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr218 PPRDFAAyRS 9606 BTO:0000782;BTO:0001271 8992971 t lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail SIGNOR-45520 0.677 CAMTA1 protein Q9Y6Y1 UNIPROT NPPA protein P01160 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002004 21857646 t Luana CAMTA1 itself stimulates the expression of the anti-proliferative peptide NPPA. SIGNOR-261570 0.44 JAK1 protein P23458 UNIPROT TYK2 protein P29597 UNIPROT up-regulates phosphorylation Tyr1054 AVPEGHEyYRVREDG 9606 8702790 t llicata These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055 and that this phosphorylation requires another kinase, most likely jak1. SIGNOR-43080 0.506 IRAK3 protein Q9Y616 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR down-regulates activity 10090 BTO:0000801 12150927 f IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. SIGNOR-259288 0.7 Hexocyclium chemical CHEBI:5707 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258389 0.8 IRX1 protein P78414 UNIPROT UGT8 protein Q16880 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. SIGNOR-261665 0.2 PRDM1 protein O75626 UNIPROT FCER2 protein P06734 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000776 11342629 f In this study, we report that PRDI-BF1/Blimp1 can bind to the same functional element in the human CD23b promoter to which BCL-6 and IRF-4 had previously been shown to bind, and that, like BCL-6, Blimp1 can repress IRF-4-transactivating ability SIGNOR-253926 0.259 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser626 SLECDMEsIIRSELM 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249688 0.397 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000944 11581251 t inferred from 70% family members lperfetto Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL. SIGNOR-270207 0.2 WNT3A protein P56704 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have SIGNOR-169660 0.782 PTPN11 protein Q06124 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 11085989 t miannu SHP-2 is thus a positive regulator of ERK by leptin receptors, and both the adaptor function and the phosphatase activity of SHP-2 are critical for this regulation. Based on these data, we conclude that tyrosinephosphorylation of SHP-2 is a mediator of ERK activation viaTyr-985. This is likely to occur via Grb-2 binding to SHP-2 atthe C terminus followed by activation of the Ras-Raf pathwayas suggested for other signaling systems (55, 56) and morerecently for the leptin receptor (33). SIGNOR-263498 0.726 CDK2 protein P24941 UNIPROT RNF4 protein P78317 UNIPROT up-regulates activity phosphorylation Thr112 DVYVTTHtPRNARDE 9606 BTO:0002181 25948581 t miannu Here we reported that CDK2 could phosphorylate RNF4 on T26 and T112 and enhance RNF4 E3 ligase activity, which is important for MDC1 degradation and proper HR repair during S phase.  SIGNOR-276901 0.2 TGFBR1 protein P36897 UNIPROT SPTBN1 protein Q01082 UNIPROT up-regulates phosphorylation 9606 12543979 t gcesareni This suggests that, upon stimulation with tgf-beta1, phosphorylation of elf could induce a conformational change that reduces its affinity for ankyrin and tropomyosin and facilitates an association with smad3 and smad4 instead. SIGNOR-97626 0.502 ITGB1BP1 protein O14713 UNIPROT Av/b6 integrin complex SIGNOR-C179 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257663 0.272 SETDB1 protein Q15047 UNIPROT SETDB1/NLK/CHD7 complex SIGNOR-C189 SIGNOR form complex binding 10090 21952300 t FFerrentino The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1)42. SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3‑L1 cells42,43. SIGNOR-253522 0.528 PARP1 protein P09874 UNIPROT THBD protein P07204 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001289 21489980 f miannu Silencing of PARP1 resulted in a strong down-regulation of TM expression in Met-5A cells, while restoring TM expression in H28 cells. We propose that methylation of the TM promoter is responsible for silencing of TM expression in MM tissue, a process that is regulated by PARP1. SIGNOR-254893 0.2 CAMK2G protein Q13555 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Thr642 RSVKRNStVDCNGVV 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275795 0.274 CABIN1 protein Q9Y6J0 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates 9606 17172641 f gcesareni Thus, cabin1 recruits chromatin-modifying enzymes, both histone deacetylases and a histone methyltransferase, to repress mef2 transcriptional activity. SIGNOR-151208 0.788 PTPRJ protein Q12913 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity dephosphorylation 9606 25386896 t lperfetto Our data demonstrate that CD148 promotes E-cadherin cell adhesion by regulating Rac1 activity, concomitant with modulation of p120, \u03b2-catenin, and Src tyrosine phosphorylation, and that this effect requires E-cadherin and p120 association.|Taken together, it is likely that CD148 dephosphorylation of \u03b2-catenin enhances the cadherin cell adhesion independent of Rho family GTPases. SIGNOR-276992 0.498 PRKACA protein P17612 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser429 PQRERKSsSSSEDRN 10116 BTO:0001009 11510412 t The in vitro phosphorylation of a site unique to B-Raf (Ser429) has been proposed to be responsible for the negative regulation of the isoenzyme by Akt. Using phosphopetide mapping and site-directed mutagenesis we showed that Ser429 is phosphorylated upon cAMP elevation in PC12 cells and proposed that PKA is a major kinase phosphorylating the B-Raf-specific site in vivo SIGNOR-259922 0.623 TBKBP1 protein A7MCY6 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity relocalization 9606 31792381 t TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation SIGNOR-272469 0.622 MAPK3 protein P27361 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates phosphorylation Ser165 LFQLGPPsPVKMPSP 9606 10906323 t gcesareni Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function. SIGNOR-79519 0.309 SL-327 chemical CHEBI:92211 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 11160424 t gcesareni The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity SIGNOR-104930 0.8 FGFR4 protein P22455 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates activity phosphorylation 10116 9182757 t lperfetto In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway. SIGNOR-242661 0.672 FGF2 protein P09038 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252279 0.7 MEF2C protein Q06413 UNIPROT CPT1B protein Q92523 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000167 15356291 f miannu Mutation analysis indicated that the MEF2 site contributed to the activation of the CPT1beta promoter by PPAR in C2C12 cells. The reporter construct containing the PPRE and the MEF2C site was synergistically activated by co-expression of PPAR, retinoid X receptor (RXR) and MEF2C in non-muscle cells. Moreover, protein-binding assays demonstrated that MEF2C and PPAR specifically bound to one another in vitro. Also for the synergistic activation of the CPT1beta gene promoter by MEF2C and PPARalpha-RXRalpha, a precise arrangement of its binding sites was essential. SIGNOR-254583 0.2 AP-2 complex complex SIGNOR-C245 SIGNOR DAB2 protein P98082 UNIPROT up-regulates activity binding 9606 BTO:0004784; BTO:0000567 11247302 t Giorgia Dab2 is alternatively spliced and its localization depends on a region of the protein that contains two DPF motifs that are present in the p96 Dab2 protein and absent in the p67 splice variant. This region is sufficient to confer Dab2 binding to the alpha‐adaptin subunit of the clathrin adaptor protein, AP‐2.|These findings suggest that in addition to previously reported signal-transduction functions, Dab2 could also act as an adaptor protein that may regulate protein trafficking. SIGNOR-260391 0.491 HCK protein P08631 UNIPROT ADAM15 protein Q13444 UNIPROT up-regulates phosphorylation Tyr735 LKGPTCQyRAAQSGP 9606 BTO:0000661 11741929 t lperfetto Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling. SIGNOR-112923 0.362 MTMR1 protein Q13613 UNIPROT 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) smallmolecule CHEBI:57795 ChEBI up-regulates quantity chemical modification 9606 18429927 t miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns SIGNOR-269805 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR MOS protein P00540 UNIPROT down-regulates activity phosphorylation Ser73 LGAGGFGsVYKATYR 9606 8622681 t Manara The purified PKA catalytic subunit was able to phosphorylate recombinant p37v-mos in vitro, suggesting that the mechanism of in vivo inhibition of v-Mos kinase involves direct phosphorylation by PKA. SIGNOR-260819 0.2 EXT1 protein Q16394 UNIPROT WNT8B protein Q93098 UNIPROT up-regulates activity 9606 24860992 f miannu Decreased Ext1 was shown to reduce the level of Wnt8 and BMP4 signaling and disrupt ventral-specific gene expression. Ext1 function is required for maintenance of normal levels of BMP and wnt, as well as their target genes. In addition, expression of xbra and the establishment of ventral mesoderm depend upon normal levels of Ext1. These findings suggest that ext1-dependent synthesis of HSPG is critical for wnt and BMP signaling, mesodermal identity, and ventral pattern. SIGNOR-264020 0.2 ERG protein P11308 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0002398 22140532 t miannu ERG deregulation induces PIM1 over-expression and aneuploidy in prostate epithelial cells. The up-regulation of PIM1 induced by tERG over-expression significantly modified Cyclin B1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability. SIGNOR-259408 0.2 PRKAA1 protein Q13131 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 SIGNOR-C15 21892142 t gcesareni Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs). SIGNOR-176487 0.276 AURKA protein O14965 UNIPROT SKI protein P12755 UNIPROT down-regulates quantity by destabilization phosphorylation Ser326 RRVPRVSsEPPASIR -1 26138431 t miannu Here we show that AURKA phosphorylates in vitro the transcripcional co-repressor Ski on aminoacids Ser326 and Ser383. Phosphorylations on these aminoacids decreased Ski protein half-life SIGNOR-276918 0.2 HTR2B protein P41595 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256886 0.268 cortisol smallmolecule CHEBI:17650 ChEBI NR3C2 protein P08235 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258707 0.8 Oxotremorine chemical CHEBI:7851 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258651 0.8 MKRN1 protein Q9UHC7 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002552 19536131 t miannu Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21.  SIGNOR-271845 0.319 TINF2 protein Q9BSI4 UNIPROT Shelterin complex complex SIGNOR-C306 SIGNOR form complex binding 9606 BTO:0000567 15383534 t lperfetto Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins. SIGNOR-263320 0.884 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus. SIGNOR-252346 0.2 IFNG protein P01579 UNIPROT DIO1 protein P49895 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 9397972 f scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. SIGNOR-267487 0.2 ULK2 protein Q8IYT8 UNIPROT ENO1 protein P06733 UNIPROT down-regulates activity phosphorylation Ser282 QLADLYKsFIKDYPV 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274037 0.2 CBP/p300 complex SIGNOR-C6 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates acetylation 9606 BTO:0000887 10944526 t lperfetto Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo. SIGNOR-217220 0.634 GRK2 protein P25098 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 21695114 t gcesareni We find that two molecules interact with mammalian smo in an activation-dependent manner: g protein-coupled receptor kinase 2 (grk2) leads to phosphorylation of smo, and beta-arrestin 2 fused to green fluorescent protein interacts with smo. Ck1a, grk2, and another still-unidentified protein kinase phosphorylate the c-tail of mammalian smo in the presence of hh proteins SIGNOR-174539 0.2 CSNK1D protein P48730 UNIPROT PPP5C protein P53041 UNIPROT up-regulates activity phosphorylation Thr362 LFSEDGVtLDDIRKI 9606 BTO:0000007 29141220 t miannu  Here, we show an "on/off switch" mechanism for PP5 regulation. The casein kinase 1δ (CK1δ) phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90.  SIGNOR-277373 0.339 CRYAB protein P02511 UNIPROT CRYGC protein P07315 UNIPROT up-regulates activity binding -1 20621668 t miannu Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age. SIGNOR-253622 0.546 HIPK2 protein Q9H2X6 UNIPROT PDX1 protein P52945 UNIPROT unknown phosphorylation Ser268 LPPGLSAsPQPSSVA 10090 BTO:0000783;BTO:0002284 20637728 t Our results suggest that HIPK2-mediated phosphorylation of PDX1 at Ser-269 might be a regulatory mechanism connecting signals generated by changes in extracellular glucose concentration to downstream effectors via changes in subnuclear localization of PDX1, thereby influencing islet cell differentiation and function SIGNOR-255539 0.36 PTPN1 protein P18031 UNIPROT ABL1 protein P00519 UNIPROT down-regulates dephosphorylation 9606 9566916 t gcesareni These results illustrate selectivity in the effects of ptps in a cellular context and suggest that ptp1b may function as a specific, negative regulator of p210 bcr-abl signalling in vivo. SIGNOR-56815 0.596 RET protein P07949 UNIPROT RET protein P07949 UNIPROT unknown phosphorylation Tyr1029 TPSDSLIyDDGLSEE 9534 BTO:0004055 8621380 t lperfetto Based on the phosphopeptide maps, we can identify six tyrosine phosphorylation sites in RET: Tyr-687, Tyr-826, Tyr-1062, Tyr-1096, Tyr-1015, and Tyr-1029. By comparing the peptide map of each mutant to the wild-type receptor, we can tentatively assign each tryptic peptide containing phosphorylation sites to individual P-labeled spots on the two-dimensional map  SIGNOR-248940 0.2 FRG1 protein Q14331 UNIPROT KMT5B protein Q4FZB7 UNIPROT down-regulates activity binding 10090 BTO:0000165 23720823 t miannu Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. SIGNOR-266639 0.2 GCM2 protein O75603 UNIPROT PTH protein P01270 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004712 20558332 f miannu We found that GCMB binds to the PTH gene 5'-promoter (-390/-383 bp) and positively regulates its transcription. SIGNOR-254200 0.417 KAT2A protein Q92830 UNIPROT H3-5 protein Q6NXT2 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269608 0.2 NDUFB11 protein Q9NX14 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 SIGNOR-262164 0.739 ARRB2 protein P32121 UNIPROT INPP5D protein Q92835 UNIPROT up-regulates activity binding 9606 24817116 t lperfetto We identified a new adaptor beta-arrestin 2 that associates with phosphorylated TIGIT and mediates recruitment of inositol phosphatase SHIP1 through the ITT-like motif (Fig. 7). Finally, SHIP1 impairs TRAF6 autoubiquitination to abolish NF-kappaB activation, leading to inhibition of IFN- gamma production in NK cells. SIGNOR-261428 0.2 sunitinib chemical CHEBI:38940 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258291 0.8 FGR protein P09769 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity phosphorylation Tyr354 SSNQELIyEGRRLVL 9606 BTO:0002181 28618271 t miannu The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.  SIGNOR-276725 0.2 GLI3 protein P10071 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity transcriptional regulation 10090 12435361 t Gianni Whereas Fgf8 expression was almost absent in Shh-/- mutants, it was up-regulated in Gli3-/-;Shh-/- double mutants, suggesting that SHH is not required for Fgf8 induction, and that GLI3 normally represses Fgf8 independently of SHH SIGNOR-268949 0.456 P2RY11 protein Q96G91 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257328 0.2 lurasidone chemical CHEBI:70735 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10030 20404009 t Luana In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype. SIGNOR-257838 0.8 NFIB protein O00712 UNIPROT NEUROD1 protein Q13562 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268897 0.286 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser100 DEDSGKGsQPPSPPS 9606 20305697 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-164613 0.574 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-254374 0.7 MST1 protein P26927 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Thr228 PQWNESFtFKLKPSD 9606 BTO:0002181 26414765 t miannu Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα.  SIGNOR-277178 0.2 MMP15 protein P51511 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272360 0.7 PRCC protein Q92733 UNIPROT MAD2L2 protein Q9UI95 UNIPROT up-regulates relocalization 9606 15218244 t miannu We found that the human papillary renal cell carcinoma-associated proteinprccinteracts with the cell cycle control proteinmad2b, and translocates this protein to the nucleus where it exerts its mitotic checkpoint function. SIGNOR-126516 0.51 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys70 GKAVRGAkGHHHPHP 9606 15831498 t gcesareni Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300 SIGNOR-135473 0.476 PSPH protein P78330 UNIPROT L-serine chemical CHEBI:17115 ChEBI up-regulates quantity chemical modification 9606 BTO:0000142 12213811 t lperfetto Human phosphoserine phosphatase (HPSP) regulates the levels of glycine and d-serine, the putative co-agonists for the glycine site of the NMDA receptor in the brain. |Phosphoserine phosphatase (PSP)1 is an important enzyme in the phosphorylated pathway of serine biosynthesis, which contributes a major portion of the endogenous l-serine|he enzymatic reaction of PSP is Mg2+-dependent and results in the dephosphorylation of phospho-l-serine with the formation of a phosphoenzyme intermediate, which is subsequently autodephosphorylated. The resulting product, l-serine, is not only a precursor for the biosynthesis of glycine but also an uncompetitive inhibitor for the enzymatic reaction of PSP SIGNOR-268571 0.8 MAPK8 protein P45983 UNIPROT EEF1A2 protein Q05639 UNIPROT down-regulates quantity by destabilization phosphorylation Ser205 GDNMLEPsPNMPWFK 9606 BTO:0002181 23608534 t miannu Ribosome-associated JNK phosphorylates the eukaryotic translation elongation factor 1A isoform 2 (eEF1A2) on serines 205 and 358 to promote degradation of NSPs by the proteasome.  SIGNOR-276491 0.382 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Ser231 LSTSSSSsPPGTPSP 9606 phosphorylation:Thr235 IFGATDYtSSIDVWS 17601773 t fspada Mass spectrometric analysis revealed that cdk2/cyclinA phosphorylates C/EBPbeta on Thr(188) and is required for phosphorylation (on Ser(184) or Thr(179)) of C/EBPbeta by GSK3beta and maintenance of DNA binding activity. However, the acquisition of dna binding and transactivation capacity of c/ebpbeta is delayed until further phosphorylation (on ser(184) or thr(179)) by gsk3beta occurs. SIGNOR-156514 0.469 PKN1 protein Q16512 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation 9606 17251915 t gcesareni Phosphorylation of mltkalpha by pknalpha enhances its kinase activity SIGNOR-152768 0.2 RPS6KA5 protein O75582 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000567 9687510 t lperfetto Msk1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates creb at ser133_ .MSK1 Is activated in vitro by mapk2/erk2 or sapk2/p38. Endogenous msk1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to uv radiation, and oxidative and chemical stres msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. SIGNOR-59458 0.72 BRF2 protein Q9HAW0 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR form complex binding 29378333 t lperfetto Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1). SIGNOR-266191 0.712 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates phosphorylation Tyr1112 DPSPLQRySEDPTVP 9606 BTO:0000149 1706616 t gcesareni However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2. SIGNOR-21211 0.2 NTS protein P30990 UNIPROT NTSR2 protein O95665 UNIPROT down-regulates binding 9606 BTO:0000975 9851594 t gcesareni Neurotensin binding to recombinant neurotensin nt2 receptor expressed in cho cells does not elicit a biological response as determined by second messenger measurements. SIGNOR-62519 0.895 CRP protein P02741 UNIPROT IL10 protein P22301 UNIPROT down-regulates quantity by repression translation regulation 9606 BTO:0000801 16917108 f Regulation miannu CRP significantly decreased IL-10 mRNA stability SIGNOR-251824 0.479 AKT1 protein P31749 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser246 LSRERVFsEDRARFY -1 16549426 t miannu Autophosphorylation of Akt on Thr-72 and Ser-246 appeared to require prior phosphorylation of Akt on Thr-308 and Ser-473. Compared with wild-type Akt, Akt/T72A/S246A mutant exhibited markedly reduced basal Akt kinase activity and response to cellular stimulation by insulin-like growth factor-1, and also conferred less cellular resistance to doxorubicin-induced apoptosis. SIGNOR-276055 0.2 DAPK1 protein P53355 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates phosphorylation Thr119 LSRRLKVtGDLFDIM 9606 BTO:0000007 19180116 t gcesareni The activated form of DAPK triggers autophagy in a beclin-1-dependent manner. DAPK phosphorylates beclin 1 on Thr 119 located at a crucial position within its BH3 domain, and thus promotes the dissociation of beclin 1 from Bcl-XL and the induction of autophagy. SIGNOR-183548 0.72 GEM protein P55040 UNIPROT ROCK2 protein O75116 UNIPROT down-regulates activity binding 9534 BTO:0000298 16757346 t miannu We have found that Gem binds specifically to ROKβ in the coiled‐coil domain adjacent to the Rho binding site. The interaction between Gem and ROKβ leads to inhibition of MLC and MBS phosphorylation but not phosphorylation of LIMK, indicating that Gem exerts its effect by altering the substrate specificity of ROKβ SIGNOR-261717 0.294 RB1 protein P06400 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 9606 21524151 f lperfetto Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time. SIGNOR-267284 0.7 ANK3 protein Q12955 UNIPROT GABARAP protein O95166 UNIPROT up-regulates activity binding 10090 BTO:0003102 30504823 t miannu Importantly, the 480 kDa ankyrin-G isoform has also been shown to stabilize GABAergic synapses on the soma and AIS of excitatory pyramidal neurons by interacting with the GABAA receptor-associated protein (GABARAP) to inhibit GABAA receptor endocytosis SIGNOR-266709 0.456 RAD50 protein Q92878 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 21763684 t gcesareni One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase. SIGNOR-175053 0.806 bis(2-ethylhexyl) phthalate chemical CHEBI:17747 ChEBI HCAR2 protein Q8TDS4 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR). SIGNOR-268772 0.8 MAP3K8 protein P41279 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 15466476 t lperfetto Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases. SIGNOR-244904 0.556 INSR protein P06213 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t lperfetto The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. SIGNOR-24782 0.412 WNT7B protein P56706 UNIPROT FZD10 protein Q9ULW2 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000763;BTO:0001260 15923619 t gcesareni Wnt7b can bind to fzd1 and -10 on the cell surface and cooperatively activate canonical wnt signaling SIGNOR-137934 0.631 CHRM1 protein P11229 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257014 0.438 Pyridostigmine chemical CHEBI:8665 ChEBI ACHE protein P22303 UNIPROT down-regulates activity chemical inhibition -1 20627738 t Luana The compounds 3-[(dimethylamino)carboxyl]oxy]-N,N,N-trimethylammonium methyl sulfate, better known as neostigmine methyl sulfate (3),1 and 3-[(dimethylcarbamoyl)oxy]-1-methylpyridinium bromide, pyridostigmine bromide (4)2 (Figure 1) are well known peripheral cholinesterase inhibitors  SIGNOR-257879 0.8 RPL3 protein P39023 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262495 0.85 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 18930133 t lperfetto Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation SIGNOR-181663 0.413 CAD protein P27708 UNIPROT CAD protein P27708 UNIPROT up-regulates activity phosphorylation Thr1037 QQCRVLGtSPEAIDS -1 11986331 t llicata Autophosphorylation resulted in a 2-fold increase in CPSase activity, an increased sensitivity to the feedback inhibitor UTP, and decreased allosteric activation by 5-phosphoribosyl-1-pyrophosphate SIGNOR-250610 0.2 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75009 0.783 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr200 LPLLVQRtIARTIVL 452646 7774578 t lperfetto The tgf-beta type ii receptor (t beta r-ii) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, t beta r-i, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling. SIGNOR-32744 0.711 GEMIN2 protein O14893 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 t lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. SIGNOR-253116 0.867 EGR2 protein P11161 UNIPROT GFI1 protein Q99684 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16923394 f miannu Impairing Egr-2 or Nab-2 induction resulted in sustained expression of Gfi-1, demonstrating that Egr-2 and Nab-2 negatively regulate Gfi-1 expression . Importantly, the Gfi-1 promoter was repressed via the Egr site by coexpression of Egr-2 and Nab-2. Thus, Egr-2 and Nab-2 directly repress the Gfi-1 gene. SIGNOR-256041 0.315 HECTD3 protein Q5T447 UNIPROT RAF1 protein P04049 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 28636940 t miannu  By western blot, we observed robust degradation of endogenous native CRAF in untransformed HEK293 cells treated with control siRNA 24 hr after the addition of AUY922, but this was substantially reduced in cells in which HECTD3 was knocked down, confirming that endogenous CRAF is a bona fide degradation target of HECTD3  SIGNOR-272328 0.2 PRKCD protein Q05655 UNIPROT TBL1XR1 protein Q9BZK7 UNIPROT up-regulates activity phosphorylation Ser123 AAASQQGsAKNGENT 9606 18374649 t Manara In addition, we describe that the functions and the specificity of these two highly- related exchange factors is tightly regulated by signal-induced phosphorylation events at the level of target gene promoters, as exemplified by the role of TBLR1 phosphorylation at Ser 123 by PKCδ upon retinoic acid or estrogen stimulation. SIGNOR-260903 0.2 TACR2 protein P21452 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256879 0.2 STK38 protein Q15208 UNIPROT YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation Ser127 PQHVRAHsSPASLQL 9606 25601544 t Luana We show that mammalian NDR1/2 kinases phosphorylate YAP1 on S127 and thereby negatively regulate YAP1 activity in tissue-cultured cells. SIGNOR-259855 0.392 AURKB protein Q96GD4 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Thr17 RVSSYRRtFGGAPGF -1 12686604 t lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro. SIGNOR-100115 0.527 ULK1 protein O75385 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR form complex binding 9606 23863160 t lperfetto In mammals, two protein complexes, namely the ULK1-Atg13-FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin–Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation. SIGNOR-209890 0.913 GATA3 protein P23771 UNIPROT T-lymphocyte_diff phenotype SIGNOR-PH112 SIGNOR up-regulates activity 10090 22267605 f Transcription factor GATA-3 is known to be vital for the development of T cells at multiple stages in the thymus and for Th2 differentiation in the peripheral organs SIGNOR-259953 0.7 WNK4 protein Q96J92 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates activity phosphorylation Ser371 VRRVPGSsGHLHKTE 16990453 t lperfetto Vitari et al. (76) and Moriguchi et al. (52) demonstrated that WNK4 bound and phosphorylated PASK at Thr-233 and Ser-373 in mammalian cells.| this phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1 SIGNOR-264641 0.521 FOXO proteinfamily SIGNOR-PF27 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-252939 0.7 SRC protein P12931 UNIPROT CLTC protein Q00610 UNIPROT up-regulates phosphorylation Tyr1477 LFITEEDyQALRTSI 9606 10089883 t gcesareni Egf-mediated clathrin phosphorylation is followed by clathrin redistribution to the cell periphery and is the product of downstream activation of src kinase by egf receptor (egfr) signaling SIGNOR-65714 0.416 NUMB protein P49757 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates binding 9606 20818436 t gcesareni Numb activates the catalytic activity of itch, releasing it from an inhibitory intramolecular interaction between its homologous to e6-ap c-terminus and ww domains. SIGNOR-167844 0.599 PIN1 protein Q13526 UNIPROT IFNB1 protein P01574 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 16699525 t lperfetto To investigate the temporal regulation of IRF3-dependent transcription by Pin1, we used a rapid-response luciferase reporter gene. Real-time reporter gene assays showed that suppression of endogenous Pin1 expression substantially prolonged both IRF3-dependent transcription and IFN-beta promoter activation after poly(I)dotpoly(C) stimulation (Fig. 4c,d). Consistent with the inhibitory effects of Pin1 on the IFN-beta promoter SIGNOR-252289 0.2 GRK4 protein P32298 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t Expression of GRK4α drastically increased the basal level of32P incorporation into B2R. GRK4α elevated the basal phosphorylation of Ser339 and Ser346/Ser348. phosphorylation of specific residues was correlated with the initiation of receptor internalization and the regulation of its desensitization. SIGNOR-251193 0.292 glycine smallmolecule CHEBI:15428 ChEBI N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI up-regulates quantity precursor of 9606 34283828 t miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). SIGNOR-267297 0.8 CALM3 protein P0DP25 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates binding 9606 11796223 t miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-266343 0.645 EP300 protein Q09472 UNIPROT PLAG1 protein Q6DJT9 UNIPROT up-regulates acetylation 9606 16207715 t miannu Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7. SIGNOR-140915 0.313 LRRK2 protein Q5S007 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Thr595 NWRGMLKtSKAEELL 9606 BTO:0002181 23813973 t miannu LRRK2 G2019S directly bound to and phosphorylated Drp1 at Threonine595, whereas P110 treatment abolished this phosphorylation.Threonine595 phosphorylation of Drp1 by LRRK2 G2019S is required for Drp1-mediated mitochondrial fragmentation and excessive autophagy SIGNOR-276495 0.584 IL15RA protein Q13261 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation 9606 30029643 t areggio Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated SIGNOR-256225 0.48 IKBKE protein Q14164 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 24622840 t miannu STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3. SIGNOR-260155 0.63 FUS protein P35637 UNIPROT MPHOSPH9 protein Q99550 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0001279 28515487 f This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease SIGNOR-262804 0.2 LATS2 protein Q9NRM7 UNIPROT PRPS1 protein P60891 UNIPROT down-regulates quantity by destabilization phosphorylation Ser285 EDKMKHCsKIQVIDI -1 34465890 t miannu  Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness. SIGNOR-276504 0.2 TCF3 protein P15923 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR form complex binding 10090 BTO:0001103 18094043 t lperfetto MyoD omodimers or heterodimers of MyoD plus E12 or E47 serve as transcription factor complexes that bind to CANNTG consensus sites in the promoter regions of genes, performing major functions in specification and differentiation of skeletl muscle precursor cells. SIGNOR-241551 0.799 CFAP53 protein Q96M91 UNIPROT DNAH11 protein Q96DT5 UNIPROT up-regulates activity binding 10090 BTO:0000379 33347437 t miannu CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B). SIGNOR-265545 0.2 6-(N-carbamoyl-2,6-difluoroanilino)-2-(2,4-difluorophenyl)-3-pyridinecarboxamide chemical CHEBI:94489 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207681 0.8 CID 132010322 chemical CID:132010322 PUBCHEM BRD2 protein P25440 UNIPROT down-regulates activity chemical inhibition 9606 31969702 t Luana ABBV-744 potently inhibited the BD2 domain of BET family proteins with more than 290× selectivity relative to the BD1 domains of BRD2, BRD3 and BRD4 SIGNOR-261103 0.8 HTR2C protein P28335 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256877 0.284 CCNF protein P41002 UNIPROT CCP110 protein O43303 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20596027 t miannu Using a mode of substrate binding distinct from other F-box protein-substrate pairs, CP110 and Cyclin F physically associate on the centrioles during the G2 phase of the cell cycle, and CP110 is ubiquitylated by the SCF(Cyclin F) ubiquitin ligase complex, leading to its degradation. SIGNOR-266364 0.555 NEFM protein P07197 UNIPROT Neurofilament L/M complex SIGNOR-C207 SIGNOR form complex binding 9606 19468066 t miannu Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H SIGNOR-255271 0.535 NDUFV1 protein P49821 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. SIGNOR-262183 0.858 CDK5 protein Q00535 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser154 AKPEPSPsPRITRKS 9606 21565170 t gcesareni We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5 SIGNOR-173685 0.365 EPHB1 protein P54762 UNIPROT EPHB1 protein P54762 UNIPROT up-regulates activity phosphorylation Tyr594 GSPGMKIyIDPFTYE 10029 BTO:0000246 12223469 t  Co-immunoprecipitation was used to confirm the interaction of Grb7 with the cytoplasmic domain of EphB1 as well as the full-length receptor in intact cells. This interaction is mediated by the SH2 domain of Grb7 and requires tyrosine autophosphorylation of EphB1. We also found that EphB1 could phosphorylate Grb7 and mutation of either Tyr-928 or Tyr-594 to Phe decreased this activity. SIGNOR-251122 0.2 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Pyl) smallmolecule CHEBI:15185 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269494 0.8 PTEN protein P60484 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0001332 19903340 f lperfetto PTEN-mediated suppression of the PI3K/AKT pathway is well established, accumulating evidence suggests that nuclear PTEN also plays a critical role in tumor suppression SIGNOR-244439 0.654 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid chemical CHEBI:125628 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194527 0.8 citrate(3-) smallmolecule CHEBI:16947 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-267100 0.8 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser626 SLECDMEsIIRSELM 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252884 0.398 USP22 protein Q9UPT9 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269578 0.651 CD3D protein P04234 UNIPROT CD3 complex SIGNOR-C432 SIGNOR form complex binding 9606 12507424 t miannu The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules. SIGNOR-255295 0.725 AGTR2 protein P50052 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni These neuropeptide gpcrs are coupled to the activation of phospholipase c, and therefore to calcium ele- vation and protein kinase c (pkc) activation, through g proteins of the alfaq family SIGNOR-106995 0.487 CDH1 protein P12830 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 20940130 t gcesareni P12Beta-catenin_ also associates to the_ wnt_ co-receptor lrp5/6, an interaction mediated by e-cadherin. SIGNOR-168464 0.371 PPP6C protein O00743 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity dephosphorylation Ser831 SAEGSHTsGQSNGRD 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276513 0.334 MAPK3 protein P27361 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Thr456 KVYFLPItPHYVTQV 9606 15890648 t lperfetto Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol SIGNOR-137179 0.2 SRC protein P12931 UNIPROT RHOU protein Q7L0Q8 UNIPROT down-regulates activity phosphorylation Tyr254 SKSWWKKyCCFV 9606 BTO:0002552 20547754 t miannu Regulation of the Rho family small GTPase Wrch-1/RhoU by C-terminal tyrosine phosphorylation requires Src. Phosphorylation at Y254 negatively regulates Wrch-1-mediated biological functions.Serum-stimulated tyrosine phosphorylation and relocalization of Wrch-1 decreases its activation of downstream effectors in a Y254-dependent manner. SIGNOR-259814 0.535 PPP6C protein O00743 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity dephosphorylation Thr830 DSAEGSHtSGQSNGR 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276515 0.334 STK39 protein Q9UEW8 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates activity phosphorylation 16990453 t lperfetto This phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1 SIGNOR-264642 0.619 FHIT protein P49789 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18077326 f miannu In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin. SIGNOR-159870 0.273 CSK protein P41240 UNIPROT LCK protein P06239 UNIPROT down-regulates phosphorylation Tyr505 FTATEGQyQPQP 9606 BTO:0000782 1639064 t gcesareni P50csk tyrosine kinase phosphorylates p56lck at tyr-505 and down regulates its catalytic activity. SIGNOR-20371 0.519 GSK3B protein P49841 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser274 TKASSVAsSDKGSCC 9606 BTO:0002181 27432879 t miannu Our previous study showed, by mass spectrometry analysis, that GSK-3β phosphorylates Foxp3 at Ser270 and Ser275 SIGNOR-277245 0.288 amitriptyline chemical CHEBI:2666 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8100134 t miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. SIGNOR-258700 0.8 MAPK1 protein P28482 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates 9606 18481201 f gcesareni In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. SIGNOR-178639 0.489 ULK1 protein O75385 UNIPROT AMPK complex SIGNOR-C15 SIGNOR down-regulates phosphorylation 9606 21460634 t lperfetto Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. SIGNOR-217484 0.469 MDM2 protein Q00987 UNIPROT DYRK2 protein Q92630 UNIPROT down-regulates quantity by destabilization ubiquitination 19965871 t lperfetto Under normal conditions, nuclear and not cytoplasmic DYRK2 is ubiquitinated by MDM2, resulting in its constitutive degradation.|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus. SIGNOR-275579 0.552 CDK18 protein Q07002 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity 9606 BTO:0000567 28361970 f lperfetto PCTK3/CDK18 regulates cell migration and adhesion by negatively modulating FAK activity SIGNOR-264561 0.2 metaproterenol chemical CHEBI:6792 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) SIGNOR-257873 0.8 PRKCA protein P17252 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Thr174 KVPVTHEtQEECLGM -1 27368100 t miannu These results suggest that PKC activates JAK2 and thereby STAT3 by directly phosphorylating T174 and S518.  SIGNOR-277262 0.262 RPS6KB1 protein P23443 UNIPROT PIP5K1C protein O60331 UNIPROT down-regulates quantity by destabilization phosphorylation Thr553 QPRYRRRtQSSGQDG 27780861 t miannu Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIγ90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIγ90 phosphorylation is essential for cell migration and invasion. These data suggest that S6K1-mediated PIPKIγ90 phosphorylation regulates cell migration and invasion by controlling PIPKIγ90 degradation. SIGNOR-277282 0.2 RAPGEF5 protein Q92565 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-183735 0.415 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 12186630 t lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. SIGNOR-249154 0.2 EIF4B protein P23588 UNIPROT 48S_initiation_complex complex SIGNOR-C454 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269165 0.2 NR5A2 protein O00482 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 f miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254873 0.371 CSNK2A1 protein P68400 UNIPROT EGR1 protein P18146 UNIPROT down-regulates activity phosphorylation Thr526 TNSFSAStGLSDMTA 10090 BTO:0000944 8662759 t llicata Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10. SIGNOR-250858 0.477 SRC protein P12931 UNIPROT CDC42 protein P60953 UNIPROT up-regulates phosphorylation Tyr64 DTAGQEDyDRLRPLS 9606 14506284 t gcesareni Epidermal growth factor-dependent regulation of cdc42 is mediated by the src tyrosine kinaseegf signaling through src appears to have dual regulatory effects on cdc42: 1). it leads to the activation of cdc42 as mediated by the vav2 guanine nucleotide exchange factor, and 2). it results in the phosphorylation of cdc42, which stimulates the binding of rhogdi, perhaps to direct the movement of cdc42 to a specific cellular site to trigger a signaling response, because cdc42-rhogdi interactions are essential for cdc42-induced cellular transformation. SIGNOR-118206 0.683 RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates activity phosphorylation Ser970 HSQCLNSsPLSHHSQ 9606 11369754 t lperfetto These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994. SIGNOR-108257 0.432 perfluorohexanesulfonic acid chemical CHEBI:132448 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 23764977 t miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  SIGNOR-268761 0.8 FYN protein P06241 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 10383400 t miannu Further indications of direct interaction are that p59fyn potentiates ?PKC Catalytic activity and that ?PKC Is a substrate for tyrosine phosphorylation by p59fyn. SIGNOR-68798 0.351 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates phosphorylation Tyr177 ADAEKPFyVNVEFHH 9606 9407116 t lperfetto The src family kinase hck interacts with bcr-abl by a kinase-independent mechanism and phosphorylates the grb2-binding site of bcr SIGNOR-53964 0.2 AKT1 protein P31749 UNIPROT GAB2 protein Q9UQC2 UNIPROT down-regulates phosphorylation Ser159 LLRERKSsAPSHSSQ 9606 11782427 t lperfetto Pkb constitutively associates with gab2, phosphorylates gab2 on a consensus phosphorylation site, ser159, in vitro and inhibits gab2 tyrosine phosphorylation. SIGNOR-252468 0.687 RHOH protein Q15669 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 BTO:0000661 17028588 t irozzo These findings suggest that RhoH is a critical regulator of thymocyte development and TCR signaling by mediating recruitment and activation of Zap70. SIGNOR-259084 0.47 NR1H4 protein Q96RI1 UNIPROT ABCB4 protein P21439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000575 14527955 f miannu Here we show that the MDR3 gene is trans-activated by the farnesoid X receptor (FXR) via a direct binding of FXR/retinoid X receptor alpha heterodimers to a highly conserved inverted repeat element (a FXR response element) at the distal promoter (-1970 to -1958). SIGNOR-254833 0.427 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 17510057 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-217071 0.748 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 BTO:0000007 8702708 t lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-42984 0.891 CDC42 protein P60953 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 9606 21902831 f lperfetto Precisely how this complex results in p38 activation is not known, but complex recruitment of the gtpase cdc42 is required for p38 phosphorylation. SIGNOR-176501 0.586 CALM2 protein P0DP24 UNIPROT KIF1A protein Q12756 UNIPROT up-regulates activity binding 10116 BTO:0003102 30021165 t miannu To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. In contrast, liprin-α and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines SIGNOR-266889 0.263 NR3C1 protein P04150 UNIPROT CEBPD protein P49716 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000011 1840554 t The expression levels of both C/EBPB and C/EBPD are increased dramatically during the time of hormonal stimulation (see Fig. 8). Furthermore, the C/EBPB- and C/EBPD encoding genes are activated directly by adipogenic hormones SIGNOR-251648 0.321 NPY protein P01303 UNIPROT NPY2R protein P49146 UNIPROT up-regulates binding 9606 9549761 t gcesareni Analogs of npy and pyy have been synthesized that contain a proline residue in position 34 of the molecule, i.e., [leu31, pro34]npy (fuhlendorff et al., 1990) or [pro34]pyy (grandt et al., 1994b), and are much more potent at y1 than y2receptors. SIGNOR-56568 0.832 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Thr151 RSYSRLEtLGSASTS -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276121 0.698 PRKCA protein P17252 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000599 15730925 f irozzo PKC-alpha asODN (antisense oligonucleotides) could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC. SIGNOR-256267 0.7 COPS5 protein Q92905 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270761 0.933 belinostat chemical CHEBI:61076 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257746 0.8 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser637 VDLSKVTsKCGSLGN -1 10090741 t miannu We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs. SIGNOR-250173 0.44 glycine smallmolecule CHEBI:15428 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 9606 18721822 t miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. SIGNOR-264985 0.8 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB5 protein Q9Y5G0 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265714 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates activity phosphorylation 9606 BTO:0003324 25323588 t miannu Earlier studies found that expression of active Akt increases mitochondrial HK activity and the anti-apoptotic effect of Akt required mitoHK SIGNOR-267577 0.497 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1100 QGCRRRHsSETFSST 9606 17360977 t lperfetto Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 SIGNOR-235675 0.2 bremazocine chemical CHEBI:3171 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258778 0.8 PHF12 protein Q96QT6 UNIPROT TLE4 protein Q04727 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 t miannu We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE. SIGNOR-266989 0.2 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr209 LCEISRGtHNFSEEL 9606 BTO:0000007 14625308 t lperfetto Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signalingthis identifies irak-1 as a novel type of adapter protein, which employs its own kinase activity to introduce negative charges adjacent to the protein interaction domain, which anchors irak-1 at the active receptor complex. Thus, irak-1 regulates its own availability as an adapter molecule by sequential autophosphorylation SIGNOR-119212 0.2 AKT1 protein P31749 UNIPROT ARFIP2 protein P53365 UNIPROT unknown phosphorylation Ser260 GTRGRLEsAQATFQA 9606 BTO:0000938 15809304 t llicata Akt phosphorylated arfaptin 2 at ser(260). we have also demonstrated that arfaptin 2 phosphorylation restores proteasome activity that is inhibited by the presence of polyq-huntingtin in cells. SIGNOR-252476 0.471 KDR protein P35968 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity relocalization 9825 BTO:0004007 phosphorylation:Tyr1175 AQQDGKDyIVLPISE 9405464 t VEGF pathway Gianni In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function. SIGNOR-261948 0.673 CDK7 protein P50613 UNIPROT CDK12 protein Q9NYV4 UNIPROT up-regulates activity phosphorylation Thr893 SEESRPYtNKVITLW 24662513 t lperfetto Although Cdk12/CycK kinase complex lacking T-loop phosphorylation showed some basal activity towards a CTD substrate prephosphorylated at position Ser7, its activity was significantly increased upon coexpression with the CAK from S. cerevisiae (Supplementary Fig. 9a). Mutation of T893 to E to mimic phosphorylation showed no effect on basal kinase activity. Quantitative phosphorylation of a single residue occurred upon coexpression with Cak1, as determined by ESI mass spectrometry (Supplementary Fig. 9b). SIGNOR-275509 0.489 CSNK2A1 protein P68400 UNIPROT AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser276 AAQQTKGsYMEVEDN 9615 BTO:0000837 11742978 t llicata We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. AQP4 phosphorylation by CKII may thus provide a mechanism that regulates AQP4 cell surface expression. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4-Cter proteins in which only one out of the three C-terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. SIGNOR-250826 0.426 NUP88 protein Q99567 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262076 0.618 GRB10 protein Q13322 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0001516 23246379 t Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation SIGNOR-255946 0.34 ARNTL protein O00327 UNIPROT MAGEL2 protein Q9UJ55 UNIPROT down-regulates activity binding 9606 BTO:0000007 22208286 t miannu Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization. SIGNOR-253517 0.377 acyl-CoA smallmolecule CHEBI:17984 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of -1 18772128 t miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. SIGNOR-268106 0.8 KRT1 protein P04264 UNIPROT APC protein P25054 UNIPROT up-regulates activity phosphorylation 9606 18359618 t Regulation of catabolism miannu Phosphorylation of this central repeat region of APC significantly enhances its affinity for β-catenin. When the repeats are phosphorylated by the cooperative action of CK1 and GSK3β, the binding interaction is significantly altered and enhanced. SIGNOR-251879 0.2 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity dephosphorylation Tyr577 YMEDSTYyKASKGKL -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254718 0.245 RPS6KA5 protein O75582 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD 10090 BTO:0000452 11909979 t lperfetto Using embryonic fibroblasts derived from these mice we were able to demonstrate an important role for these enzymes in the activation of CREB and the closely related transcription factor ATF1. | Our results clearly demonstrate that MSK1 and MSK2 are the major, if not the only, protein kinases that mediate the phosphorylation of CREB at Ser133 and of ATF1 at Ser63 in fibroblasts SIGNOR-249144 0.678 PRKACA protein P17612 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates phosphorylation Ser337 FVQLRRKsDLETSEP 9606 SIGNOR-C13 17959673 t llicata In this study, we demonstrate that the phosphorylation of p50 and p65 by the catalytic subunit of protein kinase a (pkac) is essential for nf-kappab dna binding and transactivation activity. treatment with h89 and knockdown of pkac in cells led to the inhibition of phosphorylation at p50 ser(337) and p65 ser(276) and loss of dna binding by nf-kappab. SIGNOR-158595 0.488 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr434 MSFHRNHtATVRSHA 9606 11123317 t lperfetto Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5.  SIGNOR-249070 0.346 MAPK10 protein P53779 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 20395206 t gcesareni With epidermal growth factor treatment, overexpression of erk8 in jb6 cl41 cells caused an increased phosphorylation of c-jun at ser(63) and ser(73), resulting in increased activator protein-1 transactivation. SIGNOR-164804 0.883 HCK protein P08631 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity phosphorylation Tyr394 LNTIGLIyEKISLPK 9606 BTO:0002181 28618271 t miannu The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.  SIGNOR-276727 0.2 GSK3B protein P49841 UNIPROT DROSHA protein Q9NRR4 UNIPROT up-regulates activity phosphorylation Ser302 RDNRRSPsLERSYKK -1 25699712 t lperfetto Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes.  SIGNOR-264846 0.282 SLBP protein Q14493 UNIPROT H2AC6 protein Q93077 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265400 0.2 MAPK11 protein Q15759 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR unknown phosphorylation 9606 21757713 t lperfetto Arsenite treatment of cells activates p38_ and induces interaction between p38_ and raptor, a regulatory component of mtorc1, resulting in phosphorylation of raptor on ser(863) and ser(771). The phosphorylation of raptor on these sites enhances mtorc1 activity, and contributes largely to arsenite-induced mtorc1 activation. SIGNOR-217580 0.336 RRAGD protein Q9NQL2 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates binding 9606 20006481 t lperfetto Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor SIGNOR-217550 0.635 FOXO6 protein A8MYZ6 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 f lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-236567 0.275 SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Tyr326 EVLEDNDyGRAVDWW 9534 BTO:0004055 11445557 t lperfetto Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity. SIGNOR-246377 0.664 chlorpromazine chemical CHEBI:3647 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258370 0.8 (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI up-regulates quantity precursor of 9606 18767138 t lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate SIGNOR-268246 0.8 CDK1 protein P06493 UNIPROT FEN1 protein P39748 UNIPROT down-regulates activity phosphorylation Ser187 MDCLTFGsPVLMRHL 9606 BTO:0000007 12853968 t lperfetto Phosphorylation of human fen1 by cyclin-dependent kinase modulates its role in replication fork regulation.As a functional consequence of phosphorylation by cdk1-cyclin a in vitro, endo- and exonuclease activities of fen1 are reduced whereas its dna binding is not affected. SIGNOR-103535 0.456 trimethyl-[(5-methyl-2-furanyl)methyl]ammonium chemical CHEBI:94038 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258648 0.8 HES1 protein Q14469 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000165 BTO:0000887 10066785 f lperfetto Notch signaling up-regulated hes1 mrna expression within 1 h and subsequently reduced expression of myod mrna. SIGNOR-235596 0.299 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Tyr570 VRREVGDyGQLHETE 9606 21841788 t lperfetto The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570. SIGNOR-176058 0.2 CDK1 protein P06493 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Thr135 TVQQHPStPKRHTVL 9606 BTO:0000007 21209322 t lperfetto High nacl-induced activation of cdk5 increases phosphorylation of the osmoprotective transcription factor tonebp/orebp at threonine 135, which contributes to its rapid nuclear localization. we performed in vitro kinase assays using the tonebp/orebp peptide containing t135 as substrate (figure 3b, right panel) and various recombinant kinases. The peptide is strongly phosphorylated by cdk5, less by cdk1. SIGNOR-170882 0.2 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Thr203 SSLATPPtLSSTVLI 9606 BTO:0001938 12815053 t lperfetto Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation. SIGNOR-249220 0.555 HSF4 protein Q9ULV5 UNIPROT DNASE2B protein Q8WZ79 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23507146 f miannu We found that HSF4 promoted the expression and DNase activity of DLAD by directly binding to the DLAD promoter. SIGNOR-254479 0.376 GALR3 protein O60755 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256862 0.426 LPAR4 protein Q99677 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257170 0.2 NRARP protein Q7Z6K4 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR down-regulates binding 8355 11485984 t lperfetto Overexpression of nrarp in embryos blocks notch signaling and inhibits the activation of notch target genes by icd. We show that nrarp forms a ternary complex with the icd of xnotch1 and the csl protein xsu(h) and that in embryos nrarp promotes the loss of icd. SIGNOR-219228 0.418 CSNK1A1 protein P48729 UNIPROT FADD protein Q13158 UNIPROT down-regulates activity phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 16061179 t gcesareni FADD is essential for death receptor (DR)-induced apoptosis.|Phosphorylation of FADD at serine 194 by CKIalpha regulates its nonapoptotic activities SIGNOR-139307 0.339 SSTR1 protein P30872 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256958 0.252 NANOG protein Q9H9S0 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 f miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. SIGNOR-254622 0.339 NCOA1 protein Q15788 UNIPROT ALDOB protein P05062 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255061 0.2 CUDC-907 chemical CID:54575456 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191212 0.8 SNAI1 protein O95863 UNIPROT HPGD protein P15428 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 19010907 f miannu We show an interaction between Snail and HDAC2 and the binding of HDAC2 to the 15-PGDH promoter. These data suggest that class I HDACs, specifically HDAC2, and the transcriptional repressor Snail play a central role in the suppression of 15-PGDH expression. SIGNOR-254237 0.295 ZNRF3 protein Q9ULT6 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 22575959 t gcesareni Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6 SIGNOR-197414 0.296 POT1 protein Q9NUX5 UNIPROT TERT protein O14746 UNIPROT up-regulates binding 9606 17237768 t miannu We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme. SIGNOR-152327 0.674 pirenzepine chemical CHEBI:8247 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258394 0.8 SLBP protein Q14493 UNIPROT H2BW2 protein P0C1H6 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265395 0.2 KDM6B protein O15054 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys28 LATKAARkSAPATGG 9606 24561908 t This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions. miannu Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation. SIGNOR-260018 0.2 silodosin chemical CHEBI:135929 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 10029 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258451 0.8 GLUL protein P15104 UNIPROT ammonium smallmolecule CHEBI:28938 ChEBI down-regulates quantity chemical modification 9606 30158707 t miannu Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction. SIGNOR-267825 0.8 F10 protein P00742 UNIPROT F2 protein P00734 UNIPROT up-regulates activity cleavage 10090 BTO:0000131 25769543 t lperfetto The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin. SIGNOR-263539 0.436 GRK5 protein P34947 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 t Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. SIGNOR-251209 0.467 SAE1 protein Q9UBE0 UNIPROT SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR form complex binding -1 15660128 t lperfetto E1 enzymes facilitate conjugation of ubiquitin and ubiquitin-like proteins through adenylation, thioester transfer within E1, and thioester transfer from E1 to E2 conjugating proteins. Structures of human heterodimeric Sae1/Sae2-Mg.ATP and Sae1/Sae2-SUMO-1-Mg.ATP complexes were determined at 2.2 and 2.75 A resolution, respectively. SIGNOR-263003 0.816 CDT1 protein Q9H211 UNIPROT CDT1 protein Q9H211 UNIPROT up-regulates activity binding 9606 BTO:0000007 14672932 t We further show that Cdc6 physically associates with Cdt1 via its N-terminal noncatalytic domain, a region we had previously shown to be essential for Cdc6 function. SIGNOR-261682 0.2 CAMK2A protein Q9UQM7 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 t gcesareni Receptor internalization, altered;intracellular localization SIGNOR-97546 0.575 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser50 TSTMPNSsQSSHSSS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to iratm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro. SIGNOR-81407 0.829 clozapine chemical CHEBI:3766 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258681 0.8 CDK1 protein P06493 UNIPROT ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr444 TKSSKSStPVPSKQS 9606 16247472 t lperfetto Here we show that two mitotic kinases, cdk1 and polo-like kinase 1 (plk1), phosphorylate ect2 in vitro.Moreover, ect2 t412a, but not phosphomimic t412d, displayed a diminished accumulation of gtp-bound rhoa compared with wt ect2, suggesting that phosphorylation of thr-412 is critical for the catalytic activity of ect2. SIGNOR-141175 0.593 STK11 protein Q15831 UNIPROT MARK4 protein Q96L34 UNIPROT up-regulates phosphorylation Thr214 TLGSKLDtFCGSPPY 9606 14976552 t lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold SIGNOR-122682 0.516 prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 20219869 f apalma Prostaglandins are able to affect muscle cell proliferation (142), differentiation (96) and fusion (141), and can also modulate muscle fiber growth and the synthesis and degradation of proteins in muscle SIGNOR-256213 0.7 BACE1 protein P56817 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage 28923680 t Beta-secretase 1 (BACE1) cleaves the type-I transmembrane protein APP to form the N-terminus of Aβ. SIGNOR-255480 0.786 DTL protein Q9NZJ0 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR up-regulates activity binding 9606 BTO:0000007 24962565 t miannu TDG Is Polyubiquitinated by CRL4Cdt2 E3 Ubiquitin Ligase in a PIP Degron-dependent Manner SIGNOR-272848 0.683 PRKCG protein P05129 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Ser29 ATPAARAsKKILLPE 9606 BTO:0000007 11042191 t lperfetto Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells. SIGNOR-249060 0.2 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser222 LIDSMANsFVGTRSY -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-39054 0.78 BAX protein Q07812 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. SIGNOR-261494 0.7 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 15241418 t lperfetto We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity SIGNOR-232134 0.733 MAPK14 protein Q16539 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 20626350 f lperfetto On the other hand, p38 alfa may negatively modulate akt activity, indipendently of pi3k by regulating the interaction between caveolin 1 and pp2a through a mechanism dependent on cell attachment. SIGNOR-244461 0.631 ibuprofen chemical CHEBI:5855 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 22091869 t Luana  Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2.  SIGNOR-258325 0.8 RFFL protein Q8WZ73 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 18450452 t miannu We report that CARP-2, a RING domain-containing ubiquitin protein ligase (E3), is a negative regulator of TNF-induced NF-kappaB activation. By virtue of its phospholipid-binding FYVE domain, CARP-2 localized to endocytic vesicles, where it interacted with internalized TNF-receptor complex, resulting in RIP ubiquitination and degradation. SIGNOR-271482 0.445 Aflibercept chemical SID:134445687 ChEBI PGF protein P49763 UNIPROT down-regulates activity chemical inhibition 9606 22813448 t miannu Aflibercept, a fusion protein with binding domains from native VEGF receptors, binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity.This soluble decoy receptor is produced by fusing all-human DNA sequences of the second immunoglobulin (Ig) domain of human VEGF receptor (VEGFR) 1 to the third Ig domain of human VEGFR-2, which then is fused to the Fc region of human IgG-1.2 Aflibercept binds to all VEGF-A and VEGF-B isoforms, as well as the highly related placental growth factor. SIGNOR-259385 0.8 TRAF6 protein Q9Y4K3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity ubiquitination Lys180 SPAPSSTkPGPESSV 9606 18347055 t K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-_B SIGNOR-252252 0.911 PKA proteinfamily SIGNOR-PF17 SIGNOR GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1166 SDDFKRDsVSGGGPC 9606 BTO:0000007 24431445 t miannu Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca(2+) permeation and Ca(2+) signaling in spines. SIGNOR-276617 0.2 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr52 DGFIPKNyIEMKPHP 9606 BTO:0000007 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246293 0.2 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267512 0.8 PTGER1 protein P34995 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256811 0.433 ATM protein Q13315 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser645 NLSTNADsQSSSDFE 9606 16874298 t lperfetto The artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced dna double-strand breaks (dsbs) in an atm and dna-pk dependent process. Here, we show that artemis phosphorylation by atm and dna-pk in vitro is primarily attributable to s503, s516 and s645 and demonstrate atm dependent phosphorylation at serine 645 in vivo SIGNOR-148323 0.603 SPOP protein O43791 UNIPROT MACROH2A1 protein O75367 UNIPROT up-regulates activity binding 9606 BTO:0000007 15897469 t miannu Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. BMI1 and MACROH2A1 interact with and are ubiquitinated by the CULLIN3 and SPOP ligase complex. SIGNOR-272657 0.2 DDR1 protein Q08345 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity relocalization 9615 BTO:0000837 16611743 t lperfetto Overexpression of DDR1a/b increased the interaction of DDR1 with SHP-2 and up-regulated the tyrosine phosphatase activity of SHP-2. SIGNOR-272403 0.381 TAB1 protein Q15750 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity binding 9606 11847341 t lperfetto Here, we report an unexpected activation mechanism for p38alpha MAPK that does not involve the prototypic kinase cascade. Rather it depends on interaction of p38alpha with TAB1 [transforming growth factor-beta-activated protein kinase 1 (TAK1)-binding protein 1] leading to autophosphorylation and activation of p38alpha. SIGNOR-114843 0.817 FOXL2 protein P58012 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000975 16153597 f miannu We observed that foxl2 induces apoptosis in the ovarian cells unveiling a novel function of foxl2 SIGNOR-140391 0.7 F2R protein P25116 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257353 0.549 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 12058066 t lperfetto Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association. SIGNOR-216745 0.417 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.78 MIB1 protein Q86YT6 UNIPROT DLL4 protein Q9NR61 UNIPROT up-regulates activity ubiquitination 9606 16140393 t lperfetto Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity. SIGNOR-209626 0.534 XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT down-regulates quantity by destabilization binding 9606 11242052 t lperfetto A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis SIGNOR-105702 0.92 PIP3 smallmolecule CHEBI:16618 ChEBI AKT1 protein P31749 UNIPROT up-regulates activity relocalization 9606 23119004 t lperfetto Binding of igf to igf-ir activates pi3k to generate pip3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including akt and pdk1. SIGNOR-252642 0.8 SLBP protein Q14493 UNIPROT H2AZ2 protein Q71UI9 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265410 0.2 MCHR1 protein Q99705 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257302 0.509 CDK5 protein Q00535 UNIPROT ADD1 protein P35611 UNIPROT up-regulates activity phosphorylation Thr724 KKKKKFRtPSFLKKS 9606 BTO:0000815 31548578 t miannu We found that Cdk5 directly phosphorylated the actin-binding protein adducin-1 (ADD1) at T724 in vitro and in intact cells. SIGNOR-277487 0.257 CAD protein P27708 UNIPROT (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI up-regulates quantity chemical modification 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267420 0.8 AL/b2 integrin complex SIGNOR-C169 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257712 0.447 MAPK8 protein P45983 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates phosphorylation Ser173 PCPQPLRsPSLDNPT 9606 19153595 t lperfetto In this study, we show that another kinase, c-jun-nh(2)-terminal kinase (jnk), phosphorylates irf3 on its n-terminal serine 173 residuejnk1 can synergize the action of irf3(5d), but not the s173a-irf3(5d) mutant SIGNOR-183489 0.549 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227897 0.891 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 12747827 t lperfetto Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e. SIGNOR-236694 0.753 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT down-regulates activity phosphorylation Ser686 LEELHEKsQEVIWGL -1 12852856 t lperfetto Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction SIGNOR-103348 0.688 LIF protein P15018 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 9143707 t gcesareni Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors.Some Of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2 SIGNOR-48108 0.782 CSNK2A1 protein P68400 UNIPROT DDHD1 protein Q8NEL9 UNIPROT down-regulates activity phosphorylation Ser104 GSSLRYYsEGESGGG -1 11328814 t miannu Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity SIGNOR-262974 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270376 0.8 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr426 ASAASFEyTILDPSS 12441334 t JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 SIGNOR-251349 0.805 calcium(2+) smallmolecule CHEBI:29108 ChEBI KCNMA1 protein Q12791 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 31152168 t miannu The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. The BK channel can be allosterically activated by both changes in the membrane voltage (voltage-dependent activation pathway) and intracellular [Ca2+] concentration (calcium-dependent activation pathway) SIGNOR-269199 0.8 SRMS protein Q9H3Y6 UNIPROT FKBP5 protein Q13451 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr54 PMIGDKVyVHYKGKL 9606 BTO:0000567 34077419 t miannu SRMS binds FKBP51 and phosphorylates tyrosine 54. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway. SIGNOR-277564 0.27 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 19364816 t gcesareni Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21cip1.|Phosphopeptide analysis of in vitro ERK2-phosphorylated p21(Cip1) revealed two phosphorylation sites, Thr57 and Ser130. SIGNOR-244618 0.2 CDK7 protein P50613 UNIPROT RARA protein P10276 UNIPROT up-regulates phosphorylation Ser77 EIVPSPPsPPPLPRI 9606 BTO:0000567 9230306 t llicata However, only the coexpression of cdk7 stimulated ser-77 phosphorylation in vivo and enhanced transactivation by rar alpha, but not by a s77a rar mutant. SIGNOR-49693 0.527 ARHGAP26 protein Q9UNA1 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260481 0.613 JAK1 protein P23458 UNIPROT IL2RB protein P14784 UNIPROT up-regulates activity phosphorylation Tyr418 LSGEDDAyCTFPSRD 9534 BTO:0000298 8700888 t In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc. SIGNOR-251340 0.616 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC11 protein P06899 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271980 0.2 ACOT8 protein O14734 UNIPROT glutarate(2-) smallmolecule CHEBI:30921 ChEBI up-regulates quantity chemical modification 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271813 0.8 MAPK1 protein P28482 UNIPROT CAPN2 protein P17655 UNIPROT up-regulates phosphorylation Ser50 GTLFQDPsFPAIPSA 9606 14993287 t lperfetto Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo. SIGNOR-123079 0.612 KDM5C protein P41229 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-265354 0.2 EIF2AK4 protein Q9P2K8 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation Ser52 MILLSELsRRRIRSI 9606 32513922 t gcesareni Translation initiation factor 2α [eukaryotic translation initiation factor 2α (eIF2α)] kinase phosphorylates serine51 (Ser51) of eIF2α and downregulates cellular protein synthesis. SIGNOR-246157 0.912 AKT proteinfamily SIGNOR-PF24 SIGNOR SLC2A4 protein P14672 UNIPROT up-regulates 9606 9415393 f Translocation from intracellular compartment to cell surface in muscle and adipose tissue gcesareni Akt is not only capable of stimulating the translocation of glut4 to the cell surface. Endogenous akt is likely to play a significant physiological role in insulin-stimulated glucose uptake in insulin targets such as muscle and adipose tissue SIGNOR-53968 0.2 FGFR1 protein P11362 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates phosphorylation Tyr136 AEDAKAIyDFTDTVI 9606 22195962 t llicata Mitochondrial pdhk1 is tyrosine phosphorylated and activated by fgfr1 in cancer cells further mass spectrometric analysis identified three tyrosine residues of pdhk1, including y136, y243 and y244, that are phosphorylated by fgfr1 SIGNOR-191719 0.354 E2F1 protein Q01094 UNIPROT ISYNA1 protein Q9NPH2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 15464731 f lperfetto Human myo-inositol 1-phosphate synthase (IP synthase; E.C. 5.5.1.4), encoded by ISYNA1, catalyzes the de novo synthesis of inositol 1-phosphate from glucose 6-phosphate.|Here, we have characterized the minimal promoter of ISYNA1 and show that it is upregulated by E2F1. SIGNOR-254130 0.315 FYN protein P06241 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Tyr487 DNSSDSDyDLHGAQR -1 11298344 t Tyrosine-mutated CD5 molecules have been used to show that residues Y429 and Y463 are targeted in vivo by protein tyrosine kinases following cell stimulation with anti-CD3 mAb or pervanadate. This is in agreement with data from direct in vitro kinase assays using purified recombinant Lck and Fyn protein tyrosine kinases. SIGNOR-251152 0.504 Helicase protein P0DTD1-PRO_0000449630 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 9606 BTO:0000007 32979938 t miannu We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F). SIGNOR-262512 0.2 p38 proteinfamily SIGNOR-PF16 SIGNOR CDC25B protein P30305 UNIPROT down-regulates quantity by destabilization phosphorylation Ser103 ESSLSSEsSESSDAG 9606 BTO:0000567 21807946 t miannu  Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104). SIGNOR-276349 0.2 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr720 IPKEPSNyDFVYDCN 9606 15952790 t llicata We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts. SIGNOR-138158 0.59 ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR SHC3 protein Q92529 UNIPROT up-regulates relocalization 9606 16729043 t inferred from 70% family members gcesareni Like erbb1, erbb4 recruits grb2, shc and stat5. SIGNOR-269962 0.2 ATM protein Q13315 UNIPROT RAD17 protein O75943 UNIPROT unknown phosphorylation Ser646 ETWSLPLsQNSASEL 9606 10608806 t lperfetto We determined a general phosphorylation consensus sequence for atm and identified putative in vitro targets by using glutathione s-transferase peptides as substrates. Putative atm in vitro targets include p95/nibrin, mre11, brca1, rad17, pts, wrn, and atm (s440) itself. SIGNOR-73520 0.841 GUCY1A1 protein Q02108 UNIPROT GUCY1A3-B2 complex SIGNOR-C139 SIGNOR form complex binding 9606 10977868 t gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity SIGNOR-244116 0.2 RPS6KB1 protein P23443 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 9211863 t gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. SIGNOR-49371 0.249 PYGM protein P11217 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 3346228 t miannu Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267390 0.8 S1PR3 protein Q99500 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257062 0.472 FZD4 protein Q9ULV1 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 18077588 t areggio Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction. SIGNOR-258964 0.635 AHCTF1 protein Q8WYP5 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262086 0.514 AIMP1 protein Q12904 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 t miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). SIGNOR-270359 0.916 GDC-0879 chemical CHEBI:83405 ChEBI BRAF protein P15056 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192592 0.8 MC4R protein P32245 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256797 0.501 NODAL protein Q96S42 UNIPROT ACVR1C protein Q8NER5 UNIPROT up-regulates activity binding 9606 BTO:0004094 15531507 t Indirect_regulation of expression miannu Human activin receptor-like kinase 7 (ALK7), a type I receptor for Nodal. activation of the Nodal-ALK7 signaling pathway leads to induction of apoptosis and inhibition of cell proliferation. SIGNOR-251936 0.621 dobutamine chemical CHEBI:4670 ChEBI YAP1 protein P46937 UNIPROT down-regulates 9606 23431053 f These results suggest that the activity of YAP/TAZ can be either up-regulated or down-regulated by GPCR signaling,depending on which Galfa protein is activated gcesareni Dobutamine is an agonist for the beta1 adrenergic receptor, which likely inhibits yap by activating gaalfas. SIGNOR-201259 0.8 GLI1 protein P08151 UNIPROT GLI1 protein P08151 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 f lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. SIGNOR-209617 0.2 PAPOLA protein P51003 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 19224921 f lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. SIGNOR-268325 0.7 KRAS protein P01116 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation Ser67 RQLRKVRsVELDQLP 9606 12228228 t gcesareni Activation of ras may lead to two distinct ras-dependent pathways involving either a raf1/mek/mapk module or a mekk/sek/sapk module; jnk/sapk binds to the d domain near the nh2 terminus of mekk1 from approximately residues 6270 (9, 10). Pak1 can phosphorylate mekk1 on serine 67 within its jnk/sapk-binding d domain. Phosphorylation of mekk1 on serine 67 alters the state of the d domain, thereby decreasing its affinity for jnk/sapk. Under these conditions jnk/sapk is not recruited into the mekk1 signaling module. SIGNOR-92793 0.373 HOXC13 protein P31276 UNIPROT DSG4 protein Q86SJ6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000552 19683850 f miannu we studied the transcriptional regulation of DSG4 by transcription factors/pathways that are known regulators of hair keratin or KAP expression. We show that HOXC13, LEF1 and FOXN1 repress DSG4 transcription and provide in vitro and in vivo evidence correlating the Notch pathway with the activation and/or maintenance of DSG4 expression in the hair follicle. SIGNOR-254184 0.393 CDK6 protein Q00534 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 15809340 t gcesareni Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively. SIGNOR-135189 0.76 phentolamine chemical CHEBI:8081 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258445 0.8 tandutinib chemical CHEBI:90237 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258297 0.8 PPP2CA protein P67775 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 14712210 t Phosphorylation of p53 at serine 37 is important for transcriptional activity and regulation in response to DNA damage| Furthermore, in vitro phosphatase assays show that PP2A dephosphorylates p53 at S37. SIGNOR-248619 0.573 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F8 protein P00451 UNIPROT down-regulates activity cleavage Arg759 KNNAIEPrSFSQNSR -1 10350471 t lperfetto N-Terminal sequencing along with time courses of proteolysis indicated that VIIa-TF/PL cleaved factor VIII first at R740, followed by concomitant cleavage at R336 and R372. |hus, heavy chain cleavage of factor VIII by VIIa-TF/PL produces an inactive factor VIII cofactor no longer capable of activation by thrombin. SIGNOR-263644 0.466 AKT proteinfamily SIGNOR-PF24 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates activity 9606 16293724 f lperfetto We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway. SIGNOR-244225 0.2 procaterol chemical CHEBI:135209 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  SIGNOR-257863 0.8 2-[[3-[[2-(dimethylamino)phenyl]methyl]-2-pyridin-4-yl-1,3-diazinan-1-yl]methyl]-N,N-dimethylaniline smallmolecule CHEBI:94276 ChEBI GLI1 protein P08151 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150;BTO:0001130 17494766 t gcesareni Gant61 was able to efficiently block gli1 as well as gli2-induced transcription SIGNOR-154753 0.8 BMPR1A protein P36894 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR up-regulates activity phosphorylation 10090 BTO:0004058 19620713 t ggiuliani The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17). SIGNOR-255831 0.773 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-260128 0.2 PIP4K2A protein P48426 UNIPROT 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) smallmolecule CHEBI:58456 ChEBI up-regulates quantity chemical modification 9606 9367159 t Gianni The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities'. Here we have reinvestigated the substrate specificities of these enzymes. As expected, the type I enzyme phosphorylates PtdIns-4-P at the D-5 position of the inositol ring. Surprisingly, the type II enzyme, which is abundant in some tissues, phosphorylates PtdIns-5-P at the D-4 position, and thus should be considered as a 4-OH kinase, or PIP(4)K SIGNOR-268864 0.8 MAP3K7 protein O43318 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 9278437 t lperfetto Mitogen-activated protein kinase kinase 4 (mkk4)/stress-activated protein kinase/extracellular signal-regulated kinase (sek1), a dual-specificity kinase that phosphorylates and activates jnk, synergized with tak1 in activating jnk.Taken together, these results identify TAK1 as a regulator in the HPK1 --> TAK1 --> MKK4/SEK1 --> JNK kinase cascade and indicate the involvement of JNK in the TGF-beta signaling pathway. SIGNOR-50618 0.699 PKA proteinfamily SIGNOR-PF17 SIGNOR GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates quantity phosphorylation 9606 BTO:0000938 25600368 t miannu The endocytosis of GABAARs is regulated by the interaction of the AP2 complex with β and γ2 subunits. Phosphorylation of β3 (S408/S409) and γ2 (Y365/Y367) by PKA/PKC and Src/Fyn, respectively, prevents binding to AP2 and thus stabilizes these receptors at the cell surface. SIGNOR-264991 0.2 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser180 GSSASFIsDTFSPYT 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248370 0.598 RARA protein P10276 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11788593 f gcesareni We show that retinoic acid receptor (rar)-selective ligands reduce egfr level and the magnitude and duration of egfr activation in egf-stimulated cells SIGNOR-114087 0.404 RPL32 protein P62910 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262468 0.825 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT unknown phosphorylation Ser70 EAMNYEGsPIKVTLA 9606 19933706 t gcesareni Simultaneous inactivation of two cdk phosphorylation sites at ser10 and ser70 (npm-aa) induced g(2)/m cell cycle arrest, phosphorylation of cdk1 at tyr15 (cdc2(tyr15)) and increased cytoplasmic accumulation of cdc25c. SIGNOR-161801 0.533 CAMK2G protein Q13555 UNIPROT FLNA protein P21333 UNIPROT unknown phosphorylation Ser2523 VTGPRLVsNHSLHET BTO:0001141 11290523 t llicata Our TER experiments using a CaM peptide, which functions as a specific competitive inhibitor of nonmuscle filamin phosphorylation by CaM kinase II, strongly suggest that filamin phosphorylation is involved in endothelial cell barrier regulation, although the exact mechanism is not clear and consequent signaling events are not well understood.  SIGNOR-250696 0.439 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 23151663 t gcesareni Ror1 and ror2 bind wnt5a. SIGNOR-199644 0.737 EYA1 protein Q99502 UNIPROT H2AX protein P16104 UNIPROT down-regulates dephosphorylation Tyr143 ATQASQEy 9606 20965415 t gcesareni Tyr142 is dephosphorylated by the tyr phosphatases eya1 and eya3. SIGNOR-168879 0.2 CSNK2A2 protein P19784 UNIPROT AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser285 MEVEDNRsQVETDDL 9615 BTO:0000837 11742978 t llicata We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4‐Cter proteins in which only one out of the three C‐terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. SIGNOR-250975 0.344 DSCAM protein O60469 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR down-regulates 9606 BTO:0000938 30745319 f miannu Nuclear DSCAM and DSCAML1 impair neurite outgrowth. this demonstrates that enhanced nuclear translocation of the DSCAM and DSCAML1 ICDs profoundly impairs neurite outgrowth and development of primary cortical neurons. SIGNOR-264276 0.7 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 9534 BTO:0000298 10212258 t C-Abl phosphorylates Rad51 in vitro and in vivo. phosphorylation of Rad51 by c-Abl enhances complex formation between Rad51 and Rad52, which cooperates with Rad51 in recombination and repair. c-Abl phosphorylates Rad51 Tyr315 SIGNOR-251434 0.764 Caspase 3 complex complex SIGNOR-C221 SIGNOR PARP1 protein P09874 UNIPROT down-regulates activity cleavage 10090 BTO:0000331 11907276 t amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-256465 0.767 TLN1 protein Q9Y490 UNIPROT ITGB7 protein P26010 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257633 0.579 MAML1 protein Q92585 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 11101851 t gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1. SIGNOR-84835 0.801 MAPK3 protein P27361 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser668 INTKALQsPKRPRSP 9606 10648599 t lperfetto Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation. SIGNOR-74304 0.382 USP9X protein Q93008 UNIPROT WT1 protein P19544 UNIPROT up-regulates quantity by stabilization deubiquitination 32152317 t lperfetto Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis. SIGNOR-275614 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr194 NMMDILTtPSMAKPR 8355 22354989 t gcesareni We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop SIGNOR-243403 0.51 MAP3K8 protein P41279 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity phosphorylation Thr559 TGDYIPGtETHMAPE 9606 9742107 t lperfetto In studies of NIK, we found that Thr-559 located within the activation loop of its kinase domain regulates NIK action. Alanine substitution of Thr-559 but not other serine or threonine residues within the activation loop abolishes its activity and its ability to phosphorylate and activate IKKalpha SIGNOR-249387 0.54 COX7B protein P24311 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267745 0.654 KDM6A protein O15550 UNIPROT HOXC13 protein P31276 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260027 0.27 AKT proteinfamily SIGNOR-PF24 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT down-regulates activity phosphorylation Ser571 RMRSRSRsFSRHRSC 9606 BTO:0000759 17554339 t lperfetto Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1alpha At ser570 Is required for akt to inhibit recruitment of pgc-1alpha To chromatin. SIGNOR-155532 0.2 FLT3 protein P36888 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14592841 f Thus, induction of C/EBPα and PU.1 expression is inhibited in 32D cells due to the expression of FLT3/ITD SIGNOR-261529 0.621 H2BC11 protein P06899 UNIPROT Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR form complex binding -1 21812398 t miannu The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. SIGNOR-263720 0.2 PIK3CB protein P42338 UNIPROT PIK3CB protein P42338 UNIPROT down-regulates activity phosphorylation Ser1070 TVRKDYRs -1 12502714 t lperfetto Autophosphorylation sites of both pi3k isoforms were mapped to c-terminal serine residues of the catalytic p110 subunit (i.e. serine 1070 of p110 beta and serine 1101 of p110 gamma). autophosphorylation of p110 beta On serine 1070 results in down-regulation of the lipid kinase activity of pi3k beta SIGNOR-96776 0.2 Calcineurin complex SIGNOR-C155 SIGNOR DNM1L protein O00429 UNIPROT up-regulates activity dephosphorylation Ser637 VPVARKLsAREQRDC 9606 18838687 t When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. SIGNOR-252315 0.275 CDH3 protein P22223 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265865 0.845 Norbinaltorphimine chemical CHEBI:81529 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258820 0.8 MAPK3 protein P27361 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation Thr385 APEKGLPtPQVLQRN 9606 BTO:0000567 9155018 t lperfetto Mnk1 was phosphorylated and activated in vitro by erk1 and p38 map kinasespreliminary results showed that thr344 at least was one of the major sites phosphorylated by erk1 SIGNOR-48360 0.557 CAMK2B protein Q13554 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity phosphorylation Ser257 DSFESIEsYDSCDRL BTO:0003637 12475968 t llicata Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1  SIGNOR-250685 0.314 PABIR1 protein Q96E09 UNIPROT PPP2R2A protein P63151 UNIPROT down-regulates activity binding 9606 BTO:0000007 27588481 t miannu We demonstrate that the highly conserved protein in mammals, designated FAM122A, directly interacts with PP2A-Aα and B55α rather than B56α subunits, and inhibits the phosphatase activity of PP2A-Aα/B55α/Cα complex. SIGNOR-266379 0.2 RNF126 protein Q9BV68 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23026136 t miannu E3 ubiquitin ligase RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation.We showed that RNF126 interacts with p21 and RNF126 overexpression increased p21 protein ubiquitination in an E3 ligase activity-dependent manner. SIGNOR-272033 0.337 KDM6A protein O15550 UNIPROT HOXA10 protein P31260 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260020 0.27 STK11 protein Q15831 UNIPROT BRSK1 protein Q8TDC3 UNIPROT up-regulates phosphorylation Thr189 VGDSLLEtSCGSPHY 9606 14976552 t lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold SIGNOR-122413 0.463 IL1B protein P01584 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32446778 f doi: 10.1016/j.cytogfr.2020.05.003 miannu Interleukin-6 (IL-6) deserves a more extensive discussion in view of its involvement in the coronavirus-induced cytokine storm. The production of this cytokine is increased by IL-1β and tumor necrosis factor (TNF- α) SIGNOR-260855 0.526 HLTF protein Q14527 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 11756191 f Regulation of transcription miannu DNA-dependent adenosine triphosphatase (helicaselike transcription factor) activates beta-globin transcription in K562 cells. Overexpression of HLTF in K562 cells does not affect the endogenous levels of gamma- and epsilon-globin message, but it markedly activates beta-globin transcription. SIGNOR-251812 0.2 Ast-487 chemical CID:11409972 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259693 0.8 PRKCE protein Q02156 UNIPROT KIR3DL1 protein P43629 UNIPROT down-regulates phosphorylation Ser415 QRKITRPsQRPKTPP 9606 17911614 t gcesareni Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover. SIGNOR-158129 0.2 USP7 protein Q93009 UNIPROT CHFR protein Q96EP1 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 17442268 t miannu In this study, we identified USP7 (also known as HAUSP), which is a member of a family of proteins that cleave polyubiquitin chains and/or ubiquitin precursors, as an interacting protein with Chfr by immunoaffinity purification and mass spectrometry, and their interaction greatly increases the stability of Chfr. In fact, USP7 can remove ubiquitin moiety from the autoubiquitinated Chfr both in vivo and in vitro, which results in the accumulation of Chfr in the cell.  USP7 mediates deubiquitination of Chfr. SIGNOR-271462 0.443 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1346 SFDERQPyAHMNGGR -1 8940173 t miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246260 0.2 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 9724739 t amattioni Activated jnk phosphorylates p53 SIGNOR-59812 0.789 TFE3 protein P19532 UNIPROT MCOLN1 protein Q9GZU1 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276826 0.344 RXRG protein P48443 UNIPROT MBP protein P02686 UNIPROT up-regulates quantity transcriptional regulation 31390799 f SimoneGraziosi RXRγ gene silencing reduces the ability of the drugs to promote MBP expression. SIGNOR-269266 0.2 ANXA1 protein P04083 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 27426034 f miannu Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines. we set out to examine the relationship between the different subcellular distributions of ANXA1 and the upregulation of inflammatory cytokines. When BV-2 microglial cells were transfected with ANXA1-S27A constructs following by OGD/R treatment, the pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, were found to be expressed at lower levels than those of control groups SIGNOR-261939 0.411 PTK2 protein Q05397 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 9416004 t gcesareni Pi3-kinase has also been shown to bind fak in a cell cell adhesion-dipendent manner at the major autophosphorylation site y397. This association could live to activation of pi3-kinase and its downstream effectors. SIGNOR-252726 0.552 HEY1 protein Q9Y5J3 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 16682003 t gcesareni These findings suggest a novel mechanism for negative feedback on notch signaling that requires rbp-jkappa to interact physically with hrt and hes. SIGNOR-146687 0.644 HES1 protein Q14469 UNIPROT CTNND2 protein Q9UQB3 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001033 21106062 f miannu Coordinated regulation of δ-catenin expression by both the activating transcription factor E2F1 and repressive transcription factor Hes1 in prostate cancer progression. SIGNOR-251877 0.353 Ast-487 chemical CID:11409972 PUBCHEM KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259694 0.8 PLCG2 protein P16885 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates quantity chemical modification 9606 23000145 t scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). SIGNOR-268454 0.8 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT down-regulates activity phosphorylation Ser312 ALDLEESsSSDHAER 10029 BTO:0000246 7876239 t The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization. SIGNOR-251441 0.2 NOTCH1 protein P46531 UNIPROT HOXA5 protein P20719 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 16990763 f gcesareni Other than a role in t-cell development, the hox genes may be involved in alternative notchregulated processes in hematopoietic stem cells. Notch signaling is clearly important for self-renewal of hematopoietic progenitors (reviewed by radkte et al. 57). Interestingly, hoxa5, a9 and a10 were found to be part of the stem cell profile' SIGNOR-149770 0.322 PKMYT1 protein Q99640 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Thr14 IEKIGEGtYGVVYKG 9606 BTO:0000567 9001210 t Preference on the part of Myt1Hu for the cyclin-bound form of Cdc2 gcesareni Myt1hu preferentially phosphorylates cdc2 on threonine 14 in a cyclin-dependent manner;phosphorylation of threonine 14 and tyrosine 15 is inhibitory. SIGNOR-45725 0.741 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MCL1 protein Q07820 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 18676833 t inferred from 70% family members fstefani We then showed that erk could phosphorylate mcl-1 at two consensus residues, thr 92 and 163, which is required for the association of mcl-1 and pin1, resulting in stabilization of mcl-1. SIGNOR-270158 0.2 ABL1 protein P00519 UNIPROT PRKN protein O60260 UNIPROT down-regulates phosphorylation Tyr143 SPAGRSIyNSFYVYC 9606 BTO:0000142 20823226 t llicata Here we show that the nonreceptor tyrosine kinase c-abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin e3 ligase activity and protective function. SIGNOR-167853 0.2 CDK5RAP2 protein Q96SN8 UNIPROT TUBG1 protein P23258 UNIPROT up-regulates activity binding 9606 BTO:0002181 17959831 t Giulio Immunoprecipitation of CDK5RAP2 specifically coprecipitated _TuRC components, as detected on immunoblots of _-tubulin and GCP3 (Figure 3A).| Perturbing CDK5RAP2 function delocalized gamma-tubulin from the centrosomes and inhibited centrosomal microtubule nucleation, thus leading to disorganization of interphase microtubule arrays and formation of anastral mitotic spindles. Together, CDK5RAP2 is a pericentriolar structural component that functions in gammaTuRC attachment and therefore in the microtubule organizing function of the centrosome. SIGNOR-260310 0.638 SMARCA4 protein P51532 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 t miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. SIGNOR-132922 0.912 OXTR protein P30559 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257266 0.533 quizartinib chemical CHEBI:90217 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258270 0.8 TFDP1 protein Q14186 UNIPROT CDK1 protein P06493 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253859 0.565 estramustine chemical CHEBI:4868 ChEBI MAP1A protein P78559 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001332 1647395 t miannu Estramustine is a novel anti-microtubule drug shown to bind MAP-1 and MAP-2 (microtubule-associated proteins) in vitro. In this paper we have shown that estramustine specifically binds MAP-1A in Du 145a cells, resulting in disruption of MAP-1A microtubules and inhibition of type IV collagenase secretion. SIGNOR-259297 0.8 AKT2 protein P31751 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates phosphorylation Ser571 RMRSRSRsFSRHRSC 9606 17554339 t miannu Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1? At ser?570 Is required for akt to inhibit recruitment of pgc-1? To chromatin. SIGNOR-155536 0.355 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MAP2K1 protein Q02750 UNIPROT down-regulates activity phosphorylation Thr292 ETPPRPRtPGRPLSS 9534 BTO:0004055 14993270 t lperfetto We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling. SIGNOR-244557 0.2 BCL6 protein P41182 UNIPROT FCER2 protein P06734 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000776 11342629 f In this study, we report that PRDI-BF1/Blimp1 can bind to the same functional element in the human CD23b promoter to which BCL-6 and IRF-4 had previously been shown to bind, and that, like BCL-6, Blimp1 can repress IRF-4-transactivating ability SIGNOR-253928 0.291 R547 chemical CID:6918852 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259792 0.8 PRKCG protein P05129 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 t lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization. SIGNOR-202788 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 24168260 f miannu NF-κB, which can be activated by mitogen-activated protein kinases (MAPKs) (12), is responsible for the transcription of inflammatory factors and profibrotic cytokines, which promote an inflammatory response and fibrosis SIGNOR-260446 0.7 ERBB3 protein P21860 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 16729043 t gcesareni All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor. In this study, we identify grb2 as a specific binding partner to tyrosines y1199 and y1268 of erbb3. SIGNOR-146858 0.833 MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Ser183 PTQQYAKsLPVSVPV 9606 BTO:0000007 SIGNOR-C3 SIGNOR-C3 17517883 t lperfetto The proline-rich Akt substrate of 40 kilodaltons (PRAS40) was identified as a raptor-binding protein that is phosphorylated directly by mammalian target of rapamycin (mTOR) complex 1 (mTORC1) but not mTORC2 in vitro, predominantly at PRAS40 (Ser(183)).PRAS40 binding to raptor was also abolished by mutation of the major mTORC1 phosphorylation site, Ser(183), to Asp. SIGNOR-154956 0.901 PTPN13 protein Q12923 UNIPROT ABL1 protein P00519 UNIPROT down-regulates activity dephosphorylation Tyr226 KRNKPTVyGVSPNYD 9606 28924170 t lperfetto We also found that PTPN13 dephosphorylates and inhibits c-Abl.|While the above results indicated that calpain-2 could cleave PTPN13 and that PTPN13 could dephosphorylate c-Abl at tyrosine 245, they did not determine whether calpain-2-mediated cleavage of PTPN13 resulted in its inactivation and increased tyrosine phosphorylation of c-Abl at tyrosine 245. SIGNOR-277012 0.399 LCK protein P06239 UNIPROT CTLA4 protein P16410 UNIPROT unknown phosphorylation Tyr218 CEKQFQPyFIPIN 9606 BTO:0000007 9973379 t Lck and Fyn, but not ZAP70, induce tyrosine phosphorylation of CTLA-4 in the cell line HEK293. Phosphorylation of CTLA-4 occurs on both Y201 and Y218.the role of Y218 in CTLA-4 biology is not known at the present SIGNOR-251371 0.739 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2D2 protein P62837 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271357 0.766 SUZ12/EZH2 complex SIGNOR-C77 SIGNOR YY1 protein P25490 UNIPROT up-regulates activity binding 10090 BTO:0000165;BTO:0002314 20887952 t lperfetto TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter. SIGNOR-235574 0.723 TYK2 protein P29597 UNIPROT TYK2 protein P29597 UNIPROT up-regulates activity phosphorylation Tyr1054 AVPEGHEyYRVREDG 9606 BTO:0000452 8702790 t lperfetto These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055The K930R mutant, bearing a mutation in the ATP binding site, is catalytically inactive (Fig. 3B, lanes 5 and 6). This protein is not basally phosphorylated, while the wt and the Y1054F/Y1055F proteins are (Fig. 3A), suggesting that autophosphorylation is responsible for the basal level of phosphorylation. SIGNOR-43088 0.2 abiraterone chemical CHEBI:68642 ChEBI CYP17A1 protein P05093 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-204810 0.8 CD2AP protein Q9Y5K6 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity binding 9606 BTO:0000007;BTO:0001938 29175910 t lperfetto One such regulator is the adaptor protein CD2AP, which delivers capping proteins to the barbed ends of polymerizing F-actin. Capping growing filaments can promote the formation of actin branches by increasing the G-actin pool available to form branches SIGNOR-264769 0.7 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 9606 21808241 t gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. SIGNOR-175801 0.593 Calcineurin complex SIGNOR-C155 SIGNOR BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 10195903 t Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. SIGNOR-252332 0.413 histamine smallmolecule CHEBI:18295 ChEBI HRH3 protein Q9Y5N1 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257514 0.8 TSC2 protein P49815 UNIPROT TSC1 protein Q92574 UNIPROT up-regulates activity binding 9606 BTO:0000142;BTO:0000671 10807585 t lperfetto Furthermore, tsc2 is directly phosphorylated by akt, which is involved in stimulating cell growth and is activated by growth stimulating signals, such as insulin. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1. SIGNOR-77400 0.933 EPAS1 protein Q99814 UNIPROT PTPRZ1 protein P23471 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 15833863 f miannu A second hypoxia-responsive factor, HIF-2, can activate many of the same genes as HIF-1. Ten genes were preferentially activated by HIF-2alpha, including two (CACNA1A and PTPRZ1) implicated in neurologic diseases. SIGNOR-264333 0.265 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM2 protein P0DP24 UNIPROT up-regulates chemical activation 10090 10448861 t miannu Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. SIGNOR-266318 0.8 LPAR2 protein Q9HBW0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 15856019 t gcesareni Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. Lpa2also can couple to the gi/o, g12/13, and gqfamilies. SIGNOR-135840 0.61 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248752 0.727 S1PR2 protein O95136 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257349 0.448 SEMA3B protein Q13214 UNIPROT PLXNA2 protein O75051 UNIPROT up-regulates activity binding 9606 BTO:0001176;BTO:0002036 25335892 t miannu We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.  SIGNOR-261812 0.65 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT down-regulates activity phosphorylation Ser402 GSLERSQsRKDSLDD 9534 BTO:0000298 9353340 t lperfetto  Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response.  SIGNOR-248986 0.399 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination 10090 BTO:0002572 15175328 t miannu Taken together, these data suggest that Traf2 may be the E3 ubiquitin ligase that initiates TNF-α signaling, potentially by ubiquitinating Rip1. In the absence of Traf2, TNF-alpha-induced ubiquitination of Rip1 is impaired, suggesting that Traf2 may be the E3 ubiquitin ligase responsible for the TNF-alpha-dependent, ubiquitination of Rip1. Finally, recruitment of the ubiquitinated Tak1 complex is dependent on the presence of Rip1, suggesting that Rip1 ubiquitination rather than its phosphorylation is critical in signaling. SIGNOR-271423 0.891 AKT1 protein P31749 UNIPROT DLX5 protein P56178 UNIPROT up-regulates phosphorylation 9606 22298955 t gcesareni Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5. SIGNOR-195546 0.267 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT up-regulates quantity by stabilization phosphorylation Thr191 QKQEKPRtPMPSSVE 9606 BTO:0000007 16682949 t done miannu Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. SIGNOR-274087 0.525 TFEB protein P19484 UNIPROT BLOC1S3 protein Q6QNY0 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). SIGNOR-276683 0.2 ATAD5 protein Q96QE3 UNIPROT BRD4 protein O60885 UNIPROT up-regulates binding 9606 BTO:0000007 31875566 t miannu ATAD5 Interacts with BRD4 through a Conserved BET Protein-Binding Domain. BRD4-ATAD5 binds to acetyl-histones in nascent chromatin. BRD4 release from chromatin correlates with PCNA unloading. Disruption of the interaction between BRD4 and acetyl-histones or between BRD4 and ATAD5 reduces the PCNA amount on chromatin. SIGNOR-266412 0.357 E2F1 protein Q01094 UNIPROT RASGEF1B protein Q0VAM2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18396012 f miannu We demonstrate that E2F1 induces ERK activation via a transcriptional mechanism and upregulates the expression of two guanine nucleotide exchange factors, RASGRP1 and RASGEF1B, which promote Ras activation. SIGNOR-253851 0.2 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr319 TSVYESPySDPEELK 8798643 t lperfetto Phosphopeptide encompassing the motif harboring tyr319, ysdp, interacted with lcksh2;tyr319-mediated binding of the sh2 domain of lck is crucial for zap-70 activation and consequently for the propagation of the signaling cascade leading to t-cell activation SIGNOR-43659 0.602 TBK1 protein Q9UHD2 UNIPROT TNIP1 protein Q15025 UNIPROT down-regulates quantity by destabilization phosphorylation Ser122 KPPSSGTsSEFEVVT 36574265 t lperfetto TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1 SIGNOR-275733 0.383 beta-alanine smallmolecule CHEBI:16958 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 9606 BTO:0000007 9009272 t inferred from family member miannu For each mutant GlyR we examined the agonist efficacies of taurine and beta-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where beta-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human alpha-1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and beta-alanine act as full agonists of huma nalpha-1 GlyRs when expressed in this system. SIGNOR-267795 0.8 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 17634129 t lperfetto The activity of Cdc2 is regulated by the phosphatase Cdc25C. Dephosphorylation of Cdc2 at threonine 14 and tyrosine 15 by Cdc25C results in activation of Cdc2 and initiation of an autoactivation loop between Cdc25C and Cdc2 that efficiently drives cells into mitosis.|Cdc2 is activated by Cdc25C that removes phosphate groups from tyrosine 15 and threonine 14 .|Dephosphorylation of Cdc2 at threonine 14 and tyrosine 15 by Cdc25C results in activation of Cdc2 and initiation of an autoactivation loop between Cdc25C and Cdc2 that efficiently drives cells into mitosis. SIGNOR-276945 0.852 ETV6 protein P41212 UNIPROT BBC3 protein Q96PG8 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002883 16828711 f miannu Forced expression of TEL stimulated transcription via the p53-responsive element and increased the expression of cellular target genes for p53 such as cell cycle regulator p21 and apoptosis inducer Puma. SIGNOR-254137 0.2 EGFR protein P00533 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 14967450 t lperfetto The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation SIGNOR-121962 0.728 PTPN12 protein Q05209 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity dephosphorylation Tyr397 SVSETDDyAEIIDEE 10090 BTO:0000944 19595712 t We demonstrate here that activated Ras induces tyrosine dephosphorylation and inhibition of FAK mediated by the Ras downstream Fgd1-Cdc42-PAK1-MEK-ERK signaling cascade.| PIN1 binding and prolyl isomerization of FAK cause PTP-PEST to interact with and dephosphorylate FAK Y397. Inhibition of FAK mediated by this signal relay promotes Ras-induced cell migration, invasion, and metastasis. SIGNOR-248661 0.553 ARVCF protein O00192 UNIPROT CDH3 protein P22223 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 t miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. SIGNOR-252127 0.332 magnesium(2+) chemical CHEBI:18420 ChEBI CIB2 protein O75838 UNIPROT up-regulates activity chemical activation 9606 35408910 t miannu Calcium- and integrin-binding protein 2 (CIB2) is a small EF-hand protein capable of binding Mg2+ and Ca2+ ions. SIGNOR-269666 0.8 LCK protein P06239 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr536 QKGQESEyGNITYPP 10090 BTO:0000782 8114715 t Two sites (Y-536 and Y-564) which are directly phosphorylated by Lck in vitro are also phosphorylated in vivo in LSTRA cells. . SIGNOR-251387 0.597 SIX4 protein Q9UIU6 UNIPROT UBA52 protein P62987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 9826681 f gcesareni We have demonstrated by studies of transgenic mice the importance of the mef3 motif present in the myogeninpromoter for its activation and have characterized the mef3 binding activity as consisting of two skeletal-muscle specific members of the six family, six1 and six4. SIGNOR-62178 0.2 GNG12 protein Q9UBI6 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 BTO:0000586 16293724 t gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway. SIGNOR-141792 0.387 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr288 QCPVGFNtLAFPSMK 9606 BTO:0000007 12496252 t lperfetto In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation SIGNOR-96751 0.758 IQSEC2 protein Q5JU85 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates quantity relocalization 9606 BTO:0000142 27009485 t miannu BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors. SIGNOR-264916 0.2 FFAR4 protein Q5NUL3 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257158 0.252 MMP9 protein P14780 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272399 0.7 UNII-XH2662798I chemical CID:16156006 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 20068082 t gcesareni Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation, regulated by wee1- and myt1-mediated phosphorylation and cdc25c-mediated dephosphorylation. Cdc25a may also be involved in cdk1 dephosphorylation in the g2/m-phase checkpoint. SIGNOR-163127 0.8 CD3E protein P07766 UNIPROT CD3 complex SIGNOR-C432 SIGNOR form complex binding 9606 12507424 t miannu The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules. SIGNOR-255294 0.799 TJP2 protein Q9UDY2 UNIPROT YAP1 protein P46937 UNIPROT down-regulates binding 9606 23829894 t milica The Crumbs complex component AMOT co-localizes with MST1_ 2, LATS1_ 2 and YAP in a complex at the tight junction to control cell growth. Zona occludens-2 (ZO-2) in the tight junction, and a-catenin, b-catenin, or PTPN14 in the adherence junction, also bind to YAP_TAZ. SIGNOR-230754 0.499 INS protein P01308 UNIPROT CEBPA protein P49715 UNIPROT up-regulates 9606 11279134 f fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin SIGNOR-250570 0.446 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.737 TP53 protein P04637 UNIPROT ZDHHC5 protein Q9C0B5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28775165 t Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y SIGNOR-261150 0.2 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val53 SHVTGKGvTVETVFS -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263590 0.404 GSK3B protein P49841 UNIPROT MNX1 protein P50219 UNIPROT down-regulates phosphorylation Ser77 ADRLRAEsPSPPRLL 9606 24425879 t miannu Here we show that gsk-3_ inactivates the proapoptotic activity of hlxb9 by phosphorylating hlxb9 at ser-78/ser-80 (phlxb9). SIGNOR-203657 0.3 CDK5 protein Q00535 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Ser198 TRKSAPSsPTLDCEK 10090 BTO:0000142 12796778 t llicata Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function. SIGNOR-250675 0.763 ATM protein Q13315 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates phosphorylation 9606 17396146 t gcesareni The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells. SIGNOR-154178 0.394 IRF5 protein Q13568 UNIPROT IL10 protein P22301 UNIPROT down-regulates transcriptional regulation 9606 BTO:0000801 21240265 f The role of IRF5 in inhibiting the transcription of the gene encoding IL-10 that we have identified here is important given its well- documented immunosuppressive activity. SIGNOR-254514 0.434 NOTCH proteinfamily SIGNOR-PF30 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 16990763 f gcesareni Addition of jag-1 peptide induced ikkalpha mediated nf-kappab activation, as well as increased ppargamma expression. SIGNOR-254344 0.2 ARID1B protein Q8NFD5 UNIPROT BAF250b E3 ligase complex SIGNOR-C522 SIGNOR form complex binding 9606 BTO:0000567 20086098 t miannu In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro SIGNOR-271437 0.342 VAMP8 protein Q9BV40 UNIPROT STX11-VAMP8 SNARE complex complex SIGNOR-C273 SIGNOR form complex binding 9606 BTO:0000132 22767500 t lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23.  SIGNOR-261896 0.568 ATM protein Q13315 UNIPROT ABRAXAS1 protein Q6UWZ7 UNIPROT up-regulates activity phosphorylation Ser406 GPGEYSRsPTF 9606 26778126 t IR-Induced Double Phosphorylation of Abraxas C Terminus S404 and S406 Is ATM Dependent SIGNOR-255588 0.2 TG101209 chemical CHEBI:90304 ChEBI JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207263 0.8 HTR6 protein P50406 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257443 0.252 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser183 CPHHERCsDSDGLAP 9606 22611192 t gcesareni We show that aurora b phosphorylates p53 at s183, t211, and s215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and puma). SIGNOR-197598 0.708 NF90-NF45 complex SIGNOR-C443 SIGNOR DNA-PK complex SIGNOR-C107 SIGNOR up-regulates activity binding -1 9442054 t miannu These proteins are NF90 and NF45, which are the 90- and 45-kDa subunits of a protein known to bind specifically to the antigen receptor response element of the interleukin 2 promoter, and the alpha, beta, and gamma subunits of eukaryotic translation initiation factor eIF-2. We also show that NF90, NF45, and eIF-2 beta are substrates for DNA-PK in vitro. In addition, recombinant NF90 promotes formation of a complex between DNA-PKcs, Ku, and DNA, and antibodies to recombinant NF90 or recombinant NF45 immunoprecipitate DNA-PKcs in vitro. Together, our data suggest that NF90, in complex with NF45, interacts with DNA-PKcs and Ku on DNA and that NF90 and NF45 may be important for the function of DNA-PK. SIGNOR-268489 0.414 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr222 TSHNSLTtPCYTPYY 9606 BTO:0000130 14499342 t lperfetto Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils. SIGNOR-118040 0.76 TCF12 protein Q99081 UNIPROT PTCRA protein Q6ISU1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22577461 f miannu Hebalt positively regulates t-cell genes, such as pt_ and notch3 SIGNOR-197520 0.331 GATA2 protein P23769 UNIPROT TRH protein P20396 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0000318 33201916 t scontino The rat prepro-TRH gene is activated by GATA2. SIGNOR-267259 0.266 SRC protein P12931 UNIPROT ATG9A protein Q7Z3C6 UNIPROT up-regulates activity phosphorylation Tyr8 MAQFDTEyQRLEASY 9606 27934868 t miannu Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation. SIGNOR-266367 0.348 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1763 TPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273083 0.635 TBX5 protein Q99593 UNIPROT MTA2 protein O94776 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20802524 f miannu TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. SIGNOR-255256 0.2 RFX complex complex SIGNOR-C104 SIGNOR HLA-DQB2 protein P05538 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 f The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-253997 0.2 NOX5 protein Q96PH1 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264718 0.7 IRX1 protein P78414 UNIPROT FGF7 protein P21781 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. SIGNOR-261654 0.2 GTF2F1 protein P35269 UNIPROT GTF2F1 protein P35269 UNIPROT down-regulates phosphorylation Thr389 RGNSRPGtPSAEGGS 9606 10428810 t gcesareni We show that tfiifalpha possesses a serine/threonine kinase activity, allowing an autophosphorylation of the two residues at position serine 385 and threonine 389. Mutation analysis strongly suggests that autophosphorylation of both sites regulates the transcription elongation process. SIGNOR-69771 0.2 NLK protein Q9UBE8 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser128 QHVRAHSsPASLQLG 9606 BTO:0000007 27979971 t done miannu Here, we report that osmotic stress stimulates transient YAP nuclear localization and increases YAP activity even when YAP Ser127 is phosphorylated. Osmotic stress acts via the NLK kinase to induce YAP Ser128 phosphorylation. Phosphorylation of YAP at Ser128 interferes with its ability to bind to 14-3-3, resulting in YAP nuclear accumulation and induction of downstream target gene expression.  SIGNOR-273909 0.2 PRKACA protein P17612 UNIPROT HTT protein P42858 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2548 TRFGRKLsIIRGIVE -1 35908190 t miannu Moreover, phosphorylation of C-HEAT Ser2550 by cAMP-dependent protein kinase (PKA), the top hit in kinase activity screens, was found to hasten huntingtin degradation, such that levels of the catalytic subunit (PRKACA) were inversely related to huntingtin levels. SIGNOR-277625 0.2 SLBP protein Q14493 UNIPROT H2BC14 protein Q99879 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265390 0.2 TFEB protein P19484 UNIPROT NEU1 protein Q99519 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276544 0.2 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 10037602 t gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. SIGNOR-64960 0.852 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT down-regulates activity dephosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 16778204 t The receptor-type protein tyrosine phosphatase J antagonizes the biochemical and biological effects of RET-derived oncoproteins.|PTPRJ expression induces dephosphorylation of the RET(C634R) and, probably via an indirect mechanism, RET/PTC1 oncoproteins on two key RET autophosphorylation sites (Tyr1062 and Tyr905). This results in a significant decrease of RET-induced Shc and extracellular signal-regulated kinase 1/2 phosphorylation levels SIGNOR-248700 0.281 GATAD2B protein Q8WXI9 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263845 0.766 USP7 protein Q93009 UNIPROT RPS27A protein P62979 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270824 0.639 SB 203580 chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 10512765 t gcesareni Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme. SIGNOR-71024 0.8 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser711 EEEEESDsSETEKED 21296876 t lperfetto Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2. SIGNOR-275501 0.2 TFEB protein P19484 UNIPROT CTSA protein P10619 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 t lperfetto Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants SIGNOR-276549 0.302 RNF146 protein Q9NTX7 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 21478859 t lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. SIGNOR-263336 0.658 PTPRB protein P23467 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1356 YVHVNATyVNVKCVA 9606 16101282 t gcesareni Ptp1b and shp-2 are bound to the c-met receptor to control its activity. Although the binding of ptp1b increases when there is a decrease in c-met activation and acts as a negative regulator of the receptor, the increased binding and phosphorylation of shp-2 coincide with maximal stimulation of c-met, acting as a positive regulator. SIGNOR-139560 0.372 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RHOA protein P61586 UNIPROT up-regulates activity phosphorylation Thr100 ENIPEKWtPEVKHFC 9534 BTO:0000298 26816343 t miannu We have recently reported that Rac1 is phosphorylated on threonine 108 (108T) by extracellular signal-regulated kinases (ERK) in response to epidermal growth factor (EGF) stimulation. Here, we provide evidence that RhoA is phosphorylated by ERK on 88S and 100T in response to EGF stimulation. SIGNOR-277203 0.2 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser108 DKYGQNEsFARIQVR -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276220 0.388 N'-(1,8-dimethyl-4-imidazo[1,2-a]quinoxalinyl)ethane-1,2-diamine chemical CHEBI:91340 ChEBI CHUK protein O15111 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258085 0.8 PTPRB protein P23467 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity dephosphorylation Tyr81 WEVGSITyDTLSAQA 9606 32653904 t miannu VE-PTP interacts with eNOS and dephosphorylates Tyr81 SIGNOR-277521 0.27 MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation Ser758 PVVFTVGsPPSGSTP 9606 BTO:0001938 21383122 t lperfetto When cells are replenished with rich medium, mtor is activated;it phosphorylates serine 638 and serine 758. The phosphorylation of ulk1 at serine 758 then leads to reassociation between ulk1 and ampk. SIGNOR-172541 0.844 DRD3 protein P35462 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257097 0.321 TRIM33 protein Q9UPN9 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity binding 9606 BTO:0000574;BTO:0002625;BTO:0000414 16751102 t lperfetto The ubiquitious nuclear protein transcriptional intermediary factor 1gamma (tif1gamma) selectively binds receptor-phosphorylated smad2/3 in competition with smad4. Rapid and robust binding of tif1gamma to smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to tgfbeta. Tif1gamma mediates the differentiation response while smad4 mediates the antiproliferative response with smad2/3 participating in both responses. SIGNOR-236064 0.623 LPAR3 protein Q9UBY5 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22863277 t gcesareni Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2. SIGNOR-198544 0.444 PPARGC1A protein Q9UBK2 UNIPROT ALDOB protein P05062 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255055 0.246 CALM2 protein P0DP24 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates binding 9606 BTO:0000782 BTO:0000142 9822657 t miannu The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk. SIGNOR-266329 0.556 CAMK2D protein Q13557 UNIPROT CAMK2D protein Q13557 UNIPROT up-regulates phosphorylation 9606 19725819 t areggio Upon binding of the Ca2+/calmodulin complex to the binding domain of CaMKII, it is activated via autophosphorylation, then remaining active independent of of Ca2+ levels. SIGNOR-255954 0.2 TGFb proteinfamily SIGNOR-PF5 SIGNOR Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f inferred from 70% family members lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-Œ±, TGF-Œ≤, tumor necrosis factor (TNF)-Œ±, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-270216 0.7 PRKAG2 protein Q9UGJ0 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 16054041 t gcesareni Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. SIGNOR-139176 0.736 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 29955047 t lperfetto Collectively, our findings indicate that TC-PTP negatively regulates Flk-1 and JNK signaling via direct dephosphorylation of Flk-1 on its Y1173 residue, which contributes to increased epidermal apoptosis in response to UVB exposure.|TC-PTP dephosphorylates activated Flk-1 at Y1173 after UVB irradiation, which is followed by the suppression of JNK phosphorylation.|TC-PTP promotes UVB induced apoptosis in keratinocytes by dephosphorylating Flk-1 tyrosine residue 1173. SIGNOR-276961 0.547 LCK protein P06239 UNIPROT PECAM1 protein P16284 UNIPROT up-regulates activity phosphorylation Tyr713 KKDTETVySEVRKAV 9534 9624175 t miannu We demonstrated that phosphorylation of PECAM-1 by Src or Csk family kinases was sufficient to trigger its association with SHP-2. Moreover, it was able to promote binding of PECAM-1 to SHP-1, a SHP-2-related protein-tyrosine phosphatase expressed in hemopoietic cells. Taken together, these findings indicated that the Src and Csk families of kinases are strong candidates for mediating tyrosine phosphorylation of PECAM-1 and triggering its association with SH2 domain-containing phosphatases under physiological circumstances. SIGNOR-262742 0.571 LSM5 protein Q9Y4Y9 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270649 0.794 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267516 0.8 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205743 0.8 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Pro) smallmolecule CHEBI:29177 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269493 0.8 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates activity phosphorylation Ser932 CDSGVETsFRKLSFT 9606 BTO:0000007 SIGNOR-C13 11158290 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-104811 0.848 ANK2 protein Q01484 UNIPROT PPP2R5A protein Q15172 UNIPROT up-regulates quantity relocalization 9606 BTO:0003324 19840192 t miannu Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins. SIGNOR-266729 0.286 acetyl-CoA smallmolecule CHEBI:15351 ChEBI hexadecanoic acid smallmolecule CHEBI:15756 ChEBI up-regulates quantity precursor of 9606 15507492 t miannu Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-268089 0.8 HDLBP protein Q00341 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 9925647 f miannu HBP/vigilin binds HDL and apoA-I on ligand blots; conceivably therefore apoA-I may interact with cytoplasmic vigilin promoting changes in cholesterol flux. SIGNOR-266692 0.7 GRK4 protein P32298 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 t gcesareni ...expression of GRK4ƒŽ‚ drastically increased the basal level of32P incorporation into B2R.[ƒ‚€‚]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation. SIGNOR-249674 0.292 ABL1 protein P00519 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Tyr276 SDEDDEVyQVTVYQA 9606 21081495 t lperfetto Mdm2 has three known c-abl phosphorylation sites (tyr276, tyr394, and tyr405)these data show that c-abl is important for reducing mdm2 and mdmx protein levels after genotoxic stress and suggest another cellular mechanism for the stabilization and activation of p53. SIGNOR-169699 0.704 DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 20837657 t lperfetto In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization. SIGNOR-227914 0.7 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT down-regulates phosphorylation Thr806 NQMAKGTtEEMKYVL 9606 18680479 t miannu We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / t806d mps1 was significantly less active than t806a, demonstrating a potential negative correlation between phosphorylation and activity at this site. SIGNOR-179908 0.2 SMAD1 protein Q15797 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C85 20957627 t lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common(co-Smad; Smad4 in mammals) and shuttle into the nucleus. SIGNOR-168734 0.657 RUNX3 protein Q13761 UNIPROT CFLAR protein O15519 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255087 0.2 MAPK1 protein P28482 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser674 QSPKRPRsPGSNSKV 9606 10648599 t lperfetto Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation. SIGNOR-74300 0.372 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr775 SSNYMAPyDNYVPSA -1 8940081 t miannu The SH2 domain of Grb7 can directly bind to the autophosphorylated PDGF beta-receptor in vitro. Grb7 association to the PDGF beta-receptor was dramatically reduced by replacement of tyrosine residues 716 or 775 with phenylalanine residues. SIGNOR-250259 0.2 NMUR2 protein Q9GZQ4 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257010 0.252 NR1D1 protein P20393 UNIPROT NR2E3 protein Q9Y5X4 UNIPROT up-regulates 9606 15190009 f gcesareni Our results show that nr1d1 (rev-erb?) Also functions as a transcriptional activator of rod genes in the presence of nr2e3 SIGNOR-125658 0.408 CORT protein O00230 UNIPROT GHSR protein Q92847 UNIPROT up-regulates binding 9606 12161511 t gcesareni In human tissues cst-14 as well as cst-17 but not ss-14 bind the gh secretagogue receptor (ghs-r). SIGNOR-91134 0.484 PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates activity binding 9606 27629041 t miannu Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning 15. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival SIGNOR-260174 0.685 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0000007 11691836 t lperfetto The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding SIGNOR-249393 0.649 PDPK1 protein O15530 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Thr423 PEQSKRStMVGTPYW 9534 BTO:0000298 10995762 t miannu P21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). We identify threonine 423, a conserved threonine in the activation loop of kinase subdomain VIII, as the PDK1 phosphorylation site on PAK1. SIGNOR-250267 0.364 FLT3 protein P36888 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001545 17851558 t miannu Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML. SIGNOR-260124 0.419 MACF1 protein Q9UPN3 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 9606 BTO:0000938 16815997 f gcesareni In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes. SIGNOR-147451 0.446 LATS1 protein O95835 UNIPROT PRPS1 protein P60891 UNIPROT down-regulates quantity by destabilization phosphorylation Ser285 EDKMKHCsKIQVIDI -1 34465890 t miannu  Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness. SIGNOR-276505 0.2 ATF4 protein P18848 UNIPROT IARS1 protein P41252 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269427 0.2 PTPN11 protein Q06124 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 11085989 f miannu We show here that leptin can activate ERK signaling in thehypothalamus and that this stimulation is likely to occur viatwo pathways, both involving SHP-2.We have shown above that SHP-2 is a positive mediator of ERK activation by ObRb and that this requires both the phosphatase activity and tyrosine phosphorylation of SHP-2. Furthermore,Tyr-985 is required for maximal ERK phosphorylation. SIGNOR-263499 0.861 STK38L protein Q9Y2H1 UNIPROT STK38L protein Q9Y2H1 UNIPROT up-regulates phosphorylation Ser282 NRRQLAYsTVGTPDY 9606 BTO:0000007 16314523 t lperfetto Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity. SIGNOR-142518 0.2 PPP6C protein O00743 UNIPROT CGAS protein Q8N884 UNIPROT down-regulates activity dephosphorylation Ser435 KHLDKFSsYHVKTAF 9606 32474700 t lperfetto In this study, we found that PPP6C suppressed phosphorylation of human cGAS (hcGAS) at S435 or mouse cGAS (mcGAS) at S420 in its substrate-binding pocket, thus preventing its binding to GTP and inhibiting the synthesis of cGAMP.|These data suggest that PPP6C inhibits cGAS activity. SIGNOR-276990 0.2 CAMK2A protein Q9UQM7 UNIPROT DAGLA protein Q9Y4D2 UNIPROT down-regulates activity phosphorylation Ser782 APLATMEsLSDTESL 23502535 t lperfetto Activated CaMKII interacted with the C-terminal domain of DGLalpha, phosphorylated two serine residues and inhibited DGLalpha activity. |CaMKIIalpha phosphorylates DGLalpha at Ser808 and Ser782 SIGNOR-275539 0.2 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation. SIGNOR-252851 0.908 TGFB1 protein P01137 UNIPROT ITGA2 protein P17301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001596 1744142 f lperfetto TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way. SIGNOR-253354 0.289 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 19118012 t gcesareni Phosphorylation by activated jnk protects c-jun from ubiquitination;phosphorylation of c-jun on ser73 by jnk is sufficient to protect c-jun from ubiquitination c-jun is targeted for ubiquitination by its association with inactive c-jun nh2-terminal kinase (jnk). Phosphorylation by activated jnk protects c-jun from ubiquitination, thus by prolonging its half-life targets of the jnk signal transduction pathway include the transcription factors atf2 and c-jun apoptosis, altered;apoptosis, induced;transcription, altered;cell growth, altered;jnk1(disrupts);pin1(induces);dna(disrupts) transcription, altered;cell growth, altered;jnk1(disrupts);pin1(induces);dna(disrupts) SIGNOR-183017 0.881 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation Tyr116 PNLFVALyDFVASGD -1 34144039 t miannu  PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. SIGNOR-277304 0.308 UBE2I protein P63279 UNIPROT ZHX1 protein Q9UKY1 UNIPROT up-regulates quantity by stabilization sumoylation Lys159 TFDGSFVkEENAEQA 9606 BTO:0000007 23686912 t miannu Here, we report that the SUMO-E2 conjugating enzyme Ubc9 was identified to interact with ZHX1 by an interaction screen using a yeast two-hybrid system. This interaction was confirmed by co-immunoprecipitation and co-localization assays. Further study showed that ZHX1 is SUMOylated by Ubc9 with SUMO1 at the sites K159, K454, and K626. Furthermore, we demonstrated that the SUMOylation of ZHX1 regulated the stability, ubiquitination and transcriptional activity of ZHX1. The sumoylation of zinc‐fingers and homeoboxes 1 (ZHX1) by ubc9 regulates its stability and transcriptional repression activity. However, in the current work, we demonstrated that ZHX1 was only SUMOylated by SUMO1. SIGNOR-263899 0.464 RNF135 protein Q8IUD6 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity ubiquitination Lys909 QTLYSKWkDFHFEKI 9606 BTO:0000007 19017631 t miannu Our data suggest that Riplet/RNF135 is a novel factor of the RIG-I pathway that is involved in the evoking of human innate immunity against RNA virus infection, and activates RIG-I through ubiquitination of its C-terminal region. SIGNOR-265569 0.755 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257984 0.8 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 15241418 t gcesareni We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function SIGNOR-126732 0.733 IKBKB protein O14920 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 BTO:0000150;BTO:0000782 SIGNOR-C13 16046471 t lperfetto Rela is phosphorylated at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k). We now present evidence that suggests that the upstream kinase ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. Ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. SIGNOR-138903 0.882 RPS6KA5 protein O75582 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 SIGNOR-C13 12628924 t gcesareni Transcriptional activation of the nf-kappab p65 subunit by mitogen- and stress-activated protein kinase-1 (msk1)mutational analysis of p65 revealed ser276 as a target for phosphorylation and transactivation in response to tnf. Moreover, we identified msk1 as a nuclear kinase for p65, since msk1 associates with p65 in a stimulus-dependent way and phosphorylates p65 at ser276. SIGNOR-99210 0.707 EEF1B2 protein P24534 UNIPROT EEF1B complex complex SIGNOR-C460 SIGNOR form complex binding 9606 23699257 t lperfetto An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. The requirement for a guanine nucleotide exchange factor, the eEF1B complex, which in metazoans is composed of the subunits α, δ, and γ (also called eEF1B, eEF1D, and eEF1G, respectively) SIGNOR-269390 0.822 WASHC5 protein Q12768 UNIPROT WASH complex complex SIGNOR-C258 SIGNOR form complex binding 23721880 t lperfetto The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53. SIGNOR-261019 0.2 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Phe708 YENPTYKfFEQMQN -1 8943232 t lperfetto The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261776 0.502 NR3C1 protein P04150 UNIPROT TSC22D3 protein Q99576 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001372 9430225 f In thymocytes and peripheral T cells, GILZ gene expression is induced by DEX SIGNOR-253295 0.423 WWTR1 protein Q9GZV5 UNIPROT DVL1 protein O14640 UNIPROT down-regulates binding 9606 22153608 t Activation of Wnt signaling induces the hyperphosphorylation of Dishevelled (DVL), and this, via a poorly understood mechanism, ultimately leads to a rise in beta-Catenin levels and to the activation of beta-Catenin target genes. gcesareni Taz binds to dvl proteins, thereby inhibiting dvl phosphorylation by casein kinase 1-delta and -epsilon kinases (ck1d/e), thus promoting beta-catenin degradation. SIGNOR-195212 0.365 clemastine chemical CHEBI:3738 ChEBI P2RX7 protein Q99572 UNIPROT up-regulates activity chemical activation 9606 21262970 t Luana Clemastine potentiates the human P2X7 receptor by sensitizing it to lower ATP concentrations. SIGNOR-257893 0.8 TNFRSF17 protein Q02223 UNIPROT ELK1 protein P19419 UNIPROT up-regulates 9606 10903733 f miannu Bcma overexpression activates elk-1 nuclear factor SIGNOR-79486 0.2 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL -1 8422248 t lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. SIGNOR-248925 0.719 POU5F1 protein Q01860 UNIPROT RARG protein P13631 UNIPROT up-regulates quantity 27499297 f SimoneGraziosi OCT4 positively controls the level of RARgamma SIGNOR-269222 0.306 LIF protein P15018 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 9143707 t gcesareni Lif binds at low-affinity to lifr, the structure of which is closely related to that of gp130 (42). Lifr then becomes heterodimerized with gp130 to form the high-affinity and signaling-competent complex (43). Osm utilizes this type of heterodimer, i.e. the lifr/gp130 complex (43, 44). SIGNOR-48111 0.75 TDG protein Q13569 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). SIGNOR-275713 0.7 GPI protein P06744 UNIPROT AMFR protein Q9UKV5 UNIPROT up-regulates binding 9606 12527360 t gcesareni Pgi is a housekeeping gene encoding phosphoglucose isomerase (pgi) a glycolytic enzyme that also functions as a cytokine (autocrine motility factor (amf)/neuroleukin/maturation factor) upon secretion from the cell and binding to its 78 kda seven-transmembrane domain receptor (gp78/amf-r) SIGNOR-97270 0.545 CSF1 protein P09603 UNIPROT CSF1R protein P07333 UNIPROT up-regulates activity binding 9606 BTO:0000876 BTO:0001103 24890514 t apalma The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34) SIGNOR-255568 0.937 PTGIR protein P43119 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256806 0.51 idarubicin chemical CHEBI:42068 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 20824055 t miannu Topoisomerase II (Top2) is a nuclear enzyme involved in several metabolic processes of DNA. Chemotherapy agents that poison Top2 are known to induce persistent protein-mediated DNA double strand breaks (DSB). In this report, by using knock down experiments, we demonstrated that Top2α was largely responsible for the induction of γH2AX and cytotoxicity by the Top2 poisons idarubicin and etoposide in normal human cells. SIGNOR-259327 0.8 GATA1 protein P15976 UNIPROT SPI1 protein P17947 UNIPROT down-regulates activity binding 9606 BTO:0004826 10753833 t irozzo GATA-1 represses PU.1 activity.We have in this report found that the GATA-1 transcription factor is capable of functionally interfering with the PU.1 protein and have provided evidence that this interference is mediated through interaction between the PU.1 ETS domain and the GATA-1 C-finger region. SIGNOR-256050 0.64 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-269963 0.2 GSK3B protein P49841 UNIPROT ETS1 protein P14921 UNIPROT up-regulates quantity by stabilization phosphorylation Thr265 YDSCDRLtQSWSSQS 9606 BTO:0000007 34023818 t miannu Here, we show that ETS1 forms a complex with glycogen synthase kinase-3β (GSK3β). Specifically, GSK3β-mediated phosphorylation of ETS1 at threonine 265 and serine 269 promoted protein stability, induced the transcriptional activation of matrix metalloproteinase (MMP)-9, and increased cell migration. SIGNOR-277560 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 12535517 t gcesareni One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73. SIGNOR-97485 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-244144 0.2 RNF125 protein Q96EQ8 UNIPROT IFIH1 protein Q9BYX4 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0005029 17460044 t miannu Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production. SIGNOR-271646 0.643 androst-5-ene-3beta,17beta-diol smallmolecule CHEBI:2710 ChEBI testosterone smallmolecule CHEBI:17347 ChEBI up-regulates quantity precursor of 10116 BTO:0000534;BTO:0000056 1537836 t lperfetto We have recently characterized two types of rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) isoenzymes expressed in adrenals and gonads. | However, in the presence of NADH, type III isoenzyme, in common with the type I isoform, converts 5 alpha-androstane-3,17-dione (A-dione) and 5 alpha-dihydrotestosterone (DHT) to the corresponding 3 beta-hydroxysteroids. SIGNOR-268640 0.8 DUSP6 protein Q16828 UNIPROT MAPK7 protein Q13164 UNIPROT down-regulates activity dephosphorylation 9606 18280112 t lperfetto However, whilst the interaction itself might be difficult to monitor, DUSP6 should still be able to promote the de-phosphorylation of ERK5 in cells if it is an ERK5 phosphatase.To test this HEK293 cells were transiently transfected with HA-ERK2 or HA-ERK5 together with EGFP-MEK1E (a constitutively active version of MEK1) or EGFP-MEK5D (a constitutively active version of MEK5).|Whilst one can envisage scenarios in which the interaction between DUSPs and their substrates might be transient, DUSP6 should still be able to promote the de-phosphorylation and inactivation of ERK5. SIGNOR-277007 0.632 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 19115199 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-182992 0.738 FLI1 protein Q01543 UNIPROT KLF1 protein Q13351 UNIPROT down-regulates activity binding 10090 BTO:0004475 12556498 t irozzo FLI-1 represses the transcriptional activity of EKLF.Our data indicate that the ETS domain of FLI-1 is absolutely required to inhibit EKLF activity. Since the FLI-1 ETS domain interacts with the DNA binding domain of EKLF, one possibility could be that FLI-1 inhibits the binding of EKLF to its DNA targets SIGNOR-256044 0.378 MKNK1 protein Q9BUB5 UNIPROT SPRY2 protein O43597 UNIPROT down-regulates phosphorylation Ser112 APLSRSIsTVSSGSR 9606 19864419 t llicata The spry2/nedd4 association involves the ww domains of nedd4 and requires phosphorylation of the mnk2 kinase sites, ser(112) and ser(121), on spry2. mnk2 silencing decreased spry2-nedd4 interactions and also augmented the ability of spry2 to inhibit fibroblast growth factor signaling. endogenous and overexpressed nedd4 polyubiquitinate spry2 via lys(48) on ubiquitin and decrease its stability. SIGNOR-188889 0.51 CCNE2 protein O96020 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR form complex binding 9606 19665013 t lperfetto The eukaryotic cell cycle is controlled by different cyclins and their associated kinases (murray and hunt, 1993). In mammalian cells, levels of cycline and its associated kinase, cdk2, rise in late g1/early s-phase when dna replication is initiated SIGNOR-187454 0.932 UNG protein P13051 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 27875297 f lperfetto Uracil N-glycosylase 2 (UNG2), the nuclear isoform of UNG, catalyzes the removal of uracil or 5-fluorouracil lesions that accumulate in DNA following treatment with the anticancer agents 5-fluorouracil and 5-fluorodeoxyuridine (floxuridine), a 5-fluorouracil metabolite. By repairing these DNA lesions before they can cause cell death, UNG2 promotes cancer cell survival and is therefore critically involved in tumor resistance to these agents.  SIGNOR-264889 0.7 PPM1A protein P35813 UNIPROT CDK9 protein P50750 UNIPROT down-regulates activity dephosphorylation Thr186 NSQPNRYtNRVVTLW 9606 18829461 t gcesareni Taken together, our data indicate that PPM1A and to some extent PPM1B are important negative regulators of P-TEFb function SIGNOR-248490 0.507 RASGEF1B protein Q0VAM2 UNIPROT NRAS protein P01111 UNIPROT up-regulates binding 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-161481 0.303 MAP2K6 protein P52564 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 10480932 t Luana P38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta. SIGNOR-260720 0.734 PRKACA protein P17612 UNIPROT TH protein P07101 UNIPROT up-regulates activity phosphorylation Ser40 GQGAPGPsLTGSPWP -1 11359875 t miannu HTH1 was phosphorylated at Ser40 by PKA. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation. phosphorylationof hTH1‚4 at Ser40, to a stoichiometry of up to 1.0 molphosphate per mol TH subunit, dramatically increases their binding to 14-3-3 proteins. SIGNOR-250061 0.375 5-Fluoro-8-hydroxy-2-(dipropylamino)tetralin chemical CID:122187 PUBCHEM HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258865 0.8 VPS11 protein Q9H270 UNIPROT RDX protein P35241 UNIPROT up-regulates activity binding 9606 BTO:0000567 21148287 t Sara Vps11 was found to interact with radixin. ERM proteins and the HOPS complex are required for the transition from early to late endosomes. We report that an interaction between subunits of the HOPS complex and the ERM (ezrin, radixin, moesin) proteins is required for the delivery of EGF receptor (EGFR) to lysosomes. Inhibiting either ERM proteins or the HOPS complex leads to the accumulation of the EGFR into early endosomes, delaying its degradation. SIGNOR-261312 0.354 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F9 protein P00740 UNIPROT up-regulates activity binding 9606 BTO:0000131 32665005 t lperfetto During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury. SIGNOR-263542 0.583 ADA protein P00813 UNIPROT ADORA1 protein P30542 UNIPROT up-regulates activity binding -1 18680557 t miannu The results show that human ADA, apart from reducing the adenosine concentration and thus preventing A(1)R desensitization, binds to A(1)R behaving as an allosteric effector that markedly enhances agonist affinity and increases receptor functionality. SIGNOR-269105 0.589 AGT protein P01019 UNIPROT TRPC6 protein Q9Y210 UNIPROT up-regulates activity 9606 24850910 f We demonstrated that Ang II evokes concentration-dependent activation of podocyte TRPC6 channels SIGNOR-253331 0.31 CSNK1D protein P48730 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser314 SREQSTDsGLGLGCY 9606 24715453 t lperfetto LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP) SIGNOR-234438 0.342 CLIP1 protein P30622 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates binding 17889670 t lperfetto Microtubule plus end binding proteins (+TIPs) localize to the dynamic plus ends of microtubules, where they stimulate microtubule growth and recruit signaling molecules. Three main +TIP classes have been identified (XMAP215, EB1, and CLIP-170) SIGNOR-264830 0.7 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Ser27 PFRDSPLsSRLLDDG 9606 22721717 t lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation SIGNOR-197932 0.346 ETFB protein P38117 UNIPROT ETF complex SIGNOR-C463 SIGNOR form complex binding 9606 33450351 t miannu Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors. SIGNOR-269452 0.943 JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 t lperfetto Inactive cytoplasmic STATs are recruited to the activated receptor by docking of the STAT SH2 domain to selected receptor tyrosine phosphopeptides, where they are in turn phosphorylated on a single tyrosine by Jak kinases. Has been identified tyrosine 705 of Stat3 as the likely site of phosphorylation by Jak kinases during signal transduction. SIGNOR-238638 0.811 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRA1B protein P35368 UNIPROT up-regulates activity chemical activation 10029 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258443 0.8 POLR1C protein O15160 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266145 0.91 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NCF1 protein P14598 UNIPROT up-regulates phosphorylation 9606 BTO:0000130 16778989 t inferred from 70% family members gcesareni Inhibitors of the erk1/2 pathway abrogated gm-csf-induced phosphorylation of ser345, while p38 mapk inhibitor abrogated tnf-alpha-induced phosphorylation of ser345.These results show that the ala-mutated p47phox acts as a dominant-negative inhibitor of endogenous p47phox and clearly indicate that phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells. SIGNOR-270091 0.2 AURKA protein O14965 UNIPROT CETN2 protein P41208 UNIPROT up-regulates phosphorylation Ser170 LRIMKKTsLY 9606 BTO:0000150 21731694 t llicata Our studies show that aurora a phosphorylates centrin at serine 170 in vitro and that the serine 170 phosphorylation affects the stability of centrin by regulating its interaction with apc/c. finally we demonstrated that phosphorylation of centrin serine 170 is an absolute requirement for aurora a-mediated centriole amplification. SIGNOR-174686 0.495 KIF1C protein O43896 UNIPROT RAB6B protein Q9NRW1 UNIPROT up-regulates quantity relocalization -1 20360680 t miannu Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation. SIGNOR-266878 0.2 DLK1 protein P80370 UNIPROT SOX9 protein P48436 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19254573 f fspada Pref-1 inhibits adipocyte differentiation through upregulating sox9 expression. SIGNOR-184277 0.401 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268650 0.8 (S)-duloxetine chemical CHEBI:36795 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition -1 18387300 t Luana Selective inhibition of serotonin (5-HT) and noradrenaline (NA) reuptake (SNRI) has been shown to be an attractive dual pharmacology approach for the treatment of a number of diseases.1,2 For example, dual 5- HT/NA reuptake inhibitor duloxetine (1) has shown clinical efficacy in the treatment of depression, pain, and urinary incontinence. SIGNOR-257775 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL6 protein P41182 UNIPROT down-regulates phosphorylation 9606 BTO:0000782;BTO:0000785 9649500 t inferred from 70% family members gcesareni Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway. SIGNOR-270140 0.2 MC5R protein P33032 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268712 0.436 MID1IP1 protein Q9NPA3 UNIPROT ACACA protein Q13085 UNIPROT up-regulates activity binding 10029 BTO:0000457 20952656 t miannu Recently, we reported the discovery that MIG12, a 183 amino acid protein, binds to ACC1 and ACC2, which induces polymerization and subsequently increases the enzymatic activity of the protein SIGNOR-267111 0.383 EPHA3 protein P29320 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates activity phosphorylation Tyr596 KLPGLRTyVDPHTYE 9606 11870224 t Eph receptor activation leads to tyrosine phosphorylation of three major autophosphorylation sites. these residues function to regulate kinase activity, their phosphorylation being required for full intrinsic enzyme activity. these tyrosines (EphA3 Y596, Y602 and Y779) as the prominent autophosphorylation sites of EphA3 SIGNOR-251115 0.2 NSL1 protein Q96IY1 UNIPROT MIS12 complex complex SIGNOR-C362 SIGNOR form complex binding -1 27881301 t lperfetto Human MIS12C (also known as MIND complex or Mtw1 complex in Saccharomyces cerevisiae) contains the MIS12, PMF1, NSL1, and DSN1 subunits SIGNOR-265191 0.91 SH3RF1 protein Q7Z6J0 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates binding 9606 16571722 t gcesareni We find that posh and jips directly associate with one another to form a multiprotein complex, pjac (posh-jip apoptotic complex), that includes all of the known kinase components of the pathway. Our observations indicate that this complex is required for jnk activation and cell death in response to apoptotic stimuli. SIGNOR-145393 0.287 ACSS1 protein Q9NUB1 UNIPROT acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI up-regulates quantity chemical modification 10843999 t lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. SIGNOR-271829 0.8 alvimopan chemical CHEBI:135686 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition -1 18313920 t Luana A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, l opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective l opioid receptor antagonist, which interacts selectively with l peripheral receptors. SIGNOR-257774 0.8 SIRT6 protein Q8N6T7 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity binding 9606 BTO:0000007 25083875 t miannu SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1.Importantly, SIRT6 also controls SREBP-1 recruitment to target promoters, such as Fasn, and helps maintain proper cyclic transcription. In fact, circadian metabolomics analyses reveal that SIRT6 controls lipid metabolism, contributing to the regulation of pathways involved in fatty acid synthesis and beta oxidation, triglyceride storage, signaling, and cellular membrane lipids. SIGNOR-268158 0.379 L-asparagine zwitterion smallmolecule CHEBI:58048 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 24657844 t miannu Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia. SIGNOR-267536 0.8 CTTN protein Q14247 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 11231575 t Cortactin binds directly to the Arp2/3 complex and activates it to promote nucleation of actin filaments. SIGNOR-251519 0.632 GRK6 protein P43250 UNIPROT LTB4R protein Q15722 UNIPROT down-regulates activity phosphorylation Thr308 VAKLLEGtGSEASST 9534 BTO:0000298 12077128 t Thr(308) is a major residue involved in GRK6-mediated desensitization of BLT1 signaling. SIGNOR-251213 0.486 TRIM27 protein P14373 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates 9606 12807881 f miannu We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38. SIGNOR-102028 0.2 AURKA protein O14965 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser353 VQNKRRRsVTPPEEQ 9606 16082213 t lperfetto We show that bypass of the g2/m checkpoint by the chk1 kinase inhibitor ucn-01 results in the activation of aurora-a and phosphorylation of cdc25b on s353 SIGNOR-139396 0.711 MLXIPL protein Q9NP71 UNIPROT ACACA protein Q13085 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 15496471 t Luana The present study provides evidence for a direct and dominant role of ChREBP in the glucose regulation of two key liver lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) SIGNOR-267946 0.446 CNR1 protein P21554 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257211 0.265 Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR MLL/SET subcomplex complex SIGNOR-C87 SIGNOR form complex binding 9606 24680668 t miannu Dimethylation of h3k4 requires a sub-complexincluding wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. SIGNOR-204744 0.842 SAGA complex complex SIGNOR-C465 SIGNOR H3C15 protein Q71DI3 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269635 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR ARFIP2 protein P53365 UNIPROT unknown phosphorylation Ser260 GTRGRLEsAQATFQA 9606 BTO:0000938 15809304 t llicata Akt phosphorylated arfaptin 2 at ser(260). we have also demonstrated that arfaptin 2 phosphorylation restores proteasome activity that is inhibited by the presence of polyq-huntingtin in cells. SIGNOR-135105 0.2 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269343 0.719 DNMT3A protein Q9Y6K1 UNIPROT FGF21 protein Q9NSA1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29091029 f Gianni Unbiased gene profiling studies revealed Fgf21 as a key negatively regulated Dnmt3a target gene in adipocytes with concordant changes in DNA methylation at the Fgf21 promoter region. SIGNOR-262200 0.2 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 18486448 t gcesareni The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus SIGNOR-178655 0.879 RORA protein P35398 UNIPROT NPAS2 protein Q99743 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 20817722 t miannu Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding. SIGNOR-267980 0.651 DCC-2036 chemical CHEBI:62166 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191313 0.8 FLT3 protein P36888 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity 9606 16266983 f gcesareni We show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway. SIGNOR-252626 0.442 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys17 GLGKGGAkRHRKVLR 9606 16227571 t miannu We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. SIGNOR-263944 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270422 0.8 TOM40 complex complex SIGNOR-C421 SIGNOR ATF5 protein Q9Y2D1 UNIPROT down-regulates activity relocalization 31387448 t lperfetto Central to the mtUPR is the transcription factor ATF5. When stress causes protein import and/or electron transport chain dysfunction ATF5 accumulates in the nucleus to transcribe mitochondrial chaperones and protease genes |Under normal conditions, ATF5 is imported into and sequestered within mitochondria. SIGNOR-267685 0.2 GRK5 protein P34947 UNIPROT GRK5 protein P34947 UNIPROT up-regulates activity phosphorylation Ser484 VLDIEQFsTVKGVNL -1 8144599 t Autophosphorylation of GRK5 occurs primarily at residues Ser-484 and Thr-485. Phospholipid-stimulated autophosphorylation activates the G protein-coupled receptor kinase GRK5. SIGNOR-251201 0.2 AGT protein P01019 UNIPROT AGTR1 protein P30556 UNIPROT up-regulates activity binding 10116 BTO:0004578 17346243 t AT(1) receptor (AngII type-1 receptor), a G-protein-coupled receptor, mediates most of the physiological and pathophysiological actions of AngII, and this receptor is predominantly expressed in cardiovascular cells, such as VSMCs (vascular smooth muscle cells) SIGNOR-252293 0.847 ADRA1D protein P25100 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257080 0.567 serotonin smallmolecule CHEBI:28790 ChEBI HTR2B protein P41595 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264286 0.8 CSNK2A2 protein P19784 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Ser45 LFRLSEHsSPEEEAS -1 2557337 t llicata Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase SIGNOR-251019 0.383 APC-c complex SIGNOR-C150 SIGNOR KIFC1 protein Q9BW19 UNIPROT down-regulates quantity by destabilization ubiquitination -1 24510915 t miannu Biochemical studies on the kinesins confirmed KIFC1, KIF18A, KIF2C, and KIF4A as APC/C substrates. Furthermore, we showed that the APC/CCDH1-dependent degradation of KIFC1 regulates the bipolar spindle formation and proper cell division. Our in vitro degradation assays showed a time-dependent degradation for four of the five potential substrates tested: KIF18A, KIF2C, KIFC1 and KIF4A were readily degraded in vitro, however remained stable in the presence of either APC/C inhibitor (Fig​(Fig4A4A and Supplementary Fig S3A). SIGNOR-266109 0.259 AGTR1 protein P30556 UNIPROT GNG12 protein Q9UBI6 UNIPROT up-regulates binding 9606 21289285 t gcesareni These results indicate that ang ii increases endothelial arginase activity/expression through galfa12/13 g proteins coupled to at(1) receptors and subsequent activation of rhoa/rock/p38 mapk pathways leading to endothelial dysfunction. SIGNOR-171763 0.409 BCOR protein Q6W2J9 UNIPROT HOXA7 protein P31268 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 26847029 f irozzo Importantly, our results showed that BCOR is a repressor of HoxA cluster of genes (HoxA5, HoxA7 and HoxA9) in myeloid cells. Knock-down of HoxA5, HoxA7 and HoxA9 significantly decreased the clonogenic growth of Bcor mutant and wild type cells, demonstrating the Hox genes, as targets of BCOR, played an important role in mediating BCOR’s function in regulating myeloid cell proliferation. SIGNOR-256013 0.2 SF3B2 protein Q13435 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 t lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). SIGNOR-268404 0.922 RPL38 protein P63173 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262461 0.862 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CIITA protein P33076 UNIPROT down-regulates phosphorylation 9606 18245089 t inferred from 70% family members gcesareni In this study we show that the extracellular signal-regulated kinases 1 and 2 (erk1/2) interact directly with ciita, targeting serine residues in the amino terminus of the protein, including serine 288. These data suggest a model whereby erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation. SIGNOR-270173 0.2 HNF4G protein Q14541 UNIPROT HAS2 protein Q92819 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003723 23896584 t Luana Transcription was activated by HNF4G in reporter assays using the promoter/enhancer region of the HAS2 gene. The endogenous expression of the HAS2 gene was suppressed by knockdown of HNF4G. SIGNOR-261626 0.344 YAP1 protein P46937 UNIPROT MCM3 protein P25205 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 f lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. SIGNOR-276568 0.2 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2A protein P49459 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271327 0.778 terazosin chemical CHEBI:9445 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 9606 9379432 t miannu Pharmacological management of benign prostatic hyperplasia (BPH) has most successfully been achieved by administration of α1 antagonists, which function via relaxation of prostatic smooth muscle. Terazosin2 (2), doxazosin3 (3), and alfuzosin4 (4), agents currently approved for this indication SIGNOR-258670 0.8 PPP2CA protein P67775 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates dephosphorylation Ser24 APIRRRSsNYRAYAT 9606 BTO:0000887 15769444 t lperfetto The major phosphatase thought to dephosphorylate ctni and phospholamban is type 2a protein phosphatase (pp2a) [61]. Activation of pp2a and ensuing dephosphorylation of regulatory proteins is involved in the anti-adrenergic effects of adenosine and muscarinic receptor activation see also fig2. SIGNOR-134601 0.387 CCKBR protein P32239 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256765 0.267 CDK7 protein P50613 UNIPROT ERCC3 protein P19447 UNIPROT down-regulates quantity by destabilization phosphorylation Ser90 HIFLEAFsPVYKYAQ 9606 BTO:0000567 30762924 t miannu These results led us to propose a model that spironolactone may trigger the phosphorylation of XPB at Ser90 by CDK7, which promotes the recognition and polyubiquitination of XPB by SCFFBXL18 for proteasomal degradation. SIGNOR-277433 0.891 HUWE1 protein Q7Z6Z7 UNIPROT MFN2 protein O95140 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 30217973 t lperfetto AMBRA1 regulates mitophagy at two critical steps. Upon mitophagy stimulation, AMBRA1 mediates the HUWE1 E3 ubiquitin ligase translocation from cytosol to mitochondria (light blue). AMBRA1 acts as a cofactor for HUWE1 E3 ubiquitin ligase activity, favouring its binding to its substrate MFN2 (and maybe other OMM substrates) and targeting it to the proteasome SIGNOR-272978 0.43 DLK2 protein Q6UY11 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 21419176 t gcesareni In this work, we demonstrate, for the first time, that dlk2 interacts with itself, with dlk1, and with the same notch1 receptor region as dlk1 does. We demonstrate also that the interaction of dlk2 with notch1 similarly results in an notch signaling in preadipocytes and mouse embryo fibloblasts. SIGNOR-172864 0.295 P2RY6 protein Q15077 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257398 0.2 dexamethasone chemical CHEBI:41879 ChEBI CEBPB protein P17676 UNIPROT up-regulates 9606 11279134 f fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin SIGNOR-106472 0.8 SP3 protein Q02447 UNIPROT ASNS protein P08243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 11867623 t Luana Sp1 and Sp3 Activate Transcription Driven by the AS Promoter SIGNOR-268020 0.2 PRKCA protein P17252 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000782;BTO:0000661 1370476 t llicata The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl. SIGNOR-17905 0.537 SIRT7 protein Q9NRC8 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity deacetylation Lys3016 VLMRLQEkLKGVEEG 30944854 t lperfetto Here, we report that sirtuin 7 (SIRT7)-mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. |Upon DNA damage, ATM is activated via a series of highly organized machineries, including acetylation by the histone acetyltransferase TIP60 at lysine 3016 SIGNOR-275890 0.367 AKAP12 protein Q02952 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity relocalization 14657015 t lperfetto A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. SIGNOR-271836 0.471 GSC protein P56915 UNIPROT EPHA7 protein Q15375 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000596 9417125 t Luana We demonstrate that Goosecoid can act as a repressor of its own promoter activity in transient co-transfection experiments in mouse P19 cells and in Xenopus embryos. Autorepression depends on the presence of the homeodomain and is mediated through the prd element more proximal to the transcriptional start site. SIGNOR-261613 0.2 CTSG protein P08311 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Phe55 PNDKYEPfWEDEEKN -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. SIGNOR-263563 0.577 INSR protein P06213 UNIPROT CALM2 protein P0DP24 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t miannu The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. SIGNOR-266320 0.359 TNF protein P01375 UNIPROT COMT protein P21964 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0000099 19291302 f Regulation of expression miannu COMT gene expression is downregulated by TNFα in primary rat astrocytes at both protein and mRNA levels. SIGNOR-251963 0.294 MC5R protein P33032 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256941 0.296 PHF12 protein Q96QT6 UNIPROT SIN3A protein Q96ST3 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 t miannu Pf1 interacts with mSin3A in vivo. Gal4-Pf1 repressed activity of the reporter gene fivefold relative to Gal4 alone (Fig. ​(Fig.5A),5A), suggesting that DNA-bound Pf1 was capable of recruiting functional mSin3A complexes. SIGNOR-266995 0.788 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Tyr95 KFPECGFyGMYDKIL 9606 17804414 t llicata Critical for the regulation of pkd1 activity in response to oxidative stress are src- and abl-mediated tyrosine phosphorylations that eventually lead to protein kinase cdelta (pkcdelta)-mediated activation of pkd1. our data suggest that pkd1 phosphorylation at tyr95 generates a binding motif for pkcdelta, and that oxidative stress-mediated pkcdelta/pkd interaction results in pkd1 activation loop phosphorylation and activation. SIGNOR-157716 0.42 ATM protein Q13315 UNIPROT XRCC6 protein P12956 UNIPROT up-regulates activity phosphorylation Ser27 QEENLEAsGDYKYSG 9606 BTO:0001546 26337656 t done miannu Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks. SIGNOR-274020 0.702 CAPN2 protein P17655 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains SIGNOR-251611 0.444 MRPS6 protein P82932 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261440 0.695 SMAD4 protein Q13485 UNIPROT SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR form complex binding 9606 20957627 t lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. SIGNOR-255832 0.2 DDB1 protein Q16531 UNIPROT DCX DET1-COP1 complex SIGNOR-C24 SIGNOR form complex binding 9606 17452440 t lperfetto Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes SIGNOR-154505 0.892 AR protein P10275 UNIPROT BTG2 protein P78543 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 16281084 f After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. SIGNOR-253674 0.385 SP1 protein P08047 UNIPROT MET protein P08581 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9223667 t lperfetto Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region. SIGNOR-241490 0.325 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252743 0.756 FGFR4 protein P22455 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates activity phosphorylation Tyr754 LLAVSEEyLDLRLTF -1 8576110 t Analysis of the major autophosphorylation site Y754F mutant of FGFR-4 showed that binding of p85 and its serine phosphorylation were independent of receptor autophosphorylation at this site. SIGNOR-251140 0.2 CD2AP protein Q9Y5K6 UNIPROT ACTB protein P60709 UNIPROT up-regulates activity binding 9606 BTO:0000007;BTO:0001938 29175910 t lperfetto One such regulator is the adaptor protein CD2AP, which delivers capping proteins to the barbed ends of polymerizing F-actin. Capping growing filaments can promote the formation of actin branches by increasing the G-actin pool available to form branches SIGNOR-264770 0.2 DUSP7 protein Q16829 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation 10029 BTO:0000246 12907755 t Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR SIGNOR-248726 0.318 ruxolitinib chemical CHEBI:66919 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258277 0.8 PPP1CB protein P62140 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 20186153 t gcesareni Akt activation is achieved through a series of phosphorylation steps, the first being akt phosphorylation at thr-450 by jnk kinases. Pp-1 acts as a major phosphatase to dephosphorylate akt at thr-450 and thus modulate its functions. SIGNOR-163965 0.394 PRKCD protein Q05655 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser44 PGTALVGsQKEPSEV 9606 10617144 t fspada In this study, we showed that the pkc-mediated phosphorylation of hmg-i exerted a very potent inhibition on the binding of this protein to the at-rich promoter regions of both pkc g and ng genes. The purified hmg-i can be phosphorylated by pkc a,b, g, and d but is poorly phosphorylated by pkc e and z. We have mapped two major sites of phosphorylation by pkc at ser44 and ser64 SIGNOR-73606 0.266 WNT3 protein P56703 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131823 0.635 EP300 protein Q09472 UNIPROT ALOX15 protein P16050 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 12517954 f lperfetto IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300. SIGNOR-254097 0.2 DZIP3 protein Q86Y13 UNIPROT H2AC20 protein Q16777 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHKA 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271754 0.2 CSNK2A2 protein P19784 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization phosphorylation Ser29 VSHWQQQsYLDSGIH -1 12432063 t miannu We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin.  SIGNOR-275995 0.453 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization phosphorylation Thr102 RAAMFPEtLDEGMQI -1 12432063 t miannu We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin.  SIGNOR-275996 0.541 CERS2 protein Q96G23 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI up-regulates quantity chemical modification 9606 26887952 t done miannu  Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity.  SIGNOR-273994 0.8 GRK2 protein P25098 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. SIGNOR-251445 0.2 FBXO22 protein Q8NEZ5 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000356 31138683 t lperfetto SCFFBXO22 targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis|we discovered Skp1-Cullin 1-FBXO22-ROC1 (SCFFBXO22) as the most dominating HDM2 E3 ubiquitin ligase from human proteome. The results of protein decay rate analysis, ubiquitination, siRNA-mediated silencing, and coimmunoprecipitation experiments support a hypothesis that FBXO22 targets cellular HDM2 for ubiquitin-dependent degradation. SIGNOR-273440 0.2 NBAS protein A2RRP1 UNIPROT NRZ complex complex SIGNOR-C358 SIGNOR form complex binding 25364732 t lperfetto NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay. SIGNOR-265024 0.791 coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI acetyl-CoA smallmolecule CHEBI:15351 ChEBI up-regulates quantity precursor of 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-268083 0.8 ADRB2 protein P07550 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 14500986 t We have found that signaling via the erythrocyte beta2-adrenergic receptor and heterotrimeric guanine nucleotide-binding protein (Galphas) regulated the entry of the human malaria parasite Plasmodium falciparum. SIGNOR-256149 0.646 GLUD1 protein P00367 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity chemical modification 9913 11254391 t Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate. SIGNOR-266917 0.8 PIK3CA protein P42336 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Ser608 ENTEDQYsLVEDDED -1 14729945 t miannu We find that p110 alpha phosphorylates p85 alpha Ser608 in vivo with significant stoichiometry. However, p110 beta is far less efficient at phosphorylating p85 alpha Ser608, identifying a potential difference in the mechanisms by which these two isoforms are regulated. The p85 alpha Ser608 phosphorylation was increased by treatment with insulin, platelet-derived growth factor, and the phosphatase inhibitor okadaic acid. The functional effects of this phosphorylation are highlighted by mutation of Ser608, which results in reduced lipid kinase activity and reduced association of the p110 alpha catalytic subunit with p85 alpha.  SIGNOR-276004 0.934 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RXRA protein P19793 UNIPROT down-regulates activity phosphorylation 9606 17604322 t inferred from 70% family members lperfetto In colon cancer cells, the Ras/mitogen‚Äêactivated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‚Äêmutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE SIGNOR-269995 0.2 GOT2 protein P00505 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 31422819 t Both isoforms [GOT! AND GOT2] catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. SIGNOR-266922 0.8 GRPEL2 protein Q8TAA5 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 t lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. SIGNOR-267700 0.5 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide chemical CHEBI:95082 ChEBI BRD4 protein O60885 UNIPROT down-regulates activity chemical inhibition -1 24015967 t Gianni This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation SIGNOR-262204 0.8 ATM protein Q13315 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Thr100 LKRLFSGtQISTIAE 9606 15073328 t lperfetto Individual ala substitutions at thr-100, ser-111, or ser-121 inhibited atm-catalyzed phosphate incorporationatm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp) SIGNOR-124051 0.537 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 12213813 t lperfetto In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E SIGNOR-262992 0.658 CDC20 protein Q12834 UNIPROT CCNB1 protein P14635 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000567 11285280 t miannu These results suggested that cyclin A is a target of the Cdc20-associated APC/C in human cells. SIGNOR-272578 0.966 C5AR1 protein P21730 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263462 0.7 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 22124607 t lperfetto Moreover, we reported that TCPTP knockdown in PTP1B deficient MEFS further enhanced IR activation, consistent with the two PTPs acting in a coordinated manner to attenuate insulin signalling .|Therefore, the inhibition of PTPs such as PTP1B that attenuate IR activation and signalling might be particularly effective in alleviating insulin resistance.|The prototypic family member PTP1B (encoded by PTPN1) dephosphorylates the IR beta subunit Y1162 and Y1163 activation loop autophosphorylation site to attenuate insulin signalling in vivo . SIGNOR-276947 0.78 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates phosphorylation Tyr597 FYVDFREyEYDLKWE 9606 BTO:0001271 11971190 t lperfetto Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation SIGNOR-117579 0.2 EZH2 protein Q15910 UNIPROT HOXB13 protein Q92826 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 22808286 f miannu EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex. SIGNOR-254144 0.414 SMG1 protein Q96Q15 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 15175154 t gcesareni Hsmg-1 is a stress-activated kinase that phosphorylates p53 and hupf1 in vitrothe observation that hsmg-1 exhibits p53 (ser-15) kinase activity in vitro suggested that this pikk might be involved in genotoxic stress-induced p53 phosphorylation and stabilization in intact cells. SIGNOR-125135 0.421 RAB6A protein P20340 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9534 20360680 f miannu We show that BICDR-1 interacts with the dynein/dynactin motor complex, binds to kinesin-3 motor protein Kif1C and controls the pericentrosomal localization of Rab6-positive secretory vesicles. SIGNOR-266880 0.7 ILK protein Q13418 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates activity phosphorylation Thr500 RLAYVAPtIPRRLAS -1 12030846 t miannu MYPT1 was phosphorylated by ILK and phosphorylation sites in the N- and C-terminal fragments of MYPT1 were detected. From sequence analyses, three sites were identified: a primary site at Thr(709), and two other sites at Thr(695) and Thr(495). ILK produced an intermediate level of inhibition SIGNOR-262884 0.567 PRKACA protein P17612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 9606 BTO:0000887 20151718 t miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-163752 0.278 bisphenol A chemical CHEBI:33216 ChEBI AHR protein P35869 UNIPROT up-regulates activity chemical activation -1 31995776 t miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity.In our study, BPs showed AhR agonist activity only at the highest concentrations, and the mixture did not differ from the single BPs. SIGNOR-268735 0.8 FKBP4 protein Q02790 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 10090 BTO:0000947 19545546 t We noted that FK506 altered nuclear localization of the GR and inhibited expression of GR-responsive genes. Furthermore, si-RNA knockdown of FKBP4 gene, coding for the immunophilin FKBP52, inhibited cortisol-activated GR nuclear translocation SIGNOR-252034 0.709 DNA_damage stimulus SIGNOR-ST1 SIGNOR RAD23B protein P54727 UNIPROT up-regulates 24086043 f lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). SIGNOR-275688 0.7 GRIA1 protein P42261 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264947 0.8 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2G1 protein P62253 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271349 0.702 F2RL1 protein P55085 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256752 0.2 MAPK1 protein P28482 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Ser1185 GTPPASTsPFSQLAA 9606 10660621 t lperfetto Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene. SIGNOR-74872 0.371 DRD1 protein P21728 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256939 0.557 AURKA protein O14965 UNIPROT AURKAIP1 protein Q9NWT8 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 MLVPRKMsVSPLESW 9606 BTO:0000567 17957726 t miannu AIP is phosphorylated on Serine 70 by Aurora‐A but not Aurora‐B and expression of phosphorylation mimic mutant of AIP results in prolonged protein stability compared to unphosphorylatable mutant. Phosphorylation of AIP Prolongs its Protein Stability SIGNOR-262648 0.668 NFKBIA protein P25963 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates activity binding 9606 SIGNOR-C13 1340770 t lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-17688 0.729 PRKCD protein Q05655 UNIPROT DBI protein P07108 UNIPROT up-regulates phosphorylation Thr42 ATVGDINtERPGMLD 9606 18194441 t gcesareni Acyl coenzyme a-binding protein (acbp) is phosphorylated following protein kinase c activation. SIGNOR-160393 0.2 AURKA protein O14965 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 24173284 t lperfetto The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A SIGNOR-120836 0.77 UBE3C protein Q15386 UNIPROT CAND2 protein O75155 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000165 12692129 t miannu We show that KIAA10 indeed associates with 26 S proteasomes in mammalian cells but that this interaction is likely to depend on contacts with a subunit(s) besides S2/Rpn1. Most importantly, we provide strong evidence that TIP120B (TBP-interacting protein 120B (22)) is a specific substrate that is targeted for degradation in skeletal muscle through KIAA10-catalyzed polyubiquitination. SIGNOR-271454 0.399 JAK3 protein P52333 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity phosphorylation Tyr1034 AIETDKEyYTVKDDR -1 12559972 t Phosphorylation by recombinant JAK3 of a peptide substrate corresponding to the JAK1 activation loop (KAIETDKEYYTVKD) SIGNOR-251363 0.516 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CEP76 protein Q8TAP6 UNIPROT down-regulates activity phosphorylation Ser83 VEQELPSsPKQPICF 9606 BTO:0001938 27065328 t miannu Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification. we conclude that Cep76 inhibits centriole disengagement and consequently amplification by blocking Plk1 activation at the centrosome. SIGNOR-262730 0.304 TEAD1 protein P28347 UNIPROT BMP4 protein P12644 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23673366 f gcesareni Taz induces bmp4 transcription through the tead family of transcription factors, which mediate bmp4 promoter activation through binding to tead response element 1 (tre1). SIGNOR-202049 0.261 GNA13 protein Q14344 UNIPROT ARHGEF1 protein Q92888 UNIPROT up-regulates gtpase-activating protein 9606 9641915 t gcesareni The guanine nucleotide exchange factor (gef) for rho, p115 rhogef, has an amino-terminal region with similarity to rgs proteins. Recombinant p115 rhogef and a fusion protein containing the amino terminus of p115 had specific activity as gtpase activating proteins toward the alpha subunits of the g proteins g12 and g13, but not toward members of the gs, gi, or gq subfamilies of galpha proteins. This gef may act as an intermediary in the regulation of rho proteins by g13 and g12. SIGNOR-58413 0.591 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser441 GHSPLSLsAQSVMEE 9606 24614225 t lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204736 0.529 MAPK9 protein P45984 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates activity phosphorylation Ser59 GDSCPHGsPQGPLAP 12818176 t miannu JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity. SIGNOR-250134 0.622 H2AZ1 protein P0C0S5 UNIPROT Nucleosome_H2A.Z.1 variant complex SIGNOR-C322 SIGNOR form complex binding -1 24311584 t miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. SIGNOR-263715 0.2 ROCK2 protein O75116 UNIPROT DPYSL2 protein Q16555 UNIPROT up-regulates phosphorylation Thr555 DNIPRRTtQRIVAPP 9606 BTO:0000938 10818093 t lperfetto Rho-kinase phosphorylated crmp-2 at thr-555 in vitro.we demonstrated that crmp-2 is phosphorylated by rho-kinase in drg neurons during lpa-induced growth cone collapse. SIGNOR-77543 0.392 TAF2 protein Q6P1X5 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269574 0.535 CSNK2A3 protein Q8NEV1 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser228 PGVTPSKsTSASAIM 9606 BTO:0000938 26917740 t lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. SIGNOR-275742 0.272 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NUP50 protein Q9UKX7 UNIPROT down-regulates activity phosphorylation Ser315 TQSKPVSsPFPTKPL 9606 19767751 t llicata Erk phosphorylates nup50 at ser221 and ser315 phosphorylation of nup50 reduces affinity for importin-beta SIGNOR-263043 0.2 RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 10837486 t lperfetto Rsk1, and survival factor signaling stimulate phosphorylation of bad at ser-155, blocking the binding of bad to bcl-xl. SIGNOR-78020 0.404 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser285 NHTLAPAsPAPARPR 9606 BTO:0000142 15262992 t lperfetto Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd SIGNOR-126851 0.405 KLKB1 protein P03952 UNIPROT HGF protein P14210 UNIPROT up-regulates activity cleavage Arg494 CAKTKQLrVVNGIPT -1 12372819 t miannu the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain. SIGNOR-256512 0.329 flumazenil chemical CHEBI:5103 ChEBI GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t brain lperfetto Receptors containing the alpha4 or alpha6 subunits, together with beta and gamma2, do not bind the traditional BZ agonists, including zolpidem, but demonstrate high affinity for some ligands, notably the imidazobenzodiazepines such as flumazenil and Ro15-4513, or bretazenil SIGNOR-263806 0.8 SIRT1 protein Q96EB6 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21633182 t miannu Interestingly, SIRT1 suppresses PPARγ but activates PGC-1α , and thus affects the clock network through multiple mechanisms. SIGNOR-268032 0.687 SRC protein P12931 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 8939605 t lperfetto Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway. SIGNOR-44870 0.652 LCK protein P06239 UNIPROT DAPP1 protein Q9UN19 UNIPROT up-regulates activity phosphorylation Tyr139 KVEEPSIyESVRVHT 10880360 t lperfetto Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins. SIGNOR-249373 0.631 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr86 YTLSRAQtVVVEYTH -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276128 0.644 TSC22D3 protein Q99576 UNIPROT RELA protein Q04206 UNIPROT down-regulates activity binding 9606 BTO:0000007 11468175 t GILZ inhibits NF-kappaB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-kappaB subunits. SIGNOR-253297 0.381 BRSK1 protein Q8TDC3 UNIPROT CAST protein P20810 UNIPROT up-regulates activity phosphorylation Ser45 KSQSTKLsVVHEKKS 10090 BTO:0000142 27626661 t miannu Here, we show that an AZ cytomatrix protein CAST and an AZ-associated protein kinase SAD-B coordinately regulate STD by controlling reloading of the AZ with release-ready synaptic vesicles. SAD-B phosphorylates the N-terminal serine (S45) of CAST, and S45 phosphorylation increases with higher firing rate. SIGNOR-263051 0.2 LEPR protein P48357 UNIPROT SH2B1 protein Q9NRF2 UNIPROT up-regulates activity binding 27154742 t lperfetto The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex SIGNOR-253077 0.339 PSMD4 protein P55036 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263347 0.899 PTPN7 protein P35236 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR 9606 10702794 t HePTP efficiently dephosphorylated active ERK2 on the tyrosine residue in the activation loop in vitro. Together, these data identify ERK2 as a specific and direct target of HePTP and are consistent with a model in which HePTP negatively regulates ERK2 activity as part of a feedback mechanism SIGNOR-248484 0.805 CHEK1 protein O14757 UNIPROT CLSPN protein Q9HAW4 UNIPROT up-regulates phosphorylation Thr916 DELLDLCtGKFTSQA 9606 16963448 t gcesareni We found that thr-916 on claspin is phosphorylated by chk1, suggesting that chk1 regulates claspin during checkpoint response. SIGNOR-149411 0.786 MC4R protein P32245 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257182 0.252 SGK1 protein O00141 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE 10090 19965929 t We demonstrate that SGK1 affects differentiation by direct phosphorylation of Foxo1, thereby changing its cellular localization from the nucleus to the cytosol. In addition we show that SGK1-/- cells are unable to relocalize Foxo1 to the cytosol in response to dexamethasone. SIGNOR-255925 0.602 mycophenolic acid chemical CHEBI:168396 ChEBI IMPDH2 protein P12268 UNIPROT down-regulates activity chemical inhibition -1 10677226 t Federica Mycophenolic acid (MPA) is a species-specific inhibitor of IMPDH; mammalian IMPDHsare very sensitive to MPA SIGNOR-261077 0.8 NDUFA11 protein Q86Y39 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5) SIGNOR-262142 0.801 GRM6 protein O15303 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 t miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. SIGNOR-264084 0.323 JAK2 protein O60674 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr718 IPERDSRySQPLHEE 9606 BTO:0001963 19287004 t miannu Furthermore, JAK2, but not JAK1, directly bound to and phosphorylated ASK1 at Tyr-718, leading to an enhanced association of ASK1 with SOCS1 and subsequent ASK1 degradation.  SIGNOR-276145 0.374 NLGN2 protein Q8NFZ4 UNIPROT MAGI2 protein Q86UL8 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 t miannu S-SCAM is a member of the membrane-associated guanylate kinase (MAGUK) family of PDZ-domain-containing proteins that include the synaptic organising molecule PSD-95. The PDZ domain of S-SCAM binds to the C-terminal tail of NL2, forming a ternary complex at the cell membrane (Figure 2b). The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. SIGNOR-265444 0.412 CTTNBP2NL protein Q9P2B4 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity binding 10116 23015759 t miannu CTTNBP2NL interacts with cortactin and targets cortactin to stress fibers. SIGNOR-261695 0.364 tamoxifen chemical CHEBI:41774 ChEBI ESR1 protein P03372 UNIPROT down-regulates activity chemical inhibition 9606 20512796 t miannu Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth. SIGNOR-258587 0.8 PAICS protein P22234 UNIPROT SAICAR(4-) smallmolecule CHEBI:58443 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). SIGNOR-267322 0.8 ATM protein Q13315 UNIPROT KIFC1 protein Q9BW19 UNIPROT up-regulates quantity by stabilization phosphorylation Ser26 RPLIKAPsQLPLSGS 9606 BTO:0000815 33397932 t miannu  ATM and ATR kinases phosphorylate KIFC1-S26 during DNA-damage conditions.KIFC1 was stabilized upon phosphorylation and thus promoted centrosome clustering, CIN, and tumor recurrence both in vivo and in vitro. SIGNOR-277295 0.2 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 16782899 t llicata Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain SIGNOR-147187 0.476 GW 791343 HYDROCHLORIDE chemical CID:9848159 PUBCHEM P2RX7 protein Q99572 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193116 0.8 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity phosphorylation Ser409 LRLDPTLsVDDLANS 9606 BTO:0000972 phosphorylation:Ser213 TRKLMEFsEHCAIIL 9155023 t lperfetto Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. In contrast, phosphorylation of Ser409 and Ser416, located in a segment corresponding to the substrate recognition T-loop region in a three-dimensional structural model of protein kinases, is enhanced by receptor dimerization and can occur via an intermolecular mechanism. Phosphorylation of Ser409 is essential for TbetaRII kinase signaling, while phosphorylation of Ser416 inhibits receptor function. SIGNOR-246743 0.2 SLC1A7 protein O00341 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity relocalization 9606 26687113 t miannu After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5). SIGNOR-264806 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE11A protein Q9HCR9 UNIPROT up-regulates activity phosphorylation Ser117 GNLQRRAsQKELRKS -1 18312413 t miannu The N-terminus has two phosphorylation sites for cyclic nucleotide monophosphate-dependent protein kinases (Ser117, Ser168). Phosphorylation of both by cAMP-dependent protein kinase decreased the EC50 value for cGMP from 72 to 23 μm. Effect of phosphorylations at Ser117 and Ser162. Here, serine phosphorylation by the catalytic subunit of cAK, albeit not known whether at position 117, 162 or both, increased cGMP affinity about threefold. SIGNOR-276153 0.2 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2. SIGNOR-236010 0.784 PRKACA protein P17612 UNIPROT DSP protein P15924 UNIPROT down-regulates activity phosphorylation Ser2849 RSGSRRGsFDATGNS 9606 BTO:0000567 7525582 t miannu HeLa cells treated with forskolin indicated that stimulation of protein kinase A in transfected cells could decrease the interaction of DP.AN.SerC23 with keratin IF networks. phosphorylation of Ser-C23 could destabilize interactions that occur either directly through this 20 residue sequence or that are dependent on its correct conformation SIGNOR-250353 0.334 AKT1 protein P31749 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser429 PQRERKSsSSSEDRN 9606 BTO:0000007 10869359 t Akt phosphorylates both S364 and S428. Akt downregulates B-Raf activity in vivo SIGNOR-251472 0.47 DOK1 protein Q99704 UNIPROT AX/b2 integrin complex SIGNOR-C171 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257683 0.301 EID3 protein Q8N140 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 10090 23720823 f miannu Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. The novel inhibitor of differentiation Eid3 is an FRG1/Suv4-20h1 target involved in the myogenic defects caused by FRG1 over-expression. Eid3 is down-regulated upon muscle differentiation and behaves as a myogenic inhibitor gene. SIGNOR-266641 0.7 MICU2 protein Q8IYU8 UNIPROT MCU_MICU2_variant complex SIGNOR-C502 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270877 0.645 SFRP1 protein Q8N474 UNIPROT WNT1 protein P04628 UNIPROT down-regulates binding 9606 BTO:0000782 10347172 t gcesareni Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling. SIGNOR-67806 0.776 imatinib chemical CHEBI:45783 ChEBI ABL1 protein P00519 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258120 0.8 MMUT protein P22033 UNIPROT succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI up-regulates quantity chemical modification 9606 1978672 t miannu Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme that catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA). SIGNOR-269109 0.8 PHLPP2 protein Q6ZVD8 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 17386267 t gcesareni Knockdown studies reveal that PHLPP1 specifically modulates the phosphorylation of HDM2 and GSK-3alpha through Akt2, whereas PHLPP2 specifically modulates the phosphorylation of p27 through Akt3 SIGNOR-237439 0.67 RBBP7 protein Q16576 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263836 0.828 YWHAQ protein P27348 UNIPROT GEM protein P55040 UNIPROT up-regulates quantity by stabilization binding 9534 14701738 t miannu In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase SIGNOR-261714 0.269 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr371 LLAKLEEtKEYQEPE -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276210 0.388 CSNK2A1 protein P68400 UNIPROT DDX58 protein O95786 UNIPROT down-regulates phosphorylation Ser855 PKPKQFSsFEKRAKI 9606 21068236 t lperfetto Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of rig-i are phosphorylated by casein kinase ii (ck2) in the resting state of the cell and dephosphorylated when cells are infected by rna virus. Mutation at aa position 770 or 854 to 855 of rig-i renders it constitutively active SIGNOR-169404 0.2 Zalospirone chemical CID:163925 PUBCHEM HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258864 0.8 MAPK1 protein P28482 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser664 KKTSGPLsPPTGPPG 9606 15851026 t llicata Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. s664 is the primary erk phosphorylation site on tsc2 in vitro and in vivo SIGNOR-135696 0.668 GTF2H1 protein P32780 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates quantity by destabilization phosphorylation Ser403 PEEFISLsPPHEALD -1 10428966 t TFIIH-mediated phosphorylation of E2F-1 plays a role in triggering E2F-1 degradation during S phase. E2F-1 activation domain interacts with a kinase activity which phosphorylates two sites, Ser403 and Thr433, within the activation domain. We demonstrate that TFIIH is responsible for the E2F-1 phosphorylation observed in cell extracts and that endogenous E2F-1 interacts in vivo with p62, a component of TFIIH, during S phase. SIGNOR-251259 0.445 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PLEC protein Q15149 UNIPROT down-regulates phosphorylation Thr4539 GGLIEPDtPGRVPLD 9606 BTO:0000567 19709076 t lperfetto Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane. SIGNOR-216904 0.396 MAPK3 protein P27361 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates activity phosphorylation Ser167 FLISPPAsPPVGWKQ 10090 BTO:0000165 12063245 t lperfetto Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. SIGNOR-249478 0.388 CALM2 protein P0DP24 UNIPROT EEF2K protein O00418 UNIPROT up-regulates binding 9606 11015200 t miannu The calmodulin-binding region is located between amino acids 51 and 96 SIGNOR-266321 0.473 PRKCD protein Q05655 UNIPROT OPRD1 protein P41143 UNIPROT unknown phosphorylation Ser344 CGRPDPSsFSRAREA 9606 11085981 t lperfetto In the current study, we identified a PKC-mediated phosphorylation site in the delta-opioid receptor (DOR) and demonstrated that activation of PKC by stimulation of other types of GPCR or increase in intracellular Ca2+concentration in HEK 293 cells induces heterologous phosphorylation of DOR. Our results further established that DOR phosphorylation at Ser-344 by PKC results in internalization of DOR in HEK 293 cells through a beta-arrestin- and clathrin-mediated mechanism. SIGNOR-249063 0.312 TLR4 protein O00206 UNIPROT TLR4 protein O00206 UNIPROT up-regulates activity binding 10090 22664090 t gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-252066 0.2 RAB4A protein P20338 UNIPROT RUFY1 protein Q96T51 UNIPROT up-regulates activity binding 9606 20534812 t Giulio Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn.|We also found that enlargement of early endosomes mediated by RUFY1 requires its interaction with Rab4 SIGNOR-261280 0.667 KLF15 protein Q9UIH9 UNIPROT RBP3 protein P10745 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 f miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. SIGNOR-253816 0.268 LCK protein P06239 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates activity phosphorylation Tyr194 DVQKSKEyFSKQK -1 20178744 t miannu Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation. SIGNOR-276277 0.2 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-B receptor complex SIGNOR-C336 SIGNOR up-regulates activity chemical activation 9606 9872316 t brain lperfetto GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals. SIGNOR-263795 0.8 Normorphine chemical CHEBI:7633 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258822 0.8 NOTCH proteinfamily SIGNOR-PF30 SIGNOR SNW1 protein Q13573 UNIPROT up-regulates binding 9606 10713164 t gcesareni Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta. SIGNOR-254337 0.2 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR H2AX protein P16104 UNIPROT up-regulates activity ubiquitination -1 12485996 t lperfetto Strikingly, as well as H2AX, the nucleosome core histones H2A, H2B, H3 and H4 were all ubiquitylated efficiently by BRCA1/BARD1, while the linker histone H1 was not (Figure 3).| Generally, histone proteins are required for compaction of nuclear DNA into chromatin, and their modification is thought to loosen this compaction. Therefore, one might envisage that ubiquitylation of γH2AX by BRCA1/BARD1 at DNA breaks modulates local chromatin packaging to facilitate the action of DNA repair enzymes. SIGNOR-263235 0.2 CSNK1A1 protein P48729 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Ser12 FSLHDALsGSGNPNP -1 8253806 t llicata L-29, a soluble lactose-binding lectin, is phosphorylated on serine 6 and serine 12 in vivo and by casein kinase I. SIGNOR-250789 0.313 NEK9 protein Q8TD19 UNIPROT NEK6 protein Q9HC98 UNIPROT up-regulates activity phosphorylation Ser206 SETTAAHsLVGTPYY 9606 BTO:0000007 12840024 t lperfetto Nercc1/nek9 activates the nek6 and nek7 kinases. Nercc1 catalyzes the direct phosphorylation of prokaryotic recombinant nek6 at ser206 in vitro concomitant with 20-25-fold activation of nek6 activity. SIGNOR-102996 0.677 MRPL50 protein Q8N5N7 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262338 0.677 HCK protein P08631 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Tyr291 AETSKLIyDFIEDQG 9534 12235133 t Src family kinase Hck induces phosphorylation of WASp-Tyr(291). Phosphorylation of tyrosine 291 enhances the ability of WASp to stimulate actin polymerization and filopodium formation. SIGNOR-251268 0.571 MCU protein Q8NE86 UNIPROT MCU_MICU3_variant complex SIGNOR-C501 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270869 0.678 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. SIGNOR-216809 0.373 CASP3 protein P42574 UNIPROT KDM4C protein Q9H3R0 UNIPROT down-regulates activity cleavage 9606 29207681 t miannu JMJD2C as a novel substrate for caspase-3 (cysteine-aspartic acid protease-3), and cleavage of JMJD2C by caspase-3 led to inactivation of JMJD2C demethylase activity and elevation of H3K9 methylation levels. SIGNOR-263870 0.2 Synaptonemal_complex complex SIGNOR-C351 SIGNOR Meiotic_recombination phenotype SIGNOR-PH162 SIGNOR up-regulates 9606 33262143 f miannu The synaptonemal complex (SC) is a meiosis-specific structure formed between homologous chromosomes during prophase that promotes DSB formation and biases repair of DSBs to homologs over sister chromatids. SIGNOR-264204 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR ACLY protein P53396 UNIPROT unknown phosphorylation Ser455 PAPSRTAsFSESRAD 10116 BTO:0000443 12107176 t gcesareni Taken together, these results demonstrate that serine 454 of ATP-citrate lyase is a novel and major in vivo substrate for protein kinase B. SIGNOR-245259 0.2 NDUFA4 protein O00483 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267752 0.523 BMPR1B protein O00238 UNIPROT SMAD9 protein O15198 UNIPROT up-regulates activity phosphorylation 9606 19620713 t lperfetto Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. SIGNOR-255264 0.696 NKX2-5 protein P52952 UNIPROT GATA4 protein P43694 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19479054 f Using antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased beta-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the beta-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5. SIGNOR-253654 0.844 PGM1 protein P36871 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI down-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267931 0.8 NCOA1 protein Q15788 UNIPROT CYP7A1 protein P22680 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255063 0.451 MAPK14 protein Q16539 UNIPROT MAP3K11 protein Q16584 UNIPROT down-regulates phosphorylation 9606 20626350 t gcesareni Jnk and p38 mapk activation have antagonistic effects in many cases. From a mechanicistic point of view, the p38 mapk pathway can negatively regulate jnk activity at the level of map3ks, either by phosphorylating mlk3 or the tak1 regulatory subunit tab2 SIGNOR-166605 0.309 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Thr407 SRIPASQtSVPFDHL 9606 BTO:0000007 10542239 t llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T SIGNOR-250814 0.2 SCRIB protein Q14160 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity binding 9606 BTO:0000007 20622900 t miannu These two KIM sites are found at N- and C-terminal locations on hScrib, and both are essential for directing the interaction between ERK and hScrib, but with the C-terminal site having the strongest affinity for ERK. One of the most likely consequences of this interaction is to inhibit ERK translocation to the nucleus. SIGNOR-263067 0.374 PRKCG protein P05129 UNIPROT TOP2A protein P11388 UNIPROT up-regulates activity phosphorylation Ser29 EDAKKRLsVERIYQK 9606 BTO:0000567 12569090 t lperfetto Here, we have shown that the enzymatic activity of topoisomerase II alpha protein purified from HeLa cell nuclei was strongly enhanced following phosphorylation by protein kinase C. | Site-directed mutagenesis studies indicated that phosphorylation of serine 29 generated both of these phosphopeptides. SIGNOR-249196 0.366 SS18 protein Q15532 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269782 0.64 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Tyr188 SFVGTLQyLAPELLE 9606 SIGNOR-C14 12645577 t gcesareni These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation. SIGNOR-99314 0.37 PRKACA protein P17612 UNIPROT CAD protein P27708 UNIPROT down-regulates phosphorylation Ser1406 GAGGRRLsSFVTKGY 9606 17206380 t gcesareni Protein kinase a phosphorylation at thr456 of the multifunctional protein cad antagonizes activation by the map kinase cascade. SIGNOR-151816 0.312 NFKB1 protein P19838 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9733516 f gcesareni Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2 SIGNOR-59951 0.647 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 12050114 t gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. SIGNOR-88748 0.346 AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 9829964 t The nuclear factor CREB stimulates the expression of cellular genes following its protein kinase A-mediated phosphorylation at Ser-133. Ser-133 phosphorylation, in turn, activates target gene expression by promoting recruitment of the co-activator CBP. |When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. SIGNOR-251474 0.2 SRC protein P12931 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates phosphorylation Tyr307 VTRRTPDyFL 9606 BTO:0000938 23796501 t llicata We found that ?-Syn gene overexpression in sk-n-sh cells and primary neurons led to pp2a/c phosphorylation at y307, a known target of src kinase, and consequent phosphatase inhibition. SIGNOR-202192 0.44 CCKBR protein P32239 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257037 0.277 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191021 0.8 MTA1 protein Q13330 UNIPROT COP1 protein Q8NHY2 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001938 19805145 t miannu MTA1 destabilizes COP1 by promoting its autoubiquitination. in addition to polyubiquitination of its substrates, COP1 also catalyzes its autoubiquitination for degradation as a part of an autoregulatory mechanism SIGNOR-271892 0.2 RIN1 protein Q13671 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 11784866 t gcesareni We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1. SIGNOR-113970 0.581 WNK4 protein Q96J92 UNIPROT SLC12A3 protein P55017 UNIPROT up-regulates activity phosphorylation Thr50 SHLTHSStFCMRTFG -1 22342722 t Q9BYP7:p.Glu562Lys (mutation causing interaction);Q9BYP7:p.Asp564Ala (mutation causing interaction);Q9BYP7:p.Gln565Glu (mutation causing interaction) lperfetto Threonine 48 was identified as the WNK4 phosphorylation site at mouse NCC|. Thus, WNK4 stimulates NCC in three ways: (1) direct phosphorylation and in turn increasing NCC protein abundance; (2) facilitating the phosphorylation of NCC by SPAK/OSR1 indirectly, and (3) phosphorylating and activating SPAK/OSR1.|Evidences from early studies using Xenopus oocytes and mammalian cells indicate that WNK4 inhibits NCC and PHAII-causing mutations relieve the inhibition SIGNOR-264631 0.597 PRKACA protein P17612 UNIPROT DYNLRB1 protein Q9NP97 UNIPROT up-regulates phosphorylation Ser73 LTFLRIRsKKNEIMV 9606 23333499 t llicata Our results show that km23-1 is required for camp-responsive element (cre) transcriptional activation by tgf_, with s73-km23-1 being required for the cre-dependent tgf_ stimulation of fibronectin (fn) transcription. SIGNOR-200456 0.2 RPS6KB1 protein P23443 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk. SIGNOR-186955 0.314 Sanglifehrin A chemical CID:5388925 PUBCHEM IMPDH2 protein P12268 UNIPROT down-regulates activity chemical inhibition 9606 28076787 t Monia We show that the mammalian target of SFA is inosine-50 -monophosphate dehydrogenase 2 (IMPDH2); Biochemical characterization reveals that PPIA-SFA does not inhibit the catalytic activity of IMPDH2 but rather, it modulates cell growth via binding to the cystathionine-b-synthase (CBS) domain. SIGNOR-261099 0.8 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 11904305 t gcesareni Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1. SIGNOR-116162 0.629 MLL2 complex complex SIGNOR-C88 SIGNOR ESR1 protein P03372 UNIPROT up-regulates binding 9606 16603732 t miannu Eralpha directly binds to the mll2 complex through two lxxll motifs in a region of mll2 near the c terminus in a ligand-dependent manner. Disrupting the interaction between eralpha and the mll2 complex with small interfering rnas specific against mll2 or an mll2 fragment representing the interacting region with eralpha significantly inhibited the eralpha transcription activity. SIGNOR-145868 0.466 RPGRIP1L protein Q68CZ1 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates demethylation 9606 20080798 t lperfetto Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. SIGNOR-217412 0.2 AURKB protein Q96GD4 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates phosphorylation Thr117 KNKIAKEtNNKKKEF 9606 17457057 t lperfetto Phosphorylation by aurora-b negatively regulates survivin function . hat survivin is phosphorylated at t117 during mitosis, and once phosphorylated, dephosphorylation is crucial for chromosome congression and progression into anaphaseduring mitosis SIGNOR-154569 0.786 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates activity phosphorylation Ser27 PFRDSPLsSRLLDDG 9606 BTO:0000887 11342557 t lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation SIGNOR-107676 0.346 RUNX1 protein Q01196 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29958106 t miannu RUNX1 represses MYC expression through direct binding at three downstream enhancer elements SIGNOR-260093 0.343 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates phosphorylation Tyr589 TGSSDNEyFYVDFRE 9606 BTO:0001271 11971190 t lperfetto Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation SIGNOR-117571 0.2 CSK protein P41240 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Tyr1218 MVSTFEQyQFLYDVI 9606 BTO:0000782 7507203 t llicata Tyrosine phosphorylation of cd45 phosphotyrosine phosphatase by p50csk kinase creates a binding site for p56lck tyrosine kinase and activates the phosphatase. SIGNOR-26785 0.481 IL2 protein P60568 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 22128144 f miannu We observe that the CD8(+) T-cell autocrine growth factor IL-2 coordinately increases Nab2 expression and decreases TRAIL expression. SIGNOR-253895 0.365 PIM1 protein P11309 UNIPROT SKP2 protein Q13309 UNIPROT up-regulates activity phosphorylation Ser64 SNLGHPEsPPRKRLK 9606 BTO:0000567 20663873 t miannu We found that expression of Pim-1 increases the level of Skp2 through direct binding and phosphorylation of multiple sites on this protein. Along with known Skp2 phosphorylation sites including Ser(64) and Ser(72), we have identified Thr(417) as a unique Pim-1 phosphorylation target. Phosphorylation of Thr(417) controls the stability of Skp2 and its ability to degrade p27. SIGNOR-259818 0.346 MAPKAPK2 protein P49137 UNIPROT HSPA1L protein P34931 UNIPROT up-regulates activity phosphorylation Ser241 DFDNRLVsHFVEEFK -1 31642047 t done miannu  We demonstrate that MK2 phosphorylates HspA1L solely on Ser241, a residue within the N-terminal nucleotide-binding domain of the enzyme. This phosphorylation event enhances the chaperone activity of HspA1L in vitro and renders male germ cells more resistant to heat stress-induced apoptosis. SIGNOR-273674 0.2 MAPK3 protein P27361 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates phosphorylation Ser197 SATDSDGsPLSNSQP 9606 15632084 t amattioni Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3 SIGNOR-132979 0.849 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273070 0.635 TLK1 protein Q9UKI8 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates activity phosphorylation Ser386 HENGAEDsNVALEKL 9606 BTO:0000007 35064619 t miannu We established that TLK1 phosphorylates MK5 on three residues (S160, S354 and S386), resulting in MK5 activation, and additionally, mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected HEK 293 cells. SIGNOR-276747 0.2 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr165 PSPATDLyQVPPGPG 10090 12972425 t lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs SIGNOR-246385 0.796 ABL1 protein P00519 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Tyr170 LHSEPPVyANLSNFN -1 10637231 t Active nuclear Abl efficiently phosphorylate c-Jun. After phosphorylation of c-Jun by Abl on Tyr170, both proteins interacted via the SH2 domain of Abl. SIGNOR-251428 0.541 GLI2 protein P10070 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates NBK6142 f Whilst shh signalling is required for ventral oligodendrogenesis in the entire central nervous system, Gli2 activity only regulates oligodendrocyte development in the ventral spinal cord. Gli3 plays a nonessential role in ventral oligodendrogenesis during normal development.  SimoneGraziosi SIGNOR-269215 0.7 LPCAT4 protein Q643R3 UNIPROT 1,2-diacyl-sn-glycero-3-phosphocholine chemical CHEBI:57643 ChEBI up-regulates quantity chemical modification 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272770 0.8 KAT5 protein Q92993 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity acetylation Lys3016 VLMRLQEkLKGVEEG 30944854 t lperfetto Here, we report that sirtuin 7 (SIRT7)-mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. |Upon DNA damage, ATM is activated via a series of highly organized machineries, including acetylation by the histone acetyltransferase TIP60 at lysine 3016 SIGNOR-275891 0.793 PHF10 protein Q8WUB8 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270598 0.681 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser464 LLKHVTQsSRKLIRA 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. SIGNOR-129260 0.392 LCK protein P06239 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 BTO:0000782 8114715 t llicata The two sites (y-536 and y-564) which are directly phosphorylated by lck in vitro are also phosphorylated in vivo in lstra cells. One of these sites (y-564) is phosphorylated in t cells in response to lck activation. SIGNOR-36121 0.597 LCK protein P06239 UNIPROT CD33 protein P20138 UNIPROT up-regulates phosphorylation Tyr340 EMDEELHyASLNFHG 9606 10887109 t lperfetto Human cd33 has two tyrosine residues in its cytoplasmic domain (y340 and y358). When phosphorylated, these tyrosines could function as docking sites for the phosphatases, shp-1 and/or shp-2, enabling cd33 to function as an inhibitory receptor. Lck is effective at phosphorylating y340 SIGNOR-78960 0.274 PRKACA protein P17612 UNIPROT DNAJC5 protein Q9H3Z4 UNIPROT unknown phosphorylation Ser10 DQRQRSLsTSGESLY 9606 BTO:0000938 18951872 t gcesareni Csp is phosphorylated in vivo on a single residue, ser10, and this phosphorylation regulates its cellular functions,[...]PKA Phosphorylation of full-length csp protein stimulated 14-3-3 binding, and this was abolished in a ser10-ala mutant csp, confirming the binding site as phospho-ser10 SIGNOR-181788 0.331 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1665 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273066 0.635 DMXL2 protein Q8TDJ6 UNIPROT MADD protein Q8WXG6 UNIPROT up-regulates quantity binding 10116 BTO:0000142 11809763 t miannu We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles. SIGNOR-265581 0.459 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 22492984 t lperfetto Bim, and puma bind with high affinity to all pro-survival proteins SIGNOR-196935 0.826 EGFR protein P00533 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr740 AVCPQAHyNMYPQNP 9606 11751923 t llicata Novel activation of stat5b in response to epidermal growth factor. novel activation of stat5b in response to epidermal growth factor. SIGNOR-113397 0.827 ATM protein Q13315 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser1404 EEIKSQNsQESTADE 9606 12086603 t lperfetto These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint SIGNOR-90113 0.781 MARCHF5 protein Q9NX47 UNIPROT FIS1 protein Q9Y3D6 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 16874301 t miannu MITOL associates with and ubiquitinates mitochondrial fission protein hFis1. (A) Ubiquitination of hFis1 by MITOL. Thus, MITOL may control the protein expression level of hFis1 through the ubiquitin–proteasome pathway. SIGNOR-271896 0.2 8-OH-DPAT chemical CHEBI:73364 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258847 0.8 DSCAML1 protein Q8TD84 UNIPROT AQP9 protein O43315 UNIPROT up-regulates activity binding 9606 BTO:0000938 30745319 t miannu Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels. SIGNOR-264280 0.2 MMP2 protein P08253 UNIPROT Laminin-5 complex SIGNOR-C184 SIGNOR up-regulates activity cleavage 9211848 t lperfetto Induction of Cell Migration by Matrix Metalloprotease-2 Cleavage of Laminin-5|MMP2 cleaved the Ln-5 gamma2 subunit at residue 587, exposing a putative cryptic promigratory site on Ln-5 that triggers cell motility. This altered form of Ln-5 is found in tumors and in tissues undergoing remodeling, but not in quiescent tissues. Cleavage of Ln-5 by MMP2 and the resulting activation of the Ln-5 cryptic site may provide new targets for modulation of tumor cell invasion and tissue remodeling. SIGNOR-253239 0.438 PER1 protein O15534 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267974 0.706 PPP4C protein P60510 UNIPROT ACACA protein Q13085 UNIPROT up-regulates activity dephosphorylation Ser80 LHIRSSMsGLHLVKQ 9606 BTO:0000599 25050742 t PP4 was also found to directly interact with pACC1‑Ser79 in human HepG2 cells. In conclusion, the present study showed that PP4 may be a novel regulator in hepatic lipogenesis through dephosphorylating ACC1 on serine 79, suggesting that PP4 may be a promising therapeutic target in lipid metabolism disorders. SIGNOR-267724 0.244 A9/b1 integrin complex SIGNOR-C166 SIGNOR IL6 protein P05231 UNIPROT up-regulates quantity by expression 9606 24241034 f lperfetto Importantly, autocrine and paracrine interactions of α9β1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-α and IL-1β in synovial macrophages. SIGNOR-253313 0.364 C3 protein P01024 UNIPROT C3AR1 protein Q16581 UNIPROT up-regulates activity binding 9606 cleavage:Arg671;Arg748 QPAARRRrSVQLTEK;ASHLGLArSNLDEDI 8765043 t complement C3a fragment: PRO_0000005910 lperfetto A cDNA clone encoding the human C3a anaphylatoxin receptor (C3aR) was isolated from a pcDNAI/Amp expression library prepared from U-937 cells|The cDNA clone contained an insert of 4.3 kbp and was able to confer to transfected human HEK-293 cells the capacity to bind specifically iodinated human C3a. SIGNOR-263451 0.723 7-[4-[4-(2,3-Dichlorophenyl)-1,4-diazepan-1-yl]butoxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one chemical CID:56593482 PUBCHEM DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 9606 22025698 t Luana Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands.  SIGNOR-258321 0.8 CSNK2B protein P67870 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1112 VPIAVGEsDFENLNT 9606 BTO:0000938 19064667 t lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. SIGNOR-275752 0.2 pictrelisib chemical CHEBI:65326 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 BTO:0000149 21876152 t gcesareni Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed SIGNOR-176295 0.8 A6/b1 integrin complex SIGNOR-C164 SIGNOR POU5F1 protein Q01860 UNIPROT up-regulates quantity by expression 10090 18757303 f lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. SIGNOR-253278 0.396 PLCD4 protein Q9BRC7 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates chemical modification 9606 8395015 t gcesareni Hydrolysis of phosphatidylinositol 4,5-bisphosphate (pip2) by phosphatidylinositol-specific phospholipase c (pi-plc) generates two second messengers, inositol 1,4,5-trisphosphate and 1,2-diacylglycerol. SIGNOR-39041 0.8 PRKCA protein P17252 UNIPROT PLEK protein P08567 UNIPROT up-regulates phosphorylation Ser113 GQKFARKsTRRSIRL 9606 7559487 t miannu Pleckstrin is a substrate for protein kinase c / a combination of phosphopeptide analysis and site-directed mutagenesis shows that three residues in the intervening sequence between the two pleckstrin ph domains become phosphorylated: ser113, thr114, and ser117. /these results suggest that the phosphorylation of at least two of the sites is required for maximal pleckstrin activity SIGNOR-28880 0.284 PRKAA2 protein P54646 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser314 IQEVRSKsDPIMLLK -1 33022274 t miannu AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex SIGNOR-276838 0.2 progesterone smallmolecule CHEBI:17026 ChEBI Corticotropin protein P01189-PRO_0000024969 UNIPROT down-regulates 24631756 f lperfetto ACTH and corticosterone responses to the same acute stress stimulus are higher in the pro-estrus phase of the cycle, when the serum concentrations of estrogen are the highest (Viau and Meaney, 1991). In the same study, it was shown that progesterone inhibits the sensitizing effects of estrogen on ACTH release during stress, as the ACTH levels and HPA output decreased with increasing amounts of progesterone in the estrous and diestrous phases. SIGNOR-268727 0.8 CHD8 protein Q9HCK8 UNIPROT NEUROD4 protein Q9HD90 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 t Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells SIGNOR-268918 0.2 CSNK2A2 protein P19784 UNIPROT KLF1 protein Q13351 UNIPROT up-regulates activity phosphorylation Thr23 ALGPFPDtQDDFLKW 10090 BTO:0004475 9722526 t 2 miannu Regulation of erythroid Krppel-like factor (EKLF) transcriptional activity by phosphorylation of a protein kinase casein kinase II site within its interaction domain. the transactivation capability of EKLF is augmented by co-transfection of CKIIalpha. in vitro assays demonstrate that CKIIalpha interacts with EKLF, and that the EKLF interaction domain is phosphorylated by CKII only at Thr-41 SIGNOR-241365 0.349 AKT proteinfamily SIGNOR-PF24 SIGNOR ITGB3 protein P05106 UNIPROT down-regulates activity phosphorylation Thr779 LYKEATStFTNITYR -1 10896934 t Threonine phosphorylation of the beta 3 integrin cytoplasmic tail, at a site recognized by PDK1 and Akt/PKB in vitro, regulates Shc binding.|We recently observed that phosphorylation of a threonine (Thr-753), six amino acids proximal to tyrosine 759 in beta(3) of the platelet specific integrin alpha(IIb)beta(3), inhibits outside-in signaling through this receptor.| A survey of several protein kinases revealed that Thr-753 was avidly phosphorylated by PDK1 and Akt/PKB in vitro. SIGNOR-251479 0.2 FZD1 protein Q9UP38 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity binding 9606 23151663 t areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  SIGNOR-258952 0.665 CDK8 protein P49336 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Thr119 AGTAGALtPQHVRAH -1 29967145 t miannu CDK8 phosphorylates YAP and promotes its activation. Of interest, mutating four amino acid positions (T119, S128, S289, and S367) to alanines (YAP-4A) completely blocked phosphorylation (Fig. 6J), suggesting that CDK8 phosphorylates these sites in YAP in vitro. SIGNOR-277648 0.327 PRKCA protein P17252 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Thr27 KFRFRKEtNNAAIIM -1 9030586 t lperfetto Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively. SIGNOR-248961 0.327 MAPK1 protein P28482 UNIPROT CEP55 protein Q53EZ4 UNIPROT down-regulates phosphorylation Ser425 NREKVAAsPKSPTAA 9606 16198290 t lperfetto Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis. SIGNOR-140890 0.374 PRKCA protein P17252 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR unknown phosphorylation -1 10366608 t inferred from 70% of family members lperfetto In addition, we identified threonine 830 as a potential PKC phosphorylation site. SIGNOR-269853 0.704 NDUFS8 protein O00217 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. SIGNOR-262182 0.847 RNF4 protein P78317 UNIPROT NFYA protein P23511 UNIPROT up-regulates activity binding 9606 15496512 t miannu Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter. SIGNOR-252229 0.2 GSK3A protein P49840 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 7566348 t fstefani The ability of p42 map and p44 map kinases, glycogen synthase kinases 3 alpha and 3 beta (gsk-3 alpha and gsk-3 beta) to phosphorylate tau in transfected cos cells was investigated. Both gsk-3 alpha and gsk-3 beta phosphorylated tau to produce a phf-like state of phosphorylation but the map kinases failed to induce such a transformation in tau. SIGNOR-29364 0.44 NOTCH4 protein Q99466 UNIPROT HEY2 protein Q9UBP5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12548545 f gcesareni Herp1 appears to be important particularly in the development of vascular tissue, and herp1might be regulated by vascular-specific isoforms of ligands and receptors such as dll4 and notch4 SIGNOR-97630 0.6 zotepine chemical CHEBI:32316 ChEBI HTR1B protein P28222 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0001311 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258554 0.8 RB1CC1 protein Q8TDY2 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR form complex binding 9606 23863160 t lperfetto In mammals, two protein complexes, namely the ULK1-Atg13-FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin–Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation. SIGNOR-209887 0.914 CACNA2D3 protein Q8IZS8 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 27583705 t miannu Our findings showed that increased intracellular calcium (Ca2+ ) mediated by overexpression of CACNA2D3 induced mitochondrial-mediated apoptosis, upregulation of NLK (through the Wnt/Ca2+ pathway) and inhibition of the epithelial-to-mesenchymal transition. SIGNOR-266853 0.8 ARF6 protein P62330 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 14973189 f lperfetto ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface SIGNOR-272154 0.7 ATP6V1H protein Q9UI12 UNIPROT AP-2 complex complex SIGNOR-C245 SIGNOR up-regulates activity binding 10090 BTO:0004122 29782852 t miannu ATP6V1H interacts with TGF-β receptor I and AP-2 complex to regulate the proliferation and differentiation of BMSCs. Lack of ATP6V1H function decreases bone formation in vivo SIGNOR-266887 0.228 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1143 PMGSSHAsQVCSETP 9606 BTO:0002181 11114888 t llicata Of the four potential phosphoacceptor sites in the BRCA1 (1005–1313) fragment (Ser 1143, Ser 1239, Ser 1280, Ser 1298), Ala substitutions at two sites, Ser 1143 and Ser 1280, reduced the in vitro phosphorylation of GST–BRCA1 (1005–1313) by ATR, whereas substitution of Ser 1239 or Ser 1298 with Ala had little or no effect (Fig. 2C; data not shown). A Ser 1143/Ser 1280 double mutant was a poor substrate for ATR, suggesting that these are the two major in vitro phosphorylation sites on this BRCA1 fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication. SIGNOR-250581 0.793 CYP27B1 protein O15528 UNIPROT calcitriol smallmolecule CHEBI:17823 ChEBI up-regulates quantity chemical modification 9606 BTO:0000671 12050193 t lperfetto The rate-limiting, hormonally regulated step in the biological activation of vitamin D is its 1alpha-hydroxylation to 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] in the kidney, catalyzed by the mitochondrial cytochrome P450 enzyme, P450c1alpha. SIGNOR-270559 0.8 UBE2D2 protein P62837 UNIPROT TRIM9 protein Q9C026 UNIPROT up-regulates activity binding 9606 BTO:0000142 20085810 t miannu Collectively, these results indicated that TRIM9 is an E3 ligase for its self-ubiquitination and that the ubiquitination of TRIM9 likely serves as a signal for proteasomal degradation. As shown in Fig. 1A, TRIM9 was ubiquitinated by itself when incubated with UbcH5b. In contrast, ubiquitination was observed when incubated with other E2 enzymes. These results suggest that TRIM9 cooperates with UbcH5b for its self-ubiquitination. N SIGNOR-271420 0.4 GDNF protein P39905 UNIPROT RHOQ protein P17081 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252185 0.2 SNARE_complex complex SIGNOR-C346 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 BTO:0000938 30267828 f miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. The event directly leading to membrane fusion is theassembly of the C-terminal end of the SNARE-complex,and the linker domains, which couples the releasedenergy directly to the fusion of the membranes SIGNOR-263973 0.7 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR TICRR protein Q7Z2Z1 UNIPROT up-regulates activity phosphorylation Ser1001 DIGVVEEsPEKGDEI -1 21646402 t miannu  We found that Treslin also associated with TopBP1 in a Cdk-regulated manner in human cells and that Treslin was phosphorylated within a conserved Cdk consensus target sequence (on S976 in X. laevis and S1000 in humans). Recombinant human Cdk2-cyclin E also phosphorylated this residue of Treslin in vitro very effectively. SIGNOR-273600 0.339 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257983 0.8 CGRRF1 protein Q99675 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002548 31801577 t miannu CGRRF1 ubiquitinates EGFR through K48-linked ubiquitination, which leads to proteasome degradation. SIGNOR-272220 0.2 LCK protein P06239 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 BTO:0000782 17998336 t inferred from 70% of family members gcesareni The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1. SIGNOR-269899 0.2 NBR1 protein Q14596 UNIPROT GABARAPL1 protein Q9H0R8 UNIPROT up-regulates binding 9606 BTO:0000007 19250911 t gcesareni We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family SIGNOR-184264 0.735 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273097 0.745 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity phosphorylation Tyr259 KGRFAEVyKAKLKQN -1 9169454 t lperfetto Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor. SIGNOR-48859 0.2 BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C29 SIGNOR-C29 18756288 t gcesareni Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1. SIGNOR-180545 0.616 ZFYVE26 protein Q68DK2 UNIPROT TTC19 protein Q6DKK2 UNIPROT up-regulates activity binding 9606 BTO:0000567 20208530 t miannu We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B. FYVE-CENT binds directly to TTC19 and KIF13A. SIGNOR-265542 0.474 ROCK1 protein Q13464 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 BTO:0000887;BTO:0001260 8702756 t gcesareni Rho-kinase phosphorylates the mlc of intact myosin and activates its mgatpase activity in a gtp_?Rho-dependent manner. SIGNOR-43031 0.632 GSK3B protein P49841 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Thr254 RQVAIVFRtPPYADPS 10090 BTO:0000249 22761446 t Redundant functions of GSK-3_ and GSK-3_ through phosphorylation of RelA at Thr-254 play a crucial role in early stages of chondrocyte differentiation SIGNOR-255828 0.364 PPP1CC protein P36873 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity dephosphorylation 9606 27629041 t miannu Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival SIGNOR-254119 0.422 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219320 0.749 OGT protein O15294 UNIPROT PFKP protein Q01813 UNIPROT down-regulates activity glycosylation Ser540 VMVPATVsNNVPGSD 9606 BTO:0000018 26399441 t lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. SIGNOR-267583 0.26 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI INSR protein P06213 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192871 0.8 BCL2 protein P10415 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity binding 9606 BTO:0000776;BTO:0000785 8183370 t lperfetto Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax. SIGNOR-36898 0.62 PRKCB protein P05771 UNIPROT TRPV6 protein Q9H1D0 UNIPROT down-regulates activity phosphorylation Thr728 MPSVSRStSRSSANW -1 19805577 t miannu  This regulation requires PKC(betaII) and defined phosphorylation sites within the ARD and the C-terminus. Both regulatory sites act synergistically to constitute a novel mechanism by which ATP stabilizes channel activity and acts as a metabolic switch for Ca(2+) influx. Decreases in ATP concentration or activation of PKC(betaII) disable regulation of the channels by ATP, rendering them more susceptible to inactivation and rundown and preventing Ca(2+) overload. SIGNOR-276266 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR TP53 protein P04637 UNIPROT unknown phosphorylation Ser392 FKTEGPDsD -1 10884347 t llicata Our previous data has shown that cyclin A-cdk2 is the major enzyme responsible for modifying p53 at Ser315 in vivo after irradiation damage and in this report we dissect the mechanism of cyclinA-cdk2 binding to and phosphorylation of p53. SIGNOR-250751 0.803 ARF3 protein P61204 UNIPROT Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 14973189 f lperfetto ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface SIGNOR-272150 0.7 GREB1 protein Q4ZG55 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 30154312 f miannu GREB1 is an early estrogen-responsive gene, and its expression is correlated with estrogen levels in breast cancer patients. Additionally, GREB1 responds to androgen in prostate cancer cells, and can stimulate the proliferation of breast, ovarian, and prostate cancer cells. SIGNOR-265886 0.7 KDM1A protein O60341 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 15620353 t miannu Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription. SIGNOR-264508 0.2 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser379 SKILGETsLMRTLCG 9606 BTO:0000007 18644861 t lperfetto Regulation of chk2 ubiquitination and signaling through autophosphorylation of serine 379.Thus, auto-/transphosphorylation of s379 is required for chk2 ubiquitination and effector function SIGNOR-179537 0.2 GOT1 protein P17174 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-267509 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000763 12193595 t lperfetto Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction. SIGNOR-244731 0.2 DUSP1 protein P28562 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Thr202 HDHTGFLtEYVATRW 10116 7535768 t We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively SIGNOR-248462 0.778 AKT proteinfamily SIGNOR-PF24 SIGNOR DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser143 RTPRRSKsDGEAKPE 9606 21151116 t lperfetto Akt1 kinase colocalizes and directly interacts with dnmt1 and phosphorylates ser143. Phosphorylated dnmt1 peaks during dna synthesis, before dnmt1 methylation. Depletion of akt1 or overexpression of dominant-negative akt1 increases methylated dnmt1, resulting in a decrease in dnmt1 abundance. In mammalian cells, phosphorylated dnmt1 is more stable than methylated dnmt1. SIGNOR-244232 0.2 CDH4 protein P55283 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 10090 18701479 t lperfetto Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS. SIGNOR-253103 0.277 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Thr213 SASFPHTtPSMCLNP 10090 BTO:0000667 17475908 t miannu All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells. SIGNOR-262671 0.2 STK11 protein Q15831 UNIPROT SNRK protein Q9NRH2 UNIPROT up-regulates activity phosphorylation Thr173 QPGKKLTtSCGSLAY 9606 15733851 t Manara We demonstrate that LKB1 activates SNRK by phosphorylating the T‐loop residue (Thr173) SIGNOR-260824 0.375 PRKD1 protein Q15139 UNIPROT ARFIP1 protein P53367 UNIPROT up-regulates phosphorylation Ser132 LELVRKWsLNTYKCT 9606 23695357 t lperfetto We report that arfaptins contain an amphipathic helix (ah) preceding the bar domain, which is essential for their binding to phosphatidylinositol 4-phosphate (pi(4)p)-containing liposomes and the tgn of mammalian cells. The binding of arfaptin1, but not arfaptin2, to pi(4)p is regulated by protein kinase d (pkd) mediated phosphorylation at ser100 within the ah. We also found that only arfaptin1 is required for the pkd-dependent trafficking of chromogranin a by the regulated secretory pathway. SIGNOR-202101 0.394 sirolimus chemical CHEBI:9168 ChEBI LILRB1 protein Q8NHL6 UNIPROT down-regulates quantity by repression 9606 18652845 f miannu Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells. SIGNOR-255476 0.8 CHRM5 protein P08912 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257009 0.2 CDK1 protein P06493 UNIPROT HMGA2 protein P52926 UNIPROT down-regulates phosphorylation Ser59 PKGSKNKsPSKAAQK 9606 10636877 t lperfetto Architecture of high mobility group protein i-c dna complex and its perturbation upon phosphorylation by cdc2 kinase. Phosphorylation by cdc2 reduces binding strength of the mammalian and insect hmgi proteins to dna. After phosphorylation of the protein at ser-43 and ser-58 by cdc2 kinase multiple contacts of dbds, especially with the bases, are impaired and the protein binds to dna in a different way, extending the contacts to the sugar-phosphate backbone. SIGNOR-74098 0.382 SLC44A2 protein Q8IWA5 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 12761501 f Giorgia Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways SIGNOR-260390 0.2 ABL1 protein P00519 UNIPROT TP63 protein Q9H3D4 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr290 RQSVLVPyEPPQVGT 9606 19783996 t Manara In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. SIGNOR-260933 0.524 HNRNPU protein Q00839 UNIPROT ZFY protein P08048 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 f lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. SIGNOR-262287 0.2 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1256 KGCSNEPyFGSLTAL 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t llicata Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate SIGNOR-187851 0.417 SPAG5 protein Q96R06 UNIPROT CENPF protein P49454 UNIPROT up-regulates activity 9606 BTO:0000567 17664331 f lperfetto Furthermore, although both the core kinetochore protein Hec1 and the spindle checkpoint kinase Bub1 were unaffected (Fig. 3 C), the kinetochore resident motor protein CENP-E (Yen et al., 1992) and its interaction partner CENP-F (Chan et al., 1998) were delocalized from the kinetochore in the absence of astrin. These cells remained cyclin B1 positive (unpublished data), confirming that they were still in mitosis. These data suggest that the presence of astrin is required for the kinetochore recruitment or maintenance of CENP-E and CENP-F. SIGNOR-252042 0.344 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0001412 8394219 f We expressed the PML-RARa protein in U937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of different stimuli (vitamin Ds and transforming growth factor pl), acquired enhanced sensitivity to retinoic acid, and exhibited a higher growth rate consequent to diminished apoptotic cell death. SIGNOR-255723 0.7 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7310 ADPKKSAsRPGSRAG 9606 BTO:0004905 21295697 t lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. SIGNOR-264430 0.446 calcium(2+) smallmolecule CHEBI:29108 ChEBI CIB2 protein O75838 UNIPROT up-regulates activity chemical activation 9606 35408910 t miannu Calcium- and integrin-binding protein 2 (CIB2) is a small EF-hand protein capable of binding Mg2+ and Ca2+ ions. SIGNOR-269667 0.8 XRCC3 protein O43542 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 SIGNOR-C301 23438602 t lperfetto We examined the effect of XRCC3 depletion on redistribution of RAD51 upon IR damage|Interestingly, cells expressing the XRCC3 S225A phosphomutant showed compromised chromatin loading of RAD51 upon IR damage (Fig. 4G) while the nuclear and cytosolic fractions of RAD51 were largely unchanged|It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation. SIGNOR-263258 0.738 RPS12 protein P25398 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262440 0.766 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 10090 BTO:0004052 23996074 t irozzo In this work, we have identified and mapped the protein-protein interaction site between DOT1L and MLL fusion proteins, AF9 and ENL.The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). It is known that the recruitment of DOT1L results in hypermethylation of H3K79 on the prominent MLL fusion downstream target loci Hoxa9 and Meis1 SIGNOR-255869 0.2 PCSK7 protein Q16549 UNIPROT ATF6 protein P18850 UNIPROT up-regulates phosphorylation 9606 12076252 t gcesareni We discovered that azc, an agent that causes the formation of abnormal proteins, stimulates the stress-activated kinase p38 mapk, which phosphorylates atf6 SIGNOR-89813 0.2 PPP4C protein P60510 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates activity dephosphorylation Ser1618 LTKAADIsLDNLVEG -1 24703952 t lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |Depletion of PP4C, or PP4R3beta, causes persistence of phospho-T1609 and phospho-S1618 SIGNOR-264451 0.364 PRKCD protein Q05655 UNIPROT LIMK2 protein P53671 UNIPROT down-regulates phosphorylation Ser283 EGTLRRRsLRRSNSI 9606 16820362 t Translocation from Cytosol to Nucleus gcesareni Recently we have shown that limk2 shuttles between cytoplasm and nucleus in endothelial cells and that nuclear import is inhibited by protein kinase c-mediated phosphorylation of ser-283. SIGNOR-147716 0.258 PPP1CA protein P62136 UNIPROT CAD protein P27708 UNIPROT down-regulates activity dephosphorylation Ser1406 CSGAGGRrLSSFVTK -1 4092695 t lperfetto Cyclic AMP-dependent protein kinase phosphorylates two serine residues on the protein termed sites 1 and 2| Site 1: Arg-Leu-Ser(P)-Ser-Phe-Val-Thr-Lys Site 2: Ile-His-Arg-Ala-Ser(P)-Asp-Pro-Gly-Leu-Pro-Ala-Glu-Glu-Pro-Lys | Both phosphorylation and activation can be reversed using purified preparations of the catalytic subunits of protein phosphatases 1- and -2A, and inactivation also correlates better with dephosphorylation of site 1 rather than site 2. SIGNOR-263741 0.337 MSL2 protein Q9HCI7 UNIPROT H2BC21 protein Q16778 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271976 0.2 TGFBI protein Q15582 UNIPROT a7/b1 integrin complex SIGNOR-C126 SIGNOR up-regulates activity binding 26387839 t lperfetto BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers SIGNOR-253266 0.417 PDPK1 protein O15530 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates phosphorylation Thr305 TDAATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t gcesareni The activation of pkbbeta and pkbgamma by pdk1 was accompanied by the phosphorylation of the residues equivalent to thr308 in pkbalpha, namely thr309 (pkbbeta) and thr305 (pkbgamma) SIGNOR-55937 0.637 PRKCG protein P05129 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates phosphorylation Thr115 GTIAKSGtKAFMEAL 9606 24117238 t lperfetto Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity. SIGNOR-202812 0.26 CSNK2A1 protein P68400 UNIPROT CAPZA1 protein P52907 UNIPROT up-regulates phosphorylation Ser9 ADFDDRVsDEEKVRI 9606 15831458 t lperfetto We demonstrate that ser9 of cpalpha is phosphorylated by protein kinase ck2 in vitro, that cpalpha is phosphorylated in vivo. Finally, we demonstrate that ckip-1 and ck2 inhibit the activity of actin capping protein at the barbed ends of actin filaments. SIGNOR-135422 0.2 NFIL3 protein Q16649 UNIPROT IL3 protein P08700 UNIPROT up-regulates quantity by expression transcriptional regulation 9580 7565758 t Luana NF-IL3A transactivates the IL-3 promoter through the A region sequences. SIGNOR-266222 0.542 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr86 YTLSRAQtVVVEYTH 9606 12496252 t lperfetto In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation SIGNOR-96759 0.758 AURKA protein O14965 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser94 SLLSRSSsGYFSFDT 9606 BTO:0002181 23912711 t miannu  We observed that BimEL is phosphorylated by Aurora A early in mitosis and reversed by PP2A after mitotic exit. Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL.  SIGNOR-276248 0.384 AMPK complex SIGNOR-C15 SIGNOR WDR45 protein Q9Y484 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001938 28561066 t miannu WIPI4 is stimulated by AMPK, NUAK2 and BRSK2. This finding is supported by the results of our kinome screening, which identified AMPK and the AMKP-related kinases NUAK2 and BRSK2, all of which function downstream of LKB1 (ref. 69) and stimulate the localization of WIPI4 to nascent autophagosomes. SIGNOR-268480 0.318 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1668 SPSYSPTsPSYSPTS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248772 0.442 PRKCA protein P17252 UNIPROT PLCB1 protein Q9NQ66 UNIPROT unknown phosphorylation Ser887 HSQPAPGsVKAPAKT 10090 BTO:0005065 11278470 t lperfetto . Two-dimensional phosphopeptide mapping and site-directed mutagenesis demonstrated that PKC promoted phosphorylation of PLC beta1 at serine 887 in the nucleus of IGF-I-treated cells. Overexpression of either a PLC beta1 mutant in which the PKC phosphorylation site Ser(887) was replaced by alanine, or a dominant-negative PKC alpha, resulted in a sustained activation of nuclear PLC following IGF-I stimulation. SIGNOR-249081 0.703 SOX4 protein Q06945 UNIPROT DICER1 protein Q9UPY3 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000848 22689055 t .... showed that Sox4 positively regulates Dicer expression by binding to its promoter sequences and enhancing its activity. We found that knockdown of Dicer enhances the matrigel invasion of melanoma cells by at least twofold. In addition, we revealed that overexpression of exogenous Dicer reverts the enhanced melanoma cell invasion upon Sox4 knockdown SIGNOR-258987 0.404 dopamine smallmolecule CHEBI:18243 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-264181 0.8 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CSNK1D protein P48730 UNIPROT up-regulates binding 9606 12000790 t lperfetto Complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45). SIGNOR-227908 0.519 FLT1 protein P17948 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 9398617 t gcesareni We conclude that both flt-1 and kdr have the potential to signal through plc gamma via phosphotyrosine residues located in juxta-membrane and carboxyl tail regions SIGNOR-53743 0.666 MMP10 protein P09238 UNIPROT HAPLN1 protein P10915 UNIPROT down-regulates quantity by destabilization cleavage Leu40 QAENGPHlLVEAEQA -1 7694569 t miannu Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix. SIGNOR-256332 0.329 PRKACA protein P17612 UNIPROT GPKOW protein Q92917 UNIPROT up-regulates activity phosphorylation Thr316 GTASSRKtLWNQELY -1 21880142 t miannu PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites. SIGNOR-266308 0.312 CD40 protein P25942 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 12324477 f gcesareni Cd40 ligation up-regulated bcl-2 and bcl-xl as much as 9.7- (p < 0.01) and 6.8-fold (p < 0.01), respectively (fig. 2, b and c). Under similar conditions, cd27 ligation also up-regulated bcl-2 and bcl-xl as much as 5.0- (p < 0.01) and 3.9-fold (p < 0.01), respectively. SIGNOR-93387 0.437 pazopanib chemical CHEBI:71219 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258262 0.8 NTRK3 protein Q16288 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 BTO:0000938 10092678 t gcesareni We demonstrate that the phosphotyrosine binding domain of frs-2 directly binds the trk receptors at the same phosphotyrosine residue that binds the signaling adapter shc, suggesting a model in which competitive binding between frs-2 and shc regulates differentiation versus proliferation. SIGNOR-65958 0.721 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269346 0.719 EPRS1 protein P07814 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 t miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). SIGNOR-270356 0.2 EED protein O75530 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR form complex binding 9606 23110252 t lperfetto The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48). SIGNOR-241897 0.9 SMAD7 protein O15105 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates activity binding 9534 BTO:0000298 11278251 t miannu Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with TbetaR-I via Smad7, with subsequent enhancement of turnover of TbetaR-I and Smad7.  SIGNOR-272942 0.878 PTPMT1 protein Q8WUK0 UNIPROT 1-(3-sn-phosphatidyl)-sn-glycerol 3-phosphate(3-) smallmolecule CHEBI:60110 ChEBI down-regulates quantity chemical modification 10090 21641550 t lperfetto PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle. We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. Loss of PTPMT1 leads to dramatic diminution of cardiolipin, which can be partially reversed by the expression of catalytic active PTPMT1. Our study identifies PTPMT1 as the mammalian PGP phosphatase and points to its role as a regulator of cardiolipin biosynthesis. SIGNOR-267026 0.8 PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity phosphorylation Tyr762 SDIQRSLyDRPASYK 9823 9546424 t miannu Tyr-762 is an autophosphorylation site in the human platelet-derived growth factor (PDGF) alpha-receptor. Crk proteins associate with phosphorylated Tyr-762 in the PDGF a-receptor in vivo SIGNOR-249716 0.2 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258005 0.8 TBX5 protein Q99593 UNIPROT MTSS1 protein O43312 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20802524 f miannu TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. SIGNOR-255254 0.252 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser276 PQRSRSPsPQPSSHV 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248521 0.387 YY1 protein P25490 UNIPROT FCER1A protein P12319 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000732 11971001 f Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1. The alpha-chain promoter activity was up-regulated approximately 2-fold by exogenously expressed YY1 or PU.1 and approximately 7-fold by GATA-1, respectively, in KU812 cells SIGNOR-254290 0.2 HSP90AA1 protein P07900 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 15861399 t miannu The unliganded AR resides predominately in the cytoplasm as a heteromeric complex with hsp90 and other chaperone proteins. These chaperone proteins maintain AR in a form that is receptive to ligand binding. Regulation of gene expression by androgen-activated AR occurs through receptor nuclear translocation, dimerization, and binding to androgen response elements (AREs) in the DNA of target genes. SIGNOR-251536 0.754 NEDD9 protein Q14511 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity binding 9606 16184168 t miannu HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins. SIGNOR-262653 0.587 zotepine chemical CHEBI:32316 ChEBI HTR1E protein P28566 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0000298 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258557 0.8 HIF1A protein Q16665 UNIPROT KDM1A protein O60341 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271573 0.268 CBLB protein Q13191 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000782 11087752 t miannu Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells.Here it is shown that Cbl-b interacts with and induces ubiquitin conjugation to the p85 regulatory subunit of phosphatidylinositol 3-kinase, an upstream regulator of Vav. SIGNOR-272583 0.496 HOXB8 protein P17481 UNIPROT MYLK protein Q15746 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002196 15886193 t Luana Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively SIGNOR-261640 0.2 CH5132799 chemical CID:49784945 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190952 0.8 ADRA1A protein P35348 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256812 0.295 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr492 ALGADDSyYTARSAG 9606 BTO:0000782 7642520 t lperfetto When expressed in COS cells, Y493F-mutated ZAP-70 demonstrated normal basal kinase activity, but, unlike wild type ZAP-70, could not be activated by tyrosine phosphorylation induced by incubation with pervanadate or by co-expression of constitutively activated Lck SIGNOR-30429 0.602 LRRK2 protein Q5S007 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 BTO:0000938 21658387 t lperfetto Lrrk2 directly phosphorylates akt1 as a possible physiological substrate. These data establish that lrrk2 can protect neurons from apoptotic insult through a survival pathway in which lrrk2 signals to activate akt. Lrrk2-mediated phosphorylation of akt1 (ser473) SIGNOR-244410 0.387 MLL Fusion fusion protein SIGNOR-FP14 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 t miannu Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. SIGNOR-260131 0.2 SRC protein P12931 UNIPROT ARHGEF4 protein Q9NR80 UNIPROT up-regulates phosphorylation Tyr165 VGSEEDLyDDLHSSS 9606 BTO:0000017 18653540 t llicata This observation strongly argues for the positive role of tyr94 phosphorylation in egf-induced asef activation following the activation of rac1. SIGNOR-179601 0.318 ABL1 protein P00519 UNIPROT EPHB2 protein P29323 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 11494128 t lperfetto Two-hybrid screens identified regions of abl and arg that bind to the ephb2 and epha4 receptors, suggesting a novel signaling connection involving the two kinase families.The connection between EphB2 and Abl/Arg appears to be reciprocal. Activated EphB2 causes tyrosine phosphorylation of Abl and Arg, and vice versa. Interestingly, treatment of COS cells and B35 neuronal-like cells with ephrin-B1 to activate endogenous EphB2 decreased the kinase activity of endogenous Abl. SIGNOR-109668 0.498 MYT1 protein Q01538 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005949 30312684 t miannu Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression. Examination of the gene expression changes in cells expressing Myt1 or Myt1l suggests that both repress expression of the YAP1 transcriptional coactivator, which functions primarily in the Hippo signaling pathway. Expression of YAP1 and its target genes is reduced in Myt-expressing cells, and there is an inverse correlation between YAP1 and MYT1/MYT1L expression in human brain cancer datasets. Together, our data suggest that Myt1 and Myt1l directly repress expression of YAP1, a protein which promotes proliferation and GBM growth. SIGNOR-266777 0.2 HOXA13 protein P31271 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16314414 f miannu We show that hoxd13 andhoxa13activate transcription from the epha7 promoter and that a mutation of thehoxa13/hoxd13 binding site was sufficient to abolish activation. SIGNOR-142428 0.295 FFAR1 protein O14842 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257184 0.2 INTS4 protein Q96HW7 UNIPROT DYNC1H1 protein Q14204 UNIPROT up-regulates quantity 9606 BTO:0000567 23904267 f Monia We propose a model in which nuclear localized Integrator complex, including ASUN, mediates 3′-end processing of snRNA, which in turn is required for normal processing of mRNA encoding a key regulator(s) of cytoplasmic dynein localization. When Integrator activity is compromised (e.g., by knockdown of an essential subunit), production of critical transcript(s) during interphase is impaired, leading to reduction of perinuclear dynein at G2/M. SIGNOR-261186 0.2 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT unknown phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 t Within the Jak2 kinase domain, there is a region that has considerable sequence homology to the regulatory region of the insulin receptor and contains two tyrosines, Y1007 and Y1008, that are potential regulatory sites. Y1007 and Y1008 are sites of trans- or autophosphorylation in vivo and in in vitro kinase reactions. Mutation of Y1007, or both Y1007 and Y1008, to phenylalanine essentially eliminated kinase activity, whereas mutation of Y1008 to phenylalanine had no detectable effect on kinase activity SIGNOR-251358 0.2 PPP1CB protein P62140 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 14633703 t Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-248575 0.394 MAPKAPK2 protein P49137 UNIPROT PDE4A protein P27815 UNIPROT down-regulates activity phosphorylation Ser152 SFLYRSDsDYDMSPK 9606 BTO:0000801 21323643 t miannu Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular cAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to cAMP. SIGNOR-263078 0.354 CSNK2B protein P67870 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser29 VSHWQQQsYLDSGIH 9606 BTO:0000007 12432063 t llicata We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin SIGNOR-251065 0.588 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273065 0.635 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD6 protein O43541 UNIPROT down-regulates activity relocalization 9606 22298955 t lperfetto Smurf1, with its WW domain, specifically binds to the PY motif of Smad6 and transports Smad6 into the cytoplasm. SIGNOR-253261 0.2 PTPN1 protein P18031 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2115 DIYKNDYyRKRGEGL 9606 17416557 t gcesareni In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products. SIGNOR-154207 0.381 Obatoclax chemical CID:16681698 PUBCHEM BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 23336025 t gcesareni Bcl-2 inhibitors physically antagonize their anti-apoptotic actions to create a synergistic effect. Numerous compounds have been specifically developed or identified as bcl-2 inhibitors. These compounds include abt-737 and abt-263, obatoclax, gossypol. SIGNOR-200478 0.8 COMMD5 protein Q9GZQ3 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity 9606 30021164 f miannu We found that RhoA activity is decreased following COMMD5 depletion, suggesting that COMMD5 regulates cytoskeleton organization through RhoA signaling.We found that RhoA activity is decreased following COMMD5 depletion, suggesting that COMMD5 regulates cytoskeleton organization through RhoA signaling. However, the dynamics of Rho GTPase activities are highly complex and tightly regulated in order to achieve their specific subcellular localization (Marjoram et al., 2014); thus, the mechanism by which COMMD5 directly or indirectly regulates the activity of RhoA needs to be investigated further. SIGNOR-261690 0.2 TRIM25 protein Q14258 UNIPROT AMFR protein Q9UKV5 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 24810856 t miannu We further demonstrate that TRIM25 ubiquitylates gp78 and that overexpression of TRIM25 accelerates the degradation of gp78. Our data suggest that TRIM25 not only cooperates with gp78 in polyubiquitylation of AMF but also gauges the steady-state level of gp78.  SIGNOR-272176 0.371 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity phosphorylation Ser408 GPLPRAPsISTVEPK 9606 26190112 t Luana AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. SIGNOR-259860 0.339 BAD protein Q92934 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 BTO:0000830 15526160 f miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254953 0.7 C5AR2 protein Q9P296 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263461 0.7 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2L6 protein O14933 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271319 0.634 Nalorphine chemical CHEBI:7458 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258814 0.8 belinostat chemical CHEBI:61076 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257748 0.8 sertindole chemical CHEBI:9122 ChEBI HTR1F protein P30939 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0000298 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258544 0.8 CYBB protein P04839 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264716 0.7 CASP3 protein P42574 UNIPROT SPTAN1 protein Q13813 UNIPROT down-regulates cleavage 9606 BTO:0000150;BTO:0000567 9624143 t amattioni Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis. SIGNOR-57891 0.662 ATM protein Q13315 UNIPROT SP1 protein P08047 UNIPROT unknown phosphorylation Ser101 DLTATQLsQGANGWQ 9606 18619531 t llicata Thus, phosphorylation of ser-101 on sp1 is a general response to dna damage, dependent on both atm and atr. SIGNOR-179435 0.421 CD19 protein P15391 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates 10090 BTO:0000776 25673924 f lperfetto CD19 is a crucial regulator of B cell activation. SIGNOR-242888 0.7 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219345 0.707 S100A8 protein P05109 UNIPROT Calprotectin complex complex SIGNOR-C293 SIGNOR form complex binding 9867828 t lperfetto Using the two-hybrid system we analyzed the dimerization of MRP8 (S100A8) and MRP14 (S100A9), two S100 proteins expressed in myeloid cells. It is reported that the MRP8-MRP14 heteromer is the clearly preferred complex in both man and mouse. SIGNOR-262832 0.718 MAPKAPK2 protein P49137 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser92 RFRDRSFsEGGERLL 9606 18326031 t lperfetto Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation. SIGNOR-161278 0.605 Kindlin proteinfamily SIGNOR-PF48 SIGNOR AX/b2 integrin complex SIGNOR-C171 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259026 0.412 CXCL5 protein P42830 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000584 34237033 f miannu  We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs), and subsequent cancer cell invasion and metastasis. SIGNOR-277733 0.7 CDK1 protein P06493 UNIPROT CSNK2B protein P67870 UNIPROT up-regulates phosphorylation Ser209 QAASNFKsPVKTIR 9606 BTO:0000785 7578274 t lperfetto In cells, the casein kinase ii beta-subunit is phosphorylated at an autophosphorylation site and at a site (ser-209) that is maximally phosphorylated in mitotic cells. These studies provide strong biochemical evidence that p34cdc2 is the enzyme that phosphorylates ser-209 on the beta-subunit of ckii in mitotic cells. SIGNOR-29462 0.471 SEC61 complex complex SIGNOR-C368 SIGNOR SEC63 protein Q9UGP8 UNIPROT up-regulates activity binding 33925740 t lperfetto This is where allosteric effectors of the Sec61 complex (BiP together with Sec62/Sec63 complex or TRAP complex) (Figure 2 and Figure 5) and auxiliary membrane protein insertases (EMC and TMCO1 complex) join the game SIGNOR-265274 0.887 WDR83 protein Q9BRX9 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates binding 9606 15118098 t gcesareni Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex. SIGNOR-124470 0.505 NGFR protein P08138 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14699954 f amattioni Neurotrophin binding to p75ntrhas also been shown to induce apoptosis SIGNOR-120558 0.7 IRS2 protein Q9Y4H2 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9606 22810696 t lperfetto These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients. SIGNOR-251492 0.672 EIF2S1 protein P05198 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 11381086 f miannu Translation initiation is inhibited in cells exposed to different stressful conditions. The phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) plays an important role in this stereotyped response, and is mediated by distinct kinases that are activated by specific stress signals. When phosphorylated on serine 51, eIF2α binds to and inhibits the guanine nucleotide exchange factor, eIF2B. The latter is required for the formation of the eukaryotic translational preinitiation complexes, and its sequestration in an inactive complex with phosphorylated eIF2α inhibits the initiation step of protein synthesis.  SIGNOR-260625 0.7 PGAM proteinfamily SIGNOR-PF78 SIGNOR 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity chemical modification 9606 24786789 t miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. SIGNOR-266516 0.8 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates quantity by stabilization phosphorylation Ser184 QSPRTRGsRRQIQRL 9606 BTO:0000567 19789335 t lperfetto we show that TNFalpha treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser(176) and Ser(184) and Daxx is required for the sustained activation of JNK. Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1. SIGNOR-109684 0.835 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 SIGNOR-C17 10864927 t gcesareni Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-78428 0.852 MTMR3 protein Q13615 UNIPROT 1-phosphatidyl-1D-myo-inositol 3-phosphate(3-) smallmolecule CHEBI:58088 ChEBI down-regulates quantity chemical modification 9606 18429927 t miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns SIGNOR-269810 0.8 sunitinib chemical CHEBI:38940 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 BTO:0000776 20185585 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-163944 0.8 BMP2 protein P12643 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 7791754 t lperfetto Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor. SIGNOR-217532 0.856 PNMT protein P11086 UNIPROT noradrenaline smallmolecule CHEBI:33569 ChEBI down-regulates quantity chemical modification 9606 7961964 t brain lperfetto In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline). SIGNOR-264008 0.8 PIGS protein Q96S52 UNIPROT PIGK protein Q92643 UNIPROT up-regulates activity binding 10090 BTO:0000095 11483512 t miannu To determine roles for PIG-S and PIG-T, we disrupted these genes in mouse F9 cells by homologous recombination. PIG-S and PIG-T knockout cells were defective in transfer of GPI to proteins, particularly in formation of the carbonyl intermediates. We also demonstrate that PIG-S and PIG-T form a protein complex with GAA1 and GPI8, and that PIG-T maintains the complex by stabilizing the expression of GAA1 and GPI8. SIGNOR-261362 0.941 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CASP8 protein Q14790 UNIPROT down-regulates phosphorylation 9606 BTO:0000149 24342355 t inferred from 70% family members lperfetto We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity SIGNOR-270118 0.2 nitric oxide smallmolecule CHEBI:16480 ChEBI Vascular_Permeability phenotype SIGNOR-PH140 SIGNOR up-regulates 9606 BTO:0001176 24078390 f VEGF pathway Gianni After a period of controversial reports, evidence based on eNOS knockout mice and on eNOS-depleted EC established that microvascular hyperpermeability in response to an inflammatory challenge is regulated mainly by endothelial cells through eNOS-derived NO SIGNOR-261947 0.7 CEBPB protein P17676 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates quantity transcriptional regulation 10090 22355693 t These results show that GSK3β is involved in regulating phosphorylation and activation of C/EBPβ and that this transcription factor is required to transactivate srebf1a expression, leading to the early steps of adipogenesis SIGNOR-251645 0.42 PRKACA protein P17612 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates phosphorylation Thr131 LERAKRAtIMSLEDF 9606 BTO:0000142 21677187 t lperfetto Here, we demonstrate that disc1 and pde4 modulate nde1 phosphorylation by camp-dependent protein kinase a (pka) and identify a novel pka substrate site on nde1 at threonine-131 (t131).Since phosphorylated t131 is detectable at multiple subcellular locations (centrosome, nucleus, postsynaptic density, proximal axon), there is potential for disc1/pde4 to influence several important brain processes that critically depend on the nde1/ndel1/lis1 comple SIGNOR-174410 0.374 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17967874 t lperfetto In this study, we show that the increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. SIGNOR-158632 0.838 NTN4 protein Q9HB63 UNIPROT UNC5A protein Q6ZN44 UNIPROT up-regulates binding 9606 12598531 t gcesareni The unc5hs are axon guidance receptors that mediate netrin-1-dependent chemorepulsion, and dependence receptors that mediate netrin-1-independent apoptosis. SIGNOR-98483 0.594 PIK-90 chemical CID:6857685 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206226 0.8 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Thermogenesis phenotype SIGNOR-PH192 SIGNOR up-regulates 9606 24692351 f scontino TH plays a significant role in energy expenditure through both central and peripheral actions. TH maintains basal metabolic rate, facilitates adaptive thermogenesis, modulates appetite and food intake, and regulates body weight. SIGNOR-267491 0.7 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT up-regulates quantity by stabilization phosphorylation Thr243 LDDSTGGtPLTPAAR 9606 BTO:0000007 16682949 t done miannu Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. SIGNOR-274084 0.525 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation 9606 16331690 t The effect has been demonstrated using Q13507-3 llicata The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263. SIGNOR-142964 0.417 HRAS protein P01112 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9534 BTO:0004055 8052307 t lperfetto In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-236443 0.922 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe634 VHHQKLVfFAEDVGS -1 10605825 t lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. SIGNOR-261771 0.502 CDK1 protein P06493 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates phosphorylation Thr412 DTEIANStPNPKPAA 9606 16378098 t gcesareni Here, we report that cdk1 phosphorylates thr 59 and thr 388 on inner centromere protein (incenp), which regulates the localization and kinase activity of aurora-b from prophase to metaphase. The replacement of endogenous incenp with t388a resulted in the delay of progression from metaphase to anaphase. SIGNOR-143387 0.749 MAPK14 protein Q16539 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Thr311 NSLALSLtADQMVSA 9606 12138194 t gcesareni P38 mitogen-activated protein kinase was involved in estrogen receptor activation by estrogens and mekk1. Here, we report estrogen receptor-dependent p38 activation by estrogens in endometrial adenocarcinoma cells and in vitro and in vivo phosphorylation of the estrogen receptor alpha mediated through p38. The phosphorylation site was identified as threonine-311 (thr(311)), located in helix 1 of the hormone-binding domain. SIGNOR-90823 0.61 trichostatin A chemical CHEBI:46024 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257939 0.8 PTPRG protein P23470 UNIPROT PTPRG protein P23470 UNIPROT down-regulates activity binding 9606 25624455 t miannu The main regulatory mechanism of RPTP activity consists of the reversible transition from a homodimeric inactive form to a monomeric active form. PTPRG is constitutively expressed on monocyte plasma membrane as a homodimer with the WD involved in catalytic domain blockade. SIGNOR-254737 0.2 PRKACA protein P17612 UNIPROT MCOLN1 protein Q9GZU1 UNIPROT down-regulates phosphorylation Ser559 KFRRGSGsACSLLCC 9606 17988215 t llicata The stimulatory effect of h89 on mcoln1 function was not observed when ser(557) and ser(559) were mutated to alanine residues, indicating that these two residues are essential for pka-mediated negative regulation of mcoln1. SIGNOR-158950 0.2 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser163 KRFSFKKsFKLSGFS -1 1560845 t gcesareni Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin SIGNOR-249650 0.719 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT2 protein P31751 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000782 25336630 t miannu stimulations were performed in the presence or absence of Akt inhibitor VIII, which selectively inhibits Akt1/Akt2 activity. SIGNOR-262228 0.8 SRC protein P12931 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates phosphorylation Tyr284 KIFPYEEyASWKTEK 9606 19114990 t gcesareni Tbetarii can also be phosphorylated by src, a non-rtk, on y284, which can serve as a docking site for the recruitment of grb2 and shc, thereby bridging tbetarii to mapk activation. SIGNOR-182963 0.285 F2R protein P25116 UNIPROT SDC4 protein P31431 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254852 0.2 Tifluadom chemical CHEBI:9591 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 9262330 t miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. SIGNOR-258665 0.8 MMP2 protein P08253 UNIPROT HAPLN1 protein P10915 UNIPROT down-regulates quantity by destabilization cleavage His31 LDHDRAIhIQAENGP -1 7694569 t miannu Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix. SIGNOR-256327 0.345 ARID5B protein Q14865 UNIPROT PHF2 protein O75151 UNIPROT up-regulates activity binding 9606 BTO:0000007 21532585 t miannu We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity. SIGNOR-264515 0.542 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PAX5 protein Q02548 UNIPROT down-regulates activity phosphorylation Ser189; Ser283 SGILGITsPSADTNK;DMKANLAsPTPADIG 9606 BTO:0003079 22593617 t Gianni In this study, we demonstrated that PAX5 was phosphorylated by ERK1/2 in vitro and in vivo at serines 189 and 283. This phosphorylation attenuated the transcriptional repression of BLIMP1 by PAX5. SIGNOR-269088 0.2 BCOR protein Q6W2J9 UNIPROT HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 26847029 f irozzo Importantly, our results showed that BCOR is a repressor of HoxA cluster of genes (HoxA5, HoxA7 and HoxA9) in myeloid cells. Knock-down of HoxA5, HoxA7 and HoxA9 significantly decreased the clonogenic growth of Bcor mutant and wild type cells, demonstrating the Hox genes, as targets of BCOR, played an important role in mediating BCOR’s function in regulating myeloid cell proliferation. SIGNOR-256014 0.253 RTKs proteinfamily SIGNOR-PF38 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 17306385 t miannu Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase SIGNOR-256166 0.2 SEC23B protein Q15437 UNIPROT UBA52 protein P62987 UNIPROT unknown binding 30605680 t lperfetto We validate the genotype-specific differential SEC23B–UBA52 (ribosomal protein RPL40) interaction. SIGNOR-265305 0.2 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser358 WPLSRTRsEPLPPSA 9606 BTO:0000782 15623513 t lperfetto Protein kinase d1 (pkd1) was activated after tcr engagement, interacted with hdac7, and phosphorylated three serines (ser155, ser318, and ser448) at its n terminus, leading to its export from the nucleus. SIGNOR-132898 0.491 SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding -1 10713164 t llicata SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function. SIGNOR-237617 0.585 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RAD9A protein Q99638 UNIPROT unknown phosphorylation Ser328 VLPSISLsPGPQPPK 9606 23028682 t lperfetto The forced activation of cyclin a-cdk2 in these cells by the overexpression of cyclin a,triggered rad9 phosphorylation at serine 328 and thereby promoted the interaction of rad9 with bcl-xl and the subsequent initiation of the apoptotic program. SIGNOR-217268 0.41 HIC1 protein Q14526 UNIPROT ACKR3 protein P25106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23340301 f miannu we showed that CXCR7 promoter in prostate cancer cells is negatively regulated by HIC1, which may be responsible for prostate cancer progression. SIGNOR-254238 0.289 GSK3B protein P49841 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation Ser298 ACSSAPGsGPSSPNN 9606 21118993 t lperfetto The double mutation of serines 298/302 into alanines, but also the sole mutation of serine 302, abolishes hdac4 phosphorylation by gsk3_we have shown that cells lacking gsk3_ are unable to degrade hdac4 after serum starvation SIGNOR-170144 0.371 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT up-regulates activity phosphorylation Tyr185 KQCEQAVyQTILEED 10090 BTO:0000938 11279201 t lperfetto Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons. SIGNOR-247072 0.43 RABGGTA protein Q92696 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity lipidation 9606 BTO:0000007 18532927 t miannu Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional SIGNOR-265574 0.551 MUSK protein O15146 UNIPROT DOK7 protein Q18PE1 UNIPROT up-regulates activity phosphorylation Tyr395 CLPGTVEyQVPTSLR 10090 BTO:0000165 20603078 t miannu Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes. SIGNOR-273845  0.745 PTPRG protein P23470 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254726 0.311 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser487 AAISRELsEITTAEA 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression. SIGNOR-183688 0.627 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 BTO:0004136 10208431 t miannu The AML1/ETO fusion protein is essential to the development of t(8;21) acute myeloid leukemia (AML) and is well recognized for its dominant-negative effect on the coexisting wild-type protein AML1. On physical interaction, AML1/ETO can form a complex with wild-type AML1 on chromatin, and the runt homology domain of both proteins are responsible for their interactions. More importantly, the relative binding signals of AML1 and AML1/ETO on chromatin determine which genes are repressed or activated by AML1/ETO. Further analysis of coregulators indicates that AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex. AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex SIGNOR-260094 0.2 KAT2A protein Q92830 UNIPROT H3C15 protein Q71DI3 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269601 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates binding 9606 15048128 t gcesareni Pkb inhibits smad3 by preventing its phosphorylation, binding to smad4 and nuclear translocation. [...] Regulation of smad3 by pkb occurs through a kinase-activity-independent mechanism, resulting in a decrease in smad3-mediated transcription and protection of cells against tgf-beta-induced apoptosis. SIGNOR-252345 0.2 MRPS9 protein P82933 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261438 0.771 CSNK2A1 protein P68400 UNIPROT DEK protein P35659 UNIPROT up-regulates phosphorylation Ser32 MPGPREEsEEEEDED 9606 15199154 t amattioni Dek is phosphorylated by the protein kinase ck2 in vitro and in vivo on ser32 SIGNOR-125912 0.356 FCN2 protein Q15485 UNIPROT MASP1 protein P48740 UNIPROT up-regulates activity binding 9606 BTO:0000392 11907111 t lperfetto H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. These results indicate that H-ficolin is a second ficolin which is associated with MASPs and sMAP, and which activates the lectin pathway|Proteolytic activation of complement components by H-ficolin-MASP. SIGNOR-263411 0.78 JNK proteinfamily SIGNOR-PF15 SIGNOR ANXA3 protein P12429 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000608 26095609 f miannu ANXA3 Induces a Feed-Forward Loop that Is Mediated by the MKK4/JNK Signaling Cascade. To substantiate the importance of the JNK/AP-1 pathway in ANXA3-driven HCC, we performed rescue experiments using the JNK-specific inhibitor (JNKi) SP600125. JNKi suppressed the oncogenic properties conferred by ANXA3 overexpression, as evidenced by the diminished abilities of HCC cells to form colonies, migrate, invade, induce angiogenesis, form hepatospheres, and resist apoptosis and chemotherapy (Figures 6F–6J). Interestingly, treatment of parental HCC cells or HCC cells overexpressing ANXA3 with JNKi resulted in not only a reduction in JNK activity and modulation of downstream target genes (c-MYC and p21) but also a marked decrease in ANXA3 expression, suggesting that ANXA3 induces a feed-forward loop that is mediated by MKK4/JNK signaling (Figures 6K–6L). SIGNOR-262216 0.2 SLC2A1 protein P11166 UNIPROT glucose chemical CHEBI:17234 ChEBI up-regulates quantity relocalization 9606 23506862 t miannu GLUT1 plays a critical role in cerebral glucose uptake as the major GLUT isoform expressed in brain endothelial cells. SIGNOR-267460 0.8 PTPN12 protein Q05209 UNIPROT GIT2 protein Q14161 UNIPROT down-regulates dephosphorylation Tyr286 EELAMDVyDEVDRRE 9606 16317044 t fspada Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest. SIGNOR-142711 0.351 SOX8 protein P57073 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000410 32550913 t miannu We showed for the first time that Aurora-A interacts directly with SOX8 and phosphorylates the protein at Ser327 to further regulate the SOX8/FOXK1 axis, which modulates cell senescence and glycolysis, ultimately leading to cisplatin resistance.. Our results showed that SOX8 targets FOXK1, thereby regulating its transcription, which has significant impacts on senescence, glycolysis and chemoresistance in ovarian cancer. SIGNOR-273613 0.293 NR3C1 protein P04150 UNIPROT KLF5 protein Q13887 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 t We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα SIGNOR-256118 0.296 Caspase 3 complex complex SIGNOR-C221 SIGNOR STK4 protein Q13043 UNIPROT up-regulates activity cleavage Asp349 RVASTMTdGANTMIE 9534 BTO:0004055 11517310 t lperfetto In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus. SIGNOR-256445 0.601 SCN1A protein P35498 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. SIGNOR-253448 0.7 MAPK3 protein P27361 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation Ser505 LNTSYPLsPLSDFAT 9606 8381049 t gcesareni Activated map kinase phosphorylates cpla2 at ser-505, causing increased enzymatic activity of cpla2, which is only realized upon translocation of cpla2 to the membrane. SIGNOR-38434 0.644 GRK2 protein P25098 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 15843435 t llicata Grk2 phosphorylates glutathione s-transferase (gst)-ezrin, but not an ezrin fusion protein lacking threonine 567 (t567), in vitro. These results suggest that t567, the regulatory phosphorylation site responsible for maintaining ezrin in its active conformation, represents the principle site of grk2-mediated phosphorylation. SIGNOR-135622 0.2 PKN2 protein Q16513 UNIPROT MEFV protein O15553 UNIPROT down-regulates activity phosphorylation Ser242 SGKMRPRsLEVTIST 10090 BTO:0004732 27270401 t no miannu PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. SIGNOR-275463 0.356 NCOA4 protein Q13772 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 10347167 t miannu We demonstrated that ara70 and ar physically interact and that ara70 can function as an androgen-dependent coactivator for ar. SIGNOR-67684 0.855 TRADD protein Q15628 UNIPROT TRAF5 protein O00463 UNIPROT up-regulates binding 9606 19632174 t gcesareni Upon stimulation of the tumor necrosis factor receptor1 (tnfr1), tnf-receptor-associated death domain (tradd) provides a scaffold for the assembly of complex i at the plasma membrane by binding receptor interacting protein 1 (rip1), tnfreceptor-associated factor 2 ,traf2. SIGNOR-187058 0.595 LEF1 protein Q9UJU2 UNIPROT OCA2 protein Q04671 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22234890 f miannu the SNP rs12913832 has strong statistical association with human pigmentation. It is located within an intron of the nonpigment gene HERC2, 21 kb upstream of the pigment gene OCA2, and the region surrounding rs12913832 is highly conserved among animal species.In darkly pigmented human melanocytes carrying the rs12913832 T-allele, we detected binding of the transcription factors HLTF, LEF1, and MITF to the HERC2 rs12913832 enhancer, and a long-range chromatin loop between this enhancer and the OCA2 promoter that leads to elevated OCA2 expression. SIGNOR-254555 0.255 PPP2CA protein P67775 UNIPROT PRKCB protein P05771-2 UNIPROT down-regulates activity dephosphorylation Thr641 TRHPPVLtPPDQEVI 10116 8749392 t Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme. SIGNOR-248622 0.434 COMT protein P21964 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-263997 0.8 PPP4C protein P60510 UNIPROT BANF1 protein O75531 UNIPROT up-regulates dephosphorylation Ser4 sQKHRDFV 9606 24265311 t lperfetto Herein, we demonstrate we demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. We have identified the major phosphatase responsible for dephosphorylation of ser-4 to be protein phosphatase 4 catalytic subunit. SIGNOR-203281 0.2 ATG13 protein O75143 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR form complex binding 9606 23863160 t lperfetto In mammals, two protein complexes, namely the ULK1-Atg13-FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin–Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation. SIGNOR-209884 0.916 CSNK2A2 protein P19784 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation Ser149 RRGASDLsSEEGWRL -1 8954982 t llicata Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149. SIGNOR-251035 0.329 GRB2 protein P62993 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 BTO:0001271 8402896 t GRB2 binds BCR-ABL with SH2 domain gcesareni We demonstrate that bcr-abl exists in a complex with grb-2 in vivo. Binding of grb-2 to bcr-abl is mediated by the direct interaction of the grb-2 sh2 domain with a phosphorylated tyrosine, y177, within the bcr first exon. SIGNOR-39049 0.562 CTDSP1 protein Q9GZU7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000007 17035229 t SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248795 0.494 CCR2 protein P41597 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 20219869 t areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. SIGNOR-255117 0.336 DBH protein P09172 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI down-regulates quantity chemical modification 10090 7961964 t brain lperfetto Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway. SIGNOR-264005 0.8 RASA1 protein P20936 UNIPROT HRAS protein P01112 UNIPROT down-regulates binding 9606 9219684 t gcesareni The three-dimensional structure of the complex between human h-ras bound to guanosine diphosphate and the guanosine triphosphatase (gtpase)-activating domain of the human gtpase-activating protein p120gap (gap-334) in the presence of aluminum fluoride was solved at a resolution of 2.5 angstroms. SIGNOR-49477 0.842 POFUT1 protein Q9H488 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 12909620 t Fucosylation gcesareni Notch_ is modified in its epidermal growth factor-like domains by the addition of_ fucose_ to serine or threonine residues. O-fucosylation is mediated by protein o-fucosyltransferase 1 and down-regulation of this enzyme by rna interference or mutation of the ofut1 gene in drosophila or by mutation of the pofut1 gene in mouse prevents notch signaling. SIGNOR-104627 0.735 IKK-complex complex SIGNOR-C14 SIGNOR CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000661 15870263 t gianni In response to cellular stimuli, CYLD undergoes rapid and transient phosphorylation, which is required for signal-induced TRAF2 ubiquitination and activation of downstream signaling events. Interestingly, the CYLD phosphorylation requires IkappaB kinase gamma (IKKgamma) and can be induced by IKK catalytic subunits. SIGNOR-266435 0.615 P4HB protein P07237 UNIPROT Collagen proteinfamily SIGNOR-PF103 SIGNOR up-regulates quantity by stabilization binding 9606 9545296 t miannu We also show that PDI associates independently with the C-propeptide of monomeric procollagen chains prior to trimer formation, indicating a role for this protein in coordinating the assembly of heterotrimeric molecules. This demonstrates that PDI has multiple functions in the folding of the same protein, that is, as a catalyst for disulfide bond formation, as a subunit of P4-H during proline hydroxylation, and independently as a molecular chaperone during chain assembly. SIGNOR-269731 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR SLBP protein Q14493 UNIPROT down-regulates quantity by destabilization phosphorylation Thr62 RRPESFTtPEGPKPR 9606 BTO:0000567 18490441 t lperfetto Phosphorylation of threonine 61 by cyclin a/Cdk1 triggers degradation of stem-loop binding protein at the end of S phase SIGNOR-265259 0.421 ATF4 protein P18848 UNIPROT CARS1 protein P49589 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269416 0.2 GRK1 protein Q15835 UNIPROT GRK1 protein Q15835 UNIPROT down-regulates activity phosphorylation Ser491 IQDVGAFsTVKGVAF -1 1527025 t The major autophosphorylation site yielded the following sequence: DVGAFS488T489VKGVAFEK, where Ser488 and Thr489 are phosphorylated. Additionally, a minor autophosphorylation site was identified at Ser21. we speculate that autophosphorylation of RK may lower the affinity of the enzyme for Rho* via repulsion between phosphorylated sites on Rho* and the kinase. SIGNOR-251187 0.2 SPAG9 protein O60271 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity binding 9606 BTO:0000222 17074887 t Activation of p38alpha/beta MAPK in myogenesis via binding of the scaffold protein JLP lperfetto Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants. SIGNOR-149979 0.543 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr128 SKAQQGLyQVPGPSP 9606 12601080 t lperfetto Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas. SIGNOR-98488 0.259 ATP7B protein P35670 UNIPROT copper(1+) smallmolecule CHEBI:49552 ChEBI up-regulates quantity relocalization 24706876 t lperfetto WD is caused by mutations in ATP7B, a transporter that loads Cu(I) onto newly synthesized cupro-enzymes in the trans-Golgi network (TGN) and exports excess copper out of cells by trafficking from the TGN to the plasma membrane. SIGNOR-272297 0.8 PEBP1 protein P30086 UNIPROT RAF1 protein P04049 UNIPROT down-regulates binding 9606 10490027 t gcesareni Suppression of raf-1 kinase activity and map kinase by rkip. Rkip binds to raf-1, mek and erk, but not to ras. SIGNOR-70838 0.753 (R)-carnitine smallmolecule CHEBI:16347 ChEBI O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity precursor of 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267117 0.8 Elongator complex complex SIGNOR-C466 SIGNOR TUBA3C protein P0DPH7 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 t miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. α-Tubulin Acetylation Promotes Radial Migration and Branching of Cortical Projection Neurons SIGNOR-269716 0.254 PRKCA protein P17252 UNIPROT ACO1 protein P21399 UNIPROT down-regulates phosphorylation Ser711 REFNSYGsRRGNDAV 9606 BTO:0000671 15636585 t gcesareni Irp1 ser-711 is a phosphorylation site, critical for regulation of rna-binding and aconitase activities. SIGNOR-133188 0.2 ITGB1 protein P05556 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253186 0.679 POU2F1 protein P14859 UNIPROT IL4 protein P05112 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 11781715 f Here we show that NFAT proteins are unable to bind to a combined octamer/NFAT site unless the octamer proteins are competed away SIGNOR-254505 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR PDZK1 protein Q5T2W1 UNIPROT up-regulates activity phosphorylation Ser505 MAKERAHsTASHSSS 10029 BTO:0000457 16174736 t done miannu Metabolic labeling experiments and phosphoamino acid analysis revealed that PDZK1 is phosphorylated at Ser residues within this region. Point-mutation analysis demonstrated that PDZK1 is phosphorylated at Ser-509. Interestingly, a mutant PDZK1, in which Ser-509 was replaced with Ala, lost the ability to up-regulate SR-BI protein. SIGNOR-273784 0.2 PPP1CA protein P62136 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates dephosphorylation 9606 BTO:0001271 21750978 t miannu Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway SIGNOR-174859 0.282 MAP2K6 protein P52564 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates phosphorylation Thr183 RQADSEMtGYVVTRW 9606 19230643 t gcesareni Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily . the p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms . p38mapks are activated by dual phosphorylation on a t-x-y motif in the activation loop through the action of map kinase kinases SIGNOR-184134 0.645 ROCK1 protein Q13464 UNIPROT MYL12A protein P19105 UNIPROT up-regulates activity phosphorylation Ser19 KRPQRATsNVFAMFD 9606 BTO:0000567 12185584 t miannu Phosphorylation of myosin II regulatory light chain (MRLC) is important for cell motility and cytokinesis in nonmuscle cells. Although the regulation of monophosphorylated MRLC at serine 19 throughout the cell cycle was examined in detail, MRLC diphosphorylation at both threonine 18 and serine 19 is still unclear. Here we found that Rho-kinase has an activity for MRLC diphosphorylation in nonmuscle cells using sequential column chromatographies. we showed that the inhibition of Rho-kinase reduced diphosphorylated MRLC in the center of cells even in the presence of phosphatase inhibitor, suggesting that Rho-kinase directly diphosphorylates MRLC (red arrow in Figure 6). Taken together, we propose a model of diphosphorylation of MRLC through dual pathways of both the direct phosphorylation and the inhibition of myosin phosphatase by Rho-kinase (Figure 6). SIGNOR-263073 0.554 ZFHX3 protein Q15911 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11314020 f miannu We investigated AFP gene regulation in AFP-GC by an active transcription factor, HNF1 (hepatocyte nuclear factor 1) and a repressive transcription factor, ATBF1 (AT motif binding factor 1). CAT assays showed the direct inhibition of AFP gene expression by ATBF1. SIGNOR-254436 0.426 SMARCD1 protein Q96GM5 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270694 0.787 MAD2L1BP protein Q15013 UNIPROT MCC complex SIGNOR-C382 SIGNOR down-regulates quantity by destabilization binding 9606 BTO:0000567 25092294 t miannu We have indeed showed that TRIP13 action to disassemble the Cdc20–Mad2 complex requires the presence of p31comet (Fig. 3A). We furthermore found that the joint action of TRIP13 and p31comet is also required for the release of Mad2 from MCC, for the complete disassembly of MCC and for relieving APC/C from checkpoint inhibition (Figs. 3 and ​and4).4). SIGNOR-265979 0.474 LIF protein P15018 UNIPROT MYH7 protein P12883 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 10212267 f Regulation of expression miannu Increase of protein synthesis rate and β-MHC gene expression in cardiac myocytes by ET-1 and LIF. SIGNOR-251959 0.2 TRIM28 protein Q13263 UNIPROT FBP1 protein P09467 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000594 28394358 t lperfetto In this study, we demonstrated that the tripartite motif-containing protein 28 (TRIM28) binds directly to and promotes FBP1 for ubiquitination and degradation. MAGE-A3 and MAGE-C2, which are known to be overexpressed in HCC, can enhance TRIM28-dependent degradation of FBP1 by forming ubiquitin ligase complexes with TRIM28. SIGNOR-267591 0.314 IKBKB protein O14920 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser32 LLDDRHDsGLDSMKD 11815618 t lperfetto Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. The phosphorylation of I_Balpha on Ser32 and Ser36 is initiated by an IkapapB kinase (IKK) complex that includes a catalytic heterodimer composed of I_B kinase 1 (IKK-1) and IkapapB kinase 2 (IKK-2) as well as a regulatory adaptor subunit, NF-kappaB essential modulator. SIGNOR-249365 0.92 APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates binding 9606 9390557 t gcesareni During apoptosis, apaf-1 binds to cytochrome c and in the presence of atp/datp forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 .in particular, caspase-9 is recruited and activated by apaf-1 .casp9 and apaf-1 bind to each other via their respective nh2-terminal ced-3 homologous domains in the presence of cycs and datp, an event that leads to casp9 activation. SIGNOR-53579 0.953 GLI2 protein P10070 UNIPROT IFITM5 protein A6NNB3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23530031 f miannu Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation. SIGNOR-254217 0.2 DLX3 protein O60479 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17060321 f gcesareni Here we show that bmp2 induces dlx3, a homeodomain protein that activates runx2 gene transcription. Small interfering rna knockdown studies in osteoblasts validate that dlx3 is a potent regulator of runx2. SIGNOR-150177 0.407 DDHD2 protein O94830 UNIPROT 1-acyl-sn-glycerol 3-phosphate smallmolecule CHEBI:16975 ChEBI up-regulates quantity chemical modification 9606 22922100 t miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. SIGNOR-269655 0.8 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Ser731 DPLPPVFsGTPKGSG 9606 BTO:0000567 20667468 t miannu Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803. SIGNOR-259821 0.2 ITGB1BP1 protein O14713 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257642 0.756 HIF1A protein Q16665 UNIPROT NT5E protein P21589 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000414 12370277 f miannu Examination of the CD73 gene promoter identified at least one binding site for hypoxia-inducible factor-1 (HIF-1) and inhibition of HIF-1alpha expression by antisense oligonucleotides resulted in significant inhibition of hypoxia-inducible CD73 expression SIGNOR-254423 0.296 SMARCC1 protein Q92922 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269824 0.83 SLC16A4 protein O15374 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 26384349 f lperfetto Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival. SIGNOR-256582 0.7 TICAM1 protein Q8IUC6 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 BTO:0000007 14530355 t lperfetto Toll/il-1 receptor domain-containing adaptor inducing ifn-beta (trif) associates with tnf receptor-associated factor 6 and tank-binding kinase 1, and activates two distinct transcription factors, nf-kappa b and ifn-regulatory factor-3, in the toll-like receptor signaling SIGNOR-118458 0.814 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000142 10226025 t acerquone Protein kinase b (pkb) is activated by phosphorylation of thr308 and of ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (pdk1) but the identity of the kinase that phosphorylates ser473 (provisionally termed pdk2) is unknown. SIGNOR-67363 0.737 TLRs proteinfamily SIGNOR-PF20 SIGNOR TIRAP protein P58753 UNIPROT up-regulates activity binding 9606 20404851 t lperfetto These differences are explained by the discovery of TIR domain’containing adaptor molecules, including MyD88, TIRAP (Mal), TRIF and TRAM, which are recruited by distinct TLRs and activate distinct signaling pathways SIGNOR-216298 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 f apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255355 0.569 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259019 0.408 F2RL1 protein P55085 UNIPROT WWOX protein Q9NZC7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). SIGNOR-254854 0.2 SDCBP protein O00560 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9534 BTO:0001444 25122212 f Luana Overall, these results support the hypothesis that the interaction of E protein PBM with syntenin facilitates the recruitment of syntenin in the cytosol and leads to p38 MAPK activation. SIGNOR-260753 0.2 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 7737130 t gcesareni Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro. SIGNOR-32433 0.686 FYN protein P06241 UNIPROT CD79A protein P11912 UNIPROT up-regulates activity phosphorylation Tyr199 NLDDCSMyEDISRGL -1 9531288 t Lyn and Fyn phosphorylated the CD79a cytoplasmic portion of the fusion proteins well, with >80% of phosphorylation occurring at Y182. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM). SIGNOR-251153 0.579 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr585 PPGLEYCyNPSHNPE 10116 19224897 t lperfetto Autophosphorylation of Y653 is followed by the ordered autophosphorylation of several key tyrosine residues within binding sites for the SH2 or PTB domains of signaling proteins that bind to and are phosphorylated by activated FGFR1. This second-stage autophosphorylation occurs on Y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of Y463 in the juxtamembrane region, Y766 in the C-terminal tail, and Y585 in the kinase insert region SIGNOR-235682 0.2 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Ser677 QMQPDTTsVVKDSQV 9606 19120698 t llicata Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity SIGNOR-183022 0.2 CDKN1A protein P38936 UNIPROT CDK2 protein P24941 UNIPROT down-regulates binding 9606 BTO:0000222 16982699 t gcesareni Considering that akt1 phosphorylates p21, this dissociation likely results from phosphorylation of p21 and release of cdk2. SIGNOR-149711 0.953 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser173 MLETLSQsPPKGVTI 10090 BTO:0000664 17475908 t miannu All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells. SIGNOR-262668 0.2 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser637 VDLSKVTsKCGSLGN -1 9199504 t miannu Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective. SIGNOR-250085 0.505 CAV1 protein Q03135 UNIPROT SLC1A6 protein P48664 UNIPROT down-regulates activity binding 9606 BTO:0000938 26690923 t miannu EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers. SIGNOR-264810 0.2 TNF protein P01375 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253489 0.26 LEO1 protein Q8WVC0 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR form complex binding 9606 BTO:0000567 20178742 t miannu Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A).  SIGNOR-269832 0.937 PRKACA protein P17612 UNIPROT PTPN11 protein Q06124 UNIPROT down-regulates activity phosphorylation Thr73 YGGEKFAtLAELVQY 9606 BTO:0002181 25802336 t miannu  We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.  SIGNOR-276891 0.428 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT down-regulates activity phosphorylation Ser11 SGFESYGsSSYGGAG -1 9295339 t lperfetto We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13 SIGNOR-248980 0.597 NUMA1 protein Q14980 UNIPROT TUBG1 protein P23258 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-117203 0.602 RBPJ protein Q06330 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates quantity by repression transcriptional regulation 23729744 f apalma In the absence of NICD, CSL forms complexes with a variety of co-repressors to suppress the transcription of Notch target genes SIGNOR-255373 0.949 MAPK8 protein P45983 UNIPROT ARHGAP8 protein P85298 UNIPROT up-regulates activity phosphorylation Ser455 TKPTLPPsPLMAARR 28092672 t lperfetto Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation. SIGNOR-275550 0.333 MBTPS2 protein O43462 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates activity cleavage 10029 BTO:0000246 10419520 t In order to activate transcription, the NH2-terminal domain of the SREBP must be released from the membrane so that it can enter the nucleus. This release has been studied most extensively for one of the SREBPs, namely, SREBP-2. However, the mechanism appears to be similar for the other SREBPs (SREBP-1a and -1c) (1). Release of the NH2-terminal domain is accomplished by a two-step proteolytic event that is regulated by sterols (3). In sterol-depleted mammalian cells, this proteolysis is initiated by the Site-1 protease (S1P), which cleaves human SREBP-2 between the Leu522-Ser523 bond in the sequence RSVL S (4). This cleavage requires formation of a complex between SREBP and SCAP, a polytopic membrane protein of the ER, and it is prevented when this complex is disrupted SIGNOR-267498 0.66 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Ser371 VRRVPGSsGHLHKTE 9606 17190791 t gcesareni Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1). SIGNOR-151667 0.457 RELA protein Q04206 UNIPROT MET protein P08581 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0002895 19530226 t gcesareni Together, these results indicate that the Met gene is a direct target of NFkappaB and that Met participates in NFkappaB-mediated cell survival. SIGNOR-241929 0.253 SNAI1 protein O95863 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15311212 f miannu known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT. SIGNOR-255156 0.749 cyproterone acetate chemical CHEBI:50743 ChEBI AR protein P10275 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191235 0.8 MEIS2 protein O14770 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 21746878 t miannu We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. SIGNOR-267242 0.2 MRPL18 protein Q9H0U6 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262376 0.628 UBE2E3 protein Q969T4 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates quantity by stabilization sumoylation Lys21 EGPRDGLkKERLLDD 9606 BTO:0000007;BTO:0000567 10582246 t lperfetto In the presence of an E1 SUMO-1-activating enzyme, Ubch9 conjugated SUMO-1 to IkappaBalpha primarily on K21, which is also utilized for ubiquitin modification. Thus, SUMO-1-modified IkappaBalpha cannot be ubiquitinated and is resistant to proteasome-mediated degradation.  SIGNOR-270545 0.353 PRKCZ protein Q05513 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates quantity by destabilization phosphorylation Ser249 ARTFSRMsLLHKHQE 9606 BTO:0001939 30804505 t miannu APKC kinases phosphorylate S249 of SNAI1, which leads to protein degradation. SIGNOR-277437 0.2 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Thr714 EESDSSEtEKEDDEG 21296876 t lperfetto Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2. SIGNOR-275502 0.2 ZNF804A protein Q7Z570 UNIPROT INHBE protein P58166 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 23434502 t miannu ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). SIGNOR-269462 0.2 CSNK1E protein P49674 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Ser1420 YVVHGPAsVPLGYVP 9606 16513652 t gcesareni We find that ckiepsilon binds to lrp5 and lrp6 in vitro and in vivo and identify three ckiepsilon-specific phosphorylation sites in lrp6. Two of the identified phosphorylation sites, ser1420 and ser1430, influence wnt signaling in vivo, SIGNOR-145049 0.265 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 t gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. SIGNOR-76009 0.563 ADA protein P00813 UNIPROT inosine smallmolecule CHEBI:17596 ChEBI up-regulates quantity chemical modification -1 15926889 t Luana Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates SIGNOR-269737 0.8 CYP11B2 protein P19099 UNIPROT aldosterone smallmolecule CHEBI:27584 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268685 0.8 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252850 0.908 CREB1 protein P16220 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000157 15955695 f miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. SIGNOR-253797 0.3 PRKACA protein P17612 UNIPROT GJA5 protein P36382 UNIPROT up-regulates activity phosphorylation Ser345 HSDKRRLsKASSKAR 9606 BTO:0003477 10728420 t miannu Gap junction channels formed of Cx40 are modulated by protein-kinase-A-mediated phosphorylation. Macroscopic conductance and permeability of Cx40 gap junctions is strongly increased by cAMP. two serine residues that can be phosphorylated by PKA, S120 and S345 SIGNOR-249982 0.312 PRKD2 protein Q9BZL6 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser937 SNLTRSSsSDSIHSV 9606 21525957 t gcesareni Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1. SIGNOR-173441 0.296 NANOG protein Q9H9S0 UNIPROT LAMB1 protein P07942 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 f miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. SIGNOR-254628 0.269 FOXO proteinfamily SIGNOR-PF27 SIGNOR FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18612045 t areggio These findings present new insights into the role of the GR and FOXO family of transcription factors in the transcriptional regulation of the MuRF1 gene, a direct target of the GR in skeletal muscle. SIGNOR-254991 0.2 MAPK3 protein P27361 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser8 MESEMLQsPLLGLGE 9606 BTO:0000007 SIGNOR-C3 21071439 t lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-169530 0.481 SYCP3 protein Q8IZU3 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR form complex binding 9606 22394509 t miannu The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region. SIGNOR-264200 0.623 BMP7 protein P18075 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates transcriptional regulation 9606 18719589 f Induction of mitochondrial biogenesis fspada Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16; ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha; ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways SIGNOR-210056 0.293 MECP2 protein P51608 UNIPROT IGFBP3 protein P17936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000142 17278996 f miannu We found that MeCP2 directly regulates expression of insulin-like growth factor binding protein 3 (IGFBP3) gene in human and mouse brains. IGFBP3 overexpression was observed in the brains of mecp2-null mice and human RTT patients using real-time quantitative polymerase chain reaction and Western blot analyses. SIGNOR-254580 0.253 MAPK8 protein P45983 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 8846788 t lperfetto We find that the JNKs are the predominant Elk-1 activation domain kinases in extracts of UV-irradiated cells and that immunopurified JNK1/2 phosphorylate Elk-1 on the same major sites recognized by ERK1/2, that potentiate its transcriptional activity. SIGNOR-236455 0.495 4-[6-[4-(1-piperazinyl)phenyl]-3-pyrazolo[1,5-a]pyrimidinyl]quinoline chemical CHEBI:91387 ChEBI ACVR1 protein Q04771 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193639 0.8 HIF1A protein Q16665 UNIPROT PKG proteinfamily SIGNOR-PF77 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567;BTO:0000972 8089148 f inferred from family member miannu Hypoxia-inducible factor 1 (HIF-1) activates erythropoietin gene transcription in Hep3B cells subjected to hypoxia. HIF-1 activity is also induced by hypoxia in non-erythropoietin-producing cells, suggesting a more general regulatory role. We now report that RNAs encoding the glycolytic enzymes aldolase A (ALDA), phosphoglycerate kinase 1 (PGK1), and pyruvate kinase M were induced by exposure of Hep3B or HeLa cells to inducers of HIF-1 (1% O2, cobalt chloride, or desferrioxamine). Sequences from the ALDA, PFKL, and PGK1 genes containing HIF-1 binding sites mediated hypoxia-inducible transcription in transient expression assays. SIGNOR-270291 0.481 EGR1 protein P18146 UNIPROT FAP protein Q12884 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 20515787 f Down-regulation of EGR1 resulted in a significant reduction in endogenous FAP mRNA expression. These findings identify the basal transcriptional requirements of FAP gene expression and show EGR1 is an important regulator of FAP expression. SIGNOR-254248 0.2 AURKA protein O14965 UNIPROT RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Thr206 GTSVRRRtSFYLPKD 9606 17563743 t llicata AuroraT-a appears to phosphorylate rassf1a at threonine202 and/or serine203 that reside within the known microtubule-binding domain of rassf1a. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of rassf1a, disrupt rassf1a interactions with microtubules and abolish its ability to induce m-phase cell cycle arrest. SIGNOR-155819 0.459 ATM protein Q13315 UNIPROT WRN protein Q14191 UNIPROT unknown phosphorylation Ser1292 MTIGMHLsQAVKAGC -1 10608806 t llicata We determined a general phosphorylation consensus sequence for ATM and identified putative in vitro targets by using glutathione S-transferase peptides as substrates. Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself. SIGNOR-250578 0.82 NR3C1 protein P04150 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity transcriptional regulation 9600 BTO:0000567 26652733 t inferred from family member Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB SIGNOR-270258 0.2 SMAD5 protein Q99717 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR form complex binding 9606 BTO:0000165;BTO:0002974; BTO:0002809 9442019 t ggiuliani These data suggest that activation of Smad5 and subsequent Smad5-DPC4 complex formation are key steps in the BMP signaling pathway, which mediates BMP-2-induced osteoblastic differentiation of the C2C12 mesenchymal cells. SIGNOR-255775 0.661 PIM1 protein P11309 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr90 AIKIIDKtQLNPTSL 9606 15319445 t gcesareni Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1. SIGNOR-128264 0.428 MC4R protein P32245 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268707 0.501 VAC14 protein Q08AM6 UNIPROT PAS complex complex SIGNOR-C190 SIGNOR form complex binding 9606 BTO:0000007 17556371 t miannu Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. SIGNOR-253530 0.922 STAT6 protein P42226 UNIPROT MRC1 protein P22897 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20508200 f lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. SIGNOR-249535 0.404 PRKACA protein P17612 UNIPROT NOLC1 protein Q14978 UNIPROT up-regulates activity phosphorylation Ser622 KKGEKRAsSPFRRVR -1 12167624 t miannu PKA-dependent Nopp140 phosphorylation is important for its role in agp gene activation. both Ser627 and Ser628 are phosphorylated by PKA. SIGNOR-250019 0.312 pregnenolone smallmolecule CHEBI:16581 ChEBI 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268648 0.8 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation 10029 17510057 t lperfetto In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size. SIGNOR-235748 0.753 SRC protein P12931 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 14699166 t llicata Recombinant shp-1 had elevated activity subsequent to phosphorylation by src in vitro, and shp-1 variants with mutated phosphorylation sites in the c terminus, shp-1 y538f, and shp-1 y538f,y566f were less active toward src-generated phosphoproteins in intact cells. SIGNOR-120492 0.542 DRD1 protein P21728 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257335 0.478 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates activity phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 12637538 t lperfetto Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr(432), Tyr(463), and Tyr(502)), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr(463)) leads to PKD activation. SIGNOR-247324 0.42 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr192 AGMGHDIyQVPPSMD 10090 12972425 t lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs SIGNOR-246393 0.796 MAPK1 protein P28482 UNIPROT BCL3 protein P20749 UNIPROT up-regulates activity phosphorylation Ser122 CPMEHPLsADIAMAT -1 28689659 t miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  SIGNOR-277360 0.486 UFD1 protein Q92890 UNIPROT CD4 protein P01730 UNIPROT down-regulates quantity by destabilization binding 9606 20442859 t miannu These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. SIGNOR-252421 0.2 SSTR5 protein P35346 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256969 0.283 PLK1 protein P53350 UNIPROT RAD21 protein O60216 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser175 REIMREGsAFEDDDM 9606 BTO:0000567 15737063 t lperfetto We suspected that the observed enhancement of Scc1's cleavability in the presence of Plk1 might be due to phosphorylation at two sites that are directly adjacent to the cleavage sites, Ser175 and Ser454, which we had found to be phosphorylated in mitosis in vivo (Table 1). We therefore mutated these two residues to alanine, thereby creating mutant Scc1-S175A/S454A (see Figure 1C), and tested the cleavability of this mutant in the absence or presence of Plk1 in vitro. |Scc1 phosphorylation is dispensable for cohesin dissociation from chromosomes in early mitosis but enhances the cleavability of Scc1 by separase. SIGNOR-275535 0.727 DAB2IP protein Q5VWQ8 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity binding 9606 27858941 t miannu DAB2IP inhibits the PI3K–AKT axis by directly interacting with both proteins, reducing phosphorylation and activation of AKT. The GAP activity of DAB2IP can further enforce inhibition of the PI3K–AKT axis by reducing Ras-dependent activation of PI3K p110α subunit. SIGNOR-254751 0.511 POU2F1 protein P14859 UNIPROT HOXD11 protein P31277 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25301728 f miannu Knockdown of pou2f1 significantly reduced expression of hoxd10 and d11 SIGNOR-205564 0.265 TEAD1 protein P28347 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 21211055 f gcesareni Tead1 can regulate transcription of the foxo3a gene through the binding to the m-cat element, demonstrated with independent chip-pcr analysis, emsa and luciferase reporter system assay. The over-expression and inhibition analysis suggest that foxo3a was positively regulated by tead1. SIGNOR-253003 0.309 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 18267068 t lperfetto Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. SIGNOR-249572 0.2 PRKCA protein P17252 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation Thr638 TRGQPVLtPPDQLVI 9606 15277524 t lperfetto Pkc is frequently autophosphorylated on two c-terminal sites, the turn motif (thr- 638 in human pkc) and the hydrophobic site (ser-657 in human pkc). Thus, it is becoming clear that autophosphorylation of pkc can be a regulated event and that it has significant impact on pkc function SIGNOR-127257 0.2 BRD4 protein O60885 UNIPROT KDM5C protein P41229 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30921702 f miannu  KDM5C was transcriptionally upregulated by bromodomain-containing protein 4 (BRD4), and knockdown KDM5C sensitized the therapeutic effects of CRPC cells to the bromodomain and extraterminal (BET) inhibitor.  SIGNOR-264311 0.333 NEK6 protein Q9HC98 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser403 DDSTLSEsANQVFLG -1 12023960 t miannu Here we demonstrate that in addition to phosphorylating S6K1 and SGK1 at their hydrophobic motif, NEK6 also phosphorylates S6K1 at two other sites and phosphorylates SGK1 at one other site in vitro. Analysis of the peptides phosphorylated by NEK6 (Fig 2), performed in the present study has confirmed this, and identified two novel sites on S6K1 (Ser53 and Ser403) as major sites of NEK6 phosphorylation. SIGNOR-262953 0.375 AKT1 protein P31749 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-217460 0.644 SYK protein P43405 UNIPROT PIP5K1B protein O14986 UNIPROT down-regulates activity phosphorylation Tyr105 FGIKPDDyLYSICSE 9534 BTO:0004055 19553680 t miannu We identified spleen tyrosine kinase (Syk), which is activated by oxidants, as a candidate PIP5Kbeta kinase in this pathway, and mapped the oxidant-sensitive tyrosine phosphorylation site to residue 105. The PIP5KbetaY105E phosphomimetic is catalytically inactive and cytosolic, whereas the Y105F non-phosphorylatable mutant has higher intrinsic lipid kinase activity and is much more membrane associated than wild type PIP5Kbeta.  SIGNOR-276227 0.2 PKC proteinfamily SIGNOR-PF53 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Thr175 GLLPFLLtHKKRLTD -1 19661060 t miannu Activation of the TRPV4 ion channel is enhanced by phosphorylation. TRPV4 is phosphorylated in response to activation of PKC. We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-276228 0.2 PIM proteinfamily SIGNOR-PF34 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser166 SSRRRAIsETEENSD 9606 BTO:0000785 18467333 t gcesareni Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt. SIGNOR-259433 0.2 BTG2 protein P78543 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates activity binding 9606 BTO:0000093 22493435 t miannu BTG2 stimulation of antioxidant gene expression is also NFE2L2-dependent. We further demonstrate that BTG2 is a binding partner for NFE2L2 and increases its transcriptional activity. SIGNOR-254647 0.2 belinostat chemical CHEBI:61076 ChEBI HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257960 0.8 FUS protein P35637 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR down-regulates quantity by repression post transcriptional regulation 10090 BTO:0001279 28515487 f inferred from family member This conclusion is also supported by the analysis of alternative splicing events inhFUS+/+;Smn+/‚àímice. As shown in Fig.6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected inhFUS+/+mice, is not further modified by SMN decrease SIGNOR-270231 0.286 profenamine chemical CHEBI:313639 ChEBI MAPK10 protein P53779 UNIPROT down-regulates chemical inhibition 9606 BTO:0000142 19261605 t Inhibitor of p38;ATP binding pocket gcesareni Indazole-based inhibitors exemplified by sr-3737 were potent inhibitors of both jnk3 (ic50 12 nm). SIGNOR-184443 0.8 MAPK1 protein P28482 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation Ser387 PATVEPAsPTPAHSL 9606 17311928 t llicata Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1 SIGNOR-153379 0.431 BLOC1S1 protein P78537 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 22203680 t lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. SIGNOR-265936 0.721 RNF11 protein Q9Y3C5 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity binding 9606 BTO:0000150 19131965 t lperfetto Rnf11, together with tax1bp1 and itch, is an essential component of an a20 ubiquitin-editing protein complex; rnf11 is required for a20 to interact with and inactivate rip1 to inhibit tnf-mediated nf-_kb activation. SIGNOR-183188 0.569 MMP1 protein P03956 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 BTO:0005387 19584257 f lperfetto However, we show that soluble factors secreted by SUM102 breast cancer cells stimulated the expression of MMP-1 and CXCR4 in HMFs. As a result, these stromal cells acquired an invasive and migratory phenotype SIGNOR-252265 0.7 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser38 EGRQPSPsPSPTERA 9606 BTO:0001271 15093545 t The effect has been demonstrated using P29590-4 gcesareni We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3). SIGNOR-124244 0.366 ATG7 protein O95352 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates binding 9606 22170151 t gcesareni These results indicated that the fap motif of atg7 is indispensable for formation of the atg3-lc3 e2-substrate intermediate through the interaction of atg7 with atg3. SIGNOR-195239 0.869 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2315 RSPQPVPsPRPQSQP 9606 17623675 t lperfetto Erk2-mediated c-terminal serine phosphorylation of p300 (ser-2279, ser-2315, and ser-2366) is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression. SIGNOR-244634 0.2 SB 203580 chemical CHEBI:90705 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates chemical inhibition 9606 BTO:0000222 15208625 t fstefani Pharmacological blockade of p38?/? Kinases by sb203580 inhibits the myogenic program3_5 by repressing the transcription of early (myogenin;myog) and late (muscle-creatine kinase;ckm) muscle genes in myoblasts induced to differentiate SIGNOR-126052 0.8 ARPC5 protein O15511 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 t The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc SIGNOR-251518 0.959 STK11 protein Q15831 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity phosphorylation Ser669 EDDVLSSsSCGSNSD 9606 BTO:0002181 34216621 t miannu  Resveratrol promotes the binding between LKB1 and Sirt1, which we first reported, and this binding leads to LKB1-mediated phosphorylation of Sirt1 at three different serine residues in the C terminus of Sirt1. Mechanistically, LKB1-mediated phosphorylation increases intramolecular interactions in Sirt1, such as the binding of the C terminus to the deacetylase core domain, thereby eliminating DBC1 (Deleted in Breast Cancer 1, Sirt1 endogenous inhibitor) inhibition and promoting Sirt1-substrate interaction.  SIGNOR-277321 0.59 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 19282669 t inferred from 70% family members lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-270146 0.71 NOTCH proteinfamily SIGNOR-PF30 SIGNOR HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32195003 f Notch signaling is initiated by the interaction of Notch ligands and receptors on adjacent cells, which further triggers two proteolytic cleavage events. The first cleavage releases a functional extracellular domain (NECD); the second cleavage, mediated by γ-secretase, releases the intracellular domain (NICD) into the cytoplasm. The NICD then translocates to the nucleus, binds to the transcription factor CBF/Su (H)/LAG-2 (CSL), and recruits Mastermind-like protein 1 and p300/CBP to induce transcription of Notch target genes, including Hes1, p21, Akt, cyclin D1, and mTOR SIGNOR-261534 0.2 Oxotremorine chemical CHEBI:7851 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258653 0.8 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 15821101 t gcesareni Ptp1b has been shown to regulate the activation of cytokine receptors through the dephosphorylation of specific members of the jak family, namely jak2 and tyk2 SIGNOR-134955 0.789 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219324 0.749 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 t The effect has been demonstrated using Q01196-8 gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-138936 0.2 PLK1 protein P53350 UNIPROT ZMYM2 protein Q9UBW7 UNIPROT down-regulates quantity by destabilization phosphorylation Ser309 DSLSPVAsLPKQIFQ 25855382 t lperfetto PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|Similar analyses with ZNF198 identified two clusters of putative Plk1 phosphorylation sites in vitro. A cluster of serine residues at the N-terminus of ZNF198, S303, S305, and S309, and a cluster at the C-terminus, S1056 and S1064. The triple Ser to Ala mutant, S303A/S305A/S309A, consistently exhibited the lowest level of phosphorylation in vitro, in comparison to the double S1056A/S1064A mutant SIGNOR-275560 0.384 FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 f Constitutively active Foxo1 prevents the differentiation of preadipocytes, while dominant-negative Foxo1 restores adipocyte differentiation of fibroblasts from insulin receptor-deficient mice. SIGNOR-254973 0.7 SMAD3 protein P84022 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 9843571 t gcesareni TGF-² treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-235168 0.7 PAK proteinfamily SIGNOR-PF13 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 BTO:0000567 16129686 t lperfetto Inhibition of pak kinase activity dramatically decreased phosphorylation of mek1 at ser(298) in response to either pdgf or egf. SIGNOR-244920 0.564 ACHE protein P22303 UNIPROT acetylcholine smallmolecule CHEBI:15355 ChEBI down-regulates quantity chemical modification 15841900 t Acetylcholinesterase (AChE) is one of the most crucial enzymes for nerve response and function. AChE catalyzes the hydrolysis of acylcholine esters with a relative specificity for acetylcholine.|The intracellular effects of acetylcholine are mediated by the activation of nicotinic and muscarinic acetylcholine receptors (AChRs). AChE terminates transmission of neuronal impulses by rapid hydrolysis of acetylcholine. SIGNOR-253983 0.8 LRIG1 protein Q96JA1 UNIPROT ERBB4 protein Q15303 UNIPROT down-regulates 9606 23723069 f miannu Lrig1 is a negative regulator of oncogenic receptor tyrosine kinases, including erbb and met receptors, and promotes receptor degradation. SIGNOR-202146 0.592 PPM1D protein O15297 UNIPROT KDM1A protein O60341 UNIPROT down-regulates activity dephosphorylation Ser137 LSEDEYYsEEERNAK 9606 BTO:0002181 25999347 t miannu We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites. SIGNOR-276905 0.477 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation Thr185 HDHTGFLtEYVATRW 9606 phosphorylation:Thr185 HDHTGFLtEYVATRW 16456541 t gcesareni B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk SIGNOR-143052 0.605 CDH13 protein P55290 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265853 0.514 PPM1B protein O75688 UNIPROT PAX2 protein Q02962 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000007 25631048 t PPM1B can dephosphorylate the Pax2 activation domain and displace the adaptor protein PTIP, thus inhibiting H3K4 methylation and gene activation SIGNOR-251712 0.2 LTA protein P01374 UNIPROT LTBR protein P36941 UNIPROT up-regulates binding 9606 7995952 t gcesareni These experiments point toward the lt-alpha 1/beta 2 complex as the predominant membrane form of lt on the lymphocyte surface, and this complex is the primary ligand for the lt-beta receptor. SIGNOR-35708 0.84 FN1 protein P02751 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 15721307 t lperfetto Integrin alpha8beta1-fibronectin interactions promote cell survival via PI3 kinase pathway. SIGNOR-253304 0.669 AKT2 protein P31751 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser167 GGRERLAsTNDKGSM 9534 BTO:0001538 11139588 t AKT activate ERalpha in the absence of estrogen. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT. SIGNOR-251490 0.523 MAPK7 protein Q13164 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Thr319 TPVVSVTtPSLPPQG 9606 BTO:0000567 10849446 t lperfetto We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo. SIGNOR-236579 0.699 CSNK2A1 protein P68400 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates phosphorylation 9606 19623618 t gcesareni Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex.CK1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays. SIGNOR-187209 0.308 PRKACA protein P17612 UNIPROT CACNA1H protein O95180 UNIPROT down-regulates activity phosphorylation Ser1107 LPDSRRGsSSSGDPP 9606 19131331 t miannu Here, we identify protein kinase A (PKA) as a molecular switch that allows Gbeta(2)gammax dimers to effect voltage-independent inhibition of Ca(v)3.2 channels. Inhibition requires phosphorylation of Ser(1107), a critical serine residue on the II-III loop of the channel pore protein. S1107A prevents inhibition of unitary currents by recombinant Gbeta(2)gamma(2) dimers but does not disrupt dimer binding nor change its specificity. SIGNOR-263110 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR SLC2A4 protein P14672 UNIPROT up-regulates 9606 8940145 f Translocation from intracellular compartment to cell surface in muscle and adipose tissue gcesareni The constitutively active Akt induced glucose uptake into adipocytes in the absence of insulin by stimulating translocation of the insulin-responsive glucose transporter 4 to the plasma membrane. SIGNOR-45117 0.2 MMP14 protein P50281 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Leu433 REYHTEKlVTSKGDK -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain SIGNOR-263620 0.2 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR KRAS protein P01116 UNIPROT up-regulates 9606 19483050 f lperfetto A recurrent gene fusion between echinoderm microtubule-associated protein-like 4 (EML4;and, occasionally, of other fusion partners) and the anaplastic lymphoma kinase (ALK) geneoccurs in of NSCLCs , resulting in activation of a potent ALK fusion protein.ALK fusion protein is usually found in never-smoker subjects. Although relatively rare, therelative paucity of fusion proteins known to contribute to lung cancer pathogenesis makes this a finding of biological interest. Although present understanding of the ALK fusion protein is limited, it may play a role in activating RAS. Thus it is negatively associated with thepresence of KRAS or EGFR mutations, and may favour ADC histology and never-smokerstatus. SIGNOR-253216 0.2 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity precursor of 9606 24786789 t miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. SIGNOR-266508 0.8 FLT3 protein P36888 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression 9606 25280219 f MYC expression was relatively higher (P <0Æ1) in theFLT3/ITD-positive AML samples compared to non-mutant FLT3 AML. SIGNOR-261556 0.371 AUTS2 protein Q8WXX7 UNIPROT DOCK1 protein Q14185 UNIPROT up-regulates activity binding 10090 BTO:0001909 25533347 t miannu Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development.  AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These results suggest that FL-AUTS2 can activate Rac1 via interaction with P-Rex1 and the Elmo2/Dock180 complex to regulate actin dynamics in N1E-115 cells. SIGNOR-266820 0.2 BLOC-1 complex SIGNOR-C381 SIGNOR Platelet_dense_granule_formation phenotype SIGNOR-PH181 SIGNOR up-regulates 9606 BTO:0000132 12019270 f lperfetto BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules|Interestingly, immunofluorescence and in vitro binding experiments demonstrated that pallidin/BLOC-1 is able to associate with actin filaments. We propose that BLOC-1 mediates the biogenesis of lysosome-related organelles by a mechanism that may involve self-assembly and interaction with the actin cytoskeleton. SIGNOR-265940 0.7 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270399 0.8 erlotinib hydrochloride chemical CHEBI:53509 ChEBI JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 17178722 t JAK2(V617F), a mutant of tyrosine kinase JAK2. Erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor. gcesareni This study shows that the anti-cancer drug erlotinib (tarceva) is a potent inhibitor of jak2(v617f) activity SIGNOR-151274 0.8 FGFR2 protein P21802 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates 10090 BTO:0000011 12270934 f lperfetto  Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors SIGNOR-235337 0.307 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates activity phosphorylation Thr204 NEAAARFtLGSPLTS 9606 9630228 t lperfetto Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4. SIGNOR-109768 0.573 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR HSD11B2 protein P80365 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15659537 f miannu Overexpression of p50 inhibited HSD11B2 promoter activity and overexpression of Egr-1 inhibited transactivation of the HSD11B2 promoter by p65/p50. SIGNOR-253877 0.2 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58467 ChEBI IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267328 0.8 domperidone chemical CHEBI:31515 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258381 0.8 PAK1 protein Q13153 UNIPROT GNAZ protein P19086 UNIPROT up-regulates phosphorylation Ser16 EKEAARRsRRIDRHL 9606 BTO:0000671 9166747 t gcesareni Phosphorylation of either ser(16) by pak1 or ser(27) by pkc decreased the affinity of galpha(z) for gbetagamma;phosphorylation of both residues by pkc caused no further effect. Pak1 thus regulates galpha(z) function by attenuating the inhibitory effects of both gaps and gbetagamma. SIGNOR-48673 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser42 GGRKRRSsRRSAGGG 9606 20400976 t lperfetto Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis. SIGNOR-244373 0.2 NLGN3 protein Q9NZ94 UNIPROT NRXN2 protein Q9P2S2 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264152 0.824 UVB radiation stimulus SIGNOR-ST17 SIGNOR PAH protein P00439 UNIPROT up-regulates 9606 9204951 f miannu UVB light induces GTP-CH.-1 to increase the de novo synthesis of 6-BH4 in association with a concomitant increase in PAH activities, thus providing more L-tyrosine. SIGNOR-252207 0.7 CALM2 protein P0DP24 UNIPROT GEM protein P55040 UNIPROT up-regulates activity binding 10116 BTO:0001009 14701738 t miannu Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells. SIGNOR-266325 0.2 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11486000 t lperfetto Activity of the mammalian pyruvate dehydrogenase complex is regulated by phosphorylation-dephosphorylation of the alpha subunit of the pyruvate dehydrogenase (e1) component. Phosphorylation is carried out by four pyruvate dehydrogenase kinase (pdk) isoenzymes. SIGNOR-109647 0.866 creatine smallmolecule CHEBI:16919 ChEBI CKM protein P06732 UNIPROT up-regulates activity chemical activation 9606 18502307 t miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. SIGNOR-265810 0.8 HCK protein P08631 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr759 LYDVSRMyVDPSEIN -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249364 0.532 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 t llicata Rsk phosphorylates serine 58 of ranbp3 in vitro and in vivo SIGNOR-252770 0.2 CSNK2A1 protein P68400 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 10617630 t lperfetto In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2.| together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of alpha-synuclein could affect its binding to membranes. SIGNOR-73803 0.493 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 11691836 t lperfetto The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding SIGNOR-249390 0.649 SP1 protein P08047 UNIPROT ALOX5 protein P09917 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19781662 f The 5-LO promoter possesses a unique GC-rich region which contains consensus sequences for the transcription factors Sp1 and Egr-1 (GC-boxes) which are important for basal transcriptional activity SIGNOR-254032 0.253 ARHGAP8 protein P85298 UNIPROT LAMTOR3 protein Q9UHA4 UNIPROT up-regulates activity binding 28092672 t lperfetto Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation. SIGNOR-275551 0.255 ARVCF protein O00192 UNIPROT CDH5 protein P33151 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 t miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. SIGNOR-252129 0.35 HIPK2 protein Q9H2X6 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser36 PRKQPPVsPGTALVG 9606 17960875 t gcesareni Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation. SIGNOR-158616 0.507 EPAS1 protein Q99814 UNIPROT KDM5A protein P29375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271580 0.268 MAPK1 protein P28482 UNIPROT DDHD1 protein Q8NEL9 UNIPROT unknown phosphorylation Ser727 TIPSPVTsPVLSRRH -1 11328814 t miannu Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity SIGNOR-262972 0.2 PRKCB protein P05771 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr375 GRGARGGtRGGRGRI 9606 BTO:0004974 14699138 t lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation SIGNOR-249253 0.294 T_cell_activation phenotype SIGNOR-PH73 SIGNOR IL17A protein Q16552 UNIPROT up-regulates quantity 9606 BTO:0002417 32454942 f miannu interferon gamma- (IFNγ-) and interleukin-17- (IL-17-) secreting CD4+ T cells are believed to be the pathogenic initiators of MS [22], and in MS patients, the increased production of either IFNγ or IL-17 is associated with pathology SIGNOR-263819 0.7 GMPS protein P49915 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267341 0.8 ATG14 protein Q6ZNE5 UNIPROT Vps34 Complex I complex SIGNOR-C242 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260318 0.908 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 22021368 f apalma Once genetic mutation of AML1 occurs in hematopoietic cells, aberrant activation of NF-κB signaling exerts antiapoptotic and proliferation-promoting effects via activation of BCL-XL or JUNB. SIGNOR-255693 0.7 PKN1 protein Q16512 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Thr64 ENLRRATtDLGRSLG -1 10467162 t lperfetto Autophosphorylation of wild-type PKN increased the protein kinase activity, however, substitution of Thr64, Ser374, or Thr531 in the regulatory region of PKN with alanine, abolished this effect. SIGNOR-249019 0.2 MAPK3 protein P27361 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser172 YRDPSCLsPASSLSS 9606 10652349 t Translocation from Nucleus to Cytoplasm esanto We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats. SIGNOR-74564 0.512 RPS6KA1 protein Q15418 UNIPROT L1CAM protein P32004 UNIPROT up-regulates activity phosphorylation Ser1152 RSKGGKYsVKDKEDT 10116 BTO:0001009 8663493 t lperfetto Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152. SIGNOR-248948 0.485 CLTA protein P09496 UNIPROT AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR form complex binding 9606 23103167 t lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-260678 0.756 STK3 protein Q13188 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3 SIGNOR-181056 0.2 HBA1 protein P69905 UNIPROT ADAMTS13 protein Q76LX8 UNIPROT down-regulates activity 9606 15367436 f Regulation of binding miannu Incubation of hemoglobin, recombinant and from lysed erythrocytes, with normal plasma revealed an ADAMTS13 inhibitory effect at hemoglobin concentrations of 2 g/L or higher. SIGNOR-251749 0.2 PTPN14 protein Q15678 UNIPROT BCAR1 protein P56945 UNIPROT down-regulates dephosphorylation Tyr128 SKAQQGLyQVPGPSP 9606 BTO:0000586 22710723 t lperfetto We show that p130 crk-associated substrate (p130cas) is a direct substrate of ptpn14 and that ptpn14 specifically regulates p130cas phosphorylation at tyrosine residue 128 (y128) in colorectal cancer (crc) cells. We engineered crc cells homozygous for a p130cas y128f knock-in mutant and found that these cells exhibit significantly reduced migration and colony formation SIGNOR-197923 0.403 F2RL2 protein O00254 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257234 0.2 EEF1D protein P29692 UNIPROT ITGA7 protein Q13683 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000165 16129691 t lperfetto alpha7 Integrin Expression Is Negatively Regulated by deltaEF1 during Skeletal Myogenesis SIGNOR-241773 0.2 STX11-VAMP8 SNARE complex complex SIGNOR-C273 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 BTO:0000782 22767500 f lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. |The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release. SIGNOR-261900 0.7 PDGFRA protein P16234 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 10733900 t amattioni Crk could bind to both pdgf alpha- and beta-receptors in vivo. SIGNOR-75881 0.632 PRKACA protein P17612 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser8 MPLNRTLsMSSLPGL -1 6263629 t A reinvestigation of the phosphorylation of Rabbit Skeletal-muscle glycogen synthase by cyclic AMP dependent Protein Kinase: identification of the third site of phosphorylation at Serine-7 SIGNOR-253008 0.49 PTPRG protein P23470 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1069 EDSFLQRySSDPTGA -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254699 0.494 TLX1 protein P31314 UNIPROT RB1 protein P06400 UNIPROT down-regulates activity binding 9606 BTO:0000661 15897879 t 2 miannu ectopic HOX11 expression resulted in hyperphosphorylation of the retinoblastoma protein (Rb), which correlated with inhibition of the major Rb serine/threonine phosphatase PP1. SIGNOR-240725 0.2 wortmannin chemical CHEBI:52289 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 8162590 t gcesareni The microbial product wortmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase. SIGNOR-36557 0.8 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-267037 0.8 TAF4 protein O00268 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263921 0.881 CSNK2A1 protein P68400 UNIPROT VDR protein P11473 UNIPROT up-regulates phosphorylation Ser208 SFSNLDLsEEDSDDP 9606 17368182 t lperfetto Casein kinase ii (ckii) phosphorylates vdr both in vitro and in vivo at serine 208 within the hinge domain. This phosphorylation does not affect the ability of vdr to bind dna, but increases its ability to transactivate target promoters SIGNOR-153711 0.342 SP1 protein P08047 UNIPROT LORICRIN protein P23490 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 12200429 f miannu Mutation and DNA-protein analyses show that Sp1, c-Jun, an unidentified regulator, and the co-activator p300/CREB-binding protein up-regulate whereas Sp3, CREB-1/CREMalpha/ATF-1, Jun B, and an AP2-like protein (termed the keratinocyte-specific repressor-1 (KSR-1)) suppress loricrin promoter activity. SIGNOR-254538 0.2 phosphatidic acid smallmolecule CHEBI:16337 ChEBI MTOR protein P42345 UNIPROT up-regulates chemical activation 9606 11729323 t gcesareni Pa directly interacted with the domain in mtor that is targeted by rapamycin, and this interaction was positively correlated with mtor's ability to activate downstream effectors. SIGNOR-112379 0.8 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser486 RPLSRAQsSPAAPAS 9606 BTO:0000782 15623513 t lperfetto Protein kinase d1 (pkd1) was activated after tcr engagement, interacted with hdac7, and phosphorylated three serines (ser155, ser318, and ser448) at its n terminus, leading to its export from the nucleus. SIGNOR-132902 0.491 MAPK3 protein P27361 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 BTO:0000567 19777442 t gcesareni Erk-1 map kinase prevents tnf-induced apoptosis through bad phosphorylation and inhibition of bax translocation in hela cells. SIGNOR-188172 0.46 WARS1 protein P23381 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. SIGNOR-270801 0.8 superoxide smallmolecule CHEBI:18421 ChEBI SOD3 protein P08294 UNIPROT up-regulates activity precursor of 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272274 0.8 LTB4R2 protein Q9NPC1 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256674 0.252 3-[4-(3-chlorophenyl)piperazin-1-yl]-1,1-diphenylpropan-2-ol hydrochloride chemical CHEBI:64057 ChEBI HTR1D protein P28221 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190774 0.8 FOXO proteinfamily SIGNOR-PF27 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress SIGNOR-252938 0.7 FRS2 protein Q8WU20 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates phosphorylation 9606 9632781 t gcesareni In addition to the direct interactions with grb2, tyrosine-phosphorylated frs2 forms a complex with the sh2 domain-containing protein tyrosine phosphatase shp2. This interaction results in tyrosine phosphorylation of shp2 and complex formation between shp2 and grb2. the catalytic activity of shp2 is essential for a sustained map kinase response and for potentiation of fgf-induced neurite outgrowth in pc12 cells SIGNOR-58196 0.772 ARHGEF12 protein Q9NZN5 UNIPROT RHOA protein P61586 UNIPROT up-regulates guanine nucleotide exchange factor 9606 BTO:0001271 11094164 t gcesareni Here, we show that larg can activate rho in vivo SIGNOR-84657 0.902 POU5F1 protein Q01860 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 BTO:0004180 23041284 t flangone Furthermore, in ECCs, unphosphorylated Oct4 bound to the AKT1 promoter and repressed its transcription. SIGNOR-242103 0.469 methoxamine chemical CHEBI:6839 ChEBI ADRA1D protein P25100 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258448 0.8 CDK5RAP2 protein Q96SN8 UNIPROT BUB1B protein O60566 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19282672 t Giulio These data indicate that CDK5RAP2 is a positive regulator of both the BUBR1 promoter and the MAD2 promoter SIGNOR-260312 0.273 CDK13 protein Q14004 UNIPROT EIF4B protein P23588 UNIPROT up-regulates activity phosphorylation Ser422 RERSRTGsESSQTGT 9606 BTO:0001109 36882522 t lperfetto CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. SIGNOR-273115 0.254 MYC protein P01106 UNIPROT PRODH protein O43272 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22615405 f miannu MYC not only inhibited POX/PRODH, but also markedly increased the enzymes of proline biosynthesis from glutamine, including P5C synthase and P5C reductase 1. SIGNOR-254608 0.2 EGLN1 protein Q9GZT9 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization hydroxylation 9606 BTO:0000567 32755251 t lperfetto Hypoxia-inducible factor-1 (HIF-1) is a key regulator of erythropoiesis. In this article, we report 3 novel mutations, P378S, A385T, and G206C, on the EGLN1 gene encoding the negative HIF-1α regulator prolyl hydroxylase domain-2 (PHD2) in 3 patients with isolated erythrocytosis. These mutations impair PHD2 protein stability and partially reduce PHD2 activity, leading to increased HIF-1α protein levels in cultured cells.|Oxygen-dependent hydroxylation by the prolyl hydroxylase domain-2 (PHD2) protein marks HIF-1alpha for ubiquitination by the von Hippel Lindau (VHL) tumor suppressor protein, leading to proteasomal degradation SIGNOR-261994 0.916 EGLN3 protein Q9H6Z9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates activity hydroxylation 9606 BTO:0000567 21620138 t Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1Œ± and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. SIGNOR-268146 0.447 Scribble_complex_DLG3-LLGL1_variant complex SIGNOR-C507 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 f miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270898 0.7 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr680 IEDSREAtHSSGFSG 9606 23079597 t lperfetto Phosphorylation of kard by plk1 promotes direct interaction of bubr1 with the pp2a-b56_ phosphatase that counters excessive aurora b activity at kinetochores. We propose that plk1 and bubr1 cooperate to stabilize kinetochore-microtubule interactions. Phosphorylation of t680 by plk1 is essential for kard function SIGNOR-199222 0.834 PLK1 protein P53350 UNIPROT FBXO5 protein Q9UKT4 UNIPROT down-regulates phosphorylation 9606 15469984 t gcesareni Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering scfbetatrcp-dependent destruction of the apc inhibitor emi1. SIGNOR-129813 0.774 trimetrexate chemical CHEBI:9737 ChEBI DHFR protein P00374 UNIPROT down-regulates activity chemical inhibition 9606 7981057 t miannu We examined the cytotoxicity and biochemical effects of the lipophilic antifol trimetrexate (TMQ) in two human colon carcinoma cell lines, SNU-C4 and NCI-H630, with different inherent sensitivity to TMQ. Dihydrofolate reductase (DHFR) and thymidylate synthase were quantitatively and qualitatively similar in both lines. During drug exposure, DHFR catalytic activity was inhibited by > or = 85% in both cell lines SIGNOR-258482 0.8 AURKB protein Q96GD4 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates phosphorylation 9606 10464286 t gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. SIGNOR-265321 0.2 NEDD4 protein P46934 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. SIGNOR-272753 0.463 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250557 0.2 STK4 protein Q13043 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Thr1079 EHAFYEFtFRRFFDD 9606 15688006 t milica We show that Mst2 and hWW45 interact with each other in human cells and that both Mst2 and Mst1 are able to phosphorylate Lats1 and Lats2, thereby stimulating Lats kinase activity. SIGNOR-133555 0.607 EPM2A protein O95278 UNIPROT GSK3B protein P49841 UNIPROT unknown dephosphorylation Ser9 SGRPRTTsFAESCKP 10090 16959610 t Epm2a-encoded laforin is a phosphatase for GSK-3beta and an important repressor in the Wnt signaling pathway| only GSK-3β phosphorylation on Ser9 was affected by overexpression of laforin|Although GSK-3β is inactivated by phosphorylation at the Ser9 position, it is unclear if the inactivated enzyme can be reactivated by dephosphorylation. SIGNOR-248345 0.474 TP53 protein P04637 UNIPROT PHB protein P35232 UNIPROT up-regulates activity binding 16918502 t lperfetto Our previous studies have shown that prohibitin physically interacts with the marked-box domain of E2F family members and represses their transcriptional activity; in contrast, prohibitin could bind to and enhance the transcriptional activity of p53. SIGNOR-268978 0.454 SRC protein P12931 UNIPROT GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr160 QVPQQPTyVQALFDF 9606 BTO:0000007 20554525 t lperfetto In our work we show that, in contrast to BCR-ABL and prolactin, NPM-ALK phosphorylates Grb2 mainly in Tyr160)Previous reports suggested an inhibitory role of Grb2 Tyr7, Tyr37, Tyr52, and Tyr209 phosphorylation in receptor tyrosine kinase signaling (16) (43). Instead, in our system Grb2 Tyr160 mutation was not show to have a role in ALCL proliferation. SIGNOR-247138 0.627 FGR protein P09769 UNIPROT HCLS1 protein P14317 UNIPROT unknown phosphorylation Tyr222 MEAPTTAyKKTTPIE -1 10066823 t We have now identified tyrosine 222 as the HS1 residue phosphorylated by the Src family protein kinases c-Fgr and Lyn. this interaction is weakened by phosphorylation of Tyr-222, through an allosteric mechanism that ultimately causes the detachment of fully phosphorylated HS1 from c-Fgr. SIGNOR-251144 0.447 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257975 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR BMI1 protein P35226 UNIPROT up-regulates activity phosphorylation Ser316 ANRPRKSsVNGSSAT 9606 BTO:0001033 22505453 t lperfetto The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate SIGNOR-249581 0.2 torkinib chemical CHEBI:90679 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206313 0.8 APH1B protein Q8WW43 UNIPROT PSENEN protein Q9NZ42 UNIPROT up-regulates binding 9606 12522139 t gcesareni Furthermore, overexpression of aph-1 facilitates pen-2-mediated ps1 proteolysis, resulting in a significant increase in ps1 fragments. Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex. SIGNOR-97110 0.94 CALM1 protein P0DP23 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates binding 9606 11796223 t gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-252337 0.572 CEP63 protein Q96MT8 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 t lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. SIGNOR-271725 0.381 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244494 0.2 PTP4A3 protein O75365 UNIPROT KRT8 protein P05787 UNIPROT down-regulates activity dephosphorylation Ser432 SAYGGLTsPGLSYSL 9606 BTO:0000586 19115206 t the cytoskeletal intermediate filament keratin 8 (KRT8) was identified as a physiological PRL-3-interacting protein. Indeed, treatment with the PRL-3 inhibitor effectively suppressed the phosphorylation of KRT8 at S73 and S431 SIGNOR-248341 0.275 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Tyr185 TNFMMTPyVVTRYYR 9606 11062067 t lperfetto In the present study, we found that mkk7 phosphorylates sapk2a/p38 exclusively at tyr-182, albeit at a low rate. Therefore one possibility is that the interaction of mkk7 and/or sapk1/jnk with another cellular protein alters the conformation of one of these enzymes in such a way as to facilitate phosphorylation of tyr-185 by mkk7 in vivo. SIGNOR-83748 0.622 C5AR2 protein Q9P296 UNIPROT SELL protein P14151 UNIPROT down-regulates quantity by repression 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263467 0.2 TIMM10 protein P62072 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 t lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). SIGNOR-267701 0.709 PRKCA protein P17252 UNIPROT GRIN1 protein Q05586 UNIPROT up-regulates activity phosphorylation Ser896 SSFKRRRsSKDTSTG 10116 BTO:0000938 15936117 t miannu Serines 890 and 896 of the NMDA receptor subunit NR1 are differentially phosphorylated by protein kinase C isoforms. The results show that PKC alpha phosphorylates preferentially S896 and PKC gamma preferentially S890. SIGNOR-263177 0.427 PRKD2 protein Q9BZL6 UNIPROT PKD2 protein Q13563 UNIPROT up-regulates activity phosphorylation Ser801 SSLPRPMsSRSFPRS 9615 BTO:0000837 20881056 t miannu Here, we report the identification of a previously unrecognized phosphorylation site within the polycystin-2 C terminus (Ser801), and we demonstrate that it is phosphorylated by protein kinase D. These results suggest that growth factor-stimulated, protein kinase D-mediated phosphorylation of polycystin-2 is essential for its ER channel function and links extracellular stimuli to its effects on cell growth and intracellular calcium regulation. SIGNOR-276284 0.2 prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI PTGER1 protein P34995 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257569 0.8 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser82 NPEDRSPsPEPIYNS 9606 16420481 t The effect has been demonstrated using Q15637-2 gcesareni Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding. SIGNOR-143841 0.416 HTR3D protein Q70Z44 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 18761359 f miannu The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release.  SIGNOR-264319 0.7 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ETV6 protein P41212 UNIPROT down-regulates phosphorylation 10090 15060146 t inferred from 70% family members miannu Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation. SIGNOR-270120 0.2 PRKCA protein P17252 UNIPROT LRRK1 protein Q38SD2 UNIPROT up-regulates activity phosphorylation Thr1075 NQRNRCStFRVKRNQ -1 36040231 t miannu PKCα unexpectedly does not activate LRRK1 by phosphorylating the kinase domain, but instead phosphorylates a cluster of conserved residues (Ser1064, Ser1074 and Thr1075) located within a region of the CORB domain of the GTPase domain. we postulate that phosphorylation of Ser1064, Ser1074 and Thr1075 activates LRRK1 by promoting interaction and stabilization of the αC-helix on the kinase domain. SIGNOR-276865 0.2 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 9606 BTO:0000130 12056906 t esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. SIGNOR-89237 0.458 SOS2 protein Q07890 UNIPROT HRAS protein P01112 UNIPROT up-regulates guanine nucleotide exchange factor 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-175262 0.781 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR JAK2 protein O60674 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001271 22740448 f miannu Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a).CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced. SIGNOR-260120 0.2 GEMIN4 protein P57678 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 t lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. SIGNOR-253118 0.801 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 11343802 t lperfetto Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation SIGNOR-107695 0.595 ELOVL4 protein Q9GZR5 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267892 0.8 RAGAC complex SIGNOR-C113 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity relocalization 9606 20381137 t gcesareni The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb SIGNOR-228158 0.676 GSK3B protein P49841 UNIPROT CAP1 protein Q01518 UNIPROT up-regulates activity phosphorylation Ser310 PKPQTSPsPKRATKK 9606 BTO:0000763 30123351 t lperfetto We found that GSK3 phosphorylates S307 and S309 by using inhibitors LiCl. Inhibition of GSK3beta can cause loss of cell polarity as well as accumulation of stress fibers. We propose that GSK3 regulates CAP1 through at least two mechanisms. First, GSK3 (and potentially other kinases) phosphorylate CAP1 at S309 and promote CAP1 localization to the cytosol. Second, phosphorylation at S309 affects protein-protein interactions with actin and cofilin. The loss of this phospho-regulation by GSK3 inhibition is expected to disrupt CAP1 function and actin dynamics. SIGNOR-264823 0.256 NRF1 protein Q16656 UNIPROT SLC46A1 protein Q96NT5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20724482 f miannu Overexpression of NRF-1 or a constitutively active NRF-1 VP-16 construct resulted in increased reporter activity and PCFT mRNA levels. These novel findings identify NRF-1 as a major inducible transcriptional regulator of PCFT gene expression. SIGNOR-254884 0.343 COL4A5 protein P29400 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 t Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6) SIGNOR-254669 0.7 Caspase 8 complex complex SIGNOR-C231 SIGNOR CYCS protein P99999 UNIPROT up-regulates activity 9606 BTO:0000661 10364179 f Translocation from Mitochondria to Cytosol lperfetto Caspase-8 triggered rapid cytochrome c release from mitochondria. The effect was indirect. SIGNOR-256473 0.493 VEGFB protein P49765 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252276 0.7 SDF2L1 protein Q9HCN8 UNIPROT LRP4 protein O75096 UNIPROT up-regulates activity binding 9606 BTO:0000007 24140340 t llicata Here, we show that the chaperon Mesdc2 binds to the intracellular form of Lrp4 and promotes its glycosylation and cell-surface expression. These results suggest that Mesdc2 plays an essential role in NMJ formation by promoting Lrp4 maturation. SIGNOR-237942 0.2 CYP21A2 protein P08686 UNIPROT progesterone smallmolecule CHEBI:17026 ChEBI down-regulates quantity chemical modification 9606 BTO:0000048 25855791 t lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively SIGNOR-268646 0.8 PER2 protein O15055 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates activity binding 9606 BTO:0001939 23836662 t miannu This PER2-OCT1 interaction effectively converted OCT1 sites, which normally activate expression, into repressor sites by recruitment of a polycomb repressor complex including EZH2 and SUZ12, as well as HDAC2. SIGNOR-254148 0.2 CDKN3 protein Q16667 UNIPROT CDK2 protein P24941 UNIPROT down-regulates activity dephosphorylation Thr160 GVPVRTYtHEVVTLW 9606 11463386 t The CDK-interacting protein phosphatase KAP dephosphorylates phosphoThr-160 (pThr-160) of the CDK2 activation segment, the site of regulatory phosphorylation that is essential for kinase activity. SIGNOR-248724 0.737 PRKCH protein P24723 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276014 0.2 PRKCB protein P05771 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 t lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation SIGNOR-249247 0.294 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr792 PRNSAELtVIKVSSQ 9606 17376779 t gcesareni Bubr1 was phosphorylated by plk1 in vitro at two plk1 consensus sites in the kinase domain of bubr1 SIGNOR-153867 0.834 AKT3 protein Q9Y243 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251626 0.463 TIRAP protein P58753 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 25948473 t lperfetto Stimulation of Toll-like receptor (TLR) 4 leads to the activation of both MyD88-dependent and MyD88-independent pathways through the recruitment of adaptors TIRAP/MyD88 and TRIF/TRAM, respectively. SIGNOR-110215 0.62 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR ERN1 protein O75460 UNIPROT up-regulates 9606 31226023 f miannu Besides being activated like PERK via dissociation of GRP78, IRE1 is also activated by direct binding of the unfolded protein to its N-terminal luminal domain SIGNOR-260175 0.7 REST protein Q13127 UNIPROT CARTPT protein Q16568 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 18485095 f miannu When expression of NRSF was down-regulated in HeLa cells using a RNA interfering technique, the transcriptional activity of the CART promoter or a NRSE reporter was significantly increased. Taken together, our data suggested that CART gene expression in neuroendocrine cells is strictly controlled by NRSF, via a mechanism dependent upon the CART NRSE. SIGNOR-255073 0.2 Cohesin complex complex SIGNOR-C304 SIGNOR Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 30544080 f miannu Cohesin, one of structural maintenance of chromosomes (SMC) complexes, forms a ring-shaped protein complex, and mediates sister chromatid cohesion for accurate chromosome segregation and precise genome inheritance. SIGNOR-264523 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PDE4D protein Q08499 UNIPROT down-regulates phosphorylation 9606 10828059 t The effect has been demonstrated using Q08499-2 gcesareni These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro. SIGNOR-270174 0.2 GAD1 protein Q99259 UNIPROT gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI up-regulates quantity chemical modification 9606 32041144 t miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. SIGNOR-267552 0.8 MAOB protein P27338 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-264002 0.8 PRKCA protein P17252 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Ser29 ATPAARAsKKILLPE 9606 BTO:0000007 11042191 t lperfetto Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells. SIGNOR-249058 0.2 Dynorphin B chemical CHEBI:80347 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258798 0.8 PLK1 protein P53350 UNIPROT ESPL1 protein Q14674 UNIPROT down-regulates activity phosphorylation Ser1399 KVNFSDDsDLEDPVS 9606 BTO:0002181 17974570 t miannu Although mutation of serine 1126 and threonine 1346 to alanine had no effect (lanes 2 and 5), additional mutation of threonine 1363 and serine 1399 rendered separase almost completely resistant to phosphorylation (lane 3). Serine 1399 seems to be the one residue within this large separase fragment that is most efficiently phosphorylated by polo-like kinase, because a corresponding point mutation was sufficient to reduce the labeling by 80% compared with wild type (lane 6). SIGNOR-276082 0.763 IKBKB protein O14920 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity phosphorylation Ser144 NSDESNFsEKLRAST 9606 BTO:0000007 16818229 t miannu Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling. SIGNOR-276289 0.764 PTPA protein Q15257 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 21159657 t gcesareni Consistent with previous reports (2830), we found that expression of sv40st, suppression of either pp2a c or b resulted in elevated levels of akt phosphorylation (ser473) SIGNOR-252607 0.2 GRK6 protein P43250 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. SIGNOR-251207 0.292 IL11 protein P20809 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 9143707 t gcesareni Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-4 SIGNOR-48033 0.703 AKT1 protein P31749 UNIPROT AR protein P10275 UNIPROT down-regulates phosphorylation Ser215 SGRAREAsGAPTSSK 9606 BTO:0000938 17470458 t acerquone The work presented here is the first demonstration that phosphorylation at s215 and s792 by akt regulates ligand binding, and the subcellular distribution of the receptor SIGNOR-154631 0.604 TNKS protein O95271 UNIPROT TARDBP protein Q13148 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0000142 32409565 t lperfetto Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation. SIGNOR-262115 0.2 HDAC1 protein Q13547 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16431920 f fspada These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome SIGNOR-143955 0.446 TCF4 protein P15884 UNIPROT SSTR2 protein P30874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001976 10207097 t Luana Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain. SIGNOR-261618 0.365 EEF1A2 protein Q05639 UNIPROT Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269527 0.8 ACVR1B protein P36896 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by stabilization 9606 2920215 f Regulation miannu Activin, also named FSH-releasing protein, was previously shown to induce hemoglobin accumulation in K562 cells and potentiate the proliferation and differentiation of CFU-E in human bone marrow cultures. SIGNOR-251769 0.2 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257987 0.8 SUN5 protein Q8TC36 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 t lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. SIGNOR-263289 0.329 MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 15568999 t lperfetto Msk1 (mitogen- and stress-activated protein kinase) is a kinase activated in cells downstream of both the erk1/2 (extracellular-signal-regulated kinase) and p38 mapk (mitogen-activated protein kinase) cascades. In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites SIGNOR-131375 0.595 EEF1A1 protein P68104 UNIPROT Translational_elongation phenotype SIGNOR-PH210 SIGNOR up-regulates 9606 23699257 f lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269393 0.7 STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 19029990 f lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. SIGNOR-249498 0.524 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB1 protein Q9Y5G3 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265703 0.2 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation Tyr161 QGWVPSNyITPVNSL -1 34144039 t miannu  PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. SIGNOR-277306 0.308 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 9373175 t gcesareni Evidence that the inhibition of glycogen synthase kinase-3_ by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9 SIGNOR-242578 0.2 RXR proteinfamily SIGNOR-PF44 SIGNOR PPARG protein P37231 UNIPROT up-regulates activity binding 9606 11237216 t miannu Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology SIGNOR-259057 0.2 ROS stimulus SIGNOR-ST2 SIGNOR MAP3K5 protein Q99683 UNIPROT up-regulates 9606 11266364 f lperfetto TNF- but not Fas-induced apoptosis requires ROS-dependent activation of ASK1_JNK/p38 pathways. Thus, ASK1 is selectively required for TNF- and oxidative stress-induced sustained activations of JNK/p38 and apoptosis. SIGNOR-226609 0.7 perfluorooctanoic acid chemical CHEBI:35549 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 23764977 t miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  SIGNOR-268765 0.8 HRH4 protein Q9H3N8 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256815 0.41 RAF1 protein P04049 UNIPROT STK4 protein Q13043 UNIPROT down-regulates binding 9606 22898666 t gcesareni Raf1 binding to mst2 sarah domain interdicts mst2 homodimerization and autoactivation, and recruits protein phosphates 2a thereby promoting mst2 inactivation. SIGNOR-191843 0.275 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2V1 protein Q13404 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271321 0.562 MLXIPL protein Q9NP71 UNIPROT ELOVL6 protein Q9H5J4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 27524233 t Luana In this study, we clearly show that mouse and human Elovl6 are direct targets of ChREBP.  SIGNOR-267945 0.407 TNFSF13 protein O75888 UNIPROT TNFRSF13B protein O14836 UNIPROT up-regulates binding 9606 10956646 t gcesareni Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys. SIGNOR-81308 0.699 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates activity binding 9606 BTO:0000222 16982699 t lperfetto More importantly, the consequences of phosphorylation of either Thr145 or Ser146 are distinct. When p21 is phosphorylated on Thr145, it localizes to the nucleus and results in the disruption of the association between proliferating cell nuclear antigen and p21. Furthermore, phosphorylation of Thr145 promotes stabilization of p21 SIGNOR-244187 0.2 SLC24A4 protein Q8NFF2 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264402 0.8 ING2 protein Q9H160 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001913 19437536 f miannu ING2 is upregulated in colon cancer and increases invasion by enhanced MMP13 expression. SIGNOR-254491 0.394 tRNA(Thr) smallmolecule CHEBI:29180 ChEBI Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates quantity precursor of 9606 25824639 t miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. SIGNOR-270507 0.8 MBOAT7 protein Q96N66 UNIPROT 2-acyl-sn-glycero-3-phospho-D-myo-inositol smallmolecule CHEBI:62746 ChEBI down-regulates quantity chemical modification -1 18772128 t miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. SIGNOR-267246 0.8 LRRFIP2 protein Q9Y608 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 15677333 t gcesareni In particular, a previously unrecognized activator, lrrfip2 (leucine-rich repeat in flightless interaction protein 2), was found that interacts with dvl to increase the cellular levels of _-catenin and activate _-catenin/lef/tcf-dependent transcriptional activity SIGNOR-133429 0.395 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 21079800 t gcesareni Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis. SIGNOR-169690 0.695 BRMS1 protein Q9HCU9 UNIPROT EP300 protein Q09472 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 23269275 t miannu BRMS1 suppresses lung cancer metastases through an E3 ligase function on histone acetyltransferase p300. BRMS1 induces polyubiquitination of p300, resulting in its proteasome-mediated degradation. SIGNOR-266408 0.371 MAPK1 protein P28482 UNIPROT TXNIP protein Q9H3M7 UNIPROT down-regulates quantity by destabilization phosphorylation Thr349 HRLESPTtPLLDDMD 9606 BTO:0000018 31320475 t miannu ERK-dependent Txnip ubiquitination and proteasome degradation depended upon phosphorylation of a PXTP motif threonine (Thr349) located within the C-terminal α-arrestin domain and proximal to a previously characterized E3 ubiquitin ligase-binding site.  SIGNOR-277468 0.299 4-[2-(2-chloro-4-fluoroanilino)-5-methyl-4-pyrimidinyl]-N-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]-1H-pyrrole-2-carboxamide chemical CHEBI:95049 ChEBI MAPK1 protein P28482 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001271 31482470 t miannu In the present study, we have shown that ERK2 inhibitor VX-11e demonstrates a potent synergy with voreloxin in leukemia cell lines and that this effect is associated with the inhibition of proliferation, cell cycle arrest and induction of apoptosis. SIGNOR-262244 0.8 HTR2B protein P41595 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257228 0.41 SRC protein P12931 UNIPROT CHKA protein P35790 UNIPROT up-regulates activity phosphorylation Tyr197 RSLGPKLyGIFPQGR 9606 BTO:0000093 21822308 t miannu We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333. SIGNOR-266351 0.342 PRKAA1 protein Q13131 UNIPROT KIF4A protein O95239 UNIPROT up-regulates activity phosphorylation Ser801 KLRRRTFsLTEVRGQ -1 28992084 t miannu We found that the strong direct substrate KIF4A is phosphorylated by AMPK at Ser801.Using in vitro kinase assays, we found that active AMPK and Aurora B phosphorylated KIF4A at Ser801 and Thr799 respectively in a time-dependent manner (Figure 5D). KIF4A is phosphoregulated by AMPK and Aurora B. Although AMPK phosphorylation increased the ATPase activity of KIF4A, Aurora B phosphorylation resulted in a stronger increase (Figure 5I), which might be consistent with the more powerful kinase function of Aurora B during mitosis. SIGNOR-265991 0.2 dactolisib chemical CHEBI:71952 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 BTO:0000848 21803746 t ATP-competitive inhibitor of PI3K and mTOR gcesareni The dual pi3k and mtorc1/2 inhibitor bez235 was highly specific SIGNOR-175715 0.8 SMARCD1 protein Q96GM5 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270722 0.748 tandutinib chemical CHEBI:90237 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207212 0.8 HTR1E protein P28566 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256705 0.424 PZP protein P20742 UNIPROT MMP9 protein P14780 UNIPROT down-regulates activity binding -1 9344465 t lperfetto Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. SIGNOR-261802 0.356 mTORC2 complex SIGNOR-C2 SIGNOR MYC protein P01106 UNIPROT up-regulates 9606 24856037 f miannu MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity SIGNOR-256171 0.36 PRKCI protein P41743 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000527 21419810 t lperfetto In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer SIGNOR-172886 0.325 SF3B3 protein Q15393 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270665 0.803 terazosin chemical CHEBI:9445 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001260 9379432 t miannu Pharmacological management of benign prostatic hyperplasia (BPH) has most successfully been achieved by administration of α1 antagonists, which function via relaxation of prostatic smooth muscle. Terazosin2 (2), doxazosin3 (3), and alfuzosin4 (4), agents currently approved for this indication SIGNOR-258671 0.8 GRB2 protein P62993 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates binding 9606 BTO:0000782 9891069 t gcesareni The first and second proline-rich motifs containing the grb2 n-sh3-binding consensus sequence (-p-x-x-p-x-r/k-) were implicated in the binding of hpk1 to grb2. SIGNOR-63994 0.465 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120012 0.781 RNF41 protein Q9H4P4 UNIPROT USP8 protein P40818 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 23750007 t irozzo RNF41 redistributes and ubiquitylates USP8, and reduces USP8 levels. SIGNOR-259106 0.876 MTCP1 protein P56278 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation SIGNOR-81677 0.341 NRBF2 protein Q96F24 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates activity binding 9606 BTO:0001938 phosphorylation:Ser113;Ser120 AEDAEGQsPLSQKYS;SPLSQKYsPSTEKCL 28059666 t miannu NRBF2 S113 and S120 phosphorylation negatively regulates autophagy. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity. SIGNOR-265879 0.679 GDAP1 protein Q8TB36 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 33610749 f lperfetto However, it remains elusive if additional proteins are involved in the regulation of mitochondrial fission, such as proposed fission factor GDAP1 SIGNOR-272977 0.7 LRRC4B protein Q9NT99 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 19467332 t miannu A possible function for the NGL–PSD-95 interaction is to couple trans-synaptic adhesion events to the recruitment of PSD-95 and other PSD-95-associated postsynaptic proteins. PSD-95 and liprin-α may be key synaptic scaffolding proteins that couple trans-synaptic adhesions to the assembly of synaptic proteins/vesicles SIGNOR-264052 0.378 SREBF1 protein P36956 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 t gcesareni Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk) SIGNOR-142297 0.294 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser63 AAEERRKsHEAEVLK 9606 8376365 t gcesareni Phosphorylation at either ser(16) or ser(63) strongly reduced or abolished the ability of stathmin to bind to and sequester soluble tubulin and its ability to act as a catastrophe factor by directly binding to the microtubules. The known in vivo phosphorylation sites of stathmin are ser-16 and ser-63 for cyclic amp-dependent protein kinase (pka). SIGNOR-38322 0.314 clozapine chemical CHEBI:3766 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258369 0.8 CLCN4 protein P51793 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates quantity relocalization 9606 28972156 t miannu ClC-3 and ClC-4 are two closely related intracellular chloride/proton exchangers that co-exist in neurons, glia, muscle, heart, and epithelial cells. ClC-4 is an intracellular Cl-/H+ exchanger that is highly expressed in the brain and whose dysfunction has been linked to intellectual disability and epilepsy. ClC-4 is retained in the endoplasmic reticulum (ER) upon overexpression in HEK293T cells. SIGNOR-265421 0.8 RPS6KA3 protein P51812 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 2846551 t gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. SIGNOR-23753 0.2 ITSN1 protein Q15811 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000567 30540523 t lperfetto Significantly, here we identify the long isoform of ITSN-1, which has Cdc42 GEF activity| We propose that GCC88 recruits ITSN-1-L to the TGN, which in turn activates Cdc42 at the trans-face of the Golgi (Figure 9A). SIGNOR-260612 0.843 NMDA receptor_2D complex SIGNOR-C350 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264135 0.7 CHD3 protein Q12873 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263843 0.802 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Thr105 LQTFGHNtMDAVPKI 9606 BTO:0000007 21321328 t miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). SIGNOR-276306 0.595 WT1 protein P19544 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9867871 t miannu The human copper-zinc superoxide dismutase gene (SOD1) proximal promoter is regulated by Sp1, Egr-1, and WT1 via non-canonical binding sites. Egr-1 and two splicing variants of the Egr-related protein WT1 were able to transactivate the SOD1 promoter in co-transfection experiments. SIGNOR-253898 0.268 MAPK1 protein P28482 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates activity phosphorylation Thr906 SLDNNYStPNERGDH 9615 BTO:0000837 32010791 t miannu  Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation. SIGNOR-277505 0.273 SOX4 protein Q06945 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 BTO:0000038 17875931 t irozzo We have demonstrated that Sox17 and Sox4 can directly interact with β-catenin and TCF/LEF proteins.Sox4 enhances β-catenin/TCF activity and the proliferation of SW480 cells.In contrast, Sox4 may function to stabilize β-catenin protein. SIGNOR-256138 0.576 CAMK2A protein Q9UQM7 UNIPROT SYNGAP1 protein Q96PV0 UNIPROT up-regulates activity phosphorylation Thr1077 RGKSQQLtVSAAQKP -1 15358237 t miannu Certain phosphopeptides were detected only in samples phosphorylated in vitro under conditions that favor CaMKII activity (Mg2+-ATP, Ca2+, calmodulin, and peptide inhibitors of PKA and PKC). In samples phosphorylated in vitro in the presence of Ca2+/calmodulin, we also detected the peptide (R)GKS*QQLT*VSAAQKPR with phosphorylated residues corresponding to S-1058 and T-1062 of synaptic ras GTPase activating protein (SynGAP). SIGNOR-262691 0.439 Fatty acid stimulus SIGNOR-ST19 SIGNOR SIRT6 protein Q8N6T7 UNIPROT up-regulates 9606 25815987 t miannu Intriguingly, SIRT6 is chromatin bound, controls lipid metabolism, and is enzymatically activated by fatty acids SIGNOR-268156 0.7 IKBKB protein O14920 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22056382 f Tnf-α enhanced the transcriptional activity of a classical Notch target gene via Ikk2 by inducing histone H3 phosphorylation SIGNOR-253585 0.2 TNF protein P01375 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates 9606 10485710 f gcesareni Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k) SIGNOR-70622 0.267 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 t The effect has been demonstrated using Q01196-8. gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-138961 0.599 CNOT1 protein A5YKK6 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268300 0.891 RNA Polymerase II complex SIGNOR-C391 SIGNOR precursor messenger RNA smallmolecule CHEBI:139356 ChEBI up-regulates quantity chemical modification 9606 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. SIGNOR-266176 0.8 PRPF3 protein O43395 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and L√ºhrmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-271967 0.767 EDNRB protein P24530 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257254 0.433 CH5132799 chemical CID:49784945 PUBCHEM MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190937 0.8 CSNK2A1 protein P68400 UNIPROT G3BP1 protein Q13283 UNIPROT down-regulates activity phosphorylation Ser149 VTEPQEEsEEEVEEP 9606 BTO:0001938 27920254 t miannu We also show that casein kinase 2 phosphorylates G3BP1 at serine 149 in vitro and in cells. These data support a role for casein kinase 2 in regulation of protein synthesis by downregulating stress granule formation through G3BP1.CK2 regulates SG disassembly during stress recovery.G3BP1 is among the strongest SG nucleating proteins, and previous work indicated that G3BP1 phosphorylation at S149 restricts stress granule assembly by partly inhibiting G3BP1 oligomerization SIGNOR-260748 0.241 PTPRJ protein Q12913 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr868 GSVEMCRyDPLQDNT 9606 28912580 t miannu These results support PTPRJ preferentially dephosphorylating Y813 and Y868 in JAK2.|We revealed that PTPRJ negatively regulates leptin signaling by dephosphorylating specific tyrosine residues (Y813 and Y868) in JAK2, the simultaneous phosphorylation of which plays a pivotal role in JAK2 activation. SIGNOR-277094 0.329 AURKB protein Q96GD4 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser29 ATKAARKsAPATGGV 9606 11856369 t Ser 27 (29) phosphorylation of H3 isinhibitory as induces transcription. gcesareni Histone code pathway involving h3 s28 phosphorylation and k27 acetylation activates transcription and antagonizes polycomb silencingaurora-b phosphorylates histone h3 at serine28 with regard to the mitotic chromosome condensation SIGNOR-114852 0.2 PTEN protein P60484 UNIPROT AR protein P10275 UNIPROT up-regulates activity dephosphorylation Ser83 QQQQQETsPRQQQQQ 9606 24480624 f miannu Furthermore, PTEN depletion increased AR protein instability, and this effect was further enhanced by p300 silencing in LAPC4 cells .|Our data demonstrate that loss of PTEN increases AR phosphorylation at Ser81 and that Ser81 phosphorylation acts as a molecular beacon that is required for the binding of p300, a key event that subsequently leads to AR acetylation, inhibition of AR ubiquitination and AR stabilization (XREF_FIG). SIGNOR-277077 0.597 MAPKAPK2 protein P49137 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates phosphorylation Ser522 DTSYINTsLIQDYRH 9606 BTO:0001253 23202365 t llicata T he mitogen-activated protein kinase (mapk)-activated protein kinase-2 is a proinflammatory kinase and phosphorylates pias1 at the ser522 residue. Activation of mapk-activated protein kinase-2 enhances p53-sumoylation, but a pias1 phosphorylation mutant, pias1-s522a, abolished this p53-sumoylation, suggesting a critical role for pias1-s522 phosphorylation in its sumo ligase activity. SIGNOR-199944 0.2 USP7 protein Q93009 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity deubiquitination 24317448 t lperfetto BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP|hese data indicate that BCR-ABL phosphorylation of HAUSP modulates HAUSP’s deubiquitinase activity toward PTEN. SIGNOR-276533 0.731 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269365 0.719 PPARGC1A protein Q9UBK2 UNIPROT GPX1 protein P07203 UNIPROT up-regulates 10090 18074631 f lperfetto In fact, experiments with either genetic knockouts or RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins such as catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat. SIGNOR-253396 0.321 EGFR protein P00533 UNIPROT RASA1 protein P20936 UNIPROT unknown phosphorylation Tyr460 TVDGKEIyNTIRRKT 9606 1850098 t llicata We conclude that tyr-460 is a site of gap tyrosine phosphorylation by the egf receptor in vitro and likely in vivo. Gap tyr-460 is located immediately c terminal to the second gap sh2 domain, suggesting that its phosphorylation might have a role in regulating protein-protein interactions. SIGNOR-21875 0.64 PRKACA protein P17612 UNIPROT CIITA protein P33076 UNIPROT down-regulates activity phosphorylation Ser1050 AASLLRLsLYNNCIC 9606 BTO:0000984 11416140 t lperfetto Downregulation of ciita function by protein kinase a (pka)-mediated phosphorylation phosphorylation at ciita serines 834 and 1050 accounts for the inhibitory effects of pka on ciita-driven class ii mhc transcription. SIGNOR-108569 0.314 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser19 PAPPVRMsSTIFSTG -1 10075701 t miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites SIGNOR-250224 0.2 (4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-[3-(4,4-diphenyl-1-piperidinyl)propyl] ester O3-methyl ester chemical CHEBI:103931 ChEBI ADRA1B protein P35368 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258465 0.8 HOXD12 protein P35452 UNIPROT MAF protein O75444 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221887 0.374 PPM1F protein P49593 UNIPROT PAK proteinfamily SIGNOR-PF13 SIGNOR down-regulates dephosphorylation 9606 BTO:0000150;BTO:0000093 20016286 t inferred from 70% of family members gcesareni Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity. SIGNOR-269882 0.399 MAOA protein P21397 UNIPROT 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|It undergoes oxidative deamination, catalyzed by the enzyme monoamine oxidase (MAO) in the presence of flavin adenine dinucleotide (FAD), to produce reactive aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL). SIGNOR-264003 0.8 BAK1 protein Q16611 UNIPROT DIABLO protein Q9NR28 UNIPROT up-regulates relocalization 9606 14585074 t Translocation from Mitochondria to Cytosol amattioni Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi SIGNOR-118905 0.501 RPS6KB1 protein P23443 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser477 NSMNKLPsVSQLINP 9606 18769144 t lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively SIGNOR-180771 0.2 STAT5A protein P42229 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0004479 29507660 f irozzo FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance. SIGNOR-255733 0.421 MAPK3 protein P27361 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser476 MNILGSQsPLHPSTL 9606 15952796 t lperfetto Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation SIGNOR-138175 0.303 TFIID complex SIGNOR-C343 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity binding 9606 27096372 t miannu Our structures suggest that a primary function of TFIID during PIC assembly is the proper positioning of TBP on the upstream promoter, which ultimately determines the placement of Pol II relative to the TSS. The structures presented here offer a structural framework for understanding the complex mechanism underlying TFIID function, shedding new light into the overlapping roles of TFIID as both a coactivator and a general platform for PIC assembly in the coordination of transcription initiation. SIGNOR-263934 0.525 SMAD9 protein O15198 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR form complex binding 9606 20957627 t lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. SIGNOR-255268 0.672 PTPN11 protein Q06124 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK 10090 18482983 t we identify SHP-2 and PTP-PEST as negative regulators of c-Src kinase | Inactivation of catalytically active c-Src kinase by the phosphatases SHP-2 or PTP-PEST by dephosphorylation of the tyrosine residue Tyr-416 within the c-Src kinase domain prevents the phosphorylation of villin SIGNOR-248670 0.639 PTPN2 protein P17706 UNIPROT FKBP4 protein Q02790 UNIPROT down-regulates dephosphorylation 9606 BTO:0000567 12552015 t tpavlidou We have documented that a cellular protein that binds the immunosuppressant drug fk506, termed the fk506-binding protein (fkbp52), interacts with the single-stranded d sequence within the aav inverted terminal repeats, inhibits viral second-strand dna synthesis, and consequently limits high-efficiency transgene expression. Deliberate overexpression of the murine wild-type (wt) tc-ptp gene, but not that of a cysteine-to-serine (c-s) mutant, caused tyrosine dephosphorylation of fkbp52, leading to efficient viral second-strand dna synthesis and resulting in a significant increase in aav-mediated transduction efficiency in hela cells in vitro. SIGNOR-97794 0.408 ABL1 protein P00519 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Tyr1357 HPQAASIyQSSEMKG 9606 18765637 t lperfetto Tyrosine phosphorylation of the nuclear receptor coactivator aib1/src-3 is enhanced by abl kinase and is required for its activity in cancer cellstyrosine kinase directly phosphorylates aib1/src-3 at y1357 and modulates the association of aib1 with c-abl, eralpha, the transcriptional cofactor p300, SIGNOR-180571 0.355 SPRY4 protein Q9C004 UNIPROT TESK1 protein Q15569 UNIPROT down-regulates activity binding 9606 15584898 t miannu Spry4 negatively regulates the kinase activity of TESK1 by associating with it through the C-terminal cysteine-rich region of Spry4 SIGNOR-253032 0.582 COL21A1 protein Q96P44 UNIPROT DDR1 protein Q08345 UNIPROT up-regulates activity binding 9606 BTO:0001282 17318226 t lperfetto The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75.  SIGNOR-272341 0.2 AURKB protein Q96GD4 UNIPROT NDC80 protein O14777 UNIPROT down-regulates phosphorylation Ser5 sVSSGGAG 9606 20471944 t lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). SIGNOR-165562 0.841 FOXO3 protein O43524 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates quantity transcriptional regulation 10090 BTO:0002314 24749067 f gcesareni We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration. SIGNOR-254320 0.383 MRPL42 protein Q9Y6G3 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262354 0.683 SPRY2 protein O43597 UNIPROT CBLB protein Q13191 UNIPROT down-regulates binding 9606 11053437 t gcesareni One function of hspry2 in signaling processes downstream of rtks may be to modulate c-cbl physiological function such as that seen with receptor-mediated endocytosis. SIGNOR-83507 0.499 EP300 protein Q09472 UNIPROT TBXAS1 protein P24557 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 14565864 f miannu We also showed that forced expression of p300 upregulated TXAS gene in a dose-dependent manner. Mutation of NF-E2 site, but not TATA or initiator site, abolished the p300-mediated activation of TXAS gene. SIGNOR-253906 0.2 Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity deubiquitination 9606 25481026 t miannu Here we show that PLpro also inhibits IRF3 activation at a step after phosphorylation and that this inhibition is dependent on the de-ubiquitination (DUB) activity of PLpro. We found that PLpro is able to block the type I IFN induction of a constitutively active IRF3, but does not inhibit IRF3 dimerization, nuclear localization or DNA binding. However, inhibition of PLpro’s DUB activity by mutagenesis blocked the IRF3 inhibition activity of PLpro, suggesting a role for IRF3 ubiquitination in induction of a type I IFN innate immune response. SIGNOR-260249 0.2 CDC27 protein P30260 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 t lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. SIGNOR-252003 0.888 NFIL3 protein Q16649 UNIPROT SOSTDC1 protein Q6X4U4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 25338303 f lperfetto E4BP4 is a repressor of epigenetically regulated SOSTDC1 expression in breast cancer cells. SIGNOR-242767 0.2 GP1BB protein P13224 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR form complex binding 9606 BTO:0000132 16293600 t lperfetto The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbα, disulfide-linked to GPIbβ, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1. SIGNOR-261850 0.641 CRP protein P02741 UNIPROT GCH1 protein P30793 UNIPROT down-regulates activity 9606 BTO:0004602 17942113 f miannu The gene expression and enzymatic activity of GTPCH1, the first enzyme in the de novo biosynthesis of BH(4), were significantly inhibited by CRP. Importantly, GTPCH1 is known to be regulated by cAMP-mediated pathway. In the present study, CRP-mediated inhibition of GTPCH1 activity was reversed by pretreatment with cAMP analogues. SIGNOR-252215 0.282 CHRM2 protein P08172 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates 9606 BTO:0000007 12665513 f lperfetto Here we show that m2 muscarinic receptors and go require taos and mek3/6 as the primary intermediates activating p38 mapk in 293 cells SIGNOR-235536 0.332 PAMPs stimulus SIGNOR-ST11 SIGNOR COLEC11 protein Q9BWP8 UNIPROT up-regulates activity binding -1 20956340 t lperfetto We finally show that CL-11 binds to intact bacteria, fungi, and viruses and that CL-11 decreases influenza A virus infectivity and forms complexes with DNA|it is conceivable that CL-11 plays a role in activation of the complement system and in the defense against invading microorganisms. SIGNOR-263408 0.7 arachidonic acid smallmolecule CHEBI:15843 ChEBI PTGS2 protein P35354 UNIPROT up-regulates 9606 15878913 f miannu AA increases PC-3 prostate tumor cell growth, total DNA content and endogenous PGE 2 levels via induction of c-fos , cPLA 2 and cox-2 mRNA transcription. SIGNOR-255394 0.8 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000142 20308788 t The effect has been demonstrated using P10636-8 lperfetto Abnormal hyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in alzheimer's disease (ad). Gsk-3beta phosphorylated tau at many sites, with ser199, thr205, and ser396 being the most favorable sites in cells. SIGNOR-164651 0.728 TGFB1 protein P01137 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates activity binding 9606 16885528 t lperfetto The active form of TGF-beta is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge. SIGNOR-148605 0.2 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity precursor of 9606 11431483 t miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. SIGNOR-269686 0.8 BLK protein P51451 UNIPROT FCGR2C protein P31995 UNIPROT up-regulates activity phosphorylation Tyr294 YETADGGyMTLNPRA -1 8756631 t miannu Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation SIGNOR-262672 0.2 CENPC protein Q03188 UNIPROT CENP-A nucleosome complex SIGNOR-C321 SIGNOR up-regulates activity binding 9606 BTO:0000567 20566683 t miannu CENP-C is required for centromere assembly. CENP-C and CENP-N bind to different sites on the same CENP-A nucleosomes. CENP-C, like CENP-N, interacts directly and specifically with CENP-A nucleosomes. SIGNOR-263706 0.722 TNC protein P24821 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 9606 BTO:0000007 7559467 t lperfetto The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin. SIGNOR-253306 0.415 STK11 protein Q15831 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates activity phosphorylation Thr183 SDGEFLRtSCGSPNY -1 16054095 t lperfetto The AMP-activated protein kinase (AMPK) is a critical regulator of energy balance at both the cellular and whole-body levels. Two upstream kinases have been reported to activate AMPK in cell-free assays, i.e., the tumor suppressor LKB1 and calmodulin-dependent protein kinase kinase. SIGNOR-139297 0.582 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1E protein P28566 UNIPROT up-regulates activity chemical activation 9534 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258568 0.8 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 10116 BTO:0000575 15738637 t In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver. SIGNOR-248445 0.289 CDK1 protein P06493 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1354 DFVPSDAsPPKTKTS 9606 BTO:0000567 7635160 t llicata We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. we have also shown that phosphorylation of ser1353 and ser1360 yields different phosphopeptide maps depending upon whether one or both of these sites are phosphorylated. SIGNOR-30248 0.539 RUNX2 protein Q13950 UNIPROT MMP2 protein P08253 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001610 22641097 f miannu Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells. SIGNOR-255082 0.334 IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 20966354 t lperfetto Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin. SIGNOR-252695 0.759 PTH1R protein Q03431 UNIPROT DKK1 protein O94907 UNIPROT down-regulates quantity 28363951 f lperfetto Furthermore, PTH acts on osteocytes to suppress the expression of sclerostin, an inhibitor of canonical Wnt signaling (Li, et al. 2005; Semenov, et al. 2005)). PTH action on sclerostin is primarily through cAMP signaling (Keller and Kneissel 2005) and mediated by Myocyte enhancer factor-2 (MEF2) transcriptional regulators (Leupin, et al. 2007). Using the cAMP signaling pathway in osteoblasts, PTH also inhibits the expression of Dickkopf 1 (Dkk1) (Guo et al. 2010a), which is another Wnt pathway inhibitor  SIGNOR-270553 0.316 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR Platelet_Adhesion phenotype SIGNOR-PH137 SIGNOR up-regulates 9606 BTO:0000132 25297919 f lperfetto VWF binding to GPIb-IX-V induces platelet activation, converting the major integrin αIIbβ3 from a low affinity to a high affinity receptor capable of engaging the C4 domain of VWF. This last step is essential for stable adhesion SIGNOR-261867 0.7 HTR1A protein P08908 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257197 0.252 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA5 protein Q9Y5G8 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265695 0.2 REST protein Q13127 UNIPROT PENK protein P01210 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21832040 f miannu HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK). SIGNOR-255074 0.2 ITGB2 protein P05107 UNIPROT AM/b2 integrin complex SIGNOR-C170 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253192 0.744 PIM1 protein P11309 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 18467333 t gcesareni Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt. SIGNOR-178615 0.397 NRAS protein P01111 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 21779497 t lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-252700 0.665 INCENP protein Q9NQS7 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates binding 9606 12925766 t gcesareni Using recombinant proteins, we found that aurora b kinase activity was stimulated by incenp and that the c-terminal region of incenp was sufficient for activation. SIGNOR-86218 0.973 CDK2 protein P24941 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 15964852 t lperfetto Cdk2 destabilizes p21 via the cy2 cyclin-binding motif and p21 phosphorylation at ser-130. SIGNOR-149416 0.953 MECP2 protein P51608 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates activity binding 9606 BTO:0000007 12473678 t Luana Thus, these results indicate that MeCP2-interacting Dnmt1 has significant maintenance DNA methyltransferase activity and that MeCP2 does not vanish Dnmt1 enzymatic activity. SIGNOR-264541 0.544 STK38 protein Q15208 UNIPROT PANX2 protein Q96RD6 UNIPROT up-regulates activity phosphorylation Ser514 KKHARHFsLDVHPYI 10090 BTO:0000142 22445341 t miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. SIGNOR-263032 0.2 PRKD1 protein Q15139 UNIPROT CDH1 protein P12830 UNIPROT up-regulates phosphorylation 9606 BTO:0001130 15695390 t gcesareni Our study has identified e-cadherin as a novel substrate of pkd1, and phosphorylation of e-cadherin by pkd1 is associated with increased cellular aggregation and decreased cellular motility in prostate cancer. SIGNOR-133856 0.462 MAPK12 protein P53778 UNIPROT JUNB protein P17275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10330170 f gcesareni Moreover, in addition to jnk, erk5, p38alpha, and p38gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements. SIGNOR-67532 0.371 U0126 chemical CHEBI:90693 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 11160424 t gcesareni The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. U0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2. SIGNOR-104942 0.8 BBC3 protein Q9BXH1 UNIPROT BCL2L2 protein Q92843 UNIPROT down-regulates binding 9606 15694340 t gcesareni Only bimbh3 and bbc3 had comparable strong affinitiesfor all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1. SIGNOR-133814 0.568 SMO protein Q99835 UNIPROT ARRB1 protein P49407 UNIPROT up-regulates binding 9606 23074268 t The binding occours if Smo is phosphorylated gcesareni Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2 SIGNOR-199150 0.62 PRKCD protein Q05655 UNIPROT TACSTD2 protein P09758 UNIPROT down-regulates activity phosphorylation Ser322 GELRKEPsL 9606 BTO:0001109 31177095 t done miannu  Analyses using HCT116 cells expressing WT Trop-2 (HCT116/WT) or Trop-2 alanine-substituted at Ser-303 (HCT116/S303A) or Ser-322 (HCT116/S322A) revealed that Trop-2 is phosphorylated at Ser-322. sing protein kinase C (PKC) inhibitors and PKC-specific siRNAs, we found that PKCα and PKCδ are responsible for Trop-2 phosphorylation. SIGNOR-273820 0.2 UV stress stimulus SIGNOR-ST7 SIGNOR MAP3K4 protein Q9Y6R4 UNIPROT up-regulates 9606 9305639 f lperfetto Overexpression of a dominant-negative MTK1 mutant [MTK1(K/R)] strongly inhibited the activation of the p38 pathway by environmental stresses (osmotic shock, UV and anisomycin)[]These results indicate that MTK1 is a major mediator of environmental stresses that activate the p38 MAPK pathway SIGNOR-226605 0.7 PRKDC protein P78527 UNIPROT TOP1 protein P11387 UNIPROT down-regulates quantity by destabilization phosphorylation Ser10 GDHLHNDsQIEADFR 9606 BTO:0002201 28415827 t miannu Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1.  SIGNOR-277352 0.459 SERPINA1 protein P01009 UNIPROT F2 protein P00734 UNIPROT down-regulates activity binding 9606 BTO:0000131 17635716 t lperfetto Alpha1PI, historically known as alpha1-antitrypsin, is a 51 kDa, 394 amino acid glycoprotein, synthesized in the liver, circulating at c. 1.3 mg mL-1 with a half-life of 4.5 days SIGNOR-263524 0.433 HBB protein P68871 UNIPROT Hemoglobin complex SIGNOR-C209 SIGNOR form complex binding 9606 18179859 t miannu AHSP does not bind to β-hemoglobin (βHb) or the hemoglobin tetramer, instead, it specifically binds to free αHb, avoiding its precipitation and its pro-oxidant activity. In the presence of βHb, the αHb-AHSP complex is dismembered and βHb displaces AHSP to generate the quaternary structure of hemoglobin SIGNOR-255275 0.7 AVPR1B protein P47901 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257264 0.41 DDX39B protein Q13838 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 t miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. SIGNOR-268512 0.903 SP1 protein P08047 UNIPROT CADM1 protein Q9BY67 UNIPROT up-regulates quantity by expression transcriptional regulation 18794147 f lperfetto Treatment with mithramycin A, an inhibitor of Sp1 or Sp3 binding, resulted in reduction of Cadm1 gene expression, therefore suggesting a potential role of Sp1/Sp3 in Cadm1 regulation. SIGNOR-268958 0.255 GNG3 protein P63215 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 17419683 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-154258 0.358 SHH protein Q15465 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887 17688959 f lperfetto Most importantly, we report that shh induces mapk/erk and phosphoinositide 3-kinase (pi3k)-dependent akt phosphorylation and that activation of both signaling pathways is essential for shh's signaling in muscle cells. However, the effect of shh on akt phosphorylation is more robust than that on mapk/erk, and data suggest that shh influences these pathways in a manner similar to igf-i. SIGNOR-244446 0.482 SDHB protein P21912 UNIPROT SDH complex SIGNOR-C400 SIGNOR form complex binding 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. SIGNOR-266272 0.965 FUBP1 protein Q96AE4 UNIPROT KIT protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30500954 f irozzo Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug. SIGNOR-259132 0.2 ATM protein Q13315 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation Ser162 TCSENGVsLCLPRLE 9606 23435430 t miannu Here we uncover ATM as a novel positive modulator of ITCH E3-ubiquitin ligase activity. A single residue on ITCH protein, S161, which is part of an ATM SQ consensus motif, is required for ATM-dependent activation of ITCH. SIGNOR-276488 0.267 TGFB1 protein P01137 UNIPROT ACTA2 protein P62736 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000764 20846954 f Regulation miannu We used diploid human lung fibroblasts (WI38 cells) induced by TGFβ to differentiate into myofibroblast-like cells. In order to characterize this system, we first studied the expression of the myofibroblast marker genes ACTA2 (coding for smooth muscle α-actin; SMA), COL4A1 (encoding collagen type IV α1) and SM22A (coding for smooth muscle protein 22-α). As shown in Figure 1A and B, TGFβ induced the expression all three genes. SIGNOR-251923 0.429 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Ser2612 MFVETQAsQGTLQTR 9606 BTO:0000773 12186630 t lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. SIGNOR-249155 0.2 PRKACA protein P17612 UNIPROT SOX9 protein P48436 UNIPROT up-regulates phosphorylation Ser64 EPDLKKEsEEDKFPV 9606 15889150 t llicata We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta. SIGNOR-137089 0.446 F2RL1 protein P55085 UNIPROT RARG protein P13631 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 21072196 f miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). SIGNOR-254858 0.2 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 BTO:0000007 18204439 t lperfetto Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation. SIGNOR-252959 0.71 PRKCA protein P17252 UNIPROT ICOSLG protein O75144 UNIPROT up-regulates activity phosphorylation Ser285 RDRCLQHsYAGAWAV 9606 BTO:0000567 24837102 t done miannu PKCα and PKCβ are required for phosphorylation of ICOSL and ICOSL-mediated cytokine induction. Therefore, S285 is required for PKC substrate (serine) phosphorylation of ICOSL, and each of the upstream arginines is similarly required for this phosphorylation. SIGNOR-273798 0.2 AURKB protein Q96GD4 UNIPROT RPRD1B protein Q9NQG5 UNIPROT up-regulates activity phosphorylation Ser145 KATEEKKsLKRTFQQ 30518842 t lperfetto Mechanistically, we revealed that CREPT/RPRD1B interacted with Aurora B to regulate the expression of Cyclin B1 in gastric cancer cells. Interestingly, Aurora B phosphorylates S145 in a well-conserved motif of CREPT/RPRD1B. We proposed that phosphorylation of CREPT/RPRD1B by Aurora B is required for promoting the transcription of Cyclin B1 SIGNOR-265499 0.2 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation 9606 12832467 t lperfetto Efficient rsk activation by erk requires its interaction through a docking site located near the c terminus of rsk SIGNOR-252749 0.753 KDM6A protein O15550 UNIPROT ELK3 protein P41970 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29736013 t miannu Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase SIGNOR-260037 0.2 JMJD6 protein Q6NYC1 UNIPROT MEPCE protein Q7L2J0 UNIPROT down-regulates activity cleavage Arg171 HPAFKRRrRVNSDCD 10090 BTO:0002572 32048991 t miannu JMJD6 cleaves MePCE. we propose that JMJD6 is the cognate protease of MePCE and cleaves at the R171 site within MePCE. Experiments using purified JMJD6 showed that it could make a cut in an enzyme called MePCE, which belongs to the group of proteins that hold P-TEFb in its inactive form. The levels of activated Pol II were lower in cells without JMJD6 and higher in those without MePCE. Together, the results suggest that JMJD6 cuts MePCE to release P-TEFb, which then activates Pol II. SIGNOR-261037 0.272 SMAD3 protein P84022 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 t lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229557 0.7 SLC4A10 protein Q6U841 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates quantity relocalization 9606 23056253 t miannu The sodium-driven chloride bicarbonate exchanger NCBE (Slc4a10), a member of the SLC4 family of bicarbonate transporters, uses the transmembrane gradient of sodium to drive cellular net uptake of bicarbonate and to extrude chloride, thereby modulating both intracellular pH (pH(i)) and chloride concentration ([Cl(-)](i)) in neurons.  SIGNOR-264686 0.8 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr255 DLPDMKEtKYTVDKR 9606 11152499 t tpavlidou We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity. SIGNOR-85773 0.2 L3MBTL1 protein Q9Y468 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity binding 9606 29018219 t lperfetto L3MBTL1, a tumor suppressor with high affinity for H4K20me2, can block 53BP1 binding at DSBs SIGNOR-262059 0.413 MDH2 protein P40926 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266286 0.8 CDC25B protein P30305 UNIPROT CDK1 protein P06493 UNIPROT up-regulates dephosphorylation 9606 SIGNOR-C17 7880537 t gcesareni Cdc25 dephosphorylates cdc2/cdk1 within the activation loop of the kinase domain to achieve full activity of the cyclin-cdk complex SIGNOR-34541 0.823 AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000150;BTO:0001130 16854453 t gcesareni Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity. SIGNOR-147963 0.688 CASP8 protein Q14790 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261760 0.376 GAS6 protein Q14393 UNIPROT AXL protein P30530 UNIPROT up-regulates binding 9606 16362042 t gcesareni Receptor tyrosine kinases of the axl family are activated by the vitamin k-dependent protein gas6. We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function. SIGNOR-143109 0.906 P2RY14 protein Q15391 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256723 0.377 CB-5083 chemical CID:73051434 PUBCHEM VCP protein P55072 UNIPROT down-regulates activity chemical inhibition -1 26565666 t miannu Herein we describe our lead optimization efforts focused on in vitro potency, ADME, and pharmaceutical properties that led to the discovery of a potent, ATP-competitive, D2-selective, and orally bioavailable p97 inhibitor 71, CB-5083. SIGNOR-260189 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RCAN1 protein P53805 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000165 12063245 t inferred from 70% family members lperfetto Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. SIGNOR-270026 0.2 GRM2 protein Q14416 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 t miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. SIGNOR-264079 0.341 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser221 PRTSPIMsPRTSLAE 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248518 0.387 STK24 protein Q9Y6E0 UNIPROT RAB8A protein P61006 UNIPROT up-regulates activity phosphorylation Thr72 AGQERFRtITTAYYR -1 32227113 t lperfetto In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. |Overall our data suggests that the phosphorylation of Rab8A at Ser111 may influence Switch II-binding by regulators, thus disrupting interactions with its cognate GEF and moderately impairs its interaction with GAPs.|The antagonistic interplay between Ser111 phosphorylation and Thr72 phosphorylation is genetically concordant with how respective mutations in PINK1 and LRRK2 cause Parkinson’s disease SIGNOR-260265 0.278 SL0101 chemical CID:10459196 PUBCHEM RPS6KA3 protein P51812 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207075 0.8 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser129 VNTRAGPsQHSSPAV 9606 BTO:0000671 12628002 t lperfetto Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149) SIGNOR-99127 0.691 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI IGF1R protein P08069 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258116 0.8 ERBB2 protein P04626 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 10085134 t gcesareni Shc interacts with and is an excellent substrate for erbb2 and appears to play an important role in mitogenic signaling through this receptor tyrosine kinase SIGNOR-65579 0.8 phenytoin chemical CHEBI:8107 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258160 0.8 RUNX1 protein Q01196 UNIPROT KIT protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30500954 f irozzo Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug. SIGNOR-259133 0.34 CALM2 protein P0DP24 UNIPROT GEM protein P55040 UNIPROT up-regulates activity binding 10116 BTO:0001009 14701738 t miannu Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells. SIGNOR-266326 0.2 AKT1 protein P31749 UNIPROT VCP protein P55072 UNIPROT up-regulates phosphorylation Ser746 AMRFARRsVSDNDIR 9606 BTO:0000150 16551632 t llicata Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I SIGNOR-252492 0.523 MAPK14 protein Q16539 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 t lperfetto Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif ((68)nqsllspl) and becomes phosphorylated in cultured cells and organs during mitosis, cell stress, and apoptosis. Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase.The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. SIGNOR-114079 0.575 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser257 QIRLRRDsKEANARR -1 9677319 t llicata CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. SIGNOR-250945 0.318 MAPK1 protein P28482 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Ser529 SPMFKFSsPIVKSTE 9606 19767751 t llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. SIGNOR-188123 0.397 C3 protein P01024 UNIPROT C5 convertase complex complex SIGNOR-C312 SIGNOR form complex binding cleavage:Arg748 ASHLGLArSNLDEDI 31331124 t complement C3b fragment: PRO_0000005911 lperfetto C3b associates with C3 convertase to form C5 convertase and cleaves C5. SIGNOR-263448 0.2 EEF2K protein O00418 UNIPROT EEF2K protein O00418 UNIPROT down-regulates phosphorylation Ser445 SGDSGYPsEKRGELD 9606 22669845 t gcesareni The combination of eef2k autophosphorylation (targeting ser445) and a yet to be identified kinase (targeting ser441) would be needed to generate the eef2k phosphodegron specifically in response to dna damage. SIGNOR-197725 0.2 FABP7 protein O15540 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264461 0.7 TTL protein Q8NG68 UNIPROT TUBA1C protein Q9BQE3 UNIPROT down-regulates tyrosination 9606 22020298 t miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization SIGNOR-176918 0.451 ZNRF3 protein Q9ULT6 UNIPROT FZD8 protein Q9H461 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22575959 t Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. SIGNOR-260111 0.519 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization binding 10090 BTO:0001103 24003218 t lperfetto SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 SIGNOR-252996 0.909 PSMD1 protein Q99460 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263354 0.902 PRKG1 protein Q13976 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 10090 12809504 t gcesareni Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha.  SIGNOR-188185 0.279 TNF protein P01375 UNIPROT IRS1 protein P35568 UNIPROT down-regulates 9606 11287630 f gcesareni Irs-1 tyrosine phosphorylation by tnf was blocked by rapamycin, an inhibitor of the mammalian target of rapamycin (mtor), a downstream target of akt. these results suggest that tnf impairs insulin signaling through irs-1 SIGNOR-106599 0.405 MAPK11 protein Q15759 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 t lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK SIGNOR-264447 0.2 SCYL1 protein Q96KG9 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates activity relocalization 9606 BTO:0000567 24769208 t lperfetto Moreover, TEIF closely co-localized with C-NAP1 at the proximal ends of centrioles, and centriolar loading of TEIF stimulated by EGF/Akt could displace C-NAP1, resulting in centrosome splitting. SIGNOR-265497 0.2 CDC14B protein O60729 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates dephosphorylation 9606 18662541 t lperfetto The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1 SIGNOR-227927 0.255 L-arginine chemical CHEBI:16467 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 27126896 f Luana  Importantly, asparagine/glutamine pre-load only results in mTOR activation following amino acid stimulation (Fig. 5a), indicating that it is their exchange factor roles that elicit mTORC1 activation. SIGNOR-268018 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. SIGNOR-255579 0.7 PIK3C3 protein Q8NEB9 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 10698680 f acerquone Pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1) SIGNOR-252633 0.445 SMARCD1 protein Q96GM5 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270734 0.789 IL5RA protein Q01344 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 7602114 t Jak 2 is physically associated with the IL-5b receptor. The binding of IL-5 to its receptor results in tyrosine phosphorylation and activation of Jak 2 tyrosine kinase within 1 to 3 min. SIGNOR-254352 0.585 ELF1 protein P32519 UNIPROT IL2RA protein P01589 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 7862168 f 2 miannu The interleukin 2 receptor alpha-chain (IL-2R alpha) gene is rapidly and potently induced in T cells in response to mitogenic stimuli. Previously, an inducible enhancer between nucleotides -299 and -228 that contains NF-kappa B and CArG motifs was identified. We now report the characterization of a second essential positive regulatory element located between nucleotides -137 and -64 that binds Elf-1 and HMG-I(Y). Transcription from the IL-2R alpha promoter was inhibited when either the Elf-1 or the HMG-I(Y) binding site was mutated. Coexpression of both proteins activated transcription of the -137 to -64 element in COS-7 cells. SIGNOR-240193 0.2 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266523 0.8 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates 9606 BTO:0001103 20219869 t apalma Furthermore, NF-kB activation can cause destabilization of MyoD mRNA and degradation of MyoD protein (35, 49), which would further impede muscle differentiation SIGNOR-255352 0.284 tamoxifen citrate chemical CHEBI:9397 ChEBI ESR2 protein Q92731 UNIPROT down-regulates activity chemical inhibition 9606 20512796 t miannu Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth. SIGNOR-259300 0.8 SKIL protein P12757 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR down-regulates activity binding 9606 BTO:0000848 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-253303 0.835 192927-92-7 chemical CID:11957576 PUBCHEM HTR1D protein P28221 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193814 0.8 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser88 DSGFCLDsPGPLDSK 9606 BTO:0002181 34363019 t miannu Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.  SIGNOR-276737 0.2 CXCL12 protein P48061 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 BTO:0000093 15882617 f lperfetto Stromal fibroblast-derived SDF-1 enhances tumor growth both by stimulating angiogenesis through recruiting circulating EPCs into the tumor mass (endocrine effect) and by direct paracrine stimulation of tumor cells through CXCR4 expressed on carcinoma cells SIGNOR-252267 0.7 hsa-mir-223 mirna URS000037EC34_9606 RNAcentral Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 24708856 t miannu We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2. SIGNOR-255763 0.4 NFATC2 protein Q13469 UNIPROT GPC6 protein Q9Y625 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21871017 t miannu NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype. SIGNOR-264021 0.362 PAK4 protein O96013 UNIPROT PAK4 protein O96013 UNIPROT up-regulates phosphorylation Ser474 KEVPRRKsLVGTPYW 9606 20926745 t gcesareni Intracellular localization;enzymatic activity, induced;cell growth, altered; SIGNOR-168301 0.2 DNAJB9 protein Q9UBS3 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates activity binding -1 12356756 t miannu When BAP was added to BiP (2:1 molar ratio of BAP:BiP), it increased the ATPase activity of BiP by about 2-fold, which was similar to the increase observed when the J domain of ERdj4 was added to BiP (Fig.5). When both BAP and the J domain were added to BiP, the rate of ATP hydrolysis by BiP was stimulated by about 4-fold over basal levels, indicating that both BAP and ERdj4 positively regulate the ATPase activity of BiP SIGNOR-261044 0.557 WNT2 protein P09544 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131730 0.66 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL 9606 16116087 t llicata The present experiments demonstrate that ptn stimulates phosphorylation of serines 713 and 726 in the marcks domain of _-adducin (and serine 724 in _-adducin) and serines 152 and 156 in the marcks protein itself through the activation of either pkc _ or _ and perhaps other pkc(s) isoforms. SIGNOR-139906 0.719 USH1C protein Q9Y6N9 UNIPROT TIP-LINK complex complex SIGNOR-C291 SIGNOR form complex binding 10090 BTO:0000630 23217710 t lperfetto The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction. SIGNOR-262576 0.709 MAPKAPK5 protein Q8IW41 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser19 KGFRRAVsELDAKQA 9606 12421349 t The effect has been demonstrated using P07101-3 gcesareni Recombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation of both ser40 and ser19 induced a high-affinity binding of 14-3-3 proteins, but only the interaction of 14-3-3 with ser19 increased the hth1 activity. SIGNOR-95479 0.2 NEU1 protein Q99519 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR down-regulates activity binding 9606 BTO:0003554 32164705 t miannu NEU1 disrupts FN/ α5β1 interaction. taken together, strongly indicate that overexpressed NEU1 inhibits the Akt pathway by disrupting FN-integrin α5β1 interaction. SIGNOR-260658 0.2 ROCK1 protein Q13464 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates activity phosphorylation Thr508 PDRKKRYtVVGNPYW 9606 10652353 t lperfetto Rho-associated kinase rock activates lim-kinase 1 by phosphorylation at threonine 508 within the activation loop. SIGNOR-74569 0.601 PRKCD protein Q05655 UNIPROT DAB2 protein P98082 UNIPROT down-regulates phosphorylation Ser24 QAAPKAPsKKEKKKG 9606 10542228 t gcesareni Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2. SIGNOR-71764 0.3 Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 BTO:0000938 21106647 f miannu Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. SIGNOR-268383 0.7 CRHR1 protein P34998 UNIPROT Beta-endorphin protein P01189-PRO_0000024975 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 23504413 f lperfetto CRH, as a principal mediator of endocrine stress response, activates the HPA axis (Hypothalamic–pituitary–adrenal axis) by binding to the CRHR1 in the anterior pituitary. This, through a cascade of reactions, increases the expression of proopiomelanocortin (POMC) gene and the subsequent release of POMC-derived peptides, adrenocorticotropic hormone (ACTH) and β-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal cortex (Vale et al. 1981). SIGNOR-268614 0.2 TRiC complex SIGNOR-C539 SIGNOR MYC protein P01106 UNIPROT up-regulates quantity by stabilization binding 9606 36185250 t miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). SIGNOR-272872 0.271 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation 9606 15356145 t inferred from 70% family members lperfetto Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623. SIGNOR-270133 0.2 USF2 protein Q15853 UNIPROT B2M protein P61769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12480693 f miannu Here we show that upstream stimulatory factor 1 (USF1) and USF2 bind to the E box and regulate beta(2)m transactivation. SIGNOR-254656 0.2 CSK protein P41240 UNIPROT CSK protein P41240 UNIPROT up-regulates activity phosphorylation Tyr304 DVCEAMEyLEGNNFV -1 9148770 t llicata Taken together these results indicate that Csk can be phosphorylated in vivo at Tyr-184 by an as yet unknown tyrosine kinase, and that autophosphorylation of Tyr-304 occurs only at abnormally high Csk concentrations in vitro. Furthermore, Tyr-304 is required for the maintenance of the structure of the Csk kinase domain. SIGNOR-250778 0.2 PRKAA1 protein Q13131 UNIPROT CFTR protein P13569 UNIPROT down-regulates activity phosphorylation Ser737 EPLERRLsLVPDSEQ 9606 19095655 t Luana AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites.|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions SIGNOR-259858 0.475 FYN protein P06241 UNIPROT CNN1 protein P51911 UNIPROT down-regulates activity phosphorylation Tyr261 SQRGMTVyGLPRQVY 9534 BTO:0000298 15206927 t We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin SIGNOR-251158 0.339 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 t Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. SIGNOR-252838 0.908 SYK protein P43405 UNIPROT PAX5 protein Q02548 UNIPROT down-regulates activity phosphorylation 9606 BTO:0003079 27181361 t Gianni PAX5 tyrosine phosphorylation by SYK co-operatively functions with its serine phosphorylation to cancel the PAX5-dependent repression of BLIMP1: A mechanism for antigen-triggered plasma cell differentiation. SIGNOR-269084 0.432 SF3B1 protein O75533 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 t miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription SIGNOR-268819 0.415 MFGE8 protein Q08431 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21901532 f miannu In an attempt to clarify the direct anti-inflammatory role of MFG-E8, we revealed a distinct signaling pathway where MFG-E8 activates suppressor of cytokine signaling (SOCS) 3 gene expression via STAT3 mediated pathway, which in turn served as a negative regulator for LPS induced TLR4 signaling by targeting NF-κB p65 component, thereby attenuating the down-stream signaling for TNF-α production SIGNOR-260653 0.353 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR up-regulates activity chemical activation 9606 18790874 t brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-263785 0.8 RXRA protein P19793 UNIPROT PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR up-regulates activity binding 10090 17613434 t irozzo RXR Binding Increases the DNA-Binding Affinity of PML/RARA. Here, we demonstrate that the presence of the RARA heterodimeric partner RXR in the PML/RARA complex is required for leukemogenesis in transgenic mice. RXR greatly facilitates the binding of PML/RARA to DNA, but titration of RXR by PML/RARA could also contribute to transformation. SIGNOR-255804 0.2 PRKCD protein Q05655 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Ser139 EEWTRHGsFVNKPTR 9606 16963224 t The effect has been demonstrated using P29353-2 gcesareni Pkc delta phosphorylates p52shca at ser29 to regulate erk activation in response to h2o2. SIGNOR-149398 0.55 ATF6 protein P18850 UNIPROT HYOU1 protein Q9Y4L1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001088 20861013 f miannu We recently found that in cultured gastric cells, expression of endoplasmic reticulum (ER) chaperones (such as 150-kDa oxygen-regulated protein (ORP150) and glucose-regulated protein 78 (GRP78)) is induced by NSAIDs and confers protection against NSAID-induced apoptosis, which is important in the development of NSAID-induced gastric lesions. In this study we have found that co-culture of gastric cells with H. pylori suppresses the expression of ER chaperones. This suppression was regulated at the level of transcription and accompanied by a reduction in the level of activating transcription factor 6 (ATF6), one of the transcription factors for ER chaperone genes. SIGNOR-253752 0.413 CALM1 protein P0DP23 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity binding 9606 24379783 t lperfetto Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer SIGNOR-251615 0.755 CDC25C protein P30307 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR up-regulates activity dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 BTO:0001938 10913154 t lperfetto Cyclin B-Cdc2 complexes are maintained in an inactive state until the end of G2 by phosphorylation of the Thr14/Tyr15 residues. Around the time of nuclear translocation of the complex, these residues are dephosphorylated, resulting in the formation of an active cyclin B-Cdc2 complex (2). As mentioned, this dephosphorylation occurs by a Cdc25 protein phosphatase. Three Cdc25 family members have been identified to date, A, B and C, the last one being the active one at the onset of mitosis. The activity of Cdc25C itself can be enhanced through phosphorylation by cyclin B-Cdc2 (9, 10). Therefore, activation of cyclin B-Cdc2 has been proposed to result in an autocatalytic feedback loop to ensure rapid activation of these complexes at the G2/M transition SIGNOR-251509 0.839 MAP2K7 protein O14733 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates activity phosphorylation Thr221 AGTSFMMtPYVVTRY -1 10715136 t Activation of JNK3 alpha 1 requires both MKK4 and MKK7. both MKK4 and MKK7 were required for bisphosphorylation and maximal enzyme activity. a processive mechanism for JNK3R1 activation that requires phosphorylation of Thr 221 by MKK7 prior to phosphorylation of Tyr 223 by MKK4 SIGNOR-251422 0.564 3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid chemical CHEBI:91194 ChEBI LPAR2 protein Q9HBW0 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193561 0.8 PLK4 protein O00444 UNIPROT FBXW5 protein Q969U6 UNIPROT down-regulates activity phosphorylation Ser151 SQFNKDDsLLLASGV 21725316 t lperfetto The activity of SCF-FBXW5 is in turn negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6. SIGNOR-275476 0.559 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr160 QVPQQPTyVQALFDF 9606 BTO:0000007 20554525 t lperfetto Our data show that BCR-ABL also phosphorylates Grb2 in Tyr160Previous reports suggested an inhibitory role of Grb2 Tyr7, Tyr37, Tyr52, and Tyr209 phosphorylation in receptor tyrosine kinase signaling (16) (43). Instead, in our system Grb2 Tyr160 mutation was not show to have a role in ALCL proliferation. SIGNOR-247146 0.2 RPS6KB1 protein P23443 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser560 LARLGCSsCLDYFTT 9606 18769144 t lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively SIGNOR-180775 0.2 WWTR1 protein Q9GZV5 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199211 0.7 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR2 protein O95136 UNIPROT up-regulates chemical activation 9606 23450633 t gcesareni S1p action on yap in 293a (or hacat) cells is mediated by s1p2 rather than s1p1 or s1p3 (of ? Ve known s1p receptors) and lpa receptors 1 and 3 (of six). SIGNOR-192117 0.8 F2R protein P25116 UNIPROT CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254851 0.252 MAPK1 protein P28482 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser641 DIKILIAsPSPTHIH 9606 BTO:0000567 18519666 t lperfetto We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_ SIGNOR-178723 0.572 HDAC1 protein Q13547 UNIPROT UBE2D3 protein P61077 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 21044962 f miannu knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene. SIGNOR-255175 0.267 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser939 SFRARSTsLNERPKS 9606 12172553 t gcesareni We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex. SIGNOR-91388 0.719 dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity precursor of 9606 21876184 t lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. SIGNOR-268259 0.8 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-66763 0.738 FHL2 protein Q14192 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001129 10654935 t gcesareni Fhl2 contains a strong, autonomous transactivation function and binds specifically to the ar in vitro and in vivo. SIGNOR-74703 0.537 ABL2 protein P42684 UNIPROT LGALS3 protein P17931 UNIPROT up-regulates phosphorylation Tyr79 GAPAPGVyPGPPSGP 9606 20150913 t llicata The sh (src homology)3 domains of c-abl/arg bind to a p(80)gppsgp motif of gal3, and tyr79 and tyr118 are the major tyrosine phosphorylation sites. A consequence of this interaction and phosphorylation is the significant impairment of chaperone-mediated autophagy of gal3. SIGNOR-163747 0.2 (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol chemical CHEBI:94562 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258090 0.8 USP8 protein P40818 UNIPROT BACE1 protein P56817 UNIPROT up-regulates quantity by stabilization deubiquitination Lys501 ADDISLLk 9606 BTO:0003704 27302062 t irozzo Accordingly, we reported that BACE1 is ubiquitinated at lysine 501 and that lack of ubiquitination at lysine 501 produces BACE1 stabilization.Our findings demonstrate that USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501. SIGNOR-259101 0.462 RIPK2 protein O43353 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser435 EMFSGELsWSADSIR 9606 22412986 t lperfetto Activation of interferon regulatory factor 5 by site specific phosphorylation. Phosphorylation of carboxyl serines 451 and 462 appear the primary trigger of irf5 function in nuclear accumulation, transcription, and apoptosis. Rip2 activation of the irf5 aspartic acid substitutions showed a similar positive effect of s451d and s462d function in this assay SIGNOR-196520 0.309 CSNK2A1 protein P68400 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser702 AVILTVEsEEEEEES -1 21296876 t miannu CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis SIGNOR-276253 0.2 APH1B protein Q8WW43 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t gcesareni By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. SIGNOR-93310 0.906 CCND1 protein P24385 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 BTO:0001103 20219869 f apalma Importantly, NF-kB can promote the expression and stability of cyclin D1 in muscle (4, 35, 39, 132), leading to increased cell proliferation and inhibition of differentiation. SIGNOR-255351 0.7 DYRK1B protein Q9Y463 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr288 VDLACTPtDVRDVDI 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 15546868 t lperfetto Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner SIGNOR-235801 0.42 PLCG2 protein P16885 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 31575057 t gcesareni Phosphorylation at Ser-146 by PKCδ increases p21 stability SIGNOR-262963 0.2 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259004 0.348 ADD2 protein P35612 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 BTO:0000424 33187473 t lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] SIGNOR-266039 0.377 SFRP1 protein Q8N474 UNIPROT WNT4 protein P56705 UNIPROT down-regulates binding 9606 BTO:0000671 11287180 t gcesareni Sfrp-1 binds wnt-4 with considerable avidity and inhibits the dna-binding activity of tcf, an effector of wnt signaling, SIGNOR-106556 0.721 FBXW7 protein Q969H0 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002524 17298674 t miannu Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme SIGNOR-271643 0.584 PIK3C3 protein Q8NEB9 UNIPROT 1-phosphatidyl-1D-myo-inositol 3-phosphate smallmolecule CHEBI:17283 ChEBI up-regulates chemical modification 9606 8999962 t gcesareni Vps34p phosphorylates phosphatidylinositol (ptdins) at the 3?-Position of the inositol ring, but not ptdins. SIGNOR-45606 0.8 RPS6KA1 protein Q15418 UNIPROT TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 15342917 t lperfetto The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1 SIGNOR-217900 0.712 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000007 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248299 0.422 SP1 protein P08047 UNIPROT SP1/STAT3 complex SIGNOR-C74 SIGNOR form complex binding 9606 19723038 t miannu Sp1 and stat3 seem to synergistically augment renalase transcription. SIGNOR-187790 0.467 dothiepin chemical CHEBI:36798 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 t miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. SIGNOR-258877 0.8 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7318 RPGSRAGsRAGSRAS 9606 BTO:0004905 21295697 t lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. SIGNOR-264432 0.446 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273055 0.556 methylnaltrexone chemical CHEBI:136007 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10030 19282177 t Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. SIGNOR-258148 0.8 MCM3 protein P25205 UNIPROT MCM complex SIGNOR-C268 SIGNOR form complex binding 9606 19946136 t The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. SIGNOR-261673 0.772 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR PRKAR1A protein P10644 UNIPROT up-regulates phosphorylation Ser83 DSREDEIsPPPPNPV 9606 BTO:0000093 16582606 t lperfetto In this context, we have identified rialpha as a novel substrate for the g(1)/s-cyclin-dependent kinase, cdk2/cyclin e, and found that rialpha is specifically phosphorylated at the serine residue. SIGNOR-216729 0.306 ROCK2 protein O75116 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates activity phosphorylation Thr853 PREKRRStGVSFWTQ -1 12220642 t lperfetto Rho kinase is known to control smooth muscle contractility by phosphorylating the 110 kDa myosin-targetting subunit (MYPT1) of the myosin-associated form of protein phosphatase 1 (PP1M). Phosphorylation of MYPT1 at Thr695 has previously been reported to inhibit the catalytic activity of PP1. Here, we show that the phosphorylation of Thr850 by Rho kinase dissociates PP1M from myosin, providing a second mechanism by which myosin phosphatase activity is inhibited. SIGNOR-249164 0.777 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Ser72 SKVQTTPsKPGGDRY 9606 BTO:0000567 15525512 t llicata Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.  SIGNOR-250607 0.992 MAPK1 protein P28482 UNIPROT DOCK1 protein Q14185 UNIPROT unknown phosphorylation Thr1772 QQTPPPVtPRAKLSF 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262769 0.255 PFKM protein P08237 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. SIGNOR-266467 0.8 LPAR5 protein Q9H1C0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256718 0.39 HDAC3 protein O15379 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 25726523 t lperfetto GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. SIGNOR-275662 0.26 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 8974401 t Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif. gcesareni A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subgroups of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) and p38 subgroups of map kinases, respectively. here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). SIGNOR-45360 0.733 haloperidol chemical CHEBI:5613 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258372 0.8 F2RL3 protein Q96RI0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257044 0.358 NARS2 protein Q96I59 UNIPROT asparagine smallmolecule CHEBI:22653 ChEBI down-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270462 0.8 PTPRH protein Q9HD43 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase SIGNOR-76084 0.273 CKMT2 protein P17540 UNIPROT N-phosphocreatine smallmolecule CHEBI:17287 ChEBI up-regulates quantity chemical modification 9606 18502307 t miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. SIGNOR-265789 0.8 CSNK1D protein P48730 UNIPROT SMARCA4 protein P51532 UNIPROT down-regulates quantity by destabilization phosphorylation Ser35 LGPSPGPsPGSAHSM 9606 BTO:0001225 30177679 t miannu  We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation.  SIGNOR-277407 0.2 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22703233 f lperfetto Our results establish a novel biological role for TGFbeta signaling in controlling expression of genes characteristic for alternatively activated macrophages. We speculate that lack of TbetaRII signaling reduces the anti-inflammatory M2 phenotype of macrophages because of reduced expression of these products. SIGNOR-249551 0.7 MYC protein P01106 UNIPROT CLK3 protein P49761 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002932 32453420 t done miannu C-Myc enhances transcriptional activation of CLK3 promoter in CCA cells.  SIGNOR-274123 0.2 (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI up-regulates quantity precursor of 9606 18767138 t lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate SIGNOR-268247 0.8 8-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:91845 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258860 0.8 NR2F1 protein P10589 UNIPROT LHCGR protein P22888 UNIPROT down-regulates quantity by repression transcriptional regulation 9534 10644740 t Luana Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription. SIGNOR-266218 0.278 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 15486195 t inferred from 70% family members lperfetto In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel SIGNOR-270152 0.2 PRKAB1 protein Q9Y478 UNIPROT STIM1 protein Q13586 UNIPROT down-regulates activity phosphorylation Ser257 GLHRAEQsLHDLQER 10090 BTO:0000452 31381180 t miannu STIM1 is a novel exercise‐regulated AMPK substrate. Phosphorylation of STIM1 by AMPK suppresses SOCE SIGNOR-277298 0.2 AP1G1 protein O43747 UNIPROT AP-1 complex complex SIGNOR-C248 SIGNOR form complex binding 9606 21097499 t lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) SIGNOR-260687 0.816 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT down-regulates activity phosphorylation Thr161 SDEEAEStKEAQNEL -1 12852856 t lperfetto Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction SIGNOR-103364 0.688 PTPN7 protein P35236 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates binding 9606 BTO:0000776 19047375 t gcesareni Thus, beta(2)ar stimulation on a b cell phosphorylates and inactivates heptp in a gs/camp/pka-dependent manner to release bound p38 mapk, making more available for phosphorylation and subsequent ige regulation SIGNOR-182525 0.585 CHEK2 protein O96017 UNIPROT AATF protein Q9NY61 UNIPROT up-regulates quantity by stabilization phosphorylation Ser143 SKKSRSHsAKTPGFS 9606 BTO:0001109 17157788 t lperfetto Three putative Chk2 phosphorylation sites (Stevens et al., 2003) are present in Che-1 at resides Ser141, Ser474, and Ser508. Thus, we performed in vitro Chk2 kinase assays utilizing the GST-Che-1 fusion peptides spanning these residues as substrates.| Taken together, these results indicate that Chk2 phosphorylates Che-1 and this phosphorylation contributes to increase Che-1 stability. SIGNOR-264416 0.365 MAML1 protein Q92585 UNIPROT CDK8 protein P49336 UNIPROT up-regulates relocalization 9606 15546612 t gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. SIGNOR-130718 0.581 PAK1 protein Q13153 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Ser49 EVLVDPRsRRRYVRG 9606 18427546 t llicata We show here that pak1 is required for cell proliferation, mitotic progression and plk1 activity in hela cells. phosphorylation of plk1 on ser 49 is important for metaphase-associated events. SIGNOR-178353 0.533 PTPN6 protein P29350 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2274 KNREGLNyMVLATEC 9606 11266449 t gcesareni Phosphorylated ros strongly and directly associates with shp-1.Overexpression Of shp-1 results in ros dephosphorylation and effectively downregulates ros-dependent proliferation and transformation SIGNOR-105919 0.375 IKBKE protein Q14164 UNIPROT IRF1 protein P10914 UNIPROT down-regulates activity phosphorylation Ser215 DLYNFQVsPMPSTSE 9606 BTO:0000007 24396068 t miannu We demonstrated that IKK-ε phosphorylated the transcription factor IFN regulatory factor 1 (IRF-1) at amino acid (aa) 215/219/221 in primary CD4(+) T cells and blocked its transcriptional activity.  SIGNOR-276480 0.357 PRKCE protein Q02156 UNIPROT KRT18 protein P05783 UNIPROT unknown phosphorylation Ser53 ISVSRSTsFRGGMGS -1 1374067 t lperfetto In conclusion, we have shown that the PKCe catalytic fragment physically associates with and phosphorylates CK8/18 HT29 cells. The nature of this association and its physiological significance remain to be determined. SIGNOR-248847 0.334 AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 f miannu c-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254952 0.7 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189993 0.8 PPP2CA protein P67775 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates quantity by stabilization dephosphorylation Thr66 ATRKALGtVNRATEK 9606 BTO:0000567 24781523 t miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase SIGNOR-276376 0.3 ZNF804A protein Q7Z570 UNIPROT MGAM protein O43451 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 23434502 t miannu ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). SIGNOR-269466 0.2 GRIPAP1 protein Q4V328 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity binding 9606 BTO:0002181;BTO:0000142 17761173 t Giorgia To examine whether GRASP‐1 interacts with MEKK1 and JNK1 in neurons, co‐immunoprecipitation experiments were performed with detergent‐solubilized extracts from cultured cortical neurons. Both antiJNK1 and anti‐MEKK1 antibodies immunoprecipitated GRASP‐1 from neuronal lysates. These results suggest that GRASP‐1 interacts with MEKK1 and JNK1 in neurons. GRASP-1 potently activates JNK pathway signaling, with no effect on ERK signaling. Such JNK pathway activating activity requires binding of GRASP-1 to both JNK and the upstream JNK pathway activator MEKK-1. SIGNOR-260639 0.315 SCN10A protein Q9Y5Y9 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 t miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. SIGNOR-253408 0.8 BRSK1 protein Q8TDC3 UNIPROT CDC25B protein P30305 UNIPROT down-regulates activity phosphorylation Ser375 ARVLRSKsLCHDEIE 9606 BTO:0000567 15150265 t lperfetto Hssad1 specifically phosphorylated wee1a, cdc25-c, and -b on ser-642, ser-216, and ser-361 in vitro, respectively phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 SIGNOR-107404 0.52 CRTC2 protein Q53ET0 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity transcriptional regulation 9606 26652733 t Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB SIGNOR-256103 0.2 RNF111 protein Q6ZNA4 UNIPROT SKIL protein P12757 UNIPROT down-regulates ubiquitination 9606 17591695 t gcesareni Arkadia interacts with snon and induces its ubiquitination irrespective of tgf-beta/activin signaling, but snon is efficiently degraded only when it forms a complex with both arkadia and phosphorylated smad2 or smad3 SIGNOR-156430 0.712 MRPS23 protein Q9Y3D9 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261435 0.673 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252855 0.908 KIF4A protein O95239 UNIPROT Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 9606 15297875 f miannu These results suggest that KIF4 and its binding partner PRC1 play essential roles in the organization of central spindles and midzone formation. KIF4 deficiency leads to mislocalization of PRC1, MKLP1, CENP-E and chromosomal passenger proteins SIGNOR-265986 0.7 MAPK1 protein P28482 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser150 PELCGPGsPPVLTPG 9606 15952796 t lperfetto We show that grb10 is a direct substrate of the p42/44 mitogen-activated protein kinase (mapk)we identified ser(150), ser(418), and ser(476) of human grb10zeta as mapk-mediated in vitro phosphorylation sites. Replacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation. Taken together, our findings suggest that phosphorylation of the adaptor protein may provide a feedback inhibitory mechanism by which grb10 regulates insulin signaling. SIGNOR-138163 0.381 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR arginine smallmolecule CHEBI:29016 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270365 0.8 VRK1 protein Q99986 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation 9606 22621922 t miannu The kinase vrk1 is activated by dna double strand breaks induced by ionizing radiation (ir) and specifically phosphorylates 53bp1 in serum-starved cells./ Vrk1 knockdown resulted in the defective formation of 53bp1 foci in response to ir both in number and size SIGNOR-197625 0.408 TAOK2 protein Q9UL54 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2 SIGNOR-201330 0.283 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252885 0.398 FZR1 protein Q9UM11 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 9534 BTO:0004055 12023018 t miannu We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity. SIGNOR-272611 0.846 MAPK14 protein Q16539 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates activity phosphorylation Ser79 EVTSTSQsPHSPDSS 9606 8650547 t lperfetto ...undergoes inducible phosphorylation on two adjacent serine residues (78 and 81). In vitro, chop is phosphorylated on these residues by p38 mitogen-activated protein kinase (map kinase). phosphorylation of chop on these residues enhanced its ability to function as a transcriptional activator. SIGNOR-42200 0.594 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 18394876 t lperfetto The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity SIGNOR-252859 0.908 CSAG2 protein Q9Y5P2 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity binding 9606 32761762 t miannu Here, we show that the previously undescribed CSAG2 protein is a direct activator of SIRT1.  Biochemical studies revealed that CSAG2 directly binds to and stimulates SIRT1 activity toward multiple substrates. Importantly, CSAG2 enhances SIRT1‐mediated deacetylation of p53, inhibits p53 transcriptional activity, and improves cell survival in response to genotoxic stress. SIGNOR-261670 0.2 HRAS protein P01112 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 10116 BTO:0000452 1749429 t lperfetto Expression of oncogenic ha-ras augments transactivation by c-jun and stimulates its phosphorylation. Here we describe the mapping of the ha-ras-responsive phosphorylation sites to serines 63 and 73 of c-jun. Site-directed mutagenesis indicates that phosphorylation of these serines is essential for stimulation of c-jun activity and for cooperation with ha-ras in ocogenic transformation. SIGNOR-236686 0.514 GSK3B protein P49841 UNIPROT CCND2 protein P30279 UNIPROT down-regulates phosphorylation Thr280 DELDQAStPTDVRDI 9606 17486076 t lperfetto Glycogen synthase kinase-3beta and p38 phosphorylate cyclin d2 on thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells SIGNOR-154668 0.435 DHX30 protein Q7L2E3 UNIPROT FASTKD2 protein Q9NYY8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25683715 f miannu DHX30 siRNA treatment resulted in an increase of FASTKD2 levels, and FASTKD5 was increased in cells treated with siRNA for GRSF1. SIGNOR-261225 0.392 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 8143061 t asthma gcesareni SIGNOR-251706 0.8 MRAP2 protein Q96G30 UNIPROT MC1R protein Q01726 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 t miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. SIGNOR-252365 0.505 HOXA11 protein P31270 UNIPROT HOXA10 protein P31260 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001549 17688409 f miannu Chromatin immunoprecipitation (ChIP) and chloramphenicol acetyl transferase (CAT) assays confirm that HOXA11 binds to the putative binding site, resulting in repression of HOXA10 expression. SIGNOR-254469 0.298 CYLD protein Q9NQC7 UNIPROT BCL3 protein P20749 UNIPROT down-regulates deubiquitination 9606 BTO:0001286 16713561 t gcesareni Cyld binds and deubiquitinates bcl-3in cyld+/+ keratinocytes, tpa or uv light triggers the translocation of cyld from the cytoplasm to the perinuclear region, where cyld binds and deubiquitinates bcl-3, thereby preventing nuclear accumulation of bcl-3 and p50/bcl-3- or p52/bcl-3-dependent proliferation. SIGNOR-146774 0.526 PRKCA protein P17252 UNIPROT CD163 protein Q86VB7 UNIPROT unknown phosphorylation Ser1084 QRQRLAVsSRGENLV 9606 BTO:0000801 11298324 t lperfetto Furthermore, we demonstrated that the cytoplasmic domains of CD163 variants are phosphorylated by PKC-alpha in vitro. Inhibition studies using specific kinase inhibitors reveal that both CKII and PKC are involved in the CD163 signaling mechanism resulting in the secretion of proinflammatory cytokines. SIGNOR-249082 0.328 CASP1 protein P29466 UNIPROT RNF31 protein Q96EP0 UNIPROT down-regulates activity cleavage Asp348 GTGGLEPdLARGRWA 9606 BTO:0005111 32122970 t miannu We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death. SIGNOR-272192 0.2 FLT1 protein P17948 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr320 RKDTKEIyTHFTCAT -1 33139573 t miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. SIGNOR-277231 0.26 PEX1 protein O43933 UNIPROT PEX5 protein P50542 UNIPROT up-regulates activity binding 10029 16314507 t Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. ​(Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner. SIGNOR-253618 0.565 captopril chemical CHEBI:3380 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition -1 9187274 t miannu We analyzed the inhibition of angiotensin I and AcSDKP hydrolysis as well as that of three synthetic ACE substrates by wild-type ACE and the N and C domains by using a range of specific ACE inhibitors. We demonstrate that captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, with K(i) values in the subnanomolar range. SIGNOR-258612 0.8 GLI2 protein P10070 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 33125874 f SimoneGraziosi Inhibition of Gli1 with simultaneous increase in Gli2 promotes migration of vNSC-derived cells to demyelinated lesions SIGNOR-269223 0.7 MAPK14 protein Q16539 UNIPROT BAZ1B protein Q9UIG0 UNIPROT up-regulates phosphorylation Ser158 KSDGACDsPSSDKEN 9606 19776015 t gcesareni Moreover, this region (wac domain) was also phosphorylated by recombinant proteins of p38_? And jnk2_? But not by akt1 SIGNOR-188160 0.2 MAPKAPK2 protein P49137 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser203 PRLQHSFsFAGFPSA 9606 18326031 t lperfetto Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation. SIGNOR-161270 0.605 SERPINA5 protein P05154 UNIPROT FN1 protein P02751 UNIPROT down-regulates activity binding 9606 BTO:0000594 24388360 t miannu SERPINA5 inhibits HCC cell migration by directly interacting with fibronectin. SERPINA5 disrupts the fibronectin–integrin β1 signaling pathway. SIGNOR-265881 0.318 ELP2 protein Q6IA86 UNIPROT Elongator complex complex SIGNOR-C466 SIGNOR form complex binding 9606 28601220 t miannu Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer. SIGNOR-269709 0.774 MRPL15 protein Q9P015 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262378 0.688 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Thr87 GVPAEGRtPPPFPGE 9606 22721717 t lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation SIGNOR-197936 0.346 HES1 protein Q14469 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity transcriptional regulation 10090 BTO:0000165 10066785 t gcesareni Notch signaling up-regulated HES1 mRNA expression within 1 h and subsequently reduced expression of MyoD mRNA SIGNOR-243181 0.299 RHEB protein Q15382 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 10090 BTO:0000011 19299511 t lperfetto These results suggest that Rheb induces alteration in the binding of 4E-BP1 with mTORC1 to regulate mTORC1 activation. SIGNOR-235355 0.791 pemetrexed disodium chemical CHEBI:63722 ChEBI GART protein P22102 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 14596699 t miannu Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT). SIGNOR-259291 0.8 apomorphine chemical CHEBI:48538 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258374 0.8 Phenelzine chemical CHEBI:8060 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 t miannu At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter.  SIGNOR-258743 0.8 EGFR protein P00533 UNIPROT JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR up-regulates activity phosphorylation 9606 15284024 t Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. SIGNOR-252088 0.616 UBQLN2 protein Q9UHD9 UNIPROT Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR down-regulates 10090 27477512 f lperfetto UBQLN2 recognizes client-bound HSP70 and links it to the proteasome to allow for the degradation of aggregated and misfolded proteins. SIGNOR-262267 0.7 ACTB protein P60709 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity binding 9606 28233384 t lperfetto Here, we report the highest resolution, cryo-EM structures of actin filaments with bound ATP analog β,γ-imidoadenosine 5′-triphosphate (AMPPNP) (3.1 Å) and ADP with inorganic phosphate (ADP-Pi) (3.1 Å) as well as a 3.6-Å resolution structure of the ADP filament. These structures of the three well-characterized nucleotide states of actin monomers and filaments SIGNOR-261879 0.7 MMP1 protein P03956 UNIPROT COL1A2 protein P08123 UNIPROT down-regulates quantity by destabilization cleavage Gly775 NGPPGPAgSRGDGGP -1 17318226 t lperfetto In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4.  SIGNOR-272337 0.41 DOCK10 protein Q96BY6 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260549 0.502 CNOT6 protein Q9ULM6 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268309 0.812 ceramide smallmolecule CHEBI:17761 ChEBI ceramide 1-phosphate(2-) smallmolecule CHEBI:84404 ChEBI up-regulates quantity precursor of 9606 34202192 t miannu Another relevant enzyme is Ceramide kinase (CerK), which phosphorylates Cer to produce Ceramide 1-phosphate (C1P). SIGNOR-268501 0.8 KAT2B protein Q92831 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269621 0.2 LPAR5 protein Q9H1C0 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257113 0.2 PRKD3 protein O94806 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity phosphorylation Ser155 FPLRKTVsEPNLKLR 18692497 t Conserved Phosphorylated residue Ser259 and Ser498 refer to HDAC5 sequence. Phospho-residues in HDAC7 were derived by aligning HDAC5 and HDAC7 lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. SIGNOR-275932 0.2 LATS1 protein O95835 UNIPROT CDC26 protein Q8NHZ8 UNIPROT up-regulates activity phosphorylation Thr7 tRLELKLD 25723520 t lperfetto LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C|Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C|Here, we demonstrate that LATS1 phosphorylates the Thr7 (T7) residue of the APC/C component CDC26 directly SIGNOR-275472 0.478 JNK proteinfamily SIGNOR-PF15 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 15916964 t lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities SIGNOR-137631 0.2 alpha-D-ribose 1-phosphate(2-) smallmolecule CHEBI:57720 ChEBI D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity precursor of 9606 17804405 t miannu Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. The role of phosphopentomutase is to utilize ribose 1-phosphate and deoxyribose 1-phosphate, which are formed by purine nucleoside phosphorylase and uridine phosphorylase. Using catalytic efficiency as a criterion, PGM2 acted more than 10-fold better as a phosphopentomutase (both on deoxyribose 1-phosphate and on ribose 1-phosphate) than as a phosphoglucomutase. SIGNOR-267074 0.8 KIF20B protein Q96Q89 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272528 0.7 PI-103 chemical CHEBI:90524 ChEBI PRKDC protein P78527 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206175 0.8 GSK1292263 chemical CID:24996872 PUBCHEM GPR119 protein Q8TDV5 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-192859 0.8 STK3 protein Q13188 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Ser226 LNPQWNEsFTFKLKP 9606 BTO:0002181 26414765 t miannu Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα.  SIGNOR-277177 0.2 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione chemical CHEBI:92539 ChEBI HTR1A protein P08908 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190687 0.8 CSNK1G1 protein Q9HCP0 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser322 PRTSSNAsTISGRLS -1 11980723 t llicata Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR SIGNOR-250822 0.473 ABL1 protein P00519 UNIPROT PSMA7 protein O14818 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr106 EDPVTVEyITRYIAS 9606 25620702 t Manara PSMA7 degradation is suppressed by c-Abl-mediated tyrosine phosphorylation at Y106 SIGNOR-260937 0.406 SIRT1 protein Q96EB6 UNIPROT ACAN protein P16112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21337390 f miannu The inhibition of SIRT1 by siRNA induced OA-like gene expression changes, namely the significant down-regulation of aggrecan and up-regulation of COL10A1 and ADAMTS-5. SIGNOR-255142 0.322 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA7 protein Q9Y5G6 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265687 0.2 CDK2 protein P24941 UNIPROT GATA3 protein P23771 UNIPROT down-regulates quantity by destabilization phosphorylation Thr156 HLFTFPPtPPKDVSP 9606 BTO:0000567 24820417 t miannu Phosphorylation of GATA3 Thr-156 was detected in mouse thymocytes, and cyclin-dependent kinase 2 (CDK2) was identified as a respondent for phosphorylation at Thr-156. SIGNOR-276634 0.369 SP3 protein Q02447 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9223667 t lperfetto Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region. SIGNOR-251741 0.2 linifanib chemical CHEBI:91435 ChEBI PDGFRA protein P16234 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193663 0.8 SLC1A2 protein P43004 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity relocalization 9606 26687113 t miannu After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5). SIGNOR-264803 0.8 MLL/SET subcomplex complex SIGNOR-C87 SIGNOR MLL1 complex complex SIGNOR-C89 SIGNOR form complex binding 9606 24680668 t miannu The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation. SIGNOR-204819 0.769 PMP22 protein Q01453 UNIPROT MPZ protein P25189 UNIPROT up-regulates activity binding 9606 10212299 t miannu Our data provide the first direct evidence for the formation of P0–PMP22 complexes at the plasma membrane. These protein interactions probably participate in holding adjacent Schwann cell membranes together and in stabilizing myelin compaction. SIGNOR-251898 0.592 LRRK2 protein Q5S007 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Thr164 LGSQSLHtRTSKLFQ 9606 21048939 t gcesareni Arhgef7 is interacting with lrrk2 in vitro and in vivo. Lrrk2 phosphorylates arhgef7 in vitro.Two Threonine residues, t107 and t143, within the arhgef7 n-terminus were identified with high confidence SIGNOR-169225 0.468 ARHGAP19 protein Q14CB8 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260471 0.55 CDT1 protein Q9H211 UNIPROT MCM2 protein P49736 UNIPROT up-regulates activity binding 9606 BTO:0000007 14672932 t Chromosomal DNA replication requires the recruitment of the six-subunit minichromosome maintenance (Mcm) complex to chromatin through the action of Cdc6 and Cdt1. SIGNOR-261681 0.805 ZFPM1 protein Q8IX07 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates activity 10090 BTO:0000725 22068055 f We here use conditional removal of the GATA-1 and FOG-1 transcription factors to identify FOG-1 as required for the formation of all committed Mk- and E-lineage progenitors, whereas GATA-1 was observed to be specifically required for E-lineage commitment. SIGNOR-259964 0.7 MC2R protein Q01718 UNIPROT cortisol smallmolecule CHEBI:17650 ChEBI up-regulates quantity 9606 BTO:0000047 20371771 f lperfetto Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP). SIGNOR-268621 0.8 ACTB protein P60709 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269293 0.487 PTK6 protein Q13882 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10980601 t gcesareni The phosphorylation of and association with bks by brk was also dependent on the sh2-like domain present within bks.bks is a substrate for the kinase activity of brk and has the characteristics of an adaptor protein. SIGNOR-81489 0.713 DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 10090 17158101 t gcesareni Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis. SIGNOR-236867 0.798 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RORB protein Q92753 UNIPROT down-regulates activity chemical inhibition 9606 12958591 t miannu ATRA and related retinoids inhibit ROR beta but not ROR alpha transcriptional activity suggesting that high-affinity, subtype-specific ligands could be designed for the identification of ROR beta target genes. Our results identify ROR beta as a retinoid-regulated nuclear receptor, providing a novel pathway for retinoid action. SIGNOR-266845 0.8 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser287 EPLSPVSsLQASVPG 9606 16027724 t llicata Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo. SIGNOR-250728 0.488 CDK1 protein P06493 UNIPROT OSBP2 protein Q969R2 UNIPROT up-regulates activity phosphorylation 30925160 t lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. SIGNOR-264878 0.2 CSNK2A1 protein P68400 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser20 ADDSLSNsEEEPDRQ 9606 21559372 t llicata Further investigation revealed that il-6 stabilizes twist in scchn cell lines through casein kinase 2 (ck2) phosphorylation of twist residues s18 and s20, and that this phosphorylation inhibits degradation of twist. SIGNOR-173672 0.2 M1_polarization phenotype SIGNOR-PH54 SIGNOR TNF protein P01375 UNIPROT up-regulates 9606 BTO:0000801 32454942 f miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. According to the M1/M2 model, M1 polarized cells are characterized by the release of proinflammatory mediators, such as TNF, IL-1β, and IFNγ SIGNOR-263826 0.7 PLK1 protein P53350 UNIPROT WDCP protein Q9H6R7 UNIPROT up-regulates activity phosphorylation Ser695 SHSPGAVsSLKVFTG 9606 BTO:0000007 30297404 t miannu PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11. we performed in vitro kinase assays followed by mass spectrometry and found that two sites (S686 and S695) in this cluster were phosphorylated. Thus, all of these results are in agreement that this cluster is phosphorylated by PLK1. SIGNOR-273731 0.2 PPP2CA protein P67775 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates dephosphorylation Ser520 RLQTICMsGTGMRSV 9606 20448038 t lperfetto Overexpression of pp2a catalytic subunit (pp2ac) beta-isoform results in dephosphorylation of mekk3 at thr-516 and ser-520 and termination of mekk3-mediated nf-kappab activation. SIGNOR-165229 0.379 DUSP9 protein Q99956 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates binding 9606 21908610 t gcesareni Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein. SIGNOR-176589 0.692 EIF2AK2 protein P19525 UNIPROT AIM2 inflammasome complex SIGNOR-C222 SIGNOR up-regulates activity binding 9606 BTO:0000007 22801494 t miannu Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. SIGNOR-263120 0.319 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 t Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. SIGNOR-251477 0.2 SLC24A4 protein Q8NFF2 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264392 0.8 MAPK3 protein P27361 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser150 PELCGPGsPPVLTPG 9606 15952796 t lperfetto Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation SIGNOR-138171 0.303 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser608 TAADMYLsPVRSPKK BTO:0001968 10207050 t llicata In the present assay, ΔP3,4HA repressed E2F-mediated transcription similarly to wild-type pRB, suggesting that phosphorylation at other sites on ΔP3,4HA can disrupt its interaction with E2F and that these two sites are not sufficient to regulate E2F binding on DNA. This result is consistent with another report which showed that mutation of the human sites 8 and 9 (human Ser608 and Ser612) repressed E2F-mediated transcription to the same level as wild-type pRB (2). | Surprisingly, no one CDK site regulated the interaction of pRB with E2F when E2F was bound to DNA. Instead, disruption of transcriptional repression resulted from accumulation of phosphate groups on the RB molecule. SIGNOR-250747 0.741 SLIT2 protein O94813 UNIPROT ROBO proteinfamily SIGNOR-PF14 SIGNOR up-regulates binding -1 16226035 t miannu Here we describe and compare two human robo3 isoforms, robo3a and robo3b, which differ by the insertion of 26 amino acids at the n-terminus, and these forms appear to be evolutionary conserved. We investigated the bioactivity of these isoforms and show that they have different binding properties to slit. SIGNOR-268377 0.938 HMGCS2 protein P54868 UNIPROT (3S)-3-hydroxy-3-methylglutaryl-CoA(5-) smallmolecule CHEBI:43074 ChEBI up-regulates quantity chemical modification 29597274 t lperfetto Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis SIGNOR-267660 0.8 MYC protein P01106 UNIPROT CCNE1 protein P24864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9188852 f gcesareni Our results suggest that this activation may involve at least two myc-dependent steps: the induction of cyclin e gene transcription followed by accumulation of cyclin e mrna in a protein synthesis-independent manner and the p27(kip1) association with cyce/cdk2 complexes containing newly synthesised cyce. SIGNOR-49130 0.618 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARA protein P10276 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 t Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  SIGNOR-258138 0.8 SRC protein P12931 UNIPROT DAG1 protein Q14118 UNIPROT down-regulates phosphorylation Tyr892 PYRSPPPyVPP 9606 BTO:0000887;BTO:0001103 12795607 t lperfetto Tyrosine 892 is now thought to be the principal site for recognition by the c-src tyrosine kinase;. We show that upon tyrosine phosphorylation, beta-dystroglycan undergoes a profound change in its sub-cellular localization (e.g., from the plasma membrane to an internal membrane compartment). One possibility is that the net negative charge at position 892 causes the redistribution of beta-dystroglycan to this intracellular vesicular location SIGNOR-101655 0.531 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr536 QKGQESEyGNITYPP 9606 8692915 t Manara The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites. SIGNOR-260820 0.423 PPP2CB protein P62714 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 9606 18160256 t Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248614 0.487 FBXW7 protein Q969H0 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates quantity by destabilization ubiquitination 9606 15546612 t lperfetto Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. SIGNOR-254310 0.632 TNF protein P01375 UNIPROT CTSK protein P43235 UNIPROT up-regulates quantity by expression transcriptional regulation 11920402 f lperfetto This is supported by our finding that inflammatory cytokines such as IL-1b and TNFa increase the expres- sion of cathepsin K mRNA 􏰌6–8-fold and increase the secretion of the mature enzyme. SIGNOR-253317 0.366 2-[1-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1-pyrazolyl]-3-azetidinyl]acetonitrile chemical CHEBI:95341 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity chemical inhibition 9606 20363976 t Luana INCB028050 is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM). SIGNOR-257832 0.8 NUP107 protein P57740 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262090 0.817 CDK1 protein P06493 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000887;BTO:0001260 SIGNOR-C17 20150555 t gcesareni Moreover, we showed that sp1 is a novel mitotic substrate of cdk1/cyclin b1 and is phosphorylated by it at thr 739 before the onset of mitosis. SIGNOR-163738 0.476 FYN protein P06241 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Tyr18 MEDHAGTyGLGDRKD 9606 14999081 t lperfetto In this study we determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn. SIGNOR-123099 0.551 SLC5A5 protein Q92911 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 10116 28192058 t scontino Active iodide (I-) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na+/I- symporter (NIS). In the thyroid, NIS-mediated I- uptake plays a pivotal role in thyroid hormone (TH) biosynthesis.  SIGNOR-266961 0.8 BMP7 protein P18075 UNIPROT ACTR2 protein P61160 UNIPROT up-regulates binding 9606 16446785 t acerquone The two ligands induce the formation of two ligand-receptor complexes, cbmp7 (blue) and ctgf-b (red), that share the type i receptor alk2 SIGNOR-144144 0.293 E2F1 protein Q01094 UNIPROT MCPH1 protein Q8NEM0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22136275 f miannu Overexpression of E2F1 led to the upregulation of MCPH1 transcription, and knocking down the endogenous E2F1 resulted in the inhibition of the MCPH1 promoter activity. SIGNOR-253848 0.354 ATP5ME protein P56385 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261407 0.2 AXIN1 protein O15169 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates binding 9606 SIGNOR-C110 12000790 t gcesareni Complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45). SIGNOR-87401 0.537 CDK5 protein Q00535 UNIPROT PPP1R2 protein P41236 UNIPROT unknown phosphorylation Thr73 MKIDEPStPYHSMMG -1 11320080 t llicata Neuronal Cdc2-like protein kinase (Cdk5/p25) is associated with protein phosphatase 1 and phosphorylates inhibitor-2. | NCLK Phosphorylates Thr72 of I-2 SIGNOR-250672 0.363 CDH10 protein Q9Y6N8 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265850 0.569 MAPK1 protein P28482 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 1939237 t lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. SIGNOR-22420 0.57 FYN protein P06241 UNIPROT AGAP2 protein Q99490 UNIPROT up-regulates phosphorylation Tyr1130 QGRTALFyARQAGSQ 9606 16841086 t llicata We demonstrate that fyn is essential for phosphorylating pike-a and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with pike-a and phosphorylates it on both y682 and y774 residues. Tyrosine phosphorylation in pike-a is required for its association with active fyn but not for akt. Mutation of d into a in pike-a protects it from caspase cleavage and promotes cell survival. SIGNOR-147936 0.445 RARA protein P10276 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10772826 f lperfetto Retinoic acid and its receptors repress the expression and transactivation functions of nur77 SIGNOR-76980 0.296 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Thr430 PPLPPRAtPSRPGEA 9606 11110801 t llicata In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676). SIGNOR-85000 0.453 PREX2 protein Q70Z35 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260570 0.415 FAS protein P25445 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 10090 BTO:0000944 7538908 t lperfetto Fas associates with rip. Rip is a novel form of apoptosis-inducing protein SIGNOR-235430 0.637 1-(3-chlorophenyl)piperazine chemical CHEBI:10588 ChEBI HTR2B protein P41595 UNIPROT up-regulates activity chemical activation 10036 BTO:0000452 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258684 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250554 0.2 quetiapine chemical CHEBI:8707 ChEBI HTR1E protein P28566 UNIPROT up-regulates activity chemical activation 9534 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258531 0.8 RNF8 protein O76064 UNIPROT H2AX protein P16104 UNIPROT up-regulates ubiquitination 9606 18001824 t gcesareni Rnf8 can ubiquitylate histone h2a and h2ax, SIGNOR-159309 0.2 CTDSP1 protein Q9GZU7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser187 NSHPFPHsPNSSYPN 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248798 0.477 DDX20 protein Q9UHI6 UNIPROT FOXL2 protein P58012 UNIPROT up-regulates binding 9606 BTO:0000975 16153597 t miannu Dp103 further increased the cell killing effect induced by foxl2 probably due to the direct association of dp103 with foxl2 protein. SIGNOR-140388 0.456 RERE protein Q9P2R6 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity relocalization 9606 BTO:0000932 11331249 t miannu We detected RERE protein mainly in the nucleus, where it colocalizes with the promyelocytic leukemia protein in promyelocytic leukemia oncogenic domains (PODs). Overexpression of RERE recruits a fraction of the proapoptotic protein BAX to PODS: This observation correlates with RERE-induced apoptosis, which occurs in a caspase-dependent manner. SIGNOR-264485 0.2 FOXO1 protein Q12778 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18612045 f lperfetto Transcriptional reporter assays performed in both HepG2 and C2C12 cells demonstrate that the MuRF1 promoter is highly responsive to dexamethasone-activated glucocorticoid receptor (GR) and FoxO1 individually, while co-overexpression of GR and FoxO1 leads to a dramatic synergistic increase in reporter activity SIGNOR-235367 0.414 ABCA1 protein O95477 UNIPROT APOA1 protein P02647 UNIPROT up-regulates activity binding 9606 15347662 t miannu The stimulation of cellular cholesterol and phospholipid efflux by apolipoprotein A-I is mediated by the activity of the ATP-binding cassette transporter A1 (ABCA1). ABCA1 forms a high affinity complex with apoA-I by binding amphipathic helices within the apolipoprotein. VFVNFA sequence is required for ABCA1 to form a complex with apoA-I and to transfer cholesterol to the apolipoprotein. SIGNOR-252100 0.782 MAPK1 protein P28482 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser759 KTPDGNKsPAPKPSD 9606 BTO:0001260 10514499 t lperfetto Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin. SIGNOR-71033 0.524 TFAP2A protein P05549 UNIPROT ADM protein P35318 UNIPROT up-regulates quantity by expression transcriptional regulation 9480831 t These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells. SIGNOR-254048 0.27 BAK1 protein Q16611 UNIPROT DIABLO protein Q9NR28 UNIPROT up-regulates 9606 21210296 f gcesareni Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c, (diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore. SIGNOR-170963 0.501 HSD17B11 protein Q8NBQ5 UNIPROT estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity chemical modification 9606 BTO:0000056 16166196 t lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. SIGNOR-268663 0.8 Kindlin proteinfamily SIGNOR-PF48 SIGNOR Av/b5 integrin complex SIGNOR-C178 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259006 0.356 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CC2D1A protein Q6P1N0 UNIPROT up-regulates activity phosphorylation Ser208 PASTPTYsPAPTQPA 20171170 t nucleus lperfetto We identified the Ser208 residue of Aki1 as a cyclin B1–Cdk1 phosphorylation site. Furthermore, cyclin B1–Cdk1 inhibitor treatment was shown to attenuate the level of Aki1 in complex with Scc1, suggesting that Aki1 phosphorylation by cyclin B1–Cdk1 contributes to Aki1–Scc1 complex formation. SIGNOR-268296 0.2 RNF4 protein P78317 UNIPROT PML protein P29590 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23530056 t miannu Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4. SIGNOR-272884 0.5 RFC3 protein P40938 UNIPROT RF-C complex complex SIGNOR-C375 SIGNOR form complex binding 12930972 t lperfetto RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned SIGNOR-265507 0.824 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11485553 t lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. SIGNOR-109617 0.674 LATS2 protein Q9NRM7 UNIPROT YWHAG protein P61981 UNIPROT up-regulates phosphorylation Ser59 VVGARRSsWRVISSI 9606 21118956 t lperfetto Phosphorylation of 14-3-3_ on s59 by lats2. Ser(58) phosphorylation and lys(49) acetylation of 14-3-3_ occur in a coordinated time-dependent manner to regulate 14-3-3_ homodimerization. 14-3-3_ ser(58) phosphorylation is required for star interactions under control conditions, SIGNOR-170139 0.337 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 BTO:0000007 18204439 t lperfetto Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation. SIGNOR-252958 0.71 ULK1 protein O75385 UNIPROT ATG13 protein O75143 UNIPROT up-regulates phosphorylation 9606 19211835 t gcesareni Ulks directly phosphorylate atg13 SIGNOR-183957 0.915 ITGB6 protein P18564 UNIPROT Av/b6 integrin complex SIGNOR-C179 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253210 0.865 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 BTO:0000150 19085255 t gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase. SIGNOR-182808 0.579 SLC27A3 protein Q5K4L6 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264464 0.7 Linsitinib chemical CID:11640390 PUBCHEM IGF1R protein P08069 UNIPROT down-regulates activity chemical inhibition 10090 24712877 t lperfetto Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control, β-cell functions, and β-cell proliferation in male mice SIGNOR-262028 0.8 DIABLO protein Q9NR28 UNIPROT XIAP protein P98170 UNIPROT down-regulates binding 9606 10929711 t amattioni Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. SIGNOR-171770 0.912 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding BTO:0001103 22045613 t svumbaca NICD is translocated to the nucleus where it binds recombining binding protein-Jj (RBP-Jj) SIGNOR-255364 0.95 GRPR protein P30550 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257372 0.503 LCK protein P06239 UNIPROT VAV1 protein P15498 UNIPROT unknown phosphorylation Tyr142 SVGDEDIySGLSDQI -1 10669745 t Lck recognizes preferentially the tyrosine residue of Vav located at position 174 and, with significantly less affinity, those present at positions 142 and 160. It is now clear that this posttranslational modification will be involved in the activation of Vav, in the regulation of the strength of the signals emanating from this molecule, and also in the negative regulation of its function. SIGNOR-251389 0.775 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr699 DPEGGVDyKNIHLEK 9606 15297464 t lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins. SIGNOR-127536 0.2 ARFGAP1 protein Q8N6T3 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 22363216 t The effect has been demonstrated using Q8N6T3-2 flangone The gtp hydrolysis activity of lrrk2 is markedly enhanced by arfgap1 supporting a role for arfgap1 as a gtpase-activating protein for lrrk2.Lrrk2 and arfgap1 interact in vitro in mammalian cells and in vivo in brain, and co-localize in the cytoplasm and at golgi membranes SIGNOR-196264 0.597 EPHB1 protein P54762 UNIPROT EPHB1 protein P54762 UNIPROT up-regulates activity phosphorylation Tyr928 SAIKMVQyRDSFLTA 10029 BTO:0000246 12223469 t  Co-immunoprecipitation was used to confirm the interaction of Grb7 with the cytoplasmic domain of EphB1 as well as the full-length receptor in intact cells. This interaction is mediated by the SH2 domain of Grb7 and requires tyrosine autophosphorylation of EphB1. We also found that EphB1 could phosphorylate Grb7 and mutation of either Tyr-928 or Tyr-594 to Phe decreased this activity. SIGNOR-251123 0.2 GPKOW protein Q92917 UNIPROT DHX16 protein O60231 UNIPROT up-regulates quantity binding 9606 BTO:0000567 25296192 t miannu In this report, we showed that GPKOW interacted directly with the DHX16/hPRP2 and with RNA. Immuno-depletion of GPKOW from HeLa nuclear extracts resulted in an inactive spliceosome that still bound DHX16. SIGNOR-266312 0.843 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser299 KMAFRAKsKSCHDLS -1 9677319 t lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. SIGNOR-249009 0.309 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258292 0.8 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Thr2031 CCRMGIKtSEGTPGF 9606 BTO:0000938 20595391 t lperfetto Three putative autophosphorylation sites (thr-2031, ser-2032, and thr-2035) have been identified within the activation segment of the lrrk2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of lrrk2. SIGNOR-166470 0.2 ACTA2 protein P62736 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 11988769 f miannu It has subsequently been shown that most myofibroblasts express α-SM actin (the actin isoform typically found in vascular SM cells)13,14 and that the expression of α-SM actin and collagen type I in these cells is coordinately regulated by transforming growth factor β1 (TGF-β1)15. All these observations indicate that the myofibroblast has a role in the synthesis of ECM and in force generation, which results in ECM reorganization and wound contraction SIGNOR-277682 0.7 NFYA protein P23511 UNIPROT GFI1B protein Q5VTD9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19965638 f miannu HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. SIGNOR-254434 0.2 GART protein P22102 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity chemical modification 9606 11381136 t miannu The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR. SIGNOR-267304 0.8 PPP1CA protein P62136 UNIPROT CASP2 protein P42575 UNIPROT up-regulates activity dephosphorylation Ser164 STDTVEHsLDNKDGP -1 19531356 t llicata nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2. SIGNOR-248564 0.2 E2F1 protein Q01094 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245477 0.7 abarelix chemical CHEBI:337298 ChEBI GNRHR protein P30968 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001033 22416801 t miannu Two GnRH antagonists are currently available: abarelix and degarelix. SIGNOR-259159 0.8 MAPK11 protein Q15759 UNIPROT PIAS2 protein O75928 UNIPROT up-regulates activity phosphorylation Ser116 VTPHSPSsPVGSVLL 9606 BTO:0000007 16713578 t miannu The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles SIGNOR-262947 0.267 NTS protein P30990 UNIPROT NTSR1 protein P30989 UNIPROT up-regulates binding 9606 BTO:0000975 1331689 t gcesareni The rat neurotensin receptor cdna sequence was transfected in chinese hamster ovary cells and cellular clones which stably express the corresponding protein were isolated and characterized. The scatchard analysis of the specific binding of [3h]neurotensin indicated a kd value of 0.45 +/- 0.08 nm and a bmax value of 3.27 +/- 0.29 pmol/mg of protein. ...Neurotensin Stimulated the phosphoinositides hydrolysis SIGNOR-17369 0.928 PRKAA2 protein P54646 UNIPROT INSR protein P06213 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 SIGNOR-C15 22207502 t gcesareni Ampk phosphorylates and activates theinsulinreceptor, providing a direct link between ampk and theinsulin pathway. SIGNOR-195324 0.379 AURKA protein O14965 UNIPROT NSD2 protein O96028 UNIPROT up-regulates quantity by stabilization phosphorylation Ser56 SKAQLSSsLQEGVMQ 35389552 t lperfetto Mechanistically, Aurora A phosphorylated NSD2 at S56 residue to protect the protein from cleavage and degradation, thus methylation of Aurora A and phosphorylation of NSD2 bilaterally formed a positive regulating loop. SIGNOR-275512 0.2 CSNK2A1 protein P68400 UNIPROT GPI protein P06744 UNIPROT down-regulates activity phosphorylation Ser185 GPRVWYVsNIDGTHI 9606 BTO:0000459 15637053 t llicata It is known that human PGI/AMF is phosphorylated at Ser(185) by protein kinase CK2 (CK2) | These results demonstrate that phosphorylation affects the allosteric kinetic properties of the enzyme, resulting in a less active form of PGI, whereas non-phosphorylated protein species retain cytokine activity.  SIGNOR-250869 0.339 ixabepilone chemical CHEBI:63605 ChEBI TUBB3 protein Q13509 UNIPROT down-regulates activity chemical inhibition 9606 18945860 t miannu Ixabepilone, the first drug in a new class of microtubule-stabilizing agents called epothilones, offers a new treatment option for patients with metastatic or locally advanced breast cancer who are refractory to standard chemotherapy. SIGNOR-259349 0.8 CDK1 protein P06493 UNIPROT NUP50 protein Q9UKX7 UNIPROT down-regulates phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 t gcesareni These results suggest that both ERK and Cdk1 directly phosphorylate Nup50 at Ser221 in intact cells|Notably, erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. SIGNOR-188061 0.396 ABL1 protein P00519 UNIPROT PSTPIP1 protein O43586 UNIPROT unknown phosphorylation Tyr345 PERNEGVyTAIAVQE 10090 BTO:0004055 11163214 t gcesareni These data suggest that Tyr-344 is a major c-Abl phosphorylation site, or that phosphorylation of Tyr-344 is required for subsequent phosphorylation at other tyrosine residues. SIGNOR-246219 0.615 PRKACA protein P17612 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT down-regulates activity phosphorylation Thr108 SPRAWRRPtIESHHVAI 10116 10187789 t In vitro, CaMKK is phosphorylated by PKA and this is associated with inhibition of enzyme activity. The major site of phosphorylation is threonine 108, although additional sites are phosphorylated with lower efficiency. SIGNOR-256115 0.2 HOXA9 protein P31269 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 f irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. SIGNOR-255864 0.7 WNT10B protein O00744 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates activity binding 9606 19008118 t FFerrentino In mesenchymal precursor cells, Wnt10b (and Wnt10a) binding to frizzled (FZD1) SIGNOR-253511 0.651 SRC protein P12931 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Tyr68 GQTVDDPyATFVKML 9606 19802004 t lperfetto Tyrosine phosphorylation of cofilin at y68 by v-src leads to its degradation through ubiquitin-proteasome pathway SIGNOR-188352 0.569 MAPK8IP3 protein Q9UPT6 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 15767678 t gcesareni The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk. SIGNOR-134558 0.715 SOD1 protein P00441 UNIPROT dioxygen smallmolecule CHEBI:15379 ChEBI up-regulates quantity chemical modification 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272286 0.8 NFATC3 protein Q12968 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001260 17079331 t lperfetto The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries. SIGNOR-251732 0.287 GABARAP protein O95166 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity binding 9606 11146101 t lperfetto N-terminal proline/serine rich (ps) domain of ulk1 (amino acid 287-416) is required for ulk1-gate-16 and ulk1-gabarap protein interactions SIGNOR-219391 0.334 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr315 MPMDTSVyESPYSDP 9606 BTO:0000661 11828374 t lperfetto We show here that Tyr315 and Tyr319 in the interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function. SIGNOR-247048 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 18483217 f PDGF signaling has been implicated in several fibrotic conditions and is assumed to play a role in driving proliferation of cells with a myofibroblast phenotype. SIGNOR-254373 0.7 RIMS2 protein Q9UQ26 UNIPROT RAB3C protein Q96E17 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 31679900 t miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle SIGNOR-264378 0.574 MYC protein P01106 UNIPROT UBTF protein P17480 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000539 15282543 t lperfetto MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter. SIGNOR-269644 0.364 PPP2CA protein P67775 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates dephosphorylation Thr516 GASKRLQtICMSGTG 9606 20448038 t lperfetto Overexpression of pp2a catalytic subunit (pp2ac) beta-isoform results in dephosphorylation of mekk3 at thr-516 and ser-520 and termination of mekk3-mediated nf-kappab activation. SIGNOR-165237 0.379 CADPS protein Q9ULU8 UNIPROT SNAP25 protein P60880 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 24363652 t miannu CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1 SIGNOR-264338 0.375 GATA6 protein Q92908 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression 9606 BTO:0000195 24317510 f lperfetto Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2. SIGNOR-253153 0.281 SELPLG protein Q14242 UNIPROT SELE protein P16581 UNIPROT up-regulates binding 9606 BTO:0000130 9024699 t gcesareni PSGL-1 was shown to mediate rolling of human neutrophils on p- and e-selectin in vitro. SIGNOR-46330 0.763 streptozocin chemical CHEBI:9288 ChEBI SLC2A2 protein P11168 UNIPROT down-regulates quantity chemical inhibition 10090 9421374 t miannu In this study, we report that GLUT2 is a target molecule for MLD-STZ toxicity. Ex vivo, a gradual decrement of both GLUT2 protein and mRNA expression was found in pancreatic islets isolated from MLD-STZ-treated C57BL/6 male mice, whereas mRNA expression of beta-actin, glucokinase, and proinsulin remained unaffected. GLUT2 is a crucial target molecule of MLD-STZ toxicity, and this toxicity seems to precede the immune reactions against beta-cells. SIGNOR-259314 0.8 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120184 0.321 COLGALT2 protein Q8IYK4 UNIPROT COL3A1 protein P02461 UNIPROT up-regulates activity glycosylation -1 19075007 t Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. SIGNOR-261158 0.378 HMOX1 protein P09601 UNIPROT BAD protein Q92934 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26722274 f irozzo The results of the present study indicated that knockdown of HMOX-1 significantly enhanced doxorubicin-induced apoptosis and downregulated the expression of Bcl-2 and Bcl-xL in breast cancer cells. SIGNOR-256304 0.2 JNK proteinfamily SIGNOR-PF15 SIGNOR MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation 9606 15767678 t inferred from 70% family members gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. SIGNOR-269984 0.2 NPAS2 protein Q99743 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR form complex binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. SIGNOR-267966 0.519 PP121 chemical CHEBI:50915 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206292 0.8 SMAD5 protein Q99717 UNIPROT HAND1 protein O96004 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 t Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation SIGNOR-268941 0.2 PF-03814735 chemical CID:49830590 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205953 0.8 Terfenadine chemical CHEBI:9453 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 19660947 t Luana  hERG activity was initially determined in a high throughput patch clamp screening assay (Ionworks)5 while a human H1 binding assay was used to determine H1 binding affinity.6 Selected results were confirmed in vitro using an IonWorks Quattro patch clamp assay and in vivo in the guinea pig.7, 8 Histamine H1activity was confirmed in vivo in the guinea pig.7 SIGNOR-257825 0.8 tipifarnib chemical CHEBI:141969 ChEBI FNTA protein P49354 UNIPROT down-regulates activity chemical inhibition 9606 11196150 t lperfetto In vitro, using isolated human farnesyl protein transferase, R115777 competitively inhibited the farnesylation of lamin B and K-RasB peptide substrates, with IC50s of 0.86 nM and 7.9 nM, respectively. In a panel of 53 human tumor cell lines tested for growth inhibition, approximately 75% were found to be sensitive to R115777. SIGNOR-262033 0.8 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT down-regulates activity phosphorylation Thr2074 VTPSPPGtVLTSALS 9606 BTO:0000007 12794074 t lperfetto We show that gsk-3beta directly binds at c-terminal of the notch2 ankyrin repeats and phosphorylates thr-2068 and/or ser-2070, thr-2074, and thr-2093. SIGNOR-101574 0.494 ATF4 protein P18848 UNIPROT WARS2 protein Q9UGM6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269430 0.248 FOXO1 protein Q12778 UNIPROT Metabolism phenotype SIGNOR-PH77 SIGNOR up-regulates 18391974 f Forkhead proteins, and FoxO1 in particular, play a significant role in regulating whole body energy metabolism. SIGNOR-253010 0.7 MAPK3 protein P27361 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser676 SNGRRKRsPTQSFRF 9606 15657420 t lperfetto The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity. SIGNOR-133276 0.293 (R)-salbutamol chemical CHEBI:8746 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 20590599 t Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  SIGNOR-257866 0.8 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr327 PLLREETyDVPPAFA 9606 12601080 t lperfetto Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas. SIGNOR-98500 0.259 CAD protein P27708 UNIPROT N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI up-regulates quantity chemical modification 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267425 0.8 MAPK13 protein O15264 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser68 GQNGEEKsPPNASHP -1 15850461 t miannu CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. SIGNOR-263084 0.429 DUSP3 protein P51452 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates activity dephosphorylation Tyr877 LDIDETEyHADGGKV 9606 BTO:0002552 21262974 t Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR. | We found that VHR decreased ErbB2 phosphorylation in vitro and in a cellular context, and the dephosphorylation of ErbB2 was more evident at Tyr-877 and Tyr-1221 than those at Tyr-1139 and Tyr-1248 (supplemental Fig. S1). Our data indicated that VHR was a cellular PTP against EGFR and ErbB2. SIGNOR-248533 0.271 IL1R1 protein P14778 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 9625767 t lperfetto Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab SIGNOR-249514 0.285 AKT2 protein P31751 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Thr235 QARKRKRtSIENRVR 9606 BTO:0004180 23041284 t flangone Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG. SIGNOR-242097 0.257 CSNK2A2 protein P19784 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates activity phosphorylation Ser424 CDEEFSDsEDEGEGG 9606 BTO:0000567 12082111 t llicata HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2. SIGNOR-251003 0.398 FOXO3 protein O43524 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity transcriptional regulation 10090 BTO:0002314 24749067 f gcesareni We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration. SIGNOR-244076 0.383 SLBP protein Q14493 UNIPROT H2AX protein P16104 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265405 0.2 PAK1 protein Q13153 UNIPROT ILK protein Q13418 UNIPROT up-regulates phosphorylation Ser246 CPRLRIFsHPNVLPV 9606 17420447 t lperfetto We found that pak1 phosphorylates ilk at threonine-173 and serine-246 in vitro and in vivo. together, these results suggest that ilk is a pak1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin. SIGNOR-154303 0.42 EGR1 protein P18146 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9867871 f miannu The human copper-zinc superoxide dismutase gene (SOD1) proximal promoter is regulated by Sp1, Egr-1, and WT1 via non-canonical binding sites. Egr-1 and two splicing variants of the Egr-related protein WT1 were able to transactivate the SOD1 promoter in co-transfection experiments. SIGNOR-253897 0.295 BIRC3 protein Q13489 UNIPROT RIPK4 protein P57078 UNIPROT up-regulates activity polyubiquitination lys51 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation. SIGNOR-272707 0.362 MRTFA protein Q969V6 UNIPROT KLF4 protein O43474 UNIPROT down-regulates 9606 21673106 f miR-143 and miR-145 target KLF4 gcesareni This result suggests that mrtf-a, but not myocd, is essential for bmp4-dependent induction ofmir-143/145gene transcription. Of the mirnas identified to target klf4, only mir-143 and mir-145 were induced at least 1.5-fold by both bmp4 and tgf- , suggesting that they may be critical for bmp4- and tgf- -mediated reduction of klf4. SIGNOR-174261 0.2 oxaprozin chemical CHEBI:7822 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000132;BTO:0003652 9650852 t miannu We used human platelets cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 for measuring cyclooxygenase selectivity. The presence of the enzymes was confirmed by immunoblotting and immunoprecipitation analysis, and by the reverse transcriptase-polymerase chain reaction. Mean IC50 values (microM) for human platelet cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 and cyclooxygenase-1/-2 IC50 ratio of various NSAIDs were as follows: aspirin, 3.2, 26, 0.12; diclofenac, 0.037, 0.00097, 38; etodolac, 122, 0.68, 179; ibuprofen, 3.0, 3.5, 0.86; indomethacin, 0.013, 0.044, 0.30; loxoprofen (active metabolite), 0.38, 0.12, 3.2; NS-398, 12, 0.0095, 1263; oxaprozin, 2.2, 36, 0.061; zaltoprofen, 1.3, 0.34, 3.8; respectively. SIGNOR-258930 0.8 MMP3 protein P08254 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272396 0.7 NFYC protein Q13952 UNIPROT PHGDH protein O43175 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18378410 f miannu Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y. SIGNOR-255211 0.2 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248753 0.727 SERPINE1 protein P05121 UNIPROT Fibrinolysis phenotype SIGNOR-PH6 SIGNOR down-regulates 9606 10368279 f gcesareni Pai-1 is the physiological inhibitor of the fibrinolytic pathway SIGNOR-68481 0.7 POU3F2 protein P20265 UNIPROT POU3F2 protein P20265 UNIPROT up-regulates activity binding 9606 11029584 t miannu These experiments lead to the conclusion that the full-length Brn-2 protein can interact with full-length Brn-2. Assay of homodimerization properties of Brn-2 protein on the b2s1 dimer recognition sequence also demonstrated cooperativity, indicating that protein-protein contacts would be important for synergistic interactions between the Brn-2 subunits. SIGNOR-221824 0.2 GNAI1 protein P63096 UNIPROT TNFAIP8 protein O95379 UNIPROT up-regulates activity binding 9606 20607800 t TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation SIGNOR-256491 0.2 CFL1 protein P23528 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR down-regulates quantity binding 9606 BTO:0000132 27871158 t lperfetto Cofilin also binds to actin and contributes to the disassembly of actin filaments and the subsequent release of actin monomers. SIGNOR-261836 0.7 WNT4 protein P56705 UNIPROT MYF5 protein P13349 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 9753670 f gcesareni Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. SIGNOR-60370 0.298 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr853 HLGRVLGyGAFGKVV 9606 20431062 t lperfetto Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk. SIGNOR-165055 0.492 NF1 protein P21359 UNIPROT KRAS protein P01116 UNIPROT down-regulates activity binding 9606 BTO:0000007 32697994 t miannu Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS. SIGNOR-273661 0.71 FGF4 protein P08620 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates binding 9606 1385111 t gcesareni Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides. SIGNOR-18567 0.658 RPL5 protein P46777 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262457 0.889 PRKCA protein P17252 UNIPROT KRT18 protein P05783 UNIPROT unknown phosphorylation Ser53 ISVSRSTsFRGGMGS -1 7523419 t lperfetto Ser-52 in K18 is not glycosylated and matches consensus sequences for phosphorylation by CAM kinase, S6 kinase and protein kinase C, and all these kinases can phosphorylate K18 in vitro predominantly at that site. SIGNOR-248894 0.312 HRH2 protein P25021 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257250 0.252 BMP7 protein P18075 UNIPROT DLK1 protein P80370 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20584981 f fspada Bmp7 could directly suppress pref-1 expression, thereby allowing the initiation of the adipogenic program. SIGNOR-166426 0.295 NOG protein Q13253 UNIPROT BMP2 protein P12643 UNIPROT down-regulates binding 9606 12700180 t lperfetto Noggin acts by binding bmps, thus preventing them from binding to their receptors (180). Noggin binds with various degrees of affinity bmp-2, -4, -5, -6, and -7, gdf-5, gdf-6, and vg1, but not other members of the tgf- family of peptides SIGNOR-100657 0.804 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser315 ITATSPAsMVGGKPG 9606 9335553 t gcesareni These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling. SIGNOR-52696 0.698 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 SIGNOR-244576 0.2 TEK protein Q02763 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 f lperfetto the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. SIGNOR-241541 0.2 SKA2 protein Q8WVK7 UNIPROT SKA complex complex SIGNOR-C364 SIGNOR form complex binding -1 22483620 t lperfetto We show that the structure of the Ska core complex is a W-shaped dimer of coiled coils, formed by intertwined interactions between Ska1, Ska2, and Ska3. SIGNOR-265195 0.899 Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR Organelle_transport phenotype SIGNOR-PH159 SIGNOR up-regulates 16440056 f lperfetto The most abundant cytoplasmic dynein complex, cytoplasmic dynein 1, is involved in functions as diverse as spindle-pole organization and nuclear migration during mitosis, the positioning and functioning of the endoplasmic reticulum, the Golgi apparatus, and the nucleus, and also the minus-end-directed transport of vesicles, including endosomes and lysosomes, along microtubules and retrograde axonal transport in neurons. SIGNOR-265058 0.7 MAPK3 protein P27361 UNIPROT KRT8 protein P05787 UNIPROT unknown phosphorylation Ser432 SAYGGLTsPGLSYSL 9606 22344252 t llicata Our data suggested a close relationship between k8(s431) phosphorylation and keratin reorganization in epithelial tumor cells. SIGNOR-196141 0.429 2-Amino-5,6,7,8-tetrahydro-4-(4-methoxyphenyl)-7-(naphthalen-1-YL)-5-oxo-4H-chromene-3-carbonitrile chemical CID:25223366 PUBCHEM SLC1A3 protein P43003 UNIPROT down-regulates activity chemical inhibition 9606 19161278 t Federica The most potent analogue in the series, 1o, displayed high nanomolar inhibitory activity (IC50) 0.66μM) at EAAT1, with more than 400-foldselectivity compared to EAAT2 and EAAT3. SIGNOR-261108 0.8 WNT5B protein Q9H1J7 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. SIGNOR-141440 0.622 PPARGC1A protein Q9UBK2 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20089851 f Regulation miannu PGC-1α has been reported to induce Mn-SOD expression SIGNOR-251762 0.381 RAB6C protein Q9H0N0 UNIPROT VPS13B protein Q7Z7G8 UNIPROT up-regulates activity binding 10116 BTO:0003102 25492866 t miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. We show that COH1 forms a physical and functional complex with RAB6. Our results point to a role of COH1 as a RAB6 effector protein. Depletion of COH1 leads to decreased neurite outgrowth in cultured primary hippocampal neurons. These results establish a critical role for RAB6-dependent function of COH1 in neuritogenesis by regulating Golgi complex organization. COH1 Interacts with All Three Mammalian RAB6 Homologues SIGNOR-266871 0.2 GABRB1 protein P18505 UNIPROT GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR form complex binding 9606 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263766 0.629 STAT3 protein P40763 UNIPROT IL1RN protein P18510 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000130;BTO:0000876 20032313 f miannu The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils. our findings uncover a novel mechanism whereby IL-10-activated STAT3 modulates IL-1ra transcription in LPS-treated phagocytes by making IL-1ra promoter accessible to readily available nuclear NF-kappaB. SIGNOR-254795 0.485 CDK1 protein P06493 UNIPROT ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr846 RAFSFSKtPKRALRR 9606 SIGNOR-C17 16247472 t lperfetto Thr-814 to ala greatly diminished the ability of p34cdk1/cyclin b to phosphorylate recombinant ect2-c protein (figure 1b, left panel). These data suggest that thr-814 is a major cdk1 phosphorylation site in ect2-c in vitrothe sequence thr-pro-lys-arg (tpkr) starting at amino acid 814we found that the t814a mutation slightly reduces the exchange activity of ect2 on rac1 SIGNOR-141179 0.593 FGF1 protein P05230 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates binding 9606 22298955 t gcesareni Reports also show that fgf/fgfr3 signals mediate some of the effects of tgf-beta on embryonic bone formation SIGNOR-195585 0.793 ATM protein Q13315 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser696 NVLSVALsQRTTVPE 9606 21095582 t lperfetto Here we show that hypoxia results in ataxia telangiectasia mutated (atm)-dependent phosphorylation of hypoxia-inducible factor 1-alpha (hif-1_) on serine(696) and mediates downregulation of mtorc1 signaling. phosphorylation of hif-1_ by atm is required for its stability SIGNOR-169999 0.443 D2HGDH protein Q8N465 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity 26178471 f lperfetto Here we show that wild-type D2HGDH elevates α-KG levels SIGNOR-253131 0.8 WWTR1 protein Q9GZV5 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199208 0.7 CPSF7 protein Q8N684 UNIPROT CFI complex complex SIGNOR-C388 SIGNOR form complex binding 9606 BTO:0000567 8626397 t lperfetto We report here the purification of CF Im from HeLa cell nuclear extracts. Three polypeptides of 68, 59, and 25 kDa copurified with CF Im activity. SIGNOR-266124 0.781 ARRB2 protein P32121 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity relocalization 21296876 t lperfetto Internalization of the Na(+)/H(+) exchanger NHE5 into recycling endosomes is enhanced by the endocytic adaptor proteins beta-arrestin1 and -2, best known for their preferential recognition of ligand-activated G protein-coupled receptors (GPCRs) SIGNOR-275506 0.406 INS protein P01308 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates activity 9606 BTO:0000887 9415393 f lperfetto Studies in adipose cells have demonstrated that insulin stimulates its receptor to phosphorylate tyrosine residues in irs-1, leading to activation of phosphatidylinositol 3-kinase, which plays a necessary role in mediating the translocation of the insulin-responsive glucose transporter glut4 to the cell surface. SIGNOR-236781 0.509 PPP1CA protein P62136 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates activity dephosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000007 17603999 t Protein kinases involved in the DNA damage checkpoint control, such as ATM, ATR, and hCds1/Chk2, have been shown to phosphorylate and activate BRCA1 upon DNA damage. |Altogether, these results indicate that PP1α specifically dephosphorylates BRCA1 at multiple serine sites, including S988 [12], S1423, and S1524. SIGNOR-248561 0.385 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252856 0.908 PRKCA protein P17252 UNIPROT PPP1R16B protein Q96T49 UNIPROT down-regulates activity phosphorylation Ser331 SQLRHKSsLSRRTSS -1 27939168 t done miannu PKCα phosphorylated the full length recombinant TIMAP in in vitro kinase assay and Ser331 of TIMAP was shown to be phosphorylated by PKC. Phosphorylation of TIMAP upon PKC activation in endothelial cells results in enrichment of TIMAP in the membrane, but no such change can be observed in PKC depleted cells. Phosphorylation state of TIMAP, through affecting PP1 activity, has a remarkable effect on endothelial barrier function. SIGNOR-273802 0.2 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG3-LLGL1_variant complex SIGNOR-C507 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270896 0.531 CBLL1 protein Q75N03 UNIPROT ANXA2 protein P07355 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 31952268 t miannu By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. SIGNOR-271473 0.2 TLRs proteinfamily SIGNOR-PF20 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 20404851 f lperfetto The negative regulation of TLR-induced responses is important for sup- pressing inflammation and deleterious immune responses. SIGNOR-216304 0.7 heparan sulfate octasaccharide smallmolecule CHEBI:142519 ChEBI ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 27241222 f miannu Many observations in animal models deficient for HSPGs and recent observations of human genetic mutations for biosynthesis of HSPGs have identified the importance of HSPGs for normal embryonic development and ECM organization. SIGNOR-264017 0.7 SRC protein P12931 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Tyr45 GLEPVGHyEEVELTE 9606 16640565 t llicata Src kinase phosphorylates s6k in the n-terminus. tyrosine y39/45 in s6k1/2 is a substrate for src kinase in vitro. tyrosine y39/45 in s6k1/2 is a substrate for src kinase in vivo. SIGNOR-146292 0.348 MARK4 protein Q96L34 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser396 DDKKAKTsTRSSAKT -1 21204788 t done miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). SIGNOR-273935 0.429 PRKACA protein P17612 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates phosphorylation Ser320 ASPGRPSsVDTLLSP 9606 21085490 t lperfetto Protein kinase a binds and activates heat shock factor 1hsf1 binds avidly to the catalytic subunit of pka, (pkac_) and becomes phosphorylated on a novel serine phosphorylation site within its central regulatory domain (serine 320 or s320), both in vitro and in vivo. Intracellular pkac_ levels and phosphorylation of hsf1 at s320 were both required for hsf1 to be localized to the nucleus, bind to response elements in the promoter of an hsf1 target gene SIGNOR-169853 0.32 SMAD7 protein O15105 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity relocalization 9606 19352540 t lperfetto Smad7 also recruits the HECT type of E3 ubiquitin ligases, Smurf1 and Smurf2. It binds to Smurfs in the nucleus and translocates into the cytoplasm in response to TGF-_ and recruits the ubiquitin ligases to the activated type I receptor ALK5/T_RI, leading to the degradation of the receptor through the proteasomal pathway. SIGNOR-168450 0.865 PCDH10 protein Q9P2E7 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-269034 0.2 CDK1 protein P06493 UNIPROT LMNA protein P02545 UNIPROT up-regulates phosphorylation Ser392 ERLRLSPsPTSQRSR 9606 18815303 t gcesareni Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm SIGNOR-181318 0.552 KCNJ3 protein P48549 UNIPROT KCNJ5/KCNJ3 complex SIGNOR-C56 SIGNOR form complex binding 9606 BTO:0000562 22362083 t miannu The muscarinic k(+) channel (i (k,ach)) is a heterotetramer composed of girk1 (kir3.1) andgirk4(kir3.4) subunits of a g protein-coupled inwardly rectifying channel, and plays an important role in mediating electrical responses to the vagal stimulation in the heart. SIGNOR-196202 0.484 RIN1 protein Q13671 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 11784866 t gcesareni We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1. SIGNOR-113967 0.621 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser250 TGSPAELsPTTLSPV 9606 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248298 0.422 PRLHR protein P49683 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257280 0.266 INS protein P01308 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 11279134 f lperfetto The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin SIGNOR-235619 0.502 VRK2 protein Q86Y07 UNIPROT DTNBP1 protein Q96EV8 UNIPROT down-regulates quantity by destabilization phosphorylation Ser299 RAKPPSSsSTCTDSA -1 30062698 t miannu  We show that VRK2 phosphorylates Ser 297 and Ser 299 of dysbindin using in vitro kinase assay. In addition, we found that VRK2-mediated phosphorylation of dysbindin enhanced ubiquitination of dysbindin and consequently resulted in the decrease in its protein stability through western blotting.  SIGNOR-277404 0.2 ETS1 protein P14921 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity transcriptional regulation 9606 1722028 t Furthermore, the possible involvement of an Ets protein in the control of c-fos has interesting implications for proto-oncogene cooperation in cellular growth control. SIGNOR-256495 0.707 DAXX protein Q9UER7 UNIPROT Immortality phenotype SIGNOR-PH47 SIGNOR down-regulates 9606 BTO:0000584 26428317 f Telomere length must be maintained for the immortalization of malignant cells […] alternative lengthening of telomeres status was perfectly correlated with the loss of expression of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein in pancreatic neuroendocrine tumors SIGNOR-256596 0.7 NFIA protein Q12857 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268894 0.2 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000661 15870263 t gianni In response to cellular stimuli, CYLD undergoes rapid and transient phosphorylation, which is required for signal-induced TRAF2 ubiquitination and activation of downstream signaling events. Interestingly, the CYLD phosphorylation requires IkappaB kinase gamma (IKKgamma) and can be induced by IKK catalytic subunits. SIGNOR-266436 0.529 AKT1 protein P31749 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity 9606 BTO:0001103 15829723 t apalma GSK-3beta activity can be inhibited by Akt phosphorylation (12), which may provide a mechanism for Akt to promote muscle growth through inhibition of the negative regulator GSK-3beta. SIGNOR-255109 0.784 17beta-estradiol smallmolecule CHEBI:16469 ChEBI 4-hydroxy-17beta-estradiol smallmolecule CHEBI:62845 ChEBI up-regulates quantity precursor of 9606 BTO:0000093 8790407 t Luana These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens. SIGNOR-269753 0.8 Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 BTO:0000938 21106647 f miannu Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. SIGNOR-268384 0.7 DYRK1B protein Q9Y463 UNIPROT HNF1A protein P20823 UNIPROT up-regulates phosphorylation Ser249 IQRGVSPsQAQGLGS 9606 BTO:0000887;BTO:0001103 11980910 t lperfetto Mirk phosphorylates hnf1 at amino acid 249mkk3 enhanced mirk kinase activity and the transcriptional activation of hnf1alpha by mirk SIGNOR-86728 0.516 PDGFRB protein P09619 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr155 LNDSAAYyLNDLDRI -1 33139573 t miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. SIGNOR-277232 0.2 AKT2 protein P31751 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000586 SIGNOR-C110 16293724 t lperfetto We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt by free G protein betagamma subunits and the direct association of the G protein alphas subunit with the regulator of G protein signaling (RGS) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. SIGNOR-235718 0.607 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Ser299 SQPPGEDsDTDVDDD 9606 18678890 t gcesareni The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites. SIGNOR-179875 0.353 CAV3 protein P56539 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255997 0.496 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 17591690 t llicata We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 cdk5-stabilized p53 protein is transcriptionally active SIGNOR-156422 0.722 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PLEC protein Q15149 UNIPROT down-regulates phosphorylation Thr4539 GGLIEPDtPGRVPLD 9606 BTO:0000567 8626512 t lperfetto Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane. SIGNOR-216908 0.396 PBX1 protein P40424 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription SIGNOR-265803 0.274 NAT8L protein Q8N9F0 UNIPROT N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI up-regulates quantity chemical modification 9606 19524112 t miannu The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA. SIGNOR-267523 0.8 SIRT7 protein Q9NRC8 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity deacetylation Lys38 PATGGVKkPHRYRPG 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275886 0.2 RAD1 protein O60671 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates binding 9606 18594563 t gcesareni The 9-1-1 complex functions as a clamp, encircling the dna, and recruits the brct domain-containing protein topbp1 in a phospho-dependent manner SIGNOR-179379 0.603 SMURF1 protein Q9HCE7 UNIPROT CUEDC1 protein Q9NWM3 UNIPROT unknown ubiquitination -1 20804422 t miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. SIGNOR-272682 0.2 imatinib chemical CHEBI:45783 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck;VIRAL ABL gcesareni SIGNOR-193372 0.8 RARB protein P10826 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity binding 9606 15650024 t inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs SIGNOR-267807 0.398 FLT3 protein P36888 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates quantity transcriptional regulation 9606 BTO:0004760 15574429 f Furthermore, a small but reproducible growth/survival advantage was observed in both TF-1 and TF-1/ITD cells when SHP-1 expression was knocked down by RNAi. Taken together, these data provide the first evidence that suppression of SHP-1 by FLT3/ITD signaling may be another mechanism contributing to the transformation by FLT3/ITD mutations SIGNOR-259950 0.374 AKT2 protein P31751 UNIPROT TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-235852 0.665 RPS6KA1 protein Q15418 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017877 t lperfetto We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1 SIGNOR-176887 0.506 COLGALT1 protein Q8NBJ5 UNIPROT COL3A1 protein P02461 UNIPROT up-regulates activity glycosylation -1 19075007 t Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. SIGNOR-261154 0.378 BTC protein P35070 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0000150 9528863 t gcesareni Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4. SIGNOR-56365 0.737 MT-ND2 protein P03891 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. SIGNOR-262144 0.773 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser465 HNPISSVs 9606 9335504 t llicata The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. SIGNOR-52670 0.628 TRIM2 protein Q9C040 UNIPROT NEFL protein P07196 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 18687884 t miannu Here, we show that TRIM RING finger protein TRIM2, highly expressed in the nervous system, is an UbcH5a-dependent ubiquitin ligase. We further demonstrate that TRIM2 binds to neurofilament light subunit (NF-L) and regulates NF-L ubiquitination. SIGNOR-271776 0.441 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMPH protein P49418 UNIPROT unknown phosphorylation Ser272 EEPSPLPsPTASPNH -1 11113134 t llicata Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells.  SIGNOR-250644 0.361 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 f We observed GR binding on or near Cebpβ, Cebpδ, Klf5, Klf9, Cebpα, and Pparγ gene loci at 4 h but not at 0 h of adipogenesis. Thus, at least one of the mechanisms by which GR promotes adipogenesis in culture is by directly activating the expression of multiple adipogenic TFs. SIGNOR-256120 0.401 OGA protein O60502 UNIPROT PFKL protein P17858 UNIPROT up-regulates activity deglycosylation Ser529 CVIPATIsNNVPGTD 9606 26399441 t lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. SIGNOR-267608 0.2 LRRK2 protein Q5S007 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Thr127 KVLSSLVtLNKVTAD 9606 21048939 t gcesareni Arhgef7 is interacting with lrrk2 in vitro and in vivo. Lrrk2 phosphorylates arhgef7 in vitro.Two Threonine residues, t107 and t143, within the arhgef7 n-terminus were identified with high confidence SIGNOR-169221 0.468 ADSS1 protein Q8N142 UNIPROT Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates 9606 10496970 f miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267835 0.7 SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20643654 t miannu Src-dependent pdk1 tyr373/376 tyrosine phosphorylation. / optimal activation of pdk1 requires phosphorylation of tyr373/376 SIGNOR-166722 0.567 mTORC1 complex SIGNOR-C3 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr390 DSKFTRQtPVDSPDD 9606 11914378 t azuccotti Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain [..]. Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings. SIGNOR-255842 0.476 PKG proteinfamily SIGNOR-PF77 SIGNOR 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. SIGNOR-266507 0.8 STK3 protein Q13188 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Thr228 PQWNESFtFKLKPSD 9606 BTO:0002181 26414765 t miannu Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα.  SIGNOR-277176 0.2 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Thr111 PIPQISStPKTSEEA 9606 18055457 t lperfetto Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta SIGNOR-159578 0.275 tacrolimus (anhydrous) chemical CHEBI:61049 ChEBI PPP3CA protein Q08209 UNIPROT down-regulates chemical inhibition 9606 15276472 t gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. SIGNOR-127239 0.8 AP1S1 protein P61966 UNIPROT AP-1 complex complex SIGNOR-C248 SIGNOR form complex binding 9606 21097499 t lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) SIGNOR-260684 0.862 CHAMP1 protein Q96JM3 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 21063390 f miannu Proper attachment of microtubules to kinetochores is essential for accurate chromosome segregation. These data suggest that CAMP is required for maintaining kinetochore-microtubule attachment during biorientation. SIGNOR-264901 0.7 HCRT protein O43612 UNIPROT HCRTR1 protein O43613 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9491897 t gcesareni Identification and initial biological characterization of two orexins as well as their two receptors SIGNOR-53667 0.764 FYN protein P06241 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 15537652 t gcesareni Here we provide evidence that fyn kinase, a member of the src kinase family, is involved in the uvb-induced phosphorylation of histone h3 at serine 10 SIGNOR-265330 0.2 MLNR protein O43193 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257132 0.41 CSNK2A1 protein P68400 UNIPROT AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser316 EKKGKDQsGEVLSSV 9615 BTO:0000837 11742978 t llicata We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. AQP4 phosphorylation by CKII may thus provide a mechanism that regulates AQP4 cell surface expression. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4-Cter proteins in which only one out of the three C-terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. SIGNOR-250828 0.426 FLCN protein Q8NFG4 UNIPROT RRAGC protein Q9HB90 UNIPROT up-regulates activity gtpase-activating protein 9606 BTO:0000007 24095279 t The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur SIGNOR-256503 0.686 OFD1 protein O75665 UNIPROT ATG13 protein O75143 UNIPROT down-regulates quantity by destabilization binding 9606 34027042 t miannu The OFD1 protein inhibits autophagosome biogenesis by selective autophagy-mediated degradation of Autophagy Related 13 (ATG13), a component of the unc-51-like kinase (ULK1) autophagy initiation complex. SIGNOR-269107 0.2 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKAR2B protein P31323 UNIPROT down-regulates activity chemical inhibition 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258762 0.8 HTR3C protein Q8WXA8 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 18761359 f miannu The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release.  SIGNOR-264320 0.7 GSK3B protein P49841 UNIPROT STMN3 protein Q9NZ72 UNIPROT up-regulates activity phosphorylation Ser60 SFEVILKsPSDLSPE -1 22577147 t lperfetto Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta SIGNOR-264882 0.267 N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-268102 0.8 Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR protein polypeptide chain smallmolecule CHEBI:16541 ChEBI up-regulates quantity chemical modification 9606 29735640 t miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3–guanosine triphosphate (GTP) complex. eRF1 recognizes the stop codon, and after hydrolysis of GTP by eRF3, mediates release of the nascent peptide.  SIGNOR-270818 0.8 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 12576312 t lperfetto Vasodilator-stimulated phosphoprotein activation of serum-response element-dependent transcription occurs downstream of rhoa and is inhibited by cgmp-dependent protein kinase phosphorylation. Three phosphorylation sites have been identified in vasp: ser157, ser239, and thr278, all of which can be phosphorylated by either pka or pkg in vitro SIGNOR-98139 0.729 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SCNN1B protein P51168 UNIPROT down-regulates quantity by destabilization phosphorylation -1 11805112 t inferred from 70% family members lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. SIGNOR-270050 0.2 NEDD4L protein Q96PU5 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 t miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). SIGNOR-253456 0.476 CHRM5 protein P08912 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257217 0.429 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates phosphorylation 9606 BTO:0000782;BTO:0001271 18174237 t gcesareni Constitutive activation of the c-jun n-terminal kinase (jnk) pathway in sup-t1 cells promoted phosphorylation and degradation of bimel via the proteosome. SIGNOR-160326 0.75 PRKCA protein P17252 UNIPROT UNC5A protein Q6ZN44 UNIPROT down-regulates quantity phosphorylation Ser532 EPSPDSWsLRLKKQS 10116 BTO:0003036 16554470 t miannu We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis. SIGNOR-268179 0.2 CSNK2A2 protein P19784 UNIPROT UBE2R2 protein Q712K3 UNIPROT up-regulates activity phosphorylation Ser233 DCYDDDDsGNEES 9606 12037680 t llicata UBC3B is specifically phosphorylated by CK2 in vitro and in vivo. We mapped by deletions and site directed mutagenesis the phosphorylation site to a serine residue within the C-terminal domain in position 233 of UBC3B and in the corresponding serine residue of UBC3. | Following CK2-dependent phosphorylation both UBC3B and UBC3 bind to the F-box protein beta-TrCP, the substrate recognition subunit of an SCF (Skp1, Cul1, F-box) ubiquitin ligase. Furthermore, we observed that co-transfection of CK2alpha' together with UBC3B, but not with UBC3DeltaC, enhances the degradation of beta-catenin. SIGNOR-251047 0.46 SLC25A13 protein Q9UJS0 UNIPROT aspartic acid smallmolecule CHEBI:22660 ChEBI up-regulates quantity relocalization 9606 12084073 t miannu Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. SIGNOR-265157 0.8 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000567 17868033 t Simone Vumbaca Apicidin inhibited rhHDACs 2 and 3 in the nanomolar range. SIGNOR-261127 0.8 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser290 GRIVARNsRKMAFRA -1 9677319 t lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. SIGNOR-249007 0.309 NODAL protein Q96S42 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0004094 15531507 f Regulation miannu Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7. SIGNOR-251934 0.7 NR0B2 protein Q15466 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 17909097 f inferred from family member gcesareni As shown in fig. 3a, metformin (0.5 to 2 mmol/l) induced shp gene expression and repressed the camp/dex-induced expression of pepck and g6pase in a dose-dependent manner in h4iie cells SIGNOR-270256 0.2 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0000725 21389315 f irozzo Consequently, cell cycle and apoptosis analyses suggest that MLL-AF4 conveys a selective proliferation coupled to a survival advantage, which correlates with changes in the expression of genes involved in apoptosis, sensing DNA damage and DNA repair. SIGNOR-256650 0.7 RPS4Y2 protein Q8TD47 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262448 0.2 HNF4A protein P41235 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 f gcesareni Pgc1alfa is thought to mediate transcription downstream of the nuclear receptor hepatocyte nuclear factor 4alfa (hnf4alfa) and the transcription factor foxo1 in the promoters of key gluconeogenic enzymes, including glucose-6-phosphatase (g6pase) and phosphoenolpyruvate carboxylase (pepck) SIGNOR-142204 0.356 GLI3 protein P10071 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0002572 16571352 f lperfetto The basal expression of Gli1, Ptc1, and Hip1 was positively associated with the loss of Gli3 alleles.These findings implicate Gli3 as a repressor of Hh target gene expression. SIGNOR-209638 0.437 IGF1R protein P08069 UNIPROT PIK3C2A protein O00443 UNIPROT up-regulates phosphorylation 9606 7692086 t gcesareni Analysis of the ability of the full-length igfr and its mutant receptors described above to associate with phosphatidylinositol 3 kinase indicated that the association required ptk activity and tyrosine [?] Phosphorylation of the receptors and correlated well with their transforming activities SIGNOR-32076 0.278 MTNR1B protein P49286 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256707 0.448 NFE2L3 protein Q9Y4A8 UNIPROT NQO1 protein P15559 UNIPROT down-regulates quantity by repression transcriptional regulation 15385560 t lperfetto Deletion mutation analysis revealed that Nrf3 repression of NQO1 gene expression required heterodimerization and DNA binding domains but not transcriptional activation domain of Nrf3. SIGNOR-268976 0.345 BRMS1 protein Q9HCU9 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity binding 9606 BTO:0000093 30416854 t miannu Our results have showed that BRMS1 together with LSD1 are required for inhibition of breast cancer cell migration and invasion. Collectively, these findings demonstrate that BRMS1 executes transcriptional suppression of breast cancer metastasis by associating with the LSD1 and thus can be targeted for breast cancer therapy. SIGNOR-266409 0.26 lapatinib chemical CHEBI:49603 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 17892419 t gcesareni Recently, lapatinib, a small molecule dual inhibitor of both her2 and egf receptors, has been developed to expand the options for treating her-positive breast cancer. SIGNOR-157867 0.8 TARDBP protein Q13148 UNIPROT GSK3B protein P49841 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004170 PMC7642658 t lperfetto Importantly, we found that TDP-43 protein could interact with GSK3β mRNA and regulate the level of GSK3β protein translation. Taken together, our findings suggest that TDP-43 may activate the Wnt/β-catenin pathway by targeting the inhibition of GSK3β protein translation|TDP-43 activates Wnt/β-catenin pathway probably by inhibiting the GSK3β protein translation. A. Interaction between TDP-43 protein and GSK3β mRNA was analyzed using RIP assay. SIGNOR-262113 0.27 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 22936936 t lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor SIGNOR-198747 0.677 DHX9 protein Q08211 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity binding 9606 BTO:0000007 30137501 t miannu A DNA-sensing-independent Role of a Nuclear RNA Helicase, DHX9, in Stimulation of NF-κB-mediated Innate Immunity Against DNA Virus Infection. Taken together, our results show a critical role of nuclear DHX9 (as a transcription coactivator) in the stimulation of NF-κB-mediated innate immunity against DNA virus infection, independently of DHX9's DNA-sensing function. DHX9 interacts with NF-κB p65 and RNAPII in the nucleus during DNA virus infection SIGNOR-260947 0.441 PTPN11 protein Q06124 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr771 ADIESSNyMAPYDNY -1 7545675 t Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides SIGNOR-248669 0.739 GHSR protein Q92847 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256925 0.27 MTMR4 protein Q9NYA4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 20061380 t gcesareni Here we demonstrate that myotubularin-related protein 4 SIGNOR-163034 0.496 MTSS1 protein O43312 UNIPROT GLI1 protein P08151 UNIPROT up-regulates binding 9606 BTO:0001253 15545630 t gcesareni Mim is a shh-responsive gene that can potentiate gli transcriptional activity.MIM Appears to regulate target gene expression through its association with the gli complex SIGNOR-130542 0.524 LSM7 protein Q9UK45 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270647 0.797 MAPK11 protein Q15759 UNIPROT TCF3 protein P15923 UNIPROT up-regulates phosphorylation Ser139 LNSPGPLsPSGMKGT 9606 BTO:0000887 15719023 t p38 MAPK in particular phosphorylates Ser140 of E47. Its been observed that phosphorylation of E47 improves its ability to form heterodimers with Myod transcription factor gcesareni Here we show that p38 mapk, whose activity is essential for myogenesis, regulates myod/e47 heterodimerization. Phosphorylation of e47 at ser140 by p38 induces myod/e47 association and activation of muscle-specific transcription, while the nonphosphorylatable e47 mutant ser140ala fails to heterodimerize with myod and displays impaired myogenic potentia SIGNOR-134190 0.411 ZBTB16 protein Q05516 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 10090 BTO:0002882 9710637 f fcortellessa PLZF overexpression leads to apoptosis. SIGNOR-261686 0.7 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Thr260 QPWNSDStLNSRQLE 9606 19468302 t llicata Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex. SIGNOR-185758 0.657 SMAD7 protein O15105 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR down-regulates 9606 30017632 f miannu Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. SIGNOR-260433 0.7 β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. SIGNOR-266466 0.8 PTPRB protein P23467 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity dephosphorylation Tyr81 WEVGSITyDTLSAQA 9606 32653904 t miannu VE-PTP inhibition enhances eNOS activity to improve endothelial function and decrease blood pressure indirectly, through the activation of Tie-2 and the CD31/VE, cadherin, and VEGFR2 complex, and directly by dephosphorylating eNOS Tyr81.|VE-PTP, on the other hand, formed a complex with eNOS in endothelial cells and directly dephosphorylated eNOS Tyr81 in vitro. SIGNOR-277041 0.27 clofarabine chemical CHEBI:681569 ChEBI POLB protein P06746 UNIPROT down-regulates activity chemical inhibition 9606 1707752 t miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase. SIGNOR-258358 0.8 DOK1 protein Q99704 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257671 0.321 ADAM17 protein P78536 UNIPROT EREG protein O14944 UNIPROT up-regulates activity cleavage 9606 26284334 t miannu ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF SIGNOR-259843 0.547 RPS6KA3 protein P51812 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates quantity by destabilization phosphorylation Thr263 SIRDRNGtHLDAGAL 21183680 t lperfetto The ribosomal S6 kinase 2 (RSK2) is a member of the p90 ribosomal S6 kinase (p90RSK) family of proteins and plays a critical role in proliferation, cell cycle, and cell transformation. Here, we report that RSK2 phosphorylates caspase-8, and Thr-263 was identified as a novel caspase-8 phosphorylation site. In addition, we showed that EGF induces caspase-8 ubiquitination and degradation through the proteasome pathway, and phosphorylation of Thr-263 is associated with caspase-8 stability. SIGNOR-272997 0.377 IL1RAPL1 protein Q9NZN1 UNIPROT NCS1 protein P62166 UNIPROT up-regulates activity binding 10116 BTO:0001009 12783849 t miannu IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction. SIGNOR-263962 0.614 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219341 0.707 MAPK1 protein P28482 UNIPROT TNFRSF1A protein P19438 UNIPROT down-regulates activity phosphorylation Thr280 FSPTPGFtPTLGFSP -1 11606045 t lperfetto Phosphorylation of murine CD120a by p42(mapk/erk2) has been shown to inhibit its ability to initiate apoptosis while preserving signaling events such as NF-kappaB activation.|Additionally, we demonstrated that (i) the p42(mapk/erk2)-dependent phosphorylation of CD120a and DR3 occurred on Ser and Thr residues, (ii) p42(mapk/erk2) phosphorylated residues located in the membrane proximal regions but not the death domains of CD120a and DR3, (iii) Ser 253 is a preferred site of phosphorylation on CD120a SIGNOR-249453 0.514 AFAP1L2 protein Q8N4X5 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9606 BTO:0000007 19060924 t miannu RET/PTC induced robust tyrosine phosphorylation of XB130, which promoted its subsequent association with the p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase). We identified tyrosine 54 of XB130 as the major target of RET/PTC-mediated phosphorylation and a critical binding site for the SH2 domains of p85alpha. SIGNOR-263193 0.2 ixazomib chemical CHEBI:90942 ChEBI PSMB5 protein P28074 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194509 0.8 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-34661 0.584 PRKD1 protein Q15139 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates activity phosphorylation Ser11 SFLVRKPsDPNRKPN 9606 20940406 t lperfetto Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding. Pkd1 regulates the expression of e-cadherin at the promoter level through direct phosphorylation of the transcriptional repressor snai1. Pkd1-mediated phosphorylation of snai1 occurs in the nucleus and generates a nuclear, inactive dna/snai1 complex that shows decreased interaction with its co-repressor ajuba. SIGNOR-168537 0.478 IMPDH1 protein P20839 UNIPROT 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI up-regulates quantity chemical modification 9606 19480389 t miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). SIGNOR-267332 0.8 SOCS3 protein O14543 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity binding 9606 24600449 t miannu The ability of SOCS3 to simultaneously bind to JAK and to the cytokine receptor explains the specificity of the suppression. SOCS3 binds JAK and gp130 receptor simultaneously, using two opposing surfaces: while the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by the gp130 receptor, a subdomain in the SH2 domain of SOCS3 is also required for inhibition of JAK, binding in a phospho-independent manner to a non-canonical surface of JAK2 (58, 59). The KIR of SOCS3 occludes the substrate-binding groove on JAK2. SIGNOR-255329 0.788 SLC12A2 protein P55011 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity phosphorylation 21613606 t lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  SIGNOR-264634 0.8 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Ser345 ELLCLRRsSLKAYGN -1 1848190 t lperfetto We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling. SIGNOR-248857 0.358 CKMT1A protein P12532 UNIPROT N-phosphocreatine smallmolecule CHEBI:17287 ChEBI up-regulates quantity chemical modification 9606 18502307 t miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. SIGNOR-265790 0.8 OGA protein O60502 UNIPROT PFKM protein P08237 UNIPROT up-regulates activity deglycosylation Ser530 VVIPATVsNNVPGSD 9606 26399441 t lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. SIGNOR-267607 0.2 IFNAR complex SIGNOR-C243 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 21631354 t miannu These results indicate that NF-κB activation by IFN via the PI3K pathway is distinct from the ISRE-driven mechanism in regulating gene expression. Activation of PI3K/AKT by IFN has also been described through the insulin receptor substrate 1 (Uddin and others 1997) and through the direct interaction of PI3K with IFNAR1, which also leads to induction of NF-κB activity SIGNOR-260436 0.2 ATR protein Q13535 UNIPROT USP28 protein Q96RU2 UNIPROT up-regulates activity phosphorylation Ser714 ESSTNSSsQDYSTSQ 31938050 t lperfetto Here we report that the deubiquitylase USP28 is recruited to sites of DNA damage in cisplatin-treated cells. ATR phosphorylates USP28 and increases its enzymatic activity.|Representative immunoblots of n = 3. C Immunoblotting of total and phosphorylated USP28 at serine 67 and 714 in A431 cells exposed to indicated concentrations of CPPD for 6 h. SIGNOR-275851 0.2 ACTL6A protein O96019 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269789 0.593 SEMA3A protein Q14563 UNIPROT NRP1 protein O14786 UNIPROT up-regulates activity binding 9606 25335892 t miannu Further examination of the composition of the functional Sema3B receptor revealed that, unlike Sema3A, which signals exclusively using the NP1 receptor, Sema3B utilizes both NP1 and NP2 for signal transduction. SIGNOR-261815 0.911 FYN protein P06241 UNIPROT CNN1 protein P51911 UNIPROT down-regulates activity phosphorylation Tyr182 SQQGMTAyGTRRHLY 9534 15206927 t We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin SIGNOR-251157 0.339 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS 9534 BTO:0000298 8557118 t lperfetto PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. SIGNOR-248938 0.372 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser268 VALPPGAsPQRSRSP 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248374 0.598 JAK2 protein O60674 UNIPROT SLC6A8 protein P48029 UNIPROT down-regulates activity relocalization 443947 BTO:0000964 22407360 t miannu Janus-activated kinase-2 (JAK2) participates in the regulation of the Na⁺-coupled glucose transporter SGLT1 and the Na⁺-coupled amino acid transporter SLC6A19. JAK2 is a novel regulator of the creatine transporter SLC6A8, which downregulates the carrier, presumably by interference with carrier protein insertion into the cell membrane. SIGNOR-265781 0.2 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser323 MVGGKPGsFRVRASS 9606 BTO:0000222 BTO:0000887;BTO:0001103 16611834 t gcesareni Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of ser-318 in irs1 by a janus kinase 2, irs2, and pkc-dependent pathway. we observed that insulin stimulates phosphorylation of ser(318) in irs-1, which is mediated, at least partially, by pkc-zeta. SIGNOR-146105 0.632 PTK2 protein Q05397 UNIPROT ACTN4 protein O43707 UNIPROT down-regulates phosphorylation Tyr31 GGGSMGDyMAQEDDW 9606 23454549 t lperfetto Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin SIGNOR-192195 0.54 ARNT protein P27540 UNIPROT CYP1B1 protein Q16678 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 16115918 f miannu Expressions of CYP1B1 mRNA and protein were increased in prostate cancer. The aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) heterodimer complex activates gene transcription by binding to the DREs of CYP1B1. SIGNOR-253740 0.409 STK11 protein Q15831 UNIPROT CPS1 protein P31327 UNIPROT down-regulates quantity transcriptional regulation 9606 BTO:0002553 28538732 f Luana LKB1 negatively regulates CPS1 transcription SIGNOR-267919 0.3 RBM8A protein Q9Y5S9 UNIPROT Exon junction complex complex SIGNOR-C369 SIGNOR form complex binding -1 16923391 t miannu The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. SIGNOR-265242 0.915 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI 9606 9465032 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-217090 0.753 GABBR1 protein Q9UBS5 UNIPROT GABA-B receptor complex SIGNOR-C336 SIGNOR form complex binding 9606 BTO:0000007 9872316 t brain lperfetto Heterodimerization is required for the formation of a functional GABA(B) receptor.|These results indicate that, in vivo, functional brain GABA(B) receptors may be heterodimers composed of GABA(B)R1 and GABA(B)R2. SIGNOR-263742 0.68 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000675 23616010 lperfetto The results revealed that PAR2-AP and FVIIa could upregulate c-Jun expression and c-Jun phosphorylation in SW620 cells in a time-dependent manner. The effect of FVIIa was significantly blocked by anti-TF and anti-PAR2 antibodies. Protein kinase C_ (PKC_) inhibitor safingol and extracellular signal-regulated kinase 1 and 2 (ERK1/2) inhibitor U0126 abrogated the activation of c-Jun SIGNOR-236767 0.2 Aldolase proteinfamily SIGNOR-PF75 SIGNOR D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266482 0.8 JUN protein P05412 UNIPROT SPI1 protein P17947 UNIPROT up-regulates activity binding 9606 BTO:0004136 12393465 t apalma These results indicate that AML1-ETO competes c-Jun away from binding to the β3β4 domain of PU.1. Thus, the c-Jun coactivation function of PU.1 is down-regulated and this in turn down-regulates transcriptional activity of PU.1. SIGNOR-255660 0.571 SQSTM1 protein Q13501 UNIPROT SOD1 protein P00441 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002572 19765191 t P00441:p.Ala5Val (mutation causing interaction)  This study provides a novel molecular mechanism by which mutant SOD1 can be recognized by p62 in an ubiquitin-independent fashion and targeted for the autophagy-lysosome degradation pathway. SIGNOR-262801 0.528 LEPR protein P48357 UNIPROT NPY protein P01303 UNIPROT down-regulates quantity 27154742 f lperfetto Leptin binding inhibits the neuropeptide Y/agouti-related protein (NPY/AgRP) production and stimulates pro-opiomelanocortin (POMC) production SIGNOR-253075 0.467 EIF3_complex complex SIGNOR-C401 SIGNOR EIF1 protein P41567 UNIPROT up-regulates activity stabilization 9606 17581632 t lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit SIGNOR-269152 0.604 SIRT5 protein Q9NXA8 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31815138 f Monia Western blot showed that Sirt5 overexpression upregulated Nrf2. Sirt5 attenuates apoptosis through Nrf2/HO-1 and Bcl-2. SIGNOR-261208 0.312 LPAR2 protein Q9HBW0 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257324 0.252 FYN protein P06241 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Tyr529 TITKTVEyLHAQGVV 9606 18156174 t llicata Epidermal growth factor stimulates rsk2 activation through activation of the mek/erk pathway and src-dependent tyrosine phosphorylation of rsk2 at tyr-529. By mass spectroscopy-based studies, we identified src tyrosine kinase family members src and fyn as upstream kinases of rsk2 tyr-529. SIGNOR-160048 0.332 XBP1 protein P17861-2 UNIPROT Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 9606 15598891 f miannu ATF6 and XBP1 are transcription factors activated specifically in response to endoplasmic reticulum (ER) stress. Three cis-acting elements capable of binding to ATF6, XBP1 or both have been identified to date, namely ER stress-response element (ERSE), unfolded protein response element (UPRE) and ERSE-II. ERSE controls the expression of ER-localized molecular chaperones such as BiP that can refold unfolded proteins in the ER; transcription from ERSE is fully activated by ATF6 even in the absence of XBP1. In contrast, transcription from UPRE depends solely on XBP1 and it has been suggested that UPRE may control the expression of components of the ER-associated degradation system that can degrade unfolded proteins in the ER. SIGNOR-260185 0.7 ruxolitinib phosphate chemical CHEBI:66917 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity chemical inhibition 9606 23061804 t miannu Ruxolitinib is a selective inhibitor of Janus kinases (JAK) 1 and 2, which are involved in the signalling pathway of various cytokines and growth factors essential to haematopoiesis. SIGNOR-259171 0.8 IRF3 protein Q14653 UNIPROT SOCS2 protein O14508 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22291912 f miannu SOCS2 induction by LPS was dependent on the type I IFN regulated transcription factors IRF1 and IRF3 as shown by using silencing RNAs for IRFs. SIGNOR-254495 0.37 PRKAA1 protein Q13131 UNIPROT G6PC1 protein P35575 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21892142 f gcesareni Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation SIGNOR-176475 0.2 MAOA protein P21397 UNIPROT (R)-adrenaline smallmolecule CHEBI:28918 ChEBI up-regulates quantity chemical modification 9606 BTO:0000142 20493079 t Luana The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. SIGNOR-269744 0.8 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT up-regulates activity phosphorylation Tyr144 MVPDEVEyLLKKVLS 9606 BTO:0000661 18976935 t lperfetto Here, we report that the T cell receptor (TCR)-induced translocation of SLAT to the immunological synapse required Lck-mediated phosphorylation of two tyrosine residues located in an immunoreceptor tyrosine-based activation motif-like sequence but was independent of the SLAT PH domain. This subcellular relocalization was coupled to, and necessary for, activation of the NFAT pathway|These results indicate that SLAT undergoes Lck-dependent phosphorylation on Tyr-144 and Tyr-133 upon TCR and CD28 stimulation. SIGNOR-253368 0.514 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT down-regulates activity phosphorylation Ser13 FESYGSSsYGGAGGY -1 9295339 t lperfetto We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13 SIGNOR-248982 0.597 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120208 0.321 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser300 SMSDPGVsYRTREEI -1 11485553 t lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. SIGNOR-109555 0.786 CSNK1A1 protein P48729 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Thr1493 NPPPSPAtERSHYTM 9606 16341017 t lperfetto We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin.Site ii, like site i, was phosphorylated, as detected by means of a phospho-specific antibody (ab1493, for phosphorylated t1493 in lrp6) SIGNOR-143034 0.534 WNT3A protein P56704 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates activity binding 9606 BTO:0000222 10601008 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have a complex and partially overlapping pattern of expression in different regions of the embryo, and many of them (fz1, 3, 7, 8 and 9) have specific expression in the epithelial somites as well as in the newly formed myotomes. SIGNOR-73036 0.788 GALR3 protein O60755 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257206 0.293 Obatoclax mesylate chemical CID:46930996 PUBCHEM BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194952 0.8 NEIL1 protein Q96FI4 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). SIGNOR-275718 0.7 METTL21C protein Q5VZV1 UNIPROT VCP protein P55072 UNIPROT up-regulates activity methylation Lys315 AIAPKREkTHGEVER 10090 BTO:0002319 29719249 t We reveal that METTL21C trimethylates p97 on the Lys315 residue and found that loss of this modification reduced p97 hexamer formation and ATPase activity in vivo. SIGNOR-255918 0.313 SRC protein P12931 UNIPROT ENO1 protein P06733 UNIPROT up-regulates phosphorylation Tyr44 SGASTGIyEALELRD 9606 7629021 t lperfetto The present finding suggested that the tyrosine residue at position 44 in chicken alpha-enolase is the phosphorylation site by the tyrosine kinase. Our data suggest that eno1 was upregulated by caga protein through activating the src and mek/erk signal pathways SIGNOR-30126 0.419 PRKCD protein Q05655 UNIPROT GNAZ protein P19086 UNIPROT unknown phosphorylation Ser27 DRHLRSEsQRQRREI 9606 8429024 t lperfetto Gz alpha variants containing selected substitutions of alanine for serine residues were expressed in human kidney 293 cells, and the ability of each to be phosphorylated in response to phorbol 12-myristate 13-acetate was examined. A focus was placed on Ser25 and Ser27, the 2 serine residues within a sequence of Gz alpha used to obtain a phosphorylation-sensitive antibody. The results demonstrate that Ser27 is the primary site of phosphorylation. Conversion of Ser27 to an alanine resulted in a 65% decrease in incorporation of [32P] phosphate; conversion of Ser25 had no effect. SIGNOR-248932 0.51 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT down-regulates phosphorylation Ser1112 LLEDGSEsPAKRICP 9606 12006580 t gcesareni When expressed in u2os cells, the phosphorylation-deficient mutant p130(delta)(cdk4), in which the cdk4 specific sites were mutated to alanine residues, imposed a more sustained g1 arrest than a constitutively active prb(delta)(cdk), known to repress all cellular e2f activity SIGNOR-87492 0.844 RPL4 protein P36578 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262460 0.856 KDM4C protein Q9H3R0 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR down-regulates activity demethylation 9606 29207681 t miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation SIGNOR-265315 0.2 DARS1 protein P14868 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 t miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). SIGNOR-270362 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation -1 16226275 t inferred from 70% family members lperfetto First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.| SIGNOR-270202 0.2 GSK3B protein P49841 UNIPROT BORA protein Q6PGQ7 UNIPROT up-regulates phosphorylation Ser274 TSPSPISsPTFSPIE 9606 23442801 t lperfetto It suggests that gsk3_ activity is required for hbora-mediated mitotic entry through ser274 and ser278 phosphorylation SIGNOR-201515 0.26 IL7 protein P13232 UNIPROT IL7R protein P16871 UNIPROT up-regulates binding 9606 BTO:0000782 8204885 t fspada Antibody r34.34 was further found to be directed against an epitope interfering with binding of interleukin-7 (il-7) to pre-alp cells. Expression cloning from a pre-alp cdna library showed that r34.34 antigen is cdw127, the 75- to 80-kd il-7 receptor. Proliferation of the b-lineage all cell lines reh and mieliki was inhibited by il-7, and this effect was specifically reverted by moab r34.34. In addition, antibody r34.34 specifically inhibited il-7-dependent proliferation of normal bcp, pre-alp cells, and peripheral t cells. These results imply that both inhibitory and proliferative effects of il-7 can be mediated through the same receptor on various lineages. SIGNOR-37012 0.912 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser39 TTSTRTYsLGSALRP -1 2500966 t miannu Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure. SIGNOR-250067 0.313 IKBKB protein O14920 UNIPROT NFKBIB protein Q15653 UNIPROT down-regulates phosphorylation 9606 9346241 t gcesareni We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-52932 0.756 MAPK10 protein P53779 UNIPROT PPM1J protein Q5JR12 UNIPROT down-regulates phosphorylation Ser93 HAGRAVQsPPDTGRR 9606 18553930 t gcesareni Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells. SIGNOR-178926 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BCL6 protein P41182 UNIPROT down-regulates phosphorylation 9606 BTO:0000782;BTO:0000785 9649500 t inferred from 70% family members gcesareni Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway. SIGNOR-270011 0.2 DLG1 protein Q12959 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity binding 9606 BTO:0000782 17187070 t Barakat Dlgh1 immunoprecipitates were specifically enriched for activated p38 phosphorylated at Thr180 and Tyr182; phosphorylated p38 was not detected in the unbound fraction from stimulated samples SIGNOR-274143 0.626 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr244 GRAKGSEtPGATPGS 9606 12105215 t lperfetto To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptide). Three phosphorylation sites were identified as thr244, thr248, and thr313 SIGNOR-216686 0.353 MAPK14 protein Q16539 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 9130707 t gcesareni We demonstrate here that elk-1 is barely activated by a third subclass of map kinases (p38), most likely because the critical residues ser383 and ser389 are poorly phosphorylated by p38 map kinase. SIGNOR-47634 0.506 LSM6 protein P62312 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270634 0.796 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP -1 15241418 t llicata Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. | Thr 8 and the four sites in the linker (Thr 178, Ser 203, Ser 207 and Ser 212). Each of the five sites was phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo. SIGNOR-250766 0.748 ATG16L1 protein Q676U5 UNIPROT CLTCL1 protein P53675 UNIPROT up-regulates binding 9606 20639872 t gcesareni Clathrin heavy-chain interacts with atg16l1, and is involved in the formation of atg16l1-positive early autophagosome precursors SIGNOR-166705 0.309 SMAD6 protein O43541 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR down-regulates binding 9606 12857866 t lperfetto Smad6 also inhibits bmp signaling by forming a complex with smad1 and by interfering with complex formation between smad1 and smad4 SIGNOR-217706 0.558 PTPA protein Q15257 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 21159657 t gcesareni Consistent with previous reports (2830), we found that expression of sv40st, suppression of either pp2a c or b resulted in elevated levels of akt phosphorylation (ser473) SIGNOR-170699 0.2 CNTFR protein P26992 UNIPROT STAT1 protein P42224 UNIPROT up-regulates 9606 10582086 f gcesareni Signal transduction by cntf requires that it bind first to cntfr alpha, permitting the recruitment of gp130 and lifr beta, forming a tripartite receptor complex. Cntf-induced heterodimerization of the beta receptor subunits leads to tyrosine phosphorylation (through constitutively associated jaks), and the activated receptor provides docking sites for sh2-containing signaling molecules, such as stat proteins. SIGNOR-72771 0.276 TUBA4A protein P68366 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. SIGNOR-269730 0.7 risperidone chemical CHEBI:8871 ChEBI HTR1B protein P28222 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0001311 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258526 0.8 PTEN protein P60484 UNIPROT RAB7A protein P51149 UNIPROT up-regulates activity dephosphorylation Tyr183 QETEVELyNEFPEPI -1 26869029 t lperfetto PTEN dephosphorylates Rab7 on two conserved residues S72 and Y183, which are necessary for GDP dissociation inhibitor (GDI)-dependent recruitment of Rab7 on to late endosomes and subsequent maturation. SIGNOR-276959 0.381 COLGALT2 protein Q8IYK4 UNIPROT COL1A1 protein P02452 UNIPROT up-regulates activity glycosylation -1 19075007 t Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. SIGNOR-261156 0.418 RXRA protein P19793 UNIPROT PPARA protein Q07869 UNIPROT up-regulates binding 9606 11237216 t gcesareni Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology SIGNOR-105345 0.579 TACR3 protein P29371 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257333 0.411 CDK2 protein P24941 UNIPROT ATRIP protein Q8WXE1 UNIPROT unknown phosphorylation Ser239 VIKPEACsPQFGKTS 9606 17638878 t lperfetto Two novel phosphorylation sites on atrip were identified, s224 and s239 SIGNOR-156932 0.562 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser189 YRPKPSSsPVIFAGG 9606 17475908 t miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). SIGNOR-262915 0.329 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236392 0.751 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89213 0.55 PRKCA protein P17252 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Thr475 TPLSSSNtIRRPRNY -1 1322130 t lperfetto The phosphorylation sites for both cAMP-dependent protein kinase and protein kinase C were located in a single peptide whose sequence was Arg-Arg-Asn-Ser-(P)-Phe-Thr-Pro-Leu-Ser-Ser-Ser-Asn-Thr(P)-Ile-Arg-Arg-Pro. The seryl residue nearest the N terminus was the residue specifically phosphorylated by cAMP-dependent protein kinase, whereas the threonine residue nearest the C terminus was phosphorylated by protein kinase C. | Phosphorylation of bovine heart Fru-6-P,B-kinase by either protein kinase C or CAMP-dependent protein kinase results in activation of the enzyme. SIGNOR-248844 0.45 FGF1 protein P05230 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates binding 9606 11030354 t lperfetto Crystal structure of a ternary fgf-fgfr-heparin complex reveals a dual role for heparin in fgfr binding and dimerization. SIGNOR-83143 0.912 KRAS protein P01116 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates activity binding 9606 22195963 t lperfetto Mutant K-Ras promotes MST2 activation in two ways (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex (Matallanas et al., 2008) and by forming an activating (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex K-Ras-RASSF1A€“MST2 complex, as reported here SIGNOR-249585 0.637 FZR1 protein Q9UM11 UNIPROT DNM1L protein O00429 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000567 21325626 t Barakat Here we demonstrate that changes in mitochondrial dynamics as cells exit mitosis are driven in part through ubiquitylation of Drp1 catalyzed by the APC/Ccdh1 (anaphase-promoting complex/cyclosome and its coactivator (Cdh1) E3 ubiquiting ligase complex SIGNOR-274127 0.356 AKT1 protein P31749 UNIPROT GATA2 protein P23769 UNIPROT down-regulates phosphorylation Ser401 QTRNRKMsNKSKKSK 9606 BTO:0000876 15837948 t PI-3K/Akt-dependent manner. fspada We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity SIGNOR-135614 0.539 AKAP8 protein O43823 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity binding 9606 BTO:0000007 19531803 t Giulio To determine whether AKAP95 and p105 were present in a complex in mammalian cells, FLAG-tagged AKAP95 wascoexpressed with Myc-tagged p105 in human embryonic kidney (HEK) 293 cells. Immunoprecipitation of either protein pulled down a complex containing AKAP95, p105, and PKA-Ca (Fig. 6D).|The identification of a PKA phosphorylation site in the C-terminal region of p105 suggests that p105 is a candidate substrate for AKAP95-targeted PKA. SIGNOR-260302 0.3 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR FBXO30 protein Q8TB52 UNIPROT down-regulates 10090 BTO:0000887 24076600 f BMP-Smad1/5/8 signaling negatively regulates a gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1) SIGNOR-256488 0.2 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates activity phosphorylation Ser185 KKREKRRsTSRQFVD 9606 BTO:0000567 14744859 t llicata It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1 SIGNOR-250587 0.771 fenoterol chemical CHEBI:149226 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Finally, comparisons of the rank order of ligands for the three different receptors provide information about relative intrinsic efficacies. Fenoterol is a full and efficacious agonist at the β1-adrenoceptor, ranking third out of the agonists studied. It was also a full agonist at the β2- and β3-adrenoceptors with the highest intrinsic efficacy (i.e. top of Tables 4 and ​and5,5, rank 1).  SIGNOR-257869 0.8 ATR protein Q13535 UNIPROT CCAR2 protein Q8N163 UNIPROT up-regulates activity phosphorylation Thr454 AAEAAPPtQEAQGET 9606 22735644 t lperfetto  Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death.  SIGNOR-267662 0.414 GSK3B protein P49841 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr366 ASSSTSVtPDVSDNE 9606 16107342 t lperfetto Gsk3beta Phosphorylates pten at thr-366 in intact cells phosphorylation of pten at thr-366 reduces the activity of pten in cells SIGNOR-236641 0.434 FIZ1 protein Q96SL8 UNIPROT CRX protein O43186 UNIPROT down-regulates activity binding 9913 12566383 t miannu Interaction of Fiz1 and NRL-leucine zipper was validated by GST pulldown assays and co-immunoprecipitation from bovine retinal nuclear extracts. Fiz1 suppressed NRL- but not CRX-mediated transactivation of rhodopsin promoter activity in transiently transfected CV1 cells. SIGNOR-223799 0.467 NMUR1 protein Q9HB89 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256751 0.471 TPSAB1 protein Q15661 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity binding 10116 21999702 t lperfetto Mast cells contribute to tissue repair in fibrous tissues by stimulating proliferation of fibroblasts through the release of tryptase which activates protease-activated receptor-2 (PAR-2).|Taken together, our data show that tryptase can stimulate myoblast proliferation and this effect is part of a signaling cascade dependent on PAR-2 activation and on the downstream activation of COX-2. SIGNOR-251744 0.253 SEMA3A protein Q14563 UNIPROT PLXNA1 protein Q9UIW2 UNIPROT up-regulates activity binding 9606 BTO:0001176;BTO:0002036 25335892 t miannu We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.  SIGNOR-261813 0.762 eribulin mesylate chemical CHEBI:70710 ChEBI TUBB1 protein Q9H4B7 UNIPROT down-regulates activity chemical inhibition 9606 16940412 t miannu The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin. SIGNOR-259345 0.8 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR MAP3K5 protein Q99683 UNIPROT up-regulates activity dephosphorylation Ser966 NEYLRSIsLPVPVLV 9606 27858941 t miannu DAB2IP also mediates recruitment of PP2A to ASK1, binding both proteins through its C2 domain; this favors removal of the inhibitory S967 phosphorylation and further activation of ASK1 SIGNOR-254756 0.29 SHPK protein Q9UHJ6 UNIPROT sedoheptulose smallmolecule CHEBI:16802 ChEBI down-regulates quantity chemical modification 9606 22682222 t miannu The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. CARKL bridges glycolysis and PPP by catalyzing the formation of S7P from sedoheptulose SIGNOR-267083 0.8 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18509061 t gcesareni We show for the first time that vegf stimulated phosphorylation of hdac7 at the sites of ser178, ser344, and ser479we found that phospholipase cgamma/protein kinase c/protein kinase d1 (pkd1)-dependent signal pathway mediated hdac7 phosphorylation and cytoplasmic accumulation by vegf. SIGNOR-178713 0.491 glycine smallmolecule CHEBI:15428 ChEBI GLRB protein P48167 UNIPROT up-regulates activity chemical activation 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 t miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. SIGNOR-264983 0.8 PTPN11 protein Q06124 UNIPROT CDC73 protein Q6P1J9 UNIPROT up-regulates activity dephosphorylation 9606 21726809 t miannu We found in this work that SHP2 dephosphorylates parafibromin and Cdc73, a component of the nuclear RNA polymerase II associated factor (PAF) complex, which can function as a tumor suppressor or oncoprotein in a context dependent manner. SIGNOR-277036 0.507 belinostat chemical CHEBI:61076 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257957 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KIF4A protein O95239 UNIPROT up-regulates activity phosphorylation Thr1161 FFNPVCAtPNSKILK -1 29771379 t miannu Kif4A T1161 was phosphorylated by Cdk1/Cyclin B1 in vitro. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization. SIGNOR-265995 0.462 orantinib chemical CHEBI:91088 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207438 0.8 CD19 protein P15391 UNIPROT LYN protein P07948 UNIPROT up-regulates activity binding 10090 BTO:0000776 25673924 t lperfetto CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades. SIGNOR-242894 0.764 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser19 EVCDERTsLMSAESP -1 8972483 t llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  SIGNOR-250932 0.312 IL1B protein P01584 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000766 10435048 f miannu IL-1 beta induces expression of GTP cyclohydrolase-1 which leads to increased generation of BH4 and activation of eNOS. SIGNOR-252224 0.349 ACLY protein P53396 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI up-regulates quantity chemical modification 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-267103 0.8 F2RL3 protein Q96RI0 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22318735 t gcesareni Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13) SIGNOR-196015 0.383 SRC protein P12931 UNIPROT CEACAM1 protein P13688 UNIPROT up-regulates activity phosphorylation Tyr520 LTATEIIySEVKKQ 9606 BTO:0000007 9867848 t lperfetto Recent reports have also suggested that Bgp1 behaves as a signal transduction molecule. Several physiological events promote the Tyr phosphorylation of Bgp1 on one or two Tyr residues within its cytoplasmic domain (Tyr-488 and Tyr-515). BGP becomes Tyr-phosphorylated by Src-like Tyr kinases in activated neutrophils (24) and in human colon carcinoma cellsWe have recently shown that Tyr phosphorylation of the mouse Bgp1 cytoplasmic domain in CT51 mouse colonic carcinoma cells led to its binding to the protein-Tyr phosphatase SHP-1 and that this event required the presence of both Tyr-488 and Tyr-515 SIGNOR-246475 0.436 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 21757713 t lperfetto The phosphorylation of Raptor on these sites enhances mTORC1 activity, and contributes largely to arsenite-induced mTORC1 activation. SIGNOR-217544 0.392 SOX17 protein Q9H6I2 UNIPROT GLI2 protein P10070 UNIPROT up-regulates 10090 33083751 f SimoneGraziosi Sox17 ablation lowered endogenous Gli2 and Olig2+ cells SIGNOR-269218 0.302 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161557 0.547 IL1A protein P01583 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0001573 9565970 t lperfetto Il-1ri is responsible for il-1 signaling SIGNOR-56718 0.758 BRCC3 protein P46736 UNIPROT H2AC11 protein P0C0S8 UNIPROT down-regulates deubiquitination 9606 20656690 t gcesareni Brcc36 regulates the abundance of lys(63)-linked ubiquitin chains at chromatin and that one of its substrates is diubiquitinated histone h2a SIGNOR-167142 0.2 PIP3 smallmolecule CHEBI:16618 ChEBI mTORC2 complex SIGNOR-C2 SIGNOR up-regulates activity chemical activation 9606 26293922 t gcesareni PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with SIN1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation SIGNOR-252430 0.8 Stress_granules phenotype SIGNOR-PH124 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 27920254 f miannu Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis. SIGNOR-260865 0.7 POLR3C protein Q9BUI4 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266131 0.878 EEF1A2 protein Q05639 UNIPROT Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269530 0.8 4-[2-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]ethyl]aniline chemical CHEBI:92250 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258852 0.8 bosutinib chemical CHEBI:39112 ChEBI ABL1 protein P00519 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258088 0.8 Phagocytosis phenotype SIGNOR-PH97 SIGNOR TNF protein P01375 UNIPROT down-regulates quantity BTO:0000801 22933625 f apalma Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype SIGNOR-255446 0.7 ELP4 protein Q96EB1 UNIPROT Elongator complex complex SIGNOR-C466 SIGNOR form complex binding 9606 28601220 t miannu Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer. SIGNOR-269711 0.864 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248739 0.727 PRKCA protein P17252 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Ser53 DEELEGIsPDELKDE -1 9030586 t lperfetto Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively. SIGNOR-248960 0.327 PRKCA protein P17252 UNIPROT LMNA protein P02545 UNIPROT up-regulates activity phosphorylation Ser403 QRSRGRAsSHSSQTQ -1 7925482 t lperfetto Mutation of both Ser-403/Ser-404 within a PKC motif flanking the nuclear localization signal inhibits transport of mutant lamin A to the nucleus in 64% of the cells. It is proposed that phosphorylation of the motif in vivo positively regulates nuclear localization together with the nuclear localization sequence. SIGNOR-248903 0.369 EIF2S1 protein P05198 UNIPROT HBG1 protein P69891 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24714526 f miannu Reduction of globin inclusions and induction of ATF4 and HbF by the HRI-eIF2αP signaling provide strong bases for targeting this pathway for novel pharmaceutical therapy of hemoglobinopathy. SIGNOR-251819 0.2 TIMP3 protein P35625 UNIPROT MMP14 protein P50281 UNIPROT down-regulates activity binding 10090 BTO:0005300 28709001 t FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis. SIGNOR-255908 0.585 LEPR protein P48357 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001282 18718905 t miannu These observations indicate that leptin stimulates tyrosine phosphorylation of STAT3 via LEPRb but independent of JAK2. SIGNOR-263492 0.75 PRKCB protein P05771 UNIPROT DAB2 protein P98082 UNIPROT unknown phosphorylation Ser24 QAAPKAPsKKEKKKG 9534 BTO:0004055 10542228 t lperfetto We have mapped the TPA-induced DOC-2/DAB2 protein phosphorylation site to Ser24, which appears to modulate the DOC-2/DAB2 inhibition of AP-1 transcription activity. Results indicate that phosphorylation of Ser24 is mediated by PKCbetaII, PKC_, and PKCdelta, but not CKII. This suggests that the PKC phosphorylation of Ser24 in DOC-2/DAB2 may be an underlying mechanisms for its tumor-suppressive function. SIGNOR-249026 0.301 DGC complex SIGNOR-C217 SIGNOR GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626543 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265442 0.2 NF2 protein P35240 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates activity binding 9606 33058421 t miannu The Hippo pathway tumor suppressor Merlin/NF2 is known to be regulated by phosphorylation. Here, the E3 ubiquitin ligase NEDD4L is shown to promote Hippo pathway activation via ubiquitination of Merlin. SIGNOR-263663 0.76 NR2F1 protein P10589 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 10900149 t lperfetto Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site SIGNOR-79440 0.53 FCGR1A protein P12314 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 24445665 f lperfetto Although crosslinking of activating FcgammaRs on monocytes and macrophages induces the production of several pro-inflammatory cytokines and chemokines, immune complex-mediated signalling via activating FcgammaRs together with Toll-like receptor (TLR) triggering induces a specific M2 activation state in macrophages macrophages in this state were termed M2b or regulatory macrophages. SIGNOR-249524 0.7 MAP3K3 protein Q99759 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates phosphorylation Ser167 FLISPPAsPPVGWKQ 9606 BTO:0000782 12809556 t gcesareni Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation SIGNOR-102294 0.459 ARAP3 protein Q8WWN8 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260456 0.447 NFKBIE protein O00221 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates binding 9606 BTO:0001271 SIGNOR-C13 12835716 t gcesareni Nf-kb is normally sequestered in the cell cytoplasm by binding to ikbx, ikbb, ikbe SIGNOR-102774 0.521 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PBK protein Q96KB5 UNIPROT unknown phosphorylation Thr9 EGISNFKtPSKLSEK 9606 15541388 t lperfetto Topk-thr-9 was phosphorylated by cdk1/cyclin b and topk significantly associates with mitotic spindles. SIGNOR-216896 0.567 TOB2 protein Q14106 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR down-regulates activity binding 9606 BTO:0000567 18377426 t miannu We found that Tob associates with the CCR4-NOT complex. The carboxyl-terminal half of Tob interacted with Cnot1, a core protein of the CCR4-NOT complex. We further showed that the deadenylase activity associated with the complex was suppressed in vitro by Tob.  SIGNOR-273615 0.353 CAMK2A protein Q9UQM7 UNIPROT ETS2 protein P15036 UNIPROT down-regulates phosphorylation Ser246 FPKSRLSsVSVTYCS 9606 19182667 t lperfetto Camkii caused ets-2 phosphorylation.Serine 246, 310, and 313 were the targets. Camkii to phosphorylates ets-2, thus altering ets-2 binding to its downstream promoters SIGNOR-183596 0.2 HTR7 protein P34969 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257430 0.252 SAAL1 protein Q96ER3 UNIPROT CDK6 protein Q00534 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 30513680 f Giorgia This study was performed to elucidate the molecular function of the synoviocyte proliferation-associated in collagen-induced arthritis (CIA) 1/serum amyloid A-like 1 (SPACIA1/SAAL1) in mice CIA, an animal model of rheumatoid arthritis (RA), and human RA-synovial fibroblasts (RASFs). Expression levels of cdk6, but not cdk4, which are D-type cyclin partners, were downregulated by SPACIA1/SAAL1 siRNA at the post-transcriptional level. The CDK6, expression of which is up-regulated by the SPACIA1/SAAL1 expression, might be a critical factor in the exacerbation of CIA. SIGNOR-260386 0.2 CDK4 protein P11802 UNIPROT RBL1 protein P28749 UNIPROT up-regulates activity phosphorylation Ser964 MMDAPPLsPFPHIKQ 9606 12006580 t llicata Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression.  SIGNOR-250764 0.8 STAT1 protein P42224 UNIPROT STAT1/STAT3 complex SIGNOR-C118 SIGNOR form complex binding 10090 BTO:0000667 15284024 t lperfetto Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. SIGNOR-235661 0.598 GDF11 protein O95390 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates binding 9606 BTO:0000671 16845371 t acerquone The identity of the receptors that mediate gdf11 signalling during embryogenesis remains unclear. gdf11 could only bind directly to acvr2b but not to any type i receptor SIGNOR-147940 0.644 ABCG1 protein P45844 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 16054053 f miannu ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. cholesterol efflux to HDL specifically requires ABCG1, whereas efflux to apoA1 requires ABCA1. These studies identify Abcg1 as a key gene involved in both cholesterol efflux to HDL and in tissue lipid homeostasis. SIGNOR-252111 0.7 TAL1 protein P17542 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates activity 10090 BTO:0004911 23319051 f Analysis of SclΔ40/Δ40 embryonic stem (ES) cells revealed impaired erythroid differentiation, which was accompanied by a failure to upregulate Scl when erythropoiesis was initiated. SIGNOR-259971 0.7 PTGS2 protein P35354 UNIPROT IL4 protein P05112 UNIPROT up-regulates 9606 22225874 t FFerrentino Cox2 Is a Direct Srf Target Gene and Controls Il4 Expression SIGNOR-255967 0.456 EAPP protein Q56P03 UNIPROT MAOB protein P27338 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20980443 f miannu we identified two novel transcriptional repressors of MAO B, E2F-associated phosphoprotein (EAPP) and R1 (RAM2/CDCA7L/JPO2), that down-regulate MAO B via MAO B core promoter, which contains Sp1 sites. SIGNOR-253867 0.2 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. SIGNOR-164416 0.626 ACAN protein P16112 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates activity binding 9606 BTO:0003858 16051604 t lperfetto Cartilage Oligomeric Matrix Protein/Thrombospondin 5 Supports Chondrocyte Attachment through Interaction with Integrins|We show that COMP/TSP5 can support chondrocyte attachment and that the RGD sequence in COMP/TSP5 and the integrin receptors alpha5beta1 and alphaVbeta3 on the chondrocytes are involved in mediating this attachment. The interactions of COMP/TSP5 with the integrins are dependent on COMP/TSP5 conformation. SIGNOR-266988 0.325 CSNK2A1 protein P68400 UNIPROT CBX1 protein P83916 UNIPROT down-regulates phosphorylation Thr51 GFSDEDNtWEPEENL 9606 19657222 t lperfetto Two recent papers suggest that hp1 recruitment to damage sites, rather than its rapid mobilization, is the predominant behaviour exhibited by this protein. Our findings reconcile recent findings in a new model, wherein rapid hp1beta mobilization from dsbs is mediated by its phosphorylation on thr51 by ck2 SIGNOR-187450 0.308 CDK5RAP2 protein Q96SN8 UNIPROT WDR62 protein O43379 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 t lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. SIGNOR-271723 0.561 AMP smallmolecule CHEBI:456215 ChEBI PRPS1 protein P60891 UNIPROT down-regulates activity chemical inhibition 29074724 t lperfetto PRPS1 is inhibited by the nucleotide biosynthesis products ADP, AMP, and GDP SIGNOR-265737 0.8 CSTF complex complex SIGNOR-C441 SIGNOR mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 10669729 f lperfetto Polyadenylation of mRNA precursors is a two-step reaction requiring multiple protein factors. Cleavage stimulation factor (CstF) is a heterotrimer necessary for the first step, endonucleolytic cleavage, and it plays an important role in determining the efficiency of polyadenylation. SIGNOR-268369 0.7 PBX1 protein P40424 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription SIGNOR-265777 0.274 CDK5 protein Q00535 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates activity phosphorylation Thr668 ENLDLKLtPYKVLAT 9606 BTO:0000007 20513426 t miannu Phosphorylation of Vps34 on Thr159 inhibits its interaction with Beclin 1. two additional amino acids in Vps34, Thr159 and Thr668, were found to be phosphorylated only after co-transfection with Cdk5/p25 SIGNOR-259811 0.364 ethanol chemical CHEBI:16236 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 8355 BTO:0000964 8700149 t inferred from family member miannu Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations. SIGNOR-270260 0.8 Membrane attack complex complex SIGNOR-C313 SIGNOR Membrane_disruption phenotype SIGNOR-PH151 SIGNOR up-regulates -1 30552328 f lperfetto CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers SIGNOR-263456 0.7 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17442773 f miannu Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. The transcription factor CCAAT enhancer binding protein‐α (C/EBPα), a tumor suppressor gene and a crucial regulator of granulopoiesis through inhibition of c‐JUN, was downmodulated by NUP98‐HOXA9 SIGNOR-261501 0.2 SF3B5 protein Q9BWJ5 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270673 0.761 CDC25A protein P30304 UNIPROT RAF1 protein P04049 UNIPROT down-regulates dephosphorylation 9606 7744247 t gcesareni Cdc25a can act on substrates other than cdks, since it dephosphorylates the homeodomain transcription factor cut and interacts with and dephosphorylates the proto-oncogene raf-1, resulting in a significant decrease in raf-1 kinase activity SIGNOR-32548 0.403 SMARCC2 protein Q8TAQ2 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269823 0.834 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation 9606 12792650 t inferred from 70% family members lperfetto Inhibition of caspase-9 through phosphorylation at thr 125 by erk mapk SIGNOR-270084 0.2 EIF2AK2 protein P19525 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 16179259 t lperfetto The antiviral protein kinase pkr inhibits protein synthesis by phosphorylating the translation initiation factor eif2alpha on ser51the protein kinases pkr, hri, perk, and gcn2 specifically phosphorylate ser51 on the _ subunit of the translation initiation factor eif2, a gtp binding protein that delivers the initiator methionyl-trna to the small ribosomal subunit in the first step of translation initiation. Phosphorylation of eif2_ converts eif2 from a substrate to an inhibitor of its gdp-gtp exchange factor eif2b, thereby blocking protein synthesis SIGNOR-140656 0.717 DNA_damage stimulus SIGNOR-ST1 SIGNOR CHEK2 protein O96017 UNIPROT up-regulates activity 9606 19151762 f lperfetto Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68 SIGNOR-242605 0.7 ID3 protein Q02535 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR down-regulates activity binding 10090 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241137 0.462 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT down-regulates activity phosphorylation Ser12 GFESYGSsSYGGAGG -1 9295339 t lperfetto We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13 SIGNOR-248981 0.597 NFIB protein O00712 UNIPROT SLIT1 protein O75093 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268899 0.252 NPC complex SIGNOR-C263 SIGNOR mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 28831067 f lperfetto The NXF1:NXT1 complex and NUP153 interact with the amino terminus of SUN1 |In analogy to a proposal made by Chang et al.4, Nesprins could help anchoring SUN1 near the NPC to enable it to fulfill its task in mRNA export. SIGNOR-263295 0.7 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 18372406 t gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-178145 0.692 RAB5A protein P20339 UNIPROT COMMD5 protein Q9GZQ3 UNIPROT up-regulates activity binding 9606 30021164 t miannu The N terminus of COMMD5 binds to the endosomal Rab5, and its C terminus, including the COMMD domain, binds to the cytoskeletal scaffolding. SIGNOR-261691 0.2 EVI5 protein O60447 UNIPROT PLK1 protein P53350 UNIPROT down-regulates 9606 16439210 f gcesareni Evi5 antagonizes scf(betatrcp)-dependent emi1 ubiquitination and destruction by binding to a site adjacent to emi1's dsgxxs degron and blocking both degron phosphorylation by polo-like kinases and subsequent betatrcp binding. SIGNOR-143683 0.602 AMH protein P03971 UNIPROT AMHR2 protein Q16671 UNIPROT up-regulates binding 9606 8119126 t acerquone The results point to anti-m?llerian Hormone (amh) being the most likely candidate ligand for c14. SIGNOR-36215 0.799 STK25 protein O00506 UNIPROT PDCD10 protein Q9BUL8 UNIPROT unknown phosphorylation Thr43 VNLSAAQtLRAAFIK 9606 19370760 t llicata Stk25 phosphorylates ccm3 at serine 39 and threonine 43 SIGNOR-185392 0.791 CSNK2A1 protein P68400 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser13 GFFSSSEsGAPEAAE -1 3128543 t llicata To date, the only evidence for a functional distinction of LCa and LCb is the preferential phosphorylation of LCb, which takes place at serine residues and is mediated by coated vesicle-associated casein kinase II. As a first step toward determining the function of light chain diversity, we have mapped the in vitro phosphorylation sites on LCb. We use [32P]ATP to phosphorylate LCb within coated vesicles, followed by sequencing of 32P-labeled chymotryptic peptides thereof, to identify serine residues at positions 11 and 13 as the phosphorylation sites. SIGNOR-250843 0.313 GLI1 protein P08151 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin SIGNOR-188869 0.562 CCR4-NOT complex complex SIGNOR-C439 SIGNOR PUM1 protein Q14671 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 t lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins SIGNOR-268351 0.373 AQP5 protein P55064 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR up-regulates activity binding phosphorylation:Ser156 STDSRRTsPVGSPAL 18583321 t lperfetto We performed immunoprecipitation and western blotting analysis in transfected cell lines using CDK4 and cyclin D1 antibodies. As expected, cells transfected with AQP5 WT showed an increase of the CDK4/cyclin D1 complex, whereas cells transfected with vector did not|hAQP5 Increases Phosphorylation of Retinoblastoma Protein through Cyclin D1/CDK4 Complex SIGNOR-272089 0.249 CDK11B protein P21127 UNIPROT EIF3F protein O00303 UNIPROT up-regulates activity phosphorylation Ser46 PAAAPASsSDPAAAA 19245811 t lperfetto EIF3f is phosphorylated by CDK11p46 at Ser46 during apoptosis.|Phosphorylation of eIF3f plays an important role in regulating its function in translation and apoptosis. Phosphorylation of eIF3f enhances the association of eIF3f with the core eIF3 subunits during apoptosis.  SIGNOR-273133 0.529 serotonin smallmolecule CHEBI:28790 ChEBI HTR7 protein P34969 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264289 0.8 XPA protein P23025 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 9606 30327428 f A coordinated repair process mediated by the xeroderma pigmentosum complementation group proteins (XPs), which include XPA through XPG. XPA is indispensable in this pathway and has reported functions in DNA damage verification, stabilization of repair intermediates and positioning of NER factors SIGNOR-258984 0.7 MAPK1 protein P28482 UNIPROT KRT8 protein P05787 UNIPROT unknown phosphorylation Ser432 SAYGGLTsPGLSYSL 16554440 t lperfetto Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002). SIGNOR-249411 0.39 PRKCD protein Q05655 UNIPROT FLI1 protein Q01543 UNIPROT down-regulates phosphorylation Thr312 TNGEFKMtDPDEVAR 9606 24058639 t miannu After tgf-_ stimulation, fli1 phosphorylation by protein kinase c-_ induces disassembly of this transcription repressor complex and the acetylation of fli1 by pcaf, leading to the loss of fli1 dna binding. / phosphorylation of fli1 at threonine 312 decreases its interactions with p300 and hdac1 SIGNOR-202693 0.353 PLK1 protein P53350 UNIPROT BIRC5 protein O15392 UNIPROT up-regulates phosphorylation Ser20 FLKDHRIsTFKNWPF 9606 21148584 t lperfetto Thus, we conclude that plk1-mediated phosphorylation of sur at ser20 is critical for accurate chromosome segregation|SUR (survivin) SIGNOR-170460 0.565 PHLPP1 protein O60346 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 t gcesareni Here, we identify a protein_ phosphatase, ph domain leucine-rich repeat protein_ phosphatase_ (phlpp), that specifically_ dephosphorylates_ the hydrophobic motif of_ akt_ (ser473 in akt1), triggering_ apoptosis_ and suppressing_ tumor_ growth. SIGNOR-252601 0.751 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser465 LKHVTQSsRKLIRAD 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. SIGNOR-129264 0.392 IGF1R protein P08069 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 18595745 t gcesareni Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively) SIGNOR-252690 0.685 IL10RA protein Q13651 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity 9606 BTO:0000801 26260587 t IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-253589 0.802 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR STK4 protein Q13043 UNIPROT up-regulates 9606 22683405 f milica In response to growth inhibitory signal (e.g. cell–cell contact), MST1/2 in active form phosphorylates LATS1/2 that sequentially phosphorylates YAP at Ser-127. SIGNOR-230693 0.7 PRKAG1 protein P54619 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates binding 9606 16054041 t gcesareni Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. SIGNOR-139173 0.894 pirenzepine chemical CHEBI:8247 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258396 0.8 EMSY protein Q7Z589 UNIPROT BRCA2 protein P51587 UNIPROT down-regulates activity binding 9606 BTO:0000567 14651845 t miannu The EMSY protein interacts precisely with a highly conserved transactivating region at the N terminus of the breast cancer protein BRCA2, and has endogenous transcriptional repressor activity when recruited to a high basal promoter. We have suggested that the independent activation domain of BRCA2 within exon 3 might have some role in transcription (Milner et al., 1997). The identification of the repressor protein EMSY, which binds and silences this domain, is consistent with such a function. SIGNOR-263915 0.2 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Thr74 SVLTGKLtTVFLPIV -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263596 0.381 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120016 0.781 etorphine chemical CHEBI:4912 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258803 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-244148 0.2 SPC25 protein Q9HBM1 UNIPROT Ndc80 complex complex SIGNOR-C361 SIGNOR form complex binding 27881301 t lperfetto Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits SIGNOR-265186 0.973 RPL28 protein P46779 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262472 0.819 PRKD2 protein Q9BZL6 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates activity phosphorylation Ser498 RPLSRTQsSPLPQSP 18692497 t lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. SIGNOR-275929 0.299 CBLB protein Q13191 UNIPROT FLT3 protein P36888 UNIPROT down-regulates activity ubiquitination 10090 BTO:0001516 19276253 t miannu Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo. SIGNOR-260106 0.332 GUCY1A2 protein P33402 UNIPROT GUCY1A2-B2 complex SIGNOR-C137 SIGNOR form complex binding 9606 10977868 t gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity SIGNOR-243971 0.2 ACTL6B protein O94805 UNIPROT Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270758 0.672 PTCHD1 protein Q96NR3 UNIPROT VPS35 protein Q96QK1 UNIPROT up-regulates quantity binding 10090 BTO:0000142 29118110 t miannu Using Western blotting, we validated our MS approach confirming the binding of Dgl4 (also known as PSD95) and VPS35 to the recombinant Ptchd1 C terminus. Endogenous DLG4 and VPS35 from membrane and soluble mouse brain fractions were recovered specifically on the GST fusion proteins containing the cytoplasmic but not the extracellular, negative control sequences of Ptchd1 (Fig. 5E). Binding of DLG4 was dependent on the PDZ-binding motif in Ptchd1, whereas VPS35 binding was not (Fig. 5E). These results demonstrate a biochemical interaction of Ptchd1 with postsynaptic trafficking proteins in the mouse brain. Together, these data suggest that loss of Ptchd1 results in severe alterations in synaptic function in the dentate gyrus SIGNOR-266653 0.2 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120244 0.321 UCHL3 protein P15374 UNIPROT RPS27A protein P62979 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270828 0.794 ERN1 protein O75460 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR down-regulates activity 9606 31226023 f miannu The kinase activity of IRE1 also activates a signaling cascade that ultimately activates c-Jun N-terminal kinase (JNK) SIGNOR-260177 0.322 phenytoin chemical CHEBI:8107 ChEBI SCN2A protein Q99250 UNIPROT down-regulates activity chemical inhibition 10116 1658608 t miannu This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner. SIGNOR-258352 0.8 TBXA2R protein P21731 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257139 0.555 AKT1 protein P31749 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates activity phosphorylation Ser21 CWRKRVKsEYMRLRQ 9606 16224021 t lperfetto Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3 SIGNOR-141043 0.613 MAP3K14 protein Q99558 UNIPROT CHUK protein O15111 UNIPROT up-regulates activity phosphorylation Ser176 AKDVDQGsLCTSFVG 9606 SIGNOR-C14 9520446 t lperfetto Nf-kappab-inducing kinase activates ikk-alpha by phosphorylation of ser-176. Nik preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa. SIGNOR-55942 0.685 BRAF protein P15056 UNIPROT EEF1A2 protein Q05639 UNIPROT down-regulates quantity by destabilization phosphorylation Ser21 GHVDSGKsTTTGHLI -1 22378069 t miannu Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.  SIGNOR-276406 0.332 CYP26A1 protein O43174 UNIPROT all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI down-regulates activity chemical inhibition 9606 9716180 t Gianni The RA-induced CYP26 was shown to be highly specific for the hydroxylation of all-trans-RA and did not recognize the 13-cis and 9-cis isomers. This substrate specificity is promising for finding retinoids that are not recognized by this enzyme and, therefore, could be more effective in growth inhibition of susceptible cancer cells. SIGNOR-266425 0.8 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914161 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161581 0.607 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser497 ATVKSRWsGSQQVEQ 9606 12551925 t gcesareni For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1. SIGNOR-37844 0.539 MAPK9 protein P45984 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates phosphorylation Ser165 RESSLSPsPASSISS 9606 BTO:0000782 9374467 t lperfetto Ser163 and ser165 represent the major sites of in vitro phosphorylation of nfat4 by jnk. / the negative regulation of nfat4 nuclear accumulation caused by jnk provides a mechanism for cell type?specific Responses to extracellular stimulation SIGNOR-53368 0.699 LETM1 protein O95202 UNIPROT Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR up-regulates 9606 BTO:0000567 18628306 f lperfetto LETM1 knockdown obviously reduced the formation of the supercomplexes (Fig. 5C, arrowhead). Complexes I and IV failed to form, and the assembly of complex III was significantly decreased. By contrast, the assembly of complex II (succinate dehydrogenase) and complex V (ATP synthase) – which are not proton pumps – was unaffected. SIGNOR-262546 0.291 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193546 0.8 CAPN1 protein P07384 UNIPROT CDK5R1 protein Q15078 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain SIGNOR-251583 0.553 STAT6 protein P42226 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20508200 f lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. SIGNOR-249538 0.259 masitinib chemical CHEBI:63450 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258244 0.8 MAPK14 protein Q16539 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser172 YRDPSCLsPASSLSS 9606 10652349 t Translocation from Nucleus to Cytoplasm esanto We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats. SIGNOR-74560 0.606 HTR3A protein P46098 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 18761359 f miannu The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release.  SIGNOR-264316 0.7 DZIP3 protein Q86Y13 UNIPROT H2AC4 protein P04908 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271747 0.2 5-carboxamidotryptamine chemical CHEBI:48292 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258888 0.8 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI HR protein O43593 UNIPROT up-regulates activity chemical activation 29981745 t lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. SIGNOR-273463 0.8 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9606 17158707 t lperfetto The JNK-mediated phosphorylation of both Ser63 and Ser73 within the transactivation domain of c-Jun (Table _(Table1)1) potentiates its transcriptional activity SIGNOR-36466 0.2 Melanotan II chemical CID:92432 PUBCHEM MC3R protein P41968 UNIPROT up-regulates activity binding BTO:0000614 17702843 t lperfetto Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases. SIGNOR-253065 0.8 CDC14A protein Q9UNH5 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT unknown dephosphorylation Ser368 PNPSTSAsPKKSPPP 9606 17488717 t Here, we demonstrate that SIRT2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1, and dephosphorylated by the phosphatases CDC14A and CDC14B. Overexpression of SIRT2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation|Additionally, we found that SIRT2, like other Cdk1 targets, can be dephosphorylated by the phosphatases CDC14A and CDC14B. In contrast to a published report (8), we did not observe any degradation of SIRT2 by the 26 S proteasome in response to CDC14B overexpression|However, we cannot exclude the possibility that phosphorylation of serine 368 might affect the activity of SIRT2 on other unidentified acetylated substrates. SIGNOR-248834 0.432 PTGER4 protein P35408 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256903 0.252 DOK1 protein Q99704 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257674 0.321 SP1 protein P08047 UNIPROT CBS protein P35520 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12427542 f miannu We previously described essential transactivating roles for specificity protein 1 (Sp1), Sp3, nuclear factor Y (NF-Y), and USF-1 in the regulation of the CBS-1b promoter. SIGNOR-254812 0.2 ATG4B protein Q9Y4P1 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR down-regulates activity 9606 BTO:0000586 29165041 f lperfetto In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells.| In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F1Fo-ATP synthase activity. SIGNOR-275837 0.2 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB6 protein Q9Y5F9 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265706 0.2 BAD protein Q92934 UNIPROT BCL2L2 protein Q92843 UNIPROT down-regulates binding 9606 15694340 t gcesareni Bad, however, bound tightly to bcl-2, bcl2l1, and bcl2l2. SIGNOR-133805 0.554 STXBP1 protein P61764 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity transcriptional regulation 9606 BTO:0000938 30267828 t miannu In neuronal exocytosis, Munc18-1 (aSM-protein) and Munc13-1/2 (similar to CATCHRs) arethe relevant proteins responsible for SNARE-complex formation. Munc18-1 associates with syntaxin-1 in its‘closed’ conformation, i.e. with the regulatory Habc-domain folded against the SNARE (H3-)-domain. Opening-up of syntaxin is catalyzed by the Mun-domainwithin Munc13-1/2 and allows assembly with the partnerSNARE SNAP-25 and possibly VAMP2. SIGNOR-263970 0.835 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser170 SFKLSGFsFKKNKKE -1 8557118 t gcesareni PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. SIGNOR-249671 0.372 PPP2CA protein P67775 UNIPROT PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR form complex binding 9606 23454242 t gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. SIGNOR-243424 0.934 PRKG2 protein Q13237 UNIPROT HCN2 protein Q9UL51 UNIPROT down-regulates activity phosphorylation Ser668 DRIGKKNsILLHKVQ 10090 BTO:0000142 21347269 t miannu Here, we show for the first time that in the HCN2 channel cGMP can also exert an inhibitory effect on gating via cGMP-dependent protein kinase II (cGKII)-mediated phosphorylation.We identify the proximal C-terminus of HCN2 as binding region of cGKII and show that cGKII phosphorylates HCN2 at a specific serine residue (S641) in the C-terminal end of the CNBD. The cGKII shifts the voltage-dependence of HCN2 activation to 2-5 mV more negative voltages and, hence, counteracts the stimulatory effect of cGMP on gating. SIGNOR-263185 0.2 CSNK2A1 protein P68400 UNIPROT FANCD2 protein Q9BXW9 UNIPROT down-regulates activity phosphorylation Thr884 SKTSSSDtLSEEKNS 9606 BTO:0000567 31167143 t miannu Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations.  SIGNOR-276732 0.2 CAMK4 protein Q16566 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates activity phosphorylation Ser632 RPLSRAQsSPASATF 11470791 t llicata CaMKIV phosphorylates HDAC4 in vitro and promotes its nuclear-cytoplasmic shuttling in vivo. | Thus, CaMKIV can phosphorylate HDAC4 at Ser-467 and/or Ser-632 in vitro. | Collectively, our results suggest that CaMKIV reverses the transcriptional repression activity of HDAC4 by stimulating the mobilization of HDAC4 out of the nucleus. SIGNOR-250712 0.604 GLUL protein P15104 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI down-regulates quantity chemical modification 9606 30158707 t miannu Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction. SIGNOR-267824 0.8 PRKAA1 protein Q13131 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Ser385 RRRKKRTsIETNIRV 9606 9368058 t lperfetto Mitosis-specific phosphorylation site in the homeodomain of oct-1 was phosphorylated in vitro by protein kinase a. Pka-mediated phosphorylation event was identified in the cns-specific pou domain protein brn-2/n-oct-3/pou3f2 (nieto et al. 2007). In this case, the modification, at a position homologous to oct1 s385, was found to alter binding specificity for complex dimeric sites. SIGNOR-53254 0.2 BRCA2 protein P51587 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates binding 9606 24485656 t miannu Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates SIGNOR-204538 0.534 CXCL1 protein P09341 UNIPROT PRKACA protein P17612 UNIPROT down-regulates binding 9606 17251915 t gcesareni As pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp. SIGNOR-152594 0.2 EPAS1 protein Q99814 UNIPROT KDM2B protein Q8NHM5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271582 0.2 AARS1 protein P49588 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 32314272 t miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). SIGNOR-270449 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR RARA protein P10276 UNIPROT down-regulates phosphorylation Ser96 FVCQDKSsGYHYGVS 9606 BTO:0000551 16417524 t miannu We report that akt, which is constitutively activated in nsclc cells, phosphorylates raralpha and inhibits its transactivation. / mutation of ser96 to alanine abrogated the suppressive effect of akt. SIGNOR-143721 0.2 EVX1 protein P49640 UNIPROT GSC protein P56915 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 22178155 f miannu We found that EVX1 repressed GSC expression and promoted formation of posterior streak-like progeny in response to BMP4, and conversely that GSC repressed EVX1 expression and was required for development of anterior streak-like progeny in response to activin. SIGNOR-254139 0.256 GTF2H2 protein Q13888 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10949034 t Manara TFIIH Phosphorylates Human Estrogen Receptor α at Serine 118 | We report here that Cdk7 overexpression stimulates transcription activation by ERα by stimulating phosphorylation of S118 in a ligand-dependent manner. SIGNOR-260817 0.259 BAX protein Q07812 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 8358790 t lperfetto Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered. SIGNOR-249612 0.62 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 9271428 t gcesareni Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation. SIGNOR-50598 0.2 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid chemical CHEBI:76223 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition -1 22091869 t Luana  Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2.  SIGNOR-258323 0.8 AURKA protein O14965 UNIPROT SOX8 protein P57073 UNIPROT up-regulates activity phosphorylation Ser327 SAPSASAsPTETGPP 9606 BTO:0000410 32550913 t miannu We showed for the first time that Aurora-A interacts directly with SOX8 and phosphorylates the protein at Ser327 to further regulate the SOX8/FOXK1 axis, which modulates cell senescence and glycolysis, ultimately leading to cisplatin resistance. SIGNOR-273548 0.2 CSNK2B protein P67870 UNIPROT SEC63 protein Q9UGP8 UNIPROT up-regulates activity phosphorylation Ser748 DSEGFEDsFEEEEEE 9606 BTO:0000599 23287549 t lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. SIGNOR-265272 0.2 LPAR3 protein Q9UBY5 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 11093753 t gcesareni Lpa3 can couple to gi/o SIGNOR-84562 0.435 SMCR8 protein Q8TEV9 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity transcriptional regulation 9606 BTO:0000007 28195531 t While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion. The latter phenotype involved association of SMCR8 with the ULK1 gene locus. SIGNOR-252030 0.406 UQCRC2 protein P22695 UNIPROT Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 t lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits SIGNOR-262191 0.897 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK1 protein Q15835 UNIPROT down-regulates activity phosphorylation Ser21 AFIAARGsFDGSSSQ -1 15946941 t done miannu PKA Phosphorylates GRK1 on Ser21. Phosphorylation by PKA inhibits GRK1 activity. SIGNOR-274079 0.2 CREBBP protein Q92793 UNIPROT DDX21 protein Q9NR30 UNIPROT down-regulates activity acetylation Lys600 HFKQSAEkLIEEKGA 28790157 t lperfetto Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21. SIGNOR-275906 0.247 lapatinib chemical CHEBI:49603 ChEBI CSK protein P41240 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 21443688 t Luana YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ. SIGNOR-257900 0.8 EFNA1 protein P20827 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9576626 t tpavlidou Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm SIGNOR-56901 0.935 AP1 complex SIGNOR-C154 SIGNOR IL6 protein P05231 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 f JNK phosphorylates proteins that are part of AP-1, in particular c-Jun and activating transcription factor 2 (ATF-2). With dominant-negative mutants, antisense RNA, inhibitors, and genetic ablation, it has been shown that JNK and c-Jun play a major role in IL-1–induced expression of genes encoding IL-6 and IL-8 and other IL-1–responsive genes SIGNOR-254513 0.627 RNF123 protein Q5XPI4 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25860612 t miannu  Here, we identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling. SIGNOR-272221 0.406 FOXA1 protein P55317 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 19127412 f miannu Overexpression of foxa1 promoted apoptosis SIGNOR-183153 0.7 MAPK1 protein P28482 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Thr229 HFFKNIVtPRTPPPS 9606 BTO:0000661 12760422 t lperfetto Thr94 in bovine myelin basic protein is a second phosphorylation site for 42-kDa mitogen-activated protein kinase (ERK2). SIGNOR-249419 0.57 PRKN protein O60260 UNIPROT EPS15 protein P42566 UNIPROT up-regulates ubiquitination 9606 BTO:0000938 BTO:0000142 16862145 t gcesareni Treatment of cells with egf stimulates parkin binding to both eps15 and the egfr and promotes parkin-mediated ubiquitination of eps15 SIGNOR-148218 0.2 FGF12 protein P61328 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates activity binding 9606 BTO:0000199 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253416 0.596 PKN1 protein Q16512 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation 9606 17251915 t gcesareni Rho can sensitize the ar to low levels of circulating androgens by promoting the nuclear translocation of a transcriptional co-activator, fhl2 (four and a half lim domains 2), which binds ar, and by stimulating protein kinase n (pkn), which phosphorylates ar directly. SIGNOR-152762 0.57 ATF5 protein Q9Y2D1 UNIPROT CYP2B6 protein P20813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18332083 f miannu We induced endoplasmic reticulum stress by means of amino acid limitation or selective chemicals, and assessed the time course response of ATF5 and CYP2B6. We found a post-transcriptional up-regulation of ATF5 and a parallel induction of CYP2B6 mRNA. SIGNOR-253751 0.2 pipamperone chemical CHEBI:78549 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258572 0.8 IRAK1 protein P51617 UNIPROT GLIPR2 protein Q9H4G4 UNIPROT up-regulates activity phosphorylation Ser58 ILKHSPEsSRGQCGE 9606 BTO:0001370 25544559 t miannu We found that TIRAP-MyD88 dependent kinase IRAK1 phosphorylated GAPR-1 at Serine 58 site. The phosphorylation of GAPR-1 promoted its interaction with TRAM-TRIF dependent inhibitor TMED7, and impaired TMED7-mediated disruption of the TRAM-TRIF complex to trigger IFN-β and the IL10 secretion. SIGNOR-262887 0.331 MAPK1 protein P28482 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 BTO:0000938 21079800 t gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. SIGNOR-169678 0.48 MAP3K7 protein O43318 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 9606 9480845 f lperfetto Overexpression of tak1 together with its activator protein, tak1 binding protein 1 (tab1), induced the nuclear translocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene...[]...These Results suggest that tak1 induces nf-kappa b activation through a novel nik-independent signaling pathway SIGNOR-55710 0.64 LEF1 protein Q9UJU2 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19653274 f irozzo Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation SIGNOR-256281 0.584 SETD1A protein O15047 UNIPROT Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR form complex binding 9606 BTO:0000567 12670868 t miannu Our analysis of HCF-1-associated proteins suggests that a K4 histone H3 HMT complex has been conserved from yeast to humans in both structure and activity: the Set1/Ash2 HMT. The results presented here show that this Set1/Ash2 HMT complex, in mutually exclusive interactions, can associate with HCF-1 bound to the repressive Sin3 HDAC or the transcriptional activator VP16, indicating a diversity of transcriptional regulatory roles. SIGNOR-264478 0.896 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1168 HGHVSDAsISLGESV -1 22302995 t miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. SIGNOR-262903 0.69 FKBP5 protein Q13451 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 10090 BTO:0000142 30685540 f Luana Loss of FKBP5 Affects Neuron Synaptic Plasticity | In this study, a reduction in LTP in Fkbp5 knockout (KO) mice was observed when compared to WT mice, which correlated with changes to the glutamatergic and GABAergic signaling pathways. SIGNOR-265798 0.7 HSD3B2 protein P26439 UNIPROT progesterone smallmolecule CHEBI:17026 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 2243100 t lperfetto Three beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) catalyze the oxidative conversion of delta 5-3 beta-hydroxysteroids to the delta 4-3-keto configuration and is therefore essential for the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens. SIGNOR-268634 0.8 SRP54 protein P61011 UNIPROT U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR up-regulates activity binding -1 8816452 t Monia We have now demonstrated that p54 interacts not only with SC35 and ASF/SF2 but also with U2AF. Pairwise interactions between p54 and other RS domain-containing spliceosomal proteins in comparison with SC35 and ASF/SF2 as detected by the yeast two-hybrid interaction assay. . It is conceivable that p54 can mediate 59 and 39 splice site interaction by interacting directly with U2AF65 associated with the 39 splice site and at the same time interact with other SR proteins, such as ASF/SF2 and SC35, which in turn interact with U1-70K. In this scenario, p54 is different from SC35 or ASF/SF2 in that it cannot directly interact with the 59 component (U1-70K) but can interact with the protein associated with the 39 splice site (U2AF65). SIGNOR-261162 0.341 vinorelbine L-tartrate chemical CHEBI:32296 ChEBI TUBB protein P07437 UNIPROT down-regulates activity chemical inhibition 9606 7740336 t miannu Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) and paclitaxel (Taxol; Bristol-Myers Oncology, Princeton, NJ) as single-agent therapy exhibit good activity in breast and lung cancers. Because these agents bind to distinct sites on tubulin and affect microtubules in opposite ways, a pilot study was conducted of the combination of vinorelbine and paclitaxel in patients with metastatic breast cancer or lung cancer who were refractory to first-line chemotherapy. SIGNOR-259348 0.8 C9orf72 protein Q96LT7 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR up-regulates activity binding 9606 27334615 t lperfetto C9orf72 interacts with the ULK1 initiation complex|C9orf72 regulates translocation of the ULK1 complex to the phagophore via Rab1a SIGNOR-261281 0.428 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates quantity precursor of 9606 23000145 t scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). SIGNOR-268450 0.8 MRGPRX1 protein Q96LB2 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257259 0.2 PPP1CA protein P62136 UNIPROT PREX1 protein Q8TCU6 UNIPROT up-regulates activity dephosphorylation Ser1001 IRFGRKPsLIGLDPE 9606 22242915 t lperfetto MS analysis of wild-type P-Rex1 and a PP1\u03b1-binding-deficient mutant revealed that endogenous PP1\u03b1 dephosphorylates P-Rex1 on at least three residues, Ser834, Ser1001 and Ser1165.|The phosphatase activity of PP1\u03b1 is required for P-Rex1 activation. SIGNOR-277024 0.2 GABRB2 protein P47870 UNIPROT GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263744 0.461 MTMR3 protein Q13615 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity 9606 BTO:0000007 26787466 t lperfetto The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity. SIGNOR-245108 0.313 PRKACA protein P17612 UNIPROT CSK protein P41240 UNIPROT up-regulates activity phosphorylation Ser364 ALREKKFsTKSDVWS 9606 BTO:0000782 11181701 t lperfetto Activation of the cooh-terminal src kinase (csk) by camp-dependent protein kinase inhibits signaling through the t cell receptor.Pka phosphorylates csk at s364 in vitro and in vivo leading to a two- to fourfold increase in csk activity that is necessary for camp-mediated inhibition of tcr-induced interleukin 2 secretion. SIGNOR-105229 0.344 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT unknown phosphorylation Thr440 LDSCNSLtPKSTPVK BTO:0000007 10095772 t llicata In summary, our work has identified several phosphorylation sites for cyclin A/Cdk2 in B-Myb and shown that mutation of at least one of these sites has a strong effect on the inducibility of the B-Myb transactivation potential by cyclin A/Cdk2. SIGNOR-250738 0.711 CDK4 protein P11802 UNIPROT RBL1 protein P28749 UNIPROT up-regulates activity phosphorylation Thr369 KRSFAPStPLTGRRY 9606 BTO:0001938 12006580 t llicata Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression.  SIGNOR-250765 0.8 TP53 protein P04637 UNIPROT PERP protein Q96FX8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10733530 f gcesareni Perp induction is linked to p53-dependent apoptosis, including in response to e2f-1-driven hyperproliferation. Furthermore, analysis of the perp promoter suggests that perp is directly activated by p53. SIGNOR-75877 0.626 PTPN2 protein P17706 UNIPROT AKT1 protein P31749 UNIPROT down-regulates 9606 12612081 f acerquone We found that insulin-induced ir tyrosine phosphorylation and pkb/akt sig- naling were enhanced in tcptp- cells and suppressed upon tcptp reconstitution, providing persuasive evidence that tcptp can regulate ir activation and signaling. SIGNOR-252640 0.364 CSNK2A1 protein P68400 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser321 LNSEDDVsDEEGQEL -1 11278496 t llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. SIGNOR-250877 0.387 SET protein Q01105 UNIPROT NME1 protein P15531 UNIPROT down-regulates binding 9606 12628186 t miannu Tumor suppressor nm23-h1 is a granzyme a-activated dnase during ctl-mediated apoptosis, and the nucleosome assembly protein set is its inhibitor. / nm23-h1 binds to set and is released from inhibition by gzma cleavage of set. SIGNOR-99205 0.717 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT up-regulates phosphorylation Ser106 DNQLTIKsPSKRELA 9606 SIGNOR-C83 10339564 t lperfetto Based on these results, we propose that phosphorylation of hscdc6 by cdks regulates dna replication of at least two steps: first, by promoting initiation of dna replication and, second, through nuclear exclusion preventing dna rereplication. hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106) SIGNOR-67540 0.94 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser48 KSQRTKQsTVLAPVI 9534 BTO:0001538 23519612 t miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. SIGNOR-262711 0.323 RREB1 protein Q92766 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 17550981 f RREB-1 bound to the prostate-specific antigen (PSA) promoter as assessed by chromatin immunoprecipitation. Transient expression of RREB-1 down-regulated AR-mediated promoter activity and suppressed expression of PSA protein. SIGNOR-253661 0.2 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR HJURP protein Q8NCD3 UNIPROT up-regulates activity binding -1 17256767 t miannu These data define a new protein complex in mammalian cells where 14‐3‐3 associates with FAKTS through phosphorylated S479. Our research identifies a widely expressed eukaryotic protein FAKTS, as a new Akt/PKB substrate localized in the nucleus. Akt/PKB promotes FAKTS association with 14‐3‐3, placing FAKTS under the control of 14‐3‐3 proteins. FAKTS may play an important role in transmitting Akt/PKB‐mediated signals in the complex network of intracellular signal transduction. SIGNOR-262624 0.2 TWIST1 protein Q15672 UNIPROT SRPX protein P78539 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255534 0.2 KIF5C protein O60282 UNIPROT TRAK2 protein O60296 UNIPROT up-regulates activity binding 9606 BTO:0000007 24161670 t miannu Trafficking kinesin proteins (TRAKs) are kinesin adaptors. They bind the cargo binding domain of kinesin-1 motor proteins forming a link between the motor and their cargoes. This supports the idea that the KIF5A–TRAK2 interaction is multivalent and could act to ensure stable motor-cargo interaction during intracellular trafficking; dimerization of both motor and adaptor molecules further enhances this stability (Fig. 6). A similar multivalent profile was found for the TRAK2 binding site within the kinesin-1 isoform, KIF5C. SIGNOR-264064 0.565 SHMT2 protein P34897 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI up-regulates quantity chemical modification 9606 32439610 t lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. SIGNOR-268224 0.8 NuA4 complex complex SIGNOR-C459 SIGNOR H4C1 protein P62805 UNIPROT down-regulates activity acetylation 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269286 0.2 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F5 protein P12259 UNIPROT down-regulates activity cleavage Arg737 LAAALGIrSFRNSSL -1 10026263 t lperfetto Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 SIGNOR-263646 0.496 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t inferred from 70% family members gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-270065 0.2 p38 proteinfamily SIGNOR-PF16 SIGNOR TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 t lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK SIGNOR-264445 0.2 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser88 DSGFCLDsPGPLDSK 9606 BTO:0000017 28192398 t miannu We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation.  SIGNOR-277341 0.615 APOE protein P02649 UNIPROT SORL1 protein Q92673 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 11557679 t gcesareni Lr11 binds the apolipoprotein e (apoe)-rich lipoproteins, beta-very low density lipoproteins (vldls), with a high affinity similar to that of other members, such as the ldlr and vldl receptor.Incubation For 48 hours with beta-vldl of lr11-overexpressing cells, but not of control cells, promotes the appearance of numerous intracellular lipid droplets. SIGNOR-110555 0.618 MARCHF5 protein Q9NX47 UNIPROT MFN1 protein Q8IWA4 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 20103533 t lperfetto MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion.|Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate. SIGNOR-272981 0.2 PRKAR1B protein P31321 UNIPROT PRKACB protein P22694 UNIPROT down-regulates activity binding 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258756 0.876 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 16943424 t lperfetto Recently we showed that atm- and hdm2-dependent ubiquitination and subsequent degradation of hdmx following dsb induction are mediated by phosphorylation of hdmx on s403, s367, and s342, with s403 being targeted directly by atm. SIGNOR-149296 0.725 PLK3 protein Q9H4B4 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser191 EDQAEEIsDELMEFS 9606 14968113 t lperfetto Cdc25c phosphorylation on serine 191 by plk3 promotes its nuclear translocation SIGNOR-122090 0.72 CTNNB1 protein P35222 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada Wnt-10b, is a molecular switch that governs adipogenesis. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma). SIGNOR-80592 0.554 PCSK6 protein P29122 UNIPROT INSR protein P06213 UNIPROT up-regulates activity cleavage 9606 BTO:0000666 25527501 t Giorgia Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation. SIGNOR-260366 0.2 GHSR protein Q92847 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257255 0.252 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 SIGNOR-C15 19584320 t gcesareni In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-186633 0.483 FRK protein P42685 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr391 PFLNSGTyHSRDEST 9606 BTO:0002035 35723276 t miannu Mechanistically, FRK interacted with and phosphorylated YAP on Tyr391/407/444, which recruited the classical E3 ubiquitin ligase Siah1 to catalyze ubiquitination and eventually degradation of YAP.  SIGNOR-275455 0.278 POU4F1 protein Q01851 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity binding 9606 9448000 t 2 miannu The POU domain of Brn-3a and Brn-3b was shown to interact with the DNA-binding domain of the ER. Brn-3-ER interactions also affect transcriptional activity of an ERE-containing promoter, such that in estradiol-stimulated cells, Brn-3b strongly activated the promoter via the ERE, while Brn-3a had a mild inhibitory effect. SIGNOR-241275 0.533 JAG1 protein P78504 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 10958687 t Binding Calcium-dependent. gcesareni Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch. SIGNOR-81364 0.624 PTPN2 protein P17706 UNIPROT STAT6 protein P42226 UNIPROT down-regulates activity dephosphorylation 9606 17210636 t gcesareni These results identify TCPTP as a physiological regulator of STAT6 phosphorylation and suggest that specific increases in TCPTP expression in ABC-like DLBCLs may contribute to the different biological characteristics of these tumors SIGNOR-235192 0.666 GTF2I protein P78347 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity by expression transcriptional regulation 16611241 f lperfetto For example, TFII-I binds to the Inr element of the T cell receptor Vbeta gene and activates its transcription in reporter gene assays (Cheriyath et al. 1998). TFII-I also activates transcription of c-fos and Goosecoid through binding to the serum response element and the distal element, respectively (Grueneberg et al. 1997; Ku et al. 2005). SIGNOR-268535 0.327 BAG1 protein Q99933 UNIPROT PPP1R15A protein O75807 UNIPROT down-regulates activity 9606 BTO:0000038 12724406 t lperfetto Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions.|BAG-1 negatively modulates GADD34-bound PP1 activity, and the expression of BAG-1 isoforms can also mask GADD34-mediated inhibition of colony formation and suppression of transcription. Our findings suggest that BAG-1 may function to suppress the GADD34-mediated cellular stress response and support a role for BAG-1 in the survival of cells undergoing stress. SIGNOR-254117 0.455 HRH1 protein P35367 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256921 0.2 CAPN1 protein P07384 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase SIGNOR-251586 0.301 CGA protein P01215 UNIPROT TSH complex SIGNOR-C412 SIGNOR form complex binding 9606 BTO:0001379 8196184 t scontino TSH is a heterodimer composed of common alpha subunit and unique beta subunit encoded by genes located on different chromosomes. It is known that the expression of these subunit genes is regulated in different mechanism by several extracellular factors. SIGNOR-267046 0.667 CSNK2A1 protein P68400 UNIPROT PSMA3 protein P25788 UNIPROT unknown phosphorylation Ser243 AEKYAKEsLKEEDES -1 8619999 t llicata Several C8 protein constructs allow the location of the CKII phosphorylation sites to be the COOH terminal portion of the protein, and direct mutational analyses show that Ser-243 and Ser-250 are the residues of the C8 subunit phosphorylated by CKII. The in vitro phosphorylation of the proteasome by CKII does not affect its proteolytic activity (on proteins or fluorogenic synthetic peptides), therefore suggesting its involvement in the interaction of the proteasome with other cellular proteins, i.e. in the formation of the 26S complex and/or in the interaction with the nuclear translocation machinery. SIGNOR-250938 0.389 AKT1 protein P31749 UNIPROT DLC1 protein Q96QB1 UNIPROT unknown phosphorylation Ser766 VTRTRSLsACNKRVG 10116 16338927 t gcesareni We have demonstrated that Ser-322 is phosphorylated upon insulin stimulation of intact cells and that this site is directly phosphorylated in vitro by PKB and ribosomal S6 kinase, members of the AGC (protein kinases A, G, and C) family of insulin-stimulated protein kinases SIGNOR-252550 0.508 GRK2 protein P25098 UNIPROT RPLP2 protein P05387 UNIPROT up-regulates phosphorylation Ser102 KDEKKEEsEESDDDM 9606 12379128 t gcesareni The phosphorylation sites in grk2-phosphorylated p2 are identified (s102 and s105) and are identical to the sites known to regulate p2 activity. SIGNOR-94254 0.2 sitagliptin chemical CHEBI:40237 ChEBI DPP4 protein P27487 UNIPROT down-regulates activity chemical inhibition 9606 20927248 t Luana Sitagliptin is a competitive, reversible, fast and tight binding DPP-IV inhibitor SIGNOR-257883 0.8 MAPK1 protein P28482 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 12050114 t gcesareni Tob is rapidly phosphorylated at ser 152, ser 154, and ser 164 by erk1 and erk2 upon growth-factor stimulation. SIGNOR-88720 0.361 SCN9A protein Q15858 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 t miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. SIGNOR-253403 0.8 MRPS22 protein P82650 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261434 0.724 ZBTB14 protein O43829 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 10080939 f miannu ZF5, which we have cloned as a transcriptional repressor on the mouse c-myc promoter SIGNOR-220537 0.321 CHEK1 protein O14757 UNIPROT NEK11 protein Q8NG66 UNIPROT up-regulates phosphorylation Ser273 SMLNKNPsLRPSAIE 9606 19734889 t lperfetto We demonstrate that chk1 (checkpoint kinase 1) directly activates nek11 by phosphorylating it on ser 273 SIGNOR-187863 0.267 CNOT9 protein Q92600 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268303 0.2 ETS1 protein P14921 UNIPROT TBX22 protein Q9Y458 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 25373698 t miannu TBX22 is an X-linked gene, which encodes a T-box-containing transcription factor. Loss-of-function mutation in the X-linked TBX22 promoter disrupts an ETS-1 binding site and leads to cleft palate. We first link the transcription factor ETS-1 to TBX22 pathway during embryonic palatogenesis. SIGNOR-265565 0.2 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CRKL protein P46109 UNIPROT up-regulates phosphorylation Tyr207 IPEPAHAyAQPQTTT 9606 BTO:0001271 9053848 t lperfetto Tyrosine 207 in crkl is the bcr/abl phosphorylation sitephosphorylation of y207 provides a binding site for the crkl sh2 domain and potentially for other sh2-containing proteins. SIGNOR-46893 0.2 DNA_damage stimulus SIGNOR-ST1 SIGNOR CHEK1 protein O14757 UNIPROT up-regulates 9606 26527132 f lperfetto Checkpoint kinase 1 (CHK1) is a key component of the ATR-dependent DNA damage response pathway that protects cells from RS by preventing replication fork collapse and activating homologous DNA repair. SIGNOR-242616 0.7 RIMBP3B protein A6NNM3 UNIPROT RIMS1 protein Q86UR5 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264364 0.351 SRGAP3 protein O43295 UNIPROT WASF1 protein Q92558 UNIPROT up-regulates binding 9606 12447388 t miannu Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo. SIGNOR-95967 0.569 LPAR3 protein Q9UBY5 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257141 0.252 AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 12782654 f lperfetto It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). However, the mechanism by which akt activates mtor is not fully understood. The known pathway by which akt activates mtor is via direct phosphorylation and tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor. SIGNOR-244314 0.2 D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI IDH2 protein P48735 UNIPROT up-regulates activity chemical activation 9606 32943735 t Wild-type IDH1 and IDH2 catalyze the reaction by converting isocitrate and NADP+ into α-KG and CO2 with the concomitant generation of NADPH in the cytosol and mitochondrial matrix SIGNOR-267370 0.8 PRKCA protein P17252 UNIPROT HMGN2 protein P05204 UNIPROT down-regulates phosphorylation Ser29 QRRSARLsAKPAPPK 9606 10739259 t lperfetto Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools. SIGNOR-76324 0.294 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation 9606 phosphorylation:Tyr397 SVSETDDyAEIIDEE 17828307 t gcesareni Fak y397 phosphorylation promotes src sh2 domain binding to fak, presumably leading to conformational src activation with a fak-src complex. SIGNOR-157767 0.634 mTORC1 complex SIGNOR-C3 SIGNOR ULK1 protein O75385 UNIPROT down-regulates phosphorylation 9606 19690328 t lperfetto The complementary inhibitory mechanism in which mtorc1 phosphorylates the autophagy regulatory complex containing unc-51-like kinase 1 (ulk1), the mammalian atg13 protein, and focal adhesion kinase interacting protein of 200 kd (fip200) has also been elucidated. SIGNOR-217133 0.623 F2RL1 protein P55085 UNIPROT THBS1 protein P07996 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254842 0.258 HOXB7 protein P09629 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity binding 9606 BTO:0002419 SIGNOR-C106 17308091 t miannu Ku70 and Ku80 associated with HOXB7 in vivo. Ku70/Ku80 heterodimer formation is a prerequisite for HOXB7 binding. interaction between Ku70/80 and HOXB7 may affect the catalytic activity of DNA-PK. HOXB7 stimulates DNA-PK activity SIGNOR-226063 0.338 WNT3A protein P56704 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 18697834 t Simone Vumbaca Wnt1, Wnt3a and Wnt5a all induced a statistically greater degree of proliferation than control cells SIGNOR-255650 0.802 pimozide chemical CHEBI:8212 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258718 0.8 DYRK4 protein Q9NR20 UNIPROT DYRK4 protein Q9NR20 UNIPROT up-regulates activity phosphorylation Tyr264 SSCYEHQkVYTYIQS 9606 21127067 t Manara Autophosphorylation of DYRK4 in the Activation Loop Is Required for Kinase Activity SIGNOR-260827 0.2 NVP-AEW541 chemical CID:11476171 PUBCHEM IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194892 0.8 WNK3 protein Q9BYP7 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates activity phosphorylation Thr1048 YQEKVHMtWTKDKYM 9606 24043619 t Manara WNK3, which inhibits the activity of KCC3, promoted phosphorylation of Ser-96 as well as Thr-991 and Thr-1048.  SIGNOR-260910 0.456 PTH2 protein Q96A98 UNIPROT PTH2R protein P49190 UNIPROT up-regulates binding 9606 BTO:0000142;BTO:0000671 11861531 t gcesareni Subsequent efforts led to the isolation and definition of the primary structure of a novel peptide, referred to as tip39, from bovine hypothalamus and the synthetic peptide was shown to efficiently activate human, rat, and zebrafish pth2 receptors SIGNOR-115124 0.754 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser146 PALEVSDsESDEALV 9606 10618498 t lperfetto Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability SIGNOR-73887 0.439 H3-4 protein Q16695 UNIPROT Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR form complex binding -1 20498094 t miannu A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. SIGNOR-263725 0.2 ORC4 protein O43929 UNIPROT ORC complex SIGNOR-C419 SIGNOR form complex binding 9606 32808929 t lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA SIGNOR-267564 0.965 MAPK1 protein P28482 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates quantity by destabilization phosphorylation Ser159 DGSCSSSsPPLPVLG 9606 15632084 t gcesareni In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3. SIGNOR-132967 0.901 MAPK3 protein P27361 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser62 SYTPTPRsPRFIGRR 9606 7901013 t gcesareni In this paper we have studied the phosphorylation and activation of alternatively spliced forms of human th by mapkap kinase-1 , mapkap kinase-2, map kinase, and cam kinase-11 SIGNOR-34678 0.495 AKT1 protein P31749 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser644 NLMFRKFsLERPFRP -1 24548923 t miannu Akt phosphorylates S637 and S645 in the linker region of Carma1  SIGNOR-276621 0.537 DCX DET1-COP1 complex SIGNOR-C24 SIGNOR TRiC complex SIGNOR-C539 SIGNOR down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 24298020 t miannu Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not.The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.COP1 functions as an E3 ligase by forming a supercomplex that also includes heterodimeric substrate receptor DET1, adaptor DDB1, scaffold Cul4A, and RBX1 to recruit the E2 enzyme SIGNOR-272873 0.2 COPS2 protein P61201 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270766 0.921 TP73 protein O15350 UNIPROT PMAIP1 protein Q13794 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17700533 f miannu Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis. SIGNOR-255469 0.326 AKT proteinfamily SIGNOR-PF24 SIGNOR CHEK1 protein O14757 UNIPROT down-regulates phosphorylation Ser280 AKRPRVTsGGVSESP 9606 15107605 t lperfetto The chk1 protein phosphorylated by pkb on serine 280 does not enter into protein complexes after replication arrest. Moreover, chk1 phosphorylated by pkb fails to undergo activating phosphorylation on serine 345 by atm/atr. Phosphorylation by atm/atr and association with other checkpoint proteins are essential steps in activation of chk1. SIGNOR-244206 0.2 LPCAT2 protein Q7L5N7 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272765 0.8 mTORC1 complex SIGNOR-C3 SIGNOR MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser68 PPQTSGLsPSRLSKS 9606 20516213 t lperfetto The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly. SIGNOR-217145 0.467 DOT1L protein Q8TEK3 UNIPROT MYCBP2 protein O75592 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 32814769 t miannu Overexpression of DOT1L decreased the expression of HECTD4 and MYCBP2 in LNCaP, C42B, and 22rv1 cells (Supplementary Fig. 5c), suggesting that DOT1L plays a role in repressing these targets either directly or indirectly. SIGNOR-267151 0.2 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT up-regulates activity phosphorylation Ser486 DDAFVGFsYAPPSED 10548550 t miannu SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB. SIGNOR-250278 0.473 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1090 TNTGFPRyPNDSVYA 9606 14711813 t llicata Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. SIGNOR-121145 0.2 PLK1 protein P53350 UNIPROT STK38 protein Q15208 UNIPROT down-regulates activity phosphorylation Thr7 tPCSSMSN 9606 BTO:0000567 26057687 t miannu Here, we identified a conserved signaling axis in which NDR1 kinase activity is regulated by PLK1 in mitosis. PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1-dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis.  SIGNOR-276914 0.321 TRRAP protein Q9Y4A5 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269288 0.736 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75645 0.783 CREB1 protein P16220 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16149046 f miannu Constitutively active mutants of activating transcription factor 2 (ATF2) and c-Jun additionally stimulated GTP cyclohydrolase I promoter activity, but to a lesser extent than the constitutively active CREB mutant. Enzymatic reactions that require tetrahydrobiopterin as cofactor are therefore indirectly controlled by signaling cascades involving the signal-responsive transcription factors CREB, c-Jun, and ATF2. SIGNOR-252227 0.2 HLX protein Q14774 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20008130 f Luana In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells. SIGNOR-261624 0.2 MAPK14 protein Q16539 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates phosphorylation Ser721 PSDLLPMsPSVYAVL 9606 17502367 t gcesareni All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below). SIGNOR-154787 0.582 NRZ complex complex SIGNOR-C358 SIGNOR Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 25364732 f lperfetto NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay. SIGNOR-265026 0.7 CENPE protein Q02224 UNIPROT Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 20383333 f lperfetto Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology SIGNOR-252013 0.7 WDR62 protein O43379 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity relocalization 10090 30566428 t lperfetto In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis SIGNOR-271715 0.2 1-naphthol chemical CHEBI:10319 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258163 0.8 PPP2CA protein P67775 UNIPROT MKNK1 protein Q9BUB5 UNIPROT down-regulates dephosphorylation Thr255 ITTPELTtPCGSAEY 9606 20927323 t gcesareni Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e. SIGNOR-168314 0.493 PRKG1 protein Q13976 UNIPROT PPP1R17 protein O96001 UNIPROT up-regulates phosphorylation Thr68 KKPRRKDtPALHIPP 9606 BTO:0001011 10051666 t miannu Recombinant human G-substrate was phosphorylated efficiently by cGMP-dependent protein kinase exclusively at Thr residues, and it was recognized by antibodies specific for rabbit phospho-G-substrate. The amino acid sequences surrounding the sites of phosphorylation in G-substrate are related to those around Thr-34 and Thr-35 of the dopamine- and cAMP-regulated phosphoprotein DARPP-32 and inhibitor-1, respectively, two potent inhibitors of protein phosphatase 1. SIGNOR-263148 0.645 HDAC2 protein Q92769 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23836662 f miannu We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. SIGNOR-254156 0.554 MAP1LC3C protein Q9BXW4 UNIPROT NBR1 protein Q14596 UNIPROT down-regulates binding 9606 BTO:0000007 19250911 t gcesareni We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. . downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1. SIGNOR-184258 0.545 SMURF1 protein Q9HCE7 UNIPROT SMAD6 protein O43541 UNIPROT down-regulates activity relocalization 9606 22298955 t lperfetto Smurf1, with its WW domain, specifically binds to the PY motif of Smad6 and transports Smad6 into the cytoplasm. SIGNOR-105931 0.824 2-[[3-[[2-(dimethylamino)phenyl]methyl]-2-pyridin-4-yl-1,3-diazinan-1-yl]methyl]-N,N-dimethylaniline smallmolecule CHEBI:94276 ChEBI GLI2 protein P10070 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150;BTO:0001130 17494766 t gcesareni Gant61 was able to efficiently block gli1 as well as gli2-induced transcription SIGNOR-154756 0.8 RPS6KA3 protein P51812 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 8688081 t lperfetto MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90(RSK) family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression SIGNOR-248951 0.715 PIM proteinfamily SIGNOR-PF34 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr198 PGLRRRQt 9606 18593906 t gcesareni We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro.|Pim kinases promote cell cycle progression and tumorigenesis by down-regulating p27(Kip1) expression at both transcriptional and posttranslational levels. SIGNOR-259425 0.2 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-268077 0.8 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 BTO:0000567 15070733 t gcesareni Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp. SIGNOR-123832 0.627 HOXD12 protein P35452 UNIPROT MAFK protein O60675 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221929 0.385 MDC1 protein Q14676 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 19230643 t gcesareni Mdc1 also undergoes phosphorylation by ck2 after dna damage to generate a phospho-motif on mdc1, which binds directly to nbs1. SIGNOR-184141 0.828 AKT1 protein P31749 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 15004527 t gcesareni Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity SIGNOR-252472 0.767 TNF protein P01375 UNIPROT SCN9A protein Q15858 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253488 0.254 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser275 DNVRYGIsNIDTTIE 34010649 t lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-275948 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR KLC1 protein Q07866 UNIPROT down-regulates phosphorylation 9606 21385839 t inferred from 70% family members gcesareni Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1mutation of klc1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residueklc1ser460 is a predicted mitogen-activated protein kinase (mapk) target site, and we show that extracellular-signal-regulated kinase (erk) phosphorylates this residue in vitro. SIGNOR-270072 0.2 ADORA2A protein P29274 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256766 0.304 H4C1 protein P62805 UNIPROT Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR form complex binding 9606 15776021 t miannu Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes. SIGNOR-263877 0.2 CSNK1A1 protein P48729 UNIPROT AGO2 protein Q9UKV8 UNIPROT down-regulates activity phosphorylation Ser831 SAEGSHTsGQSNGRD 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276508 0.377 PTPN1 protein P18031 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates activity dephosphorylation Tyr66 LHQEDNDyINASLIK -1 11506178 t Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions. SIGNOR-248423 0.2 JUN protein P05412 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19022561 f miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254875 0.262 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates activity phosphorylation Ser166 EPRSRHLsVSSQNPG 9534 BTO:0001538 12392720 t miannu It was shown that the recombinant MEKK3 protein and fluorescein-labeled MEKK3 peptides (FITC-(159)epRsRhlSVi(168) and FITC-(330)dpRgRlpSAd(339)) are phosphorylated by SGK1 in vitro. It was also observed that the intrinsic kinase activity of MEKK3 on Ser(189) of MKK3 (equivalent to Ser(207) of MKK6) decreased along with phosphorylation of Ser(166) and Ser(337) in MEKK3 in vitro and in vivo. Therefore, it is suggested that SGK1 inhibits MEKK3-MKK3/6 signal transduction by phosphorylation of MEKK3. SIGNOR-250004 0.2 RSPO3 protein Q9BXY4 UNIPROT SDC4 protein P31431 UNIPROT up-regulates binding 9606 21397842 t gcesareni Here, we show that rspo3 binds syndecan 4 (sdc4) and that together they activate wnt/pcp signaling. SIGNOR-172756 0.433 PPP2CA protein P67775 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates dephosphorylation Ser23 PAPIRRRsSNYRAYA 9606 BTO:0000887 15769444 t lperfetto The major phosphatase thought to dephosphorylate ctni and phospholamban is type 2a protein phosphatase (pp2a) [61]. Activation of pp2a and ensuing dephosphorylation of regulatory proteins is involved in the anti-adrenergic effects of adenosine and muscarinic receptor activation see also fig2. SIGNOR-134597 0.387 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser269 GNLLGRNsFEVRVCA 9606 20959462 t llicata Importantly, the aurora b-mediated phosphorylation on ser(269) or thr(284) significantly compromises p53 transcriptional activity. SIGNOR-168745 0.708 HSPB1 protein P04792 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates 9606 12855565 f gcesareni These data demonstrate that hsp27 inhibits the release of smac SIGNOR-103539 0.334 IL22RA2 protein Q969J5 UNIPROT IL22 protein Q9GZX6 UNIPROT up-regulates binding 9606 11390453 t gcesareni Il-22 mediates inflammation and binds class ii cytokine receptor heterodimers il-22 ra1/crf2-4. SIGNOR-86113 0.736 MMP2 protein P08253 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates cleavage 9606 10652271 t gcesareni We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-beta (tgf-beta), which constitutes a novel mechanism of tgf-beta activation SIGNOR-74384 0.571 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates phosphorylation Ser540 MDSEEPDsRGGSPQM 9606 18701453 t lperfetto Gsk3_ phosphorylates eif2b_ at ser-539 (ser-535 in the rat sequence) and inactivates it SIGNOR-180022 0.561 ARNT protein P27540 UNIPROT HIF-1 complex complex SIGNOR-C418 SIGNOR form complex binding 9606 27692180 t miannu HIF-1 consists of two subunits, HIF-1α and HIF-1β. While HIF-1β protein is constitutively expressed and present in excess, HIF-1α protein has a short half-life SIGNOR-267448 0.778 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 9606 14684878 f miannu Dendritic spines are small protrusions found on dendrites of principal neurons of mammalian brain. Serving as postsynaptic compartments for individual excitatory inputs, spines show rapid movements and shape changes that are influenced by synaptic activity. The structural modifications of spines are believed to represent morphological correlates of synaptic plasticity. The form and motility of spines are determined mainly by the actin cytoskeleton SIGNOR-266597 0.7 FGF13 protein Q92913 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates activity binding 9606 BTO:0000199 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253415 0.419 ACTR8 protein Q9H981 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270848 0.618 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 16151013 t Cytosolic p53 amattioni P53 also accumulates in the cytoplasm where it directly activates bax to promote mitochondrial outer membrane permeabilization. SIGNOR-140242 0.743 PSMC4 protein P43686 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263371 0.872 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 BTO:0000887;BTO:0001103 11705993 t gcesareni Interestingly, phosphorylation at several ser/thr residues within the c-terminal autoinhibitory tail appears to either activate or inhibit s6k1, depending on the cell cycle phase. phosphorylation of those residues (featured by the thr-421/ser-424 site) during mitosis pursued by cdk1 inactivates s6k1 we then assessed the phosphorylation status of the mitosis-specific inhibitory residue of s6k1, thr-421/ser-424, which is targeted by mitotic cdk1. SIGNOR-111507 0.392 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser330 SFRVRASsDGEGTMS -1 8349691 t llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. SIGNOR-251073 0.325 GNB3 protein P16520 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 14668344 t gcesareni Expression of the g__ sequestrant, _-transducin, inhibits both ras activation and membrane translocation of _-arrestin1, suggesting that g__ dimers from g_i2 and g_q activate different effectors to coordinately regulate the pi 3-kinase/akt pathway. , these data indicate that _-thrombin stimulates rapid pi 3-kinase activity and akt phosphorylation by the g__ dimers released from a ptx-sensitive g protein. SIGNOR-252680 0.376 TFEB protein P19484 UNIPROT CTSF protein Q9UBX1 UNIPROT up-regulates quantity by expression transcriptional regulation 30145926 f lperfetto Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB SIGNOR-276805 0.372 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 t lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40423 0.734 PTEN protein P60484 UNIPROT ABTB1 protein Q969K4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 f miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). SIGNOR-260050 0.364 TP53 protein P04637 UNIPROT LRBA protein P50851 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15064745 f miannu We also show that LRBA promoter activity and endogenous LRBA mRNA levels are reduced by p53 and increased by E2F1, indicating that mutations in the tumor suppressors p53 and Rb could contribute to the deregulation of LRBA. SIGNOR-253847 0.278 IKK-complex complex SIGNOR-C14 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser644 GLDFNFDsLISTQNV 9606 19188143 t lperfetto Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway SIGNOR-209769 0.534 ARHGEF7 protein Q14155 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates binding 9606 21048939 t gcesareni Arhgef7 is interacting with lrrk2 in vitro and in vivo. Gtpase activity of full-length lrrk2 increases in the presence of recombinant arhgef7. Arhgef7 might act as a guanine nucleotide exchange factor for lrrk2 SIGNOR-169217 0.468 CAMK2A protein Q9UQM7 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates phosphorylation Ser270 SVRMLSGsKEKDRNL 9606 BTO:0000671 10908300 t gcesareni The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microm [d-ala(2),n-mephe(4),gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative ca(2+)/calmodulin-dependent protein kinase ii (camk ii) phosphorylation sites, s261 and s266, by alanines in the third intracellular loop of the rat mu-opioid receptor (rmor1) confers resistance to camk ii-induced receptor desensitization. SIGNOR-79682 0.2 LPCAT4 protein Q643R3 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272771 0.8 MBL2 protein P11226 UNIPROT MASP2 protein O00187 UNIPROT up-regulates activity binding 9606 9087411 t lperfetto The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5). SIGNOR-263415 0.73 VHL protein P40337 UNIPROT CDKN1C protein P49918 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000037 15824735 f miannu three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL. SIGNOR-255601 0.2 alvocidib hydrochloride chemical CHEBI:90998 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192458 0.8 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKACB protein P22694 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258211 0.8 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr566 SLNQEDIyITTESLT 10029 12907755 t PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates SIGNOR-248421 0.48 EIF1 protein P41567 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates activity 9606 14600024 f lperfetto Binding of eIF1 to the 40S subunit would block access of the 60S SIGNOR-269144 0.262 SLC9A9 protein Q8IVB4 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265599 0.8 ERBB4 protein Q15303 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 16729043 t gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. SIGNOR-146882 0.464 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates binding 9606 21798082 t gcesareni Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b). SIGNOR-175621 0.561 RING1 protein Q06587 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR down-regulates activity ubiquitination 10090 BTO:0002572 16359901 t miannu Polycomb group (PcG) proteins exist in at least two biochemically distinct protein complexes, the EED-EZH2 complex and the PRC1 complex, that respectively possess H3-K27 methyltransferase and H2A-K119 ubiquitin E3 ligase activities. How the enzymatic activities are regulated and what their role is in Hox gene silencing are not clear. Here, we demonstrate that Bmi-1 and Ring1A, two components of the PRC1 complex, play important roles in H2A ubiquitylation and Hox gene silencing. We show that both proteins positively regulate H2A ubiquitylation. SIGNOR-271417 0.2 SH2B1 protein Q9NRF2 UNIPROT CD79B protein P40259 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000776 SIGNOR-C433; SIGNOR-C434; SIGNOR-C435; SIGNOR-C436 32323266 t scontino SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK. SIGNOR-268458 0.2 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207672 0.8 GTF2A2 protein P52657 UNIPROT TBP protein P20226 UNIPROT up-regulates activity binding -1 8626665 t lperfetto The general transcription factor IIA (TFIIA) binds to the TATA binding protein (TBP) and mediates transcriptional activation by distinct classes of activators. |Our results show that different activators utilize the general factor TFIIA in unique ways and that TFIIA contributes transcription activation functions in addition to the facilitation of TBP-DNA binding. SIGNOR-262591 0.897 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr464 QEGSIEVyEDAGSHY 9606 12408982 t gcesareni Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity. SIGNOR-95238 0.427 IL12A protein P29459 UNIPROT IFNG protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10653850 f miannu IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12 SIGNOR-260861 0.373 NKX2-5 protein P52952 UNIPROT TBX5 protein Q99593 UNIPROT up-regulates quantity by expression transcriptional regulation 15095414 f Mutation at the potential TBE-B and -C sites, and at the GC box and NKX2.5 sites significantly decreased luciferase activity, suggesting that the GC box and the potential TBE-B, -C, and NKX2.5 sites are functionally important for the activation of the promoter function. SIGNOR-253650 0.795 GSK3B protein P49841 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity phosphorylation Ser847 SEAASLSsLNSSESD -1 10671552 t Phosphorylation of the E-cadherin Cytoplasmic Domain by CKII and GSK-3β Increases the Binding to β-catenin. pre-phosphorylation by CKII at Ser-855 and/or Ser-853 of E-cadherin is required before GSK-3β can phosphorylate at Ser-849. SIGNOR-251225 0.574 Met-tRNA(Met) chemical CHEBI:16635 ChEBI Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 t lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. SIGNOR-269117 0.8 PLD1 protein Q13393 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI up-regulates chemical modification 9606 9873061 t gcesareni The primary known function of phospholipase d (pld) is to generate phosphatidic acid (pa) via the hydrolysis of phosphatidylcholine. . phospholipase d (pld) hydrolyzes phospholipids to generate phosphatidic acid (pa). SIGNOR-62882 0.8 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UBTF protein P17480 UNIPROT up-regulates activity phosphorylation Ser484 ERGKLPEsPKRAEEI 10090 BTO:0000944 10202152 t llicata We have identified Ser484 as a direct target for cyclin-dependent kinase 4 (cdk4)-cyclin D1- and cdk2-cyclin E-directed phosphorylation. Mutation of Ser484 impairs rDNA transcription in vivo and in vitro.  SIGNOR-250755 0.379 STXBP4 protein Q6ZWJ1 UNIPROT STX4 protein Q12846 UNIPROT up-regulates activity binding 10029 BTO:0000246 15753124 t miannu Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. These data demonstrate that insulin activation of Akt2 specifically regulates the docking/fusion step of GLUT4-containing vesicles at the plasma membrane through the regulation of Synip phosphorylation and Synip-Syntaxin4 interaction.Thus, our data demonstrate that insulin-stimulated Akt2-dependent phosphorylation of Synip on serine residue 99 results in reduced binding interactions between Synip and Syntaxin4. SIGNOR-262634 0.792 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Thr405 VGGSGIGtPPSVLKR BTO:0000007 10593981 t llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. SIGNOR-250737 0.711 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr659 VADERVDyVVVDQQK 10090 BTO:0000944 10978177 t HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin SIGNOR-251317 0.492 CCNO protein P22674 UNIPROT CDK13 protein Q14004 UNIPROT up-regulates activity binding 37197505 t lperfetto Cyclin O promotes lung cancer progression and cetuximab resistance via cell cycle regulation and CDK13 interaction|CCNO promoted tumor cell proliferation and survival in vivo via CDK13| SIGNOR-275618 0.274 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR YAP1 protein P46937 UNIPROT down-regulates activity binding 9606 23431053 t miannu The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation. SIGNOR-265820 0.2 ENMD-2076 chemical CID:16041424 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191466 0.8 PCBD1 protein P61457 UNIPROT FXYD2 protein P54710 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000482 24204001 f miannu Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg(2+) reabsorption in the DCT. SIGNOR-254908 0.354 CLOCK protein O15516 UNIPROT CLOCK/BMAL2 complex SIGNOR-C196 SIGNOR form complex binding 19605937 t lperfetto Like BMAL1, its paralog BMAL2 dimerizes with CLOCK to activate the E-box-dependent transcription SIGNOR-253711 0.67 SATB1 protein Q01826 UNIPROT AREG protein P15514 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000664 17343824 f miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. SIGNOR-255133 0.249 AURKA protein O14965 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity phosphorylation 9606 BTO:0001225 19060929 t lperfetto The recombinant human aurka protein phosphorylated the gsk-3beta protein at ser 9 in a concentration-dependent manner, in vitro. The phosphorylation of beta-catenin (ser33/37/thr41) by gsk-3beta is known to target beta-catenin towards degradation. In line with our findings, the increase in phospho-gsk-3beta level was accompanied by a significant decrease in beta-catenin phosphorylation (ser33/37/thr41) and accumulation of beta-catenin protein. SIGNOR-227923 0.348 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257470 0.8 ELOVL7 protein A1L3X0 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267895 0.8 azelastine chemical CHEBI:2950 ChEBI HRH3 protein Q9Y5N1 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 21381763 t Luana Azelastine was used as a standard, with affinities (pKi) for H1 and H3 8.9 and 6.8, respectively.  SIGNOR-257895 0.8 COL15A1 protein P39059 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. Types XV and XVIII collagen are classified as multiplexins, which are heparan sulfate proteoglycans (HSPGs). The multiplexins can bind growth factors and also aid in linking the basement membrane to other basement membrane glycoproteins and endomysium SIGNOR-254678 0.7 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser85 GSEGDSEsGEEEELG -1 2046671 t llicata Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Mutation of serine 85 alone had a smaller but significant effect on phosphorylation that may be due to alteration in the protein kinase recognition site. SIGNOR-250957 0.533 TAF1A protein Q15573 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 15970593 t lperfetto Gene promoters with a TATA box tend to be bound by the SAGA complex which includes TBP, SUPT3H, and GCN5 (Basehoar et al., 2004; Rodríguez-Navarro, 2009). Therefore, it was thought that TATA-containing genes were mainly regulated by the SAGA complex, while TATA-less genes were independently regulated by TFIID (Pugh and Tjian, 1991; Basehoar et al., 2004). However, recent studies in yeast indicate that most genes utilize both TFIID and SAGA, and that the relative contribution of each complex likely depends on the individual context SIGNOR-269591 0.353 IFNL2 protein Q8IZJ0 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 12469119 t gcesareni Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha. SIGNOR-96209 0.685 NELFB protein Q8WX92 UNIPROT NELF complex SIGNOR-C521 SIGNOR form complex binding 9606 18628398 t miannu The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. SIGNOR-271402 0.852 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser880 YNVYGIEsVKI 9606 BTO:0000007 10501226 t lperfetto Here, we show that the C terminus of GluR2 of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor is phosphorylated by protein kinase C and that serine-880 is the major phosphorylation site. This phosphorylation also occurs in human embryonic kidney (HEK) cells by addition of 12-O-tetradecanoylphorbol 13-acetate. SIGNOR-249022 0.697 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Thr189 LLLTTGGtLKISDLG 9606 BTO:0000781 11430832 t lperfetto These data suggest that the phosphorylation of thr-189 negatively regulates lkb1 activity. SIGNOR-109028 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR SKI protein P12755 UNIPROT down-regulates phosphorylation Thr458 QPRKRKLtVDTPGAP 9606 19875456 t llicata The phosphorylation of ski at threonine 458 is induced by akt pathway activators including insulin, insulin-like growth factor-1, and hepatocyte growth factor. The phosphorylation of ski causes its destabilization and reduces ski-mediated inhibition of expression of another negative regulator of tgf-beta, smad7 SIGNOR-188969 0.2 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2G2 protein P60604 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271344 0.655 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120220 0.321 FLI1 protein Q01543 UNIPROT GP6 protein Q9HCN6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001549 12359731 f miannu Deletion analyses and site-directed mutagenesis identified Sp1(227), GATA(177), and Ets(48) sites as essential for GPVI expression. We show that transcription factors GATA-1, Fli-1, and Sp1 can bind to and activate this promoter. SIGNOR-254157 0.2 AURKB protein Q96GD4 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser539 TSLSPRSsLSSPSPP 9606 21878642 t llicata We identified the highly conserved ser(539) as the primary phosphorylation site for aurora kinases. SIGNOR-176363 0.253 FGF17 protein O60258 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 t tpavlidou Fgfs bind and activate high-affinity receptor tyrosine kinases. The cloning of fgf receptors (fgfrs) has identified four distinct genes SIGNOR-42365 0.686 RAB6C protein Q9H0N0 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9534 20360680 f miannu We show that BICDR-1 interacts with the dynein/dynactin motor complex, binds to kinesin-3 motor protein Kif1C and controls the pericentrosomal localization of Rab6-positive secretory vesicles. SIGNOR-266882 0.7 adenosine smallmolecule CHEBI:16335 ChEBI PI4K2A protein Q9BTU6 UNIPROT down-regulates activity chemical inhibition -1 21704602 t Luana Both PI4K2A and PI4K2B were inhibited by adenosine at concentrations that do not significantly inhibit PI4KA and PI4KB actitvity SIGNOR-258317 0.8 arachidonic acid smallmolecule CHEBI:15843 ChEBI PLA2G4A protein P47712 UNIPROT up-regulates 9606 15878913 f miannu AA increases PC-3 prostate tumor cell growth, total DNA content and endogenous PGE 2 levels via induction of c-fos , cPLA 2 and cox-2 mRNA transcription. SIGNOR-255393 0.8 TWIST2 protein Q8WVJ9 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 19581928 f miannu we showed aberrant IL-6 production and STAT3 activation in MCF-7 cells that constitutively express Twist, a metastatic regulator and direct transcriptional repressor of E-cadherin. SIGNOR-255536 0.452 PAK6 protein Q9NQU5 UNIPROT PACSIN1 protein Q9BY11 UNIPROT up-regulates activity phosphorylation Ser346 SQAGDRGsVSSYDRG -1 22371566 t miannu We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. SIGNOR-263021 0.2 FOXO1 protein Q12778 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12913110 f lperfetto FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. SIGNOR-209654 0.555 SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR KCND3 protein Q9UK17 UNIPROT up-regulates activity phosphorylation Tyr108 GKLHYPRyECISAYD 22198508 t lperfetto Our results demonstrate that human atrial I(to) and cloned hKv4.3 channels are modulated by EGFR kinase via phosphorylation of the Y136 residue and by Src-family kinases via phosphorylation of the Y108 residue|We found that human atrial I(to) was inhibited by the broad-spectrum PTK inhibitor genistein, the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556, and the Src-family kinases inhibitor PP2. SIGNOR-275566 0.2 YY1 protein P25490 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15899857 f miannu YY1, a constitutively expressed multifunctional transcription factor, activates the Grp78 promoter only under ER stress conditions. SIGNOR-255620 0.309 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10230394 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-67387 0.523 CSNK2A1 protein P68400 UNIPROT EIF4G2 protein P78344 UNIPROT up-regulates activity phosphorylation Ser902 ETAEEEEsEEEAD 9606 BTO:0000007 29530922 t miannu DAP5(S902) is phosphorylated by CK2α. Phosphorylation of DAP5(S902) by CK2α is required for eIF2β binding. SIGNOR-266384 0.227 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr868 GSVEMCRyDPLQDNT 9606 BTO:0000007 20304997 t lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236298 0.2 BCAR1 protein P56945 UNIPROT NAB2 protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22431919 f miannu In MCF-7 cells, we identified a positive feedback loop where p130(Cas) positively regulates EGR1 and NAB2, which in turn induce p130(Cas) expression. SIGNOR-253891 0.2 PRKACA protein P17612 UNIPROT GABBR2 protein O75899 UNIPROT down-regulates activity phosphorylation Ser893 EHIQRRLsLQLPILH 9534 BTO:0001538 11976702 t miannu Here we show that the functional coupling of GABA(B)R1/GABA(B)R2 receptors to inwardly rectifying K(+) channels rapidly desensitizes. This effect is alleviated after direct phosphorylation of a single serine residue (Ser892) in the cytoplasmic tail of GABA(B)R2 by cyclic AMP (cAMP)-dependent protein kinase (PKA). SIGNOR-263150 0.2 ATM protein Q13315 UNIPROT KHSRP protein Q92945 UNIPROT up-regulates phosphorylation Ser670 GPGAPPGsQPDYSAA 9606 21329876 t lperfetto The atm kinase directly binds to and phosphorylates ksrp, leading to enhanced interaction between ksrp and pri-mirnas and increased ksrp activity in mirna processing SIGNOR-172127 0.433 sepantronium bromide chemical CHEBI:139608 ChEBI BIRC5 protein O15392 UNIPROT down-regulates activity chemical inhibition 9606 25659731 t miannu The survivin suppressant YM155 (Sepantronium Bromide) has pre-clinical activity against a range of solid cancers and leukemias, although data in AML is limited. These data suggest that YM155-mediated inhibition of survivin is a potentially beneficial therapeutic strategy for AML, particularly paediatric disease, and warrants further evaluation. SIGNOR-262245 0.8 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT up-regulates activity phosphorylation Tyr151 KKDGLKFyTDPSYFF 9606 BTO:0000815 17623672 t WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3. SIGNOR-262299 0.564 OAT protein P04181 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI down-regulates quantity chemical modification 9606 14617280 t miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256032 0.8 AKT1 protein P31749 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 12588998 t gcesareni Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro SIGNOR-265320 0.2 LPAR4 protein Q99677 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256785 0.358 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates chemical activation 9606 16014605 t gcesareni Lpa exerts its downstream signaling by binding to the lpa(1), lpa(2), and lpa(3) (formerly edg-2, -4, and -7) family of seven-transmembrane, segmented, heterotrimeric guanine nucleotide-binding protein (g protein)-coupled receptors. SIGNOR-138585 0.8 ANK1 protein P16157 UNIPROT ATP2A1 protein O14983 UNIPROT down-regulates activity binding 9986 28487373 t lperfetto We recently reported that small ankyrin 1 (sAnk1) interacts with the sarco(endo)plasmic reticulum Ca2+-ATPase in skeletal muscle (SERCA1) to inhibit its activity. SIGNOR-265927 0.298 AATF protein Q9NY61 UNIPROT KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 23146908 t Chromatin immunoprecipitation in combination with siRNA-mediated knockdown revealed that recruitment of AATF and ZIPK to the PSA enhancer was dependent on AR, whereas recruitment of TSG101 was dependent on AATF. SIGNOR-253669 0.2 GART protein P22102 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI down-regulates quantity chemical modification 9606 11381136 t miannu The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR. SIGNOR-267303 0.8 HIF1A protein Q16665 UNIPROT KDM6B protein O15054 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271571 0.27 NFE2L3 protein Q9Y4A8 UNIPROT PLA2G7 protein Q13093 UNIPROT up-regulates quantity by expression transcriptional regulation 22247257 t lperfetto Moreover, we demonstrated that nuclear factor erythroid 2-related factor 3 (Nrf3) regulates Pla2g7 gene expression through direct binding to the promoter regions of Pla2g7 gene. SIGNOR-268979 0.371 sorafenib tosylate chemical CHEBI:50928 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR down-regulates activity chemical inhibition -1 16757355 t miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. SIGNOR-259454 0.8 DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity binding 9606 19365405 t gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. SIGNOR-185274 0.566 GNAI1 protein P63096 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding -1 11007482 t Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src SIGNOR-256526 0.464 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser312 SKSHRRTsLPCIPRE 9606 19261611 t gcesareni Phosphorylation and activation of pde3a required the activation of pkc SIGNOR-184448 0.2 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Thr293 QSAQSLAtPVVSVAT 9606 9069290 t The effect has been demonstrated using Q06413-3 lperfetto We found that in monocytic cells, lps increases the transactivation activity of mef2c through p38-catalysed phosphorylation. SIGNOR-47136 0.683 MAPK10 protein P53779 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 20220133 t gcesareni Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset. SIGNOR-164085 0.247 CASP3 protein P42574 UNIPROT CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9922454 t amattioni Caspase-3 is required for the activation of caspases 6 SIGNOR-64179 0.602 FBXO6 protein Q9NRD1 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 19716789 t miannu  Here, we report that DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint. SIGNOR-271879 0.51 MAPK1 protein P28482 UNIPROT AR protein P10275 UNIPROT down-regulates phosphorylation Ser516 VSRVPYPsPTCVKSE 9606 BTO:0001130 18511414 t gcesareni Map kinase-dependent phosphorylation at ar ser-515 was supported by the decrease in intensity of the slower migrating 23-kda band after treatment with both egf and increasing concentrations of the map kinase inhibitor, u0126 SIGNOR-178718 0.525 MAPK13 protein O15264 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 BTO:0000782 8325880 t gcesareni Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase|The present study shows that the MAP kinase has a 20-fold preference for Ser25 as opposed to Ser38 of Op18, while cdc2 kinases have a 5-fold preference for the Ser38 residue. SIGNOR-37848 0.389 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser15 FSLLRGPsWDPFRDW 9606 20626350 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. gcesareni Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27. SIGNOR-166629 0.802 EEF1A2 protein Q05639 UNIPROT Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269541 0.8 CPE protein P16870 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates activity cleavage 9606 25767437 t miannu First, OT preprohormone is produced, that will be cleaved and matured by successive enzymes. The OT gene encodes for the Pre-Pro-OT-Neurophysin I (pre-pro-hormone), which is cleaved by different enzymes to give rise to different OT intermediate forms and to the Neurophysin I, and finally to the mature amidated form that is released (Figure ​2). SIGNOR-270338 0.2 PDPK2P protein Q6A1A2 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation 9606 15505410 t gcesareni Akt to the plasma membrane where it is phosphorylated and activated by phosphoinositide-dependent kinase (pdk) 1 and pdk2. SIGNOR-252628 0.2 MMP7 protein P09237 UNIPROT DCN protein P07585 UNIPROT down-regulates quantity by destabilization cleavage Glu30 GLFDFMLeDEASGIG -1 9148753 t miannu Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues. SIGNOR-256351 0.594 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Thr336 TQTSDTAtNSTLPSA -1 7836371 t gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. SIGNOR-249686 0.2 PTEN protein P60484 UNIPROT PIK3CB protein P42338 UNIPROT down-regulates activity 9606 18794881 f lperfetto The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3)). SIGNOR-236663 0.67 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates activity phosphorylation Thr388 NQAFLGFtYVAPSVL -1 11733037 t miannu  Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities. SIGNOR-250272 0.596 SCNN1B protein P51168 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 26772908 t miannu The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na(+) ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na(+) in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity. SIGNOR-269276 0.8 PRKACA protein P17612 UNIPROT SYN2 protein Q92777 UNIPROT down-regulates activity phosphorylation Ser10 NFLRRRLsDSSFIAN -1 10571231 t miannu Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I SIGNOR-250059 0.332 MAPK1 protein P28482 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 10347142 t gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation SIGNOR-67630 0.716 PRTN3 protein P24158 UNIPROT Pr3-ANCA complex SIGNOR-C475 SIGNOR up-regulates activity binding 9606 BTO:0000133 15972951 t lperfetto ANCAs comprise a group of autoantibodies directed against proteins contained in the lysosomal compartments of neutrophils and monocytes. The primary target antigens have been identified as proteinase 3 (Pr3), a 29-kd neutral serine proteinase, and myeloperoxidase (MPO), a 140-kd protein involved in the generation of reactive oxygen species.2 To date, detection of ANCAs has proven to be a helpful diagnostic tool and many clinical studies have confirmed that Pr3-ANCA and MPO-ANCA are highly specific for Wegener's granulomatosis and microscopic polyangiitis, respectively SIGNOR-270581 0.2 SF3B1 protein O75533 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000664;BTO:0000565 25428262 f irozzo Taken together, these data show that SF3B1 knockdown results in inhibition of cell growth, induction of cell cycle arrest and impairment of erythroid differentiation in myeloid cell lines.[…]SF3B1 knockdown compared with the scramble control, suggesting that normal SF3B1 function is required for erythroid differentiation. SIGNOR-256004 0.7 SOSTDC1 protein Q6X4U4 UNIPROT WNT11 protein O96014 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242721 0.279 PRKCA protein P17252 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249285 0.426 GAST protein P01350 UNIPROT CCKBR protein P32239 UNIPROT up-regulates binding 9606 BTO:0000142 10368033 t gcesareni A segment of five amino acids in the second extracellular loop of the cck-b receptor was shown to be essential for the high affinity of the natural peptide agonits, gastrin, SIGNOR-66987 0.775 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Thr21 YGGAGGYtQSPGGFG 9606 14872059 t llicata We show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro. SIGNOR-121873 0.597 PAH protein P00439 UNIPROT tyrosine smallmolecule CHEBI:18186 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors SIGNOR-263989 0.8 MINK1 protein Q8N4C8 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates binding 9606 9230439 t miannu Herg, a human homologue of the ether-a-go-go gene of the fruitfly drosophila melanogaster, encodes aproteinthat produces the rapidly activating cardiac delayed rectifier (i[kr]). / our results show that mink physically associates with herg and that the interaction leads to increased ikr current density. SIGNOR-49869 0.288 TAGLN2 protein P37802 UNIPROT ACTB protein P60709 UNIPROT down-regulates activity binding 21577206 t lperfetto Taken together, our data propose a novel, oncogene-tumor suppressor interplay, where oncogenic PFTK1 confers HCC cell motility through inactivating the actin-binding motile suppressing function of TAGLN2 via phosphorylation. SIGNOR-265104 0.421 NOTCH proteinfamily SIGNOR-PF30 SIGNOR BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates 9606 22298955 f gcesareni Similar synergy is found in notch and bmp crosstalk: activating notch signaling enhanced bmp-induced alp activity and formation of calcified nodules in vitro. SIGNOR-254335 0.361 STK4 protein Q13043 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates phosphorylation 9606 21808241 t inferred from 70% of family members gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. SIGNOR-269859 0.627 RNF216 protein Q9NWF9 UNIPROT TIRAP protein P58753 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16968706 t miannu Triad3A promotes proteolytic degradation of adapter proteins. A, Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins. SIGNOR-271607 0.395 NR3C1 protein P04150 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates activity 10090 BTO:0000944 11742987 f inferred from 70% of family members gcesareni Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. SIGNOR-269898 0.2 PTPN3 protein P26045 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr534 NFLMDNAyFCEADAK 10029 12907755 t PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates SIGNOR-248459 0.44 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275776 0.481 ODC1 protein P11926 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI down-regulates quantity chemical modification 9606 14617280 t miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256037 0.8 FOXA2 protein Q9Y261 UNIPROT AHSG protein P02765 UNIPROT up-regulates quantity by expression transcriptional regulation 16595698 f lperfetto CCAAT enhancer binding protein beta and hepatocyte nuclear factor 3beta are necessary and sufficient to mediate dexamethasone-induced up-regulation of alpha2HS-glycoprotein/fetuin-A gene expression. SIGNOR-271676 0.235 ELOVL proteinfamily SIGNOR-PF93 SIGNOR palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267901 0.8 RBBP4 protein Q09028 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263837 0.814 TAOK2 protein Q9UL54 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 BTO:0000007 11279118 t lperfetto Suggesting that tao2 selectively activates mek3 and mek6 of the p38 pathway in intact cells SIGNOR-106462 0.656 CDK1 protein P06493 UNIPROT ORC1 protein Q13415 UNIPROT up-regulates phosphorylation Thr375 AQNEATStPHRIRRK 9606 11931757 t lperfetto Horc1p contains three (s/t)px(k/r) consensus sites for cdk phosphorylation (ser258, ser273, and thr375). These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability. SIGNOR-116329 0.621 PTPN6 protein P29350 UNIPROT CSF2RB protein P32927 UNIPROT down-regulates dephosphorylation Tyr628 PPPGSLEyLCLPAGG 9606 11812650 t gcesareni However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2. SIGNOR-114597 0.501 ATM protein Q13315 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Thr449 DDIRQNFtQLPLHKN 9606 22123827 t lperfetto Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication. SIGNOR-177801 0.384 GLI2 protein P10070 UNIPROT PPARG protein P37231 UNIPROT down-regulates BTO:0004300 29205155 f areggio Molecularly, Gli2 is the principle transcription factor in the Gli family to mediate the anti-adipogenic and anti-lipogenic effects of Hh signaling SIGNOR-256224 0.278 adenosine smallmolecule CHEBI:16335 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 18957298 t miannu Adenosine is an endogenous inhibitor of excitatory synaptic transmission with potent anticonvulsant properties in the mammalian brain. Given adenosine's important role in modulating synaptic transmission, several mechanisms exist to regulate its extracellular availability. One of these is the intracellular enzyme adenosine kinase (ADK), which phosphorylates adenosine to AMP. SIGNOR-265465 0.8 TFAP2B protein Q92481 UNIPROT ADIPOQ protein Q15848 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19325541 f miannu A transcription factor, TFAP2B, has been shown to participate in the regulation of adipocyte metabolism, by facilitating glucose uptake and lipid accumulation, while simultaneously reducing insulin sensitivity, and recently a direct function for TFAP2B as an inhibitor of adiponectin expression was observed. SIGNOR-255421 0.372 NPY protein P01303 UNIPROT NPY5R protein Q15761 UNIPROT up-regulates binding 9606 11825645 t gcesareni Npy expression significantly increases whereas the gene expression of its receptors npy1r, npy2r, and npy5r initially decreases. SIGNOR-114746 0.73 AKT proteinfamily SIGNOR-PF24 SIGNOR POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Thr235 QARKRKRtSIENRVR 9606 BTO:0004180 23041284 t flangone Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG. SIGNOR-242092 0.2 F2R protein P25116 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257011 0.4 RPS6KA3 protein P51812 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 10464286 t gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-265347 0.2 HOXD11 protein P31277 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates activity binding -1 9343407 t 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. SIGNOR-241229 0.416 RBX1 protein P62877 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR form complex binding 9606 22649780 t gcesareni The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors SIGNOR-234799 0.831 SIN3A protein Q96ST3 UNIPROT TERT protein O14746 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18505829 f miannu We investigated the mechanism of NFX1-91 repression of the hTERT promoter and demonstrated that NFX1-91 interacts with the corepressor mSin3A/HDAC to maintain the deacetylated status at the hTERT promoter, thus providing a mechanism by which NFX1-91 represses hTERT expression. SIGNOR-226363 0.311 GOLGA7 protein Q7Z5G4 UNIPROT ZDHHC9 protein Q9Y397 UNIPROT up-regulates activity binding 9606 BTO:0000007 16000296 t miannu DHHC9 and GCP16 form a protein complex, and DHHC9 requires GCP16 for protein fatty acyltransferase activity and protein stability. SIGNOR-261353 0.674 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000763 12193595 t miannu Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction. SIGNOR-91722 0.711 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT up-regulates activity phosphorylation Ser2246 SSSVHASerPLASSP -1 26051540 t irozzo Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment. SIGNOR-259118 0.452 A9/b1 integrin complex SIGNOR-C166 SIGNOR IL1B protein P01584 UNIPROT up-regulates quantity by expression 9606 24241034 f lperfetto Importantly, autocrine and paracrine interactions of α9β1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-α and IL-1β in synovial macrophages. SIGNOR-253314 0.31 MAPK12 protein P53778 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser108 LPGASPKsPGLKAMV -1 15850461 t miannu Peptide T2 was sequenced and shown to comprise residues 79–112 of CapZIP, phosphorylated at Ser-108 (Figure 2B). The identity of peptide T1 is unknown. These experiments established that the SAPK3/p38γ substrate was CapZIP. Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown). An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. SIGNOR-263083 0.518 APOBEC3H protein Q6NTF7 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 f lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). SIGNOR-261330 0.7 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT down-regulates activity phosphorylation Ser184 HPPVLRQsISFSGLP -1 14688255 t miannu We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated. SIGNOR-250153 0.686 STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12565872 t We also found that the wild type SOCS-3 promoter construct has significantly greater activity in non-small-cell lung cancer cell lines than in normal cells in accordance with STAT3 disregulation in these cells SIGNOR-253583 0.697 LYN protein P07948 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Tyr88 KGSLPEFyYRPPRPP 9606 21423214 t gcesareni We previously reported that y88 phosphorylation of p27(kip1) by oncogenic tyrosine kinases impairs p27(kip1)-mediated cdk inhibition, and initiates its ubiquitin-dependent proteasomal degradation. SIGNOR-172904 0.534 CSNK2A1 protein P68400 UNIPROT AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser285 MEVEDNRsQVETDDL 9615 BTO:0000837 11742978 t llicata We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. AQP4 phosphorylation by CKII may thus provide a mechanism that regulates AQP4 cell surface expression. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4-Cter proteins in which only one out of the three C-terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. SIGNOR-250827 0.426 TKT protein P29401 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 24929114 t miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. SIGNOR-267088 0.8 COL1A1 protein P02452 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 f Collagen is the major structural protein in skeletal muscle ECM;...Several studies suggest that perimysial collagen is predominantly type I SIGNOR-254662 0.7 CYP2R1 protein Q6VVX0 UNIPROT vitamin D smallmolecule CHEBI:27300 ChEBI down-regulates quantity chemical modification 9606 BTO:0000759 30080183 t lperfetto Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. SIGNOR-270569 0.8 DYRK1A protein Q13627 UNIPROT DNM1 protein Q05193 UNIPROT down-regulates phosphorylation Ser857 ASPSRPEsPRPPFDL 9606 BTO:0000142 15287745 t lperfetto Mnb/dyrk1a was shown to phosphorylate dynamin 1 and alter its interactions with several sh3 domain-containing endocytic accessory proteins.Phosphorylation At s795 and s857 was confirmed in full-length dynamin 1, and s857 was subsequently determined to be the major mnb/dyrk1a phosphorylation site in vitro. Phosphorylation at s857 was demonstrated to be the basis for altering the binding of dynamin 1 to amphiphysin 1 and grb 2 by site-directed mutants mimicking phosphorylation. SIGNOR-127444 0.426 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SCRIB protein Q14160 UNIPROT unknown phosphorylation Ser853 LPLLPPEsPGPLRQR 9606 BTO:0000007 20622900 t miannu HScrib is a substrate of ERK and PKA. Under normal growth conditions, hScrib is phosphorylated at S853, most likely by ERK, and at S1445 by PKA. Interestingly, stimulation of MAPK by osmotic stress results in a marked loss of phosphorylation at the PKA site S1445, but a concomitant increase in phosphorylation at S1448, presumably also by ERK. At present, we have no information as to what are the functional consequences of ERK or PKA phosphorylation of hScrib. However, we can speculate that this will most likely affect the ability of hScrib to interact with some of its cellular partners, and studies are currently in progress to investigate these aspects further. SIGNOR-263065 0.2 CTBP1 protein Q13363 UNIPROT CLDN7 protein O95471 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 19277896 t lperfetto ChIP assays revealed that SNAI1P is recruited on the CLDN7 gene promoter along with the co-repressor CtBP1 and the effector HDAC1. SIGNOR-254105 0.2 CAMK1 protein Q14012 UNIPROT PPME1 protein Q9Y570 UNIPROT up-regulates activity phosphorylation Ser15 MHLGRLPsRPPLPGS 9606 BTO:0002181 24841198 t miannu When the CaMKI activity is elevated, it phosphorylates PME-1 at Ser15. SIGNOR-276636 0.404 CUDC-907 chemical CID:54575456 PUBCHEM HDAC3 protein O15379 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191209 0.8 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser155 FPLRKTVsEPNLKLR 9606 18339811 t Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs. SIGNOR-248603 0.2 KDM3B protein Q7LBC6 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9534 16603237 t miannu We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation. SIGNOR-266636 0.2 pazopanib chemical CHEBI:71219 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 18620382 t Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. SIGNOR-257736 0.8 P2RY6 protein Q15077 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257189 0.2 SLBP protein Q14493 UNIPROT Histone H2B proteinfamily SIGNOR-PF68 SIGNOR up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265375 0.2 MAPK3 protein P27361 UNIPROT CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser1409 SAPEDPTsPKRKMRR 9606 BTO:0000848 21087211 t gcesareni Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3 SIGNOR-169879 0.382 GSK3B protein P49841 UNIPROT ATXN3 protein P54252 UNIPROT up-regulates quantity by stabilization phosphorylation Ser256 LRRAIQLsMQGSSRN 9606 BTO:0000007 17434145 t lperfetto Phosphorylation of ataxin-3 by glycogen synthase kinase 3beta at serine 256 regulates the aggregation of ataxin-3| SIGNOR-264821 0.477 CAMKK2 protein Q96RR4 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 BTO:0000567 SIGNOR-C15 19958286 t gcesareni These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo. SIGNOR-161929 0.607 MAPK10 protein P53779 UNIPROT ATN1 protein P54259 UNIPROT down-regulates activity phosphorylation Ser739 EEYETPEsPVPPARS 9606 BTO:0000142 12812981 t lperfetto Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment, SIGNOR-102394 0.2 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 22298955 t inferred from 70% family members gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps SIGNOR-270214 0.2 CPT1B protein Q92523 UNIPROT palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI down-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267127 0.8 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser795 SPYKFPSsPLRIPGG 9606 SIGNOR-C18 23336272 t gcesareni Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. SIGNOR-200487 0.928 ABL1 protein P00519 UNIPROT PDP1 protein Q9P0J1 UNIPROT down-regulates activity phosphorylation Tyr94 SILKANEySFKVPEF 10090 BTO:0000944 24962578 t miannu Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients.  SIGNOR-276641 0.271 CHUK protein O15111 UNIPROT BCL3 protein P20749 UNIPROT up-regulates activity phosphorylation Ser122 CPMEHPLsADIAMAT -1 28689659 t miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  SIGNOR-277362 0.439 furtrethonium chemical CHEBI:134764 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258645 0.8 GSK3B protein P49841 UNIPROT MAFB protein Q9Y5Q3 UNIPROT up-regulates phosphorylation 9606 18042454 t miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. SIGNOR-159473 0.2 DAB2IP protein Q5VWQ8 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity relocalization 10090 20080667 t miannu DAB2IP prevents β-catenin nuclear translocation. SIGNOR-254755 0.304 SNRPD3 protein P62318 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270662 0.733 BCR protein P11274 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260526 0.584 D-fructofuranose 6-phosphate(2-) smallmolecule CHEBI:61527 ChEBI 2-ammonio-2-deoxy-D-glucopyranose 6-phosphate(1-) smallmolecule CHEBI:58725 ChEBI up-regulates quantity precursor of 9606 21310273 t miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans SIGNOR-268098 0.8 CDC14A protein Q9UNH5 UNIPROT SPAG5 protein Q96R06 UNIPROT down-regulates activity dephosphorylation 9606 27325694 t miannu We also demonstrate that Cdc14A dephosphorylates Astrin, and therefore the overexpression of Cdc14A sequesters Astrin in the centrosome and results in aberrant chromosome alignment. SIGNOR-277066 0.2 Diprenorphine chemical CHEBI:4650 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258790 0.8 AFF2 protein P51816 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity binding 9606 17135274 t miannu Here, we provide the first evidence for a direct role of AF4 in the regulation of transcriptional elongation by RNA polymerase II (Pol II). We demonstrate that mouse Af4 functions as a positive regulator of Pol II transcription elongation factor b (P-TEFb) kinase and, in complex with MLL fusion partners Af9, Enl and Af10, as a mediator of histone H3-K79 methylation by recruiting Dot1 to elongating Pol II. These pathways are interconnected and tightly regulated by the P-TEFb-dependent phosphorylation of Af4, Af9 and Enl which controls their transactivation activity and/or protein stability. SIGNOR-266797 0.2 A11/b1 integrin complex SIGNOR-C168 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257710 0.553 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR form complex binding 9606 24816100 t miannu The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin. SIGNOR-270834 0.756 LRRK2 protein Q5S007 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000938 24916379 t lperfetto Expression of wild-type LRRK2 promoted neuronal survival against apoptosis through activation of the downstream effector, Akt by phosphorylation of Ser473. Phosphorylated Akt in turn inhibited FOXO 1 signaling SIGNOR-205115 0.387 STK39 protein Q9UEW8 UNIPROT CFTR protein P13569 UNIPROT down-regulates activity phosphorylation 10090 BTO:0000988 21317537 t lperfetto WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, SIGNOR-264643 0.352 BAIAP2 protein Q9UQB8 UNIPROT WASF2 protein Q9Y6W5 UNIPROT up-regulates activity binding 10090 BTO:0000944 11130076 t miannu Here we demonstrate that IRSp53, a substrate for insulin receptor with unknown function, is the 'missing link' between Rac and WAVE. Activated Rac binds to the amino terminus of IRSp53, and carboxy-terminal Src-homology-3 domain of IRSp53 binds to WAVE to form a trimolecular complex. From studies of ectopic expression, we found that IRSp53 is essential for Rac to induce membrane ruffling, probably because it recruits WAVE, which stimulates actin polymerization mediated by the Arp2/3 complex. SIGNOR-265556 0.794 EZH2 protein Q15910 UNIPROT SSTR1 protein P30872 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004094 22144423 f miannu For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci. SIGNOR-254143 0.2 linifanib chemical CHEBI:91435 ChEBI CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258241 0.8 ILK protein Q13418 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA -1 11313365 t miannu ILK Phosphorylates PKB/Akt on Serine 473 To become fully activated, PKB/Akt requires phosphorylation at two sites, threonine 308 and serine 473, in a phosphatidylinositol (PI) 3-kinase-dependent manner. SIGNOR-252596 0.771 OPA1 protein O60313 UNIPROT Mitochondrial_fusion phenotype SIGNOR-PH218 SIGNOR up-regulates 9606 25486875 f lperfetto OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria SIGNOR-272987 0.7 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR ID1 protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 f We show that the ID1 and ID2 promoters are activated by PML-RARα but, unexpectedly, not by wild-type RARα/RXR. In contrast, PML-RARα transactivated the promoter more than 12-fold in an ATRA-dependent fashion. SIGNOR-255728 0.2 FZD8 protein Q9H461 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 BTO:0000971 21078818 t amattioni Ligands such as Wnt1, Wnt3a, and Wnt8 couple the seven-transmembrane domain receptor Frizzled (Fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (LRP5/6) to activate Wnt–Beta-catenin signaling. SIGNOR-169635 0.717 BDKRB2 protein P30411 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257399 0.2 FPR1 protein P21462 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256682 0.41 HTR2A protein P28223 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256742 0.355 ixabepilone chemical CHEBI:63605 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates activity chemical inhibition 9606 18945860 t miannu Ixabepilone, the first drug in a new class of microtubule-stabilizing agents called epothilones, offers a new treatment option for patients with metastatic or locally advanced breast cancer who are refractory to standard chemotherapy. SIGNOR-259450 0.8 BIRC2 protein Q13490 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20651737 t lperfetto Engagement of cd40 with its ligand cd40l results in the recruitment of the TRAF3/TRAF2/cIAP Complex to the receptor. At the receptor, traf3 undergoes ciap-dependent k48-linked polyubiquitylation (ub) that targets it for proteasomal degradation. In the absence of traf3, nik protein levels accumulate as it can no longer be recruited to the TRAF2/cIAP Complex. SIGNOR-167057 0.868 STAT5A protein P42229 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15626738 t FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells SIGNOR-261552 0.266 MMP13 protein P45452 UNIPROT FGG protein P02679 UNIPROT down-regulates quantity by destabilization cleavage Tyr27 LSSTCVAyVATRDNC -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain SIGNOR-263614 0.2 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr306 TTRLKEYtIKSHSSL 9606 15611134 t lperfetto Zipk autophosphorylates in vitrowe have identified six phosphorylation sites in zipk that regulate both its enzyme activity and localization, including thr180, thr225, thr265, thr299, thr306, and ser311 SIGNOR-132475 0.2 IRF8 protein Q02556 UNIPROT NCF2 protein P19878 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001412 11483597 f miannu we found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP. SIGNOR-222789 0.297 GYPB protein P06028 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 t lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  SIGNOR-266021 0.374 FRK protein P42685 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr444 QQNRFPDyLEAIPGT 9606 BTO:0002035 35723276 t miannu Mechanistically, FRK interacted with and phosphorylated YAP on Tyr391/407/444, which recruited the classical E3 ubiquitin ligase Siah1 to catalyze ubiquitination and eventually degradation of YAP.  SIGNOR-275457 0.278 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120020 0.781 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT down-regulates activity phosphorylation Ser146 MEPERRDsQDGSSYR 9606 12571245 t lperfetto Actin binding of human lim and sh3 protein is regulated by cgmp- and camp-dependent protein kinase phosphorylation on serine 146. Phosphorylation of lasp at ser-146 leads to a redistribution of the actin-bound protein from the tips of the cell membrane to the cytosol, accompanied with a reduced cell migration SIGNOR-97938 0.311 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 17151142 f [...] TNF-alpha is critical for p38 activation during the early stages of myoblast differentiation SIGNOR-253600 0.379 VPS18 protein Q9P253 UNIPROT PLK2 protein Q9NYY3 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16203730 t miannu VPS18 Ubiquitylates SNK in Vitro and in Vivo. The ubiquitylation of proteins by hVPS18 was selectively mediated by UbcH4.  SIGNOR-271550 0.2 CDK1 protein P06493 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Thr78 KTRKTTTtPGRKPRG 9606 1939057 t lperfetto Phosphorylation of the dna-binding domain of nonhistone high-mobility group i protein by cdc2 kinase: reduction of binding affinity SIGNOR-22338 0.392 PDGFRB protein P09619 UNIPROT RASA1 protein P20936 UNIPROT up-regulates binding 9606 11896619 t miannu The gtpase activating protein (gap) of ras binds only to beta-receptors / we have previously shown that the binding site for gtpase activating protein of ras (rasgap) in the pdgf beta-receptor, tyr771, is phosphorylated to a much lower extent in the heterodimeric configuration of pdgf alpha- and beta-receptors, compared to the pdgf beta-receptor homodimer. / the decreased recruitment of the rasgap to the receptor leads to prolonged activation of the ras/map kinase pathway SIGNOR-115843 0.562 HNF1B protein P35680 UNIPROT AKR1C4 protein P17516 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003846 2044952 f 2 miannu Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene.HNF-1_ binds to the target element in the rat DBP gene in the liver, while vHNF-1 recognizes a target element in extrahepatic tissues. The ability of vHNF-1-A to activate the rat DBP gene is much higher than that of vHNF-1-C. SIGNOR-239960 0.2 PRKG1 protein Q13976 UNIPROT TRPC7 protein Q9HCX4 UNIPROT up-regulates activity phosphorylation Thr15 KNMQRRHtTLREKGR 9534 BTO:0000298 21402151 t miannu In vitro and in vivo kinase assays have revealed that cGK-Iα phosphorylates mouse TRPC7 but not mouse TRPC3. Site-directed mutagenesis analysis revealed that TRPC7 was phosphorylated by cGK-Iα at threonine 15. Phosphorylation of TRPC7 significantly suppressed carbachol-induced calcium influx and CREB phosphorylation. These data indicate that cGK-Iα interacts with and phosphorylates TRPC7, contributing to the quick and accurate regulation of calcium influx and CREB phosphorylation. SIGNOR-263184 0.2 Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT ACE2 protein Q9BYF1 UNIPROT up-regulates activity binding 9606 32201502 t miannu At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function. SIGNOR-260226 0.2 PRKCA protein P17252 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates activity phosphorylation Ser259 FPLRKTAsEPNLKVR 10116 BTO:0002320 15367659 t lperfetto We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. | Finally, we assessed the ability of PKD to phosphorylate HDAC5 in cells by employing an antibody that specifically recognizes HDAC5 that has been phosphorylated at serine 259. HDAC5 was basally phosphorylated at serine 259, and phosphorylation at this site was dramatically increased by coexpression of constitutively active PKD S/E SIGNOR-249268 0.2 SGK2 protein Q9HBY8 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 11154281 t lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. SIGNOR-249130 0.512 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 12193595 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-91742 0.738 FANCF protein Q9NPI8 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 t lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263242 0.906 RAB6B protein Q9NRW1 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 25492866 f miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons SIGNOR-266874 0.7 BACH2 protein Q9BYV9 UNIPROT XBP1 protein P17861 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005014 24821775 f miannu Expression and activity of the UPR downstream effector XBP1 is regulated positively by STAT5 and negatively by the B-cell-specific transcriptional repressors BACH2 and BCL6. SIGNOR-253756 0.394 AKT1 protein P31749 UNIPROT PLN protein P26678 UNIPROT down-regulates activity phosphorylation Thr17 SAIRRAStIEMPQQA 10090 BTO:0003265 19696029 t Akt interacts with and phosphorylates PLN at Thr(17), the Ca(2+)-calmodulin-dependent kinase IIdelta site, whereas silencing Akt signaling, through the knock-out of phosphatidylinositol-dependent kinase-1, resulted in reduced phosphorylation of PLN at Thr(17). SIGNOR-252578 0.293 CASP3 protein P42574 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261749 0.414 KIF7 protein Q2M1P5 UNIPROT GLI3 protein P10071 UNIPROT up-regulates quantity by stabilization binding 10090 19592253 t lperfetto These results suggest a role for Kif7 in coordinating Hh signal transduction at the tip of cilia and preventing Gli3 cleavage into a repressor form in the presence of Hh. SIGNOR-209614 0.559 RORA protein P35398 UNIPROT CPT1B protein Q92523 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15199055 f Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. SIGNOR-254256 0.2 CDH4 protein P55283 UNIPROT CDH2 protein P19022 UNIPROT down-regulates quantity by repression 10090 BTO:0000165 18701479 f lperfetto Taken together, these data show that (a) R-cadherin decreases the expression of M-cadherin and (b) N-cadherin and M-cadherin only slightly accumulate at the cell contacts in R-cadherin–expressing myoblasts. SIGNOR-253107 0.492 HDAC3 protein O15379 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 9606 SIGNOR-C12 23213415 t gcesareni Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes. SIGNOR-199964 0.513 hydrogen peroxide smallmolecule CHEBI:16240 ChEBI MAPK7 protein Q13164 UNIPROT up-regulates 9606 BTO:0000142 11782488 f gcesareni These findings suggest that c-src mediated bmk1 activation by h(2)o(2) may counteract ischemic cellular damage probably through the activation of mef2c transcription factor. SIGNOR-113758 0.8 TBX22 protein Q9Y458 UNIPROT DLX5 protein P56178 UNIPROT down-regulates quantity by repression transcriptional regulation 9031 BTO:0005956 20033915 t miannu the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22. SIGNOR-265566 0.312 SMAD3 protein P84022 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11689553 t lperfetto Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter. SIGNOR-251494 0.672 FES protein P07332 UNIPROT PECAM1 protein P16284 UNIPROT up-regulates activity phosphorylation Tyr690 PLNSDVQyTEVQVSS 9606 BTO:0000007 12972546 t miannu PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1. SIGNOR-262867 0.28 HECTD4 protein Q9Y4D8 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001321 32814769 t miannu We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. SIGNOR-267148 0.2 TBX3 protein O15119 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25211658 t lperfetto TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS SIGNOR-249603 0.404 E2F1 protein Q01094 UNIPROT CD2AP protein Q9Y5K6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 22880102 f lperfetto Transcriptional activation of the human CD2AP promoter by E2F1 SIGNOR-254129 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000887;BTO:0001260 20150555 t lperfetto Moreover, we showed that sp1 is a novel mitotic substrate of cdk1/cyclin b1 and is phosphorylated by it at thr 739 before the onset of mitosis. SIGNOR-216940 0.424 ceramide smallmolecule CHEBI:17761 ChEBI sphingomyelin smallmolecule CHEBI:64583 ChEBI up-regulates quantity precursor of 9606 18184806 t miannu Ceramide is a common precursor for both sphingomyelin and glycosphingolipids, which are ubiquitous components of membranes in mammalian cells and play important roles in cell growth, differentiation, and apoptosis SIGNOR-268497 0.8 IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000801 17337443 t lperfetto Analyses of embryonic fibroblasts and macrophages obtained from IRAK-4 KD mice demonstrate lack of cellular responsiveness to stimulation with IL-1beta or a Toll-like receptor 7 (TLR7) agonist. IRAK-4 kinase deficiency prevents the recruitment of IRAK-1 to the IL-1 receptor complex and its subsequent phosphorylation and degradation. SIGNOR-153458 0.673 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates quantity by destabilization phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 BTO:0002181 16046550 t miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. SIGNOR-268219 0.2 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD7 protein O15105 UNIPROT down-regulates activity ubiquitination 9606 12519765 t lperfetto Smad ubiquitin regulatory factor 1 (Smurf1), a HECT type E3 ubiquitin ligase, interacts with inhibitory Smad7 and induces translocation of Smad7 to the cytoplasm SIGNOR-253260 0.2 NOTCH proteinfamily SIGNOR-PF30 SIGNOR PAX7 protein P23759 UNIPROT up-regulates quantity by expression 9606 BTO:0001103;BTO:0002314 22493066 f gcesareni We provide evidence that notch and deltex may act on e47 by inhibiting signaling through ras because (i) full e47 activity was found to be dependent on ras and (ii) both notch and deltex inhibited gal4-jun, a hybrid transcription factor whose activity is dependent on signaling from ras to sapk/jnk. SIGNOR-254343 0.2 MDM2 protein Q00987 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 30425162 t miannu We identified PER2 as a previously uncharacterized substrate for the ubiquitin ligase mouse double minute 2 homolog (MDM2) and found that MDM2 targeted PER2 for degradation in a manner independent of PER2 phosphorylation.  SIGNOR-277421 0.363 A2/b1 integrin complex SIGNOR-C160 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269009 0.7 HSCB protein Q8IWL3 UNIPROT iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI up-regulates activity relocalization 27714045 t lperfetto Cluster transfer from ISCU to recipient apoproteins is assisted by a dedicated chaperone/cochaperone (HSPA9/HSC20) system that facilitates cluster release from the primary scaffold ISCU and transfer to recipient apoproteins or to intermediate carriers SIGNOR-262130 0.8 AR protein P10275 UNIPROT NAT1 protein P18440 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17210686 f lperfetto Induction of human arylamine N-acetyltransferase type I by androgens in human prostate cancer cells|We show that NAT1 activity is induced by R1881 in androgen receptor (AR)-positive prostate lines 22Rv1 and LNCaP SIGNOR-253684 0.2 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity precursor of 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267416 0.8 STAT3 protein P40763 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11278729 t lperfetto Coexpression of activated c-Src and Stat3 synergistically induced strong HGF promoter activity in SP1 cells SIGNOR-251742 0.607 1-[4-[1-(1,4-dioxaspiro[4.5]decan-8-yl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-pyrazolo[3,4-d]pyrimidinyl]phenyl]-3-methylurea chemical CHEBI:91364 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck;ATP-competitive inhibitor mTOR gcesareni SIGNOR-207800 0.8 NEDD4L protein Q96PU5 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 t miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). SIGNOR-253463 0.326 RALGDS protein Q12967 UNIPROT RIN1 protein Q13671 UNIPROT up-regulates activity binding 9606 10545207 t miannu Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors. SIGNOR-220923 0.51 RASGEF1B protein Q0VAM2 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-183835 0.301 SLC24A3 protein Q9HC58 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264401 0.8 BTK protein Q06187 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr224 DSNSKKIyGSQPNFN 9606 12573241 t lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. For bmx, we obtained two phosphorylated sites, y215 and y223 (fig. 6c). The bmx-y215 is a conserved tyrosine, which is homologous to btk-y223 and itk-y180 SIGNOR-98032 0.341 FOXP3 protein Q9BZS1 UNIPROT T-reg_differentiation phenotype SIGNOR-PH91 SIGNOR up-regulates 9606 15785758 f mrosina Viewed as a whole, the available data demonstrate essential involvement of Foxp3 in the development and function of CD4 + CD25 + T reg cells. SIGNOR-254970 0.7 PRKAA1 protein Q13131 UNIPROT CRTC1 protein Q6UUV9 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21331044 t gcesareni Here we show that both ampk and calcineurin modulate longevity exclusively through post-translational modification of crtc-1, the sole c. elegans crtc. We demonstrate that crtc-1 is a direct ampk target. SIGNOR-172136 0.288 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2S protein Q16763 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271309 0.763 MMP28 protein Q9H239 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272372 0.7 CAMK2A protein Q9UQM7 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser142 RKILNDLsSDAPGVP 9606 BTO:0000938 11970864 t gcesareni Phosphorylation of creb1 at ser142 and ser143 is selectively activated by ca(2+) influx;phosphorylation of ser142 and ser143, disrupts the interaction of creb with its cofactor cbp. Phosphorylation of serine 142 in creb by camkii leads to dissociation of the creb dimer. SIGNOR-117344 0.577 SIRT7 protein Q9NRC8 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity deacetylation Lys38 PATGGVKkPHRYRPG 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275882 0.2 NEK2 protein P51955 UNIPROT PPP1CC protein P36873 UNIPROT down-regulates phosphorylation Thr318 TPPRGMItKQAKK 9606 10880350 t gcesareni Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity. SIGNOR-78603 0.501 phenylalanine smallmolecule CHEBI:28044 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264758 0.7 PSMD6 protein Q15008 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263350 0.886 SRC protein P12931 UNIPROT GJA1 protein P17302 UNIPROT down-regulates phosphorylation Tyr247 VKGKSDPyHATSGAL 9606 16916748 t lperfetto The oncogenic tyrosine kinase, v-src, phosphorylates connexin43 (cx43) on y247 and y265 and inhibits cx43 gap junctional communication (gjc), the process of intercellular exchange of ions and metabolites. SIGNOR-148913 0.606 FOXO1 protein Q12778 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260101 0.261 NPFFR1 protein Q9GZQ6 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256987 0.252 WWC1 protein Q8IX03 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity 9606 BTO:0000007 20159598 f Hippo pathway Gianni These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis. SIGNOR-269951 0.454 DRD5 protein P21918 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257156 0.285 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one chemical CHEBI:94732 ChEBI MAPK10 protein P53779 UNIPROT down-regulates chemical inhibition 9606 18922779 t gcesareni Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell. SIGNOR-181644 0.8 IKBKE protein Q14164 UNIPROT IRF1 protein P10914 UNIPROT down-regulates activity phosphorylation Ser219 FQVSPMPsTSEATTD 9606 BTO:0000007 24396068 t miannu We demonstrated that IKK-ε phosphorylated the transcription factor IFN regulatory factor 1 (IRF-1) at amino acid (aa) 215/219/221 in primary CD4(+) T cells and blocked its transcriptional activity.  SIGNOR-276478 0.357 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Thr434 MSFHRNHtATVRSHA 9606 11123317 t amattioni Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation. SIGNOR-85175 0.346 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser7 sDSEEEVC -1 8972483 t llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  SIGNOR-250936 0.312 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation Ser108 WKLRARPsLTVTPRR 9606 BTO:0000567 21658950 t miannu Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis. SIGNOR-263137 0.2 PPP1CB protein P62140 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser75 LGYEPEGsASPTPPY 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248567 0.2 OBSCN protein Q5VST9 UNIPROT ANK2 protein Q01484 UNIPROT up-regulates quantity relocalization 9606 BTO:0003324 19840192 t miannu Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins. SIGNOR-266726 0.512 CADPS protein Q9ULU8 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 24363652 t miannu CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly. SIGNOR-264340 0.439 selumetinib chemical CHEBI:90227 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190191 0.8 Riluzole chemical CHEBI:8863 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258053 0.8 ME1 protein P48163 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity chemical modification 9606 24769394 t miannu The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle SIGNOR-267055 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4D protein Q08499 UNIPROT up-regulates activity phosphorylation Ser125 CRAMDRTsYAVETGH 9534 12023945 t miannu Long PDE4 isoforms from all four sub-families can be phosphorylated by protein kinase A (PKA). This leads to an increase in their activity and may thus contribute to cellular desensitization processes in cells where these isoforms are selectively expressed.These were Ser89Ala-PDE4A8, Ser133Ala-PDE4B1, Ser13Ala-PDE4C2 and Ser126Ala-PDE4D5. SIGNOR-273939 0.2 MYB protein P10242 UNIPROT GSTM1 protein P09488 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 14576818 t Functional analysis of the GSTM1 promoter using reporter assays indicated that both the DNA binding and transactivation domains of Myb were required for transcriptional activation SIGNOR-253975 0.2 MAP4K5 protein Q9Y4K4 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates 9606 9405407 f gcesareni Here we report the identification of a tnf-responsive serine/threonine protein kinase termed gck related (gckr) that likely signals via mitogen-activated protein kinase (mapk)/extracellular signal-regulated kinase (erk) kinase kinase 1 (mekk1) to activate the sapk pathway. SIGNOR-53779 0.432 PPARGC1A protein Q9UBK2 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 20404331 f lperfetto Capacity of PGC-1alpha and PGC-1beta to inhibit FoxO3 and NFkappaB actions and proteolysis helps explain how exercise prevents muscle atrophy.overexpression of PGC-1_ inhibits muscle wasting induced by denervation, starvation, and even caFoxO3 expression SIGNOR-217966 0.402 MAPKAPK2 protein P49137 UNIPROT KRT20 protein P35900 UNIPROT up-regulates activity phosphorylation Ser13 RSFHRSLsSSLQAPV -1 20724476 t miannu P38 phosphorylates the type II keratin, K8 at Ser73, whereas MK2 phosphorylates the binding partners K18 at Ser52 and K20 at Ser13. SIGNOR-263071 0.2 CDH6 protein P55285 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265868 0.56 STAT5A protein P42229 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 15498859 t lperfetto Pim-1 is know to be up regulated by signal transducer and activator of transcription 5 (stat5) SIGNOR-259436 0.421 IFNG protein P01579 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19482358 f lperfetto IFN-_ induces socs1 gene expression through an inducible factor SIGNOR-236809 0.537 uridine smallmolecule CHEBI:16704 ChEBI uridine 5'-monophosphate(2-) smallmolecule CHEBI:57865 ChEBI up-regulates quantity precursor of 11306702 t lperfetto Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. SIGNOR-275856 0.8 (S)-(-)-sulpiride chemical CHEBI:64119 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258734 0.8 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1644 SPTSPSYsPTSPSYS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248781 0.442 BRIP1 protein Q9BX63 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity binding 9606 BTO:0000093;BTO:0003323 11301010 t irozzo BRCA1 interacts in vivo with a novel protein, BACH1, a member of the DEAH helicase family. BACH1 binds directly to the BRCT repeats of BRCA1. Moreover, BACH1 likely contributes to the DNA repair function of BRCA1 []. SIGNOR-259185 0.788 Rix1 complex complex SIGNOR-C373 SIGNOR Ribosome biogenesis phenotype SIGNOR-PH164 SIGNOR up-regulates 9606 BTO:0000007 22190736 f miannu In this study, we show that LAS1L forms a protein complex with PELP1, TEX10, NOL9, SENP3, and WDR18. Our data demonstrate that all the components of the LAS1L complex cosediment with the pre-60S ribosomal particle and are required for proper processing of the 32S rRNA intermediate.These findings demonstrate that the LAS1L complex is critical for ribosome biogenesis and cell proliferation and provide additional evidence that multiple protein complexes have distinct functions in the synthesis of eukaryotic ribosomes. SIGNOR-265473 0.7 PKA proteinfamily SIGNOR-PF17 SIGNOR PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser876 QGLAERIsVL 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275950 0.2 PPP1R3B protein Q86XI6 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR up-regulates binding 9606 BTO:0000759 36551183 t miannu In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2) SIGNOR-271736 0.702 AR protein P10275 UNIPROT ARG2 protein P78540 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20711410 f The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression. This observation was correlated in vivo in patients by immunohistochemistry. SIGNOR-253671 0.265 WWTR1 protein Q9GZV5 UNIPROT TTF1 protein Q15361 UNIPROT up-regulates binding 9606 BTO:0000763 19010321 t miannu Taz is a coactivator for pax8 and ttf-1, two transcription factors involved in thyroid differentiation. / we show that this interaction leads to a significant enhancement of the transcriptional activity of pax8 and ttf-1 on the thyroglobulin promoter thus suggesting a role of taz in the control of genes involved in thyroid development and differentiation. SIGNOR-182296 0.318 SRP54 protein P61011 UNIPROT SRSF2 protein Q01130 UNIPROT up-regulates activity binding -1 8816452 t Monia We have now demonstrated that p54 interacts not only with SC35 and ASF/SF2 but also with U2AF. Pairwise interactions between p54 and other RS domain-containing spliceosomal proteins in comparison with SC35 and ASF/SF2 as detected by the yeast two-hybrid interaction assay. . It is conceivable that p54 can mediate 59 and 39 splice site interaction by interacting directly with U2AF65 associated with the 39 splice site and at the same time interact with other SR proteins, such as ASF/SF2 and SC35, which in turn interact with U1-70K. In this scenario, p54 is different from SC35 or ASF/SF2 in that it cannot directly interact with the 59 component (U1-70K) but can interact with the protein associated with the 39 splice site (U2AF65). SIGNOR-261160 0.348 AKT proteinfamily SIGNOR-PF24 SIGNOR EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 15531580 t lperfetto Purified akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an atp-dependent manner. ezrin activation after initiation of na+-glucose cotransport requires akt2 expression SIGNOR-244263 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR FGFR1 protein P11362 UNIPROT down-regulates phosphorylation 9606 23405013 t inferred from 70% family members lperfetto Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling SIGNOR-270013 0.2 FGF13 protein Q92913 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253435 0.2 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 18650425 t gcesareni Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun. SIGNOR-179551 0.377 MAGED1 protein Q9Y5V3 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000222 BTO:0000887 20646279 f gcesareni These data demonstrate for the first time that maged1 is an important factor required for proper skeletal myoblast differentiation and muscle healing. SIGNOR-166896 0.7 SLIT1 protein O75093 UNIPROT ROBO proteinfamily SIGNOR-PF14 SIGNOR up-regulates binding 9606 16226035 t gcesareni Here we describe and compare two human robo3 isoforms, robo3a and robo3b, which differ by the insertion of 26 amino acids at the n-terminus, and these forms appear to be evolutionary conserved. We investigated the bioactivity of these isoforms and show that they have different binding properties to slit. SIGNOR-141111 0.893 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates activity phosphorylation Ser475 IDIEGVQsEGQDNGA 10029 BTO:0002640 15066279 t llicata We show that inhibiting XRCC1 phosphorylation by mutation of the CK2 phosphorylation sites or preventing CK2 activity using a highly specific inhibitor ablates the rapid repair of cellular DNA single-strand breaks by XRCC1. | SIGNOR-250972 0.404 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii SIGNOR-203520 0.769 DNA_damage stimulus SIGNOR-ST1 SIGNOR CDKN2A protein Q8N726 UNIPROT up-regulates activity 9606 25101116 f lperfetto ARF: a versatile DNA damage response ally at the crossroads of development and tumorigenesis. Alternative reading frame (ARF) is a tumor suppressor protein that senses oncogenic and other stressogenic signals. It can trigger p53-dependent and -independent responses with cell cycle arrest and apoptosis induction being the most prominent ones. SIGNOR-245493 0.7 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser401 VPSDNIDsQGRNCST -1 8662852 t we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). SIGNOR-251196 0.682 CDC42 protein P60953 UNIPROT USP6 protein P35125 UNIPROT up-regulates relocalization 9606 12612085 t miannu In quiescent cells, tre17 is localized to intracellular filamentous and punctate structures in the cytoplasm, folded in an inactive conformation. Upon growth factor addition, cdc42 and rac1 become activated and recruit tre17 to the plasma membrane. Stable membrane localization of tre17 also requires polymerized actin. This recruitment process leads to a conformational change in tre17, such that the n-terminal portion of the molecule further stimulates the accumulation of cortical actin. SIGNOR-98935 0.366 PRKACA protein P17612 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser496 ATPQRSGsVSNYRSC 9606 27784766 t Luana These data indicate a novel regulatory role of PKC to inhibit AMPKα1 in human cells. As PKC activation is associated with insulin resistance and obesity, PKC may underlie the reduced Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487. | AMPK activity reported in response to overnutrition in insulin-resistant metabolic and vascular tissues. SIGNOR-259865 0.402 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser248 SVQSDIWsMGLSLVE -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-39058 0.78 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR1A protein P37288 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257461 0.8 SCF-betaTRCP complex SIGNOR-C5 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23431053 t lperfetto Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ SIGNOR-230750 0.42 CSNK2A2 protein P19784 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser357 DGSGDTSsNEEIGST -1 12107178 t llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. SIGNOR-250992 0.424 KIRREL3 protein Q8IZU9 UNIPROT CASK protein O14936 UNIPROT up-regulates activity binding 9606 BTO:0000232 33853164 t miannu A Missense De Novo Variant in the CASK-interactor KIRREL3 Gene Leading to Neurodevelopmental Disorder with Mild Cerebellar Hypoplasia. KIRREL3 is a gene important for the central nervous system development-in particular for the process of neuronal migration, axonal fasciculation, and synaptogenesis-and colocalizes and cooperates in neurons with CASK gene.  SIGNOR-269078 0.47 ATXN7 protein O15265 UNIPROT CRX protein O43186 UNIPROT down-regulates activity binding 10090 11580893 t miannu We found that ataxin-7 and CRX colocalize and coimmunoprecipitate. We observed that polyglutamine-expanded ataxin-7 can dramatically suppress CRX transactivation. SIGNOR-223226 0.625 CSNK2A2 protein P19784 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1126 TEEFSSEsDMEESKE 9606 BTO:0000938 19064667 t lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. SIGNOR-275762 0.2 NF1 protein P21359 UNIPROT HRAS protein P01112 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000938 24431436 t miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-204357 0.807 GSPT1 protein P15170 UNIPROT Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR form complex binding 9606 29735640 t miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3-guanosine triphosphate (GTP) complex. SIGNOR-270814 0.972 F8 protein P00451 UNIPROT Factor VIIIa-IXa complex SIGNOR-C320 SIGNOR form complex binding 10090 BTO:0000131 25769543 t lperfetto The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin. SIGNOR-263553 0.757 EIF1AY protein O14602 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity relocalization 9606 12514125 t lperfetto Translation initiation factor 1A (eIF1A) is predicted to bind in the decoding site of the 40S ribosome and has been implicated in recruitment of the eIF2-GTP-Met-tRNA i Met ternary complex (TC) and ribosomal scanning.  SIGNOR-269148 0.2 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 23431053 t milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity SIGNOR-201310 0.897 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120004 0.781 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates phosphorylation 9606 16837009 t gcesareni A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinasesa key step in the activation process is the phosphorylation of the activation loop of one pak kinase domain by another, but little is known about the underlying recognition events that make this phosphorylation specific. SIGNOR-147874 0.2 SEC61A2 protein Q9H9S3 UNIPROT SEC61 complex complex SIGNOR-C368 SIGNOR form complex binding -1 33925740 t lperfetto The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER SIGNOR-267728 0.642 PCM1 protein Q15154 UNIPROT NIN protein Q8N4C6 UNIPROT up-regulates relocalization 9606 12403812 t miannu Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome SIGNOR-95077 0.415 CBP/p300 complex SIGNOR-C6 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates activity acetylation 9606 9865691 t lperfetto The closely related CBP and p300 proteins are also important coactivators for Smad activity. CBP and p300 act as coactivators of several transcription factors by bringing the sequence-specific activators within proximity of the general transcription machinery and by modifying the chromatin structure through histone acetylation.In response to TGF-b, Smad3 associates with CBP/p300 and TGF-b-induced C-terminal phosphorylation of Smad3 promotes this association. This association with CBP/p300 is likely to be essential for transcriptional activity of Smad3. SIGNOR-227553 0.682 DDB2 protein Q92466 UNIPROT DDB2/DDB1 complex SIGNOR-C39 SIGNOR form complex binding 9606 9418871 t miannu Ddb was identified as a heterodimeric protein (48 and 127 kda) that binds to uv-damaged dna SIGNOR-54099 0.936 BMI1 protein P35226 UNIPROT Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR form complex binding 9606 31608994 t miannu PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b SIGNOR-266812 0.788 MYCT1 protein Q8N699 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000670;BTO:0000738 30283340 f miannu Overexpression of MYCT1 Inhibits Proliferation and Induces Apoptosis in Human Acute Myeloid Leukemia HL-60 and KG-1a Cells in vitro and in vivo SIGNOR-261729 0.7 SIAH1 protein Q8IUQ4 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates ubiquitination 9606 16174773 t lperfetto Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system SIGNOR-140612 0.662 CDKN2C protein P42773 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 8891723 t miannu The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-44601 0.875 AKT1 protein P31749 UNIPROT MAPKAP1 protein Q9BPZ7 UNIPROT up-regulates activity phosphorylation Thr86 GIRRRSNtAQRLERL 10090 BTO:0002572 26235620 t miannu Akt phosphorylates SIN1 at T86, enhancing mTORC2 kinase activity, which leads to phosphorylation of Akt S473 by mTORC2, thereby catalyzing full activation of Akt. SIGNOR-276932 0.691 APC-c complex SIGNOR-C150 SIGNOR IRS2 protein Q9Y4H2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 32554797 t miannu We conducted an unbiased proteomic screen to uncover novel substrates of the Anaphase Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that controls the abundance of key cell cycle regulators. We found that IRS2 levels are regulated by APC/C activity and that IRS2 is a direct APC/C target in G1 Consistent with the APC/C's role in degrading cell cycle regulators. Consistent with this observation, we found that APC/C inhibition decreased the polyubiquitylation of HA-tagged IRS2 in HeLa cells treated with MG132 (Fig. 2G). SIGNOR-272196 0.2 INSR protein P06213 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr576 RYMEDSTyYKASKGK -1 9507031 t P125(Fak) sequence comprising amino acids 568-582, which contains tyrosines 576 and 577 of the kinase domain regulatory loop, is phosphorylated by the insulin receptor. p125(Fak) phosphorylation by the receptor results in its activation. SIGNOR-251323 0.36 HIF1A protein Q16665 UNIPROT KDM4C protein Q9H3R0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271570 0.2 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity dephosphorylation Tyr15 EKIGEGTyGVVYKAR 9606 10454565 t The phosphatase activity of Cdc25A is necessary for Cdk2 activation, most likely due to dephosphorylation on Tyr-15 and Thr-14 of Cdk2. SIGNOR-248482 0.824 F2RL1 protein P55085 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257144 0.2 CASP8 protein Q14790 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp333 DTVAENDdGGFSEEW -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261754 0.376 PTPRB protein P23467 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t gcesareni Identification of tyrosine phosphatases that dephosphorylate the insulin receptor. SIGNOR-75997 0.35 EXOSC5 protein Q9NQT4 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-261385 0.925 ATG7 protein O95352 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 22170151 t gcesareni Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe SIGNOR-195236 0.867 DAB2IP protein Q5VWQ8 UNIPROT PROX1 protein Q92786 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27476001 f miannu DAB2IP regulates EMT and metastasis of prostate cancer through targeting PROX1 transcription and destabilizing HIF1α protein. In this study, based on different PCa cell lines and knockout mice, we showed that PROX1 could be suppressed by DAB2IP, a novel member of the Ras GTPase-activating protein family and a critical player in control of epithelial-mesenchymal transition (EMT) and PCa metastasis. SIGNOR-254764 0.2 MTHFR protein P42898 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI down-regulates quantity chemical modification 9606 10720211 t lperfetto Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine. SIGNOR-268228 0.8 AKT1 protein P31749 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 10559253 t esanto Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis. SIGNOR-252587 0.575 PELI1 protein Q96FA3 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 BTO:0002552 27248820 t miannu Notably, Pellino-1 directly interacted with cIAP2 and stabilized cIAP2 through lysine63-mediated polyubiquitination via its E3 ligase activity. SIGNOR-259395 0.466 NLRP1 protein Q9C000 UNIPROT NLRP1 inflammasome complex SIGNOR-C224 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256407 0.631 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000007 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246281 0.2 MCRS1 protein Q96EZ8 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270844 0.504 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 11896587 t llicata These findings strongly suggest that jnks are the major direct signaling mediators of uvb-induced p53 phosphorylation at serine 20. furthermore, phosphorylation of p53 at serine 20 by uvb-activated jnks and uvb-induced p53-dependent transcriptional activity were suppressed in jnk1 or jnk2 knockout (jnk1(-/-) or jnk2(-/-)) cells. SIGNOR-115831 0.789 PRPF31 protein Q8WWY3 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270643 0.777 APOA1 protein P02647 UNIPROT ABCA1 protein O95477 UNIPROT up-regulates quantity by stabilization binding 9606 12869555 t miannu ApoA-I stabilization of ABCA1 is mediated by reduced PEST sequence phosphorylation, which in turn leads to decreased calpain proteolysis of ABCA1. SIGNOR-252101 0.782 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser22 FGGPGTAsRPSSSRS -1 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248878 0.288 PTPRJ protein Q12913 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation Tyr205 IMLNSKGyTKSIDIW 9606 19494114 t gcesareni In this study we show that one of these potential targets, the erk1/2, is indeed a direct dep-1 substrate in vivo. SIGNOR-161536 0.416 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT down-regulates activity phosphorylation Ser36 ELQRRRRsLALPGLQ -1 15946941 t miannu  We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA.Phosphorylation of GRK1 and GRK7 by PKA reduces the ability of GRK1 and GRK7 to phosphorylate rhodopsin in vitro. SIGNOR-276035 0.2 PTPN5 protein P54829 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates activity dephosphorylation Tyr26 IPEGSHQyELLKHAE 9606 28675297 t miannu PTPN5 dephosphorylates\nMob1a at Y26 residue. SIGNOR-277058 0.2 RNA Polymerase III complex SIGNOR-C389 SIGNOR small nuclear RNA smallmolecule CHEBI:74035 ChEBI up-regulates quantity chemical modification 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-266144 0.8 GDNF protein P39905 UNIPROT NRN1 protein Q9NPD7 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252183 0.263 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120240 0.321 CoREST-HDAC complex complex SIGNOR-C105 SIGNOR SCN3A protein Q9NY46 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 16140033 f lperfetto This suggests that the HDACs in the LSD1 complex are likely to function upstream of CoREST/LSD1, generating a hypoacetylated histone substrate, which can then be better recognized by CoREST/LSD1. Further supporting this model, we found that inhibition of HDAC activity by TSA resulted in derepression of two LSD1 target genes, the human neuronal-specific sodium channel (SCN) genes, SCNA2 and SCNA3 (Figure 1H). SIGNOR-268542 0.252 FOXO3 protein O43524 UNIPROT DIO2 protein Q92813 UNIPROT up-regulates quantity by expression transcriptional regulation 20978344 f Forkhead box O3 (FoxO3) was identified as a key molecule inducing D2 expression and thereby increasing intracellular T3 production. Accordingly, FoxO3-depleted primary myoblasts also had a differentiation deficit that could be rescued by high levels of T3. SIGNOR-256204 0.349 PPP2CB protein P62714 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation Ser645 LNEKARLsYSDKNLI 10090 BTO:0000944 11959144 t PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex SIGNOR-248595 0.304 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR HERPUD1 protein Q15011 UNIPROT up-regulates quantity by expression 9606 10922362 f miannu We demonstrate a new target gene for upr-induced transcription, herp. SIGNOR-80156 0.7 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr504 AEPLPPSyVACS 12441334 t JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 SIGNOR-251355 0.805 CDK5R1 protein Q15078 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR form complex binding 9606 11331872 t lperfetto Induced p35 forms a complex with Cdk5 and activates its kinase activity SIGNOR-250682 0.942 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 BTO:0000782 12151396 t gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk SIGNOR-91059 0.359 AXL protein P30530 UNIPROT AXL protein P30530 UNIPROT up-regulates activity phosphorylation Tyr779 ADCLDGLyALMSRCW -1 9178760 t llicata Our data showed that various receptor substrates are at least associated with the C-terminal tyrosine pY821. Two additional potential autophosphorylation sites (pY866 and pY779) may play a minor role in binding of e€ector proteins SIGNOR-250591 0.2 SHANK3 protein Q9BYB0 UNIPROT GRIA2 protein P42262 UNIPROT up-regulates quantity binding 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264602 0.2 DHCR24 protein Q15392 UNIPROT DHCR7 protein Q9UBM7 UNIPROT up-regulates activity binding 10029 BTO:0000246 25637936 t miannu DHCR7 coimmunoprecipitates DHCR24. Overexpression of functional DHCR24 increases DHCR7 activity. Because knockdown of DHCR24 has no effect on DHCR7 mRNA (Fig. 3A), this implies that this phenomenon is occurring posttranscriptionally. Thus, the interaction between the two terminal steps of cholesterol synthesis appears to have functional consequences. SIGNOR-267249 0.638 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT down-regulates activity phosphorylation Ser14 PFSFGTLsSWELEAW 9606 BTO:0000567 12876286 t llicata CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites SIGNOR-250850 0.351 DLGAP2 protein Q9P1A6 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 9115257 t miannu SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area. SIGNOR-264210 0.692 FLT3 protein P36888 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16146838 f lperfetto Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1. SIGNOR-249635 0.621 TBXA2R protein P21731 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256744 0.252 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252854 0.908 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr806 PLLLIVEyAKYGSLR 9606 14711813 t llicata Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. these facts suggest that tyr806 and tyr809, located in this unique position, play a novel supplemental role for the activation loop upon phosphorylation. SIGNOR-121153 0.2 FYN protein P06241 UNIPROT CD300LF protein Q8TDQ1 UNIPROT up-regulates activity phosphorylation Tyr236 VDQVEVEyVTMASLP 17202342 t lperfetto Y236 (YVTM) and Y263 (YCNM) fit with the consensus motif reported to bind the p85α regulatory subunit of PI3K (16). |The association between IREM-1 and p85α was only perceived in the presence of c-Fyn, suggesting that tyrosine phosphorylation of IREM-1 cytoplasmic tail of IREM-1 was required for the interaction. SIGNOR-275619 0.35 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser197 TKSIYTRsVIDPVPA -1 10075701 t miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites SIGNOR-250226 0.2 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000551 19683496 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-187591 0.813 GSK3A protein P49840 UNIPROT ARHGAP31 protein Q2M1Z3 UNIPROT up-regulates activity phosphorylation Thr789 PPAPPPPtPLEESTP 10090 BTO:0000944 17158447 t miannu We show that GSK-3alpha and -beta interact with CdGAP in mammalian cells. We also demonstrate that GSK-3 phosphorylates CdGAP both in vitro and in vivo on Thr-776, which we have previously shown to be an ERK 1/2 phosphorylation site involved in CdGAP regulation. SIGNOR-262878 0.343 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity phosphorylation Ser865 YLSSRRSsGISPCFS 9606 10693759 t lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. SIGNOR-75347 0.445 FGF2 protein P09038 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 10116 BTO:0001130 7687739 t lperfetto The FGF-R2(IIIb) isoform displays high affinity for stromal cell-derived FGF-7, whereas the FGF-R2(IIIc) isoform does not recognize FGF-7 but has high affinity for the FGF-2 member of the FGF ligand family SIGNOR-236033 0.894 WT1 protein P19544 UNIPROT SLC29A4 protein Q7RTT9 UNIPROT up-regulates quantity by expression transcriptional regulation 18523561 t lperfetto ENT4 is transcriptionally activated by both isoforms of EWS/WT1 as evidenced by promoter-reporter and chromatin immunoprecipitation (ChIP) analyses. SIGNOR-268985 0.277 L-cysteine zwitterion smallmolecule CHEBI:35235 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. SIGNOR-275815 0.8 SRC protein P12931 UNIPROT TERT protein O14746 UNIPROT down-regulates phosphorylation Tyr707 QDPPPELyFVKVDVT 9606 12808100 t lperfetto Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via src kinase family-dependent phosphorylation of tyrosine 707 SIGNOR-102097 0.428 EIF2B1 protein Q14232 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269139 0.758 WDR59 protein Q6PJI9 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR form complex binding 9606 23723239 t miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 SIGNOR-255303 0.828 UBE3A protein Q05086 UNIPROT PSMB1 protein P20618 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 28559284 t lperfetto Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits. SIGNOR-265131 0.362 SMAD6 protein O43541 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates 10090 BTO:0000165 10564272 f gcesareni We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2 SIGNOR-236861 0.727 CSNK2A1 protein P68400 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser513 GEDEESEsD -1 9045708 t llicata Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells.  SIGNOR-250952 0.351 PHLPP2 protein Q6ZVD8 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Ser474 RTHFPQFsYSASIRE 9606 BTO:0001544 19261608 t The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. SIGNOR-248729 0.588 SMARCE1 protein Q969G3 UNIPROT Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270752 0.791 CARD11 protein Q9BXL7 UNIPROT CBM complex SIGNOR-C555 SIGNOR form complex binding 9606 15122200 t miannu CARMA1, the adaptor protein BCL-10 (B-cell lymphoma 10) and the caspase-like protein MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) form a signalling complex that has a key role in antigen-receptor-mediated activation of the nuclear factor-κB (NF-κB) and JUN N-terminal kinase (JNK) pathways. SIGNOR-276296 0.819 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Thr57 GKGVTVEtVFSVDEF -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263595 0.381 RPS6KA3 protein P51812 UNIPROT H2BC3 protein P33778 UNIPROT unknown phosphorylation Ser33 DGKKRKRsRKESYSI 9606 21646345 t lperfetto Here, we studied the histone h2b core domain and found that phosphorylation of h2b serine 32 occurs in normal cycling and mitogen-stimulated cells. Notably, this phosphorylation is elevated in skin cancer cell lines and tissues compared with normal counterparts. We identified ribosomal s6 kinase 2 (rsk2) as the kinase responsible for h2bs32 phosphorylation. SIGNOR-174026 0.2 ABL1 protein P00519 UNIPROT MTOR protein P42345 UNIPROT down-regulates phosphorylation 9606 10753870 t gcesareni Abl binds directly to raft1 and phosphorylates raft1 in vitro and in vivo. c-abl inhibits autophosphorylation of raft1 and raft1-mediated phosphorylation p70(s6k). SIGNOR-76562 0.465 ABL1 protein P00519 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity phosphorylation Tyr78 SSISTPHyEDIPFTR 10090 25368164 t We show that the tyrosine kinase Abelson murine leukemia viral oncogene (cAbl) is an adipogenic key regulator. c-Abl promotes adipogenesis by phosphorylation and subsequent stabilization of PPARγ. SIGNOR-255912 0.347 alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI up-regulates quantity precursor of 9606 8631325 t miannu UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. SIGNOR-267924 0.8 NBN protein O60934 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 18854157 t gcesareni Nbs1 can also immobilize atm at the site of the dsb via direct binding of atm to a c-terminal atm interaction motif on nbs1 . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm SIGNOR-181631 0.851 CDK8 protein P49336 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 15546612 t gcesareni Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. SIGNOR-130640 0.534 CITED2 protein Q99967 UNIPROT MMP13 protein P45452 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003859 12960175 f miannu CITED2 plays a major role in shear-induced down-regulation of MMP-1 and MMP-13 via a transforming growth factor-beta-dependent pathway. SIGNOR-253777 0.377 IL1R1 protein P14778 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 9606 9625767 f lperfetto Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab) SIGNOR-249512 0.507 MAPK10 protein P53779 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates activity phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 t miannu JNK Phosphorylation of HnRNP K Increases Its Transcriptional Activity. the primary site for JNK phosphorylation consists of serines 216 and 353 on the K protein. SIGNOR-250081 0.345 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation 9606 18243099 t amattioni Direct phosphorylation of the aurora b regulator borealin by mps1 enhances aurora b activity and is essential for chromosome alignment SIGNOR-160604 0.471 PAK2 protein Q13177 UNIPROT CASP7 protein P55210 UNIPROT down-regulates phosphorylation Ser239 WRSPGRGsWFVQALC 9606 BTO:0000150 21555521 t gcesareni Pak2 can bind with caspase-7 and phosphorylate caspase-7 at the ser-30, thr-173, and ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis. SIGNOR-173655 0.357 ASXL1 protein Q8IXJ9 UNIPROT CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 26470845 t lperfetto Tumor suppressor ASXL1 is essential for the activation of INK4B expression in response to oncogene activity and anti-proliferative signals SIGNOR-241759 0.28 LIMK2 protein P53671 UNIPROT CFL1 protein P23528 UNIPROT down-regulates activity phosphorylation Ser3 sGVAVSDG 9606 BTO:0000567 11171090 t lperfetto We report here that limk1 and limk2 phosphorylate both cofilin and actin-depolymerizing factor (adf) specifically at ser-3 and exhibit partially distinct substrate specificity when tested using site-directed cofilin mutants as substrates SIGNOR-105098 0.757 RPS6 protein P62753 UNIPROT Ribosome biogenesis phenotype SIGNOR-PH164 SIGNOR up-regulates 10090 23318442 f Luana Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program SIGNOR-264619 0.7 TAB1 protein Q15750 UNIPROT ROR2 protein Q01974 UNIPROT down-regulates phosphorylation 9606 18762249 t gcesareni Tak1 (tgf-beta activated kinase 1), a map3k, interacts with ror2 and phosphorylates its intracellular carboxyterminal serine/thronine/proline-rich (stp) domain SIGNOR-180566 0.282 JAK1 protein P23458 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 17259970 t milica Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity. SIGNOR-152914 0.516 GSK3B protein P49841 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser86 TKNGLPGsRPGSPER 9606 21658600 t gcesareni We demonstrate that gsk-3 phosphorylates serine 86 of the p53-acetyltransferase tip60. A tip60(s86a) mutant was less active to induce p53 k120 acetylation, histone 4 acetylation, and expression of puma SIGNOR-174049 0.375 lenvatinib chemical CHEBI:85994 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191457 0.8 STAT5A protein P42229 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates transcriptional regulation 9606 12540601 f fspada We have shown that stat5a is associated with the glucocorticoid receptor during adipogenesis in a highly regulated manner. SIGNOR-210146 0.7 KIF13A protein Q9H1H9 UNIPROT ZFYVE26 protein Q68DK2 UNIPROT up-regulates activity binding 9606 BTO:0000567 20208530 t miannu We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B. SIGNOR-265539 0.426 PGK2 protein P07205 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. SIGNOR-266506 0.8 TLR4 protein O00206 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001545 28137827 f miannu S100A9 induces differentiation of acute myeloid leukemia cells through TLR4. SIGNOR-261923 0.7 PTPRJ protein Q12913 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 10116 15735685 t The rat tyrosine phosphatase eta increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue SIGNOR-248705 0.621 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu59 HLERECMeETCSYEE -1 9538022 t lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). SIGNOR-263668 0.598 TRIM27 protein P14373 UNIPROT STK38L protein Q9Y2H1 UNIPROT up-regulates activity ubiquitination Lys73 RRSQHARkETEFLRL 10090 35670107 t K6 corresponds to the 6th Lysine, which is in position 73 in the full length sequence lperfetto TRIM27 catalyzes non-degradative K6- and K11-linked ubiquitination of the serine/threonine kinase 38-like (STK38L) kinase. In turn, STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination of ULK1 SIGNOR-270346 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21620960 t gcesareni Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. SIGNOR-252824 0.908 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11485553 t lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. SIGNOR-109551 0.786 ICE1 protein Q9Y2F5 UNIPROT ELL/ICE1 complex SIGNOR-C48 SIGNOR form complex binding 9606 BTO:0001271 22195968 t miannu The ell-ice complex is called lec for its proposed role in transcriptional regulation of the littlesnrna genes. SIGNOR-193486 0.553 SSH1 protein Q8WYL5 UNIPROT CFL1 protein P23528 UNIPROT up-regulates activity dephosphorylation Ser3 sGVAVSDG 9606 14531860 t Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH). SIGNOR-248762 0.778 ASXL2 protein Q76L83 UNIPROT TET2 protein Q6N021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28516957 f miannu Interestingly, this identified a number of genes known to promote leukemogenesis (either alone or in the context of AML1-ETO leukemia) as differentially expressed by ASXL2 loss. These include downregulation of TET2 as well as NOTCH2 with ASXL2 loss in human AML1-ETO-expressing cells, downregulation of which have been previously shown to functionally promote myeloid leukemogenesis when altered in expression SIGNOR-260074 0.343 CSNK2A1 protein P68400 UNIPROT STARD10 protein Q9Y365 UNIPROT down-regulates phosphorylation Ser284 GGAGGEGsDDDTSLT 9606 BTO:0002181 17561512 t gcesareni Interestingly, hypotonic extracts prepared from hek293t cells expressing the serine to alanine mutant exhibited increased lipid transfer activity compared with those from wild-type stard10-expressing cells, suggesting that, in a cellular context, phosphorylation on serine 284 negatively regulates stard10 activity SIGNOR-155740 0.384 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-52859 0.817 melatonin smallmolecule CHEBI:16796 ChEBI MTNR1B protein P49286 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257546 0.8 SRC protein P12931 UNIPROT DAPK1 protein P53355 UNIPROT down-regulates activity phosphorylation Tyr490 HCAAWHGyYSVAKAL 9606 BTO:0002181 17803936 t miannu  Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation.  SIGNOR-276074 0.276 PTPN11 protein Q06124 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. SIGNOR-252094 0.668 RPS6K proteinfamily SIGNOR-PF26 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000848 18246127 t lperfetto To understand the mechanisms underlying B-RAF effects on cell survival we initially analysed the Bcl-2 family protein, Bad, that is phosphorylated by RSK1 at the inhibitory serine-75 residue in a MEK-dependent manner in melanoma cells SIGNOR-252784 0.2 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 18636076 t gcesareni Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kda fk506- and rapamycin-binding protein (fkbp12, or fkbp) and the fkbp-rapamycin binding (frb) domain of the mammalian target of rapamycin (mtor) kinase. autophagy is negatively regulated by the mammalian target of rapamycin (mtor) and can be induced in all mammalian cell types by the mtor inhibitor rapamycin. SIGNOR-179483 0.8 CSNK2A3 protein Q8NEV1 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1124 LNTEEFSsESDMEES 9606 BTO:0000938 19064667 t lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. SIGNOR-275755 0.2 SWI/SNF complex complex SIGNOR-C92 SIGNOR CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18332116 f irozzo HSNF5 reexpression in MRT cells caused SWI/SNF recruitment and activation of p15INK4b and p16INK4a, but not of p14ARF.Reexpression of hSNF5 in MRT cells overcomes epigenetic silencing and mediates transcriptional activation of p15INK4b and p16INK4a SIGNOR-256300 0.293 RANBP3 protein Q9H6Z4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity relocalization 9606 20704570 t lperfetto Importantly, PPM1A facilitates the interaction of dephosphorylated Smad2/3 with RanBP3, a nuclear export factor [75]. As a result, PPM1A-mediated dephosphorylation of Smad2/3 promotes nuclear export of Smad2/3 and shuts off TGF-_-induced anti-proliferative and transcriptional responses SIGNOR-232107 0.398 UBE2I protein P63279 UNIPROT MITF protein O75030 UNIPROT down-regulates ubiquitination Lys308 SEARALAkERQKKDN 9606 10673502 t lperfetto Furthermore, we identified lysine 201 as a potential ubiquitination site. A lysine to arginine mutation abolished mitf (k201r) degradation by hubc9 in vivo. SIGNOR-75117 0.547 PRKCA protein P17252 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Ser72 QPRFIVYsYKYQHDD -1 9030586 t lperfetto Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively. SIGNOR-248959 0.327 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269371 0.719 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Thr325 GQLRGSAtRALPPGP 9606 BTO:0000007 10542239 t llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T SIGNOR-250811 0.2 F2RL1 protein P55085 UNIPROT SDC4 protein P31431 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254844 0.2 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914168 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161646 0.547 TBP protein P20226 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR form complex binding 29378333 t lperfetto Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1). SIGNOR-266192 0.829 MAP3K7 protein O43318 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization 9606 BTO:0000567 9480845 f lperfetto Overexpression of tak1 together with its activator protein, tak1 binding protein 1 (tab1), induced the nuclear translocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene. SIGNOR-55716 0.658 FYN protein P06241 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr753 ERDINSLyDVSRMYV -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249339 0.557 ARHGAP35 protein Q9NRY4 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260493 0.713 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser758 TSTETRSsSSESSHS 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. SIGNOR-131407 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KIF22 protein Q14807 UNIPROT up-regulates phosphorylation Thr463 QGAPLLStPKRERMV 9606 12727876 t lperfetto Cdc2-mediated phosphorylation of kid controls its distribution to spindle and chromosomes. We identify ser427 and thr463 as m phase-specific phosphorylation sites and cdc2-cyclin b as a thr463 kinase. Kid with a thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind dna or chromosomes SIGNOR-216793 0.374 pemetrexed disodium chemical CHEBI:63722 ChEBI DHFR protein P00374 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 14596699 t miannu Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT). SIGNOR-259290 0.8 MAPKAPK2 protein P49137 UNIPROT PARN protein O95453 UNIPROT down-regulates phosphorylation Ser557 NHYYRNNsFTAPSTV 9606 20932473 t lperfetto Mk2 phosphorylates parn, blocking gadd45_ mrna degradation. Parn can serve as a direct substrate for mk2, and demonstrating that ser-557 is the dominant mk2 phosphorylation site. SIGNOR-168377 0.383 Thrombin smallmolecule CHEBI:9574 ChEBI F2RL2 protein O00254 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257486 0.8 PRKDC protein P78527 UNIPROT XRCC6 protein P12956 UNIPROT up-regulates activity phosphorylation Ser33 ASGDYKYsGRDSLIF 9606 BTO:0001546 26337656 t done miannu Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks. SIGNOR-274023 0.939 MAML2 protein Q8IZL2 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12370315 f gcesareni We recently cloned a mammalian homologue of the mastermind gene of drosophila melanogaster, maml1 (mastermind-like-1 molecule) and determined that it functions as a transcriptional coactivator for notch receptors. SIGNOR-94065 0.833 PPP2CB protein P62714 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation Thr507 FGESRAStFCGTPDY 10090 BTO:0000944 11959144 t PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex SIGNOR-248594 0.304 STAT3 protein P40763 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 22378047 f IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype SIGNOR-254517 0.612 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252827 0.908 NR2F1 protein P10589 UNIPROT PCDH19 protein Q8TAB3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 34215582 t miannu We demonstrated that high expression of COUP-TFI induces MEC cell fate and protocadherin 19 expression. We next demonstrated that COUP-TFI is able to directly bind to a conserved Sp1/COUP-TFI binding site in the Pcdh19 promoter region by chromatin immunoprecipitation (ChIP) (Fig. 6, E and F). SIGNOR-267223 0.2 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr536 QKGQESEyGNITYPP -1 12468540 t gcesareni Incorporation of Pmp at the 536 site led to 4-fold stimulation of the SHP-1 tyrosine phosphatase activity whereas incorporation at the 564 site led to no effect SIGNOR-246236 0.423 PRKACA protein P17612 UNIPROT PTPN11 protein Q06124 UNIPROT down-regulates activity phosphorylation Ser189 GGGERFDsLTDLVEH 9606 BTO:0002181 25802336 t miannu  We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.  SIGNOR-276892 0.428 CDKN1B protein P46527 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 9606 8033212 f gcesareni p27Kip1, a cyclin-dependent kinase inhibitor implicated in G1 phase arrest by TGF beta and cell-cell contact. p27Kip1 associates with cyclin E-Cdk2 complexes in vivo and in vitro, prevents their activation, and inhibits previously activated complexes, and p27Kip1 overexpression obstructs cell entry into S phase. SIGNOR-241967 0.7 IRX1 protein P78414 UNIPROT KDR protein P35968 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. SIGNOR-261664 0.2 PPP2CA protein P67775 UNIPROT DCK protein P27707 UNIPROT down-regulates activity dephosphorylation Ser74 EFEELTMsQKNGGNV 24462681 t lperfetto Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation SIGNOR-275803 0.2 CDK1 protein P06493 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser613 EKKQITTsPITVRKN 9606 SIGNOR-C17 12372621 t lperfetto Warts is a serine/threonine kinase and a dynamic component of the mitotic apparatus. We have found that cdc2/cyclin b forms a complex with a fraction of warts in the centrosome and phosphorylates the ser613 site of warts during mitosisit can be speculated that phosphorylation of warts by cdc2/cyclin b promotes a protein complex formation on the mitotic apparatus at early mitosis, which may be required for subsequent activation of warts kinase at the metaphase-anaphase transition. SIGNOR-94160 0.398 ATR protein Q13535 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 11865061 t gcesareni Nhibition of atr kinase activity substantially reduces hypoxia-induced phosphorylation of p53 protein on serine 15 as well as p53 protein accumulation. SIGNOR-115134 0.731 DYRK1A protein Q13627 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser330 RLSPIMAsTELDEVQ 9606 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition. SIGNOR-183674 0.366 GABA-A proteinfamily SIGNOR-PF61 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268599 0.2 PRKCA protein P17252 UNIPROT DLX3 protein O60479 UNIPROT up-regulates activity phosphorylation Thr134 KKVRKPRtIYSSYQL -1 11343707 t lperfetto Dlx3 is primarily phosphorylated by PKC alpha. By deletion and mutational analysis, we show that the serine residue S(138), located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3. SIGNOR-249097 0.312 PRKAA1 protein Q13131 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser172 GQLVRNDsLWHRSDS 9606 26816379 t gcesareni A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission. SIGNOR-249656 0.2 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000725 21389315 f irozzo Consequently, cell cycle and apoptosis analyses suggest that MLL-AF4 conveys a selective proliferation coupled to a survival advantage, which correlates with changes in the expression of genes involved in apoptosis, sensing DNA damage and DNA repair. SIGNOR-255873 0.7 GTF2IRD1 protein Q9UHL9 UNIPROT GTF2I protein P78347 UNIPROT down-regulates 9534 BTO:0004055 11438732 f lperfetto Here we describe a repressor (MusTRD1/BEN) that appears to specifically regulate the nucleocytoplasmic shuttling of TFII-I. Nuclear exclusion of TFII-I results in a repression of its target reporter gene, and such repression can be alleviated when MusTRD1/BEN is retained in the cytoplasm through targeted mutation. SIGNOR-268534 0.426 FGF14 protein Q92915 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253437 0.26 APC-c complex SIGNOR-C150 SIGNOR CCNF protein P41002 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27653696 t miannu We show that cyclin F, a cell-cycle-regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCF(cyclin F). Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1. SIGNOR-266362 0.436 SUZ12 protein Q15022 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR form complex binding 9606 23110252 t lperfetto The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48). SIGNOR-241900 0.924 UBR5 protein O95071 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 21726808 t lperfetto Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase |UBR5 ubiquitinates the acetylated PEPCK1 SIGNOR-267600 0.313 MAPK3 protein P27361 UNIPROT RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser649 PVLYMQPsPL 9606 12620228 t llicata Erk-dependent phosphorylation of the transcription initiation factor tif-ia is required for rna polymerase i transcription and cell growth. phosphopeptide mapping and mutational analysis reveals two serine residues (s633 and s649) that are phosphorylated by erk and rsk kinases. Replacement of s649 by alanine inactivates tif-ia, inhibits pre-rrna synthesis, and retards cell growth. SIGNOR-98984 0.2 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 11875057 t gcesareni In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization. SIGNOR-115344 0.838 MCTS1 protein Q9ULC4 UNIPROT DENR protein O43583 UNIPROT up-regulates activity binding 9606 BTO:0000007 17878526 t miannu The MCT-1 protein modifies mRNA translational profiles through its interaction with DENR/DRP, a protein containing an SUI1 domain involved in recognition of the translation initiation codon.  SIGNOR-269674 0.77 MAPK3 protein P27361 UNIPROT PCYT1A protein P49585 UNIPROT down-regulates phosphorylation Ser315 GRMLQAIsPKQSPSS 9606 BTO:0000763 15788406 t gcesareni Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis. SIGNOR-134841 0.44 PTPN13 protein Q12923 UNIPROT PDCD10 protein Q9BUL8 UNIPROT down-regulates activity dephosphorylation 9606 17657516 t In addition, our yeast two-hybrid analysis revealed that CCM3 also binds to the 270-kDa nonreceptor protein tyrosine phos- phatase FAP-1 in a region predicted to contain the C- terminal phosphatase domain [23]. We have shown that this catalytic domain is capable to dephosphorylate CCM3. By dephosphorylation, FAP-1 might therefore negatively reg- ulate CCM3 activity and downstream signaling. SIGNOR-248714 0.584 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu50 RANTFLEeVRKGNLE -1 10556651 t lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. SIGNOR-263676 0.655 ATF4 protein P18848 UNIPROT HSPA5 protein P11021 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16205636 f miannu Suppression of ATF4 expression by small interfering RNA (siRNA) partially inhibited the celecoxib-dependent upregulation of GRP78. SIGNOR-253749 0.653 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 BTO:0001546 26690702 t gcesareni Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation|Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis. SIGNOR-173331 0.737 NOC3L protein Q8WTT2 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 15564382 f Fad24, a mammalian homolog of Noc3p, is a positive regulator in adipocyte differentiation SIGNOR-253060 0.7 MAPK6 protein Q16659 UNIPROT KALRN protein O60229 UNIPROT up-regulates activity phosphorylation -1 22508986 t miannu The brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. The MK5 substrate Kal7, a Rho GEF and known activator of Rac GTPases, further contributes to PAK activation and actin filament reorganization. Thus, the coordinated phosphorylation of Borg proteins and Kal7 by ERK3 and MK5 constitute a novel signaling cascade involving feed-forward circuits, multiple GTPases, and cytoskeletal elements. SIGNOR-263094 0.38 NLGN3 protein Q9NZ94 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 18923512 t brain lperfetto Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions. SIGNOR-264189 0.745 BMP1 protein P13497 UNIPROT COL1A1 protein P02452 UNIPROT up-regulates activity cleavage 9534 BTO:0000298 11283002 t miannu BMP-1myc Expressed in COS-7 Cells Exhibits Procollagen C-proteinase Activity. Bone morphogenetic protein (BMP)-1, which belongs to the tolloid subgroup of astacin-like zinc metalloproteinases, cleaves the C-propeptides of procollagen at the physiologic site and is, therefore, a procollagen C-proteinase (PCP). Cleavage occurs between a specific alanine or glycine residue (depending on the procollagen chain) and an invariant aspartic acid residue in each of the three chains of procollagen. SIGNOR-256342 0.668 SDHC protein Q99643 UNIPROT Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 30030361 t lperfetto Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites SIGNOR-262186 0.953 SLC36A4 protein Q6YBV0 UNIPROT proline smallmolecule CHEBI:26271 ChEBI up-regulates quantity relocalization 8355 21097500 t lperfetto HPAT4 in Xenopus oocytes mediated sodium-independent, electroneutral uptake of [(3)H]proline, with the highest rate of uptake when the uptake medium pH was 7.4 and an affinity of 3.13 μM. Tryptophan was also an excellently transported substrate with a similarly high affinity (1.72 μM). SIGNOR-264736 0.8 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr845 TASDGKLyVSSESRF 9606 16912036 t Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. SIGNOR-260815 0.2 CSNK1E protein P49674 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity phosphorylation Ser142 TGTESMVsHRRERAR 9606 16965538 t lperfetto Phenotypic analysis of mutant mDvl-1 indicates that phosphorylation of these sites stimulates the Dvl-activated beta-catenin-dependent Wnt signaling pathway in both cell culture and in Xenopus development. SIGNOR-217849 0.622 NCKIPSD protein Q9NZQ3 UNIPROT NCK1 protein P16333 UNIPROT unknown binding 9606 14559906 t gcesareni Such phosphorylation of spin90 likely promotes the interaction of the spin90.betapix.wasp complex and nck SIGNOR-118750 0.652 AKT proteinfamily SIGNOR-PF24 SIGNOR TAL1 protein P17542 UNIPROT down-regulates phosphorylation Thr90 EARHRVPtTELCRPP 9606 BTO:0000782;BTO:0001271 15930267 t miannu Akt phosphorylates tal1 oncoprotein and inhibits its repressor activity. / our results show that akt specifically phosphorylates thr90 of the tal1 protein within its transactivation domain in vitro and in vivo. SIGNOR-137942 0.2 trandolapril chemical CHEBI:9649 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition 10116 7527095 t miannu The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively. SIGNOR-258427 0.8 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding 9606 25875593 t irozzo C-Fos dimerizes with c-Jun to form the transcription activator protein-1 (AP-1) which binds to the specific recognition site. SIGNOR-256368 0.951 GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263809 0.8 SOSTDC1 protein Q6X4U4 UNIPROT WNT7B protein P56706 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242733 0.295 POLR2F protein P61218 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266170 0.874 vemurafenib chemical CHEBI:63637 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition 9606 23094782 t miannu Metastatic melanoma is an aggressive disease resistant to chemotherapy. Recent clinical trials have reported improved survival for two novel agents; ipilimumab, a humanized, IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and vemurafenib , a BRAF (v-raf murine sarcoma viral oncogene homolog B1) inhibitor targeting an activating mutation in the serine-threonine-protein kinase BRAF gene. SIGNOR-259281 0.8 STAT6 protein P42226 UNIPROT ARG1 protein P05089 UNIPROT up-regulates BTO:0000801 BTO:0001103 25386178 f apalma Cytokines like IL-4 or IL-13 lead to STAT6 phosphorylation with consecutive arginase expression and varying further aspects of M2 polarization (mannose receptor, Ym1, Fizz1) SIGNOR-255557 0.417 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser162 FDIVSRGsTADLDGL 9606 19661060 t Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-260885 0.2 PRKACA protein P17612 UNIPROT PLIN1 protein O60240 UNIPROT down-regulates activity phosphorylation Ser277 QAVSRRRsEVRVPWL 10090 11751901 t miannu PKA increased lipolysis in cells expressing Peri A because it abrogated the inhibitory actions of Peri A on lipolysis.‚  amino-terminal PKA sites (Ser-81, Ser-222, and Ser-276) SIGNOR-250029 0.483 BUB1 protein O43683 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates activity relocalization 11402067 t lperfetto Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity SIGNOR-252018 0.958 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD4 protein Q13485 UNIPROT down-regulates activity ubiquitination 9606 BTO:0002181 15817471 t In the presence of smad6 or smad7 acting as adaptors lperfetto Smurfs, which otherwise cannot directly bind to smad4, mediated poly-ubiquitination of smad4 in the presence of smad6 or smad7. Smad signaling is negatively regulated by inhibitory (i) smads and ubiquitin-mediated processes. SIGNOR-253259 0.2 CSNK2A1 protein P68400 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates phosphorylation Ser121 PTEEEEEsESEDSED 9606 16308564 t lperfetto Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting. SIGNOR-142343 0.2 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR4 protein P31391 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257584 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUND protein P17535 UNIPROT up-regulates phosphorylation 9606 22327296 t inferred from 70% family members gcesareni Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase. SIGNOR-270183 0.2 SNTG2 protein Q9NY99 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255995 0.522 CDK5 protein Q00535 UNIPROT EPRS1 protein P07814 UNIPROT down-regulates phosphorylation Ser886 LSQSSDSsPTRNSEP 9606 19647514 t lperfetto Ser(886) phosphorylation is required for the interaction of nsap1, which blocks eprs binding to target mrnas. The same phosphorylation event induces subsequent binding of ribosomal protein l13a and gapdh and restores mrna binding. Ifn-_ activates cdk5 to phosphorylate ser(886) in the linker domain of glutamyl-prolyl trna synthetase (eprs), the initial event in assembly of the gait complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of ser(999), the second essential event in gait pathway activation SIGNOR-187383 0.2 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates activity phosphorylation Thr183 ACTNFMMtPYVVTRY -1 11062067 t MKK7 phosphorylates SAPK2a p38 exclusively at Tyr-182. Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. SIGNOR-251417 0.622 NUP58 protein Q9BVL2 UNIPROT p62_complex complex SIGNOR-C259 SIGNOR form complex binding 10116 BTO:0000154 2050741 t Simone Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function. SIGNOR-261260 0.2 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr426 NEEWYVSyITRPEAE 9606 BTO:0000782 8702662 t lperfetto A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function SIGNOR-42976 0.797 AEP complex complex SIGNOR-C117 SIGNOR MEIS1 protein O00470 UNIPROT up-regulates quantity by expression 9606 20854876 f irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. SIGNOR-256144 0.39 CSNK2A1 protein P68400 UNIPROT EIF2B5 protein Q13144 UNIPROT up-regulates activity phosphorylation Ser717 LKEAEEEsSEDD 9606 BTO:0000007 11500362 t llicata Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.  SIGNOR-250859 0.394 VEGFD protein O43915 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 9606 9435229 t gcesareni Vegf-d is a ligand for both vegf receptors (vegfrs) vegfr-2 (flk1) and vegfr-3 (flt4) and can activate these receptors. SIGNOR-55163 0.2 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates activity phosphorylation Tyr568 EEINGNNyVYIDPTQ 9606 BTO:0001271 12824176 t lperfetto Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth./ Tyr-568 and tyr-570 are significantly phosphorylated SIGNOR-102633 0.2 PRKCD protein Q05655 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser170 SFKLSGFsFKKNKKE -1 8422248 t lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. SIGNOR-248930 0.468 TARDBP protein Q13148 UNIPROT HNRNPA1 protein P09651 UNIPROT up-regulates post transcriptional regulation 9606 BTO:0000567 29562314 t in ALS TDP-43 induces alternative splicing of HNTNPA1 which increases its pathogenic aggregation. TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis SIGNOR-262824 0.414 KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t miannu The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-156906 0.872 WDR45 protein Q9Y484 UNIPROT ATG2B protein Q96BY7 UNIPROT up-regulates activity binding 9606 BTO:0001938 28561066 t miannu WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation. SIGNOR-268484 0.668 AARS1 protein P49588 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 32314272 t miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). SIGNOR-270450 0.8 SP1 protein P08047 UNIPROT SLC19A1 protein P41440 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 15652157 f Collectively, these results identify transcriptionally important regions in the hRFC-C minimal promoter that include a GC-box and CCAAT-box, and suggest that cooperative interactions between Sp1 and C/EBP beta are essential for hRFC-C transactivation. SIGNOR-254064 0.2 NOTCH proteinfamily SIGNOR-PF30 SIGNOR IL7R protein P16871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 22577461 f lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells SIGNOR-254345 0.2 CTSG protein P08311 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Leu38 RSSKGRSlIGKVDGT -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263584 0.518 MITF protein O75030 UNIPROT ACP5 protein P13686 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0003292 11481336 f miannu The combination of MITF and PU.1 synergistically activated the TRAP promoter in transient assays. SIGNOR-254584 0.353 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 7529876 t llicata We found that maximal kinase activity of fak immune complexes requires phosphorylation of both tyrosines 576 and 577. Our results indicate that phosphorylation of fak by src (or other src family kinases) is an important step in the formation of an active signaling complex. SIGNOR-27875 0.2 MECP2 protein P51608 UNIPROT FKBP5 protein Q13451 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16002417 t Luana These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress. SIGNOR-264542 0.311 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000938 16923168 t The effect has been demonstrated using P10636-8 lperfetto Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation. SIGNOR-148974 0.462 SIM1 protein P81133 UNIPROT ARNT protein P27540 UNIPROT up-regulates activity binding -1 9020169 t 2 miannu We demonstrate that both SIM1 and SIM2 can heterodimerize via their helix-loop-helix·PAS regions with ARNT, but not with AHR, and that they do not form homodimers. Furthermore, SIM1 may have a dual role, both negatively affecting AHR·ARNT binding to the XRE and also acting in concert with ARNT as a novel DNA-binding heterodimer. SIGNOR-240759 0.546 BRD8 protein Q9H0E9 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269304 0.645 MAPK1 protein P28482 UNIPROT PAX5 protein Q02548 UNIPROT down-regulates activity phosphorylation Ser189; Ser283 SGILGITsPSADTNK;DMKANLAsPTPADIG 9606 BTO:0003079 22593617 t Gianni In this study, we demonstrated that PAX5 was phosphorylated by ERK1/2 in vitro and in vivo at serines 189 and 283. This phosphorylation attenuated the transcriptional repression of BLIMP1 by PAX5. SIGNOR-269087 0.358 PTGS2 protein P35354 UNIPROT prostaglandin H2(1-) smallmolecule CHEBI:57405 ChEBI up-regulates quantity chemical modification -1 7592599 t Luana [14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2, SIGNOR-269776 0.8 IL17A protein Q16552 UNIPROT KRT17 protein Q04695 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 21796151 f miannu IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms. SIGNOR-255232 0.349 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CASP3 protein P42574 UNIPROT down-regulates activity 9606 BTO:0002882 11684015 f lperfetto BCR/ABL Tyrosine Kinase Enhances Expression of RAD51 by Stimulation of STAT5-Mediated Transactivation and Inhibition of Caspase-3-Dependent Degradation| SIGNOR-271704 0.2 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser642 NACTLTTsPRLPVF 10090 BTO:0000944 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-249444 0.616 26S Proteasome complex SIGNOR-C307 SIGNOR oligopeptide smallmolecule CHEBI:25676 ChEBI up-regulates quantity cleavage 9606 15571818 t scontino The proteasome system is the central proteolytic system of the eukaryotic cell [1] and plays an important role in the generation of MHC-class I peptides. The enzyme complex responsible for the selectivity of intracellular protein degradation is the 26S proteasome that degrades poly-ubiquitinated substrates. SIGNOR-267768 0.8 DGC complex SIGNOR-C217 SIGNOR NRXN1 protein P58400 UNIPROT up-regulates activity binding 9606 BTO:0000142 11470830 t miannu In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan. SIGNOR-265447 0.351 NF1 protein P21359 UNIPROT HRAS protein P01112 UNIPROT down-regulates activity 9606 19777070 t NF1 negatively regulates Ras as an exchangefactor converting Ras-GTP to Ras-GDP by its GTPase-activating (Ras-GAP) domain. SIGNOR-256067 0.807 PRKACA protein P17612 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 22505454 t gcesareni Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites. SIGNOR-196961 0.341 BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9534 7791754 t fspada Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor. SIGNOR-33440 0.616 CS protein O75390 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI up-regulates quantity chemical modification 9606 3013232 t miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. SIGNOR-266240 0.8 SRC protein P12931 UNIPROT FCRL3 protein Q96P31 UNIPROT up-regulates activity phosphorylation Tyr722 EEDDEENyENVPRVL -1 12051764 t miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. SIGNOR-274009 0.2 RAB3A protein P20336 UNIPROT Dense-core_vesicle_exocytosis phenotype SIGNOR-PH184 SIGNOR up-regulates 9606 31679900 f miannu Here, we identify the SEC4 ortholog RAB3 and its neuronal effector, RIM1, as essential molecules for neuropeptide and neurotrophin release from dense-core vesicles (DCVs) in mammalian neurons.  SIGNOR-264375 0.7 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Ser376 LQESQAGsDTDVEEG 9606 18678890 t gcesareni The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites. SIGNOR-179879 0.353 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser41 SLSESEEsQDSSDSI 9606 20730097 t lperfetto We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf2 SIGNOR-167568 0.2 HBA1 protein P69905 UNIPROT CYP2E1 protein P05181 UNIPROT up-regulates activity 9606 BTO:0000575 19325051 f Regulation miannu Hemoglobin dramatically stimulated CYP 2E1 activity but not the protein expression in quercetin- and ethanol-cotreated hepatocytes. SIGNOR-251765 0.2 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258006 0.8 PYCARD protein Q9ULZ3 UNIPROT NLRP3 inflammasome complex SIGNOR-C225 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256411 0.816 AKT2 protein P31751 UNIPROT BCL3 protein P20749 UNIPROT up-regulates quantity by stabilization phosphorylation Ser41 KRPLRAPsPEPAAPR -1 28689659 t miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  SIGNOR-277359 0.273 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser33 TQSQGSSsQSQGISS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir SIGNOR-81399 0.829 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Tyr632 GRKGSGDyMPMSPKS 9606 14579029 t gcesareni Map kinases and mtor mediate insulin-induced phosphorylation ofinsulinreceptor substrate-1 on serine residues 307, 612 and 632 SIGNOR-118877 0.698 AURKB protein Q96GD4 UNIPROT NDC80 protein O14777 UNIPROT down-regulates phosphorylation Ser15 SGGAGRLsMQELRSQ 9606 20471944 t lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). SIGNOR-165554 0.841 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser291 CDVKTDDsVVPCFMK -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276199 0.388 TBX2 protein Q13207 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 24470334 f TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells SIGNOR-251563 0.7 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser12 KTLYSFFsPSPARKR 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276087 0.282 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12777400 t Manara These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386 SIGNOR-260770 0.412 BCL11A protein Q9H165 UNIPROT HBG2 protein P69892 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004911 20395365 f Regulation miannu BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. SIGNOR-251800 0.458 ACVR1B protein P36896 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 9606 11389842 t Indirect_regulation of phosphorylation miannu Nodal Induces Smad Phosphorylation through ALK4 in a Cripto-Dependent Manner SIGNOR-251943 0.794 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser12 KTLYSFFsPSPARKR 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276093 0.274 PLK1 protein P53350 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Thr151 RSYSRLEtLGSASTS -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276122 0.693 IRF4 protein Q15306 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR down-regulates 9606 22378047 f lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249561 0.7 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Leu649 NKGAIIGlMVGGVVI -1 10605825 t lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. SIGNOR-261783 0.502 DSCAM protein O60469 UNIPROT SH2D2A protein Q9NP31 UNIPROT up-regulates activity binding 9606 BTO:0000938 30745319 t miannu Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels. SIGNOR-264279 0.2 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 21205641 t lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-216457 0.469 JNK proteinfamily SIGNOR-PF15 SIGNOR HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 t lperfetto Using modified jnk and its atp analogue enables the detection of novel jnk substrates. Among substrates identified using this approach is heterogeneous nuclear ribonucleoprotein k, which is involved in transcription and post-transcriptional mrna metabolism. The newly identified substrate can be phosphorylated by jnk on amino acids 216 and 353, which contribute to heterogeneous nuclear ribonucleoprotein k mediated transcriptional activities. SIGNOR-105758 0.2 PI3K complex SIGNOR-C156 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 19436055 f apalma Low pM concentrations of GM-CSF mediate βc Ser585 phosphorylation, leading to 14-3-3 binding, PI-3 kinase activation, and hemopoietic cell survival, whereas at concentrations of 10 pM or more, GM-CSF mediates βc Tyr577 phosphorylation, Shc recruitment, and PI-3 kinase activation, thereby promoting both survival and proliferation. SIGNOR-255577 0.7 PPP1CB protein P62140 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser469 AHEENPEsILDEHVQ 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248570 0.2 MMP28 protein Q9H239 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272395 0.7 CIITA protein P33076 UNIPROT HLA-DQB1 protein P01920 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11332992 f The class II transactivator (CIITA) regulates expression of the classical and non-classical MHC class II genes, HLA-DR, -DP, -DQ and -DM, SIGNOR-254017 0.496 6-(3,4-Dimethoxyphenyl)-3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole chemical CID:661498 PUBCHEM DCTPP1 protein Q9H773 UNIPROT down-regulates activity chemical inhibition 9606 28145708 t Federica Here we report on thediscovery of a series of 3,6-disubstituted triazolothiadiazolesas potent dCTPase inhibitors. SIGNOR-261113 0.8 OPHN1 protein O60890 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity gtpase-activating protein 9606 BTO:0000938 12932438 t miannu OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro SIGNOR-268397 0.621 EFNA3 protein P52797 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52387 0.74 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 BTO:0000782;BTO:0001271 8992971 t lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor SIGNOR-45512 0.677 DLL1 protein O00548 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 23729744 t apalma The NECD undergoes O-linked glycosylation during Notch synthesis and secretion, which is crucial for proper folding of the Notch receptor and the interaction with its ligand DSL (Delta, Serrate, Lag-2)(Rana and Haltiwanger, 2011). The Notch receptor on the signal-receiving cell binds directly to ligands located on the apposing signal-sending cell SIGNOR-255369 0.626 IFNB1 protein P01574 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR up-regulates activity binding 9606 11278538 t miannu Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. SIGNOR-260335 0.762 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 93934 BTO:0000475 17431006 t lperfetto One such gene was identified, encoding steroidogenic acute regulatory protein (StAR), which showed 24-h changes in expression in the F1 follicle coinciding with those of Per2. Evidence that StAR gene expression is clock driven was obtained by showing that its 5' flanking region contains E-box enhancers that bind to CLOCK/BMAL1 heterodimers to activate gene transcription SIGNOR-253700 0.289 ROR2 protein Q01974 UNIPROT ROR2 protein Q01974 UNIPROT up-regulates binding 9606 23151663 t gcesareni Wnt5a induces homodimerization and activation of ror2 receptor tyrosine kinase SIGNOR-199588 0.2 IRF2BPL protein Q9H1B7 UNIPROT PENK protein P01210 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 17627301 t miannu EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function. SIGNOR-267155 0.313 CID 122201421 chemical CID:122201421 PUBCHEM BRD4 protein O60885 UNIPROT down-regulates activity chemical inhibition 9606 26035625 t Monia Compound MZ1 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4; These data confirmed that BRD4 is removed from the cell nuclei in a time dependent manner due to the presence of MZ1 SIGNOR-261097 0.8 CHMP3 protein Q9Y3E7 UNIPROT Viral_budding phenotype SIGNOR-PH125 SIGNOR up-regulates -1 30989108 f miannu ESCRT-III has been proposed to assemble inside the membrane neck formed at a late stage of a budding vesicle or an enveloped virus. The membrane neck needs to be constricted to proceed to membrane fission, thereby splitting the vesicle or virus from the cellular membrane. CHMP2A and CHMP3 are engaged late in ESCRT-III assembly, recruit VPS4 (31, 42), and block Snf7 (CHMP4) polymerization SIGNOR-260845 0.7 CD70 protein P32970 UNIPROT CD27 protein P26842 UNIPROT up-regulates binding 9606 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000672 8120384 t gcesareni The molecule defining the cd70 ag is identical to the recently defined ligand for cd27. Bioassays demonstrated that the cd70 cdna clone expressed in african green monkey kidney cells would induce the proliferation of pha-costimulated t cells. Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated t cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner. SIGNOR-36357 0.764 CCNA2 protein P20248 UNIPROT CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR form complex binding 9606 19056339 t lperfetto We therefore compared human cyclin a1- and cyclin a2-containing cdk complexes in vitro by determining kinetic constants and by examining the complexes for their ability to phosphorylate prb and p53. Differences in biochemical activity were observed in cdk2 but not cdk1 when complexed with cyclin a1 versus cyclin a2. Further, cdk1/cyclin a1 is a better kinase complex for phosphorylating potentially physiologically relevant substrates prb and p53 than cdk2/cyclin a2. SIGNOR-182566 0.977 AKT proteinfamily SIGNOR-PF24 SIGNOR CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr39 LKKIRLDtETEGVPS 9606 18354084 t lperfetto Akt phosphorylates cdk2 at threonine 39 residue both in vitro and in vivo. Although cdk2 threonine 39 phosphorylation mediated by akt enhances cyclin-a binding, it is dispensable for its basal binding and the kinase activity. SIGNOR-244176 0.2 PCDHA11 protein Q9Y5I1 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265670 0.2 TP53BP1 protein Q12888 UNIPROT RIF1 protein Q5UIP0 UNIPROT up-regulates activity binding 10090 23333305 t miannu RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1. Thus, RIF1 and 53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination. SIGNOR-259058 0.673 TGFB3 protein P10600 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 11157754 t miannu T?RII Is known to bind the isoforms tgf??1 And tgf??3. Binding of these ligands causes recruitment of the type i receptor (t?RI) into a signalling receptor complex followed by activation of t?RI Through transphosphorylation SIGNOR-104798 0.862 SHC1 protein P29353 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 10090 BTO:0005065 17673906 t lperfetto TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. SIGNOR-236363 0.761 Gbeta proteinfamily SIGNOR-PF4 SIGNOR LIFR protein P42702 UNIPROT down-regulates phosphorylation 9606 7777512 t inferred from 70% family members gcesareni Thus, our results identify the human lifr as a substrate for mapk and suggest a mechanism of heterologous receptor regulation of lifr signaling occurring at ser-1044. SIGNOR-270001 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser540 KVMARSLsPPPELEE 10090 BTO:0000944 15851026 t lperfetto Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation. SIGNOR-249455 0.2 FOXO3 protein O43524 UNIPROT RBL2 protein Q08999 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000944 11884591 t gcesareni Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression. SIGNOR-238606 0.295 WWP1 protein Q9H0M0 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates binding 9606 15221015 t gcesareni Wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor. SIGNOR-126128 0.72 SAGA complex complex SIGNOR-C465 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269638 0.2 ABL2 protein P42684 UNIPROT SIVA1 protein O15304 UNIPROT up-regulates phosphorylation Tyr34 RGVCAERySQEVFEK 9606 11278261 t llicata Our results also demonstrate that mutation of the siva-1 tyr48 site abrogates the apoptotic function of siva-1 and that apoptosis induced by siva-1 is dependent on expression of kinase-active arg. SIGNOR-104992 0.34 4-hydroxy-17beta-estradiol smallmolecule CHEBI:62845 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of 9606 BTO:0000093 8790407 t Luana These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens. SIGNOR-269755 0.8 AXIN1 protein O15169 UNIPROT APC protein P25054 UNIPROT up-regulates activity binding 9606 BTO:0000038 9734785 t amattioni Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level. SIGNOR-60043 0.943 metformin chemical CHEBI:6801 ChEBI CRTC2 protein Q53ET0 UNIPROT down-regulates 9606 16308421 f gcesareni It has been proposed that metformin stimulates crtc2 phosphorylation in response to metabolic signals such as energy stress through the lkb1-ampk/sik1 pathways, which promotes binding to 14-3-3 proteins, thereby sequestering crtc2 from the nucleus to the cytoplasm SIGNOR-142207 0.8 G3BP1 protein Q13283 UNIPROT DDX58 protein O95786 UNIPROT up-regulates quantity 9606 31827077 f miannu We further identified that G3BP1 is able to interact with RIG-I and boost its expression. RIG-I expression could be stabilized by G3BP1 via antagonizing RNF125-mediated RIG-I degradation. Secondly, we demonstrated that G3BP1 potentiates the self-association and auto-ubiquitination of RNF125. Hence, it is more likely that G3BP1 first promotes RNF125 degradation by enhancing self-association and auto-ubiquitination of RNF125, and then RIG-I degradation mediated by RNF125 is alleviated SIGNOR-261319 0.345 NEFH protein P12036 UNIPROT Neurofilament L/H complex SIGNOR-C208 SIGNOR form complex binding 9606 BTO:0000938 19468066 t miannu Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H SIGNOR-255273 0.447 CCL4 protein P13236 UNIPROT CCR5 protein P51681 UNIPROT up-regulates activity binding 10090 20219869 t areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.  SIGNOR-255116 0.857 RNF168 protein Q8IYW5 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 31225475 f miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. SIGNOR-266789 0.7 C3AR1 protein Q16581 UNIPROT Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 9108406 f lperfetto We report here that the anaphylatoxins C3a and C5a are chemotactic factors for the human mast cell line HMC-1, human cord blood-derived mast cells (CBMC) and cutaneous mast cells in vitro. SIGNOR-263471 0.7 SNRPD2 protein P62316 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270685 0.933 KRT1 protein P04264 UNIPROT MPO protein P05164 UNIPROT up-regulates quantity binding 9606 17591979 t Regulation of binding miannu CK1 and CK9 specifically bind MPO. MPO is internalized by endothelial cells through a direct interaction with the endothelial surface protein CK1 SIGNOR-251886 0.249 AKT proteinfamily SIGNOR-PF24 SIGNOR VIM protein P08670 UNIPROT up-regulates quantity by stabilization phosphorylation Ser39 TTSTRTYsLGSALRP 9606 20856200 t llicata The binding of akt (tail region) to vim (head region) results in vim ser39 phosphorylation enhancing the ability of vim to induce motility and invasion while protecting vim from caspase-induced proteolysis. SIGNOR-167971 0.2 alvocidib hydrochloride chemical CHEBI:90998 ChEBI CDK4 protein P11802 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192464 0.8 PRKAA1 protein Q13131 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 17900900 t gcesareni The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation SIGNOR-157947 0.355 AKAP8L protein Q9ULX6 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 11402034 f miannu These results support the proposal that both RHA and HAP95 facilitated the nuclear export of unspliced, CTE-containing mRNA in human cells. we have extended this earlier study by mapping the functional domains of HAP95 and providing strong evidence for a direct role of HAP95 in RHA-mediated nuclear export of CTE-containing mRNA. SIGNOR-260953 0.7 CALM2 protein P0DP24 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates binding 9606 11796223 t miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-266324 0.536 GART protein P22102 UNIPROT N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI up-regulates quantity chemical modification 9606 34283828 t miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). SIGNOR-267300 0.8 SLBP protein Q14493 UNIPROT H2BC3 protein P33778 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265385 0.2 CEBPD protein P49716 UNIPROT IL23A protein Q9NPF7 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 23028973 f CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. SIGNOR-254061 0.2 UVB radiation stimulus SIGNOR-ST17 SIGNOR IL1A protein P01583 UNIPROT up-regulates 9606 9767234 f miannu UVB can stimulate the synthesis of IL-1, TNF-a and ET-1, and other cytokines by keratinocytes. SIGNOR-252384 0.7 ZNF774 protein Q6NX45 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR up-regulates activity binding 9606 BTO:0000578 31659254 t miannu Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. We demonstrated that ZNF774 recruits the NuRD complex to the NOTCH2 promoter and represses NOTCH2 transcription. SIGNOR-265559 0.25 IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 17063185 t flangone Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively SIGNOR-150197 0.703 EGFR protein P00533 UNIPROT SCAMP1 protein O15126 UNIPROT up-regulates activity phosphorylation Tyr37 VPPGLDEyNPFSDSR -1 9658162 t miannu In our efforts to identify cellular tyrosine kinases that phosphorylate SCAMPs, we are quite intrigued by the observation that among a number of kinases, only the EGFR exhibits activity toward SCAMPs. EGF catalyzes the progressive phosphorylation of the SCAMPs up to 1 h poststimulation and may enhance colocalization of the EGFR and SCAMP3 within the cell interior. EGF also induces SCAMP-EGFR association, as detected by coimmunoprecipitation, and phosphorylation of SCAMP3 is stimulated by the EGFR in vitro. These results suggest that phosphorylation of SCAMPs, either directly or indirectly, may be functionally linked to the internalization/down-regulation of the EGFR. we have observed that there are two tyrosines conserved in SCAMP1 and SCAMP3, which are not found in SCAMP2. Of these two tyrosines (Tyr37 and Tyr73 in SCAMP1; Tyr 41 and Tyr83 in SCAMP3), we consider Tyr37/41 to be a more likely site for tyrosine phosphorylation SIGNOR-262857 0.341 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser146 RPSQRHGsKYLATAS -1 2413024 t lperfetto MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. SIGNOR-248870 0.502 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr285 TEADGELyVFNTPSG 9606 BTO:0000018 10734310 t miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. SIGNOR-250552 0.661 PABPC4 protein Q13310 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization binding 9606 25480299 t lperfetto As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length. SIGNOR-268319 0.8 PRKN protein O60260 UNIPROT SNCA protein P37840 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000938 12666095 t lperfetto Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei|2. Parkin-associated endothelin receptor-like receptor (Pael-R). SIGNOR-249705 0.2 HOXD13 protein P35453 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates activity binding -1 9343407 t 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. SIGNOR-241235 0.513 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 30230471 f lperfetto In keeping with the overall improvement in insulin sensitivity we found that insulin-induced IR Y1162/Y1163 tyrosine phosphorylation and activation and downstream PI3K/AKT signaling in the liver (as monitored by AKT Ser-473 phosphorylation) were dramatically enhanced by POMC TCPTP deficiency (Figure 4h).|This would suggest that TCPTP deletion, or decreased TCPTP in POMC neurons in response to feeding, represses HGP by enhancing IR signaling and permitting POMC neurons to be activated by insulin. SIGNOR-276956 0.606 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT up-regulates activity phosphorylation Tyr1102 MLEERKTyVNTTLYE 10090 BTO:0000944 12082108 t lperfetto Recently, insights into Tie2 activation were provided by a solution of the Tie2 crystal structure (12). This structural analysis revealed several novel features, including two potential autoinhibitory mechanismsIn the unphosphorylated state, the hydroxyl groups of two important tyrosine residues, Tyr1101 and Tyr1112 (murine residue numbers), are hydrogen-bonded to surrounding residues, which may stabilize the C tail in this inhibitory conformationDeletion of the Tie2 C Tail Enhances Autophosphorylation and Kinase Activity in VitroDeletion of the C tail dramatically enhanced Tie2 autophosphorylation, despite the removal of Tyr1112, which was previously shown to be an important autophosphorylation site SIGNOR-246657 0.2 SP1 protein P08047 UNIPROT PCYT1A protein P49585 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 10744779 t Luana Sp1 and Sp3 function as transcriptional activators of the Ctpct promoter SIGNOR-266231 0.2 TAL1 protein P17542 UNIPROT FUBP1 protein Q96AE4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30653565 t irozzo TAL1 directly activates the FUBP1 promoter, leading to increased FUBP1 expression during erythroid differentiation. SIGNOR-259131 0.2 Elongator complex complex SIGNOR-C466 SIGNOR TUBA3D protein P0DPH8 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 t miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. α-Tubulin Acetylation Promotes Radial Migration and Branching of Cortical Projection Neurons SIGNOR-269715 0.254 SGK1 protein O00141 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18570873 t gcesareni Activated sgk1 and p27 phosphorylation at t157, and both were inhibited by short-term rapamycin treatment and by sgk1 shrna. SIGNOR-179117 0.481 RHOA protein P61586 UNIPROT PFN1 protein P07737 UNIPROT up-regulates activity 9606 BTO:0000815 22820501 t lperfetto We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells. SIGNOR-253109 0.551 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser126 NPEAESSsKEGELDA -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276123 0.613 N-[5-[(2R)-2-methoxy-1-oxo-2-phenylethyl]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-1-piperazinyl)benzamide chemical CHEBI:94490 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191280 0.8 DAPT chemical CHEBI:86193 ChEBI APP protein P05067 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191292 0.8 EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding -1 BTO:0000567 16729043 t lperfetto We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB-receptor family in an unbiased fashion by quantitative proteomics using pull-down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K. SIGNOR-236327 0.921 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea chemical CHEBI:91327 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207296 0.8 BRCA1-A complex complex SIGNOR-C296 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR down-regulates 25400280 f lperfetto Intriguingly, another BRCA1 complex, the BRCA1–A complex, which itself contains RAP80 along with MERIT40, BRCC36/45 and Abraxas, has been reported to inhibit DNA end resection, suggesting that, in some contexts, BRCA1 may function to limit and/or prevent over resection of DNA breaks. SIGNOR-263226 0.7 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257469 0.8 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Thr1795 SRSSWRLtSSEMKKS -1 9242537 t lperfetto Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.Va treated with HNE indicated cleavage at Ala341, Ile508, and Thr1767 under conditions, which the cofactor became inactivated, as measured by prothrombinase activity. SIGNOR-263634 0.373 FLT3 protein P36888 UNIPROT SOCS2 protein O14508 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12468433 f We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling SIGNOR-261545 0.439 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr302 DYGMMSDyGTARRTG -1 11382764 t lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 SIGNOR-246504 0.92 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIA4 protein P48058 UNIPROT up-regulates activity chemical activation 9606 30825796 t miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by Œ±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses SIGNOR-264611 0.8 CSNK1A1 protein P48729 UNIPROT TIAM1 protein Q13009 UNIPROT down-regulates quantity by destabilization phosphorylation Ser329 DVNAGEGsEFADSGI 9606 BTO:0002181 25124033 t miannu Phosphorylation of Ser329, Ser334, and Thr340 in Tiam1 is required for its interaction with βTrCP1. The proteolysis of Tiam1 is prevented by βTrCP silencing, inhibition of CK1 and MEK, or mutation of the Tiam1 degron site. SIGNOR-276673 0.314 NEK6 protein Q9HC98 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser377 PPFNPNVsGPNDLRH -1 12023960 t miannu In contrast, we demonstrate for the first time that NEK6 phosphorylates SGK1 efficiently at its hydrophobic motif in vitro and peptide-mapping analysis indicates that this is the major site of phosphorylation (Fig 3). Ser377 is a more minor site of phosphorylation located in the kinase domain of SGK1, which has not been reported to undergo phosphorylation previously. the phosphorylation of the hydrophobic motif of SGK1 in vitro, coupled with the phosphorylation of the T-loop with PDK1, may be a useful way of generating fully active wild type SGK1 SIGNOR-262954 0.344 LRP6 protein O75581 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity relocalization 9606 12897152 t amattioni The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism. SIGNOR-104493 0.829 SMAD6 protein O43541 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates binding 9606 SIGNOR-C85 12857866 t gcesareni Smad6 also inhibits bmp signaling by forming a complex with smad1 and by interfering with complex formation between smad1 and smad4 SIGNOR-103621 0.561 SH2B1 protein Q9NRF2 UNIPROT CD79A protein P11912 UNIPROT down-regulates activity dephosphorylation 9606 32323266 t scontino SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK. SIGNOR-268457 0.2 SRD5A1 protein P18405 UNIPROT 17beta-hydroxy-5alpha-androstan-3-one smallmolecule CHEBI:16330 ChEBI up-regulates quantity chemical modification 9606 15861399 t miannu Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5Œ±-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions. SIGNOR-251534 0.8 PRKCH protein P24723 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 t lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization. SIGNOR-202792 0.2 GSK3B protein P49841 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser114 EEDHVDLsLSCTLVP 9606 BTO:0000093 17283049 t lperfetto Glycogen synthase kinase 3beta phosphorylates p21waf1/cip1 for proteasomal degradation after uv irradiationhere, we show that ser-114 phosphorylation of p21 protein by glycogen synthase kinase 3beta (gsk-3beta) is required for its degradation in response to uv irradiation SIGNOR-152941 0.41 MT-ND1 protein P03886 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. SIGNOR-262143 0.806 MRPL49 protein Q13405 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262347 0.688 regorafenib chemical CHEBI:68647 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259214 0.8 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 10942774 t lperfetto Mammalian target of rapamycin-dependent phosphorylation of phas-i in four (s/t)p sites detected by phospho-specific antibodies. SIGNOR-236702 0.753 Quadazocine chemical CID:115077 PUBCHEM OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258420 0.8 PRKCD protein Q05655 UNIPROT G6PD protein P11413 UNIPROT up-regulates phosphorylation Thr236 NIACVILtFKEPFGT 9606 BTO:0001260 20649491 t lperfetto A pkc activator, significantly increased g6pd phosphorylation and activity, whereas single (s210a, t266a) and double (s210a/t266a) mutations at sites flanking the g6pd active site significantly inhibited phosphorylation, shifted the isoelectric point, and reduced enzyme activity. SIGNOR-167053 0.2 CEBPB protein P17676 UNIPROT GDF15 protein Q99988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 24086573 t Promoter analysis and chromatin immunoprecipitation analysis revealed that CEBPB could contribute to K7174-mediated transcriptional activation of GDF15. SIGNOR-254050 0.279 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000776 10207047 t lperfetto The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation. SIGNOR-235881 0.965 estramustine chemical CHEBI:4868 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation 9606 14755680 t miannu A variety of new estrogenic/anti‐estrogenic/selective estrogen receptor modulator (SERM)‐like compounds, including 2‐methoxyestradiol, genistein, resveratrol, licochalcone, Raloxifene, ICI 182,780, and estramustine are being evaluated for their potential in the next generation of PCa therapies. SIGNOR-259296 0.8 CHEK1 protein O14757 UNIPROT TLK2 protein Q86UE8 UNIPROT down-regulates activity phosphorylation Ser750 PHIRKSVsTSSPAGA -1 12955071 t miannu Chk1 phosphorylates GST-fusion fragments of TLK1 in vitro.When Chk1 protein was depleted in cells transfected with pSuper-Chk1, TLK activity was not suppressed after short aphidicolin treatment of S-phase cells (Figure 8a, b). SIGNOR-262740 0.272 glutaryl-CoA(5-) smallmolecule CHEBI:57378 ChEBI glutarate(2-) smallmolecule CHEBI:30921 ChEBI up-regulates quantity precursor of 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271811 0.8 SWI/SNF complex complex SIGNOR-C92 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 33941852 f Multi-subunit ATPase-dependent chromatin remodelling complexes SWI/SNF (switch/sucrose non-fermentable) are fundamental epigenetic regulators of gene transcription.  SIGNOR-268623 0.7 TAF9 protein Q16594 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263920 0.605 ARVCF protein O00192 UNIPROT ERBIN protein Q96RT1 UNIPROT up-regulates activity binding 9606 BTO:0000938 11821434 t miannu We characterized the interactions between the Erbin PDZ domain and both ARVCF and δ-catenin in vitro and in vivo. endogenous δ-catenin and Erbin co-localized in and co-immunoprecipitated from neurons. These results suggest that δ-catenin and ARVCF may function to mediate the association of Erbin with the junctional cadherin-catenin complex. SIGNOR-252119 0.2 PAMPs stimulus SIGNOR-ST11 SIGNOR FCN2 protein Q15485 UNIPROT up-regulates activity binding -1 11907111 t lperfetto H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. SIGNOR-263407 0.7 LPAR5 protein Q9H1C0 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256861 0.394 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Ser192 HMTNNKGsAAWMAPE -1 20538596 t lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-232153 0.2 WDR83 protein Q9BRX9 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates binding 9606 15118098 t lperfetto Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex. SIGNOR-244964 0.513 PPARGC1A protein Q9UBK2 UNIPROT CYCS protein P99999 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000443 23021218 f lperfetto PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). SIGNOR-253097 0.389 afatinib chemical CHEBI:61390 ChEBI ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0002058 24643470 t miannu This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. SIGNOR-259443 0.8 KLF9 protein Q13886 UNIPROT SIN3A protein Q96ST3 UNIPROT up-regulates activity binding 10029 BTO:0000246 11438660 t miannu detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A. SIGNOR-222434 0.456 FAM83G protein A6ND36 UNIPROT CSNK1A1L protein Q8N752 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 t miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. SIGNOR-273753 0.343 MEPCE protein Q7L2J0 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR down-regulates activity binding 10090 BTO:0002572 32048991 t miannu JMJD6 cleaves MePCE. we propose that JMJD6 is the cognate protease of MePCE and cleaves at the R171 site within MePCE. Experiments using purified JMJD6 showed that it could make a cut in an enzyme called MePCE, which belongs to the group of proteins that hold P-TEFb in its inactive form. The levels of activated Pol II were lower in cells without JMJD6 and higher in those without MePCE. Together, the results suggest that JMJD6 cuts MePCE to release P-TEFb, which then activates Pol II. SIGNOR-261038 0.564 vorinostat chemical CHEBI:45716 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257950 0.8 TP53 protein P04637 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14985507 t gcesareni Northern blot analysis with a specific probe demonstrates an increase in siah-1b transcription on activation of endogenous and inducible exogenous p53. To explore whether this effect is directly mediated by p53 we analyzed 20 kb of chromosome x dna, containing the siah-1b locus. A p53-binding site was identified in the siah-1b promoter, located at nucleotides -2155/-2103 relative to the translational start site. SIGNOR-122986 0.381 R547 chemical CID:6918852 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258272 0.8 SOD1 protein P00441 UNIPROT KARS1 protein Q15046 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0004055 18715867 t P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction) In the presence of mutant SOD1, mitoKARS displays a high propensity to misfold and aggregate prior to its import into mitochondria, becoming a target for proteasome degradation. SIGNOR-262800 0.2 IKBKB protein O14920 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR form complex binding 9606 20300203 t gcesareni The kinase(s) responsible for the phosphorylation of the ikb inhibitors remained elusive for many years, until the biochemical purification of a cytoplasmic high-molecular weight complex migrating around 700900 kda and containing two related catalytic subunits, ikkalfa and ikkbeta. SIGNOR-164509 0.809 MYC protein P01106 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000785 20551174 f lperfetto In tissue culture, ectopic expression of Myc suppresses the cell cycle arrest that occurs in response to several anti-mitogenic signals such as transforming growth factor β (TGFβ), since Myc represses expression of the cyclin-dependent kinase inhibitors (CKIs) p15ink4b, p21cip1, and p57kip2 via interaction with Miz1 SIGNOR-267574 0.771 PIM1 protein P11309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr198 PGLRRRQt 9606 18593906 t gcesareni We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro.|Pim kinases promote cell cycle progression and tumorigenesis by down-regulating p27(Kip1) expression at both transcriptional and posttranslational levels. SIGNOR-179300 0.39 PKN1 protein Q16512 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF 9606 BTO:0000150 12560069 t lperfetto Furthermore, estrogen induced phosphorylation and perinuclear localization of the cell survival forkhead transcription factor fkhr in the cytoplasm in a pak1-dependent manner. In addition, pak1 directly interacted with fkhr and phosphorylated it. The noticed phosphorylation-dependent exclusion of fkhr from the nucleus impaired the ability of fkhr to activate its target fas ligand promoter containing the fkhr binding motif (fre) in cells treated with estrogen or expressing catalytically active pak1. SIGNOR-252968 0.2 2-chloro-5-(2-phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)phenol chemical CHEBI:93773 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 12970777 t gcesareni The raf inhibitor l-779,450. This raf inhibitor was less effective on b-raf- or mek1-responsive cells, demonstrating the specificity of this drug. SIGNOR-100358 0.8 GPR55 protein Q9Y2T6 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256670 0.2 MAPK1 protein P28482 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001573 17671177 t gcesareni Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin. SIGNOR-157162 0.469 CIB1 protein Q99828 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR down-regulates activity binding 9606 BTO:0000132 16418530 t lperfetto In response to agonist stimulation, the alphaIIbbeta3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. This process contributes to both normal hemostasis and thrombosis. Activation of alphaIIbbeta3 is believed to occur in part via engagement of the beta3 cytoplasmic tail with talin; however, the role of the alphaIIb tail and its potential binding partners in regulating alphaIIbbeta3 activation is less clear. We report that calcium and integrin binding protein 1 (CIB1), which interacts directly with the alphaIIb tail, is an endogenous inhibitor of alphaIIbbeta3 activation; overexpression of CIB1 in megakaryocytes blocks agonist-induced alphaIIbbeta3 activation, whereas reduction of endogenous CIB1 via RNA interference enhances activation. CIB1 appears to inhibit integrin activation by competing with talin for binding to alphaIIbbeta3, thus providing a model for tightly controlled regulation of alphaIIbbeta3 activation. SIGNOR-253357 0.416 RAD51AP1 protein Q96B01 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity binding 9606 17996711 t miannu Homologous recombination (HR) repairs chromosome damage and is indispensable for tumor suppression in humans. RAD51 mediates the DNA strand-pairing step in HR. RAD51 associated protein 1 (RAD51AP1) is a RAD51-interacting protein whose function has remained elusive. Biochemical and cytological results show that RAD51AP1 functions at a step subsequent to the assembly of the RAD51-ssDNA nucleoprotein filament. Purified RAD51AP1 binds both dsDNA and a D loop structure and, only when able to interact with RAD51, greatly stimulates the RAD51-mediated D loop reaction. SIGNOR-261962 0.761 PPP3CC protein P48454 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity dephosphorylation Ser637 VPVARKLsAREQRDC 9606 18838687 t When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. SIGNOR-248506 0.265 PRKCD protein Q05655 UNIPROT CREBBP protein Q92793 UNIPROT unknown phosphorylation Ser437 CLPLKNAsDKRNQQT 11463380 t lperfetto This study demonstrates that transcriptional control of mitogen-responsive genes by AP-1 and Pit-1 response elements involves direct phosphorylation of CBP and that growth factor€“dependent phosphorylation of CBP within the GF box is indispensable for signaling via these sites.  SIGNOR-249104 0.374 FOXO proteinfamily SIGNOR-PF27 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT down-regulates 9606 16308421 f gcesareni Foxo1 antagonized ppargamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner. SIGNOR-252915 0.2 MAPK3 protein P27361 UNIPROT CCDC6 protein Q16204 UNIPROT up-regulates activity phosphorylation Ser244 QPVSAPPsPRDISME 9606 BTO:0000007 14712216 t miannu We have characterized the H4(D10S170) gene product, showing that it is a ubiquitously expressed 55 KDa nuclear and cytosolic protein that is phosphorylated following serum stimulation. This phosphorylation was found to depend on mitogen-activated protein kinase (MAPK) Erk1/2 activity and to be associated to the relocation of H4(D10S170) from the nucleus to the cytosol. S244 is the major target residue of ERK1 SIGNOR-276003 0.374 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser104 GKGSQPPsPPSPAPS 9606 20305697 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-164617 0.574 SERPING1 protein P05155 UNIPROT F12 protein P00748 UNIPROT down-regulates activity binding 9606 BTO:0000131 26707513 t lperfetto C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1). SIGNOR-263517 0.63 CSNK1G2 protein P78368 UNIPROT CERT1 protein Q9Y5P4 UNIPROT down-regulates phosphorylation Ser132 SSLRRHGsMVSLVSG 9606 BTO:0000567 BTO:0000975 19005213 t lperfetto These results indicate that ckigamma2 hyperphosphorylates the serine-repeat motif of cert, thereby inactivating cert and down-regulating the synthesis of sphingomyelin. SIGNOR-182160 0.2 EPHB1 protein P54762 UNIPROT CASKIN1 protein Q8WXD9 UNIPROT up-regulates activity phosphorylation Tyr336 TGNDRVGyFPSSLGE 9534 23181695 t miannu EphB1 phosphorylates Caskin1 on tyrosine 296 and 336. Tyrosine phosphorylated Caskin1 then likely promotes reorganization of the actin cytoskeleton leading to spine formation. SIGNOR-262861 0.287 ITCH protein Q96J02 UNIPROT GLI1 protein P08151 UNIPROT down-regulates ubiquitination 9606 BTO:0001573 17115028 t gcesareni The consequent activation of_ itch, together with the recruitment of gli1 through direct binding with_ numb, allows gli1 to enter into the complex, resulting in gli1 ubiquitination and degradation. we demonstrate that the hedgehog transcription factor gli1 is targeted by numb for itch-dependent ubiquitination, which suppresses hedgehog signals, thus arresting growth and promoting cell differentiation SIGNOR-150847 0.56 EFNA1 protein P20827 UNIPROT EPHA1 protein P21709 UNIPROT up-regulates binding 9606 9576626 t tpavlidou Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity SIGNOR-56898 0.824 AARS1 protein P49588 UNIPROT alanine smallmolecule CHEBI:16449 ChEBI down-regulates quantity chemical modification 9606 32314272 t miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). SIGNOR-270446 0.8 TLE1 protein Q04724 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates activity binding -1 19460168 t Our data shows that Groucho/TLE repression requires two sites of interaction in LEF-1 and that a central, conserved amino acid sequence within the primary region (F S/T/P/xx y I/L/V) is critical. SIGNOR-260109 0.677 MAPKAPK5 protein Q8IW41 UNIPROT RHEB protein Q15382 UNIPROT down-regulates activity phosphorylation Ser130 LHMERVIsYEEGKAL 9606 BTO:0000007 21336308 t miannu Phosphorylation of Rheb at Ser 130 by PRAK impairs the nucleotide-binding ability of Rheb and inhibits Rheb-mediated mTORC1 activation.  SIGNOR-276313 0.411 SIRT7 protein Q9NRC8 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity deacetylation Lys19 TGGKAPRkQLATKAA 22722849 t lperfetto SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. SIGNOR-275874 0.2 CHFR protein Q96EP1 UNIPROT HLTF protein Q14527 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 20388495 t miannu CHFR functions as a ubiquitin ligase for HLTF to regulate its stability and functions. CHFR negatively regulates and ubiquitinates HLTF. Taken together, this is the first report identifying the regulatory mechanism of HLTF by CHFR, suggesting that CHFR-mediated downregulation of HLTF may help protect against cancer. SIGNOR-271460 0.495 CSNK2A1 protein P68400 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity phosphorylation Ser838 LVFDYEGsGSEAASL 10090 BTO:0000944 10671552 t llicata Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. | All mutants showed a clear reduction in phosphorylation. Phosphorylation was completely abolished in the single mutant S855A and the double mutant S853/855A, and phosphorylation in S840A and S853A mutants was reduced to 43 and 28% that of wt GST-ECT. | Expression of the E-cadherin double mutant S853A/S855A in NIH3T3 cells expressing Wnt-1 reduces cell-cell adhesion. SIGNOR-250839 0.41 TGFBR2 protein P37173 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates phosphorylation Ser345 RGDGSGFsL 9606 BTO:0004183 15761148 t lperfetto We demonstrate that Par6, a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGFbeta receptors and is a substrate of the type II receptor, TbetaRII. [...] These data suggest that T_RII phosphorylates Par6 at its penultimate residue, Ser345. SIGNOR-227484 0.443 RBBP8 protein Q99708 UNIPROT BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR up-regulates activity relocalization 24832651 t lperfetto DNA damage activates ATM and CHK2 kinases, which mediate phosphorylation of CtIP and BRCA1. Phosphorylated CtIP associates with BRCA1 and with the MRN complex leading to the recruitment of the BRCC complex at the site of DNA damage where HR is initiated. SIGNOR-263202 0.592 SREBF1 protein P36956 UNIPROT MTTP protein P55157 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11111091 f miannu SREBP1 increased the expression of MTP and increased the assembly and secretion of VLDL containing apo B100. SIGNOR-252113 0.424 SYBU protein Q9NX95 UNIPROT STX1A protein Q16623 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 15459722 t miannu Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes. SIGNOR-264812 0.432 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser144 DSPALEVsDSESDEA 9606 10618498 t lperfetto Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability SIGNOR-73883 0.439 GPC4 protein O75487 UNIPROT WNT5A protein P41221 UNIPROT up-regulates binding 9606 22302992 t gcesareni Gpc4 bound to wnt3a and wnt5a which activate the beta-catenin-dependent and -independent pathways, respectively, and colocalized with wnts on the cell surface. Expression of gpc4 enhanced the wnt3a-dependent beta-catenin pathway and the wnt5a-dependent beta-catenin-independent pathway, and knockdown of gpc4 suppressed both pathways SIGNOR-195752 0.381 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18339811 t Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. SIGNOR-248649 0.322 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI orotidine 5'-phosphate(3-) smallmolecule CHEBI:57538 ChEBI up-regulates quantity precursor of 9606 2912371 t miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). SIGNOR-267435 0.8 mTORC2 complex SIGNOR-C2 SIGNOR FBXW8 protein Q8N3Y1 UNIPROT up-regulates quantity by stabilization phosphorylation Ser85 DVASRSRsPLAREGA 10090 BTO:0002572 23142081 t miannu MTORC2 stabilizes Fbw8 by phosphorylation at Ser86 SIGNOR-271940 0.267 RPS15A protein P62244 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262436 0.849 PRKCD protein Q05655 UNIPROT CYTH1 protein Q15438 UNIPROT unknown phosphorylation Thr395 RKKKVSStKRH 9606 BTO:0001948 11438522 t lperfetto We show here that a serine/threonine motif within the short polybasic stretch of cytohesin-1 is phosphorylated by purified protein kinase C delta in vitro. Furthermore, the respective residues are also found to be phosphorylated after phorbol ester stimulation in vivo. Biochemical and functional analyses show that phosphorylated cytohesin-1 is able to tightly associate with the actin cytoskeleton, and we further demonstrate that phosphorylation of the protein is required for maximal leukocyte function antigen-1-mediated adhesion of Jurkat cells to intercellular adhesion molecule 1.  SIGNOR-249099 0.329 TBL1Y protein Q9BQ87 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates quantity by destabilization binding 9606 18374649 t Luana TBL1 interacts in vivo with CtBP and promote its proteasomal degradation SIGNOR-260902 0.2 PTPN1 protein P18031 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation 9606 15632081 t gcesareni Whereas insulin-induced phosphatidylinositol 3-kinase/akt signaling was prolonged in both tcptp-/- and ptp1b-/- immortalized mouse embryo fibroblasts (mefs), mitogen-activated protein kinase erk1/2 signaling was elevated only in ptp1b- mefs SIGNOR-132959 0.732 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr753 ERDINSLyDVSRMYV 9606 BTO:0000776 11507089 t lperfetto These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2. SIGNOR-109754 0.769 MAP2K2 protein P36507 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Thr202 HDHTGFLtEYVATRW 9606 BTO:0000142 1411546 t gcesareni The primary structure of mek, a protein kinase that phosphorylates the erk gene product SIGNOR-19240 0.732 CDK1 protein P06493 UNIPROT VCPIP1 protein Q96JH7 UNIPROT down-regulates activity phosphorylation Ser768 TPTKAPYsPTTSKEK 23500464 t lperfetto We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97.  SIGNOR-265038 0.518 TGFBR1 protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 18922473 t gcesareni We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38 and its carboxyl TRAF homology domain physically interacts with TGF-² receptors SIGNOR-241918 0.438 TGFB1 protein P01137 UNIPROT PAX6 protein P26367 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001874 17251190 f Regulation miannu The effect of TGFbeta on Pax6 expression was studied in the FHL124 lens epithelial cell line and was found to cause up to a 50% reduction in Pax6 mRNA levels within 24 h. Pax6-stimulated activity of the Pax6 promoter is repressed by TGFβ signalling. SIGNOR-251874 0.277 MSTN protein O14793 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates activity binding 10090 11459935 t gcesareni The purified C-terminal myostatin dimer was capable of binding the activin type II receptors, Act RIIB and, to a lesser extent, Act RIIA SIGNOR-235153 0.662 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 25838379 f lperfetto The highly divergent ribosomes of human mitochondria (mitoribosomes) synthesize 13 essential proteins of oxidative phosphorylation complexes. SIGNOR-262333 0.7 PPP1R9B protein Q96SB3 UNIPROT TIAM1 protein Q13009 UNIPROT up-regulates quantity binding 9534 BTO:0000298 12531897 t miannu Spinophilin binding promotes the plasma membrane localization of Tiam1 and enhances the ability of Tiam1 to activate p70 S6 kinase. SIGNOR-269175 0.432 CCNK protein O75909 UNIPROT CyclinK/CDK13 complex SIGNOR-C38 SIGNOR form complex binding 9606 22012619 t miannu We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells SIGNOR-176786 0.915 LTB protein Q06643 UNIPROT LTBR protein P36941 UNIPROT up-regulates activity binding 9606 BTO:0000782 BTO:0000975 7995952 t lperfetto These experiments point toward the lt-alpha 1/beta 2 complex as the predominant membrane form of lt on the lymphocyte surface, and this complex is the primary ligand for the lt-beta receptor. SIGNOR-35759 0.838 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr307 MRHVSISyDIPPTPG -1 10734310 t lperfetto Gab1 is also phosphorylated in response to epidermal growth factor (egf) but is unable to induce tubule formation. nine tyrosines are phosphorylated by both receptors. Three of them (y307, y373, y407) bind phospholipase c-gamma (plc-gamma). SIGNOR-233233 0.751 TAF1A protein Q15573 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR form complex binding 9606 30693017 t lperfetto SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation. SIGNOR-269566 0.818 FUBP1 protein Q96AE4 UNIPROT PMAIP1 protein Q13794 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19637194 f irozzo FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In particular, elevated expression of the Bcl-2 family members Bik and Noxa was detected. SIGNOR-259128 0.2 SREBF1 protein P36956 UNIPROT FASN protein P49327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 t gcesareni Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk) SIGNOR-142294 0.509 USP5 protein P45974 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0002181 26912724 t miannu  Wnt signaling activation inhibits FoxM1 phosphorylation by GSK3-Axin complex and leads to interaction between FoxM1 and deubiquitinating enzyme USP5, thereby deubiquitination and stabilization of FoxM1. SIGNOR-277210 0.358 PPP2R1A protein P30153 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR form complex binding 9606 23454242 t gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. SIGNOR-243436 0.906 SF3B1 protein O75533 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270653 0.824 RNF216 protein Q9NWF9 UNIPROT TLR8 protein Q9NR97 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 31385713 t miannu E3 ligase RNF216 (ring finger protein 216) targets TLR8 for ubiquitination and degradation.  SIGNOR-272257 0.26 EDNRB protein P24530 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257166 0.413 PRKAB2 protein O43741 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 16054041 t gcesareni Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. SIGNOR-139167 0.854 NFATC3 protein Q12968 UNIPROT GPC6 protein Q9Y625 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21871017 t miannu NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype. SIGNOR-264024 0.2 AMPK complex SIGNOR-C15 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 11069105 t lperfetto Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. SIGNOR-216623 0.392 FLT3 protein P36888 UNIPROT SPI1 protein P17947 UNIPROT down-regulates quantity by repression transcriptional regulation 16146838 f lperfetto Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1. SIGNOR-249634 0.61 PCDH15 protein Q96QU1 UNIPROT TMC1 protein Q8TDI8 UNIPROT up-regulates activity binding 9606 BTO:0000007 BTO:0000630 25114259 t lperfetto Although several studies show that the tip links, composed of PCDH15 and CDH23, are required for normal mechanotransduction, it is unclear how they are coupled to the transduction machinery. Likewise, it has been demonstrated that the transmembrane channel-like proteins TMC1 and TMC2 are required for mechanosensitive responses in hair cells, but how they interact with other components of the mechanotransduction complex is not known. Here, we show that TMC1 and TMC2 can interact with PCDH15, thereby establishing a critical connection between the tip link and these putative components of the mechanotransduction channel in hair cells. SIGNOR-262582 0.461 PRKACA protein P17612 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity 10090 BTO:0000011 20638365 f Here we showed that cAMP-induced activation of protein kinase A (PKA) and Akt is essential for the transcriptional activation of PPAR-gamma SIGNOR-253019 0.2 NANOG protein Q9H9S0 UNIPROT GATA2 protein P23769 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 f miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. SIGNOR-254625 0.356 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PDE4D protein Q08499 UNIPROT down-regulates phosphorylation 9606 10828059 t The effect has been demonstrated using Q08499-2 gcesareni These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro. SIGNOR-270069 0.2 ARRB1 protein P49407 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity relocalization 21296876 t lperfetto Internalization of the Na(+)/H(+) exchanger NHE5 into recycling endosomes is enhanced by the endocytic adaptor proteins beta-arrestin1 and -2, best known for their preferential recognition of ligand-activated G protein-coupled receptors (GPCRs) SIGNOR-275505 0.41 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates activity phosphorylation Ser505 SPVAGVHsPMASSGN 9606 BTO:0000093 15383283 t miannu P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators. SIGNOR-250103 0.506 H3-3A protein P84243 UNIPROT Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR form complex binding 9606 15776021 t miannu Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes. SIGNOR-263876 0.2 RUNX2 protein Q13950 UNIPROT TNFSF11 protein O14788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 f gcesareni In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast SIGNOR-107242 0.488 SOD1 protein P00441 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates 10090 BTO:0004488 29371591 t P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction) Incubating SOD1G93A or SOD1G85R, another well-established misfolded SOD1 mutant, in the absence of recombinant MIF resulted in an exponential increase in thioflavin T (ThT) fluorescence (which correlates with amyloid aggregate formation) SIGNOR-262796 0.7 GSK3B protein P49841 UNIPROT TSC2 protein P49815 UNIPROT up-regulates activity phosphorylation 10116 BTO:0003293 16959574 t lperfetto Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation. SIGNOR-149380 0.72 AT9283 chemical CID:11696609 PUBCHEM JAK3 protein P52333 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190020 0.8 WDFY3 protein Q8IZQ1 UNIPROT ATG5 protein Q9H1Y0 UNIPROT up-regulates quantity binding 9606 BTO:0000452 20417604 t miannu Alfy is recruited to intracellular inclusions and scaffolds a complex between p62(SQSTM1)-positive proteins and the autophagic effectors Atg5, Atg12, Atg16L and LC3. Alfy directly interacts with Atg5 and can be found in a complex with Atg5, Atg12 and Atg16L SIGNOR-266791 0.616 HMGCS2 protein P54868 UNIPROT acetoacetyl-CoA smallmolecule CHEBI:15345 ChEBI down-regulates quantity chemical modification 29597274 t lperfetto Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis SIGNOR-267659 0.8 PIK3CG protein P48736 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates chemical modification 9606 21779497 t gcesareni The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2) SIGNOR-175244 0.8 CCNY protein Q8ND76 UNIPROT CDK14 protein O94921 UNIPROT up-regulates binding 9606 20059949 t gcesareni L63 and its vertebrate homolog pftk are regulated by the membrane tethered g2/m cyclin, cyclin y, which mediates binding to and phosphorylation of lrp6. SIGNOR-162920 0.824 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser291 EKDASKKsDSNPLTE 9534 23519612 t miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. SIGNOR-262710 0.323 DYRK1B protein Q9Y463 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates phosphorylation Tyr271 CQLGQRIyQYIQSRF 9606 10910078 t lperfetto Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site SIGNOR-79806 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 18722121 t lperfetto Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity SIGNOR-252794 0.473 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Ser68 LRDAIRQsNQILRER 9606 SIGNOR-C14 SIGNOR-C14 17977820 t lperfetto In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I SIGNOR-158659 0.962 SRF protein P11831 UNIPROT NKX3-1/SRF complex SIGNOR-C25 SIGNOR form complex binding 9606 BTO:0000887;BTO:0001260 10993896 t lperfetto A novel complex element containing a juxtaposed nkx-binding site (nke) and an srf-binding element (sre) in the proximal promoter region was found to be necessary for the nkx3-1/srf coactivation of smga transcription. SIGNOR-82090 0.405 PRKCA protein P17252 UNIPROT IL2RA protein P01589 UNIPROT unknown phosphorylation Ser268 WQRRQRKsRRTI 9606 BTO:0000782 2303462 t lperfetto The interleukin-2 (il-2) receptor, the leukocyte-specific membrane glycoprotein, t200, and the class i major histocompatibility antigens (hla) have been identified as substrates for protein kinase c from these studies, it was concluded that ser-247 is the major site of phosphorylation in the il-2 receptor and that thr-250 is a minor site. SIGNOR-22984 0.267 9-HODE chemical CHEBI:72651 ChEBI GPR132 protein Q9UNW8 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257501 0.8 CSNK2A2 protein P19784 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates activity phosphorylation Ser421 IACEEEFsDSEEEGE 9606 BTO:0000661 11602581 t llicata Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser(421) and Ser(423), were unambiguously identified. Loss of phosphorylation at Ser(421) and Ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of HDAC1. SIGNOR-250999 0.407 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 9606 21205641 t lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-216461 0.469 PRKCA protein P17252 UNIPROT CREBBP protein Q92793 UNIPROT down-regulates phosphorylation 9606 20577053 t gcesareni The action of metformin was shown to be mediated through activation of apkc?/?, Which phosphorylates cbp at ser436, and disrupts the transcriptionally active creb-cbp-crtc2 complex, SIGNOR-166368 0.263 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 15735019 t miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates SIGNOR-150492 0.634 ING1 protein Q9UK53 UNIPROT CASP3 protein P42574 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001938 15662138 f miannu Ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells. SIGNOR-254489 0.261 PKA proteinfamily SIGNOR-PF17 SIGNOR NLRP3 protein Q96P20 UNIPROT down-regulates activity phosphorylation Ser295 HKIVRKPsRILFLMD -1 27548431 t miannu PKA directly phosphorylated the cytoplasmic receptor NLRP3 and attenuated its ATPase function. We found that Ser295 in human NLRP3 was critical for rapid inhibition and PKA phosphorylation. SIGNOR-277274 0.2 2-cyclohexyl-6-methoxy-N-(1-propan-2-yl-4-piperidinyl)-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine chemical CHEBI:95074 ChEBI EHMT2 protein Q96KQ7 UNIPROT down-regulates activity chemical inhibition -1 26320100 t miannu Using a small-molecule screen, we found that UNC0638, a selective inhibitor of EHMT1 and EHMT2 histone methyltransferases, induces γ-globin expression. SIGNOR-262240 0.8 RXRB protein P28702 UNIPROT RARB protein P10826 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. SIGNOR-16677 0.651 PDPK1 protein O15530 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 15175348 t gcesareni The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation. SIGNOR-125176 0.258 NUDCD2 protein Q8WVJ2 UNIPROT PAFAH1B1 protein P43034 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 20133715 t miannu The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. However, little is known about the regulation of LIS1. Here, we identify a previously uncharacterized mammalian homolog of Aspergillus NudC, NudCL2 (NudC-like protein 2), as a regulator of LIS1. NudCL2 is localized to the centrosome in interphase, and spindle poles and kinetochores during mitosis, a pattern similar to the localization of LIS1 and cytoplasmic dynein. Depletion of NudCL2 destabilized LIS1 and led to phenotypes resembling those of either dynein or LIS1 deficiency. NudCL2 complexed with and enhanced the interaction between LIS1 and Hsp90. Either disruption of the LIS1-Hsp90 interaction with the C terminus of NudCL2 or inhibition of Hsp90 chaperone function by geldanamycin decreased LIS1 stability. SIGNOR-252167 0.451 A6/b1 integrin complex SIGNOR-C164 SIGNOR UTF1 protein Q5T230 UNIPROT up-regulates quantity by expression 10090 18757303 f lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. SIGNOR-253281 0.257 GALR1 protein P47211 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256830 0.428 glutamic acid smallmolecule CHEBI:18237 ChEBI MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity chemical activation 9606 25042998 t miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate SIGNOR-264688 0.8 MAP3K7 protein O43318 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser181 DQGSLCTsFVGTLQY 9606 SIGNOR-C14 11460167 t lperfetto Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta. SIGNOR-109494 0.746 SRC protein P12931 UNIPROT SRCIN1 protein Q9C0H9 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 8647432 t miannu Phosphorylation of multiple tyrosine-containing motifs found on Sin correlated with c-Crk and cellular phosphoprotein binding to Sin as well as increased c-Src activity. These data suggest that (1) SH2 and SH3 ligand sites on Sin cooperatively activate the signaling potential of c-Src, (2) Sin acts as both an activator and a substrate for c-Src, and (3) phosphorylated Sin may serve as a signaling effector molecule for Src by binding to multiple cellular proteins. SIGNOR-263196 0.51 ACOT4 protein Q8N9L9 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271806 0.8 ponatinib chemical CHEBI:78543 ChEBI STAT5A protein P42229 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000830 23539538 t miannu Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells SIGNOR-259274 0.8 FLT3LG protein P49771 UNIPROT FLT3 protein P36888 UNIPROT up-regulates binding 9606 10080542 t gcesareni Flt3 ligand (fl) is an early-acting potent co-stimulatory cytokine that regulates proliferation and differentiation of a number of blood cell lineages. Its receptor flt3/flk2 belongs to class iii receptor tyrosine kinases that also include the receptors for colony-stimulating factor 1 SIGNOR-65564 0.881 sphingosine 1-phosphate(1-) smallmolecule CHEBI:60119 ChEBI S1PR3 protein Q99500 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257579 0.8 BMPR1A protein P36894 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity 10090 8533096 f ggiuliani We also examined whether TAK1 was activated by bone morphogenetic protein (BMP). BMP-4 also stimulated TAK1 activity in a time- and dose-dependent manner SIGNOR-255815 0.386 CYP17A1 protein P05093 UNIPROT dehydroepiandrosterone chemical CHEBI:28689 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268651 0.8 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity SIGNOR-252905 0.52 PTGER2 protein P43116 UNIPROT EGFR protein P00533 UNIPROT up-regulates 9606 BTO:0000586 17251915 f gcesareni Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa). SIGNOR-152805 0.299 MYCL protein P12524 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002891 27546534 f irozzo Our findings demonstrate that stable expression of the L-MYC gene in NSC008 cells promotes their survival and proliferation while preserving their migration and differentiation properties in vitro and in vivo. SIGNOR-259109 0.7 UBE2I protein P63279 UNIPROT PLAG1 protein Q6DJT9 UNIPROT down-regulates sumoylation Lys244 NQELLKVkTEPVDFL 9606 15208321 t miannu Sumoylation decreases the transcriptional activity of plag1 / plag1 is sumoylated at 2 specific lysine residues (lys-244 and lys-263) SIGNOR-126044 0.281 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity dephosphorylation Tyr861 PIGNQHIyQPVGKPD -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254720 0.245 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259807 0.8 CENP-A nucleosome complex SIGNOR-C321 SIGNOR Centromere_assembly phenotype SIGNOR-PH154 SIGNOR up-regulates 9606 BTO:0000567 20566683 f miannu Centromeres contain specialized nucleosomes in which histone H3 is replaced by the histone variant centromere protein A (CENP-A). CENP-A nucleosomes are thought to act as an epigenetic mark that specifies centromere identity. SIGNOR-263704 0.7 CDC42 protein P60953 UNIPROT GSK3B protein P49841 UNIPROT down-regulates binding 9606 14657655 t gcesareni Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent. SIGNOR-119885 0.385 DDB1 protein Q16531 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates binding 9606 BTO:0000567 9418871 t miannu We show that ddb, a putative dna repair protein, associates with the activation domain of e2f1 / expression of ddb specifically stimulated e2f1-activated transcription SIGNOR-54096 0.358 ID3 protein Q02535 UNIPROT TCF4 protein P15884 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C129 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241379 0.47 DUSP1 protein P28562 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 10617468 t lperfetto The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1 SIGNOR-73614 0.798 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269237 0.763 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245428 0.2 TSPAN7 protein P41732 UNIPROT DRD2 protein P14416 UNIPROT down-regulates quantity binding 9606 BTO:0000007 28223337 t miannu Tetraspanin-7 (TSPAN7) is expressed to variable degrees in different tissues, with the highest level in the brain, and multiple mutations in TSPAN7 have been implicated in intellectual disability. Our results showed that TSPAN7 was associated with DRD2 and reduced its surface expression by enhancing DRD2 internalization.Finally, TSPAN7 negatively affects DRD2-mediated signaling. SIGNOR-265557 0.254 SMG1 protein Q96Q15 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates phosphorylation Ser1089 GLSQPELsQDSYLGD 9606 23356578 t lperfetto Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively SIGNOR-200785 0.971 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser68 PPQTSGLsPSRLSKS 9606 20233713 t gcesareni The identification of maf1 as an mtor-regulated phosphoprotein implicates mtor in the broader regulatory mechanisms governing pol iii activity in cancer cells. SIGNOR-164348 0.7 Kindlin proteinfamily SIGNOR-PF48 SIGNOR FBLIM1 protein Q8WUP2 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 t inferred from 70% family members miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. SIGNOR-269956 0.2 ARID1A protein O14497 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency. Here, we show that BAF complexes are required for the self-renewal and pluripotency of mouse ES cells but not for the proliferation of fibroblasts or other cells. Proteomic studies reveal that ES cells express distinctive complexes (esBAF) defined by the presence of Brg (Brahma-related gene), BAF155, and BAF60A, and the absence of Brm (Brahma), BAF170, and BAF60C. SIGNOR-270714 0.729 MFGE8 protein Q08431 UNIPROT Av/b5 integrin complex SIGNOR-C178 SIGNOR up-regulates activity binding 10116 BTO:0000452 31958465 t miannu Milk fat globule-EGF factor 8 (MFGE8), a protein known as lactadherin in humans, contains C domains interacting with extracellular matrices and epidermal growth factor–like domains with an RGD motif binding to integrins αvβ3 and αvβ5. SIGNOR-260645 0.523 1-phosphatidyl-1D-myo-inositol 4-phosphate(3-) smallmolecule CHEBI:58178 ChEBI 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) smallmolecule CHEBI:58456 ChEBI up-regulates quantity precursor of 9606 9367159 t miannu Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities SIGNOR-277288 0.8 ERMP1 protein Q7Z2K6 UNIPROT UPR phenotype SIGNOR-PH131 SIGNOR up-regulates activity 9606 BTO:0000093 27566589 f Furthermore, we show that this protein is an important player in the UPR and defense against oxidative stress. ERMP1 expression is strongly affected by reticular stress induced by thapsigargin and other oxidative stresses. ERMP1 silencing during reticular stress impairs the activation of PERK, a key sensor of the UPR activation. SIGNOR-261295 0.7 PRDM1 protein O75626 UNIPROT CCL2 protein P13500 UNIPROT down-regulates quantity by repression transcriptional regulation 19915049 t lperfetto Blimp-1 binds to the proinflammatory cytokine/chemokine genes, Il-6 and Ccl2, and negatively regulates their expression. SIGNOR-271679 0.2 BAK1 protein Q16611 UNIPROT AIFM1 protein O95831 UNIPROT up-regulates relocalization 9606 23003569 t gcesareni First, bax/bak-mediated momp leads to the release of a significant part of the cyt c, smac/diablo and htra2/omi proteins. in a third step, cyt c, smac/diablo and htra2/omi, which were released into the cytosol, trigger caspase activation. This is necessary to alter the physical association of aif and endog with the im to enable their relocation to the cytosol. SIGNOR-192092 0.302 ABL1 protein P00519 UNIPROT TP63 protein Q9H3D4 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr149 SVTAPSPyAQPSSTF 9606 19783996 t Manara In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. SIGNOR-260934 0.524 NME1 protein P15531 UNIPROT SMO protein Q99835 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001567 17671192 f miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. SIGNOR-255168 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252825 0.908 DEPTOR protein Q8TB45 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity binding 9606 BTO:0000007 19446321 t DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival SIGNOR-251657 0.746 CSNK1E protein P49674 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation 9606 15747065 t gcesareni Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex.CK1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays. SIGNOR-134497 0.271 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 21993628 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-176751 0.8 AKT3 protein Q9Y243 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 BTO:0000150 20231902 t gcesareni Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation. SIGNOR-164306 0.274 FZR1 protein Q9UM11 UNIPROT AURKA protein O14965 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0004055 12023018 t miannu We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity. SIGNOR-272610 0.542 CSNK2A1 protein P68400 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser102 EEGISQEsSEEEQ -1 2806554 t llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. SIGNOR-250892 0.336 PRKCZ protein Q05513 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 t lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation SIGNOR-249251 0.296 TP53 protein P04637 UNIPROT FGF2 protein P09038 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10029407 f miannu p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1. SIGNOR-255431 0.451 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 BTO:0000782 BTO:0001253 22898666 t gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1. SIGNOR-252998 0.673 PRKCB protein P05771 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Thr590 PALLEHRtGRYAPTI 9823 21864610 t miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. SIGNOR-262927 0.2 BMI1 protein P35226 UNIPROT NDN protein Q99608 UNIPROT down-regulates 9606 BTO:0000007 24392140 f lperfetto In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, whereas Bmi1 counteracts necdin-mediated repression of E2F1-dependent Cdk1 promoter activity. SIGNOR-253386 0.255 CDK1 protein P06493 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser90 LPGSRPGsPEREVPA 9606 16103124 t lperfetto Moreover, app stabilized tip60 through cdk-dependent phosphorylation SIGNOR-139653 0.491 EP300 protein Q09472 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 20660310 f amattioni Switch to beta-catenin/p300-mediated gene expression is an essential first step in initiating normal cellular differentiation SIGNOR-229780 0.7 TGFBR1 protein P36897 UNIPROT EEF1A1 protein P68104 UNIPROT down-regulates phosphorylation Ser300 EMHHEALsEALPGDN 9606 20832312 t llicata Phosphorylation of eEF1A1 at Ser300 by T_R-I results in inhibition of mRNA translation SIGNOR-167943 0.35 ASAP2 protein O43150 UNIPROT ARF5 protein P84085 UNIPROT up-regulates activity gtpase-activating protein -1 10022920 t miannu Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain.  In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6.  Pap protein exhibits Arf GAP activity in vitro. SIGNOR-269707 0.511 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266522 0.8 CDK5 protein Q00535 UNIPROT ATM protein Q13315 UNIPROT up-regulates phosphorylation Ser794 LSNCTKKsPNKIASG 9606 BTO:0000938 19151707 t lperfetto Here we show that cdk5 (cyclin-dependent kinase 5), activated by dna damage, directly phosphorylates atm at ser 794 in post-mitotic neurons. Phosphorylation at ser 794 precedes, and is required for, atm autophosphorylation at ser 1981, and activates atm kinase activity SIGNOR-183454 0.425 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27141364 f irozzo EML4-ALK enhanced HIF-1α expression through increasing transcription and decreasing ubiquitination of HIF-1α. SIGNOR-259172 0.2 ABL1 protein P00519 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates activity phosphorylation Tyr1003 KGKKFLQyNRLQLSR 9606 BTO:0002181 12652307 t miannu C-Abl induces Tyr phosphorylation of PLC-γ1 in vivo. These findings demonstrate that c-Abl phosphorylates PLC-γ1 in vivo predominantly at Tyr 771 and Tyr 1003.c-Abl phosphorylation of PLC-γ1 causes downregulation of PLC activity. SIGNOR-276002 0.572 PPP2CA protein P67775 UNIPROT BCL2 protein P10415 UNIPROT up-regulates activity dephosphorylation Ser87 AAAGPALsPVPPVVH 9606 15225643 t The phosphorylation of Bcl-2 resulted in a reduction in anti-apoptotic function, implying that dephosphorylation promoted the anti-apoptotic activity of Bcl-2 protein in human tumor cell lines. Thus, the present findings suggest that ERK and PP2A are physiological regulators of Bcl-2 phosphorylation, and these enzymes exert an influence on the anti-apoptotic function of Bcl-2.phosphorylation of Bcl2 at Ser70 is proposed to be a dynamic process regulated by the sequential action of an agonist-activated Bcl2 kinase and PP2A. SIGNOR-248624 0.458 LYST protein Q99698 UNIPROT RAB5A protein P20339 UNIPROT down-regulates activity binding 7227 33725482 t lperfetto Mauve interacts with Rab5, Msps, and gamma-tubulin|Mauve/LYST opposes Rab5, which promotes vesicle fusion affecting PCM recruitment SIGNOR-266001 0.269 DAPK3 protein O43293 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 19851336 t lperfetto More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above. SIGNOR-188793 0.5 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 26721223 f Excessive accumulation of Aβ protein in the AD brain may lead to a decrease in the levels of phosphatidylinositol-3 kinase (PI3K) and the serine/threonine protein kinase B (Akt) activity. SIGNOR-255493 0.7 SSU72 protein Q9NP77 UNIPROT STAG2 protein Q8N3U4 UNIPROT up-regulates activity dephosphorylation Ser1224 PASIMDEsVLGVSMF 20818333 t lperfetto Additional experiments revealed that Ssu72 directly interacts with Rad21 and SA2 in vitro and in vivo, and associates with sister chromatids in human cells. Interestingly, depletion or mutational inactivation of Ssu72 phosphatase activity caused the premature resolution of sister chromatid arm cohesion, whereas the overexpression of Ssu72 yielded high resistance to this resolution.|anti‐phospho SA2 serine 1224 SIGNOR-275531 0.302 CDK1 protein P06493 UNIPROT NDUFA12 protein Q9UI09 UNIPROT up-regulates activity phosphorylation Thr120 HKFNVTGtPEQYVPY 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275588 0.2 PRDM14 protein Q9GZV8 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 20953172 f miannu We showed that PRDM14 regulates directly the expression of key pluripotency gene POU5F1 through its proximal enhancer. SIGNOR-255067 0.608 CAMK2A protein Q9UQM7 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser103 RGLKRSLsEMEIGMV 10753652 t llicata Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. | Microsequencing of these phosphorylated peptides identified that both Ser-103 and a novel residue, Thr-160 in the MADS box of SRF, were sites of phosphorylation. | The location of Thr-160 in the 3-D structure of SRF suggests that its phosphorylation by nuclear CaMKII may directly influence DNA binding of SRF and other MADS box factors. SIGNOR-250638 0.377 BAZ2B protein Q9UIF8 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity binding 9606 acetylation:Lys15 ARKSTGGkAPRKQLA 31999386 t miannu The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation. SIGNOR-266619 0.2 F2RL1 protein P55085 UNIPROT TSPAN15 protein O95858 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21072196 f miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). SIGNOR-254862 0.2 CSNK2A2 protein P19784 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser230 VTPSKSTsASAIMNG 9606 BTO:0000938 26917740 t lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. SIGNOR-275741 0.312 TRAF2 protein Q12933 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates binding 9606 8069916 t amattioni Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly. Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2. SIGNOR-35881 0.62 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu79 EDSDKTNeFWNKYKD -1 9538022 t lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). SIGNOR-263674 0.598 IRF9 protein Q00978 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates activity binding 9606 BTO:0000007 17923090 t lperfetto By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2. SIGNOR-217779 0.717 RPS6K proteinfamily SIGNOR-PF26 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 15342917 t lperfetto The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1 SIGNOR-252796 0.473 LYN protein P07948 UNIPROT IRF5 protein Q13568 UNIPROT down-regulates activity phosphorylation Tyr335 QLQGQDLyAIRLCQC 9606 BTO:0002181 27521268 t miannu Lyn Kinase Suppresses the Transcriptional Activity of IRF5. Here, we found that Lyn physically interacted with IRF5 to inhibit ubiquitination and phosphorylation of IRF5 in the TLR-MyD88 pathway, thereby suppressing the transcriptional activity of IRF5 in a manner independent of Lyn's kinase activity. SIGNOR-277248 0.335 RPS6KA1 protein Q15418 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Thr355 NKRRRSVtPPEEQQE 9606 23708659 t lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. SIGNOR-202125 0.255 IL34 protein Q6ZMJ4 UNIPROT CSF1R protein P07333 UNIPROT up-regulates activity binding 9606 BTO:0000876 BTO:0001103 24890514 t apalma The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34) SIGNOR-255569 0.909 IL17A protein Q16552 UNIPROT KLF2 protein Q9Y5W3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23332504 f fspada Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic. SIGNOR-192477 0.287 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 9606 7535770 t gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. SIGNOR-28059 0.338 HIC1 protein Q14526 UNIPROT MYC protein P01106 UNIPROT down-regulates activity transcriptional regulation 9606 BTO:0000815 24067369 f miannu HIC1 suppressing the VEGF and c-Myc promoter activity and the colony formation of MDA-MB 231 cells were STAT3-dependent. SIGNOR-254245 0.329 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1214 VCDPKFHyDNTAGIS 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. SIGNOR-157093 0.2 CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates activity binding 9606 29958106 t miannu The genes encoding CBFβ and RUNX1 are frequent targets of mutations in hematologic malignancies. The chromosome inversion inv(16)(p13;q22), found in 8% of acute myeloid leukemia (AML) cases, fuses the CBFB and MYH11 genes to produce the leukemic oncoprotein CBFβ-SMMHC. This fusion protein has higher affinity and altered stoichiometry for RUNX1 relative to the native CBFβ (Cao et al., 1997; Lukasik et al., 2002). During development, CBFβ-SMMHC expression blocks definitive hematopoiesis and embryos die at mid-gestation (Castilla et al., 1996), a similar phenotype to that of Runx1- and Cbfb-knock out embryos (Wang et al., 1996a; Wang et al., 1996b), indicating that CBFβ-SMMHC has a dominant negative effect on RUNX function. SIGNOR-255743 0.2 FADS6 protein Q8N9I5 UNIPROT long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI down-regulates quantity chemical modification 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267910 0.8 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT up-regulates sumoylation Lys490 QCPRKVIkMESEEGK 9534 9756909 t lperfetto We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation. SIGNOR-261787 0.771 AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR oligopeptide smallmolecule CHEBI:25676 ChEBI up-regulates quantity relocalization 9606 25720354 t scontino APCs cell surface receptors facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. It is in these compartments that internalized antigen proteolysis and peptide–MHC class II complex formation takes place. SIGNOR-267860 0.8 MIF protein P14174 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates activity binding 10090 BTO:0000876 17435771 t gcesareni We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF [] By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. SIGNOR-252062 0.38 MAPK3 protein P27361 UNIPROT TCF3 protein P15923 UNIPROT down-regulates quantity by destabilization phosphorylation Thr355 NFSSSPStPVGSPQG 10090 14592976 t lperfetto Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG) SIGNOR-249117 0.38 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LATS1 protein O95835 UNIPROT down-regulates 10090 22863277 f milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. SIGNOR-198517 0.8 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269368 0.719 PPP2CB protein P62714 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 18586681 t Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. SIGNOR-248598 0.2 LCK protein P06239 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 22936936 t lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor SIGNOR-198755 0.745 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT down-regulates activity phosphorylation Thr19 GSRRGRAtPAQTPRS 9606 BTO:0000567 12714602 t lperfetto We report here that human mcm4, a subunit of the putative dna replicative helicase, is extensively phosphorylated in hela cells when they are incubated in the presence of inhibitors of dna synthesis or are exposed to uv irradiation. The data presented here indicate that the consecutive actions of atr-chk1 and cdk2 kinases are involved in this phosphorylation in the presence of hydroxyurea. Phosphorylation of t19 correlates with lowered level of dna helicase activity of the purified mcm4,6,7 complex. SIGNOR-100893 0.757 PTPN6 protein P29350 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates binding 9606 14551136 t gcesareni All together, our results indicate that shp-1 inhibits prlr and epor signaling by recruitment and targeting of socs-1 to jak2, highlighting a new mechanism of shp-1 regulation of cytokine-receptor signaling. SIGNOR-118572 0.331 HES1 protein Q14469 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR down-regulates activity binding 10090 BTO:0000562 16682003 t lperfetto Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression. SIGNOR-209756 0.673 NCBP1 protein Q09161 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 26382858 f lperfetto The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. SIGNOR-268361 0.7 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120228 0.321 CASP3 protein P42574 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity cleavage Asp1405 CPGYPETdHGLFEDP 9606 12907805 t lperfetto Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain. SIGNOR-104585 0.326 MASP2 protein O00187 UNIPROT C2 protein P06681 UNIPROT up-regulates activity cleavage Ser20 LYPGLADsAPSCPQN 9606 BTO:0000392 11907111 t lperfetto The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase SIGNOR-263419 0.415 FOXO proteinfamily SIGNOR-PF27 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 18423396 f fspada Akt1/pkbalpha was found to be the major regulator of phosphorylation and nuclear export offoxo1, whose presence in the nucleus strongly attenuates adipocyte differentiation. SIGNOR-252911 0.7 H2AX protein P16104 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates binding 9606 16377563 t fstefani Here, we demonstrate that mammalian mdc1/nfbd1 directly binds to phospho-h2ax (gammah2ax) by specifically interacting with the phosphoepitope at the gammah2ax carboxyl terminus. SIGNOR-143377 0.2 HOXA10 protein P31260 UNIPROT MYLK protein Q15746 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002196 15886193 t Luana Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively SIGNOR-261643 0.2 CDK20 protein Q8IZL9 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 14597612 t gcesareni P42 is essential for the phosphorylation of thr-160 and activation of cdk2. SIGNOR-118986 0.395 PRKACA protein P17612 UNIPROT PPP1R8 protein Q12972 UNIPROT down-regulates activity phosphorylation Ser199 PKRKRKNsRVTFSED -1 9407077 t miannu NIPP-1 is the RNA-binding subunit of a major species of protein phosphatase-1 in the nucleus. The purified recombinant protein was a potent (Ki = 9.9 +/- 0.3 pM) and specific inhibitor of protein phosphatase-1 and was stoichiometrically phosphorylated by protein kinases A and CK2. At physiological ionic strength, phosphorylation by these protein kinases drastically decreased the inhibitory potency of free NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A SIGNOR-250033 0.497 MAPK1 protein P28482 UNIPROT PLA2G4A protein P47712 UNIPROT unknown phosphorylation Ser505 LNTSYPLsPLSDFAT 9606 BTO:0000567 9468497 t llicata The inhibitor of the 38-kda stress-activated protein kinase (p38(mapk)), sb 203580, reduced phosphorylation of both ser-505 and ser-727 by 50 and 60%, respectively, in thrombin-stimulated platelets. SIGNOR-55706 0.642 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser641 KVTSKCGsLGNIHHK 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto Mark and pka phosphorylate several sites within the repeats (notably the kxgs motifs including ser262, ser324, and ser356, plus ser320)tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process SIGNOR-171054 0.44 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm SIGNOR-72068 0.813 PCK1 protein P35558 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI down-regulates quantity chemical modification 9606 30193097 t miannu √Ǭ†PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP).√Ǭ† SIGNOR-266588 0.8 1-phospho-alpha-D-glucuronic acid smallmolecule CHEBI:681 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation -1 7576010 t miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1.Similarly, the affinities of D3 receptors for quinpirole and dopamine were much higher than the affinities of D:! receptors for the agonists in the presence of Gpp(NH)p and NaCl when [1251]-NCQ-298 was used to label receptors; however, when Gpp(NH)p and NaCl were not present, and when [12sI]-7-OH-PIPAT was used, receptors bound quinpirole and dopamine with nearly equal affinities (Table 1). SIGNOR-258435 0.8 CKM complex complex SIGNOR-C406 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo. SIGNOR-273174 0.2 AHR protein P35869 UNIPROT AHR-ARNT complex SIGNOR-C125 SIGNOR form complex binding -1 9020169 t 2 miannu SIM1 and SIM2, and the mammalian aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) proteins are members of the basic-helix-loop-helix·PAS family of transcription factors. In the yeast two-hybrid system, we demonstrate strong constitutive interaction of ARNT with SIM1 and SIM2 and fully ligand-dependent interaction of ARNT with AHR. SIM1 inhibits binding of the AHR·ARNT dimer to the xenobiotic response element in vitro Introduction of SIM1 into hepatoma cells inhibits transcriptional transactivation by the endogenous AHR·ARNT dimer. SIGNOR-240817 0.745 ID4 protein P47928 UNIPROT SOX2 protein P48431 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21531766 f miannu We found that ID4 enhanced SOX2 protein expression by suppressing microRNA-9* (miR-9*), which can repress SOX2 by targeting its 3'-untranslated region.  SIGNOR-255180 0.419 irinotecan chemical CHEBI:80630 ChEBI TOP1MT protein Q969P6 UNIPROT down-regulates activity chemical inhibition 9606 15170677 t miannu Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin; CPT-11) is a widely used potent antitumor drug that inhibits mammalian DNA topoisomerase I (Topo I) SIGNOR-259315 0.8 ATM protein Q13315 UNIPROT BUB1 protein O43683 UNIPROT up-regulates phosphorylation Ser314 SHEDLPAsQERSEVN 9606 22099307 t lperfetto We also demonstrate that mitotically activated atm phosphorylates bub1, a critical kinetochore protein, on ser314. Atm-mediated bub1 ser314 phosphorylation is required for bub1 activity and is essential for the activation of the spindle checkpoint SIGNOR-177276 0.474 PITX1 protein P78337 UNIPROT POU1F1 protein P28069 UNIPROT up-regulates activity binding -1 8755540 t miannu A novel OTX-related homeodomain transcription factor has been identified on the basis of its ability to interact with the transactivation domain of the pituitary-specific POU domain protein, Pit-1. P-OTX is able to independently activate and to synergize with Pit-1 on pituitary-specific target gene promoters. SIGNOR-219740 0.483 PRKCE protein Q02156 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 t llicata Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm. SIGNOR-97291 0.479 sirolimus chemical CHEBI:9168 ChEBI LILRB4 protein Q8NHJ6 UNIPROT down-regulates quantity by repression 9606 18652845 f miannu Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells. SIGNOR-255478 0.8 BIRC6 protein Q9NR09 UNIPROT CASP3 protein P42574 UNIPROT down-regulates binding 9606 15200957 t gcesareni Bruce binds and thereby inhibits caspases, in particular effector caspase-3. SIGNOR-125956 0.477 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002861 18682241 t flangone We also find that SMADs bind with the NANOG promoter and that SMAD2/3 activity enhances NANOG promoter activity. SIGNOR-242044 0.535 KDM5B protein Q9UGL1 UNIPROT CBX4 protein O00257 UNIPROT up-regulates activity binding 9606 19336002 t miannu Our results clearly showed that the PcG protein hPc2 interacted with the N-terminus of JARID1B both in vivo and in vitro. It is interesting that the C-terminus of hPc2 was essential for the interaction and transcriptional co-repression. SIGNOR-226447 0.408 RAI1 protein Q7Z5J4 UNIPROT PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22578325 f miannu Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. SIGNOR-266840 0.313 MRGPRD protein Q8TDS7 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR down-regulates 10090 BTO:0000801 30918468 f Luana Our data suggested that both Ang-(1-7) and alamandine, through their respective receptors Mas and MrgD, promote an anti-inflammatory reprogramming of M(LPS+IFN-γ)/M1 macrophages under inflammatory circumstances and potentiate the reprogramming induced by IL-4. SIGNOR-262310 0.7 PXN protein P49023 UNIPROT IPP complex complex SIGNOR-C380 SIGNOR up-regulates activity relocalization 16493410 t lperfetto Integrin-linked kinase (ILK), and isoforms of particularly interesting Cys-His-rich protein (PINCH) and parvin form the IPP complex (Fig. 2) in the cytoplasm, and this complex is recruited to focal adhesions through interactions with other factors, such as paxillin. SIGNOR-265767 0.577 Telatinib chemical CID:9808844 PUBCHEM KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207227 0.8 PPM1F protein P49593 UNIPROT CAMK2A protein Q9UQM7 UNIPROT down-regulates dephosphorylation Thr286 SCMHRQEtVDCLKKF 9606 BTO:0000938 15140879 t gcesareni Ppm1f specifically dephosphorylates the phospho-thr-286 in autophosphorylated camkii substrate and thus deactivates the camkii in vitro. SIGNOR-124309 0.337 SYN3 protein O14994 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR down-regulates 9606 BTO:0000938 33809712 f miannu Synapsins are a family of peripheral proteins that bind to the SV membrane. Synapsins Maintain the SV Reserve Pool. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet. SIGNOR-264107 0.7 CEBPA protein P49715 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 17139329 f fferrentino C/EBPα induces many adipocyte genes directly, and in vivo studies indicate an important role for this factor in the development of adipose tissue. SIGNOR-132946 0.7 PRKCA protein P17252 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Thr540 KRLSRSVtMRKSQRS 9606 24505490 t llicata A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498. SIGNOR-204554 0.2 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK 9606 7493944 t lperfetto Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26582 0.2 NR5A1 protein Q13285 UNIPROT CYP11B2 protein P19099 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002588 21169726 f miannu Inhibitory SF-1 was found to decrease the sensitivity of CYP11B2 and aldosterone to Ang II stimulation, whereas a down-regulation of SF-1 enhanced basal CYP11B2 expression and aldosterone production in H295R cells. SIGNOR-254867 0.492 SHOC2 protein Q9UQ13 UNIPROT MRAS protein O14807 UNIPROT up-regulates binding 9606 10783161 t gcesareni Sur-8 interacts with ras and raf and is able to form a ternary complex with the two proteins. Thus, sur-8 may function as a scaffold that enhances ras-map kinase signal transduction by facilitating the interaction between ras and raf. SIGNOR-77082 0.682 AIMP1 protein Q12904 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates binding 9606 18448069 t lpetrilli Here, we report that aimp1 negatively regulates tgf-? Signaling via stabilization of smurf2. SIGNOR-178498 0.399 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257906 0.8 afatinib chemical CHEBI:61390 ChEBI ERBB4 protein Q15303 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 24643470 t miannu This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. SIGNOR-259295 0.8 MED23 protein Q9ULK4 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266665 0.728 PPP1CA protein P62136 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR down-regulates activity dephosphorylation 9606 14751588 t miannu Dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein, 32 kDa (DARPP-32) is a key element of dopamine/D1/DARPP-32/protein phosphatase-1 (PP-1) signaling cascades of mammalian brain. Phosphorylation of AMPA receptors due to DARPP-32/PP1 signaling cascade increases AMPA channel activity and currents SIGNOR-265060 0.504 IL19 protein Q9UHD0 UNIPROT IL20RB protein Q6UXL0 UNIPROT up-regulates binding 9606 17208301 t gcesareni Il-19 signals only through the type i il-20r complex. SIGNOR-151820 0.708 PRKCA protein P17252 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates phosphorylation Thr141 RRDARGLtPLELALQ 9606 22558186 t lperfetto Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively.we propose a sequential phosphorylation model for p19 in which modification at s76 would enable a second phosphorylation event at t141. The phosphorylation-induced structural changes could have functional implicancies for p19 in the dna damage response SIGNOR-197289 0.2 MAPK1 protein P28482 UNIPROT LIFR protein P42702 UNIPROT down-regulates phosphorylation Ser1044 WNLVSPDsPRSIDSN 9606 7777512 t gcesareni Indeed, phosphorylation of the cytoplasmic domain of the low-affinity lif receptor alpha-subunit (lifr) in mono q-fractionated, lif-stimulated 3t3-l1 extracts occurred only in those fractions containing activated mapk;ser-1044 served as the major phosphorylation site in the human lifr for mapk both in agonist-stimulated 3t3-l1 lysates and by recombinant extracellular signal-regulated kinase 2 in vitro SIGNOR-32753 0.377 Fanconi anemia core complex complex SIGNOR-C300 SIGNOR FANCD2 protein Q9BXW9 UNIPROT up-regulates activity ubiquitination 9606 17396147 t lperfetto Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263249 0.762 PRRX1 protein P54821 UNIPROT MAFG protein O15525 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221961 0.344 PDPK1 protein O15530 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Thr507 FGESRAStFCGTPDY 9606 BTO:0000007 9748166 t miannu PDK1 phosphorylated the activation loop sites of PKCzeta and PKCdelta in vitro and in a phosphoinositide 3-kinase (PI 3-kinase)-dependent manner in vivo in human embryonic kidney (293) cells. PKCδ was also phosphorylated in the activation loop site (T505) SIGNOR-250269 0.559 CSNK2A1 protein P68400 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Ser483 SMQPDNSsDSDYDLH 9606 9834084 t lperfetto In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461) SIGNOR-62307 0.349 CSNK1G1 protein Q9HCP0 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser322 PRTSSNAsTISGRLS -1 11980723 t llicata Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR SIGNOR-252901 0.473 NEFL protein P07196 UNIPROT Neurofilament L/M complex SIGNOR-C207 SIGNOR form complex binding 9606 19468066 t miannu Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H SIGNOR-255270 0.535 PLK1 protein P53350 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser24 GYLRKPKsMHKRFFV 9606 15849359 t lperfetto Phosphorylation of ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by mouse pelle-like kinase/interleukin-1 receptor-associated kinase| irs-1 mutants s24d or s24e (mimicking phosphorylation at ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of irs-1 and impaired ability of irs-1 to bind and activate pi-3 kinase in response to insulin. SIGNOR-135688 0.27 CDK2 protein P24941 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser123 EEGFGSSsPVKSPAA 9606 16085715 t gcesareni Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp. During the s and g2 phases, s123 (wee1) is phosphorylated by a cdk (possibly cdk2). SIGNOR-139469 0.652 ILK protein Q13418 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser3 sGVAVSDG 9606 18252715 t gcesareni Actin (de)polymerization is regulated by cofilin, the ser(3) phosphorylation (ps(3)cofilin) of which inhibits its actin-severing activity. To determine how ilk regulates ps(3)cofilin, we examined the effects of ilk on ps(3)cofilin using normal rie1 cells. SIGNOR-160756 0.357 DYRK1A protein Q13627 UNIPROT DNM1 protein Q05193 UNIPROT down-regulates phosphorylation Ser795 VPPARPGsRGPAPGP 9606 BTO:0000142 15287745 t lperfetto Mnb/dyrk1a was shown to phosphorylate dynamin 1 and alter its interactions with several sh3 domain-containing endocytic accessory proteins.Phosphorylation At s795 and s857 was confirmed in full-length dynamin 1, and s857 was subsequently determined to be the major mnb/dyrk1a phosphorylation site in vitro. Phosphorylation at s857 was demonstrated to be the basis for altering the binding of dynamin 1 to amphiphysin 1 and grb 2 by site-directed mutants mimicking phosphorylation. SIGNOR-127440 0.426 SMOC1 protein Q9H4F8 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20359165 f lperfetto The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells SIGNOR-260400 0.2 SHMT1 protein P34896 UNIPROT glycine zwitterion smallmolecule CHEBI:57305 ChEBI up-regulates quantity chemical modification 9606 11802770 t miannu HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. SIGNOR-269689 0.8 RIMS1 protein Q86UR5 UNIPROT RAB3C protein Q96E17 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 31679900 t miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle SIGNOR-264382 0.425 STK11 protein Q15831 UNIPROT SNRK protein Q9NRH2 UNIPROT up-regulates activity phosphorylation Thr173 QPGKKLTtSCGSLAY 9606 BTO:0000567 15733851 t lperfetto we identify the sucrose non-fermenting protein (SNF1)-related kinase (SNRK), a largely unstudied AMPK subfamily member, as a novel substrate for LKB1. We demonstrate that LKB1 activates SNRK by phosphorylating the T-loop residue (Thr173), SIGNOR-247493 0.375 HIF1A protein Q16665 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0001336 28623342 f Our results demonstrate that SF(synovial fibroblasts) are highly dependent on glycolytic metabolism and that HIF-1α plays a regulatory role in glycolysis even under aerobic conditions. SIGNOR-259380 0.7 ERCC8 protein Q13216 UNIPROT ERCC6 protein Q03468 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 16751180 t miannu We have previously shown that CSA is a subunit of an E3 ubiquitin ligase complex. Here we demonstrate that CSB is a substrate of this ligase: Following UV irradiation, CSB is degraded at a late stage of the repair process in a proteasome- and CSA-dependent manner. SIGNOR-271406 0.599 FUBP1 protein Q96AE4 UNIPROT CCND2 protein P30279 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19637194 f irozzo A positive cell cycle regulator that we found down-regulated in Hep3B cells upon FBP1 inactivation was cyclin D2. In addition, Cyclin D2 mRNA levels were diminished in the FBP1 knockdown cells, whereas the amount of Cyclin D1 mRNA remained unaffected. Numerous studies have classified D-type cyclins as cell cycle–promoting oncoproteins important for cellular transformation, and our results suggest that cyclin D2 is a candidate FBP1-regulated oncoprotein in HCC. SIGNOR-259124 0.2 TFEB protein P19484 UNIPROT NAGLU protein P54802 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276543 0.329 AGK protein Q53H12 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 t lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). SIGNOR-267708 0.362 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser855 QRVLDTSsLTQSAPA 9606 BTO:0000007 19864431 t lperfetto Strikingly, raptor Ser(863) phosphorylation is absolutely required for raptor Ser(859) and Ser(855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser(863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser(859) and Ser(855)) SIGNOR-174882 0.989 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr972 EYLGTKRyIHRDLAT 9606 BTO:0000007 20304997 t lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236294 0.2 KDM2B protein Q8NHM5 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 25533466 f miannu Here, we show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. These results suggest that FBXL10 represses adipogenesis by targeting a noncanonical PRC1 complex to repress key genes (e.g. Pparg) that control conversion of pluripotent cells into the adipogenic lineage. SIGNOR-252243 0.7 NVP-BEP800 chemical CID:25210273 PUBCHEM HSP90AB1 protein P08238 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194904 0.8 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 22343533 t gcesareni Ror1 and ror2 bind wnt5a. SIGNOR-196133 0.737 GRIK2 protein Q13002 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity relocalization 9606 BTO:0002609 12393813 t lperfetto Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine SIGNOR-268273 0.8 CACNA1D protein Q01668 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 28642685 t miannu Rab interacting molecules (RIMs) are multi-domain proteins that positively regulate the number of Ca2+ channels at the presynaptic active zone (AZ). Several molecular mechanisms have been demonstrated for RIM-binding to components of the presynaptic Ca2+ channel complex, the key signaling element at the AZ. Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α–subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs).  SIGNOR-264359 0.8 ATP(4-) smallmolecule CHEBI:30616 ChEBI 2'-3'-cGAMP(2-) smallmolecule CHEBI:143093 ChEBI up-regulates quantity precursor of 23258413 t lperfetto Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. SIGNOR-276594 0.8 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249352 0.728 SB 415286 chemical CHEBI:91107 ChEBI GSK3A protein P49840 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206751 0.8 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH9 protein Q9ULB4 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265849 0.8 CCL2 protein P13500 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32446778 f Luana In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNŒ±, IFNŒ≥, IL-1Œ≤, IL-6, IL-12, IL-18, IL-33,TNFŒ±, TGFŒ≤) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatory response. SIGNOR-261317 0.7 KIT protein P10721 UNIPROT SLA protein Q13239 UNIPROT down-regulates activity phosphorylation Tyr120 SETKKGFySLSVRHR 9534 24284075 t miannu Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity SIGNOR-263140 0.2 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates phosphorylation 9606 17419683 t gcesareni In vertebrates,pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation SIGNOR-154276 0.445 IRF5 protein Q13568 UNIPROT IL1B protein P01584 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 21240265 f Among the genes with differences in expression in the M1 and M2 subsets are those regulated by IRF5, including IL12A, IL12B, IL23A, IL1B, TNF, CCL3(encoding MIP-1α), RANTES, CD1A, CD40, CD86 and CCR7 SIGNOR-254510 0.297 UBA52 protein P62987 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262459 0.801 SRC protein P12931 UNIPROT PRKCI protein P41743 UNIPROT up-regulates phosphorylation Tyr265 RVIGRGSyAKVLLVR 9606 11713277 t llicata Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain. SIGNOR-111920 0.513 AKT1 protein P31749 UNIPROT BMI1 protein P35226 UNIPROT up-regulates activity phosphorylation Ser316 ANRPRKSsVNGSSAT 22505453 t lperfetto The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate SIGNOR-252559 0.448 PRKCE protein Q02156 UNIPROT ALDH2 protein P05091 UNIPROT up-regulates activity phosphorylation Thr429 MQILKFKtIEEVVGR -1 28056995 t lperfetto Post-translational enhancement of ALDH2 activity can be achieved by serine/threonine phosphorylation by epsilon protein kinase C (epsilonPKC). |e identified S279 as a critical εPKC phosphorylation site in the activation of ALDH2. The critical catalytic site, cysteine 302 (C302) of ALDH2 is susceptible to adduct formation by reactive aldehyde, 4HNE, which readily renders the enzyme inactive. We show that phosphomimetic mutations of T185E, S279E and T412E confer protection of ALDH2 against 4HNE-induced inactivation, indicating that phosphorylation on these three sites by εPKC likely also protects the enzyme against reactive aldehydes. SIGNOR-271866 0.285 Autophagy phenotype SIGNOR-PH31 SIGNOR Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates 32218723 f lperfetto In many neurodegenerative conditions protein aggregation may occurs without specific GOF mutations in genes encoding aggregate-prone proteins. In these conditions protein aggregation is associated to the decline of cellular degradative functions, specifically of the autophagy-lysosomal pathway (ALP) (Figure 1). SIGNOR-262269 0.7 CSNK1E protein P49674 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-250805 0.351 SOST protein Q9BQB4 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 22298955 f Interacts with LRP4 (via the extracellular domain);the interaction facilitates the Wnt signaling. Interacts with LRP5 (via the first two YWTD-EGF repeat domains);the interaction inhibits Wnt-mediated signaling. gcesareni It has been shown that both sclerostin and dkk1 act physiologically as downstream mole-cules of bmp signaling to inhibit canonical wnt sig-naling and therefore negatively regulate bone mass SIGNOR-195684 0.567 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates deacetylation 9606 15126506 t gcesareni Deacetylation of foxos involves binding of the nad-dependent deacetylase hsir2(sirt1). Accordingly, hsir2(sirt1)-mediated deacetylation precludes foxo inhibition through acetylation and thereby prolongs foxo-dependent transcription of stress-regulating genes. SIGNOR-252993 0.909 TLRs proteinfamily SIGNOR-PF20 SIGNOR Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 9606 20404851 f lperfetto TLR signaling pathways can be largely classified as either MyD88-dependent pathways, which drive the induction of inflammatory cytokines, or TRIF-dependent pathways, which are responsible for the induction of type I interferon as well as inflammatory cytokines3. SIGNOR-216310 0.7 IFNB1 protein P01574 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 10918594 f gcesareni Early events in type i ifn signaling are tyrosine phosphorylation of the type i ifn receptor subunits (ifnar1 and ifnar2), and the activation of the receptor-associated tyk-2 and jak-1 janus kinases SIGNOR-80100 0.521 TRPM6 protein Q9BX84 UNIPROT TRPM6 protein Q9BX84 UNIPROT down-regulates activity phosphorylation Thr1851 FNQVKPQtIPYTPRF 9606 18258429 t Manara Autophosphorylation of Threonine1851 in the Kinase Domain Is Essential for the Inhibitory Effect of RACK1 SIGNOR-260922 0.2 CAMK2A protein Q9UQM7 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity phosphorylation Ser325 EQLSRELsTLRNLFK -1 1314426 t llicata These studies implicate Ser276 of CIEBPP as the major in vim phosphorylation site for CaMKII. | Phosphorylation of serine at position 276 within the leucine zipper of C/EBP beta appeared to confer calcium-regulated transcriptional stimulation of a promoter that contained binding sites for C/EBP beta. SIGNOR-250617 0.332 HIF1A protein Q16665 UNIPROT KDM2A protein Q9Y2K7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271566 0.2 PRKACA protein P17612 UNIPROT FXYD1 protein O00168 UNIPROT unknown phosphorylation Ser88 RSSIRRLsTRRR 9606 21220422 t llicata We conclude that phosphorylation of plm increases its oligomerization into tetramers, decreases its binding to nka, and alters the structures of both the tetramer and nka regulatory complex. SIGNOR-171188 0.43 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN1 protein Q92952 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 18955585 t Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  SIGNOR-258026 0.8 trametinib chemical CHEBI:75998 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192823 0.8 KDM4C protein Q9H3R0 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys37 APATGGVkKPHRYRP 9606 29207681 t miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation SIGNOR-263864 0.2 MAPK1 protein P28482 UNIPROT AEBP1 protein Q8IUX7 UNIPROT up-regulates activity phosphorylation Thr621 GEPEFRYtAGIHGNE 10090 BTO:0000944 15654748 t miannu We show that DNA binding by AEBP1 requires both the N- and C-terminal domains of AEBP1, and MAPK interaction with AEBP1 (through its N terminus) results in enhanced DNA binding. A threonine at position 623 within the C-terminal domain of AEBP1 plays an important role in DNA binding by AEBP1, because the mutation results in decreased DNA binding by AEBP1, which leads to a decrease in the transcriptional repression ability of AEBP1. We also show that in vitro phosphorylation of AEBP1 by MAPK is greatly reduced upon mutation of T623. These results suggest that MAPK regulates the transcriptional activity of AEBP1 by a novel dual mechanism, in which MAPK interaction enhances and subsequent phosphorylation decreases the DNA-binding ability of AEBP1. SIGNOR-262897 0.2 CRYBB2 protein P43320 UNIPROT CRYBB1 protein P53674 UNIPROT up-regulates activity binding 9606 16319073 t miannu At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency. SIGNOR-252153 0.2 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser272 EEPSPLPsPTASPNH 9606 BTO:0000142 15262992 t lperfetto Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd SIGNOR-126843 0.405 HTR6 protein P50406 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256801 0.481 R547 chemical CID:6918852 PUBCHEM CDK4 protein P11802 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258274 0.8 DNMT1 protein P26358 UNIPROT BAG3 protein O95817 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 18413740 f lperfetto In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+) SIGNOR-254110 0.2 F2 protein P00734 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates binding 9606 8626456 t gcesareni In vitro binding studies revealed that antithrombin iii (atiii)thrombin, heparin cofactor ii (hcii)thrombin, and ?1-antitrypsin (?1AT)trypsin bound to purified lrp SIGNOR-41090 0.286 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 t The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction. SIGNOR-175809 0.845 TYK2 protein P29597 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 10542297 t lperfetto Stat3 activation requires kinase function of tyk2. SIGNOR-71781 0.675 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Arg707 ESTVMATrKMHDRLE -1 7989361 t lperfetto The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994. SIGNOR-263630 0.584 ATIC protein P31939 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI down-regulates quantity chemical modification 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267325 0.8 TRIM25 protein Q14258 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 17392790 t lys63 miannu The carboxy-terminal SPRY domain of TRIM25 interacts with the N-terminal CARDs of RIG-I; this interaction effectively delivers the Lys 63-linked ubiquitin moiety to the N-terminal CARDs of RIG-I, resulting in a marked increase in RIG-I downstream signalling activity.  Thus, we demonstrate that TRIM25 E3 ubiquitin ligase induces the Lys 63-linked ubiquitination of RIG-I, which is crucial for the cytosolic RIG-I signalling pathway to elicit host antiviral innate immunity. SIGNOR-271645 0.795 MECP2 protein P51608 UNIPROT RELN protein P78509 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 f miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. SIGNOR-254578 0.388 NOXO1 protein Q8NFA2 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 20943948 t lperfetto Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation SIGNOR-264709 0.769 STAT3 protein P40763 UNIPROT RORC protein P51449 UNIPROT up-regulates 9606 18454151 f The inflammatory cytokines IL-6, IL-21 and IL-23 share signaling pathways by activating both STAT1 and STAT3, while IL-1beta is thought to activate the kinases IRAK1 and IRAK2 through recruitment of the adaptor MyD88. Thus, STAT3 is likely to be a common denominator in the induction of RORgammaT and IL-17 expression SIGNOR-254303 0.625 PRKACA protein P17612 UNIPROT ADD2 protein P35612 UNIPROT down-regulates activity phosphorylation Ser726 KKKEKVEs -1 8810272 t miannu Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of - and -adducin, respectively, were identified as the major phosphorylation sites common for PKA and PKC. Phosphorylation by PKA, but not PKC, reduced the affinity of adducin for spectrin-F-actin complexes as well as the activity of adducin in promoting binding of spectrin to F-actin. SIGNOR-250333 0.286 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9534 BTO:0000298 phosphorylation:Tyr177 8402896 t gcesareni BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation SIGNOR-248199 0.2 RAPGEF5 protein Q92565 UNIPROT RAP1A protein P62834 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 21791615 t miannu We found here that cAMP-dependent activation of Epac1 and Rap1 but not PKA is able to activate CaMKI to mediate Ser47 (S47) phosphorylation in GCM1. Epac1 and Epac2 proteins were identified as cAMP-binding proteins with guanine nucleotide exchange factor (GEF) activities for the small GTPases, Rap1 and Rap2 SIGNOR-262682 0.638 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LATS2 protein Q9NRM7 UNIPROT down-regulates 10090 BTO:0002572 22863277 f milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. SIGNOR-198520 0.8 RCOR1 protein Q9UKL0 UNIPROT BHC complex complex SIGNOR-C353 SIGNOR form complex binding 9606 BTO:0000567; BTO:0000007 15325272 t miannu BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells SIGNOR-264498 0.823 STC2/HMOX1 complex SIGNOR-C244 SIGNOR heme smallmolecule CHEBI:30413 ChEBI down-regulates quantity by destabilization 22503972 t lperfetto Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is a heat shock protein.|Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme. SIGNOR-260405 0.8 CHMP5 protein Q9NZZ3 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 t miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. SIGNOR-265527 0.704 UCHL5 protein Q9Y5K5 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity deubiquitination 9606 16027725 t lperfetto Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases SIGNOR-217610 0.386 SREBF2 protein Q12772 UNIPROT PCSK9 protein Q8NBP7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21123766 t miannu Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes. SIGNOR-254459 0.478 OPHN1 protein O60890 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity gtpase-activating protein 9606 BTO:0000938 12932438 t miannu OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro SIGNOR-268399 0.574 NMDA proteinfamily SIGNOR-PF56 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264691 0.7 PIM3 protein Q86V86 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 16403219 t lperfetto All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death. SIGNOR-249605 0.353 BAP1 protein Q92560 UNIPROT CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 26470845 t lperfetto Since we found that ASXL1 and BAP1 both are enriched at the INK4B locus, our results suggest that activation of the INK4B locus requires ASXL1/BAP1-mediated deubiquitinylation of H2AK119ub1. SIGNOR-241656 0.2 PKI-587 chemical CID:44516953 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205992 0.8 PTPRF protein P10586 UNIPROT DAPK1 protein P53355 UNIPROT up-regulates dephosphorylation Tyr490 HCAAWHGyYSVAKAL 9606 17803936 t gcesareni Here, we show that the leukocyte common antigen-related (lar) tyrosine phosphatase dephosphorylates dapk at py491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of dapk. SIGNOR-157702 0.2 BAK1 protein Q16611 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. SIGNOR-261493 0.7 NDN protein Q99608 UNIPROT BMI1 protein P35226 UNIPROT down-regulates 9606 BTO:0000007 24392140 f lperfetto In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, SIGNOR-253384 0.255 PEX12 protein O00623 UNIPROT PEX5 protein P50542 UNIPROT up-regulates activity ubiquitination -1 19687296 t miannu Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. SIGNOR-253020 0.673 RAN protein P62826 UNIPROT XPO1 protein O14980 UNIPROT up-regulates activity binding 31075303 t Ran ID inferred from sequence: KRHLTGEFEKKYVATLGVEV lperfetto The nuclear export by CRM1 requires an interaction with the small GTPase Ras-related nuclear antigen (Ran), which cycles between GTP- and GDP-bound states. The binding of Ran GTP to CRM1 in the nucleus increases the affinity of CRM1 for cargo proteins SIGNOR-275848 0.926 GSK3B protein P49841 UNIPROT NIFK protein Q9BYG3 UNIPROT up-regulates activity phosphorylation Thr234 TVDSQGPtPVCTPTF -1 16244663 t miannu The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1. SIGNOR-262698 0.2 MAPK1 protein P28482 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Thr709 PKRLGAHtP 9606 14697653 t lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. SIGNOR-120463 0.262 EP300 protein Q09472 UNIPROT CPT1B protein Q92523 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0001538 15199055 f Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. SIGNOR-254260 0.2 WNT11 protein O96014 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. SIGNOR-141428 0.642 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation 9606 31226734 t lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. SIGNOR-265921 0.598 NFIB protein O00712 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268903 0.2 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7834749 t Nuclear p53 amattioni Bax is a p53 primary-response gene, presumably involved in a p53-regulated pathway for induction of apoptosis SIGNOR-33922 0.743 Isradipine chemical CHEBI:6073 ChEBI CACNA1C protein Q13936 UNIPROT down-regulates activity chemical inhibition 9606 10072735 t miannu The protein expression as measured by3H-(+)-PN 200-110-binding (Bmax) and Western Blot analysis withcalsequestrin as reference was similar in left ventricular failing and non-failing myocardium. However, both werereduced in atrial compared to ventricular tissue in failing and non-failing hearts. The KDremained unchanged. SIGNOR-259076 0.8 RBBP7 protein Q16576 UNIPROT HNuRF complex SIGNOR-C448 SIGNOR form complex binding 9606 BTO:0000007 14609955 t miannu hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays. SIGNOR-268815 0.559 SNAI1 protein O95863 UNIPROT PLAU protein P00749 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19055748 f lperfetto We demonstrated by both cDNA microarrays and real-time quantitative RT-PCR that the functional blockade of SNAI1 induces a significant decrease of PAI-1 and uPA transcripts. SIGNOR-252263 0.326 XAF1 protein Q6GPH4 UNIPROT XIAP protein P98170 UNIPROT down-regulates binding 9606 17613533 t gcesareni Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3. SIGNOR-155637 0.575 ULK1 protein O75385 UNIPROT PRKAG3 protein Q9UGI9 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity phosphorylation of ampk by ulk1 represents a negative feedback circuit. SIGNOR-173053 0.381 SLC25A12 protein O75746 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity relocalization 9606 12084073 t miannu Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. SIGNOR-265154 0.8 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000938 24614225 t lperfetto Thus, serine 418 is phosphorylated in vivo.Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204716 0.529 SMURF1 protein Q9HCE7 UNIPROT SMAD9 protein O15198 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps SIGNOR-195669 0.656 IL1B protein P01584 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by repression transcriptional regulation 10116 9397972 f inferred from family member scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5‚Äô-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. SIGNOR-270241 0.2 AKT1 protein P31749 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates phosphorylation 9606 21619873 t gcesareni Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5 SIGNOR-252514 0.433 ADP chemical CHEBI:16761 ChEBI AMPK complex SIGNOR-C15 SIGNOR up-regulates chemical activation 9606 21399626 t lperfetto Amp binding to the gamma-regulatory domain promotes phosphorylation by the upstream kinase, protects the enzyme against dephosphorylation, as well as causing allosteric activation.Adp also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive. SIGNOR-217475 0.8 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) smallmolecule CHEBI:57795 ChEBI 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) smallmolecule CHEBI:58456 ChEBI up-regulates quantity precursor of 9606 9367159 t Gianni The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities'. Here we have reinvestigated the substrate specificities of these enzymes. As expected, the type I enzyme phosphorylates PtdIns-4-P at the D-5 position of the inositol ring. Surprisingly, the type II enzyme, which is abundant in some tissues, phosphorylates PtdIns-5-P at the D-4 position, and thus should be considered as a 4-OH kinase, or PIP(4)K SIGNOR-268865 0.8 CSNK2A1 protein P68400 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser13 ESFTMASsPAQRRRG 9606 16446360 t gcesareni In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2 SIGNOR-144004 0.262 MAPK1 protein P28482 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Ser362 ISSVPTPsPLGPLAG 9606 BTO:0000527 19941816 t lperfetto Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity SIGNOR-161851 0.376 MYC protein P01106 UNIPROT IMPDH1 protein P20839 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 t miannu Here, we report that the majority of genes in human purine and pyrimidine biosynthesis pathway were induced and directly bound by c-Myc in the P493-6 human Burkitt's lymphoma model cell line. The mRNA levels of IMPDH1 and IMPDH2, the rate-limiting enzyme in purine de novo synthesis, increased with MYC induction both in vitro and in vivo. SIGNOR-267378 0.245 SPAG9 protein O60271 UNIPROT ABL1 protein P00519 UNIPROT unknown binding 9606 BTO:0000222 SIGNOR-C21 19470755 t lperfetto We report that abl associates with both cdo and jlp during myoblast differentiation SIGNOR-185765 0.508 JUN protein P05412 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 10871633 t irozzo These results indicate that interaction between Smad3 and c-Jun may repress Smad3 transcriptional activity. SIGNOR-256284 0.741 ABCA7 protein Q8IZY2 UNIPROT APOA1 protein P02647 UNIPROT up-regulates activity binding 9606 BTO:0000007 12917409 t miannu ATP-binding cassette transporter A7 (ABCA7) binds apolipoprotein A-I and mediates cellular phospholipid but not cholesterol efflux. HEK293 cells overexpressing ABCA7 showed specific binding and cross-linking of lipid-poor apoA-I. ABCA7 expression increased cellular phosphatidylcholine and sphingomyelin efflux to apoA-I in a manner similar to ABCA1 but had no effect on cholesterol efflux. SIGNOR-265178 0.449 AKT1 protein P31749 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 11108261 t lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. SIGNOR-84967 0.756 CASP8 protein Q14790 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 f amattioni Downstream of caspase-8 activation, apoptosis induction takes place SIGNOR-256639 0.7 CTNNB1 protein P35222 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265813 0.923 CHUK protein O15111 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000567 SIGNOR-C14 SIGNOR-C13 10521409 t lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. SIGNOR-71270 0.842 CDK1 protein P06493 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Ser362 ISSVPTPsPLGPLAG 9606 BTO:0000527 19941816 t gcesareni The mitotic phosphorylation sites on the alpha subunit of casein kinase ii can be phosphorylated in vitro by p34cdc2. SIGNOR-161839 0.361 SP1 protein P08047 UNIPROT SLC2A1 protein P11166 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9148896 f lperfetto These data suggest a regulatory model in which MyoD activation during myogenesis causes the down-regulation of Sp1, which contributes to the repression of GLUT1 gene transcription and, therefore, leads to the reduction in GLUT1 expression and glucose transport. SIGNOR-241485 0.366 FRAT1 protein Q92837 UNIPROT EIF2B5 protein Q13144 UNIPROT up-regulates activity binding 10481074 t lperfetto In contrast to the GS‐1 peptide, glycogen synthase and the eIF2B peptide, the GSK3‐catalysed phosphorylation of Tau was completely inhibited by FRATtide|This prevents GSK3 from phosphorylating and inhibiting glycogen synthase [2, 3] and protein synthesis initiation factor eIF2B SIGNOR-262835 0.292 CD38 protein P28907 UNIPROT NAD(+) smallmolecule CHEBI:15846 ChEBI down-regulates quantity chemical modification 9606 18626062 t miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. SIGNOR-264246 0.8 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr390 DSKFTRQtPVDSPDD 9606 11914378 t Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain,[…] Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings. SIGNOR-255839 0.96 SIK2 protein Q9H0K1 UNIPROT MLXIPL protein Q9NP71 UNIPROT down-regulates 10090 24841198 f lperfetto Moreover, SIK2 was shown to down-regulate the carbohydrate-responsive element-binding protein (ChREBP)-mediated lipogenesis in hepatocytes through the inhibitory phosphorylation of p300/Ser89 and to prevent steatosis in mice SIGNOR-265746 0.329 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1185 FGMTRDIyETDYYRK 10090 BTO:0000944 11579209 t lperfetto Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor. SIGNOR-235495 0.78 ERBB4 protein Q15303 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 16729043 t gcesareni Egfr and erbb4 had several docking sites for grb2, while erbb3 was characterized by six binding sites for pi3k. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength. SIGNOR-146876 0.824 SF3A3 protein Q12874 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270663 0.736 ID3 protein Q02535 UNIPROT TCF12 protein Q99081 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C128 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241152 0.478 RAI1 protein Q7Z5J4 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 BTO:0000614 22578325 f miannu Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. SIGNOR-266844 0.39 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 21157483 t lperfetto Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.Recent findings have revealed novel important roles for mTORC2 in the phosphorylation of AGC kinase family members. mTORC2 phosphorylates and activates Akt, SGK, and PKC, which regulate cell survival, cell cycle progression and anabolism SIGNOR-251982 0.634 HMGA1 protein P17096 UNIPROT POU3F1 protein Q03052 UNIPROT up-regulates activity binding 9606 BTO:0002127 7791781 t 2 miannu Direct contacts were identified between the POU domain of Tst-1/Oct-6 and a short stretch of 10 amino acids in the central portion of HMG-I/Y. In the presence of HMG-I/Y, Tst-1/Oct-6 exhibited an increased affinity for this AT-rich element. SIGNOR-240155 0.312 D-serine smallmolecule CHEBI:16523 ChEBI NMDA receptor_2A complex SIGNOR-C347 SIGNOR up-regulates activity chemical activation 9606 BTO:0002609 12393813 t lperfetto D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically SIGNOR-268277 0.8 CDK5 protein Q00535 UNIPROT PRKN protein O60260 UNIPROT down-regulates phosphorylation Ser131 HTDSRKDsPPAGSPA 9606 BTO:0000142 17327227 t llicata Phosphorylation by cdk5 decreased the auto-ubiquitylation of parkin both in vitro and in vivo. SIGNOR-153445 0.2 NFAT5 protein O94916 UNIPROT LCN2 protein P80188 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000815 22266867 t done miannu  As expected, the depletion of NFAT5 decreased the S100A4 and LCN2 mRNA levels (Figure 3a). In addition, chromatin immunoprecipitation (ChIP) assay using NFAT5 antibody indicated that NFAT5 was bound to the S100A4 and LCN2 promoters (Figure 3b, Supplementary Figure S3), as expected (Chen et al., 2009). SIGNOR-274114 0.334 Succinyl-CoA ATP variant complex SIGNOR-C398 SIGNOR succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI down-regulates quantity chemical modification 9606 27487822 t miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. SIGNOR-266267 0.8 APBA1 protein Q02410 UNIPROT STXBP1 protein P61764 UNIPROT up-regulates activity binding 10116 9395480 t miannu Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1. SIGNOR-264035 0.689 Angiotensin-2 protein P01019-PRO_0000032458 UNIPROT AGTR2 protein P50052 UNIPROT up-regulates activity binding 9606 32201502 t MIANNU Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways SIGNOR-260237 0.2 CD28 protein P10747 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 BTO:0000782 18006698 t gcesareni Cd28 can bind directly to pi3k by a well-characterized ymnm binding motif in its cytoplasmic domain. SIGNOR-159322 0.376 THEM4 protein Q5T1C6 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates binding 9606 11598301 t lperfetto Here, we describe a protein partner for pkbalpha termed ctmp, or carboxyl-terminal modulator protein, that binds specifically to the carboxyl-terminal regulatory domain of pkbalpha at the plasma membrane. Binding of ctmp reduces the activity of pkbalpha by inhibiting phosphorylation on serine 473 and threonine 308. SIGNOR-244455 0.686 PXN protein P49023 UNIPROT ILK protein Q13418 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 11304546 t gcesareni Co-immunoprecipitation from fibroblasts confirmed that the association between paxillin and ilk occurs in vivo in both adherent cells and cells in suspension. [__] thus, paxillin binding is necessary for efficient focal adhesion targeting of ilk and may therefore impact the role of ilk in integrin-mediated signal transduction events. SIGNOR-106824 0.792 MAPK3 protein P27361 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity relocalization 9606 18596912 t lperfetto The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform SIGNOR-179407 0.407 EEF1A1 protein P68104 UNIPROT Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269514 0.8 LATS2 protein Q9NRM7 UNIPROT CDC26 protein Q8NHZ8 UNIPROT up-regulates activity phosphorylation Thr7 tRLELKLD 25723520 t lperfetto LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C|Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C SIGNOR-275474 0.472 AURKA protein O14965 UNIPROT FAF1 protein Q9UNN5 UNIPROT down-regulates activity phosphorylation Ser289 ITDVHMVsDSDGDDF 9606 18790738 t llicata This study reports that aurora-a (aur-a) phosphorylates fas-associated factor-1 (faf1) at ser-289 and ser-29 our findings support the negative feedback regulation of aur-a via phosphorylation of the death-promoting protein, faf1 SIGNOR-180887 0.2 TBL1XR1 protein Q9BZK7 UNIPROT BCL3 protein P20749 UNIPROT down-regulates ubiquitination 9606 20547759 t miannu We also defined the e3 ligase tblr1 as a protein involved in bcl-3 degradation SIGNOR-166111 0.411 SRC protein P12931 UNIPROT VAMP7 protein P51809 UNIPROT up-regulates activity phosphorylation Tyr45 SENNKLTySHGNYLF 9534 BTO:0000298 23471971 t done miannu We found that TI-VAMP is phosphorylated in vitro by c-Src kinase on tyrosine 45 of the Longin domain.Mimicking tyrosine 45 phosphorylation activates both t-SNARE binding and exocytosis of TI-VAMP. SIGNOR-273819 0.29 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA6 protein Q9Y5G7 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265716 0.2 SF1 protein Q15637 UNIPROT FUS protein P35637 UNIPROT down-regulates binding 9606 9660765 t miannu We speculate that zfm1 may inhibit transcription driven by the ntds of tls SIGNOR-58967 0.541 FOXA1 protein P55317 UNIPROT SFTPB protein P07988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12161428 f miannu A homeodomain and a forkhead transcription factor, NKX2.1 and HNF-3, respectively, are known activators of Sp-B transcription SIGNOR-254181 0.287 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity phosphorylation Thr187 KRNTVIGtPFWMAPE 9534 BTO:0004055 12223493 t lperfetto Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationWe define Thr(183) in subdomain VIII as a primary site of phosphoactivation. Thr(187) is also critical for kinase activity. SIGNOR-247581 0.2 Wnt proteinfamily SIGNOR-PF40 SIGNOR LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t inferred from 70% family members gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-269961 0.2 CSNK2A2 protein P19784 UNIPROT CAV1 protein Q03135 UNIPROT unknown phosphorylation Ser88 FDGIWKAsFTTFTVT -1 8058322 t llicata Here, we have identified this serine kinase activity as a casein kinase II-like enzyme, since the phosphorylation of caveolin-rich membrane domains is stimulated and inhibited by known effectors of casein kinase II (poly-L-lysine, endogenous polyamines, and a casein kinase II inhibitor peptide), but is unaffected by modulators of other known kinases. In support of these observations, caveolin contains a consensus sequence for casein kinase II phosphorylation in its cytoplasmic N-terminal domain (Ser-88) SIGNOR-250981 0.363 FOS protein P01100 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19022561 t miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254877 0.2 STAT3 protein P40763 UNIPROT IL10 protein P22301 UNIPROT up-regulates transcriptional regulation 9606 22378047 f IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype SIGNOR-254515 0.782 HRH4 protein Q9H3N8 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256672 0.496 17beta-hydroxy-5alpha-androstan-3-one smallmolecule CHEBI:16330 ChEBI COMT protein P21964 UNIPROT up-regulates 9606 17612537 f Regulation of expression miannu Catechol O-methyltransferase expression in granulosa cells was up-regulated by insulin, DHT, and ATRA. SIGNOR-251962 0.8 RNF146 protein Q9NTX7 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 21478859 t lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. SIGNOR-263335 0.631 CDK1 protein P06493 UNIPROT USP16 protein Q9Y5T5 UNIPROT up-regulates phosphorylation Ser552 DLEVLTSsPTRNLNG 9606 24013421 t llicata Here, we report that cyclin-dependent kinase 1 (cdk1) phosphorylates the histone h2a deubiquitinase ubp-m at serine 552 (s552p), and, importantly, this phosphorylation is required for cell cycle progression. SIGNOR-202678 0.466 MAPK1 protein P28482 UNIPROT STMN3 protein Q9NZ72 UNIPROT unknown phosphorylation Ser68 PSDLSPEsPMLSSPP -1 22577147 t lperfetto Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta SIGNOR-264895 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 BTO:0000567 17615152 t lperfetto In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-244651 0.2 TRIM63 protein Q969Q1 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys74 DTGRILSkLHTVQPK -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). SIGNOR-272738 0.413 SOX9 protein P48436 UNIPROT MITF protein O75030 UNIPROT up-regulates activity binding 10090 20530484 t miannu BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles. SIGNOR-255183 0.392 ARTN protein Q5T4W7 UNIPROT GFRA3 protein O60609 UNIPROT up-regulates binding 9606 BTO:0000938 9883723 t gcesareni Here, we report the identification of artemin, a novel member of the gdnf family, and demonstrate that it is the ligand for the former orphan receptor gfralpha3-ret. Artemin can also activate the gfralpha1-ret complex. SIGNOR-63009 0.753 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser321 SKPSGNDsCELRNLK -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276212 0.388 BRAF protein P15056 UNIPROT SLC5A5 protein Q92911 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19861538 t miannu The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression. SIGNOR-251989 0.2 FBXO22 protein Q8NEZ5 UNIPROT BACH1 protein O14867 UNIPROT down-regulates quantity ubiquitination 9606 31257023 t Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22. SIGNOR-259331 0.285 CTSH protein P09668 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Gly58 RYLYQWLgAPVPYPD -1 9076588 t miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. SIGNOR-256324 0.286 YAP1 protein P46937 UNIPROT BMP4 protein P12644 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 f gcesareni In our analysis bmp4 (bone morphogenetic protein 4) and fstl3 (follistatin-related protein 3) increased their expression in response to hyap1 s127a overexpression. SIGNOR-199066 0.324 GRK1 protein Q15835 UNIPROT GRK1 protein Q15835 UNIPROT down-regulates activity phosphorylation Ser21 AFIAARGsFDGSSSQ -1 1527025 t The major autophosphorylation site yielded the following sequence: DVGAFS488T489VKGVAFEK, where Ser488 and Thr489 are phosphorylated. Additionally, a minor autophosphorylation site was identified at Ser21. we speculate that autophosphorylation of RK may lower the affinity of the enzyme for Rho* via repulsion between phosphorylated sites on Rho* and the kinase. SIGNOR-251186 0.2 PPM1A protein P35813 UNIPROT RELA protein Q04206 UNIPROT down-regulates activity dephosphorylation Ser276 SMQLRRPsDRELSEP 9606 23812431 t lperfetto 23 Here we show that PPM1A directly dephosphorylated RelA at S536 and S276, with resultant inhibition of NF-kappaB transactivation and decreased expression of target genes, notably including MCP-1 and CCL2.|Taken together, these data suggest that dephosphorylation of S276 by PPM1A may contribute to inhibit RelA transcriptional activity, but the majority of PPM1A activity to inhibit RelA transcription relies on dephos phorylation of S536 of RelA.|We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited Nuclear factor-\u03baB transcriptional activity, resulting in decreased expression of monocyte chemotactic protein-1/chemokine (C-C motif) ligand 2 and interleukin-6, cytokines implicated in cancer metastasis. SIGNOR-276963 0.36 MPHOSPH10 protein O00566 UNIPROT IMP4 protein Q96G21 UNIPROT up-regulates activity binding -1 28813493 t miannu Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome. In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA. SIGNOR-261174 0.809 pindolol chemical CHEBI:8214 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258884 0.8 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser262 DSEDYSLsEEGQELS 9606 12167711 t gcesareni Hypophosphorylation of mdm2 augments p53 stability. SIGNOR-91199 0.352 PLK1 protein P53350 UNIPROT CTNNB1 protein P35222 UNIPROT unknown phosphorylation Ser718 QDDPSYRsFHSGGYG 9606 19001871 t lperfetto Ser-718 of beta-catenin was directly phosphorylated by recombinant plk1thus it may be possible that function of the additional phosphorylation site(s) in cooperation with the ser-718 is required for the regulation of _-catenin at m phase SIGNOR-182150 0.408 PTPRG protein P23470 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity dephosphorylation Tyr754 ERKEVSKySDIQRSL -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254714 0.251 Gbeta proteinfamily SIGNOR-PF4 SIGNOR LCK protein P06239 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 8618896 t inferred from 70% family members lperfetto Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation. SIGNOR-270074 0.2 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA11 protein Q9Y5H2 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265690 0.2 NR5A2 protein O00482 UNIPROT CYP11B1 protein P15538 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002588 11564608 f miannu The ability of LRH-1 to enhance transcription of the gene encoding human 11 beta- hydroxylase (hCYP11B1) was then examined using the H295R adrenal cell line. LRH-1 co-transfection with hCYP11B1 luciferase promoter constructs caused a 25-fold induction of luciferase activity. Furthermore, co-transfection of a hCYP11B1 reporter construct containing a mutation in the SF-1 binding cis-element abolished the stimulatory effect of both SF-1 and LRH-1. Electrophoretic mobility shift assay (EMSA) demonstrated that LRH-1 could bind to the SF-1 response element. Taken together, our data suggested that LRH-1 is expressed in the adrenal, and can substitute for SF-1 to enhance transcription of genes encoding certain of the steroid-metabolizing enzymes. SIGNOR-254880 0.349 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. SIGNOR-129324 0.327 HTR1A protein P08908 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256972 0.435 CEP135 protein Q66GS9 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates activity binding -1 27477386 t miannu Here, we analyzed in detail the microtubule-binding activity of human CEP135 (HsCEP135).  Biochemical, cryo-electron, and fluorescence microscopy analyses revealed that in vitro HsCEP135-N interacts with tubulin, protofilaments, and microtubules and induces the formation of microtubule bundles SIGNOR-269678 0.2 CAMK2B protein Q13554 UNIPROT RETREG1 protein Q9H6L5 UNIPROT up-regulates activity phosphorylation Ser151 AQLWRSLsESWEVIN -1 31930741 t miannu Under ER-stress conditions, activated CAMK2B phosphorylates the reticulon-homology domain of FAM134B, which enhances FAM134B oligomerization and activity in membrane fragmentation to accommodate high demand for ER-phagy.  SIGNOR-273554 0.2 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr130 PAQLLCStPNGLDRG 9606 SIGNOR-C17 10864927 t gcesareni Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-78424 0.852 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser295 LSDTPYDsSASYEKE 9606 21750978 t miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo SIGNOR-174848 0.2 MDFI protein Q99750 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity binding 10090 BTO:0000944 8797820 t 2 miannu We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals. SIGNOR-240436 0.511 FEV protein Q99581 UNIPROT ICAM1 protein P05362 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12761502 f miannu Fev acts as a transcriptional repressor through its dna-binding ets domain and alanine-rich domain. / we show here that fev dramatically represses both basal and ectopically ets-activated transcription driven by the icam-1 promoter, and that the effect is dose dependent. SIGNOR-101246 0.2 MAPK1 protein P28482 UNIPROT THRB protein P10828 UNIPROT down-regulates activity phosphorylation Ser142 IQKNLHPsYSCKYEG 9606 12809513 t llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. SIGNOR-102216 0.39 PDPK1 protein O15530 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 10480933 t gcesareni We characterize two monoclonal antibodies raised against phosphorylated forms of the n- and c-terminal domain of rsk2 (p-s227 and p-t577, respectively). Using these two antibodies, we show that stress signals, such as uv light, induce phosphorylation and activation of the three rsks. SIGNOR-70612 0.641 NCOA1 protein Q15788 UNIPROT ESR1 protein P03372 UNIPROT up-regulates binding 9606 9427757 t miannu Steroid receptor co-activator (src1) is one of a number of transcriptional co-activators that are capable of potentiating the activity of nuclear receptors including the oestrogen receptor (er). SIGNOR-54442 0.839 PTPN1 protein P18031 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates dephosphorylation 9606 11350745 t gcesareni Dephosphorylation of tyrosine residues by ptp1b, a protein tyrosine phosphatase, reduced the enhanced pkcdelta activity. SIGNOR-107754 0.2 AMOTL2 protein Q9Y2J4 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 BTO:0001176 21937427 f lperfetto Taking together, our data indicate that Amotl2 plays a pivotal role in polarity, migration and proliferation of angiogenic endothelial cells. SIGNOR-271871 0.7 PI-103 chemical CHEBI:90524 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206169 0.8 NPFFR1 protein Q9GZQ6 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257103 0.255 HNRNPA1 protein P09651 UNIPROT TRA2B protein P62995 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31311954 t lperfetto HnRNPA1 interacts with G-quadruplex in the TRA2B promoter and stimulates its transcription in human colon cancer cells. SIGNOR-262288 0.685 TIMELESS protein Q9UNS1 UNIPROT CRY1 protein Q16526 UNIPROT up-regulates activity binding 9534 23418588 t miannu We performed a detailed molecular characterization of TIM interactions with the core clock protein CRY1 and the DNA damage signal transducer CHK1, and found that the N-terminus of TIM is required for association with both proteins, as well as for homodimerization. SIGNOR-268053 0.695 AKT2 protein P31751 UNIPROT STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr387 TMKRRDEtMQPAKPS 9606 23431053 t gcesareni Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt. SIGNOR-201125 0.264 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates quantity by destabilization phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 BTO:0000567 16085715 t miannu  In the present study, we show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms.  S123 phosphorylation creates a PBD-binding motif and accelerates S53 phosphorylation by Plk1. SIGNOR-276040 0.627 PCSK2 protein P16519 UNIPROT Neurophysin 1 protein P01178-PRO_0000020496 UNIPROT up-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270337 0.2 EIF3_complex complex SIGNOR-C401 SIGNOR EIF4G3 protein O43432 UNIPROT up-regulates activity stabilization 9606 17581632 t lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit SIGNOR-269157 0.394 SRC protein P12931 UNIPROT PROM1 protein O43490 UNIPROT unknown phosphorylation Tyr828 RMDSEDVyDDVETIP 9606 19296573 t llicata Cd133 (prominin-1) is phosphorylated on cytoplasmic tyrosine-828 and tyrosine-852 by src SIGNOR-184772 0.514 CDK8 protein P49336 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates phosphorylation 9606 15546612 t gcesareni Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. SIGNOR-254312 0.534 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176797 0.775 CDK2 protein P24941 UNIPROT PTPN12 protein Q05209 UNIPROT down-regulates activity phosphorylation Ser19 QRVQAMKsPDHNGED 9606 BTO:0000815 28842430 t miannu In the present study, we found that S19 site phosphorylation of PTPN12 by CDK2 discharged its antitumor activity by down-regulation of its inhibitory role in cell migration, but not affecting its other regulatory functions. SIGNOR-277366 0.39 MDH2 protein P40926 UNIPROT (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI down-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266284 0.8 HOXB8 protein P17481 UNIPROT ACTA2 protein P62736 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002196 15886193 t Luana Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively SIGNOR-261641 0.2 CDK1 protein P06493 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser286 TSGGVSEsPSGFSKH 9606 21765472 t lperfetto Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency SIGNOR-175071 0.419 GATA1 protein P15976 UNIPROT GATA2 protein P23769 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12432220 f irozzo Closer examination revealed a cross-regulatory mechanism by which GATA-1 can control the expression of GATA-2 and vice versa, possibly via essential GATA binding sites in their cis-acting elements.In this model, GATA-2 activates GATA-1 gene expression, while GATA-1 represses GATA-2 gene expression. SIGNOR-256058 0.419 PKA proteinfamily SIGNOR-PF17 SIGNOR CHKB protein Q9Y259 UNIPROT up-regulates activity phosphorylation Ser40 PKRRRASsLSRDAER 27149373 t lperfetto Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. | This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar. SIGNOR-275631 0.2 COLEC11 protein Q9BWP8 UNIPROT MASP1 protein P48740 UNIPROT up-regulates activity binding -1 20956340 t lperfetto On the basis of the significant concentration of CL-11 in circulation and CL-11's interaction with various microorganisms and MASP-1 and/or MASP-3, it is conceivable that CL-11 plays a role in activation of the complement system and in the defense against invading microorganisms. SIGNOR-263409 0.606 PRKAA2 protein P54646 UNIPROT PAK2 protein Q13177 UNIPROT unknown phosphorylation Ser20 APPVRMSsTIFSTGG 9606 SIGNOR-C15 22137581 t llicata Together, these results indicate that ampk phosphorylates endogenous ppp1r12c at s452 and pak2 at s20 in human cells. SIGNOR-195110 0.244 Inflammation phenotype SIGNOR-PH12 SIGNOR IL4 protein P05112 UNIPROT up-regulates 9606 BTO:0000399 11290754 f apalma Our findings indicate that chemokines acting via CCR3-initiated signaling pathways can very rapidly mobilize preformed stores of IL-4 from within human eosinophils. The means of extracellular release was by noncytotoxic, vesicular transport SIGNOR-255494 0.7 N-[4-[2-ethyl-4-(3-methylphenyl)-5-thiazolyl]-2-pyridinyl]benzamide chemical CHEBI:91360 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates activity chemical inhibition -1 16162000 t miannu A novel structural class of 4-phenyl-5-pyridyl-1,3-thiazoles was optimized as inhibitors of p38 MAP kinase and the proinflammatory cytokine TNF-α. it only significantly inhibited p38α (IC50 = 7.1 nM) and p38β (IC50 = 200 nM) in a concentration-dependent manner and was approximately 28 times more selective for p38α over p38β. SIGNOR-262223 0.8 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Arg41 TNATLDPrSFLLRNP -1 10978167 t lperfetto Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site. SIGNOR-263571 0.62 CCDC6-RET fusion protein SIGNOR-FP9 SIGNOR SHC1 protein P29353 UNIPROT up-regulates activity binding 9606 16946010 t miannu RET/PTC is tumorigenic in thyroid follicular cells; it transforms thyroid cells in culture and gives rise to thyroid carcinomas in transgenic mice. effects of RET/PTC activation require signaling along the MAPK pathway and, more specifically, the presence of the functional BRAF kinase. all breakpoints in the RET gene occur within intron 11, leaving intact the TK domain of the receptor and enabling the RET/PTC oncoprotein to bind SHC via Y1062 and activate the RAS-RAF-MAPK cascade SIGNOR-251986 0.2 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser398 VDLHISNsHPLSLTS -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178375 0.731 SAICAR(4-) smallmolecule CHEBI:58443 ChEBI 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58475 ChEBI up-regulates quantity precursor of 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-266609 0.8 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser249 AVIPINGsPRTPRRG 9606 15809340 t gcesareni Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively. SIGNOR-135181 0.928 MYC protein P01106 UNIPROT HNRNPA2B1 protein P22626 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20010808 t We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2, SIGNOR-268691 0.364 SMURF2 protein Q9HAU4 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates activity ubiquitination 9606 22298955 t lperfetto Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. SIGNOR-195681 0.578 RAC2 protein P15153 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9606 9705280 t gcesareni This report shows that rac1 binds to and stimulates the kinase activity of pak1 approximately 2- and 4-5-fold, respectively, better than rac2. SIGNOR-59546 0.773 LCK protein P06239 UNIPROT CHN2 protein P52757 UNIPROT down-regulates activity phosphorylation Tyr153 KMTTNPIyEHIGYAT 9606 BTO:0000661 19201754 t miannu We now demonstrate Lck-dependent phosphorylation of beta2-chimaerin in response to TCR triggering. We identify Tyr-153 as the Lck-dependent phosphorylation residue and show that its phosphorylation negatively regulates membrane stabilization of beta2-chimaerin, decreasing its GAP activity to Rac.  SIGNOR-276240 0.2 RFX complex complex SIGNOR-C104 SIGNOR HLA-DRB5 protein Q30154 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 f The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-254003 0.287 PAK3 protein O75914 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser744 GLKVGVSsRINEWLT 9606 BTO:0000887;BTO:0001260 20858431 t gcesareni We investigated the effects of phosphorylation by p(21)-activated kinase 3 (pak) and calmodulin on the 22 kda c-terminal fragment of caldesmon (cad22). We substituted the major pak sites, ser-672 and ser-702, with either alanine or aspartic acid to mimic nonphosphorylated and constitutively phosphorylated states of caldesmon, respectively. Phosphorylation at these sites weakened ca(2+)-calmodulin binding further and reduced the inhibitory activity of cad22 in the absence of ca(2+)-calmodulin. SIGNOR-167980 0.2 MAPK1 protein P28482 UNIPROT CEP55 protein Q53EZ4 UNIPROT down-regulates phosphorylation Ser428 KVAASPKsPTAALNE 9606 16198290 t lperfetto Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis. SIGNOR-140894 0.374 ORC5 protein O43913 UNIPROT ORC complex SIGNOR-C419 SIGNOR form complex binding 9606 32808929 t lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA SIGNOR-267563 0.964 PRKCA protein P17252 UNIPROT KCNMA1 protein Q12791 UNIPROT up-regulates phosphorylation Ser1200 SHSSQSSsKKSSSVH 9606 19592459 t gcesareni Results showed that mutating s1076 altered the effect of pkc activation on bk(ca) channels in hek-293 cells SIGNOR-186755 0.2 SMAD5 protein Q99717 UNIPROT SATB2 protein Q9UPW6 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 t Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation SIGNOR-268939 0.262 STK11 protein Q15831 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity phosphorylation Ser732 EAINEAIsVKQEVTD 9606 BTO:0002181 34216621 t miannu  Resveratrol promotes the binding between LKB1 and Sirt1, which we first reported, and this binding leads to LKB1-mediated phosphorylation of Sirt1 at three different serine residues in the C terminus of Sirt1. Mechanistically, LKB1-mediated phosphorylation increases intramolecular interactions in Sirt1, such as the binding of the C terminus to the deacetylase core domain, thereby eliminating DBC1 (Deleted in Breast Cancer 1, Sirt1 endogenous inhibitor) inhibition and promoting Sirt1-substrate interaction.  SIGNOR-277323 0.59 NFASC protein O94856 UNIPROT ANK1 protein P16157 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 t miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. SIGNOR-266718 0.672 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser240 RLSSLRAsTSKSESS 9606 21233202 t lperfetto In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity SIGNOR-171243 0.607 DLG4 protein P78352 UNIPROT DLGAP1 protein O14490 UNIPROT up-regulates activity relocalization 9606 18923512 t brain lperfetto Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). SIGNOR-264196 0.931 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 11258706 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-105741 0.764 SYN2 protein Q92777 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR down-regulates 9606 BTO:0000938 33809712 f miannu Synapsins are a family of peripheral proteins that bind to the SV membrane. Synapsins Maintain the SV Reserve Pool. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet. SIGNOR-264106 0.7 PIK3C3 protein Q8NEB9 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates relocalization 9606 10698680 t lperfetto One of the best characterized targets of pi3k lipid products is the protein kinase akt or protein kinase b (pkb). In quiescent cells, pkb resides in the cytosol in a low-activity conformation. Upon cellular stimulation, pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1). SIGNOR-75370 0.445 AARS1 protein P49588 UNIPROT tRNA(Ala) smallmolecule CHEBI:29170 ChEBI down-regulates quantity chemical modification 9606 32314272 t miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). SIGNOR-270445 0.8 trimethyl-[(5-methyl-2-furanyl)methyl]ammonium chemical CHEBI:94038 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258646 0.8 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000938 17591690 t gcesareni Here, we demonstrate for the first time that cdk5 interacts with p53 and increases its stability through posttranslational regulation, leading to accumulation of p53, particularly in the nucleus. We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 in vitro, SIGNOR-156418 0.722 USO1 protein O60763 UNIPROT GOLGB1 protein Q14789 UNIPROT up-regulates activity binding 9606 23555793 t miannu The “cis-golgin tether” is one of the most well-characterized golgin tether complexes. It is composed of the COPI vesicle-associated golgin giantin linked to Golgi membrane-associated GM130 via p115. GM130 is in turn linked to GRASP65 via a PDZ-like domain. GRASP65 is anchored to the Golgi membrane through N-terminal myristoylation as well as through binding to other Golgi proteins [10]. Together, these proteins appear to mediate vesicle tethering at the cis-Golgi membrane. SIGNOR-261237 0.834 CHKB protein Q9Y259 UNIPROT O-phosphonatoethanaminium(1-) smallmolecule CHEBI:58190 ChEBI up-regulates quantity chemical modification 29928787 t lperfetto In this study, we investigated the roles of ethanolamine kinases (Etnk-1 and 2) and choline kinases (Chk-α and β) in contributing to increased PE in human breast and pancreatic cancer cells. SIGNOR-275639 0.8 GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268596 0.2 EXOC6B protein Q9Y2D4 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270781 0.751 MTOR protein P42345 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 29789464 f Luana The mTOR complexes are essential to neurogenesis and the establishment of neural circuits. | Activation of mTOR complexes exerts profound effects on all the processes of neurogenesis, including dendrite formation. SIGNOR-265771 0.7 BBC3 protein Q9BXH1 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 22492984 t gcesareni Bim, and puma bind with high affinity to all pro-survival proteins SIGNOR-196929 0.391 4-Iodo-3-nitrobenzamide chemical CID:9796068 PUBCHEM PARP1 protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193474 0.8 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates binding 9606 12954613 t PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. gcesareni C1a domain is critical for the dag-induced activation of pkcalfa.Furthermore, calcium and diacylglycerol activate protein kinase c, resulting in the phosphorylation of a large variety of substrates. SIGNOR-100254 0.8 SCF-betaTRCP complex SIGNOR-C5 SIGNOR PER2 protein O15055 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 17876059 t miannu Here, the authors show that the F-box protein beta-transducin repeat containing protein 1 (beta-TrCP1) as part of the E3 ubiquitin ligase complex is an essential component of the mammalian circadian oscillator. Down-regulation of endogenous beta-TrCP1 as well as expression of a dominant-negative form both result in lengthening of the circadian period in oscillating fibroblasts. These phenotypes are due to an impaired degradation of PERIOD (PER) proteins, since expression of beta-TrCP interaction-deficient PER2 variants--but not wild-type PER2--results in a dramatic stabilization of PER2 protein as well as in the disruption of circadian rhythmicity. SIGNOR-268055 0.466 XL147 chemical CHEBI:71957 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252659 0.8 PTPRG protein P23470 UNIPROT STAT5A protein P42229 UNIPROT up-regulates activity dephosphorylation Tyr694 LAKAVDGyVKPQIKQ -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254730 0.268 FYN protein P06241 UNIPROT SLAMF1 protein Q13291 UNIPROT up-regulates activity phosphorylation Tyr307 QDPCTTIyVAATEPV 9534 BTO:0000298 11806999 t All 3 tyrosines of CD150 (Tyr281, Tyr307, Tyr327) are phosphorylated by the src kinase Fyn. CD150 is unique among its homologues in the immunoglobulin superfamily in that it is able to bind SAP, a floating SH2 domain, in the absence of tyrosine phosphorylation. In this study, using a detailed mutagenesis mapping approach we have shown that SAP binding to CD150 is in fact bimodal. Prior to tyrosine phosphorylation, SAP binds the membrane-proximal motif surrounding Tyr281. Following tyrosine phosphorylation by tyrosine kinases such as Fyn, SAP binds additionally to the distal motif surrounding Tyr327. SIGNOR-251182 0.647 GFs stimulus SIGNOR-ST12 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates 9606 23863153 f lperfetto Growth factors and nutrients regulate the mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] by different mechanisms. The players that link growth factors and mTORC1 activation have been known for several years and mouse models have validated its relevance for human physiology and disease. SIGNOR-219382 0.7 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CIC protein Q96RK0 UNIPROT down-regulates phosphorylation 9606 BTO:0000848 21087211 t inferred from 70% family members gcesareni Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3 SIGNOR-270090 0.2 PIAS1 protein O75925 UNIPROT STAT1 protein P42224 UNIPROT down-regulates binding 9606 14699505 t gcesareni Pias1 inhibits binding of stat1 dimers to the response elements in the promoters of target genes SIGNOR-120548 0.787 GRK6 protein P43250 UNIPROT SLC9A3R1 protein O14745 UNIPROT down-regulates activity phosphorylation Ser290 PALVRSAsSDTSEEL 9606 10446210 t GRK6A phosphorylates NHERF on Ser289, the primary site of constitutive phosphorylation of NHERF in HEK-293 cells. The interaction of NHERF and NHE3 is mediated by the region of NHERF encompassing the second PDZ domain and the tail (25), and it is therefore reasonable that phosphorylation of the serine-rich stretch in the center of this region (including Ser289) might affect the physical interaction of NHERF with NHE3. SIGNOR-251214 0.414 Avasimibe chemical CID:166558 PUBCHEM SOAT1 protein P35610 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190119 0.8 PXN protein P49023 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity 9606 BTO:0000182 phosphorylation:Tyr88 PQSSSPVyGSSAKTS 27447856 f lperfetto Together, our data suggest that phosphorylation of paxillin Y88 activates AKT through the paxillin-p130Cas-p85/PI3K-AKT signaling axis and promotes colorectal tumorigenesis SIGNOR-263979 0.917 MSH2/MSH6 complex SIGNOR-C60 SIGNOR BLM protein P54132 UNIPROT up-regulates binding 9606 15064730 t lperfetto We show that the recombinant hmsh2/6 protein complex stimulated the ability of the bloom's syndrome gene product, blm, to process holliday junctions in vitro SIGNOR-217223 0.609 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser312 TESITATsPASMVGG 10116 BTO:0004428 12510059 t lperfetto Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylationOne of the specific Ser phosphorylation sites in IRS-1 that has been proposed to negatively modulate the insulin signal is Ser312 (numbered according to the human sequence). Prior studies have demonstrated that IRS-1 associates with and is phosphorylated by JNK in vitro on Ser312 SIGNOR-236591 0.767 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257971 0.8 HAUS3 protein Q68CZ6 UNIPROT HAUS complex complex SIGNOR-C281 SIGNOR form complex binding 9606 BTO:0000567 19369198 t lperfetto Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC) SIGNOR-262322 0.662 CNR2 protein P34972 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256700 0.445 ARVCF protein O00192 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 t miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. SIGNOR-252133 0.432 N-[4-[(4-Ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[(E)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)ethenyl]-4-methylbenzamide chemical CID:53302361 PUBCHEM BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 32069833 t lperfetto HG6-64-1 is a specific BRAF inhibitor SIGNOR-261986 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR RAC1 protein P63000 UNIPROT down-regulates activity phosphorylation Ser71 YDRLRPLsYPQTDVF 9606 BTO:0003476 10617634 t gcesareni The results suggest that Akt kinase of the phosphoinositide 3-kinase signal transduction pathway phosphorylates serine 71 of Rac1 as one of its authentic substrates and modulates the Rac1 signal transduction pathway through phosphorylation. SIGNOR-248036 0.2 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2T protein Q9NPD8 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271350 0.472 HDLBP protein Q00341 UNIPROT CTCF protein P49711 UNIPROT up-regulates activity binding 9606 BTO:0000599 24725430 t miannu Vigilin interacts with CCCTC-binding factor (CTCF) and is involved in CTCF-dependent regulation of the imprinted genes Igf2 and H19. vigilin is present at several known CTCF target sites, such as the promoter regions of c-myc and BRCA1, the locus control region of β-globin, and several regions within the Igf2/H19 locus. These results reveal the functional relevance of vigilin and CTCF, and show that the CTCF-vigilin complex contributes to regulation of Igf2/H19. SIGNOR-266693 0.494 SMARCA5 protein O60264 UNIPROT WICH complex SIGNOR-C449 SIGNOR form complex binding 9606 16603771 t miannu We show here that the WICH complex (WSTF-SNF2h) interacts with several nuclear proteins as follows: Sf3b155/SAP155, RNA helicase II/Gualpha, Myb-binding protein 1a, CSB, the proto-oncogene Dek, and nuclear myosin 1 in a large 3-MDa assembly, B-WICH, during active transcription. Our results show that a WSTF-SNF2h assembly is involved in RNA polymerase III transcription, and we suggest that WSTF-SNF2h-NM1 forms a platform in transcription while providing chromatin remodeling. SIGNOR-268827 0.923 Enolase proteinfamily SIGNOR-PF74 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9534 BTO:0000318 2005901 t inferred from family member Luana This result suggests that MBP-1 in vivo acts as a sequence-specific repressor. SIGNOR-270308 0.2 JAK2 protein O60674 UNIPROT ITGB2 protein P05107 UNIPROT up-regulates activity phosphorylation 9606 25624455 t miannu PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role. SIGNOR-254738 0.268 PTPRG protein P23470 UNIPROT ITGAL protein P20701 UNIPROT down-regulates activity 9606 25624455 f miannu PTPRG activation inhibits chemoattractantinduced LFA-1 affinity triggering and mediated adhesion in human primary monocytes. we show that PTPRG is a novel negative regulator of LFA-1 high-affinity-state triggering and mediated arrest by chemoattractants in human primary monocytes. Notably, PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role (37). In our context, SRC appears inhibited by PTPRG activation (Table I), thus making it unlikely that the antiadhesive effect of PTPRG is mediated by SRC activation. SIGNOR-254736 0.2 EEF1A2 protein Q05639 UNIPROT Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269540 0.8 ABI1 protein Q8IZP0 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 17395426 t gcesareni Here we uncover a novel interaction between abi-1 and the cbl ubiquitin ligase and show that abi-1 mediates cbl accumulation to the plasma membrane upon stimulation by egf. SIGNOR-154162 0.379 ATM protein Q13315 UNIPROT DCK protein P27707 UNIPROT up-regulates activity phosphorylation Ser74 EFEELTMsQKNGGNV 27879648 t lperfetto Deoxycytidine kinase (dCK) is a key enzyme in deoxyribonucleoside salvage and the anti-tumor activity for many nucleoside analogs. dCK is activated in response to ionizing radiation (IR)-induced DNA damage and it is phosphorylated on Serine 74 by the Ataxia-Telangiectasia Mutated (ATM) kinase in order to activate the cell cycle G2/M checkpoint. SIGNOR-275798 0.409 DDX46 protein Q7L014 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270669 0.559 RNF10 protein Q8N5U6 UNIPROT MEOX2 protein P50222 UNIPROT up-regulates activity binding 10090 BTO:0000944 16335786 t miannu RFN10 co-immunoprecipitates with MEOX2. RNF10 potentiates MEOX2 transcriptional activation SIGNOR-236968 0.383 IL2 protein P60568 UNIPROT IL2RB protein P14784 UNIPROT up-regulates binding 9606 16477002 t miannu Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c). SIGNOR-144540 0.865 RAD21L Cohesin complex complex SIGNOR-C355 SIGNOR Meiotic_recombination phenotype SIGNOR-PH162 SIGNOR up-regulates 10090 BTO:0000534 21242291 f miannu RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21. SIGNOR-264539 0.7 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252883 0.398 NFATC2 protein Q13469 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001260 17079331 t lperfetto The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries. SIGNOR-251731 0.409 VARS1 protein P26640 UNIPROT Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates quantity chemical modification 9606 30755602 t miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. SIGNOR-270530 0.8 CABIN1 protein Q9Y6J0 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates 9606 17172641 f gcesareni Thus, cabin1 recruits chromatin-modifying enzymes, both histone deacetylases and a histone methyltransferase, to repress mef2 transcriptional activity. SIGNOR-151202 0.667 CERK protein Q8TCT0 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI down-regulates quantity chemical modification 9606 34202192 t miannu Another relevant enzyme is Ceramide kinase (CerK), which phosphorylates Cer to produce Ceramide 1-phosphate (C1P). SIGNOR-268500 0.8 MAPK14 protein Q16539 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates activity phosphorylation -1 9155018 t These results indicate that MNK1 is a novel class of protein kinase that is activated through both the ERK and p38 MAP kinase signaling pathways SIGNOR-253011 0.658 PRKCA protein P17252 UNIPROT F11R protein Q9Y624 UNIPROT unknown phosphorylation Ser284 KVIYSQPsARSEGEF 9606 BTO:0000130;BTO:0000876 11027562 t gcesareni We also demonstrated phosphorylation of ser 284, a putative pkc phosphorylation site, by immunoblotting with anti-phosphoserine-jam antibody in thrombin-stimulated platelets. SIGNOR-83037 0.327 SDHD protein O14521 UNIPROT Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 30030361 t lperfetto Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites SIGNOR-262187 0.924 TBX1 protein O43435 UNIPROT FLT4 protein P35916 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001176 20439995 f Regulation of expression miannu Tbx1 plays a critical role in lymphatic vessel development and regulates the expression of Vegfr3, a gene that is essential for lymphangiogenesis. Tbx1 activates Vegfr3 transcription in endothelial cells (ECs) by binding to an enhancer element in the Vegfr3 gene. SIGNOR-251869 0.312 CSNK2A1 protein P68400 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity phosphorylation Ser853 SSLNSSEsDKDQDYD 10090 10671552 t llicata Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. | Under these conditions, phosphorylation of the E-cadherin double mutant S853A/S855A was reduced by 25% as compared with wt E-cadherin. | Expression of the E-cadherin double mutant S853A/S855A in NIH3T3 cells expressing Wnt-1 reduces cell-cell adhesion. SIGNOR-250841 0.41 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr494 TGTDKLMtGVISPER 9606 16216881 t lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. SIGNOR-141030 0.2 PLK1 protein P53350 UNIPROT TNKS protein O95271 UNIPROT up-regulates quantity by stabilization phosphorylation Thr1128 VEEEMQStIREHRDG 9606 BTO:0000567 21818122 t miannu Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends.  SIGNOR-276244 0.438 GSK3B protein P49841 UNIPROT BICD1 protein Q96G01 UNIPROT up-regulates activity phosphorylation Thr597 KEPSPTKtPTISPVI 9606 BTO:0000567 17139249 t miannu Therefore, at least Ser585 and Thr597 in BICD1 are important phosphorylation sites for BICD1 to exert its functions, and GSK-3β-dependent phosphorylation is required for the interaction of BICD1 with dynein. SIGNOR-262744 0.337 YAP1 protein P46937 UNIPROT RRM2 protein P31350 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 f lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. SIGNOR-276569 0.2 POLDIP3 protein Q9BY77 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR up-regulates activity binding 9606 BTO:0000567 22928037 t miannu PDIP3 and ZC11A Function in mRNA Export. PDIP3 and ZC11A associate with UAP56 and the TREX complex in an ATP-dependent manner. SIGNOR-268515 0.602 CCND1 protein P24385 UNIPROT CDK4 protein P11802 UNIPROT up-regulates binding 9606 BTO:0000150 23562856 t gcesareni D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb, SIGNOR-201666 0.964 lidocaine chemical CHEBI:6456 ChEBI SCN5A protein Q14524 UNIPROT down-regulates activity chemical inhibition 8355 BTO:0000964 8786356 t miannu Surprisingly, hH1-beta 1 Na channels were threefold more sensitive to rested-state block by lidocaine (402 +/- 36 microM, n = 4-22) than were mu 1-beta 1 Na channels (1,168 +/- 34 microM, n = 7-19). SIGNOR-258499 0.8 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates quantity precursor of 9606 23000145 t scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). SIGNOR-268451 0.8 SYN1 protein P17600 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity binding 9606 BTO:0000938 15265865 t miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. The interaction between synapsin I and Rab3A was confirmed by photoaffinity labeling experiments on purified synaptic vesicles and by the formation of a chemically cross-linked complex between synapsin I and Rab3A in intact nerve terminals. The data indicate that synapsin I is a novel Rab3 interactor on synaptic vesicles and suggest that the synapsin-Rab3 interaction may participate in the regulation of synaptic vesicle trafficking within the nerve terminals. SIGNOR-269181 0.599 BMP2 protein P12643 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 12589053 f fspada Specific inhibitors for p38 kinase inhibited bmp2-induced adipocytic differentiation and transcriptional activation of ppargamma, whereas overexpression of smad6 had no effect on transcriptional activity of ppargamma. SIGNOR-98369 0.4 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216319 0.7 miR-495 mirna URS000075C517_9606 RNAcentral Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 10090 26344767 t Luana To further determine whether MeCP2 regulates the expression of miR-199a, we also re-expressed MeCP2 in MeCP2-KO neurons. As expected, this restored the level of mature-miR-199a expression to that in WT neurons SIGNOR-264545 0.4 ETV2 protein O00321 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24583263 f irozzo We also identify Spi1 as a common downstream target gene of Etv2 and Gata2. We provide evidence that Etv2 and Gata2 bind to the Spi1 promoter in vitro and in vivo. Etv2 and Gata2 synergistically transactivate Spi1 gene expression. SIGNOR-256006 0.261 AKT2 protein P31751 UNIPROT HTRA2 protein O43464 UNIPROT down-regulates phosphorylation Ser212 RVRVRLLsGDTYEAV 9606 17311912 t lperfetto Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212 SIGNOR-153327 0.2 BMPR1A protein P36894 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR up-regulates activity 10090 19620713 f ggiuliani The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17). SIGNOR-255787 0.701 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192617 0.8 CEBPB protein P17676 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 25451943 f gcesareni Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) β plays an essential role. SIGNOR-238297 0.7 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 BTO:0000671 15694384 t llicata Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925. SIGNOR-133837 0.2 PDGFRB protein P09619 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 BTO:0002057 15489898 t gcesareni The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells. SIGNOR-247979 0.588 MAPK14 protein Q16539 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000150 21502402 t llicata Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro SIGNOR-173409 0.272 FBXW11 protein Q9UKB1 UNIPROT PER1 protein O15534 UNIPROT down-regulates ubiquitination 9606 15917223 t miannu We have found that per1 interacts with both _-trcp1 and _-trcp2 in a manner that depends on casein kinase 1 activity, and depletion of both _-trcp1 and _-trcp2 by rnai leads to dramatic stabilization of per1 SIGNOR-137758 0.483 MZF1 protein P28698 UNIPROT PRKCA protein P17252 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26010542 t irozzo The luciferase reporter assay results revealed that the presence of both MZF-1 and Elk-1 significantly contributed to the upregulation of PKCα gene transcription activity. SIGNOR-256337 0.393 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Ser831 EPVEQDSsQPSLPLV 9606 22621922 t gcesareni Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm. SIGNOR-197615 0.869 MAP3K3 protein Q99759 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 BTO:0000298 9162092 t lperfetto These data indicate that mkk3 is preferentially activated by mekk3, whereas mkk4 is activated both by mekk2 and mekk3. SIGNOR-48625 0.539 RET protein P07949 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates binding 9606 11360177 t gcesareni Tyrosine 1062 in ret provides a site for the interaction of multiple signaling molecules and that the balance of shc and snt/frs2 binding may affect the nature of the intracellular signaling for cell proliferation, differentiation and survival induced by activated ret SIGNOR-108244 0.665 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR NUP98 protein P52948 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16036565 f miannu Nup98/Nup96 (41) and Rae1 (17)are up regulated by interferons, which revert the mRNAexport block induced by VSV M protein SIGNOR-260870 0.2 PRKG1 protein Q13976 UNIPROT TRPC6 protein Q9Y210 UNIPROT down-regulates activity phosphorylation Thr70 RLAHRRQtVLREKGR -1 19961855 t miannu PKG phosphorylated TRPC6, and both T70 and S322 were targeted. Both sites were functionally relevant, as 8Br-cGMP strongly suppressed current in wild-type TRPC6 channels, but not in those with phospho-silencing mutations (T70A, S322A or S322Q).  SIGNOR-276272 0.473 OTX1 protein P32242 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation -1 18849347 f miannu Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity. SIGNOR-254887 0.312 TACR3 protein P29371 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256794 0.2 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SNAI2 protein O43623 UNIPROT down-regulates quantity by destabilization phosphorylation Ser54 ILSSGAYsPITVWTT 9606 24662826 t miannu At G1/S transition, cyclin E-cyclin-dependent kinase 2 mediates the phosphorylation of Slug at Ser-54 and Ser-104, resulting in its ubiquitylation and degradation. SIGNOR-276628 0.291 CCKBR protein P32239 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256908 0.268 GFs stimulus SIGNOR-ST12 SIGNOR AKT2 protein P31751 UNIPROT up-regulates activity 9606 23300340 f lperfetto Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation SIGNOR-245405 0.7 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr522 SSPGSPGtPGSRSRT -1 9199504 t miannu Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective. SIGNOR-250087 0.505 PRKCA protein P17252 UNIPROT GRM1 protein Q13255 UNIPROT down-regulates activity phosphorylation Thr695 GSKKKICtRKPRFMS 9606 10823959 t lperfetto Furthermore, we demonstrate that the selectivity of PKC action on receptor signaling rests on phosphorylation of a threonine residue located in the G protein-interacting domain of the receptor. Modification at Thr(695) selectively disrupts mGluR1alpha-G(q/11) interaction without affecting signaling through G(s). SIGNOR-249043 0.393 CSNK2A1 protein P68400 UNIPROT SSRP1 protein Q08945 UNIPROT down-regulates activity phosphorylation Ser657 KSSSRQLsESFKSKE 9606 BTO:0000007 15659405 t llicata CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity. SIGNOR-250960 0.69 TRIM33 protein Q9UPN9 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 BTO:0000574;BTO:0002625;BTO:0000414 16751102 t lperfetto The ubiquitious nuclear protein transcriptional intermediary factor 1gamma (tif1gamma) selectively binds receptor-phosphorylated smad2/3 in competition with smad4. Rapid and robust binding of tif1gamma to smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to tgfbeta. Tif1gamma mediates the differentiation response while smad4 mediates the antiproliferative response with smad2/3 participating in both responses. SIGNOR-236060 0.568 N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide chemical CHEBI:95008 ChEBI MCL1 protein Q07820 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207465 0.8 CDK4 protein P11802 UNIPROT KAT2A protein Q92830 UNIPROT up-regulates activity phosphorylation Thr272 LNYWKLEtPAQFRQR 24870244 t lperfetto Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT) SIGNOR-275495 0.367 CHRM4 protein P08173 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256686 0.43 P2RY4 protein P51582 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257006 0.2 JMJD1C protein Q15652 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 32034158 t miannu We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state. SIGNOR-265171 0.2 AHR protein P35869 UNIPROT UGT1A1 protein P22309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18172616 f miannu Human UDP-glucuronosyltransferase (UGT)1A1 is a critical enzyme responsible for detoxification and metabolism of endogenous and exogenous lipophilic compounds, such as potentially neurotoxic bilirubin and the anticancer drug irinotecan SN-38, via conjugation with glucuronic acid. A 290-bp distal enhancer module, phenobarbital-responsive enhancer module of UGT1A1 (gtPBREM), fully accounts for constitutive androstane receptor (CAR)-, pregnane X receptor (PXR)-, glucocorticoid receptor (GR)-, and aryl hydrocarbon receptor (AhR)-mediated activation of the UGT1A1 gene. SIGNOR-253734 0.414 NRG4 protein Q8WWG1 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 t Does not bind to the ERBB1, ERBB2 and ERBB3 receptors gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. SIGNOR-122062 0.684 UBE2I protein P63279 UNIPROT FOXL2 protein P58012 UNIPROT up-regulates sumoylation Lys25 PETGRTVkEPEGPPP 9606 19744555 t miannu Foxl2 is sumoylated by ubc9, and this ubc9-mediated sumoylation is essential to the transcriptional activity of foxl2 on the star promoter. / the sumoylation site was identified at lysine 25 of foxl2 SIGNOR-187901 0.686 NMI protein Q13287 UNIPROT SOX10 protein P56693 UNIPROT down-regulates activity binding 9606 16214168 t miannu We identify an association of Sox10 with the N-myc interactor Nmi. Nmi modulated the transcriptional activity of Sox10 in reporter gene assays. Nmi effects varied between different Sox10 target gene promoters, indicating that Nmi function in vivo may be promoter-specific. SIGNOR-225602 0.439 FGF2 protein P09038 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 20974802 f inferred from 70% of family members gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription. SIGNOR-269929 0.598 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation Ser715 YQSTIPQsPSPAPDD 9606 BTO:0000007 10022832 t The effect has been demonstrated using Q08499-2 gcesareni These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro. SIGNOR-64326 0.36 WNT1 protein P04628 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 10090 BTO:0000887 16936075 t lperfetto Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6) SIGNOR-253126 0.758 DAPK1 protein P53355 UNIPROT PELI1 protein Q96FA3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser39 GDRGRRKsRFALFKR 9606 BTO:0003575 33052227 t miannu DAPK1, which directly binds to and phosphorylates Pellino1 at Ser39, leading to Pellino1 poly-ubiquitination and turnover. SIGNOR-277531 0.2 CSNK2A1 protein P68400 UNIPROT MYB protein P10242 UNIPROT down-regulates activity phosphorylation Ser12 PRHSIYSsDEDDEDF -1 7735324 t llicata For c-Myb mutational analysis of the CKII phosphorylation sites showed altered steady state DNA binding. Replacing Ser-11/12 by alanine residues resulted in increased DNA binding compared to wt c-Myb or Myb Asp-11/12 as demonstrated by up to 10-fold differences in the dissociation constants.  SIGNOR-250919 0.346 TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 BTO:0000459 18621737 t lperfetto The high affinity of the tradd-traf2 interaction is required for efficient suppression of apoptosis upon stimulation of the tumor necrosis factor receptor1 (tnfr1), tnf-receptor-associated death domain (tradd) provides a scaffold for the assembly of complex i at the plasma membrane by binding receptor interacting protein 1 (rip1), tnfreceptor- associated factor 2 ,traf2 these results provide evidence that tradd can serve as an adaptor protein and recruit traf1, traf2, or both to tnfrsf1a. The demonstration that tradd interacts with traf2 and fadd, and can recruit both to tnfrsf1a, suggested that traf2 and fadd may be involved in tnfrsf1a tradd-mediated signaling. That these interactions define two distinct signaling pathways emanating from tradd (figure 9) is supported by the ability of traf2 and fadd to activate nf-kb and induce apoptosis, respectively. SIGNOR-179446 0.866 CDK1 protein P06493 UNIPROT ECT2 protein Q9H8V3 UNIPROT down-regulates phosphorylation Thr373 VSMLSLNtPNSNRKR 9606 SIGNOR-C17 16170345 t lperfetto We show that phosphorylation of ect2 at threonine-341 (t341) affects the autoregulatory mechanism of ect2. In g2/m phase, ect2 was phosphorylated at t341 most likely by cyclin b/cyclin-dependent kinase 1 (cdk1) ect2 is biologically active even when it is not phosphorylated at t341 SIGNOR-140549 0.593 PAK1 protein Q13153 UNIPROT MYLK protein Q15746 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000567 10092231 t miannu P21-activated kinase 1 (PAK1) phosphorylates MLCK, resulting in decreased MLCK activity.  SIGNOR-250317 0.538 LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Ser89 AQHVRSHsSPASLQL 9606 22658639 t miannu In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. SIGNOR-256187 0.2 AURKA protein O14965 UNIPROT PHLDA1 protein Q8WV24 UNIPROT down-regulates quantity by destabilization phosphorylation Ser95 PLCLLRVsLLCALRA 9606 BTO:0006218 21807936 t miannu Aurora A directly phosphorylates PHLDA1 leading to its degradation. Aurora A phosphorylates PHLDA1 at Ser 98. SIGNOR-273545 0.423 LYN protein P07948 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268209 0.696 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 20679343 t The effect has been demonstrated using P10636-8 lperfetto Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3? SIGNOR-167294 0.728 SMARCC2 protein Q8TAQ2 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 t miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. SIGNOR-132936 0.865 4E2RCat chemical CID:2287236 PUBCHEM EIF4G1 protein Q04637 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000414 21507972 t miannu Characterization of 4E2RCat, an inhibitor of eIF4E-eIF4G interaction. Herein we describe a molecule from this screen that prevents the interaction between eIF4E (the cap-binding protein) and eIF4G (a large scaffolding protein), inhibiting cap-dependent translation. This inhibitor significantly decreased human coronavirus 229E (HCoV-229E) replication, reducing the percentage of infected cells and intra- and extracellular infectious virus titers. SIGNOR-260188 0.8 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity phosphorylation Thr185 KPGNLLLtTGGTLKI 9606 BTO:0000007;BTO:0000567 12805220 t lperfetto It was shown that thr336 and thr366 are the major autophosphorylation sites of mouse lkb1 (sapkota et al., 2002). We confirmed these data on the human orthologues thr336 and thr363. Moreover, the enhanced stoichiometry of lkb1 autophosphorylation by strad enabled us to identify two novel sites: thr185 and thr402. We show that increased lkb1 autophosphorylation of all sites correlates with the activation of its catalytic activity. SIGNOR-101840 0.2 CDK1 protein P06493 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 SIGNOR-C17 24173284 t lperfetto The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A SIGNOR-167779 0.596 PTEN protein P60484 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates activity dephosphorylation 9606 33348808 t miannu GluN2B Y1472 site is dephosphorylated by PTEN . SIGNOR-277165 0.301 GSK3A protein P49840 UNIPROT PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation Ser280 FHCCQCTsVETVTEL 10116 BTO:0003324 30745182 t miannu Fatty acids (FAs) upregulate GSK-3α, which phosphorylates PPARα at Ser280 in the ligand-binding domain (LBD). This modification ligand independently enhances transcription of a subset of PPARα targets, selectively stimulating FA uptake and storage, but not oxidation, thereby promoting lipid accumulation.  SIGNOR-277431 0.2 N-[(4-chlorophenyl)methyl]-2-[(2R,6S)-5,12-dioxo-2-phenyl-1-oxa-4-azacyclododec-8-en-6-yl]acetamide chemical CHEBI:94175 ChEBI SHH protein Q15465 UNIPROT down-regulates chemical inhibition 9606 BTO:0001253 19151731 t gcesareni More recently, robotnikinin was identified as a compound that binds to shh and blocks its ability to induce pathway activity at the level of ptch. SIGNOR-183465 0.8 YAP1 protein P46937 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 f lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. SIGNOR-276563 0.329 CASP3 protein P42574 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity cleavage -1 10579725 t lperfetto P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro SIGNOR-252624 0.621 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269337 0.719 COP1 protein Q8NHY2 UNIPROT ACACB protein O00763 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16794074 t miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). SIGNOR-271599 0.2 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser96 TSLSDEDsGKGSQPP 9606 20305697 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-164637 0.574 PRKACA protein P17612 UNIPROT CACNA1S protein Q13698 UNIPROT up-regulates activity phosphorylation Ser1575 PEICRTVsGDLAAEE -1 20937870 t miannu To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2. SIGNOR-263112 0.329 MTOR protein P42345 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser422 AEAFLGFsYAPPTDS 9606 SIGNOR-C2 18925875 t gcesareni Mtorc2 immunoprecipitated from wild-type, but not from mlst8- or rictor-knockout cells, phosphorylated sgk1 at ser(422) SIGNOR-181531 0.844 FOXE1 protein O00358 UNIPROT TPO protein P07202 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 27347897 t scontino TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8 SIGNOR-267279 0.39 KAT2A protein Q92830 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269595 0.2 RAE1 protein P78406 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 20498086 f miannu The export of mRNAs is a multistep process, involving the packaging of mRNAs into messenger ribonucleoprotein particles (mRNPs), their transport through nuclear pore complexes, and mRNP remodeling events prior to translation. Ribonucleic acid export 1 (Rae1) and Nup98 are evolutionarily conserved mRNA export factors that are targeted by the vesicular stomatitis virus matrix protein to inhibit host cell nuclear export. these data suggest that the Rae1*Nup98 complex directly binds to the mRNP at several stages of the mRNA export pathway. SIGNOR-260871 0.7 PABPC3 protein Q9H361 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization binding 9606 25480299 t lperfetto As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length. SIGNOR-268321 0.8 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr67 LSILSGGtPKRCLDL 9606 10037602 t gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. SIGNOR-64968 0.852 PDPK1 protein O15530 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007;BTO:0001914 23887393 t gcesareni Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency SIGNOR-243519 0.2 GDNF protein P39905 UNIPROT PAFAH1B1 protein P43034 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization. SIGNOR-252171 0.2 PLK2 protein Q9NYY3 UNIPROT SNCB protein Q16143 UNIPROT down-regulates activity phosphorylation Ser118 LMEPEGEsYEDPPQE 9606 19889641 t lperfetto Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. SIGNOR-189049 0.251 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr237 KQEKTPKtPKGPSSV 9606 SIGNOR-C17 12058066 t gcesareni Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association. SIGNOR-89601 0.533 SRC protein P12931 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 12645577 t lperfetto These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation. SIGNOR-217439 0.384 ITGB1BP1 protein O14713 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257645 0.756 PRKAA1 protein Q13131 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 21892142 f inferred from family member gcesareni Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation SIGNOR-270257 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR XIAP protein P98170 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 VGRHRKVsPNCRFIN 9606 BTO:0001023 14645242 t lperfetto Akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin. SIGNOR-244377 0.2 MLF1 protein P58340 UNIPROT COPS3 protein Q9UNS2 UNIPROT up-regulates binding 9606 15861129 t miannu As downstream elements of mlf1 leading to cell growth arrest due to p53 accumulation, we identified two factors, csn3, the third component of the cop9 signalosome (csn), and cop1, a recently characterized e3 ubiquitin ligase for p53 SIGNOR-135937 0.412 FYCO1 protein Q9BQS8 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates activity binding 9606 BTO:0000007 26468287 t Giulio The preferential binding to LC3A and -B was confirmed in vivo by co-immunoprecipitation experiments of Myc-tagged FYCO1 and GFP fusions of human ATG8 family pro-teins expressed in HEK293 cells (Fig. 2B). GFP-LC3A and GFP-LC3B were efficiently co-precipitated with Myc-FYCO1,whereas GFP-LC3C, GFP-GABARAP, GFP-GABARAPL1 and-L2 were not. The effects we see on late steps of basal autophagy on mutation of the FYCO1 LIR motif correlate with a role of FYCO1 in regulating kinesin-mediated transport of LC3-positive autophagic structures. SIGNOR-260597 0.532 Avacopan chemical CID:49841217 PUBCHEM C5AR2 protein Q9P296 UNIPROT down-regulates activity binding 9606 31734405 t lperfetto CCX168 (avocapan), a C5aR antagonist, has proven its safety and efficiency in phase I and phase II trials conducted in AAV patients. SIGNOR-263474 0.8 RPL10 protein P27635 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262501 0.771 STXBP1 protein P61764 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9534 11036064 t miannu We propose that all these neurexin complexes can interact with Munc18. Both Mint1 and Mint2 could function as direct adaptors of Munc18 to neurexins, whereas Mint1 in addition could recruit Munc18 to CASK-neurexin (Fig. 5 B). SIGNOR-264040 0.506 SPAST protein Q9UBP0 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9534 BTO:0000298 15716377 f Gianni Using purified components, we also show that Spastin interacts directly with microtubules and is sufficient for severing. These studies suggest that defects in microtubule severing are a cause of axonal degeneration in human disease. SIGNOR-269045 0.7 SLC6A4 protein P31645 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI up-regulates quantity relocalization 9606 BTO:0000227 16789923 t miannu The function of the serotonin transporter (SERT) is to take up and release serotonin (5-hydroxytyptamine (5-HT)) from cells and this function of SERT in the central nervous system (CNS) is well-documented; SERT is the target of selective serotonin reuptake inhibitors used in the treatment of CNS disorders, such as depression. SIGNOR-263953 0.8 RAB32 protein Q13637 UNIPROT AP-1 complex complex SIGNOR-C248 SIGNOR up-regulates activity relocalization 9606 23247405 t lperfetto Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. SIGNOR-260700 0.2 DMTF1 protein Q9Y222 UNIPROT DSPP protein Q9NZW4 UNIPROT up-regulates quantity by expression transcriptional regulation 23349460 t lperfetto In addition, our in vitro analyses showed that DMP1 and its 57-kDa C-terminal fragment significantly up-regulated the Dspp promoter activities in a mesenchymal cell line. SIGNOR-271685 0.2 TACR2 protein P21452 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257015 0.439 IRF2BP2 protein Q7Z5L9 UNIPROT IRF2 protein P14316 UNIPROT up-regulates activity binding 9606 BTO:0000567 12799427 t miannu We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation. SIGNOR-224073 0.651 EXOC7 protein Q9UPT5 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270782 0.914 HDAC1 protein Q13547 UNIPROT RELN protein P78509 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 f miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. SIGNOR-254577 0.282 PTPN2 protein P17706 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation 9606 33603165 t lperfetto Since PTPN2 dephosphorylates and inactivates Src [ xref ], the increase of pY439 might have resulted from reduced dephosphorylation or elevated Src activity or both. SIGNOR-276996 0.709 LATS2 protein Q9NRM7 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 22658639 t Together the YAP/TAZ-TEAD complex promotes proliferative and survival programs. milica In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. SIGNOR-197651 0.686 sunitinib chemical CHEBI:38940 ChEBI PDGFRA protein P16234 UNIPROT down-regulates chemical inhibition 9606 BTO:0000776 20185585 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-163953 0.8 PRKCB protein P05771 UNIPROT TP73 protein O15350 UNIPROT up-regulates activity phosphorylation Ser388 VPQPLVDsYRQQQQL 9606 19158275 t miannu Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388.  SIGNOR-276234 0.2 MAPK1 protein P28482 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser282 VGKQAPLsPGLPAMG 9606 20230789 t lperfetto Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity SIGNOR-164227 0.331 CTDSP1 protein Q9GZU7 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity dephosphorylation 9606 32764831 t miannu CTDSP1 activates DNA-PKcs and enhances DNA-PKcs dependent topoI degradation in response to irinotecan .|Our novel finding indicates that CTDSP1 dephosphorylates DNA-PKcs, changes its kinase activity, and regulates irinotecan-induced topoI degradation. SIGNOR-277101 0.2 CCR1 protein P32246 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 25230753 f CCL3, an eosinophil precursor-produced chemokine that signals through CCR1, promotes terminal differentiation of CCR1-positive eosinophil precursors in the absence of IL-5, highlighting an autocrine loop capable of sustaining eosinophil differentiation SIGNOR-254369 0.7 DUSP26 protein Q9BV47 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates activity dephosphorylation 9606 28701747 t miannu NEAP and DUSP26 dephosphorylated TrkA and FGFR1 directly.|We found that NEAP, but not its phosphatase-defective mutant, suppressed nerve growth factor (NGF) receptor TrkA and fibroblast growth factor receptor 1 (FGFR1) activation in PC12 cells SIGNOR-277104 0.2 POMT2 protein Q9UKY4 UNIPROT POMT complex SIGNOR-C372 SIGNOR form complex binding 9606 BTO:0000007 16698797 t miannu  Here we have shown that POMT1 forms a complex with POMT2 and the complex possesses protein O-mannosyltransferase activity. Results indicate that POMT1 and POMT2 associate physically and functionally in vivo.  Mutations in the POMT1 and POMT2 genes are considered to be the cause of Walker-Warburg syndrome. Here, we have demonstrated that POMT1 and POMT2 form a functional complex in vivo using immunoprecipitating techniques. Furthermore, we showed that the mutations of POMT1 protein found in WWS patients do not prevent complex formation with POMT2 but they do abolish activity of the complex. SIGNOR-265429 0.587 CDK1 protein P06493 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr221 KDEILPTtPISEQKG 9606 21871177 t gcesareni These results suggest that the phosphorylation of rps3 by cdk1 occurs at thr221 during g2/m phase and, moreover, that this event is important for nuclear accumulation of rps3. SIGNOR-176131 0.37 CDK1 protein P06493 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser684 IGIPQFHsPVGSPLK 9606 SIGNOR-C17 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. SIGNOR-164487 0.462 OTULIN protein Q96BN8 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270829 0.705 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR YAP1 protein P46937 UNIPROT down-regulates activity binding 9606 23431053 t miannu The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation. SIGNOR-265823 0.2 SMARCB1 protein Q12824 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates 9606 12226744 f miannu We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6. SIGNOR-92788 0.249 TLN1 protein Q9Y490 UNIPROT Av/b5 integrin complex SIGNOR-C178 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257630 0.572 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT up-regulates activity cleavage Asp390 LPQLTLPdSLTSAAS 17761173 t lperfetto In contrast, Caspase‐3 cleavage of GRASP‐1 releases the C‐terminal fragment, which in turn activates JNK signaling by serving as a scaffold protein SIGNOR-260613 0.405 PAK proteinfamily SIGNOR-PF13 SIGNOR MYLK protein Q15746 UNIPROT down-regulates activity phosphorylation -1 10748018 t inferred from 70% family members miannu PAK2 can directly phosphorylate MLCK, inhibiting its activity and limiting the development of isometric tension. PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991. SIGNOR-269973 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CAD protein P27708 UNIPROT up-regulates phosphorylation 9606 15890648 t inferred from 70% family members lperfetto Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol SIGNOR-269998 0.2 PPP2CB protein P62714 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity dephosphorylation Ser129 NEAYEMPsEEGYQDY 9606 21562258 t α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129 SIGNOR-248592 0.279 IL10 protein P22301 UNIPROT SCN4A protein P35499 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 23357618 f miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. SIGNOR-253500 0.2 DGC complex SIGNOR-C217 SIGNOR GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265438 0.2 PRKG2 protein Q13237 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity phosphorylation Ser254 WTYPRKEsGRLVEPV 9606 BTO:0001007 35066967 t miannu Secretory PKG II inhibited PDGF‐BB ‐induced PDGFRβ activation via phosphorylating its Ser254. SIGNOR-277577 0.275 PTPRO protein Q16827 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 24708807 t miannu In addition, this group found that PTPRO dephosphorylated STAT3 at Y705 and S727 then attenuated STAT3 signalling. SIGNOR-277062 0.384 DLX5 protein P56178 UNIPROT MSX2 protein P35548 UNIPROT down-regulates activity binding 10090 BTO:0000947 9111364 t 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. SIGNOR-240925 0.553 SET protein Q01105 UNIPROT PPP2CB protein P62714 UNIPROT down-regulates binding 9606 21806989 t miannu Here we report that both the amino terminal fragment (i(2ntf);aa 1-175) and the carboxy terminal fragment (i(2ctf);aa 176-277) of i(2)(pp2a) inhibit pp2a by binding to its catalytic subunit pp2ac SIGNOR-175722 0.286 estramustine chemical CHEBI:4868 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation 9606 14755680 t miannu A variety of new estrogenic/anti‐estrogenic/selective estrogen receptor modulator (SERM)‐like compounds, including 2‐methoxyestradiol, genistein, resveratrol, licochalcone, Raloxifene, ICI 182,780, and estramustine are being evaluated for their potential in the next generation of PCa therapies. SIGNOR-259299 0.8 FYN protein P06241 UNIPROT PTPRT protein O14522 UNIPROT down-regulates activity phosphorylation Tyr915 Y-->K 19816407 t lperfetto Synapse formation by PTPRT was inhibited by phosphorylation of tyrosine 912 within the membrane-proximal catalytic domain of PTPRT by Fyn. This tyrosine phosphorylation reduced phosphatase activity of PTPRT SIGNOR-275543 0.424 sphingosine 1-phosphate(1-) smallmolecule CHEBI:60119 ChEBI S1PR1 protein P21453 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257577 0.8 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273068 0.635 CSNK2A1 protein P68400 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser87 KTVEGAGsIAAATGF 9606 BTO:0000938 10617630 t lperfetto In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its c terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.From these data we conclude that _-synuclein is predominantly phosphorylated at serine residue 129. However, a second serine at position 87 is also used for phosphorylation to some extent. together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of _-synuclein could affect its binding to membranes. SIGNOR-73807 0.493 PAX1 protein P15863 UNIPROT MEOX1 protein P50221 UNIPROT up-regulates activity binding -1 11423130 t miannu We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family. SIGNOR-222193 0.526 SOX4 protein Q06945 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 BTO:0003104 24970928 t irozzo The findings in this study raise the possibility that Sox4 may also antagonize Lef1 (Tcf1 is not expressed in pro-B lymphocytes) function by controlling the stability of β-catenin in pro-B lymphocytes. SIGNOR-256139 0.576 CDK1 protein P06493 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Ser916 TGEAPTLsPPRDARP 9606 BTO:0000567 31981797 t miannu CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines. SIGNOR-276832 0.412 MARK2 protein Q7KZI7 UNIPROT PINK1 protein Q9BXM7 UNIPROT up-regulates activity phosphorylation Thr313 EGLGHGRtLFLVMKN -1 22238344 t miannu  MARK2 phosphorylated and activated the cleaved form of PINK1 (ΔN-PINK1; amino acids 156-581). Thr-313 was the primary phosphorylation site, a residue mutated to a non-phosphorylatable form (T313M) in a frequent variant of PD.  SIGNOR-276401 0.374 PRKCD protein Q05655 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Thr909 PKSYLPQtVRQGGYM -1 12361954 t lperfetto Finally, we identified Thr-890, a putative PKC phosphorylation site on gp130, to be critical for the effect of PKCdelta. Our data indicate that PKCdelta plays important regulatory roles in IL-6 signaling. SIGNOR-249177 0.34 SATB2 protein Q9UPW6 UNIPROT IGHM protein P01871 UNIPROT up-regulates quantity transcriptional regulation 9606 14701874 t gianni The SATB2 protein was shown to bind MAR sequences flanking the enhancer of the endogenous immunoglobulin μ heavy chain (IgH) gene in vivo, and this binding was found to correlate with an increase in the expression of a transfected rearranged μ wild-type gene SIGNOR-268933 0.2 INS protein P01308 UNIPROT INSR protein P06213 UNIPROT up-regulates activity binding 10029 16956584 t lperfetto Insulin binds to the alpha subunit of the insulin receptor (IR) on the cell surface. SIGNOR-236748 0.933 PAK1 protein Q13153 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser246 QACARTFsRMSLLHK 9606 BTO:0000150 15833848 t lperfetto Pak1 regulates the repressor activity of snail by phosphorylating on ser(246). Pak1 phosphorylation of snail supports snail's accumulation in the nucleus as well as its repressor functions. SIGNOR-135605 0.409 IFNA1 protein P01562 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates activity binding 9534 BTO:0004055 11278538 t lperfetto Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. SIGNOR-219298 0.61 DGCR8 protein Q8WYQ5 UNIPROT Microprocessor complex complex SIGNOR-C356 SIGNOR form complex binding 9606 BTO:0000552 24581491 t lperfetto Microprocessor minimally comprises the ribonuclease DROSHA and its double-stranded RNA-binding partner DGCR8 (Denli et al., 2004; Gregory et al., 2004). Microprocessor recognizes pri-miRNA through the stem-loop (Zeng et al., 2005) and the stem-loop-ssRNA junction (Han et al., 2006), and cleaves both the 5′ and 3′ flanking segments to generate pre-miRNA. SIGNOR-264849 0.922 D-serine smallmolecule CHEBI:16523 ChEBI NMDA receptor_2C complex SIGNOR-C349 SIGNOR up-regulates activity chemical activation 9606 BTO:0002609 12393813 t lperfetto D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically SIGNOR-268279 0.8 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT down-regulates phosphorylation Tyr969 PLLQPNNyQFC 9606 BTO:0001271 15297464 t lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) following ligand binding, the csf-1r is rapidly internalized and degraded. This process begins with multiubiquitination of the csf-1r mediated by c-cbl (20), an e3-type ubiquitin ligase SIGNOR-127626 0.2 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR RASSF1 protein Q9NS23 UNIPROT down-regulates binding 9606 21776416 t gcesareni Basal inactivation of rassf1a is achieved by rassf1a self association and via 14-3-3 interactions (to isoforms s and e) at serine 175/178/179 of rassf1a. SIGNOR-175121 0.2 WNT5B protein Q9H1J7 UNIPROT FZD6 protein O60353 UNIPROT up-regulates binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. SIGNOR-141443 0.655 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 28646232 t Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels SIGNOR-262519 0.358 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR KAT2A protein Q92830 UNIPROT up-regulates activity phosphorylation Ser372 EEIYGANsPIWESGF 24870244 t lperfetto Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT) SIGNOR-275496 0.403 XRCC3 protein O43542 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates quantity by stabilization binding 9606 23438602 t miannu XRCC3 activation is essential for the recruitment of RAD51 to the sites of DNA lesions. It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation. SIGNOR-262667 0.738 sapitinib chemical CHEBI:132986 ChEBI ERBB3 protein P21860 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190155 0.8 CDK1 protein P06493 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1361 SPPKTKTsPKLSNKE 9606 BTO:0000567 7635160 t llicata We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. we have also shown that phosphorylation of ser1353 and ser1360 yields different phosphopeptide maps depending upon whether one or both of these sites are phosphorylated. SIGNOR-30252 0.539 TNFSF13B protein Q9Y275 UNIPROT TNFRSF13C protein Q96RJ3 UNIPROT up-regulates activity binding 9606 BTO:0000782 15851487 t lperfetto Baff specifically binds baff receptor SIGNOR-135713 0.777 SEC23B protein Q15437 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 t lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat SIGNOR-265288 0.696 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 20086174 t lperfetto We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2. SIGNOR-244345 0.2 arginine smallmolecule CHEBI:29016 ChEBI Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270370 0.8 KAT2B protein Q92831 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates acetylation 9606 BTO:0000887 10944526 t gcesareni Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo SIGNOR-81056 0.632 mTORC1 complex SIGNOR-C3 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity 10090 BTO:0002314 25047835 f Knockdown (KD) of either mTORC or its subunit Raptor delayed SC activation without influencing the differentiation program. SIGNOR-256273 0.7 FRS2 protein Q8WU20 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10116 BTO:0002809 9182757 t fspada In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway. SIGNOR-236953 0.795 BLOC1S6 protein Q9UL45 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 BTO:0002946 22203680 t lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. SIGNOR-265931 0.724 Non-erythrocytic spectrin complex SIGNOR-C385 SIGNOR Membrane_disruption phenotype SIGNOR-PH151 SIGNOR down-regulates 9606 24302288 f lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell SIGNOR-266029 0.7 CDK2 protein P24941 UNIPROT PELP1 protein Q8IZL8 UNIPROT up-regulates phosphorylation Ser991 PALPPPEsPPKVQPE 9606 20807815 t llicata We identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we conclude that pelp1 is a novel substrate of interphase cdks and that its phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function. SIGNOR-167766 0.375 PD173955 chemical CHEBI:49791 ChEBI SRC protein P12931 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258264 0.8 CEBPA protein P49715 UNIPROT HAMP protein P81172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001950 18671304 f miannu HCV-induced ROS stabilized the expression of two negative hepcidin regulators, HIF1alpha and HIF2alpha, and its expression was decreased by a HDAC inhibitor or an anti-oxidant. HCV-induced ROS also caused hypoacetylation of histones and inhibited binding of two positive regulators, C/EBPalpha and STAT3, to the hepcidin promoter, whereas anti-oxidant treatment of cells recovered C/EBPalpha and STAT3 binding to the hepcidin promoter. SIGNOR-253770 0.301 superoxide smallmolecule CHEBI:18421 ChEBI SOD1 protein P00441 UNIPROT up-regulates activity precursor of 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272288 0.8 SESN1 protein Q9Y6P5 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR down-regulates activity binding 10090 BTO:0002572 25457612 t We describe AMPK-independent mechanism of mTORC1 regulation by the Sestrins, in which the Sestrins inhibit mTORC1 localization to the lysosomes in a Rag-dependent manner through an interaction with GATOR2 SIGNOR-253559 0.439 CASP1 protein P29466 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261748 0.325 ATG3 protein Q9NT62 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates activity binding -1 16303767 t lperfetto Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme) SIGNOR-141926 0.869 AKT proteinfamily SIGNOR-PF24 SIGNOR USP14 protein P54578 UNIPROT up-regulates activity phosphorylation Ser432 THQGRSSsSGHYVSW 9606 BTO:0000007 26523394 t lperfetto Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system|These results suggested S432 as a major and S143 as a minor phosphorylation site of Akt. SIGNOR-265055 0.2 MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 17713585 f lperfetto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs).|Current emerging structural and biological evidence suggests that MRN has 3 coupled critical roles in DSB sensing, stabilization, signaling, and effector scaffolding: (1) expeditious establishment of protein--nucleic acid tethering scaffolds for the recognition and stabilization of DSBs; (2) initiation of DSB sensing, cell-cycle checkpoint signaling cascades, and establishment of epigenetic marks via the ATM kinase; and (3) functional regulation of chromatin remodeling in the vicinity of a DSB. SIGNOR-251502 0.7 PICK1 protein Q9NRD5 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity binding 9534 BTO:0000298 25784538 t inferred from family member miannu RAB39B directs GluA2 trafficking in neurons. GTP-bound RAB39B interacts with PICK1. In line with evidence that PICK1 can dimerize, the structural model suggests that dimerization of PICK1 is a prerequisite for simultaneous recognition of both RAB39B and GluA2 each by one of the PICK1 molecules in the PICK1 dimer (Fig. 6a‚Äìc). The existence of such complex is supported by our co-immunoprecipitation experiments shown above. SIGNOR-270236 0.8 CBX1 protein P83916 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity binding 9606 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-265323 0.2 EGR1 protein P18146 UNIPROT HYAL1 protein Q12794 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004796 18718911 f miannu In 253J-Lung and HT1376 bladder cancer cell lines, which show high HYAL-1 expression, transcription factors Egr-1, AP-2, and NFκB bind the HYAL-1 promoter. Because both SP1 and Egr-1 have two overlapping binding sites within the promoter (Fig. 5), it appears that although SP1 binding to the methylated HYAL-1 promoter turns off transcription, binding of Erg-1 (and also AP-2) to the unmethylated promoter turns on transcription. SIGNOR-253878 0.2 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR NRAS protein P01111 UNIPROT up-regulates activity 9534 8402896 f miannu BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation. SIGNOR-261506 0.2 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr740 TGESDGGyMDMSKDE -1 7545675 t Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides SIGNOR-248413 0.679 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation 9606 19620713 t gcesareni Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. SIGNOR-187190 0.628 BRCA1 protein P38398 UNIPROT ERCC6 protein Q03468 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21756275 t miannu BRCA1 polyubiquitinates CSB and this polyubiquitination and subsequent degradation of CSB occur following UV irradiation, even in the absence of Cockayne syndrome A (CSA) protein.  SIGNOR-272754 0.452 GIT1 protein Q9Y2X7 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 14523024 t gcesareni Git1 interaction with plcgamma is required for plcgamma activation based on inhibition of tyrosine phosphorylation SIGNOR-118454 0.538 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246272 0.564 MAML1 protein Q92585 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 BTO:0000887 18758483 t gcesareni Unexpectedly, however, emerging evidence implicate maml proteins as exciting key transcriptional co-activators in other signal transduction pathways including: muscle differentiation and myopathies (mef2c), tumor suppressor pathway (p53) and colon carcinoma survival (beta-catenin). SIGNOR-180136 0.315 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 12056906 t esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. SIGNOR-89221 0.458 POLR1E protein Q9GZS1 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266153 0.789 ZBTB16 protein Q05516 UNIPROT ZBTB16/ZBTB32 complex SIGNOR-C80 SIGNOR form complex binding 9606 10572087 t miannu We show that fazf is a transcriptional repressor and it readily forms heterodimers with plzf. SIGNOR-72377 0.368 BTRC protein Q9Y297 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates ubiquitination 9606 11359933 t gcesareni An e3 ubiquitin ligase complex roc1-scffbw1a consisting of roc1, skp1, cullin1, and fbw1a (also termed trcp1) induces ubiquitination of smad3. SIGNOR-108237 0.398 RELA protein Q04206 UNIPROT BCL2A1 protein Q16548 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 10049356 f gcesareni Here we show thata1,abcl-2homolog up-regulated in primary lymphocytes by different mitogens, represents a novel class of rel/nf-kb-regulated prosurvival genes. SIGNOR-65020 0.499 MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Thr219 AEHQYFMtEYVATRW 9606 BTO:0000567 20667468 t miannu ERK5 is a member of the mitogen-activated protein kinase (MAPK) family that, after stimulation, is activated selectively by dual phosphorylation in the TEY motif by MAPK kinase 5 (MEK5). ERK5 is activated selectively by dual phosphorylation on Thr218 and Tyr220 in the TEY motif by its only upstream kinase, MEK5, a member of the MEK SIGNOR-259824 0.691 KRAS protein P01116 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29731393 f miannu Oncogenic proteins that regulate proliferation, such as KRAS, BRAF, and MYC increase the transcription of NRF2 SIGNOR-267361 0.435 HDAC4 protein P56524 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates binding 9606 BTO:0000887 10737771 t gcesareni We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2. SIGNOR-76231 0.581 GSK3B protein P49841 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates quantity by destabilization phosphorylation Thr269 HNSTTTWtGSRTAPY 10090 BTO:0000944 25373906 t miannu In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region.  SIGNOR-276441 0.407 TTN protein Q8WZ42 UNIPROT TCAP protein O15273 UNIPROT unknown phosphorylation Ser157 GALRRSLsRSMSQEA 10090 9804419 t lperfetto These data indicate that the activation of titin kinase in differentiating myocytes and the resulting phosphorylation of telethonin are involved in the reorganization of the cytoskeleton during myofibrillogenesis. SIGNOR-246925 0.905 GSK3B protein P49841 UNIPROT GFI1 protein Q99684 UNIPROT down-regulates quantity by destabilization phosphorylation Ser98 RPPSPSAsPASEKSM 9606 BTO:0000498 31289136 t miannu GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation. SIGNOR-277465 0.2 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258630 0.8 FER protein P16591 UNIPROT FER protein P16591 UNIPROT up-regulates activity phosphorylation Tyr714 RQEDGGVySSSGLKQ 9534 10998246 t P94fer undergoes autophosphorylation in-trans in vivo and that oligomerization mediates this process. the N-terminal sequences of the FER tyrosine kinases direct their different cellular autophosphorylation states, thereby dictating their different cellular functions. SIGNOR-251133 0.2 PRKAA1 protein Q13131 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 17900900 t gcesareni The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt. SIGNOR-157941 0.434 MAPK14 protein Q16539 UNIPROT NFATC4 protein Q14934 UNIPROT down-regulates activity phosphorylation Ser168 QGGGAFFsPSPGSSS 10029 BTO:0001131 11997522 t miannu P38 MAP kinase phosphorylates Ser168 and Ser170 of NFATc4. Mutational replacement of Ser168,170 with Ala promotes NFATc4 nuclear localization and increases NFATc4-mediated transcription activity. SIGNOR-250107 0.411 HSD17B11 protein Q8NBQ5 UNIPROT androst-5-ene-3beta,17beta-diol smallmolecule CHEBI:2710 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363 30943210 t lperfetto Testicular 17betaHSD3 converts DHEA to androstenediol and androstenedione to testosterone SIGNOR-268660 0.8 mifepristone chemical CHEBI:50692 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0000318 9727070 t miannu As shown in Fig. 4 A, hPXR was activated by the synthetic steroids dexamethasone, dexamethasone-t-butylacetate, PCN, RU486, spironolactone, and cyproterone-acetate. Dexamethasone-t-butylacetate and RU486 were the most efficacious activators of hPXR among the synthetic steroids tested. SIGNOR-258829 0.8 GTF2B protein Q00403 UNIPROT FOXF2 protein Q12947 UNIPROT up-regulates activity binding 9534 BTO:0004055 9722567 t miannu The human forkhead protein FREAC-2 contains two functionally redundant activation domains and interacts with TBP and TFIIB. FREAC-2 dependent activation of transcription by TFIIB. SIGNOR-220317 0.504 PRKACA protein P17612 UNIPROT PHOX2A protein O14813 UNIPROT down-regulates phosphorylation Ser153 RKQERAAsAKGAAGA 9606 19564421 t llicata Phox2a becomes phosphorylated by protein kinase a (pka) on ser153, which prevents association of phox2a with dna and terminates p27(kip1) transcription. SIGNOR-186462 0.312 EGFR protein P00533 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity phosphorylation Tyr179 SVYGTEEyLHPDMYE 9606 27287717 t miannu EGFRL858R/T790M phosphorylates IKBKE at tyrosine residues. While wild-type and mutant EGFR directly interacted with IKBKE, only mutant EGFR phosphorylated IKBKE on residues Y153 and Y179.  SIGNOR-277243 0.26 BCL7C protein Q8WUZ0 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269780 0.518 ARHGEF4 protein Q9NR80 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260532 0.729 HBA1 protein P69905 UNIPROT Hemoglobin complex SIGNOR-C209 SIGNOR form complex binding 9606 18179859 t miannu AHSP does not bind to β-hemoglobin (βHb) or the hemoglobin tetramer, instead, it specifically binds to free αHb, avoiding its precipitation and its pro-oxidant activity. In the presence of βHb, the αHb-AHSP complex is dismembered and βHb displaces AHSP to generate the quaternary structure of hemoglobin SIGNOR-255274 0.7 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000944 21415216 t irozzo We also found that phosphorylation of both the mitogen-activated proteinkinase (MAPK) ERK and STAT3 was markedly increased inthe cells expressing either variant of EML4-ALK[.]. Oncogenic EML4-ALK tyrosine kinase activates ERKand STAT3 signaling pathways SIGNOR-259203 0.2 RARA protein P10276 UNIPROT SLCO1B3 protein Q9NPD5 UNIPROT up-regulates quantity by expression transcriptional regulation 15322262 t lperfetto Taken together, these findings suggest that the LPS-induced down-regulation of Oatp4 is likely due to reduction in the binding of HNF1alpha, C/EBP, HNF3, and RXR:RAR to the Oatp4 promoter. SIGNOR-268989 0.2 ABL1 protein P00519 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates activity phosphorylation Tyr771 IGTAEPDyGALYEGR 9606 BTO:0002181 12652307 t miannu C-Abl induces Tyr phosphorylation of PLC-γ1 in vivo. These findings demonstrate that c-Abl phosphorylates PLC-γ1 in vivo predominantly at Tyr 771 and Tyr 1003.c-Abl phosphorylation of PLC-γ1 causes downregulation of PLC activity. SIGNOR-276001 0.572 NOX3 protein Q9HBY0 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity chemical modification 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264722 0.8 SRC protein P12931 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity phosphorylation Tyr331 PYSEYFEyFAPDFTL -1 30317579 t miannu C-Src also phosphorylated three tyrosine sites of HDAC3 at tyrosine 325, 328, and 331. Importantly, wild-type c-Src increases HDAC3 activity, but not mutant c-SrcK298M (kinase inactive form).  SIGNOR-277486 0.394 CDK1 protein P06493 UNIPROT MPLKIP protein Q8TAP9 UNIPROT up-regulates phosphorylation Ser93 YPGSYSRsPAGSQQQ 9606 17310276 t lperfetto Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1 SIGNOR-153304 0.347 VX-745 chemical CHEBI:90528 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 11892915 t gcesareni Vx-745 was reported to be active against several isotypes of p38 mapk, including p38alpha, p38beta and p38gamma SIGNOR-115782 0.8 solifenacin chemical CHEBI:135530 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition -1 21524581 t Luana The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference SIGNOR-258313 0.8 edrophonium chemical CHEBI:251408 ChEBI ACHE protein P22303 UNIPROT down-regulates activity chemical inhibition -1 9301662 t miannu With the aim of performing a rigorous test of the anti-AChE properties of our compounds, the kinetics of enzyme inhibition were studied in purified enzyme preparations. The inhibition data are shown in Table 1. Additionally, known competitive inhibitors of AChE (procainamide and edrophonium) were included in the study for comparative purposes. SIGNOR-258667 0.8 NFX1 protein Q12986 UNIPROT TERT protein O14746 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17267499 t miannu NFX1-123 positively regulated hTERT expression, as its knockdown decreased hTERT mRNA levels and telomerase activity and its overexpression increased telomerase activity. NFX1-123 was found to interact with cytoplasmic poly(A) binding proteins (PABPCs), and together they synergistically augmented expression from the hTERT promoter when activated by HPV16 E6. SIGNOR-261050 0.504 MAPK3 protein P27361 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser759 KTPDGNKsPAPKPSD 9606 BTO:0001260 10514499 t lperfetto Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin. SIGNOR-71041 0.46 GSK3B protein P49841 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates phosphorylation 9606 12123574 t gcesareni Here, we observed that gsk3beta was able to bind and phosphorylate notch1ic in vitro, and attenuation of gsk3beta activity reduced phosphorylation of notchic in vivo.Functionally, ligand-activated signaling through the endogenous notch1 receptor was reduced in gsk3beta fibroblasts, implying a positive role for gsk3beta in mammalian notch signaling. SIGNOR-90608 0.475 CSNK2B protein P67870 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-251053 0.29 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000567 BTO:0000562 12853467 t lperfetto These findings suggest that pkb-dependent binding of 14-3-3s to phospho-ser483 of cardiac pfk-2 mediates the stimulation of glycolysis by growth factor. SIGNOR-103462 0.2 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser274 ASPQRSRsPSPQPSS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248375 0.598 HPS5 protein Q9UPZ3 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR form complex binding 9606 15030569 t lperfetto Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS7 SIGNOR-260689 0.701 lurasidone chemical CHEBI:70735 ChEBI HTR7 protein P34969 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 20404009 t Luana In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype. SIGNOR-257840 0.8 MPHOSPH10 protein O00566 UNIPROT UTP3 protein Q9NQZ2 UNIPROT up-regulates activity binding -1 28813493 t miannu Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome. SIGNOR-261176 0.931 CSNK1A1 protein P48729 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity. SIGNOR-183664 0.2 CHEK1 protein O14757 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates activity phosphorylation Ser296 GFSKHIQsNLDFSPV 9606 BTO:0001938 23068608 t lperfetto TheSer296autophosphorylation ofCHK1is mainly regulated by an intramolecular mechanism in response to DNA damage. SIGNOR-217904 0.2 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273050 0.556 ADAM17 protein P78536 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity cleavage 9606 BTO:0000567 10882063 t gcesareni ... here we show that an additional processing event occurs in the extracellular part of the receptor, preceding cleavage by the gamma-secretase-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to tace (tnfalpha-converting enzyme), a member of the adam (a disintegrin and metalloprotease domain) family of metalloproteases. SIGNOR-254334 0.729 SKA3 protein Q8IX90 UNIPROT SKA complex complex SIGNOR-C364 SIGNOR form complex binding -1 22483620 t lperfetto We show that the structure of the Ska core complex is a W-shaped dimer of coiled coils, formed by intertwined interactions between Ska1, Ska2, and Ska3. SIGNOR-265196 0.916 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR LATS2 protein Q9NRM7 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0005907 25026211 t miannu CRL4 DCAF1 ubiquitylates and inhibits Lats. SIGNOR-272230 0.2 XAF1 protein Q6GPH4 UNIPROT BIRC3 protein Q13489 UNIPROT down-regulates binding 9606 17613533 t gcesareni Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3 SIGNOR-155288 0.399 AKAP5 protein P24588 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates activity relocalization 10116 BTO:0004553 20694001 t Using a viral-mediated molecular replacement strategy in rat hippocampal slices, we found that AKAP is required for NMDA receptor-dependent long-term depression solely because of its interaction with calcineurin SIGNOR-261291 0.265 PTPRH protein Q9HD43 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 t gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase SIGNOR-76072 0.273 RXRB protein P28702 UNIPROT RARG protein P13631 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. SIGNOR-16683 0.702 BCL2L1 protein Q07817 UNIPROT HIP1 protein O00291 UNIPROT down-regulates 9606 11007801 f miannu Hip-1 activity was found to be independent of the ded-containing caspase 8 but was significantly inhibited by the antiapoptotic protein bcl-x(l), implicating the intrinsic pathway of apoptosis in hip-1-induced cell death. SIGNOR-82460 0.2 SRPK2 protein P78362 UNIPROT ACIN1 protein Q9UKV3 UNIPROT up-regulates phosphorylation Ser1180 GPRSRSRsRDRRRKE 9606 BTO:0001271 18559500 t lperfetto Here, we show that srpk2 binds and phosphorylates acinus, an sr protein essential for rna splicing, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin a1 but not a2 up-regulation. Acinus s422d, an srpk2 phosphorylation mimetic, enhances cyclin a1 transcription, whereas acinus s422a, an unphosphorylatable mutant, blocks the stimulatory effect of srpk2 SIGNOR-179006 0.488 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity dephosphorylation Thr14 VEKIGEGtYGVVYKA 9606 10454565 t The phosphatase activity of Cdc25A is necessary for Cdk2 activation, most likely due to dephosphorylation on Tyr-15 and Thr-14 of Cdk2. SIGNOR-248481 0.824 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21357467 f gcesareni The nfkb p65/p50 heterodimer increases sod2, and p50/p50 suppresses it nf-kb p65/p50 binds to the enhancer and is important for cytokine-induced sod2 SIGNOR-172392 0.493 PDGFRA protein P16234 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 7535778 t miannu Tyrosine phosphorylation has been shown to increase the enzymatic activity of plc-? / we show that the human pdgf ?- And ?-Receptors differ quantitatively in their abilities to associate with and phosphorylate plc-? And to stimulate inositol phosphate production. SIGNOR-28176 0.635 zotepine chemical CHEBI:32316 ChEBI ADRA2B protein P18089 UNIPROT down-regulates activity chemical inhibition 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258559 0.8 FGF11 protein Q92914 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253438 0.2 CDK1 protein P06493 UNIPROT RAB5B protein P61020 UNIPROT unknown phosphorylation Ser123 KELQRQAsPSIVIAL 9606 10403367 t lperfetto Cdc2 kinase preferentially phosphorylates ser-123 of rab5b. More work will be required to establish how phosphorylation of the three rab5 isoforms influences their function in the endocytic pathway SIGNOR-69233 0.332 PTGS2 protein P35354 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0001103 20219869 t apalma Furthermore, COX-2 inhibition reduced MyoD expression in regenerating muscle, suggesting a role for COX-2 in modulating muscle differentiation, as well as growth SIGNOR-256214 0.267 RAI1 protein Q7Z5J4 UNIPROT PER3 protein P56645 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000614 22578325 f miannu Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. SIGNOR-266841 0.395 BS-181 hydrochloride chemical CID:49867928 PUBCHEM CDK7 protein P50613 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190783 0.8 ESR1 protein P03372 UNIPROT NCOA2 protein Q15596 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11477071 f lperfetto Er_ mutants unable to bind coactivators drastically decrease estradiol regulation of ap-1-mediated transcription and overexpression of the coactivator grip1 SIGNOR-109520 0.811 GUCY1A3-B2 complex SIGNOR-C139 SIGNOR 3',5'-cyclic GMP smallmolecule CHEBI:16356 ChEBI up-regulates quantity chemical modification 9606 10977868 t gcesareni Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types SIGNOR-244122 0.8 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 19951971 t lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. SIGNOR-249629 0.737 WNT9A protein O14904 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-132073 0.644 GAPDH protein P04406 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI down-regulates quantity chemical modification 9606 11724794 t miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion SIGNOR-266495 0.8 lanreotide chemical CHEBI:135901 ChEBI SSTR2 protein P30874 UNIPROT up-regulates activity chemical activation 9606 25060168 t miannu Octreotide long-acting release (LAR) and lanreotide Autogel (ATG) are the two somatostatin analogs currently approved for treatment of acromegaly and neuroendocrine tumors (NETs). The strength of these drugs has been their specificity for somatostatin receptor subtype 2. SIGNOR-259242 0.8 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKAR2A protein P13861 UNIPROT down-regulates activity chemical inhibition 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258761 0.8 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT down-regulates dephosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 16778204 t gcesareni Ptprj expression induces dephosphorylation of the ret(c634r) and, probably via an indirect mechanism, ret/ptc1 oncoproteins on two key ret autophosphorylation sites (tyr1062 and tyr905). in line with this finding, adoptive ptprj expression reduced the oncogenic activity of ret SIGNOR-147165 0.281 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 10090 BTO:0002572 10988287 t amattioni The temporal pattern of caspase-8 cleavage is consistent with the possibility that it may function upstream of caspase-3 during p53-dependent apoptosis. SIGNOR-256451 0.715 PRKAA1 protein Q13131 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 19491292 f gcesareni Activation of ampk reduced p21 protein and mrna expression, which was associated with re- duced g1/s cell cycle transition and p21 promoter activity. SIGNOR-186061 0.2 TNF protein P01375 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 9606 16813528 f lperfetto These observations suggest that tnf-alpha activates p38 map kinase during the inflammatory response at the injured growth plate, and tnf-alpha-p38 signaling seems to be required for marrow mesenchymal cell proliferation and migration at the growth plate injury site and in cell culture. SIGNOR-147369 0.629 SPRY1 protein O43609 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates binding 9606 11585837 t gcesareni Taken together, these results establish mammalian sprouty proteins as important negative regulators of growth factor signaling and suggest that sprouty proteins act downstream of the grb2.Sos Complex to selectively uncouple growth factor signals from ras activation and the map kinase pathway. SIGNOR-110948 0.394 STK39 protein Q9UEW8 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates binding 9606 BTO:0000142 10980603 t gcesareni Spak, a ste20/sps1-related kinase that activates the p38 pathway. p38, one of the three major mapks, can be coimmunoprecipitated with spak and with nkcc1 in an activity-dependent manner. The amount of p38 coimmunoprecipitated with the kinase and the cotransporter significantly decreases upon cellular stress, SIGNOR-81541 0.369 KIF2C protein Q99661 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272529 0.7 PPP2CB protein P62714 UNIPROT RALA protein P11233 UNIPROT down-regulates dephosphorylation Ser194 NGKKKRKsLAKRIRE 9606 17540176 t miannu Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function SIGNOR-155353 0.293 STK40 protein Q8N2I9 UNIPROT CEBPB protein P17676 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0000078 32795415 t Gianni The COP1-interacting protein STK40 (Durzynska et al., 2017), which was detected in c/EBPβ complexes from BMDMs (Figure 1B), also appeared to contribute to the suppression of c/EBPβ in microglia. Specifically, deletion of the STK40 pseudokinase increased the amount of c/EBPβ protein without increasing the amount of Cebpb mRNA SIGNOR-261925 0.283 AURKB protein Q96GD4 UNIPROT ZWINT protein O95229 UNIPROT up-regulates activity phosphorylation Ser262 MGRDPGVsFKAVGLQ -1 21775627 t lperfetto Zwint-1 is a novel Aurora B substrate required for the assembly of a dynein-binding platform on kinetochores|During prometaphase, AurB phosphorylation of zwint-1 is required for recruitment of ZW10-, pT89 dynein-, and RZZ-dependent proteins to kinetochores. This is defective after AurB inhibition or after expression of the triple-A zwint-1 mutant. Triple-E mutant zwint-1 mimics phospho–zwint-1 in RZZ recruitment, even after AurB inhibition SIGNOR-265011 0.636 Avacopan chemical CID:49841217 PUBCHEM C5AR1 protein P21730 UNIPROT down-regulates activity binding 9606 31734405 t lperfetto CCX168 (avocapan), a C5aR antagonist, has proven its safety and efficiency in phase I and phase II trials conducted in AAV patients. SIGNOR-263473 0.8 HIC1 protein Q14526 UNIPROT VLDLR protein P98155 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001938;BTO:0000815 24076391 f miannu The Reelin receptors ApoER2 and VLDLR are direct target genes of HIC1. ectopic expression of HIC1 in U2OS and MDA-MB-231 cell lines decreases expression of the ApoER2 and VLDLR genes, encoding two canonical tyrosine kinase receptors for Reelin. SIGNOR-254244 0.2 PTPRB protein P23467 UNIPROT ALK protein Q9UM73 UNIPROT down-regulates dephosphorylation 9606 BTO:0000785 17681947 t gcesareni Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation. SIGNOR-157175 0.34 CSNK2A2 protein P19784 UNIPROT SMC3 protein Q9UQE7 UNIPROT unknown phosphorylation Ser1067 GDVEGSQsQDEGEGS 9606 18442975 t gcesareni Our data provide evidence that phosphorylation of a core cohesin subunit smc3 by atm plays an important role in dna damage response and suggest that a constitutive phosphorylation by ck2 may affect intra-s phase checkpoint by modulating smc3 phosphorylation by atm. SIGNOR-178487 0.2 PPP1CA protein P62136 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 16501611 t Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. SIGNOR-248556 0.319 QRICH1 protein Q2TAL8 UNIPROT FARSB protein Q9NSD9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269404 0.2 PRKACA protein P17612 UNIPROT CACNA1H protein O95180 UNIPROT down-regulates activity phosphorylation Ser1144 AWSSRRSsWSSLGRA 9606 19131331 t miannu Here, we identify protein kinase A (PKA) as a molecular switch that allows Gbeta(2)gammax dimers to effect voltage-independent inhibition of Ca(v)3.2 channels. Inhibition requires phosphorylation of Ser(1107), a critical serine residue on the II-III loop of the channel pore protein. S1107A prevents inhibition of unitary currents by recombinant Gbeta(2)gamma(2) dimers but does not disrupt dimer binding nor change its specificity. SIGNOR-263111 0.2 EGFR protein P00533 UNIPROT STAM2 protein O75886 UNIPROT unknown phosphorylation Tyr192 HTETKSLyPSSEIQL -1 11687594 t llicata Another major tyrosine phosphorylation site of STAM2 was identified as Tyr-192 SIGNOR-251097 0.589 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr1021 PNEGDNDyIIPLPDP -1 7545675 t Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides SIGNOR-248417 0.679 GSK3B protein P49841 UNIPROT DROSHA protein Q9NRR4 UNIPROT up-regulates activity phosphorylation Ser300 RHRDNRRsPSLERSY -1 25699712 t lperfetto Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes.  SIGNOR-264845 0.282 HARS1 protein P12081 UNIPROT His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates quantity chemical modification 9606 10430027 t miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. SIGNOR-270490 0.8 DDC protein P20711 UNIPROT tyramine smallmolecule CHEBI:15760 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬† SIGNOR-263994 0.8 PHA-767491 chemical CID:11715767 PUBCHEM CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206115 0.8 LPAR4 protein Q99677 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257383 0.358 HSBP1 protein O75506 UNIPROT WASH complex complex SIGNOR-C258 SIGNOR up-regulates quantity relocalization 9606 BTO:0000007 29844016 t lperfetto The Trimeric Coiled-Coil HSBP1 Protein Promotes WASH Complex Assembly at Centrosomes SIGNOR-261007 0.2 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser40 RQPSPSPsPTERAPA 9606 BTO:0001271 15093545 t llicata We report here that as(2)o(3) treatment induces phosphorylation of the pml protein through a mitogen-activated protein (map) kinase pathway. Increased pml phosphorylation is associated with increased sumoylation of pml and increased pml-mediated apoptosis. SIGNOR-124248 0.366 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2W protein Q96B02 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271374 0.503 CDK5 protein Q00535 UNIPROT AMPH protein P49418 UNIPROT unknown phosphorylation Ser272 EEPSPLPsPTASPNH -1 11113134 t llicata Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells.  SIGNOR-250648 0.536 COMMD5 protein Q9GZQ3 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity relocalization 9606 30021164 f miannu Here, we demonstrate that COMMD5 is crucial for the stability of the cytoskeleton. Its silencing leads to a major re-organization of actin and microtubule networks. The N terminus of COMMD5 binds to the endosomal Rab5, and its C terminus, including the COMMD domain, binds to the cytoskeletal scaffolding. COMMD5 participates in long-range endosome transport, including epidermal growth factor receptor (EGFR) recycling, and provides the strength to deform and assist the scission of vesicles into sorting endosomes. This study establishes the molecular mechanism by which COMMD5 acts as an adaptor protein to coordinate endosomal trafficking and reveals its important role for EGFR transport and activity. SIGNOR-261692 0.2 STK4 protein Q13043 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 18394876 t gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1. SIGNOR-178186 0.582 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser293 GSTKRRKsMSGASPK 9606 23708659 t lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. SIGNOR-252793 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Thr417 SLPQATVtPPRKEER 9606 BTO:0000680;BTO:0001573;BTO:0001286 14551205 t lperfetto Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex SIGNOR-216953 0.426 PCGF1 protein Q9BSM1 UNIPROT Noncanonical PRC1 complex SIGNOR-C151 SIGNOR form complex binding 10090 25533466 t miannu inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. SIGNOR-255279 0.712 BLK protein P51451 UNIPROT FCGR2A protein P12318 UNIPROT up-regulates activity phosphorylation Tyr288 YETADGGyMTLNPRA -1 8756631 t lperfetto To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation. SIGNOR-249311 0.447 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252876 0.697 ABI1 protein Q8IZP0 UNIPROT WAVE complex complex SIGNOR-C271 SIGNOR form complex binding 9606 BTO:0000567 15070726 t lperfetto Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex.  SIGNOR-261872 0.856 MAPK3 protein P27361 UNIPROT MYL1 protein P05976 UNIPROT up-regulates phosphorylation 9606 BTO:0000150;BTO:0001130 16854453 t gcesareni Activation of raf/mek/erk cascade can also result in the phosphorylation of the antiapoptotic mcl-1 protein and the pro-apoptotic bim protein. SIGNOR-148002 0.291 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser400 SRDESTDsGLSMSSY 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 23431053 t milica Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ SIGNOR-201165 0.401 NFKB2 protein Q00653 UNIPROT RELB protein Q01201 UNIPROT up-regulates activity binding 9606 19098713 t lperfetto The map3k14-activated chuk/ikka homodimer phosphorylates nfkb2/p100 associated with relb, inducing its proteolytic processing to nfkb2/p52 and the formation of nf-kappa-b relb-p52 complexes. The nf-kappa-b heterodimeric relb-p52 complex is a transcriptional activator. SIGNOR-182835 0.751 MAPK8IP3 protein Q9UPT6 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates binding 9606 15767678 t inferred from 70% of family members gcesareni The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk. SIGNOR-269886 0.74 PRKCI protein P41743 UNIPROT FBXW7 protein Q969H0 UNIPROT down-regulates activity phosphorylation Ser18 KRRRTGGsLRGNPSS 9606 BTO:0000567 28850619 t miannu Here, we report that Fbw7α, the only Fbw7 isoform detected in eggs, is phosphorylated by PKC (protein kinase C) at a key residue (S18) in a manner coincident with Fbw7α inactivation. SIGNOR-277250 0.27 MAP3K8 protein P41279 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 BTO:0000007 15466476 t lperfetto Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases. SIGNOR-129698 0.415 LINC complex complex SIGNOR-C303 SIGNOR TTM complex complex SIGNOR-C305 SIGNOR up-regulates activity relocalization 30718482 t lperfetto Together, we conclude that both the TTM complex and SUN1 (the LINC complex) contribute to the stable telomere–NE association. SIGNOR-263305 0.2 CLTC protein Q00610 UNIPROT AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR form complex binding 9606 23103167 t lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-260676 0.735 PPP2CA protein P67775 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates dephosphorylation Ser253 APRRRAVsMDNSNKY 9606 20110348 t gcesareni Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a. SIGNOR-252973 0.412 D-thyroxine smallmolecule CHEBI:30659 ChEBI THRA protein P10827 UNIPROT up-regulates activity chemical activation 9606 6777394 t miannu The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response. SIGNOR-258402 0.8 EGF protein P01133 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 12648462 t lperfetto The mammalian ligands that bind the egf receptor (egfr [her1, erb-b1]) include egf, transforming growth factor- (tgf), heparin-binding egf-like growth factor (hb-egf), amphiregulin (ar), betacellulin (btc), epiregulin (epr), and epigen SIGNOR-22716 0.948 TRIM59 protein Q8IWR1 UNIPROT IRF7 protein Q92985 UNIPROT down-regulates activity 9606 BTO:0000567; BTO:0002181 22588174 f Giorgia TRIM59 also inhibited the phosphorylation of IRF3 and IRF7, which induces dimerization, suggesting that TRIM59 negatively regulates kinases for IRF3/7 (IKKe/TBK1) or their upstream signal SIGNOR-260374 0.261 AURKA protein O14965 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates activity phosphorylation -1 16824953 t lperfetto Loss of INCENP/Aurora B in Mitosis Correlates with Delocalization of MEI-S332|MEI-S332 Is Phosphorylated by Aurora B In Vitro|Of these, MEI-S332S124,125,126A was a poor substrate for Aurora B kinase in vitro SIGNOR-252046 0.2 LIG4 protein P49917 UNIPROT Lig4-Xrcc4 complex complex SIGNOR-C354 SIGNOR form complex binding -1 19837014 t miannu The DNA ligase IV-Xrcc4 complex is responsible for the ligation of broken DNA ends in the non-homologous end-joining (NHEJ) pathway of DNA double strand break repair in mammals. SIGNOR-264533 0.951 FYN protein P06241 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15537652 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Here we provide evidence that fyn kinase, a member of the src kinase family, is involved in the uvb-induced phosphorylation of histone h3 at serine 10 SIGNOR-130274 0.2 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization phosphorylation Thr112 EGMQIPStQFDAAHP -1 12432063 t miannu We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin.  SIGNOR-275997 0.541 KDM5A protein P29375 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-264300 0.2 haloperidol chemical CHEBI:5613 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258523 0.8 CSNK1A1 protein P48729 UNIPROT HNRNPC protein P07910 UNIPROT down-regulates activity phosphorylation Ser299 EGEDDRDsANGEDDS 9606 15687492 t gcesareni In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C. SIGNOR-133536 0.361 DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR NcRNA_processing phenotype SIGNOR-PH95 SIGNOR up-regulates 9606 23661684 f lperfetto To test small RNA processing by such PACT-containing complexes, we tested the substrates described above for cleavage rates (pre-let-7a, pre-miR-34c and dsRNA W1) and product length specificity (pre-miR-200a and pre-miR-34c). The results of these experiments showed that Dicer–Ago2–TRBP and Dicer–Ago2–PACT produce the same miRNA products from pre-miR-200a and pre-miR-34c substrates as observed for Dicer–TRBP and Dicer–PACT, respectively (Figure 3A). SIGNOR-255322 0.7 ROS stimulus SIGNOR-ST2 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates 10090 18074631 f lperfetto In fact, experiments with either genetic knockouts or RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins such as catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat. SIGNOR-253397 0.7 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MEF2D protein Q14814 UNIPROT down-regulates quantity by destabilization phosphorylation Ser110 GEDSLEQsPLLEDKY 10090 BTO:0000944 25733682 t miannu  MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitin-proteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding.  SIGNOR-276888 0.268 HIF1A protein Q16665 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 17415528 f HIF-1 has been known as a major transcription factor for the induction of virtually all genes encoding glucose transporters and glycolytic enzymes, which allows hypoxic tumor cells to take up glucose more efficiently and metabolize pyruvate to lactate SIGNOR-259381 0.7 ITGB1BP1 protein O14713 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257640 0.756 PKC proteinfamily SIGNOR-PF53 SIGNOR SUN1 protein O94901 UNIPROT down-regulates activity phosphorylation Ser113 HVSRQVTsSGVSHGG 9606 BTO:0000567 28831067 t lperfetto The SUN1-NXF1 association is at least partly regulated by a protein kinase C (PKC) which phosphorylates serine 113 (S113) in the N-terminal domain leading to reduced interaction. SIGNOR-263281 0.2 CSNK2A1 protein P68400 UNIPROT CBX5 protein P45973 UNIPROT up-regulates phosphorylation Ser12 TKRTADSsSSEDEEE 9606 21245376 t gcesareni Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability. SIGNOR-171699 0.354 SCARB1 protein Q8WTV0 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding 10090 26059978 t Giulio Importantly, coimmunoprecipitation of SR-BI and Src demonstrated that the two proteins are directly associated in WT macrophages (Fig. 7B), suggesting that SR-BI plays a direct role in activation of Src in macrophages. SIGNOR-260314 0.376 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition 9606 20570526 t Luana Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors], SIGNOR-257850 0.8 PLK1 protein P53350 UNIPROT TRIOBP protein Q9H2D6 UNIPROT up-regulates phosphorylation Thr447 ASSPSRAtRDNPTTS 9606 22820163 t lperfetto Here we show that tara is a novel polo-like kinase 1 (plk1) target protein. Plk1 interacts with and phosphorylates tara in vivo and in vitro. Actually, the thr-457 in tara was a bona fide in vivo phosphorylation site for plk1. Interestingly, we found that the centrosomal localization of tara depended on the thr-457 phosphorylation and the kinase activity of plk1 SIGNOR-198357 0.341 CHD8 protein Q9HCK8 UNIPROT SOX2 protein P48431 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 t Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells SIGNOR-268921 0.323 NLRP3 inflammasome complex SIGNOR-C225 SIGNOR Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32133002 f miannu Both the NLRP3 inflammasome activation and the subsequent inflammation play significant roles in defending against viral infections. However, aberrant NLRP3 inflammasome activation or chronic inflammation can also lead to severe pathological injury. Accordingly, activation of the NLRP3 inflammasome and its associated inflammation is a double-edged sword for host to defense viral infection. Modulating the NLRP3 inflammasome activity can prove to be a promising strategy for the intervention of viral diseases. SIGNOR-260346 0.7 FREM1 protein Q5H8C1 UNIPROT NPNT protein Q6UXI9 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22613833 t lperfetto The loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1-dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser syndrome. SIGNOR-253308 0.374 solifenacin chemical CHEBI:135530 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition -1 21524581 t Luana The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference SIGNOR-258311 0.8 BTRC protein Q9Y297 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates ubiquitination 9606 BTO:0000785 24469040 t lperfetto _-trcp ubiquitinates ezh2 and jak2-mediated phosphorylation on y641 directs _-trcp-mediated ezh2 degradation. SIGNOR-204481 0.384 TRIM27 protein P14373 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 BTO:0000671 12807881 f miannu We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38. SIGNOR-102031 0.274 CDK2 protein P24941 UNIPROT PTPN2 protein P17706 UNIPROT unknown phosphorylation Ser304 LSPAFDHsPNKIMTE 9606 15030318 t llicata Our studies identify ser-304 as a major phosphorylation site in human tcptp, and the tc45 variant as a novel mitotic cdk substrate. SIGNOR-123471 0.366 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Thr302 PEPEVLStQEDLFDQ 9606 22621922 t gcesareni Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm. SIGNOR-197619 0.869 GSK3B protein P49841 UNIPROT FBXO4 protein Q9UKT5 UNIPROT up-regulates phosphorylation Ser12 EPRSGTNsPPPPFSD 9606 21242966 t lperfetto Gsk3beta-mediated phosphorylation of fbx4 ser12 during the g1/s transition regulates fbx4 dimerization, which in turn governs fbx4-driven e3 ligase activity. SIGNOR-171648 0.2 FGF13 protein Q92913 UNIPROT SCN4A protein P35499 UNIPROT down-regulates activity binding 9606 BTO:0001103 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253431 0.254 KLF13 protein Q9Y2Y9 UNIPROT SIN3A protein Q96ST3 UNIPROT up-regulates activity binding 10029 BTO:0000246 11438660 t miannu detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A. SIGNOR-222437 0.443 B4GALT1 protein P15291 UNIPROT D-glucopyranose smallmolecule CHEBI:4167 ChEBI down-regulates quantity chemical modification 9606 16157350 t miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. SIGNOR-268468 0.8 KDM2B protein Q8NHM5 UNIPROT CDK1 protein P06493 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000011 25533466 f miannu We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis. SIGNOR-252244 0.284 USP14 protein P54578 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 26523394 t lperfetto The physical interaction of CXCR4 and USP14 is paralleled by USP14-catalyzed deubiquitination of the receptor|We also observed that ubiquitination of CXCR4 facilitated receptor degradation, whereas overexpression of USP14 or RNAi-induced knockdown of USP14 blocked CXCL12-mediated CXCR4 degradation SIGNOR-265057 0.459 STK11 protein Q15831 UNIPROT NUAK2 protein Q9H093 UNIPROT up-regulates phosphorylation Thr208 HQGKFLQtFCGSPLY 9606 14976552 t llicata A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold. SIGNOR-122717 0.277 SMAD4 protein Q13485 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR form complex binding 9606 20957627 t lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. SIGNOR-255267 0.661 PPP3CA protein Q08209 UNIPROT NFATC3 protein Q12968 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-176376 0.518 TMLHE protein Q9NVH6 UNIPROT N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:17311 ChEBI down-regulates quantity chemical modification 9606 11431483 t miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. SIGNOR-269681 0.8 bisphenol A chemical CHEBI:33216 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 31995776 t miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . SIGNOR-268729 0.8 SOX9 protein P48436 UNIPROT CEBPD protein P49716 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19254573 t fspada Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation SIGNOR-184283 0.275 neratinib chemical CHEBI:61397 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0000551 17311002 t gcesareni However, the same cells were highly sensitive to the irreversible dual-specificity egfr/erbb2 kinase inhibitor hki-272, as were those overexpressing wild-type erbb2. SIGNOR-153318 0.8 CTDSPL protein O15194 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000007 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248309 0.476 MAP4K1 protein Q92918 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR down-regulates 9606 BTO:0000661 17353368 f phosphorilation: Ser376 Barakat Thus, our study reveals the mechanism of a novel negative feedback loop initiated from SLP-76 to modulate signal intensity during T cell activation. SIGNOR-274563 0.7 TESK1 protein Q15569 UNIPROT TESK1 protein Q15569 UNIPROT up-regulates activity phosphorylation Ser220 EPLAVVGsPYWMAPE 9606 BTO:0000567 10207045 t lperfetto Site-directed mutagenesis analyses revealed that Ser-215 within the activation loop of the kinase domain is the site of serine autophosphorylation of TESK1. Replacement of Ser-215 by alanine almost completely abolished serine autophosphorylation and histone H3 kinase activities. SIGNOR-246667 0.2 CYLD protein Q9NQC7 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates activity deubiquitination 9606 12917691 t lperfetto Cyld also interacts directly with tumour-necrosis factor receptor (tnfr)-associated factor 2 (traf2), an adaptor molecule involved in by members of the family of tnf/nerve growth factor receptors. (articolo-abstract) SIGNOR-117860 0.664 RDX protein P35241 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 9606 BTO:0000132 35267019 f miannu Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. Taken together, these results suggest that Rev-erbα potentiates platelet activation via an OPHN-1-mediated RhoA/ERM signalling pathway. SIGNOR-268433 0.7 SPI1 protein P17947 UNIPROT CD68 protein P34810 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000801 12676954 f However, our data show that PU.1/IRF-4 and IRF-8 heterocomplexes down-regulate CD68 promoter activity in macrophages and repression is dependent on the integrity of both the IRF and PU.1 half-sites of this composite element. SIGNOR-254286 0.333 PRKD1 protein Q15139 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 20179209 t lperfetto Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated SIGNOR-163920 0.312 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity phosphorylation Thr531 NTTGSDNtDTEGS 9606 BTO:0000567 17936701 t PVHL Acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-κB Agonist Card9 by CK2 SIGNOR-262290 0.352 POU3F2 protein P20265 UNIPROT GNRH1 protein P01148 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11875100 f miannu Functional studies demonstrated that Brn-2 increased promoter activity of the human and mouse GnRH genes. SIGNOR-254928 0.283 SELPLG protein Q14242 UNIPROT SELP protein P16109 UNIPROT up-regulates binding 9606 BTO:0000130;BTO:0000150;BTO:0000551 BTO:0000975 9129046 t gcesareni The major ligand for p-selectin on leukocytes is p-selectin glycoprotein ligand-1 (PSGL-1) SIGNOR-47625 0.925 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMPH protein P49418 UNIPROT unknown phosphorylation Ser285 NHTLAPAsPAPARPR -1 11113134 t llicata Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells.  SIGNOR-250646 0.361 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGC4 protein Q9Y5F7 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265715 0.2 inosine smallmolecule CHEBI:17596 ChEBI adenosine smallmolecule CHEBI:16335 ChEBI up-regulates quantity precursor of -1 15926889 t Luana Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates SIGNOR-269734 0.8 EIF4H protein Q15056 UNIPROT EIF4A1 protein P60842 UNIPROT up-regulates activity binding -1 11418588 t Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability SIGNOR-261294 0.794 MYLK protein Q15746 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 19851336 t lperfetto More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above. SIGNOR-188801 0.832 STXBP1 protein P61764 UNIPROT STX1A protein Q16623 UNIPROT up-regulates activity binding 10116 9395480 t miannu Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1. SIGNOR-264042 0.919 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser664 QLPYYYLsPDRIPNS 9606 BTO:0000567 12670876 t lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. SIGNOR-264442 0.2 PRKCZ protein Q05513 UNIPROT PRKCZ protein Q05513 UNIPROT up-regulates phosphorylation Thr560 TSEPVQLtPDDEDAI 9606 11141077 t gcesareni Our findings suggest that insulin, via pip(3), provokes increases in pkc-zeta enzyme activity through (a) pdk-1-dependent t410 loop phosphorylation, (b) t560 autophosphorylation SIGNOR-85505 0.2 SIRT1 protein Q96EB6 UNIPROT HYOU1 protein Q9Y4L1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 22564731 f miannu Our results indicate a novel mechanism by which SIRT1 regulates ER stress by overexpression of ORP150, and suggest that SIRT1 ameliorates palmitate-induced insulin resistance in HepG2 cells via regulation of ER stress. SIGNOR-255143 0.382 CDK1 protein P06493 UNIPROT RNMT protein O43148 UNIPROT up-regulates activity phosphorylation Thr77 SSSCGKDtPSKKRKL 9606 BTO:0000007 26942677 t lperfetto We report that CDK1-cyclin B1 phosphorylates the RNMT regulatory domain on T77 during G2/M phase of the cell cycle. RNMT T77 phosphorylation activates the enzyme both directly and indirectly by inhibiting interaction with KPNA2, an RNMT inhibitor. SIGNOR-265501 0.257 BTF3 protein P20290 UNIPROT HPSE2 protein Q8WWQ2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17312387 f miannu BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. SIGNOR-253765 0.2 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH16 protein O75309 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265833 0.8 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates phosphorylation Tyr735 KYLANMNyVHRDLAA 9606 18387945 t lperfetto The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells. SIGNOR-178177 0.2 TEC protein P42680 UNIPROT STAP1 protein Q9ULZ2 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10518561 t miannu In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Efficient phosphorylation of BRDG1 by Tec required the PH and SH2 domains as well as the kinase domain of the latter. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 transcripts are abundant in the human B cell line Ramos, and the endogenous protein underwent tyrosine phosphorylation in response to BCR stimulation. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling. SIGNOR-261817 0.4 E2F1 protein Q01094 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 8649818 f lperfetto We have found that cell cycle regulation of cyclin E transcription is mediated by E2F binding sites present in the promoter. The activity of this promoter can be regulated negatively by pRB. SIGNOR-245471 0.569 PPM1B protein O75688 UNIPROT DYRK1A protein Q13627 UNIPROT down-regulates activity dephosphorylation Ser258 NTNFRGVsLNLTRKF 9606 33380426 t miannu In conclusion, our study demonstrates that DYRK1A autophosphorylates Ser258, the dephosphorylation target of PPM1B, and PPM1B negatively regulates DYRK1A activity.|We found that PPM1B dephosphorylates DYRK1A at Ser258, contributing to the inhibition of DYRK1A activity. SIGNOR-277108 0.238 GLI1 protein P08151 UNIPROT HHIP protein Q96QV1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 f lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. SIGNOR-209623 0.616 TGFB1 protein P01137 UNIPROT SKP2 protein Q13309 UNIPROT down-regulates 9606 21212736 f gcesareni Skp2, a f-box protein that determines the substrate specificity for scf ubiquitin ligase, has recently been demonstrated to be degraded by cdh1/apc in response to tgfbeta signaling. SIGNOR-171013 0.261 GFI1 protein Q99684 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity binding 9606 BTO:0002181 17213822 t miannu Co-immunoprecipitation analyses and glutathione-S-transferase pull-down assays revealed that ETS1 bound directly to GFI1 via its Ets domain, and GFI1 bound to ETS1 via its zinc-finger domain. Luciferase (Luc) assays using artificial reporters showed that GFI1 repressed ETS1-mediated transcriptional activation and ETS1 repressed GFI1-mediated transcriptional activation, in a dose-dependent manner. SIGNOR-254201 0.436 PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 9606 29203338 f miannu The PAQosome, an R2TP-Based Chaperone for Quaternary Structure Formation. The Rvb1-Rvb2-Tah1-Pih1/prefoldin-like (R2TP/PFDL) complex is a unique chaperone that provides a platform for the assembly and maturation of many key multiprotein complexes in mammalian cells. Here, we propose to rename R2TP/PFDL as PAQosome (particle for arrangement of quaternary structure) to more accurately represent its unique function. SIGNOR-270920 0.7 UBE2E1 protein P51965 UNIPROT ZSWIM2 protein Q8NEG5 UNIPROT up-regulates activity binding 9606 BTO:0000007 16522193 t miannu MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin.  SIGNOR-271555 0.344 PTPN11 protein Q06124 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity dephosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 23420874 t lperfetto Using an in vitro experiment in which purified full-length wild-type Shp2 (WT Shp2) was incubated with phosphorylated C-SH3 domain of Grb2 we demonstrated that Shp2 can dephosphorylate Grb2 on residue Y209 (XREF_FIG). SIGNOR-276995 0.726 NLK protein Q9UBE8 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000150 17563747 t gcesareni Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna. SIGNOR-155828 0.354 PTPN1 protein P18031 UNIPROT ACTN1 protein P12814 UNIPROT down-regulates activity dephosphorylation Tyr12 DSQQTNDyMQPEEDW 9534 BTO:0000298 16291744 t down-regulates binding to src lperfetto Here we report that protein-tyrosine phosphatase 1B (PTP 1B) is an alpha-actinin phosphatase. PTP 1B-dependent dephosphorylation of alpha-actinin was seen in COS-7 cells|No dephosphorylation was observed in cells coexpressing the alpha-actinin phosphorylation mutant Y12F and PTP 1B. |A reversible interaction between alpha-actinin and Src enables the dephosphorylation of alpha-actinin by PTP 1B, releasing Src SIGNOR-270539 0.341 RPS6KB1 protein P23443 UNIPROT TARBP2 protein Q15633 UNIPROT up-regulates activity phosphorylation Ser283 ILSLRSCsLGSLGAL -1 27407113 t miannu We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells.  SIGNOR-274065 0.328 SB 203580 chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 BTO:0000567 11606413 t gcesareni Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme. SIGNOR-111064 0.8 ETNK1 protein Q9HBU6 UNIPROT O-phosphonatoethanaminium(1-) smallmolecule CHEBI:58190 ChEBI up-regulates quantity chemical modification 36583229 t lperfetto ETNK1 encodes ethanolamine kinase 1, which is involved in the de novo biosynthesis of phosphatidylethanolamine and is responsible for the phosphorylation of ethanolamine to phosphoethanolamine SIGNOR-275641 0.8 FN1 protein P02751 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 9606 BTO:0000007 7559467 t lperfetto The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin. SIGNOR-253305 0.669 DLGAP2 protein Q9P1A6 UNIPROT SHANK2 protein Q9UPX8 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264590 0.844 IYD protein Q6PHW0 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-267034 0.8 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser312 TESITATsPASMVGG 10116 BTO:0000452 11287630 t lperfetto Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten SIGNOR-106574 0.757 Exosome_Complex complex SIGNOR-C255 SIGNOR XBP1 protein P17861-2 UNIPROT up-regulates quantity relocalization 9606 30319453 t miannu When the ER stress-induced unfolded protein response (UPR) is activated, the X-box binding protein 1 (XBP1) mRNA is spliced by inositol-requiring enzyme-1α (IRE1α) to produce the spliced form of XBP1 (sXBP1). In the present study, we found that sXBP1 mRNA in the cell may be incorporated into the exosomes and was released extracellularly. Spliced form of XBP1 mRNA was incorporated into the exosomes of HEK293T cells, which overexpress IRE1α. We found that one of the ER stress signal-induced transcripts, sXBP1, was incorporated into the exosomes. Our results suggest that exosomes may play a vital role in the extracellular release of ER stress signals. SIGNOR-260946 0.2 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 20626350 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. gcesareni Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27. SIGNOR-166637 0.802 BLOC-1 complex SIGNOR-C381 SIGNOR histamine smallmolecule CHEBI:18295 ChEBI up-regulates quantity relocalization 9606 23805129 t lperfetto The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). |VMAT2 also appears to mediate histamine transport into dense granules SIGNOR-265998 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR ATXN1 protein P54253 UNIPROT up-regulates quantity by stabilization phosphorylation Ser775 ATRKRRWsAPESRKL 9606 BTO:0000567 12757707 t Interaction of Ataxin-1 and 14-3-3 Requires Akt Phosphorylation at S776. 14-3-3 protein, a multifunctional regulatory molecule, mediates the neurotoxicity of ataxin-1 by binding to and stabilizing ataxin-1, thereby slowing its normal degradation. SIGNOR-251468 0.2 PHGDH protein O43175 UNIPROT 3-phosphonatooxypyruvate(3-) smallmolecule CHEBI:18110 ChEBI up-regulates activity chemical modification 9606 25406093 t lperfetto PHDGH catalyzes the first reaction of de novo serine biosynthesis, producing 3-phosphohydroxypyruvate by NAD+-coupled oxidation of 3-phosphoglycerate (3PG).|The PHGDH reaction is reversible and, under standard conditions, thermodynamically favors the direction from 3-phosphohydroxypyruvate to 3PG. SIGNOR-268568 0.8 Av/b1 integrin complex SIGNOR-C175 SIGNOR UTF1 protein Q5T230 UNIPROT up-regulates quantity by expression 10090 18757303 f lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. SIGNOR-253275 0.263 FZR1 protein Q9UM11 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 9606 BTO:0000007 23287467 t miannu  Here, we show that human REV1 undergoes proteosomal degradation mediated by the E3 ubiquitin ligase known as anaphase-promoting complex (APC). REV1 associates with APC. Overexpression of APC coactivator CDH1 or CDC20 promotes polyubiquitination and proteosomal degradation of REV1. SIGNOR-272897 0.846 GRB10 protein Q13322 UNIPROT IGF1R protein P08069 UNIPROT down-regulates binding 9606 21659604 t gcesareni Grb10 negatively regulates growth factor signaling. It binds the insulinand insulin-like growth factor 1 (igf-1) receptors, and mice without grb10 are larger and exhibit enhanced insulin sensitivity SIGNOR-174062 0.728 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr1333 ARGGQVFyNSEYGEL 9606 20431062 t lperfetto Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk. SIGNOR-165039 0.492 MTHFD2L protein Q9H903 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI up-regulates quantity chemical modification 10116 21163947 t lperfetto Conversion of these 1-carbon units to formate requires several folate-interconverting enzymes in mitochondria. The enzyme(s) responsible for conversion of 5,10-methylene-tetrahydrofolate (CH(2)-THF) to 10-formyl-THF in adult mammalian mitochondria are currently unknown. A new mitochondrial CH(2)-THF dehydrogenase isozyme, encoded by the MTHFD2L gene, has now been identified.  SIGNOR-268253 0.8 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Thr115 LTSQLHItPGTAYQS 9606 10617621 t lperfetto Sapk phosphorylates bcl-x(l) on threonine 47 (thr-47) and threonine 115 (thr-115) in vitro and in vivo. In contrast to wild-type bcl-x(l), a mutant bcl-x(l) with the two threonines substituted by alanines (ala-47, ala-115) is a more potent inhibitor of ionizing radiation-induced apoptosis SIGNOR-73638 0.2 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr768 MTSTYGRtPMYGSQT 9606 16427012 t lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif SIGNOR-143919 0.768 NGF protein P01138 UNIPROT SCN9A protein Q15858 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0003306 24493753 f miannu Long-term (more than 24 h) treatment with nerve growth factor (NGF) upregulated Nav1.7 functional expression in the strongly metastatic MAT-LyLu rat PCa cell line; acute application had no effect SIGNOR-253495 0.378 HDAC2 protein Q92769 UNIPROT CoREST-HDAC complex complex SIGNOR-C105 SIGNOR form complex binding 9606 BTO:0000567 11171972 t miannu Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function. SIGNOR-222127 0.693 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1114 HGHVSNAsIRVGENV -1 22302995 t miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. SIGNOR-262902 0.69 PTPRC protein P08575 UNIPROT LCK protein P06239 UNIPROT down-regulates activity dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 11259588 t Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr505 and Tyr394, the net effect in normal thymocytes being a decrease in enzymatic activity SIGNOR-248351 0.789 MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 9687510 t lperfetto Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38,. SIGNOR-59454 0.595 SEC61 complex complex SIGNOR-C368 SIGNOR HSPA5 protein P11021 UNIPROT up-regulates activity binding 33925740 t lperfetto This is where allosteric effectors of the Sec61 complex (BiP together with Sec62/Sec63 complex or TRAP complex) (Figure 2 and Figure 5) and auxiliary membrane protein insertases (EMC and TMCO1 complex) join the game SIGNOR-265276 0.46 DLK2 protein Q6UY11 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates activity binding 10090 BTO:0002572 21419176 t lperfetto Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts. SIGNOR-219377 0.295 NEK8 protein Q86SG6 UNIPROT NEK8 protein Q86SG6 UNIPROT up-regulates activity phosphorylation Thr162 SSKSKAYtVVGTPCY -1 11864968 t miannu Multimerization and autophosphorylation of Nek8 are important for its activation.Our data suggests that one site for Nek8 autophosphorylation may be Thr-210 within the activation loop. SIGNOR-250298 0.2 EP300 protein Q09472 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR form complex binding 9606 21131905 t lperfetto Histone acetyltransferases (hats) gcn5 and pcaf (gcn5/pcaf) and cbp and p300 (cbp/p300) are transcription co-activators. SIGNOR-170273 0.654 COL4A6 protein Q14031 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 t Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6) SIGNOR-254670 0.7 FAM13B protein Q9NYF5 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260504 0.428 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNA13 protein Q14344 UNIPROT up-regulates binding 10090 BTO:0000944 15856019 t inferred from 70% family members milica Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. SIGNOR-269965 0.2 GRK2 protein P25098 UNIPROT OPRD1 protein P41143 UNIPROT down-regulates activity phosphorylation Ser363 RVTACTPsDGPGGGA 9606 BTO:0000007 11040053 t gcesareni Taken together, we have demonstrated that agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus. SIGNOR-249660 0.2 RAD51B protein O15315 UNIPROT RAD51B/RAD51C complex SIGNOR-C65 SIGNOR form complex binding 9606 11751636 t miannu We show that two of them, rad51b and rad51c, are associated in a stable complex. Rad51b-rad51c complex has ssdna binding and ssdna-stimulated atpase activities. SIGNOR-111383 0.646 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR6 protein P50406 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257525 0.8 ATR protein Q13535 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Thr691 YGLEEYDtQDGIAIN 9606 16943440 t lperfetto In the present study, we identify two novel dna damage-inducible phosphorylation sites on fancd2, threonine 691 and serine 717. Atr phosphorylates fancd2 on these two sites, thereby promoting fancd2 monoubiquitination and enhancing cellular resistance to dna cross-linking agents SIGNOR-149309 0.66 SMAD7 protein O15105 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity binding 9606 9892110 t lperfetto SMAD7 functions as an antagonist to TGFB by binding to the TBRI and thus inhibiting activation of SMAD2 and SMAD3. SIGNOR-64088 0.781 CDK2 protein P24941 UNIPROT RPL12 protein P30050 UNIPROT unknown phosphorylation Ser38 KIGPLGLsPKKVGDD 9606 18847512 t llicata Finally, we selected one novel substrate, the ribosomal protein rl12, for further study: site-directed mutagenesis and phosphopeptide mapping confirmed that cdk2 phosphorylates rl12 in vitro and in vivo on the same site determined by our methods. SIGNOR-181603 0.2 PTGER1 protein P34995 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256954 0.252 IFNG protein P01579 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR up-regulates activity binding 9606 BTO:0000801 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249487 0.758 CALM3 protein P0DP25 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates binding 9606 11796223 t miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-266340 0.54 KDM3B protein Q7LBC6 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9534 16603237 t miannu We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation. SIGNOR-266634 0.2 ARHGAP22 protein Q7Z5H3 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260477 0.509 MYLIP protein Q8WY64 UNIPROT MYLIP protein Q8WY64 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0001976 14550572 t miannu MIR contains, beside the ERM domain, a RING zinc finger region.  The present study shows that the ubiquitin ligase activity of the RING can also be directed towards the protein itself indicating that the degradation of MIR can be regulated by autoubiquitination. SIGNOR-271480 0.2 RSPO2 protein Q6UXX9 UNIPROT LGR4 protein Q9BXB1 UNIPROT up-regulates binding 9606 21693646 t gcesareni Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation. SIGNOR-174486 0.757 SKIL protein P12757 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity binding 9606 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-236152 0.882 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Thr1462 GLRPRGYtISDSAPS 9606 12150915 t gcesareni We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex. SIGNOR-91045 0.719 ULBP2 protein Q9BZM5 UNIPROT KLRK1 protein P26718 UNIPROT up-regulates binding 9606 BTO:0000782 10894171 t gcesareni Here we describe a family of gpi-anchored cell surface proteins that function as ligands for the mouse activating nkg2d receptor. These molecules are encoded by the retinoic acid early inducible (rae-1) and h60 minor histocompatibility antigen genes on mouse chromosome 10 and show weak homology with mhc class i. SIGNOR-79233 0.604 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity precursor of 9606 27487822 t miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. SIGNOR-266266 0.8 CTDSPL2 protein Q05D32 UNIPROT HBG1 protein P69891 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 20932329 f Regulation of transcription miannu CTD small phosphatase like 2 (CTDSPL2) can increase ε- and γ-globin gene expression in K562 cells and CD34+ cells derived from umbilical cord blood. SIGNOR-251778 0.2 SCF-FBW7 complex SIGNOR-C135 SIGNOR TOP2A protein P11388 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0003492 21254166 t miannu Evidence that Fbw7 acts as the E3-ligase mediating the degradation of topoIIα in HDAC inhibitor-treated PLC5 cells.  SIGNOR-276302 0.35 Osmotic_stress stimulus SIGNOR-ST28 SIGNOR HNRNPA1 protein P09651 UNIPROT down-regulates activity relocalization 9606 BTO:0000312 33172210 f We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne SIGNOR-262816 0.7 BI 2536 chemical CID:11364421 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259702 0.8 SP1 protein P08047 UNIPROT HYAL1 protein Q12794 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004796 18718911 f miannu in cells which do not express HYAL-1, we found SP1 binding to the HYAL-1 promoter. Because both SP1 and Egr-1 have two overlapping binding sites within the promoter (Fig. 5), it appears that although SP1 binding to the methylated HYAL-1 promoter turns off transcription, binding of Erg-1 (and also AP-2) to the unmethylated promoter turns on transcription. SIGNOR-253879 0.2 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Thr393 RNLSDAAtKQEGMEG 9534 BTO:0000298 12700239 t llicata The major CK2 phosphorylation site in this domain is Thr393, a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces beta-catenin phosphorylation, cotranscriptional activity, and stability. SIGNOR-250849 0.541 MAP2K6 protein P52564 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9534 9430721 t Luana The p38 MAP kinase kinase MKK6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma MAP kinase isoforms SIGNOR-260721 0.734 MRE11 protein P49959 UNIPROT PIH1D1 protein Q9NWS0 UNIPROT up-regulates activity binding 9606 phosphorylation:Ser688;Ser689;Ser561;Ser558 SKGVDFEsSEDDDDD;KGVDFESsEDDDDDP;MANDSDDsISAATNK;AEQMANDsDDSISAA 28436950 t miannu Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. SIGNOR-265898 0.2 ADSS2 protein P30520 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267345 0.8 CAMK2A protein Q9UQM7 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser643 CFTPKGSsLKIEERA 9606 BTO:0001260 2170388 t gcesareni Smooth muscle caldesmon was phosphorylated by smooth muscle calmodulin-dependent protein kinase. Ii SIGNOR-22631 0.2 CTTNBP2NL protein Q9P2B4 UNIPROT STRN4 protein Q9NRL3 UNIPROT up-regulates activity binding 9606 BTO:0000938 23015759 t miannu Although CTTNBP2 and CTTNBP2NL are different in terms of tissue and subcellular distribution, our data indicate that, similar to CTTNBP2NL, CTTNBP2 associates with members of the striatin family, namely striatin and zinedin. Moreover, CTTNBP2 is critical for the distribution of striatin and zinedin in dendritic spines. The role of CTTNBP2 in the regulation of the synaptic distribution of striatin and zinedin suggests that CTTNBP2 regulates synaptic signaling through PP2A. SIGNOR-261701 0.687 EZR protein P15311 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 9606 BTO:0000132 35267019 f miannu Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. Taken together, these results suggest that Rev-erbα potentiates platelet activation via an OPHN-1-mediated RhoA/ERM signalling pathway. SIGNOR-268432 0.7 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii SIGNOR-203508 0.769 ZNRF3 protein Q9ULT6 UNIPROT FZD5 protein Q13467 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22575959 t Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. SIGNOR-260118 0.494 NCOA4 protein Q13772 UNIPROT KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004191 18649734 f The PSA promoter activity was detected by transient expression assay in the PC-J and LNCaP cells but not in androgen insensitive PC-3 cells. When the PC-J cells were cotransfected with androgen receptor, androgen receptor coactivators and PSA reporter vector cells, the reporter assays indicated that nuclear receptor coactivator 4 (NCOA4) but not androgen receptor activator 24 (ARA24) increased the sensitivity and maximum stimulation of dihydrotestosterone (DHT)-inducing PSA promoter activity. SIGNOR-253659 0.333 FZD3 protein Q9NPG1 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 14977528 t gcesareni Gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families. SIGNOR-122895 0.394 AURKA protein O14965 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser308 KAEFCNKsKQPGLAR 9606 14990569 t lperfetto Previous studies have shown that the brca1 breast cancer tumor suppressor also localizes to the centrosome and that brca1 inactivation results in loss of the g(2)-m checkpoint. We demonstrate here that aurora-a physically binds to and phosphorylates brca1. We propose that brca1 phosphorylation by aurora-a plays a role in g(2) to m transition of cell cycle SIGNOR-123065 0.663 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1626 SPSYSPTsPSYSPTS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248769 0.442 FGA protein P02671 UNIPROT ITGAX protein P20702 UNIPROT up-regulates binding 9606 7679388 t gcesareni To map the binding sites for four distinct ligands for mac-l: ic3b, fibrinogen, icam-1. __the i domain on the ot chain of mac-1 is an important recognition site for all four ligands. SIGNOR-31320 0.36 RFX5 protein P48382 UNIPROT HLA-DRA protein P01903 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000460 10586057 t Luana In this report, we correlate the loss of IFN-γ induction of MHC class II genes with the identification of a molecular defect in an essential regulator, namely RFX5. | We have further confirmed this finding by showing that new RFX5 leucine mutants created in vitro are incapable of transactivating a class II promoter, suggesting the identification of residues essential for RFX activity. SIGNOR-266228 0.517 SMC4 protein Q9NTJ3 UNIPROT Condensin II complex SIGNOR-C342 SIGNOR form complex binding 9606 32445620 t miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263909 0.81 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR2 protein Q9HBW0 UNIPROT up-regulates chemical activation 9606 8276865 t gcesareni Lpa activates its own g protein-coupled receptor(s) leading to stimulation of phospholipase c and inhibition of adenylate cyclase. SIGNOR-37368 0.8 PRPS1 protein P60891 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI down-regulates quantity chemical modification 9606 16939420 t miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. SIGNOR-267078 0.8 PRKACA protein P17612 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates activity phosphorylation Ser4520 GGHGSRHsLASTDEK 10029 11158305 t miannu LRP phosphorylation is mediated by PKA at residue serine 76 of its cytoplasmic tail and that this phosphorylation contributes to receptor-mediated endocytosis. SIGNOR-250000 0.33 MAPK3 protein P27361 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 15568999 t gcesareni In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. SIGNOR-131383 0.568 SRC protein P12931 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates activity phosphorylation Tyr785 STFTNITyRGT 9606 11723131 t lperfetto The phosphorylation level of beta(3) integrin was modulated using a temperature-sensitive v-Src kinase. Increased beta(3) phosphorylation abolished alpha(v)beta(3)- but not alpha(5)beta(1)-mediated adhesion to fibronectin. Thus, phosphorylation of the cytoplasmic domain of beta(3) is a negative regulator of alpha(v)beta(3)-fibronectin binding strength. SIGNOR-247207 0.647 PIEZO2 protein Q9H5I5 UNIPROT Hair cells mechanotransduction channel complex SIGNOR-C290 SIGNOR form complex binding 10090 BTO:0000630 23217710 t lperfetto The pore forming subunits of the hair cells mechanotransduction channel still need to be identified, but some candidates have emerged including TMC-1,TMC-2 (Kawashima et al., 2011), Piezo1 and Piezo2 (Coste et al., 2010; Coste et al., 2012). SIGNOR-262572 0.406 MUL1 protein Q969V5 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity sumoylation Lys594 GNWRGMLKTSKAEEL 9606 BTO:0000007 19638400 t Barakat Through a detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms. SIGNOR-274128 0.549 17beta-estradiol smallmolecule CHEBI:16469 ChEBI MAPK3 protein P27361 UNIPROT up-regulates 9606 BTO:0000150 11043579 f gcesareni Estrogen rapidly activates the mitogen-activated protein kinases, erk-1 and erk-2, via an as yet unknown mechanism. SIGNOR-83280 0.8 SOCS1 protein O15524 UNIPROT JAK1 protein P23458 UNIPROT down-regulates binding 9606 11133764 t gcesareni Jab/socs1/ssi-1 is an il-2 induced inhibitor of il-2 signaling that functions by inhibiting jak kinase activity SIGNOR-85352 0.721 GLI2 protein P10070 UNIPROT BMP2 protein P12643 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16880529 f gcesareni The zinc finger transcription factor gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling SIGNOR-148346 0.439 CSNK2A1 protein P68400 UNIPROT ATXN3 protein P54252 UNIPROT up-regulates activity phosphorylation Ser236 LQRALALsRQEIDME 9606 BTO:0000007 19542537 t miannu Here we show that protein casein kinase 2 (CK2)-dependent phosphorylation controls the nuclear localization, aggregation and stability of ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3). The main phosphorylation of ATXN3 in vivo thus occurred at serine residues within the three conserved UIMs. SIGNOR-276225 0.2 NFE2L2 protein Q16236 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000599 26194347 f irozzo Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes. SIGNOR-256262 0.7 GSK3B protein P49841 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates phosphorylation Ser159 NNTSTDGsLPSTPPP 9606 16543145 t gcesareni We investigated the role of glycogen synthase kinase-3 (gsk-3), which is inactivated by akt, for its role in the regulation of apoptosis. Upon il-3 withdrawal, protein levels of mcl-1 decreased but were sustained by pharmacological gsk-3, which prevented cytochrome c release and apoptosis. Mcl-1 was phosphorylated by gsk-3 at a conserved gsk-3 phosphorylation site (s159). S159 phosphorylation of mcl-1 was induced by il-3 withdrawal or pi3k inhibition and prevented by akt or gsk-3, and it led to increased ubiquitinylation and degradation of mcl-1. SIGNOR-145200 0.514 CADPS protein Q9ULU8 UNIPROT STX1A protein Q16623 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 24363652 t miannu CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1 SIGNOR-264336 0.411 NUP214 protein P35658 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR up-regulates activity relocalization 9606 12917407 t lperfetto We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import. SIGNOR-217719 0.537 FOXP2 protein O15409 UNIPROT AUTS2 protein Q8WXX7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 25232744 t miannu By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets. SIGNOR-266832 0.331 CHUK protein O15111 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT up-regulates activity phosphorylation Ser1043 CRPEALNsGVEYYWD 9606 BTO:0000567 30217973 t lperfetto Furthermore, we show that mitophagy function of AMBRA1 is post-translationally controlled, upon HUWE1 activity, by a positive phosphorylation on its serine 1014. This modification is mediated by the IKKα kinase and induces structural changes in AMBRA1, thus promoting its interaction with LC3/GABARAP (mATG8) proteins and its mitophagic activity. SIGNOR-272974 0.2 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser294 QLSKWPGsPTSRSSD 9606 18204439 t lperfetto Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation. SIGNOR-252957 0.71 POU4F3 protein Q15319 UNIPROT LHX3 protein Q9UBR4 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000630 17331196 t lperfetto Using oligonucleotide microarrays to generate expression profiles of inner ears of Pou4f3(ddl/ddl) mutant and wild-type mice, we have identified and validated Lhx3, a LIM domain transcription factor, as an in vivo target gene regulated by Pou4f3. Lhx3 is a hair cell-specific gene expressed in all hair cells of the auditory and vestibular system as early as embryonic day 16. The level of Lhx3 mRNA is greatly reduced in the inner ears of embryonic Pou4f3 mutant mice. Our data also show that the expression of Lhx3 is regulated differently in auditory and vestibular hair cells. SIGNOR-262586 0.407 MEF2A protein Q02078 UNIPROT MYH2 protein Q9UKX2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 t lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation SIGNOR-238703 0.331 GRIA2 protein P42262 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 30825796 f miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses SIGNOR-264612 0.7 GARS1 protein P41250 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 24898252 t miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. SIGNOR-270479 0.8 MECP2 protein P51608 UNIPROT BDNF protein P23560 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 14593183 t Luana We find that MeCP2 binds selectively to BDNF promoter III and functions to repress expression of the BDNF gene. SIGNOR-264540 0.484 COPS8 protein Q99627 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270770 0.925 N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide chemical CHEBI:125619 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258844 0.8 ZAP70 protein P43403 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr323 DEPVADPyDQSFESR 9606 BTO:0000782 15735648 t lperfetto Thus, phosphorylation of tyr323 dependent on the tyrosine kinase lck and mediated by zap70 serves as an important mechanism for tcr activation of p38 in t cells. SIGNOR-134329 0.457 LFNG protein Q8NES3 UNIPROT JAG1 protein P78504 UNIPROT down-regulates binding 9606 BTO:0000007 15574878 t gcesareni Although jagged1-induced signaling was suppressed by lfng and mfng SIGNOR-131560 0.499 prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI PTGER2 protein P43116 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257570 0.8 CTF1 protein Q16619 UNIPROT GCH1 protein P30793 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12859689 f miannu CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA. SIGNOR-252218 0.2 PFKFB4 protein Q16877 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates activity phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 BTO:0000007 29615789 t PFKFB4, a regulatory enzyme that synthesizes an allosteric stimulator of glycolysis2, was found to be a robust stimulator of SRC-3 that co-activates estrogen receptor (ER). PFKFB4 phosphorylates SRC-3 at serine 857 (S857) enhancing its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient SRC-3 mutant S857A (SRC-3S857A) significantly abolishes SRC-3-mediated transcriptional output SIGNOR-267269 0.332 RFX1 protein P22670 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12032779 f miannu Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. SIGNOR-253829 0.2 NUMA1 protein Q14980 UNIPROT TUBB2A protein Q13885 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-116936 0.2 NVP-AEW541 chemical CID:11476171 PUBCHEM INSR protein P06213 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194895 0.8 MAPK1 protein P28482 UNIPROT SORBS3 protein O60504 UNIPROT unknown phosphorylation 9606 15184391 t The effect has been demonstrated using O60504-2 llicata Vinexin was directly phosphorylated by erk2 upon stimulation with egf at the serine 189 of vinexin _. SIGNOR-125224 0.396 DUSP3 protein P51452 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity dephosphorylation 9534 BTO:0004055 10224087 t inferred from 70% of family members Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2 SIGNOR-269928 0.659 FYN protein P06241 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Tyr142 AVVNLINyQDDAELA -1 12640114 t Interaction of beta-catenin with alpha-catenin is regulated by the phosphorylation of beta-catenin Tyr-142. This residue can be phosphorylated in vitro by Fer or Fyn tyrosine kinases.  Transfection of these kinases to epithelial cells disrupted the association between both catenins. SIGNOR-251162 0.846 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NUP153 protein P49790 UNIPROT unknown phosphorylation 9606 19767751 t inferred from 70% family members llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. SIGNOR-270044 0.2 MAPK3 protein P27361 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr444 RFIGSPRtPVSPVKF 10116 15774499 t lperfetto Thr 421/Ser 424 have been reported to be targeted by ERK1, 2 (39), JNK or p38 MAPKs (36). Interestingly, with a comparable kinetics, FSH represses ERK1, 2 constitutive phosphorylation in Sertoli cells isolated from 19-d-old rats SIGNOR-134662 0.591 SRC protein P12931 UNIPROT GTF2I protein P78347 UNIPROT up-regulates activity phosphorylation Tyr248 EESEDPDyYQYNIQA 9534 BTO:0004055 11934902 t lperfetto c-Src-dependent transcriptional activation of TFII-ITFII-I is a multifunctional transcription factor that is also involved in signal transduction. Here we show that TFII-I undergoes a c-Src-dependent tyrosine phosphorylation on tyrosine residues 248 and 611 and translocates to the nucleus in response to growth factor signaling SIGNOR-247185 0.465 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC3 protein O15379 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194551 0.8 ATF4 protein P18848 UNIPROT FGF19 protein O95750 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000195 23205607 t lperfetto Reporter gene analyses using the 5'-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress SIGNOR-253727 0.2 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 16293724 t gcesareni Pge2 receptors are coupled to the G protein Gs, which causes accumulation of cyclic adenosine monophosphate (cAMP) and activates protein kinase a (PKA), we confirmed that PGE2 treatment or transfection of cells with the active catalytic subunit of PKA also stimulated the activity of a cAMP-responsive-element driven reporter gene (CRE-luc). SIGNOR-141786 0.8 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation 9606 11343802 t gcesareni Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation SIGNOR-107692 0.424 HNF4A protein P41235 UNIPROT F12 protein P00748 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 9794469 f miannu Orphan receptor hepatocyte nuclear factor-4 antagonizes estrogen receptor alpha-mediated induction of human coagulation factor XII gene. In conclusion, our findings address a direct role for HNF-4 in modulating estrogen-dependent transcription of the FXII gene promoter. SIGNOR-254073 0.221 CREBBP protein Q92793 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR form complex binding 9606 11559745 t lperfetto P300/cbp proteins: hats for transcriptional bridges and scaffolds SIGNOR-110559 0.525 CDK1 protein P06493 UNIPROT DLG1 protein Q12959 UNIPROT unknown phosphorylation Ser158 FVSHSHIsPIKPTEA 9606 19066288 t llicata We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor. SIGNOR-182753 0.402 HOXA7 protein P31268 UNIPROT IVL protein P07476 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000667 11435435 f miannu Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes. SIGNOR-254473 0.2 IKBKB protein O14920 UNIPROT BCL3 protein P20749 UNIPROT up-regulates activity phosphorylation Ser122 CPMEHPLsADIAMAT -1 28689659 t miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  SIGNOR-277364 0.373 AKT proteinfamily SIGNOR-PF24 SIGNOR CLK2 protein P49760 UNIPROT up-regulates phosphorylation Thr127 RRRRRSRtFSRSSSQ 9606 BTO:0000567 20682768 t lperfetto Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva SIGNOR-244218 0.2 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 24622840 t miannu STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3. SIGNOR-260154 0.816 IL7R protein P16871 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000776 18445337 t milica For instance, jak1 is associated with the ? Subunits of ?c Cytokines such as il-7r? And IL-4R. jak3 is associated with the ?c20,21. Cytokine binding mediates the trans-phosphorylation of receptor associated jak kinases, which in turn phosphorylate tyrosine residues on the receptors themselves. The receptor phosphotyrosines serve as docking sites for sh2 domain proteins including the stat family of transcription factors which are activated by jak-mediated phosphorylation. SIGNOR-178494 0.623 BMP1 protein P13497 UNIPROT COL5A1 protein P20908 UNIPROT up-regulates activity cleavage Asp1549 IKTEEISeVKMDAEF 9606 BTO:0002974 11741999 t miannu BMP-1 Can Efficiently Cleave Pro-α1(V) N-propeptides and Pro-α2(V) C-propeptides and Less Efficiently Cleave Pro-α1(V) C-propeptides in Vitro.NH2-terminal sequencing of an ∼35-kDa band in the BMP-1-treated material (N-α1(V), Fig. 3 B,lanes 2 and 3) showed it to correspond to the NH2-terminal portion of the pro-α1(V) N-propeptide previously shown to be cleaved in pro-α1(V)3 homotrimers by BMP-1 (39), whereas NH2-terminal sequencing of an ∼38-kDa band (C-α1(V)BMP-1, Fig. 3 B,lanes 2 and 3) showed it to correspond to pro-α1(V) C-propeptides cleaved between Asp-1594 and Asp-1595. SIGNOR-256344 0.608 MMP9 protein P14780 UNIPROT PZP protein P20742 UNIPROT down-regulates quantity by destabilization cleavage Leu778 WKAGAFClSEDAGLG -1 9344465 t lperfetto The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. SIGNOR-261785 0.356 NKX2-5 protein P52952 UNIPROT ANKRD1 protein Q15327 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0003265 9043061 f Finally, a carp promoter-lacZ transgene, which displays cardiac-specific expression in wild-type and Nkx2-5(+/-) background, was also significantly reduced in Nkx2-5(-/-) embryos, indicating that Nkx2-5 either directly or indirectly regulates carp promoter activity during in vivo cardiogenesis as well as in cultured cardiac myocytes SIGNOR-253646 0.342 GRIK5 protein Q16478 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264346 0.7 IKBKB protein O14920 UNIPROT BCL3 protein P20749 UNIPROT up-regulates activity phosphorylation Ser454 PSPAPGGs -1 28689659 t miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  SIGNOR-277365 0.373 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser29 ATKAARKsAPATGGV 9606 20129940 t gcesareni Upon activation of the erk and p38 mapk pathways, the msk1/2-mediated nucleosomal response, including h3 phosphorylation at serine 28 or 10, is coupled with the induction of immediate-early (ie) gene transcription. SIGNOR-163712 0.2 PTPN11 protein Q06124 UNIPROT CSF2RB protein P32927 UNIPROT up-regulates dephosphorylation 9606 phosphorylation:Tyr628 PPPGSLEyLCLPAGG 9162089 t gcesareni Shp2 is thought to act as a positive mediator of growth factor signals.. Hp2 could act as an adaptor between the activated c and grb2, thus leading to activation of the ras/mitogen-activated protein kinase pathway, known to be activated by il-3 SIGNOR-48557 0.49 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 10068651 t lperfetto Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro. SIGNOR-236262 0.952 SRC protein P12931 UNIPROT CHKA protein P35790 UNIPROT up-regulates activity phosphorylation Tyr333 LMLIDFEySSYNYRG 9606 BTO:0000093 21822308 t miannu We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333. SIGNOR-266350 0.342 ZNF304 protein Q9HCX3 UNIPROT CDKN2B protein P42772 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000391 24623306 t Luana Finally, we show that ZNF304 also directs transcriptional silencing of INK4-ARF in human embryonic stem cells. SIGNOR-266099 0.284 TRAF6 protein Q9Y4K3 UNIPROT MAP3K8 protein P41279 UNIPROT up-regulates activity 9606 BTO:0000007 16371247 f The activation of Cot-MKK1-ERK1/ERK2 signalling pathway by IL-1 is dependent on the activity of the transducer protein TRAF6. SIGNOR-252254 0.427 LATS2 protein Q9NRM7 UNIPROT VEPH1 protein Q14D04 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 22055343 f In the neuronal differentiation lperfetto Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r9 SIGNOR-177071 0.2 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 BTO:0000887 11940578 t gcesareni Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. SIGNOR-116485 0.601 NFATC2 protein Q13469 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15130492 t lperfetto MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA SIGNOR-251729 0.2 LRRK2 protein Q5S007 UNIPROT MSN protein P26038 UNIPROT up-regulates activity phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 17447891 t lperfetto This led to the discovery that moesin, a protein which anchors the actin cytoskeleton to the plasma membrane, is efficiently phosphorylated by lrrk2, at thr558. Moesin phosphorylation could be essential to support the cytoskeletal changes accompanying this process. SIGNOR-154498 0.568 ATR protein Q13535 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Ser539 GLITINSsQEHLTVQ 9606 22123827 t lperfetto Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication. SIGNOR-177809 0.643 GABRB1 protein P18505 UNIPROT GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR form complex binding 9606 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263760 0.605 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH5 protein P33151 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265845 0.8 DYNLL1 protein P63167 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT down-regulates binding 9606 20921139 t gcesareni The beclin 1vps34 complex is tethered to the cytoskeleton through an interaction between the beclin 1interacting protein ambra1 and dynein light chains 1/2. SIGNOR-168255 0.531 IRF2BPL protein Q9H1B7 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000498 29374064 t miannu FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation. SIGNOR-267153 0.2 ABL1 protein P00519 UNIPROT YTHDC1 protein Q96MU7 UNIPROT down-regulates phosphorylation 9606 15175272 t lperfetto We show that yt521-b is tyrosine phosphorylated by c-abl in the nucleus.We propose that tyrosine phosphorylation causes sequestration of YT521-B in an insoluble nuclear form, which abolishes the ability of YT521-B to change alternative splice sites. SIGNOR-125167 0.31 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser710 GEKSFRRsVVGTPAY 9606 12058027 t gcesareni Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs. SIGNOR-89427 0.2 PDE1C protein Q14123 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI down-regulates quantity chemical modification 9606 22014080 t PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C hydrolyses cAMP and cGMP with similar Km values SIGNOR-253399 0.8 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates activity phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 t lperfetto The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein. SIGNOR-105251 0.38 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser284 AGGGRRIsDSHEDTG 9606 BTO:0000887 20151718 t miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-163788 0.278 MAPK10 protein P53779 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates phosphorylation 9606 BTO:0000567 17686459 t gcesareni Here we demonstrate that jnk3 can phosphorylate smac. Phosphorylation of smac by jnk3 attenuates its interaction with xiap. These results suggest that jnk3 activity can attenuate the progression of apoptosis through a novel mechanism of action, the down-regulation of interaction between smac and xiap. SIGNOR-157280 0.347 IL1B protein P01584 UNIPROT MC1R protein Q01726 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000847 9767234 f miannu MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression. SIGNOR-252385 0.263 STAT4 protein Q14765 UNIPROT PRF1 protein P14222 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000914 12372421 f miannu IL-12-induced expression of the perforin gene in NK cells is directly regulated by STAT4, which binds, most likely as a homo-tetramer, to the tandem STAT-binding sequences in the perforin gene promoter. SIGNOR-255245 0.411 FGF2 protein P09038 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15564063 f miannu Increased expression of RUNX2 in OA cartilage may contribute to increased expression of MMP-13. FGF2, which is present in OA synovial fluid, activated RUNX2 via the MEK/ERK pathway and increased MMP-13 expression. SIGNOR-255079 0.431 Gbeta proteinfamily SIGNOR-PF4 SIGNOR TCF3 protein P15923 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 BTO:0000944 14592976 t inferred from 70% family members lperfetto Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG) SIGNOR-270009 0.2 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Ser20 KRPQRATsNVFAMFD 9606 8702756 t miannu Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase. SIGNOR-261709 0.633 AKT2 protein P31751 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates activity phosphorylation Thr151 FCNGRGNtSGSHIVN 9606 BTO:0002181 35675814 t miannu AKT-Mediated UPF1 Phosphorylation at T151 Promotes UPF1 Helicase Activity SIGNOR-277595 0.2 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser619 SLPKINRsASEPSLH 9606 12551925 t gcesareni Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. SIGNOR-97648 0.539 PTPN5 protein P54829 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates activity dephosphorylation Tyr1474 GSSNGHVyEKLSSIE 10090 BTO:0004102 20427654 t lperfetto  These previous results, together with the present findings, indicate that STEP61 dephosphorylates the NR2B subunit at its regulatory tyr1472 site, and dephosphorylation of this site leads to internalization of the NMDAR complex from neuronal surface membranes. SIGNOR-265744 0.563 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 t lperfetto Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both_ in vitro_ and_ in vivo. SIGNOR-74923 0.533 PSEN1 protein P49768 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 2195779 t gcesareni Importantly, our data show that binding of ps1 to cadherin mediates the effects of ps1 on the phosphorylation, ubiquitination, and destabilization of beta-catenin. Thus, cadherins mediate both the association of ps1 and beta-catenin and the effects of ps1 on the cellular levels of beta-catenin SIGNOR-22837 0.801 INSR protein P06213 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation Tyr774 SENEDDGyDVPKPPV 10090 BTO:0000944 11997497 t Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation. SIGNOR-251306 0.507 FGA protein P02671 UNIPROT Fibrinogen complex SIGNOR-C311 SIGNOR form complex binding -1 25427968 t lperfetto Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aalpha, Bbeta, and gamma, encoded by the FGA, FGB, and FGG gene, respectively). SIGNOR-263392 0.761 leucine smallmolecule CHEBI:25017 ChEBI Glutaminolysis phenotype SIGNOR-PH119 SIGNOR up-regulates activity 9606 BTO:0000567 22749528 f Luana Leucine and Glutamine Activate Glutaminolysis and mTORC1 SIGNOR-268011 0.7 PRKCE protein Q02156 UNIPROT TICAM2 protein Q86XR7 UNIPROT up-regulates phosphorylation Ser16 NSCPLSLsWGKRHSV 9606 16757566 t llicata Here we show that tram is transiently phosphorylated by pkcepsilon on serine-16 our study provides a possible target for these molecules in lps signaling. Dag may activate pkc?, Leading to the phosphorylation and activation of tram. SIGNOR-146991 0.59 INS protein P01308 UNIPROT INSR protein P06213 UNIPROT up-regulates activity binding 9606 2550426 t lperfetto Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds. SIGNOR-23001 0.933 AKT1 protein P31749 UNIPROT TERT protein O14746 UNIPROT up-regulates phosphorylation Ser824 AVRIRGKsYVQCQGI 9606 10224060 t gcesareni Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins. SIGNOR-67317 0.721 MPO protein P05164 UNIPROT APOA1 protein P02647 UNIPROT down-regulates activity oxidation 9606 20043647 t miannu When apolipoprotein A-I (apoA-I), the major HDL protein, was oxidized by MPO, its ability to promote cellular cholesterol efflux by ABCA1 was impaired. Moreover, oxidized apoA-I was unable to activate lecithin:cholesterol acyltransferase (LCAT), which rapidly converts free cholesterol to cholesteryl ester, a critical step in HDL maturation SIGNOR-252102 0.416 F10 protein P00742 UNIPROT F7 protein P08709 UNIPROT up-regulates activity cleavage Arg212 NASKPQGrIVGGKVC 9606 BTO:0000131 12524220 t lperfetto The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa. SIGNOR-263523 0.521 PPARGC1A protein Q9UBK2 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001103 SIGNOR-C13 20404331 f lperfetto In mouse muscles, overexpression of PGC-1beta (like PGC-1alpha) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFkappaB SIGNOR-217969 0.36 NRXN1 protein Q9ULB1 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 t miannu The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites. SIGNOR-265452 0.819 3-(9-Fluoro-2-(piperidine-1-carbonyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-4-(imidazo[1,2-a]pyridin-3-yl)-1H-pyrrole-2,5-dione chemical CID:10029385 PUBCHEM GSK3B protein P49841 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000183 31562256 t miannu Indeed, we demonstrated that the selective GSK3 inhibitor LY2090314 significantly reduced cell proliferation in control pancreatic cancer cell lines SIGNOR-262539 0.8 MAP3K3 protein Q99759 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity binding 9606 BTO:0000298 9162092 t lperfetto These data indicate that mkk3 is preferentially activated by mekk3, whereas mkk4 is activated both by mekk2 and mekk3. SIGNOR-48628 0.587 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-252311 0.635 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAPN1 protein P07384 UNIPROT up-regulates activity chemical activation 9606 BTO:0000590 25969760 t lperfetto The data obtained from those studies suggest that the mechanisms leading to the formation of the hallmark lesions of AD might be linked. One of such mechanisms seems to be the dysregulation of calcium homeostasis that results in the abnormal activation of calpains. Calpains are a family of Ca2+-dependent cysteine proteases that play a key role in multiple cell functions including cell development, differentiation and proliferation, axonal guidance, growth cone motility, and cell death, among others. SIGNOR-251580 0.8 DZIP3 protein Q86Y13 UNIPROT H2AC11 protein P0C0S8 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271749 0.2 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Ser41 EAAGPAPsPMRAANR 9606 BTO:0000567 15525512 t llicata Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.  SIGNOR-250606 0.992 AURKB protein Q96GD4 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14583461 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. SIGNOR-118894 0.2 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 t miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. SIGNOR-264922 0.8 SMARCA4 protein P51532 UNIPROT ZEB1 protein P37275 UNIPROT up-regulates binding 9606 20418909 t miannu Zeb1 represses e-cadherin transcription / we reported that brg1 binds to the ntr of zeb1 acting as its co-repressor in the regulation of the e-cadherin promoter. SIGNOR-165017 0.413 NR4A3 protein Q92570 UNIPROT BBC3 protein Q9BXH1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30455429 t miannu Over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax. SIGNOR-259396 0.2 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser180 GSSASFIsDTFSPYT 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252327 0.635 IFNG protein P01579 UNIPROT LPL protein P06858 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001030 10909770 f Regulation of expression miannu The suppression of lipoprotein lipase expression in J774.2 macrophages by IFN-gamma and TNF-alpha is mediated at the transcriptional level. SIGNOR-251854 0.362 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser185 SAPARMLsSNERDSS 9606 BTO:0002181 34363019 t miannu Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.  SIGNOR-276739 0.2 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation -1 31332417 t miannu In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group. SIGNOR-268757 0.8 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 20640476 t lperfetto AMPK can directly phosphorylate PGC-1a at Thr177 and Ser538 in in vitro assays PGC-1a phosphorylation might not directly affect its intrinsic coactivation activity, but, rather, release it from its repressor protein p160myb [79] and/or allow deacetylation and subsequent activation by SIRT1 SIGNOR-209936 0.483 HRH2 protein P25021 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257049 0.252 Jervine chemical CHEBI:6088 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0000527 21679342 t gcesareni Cyclopamine (c27h41no2) and jervine (c27h39no3) were discovered and in particular, a series of studies with the hh pathway inhibitor, cyclopamine, has brought about this expectation. cyclopamine suppresses the hh signaling pathway through direct interaction with smo. SIGNOR-174420 0.8 APOB protein P04114 UNIPROT LDLR protein P01130 UNIPROT up-regulates binding 9606 11986215 t gcesareni In the case of ldl, binding of apolipoprotein b (apob) to the ldl-r18-20 and proteoglycans17 21 initiates plasma clearance and lipoprotein degradation SIGNOR-87035 0.797 PARVA protein Q9NVD7 UNIPROT IPP complex complex SIGNOR-C380 SIGNOR form complex binding 16493410 t lperfetto Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton. SIGNOR-265761 0.728 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation 9606 18694962 t Translocation from Nuleus to Cytoplasm gcesareni Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. SIGNOR-269996 0.2 GNRHR protein P30968 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257331 0.455 CHD4 protein Q14839 UNIPROT CD79A protein P11912 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000776 23071088 f lperfetto However, NuRD complexes greatly reduce activation of the B cell-specific mb-1 (Cd79a) gene by the transcription factors EBF1 and Pax5|We conclude that repressive functions of MBD2-containing NuRD complexes are dependent on cooperative interactions between the major domains of CHD4 with histones and DNA and on binding of methylated DNA by MBD2. SIGNOR-254090 0.251 TRIM58 protein Q8NG06 UNIPROT DYNC1I2 protein Q13409 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 25241935 t miannu Trim58 ubiquitinates dynein and promotes its proteasomal degradation. Trim58 binds DIC directly, polyubiquitinates it in vitro, and induces proteasomal degradation of the dynein holocomplex in vivo. SIGNOR-272841 0.303 NEDD4L protein Q96PU5 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates ubiquitination 9606 19917253 t gcesareni Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation SIGNOR-161710 0.772 FASTKD2 protein Q9NYY8 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25683715 f miannu DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU. SIGNOR-261227 0.7 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr234 PNFYDETyDYGGFTM 9606 12052863 t lperfetto We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown). SIGNOR-88907 0.608 USP8 protein P40818 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000567 20736164 t irozzo USP8 is known to deubiquitinate EGFR in response to ligand stimulation. USP8 depletion accelerates receptor turnover, whereas loss of hepatocyte growth factor-regulated substrate (Hrs) rescues this phenotype, indicating that USP8 protects EGFR from degradation via an Hrs-dependent pathway. [..]As EGFR stabilization against lysosomal turnover requires deubiquitination by USP8. SIGNOR-259102 0.699 POLR2H protein P52434 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266172 0.819 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89182 0.55 SLC2A2 protein P11168 UNIPROT glucose chemical CHEBI:17234 ChEBI up-regulates quantity relocalization 9606 25421524 t The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion. SIGNOR-267386 0.8 PIWIL1 protein Q96J94 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates binding 9606 BTO:0003081 32203416 t miannu PIWIL1 leads to the constitutive activation of APC/C in PDAC cells. Here, we show that in the absence of piRNAs, human PIWIL1 in PDAC functions as an oncoprotein by activating the anaphase promoting complex/cyclosome (APC/C) E3 complex, which then targets a critical cell adhesion-related protein, Pinin, to enhance PDAC metastasis. Collectively, these results demonstrate that Pinin is an authentic substrate of APC/CPIWIL1 in PDAC cells. SIGNOR-272202 0.2 phosphatidylinositol 4-phosphate smallmolecule CHEBI:37530 ChEBI Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 9534 22253445 f lperfetto Further research suggested that PI4P plays an essential role in SARS-CoV spike-mediated entry, which is regulated by the PI4P lipid microenvironment. SIGNOR-260745 0.7 NUP214 protein P35658 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates binding 9606 SIGNOR-C9 12917407 t gcesareni We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import SIGNOR-117647 0.542 BBC3 protein Q9BXH1 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0001938 11463392 t lperfetto Puma localizes to the mitochondria, interacts with bcl-2, and function to induce cytochrome c release SIGNOR-109506 0.649 PRKD2 protein Q9BZL6 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser172 GQLVRNDsLWHRSDS 34010649 t lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-275941 0.2 OPTN protein Q96CV9 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 10090 BTO:0005118 22194658 f same result in PC12 cell miannu SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA. SIGNOR-259877 0.7 IL17A protein Q16552 UNIPROT KLF3 protein P57682 UNIPROT up-regulates transcriptional regulation 9606 23332504 f fspada Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic.  SIGNOR-210114 0.2 CNOT3 protein O75175 UNIPROT TNFRSF11A protein Q9Y6Q6 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003292 24550297 t Luana Our results reveal that CNOT3 is a critical regulator of bone mass acting on bone resorption through posttranscriptional down-regulation of RANK mRNA stability, at least in part, even in aging-induced osteoporosis. SIGNOR-261572 0.2 TRAF2 protein Q12933 UNIPROT MAP4K2 protein Q12851 UNIPROT up-regulates binding 9606 9712898 t gcesareni Both full-lenght gck and the gck-ctd can form complexes in vivo with traf2. SIGNOR-59685 0.515 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258000 0.8 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity by destabilization ubiquitination Lys784 HVKLERLkQVNGMFP 9606 BTO:0000938 17283082 t lperfetto Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage. SIGNOR-249577 0.657 TOMM7 protein Q9P0U1 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 t lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. SIGNOR-267680 0.761 EIF3G protein O75821 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266394 0.935 SOCS4 protein Q8WXH5 UNIPROT DAB1 protein O75553 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0000298 24210661 t miannu SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SIGNOR-272139 0.2 PLK1 protein P53350 UNIPROT CHEK2 protein O96017 UNIPROT unknown phosphorylation Thr26 SQPHGSVtQSQGSSS -1 12493754 t lperfetto Plk1 overexpression enhances phosphorylation of Chk2 at Thr-68. Plk1 phosphorylates recombinant Chk2 in vitro. SIGNOR-249180 0.504 NEK1 protein Q96PY6 UNIPROT ATR protein Q13535 UNIPROT up-regulates activity binding 28426283 t lperfetto It was reported that NEK1 associates with ATR/ATRIP and primes it for activation in response to a variety of genotoxic agents SIGNOR-275841 0.2 PTEN protein P60484 UNIPROT RAB7A protein P51149 UNIPROT up-regulates activity dephosphorylation Ser72 AGQERFQsLGVAFYR 9606 26869029 t lperfetto PTEN dephosphorylates Rab7 on two conserved residues S72 and Y183, which are necessary for GDP dissociation inhibitor (GDI)-dependent recruitment of Rab7 on to late endosomes and subsequent maturation. SIGNOR-276960 0.381 levomethadone chemical CHEBI:136003 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258809 0.8 STK4 protein Q13043 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates activity phosphorylation Thr18 PAPNFKAtAVMPDGQ -1 23386615 t miannu Mst1 inactivates Prdx1 by phosphorylating it at Thr-90 and Thr-183, leading to accumulation of hydrogen peroxide in cells.Prdx1 is phosphorylated by Mst1 predominantly at Thr-18, Thr-90, and Thr-183. SIGNOR-276486 0.2 denileukin diftitox smallmolecule SID:125240988 ChEBI IL2RG protein P31785 UNIPROT up-regulates activity chemical activation 9606 15757436 t miannu Denileukin diftitox (DAB389IL-2; Ontak) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells.  SIGNOR-259394 0.8 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120216 0.321 imiquimod chemical CHEBI:36704 ChEBI TLR8 protein Q9NR97 UNIPROT up-regulates activity chemical activation 9606 15661881 t miannu Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively. SIGNOR-259245 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 14967450 t lperfetto Akt negatively regulates the raf and gsk-3 kinases and the cell cycle regulatory transcription factor fkhr. SIGNOR-244333 0.2 halothane chemical CHEBI:5615 ChEBI KCNK3 protein O14649 UNIPROT up-regulates activity chemical activation 10090 20519544 t Luana We further demonstrate that TASK channels are required for normal sensitivity to immobilizing effects of halothane and isoflurane and to sedative/hypnotic effects of halothane. SIGNOR-257846 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR TKT protein P29401 UNIPROT up-regulates activity phosphorylation Thr382 GCATRNRtVPFCSTF 9606 BTO:0000567 24981175 t lperfetto Akt phosphorylates TKT on Thr382, markedly enhancing enzyme activity and increasing carbon flow through the nonoxidative PPP, thereby increasing purine synthesis. SIGNOR-265102 0.2 PTK2B protein Q14289 UNIPROT ASAP1 protein Q9ULH1 UNIPROT down-regulates activity phosphorylation Tyr767 RDKQRLSyGAFTNQI 9606 BTO:0000007 12771146 t miannu The tyrosine kinase Pyk2 regulates Arf1 activity by phosphorylation and inhibition of the Arf-GTPase-activating protein ASAP1. Pyk2 directly phosphorylates ASAP1 on tyrosine residues in vitro and increases ASAP1 tyrosine phosphorylation when co-expressed in HEK293T cells.Phosphorylation of tyrosine 308 and 782 affects the phosphoinositide binding profile of ASAP1, and fluorimetric Arf-GTPase assays with purified proteins revealed an inhibition of ASAP1 GTPase-activating protein activity by Pyk2-mediated tyrosine phosphorylation. SIGNOR-263187 0.469 Laminin-1 complex SIGNOR-C183 SIGNOR A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates activity binding 2351695 t lperfetto In combination, the anti-alpha 1- and anti-alpha 6-specific antibodies completely inhibited JAR cell attachment to LN and fragment E1. Thus, the alpha 1/beta 1 and alpha 6/beta 1 integrin heterodimers each function as LN receptors and act together to mediate the interactions of human JAR choriocarcinoma cells with LN. SIGNOR-253256 0.537 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr846 RAFSFSKtPKRALRR 9606 BTO:0001938 16247472 t lperfetto Thr-814 to ala greatly diminished the ability of p34cdk1/cyclin b to phosphorylate recombinant ect2-c protein (figure 1b, left panel). These data suggest that thr-814 is a major cdk1 phosphorylation site in ect2-c in vitrothe sequence thr-pro-lys-arg (tpkr) starting at amino acid 814we found that the t814a mutation slightly reduces the exchange activity of ect2 on rac1 SIGNOR-216928 0.499 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252082 0.2 CIITA protein P33076 UNIPROT HLA-DMB protein P28068 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11889043 f Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment. SIGNOR-254010 0.358 PPM1D protein O15297 UNIPROT MAPK12 protein P53778 UNIPROT down-regulates dephosphorylation Thr183 RQADSEMtGYVVTRW 9606 15870257 t gcesareni Ppm1d selectively inhibits p38 activation by dephosphorylating thr 180. SIGNOR-135976 0.301 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser315 ITATSPAsMVGGKPG 9606 BTO:0000887;BTO:0001103 14579029 t gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. SIGNOR-118861 0.767 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Thr170 ARILNHDtSFAKTFV 9606 17197699 t gcesareni Thus, it appears that autophosphorylation of thr-170 and/or ser-171 in nek2 may fine-tune overall activity of nek2 in vivo. regardless, the importance of thr-175 suggested by its conservation in many other kinases is underlined by the t175a mutant that shows reduced kinase activity and a significant reduction in efficiency of cs. SIGNOR-151759 0.2 PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-252703 0.784 L-arginine chemical CHEBI:16467 ChEBI NOS2 protein P35228 UNIPROT up-regulates BTO:0000801 BTO:0001103 25386178 f apalma In mammalian cells, arginine can be catabolized by four classes of enzymes (Figure ​(Figure1):1): NOS, arginase, arginine decarboxylase (ADC), and arginine:glycine amidinotransferase (AGAT) SIGNOR-255554 0.8 OXTR protein P30559 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257332 0.41 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates activity phosphorylation Tyr648 DVHNLDYyKKTTNGR 9606 BTO:0000007 11294897 t lperfetto Ligand stimulation leads to autophosphorylation of fgfr3the two tyrosine residues in the YYKK Motif of the activation loop of fgfrs are required for kinase activity of fgfr1 and fgfr3. SIGNOR-106734 0.2 MAPRE1 protein Q15691 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates binding 17889670 t lperfetto Microtubule plus end binding proteins (+TIPs) localize to the dynamic plus ends of microtubules, where they stimulate microtubule growth and recruit signaling molecules. Three main +TIP classes have been identified (XMAP215, EB1, and CLIP-170) SIGNOR-264831 0.7 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser61 PLSTPCSsVPSSPSF 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159446 0.259 MLL1 complex complex SIGNOR-C89 SIGNOR PAX7/MLL1 complex complex SIGNOR-C90 SIGNOR form complex binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-198620 0.2 CHEK2 protein O96017 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates quantity by stabilization phosphorylation Ser364 PLLSRMGsLRAPVDE 9606 22558186 t gcesareni Among these effector proteins, chk1 phosphorylates tlk12 and rad51, while brca, pik3, pml and e2f1 are chk2 substrates. SIGNOR-197278 0.5 MRPS31 protein Q92665 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261445 0.697 Gbeta proteinfamily SIGNOR-PF4 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 19282669 t inferred from 70% family members lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-270070 0.2 IRF3 protein Q14653 UNIPROT Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 10090 BTO:0002572 20610653 f lperfetto Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-126962 0.7 HMGB1 protein P09429 UNIPROT IL2RA protein P01589 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 7862168 f 2 miannu The interleukin 2 receptor alpha-chain (IL-2R alpha) gene is rapidly and potently induced in T cells in response to mitogenic stimuli. Previously, an inducible enhancer between nucleotides -299 and -228 that contains NF-kappa B and CArG motifs was identified. We now report the characterization of a second essential positive regulatory element located between nucleotides -137 and -64 that binds Elf-1 and HMG-I(Y). Transcription from the IL-2R alpha promoter was inhibited when either the Elf-1 or the HMG-I(Y) binding site was mutated. Coexpression of both proteins activated transcription of the -137 to -64 element in COS-7 cells. SIGNOR-240113 0.2 MAGEA3 protein P43357 UNIPROT TRIM28 protein Q13263 UNIPROT up-regulates activity binding 9606 BTO:0000594 28394358 t lperfetto In this study, we demonstrated that the tripartite motif-containing protein 28 (TRIM28) binds directly to and promotes FBP1 for ubiquitination and degradation. MAGE-A3 and MAGE-C2, which are known to be overexpressed in HCC, can enhance TRIM28-dependent degradation of FBP1 by forming ubiquitin ligase complexes with TRIM28. SIGNOR-267592 0.446 ERBB4 protein Q15303 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 16729043 t gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. SIGNOR-146879 0.593 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001103 21902831 t gcesareni Phosphorylation of CREB by PKA allows it to initiate the transcription of genes that contain a CRE element, two of which are PAX3 and MYF5. SIGNOR-176560 0.564 TRAF6 protein Q9Y4K3 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002181 30806153 t miannu TRAF6 catalyzes K63-linked polyubiquitination of LC3B and promotes the formation of the LC3B-ATG7 and LC3B-CTNNB1 complexes. SIGNOR-277439 0.299 PRKCA protein P17252 UNIPROT THOC5 protein Q13769 UNIPROT up-regulates phosphorylation Ser5 sSKKRKPK 9606 BTO:0000801;BTO:0000876 15221008 t llicata We conclude m-csf-mediated activation of pkcalpha can potentiate fmip action to initiate survival/differentiation signaling. SIGNOR-126568 0.333 CSNK2A1 protein P68400 UNIPROT EIF5 protein P55010 UNIPROT up-regulates phosphorylation Ser390 KEAEEESsGGEEEDE 9606 18649047 t gcesareni We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2. SIGNOR-179546 0.402 CD27 protein P26842 UNIPROT BIK protein Q13323 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12324477 f gcesareni Bik expression was weakly but significantly down-regulated by cd27 but up-regulated by cd40. SIGNOR-93323 0.2 MAP3K5 protein Q99683 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation 9606 19920149 t gcesareni Ask1 is a member of a mapkkk family and functions as an upstream kinase engaged in c-jun nh2-terminal kinase (jnk)/p38 signaling via the phosphorylation and activation of mapkks, such as mkk3, -4, -6, and -7 SIGNOR-161766 0.577 MRPS14 protein O60783 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 BTO:0000934 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261456 0.718 trametinib chemical CHEBI:75998 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck lperfetto SIGNOR-244871 0.8 PPP3CB protein P16298 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity dephosphorylation Ser637 VPVARKLsAREQRDC 9606 18838687 t When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. SIGNOR-248361 0.281 CSNK2A2 protein P19784 UNIPROT NOL3 protein O60936 UNIPROT up-regulates activity phosphorylation Thr149 SEAVQSGtPEEPEPE 9606 12191471 t miannu Phosphorylation of ARC at T149 Is Required for Its Antiapoptotic Effect. Here we report that the function of ARC is regulated by protein kinase CK2. ARC at threonine 149 is phosphorylated by CK2. This phosphorylation targets ARC to mitochondria. ARC is able to bind to caspase-8 only when it is localized to mitochondria but not to the cytoplasm. SIGNOR-262836 0.2 ESR1 protein P03372 UNIPROT NR0B2 protein Q15466 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10648597 f gcesareni We demonstrate that shp variants, carrying either interaction-defective nr box mutations or a deletion of the repressor domain, have lost the capacity to inhibit agonist-dependent transcriptional estrogen receptor activation. SIGNOR-74288 0.634 SOCS3 protein O14543 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates 9606 16543409 f lperfetto Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1-induced transcription and activation of NFkappaB and the MAPKs JNK and p38, but the mechanism is unknown SIGNOR-253052 0.399 PCNA protein P12004 UNIPROT DNA polymerase delta complex SIGNOR-C376 SIGNOR up-regulates activity binding 9534 BTO:0004055 12930972 t lperfetto Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA). SIGNOR-265511 0.764 lapatinib chemical CHEBI:49603 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 21443688 t Luana YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ. SIGNOR-257898 0.8 AP2M1 protein Q96CW1 UNIPROT EGFR protein P00533 UNIPROT down-regulates relocalization 9606 19351721 t gcesareni The removal of the epidermal growth factor receptor (egfr) from the cell surface by endocytosis is triggered by receptor activation, but many facets of egfr trafficking remain unresolvedthe ap-2 complex is involved in the internalization of activated egfr. SIGNOR-185124 0.504 Caspase 3 complex complex SIGNOR-C221 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 f amattioni Caspase-3 is responsible for apoptosis execution SIGNOR-256548 0.7 HES1 protein Q14469 UNIPROT PTGDS protein P41222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002605 15743775 f miannu knock-down of Hes-1 mRNA by RNA interference significantly enhanced the L-PGDS mRNA level, indicating that the L-PGDS gene expression is repressed by the Notch-Hes signaling. SIGNOR-255424 0.2 STK11 protein Q15831 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 9606 14657655 f gcesareni Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent. SIGNOR-119892 0.386 TEAD proteinfamily SIGNOR-PF22 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 26258633 t miannu YAP/TAZ/TEAD and AP-1 form a complex that synergistically activates target genes directly involved in the control of S-phase entry and mitosis. SIGNOR-277658 0.359 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser28 PHGSVTQsQGSSSQS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to irser28 was also found to be phosphorylated in an atm-dependent manner SIGNOR-81395 0.829 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000586 16293724 t lperfetto This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. SIGNOR-227889 0.891 SMAD5 protein Q99717 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0002729 23993924 f flangone Engagement of BMP4-mediated signaling in adult mouse ovary-derived OSCs cultured in vitro drives differentiation of these cells into IVD oocytes through Smad1/5/8 activation and transcriptional up-regulation of key meiosis-initiating genes. SIGNOR-242059 0.7 BMP2 protein P12643 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR up-regulates 9606 22298955 f inferred from 70% of family members lperfetto Neogenin, a transmembranous protein, was reported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation. SIGNOR-269848 0.689 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CAPN2 protein P17655 UNIPROT up-regulates phosphorylation 9606 14993287 t inferred from 70% family members lperfetto Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo. SIGNOR-270179 0.2 PAX3 protein P23760 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity binding 9606 20006729 t gcesareni Pax3 binds to lef1 pax3 activity may directly effect the expression of factors regulated by signal transduction pathways dependent on lef1. SIGNOR-162100 0.438 AREL1 protein O15033 UNIPROT PIAS4 protein Q8N2W9 UNIPROT down-regulates quantity by destabilization ubiquitination phosphorylation:Ser18;Thr783 MVMSFRVsDLQMLLG;T>782 27162139 t lperfetto In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFβ signaling pathway through the site-specific ubiquitination of PIAS4.FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCζ and GSK3β. Specifically, PKCζ phosphorylation of PIAS4 and GSK3β phosphorylation of FIEL1 are both essential for the degradation of PIAS4. SIGNOR-275575 0.412 IFNGR2 protein P38484 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 BTO:0000801 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249504 0.688 PTPRT protein O14522 UNIPROT PXN protein P49023 UNIPROT down-regulates activity dephosphorylation Tyr88 PQSSSPVyGSSAKTS 9606 BTO:0000182 27447856 t brain lperfetto To this end, using a phospho-proteomics approach, we identified and validated paxillin and STAT3 as the substrates of PTPRT [15, 16]|the PTPRT target site on paxillin is a previously uncharacterized tyrosine-88 residue (paxillin Y88)|In this study, we also show how pY88 paxillin transduces a signal to activate Akt SIGNOR-263978 0.474 LRRK2 protein Q5S007 UNIPROT SH3GL1 protein Q99961 UNIPROT down-regulates phosphorylation 9606 22998870 t miannu We show that lrrk2 affects synaptic endocytosis by phosphorylating endoa at s75, a residue in the bar domain / our work uncovers a regulatory mechanism that indicates that reduced lrrk2 kinase activity facilitates endoa membrane association, while increased kinase activity inhibits membrane association. SIGNOR-192068 0.479 CHEK2 protein O96017 UNIPROT AATF protein Q9NY61 UNIPROT up-regulates quantity by stabilization phosphorylation Ser510 KKVDRKAsKGRKLRF 9606 BTO:0001109 17157788 t lperfetto Three putative Chk2 phosphorylation sites (Stevens et al., 2003) are present in Che-1 at resides Ser141, Ser474, and Ser508. Thus, we performed in vitro Chk2 kinase assays utilizing the GST-Che-1 fusion peptides spanning these residues as substrates.| Taken together, these results indicate that Chk2 phosphorylates Che-1 and this phosphorylation contributes to increase Che-1 stability. SIGNOR-264418 0.365 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Ser6 sKKRKFVA 9606 19059439 t llicata Here we show that pkcdelta phosphorylates rps3 resulting in its mobilization in the nucleus to repair damaged dna. pkc? Kinase assay then indicated that at least two residues, serine 6 and threonine 221, are phosphorylated by pkc? SIGNOR-182619 0.2 RNF111 protein Q6ZNA4 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates binding 9606 14657019 t gcesareni Arkadia physically interacts with inhibitory smad, smad7, and induces its poly-ubiquitination and degradation. SIGNOR-119663 0.725 BRD7 protein Q9NPI1 UNIPROT BRD2 protein P25440 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000192 12600283 f miannu BRD7 protein could respectively interact with proteins, BRD2 and BRD3, and BRD7 could up-regulate the expression levels of BRD2 and BRD3 genes in mRNA level to some extent. SIGNOR-253763 0.421 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159458 0.259 ID2 protein Q02363 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity binding 10090 BTO:0000222 8380166 t 2 miannu Id1 and Id2 interacted strongly with MyoD and Myf-5.Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-240268 0.556 FLT3 protein P36888 UNIPROT XRCC5 protein P13010 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 21228325 f fcortellessa We detected an approximately 5-fold decrease in Ku86 expression in early pro-B cells from FLT3/ITD mice compared with the wild-type controls. These data support the finding that FLT3/ITD mutations exert a suppressive role on Ku86 expression. SIGNOR-261684 0.2 DYNLT1 protein P63172 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates activity binding 9606 BTO:0002181 29089450 t miannu Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates Ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state through binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that liver kinase B1 (LKB1) activated the microtubule affinity-regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at Ser151 This modification disrupted the interaction between ARHGEF2 and DYNLT1 by generating a 14-3-3 binding site in ARHGEF2, thus causing ARHGEF2 to dissociate from microtubules. SIGNOR-277369 0.292 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Tyr1474 GSSNGHVyEKLSSIE -1 11483655 t lperfetto We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases SIGNOR-247176 0.759 C5AR2 protein Q9P296 UNIPROT CR1 protein P17927 UNIPROT up-regulates quantity by expression 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263465 0.345 STAT3 protein P40763 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 32454942 f miannu IL-1β, an inflammatory cytokine primarily expressed in activated macrophages, monocytes, and microglia, significantly contributes to MS development. IL-1β promotes differentiation of T cells into Th17 cells via the STAT3 pathway and thereby promotes and aggravates the inflammatory environment in the CNS SIGNOR-263821 0.7 STRA6 protein Q9BX79 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI up-regulates quantity relocalization 9913 17255476 t lperfetto We identified in bovine retinal pigment epithelium cells STRA6, a multitransmembrane domain protein, as a specific membrane receptor for RBP. STRA6 binds to RBP with high affinity and has robust vitamin A uptake activity from the vitamin A-RBP complex SIGNOR-265107 0.8 RPS6KB1 protein P23443 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates 10090 BTO:0002572 20670887 f lperfetto We find that srebp1 and 2 promote proliferation downstream of mtorc1, and the activation of these transcription factors is mediated by s6k1. SIGNOR-167190 0.435 PTGER3 protein P43115 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 12038972 t gcesareni Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i) SIGNOR-88143 0.428 RARA protein P10276 UNIPROT CCNA1 protein P78396 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002136 11090075 t miannu RARα is involved in the regulation of cyclin A1. Further studies using ligands selective for various retinoic acid receptors suggested that cyclin A1 expression is negatively regulated by activated RARα. SIGNOR-249636 0.246 PPP3CB protein P16298 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 10195903 t Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. SIGNOR-248384 0.341 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PAPOLA protein P51003 UNIPROT up-regulates activity phosphorylation Ser545 PTSATKTsPLNSSGS 10090 BTO:0000964 34048556 t lperfetto Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity. SIGNOR-268342 0.2 HLA-G protein P17693 UNIPROT KIR2DL4 protein Q99706 UNIPROT up-regulates binding 9606 10190900 t gcesareni Recombinant soluble kir2dl4 binds to cells expressing hla-g but not to cells expressing other hla class i molecules. SIGNOR-66132 0.755 CDK5 protein Q00535 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR form complex binding 9606 11331872 t lperfetto Induced p35 forms a complex with Cdk5 and activates its kinase activity SIGNOR-250683 0.942 CSNK2A1 protein P68400 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates phosphorylation Ser394 EDAVHEDsGDEDGED 9606 20388487 t gcesareni Protein kinase ck2-mediated phosphorylation of hdac2 regulates co-repressor formation, deacetylase activity and acetylation of hdac2 by cigarette smoke and aldehydesstudies using unfractionated cell extracts with ck2 inhibitors suggest that protein kinase ck2 is the major source of hdac2 kinase. Finally, and perhaps most interesting, hdac2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. Together, our data indicate that like many hdacs, hdac2 is regulated by post-translational modification, particularly phosphorylation. SIGNOR-164795 0.61 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. SIGNOR-255580 0.7 romidepsin chemical CHEBI:61080 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257995 0.8 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser111 SPPSPAPsSFSSTSV 9606 15448698 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-129410 0.574 RAD51 protein Q06609 UNIPROT SYCP3 protein Q8IZU3 UNIPROT up-regulates activity binding 10090 SIGNOR-C351 10525529 t miannu The eukaryotic RecA homologues RAD51 and DMC1 function in homology recognition and formation of joint-molecule recombination intermediates during yeast meiosis. We also show that mouse RAD51 and DMC1 establish protein-protein interactions with each other and with the chromosome core component COR1(SCP3) in a two-hybrid system and in vitro binding analyses. These results suggest that the formation of a multiprotein recombination complex associated with the meiotic chromosome cores is essential for the development and fulfillment of the meiotic recombination process. SIGNOR-264205 0.369 P2RY4 protein P51582 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257288 0.2 TNFAIP1 protein Q13829 UNIPROT RHOA protein P61586 UNIPROT down-regulates quantity binding 9606 19782033 t miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. SIGNOR-264235 0.357 ATG13 protein O75143 UNIPROT ULK2 protein Q8IYT8 UNIPROT up-regulates binding 9606 19225151 t gcesareni He mammalian atg13 binds both ulk1 and ulk2 and mediates the interaction of the ulk proteins with fip200. The binding of atg13 stabilizes and activates ulk and facilitates the phosphorylation of fip200 by ulk SIGNOR-184123 0.741 NR1I2 protein O75469 UNIPROT CYP3A4 protein P08684 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000003 18540626 f miannu Among approximately 40 kinds of phytochemicals, tangeretin and ginkgolides A and B markedly induced the PXR-dependent transcriptional activity and also the activity of the human MDR1 promoter. The expression levels of MDR1 mRNA as well as of CYP3A4 mRNA, another gene regulated by PXR, were significantly increased by these phytochemicals. SIGNOR-254835 0.534 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR up-regulates 9606 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268584 0.2 FAM20C protein Q8IXL6 UNIPROT ERO1A protein Q96HE7 UNIPROT up-regulates activity phosphorylation Ser145 GAVDESLsEETQKAV 9606 BTO:0000567 29858230 t miannu We further show that ER oxidoreductin 1α (Ero1α), the pivotal sulfhydryl oxidase that catalyzes disulfide formation in the ER, is phosphorylated by Fam20C in the Golgi apparatus and retrograde-transported to the ER mediated by ERp44. The phosphorylation of Ser145 greatly enhances Ero1α oxidase activity and is critical for maintaining ER redox homeostasis and promoting oxidative protein folding. SIGNOR-277395 0.2 CYLD protein Q9NQC7 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates deubiquitination 9606 BTO:0001253 12917689 t lperfetto The nf-kappab activation by cyld is mediated, at least in part, by the deubiquitination and inactivation of tnfr-associated factor 2 (traf2) and, to a lesser extent, traf6. SIGNOR-117856 0.781 NOTCH1 protein P46531 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9528780 f gcesareni In transient-transfection assays we show that truncated notch-1 strongly induces nf-kappab2 promoter activity. SIGNOR-56097 0.292 CAV1 protein Q03135 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 16890161 t gcesareni Overall, our data suggest that wnt-3a triggers the interaction of lrp6 with caveolin and promotes recruitment of axin to lrp6 phosphorylated by glycogen synthase kinase-3beta and that caveolin thereby inhibits the binding of beta-catenin to axin. SIGNOR-148665 0.663 E2F1 protein Q01094 UNIPROT TFDP1 protein Q14186 UNIPROT up-regulates activity binding 10029 8832394 t 2 miannu The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3. SIGNOR-240547 0.807 CSNK2A1 protein P68400 UNIPROT FANCD2 protein Q9BXW9 UNIPROT down-regulates activity phosphorylation Ser882 DGSKTSSsDTLSEEK 9606 BTO:0000567 31167143 t miannu Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations.  SIGNOR-276730 0.2 CCND1 protein P24385 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18177723 f andrea cerquone perpetuini Cyclin D1 is necessary for proliferation of different cell types, including myogenic cells. SIGNOR-255412 0.7 DAB2IP protein Q5VWQ8 UNIPROT GATA1 protein P15976 UNIPROT up-regulates activity binding 9606 27858941 t miannu DAB2IP suppresses transcription of stem cell factor receptor CD117, by interacting with GATA-1 on a silencer element on its gene SIGNOR-254770 0.2 CSNK1A1 protein P48729 UNIPROT MDM4 protein O15151 UNIPROT up-regulates phosphorylation Ser289 DDLEDSKsLSDDTDV 9606 23028042 t lperfetto Previous studies showed that casein kinase 1? (ck1?) Stably associates with mdmx, stimulates mdmx-p53 binding, and cooperates with mdmx to inactivate p53ck1? Binding to the mdmx central domain and phosphorylation of s289 disrupts the intramolecular interaction, allowing the n terminus to bind p53 with increased affinity. After dna damage, the mdmx-ck1? Complex is disrupted by chk2-mediated phosphorylation of mdmx at s367, leading to reduced mdmx-p53 binding. SIGNOR-199015 0.378 HNF1A protein P20823 UNIPROT UGT1A8 protein Q9HAW9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000195 15044625 t Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter. SIGNOR-253972 0.284 PKA proteinfamily SIGNOR-PF17 SIGNOR IQGAP2 protein Q13576 UNIPROT up-regulates activity phosphorylation Thr716 EYMHRRQtFIDNTDS 9606 21776420 t miannu We show that IQGAP2 is regulated by an interaction with the A-kinase anchoring protein AKAP220. Phosphorylation of IQGAP2 via AKAP220-anchored PKA leads to enhanced Rac binding. Since AKAPs function to direct PKA toward specific substrates, we proposed that the formation of an IQGAP2/AKAP220/PKA ternary complex sharpens the response to cAMP. SIGNOR-273742 0.2 SPI1 protein P17947 UNIPROT GATA1 protein P15976 UNIPROT down-regulates activity binding 10090 10364157 t irozzo We find that PU.1 interacts directly with GATA-1, a zinc finger transcription factor required for erythroid differentiation. Interaction between PU.1 and GATA-1 requires intact DNA-binding domains in both proteins. PU.1 represses GATA-1-mediated transcriptional activation. SIGNOR-256049 0.64 HIF1AN protein Q9NWT6 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates hydroxylation 9606 18299578 t gcesareni We show that fih-1 hydroxylates notch icd at two residues (n(1945) and n(2012)) that are critical for the function of notch icd as a transactivator within cells and during neurogenesis and myogenesis in vivo. Fih-1 negatively regulates notch activity and accelerates myogenic differentiation. SIGNOR-254324 0.566 TTI1 protein O43156 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000007 20427287 t miannu MTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. Furthermore, using immunoprecipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. SIGNOR-272002 0.602 MAPK8 protein P45983 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 10090 BTO:0001086 24913968 t SP600125 prevented phosphorylation of STAT1 at Tyr701 site [..] Western blot analysis confirmed that blocking p-JNK using SP600125 markedly reduced STAT3 localization in the nucleus and STAT1 phosphorylation SIGNOR-251101 0.457 DAPK1 protein P53355 UNIPROT RPL5 protein P46777 UNIPROT unknown phosphorylation 9606 18283219 t lperfetto Here we adapted this strategy to successfully screen for dapk substrates. We report the identification of two substrates, ribosomal protein l5 and mcm3. SIGNOR-160954 0.2 PTTG1 protein O95997 UNIPROT LGALS1 protein P09382 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002428 19351864 f miannu PTTG induced S100A4 and galectin-1 mRNA and protein expression as assessed by Western blot and reverse transcription-PCR. SIGNOR-255068 0.2 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT up-regulates activity sumoylation Lys490 QCPRKVIkMESEEGK 9534 BTO:0000298 9756909 t lperfetto We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins |We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites. The PML mutant with Lys to Arg substitutions in all three sites is expressed normally, but cannot be sentrinized|Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. SIGNOR-270541 0.771 PTPN6 protein P29350 UNIPROT PTK2B protein Q14289 UNIPROT down-regulates dephosphorylation Tyr402 CSIESDIyAEIPDET 9606 10521452 t gcesareni Raftk binds constitutively to the protein tyrosine phosphatase shptp1.SHPTP1 Plays a negative role in pyk2/raftk signaling by dephosphorylating raftk on tyr-402, thereby inhibiting the interaction of the sh2 domain of c-src with raftk SIGNOR-71414 0.366 NFATC1 protein O95644 UNIPROT Myotube_hypertrophy phenotype SIGNOR-PH20 SIGNOR up-regulates transcriptional regulation 9606 BTO:0001103 14729474 f apalma To summarize, these two studies have generated important insights into the control of skeletal muscle hypertrophy by the calcineurin/NFATc1 signaling pathway SIGNOR-256215 0.7 RXRA protein P19793 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 12771132 t gcesareni Rxr agonists still inactivated endogenous beta-catenin via rxr alpha. SIGNOR-101293 0.429 Corticotropin protein P01189-PRO_0000024969 UNIPROT HSD3B1 protein P14060 UNIPROT up-regulates quantity 9606 24631756 f lperfetto CTH signaling promotes the single steroidogenic rate limiting step, which is the conversion of cholesterol to pregnenolone by Cholesterol Side-Chain Cleavage Enzyme (P450scc), encoded in the CYP11A1 gene. This is conferred by a direct stimulating effect of ACTH on the promoter of CYP11A1 (Chung et al., 1997, Liu and Simpson, 1997, Hu et al., 2001). Further, it stimulates conversion of pregnenolone to 17-hydroxypregnenolone by upregulating the expression of 3β hydroxysteroid dehydrogenase enzyme (3β-HSD) SIGNOR-268720 0.2 NFIB protein O00712 UNIPROT NFIB protein O00712 UNIPROT down-regulates activity binding 9606 9099724 t 2 miannu Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function. SIGNOR-240883 0.2 PTPN12 protein Q05209 UNIPROT PSTPIP1 protein O43586 UNIPROT down-regulates activity dephosphorylation Tyr345 PERNEGVyTAIAVQE 10090 11711533 t We also demonstrate that PTP-PEST dephosphorylates PSTPIP at tyrosine 344. Importantly, we identified tyrosine 344 as the main phosphorylation site of PSTPIP by performing tryptic phosphopeptide maps. |The biological functions of the complexes formed between PSTPIP and SH2 domain-containing tyrosine kinases may be to transmit the signals from activated EGF and PDGF receptor.|Furthermore, we show that PSTPIP is phosphorylated downstream of the activated PDGF and EGF receptors. This phosphorylation of PSTPIP is most likely mediated by c-Abl SIGNOR-248656 0.629 PCM1 protein Q15154 UNIPROT CETN3 protein O15182 UNIPROT up-regulates relocalization 9606 12403812 t miannu Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome SIGNOR-95016 0.301 WNT5A protein P41221 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity 9606 21078818 f lperfetto We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3) SIGNOR-227961 0.433 creatine smallmolecule CHEBI:16919 ChEBI CKMT1A protein P12532 UNIPROT up-regulates activity chemical activation 9606 18502307 t miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. SIGNOR-265786 0.8 RAR proteinfamily SIGNOR-PF45 SIGNOR RXRA protein P19793 UNIPROT up-regulates binding 9606 1310351 t inferred from 70% family members gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-269954 0.2 AP-2 complex complex SIGNOR-C245 SIGNOR ITSN1 protein Q15811 UNIPROT up-regulates activity binding 10116 BTO:0000142 15496985 t Giorgia Intersectins 1 and 2, epsin2, NECAP and sorting nexin9 were identified as α‐appendage ligands in mass spectrometry of these samples SIGNOR-260397 0.645 AMPK complex SIGNOR-C15 SIGNOR TSC1 protein Q92574 UNIPROT up-regulates phosphorylation 9606 14651849 t lperfetto Under energy starvation conditions, the amp-activated protein kinase (ampk) phosphorylates tsc2 and enhances its activity. SIGNOR-216441 0.411 PIM2 protein Q9P1W9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by stabilization phosphorylation 9606 24142698 t Manara Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. SIGNOR-268151 0.378 NXPH1 protein P58417 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates binding 9606 BTO:0000938 9856994 t gcesareni We show that neurexophilins 1 and 3 but not 4 (neurexophilin 2 is not expressed in rodents) bind to a single individual lns domain, the second overall lns domain in all three alpha-neurexins. SIGNOR-60643 0.383 MAPK3 protein P27361 UNIPROT LIN28A protein Q9H9Z2 UNIPROT down-regulates activity phosphorylation Ser200 EEEEEIHsPTLLPEA 9606 BTO:0000567 28179426 t miannu Here we show that Lin28a is directly phosphorylated by ERK1/2 kinases at Ser-200.  SIGNOR-277337 0.28 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000150 12167717 f lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-252710 0.784 AKT1 protein P31749 UNIPROT UBE2S protein Q16763 UNIPROT up-regulates quantity by stabilization phosphorylation Thr152 AARARLLtEIHGGAG 9606 BTO:0000007 27593939 t lperfetto Mechanistically, Akt1 physically interacted with and phosphorylated UBE2S at Thr 152, enhancing its stability by inhibiting proteasomal degradation. SIGNOR-265078 0.448 CAMK4 protein Q16566 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 17389598 t gcesareni Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. SIGNOR-153940 0.697 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270414 0.8 RPL27 protein P61353 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262474 0.844 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser107 NPMRRIHsLPQKLLG 9606 BTO:0002181 34363019 t miannu Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.  SIGNOR-276738 0.2 PRKCD protein Q05655 UNIPROT EP300 protein Q09472 UNIPROT down-regulates phosphorylation Ser89 SELLRSGsSPNLNMG 9606 12379484 t lperfetto Inhibition of histone acetyltransferase function of p300 by pkcdeltawe found that pkcdelta but not classical pkc, specifically phosphorylates p300 at serine 89 in vitro and in vivo. This phosphorylation causes inhibition of p300 intrinsic hat activity. SIGNOR-94263 0.374 lysophosphatidylinositol 22:6 smallmolecule CHEBI:138556 ChEBI GPR55 protein Q9Y2T6 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257507 0.8 TACR2 protein P21452 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256736 0.261 APEX1 protein P27695 UNIPROT SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 14630715 t Luana These data demonstrate a role for APE/Ref-1 protein in the transcriptional regulation of NIS gene expression by itself and in cooperation with PAX8.  SIGNOR-261564 0.2 PPP1CC protein P36873 UNIPROT IFIH1 protein Q9BYX4 UNIPROT up-regulates activity dephosphorylation Ser88 EALRRTGsPLAARYM 9606 BTO:0000007 25865883 t lperfetto A recent study has revealed that PP1alpha and PP1gamma phosphatases are responsible for dephosphorylating MDA5 and are essential for its activation. |PP1gamma mediates dephosphorylation of MDA5 not only at Ser-88 but also at other Ser/Thr residues. SIGNOR-264578 0.249 FOS protein P01100 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19022561 t miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254878 0.262 MAP3K11 protein Q16584 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 10727406 t gcesareni These data suggest that mlk-3 phosphorylates sek1 directly and that it does so specifically on those residues known to activate sek1 in vivo. SIGNOR-75836 0.609 AMPK complex SIGNOR-C15 SIGNOR MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser172 GQLVRNDsLWHRSDS 9606 BTO:0001938 26816379 t gcesareni A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission. SIGNOR-249655 0.2 ADORA2A protein P29274 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257239 0.306 HDAC4 protein P56524 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity binding 9534 15537544 t lperfetto Here we report that HDAC4, which is expressed in prehypertrophic chondrocytes, regulates chondrocyte hypertrophy and endochondral bone formation by interacting with and inhibiting the activity of Runx2, a transcription factor necessary for chondrocyte hypertrophy.PDPK1 SIGNOR-226680 0.539 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120188 0.321 KLF4 protein O43474 UNIPROT MEIS2 protein O14770 UNIPROT up-regulates activity binding 9606 21746878 t miannu We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. SIGNOR-267238 0.271 KDM5B protein Q9UGL1 UNIPROT PAX9 protein P55771 UNIPROT up-regulates activity binding 9606 BTO:0000007 12657635 t miannu Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9. In a reporter assay system, PLU-1 has potent transcriptional repression activity. BF-1 and PAX9 also represses transcription in the same assay, but co-expression of PLU-1 with BF-1 or PAX9 significantly enhances this repression SIGNOR-223875 0.496 DNM1L protein O00429 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 BTO:0000567 17301055 f Barakat Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission SIGNOR-274132 0.7 RFC2 protein P35250 UNIPROT RF-C complex complex SIGNOR-C375 SIGNOR form complex binding 12930972 t lperfetto RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned SIGNOR-265506 0.761 CDK1 protein P06493 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Ser1678 ITSEEERsPAKRGRK -1 30685087 t lperfetto Nuclear import of 53BP1 is required for proper localization of 53BP1 and maintenance of genome integrity. 53BP1 has a classical bipartite nuclear localization signal (NLS) of sequence 1666-GKRKLITSEEERSPAKRGRKS-1686. Ser1678 within the 53BP1 NLS can be phosphorylated by CDK1/cyclin B, and a phosphomimetic substitution of Ser1678 with aspartate has been shown to negatively regulate nuclear import of 53BP1. SIGNOR-264412 0.617 PPM1G protein O15355 UNIPROT USP7 protein Q93009 UNIPROT down-regulates activity dephosphorylation 9606 22361354 t miannu Here, we report that in response to DNA damage USP7 is downregulated by the ATM dependent protein phosphatase PPM1G, thus downregulating Mdm2 and activating the p53 response.|We have now shown that when DNA damage is detected, PPM1G is activated and dephosphorylates USP7 isoform protein that leads to its degradation and consequently to Mdm2 degradation and accumulation of p53 ( A). SIGNOR-277159 0.524 SENP1 protein Q9P0U3 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates quantity by destabilization desumoylation Lys276 NVVYRDLkLENLMLD 10090 BTO:0002572 23884910 t gcesareni Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity. SIGNOR-252738 0.284 AP1 complex SIGNOR-C154 SIGNOR CXCL8 protein P10145 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32446778 f miannu The up-regulation of the CXCL8 gene expression, could be due to a direct effect of the virus at the cellular level. Indeed, intestinal and lung cells lines infected by SARS-CoV, promptly increase their secretion of CXCL8 [88]. This observation would fit with the notion that the expression of CXCL8 is dependent on the tran-scription factor Activator protein 1 (AP-1), which was shown to bestrongly up-regulated by SARS-CoV SIGNOR-261029 0.562 KHSRP protein Q92945 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 10090 BTO:0000165 16364914 t lperfetto Importantly, KSRP knockdown in C2C12 GM cells (Figure 2D) stabilized endogenous my- ogenin and p21 transcripts (Figure 2E). Furthermore, stable knockdown of KSRP, using shRNA, induced the accumulation of p21 mRNA in C2C12 GM while it did not affect the expression of late myogenic markers (MHC and muscle-creatine kinase [MCK]) SIGNOR-235859 0.255 LAT protein O43561 UNIPROT VAV1 protein P15498 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr255;Tyr220 EEEGAPDyENLQELN;SLDGSREyVNVSQEL 11368773 t lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. SIGNOR-246045 0.742 PRKAG3 protein Q9UGI9 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 16054041 t gcesareni Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. SIGNOR-139179 0.709 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1717 SPSYSPTsPSYSPTS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248775 0.442 SRC protein P12931 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Tyr315 TFCGTPEyLAPEVLE 9534 11445557 t lperfetto Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity. SIGNOR-252620 0.664 Netrin proteinfamily SIGNOR-PF97 SIGNOR UNC5 proteinfamily SIGNOR-PF98 SIGNOR up-regulates activity binding 9606 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268174 0.848 EPS15 protein P42566 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity binding 10029 BTO:0002988 15383614 t gcesareni We suggest that the ubiquitinated EGFR or another c-Cbl substrate that is ubiquitinated upon EGFR activation recruits Eps15 to the plasma membrane via its UIM. This event would facilitate EGFR internalization via a clathrin-dependent route in which Eps15 plays a role SIGNOR-243278 0.746 SRC protein P12931 UNIPROT LPIN1 protein Q14693 UNIPROT up-regulates activity phosphorylation Tyr413 DPEVAALyFPKNGDP 9606 BTO:0002181 33203880 t miannu Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride. SIGNOR-277293 0.2 ATR protein Q13535 UNIPROT KIFC1 protein Q9BW19 UNIPROT up-regulates quantity by stabilization phosphorylation Ser26 RPLIKAPsQLPLSGS 9606 BTO:0000815 33397932 t miannu  ATM and ATR kinases phosphorylate KIFC1-S26 during DNA-damage conditions.KIFC1 was stabilized upon phosphorylation and thus promoted centrosome clustering, CIN, and tumor recurrence both in vivo and in vitro. SIGNOR-277296 0.259 dabrafenib chemical CHEBI:75045 ChEBI SIK1 protein P57059 UNIPROT down-regulates activity chemical inhibition -1 24720932 t miannu Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations SIGNOR-259219 0.8 CUX1 protein P39880 UNIPROT PIK3IP1 protein Q96FE7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24316979 t miannu We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. SIGNOR-260072 0.376 AKT1 protein P31749 UNIPROT MAP3K8 protein P41279 UNIPROT up-regulates activity phosphorylation Ser400 EDQPRCQsLDSALLE 9606 BTO:0000007 12138205 t Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator. SIGNOR-252571 0.539 ESRRA protein P11474 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15955695 f miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. SIGNOR-253790 0.255 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR HEY1 protein Q9Y5J3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21193018 t lperfetto Activated NICD-RBP-Jk complex displaces co-repressors and recruits coactivator (co-A) mediating the transcription of target genes such as Hes-1 (hairy enhancer of split), cyclin D, Hey-1 (hairy/enhancer-of-split related with YRPW motif) and others [1213]. SIGNOR-170854 0.705 pazopanib chemical CHEBI:71219 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 18620382 t Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. SIGNOR-257739 0.8 PGK1 protein P00558 UNIPROT 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. SIGNOR-266502 0.8 MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates phosphorylation 9606 12912994 t gcesareni Mek5 is the mapk kinase that phosphorylates and activates erk5 in response to growth factors, oxidative stress, and hyperosmotic conditions. SIGNOR-104631 0.691 PLK1 protein P53350 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Ser1618 LTKAADIsLDNLVEG -1 24703952 t lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |Addition of the inhibitors for PLK1 and the p38 MAPK leads to a complete loss of pT1609/pS1618 signal within 3 hr in mitotic cells SIGNOR-264413 0.614 PRKCD protein Q05655 UNIPROT TP73 protein O15350 UNIPROT up-regulates phosphorylation Ser289 GQVLGRRsFEGRICA 9606 12097319 t llicata The results show that pkcdeltacf phosphorylates the p73beta transactivation and dna-binding domains. pkcdeltacf-mediated phosphorylation of p73beta is associated with accumulation of p73beta and induction of p73beta-mediated transactivation. SIGNOR-90279 0.312 IL1RL1 protein Q01638 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity binding 9606 BTO:0000007 16286016 t miannu As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation.  SIGNOR-277706 0.587 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val48 KVDGTSHvTGKGVTV -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263589 0.404 PTK2B protein Q14289 UNIPROT ASAP2 protein O43150 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10022920 t miannu Tyrosine phosphorylation of Pap by Pyk2 or Src kinases. We have identified a new Pyk2 binding protein designated Pap. Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain. We demonstrate that Pap forms a stable complex with Pyk2 and that activation of Pyk2 leads to tyrosine phosphorylation of Pap in living cells. SIGNOR-269704 0.54 LYN protein P07948 UNIPROT DAPP1 protein Q9UN19 UNIPROT up-regulates activity phosphorylation Tyr139 KVEEPSIyESVRVHT BTO:0000776 10880360 t lperfetto Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins. SIGNOR-249378 0.61 PLAUR protein Q03405 UNIPROT ITGB3 protein P05106 UNIPROT up-regulates activity binding 9606 27383564 t Recent evidence suggests that the activation of b3 integrin in podocytes mediates uPAR-induced cellular events leading to proteinuria SIGNOR-253333 0.448 PRKCE protein Q02156 UNIPROT OPRD1 protein P41143 UNIPROT unknown phosphorylation Ser344 CGRPDPSsFSRAREA 9606 BTO:0000007 11085981 t lperfetto In the current study, we identified a PKC-mediated phosphorylation site in the delta-opioid receptor (DOR) and demonstrated that activation of PKC by stimulation of other types of GPCR or increase in intracellular Ca2+concentration in HEK 293 cells induces heterologous phosphorylation of DOR. Our results further established that DOR phosphorylation at Ser-344 by PKC results in internalization of DOR in HEK 293 cells through a beta-arrestin- and clathrin-mediated mechanism. SIGNOR-249064 0.372 MAPK14 protein Q16539 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity 9606 BTO:0001255 12839928 f miannu Activation of p38 MAPK is required for arsenite-induced apoptosis and MEK1,2 dephosphorylation in human skin fibroblasts. Our data suggest the presence of a continuous negative feedback from p38α and p38β to MEK1,2 as simultaneous inhibition of p38α and p38β isoforms in normal quiescent cells resulted in accumulation of phosphorylated MEK1,2 (Fig. 2A) ⇓ . This negative regulation of MEK1,2 in normal cells could be considered a means to control MEK1,2-mediated proliferation and expression of transformation-related genes. SIGNOR-263511 0.66 Macrophage_activation phenotype SIGNOR-PH126 SIGNOR ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. SIGNOR-261021 0.7 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 26194464 t MARCO ROSINA TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI). SIGNOR-255031 0.84 HRH2 protein P25021 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257375 0.252 SP1 protein P08047 UNIPROT PHGDH protein O43175 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18378410 f miannu Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y. SIGNOR-255208 0.2 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249626 0.907 DKK1 protein O94907 UNIPROT KREMEN2 protein Q8NCW0 UNIPROT up-regulates binding 9606 12050670 t gcesareni Dkk1 has been shown to inhibitwnt by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to blockwnt/beta-catenin . Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of thewntreceptor lrp6 from the plasma membranekremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of the wnt receptor lrp6 from the plasma membrane SIGNOR-88882 0.589 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser213 QNIPAHYsPRTSPIM 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248371 0.598 lurasidone chemical CHEBI:70735 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10030 20404009 t Luana Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 2C receptors. SIGNOR-257841 0.8 GFI1 protein Q99684 UNIPROT Granulocyte_differentiation phenotype SIGNOR-PH102 SIGNOR up-regulates 9606 20861919 f irozzo In the myeloid compartment, Gfi1 is part of a regulatory network that determines lineage fate decision between granulocyte and monocyte/macrophage development. In this compartment, Gfi1 antagonizes the function of the transcription factor Pu.1. Pu.1 promotes monocytic differentiation, whereas Gfi1 enhances granulocytic differentiation. SIGNOR-256084 0.7 RPS6K proteinfamily SIGNOR-PF26 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser153 SWTRVFQsWWDRNLG 9606 BTO:0000007 10837486 t lperfetto We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites. SIGNOR-252767 0.2 GNAI1 protein P63096 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR down-regulates activity binding 9606 15922020 t miannu Activation of receptors coupled to inhibitory G proteins (Galpha i/o) has opposing consequences for cyclic AMP accumulation and the activity of cyclic AMP-dependent protein kinase, depending on the duration of stimulation. Acute activation inhibits the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation; in contrast, persistent activation of Galpha i/o-coupled receptors produces a paradoxical enhancement of adenylate cyclase activity, thus increasing cyclic AMP accumulation when the action of the inhibitory receptor is terminated. SIGNOR-267853 0.619 PPP1CA protein P62136 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity dephosphorylation Thr125 PEVLRPEtPRPVDIG 9606 16888006 t ERK/MAPK phosphorylates caspase-9 at Thr(125), and this phosphorylation is crucial for caspase-9 inhibition. Until now, the phosphatase responsible for Thr(125) dephosphorylation has not been described. Here, we demonstrate that in IL-2-proliferating cells, phosphorylated serine/threonine phosphatase type 1alpha (PP1alpha) associates with phosphorylated caspase-9. SIGNOR-248565 0.2 calcium(2+) smallmolecule CHEBI:29108 ChEBI SLC25A12 protein O75746 UNIPROT up-regulates activity chemical activation 9606 12084073 t miannu Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. SIGNOR-265152 0.8 RPS6K proteinfamily SIGNOR-PF26 SIGNOR FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 BTO:0000848 15024089 t gcesareni We show that the n-terminal kinase domain of rsk phosphorylates flna on ser(2152) in response to mitogens SIGNOR-252790 0.2 AKT2 protein P31751 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 BTO:0000150 20231902 t gcesareni Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation. SIGNOR-164302 0.263 PRKAA2 protein P54646 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 SIGNOR-C15 16148943 t gcesareni Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2 SIGNOR-140238 0.472 desloratadine chemical CHEBI:291342 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 t Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells SIGNOR-257784 0.8 KDM4C protein Q9H3R0 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 29207681 t miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation SIGNOR-263867 0.2 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr653 RDIHHIDyYKKTTNG 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1. We demonstrate that autophosphorylation on tyrosines 653 and 654 is important for activation of tyrosine kinase activity of fgfr1 and is therefore essential for fgfr1-mediated biological responses. SIGNOR-236195 0.2 DOK1 protein Q99704 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257676 0.321 CAPN1 protein P07384 UNIPROT GSK3A protein P49840 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase SIGNOR-251585 0.2 SMAD7 protein O15105 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates activity relocalization 9606 19352540 t lperfetto Smad7 also recruits the HECT type of E3 ubiquitin ligases, Smurf1 and Smurf2. It binds to Smurfs in the nucleus and translocates into the cytoplasm in response to TGF-_ and recruits the ubiquitin ligases to the activated type I receptor ALK5/T_RI, leading to the degradation of the receptor through the proteasomal pathway. SIGNOR-185131 0.878 MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser360 TEMDPTYsPAALPQS 9606 15568999 t lperfetto Msk1 (mitogen- and stress-activated protein kinase) is a kinase activated in cells downstream of both the erk1/2 (extracellular-signal-regulated kinase) and p38 mapk (mitogen-activated protein kinase) cascades. In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites SIGNOR-130736 0.595 KLF4 protein O43474 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by repression transcriptional regulation 17308127 t lperfetto Previous work has shown that the Kruppel-like factor 4 (KLF4) transcription factor represses p53 transcription by binding to the PE21 element. SIGNOR-270544 0.576 Gbeta proteinfamily SIGNOR-PF4 SIGNOR WWC1 protein Q8IX03 UNIPROT unknown phosphorylation 9606 BTO:0000149 24269383 t inferred from 70% family members llicata We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro. SIGNOR-270121 0.2 SRC protein P12931 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 7578094 t lperfetto These data are consistent with autophosphorylation on y-419 as predicted. Intermolecular autophosphorylation is consistent with the ability of srctk to dimerize, which is analogous to activation of receptor tyrosine kinases such as the egf receptor kinase in response to growth factors. SIGNOR-29369 0.2 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Leu) smallmolecule CHEBI:29169 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269489 0.8 NEDD4L protein Q96PU5 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 t miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). SIGNOR-253459 0.323 TGFb proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 protein P37173 UNIPROT up-regulates activity binding 9606 BTO:0000801 22703233 t miannu TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. SIGNOR-256179 0.2 AKT1 protein P31749 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 BTO:0001103 15829723 t apalma Once phosphorylated, Akt can act on a broad spectrum of substrates that can influence cell survival and proliferation and protein synthesis (65). Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K SIGNOR-255844 0.719 PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 12167717 f lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-252715 0.784 SELP protein P16109 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 t lperfetto Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1. SIGNOR-261860 0.418 PKN3 protein Q6P5Z2 UNIPROT ARHGAP18 protein Q8N392 UNIPROT up-regulates activity phosphorylation Thr154 AVQKRVEtVSQTLRK -1 33092266 t lperfetto We present strong evidence that PKN3-ARHGAP18 interaction is increased upon ARHGAP18 phosphorylation and that the phosphorylation of ARHGAP18 by PKN3 enhances its GAP domain activity and contributes to negative regulation of active RhoA.|These results support our data from phosphoproteomic screen and suggest that ARHGAP18 can be phosphorylated by PKN3 on Thr154, Ser156 and Thr158. SIGNOR-264570 0.2 1-[6-(2-hydroxypropan-2-yl)-2-pyridinyl]-6-[4-(4-methyl-1-piperazinyl)anilino]-2-prop-2-enyl-3-pyrazolo[3,4-d]pyrimidinone chemical CHEBI:91414 ChEBI WEE1 protein P30291 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194423 0.8 ADX-47273 chemical CID:11383075 PUBCHEM GRM5 protein P41594 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-189338 0.8 CASP3 protein P42574 UNIPROT DFFA protein O00273 UNIPROT up-regulates activity cleavage 9606 9108473 t lperfetto DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3. SIGNOR-47416 0.746 RNF146 protein Q9NTX7 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity ubiquitination 9606 21799911 t By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins. SIGNOR-259996 0.631 L-thyroxine smallmolecule CHEBI:18332 ChEBI Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates 9606 BTO:0000759 24692351 f scontino TH stimulates both lipolysis and lipogenesis, although the direct action is lipolysis with lipogenesis thought to be stimulated to restore fat stores. Fatty acids produced from TH-induced lipolysis are the substrate for the increase in thermogenesis. SIGNOR-267489 0.7 SGCG protein Q13326 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255987 0.452 NLGN3 protein Q9NZ94 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264162 0.819 EFNA4 protein P52798 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52430 0.804 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MEF2D protein Q14814 UNIPROT down-regulates binding 9606 21902831 t lperfetto In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-216966 0.268 CDK19 protein Q9BWU1 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2513 EHPFLTPsPESPDQW -1 25344755 t lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues SIGNOR-273136 0.307 AUTS2 protein Q8WXX7 UNIPROT PREX1 protein Q8TCU6 UNIPROT up-regulates activity binding 10090 BTO:0001909 25533347 t miannu Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development.  AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These results suggest that FL-AUTS2 can activate Rac1 via interaction with P-Rex1 and the Elmo2/Dock180 complex to regulate actin dynamics in N1E-115 cells. SIGNOR-266817 0.255 SLC1A3 protein P43003 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity relocalization 9606 26687113 t miannu After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5). In glia or in neurons, EAATs mediate the re-uptake of synaptically released glutamate via the coupled co-transport of three Na+, one H+, and one glutamate, in counter-transport to one K+. SIGNOR-264802 0.8 CASP3 protein P42574 UNIPROT DFFB protein O76075 UNIPROT up-regulates cleavage 9606 9108473 t gcesareni Casp3_ cleaves the 45 kda subunit at two sites to generate an active factor that produces_ dna_ fragmentation SIGNOR-47419 0.672 CCKAR protein P32238 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257148 0.254 HECTD3 protein Q5T447 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity polyubiquitination 9606 BTO:0004461 28716524 t miannu HECTD3 binds and ubiquitinates caspase-9.HECTD3 inhibits caspase-9 oligomerization and association with Apaf-1. HECTD3 suppressing caspase-9 activation is dependent on T157 phosphorylation by ERK. SIGNOR-272329 0.2 PI4KA protein P42356 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269104 0.8 APOBEC3G protein Q9HC16 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 f lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). SIGNOR-261329 0.7 IL1R1 protein P14778 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity 9606 BTO:0000007 14625308 f lperfetto Formation of the signaling il-1 receptor complex results in the activation and hyperphosphorylation of irak-1. SIGNOR-119208 0.912 LYN protein P07948 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr252 EAYPEEAyIADLDAK 9606 BTO:0000007 32420483 t done miannu  We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. SIGNOR-274105 0.2 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Thr2647 QQHDFTLtQTADGRS 9606 BTO:0000773 12186630 t lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. SIGNOR-249160 0.2 TNK2 protein Q07912 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Tyr176 EKATGRYyAMKILKK 10090 20333297 t gcesareni Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation. SIGNOR-252446 0.437 SAV1 protein Q9H4B6 UNIPROT STK4 protein Q13043 UNIPROT up-regulates quantity by stabilization binding 9606 16930133 t Hippo pathway Gianni Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation. SIGNOR-261958 0.882 PDPK1 protein O15530 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation Thr309 SDGATMKtFCGTPEY 9606 15743829 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. Pdk1 phosphorylates akt-2 at thr 309 in the catalytic domain, leading to enzymatic activation. SIGNOR-134485 0.72 MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0001103 28163303 f apalma During early stages of myogenesis, CIITA binds directly to myogenin (MYOG) and inactivates it, preventing MYOG-mediated induction of myogenic genes that are required for muscle differentiation and function SIGNOR-255112 0.7 PRKCB protein P05771 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Thr366 QSSASRKtQKKKKKK 9606 11325528 t lperfetto We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC. SIGNOR-249093 0.286 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR unknown phosphorylation 9606 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-217376 0.865 STK38 protein Q15208 UNIPROT XPO1 protein O14980 UNIPROT up-regulates activity phosphorylation Ser1055 EKHKRQMsVPGIFNP 9606 BTO:0000567 31544310 t miannu We further uncover that STK38 modulates XPO1 export activity by phosphorylating XPO1 on serine 1055, thus regulating its own nuclear exit.  SIGNOR-277483 0.2 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245480 0.7 IFNAR complex SIGNOR-C243 SIGNOR TYK2 protein P29597 UNIPROT up-regulates activity binding 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260146 0.8 ZBTB16 protein Q05516 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0002882 9710637 f fcortellessa PLZF expression in 32DG/GM cells is associated with growth suppression and G1 arrest. SIGNOR-261685 0.7 GPC6 protein Q9Y625 UNIPROT WNT5A protein P41221 UNIPROT down-regulates activity binding 9606 BTO:0000007 31756413 t miannu GPC6 binds to Wnt5a and inhibits its release from producing cells. Based on theseresults, and in our finding that GPC6 inhibits non-canonical Wnt signaling in the developing intestine,we tested the hypothesis that GPC6 binds to Wnt5aat the surface of the Wnt5a-producing mesenchymalcells and restrains its release from them. SIGNOR-264030 0.382 CREBBP protein Q92793 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR form complex binding 9606 21131905 t lperfetto Histone acetyltransferases (hats) gcn5 and pcaf (gcn5/pcaf) and cbp and p300 (cbp/p300) are transcription co-activators. SIGNOR-170262 0.639 CDH1 protein P12830 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR down-regulates 15601859 f lperfetto A hallmark characteristic of epithelial tumor progression as well as some processes of normal development is the loss of the epithelial phenotype and acquisition of a motile or mesenchymal phenotype. Such epithelial to mesenchymal transitions are accompanied by the loss of E-cadherin function by either transcriptional or posttranscriptional mechanisms. SIGNOR-252261 0.7 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR CDH1 protein P12830 UNIPROT up-regulates quantity relocalization 9606 BTO:0000586 21598020 t miannu Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14 SIGNOR-265817 0.2 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser257 SWLGARSsRPASPCN -1 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276767 0.629 MAPK3 protein P27361 UNIPROT SOX9 protein P48436 UNIPROT up-regulates transcriptional regulation 9606 20457810 f fspada Soluble pref-1 inhibits adipocyte differentiation through the activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (erk/mapk) and the subsequent upregulation of sox9 expression. SIGNOR-209965 0.39 CDK5 protein Q00535 UNIPROT PARP1 protein P09874 UNIPROT down-regulates activity phosphorylation Ser782 YSLLRGGsDDSSKDP -1 21922195 t miannu These results would suggest that the phosphorylation of PARP-1 via Cdk5's kinase activity is necessary for its persistence at damage sites.Based on these results and the recruitment data, we hypothesize that the phosphorylation of the PARP-1 protein by Cdk5 on one or more of the serines 782, 785, and 786 results in an attenuation of its ribosylating activity facilitating its persistence at the sites of DNA damage. SIGNOR-276357 0.261 SMARCA2 protein P51531 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 t miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270610 0.818 IGF1 protein P05019 UNIPROT MMP13 protein P45452 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003858 12734180 f miannu In the present study we investigated the inhibitory effects of IGF-1 and OP-1 on MMP-13 expression in human chondrocytes. We found that the suppressive effect of IGF-1 and OP-1 on the MMP-13 promoter activity was dose-dependent at the transcriptional level with a corresponding decrease in the level of MMP-13 protein. SIGNOR-254802 0.363 RTKs proteinfamily SIGNOR-PF38 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 17306385 t miannu The adaptor protein Grb2 can bind with activated RTKs through an SH2 domain-phosphotyrosine interaction, while through the SH3 domain (a binding domain specific to proline-rich sequences) Grb2 interacts with the guanine nucleotide exchange factor, Sos. SIGNOR-256167 0.2 GART protein P22102 UNIPROT N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-267305 0.8 CASP8 protein Q14790 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity -1 10988287 f lperfetto One indirect means through which caspase-8 might regulate caspase-9 activation is through a bcl-2-regulated pathway. SIGNOR-81811 0.591 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Thr175 GLLPFLLtHKKRLTD -1 19661060 t miannu We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-276231 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270420 0.8 KCNB1 protein Q14721 UNIPROT VAPB protein O95292 UNIPROT up-regulates quantity relocalization 9606 BTO:0000007 29941597 t lperfetto Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions. SIGNOR-262121 0.2 KAT2A protein Q92830 UNIPROT H3Y1 protein P0DPK2 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkATAWQAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269597 0.2 CLP1 protein Q92989 UNIPROT CFII complex complex SIGNOR-C387 SIGNOR form complex binding 9606 BTO:0000567 30139799 t lperfetto Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1. SIGNOR-266120 0.886 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser274 ASPQRSRsPSPQPSS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248689 0.613 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f irozzo However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins. SIGNOR-255851 0.2 DACT2 protein Q5SW24 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates binding 9606 17197390 t lpetrilli Here, we provide evidence that unlike dpr1 that modulates wnt signaling, mdpr2 negatively regulates tgf-? Signaling and promotes tgf-? Receptor degradation in lysosomes. these results suggest that mdpr2 interferes with tgf-? By directly binding to and targeting the receptors for lysosomal inhibitor-sensitive degradation. SIGNOR-151750 0.4 PRKCA protein P17252 UNIPROT THOC5 protein Q13769 UNIPROT up-regulates phosphorylation Ser6 sKKRKPKV 9606 BTO:0000801;BTO:0000876 15221008 t llicata We conclude m-csf-mediated activation of pkcalpha can potentiate fmip action to initiate survival/differentiation signaling. SIGNOR-126572 0.333 TBX21 protein Q9UL17 UNIPROT GATA3 protein P23771 UNIPROT down-regulates 9606 16386358 f Conversely, T-bet is capable of inhibiting GATA-3 (Szabo et al., 2000). The mutual inhibition between GATA-3 and T-bet ensures that Th1 and Th2 cells express one or the other molecule (T-bet in Th1, and GATA-3 in Th2), but not both SIGNOR-254295 0.752 CSNK2A1 protein P68400 UNIPROT BMI1 protein P35226 UNIPROT down-regulates quantity by destabilization phosphorylation Ser110 SADAANGsNEDRGEV 9606 28270146 t miannu Here we report that CK2α, a nuclear serine threonine kinase, phosphorylates BMI1 at Serine 110 as determined by in-vitro/ex-vivo kinase assay and mass spectrometry. e-expression of the phosphorylatable but not non-phosphorylatable BMI1 rescued clonal growth in endogenous BMI1 silenced cancer cells leading us to speculate that CK2α-mediated phosphorylation stabilizes BMI1 and promotes its oncogenic function. SIGNOR-277345 0.272 IL20RA protein Q9UHF4 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15120645 t gcesareni Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain. SIGNOR-124486 0.465 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser335 GDGVPVKsRKTTLEQ -1 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276776 0.629 IMPDH2 protein P12268 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30518405 f miannu We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. SIGNOR-260960 0.2 HTR7 protein P34969 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257381 0.325 ASPA protein P45381 UNIPROT N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI down-regulates quantity chemical modification 9606 17194761 t miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. SIGNOR-267526 0.8 MYC protein P01106 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12835716 t gcesareni C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation SIGNOR-102731 0.51 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Thr141 DLSSRSKtDLDCIFG 9606 20573420 t lperfetto Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation. SIGNOR-166329 0.369 NR3C1 protein P04150 UNIPROT UGT1A1 protein P22309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18172616 f miannu This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities. SIGNOR-254439 0.286 CHMP1B protein Q7LBR1 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 t miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. SIGNOR-265524 0.705 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR STK3 protein Q13188 UNIPROT up-regulates 9606 22683405 f milica In response to growth inhibitory signal (e.g. cell–cell contact), MST1/2 in active form phosphorylates LATS1/2 that sequentially phosphorylates YAP at Ser-127. SIGNOR-230696 0.7 PTPN7 protein P35236 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 10415025 t fstefani Lc-ptp dephosphorylated erk2 in vitro. the complex formation of lc-ptp with erk is the essential mechanism for the suppression. Taken collectively, these results indicate that lc-ptp suppresses mitogen-activated protein kinase directly in vivo. SIGNOR-69448 0.805 IL1B protein P01584 UNIPROT DIO1 protein P49895 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 9397972 f scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. SIGNOR-267486 0.2 PTBP2 protein Q9UKA9 UNIPROT HNRNPH1 protein P31943 UNIPROT up-regulates activity binding 9606 BTO:0000567 11003644 t lperfetto Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA. SIGNOR-261269 0.398 S100G protein P29377 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 31731478 t miannu Intracellular calcium ion content is tightly regulated for the maintenance of cellular functions and cell survival. Calbindin-D9k (CaBP-9k) is responsible for regulating the distribution of cytosolic free-calcium ions. SIGNOR-268517 0.8 PRKACA protein P17612 UNIPROT PJA2 protein O43164 UNIPROT up-regulates activity phosphorylation Thr389 RVITQREtENNQMTS -1 21423175 t miannu In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h). SIGNOR-276323 0.2 PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 16150867 f lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-228622 0.7 PAICS protein P22234 UNIPROT 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI down-regulates quantity chemical modification 9606 33179964 t miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). SIGNOR-267317 0.8 EFNB3 protein Q15768 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52624 0.814 CDKN1B protein P46527 UNIPROT CDK2 protein P24941 UNIPROT down-regulates binding 9606 SIGNOR-C16 17409098 t gcesareni P27, an important cell cycle regulator, blocks the g(1)/s transition in cells by binding and inhibiting cdk2/cyclin a and cdk2/cyclin e complexes (cdk2/e). SIGNOR-154191 0.95 SIRT2 protein Q8IXJ6 UNIPROT PGAM proteinfamily SIGNOR-PF78 SIGNOR up-regulates activity deacetylation 9606 24786789 t miannu Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2. SIGNOR-266519 0.283 APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 BTO:0000567 9390557 t lperfetto Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation. SIGNOR-53576 0.953 ATR protein Q13535 UNIPROT PI4K2A protein Q9BTU6 UNIPROT down-regulates 9606 18082599 f gcesareni Plk1 itself is negatively regulated by the ddr in an atm/atr-dependent manner. SIGNOR-159933 0.281 MBTD1 protein Q05BQ5 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269303 0.416 LDHB protein P07195 UNIPROT (S)-lactate smallmolecule CHEBI:16651 ChEBI up-regulates quantity chemical modification 9606 24929216 t lperfetto Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. SIGNOR-267657 0.8 MAP2K2 protein P36507 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 18596912 t gcesareni The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform. SIGNOR-179393 0.2 PTPRT protein O14522 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0001109;BTO:0000182 17360477 t brain lperfetto Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T|Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position. SIGNOR-263981 0.53 SP7 protein Q8TDD2 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 11792318 f Giulio Giuliani Our results established that the novel transcription factor Osx is required for osteoblast differentiation and hence for bone formation. SIGNOR-255449 0.7 CAMK2A protein Q9UQM7 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Thr154 ICLEDIHtSRVVAHV 9606 17568776 t lperfetto Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53 SIGNOR-156068 0.301 PRKCG protein P05129 UNIPROT CYTH2 protein Q99418 UNIPROT down-regulates activity phosphorylation Ser392 AARKKRIsVKKKQEQ 9606 BTO:0000567 10531036 t lperfetto ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'. SIGNOR-249025 0.338 CPT1A protein P50416 UNIPROT Fatty_acid_oxidation phenotype SIGNOR-PH129 SIGNOR up-regulates activity 9606 31900483 f As the key rate-limiting enzyme of FAO, carnitine palmitoyltransferase I (CPT1) regulates FAO and facilitates adaptation to the environment, both in health and in disease, including cancer. The CPT1 family of proteins contains 3 isoforms: CPT1A, CPT1B, and CPT1C. This review focuses on CPT1A, the liver isoform that catalyzes the rate-limiting step of converting acyl-coenzyme As into acyl-carnitines, which can then cross membranes to get into the mitochondria SIGNOR-267757 0.7 NDUFS2 protein O75306 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. SIGNOR-262176 0.862 retinal smallmolecule CHEBI:15035 ChEBI all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI up-regulates quantity precursor of 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265127 0.8 TOB1 protein P50616 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR down-regulates activity binding 9606 BTO:0000567 18377426 t miannu We found that Tob associates with the CCR4-NOT complex. The carboxyl-terminal half of Tob interacted with Cnot1, a core protein of the CCR4-NOT complex. We further showed that the deadenylase activity associated with the complex was suppressed in vitro by Tob.  SIGNOR-273616 0.652 AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16982699 f Protein kinase B (PKB/Akt) is an important modulator of insulin signaling, cell proliferation, and survival. Using small interfering RNA duplexes in nontransformed mammalian cells, we show that only Akt1 is essential for cell proliferation SIGNOR-254353 0.7 DOT1L protein Q8TEK3 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27856324 f irozzo Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4. SIGNOR-255881 0.2 NAALAD2 protein Q9Y3Q0 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 10085079 t miannu The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. SIGNOR-267542 0.8 paclitaxel chemical CHEBI:45863 ChEBI TUBB1 protein Q9H4B7 UNIPROT down-regulates activity chemical inhibition 9606 28298489 t miannu Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a "pseudo" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap. SIGNOR-259347 0.8 PRKAA2 protein P54646 UNIPROT HAS2 protein Q92819 UNIPROT down-regulates activity phosphorylation Thr110 LQSVKRLtYPGIKVV 9534 BTO:0000298 21228273 t miannu We found that AMPK phosphorylated Thr-110 of human HAS2, which inhibits its enzymatic activity. SIGNOR-276299 0.2 PI3K complex SIGNOR-C156 SIGNOR PIK3CG protein P48736 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-252721 0.586 IRX2 protein Q9BZI1 UNIPROT CCL5 protein P13501 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003885 26560478 f Luana Our results imply that the IRX2 transcription factor might represent a novel metastasis associated protein that acts as a negative regulator of cellular motility and as a repressor of chemokine expression.  SIGNOR-266043 0.2 RUNX2 protein Q13950 UNIPROT VEGFA protein P15692 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001610 22641097 f miannu Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells. SIGNOR-255084 0.457 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val76 LTGKLTTvFLPIVYT -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263601 0.381 FST protein P19883 UNIPROT INHBA protein P08476 UNIPROT down-regulates activity binding 9606 22037168 t gcesareni Blocking activin action by pre-treatment with its binding protein, follistatin, modifies the inflammatory cytokine cascade, and reduces the severity of the subsequent inflammatory response and mortality SIGNOR-235134 0.84 PRKCD protein Q05655 UNIPROT SLC29A1 protein Q99808 UNIPROT up-regulates activity phosphorylation Ser281 QPTNESHsIKAILKN 9606 25725289 t Manara Phosphorylation of hENT1 by PKC has effects on both the function and subcellular trafficking of hENT1 SIGNOR-260888 0.2 CBY1 protein Q9Y3M2 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 12712206 t gcesareni Here we report a conserved nuclear protein, named chibby, which was identified in a screen for proteins that directly interact with the c-terminal region of beta-catenin. In mammalian cultured cells we demonstrate that chibby inhibits beta-catenin-mediated transcriptional activation by competing with lef-1 to bind to beta-catenin. SIGNOR-100835 0.681 PRKD1 protein Q15139 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 20179209 t lperfetto Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated SIGNOR-163928 0.312 ethanol chemical CHEBI:16236 ChEBI GLRA2 protein P23416 UNIPROT up-regulates activity chemical activation 8355 BTO:0000964 8700149 t miannu Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations. SIGNOR-258496 0.8 MAPK8 protein P45983 UNIPROT NFATC2 protein Q13469 UNIPROT down-regulates phosphorylation 9606 BTO:0000782 14517246 t gcesareni Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin jnk directly regulated nuclear factor of activated t-cell (nfat) activation in culture and in transgenic mice containing an nfat-dependent luciferase reporter. SIGNOR-118217 0.742 perfluorohexanesulfonic acid chemical CHEBI:132448 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation -1 31332417 t miannu In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group. SIGNOR-268755 0.8 HMGB1 protein P09429 UNIPROT HOXD10 protein P28358 UNIPROT up-regulates activity binding -1 8890171 t 2 miannu We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein. SIGNOR-240556 0.297 CCT137690 chemical CID:25154041 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190898 0.8 SMAD3 protein P84022 UNIPROT SMAD3/PIAS3 complex SIGNOR-C204 SIGNOR form complex binding 9606 26194464 t mrosina In summary, the TGF-b/IL-6/TCR-pERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation SIGNOR-255034 0.58 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267881 0.8 axitinib chemical CHEBI:66910 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258076 0.8 PRKCA protein P17252 UNIPROT DDX5 protein P17844 UNIPROT down-regulates activity phosphorylation Ser557 VSAGIQTsFRTGNPT -1 7525583 t lperfetto We report that p68 is phosphorylated by protein kinase C in vitro and binds calmodulin in a Ca(2+)-dependent manner. Both phosphorylation and calmodulin binding inhibited p68 ATPase activity | In addition, a 20-amino acid peptide corresponding to residues 549-568 of p68 was phosphorylated in a Ca- and phospholipid-dependent manner hy PKC SIGNOR-248896 0.341 SMARCD3 protein Q6STE5 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 t miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270613 0.765 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Thr345 GADSDVEtPSNFGKY 9606 BTO:0000007 27846390 t lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  SIGNOR-262986 0.2 PTK2 protein Q05397 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates activity phosphorylation Tyr35 ICGPEENyPSLQMSS 9606 BTO:0000007 22493428 t miannu  In addition, FAK directly phosphorylates Nanog in a dose-dependent manner by in vitro kinase assay and in cancer cells in vivo. The site-directed mutagenesis of Nanog tyrosines, Y35F and Y174F, blocked phosphorylation and binding by FAK. SIGNOR-276409 0.278 A6/b1 integrin complex SIGNOR-C164 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257706 0.561 NRF1 protein Q16656 UNIPROT ENOX1 protein Q8TC92 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23939472 f miannu We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. SIGNOR-261368 0.268 BMPR2 protein Q13873 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates binding 9606 10712517 t gcesareni Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii). SIGNOR-75655 0.609 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates activity phosphorylation Tyr328 YSPRSFEdCGGGYTP 9606 9467953 t Manara Thus, we propose that the phosphorylation of tyrosine 328 and 360 within Bcr by Bcr ± Abl will drastically interfere with Bcr's kinase role in either signal transduction or some other cellular mechanism. SIGNOR-260829 0.2 ATM protein Q13315 UNIPROT FBXO31 protein Q5XUX0 UNIPROT up-regulates phosphorylation Ser278 LMKFIYTsQYDNCLT 9606 BTO:0000150;BTO:0001130 19412162 t lperfetto We find that dna damage induced by gamma-irradiation results in increased fbxo31 levels, which requires phosphorylation of fbxo31 by the ddr-initiating kinase atm SIGNOR-185635 0.415 tofacitinib chemical CHEBI:71200 ChEBI JAK3 protein P52333 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258302 0.8 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273100 0.745 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Met) smallmolecule CHEBI:29173 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269491 0.8 NDN protein Q99608 UNIPROT EID1 protein Q9Y6B2 UNIPROT up-regulates activity binding 10090 BTO:0000165 18557765 t llicata The Prader-Willi syndrome protein necdin interacts with the E1A-like inhibitor of differentiation EID-1 and promotes myoblast differentiation. SIGNOR-237614 0.383 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser380 EPDHYRYsDTTDSDP 9606 21779440 t gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity SIGNOR-152348 0.667 SEC61B protein P60468 UNIPROT SEC61 complex complex SIGNOR-C368 SIGNOR form complex binding -1 33925740 t lperfetto The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER SIGNOR-265277 0.905 SMARCA2 protein P51531 UNIPROT SMARCC1 protein Q92922 UNIPROT up-regulates binding 9606 10078207 t miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. SIGNOR-65432 0.908 PTPRC protein P08575 UNIPROT JAK3 protein P52333 UNIPROT up-regulates dephosphorylation 9606 BTO:0000776;BTO:0003076 11994288 t gcesareni These negative regulatory effects on ig class switching were concomitant with the ability of cd45 to dephosphorylate the induced phosphorylation of jak1, jak3, SIGNOR-87157 0.468 POLR2J protein P52435 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266161 0.82 BBS2 protein Q9BXC9 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 t lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome SIGNOR-262557 0.807 phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI CADPS protein Q9ULU8 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 24363652 t miannu CAPS exhibits low affinity but functionally significant interactions with plasma membrane PIP2 via its central PH (pleckstrin homology) domain (82, 111). PIP2 enhanced CAPS stimulation of SNARE-dependent liposome fusion with wild-type but not with mutant PH domain CAPS proteins SIGNOR-264334 0.8 NOTCH1 protein P46531 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 9606 7566092 t Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-Jk and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. SIGNOR-254381 0.949 ID1 protein P41134 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR down-regulates activity binding 10090 BTO:0004058 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241125 0.569 ER stress stimulus SIGNOR-ST9 SIGNOR BBC3 protein Q9BXH1 UNIPROT up-regulates 9606 22492984 f miannu Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins SIGNOR-196938 0.7 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity dephosphorylation 9606 BTO:0000093 11154267 t lperfetto Expression of Cdc25A mRNA and protein was induced by E(2) in control and p16(INK4a)-expressing MCF-7 cells; however, functional activity of Cdc25A was inhibited in cells expressing p16(INK4a). Inhibition of Cdc25A activity in p16(INK4a)-expressing cells was associated with depressed Cdk2 activity SIGNOR-245449 0.824 HCFC1 protein P51610 UNIPROT ZBTB17 protein Q13105 UNIPROT down-regulates activity binding 9534 BTO:0001538 12244100 t miannu We show here that HCF-1 directly binds to the Myc-interacting protein Miz-1. HCF-1 Represses Gal4-Miz-1-mediated Transcriptional Activation SIGNOR-223590 0.35 BAG3 protein O95817 UNIPROT SIRT5 protein Q9NXA8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30910998 f Monia Ectopic BAG3 expression decreases the interaction between GLS and SIRT5. we demonstrated that BAG3 overexpression decreased SIRT5 expression in HepG2 cells (Fig. 5d). SIGNOR-261205 0.2 GNGT1 protein P63211 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 17419683 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-154261 0.408 SUZ12 protein Q15022 UNIPROT SUZ12/EED complex SIGNOR-C76 SIGNOR form complex binding 9606 16712789 t miannu Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2. SIGNOR-146761 0.942 PPM1B protein O75688 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity dephosphorylation -1 11104763 t miannu In vitro, PP2Cbeta-1 dephosphorylated and inactivated TAK1. SIGNOR-277154 0.535 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 BTO:0000938 21079800 t gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. SIGNOR-169686 0.432 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249644 0.697 CFHR1 protein Q03591 UNIPROT C3 protein P01024 UNIPROT up-regulates activity binding -1 cleavage:Arg748 ASHLGLArSNLDEDI 27814381 t complement C3b fragment: PRO_0000005911 lperfetto Finally, we have been able to establish that CFHR1 can sterically inhibit the interaction that CFH/CFHL-1 SCR1-4 makes with C3b.|CFH regulates the alternative pathway of complement in both the fluid phase and on self-surfaces: It competes with complement factor B (CFB) for binding to C3b and C3(H2O) thereby blocking the formation of the pro-convertase complexes, C3bB and C3(H2O)B. It also accelerates the decay of any existing C3bBb or C3(H2O)Bb. |these data have allowed us to consolidate one possible model of CFHR1-mediated deregulation of CFH/CFHL-1 on an activating surface in which CFHR1 directly competes with or blocks both CFH-binding sites on C3b SIGNOR-263475 0.827 ARNT protein P27540 UNIPROT CYP1A1 protein P04798 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22387692 f lperfetto The miR-24-dependent down-regulation of ARNT decreased the expression of its downstream genes such as CYP1A1 and carbonic anhydrase IX. SIGNOR-253705 0.632 CEP76 protein Q8TAP6 UNIPROT PLK1 protein P53350 UNIPROT down-regulates activity binding 9606 BTO:0001938 27065329 t miannu Here, we found that centrosomal protein of 76 kDa (Cep76), previously shown to restrain centriole amplification, interacts with cyclin-dependent kinase 2 (CDK2) and is a bona fide substrate of this kinase. Cep76 is preferentially phosphorylated by cyclin A/CDK2 at a single site S83, and this event is crucial to suppress centriole amplification in S phase. Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification. SIGNOR-262731 0.409 DYRK3 protein O43781 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C3 23415227 t lperfetto When dyrk3 is active, it allows stress granule dissolution, releasing mtorc1 for signaling and promoting its activity by directly phosphorylating the mtorc1 inhibitor pras40 SIGNOR-201002 0.346 CDK2 protein P24941 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity SIGNOR-183655 0.502 STK3 protein Q13188 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Ser438 EKNYQLKsRQILGMR 9606 21076410 t lperfetto Our data suggest that mst2 phosphorylates nek2a thereby recruiting nek2a to centrosomes and promoting phosphorylation and displacement of centrosomal linker proteins SIGNOR-169539 0.246 CSNK1E protein P49674 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity phosphorylation Ser349 QNWEEADsMKSSVES 9606 26928339 t miannu  CK1ɛ interacted with and phosphorylated TRAF3 at Ser349, which thereby promoted the Lys63 (K63)-linked ubiquitination of TRAF3 and subsequent recruitment of the kinase TBK1 to TRAF3.  SIGNOR-277212 0.312 PRKCZ protein Q05513 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser177 AKELDQGsLCTSFVG 9606 10022904 t lperfetto Activation of IkappaB kinase beta by protein kinase C isoforms. | Interestingly, recombinant active zetaPKC and alphaPKC are able to stimulate in vitro the activity of IKKbeta but not that of IKKalpha. In addition, evidence is presented here that recombinant zetaPKC directly phosphorylates IKKbeta in vitro, involving Ser177 and Ser181. Collectively, these results demonstrate a critical role for the PKC isoforms in the NF-kappaB pathway at the level of IKKbeta activation and IkappaB degradation. SIGNOR-249015 0.496 BBS7 protein Q8IWZ6 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 t lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome SIGNOR-262556 0.843 CHRM4 protein P08173 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256965 0.357 GHSR protein Q92847 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257429 0.41 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18339811 t Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs. SIGNOR-248606 0.2 KNL1 protein Q8NG31 UNIPROT KNL1 complex complex SIGNOR-C363 SIGNOR form complex binding 27881301 t lperfetto KNL1C (known as Spc105 complex in S. cerevisiae) contains the KNL1 and ZWINT subunits. SIGNOR-265193 0.2 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000093 17535811 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-155246 0.764 PKN1 protein Q16512 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Thr531 PNATGTGtFSPGASP -1 10467162 t lperfetto Autophosphorylation of wild-type PKN increased the protein kinase activity, however, substitution of Thr64, Ser374, or Thr531 in the regulatory region of PKN with alanine, abolished this effect. SIGNOR-249020 0.2 EIF3M protein Q7L2H7 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266388 0.934 TFDP1 protein Q14186 UNIPROT CCNE1 protein P24864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253857 0.552 SKIL protein P12757 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR down-regulates binding 9606 22298955 t lperfetto Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7 SIGNOR-217709 0.688 THRB protein P10828 UNIPROT GATA2 protein P23769 UNIPROT down-regulates activity binding 9606 BTO:0001073 29407449 t scontino We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2. SIGNOR-267256 0.2 SOX3 protein P41225 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10549281 t gcesareni Two additional sox proteins, xsox17alfa and xsox3, likewise bind to beta-catenin and inhibit its tcf-mediated signaling activity. SIGNOR-72039 0.475 EIF4G2 protein P78344 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates activity binding 9606 BTO:0000007 29530922 t miannu Unlike eIF4GI/II, DAP5 binds eIF2β, a subunit of the eIF2 complex that delivers methionyl-tRNA to ribosomes. SIGNOR-266385 0.743 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 8892604 t lperfetto Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function SIGNOR-44669 0.717 EGFR protein P00533 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity 10090 BTO:0000667 15284024 f JAK activation occurs upon ligand-mediated receptor multimerization because two JAKs are brought into close proximity, allowing trans-phosphorylation. The activated JAKs subsequently phosphorylate additional targets, including both the receptors and the major substrates, STATs. lperfetto Two possibilities for STAT activation exist: a janus kinase (JAK)-dependent and a JAK-independent mechanism. Herein, we demonstrate that EGFR overexpression in primary esophageal keratinocytes activates STAT in a JAK-dependent fashion SIGNOR-235870 0.6 NDUFA12 protein Q9UI09 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. SIGNOR-262152 0.824 PLK1 protein P53350 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates phosphorylation Ser65 SHLLVKHsQSRRPSS 9606 BTO:0000567 16118204 t llicata Here we demonstrate that ser-65 in pin1 is the major site for plk1-specific phosphorylation, and the polo-box domain of plk1 is required for this phosphorylation. Interestingly, the phosphorylation of pin1 by plk1 does not affect its isomerase activity but rather is linked to its protein stability. pin1 is ubiquitinated in hela s3 cells, and substitution of glu for ser-65 reduces the ubiquitination of pin1. SIGNOR-139919 0.434 PRKCG protein P05129 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser619 SLPKINRsASEPSLH 9606 8288587 t gcesareni Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. SIGNOR-37545 0.381 CDK2AP1 protein O14519 UNIPROT CDK2 protein P24941 UNIPROT down-regulates activity binding 22427660 t lperfetto The ubiquitously expressed CDK2AP1 protein is the only known specific inhibitor of CDK2, making it an important component of cell cycle regulation during G1-to-S phase transition. SIGNOR-264781 0.452 BRAF protein P15056 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser614 SHQFEQLsGSILWMA 9606 BTO:0002181 27345148 t miannu The phosphorylation of S614 is mitogen inducible and the result of autophosphorylation. These data suggest that phosphorylation at this site is inhibitory, and part of the physiological shut-down mechanism of BRAF signalling. SIGNOR-277255 0.2 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates phosphorylation Thr594 LHGKKNStVDCNGVV 9606 22514276 t miannu A stable interaction between ?(C)-camkii and the intracellular loop between domains 1 and 2 of na(v)1.5 was observed. This region was also phosphorylated by ?(C)-camkii, specifically at the ser-516 and thr-594 sites.Wild-type (wt) and phosphomutant hna(v)1.5 were co-expressed with gfp-?(C)-camkii in hek293 cells, and i(na) was recorded. As observed in myocytes, camkii shifted wt i(na) availability to a more negative membrane potential and enhanced accumulation of i(na) into an intermediate inactivated state, but these effects were abolished by mutating either of these sites to non-phosphorylatable ala residues. SIGNOR-197067 0.481 GRIA1 protein P42261 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 10090 BTO:0000938 15115814 f lperfetto The targeting and clustering of AMPA and NMDA receptors to synapses in the CNS is essential for efficient excitatory synaptic transmission SIGNOR-261433 0.7 LATS2 protein Q9NRM7 UNIPROT AMOT protein Q4VCS5 UNIPROT up-regulates quantity by stabilization phosphorylation Ser175 QGHVRSLsERLMQMS 24101513 t lperfetto Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130 SIGNOR-275846 0.531 MPHOSPH10 protein O00566 UNIPROT RPS5 protein P46782 UNIPROT up-regulates activity binding -1 28813493 t miannu Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome. SIGNOR-261175 0.609 HPS1 protein Q92902 UNIPROT BLOC-3 complex SIGNOR-C253 SIGNOR form complex binding 9606 20048159 t lperfetto Two of these genes, HPS1 and HPS4, encode components of the biogenesis of lysosome-related organelles complex-3 (BLOC-3). Herein we show that recombinant HPS1-HPS4 produced in insect cells can be efficiently isolated as a 1:1 heterodimer. SIGNOR-260691 0.743 PAX7 protein P23759 UNIPROT Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates 9606 15843801 f gcesareni We have identified a new cell population that expresses the transcription factors pax3 and pax7 (paired box proteins 3 and 7) but no skeletal-muscle-specific markers. SIGNOR-135626 0.7 NR1I2 protein O75469 UNIPROT UGT1A1 protein P22309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18172616 f miannu This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities. SIGNOR-254440 0.467 CDK16 protein Q00536 UNIPROT PRKAR1A protein P10644 UNIPROT up-regulates activity phosphorylation Ser83 DSREDEIsPPPPNPV 9606 BTO:0000567 25605337 t lperfetto PCTK1 regulates spindle orientation in a kinase-dependent manner. Phosphoproteomic analysis together with an RNA interference screen revealed that PCTK1 regulates spindle orientation through phosphorylation of Ser83 on KAP0, a regulatory subunit of protein kinase A (PKA) SIGNOR-273018 0.275 PKC proteinfamily SIGNOR-PF53 SIGNOR KCNJ1 protein P48048 UNIPROT up-regulates activity phosphorylation Ser4 sSRNVFDT -1 12221079 t miannu We conclude that ROMK1 is a substrate of PKC and that serine residues 4 and 201 are the two main PKC phosphorylation sites that are essential for the expression of ROMK1 in the cell surface. SIGNOR-275989 0.2 MAPK9 protein P45984 UNIPROT NFATC2 protein Q13469 UNIPROT down-regulates phosphorylation 9606 BTO:0000782 14517246 t gcesareni Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin SIGNOR-118223 0.556 panobinostat chemical CHEBI:85990 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257753 0.8 EEF1A1P5 protein Q5VTE0 UNIPROT Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269543 0.8 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates activity phosphorylation Tyr145 PVEDDADyEPPPSND 9606 12817019 t lperfetto Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase. SIGNOR-102515 0.797 GNAQ protein P50148 UNIPROT TRIOBP protein Q9H2D6 UNIPROT up-regulates activity binding -1 17606614 t We show that the C-terminal Rho-specific DH-PH cassette of Trio is similarly activated by Galpha(q) SIGNOR-256494 0.2 STC2 protein O76061 UNIPROT STC2/HMOX1 complex SIGNOR-C244 SIGNOR form complex binding BTO:0000298 22503972 t Giorgia Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is a heat shock protein.|Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme. SIGNOR-260387 0.351 SWI/SNF complex complex SIGNOR-C92 SIGNOR Myog/SWI/SNF complex complex SIGNOR-C94 SIGNOR form complex binding 9606 BTO:0001103 17194702 t miannu Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle SIGNOR-151706 0.519 ODC1 protein P11926 UNIPROT putrescine smallmolecule CHEBI:17148 ChEBI up-regulates quantity chemical modification 9606 14617280 t miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256034 0.8 PRKCE protein Q02156 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276020 0.2 PPM1D protein O15297 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 15870257 t PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair. SIGNOR-248319 0.575 F2RL3 protein Q96RI0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 17158345 t gcesareni Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13) SIGNOR-151162 0.358 MAPK14 protein Q16539 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates quantity by destabilization phosphorylation Ser301 S-->T -1 30301786 t miannu P38α phosphorylates and destabilizes p63. SIGNOR-277414 0.312 KDM3A protein Q9Y4C1 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 16603237 t miannu Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.  SIGNOR-276845 0.2 RAC1 protein P63000 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT up-regulates activity binding 10090 BTO:0000944 19171758 t miannu In this study, we report that Kank disrupts the function of active Rac1 through IRSp53. The binding between IRSp53 and Kank inhibits the association of active Rac1 with IRSp53 rather than the association of active cdc42 with IRSp53. Kank inhibits the formation of lamellipodia and membrane ruffles induced by active Rac1 in NIH3T3 cells. SIGNOR-265554 0.729 CENPS protein Q8N2Z9 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265205 0.2 DLG4 protein P78352 UNIPROT LRFN2 protein Q9ULH4 UNIPROT up-regulates activity binding 9606 BTO:0000938 21736948 t miannu SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. Interactions between SALMs 1–3 and PSD-95 family proteinscould serve a number of functions. SALM1 and SALM2, which lack the ability to interact with a presynaptic ligand and thus cannot be directly targeted to sites of early synaptic adhesion, may require PSD-95 binding for their localization to early synapses. SIGNOR-264094 0.739 UVB radiation stimulus SIGNOR-ST17 SIGNOR MC1R protein Q01726 UNIPROT up-regulates 9606 9767234 f miannu Melanocyte-stimulating hormone (MSH) receptor binding activity and melanocortin-1 receptor (MC1-R) gene expression on normal human melanocytes have been studied as responses to the effects of ultraviolet B (UVB), interleukin-1 (IL-1), endothelin-1 (ET-1) and tumour necrosis factor-alpha (TNF-alpha), which are known as UV sensitive regulators of melanocytic function. MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression. SIGNOR-252388 0.7 EGFR protein P00533 UNIPROT CTNND1 protein O60716 UNIPROT unknown phosphorylation Tyr228 YPGGSDNyGSLSRVT 9606 BTO:0000017 14996911 t llicata In A431 cells, epidermal growth factor induced striking p120 phosphorylation at Y228. Y228-phosphorylated p120 localized to adherens junctions and lamellipodia, and was significantly enhanced in cells around the colony periphery. SIGNOR-251092 0.626 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 SIGNOR-C16 12359725 t lperfetto In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e. SIGNOR-244614 0.2 F2RL2 protein O00254 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257360 0.389 NAE complex SIGNOR-C131 SIGNOR CUL4B protein Q13620 UNIPROT up-regulates activity neddylation 9606 25504797 t lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. SIGNOR-243163 0.598 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii SIGNOR-203592 0.769 ATM protein Q13315 UNIPROT DGCR8 protein Q8WYQ5 UNIPROT up-regulates quantity by stabilization phosphorylation Ser677 RVGKQLAsQKILQLL 9606 BTO:0002181 34188037 t miannu  Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8's binding partner RNF168 to MDC1 and RNF8 at DSBs.  SIGNOR-277307 0.273 PRKRA protein O75569 UNIPROT DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR form complex binding 9606 23661684 t lperfetto Immunoprecipitation and reconstitution experiments in various systems have shown that Dicer associates with proteins in the Argonaute (Ago) family of endonucleases and with specific double-stranded RNA-binding proteins (dsRBPs) (3–7). | In humans, these dsRBPs are protein activator of PKR (PACT) (5) and trans-activation response RNA-binding protein (TRBP) (3,4). SIGNOR-255318 0.76 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI ABL1 protein P00519 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258127 0.8 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89166 0.538 MAP3K5 protein Q99683 UNIPROT ZNF622 protein Q969S3 UNIPROT up-regulates phosphorylation Thr318 KGKSFYStEAVQAHM 9606 21771788 t gcesareni Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis. SIGNOR-175117 0.501 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX9 protein P48436 UNIPROT up-regulates transcriptional regulation 9606 20457810 f lperfetto Soluble pref-1 inhibits adipocyte differentiation through the activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (erk/mapk) and the subsequent upregulation of sox9 expression. SIGNOR-244750 0.2 PIM1 protein P11309 UNIPROT EPAS1 protein Q99814 UNIPROT up-regulates quantity by stabilization phosphorylation Ser435 GKAILPPsQPWATEL 9606 BTO:0002181 34211090 t miannu PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes. Moreover, phosphorylation of the analogous site in HIF-2α (S435) stabilizes the protein through the same mechanism, indicating post-translational modification within the oxygen-dependent degradation domain as a mechanism of regulating the HIF-α subunits. SIGNOR-277310 0.2 RPS6 protein P62753 UNIPROT Ribosome biogenesis phenotype SIGNOR-PH164 SIGNOR up-regulates -1 19812304 f Luana The stimulation of S6K1 activity by mTORC1 leads to increases in mRNA biogenesis, cap-dependent translation and elongation, and the translation of ribosomal proteins through regulation of the activity of many proteins, such as S6K1 aly/REF-like target (SKAR), programmed cell death 4 (PDCD4), eukaryotic elongation factor 2 kinase (eEF2K) and ribosomal protein S6  SIGNOR-264617 0.7 CDK1 protein P06493 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Thr344 SSMPGGStPVSSANM 9606 7592773 t lperfetto Four residues within this domain, thr-344, thr-360, ser-362, and ser-370, conform to the minimal consensus sequence for p34cdc2 phosphorylationthe high stoichiometry of phosphorylation suggests that phosphorylation could regulate functional properties of ckii and that it could in some way participate in the burst of phosphorylation that accompanies the activation of p34graphic at the ggraphic-m transition SIGNOR-29525 0.361 PIM proteinfamily SIGNOR-PF34 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 17643117 t gcesareni Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation. SIGNOR-265365 0.2 STXBP2 protein Q15833 UNIPROT STX11-VAMP8 SNARE complex complex SIGNOR-C273 SIGNOR form complex binding 9606 BTO:0000132 22767500 t lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23.¬† SIGNOR-267727 0.558 LSM3 protein P62310 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270633 0.792 PRKDC protein P78527 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Ser232 LTQLPQQsQANLLQS 9606 9368058 t lperfetto Through a similar strategy, t226 and s232 were characterized as the dna-pk phosphorylation sites SIGNOR-53258 0.335 GDNF protein P39905 UNIPROT LAMA3 protein Q16787 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252175 0.2 HSPA1A protein P0DMV8 UNIPROT FLCN protein Q8NFG4 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 27353360 t These data suggest that inhibition of Hsp70 does not lead to an increase in misfolded FLCN but instead to its degradation. SIGNOR-256506 0.2 PRKCA protein P17252 UNIPROT SRC protein P12931 UNIPROT unknown phosphorylation Ser12 KSKPKDAsQRRRSLE -1 2996780 t lperfetto We propose that protein kinase C is responsible for this modification based on the following evidence. First, the tumor promoters, 12-O-tetradecanoylphorbol-13-acetate and teleocidin, and synthetic diacylglycerol, known activators of protein kinase C in vivo, cause nearly complete phosphorylation of pp60src at serine 12. Second, among five purified serine/threonine-specific protein kinases tested, only protein kinase C phosphorylates pp60c-src and pp60v-src in vitro at serine 12. Third, purified protein kinase C phosphorylates a synthetic peptide corresponding to the N-terminal 20 amino acids of pp60c-src at serine 12. The physiological significance of this novel phosphorylation is discussed. SIGNOR-248893 0.583 TBX2 protein Q13207 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25211658 t lperfetto TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS SIGNOR-249594 0.502 MAPKAPK3 protein Q16644 UNIPROT HSPB1 protein P04792 UNIPROT unknown phosphorylation Ser82 RALSRQLsSGVSEIR -1 8774846 t miannu MAPKAP kinase-3 and MAPKAP kinase-2 phosphorylated peptide substrates with similar kinetic constants and phosphorylated the same serine residues in HSP27 at the same relative rates.The three serine residues in HSP27 phosphorylated by MAPKAPK2 were also phosphorylated at the same relative rates by MAPKAP-K3 (Ser-82>>Ser-78 >Ser-15) SIGNOR-250161 0.672 RAP1GDS1 protein P52306 UNIPROT RHOC protein P08134 UNIPROT up-regulates binding 9606 21242305 t miannu Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc SIGNOR-171399 0.303 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 30193097 t miannu √Ǭ†PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP).√Ǭ† SIGNOR-266586 0.8 SAR1A protein Q9NR31 UNIPROT SEC23A protein Q15436 UNIPROT up-regulates quantity binding SIGNOR-C370 30605680 t lperfetto Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. SIGNOR-265299 0.817 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Thr135 PKKMEDLtNVSSLLN 9606 BTO:0000567 25670858 t lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. SIGNOR-265234 0.571 ELOVL6 protein Q9H5J4 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267887 0.8 N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure. SIGNOR-267307 0.8 RAB5B protein P61020 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 t lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 SIGNOR-276874 0.461 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252831 0.908 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser190 RGAPKRGsGKDSHHP -1 2413024 t lperfetto MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. SIGNOR-248871 0.502 Caspase-2 PIDDosome complex SIGNOR-C292 SIGNOR BID protein P55957 UNIPROT up-regulates activity cleavage 9606 20158568 t miannu Inactive caspase-2 monomers are recruited to the PIDDosome in response to certain cellular stresses. This results in dimerization and activation of caspase-2. Caspase-2 cleaves and activates Bid to induce MOMP eventually resulting in activation of executioner caspases by caspase-9-mediated cleavage. SIGNOR-262644 0.554 RAB23 protein Q9ULC3 UNIPROT GLIS2 protein Q9BZE0 UNIPROT down-regulates 9606 16364285 f gcesareni Based on su(fu) function, we predict that rab23 can interact with all gli1 molecules including gli1, gli2 and gli3, and inhibit their transcriptional activities and nuclear localization. SIGNOR-143163 0.2 SKIL protein P12757 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR down-regulates binding 9606 12419246 t lperfetto Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7 SIGNOR-217703 0.688 MAPK3 protein P27361 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser789 QSVDKVTsPTKV 9606 BTO:0001260 10514499 t lperfetto Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin. SIGNOR-71045 0.46 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 15568999 t lperfetto In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 SIGNOR-249445 0.601 TRIM38 protein O00635 UNIPROT TRIM38 protein O00635 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21306652 t miannu Our study shows that, similar to other TRIM family members, TRIM38 is localized in the cytoplasm. TRIM38 increases ubiquitination of other cellular proteins and catalyzes self-ubiquitination. TRIM38 also promotes K63- and K48-linked ubiquitination of cellular proteins. An intact RING domain is important for the functions of TRIM38. In addition, enterovirus 71 infection induces TRIM38 degradation. SIGNOR-271906 0.2 ATF4 protein P18848 UNIPROT NARS1 protein O43776 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269422 0.2 CSNK1A1 protein P48729 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity phosphorylation Ser77 YEPEGSAsPTPPYLK -1 17318175 t lperfetto Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling. SIGNOR-249191 0.776 IL1B protein P01584 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by repression transcriptional regulation 10116 9397972 f inferred from family member scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells grown in TSH-containing medium. These include TNF-a, IL-lb and INF-g but not TGF-b. SIGNOR-267812 0.2 PRKCZ protein Q05513 UNIPROT ATP1A1 protein P05023 UNIPROT up-regulates activity phosphorylation Ser16 KYEPAAVsEQGDKKG 9606 BTO:0000018 12671055 t miannu Na,K-ATPase alpha(1) subunit was phosphorylated by PKC in hypoxia-treated AEC. In AEC treated with a PKC-zeta antagonist peptide or with the Na,K-ATPase alpha(1) subunit lacking the PKC phosphorylation site (Ser-18), hypoxia failed to decrease Na,K-ATPase abundance and function. SIGNOR-263181 0.2 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser321 QSLSLASsPKGTIEN 9606 BTO:0002181 34363019 t miannu Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.  SIGNOR-276735 0.2 MED25 protein Q71SY5 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266681 0.575 FERMT3 protein Q86UX7 UNIPROT ITGB3 protein P05106 UNIPROT up-regulates activity binding 10090 BTO:0000132;BTO:0003292 18278053 t lperfetto Mechanistically, Kindlin-3 can directly bind to regions of beta-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis|Kindlin-3 was also able to interact with the wild-type beta1 and beta3 integrin tails (Fig. 3c), in the presence and absence of Talin1 (Supplementary Fig. 3 online), and the F3 subdomain of Kindlin-3 was sufficient for this interaction and this interaction occurred in a direct manner SIGNOR-266066 0.639 WT1 protein P19544 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23042785 t irozzo Here, we show that Wilms' tumour 1 (WT1), a developmental master regulator that can also act as a tumour suppressor or oncoprotein, transcriptionally regulates the de novo DNA methyltransferase 3A (DNMT3A) and that cellular WT1 levels can influence DNA methylation of gene promoters genome-wide. we demonstrate that depletion of WT1 by short-interfering RNAs leads to reduced DNMT3A in Wilms' tumour cells and human embryonal kidney-derived cell lines. Chromatin immunoprecipitation assays demonstrate WT1 recruitment to the DNMT3A promoter region and reporter assays confirm that WT1 directly transactivates DNMT3A expression. SIGNOR-255904 0.388 KAT2B protein Q92831 UNIPROT H3-5 protein Q6NXT2 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269625 0.2 PHKG1 protein Q16816 UNIPROT PHKG1 protein Q16816 UNIPROT unknown phosphorylation Ser31 EILGRGVsSVVRRCI -1 7935360 t miannu Phosphopeptides correspond to sequences occurring in the gamma-subunit of phosphorylase kinase […] undergoes autophosphorylation. phosphorylation occurs primarily at Ser30 while in the latter an additional reaction takes place at Ser81. SIGNOR-250388 0.2 WNT10B protein O00744 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates binding 9606 12055200 t fspada Inhibition of adipogenesis by wnt10b is likely mediated by wnt receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 6 SIGNOR-89134 0.651 TCF3 protein P15923 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 26212009 t lperfetto The p21-activated kinase 5 (PAK5) is overexpressed in advanced cancer and the transcription factor E47 is a direct repressor of E-cadherin and inducer of epithelial-mesenchymal transition (EMT). |In this study, we found that PAK5-mediated E47 phosphorylation promoted EMT in advanced colon cancer. PAK5 interacted with E47 and phosphorylated E47 on Ser39 under hepatocyte growth factor (HGF) stimulation SIGNOR-275654 0.315 AKT proteinfamily SIGNOR-PF24 SIGNOR SLC2A1 protein P11166 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8940145 f gcesareni The constitutively active akt also increased the synthesis of the ubiquitously expressed glucose transporter 1. The increased glucose influx in the 3t3-l1 adipocytes directed lipid but not glycogen synthesis SIGNOR-45064 0.2 ELK4 protein P28324 UNIPROT INSIG2 protein Q9Y5U4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 20145255 t Luana Under these conditions, a significant reduction in INSIG2 expression was only observed when SAP1a siRNA was used. These observations provide supporting evidence that SAP1a may be one of the transactivators of the human INSIG2 promoter. SIGNOR-261592 0.2 FUS protein P35637 UNIPROT HNRNPA2B1 protein P22626 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 28515487 f This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease SIGNOR-262802 0.491 ATF6B protein Q99941 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 14973138 t Luana  Accordingly, N-terminal fragments of each ATF6 isoform (N-ATF6α and N-ATF6β) were overexpressed in HeLa cells and the effects on GRP78 induction were assessed. When expressed at similar levels, N-ATF6α conferred ∼200-fold greater GRP78 promoter activation than N-ATF6β.  SIGNOR-261566 0.459 SRC protein P12931 UNIPROT ITGAL protein P20701 UNIPROT down-regulates activity phosphorylation 9606 25624455 t miannu PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role. SIGNOR-254741 0.408 SMO protein Q99835 UNIPROT MAG protein P20916 UNIPROT up-regulates quantity transcriptional regulation 27639396 f SimoneGraziosi We found that inactivation of Shh signaling caused a dose-dependent decrease in myelin basic protein (MBP) and myelin associated glycoprotein (MAG) in differentiating OLGs. SIGNOR-269227 0.2 CDK2 protein P24941 UNIPROT TK1 protein P04183 UNIPROT down-regulates phosphorylation Ser13 LPTVLPGsPSKTRGQ 9606 12435275 t gcesareni Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase. SIGNOR-95578 0.3 RABGGTA protein Q92696 UNIPROT RAB5A protein P20339 UNIPROT up-regulates activity lipidation 9606 BTO:0000007 18532927 t miannu Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional SIGNOR-265572 0.609 PPP1CA protein P62136 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000599;BTO:0001594 19440292 t Avicins dephosphorylate Stat3 in a variety of human tumor cell lines, leading to a decrease in the transcriptional activity of Stat3.| However, PD98059, an inhibitor of MEK1/2, had no significant effects on avicin-induced dephosphorylation of Stat3 (Ser 727) SIGNOR-248563 0.335 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89288 0.402 neratinib chemical CHEBI:61397 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 23632474 t Neratinib (HKI-272) is a tyrosine kinase inhibitor, under investigation for the treatment breast cancer and other solid tumours. gcesareni Ineratinib is a potent irreversible pan-erbb tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (her)-2-positive breast cancer and other solid tumours. SIGNOR-202015 0.8 NEK9 protein Q8TD19 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT down-regulates activity phosphorylation Thr50 QLPVLDKtKFLVPDH -1 31857374 t done miannu LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1). SIGNOR-273904 0.2 succinate(2-) smallmolecule CHEBI:30031 ChEBI fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity precursor of 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions. SIGNOR-266275 0.8 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr736 FGMSRNLySGDYYRI 9606 16186108 t gcesareni Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues. SIGNOR-140728 0.388 N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:17311 ChEBI 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI up-regulates quantity precursor of 9606 11431483 t miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. SIGNOR-269685 0.8 MAPK1 protein P28482 UNIPROT MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation Thr30 PSSSEIFtPAHEENV 9606 25728771 t lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation SIGNOR-264774 0.2 DOK1 protein Q99704 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257688 0.34 CDK16 protein Q00536 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by destabilization phosphorylation Ser10 NVRVSNGsPSLERMD 9606 BTO:0000567 25205104 t lperfetto In vitro kinase assays showed PCTAIRE1 phosphorylates p27 at Ser10. PCTAIRE1 silencing modulated Ser10 phosphorylation on p27 and led to its accumulation in cancer cells but not in nontransformed cells.|Together our findings reveal an unexpected role for PCTAIRE1 in regulating p27 stability, mitosis, and tumor growth, suggesting PCTAIRE1 as a candidate cancer therapeutic target. SIGNOR-273016 0.339 HNuRF complex SIGNOR-C448 SIGNOR EN2 protein P19622 UNIPROT up-regulates quantity by expression 9606 14609955 f miannu Human NURF (hNURF) is enriched in brain, and we demonstrate that it regulates human Engrailed, a homeodomain protein that regulates neuronal development in the mid-hindbrain. Furthermore, we show that hNURF potentiates neurite outgrowth in cell culture. Taken together, our data suggess a role for an ISWI complex in neuronal growth. ) ChIP assays localize hNURF specifically to engrailed-1 (en-1) and engrailed-2 (en-2) promoters. SIGNOR-268840 0.308 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation. SIGNOR-255120 0.7 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser268 VALPPGAsPQRSRSP 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248688 0.613 tyrosine smallmolecule CHEBI:18186 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264757 0.7 EIF2AK2 protein P19525 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 10348343 t gcesareni The double-stranded rna activated protein kinase pkr physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro. SIGNOR-68033 0.553 FOXO proteinfamily SIGNOR-PF27 SIGNOR FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15109499 t The activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression. SIGNOR-252926 0.2 SMURF1 protein Q9HCE7 UNIPROT ANXA6 protein P08133 UNIPROT unknown ubiquitination -1 20804422 t miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. SIGNOR-272681 0.2 KU-55933 chemical CID:5278396 PUBCHEM ATM protein Q13315 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000793 28341201 t miannu KU-55933 blocked phosphorylation of ATM in H2O2 and Dox models of cell damage. the neuroprotective efficacy of KU-55933, a potent inhibitor of ATM, against cell damage evoked by oxidative stress (hydrogen peroxide, H2O2) has been studied in human neuroblastoma SH-SY5Y cells and compared with the efficacy of this agent in models of doxorubicin (Dox)- and staurosporine (St)-evoked cell death. SIGNOR-262536 0.8 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258897 0.8 (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI up-regulates quantity precursor of 9606 10720211 t lperfetto Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine. SIGNOR-268230 0.8 MRAP2 protein Q96G30 UNIPROT MC2R protein Q01718 UNIPROT up-regulates activity binding 10029 BTO:0000246 19329486 t miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor. SIGNOR-252361 0.552 RPS6KB1 protein P23443 UNIPROT SRPK2 protein P78362 UNIPROT up-regulates activity phosphorylation Ser494 HDRSRTVsASSTGDL 9606 BTO:0000007 29153836 t no miannu  Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins. SIGNOR-275459 0.363 ENO3 protein P13929 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266526 0.8 Loratadine chemical CHEBI:6538 ChEBI SLC6A15 protein Q9H2J7 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 25318072 t Simone Vumbaca Loratadine, a clinically used histamine H1 receptor antagonist, was identified as a selective inhibitor of B0AT2. Our studies provide thefirst chemical tool for B0AT2. SIGNOR-261092 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser324 RDLELPLsPSLLGGP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252085 0.2 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR PAX7 protein P23759 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103;BTO:0002314 22493066 t lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells NICD regulates Pax7 through interaction with RBP-J_, which binds to two consensus sites upstream of the Pax7 gene. SIGNOR-219365 0.385 belinostat chemical CHEBI:61076 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257954 0.8 RNF183 protein Q96D59 UNIPROT TNFRSF10B protein O14763 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 31889078 t miannu RNF183 mediated K63-linked ubiquitination and lysosomal degradation of DR5. SIGNOR-272212 0.2 GSK3B protein P49841 UNIPROT UNG protein P13051 UNIPROT down-regulates quantity by destabilization phosphorylation Ser64 EPGTPPSsPLSAEQL 9606 BTO:0000812 27875297 t lperfetto Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation SIGNOR-264884 0.2 MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 t lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. SIGNOR-196116 0.968 UBQLN2 protein Q9UHD9 UNIPROT HNRNPA3 protein P51991 UNIPROT up-regulates quantity by stabilization binding 25616961 t lperfetto We screened a yeast two-hybrid library using the central domain of ubiquilin-2 hoping to identify proteins whose binding is affected by the UBQLN2 mutations.||Additionally, our evidence that ubiquilin-2 is in- volved in stabilizing hnRNPA1 protein SIGNOR-262272 0.459 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PPP2R5C protein Q13362 UNIPROT down-regulates phosphorylation 9606 16456541 t inferred from 70% family members gcesareni Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit. SIGNOR-270101 0.2 CDC25A protein P30304 UNIPROT CDK4 protein P11802 UNIPROT up-regulates activity dephosphorylation Tyr17 AEIGVGAyGTVYKAR 9606 27485204 t miannu Cdc25A mainly promotes G1-S transition by dephosphorylating CDK4 (Y17)-cyclin D, CDK6 (Y24)-cyclin D and CDK2 (T14 and Y15)-cyclin E/A complexes and G2-M progression by dephosphorylating CDK1 (T14 and Y15)-cyclin A/B    .|Cdc25A mainly promotes G1-S transition by dephosphorylating CDK4 (Y17)-cyclin D, CDK6 (Y24)-cyclin D and CDK2 (T14/Y15)-cyclin E/A complexes and G2-M progression by dephosphorylating CDK1 (T14/Y15)-cyclin A/B . SIGNOR-277138 0.693 GSK3A protein P49840 UNIPROT BCL3 protein P20749 UNIPROT down-regulates quantity by destabilization phosphorylation Ser406 PSSSPSQsPPRDPPG 9606 BTO:0000007 15469820 t miannu In this report, we show that BCL-3 is a substrate for the protein kinase GSK3 and that GSK3-mediated BCL-3 phosphorylation, which is inhibited by Akt activation, targets its degradation through the proteasome pathway. SIGNOR-276012 0.401 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-asparagine zwitterion smallmolecule CHEBI:58048 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-268071 0.8 SHANK2 protein Q9UPX8 UNIPROT ACTN1 protein P12814 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264584 0.301 PTK6 protein Q13882 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000150 BTO:0001129 20606012 t gcesareni Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6. SIGNOR-252618 0.454 ATM protein Q13315 UNIPROT RNF20 protein Q5VTR2 UNIPROT up-regulates phosphorylation 9606 21763684 t gcesareni E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm. SIGNOR-174949 0.536 TCF3 protein P15923 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23684607 f miannu The transcription factor TCF3, also known as E2A, drives p21 expression while repressing PUMA across cancer cell types of multiple origins. SIGNOR-255385 0.32 TLN1 protein Q9Y490 UNIPROT ITGB2 protein P05107 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257618 0.707 BTRC protein Q9Y297 UNIPROT GLI2 protein P10070 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0002572 16611981 t The interaction between BTRC and Gli2 occur whne Gli2 is phosphorilated. lperfetto The phosphorylated gli2 protein interacts with beta-trcp, and is ubiquitinated and degraded by the proteasome SIGNOR-146109 0.637 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexenyl]methyl]-1-piperazinyl]-N-[4-[[(2R)-4-(4-morpholinyl)-1-(phenylthio)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide chemical CHEBI:94128 ChEBI BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189150 0.8 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273093 0.745 XL765 chemical CHEBI:71958 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207875 0.8 PIP3 smallmolecule CHEBI:16618 ChEBI WDR45 protein Q9Y484 UNIPROT up-regulates activity chemical activation 9606 BTO:0001938 28561066 t miannu All WIPI members fold into seven-bladed β-propeller proteins that bind PtdIns3P and co-localize at nascent autophagosomes. SIGNOR-268475 0.8 metformin chemical CHEBI:6801 ChEBI G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression 9606 17909097 f inferred from family member gcesareni In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp. SIGNOR-267789 0.8 TFG protein Q92734 UNIPROT SEC16A protein O15027 UNIPROT up-regulates binding 9606 21478858 t miannu We identify tfg-1, a new conserved regulator of protein secretion that interacts directly with sec-16 and controls the export of cargoes from the endoplasmic reticulum in caenorhabditis elegans. Hydrodynamic studies indicate that tfg-1 forms hexamers that facilitate the co-assembly of sec-16 with copii subunits. SIGNOR-173242 0.628 CAMK2A protein Q9UQM7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation Ser110 SFSEQTRsLDGRLQV 9606 SIGNOR-C8 11027280 t gcesareni Smad2 is a target substrate for cam kinase ii in vitro at serine-110, -240, and -260. furthermore, cam kinase ii blocked nuclear accumulation of a smad2 and induced smad2-smad4 hetero-oligomerization independently of tgfbeta receptor activation, while preventing tgf-beta-dependent smad2-smad3 interactions. SIGNOR-82966 0.53 PAN2-PAN3 deadenylation complex complex SIGNOR-C553 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI down-regulates quantity by destabilization chemical modification 9606 34280615 t miannu There are two major deadenylase complexes, Ccr4-Not and Pan2-Pan3, which shorten the 3′ poly(A) tail of mRNA and are conserved from yeast to human.The Ccr4-Not complex has two catalytic subunits including the Ccr4 (Carbon catabolite repressor 4) and Pop2 (PGK promoter directed overproduction). The Pan2-Pan3 complex comprises the catalytic subunit Pan2, a member of the RNase D family, and the regulatory subunit Pan3. Degradation of mRNA begins with either shortening of the poly(A) tail by deadenylases or removal of 5′ cap structure by the decapping enzyme Dcp1-Dcp2. SIGNOR-273872 0.8 AMPK complex SIGNOR-C15 SIGNOR HAT1 protein O14929 UNIPROT up-regulates activity phosphorylation Ser190 MWFIETAsFIDVDDE -1 28143904 t lperfetto Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314 SIGNOR-264787 0.31 STK39 protein Q9UEW8 UNIPROT SLC4A4 protein Q9Y6R1 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 21317537 t miannu SPAK phosphorylates the transporters to reduce their surface expression and thus their activity and consequently inhibits ductal secretion to stabilize the resting state. PP1 reverses the effect of SPAK. Molecular analysis revealed that the WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. SIGNOR-263133 0.355 FYN protein P06241 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Tyr374 PLPPAPAyLSSPLAL 9606 BTO:0000007 23131831 t miannu Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.  SIGNOR-276371 0.364 FGF11 protein Q92914 UNIPROT SCN4A protein P35499 UNIPROT down-regulates activity binding 9606 BTO:0001103 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253434 0.2 KLF10 protein Q13118 UNIPROT TGFBI protein Q15582 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 18359287 t lperfetto Analyzing the mechanism of TGFBI up-regulation in clear cell carcinoma, we identified a novel VHL target, a Kruppel-like transcriptional factor 10 (KLF10). The TGFBI promoter, which we isolated and studied in Luc-reporter assay, was induced by KLF10 but not hypoxia. SIGNOR-253212 0.244 YAP1 protein P46937 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 BTO:0000562 23607968 t gcesareni Additionally, the hippo and wnts also cooperate in the nucleus, where yap interacts with beta-catenin and induces the expression of canonical wnt target genes, such as sox2 and snai2 in mouse heart tissue. SIGNOR-201939 0.546 CSNK2A1 protein P68400 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates phosphorylation Ser1364 DDLNNYDsDDQEKQS 9606 20664522 t lperfetto Herein, we have identified polo-like kinase 1 (plk1) and casein kinase 2 (ck2) as two kinases of clip-170 and mapped s195 and s1318 as their respective phosphorylation sites.Plk1- and ck2-associated phosphorylations of clip-170 are involved in the timely formation of kinetochore-microtubule attachments in mitosis SIGNOR-167168 0.297 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT down-regulates activity phosphorylation Ser396 RPWTRGGsLERSQSR 9534 BTO:0000298 9353340 t lperfetto  Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response.  SIGNOR-248985 0.399 PRKCE protein Q02156 UNIPROT GAD1 protein Q99259 UNIPROT down-regulates activity phosphorylation Thr91 RDARFRRtETDFSNL -1 15147202 t lperfetto We have identified one specific phosphorylation site, threonine 91 (T91), in hGAD67 that can be phosphorylated by PKA using MALDI-TOF. Site-directed mutation of T91 to alanine abolished PKA-mediated phosphorylation and inhibition of GAD activity. SIGNOR-249264 0.326 LYN protein P07948 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr759 LYDVSRMyVDPSEIN -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249384 0.603 ULK1 protein O75385 UNIPROT PFKM protein P08237 UNIPROT down-regulates activity phosphorylation Ser74 EATWESVsMMLQLGG 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274035 0.2 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser910 KALGERVsIL 9606 BTO:0000776 10473617 t llicata Activation of the serine kinase protein kinase d (pkd)/pkcmicro is controlled by the phosphorylation of two serine residues within its activation loop via a pkc-dependent signaling cascade. In this study we have identified the c-terminal serine 916 residue as an in vivo phosphorylation site within active pkd/pkcmu. moreover, using different mutants of pkd/pkcmu, we show that serine 916 is not trans-phosphorylated by an upstream kinase but is rather an autophosphorylation event that occurs following activation of pkd/pkcmu. SIGNOR-70525 0.2 RAB6C protein Q9H0N0 UNIPROT VPS13B protein Q7Z7G8 UNIPROT down-regulates activity binding 9606 BTO:0000007 25492866 t miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 Golgi Localization Is Mediated by Active RAB6 . COH1 Interacts with All Three Mammalian RAB6 Homologues SIGNOR-269204 0.2 midostaurin chemical CHEBI:63452 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition 16969355 t lperfetto Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases SIGNOR-261982 0.8 MAP2K6 protein P52564 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates phosphorylation 9606 9430721 t gcesareni The p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms. SIGNOR-54947 0.69 TBX5 protein Q99593 UNIPROT FGF10 protein O15520 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18451335 f miannu TBX5 is expressed, among others, in the embryonic heart and forelimbs.8 In the heart, it regulates transcription of downstream genes such as the atrial natriuretic factor (NPPA) and fibroblast growth factor 10 (FGF10) by the binding to T-box binding elements (TBEs),11 often in combination with the NKX2-5 transcription factor. SIGNOR-255383 0.458 FGFR1 protein P11362 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates phosphorylation Tyr243 ARRLCDLyYINSPEL 9606 22195962 t llicata Mitochondrial pdhk1 is tyrosine phosphorylated and activated by fgfr1 in cancer cells further mass spectrometric analysis identified three tyrosine residues of pdhk1, including y136, y243 and y244, that are phosphorylated by fgfr1 SIGNOR-191723 0.354 HOXD12 protein P35452 UNIPROT MAFG protein O15525 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221958 0.384 NR3C1 protein P04150 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates quantity 10090 BTO:0000944 11742987 t gcesareni Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1|Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. In NIH-3T3 fibroblasts, although glucocorticoids up-regulate the MKP-1 level, they do not attenuate the proteasomal degradation of this protein and consequently they are unable to inhibit Erk-1/2 activity. SIGNOR-253546 0.562 CSNK1A1 protein P48729 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser9 LTFMASDsEEEVCDE -1 8972483 t llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  SIGNOR-250792 0.4 MASP1 protein P48740 UNIPROT C2 protein P06681 UNIPROT up-regulates activity cleavage Arg243 KTKESLGrKIQIQRS 9606 BTO:0000392 11907111 t lperfetto The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase SIGNOR-263417 0.517 ADP chemical CHEBI:16761 ChEBI PRKAG1 protein P54619 UNIPROT up-regulates chemical activation 9606 SIGNOR-C15 21399626 t gcesareni Amp binding to the gamma-regulatory domain promotes phosphorylation by the upstream kinase, protects the enzyme against dephosphorylation, as well as causing allosteric activation.Adp also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive. SIGNOR-172813 0.8 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 9727491 t gcesareni Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them. SIGNOR-256459 0.731 CARD8 protein Q9Y2G2 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 16678772 t amattioni Tucan is a recently identified card-containing protein that can complex with caspase-9 and prevent cytochrome c-induced caspase activation. SIGNOR-146663 0.436 WNK3 protein Q9BYP7 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation 21613606 t lperfetto We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs SIGNOR-264626 0.512 NARS2 protein Q96I59 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270465 0.8 NR0B2 protein Q15466 UNIPROT ESRRG protein P62508 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11705994 f gcesareni The current study also demonstrates that shp inhibits err_ transactivation. SIGNOR-111620 0.476 EXOSC7 protein Q15024 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-261386 0.918 SYK protein P43405 UNIPROT SH3BP2 protein P78314 UNIPROT up-regulates activity phosphorylation Tyr448 GDDSDEDyEKVPLPN 9534 BTO:0004055 12709437 t lperfetto By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk. SIGNOR-246596 0.568 HIF1A protein Q16665 UNIPROT ALAS2 protein P22557 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 21207956 f miannu Hypoxia-induced expression of erythroid-specific ALAS2 is mediated by HIF1 in erythroid cells. SIGNOR-254421 0.2 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr180 EFKNIFGtPEFVAPE 9606 15611134 t gcesareni Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates. SIGNOR-132459 0.2 AKT1 protein P31749 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser143 RTPRRSKsDGEAKPE 9606 21151116 t gcesareni Akt1 kinase colocalizes and directly interacts with dnmt1 and phosphorylates ser143. Phosphorylated dnmt1 peaks during dna synthesis, before dnmt1 methylation. Depletion of akt1 or overexpression of dominant-negative akt1 increases methylated dnmt1, resulting in a decrease in dnmt1 abundance. In mammalian cells, phosphorylated dnmt1 is more stable than methylated dnmt1. SIGNOR-170530 0.543 DMTF1 protein Q9Y222 UNIPROT THBS1 protein P07996 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 t Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  SIGNOR-261587 0.2 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser266 FGYGGRAsDYKSAHK -1 2413024 t lperfetto MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. SIGNOR-248873 0.502 ABL1 protein P00519 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates activity phosphorylation Tyr28 AVHSLSRiGDELYLE 9606 11971963 t Manara The SH3 domain of c-Abl interacts directly with the C-terminal region of Rad9. c-Abl phosphorylates the Rad9 Bcl-2 homology 3 domain (Tyr-28) in vitro and in cells exposed to DNA-damaging agents. | c-Abl-mediated phosphorylation of Rad9 induces binding of Rad9 to Bcl-xL |these findings indicate that Rad9 is regulated by a c-Abl-dependent mechanism in the apoptotic response to genotoxic stress. SIGNOR-260843 0.49 PAK3 protein O75914 UNIPROT MYO6 protein Q9UM54 UNIPROT up-regulates activity phosphorylation Thr405 TAGGTKGtVIKVPLK -1 11517222 t miannu P21-activated kinase 3 phosphorylated myosin VI, and the site was identified as Thr(406). The phosphorylation of myosin VI significantly facilitated the actin-translocating activity of myosin VI.  SIGNOR-250244 0.342 ARHGAP9 protein Q9BRR9 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260464 0.59 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser107 SQPPSPPsPAPSSFS 9606 15448698 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-129406 0.574 PLAUR protein Q03405 UNIPROT KRT1 protein P04264 UNIPROT up-regulates activity binding 9606 14691569 t Regulation of binding miannu Cytokeratin 1 binds to both gC1qR and u-PAR. Our data suggest that formation of HK (and Factor XII) binding sites along endothelial cell membranes consists of bimolecular com-plexes of gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1, with gC1qR binding being favored. SIGNOR-251880 0.293 PRKAB1 protein Q9Y478 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition SIGNOR-173044 0.517 PPP2CA protein P67775 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12840032 t inferred from 70% of family members gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). SIGNOR-269896 0.2 SYN1 protein P17600 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates activity binding 9606 BTO:0000938 15265865 t miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. SIGNOR-269187 0.7 KAT6A protein Q92794 UNIPROT KAT6A/KAT6B complex SIGNOR-C54 SIGNOR form complex binding 9606 BTO:0001271 17694082 t miannu Like gcn5/pcaf and p300/cbp, moz and morf are transcriptional co-activators with intrinsic hat activity. SIGNOR-157304 0.39 tandutinib chemical CHEBI:90237 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207209 0.8 CSNK2A1 protein P68400 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity phosphorylation Ser561 MANDSDDsISAATNK -1 28436950 t miannu Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. SIGNOR-265894 0.2 STAT5A protein P42229 UNIPROT IGF1 protein P05019 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 10050749 t lperfetto Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α SIGNOR-251743 0.444 FGFR4 protein P22455 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates phosphorylation Tyr642 RGVHHIDyYKKTSNG 9606 BTO:0001130 18670643 t lperfetto Binding of fgf to fgf receptors leads to receptor dimerization and subsequent tyrosine autophosphorylation and phosphorylation of target substrates. Autophosphorylation on tyrosine is considered to have at least two functions. One such function is the stimulation of the intrinsic protein tyrosine kinase activity by an allosteric mechanismthis antibody specifically recognizes tyr642/643 in fgfr-4. SIGNOR-179776 0.2 UBE3A protein Q05086 UNIPROT SOX9 protein P48436 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 24155239 t miannu We show that E6-AP ubiquitinates SOX9 in vitro and in vivo and that SOX9 levels are enhanced after addition of the proteasome inhibitor bortezomib. Similar, siRNA knockdown of E6-AP and the E2 ligase Ubc9 increased cellular SOX9 amounts, supporting the notion that SOX9 may be ubiquitinated in hypertrophic chondrocytes by E6-AP and degraded by proteasomes. SIGNOR-272134 0.264 PIK3CA protein P42336 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242649 0.7 RBPJ protein Q06330 UNIPROT PAX7 protein P23759 UNIPROT up-regulates binding 9606 22493066 t gcesareni Nicd regulates pax7 through interaction with rbp-j, which binds to two consensus sites upstream of the pax7 gene. SIGNOR-196948 0.371 KRAS protein P01116 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-175210 0.622 BDNF protein P23560 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates binding 9606 7679912 t gcesareni Its interactions with trkb can be distinguished from those of brain-derived neurotrophic factor (bdnf) with trkb SIGNOR-31597 0.81 Gbeta proteinfamily SIGNOR-PF4 SIGNOR LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000944 11581251 t inferred from 70% family members lperfetto Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL. SIGNOR-270119 0.2 GABRB1 protein P18505 UNIPROT GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263751 0.631 RNF8 protein O76064 UNIPROT XRN2 protein Q9H0D6 UNIPROT up-regulates activity ubiquitination 9606 37697435 t miannu Mechanistically, RNF8 interacts with XRN2, which is crucial for transcription termination and R-loop resolution. We report that RNF8 ubiquitylates XRN2 to facilitate its recruitment to R-loop-prone genomic loci and that RNF8 deficiency in BRCA1-mutant breast cancer cells decreases XRN2 occupancy at R-loop-prone sites, thereby promoting R-loop accumulation, transcription-replication collisions, excessive genomic instability, and cancer cell death. SIGNOR-277195 0.2 RPL15 protein P61313 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262483 0.868 1-(6,8-difluoro-2-methyl-4-quinolinyl)-3-[4-(dimethylamino)phenyl]urea chemical CHEBI:92941 ChEBI HCRTR1 protein O43613 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206733 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ARRB1 protein P49407 UNIPROT down-regulates phosphorylation 9606 10347142 t inferred from 70% family members gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation SIGNOR-270190 0.2 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-119233 0.2 DUOX2 protein Q9NRD8 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264720 0.7 2'-deoxycytidine smallmolecule CHEBI:15698 ChEBI 2'-deoxycytosine 5'-monophosphate(2-) smallmolecule CHEBI:57566 ChEBI up-regulates quantity precursor of 20637175 t lperfetto Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis SIGNOR-275810 0.8 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2E2 protein Q96LR5 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271351 0.614 E2F1 protein Q01094 UNIPROT HIC1 protein Q14526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19491197 f miannu expression of E2F1 in the p53(-/-) hepatocellular carcinoma cell line Hep3B led to an increase of endogenous HIC1 mRNA, although bisulfite genomic sequencing of the HIC1 promoter revealed that the region bearing the two E2F1 binding sites is hypermethylated. In addition, endogenous E2F1 induced by etoposide treatment bound to the HIC1 promoter. Moreover, inhibition of E2F1 strongly reduced the expression of etoposide-induced HIC1. SIGNOR-253844 0.292 DLG3 protein Q92796 UNIPROT NMDA receptor_2A complex SIGNOR-C347 SIGNOR up-regulates activity relocalization BTO:0000227 32904533 t lperfetto DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses. SIGNOR-266006 0.708 GRIK1 protein P39086 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264942 0.8 PGM2 protein Q96G03 UNIPROT 2-deoxy-alpha-D-ribose 1-phosphate smallmolecule CHEBI:11563 ChEBI down-regulates quantity chemical modification 9606 17804405 t miannu Biochemical characterization of phosphoglucomutase (PGM) isozymes indicated that one of them, designated PGM2 in man (PGM1 in mouse) was more active as a phosphopentomutase than as a phosphoglucomutase, whereas mammalian PGM1 (equivalent to PGM2 in mouse) has a phosphopentomutase activity representing only about 0.2% of its phosphoglucomutase activity. Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. SIGNOR-267094 0.8 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity phosphorylation Ser1006 GHGVRRAsDPVRTGS 9606 10693759 t lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. SIGNOR-75339 0.445 TBK1 protein Q9UHD2 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Ser403 ESLSQMLsMGFSDEG 9606 BTO:0000801 22921120 t llicata Tbk-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on ser-403, a residue essential for its role in autophagic clearance. SIGNOR-191944 0.701 TFEB protein P19484 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 t lperfetto As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes; SIGNOR-276559 0.4 AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 11108261 t lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. SIGNOR-244243 0.2 SCF-FBW7 complex SIGNOR-C135 SIGNOR DEK protein P35659 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002181 21282377 t miannu  These data suggest that the E3 ligase SCFFbxw7-α degrades p-DEK in a GSK-3β–dependent manner.Therefore, the phosphorylation of DEK by GSK-3β is a crucial step to mediate Tpm RNA splicing. SIGNOR-276304 0.293 TRIM27 protein P14373 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity by destabilization ubiquitination Lys569 DLHVVRPkLPKPPTD 10090 35670107 t lperfetto TRIM27 directly polyubiquitinates ULK1 at K568 and K571 sites with K48-linked ubiquitin chains, with proteasomal turnover maintaining control over basal ULK1 levels SIGNOR-272540 0.2 RIPK1 protein Q13546 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity phosphorylation Ser14 LNVIKMKsSDFLESA -1 18408713 t miannu These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1) SIGNOR-276161 0.2 NKD1 protein Q969G9 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates binding 9606 BTO:0000671 15064403 t gcesareni Naked (nkd)1 and nkd2 are mammalian homologs of drosophila naked cuticle, which negatively regulates canonical wnt signaling by binding dishevelled. various reports using cell culture assays indicate that nkd-mediated wnt antagonism involves dvl degradation SIGNOR-123695 0.696 FANCB protein Q8NB91 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 t lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263241 0.838 PTCH1 protein Q13635 UNIPROT SMO protein Q99835 UNIPROT down-regulates activity binding 9606 BTO:0001757;BTO:0001298 12192414 t lperfetto We show that free Ptc (unbound by Hh) acts sub-stoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity. SIGNOR-91709 0.778 HIRA complex 1 complex SIGNOR-C461 SIGNOR H3-3A protein P84243 UNIPROT up-regulates quantity by stabilization binding 9606 30285846 t miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. SIGNOR-269439 0.2 PTPRC protein P08575 UNIPROT TYK2 protein P29597 UNIPROT down-regulates activity dephosphorylation Tyr1054 AVPEGHEyYRVREDG 10090 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells SIGNOR-248357 0.416 RRAGD protein Q9NQL2 UNIPROT RAGBD complex SIGNOR-C116 SIGNOR form complex binding 9606 20381137 t gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant SIGNOR-228182 0.772 PPP1CA protein P62136 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 16630891 t We have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site of Raf proteins SIGNOR-251649 0.274 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SNAI2 protein O43623 UNIPROT down-regulates quantity by destabilization phosphorylation Ser104 KDHSGSEsPISDEEE 9606 24662826 t miannu At G1/S transition, cyclin E-cyclin-dependent kinase 2 mediates the phosphorylation of Slug at Ser-54 and Ser-104, resulting in its ubiquitylation and degradation. SIGNOR-276629 0.291 TP53 protein P04637 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-256664 0.7 SPART protein Q8N0X7 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity binding 9606 19580544 t miannu Cytosolic endogenous spartin is mono-ubiquitinated and we demonstrate that it interacts via a PPXY motif with the ubiquitin E3 ligases AIP4 [atrophin-interacting protein 4; ITCH (itchy E3 ubiquitin protein ligase homologue] [corrected] and AIP5 (WWP1). Surprisingly, the PPXY motif, AIP4 and AIP5 are not required for spartin's ubiquitination, and so we propose that spartin acts as an adaptor for these proteins. SIGNOR-261306 0.2 SNAPIN protein O95295 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 22203680 t lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. SIGNOR-265935 0.712 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser525 TSMKPRSsRGSIFTF 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275766 0.2 DLGAP5 protein Q15398 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264600 0.2 SGK1 protein O00141 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000007 11154281 t lperfetto We show here that sgk1, like akt, promotes cell survival and that it does so in part by phosphorylating and inactivating fkhrl1. However, sgk and akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on fkhrl1. While both kinases can phosphorylate thr-32, sgk displays a marked preference for ser-315 whereas akt favors ser-253. SIGNOR-252989 0.787 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 10102632 t lperfetto Autophosphorylation of kdr in the kinase domain is required for maximal vegf-stimulated kinase activity and receptor internalizationthe intensity of vegf-induced autophosphorylation is significantly reduced when using receptor mutated at y996, confirming that this is a major site of autophosphorylation. Second, tyrosines 951 and 996 are the only two tyrosines in the receptor's kinase insert domain, and there is strong evidence from studies using the pdgfr and cfms that autophosphorylation of tyrosines in this domain leads to important signaling events. SIGNOR-66040 0.2 LCK protein P06239 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity phosphorylation Tyr354 SSNQELIyEGRRLVL 9606 BTO:0002181 28618271 t miannu The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.  SIGNOR-276724 0.2 PIAS1 protein O75925 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity sumoylation Lys276 NVVYRDLkLENLMLD 10090 BTO:0002572 23884910 t gcesareni Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity. SIGNOR-252737 0.387 TIAM1 protein Q13009 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260577 0.74 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Thr205 PLKTGEQtPPHEHIC 9534 BTO:0000298 12756254 t miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. SIGNOR-250127 0.879 DLD protein P09622 UNIPROT Glycine cleavage system complex SIGNOR-C437 SIGNOR form complex binding 9606 16051266 t lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. SIGNOR-268243 0.633 CSNK2A1 protein P68400 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation Ser149 RRGASDLsSEEGWRL -1 8954982 t llicata Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149. SIGNOR-250950 0.331 Host translation inhibitor nsp1 protein P0DTD1-PRO_0000449619 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0002552 33188728 f miannu We present here data demonstrating that among all viral proteins, Nsp1 causes the most severe viability reduction in the cells of human lung origin. We found that introduction of Nsp1, but not other viral proteins, induced apoptosis in H1299 cells SIGNOR-262506 0.7 FER protein P16591 UNIPROT JUP protein P14923 UNIPROT up-regulates activity phosphorylation Tyr550 AAGTQQPyTDGVRME 10116 BTO:0004604 14517306 t The tyrosine kinase Fer, which modifies beta-catenin Tyr142, lessening its association with alpha-catenin, phosphorylates plakoglobin Tyr549 and exerts the contrary effect: it raises the binding of plakoglobin to alpha-catenin. Fer stimulation, through modification of Tyr549, causes diminished binding of plakoglobin to components of desmosomes (desmoplakin) and increased interaction with adherens junction proteins (α-catenin) SIGNOR-251134 0.505 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000007 16964285 t amattioni Casp8 induces apoptosis by directly activating casp3. SIGNOR-256458 0.715 IRF5 protein Q13568 UNIPROT IL1B protein P01584 UNIPROT up-regulates transcriptional regulation 10090 26315890 f svumbaca IL-1b was present in the sera of wild-type mice but was not detected in the sera of IRF5-/- mice SIGNOR-255340 0.297 CSNK1D protein P48730 UNIPROT WEE1 protein P30291 UNIPROT down-regulates quantity by destabilization phosphorylation Ser212 SVKLRGSsLFMDTEK -1 24817118 t miannu Casein kinase 1-mediated N-terminal Weee1 phosphorylation is required for interaction with the F-box protein β-TrCP.MS/MS spectra of human Wee1 identifying serine 212 as phosphorylated after incubation with recombinant CK1δ. SIGNOR-276631 0.313 CSNK2A2 protein P19784 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser316 VEEEPLNsEDDVSDE -1 11278496 t llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. SIGNOR-250997 0.382 MYOCD protein Q8IZQ8 UNIPROT SRF protein P11831 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 21673106 t gcesareni A coactivator of srf, myocd, interacts with srf and activates vsmc expression of contractile genes. SIGNOR-174322 0.789 PRKCD protein Q05655 UNIPROT EIF2S1 protein P05198 UNIPROT unknown phosphorylation Ser52 MILLSELsRRRIRSI -1 1677563 t lperfetto Of four other protein kinases tested only protein kinase C (PKC) phosphorylated P(45-56), with complete dependence on phosphatidylserine. Only the residue corresponding to serine-51 in eIF-2 alpha was phosphorylated by HCR, dsI or PKC. SIGNOR-248853 0.315 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser26 GTASRPSsSRSYVTT -1 11895474 t miannu In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK.  SIGNOR-250237 0.312 UQCRFS1 protein P47985 UNIPROT Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 t lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits SIGNOR-262190 0.933 CTH protein P32929 UNIPROT L-selenocysteine zwitterion smallmolecule CHEBI:57843 ChEBI up-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. SIGNOR-275821 0.8 CSNK2A1 protein P68400 UNIPROT GAP43 protein P17677 UNIPROT unknown phosphorylation Ser203 PTETGESsQAEENIE -1 1828073 t llicata Phosphorylation of neuromodulin (GAP-43) by casein kinase II. Identification of phosphorylation sites and regulation by calmodulin.| SIGNOR-250867 0.312 bufexamac chemical CHEBI:31317 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000664 21258344 t Luana  We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor. SIGNOR-257892 0.8 CDC20 protein Q12834 UNIPROT MCC complex SIGNOR-C382 SIGNOR form complex binding 9606 BTO:0000567 25092294 t miannu The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. SIGNOR-265976 0.978 LINC complex complex SIGNOR-C303 SIGNOR NPC complex SIGNOR-C263 SIGNOR up-regulates activity binding 9606 BTO:0000567 28831067 t lperfetto The NXF1:NXT1 complex and NUP153 interact with the amino terminus of SUN1 |In analogy to a proposal made by Chang et al.4, Nesprins could help anchoring SUN1 near the NPC to enable it to fulfill its task in mRNA export. SIGNOR-263292 0.2 CYC-116 chemical CID:6420138 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191224 0.8 GEM protein P55040 UNIPROT ROCK2 protein O75116 UNIPROT down-regulates activity binding 9606 14701738 t miannu Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively. SIGNOR-261721 0.294 PRKCA protein P17252 UNIPROT RPL10 protein P27635 UNIPROT unknown phosphorylation Ser168 GRQKIHIsKKWGFTK -1 9016777 t lperfetto Moreover, QM is phosphorylated by PKC and the extent of phosphorylation by PKC is correlated with the extent of inhibition of binding of QM to c-Jun.  SIGNOR-248958 0.312 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT up-regulates dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 19574738 t gcesareni Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation by cdc25c SIGNOR-186617 0.852 PTPN1 protein P18031 UNIPROT PITX1 protein P78337 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr179 EDVYAAGySYNNWAA 9606 27752061 t lperfetto PTP1B dephosphorylates PITX-1 at Y160, 175 and Y179.|Through directly dephosphorylating PITX-1 at Y160, Y175 and Y179, PTP1B promoted proteasomal degradation of PITX-1, thus leaded in downregulating p120RasGAP and CRC cell survival. SIGNOR-276973 0.361 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Thr568 SPGVPMQtPCFTLQY 9606 BTO:0000567 10806207 t llicata Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity. SIGNOR-77220 0.587 PIK3R4 protein Q99570 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates activity binding 10090 27411398 t lperfetto Vps34 PI 3-kinase activity18 is stimulated by complex formation with the protein kinase Vps15|Rab5GTP binds Vps15, enhancing Vps34 activity SIGNOR-260709 0.938 dehydroepiandrosterone chemical CHEBI:28689 ChEBI androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI up-regulates quantity precursor of 9606 BTO:0000056 2139411 t lperfetto The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione. SIGNOR-268641 0.8 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269342 0.719 ECM stimulus SIGNOR-ST20 SIGNOR Av/b6 integrin complex SIGNOR-C179 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259039 0.7 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser82 HSISYTLsRAQTVVV -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276132 0.644 CSNK1D protein P48730 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Thr1493 NPPPSPAtERSHYTM 9606 35487243 t miannu Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493 SIGNOR-275403 0.2 SP3 protein Q02447 UNIPROT CYP27A1 protein Q02318 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11867220 f miannu Therefore, Sp1, Sp3 and HNF4 co-operate in the expression of the human CYP27 gene in HepG2 cells. SIGNOR-255197 0.2 FZD3 protein Q9NPG1 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates binding 9606 17251915 t gcesareni In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families. SIGNOR-152597 0.2 CALM1 protein P0DP23 UNIPROT GEM protein P55040 UNIPROT up-regulates activity binding 10116 14701738 t miannu Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells. SIGNOR-261726 0.338 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75013 0.783 CTDSP1 protein Q9GZU7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser195 PNSSYPNsPGSSSST 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248799 0.477 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr632 GRKGSGDyMPMSPKS 10116 11416002 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells SIGNOR-236709 0.912 PLX-4720 chemical CHEBI:90295 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258267 0.8 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1081 TGALTEDsIDDTFLP 9606 BTO:0000007 10347170 t llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  SIGNOR-250622 0.378 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2V2 protein Q15819 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271335 0.543 CBL protein P22681 UNIPROT FRS2 protein Q8WU20 UNIPROT down-regulates ubiquitination 9606 11997436 t lperfetto The experiments presented in this report illustrate that in response to fgf stimulation, cbl is recruited by grb2 binding to the frs2_ multiprotein complex, resulting in ubiquitination of frs2_ and fgfr. grb2 functions as a link between frs2_ and cbl;grb2 is bound to tyrosine-phosphorylated frs2_ by means of its sh2 domain and to a proline-rich region in the c terminus of cbl by means of its sh3 domains. SIGNOR-87166 0.558 HTR2C protein P28335 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256734 0.298 RUVBL2 protein Q9Y230 UNIPROT R2SP co-chaperone complex SIGNOR-C517 SIGNOR form complex binding 9606 29844425 t miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. SIGNOR-270940 0.511 PRIM1 protein P49642 UNIPROT DNA primase complex complex SIGNOR-C261 SIGNOR form complex binding -1 24043831 t lperfetto Here, we describe the crystal structure of human primase in heterodimeric form consisting of full-length catalytic subunit and a C-terminally truncated large subunit. SIGNOR-261339 0.99 Osmotic_stress stimulus SIGNOR-ST28 SIGNOR TARDBP protein Q13148 UNIPROT down-regulates activity relocalization 9606 BTO:0000312 33172210 f We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne SIGNOR-262818 0.7 CDC42 protein P60953 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity binding 10090 BTO:0000142 8107774 t gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. SIGNOR-248243 0.941 MTNR1B protein P49286 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257102 0.252 MAPK8 protein P45983 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 BTO:0000150 18676833 t gcesareni Mcl-1 can be rapidly degraded by certain death-inducing signals, but it is able to be readily induced by diverse survival cytokines such as epidermal growth factor, vascular endothelial growth factor, granulocyt-macrophage colony-stimulating factor, and interleukin 3 through phosphatidy-linositol-3-oh kinase/akt, mek/mapk, or janus-activated kinase/stat signaling cascades SIGNOR-179816 0.542 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr730 SNCTNELyMMMRDCW 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1 SIGNOR-235686 0.2 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914161 t lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 SIGNOR-161597 0.591 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1333 ARGGQVFyNSEYGEL 9606 BTO:0000394 12881528 t lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. SIGNOR-104084 0.2 EGFR protein P00533 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr155 LNDSAAYyLNDLDRI -1 33139573 t miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. SIGNOR-277226 0.441 UPF1 protein Q92900 UNIPROT Upf-EJC complex SIGNOR-C367 SIGNOR form complex binding 9606 BTO:0000567 17803942 t miannu The three Up-frameshift (Upf) proteins, Upf1, Upf2, and Upf3 that together form the Upf complex, constitute the conserved core of NMD from yeast to humans. hUpf3b Forms Multiple Contacts with the EJC and Depends on hUpf2 for Complex Formation with hUpf1 SIGNOR-265237 0.968 PD-153035 hydrochloride chemical CHEBI:91075 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205716 0.8 PKC proteinfamily SIGNOR-PF53 SIGNOR SLITRK1 protein Q96PX8 UNIPROT up-regulates activity phosphorylation Ser695 DCGSHSLsD -1 19640509 t miannu In our studies, SICD was phosphorylated by PKA, PKC, and CK2, and association of SLITRK1 with 14-3-3 was regulated by phosphorylation at Ser695. Co-precipitation experiments demonstrated much greater recovery of 14-3-3 in SLITRK1 precipitates when wild-type or S695E was used, as compared with S695A, consistent with the results with purified peptides. SIGNOR-273635 0.2 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding BTO:0001103 12361602 t apalma Notch is cleaved and translocates to the nucleus, where it activates a family of transcription factors, exemplified by Suppressor of Hairless and CBF/RJBk SIGNOR-255380 0.95 SOSTDC1 protein Q6X4U4 UNIPROT WNT4 protein P56705 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242707 0.282 GDNF protein P39905 UNIPROT NRG1 protein Q02297 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252182 0.371 PKC proteinfamily SIGNOR-PF53 SIGNOR KCNK9 protein Q9NPC2 UNIPROT down-regulates activity phosphorylation Thr341 IEEISPStLKNSLFP 9606 BTO:0004232 17374744 t miannu PKC acts directly on hTASK3 channels to phosphorylate an identified amino acid in the C terminus region (Thr341), thereby reducing channel current.  SIGNOR-276059 0.2 FOXO3 protein O43524 UNIPROT CITED2 protein Q99967 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 18158893 f gcesareni Foxo3a induces expression of cited2 SIGNOR-160127 0.454 MAPK8 protein P45983 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 8846788 t gcesareni However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity. SIGNOR-44356 0.495 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser330 MEEDSYDsFGEPSYP -1 9558331 t llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. SIGNOR-250801 0.371 IL21 protein Q9HBE4 UNIPROT BCL6 protein P41182 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782;BTO:0000785 22486304 f miannu Interleukin-21 inhibits humoral response to an hiv dna vaccine by enhancing bcl-6 andpax-5expression. SIGNOR-196918 0.407 PCDHA7 protein Q9UN72 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265667 0.2 MAPK3 protein P27361 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr201 DIPEKPKtPQQLWYT 9606 11741541 t lperfetto Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna SIGNOR-112817 0.561 MBD2 protein Q9UBB5 UNIPROT ALOX5 protein P09917 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001412 19781662 f Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation.|Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene. SIGNOR-254026 0.2 PRKCB protein P05771 UNIPROT ANXA2 protein P07355 UNIPROT unknown phosphorylation Ser2 sTVHEILC -1 8898866 t lperfetto A comparison of the phosphorylation patterns obtained identified Ser-II as the protein kinase C site responsible for regulating the annexin II-p11 interaction. Ser-II lies within the sequence mediating p11 binding, i.e. amino-acid residues 1 to 14 of annexin II, and phosphorylation at this site most likely leads to a direct spatial interference with p11 binding. SIGNOR-248956 0.338 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI corticosterone smallmolecule CHEBI:16827 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268673 0.8 TRIM62 protein Q9BVG3 UNIPROT TRIM62 protein Q9BVG3 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23402750 t miannu A ubiquitination assay performed in HEK293T cells further confirmed the E3 ubiquitin ligase activity and self-ubiquitination activity of TRIM62 and the requirement of the RING finger domain. Importantly, the treatment of HEK293T cells with a proteasome inhibitor stabilized poly-ubiquitinated TRIM62, indicating that self-ubiquitination promoted the proteasomal degradation of TRIM62.  SIGNOR-272102 0.2 MTOR protein P42345 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity phosphorylation Ser2481 TVPESIHsFIGDGLV 10090 BTO:0000944 SIGNOR-C2 SIGNOR-C2 20022946 t lperfetto We have found that in HEK293 cells and 3T3-L1 adipocytes, insulin promotes both raptor- and rictor-associated mTOR Ser(P)-2481 in a wortmannin-sensitive manner. Thus, insulin signals via PI3K to promote both mTORC1- and mTORC2-associated mTOR Ser-2481 autophosphorylation. SIGNOR-235427 0.2 AZD-8055 chemical CHEBI:91329 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck;ATP-competitive inhibitor mTOR gcesareni SIGNOR-190215 0.8 NUPR1 protein O60356 UNIPROT ATF4 protein P18848 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 19946894 f lperfetto Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4. SIGNOR-253731 0.394 LPAR1 protein Q92633 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 20331961 t gcesareni The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits) SIGNOR-164682 0.524 CSNK2B protein P67870 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT down-regulates activity phosphorylation Ser740 TKAQRENsPAAFPDR 9606 BTO:0000567 12591939 t llicata We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified SIGNOR-251064 0.332 TGFB1 protein P01137 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates 10090 14739161 f lperfetto Tgf-beta was shown to inhibit myogenin and mef2d expression and myotube formation in c2c12. SIGNOR-235602 0.2 PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates binding 9606 14718519 t gcesareni We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate tbetari. SIGNOR-120471 0.685 APC2 protein O95996 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 9601641 t lperfetto Human axin (haxin) binds directly to beta-catenin, gsk3 beta, and apc in vitro, and the endogenous proteins are found in a complex in cells. SIGNOR-227945 0.576 SMARCD1 protein Q96GM5 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 t miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270615 0.806 IFNGR1 protein P15260 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR form complex binding 9606 BTO:0000801 19041276 t lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249485 0.732 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser639 YMPMSPKsVSAPQQI 10090 BTO:0002572 18498745 t lperfetto In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8 SIGNOR-236599 0.78 phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266538 0.8 TNFSF12 protein O43508 UNIPROT MYH3 protein P11055 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0000165 17314137 t miannu TWEAK induces ubiquitination of MyHCf and expression of atrogin-1 and MuRF1 in myotubes. our data show that TWEAK rapidly increases the conjugation of ubiquitin to MyHCf (Fig. 3A) and ubiquitination preceded the degradation of MyHCf (Fig. 2C and Fig. 3A). SIGNOR-272628 0.2 ZNRF3 protein Q9ULT6 UNIPROT FZD6 protein O60353 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22575959 t Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. SIGNOR-260114 0.598 ANK2 protein Q01484 UNIPROT CACNA1A protein O00555 UNIPROT up-regulates quantity binding 10090 24394417 t miannu Here, we demonstrate that ankyrin-B associates with Cav2.1 and Cav2.2 in cortex, cerebellum, and brain stem. Additionally, using in vitro and in vivo techniques, we demonstrate that ankyrin-B, via its membrane-binding domain, associates with a highly conserved motif in the DII/III loop domain of Cav2.1 and Cav2.2. Collectively, our findings identify an interaction between ankyrin-B and both Cav2.1 and Cav2.2 at the amino acid level that is necessary for proper Cav2.1 and Cav2.2 targeting in vivo. SIGNOR-266706 0.266 PIK3CD protein O00329 UNIPROT PIK3CD protein O00329 UNIPROT down-regulates phosphorylation Ser1039 NWLAHNVsKDNRQ 9606 10064595 t gcesareni Autophosphorylation of p110delta phosphoinositide 3-kinase: a new paradigm for the regulation of lipid kinases in vitro and in vivo in vitro autophosphorylation of p110delta completely down-regulates its lipid kinase activity. SIGNOR-65186 0.2 Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 28347630 f miannu Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation SIGNOR-266829 0.7 CSNK1A1 protein P48729 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 17419683 t gcesareni In the absence of hedgehog signaling, gli1 is transcriptionally repressed, gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation, and gli3 is processed to a cleaved repressor. SIGNOR-154222 0.55 SMARCA5 protein O60264 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 t miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription SIGNOR-268825 0.49 FUS protein P35637 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates quantity 9606 BTO:0000312 22051914 f lperfetto Similarly, cytoplasmic inclu- sions containing mutant fused in sarcoma (FUS) protein have been observed in some patients with FUS-related FALS. SIGNOR-262277 0.7 RPSA protein P08865 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262414 0.84 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser636 SGDYMPMsPKSVSAP 10090 15306821 t lperfetto Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin. SIGNOR-127912 0.78 FAF1 protein Q9UNN5 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates activity binding 9606 BTO:0002181 30472208 t miannu We find that the scaffold protein FAF1 forms aggregates that negatively regulate MAVS.FAF1 antagonizes the poly-ubiquitination and aggregation of MAVS by competing with TRIM31 for MAVS association. SIGNOR-277619 0.2 AMPK complex SIGNOR-C15 SIGNOR KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser592 KCNVKAKsNVDLRRS 9606 BTO:0000007 30279167 t miannu Thus, AMPK directly phosphorylates the α subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser559.  SIGNOR-273735 0.295 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Ser625 PIVGSNGsSRLQDSR 9823 21864610 t miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. SIGNOR-262923 0.337 Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR down-regulates 9606 15623580 f lperfetto All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage. SIGNOR-273454 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000567 17615152 t lperfetto In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-244647 0.2 EEF1A1 protein P68104 UNIPROT Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269516 0.8 MYC protein P01106 UNIPROT HLA-C protein P10321 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000848 8206526 f miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. SIGNOR-254602 0.259 FLI1 protein Q01543 UNIPROT ANKRD26 protein Q9UPS8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000843 24430186 t lperfetto In healthy individual, RUNX1/FLI1 complex negatively regulates ANKRD26 gene expression in MKs. SIGNOR-266070 0.288 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 BTO:0000093 12777400 t lperfetto The SH3 domains of c-Abl and Arg bound directly to catalase at a P293FNP site. c-Abl and Arg phosphorylated catalase at Tyr231 and Tyr386 in vitro and in the response of cells to H2O2 SIGNOR-101298 0.412 SMARCD1 protein Q96GM5 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270707 0.79 MAPK14 protein Q16539 UNIPROT COL1A1 protein P02452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 f gcesareni (tak1) and tak1 binding protein 1 (tab1) play a pivotal role as upstream sig-nal transducers by activating the mkk3-p38 mapk signaling cascade that leads to the induction of type i collagen expression by tgf-beta1. SIGNOR-192796 0.277 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPC5 protein Q9UL62 UNIPROT down-regulates activity phosphorylation Ser796 GARAKSKsVSFNLGC 9606 BTO:0000007 21734191 t done miannu Together, these results suggest that TRPC5 is directly phosphorylated by G(s)/cAMP/PKA at positions S794 and S796. These inhibitory effects were blocked by the protein kinase A (PKA) inhibitors, KT-5720 and H-89, as well as by two point mutations at consensus PKA phosphorylation sites on TRPC5 (S794A and S796A). SIGNOR-273789 0.2 HIC1 protein Q14526 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001211 22184117 f miannu The receptor tyrosine kinase EphA2 is a direct target gene of hypermethylated in cancer 1 (HIC1). we observe that inactivation of endogenous HIC1 through RNA interference in normal breast epithelial cells results in the up-regulation of EphA2 and is correlated with increased cellular migration. chromatin immunoprecipitation (ChIP) and sequential ChIP experiments demonstrate that endogenous HIC1 proteins are bound, together with the MTA1 corepressor, to the EphA2 promoter in WI38 cells. SIGNOR-254241 0.319 ATM protein Q13315 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Ser85 ELLHFQAsQREEKEF 9606 SIGNOR-C14 16497931 t lperfetto Atm phosphorylates serine-85 of nemo to promote its ubiquitin-dependent nuclear export. SIGNOR-144813 0.728 SETDB2 protein Q96T68 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity methylation Lys 10 RTKQTARkSTGGKAP 9606 BTO:0000007 20404330 t miannu Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression. SIGNOR-263895 0.2 PLAU protein P00749 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 19055748 f lperfetto Our data show that functional blockade of SNAI1 (SNAI1-dominant negative (DN)) leads to a partial re-expression of E-cadherin, and induces differential expression of EMT-related genes. This is confirmed by RT-PCR of PA system genes, where PAI-1 and uPA are decreased. SIGNOR-252264 0.7 NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity binding 10116 9428795 t We have shown that one of the functions of the GR to activate transcription of the AGP gene is to recruit C/EBPbeta and to maintain it bound at its target DNA sequences (SRU) SIGNOR-251655 0.472 POMT complex SIGNOR-C372 SIGNOR DAG1 protein Q14118 UNIPROT up-regulates activity glycosylation 9606 BTO:0000007 14699049 t miannu we showed that coexpression of both POMT1 and POMT2 (another gene homologous to yeast protein O-mannosyltransferases) was necessary for the enzyme activity, but expression of either POMT1 or POMT2 alone was insufficient. The requirement of an active enzyme complex of POMT1 and POMT2 suggests that the regulation of protein O-mannosylation is complex. Further, protein O-mannosylation appears to be required for normal structure and function of α-dystroglycan in muscle and brain. SIGNOR-265430 0.712 KITLG protein P21583 UNIPROT KIT protein P10721 UNIPROT up-regulates activity binding 9606 17259966 t miannu The most relevant and still unique mast-cell growth factor is SCF, which is the ligand of KIT, a receptor with tyrosine-kinase activity that is expressed on the surface of all human and murine mast cells SIGNOR-254946 0.933 KTN1 protein Q86UP2 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30683916 f miannu Collectively, our findings revealed a novel mechanism wherein MALAT1 interacts with c-MYC to transactivate KTN1 for enhancing EGFR protein expression, which finally contributes to the development of cSCC. SIGNOR-259906 0.2 PPP2CA protein P67775 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates dephosphorylation 9606 20626350 t lperfetto In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a. SIGNOR-244941 0.54 RET protein P07949 UNIPROT RET protein P07949 UNIPROT unknown phosphorylation Tyr826 SRKVGPGyLGSGGSR 9534 BTO:0004055 8621380 t lperfetto Based on the phosphopeptide maps, we can identify six tyrosine phosphorylation sites in RET: Tyr-687, Tyr-826, Tyr-1062, Tyr-1096, Tyr-1015, and Tyr-1029. By comparing the peptide map of each mutant to the wild-type receptor, we can tentatively assign each tryptic peptide containing phosphorylation sites to individual P-labeled spots on the two-dimensional map  SIGNOR-248942 0.2 EIF2AK2 protein P19525 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr4 yTKIEKIG 9606 20395957 t lperfetto Our findings demonstrate that (i) pkr, ser/thr kinase, phosphorylates its new substrate cdc2 at the tyr 4 residue, (ii) pkr-mediated tyr 4-phosphorylation facilitates cdc2 ubiquitination and proteosomal degradation SIGNOR-164809 0.334 RPS6KA4 protein O75676 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 17183360 t lperfetto Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) msk 1 and 2 can directly phosphorylate and activate transcription factors such as creb, atf1, the nf-kb isoform p65 and stat 1 and 3. SIGNOR-217373 0.277 STIL protein Q15468 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates binding 9606 BTO:0001271 16024801 t miannu Cell cycle-dependent phosphorylation of sil is required for its interaction with pin1, a regulator of mitosis. Point mutation of the seven (s/t)p sites between amino acids 567 and 760 reduces mitotic phosphorylation of sil, pin1 binding, and spindle checkpoint duration. SIGNOR-138677 0.368 IKK-complex complex SIGNOR-C14 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 t lperfetto Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation. SIGNOR-252950 0.536 SB-202190 chemical CHEBI:79090 ChEBI PCSK7 protein Q16549 UNIPROT down-regulates chemical inhibition 9606 BTO:0000876 9738669 t gcesareni Sb202190, a selective inhibitor of p38 mitogen activated protein kinase, is a powerful regulator of lps-induced mrnas in monocytes. SIGNOR-60130 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 12832467 t inferred from 70% family members lperfetto Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. SIGNOR-270006 0.2 TBK1 protein Q9UHD2 UNIPROT STING1 protein Q86WV6 UNIPROT up-regulates activity phosphorylation Ser358 VPSTSTMsQEPELLI 9606 BTO:0000007 18818105 t miannu MITA was phosphorylated by TBK1, which is required for MITA-mediated activation of IRF3. Our results suggest that MITA is a critical mediator of virus-triggered IRF3 activation and IFN expression and further demonstrate the importance of certain mitochondrial proteins in innate antiviral immunity. Consistent with its inability to activate IRF-E, the mutation of S358 to alanine impaired the ability of MITA to interact with TBK1 and to enhance the interaction between TBK1 and IRF3 SIGNOR-263136 0.2 IRX5 protein P78411 UNIPROT KCND2 protein Q9NZV8 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000387 16239150 t Luana Irx5 Directly Represses the Kcnd2 Promoter SIGNOR-266045 0.5 JNK proteinfamily SIGNOR-PF15 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Thr154 VVSGPAAtPTAQHLR 9606 BTO:0001938 21364637 t miannu JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells SIGNOR-277643 0.2 STAT1 protein P42224 UNIPROT IL12B protein P29460 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 19029990 f lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. SIGNOR-249500 0.445 STAT5A protein P42229 UNIPROT CISH protein Q9NSE2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15769897 t The STAT5 target gene CIS, a member of the suppressor of cytokine signaling (SOCS) protein family, was highly induced by Flt3-ITD SIGNOR-261544 0.656 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser35 SQGSSSQsQGISSSS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir SIGNOR-81403 0.829 gemcitabine chemical CHEBI:175901 ChEBI RRM2 protein P31350 UNIPROT down-regulates activity chemical inhibition -1 2233693 t miannu Direct assays of partially purified ribonucleoside diphosphate reductase (EC 1.17.4.1) demonstrated 50% inhibition by 4 microM dFdC 5'-diphosphate; dFdC 5'-triphosphate was much less inhibitory. We conclude that dFdC 5'-diphosphate acts as an inhibitor of ribonucleoside diphosphate reductase. SIGNOR-258387 0.8 PTPN2 protein P17706 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr1021 PNEGDNDyIIPLPDP 10090 BTO:0002572 14966296 t The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP. SIGNOR-248390 0.546 PRKACA protein P17612 UNIPROT APOBEC3B protein Q9UH17 UNIPROT down-regulates activity phosphorylation Thr214 LVLRRRQtYLCYEVE -1 31165764 t miannu Here we show that protein kinase A (PKA) physically binds to A3B and phosphorylates Thr214. SIGNOR-277455 0.2 TFE3 protein P19532 UNIPROT CTSS protein P25774 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276818 0.273 GALR3 protein O60755 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256998 0.281 SYP protein P08247 UNIPROT Synaptic_vesicle_recycling phenotype SIGNOR-PH161 SIGNOR up-regulates 9606 BTO:0000938 33769286 f miannu This study reveals that Syp has a single physiological role in SV recycling, the accurate trafficking, and retrieval of SybII. SIGNOR-264111 0.7 PRKCA protein P17252 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser24 GYLRKPKsMHKRFFV 9606 16574739 t flangone We show that pkcalpha is likely to be directly involved in ser24 phosphorylation...These observations are entirely consistent with a recent independent study demonstrating that the IRS1-S24D mutant shows impaired insulin-stimulated IR-IRS-1 interactions, tyrosine phosphorylation of IRS-1, recruitment/activation of PI 3-Kinase, and insulin-stimulated Glut4 translocation SIGNOR-145398 0.395 CERF complex SIGNOR-C340 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000227 15640247 f miannu CERF is an ATP-dependent chromatin remodeler. CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. SIGNOR-263892 0.7 OTX2 protein P32243 UNIPROT RBP3 protein P10745 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10354480 f miannu OTX2, as well as CRX, a homeodomain protein very similar to OTX2, activates the human IRBP promoter in co-transfection experiments. SIGNOR-254889 0.31 Complement C1q complex SIGNOR-C308 SIGNOR Complement C1 complex complex SIGNOR-C309 SIGNOR form complex binding -1 29449492 t lperfetto The complement system is part of our innate immune system. The classical complement pathway is triggered by activation of the C1 initiation complex upon binding to cell surfaces. C1, or C1qr2s2, consists of four proteases, C1r and C1s, that associate with C1q, which contains antibody-binding sites.|The reconstruction reveals densities for all C1q collagen-like triple helices and gC1q modules, C1r and C1s proteases SIGNOR-263396 0.615 LATS1 protein O95835 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 21808241 t Together,the YAP/TAZ-TEAD complex promotes proliferative and survival programs. gcesareni Activated lats1/2 in turn phosphorylate and inhibit yap/taz transcription co-activators. SIGNOR-175783 0.783 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr453 PEALHYDyIDVEMSA 9534 9655255 t lperfetto In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110. SIGNOR-246355 0.589 TWIST2 protein Q8WVJ9 UNIPROT ILK protein Q13418 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255504 0.2 RBPJ protein Q06330 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11432830 f gcesareni The rbp-jkappa protein binds directly to the endogenous p21 promoter and p21 expression is induced specifically by activated notch1 through rbp-jkappa-dependent transcription. SIGNOR-109042 0.312 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 SIGNOR-C110 SIGNOR-C110 9734785 t lperfetto Interaction with beta-catenin and GSK-3beta was required for the Axin-mediated beta-catenin reduction. SIGNOR-60046 0.918 CDK1 protein P06493 UNIPROT NINL protein Q9Y2I6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser589 NRHSPSWsPDGRRRQ 9606 20890132 t miannu In this study, we show that Nlp can be phosphorylated by cell cycle protein kinase Cdc2/cyclin B1. The phosphorylation sites of Nlp are mapped at Ser185 and Ser589. the phosphorylation at the site Ser589 by Cdc2/cyclin B1 plays an important role in Nlp protein stability probably due to its effect on protein degradation. SIGNOR-259831 0.398 CALM1 protein P0DP23 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates binding 9606 9822657 t gcesareni The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk. SIGNOR-61922 0.827 CHMP2A protein O43633 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 t miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. SIGNOR-265532 0.761 SEC61A1 protein P61619 UNIPROT SEC61 complex complex SIGNOR-C368 SIGNOR form complex binding -1 33925740 t lperfetto The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER SIGNOR-265279 0.757 PAX6 protein P26367 UNIPROT PAX6 protein P26367 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001874 17251190 f Regulation miannu Pax6-stimulated activity of the Pax6 promoter is repressed by TGFβ signalling. TGFβ receptor activation represses Pax6 promoter activity by releasing Pax6 from autoregulating its own promoter. SIGNOR-251873 0.2 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 12220227 t lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. SIGNOR-236725 0.912 MASP2 protein O00187 UNIPROT C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Gly1446 TPLQLFEgRRNRRRR -1 17204478 t lperfetto MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a). SIGNOR-263428 0.794 romidepsin chemical CHEBI:61080 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257991 0.8 RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 17251915 t gcesareni The mechanism by which pak1 induced cancer growth might involve activation of jnk in the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor. SIGNOR-152808 0.645 DUSP16 protein Q9BY84 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates binding 9606 BTO:0000938 12524447 t gcesareni Here we report that jip-1 also binds the dual-specificity phosphatases mkp7 and m3/6 via a region independent of its jnk binding domain. when mkp7 is bound to jip-1 it reduces jnk activation leading to reduced phosphorylation of the jnk target c-jun SIGNOR-97173 0.451 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM FGFR3 protein P22607 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259705 0.8 PDGFRA protein P16234 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 24743741 f To further investigate the signaling pathway through which PDGFRα promotes the proliferation of PDGFRα+ cells, we used inhibitors of PI3K-Akt and Ras-MAPK pathways, which are known to be downstream signaling pathways of PDGFRα SIGNOR-254376 0.353 PTPRE protein P23469 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR 9606 12754301 t llicata The effect of PTP epsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTP epsilon. Nonetheless, PTP epsilon is present in a molecular complex with ERK, providing PTP epsilon with opportunity to act on ERK proteins also directly. We conclude that PTP epsilon is a physiological inhibitor of ERK signaling|These enzymes are joined by the large family of dual-specificity phosphatases, which are structurally similar to tyrosine phosphatases but which can dephosphorylate both residues of the activation loop SIGNOR-248448 0.399 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269358 0.719 H4C1 protein P62805 UNIPROT BRD2 protein P25440 UNIPROT up-regulates activity relocalization 9606 acetylation:Lys21 GGAKRHRkVLRDNIQ 12776177 t lperfetto Thus, the TIP60 HAT complex is recruited to MYC-target genes and, probably with other other HATs, contributes to histone acetylation in response to mitogenic signals. SIGNOR-262062 0.2 SPRY4 protein Q9C004 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR down-regulates 9606 BTO:0002058 20501643 f miannu Spry4 expression induces a reversal of the epithelial to mesenchymal transition characteristic of tumor cells. Treatment of a non-transformed lung epithelial cell line with shRNA to Spry4 led to decreased expression of epithelial markers and increased cell growth, supporting the concept of Spry4 acting as a tumor suppressor. SIGNOR-253036 0.7 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-201695 0.8 POMT1 protein Q9Y6A1 UNIPROT POMT complex SIGNOR-C372 SIGNOR form complex binding 9606 BTO:0000007 16698797 t miannu  Here we have shown that POMT1 forms a complex with POMT2 and the complex possesses protein O-mannosyltransferase activity. Results indicate that POMT1 and POMT2 associate physically and functionally in vivo.  Mutations in the POMT1 and POMT2 genes are considered to be the cause of Walker-Warburg syndrome. Here, we have demonstrated that POMT1 and POMT2 form a functional complex in vivo using immunoprecipitating techniques. Furthermore, we showed that the mutations of POMT1 protein found in WWS patients do not prevent complex formation with POMT2 but they do abolish activity of the complex. SIGNOR-265428 0.587 ITCH protein Q96J02 UNIPROT ERBB4 protein Q15303 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 17463226 t miannu Interaction with the ErbB-4 receptors occurs via the WW domains of AIP4/Itch. Functional analyses demonstrate that AIP4/Itch is recruited to the ErbB-4 receptor to promote its polyubiquitination and degradation, thereby regulating stability of the receptor and access of receptor intracellular domains to the nuclear compartment.  SIGNOR-272618 0.59 MDM2 protein Q00987 UNIPROT TP73 protein O15350 UNIPROT down-regulates activity binding 9606 17700533 t miannu Since HDM2, a key negative regulator of p53, also binds to and inhibits p73, we asked whether p73 could mediate Nutlin-3-induced apoptosis. SIGNOR-255470 0.831 EGR1 protein P18146 UNIPROT NAB2 protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000848 20506119 f miannu In melanoma and carcinoma cells EGR1 activates NAB2 expression. we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells. Here, we show that like EGR1, EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NAB2 promoter and are more potent activators of NAB2 transcription than EGR2. SIGNOR-253881 0.611 TBCA protein O75347 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates quantity by stabilization binding 9606 28158450 t miannu These intermediates interact with a series of five tubulin-specific chaperones (termed TBCA-E); these function together as a nanomachine that assembles the α/β tubulin heterodimer SIGNOR-261169 0.2 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Thr219 ASLSLPAtPVGKGTE 10090 BTO:0000142 12796778 t llicata Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function. SIGNOR-250678 0.622 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Ser153 NRLKVLYsQKATPGS 9606 BTO:0000567 15525512 t llicata Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.  SIGNOR-250604 0.992 WNT1 protein P04628 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling. SIGNOR-169645 0.78 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu67 LERECMEeKCSFEEA 10090 BTO:0001103 11133752 t lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. SIGNOR-263691 0.67 TIMM44 protein O43615 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 t lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. SIGNOR-267689 0.718 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates activity phosphorylation Tyr760 TVTSTDEyLDLSAPF 9606 BTO:0000007 11294897 t lperfetto Ligand stimulation leads to autophosphorylation of fgfr3taken together, these results clearly implicate y724 in the activation of stat proteins by constitutively activated mutants of fgfr3 and suggest that both y724 and y760 are required for maximal stat activation. SIGNOR-106742 0.2 TRIB3 protein Q96RU7 UNIPROT COP1 protein Q8NHY2 UNIPROT up-regulates activity binding 9606 BTO:0000007 16794074 t miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). SIGNOR-271603 0.2 PBK protein Q96KB5 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation Ser533 AEMRGGRsPRPGSSA 9606 BTO:0002181 31378785 t miannu We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1.  SIGNOR-277472 0.2 CYP17A1 protein P05093 UNIPROT pregnenolone smallmolecule CHEBI:16581 ChEBI down-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268656 0.8 WNT7A protein O00755 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity 9606 BTO:0001103 21902831 f gcesareni Wnt1 and wnt7a stimulation of precursor cells activates protein kinase a (pka), which, through the phosphorylation of creb, induces the expression of the myogenic transcription factors myf5, myod and pax3, resulting in the myogenic commitment of embryonic precursors. SIGNOR-176575 0.2 SB-202190 chemical CHEBI:79090 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206697 0.8 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 f apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255357 0.621 SPAG9 protein O60271 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates binding 9606 BTO:0000222 17074887 t p38 MAPK is activated by phosphorylation in response to CDO-BOC interactions. Activated p38 MAPK may translocate into the nucleus to further activate myogenic related transcription factors. gcesareni Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants. SIGNOR-150147 0.422 ABL1 protein P00519 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates activity phosphorylation Tyr15 EKIGEGTyGTVFKAK 9534 BTO:0000298 10896159 t gcesareni Phosphorylation of Cdk5 by c-Abl occurs on tyrosine 15 (Y15), which is stimulatory for p35/Cdk5 kinase activity. SIGNOR-245288 0.567 CTH protein P32929 UNIPROT L-cystathionine dizwitterion smallmolecule CHEBI:58161 ChEBI down-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. SIGNOR-275822 0.8 MAPK1 protein P28482 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation Thr222 TSHNSLTtPCYTPYY 9606 8846784 t fstefani Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk. SIGNOR-44343 0.521 F2 protein P00734 UNIPROT F7 protein P08709 UNIPROT up-regulates activity 9606 BTO:0000131 29880919 t lperfetto Thrombin also activates the cofactors FVIII (to FVIIIa) and FV (to FVa) and activates platelets such that they provide a procoagulant membrane surface to which these proteins then bind SIGNOR-263529 0.305 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser40 ASAAGGLsPVTNLTV 9606 BTO:0000017 28192398 t miannu We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation.  SIGNOR-277340 0.638 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity dephosphorylation Tyr397 SVSETDDyAEIIDEE -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254717 0.245 CDK2 protein P24941 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates activity phosphorylation Ser151 DVSPYSLsPVSNKSQ BTO:0000007 12560341 t llicata  A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus.  SIGNOR-250732 0.734 CTTN protein Q14247 UNIPROT Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 9606 14684878 f miannu Cortactin is an F-actin binding protein and activator of the Arp2/3 actin nucleation machinery that also interacts with the postsynaptic density (PSD) protein Shank. Cortactin is concentrated in dendritic spines of cultured hippocampal neurons, and the N-terminal half of the protein containing the Arp2/3 and F-actin binding domains is necessary and sufficient for spine targeting. SIGNOR-266595 0.7 APH1A protein Q96BI3 UNIPROT PSENEN protein Q9NZ42 UNIPROT up-regulates binding 9606 12522139 t gcesareni Furthermore, overexpression of aph-1 facilitates pen-2-mediated ps1 proteolysis, resulting in a significant increase in ps1 fragments. Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex. SIGNOR-97104 0.962 LTK protein P29376 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9223670 t gcesareni Recently, we demonstrated that ltk utilizes shc and irs-1 as two major substrates and while both equally activate the ras pathway, only irs-1 suppresses apoptosis of hematopoietic cells. SIGNOR-49625 0.434 PPP2CA protein P67775 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity dephosphorylation 9606 24726876 t miannu RACK1 Negatively Regulates the Type I IFN pathway. Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection. SIGNOR-260944 0.319 PTK2 protein Q05397 UNIPROT CTNNB1 protein P35222 UNIPROT unknown phosphorylation Tyr142 AVVNLINyQDDAELA 10090 22264731 t VEGF pathway Gianni VEGF promotes tension-independent FAK activation, rapid FAK localization to cell-cell junctions, binding of the FAK FERM domain to the vascular endothelial cadherin (VE-cadherin) cytoplasmic tail, and direct FAK phosphorylation of β-catenin at tyrosine-142 (Y142) facilitating VE-cadherin-β-catenin dissociation and EC junctional breakdown. SIGNOR-261946 0.412 SP2 protein Q02086 UNIPROT PCYT1A protein P49585 UNIPROT down-regulates quantity by repression transcriptional regulation 7227 BTO:0001677 10744779 t Luana Sp3 is an activator, and Sp2 a repressor, of the Ctpct promoter in SL2 cells. SIGNOR-266230 0.2 CDK1 protein P06493 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser138 SLQLGAVsPGTLTPT 26933062 t lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. SIGNOR-276589 0.435 HCRTR2 protein O43614 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257008 0.255 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM3 protein P0DP25 UNIPROT up-regulates chemical activation 10090 10448861 t miannu Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. SIGNOR-266334 0.8 RUNX1 protein Q01196 UNIPROT ELF4/RUNX1 complex SIGNOR-C47 SIGNOR form complex binding 9606 BTO:0001271 10207087 t miannu We readily detected an in vivo physical interaction between mef and aml1 proteins in kasumi-1 cells/ coexpression of mef and aml1b synergistically activates promoter function SIGNOR-66963 0.357 MYC protein P01106 UNIPROT Enolase proteinfamily SIGNOR-PF74 SIGNOR up-regulates quantity transcriptional regulation 10116 10823814 t inferred from family member miannu C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway. SIGNOR-267785 0.421 GFI1 protein Q99684 UNIPROT EGR2 protein P11161 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16923394 f irozzo Importantly, overexpression of Gfi-1 in these cells resulted in the attenuation of both Egr-1 and Egr-2 expression, but not Nab-2. SIGNOR-256133 0.315 AKT1 protein P31749 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Thr90 EARHRVPtTELCRPP 9606 BTO:0000782;BTO:0001271 15930267 t miannu Akt phosphorylates tal1 oncoprotein and inhibits its repressor activity. / our results show that akt specifically phosphorylates thr90 of the tal1 protein within its transactivation domain in vitro and in vivo. SIGNOR-252479 0.382 FZD6 protein O60353 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 22944199 t amattioni When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp. SIGNOR-198828 0.665 HES5 protein Q5TA89 UNIPROT NEUROG2 protein Q9H2A3 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 f lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production SIGNOR-265143 0.419 PRKCB protein P05771 UNIPROT ILF3 protein Q12906 UNIPROT up-regulates activity phosphorylation Ser647 RGRGRGGsIRGRGRG 9606 20870937 t llicata Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our results support a model in which PMA stimulation activates PKCβI to phosphorylate NF90-Ser647, and this phosphorylation triggers NF90 relocation to the cytoplasm and stabilize IL-2 mRNA. SIGNOR-168173 0.2 IL17A protein Q16552 UNIPROT KLF2 protein Q9Y5W3 UNIPROT up-regulates transcriptional regulation 9606 23332504 f fspada Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic.  SIGNOR-210111 0.287 IL4R protein P24394 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates activity 10090 23582327 f Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis while inhibiting their differentiation into adipocytes SIGNOR-256482 0.7 AP3D1 protein O14617 UNIPROT Neuronal AP-3 complex SIGNOR-C445 SIGNOR form complex binding 9606 BTO:0000938 19497727 t miannu Mammals contain more than one AP-3 complex owing to the existence of pairs of genes encoding β3, μ3, and σ3 subunits (A and B isoforms). While both σ3A and σ3B are expressed ubiquitously and seem to be functionally equivalent, the B isoforms of β3 and μ3 display rather restricted expression patterns, mostly in cells of neuronal origin. This has led to the notion of the existence of two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising δ, β3A, μ3A, and σ3(A or B) subunits, and a brain-specific AP-3 complex containing δ, β3B, μ3B, and σ3(A or B) SIGNOR-268519 0.809 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr230 DSKEIFLtVPVGGGE 9606 19530738 t lperfetto We found that substitutions at borealin t230, recently identified as an mps1 phosphorylation site, can modulate the dimerization state of borealin. Mutation of this single residue to alanine or valine impairs aurora b activity during mitosis and causes chromosome segregation defects SIGNOR-186147 0.471 HSP90AB1 protein P08238 UNIPROT APAF1 protein O14727 UNIPROT down-regulates binding 9606 10944114 t gcesareni The present studies demonstrate that heat shock protein 90 (hsp90) forms a cytosolic complex with apaf-1 and thereby inhibits the formation of the active complex. SIGNOR-81043 0.397 HOXA10 protein P31260 UNIPROT PHGDH protein O43175 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19778996 f miannu PHGDH is expressed in both endometrial epithelial and stromal cells. HOXA10 represses endometrial PHGDH expression. SIGNOR-254468 0.303 PTEN protein P60484 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR down-regulates quantity by destabilization 16055704 f lperfetto PTEN represses RNA Polymerase I transcription by disrupting the SL1 complex SIGNOR-269645 0.282 HDAC2 protein Q92769 UNIPROT HPGD protein P15428 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 19010907 f miannu We show an interaction between Snail and HDAC2 and the binding of HDAC2 to the 15-PGDH promoter. These data suggest that class I HDACs, specifically HDAC2, and the transcriptional repressor Snail play a central role in the suppression of 15-PGDH expression. SIGNOR-254236 0.2 Erythrocytic spectrin complex SIGNOR-C384 SIGNOR Membrane_disruption phenotype SIGNOR-PH151 SIGNOR down-regulates 9606 24302288 f lperfetto Spectrin is multifunctional, and spectrin-based networks are important for maintaining the shape and mechanical properties of erythrocytes. SIGNOR-266028 0.7 CHUK protein O15111 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 15383283 t gcesareni Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites. SIGNOR-127064 0.404 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 BTO:0000661 11123317 t lperfetto Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5.  SIGNOR-249071 0.346 CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity cleavage 9606 14585074 t lperfetto Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation SIGNOR-90397 0.623 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 15611135 t gcesareni We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines. SIGNOR-132555 0.263 GNAQ protein P50148 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates binding 9606 8245028 t gcesareni The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits. SIGNOR-37149 0.759 BID protein P55957 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 12242151 t gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome c. these data support a two-class model for bh3 domains: bid-like domains that activate bax, bak and bad-like domains that sensitize by occupying the pocket of antiapoptotic members. SIGNOR-92942 0.816 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser246 DSVSDQFsVEFEVES 9606 20708156 t gcesareni Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination SIGNOR-167509 0.352 CD247 protein P20963 UNIPROT CD3 complex SIGNOR-C432 SIGNOR form complex binding 9606 12507424 t miannu The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules. SIGNOR-255290 0.693 nitric oxide smallmolecule CHEBI:16480 ChEBI NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 BTO:0001103 20219869 t apalma Similarly, exposure of cells to oxidative stress, in particular, nitric oxide (NO) or peroxynitrite (ONOO), can activate NF-kB and cause its translocation. SIGNOR-255350 0.8 TLN1 protein Q9Y490 UNIPROT AE/b7 integrin complex SIGNOR-C186 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257634 0.579 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA1 protein Q9Y5H4 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265708 0.2 PTGER1 protein P34995 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257083 0.425 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-235742 0.702 HOXB2 protein P14652 UNIPROT OTX2 protein P32243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000946 9556594 t Luana Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively SIGNOR-261634 0.262 AMPD1 protein P23109 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity chemical modification 9606 BTO:0001103 1631143 t miannu AMP deaminase (AMPD; EC 3.5.4.6) is encoded by a multigene family in mammals. The AMPD1 gene is expressed at high levels in skeletal muscle, where this enzyme is thought to play an important role in energy metabolism. AMP deaminase (AMPD; EC 3.5.4.6), an enzyme that catalyzes deamination of AMP to IMP, and the purine nucleotide cycle, of which AMPD is one component, play a central role in purine nucleotide interconversion in eukaryotic cells. SIGNOR-269773 0.8 YY1 protein P25490 UNIPROT SUZ12/EZH2/YY1 complex SIGNOR-C102 SIGNOR form complex binding 10090 20887952 t lperfetto TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter. SIGNOR-235580 0.2 ATF4 protein P18848 UNIPROT ASNS protein P08243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11960987 f miannu Transcription from the asparagine synthetase (A.S.) gene is increased in response to either amino acid (amino acid response) or glucose (endoplasmic reticulum stress response) deprivation. the results provide both in vitro and in vivo evidence for a role of ATF4 in the transcriptional activation of the A.S. gene in response to nutrient deprivation. SIGNOR-253747 0.636 PRKACA protein P17612 UNIPROT AKAP12 protein Q02952 UNIPROT up-regulates activity phosphorylation Ser698 RARRGSSsDEEGGPK -1 14657015 t lperfetto Following receptor activation, gravin binding to the receptor increases, a process dependent upon PKA-catalyzed phosphorylation of two canonical PKA sites (Ser696–698 and Ser772) located within the AKAP domain of gravin. SIGNOR-271844 0.2 CDK5 protein Q00535 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 15741232 t gcesareni Phosphorylation was observed 6 hours after p25 induction and was abolished in the presence of a cdk5 inhibitor, roscovitine, which does not inhibit the usual rb cyclin-d kinases cdk4 and cdk6. Furthermore, analyses of levels and subcellular localization of cdk-related cyclins did not reveal any change following cdk5 activation, arguing for a direct effect of cdk5 activity on rb protein. Rb phosphorylation was visualized using phosphorylation-dependent antibodies (p-rbser795 and p-rbser807/811). SIGNOR-134468 0.342 ITGB1BP1 protein O14713 UNIPROT ITGB8 protein P26012 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257667 0.318 PIM2 protein Q9P1W9 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 t done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  SIGNOR-273896 0.2 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Ser20 KRPQRATsNVFAMFD 9606 8702756 t miannu Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase. SIGNOR-261719 0.633 HOXB6 protein P17509 UNIPROT HBG1 protein P69891 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15269212 t Luana HOXB6 protein represses globin transcript levels in stably transfected K562 cells in a DNA-binding dependent fashion. SIGNOR-261638 0.2 afatinib chemical CHEBI:61390 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189359 0.8 AURKB protein Q96GD4 UNIPROT RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Ser207 TSVRRRTsFYLPKDA 9606 19276349 t llicata Here, we show that aurora a and b associate with and phosphorylate rassf1a on serine 203 aurora a regulates prometaphase progression by inhibiting the ability of rassf1a to suppress apc-cdc20 activity. SIGNOR-184561 0.45 NRXN2 protein P58401 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 22626542 t miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. SIGNOR-265461 0.265 lurasidone chemical CHEBI:70735 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10030 20404009 t Luana In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype. SIGNOR-259462 0.8 PCDHAC2 protein Q9Y5I4 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-269038 0.2 SB 505124 chemical CHEBI:100922 ChEBI ACVR1C protein Q8NER5 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206739 0.8 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 16076840 t gcesareni The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex. SIGNOR-139320 0.346 doramapimod chemical CHEBI:40953 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258208 0.8 DYRK1A protein Q13627 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates phosphorylation Ser167 FLISPPAsPPVGWKQ 9606 BTO:0000782 16126726 t gcesareni We show that rcan1 self-associates and forms multimers, and that this process is promoted by the dyrk1a-mediated phosphorylation of rcan1 at the thr(192) residue. these results suggest that the phosphorylation of rcan1 by dyrk1a stimulates the formation of insoluble aggregates upon aging. SIGNOR-139958 0.579 TAOK1 protein Q7L7X3 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates activity phosphorylation Thr208 TFGNKLDtFCGSPPY -1 18424437 t miannu MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase. SIGNOR-276164 0.424 GDF5 protein P43026 UNIPROT TRPS1 protein Q9UHF7 UNIPROT up-regulates activity relocalization 10090 BTO:0005092 18363966 t Regulation of localization miannu Treatment of cells with Gdf5 enhanced Trps1 protein levels and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner. Nuclear translocation of Trps1 was also induced by Gdf5. These effects were blocked by a dominant negative form of activin-linked kinase 6 (dn-Alk6) and by SB203580, an inhibitor of the p38 MAPK pathway. Conversely, Gdf5 expression was suppressed by the over-expression of Trps1. SIGNOR-251867 0.311 oxotremorine M chemical CHEBI:38322 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258654 0.8 ADCY4 protein Q8NFM4 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 t miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. SIGNOR-265006 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR SLC4A4 protein Q9Y6R1 UNIPROT up-regulates activity phosphorylation Ser1026 KKKKKKGsLDSDNDD 10090 11744745 t miannu Ser(982) in the C-terminus of kNBC1 is a target for PKA phosphorylation. Phosphorylation of Ser(982) in the sodium bicarbonate cotransporter kNBC1 shifts the HCO(3)(-) : Na(+) stoichiometry from 3 : 1 to 2 : 1 in murine proximal tubule cells Replacing Ser(982) at the C-terminus consensus PKA phosphorylation site with alanine resulted in a failure of PKA to phosphorylate the transporter and induce a stoichiometry shift. SIGNOR-263158 0.2 TOP2B protein Q02880 UNIPROT RELN protein P78509 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24463367 f lperfetto While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development SIGNOR-242207 0.2 SIK1 protein P57059 UNIPROT CRTC3 protein Q6UUV7 UNIPROT down-regulates phosphorylation Ser162 SALNRTNsDSALHTS 9606 BTO:0000007;BTO:0000567 16817901 t miannu These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities. SIGNOR-147703 0.428 VEGFC protein P49767 UNIPROT FLT4 protein P35916 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000763 9435229 t gcesareni Vegf-c, was isolated as a ligand for the tyrosine kinase vegfr-3 (flt4) SIGNOR-55205 0.934 AURKB protein Q96GD4 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Thr7 tSAARRSY -1 12686604 t lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro. SIGNOR-100173 0.449 GSK3A protein P49840 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates phosphorylation 9606 18042454 t miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. SIGNOR-159432 0.2 SREBF1 protein P36956 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12923220 t lperfetto IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells|evidence that IDH1 may regulate lipogenesis in hepatic cells SIGNOR-253132 0.286 F2RL2 protein O00254 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257301 0.358 SMOC1 protein Q9H4F8 UNIPROT Angiotensin-2 protein P01019-PRO_0000032458 UNIPROT up-regulates quantity 10090 30127878 f lperfetto In conclusion, the results of the present study suggested that SMOC1 silencing suppressed the Ang II-induced myocardial fibrosis of mouse MFBs through affecting the BMP2/Smad signaling pathway. SIGNOR-260403 0.2 SRPK1 protein Q96SB4 UNIPROT RBM8A protein Q9Y5S9 UNIPROT down-regulates phosphorylation Ser168 GGRRRSRsPDRRRR 9606 16100109 t gcesareni We demonstrate that y14 is phosphorylated at its repeated arginine/serine (rs) dipeptides, likely by sr protein-specific kinases. Phosphorylation of y14 abolished its interaction with ejc components as well as factors that function downstream of the ejc. SIGNOR-139555 0.264 GATA6 protein Q92908 UNIPROT RARB protein P10826 UNIPROT up-regulates quantity by expression 9606 BTO:0000195 24317510 f lperfetto Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2. SIGNOR-253154 0.296 KDM4B protein O94953 UNIPROT AR protein P10275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23435229 f miannu KDM4B enzymatic activity is required to enhance AR transcriptional activity SIGNOR-254541 0.336 torkinib chemical CHEBI:90679 ChEBI MTOR protein P42345 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258268 0.8 SGI-1776 chemical CID:24795070 PUBCHEM PIM2 protein Q9P1W9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206862 0.8 SP1 protein P08047 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10644769 f miannu these results indicate a role for both NF-Y and Sp1 in the transcriptional activation of the MDR1 gene by genotoxic stress, and indicate that YB-1, if involved, is not sufficient to mediate this activation. SIGNOR-253872 0.268 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257934 0.8 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1213 GSSDDVRyVNAFKFM 9606 9722576 t tpavlidou By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor. SIGNOR-59750 0.2 IPA-3 chemical CHEBI:101355 ChEBI PKN1 protein Q16512 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0003897 23894351 t lperfetto In the current study, an allosteric small molecule PAK1 inhibitor, IPA-3, was evaluated for the potential in suppressing hepatocarcinogenesis. Consistent with other reports, inhibition of PAK1 activity was observed in several human HCC cell lines treated with various dosages of IPA-3. SIGNOR-262017 0.8 MAPK7 protein Q13164 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser78 ANPSPPPsPSQQINL 9606 11254654 t lperfetto Bmk1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinasebmk1 activates sgk by phosphorylation at serine 78. SIGNOR-105728 0.396 MAPK14 protein Q16539 UNIPROT FOXC1 protein Q12948 UNIPROT up-regulates quantity by stabilization phosphorylation Ser241 PSPPQPLsPAAALGS 31650548 t lperfetto P38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation. SIGNOR-275913 0.2 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser413 SVHKLDVsRSPPLMV 9606 BTO:0000007 16862148 t lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). SIGNOR-249306 0.444 NCK1 protein P16333 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 10029 BTO:0000246 7862111 t lperfetto We also found that nck binds directly to the guanine nucleotide exchange factor sos. / by binding to sos, nckmay bring sos to cell membrane where the ras protein is located. SIGNOR-236321 0.599 RIPK2 protein O43353 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser446 DSIRLQIsNPDLKDR 9606 22412986 t lperfetto Activation of interferon regulatory factor 5 by site specific phosphorylation. Phosphorylation of carboxyl serines 451 and 462 appear the primary trigger of irf5 function in nuclear accumulation, transcription, and apoptosis. Rip2 activation of the irf5 aspartic acid substitutions showed a similar positive effect of s451d and s462d function in this assay SIGNOR-196524 0.309 COL4A5 protein P29400 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 35267698 t lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. SIGNOR-272349 0.425 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 t irozzo Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. SIGNOR-255877 0.2 MTHFR protein P42898 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000567 24769206 f miannu MTHFR promotes heterochromatin maintenance at the centromeric region. SIGNOR-263889 0.7 PRKCD protein Q05655 UNIPROT BLVRA protein P53004 UNIPROT up-regulates activity phosphorylation Ser21 VGVGRAGsVRMRDLR 22584576 t lperfetto LC-MS/MS analysis of PKCdelta-activated intact hBVR identified phosphorylated serine positions 21, 33, 230, and 237, corresponding to the hBVR Src homology-2 domain motif (Ser(230) and Ser(237)), flanking the ATP-binding motif (Ser(21)) and in PHPS sequence (Ser(33)) as targets of PKCdelta. |PKCdelta potentiated hBVR reductase activity and accelerated the rate of bilirubin formation. SIGNOR-275525 0.2 miR-142-3p mirna URS000075AE07_9606 RNAcentral MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR down-regulates quantity by repression post transcriptional regulation 10090 23132946 f irozzo In human leukemic cells with MLL rearrangements (e.g., MONOMAC-6 and THP-1 cells), we found that ectopic expression of miR-495 could significantly inhibit cell growth/proliferation and increase apoptosis while decreasing cell viability. SIGNOR-255883 0.4 FUS protein P35637 UNIPROT DHX9 protein Q08211 UNIPROT down-regulates activity relocalization 9606 BTO:0000793 27460707 t P35637:p.Pro525Leu (mutation causing interaction) We found that ALS mutants of FUS co-localized with Caprin-1, DDX3X, and DHX9 in cytoplasmic inclusions that could lead to the mis-regulation of their respective pathways, providing further clues to the mechanism of ALS pathogenesis.|FUS interacting proteins were sequestered into the cytoplasmic mutant FUS inclusions that could lead to their mis-regulation or loss of function, contributing to ALS pathogenesis. | We also demonstrated the co-localization of DHX9, DDX3X and Caprin-1 with cytoplasmic EGFP-P525L mutant FUS inclusions in primary cortical neurons SIGNOR-262810 0.459 CSNK2A2 protein P19784 UNIPROT SET protein Q01105-2 UNIPROT down-regulates phosphorylation Ser9 SAPAAKVsKKELNSN 9606 23374587 t The effect has been demonstrated using Q01105-2 miannu Ckii-mediated phosphorylation at ser9 hinders nuclear import of set SIGNOR-200802 0.262 OPRM1 protein P35372 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256711 0.586 CACNA1C protein Q13936 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30849329 t miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). SIGNOR-264325 0.8 TERT protein O14746 UNIPROT Immortality phenotype SIGNOR-PH47 SIGNOR up-regulates 11327115 f lperfetto Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers SIGNOR-252292 0.7 BAX protein Q07812 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates relocalization 9606 14585074 t Translocation from Mitochondria to Cytosol amattioni Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi SIGNOR-88590 0.318 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-236163 0.866 EEF1A2 protein Q05639 UNIPROT Translational_elongation phenotype SIGNOR-PH210 SIGNOR up-regulates 9606 23699257 f lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269394 0.7 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser634 TFLSPQCsPQHSPLG 9606 BTO:0000007 16141410 t In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity SIGNOR-251249 0.406 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr207 PRQDYSRtPGQVLSL 8355 22354989 t gcesareni We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop SIGNOR-249652 0.51 PPARG protein P37231 UNIPROT STAT3 protein P40763 UNIPROT down-regulates 9606 BTO:0000801 17681149 f lperfetto Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways SIGNOR-249556 0.385 GALR1 protein P47211 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256966 0.252 CAMK2A protein Q9UQM7 UNIPROT SYNGAP1 protein Q96PV0 UNIPROT up-regulates activity phosphorylation Ser1073 PPLQRGKsQQLTVSA -1 14970204 t miannu Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. The Major Phosphorylation Sites, Serines 764/765, 1058, and 1123, All Contribute to Regulation of GAP Activity of synGAP by CaMKII SIGNOR-262687 0.439 EIF4E protein P06730 UNIPROT eIF4F_complex complex SIGNOR-C44 SIGNOR form complex binding 9606 11408474 t miannu Eif4a interacts with a scaffold protein, eif4g, to form complexes that also contain the cap-binding protein eif4e, which binds the cap structure (m7gpppn_) at the 5_-end of the mrna. These complexes are termed eif4f. SIGNOR-108515 0.84 AT9283 chemical CID:11696609 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190017 0.8 NTN3 protein O00634 UNIPROT UNC5 proteinfamily SIGNOR-PF98 SIGNOR up-regulates activity binding 9606 BTO:0001484 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268185 0.478 CCKBR protein P32239 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257150 0.27 BTK protein Q06187 UNIPROT STAT5A protein P42229 UNIPROT up-regulates activity phosphorylation Tyr694 LAKAVDGyVKPQIKQ -1 11413148 t llicata Ectopically expressed BTK kinase domain was capable of tyrosine-phosphorylating STAT5A both in vitro and in vivo. BTK-mediated tyrosine phosphorylation of ectopically expressed wild type (but not Tyr(694) mutant) STAT5A enhanced its DNA binding activity. SIGNOR-250603 0.479 EFNB3 protein Q15768 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9484836 t gcesareni Ephrin-b3, a ligand for the receptor ephb3, expressed at the midline of the developing neural tube. SIGNOR-54711 0.814 KAT2A protein Q92830 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity acetylation 9606 SIGNOR-C465 34811519 t lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269593 0.2 CDK7 protein P50613 UNIPROT RARG protein P13631 UNIPROT up-regulates activity phosphorylation Ser79 EMVPSSPsPPPPPRV 9534 10748061 t Luana RARg Is Phosphorylated by cdk7 in Its B and F Regions | Mutation into alanine of Ser-77 and Ser-79 located in the A/B region reduced the transcriptional activity of hRARg1 (Fig. 9A), confirming that these phosphorylation sites are required for optimal transcription. SIGNOR-259852 0.393 GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268606 0.249 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-66767 0.738 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257999 0.8 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG4-LLGL1_variant complex SIGNOR-C509 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270904 0.523 GSK3B protein P49841 UNIPROT GRB14 protein Q14449 UNIPROT down-regulates activity phosphorylation Ser366 GCSSQSIsPMRSISE -1 28130417 t lperfetto Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3. SIGNOR-264869 0.329 Noncanonical PRC1 complex SIGNOR-C151 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 25533466 f miannu We show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. Interestingly, inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. SIGNOR-252248 0.7 GATA3 protein P23771 UNIPROT CEBPA protein P49715 UNIPROT down-regulates binding 9606 17139329 t fferrentino Whereas others, such as GATA2/3 and SMAD3, physically interact with C/EBPα to inhibit its transcriptional activity on the Pparg2 promoter. SIGNOR-250569 0.369 PLD2 protein O14939 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 18423386 f mrosina Altogether, these data suggest that PLD acting upstream of the MAP kinases ERK1/2 may play a key role in the regulation of IL-2 production by stimulated Jurkat cells. SIGNOR-254983 0.57 NEK2 protein P51955 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates phosphorylation Ser2394 LHHSLSHsLLAVAQA 9606 24695856 t lperfetto C-nap1 hyperphosphorylation triggers the loss of both oligomerization and, crucially, interaction with the core centriole proximal-end protein, cep135. All three of these sites were identified in our in vivo analysis but only two (s2234 and s2394) were identified as nek2 phosphorylation sites in vitro. SIGNOR-204837 0.765 BMX protein P51813 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates quantity phosphorylation Tyr12 NVLAKALyDNVAESP 10090 BTO:0002572 21937722 t miannu Recombinant Bmx kinase was found to effectively phosphorylate the wt CAS SH3 domain on Tyr-12 (Figure 2B). A novel phosphorylation site on CAS, Tyr-12 (Y12) within the ligand-binding hydrophobic pocket of the CAS SH3 domain, was identified and found to be enriched in Src-transformed cells and invasive human carcinoma cells.  SIGNOR-276384 0.52 ITGB7 protein P26010 UNIPROT AE/b7 integrin complex SIGNOR-C186 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253292 0.676 HIF-1 complex complex SIGNOR-C418 SIGNOR BNIP3 protein Q12983 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 t miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. SIGNOR-267454 0.388 oxymetazoline chemical CHEBI:7862 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258915 0.8 FOXO3 protein O43524 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0004245 10783894 t gcesareni AFX transcriptionally activates p27kip1, resulting in increased protein levels. SIGNOR-238610 0.737 PRKD1 protein Q15139 UNIPROT TLR5 protein O60602 UNIPROT up-regulates phosphorylation Ser805 YQLMKHQsIRGFVQK 9606 BTO:0002181 17442957 t lperfetto Pkd phosphorylated the tlr5-derived target peptide in vitro, and phosphorylation of the putative target serine 805 in hek 293t cell-derived tlr5 was identified by mass spectrometry. These results demonstrate that both pkd1 and pkd2 are required for inflammatory responses following tlr2, tlr4, or tlr5 activation, although pkd1 is more strongly involved SIGNOR-154473 0.36 MAPK11 protein Q15759 UNIPROT HBP1 protein O60381 UNIPROT up-regulates phosphorylation Ser402 GFSKNCGsPGSSQLS 9606 14612426 t lperfetto A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression. SIGNOR-119134 0.403 LPAR3 protein Q9UBY5 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257025 0.438 IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-216341 0.813 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu59 RKGNLEReCVEETCS -1 10556651 t lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. SIGNOR-263678 0.655 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR IGF1 protein P05019 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269258 0.34 PTPN6 protein P29350 UNIPROT LYN protein P07948 UNIPROT down-regulates activity dephosphorylation Tyr397 RVIEDNEyTAREGAK 10116 15537644 t SHP-1 efficiently inhibits Lyn autophosphorylation and suppresses FcϵRI stimulation|We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397 SIGNOR-248471 0.724 SCF-betaTRCP complex SIGNOR-C5 SIGNOR PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. SIGNOR-272751 0.523 MAP4K5 protein Q9Y4K4 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity phosphorylation 9606 16914735 t lperfetto Gckr can phosphorylate an n-terminal recombinant fusion protein of gsk3beta and enhance the in vivo phosphorylation of gsk3beta on serine 9reduction of gckr expression inhibits wnt3a-induced phosphorylation of gsk3beta at serine 9 and decreases the accumulation of cytosolic _-catenin. SIGNOR-228006 0.2 retinal smallmolecule CHEBI:15035 ChEBI all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI up-regulates quantity precursor of 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265121 0.8 EIF1 protein P41567 UNIPROT 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269161 0.659 MAP2K1 protein Q02750 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Thr125 PEVLRPEtPRPVDIG 12792650 t lperfetto Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK|The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2 SIGNOR-249385 0.45 Angiotensin-2 protein P01019-PRO_0000032458 UNIPROT AGTR1 protein P30556 UNIPROT up-regulates activity binding 9606 32201502 t MIANNU Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways SIGNOR-260238 0.2 SMURF1 protein Q9HCE7 UNIPROT ZFAND5 protein O76080 UNIPROT unknown ubiquitination -1 20804422 t miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. SIGNOR-272676 0.2 COL4A1 protein P02462 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 t Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6) SIGNOR-254665 0.7 TPX2 protein Q9ULW0 UNIPROT KIF11 protein P52732 UNIPROT down-regulates activity binding 26018074 t lperfetto Dimeric, but not monomeric, Eg5 was differentially inhibited by full-length and truncated TPX2, demonstrating that dimerization or residues in the neck region are important for the interaction of TPX2 with Eg5.  SIGNOR-265097 0.512 BAP1 protein Q92560 UNIPROT ASXL3 protein Q9C0F0 UNIPROT up-regulates activity binding 9606 BTO:0000189 32669118 t miannu We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers. SIGNOR-266761 0.546 ACTL6A protein O96019 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270847 0.577 BAIAP2 protein Q9UQB8 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10090 BTO:0001909 19171758 f miannu Ectopic expression of IRSp53 in mouse neuroblastoma N1E115 cells induces neurite outgrowth . Kank inhibits IRSp53-mediated neurite outgrowth in N1E115 cells SIGNOR-265555 0.7 NTRK1 protein P04629 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 BTO:0000938 10708759 t esanto Autophosphorylated trka binds directly to plc?, Abl, and shc. SIGNOR-75408 0.838 PPM1F protein P49593 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates dephosphorylation 9606 20016286 t gcesareni Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity. SIGNOR-162146 0.399 FOXO3 protein O43524 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222 18854138 f gcesareni Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. SIGNOR-181618 0.395 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser353 VQNKRRRsVTPPEEQ 9606 23708659 t lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. SIGNOR-252781 0.2 CDK1 protein P06493 UNIPROT STIP1 protein P31948 UNIPROT down-regulates activity phosphorylation Thr198 DEEEEIAtPPPPPPP 10090 BTO:0000944 14754904 t miannu Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions. A lower level of phosphorylation was observed for the double mutant, suggesting that T332 might also be phosphorylated by cdc2 kinase. SIGNOR-262727 0.267 serotonin smallmolecule CHEBI:28790 ChEBI HTR5A protein P47898 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264298 0.8 CDK1 protein P06493 UNIPROT DLG1 protein Q12959 UNIPROT unknown phosphorylation Ser443 FLGQTPAsPARYSPV 9606 19066288 t llicata We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor. SIGNOR-182757 0.402 Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 21812398 f miannu The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. SIGNOR-263723 0.7 EPGN protein Q6UW88 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 16829981 t gcesareni Areg (amphiregulin), btc (beta-cellulin), egf, epgn (epigen), ereg (epiregulin), hbegf, nrg1, nrg2, nrg3, nrg4 and tgfa (tgfalpha) constitute egf family ligands for erbb family receptors. SIGNOR-147835 0.403 Condensin II complex SIGNOR-C342 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 32445620 f miannu Human Condensin I and II Drive Extensive ATP-Dependent Compaction of Nucleosome-Bound DNA. the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263913 0.7 CAMK2A protein Q9UQM7 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000661 9686569 t gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. In vitro, ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. Altogether, our results favor an association of cam kinase ii activity with costimulatory signals of t lymphocyte activation and phosphorylation of stathmin on ser16. SIGNOR-59354 0.377 MRGPRX2 protein Q96LB1 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257260 0.2 NR3C1 protein P04150 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity transcriptional regulation 9606 26652733 f These results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/GR- and glucagon/CREB-signaling pathways on the key genes G6P and PEPCK. SIGNOR-256107 0.368 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1619 SPSYSPTsPSYSPTS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248804 0.849 PP2B proteinfamily SIGNOR-PF18 SIGNOR FLNA protein P21333 UNIPROT down-regulates quantity by destabilization dephosphorylation 9606 16442073 t inferred from 70% family members Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation. SIGNOR-269986 0.2 N-hydroxy-2-[4-[[(1-methyl-3-indolyl)methylamino]methyl]-1-piperidinyl]-5-pyrimidinecarboxamide chemical CHEBI:94771 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193513 0.8 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates phosphorylation Ser787 KAPEKRAsPSKPASA 9606 BTO:0000567 9398320 t lperfetto Map4 is phosphorylated by cdc2 kinase in mitotic hela/ phosphorylation by cdc2 kinase decreased the microtubule-stabilizing ability of map4, suggesting that there are critical phosphorylation sites among the five major cdc2 kinase-dependent phosphorylation sites [spots 4 (ser-696), 5, 6, 9, and 10 (ser-787)]. SIGNOR-53739 0.511 TRIM24 protein O15164 UNIPROT TP53 protein P04637 UNIPROT down-regulates ubiquitination 9606 19844164 t miannu New ring-domain e3-ubiquitin ligase trim24 that targets p53 for degradation SIGNOR-188726 0.547 PKA proteinfamily SIGNOR-PF17 SIGNOR HDAC4 protein P56524 UNIPROT up-regulates activity phosphorylation -1 30661366 t miannu  In vitro kinase assays have established that Ser584 and Ser265/266 are phosphorylated by protein kinase A (PKA). Overexpression of site-specific HDAC4 mutants (S584A, S265/266A) in HEK 293T cells, followed by HDAC activity assays, revealed the mutants to be less active than the wild-type protein. SIGNOR-277425 0.2 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN2 protein Q9H2S1 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 18955585 t Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  SIGNOR-258027 0.8 SMAD1 protein Q15797 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR form complex binding 9606 8893010 t ggiuliani Conversely, Smad1 and DPC4 formed a complex when the cells were stimulated with BMP4 but not with activin of TGF-beta. SIGNOR-255774 0.657 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Thr276 DGIMYYLtPQWDKIL 9823 21864610 t miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. SIGNOR-262920 0.337 trichostatin A chemical CHEBI:46024 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257940 0.8 SPI1 protein P17947 UNIPROT FCRL6 protein Q6DN72 UNIPROT up-regulates quantity by expression transcriptional regulation 12695521 f lperfetto Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression. SIGNOR-268966 0.208 N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide chemical CHEBI:91409 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190404 0.8 CRTC2 protein Q53ET0 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity binding 9606 26652733 t The cAMP-response element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a coactivator known to be specific to CREB and plays a central role in the glucagon-mediated activation of gluconeogenesis in the early phase of fasting SIGNOR-256102 0.909 WEE1 protein P30291 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 16096060 t gcesareni The wee1 kinase phosphorylates and inhibits cyclin-dependent kinase 1 (cdk1), thereby delaying entry into mitosis until appropriate conditions have been met SIGNOR-139491 0.853 clenbuterol chemical CHEBI:174690 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  SIGNOR-257862 0.8 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2J2 protein Q8N2K1 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271373 0.465 PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-236436 0.81 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258989 0.748 DDHD1 protein Q8NEL9 UNIPROT 1-acyl-sn-glycerol 3-phosphate smallmolecule CHEBI:16975 ChEBI up-regulates quantity chemical modification 9606 22922100 t miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. SIGNOR-269656 0.8 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 1303753 t gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. SIGNOR-16235 0.563 INO80D protein Q53TQ3 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270843 0.516 NEUROG3 protein Q9Y4Z2 UNIPROT NHLH1 protein Q02575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19028584 f miannu Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. Ngn3 overexpression increased the NSCL1-expressing domain corresponding to young ganglion cells SIGNOR-254634 0.266 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-267508 0.8 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser281 SGTPSSAsPALSRRG 10090 17213202 t lperfetto Serines 281 and 285 of the nfat3 protein might be target amino acids of rsk2 phosphorylationrsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo. SIGNOR-234465 0.393 AMPA proteinfamily SIGNOR-PF58 SIGNOR Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates -1 32527803 f inferred from family member Luana AMPAR surface diffusion tunes short-term plasticity. | Accordingly, recent studies have suggested that about half of synaptic AMPARs are organized in nanoclusters that are aligned with presynaptic transmitter release sites, supporting the concept of functional nanocolumns to increase the fidelity of fast excitatory transmission. This peculiar organization might also support the proposal that we made 10 years ago that fast surface diffusion of AMPARs tunes frequency-dependent short-term plasticity (FD-STP) by allowing the fast replacement of desensitized receptors by na√Øve ones. SIGNOR-267783 0.7 calcium(2+) smallmolecule CHEBI:29108 ChEBI FLNA protein P21333 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000132 27871158 t lperfetto Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step. Cofilin also binds to actin and contributes to the disassembly of actin filaments and the subsequent release of actin monomers. The actin cross-linking complex, GP1b/IX-filamin, translocates from the plasma membrane to the cytoskeleton during this step. SIGNOR-261845 0.8 PLK1 protein P53350 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity phosphorylation Ser378 AYHEGECsAVFEASG 9606 BTO:0002181 26387737 t miannu  Parkin Is Phosphorylated by Plk1 at Ser378 and Activated during Mitosis  SIGNOR-276938 0.2 PKC proteinfamily SIGNOR-PF53 SIGNOR MBD4 protein O95243 UNIPROT up-regulates activity phosphorylation Ser165 CSMAALTsHLQNQSN 23195996 t lperfetto Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12] SIGNOR-275675 0.2 JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 4932 9575217 t gcesareni Our mutational analysis suggests that the Stat5 SH2 domain is essential for the interaction with Jak2 and that the kinase domain of Jak2 is sufficient for Jak2-Stat5 interaction. Therefore, the Jak kinase domain may be all that is needed to cause Stat phosphorylation in situations where receptor docking is dispensable. [...] Most obviously, mutation of Tyr694 (Stat5a) or Tyr699 (Stat5b) to phenylalanine abolishes phosphorylation SIGNOR-56827 0.862 ACVR1 protein Q04771 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates phosphorylation 9606 9748228 t fspada Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2 SIGNOR-60171 0.749 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser398 VDLHISNsHPLSLTS -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178403 0.816 PREX1 protein Q8TCU6 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260569 0.708 MAF1 protein Q9H063 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR down-regulates activity binding 29378333 t lperfetto The synthesis of transfer RNA (tRNA) is directed by RNA polymerase III (Pol III) specialized in high-level transcription of short DNA templates. Pol III recruitment to tRNA genes is controlled by two general initiation factors, TFIIIB and TFIIIC. |Under stress conditions, tRNA synthesis is negatively regulated by the MAF1 protein, which interacts directly with Pol III. SIGNOR-266198 0.396 WWP1 protein Q9H0M0 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates activity ubiquitination 9606 15221015 t lperfetto Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-beta type I receptor to cause ubiquitination and degradation of the receptor. SIGNOR-227466 0.72 SOD1 protein P00441 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates 10090 BTO:0004488 18519638 f P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction) To investigate the role of ASK1 in the motor neurotoxicity by SOD1mut, we examined whether SOD1mut activates ASK1 as assessed by in vitro kinase assay. Expression of SOD1mut, but not SOD1wt, activated endogenous ASK1 (Fig. 4A, top panel). We next examined whether SOD1mut-induced ASK1 activation is mediated by ER stress. SIGNOR-262789 0.375 NAB2 protein Q15742 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22431919 f miannu Overexpression or short interfering RNA (siRNA)-mediated down-regulation of EGR1 or NAB2, and chromatin immunoprecipitations indicated that EGR1 and NAB2 act in concert to positively regulate p130(Cas)/BCAR1 expression in breast cancer cells. SIGNOR-253889 0.2 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 SIGNOR-C83 10428798 t gcesareni Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity. SIGNOR-69714 0.49 FOXJ1 protein Q92949 UNIPROT DNALI1 protein O14645 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23822649 t miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). SIGNOR-266933 0.403 PAMPs stimulus SIGNOR-ST11 SIGNOR AIM2 protein O14862 UNIPROT up-regulates activity 16037825 f lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-256423 0.7 FBLN5 protein Q9UBX5 UNIPROT ELN protein P15502 UNIPROT up-regulates activity binding 9606 18267938 t miannu The binding of tropoelastin fragments to fibulin-5 was directly proportional to their propensity to coacervate. Furthermore, the addition of fibulin-5 to tropoelastin facilitated coacervation. Taken together, the present study shows that fibulin-5 enhances elastic fiber formation in part by improving the self-association properties of tropoelastin. SIGNOR-252137 0.752 BBC3 protein Q9BXH1 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 t lperfetto Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis. SIGNOR-133811 0.751 P2RX7 protein Q99572 UNIPROT PLD2 protein O14939 UNIPROT up-regulates 9606 8573088 f mrosina This study shows that extracellular ATP, acting through the P2Z purinoceptor, stimulated PLD activity in human lymphocytes. SIGNOR-254966 0.2 GYS1 protein P13807 UNIPROT UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI down-regulates quantity chemical modification 9606 26882899 t miannu Glycogenin initiates the first step of glycogen synthesis by self glycosylation of a short 8–12 glucose oligosaccharide primer. Glycogen synthase (GYS) elongates the glucose oligossacharide primer, which utilises UDP-glucose as the glucosyl donor. SIGNOR-267938 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR ILF3 protein Q12906 UNIPROT up-regulates activity phosphorylation Ser647 RGRGRGGsIRGRGRG 9606 20870937 t llicata Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our previous work showed that CD28 costimulation of T cells activated AKT to phosphorylate NF90 at Ser647 and caused NF90 to undergo nuclear export and stabilize IL-2 mRNA. SIGNOR-168169 0.2 calcium(2+) smallmolecule CHEBI:29108 ChEBI PRKCZ protein Q05513 UNIPROT up-regulates chemical activation 9606 10777564 t gcesareni Wnt ligands working through frizzled receptors have a differential ability to stimulate release of intracellular calcium (ca(2+)) and activation of protein kinase c (pkc). SIGNOR-76991 0.8 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT3 protein Q9Y243 UNIPROT down-regulates activity chemical inhibition 25309440 t lperfetto Different agents were used to inhibit either the PI3K/Akt or MEK/ERK pathways. The PI3K inhibitor, LY294002, and the Akt inhibitor, Akt inhibitor VIII, were used to inhibit the PI3K/Akt pathway. SIGNOR-262012 0.8 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARB protein P10826 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 t Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  SIGNOR-258137 0.8 MAML1 protein Q92585 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 11101851 t gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1. SIGNOR-84827 0.921 D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of 9606 19401148 t miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. SIGNOR-268134 0.8 IKBKG protein Q9Y6K9 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser536 SGDEDFSsIADMDFS 9606 SIGNOR-C14 SIGNOR-C13 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-129947 0.857 PTPN22 protein Q9Y2R2 UNIPROT CBL protein P22681 UNIPROT down-regulates dephosphorylation Ser798 SDISNASsSFGWLSL 9606 BTO:0000782 10068674 t amattioni The tyrosine phosphatase lyp1 was found to be constitutively associated with the proto-oncogene c-cbl in thymocytes and t cells. Overexpression of lyp1 reduces cbl tyrosine phosphorylation. It is known that cbl is heavily tyrosine phosphorylated after tcr stimulation and can associate with the syk and zap tyrosine kinases, negatively regulating their activities. Tyrosine phosphatases keep cbl in a basally dephosphorylated state. SIGNOR-65405 0.395 topotecan chemical CHEBI:63632 ChEBI TOP1 protein P11387 UNIPROT down-regulates activity chemical inhibition 9606 11166732 t miannu Topotecan is a topoisomerase I inhibitor which is currently evaluated as an adjuvant agent for malignant glioma. SIGNOR-259317 0.8 CARM1 protein Q86X55 UNIPROT MAPK12/CARM1 complex SIGNOR-C218 SIGNOR form complex binding BTO:0001103 29681515 t apalma Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated SIGNOR-255980 0.347 ITGB1BP1 protein O14713 UNIPROT AD/b2 integrin complex SIGNOR-C172 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257654 0.292 ESR1 protein P03372 UNIPROT TGFA protein P01135 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 11517191 f ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression SIGNOR-253942 0.509 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 BTO:0000007 SIGNOR-C3 10579915 t lperfetto S6 kinases are under the control of the PI3K relative, mammalian Target Of Rapamycin (mTOR), which may serve an additional function as a checkpoint for amino acid availability. SIGNOR-72682 0.96 DUSP6 protein Q16828 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12840032 t inferred from 70% of family members gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). SIGNOR-269905 0.2 SGK1 protein O00141 UNIPROT WNK4 protein Q96J92 UNIPROT up-regulates activity phosphorylation Ser1201 FPTSRRNsLQRSEPP -1 23054253 t miannu In addition, we identified a novel SGK1 phosphorylation site (S1201) in WNK4, and phosphorylation at this site is reduced by Ca(2+)/CaM. SIGNOR-276421 0.425 PTPN5 protein P54829 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates activity dephosphorylation Tyr108 QPTAENAyEYFTKIA 9606 20959805 t In this study, we report that on apoptotic stimulation Bak undergoes dephosphorylation at tyrosine residue 108 (Y108), a critical event that is necessary but not sufficient for Bak activation, but is required both for early exposure of the occluded N-terminal domain and multimerisation. SIGNOR-248542 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GPHN protein Q9NQX3 UNIPROT down-regulates phosphorylation Ser268 ASLSTTPsESPRAQA 9606 BTO:0000142 23408424 t miannu Erk phosphorylates gephyrin at ser-268 to regulate size of gephyrin postsynaptic scaffold and strength of gabaergic transmission./ Ser-268 phosphorylation restricts gephyrin cluster size via calpain 1 proteolysis SIGNOR-200953 0.2 sufentanil chemical CHEBI:9316 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10030 21215785 t Luana Experiments were conducted to obtain K(i)'s for 19 approved opioid drugs using a single binding assay in a cell membrane preparation expressing recombinant human MOR. The K(i) values obtained ranged from 0.1380 nM (sufentanil) to 12.486 μM (tramadol).  SIGNOR-257890 0.8 CAMK2G protein Q13555 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates phosphorylation 9606 12482967 t gcesareni Camkii interacts with and phosphorylates tak1. SIGNOR-96422 0.2 GHSR protein Q92847 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257380 0.452 aclidinium chemical CHEBI:65346 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000131 19653626 t Luana This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. SIGNOR-258049 0.8 IKBKB protein O14920 UNIPROT COPS5 protein Q92905 UNIPROT down-regulates activity phosphorylation Ser201 KPPDEGPsEYQTIPL -1 31950832 t lperfetto Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. SIGNOR-275518 0.336 SRC protein P12931 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr168 TLMEKDSyPRFLKSP 9606 12588871 t miannu Src-mediated rgs16 tyrosine phosphorylation promotes rgs16 stability. / this result suggests src phosphorylates native rgs16 at residue tyr177 in vitro. SIGNOR-98271 0.353 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates binding 9606 BTO:0001130 1010227 t gcesareni Progressive increase in akt activation during prostate cancer progression led to increase phosphorylation of foxo3a and binding with 14-3-3, which potentially affected its transcriptional activity in age-specific manner. SIGNOR-15849 0.2 EGR2 protein P11161 UNIPROT NAB2 protein Q15742 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 20506119 f miannu In T lymphocytes EGR2 and EGR3 have been shown to inhibit NAB2 expression. SIGNOR-253885 0.593 PRKDC protein P78527 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser435 LTVLNAFsQAPSTMQ -1 8407951 t lperfetto  The carboxyl-terminal transcription activation domain was mapped within a 71-amino acid region that contains both DNA-PK phosphorylation sites. Amino acid substitutions that interfered with phosphorylation by DNA-PK at Ser-435/446 in GAL4-SRF fusion proteins were reduced in transactivation potency. From these data we suggest that DNA-PK phosphorylation may modulate SRF activity in vivo. SIGNOR-248921 0.415 AKT2 protein P31751 UNIPROT STXBP4 protein Q6ZWJ1 UNIPROT down-regulates activity phosphorylation Ser99 GAKLRLEsAWEIAFI 10029 BTO:0000246 15753124 t miannu Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. These data demonstrate that insulin activation of Akt2 specifically regulates the docking/fusion step of GLUT4-containing vesicles at the plasma membrane through the regulation of Synip phosphorylation and Synip-Syntaxin4 interaction.Thus, our data demonstrate that insulin-stimulated Akt2-dependent phosphorylation of Synip on serine residue 99 results in reduced binding interactions between Synip and Syntaxin4. SIGNOR-262635 0.431 SP1 protein P08047 UNIPROT UGCG protein Q16739 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000738 15342415 f miannu the results suggest that transcriptional up-regulation of GCS through DOX-induced activation of Sp1 is one potential mechanism to regulate ceramide increase and apoptosis in HL-60/ADR cells. SIGNOR-255205 0.2 MAPK3 protein P27361 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Ser1185 GTPPASTsPFSQLAA 9606 BTO:0001130 12163482 t lperfetto Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein SIGNOR-91139 0.271 CDK2 protein P24941 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates phosphorylation Ser76 VQDTSGTsPVHDAAR 9606 22558186 t lperfetto Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively. Nuclear translocation of p19ink4d induced by dna damage was shown to be dependent on serine 76 phosphorylation. SIGNOR-197270 0.528 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM2A protein Q9Y2K7 UNIPROT up-regulates activity chemical activation 29981745 t lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. SIGNOR-273478 0.8 PRKCE protein Q02156 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Ser87 AARARFEsKVPSFYY 12893243 t lperfetto The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚ | The phosphorylation site analysis was carried out twice after phosphorylation of centaurin-alpha1‚ with PKCalpha and once with PKC_. A similar pattern of phosphopeptides was obtained each time. SIGNOR-249224 0.318 GFI1B protein Q5VTD9 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 21261500 f miannu Here, we analyzed the MEF2C 5'-region, thus identifying potential regulatory binding sites for GFI1B, basic helix-loop-helix proteins, STAT5, and HOXA9/HOXA10. Chromatin immunoprecipitation and overexpression analyses demonstrated direct activation by GFI1B and LYL1 and inhibition by STAT5. SIGNOR-254206 0.286 OPRK1 protein P41145 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256989 0.354 NR3C1 protein P04150 UNIPROT LCK protein P06239 UNIPROT up-regulates binding 9606 16888650 t gcesareni The present study shows that the GC receptor is part of a TCR-linked multiprotein complex containing heat-shock protein (HSP)90, LCK and FYN, which is essential for TCR-dependent LCK/FYN activation. SIGNOR-251685 0.362 MECP2 protein P51608 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000452 26214522 t Luana In this study, we have demonstrated that the PTPN1 gene, which encodes PTP1B, was a direct target of MECP2 and that PTP1B protein levels were dramatically increased in Mecp2-mutant mice and in fibroblasts derived from patients with RTT. SIGNOR-264546 0.2 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259000 0.44 NANOG protein Q9H9S0 UNIPROT GATA6 protein Q92908 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 f miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. SIGNOR-254627 0.471 TALDO1 protein P37837 UNIPROT D-erythrose 4-phosphate(2-) smallmolecule CHEBI:16897 ChEBI up-regulates quantity chemical modification 9606 19401148 t miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (‚Äúdihydroxyacetone‚Äù) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. SIGNOR-267092 0.8 GSK3B protein P49841 UNIPROT CEBPA protein P49715 UNIPROT up-regulates activity phosphorylation Thr226 HLQPGHPtPPPTPVP 10090 BTO:0000944 10567568 t Glycogen synthase kinase 3 (GSK3) phosphorylates T222 and T226, causing a conformational change in C/EBPα. GSK3-mediated phosphorylation does not, in itself, dramatically alter the activity of C/EBPα in our assays. phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes. SIGNOR-251231 0.387 PTPRG protein P23470 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 BTO:0000876 25624455 t miannu Deeper examination shows that JAKs are critically involved in integrin-mediated monocyte adhesion and that PTPRG activation leads to JAK2 dephosphorylation on the critical 1007–1008 phosphotyrosine residues, implying JAK2 inhibition and thus explaining the antiadhesive role of PTPRG. SIGNOR-254690 0.291 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CEBPA protein P49715 UNIPROT up-regulates transcriptional regulation 10090 BTO:0000011 12270934 f lperfetto We demonstrate that exposure of post-confluent 3T3-L1 preadipocytes to insulin, isobutylmethylxanthine (MIX), dexamethasone (DEX), and fetal bovine serum induces a rapid but transient activation of MEK1 as indicated by extensive phosphorylation of ERK1 and ERK2 during the initial 2 h of adipogenesis. We further show that activation of MEK1 significantly enhances the transactivation of the C/EBPalpha minimal promoter during the early phase of the differentiation process. SIGNOR-235322 0.2 IL15RA protein Q13261 UNIPROT TIMP3 protein P35625 UNIPROT up-regulates 9606 30029643 f areggio Since recent study demonstrated desert Hedgehog (DHH) signaling can repressed FAP-derived adipocyte differentiation through Timp3 [30], we tested the mRNA expression of DHH and Timp3 in injured muscle with injection of IL-15. As expected, mRNA levels of DHH and Timp3 were both upregulated (Fig. 2f). SIGNOR-256232 0.2 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG3-LLGL2_variant complex SIGNOR-C504 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270884 0.536 Condensin I complex SIGNOR-C341 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 32445620 f miannu Human Condensin I and II Drive Extensive ATP-Dependent Compaction of Nucleosome-Bound DNA. the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263907 0.7 vorinostat chemical CHEBI:45716 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257948 0.8 SLBP protein Q14493 UNIPROT H2BC17 protein P23527 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265379 0.2 quizartinib chemical CHEBI:90217 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206331 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation 9606 18694962 t Translocation from Nuleus to Cytoplasm gcesareni Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. SIGNOR-270131 0.2 PRKACA protein P17612 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD -1 9016641 t miannu PKA catalytic subunit phosphorylates ATF-1 at Ser63 and that phosphorylation is essential for efficient DNA binding by ATF-1. SIGNOR-250336 0.439 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 HPGFDAEsYTFTVPR 23972993 t For phosphorylated residues see Figure 7 lperfetto Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP SIGNOR-274051 0.419 MAPK1 protein P28482 UNIPROT SP3 protein Q02447 UNIPROT up-regulates phosphorylation Ser73 CSKIGPPsPGDDEEE 9606 17685427 t llicata Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73. in the inducible cell lines, expression of wild-type form of sp3 increases vegf production whereas the s73a form has a reduced potential reflecting its lower transcriptional activity. SIGNOR-157272 0.31 CSNK2A1 protein P68400 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by destabilization phosphorylation Ser215 IKEEDTPsDNDSGIC 9606 BTO:0000567 23123191 t miannu By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form.  SIGNOR-276425 0.2 NRTN protein Q99748 UNIPROT GFRA1 protein P56159 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9182803 t gcesareni A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling SIGNOR-49119 0.728 CLTB protein P09497 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR form complex binding 9606 24789820 t lperfetto AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly.  SIGNOR-260666 0.761 MMP13 protein P45452 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Leu442 TSKGDKElRTGKEKV -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain SIGNOR-263613 0.2 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser24 APIRRRSsNYRAYAT -1 11121119 t lperfetto In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation. SIGNOR-249067 0.349 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1214 VCDPKFHyDNTAGIS 9606 BTO:0000007 18840653 t We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well. SIGNOR-248401 0.547 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89284 0.402 PTPRR protein Q15256 UNIPROT PXN protein P49023 UNIPROT down-regulates activity dephosphorylation Tyr88 PQSSSPVyGSSAKTS 9606 20133777 t Here, we show that paxillin is a direct substrate of PTPRT and that PTPRT specifically regulates paxillin phosphorylation at tyrosine residue 88 (Y88) in colorectal cancer (CRC) cells. We engineered CRC cells homozygous for a paxillin Y88F knock-in mutant and found that these cells exhibit significantly reduced cell migration and impaired anchorage-independent growth, SIGNOR-248720 0.2 LRIG1 protein Q96JA1 UNIPROT EGFR protein P00533 UNIPROT down-regulates binding 9606 BTO:0001253 15282549 t gcesareni Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation SIGNOR-127304 0.726 DLG4 protein P78352 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity relocalization 9606 9278515 t brain lperfetto The PDZ domains of PSD-95 and related proteins interact with the COOH-terminal sequences of K+channels and NMDA2 receptors (3). By these interactions, PSD-95 may mediate the clustering of K+ channels and NMDA receptors at synapses. SIGNOR-264195 0.817 BLOC1S2 protein Q6QNY1 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 22203680 t lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. SIGNOR-265937 0.716 AKT proteinfamily SIGNOR-PF24 SIGNOR NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 10559253 t esanto Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis. SIGNOR-72137 0.2 DRD3 protein P35462 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256981 0.453 HTR6 protein P50406 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256944 0.36 naproxen chemical CHEBI:7476 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 9057869 t miannu Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). SIGNOR-258602 0.8 EGFR protein P00533 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000150 22693070 t lperfetto The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation. SIGNOR-235692 0.875 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 t lperfetto Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes. SIGNOR-252321 0.635 GTF2H2C protein Q6P1K8 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 t lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269317 0.712 CCP110 protein O43303 UNIPROT CALM2 protein P0DP24 UNIPROT up-regulates activity binding 9606 BTO:0000007 16760425 t miannu We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis. SIGNOR-266332 0.2 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser63 AAEERRKsHEAEVLK 9606 8125092 t gcesareni Phosphorylation of either serine 16 or 63 is sufficient to inhibit stathmin in vitro. Phosphorylation at ser-63 reduces tubulin binding 10-fold and suppresses the mt polymerization inhibition activity. SIGNOR-36374 0.314 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Ser497 SSNIQMDsGYNTQNC 9606 18521620 t gcesareni Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp). SIGNOR-178803 0.779 MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18676376 f gcesareni € provide a novel transcriptional paradigm for the first steps of myogenesis, where a calcineurin/NFATc3 pathway regulates myogenin induction in cooperation with MyoD during myogenesis. SIGNOR-235009 0.437 APC-c complex SIGNOR-C150 SIGNOR FBXW5 protein Q969U6 UNIPROT down-regulates quantity by destabilization ubiquitination 21725316 t lperfetto We show that FBXW5 levels are controlled by the anaphase-promoting (APC/C) complex, which targets FBXW5 for degradation during mitosis and G1, thereby helping to reset the centrosome duplication machinery. SIGNOR-275477 0.374 PTPRJ protein Q12913 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by stabilization dephosphorylation Tyr1092 TFLPVPEyINQSVPK 9606 BTO:0000567 19836242 t We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex|By employing commercially available antibodies, which are supposed to recognize specific tyrosine phosphorylation sites of EGFR, we found that depletion of endogenous DEP-1 nonselectively increased receptor phosphorylation, affecting all three sites we analyzed (tyrosines 1045, 1068, and 1173 SIGNOR-248698 0.504 SKP2 protein Q13309 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR form complex binding 9606 15340381 t gcesareni The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions. SIGNOR-243560 0.925 CDO1 protein Q16878 UNIPROT SHH protein Q15465 UNIPROT up-regulates binding 9606 BTO:0000887 16647304 t gcesareni Cdo and boc bind shh through a high-affinity interaction with a specific fibronectin repeat that is essential for activity. We propose a model where cdo and boc enhance shh signaling within its target field. SIGNOR-146461 0.2 PTEN protein P60484 UNIPROT GLI1 protein P08151 UNIPROT down-regulates 9606 17845852 f PTEN is a suppressor of RAS-AKT function gcesareni Moreover, suppressors of ras akt function, such as the tumor-suppressor pten, and the attenuation of ras signaling involved in senescence, could be thus viewed as modulators of the gli code SIGNOR-157776 0.361 FOXO1 protein Q12778 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17873901 f gcesareni Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity SIGNOR-157839 0.276 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT unknown phosphorylation Ser426 CSLLLDSsLSSNWDD 9606 BTO:0000567 12738781 t lperfetto These results suggest that Ser-426 is a major phosphorylation site by Plk1, and Thr-495 is a second major site.  SIGNOR-249207 0.709 AXIN1 protein O15169 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR form complex binding 9606 BTO:0000586 9734785 t lperfetto Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level. SIGNOR-227292 0.93 LLGL1 protein Q15334 UNIPROT Scribble_complex_DLG4-LLGL1_variant complex SIGNOR-C509 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270903 0.526 HSPA1B protein P0DMV9 UNIPROT ENPP1 protein P22413 UNIPROT up-regulates quantity post transcriptional regulation 9606 19083193 t miannu We demonstrated the binding of heat shock protein 70 (HSP70) to ENPP1-3'UTR. Through this binding, HSP70 stabilizes ENPP1 mRNA and increases ENPP1 transcript and protein levels. This positive modulation of ENPP1 expression is paralleled by a reduced insulin-induced IR and IRS-1 phosphorylation. SIGNOR-252198 0.2 JUN protein P05412 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding -1 3142692 t irozzo The c-Jun and c-fos proto-oncogenes encode proteins that form a complex which regulates transcription from promoters containing AP-1 activation elements. c-Jun has specific DNA binding activity, while c-Fos has homology to the putative DNA binding domain of c-Jun. SIGNOR-256365 0.951 MAPK14 protein Q16539 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 10806218 t gcesareni More importantly, incubation of active erk2 or p38 kinase with h3 protein resulted in phosphorylation of h3 at serine 10 in vitro. These results suggest that erk and p38 kinase are at least two important mediators of phosphorylation of h3 at serine 10. SIGNOR-265338 0.2 SCN11A protein Q9UI33 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 t miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. SIGNOR-253407 0.8 CEBPB protein P17676 UNIPROT GOT1 protein P17174 UNIPROT up-regulates quantity by expression transcriptional regulation 8454627 t In cotransfection experiments, the C/EBP beta protein trans-activated 10-15-fold the cAspAT gene promoter in HepG2 cells. Deletion studies revealed that regions P2 and P4 are critical for promoter activity. In gel retardation experiments, the P4 region bound different C/EBP-related proteins in different tissues SIGNOR-254051 0.2 ANO6 protein Q4KMQ2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 24663380 f miannu Using a shRNA KD approach, we show that Ano6-KD C2C12 myoblasts exhibit reduced proliferation capacity. Our data demonstrate that Ano6 is required to maintain the proliferative status of myoblasts. SIGNOR-261213 0.7 STUB1 protein Q9UNE7 UNIPROT HSPA8 protein P11142 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 11676916 t miannu BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association SIGNOR-272588 0.731 U50488 chemical CHEBI:73358 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 9262330 t miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. SIGNOR-258666 0.8 TRIM26 protein Q12899 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25763818 t miannu TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus.  SIGNOR-272440 0.659 ELAVL3 protein Q14576 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates quantity post transcriptional regulation 9606 19221430 t miannu Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure SIGNOR-266864 0.2 ACP1 protein P24666 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 10090 17353188 t Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3 SIGNOR-248458 0.327 WAVE complex complex SIGNOR-C271 SIGNOR ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000132 27871158 t lperfetto Cdc42 can induce Arp2/3-mediated filopodia formation through the activation of WASp (Wiskott-Aldrich syndrome proteins) and neuronal N-WASp (Rohatgi et al., 1999). Similarly, Rac1-enhanced lamellipodia formation is related to Arp2/3 activation by the WAVE (WASP-family verprolin-homologous) complex SIGNOR-261876 0.527 STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11159537 f miannu STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma. SIGNOR-253050 0.697 CSNK2A2 protein P19784 UNIPROT EEF1B2 protein P24534 UNIPROT unknown phosphorylation Ser112 GSDDEEEsEEAKRLR -1 8547318 t llicata EF-1 beta was highly phosphorylated by casein kinase II, with up to 1.3 mol of phosphate incorporated per mol protein. From microsequence analysis and manual Edman degradation, the majority of the phosphate was shown to be present in serine 106 in the peptide DLFGS106DDEEES112EEA. Serine 112 was also phosphorylated by casein kinase II, but to a lesser extent. SIGNOR-250988 0.342 PDK1 protein Q15118 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates activity phosphorylation Thr779 LYKEATStFTNITYR -1 10896934 t miannu PDK1 specifically phosphorylates Thr-753 in 3. Our data argue that phosphorylation of Thr-753, which is conserved in many subunits, reduces the ability of PTB-containing proteins to bind the NXX(pY) motif in 3. SIGNOR-250264 0.31 DLG3 protein Q92796 UNIPROT NMDA receptor_2C complex SIGNOR-C349 SIGNOR up-regulates activity relocalization BTO:0000227 32904533 t lperfetto DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses. SIGNOR-266008 0.67 alvimopan chemical CHEBI:135686 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition -1 18313920 t Luana A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, l opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective l opioid receptor antagonist, which interacts selectively with l peripheral receptors. SIGNOR-257773 0.8 EEF1A1 protein P68104 UNIPROT Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269503 0.8 acadesine chemical CHEBI:28498 ChEBI AMPK complex SIGNOR-C15 SIGNOR up-regulates chemical activation 9606 16879084 t lperfetto The activation of the ampk pathway by exendin-4 was induced by aicar, which was inhibited by compound c. SIGNOR-217478 0.8 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-66771 0.738 PPP2CA protein P67775 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 t In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. SIGNOR-248645 0.429 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser293 FNTLAFPsMKRKDVV -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276130 0.644 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. SIGNOR-157089 0.2 PIK3CA protein P42336 UNIPROT AKT2 protein P31751 UNIPROT up-regulates 9606 BTO:0000586 16293724 f gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. SIGNOR-141814 0.657 CTTN protein Q14247 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 10116 23015759 f miannu Through alternative splicing, a single CTTNBP2 gene encodes three different transcripts, namely short (S), long (L), and intron forms. The interaction with cortactin is required for the function of CTTNBP2-S in dendritic spine formation because the CTTNBP2-S mutant, which no longer interacts with cortactin, is unable to rescue the spine defects resulting from CTTNBP2 knockdown. Thus CTTNBP2-S may control cortactin–F-actin cytoskeletons and regulate the formation and maintenance of dendritic spines in neurons. SIGNOR-261696 0.7 JUN protein P05412 UNIPROT TCF4 protein P15884 UNIPROT up-regulates binding 9606 16007074 t gcesareni Phosphorylation-dependent interaction between c-jun and tcf4;c-jun and tcf4 cooperatively activated the c-jun promoter in reporter assays SIGNOR-138544 0.401 MECOM protein Q03112 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 9665135 t miannu Evi-1 interacts with smad3, an intracellular mediator of tgf-beta signalling, thereby suppressing the transcriptional activity of smad3. SIGNOR-59132 0.504 CSNK2A1 protein P68400 UNIPROT FANCD2 protein Q9BXW9 UNIPROT down-regulates activity phosphorylation Ser886 TSSSDTLsEEKNSEC 9606 BTO:0000567 31167143 t miannu Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations.  SIGNOR-276731 0.2 RPS6KB1 protein P23443 UNIPROT RICTOR protein Q6R327 UNIPROT down-regulates phosphorylation Thr1135 NRRIRTLtEPSVDFN 9606 19995915 t gcesareni Phosphorylation of rictor on thr1135 did not affect mtorc2 assembly, kinase activity, or cellular localization. However, cells expressing a rictor t1135a mutant were found to have increased mtorc2-dependent phosphorylation of akt SIGNOR-161995 0.738 PAX7-FOXO1 fusion protein SIGNOR-FP11 SIGNOR SUV39H1 protein O43463 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23435416 f lperfetto In addition, KMT1A has recently been shown to play a role in ARMS by inhibiting myogenic differentiation. Although not shown directly, the authors speculated that KMT1A levels may be regulated by PAX3-FOXO1, as KMT1A expression was only increased on induction of differentiation in PAX3-FOXO1 positive cell lines SIGNOR-249598 0.2 HMOX1 protein P09601 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000356 26722274 f irozzo Heme oxygenase-1 (HO-1) protects endothelial cells (EC) from undergoing apoptosis. These results indicated that HMOX-1 may be involved in conferring the chemoresistance of breast cancer cells, by preventing apoptosis and autophagy. SIGNOR-256559 0.7 MAPK3 protein P27361 UNIPROT MYB protein P10242 UNIPROT down-regulates phosphorylation Ser532 KIKQEVEsPTDKSGN 9606 8798443 t llicata Here we describe that human c-myb can be phosphorylated by mitogen-activated protein kinases (mapk's) at serine 532 of the carboxy (c-) terminal regulatory domain in vitro. expression of a constitutively active form of ras together with c-myb in transient transfection experiments had no effect on the transcriptional activity of c-myb, while expression of a polypeptide containing the c-myb c-terminal domain stimulated c-myb activity. This effect is reduced upon mapk-dependent phosphorylation of serine 532. SIGNOR-43558 0.306 CDX2 protein Q99626 UNIPROT MEP1A protein Q16819 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22326557 t TNF-α-induced down-regulation of CDX2 suppresses MEP1A expression in colitis| SIGNOR-253965 0.483 PDPK1 protein O15530 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 15802604 t gcesareni We demonstrate that 3-phosphoinositide-dependent kinase 1 (pdk1) has an essential role in this pathway by regulating the activation of pkc and through signal-dependent recruiting of both pkc and card11 to lipid rafts. SIGNOR-134869 0.553 MLXIPL protein Q9NP71 UNIPROT FAS protein P25445 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 15496471 t Luana The present study provides evidence for a direct and dominant role of ChREBP in the glucose regulation of two key liver lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) SIGNOR-267947 0.2 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser80 PPNPEDRsPSPEPIY 9606 23175611 t The effect has been demonstrated using Q15637-2 gcesareni Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding. SIGNOR-199793 0.416 PI4K2B protein Q8TCG2 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269102 0.8 PTPRF protein P10586 UNIPROT FYN protein P06241 UNIPROT down-regulates dephosphorylation Tyr420 RLIEDNEyTARQGAK 9606 12496362 t lperfetto Regulation of lck and fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule. SIGNOR-96768 0.405 SRC protein P12931 UNIPROT INPPL1 protein O15357 UNIPROT up-regulates phosphorylation Tyr986 NSFNNPAyYVLEGVP 9606 12235291 t lperfetto Ship2 could be phosphorylated in vitro by recombinant src kinase and tyrosines 986-987 in the npxy motif of ship2 appear to be the major sites of phosphorylation for src both in vitro and in vivo. SIGNOR-92931 0.55 YES1 protein P07947 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity phosphorylation 9606 BTO:0002181 26198631 t miannu YY1 phosphorylation is mediated by Src family kinases. SIGNOR-276941 0.2 OGG1 protein O15527 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). SIGNOR-275715 0.7 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258002 0.8 DRD3 protein P35462 UNIPROT GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 21303898 t miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC SIGNOR-264994 0.428 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr468 DSGISTDySSGDSQG 12441334 t JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 SIGNOR-251352 0.805 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser291 PVSSLQAsVPGSVPG 9606 16027724 t llicata Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo. SIGNOR-250729 0.488 SYK protein P43405 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Tyr133 EMPSEEGyQDYEPEA 9606 BTO:0000975;BTO:0000142 11744621 t llicata Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers. SIGNOR-113065 0.512 ZDHHC2 protein Q9UIJ5 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity palmitoylation Cys3 cLCIVTTK 9606 23836932 t Plasma membrane targeting of DHHC2 palmitoyltransferase rapidly recruited PSD-95 to the plasma membrane and proved essential for postsynaptic nanodomain formation. SIGNOR-262296 0.388 PYGL protein P06737 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI down-regulates quantity chemical modification 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [‚Ķ] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267392 0.8 PRKACA protein P17612 UNIPROT CAD protein P27708 UNIPROT unknown phosphorylation Ser1859 PPRIHRAsDPGLPAE 11986331 t miannu CAD is down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation. SIGNOR-250343 0.312 ZFP36 protein P26651 UNIPROT EIF4E2/GIGYF2 complex complex SIGNOR-C257 SIGNOR up-regulates activity relocalization 9606 30917308 t lperfetto A key factor in this regulation is tristetraprolin (TTP), an RNA-binding protein (RBP) that recruits RNA-destabilizing factors and the translation inhibitory complex 4EHP-GIGYF1/2 to AU-rich element (ARE)-containing mRNAs SIGNOR-261015 0.2 MYCT1 protein Q8N699 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30283340 f miannu MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. SIGNOR-261732 0.2 FAM13B protein Q9NYF5 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260503 0.41 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PCYT1A protein P49585 UNIPROT down-regulates phosphorylation 9606 BTO:0000763 15788406 t inferred from 70% family members gcesareni Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis. SIGNOR-270151 0.2 CAMK2A protein Q9UQM7 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates phosphorylation 9606 12536214 t inferred from family member gcesareni Receptor internalization, altered;intracellular localization SIGNOR-270230 0.643 STAT3 protein P40763 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 25194572 f miannu Here we show that IL-6-activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. IL-6 stimulation promoted an increase in the mRNA levels of both Stat3 and Myod1. Stat3 mediated this effect, as IL-6‚Äìdependent Myod1 upregulation was impaired after infection with the shStat3 lentivirus. SIGNOR-255416 0.535 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates activity chemical inhibition -1 24556163 t miannu This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine SIGNOR-262233 0.8 ITK protein Q08881 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr667 ESQEELHyATLNFPG 9606 11733002 t lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Phosphorylation of the tyrosine located at position 667 in an itim motif appears to be necessary for the recruitment of shp-1 and partial recruitment of shp-2 SIGNOR-112475 0.2 CASP8AP2 protein Q9UKL3 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates binding 9606 22075988 t lperfetto In addition, both cleavage products of c-flip turned out to be inducers of nf-kb activity by binding to the ikk complex. SIGNOR-217385 0.248 BNIP2 protein Q12982 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity binding 9606 BTO:0000222 18678706 t lperfetto Cdo-bnip-2-cdc42 complex stimulates cdc42 activation which in turn promotes p38 alpha/beta activity and cell differentiation. SIGNOR-179861 0.697 SRC protein P12931 UNIPROT CEACAM1 protein P13688 UNIPROT up-regulates activity phosphorylation Tyr493 NKMNEVTySTLNFEA 9606 BTO:0000007 9867848 t lperfetto Recent reports have also suggested that Bgp1 behaves as a signal transduction molecule. Several physiological events promote the Tyr phosphorylation of Bgp1 on one or two Tyr residues within its cytoplasmic domain (Tyr-488 and Tyr-515). BGP becomes Tyr-phosphorylated by Src-like Tyr kinases in activated neutrophils (24) and in human colon carcinoma cellsWe have recently shown that Tyr phosphorylation of the mouse Bgp1 cytoplasmic domain in CT51 mouse colonic carcinoma cells led to its binding to the protein-Tyr phosphatase SHP-1 and that this event required the presence of both Tyr-488 and Tyr-515 SIGNOR-246471 0.436 E2F1 protein Q01094 UNIPROT TYMS protein P04818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253863 0.509 OPRL1 protein P41146 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257117 0.255 PLK1 protein P53350 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser426 VNKGSDEsIGKGDGF 9606 BTO:0000567 19509060 t lperfetto Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation. SIGNOR-272992 0.603 leucine smallmolecule CHEBI:25017 ChEBI SESN2 protein P58004 UNIPROT down-regulates activity chemical inhibition 9606 26449471 t We find that leucine, but not arginine, disrupts the Sestrin2- GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20micromolar, which is the leucine concentration that half-maximally activates mTORC1 SIGNOR-254897 0.8 LRRK2 protein Q5S007 UNIPROT NSF protein P46459 UNIPROT up-regulates activity phosphorylation Thr645 RKLLIIGtTSRKDVL 9606 BTO:0002181 26758690 t miannu LRRK2 phosphorylates full-length NSF at threonine 645 in the ATP binding pocket of D2 domain. Functionally, NSF phosphorylated by LRRK2 displays enhanced ATPase activity and increased rate of SNARE complex disassembling. SIGNOR-277196 0.374 PRKACA protein P17612 UNIPROT KDELR1 protein P24390 UNIPROT up-regulates phosphorylation Ser209 VLKGKKLsLPA 9606 14517323 t llicata We conclude that pka phosphorylation of serine 209 is required for the retrograde transport of the kdel receptor from the golgi complex to the er from which the retrieval of proteins bearing the kdel signal depends. SIGNOR-118257 0.314 FUS protein P35637 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates activity sumoylation Lys93 VCHFSPLkSDQDYIL 9606 BTO:0000007 19946338 t gcesareni Here, we show that Ebp1 p42 isoform can be sumoylated on both K93 and K298 residues, which mediate its nuclear translocation and are required for its anti-proliferative activity €.. Hence, TLS-mediated sumoylation is required for Ebp1 transcriptional repressive activity. SIGNOR-236904 0.342 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates activity dephosphorylation Tyr589 SHDSEENyVPMNPNL 9606 10068651 t lperfetto Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro. SIGNOR-236258 0.952 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257471 0.8 TRIM32 protein Q13049 UNIPROT DTNBP1 protein Q96EV8 UNIPROT down-regulates quantity ubiquitination 9534 BTO:0000298 19349376 t miannu TRIM32 is an E3 ubiquitin ligase for dysbindin. TRIM32 targets dysbindin for degradation. SIGNOR-265658 0.553 MAPKAPK2 protein P49137 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2 SIGNOR-166640 0.566 CUL1 protein Q13616 UNIPROT SCF-FBW7 complex SIGNOR-C135 SIGNOR form complex binding 9606 15340381 t gcesareni The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions. SIGNOR-243763 0.925 IKZF2 protein Q9UKS7 UNIPROT LNPEP protein Q9UIQ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003420 15894523 f miannu Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. SIGNOR-255404 0.2 POU2F1 protein P14859 UNIPROT GFI1B protein Q5VTD9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19965638 f miannu HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. SIGNOR-254432 0.2 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-126236 0.473 PRKDC protein P78527 UNIPROT XRCC4 protein Q13426 UNIPROT up-regulates activity phosphorylation Ser327 SLETLRNsSPEDLFD 9606 BTO:0002137 26774286 t miannu In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair.  SIGNOR-277198 0.905 NPEPPS protein P55786 UNIPROT peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity chemical modification 9606 11062501 t The proteasome generates exact major histocompatibility complex (MHC) class I ligands as well as NH2-terminal-extended precursor peptides| We performed in vitro peptide digests using recombinant PSA | PSA behaved exclusively as an aminopeptidase |BH and PSA act as complementary and redundant systems responsible for the final trimming of the correct NH2 terminus. SIGNOR-272468 0.8 CREBBP protein Q92793 UNIPROT MYB protein P10242 UNIPROT up-regulates activity binding 9534 BTO:0004055 8654374 t 2 miannu the nuclear co-activator CREB binding protein (CBP). This protein interacts directly with both c-Myb and v-Myb and potentiates Myb-specific transcription SIGNOR-240994 0.799 NHLRC1 protein Q6VVB1 UNIPROT DVL2 protein O14641 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 22223637 t miannu We have also found that malin enhances K48- and K63-linked ubiquitination of dishevelled2 that could lead to its degradation through both proteasome and autophagy. Altogether, our results indicate that malin regulates Wnt signaling pathway through the degradation of dishevelled2 and suggest possible deregulation of Wnt signaling in Lafora disease. SIGNOR-272005 0.474 PLK1 protein P53350 UNIPROT NPM1 protein P06748 UNIPROT up-regulates phosphorylation Ser4 sMDMDMSP 9606 BTO:0000567 15190079 t gcesareni Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis. SIGNOR-125666 0.435 JAK2 protein O60674 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation Tyr643 TSDEKVDyVQVDKEK 9606 BTO:0000130 18644434 t lperfetto In vitro, activated jak2 directly phosphorylated specific gab2 tyrosine residues. Mutagenesis studies revealed that gab2 tyrosine 643 (y643) was a major target of jak2 in vitro, and a key residue for jak2-dependent phosphorylation in intact cells. Mutation of gab2 y643 inhibited g-csf-stimulated erk1/2 activation and shp2 binding to gab2. SIGNOR-179488 0.494 Phenelzine chemical CHEBI:8060 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 t miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. SIGNOR-258744 0.8 CAMK2A protein Q9UQM7 UNIPROT CACNA1B protein Q00975 UNIPROT down-regulates phosphorylation Ser2120 ERRQPSSsSSEKQRF 9606 BTO:0000938 16982421 t gcesareni Here, we report a direct modulation of ca(v)2.2 channel inactivation properties by 14-3-3, a family of signaling proteins involved in a wide range of biological processes.Wild-type gst fusion proteins containing the putative 14-3-3-binding motif (aa 2076__?2140) werein vitro phosphorylated at s2126 by either camkii or pka, as detected by thesequence- and phosphorylation-specific antibody, anti-ps2126 (middle panel). Phosphorylation of s2126 significantly increases its binding to recombinant 14-3-3? SIGNOR-149684 0.322 RBL2 protein Q08999 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 10090 BTO:0000165 10801445 f gcesareni Although forced expression of either p130 or pRb in mouse C2 myoblasts efficiently blocked cell cycle progression, only p130 inhibited the differentiation program. SIGNOR-241946 0.7 PRKD1 protein Q15139 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 20179209 t lperfetto Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated SIGNOR-163924 0.312 KRT14 protein P02533 UNIPROT TRADD protein Q15628 UNIPROT down-regulates activity binding 9606 11684708 t Regulation of binding miannu TRADD specifically bound K18 and K14, type I (acidic) keratins. it is possible that epidermal K14 may function as an inhibitor of TNF–TNFR1 signaling through an association with TRADD. SIGNOR-251907 0.353 PRKACA protein P17612 UNIPROT ATP2B1 protein P20020 UNIPROT up-regulates activity phosphorylation Ser1178 APTKRNSsPPPSPNK -1 2548572 t miannu The ATPase is phosphorylated only at this site by the cAMP-dependent protein kinase, and the phosphorylation is inhibited by calmodulin. The effect of the phosphorylation is to decrease the Km for Ca2+ of the purified ATPase from about 10 microM to about 1.4 microM and to increase the Vmax of ATP hydrolysis about 2-fold. SIGNOR-262694 0.439 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR up-regulates 9606 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268585 0.2 DNA_damage stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates 9606 21034966 f lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. SIGNOR-242612 0.7 CREM protein Q03060 UNIPROT IL2 protein P60568 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 12626549 t Luana In this study we show that CREM is transcriptionally induced in T cells following stimulation through CD3 and CD28, binds to the IL-2 promoter in vivo, and suppresses IL-2 production. SIGNOR-261576 0.494 TERB1 protein Q8NA31 UNIPROT TTM complex complex SIGNOR-C305 SIGNOR form complex binding 9606 BTO:0000007 30718482 t lperfetto Meiotic specific proteins TERB1, TERB2, and MAJIN form a stable complex that plays a critical role in regulating the recruitment of telomeres to the NE SIGNOR-263302 0.2 RPS6KB2 protein Q9UBS0 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation 9606 BTO:0000007 BTO:0001253 18296647 t gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. SIGNOR-160992 0.449 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity binding 9606 29407449 t scontino T3 binds its receptor (TR) in the nucleus. TRs are ligand-dependent transcription factors belonging to the type II group of NHRs. TRs are encoded by two genes, Thra and Thrb. SIGNOR-267276 0.8 PCSK7 protein Q16549 UNIPROT CDC25B protein P30305 UNIPROT down-regulates phosphorylation 9606 11333986 t gcesareni We propose that regulation of cdc25b phosphorylation by p38 is a critical event for initiating the g2/m checkpoint after ultraviolet radiation SIGNOR-107423 0.2 ETV3 protein P41162 UNIPROT ETV3 protein P41162 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 22028471 t miannu ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation. SIGNOR-262778 0.2 CACNA1D protein Q01668 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 30849329 f miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). SIGNOR-264331 0.7 MAPK1 protein P28482 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by stabilization phosphorylation Thr305 IDYGKVAtQCTCRKD 9606 BTO:0001109 28945223 t miannu In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation.  SIGNOR-276741 0.2 TLK1 protein Q9UKI8 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates activity phosphorylation Ser354 VSLKPLHsVNNPILR 9606 BTO:0000007 35064619 t miannu We established that TLK1 phosphorylates MK5 on three residues (S160, S354 and S386), resulting in MK5 activation, and additionally, mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected HEK 293 cells. SIGNOR-276746 0.2 CLASP2 protein O75122 UNIPROT MAPRE1 protein Q15691 UNIPROT up-regulates activity binding 9534 BTO:0004055 19638411 t lperfetto GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells SIGNOR-264829 0.617 AURKA protein O14965 UNIPROT ALDH1A1 protein P00352 UNIPROT up-regulates activity phosphorylation Thr442 KDIDKAItISSALQA -1 28193222 t miannu AURKA phosphorylates ALDH1A1 at three critical residues which exert a multifaceted regulation over its level, enzymatic activity, and quaternary structure. While all three phosphorylation sites contribute to its increased stability, T267 phosphorylation primarily regulates ALDH1A1 activity. AURKA-mediated phosphorylation rapidly dissociates tetrameric ALDH1A1 into a highly active monomeric species.  SIGNOR-276748 0.38 FZD7 protein O75084 UNIPROT FZD7/SDC4 complex SIGNOR-C216 SIGNOR form complex binding 9606 BTO:0002314 BTO:0001103 23290138 t apalma We next examined whether endogenous Fzd7 and Sdc4 form a receptor complex in satellite cells […] Therefore, we conclude that Fzd7 and Sdc4 form a co-receptor complex in activated satellite cells. SIGNOR-255848 0.539 IRF3 protein Q14653 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 20610653 f miannu Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-260330 0.2 SIRT1 protein Q96EB6 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates deacetylation 9606 15126506 t gcesareni Deacetylation of foxos involves binding of the nad-dependent deacetylase hsir2(sirt1). Accordingly, hsir2(sirt1)-mediated deacetylation precludes foxo inhibition through acetylation and thereby prolongs foxo-dependent transcription of stress-regulating genes. SIGNOR-124714 0.734 RPS6KB1 protein P23443 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 17053147 t gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. SIGNOR-150144 0.598 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr288 QCPVGFNtLAFPSMK -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276136 0.758 RASSF1 protein Q9NS23 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002552 12024041 f Luana RASSF1A expression dramatically inhibits native cyclin D1 accumulation | Regulation of cyclin D1 accumulation by RASSF1A is independent of the cyclin D1 promoter and likely occurs through inhibition of mRNA translation. SIGNOR-259455 0.558 (R)-carnitine smallmolecule CHEBI:16347 ChEBI O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity precursor of 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267119 0.8 CUL3 protein Q13618 UNIPROT KCTD13 protein Q8WZ19 UNIPROT up-regulates activity binding 9606 19782033 t miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. SIGNOR-264233 0.552 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 t lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-260669 0.8 CTNNB1 protein P35222 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12589056 f gcesareni The resulting accumulation of beta-catenin leads to its nuclear translocation and binding to tcf/lef transcription factors to induce target genes including cyclin d1. SIGNOR-98379 0.794 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 10090 BTO:0005065 17673906 t lperfetto TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. SIGNOR-236366 0.965 CDK8 protein P49336 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser367 GTQNPVSsPGMSQEL -1 29967145 t miannu CDK8 phosphorylates YAP and promotes its activation. Of interest, mutating four amino acid positions (T119, S128, S289, and S367) to alanines (YAP-4A) completely blocked phosphorylation (Fig. 6J), suggesting that CDK8 phosphorylates these sites in YAP in vitro. SIGNOR-277651 0.327 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1222 PAFDNLYyWDQDPPE 9606 15156151 t gcesareni Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of neu/erbb2 phosphorylation at tyr 1201 or tyr 1227 SIGNOR-124860 0.2 AR protein P10275 UNIPROT TMPRSS2 protein O15393 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21761340 t lperfetto The prostate-specific TMPRSS2 gene, while upregulated by AR activity in luminal cells, is also transcribed in basal populations, confirming that AR acts as an expression modulator. SIGNOR-253687 0.593 GRIN1 protein Q05586 UNIPROT NMDA receptor_2A complex SIGNOR-C347 SIGNOR form complex binding 9606 BTO:0000938 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits SIGNOR-264120 0.715 EDNRA protein P25101 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257320 0.252 MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000222 21902831 t lperfetto TAK1 can phosphorylate and activate MAP kinase kinase 3/6 (MKK3/6), and numerous studies have demonstrated a requirement for MKK3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236093 0.484 WNT16 protein Q9UBV4 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131674 0.601 RUNX1 protein Q01196 UNIPROT Core Binding Factor complex complex SIGNOR-C214 SIGNOR form complex binding 9606 12495904 t irozzo The core binding factor (CBF) transcription complex, consisting of the interacting proteins RUNX1 and CBFβ, is essential for normal hematopoiesis SIGNOR-255710 0.842 RUNX2 protein Q13950 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22641097 f miannu Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells. SIGNOR-255080 0.404 CSNK2A1 protein P68400 UNIPROT FAF1 protein Q9UNN5 UNIPROT down-regulates activity phosphorylation Ser289 ITDVHMVsDSDGDDF 9534 12832043 t llicata We previously identified the Fas-associated factor FAF1 as an in vitro substrate of protein kinase CK2 and determined Ser289 and Ser291 as phosphorylation sites.|Therefore we assume that CK2‐mediated FAF1 phosphorylation influences the nuclear localization of FAF1 | it implies that the major function of FAF1 might not be in the cytoplasm as an interacting partner of Fas. SIGNOR-250863 0.332 pyruvate smallmolecule CHEBI:15361 ChEBI (S)-lactate smallmolecule CHEBI:16651 ChEBI up-regulates quantity precursor of 9606 24929216 t Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. SIGNOR-266920 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR PRKACA protein P17612 UNIPROT up-regulates 9606 BTO:0000938 16537363 f gcesareni Indicating that akt positively regulates shh signaling by controlling pka-mediated gli inactivation. SIGNOR-145113 0.2 CSNK2A2 protein P19784 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates activity phosphorylation Ser121 YRIQEQEsSGEEDSD -1 8288648 t llicata Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action. SIGNOR-251020 0.312 KAT6A protein Q92794 UNIPROT CCL3 protein P10147 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 12771199 t lperfetto We further demonstrate that the histone acetyltransferase, MOZ, can activate the MIP-1a promoter in T-cells and that this activation is largely dependent upon the proximal RUNX site. Moreover, we show that co-expression of MOZ and RUNX1 can activate the MIP-1a promoter. SIGNOR-251726 0.2 EEF1A2 protein Q05639 UNIPROT Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269524 0.8 FBXW7 protein Q969H0 UNIPROT PSEN1 protein P49768 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 12354302 t miannu SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production SEL-10 protein is a homologue of yeast Cdc4, a member of the SCF (Skp1-Cdc53/CUL1-F-box protein) E2-E3 ubiquitin ligase family. In this study, we show that human SEL-10 interacts with PS1 and enhances PS1 ubiquitination, thus altering cellular levels of unprocessed PS1 and its N- and C-terminal fragments. These observations suggest that SEL-10 mediated ubiquitination of PS1-CTF and PS1-NTF leads to their degradation. SIGNOR-272600 0.506 CSNK1A1 protein P48729 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 9606 22017877 t llicata Phosphorylation of all three serine residues in the deptor degron (ser286, ser287, and ser291) is necessary for - and directly mediates - the interaction with _trcp. ck1 phosphorylated the degron of deptor, as shown by western blotting with the phospho-specific antibody (fig. S3e-f). In contrast, mtor alone was unable to induce phosphorylation of deptor on ser286, ser287, and ser291. SIGNOR-176871 0.2 INSR protein P06213 UNIPROT FABP4 protein P15090 UNIPROT unknown phosphorylation Tyr20 SSENFDDyMKEVGVG -1 1648089 t Adipocyte lipid-binding protein is phosphorylated on tyrosine 19 in an insulin-stimulated fashion by the insulin receptor SIGNOR-251309 0.398 aripiprazole chemical CHEBI:31236 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 9606 BTO:0002181 22025698 t Luana Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands.  SIGNOR-258319 0.8 PRKCA protein P17252 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser188 LGERKPSsAAYQKAP -1 9244383 t lperfetto We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198. SIGNOR-248976 0.378 MAPK1 protein P28482 UNIPROT CIITA protein P33076 UNIPROT up-regulates phosphorylation Ser280 TVHGLPTsPDRPGST 9606 18245089 t gcesareni We show in this study that the nuclear localized form of ciita is a predominantly phosphorylated form of the protein, whereas cytoplasmic ciita is predominantly unphosphorylated. Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. Double mutations of these residues increased nuclear ciita, indicating that these sites are not required for nuclear import. Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation. SIGNOR-160609 0.442 TGFB3 protein P10600 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252284 0.7 NR5A1 protein Q13285 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19237537 t miannu The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes. SIGNOR-271787 0.492 MAPK3 protein P27361 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 BTO:0000150 10931950 t gcesareni These data suggest that increased signaling by erbb receptors up-regulates mapk activity, which, in turn, phosphorylates and destabilizes p27, thus contributing to dysregulated cell cycle progression. SIGNOR-80234 0.384 PFN1 protein P07737 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 18667433 f areggio  Additionally, the association of Ror2 with the actin-binding protein filamin A is required for Wnt5a-induced JNK activation and polarized cell migration. SIGNOR-258977 0.7 SMAD2 protein Q15796 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity binding 9606 9670020 t lperfetto Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGF-beta type I receptor, and this oligomerization does not require Smad4 SIGNOR-232149 0.2 nitric oxide smallmolecule CHEBI:16480 ChEBI GUCY1A2-B3 complex SIGNOR-C138 SIGNOR up-regulates activity chemical activation 9606 15036565 t gcesareni One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP) SIGNOR-243964 0.8 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates 10090 BTO:0001103 24003218 f lperfetto SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 SIGNOR-252997 0.909 NBN protein O60934 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 15758953 t gcesareni Nbs1 can also immobilize atm at the site of the dsb via direct binding of atm to a c-terminal atm interaction motif on nbs1 . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm SIGNOR-134508 0.851 FYN protein P06241 UNIPROT FCGR2A protein P12318 UNIPROT up-regulates activity phosphorylation Tyr288 YETADGGyMTLNPRA -1 8756631 t lperfetto To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation. SIGNOR-249336 0.514 BRCA1 protein P38398 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 16331276 f miannu We identified a foxa1 binding site within the brca1-responsive element of the p27(kip1) promoter and showed that foxa1 activated the promoter alone and in conjunction with brca1. SIGNOR-142888 0.351 CRH protein P06850 UNIPROT KRT14 protein P02533 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15468147 t Regulation miannu CRH stimulated the expression of cytokeratin 1 and involucrin, and inhibited cytokeratin 14 on both mRNA and protein levels. SIGNOR-251899 0.2 MCHR2 protein Q969V1 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257439 0.252 USF1 protein P22415 UNIPROT FOSL1 protein P15407 UNIPROT down-regulates activity binding 10090 9160889 t 2 miannu USF specifically interacts with Fra1. USF was repressing this modest Fra1 transactivation SIGNOR-240975 0.478 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 18936167 t gcesareni The autoactivation residues y1054 and y1059 are targeted by dep-1 and this results in the inhibition of kinase activity and the consequent general dephosphorylation of vegfr2. SIGNOR-181672 0.687 SLC38A9 protein Q8NBW4 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 25567906 f Luana SLC38A9 is a Lysosomal Membrane Protein Required for mTORC1 Activation SIGNOR-268014 0.469 AURKA protein O14965 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser215 DRNTFRHsVVVPYEP 9606 15469940 t llicata Here we show that p53 is phosphorylated by the mitotic kinase aurora-a at serine 215. Unlike most identified phosphorylation sites of p53 that positively associate with p53 function (brooks, c. L., and gu, w. (2003) curr. Opin. Cell biol. 15, 164-171), the phosphorylation of p53 by aurora-a at ser-215 abrogates p53 dna binding and transactivation activity. SIGNOR-129809 0.77 TGFB1 protein P01137 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 18586026 f gcesareni These data show that tgf-beta-induced nf-kappab activation is through tak1/mek-mediated aktactivation, which is essential for tgf-beta to support of osteoclast survival SIGNOR-179179 0.379 CSF2RA protein P15509 UNIPROT JAK2 protein O60674 UNIPROT up-regulates 9606 9028317 f gcesareni We show that the amount of jak2 physically associated with gm-csfr beta chain is increased after gm-csf stimulation and that gm-csf triggers both beta chain and jak2 tyrosine phosphorylation SIGNOR-46334 0.513 ABL2 protein P42684 UNIPROT ABL2 protein P42684 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr439 RLMTGDTyTAHAGAK -1 15735735 t miannu The results show that Arg is stabilized in response to 0.1 mM H2O2 by autophosphorylation of Y-261, consistent with involvement of the Arg kinase function in regulating Arg levels. The results further demonstrate that c-Abl-mediated phosphorylation of Arg on Y-261 similarly confers Arg stabilization.. These findings indicate that abrogation of the Arg kinase function by the Y261F mutation is dependent on phosphorylation of the Y-439 site.). Our results thus indicate that phosphorylation of Arg on Y-261 plays a dual role in retaining the Arg kinase function and preventing Arg degradation by blocking ubiquitination (Figure 6). SIGNOR-276032 0.2 retinal smallmolecule CHEBI:15035 ChEBI all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI up-regulates quantity precursor of 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265124 0.8 p38 proteinfamily SIGNOR-PF16 SIGNOR KRT20 protein P35900 UNIPROT up-regulates activity phosphorylation Ser13 RSFHRSLsSSLQAPV -1 20724476 t miannu P38 phosphorylates the type II keratin, K8 at Ser73, whereas MK2 phosphorylates the binding partners K18 at Ser52 and K20 at Ser13. SIGNOR-263070 0.2 EGFR protein P00533 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 BTO:0000017 10358079 t gcesareni We identified stat5 as a direct binding partner to egfr and erbb4 and discovered new recognition motifs for shc and stat5.Egf stimulation and subsequent phosphorylation of egfr at tyrosine y978, y998 and y869 would then subsequently lead to recruitment and activation of stat5. SIGNOR-68159 0.818 MAPK1 protein P28482 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation Ser62 LLPTPPLsPSRRSGL 9534 BTO:0004055 8386367 t lperfetto Transactivation of gene expression by myc is inhibited by mutation at the phosphorylation sites thr-58 and ser-62. SIGNOR-235700 0.724 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Ser801 VPLLREAsARDRQSA 9606 BTO:0000007 11884385 t lperfetto Direct phosphorylation of capsaicin receptor VR1 by protein kinase Cepsilon and identification of two target serine residues. | Patch clamp analysis of the point mutants where Ser or Thr residues were replaced with Ala in the total 16 putative phosphorylation sites showed that two Ser residues, Ser(502) and Ser(800) were involved in the potentiation of the capsaicin-evoked currents by either PMA or ATP. SIGNOR-249142 0.2 RNF216 protein Q9NWF9 UNIPROT TICAM1 protein Q8IUC6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16968706 t miannu Triad3A promotes proteolytic degradation of adapter proteins. A, Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins. SIGNOR-271609 0.362 MYC protein P01106 UNIPROT HLA-F protein P30511 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8206526 f miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. SIGNOR-254605 0.2 Food intake phenotype SIGNOR-PH152 SIGNOR vitamin K smallmolecule CHEBI:28384 ChEBI up-regulates quantity 31226734 f lperfetto Vitamin K obtained from the diet is considered to reach the target tissues via lipid absorption and the transport system  SIGNOR-265899 0.7 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 10660534 t lperfetto Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function SIGNOR-74844 0.717 BBsome complex complex SIGNOR-C288 SIGNOR RAB8A protein P61006 UNIPROT up-regulates activity binding 9606 17574030 t lperfetto Interestingly, the BBSome is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. SIGNOR-262562 0.455 MVD protein P53602 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity lipidation 10090 25378391 t miannu Akt modulated the pathway by phosphorylating mevalonate diphosphate decarboxylase (MDD) at Ser96. These data suggest that Akt regulates Rac1 activity by directly phosphorylating MDD at Ser96, which augments Rac1 geranylgeranylation. SIGNOR-265892 0.2 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates activity dephosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 11323411 t These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro. SIGNOR-248674 0.952 MAPK1 protein P28482 UNIPROT PDE4B protein Q07343 UNIPROT up-regulates activity phosphorylation Ser659 YQSMIPQsPSPPLDE -1 11030732 t miannu The short-form PDE4B2 isoenzyme was activated by Erk2 phosphorylation. These functional changes in PDE activity were mimicked by mutation of the target serine for Erk2 phosphorylation to the negatively charged amino acid, aspartic acid. SIGNOR-275970 0.272 PRKCD protein Q05655 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 t lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation SIGNOR-249248 0.294 CDX2 protein Q99626 UNIPROT CDX2/PAX6/P300 complex SIGNOR-C33 SIGNOR form complex binding 9606 10506141 t lperfetto In the present study, we investigated the interaction of cdx-2 and pax-6 with p300, a co-activator coupled to the basal transcription machinery. In transient transfection-expression experiments, we found that the transactivating effects of cdx-2 and pax-6 on the glucagon gene were greatly enhanced by the additional expression of p300. SIGNOR-70954 0.373 panobinostat chemical CHEBI:85990 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257754 0.8 MAPK1 protein P28482 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 BTO:0000142 16401070 t lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. SIGNOR-143477 0.57 ESRRA protein P11474 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000159 15955695 f miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. SIGNOR-253799 0.2 WNK3 protein Q9BYP7 UNIPROT SLC12A5 protein Q9H2X9 UNIPROT down-regulates activity phosphorylation 21613606 t lperfetto We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs SIGNOR-264628 0.472 LYST protein Q99698 UNIPROT RAB5B protein P61020 UNIPROT down-regulates activity binding 7227 33725482 t lperfetto Mauve interacts with Rab5, Msps, and gamma-tubulin|Mauve/LYST opposes Rab5, which promotes vesicle fusion affecting PCM recruitment SIGNOR-266002 0.2 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT down-regulates quantity phosphorylation Ser639 PDVPRLGsTFSLDTS 9606 BTO:0000782 11024037 t lperfetto However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway.  SIGNOR-249056 0.327 SEPTIN6 protein Q14141 UNIPROT SEPT6/SEPT7 complex SIGNOR-C72 SIGNOR form complex binding 9606 16914550 t miannu We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains. SIGNOR-148895 0.2 ROS stimulus SIGNOR-ST2 SIGNOR ARNT protein P27540 UNIPROT up-regulates quantity by expression 22387692 f lperfetto Although the regulation mechanism of the ARNT expression is largely unknown, earlier studies reported that the human ARNT protein level was decreased by hydrogen peroxide or reactive oxygen species. SIGNOR-253689 0.7 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257988 0.8 PRKACB protein P22694 UNIPROT PHKA1 protein P46020 UNIPROT down-regulates activity phosphorylation 9606 10487978 t Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. SIGNOR-267413 0.307 CDK2 protein P24941 UNIPROT SKP2 protein Q13309 UNIPROT up-regulates quantity by stabilization phosphorylation Ser64 SNLGHPEsPPRKRLK 18239684 t lperfetto The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1). SIGNOR-249173 0.792 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Ser171 RILNHDTsFAKTFVG 9606 17197699 t gcesareni Enzymatic activity, induced; SIGNOR-151755 0.2 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN3 protein Q9UGI6 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 18955585 t Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  SIGNOR-258024 0.8 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr494 TPLHRDKtPLHQKHA 9606 SIGNOR-C83 9840932 t lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk4 SIGNOR-62365 0.711 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257910 0.8 TNFSF14 protein O43557 UNIPROT TNFRSF14 protein Q92956 UNIPROT up-regulates binding 9606 BTO:0000763 10894944 t gcesareni A member of the tumor necrosis factor (tnf) superfamily, human tnfsf14 (htnfsf14)/hvem-l (herpes virus entry mediator ligand) was isolated as a cellular ligand for hvem/tr2 and human lymphotoxin beta receptor (ltbetar). Tnfsf14 induces apoptosis and suppresses tumor formation SIGNOR-79328 0.855 HNF4G protein Q14541 UNIPROT AKR1C4 protein P17516 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003846 2044952 f 2 miannu Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene. HNF-4_ is a necessary factor for the activation of the human DD4 gene. is much higher than that of vHNF-1-C. SIGNOR-240013 0.2 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 16782899 t llicata Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain SIGNOR-147191 0.476 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr69 PVPNQPVyNQPVYNQ 9606 11390389 t lperfetto C-abl tyrosine kinase binds and phosphorylates phospholipid scramblase 1. Phosphorylation was abolished by mutation of tyr residues tyr(69)/tyr(74) within the tandem repeat sequence (68)vynqpvynqp(77) of plscr1 SIGNOR-86013 0.393 COL2A1 protein P02458 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates binding 9606 7688313 t gcesareni Both a2b1- and a1b1- integrins are implicated in chondrocyte adhesion to native collagene i and ii SIGNOR-31881 0.451 LPAR1 protein Q92633 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257400 0.432 PPP3CB protein P16298 UNIPROT FLNA protein P21333 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 t Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation. SIGNOR-248362 0.2 WNT10A protein Q9GZT5 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131619 0.565 ZBTB47 protein Q9UFB7 UNIPROT CBFA2T3/ZNF651 complex SIGNOR-C197 SIGNOR form complex binding 9606 BTO:0000007 20116376 t Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex. SIGNOR-253957 0.466 SETBP1 protein Q9Y6X0 UNIPROT SET protein Q01105 UNIPROT up-regulates binding 9606 22566606 t miannu Setbp1 was shown to form a complex with set and pp2a, enhancing the stability of set and its inhibition of pp2a. SIGNOR-197324 0.491 BMP7 protein P18075 UNIPROT PRDM16 protein Q9HAZ2 UNIPROT up-regulates transcriptional regulation 9606 18719589 f fspada Bmp7 activates a full program of€š brown€š adipogenesis€š including induction of early regulators of€š brown€š fat fate prdm16 (pr-domain-containing 16; ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha; ref. 5), increased expression of the€š brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways SIGNOR-210053 0.413 PTPN1 protein P18031 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation 9606 15632081 t gcesareni Whereas insulin-induced phosphatidylinositol 3-kinase/akt signaling was prolonged in both tcptp-/- and ptp1b-/- immortalized mouse embryo fibroblasts (mefs), mitogen-activated protein kinase erk1/2 signaling was elevated only in ptp1b- mefs SIGNOR-252639 0.732 FLT3 protein P36888 UNIPROT HK2 protein P52789 UNIPROT up-regulates activity 9606 BTO:0002144 28194038 f FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity SIGNOR-261322 0.261 EIF3H protein O15372 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266393 0.915 CYLD protein Q9NQC7 UNIPROT CCND1 protein P24385 UNIPROT up-regulates 9606 BTO:0001286 16713561 f gcesareni Cyld was also recently shown to deubiquitylate the p50 and p52 co-activator bcl-3, leading to both cyclin d1 expression and proliferation in keratinocytes SIGNOR-146777 0.4 GLI1 protein P08151 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23074268 f gcesareni Canonical hh signaling plays an essential role in cell proliferation throught introduction of the genes encoding cyclin d1 and n-myc SIGNOR-199126 0.562 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates activity phosphorylation Tyr823 DIKNDSNyVVKGNAR 9606 12824176 t lperfetto Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth. / tyr-823 is the last tyrosine residue to be autophosphorylated SIGNOR-102641 0.2 KAT6A protein Q92794 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 SIGNOR-C54 11965546 t miannu Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation. SIGNOR-117332 0.312 ROBO proteinfamily SIGNOR-PF14 SIGNOR CDC25B protein P30305 UNIPROT down-regulates phosphorylation Ser375 ARVLRSKsLCHDEIE 9606 BTO:0000567;BTO:0000938 BTO:0000142 15150265 t lperfetto P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteinsphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 SIGNOR-124847 0.2 RPS6KA1 protein Q15418 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-138467 0.2 NEDD4 protein P46934 UNIPROT LYN protein P07948 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001931 10683340 t miannu These findings suggest that LMP2A recruits Nedd4-like ubiquitin-protein ligases and B-cell signal transduction molecules, resulting in the degradation of LMP2A and Lyn by a ubiquitin-dependent mechanism.  SIGNOR-272558 0.44 MAPK1 protein P28482 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Thr1223 AEREGPGtPPTTLAR 9606 15125835 t lperfetto Both cdk1 and erk2 induced phosphorylation of the wild-type nir2. Substitution of t794 by alanine reduced the phosphorylation by erk2, whereas the double mutations t794/1223a completely abolished it. The requirement of multiple nir2 phosphorylation sites for plk1 binding may provide a mechanism that sets a threshold for the nir2-plk1 interaction during mitosis. SIGNOR-124646 0.2 FGFR3 protein P22607 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 10918587 t Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3. SIGNOR-251139 0.615 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser361 TLRDVVPsPDTQEKG 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276109 0.29 AURKB protein Q96GD4 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Ser60 VYQVSRTsGGAGGLG -1 12686604 t lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro. SIGNOR-100111 0.527 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC20P protein Q6DN03 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271988 0.2 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates activity binding 9606 18923185 t miannu IL-6 and IL-11 are the only members of the family that signal via the induction of a gp130 homodimer after binding their specific -receptors, IL-6R and IL-11R. When IL-6 binds to the homodimerized IL-6Rα/gp130Rβ, it results in a signaling cascade that is initiated by the autophoshorylation and activation of JAK. SIGNOR-255324 0.916 MAP3K14 protein Q99558 UNIPROT CHUK protein O15111 UNIPROT up-regulates activity phosphorylation 9606 20651737 t lperfetto Once activated by autophosphorylation, nik activates ikkalpha, which in turn phosphorylates nf-kb2. This stimulates limited proteasome-mediated proteolysis of nf-kb2 to p52. Removal of the carboxy-terminal ankyrin repeats from nf-kb2 releases the p52/RELB heterodimer, allowing its translocation to the nucleus where it instigates the expression of nf-kb target genes. SIGNOR-167060 0.685 G6PC1 protein P35575 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-266568 0.8 FGF12 protein P61328 UNIPROT SCN4A protein P35499 UNIPROT down-regulates activity binding 9606 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253432 0.257 SLC24A1 protein O60721 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264395 0.8 ARID1A protein O14497 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269818 0.801 tryptophan smallmolecule CHEBI:27897 ChEBI Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates quantity precursor of 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) SIGNOR-270516 0.8 RBBP6 protein Q7Z6E9 UNIPROT YBX1 protein P67809 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 18851979 t miannu RBBP6 interacts with multifunctional protein YB-1 through its RING finger domain, leading to ubiquitination and proteosomal degradation of YB-1 SIGNOR-271773 0.322 HRAS protein P01112 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k we show here, however, that in vivo there are marked quantitative differences in the ability of ki- and ha-ras to activate raf-1 and phosphoinositide 3 kinase. the mechanism of raf-1 activation is complex, but it is clear that one important role of ras is to recruit raf-1 to the plasma membrane where a series of events is initiated that ultimately leads to full raf-1 activation. These events include tyrosine, serine, and threonine phosphorylation plus interactions with ras, phospholipids, 14-3-3 proteins and their associated proteins, and possibly dimerization. SIGNOR-175195 0.814 PRKCB protein P05771 UNIPROT GAP43 protein P17677 UNIPROT unknown phosphorylation Ser41 AATKIQAsFRGHITR -1 2140056 t lperfetto We conclude that serine-41 is the protein kinase C phosphorylation site of neuromodulin and that phosphorylation of this amino acid residue blocks binding of calmodulin to neuromodulin. SIGNOR-248859 0.353 CALU protein O43852 UNIPROT GGCX protein P38435 UNIPROT down-regulates activity binding 10116 BTO:0000759 15075329 t lperfetto Results are presented that demonstrate that the endoplasmic reticulum chaperone protein calumenin is associated with gamma-carboxylase and inhibits its activity. SIGNOR-265910 0.411 A4/b7 integrin complex SIGNOR-C187 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269031 0.7 PRKCQ protein Q04759 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates activity phosphorylation Ser309 MMKKYGKsFRKLLSL -1 14988727 t miannu Recombinant SPAK was phosphorylated on Ser-311 in its kinase domain by PKCtheta, but not by PKCalpha. This synergistic activity, as well as the receptor-induced SPAK activation, required the PKCtheta-interacting region of SPAK, and Ser-311 mutation greatly reduced these activities of SPAK. SIGNOR-276006 0.465 WARS1 protein P23381 UNIPROT tryptophan smallmolecule CHEBI:27897 ChEBI down-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) SIGNOR-270510 0.8 GATA1 protein P15976 UNIPROT HOXA10 protein P31260 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17688409 f miannu Transcription factors GATA-1 and Fli-1 regulate human HOXA10 expression in megakaryocytic cells. Mutation of the GATA-1 and the Ets-1 motifs amplified the expression of HOXA10 in HEL and K562 cells, confirming the importance of these cis-acting elements in regulating HOXA10 expression in megakaryocytic cells. Chromatin immunoprecipitation (ChIP) and chloramphenicol acetyl transferase (CAT) assays confirm that HOXA11 binds to the putative binding site, resulting in repression of HOXA10 expression. SIGNOR-254470 0.311 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120136 0.316 MNAT1 protein P51948 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10949034 t Manara Human Estrogen Receptor α Is Phosphorylated at Serine 118 In Vivo by Cdk7 SIGNOR-260837 0.406 O-phosphonato-L-serine(2-) smallmolecule CHEBI:57524 ChEBI L-serine chemical CHEBI:17115 ChEBI up-regulates quantity precursor of 9606 BTO:0000142 12213811 t lperfetto Human phosphoserine phosphatase (HPSP) regulates the levels of glycine and d-serine, the putative co-agonists for the glycine site of the NMDA receptor in the brain. |Phosphoserine phosphatase (PSP)1 is an important enzyme in the phosphorylated pathway of serine biosynthesis, which contributes a major portion of the endogenous l-serine|he enzymatic reaction of PSP is Mg2+-dependent and results in the dephosphorylation of phospho-l-serine with the formation of a phosphoenzyme intermediate, which is subsequently autodephosphorylated. The resulting product, l-serine, is not only a precursor for the biosynthesis of glycine but also an uncompetitive inhibitor for the enzymatic reaction of PSP SIGNOR-268569 0.8 6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)-4-pyrimidinyl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one chemical CHEBI:91348 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258294 0.8 NFX1 protein Q12986 UNIPROT TERT protein O14746 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17267499 f miannu NFX1-123 augments the activation of hTERT expression through interactions with PABPCs SIGNOR-226015 0.504 (2s)-1-{[5-(3-Methyl-1h-Indazol-5-Yl)pyridin-3-Yl]oxy}-3-Phenylpropan-2-Amine chemical CID:11314340 PUBCHEM AKT1 protein P31749 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259688 0.8 ZMYND8 protein Q9ULU4 UNIPROT MMP1 protein P03956 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 27477906 t lperfetto Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported SIGNOR-262042 0.2 CASK protein O14936 UNIPROT TBR1 protein Q16650 UNIPROT up-regulates binding 9534 BTO:0000298 10749215 t miannu Here we report that, through its guanylate kinase domain, CASK interacts with Tbr-1, a T-box transcription factor that is involved in forebrain development. CASK enters the nucleus and binds to a specific DNA sequence (the T-element) in a complex with Tbr-1. CASK acts as a coactivator of Tbr-1 to induce transcription of T-element containing genes, including reelin, a gene that is essential for cerebrocortical development. SIGNOR-266835 0.47 ADORA2B protein P29275 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257307 0.252 SAGA complex complex SIGNOR-C465 SIGNOR H3-2 protein Q5TEC6 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269641 0.2 HNF1A protein P20823 UNIPROT AFP protein P02771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 7549116 f miannu HNF-1 beta was found to be more potent than HNF-1 alpha in activating the AFP promoter in the HepG2 cells. SIGNOR-254637 0.335 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000017 11726515 t lperfetto Phosphorylation of grb2 by bcr/abl or egf receptor reduced its sh3-dependent binding to sos in vivo, but not its sh2-dependent binding to bcr/abl. Tyr209 within the c-terminal sh3 domain of grb2 was identified as one of the tyrosine phosphorylation sites SIGNOR-112354 0.2 LRP6 protein O75581 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization relocalization 9606 BTO:0000007 18632848 t lperfetto The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism. SIGNOR-227939 0.722 CDX2 protein Q99626 UNIPROT UGT1A10 protein Q9HAW8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000195 15044625 t Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter. SIGNOR-253968 0.259 BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0000007 18498746 t lperfetto We show that mutation of the phosphorylation site Thr-112 causes decreased binding of Bim to the antiapoptotic protein Bcl2 and can increase cell survival. SIGNOR-178676 0.812 GSK3B protein P49841 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Thr395 PLPSGLLtPPQSGKK 9606 14536078 t gcesareni Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380 SIGNOR-118559 0.456 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266476 0.8 MAP3K5 protein Q99683 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 19920149 t lperfetto Ask1 is a member of a mapkkk family and functions as an upstream kinase engaged in c-jun nh2-terminal kinase (jnk)/p38 signaling via the phosphorylation and activation of mapkks, such as mkk3, -4, -6, and -7 SIGNOR-161763 0.583 ITGB1BP1 protein O14713 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257643 0.756 RAF1 protein P04049 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates binding 9606 15618521 t inferred from 70% of family members gcesareni Raf-1 prevents dimerization and phosphorylation of the activation loop of mst2 independently of its protein kinase activity.Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (mst2) SIGNOR-269942 0.367 TNFRSF1B protein P20333 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 8069916 t lperfetto Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly. SIGNOR-34645 0.697 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition 9606 20570526 t Luana Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors], SIGNOR-257849 0.8 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR TNNC2 protein P02585 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136755 0.348 ESR2 protein Q92731 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 BTO:0001264 22169964 f miannu 17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice SIGNOR-253474 0.2 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 9606 BTO:0000130 12056906 t esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. SIGNOR-89229 0.458 ADP chemical CHEBI:16761 ChEBI PRPS1 protein P60891 UNIPROT down-regulates activity chemical inhibition 29074724 t lperfetto PRPS1 is inhibited by the nucleotide biosynthesis products ADP, AMP, and GDP SIGNOR-265736 0.8 PIK3CA protein P42336 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24367090 t AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Insulin activation of phosphoinositide 3-kinase (pi3k) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (pip3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (pten) blocks pi3k signaling by dephosphorylating pip3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent rac exchanger 2 SIGNOR-147948 0.8 STAT3 protein P40763 UNIPROT POMC protein P01189 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 19049975 t miannu We show that phospho-STAT3 activates POMC promoter in response to leptin signaling through a mechanism that requires an SP1-binding site in the POMC promoter. SIGNOR-263497 0.623 SP1 protein P08047 UNIPROT ITGA11 protein Q9UKX5 UNIPROT up-regulates quantity by expression 9606 BTO:0001282 16300938 t lperfetto We speculate that the "mesenchymal signature" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors. SIGNOR-253350 0.2 Corticotropin protein P01189-PRO_0000024969 UNIPROT CYP11A1 protein P05108 UNIPROT up-regulates quantity 9606 24631756 f lperfetto CTH signaling promotes the single steroidogenic rate limiting step, which is the conversion of cholesterol to pregnenolone by Cholesterol Side-Chain Cleavage Enzyme (P450scc), encoded in the CYP11A1 gene. This is conferred by a direct stimulating effect of ACTH on the promoter of CYP11A1 (Chung et al., 1997, Liu and Simpson, 1997, Hu et al., 2001). Further, it stimulates conversion of pregnenolone to 17-hydroxypregnenolone by upregulating the expression of 3β hydroxysteroid dehydrogenase enzyme (3β-HSD) SIGNOR-268719 0.2 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr356 DSFETQRtPRKSNLD -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250760 0.858 EP400 protein Q96L91 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269289 0.695 TEAD1 protein P28347 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22286761 f gcesareni Yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor. SIGNOR-194371 0.275 G6PC3 protein Q9BUM1 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity chemical modification 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-266566 0.8 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser932 CDSGVETsFRKLSFT 9606 BTO:0000459 SIGNOR-C13 10469655 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-70473 0.848 STOML2 protein Q9UJZ1 UNIPROT CD3E protein P07766 UNIPROT up-regulates activity binding 9606 BTO:0000661 18641330 t Giorgia We observed that SLP-2 steadily associated with the CD3-epsilon chain of the TCR complex under resting conditions and during the 60 min of stimulation|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling. SIGNOR-260375 0.2 GSK3B protein P49841 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser44 GKSSVLEsLVGRDLL 9606 BTO:0000007 25192600 t miannu  We identified glycogen synthase kinase (GSK)3β-dependent Drp1 phosphorylation at Ser(40) and Ser(44), which increases Drp1 GTPase activity and its mitochondrial distribution and could induce mitochondrial fragmentation. SIGNOR-276848 0.397 RAD21 protein O60216 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24321385 t miannu We observed that depletion of RAD21 (but not CTCF) enhanced RUNX1 transcription in human HL-60 myelocytic leukemia cells SIGNOR-259973 0.287 2''-O-acetyl-ADP-D-ribose(2-) smallmolecule CHEBI:83767 ChEBI ADP-D-ribose(2-) smallmolecule CHEBI:57967 ChEBI up-regulates quantity precursor of 9606 32257385 t miannu MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins SIGNOR-269841 0.8 WNT3A protein P56704 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt Beta-catenin signaling. SIGNOR-253128 0.802 SMCR8 protein Q8TEV9 UNIPROT WIPI2 protein Q9Y4P8 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000007 28169830 t Global mRNA expression analysis revealed that SMCR8 regulates transcription of several other autophagy genes including WIPI2 SIGNOR-252028 0.274 SPI1 protein P17947 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15767686 f irozzo These data suggest that a potential positive autoregulatory loop mediated through an upstream regulatory element is essential for proper PU.1 gene expression.These data demonstrate that PU.1 protein is in a complex binding to a site within the kb −14 URE, suggesting that autoregulation through this region might be important for expression of PU.1. SIGNOR-256070 0.2 PHF12 protein Q96QT6 UNIPROT TLE3 protein Q04726 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 t miannu We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE. SIGNOR-266993 0.2 FZD3 protein Q9NPG1 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 22944199 t amattioni When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp. SIGNOR-134288 0.645 GATOR1 complex SIGNOR-C192 SIGNOR RRAGB protein Q5VZM2 UNIPROT down-regulates activity gtpase-activating protein -1 23723238 t GATOR1 has GTPase-activating protein (GAP) activity for RagA and RagB, and its components are mutated in human cancer. SIGNOR-253563 0.731 CDK1 protein P06493 UNIPROT ANAPC1 protein Q9H1A4 UNIPROT up-regulates phosphorylation Ser355 AALSRAHsPALGVHS 9606 14657031 t lperfetto Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation SIGNOR-119705 0.575 CHEK2 protein O96017 UNIPROT PML protein P29590 UNIPROT unknown phosphorylation Ser117 ESLQRRLsVYRQIVD 9606 12402044 t llicata Hcds1/chk2 phosphorylates pml at ser 117 in vitro. hcds1/chk2 phosphorylates pml in vivo. SIGNOR-94872 0.407 afatinib chemical CHEBI:61390 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 22418700 t gcesareni Afatinib is an oral, erbb family blocker, which covalently binds and irreversibly blocks all kinase-competent erbb family members. SIGNOR-196621 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser1409 SAPEDPTsPKRKMRR 9606 BTO:0000848 21087211 t lperfetto Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3 SIGNOR-244630 0.2 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 8940173 t miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246248 0.2 ANKRD11 protein Q6UB99 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity binding 9606 BTO:0000093 18840648 t miannu Ankyrin repeat domain 11, ANKRD11 (also known as ANR11 or ANCO1), was found to be a novel p53-interacting protein that enhanced the transcriptional activity of p53. In addition, ANKRD11 itself was found to be a novel p53 target gene. These findings demonstrate a role for ANKRD11 as a p53 coactivator and suggest the involvement of ANKRD11 in a regulatory feedback loop with p53. SIGNOR-266734 0.313 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr730 SNCTNELyMMMRDCW 10116 19224897 t lperfetto Furthermore, under conditions in which wild-type or mutant FGFR1 are overexpressed, Y463, Y583, Y585, and Y730 are dispensable for tyrosine phosphorylation of Shc, the mitogen-activated protein kinase (MAPK) response, and stimulation of FGFR1-mediated cell proliferation and differentiation SIGNOR-236191 0.2 lurasidone chemical CHEBI:70735 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10030 20404009 t Luana In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype. SIGNOR-257839 0.8 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI up-regulates quantity precursor of 9606 34283828 t miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). SIGNOR-267296 0.8 Laminin-1 complex SIGNOR-C183 SIGNOR A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates activity binding 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253221 0.537 KCNMA1 protein Q12791 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31152168 t miannu The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. SIGNOR-269191 0.8 CHRM2 protein P08172 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256685 0.49 AKT1 protein P31749 UNIPROT TBC1D4 protein O60343 UNIPROT down-regulates phosphorylation 9606 BTO:0000887 12637568 t gcesareni Recently, we identified a 160-kda protein in adipocytes, designated as160, that is phosphorylated by the insulin-activated kinase akt SIGNOR-252594 0.755 SMAD2 protein Q15796 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 t gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235183 0.709 FGF2 protein P09038 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates binding 9606 15780951 t gcesareni Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts. SIGNOR-134788 0.814 CSF1R protein P07333 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24890514 f miannu CSF-1R also induces the expression/activation of several other regulators of multipotent progenitor proliferation/differentiation (Fig. 4A). These include [‚Ķ] the adaptor proteins suppressor of cytokine signaling 1 (Socs1) SIGNOR-255574 0.503 TLK1 protein Q9UKI8 UNIPROT RAD9A protein Q99638 UNIPROT unknown phosphorylation Ser328 VLPSISLsPGPQPPK 9606 24376897 t The effect has been demonstrated using Q9UKI8-2 llicata Here we show that rad9 is phosphorylated in a tlk-dependent manner in vitro and in vivo, and that t355 within the c-terminal tail is the primary targeted residue. SIGNOR-203499 0.46 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP3K8 protein P41279 UNIPROT up-regulates activity phosphorylation Ser400 EDQPRCQsLDSALLE 9606 BTO:0000007 12138205 t Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator. SIGNOR-251480 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244584 0.2 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 BTO:0000586 SIGNOR-C110 16293724 t gcesareni This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. SIGNOR-141807 0.856 TFAP2A protein P05549 UNIPROT ECM1 protein Q16610 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17187826 f miannu Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. SIGNOR-255401 0.2 MYC protein P01106 UNIPROT HLA-G protein P17693 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000848 8206526 f miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. SIGNOR-254607 0.263 ATF4 protein P18848 UNIPROT CARS2 protein Q9HA77 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269417 0.26 CDK3 protein Q00526 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Thr2511 VPEHPFLtPSPESPD -1 25344755 t lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues SIGNOR-273167 0.245 CASP4 protein P49662 UNIPROT GSDMD protein P57764 UNIPROT up-regulates activity cleavage Asp275 CLHNFLTdGVPAEGA 9606 BTO:0000007 26375003 t lperfetto Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence | SIGNOR-256417 0.636 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Thr337 PGPPTGAtANRLRSA 9606 BTO:0000007 10542239 t llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T SIGNOR-250813 0.2 CSNK2A2 protein P19784 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates phosphorylation Thr89 AAPEEAEtLAETEPE 9606 BTO:0001130 16581776 t llicata In vitro kinase assays followed by mass spectrometric analyses demonstrated that ck2 phosphorylated recombinant nkx3.1 on thr89 and thr93. We have also determined that nkx3.1 is degraded primarily through a proteasomal pathway, suggesting that phosphorylation by ck2 protects nkx3.1 from degradation. SIGNOR-145501 0.32 PTP4A3 protein O75365 UNIPROT KRT8 protein P05787 UNIPROT down-regulates activity dephosphorylation Ser74 TVNQSLLsPLVLEVD 9606 BTO:0000586 19115206 t the cytoskeletal intermediate filament keratin 8 (KRT8) was identified as a physiological PRL-3-interacting protein. Indeed, treatment with the PRL-3 inhibitor effectively suppressed the phosphorylation of KRT8 at S73 and S431|The site-specific phosphorylation of keratins induces the disassembly of these filaments, and the balance between their phosphorylation and dephosphorylation controls the continuous exchange of intermediate filament subunits between a soluble pool and polymerized filaments SIGNOR-248340 0.275 DTX1 protein Q86Y01 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates binding 9606 11564735 t gcesareni Through its binding to p300, dtx1 inhibited transcriptional activation by the neural-specific helix-loop-helix-type transcription factor mash1 SIGNOR-110626 0.264 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Thr705 WKLQRAItILDTEKS 9534 BTO:0000298 14523239 t lperfetto We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. SIGNOR-249235 0.2 SGX-523 chemical CHEBI:90624 ChEBI MET protein P08581 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258282 0.8 CALM2 protein P0DP24 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity binding 9606 BTO:0001853 24379783 t miannu Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer SIGNOR-266323 0.519 glutamic acid smallmolecule CHEBI:18237 ChEBI Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270386 0.8 GSK3B protein P49841 UNIPROT EIF2B2 protein P49770 UNIPROT down-regulates binding 9606 21798082 t gcesareni Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b). SIGNOR-175475 0.2 CSNK2A2 protein P19784 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser370 TSVTPDVsDNEPDHY -1 12297295 t llicata We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).  SIGNOR-251025 0.692 SKIL protein P12757 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR down-regulates activity binding 9606 BTO:0000848 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-253302 0.838 AKT1 protein P31749 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr384 GTMKRNAtSPQVQRP 9606 20086174 t llicata We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2. SIGNOR-163537 0.363 mTORC1 complex SIGNOR-C3 SIGNOR BTRC protein Q9Y297 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002572 33861966 t miannu mTORC1 regulates the stability of CREB2. Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). SIGNOR-267829 0.29 VTI1A protein Q96AJ9 UNIPROT LE-TGN SNARE complex SIGNOR-C157 SIGNOR form complex binding 9606 BTO:0000567 18195106 t lperfetto We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport SIGNOR-253081 0.804 AGRP protein O00253 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268709 0.766 EFNA1 protein P20827 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-51939 0.935 PRKACA protein P17612 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Thr7 tSAARRSY -1 2155236 t miannu GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments. SIGNOR-249712 0.286 SLBP protein Q14493 UNIPROT H2AB2 protein P0C5Z0 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265407 0.2 DYRK1A protein Q13627 UNIPROT DYRK1A protein Q13627 UNIPROT up-regulates activity phosphorylation Tyr321 LGQRIYQyIQSRFYR 9606 BTO:0000298 11672423 t lperfetto Direct identification of phosphorylated residues by tandem ms confirmed that tyr-321, but not tyr-319, was phosphorylated. When expressed in cos-7 cells, dyrk1a was found to be fully phosphorylated on tyr-321. A catalytically inactive mutant of dyrk1a contained no detectable phosphotyrosine, indicating that tyr-321 is autophosphorylated by dyrk1a. SIGNOR-111145 0.2 ALK protein Q9UM73 UNIPROT ATIC protein P31939 UNIPROT up-regulates activity phosphorylation Tyr104 RVVACNLyPFVKTVA 9606 BTO:0002181 18845790 t miannu ATIC and VASP phosphorylation is dependent on NPM-ALK kinase activity. ATIC activity is enhanced in the presence of NPM-ALK in vitro.The ATIC activity is enhanced by NPM-ALK in HEK-293T-Rex cells. SIGNOR-276171 0.385 AGPAT4 protein Q9NRZ5 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI up-regulates chemical modification 9606 21173190 t lperfetto The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬† SIGNOR-267014 0.8 D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI up-regulates quantity precursor of 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267063 0.8 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Gln) smallmolecule CHEBI:29168 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269485 0.8 MAP3K11 protein Q16584 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 9003778 f gcesareni The kinase-inactive mlk-3 failed to activate sapk, demonstraiting that mlk-3 catalytic activity is necessary for the induction of the sapk pathway. SIGNOR-45791 0.611 RCAN1 protein P53805 UNIPROT PPP3CA protein Q08209 UNIPROT down-regulates activity binding 9606 12554096 t MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure SIGNOR-252025 0.652 AKT1 protein P31749 UNIPROT MTOR protein P42345 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 15829723 t apalma Once phosphorylated, Akt can act on a broad spectrum of substrates that can influence cell survival and proliferation and protein synthesis (65). Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K SIGNOR-255107 0.928 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RRAS protein P10301 UNIPROT up-regulates activity phosphorylation Ser186 S-->L 9606 BTO:0002181 27086924 t miannu  In this study, we report that TC21 and R-Ras are phosphorylated on a conserved serine, Ser186 and Ser201, respectively, in intact cells. This residue is located in the C-terminal hypervariable region of the proteins and is not conserved in M-Ras. We show that the MAP kinases ERK1/2 phosphorylate TC21 and R-Ras on this C-terminal serine residue both in vitro and in vivo.  SIGNOR-277220 0.2 9,11-Methanoepoxy PGH2 chemical CID:5311493 PUBCHEM TBXA2R protein P21731 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257589 0.8 GSK3B protein P49841 UNIPROT WEE1 protein P30291 UNIPROT down-regulates quantity by destabilization phosphorylation Ser211 SSVKLRGsSLFMDTE -1 24817118 t miannu Serine 211 phosphorylation occurred under control conditions in the absence of CK1δ and in the presence of GSK3-β (Fig. 5, D and E). SIGNOR-276632 0.335 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Tyr432 KEGWMVHyTSKDTLR 9606 BTO:0000567 12637538 t gcesareni Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. [..] Mutation of the other two sites, Tyr432 and Tyr502, had no significant influence on PKD activity. SIGNOR-246211 0.345 NEDD4L protein Q96PU5 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity ubiquitination 9606 19917253 t lperfetto Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation SIGNOR-217622 0.772 PTPRA protein P18433 UNIPROT PTPRA protein P18433 UNIPROT down-regulates activity dephosphorylation Tyr798 YIDAFSDyANFK 9606 7518772 t Transient overexpression of c-Src together with RPTP alpha in human embryonic kidney 293 cells increased phosphorylation of Tyr789, suggesting that c-Src may phosphorylate RPTP alpha in vivo. RPTP alpha had autodephosphorylation activity in vitro. When expressed in 293 cells the level of Tyr789 phosphorylation was higher in a non-functional mutant of RPTP alpha than in wild type RPTP alpha, indicating that RPTP alpha may have autodephosphorylation activity in vivo as well.|We show that RPTP alpha, but not a mutant of RPTP alpha with a Tyr-->Phe mutation at position 789, bound to GRB2 in vitro. SIGNOR-248439 0.2 PKD1 protein P98161 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT up-regulates activity binding 9606 BTO:0000007 23001567 t miannu Full-length PC1 bound, stabilized and colocalized with Jade-1 and inhibited Jade-1 ubiquitination. Jade-1 ubiquitination was mediated by Siah-1, an E3 ligase that binds PC1. SIGNOR-272916 0.339 glycine smallmolecule CHEBI:15428 ChEBI GLRA2 protein P23416 UNIPROT up-regulates activity chemical activation 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 t miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. SIGNOR-264981 0.8 AKT1 protein P31749 UNIPROT CDKN1C protein P49918 UNIPROT down-regulates phosphorylation Thr310 GVGSVEQtPRKRLR 9606 BTO:0000150 23421998 t lperfetto Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination SIGNOR-252536 0.459 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 10409765 f lperfetto Nf-kappab regulation of cyclin d1 occurs at the transcriptional level and is mediated by direct binding of nf-kappab to multiple sites in the cyclin d1 promoter. SIGNOR-235648 0.482 RHEB protein Q15382 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates binding 9606 18550814 t gcesareni Rheb binds and activates pld1 in vitro in a gtp-dependent manner, strongly suggesting that pld1 is a bona fide effector for rheb. SIGNOR-178892 0.553 MAPK8 protein P45983 UNIPROT AP1 complex SIGNOR-C154 SIGNOR up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 t miannu JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain. SIGNOR-252355 0.811 ELANE protein P08246 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Val72 GLTEYRLvSINKSSP -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. SIGNOR-263567 0.441 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1672 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248751 0.727 ATM protein Q13315 UNIPROT LARP7 protein Q4G0J3 UNIPROT down-regulates quantity by destabilization phosphorylation Thr440 ANREECRtQEKVNAT 32726637 t lperfetto Altogether, the results suggest that ATM-mediated T440 phosphorylation enhances LARP7-BARD1 interaction and facilitates BRCA1/BARD1-mediated LARP7 ubiquitination and degradation. SIGNOR-275580 0.2 PRSS2 protein P07478 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity cleavage Arg36 TNRSSKGrSLIGKVD -1 10978167 t lperfetto Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3. SIGNOR-263603 0.2 SRC protein P12931 UNIPROT GIT1 protein Q9Y2X7 UNIPROT up-regulates activity phosphorylation Tyr246 PDHKNGHyIIPQMAD 9534 BTO:0000298 24699139 t miannu Tyrosines 246 and 293 are required to hold GIT1 in a closed conformation.Hyperphosphorylation of GIT1-N by Src and pervanadate does not affect its binding in vitro to full length GIT1 proteins. Mutations Y246E and Y293E of GIT1 enhance binding to paxillin. SIGNOR-276626 0.558 AKT1 protein P31749 UNIPROT PEA15 protein Q15121 UNIPROT up-regulates activity phosphorylation Ser116 KDIIRQPsEEEIIKL 9606 BTO:0000007 12808093 t lperfetto Protein kinase b/akt binds and phosphorylates ped/pea-15, stabilizing its antiapoptotic action. SIGNOR-102092 0.532 POMC protein P01189 UNIPROT OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258410 0.638 GNB1 protein P62873 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates 9606 23074268 f gcesareni Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance. SIGNOR-199129 0.382 STK16 protein O75716 UNIPROT STK16 protein O75716 UNIPROT unknown phosphorylation Ser197 AAQRCTIsYRAPELF -1 18184589 t Manara Indeed, our kinetic analysis of MPSK1 autophosphorylation showed that autophosphorylation is a slow process and that two of the three identified sites are largely buried in unphosphorylated MPSK1. However, two autophosphorylation sites are located in the P + 1 loop and phosphorylation at these locations might affect substrate recognition. SIGNOR-260804 0.2 RAD50 protein Q92878 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 18854157 t gcesareni One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase. SIGNOR-181634 0.806 EGFL7 protein Q9UHF1 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 9606 20372059 f miannu EGFL7 drives the formation of neurons from neural stem cells. In the embryonic and adult brain this process is essential for neurogenesis and homeostasis of the nervous system. In this review, we discuss the implications of our findings for adult neurogenesis and illustrate the potential of EGFL7 to serve as an agent to increase neurogenesis and the self-renewal potential of the brain SIGNOR-266859 0.7 PLK1 protein P53350 UNIPROT SUN1 protein O94901 UNIPROT down-regulates activity phosphorylation Ser138 RPPVLDEsWIREQTT 9606 25482198 t miannu Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions. SIGNOR-263098 0.465 EZH2 protein Q15910 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR form complex binding 9606 23110252 t lperfetto The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48). SIGNOR-241894 0.911 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL2 protein P13500 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 f apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255356 0.567 MIF protein P14174 UNIPROT CD74 protein P04233 UNIPROT up-regulates activity binding 9606 12782713 t gcesareni MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal-regulated kinase-1/2 MAP kinase cascade, cell proliferation, and PGE2 production SIGNOR-252060 0.724 CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 29958106 f miannu In adult hematopoiesis, allelic CBFβ-SMMHC expression alters hematopoietic stem cell (HSC) differentiation, with clonal expansion of the short-term HSCs and pre-leukemic myeloid progenitor cells SIGNOR-255736 0.7 TLN1 protein Q9Y490 UNIPROT Av/b8 integrin complex SIGNOR-C185 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257637 0.515 GRPR protein P30550 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257314 0.252 SLBP protein Q14493 UNIPROT H3C15 protein Q71DI3 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265414 0.2 ITCH protein Q96J02 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates ubiquitination 9606 BTO:0001253 10940313 t gcesareni Itch binds to the n-terminal portion of the notch intracellular domain via its ww domains and promotes ubiquitination of notch through its hect ubiquitin ligase domain. SIGNOR-80702 0.629 RBM10 protein P98175 UNIPROT CASP3 protein P42574 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30403180 f irozzo In this study, we report that RBM10 acts as a tumor suppressor in osteosarcoma via the inhibition of cell growth, cell migration and invasion and the induction of cell apoptosis by inhibiting Bcl-2, activating caspase-3, and producing TNF-α. We also found that RBM10 overexpression significantly inhibited the expression of Bcl-2 and induced the expression of caspase-3 SIGNOR-259152 0.2 EXOC2 protein Q96KP1 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270785 0.96 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser639 DEICIAGsPLTPRRV 9606 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. SIGNOR-104679 0.844 LATS2 protein Q9NRM7 UNIPROT PRPS2 protein P11908 UNIPROT down-regulates quantity by destabilization phosphorylation Thr285 EDKMKHCtKIQVIDI -1 34465890 t miannu  Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness. SIGNOR-276507 0.2 TNF protein P01375 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253493 0.28 MRPL33 protein O75394 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262364 0.685 CBFB protein Q13951 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates quantity by stabilization binding 10090 11179217 t irozzo We observed previously that the RUNX proteins are susceptible to proteolytic degradation (Ogawa et al., 1993b). In this study, we show that the ubiquitin‚proteasome system is largely responsible for this degradation. We also show that when PEBP2Œ≤ dimerizes with RUNX it inhibits the ubiquitylation of RUNX, which is necessary for the protein to be targeted for proteolysis by the proteasome. SIGNOR-255712 0.842 TP53 protein P04637 UNIPROT DRAM2 protein Q6UX65 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30755245 f irozzo DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression. SIGNOR-259148 0.311 creatine smallmolecule CHEBI:16919 ChEBI CKMT2 protein P17540 UNIPROT up-regulates activity chemical activation 9606 18502307 t miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. SIGNOR-265785 0.8 NR3C1 protein P04150 UNIPROT TIMELESS protein Q9UNS1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19805059 t miannu GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription SIGNOR-268052 0.255 SNRPB protein P14678 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270628 0.772 ADORA2A protein P29274 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256909 0.321 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI 4-(trimethylammonio)butanoate smallmolecule CHEBI:16244 ChEBI up-regulates quantity precursor of 9606 11802770 t miannu Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). SIGNOR-269696 0.8 ADSS1 protein Q8N142 UNIPROT N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI up-regulates quantity chemical modification 9606 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267348 0.8 CDK2 protein P24941 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates phosphorylation Thr141 RRDARGLtPLELALQ 9606 22558186 t lperfetto Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively.we propose a sequential phosphorylation model for p19 in which modification at s76 would enable a second phosphorylation event at t141. The phosphorylation-induced structural changes could have functional implicancies for p19 in the dna damage response SIGNOR-197274 0.528 SCF-FBW7 complex SIGNOR-C135 SIGNOR XRCC4 protein Q13426 UNIPROT up-regulates activity ubiquitination Lys296 QENQLQEkENSRPDS 9606 BTO:0002137 26774286 t miannu In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair.  SIGNOR-277200 0.306 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT up-regulates activity phosphorylation Tyr220 PETEENIyQVPTSQK 10090 11279201 t lperfetto Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons. SIGNOR-247080 0.43 NFKBIA protein P25963 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity binding 9606 SIGNOR-C13 1340770 t lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b. SIGNOR-17691 0.887 NCR2 protein O95944 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 BTO:0000914 22021614 f miannu NK cells play an important role in the early immune response to cancer. The NKp44 activating receptor is the only natural cytotoxicity receptor that is expressed exclusively by primate NK cells, yet its cellular ligands remain largely unknown. Proliferating cell nuclear Ag (PCNA) is overexpressed in cancer cells. In this study, we show that the NKp44 receptor recognizes PCNA. Their interaction inhibits NK cell function through NKp44/ITIM. SIGNOR-260044 0.7 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ECT2 protein Q9H8V3 UNIPROT down-regulates phosphorylation Thr373 VSMLSLNtPNSNRKR 9606 16170345 t lperfetto We show that phosphorylation of ect2 at threonine-341 (t341) affects the autoregulatory mechanism of ect2. In g2/m phase, ect2 was phosphorylated at t341 most likely by cyclin b/cyclin-dependent kinase 1 (cdk1) ect2 is biologically active even when it is not phosphorylated at t341 SIGNOR-216864 0.499 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 24585778 t miannu Length-dependent activation is modulated by cardiac troponin i bisphosphorylation at ser23 and ser24 but not by thr143 phosphorylation. Thr143 is a known target of protein kinase c (pkc) whose activity is increased in cardiac disease SIGNOR-204666 0.275 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1222 ESSSTRRsSEDLSAY 9606 BTO:0000975 17360977 t lperfetto Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 SIGNOR-236729 0.2 ADRA1D protein P25100 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256951 0.281 NDN protein Q99608 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by stabilization binding 9606 26971449 t lperfetto Necdin binds and stabilizes PGC-1α|Necdin strongly stabilizes PGC-1α by inhibiting its ubiquitin-dependent degradation. Forced expression of necdin enhances mitochondrial function in primary cortical neurons and human SH-SY5Y neuroblastoma cells to prevent mitochondrial respiratory chain inhibitor-induced degeneration. SIGNOR-253390 0.332 STRADA protein Q7RTN6 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity binding 9606 12805220 t Gianni Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners.LKB1 phosphorylates STRAD at Thr329 and Thr419 SIGNOR-247560 0.938 APOA1 protein P02647 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 23077142 f miannu Cholesterol efflux is the first step in the formation of HDL, which is initiated through the action of ATP binding cassette transporter (ABC) A1 on apolipoprotein (apo) A-I that produces nascent HDL (nHDL). SIGNOR-252110 0.7 HERC5 protein Q9UII4 UNIPROT NME2 protein P22392 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 BTO:0000007 18535780 t miannu HERC5 is required for ubiquitination of Nm23B. In summary, Nm23B ubiquitination is mediated by HERC5. Stable Nm23B protein in presence of HERC5 as well as proteasome-independent ubiquitination suggest that ubiquitination of Nm23B serves a different purpose than marking it for degradation. SIGNOR-271778 0.311 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation 6239 SIGNOR-C15 17900900 t lperfetto The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt. SIGNOR-252983 0.509 HES1 protein Q14469 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 16682003 t gcesareni Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression. SIGNOR-146684 0.583 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 f miannu Smad4 interacted withSmad2/3 and participated in the transcription of downstream pro-fi-brotic target genes SIGNOR-260441 0.7 PRKACA protein P17612 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Ser455 PAPSRTAsFSESRAD -1 10653665 t miannu Phosphorylation of Recombinant Human ATP:Citrate Lyase by cAMP-Dependent Protein Kinase Abolishes Homotropic Allosteric Regulation of the Enzyme by Citrate and Increases the Enzyme Activity. Ser 454, which is phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PKA) SIGNOR-250328 0.314 ZNF503 protein Q96F45 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 25538248 f Monia We asked whether higher pFAK staining in cells expressing Zpo2 correlates with reduced E-cadherin levels. Immunostaining for E-cadherin in the EpH4.9 and PyMT stable cell lines indicated a decrease in overall E-cadherin staining in Zpo2-overexpressing cells compared with the control (Fig. 6C). Similarly, Western blot analysis indicated a reduction in E-cadherin expression in Zpo2-expressing cells compared with the control (Fig. 6D). SIGNOR-261190 0.2 XRCC4 protein Q13426 UNIPROT DNA-PK complex SIGNOR-C107 SIGNOR up-regulates activity binding 9606 BTO:0002137 26774286 t miannu In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair.  SIGNOR-277201 0.815 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 9841871 t lperfetto When truncated mapkkk4 (deltamapkkk4) was overexpressed in hek293 cells, it was constitutively activeco-expressed map kinase kinase (mkk)-1, mkk-4, mkk-3 and mkk-6 were activated in vivo by deltamapkkk4. All of the above mkks purified from escherichia coli were phosphorylated and activated by deltamapkkk4 immunoprecipitates in vitro. SIGNOR-62369 0.549 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 19864431 t lperfetto Here we focus primarily although not exclusively on raptor Ser(863) phosphorylation. We report that insulin promotes mTORC1-associated phosphorylation of raptor Ser(863) via the canonical PI3K/TSC/Rheb pathway in a rapamycin-sensitive manner. mTORC1 activation by other stimuli (e.g. amino acids, epidermal growth factor/MAPK signaling, and cellular energy) also promote raptor Ser(863) phosphorylation. SIGNOR-217559 0.392 CSNK1E protein P49674 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Thr41 YSTTPGGtLFSTTPG 9606 BTO:0000150 24247720 t lperfetto Mechanistic investigations showed that ck1_ interacted with and phosphorylated 4e-bp1 at two novel sites t41 and t50, which were essential for 4e-bp1 inactivation along with increased mrna translation and cell proliferation. SIGNOR-203240 0.2 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. SIGNOR-164471 0.553 KDM2B protein Q8NHM5 UNIPROT RNF2 protein Q99496 UNIPROT up-regulates activity binding 9606 17296600 t miannu BcoR and Fbxl10/Jhdm1B are among the most abundant Ring1B/Rnf2 interactors identified with the highest confidence, and their association has been validated by coimmunoprecipitation studies; hence we call this the Fbxl10-BcoR complex. The assembly of Fbxl10-BcoR complex(es), the associations among its various subunits, and its functional significance remain to be characterized but are presently under investigation. SIGNOR-252242 0.628 CALM1 protein P0DP23 UNIPROT EEF2K protein O00418 UNIPROT up-regulates binding 9606 11015200 t gcesareni The calmodulin-binding region is located between amino acids 51 and 96 SIGNOR-82505 0.477 MAP2K2 protein P36507 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Thr125 PEVLRPEtPRPVDIG 12792650 t lperfetto Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK|The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2 SIGNOR-249386 0.354 AKT2 protein P31751 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245420 0.607 EFNA5 protein P52803 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52476 0.893 ABL1 protein P00519 UNIPROT KAT5 protein Q92993 UNIPROT down-regulates activity phosphorylation Tyr294 HPPGNEIyRKGTISF 9606 BTO:0000007 24044023 t miannu We present evidence that Tip60 is modified on tyrosine 327 by Abl kinase. We show that this causes functional changes in HAT activity and the subcellular localization of TIP60, which forms a complex with Abl kinase. The Tip60 mutation Y327F abolished tyrosine phosphorylation, reduced the inhibition of Tip60 HAT activity, and caused G0-G1 arrest and association with FE65.  SIGNOR-276598 0.633 AP2M1 protein Q96CW1 UNIPROT SLC24A2 protein Q9UI40 UNIPROT down-regulates quantity binding 9606 BTO:0000938 SIGNOR-C245 23431067 t miannu  we report that the first tyrosine motif of NCKX2 interacts with AP2M1 and that the interaction is required for endocytosis of NCKX2 from the dendritic surface. Furthermore, we show that a Src family kinase (SFK) modulates the endocytosis of NCKX2 by tyrosine-phosphorylation of the AP-2 recognition motif in NCKX2. SIGNOR-264388 0.2 docetaxel anhydrous chemical CHEBI:4672 ChEBI TUBB1 protein Q9H4B7 UNIPROT down-regulates activity chemical inhibition 9606 23337758 t miannu Tubulin exists in the cell as dimers of α and β subunits, which complexes with a variety of regulatory proteins. There is a dynamic equilibrium between free and polymerized tubulin causing a state called "dynamic instability," which is a target of anticancer drugs, which inhibit tubulin through polymerization (taxanes, epothilones) or depolymerization (vinca alkaloids). Docetaxel-based therapy was the first such treatment to demonstrate a survival benefit in men with castration-resistant prostate cancer. SIGNOR-259343 0.8 DNM1L protein O00429 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 10090 BTO:0002295 31063459 f lperfetto Mitochondrial fission is governed primarily by the cytoplasmic dynamin-related protein 1 (Drp1). Drp1 is a conserved dynamin GTPase superfamily protein that is translocated from its cytoplasmic pool to the outer mitochondrial membrane, where Drp1 then assembles into constrictive ring-like multimeric structures, ultimately driving mitochondrial fragmentation through a GTP-dependent mechanism|We have also previously reported that ROCK1-mediated Drp1S600 phosphorylation resulted in enhanced mitochondrial fission in podocytes SIGNOR-262553 0.7 SL-327 chemical CHEBI:92211 ChEBI MAPK7 protein Q13164 UNIPROT down-regulates chemical inhibition 9606 BTO:0000938 BTO:0000142 11160424 t gcesareni Pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity (impey et al., 1999) and neuronal survival (villalba and journot, 1997;meyerfranke et al., 1998;skaper et al., 1998;anderson and tolkovsky, 1999;singer et al., 1999;bi et al., 2000). Interestingly, erk5 activation by egf in cos7 cells is also blocked by these inhibitors, (kamakura et al., 1999), suggesting that the erk5 pathway may also regulate cellular processes credited previously to erk1/2. SIGNOR-104936 0.8 RAB7A protein P51149 UNIPROT PSMA7 protein O14818 UNIPROT up-regulates activity binding 10036 14998988 t Sara Rab7 Forms a Complex with the Proteasome -Subunit XAPC. In this study the proteasome alpha-subunit XAPC7 (also known as PSMA7, RC6-1, and HSPC in mammals) was identified to interact specifically with Rab7 and was recruited to multivesicular late endosomes through this interaction. SIGNOR-261303 0.349 ZDHHC5 protein Q9C0B5 UNIPROT S1PR1 protein P21453 UNIPROT up-regulates activity palmitoylation 9606 BTO:0000793 29185452 t We propose that DHHC5-mediated palmitoylation of S1P1R determines Gi coupling and its signalling in a spatio/temporal manner. SIGNOR-261140 0.2 CUL3 protein Q13618 UNIPROT RHOA protein P61586 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19782033 t miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. SIGNOR-264238 0.405 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-268095 0.8 OXSR1 protein O95747 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser130 GPKVNRPsLLEIHEQ 9606 BTO:0000007 21321328 t miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). SIGNOR-276309 0.516 AP-2 complex complex SIGNOR-C245 SIGNOR Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 10116 BTO:0000142 15496985 f lperfetto Intersectins 1 and 2, epsin2, NECAP and sorting nexin9 were identified as α‐appendage ligands in mass spectrometry of these samples SIGNOR-260416 0.7 SOD2 protein P04179 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI down-regulates quantity chemical modification 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272281 0.8 ASIP protein P42127 UNIPROT MC2R protein Q01718 UNIPROT down-regulates activity binding 9606 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and α, β, and γ melanocyte–stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268695 0.512 HES1 protein Q14469 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 14614508 f Overexpression of HES-1 fully repressed PPAR-g even in the presence of the ACREB inhibitor, showing that HES-1 acts downstream of CREB SIGNOR-254743 0.25 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000586 SIGNOR-C110 16293724 t gcesareni This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. SIGNOR-141803 0.856 GNE protein Q9Y223 UNIPROT N-acyl-D-mannosamine 6-phosphate(2-) smallmolecule CHEBI:57666 ChEBI up-regulates quantity chemical modification 10745088 t lperfetto UDP-GlcNAc 2-epimerase is a bifunctional enzyme and catalyzes the first two steps of neuraminic acid synthesis in the cytosol, the conversion of UDP-N-acetylglucosamine to ManAc and the phosphorylation to ManAc-6-phosphate. SIGNOR-266074 0.8 MAP2K4 protein P45985 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP -1 9162092 t Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4. SIGNOR-251421 0.2 PRKCB protein P05771 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1303 NKLRRQHsYDTFVDL -1 11306676 t lperfetto These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. SIGNOR-249084 0.371 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2D2 protein P62837 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271323 0.846 ITGB7 protein P26010 UNIPROT A4/b7 integrin complex SIGNOR-C187 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253294 0.853 PTPRZ1 protein P23471 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity dephosphorylation 9606 23100427 t miannu PTPRZ1 constitutively promotes the tyrosine dephosphorylation of \u03b2-catenin, and thus \u03b2-catenin participation in TCF-mediated transcription. SIGNOR-277044 0.386 CSRP3 protein P50461 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 10090 BTO:0004058 9234731 t 2 miannu we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements. SIGNOR-241116 0.48 CDCA5 protein Q96FF9 UNIPROT WAPL protein Q7Z5K2 UNIPROT down-regulates activity binding 7227 21111234 t lperfetto We show that DNA replication and cohesin acetylation promote binding of Sororin to cohesin, and that Sororin displaces Wapl from its binding partner Pds5.  SIGNOR-265266 0.2 SIK3 protein Q9Y2K2 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates activity phosphorylation Ser70 RSSHYGGsLPNVNQI 9606 BTO:0000567 16306228 t lperfetto We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression SIGNOR-249171 0.62 MAPK8 protein P45983 UNIPROT ATN1 protein P54259 UNIPROT down-regulates activity phosphorylation Ser739 EEYETPEsPVPPARS 9606 BTO:0000142 12812981 t lperfetto Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment, SIGNOR-102398 0.384 WT1 protein P19544 UNIPROT Urogenital_tract phenotype SIGNOR-PH71 SIGNOR up-regulates activity 10090 10101119 f The Wilms' Tumour gene WT1 has important functions during development. Knock-out mice were shown to have defects in the urogenital system and to die at embryonic day E13.5, probably due to heart failure. SIGNOR-252302 0.7 RCSD1 protein Q6JBY9 UNIPROT CAPZA1 protein P52907 UNIPROT up-regulates binding -1 15850461 t miannu An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B). Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. SIGNOR-263088 0.688 MTOR protein P42345 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser422 AEAFLGFsYAPPTDS 9606 SIGNOR-C3 18570873 t llicata Mtor phosphorylated sgk1, but not sgk1-s422a, in vitro. Sgk1 phosphorylated p27 in vitro. These data implicate sgk1 as an mtorc1 (mtor-raptor) substrate. mtor may promote g1 progression in part through sgk1 activation SIGNOR-179113 0.844 TWIST1 protein Q15672 UNIPROT AKR1C2 protein P52895 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255510 0.2 FOXO proteinfamily SIGNOR-PF27 SIGNOR CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17873901 f gcesareni Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity SIGNOR-252917 0.2 GFs stimulus SIGNOR-ST12 SIGNOR RTKs proteinfamily SIGNOR-PF38 SIGNOR up-regulates 9606 17306385 t miannu Multiple growth- and differentiation-inducing polypeptide factors bind to and activate transmembrane receptors tyrosine kinases (RTKs), to instigate a plethora of biochemical cascades culminating in regulation of cell fate. SIGNOR-256169 0.7 NFATC4 protein Q14934 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21871017 t miannu NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration SIGNOR-264027 0.285 TNF protein P01375 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity 10090 10485710 f lperfetto Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k). SIGNOR-70616 0.276 MYT1L protein Q9UL68 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005949 30312684 t miannu Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression. Examination of the gene expression changes in cells expressing Myt1 or Myt1l suggests that both repress expression of the YAP1 transcriptional coactivator, which functions primarily in the Hippo signaling pathway. Expression of YAP1 and its target genes is reduced in Myt-expressing cells, and there is an inverse correlation between YAP1 and MYT1/MYT1L expression in human brain cancer datasets. Together, our data suggest that Myt1 and Myt1l directly repress expression of YAP1, a protein which promotes proliferation and GBM growth. SIGNOR-266778 0.2 Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 10090 9388774 f gcesareni Myogenic precursor cells withdraw irreversibly from the cell cycle as they differentiate into mature myotubes. Cell cycle exit occurs early during the differentiation program and is required for normal expression of the contractile phenotype. SIGNOR-243206 0.7 ammonium smallmolecule CHEBI:28938 ChEBI L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity precursor of 9606 30158707 t miannu Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction. SIGNOR-267823 0.8 MS4A2 protein Q01362 UNIPROT FCER1 complex SIGNOR-C200 SIGNOR form complex binding 9606 BTO:0000830 16470226 t Alessandro Palma FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling. SIGNOR-254960 0.668 AMPK complex SIGNOR-C15 SIGNOR ZNF692 protein Q9BU19 UNIPROT down-regulates phosphorylation Ser470 VAAHRSKsHPALLLA 9606 17097062 t lperfetto Arebp is phosphorylated at ser(470) by ampk. Phosphorylation reduces the dna-binding activity of arebp. SIGNOR-216519 0.2 PRKAA1 protein Q13131 UNIPROT MCU protein Q8NE86 UNIPROT up-regulates activity phosphorylation Ser57 TVHQRIAsWQNLGAV -1 30858581 t lperfetto Cellular ATP levels drop during early mitosis, and the mitochondrial Ca2+ transients boost mitochondrial respiration to restore energy homeostasis. This is achieved through mitosis-specific MCU phosphorylation and activation by the mitochondrial translocation of energy sensor AMP-activated protein kinase (AMPK). |In vitro kinase assays showed that AMPK immunoprecipitated from cells as well as recombinant AMPK phosphorylated MCU at Ser57 SIGNOR-275547 0.2 Complement C1 complex complex SIGNOR-C309 SIGNOR C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Gly1446 TPLQLFEgRRNRRRR -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263430 0.629 DOK1 protein Q99704 UNIPROT ITGB2 protein P05107 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257680 0.301 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI up-regulates quantity precursor of 9606 BTO:0000050 25855791 t lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively SIGNOR-268642 0.8 GMPS protein P49915 UNIPROT 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI down-regulates quantity chemical modification 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267337 0.8 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-252806 0.2 MC1R protein Q01726 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256956 0.352 SRC protein P12931 UNIPROT BTK protein Q06187 UNIPROT up-regulates activity phosphorylation Tyr551 RYVLDDEyTSSVGSK 9606 8629002 t This interaction of BTK with SRC kinases transphosphorylated BTK on tyrosine at residue 551, which led to BTK activation. SIGNOR-251100 0.509 MAG protein P20916 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 17241126 f SimoneGraziosi The myelin-associated glycoprotein (MAG) is a type I transmembrane glycoprotein localized in periaxonal Schwann cell and oligodendroglial membranes of myelin sheaths where it functions in glia-axon interactions. SIGNOR-269231 0.7 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2B protein P63146 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271368 0.651 DVL1P1 protein P54792 UNIPROT PRKCA protein P17252 UNIPROT up-regulates binding 9606 23151663 t gcesareni Our findings suggest a molecular interaction between pka, hdpr1, and dvl and a possible contribution of this interaction to tumorigenesis. SIGNOR-199454 0.2 GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263811 0.8 NLK protein Q9UBE8 UNIPROT TCF4 protein P15884 UNIPROT down-regulates phosphorylation 9606 2861485 t gcesareni Whereas lef-1 and tcf-4 phosphorylation by nlk (nemo-like kinase) leads to less lef/tcf/beta-catenin complex binding to dna and to lef-1/tcf-4 degradation SIGNOR-24147 0.2 PRKAA2 protein P54646 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser295 RYHGHSMsDPGVSYR -1 33022274 t miannu AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex SIGNOR-276840 0.2 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1784 TPTSPNYsPTSPSYS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248826 0.849 GALR3 protein O60755 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257114 0.252 CSNK2A1 protein P68400 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates phosphorylation Ser737 PEEIIVLsDSD 9606 21474068 t lperfetto Daxx-sim is phosphorylated by ck2 kinase at residues s737 and s739. Phosphorylation promotes daxx-sim binding affinity toward sumo-1 over sumo-2/3, causing daxx preference for sumo-1 conjugation and interaction with sumo-1-modified factors. SIGNOR-173105 0.332 CRX protein O43186 UNIPROT RBP3 protein P10745 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10354480 f miannu OTX2, as well as CRX, a homeodomain protein very similar to OTX2, activates the human IRBP promoter in co-transfection experiments. SIGNOR-254890 0.389 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259018 0.409 EHF protein Q9NZC4 UNIPROT SPRR1B protein P22528 UNIPROT up-regulates quantity by expression transcriptional regulation 12682075 f Consistent with this, overexpression of EBS-binding proteins ESE-1 and ESE-3 significantly stimulated SPRR1B promoter activity. Furthermore, preceding SPRR1B transcription, PMA up-regulated mRNA expression of ETS family members such as ESE-1 and ESE-3 SIGNOR-254280 0.24 KDM3A protein Q9Y4C1 UNIPROT H3-2 protein Q5TEC6 UNIPROT up-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 16603237 t miannu Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.  SIGNOR-276843 0.2 MYC protein P01106 UNIPROT HLA-B protein P01889 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000848 8206526 f miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. We show here that transcription of the HLA-B locus, which is mainly affected by c-Myc, is downmodulated at the level of initiation of transcription. SIGNOR-254606 0.268 NPM1 protein P06748 UNIPROT FBP1 protein P09467 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003081;BTO:0000849 30616754 t lperfetto For instance, nucleophosmin (NPM1) and zinc-finger protein X-linked (ZFX) bind to the E-box and ZFX binding site on the FBP1 promoter, respectively, and restrain FBP1 expression to facilitate aerobic glycolysis in PDAC and melanoma SIGNOR-267594 0.2 SEMA4D protein Q92854 UNIPROT PLXNB1 protein O43157 UNIPROT up-regulates binding 9606 12198496 t gcesareni Binding of sema 4d to plexin b1 stimulates the tyrosine kinase activity of met, resulting in tyrosine phosphorylation of both receptors. SIGNOR-92201 0.801 F2 protein P00734 UNIPROT F8 protein P00451 UNIPROT up-regulates activity cleavage Arg391 SPSFIQIrSVAKKHP -1 10350471 t lperfetto Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689. SIGNOR-263640 0.746 GATA3 protein P23771 UNIPROT TBX21 protein Q9UL17 UNIPROT down-regulates 9606 16386358 f Conversely, T-bet is capable of inhibiting GATA-3 (Szabo et al., 2000). The mutual inhibition between GATA-3 and T-bet ensures that Th1 and Th2 cells express one or the other molecule (T-bet in Th1, and GATA-3 in Th2), but not both SIGNOR-254296 0.752 SPEN protein Q96T58 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 12374742 t gcesareni We identified sharp as an rbp-jkappa/cbf-1-interacting corepressor in a yeast two-hybrid screen. SIGNOR-94201 0.691 NOTCH proteinfamily SIGNOR-PF30 SIGNOR HEY1 protein Q9Y5J3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0001593 15207708 f gcesareni Deltex, meltrin beta, ifi-202, and ifi-204 were also upregulated by notchic in the 2b4.11 t cell hybridoma, whereas ifi-d3 was expressed constitutively at relatively high levels and slightly upregulated by notchic, and pre-talfa was not expressed. Deltex, meltrin beta, pre-talfa, ifi-202, and ifi-204 were upregulated by notchic expression in the akr1 dp thymoma cell line, whereas ifi-d3 was not expressed SIGNOR-254341 0.2 FGF2 protein P09038 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 20974802 f gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription SIGNOR-168998 0.386 PTCRA protein Q6ISU1 UNIPROT LCK protein P06239 UNIPROT up-regulates activity binding 9606 20626350 t lperfetto However, non-canonical mechanisms of p38alfa activation have been also described. One is apparently specific to antigen receptor stimulated t-lymphocytes. This involves phosphorylation of p38alfa on tyr323 by the tcr-proximal tyrosine kinase zap70 and p56lck. SIGNOR-166658 0.34 MAPK8 protein P45983 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 20974802 t gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription. SIGNOR-169007 0.391 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates activity phosphorylation Ser511 RREERSLsAPGNLLT 9534 BTO:0000298 32913128 t miannu  Here we show that stimulation of cAMP-dependent protein kinase A (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues.  SIGNOR-277240 0.2 ACP3 protein P15309 UNIPROT adenosine smallmolecule CHEBI:16335 ChEBI up-regulates quantity chemical modification -1 18940592 t Luana Specifically, PAP dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine and activates A1-adenosine receptors in dorsal spinal cord. SIGNOR-269739 0.8 oxandrolone chemical CHEBI:7820 ChEBI AR protein P10275 UNIPROT up-regulates activity chemical activation 9606 10077001 t miannu The anabolic steroids, oxandrolone and fluoxymesterone, have high inhibition constants for binding, yet induce the N/C interaction and stabilize AR at relatively low ligand concentrations and are AR agonists in vivo. SIGNOR-259265 0.8 AKT1 protein P31749 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates activity phosphorylation Thr779 LYKEATStFTNITYR 9606 BTO:0000132 10896934 t gcesareni A survey of several protein kinases revealed that Thr-753 was avidly phosphorylated by PDK1 and Akt/PKB in vitro. These observations suggest that activation of PDK1 and/or Akt/PKB in platelets may modulate the binding activity and/or specificity of beta(3) for signaling molecules. SIGNOR-252552 0.597 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BANP protein Q8N9N5 UNIPROT down-regulates activity phosphorylation Thr352 PSEPMMStPPPASEL 9606 BTO:0000567 26080397 t miannu ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68. SIGNOR-266378 0.2 HRK protein O00198 UNIPROT BCL2 protein P10415 UNIPROT down-regulates binding 9606 9130713 t gcesareni Hrk, physically interacts with the death-repressor proteins bcl2 and bcl2l1. Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by bcl2 and bcl2l1. SIGNOR-47794 0.484 MAOA protein P21397 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI down-regulates quantity chemical modification 9606 31024440 t brain lperfetto Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA). SIGNOR-264014 0.8 LETM1 protein O95202 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR up-regulates 9606 BTO:0000567 18628306 f lperfetto LETM1 knockdown obviously reduced the formation of the supercomplexes (Fig. 5C, arrowhead). Complexes I and IV failed to form, and the assembly of complex III was significantly decreased. By contrast, the assembly of complex II (succinate dehydrogenase) and complex V (ATP synthase) – which are not proton pumps – was unaffected. SIGNOR-262548 0.294 N-[3-[[5-bromo-4-[2-(1H-imidazol-5-yl)ethylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide chemical CHEBI:91357 ChEBI PDPK1 protein O15530 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190804 0.8 SNRPF protein P62306 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270658 0.698 MMP17 protein Q9ULZ9 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272362 0.7 TNKS protein O95271 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19759537 t lperfetto Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. SIGNOR-187975 0.764 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser795 SPYKFPSsPLRIPGG 9606 BTO:0000150 23336272 t lperfetto Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. SIGNOR-216992 0.858 ATM protein Q13315 UNIPROT PPP2R5D protein Q14738 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001938 21460856 t miannu In the present study, we demonstrate that ataxia-telangiectasia mutated (ATM) directly phosphorylates and specifically regulates B56γ3, B56γ2 and B56δ, after DNA damage. We further show that phosphorylation of B56γ3 at Ser510 leads to an increase in B56γ3-PP2A complexes, and direction of PP2A phosphatase activity toward the substrate p53, activating its tumor-suppressive functions. we show that Ser510 phosphorylation significantly enhances the ability of B56γ3 to inhibit cell proliferation and anchorage-independent growth. SIGNOR-276319 0.301 NCOA1 protein Q15788 UNIPROT OTC protein P00480 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255062 0.2 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr209 TRKHYQPyAPPRDFA 9606 BTO:0000782;BTO:0001271 8992971 t lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tailother studies demonstrated that tyr191 within the p190yap motif is one of two major phosphorylation sites in cd28-stimulated jurkat t cells, and the only tyrosine residue within the cd28 cytoplasmic tail that is essential for delivery of costimulatory signals SIGNOR-45516 0.677 TCF7L1 protein Q9HCS4 UNIPROT NANOG protein Q9H9S0 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001581 16894029 t Luana These experiments showed that Tcf3 is associated with chromatin in the Nanog promoter regions and that the DNA-binding activity of Tcf3 was required for repression. SIGNOR-266081 0.348 PPARGC1A protein Q9UBK2 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates 9606 19491292 f gcesareni Nuclear pgc-1alpha and foxo3a respond in a reciprocal manner following aicar treatment. SIGNOR-186058 0.402 CCL3 protein P10147 UNIPROT CCR5 protein P51681 UNIPROT up-regulates activity binding 10090 20219869 t areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.  SIGNOR-255115 0.738 P2RY1 protein P47900 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257185 0.2 CSNK1A1 protein P48729 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-250786 0.29 MAPK1 protein P28482 UNIPROT TNKS1BP1 protein Q9C0C2 UNIPROT unknown phosphorylation Thr1032 GGLFSPStAHVPDGA 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262781 0.2 WDR62 protein O43379 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity relocalization 10090 30566428 t lperfetto In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis SIGNOR-271716 0.299 GLA protein P06280 UNIPROT 1,3-dichloro-7-hydroxy-9,9-dimethyl-9H-acridin-2-one smallmolecule CHEBI:52012 ChEBI up-regulates quantity by expression chemical modification -1 31996391 t lperfetto DDAOG is cleaved by -galactosidase ( Lindvall et al., 2009 ) in the Trpv1 cells to produce 7-hydroxy-9H(I,3-dichloro-9,9-dimethylacridin-2-one (DDAO). SIGNOR-261334 0.8 PPP2R2A protein P63151 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity binding 10090 BTO:0000944 18042541 t gcesareni Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural |Here we report the identification of the specific B regulatory subunit that targets the PP2A holoenzyme to Akt. We found endogenous association of PP2A AB55C holoenzymes with Akt by co-immunoprecipitation analyses in pro-lymphoid FL5.12 cells.subunit (A), catalytic subunit (C), and a variable regulatory subunit (B). SIGNOR-243526 0.474 axitinib chemical CHEBI:66910 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258075 0.8 PRKACA protein P17612 UNIPROT RGS14 protein O43566 UNIPROT up-regulates activity phosphorylation Thr495 SATGKRQtCDIEGLV -1 12534294 t miannu RGS14 is phosphorylated in vitro at Ser258 and Thr494 by PKA. cAMP-induced phosphorylation as an important modulator of RGS14 function since phosphorylation could enhance RGS14 binding to Galpha(i)-GDP SIGNOR-250046 0.344 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 t gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation SIGNOR-252441 0.634 GSK3B protein P49841 UNIPROT GATA6 protein Q92908 UNIPROT down-regulates quantity by destabilization phosphorylation Ser37 REPSTPPsPISSSSS 9606 BTO:0000182 27273097 t miannu We identified the AKT-repressed signal as glycogen synthase kinase 3 (GSK3)-catalyzed phosphorylation of Ser(37) on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser(37) promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin.  SIGNOR-277241 0.314 IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates binding 9606 10986460 t fspada Molecular interactions among cytokines and cytokine receptors form the basis of many cell-signaling pathways relevant to immune function. Interferon-g (ifng) signals through a multimeric receptor complex consistingof two different but structurally related transmembrane chains: the high-affinityreceptor-binding subunit (ifn-gra) and a species-specific accessory factor (af-1 or ifn-grb). SIGNOR-81804 0.882 ADNP protein Q9H2P0 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 24365867 f miannu Here, we show for the first time that hippocampal ADNP deficiency paralleled reduced beclin1 expression which, in turn, parallels increased tauopathy and cell death. We now show that ADNP directly interacts with LC3B, implicating the requirement of a healthy ADNP system for the apoptotic/autophagy processes. SIGNOR-266760 0.252 PPP3CC protein P48454 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates relocalization 9606 BTO:0001103 11062529 t gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-84053 0.692 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr783 EGRNPGFyVEANPMP 9606 9176240 t gcesareni In contrast, egf-induced tyrosine phosphorylation of plc-gamma 1 was rather small, indicating that tyrosine phosphorylation of plc-gamma 1 is not proportional to changes in plc activity. These results suggest that autophosphorylation of theegfr may induce a conformational change of its kinase domain which enhances its kinase activity with exogenous substrates and may induce association with phospholipase c-gamma by increasing its affinity to a domain containing tyr-771. SIGNOR-48872 0.835 FOXO1 protein Q12778 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21798082 f lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-235712 0.414 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity precursor of 9606 30158707 t miannu Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction. SIGNOR-267822 0.8 TRIM58 protein Q8NG06 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity ubiquitination Lys172 ENWPKTLkLALEKER 23499489 t lperfetto Specifically, the ubiquitin E3 ligase TRIM25 ubiquitinates K172 in the CARD2 of RIG-I, which is essential for the efficient interaction of RIG-I with MAVS and thereby for antiviral signal transduction  SIGNOR-264582 0.2 ATM protein Q13315 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser1401 LQGEEIKsQNSQEST 9606 12086603 t lperfetto These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint SIGNOR-90109 0.781 IC-87114 chemical CHEBI:90686 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206190 0.8 NVP-BVU972 chemical CID:44206063 PUBCHEM MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194943 0.8 GRK2 protein P25098 UNIPROT CXCR2 protein P25025 UNIPROT down-regulates activity phosphorylation 10090 BTO:0000763 22634615 t miannu Upon activation, GRK2 phosphorylates CXCR2 and causes receptor desensitization and internalization, leading to down-regulation of neutrophil chemotaxis SIGNOR-260647 0.2 Calcineurin complex SIGNOR-C155 SIGNOR NFATC4 protein Q14934 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-252322 0.551 TPO protein P07202 UNIPROT L-tyrosine zwitterion smallmolecule CHEBI:58315 ChEBI down-regulates quantity chemical modification 9606 16098474 t scontino TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. SIGNOR-266956 0.8 8-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:91845 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258693 0.8 PTEN protein P60484 UNIPROT PPM1A protein P35813 UNIPROT up-regulates binding 9606 18482992 t lpetrilli Upon complex formation with pten, ppm1a is protected from degradation induced by the tgf-? Signaling. this study establishes a novel role for nuclear pten in the stabilization of ppm1a. SIGNOR-178643 0.312 NTRK1 protein P04629 UNIPROT ARHGAP32 protein A7KAX9 UNIPROT up-regulates relocalization 9606 12446789 t gcesareni Grit translocation was regulated by receptor stimulation SIGNOR-95809 0.585 CRHR1 protein P34998 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 22869609 t lperfetto Previous studies have indicated that CRHR could couple to multiple Galpha proteins including Gs, Gi, and Gq/11 and then go on to induce changes in AC activity and activation of PLC-beta3 SIGNOR-268617 0.472 PRKCG protein P05129 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity phosphorylation Ser346 EWEAQRDsHLGPHRS 9606 BTO:0000007 14576165 t lperfetto A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis. SIGNOR-249238 0.2 EIF2AK2 protein P19525 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 27712625 f miannu The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum. SIGNOR-260159 0.7 C9orf72 protein Q96LT7 UNIPROT RAB1A protein P62820 UNIPROT up-regulates activity binding 9606 BTO:0000007 27334615 t miannu C9orf72 acts as an effector of Rab1a that recruits active Rab1a to theULK1 complex to promote translocation of the ULK1 complex to thephagophore during autophagy initiation SIGNOR-261297 0.487 MEN1 protein O00255 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16415155 f irozzo We also found that menin is important for the proliferation of MLL oncoprotein-transformed myeloid cells, pointing to a paradoxically oncogenic role for the tumor suppressor menin in proliferation of transformed myeloid cells. SIGNOR-255895 0.7 MPP5 protein Q8N3R9 UNIPROT AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR form complex binding 9606 24366813 t lperfetto To gain a more detailed view on the organization of this cell polarity network linked to yap1 we included several proteins of the cell junction complex (amot, mpp5, lin7a), SIGNOR-203494 0.669 PPP2CA protein P67775 UNIPROT CARD11 protein Q9BXL7 UNIPROT down-regulates activity dephosphorylation Ser644 NLMFRKFsLERPFRP 9606 21157432 t NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation. SIGNOR-248650 0.314 17beta-estradiol smallmolecule CHEBI:16469 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258592 0.8 FANCG protein O15287 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 t lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263243 0.922 FGFR3 protein P22607 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). SIGNOR-276181 0.2 MAPK14 protein Q16539 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates activity phosphorylation Thr312 QATQPLAtPVVSVTT 9606 9858528 t lperfetto We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a SIGNOR-62780 0.646 PRKACA protein P17612 UNIPROT STK38 protein Q15208 UNIPROT down-regulates activity phosphorylation Ser10 MTGSTPCsSMSNHTK -1 22142472 t miannu GSK-3β phosphorylated STK38 on residues S6 and T7 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively.  Our results indicate that that GSK-3β inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress. SIGNOR-276391 0.299 risperidone chemical CHEBI:8871 ChEBI HTR1F protein P30939 UNIPROT down-regulates activity chemical inhibition 9534 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258524 0.8 HOXA9 protein P31269 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000661 21261500 f miannu Overexpression of HOXA9 or HOXA10 in JURKAT cells by lentiviral transduction resulted in decreased expression of MEF2C, indicating repression by these homeodomain proteins. HOXA9/10 inhibits expression of MEF2C via NMYC SIGNOR-254211 0.338 ATM protein Q13315 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Ser1247 AMQSNSPsQEQQQQQ 9606 15173573 t lperfetto Tonebp/orebp contains atm consensus phosphorylation sites at ser-1197, ser-1247, and ser-1367. In conclusion, signaling via atm is necessary for full activation of tonebp/orebp SIGNOR-125077 0.274 NRF1 protein Q16656 UNIPROT ENOX1 protein Q8TC92 UNIPROT up-regulates 9606 BTO:0000934 23939472 f lperfetto We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation.  SIGNOR-261488 0.268 ITGB1BP1 protein O14713 UNIPROT AM/b2 integrin complex SIGNOR-C170 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257651 0.318 MAPK8 protein P45983 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 19245816 t gcesareni In addition, for mutation of the jnk-1 phosphorylated residues of sp1, namely, sp1(t278/739a) and sp1(t278/739d), the effect of ga on sp1 stability was reversed. SIGNOR-184194 0.694 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser79 AGALYSGsEGDSESG -1 2046671 t llicata Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Nevertheless, additional mutation of serines 77 and 79 was required before phosphorylation and enhanced binding were completely abolished. Thus, serines 77 and 79 could also be recognized by CKII if serines 83 and 85 were mutated. SIGNOR-250956 0.533 PPM1D protein O15297 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity dephosphorylation 9606 23907458 t lperfetto 34 In this study, a novel function of Wip1 was identified, that is, its ability to dephosphorylate directly and thus inactivate apoptotic BAX protein in response to gamma irradiation.|To ascertain whether Wip1 dephosphorylates BAX, recombinant Wip1 was incubated with previously reported BAX-derived phosphopeptides containing Ser87, Ser163, Thr167, and Ser184 in an in vitro phosphatase assay. xref , xref Peptides containing phospho-Thr180 from p38 MAPK and phospho-Thr31 from UNG2 were used as a positive and negative control, respectively.  xref  As shown in xref , purified Wip1 did not dephosphorylate the four BAX-derived phosphopeptides. SIGNOR-276993 0.2 Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 25627476 f lperfetto Mitochondrial phospholipids are important components of this system. Phospholipids make up the characteristic outer and inner membranes that give mitochondria their shape.  SIGNOR-267005 0.7 BMPR1A protein P36894 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000165;BTO:0002974; BTO:0002809 9442019 t ggiuliani In this study, we isolated human Smad5 and found that Smad5 was involved in BMP-2 signaling cascades, which mediate the bone-inducing effects of BMP-2. Smad5 was directly serine-phosphorylated by BMPIR through a physical interaction. The activated Smad5 subsequently formed a complex with DPC4, and this complex was then translocated to the nucleus. SIGNOR-255830 0.773 KDM1A protein O60341 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 BTO:0000567 15620353 t miannu Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription. SIGNOR-265332 0.2 CPT1A protein P50416 UNIPROT palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI down-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267126 0.8 PRKACA protein P17612 UNIPROT KCNK9 protein Q9NPC2 UNIPROT up-regulates phosphorylation Ser373 RLMKRRKsV 9606 BTO:0000007 21357689 t llicata Patch clamp analysis, flow cytometry, and immunocytochemistry studies of hek293 transfected with wt hk2p3.1 and cultured in the presence of pka activators or inhibitors all confirm that activation of pka resulted in an increase in hk2p3.1 current expression (figs. 4_4?6) and demonstrate the dynamic regulatory effect of pka activity on k2p3.1 channel expression. SIGNOR-172466 0.2 CID 132010322 chemical CID:132010322 PUBCHEM BRD3 protein Q15059 UNIPROT down-regulates activity chemical inhibition 9606 31969702 t Luana ABBV-744 potently inhibited the BD2 domain of BET family proteins with more than 290× selectivity relative to the BD1 domains of BRD2, BRD3 and BRD4 SIGNOR-261104 0.8 U2AF1 protein Q01081 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 31144421 f miannu  Our results further showed that knockdown of U2AF1 significantly Western blot analysis revealed an increase in the protein levels of downstream targets of p53 following U2AF1 knockdown. The data further showed that depletion of U2AF1 altered alternatively spliced apoptosis-associated gene transcripts in CFU-E cells. Our findings elucidate the role of U2AF1 in human erythropoiesis and reveal the underlying mechanisms. SIGNOR-261512 0.2 IL23A protein Q9NPF7 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 12671732 t gcesareni Based on these analyses, we propose an integrated model of il-12rbeta1 structure and function. This significantly enhances our molecular understanding of the human il-12 and il-23 systems. SIGNOR-99716 0.631 IDH3A protein P50213 UNIPROT IDH complex SIGNOR-C396 SIGNOR form complex binding 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-266248 0.716 TFEB protein P19484 UNIPROT ANKFY1 protein Q9P2R3 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) SIGNOR-276782 0.2 CTF1 protein Q16619 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 9030543 t gcesareni In the cos-7 cell line demonstrate that gp130-gp190 heterocomplex formation is essential for ct-1 signaling SIGNOR-46509 0.611 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser287 EPLSPVSsLQASVPG -1 16027724 t GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines) SIGNOR-251228 0.389 kaempferol chemical CHEBI:28499 ChEBI AHR-ARNT complex SIGNOR-C125 SIGNOR down-regulates activity chemical inhibition 17012224 t However, kaempferol inhibited the ability of BNF to induce formation of the AHR/ARNT DNA-binding complex at all concentrations tested SIGNOR-253641 0.8 TJP2 protein Q9UDY2 UNIPROT ARVCF protein O00192 UNIPROT down-regulates activity relocalization 9615 15456900 t Regulation of binding miannu We identified ARVCF as a binding partner of ZO-1 and ZO-2 and characterized the role of PDZ-domain proteins in plasma membrane and nuclear localization of ARVCF. ZO-2, in contrast, relocated to the nucleus with ARVCF, and, given the interaction between the ZO-2 PDZ domains and ARVCF, raised the possibility that ZO-2 may play a role in nuclear localization of ARVCF. Such a role for ZO-2 is indeed supported by the ability of the ZO-2 PDZ domain to efficiently relocate ARVCF from the plasma membrane to the nucleus in a process that required the ability of the two proteins to interact and the presence of a functional NLS in the ZO-2 PDZ domains. Thus, ZO-2 could be involved in nuclear translocation and/or retention of ARVCF and play a role in regulating postulated functions of ARVCF in gene expression SIGNOR-252122 0.377 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates phosphorylation 9606 26194464 t MARCO ROSINA TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI). SIGNOR-255032 0.711 TFEB protein P19484 UNIPROT CALCOCO1 protein Q9P1Z2 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) SIGNOR-276784 0.2 LYN protein P07948 UNIPROT DOK3 protein Q7L591 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling. SIGNOR-268447 0.418 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates phosphorylation Tyr970 GEGYKKKyQQVDEEF 9606 BTO:0000150;BTO:0000527 19275932 t gcesareni These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis. SIGNOR-184556 0.507 CSNK2A1 protein P68400 UNIPROT CERS6 protein Q6ZMG9 UNIPROT up-regulates activity phosphorylation Ser347 RSDIESSsDEEDSEP 9606 BTO:0000007 26887952 t miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  SIGNOR-273989 0.2 IGF2 protein P01344 UNIPROT INSR protein P06213 UNIPROT up-regulates binding 9606 9281335 t fspada Therefore, these results provide genetic evidence that the growth-promoting function of igf-ii during mouse embryogenesis is mediated in part by signaling through the insulin receptor. SIGNOR-50719 0.707 CENPN protein Q96H22 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265210 0.716 ASXL1 protein Q8IXJ9 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity binding 9606 21047783 t miannu Our genome-wide analysis confirmed the physiological roles of ASXL1 and ASXL2 in adipogenesis at the molecular level, supporting the hypothesis that ASXL1 is an authentic corepressor of PPARγ, whereas ASXL2 is a PPARγ coactivator, and that together ASXL1 and ASXL2 fine-tune adipogenesis via differential regulation of PPARγ.  SIGNOR-260064 0.2 CKM complex complex SIGNOR-C406 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 15546612 t gcesareni Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. SIGNOR-273150 0.378 AKT proteinfamily SIGNOR-PF24 SIGNOR VCP protein P55072 UNIPROT up-regulates phosphorylation Ser748 RFARRSVsDNDIRKY 9606 BTO:0000150 16551632 t llicata Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I SIGNOR-145292 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 19282669 t inferred from 70% family members lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-270175 0.2 NELF complex SIGNOR-C521 SIGNOR RNA Polymerase II complex SIGNOR-C391 SIGNOR down-regulates activity binding 9606 18628398 t miannu The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. SIGNOR-271403 0.384 DHODH protein Q02127 UNIPROT ubiquinol smallmolecule CHEBI:17976 ChEBI up-regulates quantity chemical modification 9606 30449682 t miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway SIGNOR-267432 0.8 POLR2A protein P24928 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR up-regulates activity relocalization -1 20457598 t lperfetto The pol II CTD specifically mediates recruitment of Integrator to the promoter of snRNA genes to activate transcription and direct 3' end processing of the transcripts. SIGNOR-261476 0.65 PLEKHG6 protein Q3KR16 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260567 0.566 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser119 SFSSTSVsSLEAEAY 9606 20305697 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-164633 0.574 Shelterin complex complex SIGNOR-C306 SIGNOR Telomere_maintenance phenotype SIGNOR-PH148 SIGNOR up-regulates 33015044 f lperfetto The shelterin complex has six proteins, containing TRF1, TRF2, POT1, RAP1, TIN2, and TPP1. The shelterin complex is localized to the chromosome end and protects telomeric DNA (Palm and de Lange, 2008). The TTM complex acts as a “linker” and bridges the LINC and shelterin complexes together. The connection between TTM and shelterin complexes is well-known, which is mediated by TERB1 and TRF1 SIGNOR-263309 0.7 ARNTL protein O00327 UNIPROT PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253629 0.737 SMARCD2 protein Q92925 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269821 0.754 RSPO1 protein Q2MKA7 UNIPROT ZNRF3 protein Q9ULT6 UNIPROT down-regulates quantity relocalization 9606 BTO:0000007 22575959 t Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3. SIGNOR-260113 0.795 EPHA2 protein P29317 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 12400011 t gcesareni We also show that the interaction of epha2 with grb2 is indirect and mediated by shc and that this complex is necessary for epha2-mediated activation of erk kinases. SIGNOR-94804 0.6 PIP5K1C protein O60331 UNIPROT 1-phosphatidyl-1D-myo-inositol 4-phosphate(3-) smallmolecule CHEBI:58178 ChEBI down-regulates activity chemical modification 9606 9367159 t miannu Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities SIGNOR-277284 0.8 HMGB1 protein P09429 UNIPROT HOXC6 protein P09630 UNIPROT up-regulates activity binding -1 8890171 t miannu We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein. SIGNOR-219937 0.302 FGF12 protein P61328 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253436 0.267 UBE2L3 protein P68036 UNIPROT RNF19B protein Q6ZMZ0 UNIPROT up-regulates activity binding 9606 BTO:0000914 16709802 t miannu We demonstrated that both UbcH7 and UbcH8 bind to full-length NKLAM.  We demonstrated decreased protein expression and enhanced ubiquitination of URKL-1 in the presence of NKLAM. These data indicate that NKLAM is a RING finger protein that binds Ubcs and SIGNOR-271591 0.494 MYC protein P01106 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664;BTO:0004465 26179066 t lperfetto In the present study we demonstrate that MYC and its partner MAX bind to the BCR promoter, leading to up-regulation of BCR and BCR/ABL1 at both transcriptional and protein levels.|Here we describe a regulatory pathway modulating BCR and BCR/ABL1 expression, showing that the BCR promoter is under the transcriptional control of the MYC/MAX heterodimer. SIGNOR-272143 0.2 MAPK1 protein P28482 UNIPROT TCF3 protein P15923 UNIPROT down-regulates quantity by destabilization phosphorylation Thr355 NFSSSPStPVGSPQG 10090 14592976 t lperfetto Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG) SIGNOR-249451 0.367 IL2 protein P60568 UNIPROT NAB2 protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 22128144 f miannu We observe that the CD8(+) T-cell autocrine growth factor IL-2 coordinately increases Nab2 expression and decreases TRAIL expression. SIGNOR-253894 0.357 LYN protein P07948 UNIPROT PPP1R8 protein Q12972 UNIPROT down-regulates activity phosphorylation Tyr335 NEPKKKKyAKEAWPG -1 11104670 t Lyn phosphorylates both Tyr-264 and Tyr-335, but that the phosphorylation of Tyr-335 is dependent on the association of NIPP1 with RNA. The inhibitory potency of the C-terminal site of NIPP1 was decreased by phosphorylation of Tyr-335 and by the addition of RNA. SIGNOR-251406 0.317 proline smallmolecule CHEBI:26271 ChEBI ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 25386178 f apalma Ornithine, via the enzyme OAT, is also a precursor amino acid for the synthesis of proline, which itself is essential for the synthesis of collagen. SIGNOR-255550 0.7 SRC protein P12931 UNIPROT WWOX protein Q9NZC7 UNIPROT up-regulates phosphorylation Tyr33 TTKDGWVyYANHTEE 9606 15070730 t llicata The tyrosine kinase, src, phosphorylates wwox at tyrosine 33 in the first ww domain and enhances its binding to p73. SIGNOR-123819 0.493 PRKACA protein P17612 UNIPROT PPP1R9B protein Q96SB3 UNIPROT down-regulates activity phosphorylation Ser94 SERGVRLsLPRASSL 9606 BTO:0000007 12417592 t miannu Spinophilin is phosphorylated in vitro by protein kinase A (PKA). two major sites of phosphorylation, Ser-94 and Ser-177, that are located within the actin-binding domain of spinophilin. Phosphorylation of spinophilin by PKA modulated the association between spinophilin and the actin cytoskeleton. phosphorylation of spinophilin reduced the stoichiometry of the spinophilin-actin interaction. In contrast, the ability of spinophilin to bind to PP1 remained unchanged. SIGNOR-250035 0.315 MAP3K1 protein Q13233 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 17563747 t lperfetto Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna. SIGNOR-236346 0.295 L-homocysteine zwitterion smallmolecule CHEBI:58199 ChEBI hydrosulfide smallmolecule CHEBI:29919 ChEBI up-regulates quantity precursor of 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. SIGNOR-275816 0.8 enzalutamide chemical CHEBI:68534 ChEBI AR protein P10275 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194325 0.8 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser178 LFTQRQNsAPARMLS 9606 12676583 t Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. SIGNOR-99725 0.837 SRSF3 protein P84103 UNIPROT NXF1 protein Q9UBU9 UNIPROT up-regulates binding 9606 18364396 t miannu 9g8 and srp20 also enhance the tap rna-binding activity SIGNOR-178111 0.667 USP9X protein Q93008 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates deubiquitination Lys519 DYPRQSIkETPCWIE 9606 22298955 t gcesareni Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4. SIGNOR-195697 0.633 PP2B proteinfamily SIGNOR-PF18 SIGNOR NFATC1 protein O95644 UNIPROT up-regulates relocalization 9606 BTO:0001103 11062529 t inferred from 70% family members gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-269989 0.2 BMP7 protein P18075 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18719589 f lperfetto Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways SIGNOR-180311 0.327 SLC1A1 protein P43005 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity relocalization 9606 26687113 t miannu After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5). SIGNOR-264804 0.8 BRAP protein Q7Z569 UNIPROT KSR1 protein Q8IVT5 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 23105109 t miannu Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. SIGNOR-272028 0.647 UBASH3B protein Q8TF42 UNIPROT CBL protein P22681 UNIPROT down-regulates binding 9606 15159412 t gcesareni Sts-1 and sts-2 contain sh3 domains that interacted with cbl, ub-associated domains, which bound directly to mono-ub or to the egfr/ub chimera as well as phosphoglycerate mutase domains that mediated oligomerization of sts-1/2. Ligand-induced recruitment of sts-1/sts-2 into activated egfr complexes led to inhibition of receptor internalization, reduction in the number of egfr-containing endocytic vesicles, and subsequent block of receptor degradation followed by prolonged activation of mitogenic signaling pathways. SIGNOR-124897 0.454 UBQLN2 protein Q9UHD9 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 10090 BTO:0001976 26521126 f lperfetto We report that UBQLN2 up-regulation cause a cellular stress which leads to MAPK activation. Interestingly, kinases have been recently shown to have a critical role in TDP-43 accumulation in stress granules following a chronic stress SIGNOR-262266 0.7 FLI1 protein Q01543 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR up-regulates 9606 BTO:0000565 28052010 f irozzo The ETS-related transcription factor Fli-1 affects many developmental programs including erythroid and megakaryocytic differentiation, and is frequently de-regulated in cancer. SIGNOR-256087 0.7 RPS6KA1 protein Q15418 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser52 TRRTRTFsATVRASQ 9606 BTO:0000671 15910284 t lperfetto These and other results demonstrate that crhsp24 is phosphorylated at ser52 by pkbalpha in response to igf-1, at ser52 by pkbalpha and rsk in response to egf SIGNOR-137482 0.338 SIK2 protein Q9H0K1 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Ser1490 AILNPPPsPATERSH 9606 BTO:0006293 35277657 t miannu Mechanistically, SIK2, phosphorylated by CK1α, directly phosphorylated LRP6 in a SIK2 kinase activity-dependent manner, leading to Wnt/β-catenin signaling pathway activation. SIGNOR-275404 0.2 UBN1 protein Q9NPG3 UNIPROT HIRA complex 1 complex SIGNOR-C461 SIGNOR form complex binding 9606 30285846 t miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. SIGNOR-269433 0.714 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Thr116 SCDKSTQtPSPPCQA 9606 12591950 t The effect has been demonstrated using O43521-2 gcesareni Here, we demonstrate that jnk phosphorylates two members of the bh3-only subgroup of bcl2-related proteins (bim and bmf) that are normally sequestered by binding to dynein and myosin v motor complexes. Phosphorylation by jnk causes release from the motor complexes SIGNOR-98396 0.75 EDNRB protein P24530 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256781 0.296 UCHL3 protein P15374 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity deubiquitination Lys58 AVAYAPKkELINIKG 27941124 t lperfetto Here we report that ubiquitination of RAD51 hinders RAD51-BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51-BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. | UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2.|Our results suggested that three lysine sites (56, 57, and 63) on RAD51 that are close to E59 are deubiquitinated by UCHL3. SIGNOR-275908 0.331 NEK7 protein Q8TDX7 UNIPROT TERF1 protein P54274 UNIPROT up-regulates quantity by stabilization phosphorylation Ser114 AIIHGLSsLTACQLR 9606 BTO:0000567 28216227 t done miannu Mechanistically, Nek7 interacts with and phosphorylates TRF1 on Ser114, which prevents TRF1 from binding to Fbx4, an Skp1-Cul1-F box E3 ligase subunit, thereby alleviating proteasomal degradation of TRF1, leading to a stable association of TRF1 with Tin2 to form a shelterin complex. SIGNOR-273903 0.349 GFs stimulus SIGNOR-ST12 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 23300340 f lperfetto Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation SIGNOR-245411 0.7 CSNK1A1 protein P48729 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Ser267 PPTTSSDsEEEQEDE 9606 BTO:0000007 22025562 t miannu  Together, our findings provide evidence for CK1α-mediated destruction of c-Myc and identify c-Myc S252 as a crucial CK1α phosphorylation site for c-Myc degradation. SIGNOR-276387 0.285 AKT2 protein P31751 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 BTO:0000150 12244303 t gcesareni Akt-induced t157 phosphorylation causes retention of p27(kip1) in the cytoplasm, precluding p27(kip1)-induced g1 arrest.[__]Thus, cytoplasmic relocalization of p27(kip1), secondary to akt-mediated phosphorylation, is a novel mechanism whereby the growth inhibitory properties of p27(kip1) are functionally inactivated and the proliferation of breast cancer cells is sustained. SIGNOR-93122 0.51 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR up-regulates 9606 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268580 0.2 SLC34A2 protein O95436 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI up-regulates quantity relocalization 9606 BTO:0000671 11009570 t lperfetto Three families of NPCs have been reported to date. The type I family consists of a single species (NaPi-1), which has thus far been found only in rabbit kidney.28 The type II family consists of six species homologues, NaPi 2 to 7, that are expressed predominantly in renal epithelial tissues.The type III family is the most recently identified and consists of two members, Pit-1 (also called Glvr-1) and Pit-2 (also called Ram-1).34 SIGNOR-270578 0.8 MRPL45 protein Q9BRJ2 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262351 0.707 DYRK1A protein Q13627 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser641 YRYPRPAsVPPSPSL 9534 BTO:0000298 14593110 t miannu DYRK Family Protein Kinases Phosphorylate and Inactivate Glycogen Synthase. both protein kinases phosphorylate site 3a but no other sites that affect glycogen synthase activity. SIGNOR-260632 0.27 CSNK2A1 protein P68400 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser280 VDGTGDTsSEEDEDE -1 11278496 t llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. SIGNOR-250874 0.387 MAPK14 protein Q16539 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 9130707 t gcesareni We demonstrate here that elk-1 is barely activated by a third subclass of map kinases (p38), most likely because the critical residues ser383 and ser389 are poorly phosphorylated by p38 map kinase. SIGNOR-47630 0.506 LONP1 protein P36776 UNIPROT STAR protein P49675 UNIPROT down-regulates quantity by destabilization cleavage 10116 BTO:0000542 17579211 t lperfetto Turnover of mitochondrial steroidogenic acute regulatory (StAR) protein by Lon protease: the unexpected effect of proteasome inhibitors SIGNOR-265726 0.271 SMURF proteinfamily SIGNOR-PF29 SIGNOR SKIL protein P12757 UNIPROT down-regulates activity ubiquitination 9606 BTO:0002181;BTO:0005493 11389444 t lperfetto Tgf-beta also induces the association of smurf2 with the transcriptional co-repressor snon and we show that smad2 can function to mediate this interaction. This allows smurf2 hect domain to target snon for ubiquitin-mediated degradation by the proteasome. SIGNOR-253262 0.2 PRKACA protein P17612 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Ser685 VPLVQRGsANGL -1 11278469 t miannu PKA directly phosphorylates GRK2 on serine 685. This modification increases G subunit binding to GRK2 and thus enhances the ability of the kinase to translocate to the membrane and phosphorylate the receptor. SIGNOR-250334 0.2 AP1M1 protein Q9BXS5 UNIPROT AP-1 complex complex SIGNOR-C248 SIGNOR form complex binding 9606 21097499 t lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) SIGNOR-260686 0.888 LATS2 protein Q9NRM7 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Thr203 QGHVRTHtGEKPFSC 9606 21952048 t lperfetto Lats2 kinase potentiates snail1 activity by promoting nuclear retention upon phosphorylation. during tgf_-induced emt lats2 is activated and snail1 phosphorylated at t203. SIGNOR-176647 0.543 PRKCZ protein Q05513 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser246 QYQEERRsVKHILFS -1 16479000 t miannu HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. SIGNOR-276047 0.263 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr999 YASSNPEyLSASDVF -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-106526 0.2 NCOA2 protein Q15596 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 24239470 t miannu The NCOA2 gene encodes a transcriptional coactivator (SRC-2) that modulates gene expression by hormone receptors, including AR. NCOA2 is both amplified and rarely mutated in prostate cancers, with higher NCOA2 levels resulting in increased androgen signaling readout. Furthermore, as mentioned previously, SRC-3, a close homolog encoded by NCOA3, is a substrate of SPOP whose protein levels are increased by SPOP mutation, potentially linking these common point mutations to the androgen axis SIGNOR-251530 0.898 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation 9606 31226734 t lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. SIGNOR-265918 0.655 CARM1 protein Q86X55 UNIPROT SMARCC1 protein Q92922 UNIPROT up-regulates activity methylation Arg1064 PGNILGPrVPLTAPN 9606 BTO:0000007;BTO:0000356 24434208 t CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation. SIGNOR-251708 0.553 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAMAC protein Q9BTL3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 YLKRPPEsPPIVEEW 9606 27452456 t miannu During differentiation, ERK1/2 phosphorylates RAM serine-36, targeting it for ubiquitination and proteasomal degradation, ultimately resulting in changes in gene expression associated with loss of pluripotency. SIGNOR-277267 0.2 PRKCZ protein Q05513 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates activity phosphorylation Ser472 RPHFPQFsYSASGRE 9534 BTO:0001538 12162751 t lperfetto Full activation of the PKB enzyme requires phosphorylation of a threonine in the activation SIGNOR-249153 0.53 PBX3 protein P40426 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription SIGNOR-265805 0.2 SRC protein P12931 UNIPROT VIL1 protein P09327 UNIPROT up-regulates activity phosphorylation Tyr60 KTASSLSyDIHYWIG 9606 BTO:0000567 15342783 t lperfetto These data suggest that phosphorylation of villin by c-src is involved in the actin cytoskeleton remodeling necessary for cell migration.To further investigate the role of tyrosine phosphorylated villin in cell migration, we used phosphorylation site mutants (tyrosine to phenylalanine or tyrosine to glutamic acid) in HeLa cells. We determined that tyrosine phosphorylation at residues 60, 81, and 256 of human villin played an essential role in cell migration as well as in the reorganization of the actin cytoskeleton SIGNOR-247437 0.371 MMP16 protein P51512 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272361 0.7 ATR protein Q13535 UNIPROT MCM6 protein Q14566 UNIPROT up-regulates phosphorylation 9606 21070963 t gcesareni Together these data strongly support the conclusion that mec1 directly targets the s/tq sites in mcm4 and mcm6, although it is formally possible that mec1 and mrc1 activate a different s/tq-directed kinase to target mcm4 and mcm6. SIGNOR-169450 0.544 GSK3B protein P49841 UNIPROT RXRA protein P19793 UNIPROT up-regulates activity phosphorylation Ser66 NGMGPPFsVISSPMG 9606 BTO:0000007 29137318 t miannu GSK3β-induced RXRα phosphorylation decreased for RXRα-S49A, RXRα-S66A and RXRα-S78A in HEK293 cells compared with RXRα WT by western blot analysis.  SIGNOR-277370 0.278 PPP3CA protein Q08209 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18177723 f lperfetto Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy SIGNOR-251733 0.252 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates activity phosphorylation Ser978 SPLKRSHsLAKLGSL 21832093 t lperfetto Active PKD Isoforms Phosphorylate and Inactivate SSH1L|Here, we show that active PKD3 also mediates SSH1L phosphorylation at Ser-978 and binding to 14-3-3, further confirming the involvement of all three PKD isoforms in negatively regulating this phosphatase SIGNOR-275936 0.492 PPM1B protein O75688 UNIPROT MPRIP protein Q6WCQ1 UNIPROT down-regulates activity dephosphorylation 9606 25751141 t lperfetto Ppm1b prevents Rip3 auto-activation in resting cells.|Together, these data demonstrate that Ppm1b dephosphorylates Rip3 and thus negatively regulates TNF induced necroptosis in L929 cells. SIGNOR-277019 0.2 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1763 TPTSPSYsPTSPSYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203552 0.769 ESR1 protein P03372 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates quantity by expression transcriptional regulation 14764652 f lperfetto Estrogen-induced transcriptional activities of both ERalpha and ERbeta and mRNA expression of estrogen-responsive genes, including pS2, c-myc, and cyclin D1, were suppressed by PP5 but enhanced by PP5 antisense oligonucleotide. SIGNOR-271691 0.284 EID1 protein Q9Y6B2 UNIPROT EP300 protein Q09472 UNIPROT down-regulates activity binding 11073989 t lperfetto Here, we show that EID-1 is a potent inhibitor of differentiation and link this activity to its ability to inhibit p300 (and the highly related molecule, CREB-binding protein, or CBP) histone acetylation activity. SIGNOR-253379 0.431 AKT2 protein P31751 UNIPROT PCBP1 protein Q15365 UNIPROT down-regulates activity phosphorylation Ser43 VKRIREEsGARINIS 10090 BTO:0004183 20154680 t miannu We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation.TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs. SIGNOR-262625 0.44 SRC protein P12931 UNIPROT NECTIN2 protein Q92692 UNIPROT unknown phosphorylation Tyr505 EGEEEEEyLDKINPI -1 10962558 t miannu An inhibitor specific for Src family kinase or expression of Csk reduced tyrosine phosphorylation of nectin-2delta. In addition, Src kinase tyrosine phosphorylates the recombinant cytoplasmic region of nectin-2delta in vitro. The major tyrosine phosphorylation site of nectin-2delta was Tyr505 in the cytoplasmic region SIGNOR-263200 0.2 bromocriptine chemical CHEBI:3181 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258367 0.8 TFEB protein P19484 UNIPROT TPP1 protein O14773 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276548 0.292 PARK7 protein Q99497 UNIPROT MTA1/DJ1 complex complex SIGNOR-C123 SIGNOR form complex binding 9606 BTO:0000567 21368136 t 1 miannu we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3. SIGNOR-239448 0.333 PLK1 protein P53350 UNIPROT SUZ12 protein Q15022 UNIPROT down-regulates quantity by destabilization phosphorylation Ser546 SMSEFLEsEDGEVEQ 25855382 t lperfetto PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|In SUZ12, residues 539, 541 and 546 phosphorylated by Plk1 in vitro SIGNOR-275556 0.37 CDK1 protein P06493 UNIPROT KIF22 protein Q14807 UNIPROT up-regulates activity phosphorylation Thr463 QGAPLLStPKRERMV 9606 SIGNOR-C17 12727876 t lperfetto Cdc2-mediated phosphorylation of kid controls its distribution to spindle and chromosomes. We identify ser427 and thr463 as m phase-specific phosphorylation sites and cdc2-cyclin b as a thr463 kinase. Kid with a thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind dna or chromosomes SIGNOR-100964 0.35 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1252 CKKAGNLyDISEDNS 9606 BTO:0000007 11024032 t Tyr-1252, Tyr-1336, and Tyr-1472 of GluRε2 are phosphorylated in 293T cells when active Fyn is co-expressed. SIGNOR-251172 0.759 1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane chemical CHEBI:125354 ChEBI CXCR4 protein P61073 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206268 0.8 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257930 0.8 AKT1 protein P31749 UNIPROT PARK7 protein Q99497 UNIPROT up-regulates activity phosphorylation Thr125 GFGSKVTtHPLAKDK 32858971 t lperfetto Using a proteomic approach, we identified on DJ-1 a novel threonine phosphorylation (T125) that was found, by the in-silico tool scansite 4, as part of a putative Akt consensus. |Deglycase activity of DJ-1 on histones proteins, investigated by coupling 2D tau gel with LC-MS/MS and 2D-TAU (Triton-Acid-Urea)-Western blot, was found correlated with its phosphorylation status that, in turn, depends from Akt activation. SIGNOR-275582 0.477 ULK1 protein O75385 UNIPROT PFKM protein P08237 UNIPROT down-regulates activity phosphorylation Ser762 YEIDLDTsDHAHLEH 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274036 0.2 MAPK14 protein Q16539 UNIPROT PIP4K2B protein P78356 UNIPROT down-regulates phosphorylation Ser326 SYGTPPDsPGNLLSF 9606 16949365 t gcesareni Inhibition of pip4kbeta activity occurs through the direct phosphorylation of pip4kbeta at ser326 by the p38 stress-activated protein kinase. SIGNOR-149359 0.2 FOXO proteinfamily SIGNOR-PF27 SIGNOR NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates quantity transcriptional regulation 10090 24749067 f gcesareni We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration. SIGNOR-254306 0.2 SRC protein P12931 UNIPROT PTEN protein P60484 UNIPROT down-regulates phosphorylation 9606 BTO:0000150 12869565 t gcesareni Activated src reduces the ability of pten to dephosphorylate phosphatidylinositols in micelles and promotes akt translocation to cellular plasma membranes but does not alter pten activity toward water-soluble phosphatidylinositols. SIGNOR-103721 0.552 PLK1 protein P53350 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates quantity by destabilization phosphorylation Ser621 ALIPGNLsKEEEELS 9606 BTO:0000567 25504441 t miannu Our studies suggest new mechanisms by which Plk1 regulates MCAK: the degradation of MCAK is controlled by Plk1 phosphorylation on S621, whereas its activity is modulated by Plk1 phosphorylation on S632/S633 in mitosis.We have recently shown that S621 in MCAK is the major phosphorylation site of Plk1, which is responsible for regulating MCAK's degradation by promoting the association of MCAK with APC/CCdc20.  In the present study, we have addressed another two residues phosphorylated by Plk1, namely S632/S633 in the C-terminus of MCAK. Our data suggest that Plk1 phosphorylates S632/S633 and regulates its catalytic activity in mitosis. This phosphorylation is required for proper spindle assembly during early phases of mitosis. SIGNOR-276862 0.804 bisindolylmaleimide i chemical CID:2396 PUBCHEM PRKCG protein P05129 UNIPROT down-regulates chemical inhibition 9606 Other t CellSignaling gcesareni SIGNOR-190356 0.8 FERMT3 protein Q86UX7 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 10090 BTO:0000132;BTO:0003292 18278053 t lperfetto Mechanistically, Kindlin-3 can directly bind to regions of beta-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis|Kindlin-3 was also able to interact with the wild-type beta1 and beta3 integrin tails (Fig. 3c), in the presence and absence of Talin1 (Supplementary Fig. 3 online), and the F3 subdomain of Kindlin-3 was sufficient for this interaction and this interaction occurred in a direct manner SIGNOR-266065 0.395 iodide smallmolecule CHEBI:16382 ChEBI TPO protein P07202 UNIPROT up-regulates activity chemical activation 9606 BTO:0004708 23349248 t miannu After transport through the apical membrane, Iodide is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO). SIGNOR-268139 0.8 adenosine smallmolecule CHEBI:16335 ChEBI PI4K2B protein Q8TCG2 UNIPROT down-regulates activity chemical inhibition -1 21704602 t Luana Both PI4K2A and PI4K2B were inhibited by adenosine at concentrations that do not significantly inhibit PI4KA and PI4KB actitvity SIGNOR-258316 0.8 UCHL3 protein P15374 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity deubiquitination Lys64 KKELINIkGISEAKA 27941124 t lperfetto Here we report that ubiquitination of RAD51 hinders RAD51-BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51-BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. | UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2.|Our results suggested that three lysine sites (56, 57, and 63) on RAD51 that are close to E59 are deubiquitinated by UCHL3. SIGNOR-275909 0.331 PRKACA protein P17612 UNIPROT UBE3A protein Q05086 UNIPROT down-regulates activity phosphorylation Thr508 MYSERRItVLYSLVQ 10090 BTO:0000142 26255772 t gcesareni These data suggest that PKA phosphorylation at T485 inhibits UBE3A ubiquitin ligase activity in cells. SIGNOR-236899 0.334 STK24 protein Q9Y6E0 UNIPROT STK24 protein Q9Y6E0 UNIPROT up-regulates phosphorylation Thr190 DTQIKRNtFVGTPFW 9606 BTO:0000671 17046825 t gcesareni Inhibition of cell migration by autophosphorylated mammalian sterile 20-like kinase 3 (mst3) involves paxillin and protein-tyrosine phosphatase-pest. SIGNOR-150131 0.2 ZNF224 protein Q9NZL3 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 17900823 f inferred from family member miannu We previously reported that ZNF224, a novel Kr√ºppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor. SIGNOR-270227 0.503 IL15RA protein Q13261 UNIPROT JAK1 protein P23458 UNIPROT up-regulates BTO:0000782 30029643 t areggio Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated SIGNOR-256227 0.439 EEF1A1 protein P68104 UNIPROT Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269509 0.8 NVP-ADW742 chemical CID:9825149 PUBCHEM IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194883 0.8 PTK2B protein Q14289 UNIPROT STAP1 protein Q9ULZ2 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10518561 t miannu In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling. SIGNOR-261818 0.358 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 12466266 t gcesareni Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity;ser118 is phosphorylated by mitogen-activated protein kinase (mapk) in vitro and in cells treated with epidermal growth factor (egf) and insulin-like growth factor (igf) in vivo. SIGNOR-96072 0.657 PRKACA protein P17612 UNIPROT SLC2A2 protein P11168 UNIPROT down-regulates activity phosphorylation Ser503 AAEFQKKsGSAHRPK 9534 BTO:0004055 8626492 t miannu GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity. SIGNOR-250050 0.314 AKT1 protein P31749 UNIPROT FBXO31 protein Q5XUX0 UNIPROT down-regulates quantity by destabilization phosphorylation Ser33 AETAAADsEPDTDPE 9606 BTO:0002181 29343641 t miannu Here we show that the low levels of FBXO31 are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (APC/C). We find that the APC/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in FBXO31 to promote its polyubiquitination and degradation in a cell-cycle-regulated manner, which requires phosphorylation of FBXO31 on serine-33 by the prosurvival kinase AKT. SIGNOR-277376 0.2 GSK3B protein P49841 UNIPROT GLI2 protein P10070 UNIPROT down-regulates quantity by destabilization phosphorylation Ser832 GISPYFSsRRSSEAS 9606 BTO:0000007 16611981 t lperfetto The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3. SIGNOR-249589 0.544 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Tyr435 ARPVKGAyREHPYGR 9606 16179349 t lperfetto We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal. SIGNOR-249293 0.738 STAT1 protein P42224 UNIPROT IL12A protein P29459 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 19029990 f lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. SIGNOR-249499 0.527 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser555 RALSNSVsNMGLSES -1 17711846 t done miannu Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626). SIGNOR-274093 0.397 PTPN12 protein Q05209 UNIPROT SHC1 protein P29353 UNIPROT down-regulates dephosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 8939605 t gcesareni The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions. SIGNOR-44862 0.661 KCNE3 protein Q9Y6H6 UNIPROT KCNQ1 protein P51787 UNIPROT up-regulates activity binding 21911611 t lperfetto Sexual dimorphism and oestrogen regulation of KCNE3 expression modulates the functional properties of KCNQ1 K⁺ channels|The KCNQ1 potassium channel associates with various KCNE ancillary subunits that drastically affect channel gating and pharmacology. Co-assembly with KCNE3 produces a current with nearly instantaneous activation SIGNOR-275923 0.646 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser163 KRFSFKKsFKLSGFS -1 8557118 t gcesareni PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. SIGNOR-249651 0.372 CDC25C protein P30307 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity dephosphorylation 9606 32518522 t miannu At the interval CDC25C inhibits ASK1, dephosphorylating pThr838 in its activation loop.|CDC25C dephosphorylates ASK1 to inhibit its activity during the interphase. SIGNOR-277100 0.293 A6/b1 integrin complex SIGNOR-C164 SIGNOR TERT protein O14746 UNIPROT up-regulates quantity by expression 10090 18757303 f lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. SIGNOR-253280 0.312 NR0B2 protein Q15466 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 11368516 f inferred from family member gcesareni Shp (short heterodimer partner) is an orphan nuclear receptor lacking a dna binding domain that interacts with nuclear receptors (nr) including thyroid receptor (tr), retinoic acid receptors (rar and rxr), and estrogen receptors alpha and beta (eralpha and erbeta). Shp acts as a negative regulator of these receptors by inhibiting dna binding and transcriptional activation. SIGNOR-267806 0.378 ZAP70 protein P43403 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000782 29440413 t miannu We have found that T cell p38 MAP kinase (MAPK), which is directly phosphorylated and activated by ZAP-70 downstream of the TCR, in turn phosphorylates Thr-293 in the interdomain B region of ZAP-70. These results identify a tight negative feedback loop in which ZAP-70-activated p38 reciprocally phosphorylates ZAP-70 and destabilizes the signaling complex. SIGNOR-277385 0.457 MAPK1 protein P28482 UNIPROT RSPH3 protein Q86UC2 UNIPROT up-regulates activity phosphorylation Thr286 AFLDRPPtPLFIPAK 9606 19684019 t miannu ERK1/2 phosphorylate RSPH3. the extent of radiolabeled phosphate incorporation into RSPH3 T286A was much less than that into wild-type RSPH3, suggesting that threonine 286 is the major ERK1/2 phosphorylation site in cells. ERK2 also phosphorylates RSPH3 on threonine 243 to a lesser extent. Phosphorylation of the double mutant T243V/T286A RSPH3 was no more than 20% that of wild-type RSPH3 (Fig. 4, C and D). SIGNOR-262838 0.2 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89252 0.402 S1PR2 protein O95136 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256728 0.452 PDK1 protein Q15118 UNIPROT PDH complex SIGNOR-C402 SIGNOR down-regulates activity phosphorylation 9606 BTO:0003291 16517405 t miannu PDK1 is a direct HIF-1 target gene. We found that the gene encoding pyruvate dehydrogenase kinase 1 (PDK1) is a direct target of HIF-1. PDK1 phosphorylates the pyruvate dehydrogenase (PDH) E1α subunit and inactivates the PDH enzyme complex that converts pyruvate to acetyl-coenzyme A, thereby inhibiting pyruvate metabolism via the tricarboxylic acid (TCA) cycle SIGNOR-267445 0.63 5-(1,1-Dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol chemical CID:104895 PUBCHEM CNR1 protein P21554 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257473 0.8 PIM1 protein P11309 UNIPROT AR protein P10275 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001321 34697370 t miannu PIM1 phosphorylates the AR and 14-3-3 ζ and coordinates their interaction. PIM1 phosphorylation of the AR and 14-3-3 ζ enhances their interaction and shifts their occupancy on chromatin, resulting in 14-3-3 ζ co-regulation of AR, likely by recruiting other AR co-regulators such as hnRNPK and TRIM28. SIGNOR-277575 0.39 AR protein P10275 UNIPROT NR5A1 protein Q13285 UNIPROT up-regulates binding 9606 11518799 t gcesareni Ar suppresses transcription of the lhbeta subunit by interacting with steroidogenic factor-1. SIGNOR-109996 0.418 FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 20871233 f Atrogin-1, but not MuRF-1, was induced at both the gene and protein level as ApcMin/+ mice aged from 3 to 6 months of age, going from a pre-cachectic to a cachectic state. Atrogin-1 mRNA and protein levels were also elevated in ApcMin/+ mice when we over-expressed IL-6 in the circulation. SIGNOR-255343 0.7 ABL1 protein P00519 UNIPROT RAPH1 protein Q70E73 UNIPROT up-regulates activity phosphorylation Tyr1226 GGSHISGyATLRRGP -1 20417104 t miannu Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C). SIGNOR-262605 0.288 MAPK1 protein P28482 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser282 VGKQAPLsPGLPAMG 9606 BTO:0000007 20110267 t llicata These results demonstrated a critical role of noxa1 phosphorylation on ser-282 and ser-172 in preventing nox1 hyperactivation through the decrease of noxa1 interaction to nox1 and rac1. SIGNOR-163659 0.331 ZC3H11A protein O75152 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR up-regulates activity binding 9606 BTO:0000567 22928037 t miannu PDIP3 and ZC11A Function in mRNA Export. PDIP3 and ZC11A associate with UAP56 and the TREX complex in an ATP-dependent manner. SIGNOR-268516 0.462 MTOR protein P42345 UNIPROT Myotube_hypertrophy phenotype SIGNOR-PH20 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103;BTO:0001760 22179044 f gcesareni In differentiated myofibres, we observed that wnt7a binding to fzd7 directly activates the akt/mtor growth pathway, thereby inducing myofibre hypertrophy. SIGNOR-191564 0.7 PREX2 protein Q70Z35 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260571 0.593 SP1 protein P08047 UNIPROT CD151 protein P48509 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20149781 f miannu SP1 is required for basal activation and chromatin accessibility of CD151 promoter in liver cancer cells. SIGNOR-255195 0.2 TSC22D3 protein Q99576 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity relocalization 9606 BTO:0000738 20018851 t GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells. SIGNOR-256146 0.306 PMP22 protein Q01453 UNIPROT ITGA6 protein P23229 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21518455 f Regulation miannu Peripheral myelin protein-22 (PMP22) modulates alpha 6 integrin expression in the human endometrium. Overexpression of PMP22 was sufficient to increase α6 integrin surface expression with a concominant increase in binding to the extracellular matrix laminin, while a reduction in PMP22 suppressed α6 integrin surface expression. SIGNOR-251897 0.358 ADSL protein P30566 UNIPROT SAICAR(4-) smallmolecule CHEBI:58443 ChEBI down-regulates quantity chemical modification 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-266611 0.8 ARHGEF17 protein Q96PE2 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260542 0.53 NAA15 protein Q9BXJ9 UNIPROT NatA complex SIGNOR-C415 SIGNOR form complex binding 9606 BTO:0000007 15496142 t miannu Protein acetyltransferases and deacetylases have been implicated in oncogenesis, apoptosis and cell cycle regulation. Most of the protein acetyltransferases described acetylate epsilon-amino groups of lysine residues within proteins. We now describe the human homologue of Nat1p, NATH (NAT human), as the partner of the hARD1 (human ARD1) protein. Included in the characterization of the NATH and hARD1 proteins is the following: (i) endogenous NATH and hARD1 proteins are expressed in human epithelial, glioma and promyelocytic cell lines; (ii) NATH and hARD1 form a stable complex, as investigated by reciprocal immunoprecipitations followed by MS analysis; (iii) NATH-hARD1 complex expresses N-terminal acetylation activity; (iv) NATH and hARD1 interact with ribosomal subunits, indicating a co-translational acetyltransferase function SIGNOR-267225 0.95 L-ornithine smallmolecule CHEBI:15729 ChEBI M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates activity 24669294 f apalma While investigating the factors that regulate macrophage arginine metabolism, Mills and colleagues found that macrophages activated in mouse strains with Th1 and Th2 backgrounds differed qualitatively in their ability to respond to the classic stimuli IFN-γ or lipopolysaccharide (LPS) or both and defined an important metabolic difference in the pathway: M1 macrophages made the toxic nitric oxide (NO), whereas M2 macrophages made the trophic polyamines SIGNOR-256076 0.7 Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 BTO:0000143 25195934 f miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270759 0.7 bexarotene chemical CHEBI:50859 ChEBI RXRG protein P48443 UNIPROT up-regulates activity chemical activation 9606 BTO:0002058 17483357 t miannu Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification. SIGNOR-259232 0.8 TGFBR2 protein P37173 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0001660 9435577 t lperfetto These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells. SIGNOR-252732 0.42 SLBP protein Q14493 UNIPROT H2BC15 protein Q99877 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265392 0.2 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM2B protein Q8NHM5 UNIPROT up-regulates activity chemical activation 29981745 t lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. SIGNOR-273472 0.8 HIF-1 complex complex SIGNOR-C418 SIGNOR LDHA protein P00338 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 t miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. SIGNOR-267456 0.643 TGFB1 protein P01137 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by expression 9606 17283133 f gcesareni In normal primary endometrial epithelial cells (eecs), tgfbeta directly induced a dose-dependent increase in p27 protein levels and its nuclear localization SIGNOR-152945 0.293 cortisone chemical CHEBI:16962 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 14817168 t allergy gcesareni SIGNOR-251691 0.8 3-(4-{[5-Fluoro-2-(4-methylphenyl)phenyl]methoxy}phenyl)propanoic acid chemical CID:57522038 PUBCHEM FFAR4 protein Q5NUL3 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257491 0.8 GRPEL1 protein Q9HAV7 UNIPROT HSPA8 protein P11142 UNIPROT down-regulates activity binding 9606 BTO:0000793 11311562 t miannu As we had observed earlier,HMGE bound avidly to DnaK (Fig. 5A). In addition, bothMt-Hsp70 and Hsc70 bound to GST-HMGE, but Hsc70 appeared to bind with lower affinity. HMGE inhibitedthe co-chaperone enhancement of Hsc70 ATPase activity byapproximately 50% (Table 1). SIGNOR-261241 0.638 SHANK3 protein Q9BYB0 UNIPROT Postsynaptic density assembly phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 28179641 f miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SIGNOR-264607 0.7 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr653 QDSPDGQyENSEGGW 10090 12972425 t lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs SIGNOR-246417 0.796 HIF-1 complex complex SIGNOR-C418 SIGNOR PFKFB3 protein Q16875 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11744734 t PFKFB3, is highly induced by hypoxia and the hypoxia mimics cobalt and desferrioxamine. This induction could be replicated by the use of an inhibitor of the prolyl hydroxylase enzymes responsible for the von Hippel Lindau (VHL)-dependent destabilization and tagging of HIF-1α. The absolute dependence of the PFKFB3 gene on HIF-1 was confirmed by its overexpression in VHL-deficient cells and by the lack of hypoxic induction in mouse embryonic fibroblasts conditionally nullizygous for HIF-1α SIGNOR-267388 0.354 3-N-Me-Phe-morphiceptin chemical CID:115335 PUBCHEM OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258417 0.8 IGF1R protein P08069 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 18595745 t gcesareni Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively) SIGNOR-179386 0.706 PRKD2 protein Q9BZL6 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates activity phosphorylation Ser259 FPLRKTAsEPNLKVR 18692497 t lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. SIGNOR-275927 0.299 ROCK1 protein Q13464 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 11283607 f Cleaved by CASP3 amattioni Activation of rock i by caspase-3 seems to be responsible for bleb formation in apoptotic cells. SIGNOR-106549 0.7 AMPK complex SIGNOR-C15 SIGNOR NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 BTO:0000567 18303014 t lperfetto The central finding of this report is that rosiglitazone rapidly stimulates no production and enos ser-1177 phosphorylation in an ampk-dependent manner SIGNOR-216627 0.266 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 22975381 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-192057 0.764 NPTX1 protein Q15818 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity relocalization 10090 BTO:0000938 23069675 t lperfetto Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4 h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential SIGNOR-261483 0.2 FOXC1 protein Q12948 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 21871448 t gcesareni We demonstrate that physical interactions occur between wt1, foxc1/2 and rbpj, suggestive of the formation of multimeric transcriptional complexes. SIGNOR-176183 0.279 BUB1B protein O60566 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR up-regulates 9606 20888775 f gcesareni The multidomain protein kinases bub1 and bubr1 (mad3 in yeast, worms and plants) are central components of the mitotic checkpoint for spindle assembly (sac) SIGNOR-168195 0.7 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 24173284 t lperfetto The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A SIGNOR-145311 0.55 CDKN2A protein P42771 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 16161044 t gcesareni The cdk-inhibitor p16 is a tumor suppressor gene that is inactivated in many forms of cancer. In addition, cytoplasmic p16 bound cyclin dependent kinase (cdk)4/6, potentially indicating that p16 could have a function in the cytoplasm. SIGNOR-140409 0.902 PLK1 protein P53350 UNIPROT KIF2C protein Q99661 UNIPROT up-regulates activity phosphorylation Ser632 EELSSQMsSFNEAMT 9606 BTO:0000567 25504441 t miannu Our studies suggest new mechanisms by which Plk1 regulates MCAK: the degradation of MCAK is controlled by Plk1 phosphorylation on S621, whereas its activity is modulated by Plk1 phosphorylation on S632/S633 in mitosis.We have recently shown that S621 in MCAK is the major phosphorylation site of Plk1, which is responsible for regulating MCAK's degradation by promoting the association of MCAK with APC/CCdc20.  In the present study, we have addressed another two residues phosphorylated by Plk1, namely S632/S633 in the C-terminus of MCAK. Our data suggest that Plk1 phosphorylates S632/S633 and regulates its catalytic activity in mitosis. This phosphorylation is required for proper spindle assembly during early phases of mitosis. SIGNOR-276863 0.804 CSNK2A1 protein P68400 UNIPROT HOXB7 protein P09629 UNIPROT down-regulates activity phosphorylation Thr204 KTAGPGTtGQDRAEA 10090 BTO:0002882 11290787 t llicata Thus, we concluded that CKII can phosphorylate HOXB7 in vitro and that this phosphorylation occurs at both of the CKII target sites, S133 and T204. | Wild-type HOXB7 inhibited the differentiation of 32D cells, whereas mutations in the Pbx-binding pentapeptide motif or the DNA-binding homeodomain, as well as internal deletions of the N-terminal unique region, blocked this effect. Interestingly, mutations eliminating two target sites for casein kinase II, the glutamate-rich C terminus, or the first 14 amino acids of HOXB7, led to enhanced 32D differentiation. SIGNOR-250897 0.351 PRKCH protein P24723 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 19836308 t lperfetto Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka). SIGNOR-188585 0.2 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207935 0.8 PPP1CA protein P62136 UNIPROT TRIM28 protein Q13263 UNIPROT up-regulates activity dephosphorylation Ser824 LPGAGLSsQELSGGP 9606 20424263 t miannu PP1\u03b1 dephosphorylates KAP1 at Ser 824 . SIGNOR-277075 0.327 GP5 protein P40197 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR form complex binding 9606 BTO:0000132 16293600 t lperfetto The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbα, disulfide-linked to GPIbβ, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1. SIGNOR-261849 0.647 SIRT1 protein Q96EB6 UNIPROT EP300 protein Q09472 UNIPROT down-regulates deacetylation Lys1024 TELKTEIkEEEDQPS 9606 BTO:0000150 19047049 t gcesareni Sirt1 induces deacetylation and repression of p300 itself (81). Mutational analysis demonstrated that sirt1 repression of p300 involves both lysine 1020 and lysine 1024 SIGNOR-182511 0.829 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM FGFR2 protein P21802 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259704 0.8 prostaglandin E2 smallmolecule CHEBI:15551 ChEBI AKT1 protein P31749 UNIPROT up-regulates chemical activation 9606 16293724 t gcesareni Pge2 also stimulated akt activity in a pi3k-dependent manner. SIGNOR-141817 0.8 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2D4 protein Q9Y2X8 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271375 0.684 MRPS16 protein Q9Y3D3 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 BTO:0000934 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261454 0.767 AKT1 protein P31749 UNIPROT SLC2A1 protein P11166 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8940145 f gcesareni The constitutively active akt also increased the synthesis of the ubiquitously expressed glucose transporter 1. The increased glucose influx in the 3t3-l1 adipocytes directed lipid but not glycogen synthesis SIGNOR-252579 0.564 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 8342904 t ashma gcesareni SIGNOR-251698 0.8 Elongator complex complex SIGNOR-C466 SIGNOR RAB3IL1 protein Q8TBN0 UNIPROT up-regulates activity binding -1 15780940 t miannu Our results raise the possibility that regulation of polarized exocytosis is an evolutionarily conserved function of the entire Elongator complex and that FD results from a dysregulation of neuronal exocytosis. Our results raise the possibility that regulation of polarized exocytosis is an evolutionarily conserved function of the entire Elongator complex and that FD results from a dysregulation of neuronal exocytosis. We show that elp1Δ suppression of sec2ts is not a result of reduced transcriptional elongation and that Elp1p physically associates with Sec2p. The Sec2p interaction domain of Elp1p is necessary for both Elp1p function and for the polarized localization of Sec2p. Mutations in human Elp1p (IKAP) are a known cause of familial dysautonomia (FD). SIGNOR-269714 0.277 AKT1 protein P31749 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity phosphorylation Ser184 VAGVLTAsLTIWKKM 9606 BTO:0003473 14766748 t lperfetto Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophilsWe suggest that Bax is regulated by phosphorylation of Ser(184) in an Akt-dependent manner and that phosphorylation inhibits Bax effects on the mitochondria by maintaining the protein in the cytoplasm, heterodimerized with antiapoptotic Bcl-2 family members SIGNOR-252538 0.499 ATM protein Q13315 UNIPROT STK11 protein Q15831 UNIPROT up-regulates phosphorylation Thr367 IIYTQDFtVPGQVPE 9606 BTO:0000848 12234250 t gcesareni We demonstrate that both dna-pk and atm efficiently phosphorylate lkb1 at thr-366 in vitro and provide evidence that atm mediates this phosphorylation in vivo. SIGNOR-92873 0.588 MAGI2 protein Q86UL8 UNIPROT DGC complex SIGNOR-C217 SIGNOR up-regulates activity binding 9606 BTO:0000142 22626542 t miannu S-SCAM is a member of the membrane-associated guanylate kinase (MAGUK) family of PDZ-domain-containing proteins that include the synaptic organising molecule PSD-95. The PDZ domain of S-SCAM binds to the C-terminal tail of NL2, forming a ternary complex at the cell membrane (Figure 2b). The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. SIGNOR-265445 0.258 TGFB1 protein P01137 UNIPROT MYOCD protein Q8IZQ8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 21673106 f gcesareni These results indicate that (i) tgf- and klf4 regulate myocd transcription positively and negatively, respectively. When __90% of smad4 was down-regulated myocd mrna induction by tgf- was abolished, suggesting that smad4 plays a critical role in transcriptional activation of the myocd gene SIGNOR-174396 0.271 POMC protein P01189 UNIPROT MC1R protein Q01726 UNIPROT up-regulates activity binding 9606 BTO:0000847 19656324 t miannu Alpha-melanocyte stimulating hormone (alpha-MSH) binds to melanocortin-1 receptor (MC1R) on melanocytes to stimulate pigmentation and modulate various cutaneous inflammatory responses. SIGNOR-252370 0.757 SNAI1 protein O95863 UNIPROT CTBP1 protein Q13363 UNIPROT up-regulates activity 9606 BTO:0001570 19277896 f lperfetto We propose that CtBP1 is recruited by SNAI1P at the CLDN7 gene promoter indirectly through another yet to be identified protein. Based on our observations, we propose a model for SNAI1P-mediated down regulation of human CLDN7 gene expression by chromatin remodeling SIGNOR-254103 0.481 FYN protein P06241 UNIPROT CHN2 protein P52757 UNIPROT down-regulates phosphorylation Tyr21 VSSDAEEyQPPIWKS 9606 17560670 t llicata Ere we report that beta2-chimaerin is tyrosine-phosphorylated by src-family kinases (sfks) upon cell stimulation with epidermal growth factor (egf). these results suggest tyr-21 phosphorylation as a novel, sfk-dependent mechanism that negatively regulates beta2-chimaerin rac-gap activity. SIGNOR-155709 0.2 olaparib chemical CHEBI:83766 ChEBI PARP3 protein Q9Y6F1 UNIPROT down-regulates activity chemical inhibition 9606 25981132 t miannu The PARP inhibitor olaparib is currently tested in clinical phase 1 trials to define safe dose levels in combination with RT. SIGNOR-259320 0.8 NDUFA3 protein O95167 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND1-module builds around the Q-module with the help of TIMMDC1/C3ORF1 [47,48], which remains bound to the Q/ND1 subassembly until the last maturation steps. MT-ND1 joins first and then NDUFA3, NDUFA8 and NDUFA13 are added SIGNOR-262155 0.787 STUB1 protein Q9UNE7 UNIPROT CBX4 protein O00257 UNIPROT down-regulates quantity by destabilization ubiquitination Lys178 LQYQGGHkEAPSPTC 9606 BTO:0002181 32111827 t miannu The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα.  SIGNOR-277513 0.2 CBX2 protein Q14781 UNIPROT Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR form complex binding 9606 31608994 t miannu PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b SIGNOR-266808 0.763 C3 convertase complex complex SIGNOR-C310 SIGNOR C5 convertase complex complex SIGNOR-C312 SIGNOR form complex binding 31331124 t lperfetto C3b associates with C3 convertase to form C5 convertase and cleaves C5. SIGNOR-263447 0.54 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser21 TPPSTALsPGKMSEA 9606 BTO:0000007 21059642 t The effect has been demonstrated using Q01196-8 lperfetto Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). SIGNOR-216916 0.348 ABL1 protein P00519 UNIPROT PSTPIP1 protein O43586 UNIPROT up-regulates activity phosphorylation Tyr345 PERNEGVyTAIAVQE 9534 BTO:0004055 11163214 t PSTPIP1 was phosphorylated by c-Abl. Tyr-344 is a major c-Abl phosphorylation site.PSTPIP1 was able to bridge c-Abl to the PEST-type PTPs. SIGNOR-251431 0.615 PTPN11 protein Q06124 UNIPROT NTRK2 protein Q16620 UNIPROT down-regulates activity dephosphorylation 9606 28947394 t miannu Conversely, PTPN11 knockdown lead to increased Y 515 phosphorylation of TrkB compared to the scramble control in the neuronal cells.|This study established that TrkB activation as demonstrated by receptor phosphorylation at Tyr 515 in the SH-SY5Y cells is negatively regulated by PTPN11 actions. SIGNOR-277123 0.695 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser713 GAEIVYKsPVVSGDT 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249345 0.728 PTPRG protein P23470 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1059 DIYKDPDyVRKGDAR -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254708 0.255 CREBBP protein Q92793 UNIPROT POU1F1 protein P28069 UNIPROT up-regulates activity binding 9606 BTO:0001379 10931853 t scontino  We and others have recently shown that CBP can constitutively bind to Pit-1 and synergistically activate transcription of promoters containing Pit-1 DNA-binding sites. SIGNOR-267204 0.389 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu73 EEKCSFEeAREVFEN 10090 BTO:0001103 11133752 t lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. SIGNOR-263693 0.67 ARHGAP1 protein Q07960 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260458 0.86 PPP2R2A protein P63151 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity binding 9606 BTO:0000007 16239230 t gcesareni ... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259. SIGNOR-243417 0.44 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 14967450 t gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-121984 0.579 GATA1 protein P15976 UNIPROT GATA2 protein P23769 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21853041 t miannu GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1. SIGNOR-256060 0.419 BCL11A protein Q9H165 UNIPROT HBG1 protein P69891 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20712774 f Regulation miannu BCL11A maintains silencing of gamma-globin expression in adult erythroid cells and functions as a direct transcriptional regulator of the fetal to adult hemoglobin switch in humans. we found that BCL11A plays a central role in the evolutionarily divergent globin gene switches of mammals. As a factor critical for gamma-globin gene silencing, BCL11A should be considered as a therapeutic target to increase HbF in a directed manner in beta-thalassemia patients. SIGNOR-251774 0.458 BUB1 protein O43683 UNIPROT PLK1 protein P53350 UNIPROT up-regulates binding 9606 BTO:0000567 phosphorylation:Thr609 SAAQLAStPFHKLPV 16760428 t gcesareni The plk1-bub1 interaction requires the polo-box domain (pbd) of plk1 and is enhanced by cyclin-dependent kinase 1 (cdk1)-mediated phosphorylation of bub1 at t609 SIGNOR-147061 0.858 CSNK1G2 protein P78368 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser418 LTQMGSPsIRCSSVS 9606 18794808 t lpetrilli Cki?2 Directly phosphorylates smad3 at ser418, leading to the increased ubiquitination and proteasomal degradation of activated smad3 following tgf-? Treatment. SIGNOR-181069 0.343 FER protein P16591 UNIPROT PECAM1 protein P16284 UNIPROT up-regulates activity phosphorylation Tyr690 PLNSDVQyTEVQVSS 9606 BTO:0000007 12972546 t miannu PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1. SIGNOR-262865 0.328 Glycine cleavage system complex SIGNOR-C437 SIGNOR glycine smallmolecule CHEBI:15428 ChEBI down-regulates quantity chemical modification 9606 16051266 t lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. SIGNOR-268238 0.8 APH1A protein Q96BI3 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t gcesareni Gamma secretase subunit. Leads to ps1/ps2 eterodimer complex stabilisation. By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. SIGNOR-93265 0.921 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR up-regulates 9606 BTO:0000759 24692351 f scontino It has been previously established that T3 stimulates gluconeogenesis, especially in the hyperthyroid state, and that hypothyroidism is associated with reduced gluconeogenesis. SIGNOR-267490 0.7 NUDT3 protein O95989 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation SIGNOR-81759 0.2 PSMB2 protein P49721 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263358 0.887 PSAT1 protein Q9Y617 UNIPROT 3-phosphonatooxypyruvate(3-) smallmolecule CHEBI:18110 ChEBI up-regulates activity chemical modification 3702 30034403 t lperfetto Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction. SIGNOR-268562 0.8 Isoetharine chemical CHEBI:6005 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation -1 7576010 t miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. SIGNOR-258432 0.8 TWIST1 protein Q15672 UNIPROT NF1 protein P21359 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255530 0.28 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT up-regulates phosphorylation Ser161 SPTEDPRsPPACSSS 9606 10330152 t lperfetto The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a). SIGNOR-67520 0.579 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr999 YASSNPEyLSASDVF 10116 15738637 t In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver. SIGNOR-248443 0.289 PRKDC protein P78527 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation 9606 23620287 t gcesareni Dna-dependentprotein_ kinase_ (dna-pk) that phosphorylate h2ax at dsbs SIGNOR-192443 0.2 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159398 0.2 CHRM5 protein P08912 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256873 0.2 LRRK2 protein Q5S007 UNIPROT PRDX3 protein P30048 UNIPROT down-regulates activity phosphorylation Thr146 SHLAWINtPRKNGGL 9606 BTO:0000793 21850687 t miannu Here, we show that LRRK2 interacts with human peroxiredoxin 3 (PRDX3), a mitochondrial member of the antioxidant family of thioredoxin (Trx) peroxidases. Importantly, mutations in the LRRK2 kinase domain significantly increased phosphorylation of PRDX3 compared to wild-type. The increase in PRDX3 phosphorylation was associated with decreased peroxidase activity and increased death in LRRK2-expressing but not in LRRK2-depleted or vector-transfected neuronal cells. SIGNOR-262891 0.423 CSNK2A1 protein P68400 UNIPROT ACE protein P12821 UNIPROT up-regulates activity phosphorylation Ser1299 SHGPQFGsEVELRHS 9823 BTO:0001176 12386153 t lperfetto CK2 coprecipitated with ACE from endothelial cells, and CK2 phosphorylated both ACE and a peptide corresponding to the cytoplasmic tail. Mutation of serine(1270) within the CK2 consensus sequence almost abolished ACE phosphorylation.|These results indicate that the CK2-mediated phosphorylation of ACE regulates its retention in the plasma membrane and may determine plasma ACE levels. SIGNOR-264425 0.308 SRC protein P12931 UNIPROT GAK protein O14976 UNIPROT up-regulates activity phosphorylation Tyr1149 CTQPRPNyASNFSVI -1 28135906 t miannu GAK is phosphorylated by c-Src and translocated from the centrosome to chromatin at the end of telophase. Cyclin G-associated kinase (GAK) harbors a consensus phosphorylation motif (Y412) for c-Src; however, its physiological significance remains elusive. Here, we show that GAK is phosphorylated by c-Src not only at Y412 but also at Y1149. SIGNOR-263198 0.278 MAPK14 protein Q16539 UNIPROT CDKN1C protein P49918 UNIPROT up-regulates phosphorylation 9606 22820251 t gcesareni G1-s control by p38/hog1 sapks upon osmostress. Upon osmostress, activated p38 and hog1 sapks phosphorylate the s/cdk inhibitor p57 or sic1 respectively at one single residue. In mammalian cells (left panel), p57 phosphorylation on thr143 leads to an increase of the affinity of p57 towards the cyclin a/cdk2 complex leading to a g1 arrest. SIGNOR-198390 0.265 TRIM27 protein P14373 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity by destabilization ubiquitination Lys572 VVRPKLPkPPTDPLG 10090 35670107 t lperfetto TRIM27 directly polyubiquitinates ULK1 at K568 and K571 sites with K48-linked ubiquitin chains, with proteasomal turnover maintaining control over basal ULK1 levels SIGNOR-272541 0.2 PIP5K1C protein O60331 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates activity chemical modification 9606 9367159 t miannu Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities SIGNOR-277285 0.8 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR CEBPA protein P49715 UNIPROT down-regulates activity binding 9606 BTO:0001271 11283671 t apalma Here we show that AML1–ETO blocks C/EBPα –dependent activation of its own promoter and thereby inhibits autoregulation. SIGNOR-255672 0.2 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr216 VLNSHDLyQKVAQEI 9606 15952790 t llicata We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts. SIGNOR-138146 0.59 FYN protein P06241 UNIPROT DCC protein P43146 UNIPROT up-regulates activity phosphorylation Tyr1261 PTLESAQyPGILPSP 10090 BTO:0001909 15557120 t miannu Fyn tyrosine kinase, but not Src, regulates the phosphorylation of DCC in N1E-115 neuroblastoma cells.Both DCC phosphorylation and Netrin-1-induced axon outgrowth are impaired in Fyn(-/-) CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1. these results show that DCC is phosphorylated by Fyn, but not Src, in N1E-115 cells, and that tyrosines 1261 and 1418 are the major phosphorylation sites of Fyn in vivo. SIGNOR-268175 0.554 MAPK8 protein P45983 UNIPROT STAT6 protein P42226 UNIPROT down-regulates phosphorylation Ser707 IPPYQGLsPEESVNV 9606 21123173 t llicata Deactivation of stat6 through serine 707 phosphorylation by jnk. SIGNOR-170153 0.36 RNA Polymerase I complex SIGNOR-C390 SIGNOR ribosomal RNA smallmolecule CHEBI:18111 ChEBI up-regulates quantity chemical modification 9606 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).¬† SIGNOR-266159 0.8 DOT1L protein Q8TEK3 UNIPROT HECTD4 protein Q9Y4D8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 32814769 t miannu Overexpression of DOT1L decreased the expression of HECTD4 and MYCBP2 in LNCaP, C42B, and 22rv1 cells (Supplementary Fig. 5c), suggesting that DOT1L plays a role in repressing these targets either directly or indirectly. SIGNOR-267150 0.2 MITF protein O75030 UNIPROT PMEL protein P40967 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12819038 f miannu The results of the present work demonstrate that the essential melanocyte-specific transcription factor MITF regulates expression of the genes encoding the melanoma tumor markers MLANA and SILV. MITF up- or down-regulation is seen to correspondingly modulate expression of MLANA and SILV in parallel directions, at both mRNA and protein levels. SIGNOR-254589 0.445 MAF protein O75444 UNIPROT ETS1 protein P14921 UNIPROT down-regulates binding 9606 9566892 t miannu Full-length c-maf binds to the c-myb and ets-1. / c-maf inhibits c-myb and ets-1 transcriptional activity. SIGNOR-56808 0.435 BANP protein Q8N9N5 UNIPROT KHDRBS1 protein Q07666 UNIPROT down-regulates activity binding 9606 BTO:0000567 26080397 t miannu SMAR1 Interacts with Sam68 in a Signal-Dependent Manner. HDAC6 in complex with SMAR1 deacetylates Sam68. Here, we document that SMAR1, in cooperation with histone deacetylase 6 (HDAC6), interacts with Sam68 and maintains it in a deacetylated state, concomitantly inhibiting the inclusion of CD44 alternate exons. SIGNOR-266201 0.314 SMAD2 protein Q15796 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity 9606 BTO:0000599 10890911 f lperfetto Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity SIGNOR-78988 0.462 USP1 protein O94782 UNIPROT FANCD2 protein Q9BXW9 UNIPROT down-regulates activity deubiquitination 9606 BTO:0000567 SIGNOR-C302 18082604 t lperfetto The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2|The level of monoubiquitinated FANCD2 protein increases in response to various types of DNA damage in mammalian cells SIGNOR-263273 0.752 AMPK complex SIGNOR-C15 SIGNOR SREBF1 protein P36956 UNIPROT down-regulates phosphorylation 9606 21892142 t lperfetto Ampk was recently found to phosphorylate a conserved serine near the cleavage site within srebp1, suppressing its activation SIGNOR-216564 0.323 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT up-regulates activity phosphorylation Ser99 KLAVRLEsAWADRVR 23841590 t lperfetto Protein kinase D-mediated phosphorylation at Ser99 regulates localization of p21-activated kinase n the present study, we add another level of complexity to PAK4 regulation by showing that phosphorylation at Ser99 is required for its targeting to the leading edge. This phosphorylation is mediated by PKD1 (protein kinase D1). Phosphorylation of PAK4 at Ser99 also mediates binding to 14-3-3 protein, and is required for the formation of a PAK4-LIMK-PKD1 complex that regulates cofilin activity and directed cell migration| SIGNOR-275939 0.492 PRKD3 protein O94806 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser172 GQLVRNDsLWHRSDS 34010649 t lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-275940 0.2 P-TEFb complex SIGNOR-C238 SIGNOR AFF2 protein P51816 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0000007 17135274 t miannu P-TEFb phosphorylates Af4 and down-regulates its transactivation activity. P-TEFb also phosphorylates AF4 which down-regulates its transactivation activity, providing a negative feedback mechanism for the control of P-TEFb elongation activity SIGNOR-266798 0.398 JNJ-28312141 free base chemical CID:11676971 PUBCHEM CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259748 0.8 DLL3 protein Q9NYJ7 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209747 0.2 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates phosphorylation Ser321 LNSEDDVsDEEGQEL 9606 11278496 t llicata Taf(ii) 250 phosphorylates human transcription factor iia on serine residues important for tbp binding and transcription activity. SIGNOR-105745 0.664 KIF5A protein Q12840 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272523 0.7 TFEB protein P19484 UNIPROT PPM1D protein O15297 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 t lperfetto As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes; SIGNOR-276557 0.2 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 19115199 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-182996 0.738 RUVBL1 protein Q9Y265 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269292 0.733 PP1 proteinfamily SIGNOR-PF54 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser370 KKTIVNDsRESCVEE 9606 BTO:0001938 23277204 t lperfetto Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity. SIGNOR-264666 0.2 6-[2-tert-butyl-5-(6-methyl-2-pyridinyl)-1H-imidazol-4-yl]quinoxaline chemical CHEBI:91391 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206715 0.8 canertinib chemical CHEBI:61399 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0000017;BTO:0000195 10753475 t Canertinib is an irreversible tyrosine-kinase inhibitor with activity against EGFR (IC50 0.8 nM), HER-2 (IC50 19 nM) and ErbB-4 (IC50 7 nM). gcesareni Quinazoline analogues with 7-alkoxyamine solubilizing s were potent irreversible inhibitors of the isolated egfr enzyme, with ic(50[app]) values from 2 to 4 nm, and potently inhibited both egfr and erbb2 autophosphorylation in cells. SIGNOR-76554 0.8 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2U protein Q5VVX9 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271371 0.584 TNF protein P01375 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 10485710 t gcesareni Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k) SIGNOR-70625 0.3 PPP1CB protein P62140 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser370 KKTIVNDsRESCVEE 9606 23277204 t Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity. SIGNOR-248577 0.2 NR0B2 protein Q15466 UNIPROT NR5A2 protein O00482 UNIPROT down-regulates binding 9606 15723037 t gcesareni Modulation of human nuclear receptor lrh-1 activity by phospholipids and shpthe human nuclear receptor liver receptor homolog 1 (hlrh-1) plays an important role in the development of breast carcinomas. This orphan receptor is efficiently downregulated by the unusual co-repressor shp SIGNOR-134202 0.579 SIRT3 protein Q9NTG7 UNIPROT IDH2 protein P48735 UNIPROT up-regulates deacetylation Lys413 VESGAMTkDLAGCIH 9606 22416140 t miannu Site-specific, genetic incorporation of n(_)-acetyllysine into position 413 of idh2 revealed that acetylated idh2 displays a dramatic 44-fold loss in activity. Deacetylation by sirt3 fully restored maximum idh2 activity. SIGNOR-196617 0.643 ATM protein Q13315 UNIPROT RNF40 protein O75150 UNIPROT up-regulates activity phosphorylation Ser114 ALLRCHEsQGELSSA 9606 BTO:0000007 21362549 t miannu ATM-Mediated Phosphorylation of RNF20 and RNF40 in Response to DNA Damage and Its Requirement for Damage-Induced H2B Monoubiquitylation  SIGNOR-276315 0.455 AKT1 protein P31749 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 f lperfetto Two candidates that may function as mediators of pi3-k in the phosphorylation of mef2 proteins are pkb and big map kinase 1. SIGNOR-79338 0.585 NF1 protein P21359 UNIPROT ADCY4 protein Q8NFM4 UNIPROT up-regulates 9606 24431436 f miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-204091 0.29 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates activity phosphorylation Ser348 PGPQSPGsPLEEERQ -1 24632950 t miannu Of note, PKCδ, when it was activated by PDPK1, directly bound to the SH3-N domain of p47(phox) and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47(phox) C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation.PKCδ phosphorylates p47phox for K-Ras-induced ROS generation. PKCδ binds to the SH3-N domain and phosphorylates Ser348 and Ser379 residues in p47phox for K-RasV12-induced ROS generation and consequent malignant transformation. SIGNOR-276623 0.458 FKBP1A protein P62942 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity binding 9606 BTO:0005493 8756725 t lperfetto Blocking fkbp12/type i receptor interaction with fk506 nonfunctional derivatives enhances the ligand activity, indicating that fkbp12 binding is inhibitory to the signaling pathways of the tgf beta family ligands SIGNOR-236142 0.848 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 12050114 t gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. SIGNOR-88744 0.346 CHD2 protein O14647 UNIPROT H3-3A protein P84243 UNIPROT up-regulates quantity relocalization 9606 26895424 t miannu Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in human cells, but our understanding of how it operates in chromatin is limited. Here, we define a mechanism that plays a crucial role in regulating NHEJ in chromatin. This mechanism is initiated by DNA damage-associated poly(ADP-ribose) polymerase 1 (PARP1), which recruits the chromatin remodeler CHD2 through a poly(ADP-ribose)-binding domain. CHD2 in turn triggers rapid chromatin expansion and the deposition of histone variant H3.3 at sites of DNA damage. SIGNOR-264527 0.2 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT up-regulates phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000782 18550856 t gcesareni In this study, we present evidence that pkc isoforms are the major protein kinases that phosphorylate the c terminus of the integrin cd18 chain in leukocytes. Ser-745 is identified as a novel phosphorylation site in the integrin cytoplasmic domain. Additionally, we show that a thr-758-phosphorylated integrin peptide can interact with 14-3-3 proteins in leukocyte lysates SIGNOR-178897 0.335 USP7 protein Q93009 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates deubiquitination 9606 16082221 t gcesareni Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins. SIGNOR-139450 0.761 TLN1 protein Q9Y490 UNIPROT ITGB8 protein P26012 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257636 0.458 SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-175256 0.821 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA -1 10949026 t gcesareni Survival factors, acting through kinases such as Akt and PKA, induce endogenous BAD phosphorylation at two evolutionarily conserved sites, Ser-112 and Ser-136, which leads to the translocation of BAD from the mitochondria to the cytoplasm and the inhibition of BAD-dependent death SIGNOR-180780 0.523 PRKD3 protein O94806 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser275 DNVRYGIsNIDTTIE 34010649 t lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-275946 0.2 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser252 DIWSMGLsLVEMAVG -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-39062 0.78 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RBBP8 protein Q99708 UNIPROT up-regulates activity phosphorylation Ser327 ELPTRVSsPVFGATS 9606 BTO:0000567 15485915 t lperfetto Ser327 site is a Ser-Pro site, a preferred phosphorylation site by cyclin-dependent kinases|Unlike wild-type CtIP, the S327A mutant did not bind to BRCA1 BRCT domains in vitro (Fig. ​(Fig.1C)1C) and failed to associate with BRCA1 in vivo (Fig. ​(Fig.1D),1D), suggesting that residue Ser327 of CtIP is critical for the CtIP-BRCA1 interaction. SIGNOR-263227 0.547 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Thr28 PTMPPPEtPSEGRQP 9606 BTO:0001271 15093545 t The effect has been demonstrated using P29590-4 gcesareni We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3). SIGNOR-124313 0.366 MAPK3 protein P27361 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 BTO:0000142 16401070 t lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. SIGNOR-143481 0.516 PRKCD protein Q05655 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 9606 BTO:0000562 17075052 t gcesareni The triple aspartic acid mutation shows greater distance between the two thick myosin filaments (affects the steric arrangement of the filament distances) in heart tissue. Mutation is cardioprotective during stress (ischemia-reprofusion injury) against apoptosis similar to isoproterenol treatment. SIGNOR-150347 0.2 ADORA2A protein P29274 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257306 0.252 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser513 NLESHLMsPAEIPGQ 9606 22966201 t llicata Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress. SIGNOR-198992 0.328 carbamazepine chemical CHEBI:3387 ChEBI SCN2A protein Q99250 UNIPROT down-regulates activity chemical inhibition 10116 1658608 t miannu This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner. SIGNOR-258353 0.8 OPTN protein Q96CV9 UNIPROT BDNF protein P23560 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22194658 f same result in PC12 cell miannu SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA. SIGNOR-259878 0.283 PRKCA protein P17252 UNIPROT PTPN12 protein Q05209 UNIPROT down-regulates phosphorylation Ser435 KKLERNLsFEIKKVP 9606 7520867 t llicata Ptp-pest is phosphorylated in vitro by both cyclic amp-dependent protein kinase (pka) and protein kinase c (pkc) at two major sites, which we have identified as ser39 and ser435. our results suggest that both pkc and pka are capable of phosphorylating, and therefore inhibiting, ptp-pest in vivo SIGNOR-27304 0.327 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 8816480 t gcesareni In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1 SIGNOR-43947 0.621 RORA protein P35398 UNIPROT NR1D1 protein P20393 UNIPROT down-regulates activity binding 9606 BTO:0000599 20817722 t miannu Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding. SIGNOR-267979 0.438 PDGFRA protein P16234 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 19426560 t amattioni Crk can interact directly with tyrosine kinase receptors (for example pdgfr?) And can transmit signals downstream SIGNOR-185664 0.632 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT down-regulates activity phosphorylation Ser36 ELQRRRRsLALPGLQ -1 15946941 t done miannu PKA Phosphorylates GRK7 on Ser23 and Ser36. Phosphorylation by PKA inhibits GRK7 activity SIGNOR-274080 0.2 ADRA1A protein P35348 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257279 0.607 ABL1 protein P00519 UNIPROT TOP1 protein P11387 UNIPROT up-regulates activity phosphorylation Tyr268 AKMLDHEyTTKEIFR 9606 15448168 t Manara This study demonstrates that ABL1-dependent phosphorylation up-regulates topo I activity. The ABL1 SH3 domain bound directly to the N-terminal region of topo I. The results demonstrate that ABL1 phosphorylated topo I at Tyr268 in core subdomain II. SIGNOR-260775 0.408 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser39 TTSTRTYsLGSALRP -1 11895474 t miannu In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK.¬† SIGNOR-250239 0.312 COPS3 protein Q9UNS2 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270764 0.915 RUNX1 protein Q01196 UNIPROT CDKN2A protein Q8N726 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12091906 f irozzo AML1 binds to a six base pair DNA sequence (TGT/cGGT) that is present in many hematopoietic-specific genes.The p53 promoter does not contain any perfect AML1 DNA-binding sites (TGT/cGGT), but the human p14ARF promoter contains eight such sites (Fig. 1a), as well as multiple sites that match the broader consensus sequence (PyGPy/AGGT) or that have a single change from the consensus site.AML1 regulates the p14ARF promoter through an AML1 consensus DNA-binding site. SIGNOR-255713 0.267 Fanconi anemia ID complex complex SIGNOR-C302 SIGNOR BRCA2 protein P51587 UNIPROT up-regulates 18985065 f lperfetto Once monoubiquitinated, the ID complex becomes associated with chromatin and is redistributed to DNA-damage sites, forming foci that are visible by immunofluorescence and colocalizing with other DNA-repair molecules, notably BRCA1, BRCA2 and γH2AX. SIGNOR-263270 0.783 RALY protein Q9UKM9 UNIPROT PRMT1 protein Q99873 UNIPROT up-regulates quantity post transcriptional regulation 9606 BTO:0000567 30354839 t lperfetto RALY binds poly-U rich elements within several RNAs and regulates the expression as well as the stability of specific transcripts. Here we show that RALY binds PRMT1 mRNA and regulates its expression.|We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels SIGNOR-262273 0.249 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr594 RLYDYEItDQYIYMV -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276221 0.388 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F8 protein P00451 UNIPROT down-regulates activity cleavage Arg391 SPSFIQIrSVAKKHP -1 10350471 t lperfetto N-Terminal sequencing along with time courses of proteolysis indicated that VIIa-TF/PL cleaved factor VIII first at R740, followed by concomitant cleavage at R336 and R372. |hus, heavy chain cleavage of factor VIII by VIIa-TF/PL produces an inactive factor VIII cofactor no longer capable of activation by thrombin. SIGNOR-263642 0.466 MMP1 protein P03956 UNIPROT COL2A1 protein P02458 UNIPROT down-regulates quantity by destabilization cleavage Gly906 EGPPGPQgLAGQRGI 9606 8609233 t miannu MMP-1 cleaves type II collagen at the peptide bond Gly906-Leu907 Proteolysis of triple-helical collagen is an important step in the progression toward irreversible tissue damage in osteoarthritis. Earlier work on the expression of enzymes in cartilage suggested that collagenase-1 (MMP-1) contributes to the process. SIGNOR-256341 0.456 ITGB1 protein P05556 UNIPROT A3/b1 integrin complex SIGNOR-C161 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253174 0.797 FCN3 protein O75636 UNIPROT MASP1 protein P48740 UNIPROT up-regulates activity binding 9606 BTO:0000392 11907111 t lperfetto H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. These results indicate that H-ficolin is a second ficolin which is associated with MASPs and sMAP, and which activates the lectin pathway|Proteolytic activation of complement components by H-ficolin-MASP. SIGNOR-263410 0.659 AKT proteinfamily SIGNOR-PF24 SIGNOR TBC1D4 protein O60343 UNIPROT down-regulates phosphorylation 9606 BTO:0000887 12637568 t gcesareni Recently, we identified a 160-kda protein in adipocytes, designated as160, that is phosphorylated by the insulin-activated kinase akt SIGNOR-99300 0.2 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser978 SPLKRSHsLAKLGSL 9606 BTO:0000150 19567672 t llicata Pkd-mediated phosphorylation of serines 937 and 978 regulates ssh1l subcellular localization by binding of 14-3-3 proteins 14-3-3 proteins associate with ssh1l when phosphorylated at serines 937 and 978, thereby sequestering ssh1l in the cytoplasm and preventing translocation of the phosphatase to f-actin_rich membrane protrusions SIGNOR-186471 0.492 nafadotride chemical CHEBI:64191 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). SIGNOR-258854 0.8 C7 protein P10643 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 t lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer SIGNOR-263443 0.448 YWHAZ protein P63104 UNIPROT GEM protein P55040 UNIPROT up-regulates quantity by stabilization binding 9534 BTO:0000298 14701738 t miannu In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase SIGNOR-261715 0.307 STK11 protein Q15831 UNIPROT BRSK2 protein Q8IWQ3 UNIPROT up-regulates phosphorylation Thr174 VGDSLLEtSCGSPHY 9606 14976552 t lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold SIGNOR-122485 0.481 BCS1L protein Q9Y276 UNIPROT LETM1 protein O95202 UNIPROT up-regulates activity binding 9606 BTO:0000567 18628306 t lperfetto LETM1 was co-precipitated with BCS1L and formation of the LETM1 complex depended on BCS1L levels, suggesting that BCS1L stimulates the assembly of the LETM1 complex. SIGNOR-262543 0.476 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251593 0.695 MRGPRX2 protein Q96LB1 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257434 0.2 ROCK1 protein Q13464 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Ser364 TRLDRTGsSPTQGIV 9606 15767678 t gcesareni Identification of rock1 as an upstream activator of the jip-3 to jnk signaling axis in response to uvb damage. phosphorylation of jip-3 by rock1 was crucial for the recruitment of jnk. Inhibition of the activity of rock1 in keratinocytes resulted in decreased activation of the jnk pathway and thus a reduction in apoptosis. SIGNOR-134584 0.338 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Thr566 NTRQQMDtPMVSCGN -1 12361598 t miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) SIGNOR-265959 0.53 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR aspartic acid smallmolecule CHEBI:22660 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270373 0.8 MAPK3 protein P27361 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 12169099 t gcesareni Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. SIGNOR-91379 0.773 FLT3 protein P36888 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14981546 f FLT3-ITD signaling contributes to transcriptional inhibition of p27Kip1 and Bim gene expression SIGNOR-261525 0.328 CSNK2A1 protein P68400 UNIPROT MME protein P08473 UNIPROT down-regulates phosphorylation Ser6 sQMDITDI 9606 20957047 t lperfetto The cytoplasmic n-terminal domain of nep interacts with the phosphatase and tensin homologue deleted on chromosome 10 (pten) thereby regulating intracellular signaling via akt. Ser 6 is efficiently phosphorylated by protein kinase ck2. The phosphorylation of the cytoplasmic domain of nep inhibits its interaction with pten. SIGNOR-168673 0.328 UXT protein Q9UBK9 UNIPROT URI1 prefoldin co-chaperone complex SIGNOR-C514 SIGNOR form complex binding 9606 30484151 t miannu In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR93 SIGNOR-270916 0.627 CKB protein P12277 UNIPROT ACTB protein P60709 UNIPROT up-regulates quantity relocalization 9606 BTO:0000099 19333390 t miannu In summary, data presented here strongly suggest that locally generated ATP is an important regulator for actin-based cytoskeletal dynamics involved in cell extension and motility and that CK-B is a controlling enzyme in the compartmentalization of ATP availability. CK-B co-localizes with cortical actin and facilitates spreading of astrocytes SIGNOR-265791 0.296 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR UNG protein P13051 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 20870715 t miannu Using reconstituted CRL4(DCAF1) and CRL4(DCAF1-Vpr) E3 ubiquitin ligases in vitro reveals that UNG2 ubiquitination (ubiquitylation) is facilitated by Vpr. Co-expression of DCAF1 and Vpr causes down-regulation of UNG2 in a proteasome-dependent manner, with Vpr mutants that are defective in UNG2 or DCAF1 binding abrogating this effect. SIGNOR-271905 0.382 MRPL58 protein Q14197 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262344 0.2 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation Tyr299 HKLGGGQyGEVYVGV -1 34144039 t miannu  PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. SIGNOR-277301 0.308 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser315 ITATSPAsMVGGKPG 9606 12510059 t gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. SIGNOR-96940 0.767 ZNF76 protein P36508 UNIPROT TBP protein P20226 UNIPROT down-regulates activity binding 9606 15280358 t miannu We identified ZNF76 as a novel transcriptional repressor that targets TBP. ZNF76 interacts with TBP through both its N and C termini. ZNF76 targets TBP for transcriptional repression. SIGNOR-224650 0.408 AKT1 protein P31749 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation -1 16340011 t gcesareni It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser 485/Ser 491 phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr 172 by LKB1 and the resulting activation of AMP-activated protein kinase. SIGNOR-252739 0.296 RPS6K proteinfamily SIGNOR-PF26 SIGNOR NR4A3 protein Q92570 UNIPROT down-regulates activity phosphorylation Ser376 GRRGRLPsKPKSPLQ 9606 BTO:0000007 16223362 t lperfetto Phosphorylation of Nur77 on Ser354 has been suggested to reduce ability of Nur77 to bind DNA; however, the kinase responsible for this phosphorylation in cells has not been clearly established. In the present study, we show that Nur77 is phosphorylated on this site by RSK (ribosomal S6 kinase) SIGNOR-252771 0.2 FANCA protein O15360 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 t lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263240 0.95 IFNGR2 protein P38484 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR form complex binding 9606 BTO:0000801 19041276 t lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249486 0.732 HTR2C protein P28335 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257355 0.482 SPOP protein O43791 UNIPROT BRMS1 protein Q9HCU9 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22085717 t Gianni Intriguingly, BRMS1 turns out to be a potent substrate that is ubiquitinated by the Cul3-SPOP complex. Knockdown of SPOP increases the level of BRMS1 protein and represses the expression of BRMS1 repressive target genes such as OPN and uPA in breast cancer cells. SIGNOR-268857 0.411 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MITF protein O75030 UNIPROT down-regulates phosphorylation Ser409 HGLSLIPsTGLCSPD 9606 10673502 t The effect has been demonstrated using O75030-9 gcesareni The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73, whereas serine 409 serves as a substrate for p90 rsk-1. An unphosphorylatable double mutant at these two residues is at once profoundly stable and transcriptionally inert. SIGNOR-252791 0.2 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser202 EEDSRPRsQSSKAAI 9534 BTO:0001538 23519612 t miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. Clk1 promotes SPF45-induced exon 6 exclusion SIGNOR-262705 0.323 SHPRH protein Q149N8 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination 9606 19706603 t gcesareni We provide evidence that similar to rad5, shprh physically interacts with the human rad6rad18 and mms2ubc13 protein complexes, and importantly, we show that it exhibits an ubiquitin ligase activity and mediates mms2ubc13-dependent polyubiquitylation of pcna. Thus, shprh is a functional homolog of rad5. SIGNOR-187757 0.534 HOMER proteinfamily SIGNOR-PF59 SIGNOR SHANK1 protein Q9Y566 UNIPROT up-regulates activity binding 9606 17243894 t miannu It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD SIGNOR-264698 0.2 MIB2 protein Q96AX9 UNIPROT JAG2 protein Q9Y219 UNIPROT up-regulates ubiquitination 9606 15920166 t gcesareni Skeletrophin bound the intracellular regions of the notch ligand jagged-2, but not to those of delta-1, -3, -4, or jagged-1. Skeletrophin, but not its ring-mutated form, ubiquitinized the intracellular region of jagged-2. SIGNOR-137922 0.802 MASTL protein Q96GX5 UNIPROT MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Ser875 TAQHLTVsGFSL 8355 phosphorylation:Thr194;Thr207 NMMDILTtPSMAKPR;PRQDYSRtPGQVLSL 22354989 t gcesareni After this priming step, Gwl can intramolecularly phosphorylate its C-terminal tail at pS883; this site probably plays a role similar to that of the tail/Z motif of other AGC kinases. SIGNOR-243409 0.2 beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI PFK proteinfamily SIGNOR-PF79 SIGNOR up-regulates activity binding 9606 19454274 t The PFKFB enzymes synthesize fructose-2,6-bisphosphate (F2,6BP) which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. PFK-1 is inhibited by ATP when energy stores are abundant and F2,6BP can override this inhibition and enhance glucose uptake and glycolytic flux SIGNOR-267262 0.8 TBK1 protein Q9UHD2 UNIPROT PRPS2 protein P11908 UNIPROT up-regulates activity phosphorylation Thr228 DMADTCGtICHAADK -1 34343500 t miannu Here, we show that ionizing radiation results in TBK1-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase (PRPS)1/2 at T228, thereby enhancing PRPS1/2 catalytic activity and promoting deoxyribonucleotide synthesis.  SIGNOR-277317 0.2 PIK3AP1 protein Q6ZUJ8 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 BTO:0000801 22187458 t gcesareni This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Therefore, bcap is an essential activator of the pi3k pathway downstream of tlr signaling, providing a brake to limit potentially pathogenic excessive tlr responses. SIGNOR-191667 0.397 MAPK3 protein P27361 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser279 SSPTAPLsPMSPPGY 9606 9535909 t lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. SIGNOR-249466 0.626 TWIST2 protein Q8WVJ9 UNIPROT PFDN4 protein Q9NQP4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255507 0.2 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr5 tPRKTAAT -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250762 0.858 CDK1 protein P06493 UNIPROT CKAP2 protein Q8WWK9 UNIPROT up-regulates phosphorylation Thr623 FKELKFLtPVRRSRR 9606 SIGNOR-C17 19369249 t llicata Among these, thr-622 was specifically phosphorylated by cdk1-cyclin b1 both in vitro and in vivo. these findings suggest that cdk1-cyclin b1-mediated phosphorylation of tmap is important for and contributes to proper regulation of microtubule dynamics and establishment of functional bipolar spindles during mitosis. SIGNOR-185317 0.291 CDK3 protein Q00526 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2516 FLTPSPEsPDQWSSS -1 25344755 t lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues SIGNOR-273168 0.245 quetiapine chemical CHEBI:8707 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258533 0.8 SMURF1 protein Q9HCE7 UNIPROT TBX6 protein O95947 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 19561075 t miannu Smad6 mediates Tbx6 ubiquitination and proteasomal degradation. Tbx6 forms a ternary complex with Smad6 and Smurf1. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase. SIGNOR-272784 0.259 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation Tyr303 GGQYGEVyVGVWKKY -1 34144039 t miannu  PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. SIGNOR-277303 0.308 WNT7B protein P56706 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 22944199 f gcesareni In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod. SIGNOR-198925 0.299 UBE3A protein Q05086 UNIPROT ALDH1A2 protein O94788 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 29076503 t lperfetto Hyperactivity of E3 ubiquitin (Ub) ligase UBE3A, stemming from 15q11-q13 copy number variations, accounts for 1%-3% of ASD cases worldwide, but the underlying mechanisms remain incompletely characterized. Here we report that the functionality of ALDH1A2, the rate-limiting enzyme of retinoic acid (RA) synthesis, is negatively regulated by UBE3A in a ubiquitylation-dependent manner. SIGNOR-265135 0.2 SP1 protein P08047 UNIPROT IFITM5 protein A6NNB3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23530031 f miannu Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation. SIGNOR-254218 0.2 CHEK2 protein O96017 UNIPROT MDM4 protein O15151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 18356162 t lperfetto The chk1 and chk2 kinases have also been shown to phosphorylate ser367, leading to 14-3-3 binding (34_36, 38, 44). In both cases, the outcome differed: in chk1-mediated phosphorylation, mdmx was translocated to the cytoplasm;in chk2-mediated phosphorylation, mdmx was degraded (34_36, 38, 44). It is possible that the damage response is mediated through additional phosphorylation sites other than ser367 and that, depending on the type of damage, certain sites will be modified, leading to different outcomes. SIGNOR-178071 0.712 ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 17251915 t gcesareni Typically Gas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152546 0.8 PRKCB protein P05771 UNIPROT IBTK protein Q9P2D0 UNIPROT down-regulates phosphorylation Ser1200 ASSLHSVsSKSFRDF 9606 BTO:0000776 21482705 t llicata We found that ibtk_ is phosphorylated at serines 87 and 90 by pkc on bcr engagement;this phosphorylation causes the dissociation of the btk:ibtk_ complex and allows btk to translocate to the plasma membrane. SIGNOR-173383 0.334 MAPK3 protein P27361 UNIPROT LCK protein P06239 UNIPROT up-regulates activity phosphorylation Ser59 EGSNPPAsPLQDNLV 9606 BTO:0000567 8618896 t lperfetto Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation. SIGNOR-249469 0.548 PRKN protein O60260 UNIPROT HIF3A protein Q9Y2N7 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000793 27551449 t Parkinson miannu Here we show that IPAS is a key molecule involved in neuronal cell death in Parkinson's disease (PD). IPAS was ubiquitinated by Parkin for proteasomal degradation following carbonyl cyanide m-chlorophenyl hydrazone treatment. Phosphorylation of IPAS at Thr12 by PTEN-induced putative kinase 1 (PINK1) was required for ubiquitination to occur. SIGNOR-263089 0.2 MAPK8IP3 protein Q9UPT6 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 10523642 t gcesareni Overexpression of full-length jsap1 in cos-7 cells led to a considerable enhancement of jnk3 activation, and modest enhancement of jnk1 and jnk2 activation, by the mekk1-sek1 pathwaythe regions of jsap1 that bound jnk, sek1, and mekk1 were distinct from one another. Jnk and mekk1 also bound jsap1 in vitro, suggesting that these interactions are direct. SIGNOR-71471 0.527 TGFBR2 protein P37173 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 19114990 t lperfetto In immunoprecipitation esperiments, the TGF _ RII receptor was found to be constitutively associated with p85, the regulatory subunity of PI3K SIGNOR-252731 0.42 PRKCA protein P17252 UNIPROT GNAZ protein P19086 UNIPROT up-regulates phosphorylation Ser27 DRHLRSEsQRQRREI 9606 BTO:0000671 9166747 t gcesareni Functional role of amino-terminal serine16 and serine27 of g alphaz in receptor and effector coupling. SIGNOR-48681 0.418 IL4R protein P24394 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 9606 20824124 t Several cytokine receptors share subchains and targets. For example, the common gamma chain (CGC) is shared by IL2, IL4, IL7, IL9 and IL15 receptors that lead to the activation of STAT5 SIGNOR-254298 0.537 RFXAP protein O00287 UNIPROT RFX complex complex SIGNOR-C104 SIGNOR form complex binding -1 10825209 t miannu RFXANK and RFXAP bind to each other and form a heterodimer (step 1) that subsequently interacts with RFX5 Upon binding, the conformation of RFX5 changes (step 2) in a way that enables the RFX complex to bind to DNA (step 3) and to recruit other proteins that are required for the transcription of MHC II genes SIGNOR-221568 0.812 MYC protein P01106 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001271 12835716 f gcesareni These results suggest that e2f1 and cyclin a2 may be induced by c-myc to mediate the onset of mammary cancer, whereas overexpression of cyclins d1 and e may occur later to facilitate tumor progression. SIGNOR-102728 0.427 PCDHA5 protein Q9Y5H7 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265669 0.2 AGPAT4 protein Q9NRZ5 UNIPROT 1-acyl-sn-glycerol 3-phosphate(2-) smallmolecule CHEBI:57970 ChEBI down-regulates quantity chemical modification 9606 21173190 t lperfetto The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬† SIGNOR-267015 0.8 MAPK3 protein P27361 UNIPROT STMN2 protein Q93045 UNIPROT down-regulates activity phosphorylation Ser73 EAPRTLAsPKKKDLS 10116 BTO:0000142 9525956 t lperfetto SCG10, a growth cone-enriched MT-destabilizing protein, has been recently characterized as an in vitro substrate for various serine/threonine kinases including PKA, MAP kinase, and CDK (19). We have found that SCG10 is phosphorylated in vivo in developing rat brain.| The sites for MAP kinase phosphorylation were identified as Ser-62 and Ser-73 of SCG10|By expressing a series of phosphorylation site mutants, we showed that the MT-destabilizing effect of SCG10 could be modulated. While the nonphosphorylatable mutant showed higher activity than the wild-type protein, the activity of the mutant in which phosphorylation on all four sites was mimicked by an aspartate residue was greatly reduced. These data suggest that the nonphosphorylated state of SCG10 represents the most active form of the protein. SIGNOR-249116 0.359 DYRK1B protein Q9Y463 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates activity phosphorylation Ser279 KVAERRSsPLLRRKD 10090 15546868 t lperfetto Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent mannermirk phosphorylates hdac5 at ser-279 SIGNOR-235809 0.38 CDC42BPA protein Q5VT25 UNIPROT CDC42BPA protein Q5VT25 UNIPROT up-regulates activity phosphorylation Thr403 HLPFVGFtYTSSCVL 9534 BTO:0000298 11283256 t miannu N terminus-mediated dimerization and transautophosphorylation are essential for MRCKα catalytic activity. Three mutations, S234A, T240A, and T403A, strongly affected the in vitro autophosphorylation activity of FLAG-MRCKα-CAT1–473 (Fig. ​(Fig.5D).5D). SIGNOR-275973 0.2 GATA2 protein P23769 UNIPROT TRH protein P20396 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 33201916 t scontino The rat prepro-TRH gene is activated by GATA2. SIGNOR-267258 0.266 NFE2L2 protein Q16236 UNIPROT TBXAS1 protein P24557 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14565864 t miannu Ecotopic expression of NF-E2 related factors showed that Nrf2, but not Nrf1, Nrf3, or Bach1, activated TXAS promoter in a dose-dependent manner. SIGNOR-253907 0.248 CSNK1A1 protein P48729 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser318 SRTNSNAsTVSGRLS 9606 20110348 t lperfetto Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export SIGNOR-252899 0.393 bisphenol A chemical CHEBI:33216 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9751507 t miannu Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings.  SIGNOR-268739 0.8 PTPN6 protein P29350 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 17974954 t Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B SIGNOR-248472 0.542 DPM3 protein Q9P2X0 UNIPROT DPM complex complex SIGNOR-C289 SIGNOR form complex binding 9606 10835346 t lperfetto Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3. SIGNOR-262565 0.778 AKT1 protein P31749 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 f lperfetto Two candidates that may function as mediators of pi3-k in the phosphorylation of mef2 proteins are pkb and big map kinase 1. SIGNOR-79335 0.533 CSNK2A2 protein P19784 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization phosphorylation Thr112 EGMQIPStQFDAAHP -1 12432063 t miannu We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin.  SIGNOR-275994 0.453 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 9445476 t gcesareni A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-55310 0.716 AREG protein P15514 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation 9606 7679104 t gcesareni Amphiregulin induces tyrosine phosphorylation of the epidermal growth factor receptor SIGNOR-31199 0.613 HCK protein P08631 UNIPROT HCK protein P08631 UNIPROT down-regulates phosphorylation Tyr522 YTATESQyQQQP 9606 10934191 t gcesareni We demonstrate that autophosphorylation of the recombinant src family kinase hck leads to a 20-fold increase in its specific enzymatic activity. SIGNOR-76996 0.2 5-(1,1-Dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol chemical CID:104895 PUBCHEM CNR2 protein P34972 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257474 0.8 FZD2 protein Q14332 UNIPROT SETDB1/NLK/CHD7 complex SIGNOR-C189 SIGNOR up-regulates activity 21952300 t FFerrentino The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1)42. SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3‑L1 cells42,43. SIGNOR-253521 0.399 PPP1R1B protein Q9UD71 UNIPROT PPP1CB protein P62140 UNIPROT down-regulates activity binding 9606 BTO:0000938 10604473 t miannu DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚  SIGNOR-264959 0.425 ponatinib chemical CHEBI:78543 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001669 23539538 t miannu Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells SIGNOR-259272 0.8 buprenorphine chemical CHEBI:3216 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9262330 t miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. SIGNOR-258660 0.8 APOA1 protein P02647 UNIPROT APOE protein P02649 UNIPROT up-regulates activity relocalization 9606 20642861 t miannu ApoA-I stimulates apoE secretion in mature human adipocytes. The regulation of apoE secretion by apoA-I, is neither dependent upon an increase in gene transcription, nor upon increased release from the Golgi. It may therefore be assumed that, in macrophage models, apoE is stored mainly in the cytoplasm and/or on the cell surface, with apoA-I enabling secretion of this cytoplasmic pool SIGNOR-252105 0.727 SYN2 protein Q92777 UNIPROT ACTB protein P60709 UNIPROT up-regulates activity binding 9606 BTO:0000938 15265865 t miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. SIGNOR-269182 0.2 CLK1 protein P49759 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates activity phosphorylation -1 8617202 t miannu In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors. SIGNOR-273857 0.695 TP53INP1 protein Q96A56 UNIPROT MAP1LC3C protein Q9BXW4 UNIPROT up-regulates binding 9606 22421968 t gcesareni These data indicate that cell death observed after tp53inp1-lc3 interaction depends on both autophagy and caspase activity. We conclude that tp53inp1 could act as a tumor suppressor by inducing cell death by caspase-dependent autophagy. SIGNOR-196676 0.283 p38 proteinfamily SIGNOR-PF16 SIGNOR FH protein P07954 UNIPROT up-regulates activity phosphorylation Thr90 GVTERMPtPVIKAFG 9606 BTO:0002058 30683654 t miannu In this study, we found that TGFβ induces FH Thr 90 phosphorylation by p38. Upon Notch activation, nuclear NICD promotes the interaction between CSL and p38-phosphorylated FH and thus FH/CSL/p53/Smad complex formation; this facilitates FH recruitment to p53-targed p21 promoter, where FH inhibits KDM2A-mediated demethylation of H3K36me2 through local production of fumarate SIGNOR-266316 0.2 ropinirole chemical CHEBI:8888 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation -1 9057850 t miannu Compound (R)-6, the most active compound, showed dopaminergic D2 activity and also had affinity for the 5HT1A serotonin receptor subtype. Its dopaminergic activity was more selective for the D2 receptor subtype (259-fold D2/D3 selectivity) than propylamine analogue (R)-2 (14-fold selectivity) or other dopaminergic standards (e.g., pergolide, lisuride, bromocriptine, and ropinirole, 1.0-, 3.4-, 8.7-, and 2.6-fold selectivities, respectively) SIGNOR-258601 0.8 AMPK complex SIGNOR-C15 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser420 KHPTPGSsDPLIQPS -1 21204788 t miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). SIGNOR-273931 0.257 SRP54 protein P61011 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates activity binding -1 8816452 t Monia We have now demonstrated that p54 interacts not only with SC35 and ASF/SF2 but also with U2AF. Pairwise interactions between p54 and other RS domain-containing spliceosomal proteins in comparison with SC35 and ASF/SF2 as detected by the yeast two-hybrid interaction assay. . It is conceivable that p54 can mediate 59 and 39 splice site interaction by interacting directly with U2AF65 associated with the 39 splice site and at the same time interact with other SR proteins, such as ASF/SF2 and SC35, which in turn interact with U1-70K. In this scenario, p54 is different from SC35 or ASF/SF2 in that it cannot directly interact with the 59 component (U1-70K) but can interact with the protein associated with the 39 splice site (U2AF65). SIGNOR-261161 0.303 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MITF protein O75030 UNIPROT down-regulates phosphorylation Ser180 PGSSAPNsPMAMLTL 9606 10673502 t The effect has been demonstrated using O75030-9 gcesareni The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation. SIGNOR-249575 0.2 CFAP53 protein Q96M91 UNIPROT DNAH5 protein Q8TE73 UNIPROT up-regulates activity binding 10090 BTO:0000379 33347437 t miannu CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B). SIGNOR-265544 0.2 MAP2K1 protein Q02750 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 BTO:0001253 15020233 t lperfetto In vitro kinase assay was carried out using a recombinant human active mek1 and we found that gsk-3beta was phosphorylated on tyr(216) by this kinase in a dose- and time-dependent manner. Further, the pretreatment of fibroblasts with u0126 inhibited serum-induced nuclear translocation of gsk-3beta. These results suggested that mek1/2 induces tyrosine phosphorylation of gsk-3beta and this cellular event might induce nuclear translocation of gsk-3beta. SIGNOR-236622 0.35 PRKAA1 protein Q13131 UNIPROT LIPE protein Q05469 UNIPROT down-regulates phosphorylation Ser855 EPMRRSVsEAALAQP 9606 SIGNOR-C15 9636039 t gcesareni Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase. SIGNOR-58255 0.388 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation Tyr980 LLPLDKDyYVVREPG 9606 9391116 t gcesareni We found that jak3 is autophosphorylated on multiple sites including y980 and y981. Compared with the activity of wild-type (wt) jak3, mutant y980f demonstrated markedly decreased kinase activity, and optimal phosphorylation of jak3 on other sites was dependent on y980 phosphorylation. The mutant y980f also exhibited reduced phosphorylation of its substrates, gammac and stat5a. In contrast, mutant y981f had greatly increased kinase activity, whereas the double mutant, yy980/981ff, had intermediate activity. SIGNOR-53590 0.2 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC17 protein P23527 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271982 0.2 CASP3 protein P42574 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 f amattioni Caspase-3 is responsible for apoptosis execution SIGNOR-256638 0.7 D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI up-regulates quantity precursor of 9606 16939420 t miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. SIGNOR-267080 0.8 INPPL1 protein O15357 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI down-regulates chemical modification 9606 9111325 t gcesareni Sip specifically and markedly reduced the level of phosphatidylinositol (3,4,5) triphosphate [ptdins(3,4,5)p3] generated in oocytes in response to insulin SIGNOR-47537 0.8 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Thr273 SPSVHPAtPISPGRA 9606 16046550 t The effect has been demonstrated using Q01196-8 miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. SIGNOR-138981 0.2 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu66 EETCSYEeAREVFED -1 9538022 t lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). SIGNOR-263671 0.598 PRKDC protein P78527 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Thr226 LQAQNLLtQLPQQSQ 9606 9368058 t lperfetto Through a similar strategy, t226 and s232 were characterized as the dna-pk phosphorylation sites SIGNOR-53262 0.335 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10230394 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-67379 0.523 calcium(2+) smallmolecule CHEBI:29108 ChEBI Cadherins proteinfamily SIGNOR-PF71 SIGNOR up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265811 0.8 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 10090 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells SIGNOR-248348 0.484 BGJ-398 chemical CHEBI:63451 ChEBI FGFR4 protein P22455 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190272 0.8 CLCN3 protein P51790 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates quantity relocalization 9606 29845874 t miannu ClC-3 is a strongly outwardly rectifying, electrogenic 2Cl/H exchanger with biophysical properties that closely resemble those of its close homologues ClC-4 and ClC-5 SIGNOR-265422 0.8 CASP3 protein P42574 UNIPROT PARP1 protein P09874 UNIPROT down-regulates activity cleavage 10090 BTO:0000331 11907276 t amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-116178 0.767 ATP5PF protein P18859 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261398 0.2 SSTR5 protein P35346 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256833 0.426 ACTB protein P60709 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270599 0.486 MAPK10 protein P53779 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr286 SVPSAAVtPLNESLQ 9606 15767678 t gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. SIGNOR-134537 0.738 PRKACA protein P17612 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000782;BTO:0000661 1370476 t llicata The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl. SIGNOR-17901 0.2 TLN1 protein Q9Y490 UNIPROT Av/b6 integrin complex SIGNOR-C179 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257632 0.572 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG5-LLGL1_variant complex SIGNOR-C508 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270900 0.445 DNM1L protein O00429 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 10090 BTO:0002295 31063459 t lperfetto Importantly, we found that crosstalk between phosphorylated Drp1S600 (p-Drp1S600) and the actin-binding protein com- plex Arp2/3 is a required step in mitochondrial Drp1 recruitment and mitochondrial fission under HG conditions. SIGNOR-262550 0.287 PRKAA2 protein P54646 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser366 SPQVRTLsGSRPPLL -1 14709557 t miannu AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase SIGNOR-250319 0.48 PRKG1 protein Q13976 UNIPROT PLCB3 protein Q01970 UNIPROT down-regulates activity phosphorylation Ser26 VETLRRGsKFIKWDE 10116 BTO:0004576 11278298 t lperfetto PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG. SIGNOR-249079 0.523 FHIT protein P49789 UNIPROT AKT1 protein P31749 UNIPROT down-regulates 9606 BTO:0000551 16407838 f miannu Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis SIGNOR-252625 0.381 CHKB protein Q9Y259 UNIPROT ethanolaminium(1+) smallmolecule CHEBI:57603 ChEBI down-regulates quantity chemical modification 29928787 t lperfetto In this study, we investigated the roles of ethanolamine kinases (Etnk-1 and 2) and choline kinases (Chk-α and β) in contributing to increased PE in human breast and pancreatic cancer cells. SIGNOR-275640 0.8 CSNK2A2 protein P19784 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Ser231 KSNIVLLsAEEKKEQ 9606 BTO:0000776 7678037 t llicata These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells. SIGNOR-251011 0.312 THRA protein P10827 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 f lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. SIGNOR-268550 0.2 VEPH1 protein Q14D04 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 22055343 f In the neuronal differentiation lperfetto Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r9 SIGNOR-269858 0.2 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH3 protein P22223 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265843 0.8 P2RY1 protein P47900 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257273 0.2 PRL protein P01236 UNIPROT KRT19 protein P08727 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 20103718 f Regulation miannu PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes. SIGNOR-251905 0.263 PRKDC protein P78527 UNIPROT NHEJ1 protein Q9H9Q4 UNIPROT unknown phosphorylation Ser245 PHTSNSAsLQGIDSQ 9606 18644470 t lperfetto Here, we have identified two major in vitro dna-pk phosphorylation sites in the c-terminal region of xlf, serines 245 and 251. We show that these represent the major phosphorylation sites in xlf in vivo and that serine 245 is phosphorylated in vivo by dna-pk, while serine 251 is phosphorylated by ataxia-telangiectasia mutated (atm). SIGNOR-179532 0.653 CRYBB2 protein P43320 UNIPROT CRYBB3 protein P26998 UNIPROT up-regulates activity binding 9606 16319073 t miannu At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency. SIGNOR-252152 0.464 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 t The effect has been demonstrated using Q01196-8. gcesareni Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction. SIGNOR-138916 0.348 SRC protein P12931 UNIPROT KCNJ1 protein P48048 UNIPROT down-regulates phosphorylation Tyr337 SKTKEGKyRVDFHNF 9606 12556363 t flangone Inhibition of c-src with herbimycin a significantly decreased the tyrosine phosphorylation level of romk1... tyrosine dephosphorylation enhances the exocytosis of romk1 SIGNOR-97803 0.318 TAX1BP1 protein Q86VP1 UNIPROT TNFAIP3 protein P21580 UNIPROT up-regulates activity binding 9606 BTO:0000782;BTO:0001271 10435631 t lperfetto Tx1bp1 appears to be a novel a20-binding protein which mediate the anti-apoptotic activity of a20; tax1bp1 phosphorylation was pivotal for cytokine-dependent interactions among tax1bp1, a20, itch and rnf11 and downregulation of signaling by the transcription factor nf-Kb. SIGNOR-69921 0.67 PRKAA1 protein Q13131 UNIPROT NR0B2 protein Q15466 UNIPROT up-regulates 9606 17909097 f gcesareni We have concluded that metformin inhibits hepatic gluconeogenesis through ampk-dependent regulation of shp SIGNOR-158071 0.2 RNF4 protein P78317 UNIPROT NFYB protein P25208 UNIPROT up-regulates activity binding 9606 15496512 t miannu Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter. SIGNOR-252230 0.2 GPR17 protein Q13304 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257087 0.358 ADRA1A protein P35348 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257195 0.41 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Thr446 LKNDGKRtRSKGTLR 4932 11337501 t Trans-autophosphorylation of Thr-446 and Thr-451 by the two kinase moieties in a PKR dimer. autophosphorylation in the activation loop would promote proper alignment of key catalytic residues, or the correct orientation of the two lobes of the PKR kinase domain, required for substrate binding or phosphoryl transfer SIGNOR-251110 0.2 TTC5 protein Q8N0Z6 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity binding 9606 BTO:0001938 15448695 t miannu DNA damage activates ATM kinase which then phosphorylates Strap at Ser 203 (red circles). Phosphorylated Strap is stabilized and undergoes nuclear accumulation where it assembles into a co-activator complex, which includes p300 and cofactors such as JMY SIGNOR-262646 0.545 CAMK2G protein Q13555 UNIPROT PEA15 protein Q15121 UNIPROT unknown phosphorylation Ser116 KDIIRQPsEEEIIKL BTO:0000099 9721757 t llicata Partly purified PEA-15 was a substrate in vitro for CaMKII, but not for casein kinase II. Two-dimensional phosphopeptide mapping demonstrated that the site phosphorylated in vitro by CaMKII was also phosphorylated in intact astrocytes in response to endothelin. CaMKII phosphorylated selectively Ser116 and had no effect on Ser104, but in vitro phosphorylation by CaMKII appeared to facilitate further phosphorylation by protein kinase C.  SIGNOR-250701 0.351 PHC2 protein Q8IXK0 UNIPROT Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR form complex binding 9606 31608994 t miannu PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b SIGNOR-266810 0.78 MCM5 protein P33992 UNIPROT MCM complex SIGNOR-C268 SIGNOR form complex binding 9606 19946136 t The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. SIGNOR-261675 0.765 EGR1 protein P18146 UNIPROT SF1 protein Q15637 UNIPROT up-regulates activity binding 10090 19106114 t miannu GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity. SIGNOR-254914 0.299 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Thr5794 REFSGPStPTGTLEF 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262767 0.259 PPM1B protein O75688 UNIPROT CDK9 protein P50750 UNIPROT unknown dephosphorylation Thr186 NSQPNRYtNRVVTLW 9606 18829461 t gcesareni Taken together, our data indicate that PPM1A and to some extent PPM1B are important negative regulators of P-TEFb function SIGNOR-181396 0.38 PKM protein P14618 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates activity phosphorylation Thr126 ELMNERNtLQEENKK 9606 BTO:0002036 30297868 t miannu Here, we uncover an unexpected mechanism through which pyruvate kinase M2 (PKM2), the highly expressed PK isoform in cancer cells and a master regulator of cancer metabolic reprogramming, integrates with the DDR to directly promote DNA double-strand break (DSB) repair. In response to ionizing radiation and oxidative stress, ATM phosphorylates PKM2 at T328 resulting in its nuclear accumulation. SIGNOR-277413 0.2 YWHAQ protein P27348 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates binding 9606 12042314 t miannu 14-3-3_, 14-3-3_, and 14-3-3_ (but not 14-3-3_ and 14-3-3_) could form a complex with p27kip1 / we discovered that akt-mediated p27kip1phosphorylation directly induces p27kip1binding to 14-3-3 and cytoplasmic localization through phosphorylating the newly identified thr198residue. SIGNOR-88300 0.504 PAMPs stimulus SIGNOR-ST11 SIGNOR ITLN1 protein Q8WWA0 UNIPROT up-regulates activity binding 26148048 t Human intelectin-1 (hIntL-1) does not bind known human glycan epitopes but does interact with multiple glycan epitopes found exclusively on microbes: β-linked D-galactofuranose (β-Galf), D-phosphoglycerol-modified glycans, heptoses, D-glycero-D-talo-oct-2-ulosonic acid (KO) and 3-deoxy-D-manno-oct-2-ulosonic acid (KDO). | This ligand selectivity suggests that hIntL-1 functions in microbial surveillance. SIGNOR-272498 0.7 ERRFI1 protein Q9UJM3 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0001867 20421427 t We report here an additional mechanism of EGFR suppression mediated by RALT, demonstrating that RALT-bound EGF receptors undergo endocytosis and eventual degradation into lysosomes SIGNOR-252073 0.661 SOD1 protein P00441 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates quantity 9606 BTO:0000312 22051914 f lperfetto SOD1 inclusions are found in motor neurons of patients with FALS, SIGNOR-262279 0.7 HNF1A protein P20823 UNIPROT CDH17 protein Q12864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972;BTO:0004168 20568120 t The present study aims to identify the transcription factors which interact and regulate CDH17 promoter activity that might contribute to the up-regulation of CDH17 gene in human HCC|we identified hepatic nuclear factor 1α (HNF1α) and caudal-related homeobox 2 (CDX2) binding sites at the proximal promoter region which modulate the CDH17 promoter activities in two HCC cell lines (Hep3B and MHCC97L) SIGNOR-253970 0.318 MAPK9 protein P45984 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser6 sDPSVEPP 9606 17525747 t gcesareni Our studies revealed a novel mechanism in which phosphorylation of jnk2 is mediated by jnk1 before phosphorylation of p53, and then p53 is directly phosphorylated by jnk2 at ser6. |Role of map kinases in uvb-induced phosphorylation of p53 at serine 20. SIGNOR-155209 0.737 MMP3 protein P08254 UNIPROT HBEGF protein Q99075 UNIPROT up-regulates cleavage 9606 BTO:0000150 11043579 t gcesareni It was concluded that mmp-3 cleaves hb-egf at a specific site in the jm domain and that this enzyme might regulate the conversion of hb-egf from being a juxtacrine to a paracrine/autocrine growth factor. SIGNOR-83339 0.497 ABL1 protein P00519 UNIPROT RIN1 protein Q13671 UNIPROT up-regulates phosphorylation 9606 9144171 t gcesareni We also report that the amino-terminal domain of rin1 contains sequences that can mediate interactions with the abl tyrosine kinase and that rin1 is itself tyrosine phosphorylated by c-abl. SIGNOR-48142 0.745 RBX1 protein P62877 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000093 20130088 t miannu I3C-dependent activation of the aryl hydrocarbon receptor (AhR) initiates Rbx-1 E3 ligase-mediated ubiquitination and proteasomal degradation of ERalpha protein. SIGNOR-271434 0.35 PRKCA protein P17252 UNIPROT ARX protein Q96QS3 UNIPROT up-regulates activity phosphorylation Ser174 VSISRSKsYRENGAP 9606 BTO:0002181 30419043 t miannu We confirm that ARX is phosphorylated by PRKCA and demonstrate phosphorylation at serine 174. We demonstrate that phosphorylation is required for correct transcriptional activity of the ARX protein using transcriptome-wide analysis of gene expression of phospho-null mutants (alanines replacing serines) compared to ARX wild-type (ARX-WT) overexpressed in pancreatic alpha TC cells. SIGNOR-277418 0.2 PRKAA1 protein Q13131 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 BTO:0000887;BTO:0001103 SIGNOR-C15 17609368 t lperfetto Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538. SIGNOR-156780 0.561 SHANK1 protein Q9Y566 UNIPROT Postsynaptic density assembly phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 28179641 f miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SIGNOR-264605 0.7 APBA3 protein O96018 UNIPROT STXBP1 protein P61764 UNIPROT up-regulates activity binding 10116 9395480 t miannu Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1. SIGNOR-264036 0.48 HMGA2 protein P52926 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14645522 f miannu Transcriptional activation of the cyclin a gene by the architectural transcription factor hmga2 SIGNOR-119496 0.317 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR CDC7 protein O00311 UNIPROT up-regulates activity phosphorylation Thr376 QVAPRAGtPGFRAPE 10846177 t llicata Among four possible Cdk phosphorylation sites of huCdc7, replacement of Thr-376, corresponding to the activating threonine of Cdk, with alanine (T376A mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue. In vitro, Cdk2-Cyclin E, Cdk2-Cyclin A, and Cdc2-Cyclin B, but not Cdk4-Cyclin D1, phosphorylates the Thr-376 residue of huCdc7, suggesting possible regulation of huCdc7 by Cdks. SIGNOR-250726 0.584 JAK1 protein P23458 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000801 19041276 t lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249492 0.669 SYCE1 protein Q8N0S2 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR form complex binding 9606 22394509 t miannu The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region. SIGNOR-264201 0.655 gossypol chemical CHEBI:28584 ChEBI BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 23336025 t gcesareni Bcl-2 inhibitors physically antagonize their anti-apoptotic actions to create a synergistic effect. Numerous compounds have been specifically developed or identified as bcl-2 inhibitors. These compounds include abt-737 and abt-263, obatoclax, gossypol. SIGNOR-200469 0.8 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 19279133 t flangone Here, we show that Smad2/3, the downstream effectors of Activin/Nodal signalling, bind and directly control the activity of the Nanog gene in hESCs. SIGNOR-242055 0.432 lofexidine chemical CHEBI:51368 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 22341244 t Luana Lofexidine was selected because its scaffold is similar to that of the imidazolines of the present study and, as emerged from our functional study (Table 2), it displayed significant α2A- and α2C-AR agonism.  SIGNOR-258330 0.8 SCF-FBW7 complex SIGNOR-C135 SIGNOR SMARCA4 protein P51532 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001225 30177679 t miannu  We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation.  SIGNOR-277409 0.284 GNRHR protein P30968 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256792 0.424 TESK1 protein Q15569 UNIPROT CFL1 protein P23528 UNIPROT down-regulates activity phosphorylation Ser3 sGVAVSDG 9606 BTO:0000567 11294912 t lperfetto These results suggest that TESK1 functions downstream of integrins and plays a key role in integrin-mediated actin reorganization, presumably through phosphorylating and inactivating cofilin. We propose that tesk1 and lim-kinases commonly phosphorylate cofilin but are regulated in different ways and play distinct roles in actin reorganization in living cells. SIGNOR-106777 0.544 RAB39B protein Q96DA2 UNIPROT PICK1 protein Q9NRD5 UNIPROT up-regulates activity binding 9534 BTO:0000298 25784538 t miannu GTP-bound RAB39B interacts with PICK1. In line with evidence that PICK1 can dimerize, the structural model suggests that dimerization of PICK1 is a prerequisite for simultaneous recognition of both RAB39B and GluA2 each by one of the PICK1 molecules in the PICK1 dimer (Fig. 6a–c). The existence of such complex is supported by our co-immunoprecipitation experiments shown above. SIGNOR-264045 0.383 WNT7A protein O00755 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131903 0.634 PP2B proteinfamily SIGNOR-PF18 SIGNOR PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation 10116 11278334 t inferred from 70% family members In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. SIGNOR-269991 0.2 TFEB protein P19484 UNIPROT MTM1 protein Q13496 UNIPROT up-regulates quantity by expression transcriptional regulation 30145926 f lperfetto Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB SIGNOR-276800 0.2 EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000017 11726515 t lperfetto Phosphorylation of grb2 by bcr/abl or egf receptor reduced its sh3-dependent binding to sos in vivo, but not its sh2-dependent binding to bcr/abl. Tyr209 within the c-terminal sh3 domain of grb2 was identified as one of the tyrosine phosphorylation sites SIGNOR-235738 0.921 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252880 0.398 EGFR protein P00533 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 11887937 t gcesareni Activation of estrogen receptor-alpha (eralpha) by growth factors in the absence of estrogen is a well-documented phenomenon.Egfr tyrosine kinase in vitro stimulated the phosphorylation of recombinant er SIGNOR-115734 0.608 APC2 protein O95996 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization relocalization 9606 BTO:0000038 10980707 t lperfetto The tumour-suppressing activity of apc largely involves facilitating the proteasome-mediated degradation of b-cateninit is possible that once exported from the nucleus, apc directs b-catenin along the cytoskeletal network to sites of degradation. SIGNOR-81545 0.785 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258569 0.8 CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR TP53 protein P04637 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 9834241 f miannu CBFbeta-SMMHC, Expressed in M4eo Acute Myeloid Leukemia, Reduces p53 Induction and Slows Apoptosis in Hematopoietic Cells Exposed to DNA-damaging Agents Reduced p53 induction may be caused in part by direct inhibition of p53 gene transcription, because p53 mRNA levels were reduced by CBFβ-SMMHC. Attenuated p53 induction and slowed apoptosis may contribute to leukemogenesis by CBFβ-SMMHC. SIGNOR-256132 0.2 PPP1CC protein P36873 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity dephosphorylation Ser8 MTTEQRRsLQAFQDY 9606 BTO:0000007 23499489 t lperfetto We identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.|endogenous RIG-I and MDA5 that interacted with PP1 exhibited markedly decreased phosphorylation levels at S8 and S88, respectively  SIGNOR-264580 0.2 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9823 BTO:0001840 SIGNOR-C3 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-219273 0.924 STX11-VAMP8 SNARE complex complex SIGNOR-C273 SIGNOR Platelet_degranulation phenotype SIGNOR-PH138 SIGNOR up-regulates 9606 BTO:0000782 22767500 f lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. |The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release. SIGNOR-261902 0.7 trichostatin A chemical CHEBI:46024 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257938 0.8 PRKCD protein Q05655 UNIPROT CHN2 protein P52757 UNIPROT down-regulates phosphorylation Ser171 EKVSRRLsRSKNEPR 9606 20335173 t lperfetto A novel cross-talk in diacylglycerol signaling: the rac-gap beta2-chimaerin is negatively regulated by protein kinase cdelta-mediated phosphorylation. phosphorylation of beta2-chimaerin on ser(169) located in the sh2-c1 domain linker region via protein kinase cdelta, which retained beta2-chimaerin in the cytosol and prevented its c1 domain-mediated translocation to membranes SIGNOR-164687 0.272 CSNK2A1 protein P68400 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity phosphorylation Ser424 DHDNDKEsDVEI 9606 15805470 t llicata A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity. SIGNOR-250889 0.517 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257976 0.8 GRB2 protein P62993 UNIPROT KIT protein P10721 UNIPROT down-regulates 9606 BTO:0001271 17904548 f miannu Grb2 mediates c-kit degradation through recruitment of cbl to c-kit, leading to ubiquitination of c-kit followed by internalization and degradation SIGNOR-157956 0.635 UDP-N-acetyl-alpha-D-glucosamine smallmolecule CHEBI:16264 ChEBI N-acyl-D-mannosamine 6-phosphate(2-) smallmolecule CHEBI:57666 ChEBI up-regulates quantity precursor of 10745088 t lperfetto UDP-GlcNAc 2-epimerase is a bifunctional enzyme and catalyzes the first two steps of neuraminic acid synthesis in the cytosol, the conversion of UDP-N-acetylglucosamine to ManAc and the phosphorylation to ManAc-6-phosphate. SIGNOR-266075 0.8 RSPO3 protein Q9BXY4 UNIPROT LGR5 protein O75473 UNIPROT up-regulates binding 9606 21693646 t gcesareni Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation SIGNOR-174535 0.643 CCAN complex complex SIGNOR-C365 SIGNOR Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 18007590 f lperfetto Based on our results, we propose that the cooperative action of CENP-A NAC/CAD subunits and the KMN network drives efficient chromosome segregation and bipolar spindle assembly during mitosis. SIGNOR-265219 0.7 HSPA1A protein P0DMV8 UNIPROT APAF1 protein O14727 UNIPROT down-regulates binding 9606 10934467 t gcesareni Here we show that the documented anti-apoptotic effect of the principal heat-shock protein, hsp70, is mediated through its direct association with the caspase-recruitment domain (card) of apaf-1 and through apoptosome formation SIGNOR-80451 0.442 FOXF2 protein Q12947 UNIPROT IRF2BPL protein Q9H1B7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000498 29374064 t miannu FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation. SIGNOR-267152 0.255 MAPK1 protein P28482 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation Thr334 QSTKVPQtPLHTSRV 9606 8846784 t fstefani Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk. SIGNOR-44347 0.521 DLGAP4 protein Q9Y2H0 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264595 0.683 PIH1D1 protein Q9NWS0 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000093 24036451 t miannu PIH1D1 interacts with mTOR complex 1 and enhances ribosome RNA transcription.PIH1D1 is important for mTORC1 assembly SIGNOR-265897 0.345 CDK7 protein P50613 UNIPROT CDK4 protein P11802 UNIPROT up-regulates phosphorylation Thr172 YSYQMALtPVVVTLW 9606 8139570 t lperfetto Phosphorylation of cdk4 on threonine 172 by a cdk-activating kinase (cak). therefore, formation of the cyclin d-cdk4 complex and phosphorylation of the bound catalytic subunit are independently regulated, and in addition to the requirement for cak activity, serum stimulation is required to promote assembly of the complexes in mammalian cells. SIGNOR-36549 0.57 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Ser262 GHGLRRSsKFCLKEH -1 1848190 t lperfetto We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling. SIGNOR-248855 0.358 ULK1 protein O75385 UNIPROT HK1 protein P19367 UNIPROT up-regulates activity phosphorylation Ser364 TRLGVEPsDDDCVSV 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274033 0.259 RHOA protein P61586 UNIPROT DIAPH1 protein O60610 UNIPROT up-regulates activity 9606 BTO:0000815 22820501 t lperfetto We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells. SIGNOR-253108 0.777 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Lys32 RARRPESkATNATLD -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus SIGNOR-263573 0.62 STARD8 protein Q92502 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260520 0.49 AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR YAP1 protein P46937 UNIPROT down-regulates binding 10090 21145499 t milica Because we found that multiple domains of taz/yap interacted with multiple components of the crumbs complex, which include pals1, lin7c, patj, and the crumbs regulator amot, we propose that this multifactoral interaction serves to ensure that assembly of the hippo pathway and efficient phosphorylation of taz/yap is coupled only by the assembly of the crumbs complex, rather than by any single component. SIGNOR-170364 0.363 CSNK1D protein P48730 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates phosphorylation Ser247 KTFLSRHsLDMKFSY 9606 20699359 t lperfetto In this work, we investigate the phosphorylation of the n-terminal heterodimerization (pas) domain of hif-1alpha and identify ser247 as a major site of in vitro modification by casein kinase 1delta (ck1delta). Mutation of this site to alanine, surprisingly, enhanced the transcriptional activity of hif-1alpha SIGNOR-167476 0.33 SPI1 protein P17947 UNIPROT ACP5 protein P13686 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11481336 f miannu The combination of MITF and PU.1 synergistically activated the TRAP promoter in transient assays. SIGNOR-254585 0.353 KLKB1 protein P03952 UNIPROT HGF protein P14210 UNIPROT up-regulates activity cleavage Arg424 KNMEDLHrHIFWEPD -1 12372819 t miannu the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain. SIGNOR-256513 0.329 TLRs proteinfamily SIGNOR-PF20 SIGNOR NLRP3 protein Q96P20 UNIPROT up-regulates quantity by expression 28531279 f lperfetto The activation of NLRP3 inflammasomes in macrophages requires two stimuli. The first signal, called priming, is provided by an inflammatory stimulus such as TLRs and TNF-α receptor (TNFR) that leads to NF-κB-mediated NLRP3 expression and post-translational modifications of NLRP3 SIGNOR-256428 0.2 MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000724 7882978 f irozzo These observations indicate that continued late-stage expression of L-myc affected differentiation processes directly, rather than indirectly through deregulated growth control, whereas constitutive c-myc expression inhibited proliferative arrest, but did not appear to disturb differentiation. SIGNOR-259110 0.7 PTPN12 protein Q05209 UNIPROT WAS protein P42768 UNIPROT down-regulates activity dephosphorylation Tyr291 AETSKLIyDFIEDQG 10090 14707117 t Mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities|WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST SIGNOR-248660 0.455 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR MEIS1 protein O00470 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14701735 f irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. SIGNOR-255862 0.2 NLRX1 protein Q86UT6 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates activity binding 9606 28956771 t Giorgia Moreover, poly(rC) binding protein 2 (PCBP2) interacts with NLRX1 to participate in the NLRX1-induced degradation of MAVS and the inhibition of antiviral responses during HCV infection. SIGNOR-260359 0.409 SUFU protein Q9UMX1 UNIPROT GLI3 protein P10071 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 20463034 t Gianni We show that loss of suppressor of fused (Sufu; an inhibitory effector for Gli proteins) results in destabilization of Gli2 and Gli3 full-length activators but not of their C-terminally processed repressors, whereas overexpression of Sufu stabilizes them. SIGNOR-268868 0.885 COL4A6 protein Q14031 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253246 0.422 TP53 protein P04637 UNIPROT CCNG1 protein P51959 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 9688532 t lperfetto Individual promoter and intron p53-binding motifs from the rat Cyclin G1 promoter region support transcriptional activation by p53 but do not show co-operative activation. SIGNOR-268961 0.782 STK4 protein Q13043 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 18394876 t gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. SIGNOR-178190 0.673 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr299 PERRRLKtTRLKEYT 9606 15611134 t lperfetto Zipk autophosphorylates in vitrowe have identified six phosphorylation sites in zipk that regulate both its enzyme activity and localization, including thr180, thr225, thr265, thr299, thr306, and ser311.Abrogation of phosphorylation of thr299, thr306, and ser311 had little effect on enzyme activity, but mutation of thr299 and thr300 to alanine resulted in redistribution of zipk from the cytosol to the nucleus SIGNOR-132471 0.2 SLC16A2 protein P36021 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI down-regulates quantity relocalization 9606 28153798 t scontino T4 and T3 are released from the thyroid cell through transporters present at the basolateral plasma membrane of thyrocytes (Fig. 1). The most important transporter known to be responsible for thyroid hormone transport is the SLC16A2 monocarboxylate transporter 8 (MCT8), which can promote both uptake and efflux of TH and is involved in the release of TH from the thyroid gland. SIGNOR-267139 0.8 ERCC1 protein P07992 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR form complex binding 9606 16338413 t miannu Human ercc1/xpf interaction domains reveals a complementary role for the two proteins in nucleotide excision repair. SIGNOR-142989 0.952 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Thr213 SASFPHTtPSMCLNP 9606 BTO:0000664 17475908 t miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). SIGNOR-262917 0.329 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser82 HSISYTLsRAQTVVV 9606 BTO:0000007 12496252 t lperfetto In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation SIGNOR-96747 0.758 CCNC protein P24863 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15546612 f gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. SIGNOR-130589 0.2 TGFB1 protein P01137 UNIPROT CCNA2 protein P20248 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 7592630 f gcesareni Expression of one of these components, cyclin a, is inhibited by tgf-beta treatment. We have identified a 760-base pair fragment of the human cyclin a gene promoter that is sufficient to confer tgf-beta responsiveness. SIGNOR-29516 0.289 POLR1D protein P0DPB6 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266137 0.859 MRPL39 protein Q9NYK5 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262358 0.65 PTK6 protein Q13882 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr664 EGGWMEDyDYVHLQG 9606 BTO:0001130 22084245 t lperfetto Protein-tyrosine kinase 6 promotes peripheral adhesion complex formation and cell migration by phosphorylating p130 crk-associated substrate. Tyrosine residues 165 and 664 of p130cas were both phosphorylated by ptk6 in vitro SIGNOR-177242 0.583 CSNK2A1 protein P68400 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates phosphorylation Ser67 DTRKKDAsDDLDDLN 9606 BTO:0000567 16225457 t lperfetto The n-terminal domain of the human eif2beta subunit and the ck2 phosphorylation sites are required for its function. These results suggest that ser2 and ser67 contribute to the important role of the n-terminal region of eif2beta for its function in mammals. SIGNOR-141051 0.356 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Thr1967 QQDKASLtRTLQHRI 9606 BTO:0000938 19824698 t lperfetto We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. substitution of thr1969 located in close proximity to thr1967 had little effect on its kinase activity SIGNOR-188417 0.2 MAPK1 protein P28482 UNIPROT TP53BP2 protein Q13625 UNIPROT up-regulates activity phosphorylation Ser827 NSDMPAPsPGLDYEP -1 24312625 t lperfetto Hence ASPP2 can be phosphorylated at serine 827 by MAPK1 in vitro.|Phosphorylation of ASPP2 by MAPK is required for RAS-induced increased binding to p53 and increased transactivation of pro-apoptotic genes. SIGNOR-264414 0.266 CCT7 protein Q99832 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 t miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). SIGNOR-272867 0.743 TYSND1 protein Q2T9J0 UNIPROT ACOX1 protein Q15067 UNIPROT up-regulates activity cleavage -1 17255948 t miannu Here, we demonstrate that Tysnd1, a previously uncharacterized protein, is responsible both for the removal of the leader peptide from PTS2 proteins and for the specific processing of PTS1 proteins. All of the identified Tysnd1 substrates catalyze peroxisomal β-oxidation. In vitro cleavage of Acox1, Scp2 and prethiolase by recombinant Tysnd1. SIGNOR-261057 0.682 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST -1 17711846 t done miannu Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626). SIGNOR-274096 0.397 TNF protein P01375 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253486 0.2 AKT1 protein P31749 UNIPROT HMOX1 protein P09601 UNIPROT unknown phosphorylation Ser188 LYRSRMNsLEMTPAV 9606 BTO:0000007 15581622 t llicata We have identified a putative consensus sequence for phosphorylation by akt/pkb of ho-1 at ser188. although the changes in activity are small, this study provides the first evidence for a role of the survival kinase akt in the regulation of ho-1. SIGNOR-252506 0.576 SMARCAD1 protein Q9H4L7 UNIPROT TRIM28 protein Q13263 UNIPROT up-regulates activity binding 9606 21549307 t 1 miannu SMARCAD1 interacts with HDAC1 and KAP1 and is required for their binding to heterochromatin SIGNOR-239838 0.518 SMO protein Q99835 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates binding 9606 16885213 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-148493 0.404 Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 9606 32699605 t miannu The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6) SIGNOR-270936 0.7 STAT3 protein P40763 UNIPROT GAP43 protein P17677 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0000099 26865625 t miannu  In this study, we demonstrated for the first time that growth-associated protein 43 (GAP43), a well known growth cone protein that promotes axonal regeneration, can be induced in rat brain astrocytes by the proinflammatory endotoxin lipopolysaccharide via both nuclear factor-κB and signal transducer and activator of transcription 3-mediated transcriptional activation. SIGNOR-266772 0.305 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr319 TSVYESPySDPEELK 9606 BTO:0000661 10037717 t lperfetto We show here that Tyr315 and Tyr319 in the interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function. SIGNOR-247053 0.2 1-phosphatidyl-1D-myo-inositol 3-phosphate smallmolecule CHEBI:17283 ChEBI Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 t lperfetto PtdIns(3)P-kinase/hVPS34/p150 (VPS34) is thought to be one of the first Rab5 effector proteins to be recruited to the EE . As suggested by its name, its primary role is to generate PtdIns(3)P, which is the most abundant phosphoinositide in the EE membrane. SIGNOR-260622 0.8 PRKCE protein Q02156 UNIPROT ALDH2 protein P05091 UNIPROT up-regulates activity phosphorylation Ser296 KSPNIIMsDADMDWA -1 28056995 t lperfetto Post-translational enhancement of ALDH2 activity can be achieved by serine/threonine phosphorylation by epsilon protein kinase C (epsilonPKC). |e identified S279 as a critical εPKC phosphorylation site in the activation of ALDH2. The critical catalytic site, cysteine 302 (C302) of ALDH2 is susceptible to adduct formation by reactive aldehyde, 4HNE, which readily renders the enzyme inactive. We show that phosphomimetic mutations of T185E, S279E and T412E confer protection of ALDH2 against 4HNE-induced inactivation, indicating that phosphorylation on these three sites by εPKC likely also protects the enzyme against reactive aldehydes. SIGNOR-271864 0.285 SGCB protein Q16585 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255986 0.493 CNTNAP1 protein P78357 UNIPROT CNTN1 protein Q12860 UNIPROT up-regulates activity relocalization 10090 BTO:0001221 11069942 t Gianni These results suggest that the targeting of contactin to different axonal domains may be determined, in part, via its association with Caspr. SIGNOR-269073 0.61 SRC protein P12931 UNIPROT TNK2 protein Q07912 UNIPROT up-regulates activity phosphorylation Tyr859 KKVSSTHyYLLPERP -1 36178070 t miannu We identified two Src phosphorylation sites within the MHR (Y859, Y860). Addition of Src-phosphorylated MHR to the Ack1 KD enhanced enzymatic activity.  SIGNOR-276342 0.393 LCK protein P06239 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity phosphorylation Tyr240 RREDKFMyFEFPQPL 9606 BTO:0002035 11948419 t miannu MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e). SIGNOR-275984 0.382 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 20626350 t gcesareni In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a . p38 mapks activity stimulates the physical association between pp2a and erk complex, leading to mkk1/2 dephosphorylation by pp2a. SIGNOR-166655 0.605 Doxorubicin hydrochloride chemical CHEBI:31522 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 1963303 t miannu DNA topoisomerase II as the primary target of anti-tumor anthracyclines.Such studies have also given evidence of the peculiar features of the drug interference with DNA topoisomerase II activity. In contrast to other cytotoxic topoisomerase II inhibitors (acridines, epipodophyllotoxins), anthracyclines produce persistent DNA cleavable complexes. This property is more evident with doxorubicin derivatives than with daunorubicin derivatives. SIGNOR-259324 0.8 TRIP13 protein Q15645 UNIPROT MCC complex SIGNOR-C382 SIGNOR down-regulates quantity by destabilization binding 9606 BTO:0000567 25092294 t miannu We have indeed showed that TRIP13 action to disassemble the Cdc20–Mad2 complex requires the presence of p31comet (Fig. 3A). We furthermore found that the joint action of TRIP13 and p31comet is also required for the release of Mad2 from MCC, for the complete disassembly of MCC and for relieving APC/C from checkpoint inhibition (Figs. 3 and ​and4).4). SIGNOR-265972 0.531 tetrabenazine chemical CHEBI:9467 ChEBI SLC18A2 protein Q05940 UNIPROT down-regulates activity chemical inhibition 9606 8643547 t miannu Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2. SIGNOR-258491 0.8 PRKACA protein P17612 UNIPROT TRPM8 protein Q7Z2W7 UNIPROT up-regulates activity phosphorylation Thr17 MRNRRNDtLDSTRTL 9606 BTO:0000007 20110357 t done miannu Using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. the intracellular serine/threonine protein phosphatase 2A (PP2A) dephosphorylates TRPM8 Ser-9 and Thr-17 inhibiting the channel activity. SIGNOR-273791 0.2 PAK5 protein Q9P286 UNIPROT DDX5 protein P17844 UNIPROT up-regulates quantity by stabilization phosphorylation Thr69 HPDLARRtAQEVETY 9606 BTO:0000150 34936874 t lperfetto PAK5 promotes RNA helicase DDX5 sumoylation and miRNA-10b processing in a kinase-dependent manner in breast cancer|The increased expression levels of PAK5 and phospho-DDX5 threonine 69 are associated with metastasis and poor clinical outcomes of patients. PAK5 facilitates the phosphorylation-dependent sumoylation of DDX5 to stabilize DDX5. Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing. SIGNOR-275658 0.2 TNF protein P01375 UNIPROT MC1R protein Q01726 UNIPROT down-regulates activity transcriptional regulation 9606 BTO:0000847 9767234 f miannu MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression. SIGNOR-252381 0.293 CAPRIN2 protein Q6IMN6 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 19619488 t gcesareni A cytoplasmic protein in vertebrates, referred to as caprin-2, binds to lrp6 and facilitates lrp6 phosphorylation by gsk3 SIGNOR-187177 0.365 MTNR1A protein P48039 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257101 0.252 ARHGAP39 protein Q9C0H5 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260495 0.559 PPP2CA protein P67775 UNIPROT RELA protein Q04206 UNIPROT down-regulates dephosphorylation 9606 BTO:0000848 SIGNOR-C13 11591705 t gcesareni Rela was dephosphorylated by a purified pp2a core enzyme, a heterodimer formed by the catalytic subunit of pp2a (pp2ac) and pr65, in a concentration-dependent manner.These data suggest that the constitutive activation of rela in melanoma cells could be due, at least in part, to the deficiency of pp2a, which exhibits decreased dephosphorylation of nf-kappa b/rela. SIGNOR-110959 0.472 ACAN protein P16112 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 16051604 t lperfetto Cartilage oligomeric matrix protein/thrombospondin 5 (COMP/TSP5) is a major component of the extracellular matrix of the musculoskeletal system.  SIGNOR-266983 0.7 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Thr2620 QGTLQTRtQEGSLSA -1 12186630 t lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. SIGNOR-249158 0.2 CALM3 protein P0DP25 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT up-regulates binding 9606 10770941 t miannu The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases SIGNOR-266344 0.626 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser263 NVGSPLSsPLSSMKS 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276105 0.29 PBRM1 protein Q86U86 UNIPROT RARB protein P10826 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15601824 f miannu We found that baf180 deficiency leads to a decreased expression of select target genes, such as s100a13 and ra targets rar_2 and crabpii in heart tissues. SIGNOR-132378 0.429 MAPKAPK2 protein P49137 UNIPROT LSP1 protein P33241 UNIPROT unknown phosphorylation Ser252 PKLARQAsIELPSMA -1 8995217 t miannu LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils. . Inspection of the human LSP1 protein sequence (22) identifies two serine residues at positions 204 and 252 as potential phosphorylation sites. The results show that LSP1 is a substrate for MAPKAP kinase 2 in vitro and that the phosphorylation site(s) are located in the C-terminal 152 amino acid residues, as predicted from the sequence. SIGNOR-250148 0.622 PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr1179 GLENGLNyIDLDLVK 9606 7515062 t gcesareni The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. SIGNOR-27024 0.894 TNFRSF21 protein O75509 UNIPROT TRADD protein Q15628 UNIPROT up-regulates binding 9606 14585074 t amattioni Dr6 interacts with tradd SIGNOR-100184 0.598 FGF2 protein P09038 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 20974802 f gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription. SIGNOR-168992 0.4 ESR1 protein P03372 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11000528 f gcesareni Inhibition of ar-induced transactivation that was er cdna dose-responsive and estradiol dependent SIGNOR-82158 0.425 MDM2 protein Q00987 UNIPROT CDKN2AIP protein Q9NXV6 UNIPROT down-regulates ubiquitination 9606 18292944 t amattioni Carf interacts with hdm2 and is ubiquitinated and negatively regulated by hdm2 by proteasome-dependent degradation. SIGNOR-160974 0.378 BCL2 protein P10415 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates binding 9606 17446862 t gcesareni In mammalian cells, the antiapoptotic protein, bcl-2, binds to beclin 1 during nonstarvation conditions and inhibits its autophagy function. SIGNOR-154477 0.732 SETDB2 protein Q96T68 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity methylation 9606 20404330 t miannu Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression. SIGNOR-265351 0.2 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser276 PQRSRSPsPQPSSHV 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252333 0.635 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF 9606 10377430 t lperfetto Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus. SIGNOR-252871 0.756 MAPK1 protein P28482 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 24342355 t lperfetto We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity SIGNOR-203473 0.748 CAMK2G protein Q13555 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Ser727 TDNLLPMsPEEFDEV BTO:0000944 11972023 t llicata For maximal gene activation, S727 in the transcription activation domain of Stat1 also is inducibly phosphorylated by IFN-gamma. We previously purified a group of nuclear proteins that interact specifically with the Stat1 transcription activation domain. In this report, we identified one of them as the multifunctional Ca(2+)/calmodulin-dependent kinase (CaMK) II. We demonstrate that IFN-gamma mobilizes a Ca(2+) flux in cells and activates CaMKII. CaMKII can interact directly with Stat1 and phosphorylate Stat1 on S727 in vitro. Inhibition of Ca(2+) flux or CaMKII results in a lack of S727 phosphorylation and Stat1-dependent gene activation, suggesting in vivo phosphorylation of Stat1 S727 by CaMKII.  SIGNOR-250706 0.486 COPS3 protein Q9UNS2 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270769 0.915 CHKA protein P35790 UNIPROT PLIN3 protein O60664 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr251 ERLRQHAyEHSLGKL 9606 BTO:0000527 34929314 t lperfetto In addition, as a protein kinase, CHKα2 phosphorylates PLIN2 at Tyrosine 232 and PLIN3 at Tyrosine 251. Phosphorylated PLIN2 and PLIN3 are separated from lipid droplets and degraded by Hsc70-mediated autophagy, thereby promoting lipid droplet lipolysis, fatty acid oxidation and glioblastoma growth  SIGNOR-267650 0.2 MEF2D protein Q14814 UNIPROT MYH2 protein Q9UKX2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 t lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation SIGNOR-238712 0.332 Elongator complex complex SIGNOR-C466 SIGNOR TUBA4A protein P68366 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 t miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. SIGNOR-269722 0.254 PPP2CA protein P67775 UNIPROT RAF1 protein P04049 UNIPROT up-regulates dephosphorylation 9606 BTO:0000671 16239230 t miannu Both pp2a holoenzymes were found to associate with raf1 and catalyze dephosphorylation of inhibitory phospho-ser-259. Together these findings indicate that pp2a abalphac and abdeltac holoenzymes function as positive regulators of raf1-mek1/2-erk1/2 signaling by targeting raf1. SIGNOR-141170 0.575 TRADD protein Q15628 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 14585074 t amattioni Tradd recruits caspase-8 SIGNOR-118591 0.906 PDYN protein P01213 UNIPROT OPRK1 protein P41145 UNIPROT up-regulates activity binding 10029 BTO:0000246 9262330 t miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. SIGNOR-258411 0.655 DOT1L protein Q8TEK3 UNIPROT HOXA9 protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20854876 f irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. SIGNOR-256141 0.46 WNK3 protein Q9BYP7 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates activity phosphorylation 21613606 t lperfetto We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs SIGNOR-264629 0.456 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 1715686 t gcesareni Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta. SIGNOR-21299 0.309 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates activity phosphorylation Ser628 LSLGSGIsQCGYSST 9534 BTO:0000298 11865049 t llicata The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly.  SIGNOR-250817 0.734 AKT1 protein P31749 UNIPROT CHUK protein O15111 UNIPROT up-regulates phosphorylation Thr23 EMRERLGtGGFGNVC 9606 SIGNOR-C14 19609947 t gcesareni Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-187006 0.654 MARCHF5 protein Q9NX47 UNIPROT DNM1L protein O00429 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 16874301 t miannu We found that MITOL associated with and ubiquitinated mitochondrial fission protein hFis1 and Drp1.Pulse–chase experiment also indicated that MITOL overexpression promoted Drp1 turnover. SIGNOR-271894 0.2 OXTR protein P30559 UNIPROT DRD2 protein P14416 UNIPROT up-regulates activity binding 10116 27425032 t miannu Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling. Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling. SIGNOR-270333 0.382 KLF4 protein O43474 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates 9606 BTO:0000887;BTO:0001260 21673106 f gcesareni Finally, we demonstrate that the basal expression of both myocd and mrtf-a is negatively regulated by klf4. . The mechanism of inhibition of myocd or mrtf-a by klf4 is currently unclear and warrants future study. SIGNOR-174255 0.477 NHLRC1 protein Q6VVB1 UNIPROT EPM2A protein O95278 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 15930137 t miannu Here, we demonstrate that malin is a single subunit E3 ubiquitin (Ub) ligase and that its RING domain is necessary and sufficient to mediate ubiquitination. Additionally, malin interacts with and polyubiquitinates laforin, leading to its degradation.  SIGNOR-271547 0.779 AMPK complex SIGNOR-C15 SIGNOR AMPK complex SIGNOR-C15 SIGNOR unknown phosphorylation 9606 BTO:0000007 11171104 t lperfetto In contrast, the phosphorylation site mutations, ss24, 25aa and s182a, while having no effects on enzyme activity, are associated with nuclear redistribution of the subunit. SIGNOR-216415 0.795 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Thr273 SPSVHPAtPISPGRA 9606 BTO:0002181 16046550 t The effect has been demonstrated using Q01196-8. gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-138965 0.599 6-propyl-2-thiouracil smallmolecule CHEBI:8502 ChEBI DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001379 27347897 t inferred from family member scontino The activity of D1 but not D2 or D3 is inhibited by 6n-propylthiouracil (PTU). SIGNOR-270240 0.8 NUP50 protein Q9UKX7 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262068 0.575 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI NTRK1 protein P04629 UNIPROT down-regulates chemical inhibition 9606 21159646 t gcesareni In comparison, in the same assay conditions, the previously reported mps1 inhibitor sp600125 (13) was 10-fold less potent than nms-p715 on mps1 and, in addition, it was highly unspecific, being more active on at least 12 kinases including mitotic kinases. SIGNOR-170617 0.8 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9606 11863375 t miannu Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate, and thereby has a key role in the intermediary metabolism of glucose and amino acids. Two ALT isoenzymes are known to exist, but only one ALT gene has been cloned, GPT. In this study, we cloned a homolog of GPT and named it GPT2, and the corresponding protein ALT2 SIGNOR-266924 0.8 BCL10 protein O95999 UNIPROT IKBKG protein Q9Y6K9 UNIPROT up-regulates binding 9606 SIGNOR-C14 18287044 t gcesareni Here, we show that bcl10 undergoes k63-linked polyubiquitination in response to t cell activation and subsequently binds nemo, the regulatory subunit of ikk. SIGNOR-160967 0.821 N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]-2-pyridinyl]methanesulfonamide chemical CHEBI:91370 ChEBI PTK2 protein Q05397 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206067 0.8 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT down-regulates quantity by destabilization phosphorylation Ser146 PALEVSDsESDEALV 9606 BTO:0000567 10618498 t llicata Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo SIGNOR-251041 0.312 CSF1R protein P07333 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates 9606 24890514 t apalma Studies with multipotent precursor cell lines (Fig. 4A) indicate that CSF-1R Tyr-807 and Tyr-721 promote macrophage differentiation via the PLC-Œ≥2 pathway SIGNOR-255570 0.376 ESR1 protein P03372 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150;BTO:0000093;BTO:0000567 16144913 t lperfetto Our data show for the first time that eralpha binds to ppar response element and represses its transactivation SIGNOR-140233 0.284 YAP1 protein P46937 UNIPROT TEAD3 protein Q99594 UNIPROT up-regulates binding 9606 23431053 t Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4 gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14. SIGNOR-201471 0.844 PPP1CA protein P62136 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12840032 t fstefani P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases SIGNOR-103155 0.456 PRKD1 protein Q15139 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Ser348 EAVTSKTsNIRANFE 9606 BTO:0000150 19038333 t lperfetto Here we have investigated the possible role of pkd as a cortactin kinase. Using a mass spectrometric approach, we found that pkd phosphorylates cortactin on ser 298 examination of cortactin phosphorylation kinetics revealed that ser 298 serves as a priming site for subsequent phosphorylation of ser 348 SIGNOR-182502 0.432 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR MAP3K5 protein Q99683 UNIPROT down-regulates binding 9606 BTO:0000567 10411906 t Ser-967 is a critical component of the 14-3-3 interaction site of ASK1 and suggest that phosphorylation of this residue may be the major mode of regulation of 14-3-3 binding to ASK1 gcesareni 14-3-3 may suppress ask1-induced cell death by directly inhibiting the catalytic activity of ask1. SIGNOR-69408 0.2 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000150 10550055 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-72064 0.813 BECN1 protein Q14457 UNIPROT USP10 protein Q14694 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0003704 21962518 t lperfetto Interestingly, Beclin1 also controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities. SIGNOR-260298 0.488 PTGER3 protein P43115 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256716 0.428 POGZ protein Q7Z3K3 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates activity binding 9606 BTO:0000932 20562864 t miannu POGZ is required for the correct activation and dissociation of Aurora B kinase from chromosome arms during M phase. These results reveal POGZ as an essential protein that links HP1alpha dissociation with Aurora B kinase activation during mitosis. SIGNOR-264497 0.328 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GSK3B protein P49841 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0000680 16039586 t inferred from 70% family members lperfetto Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin. SIGNOR-270059 0.2 MYC protein P01106 UNIPROT CDK4 protein P11802 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12835716 t gcesareni C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation SIGNOR-102734 0.586 PDK1 protein Q15118 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 16436377 t gcesareni Human pdh1 and rat pdh2 were expressed previously and were shown to have different specific activities and the ability to be phosphorylated by pdk1 and pdk2 SIGNOR-143966 0.484 MLLT11 protein Q13015 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001939; BTO:0002768; BTO:0000815 26079538 f irozzo In addition, enhanced AF1q expression promotes breast cancer cell proliferation, migration, mammosphere formation, and chemo-resistance. SIGNOR-259107 0.7 GABRA4 protein P48169 UNIPROT GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263745 0.514 CD3 complex SIGNOR-C432 SIGNOR TCR complex SIGNOR-C153 SIGNOR form complex binding 9606 12507424 t miannu The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3Œ≥Œµ, CD3Œ¥Œµ, and Œ∂Œ∂ signaling modules.the TCRŒ±-CD3Œ¥Œµ and TCRŒ≤-CD3Œ≥Œµ interactions are similar since both require a lysine in the TM region of the respective TCR chain and both acidic TM residues in the relevant CD3 heterodimer. Nevertheless, formation of fully assembled Œ±Œ≤ TCR-CD3 complexes containing the Œ∂-chain strictly required both CD3Œ≥ and Œ¥ SIGNOR-269472 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001321 11909978 t NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer. SIGNOR-253667 0.267 MAP2K1 protein Q02750 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000887 11160134 t lperfetto Thus, at least three kinases mediate phosphorylation of ser307, including jnk, serine kinases in the pi 3-kinase cascade that are activated byinsulinor igf-1, and mek1-sensitive kinase cascades during tnf-alfa stimulation. SIGNOR-236611 0.359 a7/b1 integrin complex SIGNOR-C126 SIGNOR A5/b1 integrin complex SIGNOR-C163 SIGNOR down-regulates activity 9925758 f lperfetto These data indicate that alpha7 expression leads to the functional down regulation of alpha5beta1 integrin by decreasing ligand binding affinity and surface expression. In conclusion, the data reported establish the existence of a negative cooperativity between alpha7 and alpha5 integrins that may be important in determining functional regulation of integrins during myogenic differentiation. SIGNOR-253251 0.747 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1196 GAVENPEyLTPQGGA 9606 BTO:0000150 15156151 t gcesareni Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of neu/erbb2 phosphorylation at tyr 1201 or tyr 1227 SIGNOR-124856 0.2 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser59 GGQESQPsPLALLAA 9606 BTO:0000452 19318349 t gcesareni PKCalpha, which was activated in senescent cells by ROS strongly activated Erk1/2, and the SA-pErk1/2 in turn phosphorylated Sp1 on Ser(59). Sp1-enhanced transcription of p21(Sdi1) resulted in regulation of cellular senescence in primary human diploid fibroblast cells. SIGNOR-248075 0.629 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PGR protein P06401 UNIPROT down-regulates phosphorylation 9606 BTO:0000150 10655479 t inferred from 70% family members gcesareni Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation. SIGNOR-270157 0.2 PSPC1 protein Q8WXF1 UNIPROT LMX1B/SFPQ/PSPC1 complex complex SIGNOR-C106 SIGNOR form complex binding 10090 BTO:0000669 23308148 t miannu LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo. SIGNOR-223973 0.415 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258287 0.8 LCK protein P06239 UNIPROT CD3E protein P07766 UNIPROT up-regulates activity phosphorylation Tyr199 RKGQRDLySGLNQRR 9534 11855827 t Tyrosine Phosphorylation of CD8- Chimeras by Lck and ZAP-70 in COS Cells. both Y170F and Y181F chimeric proteins could be efficiently phosphorylated by Lck in vivo. phosphorylation of Y170 and Y181 within CD3- –ITAM provides to CD3- the potential to interact with multiple downstream effectors and signaling pathways. SIGNOR-251369 0.678 AURKB protein Q96GD4 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser29 ATKAARKsAPATGGV 9606 21282660 t Ser 27 (29) phosphorylation of H3 isinhibitory as induces transcription. gcesareni Histone code pathway involving h3 s28 phosphorylation and k27 acetylation activates transcription and antagonizes polycomb silencingaurora-b phosphorylates histone h3 at serine28 with regard to the mitotic chromosome condensation SIGNOR-171717 0.2 TLE1 protein Q04724 UNIPROT SIX3 protein O95343 UNIPROT up-regulates activity binding -1 12441302 t lperfetto Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. TLE1 over-expression induces an enlargement of the eye field and reinforcesSIX3/SIX6 capability of initiating retina formation SIGNOR-234595 0.409 ZM 336372 chemical CID:5730 PUBCHEM RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207911 0.8 MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0001950 21561061 t Luana Activation of JNK pathway components in 3b-expressing cells was assessed by analyzing levels of active phosphorylated formsof JNK and its upstream kinase MEK4. An enhanced phosphor-ylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP SIGNOR-260759 0.741 PHLPP1 protein O60346 UNIPROT RPS6KB1 protein P23443 UNIPROT down-regulates activity dephosphorylation Thr390 DSKFTRQtPVDSPDD 9606 21986499 t gcesareni Here we report the identification of ribosomal protein S6 kinase 1 (S6K1) as a novel substrate of PHLPP. SIGNOR-237454 0.589 BCR protein P11274 UNIPROT YWHAQ protein P27348 UNIPROT unknown phosphorylation Ser232 LTLWTSDsAGEECDA -1 16045749 t llicata We show here that BCR interacts with at least five isoforms of 14-3-3 in vivo and phosphorylates 14-3-3tau on Ser233 and to a lesser extent 14-3-3zeta on Thr233 SIGNOR-250594 0.311 SPAG9 protein O60271 UNIPROT MAP3K5 protein Q99683 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 SIGNOR-C21 22337877 t lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts SIGNOR-235545 0.363 GSK3A protein P49840 UNIPROT STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization phosphorylation Ser393 LTPEKGQsQGLIWDF 9606 BTO:0002181 31843895 t miannu GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation. SIGNOR-276762 0.266 PSMA7 protein O14818 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263365 0.822 Ibutamoren chemical CID:178024 PUBCHEM GHSR protein Q92847 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257497 0.8 GSC protein P56915 UNIPROT EVX1 protein P49640 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 22178155 f miannu We found that EVX1 repressed GSC expression and promoted formation of posterior streak-like progeny in response to BMP4, and conversely that GSC repressed EVX1 expression and was required for development of anterior streak-like progeny in response to activin. SIGNOR-254140 0.256 PCK2 protein Q16822 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 24632615 t miannu Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine. SIGNOR-266557 0.8 PRKACA protein P17612 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser444 QRKSQRSsYVSMRID -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). These data, indicate that S422 and/or S423 are the major sites of PKA-mediated phosphorylation of the 1 GABA receptor.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262750 0.29 ATM protein Q13315 UNIPROT NOP53 protein Q9NZM5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr289 PATEQAAtQESTFQE 9606 BTO:0000007 27829214 t miannu PICT-1 S233 and T289 were identified as the key phosphorylation sites in this pathway, as mutating both to alanine abolished UVB-induced increase of PICT-1 phosporylation. Inhibition of PIKKs or ATM (with wortmannin and KU55933, respectively) prevented the agglomeration and degradation of PICT-1, suggesting that ATM is a key regulator of PICT-1.  SIGNOR-273507 0.2 GLUD2 protein P49448 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity chemical modification 9913 11254391 t miannu Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate. SIGNOR-268558 0.8 FBXW7 protein Q969H0 UNIPROT SCF-FBW7 complex SIGNOR-C135 SIGNOR form complex binding 9606 15340381 t gcesareni The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions. SIGNOR-243766 0.902 HCRTR2 protein O43614 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257290 0.41 CD79A protein P11912 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268200 0.641 FGFR1 protein P11362 UNIPROT PDP1 protein Q9P0J1 UNIPROT down-regulates activity phosphorylation Tyr94 SILKANEySFKVPEF 10090 BTO:0000944 24962578 t miannu Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients.  SIGNOR-276640 0.297 CSNK2A1 protein P68400 UNIPROT TERF1 protein P54274 UNIPROT up-regulates phosphorylation Thr122 LTACQLRtIYICQFL 9606 18347021 t lperfetto Regulation of telomeric repeat binding factor 1 binding to telomeres by casein kinase 2-mediated phosphorylation. Mapping of the ck2 target site identified threonine 122 as a substrate in trf1. A threonine to alanine change at this position led to a diminished dna binding due to reduced dimerization of trf1. SIGNOR-178034 0.2 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr519 EDPYAGStDENTDSE 9606 20471329 t lperfetto Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523 SIGNOR-165431 0.404 NHLH2 protein Q02577 UNIPROT HES1 protein Q14469 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21573214 f miannu Luciferase reporter assay demonstrated that the co-expression of LMO3 and HEN2 attenuates HES1 (a negative regulator for Mash1)-dependent reduction of luciferase activity driven by the Mash1 promoter. SIGNOR-254828 0.356 eplerenone chemical CHEBI:31547 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition -1 18038968 t Luana Indeed, eplerenone, 1, also acts as a mineralocorticoid receptor antagonist and is used to treat numerous patients for hypertension and congestive heart failure. SIGNOR-257763 0.8 BRCA1 protein P38398 UNIPROT CTSD protein P07339 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 11244506 f miannu BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D. SIGNOR-253759 0.28 PBX4 protein Q9BYU1 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription SIGNOR-265780 0.2 CSNK2A1 protein P68400 UNIPROT TSPY1 protein Q01534 UNIPROT up-regulates activity phosphorylation Thr300 PPEEGTEtSGDSQLL -1 16426576 t llicata CK2-dependent C-terminal phosphorylation at T300 directs the nuclear transport of TSPY protein SIGNOR-250969 0.2 CSNK2B protein P67870 UNIPROT OCLN protein Q16625 UNIPROT unknown phosphorylation Ser408 DYTTGGEsCDELEED 9606 BTO:0002043 12804768 t llicata Mutagenesis of serine 407 to alanine resulted in reduced ability of the kinase to phosphorylate occludin. The threonine 403 to alanine mutant had a smaller effect but the double mutant (T403/S407A) was even less phosphorylated than either of the single mutants. These data are consistent with the claim that CK2 is the kinase in brain extracts responsible for phosphorylation of occludin. SIGNOR-251079 0.425 GSK3B protein P49841 UNIPROT BAX protein Q07812 UNIPROT up-regulates phosphorylation Ser163 GGWDGLLsYFGTPTW 9606 BTO:0000938 15525785 t lperfetto Glycogen synthase kinase-3beta phosphorylates bax and promotes its mitochondrial localization during neuronal apoptosis. Gsk-3beta directly phosphorylated bax(alpha) on ser163 SIGNOR-130141 0.384 ACTB protein P60709 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270748 0.484 EGFR protein P00533 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr102 YDLKLQEyQSAIKVE 9606 26718225 t miannu  Here, we found that nuclear EGFR induced phosphorylation of PPARγ at Tyr-74 leading to PPARγ ubiquitination and degradation by mouse double minute 2 (MDM2) ubiquitin ligase.  SIGNOR-277190 0.528 DVL2 protein O14641 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 17529994 t lperfetto Dishevelled (dvl) transduces the wnt signal by interacting with the cytoplasmic axin complex. SIGNOR-227920 0.638 NCF1 protein P14598 UNIPROT NOX3 protein Q9HBY0 UNIPROT up-regulates activity binding 9606 12672956 t miannu Stimulus-induced phosphorylation of p47phox causes a conformational change, by which both PX and SH3 domains become accessible to their membranous targets, phosphoinositides and p22phox, respectively. Cooperation of these two interactions, each being indispensable, enables p47phox to form a stable complex with cytochrome b558 (composed of the two subunit gp91phox and p22phox), leading to activation of the phagocyte NADPH oxidase. SIGNOR-276624 0.611 SET protein Q01105 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates binding 9606 21806989 t miannu Here we report that both the amino terminal fragment (i(2ntf);aa 1-175) and the carboxy terminal fragment (i(2ctf);aa 176-277) of i(2)(pp2a) inhibit pp2a by binding to its catalytic subunit pp2ac SIGNOR-175719 0.546 SETD5 protein Q9C0A6 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity methylation Lys37 APATGGVkKPHRYRP -1 31515109 t miannu SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription. SIGNOR-264620 0.2 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr176 PFISEGTtLKDLIYD 9606 8576253 t lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta SIGNOR-246732 0.711 SRC protein P12931 UNIPROT BDKRB2 protein P30411 UNIPROT up-regulates phosphorylation Tyr347 RKKSWEVyQGVCQKG 9606 16226010 t lperfetto Here we demonstrate that egf is capable of inducing src-mediated phosphorylation of the tyrosine residues 177 and 347 of bkr. Their replacement by phenylalanine led to bkr mutants which are unable to activate the camp pathway. SIGNOR-141107 0.264 PRKACA protein P17612 UNIPROT DUOX1 protein Q9NRD9 UNIPROT up-regulates phosphorylation Ser955 KDLCRRAsYISQDMI 9606 19144650 t llicata We analyzed the duox1 phosphorylation state with an anti-rxx(ps/pt) antibody that could potentially recognize phosphorylation on ser955 and ser1217 but not on thr1007. duox1 but not duox2 activity is stimulated by forskolin (ec50 = 0.1 _m) via protein kinase a-mediated duox1 phosphorylation on serine 955. duox1 is positively regulated by the camp-dependent protein kinase a (pka)6 cascade SIGNOR-183449 0.2 ARHGAP11A protein Q6P4F7 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260466 0.53 CAMK2A protein Q9UQM7 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 15107581 t Translocation from Endosome to Lysosome gcesareni As we have shown previously, human h1r can be phosphorylated in vitro by several kinases includingpka, pkc, pkg, and camk ii in summary, these data suggest that thr140, thr142, ser396, ser398, and thr478 can be phosphorylated by the kinases described above (table 2). SIGNOR-124344 0.286 LBX1 protein P52954 UNIPROT ZEB1 protein P37275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002181 19651985 t Luana Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively  SIGNOR-266054 0.332 MAP4K1 protein Q92918 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 t gcesareni Hpk1 binds and phosphorylates mekk1 directly, SIGNOR-43996 0.431 SNRPB2 protein P08579 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270654 0.694 KIF18A protein Q8NI77 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272526 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR ADARB1 protein P78563 UNIPROT down-regulates activity phosphorylation Thr553 LQGERLLtMSCSDKI -1 31095429 t miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively, and overexpression of the phosphomimic mutants ADAR1p110 (T738D) and ADAR2 (T553D) resulted in a 50-100% reduction in editase activity. SIGNOR-266358 0.2 PRKACA protein P17612 UNIPROT NF2 protein P35240 UNIPROT down-regulates phosphorylation Ser518 DTDMKRLsMEIEKEK 9606 18071304 t lperfetto Merlin localizes to the cell membrane where it links the actin cytoskeleton to membrane proteins.we identify a novel pka phosphorylation site, serine 10, in the n terminus of merlin. s10a reduces the amount of cellular f-actin and merlin s10d stabilizes f-actin filaments. SIGNOR-159844 0.379 RXRA protein P19793 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-16665 0.713 CAPN3 protein P20807 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity cleavage 9606 25969760 t lperfetto Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase SIGNOR-251607 0.275 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR OPTN protein Q96CV9 UNIPROT up-regulates activity polyubiquitination Lys501 LQLAVLLkENDAFED 9606 BTO:0000567 32014991 t miannu DCAF4-mediated ubiquitination of OPTN facilitates the degradation of DBR-exposed SOD1. OPTN is involved in degradation of DBR-exposed SOD1. These data demonstrate that DCAF4-including CRL4 complex mediates OPTN ubiquitination at lysine 501, and this ubiquitination is absent in the ALS-related OPTNmut. SIGNOR-272209 0.2 CACNA1D protein Q01668 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30849329 t miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). SIGNOR-264326 0.8 FLI1 protein Q01543 UNIPROT IL10 protein P22301 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20879862 f In terms of cytokine expression, increased FLI-1 levels specifically enhanced IL-10 expression SIGNOR-254516 0.2 COL4A4 protein P53420 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253245 0.432 PRKACA protein P17612 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 t gcesareni Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase aon serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no. SIGNOR-112371 0.373 MAPK1 protein P28482 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 t lperfetto Erk phosphorylates threonine 42 residue of ribosomal protein s3. SIGNOR-137955 0.2 FAS protein P25445 UNIPROT FAS protein P25445 UNIPROT up-regulates activity binding 9606 14585074 t lperfetto The fas receptor, upon binding to the fasl, trimerizes SIGNOR-85991 0.2 SMO protein Q99835 UNIPROT TIAM1 protein Q13009 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 20654717 t gcesareni This latter work suggested that inactive smo prevents rac1 activation by interacting with the rac guanine nucleotide exchange factor (gef) t-lymphoma invasion and metastasis 1 (tiam1). This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1 SIGNOR-167070 0.27 RARG protein P13631 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 t lperfetto We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs SIGNOR-133237 0.394 AKT proteinfamily SIGNOR-PF24 SIGNOR HMOX1 protein P09601 UNIPROT unknown phosphorylation Ser188 LYRSRMNsLEMTPAV 9606 BTO:0000007 15581622 t llicata We have identified a putative consensus sequence for phosphorylation by akt/pkb of ho-1 at ser188. although the changes in activity are small, this study provides the first evidence for a role of the survival kinase akt in the regulation of ho-1. SIGNOR-161283 0.2 EIF3B protein P55884 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266399 0.949 USP8 protein P40818 UNIPROT MET protein P08581 UNIPROT down-regulates quantity destabilization 9606 BTO:0000567 16520378 t Degradation of acutely stimulated receptor tyrosine kinases, epidermal growth factor receptor and Met, is strongly inhibited in UBPY knockdown cells suggesting that UBPY function is essential for growth factor receptor down-regulation. SIGNOR-266903 0.432 3-isobutyl-1-methylxanthine chemical CHEBI:48518 ChEBI PPARG protein P37231 UNIPROT up-regulates 9606 11279134 f fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin SIGNOR-106484 0.8 PRKCE protein Q02156 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 20179209 t lperfetto Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated SIGNOR-163916 0.346 Gbeta proteinfamily SIGNOR-PF4 SIGNOR DUSP6 protein Q16828 UNIPROT down-regulates phosphorylation 9606 15632084 t inferred from 70% family members amattioni Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3 SIGNOR-270116 0.2 PPP2CB protein P62714 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 BTO:0000176 19607706 t Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha|Chronic Ser 177/181 phosphorylation of IKKβ was due to UVB-induced inhibition of the catalytic subunit of the Ser-Thr phosphatase PP2A (PP2Ac) SIGNOR-248581 0.262 ELF3 protein P78545 UNIPROT SPRR1B protein P22528 UNIPROT up-regulates quantity by expression transcriptional regulation 12682075 f Consistent with this, overexpression of EBS-binding proteins ESE-1 and ESE-3 significantly stimulated SPRR1B promoter activity. Furthermore, preceding SPRR1B transcription, PMA up-regulated mRNA expression of ETS family members such as ESE-1 and ESE-3 SIGNOR-254281 0.2 CHUK protein O15111 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000007;BTO:0000567 SIGNOR-C14 SIGNOR-C13 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-129931 0.842 MYLK protein Q15746 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 19851336 t lperfetto More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above. SIGNOR-188797 0.832 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249684 0.509 PDYN protein P01213 UNIPROT OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258414 0.661 S1PR1 protein P21453 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256992 0.358 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr178 LLEDEADyVVPVEDN 9606 BTO:0000776 12456653 t llicata The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex. SIGNOR-96040 0.798 CDK1 protein P06493 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates activity phosphorylation Thr346 LEEGVHLtPFRQKVS 9606 24055156 t lperfetto The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl. SIGNOR-265263 0.2 KRAS protein P01116 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0000797 27340238 f These alterations corresponded to mutant KRAS and BRAF-dependent increases in glucose uptake and lactate production. Metabolic reprogramming and glucose conversion to lactate in RKO cells were proportional to levels of BRAF V600E protein. SIGNOR-259372 0.7 CSNK2A2 protein P19784 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates activity phosphorylation Ser518 GEDPYAGsTDENTDS 9606 BTO:0000567 15367657 t llicata XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on S518, T519, and T523 largely determines aprataxin binding to XRCC1 though its FHA domain | In addition, we present data to show that the acute loss of aprataxin by small interfering RNA (siRNA) renders HeLa cells sensitive to MMS through a mechanism that destabilizes XRCC1. SIGNOR-251050 0.472 MAPK8 protein P45983 UNIPROT ELK3 protein P41970 UNIPROT down-regulates activity phosphorylation 11042694 t miannu JNK binds to the J box in the middle of the protein, and binding is required for phosphorylation of the adjacent EXport motif. Both the binding and phosphorylation sites (the JEX element) are important for Net export. SIGNOR-250139 0.328 IL15RA protein Q13261 UNIPROT IL2RB protein P14784 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 17709786 t milica The il-15 receptor comprises a heterotrimeric complex consisting of the common ?cytokine Receptor (?c), the il-2 ? Receptor subunit (il-2r?), And an il-15-specific ? Receptor (il-15r?) SIGNOR-157418 0.792 MYOD/E12E47 complex SIGNOR-C127 SIGNOR VEGFA protein P15692 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 18094043 t lperfetto we further demonstrate that the myogenic transcription factor, MyoD, and its heterodimeric binding proteins E12 and E47, up-regulate the expression of endogenous VEGF through direct interaction with the VEGF promoter. SIGNOR-241545 0.338 RPS6KB1 protein P23443 UNIPROT TRIB2 protein Q92519 UNIPROT down-regulates quantity by destabilization phosphorylation Ser83 FRAVHLHsGEELVCK 9606 BTO:0002181 24089522 t miannu Furthermore, Smurf1-mediated ubiquitination required phosphorylation of TRIB2 by p70 S6 kinase (p70S6K) via another domain (amino acids 69-85) that is also essential for correct TRIB2 subcellular localization. Mutation of Ser-83 diminished p70S6K-induced phosphorylation of TRIB2. SIGNOR-275433 0.363 ATF1 protein P18846 UNIPROT FTH1 protein P02794 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17565989 f miannu Here we found that ATF1 (activating transcription factor 1) is a transcriptional repressor of the ferritin H ARE. SIGNOR-253741 0.2 B4GALT1 protein P15291 UNIPROT lactose smallmolecule CHEBI:17716 ChEBI up-regulates quantity chemical modification 9606 16157350 t miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. SIGNOR-268469 0.8 MACROD2 protein A1Z1Q3 UNIPROT acetate smallmolecule CHEBI:30089 ChEBI up-regulates quantity chemical modification 9606 32257385 t miannu MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins SIGNOR-269842 0.8 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA5 protein Q9Y5G8 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265717 0.2 MC4R protein P32245 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257392 0.252 ZAP70 protein P43403 UNIPROT DUSP3 protein P51452 UNIPROT up-regulates activity phosphorylation Tyr138 SPTLVIAyLMMRQKM 9534 BTO:0001538 12447358 t miannu ZAP-70 and Syk also tyrosine-phosphorylated VHR in COS-1 cells (Fig. 2d), whereas other kinases (Csk, Lck, Fyn, Jak2, Bcr-Abl and Itk) had little effect. Finally, recombinant ZAP-70 readily phosphorylated VHR in vitro (Fig. 2f).  SIGNOR-276000 0.546 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser102 GGFPPLNsVSPSPLM 9606 16076840 t gcesareni The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex. SIGNOR-139312 0.346 FADS2 protein O95864 UNIPROT long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI down-regulates quantity chemical modification 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267908 0.8 POLR3H protein Q9Y535 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266126 0.861 IL1RL1 protein Q01638 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 BTO:0000007 16286016 t miannu As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation.  SIGNOR-277704 0.641 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Arg) smallmolecule CHEBI:29171 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269481 0.8 CCT239065 chemical CID:44131523 PUBCHEM LCK protein P06239 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190910 0.8 CSNK2B protein P67870 UNIPROT CDC34 protein P49427 UNIPROT unknown phosphorylation Thr233 DDEDDSGtEES 9606 BTO:0000567 11546811 t llicata CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm.  SIGNOR-251061 0.358 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Thr309 SDGATMKtFCGTPEY 9606 18160256 t Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248630 0.737 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 t gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation SIGNOR-252450 0.426 CDK7 protein P50613 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Thr433 DCDFGDLtPLDF 9606 10428966 t lperfetto These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase. here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain. SIGNOR-69780 0.506 MAPK14 protein Q16539 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Ser266 SLPLTPEsPNDPKGS 9606 BTO:0000887 11741533 t gcesareni Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298 SIGNOR-112766 0.568 JAK2 protein O60674 UNIPROT PDP1 protein Q9P0J1 UNIPROT down-regulates activity phosphorylation Tyr94 SILKANEySFKVPEF 10090 BTO:0000944 24962578 t miannu Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients.  SIGNOR-276642 0.267 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKAR1B protein P31321 UNIPROT down-regulates activity chemical inhibition 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258760 0.8 SHH protein Q15465 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity binding 9606 15618519 t lperfetto Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. .Ptch Exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms. SIGNOR-132675 0.941 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser527 RFRKRTHsAGTSPTI -1 12351658 t IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. SIGNOR-251296 0.644 KMT2D protein O14686 UNIPROT ESR1 protein P03372 UNIPROT up-regulates binding 9606 16603732 t miannu A novel estrogen receptor (er)alpha coactivator complex, the mll2 complex, which consists of mll2, ash2, rbq3, and wdr5, was identified / disrupting the interaction between eralpha and the mll2 complex with small interfering rnas specific against mll2 or an mll2 fragment representing the interacting region with eralpha significantly inhibited the eralpha transcription activity. SIGNOR-145865 0.466 CDK16 protein Q00536 UNIPROT PRC1 protein O43663 UNIPROT up-regulates activity phosphorylation Thr481 RRGLAPNtPGKARKL 9606 BTO:0000815 35449080 t lperfetto Mechanistically, CDK16 exerts its function by phosphorylating protein regulator of cytokinesis 1 (PRC1) to regulate spindle formation during mitosis.|Indeed, immunoblot analysis showed that PRC1 phosphorylation at the T481 site (CDK-dependent major phosphorylation site) fluctuated with the abundance of CDK16 protein in the cell cycle process SIGNOR-273017 0.35 ACTR2 protein P61160 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 t The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc SIGNOR-251512 0.926 USP8 protein P40818 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity destabilization 9606 BTO:0000567 16520378 t Degradation of acutely stimulated receptor tyrosine kinases, epidermal growth factor receptor and Met, is strongly inhibited in UBPY knockdown cells suggesting that UBPY function is essential for growth factor receptor down-regulation. SIGNOR-266902 0.699 DRD4 protein P21917 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256982 0.449 SREBF1 protein P36956 UNIPROT SND1 protein Q7KZF4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29296233 t irozzo These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression. SIGNOR-259137 0.2 GSK3B protein P49841 UNIPROT ERG protein P11308 UNIPROT down-regulates quantity by destabilization phosphorylation Thr180 KDDFQRLtPSYNADI 9606 BTO:0001033 32871104 t miannu Here, we demonstrate that DNA damage induces proteasomal degradation of wild-type ERG and TMPRSS2-ERG oncoprotein through ERG threonine-187 and tyrosine-190 phosphorylation mediated by GSK3β and WEE1, respectively. SIGNOR-277528 0.2 WNT7A protein O00755 UNIPROT FZD7 protein O75084 UNIPROT up-regulates activity binding 23290138 t Simone Vumbaca Wnt7a-Fzd7 signaling stimulates symmetric stem cell divisions SIGNOR-255646 0.665 CSNK2A1 protein P68400 UNIPROT DDX58 protein O95786 UNIPROT down-regulates phosphorylation Ser854 HPKPKQFsSFEKRAK 9606 21068236 t lperfetto Phosphorylation of rig-i by casein kinase ii inhibits its antiviral response. Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of rig-i are phosphorylated by casein kinase ii (ck2) SIGNOR-169400 0.2 PRKCA protein P17252 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser703 SLVPSPKsFVYFIMR 9606 BTO:0000671 15533987 t gcesareni There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712. SIGNOR-130269 0.354 JNK proteinfamily SIGNOR-PF15 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Thr119 AGTAGALtPQHVRAH 9606 BTO:0001938 21364637 t miannu JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells SIGNOR-277641 0.2 IL1RL1 protein Q01638 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity binding 9606 BTO:0000007 16286016 t miannu As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation.  SIGNOR-277705 0.587 IL13RA1 protein P78552 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica IL-4R, ?c, and IL-13R1 All contain proline-rich box-1 regions that bind jak1, jak3, and tyk2, respectivelyil-4 uses the type ii receptor, and IL-13R1 Binds tyk2. Il-13 results in activation of jak1 and tyk2 in hematopoietic and nonhematopoietic cells. SIGNOR-100756 0.547 CDKN2A protein P42771 UNIPROT Immortality phenotype SIGNOR-PH47 SIGNOR down-regulates 9606 10648628 f Human keratinocytes that express hTERT and also bypass a p16(INK4a)-enforced mechanism that limits life span become immortal yet retain normal growth and differentiation characteristics SIGNOR-259286 0.7 DOK1 protein Q99704 UNIPROT ITGB7 protein P26010 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257695 0.33 IL1RL1 protein Q01638 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 16286016 t miannu As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation.  SIGNOR-277707 0.577 CDK5 protein Q00535 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Thr509 PVYEVPAtPKYATPA 9606 BTO:0000938 18003833 t lperfetto These findings suggest that sema3a-induced spine development is regulated by phosphorylation of crmp1 by cdk5. Introduction of crmp1-wt, but not crmp1-t509a/s522a, a crmp1 mutant that cannot be phosphorylated by cdk5, rescued the defect in sema3a responsiveness. SIGNOR-159318 0.607 WWP1 protein Q9H0M0 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates activity relocalization 9606 15221015 t lperfetto We found that WWP1 inhibited transcriptional activities induced by TGF-beta. Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-beta type I receptor to cause ubiquitination and degradation of the receptor. SIGNOR-126578 0.72 SH2B3 protein Q9UQQ2 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22101255 f miannu Our results indicated that lnk/sh2b3 constrains expression of bcl-xl and participates in the regulation of hsc homeostasis by maintaining proper responses against various proapoptotic stimuli. SIGNOR-177485 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr226 SAPVGKEtPSKRMKR 9606 11931757 t lperfetto We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability. SIGNOR-217308 0.699 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2NL protein Q5JXB2 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271336 0.2 SPI1 protein P17947 UNIPROT JUN protein P05412 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 17041602 f miannu Knockdown of the transcription factor PU.1 (encoded by Sfpi1) leads to acute myeloid leukemia (AML) in mice. We examined the transcriptome of preleukemic hematopoietic stem cells (HSCs) in which PU.1 was knocked down (referred to as 'PU.1-knockdown HSCs') to identify transcriptional changes preceding malignant transformation. Transcription factors c-Jun and JunB were among the top-downregulated targets. SIGNOR-256065 0.571 MAPK9 protein P45984 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr265 GQSSAAAtPSTTGTK 9606 15767678 t gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. SIGNOR-134568 0.653 SRC protein P12931 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates activity phosphorylation Tyr22 GVLPSHYyESFLEKK 9606 12540842 t lperfetto To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src. SIGNOR-247333 0.415 CSF1 protein P09603 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 33505964 f miannu  Exosomes from tumor cells package assorted proteins and chemokines with immunomodulatory capability, including CSF-1, CCL2, and TGF-β, to promote M2-like characterization of TAMs SIGNOR-277708 0.7 CDC42BPA protein Q5VT25 UNIPROT CDC42BPA protein Q5VT25 UNIPROT up-regulates activity phosphorylation Thr240 QSSVAVGtPDYISPE 9534 BTO:0000298 11283256 t miannu N terminus-mediated dimerization and transautophosphorylation are essential for MRCKα catalytic activity. Three mutations, S234A, T240A, and T403A, strongly affected the in vitro autophosphorylation activity of FLAG-MRCKα-CAT1–473 (Fig. ​(Fig.5D).5D). SIGNOR-275975 0.2 STK39 protein Q9UEW8 UNIPROT CFTR protein P13569 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 21317537 t miannu SPAK phosphorylates the transporters to reduce their surface expression and thus their activity and consequently inhibits ductal secretion to stabilize the resting state. PP1 reverses the effect of SPAK. Molecular analysis revealed that the WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. SIGNOR-263134 0.352 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1721 SPTSPSYsPTSPSYS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248787 0.442 YY1 protein P25490 UNIPROT ATP6V1A protein P38606 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28592880 t Giorgia We investigated the relationship between transcription factor YY1 and ATP6V1A, and found that mRNA expression of YY1 had significant correlation with that of ATP6V1A. To validate that YY1 transcriptionally regulates ATP6V1A, we discovered that the ATP6V1A core promoter region contains three YY1 binding sites. Moreover, RNAi-mediated knockdown of YY1 in GC cells significantly decreased ATP6V1A mRNA and protein expression, while YY1 overexpression increased ATP6V1A expression level. SIGNOR-260635 0.331 RPS6KB1 protein P23443 UNIPROT POLDIP3 protein Q9BY77 UNIPROT unknown phosphorylation Ser385 PRRVNSAsSSNPPAE 9606 15341740 t llicata Here we identify skar as a novel and specific binding partner and substrate of s6k1 but not s6k2. We find that serines 383 and 385 of human skar are insulin-stimulated and rapamycin-sensitive s6k1 phosphorylation sites. SIGNOR-128499 0.757 ETS2 protein P15036 UNIPROT Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR up-regulates 9606 11175361 f miannu the constitutive expression of ets2 in myeloblast leukemic cells induces their differentiation to macrophages SIGNOR-259871 0.7 ADIPOR2 protein Q86V24 UNIPROT APPL1 protein Q9UKG1 UNIPROT up-regulates binding 9606 16622416 t milica Appl1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin. SIGNOR-146215 0.735 CCL2 protein P13500 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 33505964 f miannu  Exosomes from tumor cells package assorted proteins and chemokines with immunomodulatory capability, including CSF-1, CCL2, and TGF-β, to promote M2-like characterization of TAMs SIGNOR-277709 0.7 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000552 14744793 t gcesareni We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription. SIGNOR-248070 0.639 DRAM2 protein Q6UX65 UNIPROT RAC1 protein P63000 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30755245 f irozzo Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. SIGNOR-259141 0.2 CSNK1A1 protein P48729 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity phosphorylation Ser349 SSKEVDPsTGELQSL 10090 37723657 t miannu Mechanistically, CSNK1A1 interacted with STING1 upon the CGAS-STING1 pathway activation and promoted STING1 autophagic degradation by enhancing the phosphorylation of SQSTM1/p62 at serine 351 (serine 349 in human), which was critical for SQSTM1-mediated STING1 autophagic degradation. SIGNOR-273769 0.4 ACE2 protein Q9BYF1 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage His42 RVYIHPFhLVIHNES -1 11815627 t miannu The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus. SIGNOR-256317 0.749 LTB4R protein Q15722 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257196 0.252 EP300 protein Q09472 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity acetylation 9606 SIGNOR-C6 21131905 t fspada These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription. SIGNOR-265328 0.2 LCK protein P06239 UNIPROT CD3D protein P04234 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000782 2470098 t Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex. SIGNOR-259929 0.552 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr386 YRARVANyQRDGPMC 9606 BTO:0000093 12777400 t lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases SIGNOR-101302 0.412 PRKACA protein P17612 UNIPROT KCNK3 protein O14649 UNIPROT up-regulates activity phosphorylation Ser393 GLMKRRSsV 9606 21357689 t lperfetto Mutation of the ser393 to alanine, which can neither be phosphorylated nor mimic a phosphorylated residue, resulted in the channel failing to pass current all of our findings support the conclusion that camp-dependent protein kinase is responsible for the phosphorylation of the terminal serine in both k2p3.1 and k2p9.1. SIGNOR-172430 0.2 GATA3 protein P23771 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 11021798 f fspada Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage. SIGNOR-78830 0.7 RALGAPA1 protein Q6GYQ0 UNIPROT RalGAP1 complex SIGNOR-C468 SIGNOR form complex binding 10090 BTO:0000011 21148297 t miannu Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. SIGNOR-269791 0.422 PRKCA protein P17252 UNIPROT SNAP25 protein P60880 UNIPROT unknown phosphorylation Ser187 RIMEKADsNKTRIDE 9606 12459461 t lperfetto This study establishes that SNAP-25 is differentially phosphorylated by protein kinase C and protein kinase A in neuroendocrine PC12 cells. Using phosphopeptide mapping and site-directed mutagenesis we identified both Thr138 and Ser187 as the targets of SNAP-25 phosphorylation by protein kinase C SIGNOR-249178 0.359 CSNK2A1 protein P68400 UNIPROT ABCC1 protein P33527 UNIPROT up-regulates phosphorylation Thr249 WSLNKEDtSEQVVPV 9606 22695718 t lperfetto Casein kinase 2_ regulates multidrug resistance-associated protein 1 function via phosphorylation of thr249. This study supports a model in which ck2_ potentiates mrp1 function via direct phosphorylation of thr249. SIGNOR-197844 0.382 CDK5 protein Q00535 UNIPROT LMTK2 protein Q8IWU2 UNIPROT up-regulates phosphorylation Ser1450 LQTSKYFsPPPPARS 9606 BTO:0000938 BTO:0000142 22220831 t gcesareni Here, we demonstrate that lmtk2 is phosphorylated on serine-1418 (lmtk2ser ) by cdk5/p35 and present evidence that this regulates its ability to phosphorylate pp1cthr __ SIGNOR-195329 0.511 PKA proteinfamily SIGNOR-PF17 SIGNOR PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser706 ARIIGEKsFRRSVVG 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275952 0.2 RSPO2 protein Q6UXX9 UNIPROT FZD4 protein Q9ULV1 UNIPROT down-regulates quantity ubiquitination 9606 22575959 t miannu Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. SIGNOR-260117 0.319 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT down-regulates quantity phosphorylation Ser619 RELTNRHsLPFSLPS 9606 BTO:0000782 11024037 t lperfetto However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway.  SIGNOR-249054 0.327 HOXA10 protein P31260 UNIPROT MYCN protein P04198 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 21261500 f miannu HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5. SIGNOR-254215 0.2 PRKACA protein P17612 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251617 0.373 CTNNB1 protein P35222 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity binding 9606 20492721 t FFerrentino Hypophosphorylation of β-catenin and translocation into the nucleus leads to binding with members of the lymphoid-enhancer-binding factor/T-cell-specific transcription factor (LEF/TCF) family and activation of WNT target genesAs a member of LEF/TCF family, transcription factor 7 like 2 (Tcf7l2, formerly called Tcf4) is an important transcription factor triggering the downstream responsive genes of WNT signaling SIGNOR-85757 0.897 AKT1 protein P31749 UNIPROT CYCS protein P99999 UNIPROT down-regulates activity phosphorylation Tyr47 KTGQAPGySYTAANK -1 32781572 t miannu Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain. SIGNOR-277237 0.478 STRN protein O43815 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 10090 BTO:0000938 29802198 t miannu The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms SIGNOR-261698 0.658 EIF2AK2 protein P19525 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser32 LLDDRHDsGLDSMKD 10723127 t lperfetto As described for other stimuli, following pIC treatment, PKR phosphorylates the NF-kappa B inhibitor I kappa B alpha at serine 32 before degradation. SIGNOR-249335 0.516 SMC1A protein Q14683 UNIPROT RAD21L Cohesin complex complex SIGNOR-C355 SIGNOR form complex binding 10090 BTO:0000534 21242291 t miannu RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21. SIGNOR-264538 0.776 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr869 LGAEEKEyHAEGGKV 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236487 0.2 PFKM protein P08237 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. SIGNOR-266471 0.8 SRC protein P12931 UNIPROT FCRL3 protein Q96P31 UNIPROT up-regulates activity phosphorylation Tyr662 PGDSNPIySQIWSIQ -1 12051764 t miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. SIGNOR-274010 0.2 PRKCA protein P17252 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser677 AIVSKIDsRLEQYTS 9606 BTO:0000887;BTO:0001260 8182108 t gcesareni Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase. SIGNOR-36796 0.364 LTB4R protein Q15722 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256691 0.252 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr210 LSASTVLtAQESFSG -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276219 0.388 AKT1 protein P31749 UNIPROT HK2 protein P52789 UNIPROT up-regulates activity phosphorylation Thr473 QHRARQKtLEHLQLS 9606 BTO:0000192 31435020 t K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization SIGNOR-259984 0.456 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCND1 protein P24385 UNIPROT up-regulates quantity by expression 9606 BTO:0001103 20219869 t apalma Importantly, NF-kB can promote the expression and stability of cyclin D1 in muscle (4, 35, 39, 132), leading to increased cell proliferation and inhibition of differentiation. SIGNOR-255358 0.482 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser290 GRIVARNsRKMAFRA -1 9677319 t lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. SIGNOR-249006 0.292 HIP1 protein O00291 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001130 16027218 f miannu Hip1 as a transcriptional regulator of the ar / silencing hip1 expression reduces the transcriptional activity and protein levels of the ar SIGNOR-138820 0.2 SMAD3 protein P84022 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity 9606 BTO:0000599 10890911 f lperfetto Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity SIGNOR-229308 0.529 Sin3B_complex complex SIGNOR-C409 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity binding 9606 21041483 t miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. SIGNOR-266971 0.2 HIPK2 protein Q9H2X6 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000452 19820693 f Luana We show that MeCP2 cooperates with HIPK2 in induction of apoptosis and that Ser 80 phosphorylation is required together with the DNA binding of MeCP2. | We found increased cell death in each of the tested cell lines not only, as expected, when HIPK2 was overexpressed but also with MeCP2 alone. When both proteins were expressed together, the number of dead cells increased in an additive manner. SIGNOR-264551 0.7 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22521266 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-252920 0.2 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269373 0.719 PTPRH protein Q9HD43 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation 10029 BTO:0000246 12907755 t Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR SIGNOR-248802 0.299 CDK8 protein P49336 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo. SIGNOR-273175 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates phosphorylation 28712664 t AKT phosphorylates and inhibits GSK3 in addition to many other substrates including TSC2, FOXO proteins, TBC1D4. SIGNOR-255488 0.2 SNX6 protein Q9UNH7 UNIPROT IGF1R protein P08069 UNIPROT down-regulates quantity binding 9606 BTO:0000567 32150533 t miannu Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures. SIGNOR-269445 0.2 TGFB1 protein P01137 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates activity 9606 19114990 f lperfetto First, TGF-beta can rapidly activate PI3K, as indicated by the phosphorylation of its downstream effector Akt SIGNOR-217812 0.277 PRKCB protein P05771 UNIPROT STXBP1 protein P61764 UNIPROT down-regulates activity phosphorylation Ser313 SLKDFSSsKRMNTGE 9913 BTO:0000259 12519779 t lperfetto Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation. SIGNOR-249186 0.406 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 14967450 t gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-121988 0.579 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR USP24 protein Q9UPU5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2604 HLQQGSEsPMMIGEL 9606 BTO:0000018 27991932 t lperfetto Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. SIGNOR-275609 0.26 IKBKG protein Q9Y6K9 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity binding 9606 SIGNOR-C14 SIGNOR-C14 12192055 t lperfetto The n-terminal domain of ikkgamma is required both for the binding of ikkalfa and ikkbeta and their assembly into a high-molecular-weight complex essential for activation SIGNOR-91705 0.962 CLOCK protein O15516 UNIPROT DPYD protein Q12882 UNIPROT up-regulates quantity by expression transcriptional regulation 17699798 f Regulation of Genes of the Circadian Clock in Human Colon Cancer: Reduced Period-1 and Dihydropyrimidine Dehydrogenase Transcription Correlates in High-Grade Tumors| The highly significant correlation of DPD mRNA with Per1 mRNA expression suggests control of DPD transcription by the endogenous cellular clock, which is more pronounced in women. SIGNOR-253986 0.264 IFNG protein P01579 UNIPROT HLA-B protein P01889 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 2507660 f Regulation miannu HLA-B (class I) and C13 gene expression was transcriptionally activated by IFN-gamma and IFN-alpha 2 SIGNOR-251926 0.337 pazopanib hydrochloride chemical CHEBI:71217 ChEBI SH2B3 protein Q9UQQ2 UNIPROT down-regulates activity chemical inhibition -1 17620431 t miannu Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases.  SIGNOR-259169 0.8 SRSF2 protein Q01130 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27524244 t miannu Using MDM2 P1 and P2 promoter-reporter systems, we screened clones regulating MDM2 transcriptions in a p53-independent manner by overexpression. Nine clones from the screening library showed enhanced MDM2 promoter activity and MDM2 expression in p53-deficient HCT116 cells. Among them, six clones, including NTRK2, GNA15, SFRS2, EIF5A, ELAVL1, and YWHAB mediated MAPK signaling for expressing MDM2. SIGNOR-260076 0.282 midostaurin chemical CHEBI:63452 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 12124173 t PKC412 is a potent inhibitor of mutant FLT3 and is a candidate for testing as an antileukemia agent in AML patients with mutant FLT3 receptors. SIGNOR-256308 0.8 PRKACA protein P17612 UNIPROT HDAC8 protein Q9BY41 UNIPROT down-regulates phosphorylation Ser39 AKIPKRAsMVHSLIE 9606 14701748 t lperfetto Negative regulation of histone deacetylase 8 activity by cyclic amp-dependent protein kinase athe pka phosphoacceptor site of hdac8 is ser(39) SIGNOR-120643 0.472 PPARG protein P37231 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20303941 f gcesareni The results from mammalian one-hybrid experiments showed that functional ppar gamma was necessary for ligand-dependent inhibition of beta-catenin transactivation. SIGNOR-164516 0.554 MMP12 protein P39900 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Phe540 FSPMLGEfVSETESR -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-12 20ADSGEGD a-chain| 540FVSETESRG a-chain|433LVTSKGDK a-chain SIGNOR-263623 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR GAD1 protein Q99259 UNIPROT down-regulates activity phosphorylation Thr91 RDARFRRtETDFSNL 9606 BTO:0000142 15147202 t miannu Here, we report the effect of phosphorylation on the two well-defined GAD isoforms, namely, GAD65 and GAD67, using highly purified preparations of recombinant human brain GAD65 and GAD67. GAD65 was activated by phosphorylation, while GAD67 was inhibited by phosphorylation.We further demonstrate that protein kinase A (PKA) and protein kinase C isoform epsilon are the protein kinases responsible for phosphorylation and regulation of GAD67 and GAD65, respectively. We have identified one specific phosphorylation site, threonine 91 (T91), in hGAD67 that can be phosphorylated by PKA using MALDI-TOF. SIGNOR-276009 0.2 PPP1R14B protein Q96C90 UNIPROT PPP1CB protein P62140 UNIPROT down-regulates activity binding -1 12144526 t lperfetto We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin SIGNOR-265743 0.29 FZD2 protein Q14332 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 18077588 t areggio Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction. SIGNOR-258965 0.654 TLE4 protein Q04727 UNIPROT PAX2/TLE4 complex SIGNOR-C152 SIGNOR form complex binding 9606 16631587 t miannu Several Pax proteins are able to interact with groucho (TLE) family members. Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1. SIGNOR-256360 0.468 ARID5B protein Q14865 UNIPROT MYB protein P10242 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29326336 f miannu We also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F). SIGNOR-256160 0.2 RNF11 protein Q9Y3C5 UNIPROT STAMBP protein O95630 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 14755250 t miannu RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome. SIGNOR-272953 0.546 PKC proteinfamily SIGNOR-PF53 SIGNOR GAD2 protein Q05329 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000142 15147202 t miannu Here, we report the effect of phosphorylation on the two well-defined GAD isoforms, namely, GAD65 and GAD67, using highly purified preparations of recombinant human brain GAD65 and GAD67. GAD65 was activated by phosphorylation, while GAD67 was inhibited by phosphorylation.We further demonstrate that protein kinase A (PKA) and protein kinase C isoform epsilon are the protein kinases responsible for phosphorylation and regulation of GAD67 and GAD65, respectively. SIGNOR-276010 0.2 PRKACA protein P17612 UNIPROT PARP1 protein P09874 UNIPROT up-regulates activity phosphorylation Ser785 LRGGSDDsSKDPIDV 9606 BTO:0001412 25069723 t miannu  In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain).  SIGNOR-276653 0.2 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates phosphorylation Ser342 LAHDRAPsRKDSLES 9606 23337587 t gcesareni Interestingly, sufu stability is regulated via dual phosphorylation at ser342/ser346 by pka and gsk3, and blocking sufu phosphorylation either by mutating ser346 to ala or by treating cultured cells with pka inhibitors attenuates sufu ciliary accumulation, whereas phospho-mimetic forms of sufu exhibits increased ciliary localization SIGNOR-200492 0.444 CACNA1C protein Q13936 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 30849329 f miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). SIGNOR-264330 0.7 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21620960 t gcesareni Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. SIGNOR-252847 0.908 MAPK8 protein P45983 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Thr455 ALGTPVLtPPTEAAS 9606 15538382 t lperfetto Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment. SIGNOR-130385 0.596 DLK1 protein P80370 UNIPROT FN1 protein P02751 UNIPROT up-regulates binding 9606 20457810 t fspada We show a direct interaction of pref-1 and fibronectin via the pref-1 juxtamembrane domain and fibronectin c-terminal domain SIGNOR-165347 0.378 ARID2 protein Q68CP9 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 t lperfetto We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. SIGNOR-241756 0.72 DUSP2 protein Q05923 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates activity dephosphorylation 9606 28252035 t miannu DUSP2 can dephosphorylate both ERK3 and ERK4 when expressed in mammalian cells.|Finally, we demonstrate that DUSP2 inhibits ERK3 and ERK4 mediated activation of MK5. SIGNOR-277069 0.384 TRIM25 protein Q14258 UNIPROT FBXW7 protein Q969H0 UNIPROT down-regulates activity ubiquitination Lys412 VWSAVTGkCLRTLVG 9606 BTO:0002181 31186535 t miannu This newly stabilized TRIM25 then directly ubiquitinates Lys412 of FBXW7α, a core subunit of the SKP1-Cullin-F-box (SCF) ubiquitin ligase complex involved in Myc ubiquitination, thereby stabilizing Myc.  SIGNOR-277457 0.267 PRKACA protein P17612 UNIPROT ETV1 protein P50549 UNIPROT up-regulates activity phosphorylation Ser191 HRFRRQLsEPCNSFP 9606 12213813 t lperfetto The camp-dependent protein kinase a (pka) phosphorylates er81 on ser(191)/ser(216)ser(191) and ser(216), were identified, whose mutation to alanine reduces er81 activity upon erk-mapk stimulation. SIGNOR-92447 0.297 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249645 0.2 FLNA protein P21333 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity binding 10116 BTO:0000232 11102480 t Luisa Filamin may function as a scaffold protein in the postsynaptic density, mediating a direct link between Kv4.2 and the actin cytoskeleton, and that this interaction is essential for the generation of appropriate Kv4.2 current densities. SIGNOR-269003 0.36 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser464 LLKHVTQsSRKLIRA 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. SIGNOR-129316 0.327 MUL1 protein Q969V5 UNIPROT AKT1 protein P31749 UNIPROT down-regulates quantity by destabilization ubiquitination Lys284 LENLMLDkDGHIKIT 9606 BTO:0000007 22410793 t gcesareni The results of the functional studies suggest that the degradation of Akt by MULAN suppresses cell proliferation and viability. SIGNOR-252437 0.488 Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 15776021 f miannu Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. SIGNOR-263878 0.7 TLR4 protein O00206 UNIPROT TICAM2 protein Q86XR7 UNIPROT up-regulates binding 9606 18221795 t fstefani Mappit analysis of early toll-like receptor signalling events. SIGNOR-160424 0.723 ELK1 protein P19419 UNIPROT PRKCA protein P17252 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16297876 f irozzo We demonstrated that both Elk-1 and MZF-1 were highly expressed in human poor differentiated HCC cells and involved in the up-regulation of PKCa, which was essential for cell migration and invasion. Over-expression assay confirmed that the PKCa expression may be modulated by these two factors at the transcriptional level. SIGNOR-256282 0.418 BOC protein Q9BWV1 UNIPROT CDON/BOC/PTCH1 complex SIGNOR-C95 SIGNOR form complex binding 10090 21664576 t lperfetto Secreted Hedgehog (HH) ligands signal through the canonical receptor Patched (PTCH1). However, recent studies implicate three additional HH-binding, cell-surface proteins, GAS1, CDO, and BOC, as putative coreceptors for HH ligands. SIGNOR-209599 0.511 PRKCA protein P17252 UNIPROT LCK protein P06239 UNIPROT unknown phosphorylation Ser42 TLLIRNGsEVRDPLV -1 8506364 t lperfetto In vitro kinase assays show that Ser-59 can be uniquely phosphorylated by mitogen-activated protein kinase and that Ser-42 can be phosphorylated by either protein kinase A or protein kinase C. SIGNOR-248936 0.328 AKT1 protein P31749 UNIPROT XIAP protein P98170 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 VGRHRKVsPNCRFIN 9606 BTO:0001023 14645242 t lperfetto Akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin. SIGNOR-119488 0.637 ACE2 protein Q9BYF1 UNIPROT Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 32231345 f doi.org/10.1101/2020.03.09.983247 miannu Unlike SARS-CoV, live SARS-CoV-2-infected cells were found to form typical syncytium, suggesting that SARS-CoV-2 may mainly utilize the plasma membrane fusion pathway to enter and replicate inside host cells. Consistently, in the cell–cell fusion system, SARS-CoV-2 S protein could effectively mediate the formation of syncytium between the effector cell and the target cell in the absence of an exogenous proteolytic enzyme, e.g., trypsin, while SARS-CoV S protein could not. Actually, the plasma membrane fusion pathway is more efficient than the endosomal membrane fusion pathway for most viruses because the latter is more prone to activating the host cell antiviral immunity. SIGNOR-260286 0.7 PRKACA protein P17612 UNIPROT STMN2 protein Q93045 UNIPROT down-regulates activity phosphorylation Ser50 KQINKRAsGQAFELI 9534 BTO:0000298 9525956 t miannu Using in vitro phosphorylated recombinant protein, four phosphorylation sites were identified in the SCG10 sequence. Ser-50 and Ser-97 were the target sites for protein kinase A. phosphorylation negatively regulates the microtubule-depolymerizing activity of SCG10 and that all four sites participate in this regulation SIGNOR-250056 0.314 PRKCB protein P05771 UNIPROT RAB11A protein P62491 UNIPROT unknown phosphorylation Ser177 TEIYRIVsQKQMSDR -1 22188018 t miannu This report shows for the first time that Rab11 is differentially phosphorylated by distinct PKC isoenzymes and that this post-translational modification might be a regulatory mechanism of intracellular trafficking.Our results demonstrate that classical PKC (PKCα and PKCβII but not PKCβI) directly phosphorylate Rab11 in vitro. In addition, novel PKCε and PKCη but not PKCδ isoenzymes also phosphorylate Rab11. Mass spectrometry analysis revealed that Ser 177 is the Rab11 residue to be phosphorylated in vitro by either PKCβII or PKCε. SIGNOR-263169 0.2 cabozantinib chemical CHEBI:72317 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000184 26536165 t miannu Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. SIGNOR-262242 0.8 SMURF2 protein Q9HAU4 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 11163210 t miannu Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.  SIGNOR-272939 0.578 NKX2-3 protein Q8TAU0 UNIPROT MADCAM1 protein Q13477 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 10790368 t Luana We provide evidence that NKX2.3 can activate MAdCAM-1 transcription directly SIGNOR-266219 0.439 IL12B protein P29460 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 7527811 t fspada Characterization of the p40 proteins for binding and bioactivity showed that both the p40 monomer and dimer inhibited 125i-labeled il-12 binding to il-12r, but the 80-kda species, having a 50% inhibitory concentration (ic50) of 20 to 70 ng/ml, was at least 20-fold more effective than the monomer. The results suggest that the il-12 p40 subunit contains the essential epitopes for receptor binding. SIGNOR-27690 0.663 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR PRC1 protein O43663 UNIPROT unknown phosphorylation Thr481 RRGLAPNtPGKARKL 9885575 t llicata We have shown that PRC1 is a good in vitro substrate for several CDKs, and that it is also phosphorylated in a cell cycle–dependent manner in vivo at Thr-481 (major mitosis. and Thr-470 (minor site), which are the in vitro phosphorylation sites. SIGNOR-250746 0.351 HES1 protein Q14469 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19891787 f gcesareni We earlier identified e2f-1 as a crucial transcription factor directly inhibited by hes-1. SIGNOR-189061 0.2 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273079 0.635 PIM1 protein P11309 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates quantity by stabilization phosphorylation Thr455 LAMSPLPtAETPKPL 9606 BTO:0002181 34211090 t miannu PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes. SIGNOR-277311 0.2 RPS6KB1 protein P23443 UNIPROT URI1 protein O94763 UNIPROT down-regulates activity phosphorylation Ser372 AKRKRKNsTGSGHSA 9606 BTO:0000567 17936702 t miannu Here we report that the prefoldin chaperone URI represents a mitochondrial substrate of S6K1. In growth factor-deprived or rapamycin-treated cells, URI forms stable complexes with protein phosphatase (PP)1gamma at mitochondria, thereby inhibiting the activity of the bound enzyme. Growth factor stimulation induces disassembly of URI/PP1gamma complexes through S6K1-mediated phosphorylation of URI at serine 371. SIGNOR-262943 0.35 WNT5A protein P41221 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity 9606 BTO:0000887;BTO:0001103 9753670 f gcesareni Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. SIGNOR-60379 0.326 GREB1 protein Q4ZG55 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity binding 9606 BTO:0000599 31462641 t miannu GREB1 is localized to the nucleus where it binds Smad2/3 in a competitive manner with p300 and inhibits TGFβ signaling, thereby promoting HepG2 HB cell proliferation. Binding of GREB1 to Smad2/3 inhibits transcription SIGNOR-265884 0.2 ADSS2 protein P30520 UNIPROT GDP smallmolecule CHEBI:17552 ChEBI up-regulates quantity chemical modification 9606 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267349 0.8 quetiapine chemical CHEBI:8707 ChEBI HTR2A protein P28223 UNIPROT up-regulates activity chemical activation 10090 BTO:0000331 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258532 0.8 (S)-(-)-sulpiride chemical CHEBI:64119 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258733 0.8 SMAD3 protein P84022 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity binding 9606 BTO:0000007 11331591 t lperfetto Tgf-beta inhibited the expression of the cbfa1 and osteocalcin genes, whose expression is controlled by cbfa1 in osteoblast-like cell lines. This inhibition was mediated by smad3, which interacts physically with cbfa1 and represses its transcriptional activity at the cbfa1-binding ose2 promoter sequence. SIGNOR-235902 0.727 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Arg70 ESGLTEYrLVSINKS -1 10978167 t lperfetto Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site. SIGNOR-263572 0.62 BMP7 protein P18075 UNIPROT DLK1 protein P80370 UNIPROT down-regulates transcriptional regulation 9606 20584981 f fspada Bmp7 could directly suppress pref-1 expression, thereby allowing the initiation of the adipogenic program.  SIGNOR-210074 0.295 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser275 DNVRYGIsNIDTTIE 9606 BTO:0002181 34010649 t miannu PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-277557 0.2 ILK protein Q13418 UNIPROT MYL12B protein O14950 UNIPROT up-regulates activity phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 11278951 t lperfetto Integrin-linked kinase cdna was cloned, sequenced, expressed in e. coli, and shown to phosphorylate myosin light chain in the absence of ca(2+) at ser(19) and thr(18). Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activation of myosin light chain kinase, and phosphorylation of the 20-kDa light chain of myosin at Ser(19).Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activa SIGNOR-106427 0.319 GSK3B protein P49841 UNIPROT ROR2 protein Q01974 UNIPROT down-regulates activity phosphorylation Ser864 PKPSSHHsGSGSTST 9606 SIGNOR-C110 21078818 t gcesareni We identify ror2 ser 864 as a critical residue phosphorylated by gsk3 and required for noncanonical receptor activation by wnt5a, analogous to the priming phosphorylation of low-density receptor-related protein 6 (lrp6) in response to wnt3a. SIGNOR-169642 0.317 PRKACA protein P17612 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser698 PEWPRRAsCTSSTSG -1 196939 t The results presented in this paper show that the phosphorylation of glycogen synthetase a by cyclic AMP-dependent protein kinase results in the phosphorylation of two distinct serines termed site-l and site-2, which account for 90% of the total phosphorylation SIGNOR-253009 0.49 ROS stimulus SIGNOR-ST2 SIGNOR PAX2 protein Q02962 UNIPROT up-regulates quantity by expression 10090 16985513 f High glucose-induced Pax-2 gene expression is mediated, at least in part, via ROS generation and activation of the nuclear factor kappa B signaling pathway, but not via protein kinase C, p38 mitogen-activated protein kinase (MAPK), and p44/42 MAPK signaling. SIGNOR-252295 0.7 PTPRO protein Q16827 UNIPROT LYN protein P07948 UNIPROT down-regulates activity dephosphorylation 9606 20564182 t miannu Both Lyn and ZAP70 were dephosphorylated by wild-type PTPROt, but not by its catalytic site mutant.|Lyn kinase and ZAP70 are substrates of PTPROt in B-cells: Lyn inactivation by PTPROt sensitizes leukemia cells to VEGF-R inhibitor pazopanib. SIGNOR-277144 0.331 GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu46 TRANSFLeEMKKGHL -1 9538022 t lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). SIGNOR-263664 0.598 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination 9606 16603398 t amattioni In this report, we show that ciap1 and ciap2 promote cancer cell survival by functioning as e3 ubiquitin ligases that maintain constitutive ubiquitination of the rip1 adaptor protein. SIGNOR-145036 0.759 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates phosphorylation Tyr772 EDDPEATyTTSGGKI 9606 18387945 t lperfetto The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells. SIGNOR-178181 0.2 PRKCA protein P17252 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser710 GEKSFRRsVVGTPAY 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275954 0.371 GALR2 protein O43603 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257356 0.252 MASP1 protein P48740 UNIPROT C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Gly1446 TPLQLFEgRRNRRRR -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263429 0.663 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT up-regulates activity phosphorylation Tyr337 LPAQIIEyYNPSGPP 9606 BTO:0000815 17623672 t WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3. SIGNOR-262301 0.564 UHMK1 protein Q8TAS1 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 19033656 t gcesareni This promigratory phenotype resulted from increased stathmin protein levels, caused by a lack of kis-mediated stathmin phosphorylation at serine 38 and diminished stathmin protein degradation. SIGNOR-182489 0.524 BRAF protein P15056 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 BTO:0000142 8668348 t gcesareni We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-42668 0.74 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser939 SFRARSTsLNERPKS 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex. SIGNOR-183636 0.719 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity 9606 BTO:0000801 10973958 f lperfetto NF-kB-, AP-1-, and Smad3-driven promoters all require p300/CREB-binding protein for their transactivation. Previous studies have suggested that NF-kB- and AP-1-driven promoters can be inhibited by competitive recruitment of coactivators such as p300/CPB to other unrelated promoters. We hypothesized that NF-kB and AP-1 compete with Smad3 for limiting quantities of p300. This hypothesis predicts that added p300 should alleviate TGF-b1/Smad3-mediated inhibition of inflammatory genes. Conversely, increasing doses of TGF-b1/Smad3 would compete away even overexpressed p300 from NF-kB/AP- 1-driven promoters. SIGNOR-249554 0.337 TGFBR1 protein P36897 UNIPROT ZFYVE9 protein O95405 UNIPROT up-regulates activity binding 9606 9865696 t lperfetto Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex SIGNOR-62868 0.616 MAPK14 protein Q16539 UNIPROT EPS15 protein P42566 UNIPROT up-regulates phosphorylation Ser796 RSINKLDsPDPFKLN 9606 24269888 t lperfetto Tnf-_ induces phosphorylation of eps15 at ser-796eps15 is a substrate for p38_these results suggest an attractive model in which p38 phosphorylates both eps15 and egfr to trigger efficient endocytosis SIGNOR-203315 0.352 mTORC2 complex SIGNOR-C2 SIGNOR RRM1 protein P23921 UNIPROT up-regulates activity phosphorylation Ser631 IYTRRVLsGEFQIVN 9606 BTO:0002552 34126361 t miannu Mechanistically, mTORC2 directly interacted and phosphorylated RNR large subunit RRM1 at Ser 631. Ser631 phosphorylation of RRM1 enhanced its interaction with small subunit RRM2 to maintain sufficient RNR enzymatic activity for efficient DNA replication. SIGNOR-277566 0.308 CEBPD protein P49716 UNIPROT MSTN protein O14793 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24011072 f miannu To identify whether p-Stat3 acts through C/EBPŒ¥ to stimulate myostatin, we knocked down C/EBPŒ¥ using siRNA. In this case, the IL-6-induced increase in myostatin expression was blocked when C/EBPŒ¥was suppressed even though p-Stat3 was increased SIGNOR-255332 0.29 FYN protein P06241 UNIPROT PTPRJ protein Q12913 UNIPROT up-regulates activity phosphorylation Tyr1320 NTTAMTIyENLAPVT 9606 BTO:0000007 22898603 t miannu  We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin. SIGNOR-276374 0.373 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 20444238 t gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. SIGNOR-165212 0.432 ODC1 protein P11926 UNIPROT spermine smallmolecule CHEBI:15746 ChEBI up-regulates quantity chemical modification 9606 14617280 t miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256036 0.8 EIF3E protein P60228 UNIPROT MCM7 protein P33993 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0002181 17310990 t irozzo Our data show that INT6 interacts with a C-terminal domain of MCM7. Collectively, our observations suggest that INT6 restrains the increased degradation of MCM7 occurring during DNA replication by protecting its polyubiquitylated derivatives from the proteasome activity. SIGNOR-259154 0.341 BAX protein Q07812 UNIPROT CYCS protein P99999 UNIPROT up-regulates relocalization 9606 10629050 t Translocation from Mitochondria to Cytosol amattioni The integration of bax oligomers in the outer mitochondrial membrane is followed by cytochrome crelease SIGNOR-73898 0.687 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR JUN protein P05412 UNIPROT down-regulates activity binding 9606 BTO:0004136 12393465 t RUNX1-RUNX1T1 fusion protein (AML-ETO) apalma Here we show that AML1-ETO blocks the transcriptional activity of PU.1 by displacing its coactivator c-Jun. SIGNOR-255670 0.2 PI4K2B protein Q8TCG2 UNIPROT 1-phosphatidyl-1D-myo-inositol 4-phosphate smallmolecule CHEBI:17526 ChEBI up-regulates quantity chemical modification 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269101 0.8 GARS1 protein P41250 UNIPROT Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates quantity chemical modification 9606 24898252 t miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. SIGNOR-270482 0.8 LSM2 protein Q9Y333 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270648 0.829 LYN protein P07948 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr682 SRTTDGVyEGVAIGG 9606 BTO:0000007 32420483 t done miannu  We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. SIGNOR-274103 0.2 SEC62 protein Q99442 UNIPROT Protein_translocation phenotype SIGNOR-PH176 SIGNOR up-regulates 22375059 f lperfetto Silencing the SEC62 gene inhibits post-translational transport of small presecretory proteins into the human ER SIGNOR-265280 0.7 RAF1 protein P04049 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser222 VSGQLIDsMANSFVG 9606 8157000 t gcesareni To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1. SIGNOR-262292 0.722 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity phosphorylation Ser849 NMLNRRDsSASTISS 9606 10693759 t lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. SIGNOR-75343 0.445 SHPK protein Q9UHJ6 UNIPROT sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI up-regulates quantity phosphorylation 9606 22682222 t miannu The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. CARKL bridges glycolysis and PPP by catalyzing the formation of S7P from sedoheptulose SIGNOR-267084 0.8 CREB3 protein O43889 UNIPROT HERPUD1 protein Q15011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16940180 f miannu Luman/creb3 induces transcription of the endoplasmic reticulum (er) stress response protein herp through an er stress response element. SIGNOR-149268 0.322 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249625 0.907 GNAS protein P63092 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates -1 10224115 f miannu G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics. SIGNOR-256524 0.7 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 BTO:0000130 12056906 t esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. SIGNOR-89225 0.458 fluticasone chemical CHEBI:5134 ChEBI SMO protein Q99835 UNIPROT up-regulates activity chemical activation 10090 20439738 t gcesareni We identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling. SIGNOR-248206 0.8 NR0B2 protein Q15466 UNIPROT NR5A2 protein O00482 UNIPROT down-regulates binding 9606 12198243 t gcesareni Here we show that shp can interact with the liver x receptors lxralpha (nr1h3) and lxrbeta (nr1h2), as demonstrated by glutathione-s-transferase pull-down assays, mammalian two-hybrid, and coimmunoprecipitation experiments. In transfection assays, shp inhibits the expression of an artificial reporter driven by an lxr-response element and represses the transcriptional activation by lxr of the human atp-binding cassette transporter 1 (abca1) promoter SIGNOR-92060 0.579 XAV939 chemical CHEBI:62878 ChEBI AXIN1 protein O15169 UNIPROT up-regulates 9606 19759537 f gcesareni Using a quantitative chemical proteomic approach, we discovered that xav939 stabilizes axin by inhibiting the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2 SIGNOR-188045 0.8 G1/S_transition phenotype SIGNOR-PH50 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 21524151 f lperfetto In addition to the successive phosphorylation of pRb by active Cyclin/Cdk complexes, other factors can also impact upon S-phase entry Subsequently, the initiation of replication requires the formation of a pre-initiation complex (pre-IC) that is initiated by phosphorylation of Mcm2-7 by CyclinE/Cdk2 and DDK (Dbf4- and Drf1-dependent kinase) and recruitment of Cdc45 onto the chromatin (Figure 1). This recruitment is thought to be the critical step for the activation of the Mcm2-7 helicase activity and replication initiation. Finally, unwinding of the chromatin enables DNA-polymerase _ to initiate DNA synthesis and DNA-polymerase _ to continue replication SIGNOR-245489 0.7 GSK3A protein P49840 UNIPROT GRB14 protein Q14449 UNIPROT down-regulates activity phosphorylation Ser358 MHPYQGRsGCSSQSI -1 28130417 t lperfetto Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3. SIGNOR-264871 0.267 SYK protein P43405 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates phosphorylation Ser364 GTPRSNHsAQDSAVE 9606 BTO:0001271 23071339 t miannu Syk phoshorylatesikarosat unique c-terminal serine phosphorylation sites s358 and s361, thereby augmenting its nuclear localization and sequence-specific dna binding activity. Mechanistically, we establish that syk-inducedikarosactivation is essential for its nuclear localization and optimal transcription factor function. SIGNOR-199100 0.413 PPM1F protein P49593 UNIPROT CAMK4 protein Q16566 UNIPROT down-regulates activity dephosphorylation 9606 11726284 t miannu Calmodulin-dependent protein kinase phosphatase (CaMKP) dephosphorylates and concomitantly deactivates multifunctional Ca(2+)/calmodulin-dependent protein kinases , such as CaMKI, CaMKII, and CaMKIV. SIGNOR-277157 0.355 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 BTO:0000782 18840653 t gcesareni Vegfr2 contains several critical tyrosine residues that are autophosphorylated following activation. Our phosphorylation assays showed that tcptp was able to target specific tyrosines in vegfr2. The autophosphorylation sites tyr1054/1059 and tyr1214 were dephosphorylated by tcptp. Tyr996 was a tcptp target as well. SIGNOR-181550 0.547 SRC protein P12931 UNIPROT NOS2 protein P35228 UNIPROT up-regulates phosphorylation Tyr151 IEFVNQYyGSFKEAK 9606 19875457 t llicata We identify human inos residue tyr(1055) as a target for src-mediated phosphorylation. src kinase-mediated phosphorylation stabilizes inducible nitric-oxide synthase in normal cells and cancer cells. SIGNOR-188974 0.668 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 30060484 f miannu The bacterial endotoxin LPS is a known agonist of TLR2 that activates the expression of proinflammatory cytokines and the phosphorylation of MAPKs and NFκB [49]. In addition, the activation of the MAPK and NFκB signaling cascades drive inflammation and macrophage polarization.  SIGNOR-249519 0.7 nefazodone chemical CHEBI:7494 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition -1 9871604 t miannu Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. Nefazodone has similar affinities at hSERT, hNET, and hDAT, but has low potency SIGNOR-259069 0.8 RET protein P07949 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 16153436 t gcesareni We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1). SIGNOR-140294 0.433 KAT8 protein Q9H7Z6 UNIPROT FASN protein P49327 UNIPROT down-regulates quantity by destabilization acetylation 9606 BTO:0000007 27758890 t Overexpression of Myc-KAT8 increased the acetylation level of endogenous FASN by 2.2-fold (Fig. 3C). In contrast, knockdown of KAT8 decreased endogenous FASN acetylation by as much as 55% SIGNOR-267366 0.2 CDH23 protein Q9H251 UNIPROT TIP-LINK complex complex SIGNOR-C291 SIGNOR form complex binding 10090 BTO:0000630 23217710 t lperfetto The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction. SIGNOR-262579 0.632 AKT proteinfamily SIGNOR-PF24 SIGNOR MAPK14 protein Q16539 UNIPROT down-regulates activity 9606 BTO:0000150 12697749 f lperfetto Our data indicate that akt2 inhibits cisplatin-induced jnk/p38 and bax activation through phosphorylation of ask1 SIGNOR-244288 0.2 MRPS33 protein Q9Y291 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261444 0.68 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2D protein Q13557 UNIPROT up-regulates activity chemical activation 9606 19725819 t areggio Upon binding of the Ca2+/calmodulin complex to the binding domain of CaMKII, it is activated via autophosphorylation, then remaining active independent of of Ca2+ levels. SIGNOR-255953 0.8 MAP3K14 protein Q99558 UNIPROT CHUK protein O15111 UNIPROT up-regulates activity phosphorylation Ser180 DQGSLCTsFVGTLQY 9606 SIGNOR-C14 9520446 t lperfetto NIK preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa. SIGNOR-55946 0.685 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120044 0.781 AP-2 complex complex SIGNOR-C245 SIGNOR EPN1 protein Q9Y6I3 UNIPROT up-regulates activity binding 10116 BTO:0000142 15496985 t Giorgia Some of the more minor interactors are very strongly enriched (AAK, auxilin, Dab2, eps15, epsin1 and synaptojanin170). All these enriched proteins have multiple copies of short alpha‐appendage interaction motifs SIGNOR-260395 0.55 GDF2 protein Q9UK05 UNIPROT ACVRL1 protein P37023 UNIPROT up-regulates binding 9606 17068149 t gcesareni Finally, we demonstrate that bmp9 and bmp10 potently inhibit endothelial cell migration and growth, and stimulate endothelial expression of a panel of genes that was previously reported to be activated by the constitutively active form of alk1. Taken together, our results suggest that bmp9 and bmp10 are two specific alk1 ligands that may physiologically trigger the effects of alk1 on angiogenesis. SIGNOR-150260 0.904 AUTS2 protein Q8WXX7 UNIPROT ELMO2 protein Q96JJ3 UNIPROT up-regulates activity binding 10090 BTO:0001909 25533347 t miannu Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development.  AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These results suggest that FL-AUTS2 can activate Rac1 via interaction with P-Rex1 and the Elmo2/Dock180 complex to regulate actin dynamics in N1E-115 cells. SIGNOR-266819 0.272 MET protein P08581 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 22128289 t irozzo For activation of the mitogen-activated protein kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral oncogene homolog (RAS) guanine nucleotide exchanger son of sevenless (SOS) via binding with SHC and GRB2 leading to the activation of RAS. SIGNOR-256261 0.682 HIF-1 complex complex SIGNOR-C418 SIGNOR HK1 protein P19367 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 t miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. SIGNOR-267452 0.359 MAPK9 protein P45984 UNIPROT SFN protein P31947 UNIPROT down-regulates phosphorylation Ser186 FHYEIANsPEEAISL 9606 15071501 t JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8 gcesareni Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-189 SIGNOR-124027 0.2 EIF5B protein O60841 UNIPROT Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates activity relocalization 9606 30551605 t lperfetto EIF5B was also shown to deliver Met-tRNAi into the P-site of the ribosome in an eIF2-independent translation initiation mechanism utilized by the CSFV and HCV IRESs  SIGNOR-269119 0.8 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser174 LSPASSGsSASFISD 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252326 0.635 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-251522 0.2 NKX2-5 protein P52952 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21261500 f Taken together, our results indicate that the expression of MEF2C in T-ALL cells is principally deregulated via activating leukemic transcription factors GFI1B or NKX2-5 and by escaping inhibitory developmental STAT5 signaling. SIGNOR-253656 0.73 PPP2CA protein P67775 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 17015476 t Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo. SIGNOR-248615 0.475 ITGA1 protein P56199 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253169 0.748 DDX28 protein Q9NUL7 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25683715 f miannu DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU. SIGNOR-261229 0.7 2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]-4-quinazolinyl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide chemical CHEBI:91367 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190245 0.8 CEBPD protein P49716 UNIPROT TNFAIP6 protein P98066 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 23028973 f CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. SIGNOR-254057 0.261 TRAF2 protein Q12933 UNIPROT UBE2N protein P61088 UNIPROT up-regulates activity binding 9606 BTO:0000459 18635759 t lperfetto Traf2, ubc13, and ikkgamma were required for complex assembly and activation of mekk1 and mapk cascades. SIGNOR-179479 0.439 IGF1R protein P08069 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity 10090 11715022 f lperfetto We show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy. SIGNOR-235373 0.397 GOLGA7 protein Q7Z5G4 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity palmitoylation 9606 BTO:0000007 16000296 t miannu Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein. SIGNOR-261351 0.356 FGF11 protein Q92914 UNIPROT SCN1A protein P35498 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253422 0.262 NFATC2 protein Q13469 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18676376 f gcesareni € provide a novel transcriptional paradigm for the first steps of myogenesis, where a calcineurin/NFATc3 pathway regulates myogenin induction in cooperation with MyoD during myogenesis. SIGNOR-235006 0.288 LYN protein P07948 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates activity phosphorylation Tyr120 PPTYNADyGYKSWEA -1 24970799 t miannu We report that FYN phosphorylates human COX2 on Tyr 446, and while corresponding phospho-mimetic COX2 mutation promotes COX2 activity, the phosphorylation blocking mutation prevents FYN-mediated increase in COX2 activity. FYN and LYN kinases phosphorylate COX2 on two distinct residues in vitro. SIGNOR-276643 0.394 EP300 protein Q09472 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates binding 9606 11796223 t lperfetto Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription. SIGNOR-232165 0.856 KISS1R protein Q969F8 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256893 0.41 PPP2CB protein P62714 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity dephosphorylation Ser1981 SLAFEEGsQSTTISS 9606 15510216 t Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro. SIGNOR-248601 0.272 F7 protein P08709 UNIPROT F9 protein P00740 UNIPROT up-regulates activity binding 9606 BTO:0000131 SIGNOR-C319 29880919 t lperfetto TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively. SIGNOR-263544 0.53 CCR4-NOT complex complex SIGNOR-C439 SIGNOR PUM2 protein Q8TB72 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 t lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins SIGNOR-268347 0.374 PTTG1 protein O95997 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates activity 10090 BTO:0000093 22002306 f Overexpressed hPTTG1 promotes breast cancer cell invasion and metastasis by regulating GEF-H1/RhoA signalling SIGNOR-256535 0.7 CREB1 protein P16220 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15130492 f lperfetto MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA SIGNOR-251714 0.253 (S,S)-asenapine chemical CHEBI:71257 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258566 0.8 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269366 0.719 DMTF1 protein Q9Y222 UNIPROT GAS1 protein P54826 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004532 19816943 f Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  SIGNOR-261588 0.2 MAPK8 protein P45983 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 12223490 t gcesareni We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage. SIGNOR-92597 0.542 Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity methylation 9606 12670868 t miannu The Set1/Ash2 HMT methylates histone H3 at Lys 4 (K4), but not if the neighboring K9 residue is already methylated. SIGNOR-265349 0.2 flutamide chemical CHEBI:5132 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition 9606 18571420 t Luana Among the compounds obtained, N-[4-[(benzyl)(4-nitrophenyl)amino]-1-methylpyrrole-2-carbonyl]pyrrolidine (22) is as potent an AR antagonist as the typical anilide-type AR antagonists hydroxyflutamide and bicalutamide.  SIGNOR-257807 0.8 AKT1 protein P31749 UNIPROT AGAP2 protein Q99490 UNIPROT up-regulates phosphorylation Ser985 THLSRVRsLDLDDWP 9606 BTO:0001130 19176382 t llicata In addition, we have found that activated akt can bind and phosphorylate ggap2 at serine 629, which enhances gtp binding by ggap2. SIGNOR-183543 0.511 MASP2 protein O00187 UNIPROT C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 17204478 t lperfetto MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a). SIGNOR-263422 0.794 MAPK3 protein P27361 UNIPROT SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization phosphorylation Thr507 GLGENLLtHLPEEIG 9606 BTO:0000007 30865892 t miannu Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation. SIGNOR-277443 0.341 PIK3CA protein P42336 UNIPROT BTK protein Q06187 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000899 10201980 t lperfetto Activation of Btk occurs by transphosphorylation of tyrosine 551 in the catalytic domain, resulting in a dramatic increase in the catalytic activity of the kinase (11, 12, 13). This allows for autophosphorylation at tyrosine 223 in the SH3 domain (14). Both Lyn and Syk have been demonstrated to be involved in BCR-mediated Btk activation (11), but processes that drive colocalization of these kinases are ill-defined. Recently, it was suggested that phosphatidylinositol 3-kinase (PI3-K) is also involved in Btk activation SIGNOR-249610 0.493 sorafenib tosylate chemical CHEBI:50928 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. SIGNOR-259227 0.8 NCK1 protein P16333 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity binding 10090 BTO:0002572 10026169 t lperfetto Both nck and grb4 proteins could associate with receptor tyrosine kinases and the sh3-binding proteins pak, sos1, and prk2, and they synergized with v-abl and sos to induce gene expression via the transcription factor elk-1. Association of nck with pak1 may serve to link this important regulatory kinase to cell activation by growth factor receptors. SIGNOR-236512 0.697 ASXL3 protein Q9C0F0 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR down-regulates activity binding 9606 BTO:0000972 25450400 t inferred from family member miannu We determined that ASXL3 depletion augments the ligand-induced transcriptional activities of LXRŒ± and TRŒ≤, which were repressed by ASXL3 overexpression. The ligand-dependent interactions of ASXL3 with LXRŒ± and TRŒ≤ were demonstrated by the GST pull-down and immunoprecipitation analyses. We confirmed that ASXL3 suppresses the expression of LXRŒ± target genes through its recruitment to the LXR-response elements. SIGNOR-270302 0.2 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000567 15642743 t lperfetto Recombinant p38 phosphorylated recombinant p53 on serine 46 in vitro. Inhibition of p38 MAPK by pharmacological inhibitors, dominant-negative p38, or small interfering RNA, suppressed p53S46P SIGNOR-226620 0.764 PTPN2 protein P17706 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity dephosphorylation Tyr1034 AIETDKEyYTVKDDR 10090 11909529 t The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3|We have identified JAK1 and JAK3 as physiological substrates of TCPTP.| Using a site-specific antibody directed against the activation loop phosphotyrosines in JAK1 (pY1022/pY1023), we found that these sites were in fact dephosphorylated by TCPTP SIGNOR-248395 0.758 MAPKAP1 protein Q9BPZ7 UNIPROT PRKCE protein Q02156 UNIPROT up-regulates activity binding 9606 21806543 t miannu In the present study, we have identified the mTORC2 subunit Sin1 as a direct binding partner of the PKC (protein kinase C) ε kinase domain and map the interaction to the central highly conserved region of Sin1. Exploiting the conformational dependence for PKC phosphorylation, we demonstrate that mTORC2 is essential for acute priming of PKC.  SIGNOR-276348 0.266 AKT proteinfamily SIGNOR-PF24 SIGNOR DLX5 protein P56178 UNIPROT up-regulates phosphorylation 9606 22298955 t lperfetto Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5. SIGNOR-244228 0.2 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser344 QAVALPRsEEPASCN 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 17213202 t lperfetto The results indicated that rsk2 phosphorylated two additional sites at ser289 (peptide 2) and ser344 (peptide 3)rsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo. SIGNOR-235652 0.393 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKAR1A protein P10644 UNIPROT down-regulates activity chemical inhibition 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258759 0.8 N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide chemical CHEBI:63082 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Thus, overall, salmeterol is a highly selective β2-adrenoceptor agonist because of its higher β2-affinity and not because of higher β2-intrinsic efficacy. A similar reasoning can be applied to formoterol, although this agonist has higher intrinsic efficacy at all three receptors (rank 6, 8 and 5 at β1, β2 and β3). SIGNOR-257853 0.8 ANGPT1 protein Q15389 UNIPROT MYH2 protein Q9UKX2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 f lperfetto Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. SIGNOR-241557 0.2 EIF2AK4 protein Q9P2K8 UNIPROT MARS1 protein P56192 UNIPROT down-regulates phosphorylation Ser662 NRAGMFVsKFFGGYV 9606 22106287 t lperfetto Here we demonstrate that aimp3 is released from mrs by uv irradiation-induced stress. Dissociation was induced by phosphorylation of mrs at ser662 by general control nonrepressed-2 (gcn2) following uv irradiation. Substitution of ser662 to asp (s662d) induced a conformational change in mrs and significantly reduced its interaction with aimp3. This mutant possessed significantly reduced mrs catalytic activity because of loss of trna(met) binding, resulting in down-regulation of global translation. SIGNOR-177648 0.2 (D-Ala(2)-mephe(4)-gly-ol(5))enkephalin chemical CHEBI:272 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258783 0.8 PDPK1 protein O15530 UNIPROT PRKCG protein P05129 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni One of the most studiedevents controlled by ptdins(3,4,5)p3, comprises the activation of aof agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-126072 0.2 RPS6KA1 protein Q15418 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 9606 SIGNOR-C3 18722121 t llicata Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity SIGNOR-180466 0.562 POU5F1 protein Q01860 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 16153702 f flangone Our results suggest that OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal by activating their own genes and genes encoding components of key signaling pathways and by repressing genes that are key to developmental processes. SIGNOR-242070 0.7 PRKCZ protein Q05513 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser185 SAYVGRLsARPKLKA -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276017 0.2 PCDH15 protein Q96QU1 UNIPROT TMC2 protein Q8TDI7 UNIPROT up-regulates activity binding 9606 BTO:0000007 BTO:0000630 25114259 t lperfetto Although several studies show that the tip links, composed of PCDH15 and CDH23, are required for normal mechanotransduction, it is unclear how they are coupled to the transduction machinery. Likewise, it has been demonstrated that the transmembrane channel-like proteins TMC1 and TMC2 are required for mechanosensitive responses in hair cells, but how they interact with other components of the mechanotransduction complex is not known. Here, we show that TMC1 and TMC2 can interact with PCDH15, thereby establishing a critical connection between the tip link and these putative components of the mechanotransduction channel in hair cells. SIGNOR-262583 0.447 TP53 protein P04637 UNIPROT TIGAR protein Q9NQ88 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001248 27803158 t miannu TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. TIGAR is the only known phosphatase glycolytic modulator regulated by TP53. The current study delineates the role of TIGAR in OXPHOS and glycolytic metabolic reprogramming in breast cancer. SIGNOR-267365 0.2 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI LATS1 protein O95835 UNIPROT down-regulates 9606 BTO:0000007 22863277 f milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. SIGNOR-198550 0.8 MYO1E protein Q12965 UNIPROT Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 10116 BTO:0000142 17257598 f miannu We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta. SIGNOR-265425 0.7 YY1 protein P25490 UNIPROT HOXB13 protein Q92826 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001130 19013255 f miannu Recruitment of HDAC4 by transcription factor YY1 represses HOXB13 to affect cell growth in AR-negative prostate cancers. SIGNOR-254233 0.277 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser64 EPGTPPSsPLSAEQL 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276094 0.274 COMMD5 protein Q9GZQ3 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 30021164 f miannu In this study, we identified a specific and crucial role for COMMD5 in the endocytic trafficking machinery, and especially we determined COMMD5 as an actin- and tubulin-binding protein. Our results provide further insight into the essential role of COMMD5 on every aspect of cellular processes, from membrane receptor trafficking to cytoskeleton organization, cell migration, and junctions. Here, we demonstrate that COMMD5 is crucial for the stability of the cytoskeleton. Its silencing leads to a major re-organization of actin and microtubule networks. SIGNOR-261693 0.7 imatinib chemical CHEBI:45783 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258225 0.8 KAT2B protein Q92831 UNIPROT H3-2 protein Q5TEC6 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269616 0.2 serotonin smallmolecule CHEBI:28790 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264284 0.8 INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr607 NENTEDQySLVEDDE 9534 BTO:0000298 8385099 t The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-252693 0.601 SDC4 protein P31431 UNIPROT FZD7/SDC4 complex SIGNOR-C216 SIGNOR form complex binding 9606 BTO:0002314 BTO:0001103 23290138 t apalma We next examined whether endogenous Fzd7 and Sdc4 form a receptor complex in satellite cells […] Therefore, we conclude that Fzd7 and Sdc4 form a co-receptor complex in activated satellite cells. SIGNOR-255847 0.539 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267879 0.8 HSPA5 protein P11021 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT down-regulates activity binding 9606 31226023 t miannu In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation. SIGNOR-260164 0.715 PPP3CA protein Q08209 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10195903 t Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. SIGNOR-248695 0.452 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser15 SSYRGRKsGNKPPSK 9606 9649584 t gcesareni This study investigated the molecular physiology of the nh2-terminal phosphorylation sites that regulate inactivation gating of an a-type k+ channel. The main results show that: (a) pkc acts on four phosphate acceptors (s8, s9, s15, and s21) within the inactivation domain because mutation of these residues to alanine is necessary and sufficient to remove the action of pkc on channel inactivation. SIGNOR-58498 0.2 MEF2A protein Q02078 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 19725819 f areggio In response to increases in intracellular Ca2+ levels, activated CaMKII translocates into the nucleus where it phosphorylates and deactivates HDAC4 which, as a result, dissociates from theDNA-binding domain of MEF2. This dissociation allows MEF2 to bind to its DNA-binding domain to activate transcription of the MEF2-dependent target gene products MyoD and myogenin SIGNOR-255957 0.7 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 17827393 t gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157734 0.864 3-[[6-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]phenol chemical CHEBI:91384 ChEBI GSK3B protein P49841 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207474 0.8 TRAPPC9 protein Q96Q05 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity binding 9606 BTO:0000007 15951441 t miannu We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates. SIGNOR-269673 0.503 SIRT3 protein Q9NTG7 UNIPROT CYP11A1 protein P05108 UNIPROT up-regulates quantity by stabilization deacetylation Lys148 LKKSAAWkKDRVALN 9606 BTO:0002588 22585829 t lperfetto Resveratrol stimulates cortisol biosynthesis by activating SIRT-dependent deacetylation of P450scc.|Stable overexpression of SIRT3 abrogates the cellular content of acetylated P450scc, concomitant with an increase in P450scc protein expression and cortisol secretion. Mutation of K148 and K149 to alanine stabilizes the expression of P450scc and results in a 1.5-fold increase in pregnenolone biosynthesis. SIGNOR-268717 0.2 MKNK1 protein Q9BUB5 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates activity phosphorylation Ser727 RQNPSRCsVSLSNVE 9606 BTO:0000007 10978317 t lperfetto The results suggest that MNK1 or a closely related kinase is responsible for in vivo phosphorylation of cPLA2 on Ser-727. SIGNOR-226633 0.559 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-B receptor complex SIGNOR-C336 SIGNOR up-regulates activity chemical activation 9606 18790874 t miannu Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-264962 0.8 EPHB2 protein P29323 UNIPROT RRAS protein P10301 UNIPROT down-regulates activity phosphorylation Tyr66 DPTIEDSyTKICSVD 9606 10570155 t Tyrosine 66 of R-Ras is phosphorylated by EphB2|. R-Ras, a small intracellular GTPase, regulates the binding of integrins to their ligands outside the cell. |Cells in which EphB2 is activated become poorly adherent to substrates coated with integrin ligands, and a tyrosine residue in the R-Ras effector domain is phosphorylated. SIGNOR-251125 0.595 ABL1 protein P00519 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates activity phosphorylation Tyr232 FLMTKSGyQPPRLKE 9606 BTO:0000007 11278340 t C-Abl phosphorylates HPK1 in cytoplasm and stimulates HPK1 activity. the c-Abl phosphorylation site (YXXP) in HPK1 (Y232QPP; aa 232–235) is localized in HPK1-KD SIGNOR-251429 0.387 ERRFI1 protein Q9UJM3 UNIPROT EGFR protein P00533 UNIPROT down-regulates binding 10116 11003669 t gcesareni These data indicate that the gene 33 protein is a feedback inhibitor of ErbB-2 mitogenic function and a suppressor of ErbB-2 oncogenic activity. We propose that the gene 33 protein be renamed with the acronym RALT (receptor-associated late transducer) SIGNOR-186198 0.661 PPP3CB protein P16298 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 f gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-84044 0.443 JNK proteinfamily SIGNOR-PF15 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser400 SRDESTDsGLSMSSY 9606 21364637 t miannu JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells SIGNOR-277645 0.2 CSNK2B protein P67870 UNIPROT SEC63 protein Q9UGP8 UNIPROT up-regulates activity phosphorylation Ser576 VSDKGSDsEEEETNR 9606 BTO:0000599 23287549 t lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. SIGNOR-265268 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNJ4 protein P48050 UNIPROT up-regulates activity phosphorylation Ser443 NISYRREsAI 9606 BTO:0000007 19635485 t miannu Kir2.3 can be phosphorylated by PKAin vitro. We further show that the phosphorylation/dephosphorylation of Ser443 within the C-terminal Kir2.3 PDZ-binding motif RRESAI dynamically regulates the Kir2.3/TIP-1 association in heterologous HEK293T cells. These data suggest that TIP-1 may act as an important regulator for the endocytic pathway of Kir2.3. SIGNOR-263153 0.2 AKT2 protein P31751 UNIPROT XIAP protein P98170 UNIPROT up-regulates phosphorylation Ser87 VGRHRKVsPNCRFIN 9606 14645242 t llicata Here, we demonstrate that akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin. Moreover, autoubiquitination of xiap is also inhibited by akt. SIGNOR-119492 0.43 AKT proteinfamily SIGNOR-PF24 SIGNOR NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser134 ANLNRSTsVPENPKS 9606 BTO:0000731 24291004 t lperfetto Akt1 impairs glucocorticoid-induced gene expression by direct phosphorylation of nr3c1 at position s134 and blocking glucocorticoid-induced nr3c1 translocation to the nucleus SIGNOR-236216 0.2 EP300 protein Q09472 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates binding 9606 24058639 t miannu P300 promotes the interaction of fli1 with hdac1 and increases the dna binding ability of fli1 through deacetylation of lysine 380 SIGNOR-202682 0.295 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT down-regulates phosphorylation Ser855 EPMRRSVsEAALAQP 9606 9636039 t gcesareni Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase. SIGNOR-58259 0.585 FBXW7 protein Q969H0 UNIPROT MED13 protein Q9UHV7 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 SIGNOR-C135 SIGNOR-C406 23322298 t miannu The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association. SIGNOR-266690 0.379 UBE2A protein P49459 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination Lys164 AVVISCAkDGVKFSA 9606 12226657 t gcesareni Pcna is mono-ubiquitinated through rad6 and rad18, modified by lysine-63-linked multi-ubiquitination--which additionally requires mms2, ubc13 and rad5--and is conjugated to sumo by ubc9. The first of these is monoubiquitination of lysine 164 on one or more of the pcna subunits by the e2-e3 complex of rad6-rad18. SIGNOR-92737 0.489 E2F1 protein Q01094 UNIPROT HSPA5 protein P11021 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18840615 f miannu we show that E2F1 represses GRP78/BIP at the transcriptional level, and this requires its DNA binding domain. SIGNOR-253845 0.2 MAPK14 protein Q16539 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity 9606 BTO:0000887;BTO:0001103 15466486 f lperfetto Here, we show that p38 activity facilitates myod and mef2 binding at a subset of late-activated promoters, and the binding of mef2d recruits pol ii. SIGNOR-129702 0.462 TAOK2 protein Q9UL54 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation Ser207 ISGYLVDsVAKTIDA 9606 BTO:0000007 11279118 t lperfetto Suggesting that tao2 selectively activates mek3 and mek6 of the p38 pathway in intact cells SIGNOR-106465 0.634 MAPK1 protein P28482 UNIPROT MYO9B protein Q13459 UNIPROT unknown phosphorylation Thr1346 RATGAALtPTEERRT 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262777 0.307 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1763 TPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273058 0.556 RMDN3 protein Q96TC7 UNIPROT VAPB-PTPIP51 complex complex SIGNOR-C275 SIGNOR form complex binding 10116 BTO:0000142 30841933 t lperfetto Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction. SIGNOR-262119 0.625 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Ser430 DTLTPPPsDAGSPFQ 9606 BTO:0000007 19126544 t lperfetto Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1. SIGNOR-236030 0.498 PRKCB protein P05771 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276022 0.2 LFNG protein Q8NES3 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates glycosylation 9606 BTO:0000975 12486116 t Fringe is a fucose-specific beta1,3-N-acetylglucosaminyltransferase that modifies O-fucose moieties on the epidermal growth factor-like (EGF) repeats of Notch. gcesareni We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1. SIGNOR-96540 0.747 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys135 AKRLKKEkVNVDIIN -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. SIGNOR-272747 0.475 ARHGEF7 protein Q14155 UNIPROT CBLC protein Q9ULV8 UNIPROT down-regulates binding 9606 14505571 t gcesareni Here, we show that activation of cdc42 protects the egf receptor from the negative regulatory activity of the c-cbl ubiquitin ligase. Activated cdc42 binds to p85cool-1 (for cloned-out-of-library)/beta-pix (for pak-interactive exchange factor), a protein that directly associates with c-cbl. This inhibits the binding of cbl by the egf receptor and thus prevents cbl from catalyzing receptor ubiquitination SIGNOR-118135 0.2 CLK2 protein P49760 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates activity phosphorylation -1 8617202 t miannu In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors. SIGNOR-273858 0.302 ATF4 protein P18848 UNIPROT TARS2 protein Q9BW92 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269428 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR AR protein P10275 UNIPROT down-regulates phosphorylation Ser215 SGRAREAsGAPTSSK 9606 BTO:0000938 17470458 t lperfetto The work presented here is the first demonstration that phosphorylation at s215 and s792 by akt regulates ligand binding, and the subcellular distribution of the receptor SIGNOR-244140 0.2 TCF4 protein P15884 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22777675 f miannu we show that TCF4 can transactivate the NRXN1β and CNTNAP2 promoters in luciferase assays. SIGNOR-255391 0.277 HSPA5 protein P11021 UNIPROT UPR phenotype SIGNOR-PH131 SIGNOR up-regulates 28286085 f lperfetto The HSPA5 gene encodes the binding immunoglobulin protein (BiP), an Hsp70 family chaperone localized in the ER lumen.|When unfolded/misfolded proteins in the ER overwhelm the capacity of protein folding machinery, BiP can initiate the unfolded protein response (UPR), decrease unfolded/misfolded protein load, induce autophagy, and crosstalk with apoptosis machinery to assist in the cell survival decision. SIGNOR-265282 0.7 PGK1 protein P00558 UNIPROT PGK1 protein P00558 UNIPROT up-regulates activity phosphorylation Tyr324 GPESSKKyAEAVTRA -1 31492635 t miannu PGK1 functions not only as a glycolytic enzyme but also as a protein kinase intermolecularly autophosphorylating itself at Y324 for activation.  SIGNOR-277482 0.2 HERC2 protein O95714 UNIPROT XPA protein P23025 UNIPROT down-regulates ubiquitination 9606 20304803 t miannu Herc2 may ubiquitinate xpa and thus target it for proteolytic degradation SIGNOR-164595 0.394 SCF-betaTRCP complex SIGNOR-C5 SIGNOR WEE1 protein P30291 UNIPROT down-regulates binding 9606 15340381 t lperfetto Scfb-trcp continues to have a role in this phase, however, through its induced degradation of the cdk1 inhibitor, wee1. SIGNOR-217184 0.395 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr579 VSSDGHEyIYVDPMQ 9606 BTO:0000599 9642269 t miannu We used two platelet-derived growth factor beta-receptor (beta-PDGFR) mutants to identify events that are required for full engagement (autophosphorylation and activation of the kinase activity) of the beta-PDGFR kinase. The F79/81 receptor (Tyr to Phe substitution at 579 and 581 in the juxtamembrane domain of the receptor) was capable of only very modest ligand-dependent autophosphorylation and also failed to associate with numerous SH2 domain-containing proteins. SIGNOR-250254 0.2 JAK1 protein P23458 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 23124025 t lperfetto IL-4-stimulated Stat6 activation is mediated by Jak1 whereas Tyk2 is required for Stat6 activation in IL-13-treated monocytes SIGNOR-249531 0.756 VTN protein P04004 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 9606 BTO:0000007 7559467 t lperfetto The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin. SIGNOR-253307 0.56 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR lysine smallmolecule CHEBI:25094 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270405 0.8 MLL2 complex complex SIGNOR-C88 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 24680668 t miannu Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. SIGNOR-268798 0.2 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1693 SPTSPSYsPTSPSYS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248785 0.442 CNOT2 protein Q9NZN8 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268306 0.823 LAMTOR5 protein O43504 UNIPROT LIN28B protein Q6ZN17 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23494474 f miannu We found that HBXIP was able to upregulate Lin28B in breast cancer MCF-7 cells. SIGNOR-255251 0.253 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Ser205 LATPPTLsSTVLIVR 9606 BTO:0001938 12815053 t lperfetto Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation. SIGNOR-249218 0.555 COL12A1 protein Q99715 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t Types XII and XIV collagen are fibril-associated collagens with interrupted triple helices (FACITs) localized primarily to perimysium.23 While they appear to link fibrillar collagen to other ECM components, their precise function is not known SIGNOR-254671 0.7 RIPK1 protein Q13546 UNIPROT TNFRSF10A protein O00220 UNIPROT up-regulates 9606 18545270 f gcesareni The death domain of the rip1 kinase binds to death receptors such as tumor necrosis factor-related apoptosis-inducing ligand receptor 1,trailr1. SIGNOR-177952 0.614 PRKCE protein Q02156 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser464 LLKHVTQsSRKLIRA 9606 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation SIGNOR-129300 0.317 NODAL protein Q96S42 UNIPROT LIF protein P15018 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003879 20383200 f Regulation miannu Nodal induced LIF and Cripto-1 expressions through Smad2 signaling pathway. SIGNOR-251941 0.269 HNF1A protein P20823 UNIPROT UGT1A10 protein Q9HAW8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000195 15044625 t Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter. SIGNOR-253971 0.253 MAP2K6 protein P52564 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10347227 t lperfetto However, the autocatalytic activities of both mkk6 and mkk7 were enhanced by their coexpression with either mekk3 or mekk2. SIGNOR-236122 0.2 2-(6,7-dimethoxy-4-quinazolinyl)-5-(2-pyridinyl)-1,2,4-triazol-3-amine chemical CHEBI:91330 ChEBI ATM protein Q13315 UNIPROT down-regulates activity chemical inhibition -1 18794134 t Gianni A targeted compound library was screened for potential inhibitors of the ATM kinase, and CP466722 was identified. SIGNOR-261975 0.8 RIMBP3 protein Q9UFD9 UNIPROT RIMS3 protein Q9UJD0 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264370 0.289 ADRB1 protein P08588 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257030 0.252 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser177 ASSGSSAsFISDTFS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252325 0.635 DYRK1B protein Q9Y463 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 15546868 f lperfetto Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner SIGNOR-235816 0.287 rRNA_transcription phenotype SIGNOR-PH145 SIGNOR 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR up-regulates 25838379 f lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by means of single-particle electron cryogenic microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three ribosomal RNA molecules. SIGNOR-262599 0.7 CHMP1A protein Q9HD42 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 t miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. SIGNOR-265531 0.641 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1070 ISTHTVTyGNIEGNA -1 11024032 t Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro. SIGNOR-251170 0.759 PROX1 protein Q92786 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates quantity by stabilization 9606 27476001 f miannu PROX1 is important to maintain HIF1Œ± protein stability by inhibiting the proteasome activity after DAB2IP loss, since our immunoprecipitation data showed that knocking-down PROX1 could enhance the protein‚Äìprotein interaction between HIF1Œ± and ubiquitin in DAB2IP-deficient LAPC-4 and RWPE-1 KD cells. we found that knocking-down PROX1 could decrease HIF1Œ± protein stability, because HIF1Œ± protein degradation was significantly blocked by MG132 treatment in LAPC-4 and RWPE-1 KD cells SIGNOR-254766 0.259 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914168 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161666 0.325 RXRA protein P19793 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 10976919 t gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr). SIGNOR-81446 0.652 prazosin chemical CHEBI:8364 ChEBI ADRA1B protein P35368 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258469 0.8 3C-like proteinase protein P0C6X7-PRO_0000037312 UNIPROT ATP6V1G1 protein O75348 UNIPROT down-regulates activity cleavage -1 16226257 t lperfetto Cleavage of the V-ATPase G1 fusion protein by SARS-CoV 3CLpro was found in this study (Fig. 3), implying that 3CLpro potentially cleaves the cellular V-ATPase G1, and affects the function of vacuolar H(+)-ATPase. Meanwhile, a significant intracellular acidification has been demonstrated in the 3CLpro-expressing cells (Fig. 4D). The result correlated well with previous reports in that V-ATPase-specific inhibitors cause acidic pHi [28], [29], and influences cell apoptosis SIGNOR-260264 0.2 BDKRB1 protein P46663 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257362 0.41 ketotifen chemical CHEBI:92511 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 t Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells SIGNOR-257789 0.8 (6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide chemical CHEBI:92629 ChEBI HTR2B protein P41595 UNIPROT up-regulates activity chemical activation 10036 BTO:0000452 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258688 0.8 sapitinib chemical CHEBI:132986 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 20145185 t gcesareni In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. SIGNOR-163730 0.8 PRKAA1 protein Q13131 UNIPROT CCNY protein Q8ND76 UNIPROT up-regulates activity phosphorylation Ser326 SARKRSAsADNLTLP 32723157 t lperfetto Our in vitro and cellular analyses supported the mass spectrometry data that implicated serine 326 (S326) as the phospho-acceptor site on CCNY by AMPK. |Mechanistically the S326 phosphorylation by AMPK promotes the interaction of CCNY with CDK16, which in turn autophosphorylates S336, which serves as a marker for active CCNY-CDK16 SIGNOR-273011 0.2 NFKB1 protein P19838 UNIPROT THBD protein P07204 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17211835 f miannu Blocking the transcriptional activation of NF-kappaB prevented the TNFalpha-induced downregulation of TM. SIGNOR-254811 0.2 SIK3 protein Q9Y2K2 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates activity phosphorylation Ser171 SALNRTSsDSALHTS 9606 BTO:0000567 16306228 t lperfetto We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression SIGNOR-249172 0.62 GRM1 protein Q13255 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 t miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. SIGNOR-264077 0.386 CAMK2D protein Q13557 UNIPROT CACNB2 protein Q08289 UNIPROT up-regulates phosphorylation Thr554 RGLSRQEtFDSETQE 9606 20194790 t The effect has been demonstrated using Q08289-2 gcesareni We recently identified ca(v)1.2 beta(2a) residues critical for camkii phosphorylation (thr 498) beta(2a) thr 498 and leu 493 are required for ca(v)1.2 activation by camkii in native cells. SIGNOR-164067 0.399 Carebastine chemical CID:65820 PUBCHEM HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 t Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells SIGNOR-257783 0.8 ropinirole chemical CHEBI:8888 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation -1 9057850 t miannu Compound (R)-6, the most active compound, showed dopaminergic D2 activity and also had affinity for the 5HT1A serotonin receptor subtype. Its dopaminergic activity was more selective for the D2 receptor subtype (259-fold D2/D3 selectivity) than propylamine analogue (R)-2 (14-fold selectivity) or other dopaminergic standards (e.g., pergolide, lisuride, bromocriptine, and ropinirole, 1.0-, 3.4-, 8.7-, and 2.6-fold selectivities, respectively) SIGNOR-258600 0.8 KAT2B protein Q92831 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates binding 9606 BTO:0000887 10944526 t gcesareni Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo SIGNOR-81059 0.632 TBK1 protein Q9UHD2 UNIPROT STAT6 protein P42226 UNIPROT up-regulates phosphorylation Tyr641 MGKDGRGyVPATIKM 9606 22000020 t gcesareni We now show that stat6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger sting (also named mita/eris) to recruit stat6 to the endoplasmic reticulum, leading to stat6 phosphorylation on ser(407) by tbk1 and tyr(641), independent of jaks. Phosphorylated stat6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing. SIGNOR-176775 0.66 LCK protein P06239 UNIPROT CD3E protein P07766 UNIPROT up-regulates activity phosphorylation Tyr188 PPVPNPDyEPIRKGQ 9534 BTO:0004055 11855827 t Tyrosine Phosphorylation of CD8- Chimeras by Lck and ZAP-70 in COS Cells. both Y170F and Y181F chimeric proteins could be efficiently phosphorylated by Lck in vivo. phosphorylation of Y170 and Y181 within CD3- –ITAM provides to CD3- the potential to interact with multiple downstream effectors and signaling pathways. SIGNOR-251368 0.678 CDK1 protein P06493 UNIPROT NINL protein Q9Y2I6 UNIPROT up-regulates activity phosphorylation Ser185 NRHSPSWsPDGRRRQ 9606 20890132 t miannu In this study, we show that Nlp can be phosphorylated by cell cycle protein kinase Cdc2/cyclin B1. The phosphorylation sites of Nlp are mapped at Ser185 and Ser589. Interestingly, the Cdc2/cyclin B1 phosphorylation site Ser185 of Nlp is required for its recognition by PLK1, which enable Nlp depart from centrosomes to allow the establishment of a mitotic scaffold at the onset of mitosis . SIGNOR-259830 0.398 PRKCZ protein Q05513 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 18250273 t llicata We conclude that pkc-zeta phosphorylates lkb1 at ser428, resulting in lkb1 nuclear export and hence ampk activation. SIGNOR-160681 0.326 PTPRG protein P23470 UNIPROT DOK2 protein O60496 UNIPROT up-regulates activity dephosphorylation Tyr139 CMEENELySSAVTVG -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254698 0.2 MRPL40 protein Q9NQ50 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262356 0.714 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser645 RPASVPPsPSLSRHS -1 6772446 t Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-. SIGNOR-253006 0.673 RPS6KA3 protein P51812 UNIPROT TINF2 protein Q9BSI4 UNIPROT unknown phosphorylation Ser330 ASTGKSKsPCQTLGG 9606 23977114 t lperfetto Phosphorylation of serines 295 and 330 appeared to be mediated, at least in part, by the mitotic kinase rsk2. The consequence of tin2 phosphorylation during mitosis remains to be determined SIGNOR-202536 0.35 RET protein P07949 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by destabilization phosphorylation Thr114 TMPDDLLtTLDDTCD 9606 BTO:0002181 25795775 t miannu We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA.  SIGNOR-276449 0.2 PCM1 protein Q15154 UNIPROT NEK2 protein P51955 UNIPROT up-regulates relocalization 9606 15659651 t miannu Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1 SIGNOR-133337 0.4 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT unknown phosphorylation Tyr706 RDVYSTDyYRVGGHT 10090 BTO:0000944 10533983 t miannu TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. SIGNOR-250206 0.2 PPARG protein P37231 UNIPROT GLS protein O94925 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005871 33754076 f Luana Furthermore, the protein level of the rate-limiting enzyme GLS1 but not GLUD1, GOT1, or GPT2 was consistently reduced by PPARγ agonists SIGNOR-268043 0.249 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1644 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273092 0.745 CSNK2A2 protein P19784 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates activity phosphorylation Ser422 IACDEEFsDSEDEGE 9606 BTO:0000567 12082111 t llicata HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2. SIGNOR-251002 0.398 CDK1 protein P06493 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Ser562 LGTDSDSsPQKSSRD 9606 BTO:0000567 31981797 t miannu CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines. SIGNOR-276831 0.412 STAT5A protein P42229 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15003515 f Flt3 Mutation Activates p21WAF1/CIP1 Gene Expression Through the Action of STAT5. Co-transfection of p21 promoter-luciferase constructs with Flt3-ITD plasmid into K562 and BaF3 cells results in the induction of p21 promoter activity and a -692/-684 STAT site is important for the induction. STAT5a binds specifically to this element and Flt3-ITD enhances the protein binding to this site. SIGNOR-261518 0.329 HACD1 protein B0YJ81 UNIPROT FASN protein P49327 UNIPROT up-regulates activity chemical activation 9606 18554506 t Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases, SIGNOR-267760 0.2 DPYSL2 protein Q16555 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000938 25040932 f lperfetto In the non-phosphorylated state, CRMP2 binding to tubulin induces the promotion of tubulin polymerisation leading to dendrite outgrowth while SIGNOR-264841 0.7 N-[(2S)-1-[[(2S)-1-[[3-[4-(Aminomethyl)piperidine-1-carbonyl]phenyl]methylamino]-3-methyl-1-oxopentan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]-1,2-oxazole-5-carboxamide chemical CID:49843508 PUBCHEM F2RL1 protein P55085 UNIPROT down-regulates activity chemical inhibition 9606 20873792 t Simone Vumbaca Agonist GB110 (19, EC50 0.28 μM) selectively induced PAR2-, but not PAR1-, mediated intracellular Ca2+ release in HT29 human colorectal carcinoma cells. SIGNOR-261125 0.8 APOBEC3F protein Q8IUX4 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 f lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). SIGNOR-261327 0.7 SMARCD2 protein Q92925 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270693 0.755 SMDT1 protein Q9H4I9 UNIPROT MCU_MICU3_variant complex SIGNOR-C501 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270870 0.613 PICALM protein Q13492 UNIPROT CLTC protein Q00610 UNIPROT up-regulates binding 9606 16491119 t miannu Calm interacts with the clathrin heavy chain through its c-terminal third and with phophoinositides through its ap180 n-terminal homology (anth) domain, promoting assembly of clathrin triskelia into clathrin cagesin vitro SIGNOR-144683 0.739 HTR1F protein P30939 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256816 0.426 CAMK2A protein Q9UQM7 UNIPROT PDC protein P20941 UNIPROT unknown phosphorylation Ser54 KEILRQMsSPQSRNG 11331285 t llicata In this study, we report that Pd was rapidly phosphorylated by Ca(2+)/calmodulin-dependent kinase II, resulting in 100-fold greater inhibition of Gbetagamma binding than cAMP-dependent protein kinase phosphorylation. Furthermore, Pd phosphorylation by Ca(2+)/calmodulin-dependent kinase II at Ser-54 and Ser-73 led to binding of the phosphoserine-binding protein 14-3-3. SIGNOR-250636 0.312 KDM6B protein O15054 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22378047 f lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249564 0.7 PRKAA1 protein Q13131 UNIPROT ZNF692 protein Q9BU19 UNIPROT down-regulates phosphorylation Ser470 VAAHRSKsHPALLLA 9606 SIGNOR-C15 17097062 t gcesareni Arebp is phosphorylated at ser(470) by ampk. Phosphorylation reduces the dna-binding activity of arebp. SIGNOR-150590 0.2 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRA1A protein P35348 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258458 0.8 LPAR1 protein Q92633 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256839 0.496 PRKCB protein P05771 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser185 SAYVGRLsARPKLKA -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276023 0.2 ING1 protein Q9UK53 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 14522900 f miannu  In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity. SIGNOR-254480 0.2 RASSF1 protein Q9NS23 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 22683405 t Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage gcesareni Rassf1a and mst1 co-exist as a complex localizing at microtubules throughout the cell cycle, of which the rassf1a mst1 interaction is stimulatory to the mst1 kinase activity. SIGNOR-197744 0.802 PSME3 protein P61289 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR up-regulates activity binding 35932807 t lperfetto While PA28alpha beta is responsible for promoting peptidase activity of proteasome to facilitate MHC-I antigen processing, but unable to promote protein degradation, PA28gamma is well-known to not only promote peptidase activity but also proteolytic activity of proteasome. SIGNOR-275869 0.629 PTEN protein P60484 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 11875759 t lperfetto PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT. SIGNOR-228145 0.8 SNRPG protein P62308 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270659 0.721 PTPN11 protein Q06124 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity dephosphorylation Tyr570 VRREVGDyGQLHETE 9606 30108215 t miannu Consistently, JAK2/STAT3 signaling was enhanced by overexpression of SHP2   with decreased levels of pJAK2   and increased levels of pJAK2   and pSTAT3  , while it was found suppressed by overexpression of SHP2   (Fig.\u00a06b).|We demonstrate that SHP2 can dephosphorylate JAK2 at Y570 to promote TGF\u03b2-dependent activation of JAK2 and its downstream mediator STAT3 (Supplementary Fig.\u00a04a). SIGNOR-277037 0.786 PPP2R5B protein Q15173 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Thr308 KDGATMKtFCGTPEY 9606 16495456 t gcesareni Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt. SIGNOR-144808 0.647 SYK protein P43405 UNIPROT HCLS1 protein P14317 UNIPROT up-regulates phosphorylation Tyr378 EPEPENDyEDVEEMD 9606 9104825 t llicata Here, we show that bcr-associated tyrosine kinases lyn and syk synergistically phosphorylate hs1, and that tyr-378 and tyr-397 of hs1 are the critical residues for its bcr-induced phosphorylation. once the two tyrosine residues are both phosphorylated, processive phosphorylation of hs1 by lyn and the other src family kinases would take place, producing hyperphosphorylated form of hs1. Finally, it is this hyperphosphorylated form of hs1 that translocates to the nucleus and activates b cell apoptosis. SIGNOR-47338 0.653 CAK complex complex SIGNOR-C456 SIGNOR CDK2 protein P24941 UNIPROT up-regulates activity phosphorylation Thr160 GVPVRTYtHEVVTLW -1 10085115 t llicata Phosphorylation of monomeric human CDK2 by CAK1 is more efficient than phosphorylation of the binary CDK2-cyclin A complex. Phosphorylated CDK2 exhibits histone H1 kinase activity corresponding to approximately 0.3% of that observed with the fully activated phosphorylated CDK2-cyclin A complex. Fluorescence measurements have shown that Thr160 phosphorylation increases the affinity of CDK2 for both histone substrate and ATP and decreases its affinity for ADP. SIGNOR-269330 0.611 SMURF1 protein Q9HCE7 UNIPROT CALCOCO1 protein Q9P1Z2 UNIPROT unknown ubiquitination -1 20804422 t miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. SIGNOR-272688 0.2 2',2'-difluoro-2'-deoxyuridine chemical CHEBI:83486 ChEBI TYMS protein P04818 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0003207 25562513 t miannu 2',2'-Difluoro-2'-deoxycytidine (dFdC, gemcitabine) is a cytidine analogue active against several solid tumor types, such as ovarian, pancreatic and non-small cell lung cancer. The compound has a complex mechanism of action. Because of the structural similarity of one metabolite of dFdC, dFdUMP, with the natural substrate for thymidylate synthase (TS) dUMP, we investigated whether dFdC and its deamination product 2',2'-difluoro-2'-deoxyuridine (dFdU) would inhibit TS. This study was performed using two solid tumor cell lines: the human ovarian carcinoma cell line A2780 and its dFdC-resistant variant AG6000. The specific TS inhibitor Raltitrexed (RTX) was included as a positive control. Using the in situ TS activity assay measuring the intracellular conversion of [5-(3)H]-2'-deoxyuridine or [5-(3)H]-2'-deoxycytidine to dTMP and tritiated water, it was observed that dFdC and dFdU inhibited TS. SIGNOR-259351 0.8 BMP4 protein P12644 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates activity binding 9606 8006002 t fspada BMP-4 bound to ALK-3 and ALK-6 efficiently SIGNOR-236932 0.847 DUSP4 protein Q13115 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Thr202 HDHTGFLtEYVATRW 10116 7535768 t Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK SIGNOR-248715 0.697 ADCY3 protein O60266 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 t miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. SIGNOR-265000 0.8 NOTCH1 protein P46531 UNIPROT CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001454 10933396 f gcesareni Activation of notch1 signaling in dp thymocytes and thymoma cell lines results in the upregulation of cd25 and cd44 expression SIGNOR-80333 0.427 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr306 PSNHHAVyDVPPSVS 9606 12601080 t lperfetto Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas. SIGNOR-98496 0.259 CSNK1G1 protein Q9HCP0 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser325 SSNASTIsGRLSPIM -1 11980723 t llicata Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR SIGNOR-250821 0.473 BCL3 protein P20749 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates binding 9606 16713561 t gcesareni The cyclin d1 elevation is caused not by increased p65/p50 action but rather by increased nuclear activity of bcl-3-associated nf-kappab p50 and p52. SIGNOR-146768 0.554 KMT2C protein Q8NEZ4 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30385408 t miannu MLL3 enhances the transcription of PD-L1 and regulates anti-tumor immunity. We found that MLL3 bound to the enhancer of PD-L1. SIGNOR-260040 0.2 Frizzled proteinfamily SIGNOR-PF11 SIGNOR GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni Wnt7a binding to fzd7 activates pi3k through a g protein alpha s- dependent mechanism. SIGNOR-253125 0.2 PKC proteinfamily SIGNOR-PF53 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser189 DEEFREPsTGKTCLP -1 19661060 t miannu Activation of the TRPV4 ion channel is enhanced by phosphorylation. TRPV4 is phosphorylated in response to activation of PKC. We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-276230 0.2 BMP2 protein P12643 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 SIGNOR-C29 7791754 t fspada Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor. SIGNOR-33425 0.793 CDC34 protein P49427 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR up-regulates activity binding 9606 25425648 t miannu The ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase SCF are capable of building polyubiquitin chains onto protein substrates both rapidly and processively; this may be explained at least in part by the atypically fast rate of Cdc34 and SCF association.Here, we use protein cross-linking to demonstrate that the Cdc34-SCF interaction occurs in multiple conformations, where several residues from the Cdc34 acidic tail are capable of contacting a broad region of the SCF basic canyon. Similar patterns of cross-linking are also observed between Cdc34 and the Cul1 paralog Cul2, implicating the same mechanism for the Cdc34-SCF interaction in other members of the cullin-RING ubiquitin ligases. SIGNOR-277331 0.766 TLR8 protein Q9NR97 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity 9606 BTO:0004721;BTO:0002900 15661881 f miannu TLR8 functions in monocytes and myeloid DC and is involved in the production of proinflammatory cytokines such as TNF-α. SIGNOR-259249 0.459 SCF-FBW7 complex SIGNOR-C135 SIGNOR GATA2 protein P23769 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 25670854 t miannu GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation. Substitution of threonine 176 to alanine in GATA2 inhibited binding with Fbw7, and the ubiquitylation and degradation of GATA2 by Fbw7 was suppressed. The CPD kinase, which mediates the phosphorylation of Thr(176), was cyclin B-cyclin-dependent kinase 1 (CDK1).  SIGNOR-276885 0.343 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 12213813 t lperfetto In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E SIGNOR-262991 0.658 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 t lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. SIGNOR-109547 0.786 PDPK1 protein O15530 UNIPROT OXTR protein P30559 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 35104164 t lperfetto We found that Ser261 in OXTR was phosphorylated by protein kinase D1 (PKD1).|In HEK293A cells, the PKD1-mediated phosphorylation of OXTR promoted its binding to Gq protein and, in turn, OXTR-mediated phosphorylation of PKD1, indicating a positive feedback loop. SIGNOR-268577 0.2 TNF protein P01375 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18647246 f miannu NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B. SIGNOR-252409 0.36 PIM1 protein P11309 UNIPROT HBP1 protein O60381 UNIPROT up-regulates activity phosphorylation Ser380 MARQRRAsLSCGGPG 9606 BTO:0002181 28348080 t miannu  Pim-1 binds to and phosphorylates the transcription factor high mobility group box transcription factor 1 (HBP1), activating it. SIGNOR-277347 0.2 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273095 0.745 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr458 CKTPSSNtLDDYMSC -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276222 0.388 CSNK2A1 protein P68400 UNIPROT ATXN3 protein P54252 UNIPROT up-regulates activity phosphorylation Ser347 LQAAVTMsLETVRND 9606 BTO:0000007 19542537 t miannu Here we show that protein casein kinase 2 (CK2)-dependent phosphorylation controls the nuclear localization, aggregation and stability of ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3). The main phosphorylation of ATXN3 in vivo thus occurred at serine residues within the three conserved UIMs. SIGNOR-276224 0.2 PRKCA protein P17252 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276024 0.2 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH2 protein P19022 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265842 0.8 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Thr180 GSKGQKTtQNRYSFY -1 23444369 t miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. SIGNOR-273485 0.27 FYN protein P06241 UNIPROT FCGR2C protein P31995 UNIPROT up-regulates activity phosphorylation Tyr294 YETADGGyMTLNPRA -1 8756631 t miannu Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation SIGNOR-262677 0.2 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 12213813 t lperfetto In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E SIGNOR-262993 0.658 AKT1 protein P31749 UNIPROT METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 3627513 t lperfetto The trna methylase mettl1 is phosphorylated and inactivated by pkb and rsk in vitro and in cells SIGNOR-24994 0.341 STK38L protein Q9Y2H1 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity phosphorylation Ser495 GVLARKMsLGGGRPY 10090 35670107 t STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination SIGNOR-270348 0.2 NF90-NF45 complex SIGNOR-C443 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 21969602 f miannu The NF90/NF45 complex participates in DNA break repair via nonhomologous end joining SIGNOR-268490 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PML protein P29590 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 15093545 t The effect has been demonstrated using P29590-4 gcesareni Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis. SIGNOR-270153 0.2 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Ser516 ASSQCIAsPNFGTVS -1 12361598 t miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) SIGNOR-265963 0.53 FANCL protein Q9NW38 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000567 SIGNOR-C300 17396147 t lperfetto Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263250 0.897 CSNK2A1 protein P68400 UNIPROT PPP1R8 protein Q12972 UNIPROT up-regulates activity phosphorylation Ser204 KNSRVTFsEDDEIIN -1 9407077 t llicata Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2. SIGNOR-250930 0.483 DUSP3 protein P51452 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9606 BTO:0002552 21262974 t We found that EGF receptor (EGFR) was a direct substrate of VHR and that overexpression of VHR down-regulated EGFR phosphorylation, particularly at Tyr-992 residue. Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR. SIGNOR-248532 0.364 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity phosphorylation Thr402 TEAAQLStKSRAEGR 9606 BTO:0000007;BTO:0000567 12805220 t lperfetto It was shown that thr336 and thr366 are the major autophosphorylation sites of mouse lkb1 (sapkota et al., 2002). We confirmed these data on the human orthologues thr336 and thr363. Moreover, the enhanced stoichiometry of lkb1 autophosphorylation by strad enabled us to identify two novel sites: thr185 and thr402. We show that increased lkb1 autophosphorylation of all sites correlates with the activation of its catalytic activity. SIGNOR-101852 0.2 BORA protein Q6PGQ7 UNIPROT AURKA protein O14965 UNIPROT up-regulates binding 9606 16890155 t gcesareni Both drosophila and human bora can bind to aurora-a and activate the kinase in vitro. SIGNOR-148661 0.717 YAP1 protein P46937 UNIPROT TEAD2 protein Q15562 UNIPROT up-regulates binding 9606 23431053 t Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4. gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14. SIGNOR-201468 0.879 AMER1 protein Q5JTC6 UNIPROT WT1 protein P19544 UNIPROT up-regulates binding 9606 19416806 t miannu Wtx binds wt1, a zinc-finger transcription factor that is inactivated in wilms tumor. / the ability of wtx to enhance wt1-mediated transactivation suggests a physiologically significant interaction between these 2 tumor suppressors. SIGNOR-185644 0.449 PAK3 protein O75914 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser150 TLRRVRIsADAMMQA 9606 BTO:0000887 15769444 t lperfetto In vitro addition of pak3 to skinned rat cardiac fibres increased myofilament ca2+ sensitivity with no change in maximal ca2+-activated force [67]. These effects were associated with pak3-induced phosphorylation of myofilament proteins, including ctni which was phosphorylated at a novel site, ser149, located in the region forming a ca2+-sensitive interaction with the n-terminal regulatory domain of tnc. SIGNOR-134593 0.2 GPR34 protein Q9UPC5 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256831 0.2 SLC24A2 protein Q9UI40 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264399 0.8 KMT2A protein Q03164 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 22303254 f Polycomb group (PcG) and Trithorax group (TrxG) proteins are epigenetic regulators that control gene expression through modulating chromatin structure and addition of posttranslational modifications (PTMs) on histones SIGNOR-268626 0.7 MAPK9 protein P45984 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 11896587 t llicata These findings strongly suggest that jnks are the major direct signaling mediators of uvb-induced p53 phosphorylation at serine 20. furthermore, phosphorylation of p53 at serine 20 by uvb-activated jnks and uvb-induced p53-dependent transcriptional activity were suppressed in jnk1 or jnk2 knockout (jnk1(-/-) or jnk2(-/-)) cells. SIGNOR-115835 0.737 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.748 TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser465 SPSVRCSsMS 9534 BTO:0001538 9346908 t lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-_ (TGF-_) type I receptor, T_RI. Phosphorylation sites on smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. In this report, we show that T_RI specifically phosphorylates Smad2 on serines 465 and 467.These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. SIGNOR-236107 0.818 SNIP1 protein Q8TAD8 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates binding 9606 SIGNOR-C6 10887155 t gcesareni In this study, we characterize a novel nuclear protein, termed snip1 its principal mechanism of action appears to be through transcription by binding to cbp/p300 and interfering with the ability of these coactivators to interact with smad4 SIGNOR-78984 0.573 CRYAA protein P02489 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 22982024 f miannu Aberrant protein interactions can lead to aggregation and insolubilization, such as occurs during cataract formation. Deamidation, a prevalent age-related modification in the lens of the eye, decreases stability of the major lens proteins, crystallins. Deamidation did not disrupt specific αA/βB2 interactions but favored aggregation before complex formation with αA. We conclude that deamidation contributes to cataract formation through destabilization of crystallins before they can be rescued by α-crystallin. SIGNOR-252156 0.7 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1651 SPTSPSYsPTSPSYS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248782 0.442 PRKCQ protein Q04759 UNIPROT ICAM3 protein P32942 UNIPROT up-regulates activity phosphorylation Ser518 REHQRSGsYHVREES 9606 BTO:0000661 9268366 t lperfetto Ser489 was a phosphorylation site in vitro for recombinant protein kinase Ctheta. Finally, treatment of Jurkat cells with chelerythrine chloride, a protein kinase C inhibitor, prevented ICAM-3-triggered spreading.  SIGNOR-248979 0.34 Guanabenz chemical CHEBI:5553 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258909 0.8 NME2 protein P22392 UNIPROT NME2 protein P22392 UNIPROT up-regulates activity phosphorylation Ser44 AMKFLRAsEEHLKQH 9606 BTO:0000093 8245015 t miannu An acid-stable (nonhistidine) phosphorylation was identified on autophosphorylated purified recombinant Nm23 proteins and [32P]orthophosphate-labeled human breast carcinoma and murine melanoma Nm23. Phosphoamino acid analysis identified serine as the acid-stable phosphorylation and serine 44 as the major site of phosphorylation. The biological relevance of the novel phosphorylation identified herein is suggested by the direct correlation of in vivo Nm23 acid-stable phosphorylation levels, but not Nm23 NDPK activity, with suppression of tumor metastatic potential among control and nm23-1 transfected murine melanoma cells. SIGNOR-250201 0.2 STAT5A protein P42229 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000574 9168989 f Regulation miannu We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin. SIGNOR-251784 0.246 CASP3 protein P42574 UNIPROT GSN protein P06396 UNIPROT down-regulates activity cleavage Asp403 WRDPDQTdGLGLSYL 9606 9671712 t miannu We showed that human gelsolin was cleaved during Fas-mediated apoptosis in vivo and that the caspase-3 cleavage site of human gelsolin was at D352 of DQTD352G. gelsolin seems to have dual functions, i.e., it both prevents and, once cleaved, induces cell death. SIGNOR-256357 0.624 NPTX1 protein Q15818 UNIPROT BCL2 protein P10415 UNIPROT down-regulates quantity 9606 BTO:0004168;BTO:0003227 31113871 f lperfetto We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control SIGNOR-260412 0.2 MAPK8 protein P45983 UNIPROT JUNB protein P17275 UNIPROT up-regulates activity phosphorylation Thr104 GVITTTPtPPGQYFY 10090 9889198 t miannu JunB-control of IL-4 expression is mediated by the phosphorylation of JunB at Thr102 and -104 by JNK MAP kinase. The synergy between c-Maf and JunB can be attributed to cooperative DNA binding, which is facilitated by JunB phosphorylation. SIGNOR-250121 0.72 SYK protein P43405 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Tyr658 SDFEGFSyVNPQFVH 9606 BTO:0000830 12881490 t lperfetto We present evidence that Tyr-662 and Tyr-658 of PKCbetaI and PKCalpha, respectively, are phosphorylated by Syk in the membrane compartment of FcepsilonRI-stimulated mast cells. These phosphorylations require prior PKC autophosphorylation of the adjacent serine residues (Ser-661 and Ser-657, respectively) and generate a binding site for the SH2 domain of the adaptor protein Grb-2. SIGNOR-246581 0.4 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 22021368 f apalma Once genetic mutation of AML1 occurs in hematopoietic cells, aberrant activation of NF-κB signaling exerts antiapoptotic and proliferation-promoting effects via activation of BCL-XL or JUNB. SIGNOR-256654 0.7 NEK7 protein Q8TDX7 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity phosphorylation Ser1220 NLHSSHSsGLMDKSS 9606 BTO:0000565 28630147 t miannu Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C). SIGNOR-266418 0.379 SUN1 protein O94901 UNIPROT SPDYA protein Q5MJ70 UNIPROT up-regulates activity binding 9606 BTO:0000007 SIGNOR-C305 33015044 t lperfetto In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | Taken together, we speculate that speedy A is likely capable of interacting with both telomeres and the LINC complex and thus might function as the missing linkage between telomeres and the LINC complex during prophase I, stabilizing the telomere–NE connection SIGNOR-263301 0.249 LCK protein P06239 UNIPROT SH2D2A protein Q9NP31 UNIPROT up-regulates activity phosphorylation Tyr305 GEAPSNIyVEVEDEG 9606 18541536 t miannu Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition. SIGNOR-262890 0.596 MEF2C protein Q06413 UNIPROT MECP2 protein P51608 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20513142 f Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression|In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5. SIGNOR-254025 0.353 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000661 7961936 t We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. SIGNOR-251395 0.602 SLC2A3 protein P11169 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity relocalization 9606 23506862 t miannu The SLC2A3 gene encoding GLUT3 was first cloned from a human fetal skeletal muscle cell line (Kayano et al., 1988). It shares ~64% sequence identity with SLC2A1. GLUT3 has a higher apparent affinity (lower Km) and a higher maximum turnover number for glucose than the other Class 1 GLUT proteins, and its principal physiological substrate is clearly D-glucose SIGNOR-267459 0.8 SRC protein P12931 UNIPROT ARAF protein P10398 UNIPROT up-regulates activity phosphorylation Tyr302 GYRDSGYyWEVPPSE 9534 9020159 t lperfetto A-raf behaves like raf-1, being weakly activated by oncogenic ras more strongly activated by oncogenic src, and these signals synergize to give maximal activation SIGNOR-236459 0.467 TH protein P07101 UNIPROT tyrosine smallmolecule CHEBI:18186 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH). SIGNOR-263990 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser226 IDENCLLsPLAGEDD -1 9199329 t lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. SIGNOR-93554 0.2 HOXD12 protein P35452 UNIPROT MAFF protein Q9ULX9 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221884 0.389 CDX2 protein Q99626 UNIPROT UGT1A8 protein Q9HAW9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000195 15044625 t Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter. SIGNOR-253969 0.263 BCL2 protein P10415 UNIPROT HTRA2 protein O43464 UNIPROT down-regulates 9606 14585074 f amattioni Bcl- confers protection to apoptosis by interference with bax/bak-mediated release of the pro-apoptotic mitochodrial factors smac/diablo and htra2/omi SIGNOR-89189 0.254 ADAM17 protein P78536 UNIPROT EGFR protein P00533 UNIPROT up-regulates 9606 20626350 f gcesareni Such phosphorylation is required for tace mediated ectodomain shedding of tgfalfa family ligands, which results in the activation of egfr and cell proliferation. SIGNOR-166568 0.471 CEP250 protein Q9BV73 UNIPROT Centrosome_separation phenotype SIGNOR-PH177 SIGNOR down-regulates 9606 BTO:0000567 24035387 t miannu C-Nap1 and rootletin have been previously reported to be the important centrosome linker components involved in centrosome cohesion. SIGNOR-273705 0.7 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr292 DTLNSDGyTPEPARI 9606 BTO:0000782;BTO:0000776 8756661 t lperfetto The data further support a model in which ZAP-70 is first phosphorylated by Lck at Tyr-493 to upregulate the catalytic activity of ZAP-70. This in turn per- mits additional phosphorylation of ZAP-70 mediated, in part, by autophosphorylation at sites including Tyr-292 and -492 SIGNOR-43324 0.2 RYK protein P34925 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 17035295 t gcesareni Interaction between ryk and fz has been reported, suggesting that the two proteins may form a multi-receptor complex signalling through the canonical pathway SIGNOR-150010 0.699 NTNG1 protein Q9Y2I2 UNIPROT LRRC4C protein Q9HCJ2 UNIPROT up-regulates activity binding 9606 BTO:0000938 19467332 t miannu The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively. SIGNOR-264047 0.767 sorafenib chemical CHEBI:50924 ChEBI BRAF protein P15056 UNIPROT down-regulates chemical inhibition 9606 BTO:0000848 21654832 t gcesareni Inhibition of map kinases mek, jnk, p38, and multikinases (braf, craf, vegfp by sorafenib) in wm-115 and m14 human melanoma cell lines led to either significant reduction or complete inhibition of the plk-1 protein expression. SIGNOR-174036 0.8 PTPRK protein Q15262 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 25612622 t miannu In this study, we investigated whether receptor-type tyrosine protein phosphatase kappa (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3 specifying motif, negatively regulates STAT3 activation in NKTCL.|Phosphatase substrate-trapping mutant assays demonstrated the binding of PTPRK to STAT3, and phosphatase assays showed that PTPRK directly dephosphorylated phospho-STAT3(Tyr705). SIGNOR-277060 0.382 GGCX protein P38435 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 31539109 f miannu GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05). SIGNOR-261232 0.2 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr973 RLGNGVLyASVNPEY -1 8940173 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-247193 0.564 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates activity phosphorylation Tyr594 TYVDPHTyEDPNQAV 9606 18387945 t lperfetto The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells. SIGNOR-178173 0.2 EGFR protein P00533 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity phosphorylation Tyr153 GEEGQSIyKLTDFGA 9606 27287717 t miannu EGFRL858R/T790M phosphorylates IKBKE at tyrosine residues. While wild-type and mutant EGFR directly interacted with IKBKE, only mutant EGFR phosphorylated IKBKE on residues Y153 and Y179.  SIGNOR-277242 0.26 Noncanonical PRC1 complex SIGNOR-C151 SIGNOR UHRF1 protein Q96T88 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000011 25533466 f miannu We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis. SIGNOR-252250 0.271 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates activity phosphorylation Tyr360 YSPRSFEdCGGGYTP 9606 9467953 t Manara Thus, we propose that the phosphorylation of tyrosine 328 and 360 within Bcr by Bcr-Abl will drastically interfere with Bcr's kinase role in either signal transduction or some other cellular mechanism. SIGNOR-260828 0.2 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates binding 9606 23630338 t PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. gcesareni C1a domain is critical for the dag-induced activation of pkcalfa.Furthermore, calcium and diacylglycerol activate protein kinase c, resulting in the phosphorylation of a large variety of substrates. SIGNOR-202007 0.8 CEBPG protein P53567 UNIPROT SFTPD protein P35247 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11912209 t Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D. SIGNOR-254058 0.2 SNCAIP protein Q9Y6H5 UNIPROT Lewy_body_formation phenotype SIGNOR-PH56 SIGNOR up-regulates 9606 19224863 f miannu Synphilin-1 interacts in vivo with α-synuclein, and their coexpression promotes the formation of Lewy body-like inclusions SIGNOR-272596 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 12588998 t lperfetto Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro SIGNOR-265319 0.2 AMPK complex SIGNOR-C15 SIGNOR SLC12A2 protein P55011 UNIPROT down-regulates activity phosphorylation Ser77 RPLGPTPsQSRFQVD -1 24702155 t miannu  AMPK was found to directly phosphorylate a recombinant human-NKCC1 N-terminal fragment (1-293) with the phosphorylated site identified as S77. Mutation of Serine 77 to Alanine partially prevented the inhibitory effect of A-769662 on NKCC1 activity. In conclusion, AMPK can act to reduce NKCC1-mediated transport.  SIGNOR-276630 0.2 PDGFRB protein P09619 UNIPROT NCK1 protein P16333 UNIPROT up-regulates binding 9606 10026169 t esanto Growth factor binding to receptor protein tyrosine kinases (r-ptks)1 induces their dimerization and trans-phosphorylation, creating docking sites for proteins containing sh2 and ptb protein interaction domains. Nck binds to the pdgf and egfr receptors (figure 3c). SIGNOR-64737 0.623 P2RY13 protein Q9BPV8 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257231 0.2 ATP1A3 protein P13637 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 22797008 t miannu The sodium/potassium transporting ATPase subunit alpha-3 (AT1A3; syn.: sodium pump subunit alpha-3; E.C. 3.6.3.9; UniProtKB ID: Q6PIC6) belongs to the cation transport ATPase (P-type) 3.A.3 family catalyzing hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action generates the electrochemical gradient of sodium and potassium ions thus providing energy for active transport of various nutrients. Three sodium/potassium transporting ATPase isoforms are expressed in the brain but AT1A3 is detectable in neurons exclusively. SIGNOR-265792 0.8 CARS1 protein P49589 UNIPROT tRNA(Cys) smallmolecule CHEBI:29167 ChEBI down-regulates quantity chemical modification 9606 11347887 t miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. SIGNOR-270469 0.8 indometacin chemical CHEBI:49662 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 9057869 t miannu Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). SIGNOR-258606 0.8 AURKB protein Q96GD4 UNIPROT H1-4 protein P10412 UNIPROT up-regulates quantity by stabilization phosphorylation Ser27 VKKKARKsAGAAKRK 9606 BTO:0000093 21511733 t miannu we showed previously that phosphorylation of S27 in human histone H1.4 (H1.4S27-P), prevents binding of heterochromatin protein 1 (HP1) family members (officially known as chromobox protein homologs) to the neighboring dimethylated K26. Here, we present the first functional characterization of H1.4S27-P in vivo and in vitro. We show that H1.4S27 phosphorylation is cell-cycle-regulated and its levels peak on metaphase chromosomes. We identify further Aurora B as the kinase phosphorylating H1.4S27. SIGNOR-262658 0.2 MIPOL1 protein Q8TD10 UNIPROT RELA protein Q04206 UNIPROT down-regulates activity 9606 31609475 f miannu In our results, we also showed that re-expression of MIPOL1 is associated with suppression phosphorylation of AKT and p65, a subunit of NF-ҡB. This suggests that MIPOL1 may inhibit invasion by suppression of phosphorylation of AKT and p65 to further inhibit the expression of MMP-9 SIGNOR-261136 0.2 PTGER2 protein P43116 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256756 0.41 GRIK1 protein P39086 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity relocalization 9606 BTO:0002609 12393813 t lperfetto Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine SIGNOR-268272 0.8 EXT1 protein Q16394 UNIPROT EXT1/EXT2 complex SIGNOR-C51 SIGNOR form complex binding 9606 11518722 t miannu Biochemical analysis shows that ext1 and ext2 are type ii transmembrane glycoproteins and form a golgi-localized hetero-oligomeric complex that catalyzes the polymerization of hs SIGNOR-109938 0.564 PP1 proteinfamily SIGNOR-PF54 SIGNOR MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12840032 t lperfetto P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases SIGNOR-264665 0.2 PIH1D2 protein Q8WWB5 UNIPROT R2SP co-chaperone complex SIGNOR-C517 SIGNOR form complex binding 9606 29844425 t miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. SIGNOR-270937 0.479 ENDOG protein Q14249 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 21210296 f gcesareni Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c, (diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore. SIGNOR-170972 0.357 HK2 protein P52789 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266446 0.8 ABL1 protein P00519 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Tyr449 IIQHCSNySTQELLR 9606 BTO:0000793 29022905 t miannu In this study, we found that c-Abl phosphorylated Drp1 at tyrosine 266, 368 and 449 in vitro and in vivo, which augmented the GTPase activity of Drp1 and promoted Drp1-mediated mitochondrial fragmentation. SIGNOR-277327 0.263 PRKD1 protein Q15139 UNIPROT KIDINS220 protein Q9ULH0 UNIPROT unknown phosphorylation Ser918 RTITRQMsFDLTKLL 10116 10998417 t lperfetto Our results provide the first physiological substrate for PKD and indicate that Kidins220 is phosphorylated by PKD at serine 919 in vivo. SIGNOR-249052 0.533 MAPK1 protein P28482 UNIPROT NEFH protein P12036 UNIPROT up-regulates activity phosphorylation Ser518 SPEKEAKsPVKEEAK 10116 BTO:0000938 9592082 t lperfetto The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation. SIGNOR-249423 0.375 RET protein P07949 UNIPROT RET protein P07949 UNIPROT unknown phosphorylation Tyr687 AQAFPVSySSSGARR 9534 BTO:0004055 8621380 t lperfetto Based on the phosphopeptide maps, we can identify six tyrosine phosphorylation sites in RET: Tyr-687, Tyr-826, Tyr-1062, Tyr-1096, Tyr-1015, and Tyr-1029. By comparing the peptide map of each mutant to the wild-type receptor, we can tentatively assign each tryptic peptide containing phosphorylation sites to individual P-labeled spots on the two-dimensional map  SIGNOR-248941 0.2 PRKCD protein Q05655 UNIPROT PTPRA protein P18433 UNIPROT up-regulates activity phosphorylation Ser189 QAGSHSNsFRLSNGR 9606 BTO:0000017 11676480 t lperfetto In this process, PTPalpha Ser-180 and Ser-204 phosphorylation is critical for the induction of phosphatase activity, which is required for dephosphorylation of pp60(c-src). Taken together, we demonstrate the physical and functional association between PI 3-kinase, PKCdelta and PTPalpha in a signaling complex that mediates the antitumor activity of the somatostatin analogue TT-232. SIGNOR-249113 0.334 PTPRG protein P23470 UNIPROT BTK protein Q06187 UNIPROT down-regulates activity dephosphorylation Tyr223 LKKVVALyDYMPMNA -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254694 0.265 MYOD1 protein P15172 UNIPROT SMARCD3 protein Q6STE5 UNIPROT up-regulates binding 9606 15870273 t lperfetto This suggests a novel mechanism by which myod interacts with the promoter indirectly via pbx-1 and recruits chromatin-remodeling enzymes, which then facilitate the binding of myod and other regulators. Demonstration of physical interactions between brg1 and myod and brg1 and pbx support this conclusion SIGNOR-136130 0.554 APH1A protein Q96BI3 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR form complex binding 9606 25610395 t lperfetto -Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2) SIGNOR-209714 0.958 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser645 RPASVPPsPSLSRHS -1 2117608 t llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. SIGNOR-250879 0.335 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser253 SVEFEVEsLDSEDYS 9606 20708156 t gcesareni Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination SIGNOR-167513 0.352 SLBP protein Q14493 UNIPROT H2BS1 protein P57053 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265384 0.2 GRIK5 protein Q16478 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264946 0.8 MYO9B protein Q13459 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260511 0.543 RIF1 protein Q5UIP0 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR down-regulates 9606 15342490 f miannu This result would suggest that Rif1 acts in an intra-S-phase checkpoint pathway that is separate from the Nbs1 pathway. Although a role for human Rif1 at telomeres is not excluded, our data show that the primary function of Rif1 is in the DNA-damage response. Rif1 localizes to DSBs in an ATM- and 53BP1-dependent manner and functions in the intra-S-phase checkpoint that serves to slow down DNA synthesis when DNA damage has occurred. SIGNOR-259060 0.7 neostigmine chemical CHEBI:7514 ChEBI ACHE protein P22303 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001239 17888667 t Luana AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE. SIGNOR-257758 0.8 PPP2CA protein P67775 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation Thr507 FGESRAStFCGTPDY 9606 11959144 t PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex SIGNOR-248637 0.385 FOXO4 protein P98177 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 f lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-236554 0.382 ketoprofen chemical CHEBI:6128 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001061 18667313 t Luana Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2.  SIGNOR-257811 0.8 HSD17B2 protein P37059 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification -1 8099587 t Luana 17 beta-HSD type 2 was capable of catalyzing the interconversion of testosterone and androstenedione as well as estradiol and estrone.  SIGNOR-269764 0.8 MAP2K1 protein Q02750 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 12270934 t inferred from 70% of family members lbriganti Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. SIGNOR-269909 0.2 KDM5C protein P41229 UNIPROT BDNF protein P23560 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 31691806 f miannu The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. SIGNOR-264315 0.278 KCNS3 protein Q9BQ31 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 10029 BTO:0000246 10484328 t miannu We describe the cloning and characterization of the first human members, hKv9.1 and hKv9.3, of the electrically silent delayed-rectifying-like K+ channel subfamily. SIGNOR-269448 0.8 DNAJC19 protein Q96DA6 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 t lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. SIGNOR-267694 0.669 CSNK2A1 protein P68400 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates phosphorylation Ser466 VIDLTIDsSSDEEEE 9606 19217413 t llicata Ck2 phosphorylates serine residues adjacent to the sim of pias1 these findings show that the phosphosim module mediates binding to free sumo and sumo conjugates in a phosphorylation-dependent mode, with ck2 being the critical kinase involvedin this process. SIGNOR-184039 0.338 HDAC1 protein Q13547 UNIPROT GAD1 protein Q99259 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 f miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. SIGNOR-254576 0.287 FYN protein P06241 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr323 DEPVADPyDQSFESR 10090 BTO:0000782 15735648 t miannu Lck, Fyn, and Zap70 activate p38 even in the absence of Tyr182 phosphorylation.p38 is a substrate for Fyn, Lck and Zap70.Thus, T cell Src family kinases and Zap70 activate p38 by phosphorylating Tyr323. SIGNOR-276031 0.467 NOD2 protein Q9HC29 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 BTO:0000567 19898471 f miannu Autophagy is emerging as a crucial defense mechanism against bacteria, but the host intracellular sensors responsible for inducing autophagy in response to bacterial infection remain unknown. Here we demonstrated that the intracellular sensors Nod1 and Nod2 are critical for the autophagic response to invasive bacteria. SIGNOR-252403 0.7 PCNA protein P12004 UNIPROT NCR2 protein O95944 UNIPROT down-regulates activity binding 9606 22021614 t miannu NK cells play an important role in the early immune response to cancer. The NKp44 activating receptor is the only natural cytotoxicity receptor that is expressed exclusively by primate NK cells, yet its cellular ligands remain largely unknown. SIGNOR-260043 0.312 MAPK1 protein P28482 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation Ser432 NQNVLLMsPPASDSG 9606 14988395 t lperfetto Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity. SIGNOR-123041 0.365 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Ser436 LRTKNGTsGKDSATT 9606 BTO:0000567 34198826 t miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. SIGNOR-276666 0.252 CSNK2A1 protein P68400 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates activity phosphorylation Thr80 MARKMKDtDSEEEIR -1 26675311 t miannu Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third. SIGNOR-266356 0.432 PRKCA protein P17252 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser643 CFTPKGSsLKIEERA 9606 BTO:0000887;BTO:0001260 8182108 t gcesareni Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase. SIGNOR-36788 0.364 MYCN protein P04198 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000661 21261500 f miannu HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5. SIGNOR-254214 0.305 IL1B protein P01584 UNIPROT ENPP1 protein P22413 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 7479785 f miannu Interleukin 1 beta suppresses transforming growth factor-induced inorganic pyrophosphate (PPi) production and expression of the PPi-generating enzyme PC-1 in human chondrocytes. IL-1 beta may be an important regulator of mineralization in chondrocytes by inhibiting TGF beta-induced PPi production and PC-1 expression. SIGNOR-252199 0.2 JNK proteinfamily SIGNOR-PF15 SIGNOR IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser312 TESITATsPASMVGG 10116 BTO:0004428 12510059 t lperfetto Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylationOne of the specific Ser phosphorylation sites in IRS-1 that has been proposed to negatively modulate the insulin signal is Ser312 (numbered according to the human sequence). Prior studies have demonstrated that IRS-1 associates with and is phosphorylated by JNK in vitro on Ser312 SIGNOR-235777 0.2 MAPK3 protein P27361 UNIPROT IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation Ser325 PGAPPPAsKPKLWSL -1 15133517 t miannu To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291–356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target. SIGNOR-263061 0.2 PRKAA1 protein Q13131 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17609368 f gcesareni Several in vivo studies using aicar to activate ampk chronically determined that mitochondrial enzymes [e.g., cytochrome c, uncoupling protein 3 (ucp-3)] and proteins involved in glucose uptake (glut4)are increased at the transcriptional level in skeletal muscle. SIGNOR-156786 0.306 ATF2 protein P15336 UNIPROT YTHDC2 protein Q9H6S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001911 24269672 t lperfetto Collectively, these data show that YTHDC2 plays an important role in tumor cells growth and activation/recruitment of c-Jun and ATF-2 to the YTHDC2 promoter is necessary for the transcription of YTHDC2, and that HDAC activity is required for the efficient expression of YTHDC2 in both of hepatocyte and HCC cells. SIGNOR-269001 0.278 IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 19609947 t lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. SIGNOR-216365 0.813 IKBKE protein Q14164 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates phosphorylation Ser471 GTQREGVsSLDSSSL 9606 10893229 t gcesareni In response to a viral infection, phosphorylated on ser-477 and ser-479 by tbk1 and ikbke1. Phosphorylation, and subsequent activation is inhibited by vaccinia virus protein e3. SIGNOR-79139 0.675 RAB38 protein P57729 UNIPROT AP-3 complex complex SIGNOR-C247 SIGNOR up-regulates activity relocalization 9606 23247405 t lperfetto Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. SIGNOR-260699 0.303 MMP13 protein P45452 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272381 0.7 IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 BTO:0000551 20966354 t lperfetto Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin. SIGNOR-256170 0.759 MMP27 protein Q9H306 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272371 0.7 SMARCE1 protein Q969G3 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270731 0.812 IFNG protein P01579 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity 10090 23667107 f Early inhibition of IL-1β expression by IFN-γ is mediated by impaired binding of NF-κB to the IL-1β promoter but is independent of nitric oxide. SIGNOR-255937 0.441 PLK1 protein P53350 UNIPROT CEP192 protein Q8TEP8 UNIPROT up-regulates activity phosphorylation Thr44 GLPVAVStLARDRSS 9606 BTO:0000007 26012549 t miannu In the presence of AurA binding, Plk1 preferentially phosphorylates and interacts with the T44 motif of Cep192 through the “self-priming and binding” mechanism SIGNOR-266405 0.592 SNTB1 protein Q13884 UNIPROT MAPK12 protein P53778 UNIPROT down-regulates binding 10090 BTO:0002314 BTO:0001103 29681515 t apalma Basal localization of the p38g/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through b1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38g/b1-syntrophin interactions are abrogated, resulting in enhanced Carm1 phosphorylation SIGNOR-255901 0.376 AKT1 protein P31749 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro SIGNOR-98285 0.2 DEPTOR protein Q8TB45 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR down-regulates activity binding 9606 BTO:0000007 19446321 t DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival SIGNOR-251659 0.714 DOK1 protein Q99704 UNIPROT A6/b4 integrin complex SIGNOR-C174 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257690 0.2 CUDC-101 chemical CID:24756910 PUBCHEM HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20143778 t miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. SIGNOR-262263 0.8 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR PTPRC protein P08575 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001271 22740448 f miannu Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a).CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced. SIGNOR-255686 0.2 CDK2 protein P24941 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates phosphorylation Ser224 APSVSHVsPRKNPSV 9606 17638878 t lperfetto Atrip is a cdk2 substrate, and cdk2-dependent phosphorylation of s224 regulates the ability of atr-atrip to promote cell cycle arrest in response to dna damage./ One possibility is s224 phosphorylation creates a binding site for another protein involved in the g2-m checkpoint response SIGNOR-156928 0.562 MRGPRX1 protein Q96LB2 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256786 0.2 LRFN5 protein Q96NI6 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu The SALM (synaptic adhesion-like molecule) family of adhesion molecules, also known as Lrfn, belongs to the superfamily of leucine-rich repeat (LRR)-containing adhesion molecules. Proteins of the SALM family, which includes five known members (SALMs 1-5), have been implicated in the regulation of neurite outgrowth and branching, and synapse formation and maturation.SALM3 and SALM5, but not other SALMs, possess synaptogenic activity, inducing presynaptic differentiation in contacting axons. SIGNOR-264093 0.7 ZDHHC5 protein Q9C0B5 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates activity palmitoylation 9606 BTO:0000526 28775165 t Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y. These events contributed to the development of glioma by promoting the self-renewal capacity and tumorigenicity of glioma stem-like cells, by altering the palmitoylation and phosphorylation status of the tumor suppressor EZH2. SIGNOR-261144 0.2 DAMPS stimulus SIGNOR-ST18 SIGNOR AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR up-regulates 9606 25720354 f scontino APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. SIGNOR-267858 0.7 YARS1 protein P54577 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 16429158 t miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr SIGNOR-270519 0.8 TULP3 protein O75386 UNIPROT GPR161 protein Q8N6U8 UNIPROT up-regulates activity relocalization 10090 23332756 t Upon knockdown of Tulp3 using siRNA in IMCD3 cells, ciliary localization of Gpr161 was severely reduced SIGNOR-259938 0.592 CLOCK protein O15516 UNIPROT PER3 protein P56645 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253635 0.587 RARA protein P10276 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity binding 9606 15650024 t inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. SIGNOR-267801 0.517 PIK3CB protein P42338 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 21779497 t lperfetto The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2) SIGNOR-175241 0.8 MCHR2 protein Q969V1 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257067 0.41 ACACA protein Q13085 UNIPROT malonyl-CoA smallmolecule CHEBI:15531 ChEBI up-regulates quantity chemical modification 9606 20952656 t miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA SIGNOR-267109 0.8 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexenyl]methyl]-1-piperazinyl]-N-[4-[[(2R)-4-(4-morpholinyl)-1-(phenylthio)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide chemical CHEBI:94128 ChEBI BCL2L1 protein Q07817 UNIPROT down-regulates chemical inhibition 9606 Other t The effect has been demonstrated using Q07817-1 gcesareni SIGNOR-189153 0.8 MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation Thr275 LVDSKAKtRSAGCAA 9606 9312068 t lperfetto Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1 SIGNOR-51211 0.712 AIP protein O00170 UNIPROT ESR1 protein P03372 UNIPROT down-regulates activity transcriptional regulation 9606 BTO:0000093 21984905 t The immunophilin-like protein XAP2 is a negative regulator of estrogen signaling through interaction with estrogen receptor α. SIGNOR-253644 0.296 CSNK2A1 protein P68400 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser172 GDVDVSDsDDEDDNL 9606 18559419 t llicata Here we show that ck2 phosphorylates the transcription initiation factor tif-ia at serines 170 and 172 (ser170/172), and this phosphorylation triggers the release of tif-ia from pol i after transcription initiation. SIGNOR-178943 0.206 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys22 GPRDGLKkERLLDDR 9606 7479976 t gcesareni Here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha. SIGNOR-26577 0.522 HMGA2 protein P52926 UNIPROT SCNN1A protein P37088 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0001003 11390395 f Regulation of expression miannu Expression of endogenous alpha-ENaC gene in salivary Pa-4 cells is suppressed by an ectopic HMGI-C overexpression. SIGNOR-251946 0.2 PTPN6 protein P29350 UNIPROT EGFR protein P00533 UNIPROT down-regulates dephosphorylation Tyr1197 STAENAEyLRVAPQS 9606 9733788 t tpavlidou The sh2-domain ptpase shp-1 binds to and dephosphorylates autophosphorylated egfr and may participate in modulation of egfr signaling in epithelial cells. Reduced shp-1 binding to the egfr y1173f mutant resulted in a reduced receptor dephosphorylation by coexpressed shp-1 and less interference with egf-dependent mitogen-activated protein kinase stimulation. SIGNOR-59965 0.425 PTPN1 protein P18031 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity dephosphorylation 9606 12377785 t miannu PTP1B modulates the association of beta-catenin with N-cadherin through binding to an adjacent and partially overlapping target site.|The nonreceptor tyrosine phosphatase PTP1B associates with the cytoplasmic domain of N-cadherin and may regulate cadherin function through dephosphorylation of beta-catenin.|Thus, interaction of PTP1B with N-cadherin is essential for its association with beta-catenin, stable expression at the cell surface, and consequently, cadherin function. SIGNOR-277121 0.646 CASP3 protein P42574 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity cleavage Asp326 NSEEDEMdSGTMVRA 9534 BTO:0004055 11517310 t lperfetto In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus. SIGNOR-109874 0.601 progesterone smallmolecule CHEBI:17026 ChEBI 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 25855791 t lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively SIGNOR-268631 0.8 FLT3 protein P36888 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15626738 f FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells SIGNOR-261549 0.342 PHLPP2 protein Q6ZVD8 UNIPROT RPS6KB1 protein P23443 UNIPROT down-regulates activity dephosphorylation Thr390 DSKFTRQtPVDSPDD 9606 BTO:0000182 21986499 t gcesareni We show that PHLPP preferentially dephosphorylates the hydrophobic motif T389 site in S6K1 in vitro SIGNOR-248247 0.504 MC4R protein P32245 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257440 0.252 CHL1 protein O00533 UNIPROT ANK2 protein Q01484 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 t miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. SIGNOR-266722 0.418 PRKAA2 protein P54646 UNIPROT ACACB protein O00763 UNIPROT down-regulates activity phosphorylation Ser222 PTMRPSMsGLHLVKR 9606 14613924 t miannu ACCβ(Ser221) is a known target for AMPK in human skeletal muscle SIGNOR-250316 0.638 CDH7 protein Q9ULB5 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265869 0.549 DDIT3 protein P35638 UNIPROT ASNS protein P08243 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 18940792 f miannu C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene. SIGNOR-253837 0.381 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr296 MGYDDLDyGMMSDYG -1 11382764 t lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 SIGNOR-246500 0.92 LYPLA2 protein O95372 UNIPROT GAP43 protein P17677 UNIPROT down-regulates quantity by destabilization deacetylation Cys3 cCMRRTKQ 9606 BTO:0000567 21152083 t miannu Acyl-protein thioesterase 2 catalyzes the deacylation of peripheral membrane-associated GAP-43. In this work, we investigated the deacylation of growth-associated protein-43 (GAP-43), a dually acylated protein at cysteine residues 3 and 4. Thus, the results demonstrate that APT-2 is the protein thioesterase involved in the acylation/deacylation cycle operating in GAP-43 subcellular distribution.we demonstrated that the reduction in the protein level was abrogated when cells were also treated with proteasome inhibitors (chloroquine, MG132 and lactacystin) which strongly suggest that GAP-43 deacylation is an early and necessary step for its later ubiquitination and degradation by the proteasome. In addition, it also suggests that acyl-protein thioesterase levels not only regulate palmitate turnover but also global protein turnover of GAP-43. SIGNOR-266767 0.455 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser155 GRLKRERsMSENAVR 34010649 t lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-275943 0.2 SMARCA2 protein P51531 UNIPROT CERF complex SIGNOR-C340 SIGNOR form complex binding 9606 BTO:0000227 15640247 t miannu Biochemical isolation of CECR2 revealed the presence of this protein as a component of a novel heterodimeric complex termed CECR2-containing remodeling factor (CERF). CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. Together, these data identify a novel chromatin remodeling complex with a critical role in neurulation. SIGNOR-263890 0.394 LPCAT4 protein Q643R3 UNIPROT acyl-CoA(4-) chemical CHEBI:58342 ChEBI down-regulates quantity chemical modification 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272773 0.8 BTF3 protein P20290 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17312387 f In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. SIGNOR-253950 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation -1 15133517 t inferred from 70% family members miannu To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291‚Äì356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target. SIGNOR-270097 0.2 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9606 31422819 t miannu This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267511 0.8 CDON protein Q4KMG0 UNIPROT SPAG9 protein O60271 UNIPROT up-regulates activity binding 9606 BTO:0000222 18678706 t p38 together with Bnip-2 and CDC42 to activate p38alfa/beta activity lperfetto During myoblast differentiation, the promyogenic cell surface receptor cdo binds to the p38alpha/beta pathway scaffold protein jlp and, via jlp, p38alpha/beta itself. SIGNOR-179870 0.477 1,1-dioxo-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3-one chemical CHEBI:93578 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258851 0.8 RELA protein Q04206 UNIPROT COMT protein P21964 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000100 19291302 f Regulation of expression miannu TNFα-dependent COMT downregulation was indeed mediated by the NF-κB pathway. Transient expression of p65, the essential component of NF-κB complexes, or IKKβ, the major positive regulator of NF-κB activition, significantly decreased P2-COMT reporter expression. SIGNOR-251964 0.2 CDK7 protein P50613 UNIPROT CDK11B protein P21127 UNIPROT up-regulates activity phosphorylation Thr595 GSPLKAYtPVVVTLW 9606 BTO:0000567 16327805 t gcesareni We conclude that CDK7 phsphorylates Cdk11, dependent on the conserved Thr219 residue in the CDK11 T loop, and it is therefore likely to be a genuine Cdk11 activating kinase SIGNOR-245871 0.341 MAPK1 protein P28482 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser62 SYTPTPRsPRFIGRR 9606 7901013 t The effect has been demonstrated using P07101-2 gcesareni Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylase in vitro at comparable rates to other proteins thought to be physiological substrates of these protein kinases.The effect on activity of phosphorylating both ser31 and ser40 was not additive. The possible roles of mapkap kinase-1, mapkap kinase-2 and map kinase in the regulation of tyrosine hydroxylase in vivo are discussed. SIGNOR-34674 0.452 EPM2A protein O95278 UNIPROT NHLRC1 protein Q6VVB1 UNIPROT up-regulates activity binding 10116 BTO:0003234 18029386 t miannu Here, we provide evidence indicating that the formation of the laforin–malin complex is positively regulated by AMPK. We show that laforin, but not malin, can interact physically with the catalytic subunit of AMPK and that purified AMPK phosphorylates GST::laforin in vitro. SIGNOR-271729 0.779 HAUS complex complex SIGNOR-C281 SIGNOR NEDD1 protein Q8NHV4 UNIPROT up-regulates activity relocalization 9606 19369198 t lperfetto We further found coprecipitation of HA-tagged NEDD1 [also called GCP-WD, a component of gamma-TuRC (12, 22)] with endogenous hDgt6|A link between augmin and gamma-TuRC is likely critical for these functions, because a gamma-TuRC mutant that attenuates interaction with augmin does not restore function in vivo SIGNOR-262332 0.526 INSR protein P06213 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates activity phosphorylation Tyr362 DPKEDPIyDEPEGLA 10029 BTO:0000246 11551902 t Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398. p62(dok) is a direct substrate for the IR tyrosine kinase and that phosphorylation at Tyr(362) and Tyr(398) plays an essential role for p62(dok) to interact with its effectors and negatively regulate the insulin signaling pathway. SIGNOR-251307 0.543 TP53 protein P04637 UNIPROT TBXAS1 protein P24557 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14586398 f miannu We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. SIGNOR-254086 0.2 STAT3 protein P40763 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 25194572 f lperfetto STAT3 signaling controls satellite cell expansion and skeletal muscle repair SIGNOR-245048 0.7 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR SP1 protein P08047 UNIPROT up-regulates activity binding 9606 BTO:0000552 11013220 t irozzo TGF-β induces the formation and nuclear translocation of a trimeric Smad complex, which in this case is likely to consist of one monomer each of Smad2, Smad3 and Smad4. Smad2 and Smad4 associate directly with Sp1 and co-activate the transcriptional activity of Sp1. SIGNOR-256288 0.585 NOG protein Q13253 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR down-regulates binding 9606 22298955 t Create trimers (2 typeII and 1 typeI) with serine/threonine kinase function lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors.Noggin Inhibits bmpby blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors SIGNOR-217529 0.583 MMP13 protein P45452 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272358 0.7 NFE2L2 protein Q16236 UNIPROT TKT protein P29401 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 f miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). SIGNOR-267356 0.27 dabrafenib chemical CHEBI:75045 ChEBI RAF1 protein P04049 UNIPROT down-regulates activity chemical inhibition -1 24720932 t miannu Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations SIGNOR-259218 0.8 HIF1A protein Q16665 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 8955077 f inferred from family member miannu we characterize hypoxia response elements in the promoters of the ALDA, ENO1, and Ldha genes. Our data establish that functional hypoxia-response elements consist of a pair of contiguous transcription factor binding sites at least one of which contains the core sequence 5'-RCGTG-3' and is recognized by HIF-1. These results provide further evidence that the coordinate transcriptional activation of genes encoding glycolytic enzymes which occurs in hypoxic cells is mediated by HIF-1. SIGNOR-270229 0.343 ADP chemical CHEBI:16761 ChEBI P2RY12 protein Q9H244 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257560 0.8 EEF1A1 protein P68104 UNIPROT Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269517 0.8 D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR CHEK2 protein O96017 UNIPROT up-regulates activity 9606 BTO:0000567 23438602 f lperfetto Interestingly, as with ATM (40, 41), XRCC3-deficient cells exhibited RDS and impaired CHK2 activation|Notably, early activation of CHK2 in S/G2 phase was downstream of XRCC3 recruitment as well as its phosphorylation at the sites of DSBs. NBS1 also has been shown to be involved in the early activation of CHK2 in response to IR (42). It is likely that NBS1-dependent CHK2 phosphorylation is mediated through XRCC3 activation. SIGNOR-263262 0.487 ITGB8 protein P26012 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates 9606 BTO:0000142 11970960 f lperfetto Integrin _v_8-mediated tgf_ activation is also required to regulate neurovascular homeostasis in the adult brain SIGNOR-117386 0.541 HSD17B11 protein Q8NBQ5 UNIPROT testosterone smallmolecule CHEBI:17347 ChEBI up-regulates quantity chemical modification 9606 BTO:0000056 16166196 t lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. SIGNOR-268666 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR TBC1D4 protein O60343 UNIPROT unknown phosphorylation Thr642 QFRRRAHtFSHPPSS 9606 16880201 t llicata 14-3-3 proteins interact with as160 in an insulin- and akt-dependent manner via an akt phosphorylation site, thr-642. SIGNOR-148342 0.2 ADGRG1 protein Q9Y653 UNIPROT ADGRG1 protein Q9Y653 UNIPROT up-regulates activity cleavage 24949629 t Like many other adhesion GPCRs, GPR56 is cleaved via a GPCR autoproteolysis-inducing (GAIN) domain into N- and C-terminal fragments (GPR56N and GPR56C); | We demonstrate that ligand binding releases GPR56N from the membrane-bound GPR56C and triggers the association of GPR56C with lipid rafts and RhoA activation. SIGNOR-253980 0.2 HIF-1 complex complex SIGNOR-C418 SIGNOR SLC2A1 protein P11166 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 t miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. SIGNOR-267450 0.421 PRKCD protein Q05655 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249280 0.354 EIF2AK2 protein P19525 UNIPROT NLRP1 inflammasome complex SIGNOR-C224 SIGNOR up-regulates activity binding 9606 BTO:0000007 22801494 t miannu Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. SIGNOR-263118 0.307 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-119237 0.2 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C3 17510057 t gcesareni In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-154821 0.832 LRP5 protein O75197 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity relocalization 10090 11336703 t amattioni Axin is a protein that interacts with the intracellular domain of LRP-5. LRP-5 active form bind Axin and induce LEF-1 activation by destabilizing Axin and stabilizing beta-catenin. SIGNOR-236997 0.824 ADSS1 protein Q8N142 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267346 0.8 STAT6 protein P42226 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 BTO:0000801 10982806 t lperfetto STAT6 mediates suppression of STAT1 and NF-kB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site SIGNOR-249553 0.426 CSNK2A1 protein P68400 UNIPROT MYF5 protein P13349 UNIPROT up-regulates activity phosphorylation Ser133 NAIRYIEsLQELLRE -1 9461343 t llicata Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity.  SIGNOR-250922 0.312 AKT proteinfamily SIGNOR-PF24 SIGNOR MST1R protein Q04912 UNIPROT up-regulates phosphorylation Ser1394 VRRPRPLsEPPRPT 9606 14505491 t lperfetto Akt/pkb phosphorylates ron ser-1394, thus providing a docking site for 14-3-3based on these results, we propose a mechanism based on msp-ron-dependent phosphorylation and 14-3-3 association, whereby the function of alpha6beta4 switches from a mechanical adhesive device into a signaling component, and might be critically involved in human epidermal wound healing SIGNOR-118053 0.2 CHRM4 protein P08173 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256829 0.377 BDKRB2 protein P30411 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256838 0.376 STAT1 protein P42224 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 16481475 t lperfetto Acetylated stat1 is able to interact with nf-kappab p65. As a consequence, p65 dna binding, nuclear localization, and expression of anti-apoptotic nf-kappab target genes decrease. SIGNOR-217418 0.459 CSNK2A1 protein P68400 UNIPROT HIF1A protein Q16665 UNIPROT unknown phosphorylation Thr796 ESGLPQLtSYDCEVN -1 17382325 t llicata These results implied that only Thr-796 was phosphorylated CK2.  SIGNOR-250891 0.347 FOXA1 protein P55317 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24875621 t miannu FOXA1 directly inhibits AR expression and thus the transcription of its target genes. FOXA1 inhibits AR gene expression in prostate cancer. oss of FOXA1 may lead to androgen-independent AR signaling and thus castration-resistant prostate cancer progression. Indeed, we have recently reported that FOXA1 is downregulated in CRPC SIGNOR-251541 0.757 ABL1 protein P00519 UNIPROT GPX1 protein P07203 UNIPROT up-regulates activity phosphorylation Tyr98 EILNSLKyVRPGGGF 9606 12893824 t lperfetto GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress. SIGNOR-104324 0.471 CD79A protein P11912 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268196 0.641 GABRG2 protein P18507 UNIPROT GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263755 0.624 CSNK1A1L protein Q8N752 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 21606194 t gcesareni Ck1 also phosphorylates lrp6 at the second ser residue in the pppspxs motif ck1_ in the lrp5/e-cadherin/p120-catenin complex temporally coincides with p120-catenin phosphorylation in ser268. moreover, and considering the close similarity between the catalytic domains of ck1_ and ck1_, it is possible that ck1_ is indeed responsible for the phosphorylation at ser1420 and ser1430 in lrp5/6 that negatively affects wnt signaling by still not defined mechanisms SIGNOR-173853 0.257 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219316 0.749 CTDSPL protein O15194 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser206 SSSTYPHsPTSSDPG 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248315 0.477 VRK1 protein Q99986 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 15378002 t flangone Vrk1 phosphorylates c-jun in ser63 and ser73 in vitro...VRK1 Activates c-jun dependent transcription SIGNOR-127069 0.527 SARS1 protein P49591 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. SIGNOR-270802 0.8 nepicastat chemical CHEBI:139334 ChEBI DBH protein P09172 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194625 0.8 NR3C1 protein P04150 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity transcriptional regulation 10116 11069927 f In the liver, glucocorticoids induce a 10-15-fold increase in the rate of transcription of the phosphoenolpyruvate carboxykinase (PEPCK) gene, which encodes a key gluconeogenic enzyme SIGNOR-253056 0.368 MAPK1 protein P28482 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation Thr614 AFRLEPLtPRGVLTV 9606 17311928 t llicata Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1 SIGNOR-153383 0.431 SAR1A protein Q9NR31 UNIPROT SEC24B protein O95487 UNIPROT up-regulates quantity binding SIGNOR-C370 30605680 t lperfetto Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. SIGNOR-265300 0.736 TTK protein P33981 UNIPROT HSPA9 protein P38646 UNIPROT up-regulates phosphorylation Ser65 IDLGTTNsCVAVMEG 9606 17573779 t lperfetto Mortalin binds to mps1, and is phosphorylated by mps1 on thr62 and ser65. The phosphorylated mortalin then super-activates mps1 in a feedback manner. Mps1-associated acceleration of centrosome duplication depends on the presence of mortalin and super-activation by the thr62/ser65 phosphorylated mortalin SIGNOR-156181 0.2 TERF2 protein Q15554 UNIPROT Shelterin complex complex SIGNOR-C306 SIGNOR form complex binding 9606 BTO:0000567 15383534 t lperfetto Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins. SIGNOR-263317 0.801 MECP2 protein P51608 UNIPROT RBFOX1 protein Q9NWB1 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000614 18511691 t Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. SIGNOR-264681 0.283 NOP10 protein Q9NPE3 UNIPROT TERT protein O14746 UNIPROT up-regulates activity binding 18680434 t lperfetto Dyskerin was recently found to be associated with active human telomerase (34), and mutations in dyskerin or NOP10 or deletion of the H/ACA motif of hTERC result in diminished telomerase activity SIGNOR-263331 0.612 ABRAXAS1 protein Q6UWZ7 UNIPROT BRCA1-A complex complex SIGNOR-C296 SIGNOR form complex binding 9606 BTO:0000007 20656690 t lperfetto We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1.  SIGNOR-263214 0.2 RNF168 protein Q8IYW5 UNIPROT H1-2 protein P16403 UNIPROT down-regulates polyubiquitination 9606 BTO:0000815 30517763 t miannu ITCH biochemically antagonized RNF168 and RNF8 in polyubiquitination of histone H1.2 ITCH interacts with and ubiquitinates linker histone H1.2 at K46. ITCH biochemically competes with RNF168 and RNF8 to polyubiquitinate histone H1.2. Both RNF168 and RNF8 elicited higher Ubn levels of K46R-H1.2 compared to WT-H1.2, suggesting that Ubn of H1.2 by both E3 ligases occurs at a site apart from K46. SIGNOR-272927 0.2 MAPK1 protein P28482 UNIPROT RGS19 protein P49795 UNIPROT up-regulates phosphorylation Ser151 EDYVSILsPKEVSLD 9606 15488168 t gcesareni Phosphorylation of gaip by erk2 were abrogated when serine at position 151 in the rgs domain was substituted by an alanine residue using site-directed mutagenesis. Furthermore, the lysosomal-autophagic pathway was not stimulated in s151a-gaip mutant-expressing cells when compared with wild-type gaip-expressing cells. These results demonstrate that the gtpase-activating protein activity of gaip is stimulated by erk2 phosphorylation. SIGNOR-129883 0.487 PTPN1 protein P18031 UNIPROT BCR protein P11274 UNIPROT down-regulates dephosphorylation 9606 9566916 t The effect has been demonstrated using P11274-1 gcesareni These results illustrate selectivity in the effects of ptps in a cellular context and suggest that ptp1b may function as a specific, negative regulator of p210 bcr-abl signalling in vivo. SIGNOR-56818 0.336 CAMK2G protein Q13555 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser641 RRSVKRNsTVDCNGV 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275794 0.274 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR up-regulates 9606 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268587 0.2 CRLS1 protein Q9UJA2 UNIPROT cardiolipin smallmolecule CHEBI:28494 ChEBI up-regulates chemical modification 10090 16678169 t lperfetto The mitochondrial phospholipid cardiolipin is synthesized from cytidinediphosphate-diacylglycerol and phosphatidylglycerol, a process catalyzed by the enzyme cardiolipin synthase. SIGNOR-267028 0.8 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii SIGNOR-203532 0.769 IL10 protein P22301 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 23357618 f miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. SIGNOR-253502 0.2 MAPK1 protein P28482 UNIPROT PRDX6 protein P30041 UNIPROT up-regulates phosphorylation Thr177 TAEKRVAtPVDWKDG 9606 BTO:0000763 19140803 t miannu These results show that the mapks can mediate phosphorylation of prdx6 at thr-177 with a consequent marked increase in its aipla(2) activity. SIGNOR-183379 0.68 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT down-regulates activity phosphorylation Ser23 YLQARKPsDCDSKEL -1 15946941 t miannu  We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA.Phosphorylation of GRK1 and GRK7 by PKA reduces the ability of GRK1 and GRK7 to phosphorylate rhodopsin in vitro. SIGNOR-276036 0.2 MYOG protein P15173 UNIPROT PAX7 protein P23759 UNIPROT down-regulates quantity by destabilization 10090 BTO:0004058 17548510 f Simone Vumbaca Indeed, we observed a reduction in Pax7 protein levels upon ectopic myogenin expression in MM14 myoblasts, even under proliferation conditions SIGNOR-255638 0.504 p38 proteinfamily SIGNOR-PF16 SIGNOR Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 11591790 f The p21 G protein Rho and its targets, Rho-associated coiled-coil forming protein kinases (p160ROCK/ROCK I/ROKβ and Rho kinase/ROCK II/ROKα), play a crucial role in actin cytoskeleton reorganization SIGNOR-254360 0.7 RXRA protein P19793 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 10976919 t inferred from 70% of family members gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr). SIGNOR-269877 0.715 OPHN1 protein O60890 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 BTO:0000938 12932438 f miannu These results based on the immunodetection of the endogenous protein clearly show that OPHN1 colocalizes with F-actin in both neuronal and glial cells and suggest that OPHN-1 interacts with actin. SIGNOR-268400 0.7 ITGB1BP1 protein O14713 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257639 0.756 pictrelisib chemical CHEBI:65326 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 BTO:0000149 21876152 t gcesareni Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed SIGNOR-176298 0.8 PPARGC1A protein Q9UBK2 UNIPROT NRF1 protein Q16656 UNIPROT up-regulates activity 9606 26971449 f lperfetto PGC-1 family transcriptional coactivators enhance the activities of the nuclear respiratory factors NRF1 and NRF2, which induce transactivation of many genes encoding mitochondria-specific proteins involved in respiratory chain, mitochondrial DNA transcription/replication and protein import/assembly SIGNOR-253391 0.698 YAP1 protein P46937 UNIPROT TUBB protein P07437 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 f lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. SIGNOR-276571 0.2 SP1 protein P08047 UNIPROT TBXA2R protein P21731 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000565 19747485 f Collectively, data establish that regulated WT1 followed by sequential Egr1 and Sp1 binding to elements within Prm1 mediate repression and subsequent induction of TPα during differentiation into the megakaryocytic phenotype, shedding significant insights into factors regulating TPα expression therein. SIGNOR-254254 0.2 DLG3 protein Q92796 UNIPROT NMDA receptor_2D complex SIGNOR-C350 SIGNOR up-regulates activity relocalization BTO:0000227 32904533 t lperfetto DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses. SIGNOR-266009 0.633 PLK1 protein P53350 UNIPROT CLIP1 protein P30622 UNIPROT down-regulates activity phosphorylation Ser312 ASLKRSPsASSLSSM -1 24451569 t lperfetto Plk1 phosphorylates CLIP-170 and regulates its binding to microtubules for chromosome alignment|Here, we show that phosphorylation at Ser312 in the third serine-rich region of CLIP-170 is increased during mitosis. Polo-like kinase 1 (Plk1) is responsible for this phosphorylation during the mitotic phase of dividing cells. In vitro analysis using a purified CLIP-170 N-terminal fragment showed that phosphorylation by Plk1 diminishes CLIP-170 binding to the MT ends SIGNOR-264575 0.691 MAPK1 protein P28482 UNIPROT BCL3 protein P20749 UNIPROT up-regulates activity phosphorylation Ser454 PSPAPGGs -1 28689659 t miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  SIGNOR-277361 0.486 HDAC3 protein O15379 UNIPROT FASN protein P49327 UNIPROT up-regulates quantity by stabilization deacetylation 9606 BTO:0000007 27758890 t Overexpression of HA-HDAC3 decreased the acetylation level of endogenous FASN by 35% in HEK293T cells, while the expression of a catalytic inactive mutant HDAC3Y298H (38) failed to reduce FASN acetylation (Fig. 4C). Conversely, HDAC3 knockdown increased the acetylation level of endogenous FASN by >1.5-fold in HEK293T cells SIGNOR-267367 0.2 NADP(3-) smallmolecule CHEBI:58349 ChEBI NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity precursor of 9606 33064660 t miannu Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. SIGNOR-268078 0.8 Norzotepine chemical CID:10041551 PUBCHEM SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 20223878 t Luana These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. SIGNOR-257831 0.8 PKN1 protein Q16512 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF 9606 BTO:0000150 12560069 t lperfetto Furthermore, estrogen induced phosphorylation and perinuclear localization of the cell survival forkhead transcription factor fkhr in the cytoplasm in a pak1-dependent manner. In addition, pak1 directly interacted with fkhr and phosphorylated it. The noticed phosphorylation-dependent exclusion of fkhr from the nucleus impaired the ability of fkhr to activate its target fas ligand promoter containing the fkhr binding motif (fre) in cells treated with estrogen or expressing catalytically active pak1. SIGNOR-97882 0.2 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1665 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273091 0.745 CLOCK protein O15516 UNIPROT CRY1 protein Q16526 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253631 0.943 CASP1 protein P29466 UNIPROT RNF31 protein Q96EP0 UNIPROT down-regulates activity cleavage Asp387 QPPSLVVdSRDAGIC 9606 BTO:0005111 32122970 t miannu We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death. SIGNOR-272193 0.2 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2D3 protein P61077 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271348 0.724 FYN protein P06241 UNIPROT DLG4 protein P78352 UNIPROT up-regulates phosphorylation Tyr523 REDSVLSyETVTQME 9606 BTO:0000938 BTO:0000142 18721130 t llicata Psd-95 is phosphorylated either by purified src/fyn kinases in vitro or by co-expression of constitutively active src/fyn in cos7 cells. psd-95 tyr(523) phosphorylation contributes to the post-ischaemic over-activation of nmda receptors. SIGNOR-180449 0.579 CDK1 protein P06493 UNIPROT EP300 protein Q09472 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1038 STSATQSsPAPGQSK 9606 BTO:0000551 24530506 t miannu In this study, we found that p300 was highly phosphorylated and its level was decreased during mitosis and tumorigenesis. In vitro and in vivo experiments aimed showed that cyclin-dependent kinase 1 (CDK1) and ERK1/2 phosphorylated p300 on Ser1038 and Ser2039. Mutations of Ser1038 and Ser2039 increased p300 protein stability and levels.  SIGNOR-276457 0.413 NF1 protein P21359 UNIPROT ADCY3 protein O60266 UNIPROT up-regulates 9606 24431436 f miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-204034 0.267 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr8 MSSILPFtPPVVKRL 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-66775 0.738 NRL protein P54845 UNIPROT RHO protein P08100 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 f miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. SIGNOR-253819 0.454 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000176 14967450 t inferred from 70% family members lperfetto Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-270103 0.2 SIRT1 protein Q96EB6 UNIPROT NHLH2 protein Q02577 UNIPROT up-regulates activity deacetylation Lys49 EEAEGDGkGGSRAAL 10090 BTO:0000142 22169038 t miannu SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter SIGNOR-254830 0.391 OGA protein O60502 UNIPROT PFKP protein Q01813 UNIPROT up-regulates activity deglycosylation Ser540 VMVPATVsNNVPGSD 9606 26399441 t lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. SIGNOR-267606 0.2 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates activity phosphorylation Ser187 REKRRSTsRQFVDGP 9606 BTO:0000567 14744859 t llicata It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1 SIGNOR-250588 0.771 TFAP4 protein Q01664 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001109 19505873 f miannu AP-4 Mediates E-box-dependent Complex Formation for Transcriptional Repression of HDM2 SIGNOR-226596 0.2 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Thr227 PAPPEGAtPTSPVGH 9606 BTO:0000848 BTO:0001253 20959475 t lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). SIGNOR-168758 0.2 MMP14 protein P50281 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272359 0.7 CNOT9 protein Q92600 UNIPROT GIGYF1 protein O75420 UNIPROT up-regulates activity binding 9606 BTO:0000007 20878056 t miannu Through interaction analysis of RQCD1 with full-length or partial proteins of GIGYF1 and GIGYF2, segments corresponding to 620-665th and 667-712th amino acids were identified as potential interacting regions on GIGYF1 and GIGYF2, respectively, with RQCD1. we found that RQCD1 was required for enhancement of the interaction of Grb10 with GIGYF1 and GIGYF2 SIGNOR-260059 0.2 MAPK3 protein P27361 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21071439 t lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-169534 0.481 IL22 protein Q9GZX6 UNIPROT IL22RA2 protein Q969J5 UNIPROT down-regulates binding 9606 BTO:0000763;BTO:0000149 11390453 t gcesareni We identified a gene encoding a protein of 231 aa, showing 33 and 34% amino acid identity with the extracellular domains of the il-22 receptor and of the il-20r/cytokine receptor family 2-8,the recombinant protein was found to bind il-10-related t cell-derived inducible factor/il-22, and to inhibit the activity of this cytokine on hepatocytes and intestinal epithelial cells. We propose to name this natural cytokine antagonist il-22bp for il-22 binding protein. respectively, but lacking the transmembrane and cytoplasmic domains SIGNOR-86110 0.736 SGI-1776 chemical CID:24795070 PUBCHEM PIM1 protein P11309 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206859 0.8 STUB1 protein Q9UNE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 21454478 t gcesareni In ad-dition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activities of smad1/5 by recruiting smad1/5 from the functional r-/co-smad complex and further pro-moting the ubiquitination and degradation of smad1/5 in a chaperone-independent manner SIGNOR-172993 0.334 LRFN5 protein Q96NI6 UNIPROT PTPRF protein P10586 UNIPROT up-regulates activity binding 9606 BTO:0000938 27225731 t miannu SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1). SIGNOR-264087 0.358 ANKS1B protein Q7Z6G8 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 26356309 t miannu The reversible removal of AIDA-1 from the PSD core under excitatory conditions is similar to the redistribution of another abundant PSD protein, SynGAP. Both SynGAP-alpha1 and AIDA-1 are known to bind PSD-95. SIGNOR-264228 0.462 CSNK2A1 protein P68400 UNIPROT CAST protein P20810 UNIPROT up-regulates activity phosphorylation Ser655 QDPIDALsGDLDSCP 9606 BTO:0002036 29581866 t miannu  We also showed that casein kinase 2, a pro-survival kinase overexpressed in many cancer types, phosphorylated calpastatin at Ser-633. Our results indicate that calpastatin phosphorylation promotes radiation resistance in GBM cells by increasing the activity of calpain proteases, which are known to promote survival and invasion in cancer. SIGNOR-277388 0.2 HUNK protein P57058 UNIPROT ITM2A protein O43736 UNIPROT up-regulates activity phosphorylation Thr35 TVRTQILtGKELRVA 9606 BTO:0000007 31438969 t miannu ITM2A is phosphorylated at T35 and the phosphorylation status of ITM2A contributes to breast cancer proliferation. Moreover, we found that ITM2A was phosphorylated at T35 by HUNK, a serine/threonine kinase significantly correlated with human breast cancer overall survival and HER2-induced mammary tumorigenesis. SIGNOR-273640 0.2 RPS6KA1 protein Q15418 UNIPROT RANBP3 protein Q9H6Z4 UNIPROT up-regulates quantity phosphorylation Ser57 HGTGHPEsAGEHALE 9606 BTO:0000007 18280241 t miannu RSK phosphorylates RanBP3 at Serine 58 residue in vitro and in vivo.RanBP3 phosphorylation increases its affinity towards Ran SIGNOR-276149 0.325 RBBP8 protein Q99708 UNIPROT BRCA1-C complex complex SIGNOR-C299 SIGNOR form complex binding phosphorylation:Ser327 ELPTRVSsPVFGATS 25400280 t lperfetto The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2|The interaction between BRCA1 and CtIP within this complex is mediated by CDK‐dependent phosphorylation of CtIP‐S327 SIGNOR-263220 0.2 LRIG1 protein Q96JA1 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0001253 15282549 t gcesareni We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation. SIGNOR-127298 0.572 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT up-regulates quantity by stabilization phosphorylation Ser282 RNLVYDQsPNRTGGP 9606 BTO:0000007 16682949 t done miannu Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. SIGNOR-274083 0.525 ACSS1 protein Q9NUB1 UNIPROT acetate smallmolecule CHEBI:30089 ChEBI down-regulates quantity chemical modification 10843999 t lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. SIGNOR-271830 0.8 MYOD1 protein P15172 UNIPROT DES protein P17661 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000222 25653159 t lperfetto MyoD and HDAC2 repress myogenic late genes at early times of differentiation.A time course of Ckm, Des and Acta1 gene expression demonstrated that these genes were prematurely expressed when differentiation was driven by myogenin and Mef2D1b (Figure _(Figure6A).6A). Since MyoD is not expressed under these conditions, it cannot bind to these genes; ChIP assays demonstrated that HDAC2 also was not present on the Ckm, Des and Acta1 regulatory sequences under these conditions (Figure _(Figure6B).6B). Therefore the presence of MyoD and HDAC2 prior to gene expression functions to repress late gene expression at early times of differentiation. SIGNOR-241762 0.242 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Thr180 RHADAEMtGYVVTRW 9606 BTO:0000007 10066767 t done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. SIGNOR-273952 0.646 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0000776 17339337 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-153479 0.783 RPS6KA5 protein O75582 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates activity phosphorylation Ser727 RQNPSRCsVSLSNVE 9606 BTO:0000007 10978317 t lperfetto Serine 727 phosphorylation and activation of cytosolic phospholipase A2 by MNK1-related protein kinases. SIGNOR-249051 0.359 SPX protein Q9BT56 UNIPROT GALR2 protein O43603 UNIPROT up-regulates activity binding 9606 BTO:0000007 24517231 t lperfetto Coevolution of the spexin/galanin/kisspeptin family: Spexin activates galanin receptor type II and III. SIGNOR-268574 0.345 paliperidone chemical CHEBI:82978 ChEBI HTR1D protein P28221 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000529 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258562 0.8 IL6 protein P05231 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity binding 9606 BTO:0001271 15895091 t miannu A crystal structure of the ligand-binding domains of gp130 in complex with human interleukin-6 (il-6) and its a-receptor (il-6ralpha) revealed a hexameric architecture in which the gp130 membrane-distal regions were approximately 100 a apart, in contrast to the close apposition seen between short cytokine receptor complexes. SIGNOR-48041 0.864 CDK5 protein Q00535 UNIPROT BAG3 protein O95817 UNIPROT down-regulates quantity by destabilization phosphorylation Ser291 STPLHSPsPIRVHTV 9606 BTO:0002181 31955914 t miannu CDK5-mediated phosphorylation on S297 promotes BAG3 degradation. SIGNOR-277502 0.2 CSNK2A1 protein P68400 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser99 KEEEEGIsQESSEEE -1 2806554 t llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. | After an 80 min incubation with CK-II, both serines were fully phosphorylated to 1 mol/mol and serine-99 to 0.3 mol/mol. SIGNOR-250894 0.336 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000567 12853467 t 14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling. SIGNOR-251485 0.2 NF2 protein P35240 UNIPROT STK3 protein Q13188 UNIPROT up-regulates activity binding 10090 BTO:0003324 27402866 t Hippo pathway Gianni NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart. SIGNOR-261955 0.333 NKX3-1 protein Q99801 UNIPROT ACTG2 protein P63267 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19797053 f miannu These results demonstrate the ability of MYOCD to discriminate among several juxtaposed CArG elements, presumably through its novel partnership with NKX3.1, to optimally transactivate the human ACTG2 promoter. SIGNOR-254619 0.29 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 14645234 t gcesareni Pak1 phosphorylates op18/stathmin specifically at serine 16 and inactivates its catastrophe promoting activity in biochemical and time lapse microscopy microtubule assembly assays. Furthermore, phosphorylation of either serine 16 or 63 is sufficient to inhibit op18/stathmin in vitro. SIGNOR-119483 0.382 MAVS protein Q7Z434 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates relocalization 9606 16406812 t gcesareni Another protein suggested to play a role in caspase-8 translocation to mitochondria is the mitochondrial membrane protein cardif SIGNOR-143572 0.57 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Thr175 HDTSFAKtFVGTPYY 9606 17197699 t gcesareni Enzymatic activity, induced; SIGNOR-151763 0.2 PRKACA protein P17612 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 17419683 t gcesareni In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed in vertebrates, pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation SIGNOR-154273 0.445 Kindlin proteinfamily SIGNOR-PF48 SIGNOR Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259001 0.474 CDK1 protein P06493 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Thr698 KSIQATLtPSAMKSS 9606 SIGNOR-C17 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. SIGNOR-164499 0.462 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248754 0.727 JDP2 protein Q8WYK2 UNIPROT JUN protein P05412 UNIPROT down-regulates activity binding 9606 18671972 t miannu JDP2 dimerizes with other AP-1 proteins such as activating transcription factor-2 (ATF2) and Jun to repress transcription from promoters that contain a cyclic AMP-responsive element (CRE). SIGNOR-226398 0.626 MAPK14 protein Q16539 UNIPROT SMARCD3 protein Q6STE5 UNIPROT up-regulates activity phosphorylation 9606 21902831 t lperfetto P38 phosphorylates the baf60 subunit of the swi-snf chromatin remodelling complex, and p38 recruits this complex to differentiation-specific loci. SIGNOR-176557 0.375 AKT1 protein P31749 UNIPROT NIBAN1 protein Q9BZQ8 UNIPROT unknown phosphorylation Ser602 ASPARRAsAILPGVL 9606 22510990 t llicata We demonstrate here that ultraviolet irradiation induces phosphorylation of niban at s602 by akt, which increases the association of niban with nucleophosmin and disassociation of nucleophosmin from the mdm2 complex. SIGNOR-252530 0.2 AKT1 protein P31749 UNIPROT TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 10090 BTO:0000944 12150915 t lperfetto We have shown thataktregulates the tsc1-tsc2 complex by directly phosphorylating tsc2. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1akt has been shown to directly phosphorylate two sites on tsc2 (s939 and t1462 on the full-length human protein), which are conserved and phosphorylated in drosophila tsc2, and is likely to phosphorylate two or three additional sites (s981 and s1130/s1132). SIGNOR-235628 0.777 CRKL protein P46109 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 9606 BTO:0005029 28723560 t irozzo Here, we identify CRKL as a member of the class of PI3Kβ-interacting proteins. Silencing CRKL expression in PTEN-null human cancer cells leads to a decrease in p110β-dependent PI3K signaling and cell proliferation.In conclusion, our study identified CRKL as an important regulator of PI3K activity in PTEN-deficient tumor cells through its association with p110β/p85. SIGNOR-255821 0.451 ACSL5 protein Q9ULC5 UNIPROT long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI up-regulates quantity chemical modification 9606 24269233 t ACSs catalyze the conversion of FAs to their active form acyl-CoAs. The human genome codes for 26 ACS isozymes, which are classified into six subfamilies based on their substrate specificities toward the chain length of FAs and on sequence similarity SIGNOR-267712 0.8 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1039 HSQLSDLyGKFSFKS -1 11024032 t Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro. SIGNOR-251169 0.759 olanzapine chemical CHEBI:7735 ChEBI HTR1E protein P28566 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258508 0.8 MAPK1 protein P28482 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Thr43 KVTTVVAtPGQGPDR 9606 BTO:0000150;BTO:0000680 16039586 t lperfetto Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin. SIGNOR-138894 0.391 SMAD3 protein P84022 UNIPROT NKX2-1 protein P43699 UNIPROT down-regulates activity binding 9606 BTO:0004299 18003659 t miannu TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. In this study, we found that SMAD3 interacts through its MAD domains, MH1 and MH2 with NKX2.1 and FOXA1 proteins. The sites of interaction on NKX2.1 are located within the NH2 and COOH domains, known to be involved in transactivation function. SIGNOR-254169 0.295 NLGN2 protein Q8NFZ4 UNIPROT NRXN2 protein P58401 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264161 0.823 CSNK2A1 protein P68400 UNIPROT GBF1 protein Q92538 UNIPROT down-regulates quantity by destabilization phosphorylation Ser292 VVSPSTDsGLEFSSQ 9606 BTO:0002181 29898406 t miannu We show that, in mitosis, GBF1 is phosphorylated on Ser292 and Ser297 by casein kinase-2 allowing recognition by the F-box protein βTrCP. GBF1 interaction with βTrCP recruits GBF1 to the SCFβTrCP ubiquitin ligase complex, triggering its degradation. SIGNOR-277397 0.2 CSNK2A1 protein P68400 UNIPROT WAS protein P42768 UNIPROT up-regulates phosphorylation Ser484 RSRAIHSsDEGEDQA 9606 12769847 t gcesareni Here we identify two phosphorylation sites in the vca domain of wasp at serines 483 and 484. S483 and s484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the vca domain for the arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length wasp molecule. SIGNOR-101268 0.361 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH12 protein P55289 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265830 0.8 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252747 0.753 AKT1 protein P31749 UNIPROT BTK protein Q06187 UNIPROT down-regulates quantity by destabilization phosphorylation Thr495 EMRHRFQtQQLLEMC 9606 BTO:0003289 23754751 t miannu The activated serine/threonine kinase Akt/protein kinase B (PKB) phosphorylated Btk on two sites prior to 14-3-3ζ binding. The interaction sites were mapped to phosphoserine pS51 in the pleckstrin homology domain and phosphothreonine pT495 in the kinase domain.  SIGNOR-276465 0.301 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser149 SNSLKKSsAELKKIL 9606 BTO:0000671 12628002 t lperfetto Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149) SIGNOR-99139 0.691 FOXO1 protein Q12778 UNIPROT AGRP protein O00253 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28270795 f miannu Foxo1 (when activated) stimulates the transcription of AgRP and NPY, but suppresses the transcription of POMC; thereby antagonizing the transcriptional action of STAT3 in these hypothalamic subpopulations. SIGNOR-263501 0.45 EGFL7 protein Q9UHF1 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates activity binding 10090 BTO:0002881 19503073 t miannu Here we have identified transmembrane receptors of the Notch family as EGFL7-binding molecules. Secreted EGFL7 binds to a region in Notch involved in ligand-mediated receptor activation, thus acting as an antagonist of Notch signalling. Expression of EGFL7 in neural stem cells (NSCs) in vitro decreased Notch-specific signalling and consequently, reduced proliferation and self-renewal of NSCs. SIGNOR-266860 0.487 ATM protein Q13315 UNIPROT RBBP8 protein Q99708 UNIPROT down-regulates phosphorylation Ser664 IDPGADLsQYKMDVT 9606 BTO:0000150 10910365 t llicata Atm phosphorylates ctip at serine residues 664 and 745 our study suggests another dna damage-response pathway in which the signal is transmitted through phosphorylation of ctip by atm, leading to dissociation of the ctip_ctbp repressor complex from brca1, which in turn, activate transcription of gadd45 SIGNOR-79872 0.822 17beta-estradiol 3-sulfate(1-) smallmolecule CHEBI:136582 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of -1 7779757 t Luana HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM. SIGNOR-269748 0.8 MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 11062067 t lperfetto Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). SIGNOR-83729 0.741 AKT proteinfamily SIGNOR-PF24 SIGNOR ARHGAP22 protein Q7Z5H3 UNIPROT up-regulates activity phosphorylation Ser16 ARRARSKsLVMGEQS 9606 BTO:0000007 21969604 t miannu Akt phosphorylates RhoGAP22 at the 14-3-3 binding site and is required for insulin-stimulated 14-3-3 binding. we have demonstrated that Akt is the kinase responsible for phosphorylation of Ser16 in order to mediate 14-3-3 binding to RhoGAP22. SIGNOR-262613 0.2 CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR TP53 protein P04637 UNIPROT down-regulates activity binding 10090 BTO:0002882 26387755 t Here, we show that p53 activity is inhibited in inv(16)+ AML LSCs via interactions with the CBFβ-SMMHC (CM) fusion protein and histone deacetylase 8 (HDAC8).Altogether, these results indicate that CM fusion protein binds to p53 and impairs acetylation and activation of p53. SIGNOR-255737 0.2 CDC7 protein O00311 UNIPROT PSIP1 protein O75475 UNIPROT up-regulates phosphorylation Ser206 MVKQPCPsESDIITE 9606 BTO:0001271;BTO:0000785 7231784 t llicata We now report identification of the cdc7-activator of s-phase kinase (ask) heterodimer as a novel interactor of ledgf. the kinase phosphorylated ledgf in vitro, with ser-206 being the major target, and ledgf phosphorylated at this residue could be detected during s phase of the cell cycle. Ledgf potently stimulated the enzymatic activity of cdc7-ask, increasing phosphorylation of mcm2 in vitro by more than 10-fold. SIGNOR-25763 0.34 PRKN protein O60260 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 BTO:0000007 11590439 t miannu Here we show that parkin interacts with and ubiquitinates the alpha-synuclein-interacting protein, synphilin-1. Co-expression of alpha-synuclein, synphilin-1 and parkin result in the formation of Lewy-body-like ubiquitin-positive cytosolic inclusions.  SIGNOR-272595 0.2 GSK3B protein P49841 UNIPROT SPI1 protein P17947 UNIPROT down-regulates quantity by destabilization phosphorylation Ser140 EEEGERQsPPLEVSD 9606 BTO:0002181 33188146 t miannu We demonstrate that GSK3β phosphorylates PU.1 at Ser41 and Ser140 leading to its recognition and subsequent ubiquitin-mediated degradation by E3 ubiquitin ligase FBW7. SIGNOR-277542 0.2 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 20551513 t ggiuliani Expression of a constitutively active mutant of MKK6 (MKK6-glu) (39), but not a kinase-inactive mutant of MKK6 (MKK6-K82A) (39), strongly promoted human MSC differentiation to osteoblasts as shown by increased ALP activity and extracellular matrix mineralization (Figure 4E). Furthermore, MKK6-glu‚Äìexpressing osteoblasts were treated with inhibitors of p38, JNK, and MEK (Figure 4F). Only treatment with the p38 inhibitor SB203580 blocked the effects of MKK6-glu. SIGNOR-255780 0.734 AKT3 protein Q9Y243 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue. SIGNOR-186780 0.29 SKI protein P12755 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity binding 9606 BTO:0000848 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-236074 0.814 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 BTO:0001253 9811851 t gcesareni Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms. SIGNOR-61549 0.2 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 18794113 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-180906 0.523 Shelterin complex complex SIGNOR-C306 SIGNOR ATM protein Q13315 UNIPROT down-regulates activity binding 18680434 t lperfetto It is not yet clear how the presence of TRF2 at telomeres averts the activation of the ATM kinase.> In this regard, overexpression of TRF2can dampen the activation of the ATM kinase, even at nontelomeric sites of DNA damage (95). Furthermore, TRF2 can interact with the ATM kinase as well as with the Mre11 complex SIGNOR-263322 0.492 GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263812 0.8 IL2RG protein P31785 UNIPROT JAK3 protein P52333 UNIPROT up-regulates binding 9606 BTO:0000776 18445337 t milica Jak3 is associated with the ?c20,21. Cytokine binding mediates the trans-phosphorylation of receptor associated jak kinases, which in turn phosphorylate tyrosine residues on the receptors themselves. The receptor phosphotyrosines serve as docking sites for sh2 domain proteins including the stat family of transcription factors which are activated by jak-mediated phosphorylation. SIGNOR-178491 0.736 GATA2 protein P23769 UNIPROT GATA1 protein P15976 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12432220 f irozzo Closer examination revealed a cross-regulatory mechanism by which GATA-1 can control the expression of GATA-2 and vice versa, possibly via essential GATA binding sites in their cis-acting elements.In this model, GATA-2 activates GATA-1 gene expression, while GATA-1 represses GATA-2 gene expression. SIGNOR-256056 0.419 GGCX protein P38435 UNIPROT F7 protein P08709 UNIPROT up-regulates activity carboxylation 9606 31226734 t lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. SIGNOR-265919 0.675 GALNT8 protein Q9NY28 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity glycosylation 9606 35220009 t miannu Interestingly, the O-GalNAcylation of EGFR, which is the key factor related to the metastasis cascade, was impacted by GALNT8. Furthermore, our results suggested that the GALNT8-mediated O-GalNAcylation led to the suppression of the EGFR signaling pathway and metastatic potential in breast cancer cells.  SIGNOR-269679 0.2 CBL protein P22681 UNIPROT SYK protein P43405 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 11742985 t miannu Intact tyrosine kinase-binding and RING finger domains of Cbl were found to be essential for Syk ubiquitylation in 293T cells and for in vitro Syk ubiquitylation. Altogether, our results support an essential role for Cbl ubiquitin ligase activity in the negative regulation of Syk, and establish that ubiquitylation provides a mechanism of Cbl-mediated negative regulation of cytoplasmic targets. SIGNOR-272620 0.809 SF3B6 protein Q9Y3B4 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270675 0.595 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GORASP1 protein Q9BQQ3 UNIPROT down-regulates activity phosphorylation Ser274 DPLPGPGsPSHSAPD 10116 18762583 t Giulio Supporting the conclusion that phosphorylation of GRASP65 at Ser277 by ERK is critical for Golgi polarization. We have demonstrated a closely integrated mechanism in which Golgi remodeling by phosphorylation of GRASP65 acts as a negative regulator of Golgi and, surprisingly, centrosome orientation. Our data indicate that ERK phosphorylates GRASP65 in interphase cells, resulting in the loss of GRASP65 oligomerization and causing subsequent Golgi cisternal unstacking. SIGNOR-260605 0.2 DAB2IP protein Q5VWQ8 UNIPROT ZEB1 protein P37275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27858941 f miannu Through inhibition of PI3K–AKT signaling, DAB2IP also represses ZEB1, another CSC determinant. SIGNOR-254772 0.271 OSBPL3 protein Q9H4L5 UNIPROT RRAS protein P10301 UNIPROT down-regulates activity binding 9606 BTO:0000007 18270267 t miannu We show that ORP3 interacts with R-Ras, a small GTPase regulating cell adhesion, spreading and migration. Gene silencing of ORP3 in HEK293 cells results in altered organization of the actin cytoskeleton, impaired cell-cell adhesion, enhanced cell spreading and an increase of beta1 integrin activity--effects similar to those of constitutively active R-Ras(38V). SIGNOR-277221 0.414 AKT1 protein P31749 UNIPROT JAG1 protein P78504 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 38402584 f miannu Jagged1 is upregulated by Akt upon activation by R-Ras. All three Akt isoforms influence Jagged1 expression in ECs, but Akt3 is the most prominent Akt isoform in this role, despite its low expression level compared with Akt1. Jagged1 then activates Notch to upregulate Hey1, Hes1, p21, p53, and Unc5b in adjacent cells.  SIGNOR-277222 0.419 TCF4 protein P15884 UNIPROT SOX9 protein P48436 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15240568 f The β-catenin–TCF4 complex activity is required for SOX9 expression. SIGNOR-253323 0.401 PYGB protein P11216 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity chemical modification 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267952 0.8 AURKB protein Q96GD4 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates phosphorylation Thr232 APSLRRKtMCGTLDY 9606 14722118 t lperfetto We report here that human aurora-b is phosphorylated at thr-232 through interaction with the inner centromere protein (incenp) in vivo. The phosphorylation of thr-232 occurs by means of an autophosphorylation mechanism, which is indispensable for the aurora-b kinase activity. SIGNOR-121340 0.2 GNAI3 protein P08754 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR down-regulates activity binding 9606 19703466 t miannu Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma) SIGNOR-267851 0.578 ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity relocalization 9606 20515759 t lperfetto Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor. SIGNOR-59145 0.856 NR3C1 protein P04150 UNIPROT PER1 protein O15534 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19805059 t miannu GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription SIGNOR-268050 0.271 L-isoprenaline chemical CHEBI:6257 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257458 0.8 SMAD3 protein P84022 UNIPROT FOXA1 protein P55317 UNIPROT down-regulates activity binding 9606 18003659 t miannu TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. In this study, we found that SMAD3 interacts through its MAD domains, MH1 and MH2 with NKX2.1 and FOXA1 proteins. The sites of interaction on NKX2.1 are located within the NH2 and COOH domains, known to be involved in transactivation function. SIGNOR-254168 0.337 CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 9267021 t Cytochrome C released from mitochondria lperfetto Once released from mitochondria, cytochrome c binds to Apaf-1, which may trigger the activation of caspase-3 in the presence of dATP. SIGNOR-50585 0.785 LIN7C protein Q9NUP9 UNIPROT AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR form complex binding 9606 24366813 t lperfetto To gain a more detailed view on the organization of this cell polarity network linked to yap1 we included several proteins of the cell junction complex (amot, mpp5, lin7a), SIGNOR-203491 0.669 HIF1A protein Q16665 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 16517405 t miannu Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. SIGNOR-267444 0.482 UVB radiation stimulus SIGNOR-ST17 SIGNOR EDN1 protein P05305 UNIPROT up-regulates 9606 9767234 f miannu UVB can stimulate the synthesis of IL-1, TNF-a and ET-1, and other cytokines by keratinocytes. SIGNOR-252383 0.7 pentazocine chemical CHEBI:7982 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9262330 t miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. SIGNOR-258659 0.8 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr381 EIEACQVyFTYDPYS -1 10214954 t Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510. SIGNOR-251375 0.629 NFATC1 protein O95644 UNIPROT GPC6 protein Q9Y625 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21871017 t miannu NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype. SIGNOR-264022 0.253 MEF2A protein Q02078 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7739551 t lperfetto Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. SIGNOR-238709 0.572 DNMT3A protein Q9Y6K1 UNIPROT HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24280869 f miannu HOXA9 is significantly upregulated in both categories of DNMT3A modifications and this has been associated with poor prognosis in AML before (Figure 3d). In fact, almost the entire HOXA and HOXB cluster were significantly upregulated in AML samples with either epimutation or mutation in DNMT3A. SIGNOR-256128 0.345 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Tyr182 ADAEMTGyVVTRWYR 9606 BTO:0000007 10066767 t done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. SIGNOR-273951 0.646 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 t miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. SIGNOR-264926 0.8 NCKAP1 protein Q9Y2A7 UNIPROT NHS protein Q6T4R5 UNIPROT up-regulates activity binding 9606 20332100 t miannu We show that the WHD of NHS interacts with the Abi family of proteins, HSPC300, Nap1 and Sra1, and is important for the localization of NHS to the leading edge. SIGNOR-253576 0.2 enalapril chemical CHEBI:4784 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition 10116 7527095 t miannu The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively. However, comparison of ACE inhibitory activities of the diacid forms of trandolapril and enalapril, i.e., trandolaprilat and enalaprilat, measured in vitro on various tissues, showed that trandolaprilat was only three- to fivefold more active than enalaprilat. SIGNOR-258428 0.8 TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 10090 BTO:0002572;BTO:0000801 21232017 t miannu TRADD and RIP1 contain a C‐terminal death domain which mediates binding to the death domain of TNFR1. Upon association with ligated TNFR1, TRADD further recruits the adapter protein TRAF2 via its N‐terminal TRAF‐binding domain SIGNOR-245029 0.798 TTC5 protein Q8N0Z6 UNIPROT JMY protein Q8N9B5 UNIPROT up-regulates activity binding 9606 BTO:0001938 15448695 t miannu DNA damage activates ATM kinase which then phosphorylates Strap at Ser 203 (red circles). Phosphorylated Strap is stabilized and undergoes nuclear accumulation where it assembles into a co-activator complex, which includes p300 and cofactors such as JMY SIGNOR-262647 0.511 MYO9B protein Q13459 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260509 0.765 RELA protein Q04206 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9733516 f lperfetto Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2 SIGNOR-59960 0.516 PRKCG protein P05129 UNIPROT EIF4E protein P06730 UNIPROT unknown phosphorylation Ser209 DTATKSGsTTKNRFV 10090 8662663 t lperfetto Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins. SIGNOR-248947 0.312 ponatinib chemical CHEBI:78543 ChEBI FGFR4 protein P22455 UNIPROT down-regulates activity chemical inhibition 9606 23468082 t miannu Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family. SIGNOR-259280 0.8 SMURF1 protein Q9HCE7 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 17317136 t gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. SIGNOR-153402 0.542 DMPK protein Q09013 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 10090 12809504 t llicata Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha.  SIGNOR-236982 0.293 SRC protein P12931 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates phosphorylation Tyr130 VLDVLKFyDSNTVKQ 9606 12215529 t llicata Pak2 became tyrosine phosphorylated in its n-terminal regulatory domain, where y130 was identified as the major phosphoacceptor site. Tyrosine phosphorylation-mediated superactivation of pak2 could be induced by overexpression of different src kinases or by inhibiting cellular tyrosine phosphatases with pervanadate and could be blocked by the src kinase inhibitor pp1 or by mutating the y130 residue. SIGNOR-92460 0.544 MAP3K7 protein O43318 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser177 AKELDQGsLCTSFVG 9606 SIGNOR-C14 11460167 t lperfetto Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta. SIGNOR-109490 0.746 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Tyr440 GAYREHPyGRY 9606 BTO:0000567 16179349 t lperfetto We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal. |Tyrosine 440 was identified as a principal modulator of Sam68 localization and this site was phosphorylated in response to EGF treatment in human breast tumor cell lines. SIGNOR-249294 0.738 Immunoglobulin delta heavy chain protein P0DOX3 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR form complex binding 9606 BTO:0000776 20176268 t scontino Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes. SIGNOR-268199 0.2 Nalmefene chemical CHEBI:7457 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258811 0.8 WICH complex SIGNOR-C449 SIGNOR RNA Polymerase III complex SIGNOR-C389 SIGNOR up-regulates activity binding 9606 16603771 t miannu We show here that the WICH complex (WSTF-SNF2h) interacts with several nuclear proteins as follows: Sf3b155/SAP155, RNA helicase II/Gualpha, Myb-binding protein 1a, CSB, the proto-oncogene Dek, and nuclear myosin 1 in a large 3-MDa assembly, B-WICH, during active transcription. Our results show that a WSTF-SNF2h assembly is involved in RNA polymerase III transcription, and we suggest that WSTF-SNF2h-NM1 forms a platform in transcription while providing chromatin remodeling. SIGNOR-268829 0.396 Angiotensin 1-7 protein P01019-PRO_0000420660 UNIPROT Alamandine chemical CID:44192273 PUBCHEM up-regulates activity catalytic activity -1 24389733 t Luana Newly discovered peptide, alamandine, have been identified. Alamandine is generated by catalysis of Ang A via ACE2 or directly from Ang-(1–7). SIGNOR-262307 0.8 HDAC5 protein Q9UQL6 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates deacetylation 9606 16613856 t gcesareni Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation SIGNOR-145983 0.47 TRIP11 protein Q15643 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 9256431 t miannu Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity. SIGNOR-50348 0.395 Compound A [PMID:15866883] chemical CID:51529932 PUBCHEM LTB4R2 protein Q9NPC1 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257535 0.8 BAD protein Q92934 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 7834748 t lperfetto Bad binds more strongly to Bcl-x, than Bcl-2 in mammalian cells, and it reversed the death repressor activity of Bcl-x,, but not that of Bcl-2. When Bad dimerized with Bcl-x,, Bax was displaced and apoptosis was restored. SIGNOR-249617 0.842 ESR1 protein P03372 UNIPROT AP1 complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 18247370 t miannu The primary conclusion of the results reported here is that ERα and c‐jun, c‐fos and ATF‐2, but not Fra‐2 AP‐1 factors interact “in vivo” with specific estrogen‐responsive regulatory sequences and AP‐1 cis‐elements within the F promoter of the human ERα gene in osteoblast‐like SaOS‐2 cells. SIGNOR-263656 0.71 P2RY6 protein Q15077 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256804 0.2 P4HA2 protein O15460 UNIPROT Collagen proteinfamily SIGNOR-PF103 SIGNOR up-regulates quantity by stabilization hydroxylation 9606 9211872 t miannu Prolyl 4-hydroxylase (proline hydroxylase, EC 1.14.11.2) catalyzes the hydroxylation of proline in -Xaa-Pro-Gly- triplets in collagens and other proteins with collagen-like sequences. The enzyme plays a central role in the synthesis of all collagens, as the 4-hydroxyproline residues formed in the reaction are essential for the folding of the newly synthesized collagen polypeptide chains into triple helical molecules.  SIGNOR-269733 0.2 PTGER3 protein P43115 UNIPROT GNG12 protein Q9UBI6 UNIPROT up-regulates binding 9606 BTO:0000938 12038972 t gcesareni Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i) SIGNOR-88195 0.427 Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 10090 BTO:0001086 19279220 f miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270728 0.7 KIFC1 protein Q9BW19 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 33361741 f miannu Kinesin Family Member C1 (KIFC1) Regulated by Centrosome Protein E (CENPE) Promotes Proliferation, Migration, and Epithelial-Mesenchymal Transition of Ovarian Cancer SIGNOR-266115 0.7 MTA3 protein Q9BTC8 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263852 0.776 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr395 AKHHQDAyIRIVLEN 9606 15952790 t llicata We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts. SIGNOR-138150 0.59 ITK protein Q08881 UNIPROT BMX protein P51813 UNIPROT up-regulates activity phosphorylation Tyr224 DSNSKKIyGSQPNFN -1 12573241 t Itk phosphorylated Bmx-SH3 to a low extent. pY positions correspond to the residues Y215 and Y223 in Bmx. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. SIGNOR-251332 0.34 TLN1 protein Q9Y490 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257614 0.619 MAPK1 protein P28482 UNIPROT LCK protein P06239 UNIPROT up-regulates activity phosphorylation Ser59 EGSNPPAsPLQDNLV 9606 BTO:0000567 8618896 t lperfetto Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation. SIGNOR-249412 0.565 Chaperone-mediated autophagy phenotype SIGNOR-PH118 SIGNOR Hexokinase proteinfamily SIGNOR-PF76 SIGNOR down-regulates quantity by destabilization 9606 BTO:0004424 26323688 t inferred from family member Our proteome analysis revealed that HK2 is a CMA substrate and that its degradation by CMA is regulated by glucose availability. SIGNOR-270269 0.7 ADCY2 protein Q08462 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 t miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. SIGNOR-265004 0.8 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser795 TASTRKVsLAPQANL 9606 10581361 t lperfetto Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function SIGNOR-72724 0.52 SRC protein P12931 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr220 RHSVVVPyEPPEVGS 9606 BTO:0002181 25071020 t miannu We recently found that ISGylation of the p53 tumor suppressor is an important novel mechanism to control its stability. Here we identified that Isg15-dependent regulation of p53 can be enhanced by different oncogenes. We further show that the Src-mediated phosphorylation of p53 on Tyr126 and Tyr220 has a positive effect on p53 ISGylation by enhancing Herc5 binding. SIGNOR-276669 0.539 EIF5A protein P63241 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 15371445 t miannu eIF5A regulated p53 protein expression. Further analysis by reverse transcription PCR showed eIF5A-activated p53 transcription. The effect of eIF5A on p53 transcriptional activity was further demonstrated by the increasing expressions of p21 and Bax, well known target genes of p53. SIGNOR-266375 0.372 UBE2N protein P61088 UNIPROT H2AX protein P16104 UNIPROT up-regulates ubiquitination 9606 18077395 t gcesareni In an h2ax- and mdc1-dependent manner , rnf8/ubc13 complexes go to sites of dna damage through their fha domain and initiate the synthesis of k63 polyubiquitin chains on chromatin that recruit the brca1 a complex through the uim domains of rap80. SIGNOR-159880 0.2 N-(cyanomethyl)-4-[2-[4-(4-morpholinyl)anilino]-4-pyrimidinyl]benzamide chemical CHEBI:91407 ChEBI JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191247 0.8 JAG2 protein Q9Y219 UNIPROT JAG1 protein P78504 UNIPROT up-regulates 10090 BTO:0000165;BTO:0000222 9315665 f gcesareni Immunohistochemistry revealed coexpression of jagged2 and notch1 within thymus and other fetal murine tissues, consistent with interaction of the two proteins in vivo. Coculture of fibroblasts expressing human jagged2 with murine c2c12 myoblasts inhibited myogenic differentiation, accompanied by increased notch1 and the appearance of a novel 115-kda notch1 fragment. Exposure of c2c12 cells to jagged2 led to increased amounts of notch mrna as well as mrnas for a second notch receptor, notch3, and a second notch ligand, jagged1. Constitutively active forms of notchl in c2c12 cells also induced increased levels of the same set of mrnas, suggesting positive feedback control of these genes initiated by binding of jagged2 to notch1. SIGNOR-236888 0.387 JAK1 protein P23458 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 9852261 t gcesareni Stat6 activation is mediated through jak1 and jak2 tyrosine kinases SIGNOR-62582 0.756 GSK3B protein P49841 UNIPROT APC protein P25054 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C110 SIGNOR-C110 10698523 t lperfetto Gsk-3beta-dependent phosphorylation of apc. SIGNOR-75366 0.749 PFKFB4 protein Q16877 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity chemical modification -1 30553771 t miannu PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species SIGNOR-268118 0.8 MAPK1 protein P28482 UNIPROT EWSR1 protein Q01844 UNIPROT unknown phosphorylation Thr79 QPPTGYTtPTAPQAY 9606 19076070 t lperfetto Here we report that ews and ews-fli1 become phosphorylated at thr79 in the n-terminal domain in response to mitogens or dna damage. Mitogen-induced phosphorylation of ews and ews-fli1 was weak and catalysed by erk1 (extracellular signal-regulated kinase 1) and erk2. SIGNOR-182770 0.251 CCP110 protein O43303 UNIPROT CETN2 protein P41208 UNIPROT up-regulates activity binding 9606 16760425 t miannu We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis. SIGNOR-265967 0.686 FFAR1 protein O14842 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257272 0.554 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 22926518 t miannu The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors. SIGNOR-256180 0.526 GOPC protein Q9HD26 UNIPROT CFTR protein P13569 UNIPROT down-regulates binding 9606 11707463 t miannu Cal binds to cftr / cal affects insertion of cftr to the plasma membrane as well as its half-life in the plasma membrane. SIGNOR-111671 0.71 (R)-carnitine smallmolecule CHEBI:16347 ChEBI O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity precursor of 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267118 0.8 NANOGP8 protein Q6NSW7 UNIPROT FGFR2 protein P21802 UNIPROT down-regulates quantity by repression transcriptional regulation 10900 BTO:0000667 23839044 f Luana Constitutive NanogP8 overexpression in adult L1 mice reduced CD34+α6+ and Lrig-1+ bulge stem cells, impaired keratinocyte migration, and repressed the expression of many stem cell-associated genes, including Bmp5, Fgfr2, Jmjd1a, and Jun. SIGNOR-266090 0.2 LIMK1 protein P53667 UNIPROT CFL2 protein Q9Y281 UNIPROT down-regulates activity phosphorylation Ser3 sGVTVNDE 9606 9655398 t lperfetto Cofilin is known to be a potent regulator of actin filament dynamics, and its ability to bind and depolymerize actin is abolished by phosphorylation of serine residue at 3;. Here we show that lim-kinase 1 (limk-1), a serine/threonine kinase containing lim and pdz domains, phosphorylates cofilin at ser 3, both in vitro and in vivo SIGNOR-58596 0.691 ATR protein Q13535 UNIPROT RAD17 protein O75943 UNIPROT up-regulates activity phosphorylation Ser646 ETWSLPLsQNSASEL 9606 BTO:0000567 11687627 t lperfetto Here we demonstrate that atr but not atm phosphorylates the human rad17 (hrad17) checkpoint protein on ser(635) and ser(645) in vitro.The rfc-related checkpoint protein rad17, a phosphorylation substrate of atr, is critical for atr-mediated checkpoint signaling and cell survival. SIGNOR-111248 0.853 DLD protein P09622 UNIPROT OGDC complex SIGNOR-C397 SIGNOR form complex binding 9606 15953811 t miannu The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. SIGNOR-266256 0.849 ANG protein P03950 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252280 0.7 OTX2 protein P32243 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation -1 18849347 f miannu Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity. SIGNOR-254888 0.358 PRKCE protein Q02156 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser246 QYQEERRsVKHILFS -1 16479000 t miannu HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. SIGNOR-276050 0.2 MAPK1 protein P28482 UNIPROT PPP2R5C protein Q13362 UNIPROT down-regulates phosphorylation Ser337 QLAKCVSsPHFQVAE 9606 16456541 t gcesareni Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit. SIGNOR-144313 0.492 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 10973490 t gcesareni Here we show that in vitro, atm phosphorylates the ser-gln/thr-gln (sq/tq) cluster domain (scd) on chk2, which contains seven sq/tq motifs, and thr68 is the major in vitro phosphorylation site by atm. Atm predominantly phosphorylates chk2 at thr68, promoting homodimerization and activation via intramolecular trans-autophosphorylation at thr383/387. SIGNOR-81438 0.829 KLF3 protein P57682 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18391014 f fspada We find that c/ebpalpha is derepressed in klf3 and ctbp knockout fibroblasts and adipocytes from klf3 knockout mice. SIGNOR-161370 0.305 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120060 0.781 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser568 SSRRRRSsSTAPPTS 9606 16513649 t llicata Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization SIGNOR-145040 0.2 PTEN protein P60484 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 f miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). SIGNOR-260053 0.33 CDK6 protein Q00534 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates phosphorylation Thr90 CHLAWVNtPKKQGGL 9606 11986303 t lperfetto Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown). SIGNOR-87113 0.2 GTF2A1 protein P52655 UNIPROT TFIIA complex SIGNOR-C395 SIGNOR form complex binding 9606 BTO:0000567 7724559 t lperfetto TFIIA purified from HeLa extracts consists of 35-, 19-, and 12-kDa subunits. Here we describe the isolation of a cDNA clone (hTFIIA gamma) encoding the 12-kDa subunit. SIGNOR-266197 0.938 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 17194702 f miannu Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes SIGNOR-151688 0.366 GAB2 protein Q9UQC2 UNIPROT ARHGAP32 protein A7KAX9 UNIPROT up-regulates relocalization 9606 12819203 t gcesareni Gc-gap, a rho family gtpase-activating protein that interacts with signaling adapters gab1 and gab2we propose that gab1 and gab2 in cooperation with other adapter molecules might regulate the cellular localization of gc-gap under specific stimuli. SIGNOR-102628 0.382 RPS9 protein P46781 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262415 0.874 Sin3B_complex complex SIGNOR-C409 SIGNOR H3-5 protein Q6NXT2 UNIPROT down-regulates activity binding 9606 BTO:0000007 21041484 t miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. SIGNOR-266972 0.2 DUSP4 protein Q13115 UNIPROT MAPK9 protein P45984 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 8626452 t fstefani We assayed the relative ability of mkp-2, pac1, and mkp-1 to dephosphorylate erk2 and the other related map kinases, jnk2 and p38. . Mkp-2 had detectable activity against jnk2, although full inactivation of jnk2 was not observed even at the higher phosphatase concentration. SIGNOR-40929 0.601 MAPK1 protein P28482 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity phosphorylation Ser982 KKKSEPSsPDHGSST -1 11287604 t lperfetto coimmunoprecipitation detected a specific association between the activated erk and plc beta1 within the nucleus. In vitro studies revealed that recombinant plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982 this result suggests that erk-evoked phosphorylation of plc beta1 at serine 982 plays a critical role in the activation of the nuclear pi cycle and is also crucial to the mitogenic action of igf-i. SIGNOR-106561 0.406 MAPK14 protein Q16539 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates activity binding 9606 BTO:0000007 11062068 t gcesareni Here we have shown that mkp-1 associates directly with p38 map kinase both in vivo and in vitro, and that this interaction enhances the catalytic activity of mkp-1. The point mutation asp-316-->asn in the c-terminus of p38, analogous to the erk2 (extracellular-signal-regulated kinase 2) sevenmaker mutation, dramatically decreases its binding to mkp-1 and substantially compromises its stimulatory effect on the catalytic activity of this phosphatase. SIGNOR-83752 0.798 EGFR protein P00533 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr743 PQAHYNMyPQNPDSV 9606 BTO:0000007;BTO:0000150 11751923 t llicata Novel activation of stat5b in response to epidermal growth factor. novel activation of stat5b in response to epidermal growth factor. SIGNOR-113401 0.827 NEK9 protein Q8TD19 UNIPROT NEK9 protein Q8TD19 UNIPROT up-regulates phosphorylation Thr210 SEYSMAEtLVGTPYY 9606 14660563 t lperfetto A previous study (19) using the peptide substrate demonstrated that nek9 was able to phosphorylate in vitro the thr210 residue within the activation loop, thus indicating the potential ability of nek9 to autophosphorylate.Nek9 forms a stable, approximately 600-kda complex with fact in the interphase nuclei. Its active form is characterized by phosphorylation-dependent electrophoretic mobility shift and phosphorylation at a conserved residue within the activation loop (thr(210)) SIGNOR-119897 0.2 SLC24A2 protein Q9UI40 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264389 0.8 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser217 AHYSPRTsPIMSPRT 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248517 0.387 KDM6A protein O15550 UNIPROT ZBTB16 protein Q05516 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29736013 t miannu UTX catalytic activity has been reported to upregulate expression of the master transcription factor PLZF and to modulate superenhancer accessibility in invariant natural killer T cells. SIGNOR-260038 0.316 MECP2 protein P51608 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 15870696 f miannu Valproate (VPA) induces silencing of the ERalpha, cyclin D1 and pS2 promoters. Chromatin immunoprecipitation (ChIP) analysis demonstrates that VPA induces recruitment of the 5-MeCpG binding protein MeCP2 to the ERalpha A promoter and also to the pS2 and cyclin D1 promoters SIGNOR-254571 0.276 AURKA protein O14965 UNIPROT MAPRE3 protein Q9UPY8 UNIPROT up-regulates phosphorylation Ser176 MQTSGRLsNVAPPCI 9606 19696028 t llicata Aurora-a and aurora-b phosphorylate eb3 at ser-176 in a spatial and cell cycle-specific manner, respectively during mitosis two kinases, aurora-a and aurora-b, phosphorylate eb3 at ser-176, and the resulting phosphorylation disrupts the eb3-siah-1 complex. Indeed, eb3 is stabilized during mitosis and facilitates cell cycle progression. SIGNOR-187657 0.453 BTRC protein Q9Y297 UNIPROT RAP1GAP protein P47736 UNIPROT down-regulates ubiquitination 9606 25329897 t lperfetto Here, we demonstrated that rap1gap is ubiquitinated and degraded through proteasome pathway in mitosis. Proteolysis of rap1gap requires the plk1 kinase and _-trcp ubiquitin ligase complex. SIGNOR-203548 0.349 AKT3 protein Q9Y243 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t gcesareni We show that phosphorylation of b-raf by akt occurs at multiple residues within its aminoterminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity. SIGNOR-78697 0.293 BAX protein Q07812 UNIPROT DIABLO protein Q9NR28 UNIPROT up-regulates 9606 21210296 f gcesareni Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c,(diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore. SIGNOR-170969 0.525 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT down-regulates activity phosphorylation Ser236 DDSGTEEs 9606 11546811 t lperfetto The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm. SIGNOR-110403 0.403 PLK1 protein P53350 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1791 REPLGEDsVGLKPLK 9606 BTO:0000552 31597699 t miannu As shown in Fig. S4D, the C-terminal NOTCH1 fragment was readily phosphorylated by PLK1. Additionally, when the two putative phosphorylation sites, Ser-1791 and Ser-2349, were replaced by Ala, WT NOTCH1-IC but not the mutant was efficiently phosphorylated (Fig. S4E). We found that mutation of Ser-1791/2349 promotes NOTCH1-IC stabilization (Fig. S4F). SIGNOR-277491 0.411 CCN2 protein P29279 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 18528331 t gcesareni Igfbp-4 physically interacted with a wnt receptor, frizzled 8 (frz8), and a wnt co-receptor, low-density lipoprotein receptor-related protein 6 (lrp6), and inhibited the binding of wnt3a to frz8 and lrp6. SIGNOR-178875 0.2 BCL6 protein P41182 UNIPROT SUMO1 protein P63165 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000182 22723377 f QPCR analysis of the resulting gene expression levels identified three genes that were affected in opposite sense by the downregulation of either BCL-6 or STAT5, namely cyclin D2 (CCND2), cyclin-dependent kinase inhibitor p15INK4B (CDKN2B), and SUMO1 SIGNOR-253929 0.31 H4C1 protein P62805 UNIPROT CENP-A nucleosome complex SIGNOR-C321 SIGNOR form complex binding -1 23324462 t miannu In vitro assembly of both yeast and human CENP-A nucleosomes yields standard octameric structures containing two copies each of CENP-A, H2A, H2B and H4 histones. Human CENP-A also produces rigidified homotypic CENP-A/H4 tetramers in vitro. SIGNOR-263701 0.2 GEMIN5 protein Q8TEQ6 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 t lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. SIGNOR-253119 0.737 WNT8B protein Q93098 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-132027 0.601 LLGL2 protein Q6P1M3 UNIPROT Scribble_complex_DLG3-LLGL2_variant complex SIGNOR-C504 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270883 0.559 SRC protein P12931 UNIPROT SLC6A4 protein P31645 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr47 SGQISNGySAVPSPG 10116 BTO:0000132 21992875 t miannu We found that 1) SERT exists in a tyrosine-phosphorylated form, 2) inhibition of tyrosine kinase(s) reduces SERT expression levels by facilitating SERT protein degradation, 3) Src-kinase activity up-regulates SERT protein expression with a concomitant increase in 5-HT uptake and tyrosine phosphorylation, and 4) mutation of Tyr47 or Tyr142 abolishes src-induced increases in transport function and phosphorylation of SERT.  SIGNOR-276385 0.261 GNA13 protein Q14344 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 23450633 t gcesareni Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism. SIGNOR-192111 0.556 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 10480932 t lperfetto We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta. SIGNOR-70607 0.734 ZNF239 protein Q16600 UNIPROT RBP3 protein P10745 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12409453 f miannu We have demonstrated that MOK2 can bind to the 8 bp present in the IRBP promoter and repress transcription from this promoter by competing with the CRX activator for DNA binding. SIGNOR-255629 0.313 CSNK2A1 protein P68400 UNIPROT MAZ protein P56270 UNIPROT up-regulates phosphorylation Ser460 PTAVGSLsGAEGVPV 9606 BTO:0000567 10448092 t lperfetto Site-specific mutagenesis of maz revealed that the serine residue at position 480 was the major site of phosphorylation by ckii both in vitro and in vivo. Phosphorylation of maz by ckii at this serine residue was required for maximum binding of maz to the pyrimidine-rich dna of the nuclease-hypersensitive element (nhe) in the 5'-end promoter region of the c-myc gene. Mutation of serine at position 480 to alanine eliminated the dna-binding activity of maz to this element. SIGNOR-70082 0.459 CSNK2A1 protein P68400 UNIPROT FAF1 protein Q9UNN5 UNIPROT down-regulates activity phosphorylation Ser291 DVHMVSDsDGDDFED 9534 12832043 t llicata We previously identified the Fas-associated factor FAF1 as an in vitro substrate of protein kinase CK2 and determined Ser289 and Ser291 as phosphorylation sites.|Therefore we assume that CK2‐mediated FAF1 phosphorylation influences the nuclear localization of FAF1 | it implies that the major function of FAF1 might not be in the cytoplasm as an interacting partner of Fas. SIGNOR-250864 0.332 SF3B5 protein Q9BWJ5 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 t lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). SIGNOR-268407 0.93 WIPI2 protein Q9Y4P8 UNIPROT ATG16L1 protein Q676U5 UNIPROT up-regulates quantity binding 9606 BTO:0001938 28561066 t miannu WIPI1 assists WIPI2 in recruiting ATG16L for LC3 lipidation. WIPI1-WIPI2 heterodimer may function more efficiently in ATG16L complex recruitment. SIGNOR-268478 0.723 staurosporine chemical CHEBI:15738 ChEBI PRKCH protein P24723 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258286 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation Thr277 GSRTAPYtPNLPHHQ 9606 12801888 t lperfetto Our results suggest that map kinase can phosphorylate thr276 of smad4 and that phosphorylation can lead to enhanced tgf-beta-induced nuclear accumulation and, as a consequence, enhanced transcriptional activity of smad4. SIGNOR-244739 0.2 CDK1 protein P06493 UNIPROT GATA2 protein P23769 UNIPROT down-regulates quantity by destabilization phosphorylation Thr176 HLFGFPPtPPKEVSP 9606 BTO:0000007 25670854 t miannu GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation. Substitution of threonine 176 to alanine in GATA2 inhibited binding with Fbw7, and the ubiquitylation and degradation of GATA2 by Fbw7 was suppressed. The CPD kinase, which mediates the phosphorylation of Thr(176), was cyclin B-cyclin-dependent kinase 1 (CDK1).  SIGNOR-276884 0.362 felodipine chemical CHEBI:585948 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition -1 18250364 t Luana Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression.  SIGNOR-257766 0.8 MAPK1 protein P28482 UNIPROT SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization phosphorylation Thr507 GLGENLLtHLPEEIG 9606 BTO:0000007 30865892 t miannu Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation. SIGNOR-277442 0.328 CEBPD protein P49716 UNIPROT CCL20 protein P78556 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 23028973 f CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. SIGNOR-254056 0.253 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Tyr132 CVIAVDRyFAITSPF 10029 BTO:0000246 8557631 t Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors. SIGNOR-251299 0.385 MYCN protein P04198 UNIPROT ABCC1 protein P33527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7923112 f miannu Decreased expression of the N-myc oncogene in neuroblastoma cell lines SH-SY5Y and BE(2)-C, following treatment with retinoic acid, was paralleled by down-regulation of MRP gene expression, contrasting with increased expression of the MDR1 gene. SIGNOR-254617 0.277 PRKCD protein Q05655 UNIPROT DNM1L protein O00429 UNIPROT up-regulates phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 17301055 t gcesareni Drp1 was specifically phosphorylated in mitosis by cdk1/cyclin b on ser-585. Exogenous expression of unphosphorylated mutant drp1s585a led to reduced mitotic mitochondrial fragmentation. SIGNOR-153148 0.2 HCK protein P08631 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Tyr291 AETSKLIyDFIEDQG 9534 BTO:0000298 12235133 t done miannu Hck induces tyrosine phosphorylation of WASp. Here we show that the Src family kinase Hck induces phosphorylation of WASp-Tyr(291) independently of Cdc42 and that this causes a shift in the mobility of WASp upon SDS-PAGE. A phospho-mimicking mutant, WASp-Y291E, exhibited an enhanced ability to stimulate actin polymerization in a cell-free system and when microinjected into primary macrophages induced extensive filopodium formation with greater efficiency than wild-type WASp or a Y291F mutant. We propose that phosphorylation of Tyr(291) directly regulates WASp function. SIGNOR-273957 0.571 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257978 0.8 ACE2 protein Q9BYF1 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage Pro40 GDRVYIHpFHLVIHN -1 11815627 t miannu The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus. SIGNOR-256315 0.749 PRKACA protein P17612 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation 10090 23644383 t milica Here, we show that cyclic amp (camp)-dependent protein kinase (pka) phosphorylates lats and thereby enhances its activity sufficiently to phosphorylate yap on ser381. SIGNOR-236991 0.2 MAP1LC3B protein Q9GZQ8 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 19250911 t gcesareni Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation. SIGNOR-184255 0.831 PLK3 protein Q9H4B4 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser62 SSSGTLSsLETVSTQ -1 16481012 t miannu Plk3 phosphorylates Chk2 at two residues, serine 62 (S62) and serine 73 (S73) in vitro, and this phosphorylation facilitates subsequent phosphorylation of Chk2 on T68 by ATM in response to DNA damage. When the Chk2 mutant construct GFP-Chk2 S73A (serine 73 mutated to alanine) is transfected into cells, it no longer associates with a large complex in vivo, and manifests a significant reduction in kinase activity.  SIGNOR-276052 0.645 GSK3B protein P49841 UNIPROT FRAT1 protein Q92837 UNIPROT down-regulates activity phosphorylation Ser188 RLQQRRGsQPETRTG 9606 BTO:0002181 16982607 t miannu Protein kinase A (PKA) was found to phosphorylate Ser188 in vitro as well as in intact cells. Importantly, activation of endogenous cAMP-coupled beta-adrenergic receptors with norepinephrine stimulated the phosphorylation of FRAT1 at Ser188. GSK-3 was also able to phosphorylate FRAT1 at Ser188 and other residues in vitro or when overexpressed in intact cells.  Phosphorylation of Ser188 by PKA inhibited the ability of FRAT1 to activate beta-catenin-dependent transcription. SIGNOR-276057 0.767 HIF1A protein Q16665 UNIPROT EPO protein P01588 UNIPROT up-regulates quantity transcriptional regulation 9606 8756616 t We demonstrate the involvement of HIF-1 in the activation of VEGF transcription. VEGF 5'-flanking sequences mediated transcriptional activation of reporter gene expression in hypoxic Hep3B cells SIGNOR-256593 0.629 BMP2 protein P12643 UNIPROT ALPL protein P05186 UNIPROT up-regulates 9606 22298955 f gcesareni FGF-2 null mice have impaired nuclear accumulation of Runx2 and hindered BMP-2 induced bone formation and ALP activity SIGNOR-114589 0.447 PSMC1 protein P62191 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263373 0.867 MAPK8 protein P45983 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr286 SVPSAAVtPLNESLQ 9606 15767678 t gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. SIGNOR-134549 0.715 FGF11 protein Q92914 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253430 0.254 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser396 SSSSSSHsLSASDTG 9606 10455013 t lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-236764 0.2 PPP2CA protein P67775 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates dephosphorylation 9606 23431053 t inferred from 70% of family members gcesareni Rassf1a apparently protects mst1/2 against inactivation by pp2a, the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively. SIGNOR-269940 0.735 NR3C1 protein P04150 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18612045 f areggio Consistent with these findings, DEX-induced upregulation of MuRF1 is significantly attenuated in mice expressing a homodimerization-deficient GR despite no effect on the degree of muscle loss in these mice vs. their wild-type counterparts. Finally, chromatin immunoprecipitation analysis reveals that both GR and FOXO1 bind to the endogenous MuRF1 promoter in C(2)C(12) myotubes, and IGF-I inhibition of DEX-induced MuRF1 expression correlates with the loss of FOXO1 binding. SIGNOR-254992 0.336 CDK1 protein P06493 UNIPROT RAB11FIP3 protein O75154 UNIPROT up-regulates quantity phosphorylation Ser102 GPRGQLAsPDAPGPG 9606 BTO:0000567 22401586 t done miannu FIP3 is phosphorylated on S102 in a cell cycle-dependent manner. We identify four sites of phosphorylation of FIP3 in vivo, S-102, S-280, S-347 and S-450 and identify S-102 as a target for Cdk1-cyclin B in vitro. Of these, we show that S-102 is phosphorylated in metaphase and is dephosphorylated as cells enter telophase. SIGNOR-273588 0.2 PRKAA2 protein P54646 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 SIGNOR-C15 19933840 t lperfetto Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction SIGNOR-161810 0.2 NRF1 protein Q16656 UNIPROT SPAST protein Q9UBP0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22574173 f miannu we demonstrate that SPAST transcription is positively regulated by NRF1 and SOX11. SIGNOR-254885 0.343 ITGA10 protein O75578 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253185 0.679 CLK1 protein P49759 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser242 MDKRKDPsSVDIKKV -1 10480872 t llicata The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site. SIGNOR-250773 0.353 NDUFV3 protein P56181 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. SIGNOR-262185 0.775 OTULIN protein Q96BN8 UNIPROT UBB protein P0CG47 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270819 0.658 VWF protein P04275 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 t lperfetto Many studies have contributed to shed light on the importance of von Willebrand factor (VWF) interaction with its platelet receptors, glycoprotein (GP) Ib-IX-V and αIIbβ3 integrin, in promoting primary platelet adhesion and aggregation following vessel injury SIGNOR-261854 0.67 CSF2 protein P04141 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates binding 9606 BTO:0000876 BTO:0001103 9680354 t apalma GM-CSF elicits these diverse responses through the GM-CSF receptor (GMR). SIGNOR-255581 0.857 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MITF protein O75030 UNIPROT down-regulates quantity by destabilization phosphorylation 10841026 t inferred from 70% family members lperfetto More interestingly, ERK-dependent phosphorylation of MITF at Ser 73 is essential for MITF ubiquitinilation and degradation (87). Putting together all these findings, it can be proposed that MAPK activation inhibits melanogenesis due to an increased MITF degradation which is dependent on the MAPK-induced MITF phosphorylation and ubiquitinilation. In summary, although the phosphorylation of MITF at Ser73 increases its intrinsic transcriptional activity, this phosphorylation also targets MITF to the proteasome for its degradation. Consequently, the decrease in MITF levels leads to a down-regulation of melanogenic enzymes expression and to an inhibition of melanogenesis. SIGNOR-270029 0.2 DYRK3 protein O43781 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR down-regulates phosphorylation 9606 23415227 t lperfetto When dyrk3 is active, it allows stress granule dissolution, releasing mtorc1 for signaling and promoting its activity by directly phosphorylating the mtorc1 inhibitor pras40 SIGNOR-217571 0.292 CRBN protein Q96SW2 UNIPROT SALL4 protein Q9UJQ4 UNIPROT down-regulates quantity by destabilization binding 9606 32071327 t miannu Thalidomide-induced teratogenicity is dependent on its binding to cereblon (CRBN), the substrate receptor of the Cul4A-DDB1-CRBN-RBX1 E3 ubiquitin ligase complex. Thalidomide binding to CRBN elicits subsequent ubiquitination and proteasomal degradation of CRBN neosubstrates including SALL4, a transcription factor of which polymorphisms phenocopy thalidomide-induced limb defects in humans. SIGNOR-272208 0.2 MAPK1 protein P28482 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Ser416 GFPSKTDsPSCEYSR 9606 BTO:0000007 27846390 t lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  SIGNOR-262978 0.306 SIRT7 protein Q9NRC8 UNIPROT H3-2 protein Q5TEC6 UNIPROT up-regulates activity deacetylation Lys38 PATGGVKkPHRYRPG 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275883 0.2 Neurofibrillary tangle formation phenotype SIGNOR-PH58 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 11578751 f lperfetto Alzheimer's disease, the cause of one of the most common types of dementia, is a brain disorder affecting the elderly and is characterized by the formation of two main protein aggregates: senile plaques and neurofibrillary tangles, which are involved in the process leading to progressive neuronal degeneration and death SIGNOR-251641 0.7 RAC1 protein P63000 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates binding 9606 18423204 t gcesareni We show that rac1 activates jnk2 that in turn phosphorylates beta-catenin on critical residues and controls its nuclear translocation. SIGNOR-178265 0.503 PRKACA protein P17612 UNIPROT KCNN4 protein O15554 UNIPROT down-regulates activity phosphorylation Ser334 KHTRRKEsHAARRHQ 9606 BTO:0000007 25274816 t miannu Mutating the single PKA site (S334A) in human KCa3.1 abolished the PKA-dependent regulation. CaM-affinity chromatography showed that CaM binding to KCa3.1 was decreased by PKA-dependent phosphorylation of S334, and this regulation was absent in the S334A mutant.The results above indicate that PKA activation led to a phosphorylation event that inhibited KCa3.1 channel activity SIGNOR-276855 0.2 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 19723038 t gcesareni The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases these include epidermal growth factor receptor (egfr) kinase,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1 SIGNOR-187787 0.709 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 t Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases. SIGNOR-248412 0.622 PTAFR protein P25105 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256789 0.2 BHLHE40 protein O14503 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 14672706 f lperfetto Forced expression of Clock/Bmal increased endogenous Dec1 mRNA level, and overexpression of Dec1 resulted in suppression of Dec2, Per2, and Dbp expression SIGNOR-253717 0.485 LCK protein P06239 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr597 RHSTILDyINVVPTA 9606 11733002 t lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling SIGNOR-112491 0.262 CDK2 protein P24941 UNIPROT SF3B1 protein O75533 UNIPROT unknown phosphorylation Thr313 HGSGWAEtPRTDRGG 9606 SIGNOR-C16 12105215 t llicata We indeed found that sap155-(223_322) and sap155-(1_491) are excellent substrates for in vitrophosphorylation by cyclin e-cdk2 as well as cyclin b-cdk1 SIGNOR-90442 0.353 AV412 chemical CID:11700696 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190050 0.8 CSNK2A1 protein P68400 UNIPROT SMC3 protein Q9UQE7 UNIPROT unknown phosphorylation Ser1067 GDVEGSQsQDEGEGS 9606 18442975 t gcesareni Our data provide evidence that phosphorylation of a core cohesin subunit smc3 by atm plays an important role in dna damage response and suggest that a constitutive phosphorylation by ck2 may affect intra-s phase checkpoint by modulating smc3 phosphorylation by atm. SIGNOR-178483 0.2 DUSP4 protein Q13115 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates activity dephosphorylation 10116 7535768 t inferred from 70% of family members Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK SIGNOR-269914 0.2 ATR protein Q13535 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 16908529 t gcesareni Finally, in vitro atr-mediated phosphorylation at the t2609 cluster was further confirmed by western blot analysis using phosphospecific antibodies against t2647 (fig. ?(Fig.7e),7e), suggesting that dna-pkcs could be the direct target of atr kinase. SIGNOR-148722 0.315 RANGAP1 protein P46060 UNIPROT MYCBP2 protein O75592 UNIPROT down-regulates quantity by destabilization relocalization 10090 26304119 t Monia SUMOylated RanGAP1 Inhibits MYCBP2 Activity and Mediates Its Transport to the Nucleus. Surprisingly, we did not find MYCBP2-dependent ubiquitylation of SUMOylated RanGAP1 but instead a strong inhibition of the ubiquitin ligase activity of MYCBP2 in the presence of SUMOylated RanGAP1, as determined by the presence of ubiquitylated proteins. this effect was specific for SUMOylated RanGAP1, because the unmodified form of RanGAP1 did not affect MYCBP2-dependent protein ubiquitylation. , SUMOylated RanGAP1 inhibited the ubiquitin ligase activity of MYCBP2, and it is tempting to speculate that SUMOylated RanGAP1 inhibits the ubiquitin ligase activity of MYCBP2 to ensure MYCBP2 silencing during its transport to the nucleus SIGNOR-261203 0.32 IRF8 protein Q02556 UNIPROT CYBB protein P04839 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001412 11483597 f miannu we found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP. SIGNOR-222710 0.356 NBEAL2 protein Q6ZNJ1 UNIPROT DOCK7 protein Q96N67 UNIPROT up-regulates activity binding 10090 BTO:0000132 29187380 t lperfetto In summary, from 129 binding partners of Nbeal2 identified by mass spectrometry, we have confirmed the interaction of 3, Dock7, Sec16a, and Vac14, by different biochemical and cellular approaches|Given the significant reduction of Dock7 levels and its altered localization in Nbeal2−/− platelets, we postulated that this canonical signaling pathway may be disrupted and set out to test this using control and Nbeal2−/− platelets. SIGNOR-261891 0.389 WNT6 protein Q9Y6F9 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 9753670 f gcesareni In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod. Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. SIGNOR-60418 0.329 RPS6KA3 protein P51812 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Ser947 CRLNRSDsDSSTLSK 9606 BTO:0000149 24269383 t llicata Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2. SIGNOR-203302 0.2 SGK1 protein O00141 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates phosphorylation Thr366 GTRSRSHtSEGAHLD 9606 BTO:0000567 18787837 t llicata Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1. SIGNOR-180829 0.586 TFIIE complex SIGNOR-C458 SIGNOR TFIIH complex SIGNOR-C457 SIGNOR up-regulates activity relocalization 9606 31064989 t lperfetto The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur. SIGNOR-269362 0.731 JAK1 protein P23458 UNIPROT TYK2 protein P29597 UNIPROT up-regulates phosphorylation Tyr1055 VPEGHEYyRVREDGD 9606 8702790 t llicata These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055 and that this phosphorylation requires another kinase, most likely jak1. SIGNOR-43084 0.506 SNRPD3 protein P62318 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270686 0.924 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR KLC1 protein Q07866 UNIPROT down-regulates phosphorylation 9606 21385839 t inferred from 70% family members gcesareni Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1mutation of klc1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residueklc1ser460 is a predicted mitogen-activated protein kinase (mapk) target site, and we show that extracellular-signal-regulated kinase (erk) phosphorylates this residue in vitro. SIGNOR-270176 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. SIGNOR-251525 0.2 DVL1 protein O14640 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity binding 9534 SIGNOR-C110 10196136 t lperfetto We have recently found that Dvl-1 directly binds to Axin and that the binding of Dvl-1 to Axin does not affect the interaction of GSK-3beta with Axin. It is possible that the binding of Dvl to Axin induces the structural change of the Axin complex; therefore GSK-3beta does not effectively phosphorylate Axin. This is the first demostration showing that Dvl inhibits the function of GSK-3beta directly. SIGNOR-219356 0.812 FLT3 protein P36888 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14981546 f FLT3-ITD signaling contributes to transcriptional inhibition of p27Kip1 and Bim gene expression SIGNOR-261524 0.294 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser139 DARDLEMsKKVRRSY -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276114 0.613 thioridazine chemical CHEBI:9566 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258839 0.8 SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR SLC24A2 protein Q9UI40 UNIPROT up-regulates quantity phosphorylation Tyr364 LAEELGSyGKLKYYD 9606 BTO:0000938 23431067 t miannu Src family kinase-mediated Tyr-365 phosphorylation of NCKX2 regulates its surface expression. PP2 facilitated the endocytosis of NCKX2 in both the somatodendritic and axonal compartments, suggesting that tyrosine phosphorylation of NCKX2 by SFK negatively regulates its endocytosis. Supporting this idea, activation of SFK enhanced the NCKX activity in the proximal dendrites of dentate granule cells (GCs). These results suggest that endocytosis of somatodendritic NCKX2 is regulated by SFK-dependent phosphorylation of Tyr-365. SIGNOR-264387 0.2 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT up-regulates dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 19574738 t gcesareni Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation by cdc25c SIGNOR-186621 0.852 LPCAT1 protein Q8NF37 UNIPROT 1-O-acyl-sn-glycero-3-phosphocholine chemical CHEBI:58168 ChEBI down-regulates quantity chemical modification 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272762 0.8 SREBF1 protein P36956 UNIPROT Lipogenesis phenotype SIGNOR-PH30 SIGNOR up-regulates 10090 15589694 f lperfetto In vivo studies using transgenic and knockout mice suggest that SREBP-1c is involved in FA synthesis and insulin induced glucose metabolism (particularly in lipogenesis), SIGNOR-228614 0.7 MRPS2 protein Q9Y399 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding P82664 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261449 0.735 SLBP protein Q14493 UNIPROT H2AC20 protein Q16777 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265398 0.2 TTF2 protein Q9UNY4 UNIPROT CDC5L protein Q99459 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 12927788 t miannu HLodestar/HuF2 associates with CDC5L in cell lysates and HeLa nuclear extracts. It is possible that during the cell division cycle, hLodestar/HuF2’s associates with transcription/splicing complexes in order to inhibit transcription/splicing prior to the start of mitosis and/or functions in stabilizing nuclear complexes containing splicing factors (e.g., the CDC5L complex) so that these are available for re-initiation of splicing at the end of mitosis when gene expression is re-established in cells. SIGNOR-224460 0.442 MAPK14 protein Q16539 UNIPROT CASP3 protein P42574 UNIPROT down-regulates phosphorylation Ser150 FRGDRCRsLTGKPKL 9606 BTO:0000130 14970175 t gcesareni Consequently, p38-mapk can directly phosphorylate and inhibit the activities of caspase-8 and caspase-3 and thereby hinder neutrophil apoptosis, and, in so doing, regulate the inflammatory response. SIGNOR-122099 0.767 RUVBL2 protein Q9Y230 UNIPROT R2TP core co-chaperone complex SIGNOR-C515 SIGNOR form complex binding 9606 29662061 t miannu  Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90.  SIGNOR-270929 0.801 PAK1 protein Q13153 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates activity phosphorylation Thr508 PDRKKRYtVVGNPYW 9606 10559936 t lperfetto Activation of lim-kinase by pak1 couplesp21-activated kinase (pak1) phosphorylates lim-kinase at threonine residue 508 within lim-kinase's activation loop SIGNOR-72142 0.598 DLGAP4 protein Q9Y2H0 UNIPROT SHANK2 protein Q9UPX8 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264596 0.733 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159442 0.259 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser397 SMVGGERsPPRILPP 9606 BTO:0000007 21059642 t The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). SIGNOR-169330 0.599 APH1A protein Q96BI3 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 12522139 t gcesareni Biochemical and genetic studies have recently identified nicastrin, aph-1, and pen-2 as essential cofactors that physically interact with ps1 and are necessary for the gamma-secretase activity. SIGNOR-97068 0.946 GSK3B protein P49841 UNIPROT PDX1 protein P52945 UNIPROT down-regulates quantity phosphorylation Ser61 LGALEQGsPPDISPY 10090 BTO:0000783;BTO:0002284 16407209 t Here we show that a minor portion of IPF1/PDX1 is phosphorylated on serine 61 and/or serine 66 in pancreatic beta-cells. This phosphorylated form of IPF1/PDX1 preferentially accumulates following proteasome inhibition, an effect that is prevented by inhibition of glycogen synthase kinase 3 (GSK3) activity. SIGNOR-255543 0.2 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 BTO:0000150 19085255 t gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase. SIGNOR-182804 0.579 IKK-complex complex SIGNOR-C14 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser25 AERGLGPsPAGDGPS 10090 BTO:0002572 23332762 t lperfetto Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation. SIGNOR-209776 0.266 DVL1 protein O14640 UNIPROT APC protein P25054 UNIPROT down-regulates activity binding 9606 10330181 t amattioni Dvl-1 inhibits Axin-promoted GSK-3_-dependent phosphorylation of _-catenin and APC, leading to beta-catenin stabilization. SIGNOR-167951 0.683 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR BMP7 protein P18075 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269260 0.318 EPAS1 protein Q99814 UNIPROT AP1 complex SIGNOR-C154 SIGNOR down-regulates activity binding 9606 BTO:0000093 24383088 t miannu Co-transfection experiments revealed that HIF-2α had greater potency on the GLIS1 promoter activation than HIF-1α. Subsequent studies using wild-type and mutant HIF-2α demonstrated that DNA binding activity was not necessary but TADs were critical for GLIS1 induction. Finally, co-transfection experiments indicated that HIF-2α cooperated with AP-1 family members in upregulating GLIS1 transcription. These results suggest that the hypoxic signaling pathway may play a pivotal role in regulating the reprogramming factor GLIS1, via non-canonical mechanisms involving partner transcription factor rather than by direct HIF transactivation. SIGNOR-269042 0.351 EGF protein P01133 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates binding 9606 11279155 t tpavlidou To better understand the role of the egfr tyrosine kinase, we analyzed signaling by a kinase-inactive egfr (k721m) in erbb-devoid 32d cells. K721m alone exhibited no detectable signaling capacity, whereas coexpression of k721m with erbb2, but not erbb3 or erbb4, resulted in egf-dependent mitogen-activated protein kinase (mapk) activation. The kinase activity, but not tyrosine phosphorylation, of erbb2 was required for egf-induced mapk activation. SIGNOR-106497 0.783 TLN1 protein Q9Y490 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257617 0.575 HIP1 protein O00291 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 11007801 f miannu Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain. SIGNOR-82463 0.7 EP300 protein Q09472 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 12690203 t miannu P53 is stabilized by the binding of p300 to the oncoprotein E1A, suggesting that p300 regulates p53 degradation. Purified p300 exhibited intrinsic ubiquitin ligase activity that was inhibited by E1A. In vitro, p300 with MDM2 catalyzed p53 polyubiquitination, whereas MDM2 catalyzed p53 monoubiquitination. E1A expression caused a decrease in polyubiquitinated but not monoubiquitinated p53 in cells. Thus, generation of the polyubiquitinated forms of p53 that are targeted for proteasome degradation requires the intrinsic ubiquitin ligase activities of MDM2 and p300. SIGNOR-271418 0.909 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CIITA protein P33076 UNIPROT down-regulates phosphorylation 9606 18245089 t inferred from 70% family members gcesareni In this study we show that the extracellular signal-regulated kinases 1 and 2 (erk1/2) interact directly with ciita, targeting serine residues in the amino terminus of the protein, including serine 288. These data suggest a model whereby erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation. SIGNOR-270067 0.2 DRD2 protein P14416 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256980 0.501 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 19115199 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-183000 0.738 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1249 HGHVSDAsISLGEPV -1 22302995 t miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. SIGNOR-262906 0.69 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2E3 protein Q969T4 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271330 0.708 MTOR protein P42345 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 18691976 t gcesareni Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. SIGNOR-161439 0.738 SHH protein Q15465 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887 17688959 f gcesareni Most importantly, we report that shh induces mapk/erk and phosphoinositide 3-kinase (pi3k)-dependent akt phosphorylation and that activation of both signaling pathways is essential for shh's signaling in muscle cells. However, the effect of shh on akt phosphorylation is more robust than that on mapk/erk, and data suggest that shh influences these pathways in a manner similar to igf-i. SIGNOR-157291 0.482 MAP1LC3C protein Q9BXW4 UNIPROT WDFY3 protein Q8IZQ1 UNIPROT up-regulates activity binding 9606 BTO:0000567 24668264 t miannu Here, we show that ALFY binds selectively to LC3C and the GABARAPs through a LIR in its WD40 domain. Binding of ALFY to GABARAP is indispensable for its recruitment to LC3B-positive structures and, thus, for the clearance of certain p62 structures by autophagy. SIGNOR-266795 0.612 NR3C1 protein P04150 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates activity 9606 25910399 f Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases [.. }The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged. SIGNOR-266901 0.7 SKP1 protein P63208 UNIPROT CUL1 protein Q13616 UNIPROT up-regulates binding 9606 10023660 t gcesareni The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin. SIGNOR-64511 0.958 SMAD7 protein O15105 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity relocalization 9606 11163210 t lperfetto Smurf2 is nuclear, but binding to smad7 induces export and recruitment to the activated tgf beta receptor, where it causes degradation of receptors and smad7 via proteasomal and lysosomal pathways. SIGNOR-104996 0.865 venetoclax chemical CHEBI:133021 ChEBI BCL2 protein P10415 UNIPROT down-regulates activity chemical inhibition 9606 23291630 t miannu Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers. SIGNOR-261938 0.8 MRPL1 protein Q9BYD6 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262384 0.656 TUBB protein P07437 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 17429065 t lpetrilli Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin. SIGNOR-154319 0.2 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS 9606 16116087 t llicata The present experiments demonstrate that ptn stimulates phosphorylation of serines 713 and 726 in the marcks domain of _-adducin (and serine 724 in _-adducin) and serines 152 and 156 in the marcks protein itself through the activation of either pkc _ or _ and perhaps other pkc(s) isoforms. SIGNOR-139910 0.719 GUCY1B2 protein O75343 UNIPROT GUCY1A3-B2 complex SIGNOR-C139 SIGNOR form complex binding 9606 10977868 t gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity SIGNOR-244119 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR TBC1D7 protein Q9P0N9 UNIPROT up-regulates quantity by stabilization phosphorylation Ser124 GKLPRSPsFPLEPDD 9606 BTO:0000007 30143532 t miannu  Sequence analysis identified a putative site for both Akt-mediated phosphorylation and 14-3-3 binding at Ser-124, and we found that Akt phosphorylates TBC1D7 at Ser-124. However, this phosphorylation had no effect on the binding of TBC1D7 to TSC1, but stabilized TBC1D7. SIGNOR-273541 0.2 CSNK2A1 protein P68400 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser356 VDGSGDTsSNEEIGS -1 12107178 t llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. SIGNOR-250870 0.435 PRKACA protein P17612 UNIPROT MARK2 protein Q7KZI7 UNIPROT down-regulates activity phosphorylation Ser409 NPKQRRFsDQAAGPA 9606 BTO:0000007 25512381 t miannu Here, we found the disruption of microtubule and neurite outgrowth induced by MARK2 overexpression was blocked by active PKA. The interaction between PKA and MARK2 was confirmed by coimmunoprecipitation and immunocytochemistry both in vitro and in vivo. PKA was found to inhibit MARK2 kinase activity by phosphorylating a novel site, serine 409.  SIGNOR-276870 0.2 Nalorphine chemical CHEBI:7458 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258815 0.8 PPM1D protein O15297 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity dephosphorylation Ser1981 SLAFEEGsQSTTISS 9606 16949371 t Here, we report that deficiency of Wip1 resulted in activation of the ataxia-telangiectasia mutated (ATM) kinase. In turn, overexpression of Wip1 was sufficient to reduce activation of the ATM-dependent signaling cascade after DNA damage. Wip1 dephosphorylated ATM Ser1981, a site critical for ATM monomerization and activation SIGNOR-248325 0.501 PRKCA protein P17252 UNIPROT PIP5K1B protein O14986 UNIPROT down-regulates phosphorylation Ser413 PSKKRCNsIAALKAT 9606 23909401 t lperfetto Collaboration of ampk and pkc to induce phosphorylation of ser413 on pip5k1b resulting in decreased kinase activity and reduced ptdins(4,5)p2 synthesis in response to oxidative stress and energy restriction. we demonstrate that pkc can directly phosphorylate ser413 in vitro SIGNOR-194820 0.2 CREB1 protein P16220 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity transcriptional regulation 9606 26652733 t Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB SIGNOR-256105 0.2 PTPRG protein P23470 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254725 0.311 CSNK1D protein P48730 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Thr224 MSRFSSStEQSSASR 9606 22609948 t lperfetto Ck1_/__dependent phosphorylation of dvl2 at s143 and t224and that this event is critical to interact with plk1 in early stages of the cell cycle SIGNOR-197551 0.519 EGFR protein P00533 UNIPROT MUC1 protein P15941 UNIPROT up-regulates activity phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 BTO:0000150 11483589 t lperfetto We also show that the activated egf-r phosphorylates the muc1 cytoplasmic tail on tyrosine at a yekv motif that functions as a binding site for the c-src sh2 domain. The results demonstrate that egf-r-mediated phosphorylation of muc1 induces binding of muc1 to c-src in cells SIGNOR-109538 0.595 testosterone smallmolecule CHEBI:17347 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of 9606 BTO:0000975 27702664 t lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively SIGNOR-268667 0.8 PRKDC protein P78527 UNIPROT TDP1 protein Q9NUW8 UNIPROT up-regulates phosphorylation Ser81 PKRQKSGsQEDLGWC 9606 19851285 t lperfetto Optimal function of the dna repair enzyme tdp1 requires its phosphorylation by atm and/or dna-pk. Here we show that top1-associated dna double-stranded breaks (dsbs) induce the phosphorylation of tdp1 at s81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (atm) and dna-dependent protein kinase (dna-pk) SIGNOR-188776 0.517 HDAC9 protein Q9UKV0 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates binding 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 15546868 t lperfetto Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner SIGNOR-235642 0.617 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser178 LFTQRQNsAPARMLS 9606 14559997 t Phosphorylation is the signal for ubiquitination gcesareni The order and fidelity of cell cycle events in mammals is intimately linked to the integrity of the Chk1 kinase-Cdc25A phosphatase pathway. Chk1 phosphorylation targets Cdc25A for destruction and, as shown here, inhibits interactions between Cdc25A and its mitotic substrate cyclin B1-Cdk1. Phosphorylation of Cdc25A on serine 178 and threonine 507 facilitates 14-3-3 binding, and Chk1 phosphorylates both residues in vitro. SIGNOR-118759 0.837 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser579 NVKSKIGsTENLKHQ -1 12435421 t miannu Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly SIGNOR-250008 0.443 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Ser68 GGGAGPVsPQHHELT 9606 22878263 t llicata In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis. SIGNOR-198729 0.42 PRKCA protein P17252 UNIPROT ARHGEF1 protein Q92888 UNIPROT up-regulates activity phosphorylation Ser240 TKSGDKKsGRNFFRK 9606 32881857 t miannu We showed that the first and second phase of RhoA activity are dependent on p63 and Ca2+/PKC, respectively, and further identified phosphorylation of serine 240 on p115 RhoGEF by PKC to be the mechanistic link between PKC and RhoA. SIGNOR-277530 0.45 GGCX protein P38435 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 31539109 f miannu GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05). SIGNOR-261231 0.2 PRKCB protein P05771 UNIPROT VTN protein P04004 UNIPROT up-regulates quantity by stabilization phosphorylation Ser381 RNRKGYRsQRGHSRG -1 9030777 t lperfetto Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin. SIGNOR-248963 0.307 MSN protein P26038 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 9606 BTO:0000132 35267019 f miannu Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. Taken together, these results suggest that Rev-erbα potentiates platelet activation via an OPHN-1-mediated RhoA/ERM signalling pathway. SIGNOR-268434 0.7 MED13 protein Q9UHV7 UNIPROT CKM complex complex SIGNOR-C406 SIGNOR form complex binding 9606 23563140 t miannu The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation. SIGNOR-266684 0.795 F2RL3 protein Q96RI0 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257312 0.2 RPL7A protein P62424 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262454 0.839 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates activity phosphorylation Ser543 SLLSTLSsPGPKLDN 9606 BTO:0000093 15383283 t miannu P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators. SIGNOR-250104 0.506 EGFR protein P00533 UNIPROT KCND3 protein Q9UK17 UNIPROT up-regulates activity phosphorylation Tyr136 GDCCYEEyKDRKREN 9606 BTO:0000007 22198508 t miannu These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels. SIGNOR-276397 0.2 BMPR1A protein P36894 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 10090 BTO:0000165 10564272 f lperfetto We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2 SIGNOR-235361 0.675 S1PR2 protein O95136 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22863277 t gcesareni Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2. SIGNOR-198556 0.448 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates relocalization 9606 BTO:0001103 11062529 t gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-84050 0.598 PPP2R1A protein P30153 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates binding 9606 BTO:0000567 16580887 t miannu Identification of subunits of protein phosphatase 2a (pp2a) as sgo1 binding proteins / pp2a is required for proper chromosome segregation and centromeric localization of sgo1 in hela cells SIGNOR-145486 0.2 ATG10 protein Q9H0Y0 UNIPROT ATG12 protein O94817 UNIPROT up-regulates binding 9606 18704115 t gcesareni Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein. SIGNOR-180129 0.874 GPR84 protein Q9NQS5 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256704 0.288 BIRC5 protein O15392 UNIPROT CASP3 protein P42574 UNIPROT down-regulates binding 9606 9850056 t amattioni Survivin binds specifically to caspase-3. Survivin protected from apoptosis induced by overexpression of procaspase-3 and inhibited the processing of these zymogens into active caspases. Survivin, which is commonly expressed in human tumor cell lines, can bind the effector cell death proteases caspase-3 in vitro and inhibits caspase activity SIGNOR-62484 0.502 MAPK14 protein Q16539 UNIPROT MEF2A protein Q02078 UNIPROT unknown phosphorylation Ser453 PRQEMGRsPVDSLSS 9606 BTO:0000938 BTO:0000887 12586839 t lperfetto Thr-312 and thr-319 are known phosphorylation sites important for the increased transcriptional activation of mef2a by p38 mapk. Ser-453 and ser-479 are phosphorylated in vitro but were not important functionally SIGNOR-98228 0.646 D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 24929114 t miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. SIGNOR-268141 0.8 paliperidone chemical CHEBI:82978 ChEBI HTR1E protein P28566 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0000298 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258561 0.8 PRKCD protein Q05655 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates activity phosphorylation Ser498 RHRPLSRtQSSPLPQ 9606 18332134 t Manara In this report, we show that VEGF stimulates PKD-dependent phosphorylation of HDAC5 at Ser259/498residues in ECs, which leads to HDAC5 nuclear exclusion and myocyte enhancer factor-2 (MEF2) transcriptional activation. SIGNOR-260876 0.359 DOK1 protein Q99704 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257689 0.2 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 11368773 t lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. SIGNOR-247030 0.761 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252829 0.908 DOT1L protein Q8TEK3 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27856324 f irozzo Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4. SIGNOR-255880 0.2 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 23764977 t miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  SIGNOR-268767 0.8 STX11 protein O75558 UNIPROT Platelet_degranulation phenotype SIGNOR-PH138 SIGNOR up-regulates 9606 22767500 f lperfetto In contrast to previous studies,13,15,16,19 the results of the present study show that syntaxin-2 and syntaxin-4 are not required for release, but that syntaxin-11 is critical for platelet exocytosis. SIGNOR-261893 0.7 JAK2 protein O60674 UNIPROT TET2 protein Q6N021 UNIPROT up-regulates activity phosphorylation Tyr1964 HETSEPTyLRFIKSL -1 30944118 t miannu Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964. Phosphorylated TET2 interacts with the erythroid transcription factor KLF1, and this interaction with TET2 is increased upon exposure to erythropoietin.  SIGNOR-277289 0.428 FKBP15 protein Q5T1M5 UNIPROT ACTB protein P60709 UNIPROT up-regulates activity binding 9606 BTO:0000007 19121306 t Giulio However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin. SIGNOR-260595 0.2 chelerythrine chemical CHEBI:78373 ChEBI BCL2L1 protein Q07817 UNIPROT down-regulates chemical inhibition 9606 12702731 t gcesareni Chelerythrine inhibited the bclxl-bak bh3 peptide binding with ic50 of 1.5 micro m and displaced bax, a bh3-containing protein, from bclxl. SIGNOR-100670 0.8 TAF2 protein Q6P1X5 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263931 0.881 FMR1 protein Q06787 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates quantity post transcriptional regulation 10090 32118033 t lperfetto These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets. SIGNOR-262109 0.409 GSK3B protein P49841 UNIPROT KLF5 protein Q13887 UNIPROT down-regulates phosphorylation Ser303 QATYFPPsPPSSEPG 9606 24398687 t lperfetto Stability of the klf5 is mediated by proteasomal degradation via phosphorylation by glycogen synthase kinase 3_ (gsk3_) and recognition by f-box and wd repeat domain-containing 7 (fbw7) of a phosphodegron sequence surrounding serine 303 in klf5 SIGNOR-203627 0.375 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-268121 0.8 FBXO6 protein Q9NRD1 UNIPROT ERO1A protein Q96HE7 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 27855403 t miannu Ero1L is a ubiquitination substrate of FBXO6. FBXO6 mediates the degradation of Ero1L through a ubiquitylation-dependent pathway. Overexpression of FBXO6 increased the polyubiquitination and decreased the stability of Ero1L, whereas inhibition of FBXO6 prolonged the half-life of Ero1L. FBXO6 is the substrate recognition component of a Skp1-Cullin1-F-box protein (SCF) ubiquitin E3 ligase complex SIGNOR-272326 0.2 DYRK1A protein Q13627 UNIPROT CCNL2 protein Q96S94 UNIPROT unknown phosphorylation Ser338 PAPKLVEsPKEGKGS 9534 BTO:0000298 14623875 t llicata DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. | Three phosphoserines were identified in the slower migrating bands (Fig. 9; Ser-330, Ser-338, and Ser-369). All of these serine residues are located N-terminal of proline residues, consistent with our previous classification of DYRK1A as a “proline-directed” kinase. SIGNOR-251088 0.589 PPM1A protein P35813 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 9707433 t lperfetto Moreover, when expressed in mammalian cells, pp2ca inhibited the activation of the p38 and jnk cascades induced by environmental stresses. Both in vivo and in vitro observations indicated that pp2ca dephosphorylated and inactivated mapkks (mkk6 and sek1) and a mapk (p38) in the stress-responsive mapk cascades. Furthermore, a direct interaction of pp2ca and p38 was demonstrated by a co-immunoprecipitation assay SIGNOR-59618 0.418 RNF128 protein Q8TEB7 UNIPROT ARHGDIB protein P52566 UNIPROT up-regulates quantity by stabilization polyubiquitination 9606 BTO:0000661 17114425 t miannu We found that RhoGDIα and RhoGDIβ are ubiquitin E3 substrates of GRAIL. GRAIL uses nonlysine 48-ubiquitin linkage in polyubiquitinating RhoGDI. GRAIL was subsequently demonstrated to bind and ubiquitinate RhoGDI, although GRAIL-mediated ubiquitination of RhoGDI did not result in proteosomal degradation. Our data suggest that ubiquitination of RhoGDI by GRAIL does not result in proteolytic degradation. In fact, GRAIL activity appeared to increase RhoGDI stability. SIGNOR-271621 0.2 ACSS3 protein Q9H6R3 UNIPROT acetate smallmolecule CHEBI:30089 ChEBI down-regulates quantity chemical modification 10843999 t lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. SIGNOR-271833 0.8 NPRL2 protein Q8WTW4 UNIPROT GATOR1 complex SIGNOR-C192 SIGNOR form complex binding 9606 23723238 t miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 SIGNOR-255281 0.955 GSK3B protein P49841 UNIPROT CTPS1 protein P17812 UNIPROT down-regulates activity phosphorylation Ser574 YSDRSGSsSPDSEIT 9606 BTO:0000007 17681942 t miannu We found that low serum conditions increased phosphorylation of endogenous CTPS1 and this phosphorylation was inhibited by the glycogen synthase kinase 3 (GSK3) inhibitor indirubin-3'-monoxime and GSK3beta short interfering RNAs, demonstrating the involvement of GSK3 in phosphorylation of endogenous human CTPS1. Separating tryptic peptides from [(32)P]orthophosphate-labeled cells and analyzing the phosphopeptides by mass spectrometry identified Ser-574 and Ser-575 as phosphorylated residues. Incubation with an alkaline phosphatase increased CTPS1 activity in a time-dependent manner, demonstrating that phosphorylation inhibits CTPS1 activity. SIGNOR-276068 0.2 FZD3 protein Q9NPG1 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 17251915 t gcesareni In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor. SIGNOR-152603 0.358 CSNK2A1 protein P68400 UNIPROT CDC37 protein Q16543 UNIPROT up-regulates activity phosphorylation Ser13 VWDHIEVsDDEDETH -1 12930845 t llicata Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. | In this report, we demonstrate that mammalian Cdc37 is phosphorylated on Ser13 in situ in rabbit reticulocyte lysate and in cultured K562 cells and that casein kinase II is capable of quantitatively phosphorylating recombinant Cdc37 at this site. SIGNOR-250838 0.406 CDH20 protein Q9HBT6 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265859 0.302 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1B protein Q92523 UNIPROT down-regulates activity binding 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267115 0.8 PRKCH protein P24723 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser738 ARIIGEKsFRRSVVG 9606 10197446 t llicata These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748. SIGNOR-66730 0.362 ROCK1 protein Q13464 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 12185584 t gcesareni Here we found that rho-kinase has an activity for mrlc diphosphorylation at both threonine 18 and serine 19 in nonmuscle cells using sequential column chromatographies. SIGNOR-91546 0.608 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CLIP1 protein P30622 UNIPROT up-regulates activity phosphorylation Thr287 KIGFPSTtPAKAKAN 19687009 t lperfetto Cdc2 phosphorylates T287|CLIP-170, the founding member of microtubule “plus ends tracking” proteins, is involved in many critical microtubule-related functions, including recruitment of dynactin to the microtubule plus ends and formation of kinetochore-microtubule attachments during metaphase. |These results demonstrate that Cdc2-mediated phosphorylation of CLIP-170 is essential for the normal function of this protein during cell cycle progression. SIGNOR-275471 0.464 PRKCA protein P17252 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates activity phosphorylation Thr176 ENKNLTGtARYASIN -1 31096047 t miannu In the present study we analyzed the CK1δ kinase domain for phosphorylation sites targeted by PKCα. Several phosphorylation sites were identified in vitro by initially using GST-CK1δ wild type and phosphorylation-site mutant protein fragments originating from the CK1δ kinase domain. Residues S53, T176, and S181 could finally be confirmed as targets for PKCα. Determination of kinetic parameters of full-length wild type and mutant GST-CK1δ-mediated substrate phosphorylation revealed that integrity of residue T176 is crucial for maintaining CK1δ kinase activity. SIGNOR-277450 0.2 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Tyr1105 CSEVERTyLKTKSSS -1 10195142 t lperfetto To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain. SIGNOR-247163 0.584 EFNA3 protein P52797 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52381 0.81 CAMK2D protein Q13557 UNIPROT KCNJ11 protein Q14654 UNIPROT down-regulates phosphorylation Thr224 MQVVRKTtSPEGEVV 9606 23223335 t lperfetto Results showed that activation of camkii triggered dynamin-dependent internalization of k(atp) channels. This process required phosphorylation of threonine at 180 and 224 and an intact (330)yskf(333) endocytosis motif of the k(atp) channel kir6.2 pore-forming subunit. SIGNOR-200027 0.2 PTGS2 protein P35354 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 BTO:0000007 32995789 f miannu Given our finding that COX-2 signaling does not regulate viral entry or replication, the role of COX-2 induction upon SARS-CoV-2 infection remains an area for future investigation. Rather than directly affecting viral entry or replication, COX-2 induction may regulate the severe lung inflammation and injury seen in COVID-19 patients (35, 36), though it is unclear whether COX-2 would be beneficial, neutral, or detrimental to disease. COX-2 could enhance lung injury in COVID-19, as PGE2 has been reported to induce IL-1β and exacerbate lung injury in bone marrow transplant mice SIGNOR-262509 0.7 PPP2CA protein P67775 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates dephosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 t gcesareni Pp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a. SIGNOR-252971 0.412 Membrane attack complex complex SIGNOR-C313 SIGNOR Cell_killing phenotype SIGNOR-PH149 SIGNOR up-regulates -1 30552328 f lperfetto Our work provides a structural basis for understanding how β-pore forming proteins breach the membrane and reveals a mechanism for how MAC kills pathogens and regulates cell functions. SIGNOR-263454 0.7 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 15735019 t miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates SIGNOR-150484 0.634 ATF6 protein P18850 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 14973138 t Luana  Accordingly, N-terminal fragments of each ATF6 isoform (N-ATF6α and N-ATF6β) were overexpressed in HeLa cells and the effects on GRP78 induction were assessed. When expressed at similar levels, N-ATF6α conferred ∼200-fold greater GRP78 promoter activation than N-ATF6β.  SIGNOR-261565 0.815 S1PR2 protein O95136 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257123 0.358 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A11/b1 integrin complex SIGNOR-C168 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259022 0.457 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser20 HVAGGPPsPEVGSPL 9606 11110801 t llicata In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676). SIGNOR-84980 0.453 INSR protein P06213 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr577 YMEDSTYyKASKGKL -1 9507031 t P125(Fak) sequence comprising amino acids 568-582, which contains tyrosines 576 and 577 of the kinase domain regulatory loop, is phosphorylated by the insulin receptor. p125(Fak) phosphorylation by the receptor results in its activation. SIGNOR-251324 0.36 TRBC1 protein P01850 UNIPROT TCR complex SIGNOR-C153 SIGNOR form complex binding 9606 12507424 t miannu The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules.the TCRα-CD3δε and TCRβ-CD3γε interactions are similar since both require a lysine in the TM region of the respective TCR chain and both acidic TM residues in the relevant CD3 heterodimer. Nevertheless, formation of fully assembled αβ TCR-CD3 complexes containing the ζ-chain strictly required both CD3γ and δ SIGNOR-255298 0.2 TUBGCP5 protein Q96RT8 UNIPROT g-TuRC complex complex SIGNOR-C282 SIGNOR form complex binding -1 31862189 t lperfetto Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.” SIGNOR-262329 0.816 domperidone chemical CHEBI:31515 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258721 0.8 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258203 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation 9606 14967450 t inferred from 70% family members gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-270117 0.2 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates phosphorylation Tyr1021 PNEGDNDyIIPLPDP 9606 1396585 t llicata These data show that tyrosine phosphorylation of plc-gamma is dependent on autophosphorylation of the pdgf beta-receptor at tyr1009 and tyr1021. SIGNOR-18579 0.2 GATA3 protein P23771 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 12876556 f Initiation of transcription of the gene encoding IL-4 in naive T(H) cells is regulated by the T(H) 2-specific transcription factor GATA3 SIGNOR-254500 0.501 PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation Tyr118 VGEEEHVySFPNKQK 9606 15688067 t miannu Paxillin is phosphorylated by FAK–Src on Tyr31 and Tyr118, and this can also promote SH2-mediated binding of Crk to paxillin. Overexpressing paxillin that is mutated at these phosphorylation sites inhibits the turnover of focal contacts6 and cell motility, which therefore supports the presence of multiple routes for FAK–Src-mediated signalling in modulating the dynamics of cell adhesion sites. SIGNOR-28243 0.912 PTPRF protein P10586 UNIPROT DAPK1 protein P53355 UNIPROT up-regulates activity dephosphorylation Tyr491 CAAWHGYySVAKALC 9606 BTO:0002181 17803936 t miannu  Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation.  SIGNOR-276075 0.2 PTPRF protein P10586 UNIPROT DAPK1 protein P53355 UNIPROT up-regulates activity dephosphorylation Tyr490 HCAAWHGyYSVAKAL 9606 BTO:0002181 17803936 t miannu  Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation.  SIGNOR-276076 0.2 Fanconi anemia core complex complex SIGNOR-C300 SIGNOR FANCI protein Q9NVI1 UNIPROT up-regulates activity ubiquitination 18985065 t lperfetto Phosphorylation of FANCD2 and Fanconi anemia core components (broken pink circles) affects the efficiency of, but is not essential for, ID ubiquitination by the FA core complex, together with E1 and UBE2T. Analogously, ubiquitination of FANCD2 (solid orange ovals) is essential for DNA repair, activating the ID complex for chromatin binding SIGNOR-263267 0.689 GSK3A protein P49840 UNIPROT TSC2 protein P49815 UNIPROT up-regulates phosphorylation 9606 phosphorylation:Ser1387 QPLSKSSsSPELQTL 16959574 t gcesareni Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation. SIGNOR-149377 0.369 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Thr931 VCDSGVEtSFRKLSF 9606 BTO:0000567 SIGNOR-C13 10469655 t lperfetto All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391). SIGNOR-70461 0.737 CDK4 protein P11802 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates 9606 21902831 t gcesareni Not much is known about how this occurs, but inhibition of mef2c by cdk4 prevents the association of mef2 with its transcriptional coactivator, glucocorticoid receptor-interacting protein 1 (grip1). SIGNOR-176521 0.287 FZD7 protein O75084 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 22944199 t gcesareni Wnt7a binding to fzd7 activates pi3k through a g protein alpha s- dependent mechanism. SIGNOR-198831 0.2 ZNF91 protein Q05481 UNIPROT FCGR3B protein O75015 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002269 11470777 t Luana Thus, these results indicate that these cloned ZNF140 and ZNF91 proteins function as repressors for the human Fc gamma RIIB transcription. SIGNOR-266215 0.2 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-138483 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CKAP2 protein Q8WWK9 UNIPROT up-regulates phosphorylation Thr623 FKELKFLtPVRRSRR 9606 19369249 t lperfetto Among these, thr-622 was specifically phosphorylated by cdk1-cyclin b1 both in vitro and in vivo. these findings suggest that cdk1-cyclin b1-mediated phosphorylation of tmap is important for and contributes to proper regulation of microtubule dynamics and establishment of functional bipolar spindles during mitosis. SIGNOR-216829 0.298 PTPRB protein P23467 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 t gcesareni Identification of tyrosine phosphatases that dephosphorylate the insulin receptor. SIGNOR-75989 0.35 TSC22D3 protein Q99576 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity relocalization 9606 BTO:0000738 20018851 t GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells. SIGNOR-256148 0.255 MAPK1 protein P28482 UNIPROT JUND protein P17535 UNIPROT up-regulates phosphorylation Ser100 LGLLKLAsPELERLI 9606 22327296 t gcesareni Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase. SIGNOR-196030 0.544 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA8 protein Q9Y5G5 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265680 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ARRB1 protein P49407 UNIPROT down-regulates phosphorylation 9606 10347142 t inferred from 70% family members gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation SIGNOR-270094 0.2 LAMTOR3 protein Q9UHA4 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates binding 9606 9733512 t gcesareni A protein called mp1 (mek partner 1) was identified that bound specifically to mek1 and erk1 and facilitated their activation. When overexpressed in cultured cells, mp1 enhanced activation of erk1 and activation of a reporter driven by the transcription factor elk-1. SIGNOR-59877 0.59 CCT3 protein P49368 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 t miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). SIGNOR-272864 0.742 GOT2 protein P00505 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity chemical modification 9606 31422819 t Both isoforms [GOT! AND GOT2] catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. SIGNOR-266923 0.8 STK11 protein Q15831 UNIPROT STRADA protein Q7RTN6 UNIPROT up-regulates activity phosphorylation Thr329 GLSDSLTtSTPRPSN 9606 BTO:0000007 12805220 t lperfetto Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners.LKB1 phosphorylates STRAD at Thr329 and Thr419 SIGNOR-261950 0.938 ROCK1 protein Q13464 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser72 SSAVRLRsSVPGVRL 9534 BTO:0000298 9565595 t lperfetto We found that vimentin, the most widely expressed intermediate filament protein, served as an excellent substrate for Rho-associated kinase (Rho-kinase) and that vimentin phosphorylated by Rho-kinase lost its ability to form filaments in vitro. Two amino-terminal sites on vimentin, Ser38 and Ser71, were identified as the major phosphorylation sites for Rho-kinase, and Ser71 was the most favored and unique phosphorylation site for Rho-kinase in vitro.  SIGNOR-248998 0.374 CSNK2A1 protein P68400 UNIPROT KIR3DL1 protein P43629 UNIPROT up-regulates quantity by stabilization phosphorylation Ser385 AGNRTANsEDSDEQD -1 17911614 t miannu Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of Ser(394) by protein kinase C slightly suppresses KIR3DL1 inhibitory function, and reduces receptor internalization and turnover.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII. It seems that phosphorylation of 3DL1 by CK does not significantly affect receptor inhibitory function or turnover, at least in the assays that we have used so far. SIGNOR-276077 0.2 GSK3B protein P49841 UNIPROT CCND3 protein P30281 UNIPROT down-regulates phosphorylation Thr283 QGPSQTStPTDVTAI 9606 16331257 t lperfetto We have previously shown that both basal and camp-induced degradation of cyclin d3 in reh cells is dependent on thr-283 phosphorylation by glycogen synthase kinase-3beta (gsk-3beta). SIGNOR-142880 0.415 DYRK3 protein O43781 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates activity phosphorylation Ser1330 PAFGRVSsPPNAMMS 9606 BTO:0000578 31066068 t miannu Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity. SIGNOR-275451 0.2 ZEB2 protein O60315 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15311212 f miannu known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT. SIGNOR-255159 0.501 RXRB protein P28702 UNIPROT NRIP1 protein P48552 UNIPROT up-regulates binding 9606 12403842 t gcesareni Receptor interacting protein 140 (rip140) is a coregulator for a large number of transcription factors. Rip140 interacts with retinoic acid receptor (rar) and retinoid x receptor (rxr) with or without ligands SIGNOR-95160 0.586 MAPK1 protein P28482 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 10831586 t gcesareni Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability. SIGNOR-77651 0.353 TFEB protein P19484 UNIPROT SACM1L protein Q9NTJ5 UNIPROT up-regulates quantity by expression transcriptional regulation 30145926 f lperfetto Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB SIGNOR-276801 0.2 AURKA protein O14965 UNIPROT PARD3 protein Q8TEW0 UNIPROT up-regulates phosphorylation Ser962 SSRSGREsVSTASDQ 9606 BTO:0000938 19812038 t llicata Aurora a interacts directly with the atypical protein kinase c binding domain of par3 and phosphorylates it at serine 962. The phosphorylation of par3 at serine 962 contributes to its function in the establishment of neuronal polarity. SIGNOR-188398 0.357 HJURP protein Q8NCD3 UNIPROT CENPA protein P49450 UNIPROT up-regulates activity binding 9606 BTO:0000567 19410544 t miannu Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURP. Recruitment of new CENP-A into nucleosomes at replicated centromeres is dependent on HJURP. Recognition by HJURP is mediated through the centromere targeting domain (CATD) of CENP-A, a region that we demonstrated previously to induce a unique conformational rigidity to both the subnucleosomal CENP-A heterotetramer and the corresponding assembled nucleosome. We propose HJURP to be a cell-cycle-regulated CENP-A-specific histone chaperone required for centromeric chromatin assembly. SIGNOR-263707 0.958 MC4R protein P32245 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257069 0.252 GLI2 protein P10070 UNIPROT HHIP protein Q96QV1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 f lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. SIGNOR-209635 0.569 RACK1 protein P63244 UNIPROT TRPM6 protein Q9BX84 UNIPROT down-regulates activity binding 9606 BTO:0000007 18258429 t Manara We identified RACK1 as the first TRPM6-associated protein and demonstrated that RACK1 inhibits TRPM6 channel activity depending on the phosphorylation state T1851 in the α-kinase domain. SIGNOR-260921 0.2 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269333 0.719 RPL26L1 protein Q9UNX3 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262496 0.758 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74839 0.783 UBTF protein P17480 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0002882 15169904 f miannu Pescadillo (PES1) and the upstream binding factor (UBF1) play a role in ribosome biogenesis, which regulates cell size, an important component of cell proliferation. We have investigated the effects of PES1 and UBF1 on the growth and differentiation of cell lines derived from 32D cells, an interleukin-3 (IL-3)-dependent murine myeloid cell line. Parental 32D cells and 32D IGF-IR cells (expressing increased levels of the type 1 insulin-like growth factor I [IGF-I] receptor [IGF-IR]) do not express insulin receptor substrate 1 (IRS-1) or IRS-2. 32D IGF-IR cells differentiate when the cells are shifted from IL-3 to IGF-I. Ectopic expression of IRS-1 inhibits differentiation and transforms 32D IGF-IR cells into a tumor-forming cell line. We found that PES1 and UBF1 increased cell size and/or altered the cell cycle distribution of 32D-derived cells but failed to make them IL-3 independent. PES1 and UBF1 also failed to inhibit the differentiation program initiated by the activation of the IGF-IR, which is blocked by IRS-1. 32D IGF-IR cells expressing PES1 or UBF1 differentiate into granulocytes like their parental cells. In contrast, PES1 and UBF1 can transform mouse embryo fibroblasts that have high levels of endogenous IRS-1 and are not prone to differentiation. Our results provide a model for one of the theories of myeloid leukemia, in which both a stimulus of proliferation and a block of differentiation are required for leukemia development. SIGNOR-260077 0.7 ITGB1BP1 protein O14713 UNIPROT ITGB7 protein P26010 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257664 0.291 LCK protein P06239 UNIPROT CD5 protein P06127 UNIPROT up-regulates activity phosphorylation Tyr453 ASHVDNEySQPPRNS 9606 BTO:0000782 11298344 t lperfetto Tyrosine phosphorylation of cd5 requires lck activity. We propose that t cell activation mediates cd5 tyrosine phosphorylation at residues y429 and y463 mainly through the activation of lck SIGNOR-106799 0.557 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2J1 protein Q9Y385 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271308 0.583 FUS protein P35637 UNIPROT GEMIN4 protein P57678 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 23022481 t lperfetto Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells SIGNOR-262105 0.2 CEBPB protein P17676 UNIPROT GFER protein P55789 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 20690902 f miannu In the present study, we investigated transcription of hHSS triggered by EGF (epidermal growth factor) and the role of C/EBPβ (CCAAT/enhancer-binding protein β) as a potential core factor responsible for hHSS transcription in HepG2 cells. The results show that EGF suppresses hHSS mRNA expression at early time points. Using a promoter deletion assay, we identified a proximal region (-358/-212) that is required for EGF suppression. Overexpression of C/EBPβ enhances EGF suppression of hHSS, and mutation of the C/EBPβ-binding site at -292/-279 or siRNA (short interfering RNA) interference abolishes EGF suppression. SIGNOR-253772 0.2 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-258999 0.2 POLD1 protein P28340 UNIPROT DNA polymerase delta complex SIGNOR-C376 SIGNOR form complex binding -1 12403614 t lperfetto Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme. SIGNOR-265518 0.922 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates activity phosphorylation Tyr969 VSECPHTyQNRRPFS 9606 31395582 t lperfetto A mutation at tyrosine 969, which inhibits activation of downstream signaling by FLT3-ITD. SIGNOR-271919 0.2 GRIA3 protein P42263 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264949 0.8 ADCY8 protein P40145 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 t miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. SIGNOR-265002 0.8 CALM1 protein P0DP23 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates binding 9606 11796223 t gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-114104 0.658 lovastatin chemical CHEBI:40303 ChEBI HMGCR protein P04035 UNIPROT down-regulates activity chemical inhibition -1 6933445 t miannu Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. SIGNOR-258403 0.8 Exon junction complex complex SIGNOR-C369 SIGNOR mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 11532962 f lperfetto The exon–exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay SIGNOR-268313 0.7 FNTA protein P49354 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity 9606 24294527 t lperfetto Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. SIGNOR-242568 0.423 HDAC2 protein Q92769 UNIPROT TWIST1 protein Q15672 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001939 23836662 f miannu We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. SIGNOR-254154 0.389 GXYLT1 protein Q4G148 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 22117070 t gcesareni We have previously identified two human genes, gxylt1 and gxylt2, encoding glucoside xylosyltransferases responsible for the transfer of xylose to o-linked glucose. The identity of the enzyme further elongating the glycan to generate the final trisaccharide xylose-xylose-glucose, however, remained unknown. Here, we describe that the human gene c3orf21 encodes a udp-xylose:alfa-xyloside alfa1,3-xylosyltransferase, acting on xylose-alfa1,3-glucosebeta1-containing acceptor structures. We have, therefore, renamed it xxylt1 (xyloside xylosyltransferase 1). Xxylt1 cannot act on a synthetic acceptor containing an alfa-linked xylose alone, but requires the presence of the underlying glucose. Activity on notch egf repeats was proven by in vitro xylosylation of a mouse notch1 fragment recombinantly produced in sf9 insect cells, a bacterially expressed egf repeat from mouse notch2 modified in vitro by rumi and gxylt2 and in vivo by co-expression of the enzyme with the notch1 fragment. The enzyme was shown to be a typical type ii membrane-bound glycosyltransferase localized in the endoplasmic reticulum. SIGNOR-177694 0.343 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BANP protein Q8N9N5 UNIPROT down-regulates activity phosphorylation Thr337 VKSFSRRtPNSSSYC 9606 BTO:0000567 26080397 t miannu ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68. SIGNOR-266377 0.2 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Ser366 GSYAKLPsPEPSMSP -1 12361598 t miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) SIGNOR-265960 0.53 PIM proteinfamily SIGNOR-PF34 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18593906 t gcesareni We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro. SIGNOR-259426 0.2 PP1 proteinfamily SIGNOR-PF54 SIGNOR CASP2 protein P42575 UNIPROT up-regulates activity dephosphorylation Ser164 STDTVEHsLDNKDGP -1 19531356 t lperfetto Nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2. SIGNOR-264661 0.2 SRC protein P12931 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates phosphorylation Tyr110 RGHAAIDyTQLGLRF 9606 20943948 t llicata Here, we show that the interaction of noxa1 and tks proteins is dependent on src activity. Interestingly, the abolishment of src-mediated phosphorylation of tyr110 on noxa1 and of tyr508 on tks4 blocks their binding and decreases nox1-dependent ros generation. SIGNOR-168545 0.418 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates activity phosphorylation Ser77 PGPFATRsPLFIFMR 10090 12818176 t miannu Mitochondrially localized JNKs but not their upstream activators MLKs or MKKs phosphorylated BIMEL at Ser65, potentiating its cytotoxicity without altering its subcellular distribution or integration into mitochondrial membranes. JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73 SIGNOR-250133 0.75 ribavirin chemical CHEBI:63580 ChEBI IMPDH2 protein P12268 UNIPROT down-regulates activity chemical inhibition 9606 22555152 t Federica Ribavirin, a well-known IMPDH inhibitor, was included as a reference drug. As expected, this compound markedly inhibited IMPDH activity in a dose-dependent manner in bothtumour cell lines SIGNOR-261079 0.8 PTPN6 protein P29350 UNIPROT KDR protein P35968 UNIPROT unknown dephosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 BTO:0000007 18840653 t Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175 SIGNOR-248476 0.654 EEF1A1P5 protein Q5VTE0 UNIPROT Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269547 0.8 BMPR2 protein Q13873 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C29 SIGNOR-C29 18756288 t gcesareni Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1. SIGNOR-180548 0.609 CDON protein Q4KMG0 UNIPROT BNIP2 protein Q12982 UNIPROT up-regulates activity binding 9606 18678706 t lperfetto Bnip-2 and jlp are brought together through mutual interaction with cdo. the cdo-bnip-2 interaction stimulates cdc42 activity, which in turn promotes p38alpha/beta activity and cell differentiation. SIGNOR-179864 0.485 ERBB4 protein Q15303 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates relocalization 9606 16729043 t gcesareni Like erbb1, erbb4 recruits grb2, shc and stat5. SIGNOR-146891 0.479 SCF-betaTRCP complex SIGNOR-C5 SIGNOR RAPGEF2 protein Q9Y4G8 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 24290981 t miannu Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-β and casein kinase-1α and consequently degraded by the proteasome via the SCF(βTrCP) ubiquitin ligase. SIGNOR-276606 0.2 LSM4 protein Q9Y4Z0 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270650 0.788 BLVRA protein P53004 UNIPROT bilirubin(2-) smallmolecule CHEBI:57977 ChEBI down-regulates quantity chemical modification 9606 BTO:0000759 7929092 t lperfetto This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. SIGNOR-275520 0.8 USF1 protein P22415 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7862113 f irozzo Our studies show that the human C/EBPa protein stimulates USF to bind to a USF consensus element within C/EBPa promoter and activates it by two- to threefold.The mechanism by which C/EBPa enhances USF binding and transactivation is currently under study. SIGNOR-255702 0.323 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT up-regulates dephosphorylation Thr14 VEKIGEGtYGVVYKA 9606 12411508 t gcesareni Cell division cycle 25 a (cdc25a), a dual-specificity protein phosphatase, is one of the most crucial cell cycle regulators, which removes the inhibitory phosphorylation in cyclin-dependent kinases (cdks), such as cdk2, cdk4, and cdk6, and positively regulates the activities of cdks that lead to cell cycle progression. SIGNOR-95252 0.824 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 18508628 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni In addition to ser10, msk was also found to phosphorylate a second site on h3, ser28 (75). It should be noted that while both ser10 and ser28 in h3 are extensively phosphorylated during mitosis, this is independent of msks and is catalysed by aurora kinases. In contrast, msks only phosphorylate a small proportion of the total cellular histone h3 in response to mitogens or stress. The spatial distribution of ser10 and ser28 phosphorylation is very tightly regulated in cells. In vitro, msk1 will phosphorylate one histone h3 molecule on both ser10 and ser28. Surprisingly it has been shown that in cells msk phosphorylates either ser10 or ser28 but not both on individual nucleosomes. SIGNOR-178704 0.2 MAPK1 protein P28482 UNIPROT NR4A1 protein P22736 UNIPROT up-regulates activity phosphorylation Thr143 CSAPSPStPSFQPPQ 10116 BTO:0001009 11883936 t lperfetto NGFI-B is an inducible orphan nuclear receptor that initiates apoptosis. Growth factors such as EGF activate the MAP kinase ERK, whose activity may determine if a cell survives or undergoes apoptosis. EGF stimulation of cells leads to phosphorylation of threonine in NGFI-B. Thr-142 of NGFI-B is comprised in a consensus MAP kinase site and was identified as a preferred substrate for ERK2 (but not ERK1) in vitro. SIGNOR-249430 0.66 Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-267958 0.7 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-119992 0.781 MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 t lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity SIGNOR-199371 0.968 A8/b1 integrin complex SIGNOR-C165 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257707 0.535 SNCA protein P37840 UNIPROT CADPS2 protein Q86UW7 UNIPROT down-regulates quantity transcriptional regulation 9606 28647363 f gianni This approach enabled us to disclose a differential effect of high levels of LRRK2 and aSyn on CADPS2 promoter activity. Specifically, CADPS2 transcriptional activity was enhanced by high cellular levels of LRRK2 and reduced by overexpression of aSyn. Consistently, CADPS2 mRNA levels were diminished in aSyn overexpressing cells. SIGNOR-268929 0.278 DNMT3A protein Q9Y6K1 UNIPROT MEIS1 protein O00470 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 28288143 f miannu Our results indicate that, in the absence of mixed lineage leukemia fusions, an alternative pathway for engaging an oncogenic MEIS1-dependent transcriptional program can be mediated by DNMT3A mutations.Under these circumstances, those AML patients carrying the alteration in the DNA methyltransferase would undergo a hypomethylation event at the MEIS1 promoter that would lead to the overexpression of this key oncogene in leukemia. SIGNOR-256125 0.334 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI PIN1 protein Q13526 UNIPROT down-regulates activity chemical inhibition 9606 30093655 t ATRA inhibits leukemia, breast, and liver cancer by targeting isomerase Pin1, a master regulator of oncogenic signaling networks. SIGNOR-259925 0.8 FARSB protein Q9NSD9 UNIPROT Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR form complex binding 9606 20223217 t miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. SIGNOR-270435 0.994 ELOVL3 protein Q9HB03 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267893 0.8 ponatinib chemical CHEBI:78543 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 23563700 t miannu Ponatinib was able to significantly inhibit the growth of primary lung cancer cultures in vitro. Our data indicate that pharmacological inhibition of FGFR1 kinase activity with ponatinib may be effective for the treatment of lung cancer patients whose tumors overexpress FGFR1. SIGNOR-259276 0.8 CSNK1A1 protein P48729 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser511 PIGEDEEsESD -1 9045708 t llicata Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells.  SIGNOR-250794 0.328 RNF146 protein Q9NTX7 UNIPROT RNF146 protein Q9NTX7 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 21799911 t We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation. SIGNOR-260006 0.2 LCK protein P06239 UNIPROT ACP1 protein P24666 UNIPROT up-regulates activity phosphorylation Tyr133 LIIEDPYyGNDSDFE 9534 9038134 t In co-transfected COS cells, Lck and Fyn caused phosphorylation of LMPTP. Most of the phosphate was located at Tyr-131, and some was also located at Tyr-132. Site-directed mutagenesis showed that Tyr-131 is important for the catalytic activity of LMPTP, and that thiophosphorylation of Tyr-131, and to a lesser degree Tyr-132, is responsible for the activation. SIGNOR-251367 0.361 SIK3 protein Q9Y2K2 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates activity phosphorylation Ser348 PSLQSSLsNPNLQAS 9606 BTO:0000567 16306228 t lperfetto We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression SIGNOR-249170 0.62 TFE3 protein P19532 UNIPROT WIPI1 protein Q5MNZ9 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells SIGNOR-276830 0.308 pazopanib chemical CHEBI:71219 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 18620382 t Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. SIGNOR-257734 0.8 FOXO6 protein A8MYZ6 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 f lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-236560 0.282 SRC protein P12931 UNIPROT GAK protein O14976 UNIPROT up-regulates activity phosphorylation Tyr412 KGDLDISyITSRIAV -1 28135906 t miannu GAK is phosphorylated by c-Src and translocated from the centrosome to chromatin at the end of telophase. Cyclin G-associated kinase (GAK) harbors a consensus phosphorylation motif (Y412) for c-Src; however, its physiological significance remains elusive. Here, we show that GAK is phosphorylated by c-Src not only at Y412 but also at Y1149. SIGNOR-263197 0.278 ibuprofen chemical CHEBI:5855 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition -1 9057869 t miannu Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). SIGNOR-258605 0.8 CSNK1D protein P48730 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates phosphorylation Ser46 PASYSFCsGKGVGIK 9606 SIGNOR-C110 12000790 t gcesareni We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45 . This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/mscomplex of axin and casein kinase i (cki) induces betBeta-catenin phosphorylation at a single site: serine 45 (s45) SIGNOR-87437 0.537 TWIST1 protein Q15672 UNIPROT CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002590 17487558 f miannu Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells SIGNOR-255512 0.529 EP300 protein Q09472 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity acetylation 9606 20851880 t gcesareni These results indicate that Erk signaling increases Runx2 stability and transcriptional activity, partly via increasing p300 protein levels and histone acetyltransferase activity and subsequently increasing Runx2 acetylation by p300 SIGNOR-167966 0.464 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR DPPA4 protein Q7L190 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269235 0.591 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT down-regulates activity phosphorylation Ser113 TELCRTFsESGRCRY -1 14688255 t miannu We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated. SIGNOR-250156 0.686 benazepril chemical CHEBI:3011 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition 9606 16407508 t Angiotensin-converting-enzyme inhibitors provide renal protection in patients with mild-to-moderate renal insufficiency (serum creatinine level, 3.0 mg per deciliter or less). We assessed the efficacy and safety of benazepril in patients without diabetes who had advanced renal insufficiency. SIGNOR-253343 0.8 haloperidol chemical CHEBI:5613 ChEBI HTR1D protein P28221 UNIPROT down-regulates activity chemical inhibition 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258522 0.8 MAPK1 protein P28482 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Thr219 ASLSLPAtPVGKGTE -1 12556484 t done miannu In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites SIGNOR-274076 0.291 TBP protein P20226 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR form complex binding 9606 30693017 t lperfetto SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation. SIGNOR-269562 0.739 nintedanib chemical CHEBI:85164 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition -1 18559524 t Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. SIGNOR-257801 0.8 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates binding 9606 21084559 t gcesareni Phosphorylation of yap ser127 and of the corresponding sites in yki and taz generates a protein-binding motif for the 14-3-3 family proteins, which, upon binding by a 14-3-3 protein, leads to their cytoplasmic retention. SIGNOR-169716 0.2 KLKB1 protein P03952 UNIPROT KNG1 protein P01042 UNIPROT up-regulates activity cleavage Arg381 GMISLMKrPPGFSPF 9606 BTO:0000131 cleavage:Arg390 CTTKTSTrIVGGTNS 28966616 t lperfetto Bradykinin is a nonapeptide composed of the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg and functions as an inflammatory mediator. BK is the product of the kallikrein–kinin system following activation of FXII. FXIIa leads to proteolysis of PK, and the resulting PKa cleaves HK to generate BK (Figure 1). SIGNOR-263547 0.771 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation 9606 12792650 t inferred from 70% family members lperfetto Inhibition of caspase-9 through phosphorylation at thr 125 by erk mapk SIGNOR-270184 0.2 SMAD6 protein O43541 UNIPROT HOXC8 protein P31273 UNIPROT up-regulates activity binding 9606 10722652 t gcesareni Smad6 interacts with hox transcription factors as part of the negative feedback circuit in the bmp signaling pathway SIGNOR-75823 0.544 CBL protein P22681 UNIPROT PIK3R2 protein O00459 UNIPROT down-regulates ubiquitination 9606 11526404 t lperfetto Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner. SIGNOR-110063 0.589 IGF1 protein P05019 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates 10090 BTO:0000165;BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 10448861 f lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. SIGNOR-235828 0.2 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Ser518 KGGTPAGsARGSPTR 10116 16611631 t lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro SIGNOR-146003 0.452 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 9606 BTO:0000887 20151718 t miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-163784 0.278 PRKAA1 protein Q13131 UNIPROT GBF1 protein Q92538 UNIPROT down-regulates phosphorylation Thr1337 GKIHRSAtDADVVNS 9606 SIGNOR-C15 18063581 t lperfetto These results indicate that gbf1 is a novel ampk substrate and that the ampk-mediated phosphorylation of gbf1 at thr(1337) has a critical role, presumably by attenuating the function of gbf1, in the disassembly of the golgi apparatus induced under stress conditions that lower the intracellular atp concentration. SIGNOR-159639 0.2 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA11 protein Q9Y5H2 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265712 0.2 WNT5A protein P41221 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates binding 9606 2808370 t gcesareni Fz2 was also required for the wnt3a-dependent accumulation of beta-catenin, and wnt5a competed with wnt3a for binding to fz2 in vitro and in intact cells, thereby inhibiting the beta-catenin pathway. SIGNOR-23441 0.757 STAT1 protein P42224 UNIPROT MUC4 protein Q99102 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001861 19757157 t lperfetto Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level. SIGNOR-254099 0.402 CDC42BPA protein Q5VT25 UNIPROT LIMK2 protein P53671 UNIPROT up-regulates activity phosphorylation Thr505 NDRKKRYtVVGNPYW 9534 BTO:0004055 11340065 t lperfetto These results indicate that mrckalpha phosphorylates and activates lim kinases downstream of cdc42, which in turn regulates the actin cytoskeletal reorganization through the phosphorylation and inactivation of adf/cofilin. SIGNOR-107584 0.403 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation 9606 21880741 t miannu Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-255463 0.635 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 HNSSQMKsMSTFIEE 9606 BTO:0000567 25670858 t lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. SIGNOR-265232 0.571 WIPF1 protein O43516 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR up-regulates 9606 19121306 f lperfetto However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin. SIGNOR-260611 0.2 PPARGC1A protein Q9UBK2 UNIPROT CPT1B protein Q92523 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0001538 15199055 f Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. SIGNOR-254262 0.413 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT up-regulates activity cleavage Ile1512 KEFNPLViVGLSKDG -1 9242537 t lperfetto Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.V treated with HNE indicated cleavage at Ile819 and Ile1484 under conditions during which the procofactor expressed enhanced cofactor activity in the prothrombinase complex. SIGNOR-263633 0.373 PRKCE protein Q02156 UNIPROT OCLN protein Q16625 UNIPROT up-regulates phosphorylation Thr424 IREYPPItSDQQRQL 9606 21545357 t lperfetto Thr403, thr404, thr424 and thr438 in the occludin c-terminal domain are the predominant sites of pkc_-dependent phosphorylation . The present study demonstrates that pkc_ phosphorylates occludin on specific threonine residues and promotes assembly of epithelial tight junctions. SIGNOR-173639 0.2 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser130 GPKVNRPsLLEIHEQ 9606 BTO:0000007 21321328 t miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). SIGNOR-276305 0.595 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 11875057 t gcesareni In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization. SIGNOR-115340 0.838 LPAR1 protein Q92633 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257200 0.41 MAP2K4 protein P45985 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Ser257 ISGQLVDsIAKTRDA -1 9162092 t Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4. SIGNOR-251420 0.2 SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL 9606 20643654 t miannu Src-dependent pdk1 tyr373/376 tyrosine phosphorylation. / optimal activation of pdk1 requires phosphorylation of tyr373/376 SIGNOR-166718 0.567 DLG4 protein P78352 UNIPROT TANC1 protein Q9C0D5 UNIPROT up-regulates activity binding 10116 BTO:0000142 21068316 t miannu In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses. SIGNOR-266894 0.614 2-(4-morpholinyl)-6-(1-thianthrenyl)-4-pyranone chemical CHEBI:91372 ChEBI ATM protein Q13315 UNIPROT down-regulates chemical inhibition 9606 15604286 t gcesareni Through screening a small molecule compound library developed for the phosphatidylinositol 3'-kinase-like kinase family, we identified an atp-competitive inhibitor, 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (ku-55933), that inhibits atm with an ic(50) of 13 nmol/l and a ki of 2.2 nmol/l SIGNOR-132441 0.8 N-(3-aminopropyl)-N-[(1R)-1-[7-chloro-4-oxo-3-(phenylmethyl)-2-quinazolinyl]-2-methylpropyl]-4-methylbenzamide chemical CHEBI:94692 ChEBI KIF11 protein P52732 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193483 0.8 MSX1 protein P28360 UNIPROT DLX2 protein Q07687 UNIPROT down-regulates activity binding 10090 BTO:0000944 9111364 t 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. SIGNOR-240929 0.408 FGF12 protein P61328 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253428 0.314 PRKCB protein P05771 UNIPROT ITGB7 protein P26010 UNIPROT unknown phosphorylation Thr783 PLYKSAItTTINPRF 10090 BTO:0001825 12682249 t lperfetto Beta7 subunit is phosphorylated even in unstimulated TK-1 cells. Activation of TK-1 cells with anti-CD3 (Fig. 5_A) and PDBu (Fig. 5_B) increased the phosphorylation 15€“20%. | The result shows that the fourth amino acid of the tryptic peptide was phosphorylated. This phosphorylated threonine residue is most likely the first threonine (Thr782) of threonine triplet (Thr782€“784). SIGNOR-249200 0.422 mTORC1 complex SIGNOR-C3 SIGNOR ISCU protein Q9H1K1 UNIPROT up-regulates phosphorylation Ser14 FRLRRAAsALLLRSP 9606 23508953 t lperfetto Here, we demonstrate that mtorc1 associates with iscu and phosphorylates iscu at serine 14. This phosphorylation stabilized iscu protein. SIGNOR-217082 0.2 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr642 CIAGSPLtPRRVTEV 9606 BTO:0001938 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. SIGNOR-104703 0.844 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Tyr1267 PATGEQVyQQDWAQN -1 10195142 t lperfetto To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain. SIGNOR-247167 0.584 EP300 protein Q09472 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by destabilization acetylation Lys71 GILRRLKkYDNCWLA 9606 BTO:0000007 21726808 t lperfetto Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase|P300 Acetylates and Destabilizes PEPCK1|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 SIGNOR-267603 0.526 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 f apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255354 0.666 CDK5 protein Q00535 UNIPROT DLC1 protein Q96QB1 UNIPROT up-regulates activity phosphorylation Ser946 SVSPCPSsPKQIHLD 9606 BTO:0002181 25452387 t miannu The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin.  SIGNOR-276446 0.2 WNT10A protein Q9GZT5 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 9606 21872687 f fspada We show that knockdown of Beta-catenin completely prevents the inhibition of adipogenesis and stimulation of osteoblast differentiation by wnt6, wnt10a or wnt10b SIGNOR-176187 0.478 SLBP protein Q14493 UNIPROT H2AC4 protein P04908 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265397 0.2 DUSP4 protein Q13115 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7535768 t Dephosphorylation and Inactivation of ERKs|A single protein kinase, MEK, activates ERK2 by phosphorylating threonine 183 and tyrosine 185 SIGNOR-248717 0.752 POLA1 protein P09884 UNIPROT DNA polymerase alpha:primase complex complex SIGNOR-C262 SIGNOR form complex binding -1 24043831 t lperfetto At the replication fork, primase is present in a constitutive complex with DNA polymerase α (Pol α), which extends the RNA primer with deoxynucleotides and makes the resulting RNA–DNA primer available to the leading- and lagging-strand polymerases, Pols ε and δ, for processive elongation  SIGNOR-261343 0.979 ADP chemical CHEBI:16761 ChEBI P2RY1 protein P47900 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257557 0.8 AURKA protein O14965 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates activity phosphorylation Ser307 DRSPGAGsLGSPASQ -1 22214762 t miannu Here, we report a novel functional cooperativity between Aur-A and LIMK1 through mutual phosphorylation. LIMK1 is recruited to the centrosomes during early prophase and then to the spindle poles, where it colocalizes with Aur-A. Aur-A physically associates with LIMK1 and activates it through phosphorylation, which is important for its centrosomal and spindle pole localization. Aur-A also acts as a substrate of LIMK1, and the function of LIMK1 is important for its specific localization and regulation of spindle morphology.  SIGNOR-276399 0.265 KCNJ8 protein Q15842 UNIPROT KATP channel complex SIGNOR-C274 SIGNOR form complex binding 9606 28842488 t lperfetto ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits. SIGNOR-262054 0.644 KDM6A protein O15550 UNIPROT HOXA5 protein P20719 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260023 0.274 PLK1 protein P53350 UNIPROT ESPL1 protein Q14674 UNIPROT down-regulates activity phosphorylation Thr1363 AGPHVPFtVFEEVCP 9606 BTO:0002181 17974570 t miannu Although mutation of serine 1126 and threonine 1346 to alanine had no effect (lanes 2 and 5), additional mutation of threonine 1363 and serine 1399 rendered separase almost completely resistant to phosphorylation (lane 3). Serine 1399 seems to be the one residue within this large separase fragment that is most efficiently phosphorylated by polo-like kinase, because a corresponding point mutation was sufficient to reduce the labeling by 80% compared with wild type (lane 6). SIGNOR-276083 0.763 PRKCB protein P05771 UNIPROT EEF1A2 protein Q05639 UNIPROT up-regulates activity phosphorylation Ser53 AAEMGKGsFKYAWVL 10090 20923971 t miannu PKCβI phosphorylates eEF1A at Ser53.our proteomics exploration of cPKC signaling in the nuclei of C2C12 cells demonstrated that the up-regulation of eEF1A intranuclear content, evoked by insulin, is associated with an increase in the phosphorylation of the Ser53 residue of the protein. SIGNOR-263166 0.2 CCT137690 chemical CID:25154041 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190895 0.8 RXRA protein P19793 UNIPROT THRB protein P10828 UNIPROT up-regulates binding 9606 10976919 t gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr SIGNOR-81449 0.713 rRNA_transcription phenotype SIGNOR-PH145 SIGNOR 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR up-regulates 25901680 f lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262601 0.7 DZIP3 protein Q86Y13 UNIPROT H2AC6 protein Q93077 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271759 0.2 ATXN7L3 protein Q14CW9 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269579 0.76 DUSP22 protein Q9NRW4 UNIPROT LCK protein P06239 UNIPROT down-regulates activity dephosphorylation 9606 27557500 t miannu Because JKAP dephosphorylates and inactivates Lck in T cells [ xref ], we studied whether JKAP downregulation results in Lck activation in SLE T cells. SIGNOR-277148 0.277 DUSP26 protein Q9BV47 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser20 PLSQETFsDLWKLLP 9606 20562916 t Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma|Inhibiting DUSP26 expression in the IMR-32 neuroblastoma cell line enhanced doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression as well as apoptosis SIGNOR-248765 0.374 EIF2AK1 protein Q9BQI3 UNIPROT HBB protein P68871 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19946423 f Regulation of expression miannu Translation of α- and β-globin is tightly controlled by eIF2 and downregulated by HRI. SIGNOR-251780 0.2 NPFFR1 protein Q9GZQ6 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256708 0.252 MRPL28 protein Q13084 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262367 0.687 CDK5 protein Q00535 UNIPROT KIF13B protein Q9NQT8 UNIPROT down-regulates activity phosphorylation Thr506 SEGQVMLtPQKNTRT 10029 BTO:0000246 27512725 t miannu Overexpression of Cdk5 or its activator p35 promoted and inhibition of Cdk5 activity prevented the KIF13B-TRPV1 association, indicating that Cdk5 promotes TRPV1 anterograde transport by mediating the motor-cargo association. Cdk5 phosphorylates KIF13B at Thr-506, a residue located in the FHA domain. T506A mutation reduced the motor-cargo interaction and the cell-permeable TAT-T506 peptide, targeting to the Thr-506, decreased TRPV1 surface localization, demonstrating the essential role of Thr-506 phosphorylation in TRPV1 transport. SIGNOR-262737 0.373 CHUK protein O15111 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates phosphorylation 9606 10469655 t lperfetto All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391). SIGNOR-217397 0.789 MARCHF8 protein Q5T0T0 UNIPROT HLA-DRB3 protein P79483 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys254 FIYFRNQkGHSGLQP 9606 19117940 t miannu Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination. SIGNOR-271408 0.2 SARS1 protein P49591 UNIPROT serine smallmolecule CHEBI:17822 ChEBI down-regulates quantity chemical modification 9606 24095058 t miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis SIGNOR-270494 0.8 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267339 0.8 TWIST1 protein Q15672 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255526 0.493 ENPP1 protein P22413 UNIPROT INSR protein P06213 UNIPROT down-regulates activity binding 9606 10615944 t miannu Plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor (IR) tyrosine kinase activity and subsequent cellular signaling. PC-1 may inhibit the IR by interacting directly with a specific region in the IR alpha-subunit. SIGNOR-252190 0.397 MYH9 protein P35579 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004953 32685004 t miannu Nuclear MYH9 bound to the CTNNB1 promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote CTNNB1 transcription, which conferred resistance to anoikis in GC cells in vitro and in vivo. SIGNOR-269284 0.277 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser43 PAMLHLPsEQGAPET 9606 SIGNOR-C14 SIGNOR-C14 17977820 t lperfetto In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. SIGNOR-158655 0.962 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257969 0.8 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276086 0.282 BMP2 protein P12643 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates 9606 21793042 f gcesareni Upon bmp binding to the bmpr-ii, bmpr-i is recruited to form an activated quaternary complex, which then phosphorylates and activates intracellular smad proteins. Receptor smads bind to a co-smad and translocate to the nucleus to serve as transcription factors. SIGNOR-175273 0.487 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74823 0.783 CDK2 protein P24941 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser36 PRKQPPVsPGTALVG 9606 17960875 t gcesareni Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation. SIGNOR-158612 0.267 ANK3 protein Q12955 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity binding 9606 BTO:0000007 17620337 t miannu Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. Ankyrin-G also recruits beta-2-spectrin to E-cadherin-beta-catenin complexes, thus providing a direct connection between E-cadherin and the spectrin/actin skeleton. SIGNOR-266710 0.329 MAP3K14 protein Q99558 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 9020361 f amattioni Nik stimulates nf-kappab activity SIGNOR-46212 0.358 DPF3 protein Q92784 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270690 0.738 AKT1 protein P31749 UNIPROT RARG protein P13631 UNIPROT up-regulates activity phosphorylation Ser371 YARRRRPsQPYMFPR 9606 BTO:0000093 31740618 t miannu S379 of RARγ is indispensable for the CLDN6-triggered cellular events. The most important finding of the present study is that the CLDN6/SFK/PI3K/AKT signaling controls the RARγ and ERα activities (Fig. 6). SIGNOR-277492 0.444 IRX1 protein P78414 UNIPROT DKK3 protein Q9UBP4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. SIGNOR-261658 0.264 RLN2 protein P04090 UNIPROT RXFP2 protein Q8WXD0 UNIPROT up-regulates binding 9606 BTO:0000142 11809971 t gcesareni Lgr7 and lgr8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (camp)-dependent pathway. SIGNOR-114585 0.697 PAK6 protein Q9NQU5 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 23132866 t miannu We also showed that PAK6 phosphorylates Mdm2 on Thr-158 and Ser-186, which is critical for AR ubiquitin-mediated degradation. SIGNOR-276427 0.2 SRC protein P12931 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Tyr156 YGPRAEEyEFLTPVE 9606 16943322 t llicata We show here that src kinase binds and phosphorylates rhogdi both in vitro and in vivo at tyr156. analysis of rho gtpase-rhogdi complexes using in vitro assays of complexation and in vivo by coimmunoprecipitation analysis indicates that src-mediated phosphorylation of tyr156 causes a dramatic decrease in the ability of rhogdi to form a complex with rhoa, rac1, or cdc42. SIGNOR-149282 0.409 RPL12 protein P30050 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262487 0.869 S100A9 protein P06702 UNIPROT Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR down-regulates 10090 18809714 f miannu We report here that up-regulation of S100A9 in myeloid precursors in cancer inhibits DC and macrophage differentiation and induces accumulation of MDSCs. This may represent a universal molecular mechanism of tumor-induced abnormalities in myeloid cells in cancer, directly linking inflammation and immune suppression. SIGNOR-261933 0.7 PP2B proteinfamily SIGNOR-PF18 SIGNOR IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18177723 f inferred from 70% family members lperfetto Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy SIGNOR-269987 0.2 STK4 protein Q13043 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates activity phosphorylation Thr183 GWKPGSDtIKPDVQK -1 23386615 t miannu Mst1 inactivates Prdx1 by phosphorylating it at Thr-90 and Thr-183, leading to accumulation of hydrogen peroxide in cells.Prdx1 is phosphorylated by Mst1 predominantly at Thr-18, Thr-90, and Thr-183. SIGNOR-276485 0.2 PGAM1 protein P18669 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI down-regulates quantity chemical modification 9606 24786789 t miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. SIGNOR-266511 0.8 Scribble_complex_DLG1-LLGL1_variant complex SIGNOR-C511 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 f miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270914 0.7 PKI-587 chemical CID:44516953 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205989 0.8 PTPRG protein P23470 UNIPROT INSR protein P06213 UNIPROT up-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254705 0.373 PTPN1 protein P18031 UNIPROT PITX1 protein P78337 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr160 LDLCKGGyVPQFSGL 9606 27752061 t lperfetto PTP1B dephosphorylates PITX-1 at Y160, 175 and Y179.|Through directly dephosphorylating PITX-1 at Y160, Y175 and Y179, PTP1B promoted proteasomal degradation of PITX-1, thus leaded in downregulating p120RasGAP and CRC cell survival. SIGNOR-276974 0.361 FBXW11 protein Q9UKB1 UNIPROT SKP1 protein P63208 UNIPROT up-regulates binding 9606 10023660 t gcesareni The scf is composed of skp1, cdc53/cul1, and a specificity-conferring f-box protein. F-box proteins contain two domains, an f-box motif that binds skp1 and allows assembly into skp1/cdc53 complexes, and a second proteinprotein interaction domain that interacts specifically with one or more target proteins. Cdc53/cul1, in turn, interacts with both the e2 and the skp1/f-box protein complex. SIGNOR-64505 0.793 ACTN1 protein P12814 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity by stabilization binding 9606 27871158 t lperfetto Actin exists in polymer where filamin and α-actinin act as cross-linkers with approximately 1:10 ratios SIGNOR-261852 0.7 UBE3A protein Q05086 UNIPROT NELFCD protein Q8IXH7 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 17131388 t miannu In this paper, we identify here trihydrophobin 1 (TH1), an integral subunit of the human negative transcription elongation factor (NELF) complex, as a novel E6-AP interaction protein and a target of E6-AP-mediated degradation. Overexpression of E6-AP results in degradation of TH1 in a dose-dependent manner, whereas knock-down of endogenous E6-AP elevates the TH1 protein level.  SIGNOR-271404 0.332 CAPN1 protein P07384 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Lys76 YRLVSINkSSPLQKQ -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. SIGNOR-263560 0.384 IFNL1 protein Q8IU54 UNIPROT IFNLR1 protein Q8IU57 UNIPROT up-regulates binding 9606 12469119 t gcesareni Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha. SIGNOR-96174 0.869 P2RY13 protein Q9BPV8 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257143 0.2 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL 10090 BTO:0002572 12782654 t lperfetto S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation. SIGNOR-101336 0.96 DYRK1B protein Q9Y463 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates activity phosphorylation Ser153 SMTDFYHsKRRLIFS 10090 15851482 t lperfetto Mirk exerts its anti-apoptotic effects during muscle differentiation at least in part through effects on the cell cycle inhibitor and pro-survival molecule p21cip1. Overexpression and rna interference experiments demonstrated that mirk phosphorylates p21 within its nuclear localization domain at ser-153 causing a portion of the typically nuclear p21 to localize in the cytoplasm.Translocation to the cytoplasm enables p21 to block apoptosis through inhibitory interaction with pro-apoptotic molecules. SIGNOR-235635 0.26 FANCD2 protein Q9BXW9 UNIPROT BRCA2 protein P51587 UNIPROT up-regulates activity relocalization 9606 15199141 t lperfetto FANCD2-Ub then promotes BRCA2 loading into a chromatin complex. SIGNOR-263253 0.805 GARS1 protein P41250 UNIPROT tRNA(Gly) smallmolecule CHEBI:29176 ChEBI down-regulates quantity chemical modification 9606 24898252 t miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. SIGNOR-270477 0.8 MAPK3 protein P27361 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Thr345 GADSDVEtPSNFGKY 9606 27846390 t lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  SIGNOR-262985 0.317 FBXO22 protein Q8NEZ5 UNIPROT BAG3 protein O95817 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002181 34215846 t miannu We further demonstrated BAG3, a HSP70 co-chaperone, is a bona fide substrate of SCFFBXO22. FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BAG3 phosphorylation at S377. SIGNOR-277319 0.2 ROCK1 protein Q13464 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Thr19 KKRPQRAtSNVFAMF -1 21457715 t Giulio Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation. SIGNOR-260308 0.632 MYLIP protein Q8WY64 UNIPROT VLDLR protein P98155 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 20427281 t miannu Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation. SIGNOR-271487 0.686 MAPK1 protein P28482 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity phosphorylation Thr602 TAIISIPtPPVTTPE 10116 BTO:0000601 11080179 t miannu We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP. SIGNOR-262935 0.375 ITGB1BP1 protein O14713 UNIPROT A6/b1 integrin complex SIGNOR-C164 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257644 0.756 PPP1CA protein P62136 UNIPROT MECOM protein Q03112 UNIPROT down-regulates activity dephosphorylation Ser726 PLKMEPQsPGEVKKL 23858473 t phosphorylation site remapping based on Fig 5 lperfetto We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation. SIGNOR-273430 0.2 LPAR3 protein Q9UBY5 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256747 0.252 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 20068231 t gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. SIGNOR-163274 0.2 COLGALT2 protein Q8IYK4 UNIPROT COL1A2 protein P08123 UNIPROT up-regulates activity glycosylation -1 19075007 t Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. SIGNOR-261157 0.374 RFX complex complex SIGNOR-C104 SIGNOR HLA-DQA2 protein P01906 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 f The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-253996 0.273 GATA1 protein P15976 UNIPROT RUNX1T1 protein Q06455 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002731 20487545 f Regulation miannu GATA-1 transcription factor binds and transactivates the ETO proximal promoter in an erythroid/megakaryocytic-specific manner. Thus, trans-acting factors that are essential in erythroid/megakaryocytic differentiation govern ETO expression. SIGNOR-251929 0.304 Exon junction complex complex SIGNOR-C369 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates activity relocalization 9606 11532962 t lperfetto The exon–exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay SIGNOR-268315 0.8 UNC5C protein O95185 UNIPROT DCC protein P43146 UNIPROT down-regulates activity binding 9606 BTO:0001484 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268165 0.656 VPS39 protein Q96JC1 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR down-regulates quantity binding 9534 12941698 t miannu Overexpression of TLP blocks TGF-β-induced formation of Smad3/4 complexes while it does not alter Smad2/4 complex levels. SIGNOR-261378 0.32 SRC protein P12931 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity phosphorylation Tyr328 EELPYSEyFEYFAPD -1 30317579 t miannu C-Src also phosphorylated three tyrosine sites of HDAC3 at tyrosine 325, 328, and 331. Importantly, wild-type c-Src increases HDAC3 activity, but not mutant c-SrcK298M (kinase inactive form).  SIGNOR-277485 0.394 NRXN2 protein Q9P2S2 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 22626544 t miannu The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites SIGNOR-265454 0.823 JUN protein P05412 UNIPROT KRT16 protein P08779 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000552 12954631 f miannu these results suggest that Sp1 and AP1 sites in the essential promoter region are critical for EGF response, and Sp1 showed a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of EGF-induced keratin 16 gene expression. The coactivators p300/CBP could collaborate with Sp1 and c-Jun in the activation of keratin 16 promoter. SIGNOR-253905 0.27 NRAS protein P01111 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-175222 0.838 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr534 SRTPSLPtPPTREPK 9606 17078951 t The effect has been demonstrated using P10636-8 lperfetto Here, we found that prephosphorylation by pka promotes gsk-3beta-catalyzed tau phosphorylation at thr181, ser199, ser202, thr205, thr217, thr231, ser396 and ser422 SIGNOR-150364 0.728 EGR2 protein P11161 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 9606 BTO:0001412 1864967 f irozzo Finally, we demonstrate that dexamethasone, an inhibitor of monocytic differentiation, blocks the associated increases in EGR-1 and EGR-2 expression. Taken together, the results indicate that the EGR-1 and EGR-2 early response genes are involved in the induction of myeloid leukemia cell differentiation along the monocytic lineage and in the activation of human monocytes. SIGNOR-256089 0.7 prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 3308494 f apalma The results suggest a role for prostanoids in the regulation of both human myoblast proliferation and differentiation SIGNOR-255362 0.7 PKA proteinfamily SIGNOR-PF17 SIGNOR HDAC4 protein P56524 UNIPROT up-regulates activity phosphorylation Ser584 EPGQRQPsEQELLFR -1 30661366 t miannu  In vitro kinase assays have established that Ser584 and Ser265/266 are phosphorylated by protein kinase A (PKA). Overexpression of site-specific HDAC4 mutants (S584A, S265/266A) in HEK 293T cells, followed by HDAC activity assays, revealed the mutants to be less active than the wild-type protein. SIGNOR-277423 0.2 LPAR proteinfamily SIGNOR-PF2 SIGNOR PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser189 YRPKPSSsPVIFAGG 10090 BTO:0000665 17475908 t miannu All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells. SIGNOR-262669 0.2 YAP1 protein P46937 UNIPROT FBXO32 protein Q969P5 UNIPROT down-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 f gcesareni The downregulation of fbox32 expression by high yap activity in activated satellite cells may contribute to sustaining high levels of myod in activated satellite cells. SIGNOR-199069 0.2 INPP5D protein Q92835 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 12421919 t gcesareni Two inositol phosphatases implicated in the degradation of PI(3, 4, 5)P3, namely the 5_ phosphatase Src homology 2 domain containing inositol polyphosphate phosphatase (SHIP) and the 3_ phosphatase and tensin homolog deleted on chromosome ten SIGNOR-252428 0.8 CEBPA protein P49715 UNIPROT PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22260161 f apalma We have previously shown that PER2 is a downstream CCAAT-enhancer-binding protein (C/EBP)-target gene, and its disruption might be involved in the initiation and progression of acute myelogenous leukemia (AML) SIGNOR-256369 0.406 DISP1 protein Q96F81 UNIPROT SHH protein Q15465 UNIPROT up-regulates activity binding 9606 BTO:0000007 22902404 t lperfetto We show that the vertebrate homologue, dispatched-a (dispa) interacts with human sonic hedgehog (hshh) via its cholesterol anchor, and that this interaction is necessary for hshh secretion. binding to dispa is necessary but not sufficient for hshh secretion SIGNOR-191888 0.718 FBXW11 protein Q9UKB1 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000848;BTO:0000527 10564661 t tpavlidou We found that in vitro-translated 35s- labeled slimb indeed specifically bound to su(fu) in the gst pull-down assay. In our functional gli reporter assay, slimb alone did not alter gli-induced reporter expression;however, when cotransfected with hsu(fu), slimb significantly potentiated the inhibitory effect of su(fu) on gli activity. SIGNOR-72240 0.296 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269369 0.719 CDC25A protein P30304 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 10454565 t Phosphatase activity of Cdc25A is critical for its activating capacity (data not shown). In this context, it should also be mentioned that Cdc25A is able to activate cyclin B-Cdk1 in vitro SIGNOR-248480 0.836 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser394 TRQTPVDsPDDSTLS 10090 BTO:0002572 12782654 t lperfetto S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation. SIGNOR-101328 0.96 warfarin chemical CHEBI:10033 ChEBI VKORC1 protein Q9BQB6 UNIPROT down-regulates activity chemical inhibition 9606 27941861 t lperfetto Warfarin and vitamin K compete for binding to Phe55 in human VKOR|Our results challenge the prevailing concept of noncompetitive warfarin inhibition because K vitamers and warfarin share binding sites on VKOR that include Phe55, a key residue binding either the substrate or inhibitor. SIGNOR-265911 0.8 PTPRG protein P23470 UNIPROT KIT protein P10721 UNIPROT down-regulates activity dephosphorylation Tyr703 DHAEAALyKNLLHSK -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254709 0.2 HNuRF complex SIGNOR-C448 SIGNOR Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000142 14609955 f miannu Human NURF (hNURF) is enriched in brain, and we demonstrate that it regulates human Engrailed, a homeodomain protein that regulates neuronal development in the mid-hindbrain. Furthermore, we show that hNURF potentiates neurite outgrowth in cell culture. Taken together, our data suggess a role for an ISWI complex in neuronal growth. SIGNOR-268838 0.7 CDK1 protein P06493 UNIPROT ESCO1 protein Q5FWF5 UNIPROT down-regulates phosphorylation 9606 23314252 t gcesareni We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases , cdc7-dbf4 and the gsk-3 homolog mck1. SIGNOR-200400 0.486 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 20444238 t gcesareni Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis. SIGNOR-165220 0.695 STAT6 protein P42226 UNIPROT CHI3L1 protein P36222 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 20508200 f lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. SIGNOR-249537 0.285 SPRY4 protein Q9C004 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002058 20501643 f miannu When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. SIGNOR-253040 0.27 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser579 NVKSKIGsTENLKHQ -1 8999860 t miannu Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules SIGNOR-250284 0.318 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr463 MLAGVSEyELPEDPR 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1 SIGNOR-236179 0.2 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2K protein P61086 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271333 0.839 SMO protein Q99835 UNIPROT GNB1 protein P62873 UNIPROT up-regulates binding 9606 23074268 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-199174 0.358 EEF1A1P5 protein Q5VTE0 UNIPROT Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269548 0.8 PPP2CA protein P67775 UNIPROT PREX2 protein Q70Z35 UNIPROT up-regulates activity dephosphorylation Ser1107 DTISNRDsYSDCNSN 9606 BTO:0000007 26438819 t miannu PREX2 is dephosphorylated by PP1α and PP2A.PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. SIGNOR-277184 0.2 CYP24A1 protein Q07973 UNIPROT calcitriol smallmolecule CHEBI:17823 ChEBI down-regulates quantity chemical modification 30080183 t lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). SIGNOR-270572 0.8 LYL1 protein P12980 UNIPROT ANGPT2 protein O15123 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22792348 f miannu Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation. SIGNOR-198276 0.2 PRKDC protein P78527 UNIPROT GOLPH3 protein Q9H4A6 UNIPROT up-regulates activity phosphorylation Thr143 ALKHVKEtQPPETVQ -1 BTO:0000567 24485452 t In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents SIGNOR-253557 0.323 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP2K4 protein P45985 UNIPROT down-regulates activity phosphorylation Ser80 IERLRTHsIESSGKL 9606 BTO:0002181 11707464 t miannu Akt (Protein Kinase B) Negatively Regulates SEK1 by Means of Protein Phosphorylation. In vitro and in vivo (32)P labeling indicated that Akt phosphorylated SEK1 on serine 78. The SEK1 mutant SEK1(S78A) was resistant to Akt-induced inhibition.  SIGNOR-275980 0.2 CREB5 protein Q02930 UNIPROT TGFBR3 protein Q03167 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002818 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253811 0.2 PAK1 protein Q13153 UNIPROT PGAM1 protein P18669 UNIPROT down-regulates phosphorylation Ser118 QVKIWRRsYDVPPPP 9606 BTO:0000130 12189148 t Activated pak1 gcesareni Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity. SIGNOR-91594 0.2 GLI3 protein P10071 UNIPROT MYCN protein P04198 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17419683 f gcesareni Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin. .Hedgehog Signals induce cellular proliferation through upregulation of n-myc, cyclin d/e, and foxm1. SIGNOR-154237 0.364 ABL1 protein P00519 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Tyr107 AYPATGPyGAPAGPL 9606 20600357 t llicata In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at positions 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-abl kinase. our results demonstrate that cells expressing galectin-3 y107f variant showed reduced migration in wound healing assay ( fig. 5). This result confirms the role of galectin-3 tyrosine phosphorylation in cell motility. SIGNOR-166493 0.362 KNSTRN protein Q9Y448 UNIPROT KIF2B protein Q8N4N8 UNIPROT down-regulates activity relocalization 9606 BTO:0001938 22535524 t lperfetto The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation. SIGNOR-252053 0.417 PIM2 protein Q9P1W9 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation -1 31730483 t miannu In addition to PIM1, also PIM2 and PIM3 were able to phosphorylate WT, but not MM NFATC1 in vitro (Fig. ​(Fig.22c). SIGNOR-276772 0.264 LYN protein P07948 UNIPROT FCGR2B protein P31994 UNIPROT up-regulates activity phosphorylation Tyr292 GAENTITySLLMHPD -1 8756631 t lperfetto Therefore, we conclude that FcgammaRIIb1 phosphorylation upon BCR-FcgammaR coligation is most likely due to BCR-associated Lyn SIGNOR-249380 0.44 FOXO proteinfamily SIGNOR-PF27 SIGNOR TRIM63 protein Q969Q1 UNIPROT up-regulates activity transcriptional regulation 10090 PMC3619734 f areggio Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1induction. SIGNOR-254990 0.2 PAX7 protein P23759 UNIPROT MLL2 complex complex SIGNOR-C88 SIGNOR up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t lperfetto Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-217712 0.309 GF proteinfamily SIGNOR-PF39 SIGNOR RTKs proteinfamily SIGNOR-PF38 SIGNOR up-regulates activity binding 9606 17306385 t miannu Multiple growth- and differentiation-inducing polypeptide factors bind to and activate transmembrane receptors tyrosine kinases (RTKs), to instigate a plethora of biochemical cascades culminating in regulation of cell fate. SIGNOR-256163 0.2 PRKDC protein P78527 UNIPROT DNA-PK complex SIGNOR-C107 SIGNOR form complex binding 9606 17308091 t miannu Complexes formed by interactions between Ku70, Ku80, and DNA-PKcs were well-established SIGNOR-226026 0.933 JAK2 protein O60674 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity phosphorylation Tyr340 RGQRDSSyYWEIEAS 10090 BTO:0001482 8876196 t  JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process. SIGNOR-251361 0.601 TIMM50 protein Q3ZCQ8 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 t lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. SIGNOR-267696 0.64 CDK5 protein Q00535 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates activity phosphorylation Ser1123 RSRSRSRsPRPRGDS 10116 BTO:0004102 12824184 t llicata We demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival.  SIGNOR-250663 0.347 MRGPRX2 protein Q96LB1 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257327 0.2 MAPK3 protein P27361 UNIPROT BRD4 protein O60885 UNIPROT down-regulates activity 9606 32482868 t lperfetto The MYC stabilizing kinase, ERK1, regulates MYC levels directly and indirectly by inhibiting BRD4 kinase activity. SIGNOR-262048 0.317 CCKAR protein P32238 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257410 0.463 PAK2 protein Q13177 UNIPROT CASP7 protein P55210 UNIPROT down-regulates phosphorylation Ser30 DAKPDRSsFVPSLFS 9606 BTO:0000150 21555521 t gcesareni Pak2 can bind with caspase-7 and phosphorylate caspase-7 at the ser-30, thr-173, and ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis. SIGNOR-173659 0.357 PAK5 protein Q9P286 UNIPROT PAK5 protein Q9P286 UNIPROT up-regulates activity phosphorylation His19 SGPSNFEhRVHTGFD -1 12860998 t miannu Active form of Cdc42, but not Rac1 and Rho, protein was able to activate the purified GST-Pak5 autophosphorylation and kinase activity. Mutations of Pak5, which disrupted the interaction of Cdc42 and Pak5, also abolished the induction of autophosphorylation.  The H19L/H22L mutant of Pak5 was insensitive to the Cdc42-induced autophosphorylation. SIGNOR-250248 0.2 MIB1 protein Q86YT6 UNIPROT RYK protein P34925 UNIPROT down-regulates ubiquitination 9606 21875946 t gcesareni We discovered that ryk both physically and functionally interacts with the e3 ubiquitin ligase mind bomb 1 (mib1).We Found that overexpressed ryk and mib1 colocalized and that the overexpression of mib1 leads to the loss of surface ryk expression. In addition, biochemical studies revealed that mib1 promotes the ubiquitination and degradation of ryk. Endogenous ryk and mib1 were required for the wnt-dependent activation of wnt/ctnnb1 signaling SIGNOR-176282 0.333 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-269967 0.2 SEM1 protein P60896 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263343 0.2 BCL2 protein P10415 UNIPROT CYCS protein P99999 UNIPROT down-regulates activity 9606 BTO:0000567 12624108 f lperfetto Bcl-2 blocked the release of mitochondrial cytochrome c SIGNOR-99063 0.63 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21798082 t lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-252820 0.908 LSM-1231 chemical CHEBI:91471 ChEBI NTRK2 protein Q16620 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259759 0.8 SPTB protein P11277 UNIPROT Erythrocytic spectrin complex SIGNOR-C384 SIGNOR form complex binding 9606 BTO:0000424 24302288 t lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell SIGNOR-266024 0.731 NEDD1 protein Q8NHV4 UNIPROT g-TuRC complex complex SIGNOR-C282 SIGNOR up-regulates activity binding 9606 19029337 t miannu It has been reported that NEDD1 directly interacts with and recruits the gamma-tubulin ring complex to centrosomes and to spindle MTs to promote MT nucleation and spindle assembly SIGNOR-261422 0.757 ARNT protein P27540 UNIPROT CA9 protein Q16790 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22387692 f lperfetto The miR-24-dependent down-regulation of ARNT decreased the expression of its downstream genes such as CYP1A1 and carbonic anhydrase IX. SIGNOR-253706 0.504 PAX7 protein P23759 UNIPROT KMT2A protein Q03164 UNIPROT up-regulates binding 9606 SIGNOR-C89 22863532 t miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-198626 0.2 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates phosphorylation Ser49 IEGMILLsELSRRRI 9606 3352609 t lperfetto The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases present in the reticulocyte lysate. These findings support the hypothesis that the serine 48 residue is required for high-affinity interaction between eif2 alpha(p) and eif2b. SIGNOR-24539 0.886 SLIT2 protein O94813 UNIPROT ROBO3 protein Q96MS0 UNIPROT up-regulates activity binding -1 16226035 t miannu This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. SIGNOR-268381 0.645 MARCHF5 protein Q9NX47 UNIPROT MARCHF5 protein Q9NX47 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 16874301 t miannu Rapid degradation of MITOL by autoubiquitination activity. Taken together, these results suggested that MITOL strictly controls its protein expression level by rapid degradation of MITOL through the PHD-dependent autoubiquitination activity. SIGNOR-271895 0.2 NOTCH1 protein P46531 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 16990763 f lperfetto Other notch target genes identi?ed In the thymoma cell line were dtx1 (gene for deltex1), i?-202, i?-204, i?-D3, adam19 (meltrinb).24 a number of other genes have been reported as being notch targets, including notch1 itself,28 nrarp in xenopus embryos,29 bcl2 in thymoma cells,30 ccnd1 (gene for cyclin d1) in a kidney cell line,31 dkn1a (gene for cyclindependent kinase inhibitor 1a (p21, cip1)) in keratinocytes32 and tcf3 (gene for e2a). SIGNOR-149777 0.2 MRPL19 protein P49406 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262375 0.708 CDK2 protein P24941 UNIPROT NPAT protein Q14207 UNIPROT up-regulates phosphorylation Thr1270 SDLPVPRtPGSGAGE 9606 10995387 t llicata Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter. SIGNOR-82137 0.458 NUMA1 protein Q14980 UNIPROT TUBA4A protein P68366 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-116788 0.494 RPL37A protein P61513 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262462 0.817 RPS6KA3 protein P51812 UNIPROT HMGN1 protein P05114 UNIPROT unknown phosphorylation Ser7 sSAEGAAK 10090 12773393 t lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 and HMG-14 at Ser6 after stimulation of primary embryonic fibroblasts by TPA or anisomycin. SIGNOR-249215 0.371 VAPB-PTPIP51 complex complex SIGNOR-C275 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 10116 BTO:0000142 30841933 f lperfetto Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction. SIGNOR-262120 0.7 SRC protein P12931 UNIPROT TGFA protein P01135 UNIPROT up-regulates activity 9606 17251915 f lperfetto Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network. SIGNOR-236534 0.305 FADD protein Q13158 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 22890322 t lperfetto Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8 SIGNOR-191781 0.783 EDNRA protein P25101 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257253 0.276 D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI up-regulates quantity precursor of 9606 24929114 t miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. SIGNOR-268140 0.8 SP1 protein P08047 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000944 23936544 t lperfetto MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-β mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-β production SIGNOR-251740 0.301 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257929 0.8 MAP2K7 protein O14733 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Thr180 RHADAEMtGYVVTRW 9606 BTO:0000007 10066767 t done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. SIGNOR-273954 0.412 GMIP protein Q9P107 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260506 0.421 PPP1CA protein P62136 UNIPROT CDC25C protein P30307 UNIPROT up-regulates binding 9606 14592972 t gcesareni Pp1 recognizes cdc25 directly by interacting with a pp1-binding motif in the cdc25 n-terminus. SIGNOR-118917 0.483 UNC80 protein Q8N2C7 UNIPROT NALCN protein Q8IZF0 UNIPROT up-regulates activity binding 9606 BTO:0000007 19535918 t miannu UNC80 is a protein that is associated with the NALCN Na(+) leak cation channel, and is required for the activation of this channel by the neuropeptide substance P through GPCRs in a G-protein-independent fashion. Here, we show that UNC80 binds Src kinases and recruits Src into the channel complex.  SIGNOR-265180 0.802 NEK9 protein Q8TD19 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser377 EKAGLPRsINTDTLS -1 22818914 t miannu Nek9 phosphorylates NEDD1 on Ser377 driving its recruitment and thereby that of γ-tubulin to the centrosome in mitotic cells. SIGNOR-263016 0.437 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236752 0.912 DPF2 protein Q92785 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity binding 9606 BTO:0000007 20460684 t miannu REQ is required for the oncogenic activity induced by RelB/p52. . Through in vitro binding experiments, REQ was found to bind to several SWI/SNF complex subunits and also to the p52 NF-κB subunit through its nuclear localization signal containing the N-terminal region. In this study, we present evidence that REQ is a specific adaptor protein that links RelB/p52 with Brm-type SWI/SNF complexes and thereby plays pivotal roles at the most downstream stages of the noncanonical NF-κB pathway. We further show that REQ is required for oncogenesis in several human tumor cell lines in which the noncanonical NF-κB pathway is aberrantly regulated.REQ and Brm specifically promote RelB/p52-dependent transcriptional activity. SIGNOR-261964 0.307 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser23 ARKRHAPsPEPAVQG 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276088 0.292 NBEA protein Q8NFP9 UNIPROT DLG3 protein Q92796 UNIPROT up-regulates activity binding BTO:0000227 23277425 t lperfetto Interestingly, a recent proteomic analysis (Lauks et al., 2012) revealed that Nbea binds SAP102, which interacts with glutamate receptors early in the biosynthetic route and regulates their targeting. This finding, along with the interaction of Nbea with the glycine receptor beta subunit (del Pino et al., 2011), further strengthens the notion that Nbea targets neurotransmitter receptors to synapses. SIGNOR-266004 0.43 AMPK complex SIGNOR-C15 SIGNOR EPM2A protein O95278 UNIPROT up-regulates activity phosphorylation -1 18029386 t miannu Here, we provide evidence indicating that the formation of the laforin–malin complex is positively regulated by AMPK. We show that laforin, but not malin, can interact physically with the catalytic subunit of AMPK and that purified AMPK phosphorylates GST::laforin in vitro. SIGNOR-271730 0.357 PPM1B protein O75688 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity dephosphorylation 9606 23320500 t miannu Furthermore we show that PPM1B can directly dephosphorylate PPARgamma, both in intact cells and in vitro.|In addition PPM1B increases PPARγ-mediated transcription via dephosphorylation of Ser(112).|The serine/threonine phosphatase PPM1B (PP2Cbeta) selectively modulates PPARgamma activity. SIGNOR-277073 0.379 PTPN11 protein Q06124 UNIPROT JAK2 protein O60674 UNIPROT up-regulates quantity by stabilization dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 14522994 t We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association SIGNOR-248665 0.786 BDKRB1 protein P46663 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257411 0.425 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Ala92 PAFISEDaSGYLTSS -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. SIGNOR-263576 0.43 ATM protein Q13315 UNIPROT AVEN protein Q9NQS1 UNIPROT up-regulates activity phosphorylation Ser308 NILPDQTsQDLKSKE -1 18571408 t miannu Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM after DNA damage is enhanced by ATM-mediated Aven phosphorylation. We found that mutating S135 and S308 sites to Alanine largely dampened Aven’s phosphorylation by ATM (though some phosphorylation remained, due to either a contaminating kinase or an unidentified ATM phosphorylation site). SIGNOR-262637 0.39 PPP3CB protein P16298 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18177723 f lperfetto Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy SIGNOR-251734 0.2 CUX2 protein O14529 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 10090 26221032 f miannu Genetic inactivation in mouse embryo fibroblasts or CUX2 knockdown in HCC38 cells delayed DNA repair and increased DNA damage. These results demonstrate that CUX2 functions as an accessory factor that stimulates the repair of oxidative DNA damage SIGNOR-263958 0.7 ERG protein P11308 UNIPROT ERG protein P11308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001106 21536859 f miannu We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. SIGNOR-253925 0.2 CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser124 PALKRSHsDSLDHDI 9606 20068082 t gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). SIGNOR-163134 0.851 HHAT protein Q5VTY9 UNIPROT SHH protein Q15465 UNIPROT up-regulates palmitoylation 9606 15075292 t gcesareni Our molecular analysis of knockout mice deficient in skn, the murine homolog of the drosophila ski gene, which catalyzes hh palmitoylation, and gene-targeted mice producting a non palmitoylated form of shh indicates that hh palmitoylation is essential for its activity as well as the generation of a protein gradient in the developing embryos SIGNOR-124118 0.67 ATM protein Q13315 UNIPROT AATF protein Q9NY61 UNIPROT up-regulates quantity by stabilization phosphorylation Ser189 EGDDAEDsQGESEED 9606 BTO:0001109 17157788 t lperfetto The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. |DNA damage stabilizes Che-1 protein|In addition, substitution of Che-1 Ser187 with an alanine (Che-1S187A) prevented Che-1 phosphorylation by ATM (Figure 2F), supporting this residue as an ATM-target site. SIGNOR-264415 0.362 PRKACA protein P17612 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 22310283 t gcesareni Thus, our data revealed a novel interplay between pka phosphorylation and tal1-mediated epigenetic regulation that regulates hematopoietic transcription and differentiation programs during hematopoiesis and leukemogenesis. SIGNOR-195987 0.2 SPOP protein O43791 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25278611 t miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. SIGNOR-272827 0.492 XAF1 protein Q6GPH4 UNIPROT BIRC2 protein Q13490 UNIPROT down-regulates binding 9606 17613533 t gcesareni Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3. SIGNOR-156843 0.425 entinostat chemical CHEBI:132082 ChEBI HDAC3 protein O15379 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191481 0.8 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR THBD protein P07204 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15677570 f miannu We further show evidence suggesting that NF-κB inhibits TM expression indirectly by competition for the coactivator p300/CBP. SIGNOR-253909 0.2 HLA-G protein P17693 UNIPROT LILRB1 protein Q8NHL6 UNIPROT up-regulates binding 9606 15718280 t gcesareni Hla-g binds a limited repertoire of peptides and interacts with the inhibitory leukocyte ig-like receptors lir-1 and lir-2 SIGNOR-134180 0.762 CASP3 protein P42574 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261756 0.465 NMDA proteinfamily SIGNOR-PF56 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor SIGNOR-264801 0.2 PATJ protein Q8NI35 UNIPROT AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR form complex binding 9606 24366813 t lperfetto To gain a more detailed view on the organization of this cell polarity network linked to yap1 we included several proteins of the cell junction complex (amot, mpp5, lin7a), SIGNOR-203488 0.2 PAF1C complex SIGNOR-C471 SIGNOR TCEA1 protein P23193 UNIPROT up-regulates activity binding 9606 BTO:0000567 20178742 t miannu HPAF1C Independently and Cooperatively (with SII) Stimulates Transcription Elongation. Direct Interactions of hPAF1C with Pol II and SII Are Required for Its Intrinsic and Synergistic Effects on Chromatin Transcription. SIGNOR-269838 0.619 HDLBP protein Q00341 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 33941620 f miannu Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. SIGNOR-266694 0.7 bafilomycin A1 chemical CHEBI:22689 ChEBI ATP6V1A protein P38606 UNIPROT down-regulates activity chemical inhibition 9606 9572882 t Simone Vumbaca The macrolide antibiotic bafilomycin A1 is a very potent and specific inhibitor of V-ATPases. SIGNOR-261084 0.8 RHOA protein P61586 UNIPROT FHL2 protein Q14192 UNIPROT up-regulates relocalization 9606 11847121 t gcesareni Here, we show that stimulation of the rho pathway induces translocation of the transcriptional lim-only coactivator fhl2 to the nucleus and subsequent activation of fhl2- and androgen receptor-dependent genes. SIGNOR-114071 0.354 EEF1A1P5 protein Q5VTE0 UNIPROT Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269558 0.8 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates activity dephosphorylation Tyr772 EDDPEATyTTSGGKI -1 21538645 t gcesareni The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates SIGNOR-246027 0.646 WNT5A protein P41221 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131841 0.748 TEK protein Q02763 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 f lperfetto the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. SIGNOR-241532 0.276 SMO protein Q99835 UNIPROT FYN protein P06241 UNIPROT up-regulates phosphorylation 9606 23074268 t gcesareni Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion. SIGNOR-199156 0.404 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249347 0.728 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser555 RALSNSVsNMGLSES 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249682 0.397 A4/b1 integrin complex SIGNOR-C162 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269011 0.7 ERBB2 protein P04626 UNIPROT DOCK7 protein Q96N67 UNIPROT up-regulates phosphorylation Tyr1257 METVPQLyDFTETHN 9606 18426980 t llicata We show that the nrg1 receptor erbb2 directly binds and activates dock7 by phosphorylating tyr-1118. thus, dock7 functions as an intracellular substrate for erbb2 to promote schwann cell migration. This provides an unanticipated mechanism through which ligand-dependent tyrosine phosphorylation can trigger the activation of rho gtpase-gefs of the dock180 family. SIGNOR-178348 0.511 HSD17B1 protein P14061 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification -1 8994190 t Luana Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues.  SIGNOR-269760 0.8 PBK protein Q96KB5 UNIPROT PRDX1 protein Q06830 UNIPROT up-regulates phosphorylation Ser32 QFKDISLsDYKGKYV 9606 BTO:0000782;BTO:0000848;BTO:0001286 20647304 t lperfetto We report that prx1 is newly discovered direct target of topk. Our results demonstrate that topk phosphorylation of prx1 at ser-32 inhibits uvb-induced apoptosis in rpmi7951 melanoma cells by increasing prx1 peroxidase activity and decreasing the intracellular accumulation of h2o2. SIGNOR-166901 0.262 ZNF165 protein P49910 UNIPROT PMEPA1 protein Q969W9 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 26567849 t Luana ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1. SIGNOR-266094 0.275 TOMM70 protein O94826 UNIPROT HSPA1A protein P0DMV8 UNIPROT up-regulates activity binding 9534 12526792 t miannu The Tom70 receptor is a membrane-localized cochaperone that integrates the Hsp70/Hsp90 chaperones with mitochondrial preprotein targeting and translocation. In mammals, preprotein in the cytosol is associated with both Hsp90 and Hsp70 in a multichaperone complex, and docking of Hsp90 and/or Hsp70 onto Tom70 is essential for preprotein targeting. SIGNOR-261380 0.2 UBE2D2 protein P62837 UNIPROT TRIM22 protein Q8IYM9 UNIPROT up-regulates activity binding 9606 BTO:0000007 18656448 t miannu  It was found that TRIM22 underwent self-ubiquitylation in vitro in combination with the E2 enzyme UbcH5B and the ubiquitylation was dependent on its RING finger domain. Further evidences showed that TRIM22 could also be self-ubiquitylated in vivo. Importantly, TRIM22 was conjugated with poly-ubiquitin chains and stabilized by the proteasome inhibitor in 293T cells, suggesting that TRIM22 targeted itself for proteasomal degradation through the poly-ubiquitylation. We also found that TRIM22 was located in the nucleus, indicating that TRIM22 might function as a nuclear E3 ubiquitin ligase. SIGNOR-271779 0.305 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 15895091 t gcesareni We show that the augmentation of the il6 signal by recombinant il6 receptors (ril6r) delivery allows the functional recovery of phagocytes in a peritonitis mouse model. SIGNOR-137236 0.916 SP1 protein P08047 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9223667 t lperfetto Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region. SIGNOR-251739 0.2 CDK1 protein P06493 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation Thr128 RPPQKCStPCGPLRL 9606 BTO:0000567 24413556 t miannu Phosphorylation by Cyclin B-Cdk1 allows Haspin to bind Plk1-PBD. Phosphorylation of Haspin at T128 and Plk1 target sites is required for full H3T3ph generation and normal Aurora B localization in mitosis. SIGNOR-275419 0.2 CEBPD protein P49716 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 10649448 f gcesareni We conclude that glucocorticoid-induced adipogenesis from bone marrow stromal cells is mediated through a reaction cascade in which dexamethasone transcriptionally activates C/EBPdelta; C/EBPdelta then binds to PPARgamma2 promoter and transactivates PPARgamma2 gene expression. SIGNOR-253062 0.578 F2RL1 protein P55085 UNIPROT SERPINB2 protein P05120 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). SIGNOR-254856 0.2 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-268094 0.8 ARHGAP28 protein Q9P2N2 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260483 0.483 ALDH5A1 protein P51649 UNIPROT succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity chemical modification 9606 19300440 t miannu Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix. SIGNOR-266617 0.8 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-81153 0.41 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-119996 0.781 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT down-regulates phosphorylation Ser36 AQQVSSLsESEESQD 9606 20730097 t lperfetto Although the functional impact of ck-mediated atf1 phosphorylation is still unclear, we found that mutation of ser-36 and ser-41 increased cbp kix domain binding by up to four fold (fig. 2g). This result is consistent with the negative impact of ck-mediated phosphorylation on cbp binding affinity of creb that we previously reported SIGNOR-167544 0.301 PPP3CA protein Q08209 UNIPROT FLNA protein P21333 UNIPROT down-regulates dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 t gcesareni We report that a purified c-terminal recombinant region of filamin is a suitable substrate for calcineurin in vitro. Furthermore, 1 microm cyclosporin a (csa), a specific calcineurin inhibitor, reduced the dephosphorylation of the recombinant fragment in 293ft cells SIGNOR-143979 0.262 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFA12 protein Q9UI09 UNIPROT up-regulates activity phosphorylation Thr120 HKFNVTGtPEQYVPY 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275596 0.2 ECSIT protein Q9BQ95 UNIPROT MAVS protein Q7Z434 UNIPROT up-regulates activity binding 9606 22588174 t Giorgia ECSIT interacts with IPS-1|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation SIGNOR-260371 0.439 MAPK9 protein P45984 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates phosphorylation Ser319 NSKYNAEsTERESQD 9606 18667537 t llicata This jnk phosphorylation of ps1 at ser(319)thr(320) enhances the stability of the ps1 c-terminal fragment that is necessary for gamma-secretase activity. SIGNOR-179676 0.383 LCK protein P06239 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Tyr514 TFCGTPDyIAPEILQ 9534 BTO:0000298 11381116 t The tyrosine phosphorylation sites of PKC delta in the H(2)O(2)-treated cells were identified as Tyr-311, Tyr-332, and Tyr-512 by mass spectrometric analysis with the use of the precursor-scan method and by immunoblot analysis with the use of phosphorylation site-specific antibodies. Tyr-311 was the predominant modification site among them. In an in vitro study, phosphorylation at this site by Lck, a non-receptor-type tyrosine kinase, enhanced the basal enzymatic activity and elevated its maximal velocity in the presence of diacylglycerol. phosphorylation at Tyr-311 between the regulatory and catalytic domains is a critical step for generation of the active PKC delta in response to H(2)O(2). SIGNOR-251386 0.506 MYC protein P01106 UNIPROT SURF1 protein Q15526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10858544 f miannu We show that although the Surf-1/Surf-2 promoter does not contain Myc binding sites (E-boxes), Myc over-expression, or the activation of a Myc-oestrogen receptor fusion protein, activates transcription in the Surf-1 direction and that this response to Myc requires a functional YY1 binding site. Our data suggest that the MAP kinase cascade is required for the stimulation of Surf-1 promoter activity and that the Myc-YY1 interaction mediates this response. SIGNOR-254615 0.2 Caspase 6 complex complex SIGNOR-C228 SIGNOR LMNA protein P02545 UNIPROT down-regulates cleavage 9606 11058599 t amattioni Lamin a breakdown is largely mediated by caspase-6 during the execution phase of apoptosis. SIGNOR-256457 0.649 BAZ1B protein Q9UIG0 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 t miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription SIGNOR-268826 0.553 SOD1 protein P00441 UNIPROT hydrogen peroxide smallmolecule CHEBI:16240 ChEBI up-regulates quantity chemical modification 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272287 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244152 0.2 CHEK2 protein O96017 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation Ser93 ARMMSTEsANSFTLI 9606 BTO:0002552 32187724 t lperfetto We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion.|CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, promoting autophagy via Beclin 1 release from Bcl‐2 sequestration SIGNOR-264556 0.303 AURKB protein Q96GD4 UNIPROT NSUN2 protein Q08J23 UNIPROT down-regulates phosphorylation Ser139 SRKILRKsPHLEKFH 9606 17215513 t lperfetto Aurora-b phosphorylated nsun2 at ser139. Aurora-b-phosphorylation and the phosphorylation-mimic mutation (s139e) suppressed methyltransferase activities of nsun2. SIGNOR-152001 0.709 GNA11 protein P29992 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity binding 9606 27515033 t scontino TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C. SIGNOR-267203 0.607 INSIG1 protein O15503 UNIPROT SCAP protein Q12770 UNIPROT down-regulates activity binding 10029 BTO:0000246 12202038 t Using coimmunoprecipitation and tandem mass spectrometry, we identify INSIG-1 as an ER protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP) and facilitates retention of the SCAP/SREBP complex in the ER. SIGNOR-267495 0.758 JAK2 protein O60674 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation Tyr333 QRYRLVPyGNHSYLE 9606 BTO:0001535 34131122 t miannu Mechanistically, IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. We demonstrate that BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation. SIGNOR-277567 0.302 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258289 0.8 IL4R protein P24394 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 8266078 t gcesareni Il-2r gamma was demonstrated to be a component of the il-4 receptor on the basis of chemical cross-linking data, the ability of il-2r gamma to augment il-4 binding affinity, and the requirement for il-2r gamma in il-4-mediated phosphorylation of insulin receptor substrate-1. SIGNOR-37362 0.823 MAP3K2 protein Q9Y2U5 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 11343802 t lperfetto Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation SIGNOR-244888 0.424 GSK1059615 chemical CHEBI:71955 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192771 0.8 ATP smallmolecule CHEBI:15422 ChEBI PRKAG1 protein P54619 UNIPROT down-regulates chemical inhibition 9606 SIGNOR-C15 21680840 t gcesareni AMPK is an ___ heterotrimer activated by decreasing concentrations of adenosine triphosphate (ATP) and increasing AMP concentrations. SIGNOR-228607 0.8 (-)-selegiline chemical CHEBI:9086 ChEBI MAOB protein P27338 UNIPROT down-regulates activity chemical inhibition -1 21377879 t Luana All the compounds were found as extremely potent and selective towards MAO-B, (Table 2) with at least 100 times more potent than the positive control selegiline.  SIGNOR-258136 0.8 TRAF6 protein Q9Y4K3 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates activity binding 9606 25290089 t lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205458 0.931 MYOD1 protein P15172 UNIPROT MYH7 protein P12883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 17111365 f Regulation miannu Transient transfection assays demonstrated that the calcineurin/NFATc1 signaling pathway is essential for MyHCbeta promoter activation during transformation of C2C12 myotubes but is not sufficient for complete fast MyHCIId/x promoter inhibition. Along with NFATc1, myocyte enhancer factor-2D (MEF-2D) and the myogenic transcription factor MyoD transactivated the MyHCbeta promoter in calcium-ionophore-treated myotubes in a calcineurin-dependent manner. SIGNOR-251958 0.396 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation 9606 19237534 t inferred from 70% family members lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309. SIGNOR-270201 0.2 BDKRB1 protein P46663 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257149 0.41 LEPR protein P48357 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 BTO:0001282 18718905 t miannu Janus kinase 2 (JAK2) is associated with LEPRb and autophosphorylates in response to leptin. JAK2 also phosphorylates LEPRb, STAT3, and multiple other downstream molecules. SIGNOR-263491 0.765 CAMKK1 protein Q8N5S9 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10833263 t llicata Protein kinase B (PKB) was recently reported to be activated on the phosphorylation of Thr(308) by Ca(2+)/calmodulin-dependent protein kinase kinase alpha (CaM-kinase kinase alpha), suggesting that PKB was regulated through not only the phosphoinositide 3-kinase pathway but also the Ca(2+)/calmodulin protein kinase pathway. SIGNOR-250714 0.388 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser290 GRIVARNsRKMAFRA -1 9677319 t llicata CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. SIGNOR-250948 0.318 PHF2 protein O75151 UNIPROT ARID5B protein Q14865 UNIPROT up-regulates activity binding 9606 BTO:0000007 21532585 t miannu We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity. SIGNOR-264514 0.542 MAPK14 protein Q16539 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Thr263 TTLSLPLtPESPNDP 9606 BTO:0000887 11741533 t gcesareni Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298 SIGNOR-112770 0.568 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Thr1074 QRGSSGHtPPPSGPP 26190112 t Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. SIGNOR-253543 0.301 GNB1 protein P62873 UNIPROT PLCB1 protein Q9NQ66 UNIPROT down-regulates binding 9606 8870665 t gcesareni These results indicate that g-protein beta gamma subunits constitute a mechanism by which g-protein mediate a rapid and transient plc- beta 1. SIGNOR-44369 0.461 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 31422819 t miannu Both isoforms [GOT! AND GOT2] catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. SIGNOR-266921 0.8 SRC protein P12931 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Tyr326 EVLEDNDyGRAVDWW 9534 BTO:0004055 11445557 t lperfetto Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity. SIGNOR-252623 0.664 NTRK2 protein Q16620 UNIPROT KCNA3 protein P22001 UNIPROT down-regulates phosphorylation Tyr163 FDAILYYyQSGGRIR 9606 BTO:0000938 BTO:0000671 19166614 t gcesareni Previously we have shown that acute brain-derived neurotrophic factor (bdnf) activation of neurotrophin receptor tyrosine kinase b (trkb) suppresses the shaker voltage-gated potassium channel (kv1.3) via phosphorylation of multiple tyrosine residues in the n and c terminal aspects of the channel protein. SIGNOR-183523 0.386 PTPRJ protein Q12913 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Tyr204 HTGFLTEyVATRWYR -1 19494114 t Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the RAS pathway by direct dephosphorylation of ERK1/2 kinases|Pulldown and in vitro dephosphorylation assays confirmed our prediction and demonstrated an overall specificity of DEP-1 in targeting the phosphorylated tyrosine 204 of ERK1/2. SIGNOR-248707 0.471 CSAD protein Q9Y600 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 22718265 t miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. SIGNOR-267548 0.8 FOXO proteinfamily SIGNOR-PF27 SIGNOR CITED2 protein Q99967 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 18158893 f gcesareni Foxo3a induces expression of cited2 SIGNOR-252933 0.2 XPA protein P23025 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 f lperfetto The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275704 0.7 bilirubin(2-) smallmolecule CHEBI:57977 ChEBI biliverdin(2-) smallmolecule CHEBI:57991 ChEBI up-regulates quantity precursor of 9606 BTO:0000759 7929092 t lperfetto This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. SIGNOR-275522 0.8 silodosin chemical CHEBI:135929 ChEBI ADRA1B protein P35368 UNIPROT down-regulates activity chemical inhibition 10029 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258449 0.8 PPP3CB protein P16298 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser142 AGNSAPNsPMAMLHI 9606 BTO:0000007 26000950 t Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation. SIGNOR-255307 0.385 BBOX1 protein O75936 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI down-regulates quantity chemical modification 9606 11802770 t miannu In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. SIGNOR-269698 0.8 GCK protein P35557 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266448 0.8 PRKAR2A protein P13861 UNIPROT PRKACB protein P22694 UNIPROT down-regulates activity binding 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258757 0.892 FUS protein P35637 UNIPROT ADARB1 protein P78563 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0001279 28515487 f This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease SIGNOR-262805 0.256 LRIG1 protein Q96JA1 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates 9606 23723069 f miannu Lrig1 is a negative regulator of oncogenic receptor tyrosine kinases, including erbb and met receptors, and promotes receptor degradation. SIGNOR-202143 0.412 CDK2 protein P24941 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000551 19683496 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-187607 0.663 RAB1A protein P62820 UNIPROT C9orf72 protein Q96LT7 UNIPROT up-regulates activity binding 9606 27334615 t lperfetto Thus, our data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C9orf72 haploinsufficiency and associated reductions in autophagy might be the underlying cause of C9ALS/FTD-associated p62 pathology. SIGNOR-261282 0.487 EGR1 protein P18146 UNIPROT COL4A2 protein P08572 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21931594 f Regulation miannu Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1) SIGNOR-251918 0.2 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7330 RASSRRGsDASDFDL 9606 BTO:0004905 21295697 t lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. SIGNOR-264435 0.446 OSU-03012 chemical CHEBI:131196 ChEBI PDPK1 protein O15530 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-197715 0.8 TRIM27 protein P14373 UNIPROT WASHC1 protein A8K0Z3 UNIPROT up-regulates activity ubiquitination Lys220 DAPLSISkREQLEQQ 9606 23452853 t miannu Our mechanistic studies uncovered that K63-linked ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport. These results suggest that K63-linked ubiquitination of WASH K220 by TRIM27 is required for WASH function in retrograde transport. SIGNOR-253514 0.2 DLGAP1 protein O14490 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264588 0.2 VAV1 protein P15498 UNIPROT SYK protein P43405 UNIPROT up-regulates binding 9606 11331248 t lperfetto Vav interacts with the tyrosine kinase syk SIGNOR-107049 0.918 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 BTO:0000552 14744793 t gcesareni We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription. SIGNOR-248062 0.639 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 BTO:0000007 25658205 t Barakat Here, we show that expression of oncogenic Ras or direct activation of the MAPK pathway leads to increased mitochondrial fragmentation and that blocking this phenotype, through knockdown of the mitochondrial fission-mediating GTPase Drp1, inhibits tumor growth. This fission is driven by Erk2-mediated phosphorylation of Drp1 on Serine 616, and both this phosphorylation and mitochondrial fragmentation are increased in human pancreatic cancer. SIGNOR-275407 0.2 MBD2/NuRD complex complex SIGNOR-C337 SIGNOR NOTCH2 protein Q04721 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000578 31659254 t miannu Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. We demonstrated that ZNF774 recruits the NuRD complex to the NOTCH2 promoter and represses NOTCH2 transcription. SIGNOR-265560 0.275 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DIAPH1 protein O60610 UNIPROT up-regulates quantity by stabilization phosphorylation Thr768 PVLPFGLtPKKLYKP 9606 BTO:0002588 23325789 t miannu  DIAPH1 is phosphorylated in response to dibutyryl cAMP (Bt2cAMP) at Thr-759 via a pathway that requires extracellular signal-related kinase (ERK).We also show that Bt2cAMP promotes the PKA- and ERK-dependent phosphorylation of DIAPH1 at T759 and that mutation of this site alters the stability of the protein and the rate of cAMP-stimulated mitochondrial movement. SIGNOR-276483 0.2 TFEB protein P19484 UNIPROT IL6R protein P08887 UNIPROT up-regulates quantity by expression transcriptional regulation 30145926 f lperfetto Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB SIGNOR-276798 0.2 MC3R protein P41968 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257142 0.252 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr472 KLAEGSAyEEVPTSM 9606 BTO:0000142 1689310 t llicata We have identified the sites phosphorylated in vitro by epidermal growth factor (egf) receptor kinase in bovine brain phospholipase c-gamma (plc-gamma). They are tyrosine residues 472, 771, 783, and 1254. we propose, therefore, that the phosphorylation of plc-gamma by egf receptor kinase alters its interaction with putative inhibitory proteins and leads to its activation. SIGNOR-20980 0.835 ROBO proteinfamily SIGNOR-PF14 SIGNOR CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser216 SGLYRSPsMPENLNR 9606 BTO:0000567;BTO:0000938 BTO:0000142 15150265 t lperfetto P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteinsphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 SIGNOR-124851 0.2 PRKACA protein P17612 UNIPROT ITPR1 protein Q14643 UNIPROT down-regulates activity phosphorylation Ser1764 RPSGRREsLTSFGNG -1 12529267 t miannu IP(3)R-I was phosphorylated by PKA and PKG in vitro and exclusively by PKG in vivo. Sequential phosphorylation by PKA and by PKG-Ialpha in vitro showed that PKA phosphorylated the same site as PKG (presumably S(1755)) and an additional PKA-specific site (S(1589)). Phosphorylation of IP(3)R-I in microsomes by PKG, PKA, or a combination of PKG and PKA inhibited IP(3)-induced Ca(2+) release to the same extent, implying that inhibition was mediated by phosphorylation of the PKG-specific site. SIGNOR-249997 0.537 biphenyl-4,4'-diol chemical CHEBI:34367 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 9751507 t miannu Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings. SIGNOR-268740 0.8 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1016 DVVDADEyLIPQQGF 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236475 0.2 CCR4-NOT complex complex SIGNOR-C439 SIGNOR NANOS3 protein P60323 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 t lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins SIGNOR-268350 0.341 PHLPP1 protein O60346 UNIPROT PRKCA protein P17252 UNIPROT down-regulates quantity dephosphorylation Ser657 QSDFEGFsYVNPQFV 9606 BTO:0000067 18162466 t gcesareni In addition, knockdown of PHLPP expression reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif, but not turn motif, of PKC alpha SIGNOR-237043 0.252 HSBP1 protein O75506 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates activity binding 9606 BTO:0000567 9649501 t Monia HSBP1 is nuclear-localized and interacts in vivo with the active trimeric state of HSF1 that appears during heat shock. During attenuation of HSF1 to the inert monomer, HSBP1 associates with Hsp70. HSBP1 negatively affects HSF1 DNA-binding activity, and overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1. HSF1 interacts with HSBP1 in vivo and is a nuclear localized protein. SIGNOR-261181 0.686 NR0B2 protein Q15466 UNIPROT NR1I2 protein O75469 UNIPROT down-regulates binding 9606 12805410 t gcesareni Our results suggest that shp is a negative regulator of pxr transcriptional activity. This conclusion derives from_ in vitro, cell culture, and_ in vivo_ experiments. SIGNOR-101924 0.576 CTBP1 protein Q13363 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21681822 t irozzo Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells. SIGNOR-259197 0.584 PRKCQ protein Q04759 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates activity phosphorylation Thr227 LEPEALHtPTLMTTP 9606 27816489 t Manara PKCθ-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors. SIGNOR-260879 0.2 FOXA2 protein Q9Y261 UNIPROT OTX2 protein P32243 UNIPROT down-regulates activity binding 9606 BTO:0000567 10623575 t miannu Here we show that OTX2 directly associates with LIM1 and HNF-3beta. The luciferase assay with the P3C sequence, a specific DNA binding sequence for paired-class homeobox genes, has demonstrated that LIM1 enhances, but HNF-3beta represses, OTX2-directed gene expression. SIGNOR-221164 0.564 MAPK1 protein P28482 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Thr394 SGLPPPRtAMLDGNY -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262749 0.29 JAK2 protein O60674 UNIPROT APOA1 protein P02647 UNIPROT up-regulates activity 9606 14668333 t miannu ApoA-I interactions with ABCA1 and lipid efflux to apoA-I were substantially impaired by inhibiting or abolishing JAK2, whereas ABCA1 protein levels were unaffected, and ABCA1 cholesterol translocase activity was only slightly reduced. The most likely explanation for these findings is that JAK2 promotes apolipoprotein interactions with ABCA1 or a closely proximal site, and this facilitates the removal of cellular lipids. the interaction of apolipoproteins with ABCA1-expressing cells activates JAK2, which in turn activates a process that enhances apolipoprotein interactions with ABCA1 and lipid removal from cells SIGNOR-252107 0.303 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser301 DAVLPEQsPGDFDFN 9606 22966201 t llicata Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress. SIGNOR-198984 0.328 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM5 protein P08912 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257472 0.8 MDM2 protein Q00987 UNIPROT MDM4 protein O15151 UNIPROT down-regulates ubiquitination 9606 16511560 t lperfetto The mdm2 homolog mdmx is an important regulator of p53 during mouse embryonic development. Dna damage promotes mdmx phosphorylation, nuclear translocation, and degradation by mdm2. SIGNOR-144970 0.722 MAPK8 protein P45983 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity phosphorylation Ser198 GKTKTCEsPVSPIKM -1 28943315 t miannu JNK1-mediated NLRP3 S194 phosphorylation is critical for NLRP3 deubiquitination and facilitates its self-association and the subsequent inflammasome assembly. SIGNOR-277324 0.377 WFS1 protein O76024 UNIPROT ATP1B1 protein P05026 UNIPROT up-regulates quantity binding 9534 BTO:0000298 17947299 t SARA Sodium-potassium ATPase 1 Subunit Is a Molecular Partner of Wolframin, an Endoplasmic Reticulum Protein Involved in ER Stress|We conclude that the interaction may be important for Na+/K+ ATPase beta1 subunit maturation SIGNOR-260999 0.407 CRY2 protein Q49AN0 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267976 0.927 SMO protein Q99835 UNIPROT STK36 protein Q9NRP7 UNIPROT up-regulates binding 9606 17089004 t gcesareni Smo then activates stk36 serine/threonine kinase to stabilize gli family members and to phosphorylate sufu for nuclear accumulation of gli.| sufu binds to the kinesin cos2 to transduce the hh signal downstream of smo SIGNOR-150540 0.493 DAB2IP protein Q5VWQ8 UNIPROT 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR down-regulates activity binding 9606 27858941 t miannu DAB2IP then displaces the inhibitory binding between ASK1 and 14-3-3 protein, favoring ASK1 activation SIGNOR-254773 0.303 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20577053 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-252923 0.2 serotonin smallmolecule CHEBI:28790 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity precursor of 9606 31024440 t brain lperfetto Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA). SIGNOR-264188 0.8 PYGL protein P06737 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 3346228 t miannu Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267393 0.8 pirenzepine chemical CHEBI:8247 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258395 0.8 AR protein P10275 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 15861399 t miannu The unliganded AR resides predominately in the cytoplasm as a heteromeric complex with hsp90 and other chaperone proteins. These chaperone proteins maintain AR in a form that is receptive to ligand binding. Regulation of gene expression by androgen-activated AR occurs through receptor nuclear translocation, dimerization, and binding to androgen response elements (AREs) in the DNA of target genes. SIGNOR-251537 0.2 WNT5A protein P41221 UNIPROT ROR2 protein Q01974 UNIPROT up-regulates binding 9606 BTO:0001546 26690702 t gcesareni Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation|Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis. SIGNOR-199647 0.767 ANXA3 protein P12429 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 BTO:0000018 27995049 f miannu We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells. SIGNOR-262211 0.28 MAPK10 protein P53779 UNIPROT KIF5C protein O60282 UNIPROT down-regulates activity phosphorylation Ser176 CTERFVSsPEEVMDV -1 19525941 t miannu Mass spectrometry identified a residue in the kinesin-1 motor domain that was phosphorylated by JNK3 and this modification reduced kinesin-1 binding to microtubules. JNK3 phosphorylates kinesin-1 at Ser176 SIGNOR-262950 0.325 IGF1R protein P08069 UNIPROT CRK protein P46108 UNIPROT down-regulates activity phosphorylation Tyr221 GGPEPGPyAQPSVNT 10090 BTO:0000944 9480911 t On activation of the IGF-I receptor, Crk-II binds to phosphorylated tyrosine residues, especially in the juxtamembrane region. As a result of this binding, the IGF-I receptor kinase phosphorylates Tyr-221 of Crk-II, resulting in a change in intramolecular folding and binding of the SH2 domain to the phosphorylated Tyr-221, which causes rapid disassociation of the Crk-II-IGF-I receptor complex. SIGNOR-251273 0.711 CSNK2A2 protein P19784 UNIPROT STX1A protein Q16623 UNIPROT unknown phosphorylation Ser14 ELRTAKDsDDDDDVA 10116 BTO:0000142 10844023 t llicata We generated an antibody that specifically recognizes a casein kinase II-mediated phosphorylation on serine-14 of syntaxin 1. In this report we show that this phosphorylation occurs in vivo and is developmentally regulated in the rat brain | Phosphorylated syntaxin is preferentially associated with SNAP-25 and localizes to discrete domains of the axonal plasma membrane that do not colocalize with pools of synaptic vesicles. SIGNOR-251043 0.372 PRKCG protein P05129 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 t llicata Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm. SIGNOR-97295 0.2 NDUFAB1 protein O14561 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 SIGNOR-262161 0.816 FOXO proteinfamily SIGNOR-PF27 SIGNOR TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 f lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-252946 0.2 MAPK8 protein P45983 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation Ser178 PPLPGALsPLYGVPE 10116 BTO:0004316 12853963 t miannu JNK1 phosphorylates serine 178 on paxillin, a focal adhesion adaptor, both in vitro and in intact cells. NBT-II cells expressing the Ser 178 --> Ala mutant of paxillin (Pax(S178A)) formed focal adhesions and exhibited the limited movement associated with such contacts in both single-cell-migration and wound-healing assays. In contrast, cells expressing wild-type paxillin moved rapidly and retained close contacts as the predominant adhesion. SIGNOR-250129 0.698 USH1G protein Q495M9 UNIPROT TIP-LINK complex complex SIGNOR-C291 SIGNOR form complex binding 10090 BTO:0000630 23217710 t lperfetto The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction. SIGNOR-262578 0.589 PTEN protein P60484 UNIPROT NCL protein P19338 UNIPROT up-regulates activity dephosphorylation Thr84 PAKKAAVtPGKKAAA 9606 28332494 t miannu The fact that PTEN\u03b2 interacts with nucleolin and dephosphorylates nucleolin at Thr84 raised a question as to whether nucleolin mediates PTEN\u03b2 regulation of rDNA transcription, and thus represents a direct mechanism by which PTEN\u03b2 controls ribosomal biogenesis. SIGNOR-277166 0.273 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 t MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction. SIGNOR-175833 0.897 LIFR protein P42702 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 24710148 t milica The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-204850 0.588 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser709 SEEEEEEsDSSETEK 21296876 t lperfetto Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2. SIGNOR-275504 0.2 CAMK2A protein Q9UQM7 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser772 LFKKIFPsLELNITD 9606 BTO:0004553 24614225 t gianni NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity. SIGNOR-266441 0.312 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser124 PALKRSHsDSLDHDI 9606 11298456 t Manara We conclude that Chk2-dependent phosphorylation of Cdc25A on Ser 123 represents a critical step in promoting its rapid destruction in response to IR-induced DNA damage. SIGNOR-260778 0.837 OSM protein P13725 UNIPROT OSMR protein Q99650 UNIPROT up-regulates binding 9606 16286453 t gcesareni The oncostatin m receptor (osmr) is part of receptor complexes for oncostatin m and interleukin-31. SIGNOR-141588 0.785 BLOC-3 complex SIGNOR-C253 SIGNOR RAB38 protein P57729 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23174301 t lperfetto HPS1/HPS4 was active exclusively for RAB32 and RAB38. Moreover, when overexpressed with HPS1 in HeLa cells, a mitochondrially restricted form of HPS4 preferentially recruited GFP-tagged RAB32 or RAB38 – but not the related RAB7 or RAB9 – to mitochondria. Activity in both assays required both HPS1 and HPS4. Finally, depletion of HPS1 or HPS4 by siRNA in a pigmented human melanoma cell line, MNT-1, resulted in the mislocalization of RAB32. These data provide strong evidence that BLOC-3 is a selective GEF for RAB32 and RAB38  SIGNOR-260694 0.55 MKX protein Q8IYA7 UNIPROT SOX5 protein P35711 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001592 33115953 t miannu MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2). SIGNOR-267214 0.299 HSD3B1 protein P14060 UNIPROT testosterone smallmolecule CHEBI:17347 ChEBI up-regulates quantity chemical modification 10116 BTO:0000534;BTO:0000056 1537836 t lperfetto We have recently characterized two types of rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) isoenzymes expressed in adrenals and gonads. | However, in the presence of NADH, type III isoenzyme, in common with the type I isoform, converts 5 alpha-androstane-3,17-dione (A-dione) and 5 alpha-dihydrotestosterone (DHT) to the corresponding 3 beta-hydroxysteroids. SIGNOR-268637 0.8 LYN protein P07948 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268206 0.696 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Ser) smallmolecule CHEBI:29179 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269496 0.8 PRKN protein O60260 UNIPROT GPR37 protein O15354 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 12666095 t lperfetto Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei|2. Parkin-associated endothelin receptor-like receptor (Pael-R). SIGNOR-249706 0.2 DAXX protein Q9UER7 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 BTO:0000776;BTO:0000785 11483955 t gcesareni Tgf-beta-induced apoptosis is mediated by the adapter protein daxx that facilitates jnk activation SIGNOR-109542 0.508 MECOM protein Q03112 UNIPROT TEK protein Q02763 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000669 15889140 t Luana We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2  SIGNOR-266063 0.2 GIGYF1 protein O75420 UNIPROT EIF4E2/GIGYF1 complex complex SIGNOR-C256 SIGNOR form complex binding 9606 30917308 t lperfetto 4EHP forms complexes with the GYF domain-containing proteins GIGYF1 and GIGYF2, which are critical for this translational repression SIGNOR-261011 0.628 DUSP9 protein Q99956 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates binding 9606 21908610 t inferred from 70% of family members gcesareni Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein. SIGNOR-269924 0.714 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo. SIGNOR-101123 0.924 TWIST1 protein Q15672 UNIPROT RBL2 protein Q08999 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255535 0.2 XIAP protein P98170 UNIPROT CASP7 protein P55210 UNIPROT down-regulates quantity by destabilization binding -1 11257231 t lperfetto Our crystal structure of the complex between xiap (linker-bir2) and caspase-7 surprisingly revealed that the linker is the major determinant of binding and inhibition for the caspase. SIGNOR-105732 0.854 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Ser304 RASRRSDsASSEPVG 9606 19366211 t llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. SIGNOR-185295 0.2 levomilnacipran chemical CHEBI:136040 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 18468895 t Luana Studies on a series of milnacipran analogs containing a heteroaromatic group as potent norepinephrine and serotonin transporter inhibitors SIGNOR-257943 0.8 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 17548358 t gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. SIGNOR-155381 0.338 LSM-20934 chemical CHEBI:109533 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258850 0.8 PTPRJ protein Q12913 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1349 STFIGEHyVHVNATY 9606 BTO:0000007 12475979 t When co-expressed in 293 cells, the full-length substrate-trapping mutant form of DEP-1 formed a stable complex with the chimeric receptor colony stimulating factor 1 (CSF)-Met and wild type DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1 preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr(1365)), SIGNOR-248702 0.592 EPAS1 protein Q99814 UNIPROT KDM2A protein Q9Y2K7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271581 0.2 PLK1 protein P53350 UNIPROT CCNT1 protein O60563 UNIPROT down-regulates activity phosphorylation Ser564 KTYSLSSsFSSSSST 9606 BTO:0002181 23977272 t miannu  Further analysis indicated that Plk1 could phosphorylate cyclin T1 at Ser564 and inhibit the kinase activity of cyclin T1/Cdk9 complex on phosphorylation of the C-terminal domain (CTD) of RNA polymerase II.  SIGNOR-276501 0.388 PTPRC protein P08575 UNIPROT JAK1 protein P23458 UNIPROT up-regulates dephosphorylation 9606 BTO:0000776;BTO:0003076 11994288 t gcesareni These negative regulatory effects on ig class switching were concomitant with the ability of cd45 to dephosphorylate the induced phosphorylation of jak1, jak3, SIGNOR-87154 0.466 doramapimod chemical CHEBI:40953 ChEBI TNF protein P01375 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190335 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CEBPA protein P49715 UNIPROT down-regulates phosphorylation 9606 BTO:0000876 14701740 t inferred from 70% family members lperfetto Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21. SIGNOR-270066 0.2 BCR-Mk complex SIGNOR-C433 SIGNOR SYK protein P43405 UNIPROT up-regulates activity binding 9606 BTO:0000776 32323266 t scontino The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK). SIGNOR-268439 0.703 DCTPP1 protein Q9H773 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003878 27612427 f Monia DCTPP1 attenuates the sensitivity of human gastric cancer cells to 5-fluorouracil by up-regulating MDR1 expression epigenetically; Moreover, low expression of DCTPP1 led to the increase in intracellular 5-methyl-dCTP, which was strongly associated with the promoter hyper-methylation, leading to the subsequent low-expression of MDR1 and the increased intracellular accumulation of 5-FU in DCTPP1-knockdown BGC-823 cells. These results provide new insights into the roles of DCTPP1 as a chemosensitizer in clinical application. SIGNOR-261178 0.334 AVPR1A protein P37288 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256805 0.435 ZW10 protein O43264 UNIPROT DCTN2 protein Q13561 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 SIGNOR-C357 20462495 t lperfetto ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores SIGNOR-265016 0.707 CEBPB protein P17676 UNIPROT TNFAIP6 protein P98066 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7876106 t In cotransfection experiments, the C/EBP beta protein trans-activated 10-15-fold the cAspAT gene promoter in HepG2 cells. SIGNOR-254055 0.306 LCK protein P06239 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates activity phosphorylation Tyr688 FAEPYNLySSLKELV 9534 BTO:0004055 9461588 t the regulatory p85 subunit of phosphatidylinositol 3-kinase is phosphorylated on tyrosine residues. We report that this phosphorylation event is readily catalyzed by the Abl and Lck protein-tyrosine kinases in vitro, by Bcr-Abl or a catalytically activated Lck-Y505F in co-transfected COS cells. we have mapped a major phosphorylation site to Tyr-688 in the C-terminal SH2 domain of p85. Tyrosine phosphorylation of p85 in vitro or in vivo was not associated with detectable change in the enzymatic activity of the phosphatidylinositol 3-kinase heterodimer, but correlated with a strong reduction in the binding of some, but not all, phosphoproteins to the SH2 domains of p85. SIGNOR-251383 0.607 FST protein P19883 UNIPROT MSTN protein O14793 UNIPROT down-regulates activity binding 10090 11459935 t gcesareni Binding of myostatin to Act RIIB could be inhibited by the activin-binding protein follistatin and, at higher concentrations, by the myostatin propeptide. T SIGNOR-235150 0.75 PREX2 protein Q70Z35 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity catalytic activity 9606 BTO:0000007 25829446 t irozzo Here, we used cell biology, biochemistry, and genetic approaches to show that PTEN suppresses cell movement by blocking PREX2 GEF–catalyzed activation of the GTPase RAC1. PTEN binds PREX2 and directly inhibits GEF activity. SIGNOR-259191 0.593 GADD45GIP1 protein Q8TAE8 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262385 0.625 FGFR4 protein P22455 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). SIGNOR-276182 0.2 CDK2 protein P24941 UNIPROT ZBTB16 protein Q05516 UNIPROT down-regulates phosphorylation Thr282 RGKEGPGtPTRSSVI 9606 BTO:0001271 18246121 t llicata Here we show that the main cyclin-dependent kinase involved at the g(1) to s transition (cdk2) phosphorylates plzf at two consensus sites found within pest domains present in the hinge region of the protein. This phosphorylation triggers the ubiquitination and subsequent degradation of plzf, which impairs plzf transcriptional repression ability and antagonizes its growth inhibitory effects. SIGNOR-160630 0.286 SIK2 protein Q9H0K1 UNIPROT CDK5R1 protein Q15078 UNIPROT down-regulates phosphorylation Ser91 ENLKKSLsCANLSTF 9606 24561619 t lperfetto Sik2 phosphorylates p35 at ser 91, to trigger its ubiquitylation by pja2 and promote insulin secretion. _-cell knockout of sik2 leads to accumulation of p35 and impaired secretion SIGNOR-204648 0.337 LETM1 protein O95202 UNIPROT Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 9606 BTO:0000567 18628306 f lperfetto We hypothesize a working model of the function of BCS1L and LETM1 in mitochondrial biogenesis (Fig. 8E). Because BCS1L is an AAA-ATPase, the following three functions are downstream targets: (1) respiratory chain assembly, (2) mitochondrial morphology maintenance and, (3) LETM1 complex formation. BCS1L functions directly in the formation of mitochondrial tubular networks, in addition to the assembly of the supercomplexes. LETM1 has a distinct role in maintenance of mitochondrial volume and shapes, which helps – in concert with BCS1L – to achieve the efficient assembly of the respiratory chains. SIGNOR-262545 0.7 NAE complex SIGNOR-C131 SIGNOR CUL7 protein Q14999 UNIPROT up-regulates activity neddylation 9606 25504797 t lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. SIGNOR-243172 0.462 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 16403219 t miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. SIGNOR-259423 0.2 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole chemical CHEBI:92005 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258857 0.8 IKBKG protein Q9Y6K9 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 SIGNOR-C14 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-217382 0.783 ARHGEF15 protein O94989 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260540 0.553 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000567 9535909 t inferred from 70% family members lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. SIGNOR-270148 0.2 PPP3CC protein P48454 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates relocalization 9606 BTO:0000222 BTO:0000887;BTO:0001103 18676376 t gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-179796 0.692 ID1 protein P41134 UNIPROT TCF12 protein Q99081 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C128 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241104 0.601 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 t lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. SIGNOR-109621 0.674 FOXF1 protein Q12946 UNIPROT GH2 protein P01242 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16772323 f miannu Overexpression of FOXF1 in BeWo and HepG2 cells induced the GHV promoter, whereas overexpression of FOXF2 was without effect. These studies indicate that FOXF1 induces GHV expression by interaction with a FOXF1/FOXF2 cis-element in the proximal promoter. SIGNOR-254175 0.2 pictrelisib chemical CHEBI:65326 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 BTO:0000149 21876152 t gcesareni Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed SIGNOR-176292 0.8 AKT1 protein P31749 UNIPROT RNF11 protein Q9Y3C5 UNIPROT down-regulates quantity phosphorylation Thr135 DWLMRSFtCPSCMEP 9606 BTO:0003474 16123141 t gcesareni Upon inhibition of the AKT pathway or mutation of T135, the phosphorylation at one of these sites is virtually eliminated, suggesting that AKT may phosphorylate RNF11 at T135. Moreover, RNF11 is phosphorylated by AKT in vitro and is recognized by phospho-AKT substrate antibodies. RNF11 shows enhanced binding to 14-3-3 in WM239 cells compared with that seen in the parental WM35 cells which have low AKT activity SIGNOR-252558 0.468 GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263783 0.7 GADL1 protein Q6ZQY3 UNIPROT beta-alanine zwitterion smallmolecule CHEBI:57966 ChEBI up-regulates quantity chemical modification 9606 22718265 t miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. SIGNOR-267546 0.8 GPR35 protein Q9HC97 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256717 0.2 FBXO31 protein Q5XUX0 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002181 29343641 t miannu FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2. SIGNOR-277380 0.329 CSNK2A1 protein P68400 UNIPROT C1R protein P00736 UNIPROT down-regulates activity phosphorylation Ser206 TEASGYIsSLEYPRS -1 8635594 t llicata We provide evidence that this kinase phosphorylates Clr at the level of Ser189. | Accessibility of Ser189 was low in intact C1r, due in part to the presence of one of the oligosaccharides borne by the alpha region, further reduced in the presence of calcium, and abolished when C1r was incorporated into the C1s-C1r-C1r-C1s tetramer or the C1 complex. SIGNOR-250833 0.312 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM3B protein Q7LBC6 UNIPROT up-regulates activity chemical activation 29981745 t lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. SIGNOR-273471 0.8 CSNK2A1 protein P68400 UNIPROT EIF5 protein P55010 UNIPROT up-regulates phosphorylation Ser390 KEAEEESsGGEEEDE 9606 16227438 t gcesareni We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2. SIGNOR-141159 0.402 MSL2 protein Q9HCI7 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity ubiquitination 9606 BTO:0002552 19033443 t miannu Here we describe MSL2, a novel E3 ligase for p53 that promotes ubiquitin-dependent cytoplasmic p53 localization. Unlike Mdm2 or most other p53 E3 ligases, MSL2-mediated p53 ubiquitination does not affect the stability of p53. Moreover, the MSL2-mediated effect on p53 is Mdm2-independent. Thus, our study identifies an important ubiquitin-ligase for modulating p53 subcellular localization. MSL2 ubiquitination of p53 is required for p53 cytoplasmic localization. SIGNOR-271774 0.378 TNF protein P01375 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 f lperfetto Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS SIGNOR-260258 0.7 SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR Degranulation phenotype SIGNOR-PH92 SIGNOR up-regulates 9606 16470226 f Alessandro Palma So, the association of aggregated FcεRI with the preferentially activated LYN in lipid rafts might be sufficient to shift the equilibrium of FcεRI from a nonphosphorylated state to a phosphorylated state, thereby initiating FcεRI-mediated degranulation SIGNOR-254956 0.7 CECR2 protein Q9BXF3 UNIPROT CERF complex SIGNOR-C340 SIGNOR form complex binding 9606 BTO:0000227 15640247 t miannu Biochemical isolation of CECR2 revealed the presence of this protein as a component of a novel heterodimeric complex termed CECR2-containing remodeling factor (CERF). CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. Together, these data identify a novel chromatin remodeling complex with a critical role in neurulation. SIGNOR-263891 0.394 EGR1 protein P18146 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003336 29212876 t miannu Previous studies have reported that the PPARγ proximal promoter contains an overlapping binding site for Egr-1, which is involved in the down-regulation of PPARγ. In the present study, we have provided direct evidence that leptin causes PPARγ reduction in primary cultured PASMC; this effect is coupled to leptin-induced ERK1/2 activation and subsequent induction of Egr-1, which further down-regulates PPARγ expression and results in PASMC proliferation. The present study confirmed that ERK1/2 signaling cascade mediated leptin-induced PPARγ reduction by up-regulation of Egr-1 in PASMC. SIGNOR-263508 0.605 SYVN1 protein Q86TM6 UNIPROT GPR37 protein O15354 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 18241051 t miannu We demonstrated that endogenous HRD1 interacts with Pael-R, and that HRD1 promotes the degradation of Pael-R and protects cell death caused by the accumulation of Pael-R. SIGNOR-272631 0.409 ANAPC11 protein Q9NYG5 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 t lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. SIGNOR-252010 0.86 KAT2A protein Q92830 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates activity acetylation 24870244 t lperfetto The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1alpha and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1alpha. SIGNOR-275498 0.2 SRC protein P12931 UNIPROT ARHGDIB protein P52566 UNIPROT unknown phosphorylation Tyr24 ELDSKLNyKPPPQKS 9606 19321744 t llicata Studies confirmed that activated src kinase binds and phosphorylates rhogdi2 in vitro and vivo. Mutagenesis revealed that tyr-153 and, to a lesser degree, tyr-24 were the primary src phosphorylation sites. Phosphorylation decreased the amount of rac1 in rhogdi2 complexes and increased rhogdi2 association with cell membranes. SIGNOR-184912 0.404 PKLR protein P30613 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI down-regulates quantity chemical modification 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266535 0.8 TEC protein P42680 UNIPROT TEC protein P42680 UNIPROT up-regulates phosphorylation Tyr206 RLERGQEyLILEKND 9606 12573241 t lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated SIGNOR-98098 0.2 CSNK2A1 protein P68400 UNIPROT UBE2R2 protein Q712K3 UNIPROT up-regulates activity phosphorylation Ser233 DCYDDDDsGNEES 9606 12037680 t lperfetto Ck2-dependent phosphorylation of the e2 ubiquitin conjugating enzyme ubc3b induces its interaction with beta-trcp and enhances beta-catenin degradation SIGNOR-88050 0.344 DVL2 protein O14641 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000331 10196136 t amattioni Dvl is required for lrp6 phosphorylation, which is essential for subsequent steps of signal transduction. SIGNOR-66362 0.677 NMDA receptor_2A complex SIGNOR-C347 SIGNOR CAMK2A protein Q9UQM7 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu The most abundant signaling protein in the PSD fraction is Ca2+/calmodulin–dependent protein kinase II (CaMKII), which makes up 1 to 2% of the total protein in the forebrain (21). CaMKII is a target for Ca2+ flowing through the NMDA receptor and is necessary for normal synaptic plasticity in pyramidal neurons. The cytosolic tails of the NR2 subunits of the NMDA receptor bind to CaMKII and thus can serve as docking sites for it in the PSD SIGNOR-264214 0.649 CENPW protein Q5EE01 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265202 0.621 CENPU protein Q71F23 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265203 0.807 HES1 protein Q14469 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19129776 t gcesareni HES1 binding to the promoter of the NC3C1 gene inhibits its expression and results in insufficient production of the encoded glucocorticoid receptor- rendering these cells resistant to treatment with dexamethasone SIGNOR-251674 0.2 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Thr575 SNSCRSStTTCPEQD 9606 16862148 t lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). SIGNOR-249299 0.444 TNF protein P01375 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by repression transcriptional regulation 10116 9397972 f inferred from family member scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5‚Äô-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. SIGNOR-270239 0.26 CTDSP1 protein Q9GZU7 UNIPROT NLI/Lmx1.1/Isl1 complex SIGNOR-C103 SIGNOR form complex binding 9606 BTO:0000007 9452425 t lperfetto Interactions between LIM transcription factors were also evaluated in vivo. Cotransfected FLAG-Lmx1.1 and HA-Isl1 were capable of interacting. the NLI-dependent interaction observed between Isl1 and Lmx1.1 is likely to represent a physiologically significant complex found in the endocrine cells of the pancreas. SIGNOR-236839 0.2 HDAC1 protein Q13547 UNIPROT SMAD7/HDAC1/E2F-1 complex SIGNOR-C12 SIGNOR form complex binding 9606 23213415 t gcesareni Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes SIGNOR-199958 0.641 MITF protein O75030 UNIPROT TRPM1 protein Q7Z4N2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 14744763 f miannu Mice homozygously mutated in MITF showed a dramatic decrease in TRPM1 expression. Finally, the slope of TRPM1 induction by MITF was particularly steep compared with other MITF target genes, suggesting it is a sensitive indicator of MITF expression and correspondingly of melanocytic differentiation. SIGNOR-254588 0.435 PPP2R2B protein Q00005 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR form complex binding 9606 23454242 t gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. SIGNOR-243507 0.753 DMPK protein Q09013 UNIPROT PLN protein P26678 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 15598648 t gcesareni Coimmunoprecipitation studies showed that dmpk and pln can physically associate. Furthermore, purified wild-type dmpk, but not a kinase-deficient mutant (k110a dmpk), phosphorylates pln in vitro SIGNOR-131371 0.521 E2F1 protein Q01094 UNIPROT LRBA protein P50851 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15064745 f miannu We also show that LRBA promoter activity and endogenous LRBA mRNA levels are reduced by p53 and increased by E2F1, indicating that mutations in the tumor suppressors p53 and Rb could contribute to the deregulation of LRBA. SIGNOR-253846 0.2 leuprolide acetate chemical CHEBI:63597 ChEBI GNRHR protein P30968 UNIPROT up-regulates activity chemical activation 9606 22416801 t miannu Clinical data have shown that the GnRH antagonist, degarelix, is associated with more rapid PSA suppression and improved PSA PFS compared with the GnRH agonist, leuprolide. SIGNOR-259163 0.8 tolcapone chemical CHEBI:63630 ChEBI COMT protein P21964 UNIPROT down-regulates activity chemical inhibition 10090 26919286 t miannu The present work illustrates the potential therapeutic efficacy of COMT inhibition in alleviating cognitive impairment. A brain-penetrant COMT inhibitor, tolcapone, was tested in normal and phencyclidine-treated rats and COMT-Val transgenic mice. SIGNOR-258475 0.8 CSNK2A2 protein P19784 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-250979 0.29 CSNK2A1 protein P68400 UNIPROT CCAR2 protein Q8N163 UNIPROT up-regulates activity phosphorylation Thr454 AAEAAPPtQEAQGET 9606 24962073 t lperfetto CK2alphawas bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2alphawas evidenced by co-immunoprecipitation of CK2alphaand DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. |In our results, CK2alpha affected the|These results suggest that DBC1 may be involved in the progression of gastric carcinoma by inducing the EMT and that it is closely associated with CK2alpha-mediated phosphorylation of DBC1. phosphorylation of Thr454 on DBC1 SIGNOR-267666 0.2 CDK2 protein P24941 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 SIGNOR-C83 22369944 t fspada Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity. SIGNOR-196372 0.404 ARRB2 protein P32121 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity binding -1 2163110 t The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors SIGNOR-256501 0.713 DIO2 protein Q92813 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20978344 f miannu The active thyroid hormone 3,5,3' triiodothyronine (T3) is a major regulator of skeletal muscle function. The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4). Here we show that type 2 deiodinase (D2) is essential for normal mouse myogenesis and muscle regeneration. Indeed, D2-mediated increases in T3 were essential for the enhanced transcription of myogenic differentiation 1 (MyoD) and for execution of the myogenic program. SIGNOR-256203 0.267 ARF1 protein P84077 UNIPROT Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 14973189 f lperfetto ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface SIGNOR-272149 0.7 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr450 TAQMITItPPDQDDS 10090 BTO:0002572 18566586 t gcesareni MTORC2 phosphorylates newly synthesized Akt at the TM (Thr450) site to facilitate carboxyl-terminal folding and to stabilize Akt SIGNOR-252438 0.634 DIO3 protein P55073 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 34674502 t scontino Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3. SIGNOR-266952 0.8 Hypoxia stimulus SIGNOR-ST25 SIGNOR HIF-1 complex complex SIGNOR-C418 SIGNOR up-regulates 9606 27692180 f miannu Hypoxia-Inducible Factor-1 (HIF-1) is a key transcription factor that regulates gene expression under hypoxic conditions (Semenza, 2012, 2010a). HIF-1 consists of two subunits, HIF-1α and HIF-1β. While HIF-1β protein is constitutively expressed and present in excess, HIF-1α protein has a short half-life SIGNOR-267449 0.7 PLK1 protein P53350 UNIPROT FADD protein Q13158 UNIPROT down-regulates activity phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 20890306 t gcesareni Fas-associated death domain-containing protein (FADD) was first identified as an adapter molecule involved in formation of a death-inducing signaling complex upon Fas stimulation| Plk1 phosphorylates fadd at ser-194 in response to treatment with taxol Phosphorylation by polo-like kinase 1 induces the tumor-suppressing activity of FADD SIGNOR-168204 0.471 MADD protein Q8WXG6 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity guanine nucleotide exchange factor 10116 BTO:0000142 11809763 t miannu Rab3A, a member of the Rab3 small G protein family, regulates Ca(2+)-dependent exocytosis of neurotransmitter. The cyclical activation and inactivation of Rab3A are essential for the Rab3A action in exocytosis. GDP-Rab3A is activated to GTP-Rab3A by Rab3 GDP/GTP exchange protein (Rab3 GEP), and GTP-Rab3A is inactivated to GDP-Rab3A by Rab3 GTPase-activating protein (Rab3 GAP). SIGNOR-265579 0.405 PRKCB protein P05771 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser188 LGERKPSsAAYQKAP -1 9244383 t lperfetto We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198. SIGNOR-248977 0.334 SIK2 protein Q9H0K1 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates phosphorylation Ser2392 AGLHHSLsHSLLAVA 9606 20708153 t lperfetto Here, we show that the salt inducible kinase 2 (sik2) localizes at the centrosome, plays a key role in the initiation of mitosis, and regulates the localization of the centrosome linker protein, c-nap1, through s2392 phosphorylation SIGNOR-167488 0.326 PKA proteinfamily SIGNOR-PF17 SIGNOR PHF2 protein O75151 UNIPROT up-regulates activity phosphorylation Ser757 NARVKKEsGSSAAGI 9606 BTO:0000007 21532585 t miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. Replacement of all of four serine residues by alanines (4SA: Ser 757/Ser 899/Ser 954/Ser 1056) fully abrogated PKA phosphorylation of PHF2 (Fig. 2h). SIGNOR-264510 0.2 TFAP4 protein Q01664 UNIPROT SALL2 protein Q9Y467 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000452 21228219 f miannu The transcription factor AP4 increases along with SALL2 in quiescent cells and positively regulates SALL2 expression. SIGNOR-255426 0.2 BACH1 protein O14867 UNIPROT HK2 protein P52789 UNIPROT up-regulates quantity transcriptional regulation 9606 31257027 t BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells. SIGNOR-259338 0.2 FBXO11 protein Q86XK2 UNIPROT DTL protein Q9NZJ0 UNIPROT down-regulates binding 9606 23478441 t miannu We determined that the f-box protein fbxo11 interacts with cdt2,a dcaf protein that controls cell-cycle progression, and recruits cdt2 to the scf(fbxo11)complex to promote its proteasomal degradation. SIGNOR-192325 0.559 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Thr895 KLSFRRRtDKDTEQP 9606 10488078 t lperfetto Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a) SIGNOR-70730 0.312 MAPK11 protein Q15759 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates activity phosphorylation Thr180 RQADEEMtGYVATRW -1 26976637 t miannu P38β Mitogen-Activated Protein Kinase Modulates Its Own Basal Activity by Autophosphorylation of the Activating Residue Thr180 and the Inhibitory Residues Thr241 and Ser261 SIGNOR-277216 0.2 2-[[5-methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene]amino]oxyethanamine chemical CHEBI:93274 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 t miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. SIGNOR-258880 0.8 PRKCB protein P05771 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser576 CAEMREDsARVYENV 9606 11781100 t lperfetto  In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta. SIGNOR-249136 0.336 CLTCL1 protein P53675 UNIPROT AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR form complex binding 9606 23103167 t lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-260679 0.72 GTF3A protein Q92664 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR up-regulates activity binding 9308965 t lperfetto At present, it is known that transcription factors TFIIIB, TFIIIC2, TFIIIC1, and TFIIIA (5S gene only) are involved in transcription of tRNA, VA RNA, and 5S RNA genes by human RNA Pol III. SIGNOR-266180 0.447 CAMK1 protein Q14012 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 BTO:0000887 11114197 t gcesareni Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation. SIGNOR-85022 0.429 PPARGC1A protein Q9UBK2 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by repression transcriptional regulation 10090 BTO:0001103 20404331 f lperfetto Capacity of PGC-1alpha and PGC-1beta to inhibit FoxO3 and NFkappaB actions and proteolysis helps explain how exercise prevents muscle atrophy.overexpression of PGC-1_ inhibits muscle wasting induced by denervation, starvation, and even caFoxO3 expression SIGNOR-252969 0.567 GSK3A protein P49840 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 19214430 t gcesareni Taken together, our results indicate that gsk-3alfa is a negative regulator of notch1/nicd. SIGNOR-183969 0.325 WT1 protein P19544 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 f irozzo Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation. SIGNOR-255705 0.7 WNT10B protein O00744 UNIPROT FZD2 protein Q14332 UNIPROT up-regulates binding 9606 12055200 t fspada Inhibition of adipogenesis by wnt10b is likely mediated by wnt receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 7 SIGNOR-89137 0.626 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr227 PAPPEGAtPTSPVGH 9606 BTO:0000848 BTO:0001253 20959475 t lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). SIGNOR-252954 0.703 AKT2 protein P31751 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF 9606 10377430 t lperfetto Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus. SIGNOR-68652 0.644 ELK3 protein P41970 UNIPROT MYH6 protein P13533 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 12933792 f miannu From HeLa cells an Ets family of protein, Ets-related protein (ERP), binds to double-stranded PNR element. The ERP.PNR complex inhibited the activity of the basal transcription complex from homologous as well as heterologous promoters in a PNR position-independent manner, suggesting that ERP acts as a silencer of alpha-MHC gene expression in non-muscle cells. SIGNOR-253900 0.2 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Ser4517 LYMGGHGsRHSLAST 9606 15272003 t lperfetto Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc. SIGNOR-126958 0.2 ACE2 protein Q9BYF1 UNIPROT Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT up-regulates activity cleavage Pro40 GDRVYIHpFHLVIHN -1 11815627 t miannu The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus. SIGNOR-260222 0.2 ILK protein Q13418 UNIPROT PPP1R14B protein Q96C90 UNIPROT up-regulates activity phosphorylation Thr57 VRRQGKVtVKYDRKE -1 12144526 t lperfetto We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin SIGNOR-265741 0.372 NUTF2 protein P61970 UNIPROT NUP62 protein P37198 UNIPROT up-regulates activity binding 9606 BTO:0000567 7744965 t Simone Our data suggest that NTF2 interacts directly with NPC protein 1362 and exerts its effect at a relatively late step in the nuclear protein import pathway. We obtained a cDNA encoding NTF2 and showed that the recombinant protein restores transport activity to p62-pretreated cytosol. SIGNOR-261255 0.839 ATXN7 protein O15265 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269576 0.664 DDC protein P20711 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI up-regulates quantity chemical modification 7955 23940784 t brain lperfetto AADC is responsible for the decarboxylation step in the catecholamine and dopamine biosynthesis. Dopamine and serotonin can be synthesized by AADC from L-3,4-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively [7]. A deficiency in AADC will lead to reduced biogenic monoamines, including dopamine, norepinephrine, epinephrine, and serotonin SIGNOR-263987 0.8 INPP5D protein Q92835 UNIPROT phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI up-regulates quantity chemical modification 9606 23650141 t gcesareni PtdIns(3,4)P2 is commonly reported as a product of the SH2 domain-containing inositol 5-phosphatases 1/2 (SHIP1 and SHIP2) that dephosphorylate PtdIns(3,4,5)P3 at the 5-position SIGNOR-252427 0.8 GNG2 protein P59768 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000938 16537363 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt. SIGNOR-252683 0.426 KANSL1 protein Q7Z3B3 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 26243146 f miannu Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. SIGNOR-267170 0.7 CAMK2A protein Q9UQM7 UNIPROT ETS2 protein P15036 UNIPROT down-regulates phosphorylation Ser310 LDVQRVPsFESFEDD 9606 19182667 t lperfetto Camkii caused ets-2 phosphorylation.Serine 246, 310, and 313 were the targets. Camkii to phosphorylates ets-2, thus altering ets-2 binding to its downstream promoters SIGNOR-183600 0.2 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257911 0.8 GPR119 protein Q8TDV5 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257308 0.252 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT down-regulates activity phosphorylation Ser206 ATPPTLSsTVLIVRN 9606 12815053 t lperfetto M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1 SIGNOR-102494 0.555 LCK protein P06239 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Tyr315 RADNDKEyLVLTLTK 9606 11948419 t gcesareni Thus, y240a and y315a are involved in the ability of mmac/pten to dephosphorylate ptdins and regulate tumor cell growth in vitro and in vivo. SIGNOR-116499 0.382 GFPT1 protein Q06210 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 21310273 t miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans SIGNOR-267816 0.8 ARHGEF6 protein Q15052 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 BTO:0000599 23776207 f lperfetto Activation of ARF6 promotes cortical actin assembly (9) and plasma membrane remodeling  SIGNOR-272236 0.7 MAOB protein P27338 UNIPROT 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-264004 0.8 TFEC protein O14948 UNIPROT MYH9 protein P35579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 11467950 f miannu we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies. SIGNOR-222551 0.2 NFATC2 protein Q13469 UNIPROT IL4 protein P05112 UNIPROT up-regulates transcriptional regulation 9606 23612709 f Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin SIGNOR-255460 0.524 RBPJ protein Q06330 UNIPROT NFKB2 protein Q00653 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 9528780 f gcesareni Rbp-jkappa is a strong transcriptional repressor of nf-kappab2. Moreover, this repression can be overcome by activated notch-1. SIGNOR-56100 0.27 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation Tyr936 SESTNHIySNLANCS 9606 10377264 t miannu Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr SIGNOR-68647 0.2 PRKG2 protein Q13237 UNIPROT PLCB3 protein Q01970 UNIPROT down-regulates activity phosphorylation Ser26 VETLRRGsKFIKWDE 10116 BTO:0004576 11278298 t lperfetto PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG. SIGNOR-249080 0.509 GAN protein Q9H2C0 UNIPROT CUL3 protein Q13618 UNIPROT up-regulates activity binding 10090 BTO:0000142 18680552 t miannu Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. SIGNOR-268944 0.659 RNF167 protein Q9H6Y7 UNIPROT VAMP3 protein Q15836 UNIPROT down-regulates quantity by destabilization ubiquitination Lys66 QFETSAAkLKRKYWW 9606 BTO:0000007 23353890 t miannu Here, we show that Godzilla/RNF167 regulates endosome recycling by the ubiquitylation of VAMP3 on Lys66, Lys68 and Lys77; namely, two adjacent Lys residues on the both sides of the critical interface of SNARE complex are ubiquitylated. In agreement with VAMP3 being a target for Goliath family ubiquitin ligases, we show that recycling endosome trafficking is abrogated in response to their activity. While we observed ubiquitylation of VAMP3 by Godzilla, we are unable to describe the nature of this ubiquitination, be it mono-ubiquitin or extended ubiquitin chains. SIGNOR-272093 0.334 A4/b7 integrin complex SIGNOR-C187 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257728 0.546 PRKCB protein P05771 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Thr705 WKLQRAItILDTEKS 9606 BTO:0000007 24920628 t miannu PKCβII causes the downregulation of TRPV1 by phosphorylating the channel. The increased threonine phosphorylation was substantially reduced by mutating Thr705, showing that Thr705 is indeed a major PKCβII phosphorylation site. SIGNOR-276638 0.2 KEAP1 protein Q14145 UNIPROT NFE2L2 protein Q16236 UNIPROT down-regulates quantity ubiquitination 9606 31257023 t Keap1 is a substrate receptor of a Cul3-RING ubiquitin ligase (CRL3) that, in physiological conditions, constitutively binds and targets Nrf2 for degradation SIGNOR-259335 0.807 SIRT1 protein Q96EB6 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity deacetylation Lys14 VKEGWLHkRGEYIKT 10090 BTO:0000562 21775285 t gcesareni We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation. SIGNOR-252445 0.619 CDK1 protein P06493 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 11553333 t lperfetto Phosphorylation of 4e-bp1 is critical in causing its dissociation from eif-4e, leaving 4e available to form translationally active eif-4f complexes, switching on mrna translation. We show that the cyclin-dependent kinase, cdc2, phosphorylates 4e-bp1 at thr-70 and that phosphorylation of this site is permissive for ser-65 phosphorylation. Crucially, the increased phosphorylation of 4e-bp1 during mitosis results in its complete dissociation from eif-4e. SIGNOR-110416 0.406 EPC2 protein Q52LR7 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269306 0.581 MAPK1 protein P28482 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser152 PASSVSSsPSPPFGH 9606 12050114 t gcesareni Tob is rapidly phosphorylated at ser 152, ser 154, and ser 164 by erk1 and erk2 upon growth-factor stimulation. SIGNOR-88716 0.361 AMPK complex SIGNOR-C15 SIGNOR KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser559 VQRKVSGsRGSFCKA 9606 BTO:0000007 30279167 t miannu Thus, AMPK directly phosphorylates the α subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser559.  SIGNOR-273736 0.295 MAPK1 protein P28482 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Ser523 GVSDVPTsPTLQRPT 9534 BTO:0004055 16705159 t 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner SIGNOR-236331 0.492 CACNA1G protein O43497 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 10090 33393208 t miannu Adult hippocampal neurogenesis plays an important role in neuronal plasticity and maintenance in mammals. Low-threshold voltage-gated T-type calcium channels produce calcium spikes that increase fast action potentials in newborn cells in the hippocampal dentate gyrus (DG) SIGNOR-264033 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR POLR2A protein P24928 UNIPROT down-regulates phosphorylation 9606 14662762 t inferred from 70% family members lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-270156 0.2 TWIST2 protein Q8WVJ9 UNIPROT SRPX protein P78539 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255497 0.208 CHIR 99021 chemical CHEBI:91091 ChEBI GSK3B protein P49841 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191000 0.8 PTPN18 protein Q99952 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr1248 PTAENPEyLGLDVPV 9606 BTO:0000007 25081058 t lperfetto PTPN18 knockdown selectively enhances the EGF-induced tyrosine phosphorylation of the HER2 Y1112, Y1196 and Y1248 sites. |Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop. SIGNOR-262597 0.658 N-hydroxy-1-[(4-methoxyphenyl)methyl]-6-indolecarboxamide chemical CHEBI:94192 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189684 0.8 2-(4-morpholinyl)-6-(1-thianthrenyl)-4-pyranone chemical CHEBI:91372 ChEBI ATM protein Q13315 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193600 0.8 MTCP1 protein P56278 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t lperfetto Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation SIGNOR-244413 0.459 dopamine smallmolecule CHEBI:18243 ChEBI DRD1 protein P21728 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257477 0.8 PRKD1 protein Q15139 UNIPROT PAK4 protein O96013 UNIPROT up-regulates activity phosphorylation Ser474 KEVPRRKsLVGTPYW 24840177 t lperfetto When PKD3 was knocked-down using isoform-specific shRNA (PKD3-shRNA), PAK4 activity (judged by its phosphorylation status at the activation loop using the pS474-PAK4 antibody) was decreased SIGNOR-275930 0.254 PRKD2 protein Q9BZL6 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates activity phosphorylation Ser978 SPLKRSHsLAKLGSL 21832093 t lperfetto Active PKD Isoforms Phosphorylate and Inactivate SSH1L|Here, we show that active PKD3 also mediates SSH1L phosphorylation at Ser-978 and binding to 14-3-3, further confirming the involvement of all three PKD isoforms in negatively regulating this phosphatase SIGNOR-275937 0.296 BLVRB protein P30043 UNIPROT bilirubin(2-) smallmolecule CHEBI:57977 ChEBI down-regulates quantity chemical modification 9606 BTO:0000759 7929092 t lperfetto This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. SIGNOR-275523 0.8 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258993 0.74 ERBB2 protein P04626 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 12648465 t Most breast, skin, lung, ovary, and gastrointestinal tract tumors express ErbB-3, and heterodimerization of this receptor with ErbB-2, may be involved in some cancers. gcesareni Although ErbB-2 binds no known ligand, when recruited into heterodimers it increases ligand binding affinity SIGNOR-99569 0.571 PGD protein P52209 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity chemical modification 9606 24769394 t miannu The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle SIGNOR-267053 0.8 INSR protein P06213 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Tyr607 NENTEDQySLVEDDE 9534 8385099 t The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-251322 0.656 TFEB protein P19484 UNIPROT BLOC1S2 protein Q6QNY1 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). SIGNOR-276682 0.2 mTORC1 complex SIGNOR-C3 SIGNOR MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser60 PHVLEALsPPQTSGL 9606 20516213 t lperfetto The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly. SIGNOR-217149 0.467 CYP1B1 protein Q16678 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification 9606 BTO:0000093 8790407 t Luana These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens. SIGNOR-269756 0.8 BIRC5 protein O15392 UNIPROT XIAP protein P98170 UNIPROT up-regulates binding 9606 15218035 t gcesareni Formation of a survivin-xiap complex promotes increased xiap stability against ubiquitination/proteasomal destruction and synergistic apoptosis SIGNOR-126367 0.508 DUSP10 protein Q9Y6W6 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity dephosphorylation 9606 26305722 t miannu The inactivation of IRF3 by MKP5 is dependent on MKP5 phosphatase activity or its binding to IRF3.|This is confirmed since MKP5 phosphatasedeficient mutant is unable to dephosphorylate IRF3 and MKP5 mutant lacking IRF3 binding motifs fails to suppress IRF3 nuclear translocation upon virus infection. SIGNOR-277146 0.2 MYC protein P01106 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000785 20551174 f lperfetto In tissue culture, ectopic expression of Myc suppresses the cell cycle arrest that occurs in response to several anti-mitogenic signals such as transforming growth factor β (TGFβ), since Myc represses expression of the cyclin-dependent kinase inhibitors (CKIs) p15ink4b, p21cip1, and p57kip2 via interaction with Miz1 SIGNOR-267575 0.757 RUNX2 protein Q13950 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 f gcesareni In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast SIGNOR-107175 0.502 CIB1 protein Q99828 UNIPROT ITGA2B protein P08514 UNIPROT up-regulates activity binding 10029 BTO:0000246 11756406 t Gianni The small GTPase Rac3 interacts with the integrin-binding protein CIB and promotes integrin alpha(IIb)beta(3)-mediated adhesion and spreading SIGNOR-269061 0.484 PJA2 protein O43164 UNIPROT PRKAR2A protein P13861 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21423175 t miannu Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits SIGNOR-271856 0.334 PRKACA protein P17612 UNIPROT RARA protein P10276 UNIPROT down-regulates activity phosphorylation Ser219 NSSEQRVsLDIDLWD 9606 20215566 t miannu  Mutagenesis of serine 219 (S219) and S369 at the PKA sites on RARA to either double alanines or double glutamic acids showed that both PKA sites are important for RARA activity.  SIGNOR-276281 0.379 CDK5 protein Q00535 UNIPROT SYN1 protein P17600 UNIPROT up-regulates phosphorylation Ser551 PAARPPAsPSPQRQA 9606 10880969 t lperfetto Synapsin i (syni), a major sv phosphoprotein involved in the regulation of sv trafficking and neurotransmitter release, is one of the presynaptic substrates of cdk5, which phosphorylates it in its c-terminal region at ser(549) (site 6) and ser(551) (site 7). Phosphorylation of syni by cdk5 is physiologically regulated and enhances its binding to f-actin. SIGNOR-78883 0.58 dothiepin chemical CHEBI:36798 ChEBI CHRM5 protein P08912 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8100134 t miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. SIGNOR-258695 0.8 CSNK2A2 protein P19784 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Ser484 RSRAIHSsDEGEDQA 9606 BTO:0001412 12769847 t llicata We identify two phosphorylation sites in the VCA domain of WASP at serines 483 and 484. S483 and S484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the VCA domain for the Arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length WASP molecule.  SIGNOR-251049 0.354 ETS2 protein P15036 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11175361 t miannu Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin SIGNOR-259875 0.2 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser876 QGLAERIsVL 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275959 0.2 ACAT1 protein P24752 UNIPROT PDP1 protein Q9P0J1 UNIPROT down-regulates activity acetylation 34289383 t lperfetto We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1) SIGNOR-267635 0.346 KCTD11 protein Q693B1 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity 15249678 f In absence of Hh lperfetto REN(KCTD11) seems to inhibit medulloblastoma growth by negatively regulating the Hedgehog pathway because it antagonizes the Gli-mediated transactivation of Hedgehog target genes, by affecting Gli1 nuclear transfer, and its growth inhibitory activity is impaired by Gli1 inactivation. SIGNOR-249592 0.359 AMFR protein Q9UKV5 UNIPROT GPI protein P06744 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 24810856 t miannu Gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF. SIGNOR-272177 0.545 paclitaxel chemical CHEBI:45863 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates activity chemical inhibition 9606 28298489 t miannu Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a "pseudo" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap. SIGNOR-259449 0.8 RAF1 protein P04049 UNIPROT STK3 protein Q13188 UNIPROT down-regulates binding 9606 15618521 t gcesareni Raf-1 prevents dimerization and phosphorylation of the activation loop of mst2 independently of its protein kinase activity.Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (mst2) SIGNOR-132824 0.367 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser307 TRRSRTEsITATSPA -1 12351658 t IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. SIGNOR-251292 0.644 AKT proteinfamily SIGNOR-PF24 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser1834 MLRRRMAsMQRTGVV 9606 16926151 t lperfetto We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity SIGNOR-244236 0.2 NBN protein O60934 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR form complex binding 17713585 t lperfetto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50. SIGNOR-251505 0.911 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates activity binding 9606 BTO:0000567 15573378 t ggiuliani The Runx2 WT and deletion constructs (1 √¢‚Ǩ‚Äú495, 1√¢‚Ǩ‚Äú464, and 1√¢‚Ǩ‚Äú432) all physically interact with the BMP2 responsive Smad 1 SIGNOR-255834 0.578 CUL1 protein Q13616 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 SIGNOR-C5 10023660 t lperfetto These results indicate that the cul1/skp1/beta-trcp complex forms a ubiquitin ligase that mediates the degradation of beta-catenin. SIGNOR-64499 0.581 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation Tyr200 SMESIDDyVNVPESG 9606 11368773 t lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. SIGNOR-247026 0.761 TGFB1 protein P01137 UNIPROT PPP2R2A protein P63151 UNIPROT up-regulates activity binding 9606 19114990 t lperfetto The Balpha subunit interacts directly with activated T_RI. The Balpha interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity SIGNOR-217894 0.358 CDK1 protein P06493 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser96 SFSVKDPsPLYDMLR 9606 15735705 t lperfetto Cdc2p34 phosphorylates mdmx on ser 96 in vitro. Mutation within this site (mdmx(s96a)) impairs, whereas phosphomimic substitution (mdmx(s96d)) increases the cytoplasmic localization of mdmx, suggesting that cdk2/cdc2p34 phosphorylation is required for export of mdmx from the nucleus SIGNOR-134388 0.416 Norzotepine chemical CID:10041551 PUBCHEM SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 20223878 t Luana These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. SIGNOR-257830 0.8 MLL3 complex complex SIGNOR-C446 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 34156443 t miannu MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. SIGNOR-268811 0.2 Angiotensin 1-7 protein P01019-PRO_0000420660 UNIPROT MAS1 protein P04201 UNIPROT up-regulates activity binding 9606 23488800 t miannu Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang-(1-7). SIGNOR-260229 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MKNK1 protein Q9BUB5 UNIPROT up-regulates activity phosphorylation -1 9155018 t These results indicate that MNK1 is a novel class of protein kinase that is activated through both the ERK and p38 MAP kinase signaling pathways SIGNOR-253013 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser5 sPPLRDVD 9606 BTO:0000222 14749395 t lperfetto Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21. SIGNOR-216924 0.325 MED26 protein O95402 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266664 0.656 FBXO5 protein Q9UKT4 UNIPROT ANAPC7 protein Q9UJX3 UNIPROT down-regulates binding 9606 11751633 t gcesareni Emi1 can inhibit apc already activated by cdc20 or cdh1. SIGNOR-113382 0.469 APOA1 protein P02647 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity 9606 14668333 f miannu ApoA-I Stimulates JAK2 Autophosphorylation. the interaction of apolipoproteins with ABCA1-expressing cells activates JAK2, which in turn activates a process that enhances apolipoprotein interactions with ABCA1 and lipid removal from cells SIGNOR-252108 0.303 HTR3E protein A5X5Y0 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 18761359 f miannu The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release.  SIGNOR-264318 0.7 MAP2K3 protein P46734 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Thr180 RHADAEMtGYVVTRW 9606 BTO:0000007 10066767 t done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. SIGNOR-273950 0.59 KAT2A protein Q92830 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269594 0.2 RPS6KA5 protein O75582 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR down-regulates phosphorylation 9606 15010469 t gcesareni We found that msk1 phosphorylated histone h2a on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by msk1. SIGNOR-265314 0.2 MAX protein P61244 UNIPROT MNT protein Q99583 UNIPROT up-regulates activity binding 9606 7954804 t 2 miannu the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. SIGNOR-240354 0.359 MAPK1 protein P28482 UNIPROT TAGLN2 protein P37802 UNIPROT up-regulates quantity by stabilization phosphorylation Ser145 ARDDGLFsGDPNWFP 9606 BTO:0003491 30041673 t lperfetto ERK2 interacted with 29-31 amino acids of transgelin-2 and subsequently phosphorylated the S145 residue of transgelin-2. S145 phosphorylation of transgelin-2 played important roles in cell proliferation and tumorigenesis of PDAC.| We found that the protein stability of transgelin-2 was regulated by KRAS. ERK-mediated phosphorylation resulted in accumulation of transgelin-2 protein. SIGNOR-265221 0.272 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 18794113 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-180902 0.523 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2R2 protein Q712K3 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271358 0.776 AURKA protein O14965 UNIPROT MBD3 protein O95983 UNIPROT up-regulates phosphorylation Ser24 REEVPRRsGLSAGHR 9606 BTO:0000567 12354758 t llicata These results suggest that the biochemical changes of mbd3 may be intimately related to the targeting of mbd3 to centrosomes. aurora-a phosphorylates mbd3 SIGNOR-93693 0.29 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Met666 VIVITLVmLKKKQYT -1 8943232 t lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261789 0.502 ADSL protein P30566 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-266607 0.8 IL10 protein P22301 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 t milica Functionally active il-10 receptors are composed of two distinct subunits. The il-10 receptor ? Chain is a 110-kda polypeptide that plays the dominant role in mediating high affinity ligand binding and signal transduction. The il-10 receptor ? Subunit (also known as crf2_4) is predicted to be a 40-kda polypeptide that is largely required only for signaling SIGNOR-67964 0.911 SCF-SKP2 complex SIGNOR-C136 SIGNOR CCNE1 protein P24864 UNIPROT down-regulates quantity by destabilization ubiquitination -1 phosphorylation:Ser399;Thr395 GLLTPPQsGKKQSSG;PLPSGLLtPPQSGKK 11533444 t lperfetto The amount of cyclin E protein present in the cell is tightly controlled by ubiquitin-mediated proteolysis. Here we identify the ubiquitin ligase responsible for cyclin E ubiquitination as SCFFbw7 and demonstrate that it is functionally conserved in yeast, flies, and mammals. Fbw7 associates specifically with phosphorylated cyclin E, and SCFFbw7 catalyzes cyclin E ubiquitination in vitro SIGNOR-267558 0.632 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC15 protein Q99877 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271993 0.2 TBXA2R protein P21731 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257023 0.447 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure. SIGNOR-267308 0.8 DIO1 protein P49895 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 1400883 t scontino The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production. SIGNOR-266945 0.8 TOP2A protein P11388 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 15942022 f lperfetto Down-regulation of DNA topoisomerase IIalpha leads to prolonged cell cycle transit in G2 and early M phases and increased survival to microtubule-interacting agents SIGNOR-242537 0.7 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000776 25673924 t lperfetto CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades. SIGNOR-242891 0.764 NRXN3 protein Q9Y4C0 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 22626542 t miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. SIGNOR-265463 0.2 AMT protein P48728 UNIPROT Glycine cleavage system complex SIGNOR-C437 SIGNOR form complex binding 9606 16051266 t lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. SIGNOR-268242 0.725 SGK1 protein O00141 UNIPROT SLC1A3 protein P43003 UNIPROT up-regulates activity phosphorylation Thr482 LDRLRTTtNVLGDSL -1 12911626 t miannu Site‐directed mutagenesis of the SGK1 phosphorylation sites in the Nedd4‐2 protein (S382A,S468ANedd4‐2) and in the EAAT1 protein (T482AEAAT1, T482DEAAT1) significantly blunts the effect of S422DSGK1. Introduction of a negative charge at the SGK phosphorylation site in the EAAT1 protein leads to a strong stimulation of the carrier, whereas replacement with alanine markedly decreases the EAAT1‐mediated current. These observations suggest that SGK1 exerts its effect not only by phosphorylation of Nedd4‐2 but also by phosphorylation of EAAT1. SIGNOR-263075 0.425 MAPK8 protein P45983 UNIPROT EEF1A2 protein Q05639 UNIPROT down-regulates quantity by destabilization phosphorylation Ser358 GQISAGYsPVIDCHT 9606 BTO:0002181 23608534 t miannu Ribosome-associated JNK phosphorylates the eukaryotic translation elongation factor 1A isoform 2 (eEF1A2) on serines 205 and 358 to promote degradation of NSPs by the proteasome.  SIGNOR-276492 0.382 messenger RNA smallmolecule CHEBI:33699 ChEBI 48S_initiation_complex complex SIGNOR-C454 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269164 0.8 BST1 protein Q10588 UNIPROT nicotinic acid-adenine dinucleotide phosphate smallmolecule CHEBI:76072 ChEBI up-regulates quantity chemical modification 9606 18626062 t miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. SIGNOR-264249 0.8 MYLIP protein Q8WY64 UNIPROT LRP8 protein Q14114 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 20427281 t miannu Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation. SIGNOR-271486 0.455 SIRT2 protein Q8IXJ6 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by stabilization 9606 23175188 f miannu Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. SIGNOR-255148 0.478 PK proteinfamily SIGNOR-PF80 SIGNOR STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation -1 22306293 t inferred from family member PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In¬†vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor SIGNOR-270312 0.2 MST1 protein P26927 UNIPROT H2BC3 protein P33778 UNIPROT unknown phosphorylation Ser15 APAPKKGsKKAITKA 9606 21212262 t lperfetto The mst1 is a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn activates its downstream targets, jnk/p38, histone h2b and foxo. Mst1 induces apoptosis by phosphorylating histone h2b on a relatively conserved site, ser-14 in mammalian cells SIGNOR-171005 0.2 LPAR6 protein P43657 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257212 0.397 RB1 protein P06400 UNIPROT UBTF protein P17480 UNIPROT down-regulates activity binding -1 7877691 t lperfetto Activity of RNA polymerase I transcription factor UBF blocked by Rb gene product SIGNOR-262589 0.384 CDK7 protein P50613 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser403 PEEFISLsPPHEALD 9606 10428966 t lperfetto These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase. here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain. SIGNOR-69776 0.506 C5AR2 protein Q9P296 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity by expression 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263470 0.8 CSTF1 protein Q05048 UNIPROT CSTF complex complex SIGNOR-C441 SIGNOR form complex binding 9606 10669729 t lperfetto We therefore first identified regions of the CstF subunits, CstF-77, CstF-64, and CstF-50, required for interaction with each other.  SIGNOR-268365 0.934 SUN2 protein Q9UH99 UNIPROT RAB5A protein P20339 UNIPROT up-regulates activity binding 9606 BTO:0000567 10818110 t Sara Rab5ip represents a novel rab5 interacting protein that may function on endocytic vesicles as a receptor for rab5-GDP and participate in the activation of rab5 SIGNOR-261309 0.43 CSNK1E protein P49674 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates activity phosphorylation Ser280 DGGIYIGsIMKGGAV -1 24993822 t miannu Co-expression of CK1ϵ with FLAG-Dvl3 retards electrophoretic migration and induces phosphorylation-dependent shift of Dvl (PS-Dvl3). mutations of Ser-280 and Ser-311 prevent efficient activation of Wnt/β-catenin by Dvl3. SIGNOR-276645 0.655 NARS2 protein Q96I59 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270466 0.8 TAK-901 chemical CID:16124208 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207191 0.8 RBPJ protein Q06330 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 23729744 t apalma The released NICD translocates directly to the nucleus, where it forms a transcriptional complex with the DNA-binding protein CSL (CBF1, Suppressor of Hairless, Lag1), Mastermind (Mam) and transcriptional co-activators to drive the expression of Notch target genes SIGNOR-255378 0.949 AKT3 protein Q9Y243 UNIPROT CHUK protein O15111 UNIPROT up-regulates phosphorylation Thr23 EMRERLGtGGFGNVC 9606 SIGNOR-C14 19609947 t gcesareni Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-187062 0.389 BAG5 protein Q9UL15 UNIPROT HSPA1B protein P0DMV9 UNIPROT down-regulates activity binding 9606 BTO:0000142 15603737 t Monia Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity; Thus, BAG5 interacts with Hsp70 in vitro and in vivo, and substitution of select residues within the BAG domains is sufficient to abolish this interaction. SIGNOR-261197 0.67 BMPR2 protein Q13873 UNIPROT ACVR1/BMPR2 complex SIGNOR-C30 SIGNOR form complex binding 9606 7791754 t lperfetto Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor. SIGNOR-33437 0.702 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates activity phosphorylation Thr186 KREKRRStSRQFVDG 9606 BTO:0000567 14744859 t llicata It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1 SIGNOR-250590 0.771 SMARCA2 protein P51531 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269817 0.829 TRIM22 protein Q8IYM9 UNIPROT TRIM22 protein Q8IYM9 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18656448 t miannu  Importantly, TRIM22 was conjugated with poly-ubiquitin chains and stabilized by the proteasome inhibitor in 293T cells, suggesting that TRIM22 targeted itself for proteasomal degradation through the poly-ubiquitylation. We also found that TRIM22 was located in the nucleus, indicating that TRIM22 might function as a nuclear E3 ubiquitin ligase. SIGNOR-271780 0.2 NAE complex SIGNOR-C131 SIGNOR CUL2 protein Q13617 UNIPROT up-regulates activity neddylation 9606 25504797 t lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. SIGNOR-243154 0.531 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Ser393 RGELIPIsPSTEVGG BTO:0000007 10593981 t llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. SIGNOR-250734 0.711 CYP17A1 protein P05093 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI down-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268658 0.8 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation Ser240 RRVSGNNsPSLSNGG 9606 BTO:0000007 16446428 t gcesareni Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222 SIGNOR-245323 0.644 SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000938 11560935 t lperfetto Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras SIGNOR-110566 0.771 CTSH protein P09668 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Arg94 IGFQEAYrRFYGPV -1 9076588 t miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. SIGNOR-256325 0.286 HOXD12 protein P35452 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates activity binding -1 9343407 t 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. SIGNOR-241232 0.432 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr116 LASELAKtPQKSVSF 9606 11931757 t lperfetto We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability. SIGNOR-217296 0.699 STK4 protein Q13043 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates activity phosphorylation Thr90 CHLAWVNtPKKQGGL -1 23386615 t miannu Mst1 inactivates Prdx1 by phosphorylating it at Thr-90 and Thr-183, leading to accumulation of hydrogen peroxide in cells.Prdx1 is phosphorylated by Mst1 predominantly at Thr-18, Thr-90, and Thr-183. SIGNOR-276487 0.2 D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 24929114 t miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. SIGNOR-268142 0.8 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206124 0.8 RFC4 protein P35249 UNIPROT RF-C complex complex SIGNOR-C375 SIGNOR form complex binding 12930972 t lperfetto RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned SIGNOR-265508 0.801 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR YAP1 protein P46937 UNIPROT down-regulates binding 9606 21084559 t gcesareni Phosphorylation of yap ser127 and of the corresponding sites in yki and taz generates a protein-binding motif for the 14-3-3 family proteins, which, upon binding by a 14-3-3 protein, leads to their cytoplasmic retention. One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73. SIGNOR-169719 0.2 NARS1 protein O43776 UNIPROT tRNA(Asn) smallmolecule CHEBI:29172 ChEBI down-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270453 0.8 dexamethasone chemical CHEBI:41879 ChEBI CEBPA protein P49715 UNIPROT up-regulates 9606 11279134 f fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin SIGNOR-250568 0.8 KDM3B protein Q7LBC6 UNIPROT PPARA protein Q07869 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0005964 19194461 t miannu We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression. SIGNOR-266637 0.2 MECP2 protein P51608 UNIPROT GRIA2 protein P42262 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 22262897 t Luana Bicuculline treatment also leads to an increase in the levels of the transcriptional repressor MeCP2, which binds to the GluR2 promoter along with the corepressors HDAC1 and mSin3A. SIGNOR-264684 0.329 SMAD6 protein O43541 UNIPROT TBX6 protein O95947 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 19561075 t miannu Smad6 mediates Tbx6 ubiquitination and proteasomal degradation. Tbx6 forms a ternary complex with Smad6 and Smurf1. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase. SIGNOR-272785 0.332 RBPJ protein Q06330 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression binding 9606 BTO:0000938 10520600 t gcesareni These results indicate that the two Hes genes are essential effectors for the Notch pathway and that neuronal differentiation is controlled by the pathway Notch-Hes1/Hes5-|Mash1. SIGNOR-71168 0.583 OXGR1 protein Q96P68 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257310 0.2 NALCN protein Q8IZF0 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 32698188 t miannu Persistently depolarizing sodium (Na+) leak currents enhance electrical excitability. The ion channel responsible for the major background Na+ conductance in neurons is the Na+ leak channel, non-selective (NALCN) SIGNOR-265181 0.8 ASAP2 protein O43150 UNIPROT ARF6 protein P62330 UNIPROT up-regulates activity gtpase-activating protein -1 10022920 t miannu Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain.  In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6.  Pap protein exhibits Arf GAP activity in vitro. SIGNOR-269706 0.654 KPNA3 protein O00505 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20454918 t gcesareni Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. SIGNOR-165280 0.33 DHCR7 protein Q9UBM7 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates quantity chemical modification 9606 9634533 t miannu In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme sterol D7 -reductase. This NADPH-dependent enzyme catalyzes the reduction of the D7 -diene bond in 7-DHC, to form cholesterol. SIGNOR-267252 0.8 S1PR3 protein Q99500 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256933 0.2 CHEK1 protein O14757 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 18243098 t gcesareni We identify chk1 as the kinase responsible for h3-t11 phosphorylation. H3-t11 phosphorylation occurs throughout the cell cycle and is chk1 dependent in vivo.Phosphorylation at thr-12 (h3t11ph) by pkn1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of lys-10 (h3k9me) by kdm4c/jmjd2c. SIGNOR-265326 0.2 CSNK2A1 protein P68400 UNIPROT PSMA3 protein P25788 UNIPROT unknown phosphorylation Ser250 SLKEEDEsDDDNM -1 8619999 t llicata Several C8 protein constructs allow the location of the CKII phosphorylation sites to be the COOH terminal portion of the protein, and direct mutational analyses show that Ser-243 and Ser-250 are the residues of the C8 subunit phosphorylated by CKII. The in vitro phosphorylation of the proteasome by CKII does not affect its proteolytic activity (on proteins or fluorogenic synthetic peptides), therefore suggesting its involvement in the interaction of the proteasome with other cellular proteins, i.e. in the formation of the 26S complex and/or in the interaction with the nuclear translocation machinery. SIGNOR-250939 0.389 EP300 protein Q09472 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates quantity by stabilization acetylation Lys378 TIRMSFVkGWGAEYR 9606 16862174 t miannu Smad proteins are crucial for the intracellular signaling of transforming growth factor-beta (TGF-beta). Upon their receptor-induced activation, Smad proteins are phosphorylated and translocated to the nucleus to activate the transcription of a select set of target genes. Here, we show that the co-activator p300/CBP bound and acetylated Smad3 as well as Smad2 in vivo, and that the acetylation was stimulated by TGF-beta.A major acetylation site of Smad3 by p300/CBP is Lys-378 in the MH2 domain (Smad3C) known to be critical for the regulation of transcriptional activity. SIGNOR-260431 0.726 PLK1 protein P53350 UNIPROT VIM protein P08670 UNIPROT up-regulates phosphorylation Ser83 GVRLLQDsVDFSLAD 9606 BTO:0000150 18056432 t gcesareni We observed that plk1 phosphorylates vimentin on ser82, which in turn regulates cell surface levels of 1 integrin. SIGNOR-159386 0.2 NOX1 protein Q9Y5S8 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity chemical modification 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264721 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR PHKA1 protein P46020 UNIPROT down-regulates activity phosphorylation 9606 10487978 t Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. SIGNOR-267409 0.2 IFI30 protein P13284 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI down-regulates quantity chemical modification 9606 31810556 t scontino Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol. SIGNOR-267865 0.8 GPR119 protein Q8TDV5 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256768 0.393 PRKACA protein P17612 UNIPROT AKAP12 protein Q02952 UNIPROT up-regulates activity phosphorylation Ser696 KKRARRGsSSDEEGG -1 14657015 t lperfetto Following receptor activation, gravin binding to the receptor increases, a process dependent upon PKA-catalyzed phosphorylation of two canonical PKA sites (Ser696–698 and Ser772) located within the AKAP domain of gravin. SIGNOR-271843 0.2 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 18790874 t brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-263786 0.8 C2 protein P06681 UNIPROT C3 convertase complex complex SIGNOR-C310 SIGNOR form complex binding -1 cleavage:Arg243 KTKESLGrKIQIQRS 17204478 t complement C2a fragment: PRO_0000027612 lperfetto However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex SIGNOR-263399 0.627 HDAC7 protein Q8WUI4 UNIPROT PLAGL2 protein Q9UPG8 UNIPROT down-regulates deacetylation 9606 16207715 t miannu Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7. SIGNOR-140953 0.26 PF-03814735 chemical CID:49830590 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205956 0.8 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val55 VTGKGVTvETVFSVD -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263599 0.381 TTL protein Q8NG68 UNIPROT TUBA3E protein Q6PEY2 UNIPROT down-regulates tyrosination 9606 22020298 t miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization SIGNOR-176924 0.436 RAB9A protein P51151 UNIPROT GCC2 protein Q8IWJ2 UNIPROT up-regulates activity 18195106 t lperfetto Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector SIGNOR-253087 0.52 CSNK2A1 protein P68400 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser99 AGEKEAKsD 9606 10739259 t lperfetto Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools. SIGNOR-76278 0.2 RNF111 protein Q6ZNA4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity ubiquitination 10090 BTO:0000165;BTO:0000222 17341133 t lperfetto Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling. SIGNOR-235394 0.672 valrubicin chemical CHEBI:135876 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 16019763 t miannu Valrubicin (N-trifluoroacetyladriamycin-14-valerate) is a semi-synthetic derivative of the anthracycline doxorubicin. Valrubicin inhibits the incorporation of nucleosides into nucleic acids, causing extensive chromosomal damage and cell-cycle arrest in the G2 phase. Its principal metabolites inhibit topoisomerase II, thus arresting DNA synthesis. SIGNOR-259383 0.8 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates activity phosphorylation Ser787 KAPEKRAsPSKPASA 9606 BTO:0000567 10791892 t miannu We have shown that MAP4 is phosphorylated in vivo in mitotic HeLa cells at eight sites. Five of these were phosphorylated by p34cdc2 kinase. Two of the five p34cdc2 kinase phosphorylation sites were shown to be Ser696 and Ser787 in the proline-rich region. Mutation of Ser787 to Glu strikingly reduced the MAP4's MT-polymerization activity, while Glu-mutation at Ser696 did not. These results suggest that Ser787 could be the critical phosphorylation site causing MTs to be dynamic at mitosis. SIGNOR-277459 0.511 LAMA4 protein Q16363 UNIPROT Laminin-8 complex SIGNOR-C181 SIGNOR form complex binding 10809728 t lperfetto Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. SIGNOR-253226 0.504 LGALS3 protein P17931 UNIPROT BAD protein Q92934 UNIPROT up-regulates quantity by stabilization 9606 BTO:0000664 21821001 f miannu Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells. SIGNOR-261907 0.2 LRP6 protein O75581 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 19107203 t PPPSPxS motif in LRP6/5 must be phosphorylated. lperfetto These observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence binding of wnts to the coreceptors frizzled and lrp6/5 leads to phosphorylation of pppspxs motifs in the lrp6/5 intracellular region and the inhibition of gsk3beta bound to the scaffold protein axin.These Observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence. SIGNOR-227942 0.722 PTK2 protein Q05397 UNIPROT TLN1 protein Q9Y490 UNIPROT up-regulates activity binding 9606 15688067 t miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257731 0.676 AKT1 protein P31749 UNIPROT LTB4R2 protein Q9NPC1 UNIPROT unknown phosphorylation Thr324 GGRSREGtMELRTTP 9606 22044535 t llicata Blt2 phosphorylation at thr355 by akt is necessary for blt2-mediated chemotaxis. SIGNOR-252516 0.391 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr451 PIPKALGtPVLTPPT 9606 BTO:0000848 BTO:0001253 20959475 t lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). SIGNOR-252955 0.703 PDX1 protein P52945 UNIPROT GCK protein P35557 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8866550 f miannu The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription. SIGNOR-254911 0.589 CAMK1 protein Q14012 UNIPROT GCM1 protein Q9NP62 UNIPROT up-regulates activity phosphorylation Ser47 YAKHIYSsEDKNAQR 9606 BTO:0000007 21791615 t miannu We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation. SIGNOR-262680 0.396 DOK7 protein Q18PE1 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 23467009 t gcesareni In addition, dok7, a cytoplasmic adaptor protein, is also required for musk activation in vivo. This review focuses on the physical interplay between these proteins and musk for activation and downstream signaling, which culminates in nmj formation. SIGNOR-192264 0.745 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates activity phosphorylation Ser867 SPVSVGSsPPVKNIS 9606 BTO:0000093 15383283 t miannu P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators. SIGNOR-250106 0.506 MK-2206 chemical CHEBI:67271 ChEBI AKT1 protein P31749 UNIPROT down-regulates chemical inhibition 9606 BTO:0001286 21841310 t gcesareni Treatment with the pi3k inhibitor ly294002 or the akt inhibitor mk2206 diminished s473 phosphorylation. SIGNOR-252461 0.8 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Ser311 EYTIKSHsSLPPNNS 9606 15611134 t lperfetto Zipk autophosphorylates in vitrowe have identified six phosphorylation sites in zipk that regulate both its enzyme activity and localization, including thr180, thr225, thr265, thr299, thr306, and ser311. SIGNOR-132455 0.2 NLGN4X protein Q8N0W4 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264145 0.762 PIN1 protein Q13526 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 19151708 t gcesareni Prolyl-isomerase pin1 interacts with notch1 and affects notch1 activation. Pin1 potentiates notch1 cleavage by gamma-secretase, leading to an increased release of the active intracellular domain and ultimately enhancing notch1. pin1 potentiates notch1 cleavage by gamma-secretase SIGNOR-183461 0.393 FGF14 protein Q92915 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253425 0.2 HCRTR1 protein O43613 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257404 0.252 DUSP3 protein P51452 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity dephosphorylation 9606 33777934 t lperfetto In the absence of DUSP3, these three residues remain phosphorylated and favor the dissociation equilibrium of NPM homo-oligomerization and/or its association with ARF, therefore promoting an early nuc|Therefore, here we focused on the molecular mechanisms used by DUSP3-NPM interaction to affect the abovementioned cellular responses and found out that DUSP3 dephosphorylates three tyrosine residues (Y29, Y67, and Y271) of NPM. SIGNOR-277005 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates -1 14663477 f Luana Multiple studies supporting the role of Akt in apoptosis suppression have connected Akt to cell death regulation either by demonstrating its downregulation following pro-apoptotic insults, or by using gene-transfer experiments that transduce both activated, anti-apoptotic and inactive, pro-apoptotic mutants of Akt. SIGNOR-260215 0.7 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr184 GTACDIQtHMTNNKG -1 20538596 t lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-227544 0.2 SAR1A protein Q9NR31 UNIPROT SEC24C protein P53992 UNIPROT up-regulates quantity binding SIGNOR-C370 30605680 t lperfetto Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. SIGNOR-265302 0.698 SOS2 protein Q07890 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-175265 0.705 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 16403219 t lperfetto All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death. SIGNOR-259421 0.2 CDK8 protein P49336 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo. SIGNOR-273173 0.2 INO80 complex complex SIGNOR-C498 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 25016522 f miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270858 0.7 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Ser1219 DDTESLHsQGEEEFD 9606 22621922 t gcesareni Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm. SIGNOR-197611 0.869 CEBPB protein P17676 UNIPROT CREB1 protein P16220-1 UNIPROT up-regulates activity binding 9534 BTO:0000298 12773552 t miannu We conclude that C/EBP-β can directly bind to the N-terminal Q1 domain of CREB in addition to binding to the leucine zipper domain. The transactivation potential of full-length CREB fused to the DNA-binding domain of Gal4 was increased synergistically by calcium and cGMP, and overexpression of C/EBP-β enhanced the effect, while a dominant negative C/EBP inhibited it SIGNOR-263654 0.577 EFR3A protein Q14156 UNIPROT PI4KA protein P42356 UNIPROT up-regulates quantity binding 9606 BTO:0000007 34504076 t miannu PI4KA is recruited to plasma membrane by the adapter protein EFR3, which has two isoforms, EFR3A and EFR3B SIGNOR-269092 0.482 PABPN1 protein Q86U42 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization binding 9606 25480299 t lperfetto As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length. SIGNOR-268320 0.8 MAPKAPK2 protein P49137 UNIPROT ETV1 protein P50549 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2 SIGNOR-166625 0.596 COL1A1 protein P02452 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates activity binding 9606 BTO:0001282 17318226 t lperfetto The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75.  SIGNOR-272342 0.434 pipamperone chemical CHEBI:78549 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258571 0.8 PPP2CA protein P67775 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 20704570 t gcesareni Accordingly, smad3-associated pp2a activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of tgf-beta-induced smad3 but did not affect smad2. Moreover, the influence of tgf-beta on a set of smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical pp2a inhibition. Our data demonstrate the existence of a smad3-specific phosphatase and identify a novel role for pp2a. SIGNOR-167480 0.2 VHL protein P40337 UNIPROT KLF10 protein Q13118 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003781 18359287 f lperfetto In this study, we show that both TGFBI and KLF10 are down-regulated by VHL in 786-0 cells, and that KLF10 may serve as a transactivator of the TGFBI promoter. SIGNOR-253213 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 15342917 t lperfetto The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1 SIGNOR-256311 0.713 ECM stimulus SIGNOR-ST20 SIGNOR A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259037 0.7 APOE protein P02649 UNIPROT VLDLR protein P98155 UNIPROT up-regulates binding 9606 11278667 t gcesareni Several ligands for the vldl receptor have been identified in addition to tfpi. These include apolipoprotein e (apoe) SIGNOR-106221 0.634 MRPS12 protein O15235 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261457 0.673 GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263782 0.7 PKP2 protein Q99959 UNIPROT DSP protein P15924 UNIPROT up-regulates quantity by stabilization binding 10090 BTO:0003264 22781308 t Simone In contrast to the proper membrane localization of PKP2 and DSP after cotransfection of both WT proteins, mutant PKP2 C796R protein was not able to interact with FLAG-DSP to enable assembly at the junctional plaque, indicating the requirement of functional PKP2 for DSP integration into the desmosome. SIGNOR-261254 0.778 MAPK9 protein P45984 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser191 SRHAIMRsPQMVSAI 9606 18423204 t amattioni Beta-catenin, upon entering the nucleus, in turn activates transcription of downstream target genes. Jnk2 phosphorylates Beta-catenin on critical residues (ser191 and ser605). Jnk activity is required for Beta-catenin nuclear localization in response to wnt. SIGNOR-178258 0.658 PTGS2 protein P35354 UNIPROT Prostacycline smallmolecule CID:159 PUBCHEM up-regulates chemical modification 9606 11751058 t gcesareni Cox catalyzes two enzymatic activities;namely, the conversion of aa to the hydroperoxy endoperoxide pgg2, followed by its subsequent reduction to the labile product pgh2. Pgh2_ is the common substrate for a number of different cell-specific synthases, which convert pgh2_ to the individual pgs or tx, including pge2, pgi2_ (prostacyclin), pgd2, pgf2alfa, and txa2 SIGNOR-113300 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 21440011 t lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252833 0.908 GLUL protein P15104 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity chemical modification 9606 30158707 t miannu Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction. SIGNOR-267826 0.8 Dinaciclib chemical CID:46926350 PUBCHEM CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191328 0.8 CDKL5 protein O76039 UNIPROT LRRC4C protein Q9HCJ2 UNIPROT unknown phosphorylation Ser631 PLLIRMNsKDNVQET 9606 22922712 t llicata Cdkl5 binds and phosphorylates the cell adhesion molecule ngl-1. This phosphorylation event ensures a stable association between ngl-1 and psd95. SIGNOR-192035 0.438 CDK5 protein Q00535 UNIPROT HTR1A protein P08908 UNIPROT down-regulates quantity by destabilization phosphorylation Thr314 LPSEAGPtPCAPASF 9534 BTO:0004055 30712943 t lperfetto Cyclin-dependent kinase 5 promotes proteasomal degradation of the 5-HT 1A receptor via phosphorylation|5-HT1AR was phosphorylated by the Cdk5-p35 complex at Thr314 in the third cytoplasmic loop. SIGNOR-264406 0.273 KSR1 protein Q8IVT5 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Thr269 NVHMVSTtLPVDSRM 9606 11134016 t lperfetto Here we show that phosphorylation of c-raf-1 on thr(269) by ksr is necessary for optimal activation in response to egf stimulation. SIGNOR-85386 0.639 pralidoxime chemical CHEBI:8354 ChEBI ACHE protein P22303 UNIPROT up-regulates activity chemical activation -1 21215642 t Luana These compounds were synthesized, evaluated in vitro on human AChE (hAChE) inhibited by tabun, paraoxon, methylparaoxon and DFP and then compared to commercial hAChE reactivators (pralidoxime, HI-6, trimedoxime, obidoxime, methoxime) or previously prepared compounds (K027, K203). Three of these novel compounds showed a promising ability to reactivate hAChE comparable or better than the used standards.  SIGNOR-257889 0.8 MAP3K7 protein O43318 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation 9606 SIGNOR-C14 19632174 t lperfetto Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta. SIGNOR-187242 0.746 ARHGAP31 protein Q2M1Z3 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260489 0.547 APC-c complex SIGNOR-C150 SIGNOR PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. SIGNOR-272750 0.42 PKM protein P14618 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 22306293 t llicata Pkm2 activates transcription of mek5 by phosphorylating stat3 at y705. pkm2 regulates mek5 transcription via activation of stat3 SIGNOR-195766 0.455 KIF2B protein Q8N4N8 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272534 0.7 MAPK3 protein P27361 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser282 VGKQAPLsPGLPAMG 9606 20230789 t lperfetto Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity SIGNOR-164231 0.27 MARCHF5 protein Q9NX47 UNIPROT MFN1 protein Q8IWA4 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 20103533 t Barakat MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion.|Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate. SIGNOR-274133 0.2 TFEB protein P19484 UNIPROT NDUFAF2 protein Q8N183 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). SIGNOR-276703 0.2 NBEAL2 protein Q6ZNJ1 UNIPROT SELP protein P16109 UNIPROT up-regulates 9606 BTO:0000132 28082341 f lperfetto Recent in vitro megakaryopoiesis studies using HSCs from GPS patients with NBEAL2 mutations showed normal MK differentiation with defective proplatelet formation and reduced α-granule proteins such as von Willebrand factor (VWF), thrombospondin and P-selectin. SIGNOR-261885 0.302 TLR4 protein O00206 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-252067 0.845 HMGB1 protein P09429 UNIPROT HOXD3 protein P31249 UNIPROT up-regulates activity binding -1 8890171 t miannu We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein. SIGNOR-219980 0.302 FGR protein P09769 UNIPROT SRC protein P12931 UNIPROT unknown phosphorylation Tyr530 FTSTEPQyQPGENL -1 9208935 t An eicosapeptide encompassing the C-terminal tail of c-Src (Tyr527) which is conserved in most Src-related protein kinases, is phosphorylated by C-terminal Src kinase (CSK) and by the two Src-related protein kinases c-Fgr and Lyn, with similar kinetic constants.  SIGNOR-251145 0.632 SGK1 protein O00141 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr198 PGLRRRQt 9606 18570873 t gcesareni Activated sgk1 and p27 phosphorylation at t157, and both were inhibited by short-term rapamycin treatment and by sgk1 shrna.|Akt acts downstream of PI3K to phosphorylate p27 at T157 and T198, leading to impaired nuclear p27 import, p27 accumulation in the cytoplasm, and loss of cyclin E-Cdk2 inhibition SIGNOR-179121 0.481 ACSS3 protein Q9H6R3 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI down-regulates quantity chemical modification 10843999 t lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. SIGNOR-271834 0.8 CSNK1A1 protein P48729 UNIPROT HNRNPC protein P07910 UNIPROT down-regulates activity phosphorylation Ser260 SEGGADDsAEEGDLL 9606 15687492 t gcesareni In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C. SIGNOR-133532 0.361 COL4A4 protein P53420 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 35267698 t lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. SIGNOR-272350 0.435 IGF1 protein P05019 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates 10090 10448861 f lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. SIGNOR-252306 0.269 CCNO protein P22674 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity binding 37197505 t lperfetto CDK2 is the predominant activating complex form of CCNO, but CCNO can bind to CDK1 to form an activating complex in the absence of CDK2. SIGNOR-275617 0.341 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000938 10558990 t lperfetto The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival. SIGNOR-252782 0.2 PPP2CA protein P67775 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates dephosphorylation 9606 20626350 t gcesareni In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a. SIGNOR-166649 0.54 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 17615152 t gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo. SIGNOR-156856 0.657 SLC24A1 protein O60721 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264390 0.8 ATM protein Q13315 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates activity phosphorylation Ser272 LSDTDSHsQDLGSPE 9606 BTO:0000763 11278446 t lperfetto Hyperphosphorylation of hrad9 induced by ir is dependent on atm. Ser(272) of hrad9 is phosphorylated directly by atm in vitro. / our results suggest that the atm-mediated phosphorylation of hrad9 is required for ir-induced checkpoint activation. SIGNOR-105243 0.758 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser307 TRRSRTEsITATSPA 10116 BTO:0000452 11287630 t lperfetto Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten SIGNOR-106570 0.757 MEF2C protein Q06413 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0000222 7739551 t lperfetto Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. SIGNOR-238652 0.547 PRKN protein O60260 UNIPROT MFN2 protein O95140 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000793 20871098 t miannu Parkin and PINK1 are required for ubiquitination of MFN-1 and MFN-2.  Decreases in MFN-1 and MFN-2 protein levels seen at later timepoints are difficult to interpret as it is unclear whether this is due to degradation by the proteasome and/or loss of whole mitochondria by mitophagy. SIGNOR-272780 0.2 MAPK14 protein Q16539 UNIPROT JDP2 protein Q8WYK2 UNIPROT unknown phosphorylation Thr148 VRTDSVKtPESEGNP -1 12225289 t miannu Wild-type JDP2 exhibited efficient phosphorylation by the p38 kinase, the mutant JDP2 T%)A did not incorporate labelled Figure 5 JDP2 C-terminal domain is necessary but not sufficient for p38 phosphorylation (A) p38 phosphorylated JDP2 at Thr-148. Bacterially purified His-JDP2 (Wt) or His-JDP2 T148A (Ala) were incubated with bacterially purified activated p38 F327S [21] in the presence of [γ- 32P]ATP for 30 min. Proteins were resolved by SDS/PAGE (12 % gel), dried and exposed to autoradiography. (B) The JDP2 C-terminal domain is necessary but not sufficient for phosphorylation by p38 kinase. Bacterially purified GST fusion proteins with full-length JDP2 (Wt) C-terminally truncated JDP2 (∆C) and JDP2 C-terminal fragment (Dock) were used in an in vitro kinase assay as described in (A). A representative experiment is presented. (C) In vitro kinase assay using GST-JDP2 (JDP2wt), JDP2 ∆C and JDP2-Dock as substrates with either activated p38 or HA-JNK2 kinases. Protein mixtures were resolved by SDS/PAGE, fixed, dried and analysed by PhosphorImaging. The results represent meansS.E.M. from three independent experiments. phosphate in the presence of activated p38 kinase. This indicates that both p38 and JNK kinases are able to integrate stress signals to JDP2 Thr-148 SIGNOR-250100 0.388 PRKAA1 protein Q13131 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251619 0.287 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii SIGNOR-203580 0.769 RIPK3 protein Q9Y572 UNIPROT PDH complex SIGNOR-C402 SIGNOR up-regulates activity phosphorylation -1 29358703 t miannu Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135. SIGNOR-268065 0.2 ITGB1 protein P05556 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253170 0.748 MAPK3 protein P27361 UNIPROT ARHGAP26 protein Q9UNA1 UNIPROT unknown phosphorylation Ser685 PMFSAPSsPMPTSST -1 9525907 t miannu In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling. SIGNOR-262945 0.2 CUL2 protein Q13617 UNIPROT BAF250b E3 ligase complex SIGNOR-C522 SIGNOR form complex binding 9606 BTO:0000567 20086098 t miannu In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro SIGNOR-271440 0.609 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser334 PLGDDEAsATVSKTE -1 9099669 t lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. SIGNOR-248966 0.45 TARDBP protein Q13148 UNIPROT DICER1 protein Q9UPY3 UNIPROT up-regulates quantity post transcriptional regulation 7227 32620127 t lperfetto Molecularly, we observed that TBPH regulates the expression levels of Dicer-2 by direct protein-mRNA interactions in vivo.|In agreement with this idea, we found that the suppression of TDP-43 induces the downregulation of Dicer in human neuroblastoma cell lines signifying that the TDP-43 function is required to prevent defects in Dicer protein expression or stability SIGNOR-262114 0.382 FNTA protein P49354 UNIPROT MRAS protein O14807 UNIPROT up-regulates activity 9606 24294527 t lperfetto Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. SIGNOR-242553 0.2 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Ser104 FSFDTDRsPAPMSCD 9606 12591950 t lperfetto Biml (bim long) was induced and phosphorylated parallel to jnk activitythese data demonstrate that biml is phosphorylated in vivo on thr-56 and that jnk also phosphorylates biml on at least one serine residue (ser-44 and/or ser-58) SIGNOR-98384 0.2 IQGAP1 protein P46940 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity binding 15695813 t lperfetto Although the name implies that it functions as a GTPase-activating protein, IQGAP1 actually stabilizes Cdc42 and Rac1 in the active, GTP-bound form (5, 8, 17). Thus, IQGAP1 acts as an “anti-GTPase-activating protein” for Cdc42 and Rac1, with marked effects on the cytoskeleton.  SIGNOR-261889 0.703 SRC protein P12931 UNIPROT KCND3 protein Q9UK17 UNIPROT up-regulates activity phosphorylation Tyr108 GKLHYPRyECISAYD 9606 BTO:0000007 22198508 t miannu These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels. SIGNOR-276393 0.344 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252846 0.908 CACNA1G protein O43497 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30849329 t miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). SIGNOR-264324 0.8 regorafenib chemical CHEBI:68647 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259206 0.8 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 t lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 SIGNOR-161686 0.591 EGFR protein P00533 UNIPROT VAV2 protein P52735 UNIPROT up-regulates phosphorylation Tyr142 TENDDDVyRSLEELA 9606 12454019 t miannu To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor. SIGNOR-95972 0.61 Oxotremorine chemical CHEBI:7851 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258652 0.8 CSNK2A2 protein P19784 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates phosphorylation Thr93 EAETLAEtEPERHLG 9606 BTO:0001130 16581776 t llicata In vitro kinase assays followed by mass spectrometric analyses demonstrated that ck2 phosphorylated recombinant nkx3.1 on thr89 and thr93. We have also determined that nkx3.1 is degraded primarily through a proteasomal pathway, suggesting that phosphorylation by ck2 protects nkx3.1 from degradation. SIGNOR-145505 0.32 CoREST-HDAC complex complex SIGNOR-C105 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 32101746 f miannu The CoREST complex is one of seven families of class I histone deacetylase complexes that have specialized physiological functions but are all thought to act as repressors of gene expression. CoREST is unique within these complexes in that it removes both acetyl and methyl modifications through the activity of its demethylase (LSD1) and deacetylase (HDAC1) enzymes. SIGNOR-263861 0.7 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 9922370 t gcesareni Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity SIGNOR-64169 0.616 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 11777359 t rheumatoid arthritis gcesareni SIGNOR-251699 0.8 PAX2 protein Q02962 UNIPROT PAX2/TLE4 complex SIGNOR-C152 SIGNOR form complex binding 9606 16631587 t miannu Several Pax proteins are able to interact with groucho (TLE) family members. Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1. SIGNOR-256359 0.468 MCU_MICU2_variant complex SIGNOR-C502 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270878 0.8 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser263 NVGSPLSsPLSSMKS 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276108 0.357 FYN protein P06241 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Tyr291 AETSKLIyDFIEDQG 10090 BTO:0000775 14707117 t done miannu TCR-induced WASp tyrosine phosphorylation was also disrupted in T cells lacking Fyn, a kinase shown here to bind, colocalize with, and phosphorylate WASp. Although Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation, PTP-PEST combined with PSTPIP1 inhibited WASp-driven actin polymerization and synapse formation. SIGNOR-273960 0.578 RHOQ protein P17081 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates 9606 12242347 f gcesareni Tc10 is activated afte rinsulin stimulation, and its activation is required for insulin-stimulated glucose uptake and glut4 translocation SIGNOR-93117 0.445 SYN2 protein Q92777 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates activity binding 9606 BTO:0000938 15265865 t miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. SIGNOR-269185 0.7 CALM1 protein P0DP23 UNIPROT KIF1A protein Q12756 UNIPROT up-regulates activity binding 10116 BTO:0003102 30021165 t miannu To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. We show that Ca2+/CaM-dependent modulation on KIF1A allows for binding to vesicular cargo. Our results indicate that at low calcium concentrations, the tail domain of KIF1A does not bind to vesicular cargo, whereas at high calcium concentrations, CaM binds KIF1A, allowing for subsequent DCV motility. SIGNOR-266888 0.278 hydroxyurea chemical CHEBI:44423 ChEBI RRM2 protein P31350 UNIPROT down-regulates activity chemical inhibition 9606 14583450 t miannu In PC3 cells, hydroxyurea inhibited hRRM2 and resulted in increased sensitivity to UV irradiation. SIGNOR-259355 0.8 beta-Funaltrexamine chemical CHEBI:81527 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258772 0.8 NPNT protein Q6UXI9 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 10090 22613833 t lperfetto The loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1-dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser syndrome. SIGNOR-253344 0.668 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser171 PLCLSPAsSGSSASF 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252318 0.635 HDAC3 protein O15379 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity deacetylation -1 11486036 t miannu Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs. SIGNOR-268837 0.583 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Thr697 EMDSMPYtQNFISCN 9606 BTO:0000567 34198826 t miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. SIGNOR-276661 0.252 FBXW11 protein Q9UKB1 UNIPROT ZNF281 protein Q9Y2X9 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001615 phosphorylation:Ser638 PRVDLHTsGEHSELV 29179460 t lperfetto E3 ligase the beta-transducin repeat-containing protein 2 (beta-TrCP2) governs the ubiquitination and degradation of ZNF281. In human CRC specimens, endogenous beta-TrCP2 were inversely correlated with ZNF281. SIGNOR-264897 0.2 SMAD4 protein Q13485 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 t lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229560 0.7 CDK5 protein Q00535 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 20630875 t gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. The kinases involved in phosphorylating stmn ser-16 and ser-63 include camp-dependent protein kinase (pka) and pak1, whereas stmn ser-25 and ser-38 have been shown to be targets for proline-directed serine/threonine kinases such as cyclin-dependent kinases, erk1/2, and members of the p38 mapk subfamily. SIGNOR-166682 0.385 PKI-587 chemical CID:44516953 PUBCHEM MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205986 0.8 PDIA6 protein Q15084 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates activity 10090 BTO:0004086 17420453 f Overexpression of ERp5 promotes both in vitro migration and invasion and in vivo metastasis of breast cancer cells. SIGNOR-256533 0.7 GBF1 protein Q92538 UNIPROT ARF1 protein P84077 UNIPROT up-regulates activity guanine nucleotide exchange factor 9534 BTO:0000298 15616190 t miannu GBF1 Stimulates Production of Arf-GTP In Vivo SIGNOR-277400 0.708 CEP350 protein Q5VT06 UNIPROT FGFR1OP/CEP350 complex SIGNOR-C52 SIGNOR form complex binding 9606 16314388 t miannu Here we show that cap350 and fop (fgfr1 oncogene partner) form a centrosomal complex required for mt anchoring. SIGNOR-142355 0.2 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser341 KALASIYsPDHSSNN 9606 19801649 t llicata Mlk2 inhibits e47 transactivation activity on the trkb promote SIGNOR-161523 0.2 PRKCG protein P05129 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 t gcesareni We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus. SIGNOR-97558 0.69 MYC protein P01106 UNIPROT MYCBP2 protein O75592 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 32814769 t miannu We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. SIGNOR-267145 0.425 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser178 EENVSDGsPNAGSVE 9606 10831586 t lperfetto Indeed, p27kip1 was phosphorylated by p42 mapk (erk2) in vitrothese results suggest that ser(10) is the major site of phosphorylation of p27(kip1) and that phosphorylation at this site, like that at thr(187), contributes to regulation of p27(kip1) stability. SIGNOR-244517 0.2 EFNA2 protein O43921 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 10072375 t tpavlidou Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8) SIGNOR-65413 0.809 RAB33B protein Q9H082 UNIPROT ATG16L1 protein Q676U5 UNIPROT up-regulates binding 9606 18448665 t gcesareni Olgi-resident small gtpase rab33b interacts with atg16l and modulates autophagosome formation. SIGNOR-178542 0.745 STK16 protein O75716 UNIPROT DRG1 protein Q9Y295 UNIPROT unknown phosphorylation Thr100 AYEFTTLtTVPGVIR -1 18184589 t Manara It is therefore likely that MPSK1 regulates DRG1 function by either phosphorylation or through competition with other DRG1 binding partners. SIGNOR-260806 0.4 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser227 FGSFPVHsPITQGTP 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276111 0.357 CAK complex complex SIGNOR-C456 SIGNOR CDK4 protein P11802 UNIPROT up-regulates phosphorylation Thr172 YSYQMALtPVVVTLW 9606 8139570 t lperfetto Phosphorylation of cdk4 on threonine 172 by a cdk-activating kinase (cak).  therefore, formation of the cyclin d-cdk4 complex and phosphorylation of the bound catalytic subunit are independently regulated, and in addition to the requirement for cak activity, serum stimulation is required to promote assembly of the complexes in mammalian cells. SIGNOR-269329 0.56 CHEK2 protein O96017 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation 9606 22558186 t gcesareni In this report, we characterize the binding of sh2(chk) to specific phosphotyrosine sites on the c-kit protein sequence. the sh2(chk) binding to the two sites is direct and not through phosphorylated intermediates such as fyn or shc. this indicates that chk binds to the same site on c-kit to which fyn binds, possibly bringing the two into proximity on associated c-kit subunits and leading to the down-regulation of fyn by chk. SIGNOR-197281 0.29 BMP15 protein O95972 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 BTO:0000975 SIGNOR-C29 16446785 t gcesareni Here we have performed a detailed in situ hybridization analysis of the spatial and temporal expression patterns of the bmp ligands (bmp-2, -3, -3b, -4, -6, -7, -15), receptors (bmpr-ia, -ib, -ii), and bmp antagonist, follistatin, in rat ovaries over the normal estrous cycle. SIGNOR-144098 0.552 EFNB3 protein Q15768 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52621 0.832 ANK2 protein Q01484 UNIPROT DMD protein P11532 UNIPROT up-regulates quantity relocalization 10090 BTO:0001103 19109891 t miannu We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4. SIGNOR-266712 0.545 C1QBP protein Q07021 UNIPROT C1QC protein P02747 UNIPROT down-regulates activity binding SIGNOR-C308 28018340 t lperfetto Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping. SIGNOR-263404 0.408 ZMYND8 protein Q9ULU4 UNIPROT VEGFA protein P15692 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 27477906 t lperfetto Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported SIGNOR-262041 0.2 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 9381178 t Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival. SIGNOR-252562 0.817 ZNF692 protein Q9BU19 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17097062 f gcesareni In this study, we demonstrate that a newly identified transcription factor, arebp, is a novel target of ampk. Arebps function is to repress transcription of the pepck gene upon phosphorylation by ampk. SIGNOR-150556 0.2 GABRA2 protein P47869 UNIPROT GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263753 0.596 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176817 0.775 HECTD1 protein Q9ULT8 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22431752 t Monia We demonstrate that Hectd1 is a functional ubiquitin ligase and that one of its substrates is Hsp90, a chaperone protein with both intra- and extracellular clients. Identification of Hsp90 in both proteomic screens suggested that members of the Hsp90 superfamily may be substrates of Hectd1. Myc-Hectd1ANK and HA-Hsp90bd (the fragment identified in the yeast two-hybrid screen) bind in an in vitro binding assay (Fig. 3 D) and when coexpressed in HEK293T cells. Hectd1 is required for K63-linked Ubn of Hsp90. Together, these results demonstrate that Hectd1-dependent Ubn of Hsp90 targets it away from the membrane and the secretory pathway. SIGNOR-261199 0.2 ADRA1B protein P35368 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256950 0.281 MAPK3 protein P27361 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation Tyr204 HTGFLTEyVATRWYR 1712480 t lperfetto Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.| SIGNOR-249472 0.2 CLOCK protein O15516 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR form complex binding -1 22653727 t lperfetto Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex|The structure of the CLOCK:BMAL1 complex is a starting point for understanding at an atomic level the mechanism driving the mammalian circadian clock. SIGNOR-253709 0.771 PTPRG protein P23470 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity dephosphorylation Tyr1172 ISLDNPDyQQDFFPK -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254700 0.494 MASP2 protein O00187 UNIPROT C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Arg756 KGQAGLQrALEILQE -1 17204478 t lperfetto MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a). SIGNOR-263425 0.794 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser750 RRKMKKTsTSTETRS 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. SIGNOR-131399 0.2 KAT2B protein Q92831 UNIPROT H3-5 protein Q6NXT2 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269617 0.2 EPAS1 protein Q99814 UNIPROT KDM4C protein Q9H3R0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271585 0.2 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr708 NIHLEKKyVRRDSGF 9606 BTO:0001271 15297464 t lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins. SIGNOR-127540 0.2 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120212 0.321 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser20 APPVRMSsTIFSTGG -1 10075701 t miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197. SIGNOR-250227 0.2 CAMK2D protein Q13557 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser561 PFLSRHNsKSSIFSF 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275790 0.285 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273034 0.556 Nutlin-3 smallmolecule CID:216345 PUBCHEM TP73 protein O15350 UNIPROT up-regulates 9606 17700533 t miannu These results provide the first evidence that Nutlin-3 disrupts endogenous p73-HDM2 interaction and enhances the stability and proapoptotic activities of p73 and thus, provides a rationale for the use of Nutlin-3 in the large number of human tumors in which p53 is inactivated. SIGNOR-255472 0.8 A5/b1 integrin complex SIGNOR-C163 SIGNOR DLL1 protein O00548 UNIPROT up-regulates quantity by expression 10090 25786978 f lperfetto First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs. SIGNOR-253286 0.27 CAMK2D protein Q13557 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser641 RRSVKRNsTVDCNGV 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275791 0.285 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT down-regulates activity phosphorylation Ser54 ELQPMPTsPGVDLQS 9606 SIGNOR-C83 12714602 t lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. SIGNOR-100885 0.757 PKC proteinfamily SIGNOR-PF53 SIGNOR KCNJ1 protein P48048 UNIPROT up-regulates activity phosphorylation Ser201 FSKNAVIsKRGGKLC -1 12221079 t miannu We conclude that ROMK1 is a substrate of PKC and that serine residues 4 and 201 are the two main PKC phosphorylation sites that are essential for the expression of ROMK1 in the cell surface. SIGNOR-275990 0.2 PRKAA2 protein P54646 UNIPROT PPP1R12C protein Q9BZL4 UNIPROT down-regulates phosphorylation Ser452 AGLQRSAsSSWLEGT 9606 SIGNOR-C15 22137581 t lperfetto Ampk-induced phosphorylation is necessary for ppp1r12c interaction with 14-3-3 and phosphorylation of myosin regulatory light chain. Both ampk activity and ppp1r12c phosphorylation are increased in mitotic cells and are important for mitosis completion. The interaction between ppp1r12c and 14-3-3_ may inactivate the ppp1r12c-containing phosphatase complex in vivo. SIGNOR-195148 0.262 PGM2 protein Q96G03 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI down-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-268115 0.8 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr7 yDFKATAD 9606 BTO:0000007 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246285 0.2 ATRX protein P46100 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by repression transcriptional regulation 7227 BTO:0001138 22021382 f 1 miannu XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression. SIGNOR-239733 0.414 Integrator complex complex SIGNOR-C265 SIGNOR FOSL1 protein P15407 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25675981 f lperfetto The Integrator complex controls the termination of transcription at diverse classes of gene targets.|Following INTS3 or INTS9 knockdown, the levels of SDC4, JUNB, FOSL1, and GADD45B increased, suggesting that the Integrator complex negatively regulates the transcription of these genes. SIGNOR-261477 0.2 AMPK complex SIGNOR-C15 SIGNOR VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 17082196 t lperfetto Pharmacological ampk inhibitors and activators and ampk mutants revealed that the kinase specifically targets residue thr-278 but not ser-157 or ser-239. Quantitative fluorescence-activated cell sorter analysis and serum response factor transcriptional reporter assays, which quantify the cellular f-/g-actin equilibrium, indicated that ampk-mediated vasp phosphorylation impaired actin stress fiber formation and altered cell morphology. SIGNOR-216515 0.2 WNT3A protein P56704 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins are a large family of secreted glycoproteins. Wnt proteins bind to the Frizzled receptors and LRP5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131829 0.782 FBXW5 protein Q969U6 UNIPROT SASS6 protein Q6UVJ0 UNIPROT down-regulates quantity by destabilization ubiquitination 21725316 t lperfetto We identify the centriolar protein HsSAS-6 (refs 4,5) as a critical substrate of the SCF-FBXW5 complex. FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo. |expression of the wild-type form of FBXW5 accelerated the degradation of HsSAS-6 to a half-life of less than two hours SIGNOR-275478 0.552 RHOA protein P61586 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity binding 9606 8824197 t areggio We found that in the human kidney epithelial cell line, 293T, Cdc42 and all Rho proteins, RhoA, RhoB, and RhoC, but not Rac or Ras can induce activation of JNK. SIGNOR-258974 0.821 BMS-599626 chemical CID:10437018 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 17062696 t AC480 significantly enhanced the radiosensitivity of HN-5 cells, expressing both EGFR and Her2. gcesareni The studies described here are intended to characterize the ability of bms-599626, a small-molecule inhibitor of the human epidermal growth factor receptor (her) kinase family, to modulate signaling and growth of tumor cells that depend on her1 and/or her2. SIGNOR-150190 0.8 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89197 0.55 NEK7 protein Q8TDX7 UNIPROT KIF11 protein P52732 UNIPROT up-regulates activity phosphorylation Ser1033 GINTLERsKVEETTE 10090 BTO:0000938 29899413 t done miannu NEK7 regulates these processes in part through phosphorylation of the kinesin Eg5/KIF11, promoting its accumulation on microtubules in distal dendrites.  SIGNOR-273890 0.417 MAPK8 protein P45983 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser216 SKSKAPGsPLSSEGA -1 15850461 t miannu CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. SIGNOR-263087 0.29 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270391 0.8 TRIM27 protein P14373 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000671 12807881 f miannu Here we show that ectopic expression of rfp in human embryonic kidney 293 cells causes extensive apoptosis, as assessed by multiple criteria. SIGNOR-102019 0.7 AKT2 protein P31751 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates activity phosphorylation Ser50 RNRYRDVsPFDHSRI 10090 11579209 t lperfetto We conclude that ptp1b is a novel substrate for akt and that phosphorylation of ptp1b by akt at ser(50) may negatively modulate its phosphatase activity creating a positive feedback mechanism forinsulin signaling SIGNOR-235491 0.38 MAD2L2 protein Q9UI95 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity binding -1 11459826 t miannu The APC is activated in mitosis and G1 by CDC20 and CDH1, and inhibited by the checkpoint protein MAD2, a specific inhibitor of CDC20. We show here that a MAD2 homolog MAD2B also inhibits APC. MAD2B directly inhibits activation of APC by CDC20 and CDH1 SIGNOR-264903 0.471 GSK3B protein P49841 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 SIGNOR-C13 17183360 t gcesareni Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) . SIGNOR-151422 0.364 AMFR protein Q9UKV5 UNIPROT CD3D protein P04234 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11724934 t miannu Gp78 specifically recruits MmUBC7, a ubiquitin-conjugating enzyme (E2) implicated in ER-associated degradation (ERAD), through a region distinct from the RING finger. gp78 can target itself for proteasomal degradation in a RING finger- and MmUBC7-dependent manner. Importantly, gp78 can also mediate degradation of CD3-delta, a well-characterized ERAD substrate.  SIGNOR-272670 0.486 CAMK2B protein Q13554 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity phosphorylation Ser285 QRVPSYDsFDSEDYP BTO:0003637 12475968 t llicata Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1  SIGNOR-250687 0.314 pemetrexed chemical CHEBI:63616 ChEBI DHFR protein P00374 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205819 0.8 CDK1 protein P06493 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates phosphorylation Ser337 IVSPPPSsPPSSLTT 9606 8087847 t lperfetto Association of e2f with rb inhibits its transactivation potential. phosphorylation of e2f-1 on serine residues 332 and 337 prevented its interaction with rbthese residues were phosphorylated in vivo and by p34cdc2 kinase in vitro. SIGNOR-36026 0.688 QYDAFJUKVGVEKO-PKOVDKIBSA-N smallmolecule CID:16132339 PUBCHEM MRGPRX1 protein Q96LB2 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257543 0.8 PRKCD protein Q05655 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Thr678 RHIVRKRtLRRLLQE 10090 1860884 t lperfetto These data indicate that activation of protein kinase C and subsequent phosphorylation of the EGF receptor at T654 lead to rapid physiological attenuation of EGF receptor signaling. SIGNOR-248858 0.376 IL9 protein P15248 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 t gcesareni The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex SIGNOR-108867 0.563 CDX1 protein P47902 UNIPROT VIL1 protein P09327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19371634 f miannu We concluded that cdx2 regulates intestinal villin expression through recruiting brm-type swi/snf complex to the villin promoter. SIGNOR-185483 0.3 SLC1A6 protein P48664 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity relocalization 9606 26687113 t miannu After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5). SIGNOR-264805 0.8 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation 9606 10197981 t lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 SIGNOR-66738 0.711 calcium(2+) smallmolecule CHEBI:29108 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 9651347 t gcesareni Our results indicate that ca2+ ions not only anchor the protein to membrane surfaces but also induce conformational changes resulting in pkc activation. SIGNOR-58506 0.8 DPYSL5 protein Q9BPU6 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity binding 9606 BTO:0000938 25040932 t lperfetto The studies on CRMP5 function show that, by interacting with tubulin and MAP2, this protein inhibits neurite growth especially at the dendritic level and restricts the promotional effect of CRMP2 on axon and dendrite growth SIGNOR-264836 0.2 FASN protein P49327 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI down-regulates quantity chemical modification 9606 15507492 t Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-267759 0.8 ATRX protein P46100 UNIPROT Immortality phenotype SIGNOR-PH47 SIGNOR down-regulates 9606 BTO:0000584 26428317 f Telomere length must be maintained for the immortalization of malignant cells […] alternative lengthening of telomeres status was perfectly correlated with the loss of expression of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein in pancreatic neuroendocrine tumors SIGNOR-256595 0.7 TIMM10 protein P62072 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 t lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). SIGNOR-267703 0.709 FBXO38 protein Q6PIJ6 UNIPROT KLF7 protein O75840 UNIPROT up-regulates activity binding 9534 BTO:0004055 14729953 t miannu Interaction between MoKA and KLF7 was confirmed by the in vitro glutathione S-transferase pull-down assay and by coimmunoprecipitation of the proteins overexpressed in mammalian cells. Functional assays documented that MoKA is a KLF7 coactivator SIGNOR-224621 0.594 RNF8 protein O76064 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR up-regulates ubiquitination 9606 20551964 t gcesareni Rnf8 and ubc13 ubiquitylate h2a and h2ax, but other substrates probably exist. SIGNOR-265313 0.2 FGR protein P09769 UNIPROT ACO2 protein Q99798 UNIPROT unknown phosphorylation Tyr71 TLSEKIVyGHLDDPA -1 17997986 t miannu Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are "in vitro" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations. SIGNOR-262871 0.2 TRIM27 protein P14373 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity ubiquitination 10090 35670107 t STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination SIGNOR-270349 0.2 AURKA protein O14965 UNIPROT KIF4A protein O95239 UNIPROT up-regulates activity phosphorylation Thr799 PPKLRRRtFSLTEVR -1 31881080 t miannu We show that Aurora A phosphorylates the condensin I-dependent pool of KIF4A and thus actively promotes chromosome congression from the spindle poles to the metaphase plate. In vitro kinase assays showed that recombinant KIF4A can be phosphorylated by Aurora A and that this activity is inhibited by the specific Aurora A inhibitor MLN8537 (Fig. 7 C). SIGNOR-265993 0.428 long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity precursor of 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267903 0.8 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr750 PAPDELVyQVPQSTQ -1 23770091 t done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. SIGNOR-273944 0.357 KIF14 protein Q15058 UNIPROT CIT protein O14578 UNIPROT up-regulates activity binding 9606 16431929 t miannu We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase. SIGNOR-266422 0.712 IDH complex SIGNOR-C396 SIGNOR D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI down-regulates quantity chemical modification 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-266251 0.8 PTPN1 protein P18031 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates activity dephosphorylation Tyr153 SEDIKSYyTVRQLEL -1 11506178 t Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions. SIGNOR-248425 0.2 CHFR protein Q96EP1 UNIPROT SMARCA4 protein P51532 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 22285184 t miannu Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination. SIGNOR-271457 0.339 SRC protein P12931 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 11847100 t lperfetto c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function. SIGNOR-246311 0.518 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BW1 protein Q7Z2G1 UNIPROT down-regulates activity monoubiquitination 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271989 0.2 PHKA1 protein P46020 UNIPROT PHKA1 protein P46020 UNIPROT up-regulates activity phosphorylation Ser972 KEFGVERsVRPTDSN -1 10487978 t miannu Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation) SIGNOR-250281 0.2 U69593 chemical CHEBI:73357 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258827 0.8 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Glu618 SEVKMDAeFRHDSGY -1 8943232 t lperfetto The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261767 0.502 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates activity phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 10660534 t lperfetto Rlk phosphorylated the N-terminal region of SLP-76, a region that has been previously shown to serve as a target for ZAP-70. Loss of N-terminal YESP/YEPP sites of SLP-76 or the Rlk kinase activity attenuated cooperativity between Rlk and SLP-76 SIGNOR-246929 0.717 calcium(2+) smallmolecule CHEBI:29108 ChEBI KCNMA1 protein Q12791 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 31152168 t miannu The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. The BK channel can be allosterically activated by both changes in the membrane voltage (voltage-dependent activation pathway) and intracellular [Ca2+] concentration (calcium-dependent activation pathway) SIGNOR-269192 0.8 HSPA1A protein P0DMV8 UNIPROT ENPP1 protein P22413 UNIPROT up-regulates quantity post transcriptional regulation 9606 19083193 t miannu We demonstrated the binding of heat shock protein 70 (HSP70) to ENPP1-3'UTR. Through this binding, HSP70 stabilizes ENPP1 mRNA and increases ENPP1 transcript and protein levels. This positive modulation of ENPP1 expression is paralleled by a reduced insulin-induced IR and IRS-1 phosphorylation. SIGNOR-252197 0.2 CAMK2A protein Q9UQM7 UNIPROT ETS2 protein P15036 UNIPROT down-regulates phosphorylation Ser313 QRVPSFEsFEDDCSQ 9606 19182667 t lperfetto Camkii caused ets-2 phosphorylation.Serine 246, 310, and 313 were the targets. Camkii to phosphorylates ets-2, thus altering ets-2 binding to its downstream promoters SIGNOR-183604 0.2 IKBKB protein O14920 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000007 SIGNOR-C13 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-129935 0.882 PIM proteinfamily SIGNOR-PF34 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000574 16146838 f miannu The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. SIGNOR-255732 0.7 C5AR1 protein P21730 UNIPROT SELL protein P14151 UNIPROT down-regulates quantity by repression 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263468 0.331 INSR protein P06213 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr536 QKGQESEyGNITYPP 9606 7512963 t llicata Insulin stimulates the phosphorylation of tyr538 and the catalytic activity of ptp1c, a protein tyrosine phosphatase with src homology-2 domains. these results suggest that ptp1c is a target protein for the insulin receptor tyrosine kinase SIGNOR-26870 0.366 PLK1 protein P53350 UNIPROT FBXO5 protein Q9UKT4 UNIPROT down-regulates phosphorylation 9606 16439210 t gcesareni We propose that the balance of evi5 and polo-like kinase activities determines the timely accumulation of emi1 and cyclin, ensuring mitotic fidelity. SIGNOR-142949 0.774 CDK1 protein P06493 UNIPROT EEF1D protein P29692 UNIPROT unknown phosphorylation Ser133 APQTQHVsPMRQVEP 9606 12551973 t gcesareni The sequence flanking ser-133 of ef-1delta completely matches the consensus phosphorylation site for a cellular protein kinase, cdc2, and in vitro kinase assays revealed that purified cdc2 phosphorylates ser-133 of ef-1delta. SIGNOR-97733 0.369 CD79B protein P40259 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268201 0.641 Osmotic_stress stimulus SIGNOR-ST28 SIGNOR FUS protein P35637 UNIPROT down-regulates activity relocalization 9606 BTO:0000312 33172210 f We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne SIGNOR-262815 0.7 NSMCE1 protein Q8WV22 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR form complex binding -1 27427983 t miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks SIGNOR-265483 0.874 SMN1 protein Q16637 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 t lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. SIGNOR-253115 0.727 NMDA receptor_2A complex SIGNOR-C347 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor SIGNOR-264222 0.794 ATF4 protein P18848 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260172 0.647 PTPN12 protein Q05209 UNIPROT SHC1 protein P29353 UNIPROT down-regulates dephosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 8939605 t gcesareni The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions. SIGNOR-44361 0.661 PI-103 chemical CHEBI:90524 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206172 0.8 WWTR1 protein Q9GZV5 UNIPROT PAX8 protein Q06710 UNIPROT up-regulates binding 9606 BTO:0000763 19010321 t miannu Taz is a coactivator for pax8 and ttf-1, two transcription factors involved in thyroid differentiation. / we show that this interaction leads to a significant enhancement of the transcriptional activity of pax8 and ttf-1 on the thyroglobulin promoter thus suggesting a role of taz in the control of genes involved in thyroid development and differentiation. SIGNOR-182253 0.308 sphingosine 1-phosphate(1-) smallmolecule CHEBI:60119 ChEBI S1PR5 protein Q9H228 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257580 0.8 buspirone chemical CHEBI:3223 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258885 0.8 CSNK2A1 protein P68400 UNIPROT TLE1 protein Q04724 UNIPROT up-regulates phosphorylation Ser239 KDSSHYDsDGDKSDD 9606 15367661 t lperfetto These results suggest that ck2 phosphorylation of serine 239 of gro/tle1 is important for its function during neuronal differentiation. SIGNOR-129026 0.325 PRKCZ protein Q05513 UNIPROT ADARB1 protein P78563 UNIPROT up-regulates activity phosphorylation Ser216 SASPVPAsLAQPPLP 9606 BTO:0001615 29694894 t miannu  Here, we identified ADAR2 as a direct substrate of PKCζ in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKCζ/ADAR2 axis regulates miR-200 secretion through RNA editing.  SIGNOR-277391 0.2 MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser27 ADREAASsPAGEPLR 9606 20027304 t This phosphorylation increased sirt1 nuclear localization gcesareni Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53. SIGNOR-162314 0.62 EPAS1 protein Q99814 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20534544 f Regulation miannu We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200-3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2alpha, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. SIGNOR-251791 0.288 BICRA protein Q9NZM4 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269781 0.2 DLX2 protein Q07687 UNIPROT ARX protein Q96QS3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18923043 f Regulation miannu Dlx overexpression induces ectopic expression of endogenous Arx and its isolated enhancer, whereas loss of Dlx expression results in reduced Arx expression SIGNOR-251972 0.278 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation Tyr348 LPMDTEVyESPYADP 9606 BTO:0000776 9820500 t lperfetto These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520 SIGNOR-246609 0.2 ABL2 protein P42684 UNIPROT PSMA7 protein O14818 UNIPROT down-regulates phosphorylation Tyr153 QTDPSGTyHAWKANA 9606 16678104 t lperfetto Proteasome-mediated proteolysis is a primary protein degradation pathway in cells. The present study demonstrates that c-abl and arg (abl-related gene) tyrosine kinases associate with and phosphorylate the proteasome psma7 (alpha4) subunit at tyr-153. Consequently, proteasome-dependent proteolysis is compromised SIGNOR-146589 0.591 PRLHR protein P49683 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257198 0.252 BMP7 protein P18075 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 18719589 f induction of mitochondrial biogenesis fspada Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways SIGNOR-180308 0.317 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 12110590 t gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. SIGNOR-90525 0.786 PP1 proteinfamily SIGNOR-PF54 SIGNOR AURKA protein O14965 UNIPROT down-regulates dephosphorylation 9606 11551964 t lperfetto Pp1 is shown to dephosphorylate active stk15 and abolish its activity in vitro. SIGNOR-264651 0.2 PPP1CA protein P62136 UNIPROT WWTR1 protein Q9GZV5 UNIPROT up-regulates activity dephosphorylation Ser89 AQHVRSHsSPASLQL 9606 21189257 t miannu PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase. SIGNOR-277116 0.526 MAP3K8 protein P41279 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Thr210 YDGERKKtLCGTPNY 9606 BTO:0000567 12207013 t miannu Xplkk1 phosphorylates and activates mammalian plk / xplkk1 phosphorylates thr-210 SIGNOR-92274 0.2 LRFN1 protein Q9P244 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments. SIGNOR-264100 0.7 UBE2I protein P63279 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates sumoylation Lys113 KNELKHVkYCQYAFD 9606 12621041 t gcesareni The mh1 domain of smad4 was shown to associate physically with ubc9, the ubiquitin carrier protein (e2) conjugating enzyme in sumoylation. In cultured cells, smad4 is modified by sumo-1 at the endogenous level. The sumoylation sites were identified as two evolutionarily conserved lysine residues, lys-113 and lys-159, in the mh1 domain. We found that the mutations at lys-113 and lys-159 did not alter the ability of smad4 to form a complex with smad2 and fast on the mix.2 promoter. Importantly, sumo-1 overexpression enhanced tgf-beta-induced transcriptional responses. These findings identify sumoylation as a unique mechanism to modulate smad4-dependent cellular responses SIGNOR-98993 0.61 AKT1 protein P31749 UNIPROT HK1 protein P19367 UNIPROT up-regulates binding 9606 16892082 t gcesareni The glucose dependence of the antiapoptotic effects of growth factors and akt plus a strong correlation between akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects. SIGNOR-252495 0.456 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120036 0.781 YAP1 protein P46937 UNIPROT DVL1 protein O14640 UNIPROT down-regulates binding 9606 23178811 t gcesareni Yap restricts elevated wnt independently of the axinapcgsk-3beta complex partly by limiting the activity of dishevelled (dvl). SIGNOR-199806 0.339 SMARCA4 protein P51532 UNIPROT SMARCC2 protein Q8TAQ2 UNIPROT up-regulates binding 9606 10078207 t miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. SIGNOR-65444 0.938 XRCC6 protein P12956 UNIPROT UBE2S protein Q16763 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 27593939 t lperfetto As shown in Figure 4, we found that Ku70 (Figure 4b) and Ku80 (Figure 4c) co-immunoprecipitated with UBE2S.>Taken together, these results demonstrate that ETO enhances the UBE2S–Ku70 interaction, and UBE2S can be recruited to the same sites of DSBs with Ku70 upon ETO treatment. SIGNOR-265079 0.353 CLOCK protein O15516 UNIPROT NR0B2 protein Q15466 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 20674862 t lperfetto CLOCK knockdown activated MTP promoter and reduced small heterodimer partner (SHP, NROB2). CLOCK upregulated SHP by binding to its E box. SIGNOR-253698 0.396 CAMK2G protein Q13555 UNIPROT GRIA4 protein P48058 UNIPROT unknown phosphorylation Ser862 IRNKARLsITGSVGE 10366608 t llicata We found that GluR4 is phosphorylated on serine 842 within the C-terminal domain in vitro and in vivo. Serine 842 is phosphorylated by PKA, PKC, and CaMKII in vitro and is phosphorylated in transfected cells by PKA. SIGNOR-250699 0.508 TOP2B protein Q02880 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24463367 f lperfetto While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development SIGNOR-242311 0.2 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-268093 0.8 HDAC1 protein Q13547 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 17183360 t lperfetto Phosphorylation at thr505 by the chk1 inhibits rela transactivation and results in its increased association with hdac1. SIGNOR-217409 0.557 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr225 LGETKQEtLTNISAV 9606 15611134 t gcesareni Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates. SIGNOR-132463 0.2 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr612 TLHTDDGyMPMSPGV 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236756 0.912 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser859 DTSSLTQsAPASPTN 9606 BTO:0000007 19346248 t lperfetto The phosphorylation of raptor is stimulated by insulin and inhibited by rapamycin. Importantly, the site-directed mutation of raptor at one phosphorylation site, Ser(863), reduced mTORC1 activity both in vitro and in vivo. SIGNOR-184959 0.989 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser164 TSTPGRRsCFGFEGL -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276113 0.613 CUL3 protein Q13618 UNIPROT LZTR1 protein Q8N653 UNIPROT up-regulates activity binding 9606 BTO:0000007 31337872 t Gianni Leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a member of the BTB-Kelch superfamily, which interacts with the Cullin3 (CUL3)-based E3 ubiquitin ligase complex. SIGNOR-269070 0.277 STK11 protein Q15831 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr167 NKDYHLQtCCGSLAY 9606 16216881 t fstefani Site-directed mutagenesis indicated that thr167 and ser171, located between the dfg and ape motifs in the activation loop or t-loop, need to be autophosphorylated for melk to be active as a protein kinase (fig. 5). These sites are conserved in all other ampk-related protein kinases (fig. 4a), and the site corresponding to thr167 has been shown to be phosphorylated by protein kinase lkb1 (5). SIGNOR-141038 0.2 MFGE8 protein Q08431 UNIPROT TNF protein P01375 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 22114683 f Giorgia Our study demonstrated the direct anti-inflammatory role of MFG-E8 in terms of attenuating TNF-α production in mouse peritoneal macrophages and RAW264.7 cells treated with LPS SIGNOR-260650 0.316 MAP3K4 protein Q9Y6R4 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT up-regulates activity phosphorylation Thr1494 KLKNNAQtMPGEVNS 9606 17242196 t lperfetto Gadd45 binding also induced mtk1 dimerization via a dimerization domain containing a coiled-coil motif, which is essential for the trans autophosphorylation of mtk1 at thr-1493 in the kinase activation loop. SIGNOR-152408 0.2 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Thr1462 GLRPRGYtISDSAPS 9606 12172553 t gcesareni We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex. SIGNOR-91392 0.719 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1474 GSSNGHVyEKLSSIE 9606 BTO:0000007 11024032 t Tyr-1252, Tyr-1336, and Tyr-1472 of GluRε2 are phosphorylated in 293T cells when active Fyn is co-expressed. SIGNOR-251175 0.759 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR KAT2A protein Q92830 UNIPROT up-regulates activity phosphorylation Thr272 LNYWKLEtPAQFRQR 24870244 t lperfetto Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT) SIGNOR-275497 0.403 PLK1 protein P53350 UNIPROT CDC25B protein P30305 UNIPROT up-regulates activity phosphorylation 21640712 t lperfetto These data indicated that PLK1 phosphorylates CDC25B and that pre-phosphorylation of CDC25B by CDK1/CyclinB enhances its substrate properties for PLK1 in vitro SIGNOR-267560 0.653 HECTD2 protein Q5U5R9 UNIPROT PIAS1 protein O75925 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 26157031 t miannu We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model. SIGNOR-272421 0.398 ATXN2 protein Q99700 UNIPROT DDX6 protein P26196 UNIPROT unknown binding 9606 17392519 t miannu Ataxin-2 interacts with the dead/h-box rna helicase ddx6 / ddx6 is an essential component for the assembly of p-bodies/ SIGNOR-154158 0.586 gamma-secretase complex SIGNOR-C98 SIGNOR DSCAM protein O60469 UNIPROT down-regulates quantity cleavage 9606 BTO:0000938 30745319 t miannu γ‐secretase‐mediated intra‐membrane cleavage of DSCAM receptors results in the release of the DSCAM ICD, which is likely proceeded by shedding of the DSCAM ectodomain. Interaction of IPO5 with the NLS of DSCAM then leads to importin‐mediated nuclear import of the DSCAM ICD. In the nucleus, the DSCAM ICD may regulate the transcription of genes involved in neuronal development and function, thereby regulating processes such as neurite outgrowth, branching, and repulsion, as well as synapse formation, axon guidance, and neuronal cell death and survival. SIGNOR-264271 0.2 SMO protein Q99835 UNIPROT TIMP3 protein P35625 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 28709001 f We identified that ciliary Hh signaling in FAPs regulates expression of Timp3. Future experiments will determine whether Timp3 is a direct or indirect target of Hh signaling. SIGNOR-255907 0.2 CCND1 protein P24385 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates binding 9606 15713663 t gcesareni Collectively, these studies suggest an important role of cyclin d1 in regulation of ppargamma-mediated adipocyte differentiation through recruitment of hdacs to regulate ppar response element local chromatin structure and ppargamma function. SIGNOR-134056 0.421 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser295 PARPRSPsQTRKGPP 9606 BTO:0000142 16733250 t lperfetto Here we report that amphiphysin i (amph i) is also a mnb/dyrk1a substrate. This kinase phosphorylated native amph i in rodent brains and recombinant human amph i expressed in escherichia coli. Serine 293 (ser-293) was identified as the major site, whereas serine 295 and threonine 310 were found as minor kinase sitesamph i phosphorylated by mnb/dyrk1a decreased endophilin binding in vitro. From these results we conclude that amph i at ser-293 is phosphorylated by mnb/dyrk1a and that the phosphorylation has physiological significance in controlling the interaction of amphiphysin with endocytic accessory proteins. SIGNOR-146906 0.405 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr589 SHDSEENyVPMNPNL 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236416 0.751 HCRTR1 protein O43613 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257012 0.252 RAI1 protein Q7Z5J4 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22578325 f miannu Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. SIGNOR-266843 0.322 LIMK1 protein P53667 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity phosphorylation -1 22214762 t miannu Here, we report a novel functional cooperativity between Aur-A and LIMK1 through mutual phosphorylation. LIMK1 is recruited to the centrosomes during early prophase and then to the spindle poles, where it colocalizes with Aur-A. Aur-A physically associates with LIMK1 and activates it through phosphorylation, which is important for its centrosomal and spindle pole localization. Aur-A also acts as a substrate of LIMK1, and the function of LIMK1 is important for its specific localization and regulation of spindle morphology.  SIGNOR-276400 0.265 phosphatidic acid smallmolecule CHEBI:16337 ChEBI PRKCZ protein Q05513 UNIPROT up-regulates chemical activation 9606 12401205 t gcesareni The pkc isoform pkc-zeta appear to be activated by direct interactions with pa SIGNOR-94867 0.8 M1_polarization phenotype SIGNOR-PH54 SIGNOR IL1B protein P01584 UNIPROT up-regulates 9606 BTO:0000801 32454942 f miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. According to the M1/M2 model, M1 polarized cells are characterized by the release of proinflammatory mediators, such as TNF, IL-1β, and IFNγ SIGNOR-263825 0.7 POLA1 protein P09884 UNIPROT DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 19608746 f lperfetto Mcm10 is an essential eukaryotic protein required for the initiation and elongation phases of chromosomal replication. Specifically, Mcm10 is required for the association of several replication proteins, including DNA polymerase alpha (pol alpha), with chromatin. SIGNOR-261275 0.7 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser519 SGYSSPGsPGTPGSR -1 9199504 t miannu Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective. SIGNOR-250084 0.505 PPP1CA protein P62136 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates activity dephosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000007 17603999 t Protein kinases involved in the DNA damage checkpoint control, such as ATM, ATR, and hCds1/Chk2, have been shown to phosphorylate and activate BRCA1 upon DNA damage. |Altogether, these results indicate that PP1α specifically dephosphorylates BRCA1 at multiple serine sites, including S988 [12], S1423, and S1524. SIGNOR-248562 0.385 CDK5 protein Q00535 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates phosphorylation Thr354 HLGPHRStPESRAAV 9606 12056836 t lperfetto Cyclin-dependent kinase-5/p35 phosphorylates presenilin 1 to regulate carboxy-terminal fragment stabilityhere we demonstrate that cyclin dependent kinase-5/p35 (cdk5/p35) phosphorylates ps1 on threonine(354) within c-ps1 both in vitro and in vivo. Threonine(354) phosphorylation functions to selectively stabilize c-ps1. SIGNOR-89145 0.525 CDK1 protein P06493 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates phosphorylation Thr345 LTAERIKtPPKRPGG 9606 21659531 t lperfetto Cdk1, which phosphorylates ezh2 at threonines 345 and 487.Phosphorylation of thr-345 and thr-487 promotes ezh2 ubiquitination and subsequent degradation by the proteasome SIGNOR-174054 0.591 DNM1L protein O00429 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 25486875 f lperfetto During fission, DRP1 is recruited from the cytosol to the outer mitochondrial membrane, where it assembles with FIS1 to constrict the mitochondrial tubule (2) SIGNOR-272975 0.7 CLCF1 protein Q9UBD9 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0001271 9143707 t gcesareni Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-6 SIGNOR-47959 0.542 SLC2A1 protein P11166 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 BTO:0000424 33187473 t lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] SIGNOR-266038 0.369 CDK1 protein P06493 UNIPROT TP73 protein O15350 UNIPROT down-regulates activity phosphorylation Thr86 AASASPYtPEHAASV 9606 SIGNOR-C17 12676926 t gcesareni Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86. SIGNOR-99742 0.537 ATG16L1 protein Q676U5 UNIPROT CLTC protein Q00610 UNIPROT up-regulates binding 9606 20639872 t gcesareni Clathrin heavy-chain interacts with atg16l1, and is involved in the formation of atg16l1-positive early autophagosome precursors. SIGNOR-166702 0.472 NOTCH1 protein P46531 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 16990763 f gcesareni Other notch target genes identi__ed in the thymoma cell line were dtx1 (gene for deltex1), i__-202, i__-204, i__-d3, adam19 (meltrinb).24 a number of other genes have been reported as being notch targets, including notch1 itself,28 nrarp in xenopus embryos,29 bcl2 in thymoma cells,30 ccnd1 (gene for cyclin d1) in a kidney cell line,31 dkn1a (gene for cyclindependent kinase inhibitor 1a (p21, cip1)) in keratinocytes32 and tcf3 (gene for e2a). SIGNOR-149730 0.266 Class II MHC:Antigen complex SIGNOR-C429 SIGNOR T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 31810556 f scontino Once they are formed, peptide/MHC class II molecules complexes are very stable and allow for sustained antigen presentation increasing the chances to encounter the matching CD4+ T lymphocytes. Once CD4+ T cells have become acti- vated, they in turn trigger macrophages to eliminate pathogens that have been previously internalized, and B lymphocytes to produce pathogen- specific antibodies. SIGNOR-267873 0.7 SSTR1 protein P30872 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256822 0.452 HIF1A protein Q16665 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 24352507 t lperfetto We finally confirmed that in the absence of HIF-1α there was a significant reduction at the protein level in pro-caspase-1, activated caspase-1, pro-IL-1β, and ultimately active IL-1β (Fig. 4g and h). These data show that adenosine induced up-regulation of IL-1β is dependent on a CREB/HIF-1α pathway which is distinct from the NF-kB pathway used for initial production of IL-1β in response to LPS. SIGNOR-251718 0.343 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM1 protein Q13255 UNIPROT up-regulates activity chemical activation 9606 25042998 t miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate SIGNOR-264069 0.8 CDK2 protein P24941 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity phosphorylation Ser59 GGQESQPsPLALLAA 10090 BTO:0000944 11598016 t gcesareni Mutation of Sp1 Ser59 abrogates the cyclin A€“CDK augmentation of Sp1-dependent transcriptional transactivation SIGNOR-248232 0.433 TOMM22 protein Q9NS69 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 t lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. SIGNOR-267679 0.771 FUBP1 protein Q96AE4 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26490982 f irozzo The human far upstream element (FUSE) binding protein 1 (FUBP1) belongs to an ancient family which is required for proper regulation of the c-Myc proto-oncogene. Our results indicated that FUBP1 may potentially stimulate c-Myc expression in ESCC and its expression may promote ESCC progression. SIGNOR-259123 0.423 IL18 protein Q14116 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 10653850 f miannu IL-12 Synergizes With IL-18 or IL-1beta for IFN-gamma Production From Human T Cells. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R engagement. SIGNOR-260965 0.7 PRKACA protein P17612 UNIPROT SLC2A2 protein P11168 UNIPROT down-regulates activity phosphorylation Ser491 VPETKGKsFEEIAAE 9534 8626492 t miannu GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity. SIGNOR-250049 0.314 SMURF1 protein Q9HCE7 UNIPROT PARD6/SMURF1 complex SIGNOR-C112 SIGNOR form complex binding 9606 BTO:0004183 15761148 t lperfetto The Par6-Smurf1 complex then mediates the localized ubiquitination of RhoA to enable the TGF_-dependent dissolution of tight junctions during EMT. SIGNOR-227562 0.623 CLK2 protein P49760 UNIPROT CLK2 protein P49760 UNIPROT up-regulates phosphorylation Ser142 HSSRRAKsVEDDAEG 9606 BTO:0000567 20682768 t lperfetto Clk2 was reported to regulate its nuclear localization by autophosphorylating serine 141 SIGNOR-167344 0.2 ACACA protein Q13085 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI down-regulates quantity chemical modification 9606 20952656 t miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA SIGNOR-267105 0.8 ABL1 protein P00519 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Tyr367 TYLQSRYyRAPEIIL 9606 25944899 t Manara The Tyrosine Kinase c-Abl Promotes Homeodomain-interacting Protein Kinase 2 (HIPK2) Accumulation and Activation in Response to DNA Damage SIGNOR-260936 0.412 MAPK14 protein Q16539 UNIPROT CCND1 protein P24385 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni A large number of cytosolic proteins can be phosphorylated by p38 mapks, including phospholipase a2, the microtubule-associated protein tau, nhe-1, cyclin d1, cdk inhibitors, bcl2 family proteins, growth factor receptors or keratins SIGNOR-166594 0.437 IL31 protein Q6EBC2 UNIPROT OSMR protein Q99650 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 BTO:0001253 15184896 t gcesareni Here we identify a four-helix bundle cytokine we have called interleukin 31 (il-31), which is preferentially produced by t helper type 2 cells. Il-31 signals through a receptor composed of il-31 receptor a and oncostatin m receptor. SIGNOR-125347 0.599 JAK2 protein O60674 UNIPROT BRD4 protein O60885 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr98 KLNLPDYyKIIKTPM 9606 BTO:0002181 34290255 t miannu JAK2 induces tyrosine phosphorylation of BRD4 at Y97/Y98, resulting in BRD4 stabilization.  SIGNOR-277312 0.33 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002428 31908417 t miannu The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs. SIGNOR-262253 0.8 XL-647 chemical CID:10458325 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207860 0.8 RARA protein P10276 UNIPROT RXRG protein P48443 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 1310351 f gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-16469 0.655 Dihydromorphine chemical CHEBI:4575 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258788 0.8 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10428798 t lperfetto Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity. SIGNOR-217292 0.429 AKT proteinfamily SIGNOR-PF24 SIGNOR YWHAZ protein P63104 UNIPROT unknown phosphorylation Ser58 VVGARRSsWRVVSSI 9606 BTO:0000007 11956222 t lperfetto Ese data indicate that pkb/akt phosphorylates ser-58 on 14-3-3zeta both in vitro and in intact cells. The functional relevance of this phosphorylation remains to be determined. SIGNOR-244381 0.2 ADNP protein Q9H2P0 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR up-regulates quantity binding 9606 BTO:0000007 17878164 t miannu ADNP Co-precipitates with the SWI/SNF Complex through ADNP C-terminal Interaction. Down-regulation of ADNP by shRNA resulted in morphological changes that are in line with the fact that ADNP contains a homeodomain profile (2) and with the SWI/SNF complex function that is associated with cellular differentiation. Our results suggest that ADNP functionality plays a role in these changes. SIGNOR-266757 0.361 NFIX protein Q14938 UNIPROT ETV5 protein P41161 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268886 0.2 MMP7 protein P09237 UNIPROT DCN protein P07585 UNIPROT down-regulates quantity by destabilization cleavage Glu273 ANTPHLReLHLDNNK -1 9148753 t miannu Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues. SIGNOR-256352 0.594 CLTCL1 protein P53675 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR form complex binding 9606 24789820 t lperfetto AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly.  SIGNOR-260662 0.72 GRK5 protein P34947 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. SIGNOR-251210 0.467 SRC protein P12931 UNIPROT PDCD6IP protein Q8WUM4 UNIPROT down-regulates activity phosphorylation Tyr319 KKDNDFIyHDRVPDL 9606 15557335 t miannu Src phosphorylation of Alix/AIP1 modulates its interaction with binding partners and antagonizes its activities. Phosphorylation of Alix by Src caused it to translocate from the membrane and cytoskeleton to the cytoplasm and reduced its interaction with binding partners SETA/CIN85, epidermal growth factor receptor, and Pyk2. SIGNOR-263201 0.402 zotepine chemical CHEBI:32316 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 20223878 t Luana These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. SIGNOR-257829 0.8 2-(4-(4,4-Bis(4-fluorophenyl)butyl)-1-piperazinyl)-3-pyridinecarboxylic acid methyl ester chemical CID:127728 PUBCHEM HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). SIGNOR-258949 0.8 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000007 14551213 t lperfetto The hematopoietic-specific Galpha16 protein has recently been shown to mediate receptor-induced activation of the signal transducer and activator of transcription 3 (STAT3). In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727. Galpha16QL-induced STAT3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (ERK1), SIGNOR-249450 0.709 SRC protein P12931 UNIPROT PRKCI protein P41743 UNIPROT up-regulates phosphorylation Tyr280 LKKTDRIyAMKVVKK 9606 11713277 t llicata Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain. SIGNOR-111924 0.513 PTPN18 protein Q99952 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization dephosphorylation 9606 25081058 t miannu In the present study, we demonstrated that PTPN18 specifically dephosphorylates HER2 pY 1112, pY 1196 and pY 1248 sites among ten HER2 and EGFR C-terminal tyrosine phosphorylation sites (XREF_FIG).|Taken together, these data suggest that PTPN18 promotes the proteasome dependent degradation of HER2 through K48 linked polyubiquitination. SIGNOR-277031 0.658 Ionizing radiation stimulus SIGNOR-ST16 SIGNOR CCDC6-RET fusion protein SIGNOR-FP9 SIGNOR up-regulates 9606 23128507 f miannu In PTC, genomic rearrangements juxtapose the RET tyrosine kinase domain to unrelated genes, thereby creating dominantly transforming oncogenes, denominated RET/PTC. The RET/PTC rearrangements are the 2nd most common genetic alteration described in PTC and observed in ∼13–43% of cases, mostly in pediatric cancers or in individuals exposed to ionizing radiation from nuclear accidents SIGNOR-251999 0.7 N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine chemical CHEBI:92386 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258923 0.8 PRKACA protein P17612 UNIPROT GRIK2 protein Q13002 UNIPROT up-regulates activity phosphorylation Ser715 FMSSRRQsVLVKSNE 9606 BTO:0000007 8094892 t miannu GluR6 glutamate receptor, transiently expressed in mammalian cells, is directly phosphorylated by PKA, and that intracellularly applied PKA increases the amplitude of the glutamate response. Site-specific mutagenesis of the serine residue (Ser 684) representing a PKA consensus site completely eliminates PKA-mediated phosphorylation of this site as well as the potentiation of the glutamate response. SIGNOR-250315 0.2 AKT1 protein P31749 UNIPROT ADAR protein P55265 UNIPROT down-regulates activity phosphorylation Thr1033 RLGERLRtMSCSDKI -1 31095429 t miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively SIGNOR-276193 0.285 CTNNA3 protein Q9UI47 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity relocalization 9606 BTO:0000586 21598020 t miannu Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14 SIGNOR-265492 0.553 GRM8 protein O00222 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 t miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. SIGNOR-264081 0.428 POFUT1 protein Q9H488 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 12909620 t Fucosylation gcesareni Notch_ is modified in its epidermal growth factor-like domains by the addition of_ fucose_ to serine or threonine residues. O-fucosylation is mediated by protein o-fucosyltransferase 1 and down-regulation of this enzyme by rna interference or mutation of the ofut1 gene in drosophila or by mutation of the pofut1 gene in mouse prevents notch signaling. SIGNOR-254326 0.735 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR up-regulates activity chemical activation 9606 18790874 t brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-263792 0.8 RPS6KA3 protein P51812 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates activity phosphorylation Ser21 KEEPKRRsARLSAKP 9606 BTO:0000567 11438671 t lperfetto We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets. SIGNOR-249100 0.371 FYCO1 protein Q9BQS8 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates activity binding 9606 BTO:0000007 26468287 t Giulio The preferential binding to LC3A and -B was confirmed in vivo by co-immunoprecipitation experiments of Myc-tagged FYCO1 and GFP fusions of human ATG8 family pro-teins expressed in HEK293 cells (Fig. 2B). GFP-LC3A and GFP-LC3B were efficiently co-precipitated with Myc-FYCO1,whereas GFP-LC3C, GFP-GABARAP, GFP-GABARAPL1 and-L2 were not. The effects we see on late steps of basal autophagy on mutation of the FYCO1 LIR motif correlate with a role of FYCO1 in regulating kinesin-mediated transport of LC3-positive autophagic structures. SIGNOR-260598 0.577 CSNK1A1 protein P48729 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity binding 9606 SIGNOR-C110 22083140 t gcesareni In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)] SIGNOR-177233 0.561 YY1 protein P25490 UNIPROT SURF1 protein Q15526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10858544 f miannu We show that although the Surf-1/Surf-2 promoter does not contain Myc binding sites (E-boxes), Myc over-expression, or the activation of a Myc-oestrogen receptor fusion protein, activates transcription in the Surf-1 direction and that this response to Myc requires a functional YY1 binding site. Our data suggest that the MAP kinase cascade is required for the stimulation of Surf-1 promoter activity and that the Myc-YY1 interaction mediates this response. SIGNOR-254614 0.315 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr31 SNYRAYAtEPHAKKK 9606 BTO:0000671 18986304 t llicata Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143). SIGNOR-182057 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR ETV1 protein P50549 UNIPROT up-regulates activity phosphorylation Ser216 PMYQRQMsEPNIPFP 9606 12213813 t lperfetto Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation. SIGNOR-252769 0.2 MMP14 protein P50281 UNIPROT F12 protein P00748 UNIPROT down-regulates quantity by destabilization cleavage Gly376 SMTRVVGgLVALRGA -1 10930399 t lperfetto The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage. SIGNOR-263610 0.336 MID1 protein O15344 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0004725 11685209 t miannu MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation SIGNOR-271467 0.465 FBP1 protein P09467 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI down-regulates quantity chemical modification 9606 30616754 t lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle SIGNOR-267610 0.8 dopamine smallmolecule CHEBI:18243 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|It undergoes oxidative deamination, catalyzed by the enzyme monoamine oxidase (MAO) in the presence of flavin adenine dinucleotide (FAD), to produce reactive aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL). SIGNOR-264180 0.8 GRM2 protein Q14416 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. SIGNOR-264933 0.8 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 9606 BTO:0001133 18977325 t irozzo Recent studies have identified association of multiple MLL-fusion partners including AF4, AF9, and AF10 with DOT1L, a histone H3K79 methyltransferase.This leads to a model where MLL-AF4 recruits DOT1L to MLL target genes, and promotes methylation of H3K79 at loci with existing H3K4 methylation (i.e., by wildtype MLL or other H3K4 methyltransferases) thus stimulating transcriptional elongation of genes that are normally primed but not fully transcribed. SIGNOR-255871 0.2 REEP5 protein Q00765 UNIPROT CXCR1 protein P25024 UNIPROT up-regulates activity binding 9606 27966653 t miannu In this study, we found that CXCR1 interacted with REEP5 and REEP6, but CXCR2 did not. Overexpression of REEP5 and REEP6 enhanced IL-8-stimulated cellular responses through CXCR1, whereas depletion of the proteins led to the downregulation of the responses. SIGNOR-261366 0.33 PRKCZ protein Q05513 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP. SIGNOR-249261 0.28 procaterol chemical CHEBI:135209 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  SIGNOR-257864 0.8 FAS protein P25445 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates 9606 9743501 f gcesareni Fas activation induced daxx to interact with ask1 SIGNOR-60167 0.691 NFIX protein Q14938 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268910 0.2 ADORA2B protein P29275 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257152 0.283 SAM complex complex SIGNOR-C422 SIGNOR TOM40 complex complex SIGNOR-C421 SIGNOR up-regulates activity binding 18423394 t lperfetto Homology searches led to the identification of human Sam50 that is required for the biogenesis of human Tom40 [69]. A similar involvement was reported for metaxin 1 and metaxin 2 [70], which are homologs of Sam37 and Sam35, respectively SIGNOR-267686 0.467 terbutaline chemical CHEBI:9449 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 20590599 t Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) SIGNOR-257870 0.8 KIF5B protein P33176 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272520 0.7 MAPK8 protein P45983 UNIPROT PKM protein P14618 UNIPROT up-regulates activity phosphorylation Thr365 CIMLSGEtAKGDYPL 9606 BTO:0002181 26258887 t miannu Active JNK1 specifically activates PKM2 but not PKM1. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 through phosphorylation of Thr365. SIGNOR-276933 0.379 ARNTL protein O00327 UNIPROT PER1 protein O15534 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253628 0.723 EGFR protein P00533 UNIPROT PKIA protein P61925 UNIPROT up-regulates phosphorylation Tyr8 MTDVETTyADFIASG 9606 1956339 t lperfetto The difference in inhibitory potency between pki_ and pki_ has been attributed to the absence of a tyrosine residue (tyr7) in pki_ that is present in the nh2-terminal region of pki_. This suggests that the absence of a single amino acid residue can result in variations in how the catalytic subunit of camp-dependent protein kinase interacts with pki which ultimately can result in alterations in pki inhibitory potency. SIGNOR-22455 0.312 PRKCE protein Q02156 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 20179209 t lperfetto Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated SIGNOR-163912 0.346 CDON protein Q4KMG0 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity binding 9606 BTO:0000222 19470755 t lperfetto Abl binds a proline-rich motif in cdo via its sh3 domain, and these regions of abl and cdo are required for their promyogenic effects. Cdo is important for full abl kinase activity SIGNOR-185762 0.497 PIM1 protein P11309 UNIPROT RP9 protein Q8TA86 UNIPROT unknown phosphorylation Ser212 KKRKHKSsKSNEGSD -1 10931201 t miannu PAP-1 was phosphorylated in vitro by Pim-1, but not a kinase-negative Pim-1 mutant. The two serine residues of PAP-1 at amino acids 204 and 206 near the C-terminus were phosphorylated by Pim-1. PAP-1 is thus thought to be a target protein for Pim-1 kinase. SIGNOR-263029 0.2 CFH protein P08603 UNIPROT CFB protein P00751 UNIPROT down-regulates activity binding 9606 19050261 t miannu As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity) SIGNOR-252142 0.497 PRKCE protein Q02156 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser465 LKHVTQSsRKLIRAD 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation SIGNOR-129304 0.317 Caspase 6 complex complex SIGNOR-C228 SIGNOR CASP8 protein Q14790 UNIPROT up-regulates cleavage 9606 11455969 t gcesareni This pathway can either be ampli?ed By caspase- 8-mediated cleavage of bid and by the downstream, caspase-6- mediated cleavage of caspase-8. SIGNOR-256468 0.724 GYPC protein P04921 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 BTO:0000424 33187473 t lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] SIGNOR-266034 0.37 MSX2 protein P35548 UNIPROT DLX2 protein Q07687 UNIPROT down-regulates activity binding 10090 BTO:0000945 9111364 t 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. SIGNOR-240932 0.4 AP-2 complex complex SIGNOR-C245 SIGNOR HIP1 protein O00291 UNIPROT up-regulates activity binding 10116 11517213 t Giorgia HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and adaptor protein 2.|Here we demonstrate that HIP1 colocalizes with markers of clathrin-mediated endocytosis in neuronal cells and is highly enriched on clathrin-coated vesicles (CCVs) purified from brain homogenates. HIP1 binds to the clathrin adaptor protein 2 (AP2) and the terminal domain of the clathrin heavy chain, predominantly through a small fragment encompassing amino acids 276–335 SIGNOR-260392 0.43 Av/b6 integrin complex SIGNOR-C179 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257725 0.58 AKT proteinfamily SIGNOR-PF24 SIGNOR WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Thr60 EYRRRRHtMDKDSRG 9606 16081417 t llicata Phosphorylation of wnk1 on thr-58 contributes to sgk1 activation. these data suggest that activation of sgk1 by wnk1 requires the catalytic activity of akt. SIGNOR-139391 0.2 NCAPH protein Q15003 UNIPROT Condensin I complex SIGNOR-C341 SIGNOR form complex binding 9606 32445620 t miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263906 0.969 MAPK1 protein P28482 UNIPROT CDC42EP1 protein Q00587 UNIPROT unknown phosphorylation Ser195 RRSDSLLsFRLDLDL 10090 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262766 0.2 belinostat chemical CHEBI:61076 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257743 0.8 RAR proteinfamily SIGNOR-PF45 SIGNOR RXR proteinfamily SIGNOR-PF44 SIGNOR up-regulates activity binding 9606 1310351 t miannu Cellular responsiveness to retinoic acid and its metabolites is conferred through two structurally and pharmacologically distinct families of receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Here we report that the transcriptional activity of RAR and RXR can be reciprocally modulated by direct interactions between the two proteins. SIGNOR-256198 0.714 HES5 protein Q5TA89 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 f lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production SIGNOR-265147 0.543 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr252 HDGTVTHtFCGTIEY 9606 19864428 t gcesareni A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. Phosphorylation and activation of p70s6k by pdk1. SIGNOR-188907 0.716 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 23863160 t lperfetto AMPK inhibits mTORC1 through two means: first, through phosphorylation of TSC2 to activate its GAP (GTPase-activating protein) activity that converts Rheb into an inactive GDP-bound state, thus switching off mitogenic stimulation of mTORC1 [31], and, secondly, through phosphorylation of raptor at Ser722 and Ser792, which leads to 14-3-3 protein binding and mTORC1 inhibition SIGNOR-209862 0.449 CREB5 protein Q02930 UNIPROT RDX protein P35241 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002816 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253809 0.2 MAPK3 protein P27361 UNIPROT JUND protein P17535 UNIPROT up-regulates phosphorylation Ser100 LGLLKLAsPELERLI 9606 22327296 t gcesareni Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase. SIGNOR-196034 0.471 CFLAR protein O15519 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates activity binding 9606 14585074 t amattioni Flip can be incorporated into the disc complex and blocks processing and activation of pro-caspase8 SIGNOR-96402 0.761 IQSEC2 protein Q5JU85 UNIPROT ARF6 protein P62330 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 BTO:0000142 18164504 t miannu Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull down assay demonstrated that IQ-ArfGEF/BRAG1 activated Arf6 more potently than Arf1.IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. Taken together, IQ-ArfGEF/BRAG1 forms a postsynaptic protein complex containing PSD-95 and NMDA receptors at excitatory synapses, where it may function as a GEF for Arf6. SIGNOR-264906 0.469 Linsitinib chemical CID:11640390 PUBCHEM INSR protein P06213 UNIPROT down-regulates activity chemical inhibition 10090 24712877 t lperfetto Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control, β-cell functions, and β-cell proliferation in male mice SIGNOR-262029 0.8 SMARCA4 protein P51532 UNIPROT SMARCC1 protein Q92922 UNIPROT up-regulates binding 9606 10078207 t miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. SIGNOR-65441 0.949 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser108 DVEELTAsQREAAER 9606 19647517 t lperfetto Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry SIGNOR-187388 0.961 PPM1A protein P35813 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates dephosphorylation 9606 10644691 t lperfetto Pp2c utilizes axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that pp2c is a positive regulator of wnt signal transduction and mediates its effects through the dephosphorylation of axin. SIGNOR-227955 0.369 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0001538 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252757 0.719 PPP4R3A protein Q6IN85 UNIPROT PPP4C protein P60510 UNIPROT up-regulates binding 9606 18715871 t gcesareni Our data demonstrate that pp4r4 forms a novel cytosolic complex with pp4c, independent from the complexes containing pp4r1, pp4r2.PP4R3, and alpha4, and that the regulatory subunits of pp4c have evolved different modes of interaction with the catalytic subunit. SIGNOR-180244 0.2 SP1 protein P08047 UNIPROT THBD protein P07204 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22406829 f miannu In carcinomas the expression of thrombomodulin (TM) is inversely correlated with tumour progression and metastasis. The expression of TM is negatively regulated by NF-?B- and GSK3-?-dependent signalling pathways and positively regulated by retinoic acid and transcription factor Sp1 in PrEC, LNCaP and PC-3 cells, but not in DU-145 cells. SIGNOR-255216 0.2 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252881 0.398 CYP21A2 protein P08686 UNIPROT 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI down-regulates quantity chemical modification 9606 BTO:0000050 25855791 t lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively SIGNOR-268644 0.8 SIRT1 protein Q96EB6 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress SIGNOR-267285 0.7 B-WICH complex complex SIGNOR-C447 SIGNOR RNA Polymerase III complex SIGNOR-C389 SIGNOR up-regulates activity binding 9606 BTO:0000567 25883140 t miannu The chromatin-remodelling complex B-WICH, comprised of William syndrome transcription factor, the ATPase SNF2h and nuclear myosin, specifically activates RNA polymerase III transcription of the 5S rRNA and 7SL genes. SIGNOR-268841 0.2 IL21R protein Q9HBE5 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000776 12093291 t gcesareni Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5 SIGNOR-90266 0.612 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI TEK protein Q02763 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194349 0.8 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2I protein P63279 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271312 0.547 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 10567431 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-217056 0.748 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser171 PLCLSPAsSGSSASF 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248679 0.613 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2078 EGSYETAkVLLDHFA 9606 17636029 t gcesareni This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60. SIGNOR-156923 0.424 PHLPP1 protein O60346 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 BTO:0001544 19261608 t The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. SIGNOR-248330 0.634 VIP protein P01282 UNIPROT VIPR1 protein P32241 UNIPROT up-regulates binding 9606 11897681 t gcesareni Pacap binds to a pacap-specific receptor (pac1) and to vpac receptors (vpac1 and vpac2), which share high affinity for vasoactive intestinal polypeptide (vip). SIGNOR-116122 0.859 SMARCA1 protein P28370 UNIPROT HNuRF complex SIGNOR-C448 SIGNOR form complex binding 9606 BTO:0000007 14609955 t miannu hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays. SIGNOR-268818 0.694 GLUD2 protein P49448 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9913 11254391 t miannu Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate. SIGNOR-268557 0.8 CDK7 protein P50613 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Ser12 LASDFAFsPPPGGGG 9606 BTO:0001086 31306665 t lperfetto Here, we combined molecular and cellular biology with CRISPR/Cas9-mediated genome engineering to pinpoint the function of serine 12 of OCT4 in ESCs. Using chemical inhibitors and an antibody specific to OCT4 phosphorylated on S12, we identified cyclin-dependent kinase (CDK) 7 as upstream kinase. |Phosphorylation of OCT4 on S12 has been previously implicated to stabilize OCT4 by binding to PIN1, thereby preventing ubiquitinylation by WWP2. SIGNOR-264404 0.2 PAMPs stimulus SIGNOR-ST11 SIGNOR NLRC4 inflammasome complex SIGNOR-C223 SIGNOR up-regulates activity 16037825 f miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-263124 0.7 LCK protein P06239 UNIPROT CD247 protein P20963 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 8626561 t amattioni During tcr signaling, lck interacts with numerous molecules, including tcr-zeta. The binding of lck to the tyrosine-phosphorylated zeta chain of the tcr would serve to strengthen the interaction of the associated cd4 and the tcr complex, leading to increased avidity for the antigen-major histocompatibility protein complex. SIGNOR-41361 0.754 AURKA protein O14965 UNIPROT MAP9 protein Q49MG5 UNIPROT up-regulates phosphorylation Ser625 RKQKKRHsFLESEAL 9606 17925329 t llicata Asap is a novel substrate of the oncogenic mitotic kinase aurora-a: phosphorylation on ser625 is essential to spindle formation and mitosis. SIGNOR-158210 0.332 GPC6 protein Q9Y625 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates activity binding 9606 31756413 t miannu Based on results from in vitro experiments, we had previously proposed that GPC6 stimulates Hh signaling by interacting with Hh and Patched1 (Ptc1), and facilitating/stabilizing their interaction. SIGNOR-264031 0.357 NRG3 protein P56975 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 t gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. SIGNOR-122059 0.738 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 SIGNOR-C9 15241418 t llicata We found that ser 203 and ser 207 were phosphorylated by map kinase and that thr 178 was phosphorylated mostly by cdk and to a lesser extent by map kinase SIGNOR-126748 0.736 JUN protein P05412 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 f miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254874 0.273 GNAQ protein P50148 UNIPROT ARHGEF12 protein Q9NZN5 UNIPROT up-regulates activity binding 10090 BTO:0000944 12024019 t Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA. SIGNOR-256520 0.43 FGFR4 protein P22455 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 10918587 t Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3. SIGNOR-251142 0.411 D-106669 chemical CID:16048654 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252649 0.8 SYK protein P43405 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates activity phosphorylation Tyr289 SSCGSSGyFSSSPTL 9606 BTO:0002181 34634301 t miannu We found that tyrosine (Tyr) 289 phosphorylation of DEPTOR impairs its interaction with mTOR, leading to increased mTOR activation. Using proximity biotinylation assays, we identified SYK (spleen tyrosine kinase) as a kinase involved in DEPTOR Tyr 289 phosphorylation in an ephrin (erythropoietin-producing hepatocellular carcinoma) receptor-dependent manner. SIGNOR-277572 0.2 UMPS protein P11172 UNIPROT orotic acid smallmolecule CHEBI:16742 ChEBI down-regulates quantity chemical modification 9606 18020427 t miannu Orotate phosphoribosyltransferase (OPRTase, EC 2.4.2.10) catalyzes the Mg2+-dependent condensation of orotic acid (OA) with PRPP (5-alpha-d-phosphorylribose 1-diphosphate) to yield diphosphate (PPi) and the nucleotide OMP (orotidine 5'-monophosphate). SIGNOR-253580 0.8 CHD4 protein Q14839 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263856 0.829 KAT2B protein Q92831 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 11058129 t gcesareni P/caf was found to interact directly with smad3 in vitro. Moreover, smad2 and smad3 interacted with p/caf upon tgf-beta type i receptor activation in cultured mammalian cells. these results demonstrate the co-activator function of p/caf for smad2 and smad3. SIGNOR-83607 0.663 AFF4 protein Q9UHB7 UNIPROT AEP complex complex SIGNOR-C117 SIGNOR form complex binding 9606 BTO:0000664 20153263 t 1 miannu These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells. SIGNOR-239224 0.547 ACOT4 protein Q8N9L9 UNIPROT succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI down-regulates quantity chemical modification 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271807 0.8 TAOK proteinfamily SIGNOR-PF21 SIGNOR STK4 protein Q13043 UNIPROT up-regulates phosphorylation 9606 23431053 t milica In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2. SIGNOR-230710 0.2 GSK3B protein P49841 UNIPROT NACA protein E9PAV3 UNIPROT down-regulates phosphorylation Thr2022 NIQENTQtPTVQEES 9606 BTO:0000007 15005626 t gcesareni Gsk3 beta-dependent phosphorylation of the alpha nac coactivator regulates its nuclear translocation and proteasome-mediated degradation. SIGNOR-123262 0.2 DLL4 protein Q9NR61 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209744 0.2 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203604 0.769 CDK2 protein P24941 UNIPROT TP73 protein O15350 UNIPROT down-regulates activity phosphorylation Thr86 AASASPYtPEHAASV 9606 SIGNOR-C16 12676926 t gcesareni Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86. SIGNOR-99746 0.557 FGB protein P02675 UNIPROT Fibrinogen complex SIGNOR-C311 SIGNOR form complex binding -1 25427968 t lperfetto Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aalpha, Bbeta, and gamma, encoded by the FGA, FGB, and FGG gene, respectively). SIGNOR-263391 0.755 WDFY3 protein Q8IZQ1 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 22653340 f miannu ALFY is a large, scaffolding, multidomain protein implicated in the selective degradation of ubiquitinated protein aggregates by autophagy. SIGNOR-266794 0.7 NDUFS6 protein O75380 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. SIGNOR-262180 0.838 PRKCA protein P17252 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser496 ATPQRSGsVSNYRSC -1 27784766 t miannu Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle. SIGNOR-276459 0.2 PRKCE protein Q02156 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation SIGNOR-129308 0.317 PAXIP1 protein Q6ZW49 UNIPROT PAX2 protein Q02962 UNIPROT up-regulates activity binding 9606 BTO:0000007 17925232 t PTIP promotes assembly of the ALR complex and H3K4 methylation at a PAX2-binding DNA element. Without PTIP, Pax2 binds to this element but does not assemble the ALR complex SIGNOR-251711 0.588 ORC3 protein Q9UBD5 UNIPROT ORC complex SIGNOR-C419 SIGNOR form complex binding 9606 32808929 t lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA SIGNOR-267565 0.954 DUSP2 protein Q05923 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 8626452 t gcesareni We show that the in vivo substrate specificities of individual phosphatases are unique. Pac1, mkp-2, and mkp-1 recognize erk and p38, erk and jnk, and erk, p38, and jnk, respectively SIGNOR-40918 0.607 PDX1 protein P52945 UNIPROT INS protein P01308 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11309388 t In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1. SIGNOR-255541 0.629 CYLD protein Q9NQC7 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity deubiquitination 10090 29291351 t gianni Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK-p38 cascades. SIGNOR-266437 0.621 MBD1 protein Q9UIS9 UNIPROT ALOX5 protein P09917 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001412 19781662 f Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation.|Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene. SIGNOR-254030 0.2 PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Ser380 EPDHYRYsDTTDSDP 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248544 0.2 PRKACA protein P17612 UNIPROT ARPP21 protein Q9UBL0 UNIPROT up-regulates activity phosphorylation Ser58 QERRKSKsGAGKGKL -1 10854908 t miannu The specificity of antibody G534 was examined using recombinant full-length rat ARPP-21 phosphorylated by PKA. Radiolabeled ARPP-21 from a reaction containing [γ32P]ATP correlated with the detection of phospho-Ser55-ARPP-21 by immunoblotting (Fig. 1A, left and middle panels). SIGNOR-263107 0.2 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser117 SFSLEEKsKISKNRV 9606 20573420 t lperfetto Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation. SIGNOR-166321 0.369 HIF1A protein Q16665 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 17548584 t svumbaca The loss of macrophage expression of HIF-1 led to significant decreases in the production of TNF-a, IL-1a, IL-1b, and IL-12 SIGNOR-256235 0.343 IGF1R protein P08069 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 15829723 f apalma Mechanical loading increases IGF-I release, and IGF-I can stimulate Ca2+ influx and thereby activate calcineurin SIGNOR-255100 0.8 IL1A protein P01583 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 19005488 f miannu UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription. UVB and IL-1alpha treatment synergistically enhanced TNF-alpha secretion and mRNA levels in human keratinocytes, similar to the findings reported previously in human fibroblasts. SIGNOR-252209 0.505 HDAC1 protein Q13547 UNIPROT HES1 protein Q14469 UNIPROT down-regulates quantity transcriptional regulation 10090 18762022 f These data suggest that the GR recruits cellular HDAC activities to the Hes1 promoter, thereby conferring transcriptional repression in response to GC signaling. SIGNOR-253054 0.377 TYK2 protein P29597 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 30029643 t Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated SIGNOR-256255 0.675 IKBKB protein O14920 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 t gcesareni Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway SIGNOR-252948 0.679 CRYBB2 protein P43320 UNIPROT CRYBB2 protein P43320 UNIPROT up-regulates activity binding 9606 16319073 t miannu βB2-crystallin is the major component of β-crystallin and is a dimer at low concentrations. At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency. SIGNOR-252154 0.2 GSK3B protein P49841 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates activity phosphorylation Ser789 VSAGPRPsPLPSPQP 9606 BTO:0000007 17711861 t miannu  The activation of MLK3 by GSK-3beta occurred via phosphorylation of MLK3 on two amino acid residues, Ser(789) and Ser(793), that are located within the C-terminal regulatory domain of MLK3.  SIGNOR-276071 0.342 DNA polymerase epsilon complex SIGNOR-C377 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9534 BTO:0004055 12930972 f lperfetto Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA). SIGNOR-265514 0.7 SGO1 protein Q5FBB7 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000567 24055156 t lperfetto The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl. SIGNOR-265264 0.2 MAML1 protein Q92585 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12370315 f gcesareni It has been shown that maml1 binds directly to the ankyrin repeat region of notch1 and forms a dna-binding complex with icn and csl SIGNOR-94029 0.921 MAPK14 protein Q16539 UNIPROT MAPKAPK3 protein Q16644 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000944 11157753 t lperfetto These results, taken together, suggest the importance of the docking interaction in the efficient phosphorylation and activation of 3pk by p38. SIGNOR-235451 0.702 ARHGAP5 protein Q13017 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260461 0.822 HNF1B protein P35680 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity binding 9606 BTO:0000007 9671480 t 2 miannu The mammalian two-hybrid system showed that the region aa 393 to 476 of LFB3 is involved in the interaction with CREB or ATF1. The importance of this region for mediating cAMP induction was confirmed in transient transfection assays. SIGNOR-241323 0.38 RPS6KB1 protein P23443 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 11500364 t lperfetto We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity SIGNOR-109712 0.725 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser374 GLEQAILsPGQNSGN 9606 22966201 t llicata Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress. SIGNOR-198988 0.328 PRKAR1A protein P10644 UNIPROT PRKACA protein P17612 UNIPROT down-regulates activity binding 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258751 0.881 RNF7 protein Q9UBF6 UNIPROT NF1 protein P21359 UNIPROT down-regulates activity ubiquitination 9606 23136067 t miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. SIGNOR-271453 0.251 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck lperfetto SIGNOR-244854 0.8 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270407 0.8 CBP/p300 complex SIGNOR-C6 SIGNOR YY1 protein P25490 UNIPROT up-regulates activity acetylation -1 11486036 t miannu Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs. SIGNOR-268834 0.638 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257967 0.8 CREBBP protein Q92793 UNIPROT CSK protein P41240 UNIPROT up-regulates binding 9606 10801129 t gcesareni Here we present cbp--a transmembrane phosphoprotein that is ubiquitously expressed and binds specifically to the sh2 domain of csk. Cbp is involved in the membrane localization of csk and in the csk-mediated inhibition of c-src. SIGNOR-77139 0.515 SOCS1 protein O15524 UNIPROT JAK2 protein O60674 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 14522994 t lperfetto Shp-2 regulates socs-1-mediated janus kinase-2 ubiquitination/degradation downstream of the prolactin receptor SIGNOR-118407 0.787 malonyl-CoA smallmolecule CHEBI:15531 ChEBI long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity precursor of 9606 15507492 t Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-267210 0.8 NUP160 protein Q12769 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262094 0.699 ASXL3 protein Q9C0F0 UNIPROT KDM1A protein O60341 UNIPROT down-regulates activity binding 9606 25450400 t miannu Here, we showed that ASXL3 interacts with HP1α and LSD1, leading to transcriptional repression. SIGNOR-266764 0.269 TRAF6 protein Q9Y4K3 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates activity binding 9606 BTO:0001370 29733298 t miannu Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways.  SIGNOR-273656 0.2 GSK3A protein P49840 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 9606 16023596 t gcesareni Similar to c-myc, similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation. SIGNOR-138596 0.415 SRC protein P12931 UNIPROT CNKSR1 protein Q969H4 UNIPROT up-regulates activity phosphorylation Tyr26 LDDSLQDyPFEDWQL 26319181 t lperfetto We identified Tyr 26 as a PDGF-induced and, additionally, Tyr 519 and Tyr 665 as SRC-induced tyrosine phosphorylation sites. Phosphomimetic mutants indicate that phosphorylation of Tyr 519 recruits CNK1 to the nucleus and additional phosphorylation of Tyr 26 enables CNK1 to promote SRE-dependent gene expression. SIGNOR-275919 0.485 PHGDH protein O43175 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates activity chemical modification 9606 25406093 t lperfetto PHDGH catalyzes the first reaction of de novo serine biosynthesis, producing 3-phosphohydroxypyruvate by NAD+-coupled oxidation of 3-phosphoglycerate (3PG).|The PHGDH reaction is reversible and, under standard conditions, thermodynamically favors the direction from 3-phosphohydroxypyruvate to 3PG. SIGNOR-268567 0.8 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser391 GAATPRTsQFTKYWT 9606 16216881 t lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. SIGNOR-141002 0.2 AMPK complex SIGNOR-C15 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 11971957 t lperfetto Mutation of serine 259 increased the basal raf-1 activity and rendered it largely resistant to inhibition by pka. SIGNOR-216523 0.302 ETNK2 protein Q9NVF9 UNIPROT ethanolaminium(1+) smallmolecule CHEBI:57603 ChEBI down-regulates quantity chemical modification 36866238 t lperfetto Ethanolamine kinase 2 (ETNK2) is a protein-coding gene. Spondylometaphyseal dysplasia with cone-rod dystrophy is one of the diseases linked to the ETNKT2 gene. Glycerophospholipid biosynthesis and nuclear receptor meta-pathways are two of the ETNK2-related pathways. SIGNOR-275644 0.8 EPHB2 protein P29323 UNIPROT ARHGEF15 protein O94989 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr353 PLQDEPLyQTYRAAV 9606 BTO:0000007 21029865 t miannu We have identified a RhoA guanine nucleotide exchange factor, Ephexin5, which negatively regulates excitatory synapse development until EphrinB binding to the EphB receptor tyrosine kinase triggers Ephexin5 phosphorylation, ubiquitination, and degradation. EphB2 mediates phosphorylation of Ephexin5 at tyrosine-361 SIGNOR-262864 0.498 ROCK2 protein O75116 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates phosphorylation Ser448 HRSIRHSsIQE 9606 BTO:0000782 20697158 t miannu Carock2 phosphorylated irf4 at either of 2 distinct phosphorylation sites, s446 and s447 / rock2-mediated phosphorylation of irf4 regulated the synthesis of il-17 and il-21 and the differentiation of th17 cells. SIGNOR-167471 0.427 DRAM2 protein Q6UX65 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30755245 f irozzo Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. SIGNOR-259144 0.2 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser164 TSTPGRRsCFGFEGL -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276120 0.698 STAT6 protein P42226 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22025054 f lperfetto IL-4R signals through a JAKSTAT6 pathway, and many of the genes associated with mouse M2 macrophages are regulated by STAT6, including arginase 1 (Arg1), macrophage mannose receptor 1 (Mrc1; also known as Cd206), resistin-like-? (Retnla; also known as Fizz1) and chitinase 3-like 3 (Chi3l3; also known as Ym1). SIGNOR-249541 0.7 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-268070 0.8 SYN3 protein O14994 UNIPROT ACTB protein P60709 UNIPROT up-regulates activity binding 9606 BTO:0000938 15265865 t miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. SIGNOR-269183 0.2 DUSP7 protein Q16829 UNIPROT GHR protein P10912 UNIPROT down-regulates dephosphorylation 9606 12907755 t gcesareni Identification of protein tyrosine phosphatases with specificity for the ligand-activated growth hormone receptor. SIGNOR-104545 0.318 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT up-regulates activity phosphorylation Tyr420 RLIEDNEyTARQGAK -1 9425276 t Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn. SIGNOR-251167 0.2 Hexokinase proteinfamily SIGNOR-PF76 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates activity 10090 BTO:0000452 16892090 f inferred from family member HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host SIGNOR-270309 0.7 BMPR1A protein P36894 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR form complex binding 9606 7791754 t lperfetto Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii). SIGNOR-255257 0.545 HSPA5 protein P11021 UNIPROT ERN1 protein O75460 UNIPROT down-regulates activity binding 9606 31226023 t miannu Besides being activated like PERK via dissociation of GRP78, IRE1 is also activated by direct binding of the unfolded protein to its N-terminal luminal domain SIGNOR-260176 0.814 F2RL3 protein Q96RI0 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256772 0.305 ERO1B protein Q86YB8 UNIPROT ERP44 protein Q9BS26 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 11847130 t Simone Here, we report the functional characterization of a novel UPR-induced ER resident protein (ERp44) that forms mixed disulfides with both hEROs, as well as with partially unfolded Ig subunits. SIGNOR-261048 0.2 MYLK2 protein Q9H1R3 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Thr80 NEPHESRtNSDIVET 9606 BTO:0000007 21556048 t llicata Here, we show that phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis. SIGNOR-238118 0.412 SRR protein Q9GZT4 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity chemical modification 10090 BTO:0000142 12393813 t lperfetto High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media. SIGNOR-268270 0.8 pazopanib hydrochloride chemical CHEBI:71217 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-200030 0.8 PLK1 protein P53350 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates quantity by destabilization phosphorylation Ser305 IYQLMDHsNMDCFIC phosphorylation:Ser387 YLEMDLSsPQTRYIP 24484936 t lperfetto By phosphorylating S387 in procaspase-8 Cdk1/cyclin B1 generates a phospho-epitope for the binding of the PBD of Plk1. Subsequently, S305 in procaspase-8 is phosphorylated by Plk1 during mitosis. Using an RNAi-based strategy we could demonstrate that the extrinsic cell death is increased upon Fas-stimulation when endogenous caspase-8 is replaced by a mutant (S305A) mimicking the non-phosphorylated form. Together, our data show that sequential phosphorylation by Cdk1/cyclin B1 and Plk1 decreases the sensitivity of cells toward stimuli of the extrinsic pathway during mitosis. SIGNOR-272989 0.379 LYN protein P07948 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates activity phosphorylation Tyr381 SESSDDDyDDVDIPT 9534 11514608 t BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. Tyr-379 within HPK1 is essential for binding to BASH and thus strongly suggest that the DDDYDDV sequence containing the phosphorylated Tyr-379 is the binding site for the BASH SH2 domain. SIGNOR-251403 0.389 CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser279 VLKRPERsQEESPPG 9606 20068082 t gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts); SIGNOR-163142 0.851 Complement C1 complex complex SIGNOR-C309 SIGNOR C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263433 0.629 GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268608 0.269 SLC46A1 protein Q96NT5 UNIPROT heme smallmolecule CHEBI:30413 ChEBI up-regulates quantity relocalization 9606 BTO:0000575 32621820 t lperfetto SLC46A1 contributes to hepatic iron metabolism by importing heme in hepatocytes. SIGNOR-268265 0.8 TRADD protein Q15628 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 8612133 t lperfetto We show that tradd interacts strongly with rip;rip is a serinethreonine kinase that is recruited by tradd to tnfr1 in a tnf-dependent process. SIGNOR-40043 0.936 PI3K complex SIGNOR-C156 SIGNOR PIK3CD protein O00329 UNIPROT up-regulates activity binding 9534 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-252720 0.607 Naltrindole chemical CHEBI:81528 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258818 0.8 ARVCF protein O00192 UNIPROT CDH2 protein P19022 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 t miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. SIGNOR-252128 0.478 IFNG protein P01579 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 f miannu High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity. SIGNOR-261024 0.7 RPL35 protein P42766 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262466 0.857 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT down-regulates activity phosphorylation Thr514 SVTPKTVtPASSAKT 10116 BTO:0000938 15652488 t lperfetto Here, we showed that glycogen synthase kinase-3beta (gsk-3beta) phosphorylated crmp-2 at thr-514 and inactivated it SIGNOR-133255 0.713 sphingosine 1-phosphate(1-) smallmolecule CHEBI:60119 ChEBI S1PR2 protein O95136 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257578 0.8 MAPK11 protein Q15759 UNIPROT EGFR protein P00533 UNIPROT down-regulates phosphorylation 9606 16932740 t gcesareni P38 map kinase mediates stress-induced internalization of egfrthe underlying mechanism entails phosphorylation of egfr at a short segment (amino acids 1002-1022) containing multiple serines and threonines, as well as phosphorylation of two rab5 effectors, eea1 and gdi. SIGNOR-149086 0.34 EDNRA protein P25101 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257427 0.448 PHLPP1 protein O60346 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity dephosphorylation Thr387 TMKRRDEtMQPAKPS 9606 20513427 t PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis. SIGNOR-248329 0.3 LAT protein O43561 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. SIGNOR-246060 0.801 POLR2E protein P19388 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266147 0.918 SSTR3 protein P32745 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256820 0.429 IKZF3 protein Q9UKT9 UNIPROT LNPEP protein Q9UIQ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003420 15894523 f miannu Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. SIGNOR-255405 0.2 perifosine chemical CHEBI:67272 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates chemical inhibition 9606 BTO:0001130 14617782 t Perifosine causes decrease in Akt Ser473 and Thr308 phosphorylation gcesareni Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation.| Our results demonstrate that Akt is an important cellular target of perifosine action. In addition, these studies show that the membrane translocation of certain PH domain-containing molecules can be greatly perturbed by the alkylphospholipid class of drugs and imply further that the PI3K/Akt pathway contributes to regulation of p21(WAF1/CIP1) expression. SIGNOR-119189 0.8 tazarotene chemical CHEBI:32184 ChEBI RARB protein P10826 UNIPROT up-regulates activity chemical activation 9534 19058965 t Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  SIGNOR-258028 0.8 RAF1 protein P04049 UNIPROT EEF1A2 protein Q05639 UNIPROT down-regulates quantity by destabilization phosphorylation Ser21 GHVDSGKsTTTGHLI -1 22378069 t miannu Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.  SIGNOR-276407 0.2 MAP3K5 protein Q99683 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 8974401 t lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-45353 0.596 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Arg25 PLLSARTrARRPESK -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus SIGNOR-263568 0.883 ROR2 protein Q01974 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 18667433 t gcesareni Wnt5a stimulation induces activation of the c-jun n-terminal kinase jnk at the wound edge in a ror2-dependent manner, and inhibiting jnk activity abrogates wnt5a-induced lamellipodia formation and mtoc reorientation SIGNOR-179671 0.437 PPP2R2C protein Q9Y2T4 UNIPROT SRC protein P12931 UNIPROT down-regulates activity binding 9606 BTO:0001938 18069897 t gcesareni We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC SIGNOR-247966 0.2 WDR83 protein Q9BRX9 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 15118098 t gcesareni Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex. SIGNOR-124476 0.504 NKX2-5 protein P52952 UNIPROT MYL2 protein P10916 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0003265 9043061 f The mammalian homolog of the Drosophila tinman homeobox gene, Nkx2-5, is specifi- cally required for ventricular chamber-specific myosin light chain-2 (MLC-2v) expression and looping morphogenesis during mammalian heart development. SIGNOR-253645 0.604 ETNK1 protein Q9HBU6 UNIPROT ethanolaminium(1+) smallmolecule CHEBI:57603 ChEBI down-regulates quantity chemical modification 36583229 t lperfetto ETNK1 encodes ethanolamine kinase 1, which is involved in the de novo biosynthesis of phosphatidylethanolamine and is responsible for the phosphorylation of ethanolamine to phosphoethanolamine SIGNOR-275642 0.8 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 9606 BTO:0002882 11684015 t lperfetto RAD51 is one of six mitotic human homologs of the E. coli RecA protein (RAD51-Paralogs) that play a central role in homologous recombination and repair of DNA double-strand breaks (DSBs).|Phosphorylation of the RAD51 Tyr-315 residue by BCR/ABL appears essential for enhanced DSB repair and drug resistance. SIGNOR-271707 0.2 MAPK12 protein P53778 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity phosphorylation Ser200 YSGDSDAsSPRSNCS 10090 BTO:0005930 20026657 t miannu  We determined that p38-gamma directly phosphorylated MyoD on Ser199 and Ser200, which results in enhanced occupancy of MyoD on the promoter of myogenin together with markedly decreased transcriptional activity.  SIGNOR-276274 0.422 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Ser339 SPISTPTsPGSLRKH 9606 14741103 t llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. SIGNOR-250673 0.415 MAPK1 protein P28482 UNIPROT CDC42EP2 protein O14613 UNIPROT unknown phosphorylation Ser101 RELPDGPsPLLKNAI 10090 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262770 0.25 PHLPP2 protein Q6ZVD8 UNIPROT PRKCB protein P05771 UNIPROT down-regulates quantity dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 BTO:0000067 18162466 t gcesareni Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC betaII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle SIGNOR-237039 0.334 CSNK2A1 protein P68400 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser281 DGTGDTSsEEDEDEE -1 11278496 t llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. SIGNOR-250875 0.387 CAPN3 protein P20807 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR up-regulates activity cleavage 9606 25969760 t lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain SIGNOR-251602 0.329 TTC3 protein P53804 UNIPROT AKT1 protein P31749 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000944 20059950 t gcesareni TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus SIGNOR-252436 0.404 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SP1 protein P08047 UNIPROT up-regulates binding 9606 10671503 t lperfetto Rela (p65) nf-kappab subunit interacts with the zinc finger dna-binding domain of sp1. SIGNOR-216334 0.557 MAPK1 protein P28482 UNIPROT CIITA protein P33076 UNIPROT up-regulates phosphorylation Ser280 TVHGLPTsPDRPGST 9606 15210796 t gcesareni We show in this study that the nuclear localized form of ciita is a predominantly phosphorylated form of the protein, whereas cytoplasmic ciita is predominantly unphosphorylated. Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. Double mutations of these residues increased nuclear ciita, indicating that these sites are not required for nuclear import. Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation. SIGNOR-126250 0.442 BCOR protein Q6W2J9 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 10090 BTO:0004850 26847029 f irozzo Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes. SIGNOR-256010 0.7 GRM7 protein Q14831 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. SIGNOR-264938 0.8 SCF-betaTRCP complex SIGNOR-C5 SIGNOR FOXP3 protein Q9BZS1 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys356 AILEAPEkQRTLNEI 9606 BTO:0002181 27432879 t miannu The ubiquitination site of Foxp3 is Lys356 SIGNOR-277246 0.262 PDGFRB protein P09619 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr320 RKDTKEIyTHFTCAT -1 33139573 t miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. SIGNOR-277234 0.2 CDC42BPA protein Q5VT25 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 19851336 t lperfetto More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above. SIGNOR-188781 0.531 PKM protein P14618 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI down-regulates quantity chemical modification 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266534 0.8 SMAD1/4 complex SIGNOR-C85 SIGNOR PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004058 12589053 f lperfetto Overexpression of Smad6, a natural antagonist for Smad1, blocked PPARgamma expression and adipocytic differentiation induced by BMP2 SIGNOR-236233 0.289 entinostat chemical CHEBI:132082 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257963 0.8 RASGRF2 protein O14827 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260575 0.535 Degranulation phenotype SIGNOR-PH92 SIGNOR TPSAB1 protein Q15661 UNIPROT up-regulates quantity by expression 9606 24232182 f apalma Particularly, damage-activated mast cells almost instantly begin to secrete TNFa, histamine and tryptase and then initiate the de novo synthesis of other cytokines, such as interleukin (IL)6 SIGNOR-255348 0.7 MAPK3 protein P27361 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 10347142 t gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation SIGNOR-67634 0.705 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000018 10734310 t miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. SIGNOR-250290 0.661 CDK1 protein P06493 UNIPROT KRT18 protein P05783 UNIPROT up-regulates phosphorylation Ser34 RPVSSAAsVYAGAGG 9606 9524113 t lperfetto We identified k18 ser33 as an interphase phosphorylation site, which increases its phosphorylation during mitosis in cultured cells and regenerating liver, and as an in vitro cdc2 kinase phosphorylation site. K18 ser33 phosphorylation dictates binding to 14_3_3 proteins SIGNOR-55994 0.344 NF1 protein P21359 UNIPROT ADCY9 protein O60503 UNIPROT up-regulates 9606 BTO:0000938 24431436 f miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-204354 0.309 PRKACA protein P17612 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Ser188 ARRGKKKsGCLVL 10090 12654918 t miannu PKA phosphorylates RhoA on Ser188. the addition of a negative charge to Ser188 is sufficient to diminish both RhoA activation and activity within the context of a cell. SIGNOR-250047 0.501 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1064 SCPIKEDsFLQRYSS 9606 BTO:0000007 10347170 t llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  SIGNOR-250619 0.378 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT down-regulates quantity phosphorylation Ser623 NRHSLPFsLPSQMEP 9606 BTO:0000782 11024037 t lperfetto However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway.  SIGNOR-249055 0.327 CASP3 protein P42574 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity cleavage Asp349 RVASTMTdGANTMIE 9534 BTO:0004055 11517310 t lperfetto In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus. SIGNOR-109878 0.601 ERG protein P11308 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21669963 f miannu Using in vitro and in vivo molecular assays, we showed that ERG increases OPN expression and binds to an EBS (nt -115 to -118) in the OPN promoter. SIGNOR-254066 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD86 protein P42081 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19164127 f miannu We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40. SIGNOR-254782 0.295 XAV939 chemical CHEBI:62878 ChEBI TNKS protein O95271 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207830 0.8 ZNF292 protein O60281 UNIPROT GH1 protein P01241 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 10687855 t lperfetto Rat Zn-15 is a transcription factor activating GH gene expression by synergistic interactions with Pit-1, named for 15 DNA-binding zinc fingers, including fingers IX, X, and XI that are responsible for GH promoter binding. SIGNOR-268969 0.2 SMO protein Q99835 UNIPROT GNB2 protein P62879 UNIPROT up-regulates binding 9606 16885213 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-148589 0.2 PMS1 protein P54277 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 10090 9500552 f Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer SIGNOR-257597 0.7 RPS6KA3 protein P51812 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Thr929 STIIRSKtFSPGPQS 9606 BTO:0000149 24269383 t llicata Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2. SIGNOR-203306 0.2 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 18160256 t Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248610 0.473 SLC16A4 protein O15374 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 26384349 f lperfetto Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival. SIGNOR-242519 0.7 RASGRF2 protein O14827 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260573 0.534 HDAC1 protein Q13547 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18588516 f miannu The down-regulation of slug in the ERalpha-positive MCF-7 cell line was mediated by direct repression of slug transcription by the formation of a co-repressor complex involving ligand-activated ERalpha protein, HDAC1 (histone deacetylase 1) and N-CoR (nuclear receptor co-repressor). SIGNOR-254228 0.596 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT up-regulates activity phosphorylation Tyr274 SNVVRKDyDTLSKCS -1 21840312 t miannu Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility. SIGNOR-263039 0.398 CAPN3 protein P20807 UNIPROT GSK3A protein P49840 UNIPROT up-regulates activity cleavage 9606 25969760 t lperfetto Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase SIGNOR-251606 0.2 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252857 0.908 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr362 SPPAEDVyDVPPPAP 10090 12972425 t lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs SIGNOR-246409 0.796 D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-266250 0.8 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR HIRA protein P54198 UNIPROT up-regulates phosphorylation Thr555 LSPSVLTtPSKIEPM 9606 11238922 t lperfetto Hira bound to and was phosphorylated by cyclin a- and e-cdk2 in vitrohira became phosphorylated on threonine 555 in s phase when cyclin-cdk2 kinases are active.ectopic expression of hira in cells caused arrest in s phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle. SIGNOR-216670 0.331 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9606 9687510 t lperfetto Thus, MAPK1/ERK1 and MAPK2/ERK2 activate three closely related protein kinases known as MAPK_activated protein kinases_1a, _1b and _1c (MAPKAP_K1a/b/c; also known as RSK1/2/3) SIGNOR-252753 0.753 KLF8 protein O95600 UNIPROT CTBP2 protein P56545 UNIPROT up-regulates activity binding 10090 BTO:0000944 10756197 t miannu Here we report the characterisation of KLF8/ZNF741/BKLF3 (KLF8). We demonstrate that this protein is able to bind CACCC-boxes in DNA and can repress gene expression by associating with CtBP co-repressors. SIGNOR-236962 0.546 SRC protein P12931 UNIPROT KCNJ1 protein P48048 UNIPROT down-regulates phosphorylation Tyr337 SKTKEGKyRVDFHNF 9606 12217858 t gcesareni Addition of active c-src and [32p]atp to the purified romk1 protein resulted in the phosphorylation of the romk1 protein. However, c-src did not phosphorylate r1y337a in which tyrosine residue 337 was mutated to alanine. Furthermore, phosphopeptide mapping identified two phosphopeptides from the trypsin-digested romk1 protein. SIGNOR-92513 0.318 HECTD3 protein Q5T447 UNIPROT MALT1 protein Q9UDY8 UNIPROT up-regulates quantity by stabilization polyubiquitination 9606 BTO:0000007 23358872 t miannu HECTD3 promotes MALT1 ubiquitination with nondegradative polyubiquitin chains by direct interacting with the MALT1 through its N-terminal destruction of cyclin domain. HECTD3 does not target MALT1 for degradation but stabilize it.  SIGNOR-272096 0.374 AP-2 complex complex SIGNOR-C245 SIGNOR GABA-A proteinfamily SIGNOR-PF61 SIGNOR down-regulates quantity relocalization 9606 BTO:0000938 25600368 t miannu The endocytosis of GABAARs is regulated by the interaction of the AP2 complex with β and γ2 subunits. Phosphorylation of β3 (S408/S409) and γ2 (Y365/Y367) by PKA/PKC and Src/Fyn, respectively, prevents binding to AP2 and thus stabilizes these receptors at the cell surface. SIGNOR-264990 0.2 TBK1 protein Q9UHD2 UNIPROT DDAH2 protein O95865 UNIPROT down-regulates activity phosphorylation Ser245 GGGDLPNsQEALQKL 33850055 t lperfetto TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o SIGNOR-275648 0.2 TFEB protein P19484 UNIPROT GBA protein P04062 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 t lperfetto Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants SIGNOR-276551 0.331 KLK3 protein P07288 UNIPROT PTHLH protein P12272 UNIPROT down-regulates activity cleavage Ser22 LLSYAVPsCGRSVEG -1 8753751 t lperfetto Our study demonstrates that PTHrP is a substrate for PSA. The cleavage of the amino-terminal portion of PTHrP completely disrupts its ability to interact with the PTH/PTHrP receptor and thus inhibits its PTH-like activity. | Our data show that PSA proteolytically cleaves PTHrP (1-34) after either residue 22 or 23, generating three peptide fragments. SIGNOR-270547 0.432 CPSF6 protein Q16630 UNIPROT CFI complex complex SIGNOR-C388 SIGNOR form complex binding 9606 BTO:0000567 8626397 t lperfetto We report here the purification of CF Im from HeLa cell nuclear extracts. Three polypeptides of 68, 59, and 25 kDa copurified with CF Im activity. SIGNOR-266123 0.812 COP1 protein Q8NHY2 UNIPROT COP1 protein Q8NHY2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 19805145 t miannu MTA1 destabilizes COP1 by promoting its autoubiquitination. in addition to polyubiquitination of its substrates, COP1 also catalyzes its autoubiquitination for degradation as a part of an autoregulatory mechanism SIGNOR-271893 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-262998 0.2 RPGRIP1L protein Q68CZ1 UNIPROT RELA protein Q04206 UNIPROT down-regulates demethylation Lys221 LLCDKVQkEDIEVYF 9606 SIGNOR-C13 20080798 t miannu Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. SIGNOR-163320 0.2 CNOT4 protein O95628 UNIPROT KDM5C protein P41229 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19346402 t miannu  In our study, we show that the protein level of the yeast histone H3 Lys 4 (H3 K4) demethylase Jhd2/Kdm5 is modulated through polyubiquitination by the E3 ubiquitin ligase Not4 and turnover by the proteasome.  Finally, we show that human NOT4 can polyubiquitinate human JARID1C/SMCX, a homolog of Jhd2, suggesting that this is likely a conserved mechanism. We propose that Not4 is an E3 ubiquitin ligase that monitors and controls a precise amount of Jhd2 protein so that the proper balance between histone demethylase and histone methyltransferase activities occur in the cell, ensuring appropriate levels of H3 K4 trimethylation and gene expression. SIGNOR-271468 0.56 LTBP2 protein Q14767 UNIPROT FBN1 protein P35555 UNIPROT up-regulates activity binding 9606 BTO:0000452 19681046 t Regulation miannu LTBP-2 interacts with fibrillin-1. The association of LTBP-2 with the ECM always coincided with that of fibrillin-1, and in fibroblast cultures the appearance of fibrillar fibrillin-1 structures preceded the assembly of LTBP-2 network. SIGNOR-251891 0.306 CREBBP protein Q92793 UNIPROT CREB1 protein P16220 UNIPROT up-regulates binding 9606 9829964 t gcesareni When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp. SIGNOR-62260 0.94 CD40LG protein P29965 UNIPROT CD40 protein P25942 UNIPROT up-regulates activity binding 9606 BTO:0000776 12324477 t lperfetto Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated T cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner. cd40 binds its ligand cd40l. SIGNOR-93432 0.927 cholesterol smallmolecule CHEBI:16113 ChEBI pregnenolone smallmolecule CHEBI:16581 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 33117906 t lperfetto The steroidogenic acute regulatory protein (StAR) assists in the transport of cholesterol from the cytosol to the inner mitochondria membrane to be converted into pregnenolone using the P450 side-chain cleavage (P450scc) enzyme. SIGNOR-268629 0.8 Sincalide smallmolecule CID:9833444 PUBCHEM CCKAR protein P32238 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257466 0.8 SIK2 protein Q9H0K1 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 20577053 t gcesareni Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2 SIGNOR-166372 0.733 HSP90AA1 protein P07900 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 18591668 t lpetrilli The data in fig. 5 suggest that hsp90 specifically interacts with t?RI And t?RII In vitro and in vivo. Coupled with our data showing that loss of hsp90 function decreases t?R Levels and blocks tgf?-Induced smad2/3 activation and transcription, this result suggests that hsp90 controls tgf? Signaling as an essential component for stabilizing t?Rs. SIGNOR-179268 0.424 RPS6KA4 protein O75676 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 t gcesareni Rsk1/2 phosphorylates the transcription factor c-fos on s362 and increases its activity. SIGNOR-37216 0.401 DTX1 protein Q86Y01 UNIPROT EP300 protein Q09472 UNIPROT up-regulates binding 9606 11564735 t gcesareni We found that a significant fraction of dtx1 proteins were localized in the nucleus and physically interacted with the transcriptional coactivator p300. SIGNOR-110629 0.389 GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268598 0.2 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 t lperfetto Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes. SIGNOR-233438 0.598 GPR84 protein Q9NQS5 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256983 0.252 PRKCD protein Q05655 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity phosphorylation 9606 19363025 t gcesareni We identify protein kinase c-delta as the kinase responsible for h3t45ph in vitro and in vivo. Given the nucleosomal position of h3t45, we postulate that h3t45ph induces structural change within the nucleosome to facilitate dna nicking and/or fragmentation. SIGNOR-265368 0.2 AKT1 protein P31749 UNIPROT EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 18836482 t gcesareni Using an in vitro kinase assay, we found that pkb can directly phosphorylate eif4b on serine 422 (ser422). This was prevented by pretreatment of cells with the phosphatidylinositol 3-kinase (pi3k) inhibitor ly294002 or pharmacological inhibition of pkb. Phosphorylation regultes the activation of eukaryotic translation initiation factor 4b. SIGNOR-252520 0.402 CDON protein Q4KMG0 UNIPROT CDON/BOC/PTCH1 complex SIGNOR-C95 SIGNOR form complex binding 10090 21664576 t lperfetto Secreted Hedgehog (HH) ligands signal through the canonical receptor Patched (PTCH1). However, recent studies implicate three additional HH-binding, cell-surface proteins, GAS1, CDO, and BOC, as putative coreceptors for HH ligands. SIGNOR-209596 0.554 UBE2I protein P63279 UNIPROT SOX6 protein P35712 UNIPROT down-regulates activity sumoylation Lys417 TSPVTQkVkDEAAAQP 9606 16442531 t We show that SOX6 is modified in vitro and in vivo by small ubiquitin‐related modifier (SUMO) on two distinct sites. Mutation of both sites abolished SOX6 sumoylation and increased SOX6 transcriptional activity. SUMO dependent repression of SOX6 transcription was promoted by UBC9 whereas siRNA to UBC9, cotransfection of inactive UBC9 or a SUMO protease increased SOX6 transcriptional activity. SIGNOR-256130 0.374 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F5 protein P12259 UNIPROT down-regulates activity cleavage Arg707 ESTVMATrKMHDRLE -1 10026263 t lperfetto Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 SIGNOR-263647 0.496 MAPK1 protein P28482 UNIPROT GLI1 protein P08151 UNIPROT up-regulates activity phosphorylation Ser130 HLSIGTMsPSLGFPA -1 35831023 t miannu We conclude that multisite phosphorylation of GLI1 by ERK2 or other MAP kinases weakens GLI1-SUFU binding, thereby facilitating GLI1 activation and contributing to both physiological and pathological crosstalk. SIGNOR-277600 0.329 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates activity phosphorylation Ser133 SPSPMETsGCAPAEE 9606 BTO:0000567 11242082 t lperfetto Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation. SIGNOR-105715 0.919 GSK3B protein P49841 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser62 EPDSGSHsRQSSTDS 9606 BTO:0002181 22692215 t miannu GSK3 destabilizes TAZ. TAZS58A/S62A but not the TAZ S66A mutant diminished phos- phorylation by GSK3 , suggesting that Ser-58 and Ser-62 are important for GSK3  phosphorylation, whereas the Ser-66 is not (Fig. 4D). SIGNOR-277647 0.2 HLA1 proteinfamily SIGNOR-PF87 SIGNOR Class I MHC complex SIGNOR-C425 SIGNOR form complex binding -1 28367149 t scontino One Ig domain is present in each chain of MHC class II, while the second Ig-type domain of MHC class I is provided by non-covalent association of the invariant light chain beta-2 microglobulin (beta2m) with the HC.|The MHC class I HC folds and assembles with beta2m in the lumen of the endoplasmic reticulum (ER) SIGNOR-267776 0.965 PTPN11 protein Q06124 UNIPROT GAB2 protein Q9UQC2 UNIPROT down-regulates dephosphorylation Tyr614 KSTGSVDyLALDFQP 9606 15170389 t gcesareni Expression of the gab2 tyr-614-->phe (y614f) mutant, defective in shp-2 association, prevents erk (extracellular-signal-regulated kinase) activation and expression of a luciferase reporter plasmid driven by the c-fos sre (serum response element), indicating that interaction of shp-2 with gab2 is required for erk activation in response to il-2. SIGNOR-124958 0.732 TRMT10B protein Q6PF06 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 t lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). SIGNOR-267705 0.205 PRKAB1 protein Q9Y478 UNIPROT PROX1 protein Q92786 UNIPROT down-regulates quantity by destabilization phosphorylation Ser79 KLLKRANsYEDAMMP 9606 BTO:0002181 36433955 t miannu Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation. SIGNOR-277609 0.2 PRKACA protein P17612 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1166 SDDFKRDsVSGGGPC 9606 BTO:0000007 24431445 t miannu Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca(2+) permeation and Ca(2+) signaling in spines. SIGNOR-276616 0.392 PDZD11 protein Q5EBL8 UNIPROT TSPAN33 protein Q86UF1 UNIPROT up-regulates activity binding 10116 BTO:0003618 30463011 t Simone Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. The PLEKHA7-PDZD11 Complex Clusters ADAM10 at Junctions through Tspan33 SIGNOR-261252 0.334 PER2 protein O15055 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267977 0.753 PIN4 protein Q9Y237 UNIPROT Ribosome biogenesis phenotype SIGNOR-PH164 SIGNOR up-regulates 9606 BTO:0000567 12860119 f lperfetto Par14 is a pre-rRNA processing factor involved in mammalian ribosome biogenesis, Par14 deficiency slowed cell growth (Fig. 3A) and reduced the production of 18 and 28 S rRNAs  SIGNOR-265754 0.7 GNG2 protein P59768 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 23074268 t gcesareni Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance. SIGNOR-199138 0.2 afatinib chemical CHEBI:61390 ChEBI ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259441 0.8 RPS6K proteinfamily SIGNOR-PF26 SIGNOR L1CAM protein P32004 UNIPROT up-regulates activity phosphorylation Ser1152 RSKGGKYsVKDKEDT 10116 BTO:0001009 8663493 t lperfetto Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152. SIGNOR-252766 0.2 ARNT protein P27540 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 21544813 f lperfetto Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC SIGNOR-253692 0.285 AURKA protein O14965 UNIPROT DLGAP5 protein Q15398 UNIPROT up-regulates quantity by stabilization phosphorylation Ser757 EGMELNSsITSQDVL 9606 BTO:0000007 15987997 t miannu Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life. SIGNOR-262651 0.74 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Thr116 SCDKSTQtPSPPCQA 9606 12591950 t lperfetto Biml (bim long) was induced and phosphorylated parallel to jnk activitythese data demonstrate that biml is phosphorylated in vivo on thr-56 and that jnk also phosphorylates biml on at least one serine residue (ser-44 and/or ser-58) SIGNOR-98392 0.2 NOX3 protein Q9HBY0 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264715 0.7 PCF11 protein O94913 UNIPROT CFII complex complex SIGNOR-C387 SIGNOR form complex binding 9606 BTO:0000567 30139799 t lperfetto Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1. SIGNOR-266119 0.886 GNAI2 protein P04899 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 8327893 t gcesareni Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required SIGNOR-37973 0.58 PRKDC protein P78527 UNIPROT YBX1 protein P67809 UNIPROT up-regulates activity phosphorylation Thr89 EDVFVHQtAIKKNNP 9606 BTO:0000007 36475703 t miannu The DNA-PK subunits and YB-1 phosphorylated at T89 were found colocalized suggesting their in vivo interaction.DNA-PK directly phosphorylates YB-1 and, this way, modulates YB-1 function. Point mutation of YB-1 at this residue abrogated the translocation of YB-1 into the nucleus. SIGNOR-277611 0.344 NFATC1 protein O95644 UNIPROT IL2 protein P60568 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10022916 t Barakat Together, our results demonstrate that dnNFAT inhibits the production of IL-2. Thus, the NFAT transcription factor contributes to the regulation of IL-2 gene expression and therefore plays a critical role in the initiation of immune responses. SIGNOR-275405 0.582 ZSWIM2 protein Q8NEG5 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 16522193 f miannu MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin.  SIGNOR-271556 0.7 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 21798082 t gcesareni Pip3 acts in turn as a docking site for two kinases, phosphoinositidedependent kinase 1 (pdk1) and akt, and the subsequent phosphorylation of akt at serine 308 by pdk1, leading to akt activation. SIGNOR-175675 0.737 PRKCD protein Q05655 UNIPROT CDK5 protein Q00535 UNIPROT down-regulates activity phosphorylation Thr77 LHSDKKLtLVFEFCD 9606 BTO:0001332 29511352 t miannu This generates a binding site for the C2 domain of PKCδ, which in turn phosphorylates CDK5 on T77. The resulting dissociation of the CDK5R1/CDK5 complex abolishes the activity of CDK5.  SIGNOR-277386 0.2 CDK9 protein P50750 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR form complex binding -1 34955012 t lperfetto Cyclin-dependent-kinases (CDKs) are members of the serine/threonine kinase family and are highly regulated by cyclins, a family of regulatory subunits that bind to CDKs. CDK9 represents one of the most studied examples of these transcriptional CDKs. CDK9 forms a heterodimeric complex with its regulatory subunit cyclins T1, T2 and K to form the positive transcription elongation factor b (P-TEFb).  SIGNOR-267740 0.964 TNF protein P01375 UNIPROT SCN4A protein P35499 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253490 0.26 CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 11154267 t lperfetto Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity SIGNOR-245459 0.821 MAOA protein P21397 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|It undergoes oxidative deamination, catalyzed by the enzyme monoamine oxidase (MAO) in the presence of flavin adenine dinucleotide (FAD), to produce reactive aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL). SIGNOR-264001 0.8 PRKCB protein P05771 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 17145764 t lperfetto Dynamics of protein kinase c-mediated phosphorylation of the complement c5a receptor on serine 334. Analysis of c5ar ser/ala mutants that possess a single intact serine residue either at position 334 or at neighboring positions 327, 332, or 338 revealed functional redundancy of c-terminal phosphorylation sites since all 4 serine residues could individually support c5ar internalization and desensitization SIGNOR-151011 0.2 MDM4 protein O15151 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization binding 9606 10218570 t miannu MDM2 has been shown to be degraded by the ubiquitin-proteasome pathway, while MDMX was a stable protein. Interaction of MDMX with MDM2 through the C-terminal RING finger domains resulted in inhibiting degradation of MDM2. These data indicate that MDMX functions as a regulator of MDM2. SIGNOR-272932 0.722 LMX1A protein Q8TE12 UNIPROT NLI/Lmx1.1/Isl1 complex SIGNOR-C103 SIGNOR form complex binding 9606 BTO:0000007 9452425 t lperfetto Interactions between LIM transcription factors were also evaluated in vivo. Cotransfected FLAG-Lmx1.1 and HA-Isl1 were capable of interacting. the NLI-dependent interaction observed between Isl1 and Lmx1.1 is likely to represent a physiologically significant complex found in the endocrine cells of the pancreas. SIGNOR-236812 0.346 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr814 PLHDGSRtPAQSGAW 9606 16427012 t lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif SIGNOR-143943 0.768 MAPK1 protein P28482 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Thr693 RELVEPLtPSGEAPN -1 1651322 t lperfetto A growth factor-stimulated protein kinase activity that phosphorylates the epidermal growth factor (EGF) receptor at Thr669 has been described Anion-exchange chromatography demonstrated that this protein kinase activity was accounted for by two enzymes. The first peak of activity eluted from the column corresponded to the microtubule-associated protein 2 (MAP2) kinase SIGNOR-20545 0.624 PRKCD protein Q05655 UNIPROT ADD2 protein P35612 UNIPROT unknown phosphorylation Ser726 KKKEKVEs -1 8810272 t lperfetto Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites for PKC. SIGNOR-248953 0.289 peptide smallmolecule CHEBI:16670 ChEBI Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR up-regulates activity binding 9606 29735640 t miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3–guanosine triphosphate (GTP) complex. eRF1 recognizes the stop codon, and after hydrolysis of GTP by eRF3, mediates release of the nascent peptide.  SIGNOR-270815 0.8 ATP2A2 protein P16615 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 16402920 t lperfetto In the present study, we have analysed the expression and functional characteristics of SERCA2c relative to SERCA2a and SERCA2b isoforms upon their stable heterologous expression in HEK-293 cells (human embryonic kidney 293 cells). All SERCA2 proteins induced an increased Ca2+ content in the ER of intact transfected cells. SIGNOR-262050 0.8 FOXC1 protein Q12948 UNIPROT MMP10 protein P09238 UNIPROT up-regulates quantity by expression transcriptional regulation 31650548 t lperfetto Therefore, FOXC1 is strongly suggested as a pro-metastatic gene in CRC by transcriptionally activating MMP10, SOX4 and SOX13|MMP10 was demonstrated as the direct target and mediator of FOXC1. SIGNOR-275915 0.2 MAPK1 protein P28482 UNIPROT GRB10 protein Q13322 UNIPROT unknown phosphorylation Ser418 QQRKALLsPFSTPVR -1 15952796 t lperfetto We identified Ser150, Ser418, and Ser476 of human Grb10 as MAPK-mediated in vitro phosphorylation sites. SIGNOR-249405 0.381 TWIST2 protein Q8WVJ9 UNIPROT NR2F1 protein P10589 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255506 0.2 ECM stimulus SIGNOR-ST20 SIGNOR A9/b1 integrin complex SIGNOR-C166 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259048 0.7 CDK1 protein P06493 UNIPROT KIF20B protein Q96Q89 UNIPROT up-regulates activity phosphorylation Thr1644 VKHPGCTtPVTVKIP 9606 11470801 t miannu Here we report the identification of a novel KRP, termed KRMP1, which undergoes in vivo phosphorylation. The carboxyl-terminal globular tail domain is strongly phosphorylated by mitotic kinase activities almost attributed to cdc2 kinase, which is responsible for phosphorylation on residue Thr-1604 of KRMP1. SIGNOR-262695 0.418 ORC1 protein Q13415 UNIPROT ORC complex SIGNOR-C419 SIGNOR form complex binding 9606 32808929 t lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA SIGNOR-267567 0.944 HECTD4 protein Q9Y4D8 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001321 32814769 t miannu We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. SIGNOR-267146 0.2 GRK2 protein P25098 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity phosphorylation Thr312 RSQELRKtFKEIICC 9606 12639913 t gcesareni Mutagenesis studies revealed that Thr312 and Ser329/330 in the C-terminal tail are potential sites for PKA and GRK phosphorylation and may play an essential role in the recruitment of beta-arrestin to the activated receptor. SIGNOR-247770 0.2 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 21757781 t gcesareni Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kda fk506- and rapamycin-binding protein (fkbp12, or fkbp) and the fkbp-rapamycin binding (frb) domain of the mammalian ta rget of rapamycin (mtor) kinase. autophagy is negatively regulated by the mammalian target of rapamycin (mtor) and can be induced in all mammalian cell types by the mtor inhibitor rapamycin. SIGNOR-174886 0.8 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257964 0.8 SMO protein Q99835 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 23074268 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling as pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp SIGNOR-199180 0.2 CDC20 protein Q12834 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 9606 BTO:0000007 23287467 t miannu  Here, we show that human REV1 undergoes proteosomal degradation mediated by the E3 ubiquitin ligase known as anaphase-promoting complex (APC). REV1 associates with APC. Overexpression of APC coactivator CDH1 or CDC20 promotes polyubiquitination and proteosomal degradation of REV1. SIGNOR-272896 0.873 PKNOX1 protein P55347 UNIPROT HOXB1 protein P14653 UNIPROT up-regulates activity binding -1 9482740 t 2 miannu we observe the formation of a ternary Prep1-Pbx1-HOXB1 complex on a HOXB1-responsive target in vitro. Interaction with Prep1 enhances the ability of the HOXB1-Pbx1 complex to activate transcription in a cooperative fashion from the same target. SIGNOR-241215 0.597 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 9677429 t MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade. gcesareni The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells. SIGNOR-59157 0.742 PTH1R protein Q03431 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 28363951 t lperfetto This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11. SIGNOR-270551 0.485 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT up-regulates activity phosphorylation Ser533 KKSQHRSsSSAPHHN 10441130 t miannu Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation SIGNOR-250340 0.417 PPARGC1A protein Q9UBK2 UNIPROT APOC3 protein P02656 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255059 0.28 ESR1 protein P03372 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 16169518 t gcesareni Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k. SIGNOR-252675 0.648 ARAF protein P10398 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 21779497 t lperfetto Active raf phosphorylates mek. SIGNOR-244809 0.744 cabozantinib chemical CHEBI:72317 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207842 0.8 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser29 IEDSQPEsQVLEDDS 9606 12697768 t llicata To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1 SIGNOR-100645 0.869 Kindlin proteinfamily SIGNOR-PF48 SIGNOR AL/b2 integrin complex SIGNOR-C169 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259024 0.445 RNF2 protein Q99496 UNIPROT Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR form complex binding 9606 31608994 t miannu PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b SIGNOR-266811 0.821 APOBEC3D protein Q96AK3 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 f lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). SIGNOR-261328 0.7 KREMEN1 protein Q96MU8 UNIPROT LRP6 protein O75581 UNIPROT up-regulates 9606 12050670 f gcesareni Dkk1 has been shown to inhibit wnt signalling by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to block wnt/beta-catenin signalling. SIGNOR-88891 0.626 CCP110 protein O43303 UNIPROT CALM1 protein P0DP23 UNIPROT up-regulates activity binding 9606 16760425 t miannu We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis. SIGNOR-265965 0.325 PEX14 protein O75381 UNIPROT PEX13 protein Q92968 UNIPROT up-regulates activity binding -1 15798189 t miannu Pex14 interacts via its proline-rich motif with the SH3 domain of Pex13. We conclude that the association of Pex13 with Pex14 is an essential step in peroxisomal protein import SIGNOR-253029 0.918 DKK1 protein O94907 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 22298955 f Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6. gcesareni It has been shown that both sclerostin and dkk1 act physiologically as downstream molecules of bmp signaling to inhibit canonical wnt signaling and therefore negatively regulate bone mass. SIGNOR-195573 0.724 RAC1 protein P63000 UNIPROT USP6 protein P35125 UNIPROT up-regulates relocalization 9606 12612085 t miannu In quiescent cells, tre17 is localized to intracellular filamentous and punctate structures in the cytoplasm, folded in an inactive conformation. Upon growth factor addition, cdc42 and rac1 become activated and recruit tre17 to the plasma membrane. Stable membrane localization of tre17 also requires polymerized actin. This recruitment process leads to a conformational change in tre17, such that the n-terminal portion of the molecule further stimulates the accumulation of cortical actin. SIGNOR-98938 0.345 dacomitinib chemical CHEBI:132268 ChEBI ERBB4 protein Q15303 UNIPROT down-regulates chemical inhibition 9606 23405260 t gcesareni The goal of this study was to compare dacomitinib (pf-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple her family receptors (her-1 (egfr), her-2 and her-4 tyrosine kinases), to cetuximab, the current fda approved anti-egfr medication for hnscc and erlotinib, an egfr specific small molecule tyrosine kinase inhibitor. SIGNOR-200908 0.8 WNT3A protein P56704 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131826 0.688 CSNK2A2 protein P19784 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1124 LNTEEFSsESDMEES 9606 BTO:0000938 19064667 t lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. SIGNOR-275758 0.2 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser444 PLSLSAQsVMEELNT 9606 BTO:0000938 24614225 t lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204740 0.529 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271808 0.8 USP9X protein Q93008 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270831 0.633 YES1 protein P07947 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Tyr407 SGLSMSSySVPRTPD 9606 BTO:0000578 35041461 t miannu Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C). SIGNOR-277653 0.71 YES1 protein P07947 UNIPROT WWTR1 protein Q9GZV5 UNIPROT up-regulates activity phosphorylation Tyr305 PFLNGGPyHSREQST 9606 BTO:0000578 35041461 t miannu Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C). SIGNOR-277654 0.323 CDK2 protein P24941 UNIPROT RAD54L protein Q92698 UNIPROT down-regulates activity phosphorylation Ser49 QIQECFLsPFRKPLS -1 29295984 t miannu Effect of CDK2 phosphorylation on the RAD54 activities. We find that the RAD54 N-terminal domain (NTD) is responsible for initiation of BM through two coupled, but distinct steps; specific binding to Holliday junctions and RAD54 oligomerization. Furthermore, we find that the RAD54 oligomeric state can be controlled by NTD phosphorylation at S49, a CDK2 consensus site, which inhibits RAD54 oligomerization and, consequently, BM. SIGNOR-273599 0.353 TPO protein P07202 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-267039 0.8 PGLS protein O95336 UNIPROT 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI up-regulates quantity chemical modification 9606 31586547 t miannu The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG). SIGNOR-267058 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR STAT5A protein P42229 UNIPROT up-regulates phosphorylation 9606 BTO:0000975 10194762 t inferred from 70% family members gcesareni Serine 780 is the only substrate in full-length stat5a for active erk SIGNOR-270136 0.2 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Tyr502 TTANVVYyVGENVVN 9606 BTO:0000567 12637538 t gcesareni Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. [..] Mutation of the other two sites, Tyr432 and Tyr502, had no significant influence on PKD activity. SIGNOR-246215 0.345 TBX2 protein Q13207 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 25211658 t lperfetto TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS SIGNOR-249593 0.352 SRC protein P12931 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr177 RFLKSPAyRDLAAQA 9606 12588871 t lperfetto Src-mediated rgs16 tyrosine phosphorylation promotes rgs16 stability. hosphorylation on tyr(168) was mediated by the epidermal growth factor receptor (egfr). SIGNOR-98275 0.353 GSK3A protein P49840 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization phosphorylation Ser159 NNTSTDGsLPSTPPP 9606 BTO:0000567 16543145 t  MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). Glycogen Synthase Kinase-3 Regulates Mitochondrial Outer Membrane Permeabilization and Apoptosis by Destabilization of MCL-1. threonine 163, which represents the GSK-3 priming phosphorylation in this protein SIGNOR-251217 0.468 GSK3B protein P49841 UNIPROT MAF protein O75444 UNIPROT up-regulates phosphorylation 9606 18042454 t miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. SIGNOR-159435 0.263 PCDHA8 protein Q9Y5H6 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265671 0.2 YAP1 protein P46937 UNIPROT SGK1 protein O00141 UNIPROT up-regulates quantity by expression transcriptional regulation 35216681 f lperfetto Importantly, YAP-dependent regulation of serum- and glucocorticoid-regulated kinase 1 (SGK1) is required to activate mTORC1/SREBP and stimulate de novo lipogenesis. SIGNOR-276585 0.285 STAP1 protein Q9ULZ2 UNIPROT TEC protein P42680 UNIPROT up-regulates activity binding 9606 BTO:0000007 10518561 t miannu In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling. BRDG1 may activate Tec by disrupting an intramolecular interaction. SIGNOR-261819 0.4 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT down-regulates activity phosphorylation Ser412 DSLDDSGsCLSGSQR 9534 BTO:0000298 9353340 t lperfetto  Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response.  SIGNOR-248989 0.399 PPAT protein Q06203 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 8106516 t Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed√¢‚Ǩ¬ù SIGNOR-267187 0.8 TESK1 protein Q15569 UNIPROT CFL2 protein Q9Y281 UNIPROT down-regulates activity phosphorylation Ser3 sGVTVNDE 9606 BTO:0001363 11418599 t lperfetto Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin SIGNOR-246719 0.326 PTMS protein P20962 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates activity binding 9606 BTO:0000567 16150697 t miannu Macromolecular translocation inhibitor II (MTI-II), which was first identified as an in vitro inhibitor of binding between the highly purified glucocorticoid receptor (GR) and isolated nuclei, is an 11.5-kDa Zn2+-binding protein that is also known as ZnBP or parathymosin. MTI-II Enhances GR-dependent Transcription through Its Acidic Domain. MTI-II Enhances GR-dependent Transcription in Cooperation with SRC-1 and p300 in Vivo. CBP and p300 Coprecipitate with MTI-II in a Glucocorticoid Hormone-dependent Manner. Immunoprecipitation analysis showed that in the presence of glucocorticoid hormone, p300 and CREB-binding protein are coprecipitated with MTI-II. Furthermore, the knockdown of endogenous MTI-II by RNAi reduces the transcriptional activity of GR in cells. SIGNOR-268462 0.2 NOTCH1 protein P46531 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19165418 f lperfetto Several lines of evidence have suggested that these genes are indeed direct notch target genes: a) the promoters of hes1, hes5 and hes7 as well as hey1, hey2 and heyl subfamily of hes, related with yrpw motif) can be activated by a constitutive active form of notch1. SIGNOR-183507 0.763 MAPK1 protein P28482 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 10567369 t lperfetto An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2 SIGNOR-244912 0.745 ALK protein Q9UM73 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000785 14968112 t gcesareni Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1. SIGNOR-122082 0.531 KMT2A protein Q03164 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates quantity by stabilization binding 9606 23817177 t irozzo RUNX1 wild-type protein first binds to the PU.1 URE region and recruits the MLL complex to open up part of the compact chromatin structure. The partially relaxed chromatin allows the binding of another RUNX1 at the PU.1 promoter region to further distort compact DNA structure. The relaxed form of chromatin facilitates the accumulation of transcription factors and cofactors to initiate transcriptional activity. SIGNOR-255708 0.549 LCK protein P06239 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000782 14583609 t gcesareni Endogenous notch-1 associates with p56(lck) and pi3k. p56(lck) is required for the notch-1-mediated activation of akt/pkb function SIGNOR-118902 0.468 CCT5 protein P48643 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 t miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). SIGNOR-272861 0.744 LDB1 protein Q86U70 UNIPROT LHX2 protein P50458 UNIPROT up-regulates activity binding 9606 BTO:0000007 17005264 t miannu Cofactor CLIM2 promotes the repressive action of LIM homeodomain transcription factor Lhx2 in the expression of porcine pituitary glycoprotein hormone alpha subunit gene. SIGNOR-223962 0.554 Ub:RBR_E3 complex SIGNOR-C520 SIGNOR Protein_ubiquitination phenotype SIGNOR-PH214 SIGNOR up-regulates 9606 34199813 f miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. SIGNOR-271384 0.7 MARCHF9 protein Q86YJ5 UNIPROT PTPRJ protein Q12913 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271535 0.2 CSNK2A1 protein P68400 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Ser1009 DESSDDDsDSEEPSK 9606 10066810 t gcesareni Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein, SIGNOR-65277 0.453 F2 protein P00734 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates binding 9606 BTO:0001253 11356985 t gcesareni Other major aspects of par-2 are highlighted, in particular the ability of several serine protease enzymes, in addition to trypsin, to function as activators of par-2. SIGNOR-108183 0.594 CAMK2G protein Q13555 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275779 0.295 MYO5A protein Q9Y4I1 UNIPROT Dense-core_vesicle_exocytosis phenotype SIGNOR-PH184 SIGNOR up-regulates 9606 21077886 f miannu Myosin Va regulates exocytosis of large dense-core vesicles (LDCVs). interestingly, inhibition of myosin Va potentiates LDCV exocytosis to the same extent as F-actin depolymerization does, suggesting that myosin Va cooperates with the actin cytoskeleton to impede or control LDCV exocytosis SIGNOR-269279 0.7 SOHLH2 protein Q9NX45 UNIPROT KIT protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002181 22328502 t Luana Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression. SIGNOR-266206 0.331 fenoterol chemical CHEBI:149226 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Finally, comparisons of the rank order of ligands for the three different receptors provide information about relative intrinsic efficacies. Fenoterol is a full and efficacious agonist at the β1-adrenoceptor, ranking third out of the agonists studied. It was also a full agonist at the β2- and β3-adrenoceptors with the highest intrinsic efficacy (i.e. top of Tables 4 and ​and5,5, rank 1).  SIGNOR-257868 0.8 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 BTO:0000782 9710204 t lperfetto Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2. SIGNOR-59627 0.721 GNAQ protein P50148 UNIPROT ARHGEF25 protein Q86VW2 UNIPROT up-regulates activity binding -1 17606614 t P63RhoGEF is autoinhibited by the Dbl homology (DH)-associated pleckstrin homology (PH) domain; activated Galpha(q) relieves this autoinhibition by interacting with a highly conserved C-terminal extension of the PH domain SIGNOR-256493 0.57 PDHB protein P11177 UNIPROT PDH complex SIGNOR-C402 SIGNOR form complex binding 9606 20160912 t miannu The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. SIGNOR-266547 0.934 RETREG3 protein Q86VR2 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000934 23939472 f lperfetto We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation.  SIGNOR-261490 0.7 SYK protein P43405 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Tyr136 SEEGYQDyEPEA 9606 BTO:0000975;BTO:0000142 11744621 t llicata Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers. SIGNOR-113069 0.512 USP45 protein Q70EL2 UNIPROT SPDL1 protein Q96EA4 UNIPROT up-regulates activity deubiquitination 9606 BTO:0001938 30258100 t miannu Spindly is mono-ubiquitylated and this ubiquitin can be removed by active USP45. K48 ubiquitylated complex that interacts with Spindly is also de-ubiquitylated by USP45. In the absence of USP45 catalytic activity, interaction is abolished and cell migration is affected similarly to the phenotype described for lack of Spindly. SIGNOR-268505 0.2 MCRS1 protein Q96EZ8 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. SIGNOR-267161 0.633 CSNK2A1 protein P68400 UNIPROT SEPTIN2 protein Q15019 UNIPROT down-regulates phosphorylation Ser218 YHLPDAEsDEDEDFK 9606 16857012 t lperfetto Here we show that human septin 2 is phosphorylated in vivo at ser218 by casein kinase ii. Septin 2 binds and hydrolyses gtp. The purified protein has the capacity to polymerize into long filaments when loaded with gtp or gdp. Moreover, we show that the endogenous protein in hela cells, like that produced in insect cells, is phosphorylated by casein kinase ii and that this phosphorylation alters nucleotide binding. SIGNOR-148010 0.2 PRKACA protein P17612 UNIPROT ITPKB protein P27987 UNIPROT down-regulates activity phosphorylation -1 9374536 t miannu Two isoforms of the inositol 1,4,5-trisphosphate 3-kinase have been identified, the A form and the B form. phosphorylation of isoform A by the cyclic AMP-dependent protein kinase increased activity 1.5-fold, whereas phosphorylation of isoform B decreased activity by 45%. major phosphorylation sites in the protein are Ser119 for PKA. Ser119 in the A isoform is conserved in the B isoform as Ser328 SIGNOR-249995 0.358 NLGN2 protein Q8NFZ4 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 25882190 f miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. SIGNOR-264977 0.7 NRF1 protein Q16656 UNIPROT ENOX1 protein Q8TC92 UNIPROT up-regulates 9606 BTO:0000934 23939472 f lperfetto We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation.  SIGNOR-261451 0.268 PRKCA protein P17252 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser738 ARIIGEKsFRRSVVG 9606 10197446 t llicata These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748. SIGNOR-66666 0.421 ABL1 protein P00519 UNIPROT CRKL protein P46109 UNIPROT down-regulates 9606 21779437 f lperfetto Negative regulation of crk by abl is essential for the antitumorigenic effects of ephrinb2,similar pathways may operate for crkl SIGNOR-175138 0.706 CSNK2A1 protein P68400 UNIPROT WAS protein P42768 UNIPROT up-regulates phosphorylation Ser483 KRSRAIHsSDEGEDQ 9606 12769847 t gcesareni Here we identify two phosphorylation sites in the vca domain of wasp at serines 483 and 484. S483 and s484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the vca domain for the arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length wasp molecule. SIGNOR-101264 0.361 CDK12 protein Q9NYV4 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Thr134 LKFYDSNtVKQKYLS 9606 BTO:0004828 32483448 t lperfetto Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway SIGNOR-273109 0.2 CYP17A1 protein P05093 UNIPROT progesterone smallmolecule CHEBI:17026 ChEBI down-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268657 0.8 CD38 protein P28907 UNIPROT cyclic ADP-ribose smallmolecule CHEBI:31445 ChEBI up-regulates quantity chemical modification 9606 18626062 t miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. SIGNOR-264244 0.8 CDK5RAP2 protein Q96SN8 UNIPROT CEP63 protein Q96MT8 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 t lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. SIGNOR-271722 0.68 ATM protein Q13315 UNIPROT USP10 protein Q14694 UNIPROT up-regulates quantity by stabilization phosphorylation Ser337 ASGTLPVsQPKSWAS 9606 BTO:0001109 20096447 t miannu The translocation and stabilization of USP10 is regulated by ATM -mediated phosphorylation of USP10 at Thr42 and Ser337.  SIGNOR-276276 0.254 MAPK3 protein P27361 UNIPROT SPIB protein Q01892 UNIPROT unknown phosphorylation Thr56 VAPPVPAtPYEAFDP 9606 BTO:0000776 8632909 t lperfetto The threonine 56 was defined as the erk1 phosphorylation site by using phosphoamino-acid analyses and a spi-b mutant version SIGNOR-41800 0.316 PRKCE protein Q02156 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 20179209 t lperfetto Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated SIGNOR-163908 0.346 YY1 protein P25490 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270849 0.536 APOBEC3B protein Q9UH17 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 f lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). SIGNOR-261331 0.7 MAPK1 protein P28482 UNIPROT SORBS3 protein O60504 UNIPROT unknown phosphorylation Ser530 DGPQLPTsPRLTAAA 9606 15184391 t The effect has been demonstrated using O60504-2 llicata Vinexin was directly phosphorylated by erk2 upon stimulation with egf at the serine 189 of vinexin _. SIGNOR-125221 0.396 OPHN1 protein O60890 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity gtpase-activating protein 9606 BTO:0000938 12932438 t miannu OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro SIGNOR-268398 0.622 BMI1 protein P35226 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20551323 f gcesareni One important pathway in which bmi-1 acts to promote the overall growth of mice and cellular proliferation includes cdkn2a;bmi-1 represses the expression of cdkn2a, which encodes two cyclin-dependent kinase inhibitors, p16ink4a (p16) and p19arf SIGNOR-259359 0.468 CSNK2A2 protein P19784 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity phosphorylation Ser58 ESETNQNsSSDSEAE -1 11711551 t llicata We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. SIGNOR-251044 0.386 ATM protein Q13315 UNIPROT PIDD1 protein Q9HB75 UNIPROT up-regulates activity phosphorylation Thr788 DAETGFLtQSNLLSV 9606 BTO:0000567 22854598 t miannu ATM phosphorylates PIDD on Thr788 within the DD. This phosphorylation is necessary and sufficient for RAIDD binding and caspase-2 activation. Conversely, nonphosphorylatable PIDD fails to bind RAIDD or activate caspase-2, and engages prosurvival RIP1 instead. Thus, ATM phosphorylation of the PIDD DD enables a binary switch through which cells elect to survive or die upon DNA injury. SIGNOR-262640 0.621 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000763 12193595 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-91730 0.738 EPAS1 protein Q99814 UNIPROT KDM3A protein Q9Y4C1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271583 0.268 TNKS2 protein Q9H2K2 UNIPROT BLZF1 protein Q9H2G9 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 BTO:0000007 21478859 t lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. SIGNOR-263384 0.2 STK4 protein Q13043 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 22898666 t gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. SIGNOR-191851 0.673 Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR Microtubule-based_movement phenotype SIGNOR-PH170 SIGNOR up-regulates 16440056 f lperfetto Dyneins are large multi-subunit protein complexes that undertake a wide range of roles within the cell. They are adenosine triphosphate (ATP)–driven, microtubule minus-end-directed molecular motors that can be divided, based on function, into two classes: axonemal and cytoplasmic dyneins SIGNOR-265020 0.7 PRKACA protein P17612 UNIPROT ETV1 protein P50549 UNIPROT up-regulates phosphorylation Ser334 PTYQRRGsLQLWQFL 9606 12213813 t lperfetto Pka targets er81 on ser(334) in vivo. Surprisingly, phosphorylation of ser(334) severely reduces the dna-binding ability of er81 but also enhances the transactivation potential of er81. These counteractive effects of pka phosphorylation on er81-dependent transcription may cause the selective up-regulation of promoters with high but not low affinity for er81. SIGNOR-92455 0.297 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL20 protein P78556 UNIPROT up-regulates quantity by expression transcriptional regulation 22319003 t lperfetto Combined stimulation with IL-6, sIL-6R, and IL-17 increased the recruitment of phosphorylated NF-B to the CCL20 promoter, increased binding of coactivators such as p300 and CBP, and enhanced H3 and H4 histone acetylation, consistent with a transcriptionally active gene. SIGNOR-271680 0.307 β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI up-regulates quantity precursor of 9606 9404080 t A full-length cDNA, which encodes a human placental fructose-6-phosphate,2-kinase/ fructose-2,6-bisphosphatase, was constructed and expressed in¬†Escherichia coli. [...]The expressed enzyme was bifunctional with¬†Vmax¬†values of 142 and 0.2 milliunits/mg for the kinase and phosphatase activities, respectively. SIGNOR-267261 0.8 ECM stimulus SIGNOR-ST20 SIGNOR Av/b8 integrin complex SIGNOR-C185 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259042 0.7 AVP protein P01185 UNIPROT AVPR2 protein P30518 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000671;BTO:0001260 1560825 t gcesareni We report here the cloning of a complementary dna encoding the hepatic v1a arginine vasopressin receptor. The liver cdna encodes a protein with seven putative transmembrane domains, which binds arginine vasopressin. SIGNOR-20185 0.727 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR CRY1 protein Q16526 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253679 0.938 PRKACA protein P17612 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates phosphorylation Ser173 DGEFLRTsCGSPNYA 9606 19942859 t gcesareni Pka associates with and phosphorylates ampk?1 At ser-173 to impede threonine thr-172 phosphorylation and thus activation of ampk1 by lkb1 in response to lipolytic signals SIGNOR-161860 0.399 CIT protein O14578 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity binding 9606 BTO:0000565 16431929 t miannu We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase. SIGNOR-266424 0.712 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252349 0.2 COX6A1 protein P12074 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267747 0.723 AUTS2 protein Q8WXX7 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 28505103 f miannu Cytoplasmic AUTS2 regulates actin cytoskeleton to control neuronal migration and neurite extension, while nuclear AUTS2 controls transcription of various genes as a component of the polycomb complex 1 (PRC1). SIGNOR-266816 0.7 ING1 protein Q9UK53 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001938 15662138 f miannu Ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells. SIGNOR-254488 0.2 ATM protein Q13315 UNIPROT ABL1 protein P00519 UNIPROT up-regulates phosphorylation Ser446 PYPGIDLsQVYELLE 9606 BTO:0000938 9168116 t lperfetto Ataxia telangiectasia mutant protein activates c-abl tyrosine kinase in response to ionizing radiation. Atm kinase domain corrects this defect, as it phosphorylates the c-abl tyrosine kinase in vitro at ser 465, leading to the activation of c-abl. SIGNOR-48818 0.734 MDGA2 protein Q7Z553 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26206665 f miannu Enhanced protein expression of p53 and p21 by MDGA2 was confirmed in MDGA2 overexpressed cells and xenograft tumours. SIGNOR-264241 0.2 F10 protein P00742 UNIPROT APOH protein P02749 UNIPROT down-regulates activity cleavage Lys336 HSSLAFWKTDASDVK -1 9596664 t lperfetto In the previous study, we found that factor Xa can produce the nicked form by cleaving Lys 317-Thr 318, using recombinant human domain V (r-Domain V). |The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI. SIGNOR-266997 0.394 NBEAL2 protein Q6ZNJ1 UNIPROT VAC14 protein Q08AM6 UNIPROT unknown binding 10090 BTO:0000132 29187380 t lperfetto In summary, from 129 binding partners of Nbeal2 identified by mass spectrometry, we have confirmed the interaction of 3, Dock7, Sec16a, and Vac14, by different biochemical and cellular approaches|Given the significant reduction of Dock7 levels and its altered localization in Nbeal2−/− platelets, we postulated that this canonical signaling pathway may be disrupted and set out to test this using control and Nbeal2−/− platelets. SIGNOR-261892 0.303 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys22 GPRDGLKkERLLDDR 9606 9990853 t gcesareni We report here the identification of an ikappab-ubiquitin (ub) ligase complex containing the f-box/wd40-repeat protein, beta-trcp, a vertebrate homolog of drosophila slimb. beta-trcp binds to ikappabalpha only when the latter is specifically phosphorylated by an ikappab kinase complex. here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha. SIGNOR-64321 0.522 WWP2 protein O00308 UNIPROT POLR2A protein P24928 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0001938 31048545 t lperfetto WWP2 ubiquitylates RNA polymerase II for DNA-PK-dependent transcription arrest and repair at DNA breaks|In response to DSBs, WWP2 targets the RNAPII subunit RPB1 for K48-linked ubiquitylation, thereby driving DNA-PK- and proteasome-dependent eviction of RNAPII. SIGNOR-268851 0.396 AXL protein P30530 UNIPROT AXL protein P30530 UNIPROT up-regulates activity phosphorylation Tyr866 EVHPAGRyVLCPSTT -1 9178760 t llicata Our data showed that various receptor substrates are at least associated with the C-terminal tyrosine pY821. Two additional potential autophosphorylation sites (pY866 and pY779) may play a minor role in binding of e€ector proteins SIGNOR-250593 0.2 MAPK10 protein P53779 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates activity phosphorylation Ser284 RRDYDDMsPRRGPPP 11231586 t miannu Mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) efficiently phosphorylates hnRNP-K both in vitro and in vivo at serines 284 and 353. Our results establish the role of MAPK/ERK in phosphorylation-dependent cellular localization of hnRNP-K, which is required for its ability to silence mRNA translation. SIGNOR-250082 0.345 RYK protein P34925 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 15454084 t gcesareni Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled SIGNOR-129574 0.413 GSK3B protein P49841 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization phosphorylation Ser184 NLLQSPSsILSTLDV 9606 BTO:0000567 21757741 t miannu Here, we demonstrate that glycogen synthase kinase-3β (GSK3β) phosphorylates securin to promote its proteolysis via SCF(βTrCP) E3 ubiquitin ligase. SIGNOR-276344 0.2 PRKCE protein Q02156 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity phosphorylation -1 15894802 t inferred from family member lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-270280 0.404 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207090 0.8 NFX1 protein Q12986 UNIPROT PABPC1 protein P11940 UNIPROT up-regulates activity binding 9606 BTO:0004117 17267499 t miannu NFX1-123 augments the activation of hTERT expression through interactions with PABPCs SIGNOR-226011 0.35 TFEB protein P19484 UNIPROT PPARA protein Q07869 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Notably, TFEB regulates genes involved in several steps of lipid catabolism, which occur in different cellular compartments, such as the transport of fatty acid chains across the plasma membrane (for example, Cd36 and Fabps), and the β-oxidation of FFA in mitochondria (for example, Cpt1, Crat, Acadl, Acads and Hdad) and in peroxisomes (Cyp4a genes). SIGNOR-276706 0.281 MED29 protein Q9NX70 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266658 0.761 AAK1 protein Q2M2I8 UNIPROT NUMB protein P49757 UNIPROT unknown phosphorylation Thr102 LRVVDEKtKDLIVDQ 9606 18657069 t llicata Numb is phosphorylated by aak1, while little aak1-dependent phosphorylation is observed in t102a numb immunoprecipitants SIGNOR-179610 0.471 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 t lperfetto Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes. SIGNOR-233441 0.387 PCDHA12 protein Q9UN75 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265673 0.2 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1763 TPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273108 0.745 CCR4-NOT complex complex SIGNOR-C439 SIGNOR RC3H1 protein Q5TC82 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 t lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins SIGNOR-268348 0.336 Vincristine sulfate chemical CHEBI:79401 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0000142 30599272 t miannu Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. SIGNOR-259254 0.8 PRKAA1 protein Q13131 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser358 WPLSRTRsEPLPPSA 9606 SIGNOR-C15 21892142 t gcesareni Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs). SIGNOR-176491 0.276 trametinib chemical CHEBI:75998 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity chemical inhibition 9606 26347206 t miannu Trametinib (Mekinist™) is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 with anticancer activity against metastatic melanoma carrying the BRAF V600 mutation. SIGNOR-259446 0.8 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser408 GPLPRAPsISTVEPK 26190112 t Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. SIGNOR-253541 0.301 CAMK2G protein Q13555 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser568 PQATRQTsVSGPAPP 3118371 t llicata Sites 2 and 3 are serine residues phosphorylated by calcium/calmodulin-dependent protein kinase II. SIGNOR-250707 0.457 AKT1 protein P31749 UNIPROT SOX2 protein P48431 UNIPROT up-regulates quantity by stabilization phosphorylation Thr116 KYRPRRKtKTLMKKD 9606 BTO:0002428 30894683 t miannu Phosphorylation of SOX2 at threonine 116 by AKT inhibits the interaction of UBR5 with SOX2 and thus stabilizes SOX2.  SIGNOR-277445 0.547 NLGN4Y protein Q8NFZ3 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264143 0.2 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-263007 0.784 GRK2 protein P25098 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates activity phosphorylation Thr356 FREFCIPtSSNIEQQ 9606 BTO:0000007 12123746 t gcesareni These results suggest that two C-terminal amino acids, Ser(355) and Thr(357), are required for short-term homologous desensitization and agonist-induced phosphorylation of mu-opioid receptors expressed in HEK 293 cells SIGNOR-247782 0.2 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Ser523 GVSDVPTsPTLQRPT 9606 21841788 t lperfetto The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570. SIGNOR-176054 0.2 PRKG1 protein Q13976 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser443 PQRKSQRsSYVSMRI -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The 1 IC-loop does not have consensus sequences for PKG, but we found that this enzyme phosphorylated the same sites as PKA: S422, S423 (Fig. 5A).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262756 0.322 AKT proteinfamily SIGNOR-PF24 SIGNOR NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 BTO:0000130 10559253 t esanto Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis. SIGNOR-72133 0.2 AMOT protein Q4VCS5 UNIPROT YAP1 protein P46937 UNIPROT down-regulates relocalization 9606 BTO:0000567 21205866 t gcesareni Our results indicate a potential tumor-suppressing role of AMOT family proteins as components of the Hippo pathway, and demonstrate a novel mechanism of YAP and TAZ inhibition by AMOT-mediated tight junction localization. These observations provide a potential link between the Hippo pathway and cell contact inhibition. SIGNOR-201135 0.727 TRPM7 protein Q96QT4 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser5 sEFLKQAW 9606 24103589 t lperfetto Trpm7 was responsible for phosphorylation of the serine 5 (ser5) residue [29]. In 2009, the study focused on an association between anxa1 and trpm7 confirmed the presence of a trpm7/annexin a1/mg2_+ complex, suggesting a novel pathway in bradykinin signaling, dependent on pkc and c-src [30]. Even though that pathway is not fully characterized, the same team that discovered the ser5 phosphorylation of anxa1 also reported crucial relevance of this modification for anxa1 membrane binding and especially for the interaction between annexin a1 and its known partner, the calcium binding protein s100a11 SIGNOR-202804 0.56 EPHB2 protein P29323 UNIPROT RASA1 protein P20936 UNIPROT up-regulates binding 9606 9233798 t gcesareni We have localized an in vitro rasgap-binding site to conserved tyrosine residues y604 and y610 in the juxtamembrane region of ephb2, and demonstrated that substitution of these amino acids abolishes ephrin-b1-induced signalling events in ephb2-expressing ng108-15 cells. SIGNOR-50100 0.558 PRKCZ protein Q05513 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249291 0.378 YBX1 protein P67809 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17072343 f miannu YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. SIGNOR-255612 0.249 SMURF1 protein Q9HCE7 UNIPROT UVRAG protein Q9P2Y5 UNIPROT down-regulates activity ubiquitination Lys517 ENERLQYkTPPPSYN 9606 BTO:0000007 30686098 t miannu Here we report that UVRAG is ubiquitinated by SMURF1 at lysine residues 517 and 559, which decreases the association of UVRAG with RUBCN and promotes autophagosome maturation. However, the deubiquitinase ZRANB1 specifically cleaves SMURF1-induced K29 and K33-linked polyubiquitin chains from UVRAG, thereby increasing the binding of UVRAG to RUBCN and inhibiting autophagy flux.  SIGNOR-273652 0.2 GATA6 protein Q92908 UNIPROT PLXNA2 protein O75051 UNIPROT up-regulates quantity by expression transcriptional regulation 19666519 f lperfetto Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes. SIGNOR-253149 0.247 KLF1 protein Q13351 UNIPROT FLI1 protein Q01543 UNIPROT down-regulates activity binding 10090 BTO:0004475 12556498 t irozzo The present study also shows that EKLF itself inhibits FLI-1 activity. As suggested above for the inhibition of EKLF activity, the inhibition of FLI-1 activity most probably involves the indirect recruitment of EKLF to FLI-1 target promoters by protein-protein interaction. SIGNOR-256046 0.378 MAPK3 protein P27361 UNIPROT RPS6KA2 protein Q15349 UNIPROT up-regulates phosphorylation 9606 8939914 t gcesareni Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms SIGNOR-44949 0.707 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 BTO:0000007 16582879 t Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR SIGNOR-248409 0.78 RNMT protein O43148 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity chemical modification 9606 27422871 t lperfetto Maturation and translation of mRNA in eukaryotes requires the addition of the 7-methylguanosine cap. In vertebrates, the cap methyltransferase, RNA guanine-7 methyltransferase (RNMT), has an activating subunit, RNMT-Activating Miniprotein (RAM). Here we report the first crystal structure of the human RNMT in complex with the activation domain of RAM. SIGNOR-268316 0.8 CSNK2B protein P67870 UNIPROT RNF7 protein Q9UBF6 UNIPROT up-regulates activity phosphorylation Thr10 DVEDGEEtCALASHS 9606 BTO:0000567 12748192 t llicata In the present study, we show the evidence that CKBBP1 is phosphorylated on threonine residue at position 10 by CKII in vitro and in vivo. Most importantly, disruption of this phosphorylation in CKBBP1 results in accumulation of IκBα and p27Kip1 in HeLa cells and inhibits cell proliferation that appears to be linked to defects in G1/S transition. SIGNOR-251081 0.335 NRG4 protein Q8WWG1 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 7477375 t Does not bind to the ERBB1, ERBB2 and ERBB3 receptors gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. SIGNOR-26280 0.684 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI CAPZA1 protein P52907 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000132 12788695 t lperfetto We further measured the ability of ppIs phosphorylated in positions D-3 and D-4 to release the F-actin capping proteins CapZ and gelsolin from OG-permeabilized platelets (Fig. 7A). Ten percent of platelet CapZ and gelsolin is found in the OG-insoluble fraction (4). PI3,4,5P3 and PI3,4P2 release both CapZ and gelsolin from these preparations. SIGNOR-261842 0.8 SGK1 protein O00141 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser1132 RDRVRSMsGGHGLRV -1 27451907 t miannu SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2.  SIGNOR-277265 0.596 CBS protein P35520 UNIPROT L-serine zwitterion smallmolecule CHEBI:33384 ChEBI down-regulates quantity chemical modification 9606 23981774 t lperfetto Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. SIGNOR-275829 0.8 GSK3B protein P49841 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser40 TQSSGKSsVLESLVG 9606 BTO:0000007 25192600 t miannu  We identified glycogen synthase kinase (GSK)3β-dependent Drp1 phosphorylation at Ser(40) and Ser(44), which increases Drp1 GTPase activity and its mitochondrial distribution and could induce mitochondrial fragmentation. SIGNOR-276849 0.397 JQ1 chemical CHEBI:137113 ChEBI BRDT protein Q58F21 UNIPROT down-regulates activity chemical inhibition -1 20871596 t lperfetto Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains. SIGNOR-261990 0.8 HOXB8 protein P17481 UNIPROT TAGLN protein Q01995 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002196 15886193 t Luana Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively SIGNOR-261642 0.2 NFE2L2 protein Q16236 UNIPROT TFB2M protein Q9H5Q4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15684387 f lperfetto Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC SIGNOR-268996 0.252 SLBP protein Q14493 UNIPROT H2AC21 protein Q8IUE6 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265406 0.2 PRPF6 protein O94906 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270625 0.763 CREBBP protein Q92793 UNIPROT INSM1 protein Q01101 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000944 17300785 f miannu The ngn3/E47 heterodimer selectively binds and activates the E-box3 of the INSM1 promoter. The endogenous ngn3 and CREB-binding protein (CBP) co-activator occupy the INSM1 promoter, resulting in hyper-acetylation of histone H3/H4 chromatin in a human neuroblastoma cell line, IMR-32. SIGNOR-253813 0.2 YBX1 protein P67809 UNIPROT TYMS protein P04818 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001023 17072343 f miannu YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. SIGNOR-255613 0.249 CHRNB3 protein Q05901 UNIPROT APC protein P25054 UNIPROT up-regulates activity binding 9606 BTO:0002916 14502292 t miannu Treatment of muscle cells with neural agrin causes tyrosine phosphorylation of the AChR β subunit and induces AChR clustering by promoting anchoring of the receptor protein to postsynaptic cytoskeleton. Regulation of acetylcholine receptor clustering by the tumor suppressor APC. By showing a direct requirement for APC in AChR clustering, our present study suggests that the Wnt/β-catenin pathway may crosstalk with the agrin signaling cascade during the formation of mammalian neuromuscular junction. SIGNOR-264261 0.2 TTK protein P33981 UNIPROT HSPA9 protein P38646 UNIPROT up-regulates phosphorylation Thr62 VVGIDLGtTNSCVAV 9606 17573779 t lperfetto Mortalin binds to mps1, and is phosphorylated by mps1 on thr62 and ser65. The phosphorylated mortalin then super-activates mps1 in a feedback manner. Mps1-associated acceleration of centrosome duplication depends on the presence of mortalin and super-activation by the thr62/ser65 phosphorylated mortalin SIGNOR-156185 0.2 ADRA1A protein P35348 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257084 0.568 MYOF protein Q9NZM1 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 23612709 f Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin SIGNOR-255466 0.7 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270390 0.8 TNFAIP3 protein P21580 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates quantity ubiquitination 9606 15258597 t The amino-terminal domain of A20, which is a de-ubiquitinating (DUB) enzyme of the OTU (ovarian tumour) family, removes lysine-63 (K63)-linked ubiquitin chains from receptor interacting protein (RIP), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex. The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation. SIGNOR-259978 0.641 BCL2 protein P10415 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 t gcesareni Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax bax/bak are kept in check by the pro-survival bcl-2 family members and also proposes that for apoptotic death to occur, all pro-survival bcl-2-like proteins present within a given cell need to be neutralised by bh3-only proteins, thereby derepressing bax/bak SIGNOR-152980 0.663 MAPK14 protein Q16539 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser287 EPLSPVSsLQASVPG 9606 16027724 t miannu ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation SIGNOR-250093 0.424 CTNNB1 protein P35222 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates activity 10090 BTO:0004086 17420453 f Overexpression of ERp5 promotes both in vitro migration and invasion and in vivo metastasis of breast cancer cells. SIGNOR-256534 0.7 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr605 KDLVSCAyQVARGME 9606 12601080 t lperfetto Fgfr signaling is under the control of tyrosine phosphorylation to elicit activation of cellular signaling cascades. Ligand binding induces receptor dimerization and transphosphorylation. Fgfr1 contains eleven tyrosine residues (tyr154, tyr280, tyr307, tyr463, tyr585, tyr605, tyr653, tyr654, tyr730 and tyr766), some of which are directly involved regulating the activity of the receptor and others bind to activate substrates leading to the activation of various transduction pathways. SIGNOR-98634 0.2 IL4 protein P05112 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 10090 12757709 f miannu These data demonstrate that following myotube formation, myotubes recruit myoblast fusion by secretion of IL-4, leading to muscle growth SIGNOR-255896 0.7 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser257 QIRLRRDsKEANARR -1 9677319 t lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. SIGNOR-249003 0.309 PAK4 protein O96013 UNIPROT PACSIN1 protein Q9BY11 UNIPROT up-regulates activity phosphorylation Ser346 SQAGDRGsVSSYDRG -1 22371566 t miannu We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. SIGNOR-263023 0.3 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser454 YVPMNPNsPPRQHSS 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249460 0.618 MPO protein P05164 UNIPROT MPO-ANCA complex SIGNOR-C474 SIGNOR up-regulates activity binding 9606 BTO:0000133 15972951 t lperfetto Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and idiopathic pauci-immune necrotizing crescentic glomerulonephritis are associated with myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic autoantibodies (ANCAs). SIGNOR-270585 0.2 SPRY4 protein Q9C004 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002058 20501643 f miannu When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. SIGNOR-253041 0.253 CSNK2A1 protein P68400 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser711 EEEEESDsSETEKED -1 21296876 t miannu CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis SIGNOR-276251 0.2 GRM4 protein Q14833 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 t miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. SIGNOR-264082 0.327 POT1 protein Q9NUX5 UNIPROT RPA1 protein P27694 UNIPROT down-regulates activity binding SIGNOR-C306 18680434 t lperfetto The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA SIGNOR-263325 0.299 lisinopril chemical CHEBI:43755 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition -1 12540854 t Monia The structure of tACE bound to the potent inhibitor lisinopril shows that the inhibitor binds in a highly ordered (overall B-factor of 15.26 A˚ 2) SIGNOR-261070 0.8 PRKCE protein Q02156 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249288 0.404 MMP19 protein Q99542 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272363 0.7 MAPK1 protein P28482 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Thr66 EPICSVNtPREVTLH -1 16226275 t lperfetto First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.| SIGNOR-249437 0.805 DLGAP4 protein Q9Y2H0 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264597 0.2 NEDD4 protein P46934 UNIPROT KCNH2 protein Q12809 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 26363003 t SARA We have previously shown that the E3 ubiquitin (Ub) ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2) targets the PY motif of hERG channels to initiate channel degradation. Although both immature and mature hERG channels contain the PY motif, Nedd4-2 selectively mediates the degradation of mature hERG channels. SIGNOR-260998 0.271 IRX1 protein P78414 UNIPROT H2BC21 protein Q16778 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. SIGNOR-261660 0.2 RNF4 protein P78317 UNIPROT SP1 protein P08047 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 21983342 t miannu Here, we identified RNF4 as the ubiquitin E3 ligase of Sp1. From in vitro and in vivo experiments, we found that sumoylated Sp1 can recruit RNF4 as a ubiquitin E3 ligase that subjects sumoylated Sp1 to proteasomal degradation.  SIGNOR-272720 0.398 PRKACA protein P17612 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser13 ITSAARRsYVSSGEM -1 2155236 t miannu GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments. SIGNOR-249711 0.286 PER1 protein O15534 UNIPROT SLC5A1 protein P13866 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000195 22526585 f miannu Our findings suggest that PER1 exerts an indirect suppressive effect on SGLT1, possibly acting via other clock-controlled genes binding to non-E-box sites on the SGLT1 promoter. SIGNOR-254912 0.343 PPP1CA protein P62136 UNIPROT IFIH1 protein Q9BYX4 UNIPROT up-regulates activity dephosphorylation Ser88 EALRRTGsPLAARYM 9606 BTO:0000007 23499489 t lperfetto Exogenous PP1alpha or PP1gamma substantially decreased the S88 phosphorylation of Flag-MDA5|we identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation. SIGNOR-264577 0.2 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR SAV1 protein Q9H4B6 UNIPROT up-regulates activity phosphorylation 9606 21084559 t miannu Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst. SIGNOR-256184 0.2 OGT protein O15294 UNIPROT PFK proteinfamily SIGNOR-PF79 SIGNOR down-regulates activity glycosylation 9606 BTO:0000007 22923583 t lperfetto O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway| O-GlcNAc transferase (OGT) catalyzes the transfer of N-acetylglucosamine from uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) to serine or threonine residues SIGNOR-267586 0.353 DOK1 protein Q99704 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257681 0.301 CHN1 protein P15882 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260499 0.652 FOXO1 protein Q12778 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-142147 0.2 UBE3A protein Q05086 UNIPROT PSMC2 protein P35998 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 28559284 t lperfetto Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits. SIGNOR-265132 0.394 EGFR protein P00533 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr725 AGGGSATyMDQAPSP 9606 11751923 t llicata Novel activation of stat5b in response to epidermal growth factor. novel activation of stat5b in response to epidermal growth factor. SIGNOR-113393 0.827 MC4R protein P32245 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256940 0.273 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser61 PLSTPCSsVPSSPSF 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159369 0.2 MEN1 protein O00255 UNIPROT MLL Fusion fusion protein SIGNOR-FP14 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 t miannu We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity. SIGNOR-260130 0.2 eletriptan chemical CHEBI:50922 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 BTO:0000567 10193663 t Luana This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues  SIGNOR-258339 0.8 sapropterin smallmolecule CHEBI:59560 ChEBI GCHFR protein P30047 UNIPROT up-regulates activity chemical activation 9606 11361142 t miannu The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine SIGNOR-252204 0.8 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr246 SCGVDGDyEDAELNP 9606 BTO:0000007 8955135 t lperfetto In the present study, we demonstrate that bcr tyr-246 and at least one of the closely spaced tyrosine residues, tyr-279, tyr-283, and tyr- 289 (3y cluster), are phosphorylated by fes both in vitro and in 32p(i)- labeled cells. tyrosine phosphorylation of bcr by fes suppressed bcr serine/threonine kinase activity toward the 14-3-3 protein and bcr substrate, bap-1. SIGNOR-45330 0.375 GDNF protein P39905 UNIPROT GFRA2 protein O00451 UNIPROT up-regulates binding 9606 9192898 t gcesareni Gdnf mediates its actions through a multicomponent receptor system composed of a ligand-binding glycosyl-phosphatidylinositol (gpi)-linked protein (designated gdnfr-alpha). SIGNOR-49184 0.66 PTCD3 protein Q96EY7 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding Q9Y2Q9 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261437 0.72 CAMKK2 protein Q96RR4 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates phosphorylation Thr183 SDGEFLRtSCGSPNY 9606 21918180 t gcesareni Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli. SIGNOR-176602 0.591 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser410 GLPQRSGsNIEQYIH 9606 10455013 t lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-236772 0.2 CYP11B1 protein P15538 UNIPROT 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI down-regulates quantity chemical modification 9606 BTO:0000050 9814482 t lperfetto Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. SIGNOR-268679 0.8 VAMP2 protein P63027 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 17331077 f miannu Synaptobrevin 2/VAMP2 (vesicle-associated membrane protein 2), a critical component of the synaptic vesicle-fusion machinery. On the SV membrane, VAMP2 is engaged in a complex with synaptophysin I, which is mutually exclusive with the formation of fusogenic SNARE complexes. SIGNOR-264103 0.7 ATIC protein P31939 UNIPROT 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58467 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267327 0.8 NFIB protein O00712 UNIPROT ETV5 protein P41161 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268880 0.2 DAPK1 protein P53355 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 17339337 t gcesareni A cell-free ser(20) phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser(20) kinases.Evaluation of these calcium calmodulin kinase superfamily members as candidate ser(20) kinases in vivo has shown that only chk1 or dapk-1 can stimulate p53 transactivation and induce ser(20) phosphorylation of p53. SIGNOR-153487 0.574 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4B protein Q07343 UNIPROT up-regulates activity phosphorylation Ser133 GHSQRREsFLYRSDS 9534 BTO:0001538 12023945 t miannu Phosphorylation of long PDE4 isoforms by PKA. COS1 cells were transfected to express various long PDE4 isoforms. SIGNOR-275986 0.2 CTCF protein P49711 UNIPROT MGAT5B protein Q3V5L5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001976 21771782 f miannu By EMSA and ChIP analyses we identified two regulatory proteins, NeuroD1 and CTCF that bind to and activate the GnT-IX promoter. We also revealed that GnT-IX expression was suppressed in CTCF- and NeuroD1-depleted cells, indicating that a NeuroD1- and CTCF-dependent epigenetic mechanism governs brain-specific GnT-IX expression. SIGNOR-253826 0.2 ZFP36 protein P26651 UNIPROT EIF4E2/GIGYF1 complex complex SIGNOR-C256 SIGNOR up-regulates activity relocalization 9606 30917308 t lperfetto A key factor in this regulation is tristetraprolin (TTP), an RNA-binding protein (RBP) that recruits RNA-destabilizing factors and the translation inhibitory complex 4EHP-GIGYF1/2 to AU-rich element (ARE)-containing mRNAs SIGNOR-261014 0.2 GABRA5 protein P31644 UNIPROT GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263765 0.632 JUN protein P05412 UNIPROT MTHFR protein P42898 UNIPROT up-regulates 9606 18065414 f lperfetto The induction of MTHFR was also observed after overexpression of inositol-requiring enzyme-1 (IRE1) and was inhibited by a dominant-negative mutant of IRE1. Because IRE1 triggers c-Jun signaling, we examined the possible involvement of c-Jun in up-regulation of MTHFR. Transfection of c-Jun and two activators of c-Jun (LiCl and sodium valproate) increased MTHFR expression SIGNOR-253147 0.275 RNF7 protein Q9UBF6 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates activity ubiquitination 9606 23136067 t miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. SIGNOR-271451 0.2 DYRK1B protein Q9Y463 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates phosphorylation Tyr273 LGQRIYQyIQSRFYR 9606 10910078 t lperfetto Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site SIGNOR-79810 0.2 calcium(2+) smallmolecule CHEBI:29108 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni The wnt/ca2+ signaling pathway is defined by the activation of plc (phospholipase c) through wnt/fzd resulting in an increase in intracellular ca2+ levels, which activate pkcs (protein kinase c) and camkii (calcium-calmodulin-dependent kinase ii) or cn (calcineurin), a phosphatase that activates the transcription factor nfat (nuclear factor of activated t cell). SIGNOR-198822 0.8 PRKCG protein P05129 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276018 0.2 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCB protein P05771 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191493 0.8 MAPK3 protein P27361 UNIPROT LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Thr891 NSETSSDtPEMSLSA 10090 BTO:0000944 11581251 t lperfetto Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL. SIGNOR-249470 0.425 SCF-SKP2 complex SIGNOR-C136 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity ubiquitination 9606 20852628 t gcesareni The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain SIGNOR-243551 0.573 Neuronal AP-3 complex SIGNOR-C445 SIGNOR Melanosome_assembly phenotype SIGNOR-PH180 SIGNOR up-regulates 9606 22203680 f miannu Lysosome-related organelles (LROs) 6 are present in a range of cells in multicellular eukaryotes and include lytic granules, lung lamellar bodies, platelet-dense granules, and melanosomes (1.). The melanosome of the pigment cells in the skin and eye is the best studied of the LROs (1., 2.). The biogenesis of the melanosome and other LROs requires the AP-3 adaptor complex, the class C Vps complex, and three BLOC (biogenesis of lysosome-related organelles complex) complexes SIGNOR-268522 0.7 SMO protein Q99835 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 23074268 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-199159 0.496 CDC25A protein P30304 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR up-regulates activity dephosphorylation 9606 BTO:0000093 11154267 t lperfetto Cyclin E-Cdk2 complexes from p16INK4a-expressing MCF-7 cells are activated in vitro and in vivo by Cdc25A SIGNOR-245452 0.736 MAPK8IP2 protein Q13387 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates binding 9606 10490659 t These data demonstrated that JIP2 increases JNK activation by the MLK signaling pathway gcesareni These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins. SIGNOR-70866 0.557 SMURF proteinfamily SIGNOR-PF29 SIGNOR BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 t inferred from 70% family members gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps SIGNOR-270212 0.2 EGFR protein P00533 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 14967450 t lperfetto The egf-r coimmunoprecipitated with p85 alpha SIGNOR-121959 0.803 GRIP1 protein Q9Y3R0 UNIPROT KIF5C protein O60282 UNIPROT up-regulates activity binding 9606 BTO:0000142 31757889 t miannu HAP1 and GRIP1 are kinesin-1 adaptors that have been implicated individually in the transport of vesicular cargoes in the dendrites of neurons. We find that HAP1a and GRIP1 form a protein complex in the brain, and co-operate to activate the kinesin-1 subunit KIF5C in vitro SIGNOR-264061 0.329 EIF2B4 protein Q9UI10 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269132 0.744 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MAP3K8 protein P41279 UNIPROT down-regulates binding 9606 22435554 t lperfetto Tpl-2 is stoichiometrically complexed with the nf-kb inhibitory protein, nf-kb1 p105, and the ubiquitin-binding protein abin-2, both of which are required to maintain tpl-2 protein stability. Binding to p105 also prevents tpl-2 from phosphorylating mek SIGNOR-216289 0.553 CTDSPL protein O15194 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser214 PTSSDPGsPFQMPAD 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248316 0.477 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MED1 protein Q15648 UNIPROT up-regulates phosphorylation 9606 12356758 t inferred from 70% family members lperfetto Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase SIGNOR-270106 0.2 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120000 0.781 CSNK2A1 protein P68400 UNIPROT EIF5 protein P55010 UNIPROT up-regulates activity phosphorylation Ser174 DKENGSVsSSETPPP 9606 11861906 t llicata Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis. SIGNOR-250861 0.402 KIF1C protein O43896 UNIPROT RAB6C protein Q9H0N0 UNIPROT up-regulates quantity relocalization -1 20360680 t miannu Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation. SIGNOR-266879 0.247 AURKA protein O14965 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Thr210 YDGERKKtLCGTPNY 9606 18615013 t gcesareni We find that aurora a (aurka) can directly phosphorylate plk1 on thr 210;activation of plk1 requires phosphorylation of a conserved threonine residue (thr 210). SIGNOR-179422 0.65 EIF4A3 protein P38919 UNIPROT Exon junction complex complex SIGNOR-C369 SIGNOR form complex binding -1 16923391 t miannu The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. SIGNOR-265240 0.946 AKT2 protein P31751 UNIPROT ADARB1 protein P78563 UNIPROT down-regulates activity phosphorylation Thr553 LQGERLLtMSCSDKI -1 31095429 t miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively SIGNOR-276196 0.2 nintedanib chemical CHEBI:85164 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 18559524 t Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. SIGNOR-257800 0.8 AP-3 complex complex SIGNOR-C247 SIGNOR Melanosome_assembly phenotype SIGNOR-PH180 SIGNOR up-regulates 9606 22203680 f lperfetto Lysosome-related organelles (LROs) 6 are present in a range of cells in multicellular eukaryotes and include lytic granules, lung lamellar bodies, platelet-dense granules, and melanosomes (1.). The melanosome of the pigment cells in the skin and eye is the best studied of the LROs (1., 2.). The biogenesis of the melanosome and other LROs requires the AP-3 adaptor complex, the class C Vps complex, and three BLOC (biogenesis of lysosome-related organelles complex) complexes SIGNOR-265941 0.7 CSNK1D protein P48730 UNIPROT GJA1 protein P17302 UNIPROT up-regulates activity phosphorylation Ser330 AGSTISNsHAQPFDF 10116 BTO:0000067 12270943 t lperfetto We have examined the role of casein kinase 1 (CK1) in connexin-43 (Cx43) gap junction assembly. Cellular co-immunoprecipitation experiments and in vitro CK1 phosphorylation reactions indicate that CK1 interacted with and phosphorylated Cx43, initially on serine(s) 325, 328, or 330.| To examine CK1 function, normal rat kidney cells were treated with CKI-7, and Cx43 content was analyzed by Triton X-100 extraction, cell-surface biotinylation, and immunofluorescence. Western blot analysis indicated a slight increase in total Cx43, whereas gap junctional (Triton-insoluble) Cx43 decreased, and non-junctional plasma membrane Cx43 increased (as detected by cell surface biotinylation). SIGNOR-249331 0.588 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Ala36 PESKATNaTLDPRSF -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus SIGNOR-263575 0.43 NEUROG1 protein Q92886 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 BTO:0000142 18400164 f lperfetto While the mechanisms by which Ngn2 promotes neurogenesis have been characterized, little is known about how Ngn2 confers neuronal cell-type identity during spinal cord development. Ngn1 and Ngn2, two mammalian orthologs of the Drosophila proneural bHLH gene atonal, are expressed in overlapping patterns throughout the developing nervous system and act as important regulators of developmental neurogenesis SIGNOR-265172 0.7 FOXO proteinfamily SIGNOR-PF27 SIGNOR RBL2 protein Q08999 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000944 11884591 t gcesareni Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression. SIGNOR-252934 0.2 PRKCB protein P05771 UNIPROT LASP1 protein Q14847 UNIPROT down-regulates activity phosphorylation Ser146 MEPERRDsQDGSSYR 9606 12571245 t lperfetto Actin binding of human lim and sh3 protein is regulated by cgmp- and camp-dependent protein kinase phosphorylation on serine 146. Phosphorylation of lasp at ser-146 leads to a redistribution of the actin-bound protein from the tips of the cell membrane to the cytosol, accompanied with a reduced cell migration SIGNOR-97942 0.2 GRM2 protein Q14416 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264349 0.7 TWIST2 protein Q8WVJ9 UNIPROT RAP1A protein P62834 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255508 0.2 PRKG2 protein Q13237 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization SIGNOR-186796 0.2 C3 convertase complex complex SIGNOR-C310 SIGNOR C3 protein P01024 UNIPROT up-regulates activity cleavage Arg671 QPAARRRrSVQLTEK 31331124 t lperfetto This forms the C4b2a complex, which is a classical pathway C3 convertase. C4b2a cleaves C3, which is the central component of the complement cascade, to C3a, and anaphylatoxin, and C3b results in the activation of the lytic pathway SIGNOR-263449 0.54 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR LTC4S protein Q16873 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001433 12574384 f miannu activation of NF-kappaB and p50/p65 overexpression down-regulated the LTC(4) synthase gene. LPS down-regulates cysteinyl LT release and LTC(4) synthase gene expression in mononuclear phagocytes by an NF-kappaB-mediated mechanism. SIGNOR-254799 0.26 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257926 0.8 OGDC complex SIGNOR-C397 SIGNOR succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI up-regulates quantity chemical modification 9606 15953811 t miannu The Œ±-ketoglutarate‚Äìdehydrogenase complex is a complex including multiple copies of three proteins: E1k (Œ±-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. SIGNOR-266258 0.8 ATF4 protein P18848 UNIPROT YARS2 protein Q9Y2Z4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269432 0.2 RPS6KB1 protein P23443 UNIPROT GLI1 protein P08151 UNIPROT up-regulates phosphorylation Ser84 LTKKRALsISPLSDA 9606 22439934 t gcesareni In this study, we found that an activated mtor/s6k1 pathway promotes gli1 transcriptional activity and oncogenic function through s6k1-mediated gli1 phosphorylation at ser84, which releases gli1 from its endogenous inhibitor, sufu. SIGNOR-196756 0.538 sorafenib chemical CHEBI:50924 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258285 0.8 CDK4 protein P11802 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by destabilization phosphorylation Ser105 AYTPPPVsPRFSFPG 9606 BTO:0000567 21447557 t miannu Finally, CDK4 phosphorylated GATA4 directly, which promoted the degradation of GATA4 in cultured cells. SIGNOR-276317 0.364 RAB5C protein P51148 UNIPROT EEA1 protein Q15075 UNIPROT up-regulates activity binding -1 12493736 t Federica The Rab5 effector early endosome antigen 1 (EEA1) is a parallel coiled coil homodimer with an N-terminal C(2)H(2) Zn(2+) finger and a C-terminal FYVE domain. Rab5 binds to independent sites at the N and C terminus of EEA1.|The results demonstrate that the C(2)H(2) Zn(2+) finger is both essential and sufficient for the N-terminal interaction with Rab5. SIGNOR-261266 0.827 NOTCH proteinfamily SIGNOR-PF30 SIGNOR JAG1 protein P78504 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20953350 f gcesareni Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip. SIGNOR-254348 0.2 NFY complex SIGNOR-C1 SIGNOR ID1 protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 f We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. SIGNOR-255746 0.271 PRKCB protein P05771 UNIPROT MFN1 protein Q8IWA4 UNIPROT down-regulates activity phosphorylation Ser86 AFFGRTSsGKSSVIN -1 30659190 t done miannu Here we report that βIIPKC accumulates on the mitochondrial outer membrane and phosphorylates mitofusin 1 (Mfn1) at serine 86. Mfn1 phosphorylation results in partial loss of its GTPase activity and in a buildup of fragmented and dysfunctional mitochondria in heart failure. SIGNOR-273826 0.2 CSNK1A1 protein P48729 UNIPROT CDH1 protein P12830 UNIPROT down-regulates activity phosphorylation Ser844 GSGSEAAsLSSLNSS 17353278 t lperfetto Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846 SIGNOR-274045 0.317 HDAC3 protein O15379 UNIPROT SMAD7/HDAC1/E2F-1 complex SIGNOR-C12 SIGNOR up-regulates binding 9606 23213415 t lperfetto Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes. SIGNOR-217358 0.445 RAD23B protein P54727 UNIPROT XPA protein P23025 UNIPROT up-regulates activity binding 24086043 t lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275697 0.76 TTBK2 protein Q6IQ55 UNIPROT KIF2A protein O00139 UNIPROT down-regulates activity phosphorylation Ser135 SSAQQNGsVSDISPV 9534 26323690 t Manara TTBK2 phosphorylates KIF2A primarily at growing MT ends and counteracts the depolymerization activity of KIF2A SIGNOR-260926 0.416 ADRA1B protein P35368 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257079 0.598 PRKCZ protein Q05513 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates quantity by stabilization phosphorylation Ser345 RGDGSGFsL 9606 BTO:0002181 23249950 t miannu APKC associates and phosphorylates Par6 on S345. aPKC expression stabilizes Par6 protein levels. We show that the aPKC, PKCι, interacts with TGF-β receptors through Par6 and that these proteins localize to the leading edge of migrating cells. Furthermore, Par6 phosphorylation on serine 345 by TGF-β receptors is enhanced in the presence of aPKC. aPKC kinase activity, as well as an association with Par6, were found to be important for Par6 phosphorylation. SIGNOR-276433 0.835 Immunoglobulin kappa light chain protein P0DOX7 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR form complex binding 9606 BTO:0000776 20176268 t scontino Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes. SIGNOR-268194 0.2 TP53 protein P04637 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14522900 f miannu  In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction SIGNOR-254482 0.448 SF3A2 protein Q15428 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270667 0.812 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10949026 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-81157 0.41 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267880 0.8 MAPK3 protein P27361 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 1939237 t lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. SIGNOR-22424 0.516 SCF-SKP2 complex SIGNOR-C136 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 phosphorylation:Thr187 NAGSVEQtPKKPGLR 10375532 t miannu Isolated SCF(Skp2) contained an E3 ubiquitin ligase activity towards p27. Our data thus suggest that SCF(Skp2) specifically targets p27 for degradation during cell-cycle progression.Immunodepletion of components of the complex - Cul-1, Skp1, or Skp2 - from the extract abolished p27 degradation, while addition of purified SCF(Skp2) to Skp2- depleted extract restored the capacity to degrade p27.  SIGNOR-272933 0.683 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC6 protein Q99741 UNIPROT up-regulates phosphorylation Ser106 DNQLTIKsPSKRELA 9606 10339564 t lperfetto Based on these results, we propose that phosphorylation of hscdc6 by cdks regulates dna replication of at least two steps: first, by promoting initiation of dna replication and, second, through nuclear exclusion preventing dna rereplication. hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106) SIGNOR-217272 0.94 CNR2 protein P34972 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256979 0.252 TOLLIP protein Q9H0E2 UNIPROT IRAK1 protein P51617 UNIPROT down-regulates activity binding 9606 BTO:0000007 10854325 t lperfetto Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs) SIGNOR-251980 0.792 BMI1 protein P35226 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000785 19884659 f gcesareni Chromatin immunoprecipitation assays revealed the bmi-1 transcriptionally downregulated expression of the tumor suppressor pten in tumor cells through direct association with the pten locus. SIGNOR-189040 0.566 MEF2C protein Q06413 UNIPROT CDKL5 protein O76039 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20513142 f Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression|In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5. SIGNOR-254031 0.357 Kindlin proteinfamily SIGNOR-PF48 SIGNOR AD/b2 integrin complex SIGNOR-C172 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259028 0.411 WASH complex complex SIGNOR-C258 SIGNOR ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000567 20498093 t lperfetto Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes. SIGNOR-261006 0.2 MAPK14 protein Q16539 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser291 PVSSLQAsVPGSVPG 9606 16027724 t miannu ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation SIGNOR-250094 0.424 Vincristine sulfate chemical CHEBI:79401 ChEBI TUBB protein P07437 UNIPROT down-regulates activity chemical inhibition 9606 30599272 t miannu Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. SIGNOR-259251 0.8 CSNK1E protein P49674 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-250806 0.351 PCDH19 protein Q8TAB3 UNIPROT GABRA5 protein P31644 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C335 29360992 t miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  SIGNOR-267219 0.26 SEMA3A protein Q14563 UNIPROT PLXNA2 protein O75051 UNIPROT up-regulates binding 9606 10679438 t gcesareni Plexins form stable complexes with neuropilin-1 or -2. SIGNOR-75168 0.853 CSNK1A1 protein P48729 UNIPROT AGO2 protein Q9UKV8 UNIPROT down-regulates activity phosphorylation Thr830 DSAEGSHtSGQSNGR 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276510 0.377 ANXA1 protein P04083 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0004136 17464329 f miannu We next focused on the pro-apoptotic function of ANXA1 in AML1-ETO-expressing AML cells. In this regard, FK228 was found to increase the protein levels of both the full-length and 33 kDa N-terminal cleavage products of ANXA1, which led to the localization of ANXA1 on the plasma membrane. Conversely, the inhibition of ANXA1 function (by ANXA1 neutralizing antibody, which blocked ANXA1 localization on the plasma membrane) or expression (by siRNA) significantly reduced FK228-induced apoptosis, indicating that ANXA1 is involved in apoptosis induction in response to FK228. SIGNOR-261689 0.7 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization phosphorylation Ser29 VSHWQQQsYLDSGIH -1 12432063 t miannu We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin.  SIGNOR-275998 0.541 DNMT1 protein P26358 UNIPROT RELN protein P78509 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 f miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. SIGNOR-254575 0.443 GSK3B protein P49841 UNIPROT CAP1 protein Q01518 UNIPROT up-regulates activity phosphorylation Ser308 SAPKPQTsPSPKRAT 9606 BTO:0000763 30123351 t lperfetto We found that GSK3 phosphorylates S307 and S309 by using inhibitors LiCl. Inhibition of GSK3beta can cause loss of cell polarity as well as accumulation of stress fibers. We propose that GSK3 regulates CAP1 through at least two mechanisms. First, GSK3 (and potentially other kinases) phosphorylate CAP1 at S309 and promote CAP1 localization to the cytosol. Second, phosphorylation at S309 affects protein-protein interactions with actin and cofilin. The loss of this phospho-regulation by GSK3 inhibition is expected to disrupt CAP1 function and actin dynamics. SIGNOR-264822 0.256 PLCB1 protein Q9NQ66 UNIPROT GNA11 protein P29992 UNIPROT up-regulates binding 9606 1322796 t miannu Plc-_1 stimulates hydrolysis of gq/11-bound gtp and acts as a gtpase-activating protein (gap) for its physiologic regulator, gq/11 SIGNOR-17239 0.607 MITF protein O75030 UNIPROT TPSAB1 protein Q15661 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000830 20513998 t lperfetto The transcription of tryptase gene in human mast cells is regulated by mi transcription factor |Using mutant constructs of tryptase promoter, we observed that two E-box (CANNTG) motifs including between -817 to -715 and -421 to -202 are able to involve in the transactivation of tryptase gene by MITF-A. SIGNOR-251725 0.2 SNX5 protein Q9Y5X3 UNIPROT IGF1R protein P08069 UNIPROT down-regulates quantity binding 9606 BTO:0000567 32150533 t miannu Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures. SIGNOR-269444 0.272 JQ1 chemical CHEBI:137113 ChEBI BRD2 protein P25440 UNIPROT down-regulates activity chemical inhibition -1 20871596 t lperfetto Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains. SIGNOR-261987 0.8 RELB protein Q01201 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates 9606 26385063 f miannu We have shown here for the first time the role of RelB on lymphocyte development in humans. In the absence of RelB, B cells development is arrested, resulting in poor production of immunoglobulins and specific antibodies. SIGNOR-263655 0.7 ACO2 protein Q99798 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. SIGNOR-266246 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 17053147 t gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. SIGNOR-150140 0.2 SAV1 protein Q9H4B6 UNIPROT STK3 protein Q13188 UNIPROT up-regulates binding 9606 21084559 t Sav1 interacts with Mst1/2 through the SARAH domains present in both Sav1 and Mst1/2. gcesareni Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst. SIGNOR-169829 0.827 SRC protein P12931 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr536 QKGQESEyGNITYPP 9606 14699166 t llicata Recombinant shp-1 had elevated activity subsequent to phosphorylation by src in vitro, and shp-1 variants with mutated phosphorylation sites in the c terminus, shp-1 y538f, and shp-1 y538f,y566f were less active toward src-generated phosphoproteins in intact cells. SIGNOR-120488 0.542 SMURF1 protein Q9HCE7 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity ubiquitination 9606 BTO:0002181 15817471 t In the presence of smad6 or smad7 acting as adaptors lperfetto Smurfs, which otherwise cannot directly bind to smad4, mediated poly-ubiquitination of smad4 in the presence of smad6 or smad7. Smad signaling is negatively regulated by inhibitory (i) smads and ubiquitin-mediated processes. SIGNOR-236096 0.735 PIM2 protein Q9P1W9 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by stabilization phosphorylation Thr454 RAPIIAVtRNPQTAR 9606 24142698 t miannu Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis SIGNOR-267472 0.378 MAP3K20 protein Q9NYL2 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 12220515 t gcesareni This result suggests that ZAK activates JNK/SAPK mediated by downstream target, MKK7 SIGNOR-243342 0.2 INSR protein P06213 UNIPROT BLVRA protein P53004 UNIPROT up-regulates activity phosphorylation Tyr198 EERKEDQyMKMTVCL 15870194 t lperfetto Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK).|in addition to Y198 in the YMKM motif, 2 other tyrosines, Y228 in the YLSF motif and Y291 in the C-terminus of the protein, are directly phosphorylated by IRK SIGNOR-275514 0.492 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr212 TNTYYLRtFGHNTMD 9606 16669787 t miannu We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1 SIGNOR-146521 0.539 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Ser2032 CRMGIKTsEGTPGFR 9606 BTO:0000938 20595391 t lperfetto Three putative autophosphorylation sites (thr-2031, ser-2032, and thr-2035) have been identified within the activation segment of the lrrk2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of lrrk2. SIGNOR-166466 0.2 NDN protein Q99608 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates 9606 24392140 f lperfetto In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, SIGNOR-253383 0.282 SOD1 protein P00441 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI down-regulates quantity chemical modification 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272285 0.8 PTPRC protein P08575 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity dephosphorylation Tyr1034 AIETDKEyYTVKDDR 10090 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells SIGNOR-248355 0.466 RPS6KA4 protein O75676 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD 10090 BTO:0000452 11909979 t lperfetto Using embryonic fibroblasts derived from these mice we were able to demonstrate an important role for these enzymes in the activation of CREB and the closely related transcription factor ATF1. | Our results clearly demonstrate that MSK1 and MSK2 are the major, if not the only, protein kinases that mediate the phosphorylation of CREB at Ser133 and of ATF1 at Ser63 in fibroblasts SIGNOR-249145 0.599 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu68 VEETCSYeEAFEALE -1 10556651 t lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. SIGNOR-263681 0.655 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Thr937 ADEEPEStPVPLLGS 9606 18055457 t lperfetto Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta SIGNOR-159582 0.275 CDK8 protein P49336 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Ser727 TDNLLPMsPEEFDEV 29239838 t lperfetto We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727. Here we report that phosphorylation of STAT1 S727 promotes the proliferation of AML cells with JAK-STAT pathway activation. SIGNOR-273179 0.401 MITF protein O75030 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 20530484 f miannu BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles. SIGNOR-255185 0.384 HP protein P00738 UNIPROT HBA1 protein P69905 UNIPROT down-regulates quantity binding 9606 9315856 t Regulation of binding miannu Haptoglobin forms a complex of extremely high affinity with Hb via a well-characterized globin site. Our results show that upon Hb-haptoglobin binding, the globin radical, loses its ability to be terminated by forming globin dimers. SIGNOR-251816 0.735 TFEB protein P19484 UNIPROT CD36 protein P16671 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) SIGNOR-276785 0.2 TJP1 protein Q07157 UNIPROT ARVCF protein O00192 UNIPROT up-regulates activity binding 9615 BTO:0000837 15456900 t Regulation of binding miannu We identified ARVCF as a binding partner of ZO-1 and ZO-2 and characterized the role of PDZ-domain proteins in plasma membrane and nuclear localization of ARVCF. E-cadherin, ZO-1, and ARVCF are recruited to sites of initial cell-cell contact. Binding of the ZO-1 PDZ domains per se does not facilitate membrane recruitment of ARVCF, indicating a requirement for the intact ZO-1 and possibly its association with membrane proteins and/or the cytoskeleton for this process. SIGNOR-252121 0.465 NPBWR1 protein P48145 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256675 0.41 PRKCA protein P17252 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225]. SIGNOR-96692 0.503 MAPK1 protein P28482 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR down-regulates activity phosphorylation 9606 12809513 t inferred from family member llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. SIGNOR-270303 0.425 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249317 0.754 GUCA2A protein Q02747 UNIPROT GUCY2C protein P25092 UNIPROT up-regulates binding 9606 10845107 t gcesareni Guanylins activate two receptors, gc-c and ok-gc, which are expressed in intestine and/or kidney SIGNOR-78096 0.763 MRTFB protein Q9ULH7 UNIPROT SRF protein P11831 UNIPROT up-regulates activity binding 9606 BTO:0000567 14565952 t llicata MKL2 binds to and activates SRF similar to myocardin and MKL1. SIGNOR-237671 0.2 MAPK3 protein P27361 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates activity phosphorylation Ser284 RRDYDDMsPRRGPPP 9606 11231586 t lperfetto Erk phosphorylation drives cytoplasmic accumulation of hnrnp-k and inhibition of mrna translation mitogen-activated protein kinase/extracellular-signal-regulated kinase (mapk/erk) efficiently phosphorylates hnrnp-k both in vitro and in vivo at serines 284 and 353. SIGNOR-105238 0.351 TFEB protein P19484 UNIPROT GNS protein P15586 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 f lperfetto Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14) SIGNOR-276792 0.317 PTPN2 protein P17706 UNIPROT GJA1 protein P17302 UNIPROT up-regulates dephosphorylation Tyr247 VKGKSDPyHATSGAL 9606 BTO:0000671 24849651 t lperfetto Tc-ptp dephosphorylates cx43 residues y247 and y265, dephosphorylation maintained cx43 gap junctions at the plaque and partially reversed the channel closure caused by v-src-mediated phosphorylation of cx43. SIGNOR-205097 0.33 gamma-secretase complex SIGNOR-C98 SIGNOR APP protein P05067 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 19958215 t lperfetto The production and accumulation of the beta amyloid protein (Abeta) is a key event in the cascade of oxidative and inflammatory processes that characterizes Alzheimer's disease (AD). A multi-subunit enzyme complex, referred to as gamma (gamma) secretase, plays a pivotal role in the generation of Abeta from its parent molecule, the amyloid precursor protein (APP). SIGNOR-251576 0.596 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr791 LAQAPPVyLDVLG 9606 9099755 t gcesareni In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785 SIGNOR-47183 0.2 MAPK1 protein P28482 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9534 BTO:0004055 14993270 t lperfetto We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling. SIGNOR-244916 0.745 MTA3 protein Q9BTC8 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263840 0.764 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Thr202 HDHTGFLtEYVATRW 9606 9677429 t MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade. lperfetto The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells. SIGNOR-244802 0.2 BLOC-3 complex SIGNOR-C253 SIGNOR RAB32 protein Q13637 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23174301 t lperfetto HPS1/HPS4 was active exclusively for RAB32 and RAB38. Moreover, when overexpressed with HPS1 in HeLa cells, a mitochondrially restricted form of HPS4 preferentially recruited GFP-tagged RAB32 or RAB38 – but not the related RAB7 or RAB9 – to mitochondria. Activity in both assays required both HPS1 and HPS4. Finally, depletion of HPS1 or HPS4 by siRNA in a pigmented human melanoma cell line, MNT-1, resulted in the mislocalization of RAB32. These data provide strong evidence that BLOC-3 is a selective GEF for RAB32 and RAB38  SIGNOR-260693 0.546 PRKCH protein P24723 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Ser745 FEKEKLKsQWNNDNP 9606 BTO:0000751 11700305 t lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | SIGNOR-249118 0.351 noradrenaline smallmolecule CHEBI:33569 ChEBI adrenaline smallmolecule CHEBI:33568 ChEBI up-regulates quantity precursor of 9606 7961964 t brain lperfetto In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline). SIGNOR-264183 0.8 CAPRIN2 protein Q6IMN6 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 9606 BTO:0000007 35051932 t lperfetto Transcriptional and post-transcriptional regulation of oxytocin and vasopressin gene expression by CREB3L1 and CAPRIN2|Altogether, the data indicate that CAPRIN2 binds Oxt mRNA |Therefore, we propose that CAPRIN2 facilitates post-transcriptional modifications that increase Oxt transcript stability. SIGNOR-268556 0.2 Monobutylphthalate chemical CHEBI:88522 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 9606 BTO:0000816 16326050 t miannu Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast SIGNOR-268750 0.8 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Ser85 ELLHFQAsQREEKEF 9606 SIGNOR-C14 SIGNOR-C14 17977820 t lperfetto In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I SIGNOR-158663 0.962 PTPN6 protein P29350 UNIPROT TRPV1 protein Q8NER1 UNIPROT down-regulates activity dephosphorylation 10116 25790452 t miannu Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats.|These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia. SIGNOR-277129 0.2 cetirizine chemical CHEBI:3561 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7925364 t miannu The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum. SIGNOR-258868 0.8 PTPN9 protein P43378 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation 9606 20335174 t miannu Conversely, increasing expression of PTPN9 wild type (WT) inhibits tyrosyl phosphorylation of ErbB2 and EGFR.|Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells. SIGNOR-277130 0.314 PTPRB protein P23467 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation 9606 27314562 t miannu Collectively, these results suggest that PTPRB inhibits Src activation and down -- regulation of PTPRB activates Src signalling pathway required for cell invasion in A549 cells.|Knockdown of PTPRB increased Src phosphorylation and cell invasion, which was reversed by Src inhibitor PP2. SIGNOR-277132 0.457 SESN2 protein P58004 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR down-regulates activity binding 10090 BTO:0002572 25457612 t We describe AMPK-independent mechanism of mTORC1 regulation by the Sestrins, in which the Sestrins inhibit mTORC1 localization to the lysosomes in a Rag-dependent manner through an interaction with GATOR2 SIGNOR-253560 0.709 CTCF protein P49711 UNIPROT BCL6 protein P41182 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001690 20733034 f miannu Inhibition of DNA methyltransferases decreased BCL6 mRNA abundance, suggesting a role for these methylated CpGs in positively regulating BCL6 transcription. The enhancer-blocking transcription factor CTCF bound to this intronic region in a methylation-sensitive manner. Depletion of CTCF by short hairpin RNA in neoplastic plasma cells that do not express BCL6 resulted in up-regulation of BCL6 transcription. SIGNOR-253824 0.281 IL10 protein P22301 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates activity binding 9606 BTO:0000801 26260587 t lperfetto IL10 is a classic anti-inflammatory cytokine and its molecular signalling pathway has been well characterized in macrophages and T lymphocytes. Secreted IL10 cytokine binds to the IL10 receptor 1 (IL10R1) on membrane surfaces, and IL10R1 dimerizes with IL10R2 to exert its downstream effects. SIGNOR-249544 0.911 spermine smallmolecule CHEBI:15746 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 14617280 f apalma Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism SIGNOR-255552 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR NUAK1 protein O60285 UNIPROT up-regulates phosphorylation Ser600 PARQRIRsCVSAENF 9606 12409306 t esanto Ser(600) in ark5 was found to be phosphorylated by active akt resulting in the activation of kinase activity. SIGNOR-95247 0.2 CDK2 protein P24941 UNIPROT ZBTB16 protein Q05516 UNIPROT down-regulates phosphorylation Ser197 SFGLSAMsPTKAAVD 9606 BTO:0001271 18246121 t llicata Here we show that the main cyclin-dependent kinase involved at the g(1) to s transition (cdk2) phosphorylates plzf at two consensus sites found within pest domains present in the hinge region of the protein. This phosphorylation triggers the ubiquitination and subsequent degradation of plzf, which impairs plzf transcriptional repression ability and antagonizes its growth inhibitory effects. SIGNOR-160626 0.286 MACF1 protein Q9UPN3 UNIPROT LRP6 protein O75581 UNIPROT up-regulates 9606 BTO:0000938 16815997 f flangone Macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. SIGNOR-147457 0.301 PPM1G protein O15355 UNIPROT SNRPN protein P63162 UNIPROT up-regulates quantity by stabilization dephosphorylation 9606 17984321 t lperfetto Dephosphorylation of survival motor neurons (SMN) by PPM1G and PP2Cgamma governs Cajal body localization and stability of the SMN complex.|This indicates that the catalytic activity of PPM1G promotes accumulation of the SMN complex in CBs and suggests that PPM1G is a major determinant of the SMN-complex localization in the nucleus. SIGNOR-277021 0.2 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000567 17615152 t gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-156848 0.657 lovastatin chemical CHEBI:40303 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0000318 9727070 t miannu The antihypercholesterolemic drug lovastatin also activated hPXR as did phenobarbital and the organochlorine pesticide transnonachlor (Fig. 4 A). Thus, hPXR is activated by a remarkably diverse group of synthetic compounds that are known to induce CYP3A4 gene expression (Fig. 4 C). SIGNOR-258828 0.8 ROCK1 protein Q13464 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 19386264 t lperfetto Activation of ezrin is mediated by initial pip2 binding and subsequent phosphorylation of threonine 567. We performed an in vitro kinase assay with 80 selected kinases on an ezrin peptide containing the t567 phosphorylation site (figure 3a). In this screen, we identified the mst and rock kinases as the most potent kinases for the ezrin peptide SIGNOR-185567 0.722 MAP1LC3C protein Q9BXW4 UNIPROT ATG3 protein Q9NT62 UNIPROT up-regulates activity binding 10090 BTO:0002572 22170151 t lperfetto Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe SIGNOR-191552 0.773 PFK proteinfamily SIGNOR-PF79 SIGNOR β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. SIGNOR-266470 0.8 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 20444238 t gcesareni Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis. SIGNOR-165216 0.695 DZIP3 protein Q86Y13 UNIPROT ATXN1 protein P54253 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 24326307 t miannu HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation. SIGNOR-272078 0.496 SHANK3 protein Q9BYB0 UNIPROT GRIA3 protein P42263 UNIPROT up-regulates quantity binding 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264603 0.2 NCBP3 protein Q53F19 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates activity relocalization 9606 26382858 t lperfetto The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. SIGNOR-268364 0.8 MAPK1 protein P28482 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser668 INTKALQsPKRPRSP 9606 10648599 t lperfetto Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation. SIGNOR-74296 0.372 JAG1 protein P78504 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 18660822 t Binding Calcium-dependent. gcesareni Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch. SIGNOR-179622 0.624 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates quantity by destabilization phosphorylation Thr273 SPSVHPAtPISPGRA 9606 BTO:0002181 16046550 t miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. SIGNOR-268220 0.2 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser280 RSPSPQPsSHVAPQD 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252336 0.635 FYN protein P06241 UNIPROT NMT1 protein P30419 UNIPROT unknown phosphorylation Tyr180 YTLLNENyVEDDDNM -1 11594778 t Human NMT was found to be phosphorylated by non-receptor tyrosine kinase family members of Lyn, Fyn and Lck. Tyr100 is the principle phosphorylation site on hNMT for Lyn and Fyn. The significance of a phosphorylation-dependent interaction between NMT and a tyrosine kinase is not known at present. SIGNOR-251179 0.39 GPR17 protein Q13304 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256835 0.36 LYN protein P07948 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). SIGNOR-276186 0.2 HIF-1 complex complex SIGNOR-C418 SIGNOR PDK1 protein Q15118 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16517405 t miannu Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. SIGNOR-267446 0.419 RUNX2 protein Q13950 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004958; BTO:0002648 9182762 f Giulio Giuliani Indeed, we identified Osf2/Cbfa1 binding sites in the promoter of four genes expressed only (the Osteocalcin genes) or highly (Œ±1(I) collagen, Bsp, and Osteopontin) in osteoblasts. Each of these elements was able to bind Osf2/Cbfa1. SIGNOR-255408 0.595 DVL2 protein O14641 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity 9606 19279717 t areggio Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin SIGNOR-258979 0.271 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 t lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 SIGNOR-161617 0.736 KCNC3 protein Q14003 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 11506885 t miannu Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height SIGNOR-265587 0.8 (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI up-regulates quantity precursor of 9606 21876188 t lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. SIGNOR-268233 0.8 CAK complex complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser376 LKSKKGQsTSRHKKL 9606 9315650 t llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase. SIGNOR-269328 0.446 SLITRK1 protein Q96PX8 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 19640509 f miannu Phosphorylation of SLITRK1 on the CK2 phosphorylation site modulated SLITRK1-enhanced neurite outgrowth. SIGNOR-273658 0.7 MTR protein Q99707 UNIPROT homocysteine smallmolecule CHEBI:17230 ChEBI down-regulates quantity chemical modification 9606 10520212 t lperfetto Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. SIGNOR-253142 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 20151718 t inferred from 70% family members miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-270128 0.2 HARS1 protein P12081 UNIPROT histidine smallmolecule CHEBI:27570 ChEBI down-regulates quantity chemical modification 9606 10430027 t miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. SIGNOR-270486 0.8 N-(2,6-difluorophenyl)-5-[3-[2-[5-ethyl-2-methoxy-4-[4-(4-methylsulfonyl-1-piperazinyl)-1-piperidinyl]anilino]-4-pyrimidinyl]-2-imidazo[1,2-a]pyridinyl]-2-methoxybenzamide chemical CHEBI:91401 ChEBI INSR protein P06213 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192883 0.8 Halcinonide chemical CHEBI:31663 ChEBI SMO protein Q99835 UNIPROT up-regulates activity chemical activation 10090 20439738 t gcesareni We identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling. SIGNOR-248265 0.8 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT unknown phosphorylation Ser25 SSSEDEDsDHEDKDR 9606 16717095 t lperfetto Together, these data make a strong case for ck2 phosphorylation events within the serines 18-20 and 25 sites in vivo. hey also show that phosphorylation of ser-25 and ser-296 plays no additional role in g__ expression. SIGNOR-146837 0.36 Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR Respiratory electron transport chain phenotype SIGNOR-PH141 SIGNOR up-regulates 30030361 f lperfetto The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA). SIGNOR-262141 0.7 PRKCB protein P05771 UNIPROT IBTK protein Q9P2D0 UNIPROT down-regulates phosphorylation Ser1203 LHSVSSKsFRDFLLE 9606 BTO:0000776 21482705 t llicata We found that ibtk_ is phosphorylated at serines 87 and 90 by pkc on bcr engagement;this phosphorylation causes the dissociation of the btk:ibtk_ complex and allows btk to translocate to the plasma membrane. SIGNOR-173387 0.334 G3BP1 protein Q13283 UNIPROT DDX58 protein O95786 UNIPROT down-regulates activity binding 9606 BTO:0002181 30804210 t SARA G3BP1 binds RIG-I and that this interaction involves the C-terminal RGG domain of G3BP1, G3BP1 significantly enhances RIG-I-induced ifn-b mRNA synthesis. SIGNOR-260980 0.345 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Thr514 TTTPKGGtPAGSARG 10116 16611631 t lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro SIGNOR-146015 0.452 PRR5 protein P85299 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-205621 0.665 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267515 0.8 CSNK2A2 protein P19784 UNIPROT MYCN protein P04198 UNIPROT unknown phosphorylation Ser261 TSGEDTLsDSDDEDD -1 1425701 t llicata Analysis of phosphorylation sites in synthetic peptides of this acidic region identified the major sites phosphorylated by CKII as Ser261 and Ser263. SIGNOR-251014 0.375 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates phosphorylation 9606 20086174 t inferred from 70% of family members lperfetto We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2. SIGNOR-269944 0.406 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259703 0.8 TNRC6B protein Q9UPQ9 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity binding -1 17891150 t miannu The assay showed that full-length TNRC6B binds full-length human AGO2. We have identified and molecularly dissected important sequence and structure features in the conserved Ago hooks of S. pombe Tas3 and human TNRC6B. The effect of Ago hook peptides from the shuttling P-body component TNRC6B in our miRNA-mediated translational repression assay (Fig. 5b), in particular, hints at a novel regulatory role of Ago hooks in miRNA-mediated gene repression mechanisms. SIGNOR-269680 0.788 MAPK3 protein P27361 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Ser529 SPMFKFSsPIVKSTE 9606 19767751 t llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. SIGNOR-188143 0.4 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 t Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. SIGNOR-248831 0.626 ARHGDIA protein P52565 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity guanine nucleotide exchange factor 10116 BTO:0000526 20696765 t miannu Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays.RhoGDIα is required for Sema5A-induced Rac1 inactivation and inhibition of cell invasion in C6 glioma. SIGNOR-268436 0.804 SCH 23390 chemical CHEBI:73297 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258732 0.8 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120252 0.321 TNIP1 protein Q15025 UNIPROT TAX1BP1 protein Q86VP1 UNIPROT up-regulates activity relocalization 21885437 t lperfetto ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi. SIGNOR-275735 0.462 PRTN3 protein P24158 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage Phe41 DRVYIHPfHLVIHNE -1 11747312 t miannu Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen. SIGNOR-256314 0.261 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser31 QDVLGEEsPLGKPAM 9606 SIGNOR-C14 SIGNOR-C14 12657630 t IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376. IKK≈í‚⧠mediates IKK≈í‚â• phosphorylation under physiologic signaling conditions. IKK≈í‚â• is chronically phosphorylated in cells expressing the HTLV1 Tax oncoprotein, which interfaces directly with the I≈í‚à´B kinase complex.both Tax and TNF induce phosphorylation of human IKK≈í‚â• at Ser-31, Ser-43, and Ser-376. SIGNOR-251285 0.962 AKT proteinfamily SIGNOR-PF24 SIGNOR ZNF322 protein Q6U7Q0 UNIPROT up-regulates activity phosphorylation Thr262 IVHQRVHtGEKPYKC 9606 BTO:0002552 31399647 t miannu We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A. SIGNOR-276753 0.2 2-hydroxyglutarate smallmolecule CHEBI:132941 ChEBI FOXP3 protein Q9BZS1 UNIPROT down-regulates activity chemical inhibition 9606 33114536 f Luana Moreover, glutamate oxaloacetate transaminase 1 (GOT1), an enzyme involved in glutamine metabolism, exerts pro-inflammatory effects by producing 2-hydroxyglutarate, which hinders the expression of FOXP3 and thus blocks the formation of Tregs. SIGNOR-268042 0.8 MAP1LC3A protein Q9H492 UNIPROT O-phosphoethanolamine smallmolecule CHEBI:17553 ChEBI up-regulates binding 9606 22170151 t gcesareni Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe SIGNOR-191546 0.8 MAPK7 protein Q13164 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates phosphorylation Ser180 LTDPRLLsPQQPALQ 9606 BTO:0000567 10849446 t lperfetto Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b. the sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo. SIGNOR-236041 0.693 KATNAL2 protein Q8IYT4 UNIPROT KATNB1 protein Q9BVA0 UNIPROT up-regulates activity binding 9606 BTO:0000567 10751153 t miannu Katanin, a heterodimeric microtubule-severing ATPase, is found localized at mitotic spindle poles. In this paper we demonstrate that human p60 katanin and the C-terminal domain of human p80 katanin both bind microtubules in vitro. Association of these two proteins results in an increased microtubule affinity and increased microtubule-severing activity in vitro. Association of these subunits in transfected HeLa cells increases microtubule disassembly activity and targeting to spindle poles.  SIGNOR-267180 0.603 CAMK2D protein Q13557 UNIPROT ITPR2 protein Q14571 UNIPROT down-regulates activity phosphorylation Ser150 EKNAMRVsLDAAGNE 9534 BTO:0001538 23019322 t miannu Phopho-specific antibodies demonstrate that InsP(3)R2 Ser-150 is phosphorylated in vivo by CaMKIIδ. The results of this study show that serine 150 of the InsP(3)R2 is phosphorylated by CaMKII and results in a decrease in the channel open probability. SIGNOR-262692 0.313 NMDA receptor_2B complex SIGNOR-C348 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264133 0.7 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser82 HSISYTLsRAQTVVV -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276139 0.758 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser279 VLKRPERsQEESPPG 9606 12676583 t Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. SIGNOR-99729 0.837 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates phosphorylation Ser346 RAPSRKDsLESDSST 9606 23337587 t gcesareni Interestingly, sufu stability is regulated via dual phosphorylation at ser342/ser346 by pka and gsk3, and blocking sufu phosphorylation either by mutating ser346 to ala or by treating cultured cells with pka inhibitors attenuates sufu ciliary accumulation, whereas phospho-mimetic forms of sufu exhibits increased ciliary localization SIGNOR-119099 0.444 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR NEFL protein P07196 UNIPROT down-regulates activity binding 9606 23230147 t inferred from 70% family members miannu These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments. SIGNOR-269953 0.2 dexamethasone chemical CHEBI:41879 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 20956975 t fspada Glucocorticoids, such as dexamethasone, have been used as in vitro inducers of adipogenesis. However, the roles of the glucocorticoid receptor (gr) in adipogenesis have not been well characterized yet. Here, we show that inhibition of gr activity using the gr antagonist ru486 prevents human mesenchymal stem cell and mouse embryonic fibroblast (mef) differentiation into adipocytes SIGNOR-168562 0.8 RUNX2 protein Q13950 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0001616 16670084 t gcesareni Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein. SIGNOR-245336 0.502 PHA-680632 chemical CID:11249084 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206103 0.8 BMPR1A protein P36894 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR up-regulates activity phosphorylation 10090 19620713 t ggiuliani The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17). SIGNOR-255786 0.688 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr934 AHASDEIyEIMQKCW -1 19275932 t miannu C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis.  SIGNOR-276141 0.507 HIF-1 complex complex SIGNOR-C418 SIGNOR Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 27692180 t miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. SIGNOR-267500 0.362 Hexokinase proteinfamily SIGNOR-PF76 SIGNOR Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 18350175 f inferred from family member miannu The first step in metabolism of glucose (Glc) is usually phosphorylation, catalyzed by hexokinase. SIGNOR-267782 0.7 DUSP7 protein Q16829 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 20626350 t gcesareni The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues SIGNOR-166577 0.654 MAPK1 protein P28482 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser173 MLETLSQsPPKGVTI 9606 17475908 t miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). SIGNOR-262910 0.324 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser587 YLRPRIPsPIGFTPG 9606 22966201 t llicata Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress. SIGNOR-198996 0.328 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120256 0.321 ACVR2B protein Q13705 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 10090 21966641 t areggio It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains SIGNOR-254985 0.677 EP300 protein Q09472 UNIPROT KRT16 protein P08779 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12954631 f miannu these results suggest that Sp1 and AP1 sites in the essential promoter region are critical for EGF response, and Sp1 showed a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of EGF-induced keratin 16 gene expression. The coactivators p300/CBP could collaborate with Sp1 and c-Jun in the activation of keratin 16 promoter. SIGNOR-253904 0.2 APC protein P25054 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity binding 9606 22083140 t amattioni Apc binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex. APC cooperates with Axin to promote the phosphorylation of _-catenin by GSK3 [which requires priming phosphorylation by casein kinase 1, _-isoform (CK1_)]. SIGNOR-177230 0.919 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser403 DLAHSSEsQETISSM 9606 16943424 t lperfetto Recently we showed that atm- and hdm2-dependent ubiquitination and subsequent degradation of hdmx following dsb induction are mediated by phosphorylation of hdmx on s403, s367, and s342, with s403 being targeted directly by atm. SIGNOR-149300 0.725 RANBP2 protein P49792 UNIPROT TNPO1 protein Q92973 UNIPROT up-regulates activity binding 9606 BTO:0001938 32161167 t lperfetto Nup358(806–1306), but not other regions, efficiently recruits importin β and transportin 1 SIGNOR-262111 0.466 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates activity phosphorylation Ser14 PFSCHYPsRLRRDPF 9606 BTO:0000887 11342557 t lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation SIGNOR-107684 0.312 PHLPP1 protein O60346 UNIPROT AKT2 protein P31751 UNIPROT down-regulates dephosphorylation 9606 17386267 t gcesareni These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt / phlpp1 specifically modulates the phosphorylation of hdm2 and gsk-3alpha through akt2, whereas phlpp2 specifically modulates the phosphorylation of p27 through akt3 SIGNOR-153935 0.606 SMAD7 protein O15105 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates quantity transcriptional regulation 9606 30017632 t miannu The downstream molecules including mad2, smad3, smad4 and smad7 are involved in TGF-β1-induced EMT,while Smad7 blocks the smad3 expression SIGNOR-260437 0.597 RUNX1 protein Q01196 UNIPROT BAALC protein Q8WXS3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22493267 f miannu We show that BAALC overexpression occurs in the presence of the T allele of SNP rs62527607[GT], which creates a binding site for the activating RUNX1 transcription factor in the BAALC promoter region. The mechanism is demonstrated experimentally in vitro using luciferase reporter assays and electrophoretic mobility shift assay (EMSA) analysis. SIGNOR-255077 0.336 CTBP1 protein Q13363 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23303449 f irozzo Our findings suggest an important role of CtBP1 in the transcriptional control of p16INK4a and Brca1[.]. Breast Cancer Susceptibility Gene 1(Brca1), a core protein in DNA damage repair, was repressed by CtBP1 in melanoma cells. SIGNOR-259194 0.586 DUSP1 protein P28562 UNIPROT JUN protein P05412 UNIPROT down-regulates activity dephosphorylation 9606 26734995 t miannu However, adenovirus mediated overexpression of MKP-1 only slightly decreased JNK and c-Jun phosphorylation compared with the severe inactivation of JNK activities induced by MKK7 knockdown.|The results suggested that HDACI-induced MKP-1 contributes to inactivation of JNK instead of ERK, consistent with the previous reports in other cell types SIGNOR-277102 0.466 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1190 DIYETDYyRKGGKGL -1 2449432 t lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106518 0.2 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12226093 t The effect has been demonstrated using P10636-8 lperfetto Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease. SIGNOR-251600 0.695 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser51 LRPSTSRsLYASSPG -1 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248883 0.288 trichostatin A chemical CHEBI:46024 ChEBI HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258010 0.8 pazopanib hydrochloride chemical CHEBI:71217 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 17620431 t miannu The present study describes an orally bioavailable, ATP-competitive, multitargeted kinase inhibitor, pazopanib (GW786034), and the drug concentration requirement for maximal in vivo activity. Pazopanib is a low nanomolar inhibitor of VEGFR, PDGFR, and c-Kit tyrosine kinases. Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. SIGNOR-259167 0.8 DAP3 protein P51398 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261459 0.751 MAPK11 protein Q15759 UNIPROT MAPK11 protein Q15759 UNIPROT down-regulates activity phosphorylation Ser243 MEVVGTPsPEVLAKI -1 26976637 t miannu P38β Mitogen-Activated Protein Kinase Modulates Its Own Basal Activity by Autophosphorylation of the Activating Residue Thr180 and the Inhibitory Residues Thr241 and Ser261 SIGNOR-277215 0.2 N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine chemical CHEBI:92386 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258922 0.8 EFNA2 protein O43921 UNIPROT EPHA6 protein Q9UF33 UNIPROT up-regulates binding 9606 10072375 t tpavlidou Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8) SIGNOR-65419 0.74 CAMK2B protein Q13554 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Thr642 RSVKRNStVDCNGVV 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275789 0.275 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1189 QKGELSRsPSPFTHT 9606 BTO:0000150 10550055 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-72083 0.51 ASNS protein P08243 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267532 0.8 KDM6A protein O15550 UNIPROT HOXA9 protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260025 0.329 dexamethasone chemical CHEBI:41879 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258710 0.8 RPS6KA4 protein O75676 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-263000 0.401 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser487 AAISRELsEITTAEA 9606 BTO:0000150 17693255 t gcesareni Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression. SIGNOR-157296 0.627 PRKCA protein P17252 UNIPROT AQP1 protein P29972 UNIPROT up-regulates phosphorylation Thr157 VLCVLATtDRRRRDL 9606 BTO:0000671 17522053 t llicata Activation of protein kinase c (pkc) by 1-oleoyl-2-acetyl-sn-glycerol (oag) induced a marked increase of aqp1-dependent water permeability. This regulation was abolished in mutated aqp1 channels lacking both consensus pkc phosphorylation sites thr(157) and thr(239) (termed aqp1 deltapkc). SIGNOR-155102 0.2 PTPN1 protein P18031 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates dephosphorylation 9606 16291744 t gcesareni We show that coexpression of wild-type alpha-actinin and ptp 1b causes dephosphorylation at tyr-397 in fak. SIGNOR-141637 0.353 PRKCA protein P17252 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 10090 8662663 t lperfetto Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins.[..] This suggests a two-step model for the phosphorylation (and activation) of eIF4E by growth factors and hormones: first, dissociation of eIF4E . SIGNOR-248945 0.391 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258204 0.8 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr409 TDGLGLSyLSSHIAN -1 10210201 t llicata Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624. SIGNOR-250780 0.575 ER stress stimulus SIGNOR-ST9 SIGNOR PRNP protein F7VJQ1 UNIPROT up-regulates 9606 BTO:0000007 21478263 f ER stress specifically increases the synthesis of AltPrP from PrP cDNA. SIGNOR-253609 0.7 SWI/SNF complex complex SIGNOR-C92 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002586 12226744 f irozzo The hSNF5/INI1 gene encodes a member of the SWI/SNF chromatin remodelling complexes.Here, we show that the ectopic expression of wild-type hSNF5/INI1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into S phase of MRT cells. SIGNOR-256298 0.7 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273094 0.745 BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates activity binding 10090 10712517 t ggiuliani Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known BMP type I receptors (BR-Ia and BR-Ib) and the BMP type II receptor (BR-II). Coimmunoprecipitation studies detected the formation of heteromeric and homomeric complexes among all the BMP receptor types even in the absence of ligand. SIGNOR-255781 0.616 (RS)-Ppcc chemical CID:16726095 PUBCHEM SIGMAR1 protein Q99720 UNIPROT up-regulates activity chemical activation 9606 17328523 t Federica We suggest that 4b may act as a ơ1/ơ2 agonist and that the ơ ligands may modulate TG-2 differently. SIGNOR-261107 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr237 KQEKTPKtPKGPSSV 9606 12058066 t lperfetto Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association. SIGNOR-216749 0.417 PRKCD protein Q05655 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Ser302 GRGGRGGsRARNLPL 9606 10329716 t lperfetto Ser302 is a major k protein site phosphorylated by pkcdelta in vitrothe ability of pkc_ to inducibly bind and phosphorylate k protein may serve not only to alter the activity of k protein itself, but k protein may also provide an avenue for pkc_ to engage in a cross-talk with other k protein molecular partners in response to specific changes in the extracellular environment SIGNOR-67515 0.35 IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249505 0.703 GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268589 0.253 CAD protein P27708 UNIPROT hydrogencarbonate smallmolecule CHEBI:17544 ChEBI down-regulates quantity chemical modification 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267419 0.8 SIRT1 protein Q96EB6 UNIPROT XBP1 protein P17861-2 UNIPROT down-regulates activity deacetylation 9606 BTO:0000007 20955178 t miannu P300 increases the acetylation and protein stability of XBP1s, and enhances its transcriptional activity, whereas SIRT1 deacetylates XBP1s and inhibits its transcriptional activity.. The mRNA encoding the active spliced form of XBP1 (XBP1s) is generated from the unspliced form by IRE1 (inositol-requiring enzyme 1) during the UPR. SIGNOR-260430 0.387 CDK1 protein P06493 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates phosphorylation Thr292 ETPPRPRtPGRPLSS 9606 8114697 t gcesareni P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well SIGNOR-36116 0.474 HRH1 protein P35367 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257425 0.434 HOXD12 protein P35452 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221896 0.386 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR ST7 protein Q9NRC1 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0004297 30945288 t miannu We found that both CUL4A and CUL4B can form an E3 complex with DNA damage-binding protein 1 (DDB1) and DDB1-CUL4-associated factor 4 (DCAF4). In vitro and in vivo ubiquitination analyses indicate that CRL4DCAF4 E3 ligase specifically directs degradation of ST7 (suppression of tumorigenicity 7). SIGNOR-272309 0.2 JNK proteinfamily SIGNOR-PF15 SIGNOR ATN1 protein P54259 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000142 12812981 t inferred from 70% family members lperfetto Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment, SIGNOR-269978 0.2 GSK3B protein P49841 UNIPROT MITF protein O75030 UNIPROT up-regulates quantity by stabilization phosphorylation Ser405 QARAHGLsLIPSTGL 9606 25605940 t miannu We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here. SIGNOR-276475 0.446 FYN protein P06241 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates activity phosphorylation Tyr446 DQSRQMKyQSFNEYR -1 24970799 t miannu We report that FYN phosphorylates human COX2 on Tyr 446, and while corresponding phospho-mimetic COX2 mutation promotes COX2 activity, the phosphorylation blocking mutation prevents FYN-mediated increase in COX2 activity. FYN and LYN kinases phosphorylate COX2 on two distinct residues in vitro. SIGNOR-276644 0.398 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr536 LPLNTDAyLSLQELQ -1 10214954 t Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510. SIGNOR-251379 0.629 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates phosphorylation Tyr599 VDFREYEyDLKWEFP 9606 BTO:0001271 11971190 t lperfetto Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation SIGNOR-117583 0.2 DGC complex SIGNOR-C217 SIGNOR GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265434 0.2 ULK2 protein Q8IYT8 UNIPROT DENND3 protein A2RUS2 UNIPROT up-regulates activity phosphorylation Ser490 ELAPRNSsLRLTDTA 9606 25925668 t lperfetto ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. SIGNOR-264733 0.2 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 10090 BTO:0000944 7889942 t lperfetto We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erki phosphorylates five c-terminal sites in elk-i (s324,t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-235467 0.545 NKX2-5 protein P52952 UNIPROT NPPB protein P16860 UNIPROT unknown transcriptional regulation 15837525 f In comparison to the ANF gene, less is known about BNP promoter consensus elements that regulate gene expression by mechanical or neurohumoral agonists. A number of cis-acting elements for GATA, Nkx2.5, NF-kappaB and TEF transcription factors have recently been identified within the BNP promoter that regulate BNP expression in response to specific agonists. This review focuses on the information available regarding cis-acting determinants responsible for inducible BNP transcription. SIGNOR-253649 0.333 GGCX protein P38435 UNIPROT PROZ protein P22891 UNIPROT up-regulates activity carboxylation 9606 28125048 t lperfetto Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z SIGNOR-265926 0.487 DAPK2 protein Q9UIK4 UNIPROT DAPK2 protein Q9UIK4 UNIPROT down-regulates activity phosphorylation Ser318 VRRRWKLsFSIVSLC 9606 BTO:0000007;BTO:0000356 11230133 t llicata Autophosphorylation restrains the apoptotic activity of DRP-1 kinase by controlling dimerization and calmodulin binding. | It comprises a single autophosphorylation event mapped to Ser308 within the CaM regulatory domain. SIGNOR-251084 0.2 IFNL2 protein Q8IZJ0 UNIPROT IFNLR1 protein Q8IU57 UNIPROT up-regulates binding 9606 12469119 t gcesareni Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha. SIGNOR-96206 0.699 MAPK14 protein Q16539 UNIPROT JUNB protein P17275 UNIPROT up-regulates phosphorylation Ser79 QGSDTGAsLKLASSE 9606 15308641 t lperfetto These results clearly demonstrate that phosphorylation by p38 kinase is essential for the regulation of dmp1 transcription by junb and p300. phosphorylation of junb at ser-79 was found to be essential for its interaction with p300. SIGNOR-127545 0.492 EGR2 protein P11161 UNIPROT NAB2 protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000848 20506119 f miannu In melanoma and carcinoma cells EGR1 activates NAB2 expression. we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells. Here, we show that like EGR1, EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NAB2 promoter and are more potent activators of NAB2 transcription than EGR2. SIGNOR-253883 0.593 ITGB8 protein P26012 UNIPROT Av/b8 integrin complex SIGNOR-C185 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253290 0.829 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248736 0.727 GPKOW protein Q92917 UNIPROT DHX16 protein O60231 UNIPROT up-regulates quantity binding 25296192 t miannu In this report, we showed that GPKOW interacted directly with the DHX16/hPRP2 and with RNA. Immuno-depletion of GPKOW from HeLa nuclear extracts resulted in an inactive spliceosome that still bound DHX16. SIGNOR-266300 0.843 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1172 ISLDNPDyQQDFFPK 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-236531 0.2 CAV1 protein Q03135 UNIPROT ANXA3 protein P12429 UNIPROT up-regulates quantity relocalization 9606 BTO:0000608 26095609 f miannu There has been no study regarding the route of entry of exogenous ANXA3 in any cell type thus far. We found exogenous ANXA3 to be internalized into HCC cells through caveolin-1-mediated, but not HSPG-mediated, endocytosis. SIGNOR-262215 0.295 FBXW11 protein Q9UKB1 UNIPROT BTRC protein Q9Y297 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002419 31406304 t miannu Glucose deprivation activates AMPK kinase to phosphorylate β-TrCP1 and promotes the subsequent ubiquitination and degradation of β-TrCP1 by β-TrCP2, but does not promote β-TrCP2 degradation by β-TrCP1.  SIGNOR-277476 0.574 PPP2CB protein P62714 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation Ser664 QSAFAGFsFVNPKFE 10090 BTO:0000944 11959144 t PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex SIGNOR-248596 0.304 ERAP1 protein Q9NZ08 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI down-regulates quantity chemical modification 9606 31810556 t scontino While peptides loaded onto MHC class I molecules are 8‚Äì11 amino acid residues long (a restriction based on the size and conformation of the peptide-binding groove of MHC class I molecules), peptides translocated by TAP can be significantly longer. These peptides will be trimmed to the correct length by ERAP-1. SIGNOR-267771 0.8 PBX1 protein P40424 UNIPROT HOXB1 protein P14653 UNIPROT up-regulates activity binding -1 10052460 t 2 miannu Pbx1 and exd act as cofactors that enhance the DNA binding specificity of Hox proteins. The structure of the HoxB1–Pbx1–DNA ternary complex shows that HoxB1 and Pbx1 bind to overlapping binding sites located on opposite faces of the DNA. SIGNOR-241219 0.8 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr989 VPSSRGDyMTMQMSC 10116 BTO:0000443 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-235979 0.912 RNF216 protein Q9NWF9 UNIPROT TLR4 protein O00206 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 15107846 t miannu Here we describe how a RING finger protein, Triad3A, acts as an E3 ubiquitin-protein ligase and enhances ubiquitination and proteolytic degradation of some TLRs. Triad3A overexpression promoted substantial degradation of TLR4 and TLR9 with a concomitant decrease in signaling, but did not affect TLR2 expression or signaling.  SIGNOR-271504 0.397 GTP smallmolecule CHEBI:15996 ChEBI Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR form complex binding 9606 29735640 t miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3-guanosine triphosphate (GTP) complex. SIGNOR-275394 0.8 CTTNBP2 protein Q8WZ74 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity binding 10116 BTO:0000938 22262902 t miannu Fluorescence recovery after photobleaching further suggested that CTTNBP2 modulates the mobility of cortactin in neurons. CTTNBP2 may thus help to immobilize cortactin in dendritic spines and control the density of dendritic spines. SIGNOR-269703 0.525 6-bromo-3-(1-methyl-4-pyrazolyl)-5-(3-piperidinyl)-7-pyrazolo[1,5-a]pyrimidinamine chemical CHEBI:131165 ChEBI CHEK2 protein O96017 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206841 0.8 CDH8 protein P55286 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000567 17938208 t gianni CHD8 binds to histone H3 di- and trimethylated on lysine 4. It resides on the human U6 promoter as well as the mRNA IRF3 promoter in vivo and contributes to efficient transcription from both these promoters SIGNOR-266898 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR UBTF protein P17480 UNIPROT up-regulates phosphorylation Ser389 INKKQATsPASKKPA 9606 11698641 t lperfetto Phosphorylation of ubf at serine 388 is required for interaction with rna polymerase i and activation of rdna transcription. After g(1) progression ubf is phosphorylated at serine 388 by cdk2/cyclin e and cdk2/cyclin a. Conversion of serine 388 to glycine abolishes ubf activity SIGNOR-217304 0.371 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr476 EANYVPMtPGTFDFS 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249400 0.585 PRKCD protein Q05655 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser284 AGGGRRIsDSHEDTG 9606 BTO:0000562 17075052 t gcesareni The triple aspartic acid mutation shows greater distance between the two thick myosin filaments (affects the steric arrangement of the filament distances) in heart tissue. Mutation is cardioprotective during stress (ischemia-reprofusion injury) against apoptosis similar to isoproterenol treatment. SIGNOR-150351 0.2 NFIB protein O00712 UNIPROT ID3 protein Q02535 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268879 0.253 GRK2 protein P25098 UNIPROT SNCG protein O76070 UNIPROT down-regulates activity phosphorylation Ser124 EVAEEAQsGGD -1 10852916 t GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. Mutation of Ser124 dramatically inhibits γ-synuclein phosphorylation by GRK2 SIGNOR-251204 0.2 CSNK2A1 protein P68400 UNIPROT CDC25B protein P30305 UNIPROT up-regulates activity phosphorylation Ser187 AGSGAASsSGEDKEN -1 12527891 t llicata Mass spectrometry analysis demonstrates that at least two serine residues, Ser-186 and Ser-187, are phosphorylated in vivo. | Finally, we demonstrate that phosphorylation of CDC25B by protein kinase CK2 increases the catalytic activity of the phosphatase in vitro as well as in vivo. SIGNOR-250837 0.344 ATIC protein P31939 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267329 0.8 WYE-687 chemical CID:25229450 PUBCHEM MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck;ATP-competitive inhibitor mTOR gcesareni SIGNOR-207818 0.8 Norbinaltorphimine chemical CHEBI:81529 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258821 0.8 GART protein P22102 UNIPROT 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI down-regulates quantity chemical modification 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-267314 0.8 SF3B6 protein Q9Y3B4 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 t lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). SIGNOR-268408 0.859 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249343 0.728 ROCK1 protein Q13464 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates activity phosphorylation Ser1150 LERGRKVsIVSKPVL 9534 BTO:0000298 19103606 t miannu these results indicate that Rho-kinase can phosphorylate p190A RhoGAP at Ser1150 in COS7 cells. Similarly, the immunoblot analysis, through the use of the anti-p190A RhoGAP-pT1226 and -pS1236 antibodies, revealed that Rho-kinase can phosphorylate p190A RhoGAP at Thr1226 and Ser1236 in COS7 cells SIGNOR-276177 0.424 MAPK3 protein P27361 UNIPROT RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Thr82 HSMSVPTtPTLGFST 9606 17604322 t lperfetto In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE SIGNOR-262959 0.502 MDH1 protein P40925 UNIPROT NADH smallmolecule CHEBI:16908 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266287 0.8 RUNX2 protein Q13950 UNIPROT RUNX2/EP300 complex SIGNOR-C211 SIGNOR form complex binding 10116 BTO:0002648 12697832 t Giulio Giuliani More interestingly, the bone-specific transcriptionfactor Runx2/Cbfa1 is present in the immunoprecipitated material, strongly indicating that in osteoblastic cells expressing OC, p300 and Runx2/Cbfa1 are components of the same nuclear protein complex. SIGNOR-255419 0.464 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser641 YRYPRPAsVPPSPSL -1 6772446 t Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-. SIGNOR-253005 0.673 HTR1F protein P30939 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256673 0.426 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH22 protein Q9UJ99 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265838 0.8 CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 21295084 t amattioni Triggering of the DISC leads to caspase-8 activation. Active caspase-8 cleaves caspase-3 which, in type I cells, leads to cell death induction. SIGNOR-171767 0.715 CSNK2A1 protein P68400 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Ser485 QPDNSSDsDYDLHGA 9606 9834084 t lperfetto In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461) SIGNOR-62311 0.349 PLCG1 protein P19174 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates chemical modification 9606 21918248 t gcesareni Phospholypase c is an enzyme which catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (p(4,5)p(2)) into second messangers inositol-1,4,5-triphosphate (ins(1,4,5)p3) and dag. SIGNOR-176609 0.8 TWIST1 protein Q15672 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002590 17487558 f miannu Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells SIGNOR-255516 0.295 CFI complex complex SIGNOR-C388 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity cleavage 9606 8626397 t lperfetto Purification and characterization of human cleavage factor Im involved in the 3' end processing of messenger RNA precursors|Gel retardation experiments confirmed the results obtained by UV cross-linking. In addition, we could show that CF Im stabilizes the binding of the cleavage and polyadenylation specificity factor (CPSF) to pre-mRNA and that CPSF and CF Im together form a slower migrating complex with pre-mRNA than the single protein factors. SIGNOR-266125 0.8 PTPN11 protein Q06124 UNIPROT SYK protein P43405 UNIPROT down-regulates activity dephosphorylation 9606 23182168 t miannu Another SHP isoform, SHP-2, has been linked to negative regulation of Syk.|Syk and LAT are differentially dephosphorylated by SHP-2 and SHP-1, respectively. SIGNOR-277085 0.526 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 18073771 t amattioni Active caspase-8 then proteolytically processes and activates caspase-7 SIGNOR-256454 0.731 (R)-carnitine smallmolecule CHEBI:16347 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-268108 0.8 THRAP3 protein Q9Y2W1 UNIPROT SFPQ protein P23246 UNIPROT down-regulates binding 9606 20932480 t miannu Here we demonstrate that in resting tcells psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. Upon tcell activation, reduced gsk3 activity leads to reduced psf phosphorylation, releasing psf from trap150 and allowing it to bind cd45 splicing regulatory elements and repress exon inclusion. SIGNOR-168441 0.446 MAPK3 protein P27361 UNIPROT ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser664 QLPYYYLsPDRIPNS 9606 BTO:0000567 12670876 t lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. SIGNOR-264440 0.334 PRKCA protein P17252 UNIPROT CLIP1 protein P30622 UNIPROT down-regulates phosphorylation Ser312 ASLKRSPsASSLSSM 9606 20519438 t lperfetto Furthermore, by using phosphoproteomic analysis, we determined that s309 and s311 of clip-170 are phosphorylated in cells and mapped s311 as a protein kinase a (pka) phosphorylation site.phosphorylation of s311 may be critical for establishing the ?folded Back? Conformation of clip-170clip-170 open and folded back conformations represent active and inactive modes of the protein, respectively SIGNOR-165857 0.2 caesium(1+) chemical CHEBI:49547 ChEBI KCNJ13 protein O60928 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9620703 t miannu Figure 4 shows the response of Kir7.1 to increasing [Ba2+]o. The EC50 for Ba2+ block was 1 mM (Figure 4C), independent of the type of cell in which the channel was expressed. Other known inward rectifier K+ channels are sensitive to inhibition at much lower concentrations SIGNOR-258926 0.8 SCAF11 protein Q99590 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp333 DTVAENDdGGFSEEW -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261742 0.298 FBXW11 protein Q9UKB1 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates ubiquitination 9606 11359933 t gcesareni Here, we show that smad3 activated by tgf-beta is degraded by the ubiquitin-proteasome pathway. Smad3 interacts with a ring finger protein, roc1, through its c-terminal mh2 domain in a ligand-dependent manner. An e3 ubiquitin ligase complex roc1-scf(fbw1a) consisting of roc1, skp1, cullin1, and fbw1a (also termed betatrcp1) induces ubiquitination of smad3. SIGNOR-108240 0.264 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RARA protein P10276 UNIPROT up-regulates activity chemical activation 9606 18321241 t miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). SIGNOR-259234 0.8 INSR protein P06213 UNIPROT IRS2 protein Q9Y4H2 UNIPROT down-regulates activity phosphorylation Tyr628 PKVAYHPyPEDYGDI -1 9195949 t Tyr624 and Tyr628 are involved in the interaction between the IR and the KRLB domain of IRS-2, including tyrosine phosphorylation, and Tyr628 seems to be more important than Tyr624 in this process. the binding between the insulin receptor and the KRLB domain of IRS-2 results in tyrosine phosphorylation of the KRLB domain, and this leads to decreased binding of IRS-2 to the insulin receptor. SIGNOR-251318 0.748 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser927 DSDSVCDsGVETSFR 9606 BTO:0000567 SIGNOR-C13 10469655 t lperfetto All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391). SIGNOR-70453 0.737 MK-2461 chemical CID:44137946 PUBCHEM MERTK protein Q12866 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194381 0.8 SRC protein P12931 UNIPROT GIT1 protein Q9Y2X7 UNIPROT up-regulates activity phosphorylation Tyr284 EELAMDVyDEVDRRE 9534 BTO:0000298 24699139 t miannu Tyrosines 246 and 293 are required to hold GIT1 in a closed conformation.Hyperphosphorylation of GIT1-N by Src and pervanadate does not affect its binding in vitro to full length GIT1 proteins. Mutations Y246E and Y293E of GIT1 enhance binding to paxillin. SIGNOR-276627 0.558 CEBPA protein P49715 UNIPROT Granulocyte_differentiation phenotype SIGNOR-PH102 SIGNOR up-regulates 9606 11283671 f apalma We previously reported that the transcription factor C/EBPα is sufficient to induce granulocytic differentiation in multipotential precursor cells, and that Cebpa -knockout mice have a selective block in granulocyte maturation SIGNOR-255674 0.7 GSK3B protein P49841 UNIPROT RBM38 protein Q9H0Z9 UNIPROT down-regulates phosphorylation Ser195 DQYPYAAsPATAASF 9606 24142875 t lperfetto Here, we showed that rnpc1 is phosphorylated at ser195 by glycogen synthase kinase 3 (gsk3). We also provided evidence that ser195 phosphorylation converts rnpc1 from a repressor to an activator of p53. SIGNOR-203011 0.2 GSK3B protein P49841 UNIPROT NFATC2 protein Q13469 UNIPROT down-regulates phosphorylation 9606 15276472 t lperfetto Gsk3 was previously shown to directly phosphorylate the n-terminal regulatory domain of nfatc1, thus antagonizing the action of calcineurin and inhibiting nuclear shuttling of nfat. SIGNOR-179784 0.543 HIF1A protein Q16665 UNIPROT Metabolism phenotype SIGNOR-PH77 SIGNOR up-regulates 9606 17415528 f HIF-1 has been known as a major transcription factor for the induction of virtually all genes encoding glucose transporters and glycolytic enzymes, which allows hypoxic tumor cells to take up glucose more efficiently and metabolize pyruvate to lactate SIGNOR-256591 0.7 PDPK1 protein O15530 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation Ser474 RTHFPQFsYSASIRE 9606 15743829 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. Pdk1 phosphorylates akt-2 at thr 309 in the catalytic domain, leading to enzymatic activation. SIGNOR-134481 0.72 FGF3 protein P11487 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 t gcesareni Using fgf 1 as an internal standard we have determined the relative activity of all the other members of the fgf family. These data should serve as a biochemical foundation for determining developmental, physiological, and pathophysiological processes that involve fgf signaling pathways SIGNOR-42374 0.758 FGA protein P02671 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 16418530 f lperfetto In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. SIGNOR-253372 0.7 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89280 0.402 propranolol chemical CHEBI:8499 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9205951 t miannu The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively. SIGNOR-258614 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t inferred from 70% family members gcesareni Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus SIGNOR-270137 0.2 EIF2AK2 protein P19525 UNIPROT KDM4C protein Q9H3R0 UNIPROT down-regulates quantity by destabilization phosphorylation Ser918 MFDDGSFsRDTFPED 9606 BTO:0003016 31888886 t miannu In the absence of Wnt3a, protein kinase R phosphorylated KDM4C at Ser918, inducing KDM4C ubiquitination and degradation. SIGNOR-277497 0.2 TGFb proteinfamily SIGNOR-PF5 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates 9606 SIGNOR-C9 12524424 f fspada Because tgf-beta inhibits adipogenesis by signaling through smad3, we examined physical and functional interactions of smad3 and smad4 with c/ebpbeta, c/ebpdelta, and ppargamma2. SIGNOR-97123 0.2 NCOR2 protein Q9Y618 UNIPROT AR protein P10275 UNIPROT down-regulates acetylation 9606 BTO:0000150;BTO:0001130 12771131 t gcesareni In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases. SIGNOR-101286 0.578 RAD23B protein P54727 UNIPROT PAX3 protein P23760 UNIPROT down-regulates activity binding -1 17662948 t llicata Monoubiquitinated Pax3 was shuttled to the intrinsic proteasomal protein S5a by interacting specifically with the ubiquitin-binding protein Rad23B. SIGNOR-237667 0.298 HECW2 protein Q9P2P5 UNIPROT TP73 protein O15350 UNIPROT up-regulates quantity by stabilization ubiquitination 9534 BTO:0000298 12890487 t miannu P73 was efficiently ubiquitinated but stabilized in a NEDL2-dependent manner. Accordingly, p73 decayed at faster rates in the absence of NEDL2 than in its presence. Consistent with the NEDL2-mediated stabilization of p73, NEDL2 enhanced the p73-dependent transcriptional activation. Thus, our results suggest that NEDL2 activates the function of p73 by increasing its stability. SIGNOR-269457 0.378 NMUR2 protein Q9GZQ4 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257352 0.41 17beta-estradiol smallmolecule CHEBI:16469 ChEBI estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity precursor of -1 8099587 t Luana 17 beta-HSD type 2 was capable of catalyzing the interconversion of testosterone and androstenedione as well as estradiol and estrone.  SIGNOR-269761 0.8 EFR3A protein Q14156 UNIPROT KRAS protein P01116 UNIPROT up-regulates quantity binding 9606 BTO:0000007 34504076 t miannu EFR3A directly binds to active KRAS through its C-terminus. EFR3A promotes the localization and nanoclustering of KRAS at the plasma membrane. SIGNOR-269094 0.2 PTPN6 protein P29350 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity dephosphorylation Tyr380 TDSEEQPyLEMDLSS 9606 18086677 t Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis. SIGNOR-248477 0.361 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT up-regulates activity phosphorylation Tyr37 LINLGKNyEKAVNAM -1 21840312 t miannu Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility. SIGNOR-263041 0.398 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257717 0.552 PTPN11 protein Q06124 UNIPROT HOXA10 protein P31260 UNIPROT up-regulates dephosphorylation 9606 19022774 t fspada We also identified hoxa10 as a substrate for shp2 in undifferentiated myeloid cells, an effect that diminished during myelopoiesis. However, a constitutively active form of shp2 dephosphorylated hoxa10 throughout ex vivo myelopoiesis and sustained repression of hoxa10 target genes involved in phagocyte effector functions. SIGNOR-182475 0.38 CLK1 protein P49759 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3 SIGNOR-181031 0.261 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu63 LERECVEeTCSYEEA -1 10556651 t lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. SIGNOR-263680 0.655 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr341 GQRDSSYyWEIEASE 9606 12551923 t gcesareni We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain. SIGNOR-97639 0.588 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 22926518 t miannu The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors. SIGNOR-256181 0.63 TNF protein P01375 UNIPROT SCN11A protein Q9UI33 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253492 0.2 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258288 0.8 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 15735019 t miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates SIGNOR-134212 0.634 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0001321 15659650 t lperfetto CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37 SIGNOR-217795 0.771 HDAC8 protein Q9BY41 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity deacetylation 10090 BTO:0002882 26387755 t HDAC8 mediates CM-induced deacetylation of p53.Collectively, these results indicate that although binding to p53 and HDAC8 occurs through distinct regions of the CM protein, simultaneous interaction with HDAC8 and p53 is required for aberrant deacetylation and inactivation of p53. SIGNOR-255738 0.468 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr454 PTPPHLKyLYLVVSD 12441334 t JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 SIGNOR-251350 0.805 ZEB2 protein O60315 UNIPROT VDR protein P11473 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11432806 t Luisa ZEB, a Krüppel-type transcription factor known to repress the transcription of several genes, binds to two sites within the VDR promoter and activates the transcription of this receptor in a cell-specific manner. Transfection of ZEB into SW620 colon carcinoma cells results in an up-regulation of the expression of endogenous VDR, confirming the role of ZEB in the transcriptional activation of the VDR gene. SIGNOR-268954 0.2 PRKCD protein Q05655 UNIPROT CHAT protein P28329 UNIPROT up-regulates quantity phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000930 15381704 t lperfetto Finally, basal ChAT phosphorylation in neurons is mediated predominantly by PKC at Ser-476, with PKC activation increasing phosphorylation at Ser-440 and enhancing ChAT activity. SIGNOR-249271 0.316 MARCHF9 protein Q86YJ5 UNIPROT FCGR2B protein P31994 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271541 0.2 NUMA1 protein Q14980 UNIPROT TUBA1B protein P68363 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-116472 0.266 PRKDC protein P78527 UNIPROT PRKAG1 protein P54619 UNIPROT up-regulates activity phosphorylation Ser192 KPEFMSKsLEELQIG -1 31983282 t miannu PRKDC interacted with the AMPK complex and phosphorylated its nucleotide-sensing γ1 subunit PRKAG1/AMPKγ1 at Ser192 and Thr284, both events being significantly reduced upon the activation of the AMPK complex. Alanine substitutions of PRKDC phosphorylation sites in PRKAG1 reduced AMPK complex activation without affecting its nucleotide sensing capacity.  SIGNOR-277503 0.2 KIF5C protein O60282 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272518 0.7 RUNX1 protein Q01196 UNIPROT MECOM protein Q03112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22689058 f irozzo Our results suggest that RUNX1 and EVI1 could be regulating each other. RUNX1 would activate EVI1 transcription, and when highly expressed, EVI1 could bind to RUNX1 at protein level, inhibiting its activity as a transcription factor, acting in a negative feedback. SIGNOR-255715 0.508 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr498 KTPPAPKtPPSSGEP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249326 0.754 JAK1 protein P23458 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates activity phosphorylation Tyr496 PPALAKGyLKQDPLE 10433356 t Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation of the receptor-associated Janus tyrosine kinases, JAK1 and Tyk2. These kinases then phosphorylate specific tyrosine residues (Y446 and Y496) on the intracellular domain of the IL-10R1 chain. Once phosphorylated, these tyrosine residues (and their flanking peptide sequences) serve as temporary docking sites for the latent transcription factor, STAT3 (signal transducer and activator of transcription-3). SIGNOR-251339 0.802 PAK1 protein Q13153 UNIPROT NET1 protein Q7Z628 UNIPROT down-regulates activity phosphorylation Ser539 LTAQRRAsTVSSVTQ -1 15684429 t miannu In this work we show that the Rac/Cdc42hs-regulated protein kinase PAK1 down-regulates the activity of the RhoA-specific guanine nucleotide exchange factor NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues down-regulates the activity of NET1 as an exchange factor in vitro and its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody that recognizes NET1 phosphorylated on serine 152, we show that PAK1 phosphorylates NET1 on this site in cells and that Rac1 stimulates serine 152 phosphorylation in a PAK1-dependent manner. SIGNOR-263018 0.251 CREB5 protein Q02930 UNIPROT DGKG protein P49619 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002810 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253803 0.2 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10611223 t lperfetto Pak phosphorylates bad in vitro and in vivo on ser112 and ser136, resulting in a markedly reduced interaction between bad and bcl-2 or bcl-x(l) and the increased association of bad with 14-3-3tau. SIGNOR-73529 0.341 CABIN1 protein Q9Y6J0 UNIPROT HIRA complex 1 complex SIGNOR-C461 SIGNOR form complex binding 9606 30285846 t miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. SIGNOR-269435 0.684 PRKACA protein P17612 UNIPROT PHKA1 protein P46020 UNIPROT up-regulates activity phosphorylation 9606 10487978 t miannu Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. SIGNOR-267411 0.419 CLOCK protein O15516 UNIPROT PER1 protein O15534 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253633 0.72 ANGPT1 protein Q15389 UNIPROT TIE1 protein P35590 UNIPROT up-regulates binding 9606 11172728 t gcesareni We reasoned that there may be cooperative interactions among the angiopoietins (i.e., ligands for tie2) and tie1, the orphan receptor. SIGNOR-105199 0.463 AURKA protein O14965 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. SIGNOR-98289 0.2 SHC1 protein P29353 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates activity 10090 BTO:0000944 17673906 f lperfetto We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. SIGNOR-242625 0.613 CKM complex complex SIGNOR-C406 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation -1 25344755 t lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues SIGNOR-273160 0.378 CDON protein Q4KMG0 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity binding 9606 BTO:0000222 18678706 t lperfetto During myoblast differentiation, the promyogenic cell surface receptor cdo binds to the p38alpha/beta pathway scaffold protein jlp and, via jlp, p38alpha/beta itself SIGNOR-179867 0.442 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr332 ILAIHDSyKPEFHSD 10029 12907755 t PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates SIGNOR-248418 0.48 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257980 0.8 (S)-adrenaline smallmolecule CHEBI:40751 ChEBI ADRA1B protein P35368 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258453 0.8 TSHB protein P01222 UNIPROT SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14623893 t miannu I– uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane SIGNOR-251995 0.389 HIPK1 protein Q86Z02 UNIPROT PAGE4 protein O60829 UNIPROT up-regulates activity phosphorylation Thr51 PGQEREGtPPIEERK 9606 24559171 t Manara Here, we have identified homeodomain-interacting protein kinase 1 (HIPK1), also a component of the stress-response pathway, as a kinase that phosphorylates PAGE4 at T51 | We show that phosphorylation of PAGE4 is critical for its transcriptional activity since mutating this T residue abolishes its ability to potentiate c-Jun transactivation. SIGNOR-260929 0.468 CDK1 protein P06493 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12202491 t gcesareni Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity. SIGNOR-151799 0.557 PPP1CA protein P62136 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 12840032 t gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3) SIGNOR-103152 0.457 RXRB protein P28702 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 10882139 t lperfetto The nuclear receptor ppargamma/rxralpha heterodimer regulates glucose and lipid homeostasis SIGNOR-78907 0.654 AE/b7 integrin complex SIGNOR-C186 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269030 0.7 PRKCZ protein Q05513 UNIPROT ADD2 protein P35612 UNIPROT down-regulates phosphorylation Ser713 KKKFRTPsFLKKSKK 9606 16116087 t gcesareni We now demonstrate that ptn stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (pk) c substrate domain of beta-adducin through activation of either pkc alpha or beta. SIGNOR-139914 0.278 VEZF1 protein Q14119 UNIPROT EDN1 protein P05305 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004294 11504723 t miannu Vascular endothelial zinc finger 1 (Vezf1)/DB1 is a recently identified zinc finger-containing protein that is expressed specifically within endothelial cells during development. In this report, we demonstrate that Vezf1/DB1 is a nuclear localizing protein that potently and specifically activates transcription mediated by the human endothelin-1 promoter, in a Tax-independent manner, in transient transfection assays. Regulation of endothelin-1 promoter activity by Vezf1/DB1 provides a mechanism for endothelin-1 expression in the vascular endothelium during development and to maintain vascular tone SIGNOR-266884 0.28 PPM1L protein Q5SGD2 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates dephosphorylation Thr838 GINPCTEtFTGTLQY 9606 BTO:0000142;BTO:0000671 17456047 t gcesareni Exogenous pp2cepsilon associated with exogenous ask1 in hek-293 cells under non-stressed conditions, inactivating ask1 by decreasing thr845 phosphorylation SIGNOR-154554 0.323 selumetinib chemical CHEBI:90227 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck lperfetto SIGNOR-244823 0.8 PF-04691502 chemical CID:25033539 PUBCHEM AKT1 protein P31749 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck;inhibitor of phosphorylation of AktT308 and AktS473 gcesareni SIGNOR-252631 0.8 PPP2CB protein P62714 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 t In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. SIGNOR-248602 0.305 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR XBP1 protein P17861 UNIPROT down-regulates quantity by destabilization phosphorylation Ser181 QQVQAQLsPLQNISP 9606 BTO:0001109 23277279 t miannu Phosphorylation of XBP-1u by ERK is critical for the increased interaction of XBP-1u and FoxO1. SIGNOR-276439 0.2 BRK1 protein Q8WUW1 UNIPROT NHS protein Q6T4R5 UNIPROT up-regulates activity binding 9606 20332100 t miannu We show that the WHD of NHS interacts with the Abi family of proteins, HSPC300, Nap1 and Sra1, and is important for the localization of NHS to the leading edge. SIGNOR-253574 0.2 GEM protein P55040 UNIPROT CACNB2 protein Q08289 UNIPROT down-regulates activity binding 9606 14701738 t miannu Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively. SIGNOR-261710 0.2 PGM2 protein Q96G03 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity chemical modification 9606 17804405 t miannu Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. The role of phosphopentomutase is to utilize ribose 1-phosphate and deoxyribose 1-phosphate, which are formed by purine nucleoside phosphorylase and uridine phosphorylase. Using catalytic efficiency as a criterion, PGM2 acted more than 10-fold better as a phosphopentomutase (both on deoxyribose 1-phosphate and on ribose 1-phosphate) than as a phosphoglucomutase. SIGNOR-267076 0.8 CHD8 protein Q9HCK8 UNIPROT NEUROG1 protein Q92886 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 t Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells SIGNOR-268919 0.2 PLK1 protein P53350 UNIPROT PLEKHG6 protein Q3KR16 UNIPROT up-regulates phosphorylation Thr574 HLVVTEDtDEDAPLV 9606 BTO:0000567 18694934 t lperfetto We reported previously that a guanine nucleotide exchange factor, myogef, localizes to the central spindle, activates rhoa, and is required for cytokinesis. In this study, we have found that plk1 (polo-like kinase 1) can phosphorylate myogef, thereby recruiting myogef to the central spindle as well as enhancing myogef activity toward rhoa. The in vitro kinase assay shows that plk1 can phosphorylate myogef on threonine 574. SIGNOR-179954 0.425 SLBP protein Q14493 UNIPROT H2BC4 protein P62807 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265377 0.2 PRKCZ protein Q05513 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 15381704 t The effect has been demonstrated using P28329-3 gcesareni Finally, basal chat phosphorylation in neurons is mediated predominantly by pkc at ser-476, with pkc activation increasing phosphorylation at ser-440 and enhancing chat activity. SIGNOR-129340 0.292 CSNK1D protein P48730 UNIPROT KIR3DL1 protein P43629 UNIPROT up-regulates phosphorylation Ser388 RTANSEDsDEQDPEE 9606 17911614 t gcesareni In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover. SIGNOR-158125 0.2 SP3 protein Q02447 UNIPROT LORICRIN protein P23490 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12200429 f miannu Loricrin expression is suppressed by Jun B, Sp3, and KSR-1 proteins. SIGNOR-254537 0.2 RPL3L protein Q92901 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262494 0.754 MAP2K2 protein P36507 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates phosphorylation Thr185 HDHTGFLtEYVATRW 9606 11971971 t gcesareni Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-86709 0.734 IL13 protein P35225 UNIPROT IL13RA1 protein P78552 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica It is now known that this alternate receptor is a heterodimer, the type ii il-4 receptor or the il-13 receptor, which is comprised of IL-4R And IL-13R1. SIGNOR-100750 0.847 INSR protein P06213 UNIPROT CALM3 protein P0DP25 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t miannu The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. SIGNOR-266336 0.383 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1206 SHSFRGAyGLAMKVA 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t llicata Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate SIGNOR-187847 0.417 CBFA2T3 protein O75081 UNIPROT CBFA2T3/ZNF651 complex SIGNOR-C197 SIGNOR form complex binding 9606 BTO:0000007 20116376 t Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex. SIGNOR-253956 0.466 MAPK1 protein P28482 UNIPROT MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity SIGNOR-48338 0.583 CSNK2A1 protein P68400 UNIPROT MECOM protein Q03112 UNIPROT up-regulates activity phosphorylation Ser726 PLKMEPQsPGEVKKL 23858473 t phosphorylation site remapping based on Fig 5 lperfetto We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation. SIGNOR-273428 0.2 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-118023 0.706 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr176 PFISEGTtLKDLIYD -1 8576253 t giulio giuliani From our present data, it is not easy to deduce the mechanistic significance of serine 172 and threonine 176 of TŒ≤R-I in TGF-Œ≤ signaling. Although it was reported that TGF-Œ≤-induced phosphorylation of these residues was not detected in vivo(22), it is still possible that TŒ≤R-II may phosphorylate these residues as minor phosphorylation site(s). SIGNOR-255961 0.711 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248734 0.727 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser407 SNGVESKsLTPALCR 9606 16216881 t lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. SIGNOR-141006 0.2 PLK1 protein P53350 UNIPROT RIOK2 protein Q9BVS4 UNIPROT up-regulates activity phosphorylation Ser380 PEQIKEDsLSEESAD -1 21880710 t miannu Here, we report that the atypical protein kinase Rio2 is a novel substrate of Plk1 and can be phosphorylated by Plk1 at Ser-335, Ser-380, and Ser-548. Overexpression of Rio2 causes a prolonged mitotic exit whereas knockdown of Rio2 accelerates mitotic progression, suggesting that Rio2 is required for the proper mitotic progression. SIGNOR-262938 0.439 IKBKE protein Q14164 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0000801 20717897 t lperfetto The activated ikk complex then phosphorylates ikbalfa (an inhibitor of nf-kb) thereby targeting it for ubiquitination and proteasomal degradation. SIGNOR-167524 0.497 POLR3E protein Q9NVU0 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266129 0.845 SRT1720 chemical CID:25232708 PUBCHEM SIRT1 protein Q96EB6 UNIPROT up-regulates activity chemical activation 9606 18046409 t Selleck gcesareni Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. SIGNOR-207114 0.8 RPS6KA2 protein Q15349 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 19282669 t gcesareni The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival. SIGNOR-184591 0.381 PRSS1 protein P07477 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity cleavage Lys34 QGTNRSSkGRSLIGK -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263605 0.373 TBK1 protein Q9UHD2 UNIPROT IKBKB protein O14920 UNIPROT up-regulates binding 9606 14743216 t fstefani A physical and functional map of the human tnf-alpha/nf-kappa b signal transduction pathway. SIGNOR-121576 0.412 GPR174 protein Q9BXC1 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256900 0.2 PIP3 smallmolecule CHEBI:16618 ChEBI AKT2 protein P31751 UNIPROT up-regulates activity chemical activation 9606 21779497 t lperfetto When active, pi3k converts phosphatidylinositol (4,5)-bisphosphate (pip2) into phosphatidylinositol (3,4,5)-trisphosphate (pip3). Pip3, in turn, binds the pleckstrin homology (ph) domain of akt/pkb, stimulating its kinase activity, resulting in the phosphorylation of a host of other proteins that affect cell growth, cell cycle entry, and cell survival. SIGNOR-175247 0.8 PSEN1 protein P49768 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates cleavage 9606 SIGNOR-C98 10593990 t Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface. gcesareni Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains. SIGNOR-72886 0.789 CREBRF protein Q8IUR6 UNIPROT HERPUD1 protein Q15011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 16940180 t Luana Luman/CREB3 induces transcription of the endoplasmic reticulum (ER) stress response protein Herp through an ER stress response element. SIGNOR-261575 0.2 Dynorphin A smallmolecule CHEBI:4727 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258794 0.8 PRKACA protein P17612 UNIPROT NEDD4L protein Q96PU5 UNIPROT down-regulates phosphorylation Ser448 IRRPRSLsSPTVTLS 9606 15328345 t gcesareni Nedd4-2 was a substrate for phosphorylation by pka in vitro and in cells;three nedd4-2 residues were phosphorylated by pka and were required for camp to inhibit nedd4-2 (relative functional importance ser-327 > ser-221 > thr-246). SIGNOR-128429 0.2 SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR MBD4 protein O95243 UNIPROT up-regulates activity sumoylation Lys137 KNGETSLkPEDFDFT 31476572 t lperfetto MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro. SIGNOR-275679 0.2 PTPRG protein P23470 UNIPROT LIMK1 protein P53667 UNIPROT down-regulates activity dephosphorylation Tyr507 KPDRKKRyTVVGNPY -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254711 0.263 RPS6KA1 protein Q15418 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 18722121 t lperfetto Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity SIGNOR-217553 0.471 CSNK2A1 protein P68400 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser89 KTEESPAsDEAGEKE 9606 10739259 t lperfetto Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools. SIGNOR-76274 0.2 PHF1 protein O43189 UNIPROT HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20565746 t miannu These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression. SIGNOR-260069 0.29 PRKAA1 protein Q13131 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser314 IQEVRSKsDPIMLLK -1 33022274 t miannu AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex SIGNOR-276839 0.2 DCC protein P43146 UNIPROT CACNA1A protein O00555 UNIPROT up-regulates activity 9606 12827203 t miannu DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER. SIGNOR-268293 0.2 SMAD1/4 complex SIGNOR-C85 SIGNOR BMP4 protein P12644 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 19896409 f lperfetto BMPs first bind to and activate their transmembrane serine/threonine kinase receptors, which in turn phosphorylate the transcription factors Smad1/5/8 at its two C-terminal serines (SVS). Phosphorylated Smad1Cter binds to Smad4 (co-Smad) and translocates and accumulates in the nucleus, activating BMP-responsive genes (Fig. 2) [21] and [22], such as BMP4/7 and others. SIGNOR-248842 0.582 SMURF1 protein Q9HCE7 UNIPROT RABEP2 protein Q9H5N1 UNIPROT unknown ubiquitination -1 20804422 t miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. SIGNOR-272690 0.2 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F7 protein P08709 UNIPROT up-regulates activity cleavage Arg212 NASKPQGrIVGGKVC 9606 BTO:0000131 12524220 t lperfetto The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa. SIGNOR-263521 0.932 MAS1 protein P04201 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR down-regulates 9606 23488800 f miannu The discovery that Ang-(1-7) offsets the major biological effects of Ang II has contributed to the realization that the RAS is composed of two opposing axes. The first axis is constituted by the enzyme ACE, with Ang II as the end product, and the AT1 receptor as the main effector mediating the biological actions of Ang II. The second axis results from ACE2-mediated hydrolysis of Ang II, leading to production of Ang-(1-7), with Mas receptor as the main effector conveying the vasodilator, antiproliferative, anti-inflammatory and anti-fibrotic effects of Ang-(1-7). Activation of the ACE2/Ang-(1-7)/Mas axis decreases inflammatory cell function and fibrogenesis in diverse models of human diseases. SIGNOR-260228 0.7 COPS2 protein P61201 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270772 0.92 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Ser2624 QTRTQEGsLSARWPV -1 12186630 t lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. SIGNOR-249156 0.2 TP53 protein P04637 UNIPROT GMPS protein P49915 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599;BTO:0003477;BTO:0001670 27939741 t miannu Herein, we identified GMP synthetase (GMPS), a key enzyme of de novo purine biosynthesis, as an important p53 repression target using a large-scale proteomics approach. This p53-mediated repression of GMPS could be validated by immunoblotting in Sk-Hep1, HepG2, and HuH6 cells. SIGNOR-267342 0.387 CASP9 protein P55211 UNIPROT Apoptosome complex SIGNOR-C230 SIGNOR form complex binding -1 10206961 t lperfetto  APAF-1 binds and hydrolyzes ATP or dATP to ADP or dADP, respectively. The hydrolysis of ATP/dATP and the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9.  SIGNOR-256429 0.914 PIP4K2A protein P48426 UNIPROT 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) smallmolecule CHEBI:57795 ChEBI down-regulates quantity chemical modification 9606 9367159 t Gianni The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities'. Here we have reinvestigated the substrate specificities of these enzymes. As expected, the type I enzyme phosphorylates PtdIns-4-P at the D-5 position of the inositol ring. Surprisingly, the type II enzyme, which is abundant in some tissues, phosphorylates PtdIns-5-P at the D-4 position, and thus should be considered as a 4-OH kinase, or PIP(4)K SIGNOR-268866 0.8 PTH1R protein Q03431 UNIPROT SLC34A3 protein Q8N130 UNIPROT down-regulates quantity 28363951 f lperfetto PTH inhibits reabsorption of phosphate from the glomerular filtrate in RPT by decreasing the abundance of sodium-phosphate co-transporters NPT2a and NPT2c on the apical membrane, thus enhancing renal phosphate excretion SIGNOR-270557 0.35 HAT1 protein O14929 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys13 KGGKGLGkGGAKRHR -1 28143904 t lperfetto Histone acetyltransferase 1 is the founding member of the histone acetyltransferase superfamily and catalyzes lysine acetylation of newly synthesized histone H4|Lys12 for direct attack of the acetyl group of the cofactor.| It is postulated that histone acetylation, through charge neutralization of the cationic histone tails, weakens nucleosomal electrostatic interactions with anionic DNA, thus destabilizing internucleosomal contacts and nucleosomal structure and facilitating access to the promoter region for RNA polymerase and transcription factors. SIGNOR-264790 0.2 COPS7A protein Q9UBW8 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270771 0.914 CHRM5 protein P08912 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257351 0.358 MAPK1 protein P28482 UNIPROT ETV3 protein P41162 UNIPROT down-regulates activity phosphorylation Ser139 SSGVVPQsAPPVPTA 10090 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. Among the ERK2 substrates, we identified the E-twenty six (ETS) domain-containing protein ETV3. We determined that phosphorylation of this protein by ERK2 was functionally relevant, abrogating the DNA-binding activity of ETV3 at thousands of targets across the genome, thereby providing an additional mechanism for transcriptional regulation downstream of ERK2 activation. SIGNOR-262758 0.413 NHLRC1 protein Q6VVB1 UNIPROT PPP1R3B protein Q86XI6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 18029386 t miannu Here, we show that the laforin-malin complex downregulates PTG-induced glycogen synthesis in FTO2B hepatoma cells through a mechanism involving ubiquitination and degradation of PTG. We show here that laforin and malin play a crucial role in the regulation of glycogen biosynthesis in FTO2B hepatoma cells. In these cells, the laforin–malin complex counteracts the glycogenic effect of PTG because it promotes its ubiquitination and degradation. SIGNOR-271728 0.408 FOXO3 protein O43524 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress SIGNOR-267283 0.7 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr1097 SMIRTGEtPTKKRGI 9606 BTO:0001938 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. SIGNOR-104695 0.844 ATM protein Q13315 UNIPROT USP28 protein Q96RU2 UNIPROT down-regulates activity phosphorylation Ser67 DERVKEPsQDTVATE 31938050 t lperfetto Once all the three conservative SQ sites (S67, S495, and S714), in USP28, were mutated to alanine, the pS/TQ antibody completely could not recognize the immunoprecipitated Flag-USP28-3S/A (Figure ​Figure55D), suggesting that in response to 5'-AZA-induced stress, ATM phosphorylates USP28 at all these three sites.|We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1. We also provided evidence that ATM-mediated phosphorylation of USP28 resulted in its disassociation from KLHL2 and UCK1 destabilization. SIGNOR-275852 0.317 FOXO3 protein O43524 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates activity 9606 BTO:0000007 22931788 f AMPK signaling Gianni Forkhead box O (FOXO) transcriptional protein family members, including FOXO1 and FOXO3, are involved in the modulation of autophagy. However, whether there is redundancy between FOXO1 and FOXO3 in the ability to induce autophagy remains unclear. In this study, we showed that FOXO3 induced a transcription-dependent autophagy, and FOXO1 was required for this process. SIGNOR-261952 0.7 LRRK2 protein Q5S007 UNIPROT ARFGAP1 protein Q8N6T3 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 BTO:0000142 22363216 t gcesareni Arfgap1 is an lrrk2 kinase substrate whose gap activity is inhibited by lrrk2. The phosphorylation of arfgap1 by lrrk2 was subjected to mass spectrometry to determine the sites of phosphorylation. There was 95.3% coverage and serines(s155, s246, s284) and threonine (t189, t216, t292) are phosphorylated by lrrk2. Mutational analysis of these serine and threonine amino acids to alanine reveals that no single amino acid is the predominant phospho-amino acid. SIGNOR-196267 0.597 ESR1 protein P03372 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001248 20682797 f miannu Here, we show the histone demethylase JMJD2B is regulated by both ERalpha and HIF-1alpha, drives breast cancer cell proliferation in normoxia and hypoxia, and epigenetically regulates the expression of cell cycle genes such as CCND1, CCNA1, and WEE1. these data indicate that JMJD2B is a bona fide target of ERα and its expression in ER-positive breast cancer cells is mainly dependent on ERα. SIGNOR-263737 0.59 USF1 protein P22415 UNIPROT CBS protein P35520 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12427542 f miannu We previously described essential transactivating roles for specificity protein 1 (Sp1), Sp3, nuclear factor Y (NF-Y), and USF-1 in the regulation of the CBS-1b promoter. SIGNOR-254814 0.2 FOXF2 protein Q12947 UNIPROT TBP protein P20226 UNIPROT up-regulates activity binding -1 9722567 t miannu The human forkhead protein FREAC-2 contains two functionally redundant activation domains and interacts with TBP and TFIIB. SIGNOR-220373 0.417 bremazocine chemical CHEBI:3171 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258779 0.8 MAPK14 protein Q16539 UNIPROT MAPT protein P10636 UNIPROT up-regulates phosphorylation 9606 20626350 t lperfetto A large number of cytosolic proteins can be phosphorylated by p38 mapks, including phospholipase a2, the microtubule-associated protein tau, nhe-1, cyclin d1, cdk inhibitors, bcl2 family proteins, growth factor receptors or keratins. SIGNOR-166611 0.321 ABL1 protein P00519 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). SIGNOR-276187 0.2 PIK3CD protein O00329 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242655 0.7 LCK protein P06239 UNIPROT CD3G protein P09693 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000782 2470098 t Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex. SIGNOR-259931 0.541 MAPK3 protein P27361 UNIPROT KLC1 protein Q07866 UNIPROT down-regulates phosphorylation Ser460 YKACKVDsPTVTTTL 9606 21385839 t gcesareni Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1mutation of klc1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residueklc1ser460 is a predicted mitogen-activated protein kinase (mapk) target site, and we show that extracellular-signal-regulated kinase (erk) phosphorylates this residue in vitro. SIGNOR-172642 0.267 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK1 protein Q15835 UNIPROT down-regulates activity phosphorylation Ser21 AFIAARGsFDGSSSQ 9606 15946941 t Luana Phosphorylation of GRK1 and GRK7 by cAMP-dependent Protein Kinase Attenuates Their Enzymatic Activities | We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA. SIGNOR-260841 0.2 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 18936167 t gcesareni The autoactivation residues y1054 and y1059 are targeted by dep-1 and this results in the inhibition of kinase activity and the consequent general dephosphorylation of vegfr2. SIGNOR-181676 0.687 TRIM25 protein Q14258 UNIPROT GPI protein P06744 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 24810856 t miannu Gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF. SIGNOR-272178 0.253 CARS1 protein P49589 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 11347887 t miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. SIGNOR-270471 0.8 Laminin-10 complex SIGNOR-C182 SIGNOR A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates activity binding 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253222 0.549 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. SIGNOR-164483 0.553 PLK3 protein Q9H4B4 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Thr1343 FSDFDEKtDDEDFVP 9606 18062778 t llicata The direct phosphorylation of thr(1342) of topoisomerase iialpha by plk3 was demonstrated with an in vitro kinase assay, and overexpression of plk3 induced the phosphorylation of thr(1342) in cellular topoisomerase iialpha. it is possible that plk3 regulates the activity of topoisomerase iia by phosphorylation in a cell-cycle dependent manner. Another possibility is that plk3 regulates the activity of topoisomerase iia when the checkpoint is activated. SIGNOR-159596 0.271 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 9922370 t gcesareni The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus SIGNOR-64175 0.879 RPS6KB1 protein P23443 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 t llicata Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway, which in turn promotes the transcriptional activity of myc. SIGNOR-178590 0.309 STUB1 protein Q9UNE7 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 12239347 t miannu We now show that the chaperone-binding ubiquitin ligase CHIP efficiently ubiquitinates and down-regulates ErbB2. CHIP expression shortens the half-life of both nascent and mature ErbB2 protein. In vitro ubiquitination assay shows that CHIP serves as a ubiquitin ligase for ErbB2, and both exogenously expressed and endogenous CHIP coprecipitate with the kinase.  SIGNOR-272586 0.611 RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity 9606 23151663 f gcesareni Planar cell polarity (pcp) signalling triggers activation of the small gtpases rhoa and rac1, which in turn activate rho kinase (rock) and jun-n-terminal kinase (jnk), respectively, leading to actin polymerization and microtubule stabilization. SIGNOR-199539 0.645 GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263814 0.8 MYCT1 protein Q8N699 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity 9606 30283340 f miannu Herein, we observed that overexpression of MYCT1 induced apoptosis in HL-60 and KG-1a cells, and upregulated Bax, downregulated Bcl-2, and enhanced cleavage of caspase-3 and -9. Similar proapoptotic role of MYCT1 was also found in the AML cell xenografts. These results suggest that MYCT1 affects AML cell apoptosis by modulating the endogenous apoptotic pathways. SIGNOR-261942 0.2 CSNK2A1 protein P68400 UNIPROT CEBPD protein P49716 UNIPROT up-regulates activity phosphorylation Ser57 PAMYDDEsAIDFSAY -1 25680545 t miannu Here, we have identified the CCAAT/enhancer binding protein δ (C/EBPδ) as a new substrate for CK2. Using point mutants of C/EBPδ the major phosphorylation site for CK2 was mapped to serine 57, which is located within the transactivation domain of C/EBPδ. For proper functioning as a transcription factor C/EBPδ has to be translocated into the nucleus where it forms heterodimers with other members of the C/EBP family of proteins and ATF4. Here, we found that CK2 phosphorylation does neither influence the subcellular localization of C/EBPδ nor its interaction with C/EBPβ, but rather does CK2 phosphorylation modulate the transcriptional activity of C/EBPδ.  SIGNOR-276886 0.2 CSNK2A1 protein P68400 UNIPROT CERS6 protein Q6ZMG9 UNIPROT up-regulates activity phosphorylation Ser341 KVSKDDRsDIESSSD 9606 BTO:0000007 26887952 t miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  SIGNOR-273990 0.2 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7326 RAGSRASsRRGSDAS 9606 BTO:0004905 21295697 t lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. SIGNOR-264434 0.446 P300/PCAF complex SIGNOR-C7 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates activity acetylation Lys19 VKRLLGWkKSAGGSG 9606 17074756 t lperfetto Acetylation of the short isoform of Smad2 improves its DNA binding activity in vitro and enhances its association with target promoters in vivo, thereby augmenting its transcriptional activity. Smad2(FL) and Smad2(_E3) were also acetylated by P/CAF in vivo and the acetylation of both proteins was lost following mutation of Lys19 (Fig. 2D), suggesting that Lys19 in Smad2 is also targeted by P/CAF. SIGNOR-217607 0.618 MERTK protein Q12866 UNIPROT MERTK protein Q12866 UNIPROT up-regulates phosphorylation Tyr753 KKIYSGDyYRQGRIA 9606 8702477 t gcesareni By using a vaccinia virus expression system to express a constitutively activated form of nyk, we identified the major sites of nyk autophosphorylation in tryptic peptide iy749sgdy753y754r. Tyr-749, tyr-753, and tyr-754 in this peptide lie in the activation loop of the kinase domain. SIGNOR-42918 0.2 CDC14B protein O60729 UNIPROT APC protein P25054 UNIPROT up-regulates dephosphorylation 9606 SIGNOR-C110 18662541 t gcesareni The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1 SIGNOR-179636 0.2 NADP(3-) smallmolecule CHEBI:58349 ChEBI NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity precursor of 9606 34775382 t miannu 6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule. SIGNOR-268111 0.8 CSNK1A1L protein Q8N752 UNIPROT GLIS2 protein Q9BZE0 UNIPROT up-regulates 9606 17289029 f gcesareni We decided to focus on the interaction between _-catenin and glis2. the critical role of the first zinc finger motif was confirmed by the observation that a point mutation in the first zinc finger motif, that destroys its tetrahedral configuration, abolished the interaction. _-catenin contains several functional domains, the amino terminus interacts with gsk3_ and casein kinase i_ (ck1) binding sites while its 12 armadillo repeats provides an interface for tcf/lefs, the co-activator cbp, and several other proteins SIGNOR-152962 0.2 RNA Polymerase I complex SIGNOR-C390 SIGNOR rRNA_transcription phenotype SIGNOR-PH145 SIGNOR up-regulates 22260999 f lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266177 0.7 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr666 GWMEDYDyVHLQGKE 9606 11604500 t lperfetto The loss of activity in the cas-f668/f670 mutant is consistent with the notion that src, once initially bound by its sh3 domain, phosphorylates the tyr668/670 site to further stabilize its interaction by sh2 binding. SIGNOR-111060 0.796 serotonin smallmolecule CHEBI:28790 ChEBI HTR2C protein P28335 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264283 0.8 EN2 protein P19622 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. SIGNOR-265801 0.427 DOK1 protein Q99704 UNIPROT A6/b1 integrin complex SIGNOR-C164 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257675 0.321 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 10521487 t gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. SIGNOR-71419 0.2 RAI1 protein Q7Z5J4 UNIPROT CLOCK protein O15516 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22578325 t miannu RAI1 Transcriptionally Activates CLOCK via an Intron 1 Enhancer Element. data suggest that RAI1 binds, directly or in a complex, to the first intron of CLOCK and enhances its transcriptional activity in vitro, supporting RAI1 as a positive regulator of CLOCK and an important part of the circadian loop of transcription. Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. SIGNOR-266839 0.457 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Thr718 KEDLPVItIDPASPQ 9606 11604491 t llicata Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728. SIGNOR-111051 0.553 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr319 TSVYESPySDPEELK 10318843 t lperfetto Phosphopeptide encompassing the motif harboring tyr319, ysdp, interacted with lcksh2;tyr319-mediated binding of the sh2 domain of lck is crucial for zap-70 activation and consequently for the propagation of the signaling cascade leading to t-cell activation SIGNOR-67443 0.602 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity deacetylation 9606 BTO:0000007 14976264 t lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress SIGNOR-252994 0.909 GDNF protein P39905 UNIPROT ALCAM protein Q13740 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252177 0.2 AP 23573 chemical CHEBI:79700 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 BTO:0000887 20554235 t gcesareni Deforolimus was well tolerated on the schedule tested in this trial with toxicity and pharmacokinetic profiles that were similar to that of other mtor inhibitors. SIGNOR-166186 0.8 CSNK2B protein P67870 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-251054 0.29 NLRP3 inflammasome complex SIGNOR-C225 SIGNOR Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 f miannu Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. SIGNOR-260356 0.7 CASP3 protein P42574 UNIPROT IKBKB protein O14920 UNIPROT down-regulates cleavage Asp373 PATQCISdGKLNEGH 9606 11741536 t gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. SIGNOR-112792 0.372 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity phosphorylation Ser213 TRKLMEFsEHCAIIL 9606 BTO:0002181 9155023 t lperfetto Here we show that TbetaRII kinase is regulated intricately by autophosphorylation on at least three serine residues. Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. SIGNOR-236087 0.2 HES1 protein Q14469 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 f lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production SIGNOR-265146 0.452 canertinib chemical CHEBI:61399 ChEBI EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258196 0.8 ARAP2 protein Q8WZ64 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260453 0.493 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr68 SSLETVStQELYSIP -1 16481012 t miannu Plk3 phosphorylates Chk2 at two residues, serine 62 (S62) and serine 73 (S73) in vitro, and this phosphorylation facilitates subsequent phosphorylation of Chk2 on T68 by ATM in response to DNA damage. When the Chk2 mutant construct GFP-Chk2 S73A (serine 73 mutated to alanine) is transfected into cells, it no longer associates with a large complex in vivo, and manifests a significant reduction in kinase activity.  SIGNOR-276053 0.829 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-260127 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KAT5 protein Q92993 UNIPROT up-regulates activity phosphorylation Ser90 LPGSRPGsPEREVPA 9606 BTO:0000567 12468530 t llicata Baculovirus-based expression and purification of Tip60 combined with mass spectrometry allowed the identification of serines 86 and 90 as two major sites of phosphorylation in vivo. The phosphorylation of Tip60 was found to modulate its histone acetyltransferase activity. One of the identified phosphorylated serines, Ser-90, was within a consensus cyclin B/Cdc2 site. Ser-90 was specifically phosphorylatedin vitro by the cyclin B/Cdc2 complex. SIGNOR-250642 0.428 AMBRA1 protein Q9C0C7 UNIPROT HUWE1 protein Q7Z6Z7 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 phosphorylation:Ser1043 CRPEALNsGVEYYWD 30217973 t lperfetto AMBRA1 regulates mitophagy at two critical steps. Upon mitophagy stimulation, AMBRA1 mediates the HUWE1 E3 ubiquitin ligase translocation from cytosol to mitochondria (light blue). AMBRA1 acts as a cofactor for HUWE1 E3 ubiquitin ligase activity, favouring its binding to its substrate MFN2 (and maybe other OMM substrates) and targeting it to the proteasome SIGNOR-272962 0.2 CDK4 protein P11802 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 t gcesareni In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-176527 0.526 HRH2 protein P25021 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256777 0.43 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT up-regulates activity phosphorylation Tyr1108 TYVNTTLyEKFTYAG 9606 BTO:0001176 20973951 t miannu This phosphorylation requires a kinase competent Tie2 as well as intact tyrosines 1100 and 1106 (Y1100 and Y1106) on the receptor. This suggests that Y1100 and Y1106 on Tie2 play a role in Grb14 mediated signal transduction downstream of this receptor. SIGNOR-259833 0.2 SHC3 protein Q92529 UNIPROT GRB2 protein P62993 UNIPROT up-regulates relocalization 9606 16829981 t gcesareni In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation. SIGNOR-147865 0.812 atropine chemical CHEBI:16684 ChEBI CHRM4 protein P08173 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258390 0.8 GSK3B protein P49841 UNIPROT CLASP2 protein O75122 UNIPROT down-regulates activity phosphorylation Ser533 QGCSREAsRESSRDT 9534 BTO:0004055 19638411 t lperfetto GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells SIGNOR-264825 0.529 HSP90AB1 protein P08238 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 15861399 t miannu The unliganded AR resides predominately in the cytoplasm as a heteromeric complex with hsp90 and other chaperone proteins. These chaperone proteins maintain AR in a form that is receptive to ligand binding. Regulation of gene expression by androgen-activated AR occurs through receptor nuclear translocation, dimerization, and binding to androgen response elements (AREs) in the DNA of target genes. SIGNOR-251535 0.692 PTP4A2 protein Q12974 UNIPROT CDK2 protein P24941 UNIPROT up-regulates dephosphorylation 9606 14643450 t amattioni Cells overexpressing prl-2 exhibited enhanced cyclin-dependent kinase 2 (cdk2) activity SIGNOR-119478 0.2 ADRB3 protein P13945 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256896 0.436 INTS11 protein Q5TA45 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261462 0.2 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser706 ARIIGEKsFRRSVVG 9606 12058027 t gcesareni Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs. SIGNOR-89423 0.2 RNF216 protein Q9NWF9 UNIPROT TLR9 protein Q9NR96 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 15107846 t miannu Here we describe how a RING finger protein, Triad3A, acts as an E3 ubiquitin-protein ligase and enhances ubiquitination and proteolytic degradation of some TLRs. Triad3A overexpression promoted substantial degradation of TLR4 and TLR9 with a concomitant decrease in signaling, but did not affect TLR2 expression or signaling.  SIGNOR-271505 0.415 AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates binding 10090 21145499 t milica Because we found that multiple domains of taz/yap interacted with multiple components of the crumbs complex, which include pals1, lin7c, patj, and the crumbs regulator amot, we propose that this multifactoral interaction serves to ensure that assembly of the hippo pathway and efficient phosphorylation of taz/yap is coupled only by the assembly of the crumbs complex, rather than by any single component. SIGNOR-170361 0.326 tacedinaline chemical CHEBI:90195 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258008 0.8 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation Tyr526 LRADENYyKAQTHGK 9606 BTO:0000776 9820500 t lperfetto These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520 SIGNOR-246621 0.2 bis(2-ethylhexyl) phthalate chemical CHEBI:17747 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR). SIGNOR-268774 0.8 PDGFRB protein P09619 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 19426560 t amattioni Crk can interact directly with tyrosine kinase receptors and can transmit signals downstream SIGNOR-185667 0.592 CD36 protein P16671 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 SIGNOR-252270 0.7 ACTL6B protein O94805 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270600 0.684 ITGB1 protein P05556 UNIPROT a7/b1 integrin complex SIGNOR-C126 SIGNOR form complex binding 9606 BTO:0000222;BTO:0002319 10199978 t lperfetto The alpha7beta1 integrin is a laminin receptor on the surface of skeletal myoblasts and myofibers. Alternative forms of both the alpha7 and beta1 chains are expressed in a developmentally regulated fashion during myogenesis. These different alpha7beta1 isoforms localize at specific sites on myofibers and appear to have distinct functions in skeletal muscle. SIGNOR-241512 0.764 DOK1 protein Q99704 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257673 0.321 RPS6KA3 protein P51812 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 19282669 t lperfetto The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival. SIGNOR-184595 0.393 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. SIGNOR-268785 0.8 MAPK9 protein P45984 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates phosphorylation Ser184 FYYEILNsPEKACSL 9606 15071501 t gcesareni Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-188 SIGNOR-124031 0.2 LEPR protein P48357 UNIPROT AMPK complex SIGNOR-C15 SIGNOR down-regulates activity 9606 BTO:0003336 25343030 f miannu Leptin exerts an inhibitory effect on AMPK in the hypothalamus, thereby stimulating ACC and subsequently suppressing food intake. SIGNOR-263510 0.383 PPM1A protein P35813 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity dephosphorylation Ser127 PQHVRAHsSPASLQL 9606 33630828 t lperfetto Although the authors show an in vitro kinase assay where PPM1A supposedly dephosphorylates YAP on Ser127, Fig. 4A lacks a positive control to ensure that PPM1A purified from cells is active.|The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration. SIGNOR-276984 0.272 ROCK1 protein Q13464 UNIPROT KCNK3 protein O14649 UNIPROT down-regulates phosphorylation Ser336 IPRDLSTsDTCVEQS 9606 21838752 t lperfetto Task1 channels contain two putative rho kinase phosphorylation sites, ser(336) and ser(393) . Mutation of ser(393) rendered task1 channels insensitive to et(a) - or et(b)-mediated current inhibition. In contrast, removal of ser(336) selectively attenuated et(a) -dependent task1 regulation without affecting the et(b) pathway. SIGNOR-176025 0.2 PLEKHG5 protein O94827 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260566 0.762 FNTA protein P49354 UNIPROT KRAS protein P01116 UNIPROT up-regulates activity 9606 24294527 t lperfetto Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. SIGNOR-242559 0.39 CFAP53 protein Q96M91 UNIPROT Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR up-regulates activity binding 10090 BTO:0000379 33347437 t miannu CFAP53 associates with axonemal microtubules of tracheal cilia and interacts with dynein proteins and the docking complex (DC) SIGNOR-265547 0.2 MRPL24 protein Q96A35 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262369 0.709 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 10090 BTO:0004052 14500898 t irozzo This up-regulation required BCR-ABL tyrosine kinase activity and led to IL-3Rbetac/beta chain tyrosine phosphorylation in the absence of detectable IL-3 production. These results suggested that cytokine-independent IL-3 receptor activation could be a dominant signaling component in BCR-ABL-induced leukemogenesis. However, the IL-3Rβc/β chain could act as a cofactor in BCR-ABL-induced leukemogenesis by activation of its many known oncogenic signaling pathways. SIGNOR-256123 0.2 NLGN4X protein Q8N0W4 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 18923512 t brain lperfetto Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions. SIGNOR-264192 0.745 PRKAA1 protein Q13131 UNIPROT EP300 protein Q09472 UNIPROT down-regulates phosphorylation Ser89 SELLRSGsSPNLNMG 9606 BTO:0000801;BTO:0001271;BTO:0000876 21940946 t gcesareni The mechanism of ampk-mediated anti- inflammation involves the induction of p300 ser89 phosphor- ylation and subsequent inactivation of p300 hat activity. SIGNOR-176637 0.384 JUND protein P17535 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 13679379 t Luana Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription.  SIGNOR-261603 0.81 GRK5 protein P34947 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 16957079 t llicata Grk5 phosphorylated ser-129 of alpha-synuclein at the plasma membrane and induced translocation of phosphorylated alpha-synuclein to the perikaryal area. Grk5-catalyzed phosphorylation also promoted the formation of soluble oligomers and aggregates of alpha-synuclein. SIGNOR-149372 0.621 MAPKAPK3 protein Q16644 UNIPROT HSPB1 protein P04792 UNIPROT unknown phosphorylation Ser78 PAYSRALsRQLSSGV -1 8774846 t miannu MAPKAP kinase-3 and MAPKAP kinase-2 phosphorylated peptide substrates with similar kinetic constants and phosphorylated the same serine residues in HSP27 at the same relative rates.The three serine residues in HSP27 phosphorylated by MAPKAPK2 were also phosphorylated at the same relative rates by MAPKAP-K3 (Ser-82>>Ser-78 >Ser-15) SIGNOR-250160 0.672 SKIL protein P12757 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity binding 9606 10531062 t lperfetto Thus, SnoN can interact with Smad4 and Smad2 and inhibit their abilities to activate transcription. SIGNOR-227479 0.793 SUFU protein Q9UMX1 UNIPROT GLI3 protein P10071 UNIPROT down-regulates activity relocalization 10090 10433919 t lperfetto Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling SIGNOR-129068 0.885 HOXA9 protein P31269 UNIPROT MYCN protein P04198 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 21261500 f miannu HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5. SIGNOR-254213 0.293 CSNK1A1 protein P48729 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity phosphorylation Ser469 AHEENPEsILDEHVQ -1 17318175 t lperfetto Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling. SIGNOR-249192 0.776 HIF1A protein Q16665 UNIPROT ALDOA protein P04075 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8955077 f miannu we characterize hypoxia response elements in the promoters of the ALDA, ENO1, and Ldha genes. Our data establish that functional hypoxia-response elements consist of a pair of contiguous transcription factor binding sites at least one of which contains the core sequence 5'-RCGTG-3' and is recognized by HIF-1. These results provide further evidence that the coordinate transcriptional activation of genes encoding glycolytic enzymes which occurs in hypoxic cells is mediated by HIF-1. SIGNOR-254422 0.343 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000586 16293724 f lperfetto We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein;G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt SIGNOR-252711 0.784 YAP1 protein P46937 UNIPROT FSTL3 protein O95633 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 f gcesareni In our analysis bmp4 (bone morphogenetic protein 4) and fstl3 (follistatin-related protein 3) increased their expression in response to hyap1 s127a overexpression. SIGNOR-199072 0.2 CAMK2A protein Q9UQM7 UNIPROT ATP2A2 protein P16615 UNIPROT up-regulates activity phosphorylation Ser38 KLKERWGsNELPAEE 9606 BTO:0000007 7929371 t llicata SERCA2 and SERCA2 mutants S38A, S167A, and S531A were expressed in HEK-293 cells and tested for phosphorylation with CaM kinase. Mutant S38A was not phosphorylated, while mutants S167A and S531A were phosphorylated, suggesting that Ser38 is the site of CaM kinase phosphorylation in SERCA2. This conclusion was supported by the observation that phosphorylation of SERCA2 and mutants S167A and S531A by CaM kinase increased the Vmax for Ca2+ transport, while the Vmax for Ca2+ transport by mutant S38A was unaffected by exposure to a phosphorylation reaction mix. SIGNOR-250616 0.406 chloride smallmolecule CHEBI:17996 ChEBI Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f miannu GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-264989 0.7 CCT2 protein P78371 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 t miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). SIGNOR-272860 0.748 SRC protein P12931 UNIPROT UGT2B7 protein P16662 UNIPROT up-regulates phosphorylation Tyr438 RVINDPSyKENVMKL 9606 19289110 t gcesareni Overexpression of regular or active src, but not dominant-negative src, in 2b7-transfected cos-1 cells increased 2b7 activity and phospho-y438-2b7 by 50% SIGNOR-184613 0.35 MAX protein P61244 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity binding 9606 7954804 t 2 miannu the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. SIGNOR-240357 0.305 CDH16 protein O75309 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265855 0.373 DUSP3 protein P51452 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates activity dephosphorylation 9534 BTO:0004055 10224087 t inferred from 70% of family members Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2 SIGNOR-269907 0.2 PPP2CA protein P67775 UNIPROT MAPK15 protein Q8TD08 UNIPROT down-regulates dephosphorylation Thr175 GPEDQAVtEYVATRW 9606 16336213 t lperfetto Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif. Dephosphorylation of the threonine residue by pp2a (protein serine/threonine phosphatase 2a) decreased erk8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by ptp1b (protein tyrosine phosphatase 1b) decreased activity by only 15-20% SIGNOR-142977 0.293 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 SIGNOR-C3 10942774 t lperfetto Mammalian target of rapamycin-dependent phosphorylation of phas-i in four (s/t)p sites detected by phospho-specific antibodies. SIGNOR-80797 0.924 thapsigargin chemical CHEBI:9516 ChEBI ATP2A2 protein P16615 UNIPROT down-regulates activity chemical inhibition 9534 30814986 t lperfetto Treatment of Vero cells with SERCA-specific inhibitor (Thapsigargin) at a concentration that is nontoxic to the cells significantly reduced Peste des petits ruminants virus (PPRV) and Newcastle disease virus (NDV) replication. |Thapsigargin inhibits NDV-induced SERCA2 expression in Vero cells SIGNOR-262021 0.8 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL1B protein P01584 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001412 8021507 t In these studies, we show that NF-kappa B induces transcription from the human pro-IL-1 beta (IL-1 beta) gene. SIGNOR-255938 0.569 AMP smallmolecule CHEBI:456215 ChEBI adenosine smallmolecule CHEBI:16335 ChEBI up-regulates quantity precursor of -1 18940592 t Luana Specifically, PAP dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine and activates A1-adenosine receptors in dorsal spinal cord. SIGNOR-269738 0.8 IL15 protein P40933 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 t gcesareni The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex. SIGNOR-108815 0.848 CDK1 protein P06493 UNIPROT FANCG protein O15287 UNIPROT up-regulates phosphorylation Ser387 PRFSPPPsPPGPCMP 9606 15367677 t gcesareni S387a mutant abolished fancg fusion protein phosphorylation by cdc2. SIGNOR-129061 0.361 KHDRBS1 protein Q07666 UNIPROT CREBBP protein Q92793 UNIPROT down-regulates activity binding 9606 BTO:0000093 12496368 t miannu These results suggest that Sam68 and CBP interact in vivo in a manner dependent on the FXE/DXXXL motif. Sam68 Represses CBP-dependent Transcriptional Activation SIGNOR-266202 0.387 H2AC4 protein P04908 UNIPROT CENP-A nucleosome complex SIGNOR-C321 SIGNOR form complex binding -1 23324462 t miannu In vitro assembly of both yeast and human CENP-A nucleosomes yields standard octameric structures containing two copies each of CENP-A, H2A, H2B and H4 histones. Human CENP-A also produces rigidified homotypic CENP-A/H4 tetramers in vitro. SIGNOR-263700 0.2 PROS1 protein P07225 UNIPROT AXL protein P30530 UNIPROT up-regulates binding 9606 7867073 t gcesareni We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function. SIGNOR-34483 0.477 quetiapine chemical CHEBI:8707 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258534 0.8 IL15 protein P40933 UNIPROT IL15RA protein Q13261 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 17709786 t Interleukin-15 specificity and high affinity binding are conferred by the IL-5-specific but nonsignaling IL-15R alpha subunit, which is structurally similar (but not homologous) to the alpha receptor subunit of IL-2 SIGNOR-157415 0.863 CAMK2A protein Q9UQM7 UNIPROT DAGLA protein Q9Y4D2 UNIPROT down-regulates activity phosphorylation Ser808 RSIRGSPsLHAVLER 23502535 t lperfetto Activated CaMKII interacted with the C-terminal domain of DGLalpha, phosphorylated two serine residues and inhibited DGLalpha activity. |CaMKIIalpha phosphorylates DGLalpha at Ser808 and Ser782 SIGNOR-275540 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA2 protein Q15349 UNIPROT up-regulates phosphorylation 9606 8939914 t inferred from 70% family members gcesareni Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms SIGNOR-270144 0.2 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates transcriptional regulation 10090 BTO:0000165 11073979 f ggiuliani As shown in Fig. 8A, overexpression of Smad5 by itself induced Runx2 expression even in the absence of BMP-2 (lane 5). Western blot analysis also confirmed the induced level of Runx2 protein in C2C12-Sm5 cells (Fig. 8B) SIGNOR-255835 0.578 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser385 MARVGGAsSLENTVD -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikkepsilon And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178363 0.731 JUN protein P05412 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004603 13679379 t Luana Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription.  SIGNOR-261604 0.82 KDM3B protein Q7LBC6 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9534 16603237 t miannu We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation. SIGNOR-266635 0.2 ARHGAP20 protein Q9P2F6 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260473 0.412 P2RY11 protein Q96G91 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257060 0.2 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Ser231 LSTSSSSsPPGTPSP 9606 phosphorylation:Ser237 SSPPGTPsPADAKAP 22369944 t fspada However, the acquisition of dna binding and transactivation capacity of c/ebpbeta is delayed until further phosphorylation (on ser(184) or thr(179)) by gsk3beta occurs. SIGNOR-196377 0.469 SMAD7 protein O15105 UNIPROT SMAD7/HDAC1/E2F-1 complex SIGNOR-C12 SIGNOR form complex binding 9606 23213415 t gcesareni Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes SIGNOR-199970 0.448 sumatriptan chemical CHEBI:10650 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 BTO:0000567 10193663 t Luana This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues  SIGNOR-258340 0.8 CDK5 protein Q00535 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Ser231 GTENTFPsPKAIPNG 10090 12796778 t llicata Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function. SIGNOR-250676 0.763 AMPK complex SIGNOR-C15 SIGNOR CRTC1 protein Q6UUV9 UNIPROT down-regulates phosphorylation 9606 21331044 t lperfetto Here we show that both ampk and calcineurin modulate longevity exclusively through post-translational modification of crtc-1, the sole c. elegans crtc. We demonstrate that crtc-1 is a direct ampk target. SIGNOR-216529 0.288 PAK1 protein Q13153 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity phosphorylation Thr659 KIEINLStRMDHMVS 9606 BTO:0002181 33432150 t miannu Pak1 phosphorylates NLRP3 to promote inflammasome activation. SIGNOR-277547 0.2 ALK protein Q9UM73 UNIPROT GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr160 QVPQQPTyVQALFDF 9606 BTO:0000007 20554525 t lperfetto Two phosphorylation sites on Grb2 have been identified thus far at position Tyr209 in BCR-ABL-expressing cells (16) and Tyr160 by pp60c-src (18)Previous reports suggested an inhibitory role of Grb2 Tyr7, Tyr37, Tyr52, and Tyr209 phosphorylation in receptor tyrosine kinase signaling (16) (43). Instead, in our system Grb2 Tyr160 mutation was not show to have a role in ALCL proliferation. SIGNOR-247142 0.478 CSF2 protein P04141 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 9187659 t gcesareni We have determined the nmr structure of a ligand-binding domain of the granulocyte colony-stimulating factor (g-csf) receptor comparisons between the spectra of the 15n-labelled domain with and without g-csf indicate that the major ligand-recognition site is on the fg loop just upstream of the wsxws sequence. SIGNOR-49126 0.852 UBE3A protein Q05086 UNIPROT UBE3A protein Q05086 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001968 10864652 t miannu We show here that HPV16 E6 promotes the ubiquitination and degradation of E6AP itself.  SIGNOR-271398 0.2 TIMP2 protein P16035 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 SIGNOR-252273 0.7 ATOH7 protein Q8N100 UNIPROT POU4F2 protein Q12837 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002181 11172005 t Luana Thus, these data suggest that the expression of Brn3b can be activated directly by Math5 and that it is also subject to positive feedback regulation by Brn3 proteins. SIGNOR-261567 0.487 PTPRG protein P23470 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity dephosphorylation Tyr319 TSVYESPySDPEELK -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254734 0.263 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr33 KFKNEDLtDELSLNK -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276204 0.388 IRF4 protein Q15306 UNIPROT FCER2 protein P06734 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11342629 f IFN-regulatory factor 4 (IRF-4) plays a critical role in mature B cell function. Using the transcriptional regulation of the human B cell activation marker CD23 as a model system, we have previously demonstrated that IRF-4 is induced in response to B cell-activating stimuli and that it acts as a transactivator of CD23 gene expression. SIGNOR-253933 0.269 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser363 LKNKTESsLLAKLEE -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276209 0.2 MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 15568999 t lperfetto In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 SIGNOR-249199 0.595 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. SIGNOR-129272 0.392 ROBO proteinfamily SIGNOR-PF14 SIGNOR CCND2 protein P30279 UNIPROT down-regulates phosphorylation Thr280 DELDQAStPTDVRDI 9606 17486076 t lperfetto These results indicate that cyclin d2 expression in normal and malignant hematopoietic cells is regulated by ubiquitin/proteasome-dependent degradation that is triggered by thr280 phosphorylation by gsk3beta or p38 SIGNOR-154672 0.2 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM ITK protein Q08881 UNIPROT down-regulates activity chemical inhibition -1 24556163 t miannu This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine SIGNOR-262236 0.8 PHF12 protein Q96QT6 UNIPROT Sin3B_complex complex SIGNOR-C409 SIGNOR form complex binding 9606 BTO:0000007 21041482 t miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. SIGNOR-266969 0.792 PTPRJ protein Q12913 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 10116 26556953 t lperfetto Expression of Dep1 in transformed rat thyroid PCMPSV cells increased Src activity via Y527 dephosphorylation (corresponding to Y530 in human Src) without affecting the level of phosphorylated Y416 (Y419 in human Src).|Reciprocally, Dep1 can be phosphorylated by Src and Fyn on Y1311 and Y1320, leading to the dephosphorylation of Y530 Src by Dep1 . SIGNOR-276977 0.621 HOXD9 protein P28356 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates activity binding 9606 10523646 t miannu We find that DNA binding by MEIS1A is absolutely required for the formation of a cooperative complex with HOXD9 SIGNOR-220721 0.522 HIPK2 protein Q9H2X6 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Thr880 QTIVIPDtPSPTVSV 9606 BTO:0002181 24145406 t miannu  Here, we deciphered the molecular mechanism of HIPK2 activation and show its relevance for DNA damage-induced apoptosis in cellulo and in vivo. HIPK2 autointeracts and site-specifically autophosphorylates upon DNA damage at Thr880/Ser882. Autophosphorylation regulates HIPK2 activity and mutation of the phosphorylation-acceptor sites deregulates p53 Ser46 phosphorylation and apoptosis in cellulo. SIGNOR-276601 0.2 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176805 0.775 FFAR4 protein Q5NUL3 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257420 0.436 RUNX2 protein Q13950 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 f gcesareni Tgf-beta inhibited the expression of the cbfa1 and osteocalcin genes, whose expression is controlled by cbfa1 in osteoblast-like cell lines. This inhibition was mediated by smad3, which interacts physically with cbfa1 and represses its transcriptional activity at the cbfa1-binding ose2 promoter sequence SIGNOR-107160 0.595 DMAP1 protein Q9NPF5 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269298 0.772 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 10579915 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. In response toinsulinand nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-217060 0.748 CCNF protein P41002 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27653696 t miannu We show that cyclin F, a cell-cycle-regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCF(cyclin F). Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1. SIGNOR-266363 0.518 PP1 proteinfamily SIGNOR-PF54 SIGNOR AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t lperfetto Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-264658 0.2 HDAC5 protein Q9UQL6 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity deacetylation 9606 BTO:0000007 16613856 t lperfetto HDAC4 and HDAC5 deacetylate Runx2, allowing the protein to undergo Smurf-mediated degradation SIGNOR-227550 0.47 Platelet_alpha_granule_formation phenotype SIGNOR-PH136 SIGNOR VWF protein P04275 UNIPROT up-regulates 9606 NBK559062 f lperfetto Exposed VWF bound to collagen from vascular injury and endothelial damage adheres to the GPIb receptor on platelets to initiate signaling pathways for platelet activation, the next step in primary hemostasis. VW|VWF released by Weibel-Palade bodies or alpha-granules can enter circulation or accumulate in the subendothelial matrix binding to collagen through its A3 domain. Once exposed under high shear stress conditions in the arterial circulation, VWF can bind to platelets via its A1 domain. SIGNOR-261863 0.7 GNRH1 protein P01148 UNIPROT EGR1 protein P18146 UNIPROT up-regulates activity binding 10090 19106114 t miannu EGR1 bound to two binding sites on the LHB promoter and this binding was increased by GNRH1. Mutation of either site or knockdown of endogenous EGR1 decreased basal and/or GNRH1-regulated promoter activity. SIGNOR-254918 0.454 metaproterenol chemical CHEBI:6792 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) SIGNOR-257875 0.8 PPP2R1A protein P30153 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates binding 9606 16039140 t miannu Pr65/a acts as a scaffold protein for binding pp2ac and regulatory b subunits in a heterotrimeric holoenzyme SIGNOR-138886 0.887 HDAC2 protein Q92769 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR down-regulates 9606 28793257 f Among histone-modifying enzymes, HDAC2 is a crit- ical negative regulator of structural and functional plasticity in the mammalian nervous system (Guan et al., 2009; Hanson et al., 2013). HDAC2 localizes to the promoters of numerous synap- tic-plasticity-associated genes, where it deacetylates histone substrates (Gra ̈ ff et al., 2012; Guan et al., 2009). Consistently, loss of HDAC2 or HDAC inhibitor treatments promotes synaptic gene expression, long-term synaptic plasticity, and memory pro- cesses, while HDAC2 overexpression has opposing effects SIGNOR-268624 0.7 GNAS protein P63092 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity binding 9606 8245028 t MIANNU The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits. SIGNOR-265066 0.33 PTPRG protein P23470 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity dephosphorylation Tyr690 NLQERRKyLKHRLIV -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254728 0.2 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation 9606 14967450 t gcesareni Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1. SIGNOR-121944 0.845 ZNF202 protein O95125 UNIPROT POMGNT1 protein Q8WZA1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22419172 f miannu Here, we describe the first dystroglycanopathy patient carrying an alteration in the promoter region of the POMGNT1 gene (protein O-mannose β-1,2-N-acetylglucosaminyltransferase 1), which involves a homozygous 9-bp duplication (-83_-75dup). Analysis of the downstream effects of this mutation revealed a decrease in the expression of POMGNT1 mRNA and protein because of negative regulation of the POMGNT1 promoter by the transcription factor ZNF202 (zinc-finger protein 202). SIGNOR-255626 0.252 BMP2 protein P12643 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates activity binding 9534 SIGNOR-C29 7791754 t lperfetto Under our assay conditions, bmp-2 binds better to bmpr-ii in combination with actr-i or bmpr-ib than in combination with bmpr-ia SIGNOR-144101 0.793 PIAS3 protein Q9Y6X2 UNIPROT SMAD3/PIAS3 complex SIGNOR-C204 SIGNOR form complex binding 9606 26194464 t mrosina In summary, the TGF-b/IL-6/TCR-ERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation SIGNOR-255035 0.58 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SERPINA3 protein P01011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002600 11027208 f miannu We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. SIGNOR-254805 0.2 Lewy_body_formation phenotype SIGNOR-PH56 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000938 20479780 f lperfetto The genetic causes of PD seem to participate in con­ verging pathways to pathogenesis, but it is unclear whether all or only some of these pathways need to be activated for lewy body deposition and neuronal death to occur. SIGNOR-249703 0.7 P2RY1 protein P47900 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257072 0.2 NFYA protein P23511 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15496512 f miannu Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter. SIGNOR-252232 0.2 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser402 LSGSKTNsPKNSVHK 9606 BTO:0000007 16862148 t lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). SIGNOR-249304 0.444 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr94 ATADLDItEINKLTA 9606 19530738 t lperfetto First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form. SIGNOR-186155 0.471 ILK protein Q13418 UNIPROT ILK protein Q13418 UNIPROT up-regulates activity phosphorylation Ser343 SMADVKFsFQCPGRM 9606 11313365 t lperfetto Although ilk has been shown to autophosphorylate serine 343 (s343) is in the hydrophobic motif fsf within the activation loop of the kinase domain and has previously been suggested to be the target of autophosphorylation (9). Mutation of serine 343 to alanine (s343a) resulted in the inability of ilk to stimulate phosphorylation of pkb/akt in cos cells (9). SIGNOR-106838 0.2 CAMK2A protein Q9UQM7 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser552 VVRTPPKsPSSAKSR 9606 BTO:0000590 10090741 t lperfetto We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II. SIGNOR-249316 0.579 IDH complex SIGNOR-C396 SIGNOR NADH smallmolecule CHEBI:16908 ChEBI up-regulates quantity chemical modification 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-266260 0.8 ID2 protein Q02363 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR down-regulates activity binding 10090 BTO:0004058 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241146 0.585 NMB protein P08949 UNIPROT NMBR protein P28336 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. SIGNOR-107022 0.758 MTOR protein P42345 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser293 SSGYFSSsPTLSSSP 9606 22017875 t llicata Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome. SIGNOR-176849 0.746 sertindole chemical CHEBI:9122 ChEBI HTR1E protein P28566 UNIPROT down-regulates activity chemical inhibition 9534 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258543 0.8 MT-CO2 protein P00403 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267748 0.759 NSD1 protein Q96L73 UNIPROT PRB4 protein P10163 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003233 29156722 t miannu We here demonstrate that NSD1 could bind to the promoter regions of PRB4 and activate promoter activity by reducing the binding of H3K27me2 and increasing the binding of H3K36me2 on PRB4 promoter. SIGNOR-268459 0.349 PARL protein Q9H300 UNIPROT PINK1 protein Q9BXM7 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0000007 22354088 t miannu Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy. SIGNOR-261364 0.632 S1PR3 protein Q99500 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257437 0.358 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser330 RLSPIMAsTELDEVQ 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition. SIGNOR-252907 0.52 MAP3K3 protein Q99759 UNIPROT MAP3K3 protein Q99759 UNIPROT up-regulates phosphorylation Ser526 MSGTGMRsVTGTPYW 9606 BTO:0000007 16407301 t lperfetto Phosphorylation of serine 526 is required for mekk3 activity, and association with 14-3-3 blocks dephosphorylationautophosphorylation of mekk3 at ser526 SIGNOR-143647 0.2 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-236067 0.738 IKBKE protein Q14164 UNIPROT TRAF3IP2 protein O43734 UNIPROT up-regulates activity phosphorylation Ser328 KVILNYPsPWDHEER 9606 21822257 t miannu IKKi was required for IL-17-induced phosphorylation of Act1 on Ser311, adjacent to a putative TRAF-binding motif. Substitution of the serine at position 311 with alanine impaired the IL-17-mediated Act1-TRAF2-TRAF5 interaction and gene expression. Thus, IKKi is a kinase newly identified as modulating IL-17 signaling through its effect on Act1 phosphorylation and consequent function. SIGNOR-262883 0.425 PPP2CB protein P62714 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 18586681 t Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. SIGNOR-248600 0.2 RPS6KB1 protein P23443 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 9606 22017876 t llicata Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation. SIGNOR-176858 0.658 BMP2 protein P12643 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates activity binding -1 18937504 t ggiuliani Here we report the high-resolution NMR structure of BMPR-IA ECD in solution, revealing that a large part of the ligand-binding epitope is unfolded and flexible before formation of the complex. The binding beta4beta5 loop of BMPR-IA passes through a structural rearrangement upon BMP-2 binding. SIGNOR-255771 0.927 SH3GL2 protein Q99962 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 25517094 f miannu Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. SIGNOR-263883 0.7 PEA15 protein Q15121 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates 9606 11702783 f gcesareni Here, we report that pea-15, a protein variably expressed in multiple cell types, blocks erk-dependent transcription and proliferation by binding erks and preventing their localization in the nucleus._ Pea-15 can redirect the biological outcome of map kinase signaling by regulating the subcellular localization of erk map kinase. SIGNOR-111499 0.862 PPP2CA protein P67775 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 18586681 t Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. SIGNOR-248643 0.364 RING1 protein Q06587 UNIPROT FHL1 protein Q13642 UNIPROT up-regulates binding 9606 14999091 t gcesareni The polycombprotein ring1 interacts with the lim domains of kyot2 in yeast and mammalian cells. The interaction between kyot2 and ring1 was detected both in vitro and in vivo SIGNOR-123150 0.364 DRD1 protein P21728 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257269 0.272 AGT protein P01019 UNIPROT AGTR2 protein P50052 UNIPROT up-regulates 9606 BTO:0001130 16597412 f gcesareni Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors. SIGNOR-145680 0.819 BMP7 protein P18075 UNIPROT MMP13 protein P45452 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003858 12734180 f miannu In the present study we investigated the inhibitory effects of IGF-1 and OP-1 on MMP-13 expression in human chondrocytes. We found that the suppressive effect of IGF-1 and OP-1 on the MMP-13 promoter activity was dose-dependent at the transcriptional level with a corresponding decrease in the level of MMP-13 protein. SIGNOR-254801 0.357 SALL4 protein Q9UJQ4 UNIPROT ZEB1 protein P37275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 23954296 f miannu Our shRNA-mediated SALL4 knockdown system and SALL4 overexpression system revealed that SALL4 suppresses the expression of adhesion gene CDH1, and positively regulates the CDH1 suppressor ZEB1. SIGNOR-255123 0.255 POMC protein P01189 UNIPROT MC2R protein Q01718 UNIPROT up-regulates activity binding 10029 BTO:0000047 20371771 t lperfetto Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP). SIGNOR-268615 0.775 INSR protein P06213 UNIPROT DOK5 protein Q9P104 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 f lperfetto Irs5/dok4 and irs6/dok5 represent two new signaling proteins with potential roles in insulin and igf-1 action SIGNOR-101038 0.382 SLBP protein Q14493 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265374 0.2 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA7 protein Q9Y5G6 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265709 0.2 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.78 VWF protein P04275 UNIPROT F8 protein P00451 UNIPROT up-regulates activity binding 9606 23020315 t miannu Binding of FVIII to VWF is needed to maintain appropriate plasma levels, as FVIII plasma levels and half-life are remarkably reduced in the absence of VWF SIGNOR-251967 0.781 ARAF protein P10398 UNIPROT SLC9A3R2 protein Q15599 UNIPROT up-regulates activity phosphorylation Ser303 QESGLHLsPTAAEAK 9606 BTO:0002269 26310448 t miannu We also identify A-Raf as a kinase necessary for E3KARP phosphorylation at the G2/M stage of the cell cycle. Phosphorylation of Ser-303 regulates the localization, function, and dynamics of E3KARP SIGNOR-273503 0.384 tamsulosin chemical CHEBI:9398 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 10029 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258474 0.8 GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263810 0.8 PAX7 protein P23759 UNIPROT Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates BTO:0001103 15501225 f svumbaca Our work presented here provides a possible mechanism involving Pax-7 that allow satellite cells to exit the cell cycle, down-regulate MyoD, and prevent myogenin induction, phenotypes characteristic of the quiescent satellite cell. SIGNOR-255366 0.7 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK1 protein P06493 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258071 0.8 GNAS protein P63092 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 BTO:0000586 16293724 t lperfetto We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. SIGNOR-227988 0.389 KNTC1 protein P50748 UNIPROT RZZ complex complex SIGNOR-C357 SIGNOR form complex binding 9606 BTO:0000567 20462495 t lperfetto The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico. SIGNOR-265015 0.753 RANBP2 protein P49792 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity relocalization 9606 BTO:0002932 28882106 t irozzo RanBP2 can increase the sumoylation of p27kip1. In our study, the target protein p27kip1 mainly acts as a tumor-suppressor gene in the nucleus, RanBP2 and SUMO1 act as oncogenes by promoting the nuclear-cytoplasmic translocation and debilitate the G1-arrest brought by p27kip1 accumulation in the nucleus. SIGNOR-259115 0.2 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t lperfetto The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival SIGNOR-236236 0.965 FAS protein P25445 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates binding 9606 11495919 t amattioni Ask1 binds fas SIGNOR-109676 0.681 MAPK14 protein Q16539 UNIPROT GATA2 protein P23769 UNIPROT up-regulates phosphorylation 9606 25056917 t miannu P38_ increases gata_2 activity at endogenous target genes by inducing gata_2 multi_site phosphorylation. SIGNOR-205242 0.273 KIT protein P10721 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 15526160 t miannu C-Kit stimulates rapid and transient tyrosine phosphorylation of JAK2. JAK2 was found to be constitutively associated with c-Kit, with increased association after ligand stimulation of c-Kit SIGNOR-254954 0.597 progesterone smallmolecule CHEBI:17026 ChEBI 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268649 0.8 MT-ND6 protein P03923 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. SIGNOR-262149 0.758 SLBP protein Q14493 UNIPROT H3C1 protein P68431 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265413 0.2 TFEB protein P19484 UNIPROT ACACB protein O00763 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) SIGNOR-276780 0.2 HTR7 protein P34969 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256783 0.5 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 8676083 t fspada We first observed that cultured mouse embryonic dorsal root ganglia exhibited dramatic neurite extension by simultaneous addition of il-6 and soluble il-6r (sil-6r), a complex that is known to interact with and activate a signal transducing receptor component, gp130 SIGNOR-42866 0.916 SS18L1 protein O75177 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates relocalization 9606 BTO:0000938 15488321 t miannu The calcium-responsive transactivator recruits creb binding protein to nuclear bodies. SIGNOR-129926 0.406 PPM1A protein P35813 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization dephosphorylation 9606 10644691 t In addition, PP2C expression relieves Axin-mediated repression of LEF-1-dependent transcription. PP2C utilizes Axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that PP2C is a positive regulator of Wnt signal transduction and mediates its effects through the dephosphorylation of Axin. SIGNOR-248488 0.445 GNG2 protein P59768 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000938 16537363 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt. SIGNOR-145122 0.455 ATM protein Q13315 UNIPROT UBQLN4 protein Q9NRR5 UNIPROT up-regulates activity phosphorylation Ser318 GNSDSSSsQPLRTEN 9606 BTO:0001938 30612738 t lperfetto These results suggest that UBQLN4 phosphorylation on S318 is functionally important for its role in the DSB response.>Particularly HRR is dependent on ATM activity (Dietlein et al., 2014). Here, we showed that UBQLN4 is an ATM substrate and that DSB sealing is markedly impaired in UBQLN4-depleted cells. HRR depends on a 5′-3′ DSB end resection, which is initiated by the MRE11 nuclease SIGNOR-265076 0.2 CHGA protein P10645 UNIPROT Secretory_granule_organization phenotype SIGNOR-PH87 SIGNOR up-regulates 10090 12456801 f CgA was initially identified as the major soluble matrix protein of secretory vesicles formed in neuroendocrine cells. Its functions include modulation of secretory granule stability, prohormone processing, and regulation of peptide sorting into secretory pathways SIGNOR-254274 0.7 NCOR2 protein Q9Y618 UNIPROT BHLHE41 protein Q9C0J9 UNIPROT up-regulates binding 9606 12897056 t gcesareni The spen protein, sharp (smrt/hdac1-associated repressor protein), was identified as a component of transcriptional repression complexes in both nuclear receptor and notch/rbp-jkappa signaling pathways. SIGNOR-104489 0.2 NLGN2 protein Q8NFZ4 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264146 0.819 GABPB2 protein Q8TAK5 UNIPROT HCFC1 protein P51610 UNIPROT down-regulates activity binding 9606 BTO:0000567 10675337 t miannu The C1 factor interacts with the GABP_ transactivation domain.The domain of the C1 factor required for C1–GABP interaction can inhibit GABP_dependent transcriptional activation SIGNOR-221318 0.2 MAPK3 protein P27361 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser257 ESHPKPSsPRQESTR 10090 BTO:0000944 15060146 t miannu Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation. SIGNOR-260085 0.323 HES6 protein Q96HZ4 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150;BTO:0000938 19891787 f gcesareni Expression of hes-6 resulted in induction of e2f-1, a crucial target gene for the transcriptional repressor hes-1 SIGNOR-189101 0.2 NODAL protein Q96S42 UNIPROT ACVR1B protein P36896 UNIPROT up-regulates activity binding 9606 19874624 t Regulation miannu Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors. SIGNOR-251939 0.627 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser673 RVQSKIGsLDNITHV -1 12435421 t miannu Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly SIGNOR-250007 0.443 DRAP1 protein Q14919 UNIPROT BTAF1 protein O14981 UNIPROT up-regulates activity binding 9986 15509807 t miannu We present evidence that the NC2alpha subunit interacts with BTAF1. Addition of NC2alpha or the NC2 complex can stimulate the ability of BTAF1 to interact with TBP. SIGNOR-263918 0.518 GLIS1 protein Q8NBF1 UNIPROT WNT5A protein P41221 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32047936 t miannu GLIS1, a novel hypoxia-inducible transcription factor, promotes breast cancer cell motility via activation of WNT5A SIGNOR-269040 0.25 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269335 0.719 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMBRA1 protein Q9C0C7 UNIPROT up-regulates activity phosphorylation Ser1252 QPTLPSSsPVPIPVS 9606 BTO:0000567 37584777 t phosphorylation site remapping based on mass spec table lperfetto CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects. SIGNOR-272969 0.259 PIM2 protein Q9P1W9 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 20307683 t lperfetto Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellsere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo SIGNOR-164646 0.411 MUSK protein O15146 UNIPROT MUSK protein O15146 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000887 23458718 t miannu AGRN is released by the nerve and binds to LRP4, which then binds to MuSK. This interaction leads to MuSK autophosphorylation and activation of its kinase function, leading to anterograde signalling by subsequent phosphorylation of DOK7 (not shown), which binds MuSK as a dimer. SIGNOR-273851 0.2 GSK3A protein P49840 UNIPROT GRB14 protein Q14449 UNIPROT down-regulates activity phosphorylation Ser362 QGRSGCSsQSISPMR -1 28130417 t lperfetto Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3. SIGNOR-264870 0.267 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NCOA3 protein Q9Y6Q9 UNIPROT down-regulates phosphorylation Ser728 VVKQEQLsPKKKENN 9606 22163316 t lperfetto We demonstrate that aib1 is phosphorylated on ser728 and ser867 by cdk1/cyclin b at the onset of mitosis and remains phosphorylated until exit from m phase. SIGNOR-216892 0.319 PRKAA1 protein Q13131 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates activity phosphorylation Ser792 DKMRRASsYSSLNSL 10090 BTO:0002572 SIGNOR-C15 SIGNOR-C3 18439900 t lperfetto The phosphorylation of raptor by ampk is required for the inhibition of mtorc1 and cell-cycle arrest induced by energy stress. SIGNOR-161375 0.674 PARP1 protein P09874 UNIPROT POLA1 protein P09884 UNIPROT up-regulates activity binding 9606 BTO:0000567 9518481 t Federica We provide evidence that in proliferating cells: (i) PARP is physically associated with the catalytic subunit of the DNA polymerase α–primase tetramer, an association confirmed by confocal microscopy, demonstrating that both enzymes are co-localized at the nuclear periphery of HeLa cells.|(iii) PARP-deficient cells derived from PARP knock-out mice exhibited reduced DNA polymerase activity, SIGNOR-261270 0.349 GSK3A protein P49840 UNIPROT GRB14 protein Q14449 UNIPROT down-regulates activity phosphorylation Ser366 GCSSQSIsPMRSISE -1 28130417 t lperfetto Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3. SIGNOR-264872 0.267 GSK3A protein P49840 UNIPROT NBR1 protein Q14596 UNIPROT down-regulates activity phosphorylation Thr586 HNTPVDVtPCMSPLP -1 24879152 t lperfetto The autophagy receptor NBR1 (neighbor of BRCA1 gene 1) binds UB/ubiquitin and the autophagosome-conjugated MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) proteins, thereby ensuring ubiquitinated protein degradation|Here we show that NBR1 is a substrate of GSK3. NBR1 phosphorylation by GSK3 at Thr586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation. SIGNOR-261794 0.328 SNTA1 protein Q13424 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255991 0.521 MK-2206 chemical CHEBI:67271 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates chemical inhibition 9606 BTO:0001286 21841310 t gcesareni Treatment with the pi3k inhibitor ly294002 or the akt inhibitor mk2206 diminished s473 phosphorylation. SIGNOR-176043 0.8 adenosine 5'-monophosphate smallmolecule CHEBI:16027 ChEBI IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity precursor of 9606 BTO:0001103 1631143 t miannu AMP deaminase (AMPD; EC 3.5.4.6) is encoded by a multigene family in mammals. The AMPD1 gene is expressed at high levels in skeletal muscle, where this enzyme is thought to play an important role in energy metabolism. AMP deaminase (AMPD; EC 3.5.4.6), an enzyme that catalyzes deamination of AMP to IMP, and the purine nucleotide cycle, of which AMPD is one component, play a central role in purine nucleotide interconversion in eukaryotic cells. SIGNOR-269774 0.8 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 4344326 t Bell's palsy gcesareni SIGNOR-251704 0.8 quetiapine chemical CHEBI:8707 ChEBI HTR1F protein P30939 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258536 0.8 EGR1 protein P18146 UNIPROT PDGFC protein Q9NRA1 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0001685 15247255 f The PDGF family of ligands is comprised of A, B, C, and D chains. Here, we provide the first functional characterization of the PDGF-C promoter. We examined 797 bp of the human PDGF-C promoter and identified several putative recognition elements for Sp1, Ets Egr-1, and Smad.|These findings thus demonstrate that PDGF-C transcription, activated by FGF-2, is mediated by Egr-1 and its upstream kinase ERK.|Egr-1 and Sp1 specifically bind the PDGF-C promoter SIGNOR-254268 0.253 MMP2 protein P08253 UNIPROT DCN protein P07585 UNIPROT down-regulates quantity by destabilization cleavage Glu30 GLFDFMLeDEASGIG -1 9148753 t miannu Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues. SIGNOR-256349 0.682 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR EIF2AK2 protein P19525 UNIPROT up-regulates 9606 31226023 f miannu PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. SIGNOR-260167 0.7 CAMK2A protein Q9UQM7 UNIPROT ETS1 protein P14921 UNIPROT down-regulates phosphorylation Ser282 NSLQRVPsYDSFDSE 9606 BTO:0000782 12475968 t lperfetto Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition SIGNOR-96338 0.314 GABRA4 protein P48169 UNIPROT GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263759 0.599 AATF protein Q9NY61 UNIPROT BAX protein Q07812 UNIPROT down-regulates quantity transcriptional regulation 9606 22909821 t We identify the transcriptional regulator apoptosis-antagonizing transcription factor (AATF)/Che-1 as a critical regulator of the cellular outcome of the p53 response. Upon genotoxic stress, AATF is phosphorylated by the checkpoint kinase MK2. Phosphorylation results in the release of AATF from cytoplasmic MRLC3 and subsequent nuclear translocation where AATF binds to the PUMA, BAX and BAK promoter regions to repress p53-driven expression of these pro-apoptotic genes. SIGNOR-259916 0.2 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT up-regulates activity phosphorylation Ser1005 EHDSDESsDDDSDSE 9606 BTO:0000661 10066810 t llicata Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment.  SIGNOR-251030 0.445 CSNK2A1 protein P68400 UNIPROT ATXN3 protein P54252 UNIPROT up-regulates activity phosphorylation Ser335 SDLGDAMsEEDMLQA 9606 BTO:0000007 19542537 t miannu Here we show that protein casein kinase 2 (CK2)-dependent phosphorylation controls the nuclear localization, aggregation and stability of ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3). The main phosphorylation of ATXN3 in vivo thus occurred at serine residues within the three conserved UIMs. SIGNOR-276226 0.2 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 BTO:0000567 BTO:0000887;BTO:0001103 8454633 t gcesareni Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190. SIGNOR-39151 0.385 IL10 protein P22301 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 t milica Functionally active il-10 receptors are composed of two distinct subunits. The il-10 receptor ? Chain is a 110-kda polypeptide that plays the dominant role in mediating high affinity ligand binding and signal transduction. The il-10 receptor ? Subunit (also known as crf2_4) is predicted to be a 40-kda polypeptide that is largely required only for signaling. SIGNOR-68007 0.703 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser386 LRGAQAAsPAKGEPS 9606 BTO:0000567 23348582 t phosphorylation site remapping based on mass spec table lperfetto Cdk1-cyclin B1 directly phosphorylates PTP1B at serine 386 in a kinase assay. Recombinant Plk1 phosphorylates PTP1B on serine 286 and 393 in vitro, however, it requires a priming phosphorylation by Cdk1 at serine 386 highlighting a novel co-operation between Cdk1 and Plk1 in the regulation of PTP1B.|Finally, phosphorylation on serine 286 enhanced PTP1B phosphatase activity. SIGNOR-272971 0.516 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257931 0.8 PRKCA protein P17252 UNIPROT SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization phosphorylation Thr71 VAFSVDNtIKRPNPA 29383184 t lperfetto PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8. SIGNOR-275568 0.2 BTRC protein Q9Y297 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates ubiquitination 9606 14988407 t gcesareni Here we show that beta-trcp1, a f-box protein in the scf e3 ligase complex, interacts with smad4 and induces the degradation of smad4 SIGNOR-123057 0.396 GNB1 protein P62873 UNIPROT PLCB2 protein Q00722 UNIPROT up-regulates binding 9606 1465133 t gcesareni Activation of plc-beta 2 by beta gamma subunits may be an important mechanism by which pertussis toxin-sensitive g proteins stimulate plc. SIGNOR-19447 0.535 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Thr45 PGGTLFStTPGGTRI 9606 11777913 t gcesareni Phosphorylation of 4e-bp1 is mediated by the p38/msk1 pathway in response to uvb irradiation. In the present study we demonstrated that uvb induced 4e-bp1 phosphorylation at multiple sites, thr-36, thr-45, ser-64, and thr-69, leading to dissociation of 4e-bp1 from eif-4e. Uvb-induced phosphorylation of 4e-bp1 was blocked by p38 kinase inhibitors, pd169316 and sb202190, and msk1 inhibitor, h89, but not by mitogen-activated protein kinase kinase inhibitors, pd98059 or u0126. SIGNOR-113563 0.649 PRKCD protein Q05655 UNIPROT EEF1A1 protein P68104 UNIPROT unknown phosphorylation Thr432 AVRDMRQtVAVGVIK 7890750 t lperfetto PKC delta phosphorylates eEF-1 alpha at Thr-431 SIGNOR-248902 0.34 EPX protein P11678 UNIPROT RNASE2 protein P10153 UNIPROT up-regulates activity post translational modification 9606 BTO:0000399 18694936 t miannu Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism. SIGNOR-261704 0.489 CYTH2 protein Q99418 UNIPROT ARF6 protein P62330 UNIPROT up-regulates activity guanine nucleotide exchange factor 10116 BTO:0003102 14565977 t miannu Effects of ARNO upon Axonogenesis Are Mediated by Downstream Activation of ARF6. ARNO/ARF6 signaling pathways that could modulate actin reorganization in the axonal growth cone. ARNO stimulates GTP exchange on ARF6, thereby increasing the amount of active ARF6. SIGNOR-264910 0.883 ARHGAP31 protein Q2M1Z3 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260490 0.66 HNF4A protein P41235 UNIPROT ABCG5 protein Q9H222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000398 21123766 f miannu these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α. SIGNOR-254457 0.283 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 BTO:0000938 12367505 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. gcesareni Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27. SIGNOR-94021 0.802 MCRIP1 protein C9JLW8 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates activity binding 9606 BTO:0000007 25728771 t lperfetto CtBP is recruited to promoter elements of target genes by interacting with the DNA-binding transcriptional repressor ZEB1. We found that MCRIP1 binds to CtBP, thereby competitively inhibiting CtBP-ZEB1 interaction. When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications. SIGNOR-264776 0.2 CD55 protein P08174 UNIPROT ADGRE5 protein P48960 UNIPROT up-regulates binding 9606 BTO:0000142 12417446 t gcesareni This interaction may facilitate cell activation and migration through the blood-brain barrier. In addition, cd97-cd55 interactions in the parenchyma of the brain may contribute to the inflammation. SIGNOR-95458 0.2 DOK7 protein Q18PE1 UNIPROT CRK protein P46108 UNIPROT up-regulates activity binding 10090 BTO:0000165 20603078 t miannu Here, we identify two tyrosine residues in Dok-7 that are phosphorylated by Agrin stimulation, and show that two proteins, Crk and Crk-L, are recruited to these phosphorylation sites in Dok-7. SIGNOR-273847 0.365 VEPH1 protein Q14D04 UNIPROT YAP1 protein P46937 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000938 23989952 f or inhibits the Hippo pathway to activate Yki lperfetto A double positive-feedback loop between melt and yki, wherein yki acti- vates melt expression, and melt promotes yki SIGNOR-202540 0.2 HSPA8 protein P11142 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR down-regulates quantity by destabilization binding 24789820 t lperfetto Hsc70, recruited by the J-domain protein auxilin, mediates clathrin uncoating and release of a free vesicle, primed to fuse with a target membrane. SIGNOR-260718 0.526 CSNK2B protein P67870 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Thr102 RAAMFPEtLDEGMQI 9606 BTO:0000007 12432063 t llicata We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin SIGNOR-251066 0.588 SRC protein P12931 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Tyr34 KDQFPEVyVPTVFEN 9606 BTO:0000567 23027962 t lperfetto When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity SIGNOR-271702 0.654 KATNAL2 protein Q8IYT4 UNIPROT Acrosome_assembly phenotype SIGNOR-PH156 SIGNOR up-regulates 9606 28347630 f miannu The majority of elongated spermatids also displayed a detached acrosome (Fig 5B), indicating that KATNAL2, or KATNAL2-regulated structures, have a role in the deposition of ‘adhesive components’ into the acroplaxome. The acroplaxome is an electron dense structure that overlies the anterior pole of the sperm nucleus and is thought to play a pivotal role in acrosome formation and attachment. These data strongly suggest that KATNAL2 is required for multiple aspects of male haploid germ cell development, and depending on the cellular context, KATNAL2 may act in either a KATNB1-dependent (manchette function) and KATNB1-independent manner (acrosome and axoneme development). SIGNOR-267179 0.7 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation. SIGNOR-236209 0.866 PJA2 protein O43164 UNIPROT PRKAR2B protein P31323 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21423175 t miannu Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits SIGNOR-271858 0.2 SOAT1 protein P35610 UNIPROT cholesteryl ester smallmolecule CHEBI:17002 ChEBI down-regulates quantity chemical modification 9606 31848472 t miannu Excess cholesterol is esterified by acyl coenzyme A:cholesterol acyltransferase (ACAT; also known as SOAT) to cholesteryl esters SIGNOR-265160 0.8 (2S)-3-(4-acetamidophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide chemical CHEBI:94760 ChEBI AR protein P10275 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-189623 0.8 risperidone chemical CHEBI:8871 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258529 0.8 MAP2 protein P11137 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000938 10704996 t lperfetto MAP2 interacts with MTs through its tubulin-binding domain which mainly associates with the acidic region of the C-terminal region of tubulin|no neurite growth is observed when MAP2 expression is suppressed in neuronal cell cultures after treatment with specific antisense oligonucleotides SIGNOR-264837 0.7 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser927 DSDSVCDsGVETSFR 9606 BTO:0000459 SIGNOR-C13 10469655 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-70469 0.848 MBD4 protein O95243 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). SIGNOR-275714 0.7 GSK3B protein P49841 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by stabilization phosphorylation Ser903 KTTSQAHsLPLSPAS 10090 BTO:0000452 12871932 t GSK-3 beta forms an in vivo complex with and specifically phosphorylates NF-kappa B1/p105 at Ser-903 and Ser-907 in vitro. GSK-3 beta has a dual effect on p105: it stabilizes p105 under resting conditions and primes p105 for degradation upon tumor necrosis factor (TNF)-alpha treatment. Indeed, constitutive processing of p105 to p50 occurs at a higher rate in cells lacking GSK-3 beta with respect to wild-type cells and can be reduced upon reintroduction of GSK-3 beta by transfection. S903A and S907A point mutations impair p105 proteolysis in response to TNF-α. SIGNOR-251251 0.396 CAK complex complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 9315650 t llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase. SIGNOR-269325 0.446 iloprost chemical CHEBI:63916 ChEBI PTGIR protein P43119 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257574 0.8 DAPK1 protein P53355 UNIPROT DAPK1 protein P53355 UNIPROT down-regulates activity phosphorylation Ser308 ARKKWKQsVRLISLC 9606 BTO:0000007 11579085 t lperfetto The pro-apoptotic function of death-associated protein kinase is controlled by a unique inhibitory autophosphorylation-based mechanism.These results are consistent with a molecular model in which phosphorylation on ser(308) stabilizes a locked conformation of the cam-regulatory domain within the catalytic cleft and simultaneously also interferes with cam binding. SIGNOR-110807 0.2 RNF111 protein Q6ZNA4 UNIPROT SKIL protein P12757 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23530057 t miannu Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4. SIGNOR-272885 0.712 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC18 protein Q5QNW6 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271987 0.2 RFX3 protein P48380 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 10090 32725242 f miannu RFX2 and RFX3 are key regulators of ependymal cell ciliogenesis in vitro and in vivo. We show here that RFX2 and RFX3 have both redundant and specific functions in the biogenesis of motile cilia on mouse ependymal cells, whereas RFX1 does not seem to play a key regulatory role in this process. SIGNOR-266927 0.7 FAS protein P25445 UNIPROT FAS protein P25445 UNIPROT up-regulates activity binding 9606 BTO:0000776 19305384 t lperfetto Fas/FasL, TRAIL/DR4, TRAIL/DR5 and TNF-alpha/TNFR1 are ligand/receptor pairs of the tumor necrosis factor/nerve growth factor family, which are able to induce apoptosis by trimerization of the receptor by its corresponding ligand. SIGNOR-217809 0.2 R2SP co-chaperone complex SIGNOR-C517 SIGNOR Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 9606 29844425 f miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. SIGNOR-270941 0.7 PIK3R1 protein P27986 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242640 0.846 PRKDC protein P78527 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser645 NLSTNADsQSSSDFE 9606 16600297 t lperfetto Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin SIGNOR-145841 0.687 SLC12A7 protein Q9Y666 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates quantity relocalization 21613606 t lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  SIGNOR-264639 0.8 TAB1 protein Q15750 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 8638164 t lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells. SIGNOR-41941 0.927 MMP12 protein P39900 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Ala20 VVGTAWTaDSGEGDF -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-12 20ADSGEGD a-chain| 540FVSETESRG a-chain|433LVTSKGDK a-chain SIGNOR-263622 0.2 EIF3E protein P60228 UNIPROT PLAU protein P00749 UNIPROT up-regulates quantity translation regulation 9606 BTO:0000815; BTO:0001938 20453879 f irozzo Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression. SIGNOR-259155 0.2 SOX9 protein P48436 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 20530484 f miannu BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SIGNOR-255187 0.339 RFWD3 protein Q6PCD5 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity binding 9606 BTO:0002552 20173098 t miannu RFWD3 is a positive regulator of p53 abundance and regulates the G1 checkpoint in response to IR. We found that an E3 ubiquitin ligase RFWD3 (RNF201/FLJ10520) forms a complex with Mdm2 and p53 to synergistically ubiquitinate p53 and is required to stabilize p53 in the late response to DNA damage.  SIGNOR-271945 0.372 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258097 0.8 MYOD1 protein P15172 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR form complex binding 9606 16847330 t 2 miannu The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation. SIGNOR-241100 0.69 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser236 AKRRRLSsLRASTSK 9606 17360704 t gcesareni We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism. SIGNOR-252812 0.2 NCBP1 protein Q09161 UNIPROT Cap-binding complex complex SIGNOR-C440 SIGNOR form complex binding 9606 26382858 t lperfetto The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. SIGNOR-268359 0.969 LAMTOR5 protein O43504 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR form complex binding 9606 20381137 t lperfetto Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant SIGNOR-164781 0.895 STAT3 protein P40763 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 18177723 f miannu Altogether, these data demonstrate that IL-6 loss results in deficient STAT3 signaling in activated satellite cells, leading to their reduced proliferation and myogenic progression, and highlight the major role played by the IL-6/STAT3 axis in controlling these processes during compensatory hypertrophy. SIGNOR-255632 0.7 PRKAA1 protein Q13131 UNIPROT MLXIPL protein Q9NP71 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 11724780 t gcesareni Ampk has also been suggested to phosphorylate the glucose-sensitive transcription factor chrebpthe dna binding activity, as assayed in a gel-shift assay of the truncated chrebp, was gradually inactivated with time by treatment with ampk SIGNOR-112289 0.428 GFPT1 protein Q06210 UNIPROT D-fructofuranose 6-phosphate(2-) smallmolecule CHEBI:61527 ChEBI down-regulates quantity chemical modification 9606 21310273 t miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans SIGNOR-267815 0.8 KCNN4 protein O15554 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 10116 BTO:0000078 25274816 t miannu KCa3.1 activation is expected to maintain a negative membrane potential, which will increase Ca2+ influx through nonvoltage gated Ca2+-release-activated Ca2+ (CRAC) channels that are prevalent in rat microglia SIGNOR-276856 0.8 MLL2 complex complex SIGNOR-C88 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 24680668 t miannu Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. SIGNOR-268800 0.2 CENPQ protein Q7L2Z9 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265207 0.779 LCK protein P06239 UNIPROT SH2D2A protein Q9NP31 UNIPROT up-regulates activity phosphorylation Tyr280 PKPSNPIyNEPDEPI 9606 BTO:0000782 18541536 t miannu Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition. SIGNOR-262888 0.596 PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 23119004 t lperfetto Binding of IGF to IGF-1R activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including AKT and PDK1. SIGNOR-236509 0.8 MAPK9 protein P45984 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates relocalization 9606 14517246 t gcesareni Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin. SIGNOR-103360 0.699 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT up-regulates phosphorylation Tyr685 LDARPSLyAQVQKPP 9606 BTO:0000975 16909109 t llicata In vitro src assay, the ve-cadherin cytoplasmic domain is directly phosphorylated by purified src as well as the tyrosine residue 685 (tyr)685-containing peptide finally, we found that in a vegf-induced wound-healing assay, cadherin adhesive activity was impaired by src kinase inhibitors.RPSLY(685)aqvq. SIGNOR-148818 0.584 GOT1 protein P17174 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-268064 0.8 PRKCA protein P17252 UNIPROT RORA protein P35398 UNIPROT unknown phosphorylation Ser35 ETPLNQEsARKSEPP 9606 20122401 t llicata Wnt5a/pkcalpha-dependent phosphorylation on serine residue 35 of roralpha is crucial to link roralpha to wnt/beta-catenin signaling, which exerts inhibitory function of the expression of wnt/beta-catenin target genes. SIGNOR-163702 0.254 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr89 QSSNGHItTTPTPTQ 9606 BTO:0000848 21177766 t lperfetto P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286) SIGNOR-170772 0.271 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 9305639 t lperfetto These results, therefore, suggest that mtk1 directly phosphorylates and activates mkk3, mkk6 and sek1. SIGNOR-50891 0.628 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 20185585 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-163947 0.8 MAPK3 protein P27361 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1032 SSSNRPFtPPTSTGG 9606 12356758 t lperfetto Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase SIGNOR-93989 0.266 glycine smallmolecule CHEBI:15428 ChEBI (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity precursor of 9606 16051266 t lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. SIGNOR-268237 0.8 CSNK1D protein P48730 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 12000790 t lperfetto We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the beta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or epsilon isoform, all detected in association with axin by lc/ms. SIGNOR-227973 0.519 MECOM protein Q03112 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates activity binding 10090 17575132 t irozzo The results that we present here support this model and show that EVI1 interacts with and inhibits RUNX1. As for GATA1, EVI1 seems to repress RUNX1 function by interacting specifically with its DNA-binding domain Runt, leading to destabilization and dissolution of the DNA-RUNX1 complex. SIGNOR-255716 0.508 SCF-SKP2 complex SIGNOR-C136 SIGNOR CDK9 protein P50750 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11689688 t miannu Here we report that CDK9 is ubiquitinated and degraded by the proteasome whereas cyclin T1 is stable. SCF(SKP2) was recruited to CDK9/cyclin T1 via cyclin T1 in an interaction requiring its PEST domain. CDK9 ubiquitination was modulated by cyclin T1 and p45(SKP2).  SIGNOR-272666 0.356 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2G protein Q13555 UNIPROT up-regulates chemical activation 9606 22944199 t lperfetto Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell). SIGNOR-198816 0.8 CTNND2 protein Q9UQB3 UNIPROT CDH3 protein P22223 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 t miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. SIGNOR-252130 0.298 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UBTF protein P17480 UNIPROT up-regulates phosphorylation Ser389 INKKQATsPASKKPA 9606 11698641 t lperfetto Phosphorylation of ubf at serine 388 is required for interaction with rna polymerase i and activation of rdna transcription. After g(1) progression ubf is phosphorylated at serine 388 by cdk2/cyclin e and cdk2/cyclin a. Conversion of serine 388 to glycine abolishes ubf activity SIGNOR-216678 0.379 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation 9606 21808241 t The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction. SIGNOR-270221 0.2 TLRs proteinfamily SIGNOR-PF20 SIGNOR MYD88 protein Q99836 UNIPROT up-regulates activity binding 10090 22664090 t miannu To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-260151 0.2 MN1 protein Q10571 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity binding -1 12569362 t irozzo Taken together, our results indicate that MN1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate RAR/RXR-mediated transcription through interaction with p160 and p300. SIGNOR-256020 0.349 AGTR1 protein P30556 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256738 0.252 PRKG1 protein Q13976 UNIPROT CREB1 protein P16220 UNIPROT unknown phosphorylation Ser119 EILSRRPsYRKILND -1 11175347 t lperfetto G-kinase phosphorylated GST-CREB, albeit less efficiently than A-kinase, but GST was not phosphorylated by either kinase (Figure 5a). GST-CREB purified from bacteria was similarly phosphorylated by G-kinase, whereas GST-CREB containing a serine 133 to alanine mutation was not (Figure 5b). These results demonstrate that G-kinase can directly phosphorylate CREB on serine 133. SIGNOR-249076 0.641 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr198 PGLRRRQt 9606 12042314 t lperfetto Because Thr198-phosphorylated p27Kip1 was localized only in the cytoplasm, Akt might promote 14-3-3 binding to p27Kip1 by phosphorylation at Thr198, allowing its cytoplasmic localization and degradation. SIGNOR-244194 0.2 CSNK2A1 protein P68400 UNIPROT PIP4K2A protein P48426 UNIPROT up-regulates phosphorylation Ser304 DGEEEGEsDGTHPVG 9606 BTO:0000567 10508590 t lperfetto Here, we demonstrate the partial purification of a protein kinase that phosphorylates the type iialpha pip kinase at a single site unique to that isoform - ser304. This kinase was identified as protein kinase ck2 (formerly casein kinase 2). Mutation of ser304 to aspartate to mimic its phosphorylation had no effect on pip kinase activity, but promoted both redistribution of the green fluorescent protein (gfp)-tagged enzyme in hela cells from the cytosol to the plasma membrane, and membrane ruffling. SIGNOR-71014 0.43 CREB5 protein Q02930 UNIPROT LGALS3BP protein Q08380 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002812 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253805 0.2 MMP9 protein P14780 UNIPROT A2M protein P01023 UNIPROT down-regulates quantity by destabilization cleavage Arg719 VMGRGHArLVHVEEP -1 9344465 t lperfetto The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. SIGNOR-261740 0.471 EFNB1 protein P98172 UNIPROT EPHB1 protein P54762 UNIPROT up-regulates binding 9606 11713248 t tpavlidou We show here that despite its lack of kinase activity, ephb6 undergoes inducible tyrosine phosphorylation upon stimulation with the eph-b receptor subfamily ligand ephrin-b1. Overexpression of a catalytically active member of the eph-b subfamily, ephb1, resulted in increased ephb6 phosphorylation. Ephb1-induced ephb6 phosphorylation was ligand-dependent and required the functional catalytic activity of ephb1. SIGNOR-111851 0.821 CASP3 protein P42574 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates quantity by stabilization cleavage -1 9367996 t lperfetto The cell-death protease cpp32 (caspase-3) in vitro specifically cleaved chicken and human ikappab-alpha at a conserved asp-ser sequence.Therefore, cleavage of I_B-_ by a CPP32-like protease could create what is sometimes called a super-repressor form of I_B-_ (20). That is, cleavage by CPP32 would block the ability of I_B-_ to undergo signal-induced degradation by removing the sites of signal-induced ubiquitination and by likely disrupting the ability of I_B-_ to become phosphorylated at critical Ser residues. SIGNOR-51936 0.432 rizatriptan chemical CHEBI:48273 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 10193663 t Luana This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues  SIGNOR-258342 0.8 CDK1 protein P06493 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity binding 9606 26259146 t miannu Moreover, CDK1 phosphorylates RSF1 at Ser1375, and this phosphorylation is necessary for PLK1 recruitment. Subsequently, PLK1 phosphorylates RSF1 at Ser1359, stabilizing PLK1 deposition. SIGNOR-273589 0.593 EXT1 protein Q16394 UNIPROT WNT8A protein Q9H1J5 UNIPROT up-regulates activity 9606 24860992 f miannu Decreased Ext1 was shown to reduce the level of Wnt8 and BMP4 signaling and disrupt ventral-specific gene expression. Ext1 function is required for maintenance of normal levels of BMP and wnt, as well as their target genes. In addition, expression of xbra and the establishment of ventral mesoderm depend upon normal levels of Ext1. These findings suggest that ext1-dependent synthesis of HSPG is critical for wnt and BMP signaling, mesodermal identity, and ventral pattern. SIGNOR-264019 0.2 PRKACA protein P17612 UNIPROT CSNK1A1L protein Q8N752 UNIPROT up-regulates phosphorylation 9606 16481469 t lperfetto Mutation of either the three pka sites or pka-primed cki sites prevents phosphorylation of ci by cki in vitro and blocks ci cleavage in embryos SIGNOR-144557 0.375 CENPE protein Q02224 UNIPROT BUB1B protein O60566 UNIPROT up-regulates activity binding 10090 BTO:0000452 12925705 t lperfetto Without CENP-E, diminished levels of BubR1 are recruited to kinetochores and BubR1 kinase activity remains at basal levels. CENP-E binds to and directly stimulates the kinase activity of purified BubR1 in vitro. Thus, CENP-E is required for enhancing recruitment of its binding partner BubR1 to each unattached kinetochore and for stimulating BubR1 kinase activity, implicating it as an essential amplifier of a basal mitotic checkpoint signal. SIGNOR-252043 0.839 SMURF2 protein Q9HAU4 UNIPROT SMAD2/SMURF2 complex SIGNOR-C11 SIGNOR form complex binding 9606 11389444 t gcesareni We show that in the presence of tgf-beta, smad2 interacts through its proline-rich ppxy motif with the tryptophan-rich ww domains of smurf2, a recently identified e3 ubiquitin ligases. SIGNOR-108496 0.77 CALM1 protein P0DP23 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates binding 9606 11796223 t gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-114098 0.753 NOG protein Q13253 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates activity binding 9606 BTO:0001593 BTO:0000140 SIGNOR-C29 22298955 t Create trimers (2 typeII and 1 typeI) with serine/threonine kinase function lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors.Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors (pmid 12478285) SIGNOR-195612 0.571 STAT5A protein P42229 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 16146838 t lperfetto The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. SIGNOR-249621 0.384 LYN protein P07948 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Tyr291 AETSKLIyDFIEDQG 9606 BTO:0000801 17890224 t done miannu We demonstrated that WASP is phosphorylated on tyrosine 291 in macrophages, and the WASP phosphorylation is important for the phagocytic cup formation. In addition, we showed that WASP and WASP-interacting protein (WIP) form a complex at the phagocytic cup and that the WASP.WIP complex plays a critical role in the phagocytic cup formation.  SIGNOR-273959 0.386 YIF1B protein Q5BJH7 UNIPROT HTR1A protein P08908 UNIPROT up-regulates activity relocalization 10116 BTO:0000938 18685031 t nucleus lperfetto Together, our results provide strong evidence that Yif1B is a member of the ER/Golgi trafficking machinery, which plays a key role in specific targeting of 5-HT(1A)R to the neuronal dendrites. This finding opens up new pathways for the study of 5-HT(1A)R regulation by partner proteins and for the development of novel antidepressant drugs.|We confirmed 5-HT(1A)R-Yif1B interaction by glutathione S-transferase pull-down experiments using rat brain extracts and transfected cell lines. SIGNOR-268299 0.409 TSLP protein Q969D9 UNIPROT CRLF2 protein Q9HC73 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 11418668 t gcesareni Human tslp is proposed to signal through a heterodimeric receptor complex that consists of a new member of the hemopoietin family termed human tslp receptor and the il-7r alpha-chain. SIGNOR-108920 0.922 TBP protein P20226 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263933 0.89 CCND1 protein P24385 UNIPROT CDK4 protein P11802 UNIPROT up-regulates binding 9606 7736585 t gcesareni D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb, SIGNOR-32295 0.964 PLK3 protein Q9H4B4 UNIPROT SNCB protein Q16143 UNIPROT down-regulates activity phosphorylation Ser118 LMEPEGEsYEDPPQE 9606 19889641 t lperfetto Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. SIGNOR-189057 0.389 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser670 CGKRFTRsDELQRHK 9606 BTO:0000887;BTO:0001260 18258854 t llicata Here we have used a variety of approaches to identify 3 amino acids (thr668, ser670, and thr681) in the zinc finger domain of sp1 that are modified by pkc-zeta angiotensin ii, which activates pkc-? Phosphorylation (at thr410) via the angiotensin ii type 1 receptor, stimulates sp1 phosphorylation and increases sp1 binding to the platelet-derived growth factor-d promoter. SIGNOR-160766 0.497 ASPG protein Q86U10 UNIPROT ammonia smallmolecule CHEBI:16134 ChEBI up-regulates quantity chemical modification 9606 24657844 t miannu Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia. SIGNOR-267539 0.8 MAPK1 protein P28482 UNIPROT SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation Ser225 VGSKTPAsPVVVQQG 9606 14532121 t gcesareni Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation. SIGNOR-118546 0.546 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MCM4 protein P33991 UNIPROT down-regulates phosphorylation Thr110 PRSGVRGtPVRQRPD 9606 BTO:0000567 12714602 t lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. SIGNOR-217352 0.686 EIF3_complex complex SIGNOR-C401 SIGNOR EIF4B protein P23588 UNIPROT up-regulates activity stabilization 9606 17581632 t lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit SIGNOR-269158 0.624 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys74 DTGRILSkLHTVQPK -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. SIGNOR-272742 0.475 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR SP1 protein P08047 UNIPROT up-regulates activity binding -1 18025157 t We show that PML-RARα physically interacts with Sp1 in the absence of DNA. In this report, we show that PML-RARα interacts with Sp1 and may interfere with the expression of genes that are not normally regulated by retinoic acid receptors. SIGNOR-255729 0.2 DDX41 protein Q9UJV9 UNIPROT STING1 protein Q86WV6 UNIPROT up-regulates activity binding 10090 BTO:0002572 25704810 t miannu The kinase and SH3/SH2 interaction domains of BTK bind, respectively, the DEAD-box domain of DDX41 and transmembrane region of STING. BTK phosphorylates DDX41, and its kinase activities are critical for STING-mediated IFN-β production. We show that Tyr364 and Tyr414 of DDX41 are critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identifies Tyr414 as the BTK phosphorylation site. SIGNOR-266403 0.2 pictrelisib chemical CHEBI:65326 ChEBI PIK3CA protein P42336 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258113 0.8 MAPK3 protein P27361 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser345 QARPGPQsPGSPLEE 9606 8626435 t esanto Upon activation, several serine residues on the cytosolic oxidase subunit p47phox become phosphorylated. Mitogen-activated protein kinase phophorylated only the peptide containing ser345/348. SIGNOR-40821 0.431 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr390 DSKFTRQtPVDSPDD 9606 11914378 t Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain,[…] Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings. SIGNOR-255840 0.748 JAK1 protein P23458 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates phosphorylation Tyr457 KAPTSFGyDKPHVLV 9606 7615558 t lperfetto Interferon gamma activation of stat1alpha requires both jak1 and jak2 as well as tyrosine phosphorylation of the alpha chain of the ifngamma receptor. SIGNOR-29866 0.691 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270424 0.8 belinostat chemical CHEBI:61076 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257952 0.8 EPGN protein Q6UW88 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0001253 20513444 t EPGN may stimulate the phosphorylation of EGFR and mitogen-activated protein kinases gcesareni Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling. SIGNOR-165779 0.638 BTK protein Q06187 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Tyr291 AETSKLIyDFIEDQG 9606 BTO:0000007 10068673 t done miannu These results demonstrate that WASP, under this experimental condition, can be tyrosine-phosphorylated by the kinase activity of Btk and that the direct interaction between WASP and the SH3 domain of Btk is required for this phosphorylation to occur. SIGNOR-273958 0.732 PIAS3 protein Q9Y6X2 UNIPROT STAT3 protein P40763 UNIPROT down-regulates sumoylation 9606 15138572 t gcesareni Stat3 mediated signaling pathways can be inhibited by pias3 (protein inhibitor of activated stat3), which was recently found to regulate protein stability and function by its sumo (small-ubiquitin like modifiers) ligase activity in promoting sumoylation of important nuclear proteins. SIGNOR-124723 0.72 HK2 protein P52789 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates activity 10090 16892090 f HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host SIGNOR-259979 0.7 NLGN1 protein Q8N2Q7 UNIPROT NRXN2 protein P58401 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264159 0.823 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1474 GSSNGHVyEKLSSIE 11483655 t lperfetto We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src and Fyn and compared this to phosphorylation by tyrosine kinases associated with the postsynaptic density (PSD)|Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases SIGNOR-249338 0.759 PPP1CA protein P62136 UNIPROT CASP9 protein P55211 UNIPROT up-regulates dephosphorylation Thr125 PEVLRPEtPRPVDIG 9606 22311969 t gcesareni Pp1 dephosphorylated thr125 site of caspase-9 and activated caspase-9 to mediate il-2 deprivation-induced apoptosis. SIGNOR-195992 0.2 PRKACA protein P17612 UNIPROT PRKAR2B protein P31323 UNIPROT up-regulates activity phosphorylation Ser114 NRFTRRAsVCAEAYN 9606 15187164 t gcesareni Serine 114 phosphorylation is required for both nuclear localization and down-regulation of il-2 production by riibeta. SIGNOR-125545 0.877 CAD protein P27708 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267421 0.8 C5AR2 protein Q9P296 UNIPROT ITGAM protein P11215 UNIPROT up-regulates quantity by expression 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263463 0.299 SH3KBP1 protein Q96B97 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 24167568 t gcesareni The cin85 sh3 domains interact with c-cbl, an e3 ubiquitin ligase, via an unconventional pxxxpr ligand sequence, with the highest affinity displayed by the sh3-b domain. Interaction with cin85 recruits c-cbl to the amap1 complex where its ubiquitination activity is necessary for cancer cells to develop an invasive phenotype and to degrade the matrix. SIGNOR-203139 0.737 GPR132 protein Q9UNW8 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257074 0.2 PLK3 protein Q9H4B4 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates phosphorylation Ser576 DDDFQLRsFDQLSPL 9606 BTO:0000567 18519666 t lperfetto Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1 alpha under hypoxic conditionsplk3 can potentially inhibit hif-1_ by physical interaction and direct phosphorylation SIGNOR-178739 0.355 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0001538 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252755 0.719 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity phosphorylation 9606 16293724 t lperfetto We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt by free G protein betagamma subunits and the direct association of the G protein alphas subunit with the regulator of G protein signaling (RGS) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. SIGNOR-227952 0.545 CAMK2A protein Q9UQM7 UNIPROT NOS1 protein P29475 UNIPROT down-regulates activity phosphorylation Ser852 SYKVRFNsVSSYSDS 10400690 t llicata It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation. SIGNOR-250635 0.452 PMS1 protein P54277 UNIPROT MLH1/PMS1 complex SIGNOR-C58 SIGNOR form complex binding 9606 10542278 t miannu We now show that hpms1 is expressed in human cells and that it interacts with hmlh1 with high affinity to form the heterodimer hmutl_. SIGNOR-71774 0.695 CEP43 protein O95684 UNIPROT FGFR1OP/CEP350 complex SIGNOR-C52 SIGNOR form complex binding 9606 16314388 t miannu Here we show that cap350 and fop (fgfr1 oncogene partner) form a centrosomal complex required for mt anchoring. SIGNOR-142358 0.2 KDM5D protein Q9BY66 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-264308 0.2 HOXB13 protein Q92826 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 15604291 f miannu These results suggest that HOXB13 functions as an AR repressor to modulate the complex AR signaling and subsequent growth regulation of prostate cancer cells. SIGNOR-254475 0.507 FGF2 protein P09038 UNIPROT ANKH protein Q9HCJ1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004473 19049325 f miannu FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2. SIGNOR-252193 0.2 ITGAM protein P11215 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates binding 9606 23994464 t apalma Before leaving the vessel lumen, neutrophils crawl on the endothelium, primarily using cell surface Mac-1 integrins binding to endothelial ICAM-1. SIGNOR-255041 0.764 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser8 MESEMLQsPLLGLGE 9606 SIGNOR-C3 21071439 t llicata We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-169518 0.532 ROBO proteinfamily SIGNOR-PF14 SIGNOR CCND3 protein P30281 UNIPROT down-regulates phosphorylation Thr283 QGPSQTStPTDVTAI 9606 BTO:0000782 15326477 t lperfetto P38sapk2 phosphorylates cyclin d3 at thr-283 and targets it for proteasomal degradation SIGNOR-128402 0.2 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120160 0.316 P2RY1 protein P47900 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257394 0.2 CBLB protein Q13191 UNIPROT NCK1 protein P16333 UNIPROT up-regulates activity binding 9606 BTO:0000782 16503409 t lperfetto Activated Cbl and Cbl-b interacted with Crk-L, Zap-70, Nck, PLC-gamma SIGNOR-236054 0.505 BMPR1A protein P36894 UNIPROT SMAD9 protein O15198 UNIPROT up-regulates activity phosphorylation 9606 19620713 t ggiuliani To ascertain whether overexpression of BMPr1A can initiate adipocyte lineage commitment in the absence of its BMP ligand, constitutively active (CA)-BMPr1A and CA-BMPr1B were expressed in C3H10T1/2 stem cells using a mouse stem cell virus (MSCV) retroviral system. […]Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway. SIGNOR-255772 0.695 CSNK2A1 protein P68400 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser392 FKTEGPDsD 9606 BTO:0000568 10747897 t llicata Furthermore, we demonstrate that anisomycin- and tumor necrosis factor-alpha-induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase and CK2 activities. SIGNOR-250967 0.655 MAPK1 protein P28482 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates activity phosphorylation Thr292 ETPPRPRtPGRPLSS 9534 BTO:0004055 14993270 t lperfetto We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling. SIGNOR-236335 0.74 PRKCG protein P05129 UNIPROT PEBP1 protein P30086 UNIPROT up-regulates activity phosphorylation Ser153 RGKFKVAsFRKKYEL 10116 BTO:0003036 12551925 t lperfetto Here we report that one mechanism involves dissociation of Raf kinase inhibitory protein (RKIP) from Raf-1. Classic and atypical but not novel PKC isoforms phosphorylate RKIP at serine 153 (Ser-153). RKIP Ser-153 phosphorylation by PKC either in vitro or in response to 12-O-tetradecanoylphorbol-13-acetate or epidermal growth factor causes release of RKIP from Raf-1, whereas mutant RKIP (S153V or S153E) remains bound. I SIGNOR-249190 0.389 PTPN1 protein P18031 UNIPROT EPHA3 protein P29320 UNIPROT down-regulates activity dephosphorylation Tyr779 EDDPEAAyTTRGGKI 9606 21135139 t Nevertheless, the finding that phosphorylation of the activation loop tyrosine (EphA3-Y779), a recently identified PTP1B substrate (Mertins et al., 2008), is essential for ligand-induced endocytosis (Janes et al., 2009) SIGNOR-248426 0.427 HNF4A protein P41235 UNIPROT AFP protein P02771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 9792724 f miannu AFP promoter-chloramphenicol acetyltransferase transient transfection assays demonstrated that the level of HNF1 had a direct impact on basal transcription as well as RA-mediated down-regulation of the AFP gene, and that co-transfection of HNF1 and HNF4, but not transfection of either factor alone, reversed the RA-mediated inhibition. Taken together these data point to an interaction among the RA, HNF1, and HNF4 signals, which is reflected in decreased expression of AFP. SIGNOR-254446 0.413 CYP17A1 protein P05093 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268653 0.8 PAMPs stimulus SIGNOR-ST11 SIGNOR AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR up-regulates 9606 25720354 f scontino APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. SIGNOR-267859 0.7 NRXN3 protein Q9HDB5 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 t miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. SIGNOR-265462 0.2 SMURF2 protein Q9HAU4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11016919 t miannu The ability of Smurf2 to promote Smad2 destruction required the HECT catalytic activity of Smurf2 and depended on the proteasome-dependent pathway. Consistent with these results, Smurf2 potently reduced the transcriptional activity of Smad2.  SIGNOR-272935 0.77 CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity cleavage Asp330 LRTFDQLdAISSLPT 9606 BTO:0001412 15657060 t lperfetto In turn, casp3 directs feedback cleavage of casp9 at asp-330 to generate p37 and p10 subunits. SIGNOR-133264 0.623 PCM1 protein Q15154 UNIPROT CEP250 protein Q9BV73 UNIPROT up-regulates relocalization 9606 15659651 t miannu Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1 SIGNOR-133334 0.532 RB1 protein P06400 UNIPROT TRIP11 protein Q15643 UNIPROT down-regulates binding 9606 9256431 t miannu The wild-type rb is able to interact with the rb-binding domain of trip230 / rb represses trip230-mediated activation of tr-regulated transcription. SIGNOR-50266 0.33 SMO protein Q99835 UNIPROT GATA2 protein P23769 UNIPROT up-regulates activity 10090 BTO:0000011 16399502 f fferrentino In mammalian models [...] Hh signaling also inhibits mammalian adipogenesis. Hh signals elicit this function early in adipogenesis, upstream of PPARγ, potentially diverting preadipocytes as well as multipotent mesenchymal prescursors away from adipogenesis and toward osteogenesis. Hh may elicit these effects by inducing the expression of antiadipogenic transcription factors such as Gata2. SIGNOR-251656 0.2 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser213 QNIPAHYsPRTSPIM 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248685 0.613 NPFF protein O15130 UNIPROT NPFFR1 protein Q9GZQ6 UNIPROT up-regulates binding 9606 11024015 t gcesareni Npff specifically bound to npff1 (k(d) = 1.13 nm) and npff2 (k(d) = 0.37 nm), and both receptors were activated by npff in a variety of heterologous expression systems SIGNOR-82916 0.738 SYP protein P08247 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates quantity binding 9606 26903854 t miannu Recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. These cargoes are synaptophysin (for sybII) and SV2A (for synaptotagmin-1). SV2A Acts as an iTRAP to Direct Synaptotagmin-1 Retrieval to SVs. SIGNOR-264117 0.618 GRK1 protein Q15835 UNIPROT RHO protein P08100 UNIPROT up-regulates activity phosphorylation Ser334 PLGDDEAsATVSKTE -1 8617805 t That light-dependent phosphorylation of Rho is mediated primarily by RK. Addition of an inhibitory antibody against rhodopsin kinase (RK) lowered phosphorylation at Ser334, Ser338, and Ser343, without changing the ratio between phosphorylation sites. upon illumination, Ser334c, Ser338, and Ser343 are phosphorylated. SIGNOR-251189 0.921 AMPK complex SIGNOR-C15 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser396 DDKKAKTsTRSSAKT -1 21204788 t done miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). SIGNOR-273930 0.257 EEF1A1P5 protein Q5VTE0 UNIPROT Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269549 0.8 ELAVL4 protein P26378 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates quantity post transcriptional regulation 9606 19221430 t miannu Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure SIGNOR-266865 0.2 oxymetazoline chemical CHEBI:7862 ChEBI ADRA1B protein P35368 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258461 0.8 ZIC1 protein Q15915 UNIPROT GLI3 protein P10071 UNIPROT up-regulates 9606 BTO:0002181 11238441 f fspada Moreover, gli proteins were translocated to cell nuclei by coexpressed zic proteins, and both proteins regulated each others transcriptional activity.In Nih3t3 and 293t cells, both gli1 and gli3 proteins were located predominantly in the cytoplasm (fig. 2, c, d, h, k, l, and p). Coexpression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels (fig. 2, e and m). SIGNOR-105500 0.365 GLI3 protein P10071 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin. SIGNOR-188878 0.574 NSFL1C protein Q9UNZ2 UNIPROT CTSL protein P07711 UNIPROT down-regulates activity binding -1 15498563 t lperfetto The SEP domain of p47 acts as a reversible competitive inhibitor of cathepsin L. SIGNOR-265043 0.2 pipamperone chemical CHEBI:78549 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000601 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258575 0.8 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr332 ILAIHDSyKPEFHSD 10029 BTO:0000246 12907755 t PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates SIGNOR-248391 0.299 NSD1 protein Q96L73 UNIPROT RELA protein Q04206 UNIPROT up-regulates methylation Lys221 LLCDKVQkEDIEVYF 9606 SIGNOR-C13 20080798 t miannu Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. SIGNOR-163458 0.475 DUSP3 protein P51452 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation 9606 32475380 t miannu DUSP3 interacted with the C-terminal domain of STAT3 and dephosphorylated p-Y705 of STAT3.|In summary, DUSP3 downregulated the transcriptional activity of STAT3 via dephosphorylation at Y705 and also suppressed the migratory activity of cancer cells. SIGNOR-277070 0.2 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr564 LEEADNQtLDSYRNE -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276215 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-244281 0.644 AR protein P10275 UNIPROT BTG1 protein P62324 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16281084 f After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. SIGNOR-253673 0.2 PPP1CC protein P36873 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser370 KKTIVNDsRESCVEE 9606 BTO:0001938 23277204 t Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity. SIGNOR-248504 0.2 CCK protein P06307 UNIPROT CCKAR protein P32238 UNIPROT up-regulates binding 9606 10368033 t gcesareni Cck8 interacts with nanomolar affinities with two different receptors designated cck-a and cck-b SIGNOR-68474 0.778 YES1 protein P07947 UNIPROT CDK4 protein P11802 UNIPROT down-regulates phosphorylation Tyr17 AEIGVGAyGTVYKAR 9606 18479465 t lperfetto We purified tyrosine 17 kinases from hela cells and found that the src family non-receptor tyrosine kinase c-yes contributes a large fraction of the tyrosine 17 kinase activity in hela lysatesthis site is equivalent to tyrosine 15 of cyclin dependent kinase 1, which undergoes inhibitory phosphorylation by wee1 and myt1 SIGNOR-178624 0.256 NPEPPS protein P55786 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI down-regulates quantity chemical modification 9606 11062501 t The proteasome generates exact major histocompatibility complex (MHC) class I ligands as well as NH2-terminal-extended precursor peptides| We performed in vitro peptide digests using recombinant PSA | PSA behaved exclusively as an aminopeptidase |BH and PSA act as complementary and redundant systems responsible for the final trimming of the correct NH2 terminus. SIGNOR-272467 0.8 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR HOXA9 protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14701735 f irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. SIGNOR-255863 0.2 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser641 YRYPRPAsVPPSPSL 11427888 t Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. SIGNOR-251239 0.673 NEO1 protein Q92859 UNIPROT Chemoattraction_of_axon phenotype SIGNOR-PH197 SIGNOR up-regulates 17204444 f miannu Neogenin, a close relative of the axon guidance receptor Deleted in Colorectal Cancer (DCC), has been shown to be a receptor for members of the Netrin and Repulsive Guidance Molecule (RGM) families. While Netrin-1-Neogenin interactions result in a chemoattractive axon guidance response, the interaction between Neogenin and RGMa induces a chemorepulsive response. SIGNOR-268395 0.7 Wnt proteinfamily SIGNOR-PF40 SIGNOR LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t Gianni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131577 0.2 CD300LB protein A8K4G0 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9534 BTO:0004055 20959446 t lperfetto The CD300b receptor is a non-classical activating receptor able to deliver signals by associating with the transmembrane adaptor protein DAP-12 and the intracellular mediator Grb-2. SIGNOR-264833 0.475 MAPK1 protein P28482 UNIPROT RPS6KA2 protein Q15349 UNIPROT up-regulates phosphorylation 9606 19282669 t gcesareni Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. SIGNOR-161515 0.705 CDK1 protein P06493 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates phosphorylation Ser332 TDSATIVsPPPSSPP 9606 8087847 t lperfetto Association of e2f with rb inhibits its transactivation potential. phosphorylation of e2f-1 on serine residues 332 and 337 prevented its interaction with rbthese residues were phosphorylated in vivo and by p34cdc2 kinase in vitro. SIGNOR-36022 0.688 DLG2 protein Q15700 UNIPROT Scribble_complex_DLG2-LLGL2_variant complex SIGNOR-C503 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270881 0.484 TFAP2C protein Q92754 UNIPROT ECM1 protein Q16610 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002828 17187826 f miannu Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. SIGNOR-255396 0.29 CS protein O75390 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI down-regulates quantity chemical modification 9606 3013232 t miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. SIGNOR-266238 0.8 PRKG1 protein Q13976 UNIPROT GKAP1 protein Q5VSY0 UNIPROT unknown phosphorylation Ser106 SNPVQKDsREENWQE 9534 10671526 t lperfetto Although both cGK-Ialpha and -Ibeta, but not cAMP-dependent protein kinase, phosphorylated GKAP42 in vitro, GKAP42 was a good substrate only for cGK-Ialpha in intact cells, suggesting that the association with kinase protein is required for the phosphorylation in vivo. SIGNOR-249037 0.643 KCNQ1 protein P51787 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 19298256 t miannu KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. SIGNOR-265981 0.8 ALK protein Q9UM73 UNIPROT PIK3R3 protein Q92569 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000762 27322022 t lperfetto Subsequent studies revealed that ALK promoted cell migration through the P3K-AKT pathway via the p55γ regulatory subunit of PI3K. SIGNOR-253217 0.364 GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268600 0.249 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 11504915 t lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. SIGNOR-116270 0.804 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser96 TSLSDEDsGKGSQPP 9606 15448698 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-129422 0.574 PPP1CC protein P36873 UNIPROT CDK9 protein P50750 UNIPROT up-regulates dephosphorylation Ser175 FGLARAFsLAKNSQP 9606 21533037 t gcesareni Protein phosphatase-1 activates cdk9 by dephosphorylating ser175 SIGNOR-173450 0.2 PRKDC protein P78527 UNIPROT WRN protein Q14191 UNIPROT up-regulates phosphorylation Ser467 DTSYVIEsDEDLEME 9606 BTO:0000007 24429382 t llicata Here, we identify ser-440 and -467 in wrn as major phosphorylation sites mediated by dna-pk our findings indicate that phosphorylation of ser-440 and -467 in wrn are important for relocalization of wrn to nucleoli, and that it is required for efficient dsb repair. SIGNOR-203741 0.661 AKT1 protein P31749 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11035810 t gcesareni In response to insulin, gsk3a inhibited by phosphorylation at ser-21 by pkb/akt1;phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. SIGNOR-252589 0.621 LRFN3 protein Q9BTN0 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments. SIGNOR-264101 0.7 axitinib chemical CHEBI:66910 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258074 0.8 SUV39H1 protein O43463 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 23435416 f lperfetto The methyl marks H3K9me3 on the myoD promoter and H3K27me3 on the myogenin promoter have been shown to be under the control of the histone methyl transferase KMT1A and the HDM KDM4A, respectively, during normal myogenesis. In addition, KMT1A has recently been shown to play a role in ARMS by inhibiting myogenic differentiation SIGNOR-249600 0.524 PTPN12 protein Q05209 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 19350555 t miannu PTP-PEST increases dephosphorylation of Src at Y527 and activates it.|The data presented here supports our hypothesis that PTP-PEST activates Src via dephosphorylating it at Y527 (Tyr530 in human c-Src equivalent to Tyr527 in chicken Src). SIGNOR-277086 0.543 GRIN2B protein Q13224 UNIPROT NMDA receptor_2B complex SIGNOR-C348 SIGNOR form complex binding 9606 BTO:0000938 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits SIGNOR-264123 0.717 NOG protein Q13253 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates activity binding 9031 BTO:0000140 12478285 t lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors (PMID 22298955).Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors. SIGNOR-219221 0.595 GATA2 protein P23769 UNIPROT KLF1 protein Q13351 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 8195185 f irozzo Regulation of the Erythroid Kruppel-like Factor (EKLF) Gene Promoter by the Erythroid Transcription Factor GATA-l.Accordingly,we have also demonstrated that GATA-2, like GATA-1, is able to activate the EKLF promoter in NIH3T3. SIGNOR-256052 0.441 PAK1 protein Q13153 UNIPROT NF2 protein P35240 UNIPROT down-regulates phosphorylation Ser518 DTDMKRLsMEIEKEK 9606 18071304 t lperfetto Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth, SIGNOR-159764 0.631 PRKCG protein P05129 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 t gcesareni Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway. SIGNOR-115726 0.33 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser244 LRASTSKsESSQK 9606 21233202 t lperfetto In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity SIGNOR-252764 0.2 ITGAM protein P11215 UNIPROT AM/b2 integrin complex SIGNOR-C170 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253191 0.744 BIRC2 protein Q13490 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 12525502 t miannu  Here we show that cIAP1 and cIAP2 are E3 ubiquitin-protein isopeptide ligases (ubiquitin ligases) for Smac. cIAPs stimulate Smac ubiquitination both in vivo and in vitro, leading to Smac degradation. cIAP1 and cIAP2 associate with overlapping but distinct subsets of E2 (ubiquitin carrier protein) ubiquitin-conjugating enzymes. The substrate-dependent E3 activity of cIAPs is mediated by their RING domains and is dependent on the specific interactions between cIAPs and Smac. SIGNOR-271392 0.891 PRKAA1 protein Q13131 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Ser121 LMRRSTVsLLDTYQK -1 23871434 t miannu These results indicate that HIPK2 is a substrate of AMPKα2 in vitro and in vivo. Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKα2 in vitro (Figure S5J). SIGNOR-276467 0.2 GYS1 protein P13807 UNIPROT Glycogen_synthesis phenotype SIGNOR-PH39 SIGNOR up-regulates 9534 BTO:0004055 14593110 f lperfetto Glycogen synthase, a key enzyme in the regulation of glycogen synthesis by insulin, is controlled by multisite phosphorylation. SIGNOR-235751 0.7 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr129 ITEIADLtQKIFDLR 9606 BTO:0000671 18986304 t llicata Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143). SIGNOR-182049 0.2 STK38 protein Q15208 UNIPROT AAK1 protein Q2M2I8 UNIPROT up-regulates activity phosphorylation Ser637 AGHRRILsDVTHSAV 10090 BTO:0000142 22445341 t miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. AAK1 phosphorylation regulates dendrite branching and length SIGNOR-263034 0.274 GABARAPL2 protein P60520 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity binding 9606 BTO:0000567 17580304 t lperfetto P62 binds both to lc3a and -b and the related gabarap family proteins/this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguisha SIGNOR-156307 0.861 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 t JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251356 0.2 PPP2CA protein P67775 UNIPROT DDHD1 protein Q8NEL9 UNIPROT up-regulates activity dephosphorylation Ser711 NPAKEPTsVSENEGI -1 11328814 t miannu Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity SIGNOR-262975 0.2 IL22RA1 protein Q8N6P7 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 12087100 t gcesareni Il-22 activates jak1 and tyk2 SIGNOR-90165 0.523 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS3 protein P23396 UNIPROT unknown phosphorylation 9606 15950189 t inferred from 70% family members llicata Erk phosphorylates threonine 42 residue of ribosomal protein s3. SIGNOR-270019 0.2 PPM1A protein P35813 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity dephosphorylation Ser608 ENTEDQYsLVEDDED 10090 BTO:0000944 15016818 t Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes|PP2Cα dephosphorylates the p85 subunit of PI3K, and dephosphorylation of the p85 subunit of PI3K at Ser608 increases its activity SIGNOR-248489 0.33 PPP2CA protein P67775 UNIPROT CILK1 protein Q9UPZ9 UNIPROT down-regulates dephosphorylation Thr157 IRSKPPYtDYVSTRW 9606 BTO:0002181 15988018 t lperfetto In addition, mass spectrometry showed that pp2a treatment completely abolished the dually phosphorylated form, leaving only the singly phosphorylated form (data not shown). We conclude that a portion of ick in unstimulated and asynchronized hek293t cells is dually phosphorylated on the tdy motif. SIGNOR-138428 0.2 LYRM4 protein Q9HD34 UNIPROT Mitochondrial Fe-S Cluster Assembly Complex complex SIGNOR-C276 SIGNOR form complex binding -1 27519411 t lperfetto As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry. SIGNOR-262126 0.699 CLOCK protein O15516 UNIPROT MAGEL2 protein Q9UJ55 UNIPROT down-regulates activity binding 9606 BTO:0000007 22208286 t miannu Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization. SIGNOR-253516 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270430 0.8 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F5 protein P12259 UNIPROT down-regulates activity cleavage Arg1046 HHAPLSPrTFHPLRS -1 10026263 t lperfetto Factor VIIa/tissue factor generates a form of factor V with unchanged specific activity, resistance to activation by thrombin, and increased sensitivity to activated protein C| In this study, we found that TF/VIIa was able to cleave multiple peptide bonds in the coagulation cofactor, factor V. SDS-PAGE analysis and sequencing indicated the factor V was cleaved at Arg679, Arg709, Arg1018, and Arg1192 SIGNOR-263645 0.496 WNT1 protein P04628 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates activity binding 10090 BTO:0000887 16936075 t lperfetto Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6) SIGNOR-217827 0.689 AMPK complex SIGNOR-C15 SIGNOR CRY1 protein Q16526 UNIPROT down-regulates quantity by destabilization phosphorylation Ser71 ANLRKLNsRLFVIRG 9606 19833968 t miannu We demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Phosphorylation of S71 or S280 by AMPK destabilizes CRY1 SIGNOR-268046 0.349 EGFR protein P00533 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 10090 BTO:0000944 7518560 t lperfetto Both competition experiments with synthetic phosphopeptides and dephosphorylation protection analysis demonstrated that y-1173 and y-992 are major and minor binding sites, respectively, for shc on the egfr. SIGNOR-235481 0.911 alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI up-regulates quantity precursor of 9606 24769394 t miannu G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress SIGNOR-267049 0.8 MAPK3 protein P27361 UNIPROT MITF protein O75030 UNIPROT down-regulates quantity by destabilization phosphorylation Ser180 PGSSAPNsPMAMLTL 10841026 t lperfetto More interestingly, ERK-dependent phosphorylation of MITF at Ser 73 is essential for MITF ubiquitinilation and degradation (87). Putting together all these findings, it can be proposed that MAPK activation inhibits melanogenesis due to an increased MITF degradation which is dependent on the MAPK-induced MITF phosphorylation and ubiquitinilation. In summary, although the phosphorylation of MITF at Ser73 increases its intrinsic transcriptional activity, this phosphorylation also targets MITF to the proteasome for its degradation. Consequently, the decrease in MITF levels leads to a down-regulation of melanogenic enzymes expression and to an inhibition of melanogenesis. SIGNOR-249620 0.523 PRKAG1 protein P54619 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 BTO:0000443 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000759 16054041 t lperfetto Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. SIGNOR-139170 0.756 FER protein P16591 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Tyr142 AVVNLINyQDDAELA -1 12640114 t Interaction of beta-catenin with alpha-catenin is regulated by the phosphorylation of beta-catenin Tyr-142. This residue can be phosphorylated in vitro by Fer or Fyn tyrosine kinases.  Transfection of these kinases to epithelial cells disrupted the association between both catenins. SIGNOR-251131 0.708 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MFN1 protein Q8IWA4 UNIPROT up-regulates activity phosphorylation Thr562 LPRSLASTPTAPTTP 10090 BTO:0002572 25801171 t Barakat Finally, in Mfn1 -/- cells re-expressing the MFN1 T562A mutant, phosphorylation was undetectable even in the presence of EGF. Taken together, these data indicate that ERK phosphorylates MFN1 at T562. SIGNOR-274134 0.2 PRKCD protein Q05655 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL -1 8422248 t lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. SIGNOR-248924 0.468 CCKBR protein P32239 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257305 0.431 DUSP1 protein P28562 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 10617468 t gcesareni The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1. SIGNOR-73617 0.778 oxymetazoline chemical CHEBI:7862 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258917 0.8 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR PFKP protein Q01813 UNIPROT down-regulates activity phosphorylation Ser679 MQQGGAPsPFDRNFG 9606 BTO:0000782 28607489 t lperfetto Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3–CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2.|Phosphomimicking mutants of PFKP (S679E) or PKM2 (S37E) displayed decreased catalytic activity SIGNOR-273033 0.2 IFNLR1 protein Q8IU57 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 15120645 t gcesareni Despite signaling through distinct receptor complexes, type i ifns and ifn-_s activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (fig. 6). In both cases, receptor engagement leads via the activation of the jak kinases jak1 and tyk2 SIGNOR-124483 0.541 NAB2 protein Q15742 UNIPROT EGR2 protein P11161 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000414 20506119 f miannu Our results suggest that in many cells of neuroectodermal and epithelial origin EGR1, EGR2, and EGR3 activate NAB2 transcription which is in turn repressed by NAB2, thus establishing a negative feedback loop. SIGNOR-253888 0.593 BTF3 protein P20290 UNIPROT MADCAM1 protein Q13477 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000584 17312387 f In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. SIGNOR-253945 0.2 MAOB protein P27338 UNIPROT (R)-adrenaline smallmolecule CHEBI:28918 ChEBI up-regulates quantity chemical modification 9606 BTO:0000142 20493079 t Luana The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. SIGNOR-269746 0.8 CBP/p300 complex SIGNOR-C6 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys28 LATKAARkSAPSTGG 9606 21131905 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription. SIGNOR-217214 0.2 GPR35 protein Q9HC97 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256860 0.2 PRKCA protein P17252 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Ser243 RWLVVKDsFLLYMCL 9606 15979581 t miannu The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity SIGNOR-138351 0.679 GLI1/GLI2 complex SIGNOR-C450 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000304 32766732 t GLI2 and GLI1 heterodimerize via the Zn-finger domain SimoneGraziosi GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. | RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells SIGNOR-269211 0.381 EGF protein P01133 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9168989 f Regulation miannu We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin. SIGNOR-251782 0.262 EEF2K protein O00418 UNIPROT EEF2 protein P13639 UNIPROT down-regulates phosphorylation Thr57 RAGETRFtDTRKDEQ 9606 8386634 t gcesareni The eef-2 kinase could phosphorylate a synthetic peptide based on residues 49-60 of eef-2 (ragetrftdtrk), albeit only at a very low rate, and with a very high km, compared to eef-2 itself. SIGNOR-38552 0.78 MRPL41 protein Q8IXM3 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262355 0.699 GFs stimulus SIGNOR-ST12 SIGNOR AKT3 protein Q9Y243 UNIPROT up-regulates activity 9606 23300340 f lperfetto Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation SIGNOR-245408 0.7 GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268592 0.2 MIF protein P14174 UNIPROT HBA1 protein P69905 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000664 16636133 f Regulation of expression miannu MIF inhibits cytodifferentiation and hemoglobin synthesis of MEL cells. SIGNOR-251832 0.2 PHA-680632 chemical CID:11249084 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206100 0.8 CDK2 protein P24941 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates phosphorylation Ser428 FAQSAPGsPLSSQPV 9606 20810654 t gcesareni We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis. SIGNOR-167834 0.376 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR EGR1 protein P18146 UNIPROT up-regulates binding 9606 10671503 t lperfetto The early growth response transcription factor egr-1 can also interact with rela in vitro and regulate nf-kappab transcriptional activity in vivo SIGNOR-216328 0.406 INCENP protein Q9NQS7 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity binding 7227 16824953 t lperfetto INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop SIGNOR-252048 0.714 ABL1 protein P00519 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 BTO:0001271 23399893 t gcesareni We show that the grb2-related adapter protein, gads, also associates with bcr-abl, specifically through y177 and demonstrate that bcr-abl-driven lymphoid disease requires gads SIGNOR-200871 0.27 SKIL protein P12757 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates binding 9606 SIGNOR-C85 12419246 t gcesareni Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7 SIGNOR-195636 0.494 KDM1A protein O60341 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 BTO:0000567 15620353 t miannu Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription. SIGNOR-264509 0.2 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252750 0.753 PRKAA1 protein Q13131 UNIPROT KLC2 protein Q9H0B6 UNIPROT up-regulates phosphorylation Ser582 PRMKRASsLNFLNKS 9606 SIGNOR-C15 21725060 t gcesareni Consistent with phosphorylation of both ser545 and ser582 of klc2 contributing to its 14-3-3 binding, a ser545ala mutant of klc2 could be phosphorylated in vitro by ampk on ser582 SIGNOR-174681 0.2 ELOVL1 protein Q9BW60 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267896 0.8 UBE4B protein O95155 UNIPROT FEZ1 protein Q99689 UNIPROT up-regulates activity polyubiquitination 10116 BTO:0001009 15466860 t K27 miannu  E4B mediated the polyubiquitylation of FEZ1 but did not affect its intracellular stability, suggesting that such modification of FEZ1 is not a signal for its proteolysis. Polyubiquitylation of FEZ1 by E4B required Lys(27) of ubiquitin. Expression of a dominant-negative mutant of E4B in rat pheochromocytoma PC12 cells resulted in inhibition of neurite extension induced either by nerve growth factor or by coexpression of FEZ1 and constitutively active PKCzeta. These findings indicate that E4B serves as a ubiquitin ligase for FEZ1 and thereby regulates its function but not its degradation. The polyubiquitin chain attached by E4B to FEZ1 might therefore facilitate the interaction of FEZ1 with an unidentified target that functions in neuritogenesis. SIGNOR-271510 0.4 SIAH2 protein O43255 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates 9606 17003045 f gcesareni The ring finger ubiquitin ligase siah2 controls the stability of various substrates involved in stress and hypoxia responses, including the phd3, which controls the stability of hif-1alpha SIGNOR-149893 0.369 PRKAA1 protein Q13131 UNIPROT NRF1 protein Q16656 UNIPROT up-regulates 9606 15509864 f gcesareni In muscle, it causes increased dna binding by the transcription factors nrf1 (bergeron et al., 2001) and mef2 (zheng et al., 2001), which may be involved in regulation of mitochondrial genes and glut4, respectively. SIGNOR-130076 0.2 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120084 0.316 TOMM40 protein O96008 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 t lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. SIGNOR-267681 0.736 ITGB5 protein P18084 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257722 0.581 CUL1 protein Q13616 UNIPROT ARIH1 protein Q9Y4X5 UNIPROT up-regulates activity binding 9606 BTO:0000007 24076655 t miannu Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin. SIGNOR-268844 0.363 RPS6KB1 protein P23443 UNIPROT CAD protein P27708 UNIPROT up-regulates activity phosphorylation Ser1859 PPRIHRAsDPGLPAE 9606 BTO:0002181 23429703 t miannu CAD as a direct substrate of S6K1. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. The direct regulation of CAD by S6K1 serves as a mechanism to increase the pool of nucleotides available for the RNA and DNA synthesis that accompanies cell growth. SIGNOR-267443 0.38 vitamin K epoxide smallmolecule CHEBI:28371 ChEBI vitamin K smallmolecule CHEBI:28384 ChEBI up-regulates quantity precursor of 9606 31226734 t lperfetto This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR) SIGNOR-265907 0.8 PFAS protein O15067 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 33179964 t miannu The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure. SIGNOR-267310 0.8 PRKDC protein P78527 UNIPROT CASP2 protein P42575 UNIPROT up-regulates phosphorylation Ser139 LSCDYDLsLPFPVCE 9606 19203584 t lperfetto Here we show that dna damage induced by gamma-radiation triggers the phosphorylation of nuclear caspase-2 at the s122 site within its prodomain, leading to its cleavage and activation. This phosphorylation is carried out by the nuclear serine/threonine protein kinase dna-pkcs SIGNOR-183895 0.302 GABA-B receptor complex SIGNOR-C336 SIGNOR GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 30541966 t miannu GABAB receptors are G protein-coupled receptors that mediate slow and prolonged inhibitory action, via activation of Gαi/o-type proteins. GABAB receptors mediate their inhibitory action through activating inwardly rectifying K+ channels, inactivating voltage-gated Ca2+ channels, and inhibiting adenylate cyclase. SIGNOR-264965 0.406 DOCK7 protein Q96N67 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 BTO:0000132 29187380 t lperfetto As a GEF, Dock7 exchanges GDP for GTP on Cdc42 and Rac1, causing their activation, followed by activation of downstream effectors, including the dephosphorylation (activation) of cofilin, a key regulator of actin turnover. SIGNOR-261886 0.728 PRKCZ protein Q05513 UNIPROT NR1H4 protein Q96RI1 UNIPROT up-regulates phosphorylation Thr456 GRLTELRtFNHHHAE 9606 BTO:0000195 18668687 t The effect has been demonstrated using Q96RI1-2 gcesareni The effect of fic1 on fxr phosphorylation and nuclear localization and its effects on bsep promoter activity could be blocked with protein kinase c zeta (pkc zeta) inhibitors (pseudosubstrate or small interfering rna silencing). Recombinant pkc zeta directly phosphorylated immunoprecipitated fxr. The mutation of threonine 442 of fxr to alanine yielded a dominant negative protein, SIGNOR-179771 0.389 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates activity phosphorylation Tyr724 ANCTHDLyMIMRECW 9606 BTO:0000007 11294897 t lperfetto Ligand stimulation leads to autophosphorylation of fgfr3taken together, these results clearly implicate y724 in the activation of stat proteins by constitutively activated mutants of fgfr3 and suggest that both y724 and y760 are required for maximal stat activation. SIGNOR-106738 0.2 TNK2 protein Q07912 UNIPROT SNX9 protein Q9Y5X1 UNIPROT up-regulates phosphorylation 9606 16316319 t gcesareni We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor. SIGNOR-142569 0.519 PRKCD protein Q05655 UNIPROT BLVRA protein P53004 UNIPROT up-regulates activity phosphorylation Ser33 DLRNPHPsSAFLNLI 22584576 t lperfetto LC-MS/MS analysis of PKCdelta-activated intact hBVR identified phosphorylated serine positions 21, 33, 230, and 237, corresponding to the hBVR Src homology-2 domain motif (Ser(230) and Ser(237)), flanking the ATP-binding motif (Ser(21)) and in PHPS sequence (Ser(33)) as targets of PKCdelta. |PKCdelta potentiated hBVR reductase activity and accelerated the rate of bilirubin formation. SIGNOR-275527 0.2 DVL1P1 protein P54792 UNIPROT CCDC88C protein Q9P219 UNIPROT up-regulates binding 9606 23151663 t gcesareni Daple binds to dvl and functions as a negative regulator of the wnt signalling pathway. SIGNOR-199448 0.2 CSNK2A2 protein P19784 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser99 KEEEEGIsQESSEEE -1 2806554 t llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. | After an 80 min incubation with CK-II, both serines were fully phosphorylated to 1 mol/mol and serine-99 to 0.3 mol/mol. SIGNOR-251006 0.334 MMP14 protein P50281 UNIPROT FGG protein P02679 UNIPROT down-regulates quantity by destabilization cleavage Leu92 QLIKAIQlTYNPDES -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain SIGNOR-263617 0.2 OXSR1 protein O95747 UNIPROT SLC12A3 protein P55017 UNIPROT up-regulates phosphorylation Thr60 MRTFGYNtIDVVPTY 9606 BTO:0000007 BTO:0000671 18270262 t miannu We demonstrate that the spak and osr1 kinases that are activated by wnk1 phosphorylate human ncc at three conserved residues (thr46, thr55 and thr60) / our results also indicate that phosphorylation of thr60 plays the most crucial role in triggering the activation of ncc in hek293 cells and its mutation also inhibits phosphorylation of the adjacent thr46 and thr55 sites. SIGNOR-160833 0.397 HDAC2 protein Q92769 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263850 0.789 CSNK2B protein P67870 UNIPROT MME protein P08473 UNIPROT unknown phosphorylation Ser6 sQMDITDI 9606 BTO:0003288 8943850 t llicata Taken together, these data indicate that CD10/NEP is itself phosphorylated by CKII and that CD10/NEP co-associates with additional tyrosine phosphoproteins including lyn. SIGNOR-251078 0.383 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 9335504 t llicata In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1 SIGNOR-52674 0.591 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Ser299 NQVTQRAsRRSDSAS 9606 17603046 t gcesareni Here, we demonstrate that pkcdelta undergoes in vitro autophosphorylation at three sites within its v3 region (s299, s302, s304), each of which is unique to this pkc isoform and evolutionarily conserved SIGNOR-156523 0.2 FRK protein P42685 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr1552 HDLTETSyLPRQDLE 9606 BTO:0003323 29156836 t miannu Herein, we demonstrate that Fyn-related kinase (Frk)/Rak plays an important role in maintaining genomic stability, possibly in part through positively regulating BRCA1 protein stability and function via tyrosine phosphorylation on BRCA1 Tyr1552. Rak-mediated tyrosine phosphorylation of BRCA1 is essential for its stability and function SIGNOR-275454 0.2 FGF1 protein P05230 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates activity binding 9606 BTO:0001487 18940940 t fspada Together these data highlight the unique nature of the role of FGF-1 during the earliest stages of adipogenesis and establish a role for FGFR1 in human adipogenesis, identifying FGFR1 as a potential therapeutic target to reduce obesity. SIGNOR-236936 0.912 CSNK1E protein P49674 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Thr224 MSRFSSStEQSSASR 9606 22609948 t lperfetto We demonstrated that dvl2 is phosphorylated at s143 and t224 in a manner that requires both non-canonical wnt5a ligand and casein kinase 1 epsilon (ck1_), and that this event is critical to interact with plk1 in early stages of the cell cycle SIGNOR-197555 0.68 CDK5 protein Q00535 UNIPROT MAPK10 protein P53779 UNIPROT down-regulates activity phosphorylation Thr131 ISLLNVFtPQKTLEE 9606 BTO:0000007 11823425 t llicata Here, we show that cdk5 directly phosphorylates c-Jun N-terminal kinase 3 (JNK3) on Thr131 and inhibits its kinase activity, leading to reduced c-Jun phosphorylation. SIGNOR-250668 0.352 AKT2 protein P31751 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 9812896 t gcesareni Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity SIGNOR-61561 0.508 MAPK14 protein Q16539 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates activity phosphorylation Thr692 QAAYYGQtPGPGGPQ 10090 BTO:0000165 16364914 t lperfetto KSRP, an important factor for AU-rich element (ARE)-directed mRNA decay, undergoes p38-dependent phosphorylation during muscle differentiation. KSRP phosphorylated by p38 displays compromised binding to ARE-containing transcripts and fails to promote their rapid decay, although it retains the ability to interact with the mRNA degradation machinery SIGNOR-235856 0.554 AMPK complex SIGNOR-C15 SIGNOR PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser295 RYHGHSMsDPGVSYR -1 33022274 t miannu In vitro kinase assay revealed that PDHA could be readily phosphorylated by active AMPK complex in a dose-dependent manner (Figure 6C).  SIGNOR-276835 0.257 TGFBI protein Q15582 UNIPROT A3/b1 integrin complex SIGNOR-C161 SIGNOR up-regulates activity binding 10090 BTO:0001175 10906123 t lperfetto In addition, we demonstrated the functional receptor for betaig-h3 is alpha(3)beta(1) integrin. These results, therefore, establish the essential motifs within the 2nd and the 4th domains of betaig-h3, which interact with alpha(3)beta(1) integrin to mediate HCE cell adhesion to betaig-h3 and suggest that other proteins containing Asp-Ile in their fas-1 domains could possibly function as cell adhesion molecules. SIGNOR-253211 0.431 arecoline chemical CHEBI:2814 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258639 0.8 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159470 0.259 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 7493944 t lperfetto Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26590 0.2 KNL1 protein Q8NG31 UNIPROT BUB1B protein O60566 UNIPROT up-regulates binding 9606 17981135 t gcesareni Association of the amino and middle domain of blinkin with the tpr domains in the amino termini of bubr1 and bub1 is essential for bubr1 and bub1 to execute their distinct mitotic functions SIGNOR-158894 0.2 CSNK2A1 protein P68400 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates phosphorylation Ser468 DLTIDSSsDEEEEEP 9606 19217413 t llicata Ck2 phosphorylates serine residues adjacent to the sim of pias1 these findings show that the phosphosim module mediates binding to free sumo and sumo conjugates in a phosphorylation-dependent mode, with ck2 being the critical kinase involvedin this process. SIGNOR-184047 0.338 AMPK complex SIGNOR-C15 SIGNOR RB1 protein P06400 UNIPROT unknown phosphorylation Ser811 IYISPLKsPYKISEG 9606 19217427 t lperfetto Amp-activated protein kinase phosphorylates retinoblastoma protein. Rb phosphorylation sites, ser804 (ser811 in human), resembled the ampk consensus phosphorylation site. SIGNOR-216635 0.2 RNF4 protein P78317 UNIPROT KDM5B protein Q9UGL1 UNIPROT down-regulates quantity by destabilization sumoylation 9606 33859667 t SaraGualdi Hendriks and coworkers showed that, in response to alkylation damage by methyl methanesulfonate (MMS), SUMOylated JARID1B (KDM5B) is ubiquitylated by the SUMOtargeted ubiquitin ligase RNF4 and degraded by the proteasome, whereas JARID1C (KDM5C) is SUMOylated and recruited to the chromatin to demethylate histone H3K4 (Hendriks et al., 2015). SIGNOR-271575 0.305 GRIN2A protein Q12879 UNIPROT NMDA receptor_2A complex SIGNOR-C347 SIGNOR form complex binding 9606 BTO:0000938 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits SIGNOR-264121 0.715 XL-647 chemical CID:10458325 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 22722787 t gcesareni Xl647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (egfr), vascular endothelial growth factor receptor 2, her2 and ephrin type-b receptor 4 (ephb4). SIGNOR-197962 0.8 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2NL protein Q5JXB2 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271370 0.2 PRKCE protein Q02156 UNIPROT ALDH2 protein P05091 UNIPROT up-regulates activity phosphorylation Thr202 KLGPALAtGNVVVMK -1 28056995 t lperfetto Post-translational enhancement of ALDH2 activity can be achieved by serine/threonine phosphorylation by epsilon protein kinase C (epsilonPKC). |e identified S279 as a critical εPKC phosphorylation site in the activation of ALDH2. The critical catalytic site, cysteine 302 (C302) of ALDH2 is susceptible to adduct formation by reactive aldehyde, 4HNE, which readily renders the enzyme inactive. We show that phosphomimetic mutations of T185E, S279E and T412E confer protection of ALDH2 against 4HNE-induced inactivation, indicating that phosphorylation on these three sites by εPKC likely also protects the enzyme against reactive aldehydes. SIGNOR-271865 0.285 BBS5 protein Q8N3I7 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 t lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome SIGNOR-262559 0.877 PTPN11 protein Q06124 UNIPROT SLC25A4 protein P12235 UNIPROT down-regulates activity dephosphorylation 9606 29255148 t miannu Specifically, SHP2-mediated dephosphorylation of ANT1 at Tyr 191 is essential for mitochondrial homeostasis and mitigation of NLRP3 inflammasome activation.|The interaction between SHP2 and ANT1 (Fig.\u00a0 xref ), and the opposite effects of SHP2 and ANT1 shRNAs in the activation of NLRP3 inflammasome (Figs.\u00a0 xref and xref ) raised the possibility that the SHP2 may inhibit ANT1 to suppress NLRP3 inflammasome activation.|To further determine which tyrosine phosphorylation site of ANT1 is dephosphorylated by SHP2, we created the dephosphorylated mutant of ANT1, in which tyrosine was replaced with phenylalanine (Y to F mutation). SIGNOR-277124 0.274 NCAPD2 protein Q15021 UNIPROT Condensin I complex SIGNOR-C341 SIGNOR form complex binding 9606 32445620 t miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263905 0.969 PAK1 protein Q13153 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser339 PRGQRDSsYYWEIEA 9606 18775988 t gcesareni P21-activated protein kinases (paks) are serine/threonine protein kinases that phosphorylate raf-1 at ser-338 and ser-339. SIGNOR-180812 0.585 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270398 0.8 CR2 protein P20023 UNIPROT CD19 protein P15391 UNIPROT up-regulates activity binding 9606 BTO:0000776 31732528 t scontino Complement receptor type 2 (CR2)/CD21 plays a key role in the development of high-affinity Abs and long-lasting memory to foreign Ags. When CR2 is bound by its primary C3 activation fragment–derived ligand, designated C3d, it coassociates with CD19 on B cells to amplify BCR signaling. SIGNOR-266642 0.775 NUP54 protein Q7Z3B4 UNIPROT p62_complex complex SIGNOR-C259 SIGNOR form complex binding 10116 BTO:0000154 2050741 t Simone Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function. SIGNOR-261259 0.938 EXOC7 protein Q9UPT5 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270790 0.94 NCOA1 protein Q15788 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f inferred from family member miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-270223 0.2 RPA2 protein P15927 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 19586055 t esanto The response to replication stress requires the recruitment of rpa and the mre11-rad50-nbs1 (mrn) complex. We observe a direct interaction between rpa with both nbs1 and mre11. By utilizing rpa bound to ssdna, we demonstrate that substituting rpa with phosphorylated rpa or a phosphomimetic weakens the interaction with the mrn complex. SIGNOR-186651 0.53 STK11 protein Q15831 UNIPROT NUAK1 protein O60285 UNIPROT up-regulates phosphorylation Thr211 QKDKFLQtFCGSPLY 9606 14976552 t llicata A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold. SIGNOR-122686 0.527 ATR protein Q13535 UNIPROT XPA protein P23025 UNIPROT up-regulates phosphorylation Ser196 RSLEVWGsQEALEEA 9606 23178497 t lperfetto Atr phosphorylates xpa. at serine 196. Atr-mediated xpa phosphorylation enhances xpa stability by inhibiting herc2-mediated ubiquitination and subsequent degradation. SIGNOR-199802 0.505 CTNNB1 protein P35222 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 10090 BTO:0000165 19000719 t Through Armadillo repeat domain gcesareni Beta-catenin can regulate the level and transcriptional activity of the notch1 and notch1 intracellular domain (nicd). The in vivo and in vitro results demonstrate that beta-catenin binds with notch1 and nicd, for which its armadillo repeat domain is essential. SIGNOR-236858 0.766 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT up-regulates quantity by stabilization phosphorylation Thr215 ATGSVPStPIAHRGP 9606 BTO:0000007 16682949 t done miannu Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. SIGNOR-274082 0.525 TIRAP protein P58753 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 11544529 t gcesareni Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. SIGNOR-252063 0.62 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Thr23 ESPPVSDtPDEGDEP 9606 BTO:0001271 21750978 t miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway SIGNOR-174856 0.2 MLL2 complex complex SIGNOR-C88 SIGNOR KDM6A protein O15550 UNIPROT up-regulates quantity by stabilization binding 9606 28669924 t miannu KMT2D associates with WRAD (WDR5, RbBP5, ASH2L, and DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX in one protein complex. It acts as a scaffold protein within the complex and is responsible for maintaining the stability of UTX. UTX is the complex’s H3K27 demethylase. SIGNOR-268813 0.807 TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 9606 19701891 t miannu The binding of TGF‐β1 to its receptor complex activates the intracellular kinase domain of TGF‐βRII, which leads to the phosphorylation and activation of Smad2, Smad3 and Smad4 as well as non‐Smad proteins (Smad‐independent pathway) SIGNOR-254361 0.805 4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide chemical CHEBI:49868 ChEBI PLK1 protein P53350 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258078 0.8 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL 9606 20643654 t lperfetto Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr373/376 (11, 12, 14, 17), and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr9 and then Tyr373/376 SIGNOR-166710 0.347 SOX9 protein P48436 UNIPROT CEBPB protein P17676 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19254573 f fspada Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation SIGNOR-184280 0.331 TARS1 protein P26639 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 25824639 t miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. SIGNOR-270504 0.8 GSK3B protein P49841 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Thr509 PVYEVPAtPKYATPA 9606 BTO:0000938 16611631 t lperfetto In summary, phosphorylation of thr509 of human crmp1 appears to be regulated by two mechanisms; direct phosphorylation by cdk5, or by priming of ser522 by cdk5 followed by sequential phosphorylation of ser518, thr514, and thr509 by gsk3. SIGNOR-145995 0.448 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 BTO:0000938 21079800 t gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. SIGNOR-169682 0.432 CHD8 protein Q9HCK8 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 15367660 t gcesareni Duplin (axis duplication inhibitor) interacts with beta-catenin and prevents its binding to tcf, thereby inhibiting downstream wnt signaling SIGNOR-128976 0.629 HNF4A protein P41235 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 f inferred from family member gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-267790 0.26 PDPK1 protein O15530 UNIPROT SGK2 protein Q9HBY8 UNIPROT up-regulates activity phosphorylation Ser416 SSAFLGFsYAPEDDD 10548550 t miannu SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB. SIGNOR-250376 0.582 MRPS11 protein P82912 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261458 0.761 XBP1 protein P17861 UNIPROT NPPB protein P16860 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20170659 f miannu The promoter assay with overexpression of sXBP1 or norepinephrine showed that the proximal AP1/CRE-like element in the promoter region of BNP was critical for transcriptional regulation of BNP by sXBP1. SIGNOR-255609 0.2 CADM2 protein Q8N3J6 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 BTO:0000007 29506532 f Gianni The results indicated that CADM2 […} modulates EMT process and migration ability via focal adhesion kinase (FAK) /AKT signaling pathway in HCC. SIGNOR-268855 0.2 ITGA6 protein P23229 UNIPROT PMP22 protein Q01453 UNIPROT up-regulates activity binding 10090 16436605 t Regulation miannu PMP22 is in a complex with α6β4 integrin and laminin. PMP22 and β4 integrin are in a complex in a variety of cell types. The interaction with the integrins provides PMP22 with the ability to modulate the cell–ECM communications, as well as intracellular events. Signaling between the ECM and the intracellular compartment is essential for SC myelination, as well as cellular differentiation and motility, in general. The identification of PMP22 as a binding partner for an integrin signaling complex provides a major step toward understanding the role of this disease-linked molecule in the nervous system and in non-neural cell types. SIGNOR-251895 0.358 PRKAA2 protein P54646 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 10090 SIGNOR-C3 18439900 t lperfetto These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK SIGNOR-263045 0.681 NFIA protein Q12857 UNIPROT NEUROD1 protein Q13562 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268890 0.287 IKBKB protein O14920 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity phosphorylation Ser138 NNLSRSNsDESNFSE 9606 BTO:0000007 16818229 t miannu Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling. SIGNOR-276292 0.764 glutamic acid smallmolecule CHEBI:18237 ChEBI NMDA receptor_2B complex SIGNOR-C348 SIGNOR up-regulates activity chemical activation 9606 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate SIGNOR-264129 0.8 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 9445476 t miannu A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. SIGNOR-188911 0.716 ATE1 protein O95260 UNIPROT HSPA5 protein P11021 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000567 29295953 t miannu We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway. SIGNOR-261345 0.299 IQSEC2 protein Q5JU85 UNIPROT GRIA2 protein P42262 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 27009485 t miannu BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors. SIGNOR-264913 0.2 CREB3L1 protein Q96BA8 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 35051932 f lperfetto Transcriptional and post-transcriptional regulation of oxytocin and vasopressin gene expression by CREB3L1 and CAPRIN2|By luciferase assays, we demonstrate that CREB3L1 may be a transcription factor regulating Oxt gene expression. By RNA immunoprecipitation assays and northern blot analysis of Oxt mRNA poly(A) tails, we have found that CAPRIN2 binds Oxt mRNA and regulates its poly(A) tail length.|To investigate transcriptional regulation of the OXT gene by CREB3L1, we performed luciferase assays using a proximal Oxt promoter region transfected in HEK293T cells. The expression of full-length CREB3L1 (CREB3L1FL) and a constitutively active CREB3L1 (CREB3L1CA) significantly increased luciferase activity by 5.4- and 3.2-fold, respectively, compared with controls SIGNOR-268555 0.2 STK25 protein O00506 UNIPROT CCM2 protein Q9BSQ5 UNIPROT up-regulates phosphorylation Ser384 GRGIITDsFGRHRRA 9606 BTO:0001757 22782892 t miannu CCM2 can be phosphorylated by STK25, and the kinase activity of STK25 is required for death signaling. SIGNOR-263144 0.514 CDKN2AIP protein Q9NXV6 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 16803988 t miannu In the nucleoplasm, carf interacts with p53 and enhances its function. SIGNOR-147360 0.391 carfilzomib chemical CHEBI:65347 ChEBI PSMB2 protein P49721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 17591945 t miannu Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM. SIGNOR-259310 0.8 CSNK2A2 protein P19784 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity phosphorylation Ser60 ETNQNSSsDSEAERR -1 11711551 t llicata We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. SIGNOR-251046 0.386 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI L-thyroxine smallmolecule CHEBI:18332 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-267038 0.8 MAPK14 protein Q16539 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 22933625 f apalma The IL-10-mediated shift in macrophage phenotype in injured muscle may be amplified by activation of mitogen-activated protein kinase (MAPK), especially p38 MAPK, through signaling that is antagonized by MAPK phosphatase-1 (MKP-1). SIGNOR-255447 0.7 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9823 BTO:0004007 10523831 t lperfetto Phosphorylation of the adapter protein shc by growth factor receptors provides association sites for grb2-sos, thereby activating the ras/map kinase pathway. SIGNOR-235615 0.965 MTOR protein P42345 UNIPROT NRBF2 protein Q96F24 UNIPROT up-regulates activity phosphorylation Ser120 SPLSQKYsPSTEKCL 9606 BTO:0001938 28059666 t miannu Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association. SIGNOR-265875 0.2 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT down-regulates activity phosphorylation Thr203 SSLATPPtLSSTVLI 9606 12815053 t lperfetto M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1 SIGNOR-102498 0.555 P-TEFb complex SIGNOR-C238 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation 9606 32048991 t miannu Phosphorylation of Pol II CTD by positive transcription elongation factor b (P-TEFb) is a necessary precursor event that enables productive transcription elongation. To perform this task, Pol II needs to be activated by a complex of proteins called P-TEFb; however, P-TEFb is usually found in an inactive form held by another group of proteins. Yet, it is unclear how P-TEFb is released and allowed to activate Pol II. SIGNOR-261039 0.745 PDGFRA protein P16234 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 24743741 f To further investigate the signaling pathway through which PDGFRαpromotes the proliferation of PDGFRα+ cells, we used inhibitors of PI3K-Akt and Ras-MAPK pathways, which are known to be downstream signaling pathways of PDGFRα. Thus, both PI3K-Akt and MEK2-MAPK pathways are necessary for PDGFRα-driven proliferation. SIGNOR-254377 0.33 PRKCD protein Q05655 UNIPROT TAGLN protein Q01995 UNIPROT down-regulates activity phosphorylation Ser181 VIGLQMGsNRGASQA -1 11053353 t lperfetto Of the three consensus protein kinase C or casein kinase II phosphorylation sites in SM22, only Ser-181 was readily phosphorylated by protein kinase C in vitro, and such phosphorylation greatly decreased actin binding. SIGNOR-249061 0.332 PTPRG protein P23470 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity dephosphorylation Tyr1248 PTAENPEyLGLDVPV -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254701 0.293 CSNK2A1 protein P68400 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-250831 0.29 PRKCD protein Q05655 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr375 GRGARGGtRGGRGRI 9606 BTO:0004974 14699138 t lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation SIGNOR-249254 0.294 CDK2 protein P24941 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation Thr40 DAESYTFtVPRRHLE 23972993 t For phosphorylated residues see Figure 7 lperfetto Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP SIGNOR-274050 0.44 SRP19 protein P09132 UNIPROT SRP68 protein Q9UHB9 UNIPROT up-regulates activity binding -1 30649418 t miannu Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54. SIGNOR-261167 0.949 PRKCA protein P17252 UNIPROT F11R protein Q9Y624 UNIPROT unknown phosphorylation Thr92 DRVTFLPtGITFKSV -1 7646439 t lperfetto Internal amino acid sequence analysis of the F11 antigen provided information concerning 68 amino acids and suggested two consensus phosphorylation sites for protein kinase C (PKC). The phosphorylation by PKC of the isolated F11 antigen was observed following stimulation by phorbol 12-myristate 13-acetate. SIGNOR-248901 0.327 NSD1 protein Q96L73 UNIPROT RELA protein Q04206 UNIPROT up-regulates methylation Lys218 EIFLLCDkVQKEDIE 9606 SIGNOR-C13 20080798 t miannu Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. SIGNOR-163454 0.475 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR SERPINE1 protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001615 22198637 t lperfetto Both CLOCK:ARNTL and CLOCK:ARNTL2 heterodimers powerfully activate the promoter of the PAI-1 gene, officially called SERPINE1 and located on the seventh chromosome (7q21.3-q22), underlying the circadian variation in circulating PAI-1 SIGNOR-253712 0.506 nutlin-3A chemical CID:11433190 PUBCHEM MDM2 protein Q00987 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194874 0.8 ABL1 protein P00519 UNIPROT CD19 protein P15391 UNIPROT up-regulates activity phosphorylation Tyr508 EDMRGILyAAPQLRS 10090 11120811 t gcesareni The results revealed that only tyrosine (Y)490 of CD19 was phosphorylated by c-Abl. SIGNOR-245283 0.548 PLK1 protein P53350 UNIPROT SRI protein P30626 UNIPROT unknown phosphorylation Thr155 YSTNGKItFDDYIAC 9606 24427308 t lperfetto Sorcin interacts physically with plk1, is phosphorylated by plk1 and induces plk1 autophosphorylation, thereby regulating kinase activity. SIGNOR-203732 0.383 UBE2I protein P63279 UNIPROT BHLHE40 protein O14503 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11278694 t miannu  Co-expression of STRA13 and UBC9 led to an increase of the pSTRA13 ubiquitination and subsequent degradation. These data established that UBC9/STRA13 association in cells is of physiological importance, presenting direct proof of UBC9 involvement in the ubiquitin-dependent degradation of pSTRA13. We also checked whether UBC9 is directly involved in pSTRA13 ubiquitination. Taken together, these results strongly suggest that pSTRA13 is targeted for proteolysis by the ubiquitin-dependent proteasome pathway through association with UBC9. SIGNOR-272579 0.332 MAPK11 protein Q15759 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 BTO:0000567 9687510 t gcesareni Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha SIGNOR-59443 0.598 ATM protein Q13315 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 17189255 t gcesareni Atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster. In addition, our data suggest that dna-pkcs- and atm-mediated dna-pkcs phosphorylations are cooperative and required for the full activation of dna-pkcs and the subsequent dsb repair. SIGNOR-151441 0.689 RELA protein Q04206 UNIPROT EGR1 protein P18146 UNIPROT up-regulates binding 9606 SIGNOR-C13 10671503 t gcesareni The early growth response transcription factor egr-1 can also interact with rela in vitro and regulate nf-kappab transcriptional activity in vivo SIGNOR-75001 0.443 antigen smallmolecule CHEBI:59132 ChEBI BCR-Dl complex SIGNOR-C436 SIGNOR up-regulates activity binding 9606 BTO:0000776 32323266 t scontino The recognition of antigen by the BCR initiates BCR signaling cascade. SIGNOR-268205 0.8 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 17157788 t miannu Atm/atr are generally sensors of dna damage, but, together with the checkpoint kinases chk1 and chk2, they also function as response effectors by phosphorylation of key substrates, such as p53, brca1, and nbs1. In particular, p53 phosphorylation leads to protein accumulation and activation, which in turn promotes cell-cycle arrest or apoptosis. SIGNOR-151138 0.838 phenylalanine smallmolecule CHEBI:28044 ChEBI tyrosine smallmolecule CHEBI:18186 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors SIGNOR-264172 0.8 ASH1L protein Q9NR48 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity trimethylation Lys37 APATGGVkKPHRYRP -1 21239497 t Gianni We show that human ASH1L specifically methylates histone H3 Lys-36. Our data implicate that there may be a regulatory mechanism of ASH1L histone methyltransferases SIGNOR-269055 0.2 MAPK14 protein Q16539 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser295 LQASVPGsVPGVLGP 9606 16027724 t miannu ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation SIGNOR-250095 0.424 PSAT1 protein Q9Y617 UNIPROT O-phosphonato-L-serine(2-) smallmolecule CHEBI:57524 ChEBI up-regulates activity chemical modification 3702 30034403 t lperfetto Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction. SIGNOR-268560 0.8 STAT5A protein P42229 UNIPROT NR3C1/STAT5A complex SIGNOR-C84 SIGNOR form complex binding 9606 8878484 t fspada We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter. SIGNOR-44379 0.545 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser688 RLFVENDsPSDGGTP 9606 BTO:0001938 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. SIGNOR-104687 0.844 RXRA protein P19793 UNIPROT PPARD protein Q03181 UNIPROT up-regulates binding 9606 11237216 t lperfetto Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology SIGNOR-105442 0.564 ROCK1 protein Q13464 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Ser314 RAREKRDsRNMEVQV 9606 15767678 t gcesareni Identification of rock1 as an upstream activator of the jip-3 to jnk signaling axis in response to uvb damage. phosphorylation of jip-3 by rock1 was crucial for the recruitment of jnk. Inhibition of the activity of rock1 in keratinocytes resulted in decreased activation of the jnk pathway and thus a reduction in apoptosis. SIGNOR-134580 0.338 MAPK1 protein P28482 UNIPROT IL16 protein Q14005 UNIPROT up-regulates phosphorylation Ser845 SIRQRISsFETFGSS 9606 14768064 t lperfetto The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 . the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response. SIGNOR-121852 0.268 AMPA proteinfamily SIGNOR-PF58 SIGNOR Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates -1 32527803 f inferred from family member Luana AMPAR surface diffusion tunes short-term plasticity. | Accordingly, recent studies have suggested that about half of synaptic AMPARs are organized in nanoclusters that are aligned with presynaptic transmitter release sites, supporting the concept of functional nanocolumns to increase the fidelity of fast excitatory transmission. This peculiar organization might also support the proposal that we made 10 years ago that fast surface diffusion of AMPARs tunes frequency-dependent short-term plasticity (FD-STP) by allowing the fast replacement of desensitized receptors by na√Øve ones. SIGNOR-270304 0.7 TP53 protein P04637 UNIPROT THBS1 protein P07996 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10029407 f miannu p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1. SIGNOR-255433 0.452 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 20444238 t gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. SIGNOR-165208 0.432 Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 16440056 f lperfetto A second cytoplasmic dynein complex, cytoplasmic dynein 2, has a role in intraflagellar transport (IFT), a process required for ciliary/flagellar assembly SIGNOR-265022 0.7 PPARGC1A protein Q9UBK2 UNIPROT CYP7A1 protein P22680 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255057 0.444 solifenacin chemical CHEBI:135530 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition -1 21524581 t Luana The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference SIGNOR-258312 0.8 MAPK3 protein P27361 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation 9606 10197981 t gcesareni Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus SIGNOR-66755 0.508 MAPKAPK2 protein P49137 UNIPROT RTN4 protein Q9NQC3 UNIPROT unknown phosphorylation Ser107 VAPERQPsWDPSPVS 9606 BTO:0000567;BTO:0000801 16095439 t llicata Nogo-b is phosphorylated at ser107 in vitro by mapkap-k2 SIGNOR-139486 0.2 MAPK3 protein P27361 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation Ser387 PATVEPAsPTPAHSL 9606 BTO:0000150 17311928 t llicata Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1 SIGNOR-153387 0.505 TFEB protein P19484 UNIPROT GOLPH3L protein Q9H4A5 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 f lperfetto Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14) SIGNOR-276793 0.2 RAG1 protein P15918 UNIPROT MTOR protein P42345 UNIPROT up-regulates relocalization 9606 22790199 t gcesareni Rag gtpases, together with a multi-protein complex called ragulator, mediate amino acid-mediated mtor recruitment to the lysosome surface where mtor becomes activated. SIGNOR-198242 0.259 PRKCA protein P17252 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0000017 15647376 t lperfetto Phosphorylation of ezrin is required for both conformational activation and for signaling to downstream events. The activating c-terminal threonine phosphorylation on t567 was first described to be downstream of the rho pathway (matsui et al., 1998). Additional studies have implicated protein kinase c (pkc)  in the phosphorylation of ezrin t567. SIGNOR-133223 0.531 SKIL protein P12757 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity binding 9606 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-236099 0.793 RPS6KA3 protein P51812 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates activity 9606 BTO:0000567 20383198 f lperfetto We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions. SIGNOR-252039 0.2 ALDH1A3 protein P47895 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI down-regulates quantity chemical modification 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265128 0.8 fenoterol chemical CHEBI:149226 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Finally, comparisons of the rank order of ligands for the three different receptors provide information about relative intrinsic efficacies. Fenoterol is a full and efficacious agonist at the β1-adrenoceptor, ranking third out of the agonists studied. It was also a full agonist at the β2- and β3-adrenoceptors with the highest intrinsic efficacy (i.e. top of Tables 4 and ​and5,5, rank 1).  SIGNOR-257867 0.8 EPAS1 protein Q99814 UNIPROT KDM6B protein O15054 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271586 0.2 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCNB1 protein P14635 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189969 0.8 PLK1 protein P53350 UNIPROT CENPU protein Q71F23 UNIPROT down-regulates phosphorylation Thr78 FDPPLHStAIYADEE 9606 17081991 t lperfetto S77 and t78 of pbip1 are important for plk1-dependent pbip1 phosphorylation and degradation. Here, we demonstrate that a pbd-binding protein, pbip1, is crucial for recruiting plk1 to the interphase and mitotic kinetochores. Unprecedentedly, plk1 phosphorylated pbip1 at t78. Later in mitosis, plk1 also induced pbip1 degradation in a t78-dependent manner, thereby enabling itself to interact with other components critical for proper kinetochore functions SIGNOR-150457 0.73 MSX1 protein P28360 UNIPROT LHX2 protein P50458 UNIPROT down-regulates activity binding -1 9697309 t 2 miannu Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity SIGNOR-241330 0.49 STAT6 protein P42226 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 12947222 t GATA-3 plays a central role in regulating Th1 and Th2 cell differentiation. Upon interleukin (IL)-4 binding to its receptor, GATA-3 is induced through the action of Stat6 SIGNOR-254299 0.648 Histone H2B proteinfamily SIGNOR-PF68 SIGNOR RNF168 protein Q8IYW5 UNIPROT up-regulates binding 9606 19203578 t gcesareni Rnf168 is recruited to sites of dna damage by binding to ubiquitylated histone h2a. SIGNOR-265372 0.2 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR NF2 protein P35240 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18332868 t miannu VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation. In this study, we provide evidence to show that Merlin is regulated in a Roc1-Cullin4A-DDB1-dependent manner. Following serum stimulation, Merlin is recruited to the E3 ligase complex through a direct interaction with the WD40-containing adaptor protein VprBP. Loading of Merlin to the E3 ubiquitin ligase complex resulted in its polyubiquitination, and consequently its proteasome-mediated degradation. SIGNOR-271674 0.333 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Asp572 PWHSFGAdSVPANTE -1 8943232 t lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261761 0.502 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1616 TPQSPSYsPTSPSYS -1 17157258 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248767 0.442 RNF5 protein Q99942 UNIPROT CFTR protein P13569 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 21148293 t miannu JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation. SIGNOR-271494 0.651 CDK7 protein P50613 UNIPROT CDK1 protein P06493 UNIPROT up-regulates phosphorylation Thr161 GIPIRVYtHEVVTLW 9606 8344251 t lperfetto The mo15 gene encodes the catalytic subunit of a protein kinase that activates cdc2 and other cyclin-dependent kinases (cdks) through phosphorylation of thr161 and its homologues SIGNOR-38307 0.562 TBL1X protein O60907 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 BTO:0000007 20181957 t miannu TBL1 appears to serve two roles in regulating the activity of β-catenin. Besides the initially identified role of TBL1 in recruiting β-catenin to the SCF(TBL1) complex, it has also been shown to function as a transcriptional co-activator of β-catenin in recruiting it to the promoter site of Wnt target genes. Our results indicated that TBL1 can inhibit the polyubiquitination of β-catenin by Siah-1 in vitro (Fig. 3) and stabilize β-catenin in cells by protecting it from Siah-1-mediated ubiquitination and proteasomal degradation (Fig. 4). SIGNOR-271954 0.644 PTEN protein P60484 UNIPROT STAT5A protein P42229 UNIPROT down-regulates dephosphorylation 9606 20596030 t miannu The forced expression of pten in the eol-1r cells dephosphorylated akt, erk and stat5 /eol-1r cells showed epigenetic silencing of the phosphatase and tensin homolog deleted on chromosome ten (pten) gene. Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfr? Was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib. SIGNOR-166481 0.45 GPC4 protein O75487 UNIPROT WNT3A protein P56704 UNIPROT up-regulates binding 9606 22302992 t gcesareni Gpc4 bound to wnt3a and wnt5a which activate the beta-catenin-dependent and -independent pathways, respectively, and colocalized with wnts on the cell surface. Expression of gpc4 enhanced the wnt3a-dependent beta-catenin pathway and the wnt5a-dependent beta-catenin-independent pathway, and knockdown of gpc4 suppressed both pathways SIGNOR-195749 0.357 LPAR2 protein Q9HBW0 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 15856019 t gcesareni Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. SIGNOR-135837 0.387 TCL1A protein P56279 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 10983986 t miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation SIGNOR-81683 0.532 CDK1 protein P06493 UNIPROT CUX1 protein P39880 UNIPROT down-regulates phosphorylation Ser1270 YQQKPYPsPKTIEDL 9606 11584018 t lperfetto Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter. SIGNOR-110912 0.364 IFNG protein P01579 UNIPROT NOD2 protein Q9HC29 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003355 18647246 f miannu NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B. SIGNOR-252408 0.395 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr221 KDEILPTtPISEQKG 9606 19059439 t gcesareni Here we show that pkcdelta phosphorylates rps3 resulting in its mobilization in the nucleus to repair damaged dna. Phosphorylated rps3 was only detected in non-ribosomal rps3 and the repair endonuclease activity of rps3 was increased by its phosphorylation. SIGNOR-182623 0.2 MAPK8 protein P45983 UNIPROT CDT1 protein Q9H211 UNIPROT up-regulates quantity by stabilization phosphorylation Ser391 LRSAAPSsPGSPRPA 9606 BTO:0000567 21930785 t miannu  We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2.  SIGNOR-276361 0.376 (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol chemical CHEBI:94562 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190708 0.8 CFH protein P08603 UNIPROT C3 protein P01024 UNIPROT down-regulates activity binding 9606 19050261 t miannu As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity) SIGNOR-252141 0.916 GNAI1 protein P63096 UNIPROT PLD2 protein O14939 UNIPROT down-regulates binding 9606 9148895 t gcesareni The results of this study suggest that membrane phospholipase d activity can be negatively regulated via gi SIGNOR-48256 0.312 TLR2 protein O60603 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 10090 22664090 t miannu To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266740 0.66 ATF4 protein P18848 UNIPROT AARS1 protein P49588 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269414 0.2 PRKCA protein P17252 UNIPROT ARRB1 protein P49407 UNIPROT up-regulates activity phosphorylation Ser163 EKIHKRNsVRLVIRK 9606 BTO:0000661 24502978 t miannu  We demonstrate that β-arrestin-1 recruitment to the TCR, and bystander TCR and CXCR4 downregulation, are mechanistically mediated by the TCR-triggered PKC-mediated phosphorylation of β-arrestin-1 at Ser163.  SIGNOR-276619 0.2 SIAH1 protein Q8IUQ4 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 20940030 t gcesareni The overexpression of siah1 causes the re-localization of notch from the cell surface to the cytoplasm and to the nucleus, which is indicative of notch activation SIGNOR-254330 0.263 maraviroc chemical CHEBI:63608 ChEBI CCR5 protein P51681 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194248 0.8 YAP1 protein P46937 UNIPROT GINS1 protein Q14691 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 f lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. SIGNOR-276566 0.2 KLF4 protein O43474 UNIPROT STAT6 protein P42226 UNIPROT up-regulates 9606 BTO:0000801 22378047 f lperfetto KLF4 cooperates with Stat6 to induce M2 genes (Arg-1, Mrc1, Fizz1, PPAR?) and inhibit M1 genes (TNFa, Cox-2, CCL5, iNOS) via sequestration of coactivators required for NF-kappaB activation. SIGNOR-249569 0.352 WARS1 protein P23381 UNIPROT tRNA(Trp) smallmolecule CHEBI:29181 ChEBI down-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) SIGNOR-270509 0.8 MSL acetyltransferase complex SIGNOR-C344 SIGNOR Histone H2B proteinfamily SIGNOR-PF68 SIGNOR down-regulates activity monoubiquitination 9606 BTO:0000567 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271978 0.2 FAS protein P25445 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 21959933 t lperfetto Aggregation-induced conformational changes in fas lead to the formation of the death-inducing signalling complex (disc) which involves recruitment of the adaptor protein fadd/mort1 through a homotypic interaction of death domains, present in both the intracellular region of fas and the c-terminus of fadd. SIGNOR-176651 0.908 GAD1 protein Q99259 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI down-regulates quantity chemical modification 9606 32041144 t miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. SIGNOR-267551 0.8 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Thr116 SCDKSTQtPSPPCQA 9606 18498746 t gcesareni Jnk is the physiogically relevant uv-stimulated kinase that phosphorylates bimel on thr-112/jnk-induced bim apoptotic activity SIGNOR-178683 0.677 PTPRS protein Q13332 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation 9606 12018405 t miannu Similarly, Pestana et al. (89) have reported that overexpression of RPTPsigma in human A431 carcinoma cells partially inhibits EGFR activation, whereas antisense mediated suppression of RPTPsigma expression enhances EGFR activation, substrate phosphorylation, and signalling.|These data indicate that LAR and RPTPsigma may have a significant role in GPCR induced EGFR signalling.Whereas in A431 cells LAR and RPTPsigma may act to suppress the EGFR in response to GPCR activation, it is possible that the converse may also be true in other cell types. SIGNOR-277145 0.44 GEM protein P55040 UNIPROT ROCK2 protein O75116 UNIPROT down-regulates activity binding 9534 16757346 t miannu We have found that Gem binds specifically to ROKβ in the coiled‐coil domain adjacent to the Rho binding site. The interaction between Gem and ROKβ leads to inhibition of MLC and MBS phosphorylation but not phosphorylation of LIMK, indicating that Gem exerts its effect by altering the substrate specificity of ROKβ SIGNOR-261707 0.294 EEF1A1 protein P68104 UNIPROT Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269512 0.8 LYN protein P07948 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr227 KVDATADyICKVKWG 9606 BTO:0000007 32420483 t done miannu  We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. SIGNOR-274104 0.2 ROBO proteinfamily SIGNOR-PF14 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 15916964 t lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities SIGNOR-137635 0.2 Complement C1 complex complex SIGNOR-C309 SIGNOR C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Arg756 KGQAGLQrALEILQE -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263427 0.629 CSNK2A1 protein P68400 UNIPROT SLBP protein Q14493 UNIPROT down-regulates quantity by destabilization phosphorylation Thr61 ERRPESFtTPEGPKP 9606 phosphorylation:Thr62 RRPESFTtPEGPKPR 18490441 t lperfetto Phosphorylation of Thr61 is necessary for subsequent phosphorylation of Thr60 by CK2 in vitro. Inhibitors of CK2 also prevent degradation of SLBP at the end of S phase. Thus, phosphorylation of Thr61 by cyclin A/Cdk1 primes phosphorylation of Thr60 by CK2 and is responsible for initiating SLBP degradation. SIGNOR-265260 0.333 STK39 protein Q9UEW8 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates activity phosphorylation Ser96 IEDLSQNsITGEHSQ -1 24043619 t miannu  We observed that in vitro activated STE20/SPS1-related proline/alanine-rich kinase (SPAK) complexed to its regulatory MO25 subunit phosphorylated KCC3 at Ser-96 and that in Xenopus laevis oocytes Ser-96 of human KCC3 is phosphorylated in isotonic conditions and becomes dephosphorylated during incubation in hypotonicity, leading to a dramatic increase in KCC3 function. SIGNOR-276597 0.587 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCQ protein Q04759 UNIPROT up-regulates activity binding 9606 14967450 t PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. SIGNOR-242596 0.8 BTG2 protein P78543 UNIPROT HOXB9 protein P17482 UNIPROT up-regulates activity binding 9606 BTO:0000567 10617598 t miannu The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation. SIGNOR-220987 0.672 Difluprednate chemical CHEBI:31485 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation -1 21182429 t Luana BMP had the highest K(i) value (8.4 × 10(-8) nmol/L), whereas DFB had the lowest (6.1 × 10(-11) nmol/L). The GCRBA of DFBA was intermediate to these 2 values (7.8 × 10(-10) nmol/L). SIGNOR-257886 0.8 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. SIGNOR-157081 0.2 CHD3 protein Q12873 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263855 0.81 MMP25 protein Q9NPA2 UNIPROT MMP2 protein P08253 UNIPROT up-regulates activity cleavage Asn66 GCPKESCnLFVLKDT -1 14583471 t miannu Direct activation of pro-matrix metalloproteinase-2 by leukolysin/membrane-type 6 matrix metalloproteinase/matrix metalloproteinase 25 at the asn(109)-Tyr bond. Leukolysin Cleaves ProMMP-2 at Asn66-Leu and Asn109-Tyr. SIGNOR-256346 0.383 TDGF1 protein P13385 UNIPROT TGFB1 protein P01137 UNIPROT down-regulates activity binding 9606 17030617 t lperfetto Ere, we provide evidence supporting a novel mechanism in which Cripto inhibits the tumor suppressor function of TGF-beta. Cripto bound TGF-beta and reduced the association of TGF-beta with its type I receptor, TbetaRI. SIGNOR-150006 0.2 FYN protein P06241 UNIPROT GRB10 protein Q13322 UNIPROT down-regulates phosphorylation Tyr67 NASLESLySACSMQS 9606 10871840 t lperfetto Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir. SIGNOR-78702 0.388 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr654 DIHHIDYyKKTTNGR 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1. We demonstrate that autophosphorylation on tyrosines 653 and 654 is important for activation of tyrosine kinase activity of fgfr1 and is therefore essential for fgfr1-mediated biological responses. SIGNOR-236199 0.2 CDK1 protein P06493 UNIPROT HMGA2 protein P52926 UNIPROT down-regulates phosphorylation Ser44 QEPTGEPsPKRPRGR 9606 10636877 t lperfetto Architecture of high mobility group protein i-c dna complex and its perturbation upon phosphorylation by cdc2 kinase. Phosphorylation by cdc2 reduces binding strength of the mammalian and insect hmgi proteins to dna. After phosphorylation of the protein at ser-43 and ser-58 by cdc2 kinase multiple contacts of dbds, especially with the bases, are impaired and the protein binds to dna in a different way, extending the contacts to the sugar-phosphate backbone. SIGNOR-74094 0.382 MAPK11 protein Q15759 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000150 21502402 t llicata Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro SIGNOR-173405 0.2 PTPN2 protein P17706 UNIPROT JAK3 protein P52333 UNIPROT down-regulates activity dephosphorylation 9606 15780598 t lperfetto Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5. SIGNOR-133078 0.684 canertinib chemical CHEBI:61399 ChEBI ERBB2 protein P04626 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258093 0.8 UHMK1 protein Q8TAS1 UNIPROT PAM protein P19021 UNIPROT unknown phosphorylation Ser946 DRLSTEGsDQEKEDD 9606 BTO:0004055 10574929 t lperfetto Although P-CIP2 interacts with stathmin, it does not phosphorylate stathmin. Site-directed mutagenesis, phosphoamino acid analysis, and use of synthetic peptides demonstrate that PAM-Ser(949) is the major site phosphorylated by P-CIP2. B SIGNOR-247009 0.456 N-tert-butyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-phenylpropanamide chemical CHEBI:104131 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258896 0.8 HCK protein P08631 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr771 IGTAEPDyGALYEGR -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249361 0.668 PPP1CA protein P62136 UNIPROT CCND3 protein P30281 UNIPROT up-regulates dephosphorylation Thr283 QGPSQTStPTDVTAI 9606 16331257 t lperfetto These results support the hypothesis that pp1 constitutively keeps cyclin d3 in a stable, dephosphorylated state SIGNOR-142884 0.248 SIRT1 protein Q96EB6 UNIPROT RELA protein Q04206 UNIPROT down-regulates activity deacetylation Lys310 KRTYETFkSIMKKSP 9606 BTO:0002207 15152190 t gcesareni SIRT1 physically interacts with the RelA/p65 subunit of NF-kappaB and inhibits transcription by deacetylating RelA/p65 at lysine 310. SIGNOR-238817 0.715 VHL protein P40337 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity binding 9606 BTO:0000567 17936701 t We found that pVHL associates with the NF-kappaB agonist Card9 but does not target Card9 for destruction. Instead, pVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2. SIGNOR-257603 0.402 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr809 LIVEYAKyGSLRGFL 9606 14711813 t llicata Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. these facts suggest that tyr806 and tyr809, located in this unique position, play a novel supplemental role for the activation loop upon phosphorylation. SIGNOR-121157 0.2 RPS6KA3 protein P51812 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-119229 0.2 FGF1 protein P05230 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates binding 9606 1385111 t gcesareni Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides. SIGNOR-18454 0.821 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation 9606 17900900 t lperfetto The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt. SIGNOR-252889 0.398 (R)-salbutamol chemical CHEBI:8746 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 9606 22182578 t Luana  Salbutamol is a well-known β2 adrenoceptor (β2AR) partial agonist. | In order to gain insight, we carried out binding and functional assays for BCSDs in HEK-293T cells transfected with the human β2AR (hβ2AR). The transfected hβ2AR showed similar affinity for BCSDs and salbutamol SIGNOR-258326 0.8 ITGB4 protein P16144 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 9428518 t gcesareni Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation. SIGNOR-54530 0.392 MAP3K9 protein P80192 UNIPROT MAP3K9 protein P80192 UNIPROT up-regulates activity phosphorylation Thr312 TKMSAAGtYAWMAPE 10029 15610029 t lperfetto We present here biochemical and biophysical evidence that MLK1 is activated by autophosphorylation in (or near) the activation loop. The activation loops of the MLK family are highly homologous, and so one might predict that the same residues would be key to their activation. Functional data presented here, however, demonstrate that the key residue for activation of MLK1, Thr312, differs from the key residue for activation of MLK3. SIGNOR-249388 0.2 MC3R protein P41968 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257407 0.252 WARS1 protein P23381 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) SIGNOR-270511 0.8 PRKCA protein P17252 UNIPROT HES1 protein Q14469 UNIPROT down-regulates activity phosphorylation Ser37 TASEHRKsSKPIMEK -1 9389649 t lperfetto Endogenous HES-1 DNA-binding activity is post-translationally inhibited during NGF signaling in vivo, and phosphorylation of PKC consensus sites in the HES-1 DNA-binding domain inhibits DNA binding by purified HES-1 in vitro. SIGNOR-248992 0.335 RNF149 protein Q8NC42 UNIPROT BRAF protein P15056 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001109 22628551 t miannu We showed that RNF149 bound directly to the C-terminal kinase-containing domain of wild-type BRAF and induced ubiquitination, followed by proteasome-dependent degradation, of the latter protein. Functionally, RNF149 attenuated the increase in cell growth induced by wild-type BRAF.  SIGNOR-272043 0.343 CDC14B protein O60729 UNIPROT CDCA3 protein Q99618 UNIPROT up-regulates dephosphorylation 9606 18662541 t gcesareni The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1 SIGNOR-179664 0.285 CEBPG protein P53567 UNIPROT SLCO1B3 protein Q9NPD5 UNIPROT up-regulates quantity by expression transcriptional regulation 15322262 t lperfetto Taken together, these findings suggest that the LPS-induced down-regulation of Oatp4 is likely due to reduction in the binding of HNF1alpha, C/EBP, HNF3, and RXR:RAR to the Oatp4 promoter. SIGNOR-268986 0.2 AR protein P10275 UNIPROT UCN protein P55089 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001509 23801677 t lperfetto When cells were treated with DHT alone, AR was upregulated and translocated into the nuclei, which might repress UCN1 expression via a potential androgen-responsive element found in human CRF family promoter|These data suggest that DHT differentially influences UCN1 levels under normal and inflammatory conditions in human umbilical vein endothelial cells, which involves AR-dependent and -independent mechanisms respectively. SIGNOR-253688 0.2 RPLP0 protein P05388 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262451 0.82 JNK proteinfamily SIGNOR-PF15 SIGNOR CDC25C protein P30307 UNIPROT down-regulates phosphorylation 9606 20220133 t inferred from 70% family members gcesareni Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset. SIGNOR-269983 0.2 PHKG1 protein Q16816 UNIPROT PHKG1 protein Q16816 UNIPROT unknown phosphorylation Ser82 VDILRKVsGHPNIIQ -1 7935360 t miannu Phosphopeptides correspond to sequences occurring in the gamma-subunit of phosphorylase kinase […] undergoes autophosphorylation. phosphorylation occurs primarily at Ser30 while in the latter an additional reaction takes place at Ser81. SIGNOR-250389 0.2 ARHGAP10 protein A1A4S6 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260465 0.655 PIN1 protein Q13526 UNIPROT MYC protein P01106 UNIPROT up-regulates binding 9606 BTO:0000150 23716601 t esanto Pin1 prolyl isomerase enhances recruitment of serine 62-phosphorylated myc and its coactivators to select promoters during gene activation. SIGNOR-202134 0.555 Brivanib alaninate chemical CID:11154925 PUBCHEM FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190729 0.8 GDP smallmolecule CHEBI:17552 ChEBI GNAQ protein P50148 UNIPROT down-regulates chemical inhibition 9606 12040175 t gcesareni Agonist binding triggers a conformational change in the receptor, which catalyses the dissociation of gdp from the alfa subunit followed by gtp-binding to galfa and the dissociation of galfa from gbetagamma subunits1. SIGNOR-88229 0.8 ATM protein Q13315 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation 9606 12607003 t fstefani We show that, in response to ionizing radiation, mdc1 is hyperphosphorylated in an atm-dependent manner, and rapidly relocalizes to nuclear foci that also contain the mre11 complex, phosphorylated histone h2ax and 53bp1. SIGNOR-98798 0.841 SF3A1 protein Q15459 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270668 0.72 SYT1 protein P21579 UNIPROT SNAP25 protein P60880 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 16679567 t miannu Because synaptotagmins bind SNAP-25 and Ca2+, SNAP-25 has also been linked to the Ca2+ dependence of exocytosis (42). One model suggests that synaptotagmin blocks full SNARE fusion pore formation by binding to t-SNAREs.This interaction prevents fusion from occurring in the absence of calcium. When Ca2+ is present, synaptotagmin releases the t-SNAREs so they can fully zipper with the v-SNARE, leading to fusion SIGNOR-263975 0.949 WDR5 protein P61964 UNIPROT Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR form complex binding 9606 BTO:0000567 12670868 t miannu Our analysis of HCF-1-associated proteins suggests that a K4 histone H3 HMT complex has been conserved from yeast to humans in both structure and activity: the Set1/Ash2 HMT. The results presented here show that this Set1/Ash2 HMT complex, in mutually exclusive interactions, can associate with HCF-1 bound to the repressive Sin3 HDAC or the transcriptional activator VP16, indicating a diversity of transcriptional regulatory roles. SIGNOR-264480 0.916 PRKAA1 protein Q13131 UNIPROT PRPS2 protein P11908 UNIPROT down-regulates activity phosphorylation Ser180 GGAKRVTsIADRLNV 9606 BTO:0006038 29074724 t lperfetto We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. SIGNOR-265731 0.2 NLGN2 protein Q8NFZ4 UNIPROT NRXN1 protein P58400 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264151 0.819 POLR2J3 protein Q9H1A7 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266173 0.691 TRAF6 protein Q9Y4K3 UNIPROT ECSIT protein Q9BQ95 UNIPROT down-regulates activity ubiquitination 10090 21525932 t Giorgia Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of a TLR signalling adaptor, tumour necrosis factor receptor-associated factor 6 (TRAF6), to mitochondria, where it engages the protein ECSIT (evolutionarily conserved signalling intermediate in Toll pathways), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation SIGNOR-260370 0.782 AKT1 protein P31749 UNIPROT BCL3 protein P20749 UNIPROT up-regulates quantity by stabilization phosphorylation Ser41 KRPLRAPsPEPAAPR -1 28689659 t miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  SIGNOR-277358 0.507 ITGB1 protein P05556 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253182 0.812 CDKN2A protein Q8N726 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization 9606 12091906 f apalma P14/p19 ARF functions by antagonizing MDM2 and thereby stabilizing p53 (refs. 17,18). Thus, loss of p14/p19ARF impairs p53-mediated growth arrest and/or apoptosis in response to activated oncogenes SIGNOR-255694 0.78 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 9047237 t lperfetto Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient. SIGNOR-46855 0.797 ARNT protein P27540 UNIPROT AHR-ARNT complex SIGNOR-C125 SIGNOR form complex binding -1 9020169 t 2 miannu SIM1 and SIM2, and the mammalian aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) proteins are members of the basic-helix-loop-helix·PAS family of transcription factors. In the yeast two-hybrid system, we demonstrate strong constitutive interaction of ARNT with SIM1 and SIM2 and fully ligand-dependent interaction of ARNT with AHR. SIM1 inhibits binding of the AHR·ARNT dimer to the xenobiotic response element in vitro Introduction of SIM1 into hepatoma cells inhibits transcriptional transactivation by the endogenous AHR·ARNT dimer. SIGNOR-240814 0.745 RPS6KA1 protein Q15418 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 11584304 t lperfetto S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity. SIGNOR-110917 0.366 SIRT1 protein Q96EB6 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity transcriptional regulation 9606 19553684 f gcesareni Collectively, these data indicate that SIRT1 controls PGC-1alpha gene expression in skeletal muscle and that MyoD is a key mediator of this action SIGNOR-238790 0.792 PAK1 protein Q13153 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity binding 9606 BTO:0000007 11804587 t lperfetto We show that pak1 forms homodimers in vivo and that its dimerization is regulated by the intracellular level of gtp-cdc42 or gtp-rac1. The dimerized pak1 adopts a trans-inhibited conformation. SIGNOR-236338 0.2 sunitinib chemical CHEBI:38940 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0004479 20570526 t Luana Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors], SIGNOR-257848 0.8 nicotine smallmolecule CHEBI:18723 ChEBI CHRNB3 protein Q05901 UNIPROT up-regulates activity chemical activation 9606 BTO:0000227 28901280 t miannu Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a super-family of Cysloop ligand-gated ion channels that respond to endogenous acetylcholine (ACh) or other cholinergic ligands. These receptors are also the targets of drugs such as nicotine (the main addictive agent delivered by cigarette smoke) and are involved in a variety of physiological and pathophysiological processes. SIGNOR-264259 0.8 TAOK2 protein Q9UL54 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 BTO:0000007 12665513 t lperfetto Transfection studies demonstrated that TAO2 stimulates phosphorylation of the TCF Elk1 on the major activating site, Ser383, and that TAO2 stimulates transactivation of Elk1 and the related TCF, Sap1. SIGNOR-246638 0.314 E2F1 protein Q01094 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253864 0.688 TWIST1 protein Q15672 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15311212 f miannu known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT. SIGNOR-255157 0.496 ATR protein Q13535 UNIPROT XRCC3 protein O43542 UNIPROT up-regulates activity phosphorylation Ser225 PFRCEFDsQASAPRA 9606 23438602 t miannu HXRCC3 S225 phosphorylation is mediated by ATR via an ATM-dependent signaling pathway. These data clearly indicate that ATR mediates the late activation of XRCC3 following DSB accumulation. SIGNOR-262666 0.477 [4,5,6,7-Tetrabromo-2-(Dimethylamino)-1h-Benzimidazol-1-Yl]acetic Acid chemical CID:46943415 PUBCHEM CSNK2A2 protein P19784 UNIPROT down-regulates activity chemical inhibition -1 22115617 t Federica 4,5,6,7-tetrabromo- and 4,5,6,7-tetraiodo-1H-benzimidazoles and their newly obtained N1- and 2-S-carboxyalkyl derivatives showed potent inhibitory activity against both these subunits. CK2α was up to 6 times more sensitive to the studied compounds than CK2α. SIGNOR-261112 0.8 PABPC1 protein P11940 UNIPROT NFX1 protein Q12986 UNIPROT up-regulates activity binding 9606 BTO:0000009 17267499 t Simone We identifiednew protein partners of NFX1-123, including several cytoplasmic poly(A) binding proteins (PABPCs) thatinteracted with NFX1-123 through its N-terminal PAM2 motif. Central to our findings were our observations that PABPCs copurify with NFX1-123, that a PAM2 motif is present in NFX1, and this motif and the PABPCs are important in the enhancement of hTERT activity by NFX1-123. SIGNOR-261052 0.35 TLE2 protein Q04725 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates binding 9606 19460168 t gcesareni Mapping studies reveal that groucho/tle binds two regions in lef-1. SIGNOR-185736 0.622 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. SIGNOR-268784 0.8 PRKD2 protein Q9BZL6 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser876 QGLAERIsVL 9606 11062248 t gcesareni The addition of phorbol 12,13-dibutyrate in the presence of dioleoylphosphatidylserine stimulated the autophosphorylation of pkd2 in a synergistic fashion.In addition, we could identify the c-terminal ser(876) residue as an in vivo phosphorylation site within pkd2. Phosphorylation of ser(876) of pkd2 correlated with the activation status of the kinase. SIGNOR-83834 0.2 SEH1L protein Q96EE3 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR form complex binding 9606 23723239 t miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 SIGNOR-255304 0.833 NLK protein Q9UBE8 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser329 STISGRLsPIMTEQD 9534 BTO:0001538 20061393 t done miannu Here, we report that the transforming growth factor-beta-activated kinase (TAK1)-Nemo-like kinase (NLK) pathway negatively regulates FOXO1. We show that NLK binds and phosphorylates FOXO1 at Pro-directed Ser/Thr residues in the transactivation domain. The phosphorylation by TAK1-NLK pathway inhibits the transcriptional activity of FOXO1 and excludes FOXO1 from the nucleus, which is independent of phosphatidylinositol 3-kinase/Akt pathway.  SIGNOR-273907 0.601 PTPN6 protein P29350 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates activity dephosphorylation Tyr116 EILALQIyCRNESRG 9606 BTO:0002181 32779804 t miannu We identified a direct interaction between SHP‐1 and TRAF3; the association between these two proteins resulted in diminished recruitment of CK1ε to TRAF3 and inhibited its K63‐linked ubiquitination; SHP‐1 inhibited K63‐linked ubiquitination of TRAF3 by promoting dephosphorylation at Tyr116 and Tyr446. SIGNOR-277527 0.2 PTPRJ protein Q12913 UNIPROT PLCG1 protein P19174 UNIPROT unknown dephosphorylation 9606 11259588 t Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation SIGNOR-248706 0.376 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation 9606 10567572 t amattioni Jnk was capable of phosphorylating bcl-2. Phosphorylation of bcl-2 inactivates the molecule SIGNOR-72364 0.564 prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI PTGER3 protein P43115 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257571 0.8 GPER1 protein Q99527 UNIPROT GNG2 protein P59768 UNIPROT up-regulates activity binding 10696571 t GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; GNG2 stands for the subunit γ, which dissociates from the receptor after the binding of GTP on α-subunit. SIGNOR-251104 0.358 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 23863160 f lperfetto In mammals, two protein complexes, namely the ULK1/Atg13/FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin/Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation. SIGNOR-209907 0.7 canertinib chemical CHEBI:61399 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191012 0.8 ALX4 protein Q9H161 UNIPROT NCAM1 protein P13591 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003952 11696550 f miannu Alx4 Overexpression Represses Endogenous N-CAM Expression SIGNOR-254548 0.2 LYN protein P07948 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Tyr374 PLPPAPAyLSSPLAL 9606 BTO:0000007 23131831 t miannu Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.  SIGNOR-276369 0.364 PRKN protein O60260 UNIPROT RANBP2 protein P49792 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16332688 t irozzo Our findings suggested that the intracellular levels of RanBP2 and its functional activity may be modulated by Parkin-mediated ubiquitination and proteasomal pathways. Furthermore, Parkin controls the intracellular levels of sumoylated HDAC4, as a result of the ubiquitination and degradation of RanBP2. SIGNOR-259116 0.2 GSK3B protein P49841 UNIPROT HNRNPD protein Q14103 UNIPROT down-regulates phosphorylation Ser83 DEGHSNSsPRHSEAA 9606 11903055 t gcesareni In kinase assays pka phosphorylated ser-87 of hnrnp d, whereas glycogen synthase kinase-3 beta (gsk-3 beta) phosphorylated ser-83, but only if ser-87 had been pre-phosphorylated by pka. Phosphorylation of ser-87 enhanced, whereas phosphorylation of ser-83 repressed, transactivation. SIGNOR-116140 0.353 GATA2 protein P23769 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR up-regulates activity 10090 21605981 f GATA1 and GATA2 are expressed principally in hematopoietic lineages, and have essential roles in the development of multiple hematopoietic cells, including erythrocytes and megakaryocytes. SIGNOR-259960 0.7 pazopanib hydrochloride chemical CHEBI:71217 ChEBI CSF1R protein P07333 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-199527 0.8 NLGN4X protein Q8N0W4 UNIPROT NRXN1 protein P58400 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264150 0.762 PRKCI protein P41743 UNIPROT LLGL1 protein Q15334 UNIPROT up-regulates activity phosphorylation Ser659 RVKSLKKsLRQSFRR 9615 12725730 t miannu This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner. SIGNOR-263179 0.651 Hypoxia stimulus SIGNOR-ST25 SIGNOR EGLN1 protein Q9GZT9 UNIPROT down-regulates 9606 32755251 f lperfetto Under hypoxic conditions, PHD2 activity is limited, and therefore HIF-1α protein is stabilized, leading to an increase in the transcription of erythropoietin as well as hundreds of target genes that coordinate diverse processes SIGNOR-261995 0.7 STK3 protein Q13188 UNIPROT RCC1 protein P18754 UNIPROT up-regulates phosphorylation Ser11 KRIAKRRsPPADAIP 9606 BTO:0000007 19559616 t miannu MST2 Phosphorylates RCC1 In Vitro and In Vivo. Using an antibody generated against phospho-S2/11 in RCC1 [18], we found that these two residues were also efficiently phosphorylated by MST1 and MST2 (Figure 2D), further supporting that S2 and/or S11 are genuine MST2 phosphorylation targets. SIGNOR-263145 0.2 PRKACA protein P17612 UNIPROT TPPP protein O94811 UNIPROT unknown phosphorylation Ser32 DRAAKRLsLESEGAG -1 17693641 t miannu Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP. Thus our data suggest that ERK2 or Cdk5 can perturb the interaction of TPPP with tubulin, in contrast to PKA that is ineffective in this respect. SIGNOR-262930 0.2 RORA protein P35398 UNIPROT SHH protein Q15465 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001011 19381306 t miannu RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice. SIGNOR-266846 0.254 CDK4 protein P11802 UNIPROT CELF1 protein Q92879 UNIPROT up-regulates activity phosphorylation Ser302 TSSGSSPsSSSSNSV 10090 16931514 t miannu These studies showed that both the increased levels of CUGBP1 and cdk4-mediated hyper-phosphorylation of CUGBP1 are involved in the age-associated induction of the CUGBP1-eIF2 complex. The CUGBP1-eIF2 complex is bound to C/EBPbeta mRNA in the liver of old animals, and this binding correlates with the increased amounts of liver-enriched activator protein and liver-enriched inhibitory protein. SIGNOR-262735 0.407 CEBPB protein P17676 UNIPROT S100A9 protein P06702 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001370 9706399 t Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells. SIGNOR-254044 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation 9606 20230789 t inferred from 70% family members lperfetto Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity SIGNOR-270114 0.2 PPP1CA protein P62136 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 12840032 t inferred from 70% of family members fstefani P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases SIGNOR-269927 0.457 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT up-regulates phosphorylation Tyr21 ENLEQEEyEDPDIPE 9606 10942405 t llicata Our findings suggest that, upon phosphorylation by p72syk, y8 and y21 act as docking sites for the sh2 domain of lyn, which subsequently phosphorylates band 3 at additional secondary sites. SIGNOR-80788 0.462 RAP1GDS1 protein P52306 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 21242305 t miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob SIGNOR-171415 0.426 GSK690693 chemical CHEBI:90677 ChEBI AKT1 protein P31749 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258118 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 11108261 t lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. SIGNOR-244247 0.2 EFNA5 protein P52803 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 9330863 t gcesareni Efna5 are able to activate epha8 SIGNOR-52479 0.812 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser74 TPHLPPCsPPKQGKK 9606 9889196 t lperfetto Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2. SIGNOR-217332 0.94 PIMREG protein Q9BSJ6 UNIPROT PICALM protein Q13492 UNIPROT down-regulates relocalization 9606 16491119 t miannu The cats interaction domain of calm was mapped to aa 221-335 of calm. This domain is contained in the calm/af10 fusion protein. Cats localizes to the nucleus and shows a preference for nucleoli. Expression of cats was able to markedly increase the nuclear localization of calm and of the leukemogenic fusion protein calm/af10. SIGNOR-144680 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Leu) smallmolecule CHEBI:29169 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270411 0.8 ITGB1BP1 protein O14713 UNIPROT ITGB6 protein P18564 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257662 0.291 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000763 12193595 t miannu Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction. SIGNOR-91726 0.711 WNT7B protein P56706 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000763;BTO:0001260 15923619 t gcesareni Wnt7b can bind to fzd1 and -10 on the cell surface and cooperatively activate canonical wnt signaling. SIGNOR-137931 0.656 SYCE3 protein A1L190 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR form complex binding 9606 22394509 t miannu The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region. SIGNOR-264202 0.654 Phagocytosis phenotype SIGNOR-PH97 SIGNOR IL1B protein P01584 UNIPROT down-regulates quantity BTO:0000801 22933625 f apalma Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype SIGNOR-255445 0.7 PTHLH protein P12272 UNIPROT PTH1R protein Q03431 UNIPROT up-regulates activity binding -1 8683730 t lperfetto Prostate-specific antigen was found to specifically cleave PTHrP 1-141 in a time- and dose-dependent manner.|The preferred PSA cleavage site of PTHrP 1-141 was determined to be at the carboxyl-terminus of phenylalanine 23, consistent with chymotryptic-like enzymatic activity of PSA. Cleavage of PTHrP by PSA completely abolished the ability of PTHrP to stimulate cAMP production. SIGNOR-270549 0.752 NMS protein Q5H8A3 UNIPROT NMUR2 protein Q9GZQ4 UNIPROT up-regulates binding 9606 BTO:0000142 15635449 t gcesareni Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan g protein-coupled receptor fm-4/tgr-1, which was identified to date as the neuromedin u (nmu) receptor, and designate this peptide 'neuromedin s (nms)' because it is specifically expressed in the suprachiasmatic nuclei (scn) of the hypothalamus. SIGNOR-133131 0.616 MYO10 protein Q9HD67 UNIPROT DCC protein P43146 UNIPROT up-regulates quantity relocalization 10090 BTO:0000938 17237772 t miannu Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin. SIGNOR-268282 0.673 STAP1 protein Q9ULZ2 UNIPROT STAT5A protein P42229 UNIPROT up-regulates activity binding 9606 BTO:0000007 10679268 t miannu STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells. SIGNOR-261821 0.396 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr655 GYADLDPyNSPGQEV -1 23770091 t done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. SIGNOR-273942 0.357 RPE protein Q96AT9 UNIPROT D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI down-regulates quantity chemical modification 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267065 0.8 FBXW11 protein Q9UKB1 UNIPROT IKBKB protein O14920 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 10321728 t miannu We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo.  SIGNOR-272544 0.419 paclitaxel chemical CHEBI:45863 ChEBI TUBA4A protein P68366 UNIPROT down-regulates activity chemical inhibition 9606 28298489 t miannu Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a "pseudo" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap. SIGNOR-259346 0.8 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1F protein P30939 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257520 0.8 NOG protein Q13253 UNIPROT GDF5 protein P43026 UNIPROT down-regulates activity binding 9606 21976273 t miannu Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. Antagonists such as noggin counteract BMP signaling by covering the ligand's BMP type I (BMPRI) and type II (BMPRII, ActRII, ActRIIB) interaction sites. The mutation GDF5-S94N is located within the BMPRII interaction site, the so-called knuckle epitope, and was identified in patients suffering from multiple synostoses syndrome (SYNS). SIGNOR-252420 0.687 CSNK1D protein P48730 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10606744 t gcesareni Protein kinase ck1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15. SIGNOR-73266 0.56 histamine smallmolecule CHEBI:18295 ChEBI HRH1 protein P35367 UNIPROT up-regulates activity chemical activation 10029 7925364 t miannu The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum. SIGNOR-258483 0.8 PDHX protein O00330 UNIPROT PAX6 protein P26367 UNIPROT down-regulates activity binding 9606 BTO:0000120 12783165 t miannu In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3. SIGNOR-254903 0.2 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 14732063 t miannu Tumour necrosis factor (TNF) exerts two main effects: a beneficial one as an anti-infection, anti-tumour cytokine, and a detrimental one in the systemic inflammatory response syndrome (SIRS). Two receptors (TNF-R) mediate these effects. two distinct types of TNF-Rs have been identified and molecularly cloned: TNF-R55 (also referred to as TNFR1, p55 or CD120a) and TNF-R75 (also called TNFR2, p75 or CD120b) SIGNOR-253593 0.923 HAND2 protein P61296 UNIPROT HAND2 protein P61296 UNIPROT up-regulates activity binding -1 11812799 t miannu The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer SIGNOR-223476 0.2 baicalein chemical CHEBI:2979 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258158 0.8 ROS stimulus SIGNOR-ST2 SIGNOR ATM protein Q13315 UNIPROT up-regulates 9606 BTO:0000007 26344566 f We report that the PEX5 peroxisome import receptor binds ataxia-telangiectasia mutated (ATM) and localizes this kinase to the peroxisome. In response to ROS, ATM signalling activates ULK1 and inhibits mTORC1 to induce autophagy. SIGNOR-262791 0.7 NODAL protein Q96S42 UNIPROT MMP2 protein P08253 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003879 20383200 f Regulation miannu Ectopic expression of Nodal or activation of Nodal signaling by addition of rNodal increased MMP-2 protein level and cell invasion. the expression level of Nodal correlates well with MMP-2 expression and cell invasion. SIGNOR-251940 0.2 MAPK9 protein P45984 UNIPROT BAZ1B protein Q9UIG0 UNIPROT up-regulates phosphorylation Ser158 KSDGACDsPSSDKEN 9606 19776015 t gcesareni Wstf, a specific component of two chromatin remodeling complexes (swi/snf-type winac and iswi-type wich), was phosphorylated by the stimulation of mapk cascades in vitro and in vivo. Ser-158 residue in the wac (wstf/acf1/cbpq46) domain, located close to the n terminus of wstf, was identified as a major phosphorylation target SIGNOR-188168 0.2 dactolisib chemical CHEBI:71952 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 BTO:0000848 21803746 t ATP-competitive inhibitor of PI3K and mTOR gcesareni The dual pi3k and mtorc1/2 inhibitor bez235 was highly specific SIGNOR-175706 0.8 RPS6KA5 protein O75582 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates activity phosphorylation Ser7 sSAEGAAK 12213813 t lperfetto HMGN1 (formerly known as HMG-14) phosphorylation at Ser6 occurs concomitantly with IE gene expression. | MSK2 seems to be the most important kinase responsible for this modification |Accordingly, it was suggested that HMGN1 phosphorylation reduces binding of the protein to the nucleosomes SIGNOR-262988 0.604 IL18 protein Q14116 UNIPROT IFNG protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10653850 f miannu IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR engagement. SIGNOR-260858 0.478 ATM protein Q13315 UNIPROT SMC1A protein Q14683 UNIPROT up-regulates phosphorylation Ser966 GEDSVSGsQRISSIY 9606 11877377 t lperfetto Here we report that smc1 is a component of the dna damage response network that functions as an effector in the atm/nbs1-dependent s-phase checkpoint pathway. Smc1 associates with brca1 and is phosphorylated in response to ir in an atm- and nbs1-dependent manner. Using mass spectrometry, we established that atm phosphorylates s957 and s966 of smc1 in vivo. SIGNOR-115496 0.693 SPRY2 protein O43597 UNIPROT CBLC protein Q9ULV8 UNIPROT down-regulates 9606 12234920 f gcesareni Hspry2 prevents c-cbl-mediated ubiquitylation of egfrs. hspry2 interacts specifically with the c-cbl ring finger domain and displaces ubch7 from its binding site on the e3 ligase. SIGNOR-92926 0.462 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser434 SFEPKIRsPRRFIGS 9823 BTO:0004712 23486913 t lperfetto Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway SIGNOR-201534 0.96 TSC2 protein P49815 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity 9606 BTO:0000007;BTO:0001938 12271141 f lperfetto These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor SIGNOR-93133 0.843 PRKCG protein P05129 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Ser363 ALLQSSAsRKTQKKK 9606 11325528 t lperfetto We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC. SIGNOR-249091 0.286 NANOGP8 protein Q6NSW7 UNIPROT KDM3A protein Q9Y4C1 UNIPROT down-regulates quantity by repression transcriptional regulation 10900 BTO:0000667 23918801 f Luana Constitutive NanogP8 overexpression in adult L1 mice reduced CD34+α6+ and Lrig-1+ bulge stem cells, impaired keratinocyte migration, and repressed the expression of many stem cell-associated genes, including Bmp5, Fgfr2, Jmjd1a, and Jun. SIGNOR-266092 0.2 MTOR protein P42345 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-262534 0.727 Caspase 3 complex complex SIGNOR-C221 SIGNOR IKBKB protein O14920 UNIPROT down-regulates cleavage Asp373 PATQCISdGKLNEGH 9606 11741536 t gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. SIGNOR-256436 0.372 TRIP11 protein Q15643 UNIPROT THRB protein P10828 UNIPROT up-regulates binding 9606 9256431 t miannu Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity. SIGNOR-50421 0.32 VPS33B protein Q9H267 UNIPROT CHEVI complex complex SIGNOR-C269 SIGNOR form complex binding 9606 BTO:0000007 29778605 t lperfetto It has been recently suggested that VPS33B and VIPAR comprise two subunits of a novel multi-subunit tethering complex (named "CHEVI") SIGNOR-261830 0.781 arformoterol chemical CHEBI:408174 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation -1 20655218 t Luana Table 1. Human β2- and β1-adrenoceptor binding and calculated log D7.4 values for formoterol, indacaterol, salmeterol, S1319 and the representative library members 11–41 SIGNOR-257882 0.8 RUNX2 protein Q13950 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 9182762 f gcesareni Osf2/cbfa1 as an osteoblast-specific transcription factor and as a regulator of osteoblast differentiation SIGNOR-48940 0.7 FGR protein P09769 UNIPROT KCND3 protein Q9UK17 UNIPROT up-regulates activity phosphorylation Tyr108 GKLHYPRyECISAYD 9606 BTO:0000007 22198508 t miannu These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels. SIGNOR-276394 0.2 DLK1 protein P80370 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 8500166 f This indicates that pref-1 functions as a negative regulator of adipocyte differentiation, possibly in a manner analogous to EGF-like proteins that govern cell fate decisions in invertebrates. SIGNOR-254980 0.7 FLT3 protein P36888 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15626738 f FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells SIGNOR-261550 0.254 XRCC3 protein O43542 UNIPROT D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR form complex binding 9606 18212739 t lperfetto These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3).  SIGNOR-263257 0.707 EMSY protein Q7Z589 UNIPROT ZMYND11 protein Q15326 UNIPROT up-regulates activity binding 9606 BTO:0000567 14651845 t miannu The binding sites for HP1β and BS69 with EMSY abut each other, and are found directly adjacent to the ENT domain of EMSY. This demonstrates that EMSY has the capacity to contact directly at least two proteins which contain a Royal Family domain. Since this domain is found in proteins with a chromatin connection, we assume that EMSY functions, at least partly, in the regulation of chromatin. SIGNOR-263916 0.2 USP37 protein Q86T82 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates activity binding 9606 BTO:0000007 21596315 t lperfetto Here we show that USP37 binds the APC/C coactivator CDH1|Deubiquitinase USP37 is activated by CDK2 to antagonize APC(CDH1) and promote S phase entry SIGNOR-265054 0.342 PHB protein P35232 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 16964284 f lperfetto We now present evidence that PHB, which has 54% homology at the protein level to the oestrogen receptor corepressor REA (repressor of oestrogen receptor activity), can repress androgen receptor (AR)-mediated transcription and androgen-dependent cell growth. SIGNOR-268977 0.461 KX2-391 chemical CID:23635314 PUBCHEM SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193624 0.8 valproic acid chemical CHEBI:39867 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 11742974 t Federica Here we show that VPA inhibits corepressor-associated HDACs at therapeutically employed concentrations and acts as a potent inducer of differentiation in several types of transformed cells. SIGNOR-261078 0.8 FKBP8 protein Q14318 UNIPROT MTOR protein P42345 UNIPROT down-regulates binding 9606 17991864 t gcesareni Fkbp38 binds to mtor and inhibits its activity in a manner similar to that of the fkbp12-rapamycin complex. SIGNOR-159013 0.581 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR TFAP2C protein Q92754 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269256 0.381 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 t gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. SIGNOR-163270 0.2 SMAD1/4 complex SIGNOR-C85 SIGNOR BMP7 protein P18075 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 19896409 f lperfetto BMPs first bind to and activate their transmembrane serine/threonine kinase receptors, which in turn phosphorylate the transcription factors Smad1/5/8 at its two C-terminal serines (SVS). Phosphorylated Smad1Cter binds to Smad4 (co-Smad) and translocates and accumulates in the nucleus, activating BMP-responsive genes (Fig. 2) [21] and [22], such as BMP4/7 and others. SIGNOR-248843 0.561 HCRTR1 protein O43613 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257294 0.41 DENND3 protein A2RUS2 UNIPROT RAB12 protein Q6IQ22 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 25925668 t lperfetto ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12.|active Rab12 facilitates autophagosome trafficking, thus establishing a crucial role for the ULK/DENND3/Rab12 axis in starvation-induced autophagy. SIGNOR-264734 0.608 AR protein P10275 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 15861399 f miannu AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation SIGNOR-251540 0.7 ARHGEF10 protein O15013 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260536 0.418 BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 17289999 t gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma SIGNOR-152929 0.818 KLF4 protein O43474 UNIPROT THBD protein P07204 UNIPROT up-regulates activity transcriptional regulation 9606 19661484 f miannu Thrombomodulin upregulation was independent of NF-kappaB signaling, a principal target of proteasome inhibitors, but was instead a direct consequence of increased expression of the Krüppel-like transcription factors, KLF2 and KLF4. SIGNOR-254546 0.307 EIF2B2 protein P49770 UNIPROT EIF2S3 protein P41091 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269135 0.683 TNFSF11 protein O14788 UNIPROT TNFRSF11B protein O00300 UNIPROT up-regulates binding 9606 11733492 t gcesareni Receptor activator of nf-kappa b ligand (rankl, also known as odf and opgl), a member of the tumor necrosis factor (tnf) family, triggers osteoclastogenesis by forming a complex with its receptor, rank. SIGNOR-112539 0.941 PBK protein Q96KB5 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 9606 16982762 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Pbk/topk could phosphorylate histone h3 at ser10 in vitro and in vivo, and mediated its growth-promoting effect through histone h3 modification. SIGNOR-149716 0.2 RALGAPB protein Q86X10 UNIPROT RalGAP2 complex SIGNOR-C469 SIGNOR form complex binding 10090 BTO:0000011 21148297 t miannu Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. SIGNOR-269794 0.589 BRSK1 protein Q8TDC3 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser216 SGLYRSPsMPENLNR 9606 9543386 t lperfetto Overexpression of hssad1 resulted in an increased phosphorylation of cdc25c on ser-216 in vivo.Phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 SIGNOR-56473 0.495 PTPN12 protein Q05209 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation 9606 11731619 t gcesareni In intact hc11 cells, ptp-pest was constitutively associated with jak2, and in response to egf treatment there was an increased level of ptp-pest in jak2 complexes. An in vitro phosphatase assay, using prl-activated jak2 as the substrate and lysates from hc11 cells as the source of ptp-pest, revealed that jak2 could serve as a ptp-pest substrate. SIGNOR-112383 0.385 8-OH-DPAT chemical CHEBI:73364 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258890 0.8 CYBB protein P04839 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity chemical modification 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264723 0.8 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity dephosphorylation Ser300 SMSDPGVsYRTREEI -1 7782287 t Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism SIGNOR-252056 0.722 BLK protein P51451 UNIPROT FCGR2C protein P31995 UNIPROT up-regulates activity phosphorylation Tyr310 TDDDKNIyLTLPPND -1 8756631 t miannu Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation SIGNOR-262673 0.2 BAG1 protein Q99933 UNIPROT HSPA8 protein P11142 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0001538 11676916 t miannu BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association SIGNOR-272589 0.891 SRC protein P12931 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates activity phosphorylation Tyr198 IDEAEVIySELMSDF 9606 BTO:0002181 31420453 t miannu Src activates GEF-H1. SIGNOR-277478 0.411 sirolimus chemical CHEBI:9168 ChEBI IRS1 protein P35568 UNIPROT up-regulates 9606 16452206 f gcesareni The mtor inhibitory drug rapamycin up-regulates irs-1 protein levels and induces akt phosphorylation, protein kinase activity, and downstream signaling. SIGNOR-144159 0.8 C3 convertase complex complex SIGNOR-C310 SIGNOR C3 protein P01024 UNIPROT up-regulates activity cleavage Arg748 ASHLGLArSNLDEDI 31331124 t lperfetto This forms the C4b2a complex, which is a classical pathway C3 convertase. C4b2a cleaves C3, which is the central component of the complement cascade, to C3a, and anaphylatoxin, and C3b results in the activation of the lytic pathway SIGNOR-263450 0.54 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation -1 16226275 t inferred from 70% family members lperfetto First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.| SIGNOR-270111 0.2 SRC protein P12931 UNIPROT BDKRB2 protein P30411 UNIPROT up-regulates phosphorylation Tyr177 GVRWAKLySLVIWGC 9606 16226010 t lperfetto Here we demonstrate that egf is capable of inducing src-mediated phosphorylation of the tyrosine residues 177 and 347 of bkr. Their replacement by phenylalanine led to bkr mutants which are unable to activate the camp pathway. SIGNOR-141103 0.264 CHFR protein Q96EP1 UNIPROT PARP1 protein P09874 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001109 23268447 t miannu  Here, we show that checkpoint with Forkhead-associated (FHA) and RING finger domain protein (CHFR), an E3 ubiquitin ligase, is recruited to DSBs by poly(ADP-ribose) (PAR). Moreover, CHFR ubiquitinates PAR polymerase 1 (PARP1) and regulates chromatin-associated PARP1 in vivo.  Moreover, the poly-ubiquitin chain on PARP1 could be recognized by both anti-K48 and K63-linked poly-ubiquitin chain antibodies, suggesting that CHFR mediates a mixed poly-ubiquitin chain linkage on PARP1. With MG132 treatment, ubiquitinated PARP1 was significantly accumulated (Figure 4D), suggesting that the ubiquitination of PARP1 is likely involved in protein degradation. Consistently, we found that following DNA damage, PARP1 quickly dissociated from the chromatin in the wild-type cells (Figure 4F). However, in the Chfr−/− cells, the dissociation of PARP1 from the chromatin was significantly delayed. SIGNOR-271470 0.438 dimethyloxalylglycine chemical CHEBI:102218 ChEBI EGLN3 protein Q9H6Z9 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000018 28900510 t lperfetto We treated the A549 cells with the following EGLN/PHD inhibitors: dimethyloxalyglycine (DMOG), CoCl2, inhibitors of dioxygenases, and BAY 85-3494 (BAY), a specific inhibitor of EGLNs with highest potency against EGLN1. SIGNOR-261993 0.8 CSNK2B protein P67870 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1126 TEEFSSEsDMEESKE 9606 BTO:0000938 19064667 t lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. SIGNOR-275760 0.2 MBD1 protein Q9UIS9 UNIPROT MGMT protein P16455 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 15657354 f Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT. SIGNOR-254036 0.254 JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 30029643 f areggio In summary, our results indicate IL-15 can stimulate the proliferation of FAPs through Jak-STAT pathway. SIGNOR-256230 0.7 DAMPS stimulus SIGNOR-ST18 SIGNOR NAIP protein Q13075 UNIPROT up-regulates activity 16037825 f lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-256420 0.7 RPS6KA1 protein Q15418 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-70428 0.2 MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 12694204 t Simone Vumbaca We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation. SIGNOR-255640 0.437 PRKCD protein Q05655 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 t gcesareni Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway. SIGNOR-115722 0.349 SPRY2 protein O43597 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates 9606 12414790 f gcesareni Therefore, we conclude that an increase in soluble ptp1b activity contributes to the anti-migratory, but not anti-mitogenic, actions of hspry2. SIGNOR-95313 0.427 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR CDKN2A protein Q8N726 UNIPROT down-regulates transcriptional regulation 9606 12091906 t apalma We have identified the p14(ARF) tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1 ETO. SIGNOR-255677 0.2 HMBOX1 protein Q6NT76 UNIPROT IFNG protein P01579 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002030 21839858 t Luana Additionally, by luciferase reporter assay, HMBOX1 displayed suppressive effect on the transcription activity of IFN-γ promoter.  SIGNOR-261625 0.2 tacrolimus (anhydrous) chemical CHEBI:61049 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR down-regulates chemical inhibition 9606 15276472 t gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. SIGNOR-252308 0.8 IRX1 protein P78414 UNIPROT PTGER1 protein P34995 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. SIGNOR-261656 0.2 YY1 protein P25490 UNIPROT ATP2C1 protein P98194 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15955096 f miannu when Sp1 or YY1 was overexpressed in keratinocytes, an obvious increase in ATP2C1 promoter activity was observed, which was in contrast with the case where a mutant promoter lacking the binding sites for Sp1 and YY1 was used as the reporter. SIGNOR-255193 0.2 CDK1 protein P06493 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1247 KNENTEGsPQEDGVE 9606 BTO:0000567 7635160 t llicata We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. similarly, phosphopeptide 4 was absent from a mutant protein lacking ser1246 SIGNOR-30244 0.539 GPR37 protein O15354 UNIPROT ER stress stimulus SIGNOR-ST9 SIGNOR up-regulates 9606 12666095 f lperfetto Parkin-associated endothelin receptor-like receptor (Pael-R). Overexpression of this protein causes it to become ubiquinated, insoluble, and unfolded, leading to endoplasmic reticulum stress and cell death. Furthermore, an insoluble form of Pael-R has been demonstrated to accumulate in the brains of patients with Parkin mutations, suggesting a possible toxic mechanism. SIGNOR-249701 0.7 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270432 0.8 PRKACA protein P17612 UNIPROT TPH2 protein Q8IWU9 UNIPROT up-regulates phosphorylation Ser19 YWARRGFsLDSAVPE 9606 18339632 t llicata We also demonstrate that phosphorylation of serine 19, a protein kinase a consensus site located in this n-terminal domain, results in increased tph2 stability and consequent increases in enzyme output in cell culture systems SIGNOR-178018 0.257 KAT2B protein Q92831 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269592 0.663 (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266281 0.8 PER2 protein O15055 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267973 0.74 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1A protein P35348 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257450 0.8 PRKACA protein P17612 UNIPROT PDE10A protein Q9Y233 UNIPROT unknown phosphorylation Thr15 SQHLTGLtDEKVKAY 9606 BTO:0000007 20610737 t llicata When coexpressed with the catalytic subunit of pka in transfected hek293 cells, wild-type (wt) pde10a2 (pde10a2wt) was phosphorylated at thr-16 these data confirm the previously reported findings that pka phosphorylation of pde10a2 on thr-16 results in a cytosolic localization SIGNOR-166559 0.375 ERAP2 protein Q6P179 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI down-regulates quantity chemical modification 9606 15908954 t The generation of many HLA class I peptides entails a final trimming step in the endoplasmic reticulum that, in humans, is accomplished by two 'candidate' aminopeptidases | We show here that one of these, ERAP1, was unable to remove several N-terminal amino acids that were trimmed efficiently by the second enzyme, ERAP2. SIGNOR-272495 0.8 KLF15 protein Q9UIH9 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 15664998 f lperfetto Moreover, KLF15 and C/EBPalpha acted synergistically to increase the activity of the PPARgamma2 gene promoter in 3T3-L1 adipocytes. SIGNOR-235331 0.447 CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 19436055 t miannu As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of Œ≤c, Src homology 2 and phosphotyrosine binding domain proteins are recruited to the active receptor and initiate the major tyrosine phosphorylation-dependent signaling pathways, including the Jak/signal transducer and activator of transcription, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3 (PI-3) kinase pathways SIGNOR-255585 0.447 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates activity phosphorylation Ser379 DLILNRCsESTKRKL -1 24632950 t miannu Of note, PKCδ, when it was activated by PDPK1, directly bound to the SH3-N domain of p47(phox) and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47(phox) C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation.PKCδ phosphorylates p47phox for K-Ras-induced ROS generation. PKCδ binds to the SH3-N domain and phosphorylates Ser348 and Ser379 residues in p47phox for K-RasV12-induced ROS generation and consequent malignant transformation. SIGNOR-276622 0.458 MLST8 protein Q9BVC4 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-205612 0.827 GRIP1 protein Q9Y3R0 UNIPROT GRIPAP1 protein Q4V328 UNIPROT up-regulates activity binding 10116 BTO:0000142 10896157 t Giorgia We have identified several GRIP-associated proteins (GRASPs) that bind to distinct PDZ domains within GRIP. GRASP-1 is a neuronal rasGEF associated with GRIP and AMPA receptors in vivo. GRIP1 has seven PDZ domains, which mediate protein–protein interactions, allowing the recruitment of GRASP-1 to a large signal-transducing complex SIGNOR-260638 0.523 PRKACA protein P17612 UNIPROT PARP1 protein P09874 UNIPROT up-regulates activity phosphorylation Ser465 FLQDVSAsTKSLQEL 9606 BTO:0001412 25069723 t miannu  In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain).  SIGNOR-276651 0.2 ABL1 protein P00519 UNIPROT SPTLC1 protein O15269 UNIPROT down-regulates phosphorylation Tyr164 KTEEAIIySYGFATI 9606 23629659 t llicata We demonstrated that the er-resident human protein serine palmitoyltransferase long chain-1 (sptlc1), which is the first enzyme of sphingolipid biosynthesis, is phosphorylated at tyr(164) by the tyrosine kinase abl. this occurred through the specific abl-mediated phosphorylation of sptlc1 on tyr164, leading to the attenuation of its activity. SIGNOR-202003 0.2 LCK protein P06239 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 t We show that during TCR signaling, the tyrosines Y239, Y240 and Y317 of Shc are the primary sites of tyrosine phosphorylation. CD4/Lck-dependent tyrosine phosphorylation on Shc was markedly diminished when Y317 was mutated, suggesting a preference of Lck for the Y317 site. tyrosine phosphorylation of Shc may play a key role in T lymphocyte proliferation via interaction of phosphorylated Shc with downstream molecules involved in activation of Ras and Myc proteins SIGNOR-251388 0.734 FUS protein P35637 UNIPROT SMN1 protein Q16637 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 23022481 t lperfetto Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells SIGNOR-262107 0.378 PRKG1 protein Q13976 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Ser1131 AARERKRsRGNRKSL 9606 BTO:0000887;BTO:0001260 15051728 t lperfetto Pkgi also directly phosphorylates fhod1, and studies with wild-type and mutant fhod1-derived peptides identify ser-1131 in the fhod1 c terminus as the unique pkgi phosphorylation site in fhod1. phosphorylation of three conserved residues within the dad domain activates fhod1 while binding to rac regulates fhod1 subcellular localization SIGNOR-123646 0.361 PRKAA2 protein P54646 UNIPROT ACACA protein Q13085 UNIPROT down-regulates phosphorylation Ser80 LHIRSSMsGLHLVKQ 9606 BTO:0000887;BTO:0001103 SIGNOR-C15 12015362 t gcesareni Significant negative linear correlations between phospho-acc and acc activity were observed in all models (p < 0.01). The decline in acc activity was related to the decrease in pcr and the rise in amp. A relationship between phospho-ampk (threonine 172) and activity of ampk immunoprecipitated with anti-alpha(2) subunit antibody preparation was also observed. SIGNOR-87583 0.685 PDH complex SIGNOR-C402 SIGNOR acetyl-CoA smallmolecule CHEBI:15351 ChEBI up-regulates quantity chemical modification 9606 29059435 t miannu The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics. SIGNOR-266541 0.8 FOXA2 protein Q9Y261 UNIPROT DLK1 protein P80370 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12865419 t Taken together, these data suggest that Foxa-2 is a direct transcriptional activator of the Pref-1 gene. SIGNOR-254971 0.338 MAPK14 protein Q16539 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 BTO:0000150 20727996 t gcesareni Elk-1 is a member of the e-twenty-six (ets) domain superfamily of transcription factors and has been traditionally associated with mitogen-induced immediate early gene transcription upon phosphorylation by mitogen activated protein kinases (erk/mapk). SIGNOR-167539 0.506 MAPK7 protein Q13164 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates phosphorylation Ser387 LSLPSTQsLNIKSEP 9606 9384584 t lperfetto Bmk1 dramatically enhances the transactivation activity of mef2c by phosphorylating a serine residue at amino acid position 387 in this transcription factor. SIGNOR-53545 0.756 N-(cyanomethyl)-4-[2-[4-(4-morpholinyl)anilino]-4-pyrimidinyl]benzamide chemical CHEBI:91407 ChEBI JAK1 protein P23458 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191244 0.8 ATM protein Q13315 UNIPROT L3MBTL2 protein Q969R5 UNIPROT up-regulates activity phosphorylation 9606 31225475 t miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. SIGNOR-266785 0.2 CSNK2A2 protein P19784 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr366 ASSSTSVtPDVSDNE -1 12297295 t llicata We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).  SIGNOR-251026 0.692 E2F5 protein Q15329 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR up-regulates activity binding 9606 BTO:0001938 10783242 t miannu Here we show that E2F-5 is phosphorylated by the cyclin E-Cdk2 complex, which functions in the late G1 phase, but not by the early-G1-phase-acting cyclin D-CDK complex. A phosphorylation site in the trans-activation domain of E2F-5 stimulates transcription and cell-cycle progression by the recruitment of the p300/CBP family of co-activators, whose binding to E2F-5 is stabilized upon phosphorylation by cyclin E-Cdk2. These results indicate that phosphorylation of E2F-5 at the CDK site at position 251 by cyclin E–Cdk2 augments transcription by enhancing the interaction of E2F-5 with p300/CBP co-activator proteins. SIGNOR-262733 0.558 CTSG protein P08311 UNIPROT C3 protein P01024 UNIPROT up-regulates activity cleavage Leu751 LGLARSNlDEDIIAE 9606 BTO:0001412 1861080 t miannu Plasma membrane elastase and cathepsin G from U937 cells cleave C3 into C3a- and C3b-like fragments; further incubation leads to C3c- and C3dg-like fragments, as judged from SDS-PAGE analysis of the digests. Sequencing of the C3b-like fragment purified by reverse phase chromatography indicates that initial cleavage of C3 by purified cathepsin G occurs at two positions in the amino-terminal part of the alpha-chain, at a Arg-Ser bond located between residues 748 and 749 and at a Leu-Asp bond between residues 751 and 752. SIGNOR-256348 0.582 ABL1 protein P00519 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr52 DSSKPAVyNYPEGAA 9606 BTO:0000150 20101225 t gcesareni Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes. SIGNOR-163566 0.458 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000562 23457334 t lperfetto Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (pfkfb2) isoenzyme by amino acids. SIGNOR-192260 0.2 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120128 0.316 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser175 SPASSGSsASFISDT 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248682 0.613 HMGB1 protein P09429 UNIPROT AGER protein Q15109 UNIPROT up-regulates activity binding 10090 25014009 t gcesareni HMGB1 is known to influence cellular responses within the nervous system via two distinct receptor families; the Receptor for Advanced Glycation End-products (RAGE) and Toll-like receptors (TLRs) SIGNOR-252059 0.796 AGPAT5 protein Q9NUQ2 UNIPROT 1-acyl-sn-glycerol 3-phosphate(2-) smallmolecule CHEBI:57970 ChEBI down-regulates quantity chemical modification 9606 21173190 t lperfetto The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬† SIGNOR-267012 0.8 CDK11A protein Q9UQ88 UNIPROT SPDEF protein O95238 UNIPROT down-regulates quantity by destabilization phosphorylation Ser242 WTDSEVDsSCSGQPI 9606 BTO:0000007 26885618 t lperfetto In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.| SIGNOR-273021 0.363 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 11971957 t gcesareni Serines 43, 259, and 621 are phosphorylated by PKA in vitro and induced by cAMP in vivo.cAMP increased Raf-1 serine 259 phosphorylation in a PKA-dependent manner with kinetics that correlated with ERK deactivation. SIGNOR-86141 0.482 ANK1 protein P16157 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 t lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  SIGNOR-266013 0.372 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity phosphorylation Ser877 CFSSRRSsEASQAEG 9606 10693759 t lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. SIGNOR-75351 0.445 STT3A protein P46977 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization glycosylation 9606 BTO:0001939 29765039 t Barakat Together, these results support a notion that the two STT3 isoforms regulate EMT-mediated PD-L1 induction through PD-L1 protein N-glycosylation and stabilization. SIGNOR-274975 0.2 GPR174 protein Q9BXC1 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256757 0.2 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser376 LKSKKGQsTSRHKKL 9606 9315650 t llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase. SIGNOR-51284 0.47 KDM5A protein P29375 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-264299 0.2 ZNRF3 protein Q9ULT6 UNIPROT LRP6 protein O75581 UNIPROT down-regulates ubiquitination 9606 22575959 t gcesareni Znrf3 is associated with the wnt receptor complex, and inhibits wnt by promoting the turnover of frizzled and lrp6. Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation, and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane. SIGNOR-197420 0.642 STUB1 protein Q9UNE7 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni In ad-dition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activi-ties of smad1/5 by recruiting smad1/5 from the functional r-/co-smad complex and further pro-moting the ubiquitination and degradation of smad1/5 in a chaperone-independent manne SIGNOR-195690 0.349 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216385 0.885 UVRAG protein Q9P2Y5 UNIPROT RINT1 protein Q6NUQ1 UNIPROT up-regulates activity binding 9606 BTO:0000007 24056303 t lperfetto We further show that UVRAG interacts with RINT-1, and acts as an integral component of the RINT-1-containing ER tethering complex, which couples phosphoinositide metabolism to COPI-vesicle tethering. Displacement or knockdown of UVRAG profoundly disrupted COPI cargo transfer to the ER and Golgi integrity SIGNOR-265028 0.511 long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity precursor of 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267905 0.8 E2F1 protein Q01094 UNIPROT BBC3 protein Q96PG8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003476 17263886 f miannu Up-regulation of the PUMA gene and protein by E2F-1 overexpression was detected by real-time PCR and Western blot analysis in the SK-MEL-2 melanoma cell line SIGNOR-253843 0.408 BCL3 protein P20749 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates binding 9606 15469820 t gcesareni We show that bcl-3 is a substrate for the protein kinase gsk3 and that gsk3-mediated bcl-3 phosphorylation, which is inhibited by akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with hdac1, 3 and 6. SIGNOR-129804 0.355 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT down-regulates activity phosphorylation Ser314 DLEESSSsDHAERPP 10029 BTO:0000246 7876239 t The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization. SIGNOR-251443 0.2 MAPK1 protein P28482 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates 9606 20231899 f gcesareni An erk pharmacological inhibitor, pd98059, and the pld inhibitor, 1-btoh, both attenuate (14)c-glucose uptake in muscle cells. Finally, the extracellular stresses caused by glucose deprivation or aminoimidazole carboxamide ribonucleotide (aicar;ampk activator) regulate (14)c-glucose uptake and cell surface glucose transport (glut) 4 through erk stimulation by ampk-mediated pld1 activation. SIGNOR-164286 0.34 PRKCD protein Q05655 UNIPROT ENOX2 protein Q16206 UNIPROT up-regulates phosphorylation Ser504 ENLKEKEsCASRLCA 9606 22659163 t lperfetto Tnox is phosphorylated by protein kinase c_ (pkc_) both in vitro and in vivo. Replacement of serine-504 with alanine significantly reduces phosphorylation by pkc_. C. overexpression of the s504a tnox mutant leads to diminished cell proliferation and migration, reflecting reduced stability of the unphosphorylatable tnox mutant protein. SIGNOR-197706 0.2 AKT1 protein P31749 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates activity phosphorylation Ser227 QQRRRITsVQPPTGL 9606 BTO:0000567 21620836 t miannu A reciprocal immunoprecipiation with anti-phospho-Akt substrate antibody followed by immunoblotting with anti-FLAG antibodies confirmed these findings (Fig. 1C). We concluded that Fbw7 is phosphorylated at S227 in vivo. Phosphorylation of Fbw7 is required for its biological activity. SIGNOR-276328 0.42 PPP4C protein P60510 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity dephosphorylation Thr435 PTQAGEGtLSEALLQ 9606 15073167 t Suppression of MEK/ERK signaling pathway enhances cisplatin-induced NF-kappaB activation by protein phosphatase 4-mediated NF-kappaB p65 Thr dephosphorylation SIGNOR-248549 0.368 LNPEP protein Q9UIQ6 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT down-regulates quantity by destabilization cleavage 9606 25767437 t miannu It has been shown that the steady state of the mature OT form can be controlled by an oxytocinase (P-LAP) that is produced in periphery and centrally by the OT-magnocellular neurons. Noticeably, P-LAP is also expressed in parvocellular OT neurons and in other brain structures| The OT intermediate forms are produced from E16.5 (see above) but the mature amidated OT form is detected only from birth. The released mature form is then degraded by an oxytocinase (PLAP) SIGNOR-268552 0.2 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation 10090 8387505 t lperfetto The pp90rsk phosphothreonine content paralleled the ERK1 activity more closely than the phosphoserine level. These results provide compelling evidence that in fibroblasts and PC12 cells ERK1 plays a direct role in the phosphorylation of pp90rsk and that pp90rsk represents a physiologically relevant substrate of extracellular-regulated kinases SIGNOR-252762 0.719 DUSP5 protein Q16690 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 20626350 t gcesareni The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues. SIGNOR-166574 0.53 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKA protein O14965 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258303 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser189 DEEFREPsTGKTCLP 9606 19661060 t Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-260883 0.2 SCF-betaTRCP complex SIGNOR-C5 SIGNOR TOP2B protein Q02880 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 32015321 t miannu Specifically, DNA damage signal, triggered by teniposide (VM-26) treatment, activates ATM, cooperating with CK1 to phosphorylate TOP2β on Ser1134 and Ser1130, respectively, in a canonical degron motif to facilitate β-TrCP binding and subsequent degradation.ATM binds with and phosphorylates TOP2β at Ser1134 to promote its degradation by VM-26. SIGNOR-277511 0.2 EP300 protein Q09472 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity acetylation 9606 25545885 t miannu C-terminal acetylation of p53 by p300/CBP and PCAF promotes an open conformation of p53 by preventing the occlusion of the DNA binding domain by the C-terminal tail. This enhances p53 transcriptional activity, leading to growth arrest and/or apoptosis SIGNOR-261496 0.909 FNTB protein P49356 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity 9606 24294527 t lperfetto Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. SIGNOR-242565 0.472 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267885 0.8 HIPK2 protein Q9H2X6 UNIPROT HDAC3 protein O15379 UNIPROT down-regulates activity phosphorylation Ser374 KMLNHAPsVQIHDVP 10090 BTO:0002572 34244427 t miannu Mechanistically, HIPK2 bound and phosphorylated histone deacetylase 3 (HDAC3) at serine 374 to inhibit its enzymatic activity, thus reducing the deacetylation of p65 at lysine 218 to suppress NF-κB activation. SIGNOR-277568 0.2 PROC protein P04070 UNIPROT F7 protein P08709 UNIPROT down-regulates activity cleavage 9606 BTO:0000131 29880919 t lperfetto Activated protein C (APC), which cleaves and inactivates both FVIIIa and FVa, thereby shutting down both the tenase and prothrombinase complexes SIGNOR-263527 0.238 Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR Neutrophil_degranulation phenotype SIGNOR-PH212 SIGNOR up-regulates 9606 BTO:0000133 2161532 f lperfetto ANCA cause normal human neutrophils to undergo an oxidative burst and degranulate. Both ANCA phenotypes (i.e., cytoplasmic-pattern ANCA and myeloperoxidase-specific ANCA) induce neutrophil activation. SIGNOR-270582 0.7 MAPK1 protein P28482 UNIPROT GLI1 protein P08151 UNIPROT up-regulates activity phosphorylation Ser102 LQTVIRTsPSSLVAF -1 35831023 t miannu We conclude that multisite phosphorylation of GLI1 by ERK2 or other MAP kinases weakens GLI1-SUFU binding, thereby facilitating GLI1 activation and contributing to both physiological and pathological crosstalk. SIGNOR-277601 0.329 MAPK1 protein P28482 UNIPROT GLI1 protein P08151 UNIPROT up-regulates activity phosphorylation Ser116 FINSRCTsPGGSYGH -1 35831023 t miannu We conclude that multisite phosphorylation of GLI1 by ERK2 or other MAP kinases weakens GLI1-SUFU binding, thereby facilitating GLI1 activation and contributing to both physiological and pathological crosstalk. SIGNOR-277602 0.329 RELN protein P78509 UNIPROT VLDLR protein P98155 UNIPROT up-regulates binding 9606 11278667 t gcesareni The hypothesis that the vldl receptor signals in response to reelin binding was recently supported by studies (37) showing direct binding of reelin to the vldl receptor and changes in tyrosine phosphorylation in response to reelin-vldl receptor association. SIGNOR-106295 0.783 MAML1 protein Q92585 UNIPROT NOTCH4 protein Q99466 UNIPROT up-regulates binding 9606 11101851 t gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes4 SIGNOR-84916 0.698 GRPR protein P30550 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257421 0.41 FGF12 protein P61328 UNIPROT SCN1A protein P35498 UNIPROT down-regulates activity binding 9606 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253420 0.394 MAPKAPK5 protein Q8IW41 UNIPROT DNAJB1 protein P25685 UNIPROT up-regulates phosphorylation Ser171 VTHDLRVsLEEIYSG 9606 24309468 t lperfetto Phosphorylation of heat shock protein 40 (hsp40/dnajb1) by mitogen-activated protein kinase-activated protein kinase 5 (mk5/prak). Mk5 phosphorylates hsp40/dnajb1 in vivo at ser-149 or/and ser-151 and ser-171 in the c-terminal domain of hsp40/dnajb1. Mk5 modestly stimulates the atp hydrolyse activity of hsp40/hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by hsp40/dnajb1. SIGNOR-203464 0.44 GSK3A protein P49840 UNIPROT MITF protein O75030 UNIPROT up-regulates phosphorylation Ser405 QARAHGLsLIPSTGL 9606 10587587 t The effect has been demonstrated using O75030-9 gcesareni Glycogen synthase kinase 3 (gsk3) was found to phosphorylate ser298 in vitro, thereby enhancing the binding of mitf to the tyrosinase promoter SIGNOR-72878 0.298 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC5 protein P58876 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271985 0.2 MAPKAPK2 protein P49137 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser54 GGFPRRHsVTLPSSK 9606 18326031 t lperfetto Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation. SIGNOR-161274 0.605 APBA2 protein Q99767 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9534 BTO:0000298 11036064 t miannu Mint1 and Mint2 Interact with the Cytoplasmic Domain of Neurexin I. The interaction of Mint1 with neurexins is mediated by its PDZ domains and allows the formation of mixed CASK-Mint complexes. Both CASK and Mint1 can bind directly to neurexins and to each other. Therefore, the assembly of various multimeric complexes could proceed as CASK could be indirectly recruited to neurexin-bound Mint1 and vice versa. SIGNOR-264039 0.621 TP53 protein P04637 UNIPROT MMP2 protein P08253 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10029407 f miannu p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1. SIGNOR-255432 0.456 PRKCZ protein Q05513 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization phosphorylation Ser675 QDYKKRLsVELTSSL 9606 BTO:0002181 25660024 t miannu  Yap and β-catenin are direct substrates of PKCζ. Similar MS/MS analysis to map the sites phosphorylated in β-catenin by PKCζ identified S45 and several sites of low abundance that included S552 and S675 (Figure S3C). SIGNOR-276880 0.582 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation 9606 15821101 t gcesareni Ptp1b has been shown to regulate the activation of cytokine receptors through the dephosphorylation of specific members of the jak family, namely jak2 and tyk2 SIGNOR-135207 0.789 PRKDC protein P78527 UNIPROT XRCC6 protein P12956 UNIPROT up-regulates activity phosphorylation Ser27 QEENLEAsGDYKYSG 9606 BTO:0001546 26337656 t done miannu Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks. SIGNOR-274022 0.939 PHKG1 protein Q16816 UNIPROT PYGM protein P11217 UNIPROT up-regulates activity phosphorylation Ser15 QEKRKQIsVRGLAGV 9606 BTO:0002049 22225877 t It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15 SIGNOR-267398 0.671 glutamic acid smallmolecule CHEBI:18237 ChEBI GRID2 protein O43424 UNIPROT up-regulates activity chemical activation 9606 27586965 t miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors SIGNOR-264469 0.8 CDK1 protein P06493 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates activity phosphorylation Thr287 KIGFPSTtPAKAKAN 19687009 t lperfetto Cdc2 phosphorylates T287|CLIP-170, the founding member of microtubule “plus ends tracking” proteins, is involved in many critical microtubule-related functions, including recruitment of dynactin to the microtubule plus ends and formation of kinetochore-microtubule attachments during metaphase. |These results demonstrate that Cdc2-mediated phosphorylation of CLIP-170 is essential for the normal function of this protein during cell cycle progression. SIGNOR-275470 0.468 RPS6KA3 protein P51812 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 9211863 t gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. SIGNOR-49367 0.2 PLRG1 protein O43660 UNIPROT HNRNPM protein P52272 UNIPROT up-regulates activity binding 9606 BTO:0000567 20467437 t 1 miannu hnRNP-M interacts directly with CDC5L and PLRG1 in vivo. we investigated whether the function of hnRNP-M in alternative splicing was affected by the central region mapped as essential for binding to the CDC5L/PLRG1 proteins. We conclude that loss of the CDC5L/PLRG1 interaction domain in hnRNP-M correlates with a loss of ability to modulate alternative splice site selection in this assay. SIGNOR-239444 0.736 FOXH1 protein O75593 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity binding 9606 BTO:0001538 9858566 t lperfetto FAST-2 also interacts directly with Smad2, a cytoplasmic protein which is translocated to the nucleus in response to TGF-beta, and forms a multimeric complex with Smad2 and Smad4 on the activin response element, a high-affinity binding site for FAST-1. SIGNOR-108333 0.769 SCF-betaTRCP complex SIGNOR-C5 SIGNOR TIAM1 protein Q13009 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 25124033 t miannu Phosphorylation of Ser329, Ser334, and Thr340 in Tiam1 is required for its interaction with βTrCP1. The proteolysis of Tiam1 is prevented by βTrCP silencing, inhibition of CK1 and MEK, or mutation of the Tiam1 degron site. SIGNOR-276675 0.346 BHLHE41 protein Q9C0J9 UNIPROT BHLHE40 protein O14503 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14672706 f lperfetto We show here an autofeedback loop of Dec1 encoding a basic helix–loop–helix transcription factor: CLOCK/BMAL increased the promoter activity of Dec1, and DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression. SIGNOR-253714 0.516 WNT1 protein P04628 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 10116 11149923 f gcesareni Wnt-1 signaling inhibited the cytochrome c release and the subsequent caspase-9 activation induced by chemotherapeutic drugs, including both vincristine and vinblastine. Furthermore, we found that wnt-1-mediated cell survival was dependent on the activation of beta-catenin/t cell factor (tcf) transcription SIGNOR-85760 0.734 CHUK protein O15111 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates phosphorylation Ser1386 FVDSGEMsESFPYRT 9606 BTO:0000551 17434128 t lperfetto Phosphorylation of cbp by ikkalpha promotes cell growth by switching the binding preference of cbp from p53 to nf-kappabhere, we show that ikkalpha phosphorylates cbp at serine 1382 and serine 1386 and consequently increases cbp's hat and transcriptional activities SIGNOR-154333 0.532 P2RY14 protein Q15391 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257118 0.2 CGA protein P01215 UNIPROT TSHR protein P16473 UNIPROT up-regulates binding 9606 12045258 t miannu Human thyrotropin (tsh), follitropin (fsh), lutropin (lh), and chorionic gonadotropin (cg) are members of the glycoprotein hormone family derived from heterodimerization of a common ? Subunit with hormone-specific ? Subunits. These hormones were originally purified from the anterior pituitary (tsh, lh, and fsh) and placenta (human cg) and shown to activate specific g protein_coupled receptors in the thyroid (tsh receptor) and gonads (lh and fsh receptors), respectively SIGNOR-88519 0.409 F2 protein P00734 UNIPROT Thrombin-Thrombomodulin complex SIGNOR-C316 SIGNOR form complex binding 9606 BTO:0000131 29880919 t lperfetto Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC). SIGNOR-263549 0.903 IKK-complex complex SIGNOR-C14 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser644 GLDFNFDsLISTQNV 9606 19188143 t lperfetto Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway SIGNOR-252951 0.536 CXCL8 protein P10145 UNIPROT CXCR1 protein P25024 UNIPROT up-regulates binding 9606 11350788 t gcesareni Il-8 activates both the cxcr1 and the cxcr2 on microvascular endothelial cells, using different signal transduction cascades. SIGNOR-107920 0.772 HTR1E protein P28566 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256848 0.424 CAMK2A protein Q9UQM7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation Ser260 TLSPVNHsLDLQPVT 9606 SIGNOR-C8 11027280 t gcesareni Smad2 is a target substrate for cam kinase ii in vitro at serine-110, -240, and -260. furthermore, cam kinase ii blocked nuclear accumulation of a smad2 and induced smad2-smad4 hetero-oligomerization independently of tgfbeta receptor activation, while preventing tgfbeta-dependent smad2-smad3 interactions. SIGNOR-82974 0.53 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 18650425 t gcesareni Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun. SIGNOR-179555 0.377 AKT proteinfamily SIGNOR-PF24 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C7 17964260 t lperfetto Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. SIGNOR-244239 0.2 RAP1GDS1 protein P52306 UNIPROT CDC42 protein P60953 UNIPROT up-regulates binding 9606 21242305 t miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob SIGNOR-171412 0.292 AREG protein P15514 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity binding 9606 10209155 t Amphiregulin is an autocrine growth factor lperfetto ErbB ligands include: EGF, transforming growth factor (TGF)_, and amphiregulin which only bind ErbB1 SIGNOR-67000 0.763 LCK protein P06239 UNIPROT TCR complex SIGNOR-C153 SIGNOR up-regulates activity phosphorylation 10090 2470098 t Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex. SIGNOR-259932 0.2 APBB1 protein O00213 UNIPROT TSHZ3 protein Q63HK5 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 19343227 t miannu We carried out yeast two-hybrid studies with a PTB domain of FE65, focusing on those genes that might be involved in nuclear signaling, and identified and validated Teashirt proteins as FE65 interacting proteins in neurons. Using reporter systems, we observed that FE65 could simultaneously recruit SET, a component of the inhibitor of acetyl transferase, and Teashirt, which in turn recruited histone deacetylases, to produce a powerful gene-silencing complex. SIGNOR-264813 0.374 PRKCD protein Q05655 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 17145764 t gcesareni Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation. SIGNOR-151015 0.2 MYOD1 protein P15172 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR form complex binding 9606 16847330 t 2 miannu The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation. SIGNOR-241122 0.66 CTNNB1 protein P35222 UNIPROT CEBPA protein P49715 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada Wnt-10b, is a molecular switch that governs adipogenesis. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma). SIGNOR-80589 0.406 LY-2157299 chemical CHEBI:137064 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 18039567 t gcesareni Ly2157299, a new type i receptor tgf-beta kinase antagonist, was SIGNOR-159354 0.8 FNIP2 protein Q9P278 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates activity binding 9606 BTO:0000007 27353360 t miannu FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle. SIGNOR-261414 0.421 PRKD3 protein O94806 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser155 GRLKRERsMSENAVR 34010649 t lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-275945 0.2 MAPK1 protein P28482 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser789 QSVDKVTsPTKV 9606 BTO:0001260 10514499 t lperfetto Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin. SIGNOR-71037 0.524 MC5R protein P33032 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257441 0.252 POLR1F protein Q3B726 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266157 0.2 Ethylketocyclazocine chemical CHEBI:4901 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9262330 t miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. SIGNOR-258663 0.8 MAPK1 protein P28482 UNIPROT NEFH protein P12036 UNIPROT up-regulates activity phosphorylation Ser526 PVKEEAKsPAEAKSP 10116 BTO:0000938 9592082 t lperfetto The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation. SIGNOR-249424 0.375 SEMA3C protein Q99985 UNIPROT NRP2 protein O60462 UNIPROT up-regulates binding 9606 BTO:0000938 16816121 t gcesareni Our experiments establish that small peptides containing the consensus decd sequence of sperm fertilinbeta bind specifically to an alpha6beta1 integrin receptor on the egg membrane. We conclude that fertilinbeta binds directly to the alpha6beta1 integrin on the egg surface and this partnership mediates sperm-egg fusion. SIGNOR-147564 0.602 HIF-1 complex complex SIGNOR-C418 SIGNOR SLC2A1 protein P11166 UNIPROT up-regulates quantity transcriptional regulation 10116 11120745 t Collectively these results indicate that H-Ras up-regulates the glut1 promoter, at least in part, by increasing HIF-1alpha protein levels leading to transactivation of promoter through the HIF-1 binding site. SIGNOR-267478 0.421 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 18930133 t lperfetto Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation SIGNOR-181659 0.313 MAPK1 protein P28482 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 9606 15486195 t lperfetto In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel SIGNOR-129874 0.704 PRKCA protein P17252 UNIPROT VTN protein P04004 UNIPROT up-regulates quantity by stabilization phosphorylation Ser381 RNRKGYRsQRGHSRG -1 9030777 t lperfetto Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin. SIGNOR-248962 0.323 SAGA complex complex SIGNOR-C465 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269628 0.2 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 BTO:0000938 12040039 t lperfetto Stress in primary cultured cns neurons induces phosphorylation of c-jun serines 63 and 73 and increased c-jun protein. Jnk2/3 activity selectively targets c-jun. SIGNOR-236130 0.2 OGDH protein Q02218 UNIPROT OGDC complex SIGNOR-C397 SIGNOR form complex binding 9606 15953811 t miannu The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. SIGNOR-266255 0.732 RHOXF1 protein Q8NHV9 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 23317270 f lperfetto ShRNA knock down of RHOXF1 resulted in significantly decreased BCL2 expression in both cell lines but no change in CASP8 expression. SIGNOR-268957 0.2 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000785 16847353 t lperfetto C-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma SIGNOR-209593 0.612 MYOCD protein Q8IZQ8 UNIPROT KLF4 protein O43474 UNIPROT down-regulates 9606 21673106 f miR-143 and miR-145 target KLF4 gcesareni These results further confirm that bmp4 requires mrtf-a, whereas tgf-_ requires myocd for the induction of pri-mir-143/145 and down-regulation of klf4. SIGNOR-174319 0.477 ACP1 protein P24666 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 10090 17353188 t Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3 SIGNOR-248455 0.327 EIF2S1 protein P05198 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 t lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. SIGNOR-269114 0.944 PRKACA protein P17612 UNIPROT KCNQ5 protein Q9NR82 UNIPROT up-regulates activity phosphorylation Ser88 GKQGARMsLLGKPLS 9606 BTO:0001660 30061510 t miannu We conclude that phosphorylation of S53 on the amino terminus of Kv7.5 is essential for PKA-dependent enhancement of channel activity in response to βAR activation in vascular and airway smooth muscle cells. SIGNOR-265980 0.2 ERG protein P11308 UNIPROT CDH5 protein P33151 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18195090 t Luana Erg overexpression resulted in an approximate 1.8-fold transactivation of VE-cadherin promoter activity. Thus, our data indicate that Erg drives constitutive VE-cadherin expression in human ECs  SIGNOR-261595 0.28 ADRM1 protein Q16186 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263342 0.824 ACVR1 protein Q04771 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation 9606 9748228 t fspada Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2 SIGNOR-60174 0.691 FOXO proteinfamily SIGNOR-PF27 SIGNOR FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 f lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-252945 0.2 BRCA1-B complex complex SIGNOR-C298 SIGNOR ATR protein Q13535 UNIPROT up-regulates activity binding 9606 BTO:0001938 16530042 t lperfetto These results establish that TopBP1 can activate both Xenopus and human ATR. Furthermore, these experiments provide conclusive evidence that the kinase activity that is induced by TopBP1 is intrinsic to the ATR protein itself and is not due to a kinase that associates with ATR. SIGNOR-263231 0.64 MAP3K5 protein Q99683 UNIPROT MAP3K6 protein O95382 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 17210579 t Manara C-terminal region of ASK1 binds to ASK2 and inhibits the degradation of ASK2 SIGNOR-260831 0.531 SOCS3 protein O14543 UNIPROT IL6ST protein P40189 UNIPROT down-regulates activity binding 9606 23454976 t miannu SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. The inhibitory protein SOCS3 plays a key part in the immune and hematopoietic systems by regulating signaling induced by specific cytokines. SOCS3 functions by inhibiting the catalytic activity of Janus kinases (JAKs) that initiate signaling within the cell. SIGNOR-255328 0.637 GDNF protein P39905 UNIPROT ID2 protein Q02363 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252180 0.249 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2L3 protein P68036 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271326 0.584 ATP5PD protein O75947 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261404 0.2 PRKD1 protein Q15139 UNIPROT CERT1 protein Q9Y5P4 UNIPROT down-regulates phosphorylation Ser132 SSLRRHGsMVSLVSG 9606 17591919 t lperfetto In this study, we identify cert as a novel in vivo pkd substrate. Phosphorylation on serine 132 by pkd decreases the affinity of cert toward its lipid target phosphatidylinositol 4-phosphate at golgi membranes and reduces ceramide transfer activity SIGNOR-156500 0.2 MTOR protein P42345 UNIPROT NRBF2 protein Q96F24 UNIPROT up-regulates activity phosphorylation Ser113 AEDAEGQsPLSQKYS 9606 BTO:0001938 28059666 t miannu Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association. SIGNOR-265874 0.2 CTDNEP1 protein O95476 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates binding 9606 17141153 t gcesareni We show that dullard promotes the ubiquitin-mediated proteosomal degradation of bmp receptors SIGNOR-151001 0.437 regorafenib chemical CHEBI:68647 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition 9606 26254357 t miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF SIGNOR-259176 0.8 GRIN2C protein Q14957 UNIPROT NMDA receptor_2C complex SIGNOR-C349 SIGNOR form complex binding 9606 BTO:0000938 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits SIGNOR-264125 0.595 Laminin-1 complex SIGNOR-C183 SIGNOR A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates activity binding 9606 BTO:0000414 24184828 t miannu Integrin α6β4 is a laminin receptor that is mainly expressed in the basal layer of epithelial tissues. The β4-integrin is unique because of its long cytoplasmic tail, which interacts with the intermediate filament network rather than actin. This interaction contributes to the ability of α6β4 to maintain the integrity of tissues normally exposed to shear stress. α6β4 integrin assembles its own signalling platform. SIGNOR-258998 0.505 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT up-regulates activity phosphorylation Thr482 SSQPKVStPVVKQGP 9606 BTO:0000567 30021153 t lperfetto Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. SIGNOR-265033 0.2 ENO2 protein P09104 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI down-regulates quantity chemical modification 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266529 0.8 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser639 YMPMSPKsVSAPQQI 10090 15306821 t lperfetto Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin. SIGNOR-127203 0.78 FANCG protein O15287 UNIPROT SPTAN1 protein Q13813 UNIPROT up-regulates quantity by stabilization 9606 BTO:0000773 19102630 t lperfetto In FA cells, deficiencies in FA proteins lead to decreased stability of alphaRIISp |These results demonstrate that one of the FA proteins, FANCG, contains a motif that interacts directly with the SH3 domain of alphaIISp. We propose that this binding of FANCG to alphaIISp may be important for the stability of alphaIISp in cells and the role alphaIISp plays in the DNA repair process.| SIGNOR-263275 0.374 SPP1 protein P10451 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR up-regulates activity binding 9606 24241034 t lperfetto Synovial fibroblasts and macrophages derived from arthritic joints spontaneously secreted tenascin-C and osteopontin. Synovial fibroblasts and macrophages obtained from patients with RA expressed α9β1 integrins, a common receptor for osteopontin and tenascin-C. SIGNOR-253311 0.607 ZMIZ1 protein Q9ULJ6 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 BTO:0001321 14609956 t miannu Our results demonstrate that hZimp10 is a novel AR interacting protein that augments AR-mediated transcription. Moreover, hZimp10 co-localized with AR and SUMO-1 at replication foci throughout S phase, and it was capable of enhancing sumoylation of AR in vivo. SIGNOR-263935 0.697 ATM protein Q13315 UNIPROT TTC5 protein Q8N0Z6 UNIPROT up-regulates activity phosphorylation Ser203 TGQNPKIsQQALSAY 9606 15448695 t miannu Here we report a new pathway in which ATM kinase signals the DNA damage response by targeting the transcriptional cofactor Strap. ATM phosphorylates Strap at a serine residue, stabilizing nuclear Strap and facilitating formation of a stress-responsive co-activator complex. SIGNOR-262645 0.518 CHN2 protein P52757 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260500 0.625 TIMM21 protein Q9BVV7 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 t lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. SIGNOR-267698 0.612 CHRM5 protein P08912 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256730 0.2 PCDH11X protein Q9BZA7 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR down-regulates 9606 BTO:0000227 25687328 f miannu Our previous research found that protocadherin 11 X-linked protein (Pcdh11x) is predominantly expressed in neurons and has an influence on dendritic branching. In this study, gain-of-function and loss-of-function experiments revealed that Pcdh11x acts as a negative regulator of dendritic branching in cultured cortical neurons derived from embryonic day 16 mice. Overexpression of wild-type Pcdh11x (Pcdh11x-GFP) reduced dendritic complexity, whereas knockdown of Pcdh11x increased dendritic branching. SIGNOR-265163 0.7 afatinib chemical CHEBI:61390 ChEBI ERBB2 protein P04626 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258066 0.8 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr209 TRKHYQPyAPPRDFA 9606 BTO:0000661 22936936 t lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tailother studies demonstrated that tyr191 within the p190yap motif is one of two major phosphorylation sites in cd28-stimulated jurkat t cells, and the only tyrosine residue within the cd28 cytoplasmic tail that is essential for delivery of costimulatory signals SIGNOR-198751 0.677 PRKCD protein Q05655 UNIPROT CHAT protein P28329 UNIPROT up-regulates quantity phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 BTO:0000930 15381704 t lperfetto Finally, basal ChAT phosphorylation in neurons is mediated predominantly by PKC at Ser-476, with PKC activation increasing phosphorylation at Ser-440 and enhancing ChAT activity. SIGNOR-249272 0.316 NRG2 protein O14511 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 7477375 t gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. SIGNOR-26211 0.78 bradykinin smallmolecule CHEBI:3165 ChEBI BDKRB1 protein P46663 UNIPROT up-regulates chemical activation 9606 BTO:0001130;BTO:0000189 17251915 t gcesareni Neuropeptides such as grp, endothelin, bradykinin, neuromedin b (nmb), cholecystokinin (cck) and angiotensin ii activate their cognate gpcrs to stimulate cell proliferation in various cell types, and have a crucial role in many aggressive human cancers, including small-cell lung cancer (sclc), pancreatic cancer, hnscc and prostate cancer. SIGNOR-152588 0.8 JNK proteinfamily SIGNOR-PF15 SIGNOR BAX protein Q07812 UNIPROT up-regulates 9606 15071501 f inferred from 70% family members gcesareni Demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria; these results strongly indicate that jnk regulates the activity of bax by phosphorylating 14-3-3 proteins. SIGNOR-269977 0.2 triptorelin chemical CHEBI:63633 ChEBI GNRH1 protein P01148 UNIPROT up-regulates activity chemical activation 9606 22416801 t miannu The comparative effects of degarelix and GnRH agonists were assessed in two studies in a rat model of prostate cancer.14 In a 2‐month study, rats receiving the GnRH agonist, triptorelin (0.5 mg/kg daily), experienced an initial testosterone surge, followed by suppression to castration levels by day 28, which was maintained for the remainder of the study. SIGNOR-259158 0.8 SNX9 protein Q9Y5X1 UNIPROT EGFR protein P00533 UNIPROT down-regulates 9606 16316319 f gcesareni We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor.The cdc42 target ack2 interacts with sorting nexin 9 (sh3px1) to regulate epidermal growth factor receptor degradation. SIGNOR-142566 0.556 NAT8L protein Q8N9F0 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 19524112 t miannu The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA. SIGNOR-267521 0.8 NDUFB7 protein P17568 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 SIGNOR-262170 0.815 GABARAPL1 protein Q9H0R8 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity binding 9606 BTO:0000567 17580304 t lperfetto P62 binds both to lc3a and -b and the related gabarap family proteins/this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguisha SIGNOR-156304 0.786 NEK6 protein Q9HC98 UNIPROT EML4 protein Q9HC35 UNIPROT up-regulates activity phosphorylation Ser144 QSPQIRAsPSPQPSS -1 31409757 t done miannu The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser144 and Ser146 in vitro, and depletion of these kinases in cells led to increased EML4 binding to microtubules in mitosis. An S144A-S146A double mutant not only bound inappropriately to mitotic microtubules but also increased their stability and interfered with chromosome congression. In addition, constitutive activation of NEK6 or NEK7 reduced the association of EML4 with interphase microtubules. Together, these data support a model in which NEK6- and NEK7-dependent phosphorylation promotes the dissociation of EML4 from microtubules in mitosis in a manner that is required for efficient chromosome congression. SIGNOR-273883 0.255 MYO1E protein Q12965 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity binding 9606 BTO:0000848 28348210 t miannu Myosin-1E (MYO1E), an actin-dependent molecular motor protein, directly interacts with FAK to induce Y397 autophosphorylation, which, in turn, causes changes in gene expression commonly observed in aggressive cancer. SIGNOR-265427 0.2 FABP6 protein P51161 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264460 0.7 BBS1 protein Q8NFJ9 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 t lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome SIGNOR-262558 0.865 L-thyroxine smallmolecule CHEBI:18332 ChEBI Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 24692351 f scontino Skeletal muscle has been recognized as a key TH target for contractile function, regeneration, and transport as well as for metabolism and glucose disposal (237, 238). TH stimulation favors transition to fast-twitch fibers and transition to a faster myosin heavy chain (MHC) form. SIGNOR-267620 0.7 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM7 protein Q14831 UNIPROT up-regulates activity chemical activation 9606 25042998 t miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate SIGNOR-264072 0.8 MFN2 protein O95140 UNIPROT Mitochondrial_fusion phenotype SIGNOR-PH218 SIGNOR up-regulates 9606 25486875 f lperfetto OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria SIGNOR-272985 0.7 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT up-regulates phosphorylation 9606 10828059 t The effect has been demonstrated using Q08499-4 llicata The short pde4d1 isoenzyme is activated by erk2 phosphorylation this signifies that erk2 phosphorylated pde4d1 at a single site, ser491, that is cognate to the single erk2 phosphorylation site (ser579) found in pde4d3. SIGNOR-77559 0.36 PTPRG protein P23470 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity dephosphorylation Tyr701 DGPKGTGyIKTELIS -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254727 0.2 GPR132 protein Q9UNW8 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257396 0.381 STX11-SNAP23 SNARE complex complex SIGNOR-C272 SIGNOR Platelet_degranulation phenotype SIGNOR-PH138 SIGNOR up-regulates 9606 BTO:0000782 22767500 f lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. |The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release. SIGNOR-261901 0.7 minoxidil chemical CHEBI:6942 ChEBI PLOD1 protein Q02809 UNIPROT down-regulates quantity by repression chemical inhibition 10090 BTO:0000763 30481795 t Monia treatment with minoxidil repressed the expression of the PLOD1, PLOD2, and PLOD3 genes and their encoded LH proteins, it exerted the most profound effects on PLOD1/LH1, SIGNOR-261071 0.8 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258003 0.8 GSK3B protein P49841 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 16885213 t lperfetto Gli2 and Gli3 (in vertebrates) are phosphorylated by protein kinase A and glycogen synthase kinase-3_ and are proteolytically processed SIGNOR-148475 0.517 Dihydromorphine chemical CHEBI:4575 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258787 0.8 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT up-regulates activity phosphorylation Ser350 ELKAIVSsSNQALLR 9606 20643644 t Manara We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase. SIGNOR-260794 0.2 SETD5 protein Q9C0A6 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity methylation Lys37 APATGGVkKPHRYRP -1 31515109 t miannu SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription. SIGNOR-264621 0.2 MRGPRX1 protein Q96LB2 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257171 0.2 CSNK1D protein P48730 UNIPROT PER1 protein O15534 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 11865049 t miannu We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. SIGNOR-267999 0.8 THOC5 protein Q13769 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 t miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. SIGNOR-268506 0.927 AKT1 protein P31749 UNIPROT CABLES1 protein Q8TDN4 UNIPROT down-regulates activity phosphorylation Thr309 APLRRCRtLSGSPRP -1 25361894 t miannu Here, we report that Cables1 levels are controlled by a phosphorylation and 14-3-3-dependent mechanism. Mutagenic analyses identified two residues, T44 and T150, that are specifically critical for 14-3-3 binding and that serve as substrates for phosphorylation by the cell survival kinase Akt, which by binding directly to Cables1 recruits 14-3-3 to the complex.Ectopic expression of activated Akt (AKT1) prevented Cables1-induced apoptosis. SIGNOR-276756 0.346 ERBB2 protein P04626 UNIPROT BBC3 protein Q9BXH1 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr172 PSPWRVLyNLIMGLL 9606 BTO:0000093 24236056 t miannu HER2 phosphorylates and destabilizes pro-apoptotic PUMA. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life. SIGNOR-276474 0.285 LETM1 protein O95202 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR up-regulates 9606 BTO:0000567 18628306 f lperfetto LETM1 knockdown obviously reduced the formation of the supercomplexes (Fig. 5C, arrowhead). Complexes I and IV failed to form, and the assembly of complex III was significantly decreased. By contrast, the assembly of complex II (succinate dehydrogenase) and complex V (ATP synthase) – which are not proton pumps – was unaffected. SIGNOR-262547 0.256 ABL1 protein P00519 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Tyr81 WEVGSITyDTLSAQA 9606 32653904 t miannu Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS. SIGNOR-277519 0.2 LDHA protein P00338 UNIPROT (S)-lactate smallmolecule CHEBI:16651 ChEBI up-regulates quantity chemical modification 9606 24929216 t Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. SIGNOR-266919 0.8 PAX5 protein Q02548 UNIPROT TLE4 protein Q04727 UNIPROT down-regulates activity binding 9606 BTO:0002291 10811620 t Gianni Grg4 efficiently represses the transcriptional activity of Pax5 in an octapeptide-dependent manner. Similar protein interactions resulting in transcriptional repression were also observed between distantly related members of both the Pax2/5/8 and Groucho protein families SIGNOR-269083 0.58 buprenorphine chemical CHEBI:3216 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258940 0.8 SCF-FBW7 complex SIGNOR-C135 SIGNOR MED13 protein Q9UHV7 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 SIGNOR-C406 23322298 t miannu The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association. SIGNOR-266691 0.299 MKRN1 protein Q9UHC7 UNIPROT PABPC1 protein P11940 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000007 31640799 t miannu We show that MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1) and associates with polysomes. MKRN1 is positioned upstream of poly(A) tails in mRNAs in a PABPC1-dependent manner. Ubiquitin remnant profiling and in vitro ubiquitylation assays uncover PABPC1 and ribosomal protein RPS10 as direct ubiquitylation substrates of MKRN1.Our data show that MKRN1 associates with polysomes and ubiquitylates RPS10, indicating a role in translational control. We hypothesize that ribosomes encountering the MKRN1-PABPC1 complex are stalled, possibly via ubiquitylation of RPS10 on K107 and other MKRN1 substrates. SIGNOR-272215 0.357 TFEB protein P19484 UNIPROT ACOT2 protein P49753 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) SIGNOR-276781 0.2 CHMP3 protein Q9Y3E7 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 t miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. SIGNOR-265523 0.738 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 9606 20233713 t flangone Employing an mtor active-site inhibitor wye-125132 (wye-132), we have performed quantitative phospho-proteomics and identified a ser-75-containing phosphopeptide from maf1, a known repressor of rna polymerase iii (pol iii) transcriptionmaf1 mutant proteins carrying s75a alone or with s60a, t64a, and s68a (maf1-s75a, maf1-4a) progressively enhanced basal repression of trna in actively proliferating cells and attenuated amino acid-induced trna transcription SIGNOR-164352 0.7 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC9 protein Q93079 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271991 0.2 NEK6 protein Q9HC98 UNIPROT HSPA1A protein P0DMV8 UNIPROT up-regulates activity phosphorylation Thr66 VALNPQNtVFDAKRL -1 30108182 t done miannu Mitotic phosphorylation of Hsp72 by the kinase NEK6 at Thr66 located in the NBD promotes the localization of Hsp72 to the mitotic spindle and is required for efficient spindle assembly and chromosome congression and segregation.  SIGNOR-273885 0.435 NEK6 protein Q9HC98 UNIPROT KIF11 protein P52732 UNIPROT up-regulates activity phosphorylation Ser1033 GINTLERsKVEETTE 9606 BTO:0001938 19001501 t done miannu Nek6 phosphorylated Eg5 at several sites in vitro and one of these sites, Ser1033, is phosphorylated in vivo during mitosis. Whereas CDK1 phosphorylates nearly all Eg5 at Thr926 during mitosis, Nek6 phosphorylates approximately 3% of Eg5, primarily at the spindle poles.  SIGNOR-273886 0.456 BTRC protein Q9Y297 UNIPROT PER1 protein O15534 UNIPROT down-regulates ubiquitination 9606 15917223 t miannu We have found that per1 interacts with both _-trcp1 and _-trcp2 in a manner that depends on casein kinase 1 activity, and depletion of both _-trcp1 and _-trcp2 by rnai leads to dramatic stabilization of per1 SIGNOR-137755 0.552 MAPK14 protein Q16539 UNIPROT EWSR1 protein Q01844 UNIPROT unknown phosphorylation Thr79 QPPTGYTtPTAPQAY 9606 19076070 t lperfetto Here we report that ews and ews-fli1 become phosphorylated at thr79 . but the p38_/p38_ mapks were the major kinases phosphorylating ews-fli1. It will be important to investigate how the p38_/p38_-stimulated phosphorylation of ews-fusion proteins affects their ability to transactivate and their oncogenic potential. SIGNOR-182778 0.2 AKT2 protein P31751 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 SIGNOR-C7 17964260 t gcesareni Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. SIGNOR-158627 0.333 TFEB protein P19484 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 f lperfetto Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14) SIGNOR-276796 0.2 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser256 ESWLGARsSRPASPC 9606 BTO:0001061 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276768 0.629 ROCK1 protein Q13464 UNIPROT MYL12A protein P19105 UNIPROT up-regulates activity phosphorylation Thr18 KKRPQRAtSNVFAMF 9606 12185584 t miannu Phosphorylation of myosin II regulatory light chain (MRLC) is important for cell motility and cytokinesis in nonmuscle cells. Although the regulation of monophosphorylated MRLC at serine 19 throughout the cell cycle was examined in detail, MRLC diphosphorylation at both threonine 18 and serine 19 is still unclear. Here we found that Rho-kinase has an activity for MRLC diphosphorylation in nonmuscle cells using sequential column chromatographies. SIGNOR-263074 0.554 sabcomeline chemical CHEBI:134846 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10116 9399977 t miannu SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes SIGNOR-258674 0.8 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT up-regulates activity phosphorylation Tyr156 GSRNALKyEHKEIEY -1 21840312 t miannu Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility. SIGNOR-263037 0.398 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH3 protein Q9UM47 UNIPROT up-regulates activity cleavage 9606 25610395 t lperfetto The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins. SIGNOR-209726 0.558 belinostat chemical CHEBI:61076 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257958 0.8 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 1715686 t gcesareni Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta. SIGNOR-21307 0.309 CIB2 protein O75838 UNIPROT TMC1 protein Q8TDI8 UNIPROT up-regulates activity binding 10090 BTO:0004744 28663585 t miannu  Furthermore, we report that calcium and integrin-binding protein 2 binds to the components of the hair cell mechanotransduction complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib2 mutations. We conclude that calcium and integrin-binding protein 2 is required for normal operation of the mechanotransducer channels and is involved in limiting the growth of transducing stereocilia. SIGNOR-269664 0.34 CAMK2D protein Q13557 UNIPROT VIM protein P08670 UNIPROT unknown phosphorylation Ser83 GVRLLQDsVDFSLAD BTO:0001444 16140754 t llicata Interestingly, viral DNA replication also resulted in the activation of calcium calmodulin-dependent protein kinase II (CaM kinase II) and phosphorylation of the N-terminal domain of vimentin on serine 82. Immunostaining showed that vimentin within the cage was phosphorylated on serine 82. SIGNOR-250690 0.333 KPNA1 protein P52294 UNIPROT KPNB1 protein Q14974 UNIPROT up-regulates activity binding 9534 17596301 t lperfetto Although ORF6 causes a relocalization of KPNA2 from the cytosol to the ER/Golgi membrane, KPNA2 is not directly involved in the translocation of the STAT1:STAT2:IRF9 (ISGF3) complex into the nucleus; rather, KPNA1 interacts with KPNB1 to initiate ISGF3's nuclear localization. SIGNOR-260273 0.855 HTR2A protein P28223 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257021 0.317 prazosin chemical CHEBI:8364 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258468 0.8 MAPK1 protein P28482 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser178 EENVSDGsPNAGSVE 9606 10831586 t lperfetto Indeed, p27kip1 was phosphorylated by p42 mapk (erk2) in vitrothese results suggest that ser(10) is the major site of phosphorylation of p27(kip1) and that phosphorylation at this site, like that at thr(187), contributes to regulation of p27(kip1) stability. SIGNOR-77655 0.353 ECM stimulus SIGNOR-ST20 SIGNOR A4/b1 integrin complex SIGNOR-C162 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259045 0.7 COX8A protein P10176 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267753 0.508 MYC protein P01106 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity transcriptional regulation 9606 17785433 t inferred from family member Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration. SIGNOR-270270 0.464 5-[1-(2-hydroxyethyl)-3-pyridin-4-yl-4-pyrazolyl]-2,3-dihydroinden-1-one oxime chemical CHEBI:91434 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258112 0.8 PTK2 protein Q05397 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 9416004 t gcesareni Pi3-kinase has also been shown to bind fak in a cell cell adhesion-dipendent manner at the major autophosphorylation site y397. This association could live to activation of pi3-kinase and its downstream effectors. SIGNOR-53979 0.536 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0001538 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219353 0.707 Phenelzine chemical CHEBI:8060 ChEBI MAOB protein P27338 UNIPROT down-regulates activity chemical inhibition -1 18426226 t Luana Phenylethylhydrazine stoichiometrically reduces the covalent FAD moieties of MAO A and of MAO B. Molecular oxygen is required for the inhibition reactions, and the level of O2 consumption for phenylethylhydrazine is 6-7-fold higher with either MAO A or MAO B than for the corresponding reactions with benzylhydrazine or phenylhydrazine. SIGNOR-257778 0.8 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000938 9346240 f lperfetto Growth factors can promote cell survival by activating the phosphatidylinositide-3'-OH kinase and its downstream target, the serine-threonine kinase Akt SIGNOR-252708 0.784 WNT11 protein O96014 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 22309736 t gcesareni We provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase SIGNOR-195966 0.468 A3/b1 integrin complex SIGNOR-C161 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257703 0.602 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1766 SPSYSPTsPSYSPTS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248778 0.442 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr564 LEEADNQtLDSYRNE -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276214 0.388 NFIX protein Q14938 UNIPROT PKCtheta/Nfix complex SIGNOR-C121 SIGNOR form complex binding 10090 BTO:0000165 20178747 t llicata In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A. SIGNOR-238016 0.2 17beta-estradiol smallmolecule CHEBI:16469 ChEBI GPER1 protein Q99527 UNIPROT up-regulates chemical activation 9606 18262661 t gcesareni Recent studies have revealed the contribution of a novel estrogen receptor gpr30, which belongs to the family of seven-transmembrane g-protein-coupled receptors, to many of the rapid biological responses to estrogen. SIGNOR-160778 0.8 OPTN protein Q96CV9 UNIPROT NTF3 protein P20783 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22194658 f same result in PC12 cell miannu SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA. SIGNOR-259879 0.25 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser283 RSVPEPLsPVSSLQA 9606 16027724 t llicata Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo. SIGNOR-138825 0.488 APBA2 protein Q99767 UNIPROT STXBP1 protein P61764 UNIPROT up-regulates activity binding 10116 BTO:0000142 9395480 t miannu Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1. SIGNOR-264037 0.689 PAK2 protein Q13177 UNIPROT RPS6 protein P62753 UNIPROT unknown phosphorylation Ser236 AKRRRLSsLRASTSK -1 1985906 t miannu The synthetic peptide AKRRRLSSLRASTSKSESSQK (S6-21) which corresponds to the carboxyl-terminal 21 amino acids of human ribosomal protein S6 was synthesized and tested as a substrate for S6/H4 kinase purified from human placenta. The principal phosphorylation sites were serines in the acidic carboxyl-terminal domain of the peptide. SIGNOR-250232 0.314 OSM protein P13725 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0001271 1536831 t gcesareni Oncostatin m binds the high-affinity leukemia inhibitory factor receptor SIGNOR-19873 0.715 MACF1 protein Q9UPN3 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization 9606 16815997 f gcesareni In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes. SIGNOR-147448 0.414 GATA1 protein P15976 UNIPROT AGGF1 protein Q8N302 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19556247 f miannu Overexpression of GATA1 increased expression of AGGF1. Knockdown of GATA1 expression by siRNA reduced expression of AGGF1, and resulted in endothelial cell apoptosis and inhibition of endothelial capillary vessel formation and cell migration, which was rescued by purified recombinant human AGGF1 protein. SIGNOR-254188 0.381 RORA protein P35398 UNIPROT PCP2 protein Q8IVA1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001011 19381306 t miannu RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice. SIGNOR-266849 0.2 PDGFA protein P04085 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000763 11803579 t gcesareni Platelet-derived growth factors (pdgf) constitute a family of four gene products (pdgf-a-d) acting by means of two receptor tyrosine kinases, pdgfr alpha and beta. Three of the ligands (pdgf-a, -b, and -c) bind to pdgfr alpha with high affinity. SIGNOR-114268 0.765 LPAR6 protein P43657 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256725 0.2 PPM1D protein O15297 UNIPROT RPS6KA3 protein P51812 UNIPROT down-regulates activity dephosphorylation Ser386 HQLFRGFsFVAITSD 10090 15206906 t RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity SIGNOR-248322 0.368 DAB2IP protein Q5VWQ8 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR up-regulates activity binding 9606 20080667 t miannu DAB2IP interacts via its C2 domain with GSK3β, recruiting phosphatase PP2A for S9 de-phosphorylation and leading to GSK3β activation SIGNOR-254753 0.2 DNA primase complex complex SIGNOR-C261 SIGNOR DNA polymerase alpha:primase complex complex SIGNOR-C262 SIGNOR form complex binding -1 24043831 t lperfetto At the replication fork, primase is present in a constitutive complex with DNA polymerase α (Pol α), which extends the RNA primer with deoxynucleotides and makes the resulting RNA–DNA primer available to the leading- and lagging-strand polymerases, Pols ε and δ, for processive elongation  SIGNOR-261341 0.985 ITCH protein Q96J02 UNIPROT SPART protein Q8N0X7 UNIPROT up-regulates activity binding 9606 BTO:0000567 20719964 t Sara SPG20 Protein Spartin Is Recruited to Midbodies by ESCRT-III Protein Ist1 and Participates in Cytokinesis. Spartin colocalizes with Ist1 at the midbody, and depletion of Ist1 in cells significantly decreases the number of cells where spartin is present at midbodies. SIGNOR-261308 0.2 sorafenib chemical CHEBI:50924 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258283 0.8 IFNA2 protein P01563 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates quantity by stabilization 9606 22171011 t 2 miannu IFN-I (IFN-_ and IFN-_) induces the assembly of IFN-stimulated gene factor 3 (ISGF3), a multimeric transcriptional activation complex composed of STAT1, STAT2, and IFN regulatory factor 9. SIGNOR-240684 0.469 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser385 RYSDTTDsDPENEPF 9606 21779440 t gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity SIGNOR-89822 0.667 DUOX2 protein Q9NRD8 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity chemical modification 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264727 0.8 ERBB4 protein Q15303 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 16829981 t gcesareni Egfr and erbb4 had several docking sites for grb2, while erbb3 was characterized by six binding sites for pi3k. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength. SIGNOR-147847 0.824 PLK3 protein Q9H4B4 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Thr80 RMGSSEStDSGFCLD 9606 18167338 t lperfetto Here, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cdc25a to promote its proteolysis in early cell-cycle phases. Phosphorylation by gsk-3beta requires priming of cdc25a, and this can be catalyzed by polo-like kinase 3 (plk-3) SIGNOR-160228 0.392 PRKACA protein P17612 UNIPROT CACNG2 protein Q9Y698 UNIPROT down-regulates activity phosphorylation Thr321 NTANRRTtPV 9534 11805122 t miannu phosphorylation of stargazin at T321 by PKA inhibits its interaction with PSD-95. SIGNOR-250342 0.419 SLA protein Q13239 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000661 phosphorylation:Tyr594 TYVDPHTyEDPNQAV 24457997 t lperfetto These data are consistent with a model where SLAP induces Ephrin-independent EPHA2 degradation. | This activity is independent from CBL but requires SLAP SH3 interaction with the ubiquitination factor UBE4A and SLAP SH2 interaction with pTyr594-EPHA2. SIGNOR-262964 0.424 EGFR protein P00533 UNIPROT KRT14 protein P02533 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11875647 f Regulation of expression miannu UVB increases keratin 5 and keratin 14 expression through direct activation of the EGF receptor in SVHK. SIGNOR-251901 0.47 MFGE8 protein Q08431 UNIPROT IL1B protein P01584 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 23454767 f Giorgia We show that MFGE8 is an endogenous inhibitor of inflammasome-induced IL-1β production. MFGE8 inhibited necrotic cell–induced and ATP-dependent IL-1β production by macrophages through mediation of integrin β3 and P2X7 receptor interactions in primed cells. In conclusion, we demonstrated that MFGE8 regulates innate immunity through inhibition of inflammasome-induced IL-1β production. SIGNOR-260649 0.267 vorinostat chemical CHEBI:45716 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257922 0.8 CSNK2A1 protein P68400 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser249 LSPIDMEsQERIKAE 9606 1516134 t lperfetto Casein kinase ii is a negative regulator of c-jun dna binding and ap-1 activitywe show that two of these sites, thr-231 and ser-249, are phosphorylated by casein kinase ii (ckii). SIGNOR-19603 0.575 ACSS2 protein Q9NR19 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI down-regulates quantity chemical modification 10843999 t lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. SIGNOR-271828 0.8 PHF10 protein Q8WUB8 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 t miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270614 0.714 TRIM32 protein Q13049 UNIPROT DBNDD1 protein Q9H9R9 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0000298 19349376 t miannu TRIM32 is an E3 ubiquitin ligase for dysbindin. TRIM32 targets dysbindin for degradation. SIGNOR-271422 0.2 NEK7 protein Q8TDX7 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity phosphorylation Ser1219 KNLHSSHsSGLMDKS 9606 BTO:0000565 28630147 t miannu Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C). SIGNOR-266419 0.379 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 10090 BTO:0000011 16731579 t miannu Taken together, these data show that of the NRs studied, PPARα is the most likely target of PFOA and PFOS, although PPARγ is also activated to some extent. SIGNOR-268787 0.8 SMURF1 protein Q9HCE7 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates activity ubiquitination 9606 12519765 t lperfetto Smad ubiquitin regulatory factor 1 (Smurf1), a HECT type E3 ubiquitin ligase, interacts with inhibitory Smad7 and induces translocation of Smad7 to the cytoplasm SIGNOR-97064 0.878 FFAR3 protein O14843 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256678 0.2 PRKACA protein P17612 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates activity phosphorylation Ser235 TTQLRLLsEDTDSQR 9606 BTO:0000007 33110360 t miannu We confirmed the phosphorylation of T130, S235, and S364 by developing monoclonal antibodies against phospho-specific forms of these sites and showed that their phosphorylation is cell cycle-dependent. According to our results, PKA-mediated phosphorylation of E2F1 by PKA inhibits proliferation and glucose uptake and induces caspase-3 activation and senescence. SIGNOR-277538 0.2 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR 48S_initiation_complex complex SIGNOR-C454 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269167 0.2 PDPK2P protein Q6A1A2 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9606 10191262 t gcesareni Our results are consistent with a model in which activation of sgk by igf-1 or hydrogen peroxide is initiated by a ptdins(3,4, 5)p3-dependent activation of pdk2, which phosphorylates ser422. SIGNOR-66234 0.2 CSNK2A1 protein P68400 UNIPROT HMOX2 protein P30519 UNIPROT up-regulates activity phosphorylation Ser79 TALYFTYsALEEEME 10116 BTO:0003036 14527438 t llicata Carbon monoxide neurotransmission activated by CK2 phosphorylation of heme oxygenase-2. | CK2 activation is abolished by the S79A mutation but preserved in S179A and T248A mutations, indicating that S79 is the target of CK2-dependent activation of HO2 SIGNOR-250895 0.341 PRKAA1 protein Q13131 UNIPROT DDIT3 protein P35638 UNIPROT down-regulates activity phosphorylation Ser30 EDLQEVLsSDENGGT 10090 27650555 t Luana Here, we report that phosphorylation of CHOP at Ser30 by AMPKα1 triggers CHOP degradation resulting in reduced macrophage apoptosis and subsequent ameliorated plaque vulnerability in vivo. SIGNOR-259864 0.268 CTDSP1 protein Q9GZU7 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser208 DAGSPNLsPNPMSPA 9606 17035229 t SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248792 0.409 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation -1 8929531 t lperfetto The rapid phosphorylation of bad following il-3 connects a proximal survival signal with the bcl-2 family, modulating this checkpoint for apoptosis.phosphorylatedBAD is bound to 14-3-3 within the cytosol, while only nonphosphorylated BAD is heterodimerized with membrane-bound BCL-XL. SIGNOR-244497 0.2 MAPK1 protein P28482 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation Ser58 SRGGARAsPATQPPP 9606 12478298 t lperfetto In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites SIGNOR-96410 0.652 Caspase 3 complex complex SIGNOR-C221 SIGNOR GOLGB1 protein Q14789 UNIPROT down-regulates activity cleavage Asp1881 LSQISTKdGELKMLQ 9606 14970262 t miannu Giantin and syntaxin 5 are cleaved by caspase-3. Given that both giantin and syntaxin 5 are cleaved at an early stage during apoptosis, we anticipated that, at the very least, the delivery of ER-derived transport intermediates to the Golgi would be impaired in apoptotic cells. SIGNOR-261235 0.255 CASP6 protein P55212 UNIPROT LMNA protein P02545 UNIPROT down-regulates cleavage 9606 11058599 t amattioni Lamin a breakdown is largely mediated by caspase-6 during the execution phase of apoptosis. SIGNOR-83611 0.649 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 t Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. SIGNOR-248335 0.553 SIK2 protein Q9H0K1 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser794 QHLRLSTsSGRLLYA 9606 12624099 t gcesareni These results suggest that highly expressed sik2 in insulin-stimulated adipocytes phosphorylates ser794_ of irs-1 and, as a result, might modulate the efficiency ofinsulinsignal transduction SIGNOR-99055 0.585 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 21059642 t The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). SIGNOR-273029 0.563 RUNX3 protein Q13761 UNIPROT FADD protein Q13158 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002384 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255095 0.2 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259014 0.364 AKT1 protein P31749 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates phosphorylation Ser345 ELLCLRRsSLKAYGN 9606 11809767 t lperfetto Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation. SIGNOR-252469 0.362 PAK1 protein Q13153 UNIPROT ATG5 protein Q9H1Y0 UNIPROT up-regulates quantity by stabilization phosphorylation Thr101 SALPWNItVHFKSFP 36528756 t lperfetto Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells. |As PAK1-mediated phosphorylation at residue T101 protects ATG5 from ubiquitination-dependent degradation SIGNOR-275835 0.2 CPSF3 protein Q9UKF6 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 30507380 f lperfetto Replication-dependent (RD) core histone mRNA produced during S-phase is the only known metazoan protein-coding mRNA presenting a 3' stem-loop instead of the otherwise universal polyA tail. A metallo β-lactamase (MBL) fold enzyme, cleavage and polyadenylation specificity factor 73 (CPSF73), is proposed to be the sole endonuclease responsible for 3' end processing of both mRNA classes. SIGNOR-268337 0.7 PRKG1 protein Q13976 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization SIGNOR-186784 0.277 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR BRCA1 protein P38398 UNIPROT down-regulates phosphorylation Ser632 LVVSRNLsPPNCTEL 9606 BTO:0000150 17334399 t lperfetto In particular, we have identified ser 632 of brca1 as a cyclin d1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin d1/cdk4 activity resulted in increased brca1 dna binding at particular promoters in vivo. SIGNOR-216984 0.579 MAP3K7 protein O43318 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT up-regulates activity 9606 9890973 f lperfetto These results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway. SIGNOR-63979 0.299 IFNA10 protein P01566 UNIPROT LPL protein P06858 UNIPROT down-regulates activity 10090 BTO:0000944 1632769 f Regulation miannu Interleukin-1 and interferon-alpha and gamma induce lipolysis and decrease LPL activity but do not stimulate much PG production. These results demonstrate that cytokines enhance lipolysis and decrease LPL activity in 3T3 adipocytes by a PG independent mechanism. SIGNOR-251859 0.2 PRKACA protein P17612 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Identification of a novel phosphorylation site on histone h3 coupled with mitotic chromosome condensation. SIGNOR-70424 0.2 MAJIN protein Q3KP22 UNIPROT TTM complex complex SIGNOR-C305 SIGNOR form complex binding 9606 BTO:0000007 30718482 t lperfetto Meiotic specific proteins TERB1, TERB2, and MAJIN form a stable complex that plays a critical role in regulating the recruitment of telomeres to the NE SIGNOR-263303 0.2 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273102 0.745 EZH2 protein Q15910 UNIPROT SUZ12/EZH2 complex SIGNOR-C77 SIGNOR form complex binding 9606 16712789 t miannu Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2. SIGNOR-146758 0.961 FZD3 protein Q9NPG1 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates binding 9606 14977528 t gcesareni In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families. SIGNOR-122886 0.2 BHLHE40 protein O14503 UNIPROT BHLHE41 protein Q9C0J9 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 14672706 f lperfetto Forced expression of Clock/Bmal increased endogenous Dec1 mRNA level, and overexpression of Dec1 resulted in suppression of Dec2, Per2, and Dbp expression SIGNOR-253716 0.516 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser431 ENVYTPKsAVKNEEY 9606 16216881 t lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. SIGNOR-141010 0.2 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr417 KENSPCVtPVSTATH 9606 BTO:0001938 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. SIGNOR-104699 0.844 ATM protein Q13315 UNIPROT KHDC3L protein Q587J8 UNIPROT up-regulates activity phosphorylation Thr156 VEVREAGtQRSVEVQ 9606 BTO:0001086 31609975 t miannu Notably, we identified two critical residues, Thr145 and Thr156, whose phosphorylation by Ataxia-telangiectasia mutated (ATM) is essential for KHDC3L's functions.  SIGNOR-273504 0.2 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000142 20308788 t The effect has been demonstrated using P10636-8 lperfetto Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro. SIGNOR-164675 0.2 PLK1 protein P53350 UNIPROT KIF2B protein Q8N4N8 UNIPROT up-regulates activity phosphorylation Ser204 HLDSSKIsVLEPPQE 9606 22535524 t lperfetto We show that Plk1 directly phosphorylates Kif2b at threonine 125 (T125) and serine 204 (S204), and that these two sites differentially regulate Kif2b function. Phosphorylation of S204 is required for the kinetochore localization and activity of Kif2b in prometaphase, and phosphorylation of T125 is required for Kif2b activity in the correction of k-MT attachment errors. SIGNOR-252050 0.646 NFE2L2 protein Q16236 UNIPROT PPAT protein Q06203 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 f miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). SIGNOR-267358 0.2 C5AR1 protein P21730 UNIPROT ITGAM protein P11215 UNIPROT up-regulates quantity by expression 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263464 0.378 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity methylation 9606 24987060 t miannu The presence of trimethylation of H3K27 (H3K27me3) at promoter regions is associated with gene repression. This modification is generated by the Polycomb repressive complex 2 (PRC2), composed of the SET domain-containing histone methyltransferase (HMT) EZH2 (enhancer of zeste homolog 2) or its functional homologue EZH1, and core accessory proteins (EED, SUZ12, and RbAp48) (Fig. 1A). SIGNOR-265367 0.2 WRN protein Q14191 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 9606 19652551 f Our work provides the first demonstration of the major importance of WRN in repair of a specific class of DSB in human cells. SIGNOR-258983 0.7 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr716 RPPSAELySNALPVG 9606 18567737 t gcesareni Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr. SIGNOR-179072 0.679 RPS6KA3 protein P51812 UNIPROT YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 t lperfetto We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue. SIGNOR-182165 0.554 CSNK2A1 protein P68400 UNIPROT SERINC3 protein Q13530 UNIPROT up-regulates activity phosphorylation Ser383 DTTTSGAsDEEDGQP -1 30135209 t miannu The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the μ subunits in vitro. SIGNOR-273632 0.2 NR3C1 protein P04150 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity transcriptional regulation 9606 26652733 t Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB SIGNOR-256104 0.2 AminoAcids stimulus SIGNOR-ST5 SIGNOR LAMTOR complex SIGNOR-C26 SIGNOR up-regulates 9606 BTO:0000007 SIGNOR-C3 20381137 f lperfetto The trimeric Ragulator complex, which comprises the p18, p14, and MP1 proteins, anchors the Rag GTPases to the lysosome, and, like the Rags, is necessary for mTORC1 activation by amino acids SIGNOR-228152 0.7 PPP3CC protein P48454 UNIPROT DNM2 protein P50570 UNIPROT unknown dephosphorylation Ser764 LQSASSHsPTPQRRP 10116 20496096 t CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII). SIGNOR-248508 0.253 SKI protein P12755 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates binding 9606 12419246 t gcesareni Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad6 SIGNOR-95468 0.685 EEF1A1 protein P68104 UNIPROT Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269520 0.8 TFE3 protein P19532 UNIPROT FLCN protein Q8NFG4 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto We found a TFE3-dependent increase in the amount of FLCN in ARPE-19 cells starved of nutrients for 24 hours (Fig. 3E). Accordingly, we found that overexpression of TFE3 in ARPE-19 cells resulted in an increase in FLCN protein abundance (Fig. 3F), as well as the mRNA abundance of FLCN and two FLCN-interacting proteins, FNIP1 and FNIP2 (Fig. 3G) (32). SIGNOR-276819 0.456 FGFR3 protein P22607 UNIPROT CILK1 protein Q9UPZ9 UNIPROT down-regulates activity phosphorylation Tyr15 RQLGDGTyGSVLLGR -1 30782830 t miannu FGF signaling partially abolished ICK's kinase activity, through FGFR-mediated ICK phosphorylation at conserved residue Tyr15, which interfered with optimal ATP binding. SIGNOR-277436 0.2 ASXL3 protein Q9C0F0 UNIPROT BRD4 protein O60885 UNIPROT up-regulates activity binding 9606 BTO:0000189 32669118 t miannu We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers. SIGNOR-266762 0.2 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Thr53 PPGSLSStPLSTPCS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159373 0.2 SRC protein P12931 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Tyr74 HKPLEGKyEWQEVEK 9606 17254967 t lperfetto Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27 SIGNOR-152831 0.51 MASP1 protein P48740 UNIPROT C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Gly1446 TPLQLFEgRRNRRRR -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263438 0.59 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89150 0.538 GSK3B protein P49841 UNIPROT CIITA protein P33076 UNIPROT up-regulates phosphorylation Ser373 VQARLERsSSKSLER 9606 17991736 t gcesareni Here we report that CIITA represses collagen transcription through a phosphorylation-dependent interaction between its proline/serine/threonine domain and co-repressor molecules such as histone deacetylase (HDAC2) and Sin3B. Mutation of a serine (S373A) in CIITA, within a glycogen synthase kinase 3 (GSK3) consensus site, decreases repression of collagen transcription by blocking interaction with Sin3B SIGNOR-158959 0.353 LCK protein P06239 UNIPROT VAV1 protein P15498 UNIPROT unknown phosphorylation Tyr160 VEEDEDLyDCVENEE -1 10669745 t Lck recognizes preferentially the tyrosine residue of Vav located at position 174 and, with significantly less affinity, those present at positions 142 and 160. It is now clear that this posttranslational modification will be involved in the activation of Vav, in the regulation of the strength of the signals emanating from this molecule, and also in the negative regulation of its function. SIGNOR-251390 0.775 DOK1 protein Q99704 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257670 0.321 CAMK2G protein Q13555 UNIPROT CHAT protein P28329 UNIPROT up-regulates activity phosphorylation Thr574 VDNIRSAtPEALAFV BTO:0000932 12486117 t llicata Using mass spectrometry, we identified threonine 456 as a new phosphorylation site in choline acetyltransferase from A beta-(1-42)-treated cells and in purified recombinant ChAT phosphorylated in vitro by calcium/calmodulin-dependent protein kinase II (CaM kinase II). | This phosphorylation combination was observed in choline acetyltransferase from A beta-(1-42)-treated cells. Treatment of cells with A beta-(1-42) resulted in two phases of activation of choline acetyltransferase, the first within 30 min and associated with phosphorylation by protein kinase C and the second by 10 h and associated with phosphorylation by both CaM kinase II and protein kinase C. SIGNOR-250693 0.312 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258898 0.8 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules SIGNOR-171022 0.754 MAP2K7 protein O14733 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 11062067 t lperfetto Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1). SIGNOR-83725 0.687 SMARCB1 protein Q12824 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270747 0.83 bisindolylmaleimide i chemical CID:2396 PUBCHEM PRKCD protein Q05655 UNIPROT down-regulates chemical inhibition 9606 Other t CellSignaling gcesareni SIGNOR-190350 0.8 DCX DET1-COP1 complex SIGNOR-C24 SIGNOR CRTC2 protein Q53ET0 UNIPROT down-regulates quantity by destabilization ubiquitination Lys629 DSSPGFSkEIAAALA 9606 BTO:0000007 17805301 t miannu  In the presence of relevant cofactors (DDB1, DET1), COP1 promoted the ubiquitination of wild-type but not COP1-interaction defective VP/AA TORC2 (Fig. 3e). COP1 also stimulated the ubiquitination of TORC2(K213R) but had no effect on TORC2(K628R), suggesting an important role for Lys 628 in this regard (Fig. 3e). We performed mass spectrometry studies to characterize residues in TORC2 that undergo COP1-mediated ubiquitination. This analysis revealed one major (Lys 628) and one minor (Lys 213) site on TORC2 SIGNOR-271665 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 25728771 t inferred from 70% family members lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation SIGNOR-270092 0.2 PK proteinfamily SIGNOR-PF80 SIGNOR STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 22306293 t llicata Pkm2 activates transcription of mek5 by phosphorylating stat3 at y705. pkm2 regulates mek5 transcription via activation of stat3 SIGNOR-268152 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation 9606 7889942 t inferred from 70% family members gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-270075 0.2 KATNAL2 protein Q8IYT4 UNIPROT TUBD1 protein Q9UJT1 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0001363 29136647 t miannu Here we show that KATNAL2 is critical for numerous aspects of this developmental process, including the initiation of the axoneme from the basal body, suppression of the spermatid centriole duplication cycle, sperm nuclear sculpting via the manchette, the attachment of the acrosome to the nucleus and the tethering of elongated spermatids to Sertoli cells via the tubulobulbar complex and ultimately sperm release via spermiation. KATNAL2 does not sever microtubules composed of α- and β-tubulin but does interact with δ- and ε-tubulin SIGNOR-267175 0.259 PPP1CA protein P62136 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity dephosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001176 19036824 t The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation SIGNOR-248558 0.2 PRKACA protein P17612 UNIPROT FXYD1 protein O00168 UNIPROT unknown phosphorylation Ser83 EEGTFRSsIRRLSTR 9606 21220422 t llicata We conclude that phosphorylation of plm increases its oligomerization into tetramers, decreases its binding to nka, and alters the structures of both the tetramer and nka regulatory complex. SIGNOR-171184 0.43 YEATS4 protein O95619 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269302 0.762 STAT6 protein P42226 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15632317 f miannu IL-4 induces HSD3B1 gene expression, along with IL-13, through STAT 6 activation. SIGNOR-255249 0.2 EIF2B5 protein Q13144 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269128 0.873 valine smallmolecule CHEBI:27266 ChEBI Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates quantity precursor of 9606 30755602 t miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. SIGNOR-270532 0.8 SH3GLB2 protein Q9NR46 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 25517094 f miannu Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. SIGNOR-263887 0.7 NF1 protein P21359 UNIPROT ADCY10 protein Q96PN6 UNIPROT up-regulates 9606 24431436 f miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-203921 0.276 CSNK2A1 protein P68400 UNIPROT CASQ2 protein O14958 UNIPROT unknown phosphorylation Ser385 DDDDDDNsDEEDNDD -1 1985907 t llicata Both cardiac and skeletal muscle calsequestrins were phosphorylated by casein kinase II, but cardiac calsequestrin was phosphorylated to a higher stoichiometry and at least 50 times more rapidly. The site of rapid phosphorylation of cardiac calsequestrin was localized to the distinct COOH terminus, where a cluster of three closely spaced serine residues are found (S378DEESN-DDSDDDDE-COOH). SIGNOR-250834 0.343 CXCL8 protein P10145 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 f lperfetto Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS SIGNOR-260257 0.7 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser645 RPASVPPsPSLSRHS 11427888 t Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. SIGNOR-251238 0.673 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BCL2 protein P10415 UNIPROT up-regulates phosphorylation 9606 10669763 t inferred from 70% family members gcesareni Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70 p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both in vitro and in vivo molecular association. SIGNOR-270064 0.2 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser323 MVGGKPGsFRVRASS 9606 BTO:0000671 15069075 t gcesareni Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of ser-318 in irs1 by a janus kinase 2, irs2, and pkc-dependent pathway. we observed that insulin stimulates phosphorylation of ser(318) in irs-1, which is mediated, at least partially, by pkc-zeta. SIGNOR-123734 0.632 GUCY1A2 protein P33402 UNIPROT GUCY1A2-B3 complex SIGNOR-C138 SIGNOR form complex binding 9606 10977868 t gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity SIGNOR-243977 0.2 COLGALT1 protein Q8NBJ5 UNIPROT COL1A1 protein P02452 UNIPROT up-regulates activity glycosylation -1 19075007 t Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. SIGNOR-261152 0.384 PAK4 protein O96013 UNIPROT ITGB5 protein P18084 UNIPROT up-regulates phosphorylation Ser762 AKFQSERsRARYEMA 9606 20507994 t llicata Pak4 specifically phosphorylated the integrin beta5 subunit at ser-759 and ser-762 within the beta5-sers-motif. Point mutation of these two serine residues abolished the pak4-induced cell migration, indicating a functional role for these phosphorylations in migration. SIGNOR-165706 0.462 NANOG protein Q9H9S0 UNIPROT CGA protein P01215 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 f miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. SIGNOR-254623 0.2 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser729 ASPQSPEsVDLVNEE 9606 18701649 t gcesareni Such results suggest that during apoptosis, oxidative stress could activate p38 mapk, phosphorylating nhe1 at s726 and s729. SIGNOR-180048 0.553 LATS1 protein O95835 UNIPROT PRPS2 protein P11908 UNIPROT down-regulates quantity by destabilization phosphorylation Thr285 EDKMKHCtKIQVIDI -1 34465890 t miannu  Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness. SIGNOR-276506 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000176 14967450 t inferred from 70% family members lperfetto Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-270198 0.2 EIF2B1 protein Q14232 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269124 0.823 paliperidone chemical CHEBI:82978 ChEBI HTR1B protein P28222 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0001311 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258560 0.8 brimonidine chemical CHEBI:3175 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258900 0.8 Quadazocine chemical CID:115077 PUBCHEM OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258418 0.8 TACR3 protein P29371 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257267 0.428 ADCY10 protein Q96PN6 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 t miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. SIGNOR-265008 0.8 MAFA protein Q8NHW3 UNIPROT GLP1R protein P43220 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17149590 f miannu the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. SIGNOR-254563 0.34 SP3 protein Q02447 UNIPROT PCYT1A protein P49585 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 10744779 t Luana Sp1 and Sp3 function as transcriptional activators of the Ctpct promoter SIGNOR-266232 0.2 HTR3B protein O95264 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 18761359 f miannu The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release.  SIGNOR-264317 0.7 UBE3A protein Q05086 UNIPROT MCM7 protein P33993 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 9852095 t miannu The characterization of this interaction in turn led to the discovery that Mcm7 is a substrate for both E6-AP-dependent and -independent ubiquitination and is specifically targeted for degradation by the 26 S proteasome. SIGNOR-272543 0.41 GNG3 protein P63215 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 17419683 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-252685 0.358 WNK1 protein Q9H4A3 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates phosphorylation Thr1048 YQEKVHMtWTKDKYM 9606 BTO:0000938 BTO:0000142 19665974 t gcesareni We have attempted to identify kinases and phosphatases involved in the modulation of phosphorylation at kcc3 t991 and t1048. the wnk kinases and spak/osr1 are strong candidates for kcc3 regulatory kinases. SIGNOR-187560 0.465 SMAD1 protein Q15797 UNIPROT GATA3 protein P23771 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 t Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation SIGNOR-268938 0.295 CSNK1E protein P49674 UNIPROT APC protein P25054 UNIPROT up-regulates activity phosphorylation Ser1279 SRCSSLSsLSSAEDE 9606 BTO:0000038 11487578 t lperfetto Apc can be phosphorylated by ck1epsilon at ser1279 and ser1392. Mutation of conserved serine residues in the beta-catenin regulatory motifs of APC interfered with both axin-dependent phosphorylation and phosphorylation by CKIepsilon and impaired the ability of APC to regulate beta-catenin. SIGNOR-109660 0.597 PTPN6 protein P29350 UNIPROT JAK3 protein P52333 UNIPROT up-regulates dephosphorylation 9606 11021818 t gcesareni The expression of shp-1 protein was associated with dephosphorylation of the jak3 kinase. SIGNOR-82764 0.675 PHF2 protein O75151 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 21532585 t miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. SIGNOR-264519 0.2 RNF183 protein Q96D59 UNIPROT ATP1B1 protein P05026 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 31732153 t miannu RNF183 promotes the degradation of Na, K-ATPas.  We confirmed that RNF183 interacted with both α1 and β1 subunits; however, we found that RNF183 ubiquitinated only the β1 subunit, not the α1 subunit.  SIGNOR-272218 0.2 PPP1R8 protein Q12972 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates activity binding -1 1322907 t lperfetto We have purified two of these nuclear inhibitors of PP-1 (NIPP-1a and NIPP-1b) until homogeneity. SIGNOR-264673 0.667 RIN1 protein Q13671 UNIPROT ABL2 protein P42684 UNIPROT up-regulates phosphorylation 9606 BTO:0000149 15886098 t CrkL forms a constitutive complex with Abl, thus explaining the strong preference of Bcr-Abl for CrkL. gcesareni Rin1 binds to the abl sh3 and sh2 domains, and these inetractions stimulate abl2 catalytic activity. This leads to increased phosphorylation of crk and crkl SIGNOR-136961 0.603 WDR62 protein O43379 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 t lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. SIGNOR-271726 0.246 BCORL1 protein Q5H9F3 UNIPROT CTBP1 protein Q13363 UNIPROT up-regulates activity binding 9606 BTO:0002181 17379597 t irozzo BCoR-L1 also interacts with the CtBP corepressor through a CtBP-interacting motif in its amino terminus. Furthermore, BCoR-L1 is located on the E-cadherin promoter, a known CtBP-regulated promoter, and represses the E-cadherin promoter activity in a reporter assay. SIGNOR-259193 0.448 AVEN protein Q9NQS1 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity binding -1 18571408 t miannu These data suggest that Aven overexpression can activate ATM and that Aven phosphorylation in a positive feedback loop enforces Aven activity, making it a more potent ATM activator. SIGNOR-262638 0.39 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120056 0.781 PFDN5 protein Q99471 UNIPROT Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR form complex binding 9606 32699605 t miannu The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6) SIGNOR-270934 0.964 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser248 SVQSDIWsMGLSLVE 9606 8131746 t gcesareni Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf SIGNOR-36457 0.556 romidepsin chemical CHEBI:61080 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257994 0.8 CAMK2A protein Q9UQM7 UNIPROT KRT18 protein P05783 UNIPROT unknown phosphorylation Ser53 ISVSRSTsFRGGMGS BTO:0000944 7523419 t llicata Ser-52 in K18 is not glycosylated and matches consensus sequences for phosphorylation by CAM kinase, S6 kinase and protein kinase C, and all these kinases can phosphorylate K18 in vitro predominantly at that site. Expression of K18 ser-52-->ala mutant in mammalian cells showed minimal phosphorylation but no distinguishable difference in filament assembly when compared with wild-type K18. In contrast, the ser-52 mutation played a clear but nonexclusive role in filament reorganization, SIGNOR-250633 0.29 FCER1A protein P12319 UNIPROT FCER1 complex SIGNOR-C200 SIGNOR form complex binding 9606 BTO:0000830 16470226 t Alessandro Palma FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling. SIGNOR-254959 0.668 CSNK2A1 protein P68400 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Ser289 PPQDQESsPIENDSS 9606 7678037 t llicata These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase erine threonine phosphorylation and may stimulate CKII activity in B cells. SIGNOR-250916 0.312 CYP11B2 protein P19099 UNIPROT cortisol smallmolecule CHEBI:17650 ChEBI up-regulates quantity chemical modification 9606 BTO:0000050 9814482 t lperfetto Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. SIGNOR-268676 0.8 MAP3K7 protein O43318 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 16980613 t lperfetto We further show that emk and c-tak1 phosphorylate class iia hdacs on one of their multiple 14-3-3 binding sites and alter their subcellular localization and repressive function SIGNOR-149579 0.2 ATM protein Q13315 UNIPROT BTRC protein Q9Y297 UNIPROT up-regulates quantity by stabilization phosphorylation Ser158 EFVEHLIsQMCHYQH 9606 BTO:0000093 33676897 t miannu ATM phosphorylates and stabilizes β-TrCP1 upon DNA damage. SIGNOR-277549 0.304 TGFB1 protein P01137 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11331591 f gcesareni Tgf-beta inhibited the expression of the cbfa1 and_ osteocalcin_ genes. SIGNOR-107248 0.379 FZD4 protein Q9ULV1 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity binding 9606 12958364 t amattioni Endocytosis of frizzled 4 (fz4) in human embryonic kidney 293 cells was dependent on added wnt5a protein and was accomplished by the multifunctional adaptor protein beta-arrestin 2 (betaarr2), which was recruited to fz4 by binding to phosphorylated dvl2. SIGNOR-100274 0.741 ATP(4-) smallmolecule CHEBI:30616 ChEBI ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity precursor of 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269098 0.8 RIPK1 protein Q13546 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 20404851 t lperfetto Collectively, TRIF forms a multiprotein signaling complex along with TRAF6, TRADD, Pellino-1 and RIP1 for the activation of TAK1, which in turn activates the NF-_B and MAPK pathways. SIGNOR-216325 0.646 CSK protein P41240 UNIPROT ITCH protein Q96J02 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 16888620 t gcesareni CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4. Moreover, the observed inhibition is both dependent on the interaction between CISK and AIP4 and on the activation status of CISK. Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro. SIGNOR-245327 0.2 CARS1 protein P49589 UNIPROT Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI up-regulates quantity chemical modification 9606 11347887 t miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. SIGNOR-270474 0.8 MAP3K4 protein Q9Y6R4 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 9606 21152872 f lperfetto We found that mekk1/mekk4 as opposed to ask1, are responsible for trail-induced c-jun nh2-terminal kinase (jnk) or p38 activation, SIGNOR-170534 0.396 POU5F1 protein Q01860 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 25126380 f flangone Sex determining region Y-box 2 (Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells (PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency.  SIGNOR-242067 0.7 GPR183 protein P32249 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256715 0.393 EEF1A1 protein P68104 UNIPROT Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269515 0.8 OPALIN protein Q96PE5 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 18490449 f SimoneGraziosi Opalin protein is a type 1 transmembrane sialylglycoprotein and an oligodendrocyte-specific component of myelin membranes. SIGNOR-269229 0.7 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid chemical CHEBI:91366 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194518 0.8 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation 9606 10828059 t The effect has been demonstrated using Q08499-2 llicata Long pde4d forms are inhibited by erk2 phosphorylation SIGNOR-77574 0.36 CLCF1 protein Q9UBD9 UNIPROT CNTFR protein P26992 UNIPROT up-regulates binding 9606 BTO:0000938 10966616 t gcesareni Striking phenotypic differences between cntf- and cntfr-deficient mice suggest that cntfr serves as a receptor for a second, developmentally important ligand. We have identified this factor as a stable secreted complex of cardiotrophin-like cytokine (clc) and the soluble receptor cytokine-like factor-1 (clf). SIGNOR-81376 0.691 RUVBL1 protein Q9Y265 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270855 0.708 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity precursor of 9606 BTO:0000050 2139411 t lperfetto The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione. SIGNOR-268639 0.8 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser515 SGDRSGYsSPGSPGT 9606 BTO:0000938 16923168 t The effect has been demonstrated using P10636-8 lperfetto Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation. SIGNOR-148966 0.462 TNF protein P01375 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253491 0.2 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding -1 3142692 t irozzo The c-Jun and c-fos proto-oncogenes encode proteins that form a complex which regulates transcription from promoters containing AP-1 activation elements. c-Jun has specific DNA binding activity, while c-Fos has homology to the putative DNA binding domain of c-Jun. SIGNOR-256366 0.951 ISGF3 complex complex SIGNOR-C124 SIGNOR EIF2AK2 protein P19525 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27712625 f miannu The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum. SIGNOR-260158 0.49 regorafenib chemical CHEBI:68647 ChEBI RET protein P07949 UNIPROT down-regulates activity chemical inhibition 9606 26254357 t miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF SIGNOR-259181 0.8 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Thr8 MSSILPFtPPIVKRL 9606 19114991 t lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity SIGNOR-182983 0.748 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000782;BTO:0001271 8125092 t gcesareni Phosphorylation of either serine 16 or 63 is sufficient to inhibit stathmin in vitro. Phosphorylation at ser-63 reduces tubulin binding 10-fold and suppresses the mt polymerization inhibition activity. SIGNOR-36370 0.314 NEK1 protein Q96PY6 UNIPROT VDAC1 protein P21796 UNIPROT down-regulates phosphorylation Ser193 DGTEFGGsIYQKVNK 9606 20230784 t lperfetto Nek1 phosphorylates vdac1 on ser193. Wild-type vdac1 assumes an open configuration, but closes and prevents cytochrome c efflux when phosphorylated by nek1. A vdac1-ser193ala mutant, which cannot be phosphorylated by nek1 under identical conditions, remains open and constitutively allows cytochrome c efflux. SIGNOR-164222 0.435 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 18267068 t lperfetto Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. SIGNOR-249573 0.2 TPO protein P07202 UNIPROT L-alanine zwitterion smallmolecule CHEBI:57972 ChEBI up-regulates quantity chemical modification 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-267041 0.8 Glycine cleavage system complex SIGNOR-C437 SIGNOR (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity chemical modification 9606 16051266 t lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. SIGNOR-268239 0.8 BLVRA protein P53004 UNIPROT biliverdin(2-) smallmolecule CHEBI:57991 ChEBI up-regulates quantity chemical modification 9606 BTO:0000759 7929092 t lperfetto This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. SIGNOR-275521 0.8 PCDH9 protein Q9HC56 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-269035 0.2 GATA1 protein P15976 UNIPROT TAL1 protein P17542 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7632958 f irozzo Moreover, GATA-1 but not GATA-2 or GATA-3 was able to transactivate SCL promoter 1a in a T-cell environment. These results suggest that inactivity of SCL promoter 1a in T cells reflected the absence of GATA-1 rather than the presence of trans-dominant negative regulators. SIGNOR-256047 0.776 ITK protein Q08881 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 20519342 t gcesareni In t cells, the predominant tec kinase is itk, which functions downstream of the t-cell receptor to regulate phospholipase c-gamma. SIGNOR-165803 0.621 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser327 DPEMEEDsYDSFGEP -1 9558331 t llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. SIGNOR-250800 0.371 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Ser45 FHGVAILsPLLNIEK -1 12361598 t miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) SIGNOR-265957 0.53 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120176 0.321 MDM4 protein O15151 UNIPROT MDM4 protein O15151 UNIPROT down-regulates quantity by destabilization ubiquitination -1 12393902 t miannu Here we demonstrate that MdmX acts as a ubiquitin ligase in vitro, being capable of autoubiquitination, as well as mediating the ubiquitination of p53.  SIGNOR-271390 0.2 MTCP1 protein P56278 UNIPROT AKT1 protein P31749 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation SIGNOR-81671 0.459 DNA_damage stimulus SIGNOR-ST1 SIGNOR ATR protein Q13535 UNIPROT up-regulates 9606 21034966 f lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. SIGNOR-242609 0.7 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates activity phosphorylation Ser741 TKADKRRsVRIGSYI 9823 BTO:0004007 7539802 t lperfetto We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling. SIGNOR-248898 0.511 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates quantity by destabilization phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 BTO:0002181 16046550 t miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. SIGNOR-268218 0.2 SOCS6 protein O14544 UNIPROT KIT protein P10721 UNIPROT down-regulates ubiquitination 9606 21030588 t miannu Suppressor of cytokine signaling 6 (socs6) is a member of the socs family of e3 ubiquitin ligases that can interact with c-kit and suppress c-kit-dependent pathways. / we demonstrate that socs6 has ubiquitin ligase activity toward c-kit and regulates c-kit protein turnover in cells SIGNOR-169145 0.665 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0001538 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252756 0.719 NFE2L2 protein Q16236 UNIPROT MTHFD2 protein P13995 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 f miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). SIGNOR-267359 0.2 TIGAR protein Q9NQ88 UNIPROT beta-D-fructofuranose 2,6-bisphosphate(4-) smallmolecule CHEBI:58579 ChEBI down-regulates quantity chemical modification 9606 27803158 t miannu TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. TIGAR decreases glycolysis by functioning as a bisphosphatase that reduces levels of intracellular fructose-2,6-bisphosphate (Fru-2,6-P2) and 2,3-bisphosphoglycerate (7, 9), which are regulators of glycolysis. SIGNOR-267364 0.8 ADAM17 protein P78536 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates cleavage 10090 18344021 t apalma Two ADAMs have been implicated in the S2 cleavage of Notch. In Drosophila, ADAM10 ortholog Kuzbanian is the main protease mediating Notch processing [35–38]. In mouse cells in vitro, ADAM17, and not ADAM10, appears to be a protease responsible for Notch cleavage SIGNOR-255370 0.729 MAPK1 protein P28482 UNIPROT NID1 protein P14543 UNIPROT unknown phosphorylation Ser333 YSVPSVLsPRRAATE 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262771 0.253 PAK4 protein O96013 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser675 QDYKKRLsVELTSSL 9606 22173096 t lperfetto Pak4 interacts with and phosphorylates _-catenin on ser675, which promotes the tcf/lef transcriptional activity and stabilizes _-catenin through inhibition of its degradation. SIGNOR-191557 0.291 DCC protein P43146 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity binding 9606 29479476 t miannu The initial step of signaling inside the cell after netrin-1/DCC ligation is the binding of DCC cytoplasmic P3 motif to focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK). Here we report the crystal structure of P3/FAT complex. The helical P3 peptide interacts with a helix-swapped FAT dimer in a 2:2 ratio. Dimeric FAT binding is P3-specific and stabilized by a calcium ion. We propose that netrin-1/DCC engagement creates a small cluster of P3/FAT for FAK recruitment close to the cell membrane, which exerts a concerted effect with PIP2 for FAK signaling. Axon guidance assays confirm that this DCC/FAK complex is physiologically essential for netrin-1-induced chemoattraction. SIGNOR-268370 0.708 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273044 0.556 SEMA7A protein O75326 UNIPROT PLXNC1 protein O60486 UNIPROT up-regulates binding 9606 10520995 t gcesareni Plexin-c1 is a receptor for the gpi-anchored semaphorin sema7a. The cytoplasmic domain of plexins associates with a tyrosine kinase activity. Plexins may also act as ligands mediating repulsion in epithelial cells in vitro. SIGNOR-71260 0.911 dothiepin chemical CHEBI:36798 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 t miannu At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter.  SIGNOR-258878 0.8 MMP23B protein O75900 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272367 0.7 TNFRSF10A protein O00220 UNIPROT FADD protein Q13158 UNIPROT up-regulates binding 9606 14585074 t amattioni Fadd binds to ligated trailr1 or trail-r2 SIGNOR-97869 0.825 TLN1 protein Q9Y490 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257608 0.682 ATR protein Q13535 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 10973490 t lperfetto Atm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro.Substitution of thr68 with ala reduced the extent of phosphorylation and activation of chk2 in response to ir SIGNOR-81442 0.855 TLN1 protein Q9Y490 UNIPROT ITGB5 protein P18084 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257629 0.572 CSNK2A1 protein P68400 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser418 VEEDPLNsGDDVSEQ -1 12107178 t llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. SIGNOR-250872 0.435 GLDN protein Q6ZMI3 UNIPROT ANK3 protein Q12955 UNIPROT up-regulates quantity relocalization 9606 BTO:0000227 19840192 t miannu Ankyrin-G is recruited to the nodes of Ranvier by gliomedin, which is produced by Schwann cells and accumulates in the perinodal extracellular matrix. As a ligand for neurofascin-186, gliomedin causes the nodal clustering of this cell adhesion molecule, which in turn recruits to the nodal plasma membrane an ankyrin-G protein network consisting of voltage-gated sodium or potassium channels (KCNQ2/3) and β4-spectrin. SIGNOR-266725 0.419 DRD2 protein P14416 UNIPROT GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 21303898 t miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC SIGNOR-264993 0.586 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1139 TCSPQPEyVNQPDVR -1 1706616 t  Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. SIGNOR-251127 0.2 CIT protein O14578 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Thr19 KKRPQRAtSNVFAMF -1 21457715 t Giulio Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation. SIGNOR-260306 0.542 F2 protein P00734 UNIPROT Thrombin-Thrombomodulin complex SIGNOR-C316 SIGNOR form complex binding 9606 BTO:0000131 29880919 t lperfetto Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC). SIGNOR-263550 0.903 PDPK1 protein O15530 UNIPROT TSSK3 protein Q96PN8 UNIPROT up-regulates activity phosphorylation Thr168 SHRELSQtFCGSTAY -1 16336268 t Manara We elucidated the mechanism of regulation of TSSK3 activity showing that autophosphorylation and PDK1 phosphorylation in the ‘activation loop’ are necessary for activation. SIGNOR-260786 0.264 neratinib chemical CHEBI:61397 ChEBI ERBB2 protein P04626 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258255 0.8 CDK1 protein P06493 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser321 KCQRLFRsPSMPCSV 9606 20801879 t gcesareni Ser(321) is phosphorylated in mitosis by cdk1. The mitotic phosphorylation of ser(321) acts to maintain full activation of cdc25b by disrupting 14-3-3 binding to ser(323) and enhancing the dephosphorylation of ser(323) to block 14-3-3 binding to this site. SIGNOR-167641 0.823 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Ser33 GFGSPAPsQAEKKSR -1 9139719 t lperfetto In this study, we show that efficient phosphorylation of HSSB-p34 by DNA-PK requires Ku as well as DNA. The DNA-PK phosphorylation sites in HSSB-p34 have been mapped at Thr-21 and Ser-33. Kinetic studies demonstrated that a phosphate residue is first incorporated at Thr-21 followed by the incorporation of a second phosphate residue at Ser-33. SIGNOR-248971 0.597 WNT1 protein P04628 UNIPROT MYF5 protein P13349 UNIPROT up-regulates activity 10090 BTO:0000887;BTO:0001103 9753670 f gcesareni Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5 SIGNOR-60285 0.343 PHLPP2 protein Q6ZVD8 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 9606 BTO:0001544 19261608 t The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. SIGNOR-248732 0.764 MAPK14 protein Q16539 UNIPROT FOXC1 protein Q12948 UNIPROT up-regulates quantity by stabilization phosphorylation Ser272 SSLSSGSsPPGSLPS 31650548 t lperfetto P38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation. SIGNOR-275911 0.2 PRKAA1 protein Q13131 UNIPROT CPT1C protein Q8TCG5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21892142 f gcesareni In 2010, bungard et al., reported that ampk can target transcriptional regulation through phosphorylation of histone h2b on serine3681. Cells expressing a mutant h2b s36a blunted the induction of stress genes upregulated by ampk including p21 and cpt1c. SIGNOR-176422 0.262 CHEK1 protein O14757 UNIPROT SYK protein P43405 UNIPROT down-regulates phosphorylation Ser295 GIISRIKsYSFPKPG 9606 22585575 t llicata We found that chk1 phosphorylated the tumor suppressor spleen tyrosine kinase (l) (syk[l]) and identified the phosphorylation site at ser295. Furthermore, chk1 phosphorylation of syk(l) promoted its subsequent proteasomal degradation. SIGNOR-197528 0.316 MYC protein P01106 UNIPROT DKK1 protein O94907 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17485441 f gcesareni C-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity SIGNOR-245355 0.396 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates phosphorylation 9606 11158290 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-217403 0.865 THRA protein P10827 UNIPROT RARB protein P10826 UNIPROT up-regulates binding 9606 15650024 t gcesareni Ee report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs SIGNOR-133243 0.391 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR SPI1 protein P17947 UNIPROT down-regulates activity binding 9606 BTO:0000318 18519037 t We found that AML1-ETO is able to inhibit Sp1 transactivity. We also found that this inhibition of Sp1 transactivity by AML1-ETO is achieved by interaction between Sp1 and RUNT domain of AML1 SIGNOR-255671 0.2 MOV10 protein Q9HCE1 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates activity binding 9606 27016603 t miannu MOV10 has been shown to promote mRNA degradation by associating with UPF1, this activity requires the helicase activity of MOV10. SIGNOR-261139 0.536 RFX1 protein P22670 UNIPROT HLA-DOB protein P13765 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11823510 f Class II transactivator is required for maximal expression of HLA-DOB in B cells|HLA-DO, encoded by the HLA-DOA and HLA-DOB genes, has been shown to function as a modulator of Ag presentation. DNA microarray comparisons between B cells wild-type and mutant for the master regulator of MHC class II transcription, class II transactivator (CIITA), identified HLA-DOA and HLA-DOB as being up-regulated by CIITA. SIGNOR-254022 0.2 ILK protein Q13418 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA -1 11313365 t miannu ILK Phosphorylates PKB/Akt on Serine 473 To become fully activated, PKB/Akt requires phosphorylation at two sites, threonine 308 and serine 473, in a phosphatidylinositol (PI) 3-kinase-dependent manner. SIGNOR-250261 0.771 GMIP protein Q9P107 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260505 0.628 WDCP protein Q9H6R7 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity binding 9606 BTO:0000007 30297404 t miannu PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11.  SIGNOR-273733 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Thr577 AENGLLMtPCYTANF 9606 10980595 t lperfetto We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway SIGNOR-244696 0.2 CASP3 protein P42574 UNIPROT PSIP1 protein O75475 UNIPROT down-regulates cleavage 9606 BTO:0001130 18708362 t miannu Ledgf/ p75 has a cooh-terminally truncated splice variant, p52 / during apoptosis, caspase-3 cleaved p52 to generate a p38 fragment that lacked the nh2-terminal pwwp domain and failed to transactivate the hsp27 promoter in reporter assays. However, p38 retained chromatin association properties and repressed the transactivation potential of ledgf/p75 SIGNOR-180144 0.355 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser33 LRRSQRKsGSELPSI -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276124 0.698 SIRT7 protein Q9NRC8 UNIPROT DDX21 protein Q9NR30 UNIPROT up-regulates activity deacetylation Lys600 HFKQSAEkLIEEKGA 28790157 t lperfetto Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21. SIGNOR-275905 0.262 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9606 15209375 t lperfetto Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-236637 0.635 PGR protein P06401 UNIPROT KLK4 protein Q9Y5K2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001248 19147544 f miannu we have shown that K4.pPRE interacts directly with the PR to up-regulate KLK4 gene expression in T47D cells. SIGNOR-254913 0.26 NEK10 protein Q6ZWH5 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Tyr327 KKPLDGEyFTLQIRG 9606 32561851 t miannu  Here, we describe a function for NEK10 in the regulation of p53 transcriptional activity through tyrosine phosphorylation. NEK10 loss increases cellular proliferation by modulating the p53-dependent transcriptional output. NEK10 directly phosphorylates p53 on Y327, revealing NEK10's unexpected substrate specificity. A p53 mutant at this site (Y327F) acts as a hypomorph, causing an attenuated p53-mediated transcriptional response. SIGNOR-273881 0.259 FLT3 protein P36888 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity 10090 14981546 f Immunoblot analysis indicated an increased level of Foxo3a phosphorylation on residue Thr32, as shown by the appearance of additional slower-migrating phospho-species immediately after induction of FLT3-ITD4 expression SIGNOR-261523 0.314 NRF1 protein Q16656 UNIPROT BRK1 protein Q8WUW1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23939472 f miannu We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. SIGNOR-261369 0.2 GCGR protein P47871 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 12626323 t Glucagon signals through its receptor on the cell surface (Fig.1). The binding of glucagon to the extracellular loops of the glucagon receptor results in conformational changes of the latter, leading to subsequent activation of the coupled G proteins. At least two classes of G proteins are known to be associated with and involved in the signal transduction of the glucagon receptor, namely Gsα and Gq. The activation of Gsα leads to activation of adenylate cyclase, increase in intracellular cAMP levels, and subsequent activation of protein kinase A (PKA). SIGNOR-267715 0.491 48S_initiation_complex complex SIGNOR-C454 SIGNOR MRNA_scanning phenotype SIGNOR-PH208 SIGNOR up-regulates 9606 29401259 f lperfetto The 48S complex scans mRNA from 5′ to 3′ until it identifies an AUG start codon in an appropriate sequence context (Kozak consensus) SIGNOR-269168 0.7 MC5R protein P33032 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257183 0.252 ginkgolide B chemical CHEBI:5356 ChEBI PTAFR protein P25105 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192684 0.8 PTK2B protein Q14289 UNIPROT NOS3 protein P29474 UNIPROT down-regulates phosphorylation Tyr657 FGLGSRAyPHFCAFA 9606 BTO:0000007 19934023 t gcesareni We found that fluid shear stress induces the association of enos with the proline-rich tyrosine kinase 2 (pyk2) in endothelial cells and that the enos immunoprecipitated from enos- and pyk2-overexpressing hek293 cells was tyrosine-phosphorylated on tyr657. SIGNOR-161824 0.314 SEMA3B protein Q13214 UNIPROT PLXNA4 protein Q9HCM2 UNIPROT up-regulates activity binding 9606 BTO:0001176;BTO:0002036 25335892 t miannu We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.  SIGNOR-261810 0.648 CSNK2A1 protein P68400 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity phosphorylation Ser851 SLSSLNSsESDKDQD 10090 BTO:0000944 10671552 t llicata Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. | Under these conditions, phosphorylation of the E-cadherin double mutant S853A/S855A was reduced by 25% as compared with wt E-cadherin. | Expression of the E-cadherin double mutant S853A/S855A in NIH3T3 cells expressing Wnt-1 reduces cell-cell adhesion. SIGNOR-250840 0.41 HSPA5 protein P11021 UNIPROT Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 28286085 f lperfetto The HSPA5 gene encodes the binding immunoglobulin protein (BiP), an Hsp70 family chaperone localized in the ER lumen.|When unfolded/misfolded proteins in the ER overwhelm the capacity of protein folding machinery, BiP can initiate the unfolded protein response (UPR), decrease unfolded/misfolded protein load, induce autophagy, and crosstalk with apoptosis machinery to assist in the cell survival decision. SIGNOR-265283 0.7 ABL1 protein P00519 UNIPROT RACK1 protein P63244 UNIPROT up-regulates phosphorylation Tyr52 LTRDETNyGIPQRAL 9606 19423701 t lperfetto Phosphorylation of rack1 on tyrosine 52 by c-abl is required for insulin-like growth factor i-mediated regulation of focal adhesion kinase.Tyrosine 52 is further shown to be phosphorylated by c-abl kinase, and the c-abl inhibitor sti571 disrupts fak interaction with rack1 SIGNOR-185649 0.2 ACE2 protein Q9BYF1 UNIPROT Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 9606 18554741 f miannu Endocytosis of the Receptor-Binding Domain of SARS-CoV Spike Protein Together With Virus Receptor ACE2. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells. SIGNOR-260235 0.7 CSK protein P41240 UNIPROT LYN protein P07948 UNIPROT down-regulates phosphorylation Tyr508 YTATEGQyQQQP 9606 BTO:0000776 15626731 t gcesareni Lyn tyr507 kinase, csk, is recruited by pag, which targets lipid rafts by palmitoylation.Thus, our data suggest that il-6 treatment induces the translocation of cd45 to lipid rafts sequentially, followed by the association of cd45 with lyn and pag;dephosphorylation of lyn tyr507 and pag tyr314;lyn activation;and csk release from lipid rafts SIGNOR-132912 0.518 EIF2B4 protein Q9UI10 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269127 0.864 PIM1 protein P11309 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000567 20663873 t miannu Pim-1 phosphorylates Cdh1 and impairs binding of this protein to another APC/C complex member, CDC27. These modifications inhibit Skp2 from degradation.Pim-1 Impairs Cdh1 and CDC27 Interaction and Phosphorylates Cdh1. SIGNOR-259820 0.322 CDK1 protein P06493 UNIPROT PTPN2 protein P17706 UNIPROT unknown phosphorylation Ser304 LSPAFDHsPNKIMTE 9606 15030318 t llicata Our studies identify ser-304 as a major phosphorylation site in human tcptp, and the tc45 variant as a novel mitotic cdk substrate. SIGNOR-123467 0.357 BAZ2B protein Q9UIF8 UNIPROT H3C15 protein Q71DI3 UNIPROT down-regulates activity binding 9606 acetylation:Lys15 ARKSTGGkAPRKQLA 31999386 t miannu The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation. SIGNOR-266623 0.2 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. SIGNOR-74931 0.533 PHKA1 protein P46020 UNIPROT PHKG1 protein Q16816 UNIPROT down-regulates activity binding 9606 10487978 t Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit. SIGNOR-267405 0.679 BRK1 protein Q8WUW1 UNIPROT WAVE complex complex SIGNOR-C271 SIGNOR form complex binding 9606 BTO:0000567 15070726 t lperfetto Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex.  SIGNOR-261875 0.842 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser315 DFRSRTNsNASTVSG 9606 19188143 t gcesareni Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183648 0.697 Merimepodib chemical CID:153241 PUBCHEM IMPDH2 protein P12268 UNIPROT down-regulates activity chemical inhibition 9606 11288107 t Federica These studies demonstrate that VX-497 is a potent, specific, and reversible IMPDH inhibitor that selectively inhibits lymphocyte proliferation. SIGNOR-261106 0.8 PKNOX1 protein P55347 UNIPROT SYP protein P08247 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20864515 f miannu Prep1 overexpression in HepG2 liver cells upregulated SYP and SHP1 and inhibited insulin-induced IR and IRS1/2 phosphorylation and was accompanied by reduced glycogen content. SIGNOR-254923 0.2 UBE2E1 protein P51965 UNIPROT RNF167 protein Q9H6Y7 UNIPROT up-regulates activity binding 9606 BTO:0000007 16314844 t miannu  Here, we present evidences indicating that RING105, a novel conserved RING-finger protein with a PA (protease-associated) domain and a PEST sequence, is a ubiquitin ligase for TSSC5 that can function in concert with the ubiquitin-conjugating enzyme UbcH6. The polyubiquitin target site on TSSC5 was mapped to a region in the 6th hydrophilic loop. SIGNOR-271552 0.553 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser173 PGKRRTQsLSALPKE 9606 BTO:0000848 21087211 t gcesareni Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3) SIGNOR-252778 0.2 PLK1 protein P53350 UNIPROT ERCC6L protein Q2NKX8 UNIPROT up-regulates relocalization 9606 17218258 t lperfetto Human pich was identified as an interaction partner and substrate of plk1. Our data indicate that plk1 prevents the association of pich with chromosome arms and restricts its localization to the kt/centromere region SIGNOR-152136 0.876 PRKCB protein P05771 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Ser745 FEKEKLKsQWNNDNP 9606 11700305 t lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | SIGNOR-249119 0.359 MAPK3 protein P27361 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Thr66 EPICSVNtPREVTLH -1 16226275 t lperfetto First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.| SIGNOR-249476 0.68 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser270 EFRPRSKsQSSSNCS -1 12351658 t IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. SIGNOR-251289 0.644 ERBB4 protein Q15303 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 16729043 t gcesareni We identified stat5 as a direct binding partner to egfr and erbb4 and discovered new recognition motifs for shc and stat5. SIGNOR-146894 0.804 F2RL1 protein P55085 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257232 0.34 GPC3 protein P51654 UNIPROT DPP4 protein P27487 UNIPROT down-regulates binding 9606 17549790 t miannu The interaction occurred with both the glycosylated and unglycosylated forms of gpc3 and led to the inhibition of cd26 peptidase activity. SIGNOR-155527 0.359 STX1A protein Q16623 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR form complex binding 9606 BTO:0000938 30267828 t miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. SIGNOR-263968 0.929 SOX4 protein Q06945 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001545 24183681 f miannu These data demonstrate an HSC cell intrinsic role for Sox4 on proliferation induced by loss of C/EBPα. SIGNOR-260133 0.7 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser21 TPPSTALsPGKMSEA 9606 SIGNOR-C17 21059642 t The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). SIGNOR-169318 0.348 PRKAA2 protein P54646 UNIPROT HIPK2 protein Q9H2X6 UNIPROT down-regulates activity phosphorylation Thr1116 AALGSTGtVAHLVAS 23871434 t Phosphosite positions are derived from Figure S5 lperfetto AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro SIGNOR-275487 0.2 GSK3A protein P49840 UNIPROT TSC2 protein P49815 UNIPROT up-regulates phosphorylation 9606 phosphorylation:Ser1387 QPLSKSSsSPELQTL 20226003 t gcesareni Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation. SIGNOR-164098 0.369 CDK1 protein P06493 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 SIGNOR-C17 17466630 t gcesareni Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle. SIGNOR-154626 0.44 Fanconi anemia core complex complex SIGNOR-C300 SIGNOR FANCD2 protein Q9BXW9 UNIPROT up-regulates activity ubiquitination 18985065 t lperfetto Phosphorylation of FANCD2 and Fanconi anemia core components (broken pink circles) affects the efficiency of, but is not essential for, ID ubiquitination by the FA core complex, together with E1 and UBE2T. Analogously, ubiquitination of FANCD2 (solid orange ovals) is essential for DNA repair, activating the ID complex for chromatin binding SIGNOR-263265 0.762 PIK-75 Hydrochloride chemical CID:45265864 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206211 0.8 STXBP2 protein Q15833 UNIPROT STX11 protein O75558 UNIPROT up-regulates activity binding 9606 BTO:0000782 28265073 t lperfetto Strikingly, addition of Munc18-2 substantially and selectively facilitates complete fusion mediated by lipid-anchored STX11 by promoting and stabilizing the assembly of SNARE complexes. SIGNOR-261898 0.648 PIK3C3 protein Q8NEB9 UNIPROT PTEN protein P60484 UNIPROT up-regulates binding 9606 BTO:0000567 20212113 t lperfetto Direct positive regulation of pten by the p85 subunit of phosphatidylinositol 3-kinase.Thus p85 regulates both p110-pi3k and pten-phosphatase enzymes through direct interaction SIGNOR-164075 0.651 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser245 PSTSPRAsVTEESWL 9606 BTO:0001061 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276770 0.629 NOXA1 protein Q86UR1 UNIPROT NOX3 protein Q9HBY0 UNIPROT up-regulates activity binding 9606 BTO:0000007 20943948 t lperfetto Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation SIGNOR-264711 0.617 CASP3 protein P42574 UNIPROT IKBKB protein O14920 UNIPROT down-regulates cleavage Asp242 VRQKSEVdIVVSEDL 9606 11741536 t gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. SIGNOR-112788 0.372 ITGB1BP1 protein O14713 UNIPROT ITGB2 protein P05107 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257649 0.318 resveratrol chemical CHEBI:27881 ChEBI AHR protein P35869 UNIPROT down-regulates activity chemical inhibition -1 9865727 t Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor|These data demonstrate that resveratrol inhibits CYP1A1 expression in vitro, and that it does this by preventing the binding of the AHR to promoter sequences that regulate CYP1A1 transcription. SIGNOR-253640 0.8 HTR1B protein P28222 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257207 0.252 ARIH1 protein Q9Y4X5 UNIPROT EIF4E2 protein O60573 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 14623119 t miannu Human homologue of Drosophila ariadne (HHARI) is a RING-IBR-RING domain protein identified through its ability to bind the human ubiquitin-conjugating enzyme, UbcH7. Thus, by promoting the ubiquitin-mediated degradation of 4EHP, HHARI may have a role in both protein degradation and protein translation. SIGNOR-268848 0.665 MED31 protein Q9Y3C7 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266668 0.7 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 t Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. SIGNOR-248336 0.553 SIN3B protein O75182 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity binding 9606 BTO:0001109 26181367 t miannu The present study shows that under bleomycin-induced stress, expression of Sin3B gets up-regulated and it gets recruited by p53 at its target promoters. Knockdown of Sin3B leads to impaired negative regulation of p53 target genes and thus exemplifies Sin3B as a critical player in down-regulation of p53 subset target genes. SIGNOR-266776 0.51 BIRC3 protein Q13489 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates ubiquitination 9606 20682767 t gcesareni Ciap1/2 (cellular inhibitor of apoptosis 1 and 2) ubiquitinate nik for degradation. SIGNOR-167298 0.636 HNRNPU protein Q00839 UNIPROT NHLH2 protein Q02577 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 f lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. SIGNOR-262286 0.299 D-106669 chemical CID:16048654 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191256 0.8 GPR35 protein Q9HC97 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257112 0.2 CTSG protein P08311 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Phe59 GVTVETVfSVDEFSA -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263585 0.518 TAL1 protein P17542 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR up-regulates activity 10090 BTO:0004911 29713515 f The truncated form TAL1-s is required for erythroid progenitors differentiation, while the full-length protein TAL1-l is required for megakaryocytic differentiation of progenitor cells. SIGNOR-259969 0.7 CSNK2A1 protein P68400 UNIPROT DDHD1 protein Q8NEL9 UNIPROT down-regulates activity phosphorylation Ser711 NPAKEPTsVSENEGI -1 11328814 t miannu Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity SIGNOR-262977 0.2 naloxone chemical CHEBI:7459 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 9262330 t miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. SIGNOR-258661 0.8 PRKACA protein P17612 UNIPROT FRAT1 protein Q92837 UNIPROT down-regulates phosphorylation Ser188 RLQQRRGsQPETRTG 9606 16982607 t lperfetto Phosphorylation of ser188 by pka inhibited the ability of frat1 to activate beta-catenin-dependent transcription. SIGNOR-149689 0.2 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249678 0.397 GNAL protein P38405 UNIPROT ADCY1 protein Q08828 UNIPROT up-regulates activity binding 9606 BTO:0004032 21303898 t miannu D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum. SIGNOR-264992 0.519 WNT1 protein P04628 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131571 0.612 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 9606 23431053 t milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity SIGNOR-201306 0.897 PFKP protein Q01813 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. SIGNOR-266473 0.8 TMLHE protein Q9NVH6 UNIPROT 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI up-regulates quantity chemical modification 9606 11431483 t miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. SIGNOR-269684 0.8 AGPAT5 protein Q9NUQ2 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI up-regulates chemical modification 9606 21173190 t lperfetto The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬† SIGNOR-267011 0.8 TREX complex complex SIGNOR-C444 SIGNOR mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 22928037 f miannu The conserved TREX complex, which contains UAP56, Aly, CIP29, and the multi-subunit THO complex, functions in mRNA export. SIGNOR-268514 0.7 MED20 protein Q9H944 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266679 0.765 PPP2CA protein P67775 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates dephosphorylation Ser298 ACSSAPGsGPSSPNN 9606 18045992 t lperfetto Different signal-regulated serine/threonine kinases phosphorylate class ii histone deacetylases (hdacs) to promote nuclear export, cytosolic accumulation, and activation of gene transcriptionhere we show that hdac4 forms a complex with the pp2a holoenzyme c alpha, a alpha, b/pr55 alpha. In vitro and in vivo binding studies demonstrate that the n-terminus of hdac4 interacts with the catalytic subunit of pp2a. Hdac4 is dephosphorylated by pp2a SIGNOR-159492 0.357 NRXN3 protein Q9Y4C0 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626547 t miannu The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites SIGNOR-265457 0.819 IL20RA protein Q9UHF4 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 BTO:0000782;BTO:0000876 12941475 f gcesareni Il-20 induces cheratin proliferation and stat-3 signal transduction pathway SIGNOR-86269 0.565 WNT7A protein O00755 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity 10090 BTO:0000887;BTO:0001103 22944199 f gcesareni In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod. Here we report that cells expressing wnt1 will preferentially activate myf5 while cells expressing wnt7a will preferentially activate myod SIGNOR-198922 0.354 MAPKAPK3 protein Q16644 UNIPROT EEF2K protein O00418 UNIPROT unknown phosphorylation Ser377 PPLLRPLsENSGDEN -1 12171600 t miannu Identification of Ser-377 as the site on eEF2 kinase phosphorylated in vitro by MAPKAP-K2, MAPKAP-K3 and MAPKAP-K5. Maximal phosphorylation of eEF2 kinase by MAPKAP-K2 (Figure 5) or MAPKAP-K5 (results not shown) had no effect on its activity. SIGNOR-249709 0.329 TRAF2 protein Q12933 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity binding 9606 10688666 t lperfetto Tnf receptor (tnfr) associated factor 2 (traf2), an adapter protein that couples tnfrs to the sapks and p38s, can activate ask1 in vivo and can interact in vivo with the amino- and carboxyl-terminal noncatalytic domains of the ask1 polypeptide SIGNOR-75334 0.726 MRPS10 protein P82664 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-267731 0.745 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation Ser262 TFRPRSSsNASSVST 10090 BTO:0004245 10217147 t Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. SIGNOR-252569 0.754 SOX17 protein Q9H6I2 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity 10090 33083751 f SimoneGraziosi Sox17 prevents beta-catenin activation by increasing its phosphorylation, particularly in WM lesions SIGNOR-269268 0.673 TEK protein Q02763 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9534 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242634 0.518 NTN1 protein O95631 UNIPROT UNC5 proteinfamily SIGNOR-PF98 SIGNOR up-regulates activity binding 9606 BTO:0001484 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268183 0.848 MYC protein P01106 UNIPROT BRD4 protein O60885 UNIPROT down-regulates activity 9606 32482868 t lperfetto Conversely, MYC inhibits BRD4's HAT activity, suggesting that MYC regulates its own transcription by limiting BRD4-mediated chromatin remodeling of its locus. SIGNOR-262047 0.578 ZMYND8 protein Q9ULU4 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 27477906 t lperfetto Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported SIGNOR-262040 0.2 SLC36A2 protein Q495M3 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI up-regulates quantity relocalization 9606 12748860 t lperfetto Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut. SIGNOR-264738 0.8 CDC14A protein Q9UNH5 UNIPROT WEE1 protein P30291 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser123 EEGFGSSsPVKSPAA 9606 BTO:0000007 23051732 t lperfetto In particular, we found that Cdc14A inhibits Wee1 degradation through the dephosphorylation of Ser-123 and Ser-139 residues.  SIGNOR-267469 0.561 AKT proteinfamily SIGNOR-PF24 SIGNOR CCNF protein P41002 UNIPROT up-regulates activity phosphorylation Ser577 TKRKRENsLQEDRGS 9606 BTO:0001938 28954236 t miannu AKT phosphorylation of cyclin F enhances its stability and promotes assembly into productive E3 ligase complexes. SIGNOR-266361 0.2 CD79B protein P40259 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 BTO:0000776 12324477 f gcesareni Bcr ligation resulted in p53 activation including its phosphorylation at ser15 SIGNOR-93526 0.313 HSD3B1 protein P14060 UNIPROT progesterone smallmolecule CHEBI:17026 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 2243100 t lperfetto Three beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) catalyze the oxidative conversion of delta 5-3 beta-hydroxysteroids to the delta 4-3-keto configuration and is therefore essential for the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens. SIGNOR-268635 0.8 DPDPE chemical CHEBI:73356 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258792 0.8 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR CHEK1 protein O14757 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28138032 f miannu Mechanistically, Ras-MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras-MEK signaling, thereby limiting DNA damage. Ras–MEK signaling transcriptionally activates Chk1, which appears to sustain cancer cell growth by maintaining DNA damage levels below a threshold that would otherwise drive apoptosis. SIGNOR-263069 0.2 MAPK3 protein P27361 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation Ser623 ALDFQPSsPSPHRKP 9606 15356145 t lperfetto Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623. SIGNOR-128731 0.6 TGFB1 protein P01137 UNIPROT PAX8 protein Q06710 UNIPROT down-regulates activity binding 9606 14623893 t miannu DNA Binding Activity of Pax8 to the NIS Promoter Is Reduced by Smad3. TGF-β decreases Pax8 DNA binding to the NIS promoter and also found a physical interaction between Pax8 and Smad3. SIGNOR-251993 0.2 CHRM1 protein P11229 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257130 0.376 KIF3C protein O14782 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272536 0.7 TRAF6 protein Q9Y4K3 UNIPROT TAB3 protein Q8N5C8 UNIPROT up-regulates activity binding 9606 25290089 t lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205461 0.702 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 t miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. SIGNOR-264928 0.8 PI-103 chemical CHEBI:90524 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206166 0.8 IFNG protein P01579 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by repression transcriptional regulation 10116 9397972 f inferred from family member scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells grown in TSH-containing medium. These include TNF-a, IL-lb and INF-g but not TGF-b. SIGNOR-267810 0.2 TP53 protein P04637 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10029407 f miannu p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1. SIGNOR-255435 0.601 AKT1 protein P31749 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 15048128 t gcesareni Pkb inhibits smad3 by preventing its phosphorylation, binding to smad4 and nuclear translocation. [...] Regulation of smad3 by pkb occurs through a kinase-activity-independent mechanism, resulting in a decrease in smad3-mediated transcription and protection of cells against tgf-beta-induced apoptosis. SIGNOR-123606 0.642 arecoline chemical CHEBI:2814 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258640 0.8 FOXO proteinfamily SIGNOR-PF27 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity transcriptional regulation 10090 BTO:0002314 24749067 f gcesareni We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration. SIGNOR-252940 0.2 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser168 YREPLCLsPASSGSS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248678 0.613 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2L6 protein O14933 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271353 0.62 RPS6KA2 protein Q15349 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 10837486 t lperfetto We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites. SIGNOR-249044 0.381 MAPK8 protein P45983 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 15071501 f JNK-mediated phosphorylation of 14-3-3 at Ser184 reduces its affinity for Bax. gcesareni We demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein. SIGNOR-124012 0.541 ELF4 protein Q99607 UNIPROT LYZ protein P61626 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001271 14976184 f miannu Myeloid elf-1-like factor (mef) or elf4, which is a member of the ets transcription factor family, up-regulates the basal expression of lysozyme gene in epithelial cells and is constitutively localized in the nucleus SIGNOR-122236 0.261 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120224 0.321 NRF1 protein Q16656 UNIPROT RETREG3 protein Q86VR2 UNIPROT up-regulates 9606 BTO:0000934 23939472 f lperfetto We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation.  SIGNOR-261489 0.2 IL10 protein P22301 UNIPROT IL1RN protein P18510 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20032313 f miannu The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils. SIGNOR-254793 0.6 GATA2 protein P23769 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity 9606 20510530 t fferrentino GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis SIGNOR-132949 0.377 ATM protein Q13315 UNIPROT WRN protein Q14191 UNIPROT unknown phosphorylation Ser1141 PEKAYSSsQPVISAQ -1 10608806 t llicata We determined a general phosphorylation consensus sequence for ATM and identified putative in vitro targets by using glutathione S-transferase peptides as substrates. Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself. SIGNOR-250577 0.82 ETFBKMT protein Q8IXQ9 UNIPROT ETFB protein P38117 UNIPROT down-regulates activity methylation Lys203 PNIMKAKkKKIEVIK -1 25416781 t miannu Accordingly, we found that METTL20-mediated methylation of ETFβ in vitro reduced its ability to receive electrons from the medium chain acyl-CoA dehydrogenase and the glutaryl-CoA dehydrogenase. In conclusion, the present study establishes METTL20 as the first human KMT localized to mitochondria and suggests that it may regulate cellular metabolism through modulating the interaction between its substrate ETFβ and dehydrogenases. SIGNOR-269451 0.2 CDK3 protein Q00526 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 19237534 t lperfetto In vitro, lsf is phosphorylated by cyclin e/cyclin-dependent kinase 2 (cdk2), cyclin c/cdk2, and cyclin c/cdk3, predominantly on s309. Phosphorylation by cyclin c/cyclin-dependent kinase 2 following mitogenic stimulation of murine fibroblasts inhibits transcriptional activity of lsf during g1 progression SIGNOR-184164 0.267 Elongator complex complex SIGNOR-C466 SIGNOR TUBA1A protein Q71U36 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 t miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. SIGNOR-269717 0.338 BDKRB2 protein P30411 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257344 0.2 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22863277 t milica Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription. SIGNOR-198507 0.437 AXL protein P30530 UNIPROT AXL protein P30530 UNIPROT up-regulates activity phosphorylation Tyr821 QEPDEILyVNMDEGG -1 9178760 t llicata Our data showed that various receptor substrates are at least associated with the C-terminal tyrosine pY821. Two additional potential autophosphorylation sites (pY866 and pY779) may play a minor role in binding of e€ector proteins SIGNOR-250592 0.2 GLE1 protein Q53GS7 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262096 0.577 calcium(2+) smallmolecule CHEBI:29108 ChEBI Calprotectin complex complex SIGNOR-C293 SIGNOR up-regulates activity chemical activation 9606 BTO:0001044 16690079 t miannu S100 proteins comprise the largest family of calcium-binding proteins. Members of this family usually form homo- or heterodimers, which may associate to higher-order oligomers in a calcium-dependent manner. The heterodimers of S100A8 and S100A9 represent the major calcium-binding proteins in phagocytes. Both proteins regulate migration of these cells via modulation of tubulin polymerization. SIGNOR-262826 0.8 NUP85 protein Q9BW27 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262093 0.722 copper(1+) smallmolecule CHEBI:49552 ChEBI SOD3 protein P08294 UNIPROT up-regulates activity chemical activation 1542024 t lperfetto Copper as a cofactor and regulator of copper,zinc superoxide dismutase SIGNOR-272301 0.8 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 16076840 t gcesareni The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex. SIGNOR-139316 0.346 DLGAP3 protein O95886 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264594 0.2 DUSP3 protein P51452 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity dephosphorylation 9606 28759036 t miannu Deficiency in VHR/DUSP3, a suppressor of focal adhesion kinase, reveals its role in regulating cell adhesion and migration.|In vitro assays proved that recombinant VHR directly dephosphorylated FAK and paxillin. SIGNOR-277033 0.332 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT up-regulates phosphorylation Ser246 RGGPEPLsPFPVSPL 9606 10330152 t lperfetto The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a). SIGNOR-67524 0.579 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser99 HFAIAADsEAEQDSW -1 8349691 t llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. SIGNOR-251074 0.325 RNF146 protein Q9NTX7 UNIPROT BLZF1 protein Q9H2G9 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 21478859 t lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. SIGNOR-263340 0.418 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR PRDM1 protein O75626 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269255 0.37 CSNK2A2 protein P19784 UNIPROT EEF1B2 protein P24534 UNIPROT unknown phosphorylation Ser106 DDIDLFGsDDEEESE -1 8547318 t llicata EF-1 beta was highly phosphorylated by casein kinase II, with up to 1.3 mol of phosphate incorporated per mol protein. From microsequence analysis and manual Edman degradation, the majority of the phosphate was shown to be present in serine 106 in the peptide DLFGS106DDEEES112EEA. Serine 112 was also phosphorylated by casein kinase II, but to a lesser extent. SIGNOR-250987 0.342 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT up-regulates phosphorylation Ser365 IVDQRPSsRASSRAS 9606 16474210 t lperfetto We previously showed that follicle-stimulating hormone (fsh) promoted phosphorylation of cx43 in rat primary granulosa cells. We further identified ser365, ser368, ser369, and ser373 in the carboxy-terminal tail as the major sites of phosphorylation by fsh, and found that the phosphorylation of these residues was essential for channel activity. SIGNOR-144461 0.451 RIPK1 protein Q13546 UNIPROT TAB3 protein Q8N5C8 UNIPROT up-regulates activity binding 9606 19927120 t lperfetto Tab2 and tab3 activate the jun n-terminal kinase and nuclear factor-kappab pathways through the specific recognition of lys 63-linked polyubiquitin chains by its npl4 zinc-finger (nzf) domain. SIGNOR-161787 0.556 RNF111 protein Q6ZNA4 UNIPROT SKI protein P12755 UNIPROT down-regulates ubiquitination 9606 BTO:0000150;BTO:0000551 18451154 t gcesareni On tgf-beta treatment, the e3 ubiquitin ligase arkadia mediates degradation of ski in a smad-dependent manner SIGNOR-178598 0.578 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates activity 9606 BTO:0000093 8415704 f miannu PML-RAR alpha chimera cooperates with c-Jun and, strikingly, with c-Fos to stimulate the transcription of both synthetic and natural reporter genes containing an AP-1 site SIGNOR-261507 0.2 glutamic acid smallmolecule CHEBI:18237 ChEBI NMDA proteinfamily SIGNOR-PF56 SIGNOR up-regulates activity chemical activation 9606 24564659 t miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264692 0.8 N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)sulfonyl-2-hydroxy-2-methylpropanamide chemical CHEBI:91617 ChEBI AR protein P10275 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190323 0.8 MGRN1 protein O60291 UNIPROT TSG101 protein Q99816 UNIPROT up-regulates activity monoubiquitination 9606 BTO:0000567 17229889 t miannu In the present study, we identified the first substrate of the Mahogunin E3 ubiquitin–protein ligase: TSG101, a key component of the endosomal sorting ESCRT machinery.We find that Mahogunin interacts with the ubiquitin E2 variant (UEV) domain of TSG101 via its PSAP motif and that it catalyzes monoubiquitylation of TSG101 both in vivo and in vitro.  Consistent with the results of the biochemical characterization and subcellular localization studies of Mahogunin, our functional studies provide direct evidence that Mahogunin plays an essential role in regulation of endosome-to-lysosome trafficking. We found that siRNA-mediated depletion of Mahogunin in HeLa cells causes enlargement and clustering of EEA1-positive endosomes and LAMP2-positive late endosomes/lysosomes (Figure 8B) and inhibits the endosomal trafficking of internalized EGF–EGFR complexes to lysosomes for degradation (Figures 9 and ​and10,10, A and B). These results are strikingly similar to the phenotypes that resulted from depletion of TSG101 SIGNOR-271635 0.506 POLR2F protein P61218 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266139 0.862 ESR1 protein P03372 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 f lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. SIGNOR-268546 0.437 CSNK2A1 protein P68400 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1124 LNTEEFSsESDMEES 9606 BTO:0000938 19064667 t lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. SIGNOR-275757 0.2 MAPK10 protein P53779 UNIPROT APP protein P05067 UNIPROT up-regulates phosphorylation Thr743 VEVDAAVtPEERHLS 9606 24610780 t lperfetto Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. is regulated by jnk3 via phosphorylation of app at thr668 SIGNOR-204671 0.564 TBCK protein Q8TEA7 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000142 33240423 f miannu TBCK included two types of alternatively spliced isoforms (long TBCK and short TBCK). Although there is a long way to go to fully understand the function of TBCK, recent research indicates that TBCK plays an important role in brain development. BCK deficiency would disturb activation of the mTOR complex 1 (mTORC1), thus, affecting the autophagy process and further leading to autophagosomal-lysosomal dysfunction SIGNOR-266699 0.254 MED12 protein Q93074 UNIPROT CKM complex complex SIGNOR-C406 SIGNOR form complex binding 9606 23563140 t miannu The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation. SIGNOR-266683 0.92 CSNK2A1 protein P68400 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity phosphorylation Thr155 DSTPPPGtRVRAMAI -1 12628923 t llicata CK2 phosphoryl ates Thr155, which targets p53 to degradation by the Ub system. SIGNOR-250968 0.655 BTF3 protein P20290 UNIPROT EPHB2 protein P29323 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 17312387 f In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. SIGNOR-253949 0.2 FBLIM1 protein Q8WUP2 UNIPROT FLNC protein Q14315 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 t miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. SIGNOR-266107 0.78 DDC protein P20711 UNIPROT L-dopa smallmolecule CHEBI:15765 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Subsequently, L-DOPA is converted into 3,4-dihydroxyphenethylamine (dopamine) through decarboxylation by the enzyme L-3,4-dihydroxyphenylalanine decarboxylase (DOPA decarboxylase) in the pre-synaptic terminal SIGNOR-263992 0.8 INS protein P01308 UNIPROT COMT protein P21964 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000542 17612537 f Regulation of expression miannu Catechol O-methyltransferase expression in granulosa cells was up-regulated by insulin, DHT, and ATRA. SIGNOR-251961 0.327 SLBP protein Q14493 UNIPROT H2AC14 protein Q99878 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265404 0.2 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser780 STRPPTLsPIPHIPR 9606 BTO:0000150 23336272 t lperfetto Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. SIGNOR-216988 0.858 PIM1 protein P11309 UNIPROT UHRF1 protein Q96T88 UNIPROT down-regulates quantity by destabilization phosphorylation Ser311 S-->R 9606 28394343 t miannu Here we report that UHRF1 is a novel substrate of PIM1 kinase, which could be phosphorylated at Ser311 and therefore promoted to degradation.  SIGNOR-277349 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser29 ATKAARKsAPSTGGV 9606 11278789 t Ser 27 (29) phosphorylation of H3 isinhibitory as induces transcription. miannu In the present study, ERK1, ERK2, or p38 kinase strongly phosphorylated H3 at serine 28 in vitro. JNK1 or JNK2 was able also to phosphorylate H3 at serine 28 in vitro but to a lesser degree. Histone H3 phosphorylation is related closely to chromatin remodeling and chromosome condensation. H3 phosphorylation at serine 28 is coupled with mitotic chromosome condensation in diverse mammalian cell lines. SIGNOR-263068 0.2 DLG1 protein Q12959 UNIPROT Scribble_complex_DLG1-LLGL1_variant complex SIGNOR-C511 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270913 0.529 p38 proteinfamily SIGNOR-PF16 SIGNOR CDC25B protein P30305 UNIPROT down-regulates quantity by destabilization phosphorylation Ser101 ASESSLSsESSESSD 9606 BTO:0000567 21807946 t miannu  Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104). SIGNOR-276350 0.2 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation Ser465 HNPISSVs 9606 9136927 t lperfetto Here, we report that BMP receptors phosphorylate and activate Smad1 directly. Phosphorylation of Smad1 in vivo involves serines in the carboxy-terminal motif SSXS. These residues are phosphorylated directly by a BMP type I receptor in vitro SIGNOR-217989 0.651 AKT2 protein P31751 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity 9606 BTO:0000150 12697749 f lperfetto Our data indicate that akt2 inhibits cisplatin-induced jnk/p38 and bax activation through phosphorylation of ask1 SIGNOR-100591 0.413 PIM3 protein Q86V86 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 16403219 t miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. SIGNOR-250396 0.353 AKT proteinfamily SIGNOR-PF24 SIGNOR EZH2 protein Q15910 UNIPROT down-regulates activity phosphorylation Ser21 CWRKRVKsEYMRLRQ 9606 16224021 t lperfetto Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3 SIGNOR-244259 0.2 SMO protein Q99835 UNIPROT GNG3 protein P63215 UNIPROT up-regulates binding 9606 16885213 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-148598 0.2 2-deoxy-alpha-D-ribose 1-phosphate smallmolecule CHEBI:11563 ChEBI 2-deoxy-D-ribose 5-phosphate smallmolecule CHEBI:16132 ChEBI up-regulates quantity precursor of 9606 17804405 t miannu Biochemical characterization of phosphoglucomutase (PGM) isozymes indicated that one of them, designated PGM2 in man (PGM1 in mouse) was more active as a phosphopentomutase than as a phosphoglucomutase, whereas mammalian PGM1 (equivalent to PGM2 in mouse) has a phosphopentomutase activity representing only about 0.2% of its phosphoglucomutase activity. Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. SIGNOR-267093 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR ZYX protein Q15942 UNIPROT down-regulates phosphorylation Ser142 PQPREKVsSIDLEID 9606 17572661 t lperfetto Akt binds and phosphorylates zyxin on serine 142, leading to its association with acinus zyxin is a substrate of caspases, but akt phosphorylation fails to protect its proteolytic degradation SIGNOR-244389 0.2 9-(1-anilinoethyl)-7-methyl-2-(4-morpholinyl)-4-pyrido[1,2-a]pyrimidinone chemical CHEBI:91428 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207278 0.8 GSK3B protein P49841 UNIPROT BICD1 protein Q96G01 UNIPROT up-regulates activity phosphorylation Ser585 SEPVAKEsTEASKEP 9606 BTO:0000567 17139249 t miannu Therefore, at least Ser585 and Thr597 in BICD1 are important phosphorylation sites for BICD1 to exert its functions, and GSK-3β-dependent phosphorylation is required for the interaction of BICD1 with dynein. SIGNOR-262743 0.337 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257468 0.8 HIRA complex 2 complex SIGNOR-C462 SIGNOR H3-3A protein P84243 UNIPROT up-regulates quantity by stabilization binding 9606 30285846 t miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. SIGNOR-269440 0.2 SNRPB protein P14678 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270656 0.713 SKP2 protein Q13309 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 10790373 t miannu  Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3. SIGNOR-272566 0.694 CDK4 protein P11802 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR form complex binding 9606 7736585 t gcesareni D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb, SIGNOR-32301 0.964 DRD2 protein P14416 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256701 0.461 INO80 protein Q9ULG1 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270853 0.736 NFYB protein P25208 UNIPROT GFI1B protein Q5VTD9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19965638 f miannu HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. SIGNOR-254431 0.2 CSNK2A1 protein P68400 UNIPROT ABCF1 protein Q8NE71 UNIPROT unknown phosphorylation Ser109 KKLSVPTsDEEDEVP 9606 17894550 t gcesareni We demonstrate that abc50 is a phosphoprotein and is phosphorylated at two sites by ck2. These sites, ser-109 and ser-140, lie in the nterminal part of abc50 but are not required for the binding of abc50 to eif2. SIGNOR-157933 0.2 CCNA1 protein P78396 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 15829981 f lperfetto Cyclin A1 contributes to G1 to S cell cycle progression in somatic cells. Cyclin A1 overexpression enhances S phase entry consistent with an oncogenic function. Finally, cyclin A1 might be a therapeutic target since its silencing inhibited leukemia cell growth. SIGNOR-249637 0.7 ATP5IF1 protein Q9UII2 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261400 0.2 N-(1,3-benzodioxol-5-ylmethyl)-4-(4-benzofuro[3,2-d]pyrimidinyl)-1-piperazinecarbothioamide chemical CHEBI:91389 ChEBI PDGFRA protein P16234 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189528 0.8 carfilzomib chemical CHEBI:65347 ChEBI PSMB5 protein P28074 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000873 19348473 t Luana Carfilzomib selectively inhibits the CT-L activity of the 20S proteasome and displays equivalent potency against β5 and LMP7 with minimal cross reactivity to other protease classes. SIGNOR-257818 0.8 C3 protein P01024 UNIPROT C5 convertase complex (C3bBbC3b) complex SIGNOR-C315 SIGNOR form complex binding 9606 BTO:0000089 cleavage:Arg748 ASHLGLArSNLDEDI 26489954 t complement C3b fragment: PRO_0000005911 lperfetto In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC). SIGNOR-263480 0.2 GRK1 protein Q15835 UNIPROT RHO protein P08100 UNIPROT up-regulates activity phosphorylation Ser343 TVSKTETsQVAPA -1 8617805 t That light-dependent phosphorylation of Rho is mediated primarily by RK. Addition of an inhibitory antibody against rhodopsin kinase (RK) lowered phosphorylation at Ser334, Ser338, and Ser343, without changing the ratio between phosphorylation sites. upon illumination, Ser334c, Ser338, and Ser343 are phosphorylated. SIGNOR-251191 0.921 GADD45G protein O95257 UNIPROT CDK11A protein Q9UQ88 UNIPROT down-regulates activity binding 9606 BTO:0000007 26885618 t lperfetto Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 |We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58. SIGNOR-273025 0.2 EP300 protein Q09472 UNIPROT CDX2/PAX6/P300 complex SIGNOR-C33 SIGNOR form complex binding 9606 10506141 t lperfetto In the present study, we investigated the interaction of cdx-2 and pax-6 with p300, a co-activator coupled to the basal transcription machinery. In transient transfection-expression experiments, we found that the transactivating effects of cdx-2 and pax-6 on the glucagon gene were greatly enhanced by the additional expression of p300. SIGNOR-70960 0.459 ADORA2B protein P29275 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257240 0.301 CDK1 protein P06493 UNIPROT LMNA protein P02545 UNIPROT up-regulates phosphorylation Ser390 EEERLRLsPSPTSQR 9606 18815303 t gcesareni Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm SIGNOR-181314 0.552 LTC4S protein Q16873 UNIPROT leukotriene C4(2-) smallmolecule CHEBI:57973 ChEBI up-regulates quantity chemical modification 9606 27365393 t miannu Leukotriene C4 synthase (LTC4S) catalyzes the formation of the proinflammatory lipid mediator leukotriene C4 (LTC4). SIGNOR-277257 0.8 PRKAA1 protein Q13131 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Thr1114 APAALGStGTVAHLV -1 23871434 t miannu These results indicate that HIPK2 is a substrate of AMPKα2 in vitro and in vivo. Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKα2 in vitro (Figure S5J). SIGNOR-276469 0.2 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9122197 f gcesareni P53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis SIGNOR-47541 0.743 ATM protein Q13315 UNIPROT SMC1A protein Q14683 UNIPROT up-regulates phosphorylation Ser957 ISQEEGSsQGEDSVS 9606 11877377 t lperfetto Here we report that smc1 is a component of the dna damage response network that functions as an effector in the atm/nbs1-dependent s-phase checkpoint pathway. Smc1 associates with brca1 and is phosphorylated in response to ir in an atm- and nbs1-dependent manner. Using mass spectrometry, we established that atm phosphorylates s957 and s966 of smc1 in vivo. SIGNOR-115492 0.693 GXYLT1 protein Q4G148 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates glycosylation 9606 22117070 t Xylosylation in endoplasmic reticulum membrane gcesareni Activity on notch egf repeats was proven by in vitro xylosylation of a mouse notch1 fragment recombinantly produced in sf9 insect cells, a bacterially expressed egf repeat from mouse notch2 modified in vitro by rumi and gxylt2 and in vivo by co-expression of the enzyme with the notch1 fragment. SIGNOR-177691 0.391 HES1 protein Q14469 UNIPROT ATOH1 protein Q92858 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 f lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production SIGNOR-265144 0.484 FBN1 protein P35555 UNIPROT FBLN5 protein Q9UBX5 UNIPROT down-regulates activity binding 9606 19570982 t miannu Fibulin-4 and -5 are extracellular glycoproteins with essential non-compensatory roles in elastic fiber assembly. We have determined how they interact with tropoelastin, lysyl oxidase, and fibrillin-1, thereby revealing how they differentially regulate assembly. Both fibulins differentially bound N-terminal fibrillin-1, which strongly inhibited their binding to lysyl oxidase and tropoelastin. SIGNOR-252138 0.398 EP300 protein Q09472 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by destabilization acetylation Lys594 KEVEDIEkYLEDQVN 9606 BTO:0000007 21726808 t lperfetto Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase|P300 Acetylates and Destabilizes PEPCK1|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 SIGNOR-267604 0.526 PPP2CA protein P67775 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates dephosphorylation Thr187 CDIQTHMtNNKGSAA 9606 17079228 t gcesareni Our results demonstrate that pp6 specifically down-regulates tak1 through dephosphorylation of thr-187 in the activation loop, which is likely important for suppressing inflammatory responses via tak1 signaling pathways. SIGNOR-150369 0.334 PRKCZ protein Q05513 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates activity phosphorylation Thr376 GSKFFMGtVVKKYEE 9606 BTO:0006398 32559461 t miannu To further evaluate cPLA2 as a candidate substrate for PKCζ, we developed a custom antibody recognizing the cPLA2 T376 phosphorylation site. Specificity was validated in both serum starved/stimulated samples SIGNOR-277518 0.333 FBXO30 protein Q8TB52 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0000887 24076600 f gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1) SIGNOR-256489 0.7 WNT8A protein Q9H1J5 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131984 0.606 p38 proteinfamily SIGNOR-PF16 SIGNOR HNF4A protein P41235 UNIPROT up-regulates phosphorylation Ser167 VLSRQITsPVSGING 9606 16351573 t lperfetto Our results indicate that p38 kinase-mediated ser158 phosphorylation is essential for augmentation of the dna binding and transactivation potential of hnf4alpha SIGNOR-143046 0.2 ATOH1 protein Q92858 UNIPROT MUC2 protein Q02817 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17000673 f miannu This study confirms the importance of HATH1 for the development of intestinal secretory cells. The results further suggest that HATH1 is an important factor in the up-regulation of MUC2 expression that occurs in mucinous cancers and signet ring carcinomas. SIGNOR-253755 0.2 XL765 chemical CHEBI:71958 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207872 0.8 IKK-complex complex SIGNOR-C14 SIGNOR IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Ser85 ELLHFQAsQREEKEF 9606 SIGNOR-C14 17977820 t lperfetto In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I SIGNOR-209784 0.929 GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268601 0.281 EPN1 protein Q9Y6I3 UNIPROT EGFR protein P00533 UNIPROT down-regulates relocalization 9606 19054389 t gcesareni Epsin 1 is involved in recruitment of ubiquitinated egf receptors into clathrin-coated pits this supports the contention that epsin 1 promotes endocytosis of the ubiquitinated egfr. SIGNOR-182562 0.579 SIRT2 protein Q8IXJ6 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by stabilization deacetylation Lys70 EGILRRLkKYDNCWL 9606 BTO:0000007 21726808 t lperfetto Conversely, SIRT2 deacetylates and stabilizes PEPCK1.|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 SIGNOR-267599 0.436 MSL2 protein Q9HCI7 UNIPROT MSL acetyltransferase complex SIGNOR-C344 SIGNOR form complex binding 9606 BTO:0000567 16227571 t miannu We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. SIGNOR-263941 0.894 IRS2 protein Q9Y4H2 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 12850284 t gcesareni There was a high level of irs-2 expression and insulin-stimulated tyrosyl phosphorylation as early as embryonic day 15 with robust pi3k binding and activation SIGNOR-103174 0.544 PSMD13 protein Q9UNM6 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263348 0.882 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 21460634 t miannu AMP-activated protein kinase (AMPK), which is activated by LKB1/Strad/Mo25 upon high AMP levels, stimulates autophagy by inhibiting mTORC1. SIGNOR-216418 0.449 TNF protein P01375 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates 9606 10485710 f gcesareni Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k). SIGNOR-70619 0.256 TSHR protein P16473 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 25878058 t scontino The primary signal transduction pathway for TSH receptor is activation of adenylate cyclase via a Gαs G protein-coupled receptor. SIGNOR-267136 0.649 SRC protein P12931 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Tyr81 WEVGSITyDTLSAQA 9606 32653904 t miannu Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS. SIGNOR-277520 0.43 DIO proteinfamily SIGNOR-PF83 SIGNOR 3,3'-diiodothyronine smallmolecule CHEBI:35430 ChEBI up-regulates quantity small molecule catalysis 9606 BTO:0004055 12746313 t inferred from family member scontino Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. SIGNOR-270307 0.8 SRC protein P12931 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr797 TLMSVPRyLPRPANP 31286874 t lperfetto Activated c-Src phosphorylated E-cadherin at the tyrosine 797 site to initiate RNF43-mediated E-cadherin ubiquitination at lysine 816 and subsequent degradation SIGNOR-274048 0.746 SNCAIP protein Q9Y6H5 UNIPROT SNCA protein P37840 UNIPROT up-regulates activity binding 9606 19224863 t miannu Synphilin-1 interacts in vivo with α-synuclein, and their coexpression promotes the formation of Lewy body-like inclusions SIGNOR-272597 0.793 HTATSF1 protein O43719 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270652 0.426 ULK3 protein Q6PHR2 UNIPROT GLI3 protein P10071 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 19878745 t Manara We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro SIGNOR-260799 0.543 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser1981 SLAFEEGsQSTTISS 9606 21149446 t gcesareni In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible. SIGNOR-170469 0.2 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR Core Binding Factor complex complex SIGNOR-C214 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-255971 0.2 ATG101 protein Q9BSB4 UNIPROT ATG13 protein O75143 UNIPROT up-regulates binding 9606 19597335 t gcesareni Furthermore, atg101 is important for the stability and basal phosphorylation of atg13 and ulk1 SIGNOR-186989 0.958 HTR1B protein P28222 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257115 0.252 FBXW7 protein Q969H0 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 15546612 t lperfetto Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. SIGNOR-130706 0.632 ELF3 protein P78545 UNIPROT KRT4 protein P19013 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 10773884 f Interestingly, ELF3 suppressed basal keratin 4 promoter activity in both esophageal and cervical epithelial cancer cell lines, a novel result, while simultaneously activating the late-differentiation linked SPRR2A promoter. SIGNOR-254291 0.288 AKT1 protein P31749 UNIPROT PDE3B protein Q13370 UNIPROT up-regulates phosphorylation Ser295 VIRPRRRsSCVSLGE 9606 10454575 t esanto Pde3b is a physiological substrate of akt and that akt-mediated phosphorylation of pde3b on serine-273 is important for insulin-induced activation of pde3b. SIGNOR-252583 0.679 PML protein P29590 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0001271 15093545 f gcesareni The promyelocytic leukemia (pml) protein is a potent growth suppressor and proapototic factor SIGNOR-256659 0.7 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu56 KKGHLEReCMEETCS -1 9538022 t lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). SIGNOR-263667 0.598 PDGFRB protein P09619 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 7935391 t fspada A pathway leading to activation of the gtp-binding protein ras involves the adaptor molecule grb2. Here we show that tyr-716, a novel autophosphorylation site in the pdgf beta-receptor kinase insert, mediates direct binding of grb2 in vitro and in vivo. SIGNOR-34765 0.667 STK11 protein Q15831 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 SIGNOR-C15 14614828 t gcesareni We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli SIGNOR-119179 0.611 APC-c complex SIGNOR-C150 SIGNOR PFKFB3 protein Q16875 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000793 20080744 t miannu We have recently discovered that the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3), is degraded by the E3 ubiquitin ligase APC/C-Cdh1, which also degrades cell-cycle proteins. SIGNOR-271435 0.2 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 BTO:0000007 18840653 t We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well. SIGNOR-248399 0.547 SRC protein P12931 UNIPROT DNM1 protein Q05193 UNIPROT up-regulates activity phosphorylation Tyr231 LLPLRRGyIGVVNRS 9606 BTO:0000007 9880482 t lperfetto Src-mediated tyrosine phosphorylation of dynamin is required for beta2-adrenergic receptor internalization and mitogen-activated protein kinase signalingHere we demonstrate that activation of beta2-adrenergic receptors (beta2-ARs) leads to c-Src-mediated tyrosine phosphorylation of dynamin, which is required for receptor internalization. Two tyrosine residues, Tyr231 and Tyr597, are identified as the major phosphorylation sites SIGNOR-247124 0.621 HNF4A protein P41235 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20577053 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-166355 0.2 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr492 ALGADDSyYTARSAG 9606 8756661 t lperfetto The data further support a model in which ZAP-70 is first phosphorylated by Lck at Tyr-493 to upregulate the catalytic activity of ZAP-70. This in turn per- mits additional phosphorylation of ZAP-70 mediated, in part, by autophosphorylation at sites including Tyr-292 and -492 SIGNOR-226624 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR HSPB8 protein Q9UJY1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser24 RRDPFRDsPLSSRLL -1 18298377 t miannu Human small heat shock protein with molecular mass 22 kD (HSP22, HspB8) contains two Ser residues (Ser24 and Ser57) in consensus sequence RXS and is effectively phosphorylated by cAMP-dependent protein kinase in vitro. Mutation S24D did not affect, whereas mutations S57D or S24,57D prevented phosphorylation of HSP22 by cAMP-dependent protein kinase thus indicating that Ser57 is the primary site of phosphorylation. Phosphorylation (or mutation) of Ser57 (or Ser24 and Ser57) resulted in changes of the local environment of tryptophan residues and increased HSP22 susceptibility to chymotrypsinolysis.  SIGNOR-276152 0.2 fentanyl chemical CHEBI:119915 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258938 0.8 FANCL protein Q9NW38 UNIPROT FANCI protein Q9NVI1 UNIPROT up-regulates activity ubiquitination SIGNOR-C300 18985065 t lperfetto Phosphorylation of FANCD2 and Fanconi anemia core components (broken pink circles) affects the efficiency of, but is not essential for, ID ubiquitination by the FA core complex, together with E1 and UBE2T. Analogously, ubiquitination of FANCD2 (solid orange ovals) is essential for DNA repair, activating the ID complex for chromatin binding SIGNOR-263266 0.837 PTPRG protein P23470 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1054 FGLARDIyKDPDYVR -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254707 0.255 FLT3 protein P36888 UNIPROT FZD4 protein Q9ULV1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15650056 f Microarray analyses revealed higher mRNA expression of Frizzled-4, a receptor for Wnt ligands in 32D/Flt3-ITD cells. Findings were verified by quantitative realtime reverse transcription–polymerase chain reaction (RT-PCR) and on the protein level. SIGNOR-260121 0.2 CSNK1A1 protein P48729 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 20419129 t lperfetto Specifically, ck1_ phosphorylates _-catenin at s45, which primes this n-terminal region for subsequent phosphorylations by gsk3 at t41, s37 and s33 [7]. These latter two phosphorylations are recognized by the e3-ligase component, _-trcp, for ultimate ubiquitylation and destruction by the proteosome SIGNOR-165022 0.783 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr666 GQEVYHAyAEPLPIT -1 23770091 t done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. SIGNOR-273946 0.357 PAK5 protein Q9P286 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9534 BTO:0000298 12897128 t miannu P21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Pak5 phosphorylates BAD Ser-112 SIGNOR-250247 0.2 EGFR protein P00533 UNIPROT EPS15 protein P42566 UNIPROT up-regulates phosphorylation Tyr849 NFANFSAyPSEEDMI 9606 24269888 t lperfetto Earlier studies have shown that eps15 at tyr-849 is phosphorylated in egf-stimulated cells and partly controls the internalization of mono-ubiquitinated egfr via uim domains of eps15 [10]. It has also been shown that active egfr phosphorylates tyr-849 directly; SIGNOR-203311 0.746 FAAP24 protein Q9BTP7 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 t lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263239 0.2 BDKRB1 protein P46663 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257036 0.41 ALDOB protein P05062 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266488 0.8 ROS stimulus SIGNOR-ST2 SIGNOR ATF4 protein P18848 UNIPROT up-regulates 9606 19439225 f lperfetto Oxidative and ER stress conditions induce rapid and significant activation of ATF4 downstream of eIF2alpha phosphorylation, which is responsible for Redd1 expression SIGNOR-253729 0.7 WLS protein Q5T9L3 UNIPROT WNT3A protein P56704 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 20826466 t WNT secretion requires its binding to the carrier protein wntless (WLS); SIGNOR-256599 0.627 WNT1 protein P04628 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling. SIGNOR-169648 0.821 PYHIN1 protein Q6K0P9 UNIPROT HDAC1 protein Q13547 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 18247378 f miannu We found that maspin is selectively upregulated in IFIXα-expressing cells and involved in anti-invasive activity of IFIXα. We also present evidence indicating that IFIXα downregulates histone deacetylase 1 (HDAC1), which is possibly involved in the silencing of the maspin gene in human breast cancer cells. To confirm these results, we performed a luciferase assay using a maspin-promoter-luciferase plasmid. The results showed that HDAC1 overexpression suppressed the activity of the maspin promoter (Figure 3C). Therefore, our results suggest that IFIXα enhances maspin expression through the downregulation of HDAC1. SIGNOR-268495 0.295 GRK4 protein P32298 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t gcesareni ...expression of GRK4Ž drastically increased the basal level of32P incorporation into B2R.[€]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation. SIGNOR-247902 0.292 USF1 protein P22415 UNIPROT S100A6 protein P06703 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11118618 f miannu The results indicate that USF1 binds to an E-box sequence of the calcyclin gene promoter and enhances its transcription activity. SIGNOR-255598 0.2 CCP110 protein O43303 UNIPROT CETN1 protein Q12798 UNIPROT up-regulates activity binding 9606 16760425 t miannu We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis. SIGNOR-265966 0.496 SNAI2 protein O43623 UNIPROT VDR protein P11473 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 18485278 f miannu We have shown here that the transcriptional repressor protein SLUG inhibits the expression of VDR in human breast cancer cells. SIGNOR-255177 0.382 malonyl-CoA smallmolecule CHEBI:15531 ChEBI hexadecanoic acid smallmolecule CHEBI:15756 ChEBI up-regulates quantity precursor of 9606 15507492 t miannu Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-268090 0.8 MAPK1 protein P28482 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr117 DFPKKPLtPYFRFFM 9606 11741541 t lperfetto Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna SIGNOR-112805 0.402 PPM1D protein O15297 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity dephosphorylation Ser140 PKTDPSDsQTGLAEQ 9606 31959038 t miannu Increased expression of wildtype WIP1 reduces stability of p27 Kip1 while increased expression of similar amounts of phosphatase-dead WIP1 has no effect on p27 Kip1 protein stability.|We demonstrate that wildtype, but not phosphatase-dead WIP1, efficiently dephosphorylates p27 Kip1 Ser140 both in vitro and in cells and that this dephosphorylation is sensitive to the WIP1 specific inhibitor GSK 2830371. SIGNOR-277109 0.262 ULK1 protein O75385 UNIPROT DENND3 protein A2RUS2 UNIPROT up-regulates activity phosphorylation Ser490 ELAPRNSsLRLTDTA 9606 25925668 t lperfetto ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. SIGNOR-264731 0.411 SHANK3 protein Q9BYB0 UNIPROT NMDA proteinfamily SIGNOR-PF56 SIGNOR up-regulates quantity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264701 0.2 PRKCD protein Q05655 UNIPROT BEST1 protein O76090 UNIPROT down-regulates activity phosphorylation Ser358 SAQFRRAsFMGSTFN 9606 19635817 t Manara We have identified a PKC phosphorylation site (S358) located in the C terminal region of hBest1 critical for channel rundown. Phosphorylation of this site by PKC activators and PP2A inhibitors reduces channel rundown. SIGNOR-260880 0.2 CDK1 protein P06493 UNIPROT PTPN1 protein P18031 UNIPROT unknown phosphorylation Ser386 LRGAQAAsPAKGEPS 9606 BTO:0000567 8491187 t llicata Ptp1b is phosphorylated on ser386 by p34cdc2 in vivo. SIGNOR-39233 0.516 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser123 EEGFGSSsPVKSPAA 9606 16085715 t gcesareni Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp. SIGNOR-139473 0.627 XRCC4 protein Q13426 UNIPROT Lig4-Xrcc4 complex complex SIGNOR-C354 SIGNOR form complex binding -1 19837014 t miannu The DNA ligase IV-Xrcc4 complex is responsible for the ligation of broken DNA ends in the non-homologous end-joining (NHEJ) pathway of DNA double strand break repair in mammals. SIGNOR-264532 0.951 POU5F1 protein Q01860 UNIPROT EOMES protein O95936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254930 0.432 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM3 protein P0DP25 UNIPROT up-regulates chemical activation 9606 10884684 t miannu Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘openÂ’ conformations SIGNOR-266333 0.8 CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser45 GATTTAPsLSGKGNP -1 17208333 t llicata We showed that CCND1-CDK6 phosphorylates beta-catenin on serine 45 (S45). This phosphorylation creates a priming site for glycogen synthase kinase 3beta (GSK3beta) and is both necessary and sufficient to initiate the beta-catenin phosphorylation-degradation cascade. SIGNOR-250647 0.641 CHIR 99021 chemical CHEBI:91091 ChEBI GSK3A protein P49840 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190997 0.8 TP53 protein P04637 UNIPROT BBC3 protein Q9BXH1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 16151013 f amattioni Nuclear p53 caused expression of puma, which then displaced p53 from bcl-xl, allowing p53 to induce mitochondrial permeabilization. SIGNOR-140245 0.683 MET protein P08581 UNIPROT RANBP9 protein Q96S59 UNIPROT up-regulates binding 9606 12147692 t gcesareni Our data suggest that ranbpm, functioning as an adaptor protein for the met tyrosine kinase domain, can augment the hgf-met signaling pathway. SIGNOR-91028 0.538 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12950161 t lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases SIGNOR-86585 0.412 CRY2 protein Q49AN0 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267972 0.892 Laminin-5 complex SIGNOR-C184 SIGNOR A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates activity binding 9790905 t lperfetto We propose that these alpha6 beta4/Ln-5 complexes may provide links between plasma membrane and basement membrane that resist mechanical stress and support epithelial integrity. SIGNOR-253238 0.581 SEC24C protein P53992 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 t lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat SIGNOR-265294 0.683 IGFBP5 protein P24593 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity 10090 BTO:0000165 18762576 f These findings suggest that IGFBP-5 promotes muscle cell differentiation by binding to and switching on the IGF-II auto-regulation loop. SIGNOR-255940 0.7 PRKACA protein P17612 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Thr369 DLINKKItPPFNPNV -1 11096081 t miannu In this publication, we demonstrate that cAMP can activate Sgk and that this effect is mediated by PKA, which directly phosphorylates Thr369 in Sgk.  SIGNOR-275972 0.301 EAF1 protein Q96JC9 UNIPROT ELL protein P55199 UNIPROT up-regulates binding 9606 16006523 t miannu Positive regulation of ell elongation activity depends on stable binding of eaf1 to the ell n terminus SIGNOR-138516 0.841 PPARGC1A protein Q9UBK2 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17476214 t miannu Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. SIGNOR-268031 0.499 tRNA(Gln) smallmolecule CHEBI:29168 ChEBI Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270393 0.8 VPS4A protein Q9UN37 UNIPROT CHMP3 protein Q9Y3E7 UNIPROT up-regulates activity cleavage -1 30989108 t Giorgia Here, we show, using high-speed atomic force microscopy and electron microscopy, that the AAA-type adenosine triphosphatase VPS4 constricts and cleaves ESCRT-III CHMP2A-CHMP3 helical filaments in vitro. Our results demonstrate that VPS4 actively constricts ESCRT-III filaments and cleaves them before their complete disassembly. We propose that the formation of ESCRT-III dome-like end caps by VPS4 within a membrane neck structure constricts the membrane to set the stage for membrane fission. SIGNOR-260847 0.644 SLC5A5 protein Q92911 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates activity chemical activation 9606 14623893 t miannu Iodide is an essential element in thyroid physiology as a critical component of thyroxine and triiodothyronine molecules and a key regulator of thyroid gland function. The first step in iodide metabolism is represented by thyroid trapping, which is achieved by an active, energy-dependent transport process across the basolateral plasma membrane of the thyrocytes. The protein responsible for this process, the sodium/iodide symporter (NIS),1 is an intrinsic plasma membrane protein that mediates active transport of I- in the thyroid, lactating mammary gland, stomach, and salivary glands SIGNOR-251996 0.8 SAGA complex complex SIGNOR-C465 SIGNOR H3Y2 protein P0DPK5 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkATAWQAP 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269632 0.2 NR3C1 protein P04150 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity 10090 BTO:0000944 11742987 f gcesareni Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1|Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. In NIH-3T3 fibroblasts, although glucocorticoids up-regulate the MKP-1 level, they do not attenuate the proteasomal degradation of this protein and consequently they are unable to inhibit Erk-1/2 activity. SIGNOR-251678 0.607 AKT proteinfamily SIGNOR-PF24 SIGNOR GATA1 protein P15976 UNIPROT up-regulates phosphorylation Ser310 QTRNRKAsGKGKKKR 9606 16107690 t lperfetto We found that akt directly phosphorylates the transcription factor gata-1 at serine 310 and that this site-specific phosphorylation is required for the transcriptional activation of the timp-1 promoter. SIGNOR-244267 0.2 PRKAA1 protein Q13131 UNIPROT PRPS1 protein P60891 UNIPROT down-regulates activity phosphorylation Ser180 GGAKRVTsIADRLNV 9606 BTO:0006038 29074724 t lperfetto We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. SIGNOR-265729 0.2 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys70 GKAVRGAkGHHHPHP 9606 12408818 t gcesareni Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300 SIGNOR-95169 0.476 SMARCB1 protein Q12824 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 t miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270618 0.852 FOXL2 protein P58012 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000975 16153597 f miannu We observed that foxl2 induces apoptosis in the ovarian cells unveiling a novel function of foxl2 SIGNOR-256643 0.7 LTBR protein P36941 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000007 12571250 t lperfetto Endogenous association of traf2, traf3, ciap1, and smac with lymphotoxin beta receptor reveals a novel mechanism of apoptosis. SIGNOR-97950 0.568 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Tyr354 LKAYGNGySSNGNTG 10029 BTO:0000246 8557631 t Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors. SIGNOR-251302 0.385 2-deoxy-D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:62877 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 25229427 t miannu Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase. SIGNOR-267096 0.8 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr12 FGSRSSKtFKPKKNI 9606 21808241 t MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction. SIGNOR-175837 0.846 SRC protein P12931 UNIPROT ANXA2 protein P07355 UNIPROT up-regulates phosphorylation Tyr24 HSTPPSAyGSVKAYT 9606 15302870 t lperfetto Translocation requires the presence of the annexin 2 binding partner p11 (s100a10) and the phosphorylation of annexin 2 at tyr23 through a src-like tyrosine kinase-dependent mechanism both in vitro and in vivo. SIGNOR-127872 0.563 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD9 protein O15198 UNIPROT down-regulates ubiquitination 9606 22298955 t inferred from 70% family members gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps SIGNOR-270211 0.2 ALG2 protein Q9H553 UNIPROT alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc(PP-Dol) smallmolecule CHEBI:133994 ChEBI up-regulates quantity chemical modification 9606 28575298 t lperfetto The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in eukaryotic protein N-glycosylation starts on the cytoplasmic side of the endoplasmic reticulum and includes the sequential addition of five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by the Alg1, Alg2 and Alg11 gene products and yield Dol-PP-GlcNAc2Man5, an LLO intermediate that is subsequently flipped to the lumen of the endoplasmic reticulum. SIGNOR-260419 0.8 ARHGEF25 protein Q86VW2 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260544 0.829 CDC7 protein O00311 UNIPROT MCM7 protein P33993 UNIPROT up-regulates phosphorylation 9606 21070963 t gcesareni We propose that phosphorylation of mcm4/6 s/tp sites, which are already phosphorylated in g1, allows initial mcm2-7 phosphorylation by ddk and initiation from the first origins of replication ( fig. 7ai ). SIGNOR-169506 0.94 (+)-pilocarpine chemical CHEBI:8207 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258627 0.8 motesanib chemical CHEBI:51098 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258253 0.8 PRKCA protein P17252 UNIPROT MYL9 protein P24844 UNIPROT down-regulates phosphorylation Thr10 SKRAKAKtTKKRPQR 9606 22136066 t lperfetto Rlc can also be phosphorylated at ser1/ser2/thr9 by protein kinase c (pkc). Biophysical studies show that phosphorylation at these sites leads to an increase in the km of myosin light chain kinase (mlck) for rlc, thereby indirectly inhibiting myosin ii activity SIGNOR-191536 0.282 chlorpromazine chemical CHEBI:3647 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258371 0.8 CAMK2A protein Q9UQM7 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser571 PWPLRRTsAQGQPSP 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275771 0.383 SREBF1 protein P36956 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20577053 t gcesareni Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk) SIGNOR-166381 0.294 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-236159 0.866 SMARCA4 protein P51532 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270726 0.76 IL4 protein P05112 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 t gcesareni The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex SIGNOR-108861 0.853 ABL2 protein P42684 UNIPROT GPX1 protein P07203 UNIPROT up-regulates activity phosphorylation Tyr98 EILNSLKyVRPGGGF 9606 12893824 t lperfetto GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress. SIGNOR-104328 0.327 APC-c complex SIGNOR-C150 SIGNOR KIF2C protein Q99661 UNIPROT down-regulates quantity by destabilization ubiquitination -1 24510915 t miannu Biochemical studies on the kinesins confirmed KIFC1, KIF18A, KIF2C, and KIF4A as APC/C substrates. Furthermore, we showed that the APC/CCDH1-dependent degradation of KIFC1 regulates the bipolar spindle formation and proper cell division. Our in vitro degradation assays showed a time-dependent degradation for four of the five potential substrates tested: KIF18A, KIF2C, KIFC1 and KIF4A were readily degraded in vitro, however remained stable in the presence of either APC/C inhibitor (Fig​(Fig4A4A and Supplementary Fig S3A). SIGNOR-266111 0.281 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr36 LPPGDYStTPGGTLF 9606 9465032 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-217086 0.753 N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]-2-pyridinyl]methanesulfonamide chemical CHEBI:91370 ChEBI PTK2B protein Q14289 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206070 0.8 CAMK2A protein Q9UQM7 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser641 RRSVKRNsTVDCNGV 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275785 0.282 H2AC11 protein P0C0S8 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 phosphorylation:Thr121 AVLLPKKtESHHKAK phosphorylation:Thr346 LEEGVHLtPFRQKVS 24055156 t lperfetto The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl.|The centromeric localization of Sgo1 requires histone H2A phosphorylation at T120 (H2A-pT120) by the kinase Bub1. SIGNOR-265262 0.2 FFAR4 protein Q5NUL3 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257371 0.426 SP1 protein P08047 UNIPROT RLIM protein Q9NVW2 UNIPROT up-regulates quantity by expression transcriptional regulation 23650532 t lperfetto Thus, RLIM is a novel target of p53, and p53 exerts its inhibitory effect on RLIM expression by interfering with Sp1-mediated transcriptional activation on RLIM.|Although p53 does not directly bind to the RLIM promoter, it physically interacts with and prevents the binding of Sp1 to the RLIM promoter. SIGNOR-268980 0.2 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1644 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203516 0.769 MAPK14 protein Q16539 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates phosphorylation Ser211 PGKETNEsPWRSDLL 9606 15817653 t llicata We found serine 211 of the human gr to be a substrate for p38 mapk both in vitro and intracellularly. Mutation of this site to alanine greatly diminished gr-driven gene transcription and apoptosis. SIGNOR-135198 0.49 APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 15829969 t lperfetto During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 . SIGNOR-135381 0.953 CDK1 protein P06493 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 BTO:0001130 18408765 t gcesareni Overexpression of cdk1 inhibits the transcriptional activity of foxo1 in pca cells through s249 phosphorylation on foxo1. SIGNOR-178202 0.525 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR E2 conjugating enzyme proteinfamily SIGNOR-PF105 SIGNOR up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-270840 0.2 BHC complex complex SIGNOR-C353 SIGNOR SYN1 protein P17600 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 12032298 t miannu We show that BHC interacts with the promoter of the synapsin gene and mediates its RE1-dependent repression. BHC is recruited to the endogenous synapsin gene. SIGNOR-264504 0.273 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176825 0.775 ARHGEF10 protein O15013 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260537 0.478 DRD3 protein P35462 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256702 0.528 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 9606 BTO:0000567 20543138 t fstefani Maf1, a repressor that binds and inhibits pol iii, is phosphorylated in a mtor-dependent manner both in vitro and in vivo at serine 75 SIGNOR-166054 0.7 CLTB protein P09497 UNIPROT AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 t lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-260671 0.761 PRKACA protein P17612 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation 10090 BTO:0000944 23644383 t milica Here, we show that cyclic amp (camp)-dependent protein kinase (pka) phosphorylates lats and thereby enhances its activity sufficiently to phosphorylate yap on ser381. SIGNOR-236994 0.2 MYC protein P01106 UNIPROT CUL1 protein Q13616 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12835716 t gcesareni Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2 SIGNOR-102749 0.496 MAPK1 protein P28482 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser272 FSGIESSsPEVKGYW 9606 BTO:0000664 17475908 t miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). SIGNOR-262912 0.324 RPS6KB1 protein P23443 UNIPROT POLDIP3 protein Q9BY77 UNIPROT unknown phosphorylation Ser383 ELPRRVNsASSSNPP 9606 15341740 t llicata Here we identify skar as a novel and specific binding partner and substrate of s6k1 but not s6k2. We find that serines 383 and 385 of human skar are insulin-stimulated and rapamycin-sensitive s6k1 phosphorylation sites. SIGNOR-128495 0.757 STAT3 protein P40763 UNIPROT STAT1 protein P42224 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 22693070 t miannu In summary, we report in this study that STAT1 expression is upregulated by nuclear EGFR, EGFRvIII and HER2, and that STAT3 synergizes with the three receptors to further enhance STAT1 expression. These novel findings establish a novel link between the mitogenic ErbB signaling pathway and the inflammatory pathway mediated by STAT1. The oncogenic transcription factor STAT3 binds to the STAT1 promoter and synergizes with nuclear EGFR to significantly enhance STAT1 gene expression. SIGNOR-263650 0.598 ATR protein Q13535 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Thr449 DDIRQNFtQLPLHKN 9606 22123827 t lperfetto Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication. SIGNOR-177813 0.643 SH3BP1 protein Q9Y3L3 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260514 0.388 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002428 31908417 t miannu The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs. SIGNOR-262247 0.8 CDK2 protein P24941 UNIPROT EZH2 protein Q15910 UNIPROT up-regulates activity phosphorylation Thr416 EANSRCQtPIKMKPN 9606 BTO:0000007 23241245 t Here, we demonstrate that the phosphorylation of EZH2 by cyclin-dependent kinases at Thr416 creates a docking site for the ForkHead-associated domain of NIPP1. SIGNOR-255656 0.563 ADAM17 protein P78536 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage -1 9774383 t lperfetto By the use of gene disruption (knockout), we now demonstrate that TACE (tumor necrosis factor alpha converting enzyme), a member of the ADAM family (a disintegrin and metalloprotease-family) of proteases, plays a central role in regulated alpha-cleavage of APP. Our data suggest that TACE may be the alpha-secretase responsible for the majority of regulated alpha-cleavage in cultured cells.  SIGNOR-262829 0.555 PTPN11 protein Q06124 UNIPROT MPZL1 protein O95297 UNIPROT down-regulates dephosphorylation Tyr263 NKSESVVyADIRKN 9606 10681522 t gcesareni In vitro, tyrosine-phosphorylated pzr was efficiently dephosphorylated by the full-length form of shp-2 but not by its sh2 domain-truncated form. The coexisting binding and dephosphorylation of pzr by shp-2 may function to terminate signal transduction initiated by pzr and shp-2 and to set a threshold for the signal transduction to be initiated. SIGNOR-75220 0.536 MCHR1 protein Q99705 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257034 0.413 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.78 MRPL14 protein Q6P1L8 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262379 0.639 NECTIN2 protein Q92692 UNIPROT CD226 protein Q15762 UNIPROT up-regulates activity binding 9606 BTO:0000914 15039383 t lperfetto CD226 (DNAM-1) is an adhesion molecule involved in NK and T cell-mediated cytotoxicity against certain tumors. Here, we have identified the human poliovirus receptor-related (PRR) family members CD155 [poliovirus receptor (PVR)] and CD112 (nectin-2/PRR-2) as the ligands for human CD226. SIGNOR-261426 0.2 PLK1 protein P53350 UNIPROT USP16 protein Q9Y5T5 UNIPROT up-regulates activity phosphorylation Ser486 SEYEAEMsLQGEVNI -1 26323689 t done miannu Plk1 phosphorylates and activates Usp16. In vitro phosphorylation of Usp16 with single (S330A, S386A, or S486A) or collective 3A (S330A/S386A/S486A) mutation showed that Plk1 phosphorylated Usp16 at all three sites (Fig. S2 D). SIGNOR-274017 0.35 SUGT1 protein Q9Y2Z0 UNIPROT Ndc80 complex complex SIGNOR-C361 SIGNOR up-regulates activity relocalization 9606 BTO:0000567 22869522 t lperfetto Here we identify Sgt1, a cochaperone for Hsp90, as a novel Plk1 substrate during mitosis|This phosphorylation event enhances the association of the Hsp90-Sgt1 chaperone with the MIS12 complex to stabilize this complex at the kinetochores and thus coordinates the recruitment of the NDC80 complex to form efficient microtubule-binding sites. SIGNOR-265224 0.275 FGF8 protein P55075 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002314 BTO:0000887;BTO:0001103 24209627 f gcesareni Loss of fgf signaling in fgf24 and fgf8 double-deficient zebrafish SIGNOR-203148 0.345 POU2AF1 protein Q16633 UNIPROT POU2F1 protein P14859 UNIPROT up-regulates binding 9606 BTO:0000776 12727885 t miannu Obf1 enhances transcriptional potential of oct1. SIGNOR-100968 0.641 BRD2 protein P25440 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates activity relocalization 9606 BTO:0001938 29018219 t lperfetto BRD2 is required to recruit 53BP1 to DSBs.|When BRD2 recruitment was blocked with shRNA or JQ1 (Fig. 3a and Supplementary Figure 3c) or a panel of BRD2 siRNAs (Supplementary Figure 3a), the recruitment of 53BP1 to DSBs was significantly delayed. SIGNOR-262035 0.272 FYN protein P06241 UNIPROT ACP1 protein P24666 UNIPROT up-regulates activity phosphorylation Tyr132 QLIIEDPyYGNDSDF 9534 BTO:0004055 9038134 t We identify Tyr-131 as the major phosphorylation site and Tyr-132 as a minor site and the Src family PTKs Lck and Fyn as enzymes capable of phosphorylating these sites in vivo and in vitro. Both Tyr-131 and Tyr-132 are located next to the catalytic pocket of LMPTP, and especially, Tyr-131 seems to be important for the activity of LMPTP. Phosphorylation of Tyr-131 or Tyr-132, particularly the former, caused an increase in the activity of LMPTP. SIGNOR-251149 0.39 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr1009 LDTSSVLyTAVQPNE -1 7545675 t Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides SIGNOR-248416 0.679 C3 protein P01024 UNIPROT C3 protein P01024 UNIPROT up-regulates activity cleavage Arg748 ASHLGLArSNLDEDI 9606 26806831 t lperfetto C3 autoactivates in a process known as “tick-over,” which is characterized by spontaneous hydrolysis of a reactive thiol-ester to generate C3(H2O). Although C3(H2O)Bb produces only relatively small amounts of C3b compared to the other C3 convertases, it nevertheless generates enough C3b to set the C3 convertase amplification loop in motion. SIGNOR-263484 0.2 NR5A1 protein Q13285 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19237537 t miannu The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes. SIGNOR-271788 0.485 PRKAA2 protein P54646 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 SIGNOR-C15 17082196 t lperfetto Pharmacological ampk inhibitors and activators and ampk mutants revealed that the kinase specifically targets residue thr-278 but not ser-157 or ser-239. Quantitative fluorescence-activated cell sorter analysis and serum response factor transcriptional reporter assays, which quantify the cellular f-/g-actin equilibrium, indicated that ampk-mediated vasp phosphorylation impaired actin stress fiber formation and altered cell morphology. SIGNOR-150462 0.2 MAPK1 protein P28482 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1032 SSSNRPFtPPTSTGG 9606 16314496 t fstefani We demonstrate that erk phosphorylates trap220/med1 in vivo at two specific sites: threonine 1032 and threonine 1457. importantly, we found that erk phosphorylation significantly increases the stability and half-life of trap220/med1 in vivo and correlates with increased thyroid hormone receptor-dependent transcription. SIGNOR-142458 0.361 F2RL1 protein P55085 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21072196 f miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). SIGNOR-254859 0.2 KLF16 protein Q9BXK1 UNIPROT SIN3A protein Q96ST3 UNIPROT up-regulates activity binding 10029 BTO:0000246 11438660 t miannu detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A. SIGNOR-222460 0.476 tacrolimus (anhydrous) chemical CHEBI:61049 ChEBI PPP3CB protein P16298 UNIPROT down-regulates chemical inhibition 9606 15276472 t gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. SIGNOR-127242 0.8 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser208 DINRGAPsITSVTPR 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262717 0.733 RXRB protein P28702 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity binding 9606 10976919 t inferred from family member gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr SIGNOR-267805 0.642 PRKCA protein P17252 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Thr252 LLYMCLEtGAISFVQ 9606 15979581 t miannu The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity SIGNOR-138355 0.679 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser18 RRLLFACsPPPASQP 9606 BTO:0002181 34363019 t miannu Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.  SIGNOR-276736 0.2 MOS protein P00540 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser222 LIDSMANsFVGTRSY 10090 7731726 t Manara Our data indicate that Mos activated MEK1 in vitro as well as in vivo by phosphorylating Ser 222. SIGNOR-260920 0.467 PP2 chemical CHEBI:78331 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 BTO:0000142 11782488 t gcesareni Herbimycin a and pp2, specific inhibitors of src family kinases, both inhibited h2o2-mediated c-src and bmk1 activation. SIGNOR-113776 0.8 TLN1 protein Q9Y490 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257611 0.644 MEAF6 protein Q9HAF1 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269301 0.739 CAMK1 protein Q14012 UNIPROT PPME1 protein Q9Y570 UNIPROT down-regulates activity phosphorylation Ser15 MHLGRLPsRPPLPGS 9606 BTO:0000007 24841198 t lperfetto CaMKI Is the Upstream Kinase for Phosphorylation of PME-1/Ser15|Our results also demonstrated that the phosphorylated levels of PME-1/Ser15 and CaMKI/Thr177 are inversely correlated with the phosphatase activity of SIK2·PP2A complex, further implying that the demethylase activity of phosphorylated PME-1/Ser15 may be higher than that of its unphosphorylated state. SIGNOR-265747 0.404 PRKCA protein P17252 UNIPROT ATP1A1 protein P05023 UNIPROT down-regulates activity phosphorylation Ser16 KYEPAAVsEQGDKKG 1792 BTO:0003069 14976217 t miannu Parathyroid hormone (PTH) inhibits Na+,K+-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the α1-subunit. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit. SIGNOR-262941 0.335 FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25096180 f Muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin-1 were identified more than 10 years ago as two muscle-specific E3 ubiquitin ligases that are increased transcriptionally in skeletal muscle under atrophy-inducing conditions, making them excellent markers of muscle atrophy SIGNOR-252072 0.7 FLT3 protein P36888 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates activity relocalization 10090 14982881 f We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. SIGNOR-261538 0.26 PSMB6 protein P28072 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263361 0.846 ATG4B protein Q9Y4P1 UNIPROT MAP1LC3C protein Q9BXW4 UNIPROT up-regulates activity cleavage 9606 BTO:0000007;BTO:0000567 15187094 t lperfetto Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16. SIGNOR-125489 0.747 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation 9606 15568999 t inferred from 70% family members gcesareni In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. SIGNOR-270076 0.2 MAPK15 protein Q8TD08 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 12169099 t gcesareni Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. these data suggest that erks, rather than jnks, are required for c- jun up-regulation. SIGNOR-91371 0.439 DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000567 12356755 t gcesareni Here we show that glucocorticoids synergistically enhance nthi-induced tlr2 expression via specific up-regulation of the mapk phosphatase-1 (mkp-1) that, in turn, leads to dephosphorylation and inactivation of p38 mapk, the negative regulator for tlr2 expression. SIGNOR-93873 0.798 N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide chemical CHEBI:95008 ChEBI BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207459 0.8 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9823 BTO:0001840 SIGNOR-C3 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-219262 0.924 STK39 protein Q9UEW8 UNIPROT SLC4A4 protein Q9Y6R1 UNIPROT down-regulates activity phosphorylation 10090 BTO:0000988 21317537 t lperfetto WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, SIGNOR-264644 0.355 LYN protein P07948 UNIPROT PAG1 protein Q9NWQ8 UNIPROT up-regulates activity phosphorylation Tyr387 SEEPEPDyEAIQTLN 9534 16920712 t miannu Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn. SIGNOR-262893 0.714 UCHL5 protein Q9Y5K5 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity deubiquitination 9606 16027725 t lperfetto Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases SIGNOR-232101 0.406 RUNX1 protein Q01196 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 23817177 f irozzo RUNX1 wild-type protein first binds to the PU.1 URE region and recruits the MLL complex to open up part of the compact chromatin structure. The partially relaxed chromatin allows the binding of another RUNX1 at the PU.1 promoter region to further distort compact DNA structure. The relaxed form of chromatin facilitates the accumulation of transcription factors and cofactors to initiate transcriptional activity. SIGNOR-255709 0.675 DVL2 protein O14641 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity binding 9606 17529994 t amattioni Dix domain of dvl2 mediates dynamic polymerization, which is essential for the signaling activity of dvl2. SIGNOR-155224 0.2 PTGES3 protein Q15185 UNIPROT HSP90AA1 protein P07900 UNIPROT up-regulates activity binding -1 9817749 t lperfetto The mutant Hsp90 proteins tested are defective in the binding and ATP hydrolysis-dependent cycling of the co-chaperone p23, which is thought to regulate the binding and release of substrate polypeptide from Hsp90.  SIGNOR-262831 0.913 PLCG2 protein P16885 UNIPROT Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR up-regulates 9606 24890514 f apalma Studies with multipotent precursor cell lines (Fig. 4A) indicate that CSF-1R Tyr-807 and Tyr-721 promote macrophage differentiation via the PLC-Œ≥2 pathway SIGNOR-255571 0.7 GTF2F2 protein P13984 UNIPROT TFIIF complex SIGNOR-C394 SIGNOR form complex binding -1 18218714 t lperfetto Human general transcription factor IIF (TFIIF), a component of the transcription pre-initiation complex (PIC) associated with RNA polymerase II (Pol II), was characterized by size-exclusion chromatography (SEC), electrospray ionization mass spectrometry (ESI-MS), and chemical cross-linking. Recombinant TFIIF, composed of an equimolar ratio of alpha and beta subunits, was bacterially expressed, purified to homogeneity, and found to have a transcription activity similar to a natural one in the human in vitro transcription system. SIGNOR-266195 0.962 RASSF5 protein Q8WWW0 UNIPROT KRAS protein P01116 UNIPROT up-regulates activity binding 9606 22195963 t lperfetto NORE1A can bind K-Ras.GTP through its RA domain and regulate the proapoptotic activity of MST1/2 kinases SIGNOR-249586 0.682 NANOG protein Q9H9S0 UNIPROT FOXA2 protein Q9Y261 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 f lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) SIGNOR-253166 0.464 TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21524151 t lperfetto P53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting G1/S entry. SIGNOR-173425 0.872 Naltrindole chemical CHEBI:81528 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258817 0.8 CDH18 protein Q13634 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265857 0.558 ATR protein Q13535 UNIPROT RAD17 protein O75943 UNIPROT up-regulates activity phosphorylation Ser656 SASELPAsQPQPFSA 9606 11687627 t lperfetto Here we demonstrate that atr but not atm phosphorylates the human rad17 (hrad17) checkpoint protein on ser(635) and ser(645) in vitro.The rfc-related checkpoint protein rad17, a phosphorylation substrate of atr, is critical for atr-mediated checkpoint signaling and cell survival. SIGNOR-111252 0.853 PPP2CA protein P67775 UNIPROT KRT8 protein P05787 UNIPROT unknown dephosphorylation Ser432 SAYGGLTsPGLSYSL 9606 BTO:0000182 16554440 t K8 Ser431-P is a physiologic substrate to PP2A during hyposmotic conditions and possibly other biologic contexts. SIGNOR-248623 0.2 CSNK2A1 protein P68400 UNIPROT PTPN1 protein P18031 UNIPROT unknown phosphorylation -1 9600099 t llicata In this study, we demonstrate that HPTP1B are multiple phosphorylated on threonine and tyrosine as well as serine near its N-terminus by CKII and p60c-src in vitro. SIGNOR-250941 0.447 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258713 0.8 ARHGAP6 protein O43182 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260462 0.563 CSNK2A2 protein P19784 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates activity phosphorylation Ser423 CEEEFSDsEEEGEGG 9606 BTO:0000661 11602581 t llicata Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser(421) and Ser(423), were unambiguously identified. Loss of phosphorylation at Ser(421) and Ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of HDAC1. SIGNOR-251000 0.407 PTPN2 protein P17706 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity dephosphorylation Tyr701 DGPKGTGyIKTELIS 9606 12138178 t Upon interferon (IFN) stimulation, Stat1 becomes tyrosine phosphorylated and translocates into the nucleus, where it binds to DNA to activate transcription. The activity of Stat1 is dependent on tyrosine phosphorylation, and its inactivation in the nucleus is accomplished by a previously unknown protein tyrosine phosphatase (PTP). We have now purified a Stat1 PTP activity from HeLa cell nuclear extract and identified it as TC45, the nuclear isoform of the T-cell PTP (TC-PTP). SIGNOR-248402 0.723 SMAD1/4 complex SIGNOR-C85 SIGNOR PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18854943 f fferrentino This Smad1/4 complex can directly interact with Shn-2 and C/EBP a on the PPAR g promoter thus, resulting in the transcriptional activation of PPAR g SIGNOR-253551 0.289 MNAT1 protein P51948 UNIPROT CAK complex complex SIGNOR-C456 SIGNOR form complex binding 9606 30860024 t lperfetto CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269320 0.946 FLT3 protein P36888 UNIPROT SIRT3 protein Q9NTG7 UNIPROT down-regulates activity phosphorylation Tyr226 KGLLLRLyTQNIDGL -1 34289383 t lperfetto We also hypothesize that, besides activating ACAT1 through Y407 phosphorylation (Fan et al., 2016), FLT3 might simultaneously phosphorylate and regulate SIRT3. Our mutational studies on all of the seven tyrosine sites of SIRT3 revealed that purified rFLT3 directly phosphorylated purified rSIRT3 in an in vitro kinase assay, leading to decreased SIRT3 deacetylase activity that was assessed by ability to deacetylate K413 of mIDH2 (Figure 4H, first three samples in left, middle, and right panels), whereas replacement of Y226 completely abolished inhibition of SIRT3 by FLT3 (Figure 4H, right). SIGNOR-267631 0.2 AKT1 protein P31749 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000192 31435020 t inferred from family member K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization SIGNOR-270267 0.497 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 f inferred from family member gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-270252 0.2 MARK2 protein Q7KZI7 UNIPROT RAB11FIP2 protein Q7L804 UNIPROT up-regulates phosphorylation Ser227 QRLSSAHsMSDLSGS 9606 BTO:0000671 16775013 t lperfetto We identified the kinase that phosphorylated rab11-fip2 as mark2/emk1/par-1balpha (mark2), and recombinant mark2 phosphorylated rab11-fip2 only on serine 227. In calcium switch assays, cells expressing rab11-fip2(s227a) showed a defect in the timely reestablishment of p120-containing junctional complexes. SIGNOR-147118 0.43 glutamine smallmolecule CHEBI:28300 ChEBI Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270394 0.8 belinostat chemical CHEBI:61076 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257745 0.8 VASP protein P50552 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 18508258 f miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. SIGNOR-268393 0.7 ECM stimulus SIGNOR-ST20 SIGNOR Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259036 0.7 WNT6 protein Q9Y6F9 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131891 0.613 FPR1 protein P21462 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256825 0.431 APC-c complex SIGNOR-C150 SIGNOR PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization ubiquitination 21596315 t lperfetto Complexed with the activator proteins CDC20 or CDH1 (Fang et al., 1998, Visintin et al., 1997), the APC/C recognizes, ubiquitinates, and targets for proteasomal degradation a multitude of cell cycle regulators containing KEN or D box degrons, including securin, cyclin A, and cyclin B. SIGNOR-265049 0.553 MMP9 protein P14780 UNIPROT A2M protein P01023 UNIPROT down-regulates quantity by destabilization cleavage Gly702 YEMHGPEgLRVGFYE -1 9344465 t lperfetto The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. SIGNOR-261781 0.471 PRKCA protein P17252 UNIPROT DGKD protein Q16760 UNIPROT down-regulates activity phosphorylation Ser66 MLTKQNNsFQRSKRR 9534 15228384 t lperfetto The plasma membrane translocation of diacylglycerol kinase delta1 is negatively regulated by conventional protein kinase C-dependent phosphorylation at Ser-22 and Ser-26 within the pleckstrin homology domain. SIGNOR-249265 0.373 PRKDC protein P78527 UNIPROT LIG4 protein P49917 UNIPROT down-regulates phosphorylation Thr650 HLKAPNLtNVNKISN 9606 15194694 t lperfetto Using tandem mass spectrometry, we identified a dna-pk phosphorylation site at thr-650 in human lig4 and a potential second phosphorylation site at ser-668 or ser-672. Phosphorylation of lig4 per se was not required for lig4 dna end joining activity. Substitution of these amino acids with alanine, individually or in combination, led to changes in lig4 protein stability of mouse lig4. The phosphomimetic mutation s650d returned lig4 stability to that of the wild-type protein. Furthermore dna-pk was found to negatively regulate lig4 protein stability. SIGNOR-125877 0.8 CENPN protein Q96H22 UNIPROT CENP-A nucleosome complex SIGNOR-C321 SIGNOR up-regulates activity binding 9606 BTO:0000567 20566683 t miannu CENP-C, like CENP-N, interacts directly and specifically with CENP-A nucleosomes. CENP-C and CENP-N bind to different sites on the same CENP-A nucleosomes. CENP-N also binds directly to CENP-A nucleosomes, thus providing additional CENP-A nucleosome contacts that reinforce the specificity of the centromere assembly process SIGNOR-263705 0.9 SLIT2 protein O94813 UNIPROT ROBO2 protein Q9HCK4 UNIPROT up-regulates activity binding -1 16226035 t miannu This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. SIGNOR-268380 0.858 BMP4 protein P12644 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 SIGNOR-C29 7673243 t acerquone We have isolated a cdna encoding a novel transmembrane serine/threonine kinase from human skin fibroblasts which we demonstrate here to be a type ii receptor that binds bmp-4. This receptor (brk-3) is distantly related to other known type ii receptors and is distinguished from them by an extremely long carboxyl-terminal sequence following the intracellular kinase domain. SIGNOR-30697 0.772 vincaleukoblastine sulfate chemical CHEBI:9984 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates activity chemical inhibition 9606 15579115 t miannu Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. SIGNOR-259260 0.8 SIRT2 protein Q8IXJ6 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by stabilization deacetylation Lys71 GILRRLKkYDNCWLA 9606 BTO:0000007 21726808 t lperfetto Conversely, SIRT2 deacetylates and stabilizes PEPCK1.|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 SIGNOR-267601 0.436 MAPKAPK2 protein P49137 UNIPROT LSP1 protein P33241 UNIPROT unknown phosphorylation Ser204 KLIDRTEsLNRSIEK -1 8995217 t miannu LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils SIGNOR-250147 0.622 Vps34 Complex I complex SIGNOR-C242 SIGNOR Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 30397185 f lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260323 0.7 DOT1L protein Q8TEK3 UNIPROT H3C1 protein P68431 UNIPROT unknown methylation Lys80 REIAQDFkTDLRFQS 9606 12123582 t miannu HDOT1L Is a Nucleosomal H3-K79-Specific HMTase. We identified a human DOT1-like (DOT1L) protein and demonstrated that this protein possesses intrinsic H3-K79-specific histone methyltransferase (HMTase) activity in vitro and in vivo. Furthermore, we found that K79 methylation level is regulated throughout the cell cycle. By using two different methods, we demonstrate that the K79 methylation level decreases during S phase, reaches its lowest level in G2, increases during M phase, and maintains at a high level during G1 phase. SIGNOR-267141 0.2 KAT2A protein Q92830 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269588 0.726 ITGB1 protein P05556 UNIPROT A6/b1 integrin complex SIGNOR-C164 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253180 0.813 HNF4A protein P41235 UNIPROT LDLR protein P01130 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000398 21123766 f miannu Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes. SIGNOR-254454 0.353 RPS3A protein P61247 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262420 0.847 ELOVL7 protein A1L3X0 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267888 0.8 RFX complex complex SIGNOR-C104 SIGNOR HLA-DPB1 protein P04440 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 f The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-253990 0.291 FHIT protein P49789 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates 9606 BTO:0000551 16407838 f miannu Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis SIGNOR-143706 0.251 SH2B2 protein O14492 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0000975 11498022 t gcesareni Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor. The aps adapter protein couples theinsulinreceptor to the phosphorylation of c-cbl and facilitates ligand-stimulated ubiquitination of theinsulinreceptor. SIGNOR-109691 0.632 PDHX protein O00330 UNIPROT GCG protein P01275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001731 12783165 f miannu In glucagonoma cells transduced with a Pdx1-encoding lentiviral vector, insulin gene expression was induced while glucagon mRNA levels were reduced by 50 to 60%. SIGNOR-254901 0.2 ZNF76 protein P36508 UNIPROT TCP1 protein P17987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10893243 t Luana The transcription from the minimalCcta promoter was up-regulated 3-fold by ZNF143 and 6-fold by ZNF76 when full-length proteins were co-expressed, indicating that both ZNF143 and ZNF76 can enhance Ccta transcription. SIGNOR-266221 0.354 carfilzomib chemical CHEBI:65347 ChEBI PSMB8 protein P28062 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000873 19348473 t Luana Carfilzomib selectively inhibits the CT-L activity of the 20S proteasome and displays equivalent potency against β5 and LMP7 with minimal cross reactivity to other protease classes. SIGNOR-257819 0.8 serotonin smallmolecule CHEBI:28790 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264285 0.8 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 21440011 t lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-209647 0.866 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr307 IGPDNLPyVQILKTA 9606 8443592 t lperfetto Tyrosine residues 154 and 307, which are in the extracellular domain of transmembrane receptor isoforms and are in an unusual sequence context for tyrosine phosphorylation, were also phosphorylated. SIGNOR-98630 0.2 YY1 protein P25490 UNIPROT TNFRSF10B protein O14763 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000848 34589486 t miannu Depletion of FKBP51 impairs the acetylation status of YY1 and interferes with its binding on the DR5 promoter. The lack of the repressor activity of YY1 increases DR5 transcription and sensitizes melanoma cell to TRAIL-induced apoptosis. SIGNOR-268793 0.413 CCND1 protein P24385 UNIPROT CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR form complex binding 9606 8114739 t lperfetto Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells. SIGNOR-250680 0.951 MAPK9 protein P45984 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Thr200 IARYVPStPWFLMPI 9606 15805466 t llicata Inactivation is due to phosphorylation of tif-ia by c-jun n-terminal kinase (jnk) at a single threonine residue (thr 200). Phosphorylation at thr 200 impairs the interaction of tif-ia with pol i and the tbp-containing factor tif-ib/sl1, thereby abrogating initiation complex formation. SIGNOR-134878 0.485 MMP2 protein P08253 UNIPROT LAMC2 protein Q13753 UNIPROT up-regulates activity cleavage 9211848 t lperfetto Induction of Cell Migration by Matrix Metalloprotease-2 Cleavage of Laminin-5|MMP2 cleaved the Ln-5 gamma2 subunit at residue 587, exposing a putative cryptic promigratory site on Ln-5 that triggers cell motility. This altered form of Ln-5 is found in tumors and in tissues undergoing remodeling, but not in quiescent tissues. Cleavage of Ln-5 by MMP2 and the resulting activation of the Ln-5 cryptic site may provide new targets for modulation of tumor cell invasion and tissue remodeling. SIGNOR-253240 0.449 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCB protein P05771 UNIPROT up-regulates activity binding 9606 14967450 t PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. SIGNOR-242584 0.8 ETS2 protein P15036 UNIPROT SPARC protein P09486 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11175361 t miannu Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin SIGNOR-259874 0.31 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr627 TPESWRLtPPAKVGG 9606 22094256 t lperfetto We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627) SIGNOR-177263 0.608 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation Thr263 PSRPPPPtPRRPASV 9606 BTO:0000007 16446428 t gcesareni Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222 SIGNOR-249579 0.644 USP24 protein Q9UPU5 UNIPROT DDB2 protein Q92466 UNIPROT up-regulates deubiquitination 9606 23159851 t miannu Usp24-mediated ddb2 deubiquitination prevents ddb2 degradation SIGNOR-199731 0.691 BCL2 protein P10415 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-256637 0.7 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120148 0.316 TICAM1 protein Q8IUC6 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 20404851 t lperfetto TRIF also recruits the adaptor RIP1 through the distinct RIP homotypic interaction motif. RIP1 undergoes K63-linked polyubiquitination after stimulation by TLR3 agonists, and this modification is required for NF-_B activation. SIGNOR-216313 0.723 RBBP8 protein Q99708 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity relocalization SIGNOR-C295 24832651 t lperfetto DNA damage activates ATM and CHK2 kinases, which mediate phosphorylation of CtIP and BRCA1. Phosphorylated CtIP associates with BRCA1 and with the MRN complex leading to the recruitment of the BRCC complex at the site of DNA damage where HR is initiated. SIGNOR-263203 0.836 P300/PCAF complex SIGNOR-C7 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates binding 9606 BTO:0000150 15009097 t lperfetto Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo. SIGNOR-217230 0.618 DLL1 protein O00548 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding BTO:0001103 12361602 t apalma When activated by its ligands (Delta and Jagged in vertebrates and Serrate in invertebrates), the intracellular portion of Notch is cleaved and translocates to the nucleus SIGNOR-255368 0.626 THRSP protein Q92748 UNIPROT MID1IP1 protein Q9NPA3 UNIPROT down-regulates activity binding 10029 BTO:0000457 20952657 t miannu In the current study, we have determined the crystal structure of mouse S14 to 2.65-Å resolution. The structure of S14 reveals a helical protein arranged as a symmetric dimer. Cultured cell experiments indicate that S14 can form heterodimers with MIG12, suggesting a mechanism through which S14 could modulate ACC activity and subsequently rates of fatty acid synthesis via heterodimer formation with MIG12.In the current study, we have shown that regulating the levels of S14∶MIG12 heterodimers regulates the ability of MIG12 to activate ACC. Increasing S14∶MIG12 heterodimers by the overexpression of S14 resulted in decreased ACC activity and polymerization, whereas decreasing S14∶MIG12 heterodimers by knockdown of S14 increased ACC activity and polymerization. SIGNOR-267113 0.491 PRMT1 protein Q99873 UNIPROT FUS protein P35637 UNIPROT down-regulates activity methylation 9606 BTO:0000567 30354839 t lperfetto PRMT1 catalyzes the arginine methylation of Fused in Sarcoma (FUS), an RNA-binding protein that interacts with RALY. We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels, thus reducing FUS methylation. It is known that mutations in the FUS nuclear localization signal (NLS) retain the protein to the cytosol, promote aggregate formation, and are associated with amyotrophic lateral sclerosis. SIGNOR-262274 0.499 LRRK2 protein Q5S007 UNIPROT RAB8A protein P61006 UNIPROT up-regulates activity phosphorylation Thr72 AGQERFRtITTAYYR -1 32227113 t lperfetto In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. |Overall our data suggests that the phosphorylation of Rab8A at Ser111 may influence Switch II-binding by regulators, thus disrupting interactions with its cognate GEF and moderately impairs its interaction with GAPs.|The antagonistic interplay between Ser111 phosphorylation and Thr72 phosphorylation is genetically concordant with how respective mutations in PINK1 and LRRK2 cause Parkinson’s disease SIGNOR-260267 0.336 NOG protein Q13253 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates activity binding 9031 SIGNOR-C29 12478285 t Create trimers (2 typeII and 1 typeI) with serine/threonine kinase function lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors (PMID 22298955). Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors SIGNOR-219225 0.571 LCK protein P06239 UNIPROT CD3E protein P07766 UNIPROT up-regulates activity phosphorylation 10090 2470098 t Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex. SIGNOR-259930 0.678 BCL2L1 protein Q07817 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 9670005 t amattioni The presence of an anti-apoptotic molecule such as bcl-2 or bcl-xl can inhibit the activation of bax following a death signal. SIGNOR-59141 0.734 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT down-regulates phosphorylation Tyr561 ESYEGNSyTFIDPTQ 9606 BTO:0001271 15297464 t lperfetto Csf-1-mediated wild-type (wt)-csf-1r phosphorylation was not markedly affected by sfk inhibition, indicating that lack of sfk binding is not responsible for diminished y559f phosphorylation. Unexpectedly, cells expressing y559f were hyperproliferative in response to csf-1. Hyperproliferation correlated with prolonged activation of akt, erk, and stat5 in the y559f mutant. Consistent with a defect in receptor negative regulation, c-cbl tyrosine phosphorylation and csf-1r/c-cbl co-association were almost undetectable in the y559f mutant. Furthermore, y559f underwent reduced multiubiquitination and delayed receptor internalization and degradation. In conclusion, we propose that tyr559 is a switch residue that functions in kinase regulation, signal transduction and, indirectly, receptor down-regulation. SIGNOR-127622 0.2 AURKC protein Q9UQB9 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. SIGNOR-98361 0.2 SMO protein Q99835 UNIPROT OPALIN protein Q96PE5 UNIPROT up-regulates quantity transcriptional regulation 10090 35082605 f Non-canonical pathway (Gli1-indipendent): SMO/AMPK SimoneGraziosi We show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMPactivated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell. SIGNOR-269225 0.2 FZD1 protein Q9UP38 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 22944199 t amattioni When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp. SIGNOR-253512 0.676 RPS6KA1 protein Q15418 UNIPROT PPP1R3A protein Q16821 UNIPROT up-regulates activity phosphorylation Ser46 PQPSRRGsDSSEDIY -1 10648825 t lperfetto The protein G(M), which targets protein phosphatase 1 (PP1) to the glycogen particles and sarcoplasmic reticulum (SR) of striated muscles, is known to be phosphorylated at Ser48 and Ser67 in vitro by adenosine 3',5' cyclic monophosphate-dependent protein kinase (PKA) and at Ser48 by MAP kinase-activated protein kinase-1 (MAPKAP-K1, also called p90 RSK). The phosphorylation of Ser48 increases the rate at which the glycogen-associated PP1.G(M) complex dephosphorylates (activates) glycogen synthase, but the phosphorylation of Ser67 has the opposite effect, suppressing the activity of PP1 toward glycogen-bound substrates.  SIGNOR-249036 0.417 CTF1 protein Q16619 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 11834704 t gcesareni We conclude that gp130/lif receptor and et(a) receptor activation are essential for cardiac fibroblast growth by ct-1 SIGNOR-114758 0.721 DNMT3B protein Q9UBC3 UNIPROT GSTM2 protein P28161 UNIPROT down-regulates quantity by repression transcriptional regulation 21246532 f lperfetto Knockdown of Sp1 in normal lung cells reduced GST-M2 expression, and silencing of DNMT-3b increased GST-M2 expression in lung cancer cells. SIGNOR-271687 0.333 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120180 0.321 AGTR1 protein P30556 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 21289285 t gcesareni These results indicate that ang ii increases endothelial arginase activity/expression through galfa12/13 g proteins coupled to at(1) receptors and subsequent activation of rhoa/rock/p38 mapk pathways leading to endothelial dysfunction. SIGNOR-171760 0.506 mianserin chemical CHEBI:51137 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258689 0.8 USP28 protein Q96RU2 UNIPROT MYC protein P01106 UNIPROT up-regulates deubiquitination 9606 BTO:0000150 17558397 t esanto Usp28, an ubiquitin-specific protease, binds to myc through an interaction with fbw7alpha, an f-box protein that is part of an scf-type ubiquitin ligase. Therefore, it stabilizes myc. SIGNOR-155590 0.691 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser422 LSTPVVLsPGPQKP 10090 BTO:0000944 7889942 t lperfetto We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erki phosphorylates five c-terminal sites in elk-i (s324,t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-235463 0.545 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Ser23 ITDESLEsTRRILGL 9606 12930825 t lperfetto Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion. SIGNOR-249228 0.335 ULK2 protein Q8IYT8 UNIPROT HK1 protein P19367 UNIPROT up-regulates activity phosphorylation Ser364 TRLGVEPsDDDCVSV 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274041 0.2 MAP2K2 protein P36507 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258995 0.736 testosterone smallmolecule CHEBI:17347 ChEBI SRD5A1 protein P18405 UNIPROT up-regulates activity chemical activation 9606 15861399 t miannu Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions. SIGNOR-251532 0.8 PRKCA protein P17252 UNIPROT KCNJ13 protein O60928 UNIPROT down-regulates phosphorylation Ser201 TRPSPLTsVRVSAVL 9606 18976636 t gcesareni After pharmacological pkc activation, kir7.1 currents were strongly inhibited. Co-application of pkc inhibitors attenuated this effect. Inactivation of pkc consensus sites also strongly attenuated the effect with a single site ((201)s) being essential for almost the total pkc sensitivity. SIGNOR-181863 0.2 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser221 PRTSPIMsPRTSLAE 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248373 0.598 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR SMYD2 protein Q9NRG4 UNIPROT up-regulates activity methylation 9606 BTO:0001911 28370702 t irozzo In the present study, we have shown that SMYD2‐mediated methylation of lysine 1610 on the EML4‐ALK fusion protein is likely to be critically important for autophosphorylation of some tyrosine residues and the oncogenic activity of the fused proteins. SIGNOR-259175 0.2 AKT1 protein P31749 UNIPROT SKI protein P12755 UNIPROT down-regulates phosphorylation Thr458 QPRKRKLtVDTPGAP 9606 19875456 t llicata The phosphorylation of ski at threonine 458 is induced by akt pathway activators including insulin, insulin-like growth factor-1, and hepatocyte growth factor. The phosphorylation of ski causes its destabilization and reduces ski-mediated inhibition of expression of another negative regulator of tgf-beta, smad7 SIGNOR-252527 0.343 ASH1L protein Q9NR48 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000938 35210569 t Gianni Depletion of ASH1L decreases neurite outgrowth and decreases expression of the gene encoding the neurotrophin receptor TrkB whose signaling pathway is linked to neuronal morphogenesis. SIGNOR-269058 0.2 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SF3B1 protein O75533 UNIPROT unknown phosphorylation Thr313 HGSGWAEtPRTDRGG 9606 12105215 t lperfetto We indeed found that sap155-(223_322) and sap155-(1_491) are excellent substrates for in vitrophosphorylation by cyclin e-cdk2 as well as cyclin b-cdk1 SIGNOR-216717 0.353 MRAP protein Q8TCY5 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 t miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. SIGNOR-252362 0.503 SEMA3B protein Q13214 UNIPROT NRP2 protein O60462 UNIPROT up-regulates activity binding 9606 BTO:0001176;BTO:0002036 25335892 t miannu Further examination of the composition of the functional Sema3B receptor revealed that, unlike Sema3A, which signals exclusively using the NP1 receptor, Sema3B utilizes both NP1 and NP2 for signal transduction. SIGNOR-261816 0.608 SREBF1 protein P36956 UNIPROT ACACA protein Q13085 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11994399 f Luana SREBP-1c–responsive genes include those for ATP citrate lyase (which produces acetyl-CoA) and acetyl-CoA carboxylase and fatty acid synthase (which together produce palmitate [C16:0]). SIGNOR-267957 0.467 brimonidine chemical CHEBI:3175 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258901 0.8 HAUS8 protein Q9BT25 UNIPROT HAUS complex complex SIGNOR-C281 SIGNOR form complex binding 9606 BTO:0000567 19369198 t lperfetto Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC) SIGNOR-262321 0.744 HIF1A protein Q16665 UNIPROT KDM2B protein Q8NHM5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271567 0.2 Complement C1 complex complex SIGNOR-C309 SIGNOR C2 protein P06681 UNIPROT up-regulates activity cleavage Arg243 KTKESLGrKIQIQRS 31331124 t lperfetto C1s subsequently activate serum proteins C4 and C2. C4 is cleaved to fragment C4a, which is an anaphylatoxin, and to fragment C4b, which is deposited on the adjacent surfaces. C2 is cleaved to a fragment C2b, and larger fragment C2a, which binds noncovalently to C4b on the target cell membrane. This forms the C4b2a complex SIGNOR-263418 0.477 MEIS1 protein O00470 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001271 19109563 f irozzo These results show that MEIS1 expression is important for MLL-rearranged leukemias and suggest that MEIS1 promotes cell-cycle entry.Flow cytometric analysis of PI-stained nuclei showed that Meis1 knockdown led to a cell-cycle arrest in the G0/G1 phase. SIGNOR-255859 0.7 FFAR2 protein O15552 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257075 0.312 DNMT3A protein Q9Y6K1 UNIPROT CDKN2C protein P42773 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 26350239 f miannu Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family SIGNOR-261508 0.345 TDGF1 protein P13385 UNIPROT NODAL protein Q96S42 UNIPROT up-regulates activity binding 9606 19874624 t Regulation miannu Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors. SIGNOR-251937 0.647 AKT3 protein Q9Y243 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Thr235 QARKRKRtSIENRVR 9606 BTO:0004180 23041284 t flangone Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG. SIGNOR-242107 0.26 NAB2 protein Q15742 UNIPROT EGR3 protein Q06889 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000414 20506119 f miannu Our results suggest that in many cells of neuroectodermal and epithelial origin EGR1, EGR2, and EGR3 activate NAB2 transcription which is in turn repressed by NAB2, thus establishing a negative feedback loop. SIGNOR-253887 0.499 LRRK2 protein Q5S007 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr825 LKISDFGtSKRLAGI 9606 BTO:0000007 28888991 t miannu LRRK2 phosphorylated ASK1 at Thr832 that is adjacent to Thr845, which serves as an autophosphorylation site.  SIGNOR-277251 0.33 SALL4 protein Q9UJQ4 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19440552 f miannu Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex. SIGNOR-255126 0.412 PRKCA protein P17252 UNIPROT OCLN protein Q16625 UNIPROT up-regulates activity phosphorylation Ser340 DKRFYPEsSYKSTPV 9615 11502742 t lperfetto Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X. SIGNOR-249105 0.371 SMURF proteinfamily SIGNOR-PF29 SIGNOR TGFBR1 protein P36897 UNIPROT down-regulates activity ubiquitination 9606 17317136 t lperfetto Recruitment of ww and hect domain e3-ubiquitin ligases smurf1 and 2 to induce type i receptor ubiquitination and subsequent receptor degradation SIGNOR-253264 0.2 moclobemide chemical CHEBI:83531 ChEBI MAOA protein P21397 UNIPROT down-regulates activity chemical inhibition -1 21680183 t Luana Twenty-two pyrazoline derivatives were synthesized and tested for their human MAO (hMAO) inhibitory activity. Twelve molecules with unsubstituted ring A and substituted ring C (5–16) were found to be potent inhibitors of hMAO-A isoform with SIMAO-A in the order 103 and 104.  SIGNOR-258314 0.8 OMG protein P23515 UNIPROT LINGO1 protein Q96FE5 UNIPROT up-regulates binding 9606 BTO:0000938 15694321 t flangone Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1... SIGNOR-133640 0.484 CDX2 protein Q99626 UNIPROT FUT2 protein Q10981 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000182;BTO:0000391 22547830 f miannu We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. SIGNOR-254610 0.2 WASHC4 protein Q2M389 UNIPROT WASH complex complex SIGNOR-C258 SIGNOR form complex binding 23721880 t lperfetto The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53. SIGNOR-261018 0.2 Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 20223217 t miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. SIGNOR-270437 0.8 GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268603 0.242 STOML2 protein Q9UJZ1 UNIPROT OPA1 protein O60313 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20359165 f Giorgia Of interest, induction of SLP-2 expression also resulted in significant increases in the levels of OPA-1 and mitofusin-2 (P < 0.05), both integral mitochondrial membrane proteins associated with mitochondrial fusion. SIGNOR-260381 0.317 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR STMN1 protein P16949 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 9731215 t inferred from 70% family members lperfetto Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs. SIGNOR-270182 0.2 MYOD1 protein P15172 UNIPROT VEGFA protein P15692 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 18094043 t lperfetto We further demonstrate that the myogenic transcription factor, MyoD, and its heterodimeric binding proteins E12 and E47, up-regulate the expression of endogenous VEGF through direct interaction with the VEGF promoter. SIGNOR-257598 0.4 CSNK2A1 protein P68400 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Ser1004 SEHDSDEsSDDDSDS 9606 10066810 t gcesareni Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein, SIGNOR-65269 0.453 ATXN1 protein P54253 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21315774 t Luana Overexpression of the CtBP2 protein enhanced the repression activity of the E-cadherin promoter in a dose-dependent manner, whereas overexpression of ataxin-1 increased the activity of the E-cadherin promoter in a dose-dependent manner  SIGNOR-261577 0.35 calcium(2+) smallmolecule CHEBI:29108 ChEBI S100A8 protein P05109 UNIPROT up-regulates activity chemical activation 9606 BTO:0001044 16690079 t miannu S100 proteins comprise the largest family of calcium-binding proteins. Members of this family usually form homo- or heterodimers, which may associate to higher-order oligomers in a calcium-dependent manner. The heterodimers of S100A8 and S100A9 represent the major calcium-binding proteins in phagocytes. Both proteins regulate migration of these cells via modulation of tubulin polymerization. SIGNOR-261935 0.8 GSK3B protein P49841 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 9832503 t gcesareni Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover. SIGNOR-62265 0.775 CSNK2A1 protein P68400 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Thr350 PEVKKEEtLLDLDFD 9606 BTO:0000567 16945112 t lperfetto Amphiphysins interact directly with clathrin and have a function in clathrin-mediated synaptic vesicle recycling and clathrin-mediated endocytosis. The n-terminal domain of clathrin bound to unphosphorylated amphiphysin-1, but not to the phosphorylated protein. The assumption that casein kinase 2 phosphorylates amphiphysin-1 at t350 and t387 was corroborated by experiments showing that: casein kinase 2 phosphorylated these residues directly in vitro,. upon activation by nerve growth factor, casein kinase 2 phosphorylates amphiphysin-1 and thereby regulates the endocytosis of clathrin-coated vesicles via the interaction between clathrin and amphiphysin. SIGNOR-149314 0.2 ASH2L protein Q9UBL3 UNIPROT Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR form complex binding 9606 BTO:0000567 12670868 t miannu Our analysis of HCF-1-associated proteins suggests that a K4 histone H3 HMT complex has been conserved from yeast to humans in both structure and activity: the Set1/Ash2 HMT. The results presented here show that this Set1/Ash2 HMT complex, in mutually exclusive interactions, can associate with HCF-1 bound to the repressive Sin3 HDAC or the transcriptional activator VP16, indicating a diversity of transcriptional regulatory roles. SIGNOR-264479 0.909 (1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid chemical CHEBI:94640 ChEBI GRM2 protein Q14416 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-193728 0.8 cytidine smallmolecule CHEBI:17562 ChEBI cytidine 5'-monophosphate(2-) smallmolecule CHEBI:60377 ChEBI up-regulates quantity precursor of 11306702 t lperfetto Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. SIGNOR-275857 0.8 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0003316 11777913 t miannu 4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E. SIGNOR-250097 0.444 GPIb-IX-V complex complex SIGNOR-C270 SIGNOR FLNA protein P21333 UNIPROT up-regulates activity relocalization 9606 16293600 t lperfetto The cytoplasmic domain of GPIbα of the GPIb-IX-V complex binds to actin filaments through FLNa|This immediately means that clustering of the GPIb-IX-V complex and anchoring of FLNa to actin filaments by activation could also increase avidity, which could withstand high shear stress. SIGNOR-261846 0.561 PAK3 protein O75914 UNIPROT SYN1 protein P17600 UNIPROT up-regulates activity phosphorylation Ser605 AGPTRQAsQAGPVPR 10116 BTO:0001009 12237306 t miannu Synapsin I is phosphorylated at Ser603 by p21-activated kinases. the Ser603 residue must be one of the pivotal sites for the release SIGNOR-250246 0.339 LCK protein P06239 UNIPROT CD3 complex SIGNOR-C432 SIGNOR up-regulates activity phosphorylation 9606 8626561 t The binding of Lck to the tyrosine-phosphorylated zeta chain of the TcR would serve to strengthen the interaction of the associated CD4 and the TcR complex, leading to increased avidity for the antigen-major histocompatibility protein complex SIGNOR-252305 0.631 MAP3K14 protein Q99558 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C14 9520446 t gcesareni Activation of the transcription factor nf-kappab by inflammatory cytokines involves the successive action of nf-kappab-inducing kinase (nik) and two ikappab kinases, ikk-alpha and ikk-beta. Here we show that nik preferentially phosphorylates ikk-alpha over ikk-beta SIGNOR-55949 0.702 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser196 EKSPSVCsPLNMTSS 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276102 0.357 CREB1 protein P16220 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000158 15955695 f miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. SIGNOR-253798 0.428 AKT proteinfamily SIGNOR-PF24 SIGNOR TBX3 protein O15119 UNIPROT up-regulates activity phosphorylation Ser719 AEKEAATsELQSIQR 9606 25595898 t lperfetto We have identified TBX3 as a key substrate of AKT3 in melanomagenesis. we have identified the AKT3 target site at serine residue 720 in the TBX3 protein and show that this site is phosphorylated in vivo. the phosphorylation at S720 promotes TBX3 protein stability, nuclear localization, transcriptional repression of E-cadherin, and its role in cell migration and invasion. SIGNOR-244353 0.2 EREG protein O14944 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 BTO:0000150 22891299 t gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4 SIGNOR-191785 0.575 HASPIN protein Q8TF76 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Thr4 tKQTARKS 9606 20705812 t miannu Here we show that phosphorylation of histone H3 threonine 3 (H3T3ph) by Haspin is necessary for CPC accumulation at centromeres and that the CPC subunit Survivin binds directly to H3T3ph. SIGNOR-275428 0.2 JAK2 protein O60674 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 18852293 t lperfetto Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6. SIGNOR-249532 0.657 Quadazocine chemical CID:115077 PUBCHEM OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258419 0.8 SGF29 protein Q96ES7 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269572 0.2 MRGBP protein Q9NV56 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269296 0.776 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser602 INKKLDLsNVQSKCG -1 8999860 t miannu Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules SIGNOR-250285 0.318 BBC3 protein Q9BXH1 UNIPROT BAX protein Q07812 UNIPROT up-regulates relocalization 9606 BTO:0000551 19439449 t gcesareni Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis. SIGNOR-185671 0.503 MYC protein P01106 UNIPROT GLS protein O94925 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001518 19219026 f Luana Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells.  SIGNOR-268038 0.452 phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI AKT1 protein P31749 UNIPROT up-regulates activity chemical activation 9606 18249092 t gcesareni Furthermore, overall PKB activity, primarily consisting of cytosolic enzyme, was dependent upon levels of PI(3,4)P2, while only membrane-associated PKB activity was dependent upon PI(3,4,5)P3 levels. We conclude that PI(3,4,5)P3 and PI(3,4)P2 have distinct roles in determining PKB phosphorylation and activity. Thus, when investigating PI3K-PKB pathways, the importance of both lipids must be considered SIGNOR-252432 0.8 nitric oxide smallmolecule CHEBI:16480 ChEBI GUCY1A3-B2 complex SIGNOR-C139 SIGNOR up-regulates activity chemical activation 9606 15036565 t gcesareni One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP) SIGNOR-244113 0.8 MAPK14 protein Q16539 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation Thr118 SGLPRTMtQKDVEDM 9606 19528229 t lperfetto P38 mapk phosphorylates the mrna binding protein hur on thr118, which results in cytoplasmic accumulation of hur and its enhanced binding to the p21cip1 mrna. SIGNOR-186135 0.538 RIPK1 protein Q13546 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT up-regulates activity phosphorylation Ser728 PSPARSSsYSEANEP 9913 17389591 t We further show that RIP1 (the Ser/Thr protein kinase receptor-interacting protein) associates with the GAP domain of AIP1 and mediates TNF-induced AIP1 phosphorylation at Ser-604 and JNK/p38 activation as demonstrated by both overexpression and small interfering RNA knockdown of RIP1 in EC. SIGNOR-259976 0.436 ALDH1A1 protein P00352 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI down-regulates quantity chemical modification 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265122 0.8 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates activity phosphorylation Ser293 PAPARPRsPSQTRKG 9606 16733250 t lperfetto Here we report that amphiphysin i (amph i) is also a mnb/dyrk1a substrate. This kinase phosphorylated native amph i in rodent brains and recombinant human amph i expressed in escherichia coli. Serine 293 (ser-293) was identified as the major site, whereas serine 295 and threonine 310 were found as minor kinase sitesamph i phosphorylated by mnb/dyrk1a decreased endophilin binding in vitro. From these results we conclude that amph i at ser-293 is phosphorylated by mnb/dyrk1a and that the phosphorylation has physiological significance in controlling the interaction of amphiphysin with endocytic accessory proteins. SIGNOR-146902 0.405 NLGN3 protein Q9NZ94 UNIPROT NRXN1 protein P58400 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264147 0.834 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr534 SRTPSLPtPPTREPK 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249349 0.728 EGR3 protein Q06889 UNIPROT NAB2 protein Q15742 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 20506119 f miannu In T lymphocytes EGR2 and EGR3 have been shown to inhibit NAB2 expression. SIGNOR-253884 0.499 lenalidomide chemical CHEBI:63791 ChEBI IKZF1 protein Q13422 UNIPROT down-regulates quantity by destabilization chemical inhibition 9606 24328678 t gcesareni Members of the Ikaros family of transcription factors, specifically Ikaros and Aiolos (encoded by the genes IKZF1 and IKZF3 respectively), are recruited as protein substrates for CRL4CRBN in T cells in response to lenalidomide or pomalidomide treatment. SIGNOR-236910 0.8 KLKB1 protein P03952 UNIPROT KNG1 protein P01042 UNIPROT up-regulates activity cleavage Arg389 PPGFSPFrSSRIGEI 9606 BTO:0000131 cleavage:Arg390 CTTKTSTrIVGGTNS 28966616 t lperfetto Bradykinin is a nonapeptide composed of the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg and functions as an inflammatory mediator. BK is the product of the kallikrein–kinin system following activation of FXII. FXIIa leads to proteolysis of PK, and the resulting PKa cleaves HK to generate BK (Figure 1). SIGNOR-263548 0.771 RPS6KB2 protein Q9UBS0 UNIPROT TARBP2 protein Q15633 UNIPROT up-regulates activity phosphorylation Ser286 LRSCSLGsLGALGPA -1 27407113 t miannu We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells.  SIGNOR-274069 0.34 ITGB2 protein P05107 UNIPROT AX/b2 integrin complex SIGNOR-C171 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253194 0.824 RPS6KA1 protein Q15418 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser1798 GQRKRLIsSVEDFTE 9606 BTO:0000007 15342917 t lperfetto The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1 SIGNOR-128634 0.759 mTORC1 complex SIGNOR-C3 SIGNOR MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 9606 20516213 t lperfetto The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly. SIGNOR-217153 0.467 HMOX1 protein P09601 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0004296 21037234 f irozzo In conclusion, AMPK stimulates HO-1 gene expression in human ECs via the Nrf2/antioxidant responsive element signaling pathway. The induction of HO-1 mediates the antiapoptotic effect of AMPK, and this may provide an important adaptive response to preserve EC viability during periods of metabolic stress. SIGNOR-256302 0.7 TFAP2C protein Q92754 UNIPROT CRABP2 protein P29373 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002828 17187826 f miannu Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. SIGNOR-255398 0.252 MARCHF8 protein Q5T0T0 UNIPROT HLA-DRB4 protein P13762 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys254 FIYFRNQkGHSGLQP 9606 19117940 t miannu Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination. SIGNOR-271407 0.2 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI dehydroepiandrosterone chemical CHEBI:28689 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268647 0.8 entinostat chemical CHEBI:132082 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257902 0.8 GAP43 protein P17677 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10116 26865625 f miannu Growth-associated protein 43 (GAP43), a protein kinase C (PKC)-activated phosphoprotein, is often implicated in axonal plasticity and regeneration.  SIGNOR-266771 0.7 KIT protein P10721 UNIPROT SLA protein Q13239 UNIPROT down-regulates activity phosphorylation Tyr258 KKSISLMyGGSKRKS 9534 BTO:0001538 24284075 t miannu Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity SIGNOR-263141 0.2 CSNK2A1 protein P68400 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser230 VTPSKSTsASAIMNG 9606 BTO:0000938 26917740 t lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. SIGNOR-275739 0.272 BDKRB1 protein P46663 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256764 0.252 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation Tyr703 DHAEAALyKNLLHSK 9606 10377264 t miannu Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr SIGNOR-68643 0.2 AREG protein P15514 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0001253 20513444 t Amphiregulin is an autocrine growth factor lperfetto Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling. SIGNOR-236356 0.763 dacomitinib chemical CHEBI:132268 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 23405260 t gcesareni The goal of this study was to compare dacomitinib (pf-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple her family receptors (her-1 (egfr), her-2 and her-4 tyrosine kinases), to cetuximab, the current fda approved anti-egfr medication for hnscc and erlotinib, an egfr specific small molecule tyrosine kinase inhibitor. SIGNOR-200905 0.8 WNT7B protein P56706 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15923619 t flangone These studies point to an important interaction between wnt7b, lrp5, and fzd1 and fzd10. SIGNOR-137937 0.66 MCU_MICU3_variant complex SIGNOR-C501 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270873 0.8 EFNA3 protein P52797 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9330863 t gcesareni The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. transmembrane ligands for eph receptors also exhibit properties of signal transducing molecules, suggesting that bidirectional signaling occurs when receptor-expressing cells contact ligand-expressing cells. SIGNOR-52312 0.796 MECP2 protein P51608 UNIPROT SGK1 protein O00141 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16002417 t Luana These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress. SIGNOR-264543 0.296 CDK5 protein Q00535 UNIPROT CLOCK protein O15516 UNIPROT up-regulates phosphorylation Thr461 KIPTDTStPPRQHLP 9606 24235147 t lperfetto Cdk5 phosphorylates clock at the thr-451 and thr-461 residues in association with transcriptional activation of clock. SIGNOR-203231 0.334 PIK3R3 protein Q92569 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity binding 9606 BTO:0000007 32606738 t miannu N this study, we aimed to explore the interaction of p55PIK with p53 and the role of p55PIK in regulating p53-dependent apoptosis in cancer cells. We found that p55PIK directly binds to the DBD domain of p53 via N24 domain. Moreover, the upregulation of p55PIK expression increases transcriptional levels of p53-dependent apoptosis-related genes including GADD45α, S100A9, MDM2 and AIP1. Furthermore, synthetic N24 translocated to nucleus can significantly inhibit cancer cell growth. SIGNOR-261492 0.3 HIF1A protein Q16665 UNIPROT PGK1 protein P00558 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567;BTO:0000972 8089148 f miannu Hypoxia-inducible factor 1 (HIF-1) activates erythropoietin gene transcription in Hep3B cells subjected to hypoxia. HIF-1 activity is also induced by hypoxia in non-erythropoietin-producing cells, suggesting a more general regulatory role. We now report that RNAs encoding the glycolytic enzymes aldolase A (ALDA), phosphoglycerate kinase 1 (PGK1), and pyruvate kinase M were induced by exposure of Hep3B or HeLa cells to inducers of HIF-1 (1% O2, cobalt chloride, or desferrioxamine). Sequences from the ALDA, PFKL, and PGK1 genes containing HIF-1 binding sites mediated hypoxia-inducible transcription in transient expression assays. SIGNOR-254424 0.481 PPARGC1A protein Q9UBK2 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001103 17609368 f lperfetto Furthermore, ampk directly phosphorylates pgc-1?, And this phosphorylation mediates an increase in pgc-1? Protein action on the pgc-1? Promoter. SIGNOR-156783 0.2 YY1 protein P25490 UNIPROT ACTC1 protein P68032 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 9171244 f miannu Expression of YY1 inhibited cardiac alpha-actin promoter activity, whereas coexpression of Nkx-2.5 and SRF was able to partially reverse YY1 repression. SIGNOR-255616 0.2 NMUR2 protein Q9GZQ4 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256731 0.41 RUNX2 protein Q13950 UNIPROT ENPP1 protein P22413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004473 19049325 f miannu FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2. SIGNOR-252192 0.345 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269375 0.719 PTPN6 protein P29350 UNIPROT SYK protein P43405 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 10458769 t miannu We propose that shp1 can dephosphorylate sites in zap-70 and syk that are involved in coupling these kinases to downstream signaling cascades, including erk2 and elements of the il-2 gene. SIGNOR-70234 0.726 BRAF protein P15056 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser465 TVGQRIGsGSFGTVY 9606 31929109 t miannu We previously identified that BRAFWT can autophosphorylate its P-loop (Ser-465/Ser-467) to inactivate itself in the absence of native substrate MEK SIGNOR-277498 0.2 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249643 0.697 AKT proteinfamily SIGNOR-PF24 SIGNOR KHSRP protein Q92945 UNIPROT down-regulates activity phosphorylation Ser193 GLPERSVsLTGAPES 9606 17177604 t lperfetto Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome. SIGNOR-151216 0.2 AURKB protein Q96GD4 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates activity phosphorylation Ser1342 GPLRGKTsGTEPADF 9606 BTO:0001938 28415769 t lperfetto Here we report for the first time that tumor suppressor p53-binding protein 1 (53BP1) is phosphorylated at serine 1342 (S1342) by Aurora kinase B both in vitro and in human cells, which is required for optimal recruitment of 53BP1 at kinetochores. SIGNOR-264411 0.419 PFDN6 protein O15212 UNIPROT Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR form complex binding 9606 32699605 t miannu The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6) SIGNOR-270930 0.94 NRCAM protein Q92823 UNIPROT ANK2 protein Q01484 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 t miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. SIGNOR-266719 0.726 LAMA5 protein O15230 UNIPROT Laminin-10 complex SIGNOR-C182 SIGNOR form complex binding 11821406 t lperfetto The laminin (LN) family of large heterotrimeric extracellular matrix glycoproteins has multiple functions: LNs take part in the regulation of processes such as cell migration, differentiation, and proliferation, in addition to contributing to the structure of basement membranes. LN-10, composed of alpha5, beta1, and gamma1 chains, is widely distributed in most basement membranes of both epithelia and endothelia. SIGNOR-255317 0.739 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser266 QGLSTALsVEKTSKR 9534 BTO:0001538 23519612 t miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. SIGNOR-262708 0.323 MSI1 protein O43347 UNIPROT NUMB protein P49757 UNIPROT down-regulates binding 9606 20477901 t Inhibits translation gcesareni The study confirmed p21(cip1) and numb proteins as targets of musashi1, suggesting additionally p27(kip1) in cell-cycle regulation and jagged-1 in notch . SIGNOR-165617 0.456 PRKCG protein P05129 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates phosphorylation Thr425 KKCLELFtELAEDKE 9606 24117238 t lperfetto Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_, and, more interestingly, this threonine residue set serves as a 'phosphorylation switch' for hsp90_ binding or release of pkc_. Moreover, phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity. SIGNOR-202816 0.26 DZIP3 protein Q86Y13 UNIPROT H2AC18 protein Q6FI13 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271755 0.2 PRKAA1 protein Q13131 UNIPROT CRY1 protein Q16526 UNIPROT down-regulates phosphorylation Ser71 ANLRKLNsRLFVIRG 9606 SIGNOR-C15 phosphorylation:Ser71 ANLRKLNsRLFVIRG 21892142 t gcesareni Ampk was shown to regulate the stability of the core clock component cry1 though phosphorylation of cry1 ser71, which stimulates the direct binding of the fbox protein fbxl3 to cry1, targeting it for ubiquitin-mediated degradation SIGNOR-176472 0.369 DUSP6 protein Q16828 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates activity dephosphorylation 9606 24861519 t miannu Our data demonstrate MKP-3 has differential substrate preference in astrocytes compared to other cells types, since it preferentially dephosphorylated p-JNK over p-ERK.|The main findings of our studies are (1) MKP-3 preferentially reduces p-JNK over p-ERK and p-p38 in primary astrocytes; (2) This MAPK modulation pattern in primary astrocytes significantly reduced NO and completely abolished IL-6 and TNF accumulation; and (3) These effects are specifically induced by MKP-3 since block-age of MKP-3 mRNA expression reversed its action on MAPKs and pro-inflammatory mediators in BV-2 microglia cells. SIGNOR-277150 0.617 U1 snRNP complex complex SIGNOR-C480 SIGNOR RNA_splicing phenotype SIGNOR-PH201 SIGNOR up-regulates 9606 30765414 f lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270687 0.7 CSNK2A1 protein P68400 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Ser59 NKLFQYAsTDMDKVL -1 8663403 t llicata We show that serine 59 located between the MADS and MEF2 domains of MEF2C is phosphorylated in vivo and can be phosphorylated in vitro by casein kinase-II (CKII). Phosphorylation of this site enhanced the DNA binding and transcriptional activity of MEF2C by increasing its DNA binding activity 5-fold. SIGNOR-250914 0.339 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFV1 protein P49821 UNIPROT up-regulates activity phosphorylation Thr383 HESCGQCtPCREGVD 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275602 0.2 CASP5 protein P51878 UNIPROT GSDMD protein P57764 UNIPROT up-regulates activity cleavage Asp275 CLHNFLTdGVPAEGA 9606 BTO:0000007 26375003 t lperfetto Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence | SIGNOR-256418 0.609 CTNND1 protein O60716 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 22946057 t gcesareni We demonstrate that p120-catenin participates in the stimulation of rac1 activity, binding directly to this protein. In addition we show that vav2 also binds to p120-catenin and is required for rac1 activation and for beta-catenin translocation to the nucleus.Vav2 And rac1 association with p120-catenin was modulated by phosphorylation of this protein, which was stimulated upon serine/threonine phosphorylation by ck1 and inhibited by tyrosine phosphorylation by src or fyn SIGNOR-198938 0.568 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser405 SHPLSLTsDQYKAYL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178383 0.731 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273056 0.556 Corticotropin protein P01189-PRO_0000024969 UNIPROT MC5R protein P33032 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268716 0.2 MAPK14 protein Q16539 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates activity phosphorylation Ser82 STSQSPHsPDSSQSS -1 8650547 t miannu CHOP, a member of the C/EBP family of transcription factors, mediates effects of cellular stress on growth and differentiation. It accumulates under conditions of stress and undergoes inducible phosphorylation on two adjacent serine residues (78 and 81). In vitro, CHOP is phosphorylated on these residues by p38 mitogen-activated protein kinase (MAP kinase). SIGNOR-250096 0.594 MAPK1 protein P28482 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 10090 BTO:0002572 28646232 t Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels SIGNOR-262524 0.391 SUFU protein Q9UMX1 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity binding 15367681 t lperfetto Here we characterize structural and functional determinants of Su(fu) required for Gli regulation and show that Su(fu) contains at least two distinct domains: a highly conserved carboxy-terminal region required for binding to the amino-terminal ends of the Gli proteins and a unique amino-terminal domain that binds the carboxy-terminal tail of Gli1. While each domain is capable of binding to different Gli1 regions independently, interactions between Su(fu) and Gli1 at both sites are required for cytoplasmic tethering and repression of Gli1 SIGNOR-249591 0.948 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 10116 BTO:0001009 8336722 t gcesareni The degree of CREB phosphorylation, assessed with antiserum specific for CREB phosphorylated at Ser-133, correlated with the amount of PKA liberated. The time course of phosphorylation closely paralleled the nuclear entry of the catalytic subun SIGNOR-166342 0.564 PC protein P11498 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI down-regulates quantity chemical modification 9606 24363178 t miannu As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2) SIGNOR-266554 0.8 MAPK1 protein P28482 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates activity phosphorylation Ser421 YEPAARIsPLGALQH -1 26346493 t miannu S421 resides within a Ser-Pro phosphoacceptor motif that is typical for ERK1/2 and recombinant ERK2 phosphorylated DYRK1B at S421 in vitro.  SIGNOR-276937 0.376 SOCS3 protein O14543 UNIPROT IRS1 protein P35568 UNIPROT down-regulates binding 9606 23115649 t gcesareni Irs-1 is the major signaling protein that socs3 targets to inhibit insulin signaling SIGNOR-199361 0.73 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates activity phosphorylation Ser128 LVDTASPsPMETSGC 9606 BTO:0000567 11242082 t lperfetto Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation. SIGNOR-105711 0.919 Gbeta proteinfamily SIGNOR-PF4 SIGNOR KRT8 protein P05787 UNIPROT unknown phosphorylation 16554440 t inferred from 70% family members lperfetto Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002). SIGNOR-270003 0.2 BCL2L11 protein O43521 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates binding 9606 15694340 t gcesareni Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly. SIGNOR-133829 0.955 SUZ12/EZH2 complex SIGNOR-C77 SIGNOR SUZ12/EZH2/YY1 complex SIGNOR-C102 SIGNOR form complex binding 10090 BTO:0000165;BTO:0002314 20887952 t lperfetto TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter. SIGNOR-235577 0.766 DVL1 protein O14640 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity binding 9606 SIGNOR-C110 20837657 t gcesareni In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization. SIGNOR-167957 0.606 DTX4 protein Q9Y2E6 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates ubiquitination 9606 BTO:0000938 10531053 t gcesareni Nlrp4 negatively regulates type i interferon signaling by targeting the kinase tbk1 for degradation via the ubiquitin ligase dtx4 SIGNOR-71565 0.567 FGD1 protein P98174 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260551 0.705 POLR1D protein P0DPB6 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266146 0.891 fexofenadine chemical CHEBI:5050 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 19660947 t Luana  hERG activity was initially determined in a high throughput patch clamp screening assay (Ionworks)5 while a human H1 binding assay was used to determine H1 binding affinity.6 Selected results were confirmed in vitro using an IonWorks Quattro patch clamp assay and in vivo in the guinea pig.7, 8 Histamine H1activity was confirmed in vivo in the guinea pig.7 SIGNOR-257827 0.8 MFGE8 protein Q08431 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity 9606 21901532 f miannu In an attempt to clarify the direct anti-inflammatory role of MFG-E8, we revealed a distinct signaling pathway where MFG-E8 activates suppressor of cytokine signaling (SOCS) 3 gene expression via STAT3 mediated pathway, which in turn served as a negative regulator for LPS induced TLR4 signaling by targeting NF-κB p65 component, thereby attenuating the down-stream signaling for TNF-α production SIGNOR-260654 0.28 PLK1 protein P53350 UNIPROT CDC6 protein Q99741 UNIPROT up-regulates phosphorylation Thr37 SDAKLEPtNVQTVTC 9606 21041660 t lperfetto Binding between cdc6 and plk1 occurs through the polo-box domain of plk1, and cdc6 is phosphorylated by plk1 on t37. These results suggest that plk1-mediated phosphorylation of cdc6 promotes the interaction of cdc6 and cdk1, leading to the attenuation of cdk1 activity, release of separase, and subsequent anaphase progression. SIGNOR-169184 0.582 STAT6 protein P42226 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity 10090 24948596 f IL-4 was shown to inhibit lipid accumulation in adipose tissue by a mechanism that includes activation of Stat6, which suppresses PPARα transcriptional activity SIGNOR-254682 0.528 MEF2D protein Q14814 UNIPROT MYH7 protein P12883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 17111365 f Regulation miannu Transient transfection assays demonstrated that the calcineurin/NFATc1 signaling pathway is essential for MyHCbeta promoter activation during transformation of C2C12 myotubes but is not sufficient for complete fast MyHCIId/x promoter inhibition. Along with NFATc1, myocyte enhancer factor-2D (MEF-2D) and the myogenic transcription factor MyoD transactivated the MyHCbeta promoter in calcium-ionophore-treated myotubes in a calcineurin-dependent manner. SIGNOR-251957 0.342 C5 convertase complex (C3bBbC3b) complex SIGNOR-C315 SIGNOR C5 protein P01031 UNIPROT up-regulates activity cleavage Arg751 HKDMQLGrLHMKTLL 9606 BTO:0000089 26489954 t lperfetto In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC). SIGNOR-263482 0.539 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249627 0.907 BMP7 protein P18075 UNIPROT UCP1 protein P25874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18719589 f fspada Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways SIGNOR-180354 0.439 PPARGC1A protein Q9UBK2 UNIPROT PCK2 protein Q16822 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255060 0.404 NR0B1 protein P51843 UNIPROT NR5A1 protein Q13285 UNIPROT down-regulates activity binding 9606 BTO:0002588 19237537 t miannu The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes. SIGNOR-271784 0.725 PIP3 smallmolecule CHEBI:16618 ChEBI AKT3 protein Q9Y243 UNIPROT up-regulates chemical activation 9606 21779497 t gcesareni When active, pi3k converts phosphatidylinositol (4,5)-bisphosphate (pip2) into phosphatidylinositol (3,4,5)-trisphosphate (pip3). Pip3, in turn, binds the pleckstrin homology (ph) domain of akt/pkb, stimulating its kinase activity, resulting in the phosphorylation of a host of other proteins that affect cell growth, cell cycle entry, and cell survival. SIGNOR-175250 0.8 PAFAH1B1 protein P43034 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 20133715 f miannu The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. SIGNOR-252169 0.7 GPR65 protein Q8IYL9 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 27287411 t GPR65 is playing a critical role in phagocytic cells that require high levels of V-ATPase activity to maintain phagosomal and lysosomal pH, and this activity aids in the direct clearance of enteric pathogens. SIGNOR-272502 0.274 ESR1 protein P03372 UNIPROT CRH protein P06850 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000614 8408641 t lperfetto Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction.|Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro. SIGNOR-268721 0.347 SNRPG protein P62308 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270683 0.926 FAM8A1 protein Q9UBU6 UNIPROT SYVN1 protein Q86TM6 UNIPROT up-regulates activity binding 9606 BTO:0000007 28827405 t miannu FAM8A1 enhances binding of Herp to Hrd1, an interaction that is required for ERAD. Our findings support a model of Hrd1 complex formation, where the Hrd1 cytoplasmic domain and FAM8A1 have a central role in the assembly and activity of this ERAD machinery. A conserved Hrd1 cytoplasmic domain interacts with FAM8A1 and Herp SIGNOR-261348 0.594 MACROD2 protein A1Z1Q3 UNIPROT ADP-D-ribose(2-) smallmolecule CHEBI:57967 ChEBI up-regulates quantity chemical modification 9606 32257385 t miannu MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins SIGNOR-269840 0.8 THBS2 protein P35442 UNIPROT CD47 protein Q08722 UNIPROT up-regulates binding 9606 8550562 t gcesareni We report here that iap is a receptor for the ts1 cbd and its vvm-containing peptides and that a function-blocking anti-iap mab inhibits the chemotactic response to ts1 and its cbd peptides in endothelial cells. SIGNOR-39749 0.579 PDPK1 protein O15530 UNIPROT AHCYL1 protein O43865 UNIPROT down-regulates activity phosphorylation Ser68 RSLSRSIsQSSTDSY 9534 17635105 t lperfetto Residue 68 resides in a consensus phosphorylation site for PKD (Figure 1A) [22,23]. Interestingly, phosphorylation of Ser68 could allow for subsequent phosphorylation of Ser71, Ser74, Ser77 and Ser80 by CK1, for which the consensus phosphorylation site is pS/T-X-X-S/T| We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R SIGNOR-249174 0.2 ITGB1BP1 protein O14713 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257656 0.313 sulpiride chemical CHEBI:32168 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition -1 7576010 t miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. When receptors were labeled with [lzs1]-NCQ-298, D2 and D3 receptors displayed similar potencies for sulpiride, a D2 receptor antagonist (Figure 3A, Table I). SIGNOR-258430 0.8 HSD17B1 protein P14061 UNIPROT estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity chemical modification -1 8994190 t Luana Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues.  SIGNOR-269758 0.8 CDKN1A protein P38936 UNIPROT CDK1 protein P06493 UNIPROT down-regulates binding 9606 15340381 t gcesareni P21 and p27 are key inhibitors of both cdk1 and cdk2. SIGNOR-128442 0.877 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity by destabilization ubiquitination Lys800 LNPILPPkAPAVSPL 9606 BTO:0000938 17283082 t lperfetto Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage. SIGNOR-249578 0.657 FGF2 protein P09038 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates 9606 20974802 f inferred from 70% of family members gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription. SIGNOR-269908 0.2 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 22049910 t miannu Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. SIGNOR-266906 0.8 panobinostat chemical CHEBI:85990 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257752 0.8 ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 9865696 t lperfetto We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor by controlling the subcellular localization of Smad2 and by interacting with the TGFbeta receptor complex. SIGNOR-62874 0.856 SIRT7 protein Q9NRC8 UNIPROT FBL protein P22087 UNIPROT up-regulates activity deacetylation Lys102 GVFICRGkEDALVTK 30540930 t lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) SIGNOR-275894 0.274 POU5F1 protein Q01860 UNIPROT HLX protein Q14774 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254936 0.2 ROCK2 protein O75116 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 14701738 f miannu Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively. SIGNOR-261712 0.7 NFIL3 protein Q16649 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates activity binding -1 12805554 t miannu E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins SIGNOR-224248 0.2 EIF3F protein O00303 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266395 0.922 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273073 0.635 haloperidol chemical CHEBI:5613 ChEBI SIGMAR1 protein Q99720 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000793 17419803 t Simone Vumbaca These results suggest that haloperidol may irreversibly inactivate sigma-1 receptors in guinea pig and human cells, probably after metabolism to reduced haloperidol. SIGNOR-261090 0.8 PRKD1 protein Q15139 UNIPROT ATP7B protein P35670 UNIPROT up-regulates activity phosphorylation Ser1453 DDDGDKWsLLLNGRD 9606 BTO:0000599 21189263 t lperfetto ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking. SIGNOR-272294 0.301 VHL protein P40337 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 16678111 t Here we found that pVHL directly associates with and stabilizes p53 by suppressing Mdm2-mediated ubiquitination and nuclear export of p53. SIGNOR-256594 0.463 PRKAA2 protein P54646 UNIPROT HIPK2 protein Q9H2X6 UNIPROT down-regulates activity phosphorylation Thr119 HNLMRRStVSLLDTY 23871434 t Phosphosite positions are derived from Figure S5 lperfetto AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro SIGNOR-275485 0.2 CSNK1D protein P48730 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation 9606 15747065 t gcesareni Cki_/_ binds and phosphorylates lef-1, and this phosphorylation disrupts lef-1_-catenin interaction SIGNOR-134494 0.253 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10550055 t gcesareni Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner. SIGNOR-72075 0.813 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273072 0.635 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser579 NVKSKIGsTENLKHQ -1 10090741 t miannu We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs. SIGNOR-250172 0.44 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser278 VDTGITNsQTLIPDC 9606 10839544 t lperfetto We have identified two residues of nbs1, ser 278 and ser 343 that are phosphorylated in vitro by atm and whose modification in vivo is essential for the cellular response to dna damage. This response includes s-phase checkpoint activation, formation of the nbs1/mrel1/rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation. SIGNOR-78025 0.851 SMAD7 protein O15105 UNIPROT BMPR1B protein O00238 UNIPROT down-regulates 10090 10564272 f gcesareni We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2 SIGNOR-236864 0.686 GRB2 protein P62993 UNIPROT SOS2 protein Q07890 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-175180 0.876 ITGB1BP1 protein O14713 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257657 0.283 CASP12 protein Q6UXS9 UNIPROT CASP9 protein P55211 UNIPROT up-regulates cleavage 9606 BTO:0000222 12097332 t gcesareni Caspase-12 specifically cleaves and activates procaspase-9 in cytosolic extracts. Results suggest that caspase-12 can activate caspase-9 without involvement of cytochromec. SIGNOR-90318 0.2 TLN1 protein Q9Y490 UNIPROT AM/b2 integrin complex SIGNOR-C170 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257620 0.567 beta-Funaltrexamine chemical CHEBI:81527 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258771 0.8 PRKCB protein P05771 UNIPROT CFLAR protein O15519 UNIPROT up-regulates quantity by stabilization phosphorylation Ser193 LQAAIQKsLKDPSNN 9606 BTO:0000664 19343040 t miannu  Here, we identify serine 193 as a novel in vivo phosphorylation site of all c-FLIP proteins. c-FLIP S193 phosphorylation is mediated by PKCa and PKCb.S193 phosphorylation increases the stability of the short c-FLIP proteins SIGNOR-276146 0.2 NEDD4L protein Q96PU5 UNIPROT SCNN1A protein P37088 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 15586017 t Regulation of localization miannu The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane. SIGNOR-251948 0.766 CSNK2A1 protein P68400 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser103 EGISQESsEEEQ -1 2806554 t llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. SIGNOR-250893 0.336 XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates activity binding 9606 11583623 t amattioni Xiap is an endogenous inhibitor of caspase-3 SIGNOR-110837 0.938 MAPK14 protein Q16539 UNIPROT CDC25C protein P30307 UNIPROT down-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR -1 9543386 t miannu P38 binds and phosphorylates Cdc25B at serines 309 and 361, and Cdc25C at serine 216; phosphorylation of these residues is required for binding to 14-3-3 proteins. SIGNOR-250091 0.449 ECM stimulus SIGNOR-ST20 SIGNOR A11/b1 integrin complex SIGNOR-C168 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259050 0.7 MAPK8IP1 protein Q9UQF2 UNIPROT MAP4K2 protein Q12851 UNIPROT down-regulates binding 9606 BTO:0000007 10702297 t gcesareni DLK mutants were used to demonstrate that a DLK leucine zipper-leucine zipper interaction is necessary for DLK dimerization and to show that DLK dimerization mediated by the leucine zipper domain is prerequisite for DLK activity and subsequent activation of stress-activated protein kinase (SAPK). SIGNOR-75385 0.2 bosutinib chemical CHEBI:39112 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001056 23409026 t miannu Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. SIGNOR-259271 0.8 AKT1 protein P31749 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser1834 MLRRRMAsMQRTGVV 9606 16926151 t lperfetto We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity SIGNOR-148983 0.685 PRKG2 protein Q13237 UNIPROT PTS protein Q03393 UNIPROT up-regulates phosphorylation Ser19 AQVSRRIsFSASHRL 9606 10531334 t gcesareni Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps. Addition of cgmp stimulated phosphotransferase activity 2-fold. Extracts from transfected cos-1 cells overexpressing cgkii stimulated ser(19) phosphorylation more than 100-fold.In assays with purified enzymes, wild-type but not ptps-s19a was a specific substrate for the cgmp-dependent protein kinase (cgk) type i and ii. Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps SIGNOR-71751 0.509 EIF3_complex complex SIGNOR-C401 SIGNOR EIF4G2 protein P78344 UNIPROT up-regulates activity stabilization 9606 17581632 t lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit SIGNOR-269156 0.391 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates 9606 BTO:0000007 22863277 f inferred from 70% of family members milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. SIGNOR-269864 0.8 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity precursor of 9606 24786789 t miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. SIGNOR-266509 0.8 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser462 GSPHNPIsSVS 9606 9335504 t llicata The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. SIGNOR-52662 0.628 PRKAA1 protein Q13131 UNIPROT DNMT1 protein P26358 UNIPROT down-regulates activity phosphorylation Ser714 DNIPEMPsPKKMHQG -1 28143904 t lperfetto Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK decreased DNMT1 activity SIGNOR-264783 0.2 seliciclib chemical CHEBI:45307 ChEBI TP53 protein P04637 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206577 0.8 XRCC6 protein P12956 UNIPROT PRKDC protein P78527 UNIPROT up-regulates relocalization 9606 19133841 t gcesareni Ku and dna-pkcs only interact in the presence of dna and recruitment of dna-pkcs to sites of dna damage in vivo is ku-dependent. Inward translocation of ku allows dna-pkcs to interact with the extreme termini of the dna, allowing two dna-pkcs molecules to interact across the dsb in a so-called synaptic complex . This interaction stimulates the kinase activity of dna-pkcs, promoting phosphorylation in trans across the dsb (discussed in more detail below). Once assembled at the dna ends, the dna-pkcs-ku-dsb complex serves to tether the ends of the dsb together and protects the dna ends from nuclease attack. SIGNOR-183276 0.939 RNF7 protein Q9UBF6 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity ubiquitination 9606 23136067 t miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. SIGNOR-271447 0.334 N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine chemical CHEBI:92386 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258921 0.8 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser142 AVSDSLPsNSLKKSS 9606 BTO:0000671 12628002 t lperfetto Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149) SIGNOR-99135 0.691 LCK protein P06239 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 17998336 t gcesareni The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1. SIGNOR-159168 0.548 OTUB1 protein Q96FW1 UNIPROT UBE2N protein P61088 UNIPROT down-regulates binding 9606 21763684 t gcesareni The deubiquitinating enzyme otub1 suppresses rnf168 dependent ubiquitination by direct the e2 ligase ubc13 SIGNOR-175050 0.727 lysophosphatidic acid smallmolecule CHEBI:132742 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257530 0.8 PTP4A3 protein O75365 UNIPROT EZR protein P15311 UNIPROT down-regulates activity dephosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0001109 18078820 t Here we report the identification of Ezrin as a specific and direct cellular substrate of PRL-3. In HCT116 colon cancer cell line, Ezrin was identified among the cellular proteins whose phosphorylation level decreased upon ectopic over-expression of wtPRL-3 but not of catalytically inactive PRL-3 mutants. Although PRL-3 over-expression in HCT116 cells appeared to affect Ezrin phosphorylation status at both tyrosine residues and Thr567, suppression of the endogenous protein by RNA interference pointed to Ezrin-Thr567 as the residue primarily affected by PRL-3 action. SIGNOR-248342 0.28 CSNK2A1 protein P68400 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Thr714 EESDSSEtEKEDDEG -1 21296876 t miannu CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis SIGNOR-276250 0.2 POLD3 protein Q15054 UNIPROT DNA polymerase delta complex SIGNOR-C376 SIGNOR form complex binding -1 12403614 t lperfetto Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme. SIGNOR-265515 0.932 MAPK14 protein Q16539 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser389 ARIQAAAsTPTNATA 9606 BTO:0000142 17726008 t gcesareni However p38alfa also inactivates gsk3b by direct phosphorilation of the c-terminal residue ser389. this non-canonicl p38 mapk-dependent phosphorilation of gsk3b seems to occur primarily in the brain and thymocytes. SIGNOR-157548 0.294 FUS protein P35637 UNIPROT AGRN protein O00468 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 28515487 f This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease SIGNOR-262807 0.275 EP300 protein Q09472 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity acetylation 9606 22298955 t gcesareni Bmp-induced non-smad erk signaling pathway cooperatively regulates osteoblast differentiation, in part, through increasing the stability and transcriptional activity of runx2 or increasing runx2 acetylation by p300. SIGNOR-195579 0.464 MAPK1 protein P28482 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 18204439 t lperfetto Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation. SIGNOR-160411 0.71 WNK1 protein Q9H4A3 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates phosphorylation Thr991 SAYTYERtLMMEQRS 9606 BTO:0000938 BTO:0000142 19665974 t gcesareni We have attempted to identify kinases and phosphatases involved in the modulation of phosphorylation at kcc3 t991 and t1048. the wnk kinases and spak/osr1 are strong candidates for kcc3 regulatory kinases. SIGNOR-187564 0.465 Gbeta proteinfamily SIGNOR-PF4 SIGNOR TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation 9606 19237534 t inferred from 70% family members lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309. SIGNOR-270110 0.2 WNT7A protein O00755 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity 10090 BTO:0000887;BTO:0001103 9753670 f gcesareni Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5 SIGNOR-60471 0.354 D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI up-regulates quantity precursor of 9606 11724794 t miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion SIGNOR-266496 0.8 BRCA1 protein P38398 UNIPROT ACACA protein Q13085 UNIPROT down-regulates activity binding -1 phosphorylation: ser1263 FSDSPPQsPTFPEAG 16698035 t ACCA binds BRCA1 when phosphorylated onSer1263, thus supporting a model in which controlof lipid synthesis would be mediated at least in part,viaphosphorylation of the Ser1263. SIGNOR-267474 0.564 NFYB protein P25208 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15496512 f miannu Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter. SIGNOR-252233 0.2 ROCK1 protein Q13464 UNIPROT DPYSL2 protein Q16555 UNIPROT unknown phosphorylation Thr555 DNIPRRTtQRIVAPP 9534 10818093 t lperfetto We produced an antibody that specifically recognizes CRMP-2 phosphorylated at Thr-555. Using this antibody, we found that Rho-kinase phosphorylated CRMP-2 downstream of Rho in COS7 cells.  SIGNOR-249042 0.431 Immune complexes stimulus SIGNOR-ST15 SIGNOR FCGR2B protein P31994 UNIPROT up-regulates activity 9606 BTO:0000801 25475856 f lperfetto Low affinity-activating Fcgamma receptors (FcgammaRs) that bind immune complexes are controlled by a single inhibitory receptor, FcgammaRIIb (CD32b). SIGNOR-249522 0.7 TIMP3 protein P35625 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates activity 10090 BTO:0005300 28709001 f Hh signaling through FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis. A pharmacological mimetic of TIMP3 blocked the conversion of FAPs into adipocytes SIGNOR-255906 0.7 tRNA(Phe) smallmolecule CHEBI:29184 ChEBI Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates quantity precursor of 9606 20223217 t miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. SIGNOR-270443 0.8 seliciclib chemical CHEBI:45307 ChEBI CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206574 0.8 CNKSR2 protein Q8WXI2 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 14597674 t gcesareni We show cnk2 interacts with raf. cnk2 interacts with the gef domain of rlf and with both the regulatory and catalytic domains of raf. The raf interaction was also mapped to the carboxyl-terminal half of cnk2. Overexpression of cnk2 results in inhibition of the mapk signaling pathway. SIGNOR-119039 0.758 GSK3B protein P49841 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates quantity by destabilization phosphorylation Thr273 TTWTGSRtAPYTPNL 10090 BTO:0000944 25373906 t miannu In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region.  SIGNOR-276440 0.407 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269341 0.719 EPHB2 protein P29323 UNIPROT NRCAM protein Q92823 UNIPROT up-regulates activity phosphorylation Tyr1276 DGSFIGQySGKKEKE 9606 BTO:0000007 24023801 t miannu EphB receptors were found to induce phosphorylation of NrCAM on the tyrosine residue within the FIGQY ankyrin binding motif, inhibiting ankyrin recruitment. Furthermore, NrCAM phospho-FIGQY levels in the SC were decreased in EphB1/3 and EphB1/2/3 null mice and increased in mutant mice overexpressing constitutively active EphB2 kinase.  SIGNOR-262863 0.303 CTSS protein P25774 UNIPROT peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity chemical modification 9606 31810556 t scontino Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol. SIGNOR-267867 0.8 ALPL protein P05186 UNIPROT SPP1 protein P10451 UNIPROT down-regulates activity dephosphorylation 10090 23427088 t miannu This result suggests that endogenous mouse TNAP dephosphorylates OPN in osteoblasts and that overexpressed human TNAP dephosphorylates OPN, compensating for the lack of endogenous TNAP in [Col1a1-Tnap +/\u2212 ;Alpl \u2212/\u2212 ] cells. SIGNOR-277045 0.453 PRKACG protein P22612 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 t gcesareni Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no. SIGNOR-112375 0.2 SNTG1 protein Q9NSN8 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255994 0.462 NME1 protein P15531 UNIPROT KSR1 protein Q8IVT5 UNIPROT down-regulates phosphorylation Ser406 TRLRRTEsVPSDINN 9606 12105213 t gcesareni Autophosphorylated recombinant nm23-h1 phosphorylated ksr in vitro. Using site-directed mutagenesis, we found that nm23-h1 phosphorylated ksr serine 392, a 14-3-3-binding site, consistent with the recent identification of c-tak1 as a kinase for this site. SIGNOR-90390 0.559 RIPK3 protein Q9Y572 UNIPROT PYGL protein P06737 UNIPROT up-regulates binding 9606 19632174 t gcesareni Rip3 directly interacts with glycogen phosphorylase (pygl), glutamate ammonia ligase (glul), and glutamate dehydrogenase 1 (glud1). Rip kinase activity is required to enhance the activities of all three enzymes both in vivo and in vitro. SIGNOR-186939 0.505 HDAC1 protein Q13547 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity deacetylation 10090 BTO:0000887 24463822 t Through the use of various pharmacological inhibitors to block HDAC activity, we demonstrate that class I HDACs are key regulators of FoxO and the muscle-atrophy program during both nutrient deprivation and skeletal muscle disuse. SIGNOR-256485 0.376 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser257 PERPGILsPATSEAV 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262719 0.733 RNF168 protein Q8IYW5 UNIPROT BLM protein P54132 UNIPROT up-regulates activity ubiquitination 9606 BTO:0001938 23708797 t miannu Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of RAP80.  SIGNOR-272114 0.264 CSNK2A1 protein P68400 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser8 MPKRKVSsAEGAAKE 9606 10739259 t gcesareni Peptide mass and sequence analysis showed major and minor phosphorylation sites, respectively, at ser24 and ser28 in hmg-17, and ser20 and ser24 in hmg-14 a third phosphorylation site in hmg-14 was located at either ser6 or ser7phosphorylation of ser6 and ser7 may compromise the binding of hmgn1 protein to the binding domain of importin proteins, which in turn affects the nuclear transport and sub-cellular localization of hmgn1 protein. Protein kinase ck2 could potentially be an enzyme that regulates this process. SIGNOR-76270 0.2 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG 9606 7493944 t lperfetto Insulin and insulin-like growth factor (IGF-I) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26586 0.2 DUSP1 protein P28562 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates activity dephosphorylation Ser118 AELVRTDsPNFLCSV 9606 27031422 t miannu In a separate study, MKP-1 was shown to induce osteogenesis by dephosphorylating Ser125 on Runx2 isoform type II (37).|MKP-1 increases RUNX2 activity and downregulates MAPK, cyclin D1 in differentiated osteoblasts inducing growth arrest and mineralization. SIGNOR-277143 0.361 ATF4 protein P18848 UNIPROT NARS2 protein Q96I59 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269423 0.2 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI L-tyrosine zwitterion smallmolecule CHEBI:58315 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-267031 0.8 E2F4 protein Q16254 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12110166 f fspada We show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation SIGNOR-90507 0.472 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr694 DSPSDGGtPGRMPPQ 9606 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. SIGNOR-104707 0.844 STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation 9606 14976552 t lperfetto We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli SIGNOR-217472 0.595 NFIB protein O00712 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268881 0.2 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Thr24 TDESLEStRRILGLA 9606 12930825 t lperfetto Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion. SIGNOR-249229 0.335 IC-87114 chemical CHEBI:90686 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206187 0.8 CDH4 protein P55283 UNIPROT CDH15 protein P55291 UNIPROT down-regulates quantity by repression 10090 BTO:0000165 18701479 f lperfetto Taken together, these data show that (a) R-cadherin decreases the expression of M-cadherin and (b) N-cadherin and M-cadherin only slightly accumulate at the cell contacts in R-cadherin–expressing myoblasts. SIGNOR-253106 0.389 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 14711813 t llicata Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. taken together, the results suggest that phosphorylation of tyr981 is not obligatorily required for the catalytic activity but plays a supplementary role in initiating autophosphorylation of tyr905, which brings about the overall kinase activity. SIGNOR-121165 0.2 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG -1 11955436 t β-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC) SIGNOR-260016 0.856 PIAS4 protein Q8N2W9 UNIPROT STAT1 protein P42224 UNIPROT down-regulates binding 9606 11248056 t gcesareni First, piasy interacts with stat1 both in vitro and in vivo. The in vivo piasy__stat1 interaction is dependent on cytokine stimulation. Second, piasy can inhibit stat1-mediated gene activation without blocking the dna binding activity of stat1. SIGNOR-105723 0.543 KSR1 protein Q8IVT5 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 t miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. SIGNOR-273878 0.614 USP8 protein P40818 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000567 16120644 t irozzo Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells. SIGNOR-259103 0.699 PEX2 protein P28328 UNIPROT UBE2D2 protein P62837 UNIPROT up-regulates activity binding -1 19687296 t miannu Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. SIGNOR-253025 0.595 RBSN protein Q9H1K0 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 t lperfetto Rabenosyn-5 is another FYVE-domain-containing Rab5 effector that localizes to EE SIGNOR-260624 0.2 GSK3B protein P49841 UNIPROT MARK2 protein Q7KZI7 UNIPROT down-regulates activity phosphorylation Ser212 KLDTFCGsPPYAAPE -1 18424437 t miannu MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase. SIGNOR-276163 0.355 OAT protein P04181 UNIPROT proline smallmolecule CHEBI:26271 ChEBI up-regulates quantity chemical modification 9606 14617280 t miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256033 0.8 p62_complex complex SIGNOR-C259 SIGNOR Nuclear_pore_function phenotype SIGNOR-PH130 SIGNOR up-regulates 10116 2050741 f miannu Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function. SIGNOR-261261 0.7 FOXJ1 protein Q92949 UNIPROT TEKT1 protein Q969V4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 t miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). SIGNOR-266936 0.371 RALA protein P11233 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Thr451 PIPKALGtPVLTPPT 10090 11689711 t gcesareni We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT. SIGNOR-252984 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser457 RGRKRFVsEGDGGRL 9606 16357133 t gcesareni Our results show that akt specifically phosphorylates ser(67) and ser(457) residues of pdcd4 in vitro and in vivo. We further show that phosphorylation of pdcd4 by akt causes nuclear translocation of pdcd4. SIGNOR-143098 0.2 MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 17110930 t Barakat Upon TNFα stimulation, MEKK1, ASK1, and TAK1 phosphorylate and activate MKK7, which in turn activates JNK SIGNOR-274147 0.712 POU5F1 protein Q01860 UNIPROT DLX5 protein P56178 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254935 0.315 IFNGR1 protein P15260 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15864272 t gcesareni The only type ii ifn, ifn-g, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2 SIGNOR-135952 0.691 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser1893 PANLDSEsEHFFRCC 9606 21149446 t gcesareni In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible. SIGNOR-170465 0.2 RET protein P07949 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by destabilization phosphorylation Thr119 LLTTLDDtCDLFAPL 9606 BTO:0002181 25795775 t miannu We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA.  SIGNOR-276450 0.2 DAPK1 protein P53355 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates binding 9606 15616583 t gcesareni Conversely, dapk promotes the cytoplasmic retention of erk, thereby inhibiting erk signaling in the nucleus. SIGNOR-132610 0.551 furtrethonium chemical CHEBI:134764 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258642 0.8 APC-c complex SIGNOR-C150 SIGNOR CDC6 protein Q99741 UNIPROT up-regulates activity binding 9606 BTO:0000567 10995389 t miannu Furthermore, APC, in association with CDH1, ubiquitinates CDC6 in vitro, and both APC and CDH1 are required and limiting for CDC6 proteolysis in vivo. SIGNOR-271386 0.486 Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 10090 BTO:0001086 19279220 f miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270727 0.7 AKT1 protein P31749 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 18394876 t lperfetto The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity SIGNOR-252582 0.634 RARA protein P10276 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 f lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. SIGNOR-268548 0.256 FLT3 protein P36888 UNIPROT ZBTB16 protein Q05516 UNIPROT down-regulates activity 10090 BTO:0002181 14982881 f We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. SIGNOR-261537 0.319 POLR1H protein Q9P1U0 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16373708 f miannu ZNRD1 could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene but not alter the expression of MDR-associated protein, glutathione S-transferase activity, or intracellular glutathione content in leukemia cells. SIGNOR-259908 0.2 XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT down-regulates quantity by destabilization binding -1 12620238 t lperfetto This paper reports the crystal structure of caspase-9 in an inhibitory complex with the third baculoviral iap repeat (bir3) of xiap at 2.4 a resolution. X-linked inhibitor-of-apoptosis protein (xiap) interacts with caspase-9 and inhibits its activity. SIGNOR-98988 0.92 PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT up-regulates activity binding 9606 15688067 t miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257732 0.912 PRKDC protein P78527 UNIPROT MCC protein P23508 UNIPROT up-regulates activity phosphorylation Ser120 LRSELSQsQHEVNED 9606 BTO:0001109 21779472 t miannu MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity. SIGNOR-273531 0.2 YBX1 protein P67809 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001023 17072343 f miannu YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. SIGNOR-255614 0.391 p38 proteinfamily SIGNOR-PF16 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules SIGNOR-171062 0.2 glucose chemical CHEBI:17234 ChEBI PRKAA1 protein Q13131 UNIPROT down-regulates activity 10090 BTO:0000222 18477450 f Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK). SIGNOR-256136 0.8 nalbuphine chemical CHEBI:7454 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 9262330 t miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. SIGNOR-258658 0.8 RFX complex complex SIGNOR-C104 SIGNOR HLA-DRA protein P01903 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11889043 f Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment. SIGNOR-254009 0.424 SORT1 protein Q99523 UNIPROT APOE protein P02649 UNIPROT up-regulates quantity binding 10029 BTO:0000246 23283348 t miannu Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Sortilin interacts with all human APOE isoforms. SIGNOR-273721 0.438 NEK7 protein Q8TDX7 UNIPROT EML4 protein Q9HC35 UNIPROT up-regulates activity phosphorylation Ser146 PQIRASPsPQPSSQP -1 31409757 t done miannu The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser144 and Ser146 in vitro, and depletion of these kinases in cells led to increased EML4 binding to microtubules in mitosis. An S144A-S146A double mutant not only bound inappropriately to mitotic microtubules but also increased their stability and interfered with chromosome congression. In addition, constitutive activation of NEK6 or NEK7 reduced the association of EML4 with interphase microtubules. Together, these data support a model in which NEK6- and NEK7-dependent phosphorylation promotes the dissociation of EML4 from microtubules in mitosis in a manner that is required for efficient chromosome congression. SIGNOR-273884 0.277 CSNK2A1 protein P68400 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000527 19941816 t miannu We demonstrate here that egfr activation results in disruption of the complex of beta-catenin and alpha-catenin, thereby abrogating the inhibitory effect of alpha-catenin on beta-catenin transactivation via ck2alpha-dependent phosphorylation of alpha-catenin at s641. SIGNOR-265822 0.399 CHFR protein Q96EP1 UNIPROT AURKA protein O14965 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 17442268 t miannu Chfr, a mitotic stress checkpoint, plays an important role in cell cycle progression, tumor suppression and the processes that require the E3 ubiquitin ligase activity mediated by the RING finger domain. Chfr stimulates the formation of polyubiquitin chains by ub-conjugating enzymes, and induces the proteasome-dependent degradation of a number of cellular proteins including Plk1 and Aurora A. SIGNOR-271463 0.483 PITX3 protein O75364 UNIPROT MTA1 protein Q13330 UNIPROT up-regulates activity binding 9606 BTO:0000567 SIGNOR-C123 21368136 t 1 miannu we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3. SIGNOR-239770 0.33 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000667 15866158 t Induction of the p21WAF1/Cip1 gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-J_ protein to the p21 promoter. SIGNOR-252033 0.345 NFATC3 protein Q12968 UNIPROT TFF1 protein P04155 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16219765 f miannu Overexpression of NFAT3 enhanced both ERalpha and ERbeta transcriptional activities in a ligand-independent manner and up-regulated downstream estrogen-responsive genes including pS2 and cathepsin D. Reduction of endogenous NFAT3 with NFAT3 small interfering RNA or overexpression of NFAT3 deletion mutants that lack the ER-binding sites reduced the NFAT3 coactivation of ERalpha and ERbeta. SIGNOR-254639 0.2 PTPRK protein Q15262 UNIPROT PROM1 protein O43490 UNIPROT down-regulates activity dephosphorylation -1 30947381 t miannu PTPRK dephosphorylates CD133, which is a stem cell marker; phosphorylated CD133 accelerates xenograft tumor growth of colon cancer cells through the activation of AKT, but the functional significance of this has remained elusive.|Together, these observations suggest that PTPRK suppresses CD133\u2010mediated colon cancer growth both in\u00a0vitro and in\u00a0vivo. SIGNOR-277133 0.2 SUGT1 protein Q9Y2Z0 UNIPROT MIS12 complex complex SIGNOR-C362 SIGNOR up-regulates activity binding 9606 BTO:0000567 22869522 t lperfetto Here we identify Sgt1, a cochaperone for Hsp90, as a novel Plk1 substrate during mitosis|This phosphorylation event enhances the association of the Hsp90-Sgt1 chaperone with the MIS12 complex to stabilize this complex at the kinetochores and thus coordinates the recruitment of the NDC80 complex to form efficient microtubule-binding sites. SIGNOR-265223 0.307 progesterone smallmolecule CHEBI:17026 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258705 0.8 Laminin-1 complex SIGNOR-C183 SIGNOR A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 9361014 t lperfetto Using integrin-specific antibodies, recognition sites for the alpha1beta1 and alpha2beta1 integrins were identified in the short arms of both laminin alpha1- and alpha2-chain isoforms. Comparisons with a beta-alpha chimeric short arm protein possessing beta1-chain domain VI further localized these activities to alpha-chain domain VI. SIGNOR-253254 0.539 SYK protein P43405 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates phosphorylation Ser361 LAEGTPRsNHSAQDS 9606 BTO:0001271 23071339 t miannu Syk phoshorylatesikarosat unique c-terminal serine phosphorylation sites s358 and s361, thereby augmenting its nuclear localization and sequence-specific dna binding activity. Mechanistically, we establish that syk-inducedikarosactivation is essential for its nuclear localization and optimal transcription factor function. SIGNOR-199096 0.413 dasatinib (anhydrous) chemical CHEBI:49375 ChEBI SRC protein P12931 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258103 0.8 FOXO proteinfamily SIGNOR-PF27 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT down-regulates 9606 20577053 f gcesareni Foxo1 antagonized ppargamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner. SIGNOR-252916 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR CELF1 protein Q92879 UNIPROT up-regulates activity phosphorylation Ser28 GQVPRTWsEKDLREL 10090 BTO:0000165 18570922 t miannu CUG repeat binding protein, CUGBP1, is a key regulator of translation of proteins that are involved in muscle development and differentiation. In normal myoblasts, Akt kinase phosphorylates CUGBP1 at Ser28 and increases interactions of CUGBP1 with cyclin D1 mRNA. SIGNOR-262615 0.2 FYN protein P06241 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates phosphorylation Tyr1495 TEEQKKYyNAMKKLG 9606 15831816 t llicata This study addresses the effects of the src family tyrosine kinase fyn on na(v)1.5 cardiac sodium channels. Sodium currents were acquired by whole cell recording on hek-293 cells transiently expressing na(v)1.5. Acute treatment of cells with insulin caused a depolarizing shift in steady-state inactivation, an effect eliminated by the src-specific tyrosine kinase inhibitor pp2 we provide evidence that this linker is a substrate for fyn in vitro, and that y1495 is a preferred phosphorylation site. SIGNOR-135600 0.297 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR SUDS3 protein Q9H7L9 UNIPROT up-regulates activity phosphorylation Ser228 RTLNKLKsPKRPASP 9606 BTO:0000007 15489224 t miannu Cdk5/p35 phosphorylates mSds3 and regulates mSds3-mediated repression of transcription. the dimerization of the phosphorylation-deficient mutant of mSds3 (S228A) was not greatly enhanced by p35 when compared with wild type (Fig. 5D). This finding suggests that the phosphorylation of mSds3 by active Cdk5 increases the homodimerization potential of mSds3. SIGNOR-262739 0.285 LRFN4 protein Q6PJG9 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments. SIGNOR-264097 0.7 R547 chemical CID:6918852 PUBCHEM CCND1 protein P24385 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206352 0.8 GSK3B protein P49841 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation Ser302 APGSGPSsPNNSSGS 9606 21118993 t lperfetto The double mutation of serines 298/302 into alanines, but also the sole mutation of serine 302, abolishes hdac4 phosphorylation by gsk3_we have shown that cells lacking gsk3_ are unable to degrade hdac4 after serum starvation SIGNOR-170148 0.371 EEF2K protein O00418 UNIPROT EEF2 protein P13639 UNIPROT down-regulates phosphorylation Thr59 GETRFTDtRKDEQER 9606 8386634 t gcesareni Ef-2 kinase phosphorylates ef-2 at 3 threonine residues: thr-53, thr-56, thr-58. Phosphorylation of thr56 and thr58 was found to be an ordered process, modification of thr56 preceding, and apparently being required for, phosphorylation of thr58. SIGNOR-38556 0.78 glutamine smallmolecule CHEBI:28300 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264751 0.7 MECP2 protein P51608 UNIPROT CREB1 protein P16220 UNIPROT up-regulates quantity by expression post transcriptional regulation 10090 BTO:0000614 18511691 t Luana Interestingly, Creb1 was one of the activated MeCP2 targets that we validated by quantitative real-time RT-PCR (Fig. 1C), and using ChIP analysis we found that in vivo MeCP2 binds to the promoter region of Creb1, with significantly enhanced binding in MECP2-Tg samples compared to WT (p < 0.05) | In addition, Sst and CREB1 protein levels were increased in MECP2-Tg hypothalami compared to WT, indicating that MeCP2 indeed enhances expression of Sst and Creb1 SIGNOR-264682 0.547 Diisodecyl phthalate chemical CHEBI:34709 ChEBI SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression 10116 16257484 f miannu DIDP, BBP and DOP stimulate NIS mRNA expression. Here, hNIS promoter construct (N3) was up-regulated 2.5-fold by DIDP, 2.6-fold by BBP and 2.4-fold by DOP in the presence of TSH. Likewise, these phthalates also enhanced rNIS endogenous mRNA expression, which increased ca. 2-fold after 48 h of treatment compared with the expression level generated by TSH only. At 72 h, mRNA content was unchanged. SIGNOR-268742 0.8 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 15350223 t gcesareni Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp. SIGNOR-128643 0.627 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000011 8754811 f ggiuliani Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. The dose of DEX required to promote maximal expression of PPARg mRNA is approximately 10 nM, which is within the range of the Kd for the association of DEX with the glucocorticoid receptor in 3T3-L1 cells. SIGNOR-255963 0.401 PYGM protein P11217 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI down-regulates quantity chemical modification 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267948 0.8 CEBPB protein P17676 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 16319681 f lperfetto The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder. SIGNOR-250572 0.7 MAPK8 protein P45983 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 20220133 t gcesareni Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset. SIGNOR-164089 0.421 ADCY6 protein O43306 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 t miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. SIGNOR-265001 0.8 DIABLO protein Q9NR28 UNIPROT BIRC3 protein Q13489 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000891 10929712 t amattioni Diablo may promote apoptosis by binding to iaps and preventing them from inhibiting caspases. SIGNOR-80225 0.784 MAPKAPK5 protein Q8IW41 UNIPROT DNAJB1 protein P25685 UNIPROT up-regulates phosphorylation Ser149 TNVNFGRsRSAQEPA 9606 24309468 t lperfetto Phosphorylation of heat shock protein 40 (hsp40/dnajb1) by mitogen-activated protein kinase-activated protein kinase 5 (mk5/prak). Mk5 phosphorylates hsp40/dnajb1 in vivo at ser-149 or/and ser-151 and ser-171 in the c-terminal domain of hsp40/dnajb1. Mk5 modestly stimulates the atp hydrolyse activity of hsp40/hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by hsp40/dnajb1. SIGNOR-203456 0.44 MAP2K6 protein P52564 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates activity phosphorylation Ser721 PSDLLPMsPSVYAVL 10090 BTO:0000944 10961885 t MKK6, phosphorylate STAT4 on serine 721. IL-12 induces STAT4 phosphorylation on serine 721 and that mutation of serine 721 interferes with STAT4 transcriptional activity. SIGNOR-251425 0.348 eIF4F_complex complex SIGNOR-C44 SIGNOR Translational_regulation phenotype SIGNOR-PH202 SIGNOR up-regulates 9606 30459806 f gianni The mRNA cap-binding protein, eukaryotic translation initiation factor 4E (eIF4E), is involved in the recruitment of the ribosome to the mRNA cap structure, playing a central role in the regulation of translation initiation SIGNOR-268530 0.7 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser432 KMPNTNGsIGHSPLS 9606 BTO:0000938 24614225 t lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204696 0.524 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser66 GVYATRSsAVRLRSS -1 11895474 t miannu In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK.  SIGNOR-250241 0.312 SRC protein P12931 UNIPROT TGFA protein P01135 UNIPROT up-regulates cleavage 9606 17251915 t lperfetto Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network. SIGNOR-235888 0.305 AMPK complex SIGNOR-C15 SIGNOR CCNY protein Q8ND76 UNIPROT up-regulates activity phosphorylation Ser326 SARKRSAsADNLTLP 9606 32723157 t lperfetto Our in vitro and cellular analyses supported the mass spectrometry data that implicated serine 326 (S326) as the phospho-acceptor site on CCNY by AMPK. |Mechanistically the S326 phosphorylation by AMPK promotes the interaction of CCNY with CDK16, which in turn autophosphorylates S336, which serves as a marker for active CCNY-CDK16 SIGNOR-273001 0.2 ponatinib chemical CHEBI:78543 ChEBI FGFR2 protein P21802 UNIPROT down-regulates activity chemical inhibition 9606 23468082 t miannu Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family. SIGNOR-259278 0.8 KIT protein P10721 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr703 DHAEAALyKNLLHSK 10377264 t gcesareni We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936. SIGNOR-248283 0.635 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 BTO:0000887;BTO:0001260 14593115 t gcesareni We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription. SIGNOR-248066 0.639 HDAC1 protein Q13547 UNIPROT Sin3B_complex complex SIGNOR-C409 SIGNOR form complex binding 9606 BTO:0000007 21041482 t miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. SIGNOR-266968 0.788 AKT proteinfamily SIGNOR-PF24 SIGNOR INSIG2 protein Q9Y5U4 UNIPROT down-regulates quantity by repression 10090 21723501 f miannu MTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2. SIGNOR-256211 0.2 SREBF1 protein P36956 UNIPROT ELOVL6 protein Q9H5J4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 18226595 t Luana These data demonstrated that Elovl-6 is regulated directly and primarily by SREBP-1c. SIGNOR-267943 0.462 CAMK2A protein Q9UQM7 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 BTO:0000590 10090741 t lperfetto We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II. SIGNOR-249315 0.579 ABL1 protein P00519 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Tyr78 RAIDFSPyLEPLGAP 9606 BTO:0000007 19563810 t gcesareni The y79 amino acid residue of c/ebpbeta was phosphorylated by c-abl or arg. The phosphorylation of c/ebpbeta resulted in an increased c/ebpbeta stability and a potentiation of c/ebpbeta transcription activation activity in cells SIGNOR-186423 0.408 PTH protein P01270 UNIPROT PTH2R protein P49190 UNIPROT up-regulates binding 9606 BTO:0000142;BTO:0000671 11861531 t gcesareni Pth was shown to efficiently activate the human type 2 pth receptor (pth2 receptor) SIGNOR-115104 0.688 AP1 complex SIGNOR-C154 SIGNOR NFATC1 protein O95644 UNIPROT up-regulates activity binding 9606 BTO:0000782 15928679 t Activator protein 1 (AP1) proteins are the main transcriptional partners of NFAT during T-cell activation SIGNOR-253004 0.648 CDK1 protein P06493 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser301 IQSNLDFsPVNSASS 9606 21765472 t lperfetto Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency SIGNOR-175075 0.419 AMER1 protein Q5JTC6 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000038 21498506 t lperfetto We show that Amer1 binds directly to beta-catenin via a novel interaction motif, the REA repeats. This amino acid motif, including the core sequence arginine, glutamic acid and alanine, and this REA repeats mediate binding of Amer1 to the armadillo repeats of beta-catenin. The data suggest that Amer1 exerts its negative regulatory role in Wnt signaling by acting as a scaffold protein for the beta-catenin destruction complex and promoting stabilization of Axin at the plasma membrane. SIGNOR-217950 0.768 PPARG protein P37231 UNIPROT JUN protein P05412 UNIPROT up-regulates activity 9606 BTO:0000801 17681149 f lperfetto Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways SIGNOR-249558 0.571 RAB6B protein Q9NRW1 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9534 20360680 f miannu We show that BICDR-1 interacts with the dynein/dynactin motor complex, binds to kinesin-3 motor protein Kif1C and controls the pericentrosomal localization of Rab6-positive secretory vesicles. SIGNOR-266881 0.7 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr112 PGQIVETyTEEDPEG -1 11382764 t lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 SIGNOR-246480 0.92 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 t miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. SIGNOR-264921 0.8 SMARCD1 protein Q96GM5 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269822 0.788 NEK6 protein Q9HC98 UNIPROT NUP98 protein P52948 UNIPROT down-regulates activity phosphorylation Ser839 TSRCLIKsPDRLADI -1 21335236 t done miannu To elucidate which of the identified sites can be targeted by CDK1/cyclin B1 and Nek6 in vitro (Figure S1D), we performed phosphorylation reactions using recombinant kinases and unlabeled ATP followed by phosphopeptide mapping (Table S1). MS analysis confirmed phosphorylation of S591 and S822 by Nek6 as well as phosphorylation of T529, T536, S595, S606, and T653 by CDK1. Phosphomimetic Mutants of Nup98 Show Defects in NPC Localization SIGNOR-273893 0.32 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1619 SPSYSPTsPSYSPTS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248768 0.442 JUN protein P05412 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 12553907 f In contrast, c-Jun is required for the survival of liver tumor cells. Reduced tumor formation strictly correlated with high apoptotic indices in c-Jun-deficient tumors, suggesting that increased apoptosis in c-Jun-deficient liver tumors is the primary cause for impaired tumorigenesis. SIGNOR-256560 0.7 OXSR1 protein O95747 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity phosphorylation Thr84 LPSDFEHtIHVGFDA 9606 BTO:0000567 14707132 t miannu OSR1 phosphorylated threonine 84 in the N-terminal regulatory domain of PAK1. phosphorylation of PAK1 by OSR1 desensitizes PAK1 to activation by small G proteins, providing a modulatory input to PAK1 activity. SIGNOR-250210 0.39 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr826 LPTPTKMtPRSRILV 9606 9139732 t lperfetto We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein. SIGNOR-216957 0.858 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258290 0.8 MMP9 protein P14780 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates cleavage 9606 10652271 t gcesareni We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-_ (tgf-_), which constitutes a novel mechanism of tgf-_ activation. SIGNOR-74461 0.61 FGF14 protein Q92915 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253429 0.383 MRPS30 protein Q9NP92 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262342 0.704 alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity precursor of 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-266577 0.8 LRP6 protein O75581 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity relocalization 9606 18632848 t amattioni The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism. SIGNOR-179469 0.829 NMUR2 protein Q9GZQ4 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256874 0.41 58131-57-0 chemical CID:42640 PUBCHEM MDM4 protein O15151 UNIPROT down-regulates activity chemical inhibition -1 21075910 t miannu Here we report the identification of a benzofuroxan derivative [7-(4-methylpiperazin-1-yl)-4-nitro-1-oxido-2,1,3-benzoxadiazol-1-ium, NSC207895] that could inhibit MDMX expression in cancer cells through a reporter-based drug screening. SIGNOR-262246 0.8 MUTYH protein Q9UIF7 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates binding 9606 BTO:0000007 21615992 t miannu Binding of myh directly participates in atr and topbp1 activation in dna damage signaling, leading to apoptosis. SIGNOR-173972 0.381 MIB1 protein Q86YT6 UNIPROT DAPK1 protein P53355 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 12351649 t miannu Transient expression of DIP-1 in HeLa cells antagonizes the anti-apoptotic function of DAPK to promote a caspase-dependent apoptosis. These studies also demonstrate that DAPK is an in vitro and in vivo target for ubiquitination by DIP-1, thereby providing a mechanism by which DAPK activities can be regulated through proteasomal degradation. SIGNOR-272602 0.448 HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 9020159 t lperfetto We have examined whether the other two members of the Raf family, A-Raf and B-Raf, are regulated in a similar way to Raf-1. A-Raf behaves like Raf-1, being weakly activated by oncogenic Ras more strongly activated by oncogenic Src, and these signals synergize to give maximal activation. B-Raf by contrast is strongly activated by oncogenic Ras alone and is not activated by oncogenic Src. SIGNOR-235786 0.934 CSNK2A1 protein P68400 UNIPROT CBX5 protein P45973 UNIPROT up-regulates phosphorylation Ser13 KRTADSSsSEDEEEY 9606 21245376 t gcesareni Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability. SIGNOR-171703 0.354 VKORC1 protein Q9BQB6 UNIPROT vitamin K epoxide smallmolecule CHEBI:28371 ChEBI down-regulates quantity chemical modification 9606 31226734 t lperfetto The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form SIGNOR-265900 0.8 HRH2 protein P25021 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257162 0.252 SCN5A protein Q14524 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 t miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. SIGNOR-253401 0.8 ARFGAP1 protein Q8N6T3 UNIPROT ARF1 protein P84077 UNIPROT up-regulates activity gtpase-activating protein -1 10102276 t The ARFGAP molecule binds to switch 2 and helix α3 to orient ARF1 residues for catalysis, but it supplies neither arginine nor other amino acid side chains to the GTPase active site. SIGNOR-261915 0.858 BAZ2B protein Q9UIF8 UNIPROT H3-2 protein Q5TEC6 UNIPROT down-regulates activity binding 9606 acetylation:Lys15 ARKSTGGkAPRKQLA 31999386 t miannu The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation. SIGNOR-266618 0.2 SP1 protein P08047 UNIPROT POR protein P16435 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0004428 8660656 f miannu Regulation of the NADPH-cytochrome P-450 oxidoreductase gene is controlled by both positive and negative regulatory elements, and, of the nine Sp1 consensus sites, the two proximal sites are sufficient to support basal transcription. SIGNOR-255213 0.2 8-(4-dibenzothiophenyl)-2-(4-morpholinyl)-1-benzopyran-4-one chemical CHEBI:91361 ChEBI PRKDC protein P78527 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194865 0.8 PCSK5 protein Q92824 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270334 0.2 RORC protein P51449 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24737872 t miannu As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression. SIGNOR-268004 0.516 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Thr273 SPSVHPAtPISPGRA 9606 BTO:0002181 16046550 t The effect has been demonstrated using Q01196-8 gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-138940 0.2 HSPA1B protein P0DMV9 UNIPROT PACRG protein Q96M98 UNIPROT up-regulates quantity by stabilization binding -1 12150907 t miannu Our in vitro data suggest that CHIP competes with Hsp70 in binding to Parkin, probably via suppression of the ATPase activity of Hsc/Hsp70 (Figure 4E).In fact, it acts as an inhibitory factor that suppresses the ubiquitination of Pael-R mediated by Parkin in vitro, and Hsp70 enhances the efficiency of folding of overexpressed Pael-R in vivo. SIGNOR-272891 0.2 MAPK3 protein P27361 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by destabilization phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 11733495 t gcesareni Moreover, the inhibition of erks 1 and 2 with a mek inhibitor, u1026, lead to an inhibition in the decay of ppargamma proteins, indicating that serine phosphorylation influences the degradation of ppargamma in fat cells. SIGNOR-179404 0.407 MSX2 protein P35548 UNIPROT SPEN protein Q96T58 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000661 19835636 t gcesareni Furthermore, in addition to msx2, both tlx1 and nkx2-5 proteins interacted with notch-pathway repressors, spen/mint/sharp and tle1/grg1, representing a potential mechanism for (de)regulation. SIGNOR-188572 0.494 F2RL1 protein P55085 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257300 0.381 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-141416 0.2 RELA protein Q04206 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates binding 9606 15988006 t gcesareni P65 and histone deacetylases 4 cooperate to inhibit the ability of mef2 factors to induce the klf2 promoter SIGNOR-138368 0.321 MERTK protein Q12866 UNIPROT MERTK protein Q12866 UNIPROT up-regulates phosphorylation Tyr754 KIYSGDYyRQGRIAK 9606 8702477 t gcesareni By using a vaccinia virus expression system to express a constitutively activated form of nyk, we identified the major sites of nyk autophosphorylation in tryptic peptide iy749sgdy753y754r. Tyr-749, tyr-753, and tyr-754 in this peptide lie in the activation loop of the kinase domain. SIGNOR-42922 0.2 clozapine chemical CHEBI:3766 ChEBI HTR1E protein P28566 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258514 0.8 MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000298 8974401 t lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-236110 0.741 KIF1A protein Q12756 UNIPROT Dense-core_vesicle_exocytosis phenotype SIGNOR-PH184 SIGNOR up-regulates 10116 30021165 f miannu To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. In contrast, liprin-α and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines SIGNOR-266893 0.7 MAPK14 protein Q16539 UNIPROT ATF6 protein P18850 UNIPROT up-regulates activity phosphorylation Thr166 NKTENGLtPKKKIQV 10090 BTO:0002572 25135476 t miannu This observation not only confirms the specific role for IFN-γ-induced p38 MAPK-dependent phosphorylation of ATF6 at the T166 site but also indicates a connection between phosphorylation and proteolytic activation. SIGNOR-276841 0.567 UBE2D2 protein P62837 UNIPROT UBR5 protein O95071 UNIPROT up-regulates activity ubiquitination -1 11714696 t miannu Using an in vitro reconstitution, specific E2 (ubiquitin-conjugating) enzymes (human UbcH4, UbcH5B, and UbcH5C) transferred ubiquitin molecules to hHYD, leading to the ubiquitination of TopBP1. TopBP1 was usually ubiquitinated and degraded by the proteosome, whereas X-irradiation diminished the ubiquitination of TopBP1 probably via the phosphorylation, resulting in the stable colocalization of up-regulated TopBP1 with gamma-H2AX nuclear foci in DNA breaks. SIGNOR-272668 0.522 CDK2 protein P24941 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 SIGNOR-C83 24173284 t lperfetto The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A SIGNOR-119379 0.867 domperidone chemical CHEBI:31515 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258380 0.8 PRKCD protein Q05655 UNIPROT NR2F6 protein P10588 UNIPROT down-regulates phosphorylation Ser83 CKSFFKRsIRRNLSY 9606 BTO:0000782 18701084 t esanto Ser-83 on recombinant nr2f6is a pkc substrate site;mutation of ser-83 (but not ser-89) to alanine strongly reduced pkc-mediated nr2f6 phosphorylation, confirming ser-83 as the major pkc phosphorylation site in nr2f6;the dna-binding capacity of nr2f6 is antagonized by a (p)ser-83 switch on nr2f6. SIGNOR-180017 0.2 HDAC1 protein Q13547 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates deacetylation Lys380 PTESSMYkYPSDISY 9606 24058639 t miannu Hdac1 interacts with fli1 and mediates its deacetylation / our previous studies have shown that pcaf-dependent acetylation of fli1 at lysine 380 decreases its protein stability / p300 promotes the interaction of fli1 with hdac1 and increases the dna binding ability of fli1 through deacetylation of lysine 380 SIGNOR-202689 0.2 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser682 SMNASRLsQPGQLMS 9606 BTO:0000007 10195894 t Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. SIGNOR-251278 0.2 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 10490659 t JNK bound to an NH2-terminal reagion of JIP1 (residues 283 to 660). gcesareni These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins. SIGNOR-70851 0.879 CACNA1G protein O43497 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 10090 33393208 t miannu Adult hippocampal neurogenesis plays an important role in neuronal plasticity and maintenance in mammals. Low-threshold voltage-gated T-type calcium channels produce calcium spikes that increase fast action potentials in newborn cells in the hippocampal dentate gyrus (DG) SIGNOR-264032 0.8 PPP2R5C protein Q13362 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates binding 9606 16456541 t gcesareni B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk SIGNOR-144325 0.492 EPHB1 protein P54762 UNIPROT CASKIN1 protein Q8WXD9 UNIPROT up-regulates activity phosphorylation Tyr296 TKDYCNNyDLTSLNV 9534 BTO:0000298 23181695 t miannu EphB1 phosphorylates Caskin1 on tyrosine 296 and 336. Tyrosine phosphorylated Caskin1 then likely promotes reorganization of the actin cytoskeleton leading to spine formation. SIGNOR-262860 0.287 TWIST2 protein Q8WVJ9 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 21931630 f miannu Using human MSCs, we discovered TWIST, a downstream target of HIF-1α, was induced under hypoxia and acted as a transcription repressor of RUNX2 through binding to the E-box located on the promoter of type 1 RUNX2. SIGNOR-255592 0.483 CDK2 protein P24941 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser13 ESFTMASsPAQRRRG 9606 16446360 t gcesareni In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2 SIGNOR-144000 0.724 PPP1R1B protein Q9UD71 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR down-regulates activity binding 9606 BTO:0000938 10604473 t miannu We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism. SIGNOR-265087 0.485 PDE4DIP protein Q5VU43 UNIPROT PRKAR2A protein P13861 UNIPROT up-regulates binding 9606 21569246 t miannu Mmgl acts as a dual-specific akap by anchoring pka regulatory isoforms r1a and r2a. SIGNOR-173831 0.465 VKORC1L1 protein Q8N0U8 UNIPROT vitamin K epoxide smallmolecule CHEBI:28371 ChEBI down-regulates quantity chemical modification 9606 31226734 t lperfetto This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR) SIGNOR-265906 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 t The effect has been demonstrated using Q01196-8 lperfetto We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-244711 0.2 S100A9 protein P06702 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 10090 BTO:0004730 18809714 f miannu We report here that up-regulation of S100A9 in myeloid precursors in cancer inhibits DC and macrophage differentiation and induces accumulation of MDSCs. This may represent a universal molecular mechanism of tumor-induced abnormalities in myeloid cells in cancer, directly linking inflammation and immune suppression. SIGNOR-261932 0.7 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 6958488 t nasal polyposys gcesareni SIGNOR-251688 0.8 PRKD1 protein Q15139 UNIPROT KCNH2 protein Q12809 UNIPROT down-regulates activity phosphorylation Ser284 ASVRRASsADDIEAM 9606 BTO:0000007 29949809 t miannu Based on LC-MS results from in vivo and HEK293 cell experiments we chose four KV11.1 mutant candidates for further functional analysis. Ablation of the putative PKD phosphorylation site in the mutant S284A increased the maximal current indicating S284 as a main PKD target in KV11.1. SIGNOR-277612 0.2 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Thr1394 SQSDILTtQQRDTMQ 9606 BTO:0002181 11114888 t llicata Although no single mutation eliminated the GST–BRCA1 (1314–1863) electrophoretic mobility shift, a quadruple mutant (GST–BRCA14A) containing Ala substitutions at Ser 1387, Thr 1394, Ser 1423, and Ser 1457 showed no alteration in electrophoretic mobility after phosphorylation by ATR-containing immune complexes (Fig.2D). The total incorporation of 32Pi into the GST–BRCA14Asubstrate was reduced by 70% relative to that obtained with wild-type GST–BRCA1 (1314–1863), suggesting that these four residues account for most, but not all of the phosphorylation sites in this fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication. SIGNOR-250583 0.793 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267125 0.8 GNAS protein P63092 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 22179044 t gcesareni Notably, the fzd7 receptor complex was associated with g_?(s) and pi(3)k and these components were required for wnt7a to activate the akt/mtor growth pathway in myotubes. These data led us to hypothesize that g_?s Mediates the activation of pi3kinase following wnt7a binding to fzd7. SIGNOR-191561 0.299 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 18394876 t lperfetto The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity SIGNOR-66032 0.2 MAPK1 protein P28482 UNIPROT MITF protein O75030 UNIPROT down-regulates phosphorylation Ser180 PGSSAPNsPMAMLTL 9606 10673502 t The effect has been demonstrated using O75030-9 gcesareni The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation. SIGNOR-75030 0.693 ACOT8 protein O14734 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271809 0.8 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 9606 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89205 0.55 PPP1CA protein P62136 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity dephosphorylation 9606 29335436 t miannu To address whether PP1\u03b1 activates B-Raf through these inhibitory sites, we made use of B-Raf protein mutants in which an individual inhibitory site, as well as all four sites (4A), were mutated to alanine.|We confirmed that GST-B-Raf was phosphorylated by ERK2 in vitro  xref  , mainly on S151 and T753 (Fig.\u00a0 xref ), and found that PP1\u03b1 dephosphorylated B-Raf on both ERK phosphorylation sites (Fig.\u00a0 xref ). SIGNOR-277160 0.299 CSNK1A1 protein P48729 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates activity binding 9606 22083140 t lperfetto In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)] SIGNOR-227967 0.658 NPTX1 protein Q15818 UNIPROT GRIA1 protein P42261 UNIPROT up-regulates activity binding 10090 BTO:0000938 15115814 t lperfetto We found that NP1 colocalizes and physically associates with the fast excitatory GluR1 AMPA receptors and that hypoxia induces a time-dependent increase in the NP1-GluR1 interactions. Thus hypoxia recruits NP1 protein to GluR1 subunits concurrent with the hypoxic excitotoxic cascade.|Rather we propose that through interactions with GluR1 clusters, NP1 modulates the function of AMPA receptors in a manner whereby increased NP1-GluR1 interactions sensitize neurons to hypoxia-induced excitotoxic death. SIGNOR-261430 0.3 GALR2 protein O43603 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257020 0.409 BAK1 protein Q16611 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates 9606 21210296 f gcesareni Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c, (diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore. SIGNOR-170966 0.3 CSNK2A1 protein P68400 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Ser263 PEIEDVGsDEEEEKK 9606 BTO:0000567 2492519 t llicata Both hsp 90 proteins are phosphorylated at two homologous sites. For the alpha protein, these sites correspond to serine 231 and serine 263. | Dephosphorylated hsp 90 is phosphorylated at both sites by casein kinase II from HeLa cells, calf thymus, or rabbit reticulocytes; no other hsp 90 residues were phosphorylated by casein kinase II in vitro. SIGNOR-250900 0.546 ESRRA protein P11474 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000154 15955695 f miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. SIGNOR-253794 0.357 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr632 GRKGSGDyMPMSPKS 9606 17827393 t gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157746 0.864 RPS6KA5 protein O75582 UNIPROT H2AW protein Q7L7L0 UNIPROT up-regulates activity phosphorylation Ser2 sGRGKQGG -1 15010469 t miannu We found that MSK1 phosphorylated histone H2A on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by MSK1. Furthermore, we found that acetylation of histone H3 by the p300 and CREB-binding protein associated factor, PCAF, suppressed the kinase-dependent inhibition of transcription. These results suggest that acetylation of histones may stimulate transcription by suppressing an inhibitory phosphorylation by a kinase as MSK1. SIGNOR-262942 0.2 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 BTO:0000887 11940578 t gcesareni Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. SIGNOR-116489 0.601 CREBBP protein Q92793 UNIPROT FBL protein P22087 UNIPROT down-regulates activity acetylation Lys102 GVFICRGkEDALVTK 30540930 t lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) SIGNOR-275898 0.273 FCER1 complex SIGNOR-C200 SIGNOR SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates 9606 BTO:0000830 16470226 f Alessandro Palma It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits SIGNOR-254957 0.593 MAPK3 protein P27361 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation 9606 9792677 t lperfetto Rsk-b is a p38alphamapk substrate, and activated by p38alphamapk and, more weakly, by erk1 SIGNOR-60998 0.568 F2RL1 protein P55085 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257408 0.433 SUZ12 protein Q15022 UNIPROT TWIST1 protein Q15672 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001939 23836662 f miannu We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. SIGNOR-254155 0.282 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000132 21592956 t lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. SIGNOR-251983 0.634 NSF protein P46459 UNIPROT SNAP25 protein P60880 UNIPROT down-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 16679567 t miannu NSF is an important regulator of SNARE assembly/disassembly. NSF binds to SNAP-25, while in complex with other SNAREs, and hydrolyzes adenosine triphosphate to disassemble the SNARE complex down to monomers SIGNOR-263974 0.746 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. SIGNOR-75938 0.366 SH2B3 protein Q9UQQ2 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity binding 10090 BTO:0002882 18618018 t miannu we identified Lnk as a physiological negative regulator of JAK2 in stem cells and TPO/Mpl/JAK2/Lnk as a major regulatory pathway in controlling stem cell self-renewal and quiescence. we identify a direct interaction between Lnk and the Mpl/JAK2 complex that regulates various HSC functions. SIGNOR-260075 0.629 Nalmefene chemical CHEBI:7457 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258810 0.8 NAIP protein Q13075 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 BTO:0000938 15280366 t gcesareni These results demonstrate that naip is distinct from the other iaps, both in demonstrating a ligand-dependent caspase-9 interaction and in demonstrating a distinct mechanism of inhibition. SIGNOR-127193 0.471 GTF2I protein P78347 UNIPROT ARID3A protein Q99856 UNIPROT up-regulates activity binding 9606 BTO:0000776 16738337 t lperfetto In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels. SIGNOR-268533 0.357 arachidonic acid smallmolecule CHEBI:15843 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 1357097 t miannu These results suggest that the activation of protein kinase c by both arachidonic acid and phorbol esters may play a role in the potentiation of glutamate exocytosis. SIGNOR-17809 0.8 serotonin smallmolecule CHEBI:28790 ChEBI HTR3C protein Q8WXA8 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264296 0.8 F9 protein P00740 UNIPROT F7 protein P08709 UNIPROT up-regulates activity cleavage Arg212 NASKPQGrIVGGKVC 9606 BTO:0000131 12524220 t lperfetto The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa. SIGNOR-263522 0.53 LCK protein P06239 UNIPROT SH2D2A protein Q9NP31 UNIPROT up-regulates activity phosphorylation Tyr290 PDEPIAFyAMGRGSP 9606 BTO:0000782 18541536 t miannu Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition. SIGNOR-262889 0.596 MEN1 protein O00255 UNIPROT CDKN2C protein P42773 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15640349 f irozzo Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions. SIGNOR-255888 0.501 STUB1 protein Q9UNE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni In ad-dition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activities of smad1/5 by recruiting smad1/5 from the functional r-/co-smad complex and further pro-moting the ubiquitination and degradation of smad1/5 in a chaperone-independent manner SIGNOR-195687 0.334 FBXW11 protein Q9UKB1 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates ubiquitination 9606 16885021 t gcesareni Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbetatrcp ubiquitin ligase. SIGNOR-148438 0.352 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates chemical activation 9606 10884684 t lperfetto Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘openÂ’ conformations SIGNOR-78915 0.8 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1185 FGMTRDIyETDYYRK 10116 BTO:0000575 15738637 t In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver. SIGNOR-248444 0.289 DLG1 protein Q12959 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000661 34960191 t Barakat Immunoblot analysis showed that phosphorylation of the activating ZAP70 kinase domain residue Tyr 493 was decreased in the DLG1 KD cells. Similarly, the Tyr 319 residue of ZAP70 and Tyr 83 residue of TCR- ζ also showed reduced phosphorylation. SIGNOR-274142 0.513 RHEB protein Q15382 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 19222999 t lperfetto Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1. SIGNOR-232208 0.791 JAK3 protein P52333 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr667 ESQEELHyATLNFPG 9606 11733002 t lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Phosphorylation of the tyrosine located at position 667 in an itim motif appears to be necessary for the recruitment of shp-1 and partial recruitment of shp-2 SIGNOR-112483 0.2 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR up-regulates activity chemical activation 9606 18790874 t brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-263784 0.8 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Thr590 PALLEHRtGRYAPTI 9823 21864610 t miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. SIGNOR-262921 0.337 MAPK11 protein Q15759 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr700 LSSNPLMtPDILGSS 9606 BTO:0000567 9687510 t gcesareni Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha SIGNOR-59451 0.598 CSNK2A2 protein P19784 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser13 GFFSSSEsGAPEAAE -1 3128543 t llicata To date, the only evidence for a functional distinction of LCa and LCb is the preferential phosphorylation of LCb, which takes place at serine residues and is mediated by coated vesicle-associated casein kinase II. As a first step toward determining the function of light chain diversity, we have mapped the in vitro phosphorylation sites on LCb. We use [32P]ATP to phosphorylate LCb within coated vesicles, followed by sequencing of 32P-labeled chymotryptic peptides thereof, to identify serine residues at positions 11 and 13 as the phosphorylation sites. SIGNOR-250984 0.313 NUP54 protein Q7Z3B4 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262078 0.65 RPE protein Q96AT9 UNIPROT D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI up-regulates quantity chemical modification 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267068 0.8 ADRA1A protein P35348 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256955 0.281 BMPR1A protein P36894 UNIPROT FAM83G protein A6ND36 UNIPROT up-regulates activity phosphorylation Ser610 GPGPRRPsVASSVSE 9606 24554596 t lperfetto These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway. SIGNOR-264765 0.382 JNJ-28312141 free base chemical CID:11676971 PUBCHEM CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258228 0.8 PRKACA protein P17612 UNIPROT PLCB3 protein Q01970 UNIPROT down-regulates phosphorylation Ser1105 LDRKRHNsISEAKMR 9606 10893237 t llicata These data indicate that pkc and pka act similarly in that they inhibit galpha(q)-stimulated plcbeta(3) as a result of phosphorylation of ser(1105). SIGNOR-79148 0.263 RAF1 protein P04049 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Thr268 PNVHMVStTLPVDSR -1 8349614 t lperfetto Furthermore, we find that Thr268 is the predominant Raf-1 residue phosphorylated in in vitro autokinase assays. SIGNOR-248917 0.2 CBX5 protein P45973 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity binding 9606 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-265325 0.2 BCS1L protein Q9Y276 UNIPROT Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 9606 BTO:0000567 18628306 f lperfetto We hypothesize a working model of the function of BCS1L and LETM1 in mitochondrial biogenesis (Fig. 8E). Because BCS1L is an AAA-ATPase, the following three functions are downstream targets: (1) respiratory chain assembly, (2) mitochondrial morphology maintenance and, (3) LETM1 complex formation. BCS1L functions directly in the formation of mitochondrial tubular networks, in addition to the assembly of the supercomplexes. LETM1 has a distinct role in maintenance of mitochondrial volume and shapes, which helps – in concert with BCS1L – to achieve the efficient assembly of the respiratory chains. SIGNOR-262544 0.7 SNRPF protein P62306 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270631 0.792 PIM1 protein P11309 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 19911008 t llicata In this study we show that phosphorylation of rela/p65 at ser276 prevents its degradation by ubiquitin-mediated proteolysis. importantly, we identify pim-1 as a further kinase responsible for the phosphorylation of rela/p65 at ser276. SIGNOR-189125 0.2 Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 BTO:0000567 12670868 t miannu The Set1/Ash2 HMT methylates histone H3 at Lys 4 (K4), but not if the neighboring K9 residue is already methylated. SIGNOR-264484 0.2 procainamide chemical CHEBI:8428 ChEBI ACHE protein P22303 UNIPROT down-regulates activity chemical inhibition -1 9301662 t miannu With the aim of performing a rigorous test of the anti-AChE properties of our compounds, the kinetics of enzyme inhibition were studied in purified enzyme preparations. The inhibition data are shown in Table 1. Additionally, known competitive inhibitors of AChE (procainamide and edrophonium) were included in the study for comparative purposes. SIGNOR-258668 0.8 REST protein Q13127 UNIPROT REST-CoREST complex SIGNOR-C111 SIGNOR form complex binding 9606 20080105 t 1 miannu Transcriptional repression of neural-specific genes in nonneuronal cells is dependent on the REST (RE1-silencing transcription factor)–CoREST complex. SIGNOR-239217 0.76 acetate smallmolecule CHEBI:30089 ChEBI acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI up-regulates quantity precursor of 10843999 t lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. SIGNOR-271824 0.8 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation Thr228 HEGAVTHtFCGTIEY 9606 15209375 t gcesareni A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-126076 0.596 CBP/p300 complex SIGNOR-C6 SIGNOR MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11062529 t gcesareni Cbp/p300 and pcaf are coactivators for myod and mef-2c during myogenic commitment and differentiation SIGNOR-83840 0.704 CALM3 protein P0DP25 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates binding 9606 11796223 t miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-266347 0.501 SAG protein P10523 UNIPROT CUL5 protein Q93034 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 25216516 t miannu Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. degradation.  SIGNOR-272844 0.422 RPEL1 protein Q2QD12 UNIPROT D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI down-regulates quantity chemical modification 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267066 0.8 RNF180 protein Q86T96 UNIPROT ZIC2 protein O95409 UNIPROT down-regulates quantity by destabilization ubiquitination 10116 18363970 t miannu Rinescan directly interact with Zic2. the ubiquitination of endogenous Zic2 was enhanced by Myc-Rines in rat neural stem cellline MNS70 cells. Rines-induced degradation of Zic2 SIGNOR-226303 0.381 AKT1 protein P31749 UNIPROT NQO1 protein P15559 UNIPROT down-regulates quantity by destabilization phosphorylation Thr128 FIGEFAYtYAAMYDK 9606 BTO:0000007 31358653 t miannu Akt phosphorylates NQO1 on S40 and T128 residues. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase.  SIGNOR-276869 0.377 MAPK3 protein P27361 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates phosphorylation Ser364 LQSPITTsPSC 9606 10617468 t lperfetto Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein. SIGNOR-73633 0.778 GNB3 protein P16520 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 23074268 t gcesareni Furthermore, this work suggested that the g subunits released upon gi activation activated phospholipase c (plc- ) to produce inositol 3-phosphate (ip3), which would subsequently increase intracellular ca2+ abundance. SIGNOR-199135 0.2 MCF2L protein O15068 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260559 0.604 MAP3K7 protein O43318 UNIPROT RAB8A protein P61006 UNIPROT up-regulates activity phosphorylation Thr72 AGQERFRtITTAYYR -1 32227113 t lperfetto In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. |Overall our data suggests that the phosphorylation of Rab8A at Ser111 may influence Switch II-binding by regulators, thus disrupting interactions with its cognate GEF and moderately impairs its interaction with GAPs.|The antagonistic interplay between Ser111 phosphorylation and Thr72 phosphorylation is genetically concordant with how respective mutations in PINK1 and LRRK2 cause Parkinson’s disease SIGNOR-260266 0.254 CDK6 protein Q00534 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser672 TLYDRYSsPPASTTR 9606 BTO:0001938 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. all three residues selectively targeted by cdk4(6), t401 (n-terminus), s672 (spacer region) and s1035 (c-terminus) SIGNOR-104715 0.667 CCNA2 protein P20248 UNIPROT CyclinA2/CDK1 complex SIGNOR-C420 SIGNOR form complex binding 9606 29870721 t lperfetto Here we show that cyclin A/cdk1 kinase is the factor triggering mitosis. SIGNOR-267571 0.919 SPI1 protein P17947 UNIPROT ANXA1 protein P04083 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19428102 f miannu Identification of annexin 1 as a PU.1 target gene in leukemia cells. PU.1 is a master regulator, and critical for the developmen tof a common progenitor for lymphoid-myeloid cell lineages in the hematopoietic system. From microarray analysis, we found that several genes including annexin 1 were markedly induced in K562PU.1KD cells. Annexin 1 is a calcium- and phospholipid-binding protein and increased expression leads to the constitutive activation of extracellular signal-regulated kinase (ERK) SIGNOR-261688 0.2 SCF-betaTRCP complex SIGNOR-C5 SIGNOR WEE1 protein P30291 UNIPROT down-regulates quantity by destabilization ubiquitination -1 24817118 t miannu Casein kinase 1-mediated N-terminal Weee1 phosphorylation is required for interaction with the F-box protein β-TrCP.MS/MS spectra of human Wee1 identifying serine 212 as phosphorylated after incubation with recombinant CK1δ. SIGNOR-276633 0.395 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr12 FGSRSSKtFKPKKNI 9606 23431053 t milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity SIGNOR-201290 0.81 UBQLN2 protein Q9UHD9 UNIPROT HNRNPA1 protein P09651 UNIPROT up-regulates quantity by stabilization binding 25616961 t lperfetto Confirmation of binding of recombinant full-length hnRNPA1 and hnRNPU proteins with ubiquilin-2 by GST-pull-down assays|Additionally, our evidence that ubiquilin-2 is in- volved in stabilizing hnRNPA1 protein SIGNOR-262270 0.47 S1PR2 protein O95136 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22863277 t gcesareni Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2. SIGNOR-198559 0.572 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser37 EDLTDELsLNKISAD -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276206 0.388 SNRPE protein P62304 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270657 0.721 TGFBR2 protein P37173 UNIPROT ZFYVE9 protein O95405 UNIPROT up-regulates activity binding 9606 9865696 t lperfetto Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex SIGNOR-245093 0.551 FABP1 protein P07148 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264455 0.7 ETFBKMT protein Q8IXQ9 UNIPROT ETFB protein P38117 UNIPROT down-regulates activity methylation Lys200 ATLPNIMkAKKKKIE -1 25416781 t miannu Accordingly, we found that METTL20-mediated methylation of ETFβ in vitro reduced its ability to receive electrons from the medium chain acyl-CoA dehydrogenase and the glutaryl-CoA dehydrogenase. In conclusion, the present study establishes METTL20 as the first human KMT localized to mitochondria and suggests that it may regulate cellular metabolism through modulating the interaction between its substrate ETFβ and dehydrogenases. SIGNOR-269450 0.2 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser439 SIGHSPLsLSAQSVM 9606 BTO:0000938 24614225 t lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204704 0.524 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser301 SSSPNNLsPTGWSQP 9606 16407412 t gcesareni Using mass spectrometry, we identified raf-1 phosphorylation on three sp motif sites: s289/s296/s301. These sites were phosphorylated by extracellular signal-regulated kinase (erk)-1 in vitro, and their phosphorylation in vivo was dependent on endogenous erk activity. Functionally, erk-1 expression sustains raf-1 activation in a manner dependent on raf-1 phosphorylation on the identified sites, and s289/296/301a substitution markedly decreases the in vivo activity of raf-1 s259a. SIGNOR-143696 0.622 HSD17B11 protein Q8NBQ5 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification 9606 BTO:0000056 16166196 t lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. SIGNOR-268664 0.8 CDK1 protein P06493 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser696 EKNYALPsPATTEGG 9606 20169205 t llicata Cdc2 is the raptor ser696, thr706 kinase SIGNOR-163849 0.394 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Thr202 HDHTGFLtEYVATRW 9606 9677429 t MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade. gcesareni The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells. SIGNOR-59153 0.742 IL3RA protein P26951 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 9606 15795318 f gcesareni We previously demonstrated that integrin-dependent adhesion activates stat5a, a well known target of il-3-mediated signaling SIGNOR-134862 0.556 decanoic acid chemical CHEBI:30813 ChEBI GPR84 protein Q9NQS5 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257508 0.8 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation -1 8454633 t gcesareni Intrinsic activity was demonstrated in vitro against a variety of phosphotyrosine-containing substrates including BIRK, the autophosphorylated cytoplasmic kinase domain of the insulin receptor beta subunit. SIGNOR-39155 0.385 IL4R protein P24394 UNIPROT JAK3 protein P52333 UNIPROT up-regulates 9606 BTO:0000776 7538655 f gcesareni The overlapping and distinct protein tyrosine phosphorylation and activation of the same jak1 kinase in t lymphocytes strongly suggests that il-4 and il-9 share the common signal transduction pathways. SIGNOR-28399 0.662 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PCYT1A protein P49585 UNIPROT down-regulates phosphorylation 9606 BTO:0000763 15788406 t inferred from 70% family members gcesareni Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis. SIGNOR-270028 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser367 GTQNPVSsPGMSQEL 26933062 t lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. SIGNOR-276590 0.397 ZEB1 protein P37275 UNIPROT EPCAM protein P16422 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150;BTO:0000584 23667256 f miannu We found a similar ZEB1-dependent repression of EPCAM expression in human pancreatic and breast cancer cell lines, mediated through direct binding of ZEB1 to the EPCAM promoter. SIGNOR-255622 0.441 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser29 VSHWQQQsYLDSGIH 9606 BTO:0000007 12432063 t llicata We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin SIGNOR-250846 0.541 FYN protein P06241 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity phosphorylation Tyr70 HKETGNHyAMKILDK -1 30274258 t miannu We found that the Src family kinase Fyn phosphorylates the catalytic subunit of PKA (PKA-C) at Y69, thereby increasing PKA kinase activity.  SIGNOR-277410 0.435 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-252808 0.2 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR NAMPT protein P43490 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19299583 t miannu Here we report that both the rate-limiting enzyme in mammalian nicotinamide adenine dinucleotide (NAD+) biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), and levels of NAD+ display circadian oscillations that are regulated by the core clock machinery in mice. Inhibition of NAMPT promotes oscillation of the clock gene Per2 by releasing CLOCK:BMAL1 from suppression by SIRT1. In turn, the circadian transcription factor CLOCK binds to and up-regulates Nampt, thus completing a feedback loop involving NAMPT/NAD+ and SIRT1/CLOCK:BMAL1. Transduction of Clock/Bmal1 into mouse embryonic fibroblasts appeared to up-regulate Nampt expression ∼1.6-fold (Fig. 3E). SIGNOR-268021 0.596 MAP2K1 protein Q02750 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates 9606 18481201 f gcesareni Pd98059, a specific inhibitor of mek in addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. SIGNOR-178636 0.66 LRP5 protein O75197 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 23209147 t Gianni The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization. SIGNOR-262525 0.675 RAPGEF4 protein Q8WZA2 UNIPROT RAP1A protein P62834 UNIPROT up-regulates activity guanine nucleotide exchange factor 9534 BTO:0000298 10777494 t miannu Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well. SIGNOR-263954 0.786 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser713 GAEIVYKsPVVSGDT 9606 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249320 0.754 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr74 PVYNQPVyNQPVGAA 9606 11390389 t Manara Our data establish that the Abl SH3 domain binds to the N-terminal proline-rich segment of PLSCR1 and that ABL1 phosphorylates Tyr residues of the PLSCR1 polypeptide, most likely Tyr69 and Tyr74 within the tandem repeat sequence SIGNOR-260808 0.393 RPS23 protein P62266 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262428 0.892 RAB6B protein Q9NRW1 UNIPROT VPS13B protein Q7Z7G8 UNIPROT up-regulates activity binding 10116 BTO:0003102 25492866 t miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. We show that COH1 forms a physical and functional complex with RAB6. Our results point to a role of COH1 as a RAB6 effector protein. Depletion of COH1 leads to decreased neurite outgrowth in cultured primary hippocampal neurons. These results establish a critical role for RAB6-dependent function of COH1 in neuritogenesis by regulating Golgi complex organization. SIGNOR-266870 0.2 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT unknown phosphorylation Tyr707 DVYSTDYyRVGGHTM 10090 BTO:0000944 10533983 t miannu TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. SIGNOR-250207 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NCF1 protein P14598 UNIPROT up-regulates phosphorylation 9606 BTO:0000130 16778989 t inferred from 70% family members gcesareni Inhibitors of the erk1/2 pathway abrogated gm-csf-induced phosphorylation of ser345, while p38 mapk inhibitor abrogated tnf-alpha-induced phosphorylation of ser345.These results show that the ala-mutated p47phox acts as a dominant-negative inhibitor of endogenous p47phox and clearly indicate that phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells. SIGNOR-270187 0.2 GSK3B protein P49841 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation Thr687 PRGMGPGtPAGYGRG 9606 20932480 t lperfetto We conclude that t687 is the primary site of threonine phosphorylation in psf. Gsk3 directly phosphorylates the splicing regulatory protein psf. In this phosphorylated form, psf is sequestered in a complex with trap150, precluding it from binding the ess1 sequence in cd45 alternatively spliced exons. Upon t?_Cell stimulation, reduced gsk3 activity leads to reduced psf phosphorylation, thereby releasing psf from trap150 and allowing it to participate in activation-induced cd45 exon skipping SIGNOR-168389 0.351 PRKCA protein P17252 UNIPROT IL2RA protein P01589 UNIPROT unknown phosphorylation Thr271 RQRKSRRtI 9606 BTO:0000782 2303462 t lperfetto The interleukin-2 (il-2) receptor, the leukocyte-specific membrane glycoprotein, t200, and the class i major histocompatibility antigens (hla) have been identified as substrates for protein kinase c from these studies, it was concluded that ser-247 is the major site of phosphorylation in the il-2 receptor and that thr-250 is a minor site. SIGNOR-22988 0.267 CDK2 protein P24941 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 17038621 t lperfetto Cdk2 specifically phosphorylated foxo1 at serine-249 (ser249) in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of foxo1. SIGNOR-252892 0.638 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser43 FGYQRRAsDDGKLTD 9606 7935389 t gcesareni Pka can inhibit raf-1 function directly via phosphorylation of the raf-1 kinase domain SIGNOR-34761 0.539 CTNNB1 protein P35222 UNIPROT TRRAP protein Q9Y4A5 UNIPROT up-regulates binding 9606 16510874 t gcesareni The beta-cat c-terminal activation domain associates with trrap/tip60 and mixed-lineage-leukemia (mll1/mll2) set1-type chromatin-modifying complexes in vitro, and we show that beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. SIGNOR-144966 0.562 EEF1A2 protein Q05639 UNIPROT Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269539 0.8 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA4 protein Q9Y5G9 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265675 0.2 TNKS2 protein Q9H2K2 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 19759537 t lperfetto Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin. SIGNOR-263378 0.693 DNAJC3 protein Q13217 UNIPROT EIF2AK2 protein P19525 UNIPROT down-regulates activity binding 9606 BTO:0000567 25329545 t gcesareni The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK SIGNOR-246207 0.62 ASAP2 protein O43150 UNIPROT ARF1 protein P84077 UNIPROT up-regulates activity gtpase-activating protein -1 10022920 t miannu Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain.  In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6.  Pap protein exhibits Arf GAP activity in vitro. SIGNOR-269705 0.641 CCNT1 protein O60563 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR form complex binding -1 34955012 t lperfetto Cyclin-dependent-kinases (CDKs) are members of the serine/threonine kinase family and are highly regulated by cyclins, a family of regulatory subunits that bind to CDKs. CDK9 represents one of the most studied examples of these transcriptional CDKs. CDK9 forms a heterodimeric complex with its regulatory subunit cyclins T1, T2 and K to form the positive transcription elongation factor b (P-TEFb).  SIGNOR-267739 0.964 SP1 protein P08047 UNIPROT KRT16 protein P08779 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000552 12954631 f miannu these results suggest that Sp1 and AP1 sites in the essential promoter region are critical for EGF response, and Sp1 showed a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of EGF-induced keratin 16 gene expression. The coactivators p300/CBP could collaborate with Sp1 and c-Jun in the activation of keratin 16 promoter. SIGNOR-253903 0.2 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1948 SPTSPGYsPTSPTYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203608 0.769 VHL protein P40337 UNIPROT IREB2 protein P48200 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0003781 15777842 t miannu We show here that IRP2 can interact with pVHL in co-transfection/co-immunoprecipitation assays. Furthermore, pVHL is able to promote the ubiquitination and the decay of transfected IRP2. SIGNOR-271421 0.366 NLGN4Y protein Q8NFZ3 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264163 0.2 TRPM6 protein Q9BX84 UNIPROT H2AC11 protein P0C0S8 UNIPROT down-regulates activity phosphorylation Ser2 sGRGKQGG -1 15010469 t miannu We found that MSK1 phosphorylated histone H2A on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by MSK1.  SIGNOR-276008 0.2 DMC1 protein Q14565 UNIPROT SYCP3 protein Q8IZU3 UNIPROT up-regulates activity binding 10090 BTO:0001275 SIGNOR-C351 10525529 t miannu The eukaryotic RecA homologues RAD51 and DMC1 function in homology recognition and formation of joint-molecule recombination intermediates during yeast meiosis. We also show that mouse RAD51 and DMC1 establish protein-protein interactions with each other and with the chromosome core component COR1(SCP3) in a two-hybrid system and in vitro binding analyses. These results suggest that the formation of a multiprotein recombination complex associated with the meiotic chromosome cores is essential for the development and fulfillment of the meiotic recombination process. SIGNOR-264206 0.393 SPTAN1 protein Q13813 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 9624143 f Cleaved by CASP3 amattioni A-fodrin cleavage contributes to blebbing SIGNOR-57897 0.7 GNRHR protein P30968 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257064 0.252 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser324 RDLELPLsPSLLGGP 10090 BTO:0000944 7889942 t lperfetto We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-235459 0.545 RAPGEF6 protein Q8TEU7 UNIPROT NRAS protein P01111 UNIPROT up-regulates guanine nucleotide exchange factor 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-183799 0.337 SGK1 protein O00141 UNIPROT NCSTN protein Q92542 UNIPROT down-regulates quantity by destabilization phosphorylation Ser437 FLRARNIsGVVLADH 9606 BTO:0000007 22590650 t miannu SGK1 directly bound to and phosphorylated NCT on Ser437, thereby promoting protein degradation. SIGNOR-276415 0.344 PIGF protein Q07326 UNIPROT PIGG protein Q5H8A4 UNIPROT up-regulates quantity by stabilization binding 10029 BTO:0000246 15632136 t miannu We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O. SIGNOR-261358 0.631 AKT1 protein P31749 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT down-regulates activity phosphorylation Ser971 STRLRQQsSSSKGDS 9606 27858941 t miannu DAB2IP can be phosphorylated by RIP1 on Ser 604 within the PER domain, and by AKT1 on Ser 847 within the proline-rich domain. Although RIP1-mediated phosphorylation is stimulatory,40 a recent study reported that AKT-mediated phosphorylation inhibits DAB2IP functions SIGNOR-254780 0.511 MYF6 protein P23409 UNIPROT DES protein P17661 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 8382796 t lperfetto Desmin, the muscle specific intermediate filament (IF) protein, is expressed at low levels in myoblasts and at the onset of differentiation its expression increases several fold. In an effort to explore the mechanism involved in the tissue-specific and developmentally regulated expression of desmin, we have isolated the mouse desmin gene.Co-transfection of myoD, myogenin, MRF4 and Myf5, with the desmin-CAT construct into 10T-1/2 cells demonstrated that all these factors could transactivate desmin gene expression SIGNOR-241497 0.243 PARD6A protein Q9NPB6 UNIPROT PARD6/SMURF1 complex SIGNOR-C112 SIGNOR form complex binding 9606 BTO:0004183 15761148 t lperfetto The Par6-Smurf1 complex then mediates the localized ubiquitination of RhoA to enable the TGF_-dependent dissolution of tight junctions during EMT. SIGNOR-227559 0.623 FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15109499 f lperfetto Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers. SIGNOR-232174 0.449 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT unknown phosphorylation Tyr955 ADAEEAMyQNVDGRV 10090 BTO:0001516 16627759 t lperfetto In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated. SIGNOR-271923 0.2 MEF2C protein Q06413 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103 10082551 f lperfetto During embryogenesis, the MEF2 genes are expressed throughout developing skeletal and cardiac muscle lineages, as well as in the nervous system (19, 42, 65, 68).MEF2C is the first member of the family to be expressed in developing muscle cell lineages, with transcripts appearing in precardiac cells by about embryonic day 7.75 and in skeletal muscle precursor cells within the myotome of the developing somites by embryonic day 8.5. Soon thereafter, the other MEF2 genes are expressed in overlapping patterns (19). After birth, the expression of MEF2A, -B, and -Dbecomes ubiquitous, whereas the expression of MEF2C becomes restricted to skeletal muscle, brain, and spleen SIGNOR-219368 0.7 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 BTO:0000567 9271440 t gcesareni The activation of p70s6k is associated with multiple phosphorylations at two sets of sites. The first set, s411, s418, t421, and s424, reside within the autoinhibitory domain, mutations of s371 abolished kinase activity. In mitotic hela cells, when the activity of cdc2 is high, s6k1 is phosphorylated at multiple ser/thr, pro (s/tp) sites, including ser(371), ser(411), thr(421), and ser(424). SIGNOR-50607 0.392 INS protein P01308 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity 10116 15069075 f lperfetto The mechanism by which the phosphorylation of ser307 or ser318 inhibits irs-1 tyrosine phosphorylation is not known. Prolonged insulin-stimulation inhibits irs-1 binding to the phosphorylated npey motif in the juxta-membrane region of the irbeta -subunit. SIGNOR-236625 0.668 PDPK1 protein O15530 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 19956600 t gcesareni We characterize two monoclonal antibodies raised against phosphorylated forms of the n- and c-terminal domain of rsk2 (p-s227 and p-t577, respectively). Using these two antibodies, we show that stress signals, such as uv light, induce phosphorylation and activation of the three rsks. SIGNOR-161924 0.641 EEF1B complex complex SIGNOR-C460 SIGNOR EEF1A1 protein P68104 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. SIGNOR-269387 0.919 5-azacytidine chemical CHEBI:2038 ChEBI DNMT1 protein P26358 UNIPROT down-regulates activity chemical inhibition 9606 14585280 t miannu Both Azacitidine and Decitabine may also exert antitumor activity through induction of DNA hypomethylation, by forming a covalent complex with the major DNA methyltransferase (now termed DNMT1).Azacitidine and Decitabine effectively deplete the cell of functional DNA methylating activity, which results in profound hypomethylation after several rounds of DNA replication (Fig. 2). DNMT1 is considered a bona fide anticancer target at different levels SIGNOR-259293 0.8 INTS4 protein Q96HW7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity binding 9606 16239144 t miannu The Integrator Complex Can Directly Associate with the C-Terminal Domain of RNA Polymerase II Largest Subunit SIGNOR-261185 0.522 AXIN1 protein O15169 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates binding 9606 16601693 t gcesareni Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia. SIGNOR-145851 0.7 TEC protein P42680 UNIPROT BMX protein P51813 UNIPROT up-regulates activity phosphorylation Tyr216 SSTSLAQyDSNSKKI 9606 BTO:0000873 12573241 t lperfetto Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.The major phosphorylation sites were identified as conserved tyrosines, for Itk Y180 and for Bmx Y215, both sites being homologous to the Y223 site in Btk SIGNOR-246647 0.338 CHEK2 protein O96017 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Thr288 SPDCDVKtDDSVVPC 9606 19151762 t llicata Phosphorylation at ttk/hmps1 thr288 is enhanced by chk2 in vitro and in vivo after ir SIGNOR-242665 0.296 PLK1 protein P53350 UNIPROT TPT1 protein P13693 UNIPROT down-regulates phosphorylation Ser64 PEGEGTEsTVITGVD 9606 12167714 t lperfetto Plk phosphorylates tctp on two serine residues. These results suggest that phosphorylation decreases the microtubule-stabilizing activity of tctp and promotes the increase in microtubule dynamics that occurs after metaphase SIGNOR-91348 0.705 TPO protein P07202 UNIPROT diiodine smallmolecule CHEBI:17606 ChEBI up-regulates quantity chemical modification 9606 28153798 t scontino TPO is considered the key enzyme in thyroid hormonogenesis. It catalyzes the oxidation of iodide that is necessary for the iodinationof the TG tyrosyl residues (the organification reaction). SIGNOR-266959 0.8 PRKACA protein P17612 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser491 SSTPQRSCsAAGLHRPR 10116 BTO:0002135 17023420 t These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine. SIGNOR-256112 0.402 CASP3 protein P42574 UNIPROT IKBKB protein O14920 UNIPROT down-regulates cleavage Asp78 PNVVAARdVPEGMQN 9606 11741536 t gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. SIGNOR-112800 0.372 lapatinib chemical CHEBI:49603 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 22056878 t Lapatinib (INN), used in the form of lapatinib ditosylate, (USAN) (Tykerb/Tyverb, GSK) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. gcesareni In estrogen-receptor-negative cellular models showing coamplification of erbb2 and rara, simultaneous targeting of the corresponding gene products with combinations of lapatinib and atra causes synergistic growth inhibition, cyto-differentiation and apoptosis. SIGNOR-177081 0.8 WNT3A protein P56704 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 22653731 t gcesareni Structural basis of wnt recognition by frizzled. SIGNOR-197638 0.79 PPP4C protein P60510 UNIPROT TRIM28 protein Q13263 UNIPROT down-regulates activity dephosphorylation 9606 22732494 t miannu PP4 dephosphorylated pKAP1 in vitro. SIGNOR-277163 0.365 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25A protein P30304 UNIPROT up-regulates phosphorylation Ser116 PQKLLGCsPALKRSH 9606 12411508 t lperfetto Mitotic stabilization of cdc25a reflects its phosphorylation on ser17 and ser115 by cyclin b-cdk1, modifications required to uncouple cdc25a from its ubiquitin-proteasome-mediated turnover. SIGNOR-216761 0.843 MST1 protein P26927 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Ser226 LNPQWNEsFTFKLKP 9606 BTO:0002181 26414765 t miannu Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα.  SIGNOR-277179 0.2 AKT2 protein P31751 UNIPROT ATP7A protein Q04656 UNIPROT up-regulates quantity by stabilization phosphorylation Ser1463 IVNYSRAsINSLLSD 10090 29301787 t lperfetto Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus|Immunoprecipitation, in vitro kinase assay, and mass spectrometry analysis reveal that insulin stimulates Akt2 binding to ATP7A to induce phosphorylation at Ser1424/1463/1466 SIGNOR-272268 0.263 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser214 PTSSDPGsPFQMPAD 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248303 0.479 IL7 protein P13232 UNIPROT IL7R protein P16871 UNIPROT up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 20089933 t milica This receptor (il-7r) is a heterodimer consisting of the il-7r chain and the common cytokine ? -chain. SIGNOR-163548 0.912 PTK2 protein Q05397 UNIPROT SH3GL1 protein Q99961 UNIPROT unknown phosphorylation Tyr315 QPSCKALyDFEPEND 9606 16054026 t llicata These results identified y315 of endophilin a2 as a major phosphorylation site by fak/src complex. tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp. SIGNOR-139146 0.41 SGCD protein Q92629 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255988 0.505 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr96 QDHSHLLySTIPRMQ -1 11382764 t lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 SIGNOR-246508 0.92 buprenorphine chemical CHEBI:3216 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258769 0.8 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252754 0.753 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 19584320 t lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-216491 0.469 KDR protein P35968 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 11278468 t Gianni These results demonstrate that activation of VEGFR-2 results in activation of PI3K and that activation of PI3K/S6kinase pathway, but not Ras/MAPK, is responsible for VEGFR-2-mediated cell growth. SIGNOR-261916 0.553 CDK1 protein P06493 UNIPROT CREM protein Q03060 UNIPROT down-regulates quantity phosphorylation Ser271 QGVVMAAsPGSLHSP 9606 BTO:0001033 21767532 t miannu In this report data is presented demonstrating that ICER is phosphorylated by the mitotic kinase cdk1. Phosphorylation of ICER on a discrete residue targeted ICER to be monoubiquitinated. Different from unphosphorylated, phosphorylated and polyubiquitinated ICER, monoubiquitinated ICER was found to be cytosolic. Taken together, these results hinted on a mechanism for the observed abnormal subcellular localization of ICER in human prostate tumors. SIGNOR-276346 0.301 ARNTL2 protein Q8WYA1 UNIPROT CLOCK/BMAL2 complex SIGNOR-C196 SIGNOR form complex binding 19605937 t lperfetto Like BMAL1, its paralog BMAL2 dimerizes with CLOCK to activate the E-box-dependent transcription SIGNOR-253710 0.67 SHANK3 protein Q9BYB0 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates quantity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264700 0.2 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-238813 0.397 CLOCK protein O15516 UNIPROT PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253634 0.768 KDR protein P35968 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 phosphorylation:Tyr1175 AQQDGKDyIVLPISE 16835467 t gcesareni (vegfr) phosphorylated y1175 creates a binding site for phospholipase cgamma1 (plc-gamma1) SIGNOR-147870 0.662 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser55 KPRHKIIsIFSGTEK -1 10075701 t miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197. SIGNOR-250229 0.2 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-34669 0.584 H3C1 protein P68431 UNIPROT Nucleosome_H2A.Z.1 variant complex SIGNOR-C322 SIGNOR form complex binding -1 24311584 t miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. SIGNOR-263717 0.2 serine smallmolecule CHEBI:17822 ChEBI Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates quantity precursor of 9606 24095058 t miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis SIGNOR-270500 0.8 HOXD1 protein Q9GZZ0 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001949 21501586 t Luana Consistently, ITGB1 promoter activity was decreased by HOXD1 knockdown in ECs. Furthermore, we identified the putative HOXD1-binding sites in the promoter region of ITGB1. Together, these findings suggest that HOXD1 plays a significant role in EC functions by regulating the expression of ITGB1. SIGNOR-261648 0.2 AURKA protein O14965 UNIPROT DLGAP5 protein Q15398 UNIPROT up-regulates quantity by stabilization phosphorylation Ser627 VKLFSGLsVSSEGPS 9606 15987997 t miannu Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life. SIGNOR-262649 0.74 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR KRT8 protein P05787 UNIPROT unknown phosphorylation 16554440 t inferred from 70% family members lperfetto Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002). SIGNOR-270135 0.2 ACO1 protein P21399 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. SIGNOR-266245 0.8 ATXN2L protein Q8WWM7 UNIPROT MPL protein P40238 UNIPROT down-regulates binding 9606 11784712 t miannu A2d binds to cytokine receptors mpl and epo-r. A2d is associated with these unoccupied receptorsin vivo,and stimulation with tpo or epo causes the rapid dissociation of a2d from the activated receptor. SIGNOR-113891 0.36 GFI1 protein Q99684 UNIPROT CYP27B1 protein O15528 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15947108 f miannu Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells. SIGNOR-254205 0.2 phentolamine chemical CHEBI:8081 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258444 0.8 TRAF2 protein Q12933 UNIPROT BIRC2 protein Q13490 UNIPROT up-regulates activity binding 9606 8548810 t lperfetto The c-iaps associate with traf1 and traf3 SIGNOR-39527 0.868 PRKAA1 protein Q13131 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser621 PKINRSAsEPSLHRA 9606 SIGNOR-C15 9091312 t gcesareni Ampk also phosphorylated full-length, kinase-defective raf-1 (k375m) to generate two [32p]phosphopeptides, one co-migrating with synthetic tryptic peptide containing phospho-ser621 and the other with phospho-ser259. The catalytic subunit of PKA also phosphorylated Ser621 in vitro, while its overexpression in intact cells resulted in increased phosphorylation of Ser621 and decreased activity of Raf-1. These results suggest that phosphorylation of Ser621 inactivates Raf-1, but do not prove that PKA is responsible for this in vivo. SIGNOR-47148 0.349 KIF11 protein P52732 UNIPROT Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 9606 21969468 f lperfetto The C-terminal fragment interferes with the TPX2–Eg5 interaction, relieving the inhibition of TPX2 on Eg5 and generating the observed spindle lengthening. According to this model, TPX2 and Eg5 should localize to microtubules in the spindle midzone. SIGNOR-265098 0.7 LGALS3 protein P17931 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by stabilization 9606 BTO:0000664 21821001 f miannu Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells. SIGNOR-261906 0.282 IL17R complex complex SIGNOR-C260 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 10090 BTO:0000944 8777726 f lperfetto 3T3 cells were preincubated with an IL-17Rspecific antiserum and then assayed for NF-KB activation by HVS13. Preincubation with the IL-1 7R antiserum dramatically decreased the NF-KB activity induced by HVSl3 as compared with cells preincubated with an irrelevant rat antiserum (Figure 5C). This result indicated that the engagement of the IL-17R by its ligands induced NF-KB activity. SIGNOR-261338 0.2 TYK2 protein P29597 UNIPROT DUSP3 protein P51452 UNIPROT up-regulates phosphorylation Tyr138 SPTLVIAyLMMRQKM 9606 17785772 t lperfetto Phosphorylation of vhr at tyr(138) was required for its phosphatase activity toward stat5. In addition, the src homology 2 domain of stat5 was required for the effective dephosphorylation of stat5 by vhr. The tyrosine kinase tyk2, which mediates the phosphorylation of stat5, was also responsible for the phosphorylation of vhr at tyr(138). SIGNOR-157655 0.268 DIP2A protein Q14689 UNIPROT SOD2 protein P04179 UNIPROT up-regulates activity binding 10090 BTO:0000142 33781892 t miannu DIP2a is associated with SOD in the mitochondria of mouse brain. DIP2a knockout inhibited SOD activity. In this paper, we analyzed the interacting proteins of DIP2A by mass spectrum analysis and found that DIP2A was correlated with superoxide dismutase (SOD), SOD1 and SOD2. Knockout of DIP2A decreased SOD activity and increased the level of ROS in the mouse brain. SIGNOR-266592 0.2 KAT8 protein Q9H7Z6 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. SIGNOR-267160 0.638 COX7A2 protein P14406 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267741 0.498 RAP1GDS1 protein P52306 UNIPROT RAP1B protein P61224 UNIPROT up-regulates binding 9606 21242305 t miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob SIGNOR-171552 0.423 EIF2AK2 protein P19525 UNIPROT NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates activity binding 9606 BTO:0000007 22801494 t miannu Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. SIGNOR-263119 0.331 EIF3F protein O00303 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates deubiquitination 9606 21124883 t gcesareni The activated form of notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. The enzyme accounting for this deubiquitinase activity is eif3f, known so far as a translation initiation factor. SIGNOR-254327 0.431 ATM protein Q13315 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates quantity by destabilization phosphorylation Ser729 LFFDYRYsQADALKY -1 24162653 t miannu Enhancer of zeste homolog 2 (EZH2), a core catalytic component of PRC2, is a new ATM kinase target, and ATM-mediated phosphorylation of EZH2 on Ser734 reduces protein stability.  SIGNOR-276602 0.47 SMAD3 protein P84022 UNIPROT CEBPA protein P49715 UNIPROT down-regulates activity binding 10090 12524424 t gcesareni Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPAR2 and leptin promoters SIGNOR-241924 0.383 AURKB protein Q96GD4 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. SIGNOR-70420 0.2 SMAD1/4 complex SIGNOR-C85 SIGNOR DLX5 protein P56178 UNIPROT up-regulates transcriptional regulation 10090 BTO:0000165 12815054 f ggiuliani Over-expression of Smad1 or Smad5, mediators of BMP-signaling, also induced Dlx5 expression even in the absence of BMP-2 treatment concomitant with positive ALP staining SIGNOR-255789 0.307 zinc(2+) chemical CHEBI:29105 ChEBI BRCA1-C complex complex SIGNOR-C299 SIGNOR form complex binding 25400280 t lperfetto The BRCA1‚ÄìC complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2 SIGNOR-269478 0.8 HMGB2 protein P26583 UNIPROT GFI1B protein Q5VTD9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19965638 f miannu HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. SIGNOR-254429 0.2 JAK2 protein O60674 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates phosphorylation Tyr693 TERGDKGyVPSVFIP 9606 BTO:0000782 16324152 t gcesareni Janus family tyrosine kinases jak2 and tyk2, which in turn phosphorylate stat4 on tyrosine 693. The p38 mitogen-activated protein kinase (mapk) signaling pathway is also activated in response to il-12, followed by phosphorylation of stat4 on serine 721, which is required for stat4 full transcriptional activity SIGNOR-142736 0.663 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr203 HQHYYYDtHTNTYYL 9606 12145304 t gcesareni The secretory na-k-cl cotransporter nkcc1 is activated by secretagogues through a phosphorylation-dependent mechanism. three phosphoacceptor sites were identified in the n-terminal domain of the protein (at thr184, thr189, and thr202) none of these residues occurs in the context of strong consensus sites for known ser/thr kinases. SIGNOR-90927 0.539 MAPK3 protein P27361 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1457 HSKSPAYtPQNLDSE 9606 12356758 t lperfetto Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase SIGNOR-93993 0.266 PRKCA protein P17252 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser185 SAYVGRLsARPKLKA -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276025 0.2 CMA1 protein P23946 UNIPROT EDN1 protein P05305 UNIPROT up-regulates activity cleavage Tyr83 TPEHVVPyGLGSPRS 9606 BTO:0000830 9257865 t miannu Chymase from human mast cells selectively cleaved big endothelins (ETs) at the Tyr31-Gly32 bond and produced novel trachea-constricting 31-amino acid-length endothelins, ETs(1-31), without any further degradation products. SIGNOR-256356 0.485 F2R protein P25116 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257293 0.415 GOT1 protein P17174 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI down-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-268063 0.8 PROX1 protein Q92786 UNIPROT IFNG protein P01579 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20064070 f Human PROX1 is involved in biologic functions closely tied to HIV infection, most notably as a negative regulator of interferon (IFN) gamma expression in T cells SIGNOR-254506 0.261 PAX2 protein Q02962 UNIPROT Urogenital_tract phenotype SIGNOR-PH71 SIGNOR up-regulates activity 10090 8575306 f Pax-2 is required for multiple steps during the differentiation of intermediate mesoderm. In addition, Pax-2 mouse mutants provide an animal model for human hereditary kidney diseases. SIGNOR-252301 0.7 GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263816 0.8 KPNA6 protein O60684 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20454918 t gcesareni Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of nicd and thus are directly involved in notch signaling. SIGNOR-165343 0.2 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 19584320 t lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-216495 0.469 PTPRE protein P23469 UNIPROT KCNB1 protein Q14721 UNIPROT down-regulates activity dephosphorylation Tyr128 YWGIDEIyLESCCQA 9606 BTO:0000007 10921884 t Hypomyelination and increased activity of voltage-gated K(+) channels in mice lacking protein tyrosine phosphatase epsilon SIGNOR-248450 0.362 HAUS6 protein Q7Z4H7 UNIPROT HAUS complex complex SIGNOR-C281 SIGNOR form complex binding 9606 BTO:0000567 19369198 t lperfetto Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC) SIGNOR-262320 0.889 ACE2 protein Q9BYF1 UNIPROT Spike protein-ACE2 complex SIGNOR-C240 SIGNOR form complex binding 9534 BTO:0001444 18554741 t miannu Cell entry of severe acute respiratory syndrome coronavirus (SARS-CoV) is mediated by the viral spike (S) protein. Amino acids 319-510 on the S protein have been mapped as the receptor-binding domain (RBD), which mediates binding to the SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) on SARS-CoV susceptible cells. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells. SIGNOR-260288 0.2 SV2A protein Q7L0J3 UNIPROT SYT1 protein P21579 UNIPROT up-regulates quantity binding 9606 BTO:0000938 26903854 t miannu Recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. These cargoes are synaptophysin (for sybII) and SV2A (for synaptotagmin-1). SV2A Acts as an iTRAP to Direct Synaptotagmin-1 Retrieval to SVs. SIGNOR-264116 0.55 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR DCK protein P27707 UNIPROT down-regulates activity dephosphorylation Ser74 EFEELTMsQKNGGNV 24462681 t lperfetto Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation SIGNOR-275804 0.2 DTL protein Q9NZJ0 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR up-regulates binding 9606 BTO:0000567 27906959 t miannu Here, we identify human SDE2 as a new genome surveillance factor regulated by PCNA interaction. The cleaved SDE2 products need to be degraded by the CRL4CDT2 ubiquitin E3 ligase in a cell cycle- and DNA damage-dependent manner, and failure to degrade SDE2 impairs S phase progression and cellular survival. SIGNOR-272808 0.683 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 27023846 f miannu Mitochondrial ribosomes (mitoribosomes) perform protein synthesis inside mitochondria, the organelles responsible for energy conversion and adenosine triphosphate production in eukaryotic cells. SIGNOR-261487 0.7 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CEBPB protein P17676 UNIPROT down-regulates activity transcriptional regulation 9606 17139329 t fferrentino Phosphorylation of receptor-regulated SMADs (for example, SMAD1 or SMAD3) stimulates dimer formation with SMAD4 and translocation to the nucleus, where the SMADs regulate the transcription of target gene SMAD3 binds to C/EBPs and inhibits their transcriptional activity, including their ability to transactivate the Pparg2 promoter SIGNOR-253538 0.561 ABT-737 chemical CID:11228183 PUBCHEM BCL2L1 protein Q07817 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271;BTO:0000776;BTO:0000785 17200714 t gcesareni A cell-permeant compound, abt-737, binds with high affinity to bcl2, bcl2l1, and bcl2l2, antagonizes their antiapoptotic function, and induces apoptosis in select human tumor cell lines, primary patient-derived cells. SIGNOR-151784 0.8 NFIX protein Q14938 UNIPROT WNT5A protein P41221 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268889 0.2 DRD1 protein P21728 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257391 0.267 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr496 HIIENPQyFSDACVH 9606 9099755 t gcesareni In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785 SIGNOR-47167 0.2 SLC4A1 protein P02730 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 t lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  SIGNOR-266015 0.415 MDM2 protein Q00987 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates ubiquitination 9606 23252402 t gcesareni Although the interaction between notch1 and mdm2 results in ubiquitination of notch1, this does not result in degradation of notch1, but instead leads to activation of the intracellular domain of notch1. SIGNOR-200197 0.489 albuterol sulfate chemical CHEBI:2550 ChEBI ADRB2 protein P07550 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-206682 0.8 GALR1 protein P47211 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256687 0.449 sorafenib chemical CHEBI:50924 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258284 0.8 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000586 16293724 t lperfetto Because phosphorylation of β-catenin by GSK-3β leads to its rapid ubiquitination and subsequent degradation in the proteosome, inactivation of GSK-3β is often a prerequisite for stimulating the accumulation, nuclear translocation, and functional activity of β-catenin SIGNOR-227893 0.891 TNFRSF13C protein Q96RJ3 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000776;BTO:0000785 20889926 t lperfetto Activation of br3 induces recruitment and degradation of traf3. SIGNOR-168199 0.749 MAP2K3 protein P46734 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates phosphorylation 9606 BTO:0000887;BTO:0001103 11980910 t amattioni Mkk3 enhanced mirk kinase activity. Mkk3 possibly activates mirk by phosphorylating it. SIGNOR-86731 0.355 PRKCG protein P05129 UNIPROT KIR3DL1 protein P43629 UNIPROT down-regulates phosphorylation Ser415 QRKITRPsQRPKTPP 9606 17911614 t gcesareni Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover. SIGNOR-158133 0.2 MC3R protein P41968 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256748 0.293 MBOAT7 protein Q96N66 UNIPROT 1-phosphatidyl-1D-myo-inositol smallmolecule CHEBI:16749 ChEBI up-regulates quantity chemical modification -1 18772128 t miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. SIGNOR-267248 0.8 TUBA8 protein Q9NY65 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. SIGNOR-269729 0.7 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT down-regulates activity phosphorylation Thr495 LLSLFEDtLDPT -1 12738781 t miannu Here, we have shown that Plk1 is responsible for part of the phosphorylation of Myt1 during M phase. The kinase activity of human Myt1 is reported to be decreased during M phase, and the decreased activity correlates with hyperphosphorylated forms of Myt1 (35, 37). We then tested the ability of these mutant forms of Myt1 (GST fusion proteins), to serve as a substrate for Plk1 in vitro. Quantification of the result (Fig. 5C) showed that Ser-426 is the major phosphorylation site by Plk1 in vitro and Thr-495 the second major site. SIGNOR-263097 0.709 Spike protein-ACE2 complex SIGNOR-C240 SIGNOR AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates 17522231 f lperfetto These results suggest that when SARS-CoV binds ACE2 it is internalized and penetrates early endosomes in a clathrin-dependent manner |The clathrin-dependent endocytosis is initiated by the binding of adaptor protein 2 (AP2) complexes to the cytoplasmic tail of the cell-surface receptors, which recruits clathrins SIGNOR-260711 0.2 CoV2 Spike protein-ACE2 complex SIGNOR-C254 SIGNOR AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates 17522231 f lperfetto These results suggest that when SARS-CoV binds ACE2 it is internalized and penetrates early endosomes in a clathrin-dependent manner |The clathrin-dependent endocytosis is initiated by the binding of adaptor protein 2 (AP2) complexes to the cytoplasmic tail of the cell-surface receptors, which recruits clathrins SIGNOR-260756 0.2 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu63 VQGNLEReCMEEKCS 10090 BTO:0001103 11133752 t lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. SIGNOR-263689 0.67 BZW2 protein Q9Y6E2 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 31643092 f miannu WB showed that BZW2 silence significantly decreased p‐ERK protein level in Colo205 cells, whereas BZW2 overexpression upregulated p‐ERK protein expression in HCT116 cells (Figure 3a,b) SIGNOR-261219 0.2 RAG2 protein P55895 UNIPROT MTOR protein P42345 UNIPROT up-regulates relocalization 9606 22790199 t gcesareni Rag gtpases, together with a multi-protein complex called ragulator, mediate amino acid-mediated mtor recruitment to the lysosome surface where mtor becomes activated. SIGNOR-198245 0.27 clozapine chemical CHEBI:3766 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258368 0.8 mTORC1 complex SIGNOR-C3 SIGNOR NRBF2 protein Q96F24 UNIPROT up-regulates activity phosphorylation Ser113 AEDAEGQsPLSQKYS 9606 28059666 t miannu Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association. SIGNOR-265876 0.2 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0002181 SIGNOR-C3 10942774 t lperfetto PHAS-I in adipocytes and HEK293 cells is phosphorylated in the following five sites, all of which conform to a (S/T)P motif (9, 10): Thr-36, Thr-45, Ser-64, Thr-69, and Ser-82. Thr-45 and Ser-64 flank the eIF4E-binding motif (7, 8), and phosphorylation of either site blocks eIF4E binding in vitro (10, 11). Insulin stimulates the phosphorylation of Thr-36, Thr-45, Ser-64, and Thr-69 in both fat cells and HEK293 cells, and incubating cells with rapamycin decreases the phosphorylation of these sites.Immunoprecipitated epitope-tagged mammalian target of rapamycin (mTOR) phosphorylated Thr-36/45. mTOR also phosphorylated Thr-69 and Ser-64 but only when purified immune complexes were incubated with the activating antibody, mTAb1. SIGNOR-226710 0.924 TIM22 complex complex SIGNOR-C424 SIGNOR Insertion into mitochondrial membrane phenotype SIGNOR-PH193 SIGNOR up-regulates 32901109 f lperfetto The TIM22 complex is responsible for the translocation and insertion of hydrophobic membrane proteins, including mitochondrial carrier proteins and translocase subunits (Tim17, Tim22 and Tim23) SIGNOR-267710 0.7 mTORC1 complex SIGNOR-C3 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR down-regulates 9606 23863160 f lperfetto Historically, it was known that autophagy was switched off when mTORC1 was active and that inhibition of mTORC1 was a potent autophagy inducer. SIGNOR-209922 0.7 ACE2 protein Q9BYF1 UNIPROT CoV2 Spike protein-ACE2 complex SIGNOR-C254 SIGNOR form complex binding 9534 BTO:0001444 32155444 t miannu We report here that ACE2 could mediate SARS-CoV-2 S-mediated entry into cells, establishing it as a functional receptor for this newly emerged coronavirus. The SARS-CoV-2 SB engages human ACE2 (hACE2) with comparable affinity to SARS-CoV SB from viral isolates associated with the 2002–2003 epidemic (i.e., binding with high affinity to hACE2). Tight binding to hACE2 could partially explain the efficient transmission of SARS-CoV-2 in humans, as was the case for SARS-CoV. SIGNOR-260740 0.2 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT down-regulates activity phosphorylation Ser324 LTSVSRGsSLKILSK 9606 10521508 t Manara Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization. SIGNOR-260898 0.2 TAF10 protein Q12962 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269581 0.768 ARID1A protein O14497 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270743 0.75 ECM stimulus SIGNOR-ST20 SIGNOR A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259034 0.7 WNK1 protein Q9H4A3 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Ser382 KRASFAKsVIGTPEF 9606 17190791 t gcesareni We finally establish that full-length wnk1, wnk2 and wnk3, but not wnk4, are capable of directly phosphorylating ser382 of wnk1 in vitro. This supports the notion that t-loop phosphorylation of wnk isoforms is controlled by trans-autophosphorylation. SIGNOR-151675 0.2 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI MAPK8 protein P45983 UNIPROT down-regulates chemical inhibition 9606 11717429 t gcesareni We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm). SIGNOR-111983 0.8 PRKACA protein P17612 UNIPROT KCNJ13 protein O60928 UNIPROT up-regulates phosphorylation Ser287 EICQRRTsYLPSEIM 9606 18976636 t gcesareni Pka activation induced an increase of kir7.1 currents. This effect was absent in mutant kir7.1 channels lacking pka consensus site (287)s SIGNOR-181859 0.2 TNF protein P01375 UNIPROT JAG2 protein Q9Y219 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004914 14586405 f We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues. SIGNOR-253608 0.324 BRD3 protein Q15059 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity binding 9606 BTO:0003292 28045112 t lperfetto Brd3 interacts with both IRF3 and p300, increases p300-mediated acetylation of IRF3, and enhances the association of IRF3 with p300 upon virus infection.|Brd3 enhances p300-mediated acetylation of IRF3 SIGNOR-262044 0.322 bisphenol A chemical CHEBI:33216 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 31995776 t miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . SIGNOR-268732 0.8 KDM3A protein Q9Y4C1 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 16603237 t miannu Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.  SIGNOR-276846 0.2 MAPK1 protein P28482 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 BTO:0000938 20444238 t gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. SIGNOR-165204 0.48 PTPN14 protein Q15678 UNIPROT CAV1 protein Q03135 UNIPROT down-regulates activity dephosphorylation 9606 32152405 t miannu Finally, PTPN14 overexpression in B16F10 cells reduced the ability of CAV1 to induce metastasis in vivo.|Moreover, the CAV1 (Y14F) mutant protein was shown to co-immunoprecipitate with PTPN14 even in the absence of E-cadherin, and overexpression of PTPN14 reduced CAV1 phosphorylation on tyrosine 14, as well as suppressed CAV1 enhanced cell migration, invasion and Rac-1 activation in B16F10, metastatic colon [HT29 (US)] and breast cancer (MDA-MB-231) cell lines. SIGNOR-277054 0.2 4-[4-(2-fluorophenyl)phenyl]-N-(4-hydroxyphenyl)butanamide chemical CHEBI:92949 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 15362850 t gcesareni In steady-state kinetics experiments, cmpd1 was observed to prevent the p38alpha-dependent phosphorylation (k(i)(app) = 330 nm) of the splice variant of mitogen-activated protein kinase-activated protein kinase 2 (mk2a) that contains a docking domain for p38alpha and p38beta SIGNOR-128864 0.8 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT down-regulates activity phosphorylation Ser426 CSLLLDSsLSSNWDD -1 12738781 t miannu Here, we have shown that Plk1 is responsible for part of the phosphorylation of Myt1 during M phase. The kinase activity of human Myt1 is reported to be decreased during M phase, and the decreased activity correlates with hyperphosphorylated forms of Myt1 (35, 37). We then tested the ability of these mutant forms of Myt1 (GST fusion proteins), to serve as a substrate for Plk1 in vitro. Quantification of the result (Fig. 5C) showed that Ser-426 is the major phosphorylation site by Plk1 in vitro and Thr-495 the second major site. SIGNOR-263096 0.709 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 SIGNOR-C83 10428798 t gcesareni Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity. SIGNOR-69718 0.49 alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity precursor of 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267936 0.8 IKBKE protein Q14164 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates phosphorylation Ser472 TQREGVSsLDSSSLS 9606 10893229 t gcesareni In response to a viral infection, phosphorylated on ser-477 and ser-479 by tbk1 and ikbke1. Phosphorylation, and subsequent activation is inhibited by vaccinia virus protein e3. SIGNOR-79143 0.675 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI NR3C2 protein P08235 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258714 0.8 ethanolaminium(1+) smallmolecule CHEBI:57603 ChEBI O-phosphonatoethanaminium(1-) smallmolecule CHEBI:58190 ChEBI up-regulates quantity precursor of 29928787 t lperfetto In this study, we investigated the roles of ethanolamine kinases (Etnk-1 and 2) and choline kinases (Chk-α and β) in contributing to increased PE in human breast and pancreatic cancer cells. SIGNOR-275638 0.8 DAPK1 protein P53355 UNIPROT MAP1B protein P46821 UNIPROT up-regulates binding 9606 18806760 t gcesareni Dapk-1 interacts with the microtubule-associated protein map1b, in particular in conditions of amino-acid starvation. SIGNOR-181305 0.265 entacapone chemical CHEBI:4798 ChEBI COMT protein P21964 UNIPROT down-regulates activity chemical inhibition -1 7703232 t miannu Human soluble (S) and membrane-bound (MB) catechol O-methyltransferase (COMT, EC 2.1.1.6) enzymes have been expressed at sufficiently high levels in Escherichia coli and in baculovirus-infected insect cells to allow kinetic characterization of the enzyme forms. The use of tight-binding inhibitors such as entacapone enabled the estimation of actual enzyme concentrations and, thereby, comparison of velocity parameters, substrate selectivity, and regioselectivity of the methylation of both enzyme forms. SIGNOR-258476 0.8 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CSF2RB protein P32927 UNIPROT up-regulates activity phosphorylation 9606 BTO:0005248 8758906 t irozzo We demonstrated that Bcr-Abl co-immunoprecipitates with, and constitutively phosphorylates, the common βc,subunit of the interleukin 3 and granulocyte/macrophage-colony stimulating factor receptors.We demonstrate that Bcr-Abl interacts with the common βc subunit of the IL-3 family of receptors and phosphorylates it on tyrosine. SIGNOR-255814 0.2 ARHGEF25 protein Q86VW2 UNIPROT RHOA protein P61586 UNIPROT up-regulates guanine nucleotide exchange factor 10090 BTO:0000165;BTO:0000222 16314529 t gcesareni Exogenous expression of geft promotes myogenesis ofc2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process. SIGNOR-236885 0.829 NRG2 protein O14511 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 t gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. SIGNOR-122056 0.78 PAK1 protein Q13153 UNIPROT ELF3 protein P78545 UNIPROT up-regulates phosphorylation Ser207 GTGASRSsHSSDSGG 9606 BTO:0000150 17491012 t lperfetto Phosphorylation-dependent regulation of stability and transforming potential of ets transcriptional factor ese-1 by p21-activated kinase 1. Pak1 selectively phosphorylates ese-1 at ser(207). Intriguingly, pak1 phosphorylation inactive mutant ese1-s207a is more unstable SIGNOR-154743 0.468 cis-(z)-Flupenthixol chemical CHEBI:10454 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258715 0.8 C1QA protein P02745 UNIPROT Complement C1q complex SIGNOR-C308 SIGNOR form complex binding -1 29449492 t lperfetto C1q comprises 18 polypeptide chains; three chains of C1q-A, -B, and -C trimerize to form six collagen-like triple helices connected to six globular (trimeric) ligand-recognition (gC1q) modules (fig. S1B) (1). SIGNOR-263390 0.629 ITGA3 protein P26006 UNIPROT A3/b1 integrin complex SIGNOR-C161 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253173 0.797 PRKACA protein P17612 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser8 MPLNRTLsMSSLPGL -1 2117608 t miannu Phosphorylation of rabbit muscle glycogen synthase by cyclic AMP-dependent protein kinase has been shown to enhance subsequent phosphorylation by casein kinase I . phosphorylation at Ser7 is required for modification of Ser10 by casein kinase I. SIGNOR-249988 0.49 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Thr266 TDLDAVRtPEPLEEF BTO:0000007 10593981 t llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. SIGNOR-250736 0.711 THR proteinfamily SIGNOR-PF84 SIGNOR RARG protein P13631 UNIPROT up-regulates activity binding 9606 15650024 t inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. SIGNOR-267781 0.2 AMPK complex SIGNOR-C15 SIGNOR RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser635 DTHFRSPsSSVGSPP 9606 19815529 t lperfetto We show that ampk down-regulates rrna synthesis under glucose restriction by phosphorylating the rna polymerase i (pol i)-associated transcription factor tif-ia at a single serine residue (ser-635). SIGNOR-216592 0.287 MYOCD protein Q8IZQ8 UNIPROT ACTG2 protein P63267 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19797053 f miannu  These results demonstrate the ability of MYOCD to discriminate among several juxtaposed CArG elements, presumably through its novel partnership with NKX3.1, to optimally transactivate the human ACTG2 promoter. SIGNOR-254620 0.436 RPS29 protein P62273 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262422 0.879 STK11 protein Q15831 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates activity phosphorylation Thr183 SDGEFLRtSCGSPNY -1 14976552 t lperfetto We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP_activated protein kinase (AMPK). SIGNOR-122721 0.582 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. SIGNOR-75918 0.606 AKT1 protein P31749 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser694 QTSKRHDsDTFPELK 9606 20085797 t lperfetto We identify a novel akt phosphorylation site in brca1 at s694 which is responsive to activation of these signaling pathways. These data suggest akt phosphorylation of brca1 increases total protein expression by preventing proteasomal degradation SIGNOR-163472 0.52 ITGAD protein Q13349 UNIPROT AD/b2 integrin complex SIGNOR-C172 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253195 0.731 CREB1 protein P16220 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 21902831 f gcesareni Chen et al. showed that phosphorylated creb is present at high levels in cells of the dermomyotome that express pax3, myod and myf5 and that this phosphorylation is critical for the induction of these genes. SIGNOR-176533 0.292 PCGF2 protein P35227 UNIPROT UBE2I protein P63279 UNIPROT down-regulates activity binding 9606 BTO:0000007 18211895 t miannu Based on this finding of interaction between MEL-18 and UBC9, we envisioned a mechanism in which MEL-18 bound to HSF2 inhibits its sumoylation by binding to and inhibiting the activity of UBC9 enzymes that approach HSF2. SIGNOR-226248 0.592 SGK3 protein Q96BR1 UNIPROT FLII protein Q13045 UNIPROT up-regulates phosphorylation Ser436 RLRRRKDsAQDDQAK 9606 19293151 t lperfetto Here we show that flii is an in vivo substrate of cisk that functions downstream of pi 3-kinase. Cisk can associate with flii and phosphorylate flii at residues ser(436) and thr(818).We demonstrate here that cisk can enhance er transcription, which is dependent on its kinase activity, and mutation of cisk phosphorylation sites on flii attenuates its activity as an er co-activator. SIGNOR-184688 0.363 PPP3CB protein P16298 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 t In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. SIGNOR-248379 0.383 SLC24A5 protein Q71RS6 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264403 0.8 N-[4-[2-ethyl-4-(3-methylphenyl)-5-thiazolyl]-2-pyridinyl]benzamide chemical CHEBI:91360 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates activity chemical inhibition -1 16162000 t miannu A novel structural class of 4-phenyl-5-pyridyl-1,3-thiazoles was optimized as inhibitors of p38 MAP kinase and the proinflammatory cytokine TNF-α. it only significantly inhibited p38α (IC50 = 7.1 nM) and p38β (IC50 = 200 nM) in a concentration-dependent manner and was approximately 28 times more selective for p38α over p38β. SIGNOR-262222 0.8 STAT5A protein P42229 UNIPROT PIM2 protein Q9P1W9 UNIPROT up-regulates quantity by expression transcriptional regulation 16146838 t lperfetto The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. SIGNOR-249622 0.42 NRP1 protein O14786 UNIPROT CoV2 spike protein-NRP1 complex SIGNOR-C267 SIGNOR form complex binding 9606 BTO:0000007 other t https://doi.org/10.1101/2020.06.07.137802 miannu Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system To determine whether SARS-CoV-2 uses NRP1 for virus entry, we generated replication deficient lentiviruses pseudotyped with SARS-CoV-2 spike protein (S) that drive expression of green fluorescent protein (GFP) upon infection. When expressed alone, ACE2 rendered cells susceptible to infection (Fig. 1a). NRP1 alone allowed lower, yet detectable levels of infection, both in HEK-293T and in Caco2 cells (Fig. 1a,b), while cells transfected with plasmids encoding only TMPRSS2 were not infected (Fig. 1a). The co-expression of TMPRSS2 with either ACE2 or NRP1 potentiated the infection, with ACE2 together with TMPRSS2 being twice as efficient as NRP1 with TMPRSS2 (Fig. 1c) SIGNOR-261672 0.2 DLL3 protein Q9NYJ7 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209738 0.469 CSNK2A1 protein P68400 UNIPROT CBX5 protein P45973 UNIPROT up-regulates phosphorylation Ser11 KTKRTADsSSSEDEE 9606 21245376 t gcesareni Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability. SIGNOR-171695 0.354 CSNK1A1L protein Q8N752 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates activity phosphorylation Ser158 LLDNSRMsCQDEGCG 9606 BTO:0000567 18411282 t done miannu However, the siRNA knockdown of CK1α1L significantly reduced the nuclear export of OREBP/TonEBP under hypotonic conditions (Fig. 5F). Taken together, these data suggest that CK1α1L is the kinase that phosphorylates Ser-158 in the regulation of OREBP/TonEBP export. SIGNOR-274111 0.2 ITGAV protein P06756 UNIPROT Av/b5 integrin complex SIGNOR-C178 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253207 0.763 PHA-848125 chemical CID:16718576 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206151 0.8 EIF2AK2 protein P19525 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation 9606 31226023 t miannu Besides PERK, eIF2α can also be phosphorylated by three other kinases: heme-regulated inhibitor kinase (HRI), general control nonderepressible 2 (GCN2), and PKR. PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. Together, these four eIF2α kinases and their convergent downstream signaling pathways are known as the integrated stress response (ISR) SIGNOR-260168 0.717 PHA-665752 chemical CHEBI:90197 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206088 0.8 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB4 protein P16144 UNIPROT up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259003 0.2 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding -1 2467839 t irozzo The protein products of the fos (Fos) and jun (Jun) proto-oncogenes have been shown to associate with a DNA element known as the transcription factor activator protein-1 (AP-1) binding site. Jun (previously known as the Fos-binding protein p39) and Fos form a protein complex in the nucleus. These data demonstrate a cooperative interaction between the protein products of two proto-oncogenes with a DNA element involved in transcriptional regulation. SIGNOR-256362 0.951 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX2 protein P48431 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000596 24942200 t flangone During neural fate specification, nuclear translocation of ERK1/2 is critical for its activation of Sox2 transcription. More-over, melatonin-induced Sox2 expression, through ERK1/ 2 activation, could locate between base pairs2719 and 1708 in the mouse Sox2 gene. SIGNOR-241977 0.2 CDK1 protein P06493 UNIPROT SYN3 protein O14994 UNIPROT up-regulates phosphorylation Ser470 PQGQQPLsPQSGSPQ 9606 14732590 t lperfetto A rare, missense polymorphism, s470n, was identified in the synapsin iii gene and appeared more frequently in individuals with schizophrenia than in controls. Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action. SIGNOR-121398 0.2 TCL1B protein O95988 UNIPROT AKT1 protein P31749 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t gcesareni In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation. SIGNOR-81713 0.662 Non-erythrocytic spectrin complex SIGNOR-C385 SIGNOR Cell_shape phenotype SIGNOR-PH182 SIGNOR up-regulates 9606 24302288 f lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell SIGNOR-266033 0.7 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 20670887 t lperfetto Specifically as part of mTORC1, mTOR directly phosphorylates the ribosomal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2)phosphorylation of the 4E-BPs leads to their inhibition and release from eIF4E at the 5_ cap of mRNAs SIGNOR-235745 0.753 GDNF protein P39905 UNIPROT Neural_tissue_regeneration phenotype SIGNOR-PH68 SIGNOR up-regulates 10116 15212950 f miannu The glial cell line-derived neurotrophic factor (GDNF) is involved in the development and maintenance of neural tissues. In normal development, GDNF promotes survival of sympathetic, parasympathetic, and spinal motorneurons. It even promotes regeneration of spinal motor neurons after spinal cord injury. SIGNOR-252170 0.7 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser74 TPHLPPCsPPKQGKK 9606 10339564 t lperfetto Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction. SIGNOR-217280 0.94 SIRT1 protein Q96EB6 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates activity deacetylation 9606 BTO:0001103 22395773 t lperfetto SIRT1 controls the acetylation of FOXO transcription factors, which are important regulators of lipid and glucose metabolism as well as stress response. On the other hand, SIRT1 can also stimulate the gluconeogenic transcriptional program by deacetylating and activating FOXO1. SIGNOR-253509 0.803 SIRT1 protein Q96EB6 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity deacetylation 10090 BTO:0001103 24003218 t lperfetto SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 SIRT1 activation has been reported to increase dramatically endurance exercise through the activation of PGC-1_ in muscle, which stimulates fatty acid oxidation SIGNOR-217963 0.792 FYN protein P06241 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Tyr1105 CSEVERTyLKTKSSS -1 10195142 t lperfetto To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain. SIGNOR-247151 0.724 R547 chemical CID:6918852 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206361 0.8 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT up-regulates activity phosphorylation Ser247 GALSNSEsIPTIDGL 9534 BTO:0000298 11483516 t llicata BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads. SIGNOR-250599 0.294 IRX1 protein P78414 UNIPROT NPTX1 protein Q15818 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. SIGNOR-261655 0.258 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser432 KMPNTNGsIGHSPLS 9606 24614225 t lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204724 0.529 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser59 GGQESQPsPLALLAA 9606 11904305 t gcesareni Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1. SIGNOR-116158 0.629 HSPA2 protein P54652 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates binding 9606 12391142 t gcesareni Coimmunoprecipitation analysis revealed a physical interaction between endogenous hsp72 and ask1 in nih 3t3 cells exposed to mild heat shock. Hsp72 blocked both the homo-oligomerization of ask1 and ask1-dependent apoptosis. SIGNOR-94565 0.2 (-)-anisomycin chemical CHEBI:338412 ChEBI MAPK13 protein O15264 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb gcesareni SIGNOR-189696 0.8 RPS27L protein Q71UM5 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262445 0.786 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 15241418 t gcesareni We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function SIGNOR-126736 0.733 DLG4 protein P78352 UNIPROT NOS1 protein P29475 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu Neuronal NOS, a Ca2+-activated form of NOS, can bind to PSD-95 through a class III PDZ domain interaction in which its own amino-terminal PDZ domain binds to a PDZ domain of PSD-95. PSD-95 may concentrate nNOS near the NMDA receptor at postsynaptic sites in these neurons. SIGNOR-264227 0.726 DZIP3 protein Q86Y13 UNIPROT H2AZ1 protein P0C0S5 UNIPROT up-regulates activity monoubiquitination Lys121 IHKSLIGkKGQQKTV 9606 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271748 0.2 Dihydromorphine chemical CHEBI:4575 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258786 0.8 CDC7 protein O00311 UNIPROT ESCO1 protein Q5FWF5 UNIPROT down-regulates phosphorylation 9606 23314252 t gcesareni We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases, cdc7-dbf4 and the gsk-3 homolog mck1. SIGNOR-200397 0.442 OGT protein O15294 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity glycosylation Ser84 VADIRKQsEPFFKAT 9606 BTO:0000007 26399441 t lperfetto O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth|O-GlcNAcylation of G6PD activates enzyme activity|G6PD is dynamically modified by O-GlcNAc at serine 84|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. SIGNOR-267582 0.267 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr668 SYCGKRFtRSDELQR 9606 BTO:0000887;BTO:0001260 18258854 t llicata Here we have used a variety of approaches to identify 3 amino acids (thr668, ser670, and thr681) in the zinc finger domain of sp1 that are modified by pkc-zeta angiotensin ii, which activates pkc-? Phosphorylation (at thr410) via the angiotensin ii type 1 receptor, stimulates sp1 phosphorylation and increases sp1 binding to the platelet-derived growth factor-d promoter. SIGNOR-160770 0.497 MEST protein Q5EB52 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates transcriptional regulation 9606 24827625 f areggio Our data demonstrate that Mest alleviated CCl4-induced collagen deposition in liver tissue and improved the condition of the liver in rats. Mest also significantly reduced the expression and distribution of β-catenin, α-SMA and Smad3 both in vivo and in vitro, in addition to the viability of HSCs in vitro. SIGNOR-258982 0.253 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Ser90 QHVRSHSsPASLQLG 26375055 t lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity SIGNOR-276522 0.265 phentolamine chemical CHEBI:8081 ChEBI ADRA1B protein P35368 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258446 0.8 AXIN2 protein Q9Y2T1 UNIPROT APC protein P25054 UNIPROT up-regulates binding 9606 BTO:0000142;BTO:0000671;BTO:0000763 10911903 t gcesareni It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains. SIGNOR-79944 0.834 NUMA1 protein Q14980 UNIPROT TUBA8 protein Q9NY65 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-116826 0.2 KAR proteinfamily SIGNOR-PF57 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264940 0.8 KAT2B protein Q92831 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269611 0.2 IRF2BPL protein Q9H1B7 UNIPROT GNRH1 protein P01148 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000938 17627301 t miannu EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function. SIGNOR-267154 0.427 GPR119 protein Q8TDV5 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257366 0.252 nimodipine chemical CHEBI:7575 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition -1 18250364 t Luana Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression.  SIGNOR-257765 0.8 MYOG protein P15173 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 7739551 t Simone Vumbaca [...] confirming that myogenin binds to the E1 and E2 E boxes located in close proximity to the MRF4 transcription start site. SIGNOR-255642 0.409 suprofen chemical CHEBI:9362 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001061 18667313 t Luana Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2.  SIGNOR-257808 0.8 COL21A1 protein Q96P44 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 35267698 t lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. SIGNOR-272347 0.357 serotonin smallmolecule CHEBI:28790 ChEBI HTR3A protein P46098 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264282 0.8 USF2 protein Q15853 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 9731700 f miannu Overexpression of cathepsin D (CD), a ubiquitous lysosomal protease, is closely associated with a poor clinical outcome for patients with breast cancer. Estrogen greatly induces transcription of the CD gene in estrogen receptor (ER)-positive breast cancer cells. These experiments suggest a model for ER stimulation of the CD promoter in which recruitment of USF-1/2 to the promoter is required for activation of transcription. SIGNOR-255594 0.386 AVPR2 protein P30518 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256754 0.571 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Pro) smallmolecule CHEBI:29177 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270427 0.8 CSNK2A3 protein Q8NEV1 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1112 VPIAVGEsDFENLNT 9606 BTO:0000938 19064667 t lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. SIGNOR-275751 0.2 MUTYH protein Q9UIF7 UNIPROT ATR protein Q13535 UNIPROT up-regulates binding 9606 BTO:0000007 21615992 t miannu Binding of myh directly participates in atr and topbp1 activation in dna damage signaling, leading to apoptosis. SIGNOR-173966 0.252 MRPL3 protein P09001 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262366 0.699 SRC protein P12931 UNIPROT SPRY2 protein O43597 UNIPROT up-regulates phosphorylation Tyr55 AIRNTNEyTEGPTVV 9606 15564375 t lperfetto Activation of signalling by fibroblast growth factor receptor leads to phosphorylation of the signalling attenuator human sprouty 2 (hspry2) on residue y55. we show that hspry2 is a direct substrate for src family kinases, including src itself.Phosphorylation of hspry2 is required for hspry2 to inhibit activation of the extracellular signal-regulated kinase pathway. SIGNOR-131189 0.547 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269377 0.719 BMP7 protein P18075 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 7644468 t lperfetto In transfected cos-1 cells, osteogenic protein (op)-1/bmp-7, and less efficiently bmp-4, bound to bmpr-ii. Bmpr-ii bound ligands only weakly alone, but the binding was facilitated by the presence of previously identified type i receptors for bmps. Binding of op-1/bmp-7 to bmpr-ii was also observed in nontransfected cell lines. Moreover, a transcriptional activation signal was transduced by bmpr-ii in the presence of type i receptors after stimulation by op-1/bmp-7. SIGNOR-217520 0.77 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10913193 t gcesareni Sik/brk is the first identified tyrosine kinase that can phosphorylate sam68 and regulate its activity within the nucleus, where it resides during most of the cell cycle SIGNOR-80020 0.738 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270423 0.8 QRICH1 protein Q2TAL8 UNIPROT FARS2 protein O95363 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269403 0.2 PSTPIP1 protein O43586 UNIPROT PTPN18 protein Q99952 UNIPROT up-regulates activity binding 9534 BTO:0004055 9422760 t lperfetto These data confirm the importance of these residues to the binding interaction, and they suggest that much of the COOH-terminal region of PTP HSCF may be required for highest affinity binding to PST PIP.|Because this protein-protein interaction appears to be required for the dephosphorylation of PST PIP phosphotyrosines (20), it may be a potentially important new mechanism for the regulation of the cytoskeleton. SIGNOR-262594 0.581 CDK7 protein P50613 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10949034 t lperfetto Activation of estrogen receptor alpha by s118 phosphorylation involves a ligand-dependent interaction with tfiih and participation of cdk7. SIGNOR-81170 0.423 SLBP protein Q14493 UNIPROT H3-5 protein Q6NXT2 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265420 0.2 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 BTO:0000007 11997495 t lperfetto We have shown that the interaction of the bims and bimad isoforms with bax leads to a conformational change in this protein analogous to that triggered by the bh3-only protein bid.We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome. SIGNOR-87280 0.826 BICDL1 protein Q6ZP65 UNIPROT KIF1C protein O43896 UNIPROT up-regulates activity binding -1 20360680 t miannu BICDR-1 interacts with the dynein/dynactin motor complex. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation. These results show that BICDR-1 regulates recruitment and/or activity of the anterograde kinesin motor Kif1C on Rab6 secretory carriers. SIGNOR-266876 0.2 FZD5 protein Q13467 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 23151663 t areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  SIGNOR-258957 0.645 MRAP2 protein Q96G30 UNIPROT MC5R protein P33032 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 t miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. SIGNOR-252369 0.516 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates relocalization 9606 BTO:0001103 11062529 t gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-84056 0.387 BTC protein P35070 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 14967450 t gcesareni Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4. SIGNOR-121953 0.737 MN1 protein Q10571 UNIPROT MYBBP1A protein Q9BQG0 UNIPROT up-regulates activity binding -1 12569362 t irozzo Taken together, our results indicate that MN1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate RAR/RXR-mediated transcription through interaction with p160 and p300. SIGNOR-256021 0.2 ABL1 protein P00519 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Tyr266 TDSIRDEyAFLQKKY 9606 BTO:0000793 29022905 t miannu In this study, we found that c-Abl phosphorylated Drp1 at tyrosine 266, 368 and 449 in vitro and in vivo, which augmented the GTPase activity of Drp1 and promoted Drp1-mediated mitochondrial fragmentation. SIGNOR-277328 0.263 DMD protein P11532 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255998 0.682 PTPN6 protein P29350 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation 9606 11266449 t lperfetto Overexpression of shp-1 results in ros dephosphorylation and effectively downregulates ros-dependent proliferation and transformation. We propose that shp-1 is an important downstream regulator of ros signaling. SIGNOR-105922 0.375 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257974 0.8 PTPRC protein P08575 UNIPROT FYN protein P06241 UNIPROT up-regulates activity dephosphorylation Tyr531 FTATEPQyQPGENL 9606 BTO:0000782 11909961 t On the membrane SKAP55, via its phosphorylated Tyr-271, further binds the SH2 domain of Fyn to replace the low-affinity bound inhibitory site of the kinase. Consequently, CD45 may have transiently disassociated with the Tyr-232 residue of SKAP55 through dephosphorylation and simultaneously interacted with the released the phosphorylated inhibitory tyrosine residue of Fyn for dephosphorylation, resulting in activation of the Src family kinase Fyn and initiation of TCR-engaged signal transduction. SIGNOR-248352 0.72 Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT ACE protein P12821 UNIPROT up-regulates activity binding 9606 32201502 t MIANNU Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I SIGNOR-260231 0.2 RANBP3 protein Q9H6Z4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity relocalization 9606 20704570 t lperfetto Importantly, PPM1A facilitates the interaction of dephosphorylated Smad2/3 with RanBP3, a nuclear export factor [75]. As a result, PPM1A-mediated dephosphorylation of Smad2/3 promotes nuclear export of Smad2/3 and shuts off TGF-_-induced anti-proliferative and transcriptional responses SIGNOR-217625 0.446 RPS6KA3 protein P51812 UNIPROT CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser173 PGKRRTQsLSALPKE 9606 BTO:0000848 21087211 t gcesareni Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3) SIGNOR-169887 0.2 SLC25A12 protein O75746 UNIPROT aspartic acid smallmolecule CHEBI:22660 ChEBI up-regulates quantity relocalization 9606 12084073 t miannu Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. SIGNOR-265156 0.8 IL1A protein P01583 UNIPROT FBN1 protein P35555 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000452 9036927 f Regulation miannu UVB irradiation (50 mJ) of cultured skin fibroblasts suppressed fibrillin mRNA by 50%, consistent with a direct effect of radiation. UVB irradiation (50 mJ) of cultured skin fibroblasts suppressed fibrillin mRNA by 50%, consistent with a direct effect of radiation. Addition to the cultured fibroblasts of several cytokines upregulated by UVB showed that IL-1alpha had no effect on fibrillin mRNA in unirradiated cells, but in irradiated cells, this cytokine enhanced the suppression of fibrillin mRNA. SIGNOR-251890 0.2 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1787 SPNYSPTsPSYSPTS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248779 0.442 PPM1D protein O15297 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 15870257 t gcesareni Ppm1d dephosphorylates chk1 phospho-ser 345 SIGNOR-135972 0.486 Caspase 3 complex complex SIGNOR-C221 SIGNOR NFKBIA protein P25963 UNIPROT up-regulates quantity by stabilization cleavage -1 9367996 t lperfetto The cell-death protease cpp32 (caspase-3) in vitro specifically cleaved chicken and human ikappab-alpha at a conserved asp-ser sequence.Therefore, cleavage of I_B-_ by a CPP32-like protease could create what is sometimes called a super-repressor form of I_B-_ (20). That is, cleavage by CPP32 would block the ability of I_B-_ to undergo signal-induced degradation by removing the sites of signal-induced ubiquitination and by likely disrupting the ability of I_B-_ to become phosphorylated at critical Ser residues. SIGNOR-256456 0.432 STAG2 protein Q8N3U4 UNIPROT TNF protein P01375 UNIPROT up-regulates 9606 14660624 f miannu Stag2 is able to enhance the activity of the tumor necrosis factor alpha, the cd69, and the human immunodeficiency virus long terminal repeat promoters in a nf-kappab-dependent manner. SIGNOR-119988 0.2 Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity binding 9606 30205058 t miannu The exocyst is a multisubunit protein complex that was first identified and characterized in budding yeast. This complex mediates the tethering of secretory vesicles to the plasma membrane prior to fusion mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Sec3 interacts with PI(4,5)P2 (red dots) in the plasma membrane. Its interaction with the t-SNARE protein Sso promotes the assembly of the Sso–Sec9 binary t-SNARE complex. SIGNOR-270792 0.427 SCF-FBW7 complex SIGNOR-C135 SIGNOR MED13L protein Q71F56 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 23322298 t miannu The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association. SIGNOR-266689 0.366 BIRC3 protein Q13489 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation. SIGNOR-272713 0.737 CYP17A1 protein P05093 UNIPROT 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268652 0.8 IL10RB protein Q08334 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 t milica Specifically, il-10 effects the activation of jak1 (associated with the il-10 receptor ? Chain) and tyk2 (associated with the il-10 receptor ? Chain) and induces the activation of stat1, stat3, and, in some cells, stat5. SIGNOR-68013 0.634 PPARD protein Q03181 UNIPROT TXN protein P10599 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001950 18048767 f miannu Activation of PPAR-delta upregulated the expression of antioxidant genes superoxide dismutase 1, catalase, and thioredoxin and decreased reactive oxygen species production in ECs. SIGNOR-255052 0.2 CDKN2A protein P42771 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000176 7972006 f Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation. SIGNOR-259406 0.7 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Ser185 KTTQNRYsFYSTCSG -1 23444369 t miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. SIGNOR-273494 0.27 QRICH1 protein Q2TAL8 UNIPROT WARS1 protein P23381 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269410 0.2 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000007 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248296 0.422 PPM1A protein P35813 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16931515 t lpetrilli In this study, we have found that ppm1a, a metal ion-dependent protein serine/threonine phosphatase, physically interacts with and dephosphorylates smad1 both in vitro and in vivo. considering the highly conserved nature of the sxs motif in all r-smads, we reasoned that ppm1a might also recognize the sxs motif in the bmp-activated smad1. SIGNOR-149077 0.519 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269245 0.622 BCL2L1 protein Q07817 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0003328 9393856 f fcortellessa Bcl-xL Expression Prevents Cytochrome c Redistribution and Subsequent Mitochondrial Depolarization during Apoptosis. Bcl-xL expression prevented both cytochrome c redistribution and mitochondrial membrane depolarization. In contrast, zVAD treatment could not prevent either cytochrome c redistribution or mitochondrial membrane depolarization in control transfectants withdrawn from IL-3. Thus, cytochrome c redistribution from mitochondria is an early apoptotic event that precedes mitochondrial membrane depolarization. Bcl-xL expression functions to inhibit both of these events. In at least some forms of cell death, the ability of Bcl-xL to regulate these mitochondrial events cannot be mimicked by caspase inhibition SIGNOR-261683 0.7 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr973 RLGNGVLyASVNPEY -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase. We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246252 0.2 PRKACA protein P17612 UNIPROT PARP1 protein P09874 UNIPROT up-regulates activity phosphorylation Ser782 YSLLRGGsDDSSKDP 9606 BTO:0001412 25069723 t miannu  In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain).  SIGNOR-276652 0.2 ANK1 protein P16157 UNIPROT SLN protein O00631 UNIPROT down-regulates activity binding 9606 28487373 t lperfetto These results suggest that sAnk1 interacts with SLN both directly and in complex with SERCA1 and reduces SLN's inhibitory effect on SERCA1 activity. SIGNOR-265930 0.259 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates activity binding 9606 12629049 t Activation of PKC depends on the availability of DAG,a signaling lipid that is tightly and dynamically regulated. SIGNOR-251559 0.8 DLL1 protein O00548 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 11006133 t gcesareni These results suggest that delta1, jagged1, and jagged2 are ligands for notch1 and notch3 receptors. SIGNOR-82398 0.615 TLR2 protein O60603 UNIPROT TICAM2 protein Q86XR7 UNIPROT up-regulates activity binding 10090 22664090 t scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266747 0.44 Mob1 proteinfamily SIGNOR-PF42 SIGNOR LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates activity binding 9606 21084559 t miannu Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. SIGNOR-256186 0.941 GSK3A protein P49840 UNIPROT UNG protein P13051 UNIPROT down-regulates quantity by destabilization phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000812 phosphorylation:Ser64 EPGTPPSsPLSAEQL 27875297 t lperfetto Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation SIGNOR-264887 0.2 MARCHF1 protein Q8TCQ1 UNIPROT HLA-DRB4 protein P13762 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys254 FIYFRNQkGHSGLQP 9606 19117940 t miannu Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination. SIGNOR-271409 0.2 TP53 protein P04637 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10029407 f miannu p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1. SIGNOR-255430 0.59 trichostatin A chemical CHEBI:46024 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257935 0.8 GSK3B protein P49841 UNIPROT LGALS3 protein P17931 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21821001 f miannu Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells. SIGNOR-261903 0.344 CDKN1A protein P38936 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 7626805 t gcesareni P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage.We Have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases SIGNOR-30030 0.859 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CCNB1 protein P14635 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193540 0.8 HDAC1 protein Q13547 UNIPROT FSHR protein P23945 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23086931 f miannu Chromatin modifier MTA2 participates in the down-regulation of FSHR transcription. MTA2 is a potent corepressor of FSHR transcription, because it can recruit histone deacetylase-1 onto the FSHR promoter and participates in the down-regulation of FSHR expression upon FSH treatment. SIGNOR-254225 0.2 MASP1 protein P48740 UNIPROT C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Arg756 KGQAGLQrALEILQE -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263426 0.663 PTEN protein P60484 UNIPROT PREX2 protein Q70Z35 UNIPROT down-regulates activity binding 9606 BTO:0000007 25829446 t irozzo Here, we used cell biology, biochemistry, and genetic approaches to show that PTEN suppresses cell movement by blocking PREX2 GEF–catalyzed activation of the GTPase RAC1. PTEN binds PREX2 and directly inhibits GEF activity. SIGNOR-259190 0.605 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 9305639 t lperfetto These results, therefore, suggest that mtk1 directly phosphorylates and activates mkk3, mkk6 and sek1. SIGNOR-50894 0.642 NLRC4 inflammasome complex SIGNOR-C223 SIGNOR Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 f miannu Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. SIGNOR-263122 0.7 SMARCC2 protein Q8TAQ2 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270605 0.831 MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 9712898 t lperfetto The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, SEK1 SIGNOR-236376 0.718 TAB1 protein Q15750 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 17299140 t lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells. SIGNOR-153031 0.927 UBE2D1 protein P51668 UNIPROT ZSWIM2 protein Q8NEG5 UNIPROT up-regulates activity binding 9606 BTO:0000007 16522193 t miannu MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin.  SIGNOR-271554 0.325 SYNE1 protein Q8NF91 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 t lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. SIGNOR-263287 0.559 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 18394876 t lperfetto The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity SIGNOR-252834 0.908 Core Binding Factor complex complex SIGNOR-C214 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 19813271 f The core binding factor (CBF), consisting of a Runx protein and the CBFβ protein, is a transcription factor complex that is essential for emergence of the hematopoietic stem cell (HSC) from an endothelial cell stage. The hematopoietic defects observed in either Runx1 or CBFβ knockout mice underscore the necessity of this complex for definitive hematopoiesis. SIGNOR-255740 0.7 SVIP protein Q8NHG7 UNIPROT L3MBTL1 protein Q9Y468 UNIPROT down-regulates activity binding 9606 BTO:0000007 29018219 t lperfetto In response to DNA damage, VCP/p97, an ATPase which unfolds proteins, removes L3MBTL1 from H4K20me2, creating free H4K20me2 for 53BP1 to bind to (Fig. 3b). SIGNOR-262060 0.2 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR CBFB protein Q13951 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f irozzo However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins. SIGNOR-255852 0.2 ANKRD11 protein Q6UB99 UNIPROT BDNF protein P23560 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 29274743 t miannu Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.  SIGNOR-266732 0.2 POLR1C protein O15160 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266136 0.877 ADRA2C protein P18825 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256699 0.458 FUBP1 protein Q96AE4 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19637194 f irozzo In our analysis of FBP1 shRNA-transduced Hep3B cells, we found that p21 mRNA levels increase following FBP1 knockdown, suggesting that FBP1 functions as a repressor of p21. Our results identify the tumor suppressor p21 as the second direct FBP1 target gene in addition to the proto-oncogene c-myc. SIGNOR-259125 0.2 1-[2-[bis[4-(trifluoromethyl)phenyl]methoxy]ethyl]-3,6-dihydro-2H-pyridine-5-carboxylic acid chemical CHEBI:93185 ChEBI SLC6A1 protein P30531 UNIPROT down-regulates activity chemical inhibition -1 7851497 t miannu Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1. SIGNOR-258480 0.8 BACE2 protein Q9Y5Z0 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe635 HHQKLVFfAEDVGSN 9606 10931940 t lperfetto BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Aβ is produced from the Aβ precursor protein (APP) by two proteolytic events. A β-secretase activity cleaves APP at the N terminus of Aβ (β site) between amino acids Met-671 and Asp-672 |We show here that BACE2 cleaves APP at its β site and more efficiently at sites within the Aβ region of APP, after Phe-19 and Phe-20 of Aβ. SIGNOR-261775 0.56 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI guanosine 5'-monophosphate smallmolecule CHEBI:17345 ChEBI up-regulates quantity precursor of 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-268096 0.8 INSR protein P06213 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Tyr153 SEDIKSYyTVRQLEL -1 11506178 t lperfetto Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B SIGNOR-249369 0.78 AKT1 protein P31749 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Ser695 EERMRMEsRRQATVS -1 23264741 t miannu  Here we show that soluble growth factors enhance integrin signaling through Akt phosphorylation of FAK at Ser695 and Thr700.  SIGNOR-276437 0.44 PRKAA1 protein Q13131 UNIPROT NOS2 protein P35228 UNIPROT down-regulates 9606 BTO:0000801 BTO:0000887 14985344 f gcesareni Ampk by insulin-sensitizing drugs markedly inactivates in- ducible nitric-oxide synthase (inos). SIGNOR-120827 0.325 APEX1 protein P27695 UNIPROT CYP11B2 protein P19099 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22652909 f miannu We conclude that APEX1 is a novel transcriptional repressor of CYP11B2 and that differential APEX1 binding at -1651 of CYP11B2 results in altered gene expression. SIGNOR-253736 0.35 GSK1292263 chemical CID:24996872 PUBCHEM GPR119 protein Q8TDV5 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257500 0.8 SRC protein P12931 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Tyr86 ARPLVEFyEEIKKYE 9606 BTO:0000007 16725308 t miannu Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq.  SIGNOR-266306 0.2 CSNK2A1 protein P68400 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1126 TEEFSSEsDMEESKE 9606 BTO:0000938 19064667 t lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. SIGNOR-275761 0.2 POLR2K protein P53803 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266141 0.798 CAMK2G protein Q13555 UNIPROT GRIA1 protein P42261 UNIPROT up-regulates activity phosphorylation Ser849 FCLIPQQsINEAIRT 12609872 t llicata Direct phosphorylation of the GluR1 subunit of postsynaptic AMPA receptors by Ca(2+)/calmodulin-dependent protein kinase II (CaM-KII) is believed to be one of the major contributors to the enhanced strength of glutamatergic synapses in CA1 area of hippocampus during long-term potentiation. | Validity of the approach was confirmed by modeling, and silence analysis was applied then to the GluR1 AMPA receptor mutated at S831, the site phosphorylated by CaM-KII during long-term potentiation. Silence analysis indicates that a negative charge at S831 is a critical determinant for the enhanced channel function as a charge carrier. Silence and variance analyses, when applied to the same sets of data, were in agreement on the receptor regulation upon mutations. SIGNOR-250698 0.615 CAMK2A protein Q9UQM7 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser772 LFKKIFPsLELNITD 9606 BTO:0004553 24614225 t gianni NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity. SIGNOR-266433 0.312 FOXO proteinfamily SIGNOR-PF27 SIGNOR TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 18612045 f lperfetto Transcriptional reporter assays performed in both HepG2 and C2C12 cells demonstrate that the MuRF1 promoter is highly responsive to dexamethasone-activated glucocorticoid receptor (GR) and FoxO1 individually, while co-overexpression of GR and FoxO1 leads to a dramatic synergistic increase in reporter activity SIGNOR-252927 0.2 CAPN1 protein P07384 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Lys32 RARRPESkATNATLD -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus SIGNOR-263559 0.384 DGC complex SIGNOR-C217 SIGNOR GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265440 0.2 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr519 EDPYAGStDENTDSE 9606 BTO:0000567 15367657 t lperfetto Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523 SIGNOR-128897 0.404 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN2A protein Q99250 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 32599005 t lperfetto For example, protein kinase A (PKA) and protein kinase C (PKC) have been shown to phosphorylate multiple serine residues on the interdomain I-II and III-IV linkers of Nav1.2, significantly reducing current and increasing firing thresholds SIGNOR-275749 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR PPM1B protein O75688 UNIPROT down-regulates quantity by destabilization phosphorylation Ser195 MIQRVNGsLAVSRAL 9606 BTO:0000007 23756813 t miannu Here, we show that protein kinase A (PKA) phosphorylates the PP2Cβ, which was inhibited by PKA-specific inhibitor, H89. Mutation analysis of serine residues in PP2Cβ revealed that Ser-195 in PP2Cβ is phosphorylated by PKA. Importantly, PKA inhibition by H89 abrogated the Forskolin-induced destabilization of PP2Cβ against ubiquitin-dependent proteosomal degradation pathway. SIGNOR-276494 0.2 SIK1 protein P57059 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 16817901 t miannu These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities. SIGNOR-147707 0.63 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269382 0.719 PTPRR protein Q15256 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR 9534 BTO:0004055 11493009 t Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL.|PTP-SL dephosphorylates the regulatory phosphotyrosine on the active loop of ERK1/2. Tyrosine dephosphorylation of ERK1/2 causes the inactivation of ERK1/2 and its retention in the cytoplasm SIGNOR-248840 0.817 SRC protein P12931 UNIPROT ENG protein P17813 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr612 LLTAALWyIYSHTRS 9606 BTO:0002828 25070888 t miannu We identified epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) as Src-activators that induce endoglin turnover following (612)YIY(614) phosphorylation.  SIGNOR-276655 0.393 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR up-regulates activity chemical activation 9606 18790874 t brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-263793 0.8 BECN1 protein Q14457 UNIPROT ZWINT protein O95229 UNIPROT up-regulates activity binding 9606 BTO:0000567 23478334 t lperfetto We show that Beclin-1 interacts directly with Zwint-1-a component of the KMN (KNL-1/Mis12/Ndc80) complex-which is essential for kinetochore-microtubule interactions. This suggests that Beclin-1 acts downstream of the KMN complex to influence the recruitment of outer kinetochore proteins and promotes accurate kinetochore anchoring to the spindle during mitosis. SIGNOR-265027 0.446 PCSK2 protein P16519 UNIPROT Corticotropin protein P01189-PRO_0000024969 UNIPROT up-regulates quantity cleavage 24631756 t lperfetto POMC is post-translationally cleaved by prohormone convertase enzymes 1 and 2 (PC1, PC2) into ACTH, an N-terminal glycopeptide SIGNOR-268725 0.2 F2R protein P25116 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 22318735 t gcesareni Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13). SIGNOR-196009 0.376 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI 2-ammonio-2-deoxy-D-glucopyranose 6-phosphate(1-) smallmolecule CHEBI:58725 ChEBI up-regulates quantity precursor of 9606 21310273 t miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans SIGNOR-268097 0.8 HOXA7 protein P31268 UNIPROT TGM1 protein P22735 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000667 11435435 f miannu Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes. SIGNOR-254474 0.2 BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 t lperfetto Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. SIGNOR-133820 0.812 AMOT protein Q4VCS5 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates relocalization 9606 BTO:0000567 21205866 t AMOT proteins, a family of proteins including AMOT, AMOTL1, and AMOTL2, interact extensively with multiple TJ components and are important for maintaining TJ integrity and epithelial cell polarity. gcesareni Our results indicate a potential tumor-suppressing role of AMOT family proteins as components of the Hippo pathway, and demonstrate a novel mechanism of YAP and TAZ inhibition by AMOT-mediated tight junction localization. These observations provide a potential link between the Hippo pathway and cell contact inhibition. SIGNOR-175776 0.669 TFE3 protein P19532 UNIPROT CLCN3 protein P51790 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276813 0.2 CAMK1 protein Q14012 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates activity phosphorylation Thr157 GIRKRPAtDDSSTQN 10090 23707388 t Monia We also demonstrate that i) CaMKI phosphorylates p27 at Thr157and Thr198 in human cells and at Thr170and Thr197in mouse cells to modulate its subcellular localization; SIGNOR-261195 0.309 FERMT1 protein Q9BQL6 UNIPROT FBLIM1 protein Q8WUP2 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 t miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. SIGNOR-266103 0.46 DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity ubiquitination 7227 22162134 t lperfetto The expression of dx, which physically interacts with notch, favors a mono-ubiquitinated state of the receptor, which leads to a ligand-independent intracellular activation of notch SIGNOR-219269 0.772 2-[[2-[[2-[[2-[[2-amino-3-(4-hydroxyphenyl)-1-oxopropyl]amino]-1-oxoethyl]amino]-1-oxoethyl]amino]-1-oxo-3-phenylpropyl]amino]-4-methylpentanoic acid chemical CHEBI:91634 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258806 0.8 CDK5 protein Q00535 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser133 LPYSPVSsPQSSPRL 9606 22778263 t lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. SIGNOR-198115 0.2 RORB protein Q92753 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18418469 t miannu RORβ and RORγ are also able to induce Bmal1 activity; however, RORα4 appears the most effective in inducing this activity. The ROREs in the Bmal1 promoter also bind ROR receptors. Overexpression of RORα1 and RORα4 induces Bmal1-promoter activity by interacting with these ROREs SIGNOR-266852 0.491 PRKCQ protein Q04759 UNIPROT MSN protein P26038 UNIPROT unknown phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 BTO:0001545 9856983 t lperfetto By using mass spectroscopy and direct microsequencing of CNBr fragments of phospho-moesin, the phosphorylation site was identified as KYKT*LRQIR (where * indicates the phosphorylation site) (Thr558), which is conserved in the ERM family | Thus, PKC-theta is identified as a major kinase within cells with specificity for moesin and with activation under non-classical PKC conditions. It appears likely that this activity corresponds to a specific intracellular pathway controlling the function of moesin as well as other ERM proteins. SIGNOR-249013 0.46 METTL3 protein Q86U44 UNIPROT UCK2 protein Q9BZX2 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 34430596 t lperfetto Furthermore, the m6A modification regulated by METTL3 led to UCK2 increased messenger RNA (mRNA) stability in melanoma cancer. Functional and mechanistic experiments indicated that UCK2 enhanced the metastasis of melanoma cancer cells through the WNT/β-catenin pathway. SIGNOR-275862 0.2 PRKACA protein P17612 UNIPROT CHKB protein Q9Y259 UNIPROT up-regulates activity phosphorylation Ser39 TPKRRRAsSLSRDAE 27149373 t lperfetto Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. | This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar. SIGNOR-275630 0.255 PAK1 protein Q13153 UNIPROT TBCB protein Q99426 UNIPROT up-regulates phosphorylation Ser65 GVDDKFYsKLDQEDA 9606 BTO:0000150 15831477 t lperfetto P21-activated kinase 1 regulates microtubule dynamics by phosphorylating tubulin cofactor b. Pak1 directly phosphorylated tcob in vitro and in vivo on serines 65 and 128 and colocalized with tcob on newly polymerized microtubules and on centrosomes. Pak1 phosphorylation is necessary for normal tcob function SIGNOR-135464 0.46 zotepine chemical CHEBI:32316 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 9534 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258556 0.8 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Thr169 FLPRHRDtGILDSIG -1 2413024 t miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-165 SIGNOR-250015 0.353 PAK2 protein Q13177 UNIPROT MYL12A protein P19105 UNIPROT up-regulates activity phosphorylation Ser19 KRPQRATsNVFAMFD -1 10047984 t miannu In this study we report that gamma-PAK, which is activated by the GTP-binding proteins Cdc42 and Rac, catalyses phosphorylation of intact non-muscle myosin II and isolated recombinant RLC. Phosphopeptide maps and phosphoamino acid analysis revealed that gamma-PAK phosphorylates Ser-19 but does not phosphorylate Thr-18.Taken together, these data suggest that myosin II activation by the p21-activated family of kinases may be physiologically important in regulating cytoskeletal organization. SIGNOR-263020 0.473 PELI3 protein Q8N2H9 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates ubiquitination 9606 17997719 t gcesareni These studies suggest that pellino isoforms may be the e3 ubiquitin ligases that mediate the il-1-stimulated formation of k63-pub-irak1 in cells, which may contribute to the activation of ikkbeta and the transcription factor nf-kappab, as well as other pathways dependent on irak1/4. SIGNOR-159061 0.718 WNT7A protein O00755 UNIPROT FZD7 protein O75084 UNIPROT up-regulates activity binding 9606 BTO:0002314 BTO:0001103 23290138 t apalma Our previous work has demonstrated that ligation of Wnt7a to Fzd7 activates the planar cell polarity (PCP) pathway […] Therefore, we conclude that the Fzd7/Sdc4 co-receptor complex binds both Wnt7a and FN. SIGNOR-255845 0.665 SOX9 protein P48436 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15240568 f SOX9 represses the expression of the CDX2 transcription factor, known to be mostly active in villus cells. SIGNOR-253322 0.39 CDK1 protein P06493 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Thr317 RGALVRGtPVRGAIT 9606 9315091 t lperfetto Phosphorylation of sam68 by purified cdc2. SIGNOR-51275 0.517 AKT2 protein P31751 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser1834 MLRRRMAsMQRTGVV 9606 16926151 t lperfetto We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity SIGNOR-148987 0.333 ATM protein Q13315 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser317 ENVKYSSsQPEPRTG 9606 20068082 t gcesareni Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation. SIGNOR-163106 0.84 PRSS1 protein P07477 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity cleavage Arg36 TNRSSKGrSLIGKVD -1 10978167 t lperfetto Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3. SIGNOR-263602 0.373 CDKN2A protein Q8N726 UNIPROT NPM1 protein P06748 UNIPROT down-regulates quantity by destabilization binding 9606 14636574 t gcesareni The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division SIGNOR-245077 0.569 Gbeta proteinfamily SIGNOR-PF4 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR unknown phosphorylation 9606 21071439 t inferred from 70% family members lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-270027 0.2 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates binding 9534 BTO:0000298 9482734 t lperfetto Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin SIGNOR-227862 0.891 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SIRT3 protein Q9NTG7 UNIPROT up-regulates activity phosphorylation Thr150 MVGAGIStPSGIPDF 9606 BTO:0001109 26141949 t miannu  Posttranscriptionally, SIRT3 enzymatic activity is further enhanced via Thr150/Ser159 phosphorylation by cyclin B1-CDK1, which is also induced by radiation and relocated to mitochondria together with SIRT3.  SIGNOR-276922 0.294 PRKCA protein P17252 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser742 GEKSFRRsVVGTPAY 9606 10197446 t llicata These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748. SIGNOR-66670 0.421 Vps34 Complex II complex SIGNOR-C241 SIGNOR Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 30397185 f lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260324 0.7 GRIN2C protein Q14957 UNIPROT GRIN1 protein Q05586 UNIPROT up-regulates activity binding 10090 BTO:0004278 19477150 t miannu Here, we demonstrate that PKB/Akt directly phosphorylates NR2C on serine 1096 (S1096). In addition, we identify 14-3-3epsilon as an NR2C interactor, whose binding is dependent on S1096 phosphorylation. These data are all consistent with a model in which NR1 and NR2C oligomerize, PKB phosphorylates S1096, and 14-3-3ε binds to phosphorylated NR2C thereby promoting NR2C-containing NMDA receptor surface expression in cerebellar granule cells. SIGNOR-262621 0.595 S100A8 protein P05109 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000876 16690079 t miannu Calcium-induced complexes of S100A8 and S100A9 have been shown to colocalize with microtubules (MTs) during activation of monocytes. Functional analyses demonstrated that the complexes are involved in cytoskeletal organization and that they directly bind to tubulin and promote tubulin polymerization in a calcium-dependent manner SIGNOR-261937 0.2 Fostamatinib disodium chemical CID:25008120 PUBCHEM SYK protein P43405 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206373 0.8 regorafenib chemical CHEBI:68647 ChEBI DDR2 protein Q16832 UNIPROT down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259208 0.8 CHD8 protein Q9HCK8 UNIPROT CCNE2 protein O96020 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 19255092 t miannu In order to identify CHD8 target genes, we performed a transcriptomic analysis of CHD8-depleted cells, finding out that CHD8 controls the expression of cyclin E2 (CCNE2) and thymidylate synthetase (TYMS), two genes expressed in the G1/S transition of the cell cycle. CHD8 was also able to co-activate the CCNE2 promoter in transient transfection experiments. Chromatin immunoprecipitation experiments demonstrated that CHD8 binds directly to the 5' region of both CCNE2 and TYMS genes. SIGNOR-268804 0.428 AMPK complex SIGNOR-C15 SIGNOR NEDD4L protein Q96PU5 UNIPROT up-regulates activity phosphorylation Ser795 VDLKPNGsEIMVTNE -1 21501591 t miannu The AMP-activated protein kinase (AMPK) down-regulates the inward rectifier K+ channel Kir2.1. Expression of wild type Nedd4-2 or of Nedd4-2S795A lacking an AMPK phosphorylation consensus sequence downregulated Kir2.1 currents. The effect of wild type Nedd4-2 but not of Nedd4-2S795A was significantly augmented by additional coexpression of AMPK. SIGNOR-276326 0.258 mTORC2 complex SIGNOR-C2 SIGNOR PRKCE protein Q02156 UNIPROT up-regulates activity phosphorylation Thr710 TREEPVLtLVDEAIV 9606 21806543 t miannu In the present study, we have identified the mTORC2 subunit Sin1 as a direct binding partner of the PKC (protein kinase C) ε kinase domain and map the interaction to the central highly conserved region of Sin1. Exploiting the conformational dependence for PKC phosphorylation, we demonstrate that mTORC2 is essential for acute priming of PKC.  SIGNOR-276347 0.324 MAPKAPK2 protein P49137 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni Mk2 and mk3 participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating the are-binding proteins ttp and hur, and by regulating eef2k SIGNOR-166622 0.308 CLK4 protein Q9HAZ1 UNIPROT NR5A1 protein Q13285 UNIPROT up-regulates activity phosphorylation Ser203 EYPEPYAsPPQPGLP 9606 BTO:0000007 35592512 t done miannu Immunoblotting analyses showed that the phosphorylation status of NR5A1 at Ser203 was attenuated by the CLK1/4 inhibitor. SIGNOR-274117 0.2 MDH1 protein P40925 UNIPROT (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI down-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266283 0.8 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser571 PWPLRRTsAQGQPSP 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275777 0.481 NFIA protein Q12857 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268875 0.2 EP300 protein Q09472 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 SIGNOR-C6 11062529 t gcesareni The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis. SIGNOR-83846 0.731 TWIST1 protein Q15672 UNIPROT ILK protein Q13418 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255528 0.285 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1721 SPTSPSYsPTSPSYS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248823 0.849 INPPL1 protein O15357 UNIPROT AKT1 protein P31749 UNIPROT down-regulates 9606 BTO:0000776 10942391 f gcesareni Taken together, the data presented here demonstrate that ship inhibits akt primarily through regulation of akt membrane localization. SIGNOR-80706 0.635 MECP2 protein P51608 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0004102 18952054 t Luana The interaction of MeCP2 with the 2BI3 and 2BI5 sites was strikingly reduced in neurons maintained in the presence of TTX (Fig. 2C). This result is consistent with the classical view of MeCP2 as a general transcriptional repressor, in that the reduced association leads to increased expression of NR2B. SIGNOR-264685 0.357 ATM protein Q13315 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Thr21 YGGAGGYtQSPGGFG 9606 14872059 t lperfetto Replication protein a (rpa) is a single-stranded dna (ssdna) binding protein involved in various processes, including nucleotide excision repair and dna replication. The 32 kda subunit of rpa (rpa32) is phosphorylated in response to various dna-damaging agents, and two protein kinases, ataxia-telangiectasia mutated (atm) and the dna-dependent protein kinase (dna-pk) have been implicated in dna damage-induced phosphorylation of rpa32we show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro. SIGNOR-121861 0.802 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257914 0.8 IL1RAP protein Q9NPH3 UNIPROT TOLLIP protein Q9H0E2 UNIPROT down-regulates activity binding 9606 BTO:0000007 10854325 t lperfetto Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs) SIGNOR-251979 0.623 CALM1 protein P0DP23 UNIPROT GEM protein P55040 UNIPROT up-regulates activity binding 10116 14701738 t miannu Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells. SIGNOR-261716 0.338 ponatinib chemical CHEBI:78543 ChEBI LYN protein P07948 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000830 23539538 t miannu Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells SIGNOR-259273 0.8 PHKA1 protein P46020 UNIPROT PHKA1 protein P46020 UNIPROT up-regulates activity phosphorylation Ser1007 TGIMQLKsEIKQVEF -1 10487978 t miannu Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation) SIGNOR-250280 0.2 MAPK3 protein P27361 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 23405013 t lperfetto Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling SIGNOR-200884 0.325 LPAR3 protein Q9UBY5 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 15856019 t gcesareni Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. SIGNOR-135843 0.444 MAPK14 protein Q16539 UNIPROT TCF3 protein P15923 UNIPROT up-regulates activity phosphorylation Ser139 LNSPGPLsPSGMKGT 9606 BTO:0000887 15719023 t lperfetto Here we show that p38 mapk, whose activity is essential for myogenesis, regulates myod/e47 heterodimerization. Phosphorylation of e47 at ser140 by p38 induces myod/e47 association and activation of muscle-specific transcription SIGNOR-134194 0.458 EIF1B protein O60739 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates activity 9606 14600024 f lperfetto Binding of eIF1 to the 40S subunit would block access of the 60S SIGNOR-269146 0.253 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1223 SSSTRRSsEDLSAYA 9606 BTO:0000975 17360977 t lperfetto Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 SIGNOR-236603 0.2 GAS2 protein O43903 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 24706950 f miannu Previous work has shown that members of the growth-arrest-specific 2 (GAS2) family mediate the crosstalk between filamentous actin (F-actin) and MTs, but the molecular basis of this process remained unclear. By using fluorescence microscopy, we demonstrate that three members of this family, GAS2-like 1, GAS2-like 2 and GAS2-like 3 (G2L1, G2L2 and G2L3, also known as GAS2L1, GAS2L2 and GAS2L3, respectively) are differentially involved in mediating the crosstalk between F-actin and MTs.  SIGNOR-273701 0.7 NR0B2 protein Q15466 UNIPROT CEBPA protein P49715 UNIPROT down-regulates activity binding 9606 17094771 t miannu SHP repressed C/EBPalpha (CCAAT/enhancer-binding protein alpha)-driven transcription of PEPCK through direct interaction with C/EBPalpha protein both in vitro and in vivo. The formation of an active transcriptional complex of C/EBPalpha and its binding to DNA was inhibited by SHP, resulting in the inhibition of PEPCK gene transcription. SIGNOR-254831 0.272 AUTS2 protein Q8WXX7 UNIPROT Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR down-regulates activity binding 9606 BTO:0000007 25519132 t miannu We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrate that the CK2 component of PRC1-AUTS2 neutralizes PRC1 repressive activity, whereas AUTS2-mediated recruitment of P300 leads to gene activation. SIGNOR-266814 0.361 AKT1 protein P31749 UNIPROT DOCK6 protein Q96HP0 UNIPROT up-regulates activity phosphorylation Ser1194 GQRSRLAsMLDSDTE 23462102 t lperfetto Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching SIGNOR-275666 0.381 leukotriene D4(1-) smallmolecule CHEBI:63166 ChEBI CYSLTR2 protein Q9NS75 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257476 0.8 AMPK complex SIGNOR-C15 SIGNOR TBC1D1 protein Q86TI0 UNIPROT down-regulates phosphorylation Ser237 RPMRKSFsQPGLRSL 9606 17995453 t lperfetto In rat l6 myotubes, endogenous tbc1d1 is strongly phosphorylated on ser237 and binds to 14-3-3s in response to the ampk activators aicar SIGNOR-216631 0.417 PIGBOS1 protein A0A0B4J2F0 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 31653868 f miannu We then confirmed via Western blot that TM treatment of PIGBOS-KD cells led to higher ATF4 and CHOP protein levels (Supplementary Fig. 13h). These data identified PIGBOS as a heretofore unknown mitochondrial regulator of UPR, and the only known microprotein linked to the regulation of cell stress or inter-organelle signaling. Upon UPR induction with TM, the loss of PIGBOS led to dramatic increases in the levels of all UPR target genes measured, indicating increased UPR signaling across all the branches (IRE1, PERK, and ATF6) (Fig. 6d and Supplementary Fig. 14a). Meanwhile, PIGBOS overexpressing cells showed the opposite effect, in which the UPR target genes showed less UPR activation, indicating a tunable modulation of ER stress by PIGBOS microprotein levels SIGNOR-261041 0.2 PIM1 protein P11309 UNIPROT FLT3 protein P36888 UNIPROT up-regulates quantity phosphorylation Tyr591 SSDNEYFyVDFREYE 9606 BTO:0005720 24040307 t Pim-1 Kinase Phosphorylates and Stabilizes 130 kDa FLT3 and Promotes Aberrant STAT5 Signaling in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication[...]Pim-1 inhibition also decreased phosphorylation of FLT3 at tyrosine 591 and of STAT5, and expression of Pim-1 itself, consistent with inhibition of the FLT3-ITD-STAT5 signaling pathway. SIGNOR-259927 0.43 MRGPRX1 protein Q96LB2 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256929 0.2 MAPK1 protein P28482 UNIPROT EPAS1 protein Q99814 UNIPROT up-regulates quantity by stabilization phosphorylation Ser484 SSCSTPNsPEDYYTS 9606 BTO:0006155 35191554 t miannu The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33.Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells. SIGNOR-277585 0.252 Ggamma proteinfamily SIGNOR-PF3 SIGNOR PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser272 FSGIESSsPEVKGYW 10090 BTO:0000666 17475908 t miannu All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells. SIGNOR-262670 0.2 CDK1 protein P06493 UNIPROT IREB2 protein P48200 UNIPROT down-regulates phosphorylation Ser157 LQKAGKLsPVKVQPK 9606 SIGNOR-C17 18574241 t lperfetto Irp2 ser-157 is phosphorylated by cdk1/cyclin b1 during g(2)/m / ser-157 phosphorylation during g(2)/m reduces irp2 rna-binding activity SIGNOR-179171 0.36 CACNA2D3 protein Q8IZS8 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 31746409 f miannu Overexpression of CACNA2D3 reduced proliferation and migration, but increased apoptosis and Ca2+ influx in Ishikawa and RL95-2 cells. SIGNOR-266855 0.7 EGFR protein P00533 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 14967450 t lperfetto The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation. SIGNOR-121965 0.875 HNF4A protein P41235 UNIPROT GK protein P32189 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18805788 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription SIGNOR-181274 0.2 SRC protein P12931 UNIPROT RAC1 protein P63000 UNIPROT up-regulates phosphorylation 9606 17991704 t gcesareni N attractive hypothesis consistent with our present data is that the gef responsible for rac activation in mce cells may be activated by src family kinase tyrosine phosphorylationour results present a novel mechanism by which the pi3k and src signaling cascades cooperate to activate rac and promote intestinal epithelial cell migration downstream of egfr. SIGNOR-158954 0.599 ATP smallmolecule CHEBI:15422 ChEBI ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity precursor of 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5√¢‚Ǩ¬≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-268079 0.8 LPAR6 protein P43657 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257120 0.2 PRKCA protein P17252 UNIPROT KIR3DL1 protein P43629 UNIPROT down-regulates activity phosphorylation Ser415 QRKITRPsQRPKTPP -1 17911614 t miannu Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of Ser(394) by protein kinase C slightly suppresses KIR3DL1 inhibitory function, and reduces receptor internalization and turnover.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII. SIGNOR-276080 0.2 JAK2 protein O60674 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates phosphorylation Tyr718 IPERDSRySQPLHEE 9606 19287004 t lperfetto Previously we have shown that tyrosine 718 of ask1 when phosphorylated is critical for socs1 binding and socs1-mediated degradation of ask1we identified jak2 and shp2 as a tyr-718-specific kinase and phosphatase, respectively. SIGNOR-184600 0.374 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 12510059 t gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. SIGNOR-96936 0.767 R547 chemical CID:6918852 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259793 0.8 olanzapine chemical CHEBI:7735 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258511 0.8 ROCK1 protein Q13464 UNIPROT KCNK3 protein O14649 UNIPROT up-regulates activity phosphorylation Ser393 GLMKRRSsV 9606 21838752 t lperfetto Task1 channels contain two putative rho kinase phosphorylation sites, ser(336) and ser(393) . Mutation of ser(393) rendered task1 channels insensitive to et(a) - or et(b)-mediated current inhibition. In contrast, removal of ser(336) selectively attenuated et(a) -dependent task1 regulation without affecting the et(b) pathway. SIGNOR-176029 0.2 ALK protein Q9UM73 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates phosphorylation 9606 BTO:0000785 12185581 t gcesareni Anaplastic lymphoma kinase (alk), which turned out to be one of these phosphoproteins, was constitutively activated and associated with the ptb domain of shcc in three neuroblastoma cells. In vitro kinase assay revealed that shcc is a potent substrate of the activated alk kinase. The alk gene locus was significantly amplified in both of these cell lines, suggesting that gene amplification leads to constitutive activation of the alk kinase, which results in hyperphosphorylation of shcc. SIGNOR-91537 0.451 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Asp62 VETVFSVdEFSASVL -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263593 0.381 PFAS protein O15067 UNIPROT 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure. SIGNOR-267311 0.8 GRM5 protein P41594 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 t miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. SIGNOR-264078 0.341 CCNC protein P24863 UNIPROT CKM complex complex SIGNOR-C406 SIGNOR form complex binding 9606 23563140 t miannu The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation. SIGNOR-266685 0.92 MAPK14 protein Q16539 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Thr319 TPVVSVTtPSLPPQG 9606 9858528 t lperfetto We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a SIGNOR-62784 0.646 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257977 0.8 CDK2 protein P24941 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT down-regulates phosphorylation Ser368 PNPSTSAsPKKSPPP 9606 SIGNOR-C16 18332217 t llicata We define ser-331 as the site phosphorylated by cyclin e-cdk2, cyclin a-cdk2, and p35-cdk5 both in vitro and in cells. Importantly, phosphorylation at ser-331 inhibits the catalytic activity of sirt2. SIGNOR-177972 0.404 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser74 VEIRSRHsSYPAGTE 9606 22096607 t lperfetto Bad is a pro-apoptotic member of the bcl-2 family of proteins, which can be phosphorylated on numerous sites to modulate binding to bcl-2 and 14-3-3 proteins and inhibit its pro-apoptotic activities. Together, these findings demonstrate that pak1 phosphorylates bad directly at s111, but phosphorylated s112 through raf-1. These two sites of bad serve as redundant regulatory sites for bcl-2 binding SIGNOR-177271 0.341 orotidine 5'-phosphate(3-) smallmolecule CHEBI:57538 ChEBI UMP smallmolecule CHEBI:16695 ChEBI up-regulates quantity precursor of 9606 2912371 t miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). SIGNOR-267439 0.8 RUNX3 protein Q13761 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002384 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255098 0.252 sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI D-erythrose 4-phosphate(2-) smallmolecule CHEBI:16897 ChEBI up-regulates quantity precursor of 9606 19401148 t miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. SIGNOR-268135 0.8 Caspase 3 complex complex SIGNOR-C221 SIGNOR STK4 protein Q13043 UNIPROT up-regulates activity cleavage Asp326 NSEEDEMdSGTMVRA 9534 BTO:0004055 11517310 t lperfetto In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus. SIGNOR-256444 0.601 PRKCA protein P17252 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Thr678 RHIVRKRtLRRLLQE 9606 10816576 t lperfetto Biochemical and morphological analyses indicate that threonine-phosphorylated EGFR molecules undergo normal internalization, but instead of sorting to lysosomal degradation, they recycle back to the cell surfaceThe inhibitory effects of pkc are mediated by a single threonine residue (threonine 654) of egfr SIGNOR-77421 0.592 GRIN1 protein Q05586 UNIPROT NMDA receptor_2B complex SIGNOR-C348 SIGNOR form complex binding 9606 BTO:0000938 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits SIGNOR-264122 0.717 2-[4-[3-[2-(trifluoromethyl)-9-thioxanthenylidene]propyl]-1-piperazinyl]ethanol chemical CHEBI:93235 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258729 0.8 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr228 YPGGSDNyGSLSRVT -1 11382764 t lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 SIGNOR-246484 0.92 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Ser577 RKPGLRRsPIKKVRK 9606 SIGNOR-C83 9840932 t lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk5 SIGNOR-62353 0.711 PTPRR protein Q15256 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 11711538 t gcesareni As shown, gst-ptp-sl dephosphorylated efficiently both erk2 and p38 wild typetogether, these results indicate that the defective association of the tyrosine phosphatase ptp-sl with erk2 d319n and p38 d316n mutations impairs the retention and inactivation in the cytosol of these map kinases by ptp-sl. SIGNOR-111762 0.55 SLC12A4 protein Q9UP95 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates quantity relocalization 21613606 t lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  SIGNOR-264636 0.8 AKT1 protein P31749 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates activity phosphorylation Thr151 FCNGRGNtSGSHIVN 9606 BTO:0002181 35675814 t miannu AKT-Mediated UPF1 Phosphorylation at T151 Promotes UPF1 Helicase Activity SIGNOR-277597 0.26 MAPK1 protein P28482 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser50 SPTFRSDsPVPTAPT 9606 BTO:0000007 33217317 t miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. SIGNOR-265946 0.276 MED30 protein Q96HR3 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266673 0.746 CASP1 protein P29466 UNIPROT NLRP1 inflammasome complex SIGNOR-C224 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256406 0.79 BLOC1S4 protein Q9NUP1 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 BTO:0002946 22203680 t lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. SIGNOR-265932 0.612 PTPN9 protein P43378 UNIPROT NSF protein P46459 UNIPROT down-regulates dephosphorylation Tyr83 QEIEVSLyTFDKAKQ 9606 15322554 t gcesareni Our results suggest that the molecular mechanism by which ptp-meg2 promotes secretory vesicle fusion involves the local release of nsf from a tyrosine-phosphorylated, inactive state. SIGNOR-128348 0.422 PMCH protein P20382 UNIPROT MCHR2 protein Q969V1 UNIPROT up-regulates binding 9606 BTO:0000142 10471841 t gcesareni Upon several purification steps, followed by mass spectrometric analysis and peptide sequencing, the ligand was identified as melanin concentrating hormone (mch), revealing that the orphan slc-1 is the mch receptor. SIGNOR-70520 0.596 CSK protein P41240 UNIPROT PECAM1 protein P16284 UNIPROT up-regulates activity phosphorylation Tyr713 KKDTETVySEVRKAV 9534 BTO:0001538 9624175 t miannu We demonstrated that phosphorylation of PECAM-1 by Src or Csk family kinases was sufficient to trigger its association with SHP-2. Moreover, it was able to promote binding of PECAM-1 to SHP-1, a SHP-2-related protein-tyrosine phosphatase expressed in hemopoietic cells. Taken together, these findings indicated that the Src and Csk families of kinases are strong candidates for mediating tyrosine phosphorylation of PECAM-1 and triggering its association with SH2 domain-containing phosphatases under physiological circumstances. SIGNOR-262741 0.531 GTF2F2 protein P13984 UNIPROT GTF2F1 protein P35269 UNIPROT up-regulates activity binding 9534 11278533 t miannu Direct Interaction Between the Subunit RAP30 of Transcription Factor IIF (TFIIF) and RNA Polymerase Subunit 5, Which Contributes to the Association Between TFIIF and RNA Polymerase II. we showed that RPB5 binds RAP30 but not RAP74 and associates to TFIIF through the binding to RAP30. SIGNOR-261180 0.962 CDK1 protein P06493 UNIPROT CDC27 protein P30260 UNIPROT up-regulates phosphorylation Thr446 EGKISTItPQIQAFN 9606 14657031 t lperfetto Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation SIGNOR-119877 0.692 PRKCA protein P17252 UNIPROT CYTH2 protein Q99418 UNIPROT down-regulates activity phosphorylation Ser392 AARKKRIsVKKKQEQ 9606 10531036 t lperfetto ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'. SIGNOR-249023 0.312 RNF111 protein Q6ZNA4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates ubiquitination 10090 BTO:0000165;BTO:0000222 17341133 t gcesareni Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblastsarkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling. SIGNOR-236876 0.64 GDP smallmolecule CHEBI:17552 ChEBI GNAS protein Q5JWF2 UNIPROT down-regulates chemical inhibition 9606 17095603 t gcesareni Galfa subunits cycle between inactive (GDP-bound) and active (GTP-bound) states, and the lifetime of the active state is limited by GTP hydrolysis. SIGNOR-253072 0.8 CHM protein P24386 UNIPROT RABGGTB protein P53611 UNIPROT down-regulates activity binding 9606 18532927 t miannu Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. SIGNOR-265571 0.759 TRIM39 protein Q9HCM9 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002552 23213260 t miannu Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation. SIGNOR-272020 0.358 EFNA3 protein P52797 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 t gcesareni Eph receptors are activated by their ligands, which are membrane-anchored molecules SIGNOR-52315 0.82 PPP3CB protein P16298 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Ser313 TALHRSKsHEFQLGH 10090 19560418 t These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 SIGNOR-248382 0.262 JAK1 protein P23458 UNIPROT JAK3 protein P52333 UNIPROT up-regulates 9606 10825200 f gcesareni Syk activation required jak3, probably indirectly via activation of jak1. SIGNOR-77551 0.516 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT down-regulates activity phosphorylation Ser408 REKSKKYsDVEVPAS -1 8810272 t miannu Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin. SIGNOR-250329 0.316 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr8 MSSILPFtPPVVKRL 9606 19115199 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-183004 0.738 PTPN1 protein P18031 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK 9606 BTO:0000007 11007774 t gcesareni Incubation of the inactivated c-Src with PTP1B results in a dose-dependent reactivation of c-Src tyrosine kinase activity. Incubation of c-Src with 2 or 10 g of PTP1B results in partial or full restoration of c-Src kinase activity, respectively. The activation is accompanied by dephosphorylation of c-Src, both of Tyr-419 and of Tyr-530 SIGNOR-245299 0.772 HNF4A protein P41235 UNIPROT ABCG8 protein Q9H221 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000398 21123766 f miannu these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α. SIGNOR-254458 0.286 ZFPM1 protein Q8IX07 UNIPROT GATA2 protein P23769 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21853041 t miannu GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1. SIGNOR-256061 0.736 CAPN1 protein P07384 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains SIGNOR-251584 0.34 HCFC1 protein P51610 UNIPROT Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR up-regulates activity binding 9606 BTO:0000567 12670868 t miannu Our analysis of HCF-1-associated proteins suggests that a K4 histone H3 HMT complex has been conserved from yeast to humans in both structure and activity: the Set1/Ash2 HMT. The results presented here show that this Set1/Ash2 HMT complex, in mutually exclusive interactions, can associate with HCF-1 bound to the repressive Sin3 HDAC or the transcriptional activator VP16, indicating a diversity of transcriptional regulatory roles. SIGNOR-264481 0.763 AMPK complex SIGNOR-C15 SIGNOR SIRT7 protein Q9NRC8 UNIPROT down-regulates quantity by destabilization phosphorylation Thr153 TLTHMSItRLHEQKL 27511885 t lperfetto Here, the authors show that energy stress induces an AMPK-dependent phosphorylation of Sirt7, which promotes its ubiquitin-independent degradation by REGγ, resulting in the down-regulation of rRNA transcription and cell survival.|These results strongly suggest that the phosphorylation status of SirT7 at T153 plays a crucial role in determining its subcellular distribution, degradation and binding to REGγ. SIGNOR-275865 0.2 CAPN2 protein P17655 UNIPROT CDK5R1 protein Q15078 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain SIGNOR-251610 0.546 CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 8891723 t lperfetto The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-217514 0.821 CDK1 protein P06493 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser540 HVSEDSSsPERTSPP 9606 SIGNOR-C17 19107194 t gcesareni We identified cyclinb/cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates sirt1. Mutation of two residues phosphorylated by cyclin b/cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in sirt1-deficient cells SIGNOR-182863 0.543 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 19346248 t lperfetto The phosphorylation of raptor is stimulated by insulin and inhibited by rapamycin. Importantly, the site-directed mutation of raptor at one phosphorylation site, Ser(863), reduced mTORC1 activity both in vitro and in vivo. SIGNOR-217556 0.392 KDM2B protein Q8NHM5 UNIPROT Noncanonical PRC1 complex SIGNOR-C151 SIGNOR up-regulates activity binding 10090 BTO:0000011 25533466 t miannu We show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. Interestingly, inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. SIGNOR-252247 0.675 TADA2B protein Q86TJ2 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269571 0.762 RPGRIP1 protein Q96KN7 UNIPROT RPGR protein Q92834 UNIPROT down-regulates activity binding 9606 20631154 t miannu The RPGR H98Q and F130C mutants exhibit compromised interaction with RPGRIP1, suggesting that RPGR–RPGRIP1 interaction may be an important determinant of RPGR activity. As RPGRIP1 appears to link RPGR to the cilium, it is possible that RPGR's effect on RAB8A function may occur in distinct subcellular compartments of photoreceptors and that RPGRIP1 and other interacting proteins may modulate targeting of RPGR to such compartments. SIGNOR-253031 0.737 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr621 LQADSAEyAQPLVGG -1 23770091 t done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. SIGNOR-273941 0.357 ARHGAP29 protein Q52LW3 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260484 0.533 PRKACA protein P17612 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 15228085 t gcesareni Site-directed mutagenesis analysis indicated that serine 2152 is the unique substrate in the c-terminal region of abp for endogenously activated pka. SIGNOR-126659 0.2 MAPK9 protein P45984 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr286 SVPSAAVtPLNESLQ 9606 15767678 t gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. SIGNOR-134576 0.653 SKP2 protein Q13309 UNIPROT IDH1 protein O75874 UNIPROT down-regulates quantity by destabilization ubiquitination phosphorylation:Thr157 GKVEITYtPSDGTQK 34929314 t lperfetto During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome SIGNOR-267625 0.2 PPP2CA protein P67775 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser199 PRPEHTKsVYTRSVI 10116 18586681 t Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. SIGNOR-248642 0.364 CSNK2A1 protein P68400 UNIPROT RNF7 protein Q9UBF6 UNIPROT up-regulates phosphorylation Thr10 DVEDGEEtCALASHS 9606 BTO:0000567 12748192 t lperfetto Ckbbp1 is phosphorylated in vivo and threonine to alanine mutation at residue 10 abrogates the phosphorylation of ckbbp1 observed in vivo, indicating that ckii is a major kinase that is responsible for in vivo phosphorylation of ckbbp1. As compared with the wild-type ckbbp1 or ckbbp1t10e (in which threonine 10 is replaced by glutamate), overexpression of nonphosphorylatable ckbbp1 (ckbbp1t10a) results in accumulation of ikappabalpha and p27kip1. SIGNOR-101187 0.468 ruxolitinib chemical CHEBI:66919 ChEBI JAK1 protein P23458 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258276 0.8 CDK5 protein Q00535 UNIPROT DPYSL2 protein Q16555 UNIPROT down-regulates activity phosphorylation Ser522 PASSAKTsPAKQQAP 9606 BTO:0000938 25040932 t lperfetto Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition SIGNOR-264838 0.641 Av/b5 integrin complex SIGNOR-C178 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269027 0.7 GSK3B protein P49841 UNIPROT FBXL21P protein Q9UKT6 UNIPROT up-regulates activity phosphorylation Thr33 FYSSLNQtHTHTVLL 9606 BTO:0000007 32937135 t lperfetto GSK-3beta phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation.|These results show direct GSK-3beta phosphorylation of TCAP S157 and FBXL21 T33 sites. SIGNOR-264851 0.2 palbociclib chemical CHEBI:85993 ChEBI CCND1 protein P24385 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189693 0.8 TLR5 protein O60602 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24709011 f miannu These studies demonstrate a novel function of Toll-like receptor-5 (TLR5) in a human multiple myeloma (MM) cell line, KMS28BM. These cells express high levels of both TLR5 mRNA and protein. When cells were treated with the specific TLR5 ligand flagellin, proliferation was increased, and the secretion of IgG λ antibody and the expression of the pro-inflammatory cytokine IL-6 were increased via NF-κB activation through PI3K/AKT and p38 signaling. SIGNOR-259868 0.479 DOK1 protein Q99704 UNIPROT ITGB8 protein P26012 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257698 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR GSTA4 protein O15217 UNIPROT up-regulates activity phosphorylation Ser189 QEYTVKLsNIPTIKR 9534 12646569 t lperfetto Mutational analysis show that the putative mitochondrial targeting signal resides within the C-terminal 20 amino acid residues of the protein and that the targeting signal requires activation by phosphorylation at the C-terminal-most protein kinase A (PKA) site at Ser-189 or protein kinase C (PKC) site at Thr-193. SIGNOR-264796 0.2 CSNK2B protein P67870 UNIPROT OCLN protein Q16625 UNIPROT unknown phosphorylation Thr404 HYETDYTtGGESCDE 9606 12804768 t llicata Mutagenesis of serine 407 to alanine resulted in reduced ability of the kinase to phosphorylate occludin. The threonine 403 to alanine mutant had a smaller effect but the double mutant (T403/S407A) was even less phosphorylated than either of the single mutants. These data are consistent with the claim that CK2 is the kinase in brain extracts responsible for phosphorylation of occludin. SIGNOR-251080 0.425 SYK protein P43405 UNIPROT TUBA4A protein P68366 UNIPROT up-regulates activity phosphorylation Tyr432 MAALEKDyEEVGIDS 9606 BTO:0000776 9490415 t lperfetto Syk, Activated by Cross-linking the B-cell Antigen Receptor, Localizes to the Cytosol Where It Interacts with and Phosphorylates alpha-Tubulin on Tyrosine SIGNOR-246626 0.336 MAPKAPK2 protein P49137 UNIPROT SRF protein P11831 UNIPROT unknown phosphorylation Ser103 RGLKRSLsEMEIGMV 9606 BTO:0000567 10318869 t llicata Mk2 phosphorylates srf in vitro at ser-103 SIGNOR-67448 0.566 CSNK2A1 protein P68400 UNIPROT EIF3J protein O75822 UNIPROT up-regulates activity phosphorylation Ser127 LKKLQEEsDLELAKE 9606 BTO:0000007 25887626 t miannu CK2 phosphorylates the eIF3j subunit at Ser127. CK2-phosphorylation of eIF3j triggers its association with the eIF3 complex. SIGNOR-266402 0.332 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120168 0.316 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236745 0.912 NAN 190 chemical CHEBI:64131 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258855 0.8 LPCAT1 protein Q8NF37 UNIPROT acyl-CoA(4-) chemical CHEBI:58342 ChEBI down-regulates quantity chemical modification 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272763 0.8 CSNK2A1 protein P68400 UNIPROT USP7 protein Q93009 UNIPROT up-regulates quantity by stabilization phosphorylation Ser18 KAGEQQLsEPEDMEM 22361354 t lperfetto We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. Phosphorylation stabilizes USP7S and thus contributes to Mdm2 stabilization and downregulation of p53. SIGNOR-276530 0.38 DLL1 protein O00548 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209741 0.2 SPOP protein O43791 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0005672 29160310 t Barakat Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumor-infiltrating lymphocytes (TILs) in mouse tumors and in primary human prostate cancer specimens. SIGNOR-274978 0.331 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr846 DGGGSDRyGSLRPGW 9606 BTO:0000763 20861316 t lperfetto Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity SIGNOR-168001 0.304 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG 10090 11593427 t irozzo In this report, we show that Bcr–Abl forms a complex with Jak2, and induces tyrosine phosphorylation of Jak2; full phosphorylation requires the SH2 domain of Bcr–Abl. We found that Y1007 of Jak2 was phosphorylated in Bcr–Abl positive cells; phosphorylation of Jak2 Y1007 is known to be required for Jak2 kinase activation. SIGNOR-255812 0.2 CD300LB protein A8K4G0 UNIPROT TYROBP protein O43914 UNIPROT up-regulates activity binding 9534 20959446 t lperfetto The CD300b receptor is a non-classical activating receptor able to deliver signals by associating with the transmembrane adaptor protein DAP-12 and the intracellular mediator Grb-2. SIGNOR-264834 0.691 amitriptyline chemical CHEBI:2666 ChEBI CHRM5 protein P08912 UNIPROT down-regulates activity chemical inhibition 10029 8100134 t miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. SIGNOR-258701 0.8 IC-87114 chemical CHEBI:90686 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206184 0.8 SRC protein P12931 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates activity phosphorylation Tyr4507 TNFTNPVyATLYMGG 9606 BTO:0000007 12789267 t lperfetto We recently observed that the ldl receptor-related protein 1 (lrp-1) is tyrosine phosphorylated in v-src-transformed cells.Of the four tyrosine residues present in the cytoplasmic domain of lrp-1, only tyr 63 is phosphorylated by v-src in vivo or in vitro. Using fibroblasts deficient in src, yes and fyn, we were able to show that there are multiple kinases present in the cell that can phosphorylate lrp-1. Tyrosine-phosphorylated lrp-1 associates with shc, a ptb and sh2 domain containing signaling protein that is involved in the activation of ras SIGNOR-101535 0.402 CAMKK1 protein Q8N5S9 UNIPROT CAMK1 protein Q14012 UNIPROT up-regulates activity phosphorylation Thr177 DPGSVLStACGTPGY 8253780 t llicata Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase. SIGNOR-250717 0.424 CDK1 protein P06493 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Ser242 IPNGFGTsPLTPSAR -1 12556484 t done miannu In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites SIGNOR-274073 0.646 MAPK14 protein Q16539 UNIPROT ZNHIT1 protein O43257 UNIPROT up-regulates phosphorylation Thr103 AEGPNYLtACAGPPS 9606 17380123 t llicata Our results indicate that p38 mapk plays an important role in the regulation of p18hamlet half?life. In particular, p38 mapk activation is required for the accumulation of p18hamlet induced by dna damage?inducing Agents such as uv. We also showed that several sites that are phosphorylated by p38? In vitro are also important for p18hamlet protein stability in cells. the high conservation of thr103 as a phosphorylation site in p18hamlet proteins from different species (figure 1a), together with the in vitro phosphorylation experiments, suggested that this residue could be an important target for p38 mapk SIGNOR-153899 0.319 ZNF804A protein Q7Z570 UNIPROT CLIC2 protein O15247 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 23434502 t miannu ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). SIGNOR-269465 0.2 PRKCG protein P05129 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1303 NKLRRQHsYDTFVDL -1 11306676 t lperfetto These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. SIGNOR-249085 0.407 AURKA protein O14965 UNIPROT TACC3 protein Q9Y6A5 UNIPROT unknown phosphorylation Ser552 GTSSFKEsALRKQSL -1 26134678 t lperfetto In humans, Aurora-A phosphorylates TACC3 on three residues (S34, S552 and S558); these sites are conserved in Maskin and the S558 equivalent site is also present in D-TACC [26,27,30]. In mammalian cells, phosphorylation of S558 promotes accumulation of TACC3 on spindle MTs SIGNOR-263698 0.934 PRKCZ protein Q05513 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity phosphorylation -1 15894802 t inferred from family member lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-270274 0.39 EPHB2 protein P29323 UNIPROT EPHB2 protein P29323 UNIPROT up-regulates activity phosphorylation Tyr602 IYIDPFTyEDPNEAV -1 10572014 t Our results demonstrate that autophosphorylation tyrosine 611 in the juxtamembrane region of chicken EphB2 is critical for the association of the Src SH2 domain. SIGNOR-251124 0.2 NFYA protein P23511 UNIPROT PHGDH protein O43175 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18378410 f miannu Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y. SIGNOR-255209 0.2 RBM10 protein P98175 UNIPROT BCL2 protein P10415 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30403180 f irozzo In this study, we report that RBM10 acts as a tumor suppressor in osteosarcoma via the inhibition of cell growth, cell migration and invasion and the induction of cell apoptosis by inhibiting Bcl-2, activating caspase-3, and producing TNF-α. We also found that RBM10 overexpression significantly inhibited the expression of Bcl-2 and induced the expression of caspase-3 SIGNOR-259151 0.2 ADNP protein Q9H2P0 UNIPROT CTCF protein P49711 UNIPROT down-regulates activity relocalization 10090 BTO:0001086 SIGNOR-C407 31491387 t miannu These results argue against the simultaneous binding of CTCF and ADNP to the same genomic loci. Instead, they support a model in which ADNP counteracts stable association of CTCF with DNA at over 15,000 binding sites in the mouse genome. SIGNOR-266755 0.206 FZD7 protein O75084 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 22179044 t apalma In non-canonical Wnt signalling, Wnt proteins bind Fzd and glypican-4, to activate Dsh at the cell membrane, leading to activation of Rho and JNK SIGNOR-255893 0.647 TFG protein Q92734 UNIPROT SEC16B protein Q96JE7 UNIPROT up-regulates binding 9606 21478858 t miannu We identify tfg-1, a new conserved regulator of protein secretion that interacts directly with sec-16 and controls the export of cargoes from the endoplasmic reticulum in caenorhabditis elegans. Hydrodynamic studies indicate that tfg-1 forms hexamers that facilitate the co-assembly of sec-16 with copii subunits. SIGNOR-173279 0.478 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr811 ADDSSSStSSDSLGG -1 8349691 t llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. SIGNOR-251075 0.325 CALM3 protein P0DP25 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates binding 9606 9822657 t miannu The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk. SIGNOR-266345 0.606 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257345 0.437 APPL1 protein Q9UKG1 UNIPROT STK11 protein Q15831 UNIPROT up-regulates binding 9606 BTO:0000887 19520843 t milica In this study, we identified lkb1 as a new binding partner of appl1 and showed that the bar domain of appl1 is involved in this interaction.Here we show that in muscle cells adiponectin and metformin induce ampk activation by promoting appl1-dependent lkb1 cytosolic translocation. Appl1 mediates adiponectin signaling by directly interacting with adiponectin receptors and enhances lkb1 cytosolic localization by anchoring this kinase in the cytosol. SIGNOR-186065 0.322 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr806 TPHYGSQtPLHDGSR 9606 16427012 t lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif SIGNOR-143939 0.768 APC-c complex SIGNOR-C150 SIGNOR Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR up-regulates 9606 25092294 f miannu We then found that the joint action of TRIP13 and p31comet also promotes MCC disassembly, releases APC/C from checkpoint inhibition, and inactivates the mitotic checkpoint. SIGNOR-265978 0.7 CFHR1 protein Q03591 UNIPROT CFH protein P08603 UNIPROT down-regulates activity binding -1 27814381 t lperfetto Finally, we have been able to establish that CFHR1 can sterically inhibit the interaction that CFH/CFHL-1 SCR1-4 makes with C3b.|CFH regulates the alternative pathway of complement in both the fluid phase and on self-surfaces: It competes with complement factor B (CFB) for binding to C3b and C3(H2O) thereby blocking the formation of the pro-convertase complexes, C3bB and C3(H2O)B. It also accelerates the decay of any existing C3bBb or C3(H2O)Bb. |these data have allowed us to consolidate one possible model of CFHR1-mediated deregulation of CFH/CFHL-1 on an activating surface in which CFHR1 directly competes with or blocks both CFH-binding sites on C3b SIGNOR-263476 0.517 ZFPM1 protein Q8IX07 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR up-regulates activity 10090 BTO:0000725 22068055 f We here use conditional removal of the GATA-1 and FOG-1 transcription factors to identify FOG-1 as required for the formation of all committed Mk- and E-lineage progenitors, whereas GATA-1 was observed to be specifically required for E-lineage commitment. SIGNOR-259963 0.7 NHS protein Q6T4R5 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 20332100 f miannu We demonstrate that NHS is essential for maintaining cell morphology through the regulation of actin cytoskeletal dynamics and suggest that an important mechanism of remodelling of the actin cytoskeleton during development would therefore be lost in patients with NHS. SIGNOR-253565 0.7 NFIX protein Q14938 UNIPROT SLIT1 protein O75093 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268906 0.2 KAT6A/KAT6B complex SIGNOR-C54 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 11965546 t lperfetto Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation. SIGNOR-217204 0.361 PRKCH protein P24723 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000093 28939105 t miannu Protein kinase C-eta regulates Mcl-1 level via ERK1. knockdown of PKCη but not PKCα, -δ or -ε caused a significant decrease in ERK (extracellular signal-regulated kinase) phosphorylation. Knockdown of ERK1 but not ERK2 decreased Mcl-1 level, and the decrease in Mcl-1 caused by PKCη knockdown was restored by ERK1 overexpression. These results suggest that PKCη utilizes the ERK signaling pathway to protect against ubiquitin-mediated proteasomal degradation of Mcl-1. SIGNOR-261910 0.485 CDK1 protein P06493 UNIPROT RCC1 protein P18754 UNIPROT up-regulates activity phosphorylation Thr274 SNYHQLGtPGTESCF -1 15014043 t miannu We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of hum an RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. However, when both S2 and S11 were simultaneously mutated to As, the resulting 6His-RCC1S2,11A failed to be phosphorylated, whereas all of the other double mutants were phosphorylated (Fig. 1C). As expected, mutating all four sites to As (the 6His-RCC1S2,11,387A-T274A) also blocked phosphorylation (Fig. 1C). SIGNOR-262704 0.517 SMARCC1 protein Q92922 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270724 0.74 TCP1 protein P17987 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 t miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). SIGNOR-272863 0.742 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 15486195 t inferred from 70% family members lperfetto In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel SIGNOR-270031 0.2 LMNA protein P02545 UNIPROT SUN2 protein Q9UH99 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 16380439 t Sara In the case of Sun2, there is some evidence that A-type lamins might contribute to Sun2 localization in the INM. We report that an interaction between subunits of the HOPS complex and the ERM (ezrin, radixin, moesin) proteins is required for the delivery of EGF receptor (EGFR) to lysosomes. Inhibiting either ERM proteins or the HOPS complex leads to the accumulation of the EGFR into early endosomes, delaying its degradation. SIGNOR-261310 0.641 SLC8B1 protein Q6J4K2 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 23056385 t lperfetto This study focuses on NCLX, the recently discovered mitochondrial Na(+)/Ca(2+) exchanger that is linked to Ca(2+) signalling in MIN6 and primary β cells. Suppression either of NCLX expression, using a siRNA construct (siNCLX) or of its activity, by a dominant negative construct (dnNCLX), enhanced mitochondrial Ca(2+) influx and blocked efflux induced by glucose or by cell depolarization. SIGNOR-275732 0.8 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT down-regulates phosphorylation Ser294 APMAPGRsPLATTVM 9606 BTO:0000150 10655479 t miannu Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26s proteasome SIGNOR-74708 0.453 STAT3 protein P40763 UNIPROT CEBPD protein P49716 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 25787076 f miannu P-Stat3 stimulates C/EBPδ expression and activity, which increases myostatin and MAFbx/Atrogin-1 and MuRF-1. Both pathways result in protein losses in muscle. SIGNOR-255334 0.595 perifosine chemical CHEBI:67272 ChEBI AKT1 protein P31749 UNIPROT down-regulates chemical inhibition 9606 BTO:0001130 14617782 t Perifosine causes decrease in Akt Ser473 and Thr308 phosphorylation gcesareni Perifosine is an alkylphospholipid that targets the pleckstrin homology domain of akt and blocks its membrane translocation, hence preventing akt phosphorylation and activation SIGNOR-252629 0.8 ULK3 protein Q6PHR2 UNIPROT GLI2 protein P10070 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 19878745 t Manara We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro SIGNOR-260798 0.605 FZD3 protein Q9NPG1 UNIPROT NLK protein Q9UBE8 UNIPROT up-regulates binding 9606 20828404 t gcesareni Upon ligand binding, non-canonical wnt signaling controls tissue polarity and cell movement through the activation of rhoa, c-jun n-terminal kinase (jnk), and nemo-like kinase (nlk) signaling cascades. SIGNOR-167862 0.359 MAGEL2 protein Q9UJ55 UNIPROT WASHC1 protein A8K0Z3 UNIPROT up-regulates activity binding 9606 23452853 t miannu Our mechanistic studies uncovered that K63-linked ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport. These results suggest that K63-linked ubiquitination of WASH K220 by TRIM27 is required for WASH function in retrograde transport. SIGNOR-253515 0.2 CAMK1 protein Q14012 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD -1 8663317 t llicata Phosphopeptide mapping analysis and Western blotting studies demonstrated that in vitro, CaMK II phosphorylates only Ser63 (corresponding to Ser133 of CREB), which is essential for the activation, and not Ser72 (corresponding to Ser142 of CREB), which is a negative regulation site. SIGNOR-250611 0.502 GLI2 protein P10070 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates NBK6142 f Whilst shh signalling is required for ventral oligodendrogenesis in the entire central nervous system, Gli2 activity only regulates oligodendrocyte development in the ventral spinal cord. Gli3 plays a nonessential role in ventral oligodendrogenesis during normal development.  SimoneGraziosi SIGNOR-269214 0.7 PTPN12 protein Q05209 UNIPROT GIT2 protein Q14161 UNIPROT down-regulates dephosphorylation Tyr592 NSTPESDyDNTPNDM 9606 16317044 t fspada Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest. SIGNOR-142719 0.351 MAPK13 protein O15264 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser359 GTEEKCGsPQVRTLS 9606 BTO:0000887;BTO:0001103 11500363 t lperfetto Sapk4/p38delta phosphorylated eef2k at ser359 in vitro, causing its inactivation. SIGNOR-109703 0.56 KDM5C protein P41229 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-264305 0.2 RCOR1 protein Q9UKL0 UNIPROT CoREST-HDAC complex complex SIGNOR-C105 SIGNOR form complex binding 9606 BTO:0000567 11171972 t miannu Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function. SIGNOR-222115 0.753 RUNX2 protein Q13950 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11331591 f lperfetto Together, these results suggest that the inhibition of cbfa1 transcription by TGF-_ requires both the presence of CBFA1 and CBFA1 binding to the cbfa1 promoter. SIGNOR-235533 0.2 POU5F1 protein Q01860 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254933 0.576 DEK protein P35659 UNIPROT PRDX5 protein P30044 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 19229864 f lperfetto We further demonstrated by ChIP analysis that knock-down of DEK caused hyperacetylation of histones around Prx VI promoter which is upregulated in our profile. SIGNOR-254125 0.2 ERCC6 protein Q03468 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 t miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription SIGNOR-268822 0.304 OSM protein P13725 UNIPROT AHR protein P35869 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24127753 f gcesareni The il-6-type cytokine oncostatin m induces ahr expression in a stat3-ependent manner in human hepg2 hepatoma cells. SIGNOR-202963 0.348 GTF3C4 protein Q9UKN8 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR form complex binding 9606 29378333 t lperfetto Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains SIGNOR-266185 0.884 N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide chemical CHEBI:91409 ChEBI TYRO3 protein Q06418 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190410 0.8 (1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid chemical CHEBI:94640 ChEBI GRM3 protein Q14832 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-193772 0.8 MTCP1 protein P56278 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation SIGNOR-81674 0.433 DNMT1 protein P26358 UNIPROT MBD2 protein Q9UBB5 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000815 15618232 f lperfetto We then examined the levels of DNMT1 and methylated DNA-binding protein 2 (MBD2) expressions in these cells to determine whether this reduction in uPA expression is associated with changes in the DNA methylation machinery. Our results showed that ectopic expression of RAS induced DNMT1 expression and activity and inhibited MBD2 expression. SIGNOR-254128 0.693 PTPN6 protein P29350 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates activity dephosphorylation Tyr446 SLYSQPFyTGYFGYK 9606 BTO:0002181 32779804 t miannu We identified a direct interaction between SHP‐1 and TRAF3; the association between these two proteins resulted in diminished recruitment of CK1ε to TRAF3 and inhibited its K63‐linked ubiquitination; SHP‐1 inhibited K63‐linked ubiquitination of TRAF3 by promoting dephosphorylation at Tyr116 and Tyr446. SIGNOR-277526 0.2 PSMA5 protein P28066 UNIPROT XBP1 protein P17861 UNIPROT down-regulates quantity by destabilization binding -1 19941857 t 1 miannu We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination. SIGNOR-239213 0.309 ABL1 protein P00519 UNIPROT SRCIN1 protein Q9C0H9 UNIPROT unknown phosphorylation Tyr264 IYRKEPLyAAFPGSH 9606 BTO:0000142 23383002 t llicata Furthermore, we identify abl as the major tyrosine kinase that can trigger p140cap phosphorylation on these sequences. SIGNOR-200854 0.2 PTPN11 protein Q06124 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates quantity by stabilization dephosphorylation 9606 BTO:0001963 19287004 t miannu In this study, we identified JAK2 and SHP2 as a Tyr-718-specific kinase and phosphatase, respectively. SIGNOR-276144 0.375 LCK protein P06239 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr42 DSMKDEEyEQMVKEL 14534291 t lperfetto Loss of tyrosine kinase p56lck in Jurkat cells abolished NFkappaB activation and partially suppressed and delayed phosphorylation of Tyr-42 of IkappaB upon pervanadate treatment. |Transfection of these cells with wild type Lck but not with mutant Lck F394 followed by H/R induces the tyrosine phosphorylation of inhibitor of nuclear factor kappaB (IkappaBalpha) and transcriptional activation of NFkappaB, and these are inhibited by Lck inhibitors SIGNOR-249374 0.568 MAP3K1 protein Q13233 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser222 LIDSMANsFVGTRSY 10090 BTO:0000944 8131746 t lperfetto Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity. SIGNOR-235564 0.646 CSK protein P41240 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 22479394 t Leads to Furin-cleavage activity gcesareni We found that the notch-1-furin interaction is regulated by the non-receptor tyrosine kinase, c-src. c-src and notch-1 are physically associated, and this association is responsible for notch-1 processing and activation SIGNOR-196824 0.285 CSNK1E protein P49674 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity phosphorylation Tyr446 SLYSQPFyTGYFGYK 9606 BTO:0002181 32779804 t miannu We found that the interaction of CK1ε with TRAF3Y116F, TRAF3Y446F were markedly decreased compared with interactions with WT TRAF3 by Co‐IP (Figure 6C); as expected, TRAF3Y116F and TRAF3Y446F mutants exhibited reduced K63‐linked ubiquitination (Figure 6D). These data suggest that the phosphorylation of TRAF3 at Tyr 116 and Tyr 446 regulate CK1ε‐induced K63‐linked ubiquitination. SIGNOR-277524 0.312 PRKACA protein P17612 UNIPROT RAP1GAP protein P47736 UNIPROT unknown phosphorylation Ser490 KSPTRKKsGPFGSRR -1 1406653 t miannu We have localized two of the sites of phosphorylation in vitro by cAMP-dependent kinase to serine residues 490 and 499. raplGAP undergoes phosphorylation at specific sites in vivo, the effects of phosphorylation on raplGAP have remained elusive. SIGNOR-250043 0.314 FZD2 protein Q14332 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma) SIGNOR-80604 0.2 S1PR3 protein Q99500 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257388 0.496 RARB protein P10826 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 t gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs SIGNOR-133234 0.391 RPL5 protein P46777 UNIPROT TP73 protein O15350 UNIPROT up-regulates binding 9606 25301064 t miannu We report that rpl5 and rpl11 can also enhance the transcriptional activity of a p53 homolog tap73 SIGNOR-205517 0.347 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-66759 0.738 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser54 RVKALPLsPRKRLGD 9606 9889196 t lperfetto Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2. SIGNOR-217328 0.94 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269380 0.719 PKN2 protein Q16513 UNIPROT MEFV protein O15553 UNIPROT down-regulates activity phosphorylation Ser208 VRLRRNAsSAGRLQG 10090 BTO:0004732 27270401 t no miannu PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. SIGNOR-275464 0.356 DYRK1A protein Q13627 UNIPROT CCNL2 protein Q96S94 UNIPROT unknown phosphorylation Ser330 LDGTSGFsPAPKLVE 9534 BTO:0000298 14623875 t llicata DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. | Three phosphoserines were identified in the slower migrating bands (Fig. 9; Ser-330, Ser-338, and Ser-369). All of these serine residues are located N-terminal of proline residues, consistent with our previous classification of DYRK1A as a “proline-directed” kinase. SIGNOR-251087 0.589 P-TEFb complex SIGNOR-C238 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001545 19516275 f miannu Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) inhibits the positive transcription elongation factor b (P-TEFb), which is a key RNA polymerase II (Pol II) transcriptional regulator. In transfected cells, mutated NPM1 associated with, and sequestered, HEXIM1 in cytoplasm, resulting in higher transcription of RNA pol II target genes, among which were some positive regulators of cell-cycle progression such as cyclin D1 and anti-apoptotic proteins such as Mcl-1 SIGNOR-260136 0.7 TFIIIC complex SIGNOR-C392 SIGNOR RNA Polymerase III complex SIGNOR-C389 SIGNOR up-regulates activity relocalization 9606 BTO:0000567 9308965 t lperfetto Transcription by RNA polymerase III (Pol III) requires multiple general initiation factors that, in isolated form, assemble onto the promoter in an ordered fashion. Here, it is shown that all components required for transcription of the VA1 and tRNA genes, including TFIIIB, TFIIIC, and RNA Pol III, can be coimmunopurified from a HeLa cell line that constantly expresses a FLAG epitope-tagged subunit of human RNA Pol III. SIGNOR-266182 0.447 CDON/SPAG9 complex SIGNOR-C21 SIGNOR MAP3K7 protein O43318 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 22337877 t lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts SIGNOR-235560 0.2 ATM protein Q13315 UNIPROT EXO1 protein Q9UQ84 UNIPROT up-regulates phosphorylation 9606 20019063 t gcesareni The phosphorylation of exo1 by atm appears to regulate the activity of exo1 following resection, allowing optimal rad51 loading and the completion of hr repair. SIGNOR-162304 0.824 MAPK3 protein P27361 UNIPROT PTPRR protein Q15256 UNIPROT up-regulates activity phosphorylation Thr361 EPFVSIPtPREKVAM 11493009 t lperfetto Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL. SIGNOR-249477 0.657 FFAR2 protein O15552 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256803 0.2 EP300 protein Q09472 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity acetylation Lys310 KRTYETFkSIMKKSP 9606 BTO:0002207 15152190 t gcesareni Using acetylation assays, p300 was found to effectively acetylate RelA/p65 across the amino-acid region containing 1€“317 SIGNOR-238778 0.815 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser636 SGDYMPMsPKSVSAP 9606 12510059 t gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. SIGNOR-96948 0.767 ZEB2 protein O60315 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11430829 t Luisa SIP 1 downregulates mammalian E-cadherin transcription via binding to both conserved E2 boxes of the minimal E-cadh promoter.SIP1 induction resulted in the loss of cell-cell adhesion, in activation of invasion and in at random, multidirectional migration instead of unidirectional coherent migration (required in neurulation). SIGNOR-268950 0.501 SYCP1 protein Q15431 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR form complex binding 9606 22394509 t miannu The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region. SIGNOR-264197 0.673 ADORA2B protein P29275 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257039 0.296 ABL1 protein P00519 UNIPROT RAPH1 protein Q70E73 UNIPROT up-regulates activity phosphorylation Tyr456 NVYYGQDyRNKYKAP -1 20417104 t miannu Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C). SIGNOR-262607 0.288 PAK2 protein Q13177 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Ser619 PTPPKRSsSFREMDG 9606 18161990 t lperfetto The interaction of c-abl with the abl interactor protein abi2 is shown to be negatively regulated by phosphorylation of serines 637 and 638. These serines are adjacent to the pxxp motif (ptppkrs637s638sfr) that binds the sh3 domain of abi. phosphorylation of c-abl by pak2 inhibits the interaction between the sh3 domain of abi2 and the pxxp motif of c-abl. SIGNOR-160219 0.424 RET protein P07949 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by destabilization phosphorylation Thr107 LGIDDLEtMPDDLLT 9606 BTO:0002181 25795775 t miannu We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA.  SIGNOR-276448 0.2 ATM protein Q13315 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates phosphorylation Ser135 EWETPDLsQAEIEQK 9606 19962312 t llicata We show that, upon dna damage, rassf1a is phosphorylated by atm on ser131 and is involved in the activation of both mst2 and lats1, leading to the stabilization of p73. SIGNOR-161934 0.566 VCP protein P55072 UNIPROT DDX58 protein O95786 UNIPROT down-regulates quantity by destabilization ubiquitination Lys181 ALEKERNkFSELWIV 9606 26471729 t lperfetto Here, we report a new role for p97 with Npl4-Ufd1 as its cofactor in reducing antiviral innate immune responses by facilitating proteasomal degradation of RIG-I. The p97 complex is able to directly bind both non-ubiquitinated RIG-I and the E3 ligase RNF125, promoting K48-linked ubiquitination of RIG-I at residue K181. SIGNOR-261000 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PAPOLA protein P51003 UNIPROT up-regulates activity phosphorylation Ser537 DNSMSVPsPTSATKT 10090 BTO:0000964 34048556 t lperfetto Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity. SIGNOR-268341 0.2 PRKACA protein P17612 UNIPROT PDE3A protein Q14432 UNIPROT unknown phosphorylation Ser312 SKSHRRTsLPCIPRE 9606 16153182 t llicata Ser312 of pde3a was phosphorylated in an h-89-sensitive response to forskolin, indicative of phosphorylation by pka (camp-dependent protein kinase), but phosphorylation at this site did not stimulate 14-3-3 binding. SIGNOR-140289 0.496 NPM1 protein P06748 UNIPROT CDKN2A protein Q8N726 UNIPROT up-regulates activity binding 10090 16199867 t gcesareni The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division SIGNOR-245073 0.569 LPAR2 protein Q9HBW0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 11093753 t gcesareni Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. lpa2 also can couple to the gi/o, g12/13, and gqfamilies. SIGNOR-84559 0.61 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIA1 protein P42261 UNIPROT up-regulates activity chemical activation 9606 30825796 t miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by Œ±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses SIGNOR-264616 0.8 CSNK1E protein P49674 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates phosphorylation 9606 12000790 t lperfetto We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/ms. SIGNOR-227976 0.624 MLL1 complex complex SIGNOR-C89 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 24680668 t miannu Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. SIGNOR-268801 0.2 HIF-1 complex complex SIGNOR-C418 SIGNOR PDK1 protein Q15118 UNIPROT up-regulates quantity transcriptional regulation 10090 16517405 t We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. SIGNOR-267480 0.419 PKC proteinfamily SIGNOR-PF53 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates activity dephosphorylation Ser667 SSLIRKRsTRRSVRG 9606 BTO:0000007 24333728 t Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp SIGNOR-272513 0.2 ATM protein Q13315 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity phosphorylation Ser384 KILRQELsQQQPQAG 10090 BTO:0002572 33097595 t miannu Using biochemical approaches and MS analysis, we show that upon the onset of the DNA-damage response, SMURF2 becomes phosphorylated at Ser384 by ataxia telangiectasia mutated (ATM) serine/threonine kinase, and this phosphorylation is required for its interaction with RNF20. SIGNOR-277534 0.2 edoxaban chemical CHEBI:85973 ChEBI F10 protein P00742 UNIPROT down-regulates activity chemical inhibition -1 20503967 t Luana Replacing the chloroindole P1 moiety of 100 with a 5-chloropyridin-2-yloxalamide group provided 101 (edoxaban, DU-176b). Compound 101 is a potent inhibitor of human FXa in vitro (FXa Ki = 0.56 nM), with >10 000-fold selectivity against relevant serine proteases, and demonstrated good anticoagulant activity (PT2× = 0.26 μM) and activity in various animal models of thrombosis, with minimal bleeding SIGNOR-257845 0.8 PPP2CB protein P62714 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity dephosphorylation Thr216 RSSSSEStGTPSNPD 10090 11983168 t cyclin G also binds in vivo and in vitro to Mdm2 and markedly stimulates the ability of PP2A to dephosphorylate Mdm2 at T216. Consistent with these data, cyclin G null cells have both Mdm2 that is hyperphosphorylated at T216 and markedly higher levels of p53 protein when compared to wild-type cells SIGNOR-248593 0.374 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser19 EVCDERTsLMSAESP -1 8972483 t llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  SIGNOR-250799 0.371 WWP2 protein O00308 UNIPROT POU5F1 protein Q01860 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 19274063 t lperfetto WWP2 promotes degradation of transcription factor OCT4 in human embryonic stem cells|Here, we report that human WWP2, an E3 ubiquitin (Ub)-protein ligase, interacts with OCT4 specifically through its WW domain and enhances Ub modification of OCT4 both in vitro and in vivo. SIGNOR-268850 0.464 AZD1480 chemical CID:16659841 PUBCHEM JAK1 protein P23458 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190164 0.8 CAMK2A protein Q9UQM7 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates phosphorylation Ser268 LKSVRMLsGSKEKDR 9606 BTO:0000671 10908300 t gcesareni The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microm [d-ala(2),n-mephe(4),gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative ca(2+)/calmodulin-dependent protein kinase ii (camk ii) phosphorylation sites, s261 and s266, by alanines in the third intracellular loop of the rat mu-opioid receptor (rmor1) confers resistance to camk ii-induced receptor desensitization. SIGNOR-79678 0.2 PRKG1 protein Q13976 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser24 APIRRRSsNYRAYAT 9606 15769444 t lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. SIGNOR-134644 0.365 CDK5 protein Q00535 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity phosphorylation Thr320 NPGGRPItPPRNSAK 9606 17202132 t gcesareni We observed that phosphorylation of protein phosphatase 1 (PP1) on Thr320 is reduced in brain extracts from Egr-1-/- mice, indicating that a kinase downstream of Egr-1 phosphorylates PP1. In HEK 293 cells co-transfected with PP1 and Cdk5, Cdk5 phosphorylates PP1. In vitro, Cdk5 purified from bovine brain phosphorylates bacterially expressed recombinant PP1 SIGNOR-151803 0.403 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser444 PLSLSAQsVMEELNT 9606 BTO:0000938 24614225 t lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204712 0.524 BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR CRY2 protein Q49AN0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. SIGNOR-267968 0.892 CSNK2A1 protein P68400 UNIPROT GAP43 protein P17677 UNIPROT unknown phosphorylation Ser202 PPTETGEsSQAEENI -1 1828073 t llicata Two serines located in the C-terminal end of neuromodulin, Ser-192 and Ser-193, were identified as the major casein kinase II phosphorylation sites. SIGNOR-250866 0.312 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Thr105 LQTFGHNtMDAVPKI 9606 BTO:0000007 21321328 t miannu We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity. SIGNOR-263131 0.595 NUMA1 protein Q14980 UNIPROT TUBA1A protein Q71U36 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-116640 0.409 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide chemical CHEBI:94504 ChEBI HDAC3 protein O15379 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191430 0.8 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR BRCA1-B complex complex SIGNOR-C298 SIGNOR form complex binding 25400280 t lperfetto Another BRCA1 complex, the BRCA1–B complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‐phase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‐phase checkpoint activation SIGNOR-263217 0.772 AKT proteinfamily SIGNOR-PF24 SIGNOR MEF2D protein Q14814 UNIPROT up-regulates 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 f lperfetto Two candidates that may function as mediators of pi3-k in the phosphorylation of mef2 proteins are pkb and big map kinase 1. SIGNOR-244303 0.2 SLC2A4 protein P14672 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity relocalization 9606 17403369 t Skeletal muscle both stores glucose as glycogen and oxidizes it to produce energy following the transport step. The principal glucose transporter protein that mediates this uptake is GLUT4, which plays a key role in regulating whole body glucose homeostasis SIGNOR-267291 0.8 TTL protein Q8NG68 UNIPROT TUBA8 protein Q9NY65 UNIPROT down-regulates tyrosination 9606 22020298 t miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization SIGNOR-176930 0.315 CDK11B protein P21127 UNIPROT EIF3F protein O00303 UNIPROT unknown phosphorylation Thr119 GAARVIGtLLGTVDK 9606 19245811 t lperfetto Here, we identified a second eif3f phosphorylation site (thr119) by cdk11p46 during apoptosis.Thr119 is located in the mov34 domain of eif3f which is important for both the translational inhibitory function of eif3ffurther studies of how eif3f phosphorylation regulates its function will refine insights into the mechanism and regulation of translation initiation, apoptotic signaling, and tumorigenesis. SIGNOR-184185 0.529 IL3RA protein P26951 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 15795318 t gcesareni Indeed, only upon fibronectin adhesion is janus kinase 2 (jak2) recruited to the beta1 integrin-il-3r complex and triggers il-3r beta common phosphorylation, leading to the formation of docking sites for activated stat5a. SIGNOR-134859 0.598 CASP1 protein P29466 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261755 0.393 PRKCZ protein Q05513 UNIPROT VIM protein P08670 UNIPROT up-regulates activity phosphorylation Ser34 SRSYVTTsTRTYSLG 9606 BTO:0001033 33525953 t miannu Results suggest that aPKCs target multiple activation sites (Ser33/39/56) on Vimentin and therefore is essential for VIF dynamics regulation during the metastasis of prostate cancer cells. SIGNOR-277622 0.2 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252522 0.907 Scribble_complex_DLG4-LLGL1_variant complex SIGNOR-C509 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 f miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270906 0.7 PIM1 protein P11309 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates activity dephosphorylation Ser683 QAQDRKLsTKEALDE 9606 BTO:0000007 24333728 t Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp SIGNOR-272511 0.449 ziprasidone chemical CHEBI:10119 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258500 0.8 MAPK3 protein P27361 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 22802261 t gcesareni Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1 SIGNOR-198292 0.296 EPHA8 protein P29322 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates activity phosphorylation Tyr839 LAYGERPyWNMTNRD 9606 BTO:0000007 10498895 t Tyr-615 and Tyr-838 are major autophosphorylation sites of the EphA8 receptor. phosphorylation of Tyr-615 is critical for determining the association with Fyn whereas the integrity of Tyr-838 phosphorylation is required for efficient phosphorylation at Tyr-615 as well as other major sites. SIGNOR-251121 0.2 2,5-dichloro-N-(2-methyl-4-nitrophenyl)benzenesulfonamide chemical CHEBI:125569 ChEBI PPARD protein Q03181 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001950 27489280 t lperfetto We performed reporter assays to examine the effect of NeoB on the transcriptional activity of specific nuclear hormone receptors, including PPARs, retinoic acid receptor (RAR), ER, and LXR, in uninfected Huh7-25 cells (Fig. 3A). NeoB did not have a significant effect [...] in contrast to the transcriptional repression by known antagonists as positive controls (GW6471, GSK0660, FH535, Ro41-5253, and 4-hydroxytamoxifen) (Fig. 3A) SIGNOR-262014 0.8 NMDA receptor_2B complex SIGNOR-C348 SIGNOR CAMK2A protein Q9UQM7 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu The most abundant signaling protein in the PSD fraction is Ca2+/calmodulin–dependent protein kinase II (CaMKII), which makes up 1 to 2% of the total protein in the forebrain (21). CaMKII is a target for Ca2+ flowing through the NMDA receptor and is necessary for normal synaptic plasticity in pyramidal neurons. The cytosolic tails of the NR2 subunits of the NMDA receptor bind to CaMKII and thus can serve as docking sites for it in the PSD SIGNOR-264215 0.667 EPX protein P11678 UNIPROT PRG2 protein P13727 UNIPROT up-regulates activity post translational modification 9606 BTO:0000399 18694936 t miannu Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism. SIGNOR-261703 0.445 MAPK11 protein Q15759 UNIPROT PIAS2 protein O75928 UNIPROT up-regulates activity phosphorylation Ser113 STSVTPHsPSSPVGS 9606 BTO:0000007 16713578 t miannu The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles SIGNOR-262946 0.267 MAPK10 protein P53779 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser172 YRDPSCLsPASSLSS 9606 10652349 t Translocation from Nucleus to Cytoplasm esanto We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats. SIGNOR-74556 0.425 OGDC complex SIGNOR-C397 SIGNOR 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI down-regulates quantity chemical modification 9606 15953811 t miannu The Œ±-ketoglutarate‚Äìdehydrogenase complex is a complex including multiple copies of three proteins: E1k (Œ±-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. SIGNOR-266257 0.8 Orexin A smallmolecule CHEBI:80319 ChEBI HCRTR2 protein O43614 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257511 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SREBF1 protein P36956 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000599 10915800 t inferred from 70% family members lperfetto Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo. SIGNOR-270081 0.2 FBP1 protein P09467 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates activity binding 9606 30616754 t lperfetto FBP1, but not FBP2, suppresses HIF-1a activity by directly binding to its inhibitory domain. SIGNOR-267590 0.332 vitamin K smallmolecule CHEBI:28384 ChEBI Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI up-regulates quantity precursor of 9606 31226734 t lperfetto This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR) SIGNOR-265915 0.8 POLR2L protein P62875 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266171 0.862 GRK2 protein P25098 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser205 LCDFNPKsSKQCKDV 9606 22704991 t llicata Moreover, we demonstrate that phosphorylation of ser204 in clcb is required for efficient endocytosis of a subset of gpcrs and identify g protein-coupled receptor kinase 2 (grk2) as a kinase that can phosphorylate clcb on ser204. Overexpression of clcb(s204a) specifically inhibits the endocytosis of those gpcrs whose endocytosis is grk2-dependent. SIGNOR-197873 0.2 TP53 protein P04637 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 24737129 f simone vumbaca We have identified a novel role for p53 that is specific to the regulation of several pro-inflammatory genes in human macrophages, including IL-6, IL-8 and CXCL1. Importantly, NF-κB co-activation is essential for this regulation SIGNOR-255969 0.478 AICA-Ribotide chemical CID:16760280 PUBCHEM PRKAA2 protein P54646 UNIPROT up-regulates chemical activation 9606 BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 19491292 t gcesareni Aicar-induced ampk phosphorylation inhibits cell cycle transition, reducing differentiation of myoblasts into myotubes, through pgc-1alpha-foxo3a-p21. SIGNOR-186055 0.8 MAPK1 protein P28482 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Ser544 RSVTMRKsQRSSKGS 9606 21297032 t The effect has been demonstrated using Q96PH1-4 gcesareni These results suggest that the mek/erk1/2 pathway is necessary but not sufficient to regulate the pma-dependent activation of nox5. SIGNOR-171847 0.331 CREB1 protein P16220 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 14614508 f HES-1 is a direct CREB target in vivo. SIGNOR-254742 0.252 LPAR6 protein P43657 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257347 0.337 CAMK2A protein Q9UQM7 UNIPROT DLGAP1 protein O14490 UNIPROT down-regulates quantity by destabilization phosphorylation Ser356 KAMGDEDsGDSDTSP -1 23143515 t miannu  CaMKIIα activated by the NMDA receptor phosphorylates GKAP Ser54 to induce polyubiquitination of GKAP.  SIGNOR-276429 0.406 RPS26 protein P62854 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262425 0.883 GRM3 protein Q14832 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 t miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. SIGNOR-264083 0.334 CUL1 protein Q13616 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR form complex binding 9606 15340381 t gcesareni The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions. SIGNOR-243557 0.944 2-chloro-5-(2-phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)phenol chemical CHEBI:93773 ChEBI ARAF protein P10398 UNIPROT down-regulates chemical inhibition 9606 12970777 t gcesareni At drug concentrations around the reported ic(50) for the raf inhibitor l-779,450, it suppressed dna synthesis and induced apoptosis in hematopoietic fdc-p1 cells transformed to grow in response to either raf-1 or a-raf (fd/deltaraf-1:er and fd/deltaa-raf:er) SIGNOR-100355 0.8 YWHAG protein P61981 UNIPROT NEFL protein P07196 UNIPROT down-regulates activity binding 9606 23230147 t miannu These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments. SIGNOR-252400 0.299 AKT proteinfamily SIGNOR-PF24 SIGNOR PIKFYVE protein Q9Y2I7 UNIPROT up-regulates phosphorylation Ser307 PARNRSAsITNLSLD 9606 BTO:0000887 15546921 t gcesareni Here we report that serine318 on the fyve domain-containing ptdins3p 5-kinase (pikfyve) is a novel substrate for pkb, and show that phosphorylation stimulates the ptdins3p 5-kinase activity of the enzyme. SIGNOR-130920 0.2 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser42 TRTYSLGsALRPSTS -1 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248881 0.288 BMX protein P51813 UNIPROT RUFY1 protein Q96T51 UNIPROT up-regulates activity phosphorylation Tyr389 TKVELETyKQTRQGL 9534 11877430 t miannu Etk interacts with RUFY1 through its SH3 and SH2 domains. RUFY1 is tyrosine-phosphorylated and appears to be a substrate of Etk. Phosphorylation of the two tyrosine residues, Tyr-281 and Tyr-292, located in the linker region of the two coiled-coil domains by Etk seems to be critical for RUFY1 targeting to the endosomes. SIGNOR-262678 0.619 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Ser174 LRKGTLGsKGQKTTQ -1 23444369 t miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. SIGNOR-273492 0.27 CYP17A1 protein P05093 UNIPROT androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268654 0.8 MAPKAPK5 protein Q8IW41 UNIPROT EEF2K protein O00418 UNIPROT unknown phosphorylation Ser377 PPLLRPLsENSGDEN -1 12171600 t miannu Identification of Ser-377 as the site on eEF2 kinase phosphorylated in vitro by MAPKAP-K2, MAPKAP-K3 and MAPKAP-K5. Maximal phosphorylation of eEF2 kinase by MAPKAP-K2 (Figure 5) or MAPKAP-K5 (results not shown) had no effect on its activity. SIGNOR-249708 0.299 RPS6KA3 protein P51812 UNIPROT HMGN2 protein P05204 UNIPROT down-regulates activity phosphorylation Ser29 QRRSARLsAKPAPPK 9606 BTO:0000567 11438671 t lperfetto We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets. SIGNOR-249103 0.294 HMGB1 protein P09429 UNIPROT TLR4 protein O00206 UNIPROT up-regulates activity binding 9606 20547845 t gcesareni Here we show that Toll-like receptor 4 (TLR4), a pivotal receptor for activation of innate immunity and cytokine release, is required for HMGB1-dependent activation of macrophage TNF release. SIGNOR-252057 0.795 LPR5/6 complex SIGNOR-C219 SIGNOR GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 19107203 t PPPSPxS motif in LRP6/5 must be phosphorylated. miannu These observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence. binding of wnts to the coreceptors frizzled and lrp6/5 leads to phosphorylation of pppspxs motifs in the lrp6/5 intracellular region and the inhibition of gsk3beta bound to the scaffold protein axin. SIGNOR-256177 0.697 NCL protein P19338 UNIPROT MYBL1 protein P10243 UNIPROT down-regulates activity binding 9606 BTO:0000007 10660576 t miannu We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity. SIGNOR-221233 0.427 AMPK complex SIGNOR-C15 SIGNOR ACACA protein Q13085 UNIPROT down-regulates phosphorylation Ser80 LHIRSSMsGLHLVKQ 9606 BTO:0000887;BTO:0001103 12015362 t lperfetto Significant negative linear correlations between phospho-acc and acc activity were observed in all models (p < 0.01). The decline in acc activity was related to the decrease in pcr and the rise in amp. A relationship between phospho-ampk (threonine 172) and activity of ampk immunoprecipitated with anti-alpha(2) subunit antibody preparation was also observed. SIGNOR-216655 0.541 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser25 VVLCSCPsPSMVRTQ 9606 10455013 t lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-236777 0.2 FOXM1 protein Q08050 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 BTO:0002181 26912724 t miannu Nuclear FoxM1 then directly interacted with nuclear β‐catenin, which released β‐catenin from ICAT and enhanced recruitment of β‐catenin to the promoter of Wnt target gene, hence increasing the expression of Wnt target gene. SIGNOR-277211 0.533 SAR1A protein Q9NR31 UNIPROT SEC24A protein O95486 UNIPROT up-regulates quantity binding SIGNOR-C370 30605680 t lperfetto Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. SIGNOR-265303 0.746 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR up-regulates activity chemical activation 26083061 t lperfetto Respiratory chain complexes I–III depend on Fe-S clusters for function SIGNOR-262137 0.8 CACNA1G protein O43497 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 30849329 f miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). SIGNOR-264329 0.7 RAD21 protein O60216 UNIPROT APOB protein P04114 UNIPROT down-regulates quantity transcriptional regulation 9606 25575569 t The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector. SIGNOR-259974 0.2 PRKCA protein P17252 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 21349850 t gcesareni Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth. SIGNOR-172235 0.261 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 t gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. SIGNOR-76005 0.563 G6P proteinfamily SIGNOR-PF81 SIGNOR alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-266571 0.8 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Thr455 TTERDSDtDVEEEEL 9606 18678890 t gcesareni The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites. SIGNOR-179891 0.353 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1644 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248748 0.727 KDR protein P35968 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 BTO:0001949 11278468 t Gianni SIGNOR-261917 0.484 MAP3K14 protein Q99558 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity phosphorylation Ser40 IFIIMGAsGDLAKKK 9606 BTO:0000007 33398181 t miannu Mass spectrometry identified four serine residues of G6PD phosphorylated by NIK (Extended Data Fig. 8f). All of these serines, except S278, are conserved between human and mouse G6PD proteins. In transfected cells, NIK stimulated G6PD activity, which was not affected by S8A or S486A mutation but abolished by S40A mutation (Extended Data Fig. 8g). SIGNOR-277545 0.2 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0000971 17936559 t gcesareni Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation. SIGNOR-158324 0.746 vincaleukoblastine sulfate chemical CHEBI:9984 ChEBI TUBB protein P07437 UNIPROT down-regulates activity chemical inhibition 9606 15579115 t miannu Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. SIGNOR-259256 0.8 DDIT4 protein Q9NX09 UNIPROT TSC2 protein P49815 UNIPROT up-regulates activity binding 9606 21460850 t miannu  Redd1 is a negative regulator of mTOR, mediating dissociation of 14-3-3 from tuberous sclerosis complex (TSC)2, which allows formation of a TSC-TSC2 complex. SIGNOR-277469 0.625 GSTA1 protein P08263 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000018 29928434 f irozzo Accordingly, downregulation of GSTA1 suppressed tumor growth. In conclusion, GSTA1 plays an important role in regulation of cell proliferation and cell apoptosis in A549 cell line. SIGNOR-256296 0.7 FLT4 protein P35916 UNIPROT RPS6KA3 protein P51812 UNIPROT down-regulates phosphorylation Tyr707 KGAMAATySALNRNQ 9606 12601080 t llicata Upon truncation of this c-terminal stretch, or mutation of the tyr-707 residue alone, autoinhibition is attenuated, and the kinase becomes constitutively active. Based on these findings we propose that phosphorylation of the tyr-707 represents a novel alternative regulatory mechanism for p90rsk activation. SIGNOR-98708 0.2 BIX-02188 chemical CID:66524294 PUBCHEM MAP2K5 protein Q13163 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190365 0.8 MTOR protein P42345 UNIPROT UVRAG protein Q9P2Y5 UNIPROT up-regulates activity phosphorylation Ser571 KGEDLVGsLNGGHAN 9606 BTO:0001938 26139536 t miannu MTOR phosphorylates UVRAG at serine 550 and serine 571 SIGNOR-276919 0.418 CDK1 protein P06493 UNIPROT EGFR protein P00533 UNIPROT down-regulates phosphorylation Ser1026 PQQGFFSsPSTSRTP 9606 BTO:0000017 8360196 t gcesareni Using a synthetic peptide corresponding to the sequence surrounding ser-1002, p34cdc2 was identified as a kinase capable of phosphorylating this serine residue. phosphorylation of the egf receptor by p34cdc2 was associated with a decrease in its tyrosine protein kinase activity. SIGNOR-38313 0.436 CSNK1E protein P49674 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity phosphorylation 6239 10517632 t gcesareni In addition, CKI bound to and increased the phosphorylation of dishevelled, a known component of the Wnt pathway SIGNOR-244097 0.68 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser511 RREERSLsAPGNLLT 9606 22778263 t lperfetto Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity SIGNOR-198154 0.2 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1710 HVTSKCGsLKNIRHR -1 8631898 t miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. SIGNOR-250165 0.428 DDX5 protein P17844 UNIPROT Microprocessor complex complex SIGNOR-C356 SIGNOR up-regulates activity binding 34936874 t lperfetto Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing. SIGNOR-275659 0.713 iodide smallmolecule CHEBI:16382 ChEBI 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI up-regulates quantity precursor of 9606 16098474 t scontino TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. SIGNOR-266958 0.8 PHF12 protein Q96QT6 UNIPROT TLE5 protein Q08117 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 t miannu We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE. SIGNOR-266990 0.2 GHSR protein Q92847 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257322 0.252 GOT2 protein P00505 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity chemical modification 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267514 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252741 0.756 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC13 protein Q99880 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271995 0.2 RBKS protein Q9H477 UNIPROT D-ribofuranose smallmolecule CHEBI:47013 ChEBI down-regulates quantity chemical modification 9606 25749547 t miannu Human ribokinase (RK) is a member of the ribokinase family, and is the first enzyme responsible for D-ribose metabolism, since D-ribose must first be converted into D-ribose-5-phosphate to be further metabolized and incorporated into ATP or other high energy phosphorylated compounds. SIGNOR-267072 0.8 proline smallmolecule CHEBI:26271 ChEBI Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270434 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Thr1548 YAPSRRMtSVATAKG -1 21406690 t miannu PKA phosphorylated LRP6, which enhanced the binding of Gα(s) to LRP6, its localization to the plasma membrane, and the production of cAMP in response to PTH. Only alteration of Thr1548 abolished the phosphorylation of LRP6C by PKA (Fig. 6B), and mass spectrometry analysis confirmed that Thr1548 was the PKA phosphorylation site in LRP6C (fig. S1). SIGNOR-275416 0.2 HIRA protein P54198 UNIPROT HIRA complex 1 complex SIGNOR-C461 SIGNOR form complex binding 9606 30285846 t miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. SIGNOR-269434 0.686 PLK1 protein P53350 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Thr39 PVETIETtVVGEEEE 9606 23226345 t lperfetto More recently, we identified and mapped multiple phosphorylation sites in yy1, including, threonine 39, serine 118, serine 247, threonine 348 and threonine 378. The first kinase proven to phosphorylate yy1 in vivo was plk1, which phosphorylates threonine 39 during g2/m stage of the cell cycle [25]. Ck2_ is another kinase identified as constitutively phosphorylating yy1 at serine 118. This modification protects yy1 cleavage by caspase 7 during apoptosis SIGNOR-200087 0.401 PAK2 protein Q13177 UNIPROT RPS6 protein P62753 UNIPROT unknown phosphorylation Ser242 SSLRASTsKSESSQK -1 1985906 t miannu The synthetic peptide AKRRRLSSLRASTSKSESSQK (S6-21) which corresponds to the carboxyl-terminal 21 amino acids of human ribosomal protein S6 was synthesized and tested as a substrate for S6/H4 kinase purified from human placenta. The principal phosphorylation sites were serines in the acidic carboxyl-terminal domain of the peptide. SIGNOR-250234 0.314 PPP2CA protein P67775 UNIPROT EIF4E protein P06730 UNIPROT down-regulates dephosphorylation Ser209 DTATKSGsTTKNRFV 9606 20927323 t tpavlidou A recent study using genetically engineered mouse models has clearly shown that mnk-mediated eif4e phosphorylation is absolutely required for eif4e's oncogenic action. Taken together, we conclude that pp2a negatively regulates eif4e phosphorylation and eif4f complex assembly through dephosphorylation of mnk and eif4e, thus suggesting a novel mechanism by which pp2a exerts its tumor-suppressive function. SIGNOR-168306 0.354 PTAFR protein P25105 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256932 0.2 RAB22A protein Q9UL26 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 t lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 SIGNOR-260621 0.464 PTPN11 protein Q06124 UNIPROT FGFR2 protein P21802 UNIPROT down-regulates activity dephosphorylation 9606 23420874 t miannu In forming this heterotetrameric complex Grb2 inhibits both the dephosphorylation of FGFR2 by Shp2 and the phosphorylation of Shp2 by FGFR2 (XREF_FIG, respectively).|Knockdown of Grb2 elevates Shp2 phosphorylation (XREF_FIG), strongly suggesting that the inability of Shp2 to interact directly with the receptor in the presence of Grb2 prevents FGFR2 kinase activity toward Shp2. SIGNOR-277030 0.606 THOC6 protein Q86W42 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 t miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. SIGNOR-268510 0.909 RPS6KA5 protein O75582 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD 9606 12414794 t lperfetto We find that activation of the c-jun promoter through the atf1 site requires phosphorylation of atf1 at serine 63. atf1 can be phosphorylated by mitogen- and stress-activated protein kinase 1 (msk1), which is activated by egf and erk1/2. SIGNOR-95318 0.678 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR OTX2 protein P32243 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269240 0.474 NCK1 protein P16333 UNIPROT ABL1 protein P00519 UNIPROT down-regulates activity binding 9606 11494134 t lperfetto We also show that overexpression of nck could repress the phosphorylation of cbl by abl in vivo. Studies with nck mutants suggested that the nck sh2 domain is responsible for inhibiting the activity of abl toward both cbl and nck itself, most likely by competing with the abl sh2 for tyrosine-phosphorylated binding sites SIGNOR-109672 0.409 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser243 PGETPPLsPIDMESQ 9606 1846781 t lperfetto Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity. SIGNOR-21776 0.337 HNRNPA3 protein P51991 UNIPROT C9orf72 protein Q96LT7 UNIPROT down-regulates quantity 9606 BTO:0000142 27461252 f lperfetto Thus, reduced hnRNPA3 expression in C9orf72 cases leads to increased levels of the repeat RNA as well as enhanced production and deposition of DPR proteins and RNA foci. SIGNOR-262117 0.415 ATF4 protein P18848 UNIPROT DARS2 protein Q6PI48 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269418 0.2 PRKCB protein P05771 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity phosphorylation Ser346 EWEAQRDsHLGPHRS 9606 14576165 t lperfetto A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis. SIGNOR-249237 0.2 MTSS1 protein O43312 UNIPROT GLI1 protein P08151 UNIPROT up-regulates binding 9606 17845852 t gcesareni Mim is a shh-responsive gene that can potentiate gli transcriptional activity.MIM Appears to regulate target gene expression through its association with the gli complex SIGNOR-157650 0.524 AMG 900 chemical CID:24856041 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189492 0.8 PINK1 protein Q9BXM7 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates phosphorylation Ser142 VPSPPPAsPRSQYNF 9606 17906618 t gcesareni Htra2 is phosphorylated on activation of the p38 pathway, occurring in a pink1-dependent mannerwe suggest that pink1-dependent phosphorylation of htra2 might modulate its proteolytic activity, thereby contributing to an increased resistance of cells to mitochondrial stress. SIGNOR-158052 0.626 VKORC1 protein Q9BQB6 UNIPROT vitamin K smallmolecule CHEBI:28384 ChEBI down-regulates quantity chemical modification 9606 31226734 t lperfetto This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR) SIGNOR-265904 0.8 PDHX protein O00330 UNIPROT INS protein P01308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001731 12783165 f miannu In glucagonoma cells transduced with a Pdx1-encoding lentiviral vector, insulin gene expression was induced while glucagon mRNA levels were reduced by 50 to 60%. SIGNOR-254902 0.293 FCN3 protein O75636 UNIPROT MASP2 protein O00187 UNIPROT up-regulates activity binding 17204478 t lperfetto In the lectin pathway, mannose-binding lectin (MBL) and ficolins bind to pathogens and activate MBL-associated serine protease-2 (MASP-2) SIGNOR-263412 0.532 ULK1 protein O75385 UNIPROT ENO1 protein P06733 UNIPROT down-regulates activity phosphorylation Ser282 QLADLYKsFIKDYPV 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274029 0.2 CHUK protein O15111 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 SIGNOR-C14 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-52879 0.893 N-[3-[[5-Cyclopropyl-2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide chemical CID:44465558 PUBCHEM TBK1 protein Q9UHD2 UNIPROT down-regulates activity chemical activation 10090 BTO:0001413 23099093 t Federica We herein describe the development of a novel series of 2,4-diamino-5-cyclopropyl pyrimidines as potent inhibitors of TBK1/IKKɛ, with improved kinase selectivity and drug-like properties. SIGNOR-261109 0.8 MEIS1 protein O00470 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0001271 19109563 f irozzo To discern the mechanisms by which Meis1 inhibition leads to reduced cell growth, we performed cell-cycle and apoptosis analyses.Meis1 knockdown also resulted in increased apoptosis, as evidenced by increased uptake of PI and a stain for activated caspases (CaspaTag) by M26-transduced cells compared with control cells. These results indicate that Meis1 is required for proliferation and survival of 4166 leukemia cells. SIGNOR-256648 0.7 EDNRA protein P25101 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256923 0.426 Calprotectin complex complex SIGNOR-C293 SIGNOR Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000876 16690079 t miannu Calcium-induced complexes of S100A8 and S100A9 have been shown to colocalize with microtubules (MTs) during activation of monocytes. Functional analyses demonstrated that the complexes are involved in cytoskeletal organization and that they directly bind to tubulin and promote tubulin polymerization in a calcium-dependent manner SIGNOR-262827 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR PHF20 protein Q9BVI0 UNIPROT down-regulates phosphorylation Ser291 ELRRRKIsKGCEVPL 9606 22334668 t llicata Akt phosphorylates phf20 at ser(291) in vitro and in vivo, which results in its translocation from the nucleus to the cytoplasm and attenuation of phf20 function. SIGNOR-196112 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MTHFR protein P42898 UNIPROT down-regulates activity phosphorylation Thr34 KDSSRCStPGLDPER 9606 BTO:0000007;BTO:0000567 24769206 t miannu We have demonstrated that MTHFR is phosphorylated on T34by CDK1/Cyclin B1 in vivo and this phosphorylation peaks duringmitosis and decreases its enzymatic activity. SIGNOR-263888 0.338 MPO-ANCA complex SIGNOR-C474 SIGNOR thiocyanate smallmolecule CHEBI:18022 ChEBI up-regulates quantity by expression oxidation 9606 BTO:0000133 9922160 t lperfetto Myeloperoxidase plays a fundamental role in oxidant production by neutrophils. The enzyme uses hydrogen peroxide to oxidize chloride (Cl-), bromide (Br-), iodide (I-), and the pseudohalide thiocyanate (SCN-) to their respective hypohalous acids.| Our results show that thiocyanate is an important substrate of myeloperoxidase in most environments and that hypothiocyanate is likely to contribute to leukocyte antimicrobial activity. SIGNOR-270591 0.8 GSK3A protein P49840 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity by destabilization phosphorylation Ser279 CGIQDTNsKKQSDTH 9606 BTO:0002181 33879767 t miannu We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation. SIGNOR-277552 0.2 EFNB2 protein P52799 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9330863 t gcesareni Lerk-5 is a ligand for both elk and hek and induces receptor phosphorylation SIGNOR-52583 0.879 SP1 protein P08047 UNIPROT SLC5A8 protein Q8N695 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20082847 t Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription. SIGNOR-254059 0.2 CPT1B protein Q92523 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267133 0.8 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Lys76 YRLVSINkSSPLQKQ -1 10978167 t lperfetto Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site. SIGNOR-263574 0.62 PPP3CC protein P48454 UNIPROT FLNA protein P21333 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 t Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation. SIGNOR-248507 0.2 PPP2R5B protein Q15173 UNIPROT CASP3 protein P42574 UNIPROT up-regulates dephosphorylation Ser150 FRGDRCRsLTGKPKL 9606 BTO:0000130 15569672 t gcesareni Dephosphorylation of caspase-3 at ser150 site by pp2a increased caspase-3 activity,which was essential to trigger apoptosis in neutrophils. SIGNOR-131435 0.2 MTA1 protein Q13330 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000812 18719363 f miannu MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG. SIGNOR-254596 0.477 GHRL protein Q9UBU3 UNIPROT GHSR protein Q92847 UNIPROT up-regulates binding 9606 15070777 t fspada In contrast to wild-type mice, acute treatment of ghsr- mice with ghrelin stimulated neither gh release nor food intake, showing that the ghsr is a biologically relevant ghrelin receptor. SIGNOR-123948 0.723 PRKCA protein P17252 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251620 0.305 IRS1 protein P35568 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9606 20966354 t lperfetto Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin. SIGNOR-168985 0.711 NEXMIF protein Q5QGS0 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0000938 27822498 f miannu Xpn regulates N-cadherin and β1-integrin expression at the transcriptional level in PC12 cells SIGNOR-269661 0.2 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser422 RFHSLPFsLTKMPNT 9606 BTO:0000938 24614225 t lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204692 0.524 LNX2 protein Q8N448 UNIPROT NUMB protein P49757 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 26451611 t miannu Polyubiquitination of Human Numb by LNX2. The Zn-RING-Zn domain of LNX2 is a dimer and assumes a rigid elongated structure that undergoes autoubiquitination and undergoes N-terminal polyubiquitination. LNX2 can bind numb and induce its ubiquitination and subsequent proteasomal degradation SIGNOR-272423 0.624 BRD4 protein O60885 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0000150;BTO:0001271;BTO:0000785 22509028 t llicata We report that brd4 is an atypical kinase that binds to the carboxyl-terminal domain (ctd) of rna polymerase ii and directly phosphorylates its serine 2 (ser2) sites both in vitro and in vivo under conditions where other ctd kinases are inactive. our findings may provide a mechanistic basis for several functional studies that showed that loss of brd4 causes transcription termination and embryonic lethality SIGNOR-197012 0.46 WDR24 protein Q96S15 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR form complex binding 9606 23723239 t miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 SIGNOR-255302 0.907